WO2000035276A1 - Cyanoacrylate compositions comprising a soluble antimicrobial agent - Google Patents

Cyanoacrylate compositions comprising a soluble antimicrobial agent Download PDF

Info

Publication number
WO2000035276A1
WO2000035276A1 PCT/US1999/030233 US9930233W WO0035276A1 WO 2000035276 A1 WO2000035276 A1 WO 2000035276A1 US 9930233 W US9930233 W US 9930233W WO 0035276 A1 WO0035276 A1 WO 0035276A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyanoacrylate
antimicrobial
iodine
carbon atoms
composition according
Prior art date
Application number
PCT/US1999/030233
Other languages
French (fr)
Inventor
Carlos Roberto Morales
Jonathan Eric Sterling
Shane C. Karnik
Original Assignee
Medlogic Global Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US21507898A priority Critical
Priority to US09/215,078 priority
Application filed by Medlogic Global Corporation filed Critical Medlogic Global Corporation
Publication of WO2000035276A1 publication Critical patent/WO2000035276A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01NPRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES, AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • A01N59/12Iodine, e.g. iodophors; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001Use of materials characterised by their function or physical properties
    • A61L24/0015Medicaments; Biocides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L24/00Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0014Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L26/00Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061Use of materials characterised by their function or physical properties
    • A61L26/0066Medicaments; Biocides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04Macromolecular materials
    • A61L31/048Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/202Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with halogen atoms, e.g. triclosan, povidone-iodine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404Biocides, antimicrobial agents, antiseptic agents

Abstract

Disclosed are cyanoacrylate compositions comprising a compatible antimicrobial agent and, in particular, a compatible iodine containing antimicrobial agent. These compositions provide for in situ formation of an antimicrobial polymeric cyanoacrylate film on mammalian skin.

Description

CYANOACRYLATE COMPOSITIONS COMPRISING A SOLUBLE ANTIMICROBIAL AGENT

CROSS-RFFFRFNCF TO RF.T.ATF.D APPT CATTONS This application is a continuation-in-part of U.S. Patent Application Serial No. 09/215,078 filed on December 18, 1998 which application is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Field of the nvention

This invention is directed to cyanoacrylate prepolymer compositions comprising a soluble and 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 or are an adjunct to sutures, and the like.

This invention is also directed to kits of parts comprising such prepolymer compositions and an applicator means for applying the composition to mammalian skin.

References The following publications, patent applications and patents are cited in this application as superscript numbers:

1 Hawkins, et al., Surgical Adhesive Compositions, U.S. Patent No. 3,591,676, issued July 6, 1971

2 Halpern, et al., Adhesive for Living Tissue, U.S. Patent No. 3,667,472, issued June 6, 1972 Mclntire, et al., Process for the Preparation of Poly( -Cyanoacrylates) , U.S. Patent No. 3,654,239, issued April 4, 1972 Barley, et al., Methods for Treating Non-Suturable Wounds by Use of Cyanoacrylate Adhesives, International Patent Application Publication No. WO 93/25196, published December 23, 1993 Barley, et al., Methods for Treating Suturable Wounds by Use of Sutures and Cyanoacrylate Adhesives, U.S. Patent No. 5,254,132, issued October 19, 1993 Barley, et al., Methods for Reducing Skin Irritation From Artificial Devices by Use of Cyanoacrylate Adhesives, U.S. Patent No. 5,653,789, issued

August 5, 1997 Rabinowitz, et al., Method of Surgically Bonding Tissue Together, U.S. Patent No. 3,527,224, issued September 8, 1970 Kronenthal, et al., Surgical Adhesives, U.S. Patent No. 3,995,641, issued December 7, 1976 Davydov, et al., Medical Adhesive, U.S. Patent No. 4,035,334, issued July 12, 1977 Waniczek, et al., Stabilized Cyanoacrylate Adhesives Containing Bis- Trialkylsilyl Esters of Sulfur ic Acid, U.S. Patent No. 4,650,826, issued March 17, 1987 Askill, et al., 'Methods for Draping Surgical Incision Sites" U.S. Patent No. 5,807,563, issued September 15, 1998 Greff, et al., Cyanoacrylate Adhesive Compositions, U.S. Patent No. 5,480,935, issued January 2, 1996 Greff, et al., Cyanoacrylate Compositions Comprising an Antimicrobial

Agent, U.S. Patent No. 5,684,042, issued on November 4, 1997 Greff, et al., Cyanoacrylate Compositions Comprising an Antimicrobial Agent, U.S. Patent No. 5,783,177 issued on July 21, 1998. Greff, et al., Cyanoacrylate Compositions Comprising an Antimicrobial Agent, U.S. Patent No. 5,762,919 issued on June 9, 1998

Greff, et al., Cyanoacrylate Compositions Comprising an Antimicrobial Agent, U.S. Patent No. 5,811,091 issued on September 22, 1998. O'Sullivan, et al., High Viscosity Cyanoacrylate Adhesive Compositions, and Process for Their Preparation, U.S. Patent No. 4,038,345, issued July 26, 1977

Beller, et al., Process for the Preparation of Iodine-Polyvinylpyrrolidone by Dry Mixing, U.S. Patent No. 2,706,701, issued April 19, 1955

Hosmer, Process of Stabilizing Polyvinylpyrrolidone, U.S. Patent No. 2,826,532, issued March 11, 1958

Siggin, Preparation of Iodine Polyvinylpyrrolidone Adducts, U.S. Patent No. 2,900,305, issued August 18, 1958 Joyner, et al., Plasticized Monomeric Adhesive Compositions and Articles

Prepared Therefrom, U.S. Patent Nos. 2,784,127, issued March 5, 1957 Columbus, et al., Adhesive Cyanoacrylate Compositions with Reduced Adhesion to Skin, U.S. Patent No. 4,444,933, issued April 24, 1984 Leung, et al., Biocompatible Monomer and Polymer Compositions, U.S. Patent No. 5,328,687, issued July 12, 1994 Byram, et al., Use of Cyanoacrylate Adhesive Compositions to Inhibit Acute Radiation-Induced Skin Damage, U.S. Patent No. 5,554,365, issued September 10, 1996. Leplyanin, "Medical and Surgical Adhesive Composition and Process for Its Preparation ", International Application Publication No. WO 96/23532 published August 8, 1996

Tighe, et al., "Use of Cyanoacrylate Adhesives for Providing a Protective Barrier Film for the Skin", U.S. Patent No. 5,580,565, issued on December 3, 1996. Franklin, et al., 'Process for the Production of a Polymeric Carbamate ",

U.S. Patent No. 4,243,798, issued January 6, 1981.

