WO1999055374A1 - Use of an adhesive composition over a bioactive polymerization initiator or accelerator - Google Patents
Use of an adhesive composition over a bioactive polymerization initiator or accelerator Download PDFInfo
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- WO1999055374A1 WO1999055374A1 PCT/US1999/009374 US9909374W WO9955374A1 WO 1999055374 A1 WO1999055374 A1 WO 1999055374A1 US 9909374 W US9909374 W US 9909374W WO 9955374 A1 WO9955374 A1 WO 9955374A1
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- medicament
- kit
- polymerization
- cyanoacrylate
- tissue
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
Definitions
- the invention relates to the use of monomer and polymer compositions as biomedical adhesives and sealants, and particularly to their use in conjunction with bioactive materials.
- Sutures are recognized to provide adequate wound support.
- sutures cause additional trauma to the wound site (by reason of the need for the needle and suture to pass through tissue and the need to anesthetize the wound area via needle puncture) and are time-consuming to place, and, at skin level, can cause unattractive wound closure marks.
- Surgical staples have been developed to speed wound apposition and provide improved cosmetic results.
- surgical staples also impose additional wound trauma and require the use of ancillary and often expensive devices for positioning and applying the staples. Both sutures and staples are especially problematic in pediatric cases where the patient may have a strong fear response and refuse to cooperate with their placement, and in geriatric cases where the skin tissue is weaker and prone to tearing.
- adhesives have been used in wound closure.
- adhesives have been proposed for use in wound covering and protection in such topical applications as surface lacerations, abrasions, burns, stomatitis, and other open surface wounds.
- One group of such adhesives is the 1,1- disubstituted ethylene monomers, such as the monomeric forms of ⁇ -cyanoacrylates.
- U.S. Patent No. 5,684,042 to Greff et al. discloses a cyanoacrylate composition comprising an antimicrobially-effective amount of an iodine-containing antimicrobial agent.
- the iodine-containing antimicrobial agent is dispersible in the cyanoacrylate composition 2 and does not cause premature polymerization of the cyanoacrylate adhesive (i.e., does not initiate polymerization).
- U.S. Patent No. 3,483,870 to Coover, et al. discloses the use of methyl ⁇ - cyanoacrylate as a bone cement.
- the ⁇ -cyanoacrylate may be blended with antibiotics so long as the antibiotics do not cause early polymerization (i.e., do not act as polymerization initiators) or cause adverse effects on the healing process.
- Another method for treating or preventing infections associated with wounding using adhesives involves layering a cyanoacrylate over a medicament on a wound site.
- U.S. Patent No. 5,580,565 to Tighe, et al. discloses the use of a topical ⁇ - cyanoacrylate tissue adhesive to form a protective barrier over intact or broken skin to allow healing of the skin to occur. Polymerization of the ⁇ -cyanoacrylate adhesive is initiated by contact with skin moisture and tissue protein. Tighe et al. also disclose the use of ⁇ -cyanoacrylate adhesives as a protective layer over medicaments. The only medicament exemplified by Tighe et al. is cortisone, which does not initiate polymerization of cyanoacrylate monomer compositions.
- cyanoacrylate adhesives to cover bioactive agents is also disclosed in: Miles et al., Oral Surgery, Oral Medicine, Oral Pathology, Vol. 75, No. 3, 397-402 (using triamcinolone acetonide (Kenalog) or chlorhexidine digluconate (Peridex) as the bioactive agent); and Kaufman, R.S., The Laryngoscope, 1974, 793-804 (using dexamethasone sodium phosphate (Decadron) as the bioactive agent).
- U.S. Patent No. 4,669,491 to Weisberg et al. discloses the use of biocides covered by protective acrylic artificial nails.
- the biocides may be acidic or phenolic, but are preferably selected so as not to affect the cure rate or the bond strength of the glue layer.
- antibiotics include thymol, chlorothymol, benzoic acid, p-hydroxybenzoate alkyl esters, 4- and 6-phenyl-2-chlorophenyl, carvocrol, hexachlorophene, nitroforans, allicin, 2-phenylphenol, boric acid, mercurials, and such antibiotics as Bacitracin and Griseofulvin, quaternary ammonium halides such as n-alkyldimethylbenzylammonium chloride, cetyl pyridinium bromide, 5-methyl-2-isopropyl-cyclohexanol, 2-bornanone, cineole, safrole, bornyl chloride, 2-phenoxyethanol, benzylalcohol and ethanol.
- the biocides are applied to human fingernails, then covered by solutions comprising cyanoacrylate adhesive.
- the biocides are applied to the natural fingernails in a solution, and the solution is allowed to dry, leaving the active biocides on the nails.
- the biocide- treated fingernails are roughened with an abrasive, then coated with a monomeric cyanoacrylate solution to form the artificial fingernails.
- the cyanoacrylate monomers are polymerized by the addition of a polymethacrylate ester composition containing a benzoyl peroxide catalyst. There is no suggestion of selecting the monomers and biocides such that the biocides affect polymerization.
- U.S. Patents Nos. 4,764,377 and 4,892,736 to Goodson disclose the use of a therapeutic agent and a cyanoacrylate adhesive for treatment of periodontal diseases.
- the therapeutic agent is placed within the periodontal pocket, then covered by a mechanical maintenance system (which may be in the form of a layer of an adhesive film, such as n-butylcyanoacrylate), which holds the therapeutic agent in the periodontal pocket, allowing the therapeutic agent to be administered to the periodontal site.
