Cyanoacrylate Compositions Comprising an Antimicrobial Agent

 US005684042A United States Patent [191 [11] Patent Number: 5,684,042 Grefi‘ et al. [45] Date of Patent: Nov. 4, 1997 [54] CYANOACRYLATE COMPOSITIONS FOREIGN PATENT DOCUMENTS COMPRISING AN AN ITMICROBIAL AGENT W0 96,3532 8/1996 WIPO . [75] Inventors: Richard J. Grelf St Pete Beach, Fla; - Michael M. Byraim, Colorado Springs, OTHER PUBLICATIONS C010‘ Ritter, M.A., et a1., “Retrospective Evaluation of an _ _ _ , iodophor—Incorporated Antimicrobial Plastic Adhesive [73] Asslgnec‘ gtfiggigf (é?)l££°mu°n’ Wound Drape”—Clinical Orthopedics and Related ’ ‘ Research, (1986) pp. 307-308. _ Sidorova, et a1., “Preventing Incompetence of Uterine [21] AP P 1' No" 781’409 Sutures after Ceasarian Section”, Akusherstvo I. [22] Filed: Jan. 10, 1997 Ginekologiia, (Mar. 1989) 3:30-33 (Abstract Only). 5 _ Timokhina, V.I., “Biological Properties of New Adhesion [:1] Int. Cl. ........................ .. A01N Compositions of Medical Purpose”, Biodcstmkfimysshchve E58} Fe” is rd] 558/443’ 514/527 Polim. Mater. (1932) 55-61 (Abstract Only). 1 0 ea ............................ .. ; ‘ ' . Primary Examiner—Johann Richter [56] Refemnces cued Assistant Examiner—Ebenezer Sackey U.S. PATENT DOCUMENTS Attomey, Agent, or Finn—Burns, Doane, Swecker & 2,734,127 3/1957 Joyner eta]. ........................... .. 154/43 Math1S’L'L'P' 4,374,126 2/1983 Cardarelli ct al. 424/81 [57] ABSTRACT 4,542,012 9/1985 Dell . . . . . . . . . . . . . . . . . . . . . . . . .. 424/28 4,713,235 12/1987 . . . . . . . . . . . . . . . . .. 424/5 Disclosed are cyanoacrylate compositions comprising a 2,3335% Einntsliutiat 31 al (8) compatible antimicrobial agent and, in particular, a compat- 5,0513% 9/1991 B 311853 3* -----424/402 ible iodine .(j::n§:a1n1ng antimficrobial agept. These compgsgi ’ , """"" " tions provi or in situ ormation 0 an antimicro i 5,069,907 12/1991 Mixon et al 424/445 ~ - - 5,328,687 7/1994 Leung at al 424n8.35 polymeric cyanoacrylate film on mammalian skin. 5,480,935 1/1996 Grefl’ et al. . ..... .. 524/776 5,547,662 8/1996 Khan et al. ........................ .. 424/78.03 6 Claims, No Drawings Q Q 5,684,042 1 CYANOACRYLATE COMPOSITIONS COMPRISING AN ANTIMICROBIAL AGENT BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention is directed to cyanoacrylate compositions comprising a compatible antimicrobial agent and, in particular, an iodine containing antimicrobial agent. These compositions provide for in situ formation of antimicrobial polymeric cyanoacrylate films on mammalian skin which films are useful as wound dressings, wound bandages, surgical incise drapes, wound closure materials which replace sutures, and the like. REFERENCES The following publications, patent applications and pat- ents are cited in this application as superscript numbers: 1 Hawkins, et al., U.S. Pat No. 3,591,676, for Surgical Adhesive Compositions, issued Jul. 6, 1971 2 Ha1pern,et al., U.S. Pat. No. 3,667,472, for Adhesive for Living Tissue, issued Jun. 6, 1972 3 Mclntire, et at., U.S. Pat. No. 3,654,239, for Process for the Preparation of Poly(ot-Cyanoacrylates), issued Apr. 4, 1972 4 Barley, et al., International Patent Application Publication No. WO 93/25196, for Methods for Treating Non- Suturable Wounds by Use of Cyanoacrylate Adhesives, published Dec. 23, 1993 5 Barley, et al., Methods for Treating Suturable Wounds by Use of Sutures and Cyanoacrylate Adhesives, U.S. Pat. No. 5,254,132, issued Oct. 19, 1993 6 Barley, et al., U.S. Pat No. 5,653,789, for Methods for Reducing Skin Irritation From Artificial Devices by Use of Cyanoacrylate Adhesives, filed Feb. 24, 1994 7 Rabinowitz, et al., U.S. Pat. No. 3,527,224, for Method of Surgically Bonding Tissue Together, issued Sep. 8, 1970 3 Kronenthal, et al., U.S. Pat. No. 3,995,641, for Surgical Adhesives, issued Dec. 7, 1976 9 Davydov, et al., U.S. Pat. No. 4,035,334, for Medical Adhesive, issued Jul. 12, 1977 1° Waniczek, et al., U.S. Pat. No. 4,650,826, for Stabilized Cyanoacrylate Adhesives Containing Bis—Trialkylsi1y1 Esters of Sulfuric Acid, issued Mar. 17, 1987 11 Askill, et al., U.S. patent application Ser. No. 08/7 81,279 filed concurrently herewith as Attorney Docket No. 026446-074 and entitled Methods for Draping Surgical Incision Sites 12 Gretf, et al., U.S. Pat. No. 5,480,935, for Cyanoacrylate Adhesive Compositions, issued Jan. 2, 1996 13 Hagen, et al., “A Comparison of Two Skin