Claims for Patent: 7,465,462

Summary for Patent: 7,465,462

Title:	Multiparticulate controlled release selective serotonin reuptake inhibitor formulations
Abstract:	A multiparticulate controlled release selective serotonin reuptate inhibitor (SSRI) formulation for oral administration is provided. The formulation includes particles of an SSRI or a pharmaceutically acceptable salt thereof, which are coated with a rate-controlling polymer that allows controlled release of the SSRI over a period of not less than about 12 hours after oral administration. The rate controlling polymer includes a film-forming water-insoluble polymer, or a mixture of a film-forming water-insoluble polymer and a film-forming water-soluble polymer.
Inventor(s):	Jeary; Theresa Ann (Roscommon, IE), Morrissey; Catherine Ann (County Westmeath, IE), Stark; Paul (County Westmeath, IE)
Assignee:	Elan Pharma International Limited (Monksland Athlone County Westmeath, IL)
Application Number:	09/744,169
Patent Claims:	1. A multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) composition for oral administration comprising two quantities of particles, each of the particles comprising (i) an inert non-pareil core, (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and (iii) a coating of a rate-controlling polymeric acrylate, methacrylate lacquer, or a mixture thereof disposed over the fluvoxamine, wherein the composition allows the controlled release of the fluvoxamine over a period of not less than about 12 hours following oral administration, wherein the rate-controlling polymeric acrylate or methacrylate lacquer coating of the first quantity of particles is present in a first amount, and the rate-controlling polymeric acrylate or methacrylate lacquer coating of the second quantity of particles is present in a second amount that is different from the first amount, and wherein the fluvoxamine release rate from the composition exhibits the following in vitro dissolution pattern when measured using a USP type II dissolution apparatus (paddle) according to US Pharmacopeia XXII in 0.05 M phosphate buffer at pH 6.8: (a) no more than about 15% of the total fluvoxamine is released after 0.5 of an hour of measurement in the apparatus; (b) no more than about 25% of the total fluvoxamine is released after 1 hour of measurement in the apparatus; (c) between about 20% and 75% of the total fluvoxamine is released after 2 hours of measurement in the apparatus; (d) not less than about 75% of the total fluvoxamine is released after 4 hours of measurement in the apparatus; and (e) not less than about 85% of the total fluvoxamine is released after 6 hours of measurement in the apparatus. 2. The composition according to claim 1 wherein the coating is the polymeric acrylate lacquer. 3. The composition according to claim 1 wherein the coating is the methacrylate lacquer. 4. The composition according to claim 1 wherein the coating is a lacquer which contains a mixture of acrylate and methacrylate. 5. The composition according to claim 1 wherein the coating is an acrylic resin comprising a copolymer of acrylic and methacrylic acid esters having a low content of quaternary ammonium groups. 6. The composition of claim 1 wherein the rate-controlling coating comprises an ammonio methacrylate lacquer and a plasticizer, the combined amount of the ammonio methacrylate lacquer and the plasticizer in the membrane coating being in an amount of from about 4% to about 15% of the weight of the particle. 7. The composition of claim 6 wherein the combined amount of the ammonio methacrylate lacquer and the plasticizer in the rate controlling coating of the first or second quantity of particles is in an amount of 4%, 6%, 8%, 10%, 12%, or 15% of the weight of the particle. 8. The composition of claim 1, wherein the controlled-release of the fluvoxamine is effective in supplying fluvoxamine to the blood of a patient such that, following a single application of the composition to the patient, the amount of circulating fluvoxamine (AUC.sub.0-.infin.) in the blood serum of the patient is about 128 to about 1,175 ng/ml.h. 9. A multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) composition for oral administration comprising two quantities of particles, each of the particles comprising (i) an inert non-pareil core, (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and (iii) a coating of a rate-controlling polymeric acrylate, methacrylate lacquer, or a mixture thereof disposed over the fluvoxamine, wherein the composition allows the controlled release of the fluvoxamine over a period of not less than about 12 hours following oral administration, wherein the rate-controlling polymeric acrylate or methacrylate lacquer coating of the first quantity of particles is present in a first amount, and the rate-controlling polymeric acrylate or methacrylate lacquer coating of the second quantity of particles is present in a second amount that is different from the first amount, and wherein the fluvoxamine release rate from the composition exhibits the following in vitro dissolution pattern when measured using a USP type II dissolution apparatus (paddle) according to US Pharmacopeia XXII in 0.05 M phosphate buffer at pH 6.8: (a) no more than about 20% of the total fluvoxamine is released after 4 hours of measurement in the apparatus; (b) no more than about 45% of the total fluvoxamine is released after 6 hours of measurement in the apparatus; (c) between about 45% and 80% of the total fluvoxamine is released after 8 hours of measurement in the apparatus; (d) not less than about 70% of the total fluvoxamine is released after 10 hours of measurement in the apparatus; and (c) not less than about 80% of the total fluvoxamine is released after 12 hours of measurement in the apparatus. 