CA2395109A1 - 1,1-disubstituted ethylene adhesive compositions containing polydimethylsiloxane - Google Patents

Abstract

An adhesive composition that contains cyanoacrylate monomers and cyclic or alkyl- or phenyl-terminated linear polydimethylsiloxane is particularly usef ul in applications requiring flexibility and elasticity. A method of removing, reducing or preventing scar tissue including applying an adhesive compositio n that contains cyanoacrylate monomer and cyclic or alkyl- or phenyl-terminate d linear polydimethylsiloxane.

Description

1,1-DISUBSTITUTED ETHYLENE ADHESIVE COMPOSITIONS
CONTAINING POLYDIMETHYLSILOXANE
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 industrial (including household) and medical applications. Included among these adhesives are the 1,1-disubstituted ethylene monomers and polymers, such as the a-cyanoacrylates. Since the discovery of the adhesive properties 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 use. These characteristics have made the a-cyanoacrylate adhesives the primary choice for numerous applications such as bonding plastics, rubbers, glass, metals, wood, and, more recently, biological tissues.
It is known that monomeric forms of a-cyanoacrylates are 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 a-cyanoacrylates are anionically polymerizable or free radical polymerizable, or polymerizable by zwitterions or ion pairs to form polymers. Once polymerization has been initiated, the cure rate can be very rapid.
Medical applications of 1,1-disubstituted ethylene adhesive 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 monomeric form, and the resultant polymerization gives rise to the desired adhesive bond.
A concern 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 composition 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. Patents Nos. 4,477,607, 4,533,422 and Re. 32,889, all to Litke, disclose cyanoacrylate compositions that employ fumed silicas treated with polydimethylsiloxane or trialkoxyalkylsilane to improve the thixotropic properties of the compositions. Likewise, U.S. Patents Nos. 4,764,545 and 4,686,247 to Yosida disclose an adhesive composition comprising an alpha cyanoacrylate and a silica surface-treated respectively with polydimethylsiloxane and with hexamethyldisilazane.
Similarly, JP 06-122853 discloses an adhesive composition comprising an alpha cyanoacrylate and a hydrophobic silica surface-treated with dimethyldichlorosilane; U.S.
Patent No. 4,636,539 to Harris et al. discloses an adhesive comprising cyanoacrylate adhesive, fumed silica filler treated with polydialkylsiloxane, and calixarene compound; U.S. Patent 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 applications; U.S. Patent 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 dimethyldichlorosilane and trialkyl borate; U.S. Patent No. 5,373,035 to Uemura et al. discloses an adhesive composition comprising an alpha cyanoacrylate and a hydrophobic silica surface-treated with dimethyldichlorosilane; and U.S. Patent 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. Patent No. 5,214,093 to Nell et al. discloses an adhesive 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 cyanoacrylate adhesive and two separate miscible silicon oil components that are said to provide ...,.._ ,._...- > .~..~ ,F ,.<,... ....>'~=~.~.F,m~,i,_~..~,:"'~.~,y nrlixture 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 surfaceof the tissue to some extent." 'It is noted that silanes as a general matter raise toxicityissues, although this is not discussed in the Nell patent. .
JP 57-70169, JP 57-70171, Jl' 03-126782, JP 03-296581, JP 04-146982 and JP 06-100838 disclose a-cyanoacrylate adhesive compositions eoataining specific organosilicon compounds including silicone oils and compounds related to PDMS.
However, the disclosed compounds include various side andlor terminal groups that raise issues as to the stability and utility ofthe resultant compositions.
U.5. Patent No. 4,906.317 to LIEU discloses a cyanoacrylate adhesive composition which employs silacrown compounds as additives.
U.5_ Patent No. 4,837,260 to Sato et al. discloses an adhesive composition comprising an alpha cyanoacrylate anda hydrophobic silica along with particular , curing accelerators.
t U.S, patent No. 4,650,826 to 'Waniczek et al. discloses the use of silyl ester as a stabilizer for a cyanoacrylate adhesive.
U.5. Patent No. 5,386,047 to N~kos et al, discloses a pvlymerizable composition comprising a monoz~caer component, which includes a silicon containing di-alpha-cyanopentadienoate disilvxane compound. The monomer component further includes an alpha cyanoacrylatc compound.
t U.S. Patent No. 4,705,836 to Ohtsuka et al, discloses a bonding composition including vinyl benzoic acid and cyanoacrylic said cater. The cocrrpositioa further contains a silane compound.
U.S. patent No. 5,140,084 to Mikuni et al. discloses a silicone-containing .
alpha-cyanoacrylate that is useful as au adhesive. Similar silicone-containing alpha-cyanoacrylatc compositions are also disclosed in JP 04-9388 and JP 04-8780.
FR.1,389,441 discloses an ac-cXanoacrylate surgical adhesive including a plasticizer. U.S. PatcntNo. 4,912,153~to Jeremias et al. discloses polyorganosilo~e compositions including a,u~-dihydroxypolydimcthylsiloxanc, a,oo-bis-(trimethylsiloxy)-polydimethylsiloxane, an oximinosilane, a filler, an arninoalkyl alkoxysilane, and a tin catalyst.
AMENDED SHEET _ s~
''~" CA 02395109 2002-06-14 CA 02395109 2002-06-14 b x."" , ~..._,., Q~~~~,~.~~~,sr~te~

