Extended release suspension compositions

Abstract

The present invention relates to extended release suspension compositions of an active ingredient. Said extended release suspension compositions comprise multiple coated cores of the active ingredient and a suspension base, wherein the suspension base generates a hypertonic condition such that there is no substantial change in the in-vitro dissolution release profile of the extended release suspension compositions upon storage for at least seven days. The invention also relates to processes for the preparation of said extended release suspension compositions.

1 . An extended release suspension composition comprising:
 (a) multiple coated cores comprising:
 (i) a core comprising an active ingredient; and 
 (ii) a coating layer over said core comprising one or more release-controlling polymers; 
   (b) a suspension base, wherein the suspension base generates a hypertonic condition such that there is no substantial change in the in-vitro dissolution release profile of the extended release suspension composition upon storage for at least seven days.   
     
     
         2 . An extended release suspension composition comprising:
 (a) multiple coated cores comprising:
 (i) a core comprising an active ingredient; and 
 (ii) a coating layer over said core comprising one or more release-controlling polymers; 
   (b) a suspension base, wherein the composition is characterized by having an osmolality ratio of at least about 1, and wherein there is no substantial change in the in-vitro dissolution release profile of the extended release suspension composition upon storage for at least seven days.   
     
     
         3 . The extended release suspension composition of  claim 1 , wherein the suspension base comprises an osmogent. 
     
     
         4 . The extended release suspension composition of  claim 1 , wherein the composition is a suspension or a reconstituted powder for suspension. 
     
     
         5 . The extended release suspension composition of  claim 1 , wherein the active ingredient is layered onto an inert particle to form the core. 
     
     
         6 . The extended release suspension composition of  claim 5 , wherein the inert particle is selected from the group comprising a non-pareil seed, a microcrystalline cellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, a silica bead, a tartaric acid pellet, or a wax based pellet. 
     
     
         7 . The extended release suspension composition of  claim 3 , wherein the osmogent is selected from the group comprising carbohydrates such as xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, dextrose and raffinose; water-soluble salts of inorganic acids such as magnesium chloride, magnesium sulfate, potassium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodium phosphate tribasic; water-soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; water-soluble amino acids such as glycine, leucine, alanine, methionine; urea or its derivatives; propylene glycol; glycerin; polyethylene oxide; xanthan gum; hydroxypropylmethyl cellulose; or mixtures thereof. 
     
     
         8 . The extended release suspension composition of  claim 1 , wherein the release-controlling polymer is selected from the group comprising a pH-dependent polymer, a pH-independent polymer, or mixtures thereof. 
     
     
         9 . The extended release suspension composition of  claim 8 , wherein the pH-dependent polymer is selected from the group comprising acrylic copolymers such as methacrylic acid and methyl methacrylate copolymers, e.g., Eudragit® L 100 and Eudragit® S 100, methacrylic acid and ethyl acrylate copolymers, e.g., Eudragit® L 100-55 and Eudragit® L 30 D-55, dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate copolymer e.g., Eudragit® 100, Eudragit® E PO, methyl acrylate and methacrylic acid and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymer; cellulose acetate phthalate; cellulose acetate succinates; hydroxyalkyl cellulose phthalates such as hydroxypropylmethyl cellulose phthalate; hydroxyalkyl cellulose acetate succinates such as hydroxypropylmethyl cellulose acetate succinate; vinyl acetate phthalates; vinyl acetate succinate; cellulose acetate trimelliate; polyvinyl derivatives such as polyvinyl acetate phthalate, polyvinyl alcohol phthalate, polyvinyl butylate phthalate, and polyvinyl acetoacetal phthalate; zein; shellac; or mixtures thereof. 
     
     
         10 . The extended release suspension composition of  claim 8 , wherein the pH-independent polymer is selected from the group comprising cellulosic polymers such as ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, and carboxy methylcellulose; acrylic copolymers such as methacrylic acid copolymers, e.g., Eudragit® RS, Eudragit® RL, Eudragit® NE 30 D; cellulose acetate; polyethylene derivatives e.g., polyethylene glycol and polyethylene oxide; polyvinyl alcohol; polyvinyl acetate; gums e.g., guar gum, locust bean gum, tragacanth, carrageenan, alginic acid, gum acacia, gum arabic, gellan gum, and xanthan gum; triglycerides; waxes, e.g., Compritol®, Lubritab®, and Gelucires®; lipids; fatty acids or their salts/derivatives; a mixture of polyvinyl acetate and polyvinyl pyrrolidone, e.g., Kollidon® SR; or mixtures thereof. 
     
