Oral dosage forms comprising progesterone and methods of making and using the same

• US 20060275360A1
• Filed: 05/26/2006
• Published: 12/07/2006
• Est. Priority Date: 05/26/2005
• Status: Active Grant

• Current Assignee: Teva Women's Health Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Teva Women's Health Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Gupta, Sanjeev K., Vattikonda, Chandra, Ahmed, Salah U., Gorukanti, Sudhir R., Diliberti, Charles E.
• Granted Patent: US 8,663,681 B2
• Time in Patent Office: Days
• 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 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1664 Compounds of unknown constitution, e.g. material from plants or animals oils, fats, waxes, shellac A61K9/1617
• CPC Class Codes: A61K 9/485 Inorganic compounds
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular 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 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system

Abstract

The present invention relates to an oral pharmaceutical dosage form comprising micronized progesterone, an edible oil, a disintegrant, and a hydrophilic excipient. Particularly, the invention relates to a pharmaceutical dosage form wherein the dosage form is in a powder form and is contained in a pharmaceutically acceptable capsule. The present invention is also directed toward methods of making the dosage form, methods of using the dosage form, and kits comprising the dosage form.

Claims

1. An oral pharmaceutical dosage form comprising:

(a) micronized progesterone;

(b) an edible oil;

(c) a disintegrant; and

(d) a hydrophilic excipient,

wherein the dosage form is in a powder form and is contained in a pharmaceutically acceptable capsule.

2. The dosage form of claim 1, wherein the edible oil is selected from the group consisting of safflower oil, linseed oil, soybean oil, corn oil, sunflower oil, sesame oil, olive oil, cottonseed oil, flaxseed oil, menhaden oil, and mixtures thereof.

3. The dosage form of claim 1, wherein the disintegrant is crospovidone.

4. The dosage form of claim 1, wherein the hydrophilic excipient is selected from the group consisting of corn starch, potato starch, pregelatinized starch, povidone, polysorbate, mannitol, microcrystalline cellulose, sodium starch glycolate, and mixtures thereof.

5. The dosage form of claim 1, further comprising an absorbant selected from the group consisting of silicon dioxide and its derivatives, micronized silicas, lactose, lactose monohydrate, methylcellulose, microcrystalline cellulose, sugars, maltodextrin, and mixtures thereof.

6. The dosage form of claim 1, further comprising an antioxidant selected from the group consisting of adipic acid, alpha lipoic acid, ascorbyl palmitate, biotin, boron, butylated hydroxyl toluene, butylated hydroxyanisole, carotenoids, calcium citrate, sodium metabisulfate, tocopherols, and mixtures thereof.

7. The dosage form of claim 1, further comprising a lubricant selected from the group consisting of magnesium stearate, colloidal silicon dioxide, silica gel, aluminum stearate, talc, stearic acid, sodium stearate, calcium stearate, sodium stearyl fumarate, and mixtures thereof.

8. The dosage form of claim 1, wherein the powder is free flowing.

9. The dosage form of claim 1, wherein the dosage form does not contain peanut oil or peanut particles.

10. The dosage form of claim 1, wherein the drug has a mean particle size of about 1 micron to about 15 microns.

11. The dosage form of claim 1, which contains 400 mg of the micronized progesterone.

12. The dosage form of claim 11, wherein the AUC_(0-T) for progesterone does not exceed 250 ng*hr/mL when the dosage form is administered to a subject.

13. The dosage form of claim 11, wherein the AUC_(0-T) for progesterone does not exceed 200 ng*hr/mL when the dosage form is administered to a subject.

14. The dosage form of claim 11, wherein the AUC_(0-T) for progesterone does not exceed 150 ng*hr/mL when the dosage form is administered to a subject.

15. The dosage form of claim 11, wherein the C_max for progesterone does not exceed 60 ng/mL when the dosage form is administered to a subject.

16. The dosage form of claim 11, wherein the C_max for progesterone does not exceed 50 ng/mL when the dosage form is administered to a subject.

17. The dosage form of claim 11, wherein the C_max for progesterone does not exceed 45 ng/mL when the dosage form is administered to a subject.

28. A method of oral progesterone therapy, the method comprising administering the dosage form of claim 1 to a subject in need thereof.

29. The method of claim 28, wherein the subject is in need of hormonal contraception.

30. The method of claim 28, wherein the subject is in need of treatment of secondary amenorrhea.

31. The method of claim 28, wherein the subject is in need of treatment of or protection from endometriosis.

32. The method of claim 28, wherein the subject is in need of treatment of luteal phase deficiency.

33. The method of claim 28, wherein the subject is in need of prevention of preterm delivery.

34. The method of claim 28, wherein the subject is in need of treatment of abnormal uterine bleeding due to hormonal imbalance.

35. The method of claim 28, wherein the subject is in need of assisted reproductive techniques.

36. The method of claim 28, wherein the subject is in need of prevention of endometrial hyperplasia.

37. A method of oral progesterone therapy, the method comprising administering the dosage form of claim 11 to a subject in need thereof.

38. The method of claim 37, wherein the AUC_(0-T) for progesterone does not exceed 250 ng*hr/mL when the dosage form is administered to a subject.

