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Department of Pharmaceutical Technology, Shri Vishnu College of Pharmacy, Bhimavaram 534202, Andhra Pradesh,
India
b
College of Pharmaceutical Sciences, Western University of Health Sciences, Pomona, California 91766, USA
Received 9 January 2015; received in revised form 9 May 2015; accepted 26 May 2015
KEY WORDS
Bioavailability;
Cocrystals;
Solubility;
Inclusion complexation;
Nanoparticles;
Self-emulsifying formula
tions;
Proliposomes
Abstract The emerging trends in the combinatorial chemistry and drug design have led to the
development of drug candidates with greater lipophilicity, high molecular weight and poor water
solubility. Majority of the failures in new drug development have been attributed to poor water solubility
of the drug. Issues associated with poor solubility can lead to low bioavailability resulting in suboptimal
drug delivery. About 40% of drugs with market approval and nearly 90% of molecules in the discovery
pipeline are poorly water-soluble. With the advent of various insoluble drug delivery technologies, the
challenge to formulate poorly water soluble drugs could be achieved. Numerous drugs associated with
poor solubility and low bioavailabilities have been formulated into successful drug products. Several
marketed drugs were reformulated to improve efcacy, safety and patient compliance. In order to gain
marketing exclusivity and patent protection for such products, revitalization of poorly soluble drugs using
insoluble drug delivery technologies have been successfully adopted by many pharmaceutical companies.
This review covers the recent advances in the eld of insoluble drug delivery and business prospects.
& 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical
Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
2.
2.1.
443
at pH4pKa (ionization constant) and weakly basic drugs are
soluble at pHopKa6. This pH dependent solubility was explored
extensively to formulate insoluble drugs. On the other hand, salt
formation of weakly acidic or basic drugs provided alternate
strategies for formulation of drugs which have pH dependent
solubility. Pharmaceutically acceptable counter ions in the salt can
provide favorable pH conditions upon dissolution in water, and
thus the pH of resulting solution would be close to maximum pH
of drugs. Hence salt forms may sometimes avoid pH adjustments
necessary for solubilization of drugs. In addition, salt formation
has been reported to improve crystallinity, stability and pharmaceutical processibility of drugs6.
There are many insoluble drugs on the market which are
formulated with pH modication technology. Ciprooxacin is a
classic drug which is weakly basic and practically insoluble in
water at neutral pH. However it exhibits pH-dependent solubility
with higher solubility at acidic condition. Most of the intravenous
formulations contain lactic acid as pH modier to improve
solubility7. Intravenous ciprooxacin infusions are essential for
treating different kinds of severe bacterial infections. Telmisartan
is another drug which exhibits pH-dependent solubility. The
currently marketed oral formulation of telmisartan contain alkalis,
such as sodium hydroxide and meglumine for pH modication710.
Telmisartan formulation marketed under brand name Micardiss is
manufactured using a expensive spray-drying process, wherein
drug and alkalis along with other excipients are dissolved in water
and spray-dried to produce granules11. The spray-dried granules
obtained were reported to have a pH-independent dissolution
prole. However, generic versions of the telmisartan formulation
are hard to come by, owing to the insoluble nature of the drug's
free-acid-form and the critical steps involved in its manufacturing
process that provided an additional market capitalization to the
innovator12.
Repaglinide is an example of Zwitterion drug with poor water
solubility of 37 mg/mL13. Currently repaglinide, marketed as
Prandins in USA, is formulated with meglumine as pH modier.
Various patents disclose the use of meglumine in the formulation
and spray-drying as the process for preparing the granules1417.
Tricky process and critical formulation sometimes prove to be hard
to make generic copies. In case of both telmisartan and repaglinide, actual salt forms of drugs are not used in the formulation,
instead the bases such as meglumine and sodium hydroxide were
added to the formulation. This could be due to technical reasons,
such as lack of crystallinity, poor stability and deliquescent nature
of resulting salts. On other hand, including bases in the formulation could be due to commercial reasons, in order to build
complexity in the process and product, such that it is hard to
make generic versions. These are a few examples of how a
clinically and commercially benecial drug product could be
launched in the market by altering the formulation strategies.
