Cyanoacrylate Tissue Adhesives with Desirable Permeable and Tensile Strenght

(19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0117047 A1 Zhang et al. US 20110117047A1 (43) Pub. Date: May 19, 2011 (54) (75) (73) (21) (22) (86) CYANOACRYLATE TISSUE ADHESIVES WITH DESIRABLE PERMEABILITY AND TENSILE STRENGTH Inventors: Assignee: Appl. No .: PCT Filed: PCT No.: §371(CX1L (2), (4) Date: Sheng Zhang, Hickory, NC (US); Rafael Ruiz, Sr., Hudson, NC (US) ADHEZION BIOMEDICAL, LLC, Wyomissing, PA (US) 13/000,799 Jun. 23, 2009 PCT/US09/48234 Dec. 22, 2010 Related U.S. Application Data (62) Division of application No. 61/132,844, filed on Jun. 23, 2008. Publication Classification (51) Int. Cl. A61K 31/785 (2006.01) A61P 1 7/02 (2006.01) (52) U.S. Cl. ................................................... .. 424/78.06 (57) ABSTRACT A sterilized cyanoacrylate adhesive composition including a cyanoacrylate composition and a cure speed enhancer, wherein said sterilized cyanoacrylate adhesive composition does not cure upon sterilization, and wherein the composition when cured to form a film on a patient’s tissue has water vapor transmission rate from about 950 to about 3000 g/m2/day. US 2011/0117047 A1 CYANOACRYLATE TISSUE ADHESIVES WITH DESIRABLE PERMEABILITY AND TENSILE STRENGTH CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of, and claims priority under 35 U.S.C. §120, to U.S. patent applica- tion Ser. No. 11/767,565, filed on Jun. 25, 2007, and claims priority under 35 U.S.C. §119(e) to U.S. patent application Ser. No. 61/132,844, filed on Jun. 23, 2008, the disclosures of which are incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION [0002] (1) Field of the Invention [0003] The present invention relates to cyanoacrylate adhe- sives. In particular, the present invention relates to cyanoacry- late adhesives with an enhanced cure speed for medical use and that, once cured, exhibit improved permeability and mechanical properties such as, for example, wound closure strength, overlap shear strength, peel adhesive strength, and flexibility. [0004] (2) Description of RelatedArt [0005] Cyanoacrylate compositions have long been known in the art as excellent adhesives. The cyanoacrylate adhesives are liquid monomers that polymerize on contact with tissue surfaces in an exothermic reaction creating a strong yet flex- ible film. The polymer film is generally formed rapidly. Liq- uid cyanoacrylate compositions have found application in medicine for closing wounds and incisions, especially in cases where suturing does not provide satisfactory results because of cyanoacrylate’s unique ability to bond living tis- sue and their long-term bond strength. They have found wide applications as industrial and structural adhesives, consumer products for repair of household items and in the hobby sector for assembly and repair. [0006] It is well known that cyanoacrylate adhesive com- positions are very sensitive and careful handling is required to prepare their formulations. In order to extend the applications of cyanoacrylate adhesives, a variety of additives have been incorporated in their formulations including stabilizers, vis- cosity modifiers, thixotropic agents, plasticizers, biocompat- ible agents, and polymerization activators. [0007] Cyanoacrylate polymerization is usually considered as the result of an anionic initiation with water being a sulfi- ciently strong base. In spite of the relatively fast cure speed of cyanoacrylate adhesives, polymerization enhancers have to be incorporated for specific applications. First, the cure speed would be drastically dropped if cyanoacrylate adhesives were applied to acidic substrates such as wood and paper. In this case, the cyanoacrylate adhesives with a faster cure time would offer an option. In addition, a relatively large amount of cyanoacrylate applied in certain cases will result in the slower hardening throughout the adhesives. [0008] In order to enhance the polymerization rate for such applications, a number of efforts have been made by applying accelerators through different methods. For example, a two component system has been used by packaging the cyanoacrylate adhesive and the accelerator separately. The cure speed of cyanoacrylate adhesives is improved. The dis- advantage of this method is that the accurate measurement May 19, 2011 and mixing two components homogeneously are very diffi- cult tasks to achieve since only a tiny amount of accelerators is generally required. [0009] As an example, U.S. Pat. No. 5,928,611 to Leung discloses an applicator tip for dispensing a polymerizable material, in which a polymerization accelerator was included. The accelerator initiates polymerization when the polymer- izable material is dispensed through the applicator tip. Suit- able accelerators include detergent compositions; surfac- tants, amines, urea, phosphines, alcohols, inorganic bases and salts, sulfur compounds, polymeric cyclic ethers, crown ethers, calixarenes, cyclic and acyclic carbonates, organome- tallics, and radical. The polymerizable material may also contain an initiator which is inactive until activated by a catalyst in the applicator tip. Initiators activated by stimula- tion such as heat and/ or light are also suitable if the tip and/or applicator is appropriately subjected to such stimulation. [0010] U.S. Pat. Application No. 20050196431 to Narang et al. discloses an applicator tip for an applicator for applying a polymerizable monomeric adhesive composition that can include a bioactive material, a flavorant, a polymerization initiator, and/or a polymerization rate modifier. It has been discovered that the use of methanol, alone or as a component of a mixture of low boiling point solvents, to apply a poly- merization accelerator to an applicator tip used to dispense monomer-containing adhesive compositions, provides an unexpectedly superior distribution profile of the material on, and within, the applicator tip. Applicator tips according to their invention can control the setting time of the polymerized or cross-linked adhesive, extend the shelf life of the monomer and control the flow properties of applied cyanoacrylate adhe- srves. [0011] U.S. Pat. No. 4,460,759 to Narang discloses two- component adhesive compositions. One component contains the cyanoacrylate monomer and the second component con- tains a weakly acidic or weakly basic ionic accelerator con- sisting of a cation having a pKa of at least 10 and a nucleo- philic anion. [0012] Another approach to enhance the cure speed of cyanoacrylate adhesive is to apply the diluted solutions of the accelerators in low-boiling point solvents to the cyanoacry- late adhesives. The accelerator solutions can be added to the substrate in advance or applied when the cyanoacrylate adhe- sive is still liquid. Japanese Patent Application No. JP-A-03 207 778 discloses the use of solutions of aliphatic, alicyclic and, especially, tertiary aromatic amines as the activators for the curing of cyanoacrylate adhesives. Specific examples included N,N-dimethylbenzylamine, N-methylmorpholine and N,N-diethyltoluidine. Japanese Patent Application No. JP-A-62 022 877 suggested the use of solutions of lower fatty amines, aromatic amines, and dimethylamine for the same purpose. [0013] British Patent Specification No. 1 230 560 described cyanoacrylate adhesive compositions containing certain sub- stituted heterocyclic compounds as accelerators. The compo- sitions may be presented in a two-part form, the first part comprising the cyanoacrylate adhesive and the second part comprising at least one of the substituted heterocyclic com- pounds, preferably dissolved in an organic solvent. The het- erocyclic compound is invariably present in one part of a two-part composition because iminoethylene-substituted tri- azines and pyrimido-pyrimidines accelerate the polymeriza- tion so rapidly that they must be kept apart from the cyanoacrylate composition before use. An effective adhesive US 2011/0117047 A1 bond is obtained. However it is not