Stabilized thyroid hormone preparations and methods of making same

• US 5,955,105 A
• Filed: 11/14/1996
• Issued: 09/21/1999
• Est. Priority Date: 11/14/1995
• Status: Expired due to Term

• Current Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Original Assignee: Knoll Pharmaceutical Company (Abbvie Incorporated)
• Inventors: Srinivas, Raghunath, Mitra, Amit K., Thomas, Charles L. III
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): HOWARD, SHARON LEE
• Application Number:
  US08/748,869
• Time in Patent Office: 1,041 Days
• Field of Search: 424/464, 424/465, 424/479, 514/777, 514/778, 514/781, 514/960, 514/961
• US Class Current: 424/464
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4

Abstract

Disclosed are thyroid hormone preparations useful in pharmaceutical applications. These preparations are disclosed to contain thyroxine drugs in combination with an inorganic salt, a carbohydrate having a molecular weight of greater than 500, and glycine. The preparations are also disclosed to have a free water content less than 4.5% by weight of the preparation. Also provided are compositions containing a reduced carbohydrate, a water soluble polysaccharide, or galactose. The preparations have improved stability wherein they are provided as being stable to the extent that substantially no potency loss is measured when the preparation is stored at 40° C. and 75% relative humidity for 3 months.

Claims

1. A stable, solid dosage form pharmaceutical preparation suitable for the treatment of thyroid disorders, said preparation comprising:

an effective amount of a thyroxine drug;

a water soluble glucose polymer; and

a partially soluble or insoluble cellulose polymer;

said preparation being stable to the extent that substantially no potency loss is measured when the preparation is stored at 40°

C. and 75% relative humidity for 6 months.

2. The preparation of claim 1, wherein the preparation is in a unit dose form.

3. The preparation of claim 2, wherein the unit dose form is a tablet.

4. The preparation of claim 3, wherein the tablet additionally includes a lubricant.

5. The preparation of claim 4, wherein the tablet also contains a glidant.

6. The preparation of claim 2, wherein the unit dose form is a capsule.

7. The preparation of claim 1, wherein the capsule also contain a lubricant and a glidant.

8. The preparation of claim 1, wherein the preparation is in the form of a powder.

9. The preparation of claim 1, wherein the preparation is provided in the substantial absence of lactose, glucose, sucrose, or a polyvinylpyrrolidone.

10. The preparation of claim 1 wherein the pH of the preparation is about 7 to 11.

11. The preparation of claim 1 wherein the thyroxine drug is levothyroxine sodium.

12. The preparation of claim 1 having a free water content less than 4.5% by weight of the preparation.

13. The preparation of claim 3 having a free water content less than 4.5% by weight of the preparation.

14. The preparation of claim 10, having a free water content less than 4.5% by weight of the preparation.

39. The preparation of claim 13 wherein the pH of th preparation is about 7 to 11.

40. The preparation of claim 3, 4, 5, 13, 15, 26, 30, 38 or 39 wherein the preparation is provided in the substantial absence of lactose, glucose, sucrose, or a polyvinylpyrrolidone.

41. The preparation of claim 1, 3, 4, 5, 13, 15, 26, 30, 38, or 39 wherein the partially soluble or insoluble polymer comprises microcrystalline cellulose.

42. The preparation of claim 40 wherein the partially soluble or insoluble polymer comprises microcrystalline cellulose.

43. The preparation of claims 3, 4, 5, 13, 15, 26, 30, 38, or 39 wherein the thyroxine drug comprises sodium levothyroxine.

44. The preparation of claims 39 wherein the thyroxine drug comprises sodium levothyroxine.

45. The preparation of claims 40 wherein the thyroxine drug comprises sodium levothyroxine.

46. The preparation of claims 41 wherein the thyroxine drug comprises sodium levothyroxine.

47. The preparation of claims 42 wherein the thyroxine drug comprises sodium levothyroxine.

15. A stable pharmaceutical preparation comprising:

a. an effective amount of a thyroxine drug;

b. a water soluble polysaccharide; and

c. a partially soluble or insoluble cellulose polymer.