Preps Used in Cardiac Surgical Procedures”, AORN Journal, 62(3) 2393-402 (1995) 4 Ritter, et al., “Retrospective Evaluation of an Iodophor- Incorporated Antimicrobial Plastic Adhesive Wound Drape”, Clinical Orthopedics and Related Research, pp. 307-308 (1988) 15 Osuua, et al., “Comparison of an Antimicrobial Adhesive Drape and Povidone-Iodine Preoperative Skin Prepara- tion in Dogs”, Veterinary Surgery, 2l(6):458—462 (1992) 1‘ O’S11llivan, et al., U.S. Pat. No. 4,038,345, for High Viscosity Cyanoacrylate Adhesive Compositions, and Process for Their Preparation, issued Jul. 26, 1977 17 Beller, et al., U.S. Pat. No. 2,706,701, for Process for the Preparation of lodine-Polyvinylpyrrolidone by Dry Mixing, issued Apr. 19, 1955 10 20 25 30 35 45 50 55 65 2 18 Hosmer, U.S. Pat. No. 2,826,532, for Process of Stabi- lizing Polyvinylpyrrolidone, issued Mar. 11, 1958 19 Siggin, U.S. Pat No. 2,900,305, for Preparation of Iodine Polyvinylpyrrolidone Adducts, issued Aug. 18, 1958 2° Joyner, et al., U.S. Pat. No. 2,784,127, for Plasticized Monomeric Adhesive Compositions and Articles Pre- pared Therefrom, issued Mar. 5, 1957 21 Columbus, et al., U.S. Pat. No. 4,444,933, for Adhesive Cyanoacrylate Compositions with Reduced Adhesion to Skin, issued Apr. 24, 1984 22 Leung, et al., U.S. Pat. No. 5,328,687, for Biocompatible Monomer and Polymer Compositions, issued Jul. 12, 1994 23 Byram, et al., U.S. Pat. No. 5,554,365, for Use of Cyanoacrylate Adhesive Compositions to Inhibit Acute Radiation-Induced Skin Damage, issued Sep. 10, 1996. 2‘ Leplyanin, International Application Publication N 0. WO 96/23532 for ‘Medical and Surgical Adhesive Composi- tion and Process for Its Preparation”, published Aug. 8, 1996 25 Tighe, et al., U.S. Pat. No. 5,580,565, for “Use of Cyanoacrylate Adhesives For Providing A Protective Bar- rier Film For The Skin”, issued on Dec. 3, 1996. All of the above publications, patent applications and patents are haein incorporated by reference in their entirety to the same extent as if each individual publication, patent application or patent was specifically and individually indi- cated to be incorporated by reference in its entirety. STATE OF THE ARI‘ Cyanoacrylate esters have been disclosed for a variety topical uses on mammalian skin including use as a replace- ment for sutures or staples in closing the dermal layer of an incision after surgery.1’2’5 Other disclosed topical uses include use as a hemostat3, use in covering small non- suturable wounds on skin surfaces‘, use in inhibiting surface skin irritation arising from friction between the skin surface and artificial devices such as tapes, prosthetic devices, casts, etc.5 and use in inhibiting acute radiation-induced skin damage”. Still another topical use of cyanoacrylate esters is its use in the in situ formation of a surgical incise drape“. Cyanoacrylate esters heretofore suggested for such uses include the following structures: 0 I ll CH2=C[I-COR CN wherein R is an alkyl or other suitable substituent. Such cyanoacrylate esters are disclosed in U.S. Pat Nos. 3,527, 224; 3,591,676; 3,667,472; 3,995,641; 4,035,334; and 4,650,826.1’2’7"° Cyanoacrylate ester compositions for topical sldn appli- cation typically are formulated to contain both a plasticizer to enhance flexibility of the resulting polymeric film and a polymerization inhibitor to avoid premature polymerization of the composition. When employed topically on mamma- lian skin, Grefi et al.” disclose that the cyanoacrylate composition preferably employs from about 50 to about 500 ppm sulfur dioxide as the polymmization inhibitor and from about 18-25 weight percent of a biocompatible plasticizer such as dioctyl phthalate. Notwithstanding the beneficial properties associated with such cyanoacrylate compositions and their suitability for topical applications, these compositions do not possess a sufliciently broad spectrum of antimicrobial activity includ- Q 5,684,042 3 ing activity against microbial spores and, accordingly, can- not guarantee reductions in microbial populations on matu- malian skin surface either under or adjacent a polymeric cyanoacrylate film formed in situ on the skin. Many of the uses of cyanoacrylate adhesives enumerated above would, however, significantly benefit by a broad spectrum of anti- microbial property in the polymer film. For instance, coveting small non-suturable wounds on skin surfaces with a polymeric