Details for Patent: 9,320,707

Title:	Aqueous suspensions of submicron 9-hydroxyrisperidone fatty acid esters
Abstract:	The present invention is concerned with a pharmaceutical composition suitable as a depot formulation for administration via intramuscular or subcutaneous injection, comprising: (1) as an active ingredient a therapeutically effective amount of a 9-hydroxyrisperidone fatty acid ester or a salt, or a stereoisomer or a stereoisomeric mixture thereof in submicron form and (2) a pharmaceutically acceptable carrier; wherein the pharmaceutically acceptable carrier is water and the active ingredient is suspended therein: and with a process of preparing such a composition. The invention further concerns such a pharmaceutical composition for use as a medicament in the treatment of psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioral disturbances associated with neurodegenerative disorders, e.g. in dementia, behavioral disturbances in mental retardation and autism, Tourette's syndrome, bipolar mania, depression, anxiety.
Inventor(s):	Francois; Marc Karel Jozef (Kapellen, BE), Dries; Willy Maria Albert Carlo (Merksplas, BE), Basstanie; Esther Dina Guido (Zandhoven, BE)
Assignee:	Janssen Pharmaceutica, N.V. (Beerse, BE)
Filing Date:	Jun 29, 2012
Application Number:	13/538,469
Claims:	1. An injectable pharmaceutical depot composition suitable as a depot formulation for administration by intramuscular or subcutaneous injection, comprising a dispersion of particles consisting essentially of a therapeutically effective amount of a crystalline 9-hydroxyrisperidone fatty acid ester having the formula ##STR00002## or a salt, or a stereoisomer or a stereoisomeric mixture thereof, wherein R represents a straight C.sub.9-19 alkyl radical; having a surfactant adsorbed to the surface of the particles in an amount effective to in maintaining a specific surface area of the particles in the range of from 10 to 16 m.sup.2/g as measured on a Mastersizer S in a pharmaceutically acceptable carrier comprising water wherein said injectable pharmaceutical depot composition is therapeutically effective for about one month. 2. The injectable pharmaceutical depot composition according to claim 1 wherein R represents a straight C.sub.15 (pentadecyl) chain and the active ingredient is 9-hydroxyrisperidone palmitate ester. 3. The injectable pharmaceutical depot composition according to claim 2 wherein the composition further comprises a suspending agent. 4. The injectable pharmaceutical depot composition according to claim 3 wherein the suspending agent is polyethylene glycol. 5. The injectable pharmaceutical depot composition according to claim 3 wherein the surfactant is polysorbate 20. 6. The injectable pharmaceutical depot composition according to claim 2 having a viscosity of less than 75 mPas. 7. The injectable pharmaceutical depot composition according to claim 6 comprising: (a) from 3 to 20% (w/v) of a dispersion of particles consisting essentially of a therapeutically effective amount of a crystalline 9-hydroxyrisperidone palmitate ester; (b) the surfactant adsorbed to the surface thereof of the particles is polysorbate 20; (c) one or more buffering agents sufficient to render the composition neutral to very slightly basic (up to pH 8.5); (d) a suspending agent; (e) up to 2% (w/v) preservatives; and (f) water q.s. ad 100%. 8. A method for treating a human suffering from psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, bipolar mania, depression, or anxiety comprising administering intramuscularly or subcutaneously the injectable pharmaceutical depot composition of claim 1 to said human. 9. The method of claim 8 wherein 9-hydroxyrisperidone fatty acid ester contained in the composition is 9-hydroxyrisperidone palmitate ester. 10. The method of claim 9 wherein the human is suffering from schizophrenia. 11. The method of claim 9 wherein the human is suffering from schizoaffective disorders. 12. The injectable pharmaceutical depot composition according to claim 7 wherein the suspending agent is polyethylene glycol. 13. The injectable pharmaceutical depot composition of claim 1 wherein 90 percent of the particles are less than 2000nm as measured by a Mastersizer X. 14. An injectable pharmaceutical depot composition suitable as a depot formulation for administration by intramuscular or subcutaneous injection, comprising a dispersion of particles consisting essentially of a therapeutically effective amount of a crystalline 9-hydroxyrisperidone fatty acid ester having the formula ##STR00003## or a salt, or a stereoisomer or a stereoisomeric mixture thereof, wherein R represents a straight C.sub.9-19alkyl radical; having a surfactant adsorbed to the surface of the particles in an amount effective in maintaining a specific surface area of the particles in the range of from 10 to 16 m.sup.2/g as measured on a Mastersizer S and wherein 90 percent of the particles have a particle size less than 1.15 .mu.m as measured by a Mastersizer X in a pharmaceutically acceptable carrier comprising water wherein said injectable pharmaceutical depot composition is therapeutically effective for about one month. 15. The injectable pharmaceutical depot composition according to claim 14 wherein R represents a straight C.sub.15 (pentadecyl) chain and the active ingredient is 9-hydroxyrisperidone palmitate ester. 16. The injectable pharmaceutical depot composition according to claim 15 wherein the composition further comprises a suspending agent. 17. The injectable pharmaceutical depot composition according to claim 16 wherein the suspending agent is polyethylene glycol. 18. The injectable pharmaceutical depot composition according to claim 15 wherein the surfactant is polysorbate 20. 19. The injectable pharmaceutical depot composition according to claim 15 having a viscosity of less than 75 mPas. 20. The injectable pharmaceutical depot composition according to claim 19 comprising: (a) from 3 to 20% (w/v) of the 9-hydroxyrisperidone fatty acid ester wherein the 9-hydroxyrisperidone fatty acid ester is 9-hydroxyrisperidone palmitate ester; (b) wherein the surfactant is polysorbate 20; (c) one or more buffering agents sufficient to render the composition neutral to very slightly basic (up to pH 8.5); (d) a suspending agent; (e) up to 2% (w/v) preservatives; and (f) water q.s. ad 100%. 21. The injectable pharmaceutical depot composition according to claim 20 wherein the suspending agent is polyethylene glycol. 22. A method for treating a human suffering from psychosis, schizophrenia, schizoaffective disorders, non-schizophrenic psychoses, behavioural disturbances associated with neurodegenerative disorders, bipolar mania, depression, or anxiety comprising administering intramuscularly or subcutaneously the injectable pharmaceutical depot composition of claim 14 to said human. 23. The method of claim 22 wherein 9-hydroxyrisperidone fatty acid ester contained in the composition is 9-hydroxyrisperidone palmitate ester. 24. The method of claim 23 wherein the human is suffering from schizophrenia. 25. The method of claim 23 wherein the human is suffering from schizoaffective disorders. 26. An injectable pharmaceutical depot composition suitable as a depot formulation for administration by intramuscular or subcutaneous injection, comprising a dispersion of particles consisting essentially of a therapeutically effective amount of a crystalline 9-hydroxyrisperidone fatty acid ester having the formula ##STR00004## a salt, or a stereoisomer or a stereoisomeric mixture thereof, wherein R represents a straight C.sub.9-19alkyl radical; having a surfactant adsorbed to the surface of the particles in an amount effective in maintaining a specific surface area of the particles in the range of from 10 to 16 m.sup.2/g as measured on a Mastersizer S and wherein 10 percent of the particles have a particle size less than 0.43 .mu.m as measured by a Mastersizer X in a pharmaceutically acceptable carrier comprising water wherein said injectable pharmaceutical depot composition is therapeutically effective for about one month.