Controlled onset and sustained release dosage forms and the preparation thereof

• US 6,500,459 B1
• Filed: 07/21/1999
• Issued: 12/31/2002
• Est. Priority Date: 07/21/1999
• Status: Expired due to Fees

• Current Assignee: Harinderpal Chhabra, Sarkar, Shyamal K.
• Original Assignee: Harinderpal Chhabra, Sarkar, Shyamal K.
• Inventors: Sarkar, Shyamal K., Chhabra, Harinderpal
• Primary Examiner(s): Spear, James M.
• Application Number:
  US09/358,732
• Time in Patent Office: 1,259 Days
• Field of Search: 424/468, 424/469, 424/470, 424/472, 424/474, 424/475, 424/479, 424/480
• US Class Current: 424/474
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209

Abstract

A pharmaceutical composition for controlled onset and sustained release of an active ingredient, said composition comprising:

(i) a core comprising:

(a) an active ingredient;

(b) a hydrophilic carrier;

(c) a hydrodynamic diffusion enhancer; and optionally

(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof; and

(ii) a functional coating membrane surrounding said core.

Claims

1. A pharmaceutical composition for controlled onset and sustained release of an active ingredient, said composition comprising:

(i) a core comprising;

(a) an active ingredient;

(b) a hydrophilic carrier;

(c) a hydrodynamic diffusion enhancer; and

optionally

(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof; and

(ii) a functional coating membrane surrounding said core, and optionally

(iii) a seal coating membrane between the core and the functional coating membrane, and optionally

(iv) a top coating membrane surrounding the functional coating membrane;

wherein said composition provides a sustained release of the active ingredient from the composition for about 6 to about 24 hours.

4. The pharmaceutical composition of claim 1 wherein the hydrophilic carrier is selected from the group consisting of heteropolysaccharides, xanthan gum, gellan gum, locust bean gum, propylene glycol ester, homopolysaccharides, galactomannan, glucomannan, guar gum, gum acacia, gum tragacanth, alkali metal carageenates, alginates, cellulose alkyl carboxylates, carboxymethyl cellulose, carboxyethyl cellulose, alkali metal salts of cellulose alkyl carboxylates, sodium carboxymethyl cellulose, carboxypolymethylene, hydroxypropyl methylcelluloses, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, polyethylene glycols, polyethylene oxides, alginate salts, natural polysaccharides, gum arabica, and combinations thereof.

5. The pharmaceutical composition of claim 1 or 4 wherein the hydrophilic carrier is hydroxypropyl methylcellulose.

6. The pharmaceutical composition of claim 5 wherein the hydroxypropyl methylcellulose has a viscosity between about 5 cps and 100,000 cps, a hydroxypropoxyl content between about 7 and 12%, a methoxyl content between about 19 and 30%.

7. The pharmaceutical composition of claim 4 wherein the hydrophilic carrier is a blend of hydroxypropyl methylcelluloses having different molecular weights and/or viscosities.

8. The pharmaceutical composition of claim 7 wherein the ratio of the blend can vary from 1:

99 to 99;

1 with respect to low and higher molecular weight of hydroxypropyl methylcelluloses.

9. The pharmaceutical composition of claim 1 wherein the hydrophilic carrier in said core is present in a concentration of about 5 to 99% W/W of the weight of the core.

10. The pharmaceutical composition of claim 1 wherein the hydrodynamic diffusion enhancer is selected from the group consisting of sodium starch glycolate, sodium croscarmellose, gellan gum, starches, clays, celluloses, cellulose derivatives, alginates, crospovidone and combinations thereof.

11. The pharmaceutical composition of claim 1 wherein the hydrodynamic diffusion enhancer in said core is present in a concentration of about 5 to 60% W/W of the weight of the core.

12. The pharmaceutical composition of claim 1 wherein the binders in said core are present in a concentration of about 1 to 10% W/W of the weight of the core.