cyanoacrylate film having a broad spectrum of antimicrobial activity would mitigate against possible wound infection. Likewise, when used as a surgical (incise) drape, such films would reduce microbial populations under and adjacent to the drape including those at the incision site and, accordingly, would reduce the risk of post-operative infection. Such is the basic premise of com- mercial surgical drapes containing an antimicrobial agent impregnated directly into the adhesive layer thereof where it was hoped that this agent, when bound to the skin, would be released onto the skin surface to inhibit microbe growth.13”4 Osuna, et al.” report, however, that the adhesive does not 20 release suflicient amounts of the impregnated agent to be, by itself, antimicrobial. Without being limited to any theory, it is believed that the antimicrobial agent is too strongly bound onto/into the adhesive to be released onto the skin andlor that there is insufiicient skin surface contact between the adhesive and the skin to effect release of a sufiicient amount of antimicrobial agent. As noted above, cyanoacrylates are not sufiiciently anti- microbial and, accordingly, incorporation of broad antimi- crobial properties into me cyanoacrylate polymeric film necessitates, of course, that an antimicrobially efiective amount of an antimicrobial agent be incorporated into the cyanoacrylate composition and that suflicient amounts of this agent be released from the polymeric cyanoacrylate film V such that an antimicrobial etfect is achieved. The incorpo- ration of such an antimicrobial agent into the cyanoacrylate composition is problematic at best because several disparate criteria must be simultaneously met. First, the antimicrobial agent must be soluble or dispersible in the cyanoacrylate composition at the concentrations necessary to etfect anti- microbial properties. Second, the antimicrobial agent employed must not cause premature polymerization of the cyanoacrylate adhesive. Third, the antimicrobial agent employed must not prevent in situ polymerization of the cyanoacrylate composition when applied to the skin. Fourth, the antimicrobial agent must be compatible with the intended use of the polymeric film by not inhibiting forma- tion of a flexible, durable film. Fifth, the impregnated antimicrobial agent must be released from the polymerized film in situ on the patient’s sldn in sufficient amounts to be antimicrobial. Because of these disparate properties, many conventional antimicrobial agents are unsuitable for use in the composi- tions of this invention. However, in View of the clear benefits associated with the incorporation of an antimicrobial agent directly into the monomeric cyanoacrylate composition, there is an ongoing need to formulate a cyanoacrylate composition comprising such an antimicrobial agent. SUMMARY OF THE INVENTION This invention is directed to cyanoacrylate compositions comprising an antirnicrobially effective amount of a com- patible iodine containing antimicrobial agent. These com- positions provide for in situ fonnation of an antimicrobial polymeric cyanoacrylate film on mammalian skin. The spe- cific antimicrobial agent employed is compatible with the cyanoacrylate composition insofar as the antimicrobial 4 agent neither causes premature polymerization nor prevents polymerization of the monomer, rather a flexible and durable polymer film is formed in situ on mammalian slcin by this composition. Moreover, in vitro assays evidence that the 5 antimicrobial agent is released from the polymeric film in antirnicrobially effective amounts thereby imparting antimi- crobial properties to the polymeric film. The compatible iodine containing antimicrobial agent comprises an antimicrobial complex of iodine molecules with a biocompatible polymer. Suitable biocompatible poly- mers include, by way of example only, polyvinylpyrrolidi- none polymers which is also referred to under the common name of Povidone or PVP. PVP polymers form complexes with iodine which are antimicrobial in nature and are available commercially as Povidone-Iodine. Accordingly, in one of its composition aspects, this inven- tion is directed to an antimicrobial cyanoacrylate composi- tion which comprises: (a) a polymerizable cyanoacrylate ester; and (b) an antimicrobially eifective amount of a complex of iodine molecules with a biocompatible polymer. Preferably, the polymerizable