10. The composition of claim 9, wherein the coating is the polymeric acrylate lacquer. 11. The composition of claim 9, wherein the coating is the methacrylate lacquer. 12. The composition of claim 9, wherein the coating is a lacquer which contains a mixture of acrylate and methacrylate. 13. The composition of claim 9, wherein the coating is an acrylic resin comprising a copolymer of acrylic and methacrylic acid esters having a low content of quaternary ammonium groups. 14. The composition of claim 9, wherein the rate-controlling coating comprises an ammonio methacrylate lacquer and a plasticizer, the combined amount of the ammonio methacrylate lacquer and the plasticizer in the membrane coating being in an amount of from about 4% to about 15% of the weight of the particle. 15. The composition of claim 14, wherein the combined amount of the ammonio methacrylate lacquer and the plasticizer in the rate controlling coating of the first or second quantity of particles is in an amount of 4%, 6%, 8%, 10%, 12%, or 15% of the weight of the particle. 16. The composition of claim 9, wherein the controlled-release of the fluvoxamine is effective in supplying fluvoxamine to the blood of a patient such that, following a single application of the composition to the patient, the amount of circulating fluvoxamine (AUC.sub.0-.infin.) in the blood serum of the patient is about 128 to about 1,175 ng/ml.h. 17. A multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) composition for oral administration comprising two quantities of particles, each of the particles comprising (i) an inert non-pareil core, (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and (iii) a coating of a rate-controlling polymeric acrylate, methacrylate lacquer, or a mixture thereof disposed over the fluvoxamine, wherein the composition allows the controlled release of the fluvoxamine over a period of not less than about 12 hours following oral administration, wherein the rate-controlling polymeric acrylate or methacrylate lacquer coating of the first quantity of particles is present in a first amount, and the rate-controlling polymeric acrylate or methacrylate lacquer coating of the second quantity of particles is present in a second amount that is different from the first amount, and wherein the fluvoxamine release rate from the composition exhibits the following in vitro dissolution pattern when measured using a USP type II dissolution apparatus (paddle) according to US Pharmacopeia XXII in 0.05 M phosphate buffer at pH 6.8: (a) no more than 20% of the total fluvoxamine is released after 1 hour of measurement in the apparatus; (b) no more than 60% of the total fluvoxamine is released after 2 hours of measurement in the apparatus; (c) not less than 20% of the total fluvoxamine is released after 4 hours of measurement in the apparatus; (d) not less than 35% of the total fluvoxamine is released after 6 hours of measurement in the apparatus; (e) not less than 50% of the total fluvoxamine is released after 8 hours of measurement in the apparatus; (f) not less than 70% of the total fluvoxamine is released after 10 hours of measurement in the apparatus; and (g) not less than 75% of the total fluvoxamine is released after 12 hours of measurement in the apparatus. 18. The composition of claim 17, wherein the coating is the polymeric acrylate lacquer. 19. The composition of claim 17, wherein the coating is the methacrylate lacquer. 20. The composition of claim 17, wherein the coating is a lacquer which contains a mixture of acrylate and methacrylate. 21. The composition of claim 17, wherein the coating is an acrylic resin comprising a copolymer of acrylic and methacrylic acid esters having a low content of quaternary ammonium groups. 22. The composition of claim 17, wherein the rate-controlling coating comprises an ammonio methacrylate lacquer and a plasticizer, the combined amount of the ammonio methacrylate lacquer and the plasticizer in the membrane coating being in an amount of from about 4% to about 15% of the weight of the particle. 23. The composition of claim 22, wherein the combined amount of the ammonio methacrylate lacquer and the plasticizer in the rate controlling coating of the first or second quantity of particles is in an amount of 4%, 6%, 8%, 10%, 12%, or 15% of the weight of the particle. 