Polymer release system

Abstract

A method for controlling the release of at least one therapeutically, prophylactically and/or diagnostically active substance into an aqueous medium by erosion of at least one surface of a pharmaceutical composition. The method comprises adjusting the concentration and/or the nature of the ingredients making up the matrix composition in such a manner so as to obtain an approximately zero order release of the active substance from the pharmaceutical composition when subject to an in vitro dissolution test as described herein. The composition comprises i) a matrix composition comprising a) a polymer or a mixture of polymers that may be substantially water soluble and/or crystalline, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients, and ii) a coating. Typical polymers are PEO. The coating comprises a first cellulose derivative which is substantially insoluble in the aqueous medium, and at least one of a) a second cellulose derivative which is soluble or dispersible in water, b) a plasticizer, and c) a filler. The active ingredient may be carvedilol. Stable solid dispersions of active substances having low water solubility are also disclosed.

1 . A method for controlling the release of at least one therapeutically, prophylactically and/or diagnostically active substance into an aqueous medium by erosion of at least one surface of a pharmaceutical composition comprising 
 i) a matrix composition comprising a) a substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients, and    ii) a coating having at least one opening exposing at the one surface of said matrix, the coating comprising 
 a) a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in the aqueous medium in which the composition is to be used and at least one of  
 b) a second cellulose derivative which is soluble or dispersible in water,  
 c) a plasticizer, and  
 d) a filler, and wherein the diffusion rate of the aqueous medium into the matrix composition corresponds to about 100%±30% such as, e.g. about 100%±25%, about 100%±20%, about 100%±15% or about 100%±10% or about 100% of the dissolution rate of the matrix composition, and wherein any matrix surface exposed to the aqueous medium erodes so as to obtain a zero order release of at least about 60% w/w such as, e.g. at least about 65% w/w at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w or at least about 97 or 98% w/w of the active substance from the pharmaceutical composition when subject to an in vitro dissolution test as described herein.  
   
     
     
         2 . A method according to  claim 1 , wherein the polymer is a substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers.  
     
     
         3 . A method according to  claim 1 , wherein the matrix comprises a pharmaceutically acceptable excipient functioning as a diffusion and dissolution adjusting agent.  
     
     
         4 . A method according to  claim 1 , wherein the pharmaceutically acceptable excipient is selected from the group consisting of inorganic acids, inorganic bases, inorganic salts, organic acids or bases and pharmaceutically acceptable salts thereof, saccharides, oligosaccharides, polysaccharides, and cellulose and cellulose derivatives.  
     
     
         5 . A method according to  claim 4 , wherein the organic acid is a mono-, di-, oligo, polycarboxylic acid or an amino acid selected from the group consisting of acetic acid, ethanoic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid, cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid, gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolic acid, glyoxylic acid, lactic acid, levulinic acid, malonic acid, mandelic acid, oxalic acid, oxamic acid, pimelic acid pyruvic acid, aspartic acid , and glutamic acid.  
     
     
         6 . A method according to  claim 4 , wherein the inorganic acid is selected from the group consisting of pyrophosphoric, glycerophosphoric, phosphoric such as ortho or meta phosphoric, boric acid, hydrochloric acid, and sulfuric acid.  
     
     
         7 . A method according to  claim 4 , wherein the suitable inorganic compounds include aluminium.  
     
     
         8 . A method according to  claim 4 , wherein the suitable organic bases are selected from the group consisting of p-nitrophenol, succinimide, benzenesulfonamide, 2-hydroxy-2cyclohexenone, imidazole, pyrrole, diethanolamine, ethyleneamine,tris (hydroxymethyl) aminomethane, hydroxylamine and derivates of amines, sodium citrate, aniline, and hydrazine.  
     
     
         9 . A method according to  claim 4 , wherein the suitable inorganic bases are selected from the group consisting of aluminium oxide such as, e.g., aluminium oxide trihydrate, alumina, sodium hydroxide, potassium hydroxide, calcium carbonate, ammonium carbonate, ammnonium hydroxide, KOH and the like.  
     
     
         10 . A method according to  claim 4 , wherein the pharmaceutically acceptable salt of an organic acid is e.g. an alkali metal salt or an alkaline earth metal salt selected from the group consisting of sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogenphosphate, potassium hydrogenphosphate, calcium phosphate, dicalcium phosphate, sodium sulfate, potassium sulfate, calcium sulfate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, calcium carbonate, magnesium carbonate, sodium acetate, potassium acetate, calcium acetate, sodium succinate, potassium succinate, calcium succinate, sodium citrate, potassium citrate, calcium citrate, sodium tartrate, potassium tartrate, calcium tartrate, zinc gluconate, and zinc sulphate.  
     