cyanoacrylate ester is a polyrnerizable monomer or reactive oligomer of a cyanoacrylate ester which, in monomeric form, is repre- sented by formula I: 10 15 25 o I II CH2=C —COR I 30 CN wherein R is selected from the group consisting of: alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkyl groups of from 5 to 8 carbon atoms, phenyl, 2-ethoxyethyl, Q 3-methoxybutyl, and a substituent of the formula: 35 R‘ O I II Q 45 R’ wherein each R’ is independently selected from the group consisting of: hydrogen and methyl, and R" is selected from the group consisting of: alkyl of from 1 to 6 carbon atoms, alkenyl of from 2 to 6 carbon atoms, allrynyl of from 2 to 6 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, aralkyl selected from the group consisting of benzyl, methylbenzyl and phenylethyl, phenyl, and phenyl substituted with 1 to 3 substituents selected from the group consisting of hydroxy, chloro, bromo, nitro, alkyl of 1 to 4 carbon atoms, and alkoxy of from 1 to 4 carbon atoms. More preferably, in the cyanoacrylate esters of formula I, R is alkyl of from 2 to 10 carbon atoms and still more 65 preferably alkyl of from 4 to 8 carbon atoms. Even more preferably, R is butyl, pentyl or octyl and most preferably, R is n-butyl. 55 60 5,684,042 5 Preferred complexes of iodine molecules with a biocom- patible polymer include povidone—iodine (commercially available from BASF, Mt. Olive, N.J., U.S.A.). The antimicrobial cyanoacrylate compositions preferably further comprise an effective amount of a polymerization inhibitor and a biocompatible plasticizer. The preferred polymerization inhibitor is sulfur dioxide which preferably employed at from about 50 to about 500 ppm based on the total weight of the composition absent the antimicrobial agent. The preferred biocompatible plasticizer is dioctyl phthalate which is preferably employed at from about 18 to 25 weight percent based on the total weight of the compo- sition absent the antimicrobial agent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS This invention is directed to cyanoacrylate compositions comprising an antimicrobially effective amount of a com- patible iodine containing antimicrobial agent. However, prior to discussing this invention in further detail, the following terms will first be defined. Definitions _ As used herein, the following terms have the following meanings: The term “ lymerizable cyanoacrylate esters” refers to polymerizable formulations comprising cyanoacrylate monomers or polymerizable oligomers which, in their monomeric form, are preferably compounds represented by formula I as described above. More preferably, in formula I, R is an alkyl group of from 2 to 10 carbon atoms including ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, iso-pentyl, n-hexyl, iso-hexyl, 2-ethylhexyl, n-heptyl, octyl, nonyl, and decyl. More preferably, R is butyl, pentyl or octyl and most preferably, R is n-butyl. Mixtures of such compounds can also be employed. These polymerizable cyanoacrylate esters are known in the art and are described in, for example, U.S. Pat. Nos. 3,527,224; 3,591,676; 3,667,472; 3,995,641; 4,035,334; and 4,650,8261’2’7'1° the disclosures of each are incorporated herein by reference in their entirety. A preferred cyanoacrylate ester for use in the invention is n-butyl-2—cyanoacrylate. The polymerizable cyanoacrylate esters described herein rapidly polymerize in the presence of water vapor or tissue protein, and the n—butyl-cyanoacrylate bonds human skin tissue without causing histotoxicity or cytotoxicity. The term “a biocompatible polymer” refers to polymers which, as iodine complexes (adducts), are compatible with in vivo applications on mammalian skin including human skin. Representative polymers include polyvinylpyrrolidone and the like. The molecular weight of these polymers is not critical with number average molecular weights ranging from about 10,000 to about 1,000,000 and preferably from 30,000 to 300,000 being preferred. The tenn a complex of iodine molecules with a biocom- patible polymer refers to an antimicrobial complex formed by the addition of iodine (12) to the biocompatible polymer. Such complexes are well known in the art and the resulting complex typically comprises both available iodine and iodine anions. These complexes, on contact with mammalian skin, are antimicrobial apparently by providing for a source of anti- microbial iodine. In any event, such complexes are employed only as starting materials herein and, by themselves, do not form a part of this invention. These complexes are sometimes referred to herein simply by the term “iodine/polymer complexes”. Such iodine! 