Oil-in-oil emulsified polymeric implants containing a hypotensive lipid and prostamide

• US 8,445,027 B2
• Filed: 06/03/2011
• Issued: 05/21/2013
• Est. Priority Date: 04/30/2004
• Status: Active Grant

• Current Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Original Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Inventors: Hughes, Patrick M., Boix, Michele, Sarrazin, Christian, Do, Marina
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US13/152,780
• Publication Number:
  US 20110250285A1
• Time in Patent Office: 718 Days
• Field of Search: None
• US Class Current: 424/502
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• 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 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61L 2/081 Gamma radiation
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: B01J 13/02 Making microcapsules or microballoons for medical preparations A61K9/50
• CPC Class Codes: B01J 13/04 by physical processes, e.g. drying, spraying
• CPC Class Codes: B01J 13/06 by phase separation

Abstract

Biocompatible intraocular implants, such as microparticles, include a prostamide component and a biodegradable polymer that is effective in facilitating release of the prostamide component into an eye for an extended period of time. The prostamide component may be associated with a biodegradable polymer matrix, such as a matrix of a two biodegradable polymers. Or, the prostamide component may be encapsulated by the polymeric component. The present implants include oil-in-oil emulsified implants or microparticles. Methods of producing the present implants are also described. The implants may be placed in an eye to treat or reduce at least one symptom of an ocular condition, such as glaucoma.

Claims

1. A method for producing therapeutic polymeric microparticles, comprising encapsulating a prostamide component with a polymeric component to form a population of prostamide-encapsulated microparticles by an oil-in-oil emulsion process, wherein the polymeric component comprises a poly(lactide-co-glycolide) (PLGA) copolymer, the oil-in-oil emulsion process comprising:

forming a first composition comprising a prostamide component, a poly(lactide-co-glycolide) (PLGA) copolymer, and an organic solvent;

forming a second oil-containing composition;

mixing the first composition and the second oil-containing composition to form an oil-in-oil emulsion;

drying the emulsion to form a dried emulsion product;

contacting the dried emulsion product with a solvent to form a solvent-containing composition;

removing the solvent from the solvent-containing composition to form a population of microparticles having a maximum particle diameter less than about 200 μ

m and comprising the prostamide component and the polymeric component; and

terminally sterilizing the polymeric microparticles, wherein at least 80% of the prostamide component remains stable after sterilization; and

wherein the prostamide component comprises a compound having the formula (I)

2. The method of claim 1, wherein the prostamide component comprises bimatoprost.

3. The method of claim 1, wherein the PLGA copolymer has a lactide/glycolide ratio of 75/25, a molecular weight of about 63 kilodaltons, and an inherent viscosity of about 0.6 dL/g.

4. The method of claim 1, wherein the drying comprises evaporating the oil-in-oil emulsion to form an evaporated product.

5. The method of claim 4, wherein contacting the dried emulsion product with a solvent to form a solvent-containing composition comprises suspending the evaporated product in the solvent before removing the solvent from the solvent-containing composition.

6. The method of claim 2, wherein the microparticles have a release rate of the prostamide component of about 0.7% per day in vitro.

8. The method of claim 1, wherein the population of microparticles formed by the method has a mean particle diameter from about 30 μ

m to about 50 μ

m.

9. The method of claim 1, wherein prostamide component comprises about 10% wt/wt of the microparticles.

10. The method of claim 1, wherein the prostamide component comprises about 5% wt/wt of the microparticles.

7. A method for producing therapeutic polymeric microparticles, comprising encapsulating bimatoprost with a polymeric component to form a population of bimatoprost-encapsulated microparticles by an oil-in-oil emulsion process, wherein the polymeric component comprises a poly(lactide-co-glycolide) (PLGA) copolymer,

the oil-in-oil emulsion process comprising:

forming a first composition comprising bimatoprost, a poly(lactide-co-glycolide) (PLGA) copolymer, and an organic solvent;

forming a second oil-containing composition;

mixing the first composition and the second oil-containing composition to form an oil-in-oil emulsion;

evaporating the oil-in-oil emulsion to form an evaporated product;

contacting the evaporated product with a solvent to form a solvent-containing composition; and

removing the solvent from the solvent-containing composition to form a population of microparticles having a maximum particle diameter less than about 200 μ

m and comprising bimatoprost and the polymeric component.

11. The method of claim 7, wherein the organic solvent is acetonitrile.