Cyanoacrylate Composite

(19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0241249 A1 US 20080241249A1 Quintero et al. (43) Pub. Date: Oct. 2, 2008 (54) CYANOACRYLATE COMPOSITE Publication Classification (51) Int. Cl. . . . A61K 9/00 (2006.01) (75) Inventors: Julian A. Qulntero, Rale1gh,l\IC A61K 31/78 (2006.01) (US); Jerry Y- Jonn, Shanghal A61P 1 7/00 (2005.01) (CN) (52) U.S. Cl. .................................... .. 424/487; 424/7802 (57) ABSTRACT C01Te5P011de11Ce Address? An adhesive composite composition is provided including (73) (21) (22) BRINKS, HOFER, GILSON & LIONE 2801 SLATER ROAD, SUITE 120 MORRISVILLE, NC 27560 (US) Assignee: Appl. No.: Filed: PS1) \/ Modulus 16000 14000 12000 10000 8000 6000 4000 2000 Closure Medical Corporation, Raleigh, NC (US) 11/731,839 Mar. 30, 2007 one or more polymerizable monomers and one or more metal stearates. The one or more polymerizable monomers may be a cyanoacrylate monomer. The adhesive composite compo- sition may further comprise a plasticizer, an initiator, a rate modifier, a stabilizer, a colorant, a heat dissipating agent, or other additives. Methods for the application of the adhesive composite compositions to living tissue are also provided. The adhesive composite composition provides an adhesive composite material upon polymerization which is a polymer matrix entrapping the metal stearate. Polymerization of the adhesive composite composition at a site on living tissue provides an adhesive composite material which promotes microcirculation and tissue growth at the site of application of the adhesive composite composition. Cyanoacrylaie Composite — Modulus Key to Composition 1. 55% CA 1 15% DBS/ 30% MgSt 2. 55% CA / 15% DBS/ 30% Cast 3. 65% CA/15% DBS/ 20% Mgst 4. 65% CA/15°/5 DBS/ 20% Cast 5. 65% 20CA/15°/o DBS/ 20% CaS1 3 4 5 6 Composition 7 5. 75% CA 1 15% DBS/ 10% MgSi 7. 75% CA1 15% DBS/ 8 9 10% CaSi 8. 35% CA / 15% DBS 9. 100% CA Patent Application Publication Oct. 2, 2008 Sheet 1 of 2 US 2008/0241249 A1 Cyanoacrylate Composite - Modulus Key to Composition 1. 55% CA/ 15% DBS/ 30% MgSt 2. 55% CA/ 15% DBS I 30% CaSt 3. 65% CA / 15% DBS/ 20% MgSt 4. 65% CA / 15% DBS/ 20% CaSt 5. 65% 20CA/ 15% DBS / 20% CaSt 6. 75% CA/ 15% DBS/ 10% MgS1 7. 75% CA/ 15% DBS / 10%CaSt 1 3 3 4 5 5 7 8 9 8. 85%CA/15%DBS Composition FIG. 1 9. 100% CA Cyanoacrylate Composite — Elongation at Break Key to Composition 1. 55%CA/15% DBS/ 30% MgS1 2. 55%CA/15% DBS/ 30% CaSt 3. 65% CA I 15% DBS/ 20°/o 4. 65% CA / 15°/o DBS/ 20% CaSt 5. 65% 200A / 15% DBS/ 20% CaSt 6. 75% CA/ 15% DBS/ 10% Mgst 7. 75% CA/ 15% DBS/ 1 2 3 4 5 6 7 8 9 10%CaSt 0 0 Composition 8. 85/OCA/15/ODBS FIG. 2 Elongation at Break (in) 9. 100% CA Patent Application Publication Break Stress (PSI) 1400 1200 1000 800 600 400 200 Oct. 2, 2008 Sheet 2 of 2 US 2008/0241249 A1 Cyanoacrylate Composite — Break Stress 1 2 3 4 5 6 7 8 Composition FIG. 3 9 9. Key to Composition . 55% CA / 15°/o DBSI 30% Mgst 55% CA/15% DBS/ 30% CaSt 65% CA/ 15% DBSI 20% MgSt 65% CA/15% DBS/ 20°/o CaSt 65% 20CA / 15% DBS/ 20% CaSt 75% CA/15% DBSI 10% MgSt 75% CA/ 15% DBS/ 10% Cast 85% CA/ 15% DB8 100% CA US 2008/024l249 Al CYANOACRYLATE COMPOSITE BACKGROUND [0001] 1. Field [0002] The invention relates to adhesive composite or matrix materials, and to their use for industrial and medical applications. [0003] 2. State oftheArt [0004] Monomer and polymer adhesives are used in both industrial (including household) and medical applications. Included among these adhesives are the l ,l-di sub stituted eth- ylene monomers andpolyrners, such as the or-cyanoacrylates. Since the discovery of the adhesive properties of such mono- mers and their resulting polymers, they have found wide use due to the speed with which they cure, the strength of the resulting bond formed, and their relative ease of use. These characteristics have made or-cyanoacrylate adhesives the pri- mary choice for numerous applications such as bonding plas- tics, rubbers, glass, metals, wood, and, more recently, bio- logical tissues. [0005] Polymerizable l,l-disubstituted ethylene mono- mers, and adhesive compositions comprising such mono- mers, are disclosed, forexample, in U.S. Pat. No. 5,328,687 to Leung et al. Suitable methods for applying such compositions to substrates, and particularly in medical applications, are described in, for example, U.S. Pat. Nos. 5,928,611; 5,582, 834; 5,575,997; and 5,624,669, all to Leu11g et al. [0006] Medical applications of l,l-disubstituted ethylene adhesive compositions include use as an alternate or an adjunct to surgical sutures and staples in wound closure as well as for covering and protecting surface wormds such as lacerations, abrasions, bums, stomatitis, sores, and other sur- face wounds. When an adhesive is applied, it is usually applied in its monomeric form, and the resultant polymeriza- tion gives rise to the desired adhesive bond. [0007] A need exists for cyanoacrylate adhesive composi- tions with enhanced properties for use in medical applica- tions. Such properties include suitable