Alprazolam inclusion complexes and pharmaceutical compositions thereof

Abstract

Pharmaceutical composition for transmucosal delivery contains an inclusion complex of alprazolam and a water soluble unsubstituted or substituted beta- or gamama-cyclodextiin such as 2-hydroxypropyl beta-cyclodextfin, and a pharmaceutically acceptable carrier therefor. The pharmaceutical composition is of particular application in the treatment of Generalised Anxiety Disorder or for the management of panic disorders.

1 . A pharmaceutical composition for transmucosal delivery comprising an inclusion complex of (a) alprazolam and (b) a water soluble unsubstituted or substituted beta-or gamma-cyclodextrin, and a pharmaceutically acceptable carrier therefor.  
     
     
         2 . A pharmaceutical composition according to  claim 1  wherein the cyclodextrin is a water soluble unsubstituted or substituted beta-cyclodextrin.  
     
     
         3 . A pharmaceutical composition according to  claim 2  wherein the water soluble beta-cyclodextrin is selected from the group consisting of an alkylated beta-cyclodextrin, a hydroxyalkylated beta-cyclodextrin, and a sulfoakylated beta-cyclodextrin.  
     
     
         4 . A pharmaceutical composition according to  claim 1  wherein the cyclodextrin is selected from the group consisting of 2-hydroxypropyl-beta-cyclodextrin with a degree of substitution between 3,9 and 5,1 hydroxypropyl groups per cyclodextrin molecule, a randomly methylated beta-cyclodextrin with a degree of substitution between 1,8 and 2 methyl groups per glucose unit, and sulfobutyl ether-beta-cyclodextrin with a degree of substitution between 1 and 7 sulfobutyl ether groups per cyclodextrin molecule.  
     
     
         5 . A pharmaceutical composition according to any one of  claims 1  to  4  wherein the inclusion complex has a stoichiometry of (a) to (b) of from 1:1 mol/mol to 1:10 mol/mol inclusive.  
     
     
         6 . A pharmaceutical composition according to  claim 5  wherein the inclusion complex has a stoichiometry of (a) to (b) of from 1:1 mol/mol to 1:7 mol/mol inclusive.  
     
     
         7 . A pharmaceutical composition according to any one of  claims 1  to  6  wherein the pharmaceutical composition comprises a solution of the inclusion complex of alprazolam and the cyclodextrin in a pharmaceutically acceptable liquid carrier.  
     
     
         8 . A pharmaceutical composition according to  claim 7  formulated for administration as drops, a spray or an aerosol.  
     
     
         9 . A pharmaceutical composition according to any one of  claims 1  to  6  wherein the inclusion complex of alprazolam and the beta-cyclodextrin is a solid mixed with or incorporated into a pharmaceutically acceptable solid carrier.  
     
     
         10 . A pharmaceutical composition according to  claim 9  formulated as sublingual tablets, buccal tablets, buccal patches, nasal inhalation powders, suppositories, and powder aerosols.  
     
     
         11 . An inclusion complex of alprazolam and a water soluble unsutstituted or substituted beta- or gamma-cyclodextrin.  
     
     
         12 . An inclusion complex according to  claim 11  wherein the cyclodextrin is a water soluble unsubstituted or substituted beta-cyclodextrin.  
     
     
         13 . An inclusion complex according to  claim 12  wherein the water soluble beta-cyclodextrin is selected from the group consisting of an alkylated beta-cyclodextrin, a hydroxyalkylated beta-cyclodextrin, and a sulfoakylated beta-cyclodextrin.  
     
     
         14 . An inclusion complex according to  claim 11  wherein the cyclodextrin is selected from the group consisting of 2-hydroxypropyl-beta-cyclodextrin with a degree of substitution between 3,9 and 5,1 hydroxypropyl groups per cyclodextrin molecule, a randomly methylated beta-cyclodextrin with a degree of substitution between 1,8 and 2 methyl groups per glucose unit, and sulfobutyl ether-beta-cyclodextrin with a degree of substitution between 1 and 7 sulfobutyl ether groups per cyclodextrin molecule.  
     
     
         15 . An inclusion complex according to any one of  claims 11  to  14  wherein the inclusion complex has a stoichiometry of (a) to (b) of from 1:1 mol/mol to 1:10 mol/mol inclusive.  
     
     
         16 . An inclusion complex according to  claim 15  wherein the inclusion complex has a stoichiometry of (a) to (b) of from 1:1 mol/mol to 1:7 mol/mol inclusive.  
     
     
         17 . The use of an inclusion complex of alprazolam and a water soluble unsubstituted or substituted beta- or gamma-cyclodextrin in the manufacture of a medicament for use in the treatment of generalised anxiety disorder or for the management of panic disorders.  
     
     
         18 . A method of treating a patient suffering from generalised anxiety disorder or of management of a patient suffering from a panic disorder comprising transmucosal administration of an inclusion complex of alprazolam and a water soluble unsubstituted or substituted beta- or gamma-cyclodextrin.