JP2007061658A - Monomeric compositions effective as wound closure devices - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide monomeric compositions effective as wound closure devices, which relate to monomer and polymer compositions useful to form biomedical adhesives and sealants. <P>SOLUTION: A biocompatible monomer composition includes: (A) at least one monomer, which forms a medically acceptable polymer; (B) at least one plasticizing agent present in the composition in an amount of from 0.5 to 9 wt.% of the composition; and (C) at least one acidic stabilizing agent. A film is formed in the following method; (a) at least two tissue surfaces are held together so as to form an abutted tissue surface; (b) the composition is applied to transverse the abutted tissue surface; and (c) the composition is polymerized and the film is formed on the abutted tissue surface. The film has the thickness of 0.1mm or more and has film strength being higher than that of a thinner film. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to monomeric and polymeric compositions useful for forming biomedical adhesives and sealants. In particular, the invention relates to monomeric and polymeric compositions for wound closure and the use of these compositions for medical, surgical and other biological applications.

  Products used primarily for wound closure are surgical sutures and staples. It is recognized that the suture material provides adequate wound support. However, the suture material causes additional trauma to the wound site (because the needle and suture material must be passed through the tissue and the wound area must be anesthetized using the needle). And it takes time to be in place and can result in wound closure marks that do not look good at the skin level. Surgical staples have been developed to promote wound attachment and to give cosmetically improved results. However, surgical staples also require additional trauma and the use of often expensive auxiliary means to position and apply the staples. Sutures and staples are both pediatric patients who have a strong fear response and may refuse to cooperate in positioning them in place, and skin tissue is relatively weak and tears. This is especially a problem for older elderly patients.

  Alternatively, an adhesive has been proposed as a wound closure means. One group of such adhesives is α-cyanoacrylate in monomeric form.

  For example, US Pat. No. 5,328,687 to Leung et al., US Pat. No. 3,527,841 to Vikar et al., US Pat. No. 3,722,599 to Robertson et al. See U.S. Pat. No. 995,641 and U.S. Pat. No. 3,940,362. These US patents disclose α-cyanoacrylates useful as surgical adhesives. All the above documents are incorporated herein by reference.

  In a typical example, the cyanoacrylate surgical adhesive is applied to one or both surfaces of the incision, including the wound or wound interior, rapidly removing excess adhesive from the binding surface. The wound edges are then held together until they adhere. See U.S. Pat. No. 3,559,652 to Coober Jr. et al. The adhesive may be applied twice to the wound surface. However, such application methods result in significant levels of tissue toxicity because the surgical adhesive is trapped at the wound site.

  Another method of applying cyanoacrylate surgical adhesive to a wound or incision involves forming a bridge across the wound site. Cut tissue until cyanoacrylate adhesive is applied over the incision and given the time necessary to develop a bond, as described in US Pat. No. 3,667,472 to Halpan. Hold together and maintain a fixed relationship. Excess adhesive is removed from the incision. However, the compositions used in this method result in inadequate film strength and flexibility, as well as significant tissue toxicity at the wound site.

  In general, these conventional methods of applying tissue adhesives do not define a preferred specific method, nor is there any mention of applying a greater than minimum amount of adhesive over the wound. . Conventional application techniques strive to reduce the application of excessive amounts of tissue adhesive to the wound in terms of tissue toxicity.

  A commercially available topical tissue adhesive is Histoacryl® available from B. Braun Melsungen AG, Germany. The manufacturer recommends using this adhesive only to close small skin wounds and not for internal use. In addition, the manufacturer recommends that the adhesive be used sparingly, i.e., as a thin film, which does not increase the film strength of the thick film and also causes necrosis of the surrounding tissue due to an exothermic reaction. It is because it may be invited. Moreover, the film produced from this adhesive is fragile and can cause severe wound dehiscence.

  Conventionally, plasticizers are added to cyanoacrylate surgical adhesives. See, for example, the specifications of US Pat. No. 3,759,264 to Coober Jr. et al., US Pat. No. 3,667,472 to Halpan, and US Pat. No. 3,559,652 to Banit. The contents of these US patent specifications are incorporated herein by reference. However, incorporating a plasticizer into such a composition results in a reduction in film strength of the polymerized material. Accordingly, such compositions are used only within the wound site and are not used to cross the wound site as a bridge.

  Other additives are used in cyanoacrylate surgical adhesives to alter the cure rate and shelf life of the adhesive. For example, cyanoacrylate polymerization inhibitors or Lewis acids such as sulfur dioxide, nitric oxide, boron trifluoride, and other acidic substances including hydroquinone monomethyl ether, hydroquinone, nitrohydroquinone, catechol and hydroquinone monoethyl ether There is a stabilizer. See, for example, Banit US Pat. No. 3,559,652. The contents are added here for reference. Since these compositions contain significant amounts of impurities, a substantial amount of stabilizer is required to inhibit premature polymerization of the monomers.

  Other additives include both plasticizers and stabilizers. For example, US Pat. No. 5,480,935 to Greff et al. Describes a tissue adhesive containing a plasticizer and a polymerization inhibitor. However, the plasticizers (ie, alkyl phthalates) described in this US patent are highly toxic and are not suitable for use in biocompatible medical adhesives.

  The present invention relates to a surgical technique in which the monomers described below are combined with a plasticizing material and an acidic stabilizing material to polymerize after application to a wound or incision to form a strong flexible bond on the wound or incision site. It is based on the finding that an adhesive composition is obtained.

  In addition, the present invention provides a method of applying a surgical adhesive composition as a cross-linked structure that results in a bond strength that is unexpectedly superior to the prior art of applying a polymerized composition over a wound or incision site. This method increases the effectiveness of such monomers and polymers in in vivo applications.

  This surgical adhesive forms a strong bond that is flexible over the wound or incision. Moreover, the inventive method of applying surgical adhesive to a wound or incision produces a strong flexible biocompatible bond.

One aspect of the present invention is:
A) at least one monomer that forms a medically acceptable wound closure polymer;
A wound closure monomer composition is provided comprising B) at least one plasticizing material; and C) at least one acidic stabilizing material.

  In other embodiments, the present invention is directed to the above-described monomers and methods of using the monomers for biomedical purposes.

