Sustained release preparations

• US 6,440,458 B1
• Filed: 11/05/1999
• Issued: 08/27/2002
• 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: Hashimoto, Eiji, Ideno, Toshio, Yamashita, Kazunari, Ueda, Satoshi, Saitoh, Takashi, Nomura, Yukihiro, Tamura, Shigeki, Ibuki, Rinta, Hirose, Takeo, Shimojo, Fumio
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): WARE, TODD
• Application Number:
  US09/403,787
• Time in Patent Office: 1,026 Days
• Field of Search: 424/465, 424/489, 424/468, 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

Providing an oral formulation of a macrolide compound where the dissolution of the macrolide compound is under sustained release; and a sustained-release formulation containing a composition in solid solution, where the macrolide compound is present at an amorphous state in a solid base.

Claims

1. A sustained-release formulation comprising tacrolimus or its hydrate wherein 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, as measured according to the Japanese Pharmacopoeia, the 13-th edition, Dissolution Test, No. 2 (Puddle method, 50 rpm) using a test solution which is an aqueous 0.005% hydroxypropyl cellulose solution adjusted to pH 4.5, which comprises a solid dispersion composition, wherein tacrolimus or its hydrate is present as an amorphous state in water-insoluble polymer.

2. The sustained-release formulation in claim 1, wherein the weight ratio of tacrolimus to water-insoluble polymer is 1 to 0.1-5.

3. The sustained-release formulation in claim 1, wherein the water-insoluble polymer is ethylcellulose or methacrylate copolymers.

4. The sustained-release formulation in claim 1, wherein the solid dispersion composition is characterized by

(1) lactose or calcium hydrogen phosphate is contained as an excipient and/or lubricant, and

(2) the particle size of the said solid dispersion composition is equal to or smaller than 350 μ

m.

5. The sustained-release formulation in claim 4, wherein the solid dispersion composition is characterized by

(1) tacrolimus or its hydrate is present as an amorphous state in ethylcellulose,

(2) lactose is contained as an excipient, and

(3) the particle size of the said solid dispersion composition is equal to or smaller than 250 μ

m.

6. The sustained-release formulation in claim 1, wherein water-soluble polymer is mixed with the water-insoluble polymer.

7. The sustained-release formulation in claim 6, wherein the water-soluble polymer is hydroxypropylmethyl cellulose.

8. The sustained-release formulation in claim 7, wherein the weight ratio of tacrolimus to hydroxypropylmethyl cellulose is 1 to 0.2-0.4.

9. The sustained-release formulation in claim 6, wherein the solid dispersion composition is characterized by

(1) tacrolimus or its hydrate is present as an amorphous state in a mixture of ethylcellulose and hydroxypropylmethyl cellulose,

(2) lactose is contained as an excipient,

(3) the particle size of the said solid dispersion composition is equal to or smaller than 250 μ

m.

10. The sustained-release formulation in claim 1, in which the time (T63.2%) is 1.3 to 8.2 hours.

11. The sustained-release formulation in claim 1, in which the time (T63.2%) is 2 to 5 hours.

12. The sustained-release formulation in claim 1, which is in a form of powder, fine powder, granule, tablet or capsule.