EP 611,565 discloses a compasj tion for dcrmatologic preparation containing vitamin A and at least one powdery substance or at least one silicone oil selected from dimethylpolysilaxane and methylphen~ilpolysaloxane. EP 774,482 discloses a method of spontaneously foz~.ing a highly stabi a clear microemulsion by combining water, a volatile cyclic methyl siloxsnc or volatile linear methyl siloxane, and a silicone i polyether surfactant. i The present invention provides ~ monomeric adhesive composition comprising a polymerizablc 1,1-disubstituted ethylene adhesive monomer and a polydimethylsiloxane, which is alkyl, prj ferahly methyl, or phenyl terminated or cyclic.
'fhe composition is free or substantially of silane compounds. Production of the composition includes providia~ a mixture of the polymerizable monomer and polydimethylsiloxane in a container, a~od sealing the container, and AMENDED SHEET .

SUMMARY OF THE INVEN~fIUN
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 providing a mixture of the polymerizable monomer and polydimethylsiloxane 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 friction 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 composition comprises at least one polymerizable 1,1-disubstituted ethylene monomer and at least one polydimethylsiloxane (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 relatively short or small compound, as opposed to a long chain polymer. Thus, for example, the PDMS compound preferably has a low molecular weight, e.g., has a small number of monomer units, and also a low viscosity.
The PDMS
compound is selected such that it is compatible with the monomer (i.e., does not adversely affect polymerization, cure properties, or shelf life). Preferably, the polydimethylsiloxane 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 Thus, it is preferred in embodiments that the polydimethylsiloxane exhibits an at least substantially uniform concentration 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 microemulsion (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 polydimethylsiloxanes 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 polydimethylsiloxane 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 centipoise at 25°C.
In other embodiments, the polydimethylsiloxane can be a cyclic polydimethylsiloxane.
Such cyclic PDMS compounds 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 polydimethylsiloxane can be used. In embodiments, the cyclic PDMS
can be selected from octamethylcyclotetrasiloxane (OMTS), decamethylcyclopentasiloxane (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 .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:

R3- O~Si - O ~ SiR3 wherein R' and RZ are independently selected alkyl or phenyl groups. Cyclic PDMS of the invention can be depicted by the formula:

~5i-O
II

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 polydimethylsiloxane 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.
A suitable procedure for selecting a polydimethylsiloxane involves selecting a group of potential polydimethylsiloxanes, assessing their solubility and stability in the monomer composition, and optionally testing for their compatibility with one or more sterilization procedures.
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 prematurely 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 components thereof.
In embodiments of the present invention, it is preferred that the polydimethylsiloxane exhibit stability in the monomer composition for at least five minutes after mixing or dissolving the polydimethylsiloxane in the polymerizable monomer compound. More preferably, stability of the 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 sterilization 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 packaging 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 hydrogen 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 composition 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 composition 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, irntation, 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 invention, and polymers formed therefrom, are also useful in industrial and home applications, for example in bonding rubbers, plastics, wood, composites, fabrics, and other natural and synthetic materials, 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. Patent No. 5,328,687 to Leung, et al., which is hereby incorporated in its entirety by reference herein.
Useful l,l-disubstituted ethylene monomers include, but are not limited to, monomers of the formula:
(I) HRC=CXY

