Method of manufacturing solid dispersion

• US 5,456,923 A
• Filed: 11/15/1993
• Issued: 10/10/1995
• Est. Priority Date: 04/16/1991
• Status: Expired due to Term

• Current Assignee: Nippon Shinyaku Company Limited
• Original Assignee: Nippon Shinyaku Company Limited
• Inventors: Yasuura, Hiroyuki, Izumi, Shogo, Nakamichi, Kouichi
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Spear, James M.
• Application Number:
  US08/129,133
• Time in Patent Office: 694 Days
• Field of Search: 424/464, 424/465, 424/452, 424/455, 424/489, 514/772.1, 514/772.3, 514/773, 514/777
• US Class Current: 424/489
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Abstract

The object of this invention is to provide a process for producing a solid dispersion, which has overcome the disadvantages of the conventional production technology for solid dispersions. The invention comprises employing a twin-screw extruder in the production of a solid dispersion. In accordance with the invention, a solid dispersion can be expediently produced without heating a drug and a polymer to or beyond their melting points and without using an organic solvent for dissolving both components and the resulting solid dispersion has excellent performance characteristics.

Claims

1. A process for producing a solid dispersion of a drug dissolved or dispersed in a polymer carrier or diluent which comprises passing a mixture comprising said drug and said polymer through a twin screw compounding extruder having retaining barrels, with said twin screw compounding extruder being equipped with paddle means on each of two screw shafts, whereby said mixture passes between said paddle means and is sheared and compounded thereby, and operating said twin screw extruder while sufficiently heating the barrels to obtain an extrudate in the form of said solid dispersion and wherein said heating is to a temperature below the decomposition temperature of the drug or polymer.

2. A process according to claim 1 where said drug is selected from the group consisting of antipyretic agents, analgesic agents, antiinflammatory agents, antiulcer agents, coronary vasodilators, peripheral vasodilators, antibiotics, synthetic antimicrobial agents, antispasmodic agents, antitussive and antiasthmatic agents, bronchodilators, diuretics, muscle relaxants, cerebral metabolism improving agents, minor tranquilizers, major tranquilizers, β

-blockers, antiarrhythmic agents, antigout agents, anticoagulants, antiepileptics, antihistaminics, antiemetics, antihypertensive agents, sympathomimetic agents, expectorants, oral antidiabetic agents, cardiovascular system drugs, iron preparations, vitamins, therapeutic agents for pollakiuria, and angiotensin-converting enzyme inhibitors.

3. A process according to claim 1 wherein said polymer is any natural or synthetic polymer which is capable of being employed as a raw material in the manufacture of pharmaceutical wherein said polymer'"'"'s functions are not adversely affected by passage through the twin-screw extruder.

4. A process according to claim 3 wherein said polymer is a pH-dependent polymer, a pH-independent polymer or a water-soluble polymer.

5. A process according to claim 4 wherein said process employs a combination of two or more species of said polymer.

6. A process according to claim 1 wherein said polymer has a particle diameter of not greater than 7,000 μ

m.

7. A process according to claim 1 wherein said polymer has a particle diameter of not greater than 2,000 μ

m.

8. A process according to claim 1 wherein said drug is not decomposed at any temperature below 50°

C. and is a thermally labile drug or said polymer is a thermally labile polymer and another component of the solid dispersion is an aqueous solution or dispersion of a plasticizer.

9. A process according to claim 8 wherein said plasticizer is selected from the group consisting of cetanol, medium chain triglycerides, polyoxyethylenepolyoxypropylene glycol, and macrogols (200, 300, 400, 600, 1,000, 1,500, 1,540, 4,000, 6,000, 20,000).

10. A process according to claim 4 wherein said polymer is selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer E, poly (vinyl acetal) diethylaminoacetate, polyvinyl pyrrolidone, ethylcellulose, methacrylic acid copolymer RS, polyvinyl alcohol, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, dextrin, pullulan, acacia, tragacanth, sodium alginate, propylene glycol alginate, agar powder, gelatin, starch, processed starch and glucomannan.

11. A process according to claim 1 wherein the passing step is performed while water, or an aqueous solution or dispersion of a plasticizer is added into the barrel.

12. A process according to claim 1 wherein the temperature of each barrel is in the range from 50°

C. up to a temperature at which neither the drug nor the polymer decomposes.