- Goodson and co-workers also disclose this type of system in, for example, "J. Periodont. Res", 1990, Vol. 25, 243-249, and "Recent Advances in Periodontology", Vol. 11, 61-
- the therapeutic agents include antibacterial agents such as iodine, sulfonamides, mercurials, bisbiguanides, or phenolics; antibiotics such as tetracycline, neomycin, kanamycin, metranidazole, or canamycin; anti-inflammatory agents such as indomethacin, eugenol, or hydrocortisone; immunosuppressive or stimulatory agents such as methotrexate or levamasole; dentinal desensitizing agents such as strontium chloride or sodium fluoride; odor masking agents such as peppermint oil or chlorophyll; immune reagents such as immunoglobulin or antigens; local anesthetic agents such as lidocaine or benzocaine; nutritional agents such as amino acids, essential fats, and vitamin C; antioxidants such as alphatocopherol and butylated hydroxy toluene; lipopolysaccharide complexing agents such as polymyxin;
- U.S. Patents Nos. 5,514,371 and 5,624,669 to Leung, et al. disclose the addition of a therapeutic agent in a cyanoacrylate composition.
- the cyanoacrylate adhesive forms a matrix for the therapeutic agent, with the therapeutic agent being released in vivo over time from the matrix during biodegradation of the polymer.
- the therapeutic agent is not used as a polymerization initiator or a polymerization rate modifier.
- U.S. Patent No. 4,940,579 to Randen discloses a composition comprising a medicament and a cyanoacrylate adhesive.
- the composition is used to deliver medicaments to non-mucosal areas of mammal bodies.
- Randen does not disclose the use of medicaments as polymerization initiators and/or rate accelerators.
- U.S. Patent No. 5,254,132 to Barley et al. discloses the use of cyanoacrylate adhesives in conjunction with antibiotics. The antibiotics are added to the cyanoacrylate compositions and stored in a sterile applicator for use in a single-dose application. The composition is maintained in a sealed container to avoid polymerization prior to application; therefore, the antibiotic does not initiate or accelerate polymerization of the adhesive composition.
- cyanoacrylate adhesives are applied in monomeric form to the surfaces to be joined, sealed, or otherwise treated.
- in situ anionic polymerization of the monomer occurs, giving rise to the desired adhesive bond or covering.
- Initiation of polymerization in situ typically utilizes moisture and/or proteins naturally present in the tissue being treated.
- tissue fluids it is not necessary to add polymerization initiators or rate accelerators to cyanoacrylate composition.
- the caffeine or theobromine can be mixed with the cyanoacrylate adhesive composition by stirring just prior to application of the adhesive to the substrates to be joined.
- the caffeine or theobromine is dissolved in a volatile solvent, applied to the surfaces to be joined, the volatile solvent is allowed to evaporate, and then the cyanoacrylate adhesive composition is applied to the surfaces of the substrates to be joined.
- the present invention provides methods and compositions that use pharmaceutically- effective amounts of medicaments as polymerization initiators or accelerators for monomeric adhesive compositions.
- a medicament acts as both an initiator and/or an accelerator of polymerization of a monomeric adhesive composition and as a pharmaceutically active material.
- a polymerization initiator is any material that causes a cyanoacrylate composition applied to a substantially dry tissue 6
- a polymerization accelerator is any material that accelerates the rate of polymerization of a cyanoacrylate composition such that polymerization that would normally take more than 300 seconds at ambient temperature, for example at approximately 21-25°C occurs in less than 300 seconds, preferably in less than 150 seconds, and more preferably in less than 135 seconds.
- the initiator or rate accelerator can be, for example, a catalyst, but can also be a material that is consumed or chemically modified during the polymerization reaction.
- the medicament can be any material that has both a pharmaceutical effect as applied and a polymerization initiating or rate accelerating activity, including, but not limited to, antibiotics, antimicrobials, antiseptics, bacteriocins, bacteriostats, disinfectants, steroids, anesthetics, fungicides, anti-inflammatory agents, antibacterial agents, antiviral agents, antitumor agents, and tissue growth promoting substances.
- the invention provides, among other things, a method of closing, sealing, covering, and/or protecting deep and/or surface wounds, such as those resulting from surgery or from lacerations, burns, sores, abrasions, and the like.
- the method includes laying down a medicament onto a wound or sore and applying over the medicament a polymerizable monomer-containing composition whose polymerization is initiated or accelerated by the medicament.
- the invention also provides a method of delivering a medicament locally or systemically to a human or animal by applying the medicament to a tissue site and applying over the medicament a polymerizable monomer-containing composition whose polymerization is initiated or accelerated by the medicament.
- tissue includes any tissue of a human or animal, such as skin, mucous membranes, oral/nasal tissues, gastrointestinal tissues, organ tissues, tumors, non- keratinous tissue, etc.
- the present invention also provides a kit comprising a saleable package containing (i) a container of a polymerizable monomer composition such as described herein, and (ii) a container of a medicament, preferably one that acts as a polymerization 7 initiator or polymerization rate modifier for said monomer composition.
- the containers can preferably be in the form of, or part of, an applicator or applicator system and are preferably sterilizable.
- the package and its contents can preferably be sterilized simultaneously.
- the present invention also provides a manufacture of a package comprising a polymerizable monomer composition and an instruction sheet for a method of delivering a medicament to a patient, the method comprising: applying a pharmaceutically effective amount of a medicament to a tissue of said patient, and applying a polymerizable monomer composition onto the medicament, wherein the medicament is a polymerization initiator or polymerization rate accelerator and causes polymerization of the monomer composition to form a polymeric adhesive covering to said tissue.
- the present invention provides several advantages over wound treating methods now in use, including the ability to: a) control the molecular weight distribution of the polymerized or cross- linked material (through the use of the polymerization initiator and/or polymerization rate accelerator); b) control the setting time of the polymerized or cross-linked cyanoacrylate adhesive; c) control the flow properties of polymerizable cyanoacrylate compositions; d) provide a medicament to a patient while simultaneously providing wound closure, protection, and/or coverage; e) provide a medicament to a patient through topical administration; and/or f) any combination of the above.
- a medicament is applied to a tissue prior to application of the monomer-containing composition.
- the medicament acts to initiate and/or accelerate polymerization of the monomer composition.
- the medicament provides not only a biological activity, but a chemical one as well. 8
- medicaments include, but are not limited to antibiotics, antimicrobials, antiseptics, bacteriocins, bacteriostats, disinfectants, steroids, anesthetics, fungicides, anti-inflammatory agents, antibacterial agents, antiviral agents, antitumor agents, growth promoters, and mixtures thereof.