wherein X and Y are each strong electron withdrawing groups, and R is H, -CH=CHZ or, provided that X and Y are both cyano groups, a C,-C4 alkyl group.
Examples of monomers within the scope of formula (I) include a,-cyanoacrylates, vinylidene cyanides, C,-C4 alkyl homologues of vinylidene cyanides, dialkyl methylene malonates, 5 acylacrylonitriles, vinyl sulfinates and vinyl sulfonates of the formula CHZ
CX'Y' wherein X' is -SOZR' or -S03R' and Y' is -CN, -COOR', -COCH3, -SOZR' or -S03R', and R' is H
or hydrocarbyl.
Preferred monomers of formula (I) for use in this invention are a-cyanoacrylates. These monomers are known in the art and have the formula CN
(II) HRZC =
COORS
10 wherein RZ is hydrogen and R3 is a hydrocarbyl or substituted hydrocarbyl group; a group having the formula -R4-O-RS-O-R6 or -RS-O-R6, wherein R4 is a 1,2-alkylene group having 2-4 carbon atoms, RS 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 - R' - C - O - R 8 , O
wherein R' is - (CHZ)" w -CH-, or - C(CH3)z -, wherein n is 1-10, preferably 1-5, and Rg is an organic moiety.
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 C,-C,6 alkyl groups substituted with an acyloxy 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.
The organic moiety Rg may be substituted or unsubstituted and may be straight chain, branched or cyclic, saturated, unsaturated or aromatic. Examples of such organic moieties include C,-C8 alkyl moieties, CZ C8 alkenyl moieties, CZ C8 alkynyl moieties, C3-C,2 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. Particularly 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 a-cyanoacrylates of formula (II) can be prepared according to methods known in the art. U.S. Patents Nos. 2,721,858 and 3,254,111, each of which is hereby incorporated in its entirety by reference, disclose methods for preparing a-cyanoacrylates. For example, the a-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 a-cyanoacrylate monomers prepared with low moisture content and essentially free of impurities are preferred for biomedical use.
The a-cyanoacrylates of formula (II) wherein R3 is a group having the formula R6 or -RS-O-R6 can be prepared according to the method disclosed in U.S.
Patent No. 4,364,876 to Kimura et al., which is hereby incorporated in its entirety by reference. In the Kimura et al. method, the a-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 0.5-1.5: l, preferably 0.8-1.2:1, 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 a-cyanoacrylates of formula (II) wherein R3 is a group having the formula - R' - C - O - R 8 O
can be prepared according to the procedure described in U.S. Patent No.
3,995,641 to Kronenthal et al., which is hereby incorporated in its entirety by reference. In the Kronenthal et al. method, such a-cyanoacrylate monomers are prepared by reacting an alkyl ester of an a-cyanoacrylic acid with a cyclic 1,3-dime to form a Diels-Alder adduct which is then subjected to alkaline hydrolysis followed by acidification to form the corresponding a-cyanoacrylic acid adduct. The a-cyanoacrylic acid adduct is preferably esterified by an alkyl bromoacetate to yield the corresponding carbalkoxymethyl a-cyanoacrylate adduct. Alternatively, the a-cyanoacrylic acid adduct may be converted to the a-cyanoacrylyl halide adduct by reaction with thionyl chloride. The a-cyanoacrylyl halide adduct is then reacted with an alkyl hydroxyacetate or a methyl substituted alkyl hydroxyacetate to yield the corresponding carbalkoxymethyl a-cyanoacrylate adduct or carbalkoxy alkyl a-cyanoacrylate adduct, respectively. The cyclic 1,3-dime blocking group is finally removed and the carbalkoxy methyl a-cyanoacrylate adduct or the carbalkoxy alkyl a-cyanoacrylate adduct is converted into the corresponding carbalkoxy alkyl a-cyanoacrylate by heating the adduct in the presence of a slight deficit of malefic anhydride.
Examples of monomers of formula (I) include cyanopentadienoates and a-cyanoacrylates of the formula:
CN
(III) HZC =C
COORS
wherein Z is -CH=CHZ 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. Patent No. 3,554,990, which is hereby incorporated in its entirety by reference.
Preferred a-cyanoacrylate monomers used in this invention are alkyl a-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 cyanoacrylate; 2-isopropoxyethyl cyanoacrylate; and 1-methoxy-2-propyl cyanoacrylate. More preferred monomers are n-butyl and 2-octyl a-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, trip-cresyl) phosphate, glyceryl triacetate, glyceryl tributyrate, diethyl sebacate, dioctyl adipate, isopropyl myristate, butyl stearate, lauric acid, trioctyl trimellitate, dioctyl glutarate, and mixtures 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 centipoise 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.
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 polymerized 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. Patent No. 4,720,513, and U.S. Patent Application Serial No. 09/374,207 filed August 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 alkylacrylate 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 copolymers of various acrylate and methacrylate monomers, such as poly(butylmethacrylate-co-methylmethacrylate). Biodegradable 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 composition.
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, dimes, styrenes, acrylonitriles, and mixtures thereof. Examples of suitable rubbers are disclosed in, for example, U.S. Patents 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 polymerization of the monomer.
The anionic vapor phase stabilizers may be selected from among known stabilizers, 5 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 stabilizers) chosen in combination with it, the monomer to be stabilized, as well as the packaging material to be used for the composition.
Preferably, each anionic vapor phase stabilizer is added to give a concentration of less than 200 parts per million 10 (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 determined 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 15 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 trifluoride or hydrogen fluoride is preferable in some embodiments.
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 1Ø
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 <-10), chlorosulfonic acid (pI~ -10). In embodiments, the very strong acid liquid phase anionic stabilizer is added to give a final concentration of 1 to 200 ppm.
Preferably, the very strong acid liquid phase anionic stabilizer is present in a concentration of from about 5 to 80 ppm, more preferably 10 to 40 ppm. The amount of very strong acid liquid phase anionic stabilizer to be used can be determined by one of ordinary skill in the art without undue experimentation.
Preferably, the very strong acid liquid phase anionic stabilizer is sulfuric acid, perchloric acid, or chlorosulfonic acid. More preferably, the very strong acid liquid phase anionic stabilizer is sulfuric acid.