  In one such embodiment, the wound or incision edges are held together and an excess amount of the above-described surgical adhesive composition is applied to the opposing wound edges that are already pinched, ie in contact. Apply, preferably using more than one application stroke. This method forms a flexible, high tensile strength bridge on the opposing opposing wound edges. Excessive adhesive deposited on the opposing wound edges that come into contact forms a thick film thereon, which increases the film strength unexpectedly.

  For example, in forming a biocompatible film across a contact tissue surface, the present invention includes (a) holding at least two tissue surfaces together to form a contact tissue surface, and (b) Applying an adhesive biocompatible monomer composition across, and (c) polymerizing the monomer composition on the contact tissue surface to provide at least 70 mmHg necessary to induce wound failure. Vacuum pressure, usually 70 mmHg to 400 mmHg vacuum pressure required to induce wound failure, preferably 90 mmHg to 400 mmHg vacuum pressure required to induce wound failure, more preferably required to induce wound failure A biocompatible film having a biofilm strength having a vacuum pressure strength of 100 mmHg to 400 mmHg is formed.

  The monomer is preferably α-cyanoacrylate. The monomer compositions of the present invention and the polymers produced therefrom are useful as tissue adhesives and as anti-bleeding or open wound dressing sealants, and in other biomedical applications. The monomer composition of the present invention and the polymer produced therefrom are, for example, for attaching surgically incised tissue or tissue that has been torn apart by trauma; for reducing fractured bone structures; Used to delay aging; and to help repair and regrowth of living tissue.

  As mentioned above, conventional surgical adhesive compositions contain a plasticizer that adversely affects film strength. In the present invention, contrary to conventional belief, film strength (ie, toughness) is not adversely affected by the addition of relatively large amounts of plasticizing material under certain conditions. I found out. Depending on the particular acidic stabilizing material and monomer purity used in the adhesive composition, the addition of a relatively large amount of plasticizing material can result in increased toughness of the bond formed on the wound. is there. In the present invention, the weakly acidic stabilizing material does not significantly affect the polymerization of the monomer in the monomer composition of the present invention, and increases the film strength as the amount of plasticizing material increases. I found out.

  Monomers that can be used in the present invention are polymerizable, eg, anionic polymerizable or free radical polymerizable, to form a polymer. Such monomers include monomers that form polymers, and the polymers may be biodegradable, but are not necessarily biodegradable. See, for example, US Pat. No. 5,328,687, hereby incorporated by reference. Here, “tissue toxicity” is intended to mean an adverse tissue response such as inflammation caused by the presence of toxic substances in the tissue.

Useful 1,1-disubstituted ethylene monomers include the following formula (I): CHR = CXY
(Wherein X and Y are each a strong electron withdrawing group and R is H, —CH═CH ₂ , or when X and Y are both cyano groups, C _1- but are monomers represented by C ₄ alkyl group), but are not limited to.

Examples of monomers within the scope of formula (I) include the formula CH ₂ ═CX′Y ′ (wherein X ′ is —SO ₂ R ′ or —SO ₃ R ′ and Y ′ is — CN, —COOR ′, —COCH ₃ , —SO ₂ R ′ or —SO ₃ R ′, and R ′ is H or a hydrocarbyl group), α-cyanoacrylate, vinylidene cyanide, vinylidene C ₁ -C ₄ alkyl homologues of cyanides, dialkylmethylene malonates, acylacrylonitriles, vinyl sulfinates and vinyl sulfonates are included.

｛式中のＲ²は、水素原子であり、そしてＲ³は、ヒドロカルビル基または置換ヒドロカルビル基であり；式−Ｒ⁴−Ｏ−Ｒ⁵−Ｏ−Ｒ⁶（式中のＲ⁴は、２〜４個の炭素原子を有する１，２−アルキレン基であり、Ｒ⁵は２〜４個の炭素原子を有するアルキレン基であり、Ｒ⁶は１〜６個の炭素原子を有するアルキル基である）で表される原子団であるか；または式

（式中のＲ⁷は

または−Ｃ（ＣＨ₃）₂−であり、Ｒ⁸は有機基である）で表される原子団である｝で表される。 A preferred monomer represented by formula (I) for use in the present invention is α-cyanoacrylate. These monomers are known in the industry and have the formula

{Wherein R ² is a hydrogen atom, and R ³ is a hydrocarbyl group or a substituted hydrocarbyl group; a formula —R ⁴ —O—R ⁵ —O—R ⁶ (wherein R ⁴ is 2 A 1,2-alkylene group having ˜4 carbon atoms, R ⁵ is an alkylene group having 2-4 carbon atoms, and R ⁶ is an alkyl group having 1-6 carbon atoms ) Or a group represented by the formula

(R ⁷ in the formula is

Or —C (CH ₃ ) ₂ — and R ⁸ is an organic group).

Examples of suitable hydrocarbyl or substituted hydrocarbyl groups include linear or branched alkyl groups having 1 to 16 carbon atoms; acyloxy groups, haloalkyl groups, alkoxy groups, halogen atoms, cyano groups or haloalkyl groups A linear or branched C ₁ -C ₁₆ alkyl group substituted with a linear or branched alkenyl group having 2 to 16 carbon atoms; a straight chain having 2 to 12 carbon atoms; Chain or branched alkynyl groups; cycloalkyl groups; aralkyl groups; alkylaryl groups; and aryl groups.

The organic group R ⁸ can be substituted or unsubstituted and can be linear, branched or cyclic, saturated, unsaturated or aromatic. Such Examples of organic groups, C ₁ -C ₈ alkyl group, C ₂ -C ₈ alkenyl group, C ₂ -C ₈ alkynyl group, C ₃ -C ₁₂ cycloaliphatic radical, a phenyl group and substituted phenyl Aryl groups such as a group, and aralkyl groups such as a benzyl group, a methylbenzyl group and a phenylethyl group are included. Other organic groups include substituted hydrocarbon groups, such as halo substituted hydrocarbon groups (eg, chloro, fluoro and bromo substituted hydrocarbon groups) and oxy substituted hydrocarbon groups (eg, alkoxy substituted hydrocarbon groups). Preferred organic groups are alkyl, alkenyl and alkynyl groups having 1 to about 8 carbon atoms and halo-substituted derivatives thereof. Particularly preferred are alkyl groups having 4 to 6 carbon atoms.