39. The method of claim 37, wherein the AUC_(0-T) does not exceed 200 ng*hr/mL when the dosage form is administered to a subject.

40. The method of claim 37, wherein the AUC_(0-T) does not exceed 150 ng*hr/mL when the dosage form is administered to a subject.

41. The method of claim 37, wherein the C_max does not exceed 60 ng/mL when the dosage form is administered to a subject.

42. The method of claim 37, wherein the C_max does not exceed 50 ng/mL when the dosage form is administered to a subject.

43. The method of claim 37, wherein the C_max does not exceed 45 ng/mL when the dosage form is administered to a subject.

44. A kit comprising the oral pharmaceutical dosage form of claim 1.

45. The kit of claim 44, further comprising printed instructions for its use.

46. The kit of claim 45, further comprising a printed matter describing the use of the composition to treat a condition requiring oral progesterone therapy, a pre-recorded media device describing the use of the composition to treat a condition requiring oral progesterone therapy, or a planner.

47. The kit of claim 46, wherein the printed matter is a book, booklet, brochure or leaflet.

48. The kit of claim 46, wherein the pre-recorded media device a DVD, a videotape cassette, a CD-ROM, an audiocassette, or an audio compact disk.

49. A method of delivering the oral pharmaceutical dosage form of claim 1 to a patient in need thereof, the method comprising:

(a) registering in a computer readable storage medium identity of a physician permitted to prescribe the oral pharmaceutical dosage form;

(b) providing the patient with counseling information concerning a risk attendant to the oral pharmaceutical dosage form;

(c) obtaining informed consent of the patient to receive the oral pharmaceutical dosage form despite the risk;

(d) registering the patient in the computer readable medium after obtaining the informed consent; and

(e) permitting the patient access to the oral pharmaceutical dosage form.

50. The method of claim 49, wherein the access to the oral pharmaceutical dosage form is a prescription.

51. A method of educating a consumer regarding the oral pharmaceutical dosage form of claim 1, the method comprising distributing the oral pharmaceutical dosage form to a consumer with consumer information at a point of sale.

52. The method of claim 51, wherein the consumer information is presented in a format selected from the group consisting of:

English language text, a foreign language text, a visual image, a chart, a telephone recording, a website, and access to a live customer service representative.

53. The method of claim 51, wherein the consumer information is a direction for use, appropriate age use, indication, contraindication, appropriate dosing, warning, telephone number, or website address.

54. The method of claim 51, further comprising providing professional information to a relevant person in a position to answer a consumer question regarding the oral pharmaceutical dosage form.

56. The method of claim 51, wherein the distributing is to a location with a pharmacist or a health care provider.

18. A method of producing an oral pharmaceutical dosage form, the method comprising:

(a) mixing an aqueous solution of a hydrophilic excipient with an edible oil to form an oil and aqueous mixture;

(b) spraying the oil and aqueous mixture onto a powder bed comprising micronized progesterone to form a powder;

(c) encapsulating the powder into a pharmaceutically acceptable capsule.

19. The method of claim 18, wherein the powder bed comprising micronized progesterone is formed in a fluid bed dryer or high shear mixer.

20. The method of claim 18, wherein the formed powder in (b) is passed through a screen before encapsulation.

21. The method of claim 18, wherein the powder bed further comprises a hydrophilic excipient selected from the group consisting of corn starch, potato starch, pregelatinized starch, povidone, polysorbate, mannitol, microcrystalline cellulose, sodium starch glycolate, and mixtures thereof.

22. The method of claim 18, wherein the edible oil is selected from the group consisting of safflower oil, linseed oil, soybean oil, corn oil, sunflower oil, sesame oil, olive oil, cottonseed oil, flaxseed oil, menhaden oil, and mixtures thereof.

23. The method of claim 18, wherein a lubricant is added after the powder has been formed but before the powder is encapsulated.

24. The method of claim 23, wherein the lubricant is selected from a group consisting of magnesium stearate, colloidal silicon dioxide, silica gel, aluminum stearate, talc, stearic acid, sodium stearate, calcium stearate, sodium stearyl fumarate, and mixtures thereof.

25. The method of claim 18, further comprising adding an antioxidant selected from the group consisting of adipic acid, alpha lipoic acid, ascorbyl palmitate, biotin, boron, butylated hydroxyl toluene, butylated hydroxyanisole, carotenoids, calcium citrate, sodium metabisulfate, tocopherols, and mixtures thereof.

26. The method of claim 18, further comprising adding a hydrophilic excipient selected from the group consisting of corn starch, potato starch, pregelatinized starch, povidone, polysorbate, mannitol, microcrystalline cellulose, sodium starch glycolate, and mixtures thereof.

27. The method of claim 18, further comprising adding an absorbant selected from the group consisting of silicon dioxide and its derivatives, micronized silicas, lactose, lactose monohydrate, methylcellulose, microcrystalline cellulose, sugars, maltodextrin, and mixtures thereof.

55. The method of 54, wherein the relevant person is a physician, physician assistant, nurse practitioner, pharmacist, or customer service representative.