Antipsychotic injectable depot composition

• US 10,182,982 B2
• Filed: 04/04/2018
• Issued: 01/22/2019
• 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, Gomez Ochoa, Maria Teresa
• Primary Examiner(s): Peebles, Katherine
• Application Number:
  US15/944,894
• Publication Number:
  US 20180221272A1
• Time in Patent Office: 293 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 9/0002 Galenical forms characterised by the drug release technique; Application systems commanded by energy
• 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
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants

Abstract

The present invention is directed to a composition that can be used to deliver an antipsychotic drug such as risperidone as an injectable in-situ forming biodegradable implant for extended release providing therapeutic plasma levels from the first day. The composition is in the form of drug suspension on a biodegradable and biocompatible copolymer or copolymers solution using water miscible solvents that is administered in liquid form. Once the composition contacts the body fluids, the polymer matrix hardens retaining the drug, forming a solid or semisolid implant that releases the drug in a continuous manner. Therapeutic plasma levels of the drug can be achieved since the first day up to at least 14 days or more even up to at least four weeks.

Claims

1. A method of treating schizophrenia or bipolar disorder, the method comprising administering to a subject in need thereof an amount of injectable depot composition to form an implant in the subject, wherein the amount is sufficient provide a therapeutic dose of risperidone, whereby the implant provides therapeutic plasma levels of the risperidone from within 1 day after administration throughout a dosing period of at least two weeks following administration thereof, wherein the injectable depot composition consists of:

risperidone present as particles having a particle size distribution as follows;

not more than 10% of the total volume of risperidone particles is less than 10 microns in size, not more than 10% of the total volume of risperidone particles is greater than 225 microns in size, and the d0.5 of the size distribution is in the range of about 60-130 microns; and

polymeric solution consisting of;

DMSO; and

biocompatible poly(lactide-co-glycolide) (PLGA) copolymer comprising lactic acid and glycolic acid monomers, wherein the monomers are present at a monomer ratio of lactic to glycolic acid of 48;

52 to 52;

48, the copolymer has an inherent viscosity in the range of 0.25-0.48 dl/g as measured in chloroform at 25°

C. and at a concentration of 0.1% wt/v with an Ubbelohde size 0c glass capillary viscometer;

wherein

the polymeric solution has a viscosity in the range of about 0.7 Pa·

s to about 3.0 Pa·

s; and

wherein

the risperidone content is about 13% wt with respect to the total composition weight;

the DMSO to risperidone mass ratio is about 4;

1 to 5;

1; and

the polymeric solution to risperidone mass ratio is about 6.5;

1 to 7;

1.

2. The method of claim 1, wherein the injectable composition provides a plasma profile for risperidone and/or a metabolite thereof defined as follows

3. The method of claim 1, wherein the injectable composition provides a substantially level plasma concentration profile for risperidone and/or a metabolite thereof of within ±

10% of the average or mean plasma concentration during a period of at least 14 days following administration of the composition to a subject.

4. The method of claim 1, wherein the injectable composition provides a substantially level plasma concentration profile for risperidone and/or a metabolite thereof of within ±

15% of the average or mean plasma concentration during a period of at least 14 days following administration of the composition to a subject.

5. The method of claim 1, wherein the injectable composition provides a substantially level plasma concentration profile for risperidone and/or a metabolite thereof of within ±

20% of the average or mean plasma concentration during a dosing period of at least 28 days following administration of the composition to a subject.

6. The method of claim 1, wherein the injectable composition releases at least 0.5% wt and no more than 8% wt of its charge of risperidone within 24 hours after being placed in an aqueous environment.

7. The method of claim 1, wherein the injectable composition is administered intramuscularly.

8. The method of claim 1, wherein at least 95% wt of the copolymer is dissolved in the injectable composition prior to administration.

9. The method of claim 1, wherein ≥

1% wt of the risperidone is dissolved in the DMSO or the injectable composition prior to administration.

10. The method of claim 1, wherein, prior to inclusion in the injectable composition, the copolymer has been irradiated with about 10 KGy to about 25 KGy of beta-radiation.

11. The method of claim 1, wherein the risperidone/copolymer mass ratio is about 33%, expressed as the weight percentage of the risperidone with respect to the risperidone plus copolymer.

