Preformulation for tabletting natural mixtures of conjugated estrogens

• US 20050009800A1
• Filed: 06/14/2004
• Published: 01/13/2005
• Est. Priority Date: 12/14/2001
• Status: Active Grant

• Current Assignee: Abbott Products GmbH (Abbvie Incorporated)
• Original Assignee: Solvay Pharmaceuticals GmbH (Abbvie Incorporated)
• Inventors: Bonnacker, Ingo, Lerch, Martina, Thumbeck, Bernd
• Granted Patent: US 8,273,728 B2
• Time in Patent Office: Days
• US Class Current: 514/182
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 5/30 Oestrogens

Abstract

A pharmaceutical preformulation in the form of a solid, free-flowing dry extract of a natural mixture of conjugated equine estrogens, which is particularly suitable use in for solid galenic forms, e.g. tabletting. The conjugated estrogens are available for further galenic processing in a form which assures the chemical stability of the hormones and permits advantageous processing into solid galenic forms, for example a tablet. The invention furthermore relates to a method for producing these preformulations in the form of a dry extract.

Claims

1. A pharmaceutical preformulation in the form of a tabletable, solid, free-flowing, dry extract;

(a) wherein said solid extract contains a standardized amount of a mixture of natural conjugated equine estrogens per amount of support material, defined relative to the main hormone constituents; and

(b) wherein the active-substance content is applied by spraying an aqueous solution of said mixture onto a powdered or granular pharmaceutical support material selected from the group consisting of microcrystalline celluloses and mixtures of microcrystalline cellulose with lactose, and thereafter drying.

2. A preformulation according to claim 1, wherein said preformulation of the extract of the mixture of natural conjugated equine estrogens from pregnant mares'"'"' urine has an active-substance content including free estrogens and other solids calculated as dry matter relative to the amount of the pharmaceutical support material in the preformulation lying in the range from 0.25 to 0.70 gram of dry matter per gram of support material.

3. A preformulation according to claim 2, wherein said preformulation has an active substance content lying in the range from 0.28 to 0.64 gram of dry matter per gram of support material.

4. A preformulation according to claim 1, wherein said preformulation has an active-substance content calculated as the ratio of said mixture of natural equine conjugated estrogens relative to the amount of the pharmaceutical support material lying in the range from 35 to 100 mg of conjugated estrogens per gram of support material.

5. A preformulation according to claim 4, wherein said preformulation has an active substance content calculated as the ratio of said mixture of natural equine conjugated estrogens relative to the amount of the pharmaceutical support material lying in the range from 43 to 90 mg of conjugated estrogens per gram of support material.

6. A preformulation according to claim 4, wherein said preformulation has a residual moisture content of at most 3.0% by weight, relative to the entire preformulation as 100% by weight.

7. A preformulation according to claim 6, wherein said preformulation has a residual moisture content of at most 1.0% by weight, relative to the entire preformulation as 100% by weight.

8. A preformulation according to claim 1, wherein the active-substance content, calculated as total hormone content, lies in the range from about 35 to 100 mg per gram of the pharmaceutical support material.

9. A preformulation according to claim 8, wherein the active-substance content, calculated as total hormone content, lies in the range from about 43 to 90 mg per gram of the pharmaceutical support material.

10. A preformulation according to claim 1, containing conjugated estrogens in the following proportions:

52.5 to 61.5% estrone;

22.5 to 30.5% equilin;

13.5 to 19.5% 17-α

-dihydroequilin;

2.5 to 9.5% estradiol, and

0.5 to 4.0% 17-β

-dihydroequilin.

11. A preformulation according to claim 1, wherein the proportion of free hormones relative to the total hormone content in the active substance is less than 5% by weight.

12. A preformulation according to claim 11, wherein the proportion of free hormones relative to the total hormone content in the active substance is less than 2% by weight.

13. A preformulation according to claim 1, wherein the pharmaceutical support material is a microcrystalline cellulose or a mixture of microcrystalline celluloses.

14. A preformulation according to claim 1, wherein the pharmaceutical support material is a mixture of microcrystalline cellulose and lactose.

15. A preformulation according to claim 14, wherein the weight ratio of microcrystalline cellulose to lactose lies in the range of 8:

2 to 6;

4.

16. A preformulation according to claim 15, wherein the weight ratio of microcrystalline cellulose to lactose lies in the range of about 7.5:

2.5 to 6.5;

3.5.

17. A preformulation according to claim 16, wherein the weight ratio of microcrystalline cellulose to lactose is about 7:

3.

18. A preformulation according to claim 1, wherein the mean bulk volume of the preformulation lies in the range from 1.8 to 3.0 ml/g.

19. A preformulation according to claim 1, wherein the mean bulk density of the preformulation lies in the range from 0.3 to 0.6 grams/ml.

