Claims for Patent: 10,849,894

Summary for Patent: 10,849,894

Title:	Aripiprazole prodrug composition
Abstract:	Described is a composition comprising (a) a population of particles of an aripiprazole prodrug having a volume based particle size (Dv50) of less than 1000 nm and (b) at least one surface stabilizer comprising an adsorbed component which is adsorbed on the surface of the aripiprazole prodrug particles and a free component available for solubilisation of the aripiprazole prodrug. The surface stabilizer to prodrug ratio provides the optimal quantity of free surface stabilizer for the purposes of producing a lead-in formulation. Also described are methods of treatment using the aforementioned composition.
Inventor(s):	Cresswell; Philip (Athlone, IE), Hickey; Magali (Westwood, MA), Perkin; Kristopher (Athlone, IE), Smith; Greg (Norton, MA), Liversidge; Elaine (Charlestown, MA), Steinberg; Brian (Arlington, MA), Manser; David (Keenagh, IE), Zeidan; Tarek (Waltham, MA)
Assignee:	ALKERMES PHARMA IRELAND LIMITED (Dublin, IE)
Application Number:	16/024,729
Patent Claims:	1. A method of treating a mammal having a condition selected from the group consisting of schizophrenia, bipolar I disorder, major depressive disorder (MDD), autistic disorder, agitation associated with schizophrenia, and bipolar I disorder, wherein the method comprises administering a composition comprising: (a) a population of particles of an aripiprazole prodrug having a volume based particle size (Dv50) of between 50 and 700 nm as determined by light scattering techniques, and (b) at least one surface stabilizer comprising an adsorbed component which is adsorbed on the surface of the aripiprazole prodrug particles and a free component available for solubilisation of the aripiprazole prodrug, wherein the ratio of aripiprazole prodrug to surface stabilizer is about 17:1, and wherein the aripiprazole prodrug has the formula: ##STR00005## where n is zero or an integer less than 20; and wherein the at least one surface stabilizer is selected from the group consisting of carboxymethyl cellulose and polyoxyethylene sorbitan fatty acid esters. 2. The method of claim 1, wherein said treatment further comprises administering a second composition of aripiprazole prodrug having a volume based particle size (Dv50) of greater than about 5000 nm to the mammal. 3. The method of claim 1, wherein the composition comprises polysorbate 20, a chelating agent, a tonicity agent, an aqueous buffer, and a population of particles of the formula: ##STR00006## wherein the population of particles has a volume based particle distribution size (Dv50) between about 350 nm and about 175 nm as determined by light scattering techniques, and wherein the ratio of the particles to polysorbate 20 is 17:1. 4. The method of claim 3, wherein the chelating agent is sodium citrate. 5. The method of claim 3, wherein the tonicity agent is sodium chloride. 6. The method of claim 1, wherein the composition comprises polysorbate 20, sodium citrate, sodium chloride, an aqueous buffer, and a population of particles of the formula: ##STR00007## where the population of particles has a volume based particle distribution size (Dv50) between about 350 nm and about 175 nm as determined by light scattering techniques, and wherein the ratio of the particles to polysorbate 20 is 17:1. 7. The method of claim 1, wherein the composition comprises: (a) 26 weight percent of a compound of the following formula: ##STR00008## (b) 1.53 weight percent polysorbate 20; (c) 0.76 weight percent sodium citrate; (d) 0.31 weight percent sodium chloride; (e) 0.15 weight percent sodium phosphate buffer; (f) 71.25 weight percent water for injection; and wherein the compound is provided as a population of particles having a volume based particle distribution size (Dv50) of 100 nm or 200 nm as determined by light scattering techniques. 8. The method of claim 1, wherein n is 4 or 10. 9. The method of claim 1, wherein the volume based particle size distribution (Dv50) of the aripiprazole prodrug particles is between 175 nm and 350 nm. 10. The method of claim 1, wherein the at least one surface stabilizer is a polyoxyethylene sorbitan fatty acid ester. 11. The method of claim 1, wherein the at least one surface stabilizer is polysorbate 20. 12. The method of claim 1, wherein the free component of the at least one surface stabilizer constitutes greater than 0% (w/w) and no more than 3% (w/w) of the composition. 13. The method of claim 1, wherein the method comprises a primary surface stabilizer and at least one secondary surface stabilizer. 14. The method of claim 1, wherein the composition is administered as a depot injection. 15. The method of claim 1, wherein the composition is provided in an injection device, wherein the injection device is selected from the group consisting of a pre-filled syringe, an auto-injector, a needleless syringe, and a dual chambered syringe. 16. The method of claim 15, wherein the composition is provided in one chamber of the dual chambered syringe, and the other chamber of the dual chambered syringe is provided with a second composition. 17. The method of claim 1, wherein the composition is formulated as a powder for reconstitution in a liquid medium, wherein the population or aripiprazole prodrug particles redisperse in the liquid medium such that the redispersed aripiprazole prodrug particles have a volume based particle size (Dv50) of less than 1000 nm. 18. The method of claim 1, wherein the method comprises administering an additional atypical antipsychotic other than the aripiprazole prodrug. 19. The method of claim 1, wherein the viscosity of the composition is below 0.1 Pas (10 cP) at a shear rate of 100 s.sup.-1, when measured at a temperature of 25.degree. C. 20. The method of claim 1, wherein the composition comprises a dispersion medium in which the population of aripiprazole prodrug particles is dispersed, wherein the free component of the surface stabilizer is dissolved or otherwise dispersed within the dispersion medium. 21. The method of claim 1, wherein the composition comprises a population of particles of the formula: ##STR00009## having a volume based particle distribution size (Dv50) of between 350 nm and 175 nm as determined by light scattering techniques, wherein the ratio of said particles to polysorbate 20 is about 17:1.