In embodiments, sulfur dioxide is used as a vapor phase amomc stabilizer and sulfuric acid is used as a liquid phase anionic stabilizer.
The composition may also optionally include at least one other anionic stabilizing agent that inhibits premature polymerization. These agents are herein referred to as secondary anionic active agents to contrast them with the strong or very strong liquid phase anionic stabilizers, which are referred to hereinbelow as "primary" anionic stabilizers. The secondary anionic active agents can be included in the compositions to adjust the cure speed of the adhesive composition, for example.
The secondary anionic active agent would normally be an acid with a higher pKa than the primary anionic stabilizing agent and may be provided to more precisely control the cure speed and stability of the adhesive, as well as the molecular weight of the cured adhesive. Any mixture of primary anionic stabilizers and secondary active agents is included as long as the chemistry of the composition is not compromised and the mixture does not significantly inhibit the desired polymerization of the composition. Furthermore, the mixture should not, in medical adhesive compositions, show unacceptable levels of toxicity.
Suitable secondary anionic active agents include those having aqueous pI~
ionization constants ranging from 2 to 8, preferably from 2 to 6, and most preferably from 2 to 5. Examples of such suitable secondary anionic stabilizing agents include, but are not limited to, phosphoric acid (pKa 2.2), organic acids, such as acetic acid (pKa 4.8), benzoic acid (pKa 4.2), chloroacetic acid (pKa 2.9), cyanoacetic acid, and mixtures thereof. Preferably these secondary anionic stabilizing agents are organic acids, such as acetic acid or benzoic acid. In embodiments, the amount of acetic acid and/or benzoic acid is about 25-500 ppm. The concentration of acetic acid is typically 50-400 ppm, preferably 75-300 ppm, and more preferably 100-200 ppm. When using a stronger acid such as phosphoric acid, a concentration of 20-100 ppm, preferably 30-80 ppm, and more preferably 40-60 ppm may be utilized.
Combinations of at least one vapor phase stabilizer and at least one liquid phase anionic stabilizer are preferred. For example, combinations of sulfur dioxide and sulfuric acid; sulfur dioxide and perchloric acid; sulfur dioxide and chlorosulfonic acid; boron trifluoride and sulfuric acid; boron trifluoride and perchloric acid; boron trifluoride and chlorosulfonic acid; boron trifluoride and methanesulfonic acid; hydrogen fluoride and sulfuric acid;
hydrogen fluoride and perchloric acid; hydrogen fluoride and chlorosulfonic acid; hydrogen fluoride and methanesulfonic acid; boron tritluoride, suli-'ur dioxide, and sulfuric acid; sulfur dioxide, sulfuric acid and acetic acid;
and other combinations can be used. The two types of anionic stabilizers are chosen in conjunction such that the stabilizers are compatible with the chosen adhesive composition and each other, as well as with the packaging material and the equipment used to make and package the composition.
In other words, the combination of vapor phase stabilizer(s), liquid phase stabilizer(s), radical stabilizers and monomer should be such that a stabilized, substantially unpolymerized adhesive composition is present after packaging.
It has been found, however, that compositions of the invention can require less stabilizer than corresponding compositions without the PDMS.
The stability, and thus the shelf life, of some monomeric adhesive compositions can be further enhanced and extended through careful regulation of the packaging.
Treated (e.g., fluorinated polymer) packaging such as that disclosed in copending U.S. Patent Application No. (100497.02) filed October 29, 1999, which is hereby incorporated by reference in its entirety, is preferred and may reduce the amount of stabilizer that is combined into the composition.
The compositions may also include pH modifiers to control the rate of degradation of the resulting polymer, as disclosed in U.S. Patent Application No. 08/714,288, filed September 18, 1996, the entire disclosure of which is hereby incorporated by reference.
Medical compositions of the present invention may also include at least one biocompatible agent effective to reduce active formaldehyde concentration levels produced during in vivo biodegradation of the polymer (also referred to herein as "formaldehyde concentration reducing agents"). Preferably, this component is a formaldehyde scavenger compound.
Examples of formaldehyde scavenger compounds useful in this invention include sulfites;
bisulfites; mixtures of sulfites and bisulfites; ammonium sulfite salts; amines; amides; imides;
nitrites; carbamates;
alcohols; mercaptans; proteins; mixtures of amines, amides, and proteins;
active methylene compounds such as cyclic ketones and compounds having a b-dicarbonyl group;
and heterocyclic ring compounds free of a carbonyl group and containing an NH group, with the ring made up of nitrogen or carbon atoms, the ring being unsaturated or, when fused to a phenyl group, being unsaturated or saturated, and the NH group being bonded to a carbon or a nitrogen atom, which atom is directly bonded by a double bond to another carbon or nitrogen atom.
Additional examples of formaldehyde scavenger compounds useful in this invention and methods for their implementation can be found in U.S. Patents Nos. 5,328,687, 5,514,371, 5,514,372, 5,575,997, 5,582,834 and 5,624,669, all to Leung et al., which are hereby incorporated by reference in their entireties.
To improve the cohesive strength of adhesives formed from the compositions of this invention, difunctional monomeric cross-linking agents may be added to the monomer compositions of this invention. Such crosslinking agents are known. U.S.
Patent No. 3,940,362 to Overhults, which is hereby incorporated in its entirety by reference, discloses such cross-linking agents. Examples of suitable crosslinking agents include alkyl bis(2-cyanoacrylates), triallyl isocyanurates, alkylene diacrylates, alkylene dimethacrylates, trimethylol propane triacrylate, and alkyl bis(2-cyanoacrylates). A catalytic amount of an amine activated free radical initiator or rate modifier may be added to initiate polymerization or to modify the rate of polymerization of the cyanoacrylate monomer/crosslinking agent blend.
In embodiments of the present invention, the composition and/or its applicator may contain materials such as a polymerization initiator, accelerator, rate-modifier, flavorant, and/or cross-linking agent for initiating polymerization and/or cross-linking of the polymerizable monomer material. Suitable materials and applicators and packaging systems are disclosed in U.S. Patent No. 5,928,611 and U.S. Patent Applications Serial Nos. 09/430,177, 09/430,176, 09/430,289, 09/430,290, and 09/430,180 filed October 29, 1999; 09/343,914 filed June 30, 1999; 09/385,030 filed August 30, 1999; and 09/176,889 filed October 22, 1998; the entire disclosures of which are incorporated herein by reference. A preferred initiator for some uses, especially industrial uses, is dimethyl toluidine.
The compositions of this invention may further contain fibrous reinforcement and colorants such as dyes, pigments, and pigment dyes. Examples of suitable fibrous reinforcement include PGA microfibrils, collagen microfibrils, cellulosic microfibrils, and olefinic microfibrils. Examples of suitable colorants include 1-hydroxy-4-[4-methylphenyl-amino]-9,10 anthracenedione (D+C
violet No. 2); disodium salt of 6-hydroxy-5-[(4-sulfophenyl)axo]-2-naphthalene-sulfonic acid (FD+C Yellow No. 6); 9-(o-carboxyphenoyl)-6-hydroxy-2,4,5,7-tetraiodo-3H-xanthen-3-one, disodium salt, monohydrate (FD+C Red No. 3); 2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)-2,3-dihydro-3-oxo-1H-indole-5-sulfonic acid disodium salt (FD+C Blue No. 2);
and [phthalocyaninato (2-)] copper.

