Pharmaceutical compositions of drugs and neutralized acidic polymers

Abstract

Pharmaceutical compositions comprised of low-solubility and/or acid-sensitive drugs and neutralized acidic polymers are disclosed.

What is claimed is:  
     
         1 . A pharmaceutical composition comprising a mixture of a low-solubility drug in a solubility-improved form and a neutralized acidic enteric polymer, wherein said composition provides enhanced concentration of said low-solubility drug in a use environment relative to a control composition, wherein said control composition comprises an equivalent quantity of said low-solubility drug and is free from a concentration-enhancing polymer.  
     
     
         2 . The composition of  claim 1  wherein said mixture is a solid amorphous dispersion of said low-solubility drug and said neutralized acidic enteric polymer.  
     
     
         3 . The composition of  claim 1  wherein the degree of neutralization of said neutralized acidic enteric polymer is at least 0.1.  
     
     
         4 . The composition of  claim 1  wherein the degree of neutralization of said neutralized acidic enteric polymer is at least 0.5.  
     
     
         5 . The composition of  claim 1  wherein the degree of neutralization of said neutralized acidic enteric polymer is at least 0.9.  
     
     
         6 . The composition of  claim 1  wherein the degree of neutralization of said neutralized acidic enteric polymer is about 1.  
     
     
         7 . The composition of  claim 1  wherein said neutralized acidic enteric polymer comprises a counterion selected from the group consisting of sodium, potassium, calcium, magnesium, aluminum, ammonium, iron, and amine.  
     
     
         8 . The composition of  claim 1  wherein said neutralized acidic enteric polymer comprises a blend of polymers.  
     
     
         9 . The composition of  claim 1  wherein said neutralized acidic enteric polymer is cellulosic.  
     
     
         10 . The composition of  claim 9  wherein said neutralized acidic enteric polymer is a neutralized form of a polymer selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, ethyl picolinic acid cellulose acetate, and carboxymethyl ethyl cellulose.  
     
     
         11 . The composition of  claim 10  wherein said neutralized acidic enteric polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, and carboxymethyl ethyl cellulose.  
     
     
         12 . The composition of  claim 1  wherein said neutralized acidic enteric polymer is a neutralized form of a polymer selected from the group consisting of carboxylic acid functionalized vinyl polymers, carboxylic acid functionalized polymethacrylates, and carboxylic acid functionalized polyacrylates.  
     
     
         13 . The composition of  claim 1  wherein said neutralized acidic enteric polymer has a glass transition temperature of at least 40° C.  
     
     
         14 . The composition of  claim 1  wherein said neutralized acidic enteric polymer is ionically crosslinked.  
     
     
         15 . The composition of  claim 14  wherein said neutralized acidic enteric polymer is ionically crosslinked with a multivalent cationic species.  
     
     
         16 . The composition of  claim 15  wherein said multivalent cationic species is selected from the group consisting of calcium, magnesium, aluminum, iron (II), iron (III), and a diamine.  
     
     
         17 . The composition of  claim 1  further comprising a base.  
     
     
         18 . The composition of  claim 17  wherein said base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, ammonia, ammonium hydroxide, ammonium acetate, sodium acetate, potassium acetate, calcium acetate, magnesium acetate, sodium citrate, trisodium phosphate, disodium phosphate, ethylene diamine, monoethanol amine, diethanol amine, triethanolamine, potassium citrate, sodium carbonate, sodium bicarbonate, sodium acetate, amine-functional polyacrylates, and sodium polyacrylic acid.  
     
     
         19 . The composition of  claim 17  wherein said base comprises at least 5 wt % of said composition.  
     
     
         20 . The composition of  claim 1  wherein said drug has a solubility in aqueous solution in the absence of said polymer of less than 1 mg/ml at any pH of from about 1 to about 8.  
     
     
         21 . The composition of  claim 20  wherein said drug has an aqueous solubility of less than 0.1 mg/ml.  
     
     
         22 . The composition of  claim 1  wherein said drug has a dose-to-aqueous-solubility ratio of at least 10 ml.  
     