13. The pharmaceutical composition of claim 1 wherein the fillers and binders are each selected from the group consisting of polyethylene glycols, microcrystaline cellulose, lactose, starches, starch derivatives, mannitol, sorbitol, dextros, sucrose, maltodextrin, celluloses, cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose polyvinyl pyrrolidone, ethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polysaccharides, gums, and combinations thereof.

14. The pharmaceutical composition of claim 1 wherein the fillers in said core are present in a concentration of about 2 to 4% W/W of the weight of the core.

15. The pharmaceutical composition of claim 1 wherein the lubricants and flow promoters are selected from the group consisting of stearic acid, talc, waxes, stearic acid salts, stearic acid derivatives, sodium stearyl fumarate, corn starch, silica derivatives and combinations thereof.

16. The pharmaceutical composition of claim 1 wherein the lubricants in said core are present in a concentration of about 0.25 to 4% W/W of the weight of the core.

17. The pharmaceutical composition of claim 1 wherein the functional coating membrane is an aqueous polymeric comprising dispersed plasticizers, film extenders and diffusion enhancers and wherein said aqueous polymeric dispersion is present in a concentration of about 1-25% W/W of the weight of the core.

18. The pharmaceutical composition of claim 1 wherein the ratio of the polymer to film extender in the aqueous polymeric dispersion is from about 0.25-0.75 to 0.99-0.01.

19. The pharmaceutical composition of claim 1 wherein the seal coating membrane is present in a concentration of about 0-5% W/W of the weight of the core.

20. The pharmaceutical composition of claim 1 wherein the top coating membrane is an aqueous coating dispersion, and wherein said aqueous coating dispersion is present in a concentration of about 0-5% W/W of the weight of the core.

21. The pharmaceutical composition of claim 20 wherein the aqueous coating dispersion further comprises dispersed colours.

22. The pharmaceutical composition of claim 1 wherein the release of the active ingredient from the pharmaceutical composition is delayed for about 30 minutes to about 6 hours after ingestion.

23. The pharmaceutical composition of claim 22 wherein the release of the active ingredient from the pharmaceutical composition is sustained for about 6 to about 24 hours after the predetermined time delay.

24. The pharmaceutical composition of claim 1 wherein the active ingredient is selected from the group consisting of

(I) an anti-inflammatory drug selected from the group consisting of phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, oxaprozin, prednisone and prednisolone;

(II) a coronary dilator drug selected from the group consisting of glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate;

(III) a peripheral vasodilator drug selected from the group consisting of naftidrofuryl oxalate, cyclandelate and nicotinic acid;

(IV) an anti-infective drug selected from the group consisting of erythromycin, cephalexin, naldixic acid, clarithromycin, cefuroxime, cefaclor, cefprozil, zidovudine, acyclovir, ofloxacin, ciprofloxacillin, azithromycin and flucloxacillin sodium;

(V) a psychotropic and/or an antianxiety drug selected from the group consisting of fluazepam, diazepam, amitryptaline, doxepine, thioridazine, trifluperazine, fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, imipremine, clorazepate, estazolam, lorazepam, alprazolam, bupropion, fluoxetine, buspirone, clonazepam, sertaline, zolpidem, desmethylimipramine, lithium carbonate, lithium sulfate and methylphenidate;

(VI) a central stimulant drug selected from the group consisting of isoproterinol, amphetamine sulphate and amphetamine hydrochloride;

(VII) an antihistamine drug selected from the group consisting of chlorpheniramine, bropheniramine, fexofenadine, loratidine and diphenhydramine;

(VIII) a laxative and/or antidiarrheal drug selected from the group consisting of bisacodyl, magnesium hydroxide, loperamide, diphenoxylate, and dioctyl sodium sulfosuccinate;

(IX) a decongestant drug selected from the group consisting of phenylpropanolamine and pseudoephedrine;

(X) a vitamin substance selected from the group consisting of alphatocopherol, thiamin, pyridoxine and ascorbic acid;