     
         11 . A method according to  claim 4 , wherein the inorganic salt is sodium chloride, potassium chloride, calcium chloride, or magnesium chloride etc.  
     
     
         12 . A method according to  claim 4 , wherein the pharmaceutically acceptable excipient is selected from the group consisting of glucose and other monosaccharides, ribose, arabinose, xylose, lyxose, allose, altrose, inosito, glucose, sorbitol, mannose, gulose, idose, galactose, talose, mannitol, fructose, lactose, sucrose, and other disaccharides, dextrin, dextran or other polysaccharides, amylose, xylan, cellulose and cellulose derivatives such as, e.g. microcrystalline cellulose, methyl cellulose, ethyl cellulose, ethylhydroxyethyl cellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, hydroxypropylmethyl cellulose, amylopectin, pectin, starch, sodium starch etc., kaolin, bentonit, acacia, alginic acid, sodium alginate, calcium alginate, gelatin, dextrose, molasses, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, veegum, glycollate, magnesium stearate, calcium stearate, stearic acid, talc, titanium dioxide, silicium dioxide, clays, croscarmellose, gums, and agar.  
     
     
         13 . A method according to  claim 1  further comprising a pharmaceutically acceptable excipient selected from the group consisting of fillers, diluents, disintegrants, glidants, pH-adjusting agents, viscosity adjusting agents, solubility increasing or decreasing agents, osmotically active agents and solvents.  
     
     
         14 . A method according to  claim 1 , wherein the polymer matrix comprises a polyglycol.  
     
     
         15 . A method according to  claim 1 , wherein the matrix comprises a homopolymer and/or a copolymer.  
     
     
         16 . A method according  claim 1 , wherein the matrix comprises a polyethylene glycol, a polyethylene oxide and/or a block copolymer of ethylene oxide and propylene oxide including including poly(ethylene-glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol (PEG-PLGA PEG), poly((DL-lactic acid-co-glycolic acid)-g-ethylene glycol) (PLGA-g-PEG), and polyethylene oxide-polypropylene oxide (PEO-PPO).  
     
     
         17 . A method according to  claim 16 , wherein the polyethylene glycol, a polyethylene oxide and/or a block copolymer of ethylene oxide and propylene oxide has a molecular weight of from about 20,000 daltons, such as, e.g., from about 20,000 to about 700,000 daltons, from about 20,000 to about 600,000 daltons, from about 35,000 to about 500,000 daltons, from about 35,000 to about 400,000 daltons, from about 35,000 to about 300,000 daltons, from about 50,000 to about 300,000 daltons, such as, e.g. about 35,000 daltons, about 50,000 daltons, about 75,000 daltons, about 100,000 daltons, about 150,000 daltons, about 200,000 daltons, about 250,000 daltons, about 300,000 daltons or about 400,000 daltons.  
     
     
         18 . A method according to  claim 16 , wherein the block copolymer of ethylene oxide and propylene oxide comprises up to about 30% w/w of the propylene oxide based block, and has a molecular weight of about 5,000 daltons, typically about 5,000 to about 30,000 daltons such as, e.g. from about 8,000 to about 15,000 daltons.  
     
     
         19 . A method according to  claim 1 , wherein the matrix comprises a polymer which has a melting point of about 20-120° C. such as, e.g. from about 30 to about 100° C. or from about 40 to about 80° C.  
     
     
         20 . A method according to  claim 1 , wherein the active substance is present in the matrix composition in a concentration of from about 0.1 to about 98% w/w such as, e.g. at the most about 90% w/w, at the most about 85% w/w, at the most about 80% w/w, at the most about 75% w/w, at the most about 70% w/w, at the most about 65% w/w or at the most about 60% w/w.  
     
     
         21 . A method according to  claim 1 , wherein the active substance is a substance for human or veterinary use, a vitamin or other nutritional supplement, a disinfectant, a deodorant or another substance to be administered continuously in an aqueous environment.  
     
     
         22 . A method according to  claim 1 , wherein the active substance is present in the matrix at least partly on amorphous form.  
     
     
         23 . A method according to  claim 1 , wherein the active substance is a pharmaceutically active powder.  
     
     
         24 . A method according to  claim 23 , wherein the powder has a particle size of from about 0.1 μm to about 500 μm, typically from about 0.5 μm to about 300 μm, more typically from about 1 μm to about 200 μm, especially from about 5 μm to about 100 μm.  
     
