Claims for Patent: 11,752,094

Summary for Patent: 11,752,094

Title:	Antipsychotic injectable depot composition
Abstract:	The present invention is directed to a composition that can be used to deliver an antipsychotic drug such as risperidone, paliperidone or a combination thereof, as an injectable in-situ forming biodegradable implant for extended release providing therapeutic plasma levels from the first day. The composition is in the form of drug suspension on a biodegradable and biocompatible copolymer or copolymers solution using water miscible solvents that is administered in liquid form. Once the composition contacts the body fluids, the polymer matrix hardens retaining the drug, forming a solid or semisolid implant that releases the drug in a continuous manner. Therapeutic plasma levels of the drug can be achieved from the first day up to at least 14 days or more even up to at least four weeks.
Inventor(s):	Ibon GUTIERRO ADURIZ, Maria Teresa Gomez Ochoa
Assignee:	Laboratorios Farmaceuticos Rovi SA
Application Number:	US17/746,647
Patent Claims:	1. A method of treating schizophrenia or bipolar disorder, the method comprising administering risperidone to a human subject in need thereof, wherein said risperidone is administered over a treatment period comprising plural dosing periods, said administering comprising during a first dosing period, administering to said subject by intramuscular injection an extended release injectable suspension consisting essentially of 25-150 mg of particles of risperidone suspended in a polymeric solution of DMSO and PLGA copolymer; and during a second dosing period, administering to said subject by intramuscular injection an extended release injectable suspension consisting essentially of 25-150 mg of particles of risperidone suspended in a polymeric solution of DMSO and PLGA copolymer; wherein the DMSO to risperidone mass ratio is about 4:1 to 5:1; the polymeric solution to risperidone mass ratio is about 6.5:1 to 7:1; the polymeric solution has a viscosity in the range of about 0.7 Pa·s to about 7.0 Pa·s; and the PLGA copolymer has a monomer ratio of lactic acid monomer to glycolic acid monomer of about 50:50 to about 75:25; wherein following said administering, therapeutic plasma levels of risperidone and/or active metabolite 9-OH-risperidone are achieved in the subject from the first day to at least 28 days after said administering, thereby avoiding the need for supplementary oral daily therapy with risperidone within one day of the time of administration. 2. The method of claim 1, wherein a) each dosing period is at least 4 weeks, and said dosing periods are sequential; or b) each dosing period is at least 4 weeks, and said dosing periods overlap by no more than two days. 3. The method of claim 1, wherein following said administering, plasma levels of risperidone and/or active metabolite 9-OH-risperidone achieved in the subject are defined as follows Cmin (ng/ml) Cavg (ng/ml) Cmax (ng/ml) 1-80 3-200 8-300 or a) a substantially level plasma concentration profile for risperidone and/or a metabolite thereof of within ±10% of the average or mean plasma concentration is achieved during a period of at least 14 days following said administering, wherein the average or mean is calculated over the at least 14 days; b) a substantially level plasma concentration profile for risperidone and/or a metabolite thereof of within ±15% of the average or mean plasma concentration is achieved during a period of at least 14 days following said administering, wherein the average or mean is calculated over the at least 14 days; or c) a substantially level plasma concentration profile for risperidone and/or a metabolite thereof of within ±20% of the average or mean plasma concentration is achieved during a period of at least 14 days following said administering, wherein the average or mean is calculated over the at least 14 days. 4. The method of claim 1, wherein following said administering, a) 0.5% wt up to 20% wt of said risperidone is released within 24 hours; b) 0.5% wt up to no more than 8% wt of said risperidone is released within 24 hour; or c) no more than 20% wt, no more than 12% wt, or no more than 8% wt of said risperidone is released within 24 hours, and at least 0.5% wt., at least 2% wt, or at least 3% wt of said risperidone is released within 24 hours. 5. The method of claim 1 further comprising a) dissolving said copolymer in said DMSO to form said polymeric solution and mixing risperidone with said polymeric solution to form said injectable suspension; or b) mixing said copolymer and said risperidone with said DMSO to form said injectable suspension. 