viscosity, biocompat- ibility, absorbability, flexibility and stability. SUMMARY [0008] An adhesive composite material is provided com- prising a polymer matrix comprising one or more biocompat- ible cyanoacrylate polymers and a plasticizer, and at least one metal stearate entrapped in the polymer matrix, wherein the at least one metal stearate is present in an amount of at least 10% by weight of the adhesive composite material. [0009] The adhesive composite material may further com- prise one or more of stabilizing agents, preservatives, heat dissipating agents, colorant, or combinations thereof. The metal stearate may be calcium stearate, magnesium stearate or aluminum stearate. [0010] In an embodiment, an adhesive composite compo- sition is provided comprising one or more biocompatible cyanoacrylate monomers, about I to about 20 wt. % of plas- ticizer, and greater than about 10 wt. % metal stearate. The metal stearate may provide enhanced viscosity and may serve to initiate polymerization of the polymerizable cyanoacrylate monomers. When used in a patie11t’s body, the resulting poly- merized adhesive compo site material may comprise a porous, elastic and flexible polymer matrix. [0011] In another embodiment, a system for treating living tissue is provided comprising a first reservoir containing a Oct. 2, 2008 biocompatible polymerizable cyanoacrylate monomer com- position, a second reservoir in a r1on-contacting relationship with the first reservoir containing a metal stearate, and an applicator capable of combining the biocompatible polymer- izable cyanoacrylate monomer composition and metal stear- ate to form an adhesive composite composition and then applying the adhesive composite composition to living tissue. [0012] In an embodiment, a method of treating living tissue is provided comprising providing a polymerizable monomer composition comprising one or more biocompatible poly- merizable cyanoacrylate monomers, providing a metal stear- ate, mixing the polymerizable monomer composition and metal stearate to form a biocompatible adhesive composite composition comprising a suspension of the metal stearate in the polymerizable monomer composition, applying the bio- compatible adhesive composite composition to living tissue in need of treatment, and allowing the monomer in the bio- compatible adhesive composite composition to polymerize on the living tissue to form an adhesive composite material comprising a polymer matrix comprising metal stearate entrapped within a cyanoacrylate polymer matrix. The metal stearate is present in an amount of at least 10% by weight of the adhesive composite material. BRIEF DESCRIPTION OF THE DRAWINGS [0013] FIG. 1 is a graphical representation of the modulus G’SI) of various adhesive composite materials as detailed i11 Example 1. [0014] FIG. 2 is a graphical representation of the elongation at break (inches) of various adhesive composite materials as detailed in Example 1. [0015] FIG. 3 is a graphical representation of the break stress (PSI) of various adhesive composite materials as detailed in Example 1. DETAILED DESCRIPTION [0016] An adhesive composite material is provided com- prising a polymer matrix comprising one or more biocompat- ible cyanoacrylate polymers and a plasticizer, and at least one metal stearate entrapped in the polymer matrix. The at least one metal stearate is present in an amount of at least 10% by weight of the adhesive composite material. The adhesive composite material is flexible and compliant, presenting a distinguishable forn1 from cyanoacrylate adhesive materials previously known which do not contain a metal stearate. The adhesive composite material is a thickened, elastic, flexible, bulky, and compliant polymer. The mechanical properties of the adhesive composite material are comparable to those obtained by the use of cyanoacrylate compositions without a metal stearate, while providing advantages with regard to viscosity and flexibility. [0017] In other embodiments, absorbable cyanoacrylate adhesive composite compositions may be prepared by com- bining one or more metal stearates with polymerizable cyanoacrylate monomer(s) whicl1 provide an absorbable cyanoacrylate polymer upon polymerization. The combina- tion of one or more absorbable polymerizable cyanoacrylate monomers and one or more metal stearate results in an adhe- sive composite composition or material with enhanced prop- erties, such as controlled viscosity and setting time control in the monomeric adhesive composite composition form, and flexibility, rapid partial biodegradation and pore formation once the adhesive composite composition undergoes poly- US 2008/024l249 Al merization to form a polymerized adhesive composite mate- rial which provides a polymer matrix entrapping the metal stearate. [0018] When one or more metal stearates is combined with one or more polymerizable monomers, the metal stearate and polymerizable monomer or monomers form an adhesive composite composition. “Adhesive composite composition” as used herein refers to a combination of a metal stearate with one