1,1-Disubstituted Ethylene Adhesive Compositions Containing Polydimethylsiloxan

(12) United States Patent Narang US006488944B2 (10) Patent N0.: US 6,488,944 B2 (45) Date of Patent: *Dec. 3, 2002 (54) 1, 1-DISUBSTITUTED ETHYLENE ADHESIVE COMPOSITIONS CONTAINING POLYDIMETHYLSILOXANE (75) Inventor: Upvan Narang, Raleigh, NC (US) (73) Assignee: Closure Medical Corporation, Raleigh, NC (US) ( * ) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 18 days. This patent is subject to a terminal dis- claimer. (21) Appl. No.: 09/742,056 (22) Filed: Dec. 22, 2000 (65) Prior Publication Data US 2002/0012678 A1 Jan. 31, 2002 Related U.S. Application Data (63) Continuation—in—part of application No. 09/471,392, filed on Dec. 23, 1999, now Pat. No. 6,183,593. (51) Int. Cl.7 ........................... .. A61K 6/00; A61K 7/00 (52) U.S. Cl. ................ .. 424/401; 424/78.02; 424/7803 (58) Field of Search ......................... .. 424/78.02, 78.03, 424/22, 401 (56) References Cited U.S. PATENT DOCUMENTS 2,721,858 A 10/1955 Joyner et al. 3,223,083 A 12/1965 Cobey ....................... .. 128/92 3,254,111 A 5/1966 Hawkins et al. 3,554,990 A 1/1971 Quinn et al. 3,940,362 A 2/1976 Overhults 3,995,641 A 12/1976 Kronenthal et al. 4,180,911 A 1/1980 Bullock 4,313,865 A 2/1982 Teramoto et al. 4,364,876 A 12/1982 Kimura et al. 4,477,607 A 10/1984 Litke 4,533,422 A 8/1985 Litke 4,560,723 A 12/1985 Millet et al. 4,636,539 A 1/1987 Harris et al. 4,650,826 A 3/1987 Waniczek et al. 4,686,247 A 8/1987 Yosida 4,705,836 A 11/1987 Ohtsuka et al. 4,713,405 A 12/1987 Koga et al. 4,720,513 A 1/1988 Kameyama et al. 4,764,545 A 8/1988 Yosida RE32,889 E 3/1989 Litke 4,837,260 A 6/1989 Sato et al. 4,906,317 A 3/1990 Liu 4,912,153 A 3/1990 Jeremias et al. .......... .. 524/731 5,140,084 A 8/1992 Mikuni et al. 5,214,093 A 5/1993 Nell et al. 5,248,708 A 9/1993 Uemura et al. 5,328,687 A 7/1994 Leung et al. 5,373,035 A 12/1994 Uemura et al. 5,386,047 A 1/1995 Nakos et al. 5,514,371 A 5/1996 Leung et al. 5,514,372 A 5/1996 Leung et al. 5,575,997 A 11/1996 Leung et al. 5,582,834 A 12/1996 Leung et al. 5,624,669 A 4/1997 Leung et al. 5,928,611 A 7/1999 Leung 6,183,593 B1 * FOREIGN PAl‘EN'l‘ DOCUMENTS 2/2001 Narang et al. ............ .. 156/327 EP 0 611 565 A 8/1994 EP 0 774 482 A 5/1997 FR 1389441 6/1965 JP 57-70169 4/1982 JP 57-70171 4/1982 JP 3—126782 5/1991 JP 3—296581 12/1991 JP 4-8780 1/1992 JP 4-9388 1/1992 JP 4—146982 5/1992 JP 6—100838 4/1994 JP 6—122853 5/1994 JP 6—240209 8/1994 JP 11—302602 A 11/1999 WO VVO 99/42142 8/1999 * cited by examiner Primary Examiner—Thurman K. Page Assistant Examiner—S. Howard (74) Attorney, Agent, or Firm—Oliff & Berridge, PIC (57) ABSTRACT An adhesive composition that contains cyanoacrylate mono- mers and cyclic or alkyl- or phenyl-terminated linear poly- dimethylsiloxane is particularly useful in applications requiring flexibility and elasticity. A method of removing, reducing or preventing scar tissue including applying an adhesive composition that contains cyanoacrylate monomer and cyclic or alkyl- or phenyl-terminated linear polydim- ethylsiloxane. 36 Claims, No Drawings US 6,488,944 B2 1 1, 1-DISUBSTITUTED ETHYLENE ADHESIVE COMPOSITIONS CONTAINING POLYDIMETHYLSILOXANE This application is a continuation-in-part of U.S. patent application Ser. No. 09/471,392, filed Dec. 23, 1999, now U.S. Pat. No. 6,183,593 thc cntirc disclosurc of which is incorporated herein by reference. BACKGROUND The invention relates to monomer and polymer adhesive and sealant compositions, and to their production and use for industrial and medical applications. Monomer and polymer adhesives are used in both indus- trial (including household) and medical applications. Included among these adhesives are the 1,1 -disubstituted ethylene monomers and polymers, such as the or-cyanoacrylates. Since the discovery of the adhesive prop- erties of such monomers and 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 11se. These characteristics have made the or-cyanoacrylate adhe- sives the primary choice for numerous applications such as bonding plastics, rubbers, glass, metals, wood, and, more recently, biological tissues. It is known that monomcric forms of or-cyanoacrylatcs arc extremely reactive, polymerizing rapidly in the presence of even minute amounts of an initiator, including moisture present in the air or on moist surfaces such as animal (including human) tissue. Monomers of or-cyanoacrylates are anionically polymerizable or free radical polymerizable, or polymerizable by zwitterions or ion pairs to form poly- mers. Once polymerization has been initiated, the cure rate can be very rapid. Medical applications of 1,1-disubstituted ethylene adhe- sive compositions include use as an alternate or an adjunct to surgical sutures and/or staples in wound closure, as well as for covering and protecting surface wounds such as lacerations, abrasions, burns, stomatitis, sores, minor cuts and scrapes, and other wounds. When an adhesive is applied to surfaces to be joined, it is usually applied in its mono- meric form, and the resultant polymerization gives rise to the desired adhesive bond. Aconcern in the use of adhesive compositions for treating wounds is the flexibility and elasticity of the cured adhesive, particularly in the face and body joint areas, such as hands, feet, elbows and knees. Polymerized cyanoacrylate compositions are in general not flexible. Increased flexibility would improve the utility of cyanoacrylate compositions, particularly in body joint areas. Improved flexibility and elasticity would also make cyanoacrylate compositions better suited to use as drug delivery devices and the like under some circumstances. Thus, a need exists for improved adhesive compositions, especially for medical uses, wherein the flexibility and elasticity of the adhesive