Extended-Release Composition Comprising a Somatostatin Derivative in Microparticles

Abstract

The present invention relates to improved microparticles comprising a somatostatin analogue, a process of making said microparticles and to pharmaceutical compositions comprising the same.

1 . Pharmaceutical composition for extended release comprising microparticles with a polymer matrix comprising of one or more biodegradable polymers and Compound A pamoate as active ingredient wherein the maximum plasma concentration of the active ingredient in rabbits within the first 24 hours after administration of 4 mg/kg is below 15 ng/ml. 
     
     
         2 . Pharmaceutical composition according to any one of  claims 1  wherein the maximum plasma concentration (t max ) of Compound A is reached not before day 12 after administration. 
     
     
         3 . Pharmaceutical composition according to any one of  claims 1  to  2  wherein the plasma concentration of Compound A is above 2 ng/ml between day 2 and day 35 after administration. 
     
     
         4 . Pharmaceutical composition for extended release comprising microparticles with a polymer matrix consisting of one or more biodegradable polymers and Compound A pamoate as active ingredient wherein the burst as % of Compound A content after 24 hours is between 0.5%-1.2% as measured by the in vitro dissolution test as described in Example 4. 
     
     
         5 . Pharmaceutical composition according to  claims 1  to  4  wherein the active ingredient Compound A is released over a time period of at least 4 weeks. 
     
     
         6 . Pharmaceutical composition according to any one of  claims 1  to  5  wherein the polymer matrix comprises a linear and a branched polylactide-co-glycolide. 
     
     
         7 . Pharmaceutical composition according to  claim 6  wherein the polymer matrix comprises a Resomer® RG and a star polylactide-co-glycolide polymer having a weight average molecular weight of between about 47,000 to about 63,000 Da. 
     
     
         8 . Pharmaceutical composition according to  claim 7  wherein the ratio of linear to branched polylactide-co-glycolide is about 60:40 to 40:60. 
     
     
         9 . Process of making microparticles comprising
 dissolving a mixture of a linear polylactide-co-glycolide polymer and a branched polylactide-co-glycolide polymer in methylene chloride,   adding this polymer solution to the active ingredient Compound A pamoate,   preparing an aqueous dispersion of phosphate salts and polyvinyl alcohol   mixing the polymer/active ingredient solution with the polyvinyl alcohol/phosphate solution,   evaporating the methylene chloride and filtering off the obtained microparticles,   wherein the concentration of the polymer mixture in methylene chloride is between 14.2% and 17.5% weight by weight.   
     
     
         10 . Process according to  claim 9  wherein the concentration of the polymer mixture in methylene chloride about 15.9% weight by weight. 
     
     
         11 . Microparticles obtainable by the process of  claim 9  or  10 . 
     
     
         12 . Microparticles according to  claim 11  with a diameter from 10 to 200 microns. 
     
     
         13 . Microparticles according to  claim 11  with a particle size distribution ×10<15 microns, ×50<40 microns and ×90<70 microns. 
     
     
         14 . Microparticles according to any one of  claims 11  to  13  further comprising a surfactant, a porosity influencing agent and/or a basic salt. 
     
     
         15 . A pharmaceutical composition comprising microparticles according to any one of  claims 11  to  14  and a water-based vehicle. 
     
     
         16 . A kit comprising microparticles according to any one of  claims 11  to  14  and a water-based vehicle. 
     
     
         17 . A composition according to  claim 15  or  16  wherein the water-based vehicle comprises a wetting agent, a tonicity agent and a viscosity increasing agent. 
     
     
         18 . A composition according to  claim 17  wherein the wetting agent is selected from a poloxamer and/or a polyoxyethylene-sorbitan-fatty acid ester. 
     
     
         19 . A composition according to  claim 17  wherein the tonicity agent is selected from mannitol, sodium chloride, glucose, dextrose, sucrose and glycerin. 
     
     
         20 . A composition according to  claim 17  wherein the viscosity increasing agent is selected from carboxymethyl cellulose sodium (CMC-Na), sorbitol, polyvinylpyrrolidone and aluminium monostearate. 
     
     
         21 . A composition according to  claim 17  for use in vials wherein the water-based vehicle comprises carboxymethyl cellulose sodium, mannitol and Pluronic F68. 
     
     
         22 . Use of microparticles according to any one of  claims 11  to  14  or of a pharmaceutical composition according to any one of  claims 1  to  8  for the preparation of a medicament for the treatment of a disease or disorder with an aetiology comprising or associated with excess GH- and/or IGF-1 secretion. 
     
     
         23 . A method of treating a disease or disorder with an aetiology comprising or associated with excess GH- and/or IGF-1 secretion in a subject in need thereof which comprises administering microparticles according to any one of  claims 11  to  14  or of a pharmaceutical composition according to any one of  claims 1  to  8  to the subject.