or more polymerizable monomers or with a composition comprising one or more polymerizable monomers. The expressions “composition comprising one or more polymer- izable monomers” and “polymerizable monomer composi- ion” are used interchangeably and are used herein to refer to a composition comprising one or more polymerizable mono- ners which composition may also comprise one or more additional components, such as initiator, plasticizer, inhibitor or stabilizer, preservative, rate modifier, colorant, heat dissi- oating agent, among others, which may be used in polymer- izable monomer formulations. “Adhesive composite mate- *ial” or “polymerized adhesive composite material” as used ierein refers to the polymerized material or the polymer natrix formed after polymerization of the polymerizable nonoiner composition or the adhesive composite composi- ion [0019] The metal stearate and polymerizable monomer(s) may be combined to form an adhesive composite composition 3y any means known to those of skill in the art, such as by aringing the components into contact, mixing, blending, dis- ributive mixing, dispersive mixing or other means. [0020] In forming the adhesive composite composition, when the metal stearate is combined with the polymerizable nonoiner or monomers, a small amount of the metal stearate oecomes partially dissolved while a substantial amount or najority of the metal stearate becomes suspended in the poly- nerizable monomer or polymerizable monomer composi- ion. Thus, in embodiments, the adhesive composite compo- sition is a suspension of metal stearate in polymerizable nonoiner compos 'tion. “Suspension” as used herein refers to a system in which metal stearate particles or particulates are dispersed throughout a polymerizable monomer. In embodi- nents, the metal s earate particulates are at least microscopi- cally visible, and may be physically and chemically separated from the polymerzable monomer composition in the adhe- sive composite co nposition. [0021] In embodiments, the metal stearate will form a sus- pension when combined with a polymerizable cyanoacrylate monomer compostion. Typically, a substantial portion of the metal stearate is microscopically and physically distinguish- able from the poly nerizable cyanoacrylate monomer compo- sition in the adhesve composite composition thus formed. In addition, upon polymerization of the polymerizable cyanoacrylate monomer composition, a polymer matrix forms in which the metal stearate is distinguishable from the polymerized cyanoacrylate polymer matrix. [0022] “Distinguishable” as used herein refers to the metal stearate being differentiable as a substantially separate com- ponent, e.g., a particulate component, within the suspension with the polymerizable monomer composition or, upon poly- merization, within the polymer matrix. The metal stearate combined with one or more polymerizable monomers to form a composite adhesive composition provides a viscosity enhancing effect on the monomer or monomers or the mono- mer composition, but remains a differentiable part of the adhesive composite composition. Upon polymerization, the Oct. 2, 2008 metal stearate in the adhesive composite material is substan- tially entrapped in the polymer matrix formed from the poly- merizable monomer or monomers. [0023] Without being bound to any theory, it is believed that the polymer matrix structure of the adhesive composite mate- rial, when used in the body of a patient, allows for the metal stearate to degrade or biodegrade within the polymer matrix and/or allows for the metal stearate to diffuse through and/or leach from the polymer matrix, forming a porous polymer matrix. It is further believed that the metal stearate may degrade or biodegrade orbe absorbed faster than the polymer matrix can be absorbed in a patient’s body, or that the metal stearate can diffuse through or leach from the polymer matrix prior to the biodegradation or absorption of the polymer matrix, forming a porous system. This porous polymermatrix may provide a structure that allows microcirculation and tis- sue growth through the porous polymer matrix. As used herein, “degradation” refers to any manner of the metal stear- ate exiting the polymer matrix which results in the formation of a porous matrix. This egress of the metal stearate from the polymer matrix is believed to form a porous matrix that pro- motes microcirculation and tissue growth, therefore allowing healing to take place. [0024] The adhesive composite composition has enhanced viscosity, thus avoiding previously known problems with the use of polymerizable monomers. By way of example, one problem with using monomeric cyanoacrylate compositions in many medical applications is product run-off. This run-off may cause the material to reach unintended locations. This is a drawback in applications where precision is of importance, particularly in medical applications where the cyanoacrylate composition is applied in or on the body of a patient. The adhesive composite composition and the polymerized adhe- sive composite