Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-01-29
2002-07-02
Acquah, Samuel A. (Department: 1711)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C528S272000, C528S275000, C528S354000, C528S361000, C525S439000, C525S450000, C424S078030, C424S078060, C424S425000, C424S457000, C424S462000, C424S486000, C514S506000
Reexamination Certificate
active
06413539
ABSTRACT:
FIELD OF INVENTION
This invention relates generally to biomedical and/or pharmaceutical applications of absorbable or biodegradable polymeric hydrogels. More particularly, the present invention relates to hydrogel-forming, self-solvating, absorbable polyester copolymers capable of selective, segmental association into compliant hydrogels upon contacting an aqueous environment. The invention also discloses methods of using the polyester copolymers of the invention in humans for providing a protective barrier to prevent post-surgical adhesion, a carrier of viable cells or living tissue, treatment of defects in conduits such as blood vessels, and controlled release of a biologically active agent for modulating cellular events such as wound healing and tissue regeneration or therapeutic treatment of diseases such as cancer and infection of the periodontium, eye, dry socket, bone, skin, vaginal, and nail infections.
BACKGROUND OF THE INVENTION
Hydrogels are materials which absorb solvents (such as water), undergo rapid swelling without discernible dissolution, and maintain three-dimensional networks capable of reversible deformation (Park, et al.,
Biodegradable Hydrogels for Drug Delivery,
Technomic Publishing Co., Lancaster, Pa., 1993; W. Shalaby et al.,
J. Controlled Rel.,
19, 131, 1992; and Silberberg, in
Molecular Basis of Polymer Networks
(Baumgartner, A. & Picot, C. E., Eds.), Spring-Verlag, Berlin, 1989, p. 147).
Covalently crosslinked networks of hydrophilic polymers, including water-soluble polymers are traditionally denoted as hydrogels (or aquagels) in their hydrated state. Hydrogels have been prepared to be based on crosslinked polymeric chains of methoxy poly(ethylene glycol) monomethacrylate having variable lengths of the polyoxyethylene side chains, and their interaction as hydrogels, with blood components have been studied (Nagaoka, et al., in
Polymers as Biomaterials
(Shalaby, S. W., et al., Eds.), Plenum Press, 1983, p. 381). A number of aqueous hydrogels (aquagels) have been used in various biomedical applications, such as, for example, soft contact lenses, wound management, and drug delivery. However, methods used in the preparation of these hydrogels, and their conversion to useful articles, are subject to the constraints associated with the nature of their three-dimensional thermosetting structures and, hence, deprive the users from applying the facile processing techniques employed in the production of non-crosslinked thermoplastic materials.
This, and the low mechanical strength of the hydrated networks, led a number of investigators to explore the concept of combining hydrophilic and hydrophobic polymeric components in block (Okano, et al.,
J. Biomed. Mat. Research,
15, 393, 1981), or graft copolymeric structures (Onishi, et al., in
Contemporary Topics in Polymer Science,
(W. J. Bailey & T. Tsuruta, eds.), Plenum Publ. Co., New York, 1984, p. 149), and blends (Shah,
Polymer,
28, 1212,1987; and U.S. Pat. No. 4,369,229) to form the “hydrophobic-hydrophilic” domain systems, which are suited for thermoplastic processing (Shah, Chap. 30, in
Water Soluble Polymers
(S. W. Shalaby, et al., Eds.), Vol. 467, ACS-Symp. Ser., Amer. Chem. Soc., Washington, 1991). The “hydrophobic-hydrophilic” domain system (HHDS) undergoes morphological changes which are associated with the hydration of the hydrophilic domains and formation of pseudo-crosslinks via the hydrophobic component of the system (Shah, 1991, cited above). Such morphology was considered to be responsible for the enhanced biocompatibility and superior mechanical strength of the two-phase HHDS as compared to those of covalently crosslinked, hydrophilic polymers. The mechanism of gel formation in the present invention parallels that described by Shah, 1991, cited above, for non-absorbable blends of hydrophilic-hydrophobic domain systems (HHDS). However, differences exist between the copolymers of the present invention, and more particularly, Component “A”, and HHDS. In this regard, Component A is based on a water-soluble and water-insoluble block structure (SIBS). This is not a mere physical mixture of two polymers as are the blends described by Shah, 1991, cited above. Additionally, due to the presence of covalent links between the blocks of SIBS, the resulting hydrogel displays higher elasticity compliance and tensile strength while being absorbable. In fact, the SIBS systems are, in some respects, analogous to thermoreversible gels (Shalaby, in
