Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents

• US 6,294,192 B1
• Filed: 02/26/1999
• Issued: 09/25/2001
• Est. Priority Date: 02/26/1999
• Status: Expired due to Term

• Current Assignee: Lipocine Inc.
• Original Assignee: Lipocine Inc.
• Inventors: Chen, Feng-Jing, Patel, Mahesh V.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): CHANNAVAJJALA, LAKSHMI SARADA
• Application Number:
  US09/258,654
• Time in Patent Office: 942 Days
• Field of Search: 424/450, 424/451, 424/455, 424/489, 424/464, 514/772, 514/937, 514/962, 514/963, 514/975
• US Class Current: 424/451
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: A61P 5/26 Androgens
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The present invention relates to triglyceride-free pharmaceutical compositions for delivery of hydrophobic therapeutic agents. Compositions of the present invention include a hydrophobic therapeutic agent and a carrier, where the carrier is formed from a combination of a hydrophilic surfactant and a hydrophobic surfactant. Upon dilution with an aqueous solvent, the composition forms a clear, aqueous dispersion of the surfactants containing the therapeutic agent. The invention also provides methods of treatment with hydrophobic therapeutic agents using these compositions.

Claims

1. A capsule for oral administration of a therapeutic agent, containing a composition comprised of:

(a) a hydrophobic therapeutic agent having an intrinsic water solubility of less than about 1 wt. % at 25°

C. and present in a therapeutically effective dosage for oral administration; and

(b) a carrier comprising

(i) at least one hydrophilic surfactant selected from the group consisting of hydrophilic non-ionic surfactants, hydrophilic ionic surfactants, and combinations thereof and

(ii) at least one hydrophobic surfactant having an HLB value less than about 10 and selected from the group consisting of alcohols;

polyoxyethylene alkylethers;

fatty acids;

glycerol fatty acid monoesters;

glycerol fatty acid diesters;

acetylated glycerol fatty acid monoesters;

acetylated glycerol fatty acid diesters, lower alcohol fatty acid esters;

polyethylene glycol fatty acid esters;

polyethylene glycol glycerol fatty acid esters;

polypropylene glycol fatty acid esters;

polyoxyethylene glycerides;

lactic acid derivatives of monoglycerides;

lactic acid derivatives of diglycerides;

propylene glycol diglycerides;

sorbitan fatty acid esters;

polyoxyethylene sorbitan fatty acid esters;

polyoxyethylene-polyoxypropylene block copolymers;

transesterified vegetable oils;

sterols;

sterol derivatives;

sugar esters;

sugar ethers;

sucroglycerides;

polyoxyethylene vegetable oils;

polyoxyethylene hydrogenated vegetable oils;

reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and

mixtures thereof,

said hydrophilic and hydrophobic surfactants being present in amounts such that upon dilution with an aqueous solution at an aqueous solution to carrier ratio of 100;

1 by weight, the carrier forns a clear aqueous dispersion having an absorbance of less than about 0.1 at a wavelength of about 400 nm,

wherein the composition is substantially free of water and glycerol triesters of C₆ to about C₂₅ fatty acids.

2. The capsule of claim 1, wherein the hydrophobic surfactant is present in an amount of less than about 200% by weight, relative to the amount of the hydrophilic surfactant.

3. The capsule of claim 2, wherein the hydrophobic surfactant is present in an amount of less than about 100% by weight, relative to the amount of the hydrophilic surfactant.

4. The capsule of claim 3, wherein the hydrophobic surfactant is present in an amount of less than about 60% by weight, relative to the amount of the hydrophilic surfactant.

5. The capsule of claim 1, wherein the hydrophilic surfactant comprises at least one non-ionic hydrophilic surfactant having an HLB value greater than or equal to about 10.

