Rapidly Curing Cyanoacrylates as Adhesives

(19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0029978 A1 Swords et al. US 20 1 00029978Al (43) Pub. Date: Feb. 4, 2010 (54) (76) (21) (22) (63) RAPIDLY CURING CYANOACRYLATES AS ADHESIVES Inventors: Noeleen Swords, Kiltipper (IE); Louise Gilbride, Dublin (IE); Colette Hoare, Dublin (IE) Correspondence Address: HENKEL CORPORATION One Henkel Way ROCKY HILL, CT 06067 (US) Appl. No.: 12/578,923 Filed: Oct. 14, 2009 Related U.S. Application Data Continuation of application No. 054256, filed on Apr. 9, 2008. PCT/EP2008/ (30) Foreign Application Priority Data Apr. 18, 2007 (EP) ................................ .. 07007847.2 Publication Classification (51) Int. Cl. C07C 255/03 (2006.01) (52) U.S. Cl. ...................................................... .. 558/381 (57) ABSTRACT The present invention relates to a polymerizable adhesive composition which comprises, at least as one constituent, a cyanacrylate component and which requires a comparitively short time for curing when used on surfaces. The present invention therefore also includes a method for the production of the cyanacrylate component described above, and the cyanacrylate component as such. US 2010/0029978 A1 RAPIDLY CURING CYANOACRYLATES AS ADHESIVES CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation under 35 U.S.C. Sections 365(c) and 120 of Intemational Application No. PCT/EP2008/054256, filed Apr. 9, 2008 and published on Dec. 4, 2008 as WO 2008/128888, which claims priority from European Patent Application No. 07007847.2 filed Apr. 18, 2007, which are incorporated herein by reference in their entirety. [0002] The present invention relates to a polymerizable adhesive composition that encompasses a cyanoacrylate component as at least one constituent and exhibits no over- stabilization by way of a polymerization inhibitor, so that a comparatively short time is required for curing upon applica- tion onto surfaces. The present invention therefore also con- tains a method for manufacturing the above-described cyanoacrylate component, as well as the cyanoacrylate com- ponent as such. BACKGROUND OF THE INVENTION [0003] Because of their ease of application and rapid curing rate, and the strength of the resulting adhesive bond, cyanoacrylate-based polymerizable monomeric adhesive compositions have become widely used in both industrial and medical applications. It is known that monomeric forms of cyanoacrylates are extremely reactive and polymerize rapidly in the presence of even very small quantities of a polymer- ization initiator, including moisture contained in the air or present on surfaces. Polymerization is initiated by anions, free radicals, zwitterions, or ion pairs. Once polymerization has been started, the curing rate can be very high. Cyanoacry- late-based polymerizable monomeric adhesive compositions have therefore proven to be attractive solutions, for example, for joining plastics, rubber, glass, metals, wood, and more recently also biological tissues. Medical applications of cyanoacrylate-based monomeric adhesive compositions include both utilization as altematives to or in addition to surgical sutures and staples when closing wounds, and utili- zation to cover and protect superficial wounds such as lacera- tions, abrasions, bums, stomatitis, inflammations, and other open superficial wounds. [0004] The U.S. Pat. No. 5,328,687 by Leung et al., U.S. Pat. No. 3,527,841 by Wicker et al., U.S. Pat. No. 3,722,599 by Robertson et al., U.S. Pat. No. 3,995,641 by Kronenthal et al., and U.S. Pat. No. 3,940,362 by Overhults, for example, disclose monomeric cyanoacrylates that are suitable as sur- gical adhesive agents. [0005] In the context of medical utilization of a cyanoacry- late-based adhesive composition, application is usually accomplished in monomeric form. Subsequent anionic in- situ polymerization directly on the tissue surface then causes wound adhesion or coverage. [0006] As compared with the utilization of sutures or staples for wound care, the alternative use of cyanoacrylate- based wound adhesives offers a number of advantages. Wound sutures in the direct vicinity of the injury being treated cause additional injuries because of the penetration of the needle into the tissue and the need in some cases to administer an anesthetic, and require a time-consuming procedure for application. The same is true of wound treatment using Feb. 4, 2010 staples. The result is that the use of these agents presents problems especially in pediatric cases, since because of the adverse effects associated with them, they trigger severe anxi- ety and aversion reactions in the often very young patients. [0007] The problems set forth above can be at least partially circumvented or mitigated by the inherently painless appli- cation of a cyanoacrylate-based wound adhesive in accor- dance with a method described by Halpem in U.S. Pat. No. 3,667,472 or by Banitt et al. in U.S. Pat. No. 3,559,652. [0008] Despite these advantages, the medical use of cyanoacrylate-based adhesive compositions can be associ- ated with certain problems, since it is known that both the monomers and the polymer that is formed can bring about serious irritation of the tissue in the application area. This negative tissue reaction is attributed principally to the bio- logical breakdown process of the polymer that takes place in vivo, which, as