24. The composition of claim 17, wherein the controlled-release of the fluvoxamine is effective in supplying fluvoxamine to the blood of a patient such that, following a single application of the composition to the patient, the amount of circulating fluvoxamine (AUC.sub.0-.infin.) in the blood serum of the patient is about 128 to about 1,175 ng/ml.h. 25. A multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) composition for oral administration comprising two quantities of particles, each of the particles comprising (i) an inert non-pareil core, (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and (iii) a coating of a rate-controlling polymeric acrylate, methacrylate lacquer, or a mixture thereof disposed over the fluvoxamine, wherein the composition allows the controlled release of the fluvoxamine over a period of not less than about 12 hours following oral administration, wherein the rate-controlling polymeric acrylate or methacrylate lacquer coating of the first quantity of particles is present in a first amount, and the rate-controlling polymeric acrylate or methacrylate lacquer coating of the second quantity of particles is present in a second amount that is different from the first amount, and wherein the fluvoxamine release rate from the composition exhibits the following in vitro dissolution pattern when measured using a USP type II dissolution apparatus (paddle) according to US Pharmacopeia XXII in 0.05 M phosphate buffer at pH 6.8: (a) no more than about 20% of the total fluvoxamine is released after 1 hour of measurement in the apparatus; (b) no more than about 45% of the total fluvoxamine is released after 2 hours of measurement in the apparatus; (c) between about 20% and about 70% of the total fluvoxamine is released after 4 hours of measurement in the apparatus; (d) between about 35% and about 85% of the total fluvoxamine is released after 6 hours of measurement in the apparatus; (e) not less than about 50% of the total fluvoxamine is released after 8 hours of measurement in the apparatus; (f) not less than about 70% of the total fluvoxamine is released after 10 hours of measurement in the apparatus; and (g) not less than about 75% of the total fluvoxamine is released after 12 hours of measurement in the apparatus. 26. The composition of claim 25, wherein the coating is the polymeric acrylate lacquer. 27. The composition of claim 25, wherein the coating is the methacrylate lacquer. 28. The composition of claim 25, wherein the coating is a lacquer which contains a mixture of acrylate and methacrylate. 29. The composition of claim 25, wherein the coating is an acrylic resin comprising a copolymer of acrylic and methacrylic acid esters having a low content of quaternary ammonium groups. 30. The composition of claim 25, wherein the rate-controlling coating comprises an ammonio methacrylate lacquer and a plasticizer, the combined amount of the ammonio methacrylate lacquer and the plasticizer in the membrane coating being in an amount of from about 4% to about 15% of the weight of the particle. 31. The composition of claim 30, wherein the combined amount of the ammonio methacrylate lacquer and the plasticizer in the rate controlling coating of the first or second quantity of particles is in an amount of 4%, 6%, 8%, 10%, 12%, or 15% of the weight of the particle. 32. The composition of claim 25, wherein the controlled-release of the fluvoxamine is effective in supplying fluvoxamine to the blood of a patient such that, following a single application of the composition to the patient, the amount of circulating fluvoxamine (AUC.sub.0-.infin.) in the blood serum of the patient is about 128 to about 1,175 ng/ml.h. 33. A multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) composition for oral administration comprising two quantities of particles, each of the particles comprising (i) an inert non-pareil core, (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and (iii) a coating of a rate-controlling polymeric acrylate, methacrylate lacquer, or a mixture thereof disposed over the fluvoxamine, wherein the composition allows the controlled release of the fluvoxamine over a period of not less than about 12 hours following oral administration, wherein the rate-controlling polymeric acrylate or methacrylate lacquer coating of the first quantity of particles is present in a first amount, and the rate-controlling polymeric acrylate or methacrylate lacquer coating of the second quantity of particles is present in a second amount that is different from the first amount, and wherein the fluvoxamine release rate from the composition exhibits the following in vitro dissolution pattern when measured using a USP type II dissolution apparatus (paddle) according to US Pharmacopeia XXII in 0.05 M phosphate buffer at pH 6.8: (a) no more than about 50% of the total fluvoxamine is released after 2 hours of measurement in the apparatus; (b) not less than about 35% of the total fluvoxamine is released after 6 hours of measurement in the apparatus; and (c) not less than about 80% of the total fluvoxamine is released after 22 hours of measurement in the apparatus. 34. The composition of claim 33, wherein the coating is the polymeric acrylate lacquer. 35. The composition of claim 33, wherein the coating is the methacylate lacquer. 36. The composition of claim 33, wherein the coating is a lacquer which contains a mixture of acrylate and methacrylate. 37. The composition of claim 34, wherein the coating is an acrylic resin comprising a copolymer of acrylic and methacrylic acid esters having a low content of quaternary ammonium groups. 