# US 5,705,177 A · Methods and compositions based on inhibition of cell invasion and fibrosis by anionic polymers

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- Number: US 5,705,177 A
- Document ID: US5705177A
- Status: Granted
- Kind: A
- Application number: 08/150,185
- Filed: 1994-07-26
- Granted: 1998-01-06
- Earliest claimed: 1991-05-31
- Assignees: Gliatech, Inc.
- Inventors: Dikla Roufa; Adrian Harel; Robert C. A. Frederickson; George T. Coker, III
- Web page: https://patentgrep.com/patent/US5705177A

## CPC

- A61K 31/734: Alginic acid
- A61K 31/727: Heparin; Heparan
- A61K 31/728: Hyaluronic acid
- A61K 31/737: Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate (A61K31/727 takes precedence)
- A61K 31/738: Cross-linked polysaccharides
- A61K 38/1703: {from vertebrates}
- A61K 38/39: Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
- A61L 27/20: Polysaccharides
- A61L 27/34: Macromolecular materials
- A61L 31/042: {Polysaccharides}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/00: Drugs for skeletal disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 39/00: General protective or antinoxious agents
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- Y10S 530/857: Fish; fish eggs; shell fish; crustacea
- Y10S 623/915: Method or apparatus for preparing biological material
- Y10S 623/924: Material characteristic
- Y10S 977/788: Of specified organic or carbon-based composition
- Y10S 977/793: Protein array
- Y10S 977/795: Composed of biological material
- Y10S 977/908: Mechanical repair performed/surgical
- Y10S 977/91: Strengthening cell or tissue
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

The present invention relates to the discovery that biocompatible anionic polymers can effectively inhibit fibrosis, scar formation, and surgical adhesions. The invention is predicated on the discovery that anionic polymers effectively inhibit invasion of cells associated with detrimental healing processes, and in particular, that the effectiveness of an anionic polymer at inhibiting cell invasion correlates with the anionic charge density of the polymer. Thus the present invention provides a large number of materials for use in methods of inhibiting fibrosis and fibroblast invasion. Anionic polymers for use in the invention include but are not limited to natural proteoglycans, and the glycosaminoglycan moieties of proteoglycans. Additionally, anionic carbohydrates and other anionic polymers may be used. The anionic polymers dextran sulfate and pentosan polysulfate are preferred. In a more preferred embodiment, dextran sulfate, in which the sulfur content is greater than about 10% by weight, may be used. In a more preferred embodiment, the average molecular weight is about 40,000 to 500,000 Daltons. The present invention provides compositions and methods to inhibit fibrosis and scarring associated with surgery. The invention further provides compositions and methods to inhibit glial cell invasion, detrimental bone growth and neurite outgrowth. In a preferred embodiment, the inhibitory compositions further comprise an adhesive protein.

## Claims

### Claim 1

A composition comprising:
(a) an amount of an anionic polymer selected from the group consisting of pentosan polysulfate and alginate effective to inhibit bone growth at the site of a lesion in an animal; and
(b) an amount of an adhesive protein effective to anchor the anionic polymer at the site of the lesion.

### Claim 2

A method for inhibiting glial cell invasion in an animal comprising administering a composition to the site of a lesion in an animal, said composition comprising (a) an anionic polymer selected from the group consisting of dextran sulfate, pentosan polysulfate and alginate in an amount which is effective to inhibit said glial cell invasion; and (b) an amount of adhesive protein effective to anchor the anionic polymer at the site of the lesion.

### Claim 3 (depends on 2)

The method according to claim 2 in which the glial cell invasion is caused by a disease or disorder selected from the group consisting of trauma, surgery, viral infection, bacterial infection, metabolic disease, malignancy, exposure to toxic agents, and hyperplastic situations.

### Claim 4 (depends on 2)

The method according to claim 2 in which the glial cell is an astrocyte.

### Claim 5 (depends on 1)

The composition of claim 1 in which the adhesive protein is selected from the group consisting of fibrin, mussel polyphenolic adhesion protein, barnacle polyphenolic adhesion protein, oyster polyphenolic adhesion protein, chemically polymerized peptide from an adhesion protein and an analog of an adhesion protein produced recombinantly.