material of polymerizable cyanoacrylate monomer(s) and metal stearate provides numerous advan- tages, such as the elimination/reduction of run-off, precision, elasticity, material memory, flexibility, bulkiness, and overall good compliance to tissue. By way of example, an adhesive composite composition comprising at least one cyanoacrylate monomer and one or more metal stearates thus provides a thickened material with enhanced viscosity that resists run- off. The polymerized adhesive composite material provides additional advantages, including, but not limited to, micro- circulation and tissue growth through the porous structure of the polymer matrix resulting from the degradation of the metal stearate from the cyanoacrylate polymer matrix. [0025] Another problem previously known in using poly- merizable cyanoacrylate monomers to form cyanoacrylate polymers was sometimes found in attaching tissue layers, such as in seroma management. Polycyanoacrylate formed from polymerizing cyanoacrylate monomer(s) may create a physical barrier that separates tissue planes that need to be in contact for appropriate healing. The adhesive composite material comprising a polymer matrix of one or more bio- compatible cyanoacrylate polymers and metal stearate entrapped in the polymer matrix is believed to solve this problem at least in part through rapid partial degradation, biodegradation or diffusion of the metal stearate from the adhesive composite material when used in or on the body of a patient. [0026] Previous attempts to solve the problems involved with seroma management included the use of surgical drains. The use of such drains increases cost, infection rates, and may cause other complications. However, when an adhesive com- US 2008/0241249 A1 posite composition of polymerizable cyanoacrylate mono- mer(s) and one or more metal stearates is used to form a cyanoacrylate polymer by polymerization of the one or more cyanoacrylate monomers, the need for surgical drains may be diminished as the dead space in the tissue may be eliminated by the adherence of the tissue planes with the polymerized cyanoacrylate composite material. [0027] Suitable metal stearates for use in an adhesive com- posite composition typically are substantially insoluble in the polymerizable monomer or monomers, but may be readily combined or mixed with the polymerizable monomer or monomers. The metal stearates generally are used in the form of freely flowable powders or particulates. [0028] Suitable metal stearates include magnesium stear- ate, aluminum stearate, calcium stearate, zinc stearate, or mixtures thereof. In embodiments, the metal stearate may be calcium stearate, aluminum stearate or magnesium stearate. [0029] In embodiments, a metal stearate is selected which is non-toxic or biocompatible and may be used in medical applications. Particularly for medical uses, calcium stearate may be used as the metal stearate. [0030] The metal stearate may function in embodiments as a viscosity enhancing agent. The increased viscosity, by way of example, provides the ability to apply the adhesive com- posite composition to a desired location without unwanted “run-off” from the desired location. [0031] In embodiments, a polymerizable cyanoacrylate adhesive monomer composite composition will have an effectively enhanced viscosity if it has a viscosity of about 10 to about 10,000 centipoise, preferably about 30 to about l ,500 centipoise, as measured with a Brookfield V iscometer at 25° C. When the adhesive composite composition is to be used in medical applications internally in a patient, the enhanced viscosity preferably is about 100 to about 800 CP, as measured with a Brookfield Viscometer at 25° C. When the adhesive composite composition is to be used in medical applications extemally on a patient, the enhanced viscosity preferably is about 30 to about 100 cP, as measured with a Brookfield Viscometer at 25° C. [0032] The metal stearate in embodiments may be used in an amount above about 10% of the total adhesive composite composition and the polymerizable monomer composition may be used in an amount from about 90% to about 65%. In other embodiments, the metal stearate is used in an amount from about 10 to about 25% of the total adhesive composite composition and the polymerizable monomer composition is present in an amount from about 90% to about 75%. [0033] Adhesive composite compositions a11d adhesive composite materials formed therefrom, are useful as tissue adhesives, sealants for preventing bleeding or for covering open wounds, implants for void space, and in other biomedi- cal applications. The adhesive composite compositions and the adhesive compo site materials resulting from polymeriza- tion thereof find uses in, for example, preventing body fluid leakage, sealing air leakage in the body, tissue approximation, apposing surgically incised or traumatically lacerated tissues; retarding blood flow from wounds; drug delivery; dressing burns; dressing skin or other superficial or deep tissue surface wounds (such as