(XI) an antacid selected from the group consisting of aluminum trisilicate, aluminum hydroxide, cimetidine, ranitidine, famotidine, omeprazole and nizatidine;

(XII) a gastrointestinal sedative selected from the group consisting of propantheline bromide and metoclorpramide;

(XIII) a cerebral vasodilator selected from the group consisting of soloctidilum, naftidrofuryl oxalate, co-dergocrine mesylate, papaverine and pentoxifylline;

(XIV) an anti-anginal drug selected from the group consisting of isosorbide dinitrate, pentaerythritol tetranitrate, verapamil, nifedipine, diltiazem, and glyceryl trinitrate;

(XV) an antiarrythmic selected from the group consisting of verapamil, nifedipine, diltiazem, disopyramide, bretylium tosylate, quinidine sulfate, quinidine gluconate and procainamide;

(XVI) an antihypertensive selected from the group consisting of methyldopa, captopril, hydralazine, propranolol, labetalol, sotalol, terazosin, enalapril, lisinopril, quinalapril, benazepril, ramipril, clonidine, fosinopril, felodipine, immodipine and amlodipine;

(XVII) a vasoconstrictor selected from the group consisting of ergotamine;

(XVIII) a substance which influences blood coagulability selected from the group consisting of protamine sulfate and epsilon aminocaproic acid;

(XIX) a hypnotic selected from the group consisting of dichloral phenazone, nitrazepam and temazepam;

(XX) an antinauseant selected from the group consisting of chlorpromazine and promethazine theoclate;

(XXI) an anticonvulsant selected from the group consisting of sodium valproate, phenytoin sodium, divalproex sodium and carbamezipine;

(XXII) a neuromuscular drug selected from the group consisting of dentrolene sodium;

(XXIII) a hypoglycemic agent selected from the group consisting of diabenese, insulin, glyburide, glipizide and troglitazone;

(XXIV) a drug used in treating thyroid gland disorders, selected from the group consisting of thyroxin, triiodothyronine and propylthiouracil;

(XXV) a diuretic selected from the group consisting of furosemide, chlorthalidone, hydrochlorthiazide, spironolactone, triampterene and indapamide;

(XXVI) a uterine relaxant medication selected from the group consisting of ritodrine;

(XXVII) an appetite suppressant selected from the group consisting of asphenteramine, diethylproprion hydrochloride and fenfluramine hydrochloride;

(XXVIII) an erythropoietic substance selected from group consisting of folic acid, calcium gluconate and ferrous sulphate;

(XXIX) an antiasthmatic drug selected from the group consisting of aminophylline, theophylline, orciprenaline sulphate, terbutaline sulphate, albuterol and salbutamol;

(XXX) an expectorant selected from the group consisting of carbocisteine and guaiphenesin;

(XXXI) a cough suppressant selected from the group consisting of noscapine, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxycodeinone and dextromethorphan;

(XXXII) an antiuricemic drug selected from the group consisting of allopurinol, probenecid and sulphinpyrazone;

(XXXIII) an antiseptic selected from the group consisting of cetylpyridinium chloride, tyrothricin and chlorhexidine;

(XXXIV) an antilipidimic or anticholesterol agent selected from the group consisting of lovastatin, gemfibrozil, simvastatin and pravastatin; and

pharmaceutically acceptable salts thereof.

2. A method for preparing a controlled onset sustained release pharmaceutical composition, said composition comprising:

(i) a core comprising;

(a) an active ingredient;

(b) a hydrophilic carrier;

(c) a hydrodynamic diffusion enhancer; and

optionally

(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants;

(ii) a functional coating membrane surrounding said core; and

optionally;

(iii) a seal coating membrane between the core and the functional coating membrane, and optionally;

(iv) a top coating membrane surrounding the functional coating membrane;

wherein the method comprises;

(v) blending the active ingredient with the hydrophilic carrier, the hydrodynamic diffusion enhancer and optionally with the conventional pharmaceutically acceptable excipients;