concemed with an acti- vator which is able to initiate polymerization throughout a layer of adhesive. [0014] U.S. Pat. No. 3,260,637 to von Brarner discloses the use of a range of organic amines as accelerators for cyanoacrylate adhesives, particularly for use on metallic and non-metallic substrates.According to the invention, a catalyst solution comprising one or more organic amines was employed in a suitable solvent to moisten the surfaces to be bonded and to catalyze the adhesive action of cyanoacrylate adhesive composition. [0015] U.S. Pat. No. 4,042,442 to Dombroski et al. dis- closes the addition of a polymerization initiator such as caf- feine and theobromine to a cyanoacrylate adhesive composi- tion. The caffeine or theobromine is added to the adhesive composition in different ways. Firstly, the caffeine or theo- bromine is dissolved in a volatile solvent, applied to the surfaces to be joined, the volatile solvent is allowed to evapo- rate, and then the cyanoacrylate adhesive composition is applied to the surfaces of the substrates to be joined. Sec- ondly, the caffeine or theobromine can be mixed with the cyanoacrylate adhesive composition by stirring just prior to application of the adhesive to the substrates to be joined. Both of these methods are inconvenient for the user because two separate solutions or two separate applications are required. [0016] U.S. Pat. No. 5,561,198 to Huver provided an acti- vator for cyanoacrylate adhesives based on N,N-dialkyl aniline derivatives. The activators are characterized by a molecular weight of more than 200 and by at most 3 carbon atoms for both N,N-dialkyl substituents together. Their invention also provided methods of production and use of the activator and to the combination product of the activator and the cyanoacrylate adhesive. In their inventions, the activators were tested according to criteria including reactivity, cure rate on activated aluminum test strips, cure rate after activation, tensile shear strength on sand-blasted aluminum strips, trans- parency, and odor of the reactivity. [0017] U.S. Pat. No. 6,547,917 to Hanns et al. revealed the accelerated curing of cyanoacrylate adhesives using organic compounds containing the structural element—N.dbd.C— S—S—C:N— in dilute solution as activators. Examples of such compounds include 6,6‘-dithiodinicotinic acid, dibenzo- diazyl disulfide, 2,2‘-dipyridyl disulfide or bis(4-t-butyl-1- isopropyl-2-imidazolyl)disulfide. According to their inven- tion, the activators are dissolved in readily volatile solvents, such as hydrocarbons, carboxylic acid esters, ketones, ethers or halogenated hydrocarbons. The activator solutions accord- ing to their invention are suitable for the accelerated curing of all conventional cyanoacrylate adhesives which contain as the fundamental constituent one or more cyanoacrylic acid esters, inhibitors of free-radical polymerization, inhibitors of anionic polymerization and, optionally, conventional auxil- iary substances employed in such adhesive systems. As com- pared with the known accelerators, their method provided the following advantage: good accelerating action, but they nev- ertheless require a long waiting time between application of the activator and application of the adhesive. [0018] U.S. Pat. No. 6,995,227 to Ryan et al. discloses an activator composition for the accelerated curing of cyanoacrylate adhesives, wherein the activator comprises a member selected from the group consisting of: aromatic het- erocyclic compounds having at least one N hetero atom in the ring(s) such as pyridines, quinolines and pyrimidines and substituted on the ring(s) with at least one electron-withdraw- May 19, 2011 ing group which decreases the base strength of the substituted compound compared to the corresponding unsubstituted compound, mixtures of any of the foregoing with each other, and/or with N,N-dimethyl-p-toluidine, and mixtures of any of the foregoing and/or N,N-dimethyl-p-toluidine with an organic compound containing the structural element, such as dibenzothiazyl disulfide, 6,6‘-dithiodinicotinic acid, 2,2‘- dipyridyl disulfide, and bis(4-t-butyl-1-isopropyl-2-imida- zolyl)disulfide. An activator composition may comprise a solution of one or more activators in a solvent mixture which comprises a volatile hydrocarbon and a cyclic ketone. Their invention reduced the problem of “halo” effect and provided activator solutions with different properties. [0019] In order to improve the cure speed of cyanoacrylate adhesives, another important method is to incorporate accel- erators directly to the adhesive formulations. DE-A40 09 621 proposed the use of certain cyclodextrine derivatives as an additive to improve the cure speed of cyanoacrylate adhesive, some of which are soluble in cyanoacrylates. GB-A-2 200 124 revealed the use of acyclic phenol-formaldehyde oligo- mers as an accelerating additive for cyanoacrylate adhesive formulations. [0020] German patent DE-A-22 61 261 proposed accelera- tor substances containing the structural element —N:C— S—. According to their invention, cyanoacrylate adhesives containing such accelerators do in fact show that even rela- tively large amounts of adhesive harden relatively rapidly and reliably. However, that compound has a very high volatility, so that activator solutions based thereon are unsuitable for application beforehand since the active ingredient also evapo- rates off with the solvent. [0021] U.S. Pat. No. 4,386,193 to Reich, et al. discloses a rapid-setting .alpha.-cyanoacrylate based adhesive composi- tion having good storage stability and, in particular, to an adhesive composition having a very fast setting time on wood and other substrates with a porous/ acid surface by using 3 or 4 arm polyol pod and compounds as accelerators. [0022] Japanese Patent Application No. 59-66471 dis- closes amine derivatives as a curing accelerator of cyanoacry- late adhesives. The amine compounds have a boiling point of between 50° C. and 250° C. Examples of suitable amines include propanolarnine triethyl amine, diethyl amine, isopro- pyl amine, butyl amine, tributyl amine, N,N-dimethyl-o- toluidine, N,N-dimethyl aniline, N,N-diethyl aniline, N,N- dimethyl-p-toluidine, N,N-dimethyl-m-toluidine dimethyl benzyl amine, pyridine, picoline, vinyl pyridine, ethanola- mine, and ethylene diamine. [0023] U.S. Pat. No. 4,377,490 to Shiraishi et al., discloses mixtures of aromatic and aliphatic polyols and polyethers to improve initial strength of cyanoacrylate wood bonding prod- ucts. [0024] European Patent Specification No. 0 271 675 A2 discloses a primer for cyanoacrylate resin compositions for use in bonding non-polar or highly crystallized resins such as polyolefins, polyethyleneterephthalates, nylons, fluorine- containing resins, and soft PVC films. The primer comprises (i) an organic amine and (ii) a compound selected from the group consisting of benzene ring compounds having alde- hyde group and nitrogen or oxygen atom-containing hetero- cyclic compounds having aldehyde group. The specification states that a cyanoacrylate adhesive exhibited a strong bond- ing strength at ambient temperature. [0025] U.S. Pat. No. 4,718,966 to Stephen, et al. discloses cyanoacrylate adhesive compositions which employ calix- US 2011/0117047 A1 arene compounds as accelerators give substantially reduced fixture and cure times on deactivating substrates such as wood, leather, ceramic, plastics and metals. The calixarene compounds are preferably employed at levels of about 0.1- 1% by weight of the composition. [0026] In U.S. Pat. No. 4,170,585 to Motegi et al., certain polyethylene glycols poly(ethyleneoxy) functional are dis- closed to be additives for increasing the curing speed of cyanoacrylate compositions. Such compounds, however, have the reported disadvantage that they contain water and other substances difficult to remove which spontaneously initiate polymerization of the cyanoacrylate monomer. [0027] Japanese Patent Application No. 8-310136 to Ohashi, et al. discloses 