Erdman, et al., 'Dispersant Lubricating Oil Additives ", U.S. Patent No. 4,548,722, issued October 22, 1985 Buckley, III, 'Fuel Compositions Containing Very Long Chain Alkylphenyl Poly(oxyalkylene) Aminocarbamates ", U.S. Patent No. 4881,945, issued

November 21, 1989

Bolduc, "Aerosol Spray System ", U.S. Patent No. 5,154,320, issued October 13, 1992 Blum, et al., In vitro Determination of the Antimicrobial Properties of Two Cyanoacrylate Preparations, J. Dent. Res., 5_4_(3): 500-503 (1975)

32 Berger, et al., Mixed Cyanoacrylate Ester Compositions, U.S. Patent No. 5,998,472 issued December 7, 1999

33 Greff, et al., "Methods for Sterilizing Cyanoacrylate Compositions ", U.S. Patent Application No. 09/172,858, filed October 15, 1998

All of the above publications, patent applications and patents are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent application or patent was specifically and individually indicated to be incorporated by reference in its entirety.

State of the Art

Cyanoacrylate esters have been disclosed for a variety of topical uses on mammalian skin including use as a replacement or adjunct 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 surfaces4, use in inhibiting surface skin irritation arising from friction between the skin surface and artificial devices such as tapes, prosthetic devices, casts, etc.6 and use in inhibiting acute radiation-induced skin damage.24 Still another topical use of cyanoacrylate esters is its use in the in situ formation of a surgical incise drape.11 In each case, when topically applied to mammalian skin, the cyanoacrylate rapidly polymerizes, typically within a minute, to form a coherent polymeric film which strongly adheres to the skin.

Cyanoacrylate esters suggested for such uses include the following structures:

O

II

CH2=C C OR i

I

CN wherein R is an alkyl or other suitable substituent. Such cyanoacrylate esters are disclosed in, for example, U.S. Patent Nos. 3,527,224; 3,591,676; 3,667,472; 3,995,641; 4,035,334; and 4,650,826.1A7-10

Cyanoacrylate ester compositions for application to mammalian tissue 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 mammalian skin, Greff et al.12 disclose that the cyanoacrylate composition preferably employs from about 50 to about 500 ppm sulfur dioxide as the polymerization inhibitor and from about 18-25 weight percent of a biocompatible plasticizer such as dioctyl phthalate. Alternatively, Berger, et al.32 discloses cyanoacrylate ester compositions comprising a C10 to C]2 cyanoacrylate ester which can be used in place of or in conjunction with the biocompatible plasticizer.

Notwithstanding the beneficial properties associated with such cyanoacrylate ester compositions and their suitability for application to mammalian tissue, these compositions do not possess a sufficiently broad spectrum of antimicrobial activity including activity against microbial spores31 and, accordingly, cannot assure reductions in microbial populations on mammalian tissue either under or adjacent a polymeric cyanoacrylate film formed in situ on the tissue.

To address this concern, Greff, et al.13"16 discloses cyanoacrylate ester compositions comprising a compatible, broad spectrum antimicrobial agent. These compositions are exemplified by the addition of sufficient amounts of polyvinylpyrrolidone/iodine (PVP-I2) into the cyanoacrylate ester composition such that the polymer resulting by in situ polymerization of this composition on mammalian skin has antimicrobial properties. Notwithstanding the significant advancement such PVP-I2 cyanoacrylate compositions represent, PVP-I2 is not soluble in the cyanoacrylate ester and, upon addition, a suspension of PVP-I2 in the cyanoacrylate ester is formed. In order to ensure that a homogeneous composition is applied to mammal skin, it may be necessary to vigorously shake such compositions prior to application. In addition, the presence of insoluble particles dictates against sterilization of these compositions by filtration through small pore biofilters.

In view of the above, a composition comprising a cyanoacrylate ester and a compatible antimicrobial agent soluble therein would be particularly beneficial.

SUMMARY OF THE INVENTION

This invention is directed to cyanoacrylate ester compositions comprising an antimicrobially effective amount of a complex of iodine molecules with a biocompatible polymer which complex is soluble in the cyanoacrylate ester or esters. These compositions provide for in situ formation of an antimicrobial polymeric cyanoacrylate film on mammalian skin and other mammalian tissues such as mucous membranes, etc.

The specific antimicrobial iodine complex employed is soluble in the cyanoacrylate ester or esters and, in addition, is compatible with this ester insofar as the iodine complex neither causes premature polymerization nor prevents polymerization of the monomer, rather a flexible and durable polymeric film is formed in situ on mammalian skin and other mammalian tissues by this composition.

Accordingly, in one of its composition aspects, this invention is directed to an antimicrobial cyanoacrylate composition which comprises: (a) a polymerizable cyanoacrylate ester; and (b) an antimicrobially effective amount of a complex of iodine molecules with a biocompatible polymer which complex is soluble in said polymerizable cyanoacrylate ester.

Preferably, the polymerizable cyanoacrylate ester (or esters) is/are a polymerizable monomer or reactive oligomer of a cyanoacrylate ester. Such monomers and reactive oligomers are sometimes referred to herein simply as "prepolymers" and, in monomeric form, are preferably represented by formula I:

O

II

CH2=C C OR i

I CN wherein R is selected from the group consisting of: alkyl of 1 to 20 carbon atoms, alkenyl of 2 to 20 carbon atoms, cycloalkyl groups of from 5 to 8 carbon atoms, phenyl,

2-ethoxyethyl,

3-methoxybutyl, and a substituent of formula II:

R O

— C— C— OR" ||

' 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, alkynyl 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 20 carbon atoms and still more preferably alkyl of from 4 to 12 carbon atoms. Even more preferably, R is butyl, pentyl, octyl, decyl or dodecyl and most preferably, R is «-butyl.

The soluble antimicrobial complexes of iodine molecules with a biocompatible polymer are preferably iodine complexes of polyoxyalkylene polymers. Such polymers are preferably homopolymers and copolymers, including random and block copolymers, which are represented by formula III:

Figure imgf000010_0001

wherein R2 is selected from the group consisting of hydrogen and a hydrocarbyl group of from 1 to 30 carbon atoms; each R3 is independently selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R4 is selected from the group consisting of hydrogen and a hydrocarbyl group of from 1 to 30 carbon atoms; and m is an integer from 1 to 400 and preferably 1 to 300; with the proviso that the iodine complex of the polymers of formula III have a solubility of at least 5 mg/mL in the cyanoacrylate ester composition at 20 °C and preferably at least 10 mg/mL in the cyanoacrylate ester composition. The soluble antimicrobial iodine complexes described herein preferably have an iodine content of from 1 to 30 weight percent based on the weight of the complex; more preferably 5 to 25 weight percent; and most preferably 10 to 20 weight percent.

Preferably, R2 is selected from the group consisting of hydrogen and alkylphenyl and R4 is preferably hydrogen.

In another preferred embodiment, R3 is hydrogen or methyl.