     
         23 . The composition of  claim 1  wherein said low-solubility drug is acid-sensitive.  
     
     
         24 . The composition of  claim 23  wherein said acid-sensitive drug has at least one functional group selected from the group consisting of sulfonyl ureas, hydroxamic acids, hydroxy amides, carbamates, acetals, hydroxy ureas, esters, and amides.  
     
     
         25 . The composition of  claim 23  wherein said acid-sensitive drug is selected from the group consisting of quinoxaline-2-carboxylic acid [1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; (+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea; omeprazole; etoposide; famotidine; erythromycin; quinapril; lansoprazole; and progabide.  
     
     
         26 . The composition of  claim 1  wherein said composition provides improved chemical stability of said drug relative to a second control composition, wherein said second control composition comprises a dispersion of an equivalent quantity of said low-solubility drug and an unneutralized form of said neutralized acidic enteric polymer.  
     
     
         27 . The composition of  claim 26  wherein said composition provides a relative degree of improvement in stability for said drug of at least 1.25 when stored at 40° C. and 75% relative humidity.  
     
     
         28 . The composition of  claim 27  wherein said relative degree of improvement is at least 3.  
     
     
         29 . The composition of  claim 28  wherein said relative degree of improvement is at least 10.  
     
     
         30 . The composition of  claim 1  wherein a maximum concentration of said drug in said use environment is at least 1.25-fold that of said control composition.  
     
     
         31 . The composition of  claim 1  wherein said neutralized acidic enteric polymer is present in a sufficient amount so that said composition provides in said use environment an area under the concentration versus time curve for any period of at least 90 minutes between the time of introduction into the use environment and about 270 minutes following introduction to said use environment that is at least 1.25-fold that of said control composition.  
     
     
         32 . The composition of  claim 31  wherein said composition provides in said use environment an area under the concentration versus time curve for any period of at least 90 minutes between the time of introduction into said use environment and about 270 minutes following introduction to the use environment that is at least 2-fold that of said control composition.  
     
     
         33 . The composition of  claim 1  wherein said neutralized acidic enteric polymer is present in a sufficient amount so that said composition provides a relative bioavailability that is at least 1.25 relative to said control composition.  
     
     
         34 . The composition of  claim 1 , further comprising a second concentration-enhancing polymer.  
     
     
         35 . A pharmaceutical composition comprising a solid amorphous dispersion of an acid-sensitive drug and a neutralized acidic dispersion polymer, wherein said composition provides improved chemical stability of said drug relative to a control composition comprised of a dispersion of an equivalent quantity of said drug and an unneutralized form of said acidic polymer.  
     
     
         36 . The composition of  claim 35  wherein the degree of neutralization of said neutralized acidic polymer is at least 0.1.  
     
     
         37 . The composition of  claim 35  wherein the degree of neutralization of said neutralized acidic polymer is at least 0.5.  
     
     
         38 . The composition of  claim 35  wherein the degree of neutralization of said neutralized acidic polymer is at least 0.9.  
     
     
         39 . The composition of  claim 35  wherein the degree of neutralization of said neutralized acidic polymer is at least 1.  
     
     
         40 . The composition of  claim 35  wherein said neutralized acidic dispersion polymer has a counterion selected from the group consisting of sodium, potassium, calcium, magnesium, aluminum, ammonium, iron, and amine.  
     
     
         41 . The composition of  claim 35  wherein said neutralized acidic dispersion polymer comprises a blend of polymers.  
     
     
         42 . The composition of  claim 35  wherein said neutralized acidic dispersion polymer is cellulosic.  
     
     
         43 . The composition of  claim 42  wherein said neutralized acidic dispersion polymer is a neutralized form of a polymer selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, ethyl picolinic acid cellulose acetate, carboxymethyl ethyl cellulose, carboxy methyl cellulose, and carboxy ethyl cellulose.  
     
     
         44 . The composition of  claim 43  wherein said neutralized acidic polymer is a neutralized form of a polymer selected from the group consisting of hydroxy propyl methyl cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, carboxymethyl cellulose, carboxymethyl ethyl cellulose.  
     