6. The method of claim 1, wherein a) an average daily plasma concentration of risperidone and/or 9-OH-risperidone that ranges from about 5 ng/ml to about 80 ng/ml is achieved in said subject during said dosing period when about 116 mg to about 700 mg, respectively, of said suspension comprising about 25 mg to about 150 mg, respectively, of risperidone is administered; or b) an average daily plasma concentration of risperidone and/or 9-OH-risperidone that ranges from about 5 ng/ml to about 150 ng/ml or from about 10 ng/ml to about 100 ng/ml in the steady state is achieved in said subject during said dosing period when about 116 to about 700 mg, respectively, of said suspension comprising about 25 mg to about 150 mg, respectively, of risperidone is administered, wherein the average daily plasma concentration is calculated over said dosing period. 7. The method of claim 1, wherein a) an average Cmin of said risperidone and/or 9-OH-risperidone in the range of about 1-80 ng/ml, about 5-50 ng/ml, or about 5-40 ng/ml is achieved in said subject during said dosing period when an amount of said suspension equivalent to a dose of about 25-150 mg, about 37.5-125 mg, or about 50-100 mg, respectively, of risperidone is administered, wherein the average Cmin is calculated over said dosing period; and/or b) an average Cmax of risperidone and/or active metabolite 9-OH-risperidone in the range of about 8-300 ng/ml, about 10-150 ng/ml, or 10-120 ng/ml is achieved in said subject when an amount of said suspension equivalent to a dose of about 25-150 mg, about 37.5-125 mg, or about 50-100 mg, respectively, of risperidone is administered, wherein the average Cmax is calculated over said dosing period. 8. The method of claim 1, wherein in said subject a plasma concentration profile is achieved for risperidone and/or active metabolite 9-OH-risperidone that a) exhibits one, two or more maxima is achieved; b) exhibits one, two or more minima; c) exhibits a maximum during the initial one to six days, one to three days, or one to two days after administration of said suspension; d) exhibits a maximum during 11 to 13 days or 12 to 14 days after administration of said suspension; e) exhibits a maximum during 14 to 24 days of a 4-week dosing period; or f) is within ±20% of the average or mean plasma concentration during the at least 28-day period following said administration of said suspension, wherein the average or mean plasma concentration is calculated over said at least 28-day period. 9. The method of claim 1 further comprising providing a pharmaceutical kit comprising a) risperidone in a container and said PLGA copolymer in another container; or b) risperidone and said PLGA copolymer in a container. 10. The method of claim 9, wherein said kit further comprises said DMSO in another container. 11. The method of claim 1, wherein ≥ 1% wt and ≤ 20% wt of the risperidone is dissolved in said DMSO or said suspension prior to administration. 12. A method of treating schizophrenia or bipolar disorder, the method comprising by intramuscular injection, administering to a human subject in need thereof a dose of extended release injectable suspension consisting essentially of 25-150 mg of risperidone, wherein in said suspension, particles of risperidone are suspended in a polymeric solution of DMSO and PLGA copolymer; further wherein the DMSO to risperidone mass ratio is about 4:1 to 5:1; the polymeric solution to risperidone mass ratio is about 6.5:1 to 7:1; the polymeric solution has a viscosity in the range of about 0.7 Pa·s to about 7.0 Pa·s; and the PLGA copolymer has a monomer ratio of lactic acid monomer to glycolic acid monomer of about 50:50 to about 75:25. 13. The method of claim 12 further comprising repeating said administering after at least 4 weeks. 14. The method of claim 12, wherein following said administering, therapeutic plasma levels of risperidone and/or active metabolite 9-OH-risperidone are achieved in the subject from the first day to at least 28 days after said administering, thereby avoiding the need for supplementary oral daily therapy with risperidone within one day of the time of administration. 15. The method of claim 12, wherein following said administering, a) 0.5% wt up to 20% wt of said risperidone is released within 24 hours; b) 0.5% wt up to no more than 8% wt of said risperidone is released within 24 hour; or c) no more than 20% wt, no more than 12% wt, or no more than 8% wt of said risperidone is released within 24 hours, and at least 0.5% wt., at least 2% wt, or at least 3% wt of said risperidone is released within 24 hours. 16. The method of claim 12 further comprising a) dissolving said copolymer in said DMSO to form said polymeric solution and mixing risperidone with said polymeric solution to form said suspension; or b) mixing said copolymer and said risperidone with said DMSO to form said suspension. 17. The method of claim 12, wherein a) an average daily plasma concentration of risperidone and/or 9-OH-risperidone that ranges from about 5 ng/ml to about 80 ng/ml is achieved in said subject during said dosing period when about 116 mg to about 700 mg, respectively, of said suspension comprising about 25 mg to about 150 mg, respectively, of risperidone is administered; or b) an average daily plasma concentration of risperidone and/or 9-OH-risperidone that ranges from about 5 ng/ml to about 150 ng/ml or from about 10 ng/ml to about 100 ng/ml in the steady state is achieved in said subject during said dosing period when about 116 to about 700 mg, respectively, of said suspension comprising about 25 mg to about 150 mg, respectively, of risperidone is administered, wherein the average daily plasma concentration is calculated over said dosing period. 