The compositions of this invention may further contain preservatives. In embodiments, the preservatives may be selected from among known preservatives including, but not limited to, parabens and cresols. For example, suitable parabens include, but are not limited to, alkyl parabens and salts thereof, such as methylparaben, methylparaben sodium, ethylparaben, propylparaben, propylparaben sodium, butylparaben, and the like. Suitable cresols include, but are not limited to, cresol, chlorocresol, and the like. The preservatives can also be selected from other known agents including, but not limited to, hydroquinone, pyrocatechol, resorcinol, 4-n-hexyl resorcinol, captan (i.e., 3a,4,7,7a-tetrahydro-2-((trichloromethyl)thio)-1H-isoindole-1,3(2H)-dione), methyl-4-hydroxybenzoate, benzalkonium chloride, benzalkonium chloride solution, benzethonium chloride, benzoic acid, benyzl alcohol, butylated hydroxy-anisole (BHA), cetylpyridinium chloride, chlorobutanol, dehydroacetic acid, o-phenylphenol, phenol, phenylethyl alcohol, potassium benzoate, potassium sorbate, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, thymol, phenylmercuric compounds such as phenylmercuric borate, phenylmercuric nitrate and phenylmercuric acetate, formaldehyde, and formaldehyde generators such as the preservatives Germall II~ and Germall 115~ (imidazolidinyl urea, available from Sutton Laboratories, Charthan, New Jersey). In embodiments, mixtures of two or more preservatives can also be used. See also U.S. Patent Application Serial Number 09/430,180 filed October 29, 1999, which is hereby incorporated herein in its entirety by reference.
The present invention is also directed to the use of compositions, including above-described compositions, to remove, prevent or reduce scar tissue. It has surprisingly been found that compositions including PDMS or other siloxane-containing materials, including but not limited to the above-described PDMS-containing compositions, can be applied to tissue for the purpose and effect of reducing, or even eliminating, scar tissue. In a similar manner, such compositions can also be applied to tissue surfaces for the prevention of scar tissue formation. Although the composition to be applied is preferably the above-described PDMS-containing adhesive composition, any suitable PDMS-containing adhesive composition can be used, without the PDMS compound necessarily being limited to those described in detail above.
Exemplary embodiments of the present invention for the removal, prevention or reduction of scar tissue can include various methods wherein the composition is applied to tissue areas, such as skin areas, where scar tissue is already present or where scar tissue is prone, or likely, to form. In such methods, the composition can be applied by itself or in combination with other topical compositions and/or medications to aid in the removal, prevention or reduction of scar tissue.
In an exemplary embodiment, a method for removing or reducing scar tissue already present can include applying the composition in an amount sufficient to cover a skin area where scar tissue 5 is present. The method can also include a step of covering the applied composition with a protective bandage or other adhesive composition to protect the applied composition from frictional contact with, for example, clothing. The application of the composition of the present invention can be repeated until the scar tissue is substantially removed or reduced.
According to embodiments of the present invention, the presence and/or appearance of 10 scar tissue can be partially, substantially, or even completely removed.
For example, treatment of scar tissue using compositions of the present invention can result, for example, in a reduction of scar tissue, such as measured in area, in an amount of at least about 20% or more. In embodiments, the scar tissue reduction can be in an amount of at least about 30% or about 40%
or more, and preferably is at least about 50% or more. In terms of scar tissue reduction, 15 substantial reductions of at least about 80% or more or at least about 85%
or 90% or more are preferred. In embodiments, complete reduction of 100% of the scar tissue may be realized.
Although not limited by any particular theory, it is believed that siloxane-containing compositions actually reduces the presence of scar tissue. However, regardless of the actual mechanism, a reduction in at least the appearance of the scar tissue occurs.
Thus, whether the 20 scar tissue itself is reduced, or if only its appearance is reduced such as by overgrowth of healthy tissue, the scar itself is reduced and/or eliminated.
Similarly, in an exemplary embodiment, a method of the present invention for preventing scar tissue formation can include applying an amount of the above-described composition to a tissue area wherein scar tissue may be prone, or likely, to form. Preferably, the amount of composition applied is sufficient to cover the entire tissue area and optionally a surrounding tissue area so that scar tissue formation is sufficiently prevented. Tissue areas where scar tissue may be prone, or likely, to form can include skin areas where a wound has been inflicted including, but not limited to, skin areas that are prone, or likely, to suffer from cuts, abrasions, burns, etc. These injuries can be injuries that result from medical treatment, including, for example, surgery, as well as injuries that occur in every day life. In methods of the present invention for preventing scar tissue formation, the composition is applied to the tissue, or skin, area either prior to an injury ,or wound, when the area of tissue is uncompromised or immediately after the occurrence of an injury, or wound. For instance, the composition can be applied to a skin area that one believes will suffer an injury before the injury occurs, or the composition can be applied to a skin area immediately after the injury occurs. If applied to the skin area after the injury has occurred, the applied composition may or may not be covered with a protective bandage and/or adhesive composition to prevent the composition from being removed due to frictional contact with clothing or other objects.
The present invention is also directed to a cosmetic agent comprising the above-described composition for removing, reducing or preventing scar tissue. Such an agent may comprise one or more additional components and/or medicaments together with the above-described composition to assist in the removal, reduction or prevention of scar tissue.
Furthermore, the present invention is also directed to the use of the above composition for obtaining a cosmetic agent for removing, reducing or preventing scar tissue.
The use of the above described composition for obtaining such a cosmetic agent encompasses the preparation and combination of the above composition with other materials and/or medicaments during manufacturing to obtain a cosmetic agent for scar tissue removal, reduction or prevention.
In addition to, or in place of, the above PDMS-containing compositions, the composition of the present invention can also include other siloxane or PDMS-containing materials to prevent, reduce or remove scar tissue. For example, in exemplary embodiments of the present invention the composition may include additional scar reduction agents including, but not limited to siloxane-containing monomers, siloxane-containing polymers, fluorinated siloxanes, and siloxanes.
Examples of suitable siloxane-containing monomers and siloxane-containing polymers include, but are not limited to, siloxane-containing 1,1-disubstituted ethylene monomers.
Particularly preferred suitable siloxane-containing monomers and polymers include, but are not limited to, siloxane-containing a-cyanoacrylates such as alkyl a-cyanoacrylates having an alkyl chain length of from about 1 to about 20 carbon atoms, preferably from about 2 to about 12 carbon atoms. Examples of such siloxane-containing alkyl a-cyanoacrylates include, for example, siloxane-containing ethyl, butyl, and octyl a-cyanoacrylates. Other particularly preferred suitable siloxane-containing monomers and polymers include, for example, siloxane-containing cyanopentadienoates.

