Sustained release formulation comprising octreotide and three linear polylactide-co-glycolide polymers

Abstract

The present invention relates to sustained release formulations comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof and three different linear polylactide-co-glycolide polymers (PLGAs).

1 . A sustained release pharmaceutical composition comprising as active ingredient octreotide or a pharmaceutically-acceptable salt thereof and three different linear polylactide-co-glycolide polymers (PLGAs). 
     
     
         2 . The pharmaceutical composition according to  claim 1  wherein the PLGAs are present as polymer blend. 
     
     
         3 . The pharmaceutical composition according to  claim 1  wherein the PLGAs have a lactide:glycolide monomer ratio of 90:10 to 40:60. 
     
     
         4 . The pharmaceutical composition according to  claim 3  wherein the PLGAs have a lactide:glycolide monomer ratio of 85:15 to 65:35. 
     
     
         5 . The pharmaceutical composition according to  claim 1  wherein the inherent viscosity of the PLGAs is below 0.9 dl/g in CHCl 3 . 
     
     
         6 . The pharmaceutical composition according to  claim 5  wherein the inherent viscosity of the PLGAs is below 0.8 dl/g in CHCl 3 . 
     
     
         7 . The pharmaceutical composition according to  claim 1  comprising the pamoate salt of octreotide. 
     
     
         8 . The pharmaceutical composition according to  claim 1  wherein the release of the active ingredient is three or more months. 
     
     
         9 . The pharmaceutical composition according to  claim 8  wherein the release of the active ingredient is between three and six months. 
     
     
         10 . The pharmaceutical composition according to  claim 1  in form of microparticles, a semisolid or an implant. 
     
     
         11 . The pharmaceutical composition according to  claim 10  in form of microparticles. 
     
     
         12 . The pharmaceutical composition according to  claim 11  wherein the microparticles have a diameter between 10 μm and 90 μm. 
     
     
         13 . The pharmaceutical composition according to  claim 11  wherein the microparticles are additionally covered or coated with an anti-agglomerating agent. 
     
     
         14 . The pharmaceutical composition according to  claim 13  wherein the microparticles are coated with an anti-agglomerating agent and the anti-agglomerating agent is present in an amount of less than 2% by weight of the microparticles. 
     
     
         15 . The pharmaceutical composition according to  claim 13  wherein the anti-agglomerating agent is mannitol. 
     
     
         16 . The pharmaceutical composition according to  claim 1  sterilized by gamma irradiation. 
     
     
         17 . (canceled) 
     
     
         18 . A method of administering octreotide or a pharmaceutically-acceptable salt thereof for long-term maintenance therapy in acromegalic patients, and treatment of severe diarrhea and flushing associated with malignant carcinoid tumors and vasoactive intestinal peptide tumors (vipoma tumors), said method comprising administering to a patient in need of octreotide or a pharmaceutically-acceptable salt thereof a pharmaceutical composition according to  claim 1 . 
     
     
         19 . A process of manufacturing microparticles according to  claim 11  comprising
 (i) preparation of an internal organic phase comprising
 (ia) dissolving the polymer or polymers in a suitable organic solvent or solvent mixture; 
 (ib) dissolving/suspending/emulsification of the drug substance in the polymer solution obtained in step (ia); 
 
 (ii) preparation of an external aqueous phase containing stabilizers; 
 (iii) mixing the internal organic phase with the external aqueous phase to form an emulsion; and 
 (iv) hardening the microparticles by solvent evaporation or solvent extraction, washing the microparticles, drying the microparticles and sieving the microparticles through 140 μm. 
 
     
     
         20 . An administration kit comprising the pharmaceutical composition according to  claim 1  in a vial, together with a water-based vehicle in an ampoule, vial or prefilled syringe or as microparticles and vehicle separated in a double chamber syringe.