International J. Pharm CMPD'G July - August - 2002

J U LY / A U G U S T
2 0 0 2
of PHARMACEUTICAL
I N T E R N AT I O N A L J O U R N A L
COMPOUNDING
COMPOUNDING FOR BHRT and LEGAL AND REGULATORY ISSUES Page 250 The Hormonal Link to Breast Cancer: The Estrogen Matrix Page 259 Establishing an Andropause Practice Page 263 Compounding and the Courts
VOLUME 6
Page 267 Facilities and Procedures for Compounding Hazardous Drugs Page 271 A Treatment IND Primer Page 308 Stability of Tubocurarine Chloride Injection
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DEPARTMENTS 243 PreScription From the Editor 305 Calculations Shelly J. Prince, PhD, RPh 310 Index of Advertisers 318 Continuing Education Questions 320 PostScription Richard J. Bertin, PhD, RPh FORMULATIONS 293 Dehydroepiandrosterone 25 mg/mL in Pluronic Lecithin Organogel 294 Dehydroepiandrosterone 25-mg/0.25-mL Sublingual Drops 295 Estradiol 0.5-mg Sublingual Troches 296 Estradiol 1-mg/0.1-mL Pluronic Lecithin Organogel 297 Estradiol 1-mg/0.1-g Topical Cream 298 Estriol 2-mg/mL, Estrone 0.25mg/mL, and Estradiol 0.25-mg/mL Topical Solution 299 Estriol 2-mg/mL Topical Gel 300 Estriol 2-mg and Estradiol 0.5-mg/ 0.1-mL Sublingual Drops 301 Testosterone 25 mg in Oil Capsules 302 Testosterone 50-mg/mL Topical Gel PEER REVIEWED 308 Stability of Tubocurarine Chloride Injection at Ambient Temperature and 4C in Polypropylene Syringes James T. Stewart, PhD; Meredith L. Storms, BS; and Flynn W. Warren, MS, RPh 311 Compatibility Screening of Bivalirudin During Simulated Y-Site Administration with Other Drugs Lawrence A. Trissel, BS, RPh; and Christopher A. Saenz 316 Stability of Ketamine Hydrochloride Injection After Reconstitution in Water for Injection and Storage in 1-mL Tuberculin Polypropylene Syringes for Pediatric Use Vishnu D. Gupta, PhD
COMPOUNDING FOR BHRT
245 A Review of Current Research on the Effects of Progesterone Diane Boomsma, RPh, FIACP; and Jim Paoletti, RPh, FIACP 250 The Hormonal Link to Breast Cancer: The Estrogen Matrix David T. Zava, PhD 255 Aminophylline 3%, Co-dergocrine Mesylate 0.05%, and Isosorbide Dinitrate 0.25% Cream for the Treatment of Orgasmic Dysfunction in Women Dave Mason, DPh, FIACP 259 Establishing an Andropause Practice Bruce Biundo, BS, RPh
LEGAL AND REGULATORY ISSUES
263 Compounding and the Courts Jeffrey N. Gibbs, BA, JD; and Jeffrey N. Wasserstein, BA, JD 267 Facilities and Procedures for Compounding Hazardous Drugs Hank Rahe, BSIM, MSE, RPh 271 Gaining Access to Investigational Drugs for Treatment: An Investigational New Drug Application Primer Mark A. Kramer, MS, RPh; and Bambi J. Grilley, RPh, CCRC, CCRA, CIP 274 Legal Issues: Technicians in the Compounding Pharmacy Practice Jennifer Taylor Fix, MBA, RPh
GENERAL INTEREST
278 Excerpts from and Reviews of Current Published Literature: Pharmacy Administration and Other Topics of Interest Elizabeth Foy and Mary E. MacCara, PharmD 281 Magnetic Iron Whiskers in Cereals David W. Newton, PhD, FAPhA; and Tovah G. Hoffman 284 Wish You Were Here: Chicago, Illinois Dennis B. Worthen, PhD 286 Medications Discontinued in the United States Lisa D. Ashworth, RPh 288 Basics of Compounding: Iontophoresis, Part 2 Loyd V. Allen, Jr, PhD, RPh
COMPOUNDING SUPPORT & QUALITY CONTROL
303 Featured Excipient: Topical Oil-in-Water Cream Bases Loyd V. Allen, Jr, PhD, RPh 306 Standard Operating Procedure for the Quality Assessment of Nasal Solutions
International Journal of Pharmaceutical Compounding Vol. 6 No. 4 July/August 2002
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INTERNATIONAL JOURNAL
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Editorial Editor-in-Chief Executive Editor Medical Editor Assistant to Editor-in-Chief Contributing Authors Loyd V. Allen, Jr, PhD, RPh Shelly Capps Jane Vail LaVonn Williams Lisa D. Ashworth , RPh
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Gigi Davidson , BS, RPh, FSVHP, DICVP Eric S. Kastango , RPh, MBA, FASHP Shelly J. Prince , PhD, RPh Dennis B. Worthen , PhD Contributing Editor Peter R. Ford, BSPharm, FACA, FIACP ADDRESS: 122 N. Bryant, Edmond, OK 73034-6301 USA TEL: 800-757-4572 FAX: 405-330-5622 Design Design Director Subscription & Reader Services Circulation Director Interactive Media & Special Projects Designer Andy Bernick Jordana Ford Carolyn Rose
ADDRESS: PO Box 340205, Austin, TX 78734 USA TEL: (toll free) 888-588-4572, 512-261-3179 FAX: 512-608-9828, EMAIL: subs@ijpc.com Advertising Director of Advertising Lauren Bernick
ADDRESS: PO Box 340205, Austin, TX 78734 USA TEL: 800 -661- 4572 FAX: 800-494- 4572 EMAIL: lbernick@ijpc.com Board of Directors Jake Beckel , RPh Shelly Capps Mike Collins , RPh Pat Downing , RPh Bob Scarbrough , RPh Editorial Board Harvey Ahl , RPh Diane Boomsma , RPh Marianna Foldvari , PhD, RPh Peter R. Ford , BSPharm, FACA, FIACP Paul F. Grassby , PhD, MRPharmS Hetty A. Lima , RPh, FASHP Dave Mason , RPh, FIACP John Preckshot , RPh, FIACP Lawrence A. Trissel , BS, RPh, FASHP David J. Woods , MPharm, MRPharmS, FHPA
Bioidentical hormone replacement therapy (BHRT) and regulatory and legislative issues are the dual focus of this issue. This is the fifth issue* of IJPC in which topics on BHRT (and a total of almost 100 published, prescribed compounded BHRT formulations) have been presented. In addition to the more common topics regarding BHRT for women, this issue includes an article on establishing an andropause practice, which is of particular interest to those who use BHRT to treat androgen-deficient men. Pharmacists and technicians who compound with hormones must be aware of the safety precautions that minimize the risk of adverse events from exposure to those chemicals. In this issue, we have included a presentation on compounding with hazardous drugs. The safety of personnel must always be considered when a compounding practice is established or expanded. It is more efficient to ensure that safeguards are effective when a practice is established than to retrofit a facility. There are many methods of providing a safe workplace, and standard operating procedures that pertain to the facility, its maintenance, personnel, equipment, and all aspects of handling bulk drug substances must be in place. The pharmaceutical industry has undergone many changes over the past 50 years as problems caused by the exposure of personnel to bulk chemicals have occurred, and compounding pharmacists can benefit from those experiences. This year may be another pivotal point in the history of pharmacy, as the legislative and judicial decisions of the past 10 years help to weave and shape the practice of compounding pharmacy. In the years preceding the passage of the Food, Drug, and Cosmetic Act (FDCA), pharmacists (almost all of whom were compounding pharmacists) were quite concerned about the quality of medications that were being
The International Journal of Pharmaceutical Compounding (IJPC), ISSN No. 1092-4221, is published 6 times per year by IJPC, 122 N. Bryant St, Edmond OK 73034, USA. ANNUAL SUBSCRIPTION RATES (All rates in US dollars) N o r t h A m e r i c a S t a n d a r d : $ 125 , institutional: $150, student: $ 90. All other destinations Standard: $190, institutional: $ 215, student: $95.
produced by drug manufacturers. They felt that passage of the FDCA was necessary to control manufacturers and the quality of their products. In 1936, Robert L. Swain, in the Journal of the American Pharmaceutical Association , stated It seemed monstrous that the retail pharmacist must meet a high educational standard, must satisfy exacting State Board requirements and must subject himself to almost continuous regulation and control, while the manufacturer, even though his products are much more wide-spread in distribution, is required by law to meet no standard whatsoever. Pharmacists have always been concerned about the quality of pharmaceuticals dispensed, whether they have been manufactured or compounded. Tremendous advances have been made (and are continuing to be made) in the pharmaceutical industry and in compounding to ensure that the patient receives high-quality medications. This evolving quality system will continue to progress and improve for years to come. As some compounded medications become commercially manufactured and as some commercially manufactured products become scarce or discontinued and are then compounded, manufacturers and compounders can form a synergy to provide pharmaceuticals of the highest quality and effectiveness.
cription
Loyd V. Allen, Jr, PhD, RPh *Prior issues of IJPC that are devoted to BHRT are: Volume 2, January-February; Volume 3, September-October; Volume 4, November-December; and Volume 5, September-October.
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Focus on Compounding for
BIOIDENTICAL HORMONE REPLACEMENT THERAPY
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Effects of Progesterone on Bone

Current studies 2 examining the role of progesterone on bone homeostasis indicate that the effects of progesterone are mediated by its nuclear receptors. In the 1970s, OMalley et al 2 showed that those receptors are composed of two receptor proteins, PRa and PRb, each of which binds progesterone. 2 Research by MacNamara and Loughrey 3 in 1998 indicated that PRa and PRb messenger ribonucleic acid (mRNA) transcripts are expressed in human osteoblasts and that progesterone receptor promoter activity is estrogen responsive. This provides evidence that boneforming cells are physiologically influenced by progesterone. A study 4 by Luo and Liao supports the role of progesterone in regulating the function of metalloproteinase (specifically matrix metalloproteinase [MMP]) in osteoblast cells involved in bone remodeling and resorption. MMP initiates bone resorption by degrading the bone matrix. This requires the activation of MMP-2 via a complex consisting of a membrane-type matrix metalloproteinase-1 (MT1-MMP) and a tissue inhibitor of metalloproteinase (TIMP-2) on the cell surface. In that study, progesterone was shown to increase the levels of MT1-MMP and mRNA in osteoblasts. Progesterone acted only on the MT1-MMP protein; that action may contribute to bone formation. Progesterone binding to glucocorticoid receptors is another pathway that may modulate bone remodeling. Glucocorticoids cause bone loss by blocking osteocalcin synthesis and preventing the attachment of osteoblasts to matrix proteins such as osteonectin. Some studies 5,6 indicate that progesterone exerts an antiglucocorticoid effect by acting as a ligand for glucocorticoid receptors. A study 7,8 of progesterone replacement in very premature infants yielded exciting results with respect to the role of progesterone in bone development. During pregnancy, the plasma concentrations of estradiol and progesterone in the fetus increase by a factor of 100. A prematurely delivered infant is deprived of those hormones at an early developmental stage. Seventy years ago, estradiol supplementation was used on premature infants to promote body-weight gain, but
A Review of Current Research on the Effects of
PROGESTERONE
Diane Boomsma, RPh, FIACP Williams Apothecary, Inc Lancaster, Pennsylvania Jim Paoletti, RPh, FIACP Professional Compounding Centers of America, Inc, Houston, Texas A 1997 review of a documented annotated research article 1 concludes that much is known about the effects of progesterone on the uterus but that the effects of progesterone on bone, breast tissue, and the brain are poorly understood. In this article, we review the effects of progesterone on bone, breast tissue, the brain, and the circulatory system in humans and in animal models.
the success of that treatment was minimal and the practice was abandoned. 7,8 However, because of the positive benefits of postmenopausal hormone replacement, the effect of estradiol supplementation on the prevention of the osteopenia of prematurity was again examined. When intrauterine levels of estradiol and progesterone were supplemented for 6 weeks postnatally in premature infants, an improvement in bone mineral accretion was demonstrated. 7,8
Effects of Progesterone on Breast Tissue

The controversial question about whether a combination of progestins and estrogen leads to an increase in breast cancer remains unanswered. In this article, a review of the effects produced by different types of progestins is presented. Breast tissue is of several types. 9 Epithelial tissue divides during the progesterone-dominant phase of the menstrual cycle. Ductile tissue grows and branches during pregnancy as a result of estrogen. The lobule-alveolar systems of the breast also develop during pregnancy as a result of the effect of progesterone, which causes the growth of lobules, the budding of alveoli, and an increase in the secretory capacity of alveolar cells. That process, which is termed differentiation, is the
reason for which full-term pregnancy early in life provides protection against carcinogen-induced breast cancer. 10 Cancers often develop in epithelial cells. All cells have a finite life span, and there is a balance between cell division and cell death. When stimulated by estrogen, the BCL2 gene causes breast cells to grow rapidly and prevents cell death. In ovarian carcinoma cell lines and in breast epithelial cells, progesterone induces apoptosis and upregulates the P53 gene.11,12 Formby and Wiley 13,14 demonstrated that progesterone at a concentration similar to that seen during the third trimester of pregnancy exhibited a strong antiproliferative effect on at least two breast cancer cell lines. Apoptosis was induced in the progesterone receptor expressing T47-D breast cancer cells. To promote the understanding of the action of progesterone, researchers have been trying to culture human breast epithelial cells that are nontumorigenic and that contain progesterone receptors. Those receptors are synthesized in response to estrogen. Synthetic progestins such as medroxyprogesterone acetate or norethindrone occupy the progesterone receptor site and inhibit the binding of endogenous progesterone to the receptor. Synthetic progestins do not produce the P53 gene and thus would prevent the production of progesterone and the activation of the P53
International Journal of Pharmaceutical Compounding 245 Vol. 6 No. 4 July/August 2002
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gene. This chemically induced progesterone deficiency, like natural progesterone deficiency, may increase the risk of breast cancer because the BCL2 gene is upregulated by estradiol and no corresponding downregulation opposes that action. Breast epithelial cell proliferation is greater when a combination of estrogen and medroxyprogesterone acetate is used than when estrogen only or no hormone replacement therapy is used. 15 Another study16 compared postmenopausal women who followed one of four protocols: topically applied estradiol, progesterone, estradiol plus progesterone, or placebo. The use of estradiol alone increased the proliferation index of breast epithelium 100-fold, the use of progesterone alone increased the proliferation index 15-fold, and combination treatment with estradiol plus progesterone increased that index 13-fold.
Effects of Progesterone on the Brain

We also reviewed the current literature on the effects of progesterone on the brain in adult humans and preterm infants. As noted previously, premature infants are deprived of the full benefits of estradiol and progesterone. In one study,17 15 preterm infants received progesterone and estradiol replacement at intrauterine levels. When the treated infants were examined, they exhibited a normal psychomotor pattern, but preterm infants who were not treated with progesterone and estradiol replacement (the control group) exhibited delayed psychomotor development. That area of research is new, and more extensive studies are needed to evaluate the potential benefits of and adverse side effects induced by the postnatal replacement of those hormones at intrauterine levels in premature infants. 17 Research was conducted by Wagner et al 18 to determine the differences in progesterone-receptor formation in the developing male and female human brain. The brain of the human male differs structurally and neurobiologically from that of the human female. Research studies indicate that maternal progesterone (not fetal steroids such as androgens and estrogens) induces gender differences in the human brain. Maternal progesterone en-
ters the blood and brain of the fetus, and the activation of the progestin receptor modifies the function of the brain cells. Male fetuses exhibit a greater sensitivity to progesterone and have more progestin receptors than do female fetuses. The discovery of this role of progesterone superseded the view that only androgens and estrogens are the agents of sexual differentiation. Research on neuronal differentiation, cell migration, cell death, and other cellular events that contribute to gender-based differences in the central nervous system is in progress. 18 According to Baulieu and Schumacher,19 progesterone is synthesized by Schwann cells and enhances myelin formation in the peripheral nerves. Those authors also confirmed that progesterone promotes myelin repair in the brain. When progesterone was given to animals with transplanted oligodendrocytes, significantly more axons were remyelinated after 3 to 5 weeks. Baulieu and Schumacher found that progesterone rapidly increased the expression of a transcription factor known as Krox20, which plays a critical role in the regulation of the myelin gene in Schwann cells. If the in vitro work can be duplicated in vivo, it may lead to the development of specific steroid compounds used to treat male and female multiple sclerosis patients without adversely affecting other areas of the body. Significant research today is devoted to the development of a synthetic progestin for postpartum administration to women with multiple sclerosis to prevent relapses of that disease. The effect of progesterone on excitotoxic cell death, lipid peroxidation, and the induction of specific enzymes in the neurologic recovery from brain and spinal cord injury is the focus of that research. Researchers now have evidence that it may be easier for the female brain to repair itself after injury. 20 Progesterone reduces the cerebral swelling and consequent ischemia-induced cell damage that follows brain injury. According to Wright et al, 21 progesterone given by injection may be an inexpensive and safe way to protect the brain from edematous injury. Two other key elements linked to neuroprotection lie within the signal transduction pathway in the brain. Progesterone elicits the phosphorylation of Akt, a downstream effector of the phosphoino-
sitide-3 (PI-3) kinase pathway and of extracellular-signal regulated kinase (ERK), a component of the mitogen-activated protein kinase (MAPK) pathway. These pathways offer mechanisms for neuroprotection against various insults and may lead to discoveries for the treatment of neurodegenerative disorders such as Alzheimers disease. 22 Progesterone and 19-norprogesterone also protect against glutamate toxicity, in stark contrast to the lack of such protection provided by medroxyprogesterone acetate. According to Nilsen and Brinton, 23 17 -estradiol upregulates BCL2, which prevents cell death. Progesterone and 19norprogesterone, alone or in combination with estrogen, increase the expression of BCL2. Those authors state that These results may have important implications for the effective use of hormone replacement therapy in the maintenance of neuronal function during menopause and aging and for protection against neurodegenerative diseases such as Alzheimers disease. 23 Progesterone affects the expression of several proteins in the brain. For example, progesterone stimulates -aminobutyric acid (GABA) signaling pathways in specific areas of the brain. In animal studies, those pathways regulate the signals in the brain that involve sexual response, but the effect of progesterone in the human brain is limited. In animal models, the most well-defined aspect of progesterone action is progesterone-receptor (PR) mediated effects in the hypothalamus and preoptic area. Those effects may also be mediated by the direct interaction of 5- -reduced progesterone metabolites and GABA A receptors. 24 A study 25 of the effect of finasteride, a 5- -reductase inhibitor, in the murine model revealed that the level of allopregnenolone is very important in inhibiting the anticonvulsant and sedative effects of alcohol. Increased stress levels trigger the release of corticosterone and progesterone, from which allopregnenolone is produced. A dramatic rise in the allopregnenolone level of animal subjects was observed after they had ingested ethanol. When finasteride was administered, the formation of allopregnenolone from progesterone after ethanol ingestion was blocked. This may be the reason for which
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women, who have a higher level of the steroid than do men and thus produce more allopregnenolone, can become more relaxed after consuming less ethanol than that required to relax a male counterpart. It may also explain the difference in the reactions of men and women to the ingestion of ethanol. In the study25 cited, female rats consumed more ethanol during the phase of their reproductive cycle when their progesterone level was low. Progesterone also affects the pulsatile gonadotropin-releasing hormone (GnRH) stimulus from the hypothalamus. GnRH pulses regulate the secretion of pituitary luteinizing hormone (LH) and folliclestimulating hormone (FSH). Rapid pulses of GnRH produce an LH surge that is followed by ovulation, after which the GnRH pulse slows to produce more FSH. In women with a hypothalamic dysfunction such as hypothalamic amenorrhea or polycystic ovarian syndrome, GnRH pulses can be influenced by progesterone, which slows the GnRH pulse secretion
to produce an increase in the level of FSH and subsequent follicular maturation. 26
Effects of Progesterone on the Heart and Circulatory System

Female sex hormones may confer some cardioprotective effects, because clinical observation indicates that coronary artery disease is more common in men and postmenopausal women than in premenopausal women. Estrogen deficiency is currently thought to increase the risk of coronary heart disease because many epidemiologic studies have reported a reduced risk of coronary heart disease in premenopausal women. Estrogens produce favorable changes in endothelial function, vascular reactivity, lipid levels, and blood flow. Vascular effects of added progestins ranging from neutral to detrimental have been described, but the effects of progesterone on endothelial function in
humans per se have not been reported. The American Heart and Estrogen/Progestin Replacement Study (HERS) is a large multicenter randomized study of the effects of hormone replacement therapy in postmenopausal women with heart disease. 27 Conjugated equine estrogens and medroxyprogesterone acetate were used as hormone replacement therapy in that study. HERS results revealed no reduced risk of coronary heart disease in the subjects who received hormone replacement therapy but instead indicated a higher risk of events related to coronary heart disease during the first year of treatment. When the benefits and risks of hormone replacement therapy are assessed, it is important to determine which chemicals were used as treatment because individual progestins have varying pharmacologic properties and do not produce the same side effects. Progesterone and 19-norprogesterone do not exert an androgenic action and have no negative effect on lipid levels and vascular reactivity in ani-
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mal models or on exercise-induced myocardial ischemia in humans. 2 8 - 2 9 Estrogens preserve the normal endotheliummediated dilation of coronary arteries, and progesterone does not reverse the effect of that potentially cardioprotective mechanism. In one animal study, 30 progesterone caused coronary relaxation by inhibiting Ca ++ mobilization into coronary smooth muscle and by other mechanisms. In a study by Mather et al, 31 the effect of 17- -E 2 , progesterone, and 17- - E 2 with progesterone on endothelial forearm responses was examined. The authors concluded that progesterone does not produce detrimental vascular effects in healthy menopausal women who do not have risk factors for cardiovascular disease. Progesterone also prevents the multiplication and migration of smooth muscle cells, which are involved in the formation of plaque that blocks arteries in the heart and brain. Progesterone inhibits deoxyribonucleic acid synthesis and the proliferation of the smooth muscle cells. 32 This finding was further supported by animal studies 33 in which ovariectomized female progesterone receptor (PRKO) knockout mice and wild-type (WT) litter mates were used to study the effects of progesterone on vascular smooth muscle cells. Progesterone produced no significant effect in the PRKO mice studied, but it inhibited the proliferation of vascular smooth muscle cells in the WT mice. That research may lead to the identification of the mechanism of action by which
progesterone protects against atherosclerosis. In 1992, researchers also discovered that progesterone reduces platelet aggregation via the enhancement of nitric oxide, which is an endotheliumderived relaxing factor. 34 In one study, 34 a direct effect on platelet aggregation was noted when rabbit aortic strips were exposed to progesterone, which promotes endothelium-nitric oxide relaxing factor. The effect of progesterone on the rat aorta and mesenteric arteries differed; this suggests that the effect of progesterone on the relaxant response of the endothelium differs between conduit vessels (the aorta) and resistance vessels (mesenteric arteries). 29 Another study 35 on peripheral circulation shows vasodilatation of mesenteric, renal, and iliac arteries from the release of nitric oxide as a result of progesterone infusion.
Conclusion
Todays medical professionals are taught that progesterone is used in hormone replacement therapy to prevent endometrial hyperplasia, to treat infertility, or to support progesterone-deficient pregnancies. However, in this report we have shown that bioidentical progesterone exerts many additional effects throughout the body. Progesterone is critical to ensuring bone health. It offers neuroprotection, contributes to cardiovascular health, assists normal brain development, and provides protection from some types of cancer. The use of bioidentical progesterone may soon be indicated for the treatment of a large population that includes men, women, and (possibly) infants. Synthetic progestins cannot be substituted for many of the favorable actions of bioidentical progesterone.
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References
1. Graham C. Physiological action of progesterone in target tissues. Endocr Rev 1997;18:502-519. 2. OMalley BW, Spelsberg TC, Steggles AW. Progesterone-binding components of chick oviduct v. exchange of progesterone-binding capacity from target to nontarget tissue chromatins. J Biol Chem 1972;247:1368-1374. 3. MacNamara P, Loughrey HC. Progesterone receptor A and B isoform expression in human osteoblasts. Calcif Tissue Int 1998;63:39-46. 4. Luo XH, Liao EY. Progesterone differentially regulates the membrane-type matrix metalloproteinase-1(MT1-MMP) compartment of proMMP-2 activation in MG-63 cells. Horm Metab Res 2001;33:383-388. 5. Gronowicz GA, McCarthy M-B. Glucocorticoids inhibit the attachment of osteoblasts to bone extracellular matrix proteins and decrease B1-integrin levels. Endocrinology 1995;136:598-608. 6. Prior JC. Progesterone as a bone-trophic hormone. Endocr Rev 1990;11:386-398. 7. Trotter A, Pohlandt F. The replacement of oestradiol and progesterone in very premature infants. Ann Med 2000;32:608-614. 8. Trotter A, Pohlandt F, Bokelmann B. Follow-up examination at the age of 15 months of extremely preterm infants after postnatal estradiol and progesterone replacement. J Clin Endocrinol Metab 2001;86:601-603. 9. Shyamala G. Progesterone action in human breast cancer. 1995. Available at: http://www.ucop. edu/srphome/bcrp/progressreport/abstracts/patho/1ib0448. html. Accessed October 17, 2001. 10. Sivaraman L, Conneely, OM, Medina D, et al. p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis. Proc Natl Acad Sci USA 2001;98:12379-12384. 11. Shi-Zhong B, De-Ling Y, Xiu-Hai R, et al. Progesterone induces apoptosis and upregulation of p53 expression in human ovarian carcinoma cell lines. Cancer 1997;79:10. 12. Yu S, Lee M, Shin S, et al. Apoptosis induced by progesterone in human ovarian cancer cell line SNU-840. J Cell Biochem 2001;82:445-451. 13. Formby B, Wiley TS. Progesterone inhibits growth and induces apoptosis in breast cancer cells: Inverse effects on Bcl-2 and p53. Ann Clin Lab Sci 1998;28:360-369. 14. Formby B, Wiley TS. Bcl-2, surviving and variant CD44 v 7-v10 are downregulat-
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ed and p53 is upregulated in breast cancer cells by progesterone: Inhibition of cell growth and induction of apoptosis. Mol Cell Biochem 1999;202:53-61. 15. Hofseth L, Raafat A, Osuch JR, et al. Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab 1999; 84:4559-4565. 16. Foidart JM, Colin C, Denoo X, et al. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril 1998;69:963-969. 17. Trotter A, Maier L, Pohlandt F. Management of the extremely preterm infant: Is the replacement of estradiol and progesterone beneficial? Paediatr Drugs 2001;3:629-637. 18. Wagner CK, Nakayama AY, De Vries GJ. Potential role of maternal progesterone in the sexual differentiation of the brain. Endocrinology 1998;139: 3658-3661. 19. Baulieu EE, Schumacher M. Neurosteroids, with special reference to the effect of progesterone on myelination in peripheral nerves. Mult Scler 1997; 3:105-112. 20. Groswasser Z, Cohen M, Keren O. Female TBI patients recover better than males. Brain Inj 1998; 12:805-808. 21. Wright DW, Bauer ME, Hoffman SW, et al. Serum progesterone levels correlate with decreased cere-
bral edema after traumatic brain injury in male rats. J Neurotrauma 2001;18:901-909. 22. Singh M. Ovarian hormones elicit phosphorylation of Akt and extracellular-signal regulated kinase in explants of the cerebral cortex. Endocrine 2001; 14:407-415. 23. Nilsen J, Brinton RD. Impact of progestins on estrogen-induced neuroprotection: Synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. Endocrinology 2002;143:205-212. 24. Graham JD, Clarke CL. Physiological action of progesterone in target tissues. Endocr Rev 18:502-519. 25. VanDoren MJ, Matthews DB, Janis GC, et al. Neuroactive steroid 3 -hydroxy-5 -pregnane-20one modulates electrophysiological and behavioral actions of ethanol. J Neurosci 2000;20:1982-1989. 26. Marshall JC, Eagleson CA, McCartney CR. Hypothalamic dysfunction. Mol Cell Endocrinol 2001; 183;29-32. 27. Kuttenn F, Gerson M. Hormone replacement therapy of menopause, heart and blood vessels. Arch Mal Coeur Vaiss 2001;94:685-689. 28. Sitruk-Ware R. Progestins and cardiovascular risk markers. Steroids 2000;65:651-658. 29. Chan HY, Yao X. Different role of endothelium/ nitric oxide in 17 -estradiol and progesteroneinduced relaxation in rat arteries. Life Sci 2001;69: 1609-1617.
30. Crews JK, Khalil RA. Antagonistic effects of 17 estradiol, progesterone, and testosterone on Ca++ entry mechanisms of coronary vasoconstriction. Arterioscler Thromb Vasc Biol 1999;19:1034-1040. 31. Mather KJ, Norman EG, Prior JC, et al. Preserved forearm endothelial responses with acute exposure to progesterone: A randomized cross-over trial of 17-estradiol, progesterone, and 17-estradiol with progesterone in healthy menopausal women. J Clin Endocrinol Metab 2000;85:4644-4649. 32. Lee WS, Harder JA. Progesterone inhibits arterial smooth muscle cell proliferation. Nat Med 1997;3: 1005-1008. 33. Karas RH, van Eickels M, Lydon JP, et al. A complex role for the progesterone receptor in the response to vascular injury. J Clin Invest 2001;108:611-618. 34. Jiang C, Sarrel PM, Lindsay DC, et al. Progesterone induces endothelium-independent relaxation of rabbit coronary artery in vitro. Eur J Pharmacol 1992;211: 163-167. 35. Molinari C, Battaglia A. Effect of progesterone on peripheral blood flow in prepubertal female anesthetized pigs. J Vasc Res 2001;38:569-577.
Address correspondence to: Diane Boomsma, RPh, 201 E. Chestnut Street, Lancaster, PA 17602. E-mail: custom@ w m s a p o t h . com, or to Jim Paoletti, RPh, PCCA, 9901 S. Wilcrest Dr, Houston, TX 77099.
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The Hormonal Link to Breast Cancer:
The Estrogen Matrix

David T. Zava, PhD ZRT Laboratory, Beaverton, Oregon Nearly every risk factor for breast cancer is linked either directly or indirectly to an increase in the level of unopposed estrogen or estrogen receptor activity. 1-4 The estrogen matrix diagram (Figure 1) shows that many of those risk factors and hormonal imbalances lead to excessive exposure of the breast tissue to estrogens in the absence of progesterone. The term unopposed estrogens refers to estrogens not balanced by adequate progesterone, which is the bodys natural antiestrogen. In this article, the estrogen matrix is presented in the following six sections related to biochemical and hormonal imbalances that increase the burden of unopposed estrogens in breast tissue, which in turn leads to increased breast cancer risks (Fig. 1, going counterclockwise). Estrogen dominance syndrome Obesity and insulin resistance Conventional hormone replacement Stress and adrenal dysfunction Immune system dysfunction therapy (HRT) Pollutants
cess (increased facial and body hair, acne, oily skin, loss of scalp hair). Many women with PCOS also suffer from symptoms of estrogen dominance caused by the lack of progesterone. 6,7,15 Insulin resistance is particularly problematic in breast cancer patients, because breast cancer cells overexpress receptors for insulin at levels 5 to 10 times higher than those expressed by normal breast cells.16 Moreover, glucose is a source of energy for the growth of breast cancer cells.17,18 Therefore, the breast cancer cell has a selective growth advantage in individuals with insulin resistance. 7 Insulin resistance can best be avoided by proper diet (including the avoidance of refined carbohydrates) and exercise, both of which decrease the incidence of breast cancer. 5,19,20
Conventional HRT
Conventional hormone replacement therapy (conventional HRT) refers to estrogen replacement (ie, the use of orally or transdermally delivered conjugated estrogens [such as Premarin] or estradiol combined with a synthetic progestin, such as medroxyprogesterone acetate [Provera]). Recent clinical studies21,22 have shown that the prolonged use of conventional HRT increases breast cancer risk 1.6-fold to 2fold. When combined with estrogens, synthetic progestins reduce the risk of endometrial cancer but increase the risk of breast cancer, 21,22 increase breast density (which is also a risk factor for breast cancer), and do not protect normal breast cells. Natural hormone replacement therapy with bioidentical hormones, including natural progesterone, results in less risk of breast cancer and does not increase breast density as does conventional HRT (eg, Premarin and Provera). 21-26
Obesity and Insulin Resistance

The combination of a diet high in refined carbohydrates (pastries, cookies, candy, soft drinks, etc) and a sedentary lifestyle leads to obesity, which is closely associated with insulin resistance (syndrome X), which is the resistance of tissues to take up glucose. 5 In response to this tissue resistance to glucose, the pancreas produces a higher level of insulin to compensate. Persistently high levels of both insulin and glucose in the bloodstream have devastating effects on health and increase the risk of the development of many of the diseases that plague western society (cardiovascular disease, diabetes, kidney failure, cancer). Obesity and associated insulin resistance have risen to an epidemic level in the United States as a result of poor diet and sedentary lifestyle. Smoking further exacerbates insulin resistance. 5 Insulin resistance results in the abnormal production of luteinizing hormone (LH) by the pituitary gland in the brain. 6-8 Excessive LH relative to follicle-stimulating hormone (FSH) prevents a dominant follicle in the ovaries from maturing. Under ordinary circumstances, the dominant
follicle would ripen, release an egg, and then produce copious amounts of progesterone (the corpus luteum). Instead, in insulin-resistant patients, many follicles attempt to mature, and polycystic ovarian syndrome (PCOS) can occur. 7 This cluster of unripened follicles responds to a high level of insulin and produces an excessive amount of testosterone; the normal cyclic production of estrogen followed by progesterone does not occur. 6 The excessive testosterone is converted to estrogens by the enzyme aromatase, which is found predominantly in adipose (fat) tissue. The more obese an individual, the more likely the conversion of androgens to estrogens, which results in an excessive level of unopposed estrogens. 6,9 Elevated testosterone production is common in women with breast cancer. 10-14 The clinical and/or laboratory manifestations of PCOS include an irregular menstrual cycle that is caused by inadequate production of progesterone (which enables the shedding of the uterine lining) and is associated with infertility, excessive production of androgens (testosterone and dehydroepiandrosterone [DHEA]), and symptoms of androgen ex-
Pollutants
In some geographic regions, our environment is polluted with petrochemical products. Those highly fat-soluble chemicals, which are contained in animal fats, eventually find their way to the top of the food chain (humans). Scientists have found that some petrochemical pollutants have profound effects on the endocrine system and are therefore referred to as endocrine disruptors. 27-29 Some of those pollutants have structures similar to those
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of estrogens (ie, xenoestrogens or estrogens foreign to the human body) and bind directly to estrogen receptors to cause persistent activation and excessive cell growth and proliferation. 28 Normal breast cells are embedded in fat tissue, which is a reservoir for those environmental pollutants, and continual exposure to xenoestrogens results. 27 Other pollutants such as polychlorinated biphenyls (PCBs) do not interact directly with estrogen receptors in target cells but collect in other fatty tissues such as the ovaries; this produces long-term damage and ovarian dysfunction. 27,28 Long-term exposure to PCBs can result in the reduced production of progesterone with each ovulatory cycle, although the production of estrogens remains normal. Over the years, low pro-
gesterone production with each cycle manifests as symptoms of estrogen dominance, such as fibrocystic breasts and endometrial hyperplasia. 1-4 Estrogen dominance becomes progressively worse as a woman ages and approaches menopause. The epidemic of attention deficit disorders in children (adequate progesterone during pregnancy is necessary for proper brain development) and an increase in fertility problems are also related to ovarian damage caused by excessive exposure to pollutants. 28 Avoiding exposure to petrochemical products (pesticides, etc) and consuming organic foods help reduce the bodys burden of pollutants. The sweating induced by exercise and proper nutrition also help to clear pollutants from the body. 1
Estrogen Dominance Syndrome

Ovarian dysfunction refers to the cyclic production of estrogen in each menstrual cycle, which is followed by inadequate production of progesterone. This imbalance in the ratio of estrogen to progesterone eventually leads to symptoms of estrogen dominance, which include weight gain, premenstrual syndrome (PMS), fibrocystic breasts, uterine hyperplasia and/ or fibroid tumors, water retention, and functional hypothyroidism. 1,24,30,31 The estrogen level is usually within normal range in women with symptoms of estrogen dominance. The problem of estrogen dominance is not usually caused by excess estrogen; it is caused by the lack of proges-
Figure 1. Hormonal Risk Factors for Breast Cancer: The Estrogen Matrix.
Ovarian Dysfunction ESTROGEN DOMINANCE Progesterone Prolactin SHBG Estrogens

E1, E2
Xenobiotics
eg, PCBs
POLLUTANTS Xenoestrogens
eg, DDT
Conventional HORMONE REPLACEMENT THERAPY Androgens
Polycystic Ovaries
LH/FSH
DHEA, Testosterone Aromatase
Estrogens Estrogen Receptors
Insulin Receptors
Insulin
INSULIN RESISTANCE
STRESS
Emotional Physical Surgical Dietary
Thyroid Melatonin Cortisol

17-HSD Type 2 (E1 E2) E1-Sulfatase (E1-S04 E1) Aromatase (A E1)
Refined Carbohydrates
Poor Diet
Obesity Smoking Zinc
Breast Stroma ADRENAL GLANDS DHEA IMMUNE SYSTEM Cytokines Th1 Th2
Cadmium
Pathways leading to increased levels of estrogen and estrogen-receptor activity.

