Claims for Patent: 10,335,366

Summary for Patent: 10,335,366

Title:	Risperidone or paliperidone implant formulation
Abstract:	The present invention is directed to an injectable intramuscular depot composition suitable for forming an in situ solid implant in a body, comprising a drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination, a biocompatible copolymer based on lactic and glycolic acid having a monomer ratio of lactic to glycolic acid of about 50:50 and a DMSO solvent, wherein the composition releases the drug with an immediate onset of action and continuously for at least 4 weeks and wherein the composition has a pharmacokinetic profile in vivo that makes it suitable to be administered each 4 weeks or even longer periods.
Inventor(s):	Gutierro Aduriz Ibon, Franco Rodríguez Guillermo
Assignee:	Laboratorios Farmacéuticos Rovi, S.A.
Application Number:	US14555287
Patent Claims:	1. An injectable composition consisting ofabout 13% wt of drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination; anda polymeric solution consisting of DMSO and biocompatible poly(lactide-co-glycolide) (PLGA) copolymer having a monomer ratio of lactic acid to glycolic acid of about 50:50 and an inherent viscosity in the range of 0.25-0.30 dl/g measured by gel permeation chromatography in tetrahydrofuran at 30° C. using a flow rate of 1 ml/min; whereinthe mass ratio of polymeric solution to drug is about 6.5:1 to about 7:1; andthe mass ratio of DMSO to drug is about 4:1 to about 5:1.2. A pharmaceutical kit suitable for the in situ formation of a biodegradable implant in a body comprising the injectable composition of claim 1 , wherein claim 1 , prior to mixing claim 1 , the drug and the biocompatible copolymer are contained in a first container claim 1 , and the solvent is contained in a second claim 1 , separate container.3. The pharmaceutical kit according to claim 2 , wherein at least one of the first and second containers is a syringe claim 2 , a vial claim 2 , or a cartridge.4. The injectable composition of claim 1 , wherein the biocompatible copolymer is an irradiated biocompatible copolymer that has been irradiated with beta-radiation.6. The injectable composition of claim 1 , wherein the injectable composition releases no more than 20% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.7. The injectable composition of claim 1 , wherein the injectable composition releases at least 0.1% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.8. The composition of claim 1 , wherein ≤20% wt of the drug is dissolved in the DMSO or polymeric solution to form the injectable composition.9. The injectable composition of claim 1 , wherein the copolymer is end-capped.10. The injectable composition of claim 1 , wherein the particle size distribution of the drug is selected froma) not more than 10% of the total volume of the particles are smaller than 10 microns, and not more than the 10% of the total volume of particles are greater than 225 microns;b) not more than 10% of the total volume of the particles is less than the range 1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-400 μm, and the d0.5 of the size distribution is in the range of about 40-200 μm;c) expressed as volume, d0.9 is about 150 to about 400 μm, d0.5 is about 40 to about 200 μm and d0.1 is about 10 to about 60 μm;d) not more than 10% of the total volume of the particles is less than the range 0.1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-1000 μm, and the d0.5 of the size distribution is in the range of about 10-1000 μm;e) not more than 10% of the total volume of the particles is less than the range 0.5-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-700 μm, and the d0.5 of the size distribution is in the range of about 20-700 μm; orf) not more than 10% of the total volume of the particles is less than the range 1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-400 μm, and the d0.5 of the size distribution is in the range of about 40-200 μm.11. The injectable composition of claim 1 , wherein the monomer ratio of lactic acid to glycolic acid ranges from 48:52 to 52:48.12. An injectable composition consisting ofabout 13% wt of drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination;DMSO; andbiocompatible poly(lactide-co-glycolide) (PLGA) copolymer having a monomer ratio of lactic acid to glycolic acid of about 50:50 and an inherent viscosity in the range of 0.26-0.29 dl/g measured by gel permeation chromatography in tetrahydrofuran at 30° C. using a flow rate of 1 ml/min; whereinthe mass ratio of drug to (polymer+drug) is about 33%, expressed as the percentage of the drug weight with respect to total weight of the drug plus polymer; andthe mass ratio of DMSO to drug is about 4.66:1.13. The injectable composition of claim 12 , wherein the biocompatible copolymer is an irradiated biocompatible copolymer that has been irradiated with beta-radiation.14. The injectable composition of claim 12 , wherein the injectable composition releases no more than 20% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.15. The injectable composition of claim 12 , wherein the injectable composition releases at least 0.1% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.16. The injectable composition of claim 12 , wherein ≤20% wt of the drug is dissolved in the DMSO or polymeric solution to form the injectable composition.17. A pharmaceutical kit suitable for the in situ formation of a biodegradable implant in a body comprising the injectable composition of claim 12 , wherein claim 12 , prior to mixing claim 12 , the drug and the biocompatible copolymer are contained in a first container claim 12 , and the solvent is contained in a second claim 12 , separate container.19. The injectable composition of claim 12 , wherein the copolymer is end-capped.20. The injectable composition of claim 12 , wherein the particle size distribution of the drug is selected froma) not more than 10% of the total volume of the particles are smaller than 10 microns, and not more than the 10% of the total volume of particles are greater than 225 microns;b) not more than 10% of the total volume of the particles is less than the range 1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-400 μm, and the d0.5 of the size distribution is in the range of about 40-200 μm;c) expressed as volume, d0.9 is about 150 to about 400 μm, d0.5 is about 40 to about 200 μm and d0.1 is about 10 to about 60 μm;d) not more than 10% of the total volume of the particles is less than