Aspirin is century old non-steroidal anti-inammatory drug
(NSAID), yet currently explored by various companies for
commercial benets. Soluble formulations of aspirin are currently
available on the market. Aspro Clear, is soluble, effervescent tablet
containing aspirin. The effervescence and favorable pH condition
required for solubility of aspirin are facilitated by incorporating
sodium bicarbonate and citric acid in the formulation. Aspro Clear
reported to provide faster relief of pain than plain aspirin tablets18.
This is another example, how insoluble drug formulation technology can be explored for commercial and clinical benets.
Insoluble drugs are mostly formulated using the salt forms of
weakly acid and basic drugs. Various salt forms of drugs have
444
been the area of interest for pharmaceutical companies for
commercial and clinical benets. In the following section, few
examples of such inventions are discussed. Identication of
bisulfate salt form of atazenavir is an interesting example of
how salt screening could help a molecule to progress from being
dropped at preclinical development to clinical studies and nally to
marketing approval. Atazenavir as free base is practically insoluble
in water (o1 mg/mL) and had poor oral bioavailability in
preclinical animal models19. Lack of sufcient absorption was
reported to be a hurdle in the development of this molecule. In an
effort to identify viable option to improve the bioavailability,
series of salts were screened and nally atazenavir bisulfate was
selected for further development19,20. Atazenavir bisulfate exhibited distinct advantage over other salts such as methane sulfonate
and hydrochloride in terms of solubility and solid state stability.
Hydrochloride and methane sulfonate salts of atazenavir, when
dissolved in water beyond saturation solubility of salts, there was
solid state transformation leading to dissociation of salt to free
base at pH4pHmax. Analysis of excess of solid in the suspension
revealed that material was indeed free base. Under similar
experimental conditions bisulfate was found to be stable and did
not convert to free base, and rather excess of solid was found to be
in hydrated sulfate salt20. Therefore, the absolute bioavailability of
bisulfate was multifold-higher than the free base. This invention
not only lead to superior protease inhibitor on the market but
provided additional patent protection and marketing exclusivity to
inventor company.
One of largest-selling anticancer drugs imatinib is marketed as a
salt form, imatinib mesylate. The drug exhibits poor solubility and
hence mesylate salt was used for its development, which is soluble in
water at pHo5.521,22. Among the two polymorphic forms ( and ),
generated by imatinib salt, the form is more stable with acceptable
pharmaceutical properties. However, additional marketing rights were
assigned to the innovator due to their patent protection of the
form23. Many old drugs have been reformulated as salt forms for
commercial purposes. One such example is fenobrate, which was
approved in 1993 and was included in generic competition from the
year 200024. Since then, Abbott laboratories24 continued ling NDA's
altering the dose in order to gain market exclusivity. Interestingly, the
active form of all fenobrate formulations was found to be fenobric
acid, an active metabolite of fenobrate which was responsible for the
therapeutic activity. This fact was well explored by Abbot and
developed cholin-fenobrate, a soluble and light-stable salt of
fenobric acid25. This salt form was developed into a delayed
release capsule formulation and was approved by the FDA. This
delayed release formulation was proved to be one of blockbuster
product in the recent time. In the times of innovation drought,
such inventions are becoming huge commercial success thus
improving overall investment drive in pharmaceutical research and
development.
The use of aspirin for clinical management of migraine was tested
recently. The soluble aspirin-D,L-lysine salt was formulated for
intravenous injection (IV). The clinical studies revealed that intravenous administration of aspirin was effective in relieving migraine
attack. Although sumatriptan was slightly more effective than aspirin
IV in headache relief, aspirin was well tolerated26,27. Hence the new
salt form of aspirin demonstrated safe, effective and affordable
alternative therapy for the treatment of migraine. Similarly aspirincalcium was utilized in the formulation of soluble tablet (Solorpins).
The formulation showed faster onset of action compared to the tablet
with plain aspirin28. Improved clinical benets, as well as commercial
prots, were accomplished with these salt forms.
2.2.