described in the following citations—F. Leonard et al., Journal ofApplied Polymer Science, Vol. 10, pp. 259-272 (1966); F. Leonard, Armals New York Academy of Sciences, Vol. 146, pp. 203-213 (1968); Tseng,Yin-Chao, et al., Journal ofApplied Biomalerials, Vol. 1, pp. 111-119 (1990), and Tseng, Yin-Chao, et al., Journal ofBiomedical Materials Research, Vol. 24, pp. 1355-1367 (1990)—leads to the release of formaldehyde. [0009] A number of structural modifications have therefore been made in the past in order to enhance the biocompatibility of cyanoacrylate-based adhesives. By extending the alkyl chain in the cyanoacrylate ester, for example, it has been possible to greatly reduce the speed of the biological break- down process and thus the rate of formaldehyde release into the affected tissue. Whereas short-chain cyanoacrylate esters (e.g. methyl-2-cyanoacrylate) are subject to rapid biodegra- dation, the longer-chain analogs such as, for example, butyl- 2-cyanoacrylate, octyl-2-cyanoacrylate, or decyl-2-cy- anoacrylate are notable for a much reduced breakdown rate. [0010] As described in U.S. Pat. No. 6,667,031 by M.Aze- vedo, the synthesis of cyanoacrylate monomers is based on thermal cracking, at temperatures from 1 50 to more than 200° C., of the prepolymer produced upon the reaction of cyanoac- etate with formaldehyde, and subsequent separation of the resulting monomers from the reaction solution by distillation. Thermal depolymerization is successful only when this pro- cess occurs in the presence of stabilizers, or mixtures of stabilizers, that can prevent both radical and anionic repoly- merization of the resulting monomers under the reaction con- ditions described. As disclosed in U.S. Pat. Nos. 3,559,652 and 5,582,834, the radical stabilizers are, by way of example, hydroquinone, hydroquinone monomethyl ether, nitrohydro- quinone, catechol and hydroquinone monomethyl esther. Anionic polymerization inhibitors are as a rule, but not exclu- sively, Lewis acids such as, for example, sulfur dioxide, nitro- gen monoxide, or boron trifluoride, or inorganic or organic Bronstedt acids such as, for example, sulfuric acid, phospho- ric acid, or sulfonic acids. [0011] Determining the optimum concentration of the anionic polymerization inhibitor represents a difficult techni- cal problem. Under the drastic conditions of thermal depoly- merization of the prepolymer, too low a concentration results in significant repolymerization of the monomers that have already formed. A very high concentration of the anionic stabilizer, on the other hand, causes a portion of the stabilizer to be carried over from the reaction solution upon distillative separation of the monomer. This results in a residual concen- tration of the anionic stabilizer in the distilled cyanoacrylate US 2010/0029978 Al monomer, which is responsible for an overstabilization of the product so that effective polymerization of the cyanoacrylate monomer on the tissue surface is later inhibited. [0012] The problem of a high residual concentration of an anionic stabilizer is especially important particularly in the production of long-chain high-boiling monomeric cyanoacrylate esters such as, for example, octyl-2-cy- anoacrylate or decyl-2-cyanoacrylate. As compared with short-chain cyanoacrylate esters, separating out from the reaction solution the particular monomer that has been pro- duced requires higher distillation temperatures and lower dis- tillation pressures. As an undesired side effect of this, a por- tion of the anionic stabilizer is carried over into the monomeric product, resulting in an overstabilization of the long-chain biocompatible cyanoacrylate ester that is extremely negative for later utilization. [0013] This overstabilization in terms of anionic polymer- ization affimty can be compensated for by adding polymer- ization initiators or promoters to the monomeric adhesive composition. It is possible to use as polymerization initiators or promoters, for example, amines that exhibit sufficiently good solubility under the prevailing conditions. [0014] An important consideration with all additives is that, specifically in the medical application sector, the additives must have no toxicologically objectionable effect on the par- ticular organism or on the tissue that has in any event already suffered serious prior damage. Care must therefore be taken in all cases, when developing medical wound adhesives, to limit as much as possible the number of additives contained, in order to minimize risks to the patient. [0015] In this context, U.S. Pat. No. 6,849,082 by M. Aze- vedo discloses a method for removing the anionic stabilizer from a monomeric adhesive composition prior to application onto the tissue surface. The monomeric adhesive composition is brought directly into contact with a substance for removing the stabilizer (Lewis acid or organic/ inorganic Bronstedt acid). Examples of this substance are ion exchangers, molecular sieves, zeolites, chelating agents, activated carbon systems, or other substances of an anionic nature. [0016] A related invention is described by M. Azevedo in U.S. Pat. No. 6,667,031. Here the anionic stabilizer is removed, prior to application of the monomeric adhesive composition, by contact with a silicate, a polyvinylpyrroli- done-based polymer or copolymer, or a polymer that pos- sesses functional groups such as