Method of manufacturing wax matrices

• US 5,700,410 A
• Filed: 06/07/1995
• Issued: 12/23/1997
• Est. Priority Date: 10/16/1992
• Status: Expired due to Term

• Current Assignee: Nippon Shinyaku Company Limited
• Original Assignee: Nippon Shinyaku Company Limited
• Inventors: Izumi, Shougo, Nakamichi, Kouichi, Yasuura, Hiroyuki
• Primary Examiner(s): Vargot, Mathieu D.
• Application Number:
  US08/416,816
• Time in Patent Office: 930 Days
• Field of Search: 264/177.11, 264/211.11, 264/211.23, 264/4, 264/349, 264/109, 264/122, 425/204
• US Class Current: 264/122
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: B29C 48/40 using two or more parallel screws or at least two parallel non-intermeshing screws, e.g. twin screw extruders

Abstract

A method of producing a wax matrix for controlled release of a pharmaceutically active ingredient is provided. The method includes the steps of feeding a wax and a pharmaceutically active ingredient into a multi-screw extruder and thoroughly mixing the wax with the pharmaceutically active ingredient using the multi-screw extruder to form a wax matrix. The wax matrix thus produced provides a controlled release of the active ingredient.

Claims

1. A method of producing a wax matrix for controlling release of a pharmaceutically active material contained therein, said method comprising the steps of feeding a wax and the pharmaceutically active ingredient into a multi-screw extruder and thoroughly mixing the wax with the pharmaceutically active material using the multi-screw extruder, which is maintained at a temperature below the melting point of the wax during the mixing, to form a wax matrix, wherein the wax matrix thus produced provides a controlled release of the active ingredient.

2. The method of claim 1, wherein the multi screw extruder comprises a twin screw compounding extruder equipped with kneading paddle means on screw shafts of said extruder, whereby said wax and active ingredient pass said kneading paddle means and are sheared and kneaded together thereby.

3. The method of claim 2, wherein said wax has a melting point at a specific temperature and wherein said production of the wax matrix is effected at a temperature below said melting point.

4. The method of claim 2, wherein the specific temperature at which said wax melts, is at or above a temperature at which the pharmaceutically active ingredient is degraded thereby and wherein the temperature at which the wax matrix is effected is below the degradation temperature of the active ingredient.

5. The method of claim 2, wherein the ratio of said wax to said active ingredient ranges from 1:

99 to 99;

1 by weight.

6. The method of claim 2, wherein said method is a continuous process and wherein said multi-screw extruder comprises self cleaning means.

7. The method of claim 1, wherein said wax is hydrogenated castor oil and said pharmaceutically active ingredient is selected from the group consisting of Compound A, and acetominophen.

8. The method of claim 1, wherein said wax is stearic acid and said pharmaceutically active ingredient is selected from the group consisting of 6-fluoro-1-methyl-7- 4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl!-4-oxo-4H- 1,3!thiazeto 3,2-a!quinoline-3 -carboxylic acid indomethacin, dehydrocholic acid with wheat flour, and acetominophen.

9. The method of claim 1, wherein said wax matrix is extruded through a die and cut to form pellets or granules of desired size by a continuously operating rotary cutter.

10. The method of claim 9, wherein edges of the pellets or granules are removed by continuously being fed into contact with rounding device means.

11. A method for reducing the bitterness of a pharmaceutically active ingredient comprising the steps of including said ingredient in a wax matrix in accordance with the method of claim 2.

12. The method of claim 1, wherein the wax is a higher fatty acid or its ester derivative, wherein the higher fatty acid is selected from the group consisting of lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachidonic acid, behenic acid, lignoceric acid, cerotic acid, and montanic acid.

13. The method of claim 1, wherein the wax is selected from the group consisting of saturated fatty acid glycerides of vegetable origin, saturated fatty acid glycerides of animal origin, hydrogenated oils from saturated fatty acid glycerides of the vegetable origin, hydrogenated oils from saturated fatty acid glycerides of the animal origin, pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecanol, eicosanol, wool alcohol, cholesterol, cholesteryl palmitate and phytosterol palmitate.