10 20 25 30 35 45 50 55 65 6 polymer complexes are distinguished from antibiotics which are naturally derived materials from either bacteria or fungi and whose mode of action is to interfere with bacterial processes resulting in bacterial death. Rather the complexes used in this invention are indiscriminate in destroying any microbes including fungi, viruses and bacteria apparently by release of iodine into the microbes and, accordingly, are properly referred to as antimicrobial agents. Surprising, it has been found that of the antimicrobial agents tested, only the iodine/polymer complexes are compatible in cyanoacry- late compositions. In fact, elemental (solid) iodine is incom- patible with cyanoacrylate compositions because the addi- tion of elemental iodine renders such compositions non- polymerizable on mammalian skin. Accordingly, complexation of the iodine with the biocompatible polymer is apparently essential for compatibility with the cyanoacry- late composition. A preferred iodine/polymer complex for use in the com- positions of this invention is a polyvinylpyrrolidone iodine complex which is described in, for example, U.S. Pat. Nos. 2,706,701, 2,826,532 and 2,900,305”‘19 as well as at pp. 1106-1107 of the Tenth Edition of the Merck Index, Pub- lished by Merck & Co., Rahway, N.J., U.S.A. (1983) the disclosures of which are incorporated herein by reference in their entirety. This complex is commercially available under the name “povidone-iodine” from BASF, Mt. Olive, N.J., U.S.A. The term “biocompatible plasticizer” refers to any mate- rial which is soluble or dispersible in the cyanoacrylate composition, which increases the flexibility of the resulting polymer film coating on the skin surface, and which, in the amounts employed, is compatible with the skin as measured by the lack of skin irritation. Suitable plasticizers are well known in the art and include those disclosed in U.S. Pat. Nos. 2,784,127” and 4,444,933” the disclosures of both of which are incorporated herein by reference in their entirety. Specific plasticizers include, by way of example only, acetyl tri-n-butyl citrate (~20 weight percent or less), acetyl tri- hexyl citrate (~20 weight percent or less) butyl benzyl phthalate, dibutyl phthalate, dioctylphthaiate, n-butyryl tri- n-hexyl citrate, diethylene glycol dibenzoate (~20 weight percent or less) and the like. The particular biocompatible plasticizer employed is not critical and preferred plasticizers include dioctylphthalate. The term “polymerization inhibitor” refers to conven- tional inhibitors of cyanoacrylate monomers including mate rials such as sulfur dioxide, glacial acetic acid, and the like. The polymerization inhibitor is typically employed in amounts effective to inhibit polymerization until application onto the mammalian skin. Because of its compatibility with topical skin applications, the polymerization inhibitor is preferably sulfur dioxide which is preferably employed at from about 50 to 500 ppm based on the total weight of the composition. The term “antimicrobial agent” refers to agents which destroy microbes (i.e., bacteria, fungi, viruses and microbial spores) thereby preventing their development and patho- genic action. . Compositions This invention is based on the novel and unexpected. discovery that the iodine/polymer complexes described herein are compatible with cyanoacrylate esters forming a composition which, upon polymerization, provides for an antimicrobial cyanoacrylate polymeric film. Compatibility is assessed by the fact that these complexes are dispersible in the cyanoacrylate composition at antimicrobially etfective concentrations and when so employed, do not cause prema- 5,684,042 7 ture polymerization of the cyanoacrylate adhesive and do not prevent effective polymerization of the cyanoacrylate composition when applied to mammalian skin. Moreover, the polymerizable cyanoacrylate composition comprising such complexes forms a flexible, durable polymeric film having the complex incorporated therein which complex is released from the film in suflicient amounts to provide an antimicrobial property to the film when formed in situ on mammalian skin. As