Risperidone or paliperidone implant formulation
The present invention is directed to an injectable intramuscular depot composition suitable for forming an in situ solid implant in a body, comprising a drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination, a biocompatible copolymer based on lactic and glycolic acid having a monomer ratio of lactic to glycolic acid of about 50:50 and a DMSO solvent, wherein the composition releases the drug with an immediate onset of action and continuously for at least 4 weeks and wherein the composition has a pharmacokinetic profile in vivo that makes it suitable to be administered each 4 weeks or even longer periods.
1. An injectable composition consisting of
about 13% wt of drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination; and
a polymeric solution consisting of DMSO and biocompatible poly(lactide-co-glycolide) (PLGA) copolymer having a monomer ratio of lactic acid to glycolic acid of about 50:50 and an inherent viscosity in the range of 0.25-0.30 dl/g measured by gel permeation chromatography in tetrahydrofuran at 30° C. using a flow rate of 1 ml/min; wherein
the mass ratio of polymeric solution to drug is about 6.5:1 to about 7:1; and
the mass ratio of DMSO to drug is about 4:1 to about 5:1.
2. A pharmaceutical kit suitable for the in situ formation of a biodegradable implant in a body comprising the injectable composition of claim 1 , wherein, prior to mixing, the drug and the biocompatible copolymer are contained in a first container, and the solvent is contained in a second, separate container.
3. The pharmaceutical kit according to claim 2 , wherein at least one of the first and second containers is a syringe, a vial, or a cartridge.
4. The injectable composition of claim 1 , wherein the biocompatible copolymer is an irradiated biocompatible copolymer that has been irradiated with beta-radiation.
5. The injectable composition of claim 1 , wherein the particle size distribution of the drug is described by at least one of the following distributions
Parameter
Dist. I
Dist. III
Dist. V
d0.1 (microns)
27.49
17.41
≤10
d0.5 (microns)
79.90
51.61
40-130
d0.9 (microns)
176.66
175.32
>225.
6. The injectable composition of claim 1 , wherein the injectable composition releases no more than 20% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.
7. The injectable composition of claim 1 , wherein the injectable composition releases at least 0.1% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.
8. The composition of claim 1 , wherein ≤20% wt of the drug is dissolved in the DMSO or polymeric solution to form the injectable composition.
9. The injectable composition of claim 1 , wherein the copolymer is end-capped.
10. The injectable composition of claim 1 , wherein the particle size distribution of the drug is selected from
a) not more than 10% of the total volume of the particles are smaller than 10 microns, and not more than the 10% of the total volume of particles are greater than 225 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;
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;
d) not more than 10% of the total volume of the particles is less than the range 0.1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-1000 μm, and the d0.5 of the size distribution is in the range of about 10-1000 μm;
e) not more than 10% of the total volume of the particles is less than the range 0.5-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-700 μm, and the d0.5 of the size distribution is in the range of about 20-700 μm; or
f) 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.
11. The injectable composition of claim 1 , wherein the monomer ratio of lactic acid to glycolic acid ranges from 48:52 to 52:48.
12. An injectable composition consisting of
about 13% wt of drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination;
DMSO; and
biocompatible poly(lactide-co-glycolide) (PLGA) copolymer having a monomer ratio of lactic acid to glycolic acid of about 50:50 and an inherent viscosity in the range of 0.26-0.29 dl/g measured by gel permeation chromatography in tetrahydrofuran at 30° C. using a flow rate of 1 ml/min; wherein
the mass ratio of drug to (polymer+drug) is about 33%, expressed as the percentage of the drug weight with respect to total weight of the drug plus polymer; and
the mass ratio of DMSO to drug is about 4.66:1.
13. The injectable composition of claim 12 , wherein the biocompatible copolymer is an irradiated biocompatible copolymer that has been irradiated with beta-radiation.
14. The injectable composition of claim 12 , wherein the injectable composition releases no more than 20% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.
15. The injectable composition of claim 12 , wherein the injectable composition releases at least 0.1% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.
16. The injectable composition of claim 12 , wherein ≤20% wt of the drug is dissolved in the DMSO or polymeric solution to form the injectable composition.
17. A pharmaceutical kit suitable for the in situ formation of a biodegradable implant in a body comprising the injectable composition of claim 12 , wherein, prior to mixing, the drug and the biocompatible copolymer are contained in a first container, and the solvent is contained in a second, separate container.
18. The composition of claim 12 , wherein
the particle size distribution of drug is described by at least one of the following distributions
Parameter
Dist. I
Dist. III
Dist. V
d0.1 (microns)
27.49
17.41
≤10
d0.5 (microns)
79.90
51.61
40-130
d0.9 (microns)
176.66
175.32
>225.
19. The injectable composition of claim 12 , wherein the copolymer is end-capped.
20. The injectable composition of claim 12 , wherein the particle size distribution of the drug is selected from
a) not more than 10% of the total volume of the particles are smaller than 10 microns, and not more than the 10% of the total volume of particles are greater than 225 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;
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;
d) not more than 10% of the total volume of the particles is less than the range 0.1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-1000 μm, and the d0.5 of the size distribution is in the range of about 10-1000 μm;
e) not more than 10% of the total volume of the particles is less than the range 0.5-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-700 μm, and the d0.5 of the size distribution is in the range of about 20-700 μm; or
f) 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.