14. The method of claim 1, wherein the pharmaceutically active ingredient is selected from the group consisting of an antipyretic/analgesic/antiinflammatory agent, antiulcer agent, coronary vasodilator, peripheral vasodilator, antibiotic, synthetic antimicrobial agent, anticonvulsant, antitussive/antiasthmatic agent, bronchodilator, diuretic, muscle relaxant, cerebral metabolism improving agent, tranquilizer, β

-blocker, antiarrhythmic drug, arthrifuge, anticoagulant, antiepileptic agent, antihistaminic agent, antihypertensive agent, sympathomimetic drug, expectorant, oral antidiabetic drug, cardiovascular drug, iron preparation, vitamin, drug for pollakiurea and angiotensin converting enzyme inhibitor.

15. The method of claim 14, wherein the antipyretic/analgesic/antiinflammatory agent is selected from the group consisting of indomethacin, aspirin, diclofenac sodium, ketoprofen, ibuprofen, mefenamic acid, dexamethasone, dexamethasone sulfate sodium, hydrocortisone, prednisolone, azulene, phenacetin, isopropylantipyrine, acetaminophen, benzydamine hydrochloride, phenylbutazone, flufenamic acid, mephenamic acid, sodium salicylate, choline salicylate, sasapyrine, clofezone and etodolac, the antiulcer agent is selected from the group consisting of sulpiride, cetraxate hydrochloride, gefarnate, irsogladine maleate, cimetidine, unitidine hydrochloride, femotidine, nistidine and roxatidine acetate hydrochloride, the coronary vasodilator is selected from the group consisting of nifedipine, isosorbide dinitrate, diltiazem hydrochloride, trapidil, dipyridamole, dilazep dihydrochloride, methyl 2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydropyridine-3-carboxylate, verapamil, nicardipine, nicardipine hydrochloride and verapamil hydrochloride, the peripheral vasodilator is selected from the group consisting of ifenprodil tartrate, cinepazide maleate, cyclandelate, cinnarizine and pentoxifylline, the antibiotic is selected from the group consisting of ampicillin, amoxicillin, cefalexin, erythromycin ethylsuccinate, bacampicillin hydrochloride, minocycline hydrochloride, chloramphenicol, tetracycline and erythromycin, the synthetic antimicrobial agent is selected from the group consisting of nalidixic acid, piromidic acid, pipemidic acid trihydrate, enoxacin, cinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, sulfameth oxazole trimethoprim and 6-fluor-1-methyl-7- 4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-peperazinyl!-4-oxo-4H 1,3!thiazeto 3,2-a!quinoline-3-carboxylic acid, the anticonvulsant is selected from the group consisting of propantheline bromide, atropine sulfate, oxobium bromide, timepidium bromide, butylscopolamine bromide, trospium chloride, butropium bromide, N-methylscopolamine methylsulfate, octatropine methylbromide and butropium bromide, the antitussive/antiasthmatic agent is selected from the group consisting of theophylline, aminophylline, methylephedrine hydrochloride, procaterol hydrochloride, trimetoquinol hydrochloride, codeine phosphate, sodium cromoglycate, tranilast, dextromethorphan hydrobromide, dimemorfan phosphate, clobutinol hydrochloride, fominoben hydrochloride, benproperine phosphate, tipepidine hibenzate, eprazinone hydrochloride, clofedanol hydrochloride, ephedrine hydrochloride, noscapine, carbetapentane citrate, oxeladin tannate, isoaminile citrate and eprazinone hydrochloride, the bronchodilator is selected from the group consisting of diprophylline, salbutamol sulfate, clorprenaline hydrochloride, formoterol fumarate, orciprenaline sulfate, pirbuterol hydrochloride, hexoprenaline sulfate, bitolterol mesilate, clenbuterolhydrochloride, terbutaline sulfate, mabuterol hydrochloride, fenoterol