6. The capsule of claim 1, wherein the hydrophilic surfactant comprises at least one ionic surfactant.

7. The capsule of claim 5, which further comprises at least one ionic surfactant.

8. The capsule of claim 5, wherein the non-ionic surfactant is selected from the group consisting of alkylglucosides;

alkylmaltosides;

alkylthioglucosides;

lauryl macrogolglycerides;

polyoxyethylene alkyl ethers;

polyoxyethylene alkylphenols;

polyethylene glycol fatty acid esters;

polyethylene glycol glycerol fatty acid esters;

polyoxyethylene sorbitan fatty acid esters;

polyoxyethylene-polyoxypropylene block copolymers;

polyglycerol fatty acid esters;

polyoxyethylene glycerides;

polyoxyethylene sterols, derivatives, and analogues thereof;

polyoxyethylene vegetable oils;

polyoxyethylene hydrogenated vegetable oils;

reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols;

sugar esters, sugar ethers;

sucroglycerides; and

mixtures thereof.

9. The capsule of claim 5, wherein the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers;

polyethylene glycol fatty acid esters;

polyethylene glycol glycerol fatty acid esters;

polyoxyethylene sorbitan fatty acid esters;

polyoxyethylene-polyoxypropylene block copolymers;

polyglycerol fatty acid esters;

polyoxyethylene glycerides;

polyoxyethylene vegetable oils;

polyoxyethylene hydrogenated vegetable oils;

reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and

mixtures thereof.

10. The capsule of claim 8 or claim 9, wherein the non-ionic hydrophilic surfactant comprises a reaction product of a polyol and a monoglyceride, diglyceride, triglyceride, or a mixture thereof.

11. The capsule of claim 9, wherein the non-ionic hydrophilic surfactant comprises a transesterification product of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.

12. The capsule of claim 10, wherein the polyol is glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a mixture thereof.

13. The capsule of claim 5, wherein the hydrophilic surfactant is PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 capratelcaprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, a poloxamer, or a mixture thereof.

14. The capsule of claim 5, wherein the hydrophilic surfactant is PEG-20 laurate, PEG-20 oleate, PEG-35 castor oil, PEG-40 palm kernel oil, PEG-40 hydrogenated castor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate, polyglyceryl-10 laurate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, PEG-30 cholesterol, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, PEG-24 cholesterol, sucrose monostearate, sucrose monolaurate, a poloxamer, or a mixture thereof.

15. The capsule of claim 5, wherein the hydrophilic surfactant is PEG-35 castor oil, PEG-40 hydrogenated castor oil, PEG-60 corn oil, PEG-25 glyceryl trioleate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polysorbate 20, polysorbate 80, tocopheryl PEG-1000 succinate, PEG-24 cholesterol, a poloxamer, or a mixture thereof.

16. The capsule of claim 6, wherein the ionic surfactant is selected from the group consisting of alkyl ammonium salts;

bile acids and salts, analogues, and derivatives thereof;

fatty acid derivatives of amino acids, oligopeptides, and polypeptides;

glyceride derivatives of amino acids, oligopeptides, and polypeptides;

acyl lactylates;

monoacetylated tartaric acid esters of monoglycerides, monoacetylated tartaric acid esters of diglycerides, diacetylated tartaric acid esters of monoglycerides, diacetylated tartaric acid esters of diglycerides;

succinylated monoglycerides;

citric acid esters of monoglycerides;

citric acid esters of diglycerides;

alginate salts;

propylene glycol alginate;

lecithins and hydrogenated lecithins;

lysolecithin and hydrogenated lysolecithins;

lysophospholipids and derivatives thereof;

phospholipids and derivatives thereof;

salts of alkylsulfates;

salts of fatty acids;

sodium docusate; and

mixtures thereof.

17. The capsule of claim 6, wherein the ionic surfactant is selected from the group consisting of bile acids and salts, analogues, and derivatives thereof;

lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof;

salts of alkylsulfates;

salts of fatty acids;

sodium docusate;

acyl lactylates;

monoacetylated tartaric acid esters of monoglycerides, monoacetylated tartaric acid esters of diglycerides, diacetylated tartaric acid esters of monoglycerides, diacetylated tartaric acid esters of diglycerides;

succinylated monoglycerides;

citric acid esters of monoglycerides, citric acid esters of diglycerides; and

mixtures thereof.