shown in the examples below, many other conven- tional antimicrobial agents, when added to the cyanoacrylate adhesive cause polymerization of the cyanoacrylate compo- sition as evidenced by gel formation within 24 hours of such addition or, in the case of elemental iodine, prevent in situ polymerization of the cyanoacrylate composition on mam- malian skin. Accordingly, such agents are not compatible with the cyanoacrylate compositions. The compositions of this invention are prepared by adding the iodine/polymer complex to the cyanoacrylate composi- tion. The iodinelpolymer complex is preferably added as the commercially available solid composition rather than as the commercially available aqueous or ethanolic solution inso- far as the solution can cause premature polymerization of the cyanoacrylate ester which is apparently due to solvent’s effects. Since the solid complex is typically insoluble but dispersible in the cyanoacrylate composition, mixing is employed to obtain a homogeneous suspension. The amount of iodine/polymer complex added to the cyanoacrylate composition is a suflicieut amount such that the resulting polymeric film is antimicrobial..Preferably, from about 5 to about 40 weight percent of the iodine! polymer complex and more preferably from about 10 to 25 weight percent is added to the cyanoacrylate composition based on the total weight of the composition. The specific amount of iodine/polymer complex required to effect antimicrobial properties in the resulting polymeric film can be readily measured by conventional in vitro assays measuring zones of microbial growth inhibition around the film. Zones of inhibition of at least 1 millimeter and pref- erably 3 millimeters from the edge of the film when tested in the manner of Example 2 below evidence that the poly- maic film is antimicrobial. Assessing the amount of iodine! polymer complex required in the polymeric film to eifect such a zone of inhibition is well within the sldll of the art. The composition of the antimicrobial complex and the cyanoacrylate ester can be formulated to a specific viscosity to meet disparate demands for the intended application of the composition. For example, relatively low viscosities are often preferred where application is to be made to a large surface area (e.g., abdominal surfaces). This preference results from the fact that these forms are less viscous and, accordingly, will permit more facile large surface area application of a thin application. Contrarily, where applica- tion is to be made to a specific position on the skin (e.g., elbow surfaces, knee surfaces and the like), higher viscosity materials are preferred to prevent “running" of the material to unintended locations. Accordingly, these compositions have a viscosity of from about 2 to 50,000 centipoise at 20° C. For low viscosity applications, viscosity ranges of from about 2 to 1,500 centipoise at 20° C. are preferred. More preferably, the cyanoacrylate adhesive is almost entirely in monomeric form and the composition has a viscosity of from about 5 to about 500 centipoise at 20° C. A thickening agent is optionally employed to increase the viscosity of the composition which thickening agent is any biocompatible material which increases the viscosity of the 5 10 20 25 30 A35 45 50 55 65 8 composition. Suitable thickening agents include, by way of example, polymethyl methacrylate (PMMA) or other pre- formed polymers soluble or dispersible in the composition, a suspending agent such as fumed silica and the like, with PMMA being preferred. Pumed silica is particularly useful in producing a gel for topical application having a viscosity of from about 1500 to 50,000. Suitable thickening agents for the cyanoacrylate compositions described herein also include a polymer of the alkyl cyanoacrylate as disclosed in U.S. Pat. Nos. 3,654,2393 and 4,03 8,3451‘ both of which are incorporated herein by reference in their entirety. Thickening agents are deemed to be biocompatible if they are soluble or dispersible in the composition and are com- patible with the skin as measured by the lack of moderate to severe skin irritation. The cyanoacrylate composition preferably includes a bio- compatible plasticizer and such plasticizers are preferably included from about 10 to 30 weight percent and more preferably from about 18 to 25 weight percent based on the weight of the composition absent the antimicrobial