Table 1
445
Solvent
Percentage administered
(%)
Route of
administration
Example
Cremophor EL
Cremophor RH 60
Dimethylacetamide
(DMA)
Ethanol
Glycerin
N-methyl-2-pyrrolidone
PEG 300
PEG 400
Polysorbate 80
Propylene glycol
Solutol HS-15
1165
20
6
r 10
r0.08
r3
IV infusion
IV infusion
IV infusion
Paclitaxel
Tacrolimus
Teniposide
580
1532
100
r60
1867
0.075100
1080
50
r6
r 15
100
r 50
r 18
r4
r 80
50
SC
IM, SC, IV
Subgingival
IM, IV bolus
IM
IM
IM
IV
Dihydroergotamine
Dihydroergotamine
Doxycyclin
Methocarbamil
Lorazepam
Chlordiazepoxide
Lorazepam
Propanidid
2.3.
446
Table 2
Drug
Brand name
Carrier
Manufacturer
Itraconazole
Tacrolimus
Lopinavir/Ritonavir
Nabilone
Nimodipine
Fenobrate
Etravirine
Sporanoxs
Prografs
Kaletras
Casamets
Nimotops
Fenoglides
Intelences
HPMC
HPMC
PVP/VA
PVP
PEG
PEG/Poloxamer
HPMC
1992
1994
2005
2006
2006
2007
2008
Polymeric micelles
Inclusion complexation
Table 3
Product
Incorporated drug
Status
Company
Genexol PM
Estrasorb
Medicelle
Flucide
Basulin
DO/NDR/02
NK-911
NK-105
NK-012
NC-6004
NC-4016
SP-1049C
NC-6300
Paclitaxel
Estrogen
DACH-platin-PEG-polyglutamic acid
Anti-inuenza
Insulin
Paclitaxel
Doxorubicin
Paclitaxel
SN-38
Cisplatin
Oxaliplatin
Doxorubicin
Epirubicin
Marketed
Marketed
phase I/II
phase I/II
phase II/III
phase I/II
phase II
phase II/III
phase II
phase III
phase I/II
phase II/III
phase I/II
Samyang
Novavax
NanoCarrier
Nano Viricides
Flamel Technologies
Dabur Research Foundation
Nippon Kayaku Co.
Nippon Kayaku Co.
Nippon Kayaku Co.
Nanocarrier Co.
Nanocarrier Co.
SupratekPharma Inc.
Nanocarrier Co.
447
448
Table 4
Trade name
Drug
Indication
Innovator company
Rapamunes
Emends
Tricors
Megace ESs
Triglides
Avinzas
Focalin
Rapamycin, sirolimus
Aprepitant
Fenobrate
Megestrol
Fenobrate
Morphine sulfate
Dexmethyl-phenidate HCl
ElanNanosystems
ElanNanosystems
Abbott Laboratories
ElanNanosystems
IDD-P Skyepharma
ElanNanosystems
ElanNanosystems
Wyeth
Merck & Co.
Abbott laboratories
Par Pharmaceuticals
ScielePharma Inc. King
Pharmaceuticals
Novartis
Ritalin
Zanaex Capsules
Immunosuppressant
Anti-emetic
Hypercholesterolemia
Anti-anorexic
Hypercholesterolemia
Phychostimulant drug
Attention decit hyperactivity
disorder (ADHD)
CNS stimulant
Muscle relaxant
ElanNanosystems
ElanNanosystems
Novartis
Acorda
Table 5
Key nanotechnology-based approaches for the enhancement of drug solubility and oral bioavailability.
Company
American Biosciences
(Blauvelt, USA)
Baxter
Pharmaceuticals
(Deereld, USA)
BioSante
Pharmaceuticals
(Lincolnshire, USA)
ElanPharma
International
(Dublin, Ireland)
Eurand
Pharmaceuticals
(Vandalia, USA)
iMEDDInc
(Burlingame, USA)
pSivida Ltd.
(Watertown, USA)
Paclitaxel albumin
nanoparticles76
Nano-lipid emulsion77
PharmaSol GmbH
(Berlin, Germany)
SkyePharmaPlc,
(Piccadily, London,
UK)
Calcium phosphate
nanoparticles78
Nanocrystal drug
particle79
2.7.
