Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs

• US 20030236236A1
• Filed: 05/22/2003
• Published: 12/25/2003
• Est. Priority Date: 06/30/1999
• Status: Abandoned Application

• Current Assignee: Lipocine Inc.
• Original Assignee: Lipocine Inc.
• Inventors: Zhang, Huiping, Fikstad, David T., Gilyar, Chandrashekar, Chen, Feng-Jing, Patel, Mahesh V.
• Application Number:
  US10/444,935
• Publication Number:
  US 20030236236A1
• Time in Patent Office: Days
• US Class Current: 514/171
• CPC Class Codes: A61B 17/0467 Instruments for cutting sutures surgical cutting instruments A61B17/32
• CPC Class Codes: A61B 17/0483 Hand-held instruments for holding sutures A61B17/0469 takes precedence; other holders for needles or sutures A61B17/06061; surgical forceps A61B17/28; surgical pincettes A61B17/30
• CPC Class Codes: A61B 17/0485 Devices or means, e.g. loops, for capturing the suture thread and threading it through an opening of a suturing instrument or needle eyelet
• CPC Class Codes: A61B 2017/0474 Knot pushers
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/122 having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• CPC Class Codes: A61K 31/355 Tocopherols, e.g. vitamin E
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/566 having an oxo group in position 17, e.g. estrone
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• CPC Class Codes: A61K 31/5685 having an oxo group in position 17, e.g. androsterone
• 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 31/585 containing lactone rings, e.g. oxandrolone, bufalin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/08 containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 : Organic macromolecular compounds
• CPC Class Codes: A61P 5/24 : of the sex hormones
• CPC Class Codes: A61P 5/30 : Oestrogens
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs, particularly steroids, are provided. The pharmaceutical compositions include a therapeutically effective amount of a hydrophobic drug, preferably a steroid; a solubilizer, preferably a vitamin E substance; and a surfactant. The synergistic effect between the hydrophobic drug and the vitamin E substance results in a pharmaceutical formulation with improved dispersion of both the active agent and the solubilizer. As a result of the improved dispersion, the pharamaceutical composition has improved bioavailability upon administration. Methods of improving the bioavailability of hydrophobic drugs administered to a patient are also provided.

Claims

1. A pharmaceutical composition comprising:

a. an active agent;

b. a vitamin E substance; and

c. a surfactant,

wherein upon dilution of the composition, the active agent increases the extent of dispersion of the vitamin E substance by at least 20% relative to the dispersion of the composition without the active agent.

2. The pharmaceutical composition of claim 1, wherein the active agent is a hydrophobic drug.

3. The pharmaceutical composition of claim 2, wherein the hydrophobic drug is a steroid.

4. The pharmaceutical composition of claim 2, wherein the hydrophobic drug is a benzoquinone.

5. The pharmaceutical composition of claim 1, wherein the vitamin E substance is selected from the group consisting of alpha tocopherol, alpha tocopherol acetate, alpha tocopherol succinate, and alpha tocopherol polyethyleneglycol succinate.

6. The pharmaceutical composition of claim 5, wherein the vitamin E substance is selected from the group consisting of d-alpha tocopherol, dl-alpha tocopherol, d-alpha tocopherol acetate, dl-alpha tocopherol acetate, d-alpha tocopherol succinate, and dl-alpha tocopherol succinate.

7. The pharmaceutical composition of claim 1, wherein the surfactant is selected from the group consisting of polyoxyl 35 castor oil, PEG-40 hydrogenated castor oil, caprylocaproyl macrogol-8 glycerides, polysorbate 80, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and tocopherol polyethyleneglycol 1000 succinate.

28. A method of improving the bioavailability of a hydrophobic drug administered to a patient comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 2 in a suitable dosage form.

8. A pharmaceutical composition comprising:

a. a steroid;

b. a vitamin E substance; and

c. a surfactant,

wherein after a 100×

dilution of the composition in an aqueous medium, at least 30% of the hydrophobic drug or the vitamin E substance is dispersed in the aqueous phase.

9. The pharmaceutical composition according to claim 8, wherein at least 50% of the active agent or the vitamin E substance is dispersed in the aqueous phase.

10. The pharmaceutical composition according to claim 8, wherein at least 30% of the active agent or the vitamin E substance is finely dispersed in the aqueous phase.

11. The pharmaceutical composition according to claim 10, wherein at least 50% of the active agent or the vitamin E substance is finely dispersed in the aqueous phase.

12. The pharmaceutical composition of claim 8, wherein the steroid is present in an amount ranging from 0.01% to 30% w/w of the composition, the vitamin E substance is present in an amount ranging from about 1% to 95% w/w of the composition, and the surfactant is present in an amount ranging from about 5 to 85% w/w of the composition.

13. The pharmaceutical composition of claim 12, wherein the steroid is progesterone.

14. The pharmaceutical composition of claim 12, wherein the steroid is testosterone.

15. The pharmaceutical composition of claim 12, wherein the steroid is dehydroepiantrosterone.

16. The pharmaceutical composition of claim 8, wherein the vitamin E substance is selected from the group consisting of alpha tocopherol, alpha tocopherol acetate, alpha tocopherol succinate, and alpha tocopherol polyethyleneglycol succinate.

17. The pharmaceutical composition of claim 16, wherein the vitamin E substance is selected from the group consisting of d-alpha tocopherol, dl-alpha tocopherol, d-alpha tocopherol acetate, di-alpha tocopherol acetate, d-alpha tocopherol succinate, and di-alpha tocopherol succinate.

18. The pharmaceutical composition of claim 8, wherein the surfactant is selected from the group consisting of polyoxyl 35 castor oil, PEG-40 hydrogenated castor oil, caprylocaproyl macrogol-8 glycerides, polysorbate 80, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and tocopherol polyethyleneglycol 1000 succinate.

19. The pharmaceutical composition of claim 8, wherein the steroid is progesterone, the vitamin E substance is alpha tocopherol, and the surfactant is polyoxyl 35 castor oil.

20. The pharmaceutical composition of claim 19, wherein the progesterone is present in an amount ranging from about 0.1% to 30% w/w.

21. The pharmaceutical composition of claim 20, wherein the progesterone is present in an amount ranging from about 0.01% to 0.3% w/w.

22. The pharmaceutical composition of claim 8, wherein the steroid is dehydroepiantrosterone, the vitamin E substance is alpha.tocopherol, and the surfactant is polyoxyl 35 castor oil.

23. The pharmaceutical composition of claim 22, wherein the dehydroepiantrosterone is present in an amount of at least 5% w/w.

24. The pharmaceutical composition of claim 8, wherein the steroid is testosterone, the vitamin E substance is alpha tocopherol succinate, and the surfactant is tocopherol polyethyleneglycol 1000 succinate.

25. The pharmaceutical composition of claim 24, wherein the testosterone is present in an amount of at least 1% w/w.

26. The pharmaceutical composition of claim 8, wherein the steroid is progesterone, the vitamin E substance is alpha tocopherol succinate, and the surfactant is tocopherol polyethyleneglycol 1000 succinate.

27. The pharmaceutical composition of claim 26, wherein the progesterone is present in an amount ranging from about 1% to 30%.

29. A method of improving the bioavailability of a steroid administered to a patient comprising administering to said patient a therapeutically effective amount of the pharmaceutical composition of claim 8 in a suitable dosage form.