is improved and the performance of the adhesive composition is not compromised. In particular, the need exists for a monomeric adhesive com- position that possesses improved flexibility. Polydimethylsiloxane (or PDMS) is a silicone compound that was developed for use as a dielectric coolant and in solar energy installations. However, it has also been used in other applications. U.S. Pat. Nos. 4,477,607, 4,533,422 and Re. 32,889, all to Litke, disclose cyanoacrylate compositions that employ 10 15 20 25 30 35 40 45 50 55 60 65 2 fumed silicas treated with polydimethylsiloxane or tri- alkoxyalkylsilane to improve the thixotropic properties of the compositions. Likewise, U.S. Pat. Nos. 4,764,545 and 4,686,247 to Yosida disclose an adhesive composition com- prising an alpha cyanoacrylate and a silica surface-treated respectively with polydimethylsiloxane and with hexameth- yldisilazane. Similarly, JP 06-122853 discloses an adhesive composition comprising an alpha cyanoacrylate and a hydrophobic silica surface-treated with dimethyldichlorosi- lane; U.S. Pat. No. 4,636,539 to Harris et al. discloses an adhesive comprising cyanoacrylate adhesive, fumed silica filler treated with polydialkylsiloxane, and calixarene com- pound; U.S. Pat. No. 4,180,911 to Bullock discloses a composition and method for use of a cyanoacrylate resin and a silane-treated inorganic powder in direct bonding of an orthodontic bracket structure to teeth and other dental appli- cations; U.S. Pat. No. 4,713,405 to Koga et al. discloses an adhesive composition comprising an alpha cyanoacrylate and a fumed silica having a surface treated with a dimeth- yldichlorosilane and trialkyl borate; U.S. Pat. No. 5,373,035 to Uemura et al. discloses an adhesive composition com- prising an alpha cyanoacrylate and a hydrophobic silica surface-treated with dimethyldichlorosilane; and U.S. Pat. No. 5,248,708 to Uemura et al. discloses an adhesive composition having a particular alpha cyanoacrylate, a fine silica and silanol group. U.S. Pat. No. 5,214,093 to Nell et al. discloses an adhe- sive mixture for nonsurgical blepharoplasty. In the main embodiments, the base adhesive component is an oxygen permeable polysiloxane in a solvent. A less preferred embodiment includes a homogeneous mixture of cyanoacry- late adhesive and two separate miscible silicon oil compo- nents that are said to provide lubrication and breathability to the skin surface. These components are disclosed to be used in amounts of 50% cyanoacrylate, 25% polydimethylsilox- ane and 25% 3-methacryloxy propyltris (trimethoxysiloxy) silane, and can be applied serially or in a mixture. The patent states that the mixture adheres in approximately five minutes and remains somewhat flexible during that time. It provides no further detail about the PDMS other than to indicate that it is “very oily and will penetrate the surface of the tissue to some extent.” It is noted that silanes as a general matter raise toxicity issues, although this is not discussed in the Nell patent. JP 57-70169, JP 57-70171, JP 03-126782, JP 03-296581, JP 04-146982 and JP 06-100838 disclose or-cyanoacrylate adhesive compositions containing specific organosilicon compounds including silicone oils and compounds related to PDMS. However, the disclosed compounds include various side and/or terminal groups that raise issues as to the stability and utility of the resultant compositions. U.S. Pat. No. 4,906,317 to Liu discloses a cyanoacrylate adhesive composition which employs silacrown compounds as additives. U.S. Pat. No. 4,837,260 to Sato et al. discloses an adhe- sive composition comprising an alpha cyanoacrylate and a hydrophobic silica along with particular curing accelerators. U.S. Pat. No. 4,650,826 to Waniczek et al. discloses the use of silyl ester as a stabilizer for a cyanoacrylate adhesive. U.S. Pat. No. 5,386,047 to Nakos et al. discloses a polymerizable composition comprising a monomer component, which includes a silicon containing di-alph- cyanopentadienoate disiloxane compound. The monomer component further includes an alpha cyanoacrylate com- pound. U.S. Pat. No. 4,705,836 to Ohtsuka et al. discloses a bonding composition including vinyl benzoic acid and US 6,488,944 B2 3 cyanoacrylic acid ester. The composition further contains a silane compound. U.S. Pat. No. 5,140,084 to Mikuni et al. discloses a silicone-containing alph-cyanoacrylate that is useful as an adhesive. Similar silicone-containing alph-cyanoacrylate compositions are also disclosed in JP 04-9388 and JP 04-8780. SUMMARY OF THE INVENTION The present invention provides a monomeric adhesive composition comprising a polymerizable 1,1-disubstituted ethylene adhesive monomer and a polydimethylsiloxane, which is alkyl, preferably methyl, or phenyl terminated or cyclic. The composition is free or substantially free of silane compounds. Production of the composition includes provid- ing a mixture of the polymerizable monomer and polydim- ethylsiloxane in a container, and sealing the container, and optionally sterilizing the container and the mixture. The polydimethylsiloxane is preferably selected and provided in an amount such that it is soluble in the monomer at room temperature. The compositions produced, packaged and optionally sterilized according to the present invention are stable, and have extended utility. Compositions of the present invention have increased flexibility, elasticity, tissue (e.g., skin) wettability, stability, moisture vapor transmission rate, oxygen transmission rate, reduced coefficients of fric- tion and/or scar tissue formation and retention avoidance properties. The present invention is thus also directed to methods wherein the composition of the present invention is applied to tissue areas for preventing, reducing or removing scar tissue. DETAILED DESCRIPTION OF