Sustained release formulations containing tacrolimus

• US 6,576,259 B2
• Filed: 10/17/2001
• Issued: 06/10/2003
• 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, Nomura, Yukihiro, Tamura, Shigeki, Ideno, Toshio, Ibuki, Rinta, Hirose, Takeo, Shimojo, Fumio, Yamashita, Kazunari
• Primary Examiner(s): Naff, David M.
• Assistant Examiner(s): Ware, Deborah K.
• Application Number:
  US09/978,025
• Publication Number:
  US 20020044967A1
• Time in Patent Office: 601 Days
• Field of Search: 435/174, 435/178, 424/400, 424/452, 424/455, 424/457, 424/462, 424/465, 424/468, 424/489, 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 Japanese Pharmacopoeia, the 13-th edition, Dissolution Test, No. 2 (Puddle 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 comprise a solid base which is a water-soluble polymer and/or wax. The formulation is in the form of a powder, fine powder, granule, tablet or capsule. Furthermore, the formulation is administered to a patient once a day for preventing organ or tissue rejection by transplantation or autoimmune diseases.

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.

2. The sustained-release formulation in claim 1, which comprises a solid dispersion composition, wherein the tacrolimus or its hydrate is present as an amorphous state in a solid base.

3. The sustained-release formulation in claim 2, which the solid dispersion composition is characterized by

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

(2) no disintegrator is contained, and

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

m.

4. The sustained-release formulation in claim 2, in which the solid base is selected from a group consisting if water-soluble polymer and wax.

5. The sustained-release formulation in claim 2, in which the solid base is selected from a group consisting of

1) hydroxypropylmethyl cellulose, in a weight ratio to tacrolimus of 0.2-0.4 to 1, and

2) glycerin monostearate, polyglycerin fatty acid ester or sucrose fatty acid ester, in a weight ratio to tacrolimus of 0.2-20 to 1.

6. The sustained-release formulation in claim 2, which the solid dispersion composition is characterized by

(1) tacrolimus or its hydrate is present as an amorphous state in hydroxypropylmethyl cellulose in a weight ratio to tacrolimus of 0.2-0.4 to 1,

(2) lactose is contained as an excipient,

(3) no disintegrators are contained, and

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

m.

7. The sustained-release formulation in claim 1, in which tacrolimus or its hydrate is present as fine powder characterized by a particle diameter distribution within the range of 0.1 to 50 μ

m and/or a mean particle diameter within the range of 0.2 to 20 μ

m.

8. The sustained-release formulation in claim 1, in which the time (T63.2%) is 1.0 to 12 hours.

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

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

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

12. A method for administering tacrolimus or its hydrate to a patient without the risk of an undesired effect caused by a transiently excessive concentration of tacrolimus and insuring an expression of pharmacological efficacy over a sufficiently extended period of time, by administering the sustained-release formulation of claim 1 once a day.

13. A method for treating or preventing rejection of organs or tissues by transplantation or autoimmune diseases, by administering an effective amount of the sustained-release formulation of claim 1 once a day, without the risk of an undesired effect caused by a transiently excessive concentration of tacrolimus and insuring an expression of pharmacological efficacy over a sufficiently extended period of time.