Even more preferably, the polymers of formula III are polyoxy- ethylene/polyoxypropylene copolymers (R3 is hydrogen or methyl) which polymers are random copolymers (each R3 is randomly hydrogen or methyl); block copolymers defined by formula IV and V:

CH3 R2O-(CH2CH2O)rj(CH2CHO)q F?4 )V

Figure imgf000011_0001
where R2 and R4 are as defined above andp and q are integers independently equal to 1 to 400 and preferably 1 to 200; or block terpolymers represented by formulas VI and VII:

\

RCr-(α^CH2C^(α 2CHCτ (C 2(-Η2O)tR4 VI

R2

Figure imgf000011_0002
tR4 VI I where R2 and R4 are as defined above and r, s and t are integers independently equal to 1 to 400 and preferably 1 to 100.

It is contemplated that other soluble antimicrobial complexes of iodine molecules with a biocompatible polymer include complexes of iodine with polymethyl methacrylate, polycyanoacrylate, and the like.

The antimicrobial cyanoacrylate compositions described herein preferably further comprise an effective amount of a polymerization inhibitor which is preferably selected from the group consisting of sulfur dioxide, glacial acetic acid, hydroquinone, hindered phenols (e.g., 4-methoxyphenol) and mixtures thereof. In a particularly preferred embodiment, the polymerization inhibitor is a mixture of a biocompatible acid polymerization inhibitor and a biocompatible free radical polymerization inhibitor both of which are employed in combination to inhibit polymerization of the cyanoacrylate ester. The preferred mixture of polymerization inhibitors is a biocompatible acid polymerization inhibitor such as sulfur dioxide, glacial acid acid and other well known acid polymerization inhibitors and a biocompatible free radical polymerization inhibitor including hydroquinone and hindered phenols (e.g., 4-methoxyphenol). The acid polymerization inhibitor is preferably SO2 which is preferably employed at from about 50 to 1000 ppm, more preferably from about 50 to 200 ppm, based on the total weight of the composition. The free radical inhibitor is preferably a mixture of hydroquinone and 4-methoxyphenol. This mixture is employed to stabilize the composition especially during sterilization (e.g., heat, radiation, etc. sterilization methods).

A preferred mixture of these two free radical inhibitors comprises from about 100 to 2000 ppm; more preferably from about 100 to about 1500 ppm; and even more preferably from about 600 to 1200 ppm and is preferably employed at a 10:1 to 1 :10 ratio of hydroquinone to 4-methoxyphenol. A particularly preferred mixture of polymerization inhibitors includes 100 ppm sulfur dioxide, 500 ppm hydroquinone, and 500 ppm 4-methoxyphenol. Another preferred mixture of polymerization inhibitors includes 100 ppm sulfur dioxide, 400 ppm hydroquinone, 400 ppm 4-methoxyphenol and 1000 ppm acetic acid.

In yet a further preferred embodiment, the cyanoacrylate compositions described herein further comprise a sufficient amount of a biocompatible plasticizer to enhance the flexibility of the resulting polymeric cyanoacrylate film. Preferred biocompatible plasticizers include, for example, dioctyl phthalate and/or tri-«-butyl acetyl citrate and are preferably employed at from about 18 to 25 weight percent based on the total weight of the composition absent the antimicrobial agent. Alternatively, instead of or in addition to incorporating a separate plasticizer into the composition, the cyanoacrylate composition can comprise an effective amount of a C10-C12 alkyl cyanoacrylate ester as described by Berger, et ' al.32

This invention is also directed to kits useful for applying the antimicrobial cyanoacrylate compositions described herein onto mammalian skin. In particular, such a kit of parts comprises:

(a) a container comprising therein an antimicrobial prepolymeric composition as described above; and

(b) an applicator means for applying the composition onto mammalian skin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention is directed, in part, to cyanoacrylate compositions comprising an antimicrobially effective amount of a soluble, compatible 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 "cyanoacrylate ester compositions" or "cyanoacrylate compositions" refers to polymerizable formulations comprising polymerizable cyanoacrylate ester monomers and/or oligomers which, in their monomeric form, are preferably compounds represented by formula I as described above. Such compositions are sometimes referred to herein as prepolymeric compositions.

More preferably, in formula I, R is an alkyl group of from 2 to 20 carbon atoms including, by way of example, ethyl, «-propyl, wo-propyl, «-butyl, wø-butyl, .sec-butyl, w-pentyl, ώo-pentyl, n-hexyl, wo-hexyl, 2-ethylhexyl, w-heptyl, «-octyl, nonyl, decyl and dodecyl. More preferably, R is butyl, pentyl, octyl, decyl or dodecyl and most preferably, R is «-butyl. Mixtures of such compounds can also be employed.

Polymerizable cyanoacrylate esters are known in the art and are described in, for example, U.S. Patent Nos. 3,527,224; 3,591,676; 3,667,472; 3,995,641; 4,035,334; and 4,650,8261'2'7"10 the disclosures of each are incorporated herein by reference in their entirety.

A particularly preferred cyanoacrylate ester for use in the invention is n- butyl-2-cyanoacrylate and mixtures of «-butyl-2-cyanoacrylate with C10-C12 alkyl cyanoacrylate esters as described by Berger, et al.32

The polymerizable cyanoacrylate ester compositions described herein rapidly polymerize in the presence of water vapor or tissue protein, and the n-butyl-cyanoacrylate bonds mammalian tissue without causing histotoxicity or cytotoxicity.

Such polymerizable cyanoacrylate esters are sometimes referred to herein as prepolymers and compositions comprising such esters are sometimes referred to herein as prepolymer compositions. The term "a complex of iodine molecules with a biocompatible polymer which is soluble in the cyanoacrylate ester" refers to an antimicrobial complex formed by the addition of iodine (I2) to a biocompatible polymer which complex is soluble in the cyanoacrylate ester composition at a concentration of at least 5 mg complex per mL of cyanoacrylate at 20 °C and more preferably at least 10 mg/mL. Such complexes are known in the art and are in some cases commercially available. These complexes, on contact with mammalian tissue, are antimicrobial apparently by providing for a source of antimicrobial 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 "soluble iodine/polymer complexes". Such soluble iodine/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. Contrarily, 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.

Preferred iodine/polymer complexes for use in the compositions of this invention are iodine complexes of polymers represented by formula III:

Figure imgf000015_0001

wherein R2 is selected from the group consisting of hydrogen and a hydrocarbyl group of from 1 to 30 carbon atoms; each R3 is independently selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R4 is selected from the group consisting of hydrogen and a hydrocarbyl group of from 1 to 30 carbon atoms; and m is an integer from 1 to about 400 and preferably 1 to 300; with the proviso that the iodine complex of the polymers of formula III have a solubility of at least 5 mg/mL in the cyanoacrylate ester composition at 20 °C and preferably at least 10 mg/mL.

It is understood that the integer m represents a number average of oxyalkylene groups wherein individual members have more or less than the average number.

The soluble antimicrobial iodine complexes described herein preferably have an iodine content of from 1 to 30 weight percent based on the weight of the complex; more preferably 15 to 25 weight percent; and most preferably 20 weight percent.