38. The composition of claim 33, wherein the rate-controlling coating comprises an ammonio methacrylate lacquer and a plasticizer, the combined amount of the ammonio methacrylate lacquer and the plasticizer in the membrane coating being in an amount of from about 4% to about 15% of the weight of the particle. 39. The composition of claim 38, wherein the combined amount of the ammonio methacrylate lacquer and the plasticizer in the rate controlling coating of the first or second quantity of particles is in an amount of 4%, 6%, 8%, 10%, 12%, or 15% of the weight of the particle. 40. The composition of claim 33, wherein the controlled-release of the fluvoxamine is effective in supplying fluvoxamine to the blood of a patient such that, following a single application of the composition to the patient, the amount of circulating fluvoxamine (AUC.sub.0-.infin.) in the blood serum of the patient is about 128 to about 1,175 ng/ml.h. 41. A method for the treatment of depression or obsessive compulsive disorder treatable with an SSRI, comprising administering to a patient suffering from one of the conditions a therapeutically effective amount of a multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) composition for oral administration comprising two quantities of particles, each of the particles comprise (i) an inert non-pareil core, (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and (iii) a coating of a rate-controlling polymeric acrylate, methacrylate lacquer, or a mixture thereof disposed over the fluvoxamine, wherein the composition allows the controlled release of the fluvoxamine over a period of not less than about 12 hours following oral administration, and wherein the rate-controlling polymeric acrylate or methacrylate lacquer coating of the first quantity of particles is present in a first amount, and the rate-controlling polymeric acrylate or methacrylate lacquer coating of the second quantity of particles is present in a second amount that is different from the first amount, and wherein the fluvoxamine release rate from the composition exhibits the following in vitro dissolution pattern when measured using a USP type II dissolution apparatus (paddle) according to US Pharmacopeia XXII in 0.05 M phosphate buffer at pH 6.8: (a) no more than about 15% of the total fluvoxamine is released after 0.5 of an hour of measurement in the apparatus; (b) no more than about 25% of the total fluvoxamine is released after 1 hour of measurement in the apparatus; (c) between about 20% and 75% of the total fluvoxamine is released after 2 hours of measurement in the apparatus; (d) not less than about 75% of the total fluvoxamine is released after 4 hours of measurement in the apparatus; and (c) not less than about 85% of the total fluvoxamine is released after 6 hours of measurement in the apparatus. 42. A method for the treatment of depression or obsessive compulsive disorder treatable with an SSRI, comprising administering to a patient suffering from one of the conditions a therapeutically effective amount of a multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) composition for oral administration comprising two quantities of particles, each of the particles comprise (i) an inert non-pareil core, (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and (iii) a coating of a rate-controlling polymeric acrylate, methacrylate lacquer, or a mixture thereof disposed over the fluvoxamine, wherein the composition allows the controlled release of the fluvoxamine over a period of not less than about 12 hours following oral administration, and wherein the rate-controlling polymeric acrylate or methacrylate lacquer coating of the first quantity of particles is present in a first amount, and the rate-controlling polymeric acrylate or methacrylate lacquer coating of the second quantity of particles is present in a second amount that is different from the first amount, and wherein the fluvoxamine release rate from the composition exhibits the following in vitro dissolution pattern when measured using a USP type II dissolution apparatus (paddle) according to US Pharmacopeia XXII in 0.05 M phosphate buffer at pH 6.8: (a) no more than about 20% of the total fluvoxamine is released after 4 hours of measurement in the apparatus; (b) no more than about 45% of the total fluvoxamine is released after 6 hours of measurement in the apparatus; (c) between about 45% and 80% of the total fluvoxamine is released after 8 hours of measurement in the apparatus; (d) not less than about 70% of the total fluvoxamine is released after 10 hours of measurement in the apparatus; and (e) not less than about 80% of the total fluvoxamine is released after 12 hours of measurement in the apparatus. 