In the cyanoacrylate monomer represented by the formula (II), R ³ is preferably an alkyl group having 1 to 10 carbon atoms or a group represented by the formula -AOR ⁹ (wherein A is 2 to 2). A divalent linear or branched alkylene group or oxyalkylene group having 8 carbon atoms, and R ⁹ is a linear or branched alkyl group having 1 to 8 carbon atoms. It is an atomic group represented by

Examples of the atomic group represented by the formula -AOR ⁹ include 1-methoxy-2-propyl, 2-butoxyethyl, isopropoxyethyl, 2-methoxyethyl and 2-ethoxyethyl.

  Preferred α-cyanoacrylate monomers used in the present invention are 2-octyl cyanoacrylate, dodecyl cyanoacrylate, 2-ethylhexyl cyanoacrylate, butyl cyanoacrylate, methyl cyanoacrylate, 3-methoxybutyl cyanoacrylate, 2-butoxyethyl cyano. Acrylate, 2-isopropoxyethyl cyanoacrylate or 1-methoxy-2-propyl cyanoacrylate.

  The α-cyanoacrylate represented by the formula (II) can be produced by a method known in the industry. For example, see US Pat. Nos. 2,721,858 and 3,254,111, the contents of each of which are incorporated herein by reference. For example, by reacting α-cyanoacrylate with alkyl cyanoacetate and formaldehyde in a non-aqueous organic solvent in the presence of a basic catalyst, and then thermally decomposing the anhydrous intermediate polymer in the presence of a polymerization initiator. Can be manufactured. Α-cyanoacrylate monomers prepared with low moisture and substantially free of impurities are preferred for biomedical use.

An α-cyanoacrylate represented by the formula (II), wherein R ³ is an atomic group represented by the formula —R ⁴ —O—R ⁵ —O—R ⁶ , is represented by Kimura et al. In US Pat. No. 4,364,364. Which can be manufactured by the method disclosed in US Pat. No. 876, the contents of which is incorporated herein by reference. In the method by Kimura et al., Α-cyanoacrylate can be produced by esterifying cyanoacetic acid with alcohol or transesterifying alkyl cyanoacetate with alcohol to obtain cyanoacetate; Paraformaldehyde is condensed in the presence of a catalyst in a molar ratio of 0.5 to 1.5 to 1, preferably 0.8 to 1.2 to 1, to obtain a condensate; the condensation reaction mixture is directly Alternatively, the condensation catalyst is removed and then depolymerized to obtain crude cyanoacrylate; the crude cyanoacrylate is distilled to produce high purity cyanoacrylate.

で表される原子団である、式(II)で表されるα−シアノアクリレートを、Kronenthal等による米国特許第３，９９５，６４１号明細書に開示された方法により製造することができ、この出願の内容を参照のために本明細書中に加入する。Kronenthal等による方法において、このようなα−シアノアクリレート単量体を製造するには、α−シアノアクリル酸のアルキルエステルと環式１，３−ジエンとを反応させて、ディールス−アルダー付加物を生成し、これを次にアルカリで加水分解し、その後酸性化して、対応するα−シアノアクリル酸付加物を生成する。α−シアノアクリル酸付加物を、ブロモ酢酸アルキルによりエステル化して、対応するカルバルコキシメチルα−シアノアクリレート付加物を得るのが好ましい。あるいはまた、このα−シアノアクリル酸付加物を、塩化チオニルとの反応により、ハロゲン化α−シアノアクリリル付加物に転化することができる。次に、このハロゲン化α−シアノアクリリル付加物を、ヒドロキシ酢酸アルキルまたはメチル置換ヒドロキシ酢酸アルキルと反応させて、それぞれ対応するカルバルコキシメチルα−シアノアクリレート付加物またはカルバルコキシアルキルα−シアノアクリレート付加物を得る。最後に、環式１，３−ジエン保護基を除去し、カルバルコキシメチルα−シアノアクリレート付加物またはカルバルコキシアルキルα−シアノアクリレート付加物を、対応するカルバルコキシアルキルα−シアノアクリレートに、付加物をわずかな不足量の無水マレイン酸の存在下で加熱することにより、転化する。 R ³ is the formula

Α-cyanoacrylate represented by formula (II), which is an atomic group represented by the following formula, can be produced by the method disclosed in US Pat. No. 3,995,641 by Kronenthal et al. The contents of the application are incorporated herein by reference. In the method by Kronenthal et al., Such an α-cyanoacrylate monomer can be produced by reacting an alkyl ester of α-cyanoacrylic acid with a cyclic 1,3-diene to obtain a Diels-Alder adduct. Which is then hydrolyzed with alkali and then acidified to produce the corresponding α-cyanoacrylic acid adduct. The α-cyanoacrylic acid adduct is preferably esterified with alkyl bromoacetate to give the corresponding carbalkoxymethyl α-cyanoacrylate adduct. Alternatively, the α-cyanoacrylic acid adduct can be converted to a halogenated α-cyanoacrylyl adduct by reaction with thionyl chloride. The halogenated α-cyanoacrylyl adduct is then reacted with an alkyl hydroxyacetate or methyl-substituted alkyl hydroxyacetate to give the corresponding carbalkoxymethyl α-cyanoacrylate adduct or carbalkoxyalkyl α-cyanoacrylate adduct, respectively. Get things. Finally, the cyclic 1,3-diene protecting group is removed and the carbalkoxymethyl α-cyanoacrylate adduct or carbalkoxyalkyl α-cyanoacrylate adduct is converted to the corresponding carbalkoxyalkyl α-cyanoacrylate. The adduct is converted by heating in the presence of a slight deficiency of maleic anhydride.

（式中のＺは−ＣＨ＝ＣＨ₂であり、Ｒ³は前述の通りである）で表されるα−シアノアクリレートが含まれる。Ｒ³が１〜１０個の炭素原子を有するアルキル基である、式(III) で表される単量体、即ち２−シアノペンタ−２，４−ジエノン酸エステルを、適切な２−シアノアセテートとアクロレインとを、触媒、例えば塩化亜鉛の存在下で反応させることにより、製造することができる。２−シアノペンタ−２，４−ジエノン酸エステルを製造するこの方法は、例えば米国特許第３，５５４，９９０号明細書に開示されており、同出願の内容を参照のために本明細書中に加入する。 Examples of the monomer represented by the formula (II) include cyanopentadienate and the following formula

(Wherein Z is —CH═CH ₂ and R ³ is as described above). A monomer represented by the formula (III) in which R ³ is an alkyl group having 1 to 10 carbon atoms, that is, 2-cyanopenta-2,4-dienoic acid ester is mixed with an appropriate 2-cyanoacetate. It can be produced by reacting acrolein in the presence of a catalyst such as zinc chloride. This method of producing 2-cyanopenta-2,4-dienoate is disclosed, for example, in US Pat. No. 3,554,990, the contents of which are incorporated herein by reference. join.