2-cyanoacrylate adhesive composi- tions containing a crown ether curing accelerator or a poly- alkylene oxide curing accelerator. However, these composi- tions are not suitable for medical applications. [0028] In general, cyanoacrylate combinations with accel- erators have been obtainable by separately housing the cyanoacrylate and accelerator. The cyanoacrylate is then flowed past the accelerator housing to add the accelerator to the cyanoacrylate. This method is used for industrial applica- tions, where large batches of the cyanoacrylate are needed. This method is not suitable for medical use, nor are the cyanoacrylate compositions prepared from this method ame- nable to being sterilized in preparation for medical use. [0029] Based on the descriptions above, different design systems and a variety of chemicals have been applied to accelerate the curing speed of cyanoacrylate adhesives. How- ever, most of the employed accelerators exhibited their own shortcomings at different extents. Some of them are more toxic, while others exhibit weak activation, less bond strength, high volatility and odor. In addition, irregular struc- ture is formed in some cases, which destroys transparency of film. These disadvantages thus limit the application of cyanoacrylate adhesives in different fields, especially for medical use. [0030] Moreover, in spite of the fact that many cyanoacry- late compositions have been disclosed for surgical wound dressing and management, none of the prior art cyanoacry- late-based surgical adhesives exhibit a desirable permeability or breathability. However, permeability, as measured by moisture vapor transmission rate (MVTR), is a desirable characteristic of a surgical adhesive because it prevents mac- eration of the skin due to trapped moisture, improve wound healing, and to enhance patient’s comfort during wear of the bandage. Desirable permeability can provide the following benefits: (1) removing and preventing exudates from pooling while keeping the wound moist during the process of wound healing, (2) permitting appropriate oxygen ingress and car- bon dioxide egress, and (3) minimizing the formation of trauma to surrounding or new tissue. [0031] It has been reported that adhesives with high mois- ture vapor transmission rate improve wound care (Hansen et al. Adhesive Age 22-25, 2003). The prior art has emphasized the importance of permeability of wound dressing products on the wound healing process. For example, U.S. Pat. No. 4,649,909 to Thompson teaches a wound dressing made of polyurethane film. The moisture vapor transmission feature of the dressing film contributes to the improved wound heal- ing. U.S. Pat. No. 6,495,229 to Carte et al. provides a method of speeding the healing of wounds using a rubber-based or acrylic pressure-sensitive adhesive bandage with high mois- ture vapor transmission rate. U.S. Pat. Appl. No. 20050182347 to Bishop et al. claims a multi-layered wound dressing comprising a layer having a high moisture vapor transmission rate (MVTR). The wound dressing possesses May 19, 2011 improved fluid handling capacity and high MVTR to reduce maceration of the surrounding skin and prevent wound des- iccation. [0032] Accordingly, there is a need in the art for a cyanoacrylate adhesive composition with a polymerization accelerator, which provides a desirable permeability or breathability for improved wound healing. SUMMARY OF THE PRESENT INVENTION [0033] In one aspect, the present invention provides a ster- ilized cyanoacrylate adhesive composition including a cyanoacrylate composition and a cure speed enhancer, wherein said sterilized cyanoacrylate adhesive composition does not cure upon sterilization, and wherein the composition when cured to form a film on a patient’s tissue has water vapor transmission rate from about 950 to about 3000 g/m2/day. [0034] In another aspect, the present invention provides a method of sealing tissue, including the steps of: applying the sterilized cyanoacrylate adhesive composition as a liquid to a patient’s tissue to be sealed; and curing the sterilized cyanoacrylate adhesive composition to seal the patient’s tis- sue, wherein the composition when cured to form a film on the patient’s tissue has water vapor transmission rate of from about 950 to about 3000 g/m2/day. DETAILED DESCRIPTION OF THE INVENTION [0035] The present invention provides a sterilized cyanoacrylate adhesive composition and method of preparing the same including a cure speed enhancer added to a cyanoacrylate adhesive composition. The sterilized cyanoacrylate adhesive composition is essentially a bioab- sorbable tissue adhesive for sealing and aiding in the repair of tissue. Importantly, the sterilized cyanoacrylate adhesive composition does not cure upon sterilization and, when cured, provides an advantageous quantity of permeability. [0036] The compositions of the present invention comprise cyanoacrylate monomers. Such cyanoacrylate monomers are readily polymerizable, e.g., anionically polymerizable or free radical polymerizable. Cyanoacrylate monomers suitable for use in accordance with the present invention include, but are not limited to, 1,1-disubstituted ethylene monomers of the formula: HRC:CXY (1) [0037] wherein X andY are each strong electron withdraw- ing groups, and R is H, —CH:CH2, or a C1-C4 alkyl group. [0038] Examples of monomers within the scope of formula (I) include alpha-cyanoacrylates, vinylidene cyanides, C1-C4 alkyl homologues of vinylidene cyanides, dialkyl methylene malonates, acylacrylonitriles, vinyl sulfinates and vinyl sul- fonates of the formula CH2:CX'Y wherein X‘ is —SO2R' or —SO3R' andY‘ is —CN, —COOR', %OCH3, —SO2R' or —SO3R', and R‘ is H or hydrocarbyl. [0039] Preferred monomers of formula (I) for use in this invention are alpha-cyanoacrylates. These monomers are known in the art and have the formula (11) Ri CN c=c H \ COOR3 wherein R2 is hydrogen and R3 is a hydrocarbyl or substituted hydrocarbyl group; a group having the formula —R4—O— US 2011/0117047 A1 R5—O—R6, wherein R4 is a 1,2-alkylene group having 2-4 carbon atoms, R5 is an alkylene group having 2-12 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 H2 :C ‘E?’ 0r *[C(CH3)2]n: wherein n is 1-10, preferably 1-8 carbon atoms and R8 is an organic moiety. [0040] 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. [0041] The organic moiety R8 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, C8-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- (e.g., alkoxy substituted hydrocarbons) substituted hydrocarbon 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 of4 to 8 carbon atoms. [0042] In the cyanoacrylate monomer of formula (II), R3 is preferably an alkyl group having 1-10 carbon atoms or a group having the formula -AOR9, wherein A 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. [0043] Examples of groups represented by the formula -AOR9 include 1-methoxy-2-propyl, 2-butoxy ethyl, isopro- poxy ethyl, 2-methoxy ethyl, and 2-ethoxy ethyl. [0044] The preferred alpha-cyanoacrylate monomers used in this invention are 2-octyl cyanoacrylate, n-octyl cyanoacrylate, dodecyl cyanoacrylate, 2-ethylhexyl cyanoacrylate, butyl cyanoacrylate, methyl cyanoacrylate, 3-methoxybutyl cyanoacrylate, 2-butoxyethyl cyanoacrylate, 2-isopropoxyethyl cyanoacrylate, or 1-methoxy-2-propyl cyanoacrylate. The most preferred alpha-cyanoacrylate monomer for use in accordance with the present invention is 2-octyl cyanoacrylate, which has the formula May 19, 2011 CH; H 0 E12 £12 £12 / \CH’ \C / \C / \CH | H2 H2 0 CH3 C NC/ \ C 3. I [0045] The alpha-cyanoacrylates of formula (II) can be prepared according to methods known in the art. Reference is made, for example, to U.S. Pat. Nos. 2,721,858 and 3,254, 111, each of which is hereby incorporated by reference herein. In certain embodiments, the alpha-cyanoacrylates are synthesized based on procedures known in the art. One such process includes, for example, reacting a cyanoacetate with formaldehyde in the presence of a basic condensation catalyst at