EMBODIMENTS According to the invention, a monomeric adhesive com- position comprises at least one polymerizable 1,1- disubstituted ethylene monomer and at least one polydim- ethylsiloxane (PDMS), and is at least substantially free of silane compounds. The polydimethylsiloxane suitable for use in the present invention can be alkyl- or phenyl-terminated linear or cyclic or a mixture thereof. Although not limited thereto, the PDMS used in the present invention is preferably a rela- tively short or small compound, as opposed to a long chain polymer. Thus, for example, the PDMS compound prefer- ably has a low molecular weight, e.g., has a small number of monomer units, and also a low viscosity. The PDMS com- pound is selected such that it is compatible with the mono- mer (i.e., does not adversely affect polymerization, cure properties, or shelf-life). Preferably, the polydimethylsilox- ane is soluble (i.e., dissolves) in the monomer composition at room temperature (i.e., 20—25° C.) so that it may be combined into the monomer composition without excessive heating of the monomer composition. Solubility is preferred because a higher elongation effect can be provided by the agent upon polymerization of the adhesive composition when it is dispersed throughout the monomer composition in the form of a solution. In embodiments, the adhesive composition, including the polydimethylsiloxane, can provide an elongation at break of at least 100%, preferably 200—600%, 300-500% or 400-500%, of a polymerized film of the adhesive. If the polydimethylsiloxane is not in the form of a solution, then it is possible that it may settle or otherwise agglomerate, and thereby, upon subsequent polymerization of the composition, not provide the desired consistent elongation effect to the polymerized adhesive composition 10 15 20 25 30 35 40 45 50 55 60 65 4 Thus, it is preferred in embodiments that the polydimeth- ylsiloxane exhibits an at least substantially uniform concen- tration throughout the monomer composition. Where excess polydimethylsiloxane is added to the composition, i.e., an amount above the solubility point of the PDMS, it is acceptable that a portion of the PDMS remains undissolved in the composition so long as it does not act as two separate phases. Thus for example, in embodiments a stable micro- emulsion (with only microphases) may be acceptable. The amount of polydimethylsiloxane that is added to the monomer composition can depend upon the selection of the specific PDMS and the specific monomer. For example, linear polydimethylsiloxane can often be included in a concentration of about 5—25% by weight, preferably about 5-23% by weight, such as 10-15% by weight, of the adhesive composition relative to the total monomer and polydimethylsiloxane content. Cyclic polydimethylsiloxane can often be included in a concentration of about 5-50% by weight, preferably about 10-30% by weight, such as 10-15, 20 or 25% by weight of the adhesive composition. As noted above, however, contents above these ranges can also be used as desired. The amount of polydimethylsiloxane to be used can be determined by one of ordinary skill in the art using known techniques without undue experimentation in light of the present disclosure. The polydimethylsiloxane preferably has a low weight average molecular weight. For example, suitable polydim- ethylsiloxanes preferably have a weight average molecular weight of from about 230 to about 1,500, more preferably from about 300 to about 1,000. Molecular weights outside of these ranges can also be used depending upon the specific polydimethylsiloxane and monomer composition so long as they are soluble or in a microemulsion in the adhesive composition as discussed above. In exemplary embodiments, a linear polydimethylsilox- ane averaging from two to ten, such as two to eight, for example, three, four, five or six monomer units, is preferred. One particularly preferred exemplary linear PDMS is a linear trimethylsiloxy terminated polydimethylsiloxane (TMDS) (CAS #9016-00-6), having a weight average molecular weight of 770, and a viscosity of about 5 centi- poise at 25° C. In other embodiments, the polydimethylsiloxane can be a cyclic polydimethylsiloxane. Such cyclic PDMS com- pounds are preferably also relatively small, having, for example, from two to ten, such as two to six, for example two to five monomer units. In an exemplary embodiment, a four monomer unit cyclic polydimcthylsiloxanc can be used. In embodiments, the cyclic PDMS can be selected from octamethylcyclotetrasiloxane (OMTS), decamethylcyclo- pentasiloxane (DMPS) and dodecamethylcyclohexasiloxane (DMHS). One exemplary cyclic PDMS is a product of United Chemical Technologies Inc. that has the formula C8H24O4Si4 (CAS #556-67-2) having a weight average molecular weight of 296.16, a density of 0.956 at 20° C. and a viscosity of about 2.3 centipoise at 25° C. The linear PDMS is terminated with alkyl or phenyl groups. The linear or cyclic PDMS can optionally include or be free of alkyl side chain groups. Terminal and side chain groups can include, but are not limited to, alkyl groups with one to twelve, preferably 1-8 such as 1-6 or 1-4, carbon atoms, including for example methyl, ethyl or propyl groups. Linear PDMS of the invention can be depicted by the formula: US 6,488,944 B2 CH3 R31-O—[-Si—O-],,—SiR32 CH3 wherein R1 and R2 are independently selected alkyl or phenyl groups. Cyclic PDMS of the invention can be depicted by the formula: CH3 Si—O ,, CH3 In each case, n is selected to provide the desired molecular weight. Thus n may be, for example, 2 or 3 to 12, preferably 4 to 10 or 4 to 8. One or more of the methyl groups may be alkyl substituted. The polydimethylsiloxane for use in the present invention preferably has a low viscosity, such as from about 1 to about 15 centipoise