  Preferred monomers are alkyl α-cyanoacrylates, more preferably octyl α-cyanoacrylate, especially 2-octyl α-cyanoacrylate. The monomers used in the present invention must be very pure and contain little impurities (eg surgical grade).

  Component B) of the composition of the present invention is at least one plasticizing material that imparts flexibility to the polymerized monomer formed on the wound or incision. The plasticizing material preferably contains little or no moisture and should not significantly affect the polymerization of the monomer.

  Examples of suitable plasticizers include acetyl tributyl citrate, dimethyl sebacate, triethyl phosphate, tri (2-ethylhexyl) phosphate, tri (p-cresyl) phosphate, glyceryl triacetate, glyceryl tributylate, sebacin Examples include diethyl acid, dioctyl adipate, isopropyl myristate, butyl stearate, lauric acid, trioctyl trimellitic acid, dioctyl glutarate, and mixtures thereof. Preferred plasticizing materials are tributyl citrate and acetyl tributyl citrate.

  Component C) of the composition of the present invention is at least one acidic stabilizing substance that inhibits polymerization. Such stabilizing materials can also include a mixture of an anionic stabilizing material and a radical stabilizing material.

  Examples of suitable anionic stabilizing materials include sulfur dioxide, sulfonic acid, lactone, boron trifluoride, organic acid, alkyl sulfate, alkyl sulfite, 3-sulfolene, alkyl sulfone, alkyl sulfoxide, mercaptan and alkyl sulfide and These mixtures are included. Preferred anionic stabilizers are acidic stabilizers of organic acids such as acetic acid or phosphoric acid, with acetic acid being a relatively preferred acidic stabilizer. The maximum amount of sulfur dioxide present in the adhesive composition should be less than 50 ppm, preferably less than 30 ppm.

  Examples of suitable radical stabilizing materials include hydroquinone, hydroquinone monomethyl ether, catechol, pyrogallol, benzoquinone, 2-hydroxybenzoquinone, p-methoxyphenol, t-butylcatechol, butylated hydroxyanisole, butylated hydroxytoluene and t- Butyl hydroquinone is included.

Suitable acidic stabilizing agent, from about 0 to about 7, preferably include stabilizing agent having from about 1 to about 6, more preferably from about 2 to about 5.5 ionization constant pK _a. For example, suitable acidic stabilizing materials include: hydrogen sulfide (pK _a 7.0), carbonic acid (pK _a 6.4), triacetylmethane (pK _a 5.9), acetic acid (PK _a 4.8), benzoic acid (pK _a 4.2), 2,4-dinitrophenol (pK _a 4.0), formic acid (pK _a 3.7), nitrous acid (pK _a 3.3) , Hydrofluoric acid (pK _a 3.2), chloroacetic acid (pK _a 2.9), phosphoric acid (pK _a 2.2), dichloroacetic acid (pK _a 1.3), trichloroacetic acid (pK _a 0. 7) 2,4,6-trinitrophenol (picric acid) (pK _a 0.3), trifluoroacetic acid (pK _a 0.2) and mixtures thereof.

  When adding the aforementioned weakly acidic stabilizing material to the adhesive composition, the plasticizing material is in the range of 0.5 to 16 wt%, preferably 3 to 9 wt%, more preferably 5 to 7 wt%. When added in an amount, it has been found that the film strength (eg, toughness) of the polymerized monomer is increased over polymerized monomers in which the amount of plasticizing material and acidic stabilizing material is outside the aforementioned ranges. It was.

  The concentration of acidic stabilizing material used can be varied depending on the strength of the acid. For example, when acetic acid is used, a concentration of 80 to 200 ppm (weight / weight), preferably 90 to 180 ppm (weight / weight), more preferably 100 to 150 ppm (weight / weight) can be used. When using a stronger acid, such as phosphoric acid, a concentration in the range of 20-80 ppm (weight / weight), preferably 30-70 ppm (weight / weight), more preferably 40-60 ppm (weight / weight). Can be used.

  The composition of the present invention is also at least one biocompatible material (also referred to herein as a “formaldehyde concentration reducing agent”) that is effective in reducing the active formaldehyde concentration level produced during biodegradation of the polymer. Can be included. Preferably, this component is a formaldehyde scavenger compound. Examples of formaldehyde scavenger compounds useful in the present invention include: sulfites; bisulfites; mixtures of sulfites and bisulfites; ammonium sulfites; amines; amides; imides; nitriles; carbamates; Mixtures of amines, amides and proteins; active methylene compounds, such as compounds having cyclic ketones and β-dicarbonyl groups; and heterocyclic compounds having no carbonyl groups and NH groups, wherein the ring is nitrogen Composed of atoms or carbon atoms, when the ring is unsaturated or condensed with a phenyl group, it is unsaturated or saturated and the NH group is bonded to the carbon atom or nitrogen atom; A heterocyclic compound in which this atom is directly bonded to another carbon or nitrogen atom by a double bond. It is included.

  Bisulfites and sulfites useful as formaldehyde scavenger compounds in the present invention include alkali metal salts such as lithium, sodium and potassium salts, and ammonium salts such as sodium bisulfite, potassium bisulfite, lithium bisulfite, bisulfite. Ammonium, sodium sulfite, potassium sulfite, lithium sulfite, ammonium sulfite and the like are included.

  Examples of amines useful in the present invention include aliphatic and aromatic amines such as aniline, benzidine, aminopyrimidine, toluenediamine, triethylenediamine, diphenylamine, diaminodiphenylamine, hydrazine and hydrazide.

  Suitable proteins include collagen, gelatin, casein, soy protein, plant protein, keratin and glue. A preferred protein for use in the present invention is casein.

  Amides suitable for use in the present invention include urea, cyanamide, acrylamide, benzamide and acetamide. Urea is the preferred amide.

  Suitable alcohols include phenol, 1,4-butanediol, d-sorbitol and polyvinyl alcohol.

  Examples of suitable compounds having a β-dicarbonyl group include malonic acid, acetylacetone, ethylacetone, acetate, malonamide, diethyl malonate or other malonic esters.

  Preferred cyclic ketones for use in the present invention include cyclohexanone or cyclopentanone.