     
         25 . A method according to  claim 1 , wherein the at least one therapeutically, prophylactically and/or diagnostically active substance has a solubility of at the most about 3 mg/ml such as, e.g. at the most about 1 mg/ml, at the most about 0.1 mg/ml, at the most about 0.05 mg/ml such as, e.g. at the most about 0.001 mg/ml in water at ambient temperature.  
     
     
         26 . A method according to  claim 25 , wherein the matrix composition comprises a pharmaceutically acceptable excipient which has a solubility of at least 1 mg/ml such as, e.g. at least about 3 mg/ml, at least about 5 mg/ml, at least about 10 mg/ml, at least about 25 mg/ml or at least about 50 mg/ml in water at ambient temperature.  
     
     
         27 . A method according to  claim 1 , wherein the at least one therapeutically, prophylactically and/or diagnostically active substance has a solubility of at least about 3 mg/ml such as, e.g., at least about 5 mg/ml, at least about 10 mg/ml, at least about 20 mg/ml, at least about 50 mg/ml or at least about 100 mg/ml in water at ambient temperature.  
     
     
         28 . A method according to  claim 27 , wherein the matrix composition comprises a pharmaceutically acceptable excipient, which has a solubility of at the most about 3 mg/ml such as, e.g., at the most about 1 mg/ml, at the most about 0.1 mg/ml, at the most about 0.05 mg/ml such as, e.g. at the most about 0.001 mg/ml in water at ambient temperature.  
     
     
         29 . (Cancelled).  
     
     
         30 . A method according to  claim 1 , wherein in the aqueous medium in which the composition is to be used, the coating does not completely crumble or erode before the matrix has completely eroded.  
     
     
         31 . A method according  claim 1 , wherein said first cellulose derivative is a cellulose ether which, when heated, is shapeable by molding or extrusion, including injection molding, blow molding and compression molding.  
     
     
         32 . A method according to  claim 31  in which the cellulose ether comprises at least one ethylcellulose.  
     
     
         33 . (Cancelled).  
     
     
         34 . (Cancelled).  
     
     
         35 . A method according to  claim 1  in which said first cellulose derivative is selected from the group consisting of cellulose acetate, cellulose propionate and cellulose nitrate.  
     
     
         36 . A method according to  claim 1  in which said second cellulose derivative is selected from the group consisting of methylcellulose, carboxymethylcellulose and salts thereof, cellulose acetate phthalate, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydrocyethylcellylose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose.  
     
     
         37 . A method according to  claim 36  in which said salt of carboxymethylcelllulose is selected from the group consisting of alkali metal and alkaline earth metal salts.  
     
     
         38 . A method according to  claim 1 , in which said plasticizer is selected from the group consisting of phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters thereof with polyethylene glycol, glycerin or sugars; fatty alcohols and ethers thereof with polyethylene glycol, glycerin or sugars; vegetable oils and hydrogenated vegetable oils; nitrobenzene, carbon disulfide, β-naphtyl salicylate, phthalyl glycolate, and diocyl phthalate.  
     
     
         39 . A method according to  claim 38  in which said fatty alcohol is selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol and myristyl alcohol.  
     
     
         40 . A method according to  claim 1  in which said plasticizer is a non-ionic surfactant.  
     
     
         41 . A method according to  claim 1 , wherein the matrix composition does not contain polyethylene glycol 2000 monostearate or polyethylene glycol 400 monostearate.  
     
     
         42 . (Cancelled).  
     
     
         43 . (Cancelled).  
     
     
         44 . (Cancelled).  
     
     
         45 . (Cancelled).  
     
     
         46 . (Cancelled).  
     
     
         47 . A method according to  claim 1 , wherein the polymer is a polyethylene oxide having a molecular weight of at least 100,000 daltons and at the most 300,000 daltons.  
     
     
         48 . A method according to  claim 1 , wherein the pharmaceutically acceptable excipient is present and is a mono-, di-, oligo or polycarboxylic acid selected from the group consistin of acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, and sorbic acid.  
     
     
         49 . A method according to  claim 1 , wherein the pharmaceutically acceptable excipient is present and is selected from mannitol, xylitol, sorbitol and inositol.  
     
     
         50 . A method according to  claim 1 , wherein the pharmaceutically acceptable excipient is an aluminium oxide.  
     
     
         51 . A method according to  claim 1 , wherein comprising PEO 200,000 as polymer and mannitol and/or aluminium oxide as pharmaceutically acceptable excipient.  
     
     
         52 . A method according to  claim 1 , wherein the pharmaceutically acceptable excipient is an inorganic acid such as phosphoric acid including ortho phosphoric acid and meta phosphoric acid.  
     