elevated temperature to give a low molecular weight poly- mer. A de-polymerization (or cracking) step is followed under high temperature and high vacuum in the presence of acidic and anionic inhibitors, yielding a crude monomer that can be distilled under high temperature and high vacuum in the presence of radical and acidic inhibitors. In preferred embodi- ments, the distilled 2-cyanoacrylate monomers are then for- mulated with free radical and acidic inhibitors depending upon their application to provide the necessary stability and other desired physical properties. [0046] The cyanoacrylate component of the compositions according to the present invention can be present from about 10 to about 99.9 percent by weight of the composition, more preferably from about 75 to about 99 percent by weight of the composition, and most preferably from about 90 to about 99 percent by weight of the composition. [0047] The alpha-cyanoacrylate compositions of the present invention also comprise a crown ether compound. The crown ether functions as a polymerization accelerator. Preferred crown ethers for use in accordance with the present invention include, but are not limited to, 15-crown-5,18- crown-6, dibenzo- 1 8-crown-6, tribenzo- 1 8-crown-6, dicy- clohexyl-18-crown-6, benzo-15-crown-5, dibenzo -24- crown-8, dibenzo-30-crown-10, asym-dibenzo-22-crown-6, dimethylsila-1 1-crown-4, dimethylsila-14-crown-5, dimeth- ylsila-17-crown-6, dibenzo-14-crown-4, dicyclohexyl-24- crown-8, asym-dibenzo-22-crown-6, cyclohexyl-12-crown- 4,1,2-decalyl-15-crown-5,1,2-naphtho-15-crown-5,3,4,5- naphthyl-16-crown-5,1,2-methyl-benzo-18-crown-6,1,2- methylbenzo-5,6-methylbenzo-18-crown-6, 1,2-t-butyl-18- crown-6,1,2-vinylbenzo-15 -crown-5,1,2-vinylbenzo-18- crown-6, 1,2-t-butyl-cyclohexyl-18-crown-6, and 1,2-benzo- 1,4-benzo-5-oxygen-20-crown-7. 18-crown-6 ethers are particularly preferred. [0048] The crown ether is preferably present in the amount of about 2 to about 3200 ppm by weight of the adhesive composition. In preferred embodiments, the polymerization accelerator is present in the amount of from about 40 to about 1600 ppm, and more preferably from about 100 to about 1000 ppm of the adhesive composition. [0049] The cyanoacrylate monomer compositions accord- ing to the present invention can be stabilized with a free radical polymerization inhibitor and an anionic polymeriza- tion inhibitor. The preferred free radical stabilizer included in the cyanoacrylate adhesive composition is butylated hydroxyl anisole (BHA), and the preferred anionic vapor phase stabilizer is sulfur dioxide. However, any other suitable free radical stabilizer and anionic vapor phase stabilizer can US 2011/0117047 A1 be used that are known in the art. In embodiments of the present invention where the preferred primary free radical stabilizer is BHA, BHA is typically employed in an amount of from about 200 to about 15000 ppm of the cyanoacrylate compositions, and preferably from about 1000 to about 10000 ppm, and more preferably from about 2000 to about 10000 ppm. In embodiments where the anionic vapor phase stabi- lizer is S02, the amount of S02 that is added to the monomer composition depends on the amount of polymerization accel- erator applied such that the higher the concentration of poly- merization accelerator, the higher the concentration of S02. Preferably, the anionic vapor phase stabilizer is added to give a concentration of less than 50 parts per million (ppm). [0050] In certain embodiments, the cyanoacrylate compo- sitions may contain small amounts of a dye (also referred to herein as a “colorant”) to enhance the visual detection of the compositions. Colorants such as, for example, derivatives of anthracene and other complex structures may be employed. Suitable dyes include 1-hydroxy-4-[4-methylphenylarnino]- 9,10 anthracenedione (D&C violet No. 2); 9-(o-carboxyphe- nyl)-6-hydroxy-2,4,5,7-tetraiodo-3H-xanthen-3-one-, diso- dium salt, monohydrate (FD&C Red No. 3), disodium salt of 6-hydroxy-5-[(4-sulfophenyl)axo]-2-naphthalene-sulfonic acid (FD&C Yellow No. 6), and 2-(1,3-dihydro-3-oxo-5- sulfo-2H-indole-2-ylidine)-2,3-dihydro-3-oxo-1H-ind-ole-5 sulfonic acid disodium salt (FD&C Blue No. 2). [0051] When employed, the colorant is preferably present in amount of from about 2 to about 50 ppm of the cyanoacry- late composition, more preferably from about 4 to about 40 ppm of the cyanoacrylate composition, and most preferably from about 6 to about 30 ppm of the cyanoacrylate composi- tion. [0052] In preferred embodiments of the present invention, the preferred primary colorant is D&C violet No. 2. [0053] Various other additives such as, for example, thick- eners, strength enhancers and polymerization accelerators may be added to vary the viscosity, set time, spreadability, bond strength and degradation rate of the cyanoacrylate com- positions of the present invention. [0054] The present invention provides a sterilized cyanoacrylate adhesive composition with a very fast curing speed. This is typically achieved by adding a crown ether cure speed enhancer as described above to the cyanoacrylate adhe- sive composition before sterilization of the composition. The cure time of cyanoacrylate composition can be improved up to 2-5 times depending upon the amount of the accelerator applied. The cure speed enhancer is soluble in the cyanoacry- late monomer at room temperature. The compositions pro- duced, packaged and sterilized according to the current inven- tion have a much faster cure speed compared to cyanoacrylate adhesive compositions of the prior art. [0055] The reason crown ether was chosen as the preferred cure speed enhancer, or accelerating agent, for cyanoacrylate adhesive is not only due to its excellent activation for curing. Although crown ethers are not known to possess medicinal properties themselves, they may improve drug uptake and transport properties. For example, crown ethers affected the uptake of pirarubicin by drug-resistant cells. (Biochem. Phar- macol. 1995, 50, 2069-2076; Curr. Med. Chem. 2001, 8, 51-64). The special complexing properties of crown ethers have led to applications in drug delivery systems and as targeting functionalities incorporated in drug derivatives and DNA-binding agents. It was shown in DNA binding studies that the positive charge of cation-crown ether complexes May 19, 2011 increases the affinity of crown ether linked compounds with the polyanionic phosphate backbone of DNA. Thus, crown ether derivatized drugs may gain an increased interaction with DNA by the formation of cationic complexes with ions that are abundant in cells, such as sodium or potassium. (Int. J. Pharm. 1997, 159, 207-213; Int J. Pharm. 1998, 172, 33-70; Bioorg. Med. Chem. Len. 1994, 4, 1123-1126). [0056] Preferably, the cyanoacrylate adhesive composi- tions according to the present invention are stable. As the cure speed of cyanoacrylate adhesive compositions has been dra- matically improved herein, the stability of the adhesive is still conserved. Such stability of the adhesive is sustained due to the following treatments: (a) reducing the amount of contarni- nants and extraneous additives by applying the particulate agent, (b) providing a stable cyanoacrylate adhesive compo- sition by use of the combination of free radical stabilizer and anionic stabilizing agent and (c) further stabilizing the cyanoacrylate adhesive composition by applying more anionic stabilizer. Even with the presence of the cure speed enhancer, the cyanoacrylate adhesive composition does not actually cure until it has been applied to tissue. [0057] The stability of the cyanoacrylate adhesive compo- sition with the cure speed enhancer is confirmed by both real time and accelerated aging test detailed in the Examples below. Both the set time and viscosity data indicate the sta- bility of the inventive cyanoacrylate adhesive composition, also detailed below. [0058] The cyanoacrylate adhesive composition has a vis- cosity in the range from 2.5 to 70 centipoise, and preferably 5-30 