= Higher levels. = Lower levels.
PCBs =Polychlorinated biphenyls. E 1 = Estrone. E 2 = Estradiol. DDT = Chlorophenothane. DHEA = Dehydroepiandrosterone. LH = Luteinizing hormone. FSH = Follicle-stimulating hormone. SHBG =Sex hormone-binding globulin. 17 -HSD type 2 = 17 -hydrosteroid dehydrogenase type 2. E 1 SO 4 = Estrone sulfatase. A = Aromatase. Th1 = T helper type 1 lymphocytes. Th2 = T helper type 2 lymphocytes.
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terone, which balances estrogen and prevents it from causing excessive growth and proliferation of the breasts and reproductive tissues. 1,24-26,31-33 When the amounts of estrogen and progesterone are out of balance (estrogen dominance), the prolactin level increases. Prolactin can stimulate the growth of breast cancer cells. 34 Estrogen dominance also results in a functional thyroid deficiency (a resistance to thyroid hormones). The levels of thyroid hormones may be normal, but some patients exhibit a resistance to thyroid hormones that is similar to insulin resistance. 30,35 Low levels of thyroid hormones result in a lowered level of sex hormone-binding globulin (SHBG), which ordinarily sequesters estrogens in the bloodstream and prevents them from entering target tissues and stimulating cell growth.8,32 Estrogen dominance also leads to fat deposition in the body, 3,4,7,17 which converts androgens to estrogens and further increases the estrogen burden. An exces-
sive level of estrogen (particularly when combined with synthetic progestins) leads to insulin resistance, which increases the estrogen burden as described above. 5-8
Stress and Adrenal Dysfunction

Stress can profoundly affect the adrenal glands; this causes abnormal production of cortisol and DHEA. A high level of night cortisol (a flattened circadian pattern of adrenal cortisol production) combined with a low level of DHEA appears to be a hallmark of hormonal imbalance in breast cancer patients. 14,36-40 A high stress level and adrenal imbalance (ie, a high cortisol level) are closely associated with breast cancer risk and with survival in women with metastatic breast cancer. 36,40,41 A high level of stress is also associated with high production of cortisol by the adrenal glands. Stress can be emotional, physical (a result of overexercising), sur-
gical, or dietary in origin. The emotional stress thought to contribute to the development of breast cancer is probably related to traumatic events (suppressed child abuse, divorce, the death of a loved one, serious financial problems). 36,40,41 Stress and increased production of adrenal cortisol cause estrogen dominance in several ways 39 : 1. By producing ovarian dysfunction. Stress causes ovarian dysfunction, which leads to luteal insufficiency and subsequent estrogen dominance. 2. By increasing aromatase activity. A high level of cortisol increases aromatase activity in adipose tissue, which converts androgens to estrogens. 3. By producing insulin resistance and a resistance to thyroid hormones. A high level of cortisol causes insulin resistance and a resistance to thyroid hormones, both of which increase the estrogen burden (see above). 4. By reducing the level of melatonin. A high level of cortisol, particularly at night, is inversely related to the production of melatonin by the brain. A low melatonin level results in the overproduction of estrogens and the activation of estrogen receptors in breast cells. 42,43 Women with a calcified pineal gland, which is associated with a low production of melatonin, have a significantly greater risk of developing breast cancer. 42
Immune System Dysfunction

A dysfunctional immune system caused by an imbalance in adrenal cortisol and DHEA can lead to excessive estrogen production selectively and specifically around the confines of a new colony of breast cancer cells. 39 In essence, the signals released by the breast cancer cells initiate the immune defense, in which normal biochemical pathways and hormone precursors are used to produce an exceptionally high level of estradiol that selectively stimulates the growth of breast cancer cells. 39 A high level of cortisol and a low DHEA level, both of which are caused by excessive stress, result in a higher production of T helper type 2 (Th2) lymphocytes relative to the production of T helper type 1 (Th1) lymphocytes. 39 Both types of T helper lymphocytes are important for normal immune system function, but im-
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balances such as an excess of Th2 cells relative to Th1 cells are associated with disease states. Breast cancer appears to be associated with an excess of Th2 lymphocytes, which is caused by a high cortisol level and a low DHEA level. 39 When cancer cells grow, they release chemokines, which are chemical signals. Chemokines attract the T helper cells, which recognize and initiate a complex series of immune reactions to attack and kill cancer cells. Th2 lymphocytes that infiltrate a tumor produce a high level of the cytokine interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF- ). Those cytokines activate enzymes (aromatase, estrone sulfatase, and 17 -hydrosteroid dehydrogenase type 1) in the normal breast stroma surrounding the tumor, as well as enzymes within the cancer cells themselves. The enzymes then produce estrogens from estrone sulfate and androgens. Estrone sulfate is not an active estrogen but is converted to the potent estrogen estradiol when its sulfate is removed by sulfatase and the estrone is converted to estradiol by 17-hydrosteroid dehydrogenase type 1.39 By subverting the function of the T helper lymphocytes, breast cancer cells produce estradiol locally within the immediate confines of the tumor at a level as much as 10 times higher than that in the circulation.39 Excessive estrogen produced in this manner around the confines of the tumor would be expected to have other insidious effects associated with survival of the tumor. For example, excess estrogen suppresses natural killer cells, which are the first line of defense against cancer. 44,45 Excess estrogen also causes angiogenesis and vasodilatation: New blood vessels are formed to feed the tumor, and a ballooning effect occurs in the capillaries45,46 so that tumor cells escape through those capillaries to distant sites in the body (metastasis). Estrogens increase the levels of enzymes released by tumor cells that permit those tumor cells to invade surrounding tissues.47 Estrogens also increase clotting, so that tumor cells can embed into a fibrin clot and escape to distant sites through expanded capillary beds without being recognized by the immune system. 45,48-50 Stress reduction, adrenal support, exercise, and rebalancing DHEA and progesterone to normal levels are effective ways of preventing adrenal imbalance
(ie, a high cortisol level and a low DHEA level) that can lead to immune dysfunction and excessive production of estrogens around the confines of newly formed breast cancer cells. 19,36,40,41,45 Progesterone prevents the biochemical events listed above in several ways and thus helps lower the estrogen burden that stimulates breast tumor growth. 32 Some of the ways in which progesterone counters the effect of adrenal imbalance and resultant immune dysfunction are listed below. 1. Progesterone, which has a calming effect, helps with perceived stress issues; this lowers excessive adrenal cortisol production. 51,52 2. Progesterone competes with cortisol at the cellular level. 52 3. Progesterone reduces the overall estrogen burden by increasing the levels of enzymes that convert estradiol to inactive estrone sulfate. 32,52,53 Progesterone increases the level of 17 -hydrosteroid de-
hydrogenase type 2 by converting estradiol to estrone and the level of sulfur transferase by converting estrone to estrone sulfate. 4. Progesterone stabilizes the vasculature, which prevents ballooning of the capillaries caused by excess estrogen. 39,45 This prevents clusters of tumor cells from traveling to distant sites. 5. Progesterone activates natural killer cells. 44,45 6. Progesterone inhibits angiogenesis. 46 7. P r o g e s t e r o n e l o w e r s t h e e s t r o g e n burden in the breast tissue and decreases the probability of clotting. 23,24,49,50
Conclusion
The estrogen matrix is an excellent tool that facilitates the understanding of the ways in which poor diet, sedentary lifestyle, synthetic hormone replacement therapy, exposure to pollutants, failing production of progesterone by the ovaries, stress, adrenal imbalance, and immune dysfunction
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lead to an overproduction of estrogen that promotes the growth of breast cancer cells. That knowledge enables the creation of a prevention strategy for breast cancer that includes improved diet, exercise, the avoidance of pollutants, bioidentical hormone replacement with natural progesterone, adrenal support, and stress reduction.
References
1. Lee JR, Zava DT, Hopkins V. What Your Doctor May Not Tell You About Breast Cancer, How Hormone Balance Can Help Save Your Life. New York:Warner Books; 2002. 2. Bernstein L, Ross RK. Endogenous hormones and breast cancer risk. Epidemiol Rev 1993;15:48-65. 3. Hulka B, Liu ET, Lininger RA. Steroid hormones and risk of breast cancer. Cancer 1994;73(suppl 3):3. 4. Henderson BE, Ross R, Bernstein L. Estrogens as a cause of human cancer: The Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res 1988;48: 246-253. 5. Reaven GM. Insulin resistance and human disease: A short history. J Basic Clin Physiol Pharmacol 1998; 9:387-406. 6. Stoll BA. Western nutrition and the insulin resistance syndrome: A link to breast cancer. Eur J Clin Nutr 1999;53:83-87. 7. Kaaks R. Nutrition, hormones, and breast cancer: Is insulin the missing link? Cancer Causes Control 1996;7: 605-625. 8. Nagata C, Shimizu H, Takami R, et al. Relations of insulin resistance and serum concentrations of estradiol and sex hormone-binding globulin to potential breast cancer risk factors. Jpn J Cancer Res 2000;91:948-953. 9. Stoll BA. Dietary supplements of dehydroepiandrosterone in relation to breast cancer risk. Eur J Clin Nutr 1999;53:771-775. 10. Cauley JA, Lucas FL, Kuller LH, et al. Elevated serum estradiol and testosterone concentration are associated with a high risk for breast cancer: Study of Osteoporotic Fractures Research Group. Ann Intern Med 1999;130:270-277. 11. Grattarola R, Secreto G, Recchione C. Androgens in breast cancer. III. Breast cancer recurrences years after mastectomy and increased androgenic activity. Am J Obstet Gynecol 1975;121:169-172. 12. Preda F, Pizzocaro G, Oriana S, et al. Correlation between clinical response to bilateral oophorectomy, estrogen receptors and urinary androgen excretion in 49 patients with advanced breast cancer. Tumori 1979;65:325-330. 13. Secreto G, Sumoff B. Abnormal production of androgens in women with breast cancer. Anticancer Res 1994;14:2113-2117. 14. Zeleniuch-Jacquotte A, Bruning PF, Bonfrer JM, et al. Relation of serum levels of testosterone and dehydroepiandrosterone sulfate to risk of breast cancer in postmenopausal women. Am J Epidemiol 1997;145: 1030-1038. 15. Ciampelli M, Lazone A. Insulin and polycystic ovary syndrome: A new look at an old subject. Gynecol Endocrinol 1998;12:277-292. 16. Papa V, Pezzino V, Costantino A, et al. Elevated insulin receptor content in human breast cancer. J Clin Invest 1990;86:1503-1510.
17. Del Giudice ME, Fantus IG, Ezzat S, et al. Insulin and related factors in premenopausal breast cancer risk. Breast Cancer Res Treat 1998;47:111-120. 18. Yee D, Lee AV. Crosstalk between the insulin-like growth factors and estrogens in breast cancer. J Mammary Gland Biol Neoplasia 2000;5:107-115. 19. Kushi LH. Physical activity and mortality in postmenopausal women. JAMA 1997;277:1287-1292. 20. Pate RR, Pratt M, Blair SN, et al. Physical activity and public health: A recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 1995;273:402-407. 21. Chen C, Weiss NS, Newcomb P, et al. Hormone replacement therapy in relation to breast cancer. JAMA 2002;287:734-741. 22. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-491. 23. Chang KJ, Lee TT, Linares-Cruz G, et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril 1995;63:785-791. 24. Mauvais-Jarvis P, Kuttenn F, Gompel A. Antiestrogen action of progesterone in breast tissue. Horm Res 1987;28:212-218. 25. Mohr PE, Wang DY, Gregory WM, et al. Serum progesterone and prognosis in operable breast cancer. Br J Cancer 1996;73:1552-1555. 26. Leis HP. Endocrine prophylaxis of breast cancer with cyclic estrogen and progesterone. Intern Surg 1966; 45:496-503. 27. Davis DL, Bradlow HL, Wolff M, et al. Medical hypothesis: Xenoestrogens as preventable causes of breast cancer. Environ Health Perspect 1993;101:372-377. 28. Zava DT, Blen M, Duwe G. Estrogenic activity of natural and synthetic estrogens in human breast cancer cells in culture. Environ Health Perspect 1997;105 (suppl 3):637-645. 29. Epstein SS. Environmental and occupational pollutants are avoidable causes of breast cancer. Int J Health Serv 1994;24:145-150. 30. Shames RL, Shames KH. Thyroid Power: Ten Steps to Total Health. New York:Harper Collins Publishers; 2001. 31. Arpels JC, Nachtigall RD. Gonadal hormones and breast cancer risk: The estrogen window hypothesis revisited. The Journal of the North American Menopause Society 1994;1:49-55. 32. Clarke CL, Sutherland RL. Progestin regulation of cellular proliferation. Endocr Rev 1990;11:266-301. 33. Cowan LD, Gordis L, Tonascia JA, et al. Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiol 1981;114:209-217. 34. Zumoff B. Hormonal profiles in women with breast cancer. Obstet Gynecol Clin North Am 1994;21:751-772. 35. Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 2001;344:1784-1785. 36. Andersen BL, Farrar WB, Golden-Kreutz D, et al. Stress and immune responses after surgical treatment for regional breast cancer. J Natl Cancer Inst 1998; 90:30-36. 37. Dorgan JF. Relationship of serum dehydroepiandrosterone (DHEA), DHEA sulfate, and 5-androstene-3 beta, 17 beta-diol to risk of breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev 1997; 6:177-178. 38. Lissoni P, Rovelli F, Giani L, et al. Dehydroepiandroster-
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
one sulfate (DHEA) secretion in early and advanced solid neoplasms: Selective deciency in metastatic disease. Int J Biol Markers 1998;13:154-157. Reed MJ, Purohit A. Breast cancer and the role of cytokines in regulating estrogen synthesis: An emerging hypothesis. Endocr Rev 1997;18:701-715. Sephton SE, Sapolsky RM, Kraemer HC, et al. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst 2000;92:994-998. Turner-Cobb JM, Sephton SE, Koopman C, et al. Social support and salivary cortisol in women with metastatic breast cancer. Psychosom Med 2000;62:337-345. Cos S, Sanchez-Barcelo EJ. Melatonin and mammary pathological growth. Front Neuroendocrinol 2000;21:133-170. Hill SM, Collins A, Kiefer TL. The modulation of oestrogen receptor-alpha activity by melatonin in MCF-7 human breast cancer cells. Eur J Cancer 2000;36 (suppl 4):117-118. Callewaert DM, Moudgil VK, Radcliff G, et al. Hormone specific regulation of natural killer cells by cortisol. Direct inactivation of the cytotoxic function of cloned human NK cells without an effect on cellular proliferation. FEBS Lett 1991;285:108-110. Hrushesky WJ, Gruber SA, Sothern RB, et al. Natural killer cell activity: Age, estrous- and circadian-stage dependence and inverse correlation with metastatic potential. J Natl Cancer Inst 1988;80:1232-1237. Iruela-Arispe ML, Porter P, Bornstein P, et al. Thrombospondin-1, an inhibitor of angiogenesis, is regulated by progesterone in the human endometrium. J Clin Invest 1996;97:403-412. Rochefort H, Chalbos D, Cunat S, et al. Estrogen regulated proteases and antiproteases in ovarian and breast cancer cells. J Steroid Biochem Mol Biol 2001; 76:119-124. Schmitt M, Kuhn W, Harbeck N, et al. Thrombophilic state in breast cancer. Semin Thromb Hemost 1999; 25:157-166. Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone replacement therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/Progestin Replacement Study. Ann Intern Med 2000;132:689-696. He S, Bremme K, Silveira A, et al. Hypercoagulation in surgical postmenopausal women having hormone replacement with overdose estradiol. Blood Coagul Fibrinolysis 2001;12:677-681. Rupprecht R, Holsboer F. Neuroactive steroids: Mechanisms of action and neuropsychopharmacological perspectives. Trends Neurosci 1999;22:410-416. Mahesh VB, Brann DW, Hendry LB. Diverse modes of action of progesterone and its metabolites. J Steroid Biochem Mol Biol 1996;56:209-219. Gompel A, Malet C, Spritzer P, et al. Progestin effect on cell proliferation and 17beta-hydroxysteroid dehydrogenase activity in normal human breast cells in culture. J Clin Endocrinol Metab 1986;63:1174.
Address correspondence to: David T. Zava, PhD, President, ZRT Laborator y, 1815 NW 169th Place, Suite 5050, Beaverton, Oregon 97006. E-mail: dzava@ zrtlab.com
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Physiologic Mechanism of Orgasm

Because of compounded formulations used to treat impotence (phentolamine and papaverine injection and prostaglandin E 1 injection) and the availability of the Medicated Urethral System for Erection (MUSE) and erectile pumps, many pharmacists are familiar with the physiologic mechanism of erectile dysfunction. Much of that knowledge can be extrapolated for the treatment of female sexual dysfunction. The clitoris is the homologue of the penis. It contains the corpus cavernosum clitoridis (two columns of erectile tissue that fuse to form the body of the clitoris) and is composed of the clitoral glans and shaft.5,6 Its blood supply is similar to that of the penis. The female sexual response cycle is initiated by neurotransmitter-mediated vascular and nonvascular smooth muscle relaxation, which results in increased pelvic blood flow, vaginal lubrication, and clitoral and labial engorgement. 7 The clitoris exhibits phases of enlargement and engorgement during sexual stimulation. 8 It is believed that vaginal engorgement and clitoral erection depend on increased blood flow and that a lack of blood flow from a variety of causes such as atherosclerosis 9,10 is a major factor in the pathophysiologic mechanism of arousal disorders. A recent study 11 showed an age-related decrease in clitoral cavernosal smooth muscle. Smooth muscle relaxation is a crucial element for clitoral engorgement.
Aminophylline 3%, Co-dergocrine Mesylate 0.05%, and Isosorbide Dinitrate 0.25% Cream for the Treatment of
Orgasmic Dysfunction in Women

David Mason, DPh, FIACP Innovative Pharmacy Solutions, Edmond, Oklahoma
Agents That Promote Engorgement and Erection

Of the many chemotactic agents that maximize erection and promote blood flow, the vasocongestive agent nitric oxide (NO) has been the greatest focus of attention. NO is a potent vasodilator that is crucial in scores of reactions throughout the body. 12 It activates soluble guanylate cyclase in cavernous smooth muscle cells, and the formation of cyclic guanosine monophosphate (c-GMP) induces penile erection.13,14 NO is donated from the amino acid arginine. 15 It has been delivered to humans in the form of nitrates: glyceryl trinitrate, isosorbide dinitrate, and sodium nitroprusside. 12 In the literature, sildenafil (Viagra) is of-
Introduction Orgasmic dysfunction, a significant problem that affects the quality of life of many women,1 is of two types: dysorgasmia (difficult orgasm) or anorgasmia (the inability to achieve orgasm). Either dysfunction can have a negative impact on libido. Our practice has expanded to include counseling about hormone replacement therapy, and many women to whom we provide that service exhibit some type of hormonal deficiency or imbalance. Such hormonal deficiency, coupled with emotional and/or physiologic states, can result in orgasmic dysfunction. In 1998, orgasmic dysfunction in women was termed female sexual dysfunction.2 Estimates indicate that 43% to 76% of women, according to their age, experience the symptoms of sexual dysfunction (decreased libido, vaginal dryness, painful intercourse, decreased genital sensation, difficulty in achieving or the inability to experience orgasm).1,2 During counseling with patients who experience orgasmic dysfunction, we were told about a nonprescription orgasm enhancer referred to as Dream Cream, a product also mentioned in popular magazines such as Glamour , Harpers Bazaar , Redbook , New York Magazine , The New York Post , and Vibe . Dream Cream contains aminophylline (a vasodilator) and L-arginine (an amino acid). 3 A search of the literature identified an article by Gomaa et al 4 on the successful treatment of erectile dysfunction with a cream containing aminophylline 3%, co-dergocrine mesylate (ergoloid mesylates) 0.05%, and isosorbide dinitrate 0.25% (active cream). Male subjects applied the active cream from individual packages of 2 g each to the penis daily for 1 week and then applied the placebo (2 g daily) for 1 week. More than half the subjects reported satisfactory results from the active cream, and no major side effects were reported. 4 However, obstetrician-gynecologists who treat many of our patients for hormonal imbalances expressed concern about the side effects produced by those vasodilators. One of those experienced specialists with whom we have a very good professional relationship was very concerned because the active cream contains nitrates. As a result of his concern for his patients cardiac health, he refused to prescribe that preparation until we could conduct a literature search to substantiate the safety of its use. This physicians concern led us to undertake such a search and to develop a chart (Table 1) in which the topical and oral administration of the active ingredients in the cream are compared. Our dispensing of the active cream containing aminophylline 3%, co-dergocrine mesylate (ergoloid mesylates) 0.05%, and isosorbide dinitrate 0.25% in 1-mL syringes included directions to rub 0.05 mL into and around the clitoris shortly (5 to 15 minutes) before intercourse, with a possible dose of up to 0.1 mL. As indicated in Table 1, the doses delivered orally are significantly greater than those delivered topically. Thus side effects produced by the topically applied cream are almost nonexistent. The physicians then prescribed this formulation for a select group of patients. The treatment was successful, and no side effects were reported.
ten listed as potential drug therapy for sexual dysfunction in men and women. Sildenafil is a selective inhibitor of c-GMP specific phosphodiesterase, which has been
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Table 1. Comparison of Doses for Oral Delivery and Topical Delivery of the Active Cream Ingredients.
Approximate Topically Delivered Dose (0.05 mL) (0.1 mL) Usual Adult Delivered Oral Dose 1.5 mg 3 mg 250 to 500 mg 3 to 4 times daily 0.025 mg 0.125 mg 0.05 mg 0.25 mg 1 mg 3 times daily in United States 3 mg 4 times daily worldwide 2.5 to 5 mg sublingually 5 to 10 mg sublingually or chewed 5 to 50 mg every 6 hr 40 to 80 mg every 8 to 12 hr
Adapted from: Needleman P, Johnson EM Jr, Gilman AG, et al . Goodman and Gilmans The Pharmacological Basis for Therapeutics . 6th ed. New York:Macmillan Publishing Co; 1980:826.
Ingredient (per 100 g) Aminophylline 3% Co-dergocrine mesylate 0.05% Isosorbide dinitrate 0.25%
shown to have an effect greater than that of placebo on erectile function in men. The effectiveness of oral sildenafil is being tested in women in the oral form, but to date there are no studies that report significant results in men. In one study, sildenafil was effective in treating sexual dysfunction caused by selective serotonin reductase inhibitors (SSRIs) in men and women. That treatment may be effective in patients in whom doses of 50 mg to 100 mg are used routinely. 16 Orally administered sildenafil exerts a systemic effect and inhibits the breakdown of NO throughout the body.16 Because topically applied sildenafil is effective only in the area to which it is applied, the probability of drug-related side effects is significantly reduced. The cream containing aminophylline 3%, co-dergocrine mesylate 0.05%, and isosorbide dinitrate 0.25% delivers NO in the form of isosorbide dinitrate. The authors 4 of one of the studies cited previously noted that during their research, they avoided the use of glyceryl trinitrate (NTG), which (in all concentrations used) produced headaches in the subjects studied. 4 Isosorbide dinitrate may have been chosen for use in the study instead, because when compared with NTG, it acts more slowly and delivers only two thirds of the NO that NTG does. Aminophylline releases theophylline after crossing the skin. It also inhibits the action of phosphodiesterase, which pre-
vents the breakdown of c-AMP to 5-AMP and subsequently causes sinusoidal smooth muscle relaxation and consequent erection.4 Ergoloid mesylates, which acts as an receptor blocking agent and regulates the responsiveness of smooth muscle, appears to be only a facilitator in this preparation. 4
Conclusion
Because of our knowledge of the physiologic effects of and side effects produced by medicines, we prefer to deliver a small amount of NO to a target area rather than to interfere with its breakdown in almost every cell in the body. The old adage start low, go slow applies to the use of this cream. Table 1 indicates that the doses of NO delivered by the cream are tiny fractions of daily exposures from endogenous NO in a normal adult; as a result, this treatment produces few side effects. Because the male subjects in the original study, who applied 2 g of the cream daily, experienced no major cardiovascular side effects, it is reasonable to assume that the application of 1/40 to 1/10 of that dose poses no significant threat to female patients who use it for climax enhancement.
Suggested Reading
[No author listed.] Libido cream. IJPC 2001;5:376.
2. Stipp D. The executive body: Middle age aint what it used to be. Heres how to stay on top of your game. Fortune 2002;145:44-55. 3. Pesmen C. Lust lotions. Glamour Magazine . Aug u s t 1 9 9 9 . Av a i l a b l e a t : h t t p : / / w w w. f e m a l e orgasm.md/articles_glamour.html. Accessed February 24, 2002. 4. Gomaa A, Shalaby M, Osman M, et al. Topical treatment of erectile dysfunction: Randomised doubleblind placebo controlled trial of cream containing aminophylline, isosorbide dinitrate, and co-dergocrine mesylate. BMJ 1996;312:1512-1515. 5. van Turnhout AA, Hage JJ, van Diest PJ. The female corpus spongiosum revisited. Acta Obstet Gynecol Scand 1995;74:767-771. 6. Park JK, Kim SZ, Kim SH, et al. Renin angiotensin system of rabbit clitoral cavernosum: Interaction with nitric oxide. J Urol 2000;164:556-561. 7. Berman JR, Adhikari SP, Goldstein I. Anatomy and physiology of female sexual function and dysfunction: Classification, evaluation and treatment options. Eur Urol 2000;38:20-29. 8. Masters WH, Johnson VE. Human Sexual Response. 1st ed. Boston, MA:Little, Brown and Co; 1996:56-58. 9. Goldstein I, Berman JR. Vasculogenic female sexual dysfunction: Vaginal engorgement and clitoral erectile insufficiency syndromes. Int J Impot Res 1998;10 (suppl 2):S84-90; discussion, S98-101. 10. Park K, Goldstein I, Andry C, et al. Vasculogenic female sexual dysfunction: The hemodynamic basis for vaginal engorgement insufficiency and clitoral erectile insufficiency. Int J Impot Res 1997;9:27-37. 11. Tarcan T, Park K, Goldstein I, et al. Histomorphometric analysis of age-related structural changes in human clitoral cavernosal tissue. J Urol 1999;161:940-944. 12. Ferlito S. Physiological, metabolic, neuroendocrine and pharmacological regulation of nitric oxide in humans. Minerva Cardioangiol 2000;48:169-176. 13. Saenz de Tejada I. Molecular mechanisms for the regulation of penile smooth muscle contractility. Int J Impot Res 2002;14(suppl 1):S6-S10. 14. Ayajiki K, Toda N, Okamura T. Nitroxidergic (nitrergic) nerve and erectile dysfunction. Nippon Yakurigaku Zasshi 2002;119:21-28. 15. Melis MR, Argiolas A. Role of central nitric oxide in the control of penile erection and yawning. Prog Neuropsychopharmacol Biol Psychiatry 1997;21:899-922. 16. Fava M, Rankin MA, Alpert JE, et al. An open trial of oral sildenafil in antidepressant-induced sexual dysfunction. Psychother Psychosom 1998;67:328-331.
References
1. Berman JR, Berman LA, Werbin TJ, et al. Female sexual dysfunction: Anatomy, physiology, evaluation and treatment options. Curr Opin Urol ; 1999;9:563-568.
Address correspondence to: David Mason, D P h , F I A C P, I n n o v a t i v e P h a r m a c y S o l u t i o n s , 1 7 1 6 S . K e l l y, E d m o n d , O K 73013. E-mail: dave@innovative pharmacy.com
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The Community Pharmacists Role

Estimates suggest that as many as 5 million to 10 million American men are experiencing some form of andropausal change. 1 Many men in their fifties or sixties experience depression, increased girth, loss of muscle mass and strength, and changes in sexual function. Those symptoms can be caused by inadequate levels of specific hormones. Many hormonedeficient men could be healthier and could enjoy an improved quality of life if the levels of those hormones (especially testosterone) were restored to a normal physiologic range. As knowledgeable and accessible healthcare professionals, pharmacists are in a unique position to collaborate with physicians to help men toward the goal of better health. Incorporating treatment for andropause into your pharmacy practice can benefit you professionally, educationally, and financially. In this article, some of the key steps involved in developing an andropause practice (education, collaboration with physicians, presenting seminars, in-store screenings, diagnostic testing, and treatment plans) are presented.
Establishing an ANDROPAUSE PRACTICE

Bruce Biundo, BS, RPh Professional Compounding Centers of America, Inc, Houston, Texas Andropausemens healthtestosterone deficiency in the aging male. Youre often hearing those words these days. In February 2002, more than 9600 references on andropause were identified by the search engine Google. The National Community Pharmacists Association (NCPA) recently instituted a screening program called A Mens Health Initiative. In November 2001, hormonal changes in men were the focus of the first World Congress on Mens Health, which was held in Vienna. Currently, more than 75 published medical articles in which the term andropause occurs are referenced in the electronic medical information service PubMed.
How To Identify Prospective Physician Prescribers

It is essential that pharmacists collaborate with physicians. Consider those prescribers with whom you already have a good professional relationship. Who are the leading primary care physicians in your area? They may be internists or family practice physicians; clinicians whose patients may be candidates for andropause treatment. Urologists and cardiologists treat many men with testosterone deficiencies that are related to erectile dysfunction; those specialists may be able to help their patients even more by being aware of the larger spectrum of treatments for andropause. For physicians who offer antiaging treatment or wellness care to their patients, therapy for andropause is a logical inclusion to the range of services offered. Naturopathic practitioners are often very open to working with pharmacists to provide hormone therapy for men. Endocrinologists may also be interested in providing treatment for andropause. Geriatricians are in a tremendous position to improve the health and quality of life of aging men and can do even more if they are knowledgeable about andropause. RS Tan, MD, from Houston is one such physician; he has written extensively about testosterone and the aging man. In establishing an andropause practice, pharmacists will find it essential to earn the trust of and collaborate effectively with physicians whose patients could benefit from the treatment of this condition.
How To Educate Prospective Prescribers About Treatment Options

Although physicians may be interested in your opinions about the treatment of andropause, they will probably request published research information and/or clinical data on that subject. Do not inundate a prospective prescriber with too much information; instead, offer one or two articles that are three to five pages in length in which an overview or summary of andropause is presented. (See the Suggested Reading at the conclusion of this article.) If the prospective prescriber is interested, you can offer more information. Some physicians (as well as pharmacists) are concerned about the effects of testosterone because of reports of anabolic steroid abuse and the side effects associated with synthetic androgens. Your knowledge and expertise will be of great service here, especially if you have a command of the subject.
The Importance of Education

The first step in establishing an andropause practice is to educate yourself. Pharmacists should become well informed in this field because their knowledge and expertise will be key to their being of service. Although andropause treatment is a new area of health care, extensive information from experts on testosterone supplementation is available because interest in andropause is increasing in the medical community and the general public. A list of those resources is featured in this article as Suggested Reading. A r e v i e w b y Te n o v e r 2 i n d i c a t e s t h e extent of available information about testosterone supplementation in men. The Internet provides many easy-to-read and readily accessible articles on that topic for the lay public, and abstracts of articles published in medical journals can be viewed on PubMed. Youll find that as you learn more, your interest in andropause will increase, and youll want to share that information with your colleagues, prescribers, and patients.
How To Establish a Patient Base

In general, men are less likely than women to be aware of their health needs. Many men in the United States suffer the symptoms of andropause but are unaware of the options for treatment. Ask prospective patients to complete an in-store screening form (page 261) that can be completed and given to the pharmacist. If the patient seems to exhibit the signs of andropause, suggest that appropriate treatment can improve
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his health and then refer him to a physician. Be sure that literature indicating your interest in mens health is prominently displayed and readily available in your pharmacy. Tom Jones, RPh, (Tom Jones Compounding Pharmacy, Garner, North Carolina) has found that type of marketing effective. Many pharmacists are now using their caller-on-hold telephone system to publicize services such as andropause management. Others are using in-store pamphlets that emphasize services and preparations for improving mens health. Mark Pimley, RPh, (The Compounding Pharmacist, Wayne, Pennsylvania) often suggests to a female patient who is receiving hormone replacement therapy that he can offer treatment for her husband as well. Those husbands then often consult a pharmacist in Marks practice about their own health care. Other pharmacists have taken a more active approach by presenting talks on andropause to the public. David Nicoletti, RPh, (Prescription Lab Compounding Pharmacy, Tucson, Arizona) has experienced outstanding success by collaborating with a local physician to conduct (at the pharmacy) evening meetings at which topics on health care for men are discussed. Attendance at those meetings has ranged from 10 to 15 men. In many cases, both the physician and David have later provided patient care for the attendees. If you are interested in conducting similar meetings, you may find it helpful to develop a PowerPoint presentation of salient points.
How To Diagnose Andropause

