| Tissue adhesive sealant -> Monitor Keywords |
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Tissue adhesive sealantRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Solid Synthetic Organic Polymer As Designated Organic Active Ingredient (doai), Aftertreated Polymer (e.g., Grafting, Blocking, Etc.), Polymer Derived From Ethylenic Monomers Only, Chemical Treating Agent Contains Element Other Than C, H, O, Alkali, Or Alkaline Earth Metal, Nitrogen Or SulfurTissue adhesive sealant description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070025955, Tissue adhesive sealant. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application is a divisional of U.S. patent application Ser. No. 10/894,609 filed Jul. 20, 2004, which claims priority of U.S. Provisional Patent Application Ser. No. 60/489,438 filed Jul. 23, 2003. FIELD OF THE INVENTION [0002] The present invention generally relates to a tissue adhesive sealant capable of bonding or sealing living tissues, and in particular, relates to a two-component composition that cross-links under surgical conditions with mechanical properties that are superior to those of undamaged tissue. BACKGROUND OF THE INVENTION [0003] A surgeon, regardless of specialty, in the course of a procedure is concerned with the repair of damaged tissues and vessels. Restoring tissue and circulation integrity is critical in the positive outcome of a procedure regardless of whether the damage was the result of trauma or the surgical procedure itself. [0004] The oldest method of joining damaged tissues is the use of mechanical securements such as clamps, staples or sutures. Mechanical tissue securements have proved to suffer a variety of limitations. Mechanical securements require significant skill and are slow to apply. Further, mechanical securements are ineffectual in a number of highly vascularized organs such as the liver, lung and brain. A mechanical securement also often leaks along the line of joinder and itself causes additional trauma to surrounding tissue. These characteristics of a mechanical securement further slow the surgical procedure and healing time. [0005] The inability of mechanical securements to staunch blood loss associated with trauma has cost innumerable lives and led to research intent on overcoming the difficulties associated with the mechanical securement. These efforts have focused on the use of an adhesive or glue capable of bonding tissue surfaces together rapidly while promoting or at least not inhibiting normal healing. [0006] A common class of tissue adhesives is fibrin-based and contains a concentrate of fibrinogen and thrombin. The fibrin adhesives are typically two-component adhesives that when mixed together react to simulate the last stages of the clot-forming cascade. The resulting clot adheres to tissue and bridges a gap therebetween until healing can occur. However, fibrin-based adhesives have met with limited success owing to low strength and the risk of infection associated with harvesting fibrin from pooled human blood. Blood-born hepatitis and HIV, along with other possible diseases, are a matter of great concern. The use of autologous plasma to prepare a fibrin sealant overcomes this difficulty, yet is time consuming and of little value in instances of direct trauma such as that inflicted in automobile accidents or gunshot wounds. [0007] Glues based on gelatin cross-linked with an aldehyde have also met with limited success. Representative of this class of glues are gelatin-resorcinol cross-linked with formaldehyde (GRF) or glutaraldehyde (GRFG). While gelatin-based glues have been extensively studied and shown to generally be effective, these compositions have met with limited success owing to the use of hot gelatin solutions, tissue irritation associated with the aldehyde, and the criticality of handling procedures needed to obtain proper cross-linking at the joinder site. [0008] A variety of adhesives found in nature, such as barnacle glue, appear to have excellent polymerization and mechanical properties. However, development of natural product based glues has been hampered by the ability to purify appreciable quantities of such materials, as well as persistent concerns about the triggering of an immune response by foreign glycoproteins. [0009] Owing to the above-described limitations, considerable development effort has been directed towards finding a suitable synthetic composition operative as a tissue glue. To this end, cyanoacrylates, polyurethanes, polymethylmethacrylates, among other synthetic polymers, have been investigated as tissue glues. Each of these synthetic compositions has met with limited success owing to a variety of problems such as toxic degradation products, poor mechanical properties, cure exotherms that overheat surrounding tissue, and not being biodegradable. [0010] Tissue welding or laser light induced tissue glue cure have also been investigated and proven only partly successful. Laser associated tissue repair has met with limited success owing to transmural thermal injury and the need for a highly skilled and well equipped surgical team. [0011] In view of the enormous development efforts that have taken place, there are few available tissue glue compositions that meet the requirements of sufficient mechanical strength, biocompatibility and bioavailability, in addition to handling properties consistent with a variety of surgical settings. Upon consideration of these stringent requirements for a tissue glue, the cross-linking of a water soluble protein by a biocompatible aldehyde appears to be one of the few possible solutions. Illustrative of developments in this area include U.S. Pat. Nos. 5,385,606 and 