Claims for Patent: 9,446,135

Summary for Patent: 9,446,135

Title:	Risperidone sustained release microsphere composition
Abstract:	A risperidone sustained release microsphere formulation is provided. The microsphere formulation comprise risperidone or 9-hydroxy risperidone or salts thereof, and a polymer blend having a first uncapped lactide-glycolide copolymer and a second uncapped lactide-glycolide copolymer, in which the first uncapped lactide-glycolide copolymer is a copolymer with a high intrinsic viscosity and the second uncapped lactide-glycolide copolymer is a copolymer with a low intrinsic viscosity. The sustained release micro sphere formulation according to an embodiment of the present disclosure is suitable for large-scale industrialized production with improved stability, the in vivo release behavior of which will not change after long-term storage.
Inventor(s):	Sun Kaoxiang, Liang Rongcai, Wang Qilin, Wang Wenyan, Liu Wanhui, Li Youxin
Assignee:	Shandong Luye Pharmaceutical Co., Ltd.
Application Number:	US14113738
Patent Claims:	1. A pharmaceutical composition suitable for parenteral administration , comprising:an active component selected from the group consisting of risperidone, or a salt thereof, and 9-hydroxy risperidone or a salt thereof; anda polymer blend consisting essentially of a first uncapped poly(lactide-co-glycolide) and a second uncapped poly(lactide-co-glycolide),wherein the weight content of the active component in the pharmaceutical composition is within a range from 10% to 60%; a weight content of the polymer blend in the pharmaceutical composition is within a range from 40% to 90%; and the pharmaceutical composition is present in the form of microspheres; andwherein the first uncapped poly(lactide-co-glycolide) has an intrinsic viscosity of 0.4-0.9 dl/g, a molar ratio of lactide to glycolide of 65:35 to 90:10; and the second uncapped poly(lactide-co-glycolide) has an intrinsic viscosity of 0.1-0.35 dl/g a molar ratio of lactide to glycolide of 50:50 to 75:25.2. The pharmaceutical composition of claim 1 , wherein a weight ratio of the first uncapped poly(lactide-co-glycolide) to the second uncapped poly(lactide-co-glycolide) is (50-95):(5-50).3. The pharmaceutical composition of claim 1 , wherein the first uncapped poly(lactide-co-glycolide) has a weight average molecular weight of 50 claim 1 ,000-145 claim 1 ,000 and the second uncapped poly(lactide-co-glycolide) has a weight average molecular weight of 4 claim 1 ,000 to 45 claim 1 ,000.4. The pharmaceutical composition of claim 3 , wherein a weight ratio of the first uncapped poly(lactide-co-glycolide) to the second uncapped poly(lactide-co-glycolide) is (50-95):(5-50).5. The pharmaceutical composition of claim 1 , wherein the weight content of risperidone is 45% claim 1 , the weight content of the polymer blend is 55% claim 1 , the weight ratio of the first uncapped poly(lactide-co-glycolide) to the second uncapped poly(lactide-co-glycolide) is 80:20 claim 1 , the molecular weight of the first uncapped poly(lactide-co-glycolide) is 55 claim 1 ,000˜85 claim 1 ,000 and the molecular weight of the second uncapped poly(lactide-co-glycolide) is 15 claim 1 ,000˜35 claim 1 ,000 claim 1 , the intrinsic viscosity of the first uncapped poly(lactide-co-glycolide) is 0.45˜0.55 dL/g and the intrinsic viscosity of the second uncapped PLGA is 0.2˜0.3 dL/g claim 1 , and a molar ratio of lactide to glycolide in the first uncapped poly(lactide-co-glycolide) is 75:25 and a molar ratio of lactide to glycolide in the second uncapped poly(lactide-co-glycolide) is 50:50.6. The pharmaceutical composition of claim 1 , wherein a salt of risperidone or 9-hydroxy risperidone is selected from an inorganic acid salt and an organic acid salt; the inorganic acid salt being selected from hydrochlorate claim 1 , hydrobromate claim 1 , nitrate claim 1 , sulfate and phosphate; and the organic acid salt being selected from acetate claim 1 , propionate claim 1 , hydroxy acetate claim 1 , 2-hydroxy propionate claim 1 , pamoate claim 1 , 2-oxo propionate claim 1 , oxalate claim 1 , malonate claim 1 , succinate claim 1 , 2-butenedioate claim 1 , methanesulfonate claim 1 , ethanesulfonate claim 1 , benzenesulfonate and toluenesulfonate.7. A method of treating a psychosis comprising administering the composition of claim 1 , where the psychosis is selected from the group consisting of acute schizophrenia claim 1 , chronic schizophrenia claim 1 , significant positive symptoms or significant negative