Paliperidone Implant Formulation

• US 20190328654A1
• Filed: 06/03/2019
• Published: 10/31/2019
• 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
• Granted Patent: US 11,013,683 B2
• Time in Patent Office: Days
• 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

An injectable intramuscular depot composition suitable for forming an in situ solid implant in a body, comprising a drug which is paliperidone and/or its pharmaceutical acceptable salts in any combination thereof, a biocompatible copolymer based on lactic and glycolic acid having a monomer ratio of lactic to glycolic acid of about 50:50 and DMSO as solvent, wherein the composition releases the drug with an immediate onset of action and continuously for at least 8 weeks and wherein the composition has a pharmacokinetic profile in vivo suitable for the formulation to be administered each 8 weeks or even longer periods.

Claims

1. ) A method of administering paliperidone to a subject in need thereof, the method comprising administering to said subject an injectable depot composition consisting of

a) 13% wt±

10% of the drug paliperidone having a particle size distribution described as follows al less than 10% of the total volume of particles being smaller than 10 microns;

less than 10% of the total volume of particles being larger than 225 microns, and a d0.5 value in the range of 40-130 microns;

b) less than 10% of the total volume of particles being smaller than 10 microns;

less than 10% of the total volume of particles being larger than 200 microns, and a d0.5 value in the range of 40-90 microns;

c) not more than 10% of drug particles smaller than 25 microns, not more than 10% of drug particles larger than 225 microns;

d) less than 10% of the particles being smaller than 10 microns;

less than 10% of the particles being larger than 225 microns, and a d0.5 value in the range of 60-130 microns;

e) a d0.5 in the range of 60-130 microns;

or f) d(0.1)=17.41 microns, d(0.5)=51.61 microns and d(0.9)=175.32 microns;

b) 25-27% wt of biocompatible poly(lactide-co-glycolide) copolymer (PLGA) having a monomer ratio of lactic acid to glycolic acid of about 50;

50, wherein the copolymer is end-capped, has an inherent viscosity in the range of 0.27 to 0.31 dl/g measured by gel permeation chromatography in tetrahydrofuran at 30°

C. using a flow rate of 1 ml/min; and

c) DMSO,

wherein the DMSO to paliperidone mass ratio is about 4;

1 to 5;

1; and

wherein the weight percentages are relative to the weight of the injectable depot composition.

2. ) The method of claim 1, wherein said subject is in need of an antipsychotic drug.

3. ) The method of claim 1, wherein said injectable composition is administered intramuscularly, intraperitoneally, intrathecally, intravaginally, subcutaneously, intracranially or intracerebrally.

4. ) The method of claim 1, wherein said composition is administered every two weeks, every three weeks, every four weeks, every five weeks, every 4-5 weeks, or every 8-10 weeks during a treatment period.

5. ) The method of claim 1, wherein said composition comprises about 25 mg to about 150 mg of said drug.

6. ) The method of claim 1, wherein after administration said composition

a) provides an average plasma concentration of said drug that ranges from about 5 to about 80 ng/ml when about 116 to about 700 mg, respectively, of said composition comprising about 25 mg to about 150 mg, respectively, of said drug are administered;

b) provides an average plasma concentration of said drug that ranges from about 5 to about 150 ng/ml or from about 10 to about 100 ng/ml in the steady state during a dosing period;

c) provides an average Cmin of said drug in the range of about 1-80 ng/ml, 5-50 ng/ml, or about 5-40 ng/ml when an amount of said injectable composition equivalent to a dose of about 25-150 mg, about 37.5-125 mg, or about 50-100 mg, respectively, of said drug is administered;

d) provides an average Cmax of said drug in the range of about 8-300 ng/ml, 10-150 ng/ml, or 10-120 ng/ml when an amount of said injectable composition equivalent to a dose of 25-150 mg, 37.5-125 mg, or 50-100 mg, respectively, of said drug is administered;

or

e) provides therapeutic plasma levels of said drug from the first day to at least 14 days, at least 21 days, at least 28 days, at least 31 days, or at least 36 days after administration.

7. ) The method of claim 1, wherein said composition provides a plasma concentration profile of said drug that

a) exhibits one, two or more maxima;

b) exhibits one, two or more minima;

c) exhibits a maximum during the initial one to six days, one to three days, or one to two days after administration;

d) exhibits a maximum during 11 to 13 days or 12 to 14 days after administration;

e) exhibits a maximum during 14 to 24 days of a 4-week dosing period;

or

f) is within ±

20% of the average or mean plasma concentration during a dosing period.

8. ) The method of claim 1, wherein plural doses of said composition are administered and

a) said doses are administered sequentially or in an overlapping manner;

or

b) said dose are administered to one or more injection sites.

9. ) The method of claim 1 further comprising sterilizing said copolymer, said polymeric solution and/or said drug prior to administration.

10. ) The method of claim 9, wherein said sterilizing comprises exposure to a dose of beta-irradiation in the range of 5-25 KGy;

or wherein said sterilizing comprises filtering said polymeric solution through a filtration medium having a nominal pore size of 22 microns or less.

11. ) The method of claim 1, wherein said composition releases 0.5% wt up to 20% wt of its charge of said drug within 24 hours after being placed in an aqueous environment.

12. ) The method of claim 1, wherein the viscosity of a polymeric solution comprising the copolymer and the DMSO is in the range of 1.6 to 2.5 Pa·

s.