21. The injectable composition of claim 12 , wherein the monomer ratio of lactic acid to glycolic acid ranges from 48:52 to 52:48.
22. An injectable composition consisting of
about 13% wt of drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination;
DMSO; and
25-27% wt of biocompatible poly(lactide-co-glycolide) (PLGA) copolymer having a monomer ratio of lactic acid to glycolic acid of about 50:50 and an inherent viscosity in the range of 0.25-0.30 dl/g measured by gel permeation chromatography in tetrahydrofuran at 30° C. using a flow rate of 1 ml/min; wherein
the mass ratio of DMSO to drug is about 4:1 to about 5:1.
23. The injectable composition of claim 22 , wherein the biocompatible copolymer is an irradiated copolymer that has been irradiated with beta-radiation.
24. The injectable composition of claim 22 , wherein the injectable composition releases no more than 20% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.
25. The injectable composition of claim 22 , wherein the injectable composition releases at least 0.1% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.
26. The injectable composition of claim 22 , wherein ≤20% wt of the drug is dissolved in the DMSO or polymeric solution to form the injectable composition.
27. A pharmaceutical kit suitable for the in situ formation of a biodegradable implant in a body comprising the injectable composition of claim 22 , wherein, prior to mixing, the drug and the biocompatible copolymer are contained in a first container, and the solvent is contained in a second, separate container.
28. The injectable composition of claim 22 , wherein the particle size distribution of the drug is selected from
a) not more than 10% of the total volume of the particles are smaller than 10 microns, and not more than the 10% of the total volume of particles are greater than 225 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;
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;
d) not more than 10% of the total volume of the particles is less than the range 0.1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-1000 μm, and the d0.5 of the size distribution is in the range of about 10-1000 μm;
e) not more than 10% of the total volume of the particles is less than the range 0.5-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-700 μm, and the d0.5 of the size distribution is in the range of about 20-700 μm; or
f) 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.
29. The injectable composition of claim 22 , wherein the particle size distribution of the drug is described by at least one of the following distributions
Parameter
Dist. I
Dist. II
Dist. III
d0.1 (microns)
27.49
17.41
≤10
d0.5 (microns)
79.90
51.61
40-130
d0.9 (microns)
176.66
175.32
>225.
30. The injectable composition of claim 22 , wherein the monomer ratio of lactic acid to glycolic acid ranges from 48:52 to 52:48.
31. An injectable composition consisting of
about 13% wt of drug which is risperidone and/or paliperidone or any pharmaceutically acceptable salt thereof in any combination;
DMSO; and
25-27% wt of biocompatible poly(lactide-co-glycolide) (PLGA) copolymer having a monomer ratio of lactic acid to glycolic acid of about 50:50 and a molecular weight in the range of 28-43 kDa; wherein
the mass ratio of DMSO to drug is about 4:1 to about 5:1.
32. The injectable composition of claim 31 , wherein the biocompatible copolymer has molecular weight in the range of 30-36 kDa.
33. The injectable composition of claim 31 , wherein the biocompatible copolymer is an irradiated copolymer that has been irradiated with a beta-radiation.
34. The injectable composition of claim 31 , wherein the injectable composition releases no more than 20% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.
35. The injectable composition of claim 31 , wherein the injectable composition releases at least 0.1% wt of its charge of the drug within 24 hours after being placed in an aqueous environment.
36. The injectable composition of claim 31 , wherein ≤20% wt of the drug is dissolved in the DMSO or polymeric solution to form the injectable composition.
37. A pharmaceutical kit suitable for the in situ formation of a biodegradable implant in a body comprising the injectable composition of claim 31 , wherein, prior to mixing, the drug and the biocompatible copolymer are contained in a first container, and the solvent is contained in a second, separate container.
38. The injectable composition of claim 31 , wherein the particle size distribution of the drug is selected from
a) not more than 10% of the total volume of the particles are smaller than 10 microns, and not more than the 10% of the total volume of particles are greater than 225 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;
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;
d) not more than 10% of the total volume of the particles is less than the range 0.1-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-1000 μm, and the d0.5 of the size distribution is in the range of about 10-1000 μm;
e) not more than 10% of the total volume of the particles is less than the range 0.5-10 μm, not more than the 10% of the total volume of particles is greater than the range 225-700 μm, and the d0.5 of the size distribution is in the range of about 20-700 μm; or
f) 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.
39. The injectable composition of claim 31 , wherein the particle size distribution of the drug is described by at least one of the following distributions
Parameter
Dist. I
Dist. II
Dist. III
d0.1 (microns)
27.49
17.41
≤10
d0.5 (microns)
79.90
51.61
40-130
d0.9 (microns)
176.66
175.32
>225.
40. The injectable composition of claim 31 , wherein the monomer ratio of lactic acid to glycolic acid ranges from 48:52 to 52:48.