One way of diagnosing andropause is to measure the patients testosterone and estradiol levels (if baseline values have been established) and to correlate those levels with the patients symptoms and state of health. Hormone levels can be determined in various ways. Some pharmacists have chosen to involve themselves with laboratories that offer testing services. Those pharmacists can now purchase for their patients saliva test kits that offer the convenience of at-home use and direct access to results. Test results that indicate a low or borderline testosterone level and/or a borderline or high estradiol level in addition to the presence of symptoms noted on the screening form featured in this article should result in a referral to a treating physician. In addition, it may be useful for preandropausal men to have their levels of testosterone and estradiol checked to establish a baseline against which future results could be compared. Thus, patients can become better attuned to their hormonal changes and will be more adequately prepared to manage them. Pharmacists who establish themselves as knowledgeable and competent and who have established professional relationships with physicians are likely to become involved in therapeutic decision making. They must become familiar with all treatment options for andropause, the various dosage forms available, and the topical vehicles in which testosterone and other agents can be effectively delivered. Treating andropause and improving mens health offer tremendous opportunities for the enterprising and innovative pharmacist to carve out a healthcare niche and to serve as a valuable resource for the community. Interest in those topics is increasing rapidly, and research is pouring forth. This is a great time to become a leader in that field!
Suggested Reading
Bain J. Andropause: Testosterone replacement therapy for men. Can Fam Physician 2001;47:91-97. Biundo B, Shippen E. Testosterone deficiency in men: New treatments for andropause. IJPC 2000;4:429-431. Carruthers M. Maximizing Manhood: Beating the Male Menopause . London:Harper Collins Publishers; 1996. Morley JE. Andropause, testosterone therapy, and quality of life in aging men. Cleve Clin J Med 2000;67:880-882. Shippen E, Fryer W. The Testosterone Syndrome . NY:M Evans and Company; 1998. Tan RS. The Andropause Mystery: Unraveling Truths About the Male Menopause . 1st ed. Houston, TX:Amred Publishing; 2001. Nieshlag E, Behre HM, eds. Testosterone: Action, Deficiency, Substitution . 2nd ed. NY:Springer Verlag; 1999.
References
1. 2. Bhasin S. Therapeutic perspective: Issues in testosterone replacement in older men. J Clin Endocrinol Metab 1998;83:3435-3447. Tenover JL. Male hormone replacement therapy including andropause. Endocrinol Metab Clin North Am 1998;4;969-987.
Address correspondence to: Bruce Biundo, BS, RPh, PCCA, 9901 S. Wilcrest, Houston, TX 77099; E-mail: bbiundo@pccarx.com
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MALE HORMONE SCREENING FORM

Name Address Rate the following as they apply to you. Use numbers from 1 to 4; 1 represents rare or mild, and 4 represents frequent or severe. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Fatigue, tiredness, or loss of energy Decrease in physical stamina Feelings of depression; a sense that work, marriage, and/or recreational activities have lost significance Decreased libido Loss of erection (impotence) Loss of early morning erection Dry skin on face or hands Increase in waist size or midsection, weight gain Increased fat distribution in the chest area or on the hips Feeling burned out, loss of motivation Increase in aches or joint and muscle pain Frequent use of alcohol (now or in the past) Increase in irritability, anger, or bad temper Decrease in muscle mass The age you feel (years) Date of birth
Date Height Telephone Weight
Rare/ Mild 1 1 1 1 1 1 1 1 1 1 1 1 1 1
2 2 2 2 2 2 2 2 2 2 2 2 2 2
3 3 3 3 3 3 3 3 3 3 3 3 3 3
Frequent/ Severe 4 4 4 4 4 4 4 4 4 4 4 4 4 4
Your age (years)
Which nonprescription drugs are you taking (include vitamins, herbal products, and other supplements)?
For which medical conditions are you being treated?
For which medical conditions have you been treated during the past 5 years?
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Focus on LEGAL and REGULATORY ISSUES for COMPOUNDING
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Jeffrey N. Gibbs, BA, JD Jeffrey N. Wasserstein, BA, JD Hyman, Phelps & McNamara, PC Washington, DC
Compounding and the
COURTS
Inception of Compounding to the 1980s: A Legislative Overview

When Congress passed the Federal Food, Drug, and Cosmetic Act (FDCA) in 1938, pharmacists played a pivotal role in providing healthcare solutions and supplied a significant proportion of prescription medications. There is no evidence that Congress, in passing the FDCA, intended to limit compounding in any way. Indeed, the contemporaneous evidence is to the contrary. As time went by, the amount of compounding diminished because of economic and financial factors, not legislative issues. The use of manufactured drugs became more prevalent, but not because the Food and Drug Administration (FDA) attempted to limit the right of pharmacists to compound. New drugs could be produced more efficiently and were more easily disseminated nationally with greater standardization by drug manufacturers than by pharmacists. Even when pharmaceutical compounding became less common, it was still authorized in every state, pharmacy schools continued to teach compounding, and many states required that pharmacists pass examinations in compounding as part of the educational curriculum or to obtain licensure. Most, if not all, states required that pharmacists maintain compounding equipment. No cases were brought by the FDA against pharmacists for allegedly manufacturing drugs until the late 1970s, when two different pharmacies in Florida were the subject of successful enforcement actions for acting as manufacturers. Then, several years later, the FDA instituted enforcement action against a central facility in which large quantities of antibiotics were compounded. The FDA classified that endeavor as manufacturing, and the court agreed.
Pharmaceutical compounding has been an integral part of the practice of pharmacy since the first curative ingredients were blended for the good of the patient. Compounding is an art, a practice, a skill, and a science. It is the ancillary arm of medical treatment. A skilled compounding pharmacist provides invaluable service to the patient and to his or her physician. The advent of mass-produced drugs in the mid1900s shifted the focus of mainstream pharmacy away from compounding, which, though never abandoned, became a more select specialty. Because patients and prescribers are recognizing that the one size fits all approach to dose and dosage is not always the most suitable alternative, compounding pharmacy is again beginning to flourish. Today, a delicate balance exists between the well-placed legislative oversight of prepared medications and the right and duty of skilled compounding pharmacists to customize preparations that better treat individual patients. In this article, attorneys Jeffrey N. Gibbs, JD, and Jeffrey N. Wasserstein, JD, present an overview of the legislative history of compounding pharmacy from its inception to current compounding-related issues in the United States courts.
The Current Story of Compounding

The current story of federal compounding regulations really begins in the late 1980s. Before that time, the volume of compounding was relatively small, even though states permitted compounding and the FDA did not take enforcement action against compounders. In the late 1980s, the volume of compounding increased, most notably in (but not limited to) inhalation therapy. Compounding pharmacists would receive a prescription, compound a product, and dispense that product to identified patients. Thus, the triad was intact. Nevertheless, complaints were registered with the FDA against some of those pharmacists; a few pharmaceutical manufacturers argued that such compounding was akin to that of a drug company and that in those cases, the compounding pharmacists should be held to the same standards under the FDCA as drug companies. For example, if a drug manufacturer had to obtain a new drug application (NDA) approval, then the compounding pharmacists should also be required to do so. In the early 1990s, the FDA sent warning letters to certain pharmacists advising them that they need-
ed NDAs and/or needed to comply with good manufacturing practices (GMPs). Then, in March 1992, the FDA unveiled its new compliance policy guide (CPG), which was designed to provide criteria for distinguishing compounding pharmacy from manufacturing. The legality of the CPG was subsequently challenged by the organization P2C2 (later named the International Academy of Compounding Pharmacists [IACP]), which led suit against the FDA. The basic argument made by P2C2 was that the FDA had developed rules regarding compounding that had not been promulgated through the Administrative Procedure Act (APA). The APA requires that the FDA (and other federal agencies) allow comment on rules before they are adopted so that the agency issuing those rules can benefit from insights offered by regulated industry and other interested parties. After the CPG was issued, a few warning letters were sent by the FDA to compounding pharmacists saying that they had violated the criteria in the CPG. Those letters were unusual, for a CPG cannot be violated; it is simply a description of what policy is. Shortly after that lawsuit was filed, the FDA stopped referring to violations of the
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CPG in warning letters. The district court and the court of appeals ultimately agreed with the FDA that there had been no violation of the APA. In defending the CPG, the FDA asserted that the CPG was not legally binding and did not create rules per se. The courts accepted that argument. At about the same time, the FDA staff began to realize that although they had been focusing on the manufacturing-versuscompounding issue, it was difficult to prove that compounding pharmacists were actually drug manufacturers subject to NDAs and GMPs. The CPG notwithstanding, it was still difficult to draw the line. At this point, the FDA advanced the position that all compounded drugs were unlawful. However, the FDA said it would exercise its enforcement discretion and would not take legal action against compounders unless the compounding pharmacist was deemed to be a manufacturer. This view of compounded drugs by the FDA placed pharmacists who compounded at greater risk of malpractice suits or liability suits, because they were then allegedly engaging in illegal conduct under federal law. It also cast a shadow over the legality of a central part of the practice of pharmacy. In 1995, stand-alone legislation was introduced in Congress to limit the FDAs authority over compounded drugs. That legislation was eventually folded into the Food and Drug Administration Modernization Act (FDAMA), which was passed in 1997.
The Effect of FDAMA Section 503A

The FDAMA added section 503A to the FDCA. Section 503A regulates the practice of pharmacy compounding by, among other things, limiting who may compound (licensed pharmacists and physicians), what may be compounded and with what type of ingredients, and which percentage of a compounded drug product may be shipped to a state other than that in which it was prepared. (After enactment of the FDAMA, the FDA repealed the CPG.) Section 503A also restricted the advertising of compounding by pharmacists to the simple statement that the pharmacist was able to compound drugs. Pharmacists were not permitted to advertise specific products or the classes of products that they could compound. That restriction triggered litigation that ultimately led to the case now before the United States Supreme Court. Shortly before section 503A was to take effect, several large compounding pharmacies that included Western States Medical Center (the lead plaintiff) sued the FDA in federal district court to prevent the FDA from enforcing section 503A. The plaintiffs alleged that the advertising restrictions violated the First Amendment protections of speech (which the Supreme Court has held includes advertising) and that the limitations on shipping compounded drug products to another state were unconstitutional. After the FDA agreed not to enforce the limitations on shipping compounded drug products to another state, the pharmacies dropped the issue. The plaintiffs moved for a temporary restraining order to prevent any enforcement by the FDA of the restricting of advertising, which the district court granted. The FDA did not argue before the district court that the practice of compounding was illegal. However, the FDA still argued that Congress was justified in restricting advertisements by compounding pharmacists for several reasons. First,
the FDA argued that advertisements were inherently misleading because they implied that the FDA had approved the compounded drug products as safe and effective. The FDA then argued that even if the advertisements were not inherently misleading, they were potentially misleading. According to the FDA, Congress was therefore justified in restricting advertisements for three reasons: to protect the public health and safety from untested and unproven drugs, to maintain the integrity of the drug-approval process by preventing compounding pharmacies from devising a new drug product and then stimulating demand through advertising, and to balance the continued availability of compounded drug products as a component of individualized drug therapy, while limiting the scope of compounding so as to prevent manufacturing under the guise of compounding. 1 The district court rejected those arguments and ruled for the pharmacies. The court first held that the advertisements were not inherently misleading. The district court also held that although the advertisements were potentially misleading, the speech restrictions did not directly advance the governmental interests. The district court struck down the advertising restrictions in section 503A but left the rest of section 503A in effect. The FDA appealed to the United States court of appeals for the Ninth Circuit and reiterated the arguments raised before. The FDA also argued that if the advertising restrictions were found to be unconstitutional, all of section 503A had to be struck down because that section was part of a compromise in Congress to explicitly authorize compounding, but only upon certain conditions. The FDA stated that the structure, purpose and legislative history of section [503A] made clear that Congress intended the various provisions of section [503A] to operate together or not at all. 2 The court of appeals went even further than the district court in rejecting that FDA argument and found that the FDA had presented no evidence supporting the claim that compounded drugs posed a public health risk. The court of appeals stated that: There is insufficient evidence in the record to conclude that the government has a substantial interest in preventing widespread compounding. The government asserts that increased distribution of compounded drugs is dangerous because of the health risks associated with large numbers of patients taking such drugs. The government neither explains nor supports this contention. In fact, most of the evidence runs to the contrary. 3 The court of appeals held, however, that advertising restrictions are inextricably intertwined with the rest of section 503A, and all of section 503A was therefore struck down. The FDA subsequently maintained that section 503A was invalid in the Ninth Circuit (California and some other western states) but that it was valid elsewhere. In the summer of 2001, the FDA sent several warning letters to pharmacies that were alleged to have violated section 503A. On August 24, 2001, the FDA filed a petition with the United States Supreme Court asking it to review that case. For the first time, the FDA argued that section 503A was justified because pharmacy compounding was rendered illegal in 1938 by the passage of the FDCA. The FDA had hinted in earlier briefs that compounded drug products were not exempt from the FDCA new drug, adulteration, and misbranding provisions, but the FDA pe-
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tition to the Supreme Court was the first instance in which the FDA explicitly stated that pharmacy compounding had been banned in 1938 with the passage of the FDCA. The FDA argued that after the passage of that law, all compounded drugs were considered unapproved new drugs unless an NDA had been approved. The FDA added that pharmacies had been able to compound because the FDA had chosen to exercise enforcement discretion and not because compounding was legal. Under the FDA theory, a pharmacist violated the law every time he or she compounded, and that compounding took place solely at the sufferance of the FDA. The FDA also refined its arguments and argued that section 503A was a necessary balance between making compounded drugs available to patients and preventing compounding pharmacies from avoiding the NDA requirements. The FDA argued that compounding pharmacies could develop a drug product, market it, and stimulate a demand for the product by advertising, thereby impair[ing] the integrity of the drug approval process. 4 The Supreme Court granted the FDAs petition to hear the case. After the FDA had filed its brief on the merits of the case, the plaintiff pharmacies countered by arguing that the FDA had not shown that there was a government interest substantial enough to justify the advertising restrictions, that those restrictions did not directly advance the interests asserted by the FDA, that compounded drug products are not new drugs, and that the FDCA did not ban compounding.
mid-1960s. This was a novel argument never previously advanced. Neither of the parties challenged the Ninth Circuits decision on severability. Thus, both the FDA and the pharmacists involved agreed that if the advertising restriction is invalid, the entire law is also invalid. Oral argument was held on February 26, 2002. Several of the justices challenged the government attorney about the advertising ban and wondered aloud about the policy justifications for the ban. The justices, though, did not challenge the FDA assertion that compounded drugs are not exempt from the NDA process. They did seem troubled as to whether an advertising ban designed to reduce the volume and scope of compounding was justified. One of the justices seemed somewhat hostile to consumer-directed advertising and indicated that the advertising ban could be more easily defended if it had been limited to direct-to-consumer advertising. The attorney for the pharmacies spent a great deal of time trying to articulate a bright-line rule distinguishing compounding from manufacturing. It is difficult to predict the outcome of cases based on oral argument. The Supreme Court is likely to decide the case by June 2002. Whatever the decision, it will affect the regulatory status of compounding. Note: After oral argument, the Supreme Court asked the government to provide a copy of the National Association of
Legislation to Date: Additional Briefs and Arguments

Amicus curiae (friend of the court) briefs were filed by the IACP, the American Pharmaceutical Association, the National Community Pharmacy Association, a physician, and a dietary supplement manufacturer. No amicus briefs were filed in support of the FDA position. The one group (the Pharmaceutical Manufacturers Association) that had supported the FDA before the Ninth Circuit Court did not file a brief with the Supreme Court. The amicus briefs focused primarily on the value of compounding and the history of the regulation of compounding and attempted to demonstrate that compounding was legal even after the 1938 passage of the FDCA. For example, the IACP brief stated that: Far from being illegal for 59 years, pharmaceutical compounding has long been an essential part of the practice of pharmacyas ample historical evidence makes clear. Because compounding has always been legal, the government can have no interest, much less a substantial one, in saying that it can be made legal only if coupled with a restriction on advertising. 5 The FDA filed a reply brief on February 19, 2002; it seemed to retreat from the position that all compounding had been banned in 1938. Instead, the FDA argued that compounding had become illegal in the 1960s. At that time, the FDA stopped rendering opinions that unapproved products based on drugs grandfathered under the FDCA were not new drugs, revoked all previously issued opinions, and made clear that any change in formulation, manufacture, control, or labeling could render a drug product a new drug.6 Therefore, according to the FDA, most compounded drugs were not new drugs subject to premarket approval until the
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Boards of Pharmacy model guidelines. That document, according to the government, supports the view that a ban on the advertising of compounded drugs is permissible. The reason why the Supreme Court asked for that document is unclear, except that the government lawyer mentioned the document during oral argument.
Addendum: United States Supreme Court Decision of April 29, 2002

On April 29, 2002, the United States Supreme Court issued its opinion on the case. The Supreme Court affirmed the decision of the Ninth Circuit Court striking down section 503A. The Court like the district court and the Ninth Circuit Courtheld that section 503A violated the First Amendment by prohibiting compounding pharmacies from advertising their ability to compound specific products. Because the Court did not address the severability issue, section 503A is now void in its entirety. The Supreme Court disagreed with the governments argument that the advertising restrictions in section 503A were necessary to balance the competing interests of protecting the new drug approval process by ensuring the availability of compounded drugs. In an opinion written by Justice Sandra Day OConnor for five members of the Court, the Court held that 503As provisions regarding advertisement and promotion amount to unconstitutional restrictions on commercial speech 7 Justice OConnor was joined by justices Antonin Scalia, Anthony M. Kennedy, David
Hackett Souter, and Clarence Thomas. Justice Stephen Breyer, joined by Chief Justice William H. Rehnquist, Justice John Paul Stevens, and Justice Ruth Bader Ginsburg, dissented. The dissent focused on advertisements aimed at patients, not physicians. Although the Court recognized that [p]reserving the effectiveness and integrity of the FDCAs new drug approval process is clearly an important government interest,8 the Court did not specifically adopt the governments argument that in the absence of section 503A, all compounding was illegal. Indeed, the Court recognized the long-standing history of compounding and its value in serving special medical needs and gave as examples alternate routes of administration and improving the taste of pediatric medications. The Court also noted that compounding is part of the standard curriculum at most pharmacy schools and that some states specifically require all pharmacies to offer compounding services.9 The Court also rejected the view that advertising could be banned because physicians might prescribe unnecessary medications. We have previously rejected the notion that the Government has an interest in preventing the dissemination of truthful commercial information in order to prevent members of the public from making bad decisions with the information. 10 The Court found that using advertising as a proxy for determining whether compounding had crossed the line into manufacturing was inappropriate. However, the Court agreed that distinguishing compounding from large-scale manufacturing was reasonable. The Court suggested that many of the factors that were part of the FDAs 1992 Compliance Policy Guide could be used.11 The decision is very unlikely to end the FDAs efforts to play a regulatory role in the field of compounding. Throughout the litigation, the FDA expressed its concern that large-scale compounding could erode the NDA process and presented greater safety risks. All members of the Court agreed that it would be appropriate for the FDA to require large-scale drug compounding to go through the new drug approval process. At the same time, the Court clearly articulated that the Government also has an important interestin permitting the continuation of the practice of compounding so that patients with particular needs may obtain medications suited to those needs. 8
References
1. Western States Medical Center v. Shalala, 69 F Supp 2d 1288, 1302 (D Nev 1999). Governments Appellate Brief at 54. Western States Medical Center v. Shalala, 238 F3d 1090, 1094 (9th Cir 2001). Petition for Certiorari at 13. Available at: http://www.usdoj.gov/ osg/briefs/ 2001/2pet/7pet/20010344.pet.aa.html. Brief of the International Acad-
2. 3.
4.
5.
emy of Compounding Pharmacists, amicus curiae, 1-2 (Jan. 2002). 6. Government Reply Brief at 12. Available at: http://www.usdoj.gov/ osg/briefs/2001/3mer/2mer/20010344.mer.rep.html. 7. Thompson v. Western States Medical Center, No. 01-344 (Apr. 29, 2002), slip op. at 2. 8. Slip op. at 11. 9. Slip op. at 2-3. 10. Slip op. at 16. 11. Slip op. at 14.
Address correspondence to: Jeffrey N. Gibbs, JD, Hyman, Phelps & M c N a m a r a , P C , 7 0 0 1 3 t h S t r e e t , N W, Wa s h i n g t o n , D C 20005. E-mail: jng@hpm.com
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The manufacturing and compounding of hazardous drugs (new and more potent drug compounds and hormones that have been manufactured and compounded for years) are of increasing concern across the entire spectrum of health care. Hormones, which were commercialized in 1942 with the introduction of conjugated estrogens (Premarin) by Ayerst Laboratories and again in the 1960s with the introduction of oral contraceptive tablets, are drugs that are highly active in humans. First Syntex and then several other pharmaceutical companies brought a variety of such products to market. Pharmaceutical companies that manufactured estrogen-based products experienced exposure problems that resulted in negative health effects for their employees. The effects varied from mild to irreversible lifelong changes in overexposed individuals. If a pharmacy in which formulations containing hormones are compounded lacks necessary containment equipment, the compounding staff can be exposed to unsafe levels of hazardous drugs. Estradiol, USP, (estradiol) a naturally occurring estrogen used in most hormone replacement formulations, has been declared a carcinogen. The exposure limit of estradiol is less than 200 ng as an 8-hour timeweighted average (Table 1). An exposure limit is the level of active drug substance in air considered to be safe for most employees who work with that substance 8 hours per day and 40 hours per week. Pharmaceutical companies who manufacture the compounds have developed exposure limits for the drugs; those limits are based on the quantity of the compound required to cause an effect plus a safety factor. The safety factor is determined by: 1) the effect of the drug, 2) whether the effect is life-threatening, 3) whether the effect can be reversed, 4) the long-term health implications of exposure, and 5) whether the effect of that exposure will affect future generations. As a rule of thumb, the exposure limit is at least 10 times less than the therapeutic dose given the patient. For products that are life-threatening or that cause changes in the structure of deoxyribonucleic acid, the exposure limit can be as much as 1000 times less than the therapeutic dose. If visible powder is observed on surfaces outside the compounding containment device, it is likely that the airborne concentration of the active drug substance will exceed the exposure limit. Exposure limits for such compounds are in the low nanogram range, and any open operation involving quantities as small as milligrams can lead to potential overexposure. The risk of ex-
Facilities and Procedures for COMPOUNDING HAZARDOUS DRUGS

Hank Rahe, BSIM, MSE, RPh Containment Technologies Inc, Indianapolis, Indiana ceeding the exposure limit is greatest when the concentrated drug substance is being manipulated or when manipulations cause the powder to become airborne. Operations such as weighing, mixing, the handling of dry granulations, tableting, and capsule filling can cause the powder to become airborne, and performing those tasks without proper containment can create an exposure problem. Exposure to a toxic drug occurs when the drug enters the body via inhalation, absorption through the skin, or ingestion. The inhalation of airborne drug particles leads to the greatest risk of adverse effects from exposure. The second-highest risk of effects from exposure results from absorption of the drug through the skin and other soft membranes. Significant quantities of ineffectively contained drugs used in formulations are often found on telephones, doors, switch plates, paperwork, and restroom fixtures. Individuals who have touched those surfaces carry that powder on hands, feet, and clothing to areas adjacent to the site of compounding. Ingestion of drug particles occurs when contaminated foods or liquids are consumed. Drug particles can also be spread by air currents, which can carry the drug into surrounding areas of the pharmacy or adjacent office areas if the air handling system has not been designed properly. It has been estimated that particles up to 5 m in size can remain suspended in air for as long as 5 days. Many buildings have airhandling systems that recirculate some portion of the air among all building occupants; this can become a problem for pharmacies housed in multiuse buildings. Providing a safe workplace in which to compound formulations used in hormone replacement therapy was a major concern for one high-volume compounding pharmacy. The owners of the pharmacy discovered that the then-current handling practices and containment devices used provided inadequate protection from exposure to hazardous drugs. An expert in drug containment protection was hired on a project basis to review the facilities and handling practices. The consultant suggested that the improvement of engineering controls, the revision of standard handling procedures, and the creation of a procedure-based employee training program would increase the safety of the workplace. This information came at an ideal time, because the pharmacy owners were planning to move the pharmacy to a new facility. The consultants recommendations (Table 2) were used to develop a containment strategy for the new pharmacy.
Table 1. Typical Occupational Exposure Limits (8-Hour Time-Weighted Average Expressed in Micrograms Per Cubic Meter).
Compound Estrogens Exposure Limit 0.100 0.050 0.035 0.200 0.100 0.050
Estradiol, USP (estradiol) Mestranol Ethinyl estradiol Progesterone Norethindrone Levonorgestrel
Progestins
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Table 2. Key Elements for the Safe Compounding of Hazardous Drugs.

Review and Evaluate the Hazard
Evaluate the occupational health effects produced by exposure to the drug. Contact the drug manufacturer to obtain information about safe handling. Review the physical state of the material being handled. Review the handling steps for preventing exposure via inhalation and/or contact.
Develop Engineering Controls for Containment
in containment technology. Select engineering controls that will meet the exposure-limit requirement.
Develop Standard Handling Practices
Develop written procedures for the handling and disposal of hazardous drugs. Develop specific procedures for each operation (weighing, mixing, granulation, capsule filling, tableting, packaging).
Develop Training Programs for the Safe Handling of Hazardous Drugs
before they handle hazardous drugs. Require that all employees be retrained annually and that they show proficiency in the safe handling of hazardous drugs. Establish a record of employee training. Train the trainer to ensure that he or she has an excellent command of the training program.
Evaluate and Measure the Effectiveness of the Program
Consider the required control level (based on the exposure limit). Select a company with a proven record
Establish a formal written training program. Require that all new employees be trained
Establish an air-sampling program to verify that the program is effective. Establish employee medical monitoring programs.
Upgrading the Containment System for Compounded Drugs

After the consultants recommendations had been reviewed and accepted, an inspection of the pharmacy previously mentioned was conducted. Visible powder was noted on surfaces in the compounding area, which indicated that employees were at high risk of exposure to a hormone (estrogen) used in compounding. In that pharmacy, the usual steps for compounding capsules or tablets (weighing, mixing, granulations, drying, tableting, capsule filling) were performed; those functions often cause the release of airborne drug particles. Changes in the engineering controls and the standard handling practices were deemed necessary.
Upgrading Engineering Control Technology

Engineering control technologies for containment of powders, liquids, and gases are categorized as follows: by control of the airflow in the area adjacent to that in which the hazardous drug is being handled; directionalized airflow, which channels the airborne hazardous drug away from the breathing zone of the individual working with the compound; and a closed system, in which the compounder is protected from the hazardous material by a physical barrier. Each of those technologies has a limited ability to contain hazardous materials, which is reflected in the airborne concentration of materials that escape from the area of containment. In Table 3 (a hierarchy of control technologies), the results of airflow control provided by different types of containment devices for hazardous drugs are listed. Managing the risk of exposure to hazardous drugs requires an understanding of the function of engineering control technologies. After lengthy discussions with several specialists in the engineering control of hazardous materials, the owners of the pharmacy decided that the primary compounding of hazardous drugs should be performed in barrier isolators with limited use of ventilated enclosures and glove bags. The containment devices were selected according to the following criteria: the capacity for containing hazardous drug particles to the level required during compounding, dependability, and cost-effectiveness.
A barrier isolator was selected. That equipment was not the least expensive, but the manufacturer offered a proven record of the integration of compounding operations, technical support in the area of handling practices, and support in development of training programs. The design of the systems included the integration of several barrier isolators, which enabled the transfer of drug powders between operations without exposure. The modular design of the barrier isolator systems will accommodate future changes in compounding technology and an increased demand for different product formulations. A team approach was used to gain an understanding of individual compounding operations and to integrate ergonomically friendly containment devices into the compounding routine. That approach involved a review of each step in formulating a preparation. Next, the ergonomics of compounding procedures was evaluated; the time required to compound was important because of the high volume of compounded prescriptions. The barrier isolators selected were functional and easy to clean between compounding activities. The improved layout of the compounding area and the design of the barrier isolators enabled an efficient workflow. The engineering controls also included ventilated enclosures, which were used for compounding materials that did not have low exposure limits or for the manipulation of limited-use hormones. The glove bag application, which involved the transfer of powder from a bulk drug drum to individual containers, was also incorporated into the containment design of the pharmacy. The barrier isolator company provided the glove bags and technical support for the setup and use of the devices. Standard handling practices for operations and cleaning procedures are essential to the safe handling of hazardous drugs. Those practices should be developed for the handling of active drugs from the time they are received from the supplier until the delivery of the prescription to the patient and should address the use of barrier isolators, the handling of materials outside the barrier isolators, and cleaning procedures. Cleaning performed without proper training and tools is a high-risk procedure that can result in exposure to hazardous drugs. A procedure manual
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outlining the proper method of performing standard compounding operations and cleaning was written. Handling practices and cleaning procedures were included in the training program for staff who would be compounding with hazardous drugs. The procedure manual for standard handling practices and procedures was found to be an ideal training guide.
Table 3. Hierarchy of Control Technologies.

Technology Barrier isolators Directionalized airow Area airow or room ventilation Control Capability > .01 g per cubic meter of air < 15 g per cubic meter of air < 100 g per cubic meter of air
The Importance of Training

A training program increases employees understanding of the drugs being compounded, safe handling practice guidelines, and the need to follow procedures to ensure a safe workplace. The training program also sets a standard for work practices by establishing the proper methods of performing individual compounding operations. Such a program should include examples of the ways in which materials can be disseminated by air and by contact with contaminated surfaces when proper containment procedures and work practices are not followed.
The Hazards of Casual Exposures to Hazardous Drugs

Casual exposures occur from contact with a drug outside the normal compounding area. Sources of casual exposures include the tracking of hazardous drugs from the workplace by employees who do not comply with safe handling practices, the failure to follow standard work practices, and the use of improperly
designed air-handling systems. Tracking is a major cause of casual exposure. Examples of ways in which materials can be tracked to adjacent areas or objects (restrooms, drinking fountains, telephones, doors) can be used to increase employees understanding of the need to comply with safe handling practices. Training programs with written evaluations should be included in new employee orientations and in the continuing education of all employees. All employees should review training materials and should take a written proficiency test annually. An employee should be designated to conduct the training program. A program to train the trainer should be implemented, and the trainer should routinely review current programs and ensure that the curriculum is current with respect to safe handling practices.
The Benets of an Air-Sampling Program

An industrial hygiene air-sampling program that includes
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monitoring the facility and employees should be incorporated into the evaluation of engineering controls, work practices, and the training program. That program, which should be conducted with a predetermined frequency, will demonstrate that the barrier isolators are providing sufficient protection from exposure to hormones being compounded. Air sampling, when combined with safe work practices and a training program, provides a safe workplace. It also serves as a safeguard by alerting employees and management to failures in the system.
Conclusion
The following factors are important to consider before hazardous drugs are used in compounding: The compounding of hazardous drugs, such as hormones, is a complicated activity that can result in the exposure of employees to potentially harmful substances. Proper containment of those substances must be ensured, appropriate work practices must be followed, and ongoing training in the handling of hazardous drugs must be implemented. The use of ventilated enclosures is not adequate containment for the routine compounding of hormone replacement compounds. Exposure levels are a function of the drug being compounded, and even small quantities of potent drugs such as estrogens can result in overexposure of the compounding staff. Visible dust noted during the compounding of estrogen-con-
taining products is a reliable indication that active drug is present on the work surfaces. The three elements of a successful containment program are engineering controls with proper characteristics, written procedures that outline safe handling practices, and a formal training program. The selection of a full-service containment company that can work with you to evaluate the needs of your pharmacy is critical. Selecting and integrating the proper size of ergonomically designed compounding equipment enables employees to use that equipment at peak efficiency. Work practices must be formalized and incorporated into the new-employee orientation and into continuing education. Proper training is important in reinforcing the correct use of containment equipment and in ensuring compliance with safe handling practices. That formal training should include feedback (a written evaluation of each employees performance) from the instructor. Monitoring is essential to the assessment of a safe workplace. Continued monitoring of facilities and employee performance provides documentation to employees and government agencies that compliance with OSHA regulations is in effect. Address correspondence to: Hank Rahe, Containment Technolog i e s I n c , 1 0 3 2 9 Va n d e r g r i f f R o a d , I n d i a n a p o l i s , I N 4 6 2 3 9 . E-mail: hrahe@mic4.com
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Introduction
The US Food and Drug Administration (FDA) is the federal agency to which oversight responsibility for manufactured drugs, devices, and biologics in the United States has been assigned. 1 FDA oversight for drugs is quite similar to that for biologics, but the regulation of devices differs significantly. Within the FDA, the Center for Drug Evaluation and Research (CDER) regulates the manufacture, labeling, and advertising of drug products, and the Center for Biologics Evaluation and Research (CBER) performs a similar function for biologics. The procedure for gaining access to investigational drugs and biologics is addressed in this article.
Gaining Access to Investigational Drugs for Treatment :
AN INVESTIGATIONAL NEW DRUG APPLICATION PRIMER

Mark A. Kramer, MS, RPh M. D. Anderson Cancer Center, Houston, Texas Bambi J. Grilley, RPh, CCRC, CCRA, CIP Texas Childrens Cancer Center and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas such cases, the patients physician can act as the study sponsor. The physician must obtain the drug from the drugs manufacturer or must arrange for the preparation of the drug if no commercial manufacturer produces the investigational agent. The treatment IND must also be reviewed and approved by an IRB committee and by the FDA. A treatment IND may be viewed as authorization to give a single patient investigational therapy or treatment for a condition that is considered refractory to all appropriate conventional therapies and for which no approved experimental research protocol exists. This authorization is provided from compassion for the patients needs and not as a mechanism for conducting clinical research. The treatment IND does not apply to the use of an approved drug product that is used in the practice of medicine for an unlabeled indication. 5 The following information describes the procedure for obtaining approval for a treatment IND. 1. To obtain the drug product, gain permission from the manufacturer. If no manufacturer exists, the physician may arrange for preparation of the drug product. This article includes the FDA checklist for obtaining a treatment IND, which furnishes additional information regarding required documentation for the use of certain drugs. 2. Obtain approval from the IRB for the treatment plan and for the informed consent document. The simplest way to obtain IRB approval is to collaborate with an institution (usually a hospital or a medical school) and obtain approval from its IRB. Commercial IRB committees (Western IRB, 6 Patient Advocacy Council IRB, 7 Independent Review Consulting 8 ) can also grant approval for the treatment plan and the informed consent document. The cost of an IRB review (approximately $1000 per review) varies. It is possible to establish an IRB that is not affiliated with an institution. The FDA-required role and functions of the IRB and the required components of the informed consent are specified in Title 21 9,10 of the Code of Federal Regulations (CFR). The role and functions of the IRB and the required components of informed consent according to the Department of Health and Human Services (DHHS) are specified in Title 45 1 1 of the CFR. The regulations, which vary slightly, must be thoroughly understood by an existing IRB before a new IRB is established. 12
The Investigational New Drug Application

