Sustained-release liothyronine formulations, method of preparation and method of use thereof

• US 10,695,309 B2
• Filed: 03/30/2018
• Issued: 06/30/2020
• Est. Priority Date: 03/31/2017
• Status: Active Grant

• Current Assignee: Western New England University
• Original Assignee: Western New England University
• Inventors: Sani, Shabnam N., Bakhteyar, Hamid
• Primary Examiner(s): Song, Jianfeng
• Application Number:
  US15/941,644
• Publication Number:
  US 20180280330A1
• Time in Patent Office: 823 Days
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/4825 Proteins, e.g. gelatin gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816
• 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

Disclosed herein are sustained release Liothyronine oral capsule formulations, methods of making the formulations and use to treat hypothyroidism, a thyroid deficient disease state, or thyroid dysfunction.

Claims

1. A sustained release oral capsule formulation, comprising:

a capsule fill comprising liothyronine or a pharmaceutically acceptable salt thereof, a hydroxypropyl methylcellulose, and a filler;

the liothyronine or a pharmaceutically acceptable salt thereof is present in an amount equivalent to about 0.1 to about 25 micrograms of liothyronine;

about 25 to about 95% wt of a hydroxypropyl methylcellulose based on the total weight of the hydroxypropyl methylcellulose and filler, wherein the hydroxypropyl methylcellulose has 19-30% methoxyl content, 7-12% hydroxypropoxyl content, and 3000-120000 cP apparent viscosity as a 2% solution in water at 20°

C.; and

about 5 to about 75% wt of a filler based on the total weight of the hydroxypropyl methylcellose and filler, wherein the filler is lactose or microcrystalline cellulose;

wherein the capsule formulation exhibits a Higuchi release kinetic pattern.

2. The capsule formulation of claim 1, comprising liothyronine sodium equivalent to about 1, about 2, about 3, about 5, about 7.5, about 10, about 12.5, about 15, about 17.5, about 20 or about 25 micrograms of liothyronine.

3. The capsule formulation of claim 1, wherein the hydroxypropyl methylcellulose has

a 28-30% methoxyl content, 7-12% hydroxypropoxyl content, and a 3000-5600 cP apparent viscosity as a 2% solution in water at 20°

C.;

or

a 19-24% methoxyl content, 7-12% hydroxypropoxyl content, 80000-120000 cP apparent viscosity as a 2% solution in water at 20°

C.

4. The capsule formulation of claim 1, comprising

about 30 to about 90% wt of the hydroxypropyl methylcellulose, and

about 10 to about 70% wt of the filler.

5. The capsule formulation of claim 1, comprising

about 30 to about 50% wt of the hydroxypropyl methylcellulose, and

about 50 to about 70% wt of the filler.

6. The capsule formulation of claim 1, comprising

about 85 to about 95% wt of the hydroxypropyl methylcellulose, specifically where the hydroxypropyl methylcellulose has a 28-30% methoxyl content, 7-12% hydroxypropoxyl content, and a 3000-5600 cP apparent viscosity as a 2% solution in water at 20°

C.; and

about 5 to about 15% wt of the filler, specifically where the filler is lactose.

7. The capsule formulation of claim 1, comprising

about 25 to about 35% wt of the hydroxypropyl methylcellulose, specifically where the hydroxypropyl methylcellulose has a 28-30% methoxyl content, 7-12% hydroxypropoxyl content, and a 3000-5600 cP apparent viscosity as a 2% solution in water at 20°

C.; and

about 65 to about 75% wt of the filler.

8. The capsule formulation of claim 1, comprising

about 35 to about 55% wt of the hydroxypropyl methylcellulose, specifically where the hydroxypropyl methylcellulose has a 19-24% methoxyl content, 7-12% hydroxypropoxyl content, 80000-120000 cP apparent viscosity as a 2% solution in water at 20°

C.; and

about 65 to about 45% wt of the filler.

9. The capsule formulation of claim 1, comprising

about 40 to about 50% wt of the hydroxypropyl methylcellulose, specifically where the hydroxypropyl methylcellulose has a 19-24% methoxyl content, 7-12% hydroxypropoxyl content, 80000-120000 cP apparent viscosity as a 2% solution in water at 20°

C.; and

about 60 to about 50% wt of the filler.

10. The capsule formulation of claim 1, wherein the capsule formulation exhibits an in vitro dissolution profile that is substantially a Higuchi release kinetic pattern when tested using a USP paddle (Type II) apparatus at a temperature of 37°

C.±

0.2°

C. and RPM of 50±

0.1 per minute using 1000 mL phosphate buffered saline (pH=7.3±

0.1) as the dissolution medium.

11. The capsule formulation of claim 1, wherein the capsule formulation exhibits an in vitro dissolution profile when tested using a USP paddle (Type II) apparatus at a temperature of 37°

C.±

0.2°

C. and RPM of 50±

0.1 per minute using 1000 mL phosphate buffered saline (pH=7.3±

0.1) as the dissolution medium of

about 20 to about 30% release at 1 hour,

about 50 to about 60% release at 6 hours, and

about 90 to about 100% release at 12 hours; and

optionally further wherein the capsule formulation exhibits an in vitro dissolution profile of

about 25 to about 35% release at 2 hours,

about 40 to about 50% release at 4 hours,

about 75 to about 85% release at 8 hours,

about 80 to about 95% release at 10 hours, and

about 95 to about 100% release at 20 hours.

12. The capsule formulation of claim 1, wherein the capsule is a number 3 capsule or a number 3 hard gelatin capsule.

13. The capsule formulation of claim 1, wherein the capsule comprises a fill weight that is no more than 325 mg.

14. The capsule formulation of claim 1, wherein the liothyronine salt is liothyronine sodium.

15. The capsule formulation of claim 1, which releases the liothyronine or pharmaceutically acceptable salt thereof over a period of about 12 to about 24 hours.

16. The capsule formulation of claim 1, wherein the capsule fill further comprises a glidant, a disintegrant, a lubricant, or a combination thereof.

17. The capsule formulation of claim 16, wherein the glidant is colloidal silicon dioxide, the disintegrant is sodium starch glycolate, and the lubricant is sodium stearyl fumarate.