  Examples of heterocyclic compounds suitable for use as formaldehyde scavengers in the present invention are disclosed, for example, in US Pat. No. 4,127,382 (Perry), the contents of which are hereby incorporated by reference. This is incorporated herein. Such heterocyclic compounds include, for example, benzimidazole, 5-methylbenzimidazole, 2-methylbenzimidazole, indole, pyrrole, 1,2,4-triazole, indoline, benzotriazole, indoline and the like.

  A preferred formaldehyde scavenger for use in the present invention is sodium bisulfite.

  In practicing the present invention, a formaldehyde reducing agent, such as a formaldehyde scavenger compound, is added to the cyanoacrylate in an effective amount. An “effective amount” is an amount sufficient to reduce the amount of formaldehyde generated during the subsequent biodegradation of the polymerized cyanoacrylate. This amount depends on the type of active formaldehyde lowering substance and can be easily determined by one skilled in the art without undue experimentation.

  Formaldehyde concentration-reducing substances can be used in the present invention either in free form or in microencapsulated form.

  During microencapsulation, the formaldehyde-reducing substance is continuously released from the microcapsule over a long period of time during biodegradation of the cyanoacrylate polymer.

  For the purposes of the present invention, a formaldehyde reducing substance in microencapsulated form is preferred. The reason is that in this example, the polymerization of the cyanoacrylate monomer is prevented or significantly reduced by the formaldehyde lowering substance, which increases the shelf life and reduces the monomer composition in use. This is because handling becomes easy.

  Formaldehyde scavenger microencapsulation can be achieved by a number of known microencapsulation techniques. For example, microencapsulation can be achieved by dissolving the coating polymer in a volatile solvent such as methylene chloride to a polymer concentration of about 6% by weight; the formaldehyde scavenger compound in particulate form into the coating polymer / solvent solution. Add with stirring to obtain a scavenger concentration of 18% by weight; slowly add the surfactant-containing mineral oil solution to the polymer solution while stirring rapidly; allow the volatile solvent to evaporate while stirring; remove the agitator; This can be done by separating the solid from the mineral oil; washing the microparticles and drying. The size of the microparticles is in the range of about 0.001 to about 1000 microns.

  The coating polymer for microencapsulating formaldehyde reducing substances should be a polymer that is subject to biocorrosion in the organism, preferably at a rate similar to or higher than that of the cyanoacrylate polymer formed by the monomer. Must have a low intrinsic moisture content. Such “biocorrosion” is a result of physical or chemical degradation of the encapsulated material, such as the transition of the encapsulated material from a solid to a solute in the presence of body fluids, or the production of the encapsulated material by materials present in the body. May occur due to degradation.

  Examples of coating materials that can be used to microencapsulate formaldehyde reducing substances include polyesters such as polyglycolic acid, polylactic acid, copolymers of polyglycolic acid and polylactic acid, polycaprolactone, poly-β -Hydroxybutyrate, copolymer of ε-caprolactone and δ-valerolactone, copolymer of ε-caprolactone and DL-dilactide and polyester hydrogel; polyvinylpyrrolidone; polyamide; gelatin; albumin; protein; collagen; Poly (anhydride); poly (alkyl-2-cyanoacrylate); poly (dihydropyran); poly (acetal); poly (phosphazene); poly (urethane); poly (dioxynone); cellulose; and starch But Murrell.

  Examples of surfactants that can be added to mineral oil include those commercially available under the designations Triton x-100, Tween 20 and Tween 80.

  The composition of the present invention may further comprise one or more auxiliary substances, such as thickeners, drugs, etc., to improve the medical usefulness of the monomer for a particular medical use. it can.

  Suitable thickeners include, for example, polycyanoacrylate, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, polycaprolactone, lactic acid-caprolactone copolymer, poly-3-hydroxybutyric acid, polyorthoester Polyalkyl acrylates, copolymers of alkyl acrylates and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl methacrylates and butadienes.

  In order to improve the cohesive strength of the adhesive formed from the composition of the present invention, a bifunctional monomer crosslinking agent can be added to the monomer composition of the present invention. Such crosslinkers are known. See, for example, Overhults US Pat. No. 3,940,362, the contents of which are incorporated herein by reference. Examples of suitable crosslinkers include alkyl bis (2-cyanoacrylate), triallyl isocyanurate, alkylene diacrylate, alkylene dimethacrylate, trimethylolpropane triacrylate and alkyl bis (2-cyanoacrylate). A catalytic amount of amine activated free radical initiator is added to initiate polymerization of the cyanoacrylate monomer / crosslinker blend.

  The compositions of the present invention can further comprise fibrous reinforcements and colorants, i.e. dyes and pigments. Examples of suitable fibrous reinforcements include PGA microfibrils, collagen microfibrils, cellulosic microfibrils and olefinic microfibrils. Examples of suitable colorants include 1-hydroxy-4- [4-methylphenylamino] -9,10-anthracenedione (D + C violet No. 2); 6-hydroxy-5-[(4-sulfophenyl) Axo] -2-naphthalenesulfonic acid disodium salt (FD + C yellow No. 6); 9- (o-carboxyphenyl) -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-indole-2-ylidene) -2,3-dihydro-3-oxo -1H-indole-5-sulfonic acid disodium salt (FD + C Blue No. 2); and [phthalocyaninato (2-)] copper.

  Using the composition of the present invention, two surfaces can be joined by applying the composition of the present invention to the opposing wound surfaces to be joined. Depending on the specific requirements of the user, the adhesive composition of the present invention can be applied by known means such as a glass stir bar, sterile brush or drug drop bottle. However, in many situations, a pressurized aerosol dispensing package is preferred, where the adhesive composition is a solution containing a compatible anhydrous blowing agent.

  In one embodiment, the present invention is a method of joining two surfaces of a living body, comprising: (a) joining the wound or incision tissue surfaces to form a contact tissue surface; (b) the contact tissue described above The composition of the present invention on the surface, for example 1) at least one monomer (for example a monomer represented by formula (I)) forming a medically acceptable polymer, 2) a plasticizing material and 3) Applying a composition comprising a suitable acidic stabilizing substance; (b) holding these surfaces in contact until the composition is polymerized.

  As noted above, conventional surgical adhesive compositions are applied to the wound surface in very small amounts prior to contacting the surface, with care being taken to remove excess adhesive. It was. Thick films formed on the wound surface have, in the past, increased tissue toxicity of the wounded tissue, increased film brittleness, and did not increase film strength.

