Process for producing stable medicinal composition, and pharmaceutical preparation

• US 5,688,510 A
• Filed: 05/17/1996
• Issued: 11/18/1997
• Est. Priority Date: 11/18/1993
• Status: Expired due to Fees

• Current Assignee: Nippon Shinyaku Company Limited
• Original Assignee: Nippon Shinyaku Company Limited
• Inventors: Yasuura, Hiroyuki, Izumi, Shougo, Nakamichi, Kouichi
• Primary Examiner(s): Rollins, John W.
• Application Number:
  US08/648,174
• Time in Patent Office: 550 Days
• Field of Search: 424/195.1, 424/6, 424/43, 424/46, 424/47, 424/483-489, 424/490-498, 514/951-53, 514/959, 514/960
• US Class Current: 424/736
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00

Abstract

A process for producing a pharmaceutical composition is disclosed. In the process, 1 part by weight of a physiologically inert powdery additive, 0.001-1 part by weight of a macromolecular additive per part by weight of said insert powdery additive, and at least one drug substance are used as ingredients and processed en bloc by means of a multi-screw extruder. The drug substance used in the process can be selected from the following group: subliminable drug, volatile drug, drug hydrolyzable in the presence of water, drug which develops whiskers, and hygroscopic or deliquescent drug. The process confers increased physicochemical stability to the pharmaceutical composition and the drug substance contained therein.

Claims

1. A method of increasing the physicochemical stability of a drug substance, comprising:

providing ingredients comprising 1 part by weight of a physiologically inert powdery additive, 0.001-1 part by weight of a macromolecular additive per part by weight of said physiologically inert additive, and a drug substance selected from the group consisting of subliminal drug, volatile drug, drug hydrolyzable in the presence of water, drug with tendency to develop whiskers, hygroscopic drug, and deliquescent drug; and

processing said ingredients en bloc by means of a multi-screw extruder to produce a pharmaceutical composition containing said drug substance, wherein the substance in the composition exhibits increase physicochemical stability.

2. The method of claim 1, wherein the multi-screw extruder is a twin-screw extruder.

3. The method of claim 1, wherein said macromolecular additive is 0.005 to 0.9 part by weight per part by weight of said physiologically inert powdery additive.

4. The method of claim 1, wherein said drug substance is 0.0001-10 times, by weight, the combined amount of said inert powdery additive and macromolecular additive.

5. The method of claim 4, wherein said drug substance is 0.001-5 times, by weight, the combined amount of said physiologically inert powdery additive and macromolecular additive.

6. The method of claim 5, wherein said drug substance is 0.01-1 times, by weight, the combined amount of said physiologically inert powdery additive and macromolecular additive.

7. The method of claim 1, wherein said drug substance is selected from the group consisting of drug hydrolyzable in presence of water, hygroscopic drug, and deliquescent drug, the method further comprising the step of adding a solvent to said ingredients prior to or during said en bloc processing.

8. The method of claim 1, wherein said drug substance is selected from the group consisting of subliminal drug, volatile drug, and drug with tendency to develop whiskers, the method further comprising the step of adding a plasticizer or a fluidizing agent to said ingredients prior to or during said en block processing.

9. The method of claim 1, wherein said drug substance is the sublimable drug selected from the group consisting of sodium 1,4-dimethylisopropyl-azulene-3-sulfonate, L-menthol, paraform, trimethadione, camphor, and naphthalene.

10. The method of claim 1, wherein said drug substance is the volatile drug selected from the group consisting of cinnamyl alcohol, anethole, eugenole, cinnamon oil, eucalyptus oil, lemon oil, fennel oil, clove oil, and mint oil.

11. The method of claim 1, wherein said drug substance is the drug hydrolyzable in the presence of water selected from the group consisting of aspirin, pipethanate hydrochloride, L-ethylcysteine hydrochloride, pyridostigmine bromide, calcium pantothenate, mepitiostane, pentobarbital sodium, and trichloroisocyanuric acid.

12. The method of claim 1, wherein said drug substance is the drug which develops whiskers and is selected from the group consisting of ethenzamide, caffeine, acetaminophen, bromvalerylurea, and clofedanol hydrochloride.

13. The method of claim 1, wherein said drug is the hygroscopic or deliquescent drug and is selected from the group consisting of sodium valproate, cyanocobalamin, diethylcarbamazine citrate, isosorbide, diclofenac sodium, betahistine mesylate, carpronium chloride, tolazoline hydrochloride, reserpilic acid dimethylaminoethyl ester dihydrochloride, carbachol, choline theophyllinate, choline salicylate, citicoline, hexamethonium bromide, chlorophyllin sodium-copper salt, panthenol, dexamethazone phosphate disodium salt, plant extracts, procainamide hydrochloride, L-proline, and calcium chloride.

14. A pharmaceutical composition produced by the method of claim 1.