Sustained release formulation containing tacrolimus

• US 6,884,433 B2
• Filed: 04/14/2003
• Issued: 04/26/2005
• Est. Priority Date: 03/26/1998
• Status: Expired due to Term

• Current Assignee: Astellas Pharma Incorporated
• Original Assignee: Fujisawa Pharmaceutical Co., Ltd. (Astellas Pharma Incorporated)
• Inventors: Ueda, Satoshi, Hashimoto, Eiji, Saitoh, Takashi, Ideno, Toshio, Ibuki, Rinta, Hirose, Takeo, Shimojo, Fumio, Yamashita, Kazunari, Nomura, Yukihiro, Tamura, Shigeki
• Primary Examiner(s): Naff, David M.
• Assistant Examiner(s): Ware, Deborah K.
• Application Number:
  US10/412,281
• Publication Number:
  US 20030235614A1
• Time in Patent Office: 743 Days
• Field of Search: 424/400, 424452-489, 424/404, 435174- 78, 514/294
• US Class Current: 424/468
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/453 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 9/141 Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers (co) spray-dried products A61K9/16, (co) lyophilised products A61K9/19; the carrier being chemically bound to the active ingredient A61K47/50
• CPC Class Codes: A61K 9/143 with inorganic compounds
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection

Abstract

Sustained release formulation containing tacrolimus or its hydrate is provided. The time (T63.2%) required for 63.2% of the maximum amount of tacrolimus or its hydrate to be dissolved is 0.7 to 15 hours. The time is measured in accordance to the Japanes Pharmacopocia, the 13-th edition, Dissolution Test, No. 2 (Puddles method, 50 rpm) using an aqueous 0.005% hydroxypropyl cellulose solution. This aqueous test solution is adjusted to pH 4.5, accordingly. The formulation further comprises a solid base which is a water-soluble or water-insoluble polymer. The formulation is in the form of a powder, fine powder, granule, tablet or capsule. The formulation is administered to a patient once a day for preventing organ or tissue rejection by transplantation or autoimmune disease. In addition, a solid dispersion composition is provided. The solid dispersion comprises tacrolimus or its hydrate in a mixture containing water-soluble or water-insoluble polymer and an excipient.

Claims

1. A sustained-release formulation comprising a solid dispersion composition, wherein the solid dispersion composition comprises tacrolimus or its hydrate, in a mixture comprising a water-soluble polymer and a water-insoluble polymer, and an excipient.

2. The sustained-release formulation of claim 1, wherein the solid dispersion composition has a particle size equal to or smaller than 250 μ

m.

3. The sustained-release formulation of claim 1, wherein the weight ratio of the water-soluble polymer to tacrolimus is 0.2-0.4:

1, and the weight ratio of the water-insoluble polymer to tacrolimus is 0.1-5;

1.

4. The sustained-release formulation of claim 3, wherein the weight ratio of the water-insoluble polymer to tacrolimus is 0.1-1:

1.

5. The sustained-release formulation of claim 1, wherein the water-insoluble polymer is ethylcellulose.

6. The sustained-release formulation of claim 1 wherein the water-soluble polymer is hydroxypropylmethyl cellulose.

7. The sustained-release formulation of claim 1, wherein the excipient is lactose.

8. The sustained-release formulation of claim 7, wherein the weight ratio of lactose to tacrolimus is 2, 3 or 5:

1.

9. The sustained-release formulation of claim 1, wherein the solid dispersion composition does not substantially contain any disintegrators.

10. The sustained-release formulation of claim 1, wherein tacrolimus or its hydrate is present as an amorphous state.

11. The sustained-release formulation of claim 2, wherein the weight ratio of the water-soluble polymer to tacrolimus is 0.2-0.4:

1, and the weight ratio of the water-insoluble polymer to tacrolimus is 0.1-5;

1.

12. The sustained-release formulation of claim 11, wherein the weight ratio of the water-insoluble polymer to tacrolimus is 0.1-1:

1.

13. The sustained-release formulation of claim 6, wherein the water-insoluble polymer is ethylcellulose.

14. The sustained-release formulation of claim 13, wherein the excipient is lactose.

15. The sustained-release formulation of claim 1, wherein tacrolimus or its hydrate is present as an amorphous state in a mixture of ethylcellulose and hydroxypropylmethyl cellulose.

16. The sustained-release formulation of claim 15, wherein the weight ratio of the ethylcellulose to tacrolimus is 0.3:

1, and the weight ratio of the hydroxypropylmethyl cellulose to tacrolimus is 0.3;

1.

17. The sustained-release formulation of claim 16, wherein the excipient is lactose.

18. The sustained-release formulation of claim 17, wherein the weight ratio of lactose to tacrolimus is 2:

1.

19. The sustained-release formulation of claim 18, wherein the solid dispersion composition has a particle size equal to or smaller than 212 μ

m.

20. The sustained-release formulation of claim 3, wherein the water-insoluble polymer is ethylcellulose and the water soluble polymer is hydroxypropylmethyl cellulose.

21. The sustained-release formulation of claim 1, in a form of a powder, granule, tablet or capsule.