Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2003-05-19
2004-11-23
Acquah, Samuel A. (Department: 1711)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S460000, C424S469000, C514S002600, C514S782000, C514S783000, C514S801000, C528S129000, C528S137000, C528S270000, C525S054100, C525S398000, C525S480000, C525S540000, C524S841000, C524S843000, C524S017000, C428S297400, C428S304400, C428S317900, C428S318400, C428S322700, C428S492000
Reexamination Certificate
active
06821530
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to polymer composite compositions.
BACKGROUND OF THE INVENTION
Soluble collagen isolated from tissue sources such as tendon and skin forms native fibrils at 37° C. in physiological buffers. Although these fibrils can be extruded to form synthetic fibers of various dimensions, the tensile strength of these fibers is relatively weak due to a lack of intermolecular cross-linking between collagen polypeptides. This physical weakness limits the use of these fibers in tendon and ligament reconstruction. To strengthen these collagen fibers, cross-linkers such as glutaraldehyde and carbodiimide have been used to re-establish the intermolecular cross-link. A drawback of glutaraldehyde cross-linked materials for use in vivo, however, is that glutaraldehyde and its reaction products are toxic to cells.
SUMMARY OF THE INVENTION
The invention is based on the discovery that polymeric materials, e.g., collagen, including collagen fibers, can be strengthened by adding particular catechol-containing compounds (especially compounds having two or more catechol groups) to the polymeric material and forming a polymer of the compounds that intercalate within the polymeric material, e.g., forming a polymer composite. It is believed that the resulting polymer forms a scaffold-like structure throughout the polymeric material without the necessity of cross-linking the individual polymeric materials, e.g., collagen polypeptides. This scaffolding provides synthetic polymer fibers having a tensile strength, stiffness, and strain at failure that is comparable to or better than natural polymeric material fibers.
Accordingly, the invention features a method of treating a polymeric material, e.g., collagen, by providing a mixture comprising the polymeric material and a monomer having a first catechol group; oxidizing the mixture; and polymerizing the monomer via the first catechol group to form a polymer in which the first catechol group has been oxidized to a quinone group, and the polymer intercalates into the polymeric material. The method optionally includes removing unpolymerized monomer from the mixture after the polymerizing step. The monomer can further contain a reactive group, such as a second catechol group or an aldehyde group. Alternatively, the monomer can contain, other than the first catechol group, a reactive group and a linker of at least three carbon atoms between the first catechol group and the reactive group, where no more than one peptide bond, or alternatively no peptide bond, separates the first catechol group from the reactive group. In another example, the monomer can contain a first catechol group and a reactive group, provided that the reactive group is not a carboxyl group or a primary amine. The reactive group can participate in a covalent bond with a collagen polypeptide (e.g., when the reactive group is an aldehyde, amino, or carboxyl group) or with another monomer (e.g., when the reactive group is a catechol group). When the reactive group is a second catechol group, the monomer can form a homopolymer of the monomer.
Specific examples of monomers include 2,3-dihydroxybenzaldehyde, 3,4-dihydroxybenzaldehyde, rosemarinic acid, nordihydroguaiaretic acid, and the multi-armed structures described in the Examples.
A polymeric material is any polymer that can be synthetic, natural, or derived from natural sources, e.g., marine or terrestrial animal or plant (e.g., bovine, porcine, equine, skate, or sea cucumber). The polymeric material may be in any form including solid, liquid, or gel. Polymers include, for example, collagen, gelatin (included denatured gelatin), alginates, chitosan, silk, and cellulose.
The collagen can be of any form and from any origin. For example, the collagen can be sea cucumber dermis collagen, bovine tendon collagen, molecularly engineered collagen, or gelatin (e.g., in any suitable form including hydrogels, liquids, or foams). In addition, the collagen can be digested with a protease before the oxidizing and polymerizing steps. The collagen can be in the form of microfibrils, fibrils, natural fibers, or synthetic fibers. The polymeric material, e.g., collagen, can be at least 50% (e.g., at least 75, 90, or 95%) by weight of the mixture.
In the oxidation step, oxygen can be introduced into the mixture in the form of dissolved molecular oxygen or in the form of periodate (e.g., sodium meta-periodate). The oxidation step can be carried out more rapidly by the introduction of chemical oxidants, like periodate. Oxygen introduced merely by atmospheric exposure or in vivo are suitable methods for carrying out the oxidation step. Alternatively, in areas where exposure to air is not possible or desirable, oxygen or other oxidants can be introduced from exogenous sources via, for example, tube, feed line, or cannula (e.g., arthroscopically).
In another aspect, the invention includes a method of increasing the tensile strength or the protease resistance of a composition containing collagen by adding a monomer as described above; and treating the mixture using the methods described above.
In another aspect, the invention features a composition containing a polymeric material, e.g., collagen, and a polymer that intercalates into the polymeric material, e.g., collagen, the polymer formed of monomers, each monomer having a first quinone group, a second quinone group, and a linker of at least three carbon atoms between the first quinone group and the second quinone group, where no more than one peptide bond separates the first quinone group from the second quinone group, alternatively where at least one peptide bond separates the first quinone group from the second quinone group, or alternatively where there is no peptide bond between the first quinone group and the second quinone group. Alternatively, the monomer has a quinone group and a reactive group, provided that the reactive group is not an amino or carbonyl group participating in a peptide bond within the monomer, or alternatively wherein the reactive group is an aldehyde or a second catechol.
In another aspect, the invention features a composition containing a polymeric material, e.g., collagen, and a polymer that cross-links with the polymeric material, e.g., collagen, the polymer formed of monomers, each monomer having a first quinone group, a second quinone group, and a linker of at least three carbon atoms between the first quinone group and the second quinone group, where no more than one peptide bond separates the first quinone group from the second quinone group, alternatively where at least one peptide bond separates the first quinone group from the second quinone group, or alternatively where there is no peptide bond between the first quinone group and the second quinone group; and wherein a functional group (e.g., sulfur or nitrogen or oxygen atom), from the polymeric material, e.g., collagen, chemically reacts to form a bond (either reversible or irreversible) between the monomer and the polymeric material, e.g., collagen. Alternatively, the monomer has a quinone group and a reactive group (e.g., an aldehyde or aldehyde functional equivalent, such as imine), provided that the reactive group is not an amino or carbonyl group participating in a peptide bond within the monomer.
Although the polymers of monomers described above have a first and a second quinone group, the quinone group may be reacted with another functional group in the polymer or may be cross-linked with another group in the polymeric material (e.g., collagen) to ultimately form a quinone derivative. Such quinone derivatives are deemed to be quinone groups in the polymers of monomers of the invention. For example, if a quinone group reacts with an amino group from the polymeric material, an imine (a quinone derivative) forms. It is also possible for two quinones to react, in which case a coupled quinone results. In such instances, the resulting product is considered to have two quinone groups, however, they are separated by a substituted-ethylene group formed from two of the quinone groups of
Hernandez Daniel J.
Koob Thomas J.
Acquah Samuel A.
Shriners Hospitals for Children
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