Stability of progestogen formulations

• US 20060257472A1
• Filed: 03/17/2006
• Published: 11/16/2006
• Est. Priority Date: 09/29/2003
• Status: Abandoned Application

• Current Assignee: Novo Nordisk Health Care AG (Novo Nordisk A/S)
• Original Assignee: NOVO Nordisk Femcare AG (Novo Nordisk A/S)
• Inventors: Nielsen, Vibeke Friis
• Application Number:
  US11/378,977
• Publication Number:
  US 20060257472A1
• Time in Patent Office: Days
• US Class Current: 424/464
• 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 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/567 substituted in position 17 alpha, e.g. mestranol, norethandrolone
• 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 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 5/34 Gestagens

Abstract

In a preparation for hormone replacement therapy having a low content of progestogen, the stability of the progestogen component can be enhanced by using a cellulosic binder, for example hydroxypropylcellulose, in stead of a non-cellulosic binder.

Claims

1. A pharmaceutical formulation comprising (i) a progestogen and (ii) a cellulosic binder, having a content of NETA in the range from about 0.05 to about 1.5% (w/w) relative to the total formulation or an equivalent amount of a non-NETA progestogen.

2. The formulation according to claim 1, wherein the content of said progestogen is not more than about 1.3% (w/w) relative to the composition.

3. The formulation according to claim 2, wherein the content of said progestogen is not more than about 0.75% (w/w).

4. The formulation according to claim 3, wherein the content of said progestogen is not more than about 0.5% (w/w).

5. The formulation according to claim 4, wherein the content of said progestogen is not more than about 0.25% (w/w).

6. The formulation according to claim 5, wherein the content of said progestogen is not more than about 0.1% (w/w).

8. The formulation according to claim 1, wherein the stability of said progestogen in said formulation is enhanced relative to the stability of progestogen in an identical formulation which deviates only in that the cellulosic binder has been exchanged by an identical amount of polyvinylpyrrolidone and, said enhancement is preferably at least 5%, more preferred at least 10%, even more preferred at least 15%.

9. The formulation according to claim 1, wherein said cellulosic binder is selected from the group consisting of methylcellulose, sodium carboxymethylcellulose, preferably Tylose™

, ethylcellulose, preferably Ethocel™

, hydroxypropyl methyl cellulose (herein designated HPMC), and hydroxypropyl cellulose, preferably Klucel™

.

10. The formulation according to claim 1, wherein the content of cellulosic binder is in the range from about 2 to about 10% (w/w) relative to the total composition.

11. The formulation according to claim 1, wherein said cellulosic binder is hydroxypropyl cellulose, preferably Klucel™

.

12. The formulation according to claim 1, wherein said cellulosic binder is hydroxypropyl cellulose having a molecular weight in the range from about 30,000 to about 1,500,000, preferably in the range from about 50,000 to about 150,000.

13. The formulation according to claim 1, wherein said cellulosic binder is hydroxypropyl cellulose, preferably hydroxypropyl cellulose fulfilling the requirements of European Pharmacopoeia and the United States National Formulary.

14. The formulation according to claim 1, wherein said progestogen is selected from the group consisting of medroxyprogesterone acetate, chlormadinone acetate, megestrol acetate, cyproterone acetate, norethindrone, norethynodrel, lynestrenol, norethindrone acetate (herein designated NETA), ethynodiol acetate, and norethindrone enanthate, norgestrel (-d or -l), norgestimate, desogestrel, gestodene, osaterone, dienogest, chlormadinone acetate, and drospirenone.

15. The formulation according to claim 1, wherein said progestogen is a 19-nortestosterone derivative, preferably norgestrel, laevonorgestrel, NET or NETA.

16. The formulation according to claim 1, wherein said progestogen is a soluble ester or salt of norethindrone, preferably a soluble ester, more preferred NETA or norethindrone enanthate.

17. The formulation according to claim 16, wherein said progestogen is NETA.

18. The formulation according to claim 17, wherein the content of NETA is in the range from about 0.07 to about 1.3 mg per unit dosage.

19. The formulation according to claim 18, wherein the content of NETA is in the range from about 0.07 to about 0.13 mg per unit dosage.

20. The formulation according to claim 18, wherein the content of NETA is in the range from about 0.1 to about 0.35 mg per unit dosage.

21. The formulation according to claim 18, wherein the content of NETA is in the range from about 0.3 to about 0.7 mg per unit dosage.

22. The formulation according to claim 18, wherein the content of NETA is in the range from about 0.7 to about 1.3 mg per unit dosage.

23. The formulation according to claim 1, containing an oestrogen.

24. The formulation according to claim 23, wherein said estrogen is estradiol, optionally as a hydrate such as the hemihydrate.