18. The capsule of claim 6, wherein the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, monoacetylated tartaric acid esters of monoglycerides, monoacetylated tartaric acid esters of diglycerides, diacetylated tartaric acid esters of monoglycerides, diacetylated tartaric acid esters of diglycerides, citric acid esters of monoglycerides, citric acid esters of diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, chenodeoxycholate, glycodeoxycholate, glycochenodeoxycholate, taurochenodeoxycholate, ursodeoxycholate, tauroursodeoxycholate, glycoursodeoxycholate, cholylsarcosine, N-methyl taurocholate, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, and salts and mixtures thereof.

19. The capsule of claim 6, wherein the ionic surfactant is selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, monoacetylated tartaric acid esters of monoglycerides, monoacetylated tartaric acid esters of diglycerides, diacetylated tartaric acid esters of monoglycerides, diacetylated tartaric acid esters of diglycerides, citric acid esters of monoglycerides, citric acid esters of diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.

20. The capsule of claim 6, wherein the ionic surfactant is selected from the group consisting of lecithin, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, monoacetylated tartaric acid esters of monoglycerides, monoacetylated tartaric acid esters of diglycerides, diacetylated tartaric acid esters of monoglycerides, diacetylated tartaric acid esters of diglycerides, citric acid esters of monoglycerides, citric acid esters of diglycerides, taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.

21. The capsule of claim 1, wherein the hydrophobic surfactant is selected from the group consisting of fatty acids;

lower alcohol fatty acid esters;

polyethylene glycol glycerol fatty acid esters;

polypropylene glycol fatty acid esters;

polyoxyethylene glycerides;

glycerol fatty acid monoesters;

glycerol fatty acid diesters;

acetylated glycerol fatty acid monoesters;

acetylated glycerol fatty acid diesters;

lactic acid derivatives of monoglycerides;

lactic acid derivatives of diglycerides;

sorbitan fatty acid esters;

polyoxyethylene sorbitan fatty acid esters;

polyoxyethylene-polyoxypropylene block copolymers;

polyoxyethylene vegetable oils;

polyoxyethylene hydrogenated vegetable oils;

reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and

mixtures thereof.

22. The capsule of claim 1, wherein the hydrophobic surfactant is selected from the group consisting of lower alcohol fatty acid esters;

polypropylene glycol fatty acid esters;

propylene glycol fatty acid esters;

glycerol fatty acid monoesters;

glycerol fatty acid diesters;

acetylated glycerol fatty acid monoesters;

acetylated glycerol fatty acid diesters;

lactic acid derivatives of mono/diglycerides;

sorbitan fatty acid esters;

polyoxyethylene vegetable oils; and

mixtures thereof.

23. The capsule of claim 22, wherein the hydrophobic surfactant is a glycerol fatty acid monoester, a glycerol fatty acid diester, an acetylated glycerol fatty acid monoester, an acetylated glycerol fatty acid diester, or a mixture thereof.

24. The capsule of claim 23, wherein the hydrophobic surfactant is a glycerol fatty acid monoester, a glycerol fatty acid diester, or a mixture thereof.

25. The capsule of claim 24, wherein the fatty acid of the glycerol fatty acid ester is a C₆ to C₂₀ fatty acid or a mixture thereof.

26. The capsule of claim 1, wherein the hydrophobic surfactant is a reaction product of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.

27. The capsule of claim 26, wherein the hydrophobic surfactant comprises a transesterification product of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.

28. The capsule of claim 26, wherein the polyol is polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or a mixture thereof.