     
         53 . A pharmaceutical composition for controlled release of at least one therapeutically, prophylactically and/or diagnostically active substance into an aqueous medium by erosion of at least one surface of the composition, the composition comprising 
 i) a matrix composition comprising a) a polymer or a mixture of polymers, b) an active substance and, optionally, c) one or more pharmaceutically acceptable excipients, and    ii) a coating having at least one opening exposing at the one surface of said matrix, the coating comprising 
 a) a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in the aqueous medium in which the composition is to be used, and at least one of  
 b) a second cellulose derivative which is soluble or dispersible in water,  
 c) a plasticizer, and  
 d) a filler,  
 and wherein the diffusion rate of the aqueous medium into the matrix composition corresponds to about 100%±30% such as, e.g. about 100%±25%, about 100%±20%, about 100%±15% or about 100%±10% or about 100% of the dissolution rate of the matrix composition, and wherein any matrix surface exposed to the aqueous medium erodes at a substantially constant rate, so as to obtain a zero order release of at least about 60% w/w such as, e.g. at least about 65% w/w at least about 70% w/w, at least about 75% w/w, at least about 80% w/w, at least about 85% w/w, at least about 90% w/w, at least about 95% w/w or at least about 97 or 98% w/w of the active substance from the pharmaceutical composition when subject to an in vitro dissolution test as described herein.  
   
     
     
         54 . A stable controlled release pharmaceutical composition for oral use comprising a solid dispersion of component i) and ii) 
 i) at least one therapeutically, prophylactically and/or diagnostically active substance, which at least partially is in an amorphous form,    ii) a pharmaceutically acceptable polymer that has plasticizing properties and which has a melting point or melting interval of a temperature of at the most 200° C.,    and, optionally, iii) a stabilizing agent, wherein the at least one therapeutically, prophylactically and/or diagnostically active substance has a water solubility of at the most 3 mg/ml at 25° C. such as, e.g. at the most about 2 mg/ml, at the most about 1 mg/ml, and the concentration of the active substance in the composition corresponds to a concentration of at the most the saturated concentration in component ii) at a temperature corresponding to the melting point or the lowest end point of the melting interval of component ii) optionally together with component iii).    
     
     
         55 . A composition according to  claim 54 , wherein component ii) is a polyethylene glycol and/or a polyethylene oxide having a molecular weight of at least about 20,000 in crystalline and/or amorphous form or a mixture such polymers.  
     
     
         56 . A composition according to  claim 54 , wherein component ii) is of a quality that ensures that free radicals formed, if any, do not significantly increase the degradation of the active substance in the composition.  
     
     
         57 . A composition according to  claim 53  or  54  comprising a stabilizing agent.  
     
     
         58 . A composition according to  claim 54  comprising one or more antioxidants that inhibits the formation of peroxides and/or inactivates any peroxides present.  
     
     
         59 . A composition according to claims  53  or  54 , wherein the composition is stable with respect to physical stability.  
     
     
         60 . A composition according to claims  53  or  54 , wherein the composition is stable with respect to in vitro dissolution of the active substance from the composition.  
     
     
         61 . A composition according to  claim 60 , wherein the composition is stable with respect to in vitro dissolution behaviour in such a manner that t 50 %, i.e. the time for 50% w/w of the active substance to dissolve in a dissolution medium, differs at the most ±20% w/w such as, e.g., at the most ±15% w/w, at the most ±10% w/w, at the most ±7.5% w/w, at the most ±5% w/w, at the most ±2.5% w/w, at the most ±1.5% w/w or at the most 1% w/w when two compositions from the same batch is compared with a time difference of 2 weeks under similar storage and test conditions.  
     
     
         62 . A composition according to claims  53  or  54 , wherein the composition is stable with respect to chemical stability of the active substance.  
     
     
         63 . A composition according to  claim 62 , wherein the concentration of the active substance in the composition decreases at the most 20% w/w such as, e.g. at the most 15% w/w, at the most 10% w/w, at the most 7.5% w/w or at the most 5% w/w when stored at room temperature for a time period of at least 3 months such as, e.g. 6 months, 12 months, 18 months or 24 months and a relative humidity of at the most 75% such as, e.g., at the most 70%, at the most 65%, at the most 60%, at the most 55%, at the most 50% or at the most 45%.  
     
     
         64 . A composition according to claims  53  or  54  containing carvedilol as active substance in a concentration of at the most about 23% w/w such as, e.g., at the most about 22% w/w, at the most about 21% w/w or at the most about 20% w/w.  
     
     
         65 . A composition according to  claim 64  containing carvedilol as active substance and PEO 200,000 as component ii) and wherein the concentration of carvedilol in PEO 200,000 is at the most about 22% w/w, at the most about 21% w/w or at the most about 20% w/w.