Glycogen phosphorylase inhibitor

Abstract

Pharmaceutical compositions of a particularly effective sparingly soluble glycogen phosphorylase inhibitor are disclosed, as well as methods of making such compositions and dosage forms from such compositions.

1 . A pharmaceutical composition comprising an amorphous solid dispersion of the drug 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide in concentration-enhancing polymer.  
     
     
         2 . A pharmaceutical composition comprising (a) an amorphous solid dispersion of the drug 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide in concentration-enhancing polymer, and (b) additional concentration-enhancing polymer.  
     
     
         3 . A pharmaceutical composition comprising an amorphous form of the drug 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide and a concentration-enhancing polymer.  
     
     
         4 . The composition of    claim 2    or    3    wherein said composition is formed outside an environment of use.  
     
     
         5 . The composition of    claim 2    or    3    wherein said composition is formed inside an environment of use.  
     
     
         6 . The composition of any of claims  1 - 3  wherein said polymer is an ionizable polymer.  
     
     
         7 . The composition of any of claims  1 - 3  wherein said polymer is selected from the group consisting of ionizable cellulosic polymers, nonionizable cellulosic polymers, and vinyl polymers and copolymers having substituents selected from the group consisting of hydroxyl, alkylacyloxy, and cyclicamido.  
     
     
         8 . The composition of any of claims  1 - 3  wherein said polymer is a cellulosic polymer.  
     
     
         9 . The composition of    claim 8    wherein said polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose.  
     
     
         10 . The composition of    claim 8    wherein said polymer is 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, carboxyethyl cellulose, carboxymethyl cellulose, 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, 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, and ethyl picolinic acid cellulose acetate.  
     
     
         11 . The composition of    claim 8    wherein said polymer is selected from the group consisting of 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, 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, and ethyl picolinic acid cellulose acetate.  
     
     
         12 . The composition of    claim 8    wherein said polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, methyl cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate and cellulose acetate isophthalate.  
     
     
         13 . The composition of    claim 12    wherein said polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate.  
     
     
         14 . The composition of any of claims  1 - 3  in the form of granules.  
     
     
         15 . The composition of    claim 14    wherein the average size of said granules is from 50 to 1000 μm in diameter.  
     
     
         16 . The composition of    claim 14    wherein said granules are made by a method selected from the group consisting of roller compaction, low shear granulation, high shear granulation, fluid bed granulation, melt congealing and extrusion spheronization.  
     
     
         17 . The composition of any of claims  1 - 3  in a dosage form selected from the group consisting of a tablet, a caplet, a capsule, a bead, a suspension, a multiparticulate, a powder and combinations thereof.  
     
     
         18 . The composition of    claim 17    in a tablet dosage form comprising an amorphous solid dispersion in a concentration-enhancing polymer selected from the group consisting of hydroxypropylmethyl cellulose acetate succinate and cellulose acetate phthalate; a disintegrant; a lubricant; and a tablet binder or filler.  
     
     
         19 . The composition of    claim 18    wherein said amorphous solid dispersion contains from about 10 to about 60 wt % 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide; said disintegrant is selected from the group consisting of crospovidone and croscarmellose sodium; said lubricant is magnesium stearate; and said tablet binder is selected from the group consisting of microcrystalline cellulose and dibasic calcium phosphate.  
     
     
         20 . The composition of    claim 19    wherein said tablet dosage form comprises the following components in the following approximate weight percentages: 
 (a) solid amorphous dispersion from about 10 to about 75 wt %;  
 (b) dibasic calcium phosphate from about 5 to about 40 wt %;  
 (c) microcrystalline cellulose from about 5 to about 40 wt %;  
 (d) crospovidone from about 5 to about 25 wt %; and  
 (e) magnesium stearate from about 0.2 to about 2 wt %.  
 
     
     
         21 . The composition of    claim 19    wherein said tablet dosage form comprises the following components in the following approximate weight percentages: 
 (a) solid amorphous dispersion from about 10 to about 70 wt %;  
 (b) croscarmellose sodium from about 1 to about 10 wt %;  
 (c) magnesium stearate from about 0.2 to about 2 wt %; and  
 (d) balance microcrystalline cellulose.  
 
     
     
         22 . The composition of    claim 17    wherein said dosage form is an oral powder for constitution.  
     
     
         23 . The composition of    claim 17    wherein said dosage form is designed for immediate release of said drug.  
     
     
         24 . The composition of    claim 17    wherein said dosage form is designed for controlled release of said drug.  
     
     
         25 . The composition of    claim 24    wherein said dosage form is coated with a pH-sensitive coating.  
     