  However, the present invention applies the two tissue surfaces of the living body to the already contacted tissue surface of the wound or incision, preferably the composition of the present invention, preferably in one or more applications or applications on the contact tissue surface. It is related with the method of joining by doing. Excess adhesive applied directly on the surface of the contact tissue or applied in the immediate vicinity of the wound or incision should preferably not be removed, but adhesive applied excessively to the surrounding tissue not near the wound area May be removed.

  The next coating can be applied immediately after applying the previous coating or after the previous coating is fully polymerized. Preferably, the monomer composition applied to the contact tissue surface is allowed to stand and then at least partially polymerize prior to applying or applying additional monomer composition. A coating of the adhesive composition of the present invention having a monomer different from the monomer of the first or previous coating can be applied as the second or subsequent coating. Due to the addition of plasticizing material and acidic stabilizing material, the polymer formed on the contact tissue surface has sufficient adhesion strength and flexibility even at significantly larger film thicknesses or coating thicknesses. . Suitable film thickness is 0.1 mm to 2.0 mm or 3.0 mm or thicker, preferably 0.2 mm to 1.5 mm, and even more preferably 0.4 to 0.8 mm. Is within the range.

  In another example, the present invention relates to a method for joining two tissue surfaces of a living body by applying the adhesive composition of the present invention using various applicators. Such applicators include breakable swab applicators, syringes with various dispensing nozzles or tips or glass bottles.

  For example, the applicator tip can be removable from the applicator container that holds the polymerizable and / or crosslinkable material. Such applicator tips can be attached to the applicator container before use and removed from the applicator container after use to prevent premature polymerization or crosslinking of unapplied substances in the applicator container. it can. At this point, the applicator tip can be discarded and a new applicator tip can be attached to the applicator container for later use or the applicator tip can be reused.

  Furthermore, the applicator tip according to the invention can be composed of a number of parts, at least one part having an initiator. For example, the component comprising the initiator can be manufactured separately from other components (one or more) of other applicator chips and assembled prior to installation of the applicator container.

  The applicator tip can also be in the form of a nozzle for atomizing a liquid polymerizable and / or crosslinkable substance. Conical nozzles, flat nozzles or condensed flow nozzles are preferred.

  The applicator chip according to the present invention can be used in various apparatuses. For example, manual application methods can include the use of handheld devices such as syringes, adhesive pushers, pipettes, droppers and the like.

  The applicator tip and applicator container may be an integral unit. The unitary unit can be preformed as a single piece and loaded with a polymerizable and / or crosslinkable material. After applying the polymerizable and / or crosslinkable material from the applicator container, the integral unit can be discarded. Also, such an integrated unit of applicator tip and applicator container can be configured to have the ability to refill new materials as a multi-use device.

  The applicator tip can be composed of any of various materials such as polymer materials such as plastics, foams, rubber, thermosetting resins, films or thin films. The applicator chip can be made of a material such as metal, glass, paper, ceramics, and cardboard. The applicator tip material can be porous, adsorbent or absorbent to enhance and facilitate the loading of initiator on or within the applicator tip. For example, the applicator tip can be composed of a material having random porosity, a honeycomb-like material, a material having a woven pattern, or the like. The degree of porosity varies depending on the substance used.

  The applicator tip according to the present invention can have an elongated tubular portion where it comes into contact with the applicator container, and the polymerizable and / or crosslinkable substance mixed from the tubular portion can be discharged outward. . The applicator tip portion immediately downstream of the applicator vessel is advantageously porous to avoid a sudden pressure drop and to ensure a constant mixing ratio profile. Such a structure can suitably collect all obstacles or substances used to separate a large number of components inside the applicator container. Thus, all such obstacles do not block the device.

  The initiator that initiates polymerization and / or crosslinking of the polymerizable and / or crosslinkable material can be applied to the entire surface or one surface portion of the applicator tip, including inside and outside the applicator tip. Alternatively, the initiator can be coated only on the inner surface of the applicator tip. It is preferred that only a portion of the interior of the applicator tip is coated with the initiator.

  The initiator on the applicator chip may be in a solid form such as a powder or a solid film, or in a liquid form such as a viscous substance or a paste-like substance. The initiator can also contain various additives such as surfactants or emulsifiers. Preferably, the initiator is soluble in the polymerizable material and / or the crosslinkable material and / or comprises or is accompanied by at least one surfactant and the surfactant In an embodiment, the initiator helps co-elute with the polymerizable material and / or the crosslinkable material. In embodiments, the surfactant can help the initiator dissolve in the polymerizable material and / or the crosslinkable material.

  The particular initiator for a particular system can be readily selected by one skilled in the art without the need for undue experimentation. Suitable initiators include detergent compositions, surfactants such as nonionic surfactants such as polysorbate 20 (eg Tween 20®), polysorbate 80 (eg Tween 80®) and poloxamers, cationic surfactants Agents such as benzalkonium chloride and tetrabutylammonium bromide, anionic surfactants such as sodium tetradecyl sulfate, and amphoteric or bipolar surfactants such as dodecyldimethyl (3-sulfopropyl) ammonium hydroxide, inner salts, amines, Imines and amides such as imidazole, tryptamine, urea, arginine and povidone, phosphines, phosphites and phosphonium salts such as triphenylphosphine and triethyl phosphite, alcohols such as ethylene glycol , Methyl gallate, ascorbic acid, tannin and tannic acid, inorganic bases and salts such as sodium bisulfite, magnesium hydroxide, calcium sulfate and sodium silicate, sulfur compounds such as thiourea and polysulfides, cyclic ethers of polymers such as monensin, Nonactin, crown ethers, calixarene and polymeric epoxides, cyclic and acyclic carbonates such as diethyl carbonate, phase transfer catalysts such as Aliquat 336, organometallics such as cobalt naphthenate and manganese acetylacetoacetate, and free radical initiators And free radicals such as, but not limited to, di-t-butyl peroxide and azobisisobutyronitrile. Polymeric and / or crosslinkable materials are inactive until activated by a catalyst or accelerator in the applicator tip (included within the term “initiator” as used herein). Agents can also be included. Initiators that are activated by stimuli such as heat and / or light (eg ultraviolet light or visible light) are also suitable if the applicator tip and / or applicator is suitably exposed to such stimuli. .

