Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2001-02-15
2004-06-15
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S094600, C424S094610, C424S485000, C424S486000, C424S487000, C424S488000, C435S177000, C435S178000, C435S180000, C435S181000, C436S528000, C436S532000, C514S002600, C530S408000, C530S812000, C530S816000
Reexamination Certificate
active
06749865
ABSTRACT:
BACKGROUND OF THE INVENTION
Biopolymers are biocompatible polymers that are useful for a wide variety of biomedical applications, such as for surgical aids, to prevent or reduce the formation of surgical adhesions, and for drug delivery applications. Many biopolymers are naturally occurring substances found in the body, and therefore do not have any unacceptable toxic or injurious effects on biological function. An example of such a biopolymer is hyaluronic acid (“HA”), a naturally occurring mucopolysaccharide found, for example, in synovial fluid, in vitreous humor, in blood vessel walls and the umbilical cord, and in other connective tissues. Hyaluronic acid 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.
U.S. Pat. No. 4,582,865, to Balazs et al. states, inter alia, that cross-linked gels of HA can slow the release of a low molecular weight substance that is dispersed therein but not covalently attached to the gel macromolecular matrix. See, also, U.S. Pat. No. 4,636,524, which contains a disclosure of related technology. Both of these patents describe HA compositions in which the HA is crosslinked by reaction with divinyl sulfone, and the use of the crosslinked HA compositions in drug delivery applications.
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 by an ester linkage, either directly or in an ester complex including an alanine bridge as an intermediate linking group. The HA is modified by attaching cysteine residues to the HA via amide bonds, and then the cysteine-modified HA is crosslinked by forming disulfide bonds between the attached cysteine residues. Similarly, I. Danishefsky et al., 1971, in
Carbohydrate Res
., Vol. 16, pages 199-205, 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. See, also, U.S. Pat. No. 4,937,270 and U.S. Pat. No. 5,760,220 which describe the modification of hyaluronic acid by reaction of the carboxyl groups of the biopolymer with a nucleophile to produce a water insoluble amide, and the use of those compositions for controlled release drug delivery.
A series of patents assigned to VivoRx Pharmaceuticals, Inc., describe compositions for the in vivo delivery of insoluble pharmaceutically active agents. Delivery of the drug substances is achieved, for instance, by encasing the active agent in a polymeric shell formed from a biocompatible polymer. The biocompatible polymer may be protein, lipid, DNA molecule or polysacharide, and the pharmaceutically active agent may be a therapeutic protein such as taxol. The polymer contains covalently attached sulfhydryl groups or disulfide linkages which can be crosslinked to form disulfide bonds. The polymeric shell is formed using ultrasonic irradiation techniques. These compositions are described as being less toxic, being more soluble, and having improved targeting as compared to prior art compositions. Relevant VivoRx patents include U.S. Pat. Nos. 5,498,421; 5,439,686; U.S. Pat. No. 5,362,478; U.S. Pat. No. 5,635,207; U.S. Pat. No. 5,560,933; U.S. Pat. No. 5,635,207 and U.S. Pat. No. 5,639,473.
U.S. Pat. No. 5,496,872 relates to biocompatible and biodegradable crosslinkable polymers having reactive thiol groups. The reactive thiol groups can be crosslinked to form disulfide linkages between adjacent molecules, resulting in a three dimensional network. These polymers can be used for binding tissues or binding tissues with implanted biomaterials.
U.S. Pat. No. 5,932,552 describes a keratin hydrogel having biomedical applications. The hydrogel is formed from crosslinked keratin bound by disulfide linkages. Among the biomedical applications described in the patent are uses of the hydrogels for cell scaffolding in tissue repair.
U.S. Pat. Nos. 5,354,853 and 5,451,661 describe, respectively, the preparation of phospholipid-saccharide conjugates, and lipids conjugated to biologically active agents such as peptides, proteins and nucleic acids. These conjugates are described as being particularly useful in drug delivery applications.
U.S. Pat. No. 5,902,795, to Toole et al., discloses hyaluronic acid oligosaccharides, having between one and sixteen repeating units, which are used to treat tumors in mammals. The patent states that the oligosaccharides act to reduce the level of membrane-associated hyaluronan-binding proteins, which are expressed on the surface of certain tumor cells during cell migration. The treatment is believed to reduce the incidence of tumor metastasis in the mammals.
A. Burnkop-Schnurch et al.,
J. Controlled Release,
2000, 66, 39, describes the synthesis of carboxymethyl cellulose (“CMC”) and polycarbophil modified with L-cysteine using carbodiimide chemistry. The polymers are reacted with the cysteine to form an amide bond between the primary amino group of the amino acid and the carboxylic acid of the polymer. The thiolated polymers were allowed to oxidize to form disulfide bridges. The dissolution of these tablets, both with and without drugs, was analyzed. The tablets were found to have improved stability and viscoelasticity.
Copending U.S. patent application Ser. No. 09/430,857 now abandoned relates to surfaces that have been modified by the attachment of hyaluronic acid. The surface can be part of a medical device, such as a stent or a surgical tubing. The surface is modified to include a reactive amino group that reacts with a derivatized hyaluronic acid. The modified devices and instruments are hydrophilic, and have anti-fouling and anti-platelet adhesion characteristics, thereby producing a reduction in risks associated with thrombosis.
The conjugated biopolymers of this invention represent a significant improvement over drug delivery vehicles of the prior art due, in part, to the site-specific reaction between the biopolymer and the therapeutic agent which increases the stability and activity of the therapeutic agent upon delivery to the desired site within a subject.
SUMMARY OF THE INVENTION
The present invention features a biopolymer-therapeutic agent conjugate in which the biopolymer and therapeutic agent are joined by a disulfide bond. The biologically active conjugate of this invention is useful as a drug delivery vehicle for the in vivo delivery of the therapeutic proteins to specific cells, organs or tissues in a subject. Drug delivery specificity is achieved by appropriate selection of the structure and molecular weight of the biopolymer.
The chemistry used to prepare the conjugates permits the site-specific reaction between the biopolymer and the therapeutic agent. The therapeutic agent contains a reactive thiol group, which can be present in an unmodified version of the therapeutic agent, as in the case of cysteine for example. Alternatively, the thiol group can be introduced into a modified version of a therapeutic agent that does not normally contain a reactive thiol group.
In one embodiment, the therapeutic agent can be reacted, through the reactive thiol group, with a chemically modified version of the biopolymer. This reaction typically occurs at a pH in the range of from about 6.0 to about 10. The biopolymer is activated and modified by reaction with an activating agent, such as a carbodiimide, and reacted with an organic disulfide compound. The organic disulfide compound contains a terminal group, such as an amino group or
Calias Pericles
Miller Robert J.
Blundell Isabelle A. S.
Genzyme Corporation
Naff David M.
LandOfFree
Modification of biopolymers for improved drug delivery does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Modification of biopolymers for improved drug delivery, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Modification of biopolymers for improved drug delivery will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3307624