Chemistry: molecular biology and microbiology – Carrier-bound or immobilized enzyme or microbial cell;... – Enzyme or microbial cell is immobilized on or in an organic...
Reexamination Certificate
1999-06-22
2003-02-18
Naff, David M. (Department: 1651)
Chemistry: molecular biology and microbiology
Carrier-bound or immobilized enzyme or microbial cell;...
Enzyme or microbial cell is immobilized on or in an organic...
C424S484000, C424S486000, C424S489000, C424S093100, C424S093700, C435S174000, C435S178000, C435S180000, C435S395000, C530S812000, C530S813000, C530S815000, C514S04400A
Reexamination Certificate
active
06521431
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel cross-linking agents, more particularly to novel biodegradable cross-linking agents. Earlier use of cross-linking agents in a variety of fields involving proteins, carbohydrates or polymers is well established. Even biodegradable cross-links have previously been prepared and utilized. However, none before have utilized particular and advantageous cross-linker designs of the present invention.
Within the pharmaceutical, agricultural, veterinary, and environmental industries, much attention has been directed to the applications of biodegradable polymers. The Oxford English dictionary defines biodegradable as: “susceptible to the decomposing action of living organisms especially bacteria or broken down by biochemical processes in the body.” However, due to the advent of the widespread use of polyhydroxyacids as degradable polymers, this definition should be extended to include non-enzymatic chemical degradation which can progress at an appreciable rate under biologically relevant conditions (the most relevant condition being water at pH 7; 100 mM salt and 37° C.). Thus, the meaning of the term biodegradation can be broadened to include the breakdown of high molecular weight structures into less complicated, smaller, and soluble molecules by hydrolysis or other biologically derived processes.
In the biomaterials/pharmaceutical area, there is great interest in the use of biodegradable materials in vivo, due to performance and regulatory requirements. However, most of the reports on biodegradable materials have focused on linear water-insoluble hydroxyacid polyesters. Much less work has been done on biodegradable network polymers which are cross-linked. Therefore, due to the unique properties of network polymers, it is to be expected that biodegradable networks will find many new and important applications
Biodegradable Polymers
Much work has been accomplished in the last 20 years in the area of hydrophobic biodegradable polymers, wherein the biodegradable moieties comprise esters, lactones, orthoesters, carbonates, phosphazines, and anhydrides. Generally the polymers made of these biodegradable linkages are not water soluble and therefore in themselves are not amenable for use in systems where water is required, such as in hydrogels.
Since the mechanism of biodegradation in these polymers is generally through the hydrolytically-active components of water (hydronium and hydroxide ions), the rate of hydrolytic scission of the bonds holding a polymer network together is generally pH sensitive, with these moieties being susceptible to both specific-acid catalyzed hydrolysis and base hydrolysis. Other factors affecting the degradation of materials made of these polymers are the degree of polymer crystallinity, the polymer volume fraction, the polymer molecular weight, the cross-link density, and the steric and electronic effects at the site of degradation.
Degradable Network Structures
Biodegradable network structures are prepared by placing covalent or non-covalent bonds within the network structure that are broken under biologically relevant conditions. This involves the use of two separate structural motifs. The degradable structure is either placed into (i) the polymer backbone or (ii) into the cross-linker structure. The method described herein creates a degradable structure through placing degradable regions in the cross-linking domain of the network. One of the first occurrences of degradable hydrogels was published in 1983 by Heller. This system contains a water soluble linear copolymer containing PEG, glycolylglycolic acid and fumaric acid linkages. The fumaric acid allowed the linear polymer to be cross-linked through free radical polymerization in a second network forming polymerization step, thus creating a polymer network which could degrade through hydrolysis of the glycolic ester linkages. This is an example of creating degradable linkages in the polymer backbone.
Biodegradable Cross-linkers
The first truly degradable cross-linking agents were made from aryl diazo compounds for delivery of drugs in the digestive tract. The diazo moiety is cleaved by a bacterial azoreductase which is present in the colon. This has been used to create colon specific delivery systems (Brondsted et al. & Saffan et al.). Another biodegradable cross-linking agent appears in the work of Ulbrich and Duncan where a bis-vinylic compound based on hydroxyl amine was synthesized. Hydrogels made from this degradable cross-linker were shown to undergo hydroxide induced hydrolysis of the nitrogen-oxygen bond.
Hubbell et al. have made hydrogels composed of macromonomers composed of a central PEG diol which was used as a bifunctional alcohol in the tin octanoate catalyzed transesterifying ring opening polymerization of lactide to give a bis-oligolactate PEG. This compound was then reacted with acryloyl chloride to give a macromolecular cross-linker which could be formed into a homo-polymer interpenetrating network of PEG and oligolactylacrylate through free radical polymerization (Pathak et al.). Hubbell mostly intended these compounds for use as photopolymerizable homo-polymers useful to prevent surgical adhesions.
A second solution to this problem has been recently reported in the work of Van Dijk et al. which is the first report of a biodegradable cross-linking macromonomer composed of alpha-hydroxy esters (Van Dijk-Wolthius et al.). This work combines natural polymers with synthetic polymers in an interpenetrating network. This group functionalized dextran with oligo-alpha hydroxy acid domains which were end capped with vinyl regions that were polymerized into biodegradable networks via free radical polymerization.
The most recent report of a biodegradable cross-linking agent was one designed to undergo enzymatic degradation. This cross-linker is composed of a centro-symmetric peptide terminated by acrylamide moieties with a central diamine linking the two ends (Kurisawa et al.). This report is related to the invention described herein in that the property of biodegradability is built into the polymer network by first synthesizing a small symmetrical cross-linker which can undergo cleavage, then incorporating this in a polymer network.
Properties of Degradable Gels: Swelling and Porosity
Since degradability is a kinetic effect, the properties of degradable gel networks are the similar to those standard gel networks, except they change with time. The two main properties that are exhibited by degradable hydrogel networks are swelling and network porosity that increase with time as the network degrades.
The main feature observed with degradable cross-linked polymer networks in solvents which cause them to swell is that the polymer network swells as it degrades. This is because network degradation results in a decrease in cross-link density. As the cross-link density decreases there is more available volume for solvent within the network. The solvent increasingly permeates the network structure, driven by a favorable thermodynamic mixing of solvent with the polymer network.
Important uses envisioned for degradable gels are as controlled drug delivery devices and as degradable polymers for other in vivo uses. These devices are able to change from a high viscosity material (gel) to a lower viscosity soluble material (sol). The resulting water soluble linear polymer can then be readily transported and excreted or degraded further.
Degradable hydrogel networks offer the opportunities to effect the diffusitivity of materials bound in the hydrogel network, because as the network degrades the diffusion coefficient of molecules in the network increases with time thus facilitating the release of materials locked within the polymer network (Park).
Moreover, because the hydrogel network structure itself is of such a high molecular weight, transport of the hydrogel network out of the body or environment is slow. This is especially true in vivo where non-degradable implanted hydrogel networks can remain in the body for many years (Torchilin et al.). Th
Kiser Patrick F.
Thomas Allen A.
Access Pharmaceuticals Inc.
Jackson & Walker, LLP
Naff David M.
LandOfFree
Biodegradable cross-linkers having a polyacid connected to... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Biodegradable cross-linkers having a polyacid connected to..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Biodegradable cross-linkers having a polyacid connected to... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3174636