6,310,036. While the adhesives disclosed in these patents afford satisfactory biocompatibility and bioabsorbability, the usage properties and mechanical strength properties of these prior art tissue adhesives are not optimal. Thus, there exists a need for a tissue adhesive sealant that is not only biocompatible, but also is a well-defined cure and affords a bond line that exceeds in strength physiological forces encountered in the course of healing. SUMMARY OF THE INVENTION [0012] A tissue adhesive sealant includes a cross-linkable protein in the form of a solution or suspension. A cross-linking agent solution includes an aldehyde and an amino acid containing species reactive with the aldehyde. The aldehyde and the amino acid containing species are present in a ratio between 20:1 and 1:1. The cross-linkable protein and the cross-linking agent active components are present in a ratio of between 15:1 and 1:1. Upon combining the protein solution and cross-linking agent solution and allowing sufficient time for reaction to occur therebetween, a seal is formed capable of withstanding burst pressures of greater than physiological forces encountered. A body tissue defect is sealed, the appearance of wrinkles reduced, medical implants are formed and implanted through the use of the tissue adhesive described herein. [0013] An amino acid containing species is reacted with a multivalent aldehyde to form an oligomeric cross-linking agent. The amino acid containing species reactive with the multivalent aldehyde includes .alpha.amino acids, .beta.amino acids, dipeptides, polypeptides, proteins, glycoproteins, and combinations thereof. [0014] A commercial kit is taught that has an at least two-component syringe having a first barrel loaded with a cross-linkable protein solution and a second barrel loaded with a cross-linking agent solution comprising an aldehyde and an amino acid containing species reactive with said aldehyde, said aldehyde and said amino acid containing species being present in a ratio between 20:1 and 1:1 and said protein and said cross-linking agent are present in a ratio of between 15:1 and 1:1 together with instructions for the use thereof as a tissue adhesive sealant delivery system. The syringe may have a third barrel containing a patch material dispensable in liquid, gel, or powder form. Alternatively, the patch material is loaded in concert with the cross-linkable protein portion of a two-barrel syringe. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0015] The present invention forms high strength seals and coatings with tissue masses or prosthetic materials through the cross-linking of an aqueous solution soluble protein with an oligomer formed by the reaction between an aldehyde and an amino acid containing species. The present invention has utility alone, or in combination with a patch material to stop bleeding from a tissue. The present invention further has utility to form a seal or a seal with a reinforcing patch thereover. A cross-linkable protein according to the present invention is defined herein to include a protein capable of dissolving to form a solution or forming a suspension with a physiologically suitable aqueous solvent. The preferred proteins operative in the present invention are ova alburnins, serum albumins and gelatins of human or animal origin from animals illustratively including: horse, pig, cow, sheep, kangaroo, chicken, and fish. Suspension of collagen fibers is appreciated to be operative herein as a cross-linkable protein. It is appreciated that recombinant whole or truncated proteins are operative herein so long as the recombinant proteins remain cross-linkable. Recombinant human serum albumin is well known as detailed in U.S. Pat. Nos. 5,633,146; 5,986,062; 5,521,287 and 5,440,018. A recombinant protein is appreciated to lack viral prions or bacterial contaminants associated with harvested proteins. An albumin operative herein may contain lesser amounts of other proteins such as those found in blood plasma. Human serum albumin is a particularly preferred cross-linkable protein operative in the present invention as utilized in the context of human tissue repair. It is further appreciated that ultrafiltration or other purification technique as applied to an albumin is successful in reducing the risk of immunological response or infectious agent introduction through the use of the present invention. [0016] To form the first component of an inventive tissue adhesive sealant, a cross-linkable protein is dissolved in water or suspended in water to form a solution containing from 1 to 55 weight percent cross-linkable protein. While aqueous solution proteins are typically present from 10 to 55 total weight percent, aqueous suspension proteins are typically present from 0.3 to 9 total weight percent. Preferably, the cross-linkable protein is dissolved in an aqueous solution of physiologically acceptable buffer. Alternatively, the protein may be maintained in a dry or powder form until mixed with the cross-linking agent. Saline is an exemplary physiological buffer. Optionally, a cross-linkable protein solution includes an additive that illustratively includes an electrolyte, a thickener, an anti-microbial, a preservative, and a colorant. An electrolyte additive, if present, is typically found in an amount that ranges from 0 to 5 total weight percent and illustratively includes sodium chloride, potassium chloride and sodium phosphate. A cross-linkable protein solution thickener according to the present invention is present from 0 to 50 total weight percent. Thickeners operative in the cross-linkable protein solution illustratively include sterilized collagen particulate, implantable grade