Before research on a new agent can be conducted, the sponsor of a drug must file an investigational new drug application (IND) with the FDA. 2 When applying for an IND, the sponsor (a physician or a hospital or other institution, but usually the drug manufacturer) must correspond with the CDER staff who oversee investigational drugs or with CBER personnel who oversee investigational biologics. The IND should contain detailed information about the formulation, pharmacologic and toxicologic effects, pharmacokinetics, safety, effectiveness, dose to be studied, route of administration, potential risks and/or side effects of the agent, and safety and efficacy data from previous human studies of the drug if such studies have been conducted. (Not all of this information may be available at this point.) Before the sponsor can test this new agent on human subjects, a clinical protocol that lists the purpose and objectives of the research study, inclusion and exclusion criteria for patient selection, the number of patients involved in the study, the study design, the recommended dose, the route of administration, information about the administration of the drug, monitoring parameters, and the proposed duration of use must be submitted to the FDA. The main objectives of the FDA review of an IND and the associated protocol are to ensure the safety of subjects treated. 3 Only patients who meet eligibility criteria may be treated under the IND protocol, and participating in such a protocol is the way in which patients most often gain access to investigational agents. Before the initiation of a clinical trial of an investigational drug, an institutional review board (IRB) committee in the hospital or medical school in which the trial is to be conducted must evaluate the protocol on the basis of ethical and legal considerations and must approve its use. 4 IRB committees are often composed primarily of physicians, but federal requirements mandate the inclusion of individuals (pharmacists, lawyers, clergy, those with a nonscientific background) not affiliated with the hospital or institution in which the trial will be conducted.
The Treatment Investigational New Drug Application

A patient who does not meet the eligibility criteria specified in an IND protocol can, by filing a treatment investigational new drug application (treatment IND), still receive treatment with an investigational agent for emergency or compassionate use. In
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Finally, after approval has been obtained from the manufacturer of the drug and from the reviewing IRB, the physician must prepare and assemble the information listed below and must then send it to the appropriate division at the FDA. Items 6 and 7 (below) require the use of specific forms, but the other information can be provided as text organized into the items noted.
FDA Checklist for Obtaining a Treatment IND

1. The words Request for a single patient IND for special exception (compassionate) use should be positioned at the top of the letter. 2. A brief clinical history of the patient (including the diagnosis, the disease status, prior therapy, the patients response to prior therapy, and the rationale for requesting the proposed treatment) should be prepared. 3. A proposed treatment plan should be described; that plan should include the dose, route of administration, planned duration of treatment, monitoring procedures,
and modifications to treatment (such as dose reduction or treatment delay) used if toxicity occurs. Reference to a published protocol or journal article should be included if appropriate. 4. A drug supply reference statement (a letter of cross-reference) in which the manufacturer of the drug is named and a statement regarding a letter of authorization to cross-reference an appropriate IND of the drug supplier or the drug master file (DMF) of the manufacturer should be included. The treating physician must contact the manufacturer of the drug to obtain such statements. If no manufacturer of the drug product exists, the treating physician must supply the drug product information, including the source of the raw material and excipients, preparation procedures, appropriate quality control tests and results, and packaging and labeling specifications. 5. An informed consent statement should be prepared. That document must state that informed consent will be obtained
from the patient or his or her representative and that approval by an appropriate IRB will be obtained before treatment is initiated. 6. An investigator qualification statement (such as a curriculum vitae) that specifies the training, experience, and licensure of the treating physician is required. Also required is FDA Form 1572, in which the qualifications of and demographic data pertaining to the investigator(s) and associated personnel involved in the clinical trial, the reviewing IRB, and the associated laboratories are provided. The signature of the investigator is required on page 2 of that form, which can be downloaded from the FDA Website.13 7. FDA Form 1571, which is a cover sheet that should be submitted with any documents sent to the FDA, should also be completed; the treating physician should be listed as the sponsor. The signature of the investigator is required on page 2 of that form, which can be downloaded from the FDA Website.14 The IND number assigned by the FDA should be included on Form 1571, as should a serial number assigned by the physician. The initial serial number on the application submitted to the FDA is number 000, and all serial numbers following the initial submission should be assigned sequentially. 8. Include the contact telephone number and facsimile number. If the request is approved, an IND number will be issued by the FDA, and the treating physician will be contacted first by phone or fax and then by letter. The treatment IND is considered active upon issuance of the IND number. The treatment IND sponsor (the treating physician) will then contact the drug manufacturer and will provide the IND number. The manufacturer may then ship the drug directly to the treating physician. As sponsor of the treatment IND, the treating physician is responsible for compliance with the Federal Food, Drug, and Cosmetic Act and with relevant regulations.15,16 Those responsibilities include expeditiously reporting unexpected fatal or life-threatening adverse events associated with the drug to the FDA 17 and also submitting annual progress reports to the FDA within 60 days of the anniversary of the date on which the IND went into effect. The treating physician is responsible for accounting for any investigational drug shipped to the use site. The drug dispo-
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sition records should indicate when the patient received treatment and the dose administered. When the treatment has been completed, the FDA should be notified that the IND or the treatment IND will be withdrawn.18 Any unused supplies of the investigational agent should be accounted for and either destroyed or returned to the manufacturer (at the discretion of the manufacturer). Permission to charge (cost recovery) for the drug must be obtained from the FDA.
hospital or institutional setting. Although it is possible to obtain IRB approval outside an institutional or hospital setting, considerably more resources (financial, administrative, and time) are required.
References
1. FDA mission statement. Available at: http://www. fda. gov/opacom/hpview.html. Accessed: March 29, 2002. 2. Code of Federal Regulations, Title 21 312.20. Available at: http://www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/cfrsearch.cfm. Accessed March 29, 2002. 3. Code of Federal Regulations, Title 21 312.22. Available at: http://www.accessdata.fda.gov/ scripts/ cdrh/ cfdocs/cfcfr/cfrsearch.cfm. Accessed March 29,2002. 4. Code of Federal Regulations, Title 21 56.103. Available at: http://www.accessdata.fda.gov/ scripts/cdrh/ cfdocs/cfcfr/cfrsearch.cfm. Accessed March 29, 2002. 5. Code of Federal Regulations, Title 21 312.2. Available at: http://www.accessdata.fda.gov/ scripts/ cdrh/cfdocs/cfcfr/cfrsearch.cfm. Accessed March 29, 2002. 6. FDA Information Sheets: Guidance for Institutional Review Boards and Clinical Investigators. 1998 Update. Available at: http://www. fda.gov/oc/ ohrt/irbs/default.htm. Accessed March 29, 2002.
Conclusion
The purpose of the FDA review and approval of the IND or the treatment IND use of investigational agents is to protect the safety and rights of individuals treated with those agents. This protection is conducted as a team effort by the treating physician, the IRB, the drug manufacturer, and the FDA. The necessary steps, procedures, and approvals that are required before the treatment IND therapy can occur have been specified. Obtaining the necessary IRB approval is simplest in a
7. FDA Form 1572. Available at: http://www.fda.gov/ cder/ regulatory/applications/Forms.htm. Accessed March 29, 2002. 8. FDA Form 1571. Available at: http://www.fda.gov/ cder/ regulatory/applications/Forms.htm. Accessed March 29, 2002. 9. Code of Federal Regulations, Title 21 312.60. Available at: http://www.accessdata.fda.gov/scripts/ cdrh/ cfdocs/cfcfr/cfrsearch.cfm. Accessed March 29, 2002. 10. Code of Federal Regulations, Title 21 Part 50. Available at: http://www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/cfrsearch.cfm. Accessed March 29, 2002. 11. Code of Federal Regulations, Title 21 312.32. Available at: http://www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/cfrsearch.cfm. Accessed March 29, 2002. 12. Code of Federal Regulations, Title 21 312.38. Available at: http://www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/cfrsearch.cfm. Accessed March 29, 2002.
Address correspondence to: Mark A. Kramer, MS, RPh, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd-Box 90, Houston, TX 77030.
R E G U L A T O R Y
Legal Issues: TECHNICIANS IN THE COMPOUNDING PHARMACY PRACTICE

Jennifer Taylor Fix, MBA, RPh Fort Worth, Texas
Introduction
What are the legal and appropriate roles of the technician in the compounding laboratory? Which quality assurance procedures can be used to validate the competence of the pharmacy technician? In this article, those and other legal issues of interest to the compounding pharmacist will be discussed. If you are too busy working at the prescription counter to compound, consider promoting a technician to work in your compounding laboratory. Technicians are permitted to assist the pharmacist by preparing extemporaneous nonsterile prescription drug orders, and they are trained to use aseptic technique to prepare sterile formulations.
technician are specified by the supervising pharmacist. The technician will be a vital asset to your compounding practice after he or she has demonstrated competence in compounding and can, as verified
by the pharmacist in charge, perform assigned duties. Basic compounding and sterile compounding certificate courses are available from the National Pharmacy Technician Association (NPTA),
Checklist: The Training and Competence of the Pharmacy Technician

The following checklist can be used to document training and the competence of a compounding technician.
Pharmacy technician certification (board certified) Basic compounding knowledge? Knows how to calibrate the scale? Knows how to weigh small quantities? Knows how to triturate powders? Understands geometric dilution? Understands aliquots? Can perform basic calculations? Can document a formula in a database? Follows a formula accurately? Wears appropriate protective gear? Can compound topicals? Can compound gels? Can compound troches? Can compound capsules? Can compound tablet triturates? Can compound suspensions? Can compound suppositories? Chooses correct dispensing container? Technicians name Technicians signature Pharmacists signature Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No No No No No No No No No No No No No No No No No No Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Needs improvement Date Date Date
Legal Duties
It is the legal duty of the pharmacy technician to perform nonjudgmental technical duties associated with the preparation and distribution of prescription drugs, provided that a pharmacist verifies the accuracy of all acts, tasks, and functions performed by the technician and that the technician functions under the direct supervision of and is responsible to a pharmacist. 1 In some states, a compounding technician must be a certified pharmacy technician (CPhT). To become certified, technicians must pass the Pharmacy Technician Certification Examination, the registration for which is available online at www.PTCB. org. An online preparation course for the examination is available from P*ceutics Institute of PCCA (Houston, Texas; course registration, www.pceutics.com).
Training for the Compounding Technician

Tasks to be performed by the compounding
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www.pharmacytechnician.org. Proper training and preparation are necessary to ensure the quality and safety of each formulation prepared by the pharmacy technician. Advanced training is required for the technician who prepares sterile products.
Record Keeping
A unique lot number and a pharmacistassigned beyond-use date must be assigned to each compounded preparation. 2 If an audit is conducted by the respective state board of pharmacy, those data are essential. Keeping a record of each formula also ensures that a uniform and consistent preparation is compounded and dispensed. Accurate record keeping can be facilitated by a pharmacy technician, who can maintain a control log of all ingredients, lot numbers, and amounts used in compounded preparations, as well as
assigned prescription numbers. Each compounding pharmacist should have a readily available policy and procedure manual, a technician training manual, and (if sterile products are compounded) a policy and procedure manual for sterile compounding, all of which may be requested during an inspection by individual state boards of pharmacy. Documentation of the pharmacy technicians competence and his or her ongoing training should also be accessible.
consultation, which must be provided by a pharmacist, is also required when all compounded prescriptions are dispensed. Helping the patient understand the uniqueness of the product that has been specially prepared for him or her and its appropriate use is essential to the success of treatment.
References
1. State Preservation Board. Texas Board of Pharmacy. Available at: http://www.tspb.state.tx. us. Accessed: March 27, 2002. Texas rules and regulations. United States Pharmacopeia XXV/National Formulary 20. Rockville, MD:US Pharmacopeial Convention; 2001:2053-2057.
The Pharmacists Responsibility

Pharmacy technicians who compound are counted in the pharmacist-to-technician ratio. 1 The pharmacist who is responsible for the actions of the technician and the quality of each preparation must evaluate the preparation of the compounded prescription as it is prepared by the pharmacy technician and must review that prescription before it is dispensed. Patient
2.
Address correspondence to: Jennifer Taylor Fix, MBA, RPh, E-mail: FixRx@msn. com
G E N E R A L
I N T E R E S T
Excerpts from and Reviews of Current Published Literature:
Biotechnology and managed care. Salvado AJ, Lawless G. J Manag Care Pharm 2000;6:285-292. The authors, a physician-director in the biotechnology industry and a physician-pharmacist in a medical insurance company, discuss biotechnology and its impact on managed care. The trend toward the rapid availability of biotechnologic products in the marketplace is presented, as are genomics and therapeutic applications of biotechnologic developments. To assist pharmacists who work with managed care clients, a four-phased, long-term business plan that includes strategy formulation, implementation, and analysis as well as environmental planning is provided. The authors views of future trends in biotechnology are also presented. Pharmacists evaluation of key communication skills in practice. Hargie OD, Morrow NC, Woodman C. Patient Educ Couns 2000;39:61-70. The objectives of this research were to define and identify effective communication skills used by community pharmacists during consultations with patients. Forty-five key behaviors noted by the authors were identified as the communication skills and subskills that are essential elements of pharmacy practice. For example, building rapport was deemed the most important skill, and preserving confidentiality was considered a key subskill of that element. The level of skill necessary for effective communication was determined according to the topic of the consultation. For example, consultations concerning pregnancy testing, leg ulceration, or prescription medications required more effective communication skills than did those concerning a request for a cough syrup or eye drops. The frequency with which effective communication skills were used in 30 test consultations was also noted. Strategies to improve compensation for pharmaceutical care services. Bennett MS, Blank D, Bopp J, et al. J Am Pharm Assoc 2000;40:747-755. The five authors, each of whom is affiliated with a different pharmacy or practice site in the United States, state that Despite significant advances in the delivery of pharmaceutical care, pharmacists continue to face difficulty in obtaining compensation for these services. For many, this challenge remains the major roadblock limiting the wider adoption of pharmacy-based patient care services. In this review, they provide a summary of methods for overcoming barriers within the pharmacy profession and improving reimbursement from third-party insurers. They also suggest ways of finding new markets or purchasers (including patients or employers) for pharmaceutical care. According to the authors, cash-based consultations about the use of dietary supplements, emergency contraception, immunization, natural hormone replacement therapy, smoking cessation, or weight management can increase revenue. Two consultations (one on natural hormone replacement therapy and the other on pediatric asthma education) are presented. In their summary, the authors state, In the long run, pharmacists are likely to
Pharmacy Administration
and Other Topics of Interest
Elizabeth Foy College of Pharmacy Mary E. MacCara, PharmD College of Pharmacy and Department of Family Medicine Dalhousie University, Halifax, Nova Scotia, Canada
PHARMACY ADMINISTRATION
An exploratory study of community pharmacy practice change. Doucette WR, Koch YD. J Am Pharm Assoc 2000;40:384-391. Researchers at the College of Pharmacy at the University of Iowa designed a multiple-case study in which the resources and practitioner activities of community pharmacists who had made changes over the previous 2 years were compared with those in pharmacies that remained the same. The authors identified 14 criteria (changes in tangible and intangible resources) that can in turn cause a change in pharmacy practice. They also identified categories of variables that can influence the ease with which pharmacy practice can be changed: environmental and organizational variables, owner-manager characteristics, strategy-making features, and the attributes of the changes themselves. Using these criteria and evaluating six study pharmacies, they identified 20 factors that distinguished pharmacies in which practice had changed from those that did not change. This study can be used to guide future community pharmacy research on practice change and to assist pharmacists who want to incorporate the philosophy of pharmaceutical care into everyday practice. Closing the loop Implementing quality improvement processes and advances in technology to decrease medication errors. Lombardi TP. Medscape Pharmacists [serial online]. 2000. Available at: http://www.medscape.com/viewarticle/408564. Accessed December 20, 2000. The pharmacist-author of this article explores methods used by St. Peters Hospital, a 450-bed acute-care facility in Albany, New York, to reduce the number of medication errors. The hospital addressed its medication-use process, a quality improvement system for interdisciplinary medication use, and the implementation of technologies such as computerized order entry systems, bar-coded medications, and radiofrequency handheld devices. The procedures for two quality improvement programs (the Medication Prescribing Variance Program and the Medication Dispensing Variance Program ) implemented by St. Peters Hospital are described in detail in the appendices. The role of the hospital Medication Safety team is also examined.
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receive greater net profits from pharmaceutical care than from dispensing. 8 ways to prevent malpractice when writing prescriptions. Buppert C. Gold Sheet 2000;2. Available at: http://www.medscape. com/viewarticle/407040. Accessed December 21, 2000. In this article published on the Medscape Nursing Web page, the author (an attorney) offers advice useful to any healthcare professional with prescriptive authority, including pharmacists. She provides eight suggestions for safe prescribing and the details of eight successful lawsuits on which the suggestions are based. The suggestions for safe prescribing are summarized below: Writing clearly or prescribing via a computer terminal to ensure the legibility of the prescription Limiting a patient to a 7-day supply of a potentially lethal drug if he or she has exhibited suicidal ideation Warning patients about drug side effects Advising discontinuation of a drug if adverse effects appear Obtaining informed consent when a prescribed drug that can cause serious side effects is used, even though other drugs are available for treatment Documenting the rationale for off-label drug use and verifying that off-label use meets the standard of care, even if that use
is not recognized on the official package insert Monitoring the patient for gastrointestinal or renal adverse effects when nonsteroidal anti-inflammatory drugs are prescribed as long-term therapy and addressing those adverse effects if they occur Obtaining thorough medical histories from patients, listening to the medication-related problems of patients, and being willing to change therapies The author also lists four elements that must be proven to obtain a successful damage award in a malpractice suit: duty, breach of standard of care, injury, and proximal cause.
OF INTEREST TO DISPENSING PHARMACISTS

How much antibiotic suspension is enough? Dusdieker LB, Murph JR, Milavetz G. Pediatrics 2000;106:E10. Available at: http://www.pediatrics.org/cgi/content/full/106/1/e10. Accessed November 16, 2000. Researchers from the University of Iowa Colleges of Pharmacy and Medicine present a study designed, according to the authors, to determine the frequency of inadequate antibiotic suspension dispensed by local pharmacies; establish guidelines for prescription writing that will facilitate adequate dispensing of antibiotic suspension volumes; and document adequacy of verbal
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and written counselling provided by pharmacists. They determined that the volumes of potassium penicillin oral suspension and (especially) of sulfamethoxazole-trimethoprim suspension dispensed were frequently insufficient for the completion of 10 days of therapy. In addition, one-third of the 61 pharmacies studied did not provide a measuring device with the suspensions, and the oral and written counseling provided by pharmacists varied considerably in completeness. The authors suggest several methods of ensuring that patients receive appropriate medication volumes, including increasing the calculated volume of antibiotic needed by 10% to 30% (depending on the medication viscosity), requesting that a medication measurement device be dispensed with the prescription, and increasing the amount of patient instruction and counseling.
tients who ranged in age from 5 to 18 years and who had treatment-resistant oral and/or ulcerating perineal Crohns disease. The treatment was successful in seven of the eight patients, and no evidence of significant systemic absorption was seen as a result of the use of topically applied tacrolimus. However, rapid weaning or abrupt cessation of treatment with that form of the drug caused rebound worsening in two patients who responded to treatment. Dithranol in a cream preparation: Disperse or dissolve? Prins M, Swinkels OQ, Bouwhuis S, et al. Skin Pharmacol Appl Skin Physiol 2000: 13: 273 -279. The authors, all of whom are affiliated with institutions in the Netherlands, conducted a 10-patient, double-blind, left-right comparing study to determine which of two dithranol cream preparations was most effective, produced fewer side effects, and was more acceptable to patients. They wanted to determine which was the ideal formulation for the short-contact treatment of psoriasis: a cream containing dithranol that had been dissolved at the time of preparation or a cream in which dithranol was dispersed at the time of preparation. Overall, both preparations were deemed comparably effective and acceptable to patients. The authors state, As the dispersed dithranol formulation is easier to be manufactured, its quality will be less dependent on the pharmacists experience and equipment, and so more reliable. Besides, it will be less expensive to prepare. We advise the use of this formulation for short-contact treatment. Formulation ingredients and instructions for the preparation of both creams are provided, and the effectiveness and side effects (such as irritation and staining) produced by different formulations containing dithranol are summarized. Clinical observations of the treatment of canine perianal stulas with topical tacrolimus in 10 dogs. Misseghers BS, Binnington AG, Mathews KA. Can Vet J 2000;41:623-627. The authors, who are affiliated with the Department of Clinical Studies in Ontario Veterinary College at the University of Guelph in Ontario, describe an uncontrolled trial of 10 dogs suffering from perianal fistula (PAF) that were treated with application of a compounded 0.1% tacrolimus ointment. The PAFs were completely resolved in five dogs and were partially resolved in four. There was no improvement in one dogs condition. Other treatments for PAF include surgery and the use of oral cyclosporine. The authors believe that topical treatment (as opposed to oral treatment) offers several advantages. Because PAF is a localized condition, systemic immunosuppression may not be necessary. Topical administration causes fewer dose-related adverse effects than does oral drug administration and may create a higher concentration of the drug in the affected tissue. The cost of topically administered tacrolimus for the treatment of PAF is much lower than that of orally administered cyclosporine. The formulation of topical tacrolimus used by the authors is included in the article, as are instructions for the application of the ointment. Address correspondence to: Elizabeth Foy, College of Pharmacy, Dalhousie University, Halifax, NS B3H 3J5, Canada. E-mail: elizabeth.foy@dal.ca
OF INTEREST TO COMPOUNDING PHARMACISTS

Topical tacrolimus may be effective in the treatment of oral and perineal Crohns disease. Casson DH, Eltumi M, Tomlin S, et al. Gut 2000;47:436-440. This report from the University Department of Paediatric Gastroenterology in the Royal Free and University College School of Medicine in London describes the preparation of topical tacrolimus (0.5 mg/g) from the intravenous and/or oral formulation. The topically applied drug was used in eight pediatric pa-
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Editors note: This article is included as a general interest topic; it resulted from a student project at a college of pharmacy. The authors have conducted a study on the presence of iron in cereals; however, many natural and/or health food products and some of the vitamin or mineral supplements sold in pharmacies may supply dietary iron in a form that is poorly or insufficiently absorbed. This study addresses the development of a method of quantifying the amount of undissolved iron in foods and determining the availability of that iron for absorption. Manufacturers may periodically change the form of iron in some products, and consumers may not be aware of those changes. Pharmacists must have a command of this topic to enable the most appropriate selection of vitamins and/or minerals used in formulations so that patients can be counseled accurately about their choice of products and preparations.
Magnetic Iron Whiskers in Cereals

David W. Newton, PhD, FAPhA Bernard J. Dunn School of Pharmacy, Shenandoah University Winchester, Virginia Tovah G. Hoffman Student, Virginia Polytechnic Institute and State University Blacksburg, Virginia is reduced relative to ferric iron (Fe +3 ). Depending on the chemical forms of iron present in the cereals studied, the percentage weights of elemental iron varied widely, and the magnetic property of the iron ranged from strong to nonexistent.
Introduction
Undissolved iron in cereals may not be available for absorption and assimilation by the human body. During the past decade, General Mills Sales, Inc, has used television advertising to promote Whole Grain Total cereal. The ads promoting that product are meant to illustrate nutritional equivalency: One bowl of Whole Grain Total is shown as providing the nutrition supplied by several bowlsful of another cereal product. In this article, we present a semiquantitative study in which the iron contained in each of three whole-grain cereals, including Whole Grain Total, was isolated and weighed. We attempted to use magnetic force to separate iron whiskers from the finely ground flaked cereals. The whiskers were then placed in 0.01 M HCl for 1 hour to simulate a human gastric environment favorable to the dissolution of iron, and the results of the experiment were noted.
Experimental Methods
The labeled serving sizes and iron content of the three cereals tested are described in Table 1. On December 9, 2000, each cereal was purchased from a local grocery store, and the experiments were completed by late January 2001.
Isolation of Iron Whiskers

Three standard serving-size portions of each cereal were accurately weighed to within 1% of the quantity labeled on the box before they were ground to the finest particle size possible with a large Wedgwood mortar and pestle. The finely ground cereal was transferred to a 600-mL glass beaker containing a Tefloncoated white magnetic stirring bar that had a 3/ 8 -inch diameter and was 2 1/ 2 inches in length. Three hundred milliliters of deionized water was added, and the mixture was magnetically stirred (Figure 1) at ambient room temperature (72F to 75F) for 10 minutes. The stirring bar was then removed with plastic tweezers and was rinsed gently, first with deionized water to remove
Recommendations for Oral Iron Requirements

The recommended dietary allowances (RDAs) for healthy men, women, and children who are without nutritional deficiencies are established by the Food and Nutrition Board of the National Research Council of the National Academy of Sciences. The RDAs are recommendations, not requirements. The RDAs for elemental iron are as follows: 10 mg for infants and children (age range, 0.5 to 10 years), 12 mg for male adolescents (11 to 18 years of age), 10 mg for men (19 years of age or older), 15 mg for female adolescents and women (11 to 50 years), 10 mg for women older than 51 years of age, and 30 mg for pregnant women. In contrast, the US recommended daily allowances (US-RDAs) are legal standards for nutritional information that must appear on product labeling under the authority of the US Food and Drug Administration (FDA). 1 Elemental iron (Fe 0 ) may be identified as iron or reduced iron on food product labels. The manufacturers of two cereals studied did not define reduced iron; thus, that term could represent salts or complexes of ferrous iron (Fe +2 ), which
Table 1. Labeled Serving Sizes and Iron Content in Three Whole-Grain Cereals.
Cereal Name Serving Size RDA Iron Content a
Whole Grain Total b 3/4 cup (30 g) 100% as iron Raisin Bran c Corn
a b c d
1 cup (59 g) d 1 cup (28 g)
60% as reduced iron 45% as reduced iron
Flakes e
Labeled percentages did not reference an RDA amount of iron. General Mills Sales, Inc, Minneapolis, MN. Post brand, Kraft Foods, Inc, Rye Brook, New York. The labeling did not differentiate
between iron content in the akes and in the raisins. Kellogg USA, Inc, Battle Creek, Michigan. RDA = Recommended dietary allowance.
e
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Figure 1.
Figure 2.
each cereal product was placed in 100 mL of 0.01 M HCl (pH ~ 2) to simulate optimum conditions for the dissolution of iron in human stomach contents. After having been stirred at low speed for 1 h o u r, t h e m a g n e t w i t h i r o n w h i s k e r s was rinsed gently with deionized water, after which it was rinsed again with acetone to promote rapid drying. The magnet was then weighed again so that the weight of the iron that had dissolved in the HCl could be estimated.
Results
Photograph of one serving of finely ground cereal flakes during magnetic stirring with 300 mL of deionized water. cereal-grain residue and then with acetone for rapid drying. In Figure 2, the tiny gray-black iron particles from a sample of Whole Grain Total cereal are visible on the two ends of the white magnetic stirring bar. Those particles appear to be no more than approximately 0.1 mm in diameter and 1 mm in length. They closely resemble a days growth of human male facial whiskers. The magnetic strength of the stirring bar was confirmed when it failed to dislodge 100 mg of 40-mesh iron filings (Catalog # I57500, Fisher Scientic Co, Pittsburgh, Pennsylvania), which represented a mass of larger particles at least 5-fold greater than that extracted from any cereal sample. Photograph of iron whiskers on a magnetic stirring bar in a plastic weighing boat. The results of the measurements of magnetically isolated iron whiskers and the extent of their dissolution in 0.01 M HCl are reported in Table 2.
Weighing and Dissolution of Iron Whiskers

The magnet and the iron whiskers were weighed together to the nearest 0.001 g, and the previously recorded weight of the magnet was subtracted to determine the weight of the iron whiskers. The magnetic stirring bars were weighed on top of an inverted 4-ounce conical plastic apothecary graduate that was 5 3/4 inches high to eliminate magnetic-field-related interference with the accuracy of the magnetically damped toploading electronic balance. One magnet with iron whiskers from
Possible Experimental Discrepancies

One of the authors (TH) telephoned all three cereal manufacturers in January 2001 at the contact numbers on the respective cereal boxes to acquire the chemical form and formulation method for the iron in each cereal. That information is summarized in Table 3. Accurately determining a theoretical yield was impossible because the chemical form (and thus the molecular weight of the iron source in the cereals) was unknown. Possible additional limitations of this study include the following factors: 1. Not all the iron in the cereal products was attracted by the magnetic stirring
Table 2. Iron Whiskers Magnetically Isolated from Cereal and Dissolved in 100 mL of 0.01 M HCl.
Cereal Name (mean weight of samples) a
Iron Isolated from One Serving, mg (%) b Mean
Range
Iron Dissolved in 0.01 M HCl from One Sample in Milligrams Dissolved per Milligram Isolated (%) c
Whole Grain Raisin Bran e
Total d gf)
(30 g)
13.3 (88.6%) 6.0 (66.6%) 2.7 (45%)

c
11 - 17 4-9 1-4
f
2/12 (16.7%) 3/4 (75%) 0/3 (0%)

The raisins were removed from the sample tested, so the sample weight represents only the weight of flakes. The per-serving iron content contained in flakes and in raisins was not indicated. g Kellogg USA, Inc, Battle Creek, Michigan. HCl = Hydrochloric acid. RDA = Recommended dietary allowance.
(30
Corn Flakes g (28 g)

a b
The individual weights of three samples of each cereal were within 0.5% of the mean. The reference iron content can be determined according to the following equation: [(15 mg x percent of RDA claimed on the label)/100] (Table 1). The cereal labels lacked a value of elemental iron expressed in milligrams that represented the RDA; therefore, 15 mg was the
d e
amount selected to represent 100% of the RDA. All values are less than the 40-mg minimum for a weighing error of no more than 5% on the balance used in the study; thus weights are assumed to be less than 95% accurate. General Mills Sales, Inc, Minneapolis, MN. Post brand, Kraft Foods, Inc, Rye Brook, New York.
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Table 3. Iron Content in Cereal Products: Information from Manufacturers of Whole-Grain Cereals.
Cereal Brand (company) Whole Grain Total (General Mills Sales, Inc) Raisin Bran (Post brand, Kraft Foods, Inc) Corn Flakes (Kellogg USA, Inc)
a Source:
after the ingestion of cereals that are a prime source of phytates.
Conclusion
on Iron Content in Cereal Products Elemental iron via hydrogen reduction. Sprayed on akes at the end of the manufacturing process. Sprayed on as reduced iron gray dust. Sprayed or baked on in elemental Fe, ferric, or ferrous form. Comments a Whole-grain cereals appear to be an unreliable source of bioavailable human iron supplementation, regardless of the chemical form of the iron and its valence. In two of three whole-grain cereals evaluated, magnetically isolated iron did not dissolve under favorable in vitro conditions in 0.01 M HCl. Furthermore, phytates from cereal grains probably cause iron to precipitate after its initial dissolution following exposure to gastric HCl in cereal-containing chyme.
Interview with respective manufacturers staff representative.
bar used. 2. Three specimens of each cereal are too few samples from which to infer valid results. 3. The cereal flakes were not ground finely enough to release all minute iron particles. 4. Stirring with 100 mL of 0.01 M HCl for 1 hour was not adequate for the dissolution of the magnetically isolated iron. Organic iron complexes from vegetable sources are less soluble in dilute mineral acids than are inorganic iron salts. 2 5. The limited accuracy of the balance resulted in a substantial error regarding the weight of some samples of iron whiskers on the magnetic stirring bars. All samples were weighed to the nearest 0.001 g on a Model XL-410D dual range top-loading electronic balance (Denver Instruments Company, Arvada, Colorado). The XL-410D balance has a constant linear error of 0.002 g. Thus the percent weighing error of an iron whiskers sample of 0.002 g could be as great as 50%, according to the formula below: 3 Percent weighing accuracy = (0.002 g/mass weighed, g)100
The Irony of Iron Absorption

Factors that enhance oral iron absorption include the presence of gastric HCl (which dissolves iron in the ferric state), citric acid, and vitamin C (ascorbic acid).
Approximately 200 mg of vitamin C is needed to solubilize 30 mg of elemental iron. In addition, some sugars and amino acids (in addition to citric acid and vitamin C) either sequester or form soluble absorbable complexes with iron. 4-6 Antacids and other sources of hydroxide from alkaline pH, phosphates, phytates, tannins, and tetracyclines form salts and complexes with iron cations that are absorbed very poorly. 4 - 6 According to Allen and Glasnapp, 4 most dietary iron is supplied by nonmeat sources and is poorly absorbed. Other authors 6 note that average-to-poor sources of iron are reduced iron (ferric oxide is a poor source) and that the degree of intestinal absorption of elemental iron increases as the particle size of the iron decreases. The absorption of iron can be decreased by several factors. Histamine 2 (H 2 ) antagonists and proton pump inhibitors may impair the absorption of dietary iron by decreasing gastric acid and thus increasing gastric pH. 4,5 Pancreatic fluid, which enters the upper duodenum (the site at which most absorption of iron occurs), is slightly alkaline and rich in phosphates (an environment that decreases iron solubility). Finally, cereal grains are a primary source of phytates, which are salts of phytic acid. Formed of a cyclohexyl ring with the phosphate group -OPO(OH) 2 on each of the six ring carbons, phytic acid is used industrially to precipitate and remove metal ions, including iron. 7 It is surprising that tiny iron whiskers would be thought to dissolve before being absorbed
Acknowledgment
The authors thank Thomas W. Prasthofer, PhD, for sharing his observation of magnetically isolating tiny iron particles from a finely ground, dry, whole-grain cereal.
References
1. Short RM. Drug Facts and Comparisons . St. Louis, MO: Drug Facts and Comparisons; 2000:3-4. Callahan KS. Blood, fluids, electrolytes, and hematological drugs. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy . 20th ed. Philadelphia, PA:Lippincott Williams & Wilkins; 2000:1269. Newton DW. Balances and weighing accuracy. IJPC 1998;2:376-377. Allen LV Jr, Glasnapp A. Nutritional deficiencies. In: Allen LV Jr, Berardi RR, DeSimone EM II, et al, eds. Handbook of Nonprescription Drugs . 12th ed. Washington, DC:American Pharmaceutical Association; 2000:420-423. [No author listed.] Iron absorption. Available at: http://sickle.bwh.harvard.edu/iron_absorption.html. Accessed on March 7, 2001. Vanderveen E, Vanderveen JE. Vitamins and other nutrients. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy . 20th ed. Philadelphia, PA:Lippincott Williams & Wilkins; 2000:1823. Budavari S. The Merck Index . 12th ed. Whitehouse Station, NJ:Merck & Co, Inc; 1996:1271.
2.
3. 4.
5.
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7.
A d d r e s s c o r r e s p o n d e n c e t o D a v i d W. N e w t o n , P h D , B e r n a rd J . D u n n S c h o o l o f P h a r m a c y, S h e n a n d o a h U n i v e r s i t y, 1460 University Drive, Winchester, VA 22601. E-mail: dnewton@su.edu
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WishYou Were Here:

C H I C A G O, I L L I N O I S
Dennis B. Worthen, PhD Lloyd Scholar, Lloyd Library and Museum Cincinnati, Ohio Where was the seventh college of pharmacy in the United States established? Where is the birthplace of the National Association of Retail Druggists? Where was one of the oldest drugstore chains established? Where is a Big Ten university football stadium named for a pharmacist? The answer to the questions above is, of course, Chicago. The College of Pharmacy at the University of Illinois, which was formed in 1859 as the Chicago College of Pharmacy in downtown Chicago, became part of the University of Illinois in 1896. In 1898, the National Association of Retail Druggists (now the National Community Pharmacists Association) was formed in Chicago, and its offices remained there until the Association was moved to Washington, DC, in 1977. Charles R. Walgreen bought his first store in Chicago in 1901 and his second in 1909. Northwestern University named its football stadium in honor of William A. Dyche, a graduate pharmacist of the Chicago College of Pharmacy. Dyche received a masters degree from Northwestern and served as a university trustee from 1894 until his death in 1936. That stadium was recently renamed Ryan Field in honor of a nonpharmacist donor. of a closed representation of the first Walgreens pharmacy. Viewers can see into the front of the store through glass windows. Inside the pharmacy display, a small soda fountain, proprietary medicines, and other types of products are exhibited. The display is small, and the contents can be viewed easily. The pharmacists dispensing area is on one side of the pharmacy and cannot be seen well from the front windows, but the outside wall of the exhibit has full-length windows that enable viewing of the script area. It is easy to imagine that the pharmacist has just stepped away from his compounding area to help a patron at the front of the store. The Walgreens pharmacy is supposed to be a period piece, but that was not a rigid mandate: The display contains several charming inconsistencies. Products from the 1960s can be found in the front part of the store, and in the pharmacists work area, the exempt narcotic book is open to its last entry, the date of which is in the early 1960s. The Finnegan Ice Cream Parlor display, from which fountain treats can still be bought, is near the Walgreens pharmacy. The ice cream parlor was opened in 1917 in a bankrupt pharmacy purchased by Finnegan and his partner. The cases along both walls of the display are old pharmacy cabinets, and the shelves contain antique fountain glassware as well as specimens of proprietary medicines of the period.
T H E I N T E R N AT I O N A L M U S E U M of SURGICAL SCIENCE
The International Museum of Surgical Science is located on North Lake Shore Drive, a few miles north of the Museum of Science and Industry. Although that museum is a division of the International College of Surgeons, it has a pharmacy exhibit that is worth visiting. The Museum is housed in a landmark building built as a wedding gift for Eleanor Robinson Countiss, the Diamond Match Company heiress. Its architecture is patterned after a French chateau in Versailles that was built for Louis XVI and Marie Antoinette. The Museum contains a 19th century apothecary shop in which features of the Sackett & Tabor Drugstore in Addison, New York, are combined with those of Dr.
THE CHICAGO MUSEUM o f S C I E N C E a n d I N D U S T RY

In 1986, on the 85th anniversary of the founding of the Walgreen Company, a new exhibit opened at the Chicago Museum of Science and Industry. A replica of the original Walgreens pharmacy at 3134 Cottage Grove Avenue in Chicago was added to the section of the Museum titled Yesterdays Main Street. Now, the drugstore display is part of a collection of period shops that include a physicians office, a grocery, a dental office, and an ice cream parlor. The Walgreens exhibit consists
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INTERNATIONAL MUSEUM of SURGICAL SCIENCE

Address Contact Phone Website Hours Admission 1524 North Lake Shore Drive Chicago, IL 60610 Hilary Hansen or Leonard Kliwinski 312-642-6502 www.imss.org Tuesday through Saturday: 10:00 am to 4:00 pm Adults, $6.00; students and seniors, $3.00
CHICAGO MUSEUM of SCIENCE and INDUSTRY

Address Phone Website Hours 57th Street and South Lake Shore Drive Chicago, IL 60637 773-684-9844 www.msichicago.org Memorial Day through Labor Day: Daily, 9:30 am to 5:30 pm Rest of the year: Monday through Friday: 9:30 am to 4:00 pm Saturday, Sunday, holidays: 9:30 am to 5:30 pm $9.00
formal museum, many historical items (including many pictures dating from the late 1880s and early 1900s) are on display in various areas. The deans office will be pleased to have you visit. In addition, the University of Illinois at the Chicago Library of the Health Sciences has several displays, including one pertaining to pharmacy, on a rotating basis. The Chicago Historical Society is also of interest. No collection of pharmacy artifacts is exhibited there, but you will find interesting items in the Chicago history exhibit. The Historical Society has a number of items (primarily bottles) that can be seen by appointment with Rob Kent, the collection manager. The Research Center there, which is open to the public from Tuesday through Saturday, is also a rich source of information. Visit the Historical Society in person or at www.chicagohistory.org.
Wish you were here!