Preferably, where siloxane-containing cyanopentadienoates are used, it is preferred, although not required, that the compound not be a di-a-cyanopentadienoate disiloxane of the formula:
(CHz=CH-CH=C(CN)-C(=O)-O-CHZ R-Si(R")z)2 O
wherein R is -CH=CH- or -C(=CHz)- and R" are the same or different hydrocarbon or halosubstituted hydrocarbon groups, as disclosed in U.S. Patent No. 5,386,047 to Nakos et al., the entire disclosure of which is incorporated herein by reference. However, when such compounds are used as anti-scar agents, they are preferably used in the composition in combination with non-siloxane containing polymerizable adhesive monomers.
Suitable siloxane groups incorporated into the monomer or polymer include, but are not limited to, disiloxane having the formula -SiHz-O-SiH~, trisiloxane such as linear trisiloxane having the formula -(SiHz-O)z-SiH3 or branched trisiloxane having the formula -SiH(-O-SiH3)z, or linear or branched longer siloxane units such as those having the formulas -(SiHz-O)~ SiH3, -(Sl(CH3)z-O)"-S1H3, -(S1(CH3)z-O)"-Sl(CH3)3, or -SiH(-O-SiH3)"(-O-SiH3)m, where n and m are integers of any suitable number to provide a desired molecular 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 a-cyanoacrylates include, but are not limited to, monomers of the formula:
CN
HZC=C
COOR
wherein R is a siloxane-containing group of the formula -(O-Si(CH3)z)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-(-C-C-)m H
$ COO-(CHZ)8 (O-Si(CH3)Z)n O-Si(CH3)s 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 polyethylene glycol.
The dimethicone copolyol suitable for use in the present invention can include a polydimethylsiloxane (PDMS) segment 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 compound.
Still other examples of suitable siloxane containing polymers include, but are not limited to, the MASIL~ series of products available from BASF Corporation and the SILWET~ series of products available from Union Carbide.
When the scar prevention, reduction or removal agent is a fluorinated 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 polymerization. However, in other embodiments, the fluorinated 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 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 polymerizable monomer of the adhesive composition, and the polymer formed therefrom Furthermore, in the case of the siloxane-containing monomer 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 preferably does not include any 2-cyanoacryloyl groups, although the compound may have a 2-cyanoacryloyl group at one end, but the other end of the compound is preferably terminated by a different group.
However, where such siloxane compounds having a 2-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, suitable 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 viscosities outside of these ranges can also be used.
Suitable fluorinated siloxanes include, for example, the fluoropropyl fluids FF157, 150-l OM 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, California); 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, Pennsylvania).
The MED-400 product is identified as a 100% fluorinated siloxane; the MED-420 product is identified as a copolymer of fluorosiloxane and polydimethylsnoxane, of which about 2U mol%
is fluorosiloxane; and the MED-460 product is identified as a copolymer of fluorosiloxane and polydimethylsiloxane, of which about 60 mol% is fluorosiloxane.
Suitable fluorinated siloxanes include, but are in no way limited to, fluroinated siloxanes 5 such as polymethyl-3,3,3-trifluoropropyl siloxane of the formula:
CHz CF3 10 CH3 Si-O-(-Si- O-)n Si-CH3 where n represents the number of repeating units and can range, for example, from about 1 to about 15 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 octadecyl siloxane have the following formula:

CH3 (CHz)m CHs CH3 Si-O-(-Si- O-)n Si-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 component in the composition, and not be added to the composition 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 reduce the composition's coefficient of friction.
Examples Examples of formulations of the invention are presented in the following Table I in which the a-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 packaged in a post-fluorinated HDPE container.

TABLE I - Compositions Stabilized PDMS Plasticizer Monomer (Wt %) Wt % Wt n-butyl CA (75) TMDS (20) PEG (5) n-butyl CA (75) TMDS (25) ---n-butyl CA (75) OMTS (20) ATBC (5) n-butyl CA (75) OMTS (25) ---n-butyl CA (75) DMPS (20) PMMA (5) n-butyl CA (75) DMPS (25) ---n-butyl CA (75) DMHS (20) HDMS (5) n-butyl CA (75) DMHS (25) ---2-octyl CA (75) TMDS (20) PEG (5) 2-octyl CA (75) TMDS (25) ---2-octyl CA (75) OMTS (20) ATBC (5) 2-octyl CA (75) OMTS (25) ---2-octyl CA (75) DMPS (20) PMMA (5) 2-octyl CA (75) DMPS (25) ---2-octyl CA (75) DMHS (20) HDMS (5) 2-octyl CA (75) DMHS (25) ---Experimental Results TABLE II- Elongation of 2-Octyl Cyanoacrylate Film Sample Peak Stress (psi~Elongation at Break Modulus (inches) ~psi) 0% OMTS 1370 +/-.41 3.1+/- 1.6 18624 +/-2% OMTS 1035 +/- 77 7.0 +/-1.5 12343 +/-10% OMTS 686 +/- 95 10.5 +/- 1.4 5753 +/-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 version 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 l Olbf 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 x 0.5 inches with variance in thickness. A
gage length of 3 inches was used, allowing 0.5 inches of each end of the film to be secured in the grips.
Elongation at break, peak stress and modulus were calculated using this procedure.
This table demonstrates improved elasticity and elongation that may be achieved by way of the invention.
TABLE III-Solubilities of TMDS and OMTS in 2-Octyl Cyanoacrylate PDMS TMDS solutions TMDS films OMTS solutions OMTS films 0 Clear Clear Clear Clear 2 Clear Clear Clear Clear 5 Clear Clear Clear Clear 10 Slightly Cloudy Clear Clear Clear 15 Slightly Cloudy Clear Clear Clear Cloudy Cloudy Clear Clear This table demonstrates higher levels of soluble PDMS achievable by way of cyclic PDMS embodiments of the invention.

While the invention has been described with reference to preferred embodiments, the invention is not limited to the specific examples given, and other embodiments and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention.

Claims (58)

WHAT IS CLAIMED IS:

1. An adhesive composition, comprising polydimethylsiloxane and polymerizable 1,1-disubstituted ethylene adhesive monomer; wherein said composition is substantially free of silanes, said polydimethylsiloxane is dissolved in, or in a microemulsion in, said monomer; said polydimethylsiloxane is cyclic, or alkyl-or phenyl-terminated linear, polydimethylsiloxane; and said polydimethylsiloxane is optionally alkyl substituted.

2. The composition of claim 1, wherein said monomer is .alpha.-cyanoacrylate monomer.

3. The composition of claim 1, wherein said monomer is alkyl .alpha.-cyanoacrylate monomer.

4. The composition of claim 1, wherein said monomer comprises at least one member selected from the group consisting of ethyl cyanoacrylate, butyl cyanoacrylate, and 2-octyl cyanoacrylate.

5. The composition of claim 1, wherein said polydimethylsiloxane is linear.

6. The composition of claim 5, wherein said polydimethylsiloxane has an average of about 2-12 monomer units.

7. The composition of claim 5, wherein said polydimethylsiloxane has an average of about 3-4 monomer units.

8. The composition of claim 1, wherein said polydimethylsiloxane is linear trimethylsiloxy terminated polydimethylsiloxane.

9. The composition of claim 1, wherein said polydimethylsiloxane has a weight average molecular weight of from about 150 to about 1500.

10. The composition of claim 5, wherein said polydimethylsiloxane has a viscosity of less than 8 centipoise at 25°C.

11. The composition of claim 1, wherein said polydimethylsiloxane is cyclic.

12. The composition of claim 11, wherein said polydimethylsiloxane has an average of about 3-12 monomer units

13. The composition of claim 1, wherein said polydimethylsiloxane is at least one member selected from the group consisting of octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane.

14. The composition of claim 1, wherein said polydimethylsiloxane is present in the composition in an amount of between about 5% and about 30% by weight relative to the total monomer and polydimethylsiloxane content.

