Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active...
Reexamination Certificate
2000-02-14
2003-02-18
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
C424S422000, C424S423000, C424S400000, C514S781000
Reexamination Certificate
active
06521223
ABSTRACT:
Throughout this application, various publications are referenced. All publications referenced herein, including published patent applications and issued or granted patents, are hereby incorporated by reference in their entireties into this application.
BACKGROUND OF THE INVENTION
This invention relates to single phase gel products formed by the reaction of a polyanionic polysaccharide and divinyl sulfone (“DVS”), and preferably formed by the reaction of hyaluronic acid (“HA”) and divinyl sulfone. The single phase gel products of this invention are particularly useful for preventing the formation of adhesions between affected tissue surfaces of a subject who has undergone a surgical procedure.
Adhesion formation is a well known complication of many types of surgical procedures, and particularly abdominal and bowel surgeries. Adhesion formation typically occurs as a result of the formation of a fibrin clot which transforms into scar tissue connecting different tissues which are normally separated. Surgical intervention is frequently required in order to eliminate the adhesions, although the adhesions can, and often do, reappear following the surgery. The primary objective of adhesion prevention formulations is to interrupt the adhesion formation mechanism, which is believed to result from the diffusion of fibrinogen into the space between the tissues subject to surgical trauma, thereby causing the formation of fibrin clots in the space.
In addition to acting as an adhesion barrier, a successful anti-adhesion formulation should be “biocompatible”, meaning that it has no medically unacceptable toxic or injurious effects on the biological function of the subject, and “bioabsorbable”, meaning that it can be absorbed by the tissue without remaining in the subject as an implant device. Thus, the formulation should remain in the body for a sufficient period of time to be effective in separating the tissue and preventing adhesions, while being absorbed by the tissue once the danger of adhesion formation has ended, thereby minimizing any long term effects which may result from the use of an implant device.
Hyaluronic acid (“HA”) is a naturally occurring mucopolysaccharide found, for example, in synovial fluid, in vitreous humor, in blood vessel walls, the umbilical cord, and in other connective tissues. The polysaccharide consists of alternating N-acetyl-D-glucosamine and D-glucuronic acid residues joined by alternating &bgr;1-3 glucoronidic and &bgr;1-4 glucosaminidic bonds, so that the repeating unit is —(1→4)-&bgr;-D-G1cA-(1→3)-&bgr;D-G1cNAc-. In water, hyaluronic acid dissolves to form a highly viscous fluid. The molecular weight of hyaluronic acid isolated from natural sources generally falls within the range of from about 5×10
4
up to about 1×10
7
daltons.
Hyaluronic acid, in chemically modified form, is known to be useful as a surgical aid to prevent adhesions and accretions of body tissues during the post-operation period. The chemically modified hyaluronic acid gel or film is injected or inserted into the locus between the tissues that are to be kept separate to inhibit their mutual adhesion. Chemically modified hyaluronic acid can also be useful for controlled release drug delivery. See U.S. Pat. No. 4,937,270 and U.S. Pat. No. 5,017,229, which disclose chemically modified versions of HA, or HA in combination with other polyanionic polysaccharides, such as carboxymethylcellulose, which are prepared by reacting the HA with a carbodiimide. The chemically modified version of HA and carboxymethylcellulose is commercially available in film form as Seprafilm® membranes from the Genzyme Corporation.
I. Danishefsky et al.,
Carbohydrate Res
., Vol. 16, pages 199-205, 1971, describe the modification of 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. Danishefsky et al. react 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 by amide bonds, and then cross-linking the cysteine-modified HA by forming disulfide bonds between the attached cysteine residues.
U.S. Pat. No. 5,676,964 describes the preparation of cross-linked polysaccharides, including HA, wherein the cross-linking reaction occurs as a result of covalent bonds formed between carboxyl groups and hydroxyl groups of adjacent polysaccharide molecules.
U.S. Pat. No. 4,582,865; U.S. Pat. No. 4,636,524 and U.S. Pat. No. 5,128,326 describe HA compositions in which the HA is cross-linked by reaction with divinyl sulfone, and further describe the use of these compositions for drug delivery applications. U.S. Pat. No. 4,605,691 describes a method for preparing cross-linked HA compositions using divinyl sulfone as a cross-linking agent in an alkali solution.
U.S. Pat. No. 5,143,724; U.S. Pat. No. 5,247,698 and U.S. Pat. No. 5,399,351 disclose biocompatible, viscoelastic polymeric gel slurries prepared by reacting hyaluronic acid and a cross-linking agent such as divinyl sulfone, which are used in anti-adhesion formulations. The gel slurry is a two phase composition comprising discrete particles distributed in a polymer solution. In one embodiment, the slurry is formed from cross-linked hyaluronic acid particles contained in a solution of hyaluronic acid. The two phase slurries are believed to be effective in preventing adhesion formation due to their ability to separate affected tissue surfaces coupled with the ability to restrict diffusion at the site of potential adhesion formation.
U.S. Pat. No. 5,783,691 relates to hyaluronic acid compositions which are prepared by crosslinking hyaluronic acid with a phosphorus-containing reagent, such as sodium phosphate, in an alkaline medium to form a gel product. The crosslinking reagents described in this patent are not completely soluble, resulting in a two phase system, with one phase containing the crosslinked product. The gels can contain drugs and can be used as drug release vehicles upon administration to a subject.
Two phase gel slurries do suffer from certain drawbacks, however. For instance, the material must be processed correctly in order to improve the handling properties of the material, and to permit its therapeutic application through the narrow openings of needles and other applicators, particularly for minimally invasive surgical indications. Such processing requires the use of processing equipment and the application of shear forces to the material, which in turn can result in a decrease in viscosity (thinning). Two phase materials contain dispersed, heterogeneous particles which tend to plug the narrow openings of such delivery systems. A single phase, homogeneous composition is more useful in minimally invasive surgical applications where devices are introduced into the body through narrow access ports.
It would therefore be highly desirable to formulate a single phase gel solution which is capable of preventing the formation of adhesions, and which can be easily handled and stored for future use, and which possesses the advantageous characteristics of two phase gels.
SUMMARY OF THE INVENTION
The present invention features a cross-linked polyanionic composition which is useful for the prevention of adhesions which can arise as the result of a surgical procedure performed on a subject. The cross-linked composition is prepared by the reaction of the polyanionic polysaccharide with divinyl sulfone. The reaction occurs in an aqueous solution and results in the formation
Calias Pericles
Miller Robert J.
Blundell Isabelle A. S.
Genzyme Corporation
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