- Exemplary medicaments include, but are not limited to, quaternary ammonium halides such as benzalkonium chloride and benzethonium chloride; chlorhexidine sulfate; gentamicin sulfate; hydrogen peroxide; quinolone thioureas; silver salts, including, but not limited to, silver acetate, silver benzoate, silver carbonate, silver chloride, silver citrate, silver iodide, silver nitrate, and silver sulfate; sodium hypochlorite; salts of sulfadiazine, including, but not limited to silver, sodium, and zinc salts; and mixtures thereof.
- quaternary ammonium halides such as benzalkonium chloride and benzethonium chloride
- chlorhexidine sulfate such as benzalkonium chloride and benzethonium chloride
- gentamicin sulfate gentamicin sulfate
- Preferable medicaments are those that are anions or help in radical generation or that are ion pairs or are themselves radicals.
- the medicament is preferably a quaternary ammonium halide such as alkylbenzyldimethylammomum chloride (benzalkonium chloride; BAC) with an alkyl containing 6-18 carbon atoms, its pure components, or mixtures thereof, or benzethonium chloride; or a salt of sulfadiazine, such as a silver, sodium, or zinc salt.
- a quaternary ammonium halide such as alkylbenzyldimethylammomum chloride (benzalkonium chloride; BAC) with an alkyl containing 6-18 carbon atoms, its pure components, or mixtures thereof, or benzethonium chloride; or a salt of sulfadiazine, such as a silver, sodium, or zinc salt.
- the medicaments can be tested for initiation ability by pipetting an appropriate volume of a solution of the medicament prepared in a volatile solvent in a differential scanning calorimetric aluminum pan.
- the volatile solvent is allowed to dry under ambient conditions.
- the appropriate quantity of the medicament is dispensed directly onto the differential scanning calorimetric pan.
- 25 ⁇ l of the chosen monomer solution is pipetted into the pan.
- the time taken for the monomer composition to polymerize to the point of a gel is the polymerization time.
- the composition can comprise other polymerization initiators and/or rate accelerators in addition to the medicament.
- additional initiators for particular systems may be readily selected by one of skill in the art without undue experimentation.
- Suitable additional polymerization initiators for the cyanoacrylate compositions include, but are not limited to, other medicaments; detergent compositions; surfactants: e.g., nonionic surfactants such as polysorbate 20 (e.g., Tween 20TM; ICI Americas), polysorbate 80 (e.g., Tween 80TM; ICI Americas), and poloxamers; 9 cationic surfactants such as tetrabutylammomum bromide and benzethonium chloride or its pure components; anionic surfactants such as, stannous octoate (tin (LI) 2- ethylhexanoate), and sodium tetradecyl sulfate; and amphoteric or zwitterionic surfactants such as dodec
- the polymerizable and/or cross-linkable material may also contain an initiator which is inactive until activated by a catalyst or accelerator (included within the scope of the term "initiator” as used herein).
- a catalyst or accelerator included within the scope of the term "initiator” as used herein.
- These initiators can be activated by appropriate stimulation such as heat and/or light (e.g., ultraviolet or visible light).
- compositions employed in the invention are preferably sterilizable.
- the amount of medicament applied should be an amount sufficient to cause initiation or acceleration of the rate of polymerization upon contact and mixing of the medicament with the monomeric composition.
- the medicament should also be applied in a pharmaceutically-effective amount and should be selected in conjunction with the specific polymerizable monomeric compound such that the medicament will function as a polymerization imtiator and/or rate accelerator for the chosen monomer. Such a selection process can easily be performed by one of skill in the art.
- the medicament can have a pharmaceutical effect only at the site of application (i.e., limited to the tissue on/in which it is applied), or it can have a systemic effect (by systemic, it is not only meant that the medicament has an effect throughout the patient's body, but also at a specific site other than the site of application).
- systemic it is not only meant that the medicament has an effect throughout the patient's body, but also at a specific site other than the site of application.
- the medicament can be absorbed, transported, or otherwise distributed to the 10 site or sites within the patient where the pharmaceutical activity is desired, e.g., through the cardiovascular or lymph systems.
- the medicament and adhesive compositions of this invention can be applied by any appropriate device, which can be the same or different for the medicament and adhesive composition.
- examples include, but are not limited to, a glass stirring rod, sterile brush, or medicine dropper.
- a pump or pressurized aerosol dispensing package is preferred in which the adhesive composition is in solution with a compatible anhydrous propellant.
- a preferred device is an absorbent swab or wipe.
- the medicament may be in the form of a solid, such as a powder or a solid film, or in the form of a liquid, such as a watery, viscous, or paste-like material.
- the medicament may also be compounded with a variety of additives, such as surfactants or emulsif ⁇ ers, and vehicles.
- the methods of this invention can be used to join together two surfaces, as a replacement for or in addition to sutures, by applying the present compositions to opposing wound surfaces that are then held together while polymerization proceeds.
- the methods of this invention can also be used to coat, protect, or otherwise cover surface, superficial, or otherwise topical wounds or pathologies including, but not limited to, superficial lacerations, abrasions, burns, sores, and stomatitis.
- the methods of the invention can also be used on tissues that do not show any signs of tissue damage.
- the methods can be used to deliver medicaments to a patient through healthy tissue. They can also be used, for example, to locally deliver medicaments to tissues such as tumors or organs.
- the present invention provides a replacement for sutures and includes a method of delivering a medicament to a tissue by forming a biocompatible film across abutted tissue surfaces, comprising: (a) holding together at least two tissue surfaces to form abutted tissue surfaces, (b) applying a medicament which is a polymerization initiator or polymerization rate accelerator to the abutted tissue surfaces, (c) applying on to the medicament and across the abutted tissue surfaces a polymerizable adhesive monomer composition, and (d) allowing the composition to polymerize and form a biocompatible film on the abutted tissue surfaces.