abrasions, chaffed or raw skin, and/or sto- matitis); and aiding repair and regrowth of living tissue. Adhesive composite compositions and adhesive composite materials formed therefrom, have broad application for seal- ing wounds in various living tissue, internal organs and blood vessels, and can be applied, for example, 011 the interior or Oct. 2, 2008 exteriorofbloodvessels and various organs or tissues. “Treat- ing living tissue” as used herein refers to any of the above uses or any other use wherein the adhesive composite composition is applied on, to or into the body of a patient for either a prophylactic or therapeutic purpose. ln embodiments, the treatment of living tissue will be for a medical therapeutic purpose. [0034] Adhesive composite compositions, and polymers formed therefrom, are also useful in industrial and home applications, for example in bonding rubbers, plastics, wood, composites, fabrics, and other natural and synthetic materials. [0035] Suitable monomers are readily polymerizable, e.g. anionically polymerizable or free radical polymerizable, or polymerizable by zwitterions or ion pairs to form polymers. Some such monomers are disclosed i11, for example, U.S. Pat. No. 5,328,687 to Leung, et al., which is hereby incorporated by reference herein in its entirety. Preferred monomers include l,l-disubstituted ethylene monomers, such as a-cy- anoacrylates. Preferably, the adhesive composite composi- tions comprise one or more polymerizable cyanoacrylate monomers and are biocompatible. The adhesive composite compositions comprising one or more polymerizable cyanoacrylate monomers may include combinations or mix- tures of cyanoacrylate monomers. [0036] The term “biocompatible” refers to a material being suited for and meeting the requirements of a medical device, used for either long or short term implants or for non-implant- able applications, such that when implanted or applied in an intended location, the material serves the intended function for the required amount of time without causing an unaccept- able response. Long term implants are defined as items implanted for more than 180 days. [0037] By way of example, useful monomers include a-cy- anoacrylates of formula (I). These monomers are known in the art and have the formula (1) CN R2HC=C COOR3 wherein R2 is hydrogen and R3 is a hydrocarbyl or substituted hydrocarbyl group; a group having the formula —R4—O— R5—O—R6, wherein R4 is a l,2-alkylene group having 2-4 carbon atoms, R5 is an alkylene group having 1-4 carbon atoms, and R6 is an alkyl group having 1-6 carbon atoms; or a group having the formula —R7—c—o—R8 0 wherein R7 is CH3 —(cH2),,—» —CH—» °I —c(cH3)2—» wherein n is l-l0, preferably l-5 carbon atoms, and R8 is an organic moiety. US 2008/0241249 A1 [0038] Examples of suitable hydrocarbyl and substituted hydrocarbyl groups include straight chain or branched chain alkyl groups having 1-16 carbon atoms; straight chain or branched chain C1-C16 alkyl groups substituted with an acy- loxy group, a haloalkyl group, an alkoxy group, a halogen atom, a cyano group, or a haloalkyl group; straight chain or branched chain alkenyl groups having 2 to 16 carbon atoms; straight chain or branched chain alkynyl groups having 2 to 12 carbon atoms; cycloalkyl groups; aralkyl groups; alkylaryl groups; and aryl groups. [0039] The organic moiety R3 may be substituted or unsub- stituted and may be straight chain, branched or cyclic, satu- rated, unsaturated or aromatic. Examples of such organic moieties include C1-C8 alkyl moieties, C2-C8 alkenyl moi- eties, C2-C8 alkynyl moieties, C3-C12 cycloaliphatic moi- eties, aryl moieties such as phenyl and substituted phenyl and aralkyl moieties such as benzyl, methylbenzyl, and phenyl- ethyl. Other organic moieties include substituted hydrocar- bon moieties, such as halo (e.g., chloro-, fluoro- and bromo- substituted hydrocarbons) and oxy-substituted hydrocarbon (e.g., alkoxy substituted hydrocarbons) moieties. Preferred organic radicals are alkyl, alkenyl, and alkynyl moieties hav- ing from 1 to about 8 carbon atoms, and halo-substituted derivatives thereof. Particularly preferred are alkyl moieties of 4 to 6 carbon atoms. [0040] In the cyanoacrylate monomer of formula (I), R3 may be an alkyl group having 1-10 carbon atoms or a group having the formula -AOR9, WhereinA is a divalent straight or branched chain alkylene or oxyalkylene moiety having 2-8 carbon atoms, and R9 is a straight or branched alkyl moiety having 1-8 carbon atoms. [0041] Examples of groups represented by the formula -AOR include 1-methoxy-2-propyl, 2-butoxy ethyl, isopro- poxy ethyl, 2-methoxy ethyl, and 2-ethoxy ethyl. [0042] The (x-cyanoacrylates of formula (I) canbe prepared according to methods known in the art. U.S. Pat. Nos. 2,721, 858 and 3,254,111, each of which is hereby incorporated in its entirety by reference, disclose methods for preparing ot-cy- anoacrylates. For example, the 0.