43. A method for the treatment of depression or obsessive compulsive disorder treatable with an SSRI, comprising administering to a patient suffering from one of the conditions a therapeutically effective amount of a multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) composition for oral administration comprising two quantities of particles, each of the particles comprise (i) an inert non-pareil core, (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and (iii) a coating of a rate-controlling polymeric acrylate, methacrylate lacquer, or a mixture thereof disposed over the fluvoxamine, wherein the composition allows the controlled release of the fluvoxamine over a period of not less than about 12 hours following oral administration, and wherein the rate-controlling polymeric acrylate or methacrylate lacquer coating of the first quantity of particles is present in a first amount, and the rate-controlling polymeric acrylate or methacrylate lacquer coating of the second quantity of particles is present in a second amount that is different from the first amount, and wherein the fluvoxamine release rate from the composition exhibits the following in vitro dissolution pattern when measured using a USP type II dissolution apparatus (paddle) according to US Pharmacopeia XXII in 0.05 M phosphate buffer at pH 6.8: (a) no more than 20% of the total fluvoxamine is released after 1 hour of measurement in the apparatus; (b) no more than 60% of the total fluvoxamine is released after 2 hours of measurement in the apparatus; (c) not less than 20% of the total fluvoxamine is released after 4 hours of measurement in the apparatus; (d) not less than 35% of the total fluvoxamine is released after 6 hours of measurement in the apparatus; (e) not less than 50% of the total fluvoxamine is released after 8 hours of measurement in the apparatus; (f) not less than 70% of the total fluvoxamine is released after 10 hours of measurement in the apparatus; and (g) not less than 75% of the total fluvoxamine is released after 12 hours of measurement in the apparatus. 44. A method for the treatment of depression or obsessive compulsive disorder treatable with an SSRI, comprising administering to a patient suffering from one of the conditions a therapeutically effective amount of a multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) composition for oral administration comprising two quantities of particles, each of the particles comprise (i) an inert non-pareil core, (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and (iii) a coating of a rate-controlling polymeric acrylate, methacrylate lacquer, or a mixture thereof disposed over the fluvoxamine, wherein the composition allows the controlled release of the fluvoxamine over a period of not less than about 12 hours following oral administration, and wherein the rate-controlling polymeric acrylate or methacrylate lacquer coating of the first quantity of particles is present in a first amount, and the rate-controlling polymeric acrylate or methacrylate lacquer coating of the second quantity of particles is present in a second amount that is different from the first amount, and wherein the fluvoxamine release rate from the composition exhibits the following in vitro dissolution pattern when measured using a USP type II dissolution apparatus (paddle) according to US Pharmacopeia XXII in 0.05 M phosphate buffer at pH 6.8: (a) no more than about 20% of the total fluvoxamine is released after 1 hour of measurement in the apparatus; (b) no more than about 45% of the total fluvoxamine is released after 2 hours of measurement in the apparatus; (c) between about 20% and about 70% of the total fluvoxamine is released after 4 hours of measurement in the apparatus; (d) between about 35% and about 85% of the total fluvoxamine is released after 6 hours of measurement in the apparatus; (e) not less than about 50% of the total fluvoxamine is released after 8 hours of measurement in the apparatus; (f) not less than about 70% of the total fluvoxamine is released after 10 hours of measurement in the apparatus; and (g) not less than about 75% of the total fluvoxamine is released after 12 hours of measurement in the apparatus. 45. A method for the treatment of depression or obsessive compulsive disorder treatable with an SSRI, comprising administering to a patient suffering from one of the conditions a therapeutically effective amount of a multiparticulate controlled release selective serotonin reuptake inhibitor (SSRI) composition for oral administration comprising two quantities of particles, each of the particles comprise (i) an inert non-pareil core, (ii) an SSRI layer comprising fluvoxamine or a pharmaceutically-acceptable salt thereof disposed over the inert core, and (iii) a coating of a rate-controlling polymeric acrylate, methacrylate lacquer, or a mixture thereof disposed over the fluvoxamine, wherein the composition allows the controlled release of the fluvoxamine over a period of not less than about 12 hours following oral administration, and wherein the rate-controlling polymeric acrylate or methacrylate lacquer coating of the first quantity of particles is present in a first amount, and the rate-controlling polymeric acrylate or methacrylate lacquer coating of the second quantity of particles is present in a second amount that is different from the first amount, and wherein the fluvoxamine release rate from the composition exhibits the following in vitro dissolution pattern when measured using a USP type II dissolution apparatus (paddle) according to US Pharmacopeia XXII in 0.05 M phosphate buffer at pH 6.8: (a) no more than about 50% of the total fluvoxamine is released after 2 hours of measurement in the apparatus; (b) not less than about 35% of the total fluvoxamine is released after 6 hours of measurement in the apparatus; and (c) not less than about 80% of the total fluvoxamine is released after 22 hours of measurement in the apparatus.