Preferably, R2 is selected from the group consisting of hydrogen and alkylphenyl and R4 is preferably hydrogen. In another preferred embodiment, R3 is hydrogen or methyl.

Even more preferably, the polymers of formula III are polyoxy- ethylene/polyoxypropylene copolymers (R3 is hydrogen or methyl) which polymers are random copolymers (each R3 is randomly hydrogen or methyl); block copolymers defined by formula IV and V:

Figure imgf000016_0001

CH,

R2Q— (CH2CHO)-(CH2CH2O)p R« v where R2 and R4 are as defined above andp and q are integers independently equal to 1 to 400 and preferably 1 to 200; or block terpolymers represented by formulas VI and VII:

<?H '33

R2θ-(CH2CH2O)r(CH2CHO)i-(CH2CH2O)tR4 VI

CH3 CH

I 1

R2O-(CH2CHO)r<CH2CH2O)s(CH2CHO)tR* VII

where R2 and R4 are as defined above and r, s and t are integers independently equal to 1 to 400 and preferably 1 to 100.

Such iodine/polymers complexes are commercially available from, for example, WestAgro, Kansas City, Missouri, USA. Alternatively, methods for preparing iodine complexes by iodinating a biocompatible polymer are well known in the art and are described in, for example, U.S. Patent Nos. 2,706,701, 2,826,532 and 2,900,305.18"20 In addition, the underlying polymers are well known materials available, for example, from Aldrich Chemical Company, Milwaukee, Wisconsin, USA as either a di-alcohol polymer (R2 and R4 are hydrogen), a monocapped, mono-alcohol polymer (R2 is hydrocarbyl and R4 is hydrogen) and a dicapped polymer (R2 and R4 are hydrocarbyl). In addition, monocapped products are described in numerous patents including, by way of example only, U.S. Patent

Nos. 4,243,798; 4,548,722; and 4,881,94527"29 each of which is incorporated herein by reference in its entirety.

Particularly preferred soluble iodine/polymer complexes include iodine complexes with alpha-(p-nonylphenyl)-omega-hydroxypoly(oxyethylene) [i.e., in Formula III, R2 = nonylphenyl; R3 = hydrogen; and R4 = H]; iodine complexes with polyethyoxy polypropoxy polyethoxy ethanol. Both of these complexes can be produced in the laboratory or purchased from commercial sources. Alternatively, a soluble biocompatible polymer can be added to the cyanoacrylate ester along with iodine to form the iodine/polymer complex in situ.

The term "biocompatible plasticizer" refers to any material 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 moderate to severe skin irritation. Suitable plasticizers are well known in the art and include those disclosed in U.S. Patent Nos. 2,784,12721 and 4,444,93322 the disclosures of both of which are incorporated herein by reference in their entirety. Specific plasticizers include, by way of example only, tri-w-butyl acetyl citrate (preferably -20 weight percent or less), acetyl trihexyl citrate (preferably -20 weight percent or less) butyl benzyl phthalate, dibutyl phthalate, dioctylphthalate, w-butyryl tri-«- hexyl citrate, diethylene glycol dibenzoate (preferably -20 weight percent or less). The particular biocompatible plasticizer employed is not critical and preferred plasticizers include tri-n-butyl acetyl citrate.

The term "polymerization inhibitor" refers to conventional inhibitors of cyanoacrylate esters including materials such as sulfur dioxide, glacial acetic acid, hydroquinones, 4-methoxyphenol, combinations of such materials, and the like. The polymerization inhibitor is typically employed in amounts effective to inhibit polymerization until application onto the mammalian skin.

The term "hydrocarbyl" refers to an organic radical or group composed of carbon and hydrogen which may be aliphatic, alicyclic, aromatic or combinations thereof, e.g., aralkyl. Preferably, the hydrocarbyl group will be relatively free of aliphatic unsaturation, i.e., ethylenic and acetylenic, particularly acetylenic unsaturation. The hydrocarbyl group preferably contains from 1 to 30 carbon atoms and more preferably from 1 to 20. When the hydrocarbyl group is aralkyl, the aralkyl group preferably contains from 7 to 30 carbon atoms. The term "antimicrobial agent" refers to agents which destroy microbes (i.e., bacteria, fungi, viruses and microbial spores) thereby preventing their development and pathogenic action.

Compositions This invention is based on the novel and unexpected discovery that the iodine/polymer complexes described herein are both compatible with and soluble in cyanoacrylate esters forming a soluble prepolymer 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 ester composition at antimicrobially effective concentrations and when so employed, do not cause premature polymerization of the cyanoacrylate ester composition and do not prevent effective polymerization of the cyanoacrylate ester composition when applied to mammalian tissue. Moreover, the polymerizable cyanoacrylate ester composition comprising such complexes forms a flexible, durable polymeric film having the complex incorporated therein which complex is released from the film in sufficient amounts to provide antimicrobial properties to the film.

Solubility is assessed by the fact that these iodine complexes are soluble in the cyanoacrylate ester at a concentration of at least 5 mg/mL at 20 °C; preferably at least 10 mg/mL at 20°C; and more at least 30 mg/mL at 20°C. In a particularly preferred embodiment, the concentration of the iodine complex in the composition is from 0.5 to 40 weight percent, more preferably from 1 to 10 weight percent and most preferably from 1 to 5 weight percent.

As shown in the examples below, the soluble compositions of this invention have antimicrobial properties, have prolonged self-life and may be sterile filtered using a 0.2 μm Nylon or Teflon filter. In one embodiment, the compositions of this invention are prepared by adding the iodine/polymer complex (i.e., the iodophor) to the cyanoacrylate ester composition. Upon addition of the iodine/polymer complex to the cyanoacrylate prepolymer composition, the resulting system is thoroughly mixed to obtain a homogeneous solution. Alternatively, the iodine/polymer complex can be made by direct addition of iodine to a solution of cyanoacrylate ester and polymer. In this method, the polymer of choice is homogeneously mixed with the cyanoacrylate ester, then iodine is added directly to this solution. The resulting system is mixed to obtain a homogeneous solution. Conversely this can be done by first adding iodine to cyanoacrylate ester, then adding a selected polymer to this system.

Care should be taken when selecting commercial iodophors for use in this invention. Specifically, the commercial preparation of these iodophors can affect the performance of the antimicrobial cyanoacrylate composition when applied to the mammalian tissue. For instance, some commercial iodophors have been found to contain large amounts of hydroiodic acid and water. The acid can cause skin irritation and delayed setting. The water and other impurities can cause reduced product life and increased instability. Accordingly, in one embodiment, the iodine/polymer complexes used in the compositions of this invention comprise less than about 10 weight percent water; preferably less than about 1 percent water and more preferably less than about 0.05 weight percent. In another embodiment, the iodine/polymer complexes used in the compositions of this invention comprise less than about 1 weight percent hydroiodic acid; preferably less than about 0.1 percent water and more preferably less than about 0.05 weight percent.