fibrous materials such as polyamides, fluoropolymers and silk. A thickener in the present invention serves to modify the handling properties of the cross-linkable protein solution as well as to modify the mechanical properties of the resulting tissue adhesive seal. Other optional additives such as an anti-microbial, preservative and a colorant are those conventional to the art and are each present in an amount that typically ranges from 0 to 3 total weight percent. Remington's Pharnaceutical Sciences, 16th Ed., 1980, Mack Publishing Co., Easton, Pa. and in Goodman and Gilman's The Pharmacological Basis of Therapeutics by Hardman and Limbird, 9th Ed., 1996, McGraw-Hill, New York and in The Merck Index: an encyclopedia of chemicals, drugs, and biologicals, 12th Edition, 1996, Merck & Co., Whitehouse Station, N.J. While it is appreciated that the viscosity of a cross-linkable protein solution according to the present invention is controlled through parameters that include cross-linkable protein concentration, the amount and identity of thickener, and the presence of various other additives. A cross-linkable protein solution viscosity is readily tailored to a specific task and has viscosity between that of water and 10,000 centipoise. It generally is preferred that a cross-linkable protein solution have a viscosity sufficient to prevent runnage and therefore is generally in a range of between 10 and 1,000 centipoise. [0017] A cross-linking agent solution component that upon combination with the cross-linkable protein solution forms an inventive tissue adhesive sealant includes a multivalent aldehyde and an amino acid containing species reactive therewith. The multivalent aldehyde according to the present invention is preferably a divalent aldehyde having a molecular weight of less than 1,000 Daltons. More preferably, the multivalent aldehyde has a C.sub.0-C.sub.16 alkyl or aryl backbone intermediate between two terminal aldehyde groups. The most preferred is a C.sub.3-C.sub.8 linear alkyl dialdehyde. Glutaraldehyde is a particularly preferred species of linear alkyl dialdehyde. It is appreciated that the introduction of a lesser quantity of a tri- or polyaldehyde with a majority of a dialdehyde creates cross-linkages within the cross-linking agent resulting in modified solution viscosity and final tissue adhesive mechanical properties. Typically, a tri- or polyaldehyde is present at a stoichiometric molar ratio relative to a dialdehyde of 1:1000-1:30. [0018] An amino acid containing species is reacted with a multivalent aldehyde to form an oligomeric cross-linking agent. The amino acid containing species reactive with the multivalent aldehyde includes .alpha.amino acids, .beta.amino acids, dipeptides, polypeptides, proteins, glycoproteins, and combinations thereof. It is appreciated that both d- and l- conformers of a given amino acid are operative herein with the corresponding bioabsorbability associated with each conformer. It is appreciated that an amino acid containing species according to the present invention includes salts, esters and derivatized forms thereof. Additionally, where the amino acid is a .beta.amino acid, the resulting adhesive is comparatively resistive to bioabsorption. Derivatives to an amino acid containing species according to the present invention include solvation enhancing moieties such as hydroxyls, thiols, sulfonyls, halos; antibiotics; radioisotopes; magnetic markers, and antibodies. Particularly preferred amino acids include acidics: glutamic and aspartic acid; aliphatics: alanine, valine, leucine and isoleucine; and amides glutamine and asparagine. A most preferred amino acid containing species is shown in Formula I: where Q is CH.sub.2 or a nullity, R.sup.1 is independently in each occurrence H, Na, K, C.sub.2-C.sub.6 alkyl; R.sup.2 is independently H, C.sub.1-C.sub.20 alkyl group, a C.sub.0-C.sub.4 alkyl group having a substituent selected sulfonate, carboxylate, hydroxyl, quaternary amines, a radio isotopic ion, a magnetically detectable ion, an antibiotic moiety and an antibody; and n is an integer between 1 and 6 inclusive; hydrohalide salts thereof; and combinations thereof. [0019] Preferred embodiments of the amino acid containing species of Formula I are L-glutamic acid, L-glutamic acid hydrochloride, sodium L-glutamate, potassium L-glutamate, monosodium L-glutamate, monopotassium L-glutamate, L-aspartic acid, L-aspartic acid hydrochloride, sodium L-aspartate, potassium L-aspartate, monosodium L-aspartate, and monopotassium L-aspartate, and combinations thereof. L-glutamic acid and L-aspartic acid are particularly preferred owing to the resulting cross-linking efficacy. It is appreciated that monosodium L-glutamate, L-glutamic acid hydrochloride, monopotassium L-glutamate, monosodium L-aspartate, L-aspartic acid hydrochloride, and monopotassium L-aspartate into a cross-linking solution for a longer period of time yield similarly effective cross-linking solutions relative to L-glutamic acid. Continue reading about Tissue adhesive sealant... Full patent description for Tissue adhesive sealant Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Tissue adhesive sealant patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Tissue adhesive sealant or other areas of interest. ### Previous Patent Application: Ionene polymers and their use as antimicrobial agents Next Patent Application: Linear cyclodextrin copolymers Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Tissue adhesive sealant patent info. IP-related news and info Results in 0.2243 seconds Other interesting Feshpatents.com categories: Tyco , Unilever , Warner-lambert , 3m 174 |
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