PS. There are many wonderful museums and displays that will capture your attention during a Chicago jaunt. Dont forget to try the original Chicago-style pizza! A d d r e s s c o r r e s p o n d e n c e t o : D e n n i s B . Wo r t h e n , P h D , T h e Lloyd Library and Museum, 917 Plum Street, Cincinnati, OH 45202. E-mail: dbworthen@fuse.net
Admission
CHICAGO HISTORICAL SOCIETY

Address Phone Website Hours Clark Street at North Avenue Chicago, IL 60614 312-799-2065 www.chicagohistory.org Monday through Saturday: 9:30 am to 4:30 pm Sunday: 11:00 am to 4:30 pm
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Uriah C. Jones Apothecary in Breda, Iowa. The exhibit contains the fixtures and furnishings of a typical drugstore of the period. There is a massive prescription book at the entrance to the exhibit, and the shelves are filled with proprietary medicines, veterinary goods, and toys. The visitors view is from front to back, so the items behind the prescription front are out of view. Because the general layout of the Museum is geographic (as befits an exhibit designed by an international association), numerous small artifacts of interest to pharmacists are scattered throughout. There are several examples of 18th-century physicians carrying cases in the Canada room. In some respects, the presentation of the healing arts as they were before medicine and pharmacy were separated (and the interdependence of those two sciences) is the strength of this collection and its arrangement.
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AND WHILE YOU ARE THERE

When you are in Chicago, there are other stops that you might w a n t t o c o n s i d e r. T h e f i r s t i s t h e U n i v e r s i t y o f I l l i n o i s at Chicago College of Pharmacy. Although the College has no
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MEDICATIONS DISCONTINUED IN THE UNITED STATES

Lisa D. Ashworth, RPh Coppell, Texas In this article, five medications discontinued from the market by the manufacturer are featured. I am amazed at the difficulty of finding information about medications that have been discontinued in the United States, especially with respect to the Dont reason production miss the related was stopped. The formulas featured on the topical tetracycline IJPC Website at product described www.ijpc.com. below is an excellent example of this problem. That product was particularly interesting because of the associated Food and Drug Administration (FDA) warning letters, which resulted in my making numerous telephone calls to obtain information. Some information, such as the strength of phenytoin suspension mentioned below, is difficult to obtain because the discontinued product was not on the market very long, and pertinent records are scarce. Minocycline suspension is another product that was recently discontinued from the market. Thanks to our readers telephone calls to the editor-in-chief of The International Journal of Pharmaceutical Compounding ( IJPC) , we are alerted in a timely fashion about products that have been discontinued. Sometimes we cannot publish information about a product in this series because the chemical required to compound the preparation is not available. I maintain a database on those products, so please keep sending this information to us! I hope that you find these pieces of pharmaceutical history as interesting to read as I have found them to investigate, especially because many of these products are still in demand. Minocycline hydrochloride is a semisynthetic tetracycline analog antibiotic first derived from tetracycline around 1969. The tetracycline family originates from cultures of Streptomyces. 2 Minocycline hydrochloride occurs as a yellow crystalline powder that is soluble in water and is slightly soluble in alcohol. 2 It was discontinued from the market on January 30, 2001. Indications: The tetracyclines are bacteriostatic in action and exert their antimicrobial effect by inhibiting protein synthesis in susceptible organisms. They are active against a wide range of gram-negative and gram-positive organisms and are used in the treatment of syphilis; uncomplicated urethral, endocervical, or rectal infections in adults caused by Chlamydia trachomatis or Ureaplasma urealyticum ; and uncomplicated gonococcal urethritis in men. Tetracyclines are also used to treat meningococcal carrier states, Mycobacterium marinum infections, and patients with gonorrhea who are sensitive to penicillin. This medication should not be used in children younger than 8 years of age. 1,2 advised IJPC that Pfizers database indicates that this drug was discontinued from the market in 1967 (probably because of lack of demand). Phenytoin suspension was listed in various editions of Facts and Comparisons until 1996. 1 Since 1996, the only suspension concentration commercially available has been 125 mg/5 mL. Indications: Phenytoin is indicated for the prevention and treatment of tonic-clonic and psychomotor seizures. 2 The concentration of 30 mg/5 mL was designed for the pediatric population to simplify dosing, and phenytoin was available in 5-mL unit dose cups and 240-mL bottles. 1
References
1. Olin BR, ed. Drug Facts and Comparisons . 50th ed. St. Louis, MO:Facts and Comparisons; 1996: 1667-1674. 2. Kamenov KG. Curriculum vitae. Phenytoin-10 research results. Available at: http://www. asystbg.com/kgk/ph10_e.html. Accessed: March 19, 2002.
References
1. Olin BR, ed. Drug Facts and Comparisons . 50th ed. St. Louis, MO:Facts and Comparisons; 1996: 2103. 2. McEvoy GK, ed. American Hospital Formulary Service (AHFS). Bethesda, MD:American Society of Health-System Pharmacists; 2000:440-441.
Tetracycline Hydrochloride Topical Solution 0.22% (Topicycline)

Each carton of tetracycline hydrochloride topical solution 0.22% contained a vial of powder of 4-epitetracycline hydrochloride and sodium bisulfite and a vial of diluent containing 40% ethanol, citric acid, and n-decylmethyl sulfoxide to make 70 mL.1-3 After reconstitution with the diluent provided by the manufacturer, tetracycline hydrochloride topical solution is stable for 2 months at room temperature. 1 Timeline: This product was marketed in 1983 by Procter and Gamble. From 1984 through 1992, it was marketed by Norwich Eaton, 4 and from 1993 through 1995 by Procter & Gamble Pharm. From 1996 to 1998, it was marketed by Roberts Laboratories (Roberts Pharmaceutical Corp). 1 In February and December of 1997, Roberts Pharmaceutical Corp received warning letters from the FDA stating that Roberts Pharmaceutical had extended the expiration date of Topicycline from 24 months to 48 months from the time of manufacture without a written stability testing pro-
Phenytoin Suspension 30 mg/5 mL (Dilantin-30 Pediatric)

Phenytoin suspension 30 mg/5 mL was manufactured with up to 0.6% alcohol by Parke-Davis in a banana-orange-vanilla flavor. 1 Phenytoin (diphenylhydantoin) was synthesized in 1908 by German chemist Heinrich Blitz, who at that time sold this compound, along with others, to ParkeDavis (currently Pfizer). 2 It was not until 1937 that doctors Putnam and Merritt discovered the clinical use of phenytoin in the treatment of epilepsy. 2 In 1938, the FDA approved Dilantin Kapseals by ParkeDavis. 2 On March 19, 2002, one of Pfizers medical information representatives
Minocycline Hydrochloride Suspension (Minocin)

This drug was available in 60-mL bottles at a concentration of 50 mg/5 mL in a custard flavor; it contained 5% alcohol. 1
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gram and without appropriate stability data (Department of Health and Human Services, Food and Drug Administration, MidAtlantic Region, written communication, Document 1316B, February 24, 1997, and Document D10561, December 31, 1997). Sometime during 1999 or 2000, Roberts Pharmaceutical Corp merged with Shire Pharmaceuticals. Shire stated that this product was not purchased as part of the merger. Topical tetracycline solution has not been commercially available on the market since that merger. Indications: This topical anti-infective is usually effective in the treatment of the mild, papular acne of puberty and early adolescence (acne vulgaris) and papularpustular acne in adult women. In most patients, a decrease in the number of inflammatory lesions occurs after 2 to 8 weeks of therapy, and maximum benefit is not seen for up to 12 weeks. 1 The safety and efficacy of topical tetracycline in children younger than 11 years of age have not been established. 1
References
1. Olin BR, ed. Drug Facts and Comparisons . 50th ed. St. Louis, MO:Facts and Comparisons; 1996:2623. 2. Billups NF, Billups SM. American Drug Index. 42nd ed. St. Louis, MO:Facts and Comparisons; 1998:343. 3. Olin BR, ed. Drug Facts and Comparisons . 44th ed. St. Louis, MO:Facts and Comparisons; 1983:506. 4. Olin BR, ed. Drug Facts and Comparisons . 47th ed. St. Louis, MO:Facts and Comparisons; 1995:2497.
Dexamethasone Sodium Phosphate (Decadron Phosphate Cream 0.1%)

The release date of this dexamethasone sodium phosphate medication delivery system was September 14, 1959, for the 5- and 15-g sizes and January 4, 1965, for the 30-g size. On February 8, 2002, the Merck Human Health Division (West Point, Pennsylvania) announced that in 1995, when Merck & Co discontinued these products, a generic form was unavailable.
Indications: Dexamethasone is a synthetic adrenocortical steroid used as an antiinflammatory and antipruritic agent. Dexamethasone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability, which suppresses the normal immune response. 1 A thin coat is to be applied topically 1 to 4 times daily to treat chronic inflammation, allergic reactions, and autoimmune diseases. If dexamethasone is used to treat the diaper area, the patient should not wear tight-fitting diapers or plastic pants.
Reference
1. Lacy CF, Armstrong LL, Goldman MP, et al. Drug Information Handbook 1999-2000. 7th ed. Hudson, OH:Lexi-Comp, Inc; 2000:337-339.
Address correspondence to: Lisa D. Ashworth, RPh, 638 Havencrest Lane, Coppell, TX 75019-5722.
References
1. McEvoy GK. American Hospital Formulary Service (AHFS) Drug Information. Bethesda, MD:American Society of Health-System Pharmacists; 1998: 2863-2865. 2. Olin BR, ed. Drug Facts and Comparisons. 50th ed. St. Louis, MO:Facts and Comparisons 1996:2721-2722. 3. Olin BR, ed. Drug Facts and Comparisons. 49th ed. St. Louis, MO:Facts and Comparisons 1995:2584. 4. McEvoy GK. American Hospital Formulary Service (AHFS) Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 1991:2085-2087.
Glucose Topical Ophthalmic Ointment (Glucose-40)

Glucose topical ophthalmic ointment is a hyperosmolar preparation of liquid glucose 40% in white petrolatum, anhydrous lanolin, and parabens in a 3.5-g size. 1,2 Information dating from 1983 is available on this product. From 1983 to 1993, it was marketed by CooperVision, 3 and from 1993 to 1995 by Iolab.4 In 1996, it became a product of Ciba Vision1 (Novartis Ophthalmics at the time of this writing) and was discontinued from the market in September 1996. Indications: Glucose topical ophthalmic ointment is used to reduce corneal edema of the eye. It should be administered 2 to 6 times daily.
G E N E R A L
I N T E R E S T
BASICS OF COMPOUNDING
Loyd V. Allen, Jr, PhD, RPh
IONTOPHORESIS
Introduction
Iontophoresis, the transdermal delivery of ionized drugs via electrical current, has long been used in health care (see Part 1 of this two-part series). The transdermal route of drug administration, which is most applicable in the delivery of nonionized drugs composed of small molecules and given in small doses, has proven very successful. That success has caused a renewed interest in iontophoresis, which can be used for the administration of drugs with either large or small molecules and for drugs that are ionized to some extent when in solution.
PART 2
Mechanism of Action
Topically applied ionized drugs or chemicals do not usually produce a therapeutic level of drug because they cannot adequately penetrate dermal membrane barriers rich in lipids or fats. Lipid-soluble drugs are more readily absorbed by membranes than are water-soluble ionized substances. When salts of drugs are dissolved in aqueous solutions, ionized particles are formed. This process of ion formation is called dissociation or ionization. Many (if not most) drug substances today are available in salt form that is usually water soluble. The problem of inadequate membrane penetration by ionic drugs can be overcome by providing an energy source that increases the rate of penetration. Electrical energy in the form of a small direct current assists the movement of ions. According to electrical principles, like charges repel each other and opposite charges attract. Thus positive drug ions are repelled from the positive electrode, and negative drug ions are repelled from the negative electrode. When iontophoresis is performed, the active electrode is placed over the tissues that require medication. The charge of that electrode is identical to that of the drug. The indifferent or return electrode, which contains an indifferent
electrolyte, is placed at a convenient site elsewhere on the body. The charge of the indifferent electrode is the opposite of that of the drug. The electrodes are connected to the direct current source (the iontophoresis device). The current is then gradually increased to the proper level for the time duration required. Several relationships are important in iontophoresis. Ohms law states that V=IR where V is the electromotive force in volts, I is the current in amperes, and R is the resistance in ohms. This relationship is important because in an electric current at a constant voltage, any change in resistance produces a change in the current level. Very often, resistance decreases during a procedure; as a result, the current (which is expressed in milliamperes) increases. The changes in current may require some adjustment during the procedure, unless the iontophoresis device is microprocessor controlled to compensate for the increased current, as most are today. Coulombs law states that Q=IT where Q is the quantity of electricity, I is the current in amperes, and T is the time in minutes. Thus mA-min is the quantity of the electric charge, and iontophoresis procedures should be conducted according to the recommended and/or maximum mAmin dosage. When stated as a maximum , mA-min (maximum mA) must be observed to prevent damage to exposed tissues. Faradays law states that IT D= ZF where D is the amount of drug delivered in gram equivalents, I is the current in amperes, T is time, Z is valence, and F is Faradays constant. Thus the more electricity delivered, the more drug delivered, and electrical dosage and drug dosage are described
Continuing Education Goal: To provide pharmacists, pharmacy students, and pharmacy technicians with supportive information on the basics of compounding solutions for iontophoretic administration. Objectives: After reading and studying the article, the reader will be able to: 1. Discuss the theory behind iontophoresis 2. Discuss the basic requirements for successful iontophoresis 3. Describe the variables that affect iontophoresis 4. Discuss the methods of extemporaneously preparing solutions for iontophoretic administration 5. Discuss the desired characteristics of a potential iontophoresis patch in terms of mA-min. The rate of migration (M) of ions in the presence of electrolytes in an electric eld is directly proportional to eld strength (H) and to the effective charge (e) of a particle. M is inversely proportional to the radius of the particle (r, which includes the hydrate and ion shell in the calculation) and to the viscosity ( ) of the medium in which the particles are moving. The rate of particle migration is given by M = He 6 r Iontophoresis involves a number of variables that must be controlled to ensure patient safety and optimal drug delivery. Faradays law has been used by some to derive information about the rate of deposition of the drug at the skin surface. However, because of the complexity of iontophoresis, theoretical predictions of the rate of drug deposition are often inaccurate. Abramson 1 used Coulombs law, independent of the area of the electrode, to predict an electrophoretic treatment unit. Abramson and Gorin 2 developed an equation that relates the dose of drug effectively administered by iontophoresis to various factors (electrical mobility, electro-osmosis, simple diffusion) by which the procedure is influenced. Another equation defines the relationship of factors
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that influence iontophoresis, which is often used in in vitro experiments, as follows: As the iontophoretic current (I) passes through an electrode tip, resistance (RE) develops, and surrounding tissues release energy (P) in the form of heat.3 Thus: P = I2(RE + Re) where Re is the resistance of the tissues. Using predictions based on the NernstPlanck flux equations, Burnette and Marerro 4 found agreement with their predictions when they measured the iontophoretic transport of thyrotropin-releasing hormone on hairless mouse skin. The relationship they discussed is: Ji = [h(qei + qc i)(dR i/dx) + k']CiIDA where Ji is the flux of the i-th species; h and k' are proportionality constants; qe is a constant resulting from direct electrically induced ion motion; qc is a constant pertaining to electrically induced convective flow; C is the solute concentration in the pore; R is the resistance of the solute; ID is the total
applied current density; and A is the surface area of the skin. This equation shows that the flux of the drug is directly proportional to the total applied current density.
Drug Concentration
An increased drug uptake by the skin after iontophoresis with increased drug concentration has been reported. 5,6
Drug Salt Form

According to one study, 7 various salt forms possess different specific conductivities, and conductivity experiments in vitro provide information about the general suitability of a drug for use in iontophoresis. The salt form of the drug and the pH of the resultant iontophoresis solution must be considered when the amount of drug in the ionized state is determined.
Variables
In summary, the following variables control or affect the process of iontophoresis: the drug concentration; the drug salt form; the pH of the drug microenvironment; the type of electrical source used; the intensity, duration, and type of the current; the electrolyte in the donor and receptor cells; the conductivity of the drug solution; the mobility of the drug moiety; the ionic strength of the drug solution; the viscosity and dielectric constant of the medium; the stability of the drug during iontophoresis; the type of matrix containing the drug (ie, solution vs gel); and the size, charge, and nature of the electrode. Explanations of those factors follow.
pH of the Drug Microenvironment

In one study, 5 changes in the pH of the fluid at the active electrode produced only minor changes in the uptake of radioactive phosphorus by various tissues in rats. The release of histamine from aqueous media during iontophoresis produced
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G E N E R A L
I N T E R E S T
Example solutions used for iontophoretic delivery include the following: Dexamethasone 4-mg/mL Solution for Iontophoresis Rx For 100 mL Dexamethasone sodium phosphate 527 mg (equivalent to 400 mg dexamethasone) Sterile water for injection qs 100 mL Method of Preparation 1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Dissolve the dexamethasone sodium phosphate in the sterile water for injection. 4. Filter through a sterile 0.2-m lter into a sterile container. 5. Package into individual dose containers and label. Stability A beyond-use date of 6 months can be used for this formulation. 15 a similar reaction. 6 However, Harpuder 8 has demonstrated a significant dependence on pH during electrophoretic therapy. The change in the flux of lidocaine HCl during iontophoresis has been related to the degree of ionization of the drug in solution. 9 The results obtained from iontophoretically administered sulfonamides 10 parallel the degree of ionization. pH is the determining factor that governs the amount of ionized drug during iontophoresis, according to the Henderson-Hasselbalch equation. A relatively large proportion of the drug in the ionized state must be present for optimum results from iontophoresis to occur.
Lidocaine Hydrochloride 4% Solution for Iontophoresis Rx For 100 mL
Acetic Acid 2% Solution for Iontophoresis Rx For 100 mL Glacial acetic acid 2 mL Sterile water for injection qs 100 mL Method of Preparation 1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Mix the glacial acetic acid with the sterile water for injection. 4. Filter through a sterile 0.2-m lter into a sterile container. 5. Package into individual dose containers and label. Stability A beyond-use date of 6 months can be used for this formulation.15
Lidocaine hydrochloride 4g Sterile water for injection qs 100 mL Method of Preparation 1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Dissolve the lidocaine hydrochloride in the sterile water for injection. 4. Filter through a sterile 0.2-m lter into a sterile container. 5. Package into individual dose containers and label. Stability A beyond-use date of 6 months can be used for this formulation. 15 According to Faradays law, the transported quantity of electricity in an electrolytic solution depends on the strength of the current and the duration of its passage. 11 The same number of ions will be transported at different strengths of current if the time for current flow is inversely related to those strengths. The rate at which the ions are introduced into the body with various current strengths can play an important role in the efficacy of iontophoresis. When the current is strong, more ions simultaneously penetrate the dermal layers. The accumulation of those ions produces the desired local effect and possibly even a reserve of ions that is eventually diffused deeply into tissues to produce a prolonged drug effect. The strength of the current used also depends on the patients ability to tolerate the treatment. 12
Electrolytes in Donor and Receptor Cells

Electrical current is carried by positive and negative ions in solution. There is no major distinction among ions of the same charge, even though they are composed of different chemical elements. Therefore, solutions for iontophoresis should be as pure as is practical and should contain as few extraneous substances as possible. Ultrapure water should be used to prepare drug solutions. It has been shown that excipients in dosage forms (ie, preservatives in injections) reduce the conductivity of solutions by as much as 5% to 10% (LA, personal communication, EMPI, Inc, St. Paul, Minnesota, July 1998). The total current supplied by the amperometer is transported in two ways: by drug ions with a charge identical to that of the drug ions in the donor cell and by counter ions (those with an opposite charge) in the receptor cell. Therefore, the competing ions in the donor cell and the counter ions in the receptor cell affect the current c a r r i e d b y t h e d r u g m o i e t y. T h e i o n tophoretic rate of drug transfer can therefore be adjusted by varying the concentration of electrolyte in the donor cells and receptor cells.
Type of Electrical Source

Some iontophoresis devices are of the constant-voltage type. However, as the resistance changes during iontophoresis, so do the voltage and current. As a result, devices that provide a constant current (even when resistance changes during iontophoresis) have been developed.
Type of Current
Most iontophoresis devices use a constant current, which is initiated at a low level and is slowly increased to an operating level, after which it is lowered again to zero. A pulsed current that effectively delivers the drug is produced by some iontophoresis devices.
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Ketorolac 6-mg/mL Solution for Iontophoresis Rx For 100 mL Ketorolac tromethamine 600 mg Sterile water for injection qs 100 mL Method of Preparation 1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Obtain the required number of ketorolac tromethamine tablets and thoroughly pulverize them. 3. To the powder, add sufficient sterile water for injection to volume. 4. Filter through a paper lter to remove insoluble tablet excipients. 5. Filter through a sterile 0.2-m lter into a sterile container. 6. Package into individual dose containers, replace the headspace in each container with nitrogen, and label, or package the solution in syringes and remove air from each syringe by displacement with the plunger. Stability A beyond-use date of 6 months can be used for this formulation. 15
Stability of the Drug During Iontophoresis

An iontophoretically administered drug must be stable in solution until the time of and during iontophoresis. Little information about drug stability during iontophoresis is available. Drugs that are easily oxidized or reduced must be appropriately formulated for two reasons: the oxidation or reduction of a drug decreases the total amount of drug available, and degradation compounds that possess the same charge as that of the drug ion compete with the drug ion and reduce the overall transmembrane rate of the drug.
been conducted on that topic. Bannon et al 13,14 have reported on the iontophoretic use of hydrogels with cellulose membranes. They observed that the passive release of salbutamol from hydrogel across the membrane was matrix controlled and that the transfer of drug transported by the electrical current increased linearly with the strength of the current.
Size, Charge, and Nature of Electrodes

Material used for electrodes should be harmless to the body and flexible enough to be applied to the body surface. The distribution of the active drug species within the skin depends on the size and position of the electrodes. Greater amounts of drugs are usually (but not always) introduced by larger electrodes. The most desirable electrode is disposable, conforms to irregular skin surfaces, is made of a flexible material, has one surface coated with
Matrices Containing Drug Gel vs Solution

Because of differences in viscosity, material electrical charge, and porosity, the migration of a drug transported by an electric current varies when the matrices are different. A limited amount of research has
Conductivity of the Drug Solution and Mobility of the Drug Moiety

The conductivity and mobility of the same drug solution differ by a factor of the ionic charge on the drug; therefore, those two parameters should be evaluated together.
Ionic Strength of the Drug Solution

Little information about the effect of the ionic strength of drug solutions used during iontophoresis is available. However, a report 5 on a decrease in the uptake of phosphorous by tissue has been published.
Viscosity of the Medium

The migration of a drug molecule is usually inversely related to the viscosity of the medium in which it is contained.
G E N E R A L
I N T E R E S T
an adhesive that can be applied directly to the skin of the patient, and has, on the nonconductive planar body, a tab to which an electrical connection can be made.
Clinical Applications
The clinical applications of iontophoresis must also be considered. Iontophoresis devices are small, but in the future, an iontophoresis patch may be available as a self-contained unit that enables the alteration of the delivery rate of single or multiple doses of drugs. Ideally, the iontophoresis patch would contain drug sufficient for administration for up to 7 days, could be easily applied and not easily washed off, and would deliver the drug at a predetermined rate over a specified period of time. The quantity of drug that had been delivered could be determined by the amount of drug remaining in the patch after iontophoresis. Patient compliance with that dosage form could easily be monitored, and new patches could be delivered to the patient weekly. The patches might be designed so that visual examination could be used to detect tampering and their removal would disconnect electrodes and terminate drug delivery.
tophoretic transfer it is best to have only the drug in solution, unless there is justification for having other ingredients present (such as acid or base for pH adjustment) to increase the ratio of ionized to unionized drug present. The following factors must also be considered when iontophoresis solutions are compounded:
Packaging
Solutions for iontophoresis do not contain preservatives, so they should be packaged in individual unit-of-use containers.
Labeling
For professional use only. For use by iontophoresis. Not for injection.
Quality Control
Theoretical yield compared with actual yield, physical observation, pH, sterility tests.
References
1. Abramson HA. Skin reactions X: Preseasonal treatment of hay fever by electrophoresis of ragweed pollen extracts into the skin: Preliminary report. J Allergy 1941;12:169-175. Abramson HA, Gorin MH. Skin Reactions. IX: The electrophoretic demonstration of the patent pores of the living human skin; Its relation to the charge of the skin. J Phys Chem 1940;44:1094-1102. Globus A. In: Thompson RF, Patterson MM, eds. Bioelectric Recording Techniques, Part A: Cellular Processes and Brain Potentials. NY:Academic Press; 1973:23-28. Burnette RR, Marerro D. Comparison between the iontophoretic and passive transport of thyrotropin releasing hormone across excised nude mouse skin. J Pharm Sci 1986;75:738-743. OMalley EP, Oester YT. Influence of some physical chemical factors on iontophoresis using radio-isotopes. Arch Phys Med Rehab 1955; 36:310-316. Abramson HA, Alley A. Skin reactions I: Mechanism of histamine iontophoresis from aqueous media. Arch Phys Ther X-Ray, Radium 1937;18:327. Gangarosa LP, Park NH, Fong BC, et al. Conductivity of drugs used for iontophoresis. J Pharm Sci 1978;67:1439-1443. Harpuder K. Electrophoresis in physical therapy. Arch Phys Ther X-Ray, Radium 1937;18:221-225. Siddiqui O, Roberts MS, Polock AE. The effect of iontophoresis and vehicle pH on the in vitro permeation of lignocaine through human stratum corneum. J Pharm Pharmacol 1985;37:732-735. von Sallman L. Sulfadiazine iontophoresis in Pyocyaneus infection of rabbit cornea. Am J Ophthalmol 1942;25:1292-1300. Siddiqui O, Roberts MS, Polack AE. Iontophoretic transport of weak electrolytes through the excised human stratum corneum. J Pharm Pharmacol 1989;41:430-432. Kno PC, Cliu J, Chang SF, et al. In: Proceedings of the Japan-United States Congress on Pharmaceutical Sciences; December 2-8, 1987; Honolulu, HI. Abstract PD-508. Bannon Y, Corish J, Corrigan O, et al. Iontophoretically induced transdermal delivery of salbutamol. Drug Development and Industrial Pharmacy 1988;14:2151-2166. Bannon Y, Corish J, Corrigan O, et al. Iontophoretic transport of model compounds from a gel matrix across a cellophane membrane. Drug Development and Industrial Pharmacy 1987;13:2617-2630. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXIV/ National Formulary 19. Rockville, MD:US Pharmacopeial Convention, Inc; 2001:2053-2057.
Compounding Solutions for Iontophoresis