29. The capsule of claim 1, wherein the hydrophobic surfactant is selected from the group consisting of myristic acid;

oleic acid;

lauric acid;

stearic acid;

palmitic acid;

PEG 1-4 stearate;

PEG 2-4 oleate;

PEG-4 dilaurate;

PEG-4 dioleate;

PEG-4 distearate;

PEG-6 dioleate;

PEG-6 distearate;

PEG-8 dioleate;

PEG 3-16 castor oil;

PEG 5-10 hydrogenated castor oil;

PEG 6-20 corn oil;

PEG 6-20 almond oil;

PEG-6 olive oil;

PEG-6 peanut oil;

PEG-6 palm kernel oil;

PEG-6 hydrogenated palm kernel oil;

PEG-4 capric/caprylic triglyceride, mono, di, tri, tetra esters of vegetable oil and sorbitol;

pentaerythrityl di, tetra stearate, isostearate, oleate, caprylate, or caprate;

polyglyceryl 2-4 oleate, stearate, or isostearate;

polyglyceryl 4-10 pentaoleate;

polyglyceryl-3 dioleate;

polyglyceryl-6 dioleate;

polyglyceryl-10 trioleate;

polyglyceryl-3 distearate;

propylene glycol monoesters of a C₆ to C₂₀ fatty acid, propylene glycol diesters of a C₆ to C₂₀ fatty acid;

monoglycerides of a C₆ to C₂₀ fatty acid;

acetylated monoglycerides of C₆ to C₂₀ fatty acid;

diglycerides of C₆ to C₂₀ fatty acids;

lactic acid derivatives of monoglycerides;

lactic acid derivatives of diglycerides;

cholesterol;

phytosterol;

PEG 5-20 soya sterol;

PEG-6 sorbitan tetra, hexastearate;

PEG-6 sorbitan tetraoleate;

sorbitan monolaurate;

sorbitan monopalmitate;

sorbitan mono, trioleate;

sorbitan mono, tristearate;

sorbitan monoisostearate;

sorbitan sesquioleate;

sorbitan sesquistearate;

PEG 2-5 oleyl ether;

POE 2-4 lauryl ether;

PEG-2 cetyl ether;

PEG-2 stearyl ether;

sucrose distearate;

sucrose dipalmitate;

ethyl oleate;

isopropyl myristate;

isopropyl palmitate;

ethyl linoleate;

isopropyl linoleate;

poloxamers; and

mixtures thereof.

30. The capsule of claim 1, wherein the hydrophobic surfactant is selected from the group consisting of oleic acid;

lauric acid;

glyceryl monocaprate;

glyceryl monocaprylate;

glyceryl monolaurate;

glyceryl monooleate;

glyceryl dicaprate;

glyceryl dicaprylate;

glyceryl dilaurate;

glyceryl dioleate;

acetylated monoglycerides;

propylene glycol oleate;

propylene glycol laurate;

polyglyceryl-3 oleate;

polyglyceryl-6 dioleate;

PEG-6 corn oil;

PEG-20 corn oil;

PEG-20 almond oil;

sorbitan monooleate;

sorbitan monolaurate;

POE-4 lauryl ether;

POE-3 oleyl ether;

ethyl oleate;

poloxamers;

d mixtures thereof.

31. The capsule of claim 1, wherein the clear aqueous dispersion has a particle size distribution having an average particle size of less than about 50 nm.

32. The capsule of claim 31, wherein the clear aqueous dispersion has a particle size distribution having an average particle size of less than about 20 nm.

33. The capsule of claim 1, wherein the absorbance is less than about 0.01.

34. The capsule of claim 1, wherein the intrinsic water solubility is loss than about 0.1% by weight at 25°

C.

35. The capsule of claim 34, wherein the intrinsic water solubility is less than about0.01% by weight at 25°

C.

36. The capsule of claim 1, wherein the therapeutic agent is a drug, a vitamin, a nutritional supplement, a cosmeceutical, or a mixture thereof.