25. The formulation according to claim 24, wherein the content of estradiol hemihydrate is in the range from about 0.3 to about 2.5 mg per unit dosage.

26. The formulation according to claim 25, wherein the content of estradiol hemihydrate is in the range from about 0.3 to about 0.7 mg per unit dosage.

27. The formulation according to claim 25, wherein the content of estradiol hemihydrate is in the range from about 0.7 to about 1.3 mg per unit dosage.

28. The formulation according to claim 25, wherein the content of estradiol hemihydrate is in the range from about 1.7 to about 2.3 mg per unit dosage.

29. The formulation according to claim 1, containing lactose in an amount in the range from about 30 to about 45 mg, optionally as lactose monohydrate.

30. The formulation according to claim 1, containing maize starch in an amount in the range from about 30 to about 45 mg.

31. The formulation according to claim 1, containing hydroxypropylcellulose in an amount in the range from about 2 to about 10 mg.

32. The formulation according to claim 1, containing talc in an amount in the range from about 0.5 to about 2 mg.

33. The formulation according to claim 1, containing magnesium stearate in an amount in the range from about 0.1 to about 1 mg.

34. The formulation according to claim 1, containing hydroxypropylmethyl cellulose as film coater in an amount in the range from about 0.5 to about 3 mg.

35. The formulation according to claim 1, containing glycerol triacetate in an amount in the range from about 0.05 to about 0.2 mg.

36. The formulation according to claim 1, comprising an amount in the range from about 0.2 to about 1 mg of estradiol hemihydrate, an amount in the range from about 0.05 to about 0.5 mg of NETA, and an amount in the range from about 2.5 to about 4 mg of a cellulosic binder, wherein said cellulosic binder is selected from the group consisting of methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropyl methyl cellulose, and hydroxypropyl cellulose.

37. The formulation according to claim 1, comprising about 0.5 mg of estradiol hemihydrate, about 0.1 mg NETA, about 40 mg of lactose monohydrate, about 40 mg of maize starch, about 3 mg of hydroxypropyl celleulose or hydroxypropyl methyl cellulose, about 0.8 mg of talc, and about 0.4 mg of magnesium stearate.

38. The formulation according to claim 1, further comprising a cellulosic coating.

39. The formulation according to claim 1, wherein said cellulosic coating is selected from the group consisting of methylcellulose, sodium carboxymethylcellulose, preferably Tylose™

, ethylcellulose, preferably Ethocel™

, hydroxypropyl methyl cellulose (herein designated HPMC), and hydroxypropyl cellulose, preferably Klucel™

.

40. The formulation according to claim 1, wherein said cellulosic coating is hydroxypropyl methyl cellulose.

41. The formulation according to claim 1, wherein said coating is present in an amount in the range from about 0.5 to about 5% (w/w) relative to the total formulation.

42. The formulation according to claim 41, wherein said coating is present in an amount in the range from about 2 to about 4% (w/w) relative to the total formulation.

43. The formulation according to claim 1, wherein said coating is present in an amount in the range from about 2.5 to about 3.5% (w/w) relative to the total formulation.

44. The formulation according to claim 1, wherein the total amount of said coating is in the range from about 2 to about 3 mg per unit dosage.

45. The formulation according to claim 1, which is a pellet, tablet or capsule.

46. The formulation according to claim 1, which has a loss of mass (w/w) of not more than 15%, preferably of not more than 10%, when tested according to European Pharmacopoeia 4^th edition 2002, item 2.2.32, test C.

47. The formulation according to claim 1, which by the method described in European Pharmacopoeia 4^th edition 2002, item 2.9.1, test A, disintegrates within 2 hours, preferably 1 hour, more preferred 30 minutes, most preferred 15 minutes.

49. A method for treating a progestogen-responsive syndrome, said method comprising administerinq to a patient in need of such treatment an effective amount for treating said syndrome of a formulation according to claim 1.

50. A method of providing progestogen to a subject in need of such providing, said method comprising administering to said subject a formulation according to claim 1.

7. A pharmaceutical formulation comprising. (i) a progestogen and (ii) a cellulosic binder, said formulation containing NETA in the range from about 0.05 to about 1.3 mg or containing an equivalent amount of a non-NETA progestogen per unit dosage form.

48. A method for stabilizing a progestogen component of a pharmaceutical formulation, said method comprising contacting said progestogen with a stabilizing-effective amount of a cellulosic binder, wherein said progestogen is present in an such an amount that the content of said progestogen is in the range from about 0.05 to about 1.5% (w/w) relative to the total weight of the formulation.