POLYMERIC DELIVERY FORMULATIONS OF LEUPROLIDE WITH IMPROVED EFFICACY
The present invention is directed to a flowable composition that is suitable for use as a controlled release implant. The flowable composition includes a biodegradable thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid. The flowable composition also includes a biocompatible polar aprotic solvent. The biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid. The flowable composition also includes leuprolide acetate.
1 . (canceled)
2 - 46 . (canceled)
47 . A method of treating precocious puberty in a patient comprising administering to the patient in need of such treatment or prevention an effective amount of a flowable composition suitable for use as a controlled release implant, the composition comprising:
(a) a biodegradable thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid;
(b) a biocompatible polar aprotic solvent selected from the group consisting of an amide, an ester, a carbonate, a ketone, an ether, and a sulfonyl; wherein the biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid; and
(c) leuprolide acetate.
48 . The method of claim 47 wherein the biodegradable thermoplastic polyester is a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, or any combination thereof.
49 . The method of claim 47 wherein the biodegradable thermoplastic polyester is a polylactide, a polyglycolide, a copolymer thereof, a terpolymer thereof, or a combination thereof.
50 . The method of claim 49 wherein the biodegradable thermoplastic polyester includes a diol and has only hydroxyl terminal groups.
51 . The method of claim 47 wherein the biodegradable thermoplastic polyester is 50/50 poly (DL-lactide-co-glycolide) having a carboxy terminal group.
52 . The method of claim 47 wherein the biodegradable thermoplastic polyester is 75/25 poly (DL-lactide-co-glycolide) without a carboxy terminal group.
53 . The method of claim 47 wherein the biodegradable thermoplastic polyester has an average molecular weight of about 23,000 to about 45,000 or about 15,000 to about 24,000.
54 . The method of claim 47 wherein the biocompatible polar aprotic solvent is N-methyl-2-pyrrolidone, 2-pyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin, or any combination thereof.
55 . The method of claim 47 wherein the biocompatible polar aprotic solvent is N-methyl-2-pyrrolidone.
56 . The method of claim 47 wherein the biocompatible polar aprotic solvent is present in about 60 wt. % to about 70 wt. % of the composition.
57 . The method of claim 47 wherein the biocompatible polar aprotic solvent is present in about 50 wt. % to about 60 wt. % of the composition.
58 . The method of claim 47 wherein the leuprolide acetate is present in about 2 wt. % to about 4 wt. % of the composition.
59 . The method of claim 47 wherein the leuprolide acetate is present in about 4 wt. % to about 8 wt. % of the composition.
60 . The method of claim 47 wherein the composition is formulated as an injectable subcutaneous delivery system.
61 . The method of claim 60 wherein the composition has a volume of about 0.20 mL to about 0.40 mL.
62 . The method of claim 60 wherein the composition has a volume of about 0.30 mL to about 0.50 mL.
63 . The method of claim 60 wherein the composition is formulated for administration about once per month.
64 . The method of claim 60 wherein the composition is formulated for administration about once per three months.
65 . The method of claim 60 wherein the composition is formulated for administration about once per four months to about once per six months.
66 . The method of claim 47 wherein the patient is a human.
67 . A method of reducing LHRH levels in a patient exhibiting precocious puberty comprising administering to the patient in need of such LHRH reduction an effective amount of a flowable composition of a flowable composition suitable for use as a controlled release implant, the composition comprising:
(a) a biodegradable thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid;
(b) a biocompatible polar aprotic solvent selected from the group consisting of an amide, an ester, a carbonate, a ketone, an ether, and a sulfonyl; wherein the biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid; and
(c) leuprolide acetate.
68 . A biodegradable implant formed in situ, in a patient exhibiting precocious puberty, by the steps comprising:
(a) injecting a composition within the body of the patient; and
(b) allowing the biocompatible polar aprotic solvent to dissipate to produce a solid biodegradable implant, wherein the composition comprises an effective amount of a biodegradable thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid; an effective amount of a biocompatible polar aprotic solvent selected from the group consisting of an amide, an ester, a carbonate, a ketone, an ether, and a sulfonyl, wherein the biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid; and an effective amount of leuprolide acetate;
the implant retarding, ameliorating or preventing precocious puberty.
69 . The biodegradable implant of claim 68 wherein the patient is a human.
70 . The biodegradable implant of claim 68 wherein the solid implant releases the effective amount of leuprolide as the solid implant biodegrades in the patient.
71 . The biodegradable implant of claim 68 wherein the solid biodegradable implant adheres to tissue within the body of the patient.
72 . A kit for the treatment of precocious puberty comprising:
(a) a first container comprising a composition comprising a biodegradable thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid and a biocompatible polar aprotic solvent selected from the group consisting of an amide, an ester, a carbonate, a ketone, an ether, and a sulfonyl; wherein the biocompatible polar aprotic solvent is miscible to dispersible in aqueous medium or body fluid; and
(b) a second container comprising leuprolide acetate.
73 . The kit of claim 72 wherein the first container is a syringe.
74 . The kit of claim 72 wherein the second container is a syringe.
75 . The kit of claim 72 wherein the leuprolide acetate is lyophilised.
76 . The kit of claim 72 further comprising instructions.
77 . The kit of claim 72 wherein the first container can be connected to the second container.
78 . The kit of claim 72 wherein the first container and the second container are each configured to be directly connected to each other.
79 . A solid implant for treatment of precocious puberty comprising:
(a) a biocompatible thermoplastic polyester that is at least substantially insoluble in aqueous medium or body fluid; and
(b) leuprolide acetate; wherein
the solid implant has a solid or gelatinous microporous matrix, the matrix being a core surrounded by a skin and the solid implant is present in a patient exhibiting precocious puberty;
the implant retarding, ameliorating or preventing precocious puberty.
80 . The solid implant of claim 79 further comprising a biocompatible organic solvent that is miscible to dispersible in aqueous or body fluid and dissolves the thermoplastic polyester.
81 . The solid implant of claim 80 wherein the amount of biocompatible organic solvent is minimal.
82 . The solid implant of claim 80 wherein the amount of biocompatible organic solvent decreases over time.
83 . The solid implant of claim 79 wherein the core contains pores of diameters from about 1 to about 1000 microns.
84 . The solid implant of claim 79 wherein the skin contains pores of smaller diameters than those of the core pores.
85 . The solid implant of claim 79 wherein the skin pores are of a size such that the skin is functionally non-porous in comparison with the core.