Any ionized substance in solution can compete for the electrical current during iontophoresis. Consequently, for efficient ion-
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F O R M U L A T I O N S
Dehydroepiandrosterone 25 mg/mL in Pluronic Lecithin Organogel
Rx
For 100 mL Dehydroepiandrosterone Propylene glycol Lecithin:isopropyl palmitate solution a Pluronic F127 20% gel b qs
a
2.5 g 1 mL 20 g 100 mL
The lecithin:isopropyl palmitate solution can be prepared by mixing 10 g of soy lecithin and 10 g of isopropyl palmitate; allow the mixture to stand overnight so that complete dissolution occurs. The Pluronic F127 20% gel solution can be prepared by adding 20 g of Pluronic F127 to sufficient cold (ice) water to make 100 mL. To facilitate complete dissolution, place the mixture in a refrigerator, agitate it periodically, and allow it to set.
METHOD OF PREPARATION
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Prepare a paste of the dehydroepiandrosterone in the propylene glycol. 4. Add the lecithin:isopropyl palmitate solution and mix well. 5. Add sufficient Pluronic F127 20% gel to volume and mix well. 6. Package and label.
PACKAGING
Package in tight, light-resistant containers.
LABELING
For external use only. Use only as directed.
Lecithin (egg lecithin, soybean lecithin, vegetable lecithin) is a complex mixture of acetone-insoluble phosphatides consisting primarily of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol in combination with triglycerides, fatty acids, and carbohydrates. The composition and physical properties of lecithin vary depending on the source and degree of purification. Lecithin derived from vegetable sources has a bland or nut-like taste and varies in color f r o m b r o w n t o l i g h t y e l l o w, d e p e n d i n g o n w h e t h e r i t i s bleached or unbleached. Lecithin is practically insoluble in water, in polar solvents, and in cold vegetable and animal oils; however, when mixed with water, it hydrates to form emulsions. It is soluble in aliphatic and aromatic hydrocarbons, in mineral oil, and in fatty acids. Lecithin decomposes at extremes of pH, is hygroscopic, and is subject to microbial degradation. It should be stored in well-closed containers and be protected from light. 6 Isopropyl palmitate (C 19 H 38 O 2 , MW 298.51) is a colorless mobile liquid with a very slight odor. It is used as an emollient, an oleaginous vehicle, and a solvent and has good spreading characteristics. It is soluble in each of the following: acetone, castor oil, cottonseed oil, alcohol, and mineral oil. Isopropyl palmitate is insoluble in water, in glycerin, and in propylene glycol. It should be stored in well-closed containers and protected from light. 7 Poloxamer 407 (Pluronic F127) is usually available in powdered form. It is either odorless or may have a very mild odor. It melts at about 56C and is freely soluble in water, in alcohol, and in isopropyl alcohol. The pH of a 2.5% w/v aqueous solution of Pluronic F127 is in the range of 6.0 to 7.4. Poloxamers are stable, and their aqueous solutions are stable in the presence of acids, alkalis, and metal ions (although they do support mold growth). 8
STABILITY
A beyond-use date of 30 days can be used for this formulation. 1
References
1. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXV/ National Formulary 20. Rockville, MD:US Pharmacopeial Convention, Inc; 2001:2053-2057. Allen LV Jr. Standard operating procedure for performing physical quality assessment of ointments/creams/gels. IJPC 1998;2:308-309. Reynolds JEF, ed. MARTINDALE: The Extra Pharmacopoeia . 28th ed. London:The Pharmaceutical Press; 1982:1410. Arlt W, Callies F, van Vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999; 341:1013-1020. Dandiker Y. Propylene glycol. In: Kibbe A. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:442-444. Fowler K. Lecithin. In: Kibbe A. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000: 292-294. Taylor AK. Isopropyl palmitate. In: Kibbe A. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:267-268. Collett JH, Popli H. Poloxamer. In: Kibbe A. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:386-388.
USE
Dehydroepiandrosterone Pluronic lecithin organogel has been used for hormonal supplementation.
2. 3. 4.
QUALITY CONTROL
Quality control assessment can include weight and/or volume, pH, specific gravity, active drug assay, color, clarity, texture-surface, rheologic properties, and physical observation. 2
DISCUSSION
Dehydroepiandrosterone (C 19 H 28 O 2 , MW 288.4) is a naturally occurring, relatively weak androgen. It has been commercially available and marketed in several countries. The role of dehydroepiandrosterone in adrenal insufficiency has been studied, and it is a precursor to androgens in hormone replacement therapy. 3,4 Propylene glycol (C 3 H 8 O 2 ) occurs as a clear, colorless, viscous, practically odorless liquid with a sweet taste resembling that of glycerin. It has a specific gravity of 1.038 g/mL and is miscible with each of the following: acetone, chloroform, 95% ethanol, glycerin, and water. Because propylene glycol is hygroscopic, it should be stored in an airtight container and protected from light.5
5.
6.
7.
8.
Dehydroepiandrosterone 25-mg/0.25-mL Sublingual Drops
Rx
For 10 mL Dehydroepiandrosterone Saccharin Silica gel Almond oil or sesame oil Flavor qs 1g 100 mg 200 mg 10 mL qs
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh each ingredient. 3. Triturate the dehydroepiandrosterone, saccharin, and silica gel in a mortar. 4. Add a small amount of almond oil or sesame oil and triturate to a smooth paste. 5. Add sufficient avor and almond oil or sesame oil to volume and mix well. 6. Package and label.
PACKAGING
LABELING
Use only as directed. Keep away from children.
STABILITY
A beyond-use date of 6 months can be used for this preparation. 1
USE
Dehydroepiandrosterone sublingual drops are used for hormonal supplementation.
it has a metallic aftertaste that is experienced by approximately 25% of the population. It is soluble to the extent of 1 g in 290 mL of water, in 50 mL of glycerin, and in 31 mL of 95% ethanol. In aqueous preparations, the sodium salt is used. 5 Silica gel, a form of silicon dioxide, occurs as a ne, white, hygroscopic, odorless, amorphous powder with a usual particle size in the range of 2 to 10 . It is insoluble in water, in alcohol, and in other organic solvents but is soluble in hot solutions of alkali hydroxides. It is used as a desiccant, a suspending agent, and a viscosity-increasing agent. 1,6 Almond oil (sweet almond oil) is a clear, pale, straw-colored or colorless, almost odorless, oily liquid with a bland, nutty taste. It contains primarily glycerides of oleic acid, as well as smaller amounts of linoleic, myristic, and palmitic acids. It is expressed without heat from the seeds of the bitter or sweet almond. Its specic gravity is 0.910 to 0.915, and it is slightly soluble in alcohol but is miscible with mineral oil. Almond oil should be protected from light and stored in a cool place in well-lled, airtight containers. It is used as a nutritive (15 mL to 30 mL) and as an emollient. 1 Sesame oil (benne oil, gingelly oil, gingili oil, jinjili oil, teel oil) is a clear, pale yellow liquid with a slight, pleasant odor and a bland taste. It is obtained from the seeds of one or more varieties of Sesamum indicum (L.). It is used as an oleaginous vehicle and solvent. The oil solidies at about -4C and has a density of about 0.918 g/cm 3 . Sesame oil is insoluble in water and is practically insoluble in 95% ethanol. It is more stable than most xed oils and does not readily become rancid because of the antioxidant effect of some of its constituents. The oil should be stored in well-lled, airtight, light-resistant containers at less than 40C. 7
References
1. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXV/National Formulary 20 . Rockville, MD:US Pharmacopeial Convention, Inc; 2001:2053-2057, 2365, 2396, 2505-2506. Allen LV Jr. Standard operating procedure for quality assessment of oral and topical liquids. IJPC 1999;3:146-147. Reynolds JEF, ed. MARTINDALE: The Extra Pharmacopoeia . 28th ed. London:The Pharmaceutical Press; 1982:1410. Arlt W, Callies F, van Vlijmen JC, et al. Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999;341:1013-1020. Higton FR, Thurgood DM. Saccharin. In: in Wade A, Weller PJ. Handbook of Pharmaceutical Excipients . 2nd ed. Washington, DC:American Pharmaceutical Association; 1994:415-417. Moreeld E. Colloidal silicon dioxide. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:143-145. Cable CG. Sesame oil. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:460-461.
QUALITY CONTROL
The quality assessment of these oral drops can include weight and/or volume, specic gravity, active drug assay, color, clarity, rheologic properties and/or pourability, physical observation, and physical stability. 2
2. 3. 4.
DISCUSSION
Dehydroepiandrosterone (C 19 H 28 O 2 , MW 288.4) is a naturally occurring, relatively weak androgen. It has been a commercially available and marketed pharmaceutical in several countries. Dehydroepiandrosterone has been studied for the treatment of adrenal insufficiency and as a precursor to androgens in hormone replacement therapy. 3,4 Saccharin (C 7 H 5 NO 3 S, MW 183.18) is an intense sweetening agent widely used in commercial products, including foods, drinks, and pharmaceuticals. It is used (usually in concentrations ranging from 0.02% to 0.5%) in oral formulations as a sweetener. Saccharin is approximately 500 times sweeter than sucrose and can be used to mask some unpleasant tastes of various medications. It occurs as odorless white crystals or as a white crystalline powder. In addition to its intense sweet taste,
5.
6.
7.
294
Estradiol 0.5-mg Sublingual Troches
Rx
For 100 troches Estradiol Polyethylene glycol 1540 Citric acid Aspartame Bentonite Acacia Flavor 50 mg qs* 430 mg 360 mg 150 mg 280 mg qs
* The quantity will depend upon the size of the mold being used.
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Mix the estradiol, citric acid, aspartame, bentonite, and acacia powders together. 4. Melt the polyethylene glycol 1540 at 55C to 60C. 5. Remove from heat, add the mixed powders, and mix well. 6. Add the flavor and mix well. 7. Pour into molds and cool. 8. Package and label.
PACKAGING
Package in a tight, light-resistant container.
LABELING
Keep out of the reach of children. Use only as directed. Protect from heat. Store in a refrigerator.
melting range for PEG 1540 is in the range of 40C to 48C, and it is soluble in water. The PEGs are chemically stable, do not support microbial growth, and do not become rancid. 6 Citric acid (C 6 H 8 O 7 .H 2 O, citric acid monohydrate) occurs as colorless or translucent crystals or as a white, crystalline, efflorescent powder that is odorless and has a strong, tart, acidic taste. The hydrated form of citric acid may contain up to 8.8% water, and the pH of a 1% w/v aqueous solution is about 2.2. Citric acid has a density is 1.542 g/mL. Depending on the degree of humidity in the air, the hydrated form of citric acid effloresces, and the anhydrous form is hygroscopic. If stored in air that is too dry, citric acid may lose its water if the temperature reaches about 40C. The melting point of citric acid is about 100C, but it softens at about 75C. One gram is soluble in less than 1 mL of water and in 1.5 mL of ethanol. 7 Aspartame (NutraSweet, Equal, MW 294.31) is an off-white, almost odorless, crystalline powder with an intensely sweet taste. It is sparingly soluble in water and is only slightly soluble in 95% ethanol. Aspartame degrades during prolonged heating; this can be minimized by heating it to a higher temperature for short time periods that are followed by rapid cooling. 8 Bentonite (mineral soap, soap clay) is a crystalline clay-like mineral that occurs as an odorless, hygroscopic, pale buff or creamto-grayish fine powder. It is often used as a suspending agent in troche formulations. 9 Acacia (gum acacia, gum arabic) is the dried gummy exudate obtained from the stems and branches of some species of the genus Acacia ( Leguminosae ), which occurs primarily in Sudan and Senegal. 10
References
1. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXV/ National Formulary 20 . Rockville, MD:US Pharmacopeial Convention, Inc; 2001:689-690, 2053-2057, 2377. 2. Allen LV Jr. Standard operating procedure for performing physical quality assessment of suppositories, troches, lollipops and sticks. IJPC 1999;3:56-57. 3. McEvoy GK. AHFS Drug Information-2002 . Bethesda, MD:American Society of Health-System Pharmacists; 2002:2974-2979. 4. Lacy C, Armstrong, LL, Ingrim NB, et al. Drug Information Handbook . 4th ed. Hudson, OH:Lexi-Comp, Inc; 1996:445-447. 5. Hardman JG, Limbird LE. Goodman & Gilmans The Pharmacological Basis of Therapeutics . 9th ed. New York:McGraw-Hill; 1996:1411-1437. 6. Price JC. Polyethylene glycol. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:392-398. 7. Amidon GE. Citric acid monohydrate. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:140-142. 8. Russell G, Thurgood DM. Aspartame. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:27-29. 9. Palmieri A. Bentonite. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:30-32. 10. Shefter E. Acacia. In: Kibbe A., ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:1-2.
STABILITY
USE
Estradiol sublingual troches are used for bioidentical hormone replacement therapy.
QUALITY CONTROL
The quality assessment of estradiol troches can include physical observation (color, texture-surface, appearance, feel, odor), weight, weight variation, specific gravity, melting range, dissolution, physical stability, and active drug assay. 2
DISCUSSION
Estradiol is a naturally occurring steroidal estrogen that occurs as white or creamy white small crystals or as a crystalline powder. It is odorless and hygroscopic. Estradiol is practically insoluble in water but has a solubility of about 35.7 mg/mL in alcohol at 25C. It should be stored in tight, light-resistant containers. Estradiol is indicated in the treatment of mild-to-severe vasomotor symptoms associated with menopause. 1, 3-5 Polyethylene glycol (Carbowax, PEG, polyoxyethylene glycol) is an addition polymer of ethylene oxide and water. Solid polyethylene glycols are white or off-white pastes or waxy flakes. The
Estradiol 1-mg/0.1-mL Pluronic Lecithin Organogel
Rx
For 100 mL Estradiol Propylene glycol Lecithin:isopropyl palmitate solution a Pluronic F127 20% gel b qs
a
1g 1 mL 20 g 100 mL
The lecithin:isopropyl palmitate solution can be prepared by mixing 10 g of soy lecithin and 10 g of isopropyl palmitate; allow the mixture to stand overnight for complete dissolution to occur. The Pluronic F127 20% solution can be prepared by adding 20 g of Pluronic F127 to sufficient cold (ice) water to make 100 mL. To facilitate complete dissolution, place the mixture in a refrigerator, agitate it periodically, and allow it to set.
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Prepare a paste of the estradiol in the propylene glycol. 4. Add the lecithin:isopropyl palmitate solution and mix well. 5. Add sufficient Pluronic F127 20% gel to volume and mix well. 6. Package and label.
PACKAGING
LABELING
For external use only. Use only as directed.
should be stored in an airtight container and protected from light. 6 Lecithin (egg lecithin, soybean lecithin, vegetable lecithin) describes a complex mixture of acetone-insoluble phosphatides consisting primarily of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol in combination with triglycerides, fatty acids, and carbohydrates. Lecithin derived from vegetable sources has a bland or nut-like taste and varies from brown to light yellow, depending on whether it is bleached or unbleached. It is practically insoluble in water, in polar solvents, and in cold vegetable and animal oils. It is soluble in aliphatic and aromatic hydrocarbons, in mineral oil, and in fatty acids. Lecithin should be stored in well-closed containers and protected from light. 7 Isopropyl palmitate (C 19 H 38 O 2 , MW 298.51) is a colorless, mobile liquid with a very slight odor. It is used as an emollient, an oleaginous vehicle, and a solvent and has good spreading characteristics. Isopropyl palmitate is soluble in each of the following: acetone, castor oil, cottonseed oil, alcohol, and mineral oil. It is insoluble in water, in glycerin, and in propylene glycol. It should be stored in well-closed containers and protected from light. 8 Poloxamer 407 (Pluronic F127) is usually available in powdered form. It is either odorless or may have a very mild odor. It melts at about 56C and is freely soluble in water, in alcohol, and in isopropyl alcohol. The pH of a 2.5% w/v aqueous solution of Pluronic F127 is in the range of 6.0 to 7.4. The poloxamers are stable, and their aqueous solutions are stable in the presence of acids, alkalis, and metal ions but do support mold growth. 9
References
1. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXV/National Formulary 20 . Rockville, MD:US Pharmacopeial Convention, Inc; 2001:2053-2057. Allen LV Jr. Standard operating procedure for performing physical quality assessment of ointments/creams/gels. IJPC 1998;2:308-309. McEvoy GK. AHFS Drug Information-2002 . Bethesda, MD:American Society of Health-System Pharmacists; 2002:2974-2979. Lacy C, Armstrong, LL, Ingrim NB, et al. Drug Information Handbook . 4th ed. Hudson, OH:Lexi-Comp, Inc; 1996:445-447. Hardman JG, Limbird LE. Goodman & Gilmans The Pharmacological Basis of Therapeutics . 9th ed. New York:McGraw-Hill; 1996:1411-1437. Dandiker Y. Propylene glycol. In: Kibbe A. Handbook of Pharmaceutical Excipients. 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:442-444. Fowler K. Lecithin. In: Kibbe A. Handbook of Pharmaceutical Excipients . 3rd ed. Washington DC: American Pharmaceutical Association; 2000:292-294. Taylor AK. Isopropyl palmitate. In: Kibbe A. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:267-268. Collett JH, Popli H. Poloxamer. In: Kibbe A. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:386-388.
STABILITY
A beyond-use date of 30 days can be used for this formulation. 1
USE
Estradiol Pluronic lecithin organogel is used in bioidentical hormone replacement therapy.
2. 3. 4. 5. 6.
QUALITY CONTROL
DISCUSSION
Estradiol, a naturally occurring steroidal estrogen, is indicated in the treatment of mild-to-severe vasomotor symptoms associated with menopause. 3-5 It occurs as white or creamy white small crystals or as a crystalline powder. It is odorless and hygroscopic and is practically insoluble in water but has a solubility of about 35.7 mg/mL in alcohol at 25C. Estradiol should be stored in tight, light-resistant containers. Propylene glycol (C 3 H 8 O 2 ) occurs as a clear, colorless, viscous, practically odorless liquid with a sweet taste resembling that of glycerin. It has a specific gravity of 1.038 g/mL and is miscible with each of the following: acetone, chloroform, 95% ethanol, glycerin, and water. Because propylene glycol is hygroscopic, it
7.
8.
9.
296
Estradiol 1-mg/0.1-g Topical Cream
Rx
For 100 g Estradiol Glycerin Hydrophilic ointment or other suitable oil-in-water emulsion vehicle qs 1g 5 mL 100 g
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Add the glycerin to the estradiol and form a smooth paste. 4. Geometrically incorporate the hydrophilic ointment (or other suitable oil-in-water cream vehicle) and mix until uniform. 5. Package and label. Dosing syringes are convenient for patients to use; each dose can be accurately measured, and the syringes protect the cream from exposure to the drying effect of air.
PACKAGING
LABELING
For external use only.
STABILITY
A beyond-use date of 30 days should be appropriate for this formulation. 1
USE
Estradiol topical cream is used in bioidentical hormone replacement therapy.
QUALITY CONTROL
Quality control assessment can include weight and/or volume, specific gravity, active drug assay, color, clarity, texture-surface, rheologic properties, and physical observation. 2
Glycerin (glycerol, 1,2,3-propane triol) occurs as a clear, colorless, odorless, viscous, hygroscopic liquid with a sweet taste that is about two thirds as sweet as that of sucrose. It is used as a solvent, a levigating agent, an antimicrobial preservative, an emollient, and a humectant, as well as for other purposes. Glycerin has a specific gravity of about 1.25 and a melting point of 17.8C; if cooled to crystallization, it must be heated to about 20C to melt. It is miscible with water, with methanol, and with 95% ethanol; is practically insoluble in oils and in chloroform; and is slightly soluble in acetone. Glycerin is hygroscopic and should be stored in airtight containers in a cool place. It is not prone to oxidation but will decompose when heated. Mixtures consisting of glycerin and water, glycerin and ethanol, or glycerin and propylene glycol are chemically stable. 6 Hydrophilic ointment, USP is a water-washable, oil-in-water emulsion base containing methylparaben, propylparaben, sodium lauryl sulfate, propylene glycol, stearyl alcohol, white petrolatum, and purified water. It is miscible with water and with aqueous solutions, and some amount of oil solutions can be incorporated into the inner phase of the emulsion. The water content can be varied to produce cream vehicles of different consistencies. Several similar commercial products are available that are variations on this basic formula, such as Dermabase and Vanicream. 1 Dermabase cream (Paddock Laboratories, Inc) is an unscented, washable, oil-in-water emulsion cream base. It contains purified water (about 45%), mineral oil, petrolatum, cetostearyl alcohol, propylene glycol, sodium lauryl sulfate, isopropyl palmitate, imidazolidinyl urea, methylparaben, and propylparaben. It is a smooth, white, water-washable cream with a slight, pleasant odor. It is preserved and is compatible with a wide variety of agents. 7 Vanicream (Pharmaceutical Specialties, Inc) is an oil-in-water emulsion base containing white petrolatum, cetearyl alcohol, ceteareth-20, sorbitol, propylene glycol, simethicone, glyceryl monostearate, polyethylene glycol monostearate, and sorbic acid. It is free of dyes, perfume, lanolin, parabens, and formaldehyde and is a stable and widely compatible cream. 8
REFERENCES
1. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXV/National Formulary 20 . Rockville, MD:US Pharmacopeial Convention, Inc; 2001:689-690, 2053-2057, 2377. Allen LV Jr. Standard operating procedure for performing physical quality assessment of ointments/creams/gels. IJPC 1998;2:308-309. McEvoy GK. AHFS Drug Information-2002 . Bethesda, MD:American Society of Health-System Pharmacists; 2002:2974-2979. Lacy C, Armstrong, LL, Ingrim NB, et al. Drug Information Handbook . 4th ed. Hudson, OH:Lexi-Comp, Inc; 1996:445-447. Hardman JG, Limbird LE. Goodman & Gilmans The Pharmacological Basis of Therapeutics . 9th ed. New York:McGraw-Hill; 1996:1411-1437. Price JC. Glycerin. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:220-222. Dermabase [product information]. Minneapolis MN:Paddock Laboratories, Inc. Vanicream [product information]. Rochester MN:Pharmaceutical Specialties, Inc.
DISCUSSION
Estradiol is a naturally occurring steroidal estrogen in the form of white or creamy white small crystals or a crystalline powder. It is odorless and hygroscopic and is practically insoluble in water, but it has a solubility of about 35.7 mg/mL in alcohol at 25C. It should be stored in tight, light-resistant containers. In the body, estradiol is reversibly oxidized to estrone, and both estradiol and estrone can be converted to estriol. Usually, estradiol is not administered orally because of extensive first-pass hepatic metabolism. Estradiol is indicated in the treatment of atrophic vaginitis; atrophic dystrophy of the vulva; menopausal symptoms, including mild-to-severe vasomotor symptoms; female hypogonadism; and the symptoms produced by ovariectomy, primary ovarian failure, inoperable breast cancer, or inoperable cancer of the prostate. 3-5
2. 3. 4. 5. 6.
7. 8.
Estriol 2-mg/mL, Estrone 0.25-mg/mL, and Estradiol 0.25-mg/mL Topical Solution
Rx
For 100 mL Estriol Estrone Estradiol Benzyl alcohol Dimethyl sulfoxide Alcohol, absolute Propylene glycol 200 mg 25 mg 25 mg 20 mL 20 mL 20 mL 100 mL
qs
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Add the estriol, estrone, and estradiol to the previously combined benzyl alcohol, dimethyl sulfoxide, and absolute alcohol and mix well. 4. Add sufficient propylene glycol to make 100 mL and mix well. 5. Package and label.
PACKAGING
LABELING
Use only as directed.
STABILITY
A beyond-use date of 6 months is appropriate for this preparation. 1
USE
Estriol, estrone, and estradiol topical solution is used in bioidentical hormone replacement therapy.
Estradiol is a naturally occurring steroidal estrogen. It occurs as white or creamy white small crystals or as a crystalline powder. It is odorless and hygroscopic. Estradiol is practically insoluble in water but has a solubility of about 35.7 mg/mL in alcohol at 25C. It should be stored in tight, light-resistant containers. 4-6 Benzyl alcohol (C 7 H 8 O, MW 108.14) is an antimicrobial preservative, a disinfectant, and a solvent. It is a clear, colorless, oily liquid that has a faint, aromatic odor and a sharp, burning taste. It has a specific gravity of about 1.045. Benzyl alcohol is soluble 1 g in 25 mL of water at 25C and is miscible with ethanol. It should be protected from light. 7 Dimethyl sulfoxide [(CH 3 ) 2 SO, sulfinylbismethane, methyl sulfoxide, DMSO, MW 78.14) occurs as a clear, colorless, hygroscopic liquid with a bittersweet taste and faint to no odor. It boils at about 190C and freezes at about 18.55C. It is miscible with water and with most alcohols. The specific gravity of dimethyl sulfoxide is in the range of 1.095 to 1.101. 8 Alcohol (ethyl alcohol, ethanol, grain alcohol) is a clear, colorless, mobile, volatile liquid with a slight, characteristic odor and a burning taste. It is used as a solvent in topical products (60% to 90% concentration). Alcohol, USP refers to 95% ethanol, and dehydrated alcohol (absolute alcohol) refers to 99.5% alcohol. The specific gravity of alcohol is between 0.812 and 0.816, and its boiling point is 78.15C. 9 Propylene glycol (C 3 H 8 O 2 ) occurs as a clear, colorless, viscous, practically odorless liquid with a sweet taste resembling that of glycerin. The specific gravity of propylene glycol is 1.038 g/mL. It is miscible with each of the following: acetone, chloroform, 95% ethanol, glycerin, and water. Because propylene glycol is hygroscopic, it should be stored in an airtight container and protected from light. 10
References
1. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXV/National Formulary 20 . Rockville, MD:US Pharmacopeial Convention, Inc; 2001:2053-2057. 2. Allen LV Jr. Standard operating procedure for quality assessment of oral and topical liquids. IJPC 1999;3:146-147. 3. Reynolds JEF, ed. MARTINDALE: The Extra Pharmacopoeia . 30th ed. London:The Pharmaceutical Press; 1993:1192. 4. Hardman JG, Limbird LE. Goodman & Gilmans The Pharmacological Basis of Therapeutics . 9th ed. New York:McGraw-Hill; 1996:1411-1437. 5. McEvoy GK. AHFS Drug Information-2002 . Bethesda, MD:American Society of Health-System Pharmacists; 2002:2974-2979, 2981-2983. 6. Lacy C, Armstrong, LL, Ingrim NB, et al. Drug Information Handbook . 4th ed. Hudson, OH:Lexi-Comp, Inc; 1996:445-447, 451-452. 7. Brunson EL. Benzyl alcohol. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:41-43. 8. Dimethyl sulfoxide [product literature]. Mandeville, LA: Gaylord Chemical Corporation. 9. Weller PJ. Alcohol. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:7-9. 10. Dandiker Y. Propylene glycol. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:442-444.
QUALITY CONTROL
Quality assessment of this topical solution can include weight and/or volume, specific gravity, active drug assay, color, clarity, rheologic properties and/or pourability, physical observation, and physical stability. 2
DISCUSSION
Many patients prefer a dosage form that is easily applied and leaves almost no film or residue. This formulation meets that requirement and is also clear, colorless, and elegant. Estriol is a naturally occurring estrogen purported to exert a selective action on the cervix, vagina, and vulva and to produce relatively little effect on the endometrium. It is a crystalline powder that is practically insoluble in water but is soluble in alcohol and vegetable oils. 3,4 Estrone is a naturally occurring steroidal estrogen. It occurs as small white crystals or as a white to creamy white crystalline powder that is odorless and is practically insoluble in water. It is soluble to the extent of 4 mg/mL in alcohol and is soluble in vegetable oils. 4-6
298
Estriol 2-mg/mL Topical Gel
Rx
For 100 mL Estriol Hydroxyethyl cellulose (HEC) Alcohol, 95% Puried water qs 200 mg 3g 35 mL 100 mL
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Use a magnetic mixer to dissolve the estriol in the alcohol. Add about 60 mL of the purified water as the mixture is stirred. 4. Increase the stirrer speed to obtain a moderate vortex and add the HEC slowly by sprinkling it onto the mixture. 5. Add sufficient purified water to volume, mix well, cover, and allow the mixture to set for about 2 hours so that complete hydration occurs. 6. Package and label.
PACKAGING
LABELING
For external use only. Use only as directed. Keep out of the reach of children.
STABILITY
A beyond-use date of 30 days can be used for this preparation. 1
USE
Estriol topical gel is used in bioidentical hormone replacement therapy.
QUALITY CONTROL
Hydroxyethyl cellulose (HEC) occurs as a light tan or cream to white, odorless, tasteless powder. It is used as a coating agent, a suspending agent, a tablet binder, a thickening agent, and a viscosity-increasing agent. It is also widely used in cosmetics and pharmaceuticals. The pH of a 1% aqueous solution of HEC is in the range of 5.5 to 8.5. HEC powder has a bulk density in the range of 0.35 g/mL to 0.6 g/mL and a density of about 1.38 to 1.4. HEC is soluble in hot or cold water but is practically insoluble in acetone, in ethanol, and in most organic solvents. Solutions can be easily made by dispersing HEC in mildly agitated water at room temperature. When HEC powder has been thoroughly wetted, increasing the temperature to 60C to 70C accelerates dispersion. Adding a small amount of an alkalizing agent to the solution enhances dispersion, and preparing a slurry of HEC powder and a nonaqueous solvent (eg, ethanol) before dispersion also facilitates that process. HEC is a stable powder, but it is hygroscopic. Solutions of HEC are more stable at a pH value above 5, even though the dispersions are categorized as stable between pH values of 2 and 12. Dispersions are subject to enzymatic degradation, so antimicrobial preservatives should be used if prolonged storage is required. 5 Alcohol (ethyl alcohol, ethanol, grain alcohol) is a clear, colorless, mobile, volatile liquid with a slight, characteristic odor and a burning taste. Alcohol, USP refers to 95% ethanol, and dehydrated alcohol refers to 99.5% alcohol. The specific gravity of alcohol is between 0.812 and 0.816, and its boiling point is 78.15C. Alcohol is miscible with chloroform, with glycerin, and with water, and its solutions may be sterilized by autoclaving or by filtration. It should be stored in a cool place. Alcohol is incompatible with oxidizing materials in acidic conditions. 6 Purified water is water that is obtained by distillation, ion exchange, reverse osmosis, or some other suitable process. It has a specific gravity of 0.9971 at room temperature, a melting point at 0C and a boiling point at 100C. It is miscible with most polar solvents and is chemically stable in all physical states (ice, liquid, and steam).7
References
1. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXV/National Formulary 20. Rockville , MD:US Pharmacopeial Convention, Inc; 2001:2053-2057. Allen LV Jr. Standard operating procedure for performing physical quality assessment of ointments/creams/gels. IJPC 1998;2:308-309. Reynolds JEF, ed. MARTINDALE: The Extra Pharmacopoeia . 30th ed. London: The Pharmaceutical Press; 1993:1192. Hardman JG, Limbird LE. Goodman & Gilmans The Pharmacological Basis of Therapeutics . 9th ed. New York:McGraw-Hill; 1996:1411-1437. Harwood RJ. Hydroxyethyl cellulose. In: Kibbe A, ed . Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:240-243. Weller PJ. Alcohol. In: Kibbe A, ed . Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:7-9. Ellison A, Nash RA, Wilkin MJ. Water. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:580-584.
DISCUSSION
An alcohol-containing gel is often prescribed when the patient desires a topical product that is nongreasy and that disappears on the skin. When the solvent in this formulation evaporates, a thin film of HEC forms on the skin. The estriol is trapped in that film, and the residual alcohol-water, body perspiration, and oils in the skin, which are also trapped, enable the estriol to be slowly absorbed. Estriol is a naturally occurring estrogen that is purported to have a selective action on the cervix, vagina, and vulva and to produce relatively little effect on the endometrium. It is often administered in combination with estrone and estradiol in estrogen replacement therapy. It is a crystalline powder that is practically insoluble in water but is soluble in alcohol and in vegetable oils. In the body, estradiol is reversibly oxidized to estrone, and both estradiol and estrone can be converted to estriol. 3,4
2. 3. 4. 5.
6.
7.
Estriol 2-mg and Estradiol 0.5-mg/0.1-mL Sublingual Drops
Rx
For 10 mL Estriol Estradiol Saccharin Silica gel Almond oil Flavor 200 mg 50 mg 100 mg 200 mg 10 mL qs
qs
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh each ingredient. 3. Triturate the estriol, estradiol, saccharin, and silica gel in a mortar. 4. Add a small amount of almond oil and triturate to a smooth paste. 5. Add sufficient flavor and almond oil to volume and mix well. 6. Package and label.
PACKAGING
LABELING
Use only as directed. Keep away from children.
STABILITY
tainers. Estradiol is indicated in the treatment of atrophic vaginitis; atrophic dystrophy of the vulva; menopausal symptoms, including mild-to-severe vasomotor symptoms; female hypogonadism; and the symptoms caused by ovariectomy, primary ovarian failure, inoperable breast cancer, or inoperable cancer of the prostate. 4-6 Saccharin (C 7 H 5 NO 3 S, MW 183.18) is an intense sweetening agent that is widely used in commercial products including foods, drinks, and pharmaceuticals. As a sweetener in oral formulations, it is usually used in concentrations ranging from 0.02% to 0.5%. It is about 500 times sweeter than sucrose and can be used to mask some unpleasant tastes of various medications. It occurs as odorless white crystals or as a white crystalline powder. Saccharin is soluble to the extent of 1 g in 290 mL of water, in 50 mL of glycerin, and in 31 mL of 95% ethanol.7 In aqueous preparations, the sodium salt is used. 7 Silica gel occurs as a fine, white hygroscopic, odorless, amorphous powder with a usual particle size range of between 2 and 10 . It is insoluble in water, in alcohol, and in other organic solvents but is soluble in hot solutions of alkali hydroxides. It is used as a desiccant, a suspending agent, and a viscosity-increasing agent. 1,8 Almond oil (sweet almond oil) is a clear, pale, straw-colored or colorless, almost odorless, oily liquid with a bland, nutty taste. It contains primarily glycerides of oleic acid, as well as smaller amounts of linoleic, myristic, and palmitic acids. Its specific gravity is 0.910 to 0.915, and it is slightly soluble in alcohol but is miscible with mineral oil. It should be protected from light, stored in a cool place, and packaged in well-filled, airtight containers. Almond oil is used as a nutritive (15 mL to 30 mL) and as an emollient. 1
USE
Estriol and estradiol sublingual drops are used in bioidentical hormone replacement therapy.
References
1. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXV/National Formulary 20 . Rockville, MD:US Pharmacopeial Convention, Inc; 2001:2053-2057, 2365, 2396, 2505-2506. Allen LV Jr. Standard operating procedure for quality assessment of oral and topical liquids. IJPC ; 1999;3:146-147. Reynolds JEF, ed. MARTINDALE: The Extra Pharmacopoeia . 30th ed. London:The Pharmaceutical Press; 1993:1192. Hardman JG, Limbird LE. Goodman & Gilmans The Pharmacological Basis of Therapeutics . 9th ed. New York:McGraw-Hill; 1996:1411-1437. McEvoy GK. AHFS Drug Information-2002 . Bethesda, MD:American Society of Health-System Pharmacists; 2002:2974-2979, 2981-2983. Lacy C, Armstrong, LL, Ingrim NB, et al. Drug Information Handbook . 4th ed. Hudson, OH:Lexi-Comp, Inc; 1996:445-447, 451-452. Higton FR, Thurgood DM. Saccharin. In: Wade A, Weller PJ. Handbook of Pharmaceutical Excipients , 2nd Ed. Washington, DC:American Pharmaceutical Association; 1994:415-417. Morefield E. Colloidal silicon dioxide. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:143-145.
QUALITY CONTROL
Quality assessment of this topical solution can include weight and/or volume, specific gravity, active drug assay, color, clarity, rheologic properties and/or pourability, physical observation, and physical stability. 2
2. 3. 4. 5. 6. 7.
DISCUSSION
Estriol is a naturally occurring estrogen that is purported to exert a selective action on the cervix, vagina, and vulva and to produce relatively little effect on the endometrium. It is a crystalline powder that is practically insoluble in water but is soluble in alcohol and in vegetable oils. In the body, estradiol is reversibly oxidized to estrone, and both estradiol and estrone can be converted to estriol. 3,4 Estradiol is a naturally occurring steroidal estrogen. It occurs as white or creamy white small crystals or as a crystalline powder. It is odorless and hygroscopic, and it is practically insoluble in water but has a solubility of about 35.7 mg/mL in alcohol at 25C. It should be stored in tight, light-resistant con-
8.
300
Testosterone 25 mg in Oil Capsules
Rx
For 100 capsules Testosterone Peanut or sesame oil qs 2.5 g 30 mL
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Add the peanut or sesame oil in small portions to the testosterone and mix to form a smooth paste. 4. Add additional peanut or sesame oil to about 25 mL and mix well. 5. Transfer the mixture to a graduate and add sufficient peanut or sesame oil to volume and mix well. 6. Load a capsule machine with 100 No. 1 empty gelatin snaplock capsules. 7. Use a micropipette to add 300 L of the mixture to each of the 100 capsules. 8. Remove the filled capsules from the capsule machine. 9. Package and label.
PACKAGING
Package in a tight, light-resistant container.
layed male puberty and in the treatment of postpartum breast pain and engorgement, inoperable breast cancer, and male hypogonadism. 3-5 Peanut oil (earthnut oil, groundnut oil, katchung oil, nut oil) is a colorless or pale yellow liquid with a bland, nutty taste and a faint nutty odor. It is usually composed of the glycerides of about 56% oleic acid, 26% linoleic acid, 8.3% palmitic acid, and less than 5% of each of the following: arachidic acid, behenic acid, stearic acid, and lignoceric acid. It is used as an oleaginous vehicle and solvent. It has a density of about 0.910 to 0.915 and a freezing point of -5C. If cooled to about 3C, it becomes cloudy and will partially solidify as the temperature is further lowered. It is very slightly soluble in 95% ethanol, is soluble in oils, and is miscible with chloroform. Peanut oil is relatively stable but can slowly thicken and become rancid when exposed to air. Storage in well-filled, airtight, light-resistant containers is recommended. 6 Sesame oil (benne oil, gingelly oil, gingili oil, jinjili oil, teel oil) is a clear, pale yellow liquid with a slight, pleasant odor and a bland taste. It usually consists of about 0.8% arachidic acid, 40.4% linoleic acid, 45.4% oleic acid, 9.1% palmitic acid, and 4.3% stearic acid. It is used as an oleaginous vehicle and solvent. Sesame oil solidifies at about -4C and has a density of about 0.918 g/cm3. It is insoluble in water and is practically insoluble in 95% ethanol. It is more stable than most fixed oils and does not readily become rancid because of the antioxidant effect of some of its constituents.7
References
1. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXV/National Formulary 20 . Rockville, MD:US Pharmacopeial Convention, Inc; 2001:2053-2057. Allen LV Jr. Standard operating procedure for quality assessment of special hard-gelatin capsules. IJPC 1999;3:312-313. McEvoy GK, ed. AHFS Drug Information-2002 . Bethesda, MD:American Society of Health-System Pharmacists; 2002:2944-2951. Testosterone. In: Lund W, ed. The Pharmaceutical Codex . 12th ed. London:The Pharmaceutical Press; 1994:1135-1136. Hardman JG, Limbird LE. Goodman & Gilmans The Pharmacological Basis of Therapeutics . 9th ed. New York:McGraw-Hill; 1996:1441-1455. Kibbe AH. Peanut oil. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:360-361. Cable CG. Sesame oil. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:460-461.
LABELING
Store in a cool, dry place. Storage in a refrigerator is recommended.
STABILITY
No stability studies have been reported on this specific formulation. A beyond-use date of 6 months can be used. 1
2. 3. 4. 5. 6.
USE
Testosterone-in-oil capsules are used for bioidentical hormone replacement in men.
QUALITY CONTROL
Quality assessment for oil-filled hard gelatin capsules can include average weight, weight variation, dissolution of the capsule shell, physical appearance, physical stability, and active drug assay. 2
7.
DISCUSSION
Testosterone occurs as white or slightly creamy white crystals or crystalline powder that is odorless and stable in air. It is practically insoluble in water and is soluble 1 g in 5 mL of ethanol, in 2 mL of chloroform, and in 100 mL of ether. It is soluble in vegetable oils and melts between 153C and 157C. Testosterone is subject to photodegradation in the presence of light. It is not very bioavailable when given as an oral-swallow preparation, but it is absorbed when administered buccally and sublingually. The different esters of testosterone are hydrolyzed to free testosterone and are subsequently metabolized as is testosterone itself. Testosterone is indicated as androgen replacement for de-
Testosterone 50-mg/mL Topical Gel
Rx
For 100 mL Testosterone Hydroxyethyl cellulose (HEC) Alcohol, 95% Puried water qs 5g 3g 35 mL 100 mL
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Use a magnetic mixer to dissolve the testosterone in the alcohol and add about 60 mL of the purified water. 4. Increase the stirrer speed to obtain a moderate vortex and add the HEC slowly by sprinkling it onto the mixture. 5. Add sufficient purified water to volume, mix well, cover, and allow the mixture to set for about 2 hours so that complete hydration occurs. 6. Package and label.
PACKAGING
LABELING
For external use only. Use only as directed. Keep out of the reach of children.
STABILITY
A beyond-use date of 30 days can be used for this preparation. 1
USE
Testosterone topical gel is used for bioidentical hormone replacement in men.
QUALITY CONTROL
cosity-increasing agent. It is also widely used in cosmetics and pharmaceuticals. HEC is a nonionic, water-soluble polymer used especially as a thickening agent in ophthalmic formulations. The pH of a 1% aqueous solution is in the range of 5.5 to 8.5. HEC is soluble in hot or cold water but is practically insoluble in acetone, in ethanol, and in most organic solvents. Solutions can be easily made by dispersing the HEC in mildly agitated water at room temperature. When the powder has been thoroughly wetted, increasing the temperature to 60C to 70C accelerates dispersion. Adding a small amount of an alkalizing agent to the solution enhances dispersion, and preparing a slurry of the HEC powder with a nonaqueous solvent (eg, ethanol) before dispersion also facilitates that process. HEC is a stable powder, but it is hygroscopic. Solutions are more stable at a pH value above 5, even though the dispersions are categorized as stable between pH values of 2 and 12. Dispersions are subject to enzymatic degradation, so if prolonged storage is required, antimicrobial preservatives should be used. 6 Alcohol (ethyl alcohol, ethanol, grain alcohol) is a clear, colorless, mobile, volatile liquid with a slight, characteristic odor and a burning taste. Alcohol, USP refers to 95% ethanol, and dehydrated alcohol refers to 99.5% alcohol. The specific gravity of alcohol is between 0.812 and 0.816, and its boiling point is 78.15C. It is miscible with chloroform, with glycerin, and with water, and its solutions may be sterilized by autoclaving or by filtration. It should be stored in a cool place. Alcohol is incompatible with oxidizing materials in acidic conditions. When combined with alkalies, alcohol may darken in color. Aqueous solutions of organic salts or acacia may precipitate when combined with alcohol. 7 Purified water is water that is obtained by distillation, ion exchange, reverse osmosis, or some other suitable process. It has a specific gravity of 0.9971 at room temperature, a melting point at 0C, and a boiling point at 100C. It is miscible with most polar solvents and is chemically stable in all physical states (ice, liquid, and steam).8
References
1. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXV/ National Formulary 20 . Rockville, MD:US Pharmacopeial Convention, Inc; 2001:2053-2057. Allen LV Jr. Standard operating procedure for performing physical quality assessment of ointments/creams/gels. IJPC 1998;2:308-309. McEvoy GK, ed. AHFS Drug Information-2002 . Bethesda, MD:American Society of Health-System Pharmacists; 2002:2944-2951. Testosterone. In: Lund W, ed. The Pharmaceutical Codex . 12th ed. London:The Pharmaceutical Press; 1994:1135-1136. Hardman JG, Limbird LE. Goodman & Gilmans The Pharmacological Basis of Therapeutics . 9th ed. New York:McGraw-Hill; 1996:1441-1455. Harwood RJ. Hydroxyethyl cellulose. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:240-243. Weller PJ. Alcohol. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:7-9. Ellison A, Nash RA, Wilkin MJ. Water. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:580-584.
DISCUSSION
This alcohol-containing gel is nongreasy, cooling, and soothing, and it disappears upon application. After the solvent has evaporated, the HEC forms a thin, occlusive film on the skin. That film entraps the testosterone, which is then slowly absorbed into the skin. Testosterone occurs as white or slightly creamy white crystals or crystalline powder that is odorless and stable in air. It is practically insoluble in water and is soluble 1 g in 5 mL of ethanol, in 2 mL of chloroform, and in 100 mL of ether. It is soluble in vegetable oils. It melts between 153C and 157C. Testosterone is subject to photodegradation in the presence of light. It is not very bioavailable when given as an oral-swallow preparation, but it is absorbed when administered buccally and sublingually. 3-5 Hydroxyethyl cellulose (HEC) occurs as a light tan or cream to white, odorless, tasteless powder. It is used as a coating agent, a suspending agent, a tablet binder, a thickening agent, and a vis-
2. 3. 4. 5. 6.
7.
8.
302
S U P P O R T
Introduction
Creams, which are sometimes referred to as ointments, are opaque, soft solids or thick liquids intended for external application. Creams consist of medicaments dissolved or suspended in waterremovable bases (vanishing cream) or emollient bases. Creams are of two types: water-in-oil (w/o) or oil-in water (o/w). The term cream is most frequently applied to soft, cosmetically acceptable, o/w preparations. Creams are usually applied to moist, weeping lesions because they produce a rather drying effect; the fluids of such lesions are miscible with the aqueous external phase of the cream applied. Several high-quality dermatologic cream bases are currently available. It is important for the compounding pharmacist to know the ingredients of the vehicle (which may itself contain active ingredients) used in cream formulations for patients with a sensitivity to certain preservatives, perfumes, etc (Table 1). The following factors should be considered when a cream is compounded: 1. Powders must be in a very fine state of subdivision before they are incorporated into the base used in the cream. That fine texture is necessary because a gritty preparation may injure or irritate the skin and impede the healing process and because more finely divided powders increase the medication surface area and thus improve the effectiveness of treatment. A mortar and pestle, a mechanical grinder, or a pill tile and spatula can be used to achieve the desired degree of fineness. 2. Levigating agents must be compatible with the vehicle used. The levigating agents used in creams are usually selected according to compatibility with the external phase of the emulsion. For example, the levigating agent for the o/w emulsions described in this article should be water, glycerin, propylene glycol, polyethylene glycol 300 or 400, alcohol, or a liquid that is miscible with water. 3. When a levigating agent is necessary for the incorporation of insoluble powders, geometric dilution should be used to ensure thorough mixing of the active ingredient with the vehicle. 4. When soluble powders are incorporated, solvents that have a low vapor pressure (water, glycerin, propylene glycol) should be used. Volatile solvents should usually not be used (especially in oleaginous bases), because if the solvent evaporates, the drug may crystallize out in the base and the formed crystals can cause irritation when they are applied to the skin. 5. A water bath should be used for vehicles that must be heated before an emulsion is prepared. In those cases, do not heat the cream vehicle more than necessary. Remember that water is lost during heating. Continuing Education Objectives: After reading and studying the article, the reader will be able to: 1. Describe the composition of the more commonly used oil-in-water cream vehicles 2. Select a suitable preservative-free vehicle 3. Select suitable vehicles when specic ingredients (lanolin, simethicone) are or are not desired 4. Select a suitable levigating or solubilizing agent for the incorporation of active drugs into oil-in-water vehicles.
Featured Excipient: TOPICAL OIL-INWATER CREAM BASES