20. A preformulation according to claim 1, wherein the preformulation has a particle-size distribution corresponding to the following sieve analysis:

100% by weight of the particles pass through a sieve mesh size of 500 μ

m;

at least 98% by weight of the particles pass through a sieve mesh size of 250 μ

m;

about 65 to 99.5% by weight of the particles pass through a sieve mesh size of 160 μ

m;

about 35 to 87% by weight of the particles pass through a sieve mesh size of 125 μ

m; and

fines of less than 23% by weight passing through a sieve mesh size of 63 μ

m.

21. A preformulation according to claim 1, wherein the preformulation has a particle-size distribution corresponding to the following sieve analysis:

about 0.15% to at most 2% by weight of the particles larger than a mesh size of 250 μ

m;

about 3 to 31% by weight of the particles larger than a mesh size of 160 μ

m;

about 8 to 36% by weight of the particles larger than a mesh size of 125 μ

m; and

fines of the particles of about 3 to at most 23% by weight passing through a sieve mesh size of 63 μ

m.

22. A preformulation according to claim 1, wherein the preformulation has a mean particle size lying in the range from 50 to 250 μ

m.

23. A preformulation according to claim 22, wherein the preformulation has a mean particle size lying in the range from 75 to 150 μ

m.

24. A method of producing a pharmaceutical preformulation in the form of a tabletable, solid, free-flowing, dry pharmaceutical extract, said method comprising:

spraying an aqueous solution containing a mixture of natural conjugated equine estrogens onto a powdered or granular pharmaceutical support material in an amount corresponding to a desired standardized estrogen content in a fluidized bed to obtain estrogen-containing particles, said support material being selected from the group consisting of microcrystalline celluloses and mixtures of microcrystalline cellulose with lactose; and

drying the resulting estrogen-containing particles.

25. A method according to claim 24, wherein said aqueous solution further comprises at least one water-miscible organic solvent.

26. A method according to claim 25, wherein said water-miscible organic solvent is a lower alcohol.

27. A method according to claim 24, wherein said aqueous solution consists essentially of an aqueous solution of said mixture of natural conjugated equine estrogens.

28. A method according to claim 24, wherein said aqueous solution has a total hormone content including conjugated estrogens, free estrogens and other solids, in the range from about 3.5 to 20% by weight, calculated as dry matter, relative to the aqueous solution as 100% by weight.

29. A method according to claim 24, wherein said aqueous solution has a total hormone content including conjugated and free estrogens in the range from 10 to 40 mg per gram of the aqueous solution.

30. A method according to claim 24, wherein said aqueous solution is a concentrate having a total hormone content including conjugated estrogens, free estrogens and other solids of more than 20% by weight, calculated as dry matter, relative to the concentrate as 100% by weight.

31. A method according to claim 24, wherein said aqueous solution is a concentrate containing more than 40 mg of said mixture of natural equine conjugated estrogens per gram of said concentrate.

32. A method according to claim 24, said aqueous solution has a total hormone content including conjugated estrogens and free estrogens in the range from 18 to 31% by weight, calculated as dry matter, relative to the aqueous solution as 100% by weight.

33. A method according to claim 24, wherein the estrogen-containing particles are produced in a fluidized bed having an exhaust air temperature in the range from 25 to 60°

C.

34. A method according to claim 33, wherein the fluidized bed has an exhaust air temperature in the range from 45 to 55°

C.

35. A method according to claim 24, wherein the estrogen-containing particles are produced in a fluidized bed having an exhaust air relative humidity in the range from 50 to 80% relative humidity.

36. A method according to claim 24, wherein said aqueous solution is sprayed onto the support material at a spraying rate of 20 to 50 grams/min.

37. A method according to claim 24, wherein the powdered or granular support material has a particle-size distribution corresponding to the following sieve analysis:

100% by weight of the particles pass through a sieve mesh size of 500 μ

m;

at least 99% by weight of the particles pass through a sieve a mesh size of 250 μ

m;

about 85 to 95% by weight of the particles pass through a sieve mesh size of 160 μ

m;

about 70 to 80% by weight of the particles pass through a mesh size of 125 μ

m, and

fines of up to about 50% by weight of the particles pass through a sieve mesh size of 63 μ

m.

38. A method according to claim 24, wherein said support material is microcrystalline cellulose.

39. A method according to claim 24, wherein the powdered or granular support material has a mean particle size in the range from 50 to 130 μ

m.

40. A method according to claim 39, wherein said support material is microcrystalline cellulose.

41. A method according to claim 24, wherein the powdered or granular support material has a bulk density in the range from about 25 to 35 g/ml.

42. A method according to claim 24, wherein said support material has a water content of at most about 6% by weight.