Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...
Reexamination Certificate
2001-11-05
2003-09-23
Nutter, Nathan M. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Mixing of two or more solid polymers; mixing of solid...
C525S419000, C525S420000, C525S425000, C604S891100
Reexamination Certificate
active
06624245
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to biocompatible polymer compositions that rapidly crosslink to form a gel. More particularly, the invention relates to a composition prepared by admixture of individually reactive polymer components, wherein the admixture initiates rapid crosslinking and gel formation. Such compositions are particularly well suited for use in a variety of tissue-related applications in which rapid adhesion to the tissue and gel formation is desired. Accordingly, the invention additionally relates to methods of using the compositions as bioadhesives, for tissue augmentation, in the prevention of surgical adhesions, for coating surfaces of synthetic implants, as drug delivery matrices, for ophthalmic applications, and in other applications, as discussed herein and/or as appreciated by one of ordinary skill in the art.
BACKGROUND OF THE INVENTION
The use of polymer compositions in tissue engineering is now widely recognized, particularly those compositions manufactured with synthetic polymers. In contrast to many naturally derived compositions, synthetic polymer compositions can be formulated to exhibit predetermined physical characteristics, such as gel strength, as well as biological characteristics, such as biodegradability.
In a variety of tissue engineering applications, it is desirable to use compositions that can be administered as liquids, but which subsequently form gels at the site of administration. Such in situ gel-forming compositions are convenient to use since they can be administered as liquids from a variety of different devices, and are adaptable for administration to any site, since they are not preformed. Many different mechanisms have been described that can be used to promote gel formation in situ. For example, photoactivatable mixtures of water-soluble co-polyester prepolymers and polyethylene glycol have been described as useful in the preparation of gel barriers and drug release matrices. In another approach, block copolymers of a Pluronic™ poloxamer have been designed that are soluble in cold water, but form insoluble gels that adhere to tissues at body temperature (Leach et al. (1990)
Am. J. Obstet. Gynecol.
162: 1317-1319 (1990)). Polymerizable cyanoacrylates have also been described for use as tissue adhesives (Ellis, et al. (1990)
J. Otolaryngol.
19:68-72 (1990). In yet another approach, two-part synthetic polymer compositions have been described that, when mixed together, form covalent bonds with one another, as well as with exposed tissue surfaces. (PCT WO 97/22371, which corresponds to U.S. application Ser. No. 08/769,806.) In a similar approach involving a two-part composition, a mixture of a protein and a bifunctional crosslinking agent has been described for use as a tissue adhesive (U.S. Pat. No. 5,583,114.) One difficulty encountered when designing in situ gel forming compositions is that optimizing the composition to enhance gel formation may worsen tissue inflammation at the site of administration. A possible explanation for this effect is that highly reactive composition components that are capable of rapid gel formation may adversely affect tissue surfaces.
The compositions of the present invention have been formulated to provide for rapid gelation, while decreasing the likelihood and/or severity of tissue inflammation at the site of administration relative to that associated with the previously described compositions.
SUMMARY OF THE INVENTION
Accordingly, in one aspect of the invention, a reactive polymer composition is provided that comprises an admixture of two or more biocompatible, reactive components selected so as to rapidly react with each other to form a crosslinked gel. The first component, component “A,” is a sulfhydryl-containing component having m sulfhydryl groups, and the second component, component “B,” is a sulfhydryl-reactive component B having n sulfhydryl-reactive groups capable of reaction with the m sulfhydryl groups to form covalent bonds, wherein m≧2 and n≧2, and generally the sum of m+n≧4. Preferably, at least one of m and n≧3, and more preferably, m and n are each ≧4; in this way, sufficient reactivity for rapid formation of a three-dimensional polymeric gel is ensured. For extremely fast-reacting compositions, both m and n are each ≧12. The compositions may be used either in situ or ex situ, to give a biocompatible crosslinked gel having utility in a host of different contexts, e.g., in bioadhesion, biologically active agent delivery, tissue augmentation, and other applications. The preferred context, however, involves crosslinking and gelation in situ.
The reaction conditions necessary for the rapid crosslinking reaction to take place will depend on the particular components A and B. When neither component is a liquid at room temperature, the reaction must be carried out in an added solvent, preferably a sterile aqueous medium. If at least one of the components is a liquid and capable of serving as a reaction solvent, the reaction may be conducted “neat” (also referred to as “in bulk”), i.e., no added solvent is necessary. In addition, for components that crosslink via a nucleophilic substitution mechanism, such that covalent bonds are formed by nucleophilic attack of the sulfhydryl groups on electrophilic sulfhydryl-reactive groups, an added base is typically necessary to increase the nucleophilicity of the sulfhydryl groups such that the crosslinking reaction occurs sufficiently rapidly. For components that crosslink via other mechanisms, an added base is generally not required (although one may be present). For example, reaction of unconjugated olefins with sulfhydryl groups does not involve nucleophilic substitution, but rather requires light or other radiation effective to generate the sulhydryl radical R—S—, and a suitable free radical initiator.
The components of the composition will generally be admixed, under the reaction conditions appropriate to promote rapid crosslinking of the selected components, e.g., in bulk, in an aqueous liquid, with added base, and/or in the presence of radiation and/or a free radical initiator), immediately prior to administration. Alternatively, the components may be individually applied to the site of administration under appropriate reaction conditions, such that admixture occurs at the administration site.
It will be appreciated that more than one sulfhydryl-containing component and/or more than one sulfhydryl-reactive component may be present in the reactive composition.
At least one of the reactive components A and B is a polymer, preferably a hydrophilic polymer, and may be naturally occurring, purely synthetic, or semisynthetic polymer, wherein “semi-synthetic” refers to a chemically modified naturally occurring polymer. The non-reactive portion of the polymer is referred to as its “core,” with either sulhydryl groups or sulfhydryl-reactive groups bound thereto. Suitable polymer cores include synthetic polymers, as noted above, polyamino acids, polysaccharides, and the like. The molecular weight of the polymer can vary depending on the desired application. In most instances, the weight average molecular weight is about 100 to about 2,000,000, preferably about 1,000 to 1,000,000, more preferably about 1,000 to about 100,000, and most preferably about 1,000 to about 20,000. When the polymer core is polyethylene glycol, the preferred molecular weight is in the range of about 1000 to about 20,000, optimally about 10,000.
One or more of the reactive components in the composition may be a low molecular weight crosslinking agent, although it is preferred that not more than one of the components is comprised of such an agent. Typical low molecular weight crosslinking agents are comprised of a hydrocarbyl moiety containing 2 to 14 carbon atoms and at least two functional groups, i.e., sulfhydryl groups or sulfhydryl-reactive groups. Generally, although not necessarily, any low molecular weight component that is employed serves as the sulfhydryl-reactive component rather than as the sulfhydryl-containing component, a
Coker, III George T.
Cruise Gregory M.
Maroney Marcee M.
Rhee Woonza M.
Schroeder Jacqueline Anne
Cohesion Technologies, Inc.
Nutter Nathan M.
Reed Dianne K.
Reed & Eberle LLP
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