Water-Soluble Polymers,
(Shalaby, S. W., et al., Eds.), Vol. 467, Chapt. 33, ACS Symp. Ser., Amer. Chem. Soc., Washington, DC, 1991a) in displaying a hydration-dehydration equilibrium governing the system transformation, i.e., the gel/liquid equilibrium is driven by the water content of the SIBS. Thus, in the absence of water, the polyoxyalkylene blocks undergo intermolecular segmental mixing with the neighboring hydrophobic blocks to produce a viscous liquid. In the presence of water, competition between the water as an extrinsic solvent and the polyester block for the polyoxyalkylene (POA) block forces the hydration of the POA, and aggregation or association of the polyester blocks to establish pseudo-crosslinks which maintain a 3-dimensional integrity. Since gel formation takes place in an aqueous environment, the POA block will preferentially migrate to the exterior of the gel and interface with the adjoining tissues to establish an adhesive joint, which prevents gel migration from target site and sustains its intended efficacy. As for example, for periodontal and dry socket applications, post-surgical adhesion prevention and treatment of vaginal and bone infections, and other applications where predictable site residence of the gel cannot be compromised.
Synthesis and biomedical and pharmaceutical applications of absorbable or biodegradable hydrogels based on covalently crosslinked networks comprising polypeptide or polyester components as the enzymatically or hydrolytically labile components, respectively, have been described by a number of researchers (Jarrett, et. al.,
Trans. Soc. Biomater.,
Vol. XVIII, 182, 1995; Pathak, et. al.,
Macromolecules,
26, 581, 1993; Park, et. al.,
Biodegradable Hydrogels for Drug Delivery,
Technomic Publishing Co., Lancaster, Pa., 1993; Park, Biomaterials, 9, 435, 1988; and W. Shalaby, et. al., 1992, cited elsewhere herein). The hydrogels most often cited in the literature are those made of water-soluble polymers, such as polyvinyl pyrrolidone, which have been crosslinked with naturally derived biodegradable components such as those based on albumin (Park, et. al., 1993, cited elsewhere herein; and W. Shalaby, et. al., 1992, cited elsewhere herein). Totally synthetic hydrogels which have been studied for controlled drug release and membranes for the treatment of post-surgical adhesion are based on covalent networks formed by the addition polymerization of acrylic-terminated, water-soluble chains of polyether dl-polylactide block copolymers (Jarrett, et. al., 1995, cited elsewhere herein; and Pathak, et al., 1993, cited elsewhere herein).
Polymer solutions which undergo reversible gelation by heating or cooling about certain temperatures (lower critical solution temperature, LCST) are known as thermoreversible gels. Theoretical and practical aspects of key forms of thermoreversible gels are described by Shalaby, 1991a, cited elsewhere herein. Among the thermoreversible gels discussed by Shalaby are those of amorphous N-substituted acrylamides in water and amorphous polystyrene and crystalline poly(4-methyl pentene) in organic solvents. Prevailing gel formation mechanisms include molecular clustering of amorphous polymers and selective crystallization of mixed phases of crystalline materials. Thermodynamic parameters (enthalpy and entropy) which favor gel formation in terms of LCST are discussed by Shalaby only with respect to the solvent-polymer interaction. Shalaby fails, however, to address self-solvating chains.
U.S. Pat. No. 4,911,926, discloses aqueous and non-aqueous compositions comprised of block polyoxy
Acquah Samuel A.
Nixon & Peabody LLP
Poly-Med, Inc.
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