13. ) The method of claim 1, wherein the paliperidone/(copolymer+paliperidone) mass ratio is about 33%.

14. ) The method of claim 1, wherein said monomer ratio ranges from 48:

52 to 52;

48.

30. ) The method of claim 1 further comprising the step of providing a kit comprising

a first container comprising paliperidone;

a second container comprising PLGA; and

DMSO in said first container, said second container, or a third container.

31. ) The method of claim 30 further comprising the step of mixing the paliperidone, PLGA and DMSO to form said injectable depot composition.

15. ) A method of administering paliperidone to a subject in need thereof, the method comprising administering to said subject an injectable depot composition consisting ofwt of the drug paliperidone having a particle size distribution described as follows a) less than 10% of the total volume of particles being smaller than 10 microns, less than 10% of the total volume of particles being larger than 225 microns, and a d0.5 value in the range of 40-130 microns;

b) less than 10% of the total volume of particles being smaller than 10 microns, less than 10% of the total volume of particles being larger than 200 microns, and a d0.5 value in the range of 40-90 microns;

c) not more than 10% of drug particles smaller than 25 microns, not more than 10% of drug particles larger than 225 microns;

d) less than 10% of the particles being smaller than 10 microns, less than 10% of the particles being larger than 225 microns, and a d0.5 value in the range of 60-130 microns;

e) a d0.5 in the range of 60-130 microns;

or f) d(0.1)=17.41 microns, d(0.5)=51.61 microns and d(0.9)=175.32 microns;

26% wt of biocompatible poly(lactide-co-glycolide) copolymer (PLGA) having a monomer ratio of lactic acid to glycolic acid of about 50;

50, wherein the copolymer is end-capped, has an inherent viscosity in the range of 0.27 to 0.31 dl/g measured by gel permeation chromatography in tetrahydrofuran at 30°

C. using a flow rate of 1 ml/min; and

DMSO,

wherein the weight percentages are relative to the weight of the injectable depot composition.

16. ) The method of claim 15, wherein said subject is in need of an antipsychotic drug.

17. ) The method of claim 15, wherein said injectable composition is administered intramuscularly, intraperitoneally, intrathecally, intravaginally, subcutaneously, intracranially or intracerebrally.

18. ) The method of claim 15, wherein said composition is administered every two weeks, every three weeks, every four weeks, every five weeks, every 4-5 weeks, or every 8-10 weeks during a treatment period.

19. ) The method of claim 15, wherein said composition comprises about 25 mg to about 150 mg of said drug.

20. ) The method of claim 15, wherein after administration said composition

a) provides an average plasma concentration of said drug that ranges from about 5 to about 80 ng/ml when about 116 to about 700 mg, respectively, of said composition comprising about 25 mg to about 150 mg, respectively, of said drug are administered;

b) provides an average plasma concentration of said drug that ranges from about 5 to about 150 ng/ml or from about 10 to about 100 ng/ml in the steady state during a dosing period;

c) provides an average Cmin of said drug in the range of about 1-80 ng/ml, 5-50 ng/ml, or about 5-40 ng/ml when an amount of said injectable composition equivalent to a dose of about 25-150 mg, about 37.5-125 mg, or about 50-100 mg, respectively, of said drug is administered;

d) provides an average Cmax of said drug in the range of about 8-300 ng/ml, 10-150 ng/ml, or 10-120 ng/ml when an amount of said injectable composition equivalent to a dose of 25-150 mg, 37.5-125 mg, or 50-100 mg, respectively, of said drug is administered;

or

e) provides therapeutic plasma levels of said drug from the first day to at least 14 days, at least 21 days, at least 28 days, at least 31 days, or at least 36 days after administration.

21. ) The method of claim 15, wherein said composition provides a plasma concentration profile of said drug that

a) exhibits one, two or more maxima;

b) exhibits one, two or more minima;

c) exhibits a maximum during the initial one to six days, one to three days, or one to two days after administration;

d) exhibits a maximum during 11 to 13 days or 12 to 14 days after administration;

e) exhibits a maximum during 14 to 24 days of a 4-week dosing period;

or

f) is within ±

20% of the average or mean plasma concentration during a dosing period.

22. ) The method of claim 15, wherein plural doses of said composition are administered and

a) said doses are administered sequentially or in an overlapping manner;

or

b) said dose are administered to one or more injection sites.

23. ) The method of claim 15 further comprising sterilizing said copolymer, said polymeric solution and/or said drug prior to administration.

24. ) The method of claim 23, wherein said sterilizing comprises exposure to a dose of beta-irradiation in the range of 5-25 KGy;

or wherein said sterilizing comprises filtering said polymeric solution through a filtration medium having a nominal pore size of 22 microns or less.

25. ) The method of claim 15, wherein said composition releases 0.5% wt up to 20% wt of its charge of said drug within 24 hours after being placed in an aqueous environment.

26. ) The method of claim 15, wherein the viscosity of a polymeric solution comprising the copolymer and the DMSO is in the range of 1.6 to 2.5 Pa·

s.

27. ) The method of claim 15, wherein said monomer ratio ranges from 48:

52 to 52;

48.

28. ) The method of claim 15 further comprising the step of providing a kit comprising

a first container comprising paliperidone;

a second container comprising PLGA; and

DMSO in said first container, said second container, or a third container.

29. ) The method of claim 28 further comprising the step of mixing the paliperidone, PLGA and DMSO to form said injectable depot composition.