  The initiator can be applied to the surface of the applicator tip or can be impregnated or introduced into the parent or internal portion of the applicator tip. For example, the initiator can be administered to the applicator tip by spraying, dipping or brushing a liquid medium containing the initiator onto the applicator tip. Liquid media include non-aqueous solvents such as ether, acetone, ethanol, pentane or mixtures thereof, or aqueous solutions. It is preferred that the liquid medium is a low boiling point solvent.

  A suitable applicator for administering the adhesive of the present invention is that described in the corresponding US patent application Ser. No. 08 / 488,411, the subject matter of which is incorporated herein by reference. . A suitable applicator is a breakable swab applicator.

  A specific method in which the adhesive composition of the present invention can be used is to hold and contact the ends of the damaged biological tissue together in contact to prevent fluid from escaping from the damaged biological tissue. A method of repairing damaged biological tissue by applying the monomer composition of the present invention to the tissue and polymerizing the monomer composition, and holding the damaged area of the blood vessel together In order to promote the healing of weak or broken bone by applying the monomer composition of the present invention to the region and polymerizing the monomer composition to stop blood flow from blood vessels There is a method of bonding bone tissue by holding damaged bone tissue together, applying the monomer composition of the present invention to the damaged tissue, and polymerizing the monomer composition.

  Damaged tissue repair (eg, for bleeding control) is usually exposed by applying a sponge to remove surface fluid and holding the damaged tissue surfaces together in contact. Applying the monomer composition of the present invention to the contacted tissue. The monomer composition of the present invention is polymerized while being in contact with the contacting tissue surface to form a thin polymer film. Tissues that are not bleeding or that are not covered with body fluids do not need to be first sponged. The monomer composition can be applied or applied more than once to the contacting tissue surface.

  The monomers of the present invention readily polymerize into addition polymers and copolymers, which are usually optically transparent (as a film).

  In most binding applications using the composition of the present invention, the monomer is contact polymerized by a small amount of moisture on the surface of the adherend, so that the required tissue binding or hemostasis is achieved by blood and other body fluids. Progress well in the presence of. The formed bone has sufficient flexibility and strength to withstand the normal movement of the tissue. Also, the bond strength is maintained as natural wound healing progresses.

  The composition used in the present invention is preferably sterilized by an ordinary method such as an autoclave or an aseptic filtration technique, and the sterilization ordinary method is not limited to an autoclave or an aseptic filtration technique.

Examples I-VI
The composition according to the invention is prepared using a conventional mixing device. For example, the preparation process is performed as follows.

  To the surgical grade cyanoacrylate in the round bottom flask is added plasticizer, acid stabilizer and other ingredients as noted here. The mixture thus produced is mechanically stirred until homogeneous.

  Hereinafter, the present invention will be further described with reference to the following examples, but the present invention is not limited to these examples.

  In the following examples, various amounts of plasticizer (ie, acetyl tributyl citrate) are used in the adhesive composition of the present invention to illustrate the effect on the strength of the bond produced by the adhesive.

The data shown in Table I was created using the following method.
1.5 1/2 inch x 5 1/2 inch latex sheet (1/16 inch thick) was made with a 2 inch incision.
2. The adhesive composition (i.e. 2-octyl cyanoacrylate) was applied topically to the incision using a breakable swab with an initiated chip. The incision interface should not be inadvertently applied with adhesive.
3. After curing for 1 hour, the sheet was fixed between two plexiglasses. The lower glass plate had a pressure transducer and a gas inlet. The upper glass plate is 3 in the center
It had 5/8 inch holes. The specimens were placed with the adhesive side facing the top plexiglass with a 35/8 inch hole.
4). The test substance was pressed by opening the gas flow control valve. The pressure was increased until it broke.
5). The peak pressure was recorded by a pressure transducer and recorded on a chart recorder. Ten measurements were recorded for one test substance.
The results were as follows.

Examples VII-X
To clearly illustrate the unexpected superiority of the biofilm strength afforded by the adhesive composition and method of application according to the present invention, for wound closure and topical administration with respect to various surgical wound closure closure devices. Various methods and materials were evaluated (Examples VII-X). Biofilm strength is objectively determined by the amount of maximum pressure required to induce wound failure (ie, the amount of vacuum pressure required to open the wound). This biomechanical analysis was performed using Dimensional Analysis Systems (DAS) from Dimensional Analysis Systems of Leonia, NJ. This technique is specifically designed for objective in vivo biomechanical characterization of linear incision wounds. In contrast to previous biomechanical analysis (eg uniaxial tensiometer), DAS applies multiaxial stress to the wound, which is more similar to the stress experienced in clinical symptoms. Also, DAS does not require manual manipulation or destructive dissection of the specimen tissue prior to treatment. Thus, a sensitive and reproducible measurement of fragile wounds is obtained in the early phase of healing. In addition, DAS eliminates all the man-made structural errors and experimental variations caused by non-viable tissue samples, inconsistent variations in sample size, and methods of excision of crack edges from tissue excision.

  Male Sprague Dawley rats were selected for animal models because of their genetic homogeneity, ease of handling and containment, and their general generality as a linear incision wound model, and other similar studies. Comparison data for This model is widely used for incisional wound studies well documented in the literature.

  Male Sprague Dawley rats purchased from Harlan Sprague Dawley, Indianapolis, Indiana, were used for the study. All animals were kept for 7 days prior to treatment for food and behavioral stabilization. Four groups (Groups A to D) of rats with different wound closure methods and / or surgical adhesive in each group were tested under the same conditions. Each specimen was tested for film strength 1 hour after closure of the linear incision wound.

Example VII
Group 1 rats, designated Group A, used the one-stroke technique for tissue adhesive application. An adhesive of the present invention having about 6% by weight plasticizer and acetic acid dissolved in 2-octyl α-cyanoacrylate as an acidic stabilizer (pK _a = 4.8) was formed into a swab tip (destructible swab applicator). ) And was passed in a one-stroke manner for topical administration along the opposing wound edges.

Example VIII
A second group of rats, defined as group B, closed the linear incision using the same adhesive by a multi-stroke technique. The adhesive was passed more than once in a multi-stroke manner using a compressible ampoule along the opposing wound edges, resulting in 2-3 distinct applications of the adhesive.

Example IX
Group 3 rats, designated Group C, closed the linear incision with the same adhesive using minimal surface exposure techniques. Under an attempt to limit the amount of adhesive exposed on the skin surface, the adhesive is applied by applying approximately 3-4 drops using a Uniject® syringe available from Horizon, Santa Ana, Calif. Adhesive was applied only to the wound edges.

