Sustained delivery formulations of risperidone compounds
The present invention relates to a risperidone sustained release delivery system for treatment of medical conditions relating delusional psychosis, schizophrenia, bipolar disorder, psychotic depression, obsessive-compulsion disorder, Tourette syndrome, and autistic spectrum disorders. The sustained release delivery system includes a flowable composition containing risperidone, a metabolite, or a prodrug thereof and an implant containing risperidone, a metabolite, or a prodrug thereof. The flowable composition may be injected into tissue whereupon it coagulates to become the solid or gel, monolithic implant. The flowable composition includes a biodegradable, thermoplastic polymer, an organic liquid, and risperidone, a metabolite, or a prodrug thereof.
1. A flowable composition comprising: 10 wt % to 20 wt % of risperidone base in a solution comprising (i) 40 wt % to 50 wt % of an 80/20 poly(DL-lactide-co-glycolide) with a carboxylic acid end group, and (ii) 50 wt % to 60 wt % of N-methyl-2-pyrrolidone.
2. The composition of claim 1 , comprising about 60 mg of risperidone base.
3. The composition of claim 1 , comprising about 90 mg of risperidone base.
4. The composition of claim 1 , comprising about 120 mg of risperidone base.
5. The composition of claim 1 , wherein the composition produces a maximum plasma concentration (C max ) of risperidone and/or 9-hydroxyrisperidone within about 2 hours after injection into a patient.
6. The composition of claim 1 , wherein the composition produces a steady state plasma level of risperidone and/or 9-hydroxyrisperidone within about three days after injection into a patient.
7. The composition of claim 1 , wherein the composition produces a risperidone and/or 9-hydroxyrisperidone concentration of at least 15.8 ng/mL for about 28 days after injection into a patient.
8. The composition of claim 1 , wherein the composition produces a linear sustained release of risperidone and/or 9-hydroxyrisperidone for at least 28 days.
9. The composition of claim 1 , consisting of the risperidone base, the 80/20 poly(DL-lactide-co-glycolide) with the carboxylic acid end group, and the N-methyl-2-pyrrolidone.
10. The composition of claim 1 , consisting of the risperidone base, the 80/20 poly(DL-lactide-co-glycolide) with the carboxylic acid end group, and the N-methyl-2-pyrrolidone.
11. The composition of claim 1 , wherein the composition produces a steady state plasma level of risperidone and/or 9-hydroxyrisperidone from about three days to about forty-two days after injection into a patient.
12. The composition of claim 11 , wherein the steady state plasma level of risperidone and/or 9-hydroxyrisperidone is from about 28.9 ng/ml to about 50.7 ng/ml.
13. The composition of claim 1 , wherein the composition provides an AUC Dayo-1 of risperidone and/or 9-hydroxyrisperidone from about 63.1 ng·day/ml to about 111.7 ng·day/ml.
14. The composition of claim 1 , wherein the composition provides an AUC Day0-42 of risperidone and/or 9-hydroxyrisperidone from about 1243.3 ng·day/ml to about 2238.9 ng·day/ml.
15. The composition of claim 1 , wherein the composition provides an AUC Day0-56 of risperidone and/or 9-hydroxyrisperidone from about 1417.6 ng·day/ml to about 3049.2 ng·day/ml.
16. The composition of claim 1 , wherein a dose normalized AUC Day0-42 of risperidone and/or 9-hydroxyrisperidone from about 15.9 ng·day/ml·mg to about 20.9 ng·day/ml·mg.
17. The composition of claim 1 having a volume from about 0.75 ml to about 1.0 ml.
18. A flowable composition comprising: (i) 1 wt % to 30 wt % of risperidone base; (ii) 20 wt % to 60 wt % of an 80/20 poly(DL-lactide-co-glycolide) with a carboxylic acid end group; and (iii) 30 wt % to 70 wt % of N-methyl-2-pyrrolidone.
19. The composition of claim 18 , wherein the composition provides a linear sustained release of risperidone and/or 9-hydroxyrisperidone for at least 28 days.
20. The composition of claim 18 , comprising about 60 mg to about 120 mg of risperidone base.
21. The composition of claim 18 , wherein the composition provides (i) a maximum plasma concentration (C max ) of risperidone and/or 9-hydroxyrisperidone occurs within about 2 hours after injection into a patient and (ii) a linear sustained release of risperidone and/or 9-hydroxyrisperidone for at least 28 days after injection into a patient.
22. The composition of claim 18 , wherein the composition provides a risperidone and/or 9-hydroxyrisperidone concentration of at least 15.8 ng/mL for at least 28 days after injection into a patient.
23. The composition of claim 18 , wherein the composition produces a steady state plasma level of risperidone and/or 9-hydroxyrisperidone about three days after injection into a patient.
24. The composition of claim 18 , wherein the composition produces a risperidone or 9-hydroxyrisperidone concentration of at least 15.8 ng/mL for at least 28 days after injection into a patient.
25. The composition of claim 18 , consisting of the risperidone base, the 80/20 poly(DL-lactide-co-glycolide) with the carboxylic acid end group, and the N-methyl-2-pyrrolidone.
26. The composition of claim 18 having a volume from about 0.75 ml to about 1.0 ml.
27. A method of forming a biodegradable implant in situ in a patient in need thereof comprising the steps of:
(a) injecting the flowable composition of claim 1 into the body of the patient; and
(b) allowing the N-methyl-2-pyrrolidone to dissipate to produce the implant in the body of the patient.
28. A composition comprising about 15 wt % of risperidone base in a solution comprising: (i) about 45 wt % of an 80/20 poly(DL-lactide-co-glycolide) with a carboxylic acid end group; and (ii) about 55 wt % of N-methyl-2-pyrrolidone.
29. The composition of claim 28 , comprising about 60 mg of risperidone base.
30. The composition of claim 28 , comprising about 90 mg of risperidone base.
31. The composition of claim 28 , comprising about 120 mg of risperidone base.
32. The composition of claim 28 having a volume from about 0.75 ml to about 1.0 ml.