Risperidone or paliperidone implant formulation

• US 10,335,366 B2
• Filed: 11/26/2014
• Issued: 07/02/2019
• Est. Priority Date: 05/31/2010
• Status: Active Grant

• Current Assignee: Laboratorios Farmaceuticos Rovi, S.A. (Norbel Inversiones SL)
• Original Assignee: Laboratorios Farmaceuticos Rovi, S.A. (Norbel Inversiones SL)
• Inventors: Gutierro Aduriz, Ibon, Franco Rodriguez, Guillermo
• Primary Examiner(s): Peebles, Katherine
• Application Number:
  US14/555,287
• Publication Number:
  US 20150150791A1
• Time in Patent Office: 1,679 Days
• Field of Search: None
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L

Abstract

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.

Claims

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

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 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-400 μ

m, and the d0.5 of the size distribution is in the range of about 40-200 μ

m;

c) expressed as volume, d0.9 is about 150 to about 400 μ

m, d0.5 is about 40 to about 200 μ

m and d0.1 is about 10 to about 60 μ

m;

d) not more than 10% of the total volume of the particles is less than the range 0.1-10 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-1000 μ

m, and the d0.5 of the size distribution is in the range of about 10-1000 μ

m;

e) not more than 10% of the total volume of the particles is less than the range 0.5-10 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-700 μ

m, and the d0.5 of the size distribution is in the range of about 20-700 μ

m;

or

f) not more than 10% of the total volume of the particles is less than the range 1-10 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-400 μ

m, and the d0.5 of the size distribution is in the range of about 40-200 μ

m.

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

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 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-400 μ

m, and the d0.5 of the size distribution is in the range of about 40-200 μ

m;

c) expressed as volume, d0.9 is about 150 to about 400 μ

m, d0.5 is about 40 to about 200 μ

m and d0.1 is about 10 to about 60 μ

m;

d) not more than 10% of the total volume of the particles is less than the range 0.1-10 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-1000 μ

m, and the d0.5 of the size distribution is in the range of about 10-1000 μ

m;

e) not more than 10% of the total volume of the particles is less than the range 0.5-10 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-700 μ

m, and the d0.5 of the size distribution is in the range of about 20-700 μ

m;

or

f) not more than 10% of the total volume of the particles is less than the range 1-10 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-400 μ

m, and the d0.5 of the size distribution is in the range of about 40-200 μ

m.

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 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-400 μ

m, and the d0.5 of the size distribution is in the range of about 40-200 μ

m;

c) expressed as volume, d0.9 is about 150 to about 400 μ

m, d0.5 is about 40 to about 200 μ

m and d0.1 is about 10 to about 60 μ

m;

d) not more than 10% of the total volume of the particles is less than the range 0.1-10 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-1000 μ

m, and the d0.5 of the size distribution is in the range of about 10-1000 μ

m;

e) not more than 10% of the total volume of the particles is less than the range 0.5-10 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-700 μ

m, and the d0.5 of the size distribution is in the range of about 20-700 μ

m;

or

f) not more than 10% of the total volume of the particles is less than the range 1-10 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-400 μ

m, and the d0.5 of the size distribution is in the range of about 40-200 μ

m.

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

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 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-400 μ

m, and the d0.5 of the size distribution is in the range of about 40-200 μ

m;

c) expressed as volume, d0.9 is about 150 to about 400 μ

m, d0.5 is about 40 to about 200 μ

m and d0.1 is about 10 to about 60 μ

m;

d) not more than 10% of the total volume of the particles is less than the range 0.1-10 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-1000 μ

m, and the d0.5 of the size distribution is in the range of about 10-1000 μ

m;

e) not more than 10% of the total volume of the particles is less than the range 0.5-10 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-700 μ

m, and the d0.5 of the size distribution is in the range of about 20-700 μ

m;

or

f) not more than 10% of the total volume of the particles is less than the range 1-10 μ

m, not more than the 10% of the total volume of particles is greater than the range 225-400 μ

m, and the d0.5 of the size distribution is in the range of about 40-200 μ

m.

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

40. The injectable composition of claim 31, wherein the monomer ratio of lactic acid to glycolic acid ranges from 48:

52 to 52;

48.