- a subsequent coating may be applied immediately after application of a previous coating or after a 11 previous coating has been completely polymerized.
- the monomer composition applied to the abutted tissue surface is allowed to at least partially polymerize prior to subsequent coatings or applications of additional monomer composition.
- a coating of an adhesive composition having a monomer different from the monomer of the first or previous coating may be applied as the second or subsequent coating.
- Suitable film thickness range from 0.1 mm to 2.0 mm or 3.0 mm or higher, preferably from 0.2 mm to 1.5 mm, and more preferably from 0.4 mm to 0.8 mm.
- the biocompatible film formed as a replacement for sutures may have an in vivo film strength of at least 70 mm Hg of vacuum pressure required to induce wound failure, generally from 70 mm Hg to 400 mm Hg of vacuum pressure required to induce wound failure, preferably from 90 mm Hg to 400 mm Hg of vacuum pressure required to induce wound failure, and more preferably from 100 mm Hg to 400 mm Hg of pressure required to induce wound failure.
- the invention comprises first sponging the site to be repaired to remove superficial or body tissue fluids. Desired bonding of tissues or hemostasis can also proceed well in the presence of blood and other body fluids as well as on dry tissue. The bonds formed are of adequate flexibility and strength to withstand normal movement of tissue. In addition, bond strength is maintained as natural wound healing proceeds.
- the present invention is directed to a method of treating a superficial or topical pathology, including, but not limited to a skin wound such as a superficial laceration, burn, or abrasion, or a sore on a mucous membrane.
- the method comprises (a) applying a medicament that is a polymerization initiator or rate accelerator to the affected tissue, (b) applying a polymerizable monomer-containing composition over the medicament; (c) allowing the composition to polymerize; and (d) optionally, applying the composition at least once more to the same site.
- Suitable film thickness for such topical applications is preferably between 1 and 10,000 ⁇ m, for example between 1 and 1000 ⁇ m.
- the biocompatible 12 film so formed may have a film strength of at least 5 mm Hg, such as 5-400 mm Hg, preferably from 50-400 mm Hg.
- the present invention provides a method of delivering a medicament to a tissue by (a) applying a medicament that is a polymerization initiator and/or polymerization rate accelerator to a site (e.g., directly to tissue); (b) applying a polymerizable monomer-containing composition over the medicament; and (c) optionally, applying the composition at least once more to the same site.
- a medicament that is a polymerization initiator and/or polymerization rate accelerator to a site (e.g., directly to tissue);
- a site e.g., directly to tissue
- a polymerizable monomer-containing composition e.g., directly to tissue
- Suitable film thickness and strength are preferably those disclosed above for other uses.
- the medicament is released to the tissue to which it is in contact at a constant, or near constant, rate over a period of time while in contact with the affected tissue.
- the present invention also provides a kit for delivering a medicament to a patient.
- the kit comprises a container with a polymerizable monomer composition, such as a cyanoacrylate adhesive.
- the kit also comprises another container with a medicament.
- the medicament is selected so that it functions in conjunction with the co- packaged polymerizable monomer composition to initiate polymerization of the monomer or modify (e.g., accelerate) the rate of polymerization for the monomer to form a polymeric adhesive.
- the proper combination of medicament and polymerizable monomer can be determined easily by one of skill in the art.
- the medicament is supplied in the kit in an amount that will be pharmaceutically effective when applied topically (i.e., directly to tissue).
- the monomer composition in embodiments, is preferably a monomeric (including prepolymeric) adhesive composition.
- the monomer is a 1,1- disubstituted ethylene monomer, e.g., an ⁇ -cyanoacrylate.
- Preferred monomer compositions of the present invention and polymers formed therefrom are useful as tissue adhesives, sealants for preventing bleeding or for covering open wounds, and in other biomedical applications.
- Monomers that may be used in this invention are readily polymerizable, e.g. anionically polymerizable or free radical polymerizable, or polymerizable by zwitterions or ion pairs to form polymers.
- Such monomers include those that form polymers, that may, but do not need to, biodegrade.
- Such monomers are disclosed in, for example, U.S. Patent No. 5,328,687 to Leung, et al., which is hereby incorporated in its entirety by reference herein.
- Useful 1,1-disubstituted ethylene monomers include, but are not limited to, monomers of the formula:
- Preferred monomers of formula (I) for use in this invention are alpha- cyanoacrylates. These monomers are known in the art and have the formula
- R 2 is hydrogen and R 3 is a hydrocarbyl or substituted hydrocarbyl group; a group having the formula -R 4 -O-R 5 -O-R 6 , wherein R 4 is a 1,2-alkylene group having 2-4 carbon atoms, R 5 is an alkylene group having 2-4 carbon atoms, and R 6 is an alkyl group having 1-6 carbon atoms; or a group having the formula
- n 1-10, preferably 1-5 carbon atoms and R 8 is an organic moiety.
- suitable hydrocarbyl and substituted hydrocarbyl groups include straight chain or branched chain alkyl groups having 1-16 carbon atoms; straight chain or branched chain C,-C, 6 alkyl groups substituted with an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom, a cyano group, or a haloalkyl group; straight chain or branched chain alkenyl groups having 2 to 16 carbon atoms; straight chain or branched chain alkynyl groups having 2 to 12 carbon atoms; cycloalkyl groups; aralkyl groups; alkylaryl groups; and aryl groups.
- the organic moiety R 8 may be substituted or unsubstituted and may be straight chain, branched or cyclic, saturated, unsaturated or aromatic.
- organic moieties include C,-C 8 alkyl moieties, C 2 -C 8 alkenyl moieties, C 2 -C 8 alkynyl moieties, C 3 -C I2 cycloaliphatic moieties, aryl moieties such as phenyl and substituted phenyl and aralkyl moieties such as benzyl, methylbenzyl and phenylethyl.
- organic moieties include substituted hydrocarbon moieties, such as halo (e.g., chloro-, fluoro- and bromo- substituted hydrocarbons) and oxy- (e.g., alkoxy substituted hydrocarbons) substituted hydrocarbon moieties.
