# US 8,784,893 B2 · Polymer formulations for delivery of bioactive agents

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- Number: US 8,784,893 B2
- Document ID: US8784893B2
- Status: Granted
- Kind: B2
- Application number: 12/526,027
- Filed: 2008-02-05
- Published: 2011-02-10
- Granted: 2014-07-22
- Earliest claimed: 2007-02-05
- Assignees: Carbylan Therapeutics, Inc.
- Applicants: George Daniloff; David Gravett; Robert C. Spiro
- Inventors: George Daniloff; David Gravett; Robert C. Spiro
- Web page: https://patentgrep.com/patent/US8784893B2

## CPC

- 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)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61L 27/20: Polysaccharides
- A61L 27/52: Hydrogels or hydrocolloids
- C08L 5/08: Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
- 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)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)

## Abstract

Disclosed in the present application are compositions comprising a bioresorbable polymer matrix and a bio active agent, wherein the bioactive agent is dispersed within polymer matrix as a solid. Also provided herein are methods for preparing a bioactive agent formulation, wherein the agent is present in a solid form and, wherein the agent is occluded into a polymeric matrix by polymerization of polymer matrix precursors or by self assembly of the polymer.

## Claims

### Claim 1

A hydrogel composition formed by combining an aqueous buffer, a thiol-functionalized hyaluronic acid and a crosslinking accelerant in the presence of a gel-persistence-enhancing compound selected from the group consisting of N-acetyl cysteine, glutathione, 2,3-dimercapto-1-propanesulfonic acid, 2,3-dimercapto-1-propanesulfonic acid sodium salt monohydrate, cysteine, dihydrolipoic acid, and pharmaceutically acceptable salts thereof, wherein the hydrogel comprises disulfide crosslinks.

### Claim 2 (depends on 1)

The composition of claim 1 further comprising an excipient.

### Claim 3 (depends on 1)

The composition of claim 1 having a pH of between 5 and 8 when in aqueous solution.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the thiol-functionalized hyaluronic acid has a formula:
wherein:
n≧2;
Y is a residue of the hyaluronic acid; and
L is a substituted or unsubstituted hydrocarbyl group, a substituted or unsubstituted heterohydrocarbyl group, a polyether group, a polyamide group, a polyimino group, an aryl group, a polyester, a polythioether group, a polysaccharyl group or a combination thereof.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the thiol-functionalized hyaluronic acid has a formula:
wherein HA is a residue of hyaluronic acid and n≧2.

### Claim 6 (depends on 1)

The composition of claim 1, where the gel-persistence-enhancing compound is cysteine or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The composition of claim 1, further comprising a bioactive agent as solid particles.

### Claim 8 (depends on 7)

The composition of claim 7, wherein the bioactive agent is a steroid.

### Claim 9 (depends on 8)

The composition of claim 8, wherein the steroid is selected from the group consisting of triamcinolone, triamcinolone diacetate, triamcinolone acetonide, triamcinolone hexacetonide, methylprednisolone and dexamethasone.

### Claim 10 (depends on 8)

The composition of claim 8, wherein the steroid is triamcinolone acetonide.

### Claim 11 (depends on 7)

The composition of claim 7, wherein the solid particles have a particle size between about 0.1 micron and 2 mm.

### Claim 12 (depends on 7)

The composition of claim 7, wherein the bioactive agent is not covalently bound to the thiol-functionalized hyaluronic acid.

### Claim 13 (depends on 1)

The composition of claim 1, which forms in about 1 second to 30 minutes after combining the thiol-functionalized hyaluronic acid, the gel-persistance enhancing compound, and the crosslinking accelerant in aqueous buffer.

### Claim 14 (depends on 1)

A kit for providing a hydrogel composition of claim 1, the kit comprising, in one or more first containers, a thiol-functionalized hyaluronic acid, a gel-persistence enhancing compound as recited in claim 1, and a crosslinking accelerant, and, in a second containiner, an aqueous buffer.

### Claim 15 (depends on 14)

The kit of claim 14, further comprising in the one or more first containers or in a third container, a steroid selected from the group consisting of triamcinolone, triamcinolone diacetate, triamcinolone hexacetonide, triamcinolone acetonide, methylprednisolone and dexamethasone.

### Claim 16 (depends on 1)

A method of treating a medical condition in a mammal in need thereof, the method comprising contacting a tissue site of mammal with the composition of claim 1.

### Claim 17 (depends on 15)

The kit of claim 15, wherein the steroid is triamcinolone acetonide.

### Claim 18 (depends on 1)

The composition of claim 1, wherein the crosslinking accelerant is an oxidant.

### Claim 19 (depends on 18)

The composition of claim 18, wherein the oxidant is selected from the group consisting of air, molecular iodine, hydrogen peroxide, an alkyl hydroperoxide, a peroxy acid, a dialkyl sulfoxide, a persulfate, Co3+, Ce4+, a metal oxide and a halogen transfer agent.