### Claim 6 (depends on 1)

An improved implant in which the improvement comprises a coating on the implant of a suitable amount of the composition of claim 1 effective to inhibit bone growth.

### Claim 7 (depends on 6)

The improved implant of claim 6 in which the polymer implant is selected from the group consisting of nephrostomy tube, peritoneal drainage tube, artificial hip joint, artificial heart valve, and peripheral nerve repair prosthesis.

### Claim 8

A method for inhibiting undesirable bone growth in an animal comprising administering to the animal dextran sulfate in an amount which is effective to inhibit said undesirable bone growth.

### Claim 9

A method for inhibiting undesirable bone growth in an animal comprising administering a composition to the site of a lesion in an animal, said composition comprising (a) dextran sulfate in an amount which is effective to inhibit said undesirable bone growth; and (b) an amount of adhesive protein effective to anchor the dextran sulfate at the site of the lesion.

### Claim 10 (depends on 8, 9)

The method according to claim 8 or 9 wherein the sulfur content is greater than about 10% by weight.

### Claim 11 (depends on 8, 9)

The method according to claim 8 or 9 wherein the average molecular weight of the dextran sulfate is about 40,000 to 50,000 Daltons.

### Claim 12

A method for inhibiting undesirable bone growth in an animal comprising administering a composition to the animal, said composition comprising a solution of about 2-20 mg/ml of dextran sulfate and denatured collagen.

### Claim 13

A method for inhibiting undesirable bone growth in an animal comprising administering to the animal cross-linked dextran sulfate in an amount which is effective to inhibit said undesirable bone growth and a pharmaceutically acceptable carrier.

### Claim 14 (depends on 9)

The method according to claim 9 wherein the dextran sulfate is covalently cross-linked to the adhesive protein.

### Claim 15 (depends on 9)

The method according to claim 9 in which the adhesive protein is selected from the group consisting of fibrin, mussel polyphenolic adhesion protein, barnacle polyphenolic adhesion protein, oyster polyphenolic adhesion protein, chemically polymerized peptide from an adhesion protein and an analog of an adhesion protein produced recombinantly.

### Claim 16 (depends on 12, 13)

The method according to claim 12 or 13 wherein the sulfur content of the dextran sulfate is greater than approximately 10% by weight.

### Claim 17

The method according to 8, or 9 in which the animal is a human.

### Claim 18 (depends on 8)

The method according to claim 8 in which said administering is to the site of a lesion in the animal.

### Claim 19 (depends on 18)

The method according to claim 18 in which the lesion is a surgical lesion.

### Claim 20 (depends on 18)

The method according to claim 18 in which the lesion results from traumatic injury.

### Claim 21 (depends on 19)

The method according to claim 19 in which the surgical lesion results from a laminectomy.

### Claim 22 (depends on 19)

The method according to claim 19 in which the surgical lesion results from discectomy or surgery to treat temporomandibular joint dysfunction.

### Claim 23 (depends on 19)

The method of claim 19 in which the surgical lesion results from joint surgery, tendon surgery, thoracic surgery, vascular surgery, cardiac surgery, heart bypass surgery, heart valve replacement surgery, or open heart surgery.

### Claim 24

A method for inhibiting glial cell invasion in an animal comprising administering to the animal an anionic polymer selected from the group consisting of dextran sulfate, pentosan polysulfate, and alginate in an amount which is effective to inhibit said glial cell invasion.

### Claim 25 (depends on 2, 3, 4, 24)

The method according to claim 2, 3, 4 or 24 in which the anionic polymer is dextran sulfate.

### Claim 26 (depends on 24)

The method according to claim 24 in which said administering is to the site of a lesion in the animal.

### Claim 27 (depends on 24)

The method according to claim 24 in which the glial cell invasion is caused by a disease or disorder selected from the group consisting of trauma, surgery, viral infection, bacterial infection, metabolic disease, malignancy, exposure to toxic agents, and hyperplastic situations.

### Claim 28 (depends on 8, 9, 18)

The method according to claim 8, 9, 18, or 19 in which the undesirable bone growth follows craniosternostosis.