If suitable commercial iodophors cannot be found, iodine/polymer complexes can be readily made by bringing the selected polymer, either in a liquid or powder form, into intimate contact with elemental diatomic iodine with or without heat. Once complexation has occurred, the iodine/polymer complex can be directly added to the cyanoacrylate ester composition. The amount of iodine/polymer complex added to the cyanoacrylate composition is a sufficient amount such that the resulting polymeric film is antimicrobial. Preferably, from about 0.5 to about 40 weight percent of the iodine/polymer complex and more preferably from about 1 to 10 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 preferably 3 millimeters from the edge of the film when tested in the manner of Example 10 below evidence that the polymeric film is antimicrobial. Assessing the amount of iodine/polymer complex required in the polymeric film to effect such a zone of inhibition is well within the skill 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 film. Contrarily, where application is to be made to a more complex curvature of the skin (e.g., elbow surfaces, knee surfaces and the like), higher viscosity compositions, including those containing thixotropic materials, are preferred to prevent "running" of the compositions 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 500 centipoise at 20 °C are preferred. More preferably, the cyanoacrylate ester employed in the composition is almost entirely in monomeric form and the composition has a viscosity of from about 2 to about 100 centipoise at 20 °C. Even more preferably, the cyanoacrylate ester employed in the composition is almost entirely in monomeric form and the composition has a viscosity of from about 5 to about 100 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 composition. Suitable thickening agents include, by way of example, polymethyl methacrylate (PMMA) or other preformed polymers soluble or dispersible in the composition, a suspending agent such as fumed silica and the like, with PMMA being preferred. Fumed 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. Patent Nos. 3,654,2393 and 4,038,34517 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 compatible with the skin as measured by the lack of moderate to severe skin irritation.

The cyanoacrylate composition can optionally include a biocompatible plasticizer and, when so employed, 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. Particularly preferred biocompatible plasticizers for use in the compositions described herein are dioctylphthalate, octyl tributyl citrate or tributyl acetyl citrate.

Additionally, the cyanoacrylate compositions described herein preferably include polymerization inhibitors in effective amounts to inhibit premature polymerization of the composition. The cyanoacrylate ester compositions may additionally contain one or more optional additives such as perfumes, 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. Compatible additives are those that do not prevent the use of the cyanoacrylates in the manner described herein.

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 composition is an amount necessary to achieve the desired effect.

Additionally, the cyanoacrylate composition can optionally comprise a formaldehyde scavenger compound such as those described by Leung, et al.23 The use of such scavengers has been suggested as enhancing internal in vivo applications of cyanoacrylates.

Still further, it is contemplated that the cyanoacrylate composition can optionally comprise an acrylic monomer that will act as a polymeric plasticizer when it copolymerizes with the cyanoacrylate composition. In this regard, a particularly preferred embodiment comprises the addition of a C10 to C12 cyanoacrylate, an example of which is disclosed by Berger32. Other acrylic monomers which can be optionally employed include those disclosed by Leplyanin.25

After the composition has been prepared, this composition can optionally be sterilized by, for example, E-beam sterilization techniques in the manner described by Greff, et al.33 or by sterile filtration through a Nylon or Teflon biofilter having a pore size of no more than 0.22μm or by γ-irradiation as disclosed in U.S. Patent No. 5,530,037 which is incorporated herein by reference in its entirety. Utility

The compositions described herein are useful in forming in situ a broad spectrum antimicrobial polymeric film on the tissue surface of a mammalian patient. Such mammalian patients preferably include humans as well as, for example, 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 immediately adjacent thereto. Accordingly, such polymeric films can be used to topically cover small non- suturable wounds on skin surfaces which wounds do not penetrate through the dermal layer of the skin as in the manner described in Barley, et al.4 When so employed, the antimicrobial cyanoacrylate composition is applied over the small non-suturable wound. Upon polymerization, an antimicrobial polymeric film is formed over the wound which provides for broad spectrum antimicrobial properties at the wound surface while also preventing exogenous contaminants from entering the wound.

It is further contemplated that the compositions of this invention can be used for the topical treatment of infectious skin diseases by topically applying an antimicrobial effective amount of the compositions of this invention for a sufficient amount of time to ameliorate the condition.

Additionally, the polymeric films formed from the antimicrobial 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.11 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 skin for a period of about 1-4 days after which time it sloughs off. This occurs because the cyanoacrylate polymer adheres only to the uppermost portion of the epidermal layer which is continuously in the process of being sloughed off 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 a material such as 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.6, use in forming polymeric films in inhibiting acute radiation-induced skin damage24, use in treating incontinence and areas adjacent to stomas26 and use as substitutes for sutures, staples, steristrips, and other tissue adhesives in closing surgical wounds.

Kits In view of the many different uses for application to mammalian tissue, this invention also encompasses a kit of parts useful for applying the antimicrobial cyanoacrylate compositions described herein onto mammalian tissue. In particular, such a kit of parts comprises (a) a container comprising therein an antimicrobial prepolymeric composition as described above and (b) an applicator means for applying the composition to mammalian tissue.

The container comprises any compatible material which stores the cyanoacrylate composition without degradation of the container or prematurely polymerizing the cyanoacrylate prepolymer. Such materials include, by way of example, inorganic materials such as Type 1 glass (including amber glass), ceramics, metals (e.g., aluminum, tin and tin coated tubes), etc. and organic materials such as inert polymers including polyolefms (e.g., high density polyethylene), fluorinated polyolefms, and the like. Examples of suitable containers include those recited in Bolduc, U.S. Patent No. 5,154,320,30 which is incorporated herein by reference in it entirety.

Suitable applicator means include brushes, rollers, aerosols, swabs, foams (e.g., polyethylene foam) and the like. A particularly preferred applicator is described in U.S. Patent No. 4,183,684.

In one embodiment, the container and applicator means are combined into a single article such as a brush affixed to the terminal portion of the container wherein means are employed to prevent premature release of the cyanoacrylate prepolymeric composition. For example, the brush may be overlayed with a removable impermeable barrier. When application of the cyanoacrylate prepolymer composition is intended, the barrier is simply removed.

