Bioadhesive hydrogels with functionalized degradable crosslinks

Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices

Reexamination Certificate

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C424S484000, C424S422000, C424S489000, C424S426000

Reexamination Certificate

active

06514535

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to excretable polymer networks that are susceptible to enzymatic cleavage, exchange reactions with mucin, reduction, and oxidation.
BACKGROUND OF THE INVENTION
Hydrogels are polymers that swell in water. They have a large molecular weight that generally cannot be measured by conventional methods because they are too large. Hydrogels are made up of a polymer backbone and crosslinks. Crosslinks can be used to extend the molecular weight of a polymer if the ratio of crosslinker to non crosslinker is low and polymerization is confined below the gel point. Nevertheless if the ratio of crosslinking monomer to non crosslinker monomer is high enough, a gel is formed that swells in a good solvent but does not truly dissolve.
Carbomer resins are high molecular weight, crosslinked, acrylic acid-based polymers. A number of agencies, including the USP-NF, and United States Adopted Names Council (USAN) have adopted the generic name “carbomer” for polyacrylic acid types of resins, exemplified by Carbopol®. Carbopol® resins are water swellable poly(acrylic acids) that are commercially available from the B. F. Goodrich Co. (Specialty Polymers and Chemical Division, Cleveland, Ohio) in several formulations. Polyacrylic acid polymers that are lightly crosslinked with a polyalkenyl polyether are commercially available from B. F. Goodrich under trademarks such as Carbopole® and NOVEON®
Several crosslinked ionic hydrogel materials have been disclosed in the literature. As disclosed by Shah in U.S. Pat. No. 4,693,887, the nature of the crosslinkages in stable or permanent hydrogels is generally of the covalent type, although ionic crosslinkages in polyelectrolyte complexes are also found. Certain block and graft copolymer hydrogels, possessing a hydrophobic-hydrophilic microphase morphology, have been reported by Milkovich (U.S. Pat. No. 4,085,168), Wichterle (U.S. Pat. No. 4,095,877), Nakashima, et al. (
J. Biomed. Materials Res.,
11, 787 (1977)), and Okano, et al. (
J. Appl. Polymer Sci.,
22, 369 (1978)). In these hydrogels, the hydrophobic and hydrophilic phases are connected to one another by means of covalent bonds.
A neutral hydrogel of a polymer of ethylene glycol methacrylate or similar monomer crosslinked sufficiently to make the polymer insoluble is disclosed in U.S. Pat. No. 3,551,556. U.S. Pat. No. 3,641,237 discloses hydrogels films prepared by polymerization of lower alkoxy lower alkyl acrylates and methacrylates along with a 0 to 40 percent of a hydrophilic acrylic monomer in the presence of a crosslinking agent. Various monomers are disclosed as useful for the 0 to 40 percent co-monomers, including hydroxyalkyl acrylates and methacrylates, salts of &agr;,&bgr;-unsaturated organic acids and strong acid salts of polymerizable ethylenically unsaturated amine-containing monomers.
For a polymer to be used safely in the body it must be either bio-durable, biodegradable or excretable through the reticuloendothelial system (RES) system. The above mentioned references would be examples of systems that are resistant to degradation by the body. Often resistant materials produce byproducts or lose their material properties in such a manner which give grave concerns to using them in implantable applications. Many of the examples given above would give byproducts that are not easily cleared by the body. It has long been known that the size or Stokes radius of macromolecules is the chief parameter controlling the rate of clearance from the serum compartment by glomerular filtration. Hardwicke, J.; Hulme, B.; Jones, J. H.; Rickets, C. R.; “Measurement of glomerular permeability to polydisperse radioactivity labeled macromolecules in normal rabbits”;
Clin. Sci.
34, 505 (1968). The term size is used here to descriptively cover both the molecular weight of a polymer sample and also the shape of the polymer molecules. The size filtered by the kidney is generally thought to be 40 angstroms which is often related to the molecular weight of the polymer and viewed as 45,000 Daltons (i.e., 45 kD). Excretability is also a function of the hydrophobicity of the polymer as certain hydrophobic side groups have been shown to lead to deposition in kidney tissue. See for example, Rypacek, F.; Drobnik, J.; Chmelar, V.; Kalal, J.; “The renal excretion and retention of macromolecules, the Chemical structure effect,”
Pfluger Arch,
392, 211 (1982).
The main purpose of this invention is to produce bioadhesive polymeric networks or hydrogels for use in the body while ensuring that the polymeric network or hydrogel will break down into molecular weights that can be cleared by the body. This invention uses a low degradation bioadhesive backbone, synthesized with crosslinks that gel the backbones into a network. This bioadhesive hydrogel can degrade back to a low molecular weight backbone that can be cleared from the body. Thus the matrix is lost via degradation of the crosslinks. This mechanism of degradation may also give different control over the release of materials than that of a matrix, which is degrading via equal scission of the backbone and crosslink junctions.
It has been previously shown that non-ionic, non-bioadhesive electrophoresis hydrogels may be made with disulfide functional crosslinkers. These polyacrylamide electrophoresis gels may be digested to release the material being separated (RNA fragments). See for example, Hansen, H. J.,
Anal. Biochem.,
76, 37 (1976). Electrophoresis, as known to those skilled in the art, uses electrical current and mobility to separate proteins and other such biological compounds in a gel matrix. Therefore, the gel matrix should show little interaction with biological materials and is not considered bioadhesive.
Yip discloses in U.S. Pat. No. 4,898,824 a crosslinked polyacrylamide-sulfhydryl polymer for immobilization of biologically active substances. Saffran, et al. disclose in U.S. Pat. No. 4,663,308 high molecular weight polymers of one or more ethylenically unsaturated monomers copolymerized with a divinylazobenzene compound to coat or otherwise entrap drugs that are labile in the stomach, have an undesirable effect in the stomach, or are targeted at the colon. Release of drug occurs via the cleavage of the azobonds by the azoreductases that abound in the colon but are not prevalent in the stomach or small intestine. U.S. Pat. No. 4,663,308 suggests various acrylic acid esters and amides as well as unsaturated acids as possible monomers. However, the only copolymer exemplified in the patent is a hydroxyethyl-methacrylate (HEMA)-styrene copolymer that contains no ionizable group. This copolymer has low bioadhesion because there are no carboxyl or other ionizable co-monomers. Further, the copolymers of U.S. Pat. No. 4,663,308 are crosslinked under the gel point (branched) and are thus soluble in organic solvents.
Kopecek, et al. disclose in U.S. Pat. No. 5,415,864 colonic-targeted oral drug-dosage forms based on crosslinked hydrogels containing azobonds and exhibiting pH-dependent swelling. These include crosslinked hydrogels that undergo pH-dependent swelling and contain azobonds that are enzymatically cleavable by the azoreductases that reside in the colon; conjugates of hydrogels which exhibit pH-dependent swelling, and optionally include enzymatically-cleavable azobonds, and amino group-containing drugs that are covalently bound to the hydrogel via an aromatic azobond; and a process for making such conjugates. U.S. Pat. No. 5,415,864 does not address the concept of excretable polymer backbones and although the crosslinks are degradable the resulting polymer backbone molecular weight and hydrodynamic radius would be above the limit for renal clearance and the resulting polymer would not be renally cleared from the body.
Schacht, et al. disclose in U.S. Pat. No. 5,407,682 reduction sensitive polymers which are linear macromolecules containing an azo and/or a disulfide bond in their polymer backbone. These are not hydrogel materials and as such will not swell and retain water within the polymeric network. Furthermore, th

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