     
         45 . The composition of  claim 35  wherein said neutralized acidic dispersion polymer is a neutralized form of a polymer selected from the group consisting of carboxylic acid functionalized vinyl polymers, carboxylic acid functionalized polymethacrylates, and carboxylic acid functionalized polyacrylates.  
     
     
         46 . The composition of  claim 35  wherein said neutralized acidic dispersion polymer has a glass transition temperature of at least 40° C.  
     
     
         47 . The composition of  claim 35  further comprising a base.  
     
     
         48 . The composition of  claim 47  wherein said composition comprises a physical mixture of said dispersion and said base.  
     
     
         49 . The composition of  claim 47  wherein said base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, ammonia, ammonium hydroxide, ammonium acetate, sodium acetate, potassium acetate, calcium acetate, magnesium acetate, sodium citrate, trisodium phosphate, disodium phosphate, ethylene diamine, monoethanol amine, diethanol amine, triethanolamine, potassium citrate, sodium carbonate, sodium bicarbonate, sodium acetate, amine-functional polyacrylates, and sodium polyacrylic acid.  
     
     
         50 . The composition of  claim 35  wherein said dispersion further comprises a base.  
     
     
         51 . The composition of  claim 50  wherein said base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, ammonia, ammonium hydroxide, ammonium acetate, sodium acetate, potassium acetate, calcium acetate, magnesium acetate, sodium citrate, trisodium phosphate, disodium phosphate, ethylene diamine, monoethanol amine, diethanol amine, triethanolamine, potassium citrate, sodium carbonate, sodium bicarbonate, sodium acetate, amine-functional polyacrylates, and sodium polyacrylic acid.  
     
     
         52 . The composition of  claim 50  wherein said dispersion has a pH greater than 5.  
     
     
         53 . The composition of  claim 35  wherein said acid-sensitive drug has a solubility in aqueous solution in the absence of said neutralized acidic polymer of less than 1 mg/ml at any pH of from about 1 to about 8.  
     
     
         54 . The composition of  claim 53  wherein said acid-sensitive drug has an aqueous solubility of less than 0.1 mg/ml.  
     
     
         55 . The composition of  claim 35  wherein said acid-sensitive drug has a dose-to-aqueous-solubility ratio of at least 10 ml.  
     
     
         56 . The composition of  claim 35  wherein said acid-sensitive drug has at least one functional group selected from the group consisting of sulfonyl ureas, hydroxamic acids, hydroxy amides, carbamates, acetals, hydroxy ureas, esters, and amides.  
     
     
         57 . The composition of  claim 35  wherein said acid-sensitive drug is selected from the group consisting of quinoxaline-2-carboxylic acid [1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; (+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea; omeprazole; etoposide; famotidine; erythromycin; quinapril; lansoprazole; and progabide.  
     
     
         58 . The composition of  claim 35  wherein said composition provides a relative degree of improvement for said drug of at least 1.25 when stored at 40° C. and 75% relative humidity.  
     
     
         59 . The composition of  claim 58  wherein said relative degree of improvement is at least 3.  
     
     
         60 . The composition of  claim 59  wherein said relative degree of improvement is at least 10.  
     
     
         61 . The composition of  claim 35  wherein said neutralized acidic polymer is concentration-enhancing and present in a sufficient amount to provide a maximum concentration of said acid-sensitive drug in a use environment that is at least 1.25-fold that of a second control composition, said second control composition comprising an equivalent quantity of said acid-sensitive drug but free from a concentration-enhancing polymer.  
     
     
         62 . The composition of  claim 35  wherein said neutralized acidic polymer is concentration-enhancing and is present in a sufficient amount so that said composition provides in a use environment an area under the concentration versus time curve for any period of at least 90 minutes between the time of introduction into the use environment and about 270 minutes following introduction to the use environment that is at least 1.25-fold that of a control composition, said second control composition comprising an equivalent quantity of said acid-sensitive drug and free from a concentration-enhancing polymer.  
     
