Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1999-04-16
2001-11-06
Nutter, Nathan M. (Department: 1711)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S485000, C424S486000, C424S488000, C424S078020, C424S078060, C424S078070, C424SDIG001, C427S002140, C427S002310, C427S331000, C427S337000, C427S340000, C523S105000, C523S111000, C435S975000
Reexamination Certificate
active
06312725
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to two-part polymer compositions that rapidly form covalent linkages when mixed together. Such compositions are particularly well suited for use in a variety of tissue related applications when rapid adhesion to the tissue and gel formation is desired. In particular, they are useful as tissue sealants, in promoting hemostasis, for drug delivery, in effecting tissue adhesion, in providing tissue augmentation, and in the prevention of surgical adhesions.
BACKGROUND OF THE INVENTION
The use of polymer compositions in tissue engineering is now widely recognized, particularly those consisting of 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 degradability.
In a variety of tissue engineering applications, it is desirable to use compositions that can be administered as liquids, but subsequently form hydrogels at the site of administration. Such in situ hydrogel forming compositions are more convenient to use since they can be administered as liquids from a variety of different devices, and are more adaptable for administration to any site, since they are not preformed. Many different mechanisms have been described that can be used to promote hydrogel formation in situ. For example, photoactivatable mixtures of water-soluble co-polyester prepolymers and polyethylene glycol have been described to create hydrogel barriers, as well as drug release matrices. In another approach, block copolymers of Pluronic and Poloxamer have been designed that are soluble in cold water, but form insoluble hydrogels that adhere to tissues at body temperature (Leach, et al.,
Am. J. Obstet. Gynecol.
162:1317-1319 (1990)). Polymerizable cyanoacrylates have also been described for use as tissue adhesives (Ellis, et al.,
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 U.S. Pat. No. 5,874,500.) In a similar approach involving a two-part composition, a mixture of 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 hydrogel 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, and also cause less tissue inflammation at the site of administration than previously described compositions.
SUMMARY OF THE INVENTION
The present invention discloses generally two-component polymer compositions that, when mixed together, rapidly react to form a matrix at the site of administration. Such compositions exhibit gel times of less than one minute. In one aspect of the present invention, one of the components is a sulfhydryl-containing compound. In another aspect of the present invention, both components contain multiple functional groups, and at least one of the compounds contains three or more functional groups. This ensures sufficient reactivity for formation of a three-dimensional polymer matrix. Preferably, both compounds contain four or more functional groups. For extremely fast reacting compositions, both compounds contain 12 functional groups.
In one aspect of the present invention, at least one and preferably both of the compounds are polymers. The non-reactive portion of the polymeric compound is referred to as its “core”. Suitable polymer cores are synthetic polymers, polyamino acids, and polysaccharides. In a preferred embodiment, the core is a polyalkylene oxide, and more preferably it is polyethylene glycol.
The molecular weight of the compounds can vary depending on the desired application. In most instances, the molecular weight is about 100 to I100,000 mol. wt., and more preferably about 1,000 to about 20,000 mol. wt. When the core material is polyethylene glycol, the molecular weight of the compound(s) is/are about 7,500 to about 20,000 mol. wt., and most preferaby they are about 10,000 mol. wt.
When only one of the compounds is a polymer, the other is a multifunctionally activated small organic molecule. Suitable small organic molecules include functionally activated succinimidyl and maleimidyl compounds.
The linkage group formed by reacting the two compounds of the present invention together is a covalent bond formed between the sulfur atom in the sulfhydryl group of one compound with, e.g., the carbon or sulfur atom in the sulfhydryl-reactive group of the other compound. The linkage may be a thioester, thioether or a disulfide, although a thioester linkage is preferred.
In another aspect of the present invention, the compounds further comprise chain extenders between the polymer core and the functional groups. Such chain extenders can activate or suppress reactivity of the functional groups, and can also be used to provide sites for hydrolysis or degradation. Suitable chain extenders include poly(amino acids), poly(lactones), poly(anhydrides), poly(orthoesters), poly(orthocarbonates), poly(phosphoesters), and enzymatically cleavable peptide groups.
The compositions of the present invention form gels with gel times of less than 1 minute, and more preferably less than 30 seconds, and most preferably less than 15 seconds. The strength (i.e., elastic modulus or G′) of the resultant gels depends on the application for which the composition is adapted, but is preferably between about 10
2
to 10
4
dynes/cm
2
for a soft gel, or between about 10
5
to 10
8
for a harder gel.
In addition to the two reactive components of the compositions of the present invention, optional materials can also be included, such as glycosaminoglycans, proteins such as collagen, drugs, cells, hemostatic agents, genes, DNA, therapeutic agents, antibiotics, growth factors, and the like.
The compositions of the present invention are applied in liquid or solid form to the site of administration. It is also possible to supply them premixed but inactive, and then activate them at the site of administration.
In another aspect of the present invention, there is provided a method of treating tissues for the purpose of sealing tissues, preventing adhesions, providing a platform for delivery of biologically active agents, or augmenting tissues, comprising mixing together the two components as described herein at the site of administration to produce the desired medical affect.
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Bentley, M., “PEG Derivatives of Small Drug Molecules,”Shearwater Polymers, Inc., vol. 1, Issue 3 (Dec. 1998).
Bodanszky, M.,Principles of Peptide Synthesis, 2ndEd, Springer-Verlog, Berlin (1993) p. 21-37.
Braatz, James, et al., “A new hydrophilic polymer for biomaterial coatings with low protein adsorption,”J. Biomater. Sci. Polymer Edn.(1992) 3(6):451-462.
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Coker, III George T.
Cruise Gregory M.
Maroney Marcee M.
Rhee Woonza M.
Schroeder Jacqueline Anne
Axord Laurie A.
Cohesion Technologies, Inc.
Nutter Nathan M.
Reed Dianne E.
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