centipoise, as measured with a Brookfield Viscometer at 25° C. Additionally, the viscosity of the composition should be maintained or increased by a controlled and acceptable amount after sterilization. [0059] The cure time of cyanoacrylate adhesives in the absence of the cure speed enhancer is up to 90 seconds depending upon the amount of free radical and anionic stabi- lizers included. However, the cure speed is dramatically increased after applying the cure speed enhancer to the cyanoacrylate composition. An increase of up to a few sec- onds can be achieved depending on the amount of the cure speed enhancer applied. [0060] According to embodiments of the present invention, the stability, and thus the shelf-life, of the cyanoacrylate adhesive compositions in the presence of the cure speed enhancer can be maintained during the accelerated aging, the packaging and sterilizing procedures. In preferred embodi- ments, there is substantially no initiation of polymerization of monomeric liquid adhesive compositions that affects the util- ity of the monomer caused by the sterilization process. [0061] The accelerated aging test of cyanoacrylate adhe- sive composition was performed in the oven at 80° C. for a period of 12 days. Based on the calculation, 12 days acceler- ated aging at 80° C. is equal to 2 years of shelf life, and 1 day of accelerated aging at 80° C. is equal to 60.8 days. Through- out the entire aging procedure, all cyanoacrylate adhesive samples remained fluid consistency and in good color. The stability of the aged cyanoacrylate adhesive samples was confirmed by set time and viscosity test. [0062] The viscosity of the cyanoacrylate adhesive compo- sition with the cure speed enhancer increased as the acceler- ated aging proceeded but the viscosity of the aged sample after day 12 was in the acceptable range. As an example, the average viscosity of cyanoacrylate adhesive composition in the presence of the cure speed enhancer at accelerated aging US 2011/0117047 A1 day 0, day 3, day 6, day 9, and day 12 was 4.29, 5.72, 10.6, 25.5, and 53.1 centipoise, respectively. [0063] The cure time of the cyanoacrylate adhesive com- position with cure speed enhancer varied a little after the 12 days aging at 80° C. However, the cure time of the cyanoacry- late adhesive composition in the absence of the cure speed enhancer might be dropped a lot during the accelerated aging process. For example, the average set time of one adhesive made from 2-octyl cyanoacrylate was increased from 40 sec- onds before the accelerated aging to 65 and 112 seconds at day 6 and day 12, respectively. [0064] Vinyl pyrrolidone polymers and copolymers can be applied to reduce the amount of contaminants and extraneous additives in the resulting adhesives from the cyanoacrylate adhesive formulation. These particulate agents are combined with the monomer adhesive in mutual contact until the adhe- sive is destabilized, whereupon the adhesive becomes iso- lated from the destabilizing agent by various means such as to effect isolation of the adhesive from the destabilizing com- ponent. It is only a requisite that enough excess stabilizer is left behind so as to provide the desirable speed of cure. [0065] The purity of cyanoacrylate adhesive compositions was checked by GC-MS. More than 99% of the adhesive composition is 2-octyl cyanoacrylate. No plasticizer or thixo- tropic agent is incorporated in the inventive cyanoacrylate adhesive composition. [0066] The cyanoacrylate adhesive compositions are ster- ilized. This is one novel aspect of the invention, as prior cyanoacrylate compositions with accelerators were not ster- ilized for medical use. The sterilization can be accomplished by common techniques, and is preferably accomplished by methods including, but not limited to, chemical, physical, and irradiation methods. Examples of chemical methods include, but are not limited to, exposure to ethylene oxide. Examples of irradiation methods include, but are not limited to, gamma irradiation, electron beam irradiation, and microwave irradia- tion. Preferred methods are chemical sterilization and elec- May 19, 2011 tron beam sterilization. Also, the cyanoacrylate compositions can be sterilized with ultraviolet (UV) radiation. Further, upon sterilization with any of these methods, the cyanoacry- late adhesive compositions are not cured. In other words, curing does not occur until application to tissue. [0067] The sterility of the cyanoacrylate monomer compo- sition with the cure speed enhancer was analyzed by Bacte- riostasis and Fungistasis tests. The test sample consisted of the sample with a puncture created to allow the liquid inside of the sample to mix with the test media. All were immersed into 500 ml of Soybean Casein Digest Medium (SCDM). The test microorganism such as Bacillus subzilis, Candida albi- cans, and Aspergillus niger, at less than 100 colony forming units, was inoculated into each of the test sample containers and into a positive control container of the same medium. After inoculation, the test sample and positive control con- tainer were incubated at 20-25 DC for a five day maximum incubation period. The growth of Bacillus subzilis, Candida albicans, and Aspergillus niger was observed for the inven- tive cyanoacrylate adhesive before the sterilization, while the inventive adhesives after sterilization exert a gross fungistatic effect on Bacillus sublilis, Candida albicans, andAspergillus nigen [0068] In vivo biomechanical evaluation was performed using the rat linear incision wound model in order to assess and evaluate the efiicacy of the cyanoacrylate composition with the cure speed enhancer as a new topical surgical tissue adhesive for the application of incisional wound closure. For direct comparison, the commercially available product Dermabond® topical skin adhesive was also evaluated. The male Sprague-Dawley rat was chosen as the animal model and this animal model has been used extensively for inci- sional wound strength studies, which has been well docu- mented in the literature. All study animals were acclimatized to their designated housing for approximately 7 days prior to the day of treatment. Prior to surgery, final selection of the animals was based on a visual appraisal of good clinical condition, and body weight specifications. TABLE 1 Biomechanical wound strength results for the cyanoacrylate adhesive of the present invention and Dennabond ® topical skin adhesive. Raw Data Study Ultimate Time Study Side [L = Lefi/ Wound Termination Pressure Date Point Animal Group Group Description R = Kight] Size Weight (g) (mmHg) Comments May 8, 2006 acu e 1 A DERMABOND ® Higi Viscosity 3 275 271 May 8, 2006 acu e 2 A DERMABOND ® Higi Viscosity K 297 230 May 8, 2006 acu e 3 A DERMABOND ® Higi Viscosity 3 286 291 May 8, 2006 acu e 4 A DERMABOND ® Higi Viscosity K 285 163 May 8, 2006 acu e 5 A DERMABOND ® Higi Viscosity 3 290 226 May 8, 2006 acu e 6 A DERMABOND ® Higi Viscosity K 297 169 May 8, 2006 acu e 7 A DERMABOND ® Higi Viscosity 3 280 162 May 8, 2006 acu e 8 A DERMABOND ® Higi Viscosity K 277 200 May 8, 2006 acu e 9 A DERMABOND ® Higi Viscosity 3 294 161 May 8, 2006 acu e 10 A DERMABOND ® Higi Viscosity K 284 276 May 8, 2006 acu e 11 A DERMABOND ® Higi Viscosity 3 282 320 May 8, 2006 acu e 12 A DERMABOND ® Higi Viscosity K 287 105 May 8, 2006 acu e 13 A DERMABOND ® Higi Viscosity 3 280 326 May 8, 2006 acu e 14 A DERMABOND ® Higi Viscosity K 205 372 Mean 255.5 240.0 St. Dev. 5.3 70.1 May 8, 2006 acu e 1 B nventive Adhesive K 275 210 May 8, 2006 acu e 2 B nventive Adhesive 3 297 220 May 8, 2006 acu e 3 B nventive Adhesive K 286 164 May 8, 2006 acu e 4 B nventive Adhesive 3 285 215 US 2011/0117047 A1 May 19, 2011 TABLE 1-continued Biomechanical wound strength results for the cyanoacrylate adhesive of the present invention and Dermabond ® topical skin adhesive. Raw Data Study Ultimate Time Study Side [L = Left/ Wound Termination Pressure Date Point Animal Group Group Description R = Right] Size Weight (g) (mmHg) Comments May 8, 