     
         63 . The composition of  claim 62  wherein said area under the concentration versus time curve for any period of at least 90 minutes between the time of introduction into the use environment and about 270 minutes following introduction to the use environment is at least 2-fold that of said second control composition.  
     
     
         64 . The composition of  claim 35  wherein said neutralized acidic polymer is concentration-enhancing and is present in an amount so that said dispersion provides a relative bioavailability that is at least 1.25 relative to a second control composition, said second control composition comprising an equivalent quantity of said acid-sensitive drug and free from a concentration-enhancing polymer.  
     
     
         65 . The composition of  claim 35  wherein said composition further comprises a second polymer, said second polymer being concentration-enhancing.  
     
     
         66 . The composition of  claim 1  or  35 , wherein the drug comprises a CETP inhibitor or a CCR1 inhibitor.  
     
     
         67 . The composition of  claim 1  or  35 , wherein the drug comprises [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester; [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester; or [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.  
     
     
         68 . The composition of  claim 1  or  35 , wherein the drug comprises quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide; quinoxaline-2-carboxylic acid [1-benzyl-4-(4,4-difluoro-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide; or quinoxaline-2-carboxylic acid [1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide.  
     
     
         69 . A method for treating a condition in an animal comprising administering to an animal in need of such treatment a therapeutic amount of a composition of  claim 1 .  
     
     
         70 . A method for treating a condition in an animal comprising administering to an animal in need of such treatment a therapeutic amount of a composition of  claim 35 .  
     
     
         71 . A method for forming a solid pharmaceutical composition, comprising the steps of: 
 (a) neutralizing an acidic enteric polymer to form a neutralized acidic enteric polymer; and    (b) combining a low-solubility drug with said neutralized acidic enteric polymer, said neutralized acidic enteric polymer being present in a sufficient amount in said composition so as to be concentration-enhancing.    
     
     
         72 . The method of  claim 71  wherein said step (a) further comprises the steps of (1) dissolving said acidic enteric polymer in a solvent to form a solution and (2) adding a base to said solution.  
     
     
         73 . The method of  claim 71  wherein said low-solubility drug and said acidic enteric polymer are both dissolved in a common solvent to form a solution.  
     
     
         74 . The method of  claim 73 , further comprising the step of adding a base to said solution.  
     
     
         75 . The method of  claim 73  wherein said solvent is removed from said solution forming a solid amorphous dispersion.  
     
     
         76 . The method of  claim 71  wherein said acidic enteric polymer is neutralized prior to being combined with said drug.  
     
     
         77 . The method of  claim 71  wherein said acidic enteric polymer is combined with said drug prior to neutralizing said acidic enteric polymer.  
     
     
         78 . The method of  claim 71  wherein said drug and said neutralized acidic enteric polymer are combined to form a solid amorphous dispersion.  
     
     
         79 . The method of  claim 71  wherein said drug at least partially neutralizes said polymer.  
     
     
         80 . A method for forming a pharmaceutical composition, comprising the steps of: 
 (a) neutralizing an acidic polymer to form a neutralized acidic polymer; and    (b) forming a solid amorphous dispersion of an acid-sensitive drug and said neutralized acidic polymer, said dispersion providing improved chemical stability relative to a control composition comprised of an equivalent quantity of said acid-sensitive drug and the unneutralized form of said neutralized acidic polymer.    
     
     
         81 . The method of  claim 80  wherein said acidic polymer is neutralized prior to being combined with said acid-sensitive drug.  
     
     
         82 . The method of  claim 80  wherein said acidic polymer and said drug are combined prior to neutralizing said acidic polymer.  
     
     
         83 . A method for forming a pharmaceutical composition, comprising the steps of: 
 (a) forming a solid amorphous dispersion of an acid-sensitive drug and an acidic polymer; and    (b) neutralizing said acidic polymer after forming said dispersion.    
     
     
         84 . The method of  claim 83  wherein said acidic polymer is neutralized by combining said dispersion with a base.