     
         11 . The extended release suspension composition of  claim 1 , wherein the active ingredient is selected from the group comprising metformin, acarbose, miglitol, voglibose, repaglinide, nateglinide, glibenclamide, glimepride, glipizide, gliclazide, chloropropamide, tolbutamide, phenformin, aloglitin, sitagliptin, linagliptin, saxagliptin, rosiglitazone, pioglitazone, troglitazone, faraglitazar, englitazone, darglitazone, isaglitazone, zorglitazone, liraglutide, muraglitazar, peliglitazar, tesaglitazar, canagliflozin, dapagliflozin, remogliflozin, sergliflozin, verapamil, albuterol, salmeterol, acebutolol, sotalol, penicillamine, norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, trovafloxacin, gatifloxacin, cefixime, cefdinir, cefprozil, cefadroxil, cefuroxime, cefpodoxime, tetracycline, demeclocycline hydrochloride, amoxicillin, clavulanate potassium, azithromycin, losartan, irbesartan, eprosartan, valsartan, diltiazem, isosorbide mononitrate, ranolazine, propafenone, hydroxyurea, hydrocodone, delavirdine, pentosan polysulfate, abacavir, amantadine, acyclovir, ganciclovir, valacyclovir, valganciclovir, saquinavir, indinavir, nelfinavir, lamivudine, didanosine, zidovudine, nabumetone, celecoxib, mefenamic acid, naproxen, propoxyphene, cimetidine, ranitidine, albendazole, mebendazole, thiobendazole, pyrazinamide, praziquantel, chlorpromazine, sumatriptan, bupropion, aminobenzoate, pyridostigmine bromide, potassium chloride, niacin, tocainide, quetiapine, fexofenadine, sertraline, chlorpheniramine, rifampin, methenamine, nefazodone, modafinil, metaxalone, morphine, sevelamer, lithium carbonate, flecainide acetate, simethicone, methyldopa, chlorthiazide, metyrosine, procainamide, entacapone, metoprolol, propanolol hydrochloride, chlorzoxazone, tolmetin, tramadol, bepridil, phenytoin, gabapentin, fluconazole, terbinafine, atorvastatin, doxepine, rifabutin, mesalamine, etidronate, nitrofurantoin, choline magnesium trisalicylate, theophylline, nizatidine, methocarbamol, mycophenolate mofetil, tolcapone, ticlopidine, capecitabine, orlistat, colsevelam, meperidine, hydroxychloroquine, guaifenesin, guanfacine, amiodarone, quinidine, atomoxetine, felbamate, pseudoephedrine, carisoprodol, venlafaxine, etodolac, chondrotin, lansoprazole, pantoprazole, esomeprazole, dexlansoprazole, dexmethylphenidate, methylphenidate, sodium oxybate, and isotretinoin. 
     
     
         12 . The extended release suspension composition of the  claim 3 , wherein the suspension base further comprises one or more pharmaceutically acceptable excipients selected from the group comprising suspending agents, anti-caking agents, wetting agents, preservatives, buffering agents, flavoring agents, anti-oxidants, and chelating agents. 
     
     
         13 . A process for the preparation of the extended release suspension composition of  claim 1 , wherein the process comprises the steps of:
 (i) preparing cores comprising an active ingredient and one or more pharmaceutically acceptable excipients;   (ii) dissolving/dispersing a release-controlling polymer and one or more pharmaceutically acceptable coating additives in a suitable solvent;   (iii) applying the coating composition of step (ii) over the cores of step (i);   (iv) dissolving one or more osmogents and pharmaceutically acceptable excipients into a pharmaceutically acceptable vehicle to form a suspension base; and   (v) dispersing the coated cores of step (iii) in the suspension base of step (iv) to obtain the extended release suspension composition.   
     
     
         14 . A process for the preparation of the extended release suspension composition of  claim 1 , wherein the process comprises the steps of:
 (A) preparing a powder for suspension comprising the steps of:
 (i) preparing cores comprising an active ingredient and one or more pharmaceutically acceptable excipients; 
 (ii) dissolving/dispersing a release-controlling polymer and one or more pharmaceutically acceptable coating additives in a suitable solvent; 
 (iii) applying the coating composition of step (ii) over the cores of step (i); 
 (iv) mixing one or more pharmaceutically acceptable excipients with the coated cores of step (iii) to obtain the powder for suspension; 
   (B) preparing a suspension base by dissolving one or more osmogents and pharmaceutically acceptable excipients into a pharmaceutically acceptable vehicle; and   (C) reconstituting the powder for suspension of step (A) with a suspension base of step (B) to obtain the extended release suspension composition.   
     