Loyd V. Allen, Jr, PhD, RPh 6. A cream (o/w emulsion) can often be diluted with purified water or an aromatic water such as rose water to prepare a lotion. The water should be added slowly to the cream while the mixture is continuously stirred. However, this results in the dilution of any added preservative, and bacterial growth in the lotion might not be inhibited. Therefore, a short beyond-use date should be assigned to lotions prepared in that manner.
Purpose of the Ingredients

In the products used as examples in this article, water is the ingredient in the external phase of the cream. The oil phase or emollient ingredients include isopropyl palmitate, lanolin oil, mineral oil, and white petrolatum. Emulsiers and surfactants include ceteareth-20, cetearyl alcohol, glyceryl monostearate, glyceryl stearate, polyethylene glycol monostearate, polyoxyethylene stearyl ether, sodium cetearyl sulfate, and sodium lauryl sulfate. Humectants include glycerin, propylene glycol, and sorbitol. Stiffeners include synthetic beeswax, cetyl esters wax, and stearyl alcohol. Simethicone provides water repellency and coating. Preservatives include butylparaben, calcium acetate, captan, imidazolidinyl urea, methylparaben, and propylparaben.
Types of Oil-in-Water Creams

Acid Mantle1 (Doak Dermatologics, West Fairfield, New Jersey) is a skin-acidier cream formulated to provide an acid pH of 5.5, which fosters skin healing. It is promoted as a highly effective compounding base that provides a protective barrier against harmful bacteria and promotes a superior healing environment for damaged skin. Aquaphilic Ointment2 (Medco Lab, Inc, Sioux City, Iowa) is a hydrated hydrophilic ointment. Cream Base3 (Medco Lab, Inc) is a vanishing cream base. Dermabase4 (Paddock Laboratories, Inc, North Minneapolis, Minnesota) is an elegant emulsion cream base that has a slight, pleasant odor. It is used to compound dermatologic preparations. It is a washable, unscented, o/w emulsion base that can also be used alone to alleviate dry skin, particularly when the use of a waterwashable base is indicated. Dermabase retains pharmaceutical integrity and elegance in spite of the incorporation of any of a wide variety of agents. Water can be added to Dermabase to produce a lotion. Dermovan5 (Healthpoint, Ltd, San Antonio, Texas) is a lanolin-free, water-miscible vehicle that is compatible with a wide range of ingredients. It is a vanishing cream base that is especially suitable for water-soluble additives. The pH of Dermovan ranges from 3.0 to 4.0.
S U P P O R T
Table 1. Composition of Various Cream Bases.

Acid Mantle Cetearyl alcohol Sodium lauryl sulfate Sodium cetearyl sulfate Petrolatum Glycerin Synthetic beeswax Mineral oil Methylparaben Aluminum sulfate Calcium acetate White potato dextrin Puried water Aquaphilic Ointment Stearyl alcohol White petrolatum Isopropyl palmitate Sorbitol and/ or propylene glycol Preservatives Sodium lauryl sulfate Puried water qs Cream Base Stearyl alcohol Cetyl esters wax Glyceryl monostearate Polyoxyethylene stearyl ether Sorbitol Isopropyl palmitate Methylparaben Propylparaben Captan Puried water Not available Not available Not available Not available Not available Not available Not available Not available Not available Not available Not available Not available 20% 20% 0.4% 10% 0.2% 1% 100% 14% 3.5% 2% 3% 10% 2% 0.16% 0.4% 0.5% 65% Dermabase Cream Mineral oil Not available Petrolatum Not available Cetostearyl alcohol Not available Propylene glycol Not available Sodium lauryl sulfate Not available Isopropyl palmitate Not available Imidazolidinyl urea Not available Methylparaben Not available Propylparaben Not available Puried water Approximately 55% Dermovan Glyceryl stearate Stearamidoethyl diethylamine Glycerin Mineral oil, light Cetyl esters Cetyl alcohol Butylparaben Methylparaben Propylparaben Puried water Not available Not available Not available Not available Not available Not available 0.22% 0.1% 0.04% Not available 0.25 g 0.15 g 10 g 120 g 250 g 250 g 370 g Lanaphilic Ointment Stearyl alcohol White petrolatum Sorbitol and/ or propylene glycol Preservatives Sodium lauryl sulfate Lanolin oil Isopropyl palmitate Puried water qs Vanicream White petrolatum Cetearyl alcohol Ceteareth-20 Sorbitol solution Propylene glycol Simethicone Glyceryl monostearate Polyethylene glycol monostearate Velvachol White petrolatum Mineral oil, light Stearyl alcohol Sodium lauryl sulfate Cholesterol Butylparaben Methylparaben Propylparaben Puried water qs 20% 20% 10% 0.2% 1% 2% 1.5% 100% Not available Not available Not available Not available Not available Not available Not available Not available
Hydrophilic Ointment, USP Methylparaben Propylparaben Sodium lauryl sulfate Propylene glycol Stearyl alcohol White petrolatum Puried water
Not available Not available Not available Not available Not available 0.1% 0.1% 0.04% 100%
Hydrophilic Ointment, USP6 The classic o/w emulsion base has undergone only one reformulation since it was first cited in the United States Pharmacopeia XIII in 1947; glycerin has been replaced with propylene glycol. It has been commercially marketed by a number of firms. Lanaphilic Ointment7 (Medco Lab, Inc) is a brand of hydrated hydrophilic ointment that contains lanolin. Vanicream8 (Pharmaceutical Specialties, Inc, Rochester, Minnesota) contains no perfume, lanolin, formaldehyde, parabens, or dyes. It is promoted as a pharmaceutically elegant moisturizing cream that can be used to produce long-lasting, effective hydration. Vanicream is compatible with a number of ingredients. Velvachol9 (Healthpoint, Ltd) is a water-miscible vehicle that is lanolin-free, nonsticky, nongreasy, and odorless. The base is compatible with a wide variety of chemicals used in topical therapy and is especially suitable for use with fat-soluble additives. The pH of Velvachol ranges from 5.5 to 7.5. It is stable and neutral in reaction
and washes easily from the skin, hair, and clothing before and after the incorporation of medications. It may be irritating to the eye. Velvachol is physically compatible with acids, bases, strong electrolytes, and many other medications commonly applied to the skin.
References
1. 2. 3. 4. 5. 6. 7. 8. 9. Acid Mantle [package insert]. West Fairfield, NJ:Doak Dermatologics. Aquaphilic Ointment [package insert]. Sioux City, IA:Medco Lab, Inc. Cream Base [package insert]. Sioux City, IA:Medco Lab, Inc. Dermabase [package insert]. North Minneapolis, MN:Paddock Laboratories, Inc. Dermovan [package insert]. San Antonio, TX:Healthpoint, Ltd. Hydrophilic Ointment, USP. United States Pharmacopeia XXV/National Formulary 20. Rockville, MD:US Pharmacopeial Convention Inc; 2001:224. Lanaphilic Ointment [package insert]. Sioux City, IA:Medco Lab, Inc. Vanicream [package insert]. Rochester, MN:Pharmaceutical Specialties, Inc. Velvachol [package insert]. San Antonio, TX:Healthpoint, Ltd.
304
S U P P O R T
Calculations
1
Two estradiol transdermal patches are compared below: Vivelle Surface area = 11 cm 2 Total estradiol content = 3.28 mg Vivelle-Dot Surface area = 3.75 cm 2 Total estradiol content = 0.585 mg Both of those patches release estradiol at a rate of 0.0375 mg/24 hr and should be worn for 3 to 4 days and then replaced with a new patch. 1 Shelly J. Prince, PhD, RPh Southwestern Oklahoma State University School of Pharmacy Weatherford, Oklahoma A patient has been using Vivelle patches 0.0375 mg/day and has requested to change to a bioidentical hormone replacement regimen. Her physician prescribes the following formula 2 :
A. How much drug remains in each patch after 4 days? 0.0375 mg/24 hr x 24 hr/day x 4 days = 0.15 mg released from patch Vivelle: 3.28 mg - 0.15 mg = 3.13 mg remaining Vivelle-Dot: 0.585 mg - 0.15 mg = 0.435 mg remaining B. What percent of the total amount of drug in each patch remains after 4 days? Vivelle: 3.13 mg/3.28 mg x 100 = 95.43% Vivelle-Dot: 0.435 mg/0.585 mg x 100 = 74.36% C. How long would it take for all of the drug to be released from each patch if the release rate remains constant until all the drug is delivered? Vivelle: 3.28 mg x 1 day/0.0375 mg = 87.47 days Vivelle-Dot: 0.585 mg x 1 day/0.0375 mg = 15.6 days D. If a patient mistakenly applies a new patch every 3 to 4 days without removing the old patch, what is the maximum amount of estradiol that she will receive from the patches daily? The patient will apply a new patch approximately every 3.5 days, and estradiol will be continuously released from the patches until no more drug remains in the patch. Therefore, the information from part 1D above can be used to estimate how many patches will be applied before all the drug has been released from the rst patch. Vivelle: 87.47 days x 1 patch/3.5 days = 24.99 patches, or 25 patches Vivelle-Dot: 15.6 days x 1 patch/3.5 days = 4.46 patches, or 5 patches Vivelle: The patient will apply approximately 24 patches before the rst patch releases all its medication (total = 25 patches). Therefore, the total amount of estradiol that she will receive is: 25 patches x 0.0375 mg/day/patch = 0.9375 mg/day Vivelle-Dot: The patient will apply approximately 4 patches before the rst patch releases all its medication (total = 5 patches). Therefore, the total amount of estradiol she will receive is: 5 patches x 0.0375 mg/day/patch = 0.1875 mg/day
Rx Estriol Estradiol Ethoxy diglycol or propylene glycol Lecithin and isopropyl palmitate solution Pluronic F127 20% solution qs
200 mg 50 mg 1 mL 22 mL 100 mL
How much of this mixture must she apply daily to receive a dose of estradiol equivalent to that of a Vivelle patch? 0.0375 mg/day x 100 mL/50 mg = 0.075 mL
The following is a formula for 100 triple estrogen 2.5-mg tablet triturates 3 : 200 mg 25 mg 25 mg 600 mg 5.65 g qs
Rx Estriol Estrone Estradiol Polyethylene glycol 3350 Lactose 50% Ethanol in puried water
How would you prepare this formula if you used a balance with a minimum weighable quantity of 90 mg? To weigh the quantities of estrone and estradiol accurately, the aliquot method can be used to prepare a dilution as follows: 25 mg x 4 = 100 mg each of estrone and estradiol to weigh The weight of the aliquot must be greater than or equal to the minimum weighable amount of the balance, so 100 mg can be used as the aliquot. 100 mg x 4 = 400 mg of dilution to prepare 400 mg - 100 mg (estrone) - 100 mg (estradiol) = 200 mg of lactose to weigh for the dilution The dilution will consist of 100 mg of estrone, 100 mg of estradiol, and 200 mg of lactose. A 100-mg aliquot that contains 25 mg of estrone, 25 mg of estradiol, and 50 mg of lactose can be weighed from this dilution. The other ingredients can then be added to this aliquot, and the tablet triturates can be prepared.
References
1. CliniSphere 2.0 [book on CD Rom]. St. Louis, MO: Facts and Comparisons; 2002. 2. Estriol 2 mg/mL and estradiol 0.5 mg/mL in Pluronic lecithin organogel. IJPC 2001;5:374. 3. Triple estrogen 2.5 mg tablet triturates. IJPC 2000;4:467.
S U P P O R T
Standard Operating Procedure for the
Quality Assessment of Nasal Solutions

Purpose
The purpose of this procedure is to provide a method of documenting physical quality assessment tests and observations of nasal solutions. or measure the quantity in a graduate. pH Calibrate the pH meter and then determine the apparent pH of the product. Specic Gravity If a pycnometer is available, verify that it is clean and dry. Weigh the empty pycnometer. Fill the pycnometer with the prepared product and be careful not to entrap air bubbles. Weigh the pycnometer a second time. Subtract the first weight from the second weight to obtain the net weight of the product. Divide this weight (in grams) by the volume (in milliliters) of the pycnometer to obtain the density and/or specific gravity of the product. Active Drug Assay Results Have representative samples of the product assayed for active drug content by a contract analytical laboratory, as appropriate. Stability can be assessed by storing samples of the same batch of the product at room temperature or in a refrigerator or freezer and repeating the assay of the stored samples over time. Product Color It may be advisable to use a color chart to determine the color of the product, if appropriate. Clarity Evaluate clarity by visual inspection. A light-dark background may be used for that evaluation. Physical Observation Describe the appearance and organoleptic qualities of the product. Physical Stability Prepare an additional quantity of the product on which to conduct physical stability observations, package that sample, and label it. Observe the product weekly for signs of discoloration, foreign materials, gas formation, mold growth, etc. Record a descriptive observation of the product on the Physical Quality Assessment Form for Nasal Solutions at each observation interval. The form includes lines for four observations. Sterility Conduct a sterility test on a representative sample according to the standard operating procedures of the pharmacy or send a representative sample to a contract laboratory for testing. Osmolality Determine the osmolality of the sample according to the standard operating procedures of the pharmacy or send a representative sample to a contract laboratory for testing.
Materials
Balance, graduates, pH meter, osmometer (optional), pycnometer (optional), sterility test equipment (optional).
Procedures
Conduct the appropriate tests and record test results and observations on the Physical Quality Assessment Form for Nasal Solutions. Weight and Volume Accurately weigh the product on a balance
Analytical Research Laboratories
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Pharmaceutical analysis including USP methods Sterility and endotoxin testing Stability studies (shelf life determination)
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306
S U P P O R T
PHYSICAL QUALITY ASSESSMENT FORM FOR NASAL SOLUTIONS

Product Lot/Rx number Characteristic Weight/volume pH Specific gravity Active drug assay results Initial assay After storage no. 1 After storage no. 2 Color of product Clarity Physical observation Physical stability Sterility Osmolality Sterile 290 mOsm/kg Sterile Clear 1 2 3 4 5 Opaque Theoretical Actual Normal Range Date
Sample set aside for physical observation If yes, results: Date Observation
Yes
No
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Stability of Tubocurarine Chloride Injection at Ambient Temperature and 4C in Polypropylene Syringes

Abstract
The stability of 3 mg/mL tubocurarine chloride (Figure 1) injection in 3-mL polypropylene syringes stored at ambient temperature and at 4C for up to 90 days was investigated. A high-performance liquid chromatographic stability-indicating assay was used to determine concentration levels of tubocurarine chloride injection 0, 1, 4, 7, 15, 30, 45, 60, and 90 days after preparation of the syringes. Benzyl alcohol, which was used as a preservative, did not interfere with the assay. At 25C, the loss in potency was less than 10% after the syringes had been stored for 45 days; at 4C, that loss was less than 1% after 90 days of storage. The pH of tubocurarine chloride injection did not change appreciably during the 90day study period. James T. Stewart, PhD Meredith L. Storms, BS Flynn W. Warren, MS, RPh Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, University of Georgia Athens, Georgia loading polypropylene syringes with tubocurarine chloride injection saved time for hospital personnel and reduced costs previously increased by wasted materials; however, the stability of that solution in polypropylene syringes had to be assessed. 2-4 The sorption of tubocurarine chloride injection to plastic intravenous fluid bags has been studied 5,6 ; however, stability studies for tubocurarine chloride injection stored in polypropylene syringes for 90 days at ambient temperature under continuous fluorescent light and 4C are not available. The purpose of this study was to investigate the stability of 3 mg/mL tubocurarine chloride injection prepared in polypropylene syringes. The syringes were prepared at ambient temperature (23C 1C) and were stored either at ambient temperature or under refrigeration (4C) for up to 90 days. Each preparation was assayed for drug concentration, and pH was measured 0, 1, 4, 7, 15, 30, 45, 60, and 90 days after the syringes had been prepared. The United States Pharmacopeia XXIV/National Formulary 19 high-performance liquid chromatographic assay for tubocurarine chloride injection was modified to determine the drug concentration in each sample. 7
Introduction
Tubocurarine chloride is a neuromuscular blocking agent. 1 Because tubocurarine chloride injection (3 mg/mL) is not available prepackaged in syringes, hospital pharmacies aseptically preload tubocurarine chloride injection into sterile syringes and store the resultant dosage form for short periods at room temperature or in a refrigerator or freezer. In a local hospital pharmacy, pre-
Figure 1. Chemical Structure of Tubocurarine Chloride.
H3CO CH3 N+ HO O CH3 CI- . HCl
Materials and Methods

Chemicals and Reagents
All chemicals (J.T. Baker, Phillipsburg, New Jersey) were highperformance liquid chromatography (HPLC) grade. The tubocurarine chloride injection, USP was from Lot 69165DK obtained from Abbott Laboratories (North Chicago, Illinois). The tubocurarine chloride reference standard was purchased from the United States Pharmacopeial Convention, Inc (Rockville, Maryland).
Equipment
The HPLC system consisted of a pump (Model 760, Micromeritics, Norcross, Georgia), an autosampler (Model 728, Micromeritics) equipped with a 50-L loop, an ultraviolet variable wavelength detector (Model 757, Kratos, Ramsey, New Jersey) set at 214 nm, and a column (silica, 25 cm, 4.6 mm id, 3m, Phenomenex, Torrance, California). The peak heights were monitored with a Hewlett-Packard Model 3395 integrator (Avondale, Pennsylvania).
OH O N H3C OCH3
Chromatographic Conditions
The isocratic elution was performed at 0.50 mL/min. The mobile phase was prepared by combining acetonitrile-methanol (3:2 % v/v), water, and 25% tetramethylammonium chloride in methanol (27:71:2 % v/v/v) and adjusting the pH to 4.0 with hy-
308
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drochloric acid. The mobile phase was filtered through a 0.45-m polymeric membrane filter (Alltech, Deerfield, Illinois).
Preparation of Injection for Stability Studies

A pooled sample of 3 mg/mL tubocurarine chloride injection was prepared by adding 150 mL of tubocurarine chloride injection (3 mg/mL) to a suitably sized beaker. After having been thoroughly mixed, 6 mL of the solution was removed for the zero-hour assay, and the remaining 144 mL was divided into forty-eight 1.5-mL portions by drawing 1.5 mL of solution into each of forty-eight 3-mL polypropylene syringes (Becton, Dickinson and Company, Franklin Lakes, New Jersey). The syringes were divided into two sets of 24 each; one set was stored in the refrigerator at 4C ( 1C), and the other set was stored at 25C ( 1C) under continuous fluorescent light. On day zero, the pooled sample was assayed, and the pH was measured with a calibrated pH meter. The drug content in each sample was determined by a stability-indicating HPLC assay on days 1, 4, 7, 15, 30, 45, 60, and 90, and the pH values were also recorded.
tubocurarine chloride concentration of 40 g/mL was made. Injections of 50 L were made into the HPLC system to calculate the response factor (RF) for tubocurarine chloride. The solution was prepared fresh before sampling from the syringes was performed on the days listed above.
Degradation of Tubocurarine Chloride

Tubocurarine chloride was forced to degrade under acidic, basic, and oxidative conditions. Under acidic conditions, 1 mL of 0.1 N HC1 was added to 1 mL of tubocurarine chloride (1 mg/mL). The mixture was heated for 15 minutes. It was then cooled, neutralized, diluted to 40 g/mL tubocurarine chloride, and injected into the HPLC. In another experiment, a 1-mL quantity of 0.1 N HCl was substituted with 1 mL of 0.1 N NaOH solution. Tubocurarine chloride (1 mg/mL) was forced to degrade under oxidative conditions produced by the addition of 3% H2O2. Brief, gentle heating stopped the reaction after 1 hour. The solution was diluted to 40 g/mL and was injected into the HPLC.
in the syringes and five injections of the standard solution were made into the HPLC system. Peak heights from the chromatograms were used to calculate the mean response factor (MRF) for each drug standard. The appropriate MRF and the peak height of the analyte in the syringe and standard samples were used to calculate the drug concentration in each analytical sample. The following procedure was used to determine the drug concentration in each analytical sample: A. RF = Drug standard (mg/mL)/Drug peak height of standard. B. Calculate the MRF, which should be based on 5 replicates of the standard. C. Drug concentration (mg/mL) = MRF x drug peak height of sample.
Results
Tubocurarine chloride was forced to degrade under acidic, basic, and oxidative conditions. The objective was to force degradation to observe a 10% to 30% loss of the active drug when compared with the percent of drug loss in the nondegraded tubocurarine chloride. 8 A typical HPLC chromatogram of tubocurarine chloride
Preparation of Assay Solutions

The entire content of each of three syringes stored at ambient temperature and 4C at 1, 4, 7, 15, 30, 45, 60, and 90 days was removed and assayed by means of HPLC. A 1:75 dilution was made; mobile phase was used as the diluent.
Preparation of Standard Solutions

A 1.0-mg quantity of tubocurarine chloride reference standard was added to a 5-mL test tube; 1.0 mL of the mobile phase was then added to produce a concentration of 1.0 mg/mL succinylcholine chloride. A 1:25 dilution that resulted in a
Calculation of Medication Content

Triplicate injections of the analytical samples prepared from the mixtures contained
Figure 2. Typical High-Performance Liquid Chromatogram of Benzyl Alcohol (A) and Tubocurarine Chloride (B) on a Silica Column.
6.6
Table 1. Assay Results of Tubocurarine Chloride Injection Stored at Ambient Temperature and 4C for 90 Days in 3-mL Polypropylene Syringes. a
Detector Response
Time (days) 1 4 7 15 30 45 60 90
a
Percent of the Label Claim Based on 100% on Day Zero 25C (percent RSD)b 4C (percent RSD) b 99.9 (0.0) 99.9 (0.2) 99.6 (0.2) 99.8 (0.2) 98.6 (0.1) 99.8 (0.2) 97.1 (0.1) 99.9 (0.2) 96.3 (0.2) 99.9 (0.2) 92.8 (0.1) 99.9 (0.1) 89.4 (0.2) 99.8 (0.1) 86.7 (0.1) 99.8 (0.2)
8.8
The injections remained clear and the pH values (3.45 0.03) did not change significantly throughout the study. The initial assay indicated that the concentration was 3.01 0.02 mg/mL. RSD = Relative standard deviation (n = 9).
Retention time (minutes)
For assay conditions, see Methods.
P E E R
R E V I E W E D
and the preservative, benzyl alcohol, is shown in Figure 2. The tubocurarine chloride injections stored in 3-mL polypropylene syringes were judged to be stable if the drug levels remained greater than 90% of the initial concentration at the time of preparation.9 The percentages of the initial concentration of tubocurarine chloride injection remaining are shown in Table 1. The potency of tubocurarine chloride injection decreased to 92.8% after 45 days of storage at 25C under continuous fluorescent light. After 60 days at 25C, the potency decreased to 89.4%. At 4C, the loss in potency after 90 days of storage was less than 1%. The pH of the syringe injections did not change appreciably during the study period. The pH of the samples usually ranged from 3.41 to 3.46. According to the results of the Students t -test ( P = 0.0072, 11 df) and because of the assumption that drug concentration and pH value are normally distributed at
both temperatures, the following null hypothesis is retained: During 45 days of storage, temperature does not affect the drug concentration or pH of tubocurarine chloride injection (3 mg/mL) stored in 3-mL polypropylene syringes.
5.
6.
Conclusion
Tubocurarine chloride injection (3 mg/mL) stored in 3-mL polypropylene syringes was stable for 45 days at 25C and for at least 90 days at 4C.
7.
References
1. Foye W, Lenke T, Williams D. Principles of Medicinal Chemistry . 4th ed. Media, PA:Williams and Wilkins; 1995. 2. Vipond A, de Mello W. Drugs used in anaesthetic emergencies: Current practice and a cost analysis of prefilled syringes. Anaesthesia 2000;55:303-304. 3. Ducat CM, Merry AF, Webster CS. Attitudes and practices of New Zealand anaesthetists with regard to emergency drugs. Anaesth Intensive Care 2000;28:692-697. 4. Casasin ET, Roca-Mason A, Soy MD. Distribu-
8.
9.
tion system of anesthetic drugs with preloaded syringes: Stability study. Farmacia Hospitalaria 1996;20:55-59. Trissel LA. Handbook on Injectable Drugs . 11th ed. Bethesda, MD:American Society of HealthSystem Pharmacists, Inc; 2001. Moorhatch P, Chiou W. Interactions between drugs and plastic intravenous fluid bags. Part I. Sorption studies on 17 drugs. Am J Hosp Pharm 1974;31:72-78. United States Pharmacopeial Convention, Inc. United States Pharmacopeia XXIV. Rockville, MD:US Pharmacopeial Convention, Inc; 2000:1554-1555. Weiser W. Developing analytical methods for stability testing . Pharmaceutical Technology 1998;Validation Supplement:20-29. Trissel LA. Avoiding common flaws in stability and compatibility studies of injectable drugs. Am J Hosp Pharm 1983;40:1159-1160.
Address correspondence to: James T. Stewart, PhD, Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30606. E-mail: jstewart@rx.uga.edu
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For advertising information, contact Lauren Bernick PO Box 340205, Austin TX 78734 USA Tel: 800-661- 4572 Fax: 800-494-4572 Email: lbernick@ ijpc.com 310
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Compatibility Screening of Bivalirudin During Simulated Y-Site Administration with Other Drugs
Abstract
The physical compatibility of bivalirudin (Angiomax) with 96 selected other drugs during simulated Y-site injection was evaluated by visual observation, turbidity measurement, and electronic particle content assessment (when appropriate). Five-milliliter samples of bivalirudin 5 mg/mL in 5% dextrose injection were combined with 5 mL of 96 other drugs (anti-infectives, analgesics, antihistamines, diuretics, steroids, or other supportive-care drugs that were either undiluted or diluted with either 5% dextrose injection or 0.9% sodium chloride injection [the diluent for drugs incompatible with 5% dextrose injection]). Visual examinations were performed with the unaided eye in normal, diffuse fluorescent light with a Tyndall beam (a high-intensity monodirectional light beam) to enhance the visualization of small particles and low-level turbidity. The turbidity of each sample was measured as well. The particle content of samples that did not exhibit a visible incompatibility was measured. Evaluation of the samples was performed initially and at 1 and 4 hours after preparation. Eighty-seven of the 96 test drugs were compatible with the bivalirudin dilution during the 4-hour observation period. However, the combination of bivalirudin solution with each of nine drugs resulted in haze formation, microparticulate formation, or gross precipitation. Bivalirudin should not be administered simultaneously with those incompatible drugs. Lawrence A. Trissel, BS, RPh Christopher A. Saenz Division of Pharmacy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas tion was reconstituted with 5 mL of sterile water for injection and was diluted to a concentration of 5 mg/mL in 5% dextrose injection, USP (Lot # C490110, Baxter Healthcare Corporation, Deerfield, Illinois), as is recommended in the product labeling. 1 The 96 secondary additives were studied at the concentrations cited in Table 1. The secondary additives were tested undiluted or diluted in either 5% dextrose injection, USP or in 0.9% sodium chloride injection, USP (Lot # 64-137-JT, Abbott Laboratories, Inc, Abbott Park, Illinois). The epoprostenol (Flolan) was prepared with its special diluent.
Methods
Allen et al 2 reported that the mixing of an intravenous fluid in an administration set with a secondary additive through a Y-injection site occurs in a 1:1 ratio. To simulate this inline mixing, a 5-mL sample of bivalirudin 5 mg/mL was combined with a 5mL sample of each of the study drug solutions individually in colorless 15-mL borosilicate glass screw-cap culture tubes (Kimble, Div of Owens-Illinois, Toledo, Ohio) with polypropylene caps (Kimble) as described elsewhere. 3 Except for drugs that should not be filtered, the sample solutions were filtered through 0.22-m filters (Millex-GS, Millipore Corporation, Bedford, Massachusetts) into the tubes. Each combination was prepared in duplicate, and the order of drug addition in the two samples was then reversed. All manipulations were carried out in a class 100 biological safety cabinet. Visual examination of all samples was performed with the unaided eye under normal laboratory fluorescent light. Combinations with no obvious visual incompatibility were examined further with a Tyndall beam, a high-intensity monodirectional light source (Dolan-Jenner Industries, Woburn, Massachusetts), as described elsewhere. 4 Inspections were performed over the first 15 minutes after sample preparation and at intervals of 1 and 4 hours after sample preparation. The samples were stored at room temperature (approximately 2C) under constant fluorescent light. Control solutions for this study included the following: Bivalirudin 5 mg/mL in 5% dextrose injection Bivalirudin 5 mg/mL in 5% dextrose injection diluted to 2.5 mg/mL as an equal parts mixture with 5% dextrose injection Bivalirudin 5 mg/mL in 5% dextrose injection diluted separately to 2.5 mg/mL with 0.9% sodium chloride injection Secondary additive solutions Incompatibility was defined as any visible particulate matter, a turbidity change or change in color from that in the controls, a substantial haze, or gas evolution. The samples were also assessed with a color-correcting tur-
Introduction
Bivalirudin (Angiomax; The Medicines Company, Cambridge, Massachusetts) is a synthetic peptide that acts as a specific and reversible direct thrombin inhibitor. 1 Bivalirudin is administered as an intravenous bolus dose and a subsequent intravenous infusion.1 In addition to bivalirudin, patients may be receiving many other drugs (anti-infectives, antiemetics, antihistamines, diuretics, steroids, analgesics, other supportive-care drugs) by simultaneous or sequential Y-site administration. However, the physical incompatibility of bivalirudin with one of those agents or components of the bivalirudin formulation may develop during Ysite administration. The purpose of this study was to evaluate by visual observation, turbidity measurement, and electronic particle content measurement (where warranted) the physical compatibility of bivalirudin (diluted for infusion during simulated Y-site administration) with 96 other drugs.

