Levothyroxine compositions and methods

• US 20030199585A1
• Filed: 08/10/2002
• Published: 10/23/2003
• Est. Priority Date: 08/10/2001
• Status: Abandoned Application

• Current Assignee: Elaine A. Strauss, Franz G. Andrew, Phillip A. Dimenna, Rocco L. Gemma
• Original Assignee: Elaine A. Strauss, Franz G. Andrew, Phillip A. Dimenna, Rocco L. Gemma
• Inventors: Gemma, Rocco L., Franz, G. Andrew, Strauss, Elaine A., DiMenna, Phillip A.
• Application Number:
  US10/215,903
• Publication Number:
  US 20030199585A1
• Time in Patent Office: Days
• US Class Current: 514/567
• CPC Class Codes: A61K 31/195 having an amino group
• 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 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2072 characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms A61K9/0004, A61K9/0056, A61K9/0065 take precedence

Abstract

The present invention generally relates to stable pharmaceutical compositions, and methods of making and administering such compositions. In one aspect, the invention features stabilized pharmaceutical compositions that include pharmaceutically active ingredients such as levothyroxine (T4) sodium and liothyronine (T3) sodium (thyroid hormone drugs), preferably in an immediate release solid dosage form. Also provided are methods for making and using such immediate release and stabilized compositions.

Claims

1. A pharmaceutical composition comprising a levothyroxine salt and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition exhibits a levothyroxine (T4) plasma Cmax of between from about 10 μ

g/dl to about 20 μ

g/dl as determined by a standard Cmax test.

2. The composition of claim 1, wherein the composition exhibits a levothyroxine (T4) plasma Cmax of between from about 12 μ

g/dl to about 16 μ

g/dl as determined by the standard Cmax test.

3. The composition of claim 1, wherein the In(Cmax) of the levothyroxine (T4) plasma level is between from about 1 to about 3.

4. The composition of claim 2, wherein the In(Cmax) of the levothyroxine (T4) plasma level is between from about 1 to about 3.

5. The composition of claim 1, wherein the composition exhibits a triiodothyronine (T3) plasma Cmax of between from about 0.1 ng/mlL to about 10 ng/mlL as determined by the standard Cmax test.

6. The composition of claim 1, wherein the composition exhibits a triiodothyronine (T3) plasma Cmax of between from about 0.5 ng/mlL to about 2 ng/mlL as determined by the standard Cmax test.

7. The composition of claim 1, wherein the In(Cmax) is between from about 0.01 to about 5.

8. The composition of claim 1, wherein the composition exhibits a levothyroxine (T4) plasma Tmax of between from about 0.5 hours to about 5 hours as determined by a standard Tmax test.

9. The composition of claim 1, wherein the composition exhibits a levothyroxine (T4) plasma Tmax of between from about 1 hour to about 3 hours as determined by the standard Tmax test.

10. The composition of claim 1, wherein the composition exhibits a triiodothyronine (T3) plasma Tmax of between from about 10 hours to about 20 hours as determined by the standard Tmax test.

11. The composition of claim 1, wherein the composition exhibits a triiodothyronine (T3) plasma Tmax of between from about 12 hours to about 16 hours as determined by the standard Tmax test.

12. The composition of any of claims 1, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 μ

g-hour/dl to about 600 μ

g-hour/dl.

13. The composition of any of claims 2, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 μ

g-hour/dl to about 600 μ

g-hour/dl.

14. The composition of any of claims 3, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 μ

g-hour/dl to about 600 μ

g-hour/dl.

15. The composition of any of claims 4, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 μ

g-hour/dl to about 600 μ

g-hour/dl.

16. The composition of any of claims 5, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 μ

g-hour/dl to about 600 μ

g-hour/dl.

17. The composition of any of claims 6, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 μ

g-hour/dl to about 600 μ

g-hour/dl.

18. The composition of any of claims 7, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 μ

g-hour/dl to about 600 μ

g-hour/dl.

19. The composition of any of claims 8, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 μ

g-hour/dl to about 600 μ

g-hour/dl.

20. The composition of any of claims 9, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 μ

g-hour/dl to about 600 μ

g-hour/dl.

21. The composition of any of claims 10, wherein the composition features a levothyroxine (T4) plasma AUC (0-t) of between from about 450 μ

g-hour/dl to about 600 μ

g-hour/dl.