In another embodiment, the container and applicator means are separate articles designed to mate with each other. For example, the cyanoacrylate prepolymer composition could be stored in an amber vial sealed with a screw cap and the applicator means includes a screw mechanism which mates with the screw mechanism on the top of the vial. When application of the cyanoacrylate prepolymer composition is intended, the cap is removed from the vial and the applicator is attached. The particular container/applicator means are not critical and other such means are well within the scope of the skilled artisan including those set forth by Bolduc, U.S. Patent No. 5,154,320.30

The following examples illustrate certain embodiments of the invention but are 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). Additionally, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

gr.am kGry kiloGray mL milliliters mm millimeters

M-bca M-butyl cyanoacrylate

«-dca «-decyl cyanoacrylate

Pluronics L62 a liquid, blocked copolymer of propylene oxide and ethylene oxide with an average molecular of 2450 and comprising approximately 20 percent ethylene units

Pluronics F-68 a solid, blocked copolymer of propylene oxide and ethylene oxide with an average molecular of 8350 and comprising approximately 80 percent ethylene units ppm parts per million TSA trypticase soy agar

EXAMPLES 1-6 The following examples illustrate the preparation of several soluble antimicrobial cyanoacrylate compositions. In each of these examples, the cyanoacrylate composition comprises a mixture of the following components:

Mixture A: 80 weight percent of «-bca 20 weight percent of «-dca Mixture B: 50 weight percent of «-bca

50 weight percent of «-dca wherein the recited weight percents are weight percents based solely on the amount of each of the two components. In addition, each of Mixtures A and B comprise the following combination of polymerization inhibitors: 100 ppm SO2, 500 ppm hydroquinone, and 500 ppm 4-methoxyphenol.

Each of the above mixtures were then used to prepare antimicrobial cyanoacrylate compositions by the addition of 0.5 weight percent, 1.5 weight percent or 3 weight percent, based on the total weight of the composition, of Tamed Iodine III®, an iodine complex of polyethoxy-polypropoxy ethanol (containing approximately 20 weight percent of iodine in the complex) available from WestAgro, Kansas City, Missouri, USA) to provide for Examples 1-6 as illustrated in Table I below:

TABLE I

Figure imgf000028_0001

Each of the compositions was mixed until homogenous and approximately 10 mL of each of these compositions were separately packaged into ampules having a volume of approximately 20 mL. After filling the ampule, the open end of the ampule was capped either with a Teflon lined screw cap or crimp top. To achieve sterilization, the vials were exposed to 20 to 25 kGry of E-beams.

Certain of these compositions were tested for their ability to form a polymeric film on mammalian skin. In all cases, the tested composition cured rapidly upon contact with mammalian skin to provide a flexible and durable film where flexibility was assessed by visual evaluation to determine the ability of the film to be retained on the skin without cracking or peeling for at least 24 hours and durability was assessed by determining whether the film was retained on the skin surface for at least 24 hours EXAMPLES 7 to 9

The following examples were conducted to determine the stability of the cyanoacrylate compositions of this invention under accelerated storage conditions. In each of these examples, the cyanoacrylate composition is «-bca to which has been added the following combination of polymerization inhibitors: 100 ppm SO2, 250 ppm hydroquinone, and 250 ppm 4-methoxyphenol.

This mixture was then used to prepare soluble antimicrobial cyanoacrylate compositions by the addition of Tamed Iodine III® which is an iodine complex of polyethoxy polypropoxy ethanol available from WestAgro, Kansas City, Missouri, USA as shown in Table II. The weight concentration of the iodine complex is based on the total weight of the composition.

TABLE II

Figure imgf000029_0001

Each of the above formulations (about 10 mL) were added to 20 mL screw capped or crimp capped vials and then stored in a 50 °C oven maintained at ambient humidity for the length of time indicated in Table II. Storage under these accelerated aging conditions corresponds to about the number of months stability at ambient storage conditions as indicated in Table II.

At the end of this period, the compositions were removed and evaluated for premature polymerization, presence of solids and ability to form a polymeric film on mammalian skin. In all cases, the compositions did not polymerize under these accelerated storage conditions. In addition, there was no precipitate present in the tested formulations evidencing that the iodine complex did not precipitate from solution. Finally, as to each composition tested, it rapidly formed a cyanoacrylate film on mammalian skin.

EXAMPLE 10

The following example was conducted to determine whether the polymeric cyanoacrylate film formed from the compositions of this invention was antimicrobial. Specifically, this example employed the composition of Example 5 (mixture B with 1.5 weight percent of Tamed Iodine III — , an iodine complex of polyethoxy-polypropoxy ethanol containing approximately 20 weight percent of iodine in the complex available from WestAgro, Kansas City, Missouri, USA) and is referred to herein as the "Test Composition". This composition was tested as follows.

In all cases, a stock solution of the microbe under study was diluted in 0.9% USP sodium chloride for injection to a No. 2 McFarland Standard [provides for 106 to 107 colony forming units (CFU) per mL]. The standardized culture was added to molten Trypticase Soy Agar (TSA) at a 1 : 100 ratio. The seeded agar was poured into a sterile 100 mm diameter Petri dish and allowed to harden at room temperature. The Test Composition and the control (Penicllin G 1.0 U/mL) were applied directly into penicylinder of the seeded agar. The seeded TSA plate was then incubated at 30-35 °C for 24 hours. Following incubation, zones of inhibition were measured in mm. The zone of inhibition was measured for four replicate tests and the average given in Table III below:

Table III

Figure imgf000031_0001

The above data demonstrates that the composition of this invention possesses antimicrobial activity. EXAMPLE 11

The following example was conducted to determine whether it was possible to pass the composition composition of Mixture A described in Example 3 through a sterilizing filter assembly.

The monomeric cyanoacrylate composition of Example 3 was passed through a 0.2 μm sterile nylon filter (Millipore Corp, MA) using sterile technique into a sterile vial. The composition passed freely through the filter.

Accordingly, this demonstrates that the compositions of this invention may be readily sterilized by filtration.

EXAMPLE 12

In this example, several compositions were prepared to demonstrate the ability to form an iodine/polymer complex in situ in the cyanoacrylate ester composition by direct addition of iodine to a solution of cyanoacrylate ester and polymer. In each of these examples, the cyanoacrylate ester and polymer mixture comprised the following components:

Mixture C: 97 weight percent n-butylcyanoacrylate; 3 weight percent Pluronics L62;

Mixture D: 77.7 weight percent n-butylcyanoacrylate; 19.3 weight percent tributyl-o-acetylcitrate 3.0 weight percent Pluronics L62;

In addition, both Mixtures C and D further contained the following amounts of polymerization inhibitors:

100 ppm SO2 400 ppm hydroquinone 400 ppm 4-methoxyphenol

1000 ppm acetic acid Each of Mixtures C and D were then used to prepare antimicrobial cyanoacrylate compositions by the addition of 0.3 weight percent of iodine, based on the total weight of the composition. After addition, the compositions were mixed until the iodine dissolved and a homogeneous solution was obtained.

Both compositions were tested for their ability to form a polymeric film on mammalian skin. In both cases, the tested compositions cured rapidly upon contact with mammalian skin to provide a flexible and durable film. The films remained on the skin for at least 24 hours.

EXAMPLE 13 This example was conducted to demonstrate the synthesis of an iodine/polymer complex which can be added to the cyanoacrylate ester composition to provide for a homogeneous composition.

Diatomic iodine chips (18 g, Aldrich Chemical Company, Milwaukee, Wisconsin, USA) were added to a polyoxyalkylene polymer (82 g, Pluonics F-68, BASF Corporation, North Mount Olive, New Jersey, USA). The mixture was heated at 60 °C with stirring for one hour whereupon the solution was a rich dark brown color.