carbonyl, hydroxyl, amide, carboxylate, amine, ether, anhydride, ester, urethane, or sul- fone, by the creation of physical interactions such as adsorp- tion or absorption, hydrogen bridge bonds, or the occurrence of a chemical reaction. [0017] The approach common to the methods described above is that overstabilization of the monomeric cyanoacry- late-based adhesive composition is to be counteracted by the addition of an initiator or by way of a purification step, so as thereby to enable effective polymerization on the tissue sur- face or to increase the polymerization rate. What would be desirable in this context would be a cyanoacrylate-based adhesive composition that, because of its manufacturing pro- cess, exhibits such a low concentration of undesirable poly- merization inhibitors that overstabilization of the polymeriz- able adhesive composition does not occur, thereby making possible direct application with no preceding purification steps and without the addition of additives. [0018] The object that accordingly results for the present invention is that of making available a cyanoacrylate-based Feb. 4, 2010 polymerizable adhesive composition that exhibits no oversta- bilization resulting from a polymerization inhibitor, so that upon application to surfaces, curing of the adhesive compo- sition occurs within a comparatively short period of time. [0019] It has now been found, surprisingly, that in the con- text of cyanoacrylate components having an at least 90 wt %, by preference at least 95 wt %, particularly preferably at least 98 wt %, and very particularly preferably at least 99 wt % weight proportion of cyanoacrylate, or of mixtures of a cyanoacrylate with further cyanoacrylates, curing on anABS surface occurs in less than 80 s without the addition of a polymerization initiator or polymerization accelerator. [0020] Suitable polymerization initiators or polymeriza- tion accelerators are well known to one skilled in the art. The addition of these substances or substance mixtures to mono- meric cyanoacrylates causes the polymerization process to proceed in accelerated fashion as compared with identical monomeric cyanoacrylates to which the relevant substances or substance mixtures have not been added. [0021] In a preferred embodiment of the present invention, the inventive cyanoacrylate component consists essentially of only the aforementioned cyanoacrylate or a mixture of said cyanoacrylates. [0022] In another preferred embodiment of the present invention, the inventive cyanoacrylate component consists of the inventive cyanoacrylate as well as primary and secondary anionic polymerization inhibitors and optionally at least one free radical chain polymerization inhibitor. [0023] The general structure of the cyanoacrylate accord- ing to the present invention is described by formula (I), R being a substituted or unsubstituted, straight-chain, branched or cyclic alkyl group having 5 to 18 C atoms and/or an aromatic group or acyl group. formula (I) HZC CN [0024] Preferred embodiments encompass, without being limited thereto, n-pentyl 2-cyanoacrylate, iso-pentyl 2-cy- anoacrylate (such as l-pentyl, 2-pentyl, and 3-pentyl), cyclo- pentyl 2-cyanoacrylate, n-hexyl-2-cyanoacrylate, iso-hexyl 2-cyanoacrylate (such as l-hexyl, 2-hexyl, 3-hexyl, and 4-hexyl), cyclohexyl 2-cyanoacrylate, n-heptyl 2-cyanoacry- late, isoheptyl 2-cyanoacrylate (such as l-heptyl, 2-heptyl, 3-heptyl, and 4-heptyl), cycloheptyl 2-cyanoacrylate, n-octyl 2-cyanoacrylate, l-octyl 2-cyanoacrylate, 2-octyl 2-cy- anoacrylate, 3-octyl 2-cyanoacrylate, 4-octyl 2-cyanoacry- late, decyl 2-cyanoacrylate, dodecyl 2-cyanoacrylate. Par- ticularly preferred cyanoacrylates of general formula (I) are n-octyl-2-cyanoacrylate or 2-octyl-cyanoacrylate. Mixtures of said cyanoacrylates are also preferred. [0025] In preferred embodiments of the present invention, the inventive cyanoacrylates may also be combined with other cyanoacrylates. For example, a mixture of at least one of said cyanoacrylates with n-butyl 2-cyanoacrylate, such as a mixture of 2-octyl 2-cyanoacrylate with n-butyl 2-cyanoacry- late is preferred. [0026] In a preferred embodiment of the present invention, the inventive cyanoacrylates of general formula (I) may also US 2010/0029978 A1 be present in essentially monomeric form, i.e., the proportion of the corresponding polymer and/or oligomer is less than 5 wt %, preferably less than 1 wt %, and most preferably less than 0.1 wt %, each based on the total amount of inventive cyanoacrylates of general formula (I). [0027] The cyanoacrylates according to the present inven- tion of formula (I) may be manufactured in accordance with methods that are known in the technical sector. U.S. Pat. Nos. 2,721,858 and 3,254,1 11 disclose methods for manufactur- ing cyanoacrylates. The cyanoacrylates can be manufactured, for example, by reacting an alkyl cyanoacetate with formal- dehyde in a nonaqueous organic solvent and in the presence of a basic catalyst, followed by thermal depolymerization of the anhydrous prepolymer in the presence of a stabilizer. Cyanoacrylate monomers that have been manufactured with a low moisture content and in a marmer substantially free of contaminants are preferred for biomedical applications. [0028] The moment at which curing of the adhesive bond has been achieved, is determined with the help of specimen bodies with the dimensions 100 mm>