Novel pharmaceutical composition containing estradiol and progesterone for oral administration

• US 4,900,734 A
• Filed: 08/27/1987
• Issued: 02/13/1990
• Est. Priority Date: 08/27/1987
• Status: Expired due to Term

• Current Assignee: Joe H. Delk, Joel T. Hargrove, Wayne S. Maxson
• Original Assignee: Joe H. Delk, Joel T. Hargrove, Wayne S. Maxson
• Inventors: Maxson, Wayne S., Hargrove, Joel T., Delk, Joe H.
• Primary Examiner(s): Sneed, H. M. S.
• Assistant Examiner(s): Saba, James
• Application Number:
  US07/090,095
• Time in Patent Office: 901 Days
• Field of Search: 514/899, 514/951, 514/960, 514/177, 514/170, 514/182, 514/935, 514/171
• US Class Current: 514/171
• 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 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/4858 Organic compounds

Abstract

A pharmaceutical composition is provided for oral administration. The composition comprises estradiol dissolved in an oil vehicle containing a suspension of micronized progesterone. The oil vehicle is high in glycerides of polyunsaturated fatty acids. The estradiol and micronized progesterone contained in the oil are more readily absorbable in the blood stream and achieve enhanced estradiol and progesterone blood serum levels. The pharmaceutical composition according to the invention can be readily formulated into capsules and administered for the treatment of menopausal symptoms.

Claims

1. A pharmaceutical composition for treating menopausal symptoms in women which comprises estradiol dissolved in a highly unsaturated edible oil containing a suspension of micronized progesterone particles;

said oil comprising glycerides of one or more polyunsaturated fatty acids;

said estradiol and progesterone being present in a therapeutically effective amount for treating menopause; and

said estradiol and progesterone being present in an amount so that the composition can be orally administered to provide a daily dosage rate of 0.9-1.2 mg. estradiol and 150-300 mg. progesterone.

2. The composition of claim 1, wherein at least 51% of the glycerides are glycerides of polyunsaturated fatty acids.

3. The composition of claim 2, wherein said oil has an acid value in the range of 0.4-10, a saponification value in the range of 186-194, an iodine value in the range of 130-150, a thiocyanogen value in the range of 82-87, a R-M value of less than 0.5, an hydroxyl value in the range of 1-12, an unsaponifiable content of less than 1.5 wt.%, and a specific gravity in the range of 0.919-0.924.

4. The pharmaceutical composition of claim 1, wherein the oil consists essentially of glycerides having 5-10 wt.% saturated fatty acids;

13-22 wt.% oleic acid, and 72-79 wt.% linoleic acid.

5. The composition of claim 1, wherein the oil is selected from the group consisting of safflower oil, linseed oil, soybean oil, corn oil, sunflower oil, and mixtures thereof.

6. The composition of claim 4, wherein the oil is safflower oil.

7. A pharmaceutical composition which comprises estradiol dissolved in a edible glyceride oil and micronized progesterone particles suspended in the oil;

said oil having an iodine value of at least 110 and comprising glycerides of one or more polyunsaturated fatty acids; and

said progesterone particles being of a particle size wherein at least 99% of the particles are less than 10 microns in diameter and at least 78% of the particles are less than 5 microns in diameter;

said estradiol and progesterone being present in a therapeutically effective amount for treating menopause; and

said estradiol and progesterone being present in an amount so that the composition can be orally administered to provide a daily dosage rate of 0.9-1.2 mg. estradiol and 150-300 mg. progesterone.

8. The composition of claim 7, wherein the oil has an iodine value of 130-160.

9. The composition of claim 8, wherein the oil has an iodine value of 140-150.

10. The composition of claim 7, wherein the oil has an acid value in the range of 0.4-10, a saponification value in the range of 186-194, an iodone value in the range of 130-150, a thiocyanogen value in the range of 82-87, and R-M value of less than 0.5, a hydroxyl value in the range of 1-12, an unsaponifiable content of less than 1.5 wt.%, and a specific gravity in the range of 0.919-0.924.

11. The composition of claim 7, wherein the oil consists of glycerides having 5-10 wt.% saturated fatty acids;

13-22 wt.% oleic acid, and 72-79 wt.% linoleic acid.

