Risperidone sustained release microsphere composition
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.
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; and
a 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; and
wherein 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 50,000-145,000 and the second uncapped poly(lactide-co-glycolide) has a weight average molecular weight of 4,000 to 45,000.
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%, the weight content of the polymer blend is 55%, the weight ratio of the first uncapped poly(lactide-co-glycolide) to the second uncapped poly(lactide-co-glycolide) is 80:20, the molecular weight of the first uncapped poly(lactide-co-glycolide) is 55,000˜85,000 and the molecular weight of the second uncapped poly(lactide-co-glycolide) is 15,000˜35,000, 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, 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, hydrobromate, nitrate, sulfate and phosphate; and the organic acid salt being selected from acetate, propionate, hydroxy acetate, 2-hydroxy propionate, pamoate, 2-oxo propionate, oxalate, malonate, succinate, 2-butenedioate, methanesulfonate, ethanesulfonate, 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, chronic schizophrenia, significant positive symptoms or significant negative symptoms of other psychotic states, and affective symptoms related to schizophrenia.
8. A sustained release microsphere formulation for injection, comprising the pharmaceutical composition of claim 1 .
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, a pH regulator, an isoosmotic adjusting agent, a surfactant, water, 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 55,000-110,000.
23. The pharmaceutical composition of claim 1 , wherein the first uncapped poly(lactide-co-glycolide) has a weight average molecular weight of 55,000-85,000.
24. The pharmaceutical composition of claim 1 , wherein the second uncapped poly(lactide-co-glycolide) has a weight average molecular weight of 4,000-35,000.
25. The pharmaceutical composition of claim 1 , wherein the second uncapped poly(lactide-co-glycolide) has a weight average molecular weight of 15,000-35,000.
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, polyvinyl alcohol, polyvinyl pyrrolidone, sodium alginate, and glycerol.
31. The sustained release microsphere formulation for injection of claim 9 , wherein the isoosmotic adjusting agent is selected from sodium chloride, glucose, mannitol, 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.