agent. A particularly preferred biocompatible plasticizer for use in the compositions described herein is dioctylphthalate. Additionally, the cyanoacrylate compositions described herein preferably include a polymerization inhibitor in an efl“ective amount to inhibit premature polymerization of the composition. In a particularly preferred embodiment, this inhibitor is sulfur dioxide which is employed at from about 50 to 500 ppm based on the total weight of the composition absent the antimicrobial agent. The cyanoacrylate adhesive compositions may addition- ally contain one or more optional additives such as colorants, perfumes, anti-di.fl’usion agents, rubber modifiers, modifying agents, etc. In practice, each of these optional additives should be both miscible and compatible with the cyanoacrylate composition and the resulting polymer. Com- patible additives are those that do not prevent the use of the cyanoacrylates in the manner described herein. In general, colorants are added so that the polymer layer formed on the skin will contain a discrete and discernible color. Perfumes are added to provide a pleasant smell to the formulation. Rubber modifiers are added to further enhance the flexibility of the resulting polymer layer. The amount of each of these optional additives employed in the composi- tion is an amount necessary to achieve the desired eifect. Additionally, the cyanoacrylate composition can option- ally comprise a formaldehyde scavenger compound such as those described by Leung, et al.” The use of such scaven- gers has been suggested as enhancing internal in vivo applications of cyanoacrylates. Still further, the cyanoacrylate composition can optionally comprise an acrylic monomer that will act as a polymeric plasticizer when it copolyrnerizes with the cyanoacrylate composition?‘ Utility The methods described herein are useful in forming in situ a broad spectrum antimicrobial polymeric film on the skin surface of a mammalian patient. Such mammalian patients preferably include humans as well as domestic animals such as horses, cows, dogs, sheep, cats, etc. The polymeric film finds particular utility in inhibiting microbial contamination thereunder and in the areas i.mme- diately adjacent thereto. Accordingly, such polymeric films can be used to topically cover small non-suturable wounds on skin surfaces which wounds do not penetrate tln'ough the dennat layer of the skin as in the manner described in Barley, et al.4 When so employed, the antimicrobial cyanoacrylate composition is applied over me small non-suturable wound. 5,684,042 9 Upon polymerization, an antimicrobial polymeric film is fonned over the wound which provides for broad spectrum antimicrobial properties at the wound surface while also preventing exogenous contaminants from entering the wound. Additionally, the polymeric films formed from the anti- microbial cyanoacrylate compositions described herein can also be used in the in situ formation of a surgical incise drape in the manner described by Askill, et al.“. When so employed, the in situ formed film strongly adheres to the mammalian skin surface to provide for a surgical incise drape which does not lift during surgery and has broad spectrum antimicrobial properties. When used as either a small wound covering or as a surgical incise drape, the antimicrobial polymeric film will ‘only adhere to the sldn for a period of about 2-4 days after which time it sloughs off. This occurs because the cyanoacrylate polymer adheres only to the uppermost por- ’ tion of the epidermal layer which is continuously in the process of being sloughed ofl° and replaced by the underlying cells. Accordingly, the antimicrobial cyanoacrylate film need not be removed after in situ formation. However, if removal of the polymeric film is required, such can be accomplished with acetone (nail polish remover). Other utilities for the compositions of this invention include their use to form polymeric hemostatic films3, use to form polymeric films in inhibiting surface skin irritation arising from friction between the skin surface and artificial devices such as tapes, prosthetic devices, casts, etc.