     
         26 . The composition of    claim 24    where said dosage form is coated by a substantially water-permeable polymeric coating and has at least one delivery port in said coating.  
     
     
         27 . The composition of    claim 26    wherein said coating of said dosage form comprises at least one asymmetric membrane.  
     
     
         28 . The composition of    claim 26    wherein said coating of said dosage form is formed from a polymer selected from the group consisting of poly(acrylic) acids and esters; poly(methacrylic ) acids and esters; copolymers of poly(acrylic) and poly(methacrylic) acids and esters; cellulose esters; cellulose ethers; and cellulose ester/ethers.  
     
     
         29 . The composition of    claim 26    wherein said at least one delivery port in said coating is formed by laser drilling.  
     
     
         30 . The composition of    claim 26    wherein said at least one delivery port in said coating is formed in an environment of use.  
     
     
         31 . The composition of    claim 28    wherein said coating of said dosage form is rupturable to form said at least one delivery port.  
     
     
         32 . The composition of    claim 26    wherein said dosage form includes at least one osmotic agent.  
     
     
         33 . The composition of    claim 32    wherein said osmotic agent is selected from the group consisting of an osmotically effective solute and a water-swellable hydrophilic polymer.  
     
     
         34 . The composition of    claim 24    wherein said dosage form comprises a core of Drug A and an osmotic agent, and said core is surrounded by a substantially water-permeable polymeric coating having at least one delivery port therein.  
     
     
         35 . The composition of    claim 34    wherein said osmotic agent is selected from the group consisting of an osmotically effective solute and a water-swellable hydrophilic polymer.  
     
     
         36 . The composition of    claim 35    wherein said osmotic agent is in a first layer and said solid dispersion is in a second layer.  
     
     
         37 . The composition of    claim 34    wherein said osmotic agent and said concentration-enhancing polymer are the same.  
     
     
         38 . The composition of    claim 24   , including an erodible polymeric matrix having said drug incorporated therein.  
     
     
         39 . The composition of    claim 38    wherein said erodible polymeric matrix is formed from a polymer selected from the group consisting of polyoxamers; aqueous-soluble cellulosics; aqueous-erodible cellulosics; acrylic acid derivatives and polymers of the same; naturally occurring polysaccharides; and naturally occurring proteins.  
     
     
         40 . The composition of    claim 39    wherein said erodible polymeric matrix is formed from hydroxypropylmethyl cellulose.  
     
     
         41 . The composition of    claim 38    wherein said erodible polymeric matrix is coated with a pH-sensitive polymer.  
     
     
         42 . The composition of    claim 39    wherein said coating further comprises at least one non-pH-sensitive polymer to modulate either the delay of release or the rate of release of said drug.  
     
     
         43 . The composition of any of claims  1 - 3  in a multiparticulate dosage form.  
     
     
         44 . The composition of    claim 43    wherein said drug is incorporated into a solid matrix comprising pharmaceutical excipients having a melting point of from about 40° C. to about 250° C.  
     
     
         45 . The composition of    claim 44    wherein said drug is incorporated into a solid matrix selected from the group consisting of hydrogenated and partially hydrogenated vegetable oils; mono-, di-, and tri-glycerides of fatty acids; propylene glycol and ethylene glycol mono- and di-esters of fats and fatty acids; waxes; and long chain alcohols.  
     
     
         46 . A method of making a composition comprising an amorphous solid dispersion of the drug 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide in an aqueous-soluble concentration-enhancing polymer, said method being selected from the group consisting of solvent processing, mechanical processing, thermal processing and combinations thereof.  
     
     
         47 . The method of    claim 46    wherein said method is solvent processing selected from the group consisting of spray-drying, spray-coating, pan-coating, vacuum drying, fluid bed drying, evaporation, precipitation and combinations thereof  
     
     
         48 . The method of    claim 47    wherein the solvent used in said solvent processing comprises substantially pure solvent.  
     
     
         49 . The method of    claim 47    wherein the solvent used in said solvent processing comprises a mixture of solvents.  
     
     
         50 . The method of    claim 47    wherein the solvent used in said solvent processing comprises a mixture of solvent and water.  
     
     
         51 . The method of    claim 46    wherein said method is mechanical processing selected from the group consisting of ball milling, twin-screw extrusion and trituration.  
     
     
         52 . The method of    claim 46    wherein said method is thermal processing selected from the group consisting of melt congealing and flash flow processing.  
     
