Storage stable thyroxine active drug formulations and methods for their production

• US 20040013725A1
• Filed: 05/20/2003
• Published: 01/22/2004
• 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 7,052,717 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 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4

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 and an antioxidant, and, optionally, additional pharmaceutically accepted excipients. Levothyroxine sodium is the preferred active drug substance, butylated hydroxyanisole is the preferred antioxidant. Additional preferred excipients include, for example, microcrystalline cellulose, sucrose, mannitol, 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 and an amount of an antioxidant sufficient to inhibit oxidative degradation of said drug.

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

3. A composition of claim 1, wherein said antioxidant is selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, ascorbyl palmitate, propyl gallate, dodecyl gallate, ethyl gallate, octyl gallate, alpha tocopherol, sodium ascorbate, sodium metabisulfite, fumaric acid and malic acid.

4. A composition of claim 1 wherein said amount of antioxidant sufficient to inhibit oxidative degradation of said drug is from about 0.001% to about 2% of the total weight of said composition.

5. A composition of claim 1 wherein said amount of antioxidant sufficient to inhibit oxidative degradation of said drug is from about 0.005% to about 1% of the total weight of said composition.

6. A composition of claim 1 wherein said amount of antioxidant sufficient to inhibit oxidative degradation of said drug is from about 0.01% to about 0.5% of the total weight of said composition.

8. A composition of claims 1 or 7 wherein said antioxidant is butylated hydroxyanisole.

26. A composition of claims 1, 7, 9, 10, 24, or 25 which comprises at least one further pharmaceutical excipient.

34. A method for the treatment of thyroid disorders comprising orally administering the composition of claims 1, 7, 9, 10, 24, 25, 27, 31, 32, or 33 to a human.

35. A composition of claims 1, 7, 9, 10, 24, 25, 27, 31, 32, or 33 which is a solid oral dosage form.

36. A composition of claims 1, 7, 9, 10, 24, 25, 27, 31, 32, or 33 which is a tablet.

7. A storage stable pharmaceutical composition in unit dosage form which comprises a therapeutically effective amount of a thyroxine active drug and an antioxidant in the amount of about 0.001% to about 2% of the total weight of said composition.

9. A storage stable pharmaceutical composition in unit dosage form which comprises levothyroxine sodium in a therapeutically effective amount and butylated hydroxyanisole in an amount of about 0.01% of the total weight of said composition.

10. A storage stable pharmaceutical composition in unit dosage form which comprises a therapeutically effective amount of a thyroxine active drug, an amount of an antioxidant sufficient to inhibit oxidative degradation of said drug, a stabilizing amount of an alditol, a stabilizing amount of a saccharide, and optionally further comprises other pharmaceutically acceptable excipients.

11. A composition of claim 10 wherein said thyroxine active drug is levothyroxine sodium.

12. A composition of claim 10, wherein said antioxidant is selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, ascorbyl palmitate, propyl gallate, dodecyl gallate, ethyl gallate, octyl gallate, alpha tocopherol, sodium ascorbate, sodium metabisulfite, fumaric acid and malic acid.

13. A composition of claim 10 wherein said amount of antioxidant sufficient to inhibit oxidative degradation of said drug is from about 0.001% to about 2% of the total weight of said composition, wherein said stabilizing amount of alditol is from about 5% to about 90% of the total weight of said composition and wherein said stabilizing amount of saccharide is from about 5% to about 70% of the total weight of said composition.

14. A composition of claim 10 wherein said amount of antioxidant sufficient to inhibit oxidative degradation of said drug is from about 0.005% to about 1% of the total weight of said composition, wherein said stabilizing amount of alditol is from about 15% to about 80% of the total weight of said composition and wherein said stabilizing amount of saccharide is from about 10% to about 60% of the total weight of said composition.

15. A composition of claim 10 wherein said amount of antioxidant sufficient to inhibit oxidative degradation of said drug is from about 0.01% to about 0.5% of the total weight of said composition, wherein said stabilizing amount of alditol is from about 25% to about 70% of the total weight of said composition and wherein said stabilizing amount of saccharide is from about 20% to about 40% of the total weight of said composition.

16. A composition of claim 10 wherein said antioxidant is butylated hydroxyanisole.

17. A composition of claim 10, wherein said alditol is selected from the group consisting of mannitol, sorbitol, maltitol and xylitol.

18. A composition of claim 10 wherein said alditol is mannitol.

19. A composition of claim 10, wherein said saccharide is selected from a reducing sugar, an aldose, a hemiacetal, a cyclic hemiacetal and a cyclized aldose.

20. A composition of claim 10, wherein said saccharide is selected from the group consisting of a monosaccharide, a disaccharide, and an oligosaccharide.

21. A composition of claim 10, wherein said saccharide is selected from the group consisting of sucrose, maltose, cellobiose, lactose, trehalose, glucose, fructose, galactose, ribose and deoxyribose.

22. A composition of claim 10, wherein said saccharide is a disaccharide.

23. A composition of claim 22, wherein said disaccharide is sucrose.

24. A storage stable pharmaceutical composition in unit dosage form which comprises a therapeutically effective amount of a thyroxine active drug, an antioxidant in an amount of about 0.001% to about 2% of the total weight of said composition, 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.

25. A storage stable pharmaceutical composition in unit dosage form which comprises levothyroxine sodium in a therapeutically effective amount, butylated hydroxyanisole in an amount of about 0.01% of the total weight of said composition, 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.

27. A storage stable oral pharmaceutical composition in unit dosage form which comprises a therapeutically effective amount of levothyroxine sodium, an amount of butylated hydroxyanisole sufficient to inhibit oxidative degradation of said drug, a stabilizing amount of mannitol, a stabilizing amount of sucrose, and optionally further comprises other pharmaceutically acceptable excipients.

28. A composition of claim 27 wherein said amount of butylated hydroxyanisole sufficient to inhibit oxidative degradation of said drug is from about 0.001% to about 2% of the total weight of said composition, 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.

29. A composition of claim 27 wherein said amount of butylated hydroxyanisole sufficient to inhibit oxidative degradation of said drug is from about 0.005% to about 1% of the total weight of said composition, 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.

30. A composition of claim 27 wherein said amount of butylated hydroxyanisole sufficient to inhibit oxidative degradation of said drug is from about 0.01% to about 0.5% of the total weight of said composition, 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.

31. A storage stable oral pharmaceutical composition in unit dosage form which comprises a therapeutically effective amount of levothyroxine sodium, butylated hydroxyanisole in an amount of about 0.001% to about 2% of the total weight of said composition, 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.

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

(a) a therapeutically effective amount of levothyroxine sodium;

(b) about 0.01% by weight butylated hydroxyanisole;

(c) about 58% by weight mannitol;

(d) about 14% by weight sucrose;

(e) about 25% by weight microcrystalline cellulose;

(f) about 1.5% by weight polyvinylpyrrolidone;

(g) about 1.4% by weight magnesium stearate;

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

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

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

(a) a therapeutically effective amount of levothyroxine sodium;

(b) about 0.01% by weight butylated hydroxyanisole;

(c) about 39% by weight mannitol;

(d) about 23% by weight sucrose;

(e) about 28% by weight microcrystalline cellulose;

(f) about 1.5% by weight polyvinylpyrrolidone;

(g) about 6% by weight crospovidone;

(h) about 2% by weight magnesium stearate;

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

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