hydrobromide and methoxyphenamine hydrochloride, the diuretic is selected from the group consisting of furosemide, acetazolamide, trichlormethiazide, methylclothiazide, hydrochlorothiazide, hydroflumethiazide, ethiazide, cyclopenthiazide, spironolactone, triamterene, chlorothiazide, piretanide, mefruside, etacrynic acid, azosemide and clofenamide, the muscle relaxant is selected from the group consisting of chlorphenesin carbamate, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, mephenesin, chlorzoxazone, phenprobamate, methocarbamol, chlormezanone, pridinol mesylate, afloqualone, baclofen and dantrolene sodium, the cerebral metabolism improving agent is meclofenoxate hydrochloride, the tranquilizer is selected from the group consisting of oxazolam, diazepam, clotiazepam, medazepam, temazepam, fludiazepam, meprobamate, nitrazepam, clordiazepoxide, sulpiride, clocaproamine dihydrochloride, zotepine, chlorpromazine and haloperidol, the B-blocker is selected from the group consisting of pindolol, propranolol hydrochloride, carteolol hydrochloride, metoprolol tartrate, labetalol hydrochloride, oxaurenol hydrochloride, acebutolol hydrochloride, bufetolol hydrochloride, alprenolol hydrochloride, arotinolol hydrochloride, oxprenolol hydrochloride, nadolol, bucumolol hydrochloride, indenonol hydrochloride, timolol maleate, bufenolol hydrochloride and bupranolol hydrochloride, the antiarrhythmic drug is selected from the group consisting of procainamide hydrochloride, disopyramide, ajamline, guanidine sulfate, aprindine hydrochloride, propafenone hydrochloride, the arthrifuge is selected from the group consisting of allopurinol, probenecid, colchicine, sulfinpyrazone, benzbromarone and bucolome, the anticoagulant is selected from the group consisting of ticlopidine hydrochloride, dicumarol and warfarin potassium, the antiepileptic agent is selected from the group consisting of phenytoin, sodium valproate, metharbital and carbamazepine, the antihistaminic agent is selected from the group consisting of chlorpheniramine maleate, clemastine fumarate, mequitazine, alimemazine tartrate and cycloheptazine hydrochloride, the antiemetic is selected from the group consisting of difenidol hydrochloride, metoclopramide, domperidone, betahistine mesylate and trimebutine maleate, the antihypertensive agent is selected from the group consisting of dimethylaminoethyl reserpilinate dihydrochloride, rescinnamine, methyldopa, prazosin hydrochloride, bunazosin hydrochloride, clonidine hydrochloride, budralazine and urapidil, the sympathomimetic drug is selected from the group consisting of dihydroergotamine mesylate, isoproterenol hydrochloride and etilefrine hydrochloride, the expectorant is selected from the group consisting of bromhexine hydrochloride, carbocisteine, cysteine ethyl ester hydrochloride and cysteine methyl ester hydrochloride, the oral antidiabetic drug is selected from the group consisting of glibenclamide, tolbutamide and glymidine sodium, the cardiovascular drug is selected from the group consisting of ubidecarenone and ATP-2Na, the iron preparation is selected from the group consisting of ferrous sulfate and anhydrous iron sulfate, the vitamin is selected from the group consisting of vitamin B₁, vitamin B₂, vitamin B₂, vitamin C and folic acid, the drug for pollakiurea is selected from the group consisting of falvoxate hydrochloride, oxybutynin hydrochloride, terodiline hydrochloride and 4-diethylamino-1,1-dimethyl-2-butinyl (±

)-α

-cyclohexyl-α

-phenylglycolate hydrochloride monohydrate and the angiotensin converting enzyme inhibitor is selected from the group consisting of enalapril maleate, alacepril and delapril hydrochloride.