Claims for Patent: 11,241,377

Summary for Patent: 11,241,377

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):	Gutierro Aduriz Ibon, Gomez Ochoa Maria Teresa
Assignee:	LABORATORIOS FARMACEUTICOS ROVI S.A.
Application Number:	US16656167
Patent Claims:	1. A method of administering risperidone to a human subject in need thereof , the method comprisingadministering to said subject by intramuscular injection an injectable depot composition consisting essentially of 25-150 mg of risperidone suspended in a polymeric solution of solvent DMSO and PLGA copolymer, thereby forming a solid implant at the injection site in the muscle of said human subject;wherein during the month following said administering, said implant provides therapeutic plasma levels of risperidone and/or its active metabolite 9-OH-risperidone from the first day to at least 28 days after administration; and whereinthe 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; andthe PLGA copolymer has a monomer ratio of lactic acid monomer to glycolic acid monomer of about 50:50 to about 75:25.2. The method ofwherein during the month following said administering, said implant provides therapeutic plasma levels of risperidone and/or its active metabolite 9-OH-risperidone from the first day to at least 28 days after administration thereby avoiding the need for supplementary oral daily therapy with risperidone within one day of the time of administration.3. The method of claim 1 , wherein said implant releases 0.5% wt up to 20% wt of its charge of risperidone within 24 hours after administration of said composition claim 1 , or wherein said implant releases 0.5% wt up to no more than 8% wt of its charge of risperidone within 24 hours after administration of said composition.4. The method of claim 1 , wherein said implant releases a) no more than 20% wt claim 1 , no more than 12% wt claim 1 , or no more than 8% wt of its charge of risperidone within 24 hours after administration of said composition claim 1 , and b) at least 0.1% wt claim 1 , at least 0.5% wt. claim 1 , at least 2% wt claim 1 , or at least 3% wt of its charge of risperidone within 24 hours after administration of said composition.5. The method of further comprising: a) dissolving said polymer in said solvent to form said polymeric solution and mixing risperidone with said polymeric solution to form said injectable depot composition; or b) mixing said polymer and said risperidone with said solvent to form said injectable depot composition.6. The method ofwherein during the month following said administering, said implant provides an average daily plasma concentration of risperidone and/or its active metabolite 9-OH-risperidone that ranges from about 5 ng/ml to about 80 ng/ml when about 116 mg to about 700 mg, respectively, of said composition comprising about 25 mg to about 150 mg, respectively, of risperidone is administered.7. The method ofwherein during the month following said administering, said implant provides an average daily plasma concentration of risperidone and/or its active metabolite 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 when about 116 to about 700 mg, respectively, of said composition comprising about 25 mg to about 150 mg, respectively, of risperidone is administered.8. The method ofwherein during the month following said administering, said implant provides an average daily Cmin of risperidone and/or its active metabolite 9-OH-risperidone in the range of about 1-80 ng/ml, about 5-50 ng/ml, or about 5-40 ng/ml when an amount of said injectable composition equivalent to a dose of about 25-150 mg, about 37.5-125 mg, or about 50-100 mg, respectively, of risperidone is administered.9. The method of wherein during the month following said administering claim 1 , said implant provides an average Cmax of risperidone and/or its active metabolite 9-OH-risperidone in the range of about 8-300 ng/ml claim 1 , about 10-150 ng/ml claim 1 , or 10-120 ng/ml when an amount of said injectable composition equivalent to a dose of about 25-150 mg claim 1 , about 37.5-125 mg claim 1 , or about 50-100 mg claim 1 , respectively claim 1 , of risperidone is administered.10. The method of claim 1 , wherein said implant provides a plasma concentration profile for risperidone and/or its active metabolite 9-OH-risperidone that a) exhibits one claim 1 , two or more maxima; b) exhibits one claim 1 , two or more minima; c) exhibits a maximum during the initial one to six days claim 1 , one to three days claim 1 , or one to two days after administration of said composition; d) exhibits a maximum during 11 to 13 days or 12 to 14 days after administration of said composition; 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 composition.11. The method of claim 1 , wherein said implant provides a plasma concentration profile 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 composition.12. The method of further comprising providing a pharmaceutical kit comprising risperidone in a container and said biodegradable polymer in a container.13. The method of further comprising sterilizing said risperidone and biodegradable polymer by irradiation.14. The method of claim 1 , wherein ≥1% wt and ≤20% wt of the risperidone is dissolved in said solvent DMSO or said injectable composition prior to administration.15. A method of administering risperidone to a human subject in need thereof claim 1 , the method comprisingadministering to said subject by intramuscular injection an injectable depot composition consisting essentially of 25-150 mg of risperidone freebase, or metabolite, salt, or prodrug thereof, said metabolite, salt or prodrug thereof having a water solubility of less than or about 2 mg/ml, suspended in a polymeric solution of DMSO and PLGA copolymer, thereby forming a solid implant at the injection site in the muscle of said subject;wherein during the month following said administering, said implant provides therapeutic plasma levels of risperidone and/or its active metabolite 9-OH-risperidone from the first day to at least 28 days after administration thereby avoiding the need for supplementary oral daily therapy with risperidone within one day of the time of administration; and whereinthe 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; andthe PLGA copolymer has a monomer ratio of lactic acid monomer to glycolic acid monomer of about 50:50 to about 75:25.16. A method of administering risperidone to a human subject in need thereof claim 1 , the method comprisingproviding a kit comprising a) a first container comprising reconstitutablo PLGA copolymer and 25-150 mg of risperidone; and b) a second container comprising DMSO solvent;mixing the contents of said first container and said second container to form an injectable depot composition comprising risperidone suspended in a polymeric solution of said DMSO and said PLGA copolymer;administering to said subject by intramuscular injection said injectable depot composition, thereby forming a solid implant at the injection site in the muscle of said subject;{'b': '28', 'wherein during the month following said administering, said implant provides therapeutic plasma levels of risperidone and/or its active metabolite 9-OH-risperidone from the first day to at least days after administration thereby avoiding the need for supplementary oral daily therapy with risperidone within one day of the time of administrations; and 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; andthe PLGA copolymer has a monomer ratio of lactic acid monomer to glycolic acid monomer of about 50:50 to about 75:25.17. The method of claim 16 , wherein said composition comprises a dose of about 37.5-125 mg claim 16 , about 50-100 mg claim 16 , about 25 mg claim 16 , about 37.5 mg claim 16 , about 50 mg claim 16 , about 100 mg claim 16 , about 125 mg claim 16 , or about 150 mg of risperidone.18. The method of claim 1 , wherein the risperidone /copolymer mass ratio is about 33% claim 1 , expressed as the weight percentage of the risperidone with respect to the risperidone plus copolymer.19. The method of claim 16 , wherein the risperidone /copolymer mass ratio is about 33% claim 16 , expressed as the weight percentage of the risperidone with respect to the risperidone plus copolymer.20. The method of claim 16 , wherein ≥1% wt and ≤20% wt of the risperidone is dissolved in said DMSO or said injectable composition prior to administration.