22. The composition of claim 12, wherein the composition features a levothyroxine (T4) AUC (0-t) of between from about 500 μ

g-hour/dlL to about 550 μ

g-hour/dlL.

23. The composition of claim 12, wherein the In[AUC(0-t)] is between from about 1 to about 10.

24. The composition of claim 12, wherein the composition features a triiodothyronine (T3) AUC (0-t) of between from about 10 ng-hour/mlL to about 100 ng-hour/mlL.

25. The composition of claim 12, wherein the composition features a triiodothyronine (T3) AUC (0-t) of between from about 20 ng-hour/ml to about 60 ng-hour/ml.

26. The composition of claim 12, wherein the In[AUC(0-t)] is between from about 1 to about 5.

27. The composition of claim 1, wherein the composition is essentially sugar free.

28. The composition of claim 1, wherein the composition is essentially non-granular.

29. The composition of claim 1, wherein the composition further comprises microcrystalline β

-cellulose.

30. The composition of claim 29, wherein the microcrystalline β

-cellulose has a bulk density of between from about 0.10 g/cm³ to about 0.35 g/cm³.

31. The composition of claim 29, wherein the microcrystalline β

-cellulose has a bulk density of between from about 0.19 g/cm³ to about 0.21 g/cm³.

32. The composition of claim 29, wherein the microcrystalline β

-cellulose has a conductivity of less than about 200 μ

S/cm.

33. The composition of claim 29, wherein the microcrystalline β

-cellulose has a conductivity of between from about 0.5 μ

S/cm to 50 μ

S/cm.

34. The composition of claims 1, wherein the composition has a post-packaging potency of between from about 90% to about 110% as determined by a standard potency test.

35. The composition of claims 12, wherein the composition has a post-packaging potency of between from about 90% to about 110% as determined by a standard potency test.

36. The composition of claims 29, wherein the composition has a post-packaging potency of between from about 90% to about 110% as determined by a standard potency test.

37. The composition of claim 30, wherein the composition has a post-packaging potency of between from about 90% to about 110% as determined by the standard potency test.

38. The composition of claim 1, wherein the composition is formulated as a tablet.

39. The composition of claim 38, wherein the tablet has a total hardness of between from about 6 to about 14 KP, as determined by a standard hardness test.

40. The composition of claim 38, wherein the tablet is configured to increase heat transfer away from the tablet.

41. The composition of claim 40, wherein the tablet has a surface area of between from about 0.9 in.² to about 0.15 in.².

42. The composition of claim 38, wherein the tablet is beveled.

43. The composition of claim 42, wherein the tablet further comprises a notch.

44. The composition of claim 43, wherein the tablet has a raised violin configuration.

45. The composition of claim 1, wherein the composition contains less than about 5% total of diiodothyronine (T2), triiodothyronine (T3), triiodothyroacetic acid amide, triiodothyroethylamine, triiodothyroacetic acid, triiodothyroethyl alcohol, tetraiodothyroacetic acid amide, tetraiodothyroacetic acid, triiodothyroethane, and tetraiodothyroethane.

46. The composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable croscarmellose salt.

47. The composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable magnesium salt.

48. A pharmaceutical composition in tablet form comprising levothyroxine sodium, the composition comprising:

a) between from about 1 μ

g/tablet to about 1000 μ

g/tablet levothyroxine sodium (USP),

b) between from about 100 mg/tablet to about 110 mg/tablet of microcrystalline β

-cellulose, NF (Ceolus) having a bulk density of between from about 0.10 g/cm³ to about 0.35 g/cm³,

c) between from about 25 mg/tablet to about 50 mg/tablet of crosscarmellose sodium, NF (Ac-di-sol); and

d) between from about 0.5 mg/tablet to about 5 mg/tablet of magnesium stearate, NF.

49. A method of preparing a solid dosage form of a pharmaceutically active ingredient comprising forming a blend comprising the pharmaceutically active ingredient and β

-sheet form of microcrystalline cellulose, and forming therefrom a solid dosage by compressing the blend in a tableting machine.

50. The method of claim 49, wherein the blend is compressed in a ratio of initial volume to final volume from 3.3:

1 to 4.0;

1.

51. The method of claim 50, wherein the pharmaceutically active ingredient comprises levothyroxine sodium.

52. The method of claim 51, wherein the tableting machine further comprises extra deep tablet dies that maintain a free clearance of at least 3.0 mm during filling.