- Preferred organic radicals are alkyl, alkenyl and alkynyl moieties having from 1 to about 8 carbon atoms, and halo-substituted derivatives thereof. Particularly preferred are alkyl moieties of 4 to 6 carbon atoms.
- R 3 is preferably an alkyl group having 1-10 carbon atoms or a group having the formula -AOR 9 , wherein A is a divalent straight or branched chain alkylene or oxyalkylene moiety having 2-8 carbon atoms, and R 9 is a straight or branched alkyl moiety having 1-8 carbon atoms.
- groups represented by the formula -AOR 9 include l-methoxy-2- propyl, 2-butoxy ethyl, isopropoxy ethyl, 2-methoxy ethyl, and 2-ethoxy ethyl.
- Preferred ⁇ -cyanoacrylate monomers used in this invention include 2-octyl cyanoacrylate, dodecyl cyanoacrylate, 2-ethylhexyl cyanoacrylate, butyl cyanoacrylate, methyl cyanoacrylate, 3-methoxybutyl cyanoacrylate, 2-butoxyethyl cyanoacrylate, 2- isopropoxyethyl cyanoacrylate, or l-methoxy-2-propyl cyanoacrylate. 15
- the ⁇ -cyanoacrylates of formula (II) can be prepared according to methods known in the art.
- the ⁇ -cyanoacrylates can be prepared by reacting an alkyl cyanoacetate with formaldehyde in a non-aqueous organic solvent and in the presence of a basic catalyst, followed by pyrolysis of the anhydrous intermediate polymer in the presence of a polymerization inhibitor.
- the ⁇ -cyanoacrylate monomers prepared with low moisture content and essentially free of impurities are preferred for biomedical use.
- R 4 -O-R :> -O-R 6 can be prepared according to the method disclosed in U.S. Patent No. 4,364,876 to Kimura et al, which is hereby incorporated in its entirety by reference. In the Kimura et al.
- the ⁇ -cyanoacrylates are prepared by producing a cyanoacetate by esterifying cyanoacetic acid with an alcohol or by transesterifying an alkyl cyanoacetate and an alcohol; condensing the cyanoacetate and formaldehyde or para-formaldehyde in the presence of a catalyst at a molar ratio of 0.5-1.5:1, preferably 0.8-1.2:1, to obtain a condensate; depolymerizing the condensation reaction mixture either directly or after removal of the condensation catalyst to yield crude cyanoacrylate; and distilling the crude cyanoacrylate to form a high purity cyanoacrylate.
- ⁇ -cyanoacrylate monomers are prepared by reacting an alkyl ester of an ⁇ -cyanoacrylic acid with a cyclic 1,3-diene to form a Diels- Alder adduct which is then subjected to alkaline hydrolysis followed by acidification to form the corresponding ⁇ -cyanoacrylic acid adduct.
- the ⁇ -cyanoacrylic acid adduct is preferably esterified by an alkyl bromoacetate to yield the corresponding carbalkoxymethyl ⁇ -cyanoacrylate adduct.
- the ⁇ -cyanoacrylic acid adduct may be converted to the ⁇ -cyanoacrylyl halide adduct by reaction with thionyl 16 chloride.
- the ⁇ -cyanoacrylyl halide adduct is then reacted with an alkyl hydroxyacetate or a methyl substituted alkyl hydroxyacetate to yield the corresponding carbalkoxymethyl ⁇ -cyanoacrylate adduct or carbalkoxy alkyl ⁇ -cyanoacrylate adduct, respectively.
- the cyclic 1,3-diene blocking group is finally removed and the carbalkoxy methyl ⁇ -cyanoacrylate adduct or the carbalkoxy alkyl ⁇ -cyanoacrylate adduct is converted into the corresponding carbalkoxy alkyl ⁇ -cyanoacrylate by heating the adduct in the presence of a slight deficit of maleic anhydride.
- Examples of monomers of formula (II) include cyanopentadienoates and ⁇ - cyanoacrylates of the formula:
- the monomers of formula (III) wherein R 3 is an alkyl group of 1-10 carbon atoms i.e., the 2-cyanopenta-2,4-dienoic acid esters
- R 3 is an alkyl group of 1-10 carbon atoms
- a catalyst such as zinc chloride
- Preferred monomers are alkyl ⁇ -cyanoacrylates and more preferably octyl ⁇ - cyanoacrylates, especially 2-octyl ⁇ -cyanoacrylate.
- Monomers utilized in the present application should be very pure and contain few impurities (e.g., surgical grade).
- the composition nay optionally also include at least one plasticizing agent that imparts flexibility to the polymerized monomer formed o the wound, incision, or abrasion.
- the plasticizing agent preferably contains little or no moisture and should not significantly affect the polymerization of the monomer.
- plasticizers examples include acetyl tributyl citrate, dimethyl sebacate, triethyl phosphate, tri(2-ethylhexyl)phosphate, tri(p-cresyl) phosphate, glyceryl triacetate, glyceryl tributyrate, diethyl sebacate, dioctyl adipate, isopropyl 17 myristate, butyl stearate, lauric acid, trioctyl trimellitate, dioctyl glutarate and mixtures thereof.
- Preferred plasticizers are tributyl citrate and acetyl tributyl citrate.
- suitable plasticizers include polymeric plasticizers, such as polyethylene glycol (PEG) esters and capped PEG esters or ethers, polyester glutarates and polyester adipates.
- composition may also optionally include at least one stabilizing agent that inhibits polymerization.
- stabilizing agents may also include mixtures of anionic stabilizing agents and radical stabilizing agents.
- anionic stabilizing agents include, but are not limited to, sultones (e.g., ⁇ -chloro- ⁇ -hydroxy-o-toluenesulfonic acid- ⁇ -sultone), sulfur dioxide, sulfuric acid, sulfonic acid, lactone, boron trifluoride, organic acids, such as acetic acid or phosphoric acid, alkyl sulfate, alkyl sulfite, 3-sulfolene, alkylsulfone, alkyl sulfoxide, mercaptan, and alkyl sulfide and mixtures thereof.