2006 acute 5 B Inventive Adhesive R 1 290 119 May 8, 2006 acute 6 B Inventive Adhesive L 1 287 274 May 8, 2006 acute 7 B Inventive Adhesive R 1 280 314 May 8, 2006 acute 8 B Inventive Adhesive L 1 277 243 May 8, 2006 acute 9 B Inventive Adhesive R 1 294 251 May 8, 2006 acute 10 B Inventive Adhesive L 1 284 235 May 8, 2006 acute 11 B Inventive Adhesive R 1 282 291 May 8, 2006 acute 12 B Inventive Adhesive L 1 287 261 May 8, 2006 acute 13 B Inventive Adhesive R 1 280 285 May 8, 2006 acute 14 B Inventive Adhesive L 1 292 175 Mean 255.5 231.7 St. Dev. 6.3 52.5 ANOVA p-value (p = 0.05) 0.736201604 [0069] The animals were anesthetized, placed on a surgical table with a water-heating pad, and prepped with Betadine surgical skin prep and 70% alcohol solution. To control inci- sion length and location, a template and surgical skin-mark- ing pen were used to mark two symmetric 0.75-inch linear incisions over each dorsolateral flank area. All animals under- went the same surgical procedure. All incisions were made by the same surgeon and extend through the skin, subcutaneous tissue and parmiculus carnosus. The incisional wounds were then biomechanically tested for incisional wound strength. [0070] A BTC disposable acrylic test ring (ID 2.5 cm) was placed around the wound and secured to the skin using cyanoacrylate adhesive with the cure speed enhancer or com- mercially available Dermabond® topical skin adhesive. A small amount of perfluorinated grease was applied to the top of the ring interface to assure a tight vacuum seal. The BTC- 2000.TM. test chamber was integrated with the test ring until the chamber and ring were securely interconnected. The test chamber was held by hand comfortably to assure that no positive force was being exerted on the wound. A constant negative pressure was applied to the wound at a rate of 10 mmHg/ second, producing a multi-axial stress on the wound. A displacement laser captured displacement of wound mar- gins. [0071] Based on the wound strength raw data presented in Table 1, the average ultimate pressure applied in wound site for the inventive cyanoacrylate adhesive and the commercial Dermabond® topical skin adhesive was in the same level, indicating the cyanoacrylate with the cure speed enhancer possesses a bond strength strong enough to be used for wound closure as a medical product. [0072] In vitro cytotoxicity of the cyanoacrylate adhesive with the cure speed enhancer was evaluated. For comparison, the commercially available Dermabond® topical skin adhe- sive was also evaluated. A 2 cm2 sterile disc of filterpaper was saturated with 2-octylcyanoacrylate adhesive composition with the cure speed enhancer prior to dosing. L 929 mamma- lian fibroblast cell, seeded at a density of about 100,000 cells per mL at 7 mL per 60.times.15 mm plate, were allowed to propagate in serum supplemented minimum essential medium in a single test plate until greater than 80% conflu- ence was ob served. Growth generally requires about 48 to 72 hours in a humidified carbon dioxide incubator at 3721° C. When the cell culture reached confluence, the growth media was removed aseptically and triplicate plates were refilled with serum supplemented culture media containing not more than 2% agar overlay. The flat surface of the cyanoacrylate adhesive sample, positive and negative controls, and media control was then placed in contact with solidified agar sur- face. The test plates were then returned to the incubator for 24 hours. At the end of the additional incubation, the plates were individually observed under an inverted light microscope for signs of cell toxicity. The test results (Table 2) indicated that only minimal cytotoxicity was observed for the cyanoacrylate adhesive with the cure speed enhancer, while minimal to mild cytotoxicity was observed for the control Dermabond® topi- cal skin adhesive. TABLE 2 Results of test for in vitro cytotoxicity. Test article Evaluation of cytotoxicity The inventive adhesive 2, 2, 2 Dermabond ® topical skin adhesive 2, 2, 1 USP HDPE RS (Negative control) 0, 0, 0 USP Bioreaction RS (Positive control) 2, 2, 2 Media Control (MEM) 0, 0, 0 Ratings 0 Noncytotoxic No detectable zone around or under specimen 2 Slight cytotoxic Some malformed or degenerated cells under specimen 1 Mildly cytotoxic Zone limited to area under specimen 2 Moderate Zone extends 0.5 to 1.0 cm beyond specimen cytotoxic 3 Severely Zone extends greater than 1.0 cm beyond cytotoxic specimen [0073] The above results of the in vivo biomechanical evaluation using the rat linear incision wound model revealed that the inventive cyanoacrylate adhesive has comparable bond strength as the commercial Dermabond® product. In addition, in vitro cytotoxicity provided additional evidence that the cyanoacrylate adhesive is more suitable for medical US 2011/0117047 A1 use. The inventive cyanoacrylate adhesive exhibits only mini- mally cytotoxicity, while minimally to mild cytotoxicity was observed for the control Dermabond® product. Therefore, the cyanoacrylate adhesive of the present invention has advantages over the prior art. [0074] The cyanoacrylate compositions of the present invention are especially suitable for use in medical applica- tions. In use, the cyanoacrylate adhesive composition is applied to the desired tissue area as a liquid which then polymerizes upon contact with tissue. The cure speed enhancer allows for quick polymerization and setting of the cyanoacrylate adhesive composition, i.e., quick curing. The polymerized patch of cyanoacrylate adhesive allows the tis- sue to heal properly. Over time, water is drawn into the adhe- sive, causing it to degrade. The components of the adhesive then are cleared from the body. [0075] A surprising advantage of the cyanoacrylate adhe- sive compositions according to the present invention is that the adhesives exhibit a desirable permeability or breathabil- ity. The cyanoacrylate adhesive films according to the present invention typically exhibit a moisture vapor transmission rate of at least 950 g/m2/ day when measured according to ASTM D-6701 using a Mocon Perrnatran-W101 water vapor perme- ability instrument. Preferably, the cyanoacrylate adhesive films exhibit a moisture vapor transmission rate of from about 950 to about 3000 g/m2/ day, more preferably from about 1000 to about 2500 g/m2/day, still more preferably from about 1500 to about 2200 g/m2/ day, still more preferably from about 1800 to about 2100 g/m2/day, and most preferably from about 1900 to about 2100 g/m2/day. Such transmission rates are important in surgical applications because if the moisture vapor transmission rate is too low, a large quantity of exudates are prone to be trapped next to the wound at a significant fluid pressure, which usually results in extensive skin macerations. On the other hand, if the moisture vapor transmission rate of the adhesive film is too high, the exudates moisture would be removed so fast as to desiccate the wound. Therefore, using a surgical adhesive with a desirable perme- ability rate is highly important in maintaining an optimal microenvironment at wound closing site. [0076] The cyanoacrylate compositions of the present invention also provide a cyanoacrylate-based adhesive that strongly bonds to human skin while maintaining the desired high moisture vapor transmission rate for a better wound healing microenvironment. The strong bonding strength of the cynoacrylate adhesive compositions with the polymeriza- tion accelerator was confirmed by following ASTM method to measure the mechanical strengths, included but not limited to, T-peel tensile strength, lap-shear tensile strength, tensile strength in tension, and wound closure tensile strength. [0077] Lap-shear tensile strength of the cyanoacrylate adhesive compositions including a polymerization accelera- tor with a desired high MVTR was measured in accordance with ASTM F2255-05. The lap shear tensile strength is the force required to break two overlapped pieces of pig skin adhered by the disclosed cyanoacrylate