Storage stable thyroxine active drug formulations and methods for their production

• US 7,052,717 B2
• Filed: 05/20/2003
• Issued: 05/30/2006
• Est. Priority Date: 11/13/2001
• Status: Expired due to Term

• Current Assignee: Mylan Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Mylan Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Wargo, David John, Hanshew, Dwight D. Jr.
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): Lamm, Marina
• Application Number:
  US10/441,259
• Publication Number:
  US 20040013725A1
• Time in Patent Office: 1,106 Days
• Field of Search: 424/464, 424/465
• US Class Current: 424/464
• 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, an amount of an antioxidant sufficient to inhibit oxidative degradation of said drug, a stabilizing amount of an alditol which is from about 5% to about 90% of the total weight of said composition, a stabilizing amount of a saccharide which is from about 20% to about 40% of the total weight of said composition, and optionally further comprises other pharmaceutically acceptable excipients wherein said antioxidant is selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, dodecyl gallate, ethyl gallate, octyl gallate, sodium metabisulfite, fumaric acid and malic acid.

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

3. 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.

4. 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 and wherein said stabilizing amount of alditol is from about 15% to about 80% 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 0.01% to about 0.5% of the total weight of said composition and wherein said stabilizing amount of alditol is from about 25% to about 70% of the total weight of said composition.

6. A composition of claim 1 wherein said antioxidant is butylated hydroxyanisole.

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

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

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

10. A composition of claim 9, wherein said saccharide is sucrose.

16. A method for the treatment of thyroid disorders comprising orally administering the composition of claim 1 to a human.

18. A composition of claim 1 which is a solid oral dosage form.

20. A composition of claim 1 which is a tablet.

11. 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 which is from about 0.001% to about 2% of the total weight of said composition, a stabilizing amount of mannitol which is from about 5% to about 90% of the total weight of said composition, a stabilizing amount of sucrose which is from about 20% to about 40% of the total weight of said composition, and optionally further comprises other pharmaceutically acceptable excipients.

12. A composition of claim 11 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 and wherein said stabilizing amount of mannitol is from about 15% to about 80% of the total weight of said composition.

13. A composition of claim 11 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 and wherein said stabilizing amount of mannitol is from about 25% to about 70% of the total weight of said composition.

14. 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 20% to about 40% of the total weight of said composition, and optionally further comprises microcrystalline cellulose, polyvinylpyrrolidone, crospovidone, magnesium stearate, sodium lauryl sulfate, and colloidal silicon dioxide.

15. 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.

17. A method for the treatment of thyroid disorders comprising orally administering the composition of claim 15 to a human.

19. A composition of claim 15 which is a solid oral dosage form.

21. A composition of claim 15 which is a tablet.