Extended-Release Composition Comprising a Somatostatin Derivative in Microparticles
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.