the range 0.1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-1000 μm, and the d0.5 of the size distribution is in the range of about 10-1000 μm;e) not more than 10% of the total volume of the particles is less than the range 0.5-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-700 μm, and the d0.5 of the size distribution is in the range of about 20-700 μm; orf) not more than 10% of the total volume of the particles is less than the range 1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-400 μm, and the d0.5 of the size distribution is in the range of about 40-200 μm.21. The injectable composition of claim 12 , wherein the monomer ratio of lactic acid to glycolic acid ranges from 48:52 to 52:48.22. An injectable composition consisting ofabout 13% wt of drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination;DMSO; and25-27% wt of biocompatible poly(lactide-co-glycolide) (PLGA) copolymer having a monomer ratio of lactic acid to glycolic acid of about 50:50 and an inherent viscosity in the range of 0.25-0.30 dl/g measured by gel permeation chromatography in tetrahydrofuran at 30° C. using a flow rate of 1 ml/min; whereinthe mass ratio of DMSO to drug is about 4:1 to about 5:1.23. The injectable composition of claim 22 , wherein the biocompatible copolymer is an irradiated copolymer that has been irradiated with beta-radiation.24. The injectable composition of claim 22 , wherein the injectable composition releases no more than 20% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.25. The injectable composition of claim 22 , wherein the injectable composition releases at least 0.1% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.26. The injectable composition of claim 22 , wherein ≤20% wt of the drug is dissolved in the DMSO or polymeric solution to form the injectable composition.27. A pharmaceutical kit suitable for the in situ formation of a biodegradable implant in a body comprising the injectable composition of claim 22 , wherein claim 22 , prior to mixing claim 22 , the drug and the biocompatible copolymer are contained in a first container claim 22 , and the solvent is contained in a second claim 22 , separate container.28. The injectable composition of claim 22 , wherein the particle size distribution of the drug is selected froma) not more than 10% of the total volume of the particles are smaller than 10 microns, and not more than the 10% of the total volume of particles are greater than 225 microns;b) not more than 10% of the total volume of the particles is less than the range 1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-400 μm, and the d0.5 of the size distribution is in the range of about 40-200 μm;c) expressed as volume, d0.9 is about 150 to about 400 μm, d0.5 is about 40 to about 200 μm and d0.1 is about 10 to about 60 μm;d) not more than 10% of the total volume of the particles is less than the range 0.1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-1000 μm, and the d0.5 of the size distribution is in the range of about 10-1000 μm;e) not more than 10% of the total volume of the particles is less than the range 0.5-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-700 μm, and the d0.5 of the size distribution is in the range of about 20-700 μm; orf) not more than 10% of the total volume of the particles is less than the range 1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-400 μm, and the d0.5 of the size distribution is in the range of about 40-200 μm.30. The injectable composition of claim 22 , wherein the monomer ratio of lactic acid to glycolic acid ranges from 48:52 to 52:48.31. An injectable composition consisting ofabout 13% wt of drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination;DMSO; and25-27% wt of biocompatible poly(lactide-co-glycolide) (PLGA) copolymer having a monomer ratio of lactic acid to glycolic acid of about 50:50 and a molecular weight in the range of 28-43 kDa; whereinthe mass ratio of DMSO to drug is about 4:1 to about 5:1.32. The injectable composition of claim 31 , wherein the biocompatible copolymer has molecular weight in the range of 30-36 kDa.33. The injectable composition of claim 31 , wherein the biocompatible copolymer is an irradiated copolymer that has been irradiated with a beta-radiation.34. The injectable composition of claim 31 , wherein the injectable composition releases no more than 20% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.35. The injectable composition of claim 31 , wherein the injectable composition releases at least 0.1% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.36. The injectable composition of claim 31 , wherein ≤20% wt of the drug is dissolved in the DMSO or polymeric solution to form the injectable composition.37. A pharmaceutical kit suitable for the in situ formation of a biodegradable implant in a body comprising the injectable composition of claim 31 , wherein claim 31 , prior to mixing claim 31 , the drug and the biocompatible copolymer are contained in a first container claim 31 , and the solvent is contained in a second claim 31 , separate container.38. The injectable composition of claim 31 , wherein the particle size distribution of the drug is selected froma) not more than 10% of the total volume of the particles are smaller than 10 microns, and not more than the 10% of the total volume of particles are greater than 225 microns;b) not more than 10% of the total volume of the particles is less than the range 1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-400 μm, and the d0.5 of the size distribution is in the range of about 40-200 μm;c) expressed as volume, d0.9 is about 150 to about 400 μm, d0.5 is about 40 to about 200 μm and d0.1 is about 10 to about 60 μm;d) not more than 10% of the total volume of the particles is less than the range 0.1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-1000 μm, and the d0.5 of the size distribution is in the range of about 10-1000 μm;e) not more than 10% of the total volume of the particles is less than the range 0.5-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-700 μm, and the d0.5 of the size distribution is in the range of about 20-700 μm; orf) not more than 10% of the total volume of the particles is less than the range 1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-400 μm, and the d0.5 of the size distribution is in the range of about 40-200 μm.40. The injectable composition of claim 31 , wherein the monomer ratio of lactic acid to glycolic acid ranges from 48:52 to 52:48.