Materials
Bivalirudin (Lot # 42376, The Medicines Company, Cambridge, Massachusetts) was supplied as a lyophilized powder in vials containing 250 mg of drug. For this testing, the bivalirudin injec-
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bidimeter (Ratio X/R, Hach Company, Loveland, Colorado) immediately after preparation and at 1 and 4 hours after preparation, as previously described. 4,5 Some drug products are inherently hazy. The use of the turbidimeter permits quantification of that haze and the assessment of apparent or inapparent changes. Incompatibility of relatively clear drugs such as bivalirudin has been defined as an increase in measured turbidity exceeding 0.5 nephelometric turbidity unit (NTU) that did not occur upon simple dilution alone. All combinations without visible incompatibility were evaluated further with an electronic particle sizer/counter (Model 8003, Hiac-Royco, Div of Pacific Scientific Company, Silver Spring, Maryland) to document the absence of substantial subvisual particle burdens. Three-milliliter portions were tested to evaluate particles in the size range of 1.04 to 112 m (the validated detection limits of the particle sizer/counter).
Results and Discussion

Bivalirudin 5 mg/mL in 5% dextrose injection appeared clear and colorless in normal diffuse fluorescent room light; a very slight haze was observed when that sample was viewed with a Tyndall beam. The haze level in the solution was very low; the measured turbidity was near 0.1 NTU. Dilution of that solution with an equal quantity of 5% dextrose injection or 0.9% sodium chloride injection resulted in solutions with essentially no haze and measured turbidities near 0.1 NTU throughout the 4hour observation period. Of the 96 drug combinations tested with bivalirudin, 87 were physically compatible; when observed in normal, diffuse fluorescent room light with a Tyndall beam, the combination solutions were clear and exhibited no haze or particulate formation. Measured haze levels for the compatible combinations were near the expected normal level of diluted bivalirudin (0.1 NTU). The absence of substantial particle burden in the samples with no visually apparent incompatibility was documented by means of electronic particle counting. Those compatible combinations exhibited little change in measured turbidities throughout the study period; the particle content (size range, 1.04 to 112 m) of those solutions was low. However, nine drugs exhibited physical incompatibilities (the development of visible or measurable haze, gross precipitation, and the formation of microparticulates) when combined with bivalirudin (Table 2). In Table 3, the measured turbidity values for combinations that demonstrated changes in turbidities, including those with obvious precipitation, are listed. Particle content assessment was not feasible for samples containing amphotericin B, chlorpromazine HCl, diazepam, prochlorperazine edisylate, or vancomycin HCl, all of which contained a gross precipitate, because the quantity of particulates overwhelmed the capacity of the particle/sizer counter. A gross flocculent precipitate visible to the unaided eye was observed when amphotericin B was admixed with the bivalirudin. The measured turbidity for that combination was substantially higher than that of bivalirudin or amphotericin B alone. Such gross precipitation has been reported to occur when many other drugs are mixed with amphotericin B. 6 A dense, white, turbid precipitate developed when diazepam
samples were mixed with bivalirudin samples; the turbidity could easily be seen in normal room light. Because of its poor water solubility, diazepam is formulated for injection with a mixed solvent system that includes propylene glycol 40%, ethanol 10%, benzyl alcohol 1.5%, and benzoic acid/sodium benzoate 5%. 6 The final diazepam concentration in these study samples after dilution for testing was 2.5 mg/mL, which is higher than the aqueous solubility of diazepam (0.05 mg/mL). 7 A similar precipitate forms when diazepam is diluted to 2.5 mg/mL with 5% dextrose injection alone or with other drugs. 6,8-10 In those cases, the precipitate that forms is likely to be the result of the dilution of diazepam in an aqueous medium rather than a specific incompatibility with the bivalirudin formulation. Vancomycin HCl is subject to pH-dependent precipitation. Precipitation has occurred when vancomycin HCl is mixed with a drug that increases the pH of the mixture, as bivalirudin would do. 6 The source of the precipitation resulting from the mixture of chlorpromazine HCl and prochlorperazine edisylate is less obvious. It is unclear whether that precipitation was caused by the addition of the phenothiazine or the bivalirudin or was a result of a coprecipitation. Small aggregates and filaments characteristic of protein denaturation developed when bivalirudin 5 mg/mL in 5% dextrose injection was mixed with the protein drugs alteplase, reteplase, or streptokinase; measured particulates increased to over 2000/mL, but most particles were less than 5 m in size. Because of the potential for protein denaturation, alteplase, reteplase, and streptokinase are considered incompatible with bivalirudin.
Conclusion
Bivalirudin is physically compatible for 4 hours at room temperature with 87 drugs evaluated in this study during simulated Y-site administration. However, the combination of bivalirudin with nine of the drugs tested resulted in haze, microparticulate formation, or gross precipitation. None of those nine drugs should be administered simultaneously with bivalirudin.
Acknowledgment
This article was supported by a research grant (LS01-118) from The Medicines Company, Cambridge, Massachusetts.
References
1. 2. Angiomax injection [package insert]. Cambridge, MA:The Medicines Company; 2000. Allen LV Jr, Levinson RS, Phisutsinthrop D. Compatibility of various admixtures with secondary additives at Y-injection sites of intravenous administration sets. Am J Hosp Pharm 1977;34:939-943. Trissel LA, Martinez JF. Physical compatibility of melphalan with selected drugs during simulated Y-site administration. Am J Hosp Pharm 1993;50:23592363. Trissel LA, Bready BB. Turbidimetric assessment of the compatibility of taxol with selected other drugs during simulated Y-site injection. Am J Hosp Pharm 1992;49:1716-1719. Trissel LA, Martinez JF. Turbidimetric assessment of the compatibility of taxol with selected other drugs during simulated Y-site injection, Part 2. Am J Hosp Pharm 1993;50:300-304. Trissel LA. Handbook on Injectable Drugs . 11th ed. Bethesda, MD:American Society of Health-System Pharmacists, 2000. Trissel LA. Trissels Stability of Compounded Formulations . 2nd ed. Washington, DC:American Pharmaceutical Association, 2000.
3.
4.
5.
6. 7.
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8.
9.
Trissel LA, Williams KY, Gilbert DL. Compatibility screening of linezolid during simulated Y-site administration with other drugs and infusion solutions. J Am Pharm Assoc 2000;40:515-519. Trissel LA, Gilbert DL, Williams KY. Compatibility screening of gatifloxacin during simulated Y-site administration with other drugs. Hosp Pharm 1999;34:1409-1416.
10. Trissel LA, Williams KY, Baker MB. Compatibility of Hextend during simulated Y-site administration with other drugs. IJPC 2001;5:69-73.
Address correspondence to: Lawrence A. Trissel, BS, RPh, Division of Pharmacy, Box 90, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.
Table 1. Solutions and Drugs Tested for Compatibility with Bivalirudin 5 mg/mL.
Drug Supportive-care and other drugs Abciximab Alfentanil HCl Alteplase Aminophylline Amiodarone HCl Bretylium tosylate Bumetanide Butorphanol tartrate Calcium gluconate Chlorpromazine HCl Cimetidine HCl Dexamethasone sodium phosphate Diazepam Digoxin Diltiazem HCl Diphenhydramine HCl Dobutamine HCl Dopamine HCl Droperidol Enalaprilat Ephedrine HCl Eptibatide Epinephrine HCl Epoprostenol Esmolol Famotidine Fentanyl citrate Furosemide Haloperidol lactate Heparin sodium Hydrocortisone sodium succinate Hydromorphone HCl Inamrinone lactate Isoproterenol HCl Labetalol Lidocaine HCl Lorazepam Magnesium sulfate Mannitol Meperidine HCl Methylprednisolone sodium succinate Metoclopramide HCl Midazolam HCl Milrinone lactate Morphine sulfate Nalbuphine HCl Manufacturer Centocor Taylor Genentech Abbott Wyeth-Ayerst American Regent Ohmeda Apothecon American Pharmaceutical Partners Elkins-Sinn Abbott American Pharmaceutical Partners Abbott Glaxo Wellcome Baxter Elkins-Sinn Abbott Abbott American Regent Bedford Taylor Key American Regent Glaxo Wellcome Baxter Merck Abbott American Regent McNeil Abbott Pharmacia & Upjohn Astra Abbott Abbott Faro Pharma Astra ESI Lederle American Pharmaceutical Partners Baxter Astra Pharmacia & Upjohn Faulding Baxter Sano Astra Astra Lot No 00608AA 61230 L9029A 59-141-DK 090120 0363 P85019 9K16110 303466 039022 66-659-DK 100492 6871138 011333 00H108 089076 62-405-DK 63-206-DK 0612 188662 51080 S0274A1 0795 A9G3549 0042 1598K 71-062-DK 9467 TE1527 70-546-DK 59FAT 002002 65-121-DK 65-370-DK 0ZP0100 001019 0200031 100636 C463851 004003 09DYX 0054-37 YP0941A B670TJ 002048 908034 Concentration (mg/mL)a,b 0.01 0.125 1c 2.5 4 50 c 0.04 0.04 40 2 12 1 5c 0.25c 5c 2 4 3.2 2.5c 0.1 5 2c 0.05 0.01 d 10 2 0.05 3 0.2 100 c,e 1 0.5 2.5 f 0.02 2 10 0.5 100 15% c 10 5 5c 1 0.2 1 10 c Continued on next page
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Table 1, continued
Drug Nitroglycerin Norepinephrine bitartrate Phenylephrine HCl Potassium chloride Procainamide HCl Prochlorperazine edisylate Promethazine HCl Ranitidine HCl Reteplase Sodium bicarbonate Sodium nitroprusside Streptokinase Sufentanil citrate Theophylline Thiopental sodium Tiroban HCl Verapamil HCl Warfarin sodium Anti-infective drugs Amikacin sulfate Amphotericin B Ampicillin sodium Ampicillin sodium-sulbactam sodium Azithromycin Aztreonam Cefazolin sodium Cefepime HCl Cefoperazone sodium Cefotaxime sodium Cefotetan sodium Cefoxitin sodium Ceftazidime i Ceftizoxime sodium Ceftriaxone sodium Cefuroxime sodium Ciprooxacin Clindamycin phosphate Doxycycline hyclate Erythromycin lactobionate Fluconazole Gentamicin sulfate Levooxacin Metronidazole Ooxacin Piperacillin sodium Piperacillin sodium-tazobactam sodium Sulfamethoxazole-trimethoprim Ticarcillin disodium Ticarcillin disodium-clavulanate potassium Tobramycin sulfate Vancomycin HCl
a
Manufacturer American Regent Abbott American Regent American Pharmaceutical Partners Elkins-Sinn SmithKline Beecham Elkins-Sinn Glaxo Wellcome Centocor American Regent Baxter Hoechst Marion Roussel Elkins-Sinn Abbott Baxter Merck Abbott DuPont Apothecon Apothecon Apothecon Pzer Pzer Dura Apothecon Bristol-Myers Squibb Roerig Hoechst-Roussel Zeneca Merck Glaxo Wellcome Fujisawa Roche Glaxo Wellcome Bayer Abbott American Pharmaceutical Partners Abbott Pzer Abbott Ortho-McNeil Baxter Ortho-McNeil Lederle Lederle Gensia Sicor SmithKline Beecham SmithKline Beecham Gensia Sicor Abbott
d Tested e Units
Lot No 9927 66-582-DK 0216 392744 080037 90C43 090151 0ZP2100 760965C 0460 99J102 5482571 011011 51-192-JT 00K203 C450544 69-420-DK M0B545A 0G26873 0G29503 9F17265 T270A 197542 0A36880 C2736 0G32968 W499A 040497 3071C 3838K 0ZP1564 302173 U6171 9ZP1344 0BAA 65-384-DK 100671 69879Z7 PS095612 71-268-DK 68-178-FJ PS103515 7GAB5 800-104 464-693 99H123 62 655 DA RR 3693 00P110 69840Z7
Concentration (mg/mL) a,b 0.4 0.12 1 0.1 g 10 0.5 2 2 1e 1 c,g 2h 30,000 e 0.05 c 4c 25 c 0.05 c 1.25 2c 5 0.6 20 f 20/10 f 2 40 20 20 40 20 20 20 40 20 20 30 2 10 1 5f 2c 5 5 5c 4 40 40/5 4/0.8 30 31 5 10
from light. carbonate formulation.
Nominal concentration. ified otherwise. undiluted.
b Tested in 5% dextrose injection, USP unless specc Tested
in the special Flolan diluent. per milliliter. f Tested in 0.9% sodium chloride injection, USP. g Milliequivalents per milliliter.
h Protected i Sodium
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Table 2. Drugs Incompatible with Bivalirudin 5 mg/mL.

Drug Remarks a
Alteplase Amiodarone HCl Amphotericin B Chlorpromazine HCl Diazepam Prochlorperazine edisylate Reteplase Streptokinase Vancomycin HCl
a All b
Small aggregates b formed immediately Haze b formed immediately Gross, yellow, occulent precipitate formed immediately Gross white precipitate formed immediately Yellowish-white gross precipitate formed immediately Gross white precipitate formed immediately Small aggregates b formed immediately Small aggregates b and laments b formed immediately Gross white precipitate formed immediately
observations were made in normal diffuse light with the unaided eye unless specified otherwise. Visible with a Tyndall beam only.
Table 3. Measured Turbidities of Selected Incompatible Bivalirudin-Test Drug Combinations.

Mean SD Nephelometric Turbidity Unit(s) (n = 3) 0 hr 1 hr
Test Drug and Sample
4 hr
Bivalirudin 5 mg/mL in
D5W a
0.107 0.002 0.105 0.003 0.107 0.002 0.181 0.004 0.814 0.003 0.824 0.002 3.31 0.03 8.93 0.05 10.0 0.15 0.127 0.002 > 2000 > 2000 0.107 0.002 892 3 847 1 0.112 0.003 174 2 171 2 0.132 0.008 > 2000 > 2000
0.110 0.001 0.097 0.001 0.103 0.004 0.177 0.004 0.793 0.003 0.803 0.002 3.61 0.05 9.20 0.55 10.2 0.12 0.118 0.002 1371 5 886 5 0.101 0.003 659 3 718 4 0.114 0.002 151 2 147 1 0.124 0.001 > 2000 > 2000
0.087 0.004 0.093 0.002 0.098 0.003 0.176 0.002 0.794 0.002 0.809 0.002 5.27 0.04 10.5 0.44 10.8 0.1 0.116 0.002 99.8 3.0 83.0 0.8 0.100 0.002 344 7 371 8 0.114 0.005 106 3 75.6 0.1 0.134 0.009 > 2000 > 2000
Bivalirudin 2.5 mg/mL in D5W b Bivalirudin 2.5 mg/mL in NS c Amiodarone HCl A B Amphotericin B A B Chlorpromazine HCl A B Diazepam A B Prochlorperazine edisylate A B Vancomycin HCl A B
a
Representative bivalirudin infusion admixture. b Representative bivalirudin infusion samples diluted with an equal volume of 5% dextrose injection to a concentration of 2.5 mg/mL as a control. c Representative bivalirudin infusion samples diluted with an equal volume of 0.9% sodium chloride injection to a concentration of 2.5 mg/mL as a control. D5W = 5% Dextrose injection. NS = Normal saline injection (0.9% sodium chloride injection). A = Test drug solution added to bivalirudin. B = Bivalirudin added to test drug solution.
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Stability of Ketamine Hydrochloride Injection After Reconstitution in Water for Injection and Storage in 1-mL Tuberculin Polypropylene Syringes for Pediatric Use Abstract
The stability of ketamine hydrochloride (10 mg/mL) in water for injection stored in polypropylene syringes has been studied at 25C by means of a stability-indicating high-performance liquid chromatographic assay method. The concentrations of the drug were directly related to peak heights, and the percent relative standard deviation based on five injections was 1.9. The drug decomposed only when the solution was boiled after sodium hydroxide was added. It did not decompose in the presence of an acid or after 30 minutes of boiling. The injection did not lose potency after 30 days of storage at 25C, and the pH value of 4.2 did not change. Ketamine hydrochloride appears to be a very stable drug. Vishnu D. Gupta, PhD Pharmaceutics Division University of Houston Houston, Texas
Preparation of Injection for Stability Studies

Ketamine hydrochloride injection (100 mg/mL) was diluted with sterile water for injection without preservative (Lot # 302661, American Pharmaceutical Partners, Los Angeles, California) to a concentration of 10 mg/mL. The injection was immediately filled into 1-mL tuberculin polypropylene syringes (Becton, Dickinson and Company, Franklin Lake, New Jersey) and was stored at 25C ( 1C). On day zero, the injection was assayed and the pH value was recorded. The contents of the syringes were assayed again after 3, 7, 11, and 30 days. The pH values were also recorded.
Introduction
Ketamine hydrochloride (Figure 1) injection is extensively used as a rapidly acting anesthetic agent because it produces minimal respiratory depression. 1 It is usually diluted with water from 100 mg/mL (the commercially available strength) to 10 mg/mL for use in pediatric patients. The diluted injection is usually filled into 1-mL tuberculin polypropylene syringes that are stored at room temperature. The stability of the diluted injection has not been reported in the literature. The purpose of this investigation was to develop a stability-indicating assay method for the quantitation of ketamine hydrochloride injection and (for use in pediatric patients) to study the stability of the diluted injection after storage in 1-mL tuberculin polypropylene syringes at 25C.

Chemicals and Reagents
All the chemicals and reagents, which were USP-NF or ACS grade, were used without further purification. Ketamine hydrochloride powder (Lot # 72416) was generously supplied by Professional Compounding Centers of America (Houston, Texas), and the injection (100 mg/mL) (commercial Lot # 653153A) was obtained from Abbott Laboratories (North Chicago, Illinois).
Preparation of Standard Solutions

A 115.4-mg quantity of the ketamine hydrochloride powder was accurately weighed (115.4 mg of the powder is equivalent to 100 mg of ketamine free base) and was dissolved in sufficient water to make 25 mL of solution. That stock solution was used to prepare solutions of lower concentrations as needed. The most commonly used standard solution of the drug (400 g/mL) was prepared by diluting 2.5 mL of the stock solution to 25 mL with water.
Equipment
A high-performance liquid chromatographic system (ALC 202 Waters Associates, Milford, Massachusetts) equipped with a universal injector (Rheodyne Model 7125, Cotati, California), a multiple wavelength detector (Schoeffels SF 770, Applied Biosystems, Ramsey, New Jersey), and a recorder (Omniscribe 5213-12, Houston Instruments, Austin, Texas) was used. The column used (Beckman, Ultrasphere, 15 cm, 4.6 mm id, 5 m) was obtained from Phenomenex Inc, Torrance, California.
Preparation of Assay Solutions

A 2.0-mL quantity of the assay solution was diluted to 50 mL with water.
Figure 1. Structure of Ketamine Hydrochloride.
Decomposition of Ketamine Hydrochloride

Three solutions were prepared for analysis according to the following procedures: Procedure 1. A 25-mL quantity of the standard solution (400 g/mL) was transferred to a 150-mL beaker and was heated to boiling by means of a hot plate. More water was added as needed. After 30 minutes, the solution was allowed to cool, and volume was brought to 25 mL with water. Procedure 2. Procedure 1 was repeated, except that 1 mL of 0.5 N NaOH solution
Chromatographic Conditions
CI
NHCH3 O
HCI
The mobile phase contained 23% (v/v) acetonitrile in water containing 0.01 M potassium dihydrogen phosphate buffer. The pH of the mobile phase was adjusted to approximately 3.9. The flow rate was 1.6 mL/min, the sensitivity was 0.1 AUFS at 269 nm, the chart speed was 30.5 cm/hr, and the temperature was ambient.
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was added before the solution was heated, and the solution was allowed to cool after 5 minutes of boiling. The resultant mixture was made weakly acidic by the addition of 0.5 N H 2 SO 4 solution and was brought to volume (25 mL) with water. Procedure 3. Procedure 2 was repeated, except that 1 mL of 0.5 N H 2 SO 4 solution was added before the solution was boiled. Before it was brought to volume (25 mL) with water, the solution was made weakly acidic by the addition of 0.5 N NaOH solution. These solutions were injected into the chromatograph according to the procedure described below.
Table 1. Assay Results for Ketamine Hydrochloride Injection (10 mg/mL) Stored at 25C in Becton-Dickinson 1-mL Tuberculin Syringes.
Time (days) 3 7 11 30
a
Percent of Label Claim (based on 100% on day zero)a 100.8 100.2 101.4 101.5
Percent RSD n=5 1.9 1.8 1.9 1.9
The injections remained clear throughout this study; the pH, which was 4.2, did not change after 30 days of storage. RSD = Relative standard deviation.
Assay Procedure and Calculations

An 80-L quantity of assay solution was injected into the chromatograph under the conditions described. For comparison, a similar volume of the standard solution containing the same concentration of the drug (based on the label claim) was injected. Because peak heights of the drug were directly related to the concentrations (320 to 440 g/mL), the results were calculated by means of a simple equation: (Ph) a /(Ph) s x 100 = Percentage of the label claim found where (Ph) a is the peak height of drug of the assay solution and (Ph) s is that of the standard solution. The results of these evaluations are presented in Table 1.
Figure 2. Sample Chromatograms from Ketamine, Standard Solution, and Solution Decomposed with Sodium Hydroxide. A
1
1 Detector Response
Inject
Results and Discussion

Assay Method
The assay method developed is precise and accurate; the percent relative standard deviation is 1.9 (based on five readings). Apparently, the large injection volume (80 L) produced accurate and precise results without the use of an internal standard. The concentrations of the drug were directly related to the peak heights (range tested, 320 to 440 g/mL). It is important that the volume of injection (80 L) remain constant to ensure a linear relationship between the concentrations and the peak heights. A chromatogram of intact ketamine is shown in Figure 2A. The standard solution, which was decomposed by heat and sodium hydroxide, decreased in potency by approximately 20% (Figure
Time (minutes)
Inject 0
Peak 1 is from ketamine. Chromatogram A is from a standard solution, and B is from a solution decomposed by the addition of sodium hydroxide (see the text). For the chromatographic conditions, see the text. 2B). There was no new peak from the products of decomposition. The standard solution, which was decomposed with either sulfuric acid or by having been boiled for 30 minutes, did not decrease in potency. The potency or pH value of the ketamine injection (10 mg/mL), which was stored at 25C for 30 days in 1-mL tuberculin syringes, did not change (Table 1). Ketamine hydrochloride is a very stable compound because the potency of the standard solution did not decrease during the study, even after 30 minutes of boiling.
Reference
1. Ketamine hydrochloride injection [package insert]. North Chicago, IL:Abbott Laboratories; 1998:1.
A d d r e s s c o r r e s p o n d e n c e t o : Vi s h n u D . Gupta, PhD, Pharmaceutics Division, University of Houston, 1441 Moursund St, Houston, TX 77030. E-mail: vgupta @ uh.edu
C O N T
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Two Hours of Continuing Education from the International Journal of Pharmaceutical Compounding
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obtaining a grade of 70% or higher) will receive 2 contact hours (0.2 CEUs) within 4 to 5 weeks after we receive the answer sheet or the online form.
PROGRAM EXAMINATION. Please indicate your exam responses by circling only ONE answer for each question.
Basics of Compounding: Iontophoresis, Part 2. Page 288

1. Topically applied aqueous solutions of ionized drugs can usually penetrate into the surface tissues of the skin to achieve therapeutic levels. A. True B. False 2. Which of the following classes of drugs is usually more readily absorbed by the membranes in the body? Hydrophilic Ionized Lipophilic Amphipathic Electrolytes Usually, water-soluble forms of drugs are salts that will in aqueous solution. Disintegrate Effloresce Deliquesce Form eutectics Dissociate
6. A. B. C. D. E. 7.
The dosage in iontophoresis is often expressed as: Volts per milligram Volts per minute MilliAmp-minutes Milliamperes per milligram MilliVolt-seconds
reservoir of that drug, which ultimately diffuses into the body, may accrue. A. True B. False 13. Delivery of the active drug can be decreased by the presence of other ions in solution that compete with the active drug. A. True B. False 14. Usually, a larger quantity of drug is delivered when a larger electrode is used. A. True B. False 15. Which of the following is not necessarily a significant characteristic of the new iontophoretic patch of the future? A. Provides the administration of the drug over 7 days B. Is easy to apply and resistant to accidental removal C. Supplies drug delivery at a predetermined rate D. Is tamper evident E. Is color-coded for different patients 16. Iontophoretic solutions should be preserved and buffered for stability and efficient iontophoretic transfer. A. True B. False 17. Solutions for iontophoresis should be packaged in unit-dose containers. A. True B. False
A. B. C. D. E. 3.
A c c o r d i n g t o F a r a d a y s l a w a n d the principles of iontophoresis, the greater the quantity of electricity moving across a surface, the greater the amount of drug delivered. A. True B. False 8. In the iontophoretic process, the rate of migration of ions is usually inversely proportional to the viscosity of the medium containing the ions. A. True B. False 9. Usually, the greater the concentration of drug in solution, the greater the quantity of drug that will be delivered. A. True B. False 10. All salt forms of a specific active drug migrate at the same rate in an electric field. A. True B. False 11. Most of the iontophoretic devices available today are of the constantcurrent type. A. True B. False 12. When iontophoresis with a high concentration of drug is rapid, a
A. B. C. D. E. 4.
The basic principle of iontophoresis is this: An electrode with the same charge as that of the active drug in solution will push the drug away. A. True B. False 5. In iontophoresis, a second electrode is required, but it can be placed on the body away from the active electrode. A. True B. False
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18. The rate of delivery of a specific drug during iontophoresis may be different in solutions of different pH values. A. True B. False
for an oil-in-water emulsion. A. True B. False 21. Acetone, which is miscible with water and evaporates quickly, is an ideal solvent in which a drug can be dissolved for incorporation into a cream vehicle. A. True B. False 22. When dilution with purified water or aromatic water is used to prepare a lotion from a cream, it may be necessary to add additional: A. Stiffening agent B. Antioxidant C. Preservative D. Oil phase E. Surfactant 23. I n D e r m a b a s e c r e a m , s o d i u m lauryl sulfate serves as a(n):
A. B. C. D. E.
Antioxidant Preservative Stiffening agent Humectant Emulsifying agent
Featured Excipient: Topical Oil-in-Water Cream Bases. Page 303

19. Opaque, soft solids or thick liquids that are intended for external application and consist of medications dissolved or suspended in waterremovable or emollient bases are called: A. Pastes B. Gels C. Ointments D. Liposomes E. Creams 20. Mineral oil is a good levigating agent
24. What is the purpose of the propylene glycol in hydrophilic ointment, USP? A. An antioxidant B. A stiffener C. A humectant D. An emulsifying agent E. A solubilizing and/or levigating agent 25. The glyceryl monostearate in Vanicream serves as a(n): A. Antioxidant B. Stiffener C. Humectant D. Emulsifying agent E. Solubilizing and/or levigating agent
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P O S T S C R I P T I O N
Post cription
Certication: Now Is the Time
Richard J. Bertin, PhD, RPh Board of Pharmaceutical Specialties, Washington, DC These are challenging times for all compounding pharmacists, whether they are compounding nonsterile or sterile preparations. Facing even greater challenges are those pharmacists who perform significant amounts of compounding in community, institutional, home health care, and other settings. Compounding pharmacists are facing challenges such as an increased demand for their services to meet patient needs, diminished training in compounding that pharmacy students receive, and various regulatory challenges. Patients and payers alike are demanding more accountability from the pharmacists who compound the preparations that are vital to todays advanced health care. To achieve appropriate recognition of their specialized knowledge and skills, compounding pharmacists have stepped up their discussions concerning professional certification. Because of the issues pertaining to compounding today, these certification discussions are very important and are probably overdue. As executive director of the Board of Pharmaceutical Specialties (BPS), I have been privileged to observe and participate in some of that dialogue. Founded more than 25 years ago to recognize specialties in pharmacy and to certify pharmacists demonstrated knowledge and skill in those specialties, BPS has a long and successful record in the pharmacy profession. It provides good models that meet the needs of compounding pharmacists in five specialty practice areas: nuclear pharmacy, nutrition support pharmacy, oncology pharmacy, pharmacotherapy, and psychiatric pharmacy. The initial BPS specialty was nuclear pharmacy, in which it was acknowledged that the safe, effective handling and formulating of complex pharmaceuticals required a level of knowledge and skill greater than that possessed by the average licensed pharmacist. The same argument might be made today, 25 years later. Compounding has been acknowledged as a legitimate BPS specialty in pharmacies that have a set of nationally recognized standards and a certification program that is psychometrically sound and legally defensible. It is important for compounders considering their options to understand what a quality certification program entails from the viewpoints of the organizational sponsor and the individual pharmacist. A BPS model is used to identify a representative body that represents the pharmacists interested in establishing a new specialty. That body is responsible for identifying leaders in its community who can help develop and define the specialty, fund the developmental phase of the specialty, establish eligibility criteria, develop the examination content outline, write the examination questions, and determine the passing score. For other BPS specialties, a professional association with members who have interests in the specialty area has served as the representative body (eg, the American Pharmaceutical Association sponsored the nuclear pharmacy specialty and the American College of Clinical Pharmacy sponsored the pharmacotherapy specialty). For the individual pharmacist, earning a meaningful certification requires a commitment of time, as well as the willingness to pay for the cost of the process. Depending on the nature of the pharmacy practice, a certain amount of study and review is required to prepare for a specialty examination. Many pharmacists participate in preparatory courses or study groups before the examination; others prefer home study or read the professional literature. BPS certification is effective for 7 years, after which the specialist must either pass another written examination or, in some specialties, complete an approved continuing education program that includes a rigorous assessment component. Periodic recertification is also required. Given these requirements, it is reasonable to consider the advantages of having specialty certification in pharmacy. BPS has found that the benefits to an individual fall into three major categories: 1. Personal satisfaction from setting a professional goal and attaining it 2. Having peers, other healthcare professionals, and patients recognize knowledge and skill that uncredentialed pharmacists cannot demonstrate 3. A personal monetary reward (a salary increase, a bonus, a promotion) or receiving hiring preference. Payers are interested in ensuring that advanced-level services are provided by qualified pharmacists, and it is likely that specialized credentials will become more important in payment policies. In todays environment, it is very likely that having an advanced practice credential would benefit the compounding community in several ways. Specialty certification in compounding pharmacy could provide: 1. A respected, independent, national standard against which pharmacists knowledge and skill in compounding can be measured 2. A credential in pharmacy that can be cited by individuals and employers as an indicator of quality 3. An indication to the external community (regulators, payers, and employers) that compounders believe that adhering to a standard and having credentials are important 4. A credential that is primarily managed and directed by leaders in the specialty area and for which oversight is provided by a respected board representing pharmacy, other healthcare professions, and the public In the current absence of recognized national standards and assessment mechanisms, there is no reliable method by which the public (and even other pharmacists) can readily identify qualified compounding specialists. As a result, regulatory bodies may be impartially strict and conservative, and when an unqualified compounder is exposed in a news story, there is often little evidence of how he or she really differs from more qualified pharmacists. Address correspondence to: Richard J. Bertin, PhD, RPh, Executive Director, Board of Pharmaceutical Specialties, 2215 Constitution Avenue NW, Washington, DC 20037. E-mail: rbertin@aphanet.org
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to produce an increase in the level of FSH and subsequent follicular maturation. 26

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The Hormonal Link to Breast Cancer:

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Thyroid Melatonin Cortisol

Obesity Smoking Zinc

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Stress and Adrenal Dysfunction

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Agents That Promote Engorgement and Erection

International Journal of Pharmaceutical Compounding 255 Vol. 6 No. 4 July/August 2002

Address correspondence to: David Mason, D P h , F I A C P, I n n o v a t i v e P h a r m a c y S o l u t i o n s , 1 7 1 6 S . K e l l y, E d m o n d , O K 73013. E-mail: dave@innovative pharmacy.com

International Journal of Pharmaceutical Compounding Vol. 6 No. 4 July/August 2002

The Community Pharmacists Role

Establishing an ANDROPAUSE PRACTICE

How To Identify Prospective Physician Prescribers

How To Educate Prospective Prescribers About Treatment Options

The Importance of Education

How To Establish a Patient Base

International Journal of Pharmaceutical Compounding 259 Vol. 6 No. 4 July/August 2002

How To Diagnose Andropause

International Journal of Pharmaceutical Compounding Vol. 6 No. 4 July/August 2002

MALE HORMONE SCREENING FORM

Date Height Telephone Weight

Your age (years)

For which medical conditions are you being treated?

International Journal of Pharmaceutical Compounding 261 Vol. 6 No. 4 July/August 2002

Focus on LEGAL and REGULATORY ISSUES for COMPOUNDING

International Journal of Pharmaceutical Compounding Vol. 6 No. 4 July/August 2002

Compounding and the

Inception of Compounding to the 1980s: A Legislative Overview

The Current Story of Compounding

International Journal of Pharmaceutical Compounding 263 Vol. 6 No. 4 July/August 2002

The Effect of FDAMA Section 503A