12. The composition of claim 7, wherein the oil is selected from the group consisting of safflower oil, linseed oil, soybean oil, corn oil, sunflower oil, and mixtures thereof.

13. The composition of claim 12, wherein the oil is safflower oil.

14. A capsule for oral administration of estradiol and progesterone which comprises a pharmaceutically acceptable capsule containing estradiol dissolved in a highly unsaturated edible oil containing a suspension of micronized progesterone particles therein;

said oil comprising glycerides of one or more polyunsaturated acids;

said capsule containing estradiol and progesterone in a therapeutically effective amount for treating menopause; and

said capsule containing estradiol and progesterone in an amount so that the capsules can be orally administered to provide a daily dosage rate of 0.9-1.2 mg. estradiol and 150-300 mg. progesterone.

15. The capsule of claim 14, wherein the oil has an iodine value of at least 110.

16. The capsule of claim 15, wherein the progesterone particles are of a particle size wherein 99% of the particles are less than 10 microns in diameter and at least 78% of the particles are less than 5 microns in diameter.

17. The capsule of claim 16, wherein the oil is selected from the group consisting of safflower oil, linseed oil, soybean oil, corn oil, sunflower oil, and mixtures thereof.

18. The capsule of claim 17, wherein the oil is safflower oil.

19. The capsule of claim 14, which contains 0.2-0.5 mg. estradiol and 50-100 mg. progesterone.

20. The capsule of claim 14, which contains 0.2-0.5 mg. estradiol and 50-100 mg. progesterone.

21. The capsule of claim 19, which contains 0.35 mg. estradiol and 100 mg. progesterone.

23. The method of claim 21, wherein the progesterone particles are of a particle size wherein 99% of the particles are less than 10 microns in diameter and at least 78% of the particles are less than 5 microns in diameter.

24. The method of claim 23, wherein the composition is contained in a digestible capsule.

25. The method of claim 23, wherein the daily dosage rate is adminstered in the form of capsules containing 0.2-0.5 mg. estradiol and 50-100 mg. progesterone.

26. The capsule of claim 25, wherein the oil is selected from the group consisting of safflower oil, linseed oil, soybean oil, corn oil, sunflower oil, and mixtures thereof.

27. The method of claim 26, wherein the capsule contains 0.35 mg. estradiol and 100 mg. progesterone.

28. The method of claim 27, wherein the oil is safflower oil.

22. A method for treating menopausal symptoms in women which comprises orally administering to a woman suffering from menopausal symptoms a therapeutically effective amount of a pharmaceutical composition which comprises estradiol dissolved in a highly unsaturated oil containing a suspension of micronized progesterone particles;

said oil comprising glycerides of one or more polyunsaturated fatty acids;

said composition containing estradiol and progesterone in a therapeutically effective amount for treating menopause; and

said composition being orally administered in an amount to provide a daily dosage rate of 0.9-1.2 mg. estradiol and 150-300 mg. progesterone.

29. The method of increasing blood serum estradiol and progesterone levels in humans which comprises orally administering to humans to composition comprising estradiol dissolved in an edible oil containing a suspension of micronized progesterone particles, said oil comprising glycerides of one or more polyunsaturated fatty acids.

30. The method of claim 29, wherein the oil has an iodine value of at least 110 and the progesterone particles are of a particle size wherein 99% of the particles are less than 10 microns in diameter and at least 78% of the particles are less than 5 microns in diameter.

31. The method of claim 30, wherein the oil is selected from the group consisting of safflower oil, linseed oil, soybean oil, corn oil, sunflower oil, and mixtures thereof.

32. The method of claim 31, wherein the oil is safflower oil and the estradiol, progesterone and oil containing composition is contained in a digestible capsule.

33. A method for preparing an orally active pharmaceutical composition comprising estradiol, progesterone and a glyceride oil of one or more polyunsaturated acids, which method comprises the steps of:

heating a quantity of the oil;

dissolving a quantity of estradiol in the oil to form a solution;

cooling the solution to room temperature;

stirring and mixing micronized progesterone into the solution, whereby a composition is formed containing estradiol dissolved in the oil which contains suspended micronized particles of progesterone and solubilized progesterone.

34. The method of claim 33, wherein the mixture formed in claim 33 is further diluted with additional quantities of oil.