at 25° C., as measured by a Brookfield Viscometer. More preferably, the polydimethylsiloxane has a viscosity of from about 2 to about 10 centipoise, such as from about 5 to about 7.5 centipoise at 25° C. In embodiments, the polydimethylsiloxane is purified prior to mixing with the polymerizable monomer. A poly- dimethylsiloxane that is at least 98.5% by weight pure (i.e., containing 1.5% by weight or less impurities or ingredients other than polydimethylsiloxane) is preferred. Purification can be achieved, for example, by distillation. Asuitable procedure for selecting a polydimethylsiloxane involves selecting a group of potential polydimethylsiloxanes, assessing their solubility and stabil- ity in the monomer composition, and optionally testing for their compatibility with one or more sterilization proce- dures. Potential polydimethylsiloxanes for testing can readily be selected by one of ordinary skill in the art from known sources in accordance with the disclosure herein. Once a potential agent is selected, it can be tested for solubility and stability in the monomer composition, such as by mixing an appropriate amount of the polydimethylsiloxane with a desired amount of the monomer composition and any other desired additives. It is important to maintain the stability of the monomer composition within acceptable levels, such as commercially acceptable levels whereby the composition is not prema- turely polymerized prior to application of the monomer composition to a desired substrate. One measure of the stability of the composition, other than a visual examination of the properties of the composition, is a measure of any changes in viscosity of the composition from a time prior to adding the polydimethylsiloxane to a time after adding the polydimethylsiloxane. For example, dramatic increases or decreases in viscosity can indicate instability of the composition, such as premature polymerization or other chemical degradation of the monomer composition or com- ponents thereof. In embodiments of the present invention, it is preferred that the polydimethylsiloxane exhibit stability in the mono- mer composition for at least five minutes after mixing or dissolving the polydimethylsiloxane in the polymerizable monomer compound. More preferably, stability of the 10 15 20 25 30 35 40 45 50 55 60 65 6 monomer composition is maintained for a time period sufficient to provide a commercially significant shelf-life to the monomer composition, such as 12, 18, or preferably 24 or more months. As used herein, “stability” refers to the composition maintaining a commercially acceptable form for the prescribed amount of time. That is, the composition does not prematurely polymerize or otherwise change form or degrade to the point that the composition is not useful for its intended purpose. Thus, while some polymerization or thickening of the composition may occur, such as can be measured by changes in viscosity of the composition, such change is not so extensive as to destroy or significantly impair the usefulness of the composition. In embodiments, the adhesive composition has a viscosity of about 1-5000 centipoise, preferably 1-600 centipoise, more preferably 1-100 or 2-50 centipoise such as 2-18, 2-10 or 5-7 centipoise, or 30-500 such as 50-100 or 100-200 centipoise at 25° C. The viscosity can be selected according to the proposed use—e.g., 1-100 centipoise for certain uses and 100-200 centipoise for other uses. Additionally, the composition may be a gel, e.g., 50,000-500,000 centipoise at 25° C. The viscosity of the adhesive composition can be measured with a Brookfield Viscometer. Additionally, in embodiments where a steriliza- tion treatment is applied, the viscosity of the composition should preferably be maintained or increased by a controlled and acceptable amount after sterilization. Compatibility of the polydimethylsiloxane-containing composition with one or more sterilization procedures is preferred in embodiments of the present invention because many uses of the polymerizable monomer compositions, such as many surgical and other medical applications, require sterilized products. In preferred embodiments, there is substantially no initiation of polymerization of monomeric liquid adhesive compositions that affects the utility of the monomer or monomers caused by the sterilization process. Sterilization of the monomer composition and/or its pack- aging can be accomplished by techniques known to the skilled artisan, and is preferably accomplished by methods including, but not limited to, chemical, physical, and/or irradiation methods. Examples of chemical methods include, but are not limited to, exposure to ethylene oxide or hydro- gen peroxide vapor. Examples of physical methods include, but are not limited to, sterilization by heat (dry or moist) or retort canning. Examples of irradiation methods include, but are not limited to, gamma irradiation, electron beam irradiation, and microwave irradiation. A preferred method is electron beam irradiation. In embodiments where a com- position is to be used for medical applications, the sterilized composition must show low levels of toxicity to living tissue during its useful life. The monomer (including prepolymeric) adhesive compo- sition may include one or more polymerizable monomers. Preferred monomer compositions of the present invention, and polymers formed therefrom, are useful as tissue adhesives, sealants for preventing bleeding or for covering open wounds, and in other biomedical applications. They find uses in, for example, apposing surgically incised or traumatically lacerated tissues; retarding blood flow from wounds; dressing burns; dressing skin or other superficial or surface wounds such as compromised skin or other tissue (such as abrasions, chaffed or raw skin, minor cuts and