Storage stable thyroxine active drug formulations and methods for their production

• US 20030099698A1
• Filed: 11/13/2001
• Published: 05/29/2003
• Est. Priority Date: 11/13/2001
• Status: Active Grant

• Current Assignee: Mylan Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Mylan Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Wargo, David John, Hanshew, Dwight D. Jr.
• Granted Patent: US 6,645,526 B2
• Time in Patent Office: Days
• US Class Current: 424/465
• 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 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• 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: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Abstract

This invention provides a storage-stable dosage form of a thyroxine active drug composition which exhibits an improved stability. The formulation contains a thyroxine active drug substance, an alditol, and a saccharide, and, optionally, additional pharmaceutically accepted excipients. Levothyroxine sodium is the preferred active drug substance, mannitol is the preferred alditol, and sucrose is the preferred saccharide. Additional preferred excipients include, for example, microcrystalline cellulose, crospovidone, magnesium stearate, colloidal silicon dioxide, and sodium lauryl sulfate.

Claims

1. A storage stable pharmaceutical composition in unit dosage form which comprises a therapeutically effective amount of a thyroxine active drug, a stabilizing amount of an alditol, a stabilizing amount of a saccharide, and optionally further comprises other pharmaceutically acceptable excipients.

2. A composition of claim 1 wherein said thyroxine active drug is levothyroxine sodium.

3. A composition of claim 1, wherein said aiditol is selected from the group consisting of mannitol, sorbitol, maltitol and xylitol.

4. A composition of claim 1 wherein said alditol is mannitol.

5. A composition of claim 1, wherein said saccharide is selected from a reducing sugar, an aldose, a hemiacetal, a cyclic hemiacetal and a cyclized aldose.

6. A composition of claim 1, wherein said saccharide is selected from the group consisting of a monosaccharide, a disaccharide, and an oligosaccharide.

7. A composition of claim 1, wherein said saccharide is selected from the group consisting of sucrose, maltose, cellobiose, lactose, trehalose, glucose, fructose, galactose, ribose and deoxyribose.

8. A composition of claim 1, wherein said saccharide is a disaccharide.

9. A composition of claim 8, wherein said disaccharide is sucrose.

12. A composition of claim 1, 10, or 11 which comprises at least one further pharmaceutical excipient.

20. A method for the treatment of thyroid disorders comprising orally administering the composition of claim 1, 10, 11, 13, 17, or 18 to a human.

21. A composition of claim 1, 10, 11, 13, 17, or 18 which is a solid oral dosage form.

22. A composition of claim 1, 10, 11, 13, 17, or 18 which is a tablet.

10. A storage stable pharmaceutical composition in unit dosage form which comprises a therapeutically effective amount of a thyroxine active drug, an alditol in the amount of about 5% to about 90% of the total weight of said composition, and a saccharide in an amount of about 5% to about 70% of the total weight of said composition.

11. A storage stable pharmaceutical composition in unit dosage form which comprises levothyroxine sodium in a therapeutically effective amount, mannitol in the amount of about 58% of the total weight of said composition, and sucrose in an amount of about 14% of the total weight of said composition.

13. A storage stable oral pharmaceutical composition in unit dosage form which comprises a therapeutically effective amount of levothyroxine sodium, a stabilizing amount of mannitol, a stabilizing amount of sucrose, and optionally further comprises other pharmaceutically acceptable excipients.

14. A composition of claim 13 wherein said stabilizing amount of mannitol is from about 5% to about 90% of the total weight of said composition and wherein said stabilizing amount of sucrose is from about 5% to about 70% of the total weight of said composition.

15. A composition of claim 13 wherein said stabilizing amount of mannitol is from about 15% to about 80% of the total weight of said composition and wherein said stabilizing amount of sucrose is from about 10% to about 60% of the total weight of said composition.

16. A composition of claim 13 wherein said stabilizing amount of mannitol is from about 25% to about 70% of the total weight of said composition and wherein said stabilizing amount of sucrose is from about 20% to about 40% of the total weight of said composition.

17. A storage stable oral pharmaceutical composition in unit dosage form which comprises a therapeutically effective amount of levothyroxine sodium, mannitol in an amount of about 5% to about 90% of the total weight of said composition, sucrose in an amount of about 5% to about 70% of the total weight of said composition, and optionally further comprises microcrystalline cellulose, polyvinylpyrrolidone, crospovidone, magnesium stearate, sodium lauryl sulfate, and colloidal silicon dioxide.

18. A storage stable oral pharmaceutical composition in unit dosage form which comprises:

(a) a therapeutically effective amount of levothyroxine sodium;

(b) about 58% by weight mannitol;

(c) about 14% by weight sucrose;

(d) about 25% by weight microcrystalline cellulose;

(e) about 1.5% by weight polyvinylpyrrolidone;

(f) about 1.4% by weight magnesium stearate;

(g) about 0.3% by weight colloidal silicon dioxide; and

(h) about 0.1% by weight sodium lauryl sulfate.

19. A storage stable oral pharmaceutical composition in unit dosage form which comprises:

(a) a therapeutically effective amount of levothyroxine sodium;

(b) about 39% by weight mannitol;

(c) about 23% by weight sucrose;

(d) about 28% by weight microcrystalline cellulose;

(e) about 1.5% by weight polyvinylpyrrolidone;

(f) about 6% by weight crospovidone;

(g) about 2% by weight magnesium stearate;

(h) about 0.3% by weight colloidal silicon dioxide; and

(i) about 0.1% by weight sodium lauryl sulfate.