Crystalline microparticles of a beta-agonist coated with a fatty acid

Abstract

Crystalline microparticles consisting of a phenylalkylamino beta 2 -adrenergic agonist coated with a C12-C20 fatty acid are useful for the preparation of pharmaceutical aerosol formulations in form of suspension in a liquefied propellant gas or powder formulations.

1 . Crystalline microparticles, comprising a phenylalkylamino beta 2 -adrenergic agonist coated with at least one C12-C20 fatty acid in an amount of 0.2 to 2.5% by weight based on the weight of said microparticles. 
     
     
         2 . Crystalline microparticles according to  claim 1 , which consist of a phenylalkylamino beta 2 -adrenergic agonist coated with at least one C12-C20 fatty acid in an amount of 0.2 to 2.5% by weight based on the weight of said microparticles. 
     
     
         3 . Crystalline microparticles according to  claim 1 , wherein said beta 2 -agonist is a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is CH 2 OH or NHCOR 10    
 with the proviso that, when R 1  is CH 2 OH, R 2  is always hydrogen, while, when R 1  is NHCOR 10 , R 2  and R 10  can be independently hydrogen or form together a vinylene (—CH═CHμ) or ethoxy (—CH 2 —O—) radical; 
 m is an integer from 0 to 5; 
 n is an integer from 0 to 4; 
 p is an integer from 0 to 2; 
 A represents oxygen or a bond; 
 B represents oxygen or a bond; 
 R 3  and R 4  are hydrogen or methyl; or, when m is 1, n and p are 0, A and B are bonds, and R 3  is hydrogen, R 4  can form with R 5  a methylene bridge —(CH 2 )q- with q corresponding to 1 or 2, preferably 1; and 
 R 5 , R 6 , R 7 , R 8 , and R 9 , which are the same or different, are each independently hydrogen, hydroxyl, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halogen, SO 2 NH 2 , or 2-hydroxy-2-phenyl-ethylamino, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         4 . Crystalline microparticles according to  claim 3  wherein R 1  is NHCOR 10 , and R 2  and R 10  are H. 
     
     
         5 . Crystalline microparticles according to  claim 1 , which are coated with said C12-C20 fatty acid in an amount of 0.5 to 2.0% by weight. 
     
     
         6 . Crystalline microparticles according to  claim 1 , wherein said at least one C12-C20 fatty acid is selected from the group consisting of lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, arachidic acid, and a mixture thereof. 
     
     
         7 . Crystalline microparticles according to  claim 6  wherein said at least one fatty acid is selected from the group consisting of myristic acid, palmitic acid, stearic acid, arachidic acid, and a mixture thereof. 
     
     
         8 . Crystalline microparticles according to  claim 1 , which have a [d(v,0.5)] of 1.5 to 3.0 microns. 
     
     
         9 . A pharmaceutical aerosol formulation for a pressurized metered dose inhaler, comprising microparticles according to  claim 1 , in suspension in a liquefied propellant gas. 
     
     
         10 . A pharmaceutical formulation according to  claim 9 , wherein said liquefied propellant gas is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or 1,1,1,2-tetrafluoroethane (HFA 134a), or a mixture thereof. 
     
     
         11 . A pressurized metered dose inhaler, comprising a canister containing an aerosol pharmaceutical formulation according to  claim 9  and a metering valve for delivering a daily therapeutically effective dose of said phenylalkylamino beta 2 -adrenergic agonist. 
     
     
         12 . A dry powder pharmaceutical formulation, comprising microparticles according to  claim 1 . 
     
     
         13 . A dry powder pharmaceutical formulation, comprising microparticles according to  claim 1  and a carrier. 
     
     
         14 . A process for preparing microparticles according to  claim 1 , said process comprising:
 (a) preparing a solution of said C12-C20 fatty acid in a fluorinated model propellant in which said beta 2 -agonist is substantially insoluble, selected from the group consisting of perfluoropentane, 2H,3H-perfluoropentane (HPFP), perfluorohexane, and 1H-perfluorohexane;   (b) adding said beta 2 -agonist as a micronized powder to said solution of said fatty acid, to obtain a mixture;   (c) mixing said mixture to obtain a homogeneous suspension; and   (d) subjecting said suspension to spray-drying, to obtain coated microparticles.   
     
     
         15 . A process according to  claim 14 , wherein said fluorinated model propellant is 2H,3H-perfluoropentane (HPFP). 
     
     
         16 . A method for the prevention and/or treatment of a respiratory disease, comprising administering to a subject in need thereof an effective amount of microcparticles according to  claim 1 . 
     
     
         17 . A method according to  claim 16 , wherein said disease is asthma or chronic obstructive pulmonary disease. 
     
     
         18 . Crystalline microparticles, comprising of a phenylalkylamino beta 2 -adrenergic agonist coated with a C12-C20 fatty acid in an amount of 0.2 to 2.0% by weight, based on the weight of said microparticles, which are produced by a process comprising:
 (a) preparing a solution of said C12-C20 fatty acid in a fluorinated model propellant in which said beta 2 -agonist is substantially insoluble, selected from the group consisting of perfluoropentane, 2H-3H-perfluoropentane (HPFP), perfluorohexane, and 1H-perfluorohexane;   (b) adding said beta 2 -agonist as a micronized powder to said solution of said fatty acid, to obtain a mixture;   (c) mixing said mixture to obtain a homogeneous suspension; and   (d) subjecting said suspension to spray-drying, to obtain coated microparticles.