37. The capsule of claim 1, wherein the therapeutic agent is a polyfunctional hydrophobic drug, a lipophilic drug, a pharmaceutically acceptable salt, isomer or derivative thereof, or a mixture thereof.

38. The capsule of claim 36, wherein the therapeutic agent is selected from the group consisting of analgesics, anti-inflanunatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β

-blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine H₁ and H₂ receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, nutritional agents, opioid analgesics, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.

39. The capsule of claim 36, wherein the therapeutic agent is tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine, rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz, dicournarol, tirofibran, cilostazol, ticlidopine, clopidrogel, oprevelkin, paroxetine, sertraline, venlafaxine, bupropion, clomipramine, miglitol, repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine, vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole, flucanazole, miconazole, ketoconazole, metronidazole, griseofulvin, nitrofurantoin, spironolactone, lisinopril, benezepril, nifedipine, nilsolidipine, telmisartan, irbesartan, eposartan, valsartan, candesartan, minnoxidil, terzosin, halofantrine, mefloquine, dihydroergotamine, ergotamine, frovatriptan, pizofetin, sumatriptan, zolmitriptan, naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide, pseudo-ephedrine, toremifene, atovaquone, metronidazole, furazolidone, paricalcitol, benzonatate, mnidazolam, zolpidem, gabapentin, zopiclone, digoxin, beclomethsone, budesonide, betamethasone, prednisolone, cisapride, cimetidine, loperamide, famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene, calciprotiene, calcitriol, targretin, ergocalciferol, cholecalciferol, isotreinoin, tretinoin, calcifediol, fenofibrate, probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin, tizanidine, dantrolene, isosorbide dinatrate, a carotene, dihydrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, an essential fatty acid source, codeine, fentanyl, methadone, nalbuphine, pentazocine, clomiphene, danazol, dihydro epiandrosterone, medroxyprogesterone, progesterone, rimexolone, megesterol acetate, osteradiol, finasteride, mefepristone, amphetamine, L-thryroxine, tamsulosin, methoxsalen, tacrine, donepezil, raloxifene, vertoporfin, sibutramine, pyridostigmine, a pharmaceutically acceptable salt, isomer, or derivative thereof, or a mixture thereof.

40. The capsule of claim 1, wherein the hydrophobic therapeutic agent is selected from the group consisting of tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine, rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz, miglitol, repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine, vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole, flucanazole, miconazole, ketoconazole, metronidazole, griseofulvin, nitrofurantoin, spironolactone, halofantrine, mefloquine, dihydroergotamihe, ergotamine, frovatriptan, pizofetin, sumatriptan, zolmitriptan, naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide, pseudo-ephedrine, toremifene, atovaquone, metronidazole, furzolidone, paricalcitol, benzonatate, midazolam, zolpidem, gabapentin, zopiclone, digoxin, cisapride, cimetidine, loperamnide, famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene, calciprotiene, calcitriol, targretin, ergocalciferol, cholecaliferol, isotreinoin, tretinoin, calcifediol, fenofibrate, probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin, tizanidine, dantrolene, carotenes, dihyrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, essential fatty acid sources, codeine, fentanyl, methdone, nalbuphine, pentazocine, clomiphene, danazol, dihydro epiandrosterone, mmedroxyprogesterone, progesterone, rimexolone, megesterol acetate, osteradiol, finasteride, mefepristone, amphetamine, L-thryroxine, tarnsulosin, methoxsalen, tacrine, donepezil, raloxifene, vertoporfin, sibutramine, pyridostigmine, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.