scrapes, irritation, sores and/or stomatitis); protecting intact skin; and aiding repair and regrowth of living tissue. They are particularly useful for treating tissues that are subjected to flexing, such as faces and joints such as on hands, feet, elbows and knees. Monomer compositions of the present US 6,488,944 B2 7 invention, and polymers formed therefrom, are also useful in industrial and home applications, for example in bonding rubbers, plastics, wood, composites, fabrics, and other natu- ral and synthetic materials, particularly when applied at an area that is subjected to flexing. Preferred monomers that may be used in this invention are readily polymerizable, e.g. anionically polymerizable or free radical polymerizable, or polymerizable by zwitterions or ion pairs to form polymers. Such monomers include those that form polymers, that may, but do not need to, biodegrade. Such monomers are disclosed in, for example, U.S. Pat. No. 5,328,687 to Leung, et al., which is hereby incorporated in its entirety by reference herein. Useful 1,1-disubstituted ethylene monomers include, but are not limited to, monomers of the formula: HRC:CXY (1) wherein X and Y are each strong electron withdrawing groups, and R is H, —CH=CH2 or, provided that X and Y are both cyano groups, a C1-C4 alkyl group. Examples of monomers within the scope of formula (I) include ot-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‘ and Y‘ is —CN, —COOR‘, —COCH3, —SO2R‘ or —SO3R‘, and R‘ is H or hydrocarbyl. Preferred monomers of formula (I) for use in this inven- tion are ot-cyanoacrylates. These monomers are known in the art and have the formula (11) CN HR2c= C COOR3 wherein R2 is hydrogen and R3 is a hydrocarbyl or substi- tuted hydrocarbyl group; a group having the formula —R4— O—R3—O—R6 or —R3—O—R5, wherein R4 is a 1,2- alkylene group having 2-4 carbon atoms, R3 is an alkylene group having 2-4 carbon atoms, and R6 is an alkyl group having 1-6 carbon atoms; or a group having the formula —R7— C-0 —R8, 0 wherein R7 is , —cH—, j (CH2)n or : C(CH3)2 , wherein n is 1-10, preferably 1-5, and R8 is an organic moiety. Examples of suitable hydrocarbyl and substituted hydro- carbyl 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 acyloxy group, a haloalkyl group, an alkoxy group, a halo- gen 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. The organic moiety R8 may be substituted or unsubsti- tuted and may be straight chain, branched or cyclic, 10 15 20 25 30 35 40 45 50 55 60 65 8 saturated, unsaturated or aromatic. Examples of such organic moieties include C1-C8 alkyl moieties, C2-C8 alk- enyl moieties, C2-C8 alkynyl moieties, C3-C12, cycloaliphatic moieties, aryl moieties such as phenyl and substituted phenyl and aralkyl moieties such as benzyl, methylbenzyl, and phenylethyl. Other organic moieties include substituted hydrocarbon 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 having from 1 to about 8 carbon atoms, and halo—substituted derivatives thereof. Par- ticularly preferred are alkyl moieties of 4 to 6 carbon atoms. 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. Examples of groups represented by the formula —AOR9 include 1-methoxy-2-propyl, 2-butoxy ethyl, isopropoxy ethyl, 2-methoxy ethyl, and 2-ethoxy ethyl. The ot-cyanoacrylates of formula (II) can be prepared according to methods known in the art. U.S. Pat. Nos. 2,721,858 and 3,254,111, each of which is hereby incorpo- rated in its entirety by reference, disclose methods for preparing ot-cyanoacrylates. For example, the ot-cyanoacrylates can be prepared by reacting an alkyl cyanoacetate with formaldehyde in a non-aqueous 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. The on-cyanoacrylate monomers prepared with low moisture content and essen- tially free of impurities are preferred for biomedical use. The ot-cyanoacrylates of formula (II) wherein R3 is a group having the formula R4—O—R3—O—R6 or —R3— O—R5 can be prepared according to the method disclosed in U.S. Pat. No. 4,364,876 to Kimura et al., which is hereby incorporated in its entirety by reference. In the Kimura et al. method, the ot-cyanoacrylates are prepared by producing a cyanoacetate by esterifying cyanoacetic acid with an alcohol or by transesterifying 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 0.5-1.521, preferably 08-1221, to obtain a condensate; depolymerizing the condensation 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. The ot-cyanoacrylates of formula (II) wherein R3 is a group having the formula —R7—C—o —R3 ll 0 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 ot-cyanoacrylate monomers are prepared by reacting an alkyl ester of an (x-cyanoacrylic acid with a cyclic 1,3-diene to form a Diels-Alder adduct which is then subjected to alkaline hydrolysis followed by acidification to form the corresponding or-cyanoacrylic acid adduct. The ot-cyanoacrylic acid adduct is preferably esterified by an alkyl bromoacetate to yield the corresponding carbalkoxym- ethyl ot-cyanoacrylate adduct. Alternatively, the US 6,488,944 B2 9 ot-cyanoacrylic acid adduct may be converted to the ot-cyanoacrylyl halide adduct by reaction with thionyl chlo- ride. The ot-cyanoacrylyl halide adduct is then reacted with an alkyl hydroxyacetate or a methyl substituted alkyl hydroxyacetate to yield the corresponding carbalkoxym- ethyl ot-cyanoacrylate adduct or carbalkoxy alkyl ot-cyanoacrylate adduct, respectively. The cyclic 1,3-diene blocking group is finally removed and the carbalkoxy methyl ot-cyanoacrylate adduct or the carbalkoxy alkyl ot-cyanoacrylate adduct is converted into the corresponding carbalkoxy alkyl ot-cyanoacrylate by heating the adduct in the presence of a slight deficit of maleic anhydride. Examples of monomers of formula (I) include cyanopen- tadienoates and (ot-cyanoacrylates of the formula: (III) CN HZC: C COOR3 wherein Z is —CH=CH2 and R3 is as defined above. The monomers of formula (III) wherein R3 is an alkyl group of 1-10 carbon atoms, i.e., the 2-cyanopenta-2,4-dienoic acid esters, can be prepared by reacting an appropriate 2-cyanoacetate 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. Preferred ot-cyanoacrylate monomers used in this inven- tion are alkyl ot-cyanoacrylates including octyl cyanoacrylate, such as 2-octyl cyanoacrylate; dodecyl cyanoacrylate; 2-ethylhexyl cyanoacrylate; butyl cyanoacrylate such as n-butyl, iso-butyl or tert-butyl cyanoacrylate; ethyl cyanoacrylate; methyl cyanoacrylate; 3-methoxybutyl cyanoacrylate; 2-butoxyethyl cyanoacry- late; 2-isopropoxyethyl cyanoacrylate; and 1-methoxy-2- propyl cyanoacrylate. More preferred monomers are n-butyl and 2-octyl ot-cyanoacrylate. Monomers utilized for medical purposes in the present application should be very pure and contain few impurities (e.g., surgical grade). Monomers utilized for industrial purposes need not be as pure. The composition may optionally also include at least one other plasticizing agent that assists in imparting flexibility to the polymer formed from the monomer. The plasticizing agent preferably contains little or no moisture and should not significantly affect the stability or polymerization of the monomer. Examples of suitable plasticizers include tributyl citrate, acetyl tri-n-butyl citrate (ATBC), dimethyl sebacate, triethyl phosphate, tri(2-ethylhexyl)phosphate, tri(p-cresyl) phosphate, glyceryl triacetate, glyceryl tributyrate, diethyl sebacate, dioctyl adipate, isopropyl myristate, butyl stearate, lauric acid, trioctyl trimellitate, dioctyl glutarate, and mix- tures thereof. Preferred plasticizers are tributyl citrate and acetyl tributyl citrate. In embodiments, suitable plasticizers include polymeric plasticizers, such as polyethylene glycol (PEG) esters and capped PEG esters or ethers, polyester glutarates and polyester adipates. Some thickeners, such as poly-2-ethylhexylcyanoacrylate, can also impart flexibility to the polymer. Polymethyl methacrylate (PMMA) and hexadimethylsilazane (HDMS) are particularly useful as plasticizers in high viscosity (e.g., greater than 100 centi- poise at 25° C.) formulations containing PDMS, while tributyl citrate and acetyl tributyl citrate are particularly useful as plasticizers in low viscosity (e.g., less than 50 centipoise at 25° C.) formulations containing PDMS. 10 15 20 25 30 35 40 45 50 55 60 65 10 The addition of other plasticizing agents, in addition to the polydimethylsiloxane, in amounts ranging from about 0.5 wt. % to about 25 wt. %, or from about 1 wt.% to about 20 wt .%, or from about 3 wt. % to about 15 wt. % or from about 4 wt. % to about 6 wt. %, based on the entire composition, may further increase elongation and toughness of the poly- merized monomer over polymerized monomers not having the additional plasticizing agents. The composition may also optionally include at least one thixotropic agent. Suitable thixotropic agents are known to the skilled artisan and include, but are not limited to, silica gels such as those treated with a silyl isocyanate, and optionally surface treated titanium dioxide. However, in some embodiments, the adhesive composition contains no, or substantially no, silica. Examples of suitable thixotropic agents and thickeners are disclosed in, for example, U.S. Pat. No. 4,720,513, and U.S. patent application Ser. No. 09/374, 207 filed Aug. 12, 1999, the entire disclosures of which are hereby incorporated in their entirety. The thickening agents may be selected from among known thickeners, including, but not limited to, poly(2- ethylhexyl methacrylate), poly(2-ethylhexyl acrylate) and celluose acetate butyrate. Suitable thickeners include, for example, polycyanoacrylates, polyoxalates, lactic-glycolic acid copolymers, polycaprolactone, lactic acid-caprolactone copolymers, poly(caprolactone+DL-lactide+glycolide), polyorthoesters, polyalkyl acrylates, copolymers of alky- lacrylate and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl methacrylates and butadiene. Examples of alkyl methacrylates and acrylates are poly (butylmethacrylate) and poly(butylacrylate), also copoly- mers of various acrylate and methacrylate monomers, such as poly(butylmethacrylate-co-methylmethacrylate). Biode- gradable polymer thickeners are preferred for some uses such as some surgical uses. Preferably, the thickening agent is soluble in a monomer composition at room temperature (i.e., 20—25° C.) so that it may be added to the monomer composition without excessive heating of the monomer composition and remain uniformly combined in the com- position. The composition may also optionally include at least one natural or synthetic rubber to impart impact resistance, which is preferable especially for industrial compositions of the present invention. Suitable rubbers are known to the skilled artisan. Such rubbers include, but are not limited to, dienes, styrenes, acrylonitriles, and mixtures thereof. Examples of suitable rubbers are disclosed in, for example, U.S. Pat. Nos. 4,313,865 and 4,560,723, the disclosures of which are hereby incorporated in their entireties. The composition may also optionally include one or more stabilizers, preferably both at least one anionic vapor phase stabilizer and at least one anionic liquid phase stabilizer. These stabilizing agents inhibit premature polymerization. Such stabilizing agents may also include mixtures of anionic stabilizing agents and radical stabilizing agents such as hydroquinone, p-methoxyphenol and butylated hydroxy- anisole (BHA). Any mixture of stabilizers is included as long as the mixture does not inhibit the desired polymer- ization of the monomer. The anionic vapor phase stabilizers may be selected from among known