Cyclodextrin
nanoparticle80
Stretchable silicon
nanomembrane81
Silicon nanoparticles
Table 6
449
Drug
Lipid used
Biopharmaceutical application
5-Fluoro uracil
Apomorphine
Calcitonin
Clozapine
Cyclosporin A
Gonadotropin release
hormone
Ibuprofen
Idarubicin
Insulin
Emulsifying wax
Stearin acid, octadecyl alcohol, cetylpalmitate,
glycerylpalmitostearate, glyceryltripalmitate,
glycerylbehenate and glycerylmonostearate.
Campritol 888 ATO
Glycerylbehanate, palmitostearate, glyceryltristearate
Monostearin, stearic acid and oleic acid
Glycerylmonostearate and tristearin
Gycerylmonostearate and stearic acid
Lopinavir
Nimusulide
Progesterone
Repaglinide
Tetracycline
2.9.
450
Table 7
Product
Drug
Company
Indication target
Atragen
Amphotec
Ambisome
Amphocil
Abelcet
ALEC
Tretinoin
Amphotericin B
Amphotericin B
Amphotericin B
Amphotericin B
Dry protein free powder of
DPPC-PG
Killed avian retrovirus
Chicken pox
Daunorubicin citrate
Morphine
Daunorubicin citrate
Cytarabin
Doxorubicin
estradiol
Doxorubicin
Inactivated hepatitis-A
Virions
Amphotericin B
Amikacin
Nystatin
Terbutalinesulphate
Prostoglandin-E1
Vincristine
SequusPharmaceutical Inc.
Novavax
The liposome company, USA
Swiss serum & vaccine institute,
Switzerland.
Bristol-Myers Squibb, Netherland
NeXstar Pharmaceutical Inc., Co.
Aronex pharmaceuticals Inc.
Ozone Pharmaceuticals Ltd.
The liposome company, Inc.
NeXstar Pharmaceutical Inc., Co.
Avian retrovirus
vaccine
DaunoXome
DepoDur
DaunoXome
Depocyt
Doxil
Estrasorb
Evacet
EpaxalBernas Vaccine
Fungizone
MiKasomes
Nyotran
Topex-Br
Ventus
VincaXome
Table 8
Drug
Product name
Company
Therapeutic area
Cyclosporine A
Diazepam
DexamethazonePalmitate
Etomidate
Flurbiprofen
Prostaglandin-E1
Propofol
Restasis
Diazemuls
Limethason
Etomidat
Lipfen
Liple
Propofol
Diprivan
Fluosol-DA
Vitalipid
Allergan
Braun Melsungen
Green Cross
Dumex (Denmark)
Green Cross
Green Cross
Baxter Anesthesia
AstraZeneca
Green Cross
Kabi
Immunomodulation
Sedation
Carticosteroid
Anesthesia
Analgesia
Vasodilator
Anesthesia
Anesthesia
Analgesia
Nutrition
PerurodecalinPerurotripropylamine
Vitamins A, D, E and K
Table 9
451
Marketed oral products which yield an emulsion or microemulsion in the gastrointestinal tract.
Drug
Product name
Company
Therapeutic area
Cyclosporine
Cyclosporine
Calcitrol
Clofazimine
Doxercalciferol
Dronabionol
Dutasteride
Isotretionoin
Ritonavir
Ritonavir/lopinavir
Paricalcitol
Progesterone
Saquinavir
Sirolimus
Tritionoin
Tipranavir
Valproic acid
Sandimmune oral
Neoral
Rocaltrol
Lamprene
Hectoral
Marinol
Avodart
Accutane
Norvir
Kaletra
Zemplar
Prometrium
Fortovase
Rapumune
Vesanoid
Aptivus
Depakene
Novartis
Novartis
Roche
Geigy
Bone care
Roxane
GSK
Roche
Abbott
Abbott
Abbott
Solvay
Roche
Wyeth-ayerst
Roche
Boehringer Ingelheim
Abbott
Immunosuppressant
Immunosuppressant
Calcium regulator
Leprosy
Calcium regulator
Anoxeria
Benign Prostatic Hyperplasia (BPH)
Acne
AIDS
AIDS
Calcium regulator
Endometrial hyperplasia
AIDS
Immunosuppressant
Acne
AIDS
Epilepsy
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