Much work has been accomplished in the last 20 years in the area of hydrophobic biodegradable polymers, wherein the biodegradable moieties include 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.
Biodegradable network structures are prepared by placing covalent or non-covalent bonds within the network structure that may be 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. In 1983, a system of degradable hydrogels was disclosed that reportedly included a water-soluble linear copolymer containing PEG, glycolylglycolic acid, and fumaric acid linkages (Heller, J.; Helwing, R. F.; Baker, R. W.; and Tuttle, M. E. “Controlled release of water-soluble macromolecules from bioerodible hydrogels.” Biomaterials, 4; (1983) 262-266). The fumaric acid reportedly allowed the linear polymer to be cross-linked through free radical polymerization in a second network forming polymerization step, thus creating a polymer network that 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 reportedly made from aryl diazo compounds for delivery of drugs in the digestive tract. According to Brondsted (Brondsted, H.; and Kopccek, J. “Hydrogels for site-specific oral drug deliver: synthesis and characterization.” Biomaterials, 12; (1991) 584-592), the diazo moiety may be cleaved by a bacterial azoreductase that is present in the colon. These agents are reportedly useful in the creation of colon specific delivery systems. A bis-vinylic compound based on hydroxylamine has been disclosed as a biodegradable cross-linking agent by Ulbrich and Duncan (Ulbrich, K.; Subr, V.; Seymour, L. W.; and Duncan, R. “Novel biodegradable hydrogels prepared using the divinylic crosslinking agent N,O-dimethacryloylhydroxylamine. 1. Synthesis and characterisation of rates of gel degradation, and rate of release of model drugs, in vitro and in vivo.” Journal of Controlled Release, 24; (1993) 181-190). Hydrogels made from this degradable cross-linker were said to undergo hydroxide-induced hydrolysis of the nitrogen-oxygen bond.
Hubbell et al. (U.S. Pat. Nos. 5,801,033; 5,834,274; and 5,843,743) have disclosed hydrogels composed of macro monomers derived in a multi step synthetic process. According to Hubbell, the macromonomers are composed of a central PEG diol which was transesterified using tin octanoate catalyzed ring opening polymerization of lactide to give a bis-oligolactate PEG. Following this step, the resultant bis-oligolactate PEG was then reportedly reacted with acryloyl chloride to give a macromolecular cross-linker. Hubbell disclosed that the macromolecular cross-linker could be converted into a homo-polymer interpenetrating network of PEG and oligolacetylacrylate through free radical polymerization (Pathak et al, U.S. Pat. No. 6,887,974). Hubbell (U.S. Pat. Nos. 5,801,033; 5,834,274; and 5,843,743) disclosed these compounds as photopolymerizable homo-polymers reportedly useful in preventing surgical adhesion.
Van Dijk-Wolthius et al. (van Dijk-Wolthuis, W. N. W.; Hoogeboom, J.; van Steenbergen, M.; Tsang, S.; and Hennick, W. “Degradation and Release Behavior of Dextran-Based Hydrogels.” Macromolecules, 30; (1997) 4639-4645; van Dijk-Wolthuis, W. N. E.; Tsang, S.; Kettenes-van den Bosch, J.; and Hennick, W. “A new class of polymerizable dextrans with hydrolyzable groups: hydroxyethyl methacrylated dextran with and without oligolactate spacer.” Polymer, 38(25); (1997) 6235-6242) has recently reported a second solution to this problem, using a biodegradable cross-linking macromonomer composed of alpha-hydroxy esters This work reportedly combines natural polymers with synthetic polymers in an interpenetrating network. This group disclosed 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 involved an agent designed to undergo enzymatic degradation. This cross-linker is indicated to include a centro-symmetric peptide terminated by acrylamide moieties with a central diamine linking the two ends (Kurisawa et al, Macromol. Chem. Phys. 199, 705-709 (1998).
Pathak (U.S. Pat. No. 6,887,974) described polymeric cross-linking agents reportedly having an inert water-soluble polymeric component, a biodegradable component, and functional components that are reactive with chemical groups on a protein such as amine or thiol. According to Pathak, the inert polymeric component may be flanked at each end with a biodegradable component, which is flanked at each end with a protein reactive functional component. Pathak also disclosed a polymeric crosslinking agent having a biodegradable component, polyalkylene oxide, and at least three reactive functional groups, each of them reportedly capable of forming a covalent bond in water with at least one functional group such as an amine, thiol, or carboxylic acid.
Ashton et al. (US Patent Application Ser. No. 20030158598) disclosed medical devices having a coating disposed on at least one surface, wherein the coating reportedly includes a polymer matrix and a low solubility anti-inflammatory corticosteroid formulation or low solubility codrug or prodrug of an anti-inflammatory corticosteroid formulation.