(vi) granulating the blend with a binder to obtain a wet mass;

(vii) drying the wet mass at 60°

C. for 3 hours;

(viii) lubricating the granules with a lubricant;

(ix) compressing the lubricated granules to form a core;

(x) applying a functional coating membrane containing aqueous polymeric dispersions, with dispersed plasticizers, and film extenders/diffusion enhancers to the surface of the core; and

(xi) curing of the coated core at a temperature range of 30°

C.-80°

C. for up to 12 hours; and

optionally

(xii) after forming the core, applying a seal coating membrane to the surface of the core to smooth out the surface; and

optionally

(xiii) after applying the functional coating membrane, applying a top coating membrane containing aqueous coating dispersions to the surface of the functional coating membrane.

26. The method of claim 2, 3 or 25 wherein the seal coating membrane is present in a concentration of about 0-5% W/W of the weight of the core.

27. The method of claim 2, 3 or 25 wherein the top coating membrane is an aqueous coating dispersion, and wherein said aqueous coating dispersion is present in a concentration of about 0-5% W/W of the weight of the core.

28. The method of claim 27 wherein the aqueous coating dispersion further comprises dispersed colours.

29. The method of claim 2, 3 or 25 wherein the release of the active ingredient from the pharmaceutical composition is delayed for about 30 minutes to about 6 hours after ingestion.

30. The method of claim 2, 3 or 25 wherein the release of the active ingredient from the pharmaceutical composition is sustained for about 6 to about 24 hours after the predetermined time delay.

32. The method of claim 2, 28 or 29 wherein the hydrophilic carrier is selected from the group consisting of heteropolysaccharides, xanthan gum, locust bean gum, propylene glycol ester, homopolysaccharides, galactomannan, glucomannan, guar gum, gum acacia, gum tragacanth, alkali metal carageenates, alginates, cellulose alkyl carboxylates, carboxymethyl cellulose, carboxyethyl cellulose, alkali metal salts of cellulose alkyl carboxylates, sodium carboxymethyl cellulose, carboxypolymethylene, hydroxypropyl methylcelluloses, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, polyethylene glycols, polyethylene oxides, alginate salts, natural polysaccharides, gum arabica and combinations thereof.

33. The method of claim 32 wherein the hydrophilic carrier is hydroxypropyl methylcellulose.

34. The method of claim 33 wherein the hydroxypropyl methylcellulose has a viscosity between about 5 cps and 100,000 cps, a hydroxypropoxyl content between about 7 and 12%, a methoxyl content between about 19 an d 30%.

35. The method of claim 32 wherein the hydrophilic carrier is a blend of hydroxypropyl methylcelluloses having different molecular weights and/or viscosities.

36. The method of claim 35 wherein the ratio of the blend can vary from 1:

99 to 99;

1 with respect to low and higher molecular weight of hydroxypropyl methylcelluloses.

41. The method of claim 2, 3 or 25 wherein the fillers and binders are each selected from the group consisting of polyethylene glycols, microcrystalline cellulose, lactose, starches, starch derivatives, mannitol, sorbitol, dextrose, sucrose, maltodextrin, celluloses, cellulose derivatives, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, polyvinyl pyrrolidone, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polysaccharides, gums, and combinations thereof.

3. A method for administering an active ingredient to a patient in need of therapy, which method comprises:

administering a controlled onset sustained release pharmaceutical composition to the patient, said composition comprising;

(i) a core comprising;

(a) an active ingredient;

(b) a hydrophilic carrier;

(c) a hydrodynamic diffusion enhancer; and

optionally

(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof; and

(ii) a functional coating membrane surrounding said core, and optionally

(iii) a seal coating membrane between the core and the functional coating membrane, and optionally

(iv) a top coating membrane surrounding the functional coating membrane;

wherein said composition provides a sustained release of the active ingredient from the composition for about 6 to about 24 hours.