-cyanoacrylates can be pre- pared by reacting an alkyl cyanoacetate with formaldehyde in a nonaqueous organic solvent and in the presence of a basic catalyst, followed by pyrolysis of the anhydrous intermediate polymer in the presence of a polymerization inhibitor. [0043] The CL-cyanoacrylates of formula (I) wherein R3 is a group having the formula R44)—R3%)—R6 can be pre- pared according to the method disclosed i11 U.S. Pat. No. 4,3 64,876 to Kimura et al., which is hereby incorporated in its entirety by reference. In the Kimura et al. method, the (x-cy- anoacrylates are prepared by producing a cyanoacetate by esterifying cyanoacetic acid with an alcohol or by transesteri- fying an alkyl cyanoacetate and an alcohol; condensing the cyanoacetate and formaldehyde or para-formaldehyde in the presence of a catalyst at a molar ratio of 0.5-1.5: 1, preferably 08-1221, to obtain a condensate; depolymerizing the con- densation reaction mixture either directly or after removal of the condensation catalyst to yield crude cyanoacrylate; and distilling the crude cyanoacrylate to form a high purity cyanoacrylate. [0044] The CL-cyanoacrylates of formula (I) wherein R3 is a group having the formula Oct. 2, 2008 ——R1—c——o——N can be prepared according to the procedure described in U.S. Pat. No. 3,995,641 to Kronenthal et al., which is hereby incorporated in its entirety by reference. In the Kronenthal et al. method, such or-cyanoacrylate monomers are prepared by reacting an alkyl ester of an CL-cyanoacrylic acidwith a cyclic 1,3-diene to form a Diels-Alder adduct which is then sub- jected to alkaline hydrolysis followed by acidification to form the corresponding or-cyanoacrylic acid adduct. The (2-cy- anoacrylic acid adduct is preferably esterified by an alkyl bromoacetate to yield the corresponding carbalkoxymethyl or-cyanoacrylate adduct. Altematively, the o.-cyanoacrylic acid adduct may be converted to the or-cyanoacrylyl halide adduct by reaction witl1 thionyl chloride. The or-cyanoacrylyl halide adduct is then reacted with an alkyl hydroxyacetate or a methyl substituted alkyl hydroxyacetate to yield the corre- sponding carbalkoxymethyl or-cyanoacrylate adduct or car- balkoxy alkyl or-cyanoacrylate adduct, respectively. The cyclic 1,3-diene blocking group is finally removed and the carbalkoxy methyl on-cyanoacrylate adduct or the carbalkoxy alkyl or-cyanoacrylate adduct is converted into the corre- sponding carbalkoxy alkyl or-cyanoacrylate by heating the adduct in the presence of a slight deficit of maleic anhydride. [0045] Examples of monomers of formula (I) include cyanopentadienoates and or-cyanoacrylates of the formula: (11) CN ZHC==C COOR3 wherein Z is —CH:CH2 and R3 is as defined above. The monomers of formula (II) wherein R3 is a11 alkyl group of 1-10 carbon atoms, i.e., the 2-cyanopenta-2,4-dienoic acid esters, canbe prepared by reacting an appropriate 2-cyanoac- etate with acrolein in the presence of a catalyst such as zinc chloride. This method of preparing 2-cyanopenta-2,4-dienoic acid esters is disclosed, for example, in U.S. Pat. No. 3,554, 990, which is hereby incorporated in its entirety by reference. [0046] Suitable on-cyanoacrylate monomers which may be used, alone or in combination, include alkyl oi-cyanoacrylates such as 2-octyl cyanoacrylate; dodecyl cyanoacrylate; 2-eth- ylhexyl cyanoacrylate; butyl cyanoacrylate such as 11-butyl cyanoacrylate; ethyl cyanoacrylate; methyl cyanoacrylate or other 0.-cyanoacrylate monomers such as methoxyethyl cyanoacrylate; 2-ethoxyethyl cyanoacrylate; 3-methoxybutyl cyanoacrylate; 2-butoxyethyl cyanoacrylate; 2-isopropoxy- ethyl cyanoacrylate; and 1-methoxy-2-propyl cyanoacrylate. In embodiments, the monomers are ethyl, n-butyl, or 2-octyl or-cyanoacrylate. [0047] Other cyanoacrylates which may be used include alkyl ester cyanoacrylates. Besides the process detailed above, alkyl ester cyanoacrylates can also be prepared through the Knoevenagel reaction of an alkyl cyanoacetate, or an alkyl ester cyanoacetate, with paraformaldehyde. This leads to a cyanoacrylate oligomer. Subsequent thermal crack- ing of the oligomer results in the formation of a cyanoacrylate US 2008/0241249 A1 monomer. After further distillation, a cyanoacrylate mono- mer with high purity (greater than 95.0%, preferably greater than 99.0%, and more preferably greater than 99.8%), may be obtained. [0048] Monomers prepared with low moisture content and essentially free of impurities (e.g., surgical grade) are pre- ferred for biomedical use. Monomers utilized for industrial purposes need not be as pure. [0049] In some embodiments, the alkyl ester cyanoacrylate monomers may have the formula: 0 R1’ R2’ NC 0 CH; 0 wherein R1’ a11d R2’ are, independently, H, a straight, branched or cyclic alkyl, or are combined together in a cyclic alkyl group, R3’ is a straight, branched or cyclic alkyl group, andm is 1-8. Preferably, R1’ is H ora C1, C3 or C3 alkyl group, such as methyl or ethyl; R2‘ is H or a C 1, C2 or C3 alkyl group, such as methyl or ethyl; R3’ is a Cl-C16 alkyl group, more preferably a C1-C10 alkyl group, such as methyl, ethyl, pro- pyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl, and even more preferably a C3, C3 or C4 alkyl group, and m is preferably l-4. [0050] Examples of the alkyl ester monomers may include, but are not limited to: CN H O O or W27!