Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-08-18
2001-05-22
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S424000, C514S054000, C514S060000, C514S944000, C514S945000, C514S964000
Reexamination Certificate
active
06235726
ABSTRACT:
Hyaluronic acid (“HA”) is a naturally occurring mucopolysaccharide found, for example, in synovial fluid, in vitreous humor, in blood vessel walls and 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 glucuronidic and &bgr; 1-4 glucosaminidic bonds, so that the repeating unit is -(1→4)-&bgr;-D-GlcA-(1→3)-&bgr;-D-GlcNAc-. 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 5×10
4
up to 1×10
7
daltons.
As used herein the term “HA” means hyaluronic acid and any of its hyaluronate salts, including, for example, sodium hyaluronate (the sodium salt), potassium hyaluronate, magnesium hyaluronate, and calcium hyaluronate.
HA, in chemically modified (“derivatized”) form, is useful as a surgical aid, to prevent adhesions or accretions of body tissues during the post-operation period. The derivatized HA gel or film is injected or inserted into the locus between the tissues that are to be kept separate to inhibit their mutual adhesion. To be effective the gel 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.” 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, 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.
I. 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. (T. C. Laurent et al., 1964, Acta Chem. Scand., vol. 18, page 274); divinyl sulfone in alkaline medium (E. A. Balasz 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 (E. A. Balasz et al., U.K. Patent Appl. No. 84 20 560 (1984). T. Malson 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. T. Malson 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
The invention features a method for preparing a water insoluble composition by-combining a polyanionic polysaccharide and an activating agent under conditions sufficient to form the composition.
Preferred polyanionic polysaccharides include hyaluronic acid (HA), carboxymethylcellulose (CMC), carboxymethylamylose (CMA), chondroitin-6-sulfate, dermatan sulfate, heparin, and heparan sulfate; HA, CMC, and CMA are particularly preferred.
The preferred pH for carrying out the reaction is 3.5 to 8.0, more preferably 4.0 to 5.1 and most preferably 4.7 to 5.1. The preferred concentration for the polysaccharide is. 0.005-0.1M, more preferably 0.01-0.02M. The molar ratio of polysaccharide to activating agent is preferably 1 mole or less of carboxyl groups of polysaccharide per mole of carbodiimide, more preferably 1 mole of carboxyl groups of polysaccharide per 4 moles of carbodiimide. The preferred activating agent is a carbodiimide, e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide methiodide.
The activated-polyanionic polysaccharides which comprise the water insoluble compositions produced by the method of the invention may be in the form of a gel, or in the form of fibers. Blends can also be prepared by mixing various amounts of two or more different activated-polyanionic polysaccharides, more preferably blends consist of activated-HA and activated-CKC, or activated-HA and activated-CMA.
The compositions and blends of the invention may be provided in the form of an adhesion prevention composition, e.g., in the form of a film, foam, or composition suitable for incorporation in a syringe. They may also include a pharmaceutically active substance dispersed throughout making them useful as a drug delivery system. Suitable substances include proteins, growth factors, enzymes, drugs, biopolymers, and biologically compatible synthetic polymers.
The term “film”, as used herein, means a substance formed by compressing a gel or fibers, or by allowing or causing a gel or fibers to dehydrate. Any gel or fibers of the invention may be formed into such a film.
The term “foam”, as used herein, means a substance formed by introducing gas bubbles into the gels or fibers of the invention.
A “biocompatible” substance, as the term is used herein, is one that has no medically unacceptable toxic or injurious effects on biological function.
A “polyanionic polysaccharide” is a polysaccharide containing more than one negatively charged group, e.g., carboxyl groups at pH values above about pH 4.0.
We have discovered that a gel, foam, or film produced by treating a polyanionic polysaccharide with a suitable activating agent, may be made having decreased water solubility, without the use of any separately added bi- or polyfunctional cross-linking agent.
A “water soluble” gel, or film, as that term is used herein, is one which, formed by drying an aqueous solution of 1% weight/weight (“w/w”) sodium hyaluronate in water, having dimensions 3 cm×3 cm×0.3 mm, when placed in a beaker of 50 ml of distilled water at 20° C. and allowed to stand without stirring, loses its structural integrity as a film after 3 minutes, and becomes totally dispersed within 20 minutes. A “water insoluble” film of the invention, as that phrase and like terms are used herein, formed using a 1% aqueous solution of a polyanionic polysaccharide, modified according to the invention, having the same dimensions and similarly allowed to stand without stirring in a beaker of 50 ml of distilled water at 20° C., is structurally intact after 20 minutes; the film boundaries and edges are still present af
Burns James W.
Miller Robert
Geist Gary
Genzyme Corporation
Genzyme Corporation
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