adhesive composi- tion, which were attached onto two steel substrates. The cyanoacrylate adhesive composition including a polymeriza- tion accelerator has a lap shear tensile strength of from about 12 to about 18 lbs/inz. [0078] T-peel strength is the force required to yield the separation of two flexible adherends bonded by the disclosed cyanoacrylate adhesives, which is measured according to May 19, 2011 ASTM F2256-05. The cyanoacrylate adhesive disclosed herein provides a T-peel tensile strength of from about 34 to about 48 lbs. [0079] Tensile strength in tension of the cyanoacrylate adhesive including the polymerization accelerator with a desired high permeability was measured in accordance with ASTM F2258-05. The tensile strength in tension is the force required to break two pieces of pig skins adhered by the inventive adhesive, which are attached onto the stamp-shape steel substrate. The cyanoacrylate adhesive composition has a tensile strength in tension of from about 12 to about 16 lbs/ 1112 [0080] Wound closure strength of the cyanoacrylate adhe- sive including the polymerization accelerator with a desired permeability was evaluated based on ASTM F2458-05. Wound closure strength is the force required to break two pieces of pig skin connected by the inventive adhesive mim- icking the wound closure of the incision. The inventive cyanoacrylate adhesive composition has a wound closure strength of from about 1.5 to about 4 lbs/inz, and preferably from about 2 to about 4 lbs/inz. [0081] The present invention further provides for a kit for applying the cyanoacrylate adhesive composition of the present invention, including an applicator containing therein an effective amount of the cyanoacrylate composition. The applicator can be any suitable applicator such as, but not limited to, Q-tips, a swab, or an applicator tip on a container with the cyanoacrylate composition therein. The kit can fur- ther contain directions for application. When the present invention is used with other therapeutics, separate containers can be provided for the cyanoacrylate composition and the therapeutic for application. [0082] Individual applicators canbe packaged separately to maintain sterile conditions. For example, each applicator can be packaged in plastic or any other suitable enclosing mate- rial. Multiple applicators can then be packaged in a box for shipping. [0083] The compound of the present invention is adminis- tered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight and other fac- tors known to medical practitioners. The pharmaceutically “effective amount” for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve improvement including but not limited to improved survival rate or more rapid recovery, or improve- ment or elimination of symptoms and other indicators as are selected as appropriate measures by those skilled in the art. [0084] In the method of the present invention, the com- pound of the present invention can be administered in various ways. It should be noted that it can be administered as the compound and can be administered alone or as an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants and vehicles. The compounds can be administered in any suitable way. Implants of the compounds are also useful. The patients being treated are warm-blooded animals and, in particular, mammals includ- ing human beings. The pharmaceutically acceptable carriers, diluents, adjuvants and vehicles as well as implant carriers generally refer to inert, nontoxic solid or liquid fillers, dilu- ents or encapsulating material not reacting with the active ingredients of the invention. US 2011/0117047 A1 [0085] The doses can be single doses or multiple doses over a period of several days. The treatment generally has a length proportional to the length of the disease process and drug effectiveness and the patient species being treated. [0086] When administering the compound of the present invention parenterally, it will generally be formulated in a unit dosage inj ectable form (solution, suspension, emulsion). The pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or disper- sions. The carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. [0087] Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Nonaqueous vehicles such a cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems for compound compositions. Addi- tionally, various additives which enhance the stability, steril- ity, and isotonicity of the compositions, including antimicro- bial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. In many cases, it will be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorp- tion, for example, aluminum monostearate and gelatin. According to the present invention, however, any vehicle, diluent, or additive used would have to be compatible with the compounds. [0088] Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various of the other ingredients, as desired. May 19, 2011 closed in U.S. Pat. Nos. 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other such implants, delivery systems, and modules are well known to those skilled in the art. [0090] Additional objects, advantages, and novel features of this invention will become apparent to those skilled in the art upon examination of the following examples of the inven- tion. The examples are included to more clearly demonstrate the overall nature of the invention and, thus, are illustrative and not restrictive of the invention. EXAMPLES Example 1 [0091] 197.4 g of 2-octyl cyanoacrylate was mixed with 0.20 g of poly vinyl pyrrolidone (PVP) under vacuum for 2 hours and solid powder was removed by filtration. The result- ing solution was mixed with certain amounts of stabilizer, BHA, and colorant, D & C Violet under vacuum for a mim- mum of 0.5 hour. A sulfur dioxide solution in 2-octyl cyanoacrylate was charged into the solution to further stabi- lize the cyanoacrylate composition. The resulting purple solution was then filtered with a micrometer filter to yield the activated 2-octyl cyanoacrylate adhesive composition. Example 2 [0092] 27 pounds of the activated 2-octyl cyanoacrylate was charged into stainless steel container equipped with the mechanical agitator. 0.12 g of S02 solution (5.8%) in 2-octyl cyanoacrylate was added to the container and stirred for a minimum of 0.5 hour. 3 .3 g of 18-crown-6 was dissolved in 30 mL of 2-octyl cyanoacrylate in microwave, which was added to the bulk solution of 2-octyl cyanoacrylate in the stainless steel container and stirred for a minimum of 0.5 hour. After the filtration, the resulting cyanoacrylate adhesive composi- tion was subjected to viscosity, set time, bond strength and accelerated aging tests (see Table 3). The bond strength mea- sured for the samples at day 0 and day 12 are 773.9, and 723 .2 lbs/inchz, respectively. TABLE 3 Set time and viscosig results of examples 2 and 3. Day 0 Day 6 Day 9 Day 12 Set Set Set Set Aging time Viscosity time Viscosity time Viscosity time Viscosity condition (s) (cps) (s) (cps) (s) (cps) (s) (cps) Example 2 12 days 22 4.35 20 4.56 18 4.78 28 5.65 80° C. Example 3 12 days 35 5.43 33 4.99 24 6.30 28 6.52 80° C. [0089] A pharmacological formulation of the present invention can be administered to the patient in an injectable formulation containing any compatible carrier, such as vari- ous vehicles, adjuvants, additives, and diluents; or the com- pounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcu- taneous implants or targeted delivery systems such as mono- clonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres. Examples of delivery systems useful in the present invention include those dis- Example 3 [0093] 18 pounds of the activated 2-octyl cyanoacrylate was charged into stainless steel container equipped with the mechanical agitator. 