16. The preparation of claim 15 wherein the water soluble polysaccharide is a polysaccharide having a dextrose value of less than 25.

17. The preparation of claim 15 wherein the water soluble polysaccharide is a polysaccharide having a dextrose value of less than 10.

18. The preparation of claim 15 wherein the water soluble polysaccharide comprises a polysaccharide selected from group consisting of maltodextrin, β

cyclodextrin, and hydroxypropyl-β

-cyclodextrin.

19. The preparation of claim 15, wherein the preparation is a unit dose form.

20. The preparation of claim 16, wherein the preparation is a unit dose form.

21. The preparation of claim 17, wherein the preparation is a unit dose form.

22. The preparation of claim 18, wherein the preparation is a unit dose form.

23. The preparation of claim 19, wherein the unit dose form is a tablet.

24. The preparation of claim 20, wherein the unit dose form is a tablet.

25. The preparation of claim 21, wherein the unit dose form is a tablet.

26. The preparation of claim 22, wherein the unit dose form is a tablet.

27. The preparation of claim 23, wherein the tablet additionally includes a lubricant.

28. The preparation of claim 24, wherein the tablet additionally includes a lubricant.

29. The preparation of claim 25, wherein the tablet additionally includes a lubricant.

30. The preparation of claim 26, wherein the tablet additionally includes a lubricant.

31. The preparation of claim 23, wherein the tablet also contains a glidant.

32. The preparation of claim 24, wherein the tablet also contains a glidant.

33. The preparation of claim 25, wherein the tablet also contains a glidant.

34. The preparation of claim 26, wherein the tablet also contains a glidant.

35. The preparation of claim 27, wherein the tablet also contains a glidant.

36. The preparation of claim 28, wherein the tablet also contains a glidant.

37. The preparation of claim 29, wherein the tablet also contains a glidant.

38. The preparation of claim 30, wherein the tablet also contains a glidant.

48. A stable pharmaceutical preparation comprising:

a. an effective amount of sodium levothyroxine;

b. maltodextrin; and

c. microcrystalline cellulose;

wherein the combined weight of the maltodextrin and microcrystalline cellulose is from 50% to 99% of the total weight of the preparation.

49. The preparation of claim 48 comprising at least one lubricant selected from the group consisting of magnesium stearate, zinc stearate, sodium stearate fumarate and sodium lauryl sulfate wherein the weight of the lubricant is in the range up to 2% by weight of the preparation.

50. The preparation of claim 49 comprising a glidant selected from the group consisting of colloidal silicon dioxide and talc wherein the weight of the glidant is up to 3% by weight of the preparation.

51. The preparation of claim 50 wherein the preparation is provided in the substantial absence of lactose, glucose, sucrose, or polyvinylpyrrolidone.

52. The preparation of claim 51 comprising a free water content less than 4.5% by weight of the preparation.

53. The preparation of claim 52 wherein the pH of the preparation is about 7 to 11.

54. The preparation of claim 50 comprising about 49.4% by weight maltodextrin, about 49.4% by weight microcrystalline cellulose, about 0.5% by weight sodium lauryl sulfate, about 0.5% by weight magnesium stearate and about 0.02% colloidal silicon dioxide.

55. The preparation of claim 51 comprising about 49.4% by weight maltodextrin, about 49.4% by weight microcrystalline cellulose, about 0.5% by weight sodium lauryl sulfate, about 0.5% by weight magnesium stearate and about 0.02% colloidal silicon dioxide.

56. The preparation of claim 52 comprising about 49.4% by weight maltodextrin, about 49.4% by weight microcrystalline cellulose, about 0.5% by weight sodium lauryl sulfate, about 0.5% by weight magnesium stearate and about 0.02% colloidal silicon dioxide.

57. The preparation of claim 53 comprising about 49.4% by weight maltodextrin, about 49.4% by weight microcrystalline cellulose, about 0.5% by weight sodium lauryl sulfate, about 0.5% by weight magnesium stearate and about 0.02% colloidal silicon dioxide.