- Preferable anionic stabilizing agents are acidic stabilizing agents of organic acids such as acetic acid or phosphoric acid.
- the amount of sulfur dioxide stabilizer is less than 100 ppm, preferably 5-
- the amount of sultone and/or trifluoracetic acid is about 500-3000 ppm.
- radical stabilizing agents examples include hydroquinone, hydroquinone monomethyl ether, catechol, pyrogallol, benzoquinone, 2- hydroxybenzoquinone, p-methoxy phenol, t-butyl catechol, butylated hydroxy anisole
- BHA butylated hydroxy toluene
- t-butyl hydroquinone the amount of BHA is about 1,000-5,000 ppm.
- Suitable acidic stabilizing agents include those having aqueous pK, ionization constants ranging from -12 to 7, about -5 to about 7, preferably from about -3.5 to about 6.
- suitable acidic stabilizing agents include: hydrogen sulfide (pI 7.0), carbonic acid (pK, 6.4), triacetylmethane (pK, 5.9), acetic acid (pK, 4.8), benzoic acid (pK, 4.2), 2,4-dinitrophenol (pK, 4.0), formic acid (pK, 3.7), nitrous acid (pK, 3.3), hydrofluoric acid (pK, 3.2), chloroacetic acid (pK, 2.9), phosphoric acid (pK, 2.2), dichloroacetic acid (pK, 1.3), trichloroacetic acid (pK, 0.7), 2,4,6-trinitrophenol (picric acid) (pK,, 0.3), trifluoroacetic acid (pK, 0.2), sulfuric acid (pK
- the amount of trifluoroacetic acid is about 500-1,500 ppm.
- Combinations of the above stabilizers such as sulfur dioxide and 18 sulfuric acid, boron trifluoride and sulfuric acid, sulfur dioxide and chloroacetic acid, boron trifluoride and chloroacetic acid, sulfur dioxide and trifluoroacetic acid, and boron trifluoride and triflouroacetic acid can be used.
- the addition of plasticizing agents in amounts ranging from about 0.5 wt.% to about 16 wt.%, preferably from about 3 wt.% to about 9 wt.%, and more preferably from about 5 wt.% to about 7 wt.% provides increased film strength (e.g., toughness) of the polymerized monomer over polymerized monomers having amounts of plasticizing agents and acidic stabilizing agents outside of the above ranges.
- the concentration of the acidic stabilizing agents utilized may vary depending on the strength of the acid.
- a concentration of 80- 200 ppm (wt/wt), preferably 90-180 ppm (wt/wt), and more preferably 100-150 ppm (wt/wt) may be utilized.
- a concentration range of 20-80 ppm (wt/wt), preferably, 30-70 ppm (wt/wt) and more preferably 40-60 ppm (wt/wt) may be utilized.
- the amount of trifluoroacetic acid is about 100 to 3000 ppm, preferably 500-1500 ppm.
- the amount of phosphoric acid is about 10-200 ppm, preferably about 50- 150 ppm, and more preferably about 75-125 ppm.
- compositions of the present invention may also include at least one biocompatible agent effective to reduce active formaldehyde concentration levels produced during in vivo biodegradation of the polymer (also referred to herein as "formaldehyde concentration reducing agents").
- this component is a formaldehyde scavenger compound.
- formaldehyde scavenger compounds useful in this invention include sulfites; bisulfites; mixtures of sulfites and bisulfites; ammonium sulfite salts; amines; amides; imides; nitriles; carbamates; alcohols; mercaptans; proteins; mixtures of amines, amides, and proteins; active methylene compounds such as cyclic ketones and compounds having a b-dicarbonyl group; and heterocychc ring compounds free of a carbonyl group and containing an NH group, with the ring made up of nitrogen or carbon atoms, the ring being unsaturated or, when fused to a phenyl group, being unsaturated or saturated, and the NH group being bonded to a carbon or a nitrogen atom, which atom is directly bonded by a double bond to another carbon or nitrogen atom. 19
- Bisulfites and sulfites useful as the formaldehyde scavenger compound in this invention include alkali metal salts such as lithium, sodium and potassium salts, and ammonium salts, for example, sodium bisulfite, potassium bisulfite, lithium bisulfite, ammonium bisulfite, sodium sulfite, potassium sulfite, lithium sulfite, ammonium sulfite, and the like.
- amines useful in this invention include the aliphatic and aromatic amines such as, for example, aniline, benzidine, aminopyrimidine, toluene-diamine, triethylenediamine, diphenylamme, diaminodiphenylamine, hydrazines and hydrazide.
- Suitable proteins include collagen, gelatin, casein, soybean protein, vegetable protein, keratin, and glue.
- the preferred protein for use in this invention is casein.
- Suitable amides for use in this invention include urea, cyanamide, acrylamide, benzamide, and acetamide.
- Urea is a preferred amide.
- Suitable alcohols include phenols, 1,4-butanediol, d-sorbitol, and polyvinyl alcohol.
- suitable compounds having a b-dicarbonyl group include malonic acid, acetylacetone, ethylacetone, acetate, malonamide, diethylmalonate or another malonic ester.
- Preferred cyclic ketones for use in this invention include cyclohexanone or cyclopentanone.
- suitable heterocychc compounds for use as the formaldehyde scavenger in this invention are disclosed, for example, in U.S. Patent No. 4,127,382 (Perry) which is hereby incorporated in its entirety by reference.
- Such heterocychc compounds include, for example, benzimidazole, 5-methyl benzimidazole, 2- methylbenzimidazole, indole, pyrrole, 1,2,4-triazole, indoline, benzotriazole, indoline, and the like.
- a preferred formaldehyde scavenger for use in this invention is sodium bisulfite.