“ T] V H O O 3—(2—Cyano—acryloyloxy)—butyric acid ethyl ester (Et—[$-HBT-CA) CN “W0 O“ H O O 3-(:2—Cyano-acryloyloxy)-hexanoic acid ethyl ester (Et-|3—CPL-CA) [0051] Additional examples of alkyl ester cyanoacrylates include, but are not limited to, butyl lactoyl cyanoacrylate (BLCA), butyl glycoloyl cyanoacrylate (BGCA), isopropyl glycoloyl cyanoacrylate (IPGCA), ethyl lactoyl cyanoacry- late GELCA), and ethyl glycoloyl cyanoacrylate (EGCA) and combinations thereof. BLCA may be represented by the for- mula above, wherein R1’ is H, R2’ is methyl and R3’ is butyl. BGCA may be represented by the formula above, wherein R1‘ is H, R2’ is H and R3 V is butyl. lPGCA may be represented by the formula above, wherein R1’ is H, R2’ is H and R3’ is isopropyl. ELCA may be represented by the formula above, wherein R1’ is H, R2’ is methyl and R3 is ethyl. EGCA may be represented by the formula above, wherein R1’ is H, R2‘ is H and R3 V is ethyl. Oct. 2, 2008 [0052] Other examples of alkyl ester cyanoacrylates include alkyl alpha-cyanoacryloyl caprolactate and alkyl alpha-cyanoacryloyl butrylactate. Other cyanoacrylates use- ful in the present invention are disclosed in U.S. Pat. No. 3,995,641 to Kronenthal et al., the entire disclosure of which is hereby incorporated by reference. [0053] Altematively, or in addition, alkyl ether cyanoacry- late monomers may be used. Alkyl ethyl cyanoacrylates have the general formula: NC R” R” wherein R1” is a straight, branched or cyclic alkyl, and R2” is a straight, branched or cyclic alkyl group. Preferably, R1" is a C1, C2 or C3 alkyl group, such as methyl or ethyl; and R2” is a C1-C16 alliyl group, more preferably a C1-C10 alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pen- tyl, hexyl, heptyl, octyl, nonyl or decyl, and even more pref- erably a C2, C3 or C4 alkyl group. [0054] Examples of alkyl ether cyanoacrylates include, but are not limited to, isopropyoxy ethyl cyanoacrylate (IPECA) and methoxy butyl cyanoacrylate (MBCA) or combinations thereof. IPECA may be represented by the formula above, wherein R1” is ethylene and R2” is isopropyl. MBCA may be represented by the formula above, wherein R1” is n-butylene and R2" is methyl. [0055] Alkyl ester cyanoacrylates and alkyl ether cyanoacrylates are particularly useful for medical applica- tions because of their absorbability by living tissue and asso- ciated fluids. The terms “absorbable” or “absorbable adhe- sive” or variations thereof mean the ability of a tissue- compatible material to degrade or biodegrade at some time after implantation into products that are eliminated from the body or metabolized therein. Thus, as used herein, absorb- ability means that the polymerized adhesive is capable of being absorbed, either fully or partially, by tissue after appli- cation of the adhesive. [0056] Likewise, the terms “non-absorbable” or “non-ab- sorbable adhesive” or variations thereof mean completely or substantially incapable of being absorbed, either fully or par- tially, by tissue after application of the adhesive. Furthermore, relative terms such as “faster absorbing” and “slower absorb- ing” are used relative to two monomer species to indicate that a polymer produced from one monomer species is absorbed faster (or slower) than a polymer formed from the other monomer species. [0057] For the purposes herein, the term “substantially absorbed” means at least 90% absorbed within about three years. Likewise, the term “substantially non-absorbed” means at most 20% absorbed within about three years. Pref- erably, l00% of the polymerized and applied cyanoacrylate when using these types of cyanoacrylate monomers may be absorbed in a period of less than 3 years, preferably approxi- mately 2-24 months, more preferably 3-18 months, and most preferably 6-12 months after application of the adhesive to living tissue. The absorption time may vary depending on the particular uses and tissues involved. Thus, for example, longer absorption time may be desired where the adhesive composition is applied to hard tissues, such as bone, but a US 2008/0241249 A1 faster absorption time may be desired where the adhesive composite composition is applied to softer tissues. [0058] The selection of monomer will affect the absorption rate of the resultant polymer, as well as the polymerization rate of the monomer. Two or more different monomers that have varied absorption and/or polymerization rates may be used in combination to give a greater degree of control over the absorption rate of the resultant polymer, as well as the polymerization rate of the monomer. [0059] According to some embodiments, the adhesive composite composition comprises a mixture of monomer species with varying absorption rates. Where two monomer species having different absorption rates are used, it is pre- ferred that the absorption rates be sufiiciently different that a mixture of the two monomers can yield a