# US 8,465,778 B2 · Method of making tyrosine kinase microspheres

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- Number: US 8,465,778 B2
- Document ID: US8465778B2
- Status: Granted
- Kind: B2
- Application number: 13/527,344
- Filed: 2012-06-19
- Published: 2012-10-11
- Granted: 2013-06-18
- Earliest claimed: 2004-04-30
- Assignees: Allergan, Inc.
- Applicants: Patrick M. Hughes; Christian Sarrazin; Elisabeth Rossi; Michèle Boix
- Inventors: Patrick M. Hughes; Christian Sarrazin; Elisabeth Rossi; Michèle Boix
- Web page: https://patentgrep.com/patent/US8465778B2

## CPC

- A61K 9/0051: {Ocular inserts or implants}
- A61K 9/1647: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- Y10T 428/2985: Solid-walled microcapsule from synthetic polymer
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y10T: TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION

## Abstract

Biocompatible intraocular microspheres include a tyrosine kinase inhibitor and a biodegradable polymer that is effective to facilitate release of the tyrosine kinase inhibitor into the vitreous of an eye for an extended period of time. The therapeutic agents of the microspheres can be associated with a biodegradable polymer matrix, such as a matrix that is substantially free of a polyvinyl alcohol. The microspheres can be placed into an eye to treat or reduce the occurrence of one or more ocular conditions.

## Claims

### Claim 1

A process for making biodegradable microspheres encapsulating a tyrosine kinase inhibitor (TKI), the process comprising the steps of:
(a) preparing an organic phase comprising a tyrosine kinase inhibitor, a biodegradable poly(lactide-co-glycolide) polymer, and an organic solvent for the tyrosine kinase inhibitor and the polymer;
(b) preparing a first aqueous phase;
(c) crystallizing the tyrosine kinase inhibitor in the organic phase;
(d) combining the organic and the first aqueous phase with stirring to form an emulsion;
(e) preparing a second aqueous phase;
(f) adding the second aqueous phase to the emulsion to form a solution;
(g) stirring the solution; and
(h) evaporating the organic solvent, thereby making biodegradable microspheres encapsulating a tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor is 10-30 wt % of the microspheres.

### Claim 2 (depends on 1)

The process of claim 1, wherein the organic phase is a viscous fluid.

### Claim 3 (depends on 1)

The process of claim 1, wherein the pH of the first aqueous phase is between about pH 6 and about pH 8.

### Claim 4 (depends on 1)

The process of claim 1, wherein the pH of the second aqueous phase is between about pH 4 and about pH 9.

### Claim 5

A process for making biodegradable microspheres encapsulating a tyrosine kinase inhibitor (TKI), the process comprising the steps of:
(a) preparing a viscous organic phase comprising a tyrosine kinase inhibitor, a biodegradable PLGA polymer, and an organic solvent for the tyrosine kinase inhibitor and the PLGA polymer;
(b) crystallizing the tyrosine kinase inhibitor in the viscous organic phase;
(c) preparing a first aqueous phase with a pH between about pH 6 and about pH 8;
(d) combining the organic and the first aqueous phase with stirring to form an emulsion;
(e) preparing a second aqueous phase with a pH between about pH 4 and about pH 9;
(f) adding the second aqueous phase to the emulsion to form a solution;
(g) stirring the solution; and
(h) evaporating the organic solvent, thereby making biodegradable microspheres encapsulating a tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor is 10-30 wt % of the microspheres.