25. A method for producing a delay of from about 30 minutes to about 6 hours in the onset of release of an active ingredient from a pharmaceutical composition in a patient in need of therapy, wherein the method comprises:

(A) administering a controlled onset sustained release pharmaceutical composition to the patient, said composition comprising;

(i) a core comprising;

(a) an active ingredient;

(b) a hydrophilic carrier;

(c) a hydrodynamic diffusion enhancer; and

optionally

(d) conventional pharmaceutically acceptable excipients selected from the group consisting of binders, fillers and lubricants and combinations thereof; and

(ii) a functional coating membrane surrounding said core, and optionally

(iii) a seal coating membrane between the core and the functional coating membrane, and optionally

(iv) a top coating membrane surrounding the functional coating membrane.

31. The method of claim 25, 28, or 29 wherein the active ingredient is selected from the group consisting of

(I) an anti-inflammatory drug selected from the group consisting of phenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen, diclofenac, dexamethasone, oxaprozin, prednisone and prednisolone;

(II) a coronary dilator drug selected from the group consisting of glyceryl trinitrate, isosorbide dinitrate and pentaerythritol tetranitrate;

(III) a peripheral vasodilator drug selected from the group consisting of naftidrofuryl oxalate, cyclandelate and nicotinic acid;

(IV) an anti-infective drug selected from the group consisting of erythromycin, cephalexin, naldixic acid, clarithromycin, cefuroxime, cefaclor, cefprozil, zidovudine, acyclovir, ofloxacin, ciprofloxacillin, azithromycin and flucloxacillin sodium;

(V) a psychotropic and/or an antianxiety drug selected from the group consisting of fluazepam, diazepam, amitryptaline, doxepine, thioridazine, trifluperazine, fluphenazine, piperothiazine, haloperidol, maprotiline hydrochloride, imipremine, clorazepate, estazolam, lorazepam, alprazolam, bupropion, fluoxetine, buspirone, clonazepam, sertaline, zolpidem, desmethylimipramine, lithium carbonate, lithium sulfate and methylphenidate;

(VI) a central stimulant drug selected from the group consisting of isoproterinol, amphetamine sulphate and amphetamine hydrochloride;

(VII) an antihistamine drug selected from the group consisting of chlorpheniramine, bropheniramine, fexofenadine, loratidine and diphenhydramine;

(VIII) a laxative and/or antidiarrheal drug selected from the group consisting of bisacodyl, magnesium hydroxide, loperamide, diphenoxylate, and dioctyl sodium sulfosuccinate;

(IX) a decongestant drug selected from the group consisting of phenylpropanolamine and pseudoephedrine;

(X) a vitamin substance selected from the group consisting of alphatocopherol, thiamin, pyridoxine and ascorbic acid;

(XI) an antacid selected from the group consisting of aluminum trisilicate, aluminum hydroxide, cimetidine, ranitidine, famotidine, omeprazole and nizatidine;

(XII) a gastrointestinal sedative selected from the group consisting of propantheline bromide and metoclorpramide;

(XIII) a cerebral vasodilator selected from the group consisting of soloctidilum, naftidrofuryl oxalate, co-dergocrine mesylate, papaverine and pentoxifylline;

(XIV) an anti-anginal drug selected from the group consisting of isosorbide dinitrate, pentaerythritol tetranitrate, verapamil, nifedipine, diltiazem, and glyceryl trinitrate;

(XV) an antiarrythmic selected from the group consisting of verapamil, nifedipine, diltiazem, disopyramide, bretylium tosylate, quinidine sulfate, quinidine gluconate and procainamide;

(XVI) an antihypertensive selected from the group consisting of methyldopa, captopril, hydralazine, propranolol, labetalol, sotalol, terazosin, enalapril, lisinopril, quinalapril, benazepril, ramipril, clonidine, fosinopril, felodipine, immodipine and amlodipine;

(XVII) a vasoconstrictor selected from the group consisting of ergotamine;

