Methods for the preparation of injectable depot compositions

• US 10,058,504 B2
• Filed: 11/30/2012
• Issued: 08/28/2018
• 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:
  US13/690,707
• Publication Number:
  US 20130177603A1
• Time in Patent Office: 2,097 Days
• Field of Search: None
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• 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 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Abstract

Injectable depot compositions, comprising a biocompatible polymer which is a polymer or copolymer based on lactic acid and/or lactic acid plus glycolic acid having a monomer ratio of lactic to glycolic acid in the range from 48:52 to 100:0, a water-miscible solvent having a dipole moment of about 3.7-4.5 D and a dielectric constant of between 30 and 50, and a drug, were found suitable for forming in-situ biodegradable implants which can evoke therapeutic drug plasma levels from the first day and for at least 14 days.

Claims

1. An injectable depot composition consisting of risperidone, and a polymeric solution of DMSO and PLGA copolymer, wherein:

the content of risperidone is 13% wt±

10%, based upon the weight of the composition, and the risperidone possesses a particle distribution selected from;

a. not more than 10% of the total volume of the particles is smaller than 10 microns, not more than the 10% of the total volume of particles is greater than 225 microns, and the d0.5 is in the range of 10-200 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;

or

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;

the mass ratio of DMSO to risperidone is 4.66±

10%;

1;

the mass ratio of polymeric solution to risperidone is about 6.66±

10%;

1;

the PLGA copolymer is an end-capped biodegradable poly(lactide-co-glycolide) copolymer having a monomer ratio of lactic acid to glycolic acid of 50;

50 and an inherent viscosity in the range of 0.20±

10% dl/g to 0.50±

10% dl/g as measured in chloroform at 25°

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

the polymeric solution has a viscosity in the range of 0.5-3.0 Pa·

s; and

the amount of risperidone dissolved in the injectable composition is 20% wt.

2. The injectable depot composition according to claim 1, wherein the composition is a sterilized composition.

3. The injectable depot composition according to claim 2, wherein the sterilization has been carried out by sterilizing at least one of the drug and the biocompatible polymer by beta-irradiation in the range 5-25 KGy.

4. A pharmaceutical kit suitable for preparation of the injectable depot composition according to claim 1, the kit comprising:

a first container comprising the PLGA copolymer; and

a second container comprising the DMSO; and

wherein the risperidone is present in the first container, second container or a third container,

whereby mixing of the PLGA copolymer, DMSO and risperidone results in formation of the injectable depot composition.

5. The injectable depot composition according to claim 1, wherein the viscosity of the injectable composition is in the range of about 0.7 Pa·

s to about 4.0 Pa·

s.

6. The injectable depot composition according to claim 1, wherein

a) the PLGA copolymer has been exposed to 5 to 25 KGy of beta-radiation sufficient to sterilize the PLGA copolymer prior to inclusion in the injectable composition or prior to addition of the DMSO;

or

b) the PLGA copolymer has been exposed to 10-25 KGy of beta-radiation sufficient to reduce the molecular weight of the PLGA copolymer prior to inclusion in the injectable composition or prior to addition of the DMSO, and thereby the intrinsic viscosity thereof.

7. The injectable depot composition according to claim 1, wherein the composition is injectable by hand through a 18 to 22 gauge needle.

8. The injectable depot composition according to claim 1, wherein the composition forms a biodegradable solid single body implant in situ in a subject to which it is administered.

9. The injectable depot composition of claim 1, wherein the 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.

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

15% of the average or mean during a period of at least 14 days following administration of the composition to a subject, wherein the average or mean is calculated over the 14 days.

11. The injectable depot composition of claim 10, wherein the composition provides a plasma profile, for the risperidone, and/or metabolite thereof, defined as follows:

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

20% of the average or mean during a dosing period of at least 28 days following administration of the composition to a subject, wherein the average or mean is calculated over the 28 days.

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

10% of the average or mean during a period of at least 14 days following administration of the composition to a subject, wherein the average or mean is calculated over the 14 days.