Example X
In a fourth group of rats, referred to as Group D, a linear incisional wound is available from Histoacryl® (available from B. Brown Melsangen, Germany) using the application technique of Example IX. The surgical adhesive).

  The results obtained from in vivo bioanalysis are shown in Table II below. As shown in Table II, there are significant differences between all groups in the 1 hour studied. Group B, the multiple motion technique, demonstrates a significant increase in final pressure compared to Group A and Group C. This data shows that: increasing the amount of adhesive allows higher in vivo strength. Group D reveals a very high increase in in vivo strength compared to all groups evaluated.

Example XI
The efficiency of the same tissue adhesive as the tissue adhesive according to the present invention was tested for its ability to close skin incisions in a pig model. The tissue adhesive Histoacryl® was used as a control.

Incisions were made on either side of the back of these pigs to a controlled depth for the incision using a sterile knife blade. The incision was closed using either the test substance or the control substance. The same adhesive as that of the present invention introduced in the applicator is polymerized at the opposing contacting ends of the wound (ie, the adhesive is no longer sticky to the contact) Applied. The applicator is a transparent and flexible plastic cylinder with an absorbent head (grinding swab). Within this cylinder was a glass bottle containing an adhesive that was broken by tightening the cylinder. When the applicator was inverted, the adhesive was squeezed from the cylinder into the head and then onto the skin. Histacryl (registered trademark) was also applied using an applicator, which was a sealed plastic ampoule with a narrow neck. This ampoule was attached to a 27 gauge hypodermic needle. The ampoule was turned upside down and the adhesive was applied by tightening the ampoule and dropping a drop from the end of the needle onto the opposite end of the cut. Care was taken that the tip of the needle did not touch the skin. A method for applying histoacryl® was described by J. Quinn and J. Kissick (1994, “Tissue adhesives for laceration repair during sporting events”, Clin. J. Sport Med., 4: 245-248. ).

  Frequent observations during the recovery phase, recorded approximately 4 hours after surgery and then daily, confirming that all incisions were partially separated (dehiscence) or completely separated (dehiscence), and It was measured whether there was an adverse tissue response. If the wound opened during the observation period, it was not closed again.

  Pigs were observed for 10 days for wound dehiscence. No dehiscence was observed in cuts closed with the adhesive according to the present invention. Partial or complete dehiscence was observed in 7 out of 12 incisions closed with Histoacryl®. No complications such as infection or necrosis were observed.

Claims (14)

A biocompatible monomer composition for forming a film that bonds together biological tissue surfaces, the following AC:
A. At least one monomer forming a medically acceptable polymer;
B. C. at least one plasticizing material present in the composition in an amount of 0.5% to 9% by weight of the composition; Comprising at least one acidic stabilizing substance, wherein the film comprises the following (a) to (c):
(A) holding at least two tissue surfaces together to form a contact tissue surface;
(B) by applying the composition across the contact tissue surface; and (c) polymerizing the composition and then forming the film on the contact tissue surface. A composition, wherein the film has a thickness of 0.1 mm or greater and the film has a higher film strength than a thinner film.   The plasticizing material is acetyl tributyl citrate, dimethyl sebacate, triethyl phosphate, tri (2-ethylhexyl) phosphate, tri (p-cresyl) phosphate, glyceryl triacetate, glyceryl tributylate, diethyl sebacate, adipine The composition of claim 1 selected from the group consisting of dioctyl acid, isopropyl myristate, butyl stearate, lauric acid, trioctyl trimellitic acid, dioctyl glutarate and tributyl citrate.   3. A composition according to claim 1 or 2, wherein the plasticizing material is selected from the group consisting of acetyl tributyl citrate, tributyl citrate and mixtures thereof.   The monomer is 2-octyl cyanoacrylate, dodecyl cyanoacrylate, 2-ethylhexyl cyanoacrylate, butyl cyanoacrylate, methyl cyanoacrylate, 3-methoxybutyl cyanoacrylate, 2-butoxyethyl cyanoacrylate, 2-isopropoxyethyl cyano. The composition according to any one of claims 1 to 3, which is an acrylate or 1-methoxy-2-propylcyanoacrylate.   The composition according to any one of claims 1 to 4, wherein the composition contains at least two different monomers. A film for bonding biological tissue surfaces together, wherein the film comprises the following (a) to (c):
(A) holding at least two tissue surfaces together to form a contact tissue surface;
(B) A composition is applied across the contact tissue surface and the composition comprises the following AC:
A. At least one monomer forming a medically acceptable polymer;
B. C. at least one plasticizing material present in the composition in an amount of 0.5% to 16% by weight of the composition; At least one acidic stabilizing material; and (c) made by a method comprising polymerizing the composition and then forming the film on the contact tissue surface, A film characterized in that the film has a thickness of 0.1 mm or thicker and said film has a higher film strength than a thinner film. A film for bonding biological tissue surfaces together, wherein the film comprises the following (a) to (c):
(A) holding at least two tissue surfaces together to form a contact tissue surface;
(B) A composition is applied across the contact tissue surface and the composition comprises the following AC:
A. At least one monomer forming a medically acceptable polymer;
B. C. at least one plasticizing material present in the composition in an amount of 0.5% to 16% by weight of the composition; At least one acidic stabilizing material; and (c) made by a method comprising polymerizing the composition and then forming the film on the contact tissue surface, A film characterized in that the film has a film strength of withstanding the pressure required to open a wound of at least 70 mmHg.   8. A film according to claim 6 or 7, wherein the composition is applied more than once across the contact tissue surface.   9. A film according to any one of claims 6 to 8, wherein the composition applied across the contact tissue surface is at least partially polymerized prior to subsequent application or application of the composition.   The film according to claim 8 or 9, wherein a composition having a monomer different from the monomer of the previous coating is applied as a subsequent coating.   The film according to any one of claims 6 to 10, wherein the film has a thickness of up to 3.0 mm.   12. A film according to any one of claims 6 to 11, wherein the film has a strength to withstand the pressure required to open a wound of at least 90 mmHg.   13. The film of claim 12, wherein the film is strong enough to withstand the pressure required to open a wound of at least 100 mmHg.   The film according to any one of claims 6 to 13, wherein the method further comprises sterilizing the composition.