12. A method of treating schizophrenia or bipolar disorder, the method comprising administering to a subject in need thereof an amount of injectable depot composition to form an implant in the subject, wherein the amount is sufficient provide a therapeutic dose of risperidone, whereby the implant provides therapeutic plasma levels of the risperidone from within 1 day after administration throughout a dosing period of at least two weeks following administration thereof, wherein the injectable depot composition consists of:

risperidone present as particles having a particle size distribution as follows;

not more than 10% of the total volume of risperidone particles is less than 10 microns in size, not more than 10% of the total volume of risperidone particles is greater than 225 microns in size, and the d0.5 of the size distribution is in the range of about 60-130 microns; and

polymeric solution consisting of;

DMSO; and

biocompatible poly(lactide-co-glycolide) (PLGA) copolymer comprising lactic acid and glycolic acid monomers, wherein the monomers are present at a monomer ratio of lactic to glycolic acid of 48;

52 to 52;

48, the copolymer has an inherent viscosity in the range of 0.25-0.48 dl/g as measured in chloroform at 25°

C. and at a concentration of 0.1% wt/v with an Ubbelohde size 0c glass capillary viscometer;

wherein

the polymeric solution has a viscosity in the range of about 0.7 Pa·

s to about 3.0 Pa·

s;

the risperidone content is about 13% wt with respect to the total composition weight;

the DMSO to risperidone mass ratio is about 4.66;

1; and

the polymeric solution to risperidone mass ratio is about 6.66;

1.

13. The method of claim 12, wherein the injectable composition provides a plasma profile for risperidone and/or a metabolite thereof defined as follows

14. The method of claim 12, wherein the injectable composition provides a substantially level plasma concentration profile for risperidone and/or a metabolite thereof of within ±

15% of the average or mean plasma concentration during a period of at least 14 days following administration.

15. The method of claim 12, wherein the injectable composition provides a substantially level plasma concentration profile for risperidone and/or a metabolite thereof of within ±

20% of the average or mean plasma concentration during a dosing period of at least 28 days following administration.

16. The method of claim 12, wherein the injectable composition releases at least 0.5% wt and no more than 8% wt of its charge of risperidone within 24 hours after administration.

17. The method of claim 12, wherein the injectable composition is administered intramuscularly.

18. The method of claim 12, wherein at least 95% wt of the copolymer is dissolved in the injectable composition prior to administration.

19. The method of claim 12, wherein 1% wt of the risperidone is dissolved in the DMSO or the injectable composition prior to administration.

20. The method of claim 12, wherein, prior to inclusion in the injectable composition, the copolymer has been irradiated with about 10 KGy to about 25 KGy of beta-radiation.

21. A method of treating schizophrenia or bipolar disorder comprising administering to a subject in need thereof an amount of injectable depot composition to form an implant in the subject, wherein the amount is sufficient provide a therapeutic dose of risperidone, whereby the implant provides therapeutic plasma levels of the risperidone from within 1 day after administration throughout a dosing period of at least two weeks following administration thereof, wherein the injectable depot composition consists of:

risperidone present as particles having a particle size distribution as follows;

not more than 10% of the total volume of risperidone particles is less than 10 microns in size, not more than 10% of the total volume of risperidone particles is greater than 225 microns in size, and the d0.5 of the size distribution is in the range of about 60-130 microns; and

polymeric solution consisting of;

DMSO; and

biocompatible poly(lactide-co-glycolide) (PLGA) copolymer comprising lactic acid and glycolic acid monomers, wherein the monomers are present at a monomer ratio of lactic to glycolic acid of 48;

52 to 52;

48, the copolymer has an inherent viscosity in the range of 0.25-0.48 dl/g as measured in chloroform at 25°

C. and at a concentration of 0.1% wt/v with an Ubbelohde size 0c glass capillary viscometer;

wherein

the polymeric solution has a viscosity in the range of about 0.7 Pa·

s to about 3.0 Pa·

s; and

wherein

the risperidone content is about 13% wt with respect to the total composition weight;

the DMSO to risperidone mass ratio is about 4;

1 to 5;

1;

the polymeric solution to risperidone mass ratio is about 6.5;

1 to 7;

1;

wherein the injectable composition provides a plasma profile for risperidone and/or a metabolite thereof defined as follows