stabilizers, including, but not limited to, sulfur dioxide, boron trifluoride, and hydrogen fluoride. The amount of anionic vapor phase stabilizer that is added to the monomer composition depends on the identity of the liquid phase stabilizer(s) chosen in combination with it, the mono- mer to be stabilized, as well as the packaging material to be used for the composition. Preferably, each anionic vapor US 6,488,944 B2 11 phase stabilizer is added to give a concentration of less than 200 parts per million (ppm). In preferred embodiments, each anionic vapor phase stabilizer is present from about 1 to 200 ppm, more preferably from about 10 to 75 ppm, even more preferably from about 10 to 50 ppm, and most preferably from 10 to 20 ppm. The amount to be used can be deter- mined by one of ordinary skill in the art using known techniques without undue experimentation. In embodiments, the vapor phase comprises, among other things, an anionic stabilizer that is sulfur dioxide. In embodiments, the vapor phase comprises, among other things, a stabilizer that is boron trifluoride or hydrogen fluoride. A combination of sulfur dioxide and boron trifluo- ride or hydrogen fluoride is preferable in some embodi- ments. 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 pKa 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 (pKa -3.0), perchloric acid (pKa -5), hydrochloric acid (pKa -7.0), hydrobromic acid (pKa -9), fluorosulfonic acid (pKa —(Si(CH3)2—O)n—Si(CH3)3> or —SiH(—O—Si H3)n(—O—SiH3)m, where n and m are integers of any suitable number to provide a desired molecu- lar weight of the monomer. For example, n and m can independently be an integer of from about 1 to about 100, preferably from about 1 to about 50. Thus, for example, examples of suitable siloxane- containing ot-cyanoacrylates include, but are not limited to, monomers of the formula: CN / H2C= C COOR wherein R is a siloxane-containing group of the formula —(O—Si(CH3)2)n—O—Si(CH3)3, where n is from about 1 to about 100, preferably from about 1 to about 50. Polymers of the above monomeric units may also be included in the adhesive composition, in embodiments. Thus, for example, poly(siloxane-containing cyanoacrylate) can be used as an anti-scar agent. Thus, for example, a poly(siloxane-cyanoacrylate of the following formula can be used: CN H—6C—(:Zfi?H COO j (CH2)3* (O * Sl(CH3)2),,j O jSl(CH3)3 where m represents the number of repeating units in the polymer and n is from about 1 to about 100, preferably from about 1 to about 50. Where the siloxane-containing polymer is added to the adhesive composition as a separate component, the polymer is preferably a low molecular weight polymer in which m ranges, for example, from about 2 to about 2000 or more, preferably from about 2 to about 1000 or from about 500 to about 1800, more preferably from about 100 to about 500 or from about 1000 to about 1700. Other examples of suitable siloxane containing polymers include, but are not limited to, siloxane-containing copolyols, such as copolymers of siloxane and polyethylene glycol. Particularly suitable copolyols include dimethicone copolyol, also referred to as polydimethylsiloxane polyeth- ylene glycol. The dimethicone copolyol suitable for use in the present invention can include a polydimethylsiloxane (PDMS) seg- ment that can be alkyl- or phenyl-terminated linear or cyclic or a mixture thereof. Although not limited thereto, the PDMS segment of the dimethicone copolyol used in the present invention is preferably a relatively short or small compound, as opposed to a long chain polymer. Thus, for example, the PDMS segment preferably has a low molecular weight, e.g., has a small number of monomer units, and also a low viscosity. Preferably, in embodiments, the PDMS segment is a linear compound, rather than a cyclic com- pound. US 6,488,944 B2 17 Still other examples of suitable siloxane containing poly- mers include, but are not limited to, the MASIL® series of products available from BASF Corporation and the SIL- WET® series of products available from Union Carbide. When the scar prevention, reduction or removal agent is a fluorinated monomer or a siloxane-containing monomer, it is preferred that the monomer be polymerizable with the polymerizable adhesive monomer contained in the adhesive composition. In this embodiment, the agent will thus become an integral part of the polymer film during poly- merization. However, in other embodiments, the fluorinated monomer or siloxane—containing monomer need not be polymerizable with the polymerizable adhesive monomer, and can thus exist as a separate species in the resultant polymer film. When the agent is a fluorinated monomer or polymer or a siloxane-containing monomer or polymer, or even any of the other agents described herein, it is preferred that the agent be soluble both in the polymerizable monomer of the adhesive composition, as well as in the polymer formed therefrom. However, in embodiments, it may be acceptable for the agent to be insoluble in one or both of the polymer- izable monomer of the adhesive composition, and the poly- mer formed therefrom Furthermore, in the case of the siloxane-containing mono- mer or polymer, it is preferred, although not required, that the compound not be a siloxane compound having a 2-cyanoacryloyl group at each end. Instead, in such cases, the compound preferable does not include any 2-cyanoacryloyl groups, although the compound may have a 2-cyanoacryloyl group at one end, but other end of the compound is preferably terminated by a different group. However, where such siloxane compounds having a2-cyanoacryloyl group at each end are used as agents in embodiments of the present invention, it is preferred that the compounds be used in amounts of less than 1 weight percent, or more than 50 weight percent, based on the total