     
         53 . The method of    claim 46    comprising the steps of: 
 (a) providing a spray-drying solution comprising 0.1-10 wt % of said drug, 0.1-10 wt % of said concentration-enhancing polymer and a solvent;  
 (b) providing an atomizing gas;  
 (c) directing said spray-drying solution and said atomizing gas to an atomizing nozzle to produce droplets of said spray-drying solution wherein said droplets range in size from 1 to 500 μm;  
 (d) providing a drying gas  
 (e) providing a drying chamber; and  
 (f) directing said droplets and said drying gas to said drying chamber to cause evaporation of said solvent from said droplets and solidification of said droplets in less than 20 seconds to form a spray-dried dispersion wherein said spray-dried dispersion comprises solid particles of less than about 200 μm in diameter.  
 
     
     
         54 . The method of    claim 53   , including an additional step (g) comprising evaporating additional solvent from said solid particles of step (f).  
     
     
         55 . The method of    claim 54    wherein step (g) is conducted in an evaporation chamber selected from the group consisting of a vacuum dryer, a tray dryer, a fluid bed dryer, a microwave dryer and a rotary drum dryer.  
     
     
         56 . The method of    claim 54   , including an additional step (h) comprising granulating said solid particles of step (g).  
     
     
         57 . The method of    claim 56    wherein step (h) is conducted by a method selected from the group consisting of roller compaction, low shear granulation, high shear granulation, fluid bed granulation, melt congealing and extrusion spheronization.  
     
     
         58 . The method of    claim 53    wherein said solvent in step (a) is selected from the group consisting of acetone, methanol, and mixtures of acetone, methanol and water.  
     
     
         59 . The product of the method of any of claims  53 - 56 .  
     
     
         60 . The product of the method of    claim 56    comprising granules of from 50 to 1000 μm in diameter.  
     
     
         61 . A method of suppressing hepatic glucose production in a human in need of such therapy comprising administering a therapeutic amount of a pharmaceutical composition comprising an amorphous solid dispersion of the drug 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R) -hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide in concentration-enhancing polymer.  
     
     
         62 . A method of suppressing hepatic glucose production in a human in need of such therapy comprising administering a therapeutic amount of a pharmaceutical composition comprising (a) an amorphous solid dispersion of the drug 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R) -hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl] amide in concentration-enhancing polymer and (b) additional concentration-enhancing polymer.  
     
     
         63 . A method of suppressing hepatic glucose production in a human in need of such therapy comprising administering a therapeutic amount of a pharmaceutical composition comprising (a) an amorphous form of the drug 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide and (b) a concentration-enhancing polymer.  
     
     
         64 . A method of suppressing hepatic glucose production in a human in need of such therapy comprising administering substantially simultaneously therapeutic amounts of component (a) and component (b), wherein component (a) comprises an amorphous solid dispersion of the drug 5-chloro-4H-indole-2-carboxylic acid [(1S)-benzyl-(2R) -hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl] amide in concentration-enhancing polymer, and component (b) comprises additional concentration-enhancing polymer.  
     
     
         65 . The method of    claim 64    wherein component (a) is in a pharmaceutically acceptable dosage form.  
     
     
         66 . The method of    claim 64    wherein components (a) and (b) are each in a pharmaceutically acceptable dosage form.  
     
     
         67 . A method of suppressing hepatic glucose production in a human in need of such therapy comprising administering substantially simultaneously therapeutic amounts of component (a) and component (b), wherein component (a) comprises an amorphous form of the drug 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide and component (b) comprises concentration-enhancing polymer.  
     
     
         68 . The method of    claim 67    wherein component (a) is in a pharmaceutically acceptable dosage form.  
     
     
         69 . The method of    claim 67    wherein components (a) and (b) are each in a pharmaceutically acceptable dosage form.  
     
     
         70 . The method of any of claims  61 - 69  wherein said concentration-enhancing polymer is selected from the group consisting of: 
 (a) an ionizable polymer;  
 (b) a cellulosic polymer;  
 (c) an ionizable cellulosic polymer;  
 (d) a nonionizable cellulosic polymer; and  
 (e) vinyl polymers and copolymers having substituents selected from the group consisting of hydroxyl, alkylacyloxy and cyclidamido.  
 
     
     
         71 . The method of any of claims  61 - 69  wherein said pharmaceutical composition is in a dosage form selected from the group consisting of a tablet, a caplet, a capsule, a bead, a suspension, a multiparticulate, a powder and combinations thereof.  
     
     
         72 . The method of    claim 71    wherein said dosage form is designed for immediate release of said drug.  
     
     
         73 . The method of    claim 71    wherein said dosage form is designed for controlled release of said drug.