Uhrich et al (US Patent Application Ser. No. 20040096476) described therapeutic devices including a polymeric anti-inflammatory agent that reportedly biodegrades to release anti-inflammatory agents. The therapeutic devices are disclosed as being useful for repair and regeneration of a variety of injured tissues.
Carpenter, et al, (US Patent Application Ser. No. 20050238689) disclosed a bioactive implantable stent including a stent structure with a surface coating of a biodegradable, bioactive polymer, wherein the polymers said to include at least one bioligand covalently bound to the polymer and wherein the bioligand are said to specifically bind to integrin receptors on progenitors of endothelial cells (PECs) in circulating blood.
Giroux (US Patent Application Ser. No. 20060013851) described polyanhydrides which link low molecular weight drugs containing a carboxylic acid group and an amine, thiol, alcohol, or phenol group within their structure into polymeric drug delivery systems. Also reported are methods of producing polymeric drug delivery systems via these polyanhydride linkers as well as methods of administering low molecular weight drug to a host via the polymeric drug delivery systems. Medical implants based on the polymeric drug delivery system of the invention are also disclosed.
The use of isocyanate linkers to make hydrolysable active agent biopolymer conjugates was described in WO2004008101.
Biodegradable linkers for molecular therapies were described in WO2006052790.
Ptchelintsev et al. described the use of oxa acids and related compounds for treatment of skin conditions in U.S. Pat. Nos. 5,932,229 and 5,834,513 respectively.
Kiser et al. (U.S. Pat. No. 5,521,431) disclosed biodegradable cross-linkers having a polyacid core with at least two acidic groups covalently connected to reactive groups reportedly usable to cross-link polymer filaments. A biodegradable region is disclosed by Kiser between at least one reactive group and an acidic group of the polyacid preferably consisting of a hydroxyalkyl acid ester sequence having 1 to 6 hydroxyalkyl acid ester groups.
According to Kiser, the polyacid may be attached to a water-soluble region that is attached to the biodegradable region having attached reactive groups. Lactate or glycolate is reportedly preferred as the hydroxyalkyl acid ester group. Polyacids include diacids; triacids, tetraacids, pentaacids and the reactive group may contain a carbon-carbon double bond. A network of cross-linked polymer filaments having a defined biodegradation rate is said to be formed using the cross-linkers. Kiser discloses that the network may contain biologically active molecules, and may be in the form of a microparticle or nanoparticle, or hydrogel. The polymer filaments are reportedly derived from polymer filaments of polynucleic acids, polypeptides, proteins or carbohydrates. Reportedly, the cross-linkers may be copolymerized with charged monomers such as acrylic monomers containing charged groups. Applications of the cross-linkers and network are said to include controlled release of drugs and cosmetics, tissue engineering, wound healing, hazardous waste remediation, metal chelation, swellable devices for absorbing liquids and prevention of surgical adhesions.
In U.S. Pat. No. 4,829,099, Fuller disclosed metabolically acceptable polyisocyanate or polyisothiocyanate monomers as tissue adhesives. More particularly, this invention discloses surgical adhesive polymers derived from these polyisocyanate monomers, wherein the surgical polymers do not metabolize to toxic products. Amine precursors of these polyisocyanates were not isolated or identified and were not described for any applications.
The majority of biodegradable polymers are not soluble in water. As a consequence, a hydrophilic drug must be formulated in these polymers by, for example, a dispersion method using a two-phase system of water (containing drug) and organic solvent (containing the polymer). The solvent is removed by evaporation resulting in a solid polymer containing aqueous droplets. This type of system suffers from the need to use organic solvents. The use of these solvents is undesirable for protein delivery and may lead to denaturation of the protein, among other things.
Several problems associated with prior art biodegradable polymers have limited their commercial use. Biodegradable polymers typically have a polydispersed molecular architecture, which at least in part, is a function of their standard mode of preparation, i.e., stepwise condensation. As an undesirable consequence of this stepwise condensation, the resultant material will contain cross-links with a variety of degradation rates, in contrast to a more preferred tunable degradation profile, because the rate of degradation is related to the polydispersed molecular architecture. Synthetic biodegradable polymers are generally water insoluble as are a significant number of their precursors. The water insolubility of these materials adversely affects their biodegradability. Thus, there is a need for enhancing water solubility to improve biodegradability of certain polymers.
Thus, there is still an unfulfilled need for new materials (e.g., linkers and polymers derived therefrom) that are easily synthesized, composed of biocompatible components, and/or have improved water compatibility, that avoid the use of during their use in drug formulation, and/or have a well defined and/or controllable molecular structure leading to defined biodegradation rates. The present invention is directed to these, as well as other important ends.
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