18. The method of claim 12, wherein a) an average Cmin of said risperidone and/or 9-OH-risperidone in the range of about 1-80 ng/ml, about 5-50 ng/ml, or about 5-40 ng/ml is achieved in said subject during said dosing period when an amount of said suspension equivalent to a dose of about 25-150 mg, about 37.5-125 mg, or about 50-100 mg, respectively, of risperidone is administered, wherein the average Cmin is calculated over said dosing period; and/or b) an average Cmax of risperidone and/or active metabolite 9-OH-risperidone in the range of about 8-300 ng/ml, about 10-150 ng/ml, or 10-120 ng/ml is achieved in said subject when an amount of said suspension equivalent to a dose of about 25-150 mg, about 37.5-125 mg, or about 50-100 mg, respectively, of risperidone is administered, wherein the average Cmax is calculated over said dosing period. 19. The method of claim 12, wherein in said subject a plasma concentration profile is achieved for risperidone and/or active metabolite 9-OH-risperidone that a) exhibits one, two or more maxima; b) exhibits one, two or more minima; c) exhibits a maximum during the initial one to six days, one to three days, or one to two days after administration of said suspension; d) exhibits a maximum during 11 to 13 days or 12 to 14 days after administration of said suspension; e) exhibits a maximum during 14 to 24 days of a 4-week dosing period; or f) is within ±20% of the average or mean plasma concentration during the at least 28-day period following said administration of said suspension, wherein the average or mean plasma concentration is calculated over said at least 28-day period. 20. The method of claim 12, wherein in said subject a plasma concentration profile is achieved for risperidone and/or its active metabolite 9-OH-risperidone that is within ±15% of the average or mean plasma concentration during the period of at least 14 days following administration of said suspension, wherein the average or mean plasma concentration is calculated over said at least 14-day period. 21. The method of claim 12 further comprising providing a pharmaceutical kit comprising a) risperidone in a container and said PLGA copolymer in another container; or b) risperidone and said PLGA copolymer in a container. 22. The method of claim 21, wherein said kit further comprises said DMSO in another container. 23. The method of claim 12, wherein ≥ 1% wt and ≤ 20% wt of the risperidone is dissolved in said DMSO or said suspension prior to administration. 24. A method of treating schizophrenia or bipolar disorder, the method comprising providing a kit comprising a) a first container containing PLGA copolymer and risperidone; and b) a second container containing DMSO; mixing contents of said first container and said second container to form an extended release injectable suspension consisting essentially of particles of risperidone suspended in a polymeric solution of said DMSO and said PLGA copolymer; and administering to said subject by intramuscular injection a dose of said suspension comprising 25-150 mg of said risperidone; wherein, in said dose, the DMSO to risperidone mass ratio is about 4:1 to 5:1; the polymeric solution to risperidone mass ratio is about 6.5:1 to 7:1; the polymeric solution has a viscosity in the range of about 0.7 Pa·s to about 7.0 Pa·s; and the PLGA copolymer has a monomer ratio of lactic acid monomer to glycolic acid monomer of about 50:50 to about 75:25. 25. The method of claim 24, further comprising a) at least 4 weeks after said administering, administering to said subject by intramuscular injection another said dose; or b) every at least for weeks, administering to said subject by intramuscular injection another said dose. 26. The method of claim 24, wherein said suspension forms an extended release depot after administration. 27. The method of claim 1, wherein said suspension forms an extended release depot after administration. 28. The method of claim 12, wherein said suspension forms an extended release depot after administration. 29. The method of claim 8, wherein in said subject a plasma concentration profile is achieved for risperidone and/or active metabolite 9-OH-risperidone that exhibits a maximum during the initial one to two days after administration of said suspension and exhibits a maximum during 14 to 24 days of a 4-week dosing period. 30. The method of claim 19, wherein in said subject a plasma concentration profile is achieved for risperidone and/or active metabolite 9-OH-risperidone that exhibits a maximum during the initial one to two days after administration of said suspension and exhibits a maximum during 14 to 24 days of a 4-week dosing period.