(XVIII) a substance which influences blood coagulability selected from the group consisting of protamine sulfate and epsilon aminocaproic acid;

(XIX) a hypnotic selected from the group consisting of dichloral phenazone, nitrazepam and temazepam;

(XX) an antinauseant selected from the group consisting of chlorpromazine and promethazine theoclate;

(XXI) an anticonvulsant selected from the group consisting of sodium valproate, phenytoin sodium, divalproex sodium and carbamezipine;

(XXII) a neuromuscular drug selected from the group consisting of dentrolene sodium;

(XXIII) a hypoglycemic agent selected from the group consisting of diabenese, insulin, glyburide, glipizide and troglitazone;

(XXIV) a drug used in treating thyroid gland disorders, selected from the group consisting of thyroxin, triiodothyronine and propylthiouracil;

(XXV) a diuretic selected from the group consisting of furosemide, chlorthalidone, hydrochlorthiazide, spironolactone, triampterene and indapamide;

(XXVI) a uterine relaxant medication selected from the group consisting of ritodrine;

(XXVII) an appetite suppressant selected from the group consisting of asphenteramine, diethylproprion hydrochloride and fenfluramine hydrochloride;

(XXVIII) an erythropoietic substance selected from group consisting of folic acid, calcium gluconate and ferrous sulphate;

(XXIX) an antiasthmatic drug selected from the group consisting of aminophylline, theophylline, orciprenaline sulphate, terbutaline sulphate, albuterol and salbutamol;

(XXX) an expectorant selected from the group consisting of carbocisteine and guaiphenesin;

(XXXI) a cough suppressant selected from the group consisting of noscapine, codeine phosphate, codeine sulfate, oxycodone, dihydrocodeine tartrate, oxycodeinone and dextromethorphan;

(XXXII) an antiuricemic drug selected from the group consisting of allopurinol, probenecid and sulphinpyrazone;

(XXXIII) an antiseptic selected from the group consisting of cetylpyridinium chloride, tyrothricin and chlorhexidine;

(XXXIV) an antilipidimic or anticholesterol agent selected from the group consisting of lovastatin, gemfibrozil, simvastatin and pravastatin; and

pharmaceutically acceptable salts thereof.

37. The method of claim 25, 28 or 29 wherein the hydrophilic carrier in said core is present in a concentration of about 5 to 99% W/W of the weight of the core.

38. The method of claim 25, 28 or 29 wherein the hydrodynamic diffusion enhancer is selected from the group consisting of sodium starch glycolate, sodium croscarmellose, gellan gum, crospovidone, starches, clays, celluloses, cellulose derivatives, alginates and combinations thereof.

39. The method of claim 25, 28 or 29 wherein the hydrodynamic diffusion enhancer in said core is present in a concentration of about 5 to 60% W/W of the weight of the core.

40. The method of claim 25, 28 or 29 wherein the binders in said core are present in a concentration of about 1 to 10% W/W of the weight of the core.

42. The method of claim 25, 28 or 29 wherein the fillers in said core are present in a concentration of about 2 to 40% W/W of the weight of the core.

43. The method of claim 25, 28 or 29 wherein the lubricants and flow promoters are selected from the group consisting of stearic acid, talc, waxes, stearic acid salts, stearic acid derivatives, sodium stearyl fumarate, corn starch, silica derivatives and combinations thereof.

44. The method of claim 25, 28 or 29 wherein the lubricants in said core are present in a concentration of about 0.25 to 4% W/W of the weight of the core.

45. The method of claim 25, 28 or 29 wherein the functional coating membrane is an aqueous polymeric dispersion comprising dispersed plasticizers, film extenders and diffusion enhancers and wherein said aqueous polymeric dispersion is present in a concentration of about 1-25% W/W of the weight of the core.

46. The method of claim 45 wherein the ratio of the polymer to film extender in the aqueous polymeric dispersion is from about 0.25-0.75 to 0.99-0.01.