     
         15 . A process for the preparation of the extended release suspension composition of  claim 1 , wherein the process comprises the steps of:
 (A) preparing a powder for suspension comprising the steps of:
 (i) preparing cores comprising an active ingredient and one or more pharmaceutically acceptable excipients; 
 (ii) dissolving/dispersing a release-controlling polymer and one or more pharmaceutically acceptable coating additives in a suitable solvent; 
 (iii) applying the coating composition of step (ii) over the cores of step (i); 
 (iv) mixing one or more osmogents and one or more pharmaceutically acceptable excipients with the coated cores of step (iii) to obtain the powder for suspension; and 
   (B) reconstituting the powder for suspension of step (A) with a pharmaceutically acceptable vehicle to obtain the extended release suspension composition.   
     
     
         16 . The extended release suspension composition of  claim 2 , wherein the suspension base comprises an osmogent. 
     
     
         17 . The extended release suspension composition of  claim 2 , wherein the composition is a suspension or a reconstituted powder for suspension. 
     
     
         18 . The extended release suspension composition of  claim 2 , wherein the active ingredient is layered onto an inert particle to form the core. 
     
     
         19 . The extended release suspension composition of  claim 18 , wherein the inert particle is selected from the group comprising a non-pareil seed, a microcrystalline cellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, a silica bead, a tartaric acid pellet, and a wax based pellet. 
     
     
         20 . The extended release suspension composition of  claim 16 , wherein the osmogent is selected from the group comprising carbohydrates such as xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, dextrose, and raffinose; water-soluble salts of inorganic acids such as magnesium chloride, magnesium sulfate, potassium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodium phosphate tribasic; water-soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; water-soluble amino acids such as glycine, leucine, alanine, and methionine; urea or its derivatives; propylene glycol; glycerin; polyethylene oxide; xanthan gum; hydroxypropylmethyl cellulose; and mixtures thereof. 
     
     
         21 . The extended release suspension composition of  claim 2 , wherein the release-controlling polymer is selected from the group comprising a pH-dependent polymer, a pH-independent polymer, and mixtures thereof. 
     
     
         22 . The extended release suspension composition of  claim 21 , wherein the pH-dependent polymer is selected from the group comprising acrylic copolymers such as methacrylic acid and methyl methacrylate copolymers, e.g., Eudragit® L 100 and Eudragit® S 100, methacrylic acid and ethyl acrylate copolymers, e.g., Eudragit® L 100-55 and Eudragit® L 30 D-55, dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate copolymers, e.g., Eudragit® E 100 and Eudragit® E PO, methyl acrylate and methacrylic acid and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymers; cellulose acetate phthalates; cellulose acetate succinates; hydroxyalkyl cellulose phthalates such as hydroxypropylmethyl cellulose phthalate; hydroxyalkyl cellulose acetate succinates such as hydroxypropylmethyl cellulose acetate succinate; vinyl acetate phthalates; vinyl acetate succinates; cellulose acetate trimelliate; polyvinyl derivatives such as polyvinyl acetate phthalate, polyvinyl alcohol phthalate, polyvinyl butylate phthalate, and polyvinyl acetoacetal phthalate; zein; shellac; and mixtures thereof. 
     
     
         23 . The extended release suspension composition of  claim 21 , wherein the pH-independent polymer is selected from the group comprising cellulosic polymers such as ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, and carboxy methylcellulose; acrylic copolymers such as methacrylic acid copolymers, e.g., Eudragit® RS, Eudragit® RL, and Eudragit® NE 30 D; cellulose acetate; polyethylene derivatives, e.g., polyethylene glycol and polyethylene oxide; polyvinyl alcohol; polyvinyl acetate; gums, e.g., guar gum, locust bean gum, tragacanth, carrageenan, alginic acid, gum acacia, gum arabic, gellan gum, and xanthan gum; triglycerides; waxes, e.g., Compritol®, Lubritab®, and Gelucires®; lipids; fatty acids or their salts/derivatives; a mixture of polyvinyl acetate and polyvinyl pyrrolidone, e.g., Kollidon® SR; and mixtures thereof. 
     