The resulting iodine/polymer mixture (3 g) was added to n-butyl cyanoacrylate (97 g) formulated with 500 ppm hydroquinone, 500 ppm 4- methoxyphenol and 250 ppm acetic acid. The solution was mixed until homogeneous. A sample of the resulting solution was applied to mammalian skin where it cured rapidly upon contact to form a flexible and durable film (for at least 24 hours).

EXAMPLE 14 This example was conducted to demonstrate the synthesis of an iodine/polymer complex in situ by addition of iodine to the cyanoacrylate ester composition followed by addition of a biocompatible polymer which forms a complex with the iodine.

Diatomic iodine chips (0.3 g) were added to n-butyl cyanoacrylate (9.7 g) and the resulting mixture was slowly agitated until all of the iodine was dissolved. Afterwards, a polyoxyalkylene polymer (3 g, Pluonics L62, BASF Corporation, North Mount Olive, New Jersey, USA) was added to the solution and mixed for five minutes at low agitation until a homogeneous solution was obtained. A sample of the resulting solution was applied to mammalian skin where it cured rapidly.

EXAMPLE 15

This example was conducted to demonstrate the affinity of the iodine for the biocompatible polymer rather than the cyanoacrylate ester.

Polyoxyalkylene polymer (3 g, Pluronics L62, BASF Corporation, North Mount Olive, New Jersey, USA) was added to a test tube. Subsequently, n-butyl cyanoacrylate (7 g) was carefully added so as to form a cyanoacrylate ester layer separate from the liquid polymer layer. At this time, diatomic iodine chips (0.1 g) were added to the test tube and dissolved without agitation. During dissolution, the polyoxyalkylene polymer layer became dark brown whereas the cyanoacrylate ester layer remained clear. After one hour, the iodine had totally dissolved and could only be seen in the polyoxyalkylene polymer layer (determined visually). The two layers were then mixed with agitation to form a homogenous solution which, when applied to mammalian skin, rapidly cured to form a polymeric film thereon.

From the foregoing description, various modifications and changes in the composition and method will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein.

Claims

WHAT IS CLAIMED IS:
1. An antimicrobial cyanoacrylate composition which comprises:
(a) a polymerizable cyanoacrylate ester; and
(b) an antimicrobially effective amount of a complex of iodine molecules with a biocompatible polymer which complex is soluble in said polymerizable cyanoacrylate ester.
2. The antimicrobial cyanoacrylate composition according to Claim 1 wherein the polymerizable cyanoacrylate ester is a polymerizable monomer or oligomer of a cyanoacrylate ester which, in monomeric form, is represented by formula I or mixtures thereof:
O CH2=C C OR i
CN wherein R is selected from the group consisting of: alkyl of 1 to 20 carbon atoms, alkenyl of 2 to 20 carbon atoms, cycloalkyl groups of from 5 to 8 carbon atoms, phenyl,
2-ethoxyethyl,
3-methoxybutyl, and a substituent of formula II:
Figure imgf000035_0001
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, alkynyl 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.
3. The antimicrobial cyanoacrylate composition according to Claim 2 wherein R is alkyl of from 2 to 20 carbon atoms.
4. The antimicrobial cyanoacrylate composition according to Claim 3 wherein R is alkyl of from 4 to 12 carbon atoms.
5. The antimicrobial cyanoacrylate composition according to Claim 2 wherein R is selected from the group consisting of methyl, butyl, pentyl, octyl, decyl or dodecyl.
6. The antimicrobial cyanoacrylate composition according to Claim 5 wherein R is «-butyl.
7. The antimicrobial cyanoacrylate composition according to Claim 1 which further comprises a biocompatible plasticizer.
8. The antimicrobial cyanoacrylate composition according to Claim 7 wherein said biocompatible plasticizer is selected from the group consisting of dioctylphthalate, octyl tributyl citrate or tributyl acetyl citrate.
9. The antimicrobial cyanoacrylate composition according to Claim 1 which further comprises a polymerization inhibitor.
10. The antimicrobial cyanoacrylate composition according to Claim 9 wherein said polymerization inhibitor is a mixture comprising hydroquinone and SO2.
11. The antimicrobial cyanoacrylate composition according to Claim 1 wherein said complex of iodine molecules with a biocompatible polymer are iodine complexes of polyoxyalkylene polymers.
12. The antimicrobial cyanoacrylate composition according to Claim 1 wherein the polyoxyalkylene polymers of said iodine complexes of polyoxyalkylene polymers are represented by formula III:
Figure imgf000037_0001
wherein R2 is selected from the group consisting of hydrogen and a hydrocarbyl group of from 1 to 30 carbon atoms; each R3 is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms; R4 is selected from the group consisting of hydrogen and a hydrocarbyl group of from 1 to 30 carbon atoms; and m is an integer from 1 to 400; with the proviso that the iodine complex of the polymers of formula III have a solubility of at least 10 mg/ml in the cyanoacrylate ester composition at 20°C.
13. The antimicrobial cyanoacrylate composition according to Claim 12 wherein R2 is selected from the group consisting of hydrogen and alkylphenyl and R4 is hydrogen.
14. The antimicrobial cyanoacrylate composition according to Claim 12 wherein R3 is hydrogen or methyl.
15. The antimicrobial cyanoacrylate composition according to Claim 12 wherein the polymers of formula III are random copolymers comprising oxyethylene and oxypropylene units.
16. The antimicrobial cyanoacrylate composition according to Claim 12 wherein the polymers of formula III are block copolymers defined by formula IV and V:
Figure imgf000038_0001
CH,
R2Q— (CH.CHO^CH^CH^p R V
where R and R are as defined above andp and q are integers independently equal to 1 to 400.
17. The antimicrobial cyanoacrylate composition according to Claim 12 wherein the polymers of formula III are block terpolymers represented by formulas VI and VII:
Figure imgf000039_0001
?H3 CH3
I I
R2Q-(CH2CHO)r-(CH2CH20)s (CΗ2CHO)tR* VI I
where R2 and R4 are as defined above and r, s and t are integers independently equal to 1 to 400.
18. A method for the preparation of antimicrobial cyanoacrylate compositions which comprises a polymerizable cyanoacrylate ester and an antimicrobially effective amount of a complex of iodine molecules with a biocompatible polymer which complex is soluble in said polymerizable cyanoacrylate ester which method comprises:
(a) adding a biocompatible polymer to a polymerizable cyanoacrylate ester;
(b) adding diatomic iodine to the composition provided in (a) above and mixing the resulting composition under conditions wherein the iodine complexes with the biocompatible polymer and forms a homogeneous solution wherein the amount of biocompatible polymer and iodine employed is sufficient to provide from about 0.5 to about 40 weight percent of the polymer/iodine complex in said cyanoacrylate ester such that the resulting composition polymer film is antimicrobial.
19. The method according to Claim 18 wherein the cyanoacrylate ester composition further comprises a polymerization inhibitor.
20. The method according to Claim 19 wherein said polymerization inhibitor is a mixture comprising hydroquinone and SO2.
PCT/US1999/030233 1998-12-18 1999-12-17 Cyanoacrylate compositions comprising a soluble antimicrobial agent WO2000035276A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US21507898A true 1998-12-18 1998-12-18
US09/215,078 1998-12-18