- the formaldehyde concentration reducing agent e.g., formaldehyde scavenger compound
- the "effective amount” is that amount sufficient to reduce the amount of formaldehyde generated during subsequent in vivo biodegradation of the polymerized cyanoacrylate. This amount will depend on the type of active formaldehyde 20 concentration reducing agent, and can be readily determined without undue experimentation by those skilled in the art.
- the formaldehyde concentration reducing agent may be used in this invention in either free form or in microencapsulated form.
- Other compositions are exemplified by U.S. Patent Application Serial No. 08/714,288, incorporated by reference herein in its entirety.
- the formaldehyde concentration reducing agent When microencapsulated, the formaldehyde concentration reducing agent is released from the microcapsule continuously over a period of time during the in vivo biodegradation of the cyanoacrylate polymer.
- the microencapsulated form of the formaldehyde concentration reducing agent is preferred because this embodiment prevents or substantially reduces polymerization of the cyanoacrylate monomer by the formaldehyde concentration reducing agent, which increases shelf-life and facilitates handling of the monomer composition during use.
- Microencapsulation of the formaldehyde scavenger can be achieved by many known microencapsulation techniques.
- microencapsulation can be carried out by dissolving a coating polymer in a volatile solvent, e.g., methylene chloride, to a polymer concentration of about 6% by weight; adding a formaldehyde scavenger compound in particulate form to the coating polymer/solvent solution under agitation to yield a scavenger concentration of 18% by weight; slowly adding a surfactant- containing mineral oil solution to the polymer solution under rapid agitation; allowing the volatile solvent to evaporate under agitation; removing the agitator; separating the solids from the mineral oil; and washing and drying the microparticles.
- the size of the microparticles will range from about 0.001 to about 1000 microns.
- the coating polymer for microencapsulating the formaldehyde concentration reducing agent should be polymers which undergo in vivo bioerosion, preferably at rates similar to or greater than the cyanoacrylate polymer formed by the monomer, and should have low inherent moisture content. Such bioerosion can occur as a result of the physical or chemical breakdown of the encapsulating material, for example, by the encapsulating material passing from solid to solute in the presence of body fluids, or by biodegradation of the encapsulating material by agents present in the body. 21
- polyesters such as polyglycolic acid, polylactic acid, poly-l,4-dioxa-2-one, polyoxaltes, polycarbonates, copolymers of polyglycolic acid and polylactic acid, polycaprolactone, poly-b-hydroxybutyrate, copolymers of epsilon-caprolactone and delta- valerolactone, copolymers of epsilon- caprolactone and DL-dilactide, and polyester hydrogels; polyvinylpyrrolidone; polyamides; gelatin; albumin; proteins; collagen; poly(orthoesters); poly(anhydrides); poly(alkyl-2-cyanoacrylates); poly(dihydropyrans); poly(acetals); poly(phosphazenes); poly(urethanes); poly(dioxinones); cellulose; and starches.
- surfactants which can be used to microencapsulate the formaldehyde concentration reducing agent.
- the composition may also optionally include at least one thickening agent.
- suitable thickeners include, for example, polycyanoacrylates, polylactic acid, poly- 1,4- dioxa-2-one, polyoxalates, polyglycolic acid, lactic-glycolic acid copolymers, polycaprolactone, lactic acid-caprolactone copolymers, poly-3-hydroxybutyric acid, polyorthoesters, polyalkyl acrylates, copolymers of alkylacrylate and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl methacrylates and butadiene.
- alkyl methacrylates and acrylates are poly(2-ethylhexyl methacrylate) and poly(2-ethylhexyl acrylate), also poly(butylmethacrylate) and poly(butylacrylate), also copolymers of various acrylate and methacrylate monomers, such as poly(butylmethacrylate-co-methylacrylate).
- difunctional monomeric cross-linking agents may be added to the monomer compositions of this invention.
- Such crosslinking agents are known. U.S.
- Patent No. 3,940,362 to Overhults discloses such cross-linking agents.
- suitable crosslinking agents include alkyl bis(2-cyanoacrylates), triallyl isocyanurates, alkylene diacrylates, alkylene dimethacrylates, trimethylol propane triacrylate, and alkyl bis(2-cyanoacrylates).
- a catalytic amount of an amine activated free radical initiator or rate modifier may be added to initiate polymerization or to modify the rate of polymerization of the cyanoacrylate monomer/crosslinking agent blend. 22
- compositions of this invention may further contain fibrous reinforcement and colorants, i.e., dyes and pigments.
- fibrous reinforcement include PGA microfibrils, collagen microfibrils, cellulosic microfibrils, and olefinic microfibrils.
- suitable colorants include l-hydroxy-4-[4-methylphenyl- amino]-9,10 anthracenedione (D+C violet No. 2); disodium salt of 6-hydroxy-5-[(4- sulfophenyl)axo]-2-naphthalene-sulfonic acid (FD+C Yellow No.