41. The capsule of claim 1, wherein the therapeutic agent is selected from the group consisting of tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, rifabutine, rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz, miglitol, repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine, vigabatrin, terbenafine, itraconazole, flucanazole, miconazole, ketoconazole, metronidazole, nitrofurantoin, dihydroergotamine, ergotamine, frovatriptan, pizofetin, zolmitriptan, pseudo-ephedrine, naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide, toremifene, atovaquone, metronidazole, fruzolidone, paricalcitol, benzonatate, cisapride, cimetidine, loperamide, famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine, chlorpheniramine, acutretin, tazarotene, calciprotiene, calcitriol, targretin, ergocalciferol, cholecaliferol, isotreinoin, tretinoin, calcifediol, fenofibrate, probucol, simvastatin, atorvastatin, tizanidine, dantrolene, carotenes, dihyrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, essential fatty acid sources, danazol, dihydro epiandrosterone, medroxyprogesterone, progesterone, rimexolone, megesterol acetate, osteradiol, finasteride, mefepristone, raloxifene, L-thryroxine, tamsulosin, methoxsalen, pharmaceutically acceptable salts, isomers and derivative thereof, and mixtures thereof.

42. The capsule of claim 1, wherein the hydrophobic therapeutic agent is selected from the group consisting of sildenafil citrate, amlodipine, tramadol, celecoxib, refocoxib, oxaprozin, nabumetone, ibuprofen, terbenafine, itraconazole, zileuton, zafirlukast, cisapride, fenofibrate, tizanidine, nizatidine, fexofenadine, loratadine, famotidine, paricalcitol, atovaquone, nabumetone, tetrahydrocannabinol, megesterol acetate, repaglinide, progesterone, rimexolone, cyclosporine, tacrolimus, sirolimus, teniposide, paclitaxel, pseudo-ephedrine, troglitazone, rosiglitazone, finasteride, vitamin A, vitamin D, vitamin E, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.

43. The capsule of claim 1, wherein the hydrophobic therapeutic agent is progesterone or cyclosporin.

44. The capsule of claim 1, wherein the carrier further comprises a solubilizer.

45. The capsule of claim 44, wherein the solubilizer is selected from the group consisting of alcohols, polyols, amides, esters, propylene glycol ethers and mixtures thereof.

46. The capsule of claim 45, wherein the solubilizer is an alcohol or polyol selected from the group consisting of ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, and mixtures thereof.

47. The capsule of claim 45, wherein the solubilizer is an amide selected from the group consisting of 2-pyrrolidone, 2-piperidone, ε

-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamnide, polyvinylpyrrolidone, and mixtures thereof.

48. The capsule of claim 45, wherein the solubilizer is an ester selected from the group consisting of ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε

-caprolactone and isomers thereof, δ

-valerolactone and isomers thereof, β

-butyrolactone and isomers thereof, and mixtures thereof.

49. The capsule of claim 44, wherein the solubilizer is selected from the group consisting of ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaeryiritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins, clodextrins and derivatives thereof, ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol diacetate, ε

-caprolactone and isomers thereof, δ

-valerolactone and isomers thereof, β

-butyrolactone and isomers thereof, 2-pyrrolidone, 2-piperidone, ε

-caprolactam, N-methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethyl pyrrolidone, N-octylpyrrolidone, N-laurylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, glycofurol, methoxy PEG, and mixtures thereof.

50. The capsule of claim 44, wherein the solubilizer is selected from the group consisting of ethanol, isopropanol, benzyl alcohol, ethylene glycol, propylene glycol, 1,3-butanediol, glycerol, pentaerythritol, sorbitol, glycofurol, transcutol, dimethyl isosorbide, polyethylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxypropylcyclodextrins, sulfobutyl ether derivatives of cyclodextrins, ethyl propionate, tributylcitrate, triethylcitrate, ethyl oleate, ethyl caprylate, triacetin, β

-butyrolactone and isomers thereof, 2-pyrrolidone, N-methylpyrrolidone, N-ethylpyrrolidone, N-hydroxyethylpyrrolidone, N-octylpyrrolidone, N-lauiylpyrrolidone, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof.

51. The capsule of claim 44, wherein the solubilizer is triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofuirol, transcutol, propylene glycol, dirnethyl isosorbide, or a mixture thereof.

