STABLE TABLET FORMULATION

• US 20080207626A1
• Filed: 04/21/2008
• Published: 08/28/2008
• Est. Priority Date: 11/17/2004
• Status: Active Grant

• Current Assignee: Biomarin Pharmaceutical Incorporated (Amgen Inc.)
• Original Assignee: Biomarin Pharmaceutical Incorporated (Amgen Inc.)
• Inventors: Henderson, Mark, Baffi, Robert, Sluzky, Victoria, Jungles, Steven
• Granted Patent: US 7,566,462 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00

Abstract

The present invention is directed to a stable solid formulations of tetrahydrobiopterin, processes for producing them, and treatment methods using such formulations.

Claims

1. A stable tablet formulation comprising an initial amount of a crystalline polymorph, designated polymorph B, of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride, and a pharmaceutically acceptable excipient, diluent, or carrier in the form of a tablet, wherein after six months in a container at room temperature and about 60% humidity the stable tablet formulation retains at least about 95% of the initial amount of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride,

and wherein said crystalline polymorph B exhibits an X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å

) 8.7 (vs), 5.63 (m), 4.76 (m), 4.40 (m), 4.00 (s), 3.23 (s), and 3.11 (vs).

2. The stable tablet formulation of claim 1, wherein the crystalline polymorph B further exhibits characteristic peaks expressed in d-values (Å

);

8.7 (vs), 6.9 (w), 5.90 (vw), 5.63 (m), 5.07 (m), 4.76 (m), 4.40 (m), 4.15 (w), 4.00 (s), 3.95 (m), 3.52 (m), 3.44 (w), 3.32 (m), 3.23 (s), 3.17 (w), 3.11 (vs), 3.06 (w), 2.99 (w), 2.96 (w), 2.94 (m), 2.87 (w), 2.84 (s), 2.82 (m), 2.69 (w), 2.59 (w), and 2.44 (w).

3. The stable tablet formulation of claim 1, wherein after six months in a container at room temperature and about 60% humidity the stable tablet formulation retains at least about 98% of the initial amount of (6R)-L-erythro-tetrahydrobiopterin.

4. The stable tablet formulation of claim 1, wherein after nine months in a container at room temperature and about 60% humidity the stable tablet formulation retains at least about 95% of the initial amount of (6R)-L-erythro-tetrahydrobiopterin.

5. The stable tablet formulation of claim 1, wherein after twelve months in a container at room temperature and about 60% humidity the stable tablet formulation retains at least about 95% of the initial amount of (6R)-L-erythro-tetrahydrobiopterin.

6. The stable tablet formulation of claim 1, wherein the initial amount of (6R)-L-erythro-tetrahydrobiopterin is in a range of about 30 wt % to about 40 wt % of the formulation.

7. The stable tablet formulation of claim 1, wherein the initial amount of (6R)-L-erythro-tetrahydrobiopterin in a tablet is selected from the group consisting of 100 mg, 200 mg, and 300 mg.

8. The stable tablet formulation of claim 1, wherein the initial amount of (6R)-L-erythro-tetrahydrobiopterin in a tablet is 400 mg.

9. The stable tablet formulation of claim 1, further comprising a disintegration agent.

10. The stable tablet formulation of claim 9, wherein the disintegration agent is crospovidone.

11. The stable tablet formulation of claim 1, further comprising a lubricant.

12. The stable tablet formulation of claim 11, wherein the lubricant is stearyl fumarate.

13. The stable tablet formulation of claim 12, wherein the stearyl fumarate is sodium stearyl fumarate.

14. The stable tablet formulation of claim 11, wherein the lubricant is present in a range of about 1.0 wt % to about 1.8 wt % of the formulation.

15. The stable tablet formulation of claim 12, further comprising microcrystalline cellulose.

16. The stable tablet formulation of claim 1, comprising an initial amount of the (6R)-L-erythro-tetrahydrobiopterin of about 400 mg, crospovidone in a range of about 3 wt % to about 5 wt % of the formulation, and stearyl fumarate in a range of about 1 wt % to 1.7 wt % of the formulation.

17. The stable tablet formulation of claim 1, comprising an initial amount of the (6R)-L-erythro-tetrahydrobiopterin in a range of about 32 wt % to about 35 wt % of the formulation, crospovidone in a range of about 3 wt % to about 5 wt % of the formulation, anhydrous dibasic calcium phosphate in a range of about 1.5 wt % to about 3 wt % of the formulation, and stearyl fumarate in a range of about 0.5 wt % to about 1 wt % of the formulation.

18. A stable tablet formulation, comprising an initial amount of a crystalline polymorph, designated polymorph B, of (6R)-L-erythro-tetrahydrobiopterin dihydrochloride and a pharmaceutically acceptable excipient, diluent, or carrier, wherein after six months in a container at room temperature and about 60% humidity the stable tablet formulation retains at least about 95% of the initial amount of (6R)-L-erythro-tetrahydrobiopterin,

wherein said crystalline polymorph B exhibits an X-ray powder diffraction pattern with the following characteristic peaks expressed in d-values (Å

);

8.7 (vs), 5.63 (m), 4.76 (m), 4.40 (m), 4.00 (s), 3.23 (s), and 3.11 (vs), and

wherein the stable tablet formulation is made by a process that does not include adding liquid water.

19. The stable tablet formulation of claim 18, wherein the formulation is produced under controlled humidity conditions.

20. The stable tablet formulation of claim 18, wherein the crystalline polymorph B further exhibits characteristic peaks expressed in d-values (Å

);

8.7 (vs), 6.9 (w), 5.90 (vw), 5.63 (m), 5.07 (m), 4.76 (m), 4.40 (m), 4.15 (w), 4.00 (s), 3.95 (m), 3.52 (m), 3.44 (w), 3.32 (m), 3.23 (s), 3.17 (w), 3.11 (vs), 3.06 (w), 2.99 (w), 2.96 (w), 2.94 (m), 2.87 (w), 2.84 (s), 2.82 (m), 2.69 (w), 2.59 (w), and 2.44 (w).