0.078 g of S02 solution (5 .8%) in 2-octyl cyanoacrylate was added to the container and stirred for a minimum of 0.5 hour. 1.5 g of 18-crown-6 was dissolved in 30 mL of 2-octyl cyanoacrylate in microwave, which was added to the bulk solution of 2-octyl cyanoacrylate in the stainless steel container and stirred for a minimum of 0.5 hour. After US 2011/0117047 Al the filtration, the resulting cyanoacrylate adhesive composi- tion was subjected to viscosity, set time, bond strength and accelerated aging tests (see Table 3). The bond strength mea- sured for the samples at day 0 and day 12 are 714.5, and 703 .1 lbs/inch2, respectively. Example 4 [0094] 864.4 g of the activated 2-octyl cyanoacrylate was put into 1 L of opaque polyethylene bottle. 0.142 g of S02 solution (5.8%) in 2-octyl cyanoacrylate was added to the container and stirred for a minimum of 1 hour. Example 5 [0095] To a polyethylene bottle, 30.8 g of 2-octyl cyanoacrylate from Example 4 was mixed with 98.6 mg of 18-crown-6 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 6.7, 7.3, and 9.4 s, respectively. The average viscosity for the samples at day 0, day 6, and day 12 are 3.27, 2.86, and 28.8 cps, respectively. Example 6 [0096] To a polyethylene bottle, 30.1 g of 2-octyl cyanoacrylate from Example 4 was mixed with 72.4 mg of 18-crown-6 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 8.3, 9, and 14 s, respectively. The average viscosity for the samples at day 0, day 6, and day 12 are 2.86, 2.86, and 24.3 cps, respectively. Example 7 [0097] To a polyethylene bottle, 30.9 g of 2-octyl cyanoacrylate from Example 4 was mixed with 30.9 mg of 18-crown-6 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 14.7, 14.7, and 19.3 seconds, respectively. The average viscosity for the samples at day 0, day 6, and day 12 are 3.06, 3.06, and 20.4 cps, respectively. Example 8 [0098] To a polyethylene bottle, 30.5 g of 2-octyl cyanoacrylate from Example 4 was mixed with 21.4 mg of 18-crown-6 and stirred at room temperature for 2 hours. Example 9 [0099] In a polyethylene bottle, 4.4 g of 2-octyl cyanoacry- late composition from example 8 was diluted to 30.8 g by 2-octyl cyanoacrylate composition from Example 4 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 33, 35.3, and 39 seconds, respectively. The average viscosity for the samples at day 0, day 6, and day 12 are 2.65, 2.65, and 9.19 cps, respectively. Example 10 [0100] In a polyethylene bottle, 0.616 g of 2-octyl cyanoacrylate composition from Example 9 was diluted to May 19, 2011 30.8 g by 2-octyl cyanoacrylate composition from example 4 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 70.3, 73.7, and 75 seconds, respectively. The average viscosity for the samples at day 0, day 6, and day 12 are 2.87, 2.65, and3.06 cps, respectively. Example 11 [0101] 473.4 g of the activated 2-octyl cyanoacrylate was put into 1 L of opaque polyethylene bottle. 4.5 mg of S02 solution (5.8%) in 2-octyl cyanoacrylate was added to the container and stirred for a minimum of 1 hour. Example 12 [0102] To a polyethylene bottle, 30.1 g of 2-octyl cyanoacrylate from Example 11 was mixed with 96.5 mg of 18-crown-6 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 6.7, 6.3, and 7.7 seconds, respectively. The average viscosity for the samples at day 0, day 6, and day 12 are 2.86, 3.47, and 11.4 cps, respectively. Example 13 [0103] To a polyethylene bottle, 30.1 g of 2-octyl cyanoacrylate from Example 11 was mixed with 48.3 mg of 18-crown-6 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 10, 9.7, and 11 seconds, respectively. The average viscosity for the samples at day 0, day 6, and day 12 are 3.06, 3.27, and 7.33 cps, respectively. Example 14 [0104] To a polyethylene bottle, 29.9 g of 2-octyl cyanoacrylate from Example 11 was mixed with 29.9 mg of 18-crown-6 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 12.7, 11, and 12.3 seconds, respectively. The average viscosity for the samples at day 0, day 6, and day 12 are 2.65, 3.24, and 3.68 cps, respectively. Example 15 [0105] To a polyethylene bottle, 30.0 g of 2-octyl cyanoacrylate from Example 11 was mixed with 8.10 mg of 18-crown-6 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 17, 15, and 17.3 seconds, respectively. The average viscosity for the samples at day 0, day 6 and day 12 are 2.87, 2.65, and 3.27 cps, respectively. Example 16 [0106] To a polyethylene bottle, 19.6 g of 2-octyl cyanoacrylate from Example 11 was mixed with 9.9 mg of 18-crown-6 and stirred at room temperature for 2 hours. Example 17 [0107] In a polyethylene bottle, 2.4 g of 2-octyl cyanoacry- late composition from Example 16 was diluted to 30 g by US 2011/0117047 A1 2-octyl cyanoacrylate composition from Example 11 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 42.3, 55.3, and 47 seconds, respectively. The average viscosity for the samples at day 0, day 6, and day 12 are 2.87, 3.27, and 2.65 cps, respectively. Example 18 [0108] In a polyethylene bottle, 0.59 g of 2-octyl cyanoacrylate composition from Example 16 was diluted to 30 g by 2-Octyl cyanoacrylate composition from Example 1 1 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 53.7, 67, and 61.7 seconds, respectively. The average viscosity for the samples at day 0, day 6, and day 12 are 3.06, 2.87, and 3.47 cps, respectively. Example 19 [0109] 33.4 pounds of the activated 2-octyl cyanoacrylate was charged into stainless steel container equipped with the mechanical agitator. 0.144 g of S02 solution (5.8%) in 2-octyl cyanoacrylate was added to the container and stirred for a minimum of 0.5 hour. 4.06 g of 18-crown-6 was added to the bulk solution of 2-octyl cyanoacrylate in the stainless steel container and stirred for a minimum of 0.5 hour. After the filtration, the resulting cyanoacrylate adhesive composition was subjected to viscosity, set time, bond strength and accel- erated aging tests. Example 20 [0110] To a polyethylene bottle, 30.8 g of 2-octyl cyanoacrylate composition from Example 19 was mixed with 90.5 mg of 18-crown-6 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 8.67, 11, and 11.3 seconds, respectively. The average viscosity for the samples at day 0, day 6, and day 12 are 3.06, 2.86, and 55.2 cps, respectively. Example 21 [0111] To a polyethylene bottle, 30.8 g of 2-octyl cyanoacrylate composition from Example 19 was mixed with 41.3 mg of 18-crown-6 and stirred at room temperature for 2 hours. The sample was subjected to the accelerated aging test at 80° C. The average set time for the samples at day 0, day 6, and day 12 are 17, 24.3, and 22 seconds, respectively. The average viscosity for the samples at day 0, day 61 and day 12 are 2.45, 2.65, and 23.8 cps, respectively. Example 22 [0112] The shelf-life study for the inventive adhesive (2-oc- tyl cyanoacrylate with 18-crown-6) was investigated by real- time aging at room temperature. The real -time shelf-life study is verified on the increments of Day 0, Month 1, 3, 6, 9, 12 and 24. The stability was assessed by viscosity and set time. Table 4 shows the average viscosity and set time of the inventive adhesive at different time of the shelf life study. May 19, 2011 TABLE 4 Viscosity Set-Time Initial 3.47 cps 15 sec Month 1 4.29 cps 16 sec Month 3 4.29 cps 16 sec Month 6 3.88 cps 19 sec Month 9 4.70 cps 16 sec Month 12 6.74 cps 21 sec Month 24 6.70 cps 45.5 sec Example 23 [0113] Heat of polymerization of 2-octyl cyanoacrylate adhesives with cure speed enhancer was measured with DSC. Samples were transferred to an aluminum DSC pan via dis- posable pipette from a freshly opened applicator. Each sample was heated from 30° C. to 300° C. at a rate of 10° C./min in an atmosphere of nitrogen flowing at a rate of 20 cc/min. In each product there appears to be a two stage poly- merization which carmot be accurately separated using a tem- perature ramp of 10° C. per minute. The average heat of polymerization is 225 ug. Example 24 Permeability [0114] Permeability of the inventive surgical adhesive (2-Octyl cyanoacrylate with 18-crown-6 polymerization accelerator) was determined by measuring moisture vapor transmission rate (MVTR) using the PERMATRAN-W Model 101K in accordance with ASTM D06701. The adhe- sive sample was applied and cured on collagen film with a dimension of 2">