Pharmaceutical compositions containing polymer and drug assemblies

An aqueous solution comprising:

• (a) a low-solubility drug;
• (b) an amphiphilic polymer that is at least partially dissolved in said solution;
• (c) a portion of said drug and a portion of said polymer being present in said solution as amorphous polymer/drug assemblies, said polymer/drug assemblies having a diameter of from 20 nm to 5000 nm;
• (d) said solution having a total dissolved drug concentration of at least 2-fold that of an equilibrium concentration of said drug provided by a control composition consisting of an equivalent amount of said drug in crystalline form alone;
• (e) said solution having a free drug concentration of at least 1.5-fold that of said equilibrium concentration provided by said control composition;
• and
• (f) said amphiphilic polymer comprises a neutral cellulosic polymer provided said amphiphilic polymer is not solely hydroxypropyl methyl cellulose.

An aqueous solution comprising:

• (a) a low-solubility drug;
• (b) an amphiphilic polymer that is at least partially dissolved in said solution;
• (c) a portion of said drug and a portion of said polymer being present in said solution as amorphous polymer/drug assemblies, said polymer/drug assemblies having a diameter of from 20 nm to 5000 nm;
• (d) said solution having a total dissolved drug concentration of at least 2-fold that of an equilibrium concentration of said drug provided by a control composition consisting of an equivalent amount of said drug in crystalline form alone;
• (e) said solution having a free drug concentration of at least 1.5-fold that of said equilibrium concentration provided by said control;
• and
• (f) said amphiphilic polymer is an ionizable cellulosic polymer, provided said cellulosic polymer is not solely hydroxypropyl methyl cellulose acetate succinate.

An aqueous solution comprising:

• (a) a low-solubility drug;
• (b) an amphiphilic polymer that is at least partially dissolved in said solution;
• (c) a portion of said drug and a portion of said polymer being present in said solution as amorphous polymer/drug assemblies, said polymer/drug assemblies having a diameter of from 20 nm to 5000 nm;
• (d) said solution having a total dissolved drug concentration of at least 2-fold that of an equilibrium concentration of said drug provided by a control composition consisting of an equivalent amount of said drug in crystalline form alone;
• (e) said solution having a free drug concentration of at least 1.5-fold that of said equilibrium concentration provided by said control composition;
• and
• (f) wherein said drug is a CETP inhibitor.

A composition as defined in claim 66 wherein said CETP inhibitor is an oxy substituted 4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinoline having the Formula I

• 64
• or a pharmaceutically acceptable salt, enantiomer, or stereoisomer of said compound;
• wherein RI-1 is hydrogen, YI, WI—XI, WI—YI;
• wherein WI is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;
• XI is —O—YI, —S—YI, —N (H) —YI or —N—(YI) 2;
• wherein YI for each occurrence is independently ZI or a fully saturated, partially unsaturated or fully unsaturated one to ten membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with ZI;
• wherein ZI is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said ZI substituent is optionally mono-, di- or tri-substituted independently with halo, (C2-C6)alkenyl, (C1-C6) alkyl, hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxyl, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1-C6)alkylamino wherein said (C1-C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxyl, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1-C6)alkylamino, said (C1-C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• RI-3 is hydrogen or QI;
• wherein QI is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with VI;
• wherein VI is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said VI substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1-C6)alkyl, (C2-C6)alkenyl, hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carbamoyl, mono-N- or di-N,N- (C1-C6) alkylcarbamoyl, carboxyl, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1-C6)alkylamino wherein said (C1-C6)alkyl or (C2-C6)alkenyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxyl, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1-C6)alkylamino, said (C1-C6)alkyl or (C2-C6)alkenyl substituents are also optionally substituted with from one to nine fluorines;
• RI-4 is QI-1 or VI-1,
• wherein QI-1 is a fully saturated, partially unsaturated or fully unsaturated one to six membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one heteroatom selected from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono-, or di-substituted with oxo, and said carbon chain is optionally mono-substituted with VI-1;
• wherein VI-1 is a partially saturated, fully saturated or fully unsaturated three to six membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen;
• wherein said VI-1 substituent is optionally mono-, di-, tri-, or tetra-substituted independently with halo, (C1-C6)alkyl, (C1-C6)alkoxy, amino, nitro, cyano, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1-C6)alkylamino wherein said (C1-C6)alkyl substituent is optionally mono-substituted with oxo, said (C1-C6)alkyl substituent is also optionally substituted with from one to nine fluorines;
• wherein either RI-3 must contain VI or RI-4 must contain VI-1;
• and
• RI-5, RI-6, RI-7 and RI-8 are each independently hydrogen, hydroxy or oxy wherein said oxy is substituted with TI or a partially saturated, fully saturated or fully unsaturated one to twelve membered straight or branched carbon chain wherein the carbons, other than the connecting carbon, may optionally be replaced with one or two heteroatoms selected independently from oxygen, sulfur and nitrogen and said carbon is optionally mono-, di- or tri-substituted independently with halo, said carbon is optionally mono-substituted with hydroxy, said carbon is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, said nitrogen is optionally mono- or di-substituted with oxo, and said carbon chain is optionally mono-substituted with TI;
• wherein TI is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
• wherein said TI substituent is optionally mono-, di- or tri-substituted independently with halo, (C1-C6)alkyl, (C2-C6)alkenyl, hydroxy, (c1-C6)alkoxy, (C1-6) alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1-C6)alkylamino wherein said (C1-C6)alkyl substituent is optionally mono-, di- or tri-substituted independently with hydroxy, (C1-C6)alkoxy, (C1-C4)alkylthio, amino, nitro, cyano, oxo, carboxy, (C1-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C1-C6)alkylamino, said (C1-C6)alkyl substituent is also optionally substituted with from one to nine fluorines. cm 68. A composition according to claim 67 further comprising a compound which is [2R,4S] 4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester;
• or a compound which is [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 a compound which is [2R, 4S] 4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.