Claims for Patent: 10,058,504

Summary for Patent: 10,058,504

Title:	Methods for the preparation of injectable depot compositions
Abstract:	Injectable depot compositions, comprising a biocompatible polymer which is a polymer or copolymer based on lactic acid and/or lactic acid plus glycolic acid having a monomer ratio of lactic to glycolic acid in the range from 48:52 to 100:0, a water-miscible solvent having a dipole moment of about 3.7-4.5 D and a dielectric constant of between 30 and 50, and a drug, were found suitable for forming in-situ biodegradable implants which can evoke therapeutic drug plasma levels from the first day and for at least 14 days.
Inventor(s):	Ibon GUTIERRO ADURIZ, Maria Teresa Gomez Ochoa
Assignee:	Laboratorios Farmaceuticos Rovi SA
Application Number:	US13/690,707
Patent Claims:	1. An injectable depot composition consisting of risperidone, and a polymeric solution of DMSO and PLGA copolymer, wherein: the content of risperidone is 13% wt±10%, based upon the weight of the composition, and the risperidone possesses a particle distribution selected from: a. not more than 10% of the total volume of the particles is smaller than 10 microns, not more than the 10% of the total volume of particles is greater than 225 microns, and the d0.5 is in the range of 10-200 microns; b. not more than 10% of the total volume of the particles is less than the range 1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-400 μm, and the d0.5 of the size distribution is in the range of about 40-200 μm; or c. expressed as volume, d0.9 is about 150 to about 400 μm, d0.5 is about 40 to about 200 μm and d0.1 is about 10 to about 60 μm; the mass ratio of DMSO to risperidone is 4.66±10%:1; the mass ratio of polymeric solution to risperidone is about 6.66±10%:1; the PLGA copolymer is an end-capped biodegradable poly(lactide-co-glycolide) copolymer having a monomer ratio of lactic acid to glycolic acid of 50:50 and an inherent viscosity in the range of 0.20±10% dl/g to 0.50±10% dl/g as measured in chloroform at 25° C. at a concentration of 0.1% wt/v with a Ubbelohde size 0c glass capillary viscometer; the polymeric solution has a viscosity in the range of 0.5-3.0 Pa·s; and the amount of risperidone dissolved in the injectable composition is 20% wt. 2. The injectable depot composition according to claim 1, wherein the composition is a sterilized composition. 3. The injectable depot composition according to claim 2, wherein the sterilization has been carried out by sterilizing at least one of the drug and the biocompatible polymer by beta-irradiation in the range 5-25 KGy. 4. A pharmaceutical kit suitable for preparation of the injectable depot composition according to claim 1, the kit comprising: a first container comprising the PLGA copolymer; and a second container comprising the DMSO; and wherein the risperidone is present in the first container, second container or a third container, whereby mixing of the PLGA copolymer, DMSO and risperidone results in formation of the injectable depot composition. 5. The injectable depot composition according to claim 1, wherein the viscosity of the injectable composition is in the range of about 0.7 Pa·s to about 4.0 Pa·s. 6. The injectable depot composition according to claim 1, wherein a) the PLGA copolymer has been exposed to 5 to 25 KGy of beta-radiation sufficient to sterilize the PLGA copolymer prior to inclusion in the injectable composition or prior to addition of the DMSO; or b) the PLGA copolymer has been exposed to 10-25 KGy of beta-radiation sufficient to reduce the molecular weight of the PLGA copolymer prior to inclusion in the injectable composition or prior to addition of the DMSO, and thereby the intrinsic viscosity thereof. 7. The injectable depot composition according to claim 1, wherein the composition is injectable by hand through a 18 to 22 gauge needle. 8. The injectable depot composition according to claim 1, wherein the composition forms a biodegradable solid single body implant in situ in a subject to which it is administered. 9. The injectable depot composition of claim 1, wherein the composition releases at least 0.5% wt and no more than 8% wt of its charge of risperidone within 24 hours after being placed in an aqueous environment. 10. The injectable depot composition of claim 1, wherein the composition provides a substantially level plasma profile, for the risperidone, and/or metabolite thereof, of within ±15% of the average or mean during a period of at least 14 days following administration of the composition to a subject, wherein the average or mean is calculated over the 14 days. 11. The injectable depot composition of claim 10, wherein the composition provides a plasma profile, for the risperidone, and/or metabolite thereof, defined as follows: Dose (mg) Cmin (ng/ml) Cavg (ng/ml) Cmax (ng/ml) 25-150 1-80 3-200 8-300 during a dosing period of at least 14 days following administration to a subject of an amount of the injectable composition equivalent to the dose indicated. 12. The injectable depot composition of claim 1, wherein the composition provides a substantially level plasma profile, for the risperidone, and/or metabolite thereof, of within ±20% of the average or mean during a dosing period of at least 28 days following administration of the composition to a subject, wherein the average or mean is calculated over the 28 days. 13. The injectable depot composition of claim 1, wherein the composition provides a substantially level plasma profile, for the risperidone, and/or metabolite thereof, of within ±10% of the average or mean during a period of at least 14 days following administration of the composition to a subject, wherein the average or mean is calculated over the 14 days.