symptoms of other psychotic states claim 1 , and affective symptoms related to schizophrenia.8. A sustained release microsphere formulation for injection claim 1 , comprising the pharmaceutical composition of .9. The sustained release microsphere formulation for injection of claim 8 , wherein the microspheres are suspended in a pharmaceutically acceptable dispersion solvent; the dispersion solvent is selected from a suspending agent claim 8 , a pH regulator claim 8 , an isoosmotic adjusting agent claim 8 , a surfactant claim 8 , water claim 8 , and physiological saline.10. The pharmaceutical composition of claim 1 , wherein the weight content of the active component in the pharmaceutical composition is within a range from 35% to 55%.11. The pharmaceutical composition of claim 1 , wherein the weight content of the active component in the pharmaceutical composition is within a range from 40% to 50%.12. The pharmaceutical composition of claim 1 , wherein the weight content of the polymer blend in the pharmaceutical composition ranges from 45% to 65%.13. The pharmaceutical composition of claim 1 , wherein the weight content of the polymer blend in the pharmaceutical composition ranges from 50% to 60%.14. The pharmaceutical composition of claim 1 , wherein the first uncapped poly(lactide-co-glycolide) has a high intrinsic viscosity of 0.45-0.8 dl/g.15. The pharmaceutical composition of claim 1 , wherein the first uncapped poly(lactide-co-glycolide) has a high intrinsic viscosity of 0.45-0.55 dl/g.16. The pharmaceutical composition of claim 1 , wherein the second uncapped poly(lactide-co-glycolide) has a low intrinsic viscosity of 0.1-0.3 dl/g.17. The pharmaceutical composition of claim 1 , wherein the second uncapped poly(lactide-co-glycolide) has a low intrinsic viscosity of 0.2-0.3 dl/g.18. The pharmaceutical composition of claim 1 , wherein a weight ratio of the first uncapped poly(lactide-co-glycolide) to the second uncapped poly(lactide-co-glycolide) is (70-90):(10-30).19. The pharmaceutical composition of claim 1 , wherein a weight ratio of the first uncapped poly(lactide-co-glycolide) to the second uncapped poly(lactide-co-glycolide) is 80:20.20. The pharmaceutical composition of claim 1 , wherein a molar ratio of lactide to glycolide in the first uncapped poly(lactide-co-glycolide) is 75:25.21. The pharmaceutical composition of claim 1 , wherein a molar ratio of lactide to glycolide in the second uncapped poly(lactide-co-glycolide) is 50:50.22. The pharmaceutical composition of claim 1 , wherein the first uncapped poly(lactide-co-glycolide) has a weight average molecular weight of 55 claim 1 ,000-110 claim 1 ,000.23. The pharmaceutical composition of claim 1 , wherein the first uncapped poly(lactide-co-glycolide) has a weight average molecular weight of 55 claim 1 ,000-85 claim 1 ,000.24. The pharmaceutical composition of claim 1 , wherein the second uncapped poly(lactide-co-glycolide) has a weight average molecular weight of 4 claim 1 ,000-35 claim 1 ,000.25. The pharmaceutical composition of claim 1 , wherein the second uncapped poly(lactide-co-glycolide) has a weight average molecular weight of 15 claim 1 ,000-35 claim 1 ,000.26. The pharmaceutical composition of claim 3 , wherein a weight ratio of the first uncapped poly(lactide-co-glycolide) to the second uncapped poly(lactide-co-glycolide) is (70-90):(10-30).27. The pharmaceutical composition of claim 3 , wherein a weight ratio of the first uncapped poly(lactide-co-glycolide) to the second uncapped poly(lactide-co-glycolide) is 80:20.28. The pharmaceutical composition of claim 3 , wherein a molar ratio of lactide to glycolide in the first uncapped poly(lactide-co-glycolide) is 75:25.29. The pharmaceutical composition of claim 3 , wherein a molar ratio of lactide to glycolide in the second uncapped poly(lactide-co-glycolide) is 50:50.30. The sustained release microsphere formulation for injection of claim 9 , wherein the suspending agent is selected from sodium carboxymethyl cellulose claim 9 , polyvinyl alcohol claim 9 , polyvinyl pyrrolidone claim 9 , sodium alginate claim 9 , and glycerol.31. The sustained release microsphere formulation for injection of claim 9 , wherein the isoosmotic adjusting agent is selected from sodium chloride claim 9 , glucose claim 9 , mannitol claim 9 , and glucitol.32. The sustained release microsphere formulation for injection of claim 9 , wherein the surfactant is a nonionic surfactant and is selected from polysorbate series and poloxamer series.