Sustained release preparations

• US 20020044967A1
• Filed: 10/17/2001
• Published: 04/18/2002
• Est. Priority Date: 03/26/1998
• Status: Active Grant

• 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
• Granted Patent: US 6,576,259 B2
• Time in Patent Office: Days
• 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 of a macrolide compound, wherein the time (T63.2%) required for 63.2% of the maximum amount of macrolide compound 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, wherein the macrolide compound is a tricyclic compound represented by the general formula I and a pharmaceutically acceptable salt thereof.

3. The sustained-release formulation in claim 1, which comprises a solid dispersion composition, wherein the macrolide compound is present as an amorphous state in a solid base.

4. A solid dispersion composition usable in the sustained-release formulation in claim 3, wherein the macrolide compound is present as an amorphous state in a solid base.

5. The composition in claim 4, wherein its particle size is equal to or smaller than 500 μ

m.

6. The composition in claim 4, wherein the solid base is a water-soluble base and the weight ratio of the macrolide compound and the water-soluble base is 1:

0.05 to 1;

2.

7. The composition in claim 4, wherein the water-soluble base is a water-soluble polymer.

8. The composition in claim 7, wherein the water-soluble polymer is hydroxypropylmethyl cellulose.

9. The composition in claim 4, wherein the composition does not substantially contain any disintegrator.

10. The composition in claim 4, wherein the solid base is a water-insoluble base.

11. The composition in claim 10, wherein the water-insoluble base is wax.

12. The composition in claim 11, wherein the wax is the one selected from the group consisting glycerin monostearate, polyglycerin fatty acid ester and sucrose fatty acid ester.

13. The composition in claim 10, wherein the water-insoluble base is a water-insoluble polymer.

14. The composition in claim 13, wherein the weight ratio of the macrolide compound and the water-insoluble polymer is 1:

0.01 to 1;

10.

15. The composition in claim 13, wherein the water-insoluble polymer is ethylcellulose.

16. The formulation in claim 2 or the composition in claim 4, wherein the macrolide compound is tacrolimus or a hydrate thereof.

17. The formulation in claim 2 or the composition in claim 4, wherein the macrolide compound is 33-epi-chloro-33-desoxyascomycin.

18. The formulation in claim 1, which comprises fine powder of the macrolide compound 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.

19. The fine powder of the macrolide compound usable in the sustained-release formulation in claim 1, which has a particle diameter distribution within the range of 0.1 to 50μ

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

m

20. A sustained-release formulation of a macrolide compound, the dissolution rate of which is expressed by the following equation:

Dissolution rate (%)=D_max×

{1−

exp[−

((T−

Ti)ⁿ)/m]}

, wherein T is a time for evaluation,

D_max (maximum dissolution rate) is 80% or more,

m (scale parameter) is 0.7˜

20,

n (shape parameter) is 0.2˜

5, and

Ti (position parameter) is 0˜

12,

when the dissolution test therefor is performed 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; and

each parameters are calculated by a nonlinear least square method.

21. A dissolution test method for a solid formulation comprising macrolide compound, which uses a test solution containing a suitable amount of cellulose polymer.

22. The dissolution test method in claim 21, in which cellulose polymer is hydroxypropyl cellulose or its equivalent and the concentration of which is 0.001 to 0.1%.

23. The dissolution test method in claim 22, in which pH of the test solution was adjusted to not higher than 7.

24. The dissolution test method in claim 21, in which the dissolution test is performed according to Dissolution Test, Method 2 (Paddle method, 50 rpm), JP XIII or dissolution test shown in USP 23, NF18 or European Pharmacopoeia (3rd edition).

25. The dissolution test method in claim 21, wherein the solid formulation comprising the macrolide compound is a rapid-release formulation or sustained-release formulation comprising tacrolimus or a hydrate thereof.

26. The dissolution test method in claim 22, wherein the level of addition of said hydroxypropyl cellulose or its equivalent is 0.005% and the test solution is adjusted to pH 4.5.