52. The capsule of claim 44, wherein the solubilizer is triacetin, ethanol, polyethylene glycol 400, glycofurol, propylene glycol or a mixture thereof.

53. The capsule of claim 44, wherein the solubilizer is present in the composition in an amount of about 400% or less by weight, based on the total weight of the surfactants.

54. The capsule of claim 53, wherein the solubilizer is present in the composition in an amount of about 200% or less by weight, based on the total weight of the surfactants.

55. The capsule of claim 54, wherein the solubilizer is present in the composition in an amount of about 100% or less by weight, based on the total weight of the surfactants.

56. The capsule of claim 55, wherein the solubilizer is present in the composition in an amount of about 50% or less by weight, based on the total weight of the surfactants.

57. The capsule of claim 56, wherein the solubilizer is present in the composition in an amount about 25% or less by weight, based on the total weight of the surfactants.

58. The capsule of claim 1, wherein the composition further comprises an antioxidant, a preservative, a chelating agent, a viscomodulator, a tonicifier, a flavorant, a colorant, an odorant, an opacifier, a suspending agent, a binder, or a mixture thereof.

59. The capsule of claim 1, wherein the composition is multiparticulate.

60. The capsule of claim 1, wherein the capsule is selected from the group consisting of a hard gelatin capsule, a soft gelatin capsule, and a starch capsule.

61. A The capsule of claim 1, wherein the composition further comprises an additional amount of a hydrophobic therapeutic agent, said additional amount not solubilized in the carrier.

62. A method of treating an animal with a hydrophobic therapeutic agent, the method comprising:

orally administering to the animal a dosage form comprising the capsule of claim 1.

63. The method of claim 62, wherein the animal is a mammal.

64. The method of claim 63, wherein the mammal is a human.

65. The capsule of claim 1, wherein the clear aqueous dispersion is comprised of mixed micelles of the hydrophilic and hydrophobic surfactants.

71. The capsule of claim 1, wherein the hydrophobic surfactant is selected from the group consisting of monoglycerides, diglycerides, acetylated monoglycerides, acetylated diglycerides, propylene glycol mono fatty acid esters, propylene glycol di fatty acid esters, and mixtures thereof.

72. The capsule of claim 60, coated with an enteric coating.

66. A capsule containing a pharmaceutical composition comprising:

(a) a hydrophobic therapeutic agent having an intrinsic water solubility of less than about 1 percent by weight and present in a therapeutically effective dosage for oral administration, and

(b) a carrier comprised of

a hydrophilic surfactant selected from the group consisting of hydropllilic non-ioliic suifactants, hydrophilic ionic surfactants, and combinations thereof,

a hydrophobic surfactant selected from the group consisting of monoglycerides, diglycerides, acetylated monoglycerides, acetylated diglyceridcs, propylene glycol mono fatty acid esters, propylene glycol di fatty acid esters, and mixtures thereof, and

a solubilizer selected from the group consisting of alcohols, polyols, amides, esters, propylene glycol ethers and mixtures thereof and present in an amount of about 1% to about 100% by weight relative to the combined weight of the hydroplhilic and hydrophobic surfactants,

wherein the hydrophobic surfactant is present in an amount of about 5% to about 100% by weight relative to the hydrophilic surfactant, and the hydrophilic and hydrophobic surfactants are each present in amounts such that upon dilution with an aqueous solution at an aqueous solution to carrier ratio of 100;

1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.1 at a wavelength of about 400 nm, and further wherein the composition is substantially free of water and glycerol triesters of C₆ to about C₂₅ fatty acids.

67. The capsule of claim 66, wherein the solubilizer is an alcohol, a polyol, or a mixture thereof.

68. The capsule of claim 67, wherein the solubilizer is selected from the group consisting of ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose, cyclodextrins, and mixtures thereof.

69. The capsule of claim 66, wherein the hydrophobic surfactant is present in an amount of less than about 60% by weight relative to the amount of the hydrophilic surfactant.