composition. Various fluorinated siloxanes can also be used as anti-scar agents in the compositions of the present invention. By fluorinated siloxanes is meant a compound containing silicon, oxygen and fluorine atoms, where the silicon atoms are bonded either to a fluorine atom or an oxygen atom. Additionally, the fluorinated siloxanes can also include hydrogen atoms, where a hydrogen atom is bonded to a silicon atom in place of a fluorine or oxygen atom. According to embodiments of the present invention, suit- able fluorinated siloxanes includes those having a weight average molecular weight of from about 200 to about 20,000, and/or those having a viscosity, as measured at 25° C., of from about 100 to about 100,000 cP. However, fluorinated siloxanes having molecular weights and/or vis- cosities outside of these ranges can also be used. Suitable fluorinated siloxanes include, for example, the fluoropropyl fluids FF157, 150-10M and F160 as well as similar products, available from GE (Waterford, New York); the MED series of products, such as MED-400, MED-420 and MED-460 and similar products, available from NuSil (Carpinteria, Calif); and the PS series of products, such as PS 181, PS 182, PS 1836, PS 184.5, and PS 187 and similar products available from UCT (Bistol, Penn.). The MED-400 product is identified as a 100% fluorinated siloxane; the MED-420 product is identified as a copolymer of fluorosi- loxane and polydimethylsiloxane, of which about 20 mol% is fluorosiloxane; and the MED-460 product is identified as a copolymer of fluorosiloxane and polydimethylsiloxane, of which about 60 mol% is fluorosiloxane. 10 15 20 25 30 35 40 45 50 55 60 65 18 Suitable fluorinated siloxanes include, but are in no way limited to, fluroinated siloxanes such as polymethyl-3,3,3- trifluoropropyl siloxane of the formula: CH2: CF3 CH3 CH3 CH3 CH3—si—o—esi—oa,,—si— CH3 CH3 CH3 CH3 where n represents the number of repeating units and can range, for example, from about 1 to about 2000, preferably from about 2 or 10 to about 1500 or 1900, such as from about 2 to about 50 or about 100, or from about 500 or about 1000 to about 1500 or about 1800. Likewise, siloxanes in and of themselves are also suitable for use as the anti-scar agent in the present invention. Thus, for example, suitable siloxanes such as octyl siloxane and octadecyl siloxane can be used. Octyl siloxane and octade- cyl siloxane have the following formula: CH3 CH3 (CH2)m CH3 CH3—si—o—¢si—oa,,—si— CH3 CH3 CH3 CH3 where m is 7 for octyl siloxane or 17 for octadecyl siloxane, and n represents the number of repeating units and can range, for example, from about 1 to about 2000, preferably from about 2 or 10 to about 1500 or 1900, such as from about 2 to about 50 or about 100, or from about 500 or about 1000 to about 1500 or about 1800. In embodiments of the present invention where siloxanes are used as the anti-scar agent, it is also preferred, although not required, that the siloxane be used as a separate com- ponent in the composition, and not be added to the compo- sition in the form of a surface treatment agent on silica or similar particles. It is also preferred, although not required, that the siloxane not have any hydrogensilyl groups. Thus, for example, it is preferred in embodiments that the siloxane be a siloxane other than acyclic hydrogen-polysiloxane compounds, such as tetramethyldisiloxane and polymethylhydrosiloxane, or a cyclic hydrogenpolysiloxane such as 1,3,5,7-tetramethylcyclotetrasiloxane. However, where such compounds are used as anti-scar agents in embodiments of the present invention, it is preferred that the compounds be used in amounts of less than 0.001 parts by weight, or more than 10 parts by weight, based on 100 parts by weight of the adhesive component, i.e., the polymerizable monomer compound. In addition the ability to prevent, reduce or remove scars, the above agents can also serve as friction reducing agents or slip additives. Thus, in addition to preventing, reducing or removing scar tissue, the above agents can also reducing the composition’s coefficient of friction. EXAMPLES Examples of formulations of the invention are presented in the following Table I in which the ot-cyanoacrylate monomer is stabilized with anionic and radical stabilizers, and the composition includes a colorant, 0.5% or less of each of methyl paraben and BHA as preservatives, and is pack- aged in a post-fluorinated HDPE container. US 6,488,944 B2 19 TABLE I Compositions S aailized PDMS Plasticizer Monomer (Wt %) (Wt %) (Wt %) n—bu y CA (75) TMDS (20) PEG (5) n—bu y CA (75) TMDS (25) — n—bu y CA (75) OMTS (20) ATBC (5) n—bu y CA (75) OMTS (25) — n—bu y CA (75) DMPS (20) PMMA (5) n—bu y CA (75) DMPS (25) — n—bu y CA (75) DMHS (20) HDMS (5) n—bu y CA (75) DMHS (25) — 2-oc y CA (75) TMDS (20) PEG (5) 2-oc y CA (75) TMDS (25) — 2-oc y CA (75) OMTS (20) ATBC (5) 2-oc y CA (75) OMTS (25) — 2-oc y CA (75) DMPS (20) PMMA (5) 2-oc y CA (75) DMPS (25) — 2-oc y CA (75) DMHS (20) HDMS (5) 2-octy CA (75) DMHS (25) — EXPERIMENTAL RESULTS TABLE II Elongation of 2-Octyl Cyanoacrylate Film Elongation at Break Sample Peak Stress (psi) (inches) Modulus (psi) 0% OMTS 1370 +/— 41 3.1 +/— 1.6 18624 +/— 703 2% OMTS 1035 +/— 77 7.0 +/— 1.5 12343 +/— 502 10% OMTS 686 +/— 95 10.5 +/— 1.4 5753 +/— 353 20% OMTS 441 +/— 65 11.3 +/— 2.0 3189 +/— 316 Film tensile properties were tested using a MTS Sintech 2/G mechanical testing machine with TestWorks software ver- sion 3.08. The procedure used for this determination is a modified version of ASTM D882-95a (Standard Test Method for Tensile Properties of Thin Plastic Sheeting). A 10lbf load cell was used to determine these properties with a constant crosshead speed of 3.0 inches/minute. Small pneumatic grips were used to clamp the film on each end. The size of the films was 4 inches>