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
AU21964/00A AU2196400A (en) 1998-12-18 1999-12-17 Cyanoacrylate compositions comprising a soluble antimicrobial agent

Publications (1)

Publication Number Publication Date
WO2000035276A1 true WO2000035276A1 (en) 2000-06-22

Family

ID=22801551

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/030233 WO2000035276A1 (en) 1998-12-18 1999-12-17 Cyanoacrylate compositions comprising a soluble antimicrobial agent

Country Status (2)

Country Link
AU (1) AU2196400A (en)
WO (1) WO2000035276A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002058757A1 (en) * 2001-01-23 2002-08-01 Creavis Gesellschaft Für Technologie Und Innovation Mbh Antimicrobial incision films
EP1305049A1 (en) * 2000-07-27 2003-05-02 Flowers Park Limited Methods for treating burns on mammalian skin to reduce the risk of infection and to minimize fluid loss
US6585967B2 (en) 2001-07-05 2003-07-01 Closure Medical Corporation Adhesive treatment for tinea cruris
US6602496B2 (en) * 2001-07-05 2003-08-05 Closure Medical Corporation Adhesive treatment for tinea corporis
US6746667B2 (en) * 2001-07-05 2004-06-08 Closure Medical Corporation Adhesive treatment for tinea pedis
US6767552B2 (en) 2001-07-05 2004-07-27 Closure Medical Corporation Adhesive treatment for oral fungal infection
WO2005025629A1 (en) * 2003-09-08 2005-03-24 Ethicon, Inc. Cyanoacrylate monomer formulation containing diiodomethyl-p-tolylsulfone
US6942875B2 (en) 2001-07-05 2005-09-13 Closure Medical Corporation Adhesive treatment for skin yeast infections
US20120219497A1 (en) * 2003-02-12 2012-08-30 Syncera, Inc. Random ethylene oxide and non-random alkylene oxide(s) polymers

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5335373A (en) * 1991-11-29 1994-08-09 Dresdner Jr Karl P Protective medical gloves and methods for their use
US5807563A (en) * 1997-01-10 1998-09-15 Medlogic Global Corporation Methods for draping surgical incision sites

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5335373A (en) * 1991-11-29 1994-08-09 Dresdner Jr Karl P Protective medical gloves and methods for their use
US5807563A (en) * 1997-01-10 1998-09-15 Medlogic Global Corporation Methods for draping surgical incision sites

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1305049A1 (en) * 2000-07-27 2003-05-02 Flowers Park Limited Methods for treating burns on mammalian skin to reduce the risk of infection and to minimize fluid loss
EP1305049A4 (en) * 2000-07-27 2004-04-21 Medlogic Global Ltd Methods for treating burns on mammalian skin to reduce the risk of infection and to minimize fluid loss
WO2002058757A1 (en) * 2001-01-23 2002-08-01 Creavis Gesellschaft Für Technologie Und Innovation Mbh Antimicrobial incision films
US6585967B2 (en) 2001-07-05 2003-07-01 Closure Medical Corporation Adhesive treatment for tinea cruris
US6602496B2 (en) * 2001-07-05 2003-08-05 Closure Medical Corporation Adhesive treatment for tinea corporis
US6746667B2 (en) * 2001-07-05 2004-06-08 Closure Medical Corporation Adhesive treatment for tinea pedis
US6767552B2 (en) 2001-07-05 2004-07-27 Closure Medical Corporation Adhesive treatment for oral fungal infection
US6942875B2 (en) 2001-07-05 2005-09-13 Closure Medical Corporation Adhesive treatment for skin yeast infections
US20120219497A1 (en) * 2003-02-12 2012-08-30 Syncera, Inc. Random ethylene oxide and non-random alkylene oxide(s) polymers
US9919074B2 (en) * 2003-02-12 2018-03-20 Syncera, Inc. Random ethylene oxide and non-random alkylene oxide(s) polymers
WO2005025629A1 (en) * 2003-09-08 2005-03-24 Ethicon, Inc. Cyanoacrylate monomer formulation containing diiodomethyl-p-tolylsulfone
US8337881B2 (en) 2003-09-08 2012-12-25 Ethicon, Inc. Cyanoacrylate monomer formulation containing diiodomethyl-p-tolylsulfone

Also Published As

Publication number Publication date
AU2196400A (en) 2000-07-03

Similar Documents

Publication Publication Date Title
Balamurugan et al. An in vitro biological and anti-bacterial study on a sol–gel derived silver-incorporated bioglass system
DE69433939T2 (en) hemostatic plaster
EP0398489B1 (en) Film-forming emulsion containing iodine and methods of use
US7122205B2 (en) Bioerodable polymeric adhesives for tissue repair
US6281265B1 (en) Curable compositions with antimicrobial properties
JP2761392B2 (en) Medical sealant compositions and methods for their preparation
JP4663983B2 (en) Disinfectant compositions and methods
JP3299513B2 (en) Stabilizing monomer adhesive composition
DE69637198T2 (en) Redox and substrates photoinitiator system for primer of improved adhäsion of gelen
De Deus et al. Cytotoxicity of MTA and Portland cement on human ECV 304 endothelial cells
US6306243B1 (en) pH-modified biocompatible monomer and polymer compositions
US4191740A (en) Synthetic resin-base, antibiotic compositions containing amino acids
AU720106B2 (en) Antimicrobial containing solventless hot melt adhesive composition
US7641893B2 (en) Conformable solvent-based bandage and coating material
Montanaro et al. Cytotoxicity, blood compatibility and antimicrobial activity of two cyanoacrylate glues for surgical use
US6620846B1 (en) Absorbable adhesive compositions
US5733949A (en) Antimicrobial adhesive composition for dental uses
Quinn et al. N-2-butylcyanoacrylate: risk of bacterial contamination with an appraisal of its antimicrobial effects
EP0109310B1 (en) Absorbable hemostatic composition
Hauman et al. Biocompatibility of dental materials used in contemporary endodontic therapy: a review. Part 1. Intracanal drugs and substances
US5580565A (en) Use of cyanoacrylate adhesives for providing a protective barrier film for the skin
US7795326B2 (en) Conformable bandage and coating material
CN1780596B (en) Random and non-random alkylene oxide polymer alloy compositions
Alt et al. An in vitro assessment of the antibacterial properties and cytotoxicity of nanoparticulate silver bone cement
Zhang et al. Mussel-inspired hyperbranched poly (amino ester) polymer as strong wet tissue adhesive

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase