Title:  Biocompatible surfaces and a method for their preparation

United States Patent:  6,204,254

Assignee:  Baxter International, Inc. (Deerfield, IL)

Filed:  September 12, 1997

A novel group of compounds is disclosed for decorating the surface of synthetic polymeric or tissue derived prostheses to prevent adverse rejection events. The decorating molecules are obtained as derivatives of naturally occurring polysaccharides, derivatized to provide functionally reactive groups at the termini thereof, and the reacting with nucleophilic or other groups on the surface of the prosthesis in a simple one step reaction. Some of these reagents are useful in noncovalent adsorption to polyolefinic or perfluorocarbon based materials. Finally, phospholipids partially substituted with the nonantigenic polysaccharides provide a superior bipolar component for liposome formation.

SUMMARY OF THE INVENTION

For many medical conditions there is no available substitute for the implantation of prosthetic devices in the body. Many of these are made of plastic such as immunoisolation chambers, joint parts, bone replacements, or other polymer fabrics. Other prostheses are derived from human or animal tissue such as heart valves, skin, etc. While some prostheses are intended only for short term use (as an artificial heart), others will reside in the body indefinitely.

It is an object of the present invention to provide a decorating molecule capable of disguising or masking determinants on prosthetic surfaces which induce immune or sensitization responses leading to eventual rejection or failure of the prosthesis. It is a further object to provide a coating of negative charge which will help to repel red blood cells and platelets, whose contact with prostheses leads to immune activation. It is a still further object to devise chemistries that permit covalent or noncovalent attachment between the protective decorative molecule and the prosthetic surface.

In accordance with the invention, polysaccharides containing a linker and reactive groups for combining chemically with moieties on the surface of prostheses of either tissue or synthetic origin are derived by hydrolysis from chondroitin or hyaluronic acid. These compounds are ubiquitous in the mammalian body, and are not perceived by the immune system as antigenic because of their prevalence in the tissues and the high level of access of the molecules to the blood.

These polysaccharides may be broken down into oligosaccharides of repeating sugar units, and the reducing end may be modified chemically to react with groups capable of attaching to the surface of prothesis. It is desirable also to include a linker, also of benign immunogenicity (e.g. of low antigenicity or not immunogenic in the species to which it is administered), to prevent steric hindrance between the reactive group on the oligosaccharide linker molecule and a nucleophilic group on the substrate therapeutic agent surface.

Compounds are provided with the following formula I:

B'--(A--B)_n --A'--L--Z--

wherein A and B are sugars which may be of N-acetylgalactosamine, N-acetylglucosamine, glucuronic acid, iduronic acid or glucose forming a repeating disaccharide unit in which A and B are joined covalently by a glycosidic bond between C-1 of sugar A and C-3 or C-4 of sugar B. The A--B disaccharide units are joined covalently to form an oligosaccharide by a glycosidic bond between C-1 of penultimate sugar B of a first disaccharide unit and C-3 or C-4 of sugar A in the next successive disaccharide unit. B' is a sugar at the non-reducing terminus of the oligosaccharide of ring structure identical to sugar B, and A' is a 1 -amino, 1-amido, or 1-imino acyclic hexose joined covalently by a glycosidic bond between C-1 of sugar B at the terminus opposite the non-reducing terminus of said oligosaccharide and C-3 or C-4 of sugar A'. This structure is further joined covalently by a 1-amino, 1-amido, or 1-imino linkage to linker L comprising an aliphatic, acyclic carbon chain containing one or more moieties, which can be an ether, thio ether, or amide. The linker bridges sugar A' and one or more electrophilic groups Z, which may be an aldehyde, an activated ester of a carboxylic acid, a maleimide, an epoxide, a tosyl or tresyl ester, or a halide.

The foregoing compounds are constructed from oligosaccharides which may be derived from chondroitin-4-sulfate, chondroitin-6-sulfate or hyaluronic acid. "Derived" herein means hydrolyzing these native polysaccharides by acid hydrolysis, down to oligosaccharides of a molecule size range of 1,000 to 15,000 Daltons.

Oligosaccharide-polymer conjugates for masking biologically reactive sites on the surface of prosthesis have the structure of the masking molecule set forth above and a formula II:

B'(A--B)_n --A'--L--Y--Prosthesis

wherein the letter symbols have the structures stated in the above disclosure, and Y is selected from a methylene radical, beta-hydroxyethylene radical, carboxyl radical, succinimide alpha radical, and nullity. The method of making these conjugates is a simple one step reaction in which the polysaccharide reagents set forth above are reacted with the nucleophilic moieties such as an amino or sulfhydryl group presented in abundance on the surface of the prosthesis, either a synthetic polymer surface or surface derived from tissue.

The polysaccharides having a terminus consisting of either an n-alkyl group of 5 to 30 carbon atoms, or a perfluorinated tail group, also of 5 to 30 carbon atoms are useful in decorating a polyolefinic or perfluorocarbon based prosthesis respectively. These alkyl or perfluorinated tails are added to the linker by conventional chemistries.

Finally, the present invention provides a novel "stealth" type liposome, capable of delivering a therapeutic agent on a continuous basis, or by repeated administration, without causing immune mediated reactions. The liposome contains one or more phospholipids in which one fatty acid in the 1 or 2 carbon position on the glycerol backbone is substituted with the polysaccharide-linker substituents set forth above. The composition of the lipid fraction may either be defined by hydrolyzing all the ester bonds, removing the released fatty acids, and then re-esterifying in the desired position by a fatty acid of defined structure, or a group of fatty acids of desired ratio. Alternatively, the naturally occurring fatty acids at a given desired position can be retained, and the polysaccharide substituted at the open position. These liposomes will contain the usual mixture of phopholipids, cholesterol, and an aqueous component or phase, in addition to the present substituted phospholipid, and be made according to a variety of conventional liposome forming methods.

Claim 1 of 16 Claims

What is claimed is:

1. A compound having a formula: 

wherein

A and B are sugars forming a repeating disaccharide unit in which A and B are joined covalently by a glycosidic bond between C-1 of sugar A and C-3 or C-4 of sugar B, and the repeating disaccharide units are joined covalently to form an oligosaccharide by a glycosidic bond between C-1 of sugar B of a first disaccharide unit and C-3 or C-4 of sugar A in a next successive disaccharide unit,

B' is a sugar at a non-reducing terminus of said oligosaccharide of ring structure identical to sugar B,

A' is an acyclic hexose joined covalently by a glycosidic bond between C-1 of sugar B at a terminus opposite the non-reducing terminus of said oligosaccharide and C-3 or C-4 of sugar A',

n is an integer from 2 to 20,

L is an aliphatic, acyclic carbon chain which links Y to the 1-amino, 1-amido or 1-imino group attached to C-1 of sugar A', the aliphatic, acyclic carbon chain containing one or more moieties selected from the group consisting of ether, thio ether, and amide;

Y is selected from the group consisting of a methylene radical, .beta.-hydroxyethylene radical, carboxyl radical, succinimide .alpha. radical, and a covalent bond; and

PR is a prosthetic surface.

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