70. The capsule of claim 66, wherein the solubilizer is present in an amount of about 5% to 25% by weight relative to the combined weight of the hydrophilic and hydrophobic surfactants.

73. A nultiparticulate dosage form for oral administration of a therapeutic agent, comprised of a plurality of beads each coated with a composition comprising

(a) a hydrophobic therapeutic agent having an intrinsic water solubility of less than about 1 wt. % at 25°

C., and present in a therapeutically effective amount for oral administration, and

(b) a carrier comprised of

(i) at least one hydrophilic surfactant selected from the group consisting of hydrophilic non-ionic surfactants, hydrophilic ionic surfactants, and combinations thereof, and

(ii) at least one hydrophobic surfactant having an HLB value less than about 10 and selected from the group consisting of alcohols;

polyoxyethylene alkylethers;

fatty acids;

glycerol fatty acid monoesters;

glycerol fatty acid dicstets;

acetylated glycerol fatty acid monoestors;

acetylated glycerol fatty acid diesters, lower alcohol fatty acid esters;

polyethylene glycol fatty acid esters;

polyethylene glycol glycerol fatty acid esters;

polypropylene glycol fatty acid esters;

polyoxyethylene glycerides;

lactic acid derivatives of monoglycerides;

lactic acid derivatives of diglycerides;

propylene glycol diglycorides;

sorbitan fatty acid esters;

polyoxyethylene sorbitan fatty acid esters;

polyoxyethylene-polyoxypropylene block copolymers;

transesterilied vegetable oils;

sterols;

sterol derivatives;

sugar esters;

sugar ethers;

sucroglycerides;

polyoxyethylene vegetable oils;

polyoxyctlhylene hydrogenated vegetable oils;

reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and

mixtures thereof,

said hydrophilic and hydrophobic surfactants being present in amounts such that upon dilution with an aqueous solution at an aqueous solution to carrier ratio of 100;

1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.1 at a wavelength of about 400 nm, and wherein the composition is substantially free of water and glycerol triesters of C₆ to about C25 fatty acids.

74. A multiparticulate dosage form for oral administration of a therapeutic agent, comprised of a plurality of particles each comprising a composition of

(a) a hydrophobic therapeutic agent having and intrinsic water solubility of less than about 1 wt. % at 25°

C. and present in a therapeutically effective amount for oral administration, and

(b) a carrier comprised of

(i) at least one hydrophilic surfactant selected from the group consisting of hydrophilic non-ionic surfactants, hydrophilic ionic surfactants, and combinations thereof, and

(ii) at least one hydrophobic surfactant having an HLB value less than about 10 and selected from the group consisting of alcohols;

polyoxyethylene alkylethers;

fatty acids;

glycerol fatty acid monoesters;

glycerol fatty acid diesters;

acetylated glycerol fatty acid monoesters;

acetylated glycerol fatty acid diesters, lower alcohol fatty acid esters;

polyethylene glycol fatty acid esters;

polyethylene glycol glycerol fatty acid esters;

polypropylene glycol fatty acid esters;

polyoxyethylene glycerides;

lactic acid derivatives of monoglycorides;

lactic acid derivatives of diglycerides;

propylene glycol diglycerides;

sorbitan fatty acid esters;

polyoxyetliylene sorbitan fatty acid esters;

polyoxyethylene-polyoxypropylene block copolymers;

transesterilied vegetable oils;

sterols;

sterol derivatives;

sugar esters;

sugar ethers;

sucroglycerides;

polyoxyethylene vegetable oils;

polyoxyethylene hydrogenated vegetable oils;

reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and

mixtures thereof,

said hydrophilic and hydrophobic surfactants being present in amounts such that upon dilution with an aqueous solution at an aqueous solution to carrier ratio of 100;

1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.1 at a wavelength of about 400 nm, and wherein the composition is substantially free of water and glycerol triesters of C₆ to about C₂₅ fatty acids.