Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1994-10-06
2001-09-25
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S443000
Reexamination Certificate
active
06294202
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to water-insoluble biocompatible compositions formed from one or more chemically modified polyanionic polysaccharides, and more specifically to compositions of these chemically modified polyanionic polysaccharides and hydrophobic bioabsorbable polymers.
Polyanionic polysaccharides are polysaccharides, also called glycans, containing more than one negatively charged group (e.g., carboxyl groups at pH values above 4.0); they consist of long chains having hundreds or thousands of basic repeat units. These molecules may differ in the nature of their recurring repeat units, in the length of their chains, and in the degree of branching. There are two major types of polyanionic polysaccharides: homopolysaccharides, which contain only a single type of monomeric unit, and heteropolysaccharides, which contain two or more different types of monomeric units.
Polysaccharides naturally occur in a variety of tissues in the body and in some cases associate with proteins in complex macromolecular structures. Examples include proteoglycans, found in the jellylike ground substance, or extracellular matrix, filling the space between the cells of most tissues. Proteoglycans are also present in cartilage, tendons, skin, and in the synovial fluid. Likewise, glycosaminoglycans are water-soluble polysaccharides found in the ground substance of connective tissue, and are highly charged linear polyanions having the general formula (AB)
n
, where A is a uronic acid residue and B is a hexosamine.
Hyaluronic acid (HA) and its salt sodium hyaluronate is an example of a naturally occurring glucosaminoglycan, or mucopolysaccharide that is a common extracellular matrix component. HA is ubiquitous within the human body and exists in a wide range of forms in a variety of tissues including synovial fluid, vitreous humor, blood vessel walls, pericardial fluid, and umbilical cord.
Hyaluronic acid in chemically modified (“derivatized”) forms, is useful as a surgical aid, to prevent adhesions or accretions of body tissues during the post-operation period (e.g., U.S. Pat. No. 5,017,229). The derivatized HA in the form of a gel or membrane is placed over and between damaged tissue surfaces in order to prevent adhesion formation between apposing surfaces. To be effective, the gel or film must remain in place and prevent tissue contact for a long enough time so that when the gel finally disperses and the tissues do come into contact, they will no longer have a tendency to adhere.
Chemically modified HA can also be useful for controlled release drug delivery. Balazs et al., 1986, U.S. Pat. No. 4,582,865, states that “cross-linked gels of HA can slow down the release of a low molecular weight substance dispersed therein but not covalently attached to the gel macromolecular matrix.” Sparer et al., 1983, Chapter 6, pages 107-119, in Roseman et al.,
Controlled Release Delivery Systems
, Marcel Dekker, Inc., New York, describes sustained release of chloramphenicol covalently attached to hyaluronic acid via ester linkage, either directly or in an ester complex including an alanine bridge as an intermediate linking group.
Danishefsky et al., 1971
, Carbohydrate Res
., Vol. 16, pages 199-205, describes modifying a mucopolysaccharide by converting the carboxyl groups of the mucopolysaccharide into substituted amides by reacting the mucopolysaccharide with an amino acid ester in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (“EDC”) in aqueous solution. They reacted glycine methyl ester with a variety of polysaccharides, including HA. The resulting products are water-soluble; that is, they rapidly disperse in water or in an aqueous environment such as is encountered between body tissues.
Proposals for rendering HA compositions less water-soluble include cross-linking the HA. R. V. Sparer et al., 1983, Chapter 6, pages 107-119, in T. J. Roseman et al.,
Controlled Release Delivery Systems
, Marcel Dekker, Inc., New York, describe modifying HA by attaching cysteine residues to the HA via amide bonds and then cross-linking the cysteine-modified HA by forming disulfide bonds between the attached cysteine residues. The cysteine-modified HA was itself water-soluble and became water-insoluble only upon cross-linking by oxidation to the disulfide form.
De Belder et al., PCT Publication No. WO 86/00912, describe a slowly-degradable gel, for preventing tissue adhesions following surgery, prepared by cross-linking a carboxyl-containing polysaccharide with a bi- or polyfunctional epoxide. Other reactive bi- or polyfunctional reagents that have been proposed for preparing cross-linked gels of HA having reduced water-solubility include: 1,2,3,4-diepoxybutane in alkaline medium at 50° C. (Laurent et al., 1964
, Acta Chem. Scand
., vol. 18, page 274); divinyl sulfone in alkaline medium (Balazs et al., U.S. Pat. No. 4,582,865, (1986); and a variety of other reagents including formaldehyde, dimethylolurea, dimethylolethylene urea, ethylene oxide, a polyaziridine, and a polyisocyanate (Balasz et al., U.K. patent Application No. 84 20 560 (1984). Mälson et al., 1986, PCT Publication No. WO 86/00079, describe preparing cross-linked gels of HA for use as a vitreous humor substitute by reacting HA with a bi- or polyfunctional cross-linking reagent such as a di- or polyfunctional epoxide. Mälson et al., 1986, EPO 0 193 510, describe preparing a shaped article by vacuum-drying or compressing a cross-linked HA gel.
SUMMARY OF THE INVENTION
In one aspect, the invention features a biocompatible composition containing one or more polyanionic polysaccharides combined with one or more hydrophobic bioabsorbable polymers or copolymers.
In preferred embodiments, the polyanionic polysaccharide is carboxymethylcellulose (CMC), carboxymethylamylose (CMA), hyaluronic acid (HA), chondroitin-6-sulfate, dermatin sulphate, heparin, heparin sulfate, heparan sulfate, or dermatin-6-sulfate. Preferably, the polyanionic polysaccharide is HA, CMC, or CMA. Most preferably, the polyanionic polysaccharide is in the form of a water-insoluble derivative. Also in preferred embodiments, the biocompatible composition includes two or more polyanionic polysaccharides or their water-insoluble derivatives, e.g., hyaluronic acid and carboxymethylcellulose or hyaluronic acid and heparin.
The hydrophobic bioabsorbable polymer is chosen from the group consisting of polyglycolide, polylactide (D, L, DL), polydioxanones, polyestercarbonates, polyhydroxyalkonates, polycaprolactone (polylactones), and copolymers thereof; preferably polyglycolide or polylactide, or a copolymer or polyglycolide-caprolactone of polyglycolide and polylactide, polylactide-polycaprolactone.
The compositions of the invention can be provided in the form of an adhesion prevention composition, e.g., in a membrane, foam, film, or composition suitable for extrusion. When the composition contains a water-insoluble polyanionic polysaccharide derivative the composition can also be produced in the form of fibers, or knitted or weaved fabric.
Compositions of the invention which contain a water-insoluble polyanionic polysaccharide derivative can also be provided as a composite matrix to support cell and tissue growth and proliferation. For example, any desired cell type may be cultured in vitro in the presence of one of the water-insoluble compositions of the present invention to form a water-insoluble matrix that is coated, impregnated or infiltrated with the cells. Preferably, the cells are derived from a mammal, and most preferably from a human. In one example, fibroblast infiltrated matrices may be placed at the site of a skin lesion (e.g., wound or ulcer) to promote healing of the lesion. Other cell types that can be cultured on the matrices of this invention include but are not limited to, osteocytes, chondrocytes, keratinocytes, and tenocytes. Matrices impregnated with these cells can be used to aid in the healing of bone, cartilage, skin, and tendons and ligaments, respectively. Matrices can also be generated which contain a mixture of
Burns James W.
Greenawalt Keith E.
Masi Louis
Cobert Robert J.
DesRosier Thomas J.
Genzyme Corporation
Genzyme Corporation
Webman Edward J.
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