third absorption rate that is effectively different from the absorption rates of the two monomers individually. Compositions according to these embodiments are described, for example, in U.S. patent application Ser. No. 09/919,877, filed Aug. 2, 2001, pub- lished as U.S. Patent Publication No. 2002/0037310 on Mar. 28, 2002, and U.S. Pat. No. 6,620,846, both incorporated herein by reference in their entireties. [0060] Absorbable cyanoacrylates have broad application for closure and hemostatic sealing of wounds and the like in various livi11g tissue, including but not limited to internal organs and blood Vessels. These absorbable formulations can be applied on the interior or exterior of various organs and tissues. [0061] Adhesive composite compositions as disclosed preferably are biocompatible and may be applied internally or extemally in or on living tissue. The adhesive composite compositions are preferably sterilized for use in medical applications. More preferably, the adhesive composite com- positions may be sterilized by dry heat sterilization while retaining suitability for medical applications. [0062] For example, suitable adhesive composite composi- tions according to embodiments can be prepared by mixing suitable quantities of an alkyl alpha cyanoacrylate such as 2-octyl alpha-cyanoacrylate with one of butyl lactoyl cyanoacrylate (BLCA), butyl glycoloyl cyanoacrylate (BGCA), isopropyl g ycoloyl cyanoacrylate (IPGCA), ethyl lactoyl cyanoacryla e GELCA), and ethyl glycoloyl cyanoacrylate (EGCA). Such mixtures may range from ratios of about 90:10 to about 10:90 by weight, preferably about 75:25 to about 25:75 3y weight such as from about 60:40 to about 40:60 by weight. [0063] In embodiments, the metal stearate and the polymer- izable monomer comoosition are not combined to form the adhesive composite composition until just prior to or at the time of use. Thus, the metal stearate may comprise a first component and the polymerizable monomer composition may comprise a seco id component in a system for treating livi11g tissue. A two component system may be used, by way of example, where the metal stearate effectively initiates or accelerates the polymerization of the polymerizable mono- mer composition. Besides polymerizable monomer(s), the polymerizable monomer composition may comprise one or more additional constituents. [0064] By way of example, stabilizing agents may be used in the polymerizable monomer composition. Suitable free radical stabilizing agents foruse in polymerizable cyanoacry- late adhesive composite compositions comprising one or more polymerizable cyanoacrylate monomers include hydro- quinone, hydroquinone monomethyl ether, catechol, pyro- Oct. 2, 2008 gallol, benzoquinone, 2-hydroxybenzoquinone, p-methoxy phenol, t-butyl catechol, butylated hydroxy ani sole, butylated hydroxy toluene, and t-butyl hydroquinone and mixtures or combinations thereof. The free radical stabilizing agents may be used in amounts from about 5 to about 10,000 ppm. In embodiments, if hydroquinone is used, the amount may be from about 5 to about 70 ppm and may be used in conjunction with butylated hydroxy anisole in an amount of about 500 to about 10,000 ppm. [0065] Cyanoacrylate adhesive composite compositions comprising one or more polymerizable cyanoacrylate mono- mers may also optionally include both at least one anionic vapor phase stabilizer and at least one anionic liquid phase stabilizer. These stabilizing agents inhibit polymerization. Examples of such anionic agents are described for example, in U.S. Pat. No. 6,620,846, incorporated herein by reference in its entirety. [0066] The anionic vapor phase stabilizers may be selected from among known stabilizers, including, but not limited to, sulfur dioxide or hydrogen fluoride. The amount of anionic vapor phase stabilizer that is added to the monomer compo- sition depends on the identity of the liquid phase stabilizer(s) chosen in combination with it, the monomer to be stabilized, as well as the packaging material to be used for the compo- sition. Typically, each anionic vapor phase stabilizer is added to give a concentrationof less than about 200parts per million (ppm). In embodiments, each anionic vapor phase stabilizer is present in an amount from about 1 to about 200 ppm, prefer- ably from about 10 to about 75 ppm, even more preferably from about 10 to about 50 ppm, and most preferably from about 10 to about 20 ppm. The amount to be used can be determined by one of ordinary skill in the art using known techniques without undue experimentation. [0067] In embodiments, the liquid phase anionic stabilizer is a very strong acid. As used herein, a very strong acid is an acid that has an aqueous pK,, of less than 1.0. Suitable very strong acidic stabilizing agents include, but are not limited to, very strong mineral and/or oxygenated acids. Examples of such very strong acids include, but are not limited to, sulfuric acid (pK,,—3 .0), perchloric acid (pKa—5), hydrochloric acid (pK,,—7.0), hydrobromic acid (pK,,—9), fluorosulfonic acid (pK,,