‘, use in forming polymeric films in inhibiting acute radiation- induced skin damage”, and use in treating incontinence and areas adjacent to stomas.” The following examples illust:rates certain embodiments of the invention but is not meant to limit the scope of the claims in any way. EXAMPLES In the examples below, all temperatures are in degrees celsius (unless otherwise indicated) and all percents are weight percent (also unless otherwise indicated) except for percent inhibition which is true mathematical percentage. Additionally, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. CFU=colony forming units conc.=concentration flex.=flexibility dur.=durability mL—-milliliters mm=millimeters ppm=parts per million PVP—I2=polyvinylpyrro1idone iodine complex SAB-DEX=Sabouraud Dextrose 'I‘SA=trypt:icase soy agar EXAMPLE] The following example examines the compatibility of dijferent antimicrobial agents in cyanoacrylate composi- tions. In particular, the composition employed monomeric n-butyl cyanoacrylate containing 100 ppm sulfur dioxide and 20 weight percent of dioctyl phthalate absent the anti- microbial agent. In each case, either 5 weight percent, 10 weight percent or 20 weight percent of the antimicrobial agent, based on the total weight of the composition, was 10 15 20 25 30 35 45 50 55 65 10 added thereto and the properties of the resulting composition measured. The antimicrobial agents tested were elemental iodine, solid polyvinylpyrrolidone iodine, a 30% aqueous solution of polyvinylpyrrolidone iodine, sflver nitrate, hexachlorophene, merbromin, tetracycline HCl, tetracycline hydrate, and erythromycin (each of these antimicrobial agents were obtained from commercial sources). The evaluation included assessing whether the antimicro- bial agent was soluble or suspendable in the composition; whether the resulting composition cured upon contact with skin; whether curing provided for a polymeric film in situ on the skin; whether the polymeric film was flexible and durable. Solubility and suspendability were determined by conventional standards. The ability of the resulting compo- sition to clue in situ upon application to skin was measured by applying the cyanoacrylate composition onto the upper arm of a male human subject and determining whether polymerization proceeded (up to 5 minutes) and, if so, the time required for polymerization. Film forming capabilities on the skin were assessed by visual evaluation. Durability was assessed by determining whether the film was retained on the skin surface for at least 24 hours and flexibility was measured by the abilityof the film to be retained on the skin without cracking or peeling for at least 24 hours. The results of this evaluation are summarized in Table I below: TABLE I Anti- microbial Film Agent Cone. Soluble Curable Formed Flex. Dur. elemental —-20% partially No -—- — — iodine (1,) (when tested for 5 minutes) PVP-I, 10% no Yes Yes Yes Yes solid sus- (30 pension‘ seconds) PVP-I2 10% no, gelled‘ —- — —— — solution Silver 5% no, gelled‘ — — — — nitrate I{exaehloro- 5% no, gelled‘ —— — — — phene Merbromin 5% no, gelled‘ —— — — — tet1a- 5% no, gelled‘ —— —— — — eyc1ine.I-[Cl tetracycline 5% no, gelled‘ -—- — — — hydrate Eryt.hro- 5% no, gelled‘ -—- — — —— mycin ‘gel fonnation within 24 hours of addition of the antimicrobial agent evidences premature polymerization of the cyanoacrylate. In such cases, the antimicrobial agent initiates pol ' ation. 2the mixture is readily resmpended with mild agitation. No gel formed over an 8 week period when stored at room temperature. The above data demonstrates that of the antimicrobial agents tested, only polyvinylpyrrolidone iodine complex was compatible with the cyanoacrylate composition and, of the polyvinylpyrrolidone iodine complexes tested, only the solid form was compatible. Evidently, the solvent in the solution form of polyvinylpyrrolidone iodine complex ini- tiated polyrnerization of the cyanoacrylate. Significantly, the suspension formed by the addition of solid polyvinylpyr- rolidone iodine complex was curable in situ on human skin resulting in a flexible and durable polymeric film. In addition to the above, polyvinylpyrrolidone is a well known biocompatible polymer thereby evidencing that such polymers, when complexed with iodine, are suitable for use in the compositions described herein. 5,684,042 11 EXAMPLE 2 The following example was conducted to determine whether suflicient polyvinylpyrrolidone iodine complex was incorporated into the polymeric cyanoacrylate film fanned in situ to render this film antimicrobial. A. Preparation of the Inoculum Specifically, the surfaces of two TSA plates, l00>