15. The composition of claim 14, wherein said amount is between about 10% and about 25% by weight.

16. The composition of claim 14, wherein said amount is about 10-20% by weight.

17. The composition of claim 5, wherein said polydimethylsiloxane is alkyl-terminated.

18. The composition of claim 5, wherein said polydimethylsiloxane has methyl, ethyl or propyl terminal groups.

19. The composition of claim 5, wherein said polydimethylsiloxane is methyl terminated.

20. The composition of claim 1, wherein said polydimethylsiloxane is unsubstituted.

21. The composition of claim 1, wherein said composition is free of silica.

22. The composition of claim 1, wherein said composition further comprises at least one stabilizing agent.

23. The composition of claim 1, further comprising at least one plasticizer different from said polydimethylsiloxane.

24. The composition of claim 23, wherein said plasticizer is selected from the group consisting of tributyl citrate, acetyl tributyl citrate, polymethylmethacrylate and hexadimethylsilazane.

25. The composition of claim 23, wherein a viscosity of said composition is at least 100 centipoise at 25°C and said plasticizer is at least one member selected from the group consisting of polymethylmethacrylate and hexadimethylsilazane.

26. The composition of claim 1, further comprising at least one antimicrobial preservative selected from the group consisting of cresols and parabens.

27. The composition of claim 1, wherein said composition is sterile.

28. The composition of claim 1, packaged in a post-fluorinated polymeric container.

29. A method of making the composition of claim 1, comprising dissolving a polydimethylsiloxane in a polymerizable 1,1-disubstituted ethylene adhesive monomer to form a solution.

30. The method of claim 29, wherein the polydimethylsiloxane is at least 98.5% by weight pure prior to said mixing.

31. The method of claim 29, wherein the polydimethylsiloxane is cyclic.

32. The method of claim 29, further comprising sterilizing said solution.

33. An adhesive composition comprising a polymerizable 1,1-disubstituted ethylene adhesive monomer and a cyclic polydimethylsiloxane.

34. The composition of claim 33, wherein said monomer is .alpha.-cyanoacrylate monomer.

35. The composition of claim 33, wherein said monomer is alkyl .alpha.-cyanoacrylate monomer.

36. The composition of claim 33, wherein said monomer comprises at least one member selected from the group consisting of ethyl cyanoacrylate, butyl cyanoacrylate, and 2-octyl cyanoacrylate.

37. The composition of claim 33, wherein said polydimethylsiloxane is at least one member selected from the group consisting of octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane.

38. The composition of claim 33, wherein the cyclic polydimethylsiloxane has a viscosity of about 5-7.5 centipoise at 25°C.

39. An adhesive composition comprising:

(a) 2-alkyl cyanoacrylate ~~65-90 wt%;
(b) cyclic polydimethylsiloxane~10-35 wt%;
(c) plasticizer ~~ 0-10 wt%;
(d) anionic stabilizer ~~ 0-1 wt%;
(e) radical stabilizer ~~ 0-1 wt%;
(f) antimicrobial preservative~ 0-1 wt%; and (g) colorant ~~~ 0-0.01 wt%.

40. The composition of claim 39, wherein said alkyl cyanoacrylate is 2-octyl cyanoacrylate and said cyclic polydimethylsiloxane is octamethyltetracyclosiloxane.

41. The composition of claim 40, wherein said plasticizer is selected from the group consisting of polymethylmethacrylate, hexadimethylsilazane, tributyl citrate and acetyl tributyl citrate.

42. The composition of claim 40, wherein said preservative is methyl paraben.

43. A method of making a sterile composition comprising:
placing a mixture of a polymerizable cyanoacrylate monomer and a polydimethylsiloxane in a container, sealing said container, and sterilizing the mixture in the container.

44. The method of claim 43, wherein said polydimethylsiloxane is cyclic.

45. The method of claim 43, wherein said polydimethylsiloxane is selected from the group consisting of octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane and dodecamethylcyclohexasiloxane.

46. The method of claim 43, wherein said sterilizing is performed by dry heat, moist heat, retort canning, gamma irradiation, electron beam irradiation, or microwave irradiation.

47. The method of claim 43, wherein said sterilizing is performed by electron beam irradiation.

48. A process for manufacturing a medicament for use in treating tissue, comprising formulating the composition of claim 1 for use in treating tissue.

49. The process of claim 48, wherein said tissue is at or adjacent a joint of a mammal.

50. The process of claim 49, wherein said joint is a human knee or elbow.

51. The process of claim 49, wherein said joint is on a human hand or foot.

52. The process of claim 48, wherein said tissue is on a human face.

53. The process of claim 48, wherein said monomer is 2-octyl cyanoacrylate and said polydimethylsiloxane is cyclic.

54. The process of claim 48, wherein said tissue is compromised.

55. The process of claim 54, wherein said tissue is burned, lacerated, irritated, abraded or incised.

56. The process of claim 48, wherein said tissue is skin.

57. The process of claim 56, wherein said skin is compromised.

58. The process of claim 56, wherein said skin is intact.

58. The process of claim 56, wherein said skin is intact.

58. The process of claim 56, wherein said skin is intact.

58. The process of claim 56, wherein said skin is intact.