Unadsorbed levothyroxine pharmaceutical compositions, methods of making and methods of administration

• US 20030195253A1
• Filed: 08/14/2002
• Published: 10/16/2003
• Est. Priority Date: 08/14/2001
• 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:
  US10/218,304
• Publication Number:
  US 20030195253A1
• Time in Patent Office: Days
• US Class Current: 514/567
• 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

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, wherein the levothyroxine is unadsorbed. also provided are methods for making and using such immediate release and stabilized compositions.

Claims

1. A stabilized solid pharmaceutical composition comprising a levothyroxine salt and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is substantially free of adsorbed levothyroxine and at least about 85% of the levothyroxine dissolves in aqueous solution in less than about 20 minutes as determined by a standard dissolution test.

2. A composition of claim 1, wherein at least about 80% of the levothyroxine dissolves in aqueous solution by about 15 minutes as determined by the standard dissolution test.

3. A composition of claims 1, wherein at least about 80% of the levothyroxine dissolves in aqueous solution by about 5 minutes as determined by the standard dissolution test.

4. A composition of claims 1, wherein the compisiton further includes a microcrystalline β

-cellulose.

5. A composition of claim 4, wherein the microcrystalline β

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

6. A composition of claim 4, wherein the microcrystalline β

-cellulose has a conductivity of less than about 200 μ

S/cm.

7. A composition of claims 4, wherein the microcrystalline β

-cellulose. has a conductivity of between from about 0.5 μ

S/cm. to 50 μ

S/cm.

8. A composition of claims 1, wherein the composition further comprises a pharmaceutically acceptable crosscarmellose salt.

9. A composition of claims 1, wherein the In[AUC(0-t)] is between from about 1 to about 5.

10. A composition of claims 1, wherein the composition is essentially free of a sugar.

11. A composition of claims 1, wherein the composition is essentially starch free.

12. A composition of claims 1, wherein the composition is a non-granulated composition.

13. A composition of claims 1, wherein the composition is an immediate release composition.

14. A composition of claims 1, wherein the composition is formulated as a tablet.

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

16. A composition of claims 14, wherein the tablet is beveled.

17. A composition of claims 14, wherein the tablet contains a score line.

18. A composition of claims 14, wherein the tablet has a raised violin configuration

19. A composition of claim 14, wherein the tablet is configured to increase heat transfer away from the tablet.

20. A stabilized 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 croscarmellose sodium, NF (Ac-di-sol);

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

e) wherein the composition is substantially free of adsorbed levothyroxine.

21. An immediate released solid pharmaceutical composition comprising a levothyroxine and a pharmaceutically acceptable carrier, wherein the composition is substantially free of adsorbed evothyroxine and the pharmaceutical composition loses less than about 0.7% of its activity per month for up to about 18 months.

22. A pharmaceutical composition of claim 21, wherein the pharmaceutical composition loses less than 0.7% of its activity per month for up to 18 months.

23. A pharmaceutical composition of claim 21, wherein the pharmaceutical composition loses less than about 0.5% of its activity per month for up to about 18 months.

24. A pharmaceutical composition of claim 21, wherein the pharmaceutical composition loses less than 0.3% of its activity per month for up to about 18 months.

25. A pharmaceutical composition of claims 21-24, wherein the compisition further includes a β

-sheet form of microcrystalline cellulose.

26. A pharmaceutical composition of claim 25, wherein at least about 50 weight % of the composition weight is a β

-sheet form of microcrystalline cellulose.

27. A stabilized pharmaceutical composition comprising a levothyroxine, wherein the the composition is substantially free of adsorbed levothyroxine and 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.

28. A stabilized composition of claim 27, 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.

29. A stabilized composition of claim 27, wherein the In[AUC(0-t)] is between from about 1 to about 10.

30. A stabilized composition of claims 28, wherein the In[AUC(0-t)] is between from about 1 to about 10.

31. A non-granulated, sugar-free, starch-free, stabilized pharmaceutical composition comprising levothyroxine and a pharmaceutically acceptable carrier, in tablet form, wherein the composition is substantially free of adsorbed levothyroxine.

32. A pharmaceutical composition of claim 31, wherein the compisition further includes a microcrystalline β

-cellulose.

33. A pharmaceutical composition of claims 32, wherein the microcrystalline β

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

34. The composition of claims 32, wherein the microcrystalline β

-cellulose. has a bulk density of between from about 0.15 g/cm³ to about 0.25 g/cm³.

35. A pharmaceutical composition of claims 32, wherein the microcrystalline β

-cellulose has a conductivity of less than about 200 μ

S/cm.

36. A pharmaceutical composition of claim 32, wherein the microcrystalline β

-cellulose. has a conductivity of between from about 0.5 μ

S/cm. to 50 μ

S/cm.

37. A pharmaceutical composition of claims 31, wherein tablet has a total hardness of between from about 6 KP to about 14 KP as determined by a standard hardness test.

38. A non-granulated, sugar-free, starch-free, immediate release pharmaceutical composition comprising levothyroxine and a pharmaceutically acceptable carrier, in tablet form, wherein the composition is substantially free of adsorbed levothyroxine.

39. A composition of claim 38, wherein the composition further includes a microcrystalline β

-cellulose.

40. A composition of claims 38, wherein the microcrystalline β

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

l cm³.

41. A composition of claims 38, wherein the microcrystalline β

-cellulose has a bulk density of between from about 0.15 g/cm³ to about 0.25 g/cm³.

42. A composition of claim 38, wherein the microcrystalline β

-cellulose has a conductivity of less than about 200 μ

S/cm.

43. A composition of claim 38, wherein the microcrystalline β

-cellulose has a conductivity of between from about 0.5 μ

S/cm to 50 μ

S/cm.

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