- compositions that are contemplated by the present invention are exemplified by U.S. Patents Nos. 5,624,669; 5,582,834; 5,575,997; 5,514,371; 5,514,372; and 5,259,835; the disclosures of all of which are hereby incorporated in their entirety by reference.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU38730/99A AU759076B2 (en) | 1998-04-30 | 1999-04-30 | Use of an adhesive composition over a bioactive polymerization initiator or accelerator |
EP99921545A EP1073468A1 (en) | 1998-04-30 | 1999-04-30 | Use of an adhesive composition over a bioactive polymerization initiator or accelerator |
BR9910063-0A BR9910063A (en) | 1998-04-30 | 1999-04-30 | Set to supply a medicine to a patient, and manufacture a package |
JP2000545571A JP2002512980A (en) | 1998-04-30 | 1999-04-30 | Method of using adhesive composition for bioactive polymerization initiator or accelerator |
CA002330479A CA2330479A1 (en) | 1998-04-30 | 1999-04-30 | Use of an adhesive composition over a bioactive polymerization initiator or accelerator |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US6987598A | 1998-04-30 | 1998-04-30 | |
US09/069,875 | 1998-04-30 |
Publications (1)
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WO1999055374A1 true WO1999055374A1 (en) | 1999-11-04 |
Family
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Application Number | Title | Priority Date | Filing Date |
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PCT/US1999/009374 WO1999055374A1 (en) | 1998-04-30 | 1999-04-30 | Use of an adhesive composition over a bioactive polymerization initiator or accelerator |
Country Status (7)
Country | Link |
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EP (1) | EP1073468A1 (en) |
JP (1) | JP2002512980A (en) |
CN (1) | CN1299289A (en) |
AU (1) | AU759076B2 (en) |
BR (1) | BR9910063A (en) |
CA (1) | CA2330479A1 (en) |
WO (1) | WO1999055374A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2001030408A2 (en) * | 1999-10-29 | 2001-05-03 | Closure Medical Corporation | Adhesive composition over a bioactive polymerization initiator |
WO2001032319A2 (en) * | 1999-10-29 | 2001-05-10 | Closure Medical Corporation | Adhesive applicator |
US6582713B2 (en) | 2000-04-06 | 2003-06-24 | Univ. Of Colorado - Colorado Springs | Compositions and methods for promoting wound healing |
US7534907B2 (en) * | 2005-03-24 | 2009-05-19 | Ethichon, Inc. | Absorbable α-cyanoacrylate compositions |
WO2020248010A1 (en) * | 2019-06-11 | 2020-12-17 | Animal Ethics Pty Ltd | Pain relieving method |
US10870102B2 (en) | 2015-12-18 | 2020-12-22 | Acenet Inc. | Radical generating catalyst, method for producing radical, method for producing oxidation reaction product, drug, and drug for agriculture and livestock |
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US20050182443A1 (en) | 2004-02-18 | 2005-08-18 | Closure Medical Corporation | Adhesive-containing wound closure device and method |
US20060009099A1 (en) * | 2004-07-12 | 2006-01-12 | Closure Medical Corporation | Adhesive-containing wound closure device and method |
JP6236057B2 (en) * | 2015-12-18 | 2017-11-22 | 株式会社 エースネット | Drug |
JP6268152B2 (en) * | 2015-12-18 | 2018-01-24 | 株式会社 エースネット | Method for producing radical and method for producing oxidation reaction product |
JP6268151B2 (en) * | 2015-12-18 | 2018-01-24 | 株式会社 エースネット | Radical generation catalyst, method for producing radical, and method for producing oxidation reaction product |
US10687986B2 (en) | 2016-09-29 | 2020-06-23 | Ethicon, Inc. | Methods and devices for skin closure |
USD848624S1 (en) | 2016-09-29 | 2019-05-14 | Ethicon, Inc. | Release paper for wound treatment devices |
US10470935B2 (en) | 2017-03-23 | 2019-11-12 | Ethicon, Inc. | Skin closure systems and devices of improved flexibility and stretchability for bendable joints |
CN109303918A (en) * | 2018-09-28 | 2019-02-05 | 中国人民解放军军事科学院军事医学研究院 | It can be used for the cyanoacrylate and combinations thereof of cutaneous penetration |
CN112480830A (en) * | 2020-12-09 | 2021-03-12 | 山东禹王和天下新材料有限公司 | Transparent nail polish gel and preparation method and application thereof |
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- 1999-04-30 EP EP99921545A patent/EP1073468A1/en not_active Withdrawn
- 1999-04-30 BR BR9910063-0A patent/BR9910063A/en not_active IP Right Cessation
- 1999-04-30 JP JP2000545571A patent/JP2002512980A/en active Pending
- 1999-04-30 AU AU38730/99A patent/AU759076B2/en not_active Expired
- 1999-04-30 WO PCT/US1999/009374 patent/WO1999055374A1/en active IP Right Grant
- 1999-04-30 CN CN 99805653 patent/CN1299289A/en active Pending
- 1999-04-30 CA CA002330479A patent/CA2330479A1/en not_active Abandoned
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Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6455064B1 (en) | 1998-04-30 | 2002-09-24 | Closure Medical Corporation | Method of applying an adhesive composition over a bioactive polymerization initiator or accelerator |
WO2001030408A2 (en) * | 1999-10-29 | 2001-05-03 | Closure Medical Corporation | Adhesive composition over a bioactive polymerization initiator |
WO2001032319A2 (en) * | 1999-10-29 | 2001-05-10 | Closure Medical Corporation | Adhesive applicator |
WO2001032319A3 (en) * | 1999-10-29 | 2001-12-06 | Closure Medical Corp | Adhesive applicator |
WO2001030408A3 (en) * | 1999-10-29 | 2002-01-10 | Closure Medical Corp | Adhesive composition over a bioactive polymerization initiator |
US6582713B2 (en) | 2000-04-06 | 2003-06-24 | Univ. Of Colorado - Colorado Springs | Compositions and methods for promoting wound healing |
US7534907B2 (en) * | 2005-03-24 | 2009-05-19 | Ethichon, Inc. | Absorbable α-cyanoacrylate compositions |
US10870102B2 (en) | 2015-12-18 | 2020-12-22 | Acenet Inc. | Radical generating catalyst, method for producing radical, method for producing oxidation reaction product, drug, and drug for agriculture and livestock |
US11673129B2 (en) | 2015-12-18 | 2023-06-13 | Acenet Inc. | Radical generating catalyst, method for producing radical, method for producing oxidation reaction product, drug, and drug for agriculture and livestock |
WO2020248010A1 (en) * | 2019-06-11 | 2020-12-17 | Animal Ethics Pty Ltd | Pain relieving method |
Also Published As
Publication number | Publication date |
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EP1073468A1 (en) | 2001-02-07 |
AU3873099A (en) | 1999-11-16 |
CN1299289A (en) | 2001-06-13 |
JP2002512980A (en) | 2002-05-08 |
AU759076B2 (en) | 2003-04-03 |
BR9910063A (en) | 2000-12-26 |
CA2330479A1 (en) | 1999-11-04 |
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