Therapv

Topical corticosteroid compounding: Effects on

physicochemical stability and skin penetration rate
Lincoln Krochmal, MD, Jonas C. T. Wang, PhD, B. Patel, PhD, and 1. Rodgers, BS
Buffalo, New York
Compoundingcompatibilitystudiesoffour corticosteroidcreamproductsandfourcommonly
added chemicals are presented. Physical alteration, chemical stability, micropreservative
challenge status, and in vitro skin penetration were evaluated at ambient conditions for 2
months. The study was designedtogenerateuseful,previouslyunavailableinformation toaid
dispensingpharmacists and dermatologists. (J AM ACAD DERMATOL 1989;21:979-84.)
Uncontrolled compounding of topical medica-
tions, especially in the pharmacy, can diminish ther-
apeutic efficacy because the interaction of com-
pounded agents can affect physicochemical stability
and skin penetration rate. Current use of topical ste-
roids frequently includes compounding with a vari-
ety of chemicals aimed at a particular purpose or
symptom (or both). Many products, however, are
not physically, chemically, or microbiologicallycom-
patible, although dermatologists may order ad hoc
compounding of two products into a single formula-
tion. In galenic compounding of topical steroids, the
horny layer's absorptive capacityfor the steroidmay
be increased or decreased by influencing its struc-
tural-functional condition. By changing the pene-
tration conditions of the skin, the therapeutically
effective concentration of the steroid may be opti-
mized or compromised. Changes in physicochemical
stability and micropreservative status caused by the
compounding process also have been given scant at-
tention. Typical physicochemical problems that 0c-
cur commonly in the compounding process are listed
in Table I.
The objective of this studywas to demonstrate the
problems associated with extemporaneous com-
pounding. Four corticosteroid cream products listed
in UnitedStates Pharmacopeia (USP)XXI and four
commonly added chemicals were chosen for study.
From the Pharmaceutical Research and Development Division, Bristol-
Myers Co.
Reprint requests: Jonas C. T. Wang, Johnson & Johnson Baby Prod-
ucts Co., Grandview Rd., Skillman, NJ 08558.
16/1/10365
TableI. Potential physicochemical problems that
could occur with extemporaneous compounding
process
1. Oxidationor hydrolysis could occur as a result
of exposure to light and moisture during the
compounding process.
2. Changes in pH couldoccur becausesome adju-
vants (i.e, salicylic acid, phenol, urea) could
acceleratethe degradation process of the active
agent.
3. Micropreservative capability couldbe damaged
because the compounding process may dilute
the preservative concentration of the original
product or enhance the interaction between
preservatives and added chemicals or packag-
ing materials.
4. The particle size or crystal form of the active
agent could be changed, which may reduce the
bioavailability of the active agent.
5. The physical characteristics of the original
product (e.g., viscosity, precipitation, or sedi-
mentation) couldbe changed, whichmay cause
physical separation duringstorage.
6. Because there is no stability profile for the
preparation after compounding, improper stor-
age could acceleratethe degradation process of
the active agent, which may lead to a loss of
potency.
The corticosteroid creamproducts were selected be-
cause the method for analysis (i.e., high-perfor-
mance liquid chromatography [HPLC]) has been
published in USP XXI Physical alteration, chemi-
cal stability, micropreservative challenge status, and
in vitro skin penetration rates were evaluated at am-
bient conditions for 2 months.
979
980 Krochmal et al.
Journal of the
American Academy of
Dermatology
*As listed in the United States Pharmacopeia XXI.
EXPERIMENTAL DESIGN
Table II. Compounding products and chemicals
Material and reagents
Four corticosteroidcreamproducts wereselected: 0.2%
hydrocortisone 17-valerate (Westcort cream) (Lot No.
EXP1188), 0.1% triamicinolone acetonide (Kenalog)
(Lot No. 3L029), 0.05%fluocinonide (Lidex) (Lot No.
42819), and 0.25% desoximetasone (Topicort) (Lot No.
110234). Four chemicals were selected: 2%salicylic acid,
10% urea, 0.25% camphor (reagent grade) + 0.25%
menthol +0.25% phenol, and 5%USP coal tar solution
(Liquor Carbonis Detergens [LCD]). The salicylic acid,
urea, menthol, and phenolwere ACS (American Chem-
ical Society) grade.
Compounding directions for galenic
preparations
The four selected topical corticosteroid creams were
prepared withfour commonlyadded chemicals (Table II)
by a licensed pharmacist with the use of a conventional
compoundingtechnique. The compounding direction for
each galenic preparation is as follows:
-2% Salicylicacid, 10%urea, and5%LCD:Weigh out each
chemical solid or solution. Levigate the solid or solution into
a small amount of glycerinor water to form a smooth paste.
Incorporate the paste intothe steroid cream geometrically.
-0.25% Camphor +0.25%menthol+ 0.25% phenol.'Weigh
out phenol, menthol, and camphor. Triturate to form a
eutectic mixture. Incorporate the solution into the steroid
cream geometrically.
All galenic preparations were packaged in 15 ml am-
ber glass jars with black, polyethylene-lined, phenolic
caps and stored at ambient conditions for stability eval-
uation.
High-performance liquid chromatography
chemical analysis method
The HPLC methods listed in the USP XXI for triam-
cinolone acetonide cream (p. 1078), desoximetasone
cream (p. 285), hydrocortisone 17-valerate cream (p.
508), and fluocinonidecream(p. 436) wereadopted in the
study.
Physical and chemical stability study
Physical stability was carried out by visual observation
of color, odor, and fluidity as compared with samples
stored at 50 C as a positive control. Both physical and
chemical stabilities were evaluated at ambient conditions
before compounding and at 24 hours, 1 month, and 2.
months after compounding. Microbiologic evaluation in-
cluded bacterial count and micropreservative chal-
lenge test with the use of USP standard methods after
In vitro human skin permeation studies
Skin samples were obtainedfromtheabdomen or chest
of human donors at autopsy. Skin specimens were imme-
diately labeled, wrapped, and placedon ice. Only skin that
appeared grosslynormal was used. Historical evidence of
chronic illness, skin disease, or skin injury in the donor
were criteria for exclusion from study. Within 2 hours
of collection, the skin specimens were stored in a
freezer at -30
0
C until needed. Before a skin perme-
ation study was begun, a sample was thawed at room
temperature in normal saline solution. Skin was then
frozen on the microtome with C02 and sectioned (150
to 240 /-lm). The prepared skin section was labeled and
stored in normal saline solution at 50 C until used in a
permeation study.
Franz diffusioncells (9 mminner diameter), filled with
the necessary volume of normal saline solution as recep-
tor fluid, were adapted for the study. The designated
specimen of prepared skin section was mounted on each
cell, dermis side down. The membrane was secured with
an 0 ring and an open cap for the cell. A 50 mm! sample
(a doseto ensure an infinite supply for penetration) of the
compounded cream was then dispensed from a pipette
calibrated in microliters and applied in an even layer onto
the skin section. The receptor fluid was maintained at
34
0
0.1
0
C throughout the study. Receptor fluid (200
mm-) was collected at 1,2,3,4,7,8,12,24,32, and 48
hours for chemical assay with the use of USP HPLC
methods. Original creams alone and galenic preparations
2 months after compounding were investigated in the in
vitro human skin penetration study.
The concentration-time course data collected from
diffusion studies were analyzed statistically with the use
of Tukey's studentized range test.
Commonly added
chemicals
10%Urea
0.25% Camphor +
0.25% menthol +
0.25% phenol
5% USP coal tar
solution (liquor
carbonis
detergens
[LCD]
2% Salicylic acid
0.05% Fluocinonide (Lidex)
Corticosteroid cream products*
0.2% Hydrocortisone
17-valerate (Westcort)
0.1%Triamcinolone acetonide
(Kenalog)
0.25% Desoximetasone
(Topicort)
Volume 21
Number 5, Part 1
November 1989 Topical corticosteroid compounding and penetration rate 981
Table III. Physicochemical results of compounding studies of four corticosteroid products with four
commonly added chemicals at ambient conditions for two months
0.2 % Hydrocortisone 0.25 % Desoximetazone 0.1 % Triamcinolone 0.05% Fluocinonide
17-valerate cream, pH 4.8 cream, pH 4.4 acetonide cream, pH 6.2 cream, pHS.O
Initial I 1 mo I
2rno Initial lImo I 2 rno Initial lImo I 2 mo Initial lImo I 2 mo
10%Urea 91% 89% 89% 80% 81% 81% 75% 67% 55% 90% 74% 66%
pH 5.0 5.3 5.4 4.7 4.8 5,8 8.0 8.6 8.7 6.2 6.8 6.8
0.25%Camphor+
0.25%menthol+ 101% 102% 100% 102% 106% 102% 99% 105% 100% 99% 105% 100%
0.25%phenol
pH 4.8 4.9 4.8 4.2 4.4 4.9 6.2 6.7 7.0 5.2 5.1 5.1
2%Salicylic 97% 104% 90% 100% 105% 104% 99% 103% 99% 97% 100% 101%
acid
pH 3.2 3.1* 3.3* 3.3 2.9 2.8* 2.6 2.6 2.5 2.7 3.0 3.0
5% USPLCD 90% 87% 96% 103% 97% 103% 101% ~
95% 103% 157% 102%
solution
pH 4.9 4.8 5.1 5.5 4.7 S.n 6.4 6.4 6.6 5.4 S.4 5.6
*Uquid separation; can be shaken back to uniform emulsion with mixing.
tLiquid separation; cannot be shaken baek to uniform emulsion.
~ o t measured.
Interfering peaks caused the high value.
initial compounding and again 2 months after com-
pounding.
RESULTS
Physical and chemical stability study
Results of the stability study are shown in Table
III. After compounding with 10%urea, the decrease
in steroid content after 2 months at ambient condi-
tions was 10% for hydrocortisone l7-valerate, 20%
for desoximetasone, 45% for triamcinolone ace-
tonide, and 34% for fluocinonide. The steroid con-
centration decreased by more than 10% immedi-
ately after it was mixed with urea, suggesting that
chemical degradation had occurred. No significant
chemical degradation was observed when the steroid
was compounded with 0.25% camphor +0.25%
menthol +0.25% phenol, 2% salicylic acid, or 5%
LCD solution.
No physical incompatibilities were observed in
the compounding of the triamcinolone acetonide
and fluocinonide creams. Physical separation was
observed in the compounding of hydrocortisone 17-
valerate and desoximetasone creams with 2% sali-
cylic acid; however, with shaking, a uniform emul-
sion of each could be obtained with little difficulty.
Severe physical separation was observed in the
compounding of desoximetasone cream with 5%
LCD solution, and the uniformityof the cream could
not be recovered, even with vigorous shaking. The
pH of topical creams varied slightly by product. In
general, after compounding, 2%salicylicacid acid-
ifiescream preparations and reduces the pH by ap-
proximately 2 units for all compounded prepara-
tions. The pH of the triamcinolone acetonide cream
with 10%urea was exceptionallyhigher than that of
other preparations. Why the pH increased is not
known, but a vehicle-adjuvantinteractionmay occur
between the triamcinolone acetonide vehicle and
10%urea. The pH of most of the preparations was
unchanged at ambient conditionsfor 2 months. Pre-
servative challenge tests revealed that all galenic
preparations were adequately preserved microbio-
logicallyfor up to 2months after mixingat ambient
conditions.
In vitro permeability of human skin to the test
galenic preparations
The in vitrohuman skinpermeation rates for the
test creams and their galenic preparations are shown
in Figs. I to 4. The shape of the skin penetration
curves suggeststhat under the conditionsused in the
study penetration is generally not a simple first-
order process. With few exceptions the penetra-
tion profiles include a time lag to reach steady
state.
982 Krochmal et al.
Journal of the
American Academy of
Dermatology
Fig. 2. Amount of desoximetasone penetrated through
6.36 X10-
1
cm
2
of human skin at 34
0
0.1
0
C. Bars
indicate standard error of the mean (n =4). e, 0.25%
Desoximetasone + 2% salicylic acid; .6., 0.25%
desoximetasone +0.25% camphor, 0.25% menthol,
0.25% phenol; X, 0.25% desoximetasone + 5% LCD; 0,
0.25% desoximetasone; D, 0.25% desoximetasone + 10%
urea.
triamcinolone acetonide also was observed by com-
pounding with 2% salicylic acid. In contrast, pene-
tration of triamcinolone acetonide with 10% urea
was twice as high (statisticallysignificant, p -< 0.05)
as that of cream alone. Evidence presented by
others 1,2 suggests the mechanism of this penetration
enhancement by urea can be attributed to the inter-
action of several factors, including the solubility en-
hancement by urea, skin structural-functional
change by urea, and an increase in the horny layer's'
water-binding and absorptive capacity for the ste-
roids.
Similar observations were made when fluocino-
nidewas compoundedwith 0.25%camphor +0.25%
menthol +0.25% phenol or 5%USP LCD (Fig. 4).
An approximately twofold, statistically significant
(p <: 0.05) absorption enhancement also was ob-
served with 2%salicylic acid. Interestingly, the skin
penetration of fluocinonide after compounding flu-
ocinonide cream and 10% urea demonstrated a to-
tally different result: no penetration of fluocinonide
was detected in 72 hours. After the penetration
study, only 2%to 3%of active steroid was recovered
from the skin surface, suggesting that chemical in-
stability could be the main reason for the disappear-
ance of fluocinonide. The chemical instability of flu-
ocinonide after compounding with 10% urea has
been demonstrated in the physicochemical stability
study (Table II).
2
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-
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o
o
Penetrationofhydrocortisone 17-valeratethrough
human skin (Fig. 1) was not affected by compound-
ingwith0.25%camphor + 0.25%menthol +0.25%
phenol, 5% LCD, or 10% urea. Penetration of
hydrocortisone 17-valerate compounded with 2%
salicylic acid, however, was approximately three
timeshigher than that of hydrocortisone 17-valerate
alone.
As with hydrocortisone l7-valerate, penetration
ofdesoximetasonethrough human skin (Fig. 2) was
affected slightly (not statistically significant) by
compounding with 0.25% camphor +0.25%
menthol + 0.25%phenol, 10%urea, or 5%LCD. A
twofold to threefold, statistically significant
(p-< 0.05) penetration enhancement was also ob-
served by compounding desoximetasone with 2%
salicylic acid.
Penetration of triamcinolone acetonide through
human skin (Fig. 3) was not affected by compound-
ingwith0.25%camphor +0.25%menthol +0.25%
phenol or 5%LCD, as compared with that of cream
alone. Approximately a twofold, statistically signif-
icant (p -< 0.05) increase in penetration rate of
3
40 60
Time. hr.
Fig. 1. Amount of hydrocortisone 17-valerate pene-
trated through 6.36 X 10-
1
cm
2
of human skin at
34
0
0.1
0
C. Barsindicate standard error of the mean
(n =4). e, 0.2% Hydrocortisone 17-valerate +2% sali-
cylic acid; .6., 0.2% hydrocortisone 17-valerate +0.25%
camphor, 0.25% menthol, 0.25% phenol; 0, 0.2% hydro-
cortisone 17-valerate; X, 0.2% hydrocortisone
17-valerate + 5% LCD; D, 0.2% hydrocortisone
17-valerate + 10%urea.
'"
::l..
2

al
J
c: j
:J
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<t
Volume 21
Number 5, Part 1
November 1989 Topical corticosteroid compounding and penetration rate 983
0.3
Ol
~ f
:i.

0.2
-c
oS
c
..
.....
OJ
c:
OJ
a.
~
.....
c::
0.1
:::>
0
E

t ~ ~
0
0 20 40 60 80
Time, hr.
Fig. 3. Amount of triamcinolone acetonide penetrated
through 6.36 X 10-
1
cm-of'hamanskln at 34
0
0.10 C.
Bars indicate standard error ofthemean (n = 4).0,0.1%
Triamcinolone acetonide + 10% urea; e, 0.1% triamci-
nolone acetonide +2% salicylic acid; 0, 0.1%triamcino-
lone acetonide; X, 0.1%triamcinolone acetonide +0.25%
camphor, 0.25% menthol, 0.25% phenol; D., 0.1%triam-
cinolone acetonide + 5% LCD.
DISCUSSION
The enhancement of penetration and clinical ef-
ficacy of active agents by addition of different
chemicals has been practiced commonly by derma-
tologists. Results of our study indicate the physico-
chemical stability and skin permeation rate of top-
ically applied steroids after galenic preparation by
compounding with commonly added chemicals are
vehicle dependent. Results also suggest that it is im-
possibleto developuniversal guidelines to predict the
influences of extemporaneous compounding pro-
cesses because there are many unknown factors.
These include vehicle properties, solubility of ste-
roids in the vehicles, physicochemical and solubility
changes after compounding with added chemicals,
and changes in the horny layer's water-binding and
absorptive capacity that are involved in the com-
pounding process.
Generally, penetration enhancement is expected
for steroid preparations compounded with salicylic
acid.' Similar observations of approximately two-
fold to threefold penetration enhancement also were
noted in this study for the four commonly used top-
ical steroid creams when compounded with 2% sal-
0.2
0>
:l..
-

-0
~
e
0.1
.....
Q)
c:
~ E
Q)
Q...
.....
c::
:::>
0
E [-

00
40 60 80
Time, hr.
Fig. 4. Amount of fluocinonide penetrated through
6.36 X 10-
1
cm
2
of human skin at 34 0.1
0
C. Bars
indicate standard error of the mean (n == 4) ., 0.05%
Fluocinonide+2%salicylic acid; 0, 0.05%fluocinonide;
X, 0.05% fluocinonide+5% LCD; D., 0.05%
fluocinonide+0.25% camphor, 0.25% menthol, 0.25%
phenol.
icylicacid. Thepenetration enhancement of salicylic
acid could be due to its keratolytic effect on the
horny layer that reduces the resistance of horny
layer to steroid molecules. No physicochemical sta-
bility problem was found in compounding with 2%
salicylic acid at ambient conditions for 2 months.
Compounding of 0.25% camphor +0.25% men-
thol +0.25% phenol and 5% LCD with four test
steroid creams produced no significant changes in
physicochemical stability or invitro skinpenetration
rate through human skin.
In contrast to conventional belief, results of our
study reveal that 10%urea enhances the penetration
of only triamcinolone acetonide through human
skin, which supports the finding of Wohlrab
1
and
Feldmann and Maibach.i No penetration enhance-
ment of 10%urea was observed for hydrocortisone
17-valerate and desoximetasone. The penetration
enhancement of fluocinonide by 10%urea was not
demonstrated in this study mainly because of its
chemical instability. As suggested by others.v 4 urea
may increase the horny layer's water-binding and
absorptive capacity that changes the skinstructural-
functional condition and, hence, changes the pene-
tration conditions under which the therapeutically
effective concentration of the steroid may be opti-
mized. Urea's enhancement of steroid penetration
and clinical effectiveness,however, alsois dependent
on the vehicle." The absorption enhancement also
could be attributed to the interaction of several other
984 Krochmal et al.
factors, such as the solubilityincrease by urea or the
complexation between the steroid and urea, vehicle
and urea, or skin and urea. Results of this study
demonstrate that urea is not a universal absorption
enhancer for every steroid.
Results also disclosethat compounding should be
practiced with care. Previous knowledge of the
commonly added chemicals is required so that a
maximum clinical benefit can be achieved through
the compounding process.
Journal of the
American Academy of
Dermatology
REFERENCES
1. Wohlrab W. The influence of urea on the penetration
kinetics of topically applied corticosteroids. Acta Derm
Venereol (Stockh) 1984;64:233-8.
2. Feldmann RJ, Maibach HI. Percutaneous penetration of
hydrocortisone with urea. Arch Dermatol 1974;109:58-9.
3. Burrows D, Shanks RG, Stevenson CJ. Therapeutics 111-
quarterly review. Br J DennatoI1968;80:550-3.
4. Weirich EG. Dermatophannacology of salicylic acid. Der-
matologica 1975;151:268-73.
ABSTRACfS
Skin hypersensitivity to IgE reverse reaginic tests in patients
with Brazilian pemphigus foliaceus
Rocha AMF, Antunes L, Patrus OA. Anais Bras Dermatol
1988;63:347-9 (Portuguese)
The IgE immune responsewas assessed by the reverse reaginic test in
16patientswithBrazilianendemicpemphigusand in an equalnumber
of healthy controlsubjects. In both groups skin tests wereperformed
withthe useof housedust, airbornefungi,and dermatophytidantigens.
Noneof the patientsor control subjectshad a historyof atopy. Positive
skintest reactionstohouse dust and airbornefungi were morecommon
in patients withBrazilianpemphigusfoliaceus in comparison with the
control group.The IgE immune response may playa roleinthe patho-
genesis of Brazilianpemphigusfoliaceus,
Yehudi M. Felman, MD
Postoperative interferon/hydrogel treatment for chronic
persisting giant condylomata acuminata
Gross G, Roussake A, Pfister H. Hautarzt 1988;39:684-7
(German)
The local application of recombinant interferonalfa-2c withhydrogel
(1 X 10
6
IV recombinant interferon alfa-Zc per gram of hydrogel),
given asan adjuvanttherapy after electrosurgery, ledto a completecure,
withoutrelapse, ofpreviously recalcitrantgiant condylomataacuminata
similarto the Buschke-Ldwenstein tumor in a 19-year-old womanwith
Hodgkin'sdisease (stage 11/11I). Recombinant interferonalfa-2c-hy-
drogel givenas an adjuvant therapyto surgerymay have moreantiviral
and antiproliferative effects than immunomodulatory activity. This
form of interferon alfa is safe and effective and is especially recom-
mended in immunocompromised persons with genital human papillo-
mavirus infection unresponsive to conventional therapeutic modalities.
Yehudi M. Felman, MD
Hyperpigmented striae after bleomycin therapy
Massone L, Pestarino A, Borghi S, et al. Ital DermatoI Venereol
1988;123:225-7 (Italian)
Hyperpigmented linear striae appeared on the trunk of a 65-year-old
irianwitha 7-yearhistoryof Hodgkin'sdisease. He had beentreatedfor
a fewmonthswitha cumulative bleomycin doseof 112mg. Streaking
on the skinwas first notedsomeweeks after the onset of veryintense
pruritus. Biopsy specimens showed melanotic hyperpigmentation with
nochangeinthe morphology of theskin.Theauthorssuggestthat bleo-
mycin, accumulated in the skin because ofscratching-induced vasodi-
lation, mayreduce epidermal turnover timeand allow a longer period
of contact between keratinocytes and melanocytes. This mayincrease
in the transfer of melanosomes toepidermal cells. Therapywithcime-
tidineinsingledailydoses of800mgreduced theintensity of itching for
several months.
Yehudi M. Felman, MD
Long-term skin effects of optical radiation
Wiskemann A. Aktuel Dermatol1988;14:320-2 (German)
Long-term effects of excessive sun exposure include alterationof Con-
nective tissue(photoaging), multiplesolarkeratoses, skincancer(pho-
tocarcinogenesls), and pigmented lesions (solarlentigines, lentigo ma-
ligna,lentigo rnaligna melanoma). Fair-skinned persons are at highest
risk. In hairless mice,connective tissue damageis induced mostby the
VVBwaveband and least by the UVA waveband of simulated global
radiation. Radiant heat fromthe visible and infraredwavebands also
damages connective tissue. The actionspectrum for photocarcinogene-
sisin miceresembles that of ultraviolet radiation-induced erythema in
humanbeings. UVAradiation(340nm) produces noskincancerin an-
imalexperiments, but radiantheat mayaugment carcinogenesis inmice
or produce skin cancer by itself. Besides carcinogenesis by direct ra-
dioexposure, the induction of specific immunotolerance againstpreex-
istingtumorcellsbysmallbut accumulating singledoses of UVBradi-
ation,as demonstrated byexperiments inanimals, must be considered.
An increased riskof skincancer byexposure to tanningequipment or
to phototherapy canbe estimatedby the amountof additional ultravi-
oletexposures inminimalerythemadoses peryear andcanberestricted
by optimizing the spectra. Alreadyexisting radiationdamage (except
forskincancer)mayregress iftheskin istotally protectedbysunscreens.
Tretinoincream0.1%to 0.01% accelerates the regression.
Yehudi M. Felman, MD