Levothyroxine compositions and methods

• US 6,555,581 B1
• Filed: 02/15/2002
• Issued: 04/29/2003
• Est. Priority Date: 02/15/2001
• Status: Expired due to Term

• Current Assignee: King Pharmaceuticals Research And Development Incorporated (Pfizer Inc.)
• Original Assignee: Jones Pharma Incorporated (Pfizer Inc.)
• Inventors: Gemma, Rocco L., Franz, G. Andrew, Strauss, Elaine A., DiMenna, Philip A.
• Primary Examiner(s): Pak, John
• Application Number:
  US10/077,677
• Time in Patent Office: 438 Days
• Field of Search: 514/567, 514/492, 514/781, 514/951, 514/952, 514/960, 514/961, 514/962, 514/970, 424/451, 424/452, 424/464-466, 424/474, 424/480, 424/489, 424/490, 424/494
• 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
• CPC Class Codes: B01F 23/60 Mixing solids with solids
• CPC Class Codes: B01F 25/433 Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
• CPC Class Codes: B01F 25/4334 Mixers with a converging cross-section
• CPC Class Codes: B01F 25/82 uniting flows of material taken from different parts of a receptacle or from a set of different receptacles

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 stable, solid, immediate release pharmaceutical composition for oral administration to treat a thyroid disorder, said composition comprising:

(a) about 0.00005 wt % to about 5 wt % of a levothyroxine salt;

(b) at least about 50 wt % of a β

-form microcrystalline cellulose particles, said β

-form microcrystalline cellulose particles having generally flat needle-shapes, a bulk density in a range of from about 0.10 g/cm³ to about 0.23 g/cm³, and a conductivity of less than about 200 μ

S/cm; and

(c) about 0.5 wt % to about 30 wt % disintegrating agent;

wherein (1) at least about 90 wt % of the levothyroxine salt in the composition dissolves in an aqueous solution in less than about 5 minutes, (2) potency loss for said levothyroxine salt is no more than about 0.3% per month for a period of at least about 18 months, and (3) said composition is essentially sugar-free.

2. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein at least about 90 wt % of the levothyroxine salt in the composition dissolves in an aqueous solution in less than about 2.5 minutes.

3. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition exhibits a levothyroxine (T4) plasma Cmax of from between about 10 μ

g/dL to about 20 μ

g/dL.

4. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition exhibits a levothyroxine (T4) plasma Cmax of from between about 12 μ

g/dL to about 16 μ

g/dL.

5. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition exhibits a triiodothyronine (T3) plasma Cmax of from between about 0.1 ng/mL to about 10 ng/mL.

6. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition exhibits a triiodothyronine (T3) plasma Cmax of from between about 0.5 ng/mL to about 2 ng/mL.

7. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition exhibits a levothyroxine (T4) plasma Tmax of from between about 1 hours to about 3 hours.

8. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition exhibits a triiodothyronine (T3) plasma Tmax of from between about 12 hours to about 16 hours.

9. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition exhibits a levothyroxine (T4) AUC(0-t) of between from about 500 μ

g-hour/dL to about 550 μ

g-hour/dL.

10. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition exhibits a triiodothyronine (T3) AUC(0-t) of between from about 20 ng-hour/mL to about 60 ng-hour/mL.

11. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition is a non-granular composition.

12. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said β

-form microcrystalline cellulose particles have a bulk density in a range of from about 0.17 g/cm³ to about 0.23 g/cm³.

13. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition is formulated as a tablet.

14. A stable, solid, immediate release pharmaceutical composition of claim 13, wherein said tablet has a total hardness of from between about 5 KP to about 15 KP.

15. A stable, solid, immediate release pharmaceutical composition of claim 13, wherein said tablet has a surface area of from between about 0.9 in.² to about 15 in.².

16. A stable, solid, immediate release pharmaceutical composition of claim 13, wherein said tablet is beveled.

17. A stable, solid, immediate release pharmaceutical composition of claim 13, wherein said tablet is scored.

18. A stable, solid, immediate release pharmaceutical composition of claim 13, wherein said tablet has a raised violin configuration.

19. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition includes less than about 10% total impurities.

20. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition includes less than about 5% total impurities.

21. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said disintegrant is a croscarmellose salt.

22. A stable, solid, immediate release pharmaceutical composition of claim 1, wherein said pharmaceutical composition further includes at least one pharmaceutically acceptable coloring agent.

23. A stable, solid, immediate release pharmaceutical tablet for oral consumption comprising:

(a) between from about 0.01 mg to about 0.8 mg levothyroxine sodium;

(b) between from about 100 mg to about 110 mg of β

-microcrystalline cellulose particles, said β

-form microcrystalline cellulose particles having generally flat needle-shapes, a bulk density in a range of from about 0.10 g/cm³ to about 0.23 g/cm³, and a conductivity of less than about 200 μ

S/cm;

(c) between from about 25 mg to about 50 mg of croscarmellose sodium; and

(d) between from about 0.5 mg to about 5 mg of magnesium stearate,

wherein (1) at least about 90 wt % of the levothyroxine salt in the composition dissolves in an aqueous solution in less than about 5 minutes, (2) potency loss for said levothyroxine salt is no more than about 0.3% per month for a period of at least about 18 months, and (3) said composition is essentially sugar-free.

24. A stable, solid, immediate release pharmaceutical tablet of claim 23, wherein said tablet further includes at least one pharmaceutically acceptable coloring agent.

25. A stable, solid, immediate release pharmaceutical composition for oral administration to treat a thyroid disorder, said composition comprising:

(a) about 0.00005 wt % to about 5 wt % of a levothyroxine salt;

(b) at least about 50 wt % of a β

-form microcrystalline cellulose particles, said β

-form microcrystalline cellulose particles having generally flat needle-shapes, a bulk density in a range of from about 0.10 g/cm³ to about 0.23 g/cm³, and a conductivity of less than about 200 μ

S/cm; and

(c) about 0.5 wt % to about 30 wt % disintegrating agent;

wherein (1) at least about 90 wt % of the levothyroxine salt in the composition dissolves in an aqueous solution in less than about 5 minutes, (2) potency loss on average for said levothyroxine salt is no more than about 0.2% per month for a period of at least about 18 months, and (3) said composition is essentially sugar-free.