     
         24 . The extended release suspension composition of  claim 2 , wherein the active ingredient is selected from the group comprising metformin, acarbose, miglitol, voglibose, repaglinide, nateglinide, glibenclamide, glimepride, glipizide, gliclazide, chloropropamide, tolbutamide, phenformin, aloglitin, sitagliptin, linagliptin, saxagliptin, rosiglitazone, pioglitazone, troglitazone, faraglitazar, englitazone, darglitazone, isaglitazone, zorglitazone, liraglutide, muraglitazar, peliglitazar, tesaglitazar, canagliflozin, dapagliflozin, remogliflozin, sergliflozin, verapamil, albuterol, salmeterol, acebutolol, sotalol, penicillamine, norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, trovafloxacin, gatifloxacin, cefixime, cefdinir, cefprozil, cefadroxil, cefuroxime, cefpodoxime, tetracycline, demeclocycline hydrochloride, amoxicillin, clavulanate potassium, azithromycin, losartan, irbesartan, eprosartan, valsartan, diltiazem, isosorbide mononitrate, ranolazine, propafenone, hydroxyurea, hydrocodone, delavirdine, pentosan polysulfate, abacavir, amantadine, acyclovir, ganciclovir, valacyclovir, valganciclovir, saquinavir, indinavir, nelfinavir, lamivudine, didanosine, zidovudine, nabumetone, celecoxib, mefenamic acid, naproxen, propoxyphene, cimetidine, ranitidine, albendazole, mebendazole, thiobendazole, pyrazinamide, praziquantel, chlorpromazine, sumatriptan, bupropion, aminobenzoate, pyridostigmine bromide, potassium chloride, niacin, tocainide, quetiapine, fexofenadine, sertraline, chlorpheniramine, rifampin, methenamine, nefazodone, modafinil, metaxalone, morphine, sevelamer, lithium carbonate, flecainide acetate, simethicone, methyldopa, chlorthiazide, metyrosine, procainamide, entacapone, metoprolol, propanolol hydrochloride, chlorzoxazone, tolmetin, tramadol, bepridil, phenytoin, gabapentin, fluconazole, terbinafine, atorvastatin, doxepine, rifabutin, mesalamine, etidronate, nitrofurantoin, choline magnesium trisalicylate, theophylline, nizatidine, methocarbamol, mycophenolate mofetil, tolcapone, ticlopidine, capecitabine, orlistat, colsevelam, meperidine, hydroxychloroquine, guaifenesin, guanfacine, amiodarone, quinidine, atomoxetine, felbamate, pseudoephedrine, carisoprodol, venlafaxine, etodolac, chondrotin, lansoprazole, pantoprazole, esomeprazole, dexlansoprazole, dexmethylphenidate, methylphenidate, sodium oxybate, and isotretinoin. 
     
     
         25 . The extended release suspension composition of the  claim 16 , wherein the suspension base further comprises one or more pharmaceutically acceptable excipients selected from the group comprising suspending agents, anti-caking agents, wetting agents, preservatives, buffering agents, flavoring agents, anti-oxidants, and chelating agents. 
     
     
         26 . A process for the preparation of the extended release suspension composition of  claim 2 , wherein the process comprises the steps of:
 (i) preparing cores comprising an active ingredient and one or more pharmaceutically acceptable excipients;   (ii) dissolving/dispersing a release-controlling polymer and one or more pharmaceutically acceptable coating additives in a suitable solvent;   (iii) applying the coating composition of step (ii) over the cores of step (i);   (iv) dissolving one or more osmogents and pharmaceutically acceptable excipients into a pharmaceutically acceptable vehicle to form a suspension base; and   (v) dispersing the coated cores of step (iii) in the suspension base of step (iv) to obtain the extended release suspension composition.   
     
     
         27 . A process for the preparation of the extended release suspension composition of  claim 2 , wherein the process comprises the steps of:
 (A) preparing a powder for suspension comprising the steps of:
 (i) preparing cores comprising an active ingredient and one or more pharmaceutically acceptable excipients; 
 (ii) dissolving/dispersing a release-controlling polymer and one or more pharmaceutically acceptable coating additives in a suitable solvent; 
 (iii) applying the coating composition of step (ii) over the cores of step (i); 
 (iv) mixing one or more pharmaceutically acceptable excipients with the coated cores of step (iii) to obtain the powder for suspension; 
   (B) preparing a suspension base by dissolving one or more osmogents and pharmaceutically acceptable excipients into a pharmaceutically acceptable vehicle; and   (C) reconstituting the powder for suspension of step (A) with a suspension base of step (B) to obtain the extended release suspension composition.   
     
     
         28 . A process for the preparation of the extended release suspension composition of  claim 2 , wherein the process comprises the steps of:
 (A) preparing a powder for suspension comprising the steps of:
 (i) preparing cores comprising an active ingredient and one or more pharmaceutically acceptable excipients; 
 (ii) dissolving/dispersing a release-controlling polymer and one or more pharmaceutically acceptable coating additives in a suitable solvent; 
 (iii) applying the coating composition of step (ii) over the cores of step (i); 
 (iv) mixing one or more osmogents and one or more pharmaceutically acceptable excipients with the coated cores of step (iii) to obtain the powder for suspension; and 
   (B) reconstituting the powder for suspension of step (A) with a pharmaceutically acceptable vehicle to obtain the extended release suspension composition.