Stabilization of solid thyroid drug formulations

• US 6,855,333 B1
• Filed: 10/18/2000
• Issued: 02/15/2005
• Est. Priority Date: 10/03/2000
• Status: Expired due to Term

• Current Assignee: Sigmapharm, Sun Pharmaceutical Industries, Inc. (Sun Pharmaceutical Industries Limited)
• Original Assignee: Mutual Pharmaceutical Company (Takeda Pharmaceutical Company Limited)
• Inventors: Spireas, Spiridon
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Nola-Baron, Liliana Di
• Application Number:
  US09/690,973
• Time in Patent Office: 1,581 Days
• Field of Search: 424/452, 424/451, 424/484, 424/486, 424/488, 424/489, 424/494, 424/495, 424/499
• US Class Current: 424/452
• 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 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4816 Wall or shell material
• CPC Class Codes: A61K 9/485 Inorganic compounds
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4

Abstract

Pharmaceutical formulations and dosage forms are provided having improved stability to moisture-induced degradation when compared with conventional dosage forms, especially tablets. The invention features low compression forms of thyroid drugs together with excipients, preferably in encapsulated forms. In other embodiments, relatively non-volatile oils can be admixed with the drug and/or the excipients to stabilize the formulation toward moisture-induced degradation. Hydrophobic powders are also optionally added to the formulations.

Claims

1. A stable drug dosage form prepared be compression techniques comprising:

a thyroid hormone susceptible to moisture induced degradations, and

particles of at least one pharmaceutically acceptable excipient, each particle having an exterior surface, an interior, equilibrium moisture disposed within the interior of the particles, the thyroid hormone being in contact with the exterior surface of the particles of the at least one pharmaceutically acceptable excipient;

the dosage form prepared by;

admixing the thyroid hormone and the at least one pharmaceutically acceptable excipient; and

compacting the thyroid hormone and the at least one pharmaceutically acceptable excipient into unit dosage forms using compression pressures of less than about 5000 psi/g;

wherein the compression pressure limits the amount of equilibrium moisture available to react with the thyroid hormone at the exterior surface of the particles of the at least one pharmaceutically acceptable excipient.

2. The drug dosage form of claim 1 comprising a capsule.

3. The drug dosage form of claim 1 comprising a capsule formed of hydroxypropyl methylcellulose.

4. The drug dosage form of claim 1 wherein the hormone is contained in solid form within a capsule.

5. The drug dosage form of claim 1 wherein the form is subjected to no compression in excess of about 2,000 psi/g.

6. The drug dosage form of claim 1 wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of hydroxypropyl methylcellulose, carboxymethyl cellulose, microcrystalline cellulose, amorphous silicon dioxide, magnesium stearate, starch, sodium starch glycolate, and combinations thereof.

7. The drug dosage form of claim 1 wherein the excipient has a residual moisture content of less than about 10% by weight.

8. The drug dosage form of claim 1 exhibiting improved stability to moisture-induced degradation of the hormone as compared with a tabletted form of the hormone.

9. The drug dosage form of claim 1 comprising a unit dosage form.

10. A stable drug dosage form comprising:

a hydrophobic solid powder;

a thyroid hormone susceptible to moisture induced degradation, treated with said hydrophobic solid powder to substantially water-proof said thyroid hormone; and

at least one pharmaceutically acceptable excipient.

11. The drug dosage form of claim 10 comprising a capsule.

12. The drug dosage form of claim 10 comprising a capsule formed of hydroxypropyl methylcellulose.

13. The drug dosage form of claim 10 wherein the thyroid hormone is contained in solid form within a capsule.

14. The drug dosage form of claim 10 wherein the form is subjected to no compression in excess of about 10,000 psi/g.

15. The drug dosage form of claim 10 wherein the form is subjected to no compression in excess of about 5,000 psi/g.

16. The drug dosage form of claim 10 wherein the form is subjected to no compression in excess of about 2,000 psi/g.

17. The drug dosage form of claim 10 wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of hydroxypropyl methylcellulose, caboxymethyl cellulose, microcrystalline cellulose, amorphous silicon dioxide, magnesium stearate, starch, sodium starch glycolate, and combinations thereof.

18. The drug dosage form of claim 10 wherein the excipient has a residual moisture content of less than about 10% by weight.

21. The drug dosage form of claim 10 wherein said pharmaceutically acceptable excipient is treated by admixing said thyroid hormone and said hydrophobic powder, each particle of thyroid hormone being substantially enveloped by said hydrophobic powder.

22. The drug dosage form of claim 10 wherein said drug dosage form is prepared by:

admixing said thyroid hormone with said hydrophobic powder, each particle of thyroid hormone being substantially enveloped by said hydrophobic powder,

adding said at least one pharmaceutically acceptable excipient to said admixture of said thyroid hormone and said hydrophobic powder,

compacting said enveloped thyroid hormone, said at least one pharmaceutically acceptable excipient, and said hydrophobic powder using a compression pressure of less than 5000 psi/g.

23. The drug dosage form of claim 10 wherein said at least one pharmaceutically acceptable excipient comprises less than 10 percent by weight, based on the weight of said pharmaceutically acceptable excipient, of equilibrium moisture, said moisture disposed within the interior bulk of each particle of said at least one pharmaceutically acceptable excipient.

24. The drug dosage form of claim 10 wherein said hydrophobic powder comprises magnesium stearate, antioxidants, or combinations thereof.

25. The drug dosage form of claim 10 wherein said drug dosage form comprises from about 0.5 weight percent to about 5.0 weight percent, based on the weight of the drug dosage form, of hydrophobic powder.

26. The drug dosage form of claim 10 comprising a tablet.

27. The drug dosage form of claim 10 wherein the decrease in weight percent of thyroid hormone after being stored at 60°

C., and a relative humidity of 75% for 5 days is less than 9.5 percent.

19. A method for administering a thyroid hormone to a patient comprising:

providing a unit dose comprising;

a hydrophobic solid powder;

a thyroid hormone susceptible to moisture induced degradation, treated with said hydrophobic solid powder to substantially waterproof said thyroid hormone; and

at least one pharmaceutically acceptable excipient;

said stable dosage form prepared by;

admixing said thyroid hormone with said hydrophobic powder, each particle of thyroid hormone being substantially enveloped by said hydrophobic powder,

adding said at least one pharmaceutically acceptable excipient to said admixture of said thyroid hormone and said hydrophobic powder;

compacting said enveloped thyroid hormone, said at least one pharmaceutically acceptable excipient, and said hydrophobic powder using a compression pressure of less than 5000 psi/g.

20. The method for administering a thyroid hormone to a patient of claim 19 wherein the thyroid hormone is levothyroxine.

28. A method for preparing a stable drug dosage form comprising:

a hydrophobic solid powder;

a thyroid hormone susceptible to moisture induced degradation, treated with said hydrophobic solid powder to substantially water-proof said thyroid hormone; and

at least one pharmaceutically acceptable excipient;

the method comprising the steps of;

admixing said thyroid hormone with said hydrophobic powder, each particle of thyroid hormone being substantially enveloped by said hydrophobic powder,

adding said at least one pharmaceutically acceptable excipient to said admixture of said thyroid hormone and said hydrophobic powder;

compacting said enveloped thyroid hormone, said at least one pharmaceutically acceptable excipient, and said hydrophobic powder using a compression pressure of less than 5000 psi/g.