CN1299289A - 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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- CN1299289A CN1299289A CN 99805653 CN99805653A CN1299289A CN 1299289 A CN1299289 A CN 1299289A CN 99805653 CN99805653 CN 99805653 CN 99805653 A CN99805653 A CN 99805653A CN 1299289 A CN1299289 A CN 1299289A
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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
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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
- A61K9/0012—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
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Abstract
A composition comprising a polymerizable adhesive monomer is applied over a biologically active initiator or accelerator for polymerization of the monomer. The biologically active initiator or accelerator is a medicament that provides a desired medical or therapeutic activity as well as enhancing polymerization of the adhesive.
Description
Background technology
Invention field
The present invention relates to monomer and polymer composition purposes, be specifically related to the purposes of it and bioactive materials associating as biological medicine adhesive and sealant.
Association area is described
The product that is used for wound closure at first is sutures and staple.Think that suture provides sufficient wound support.Yet suture has caused additional wound (because pin and suture need be passed tissue, and needing puncture needle anesthesia wound) to the wound site, and is time-consuming and cause disagreeable wound closure vestige in the skin level.Developed the operation staple and come accelerated in wounds involutory, and the aesthetic of improvement is provided.Yet the operation staple has caused additional wound equally, and requires to fix and staple is installed with auxiliary common expensive equipment.Suture and staple difficulty especially in pediatric operation because the patient can produce intensive fear reaction, and the refusal cooperation settles them, and in the operation in old age also difficulty especially because skin histology is weak and be easy to tear.
As the substitute of sutures and staple, proposed to be used for the adhesive of wound closure.Similarly, oneself proposes to be used for the wound covering of those local applications and the adhesive of protection, as is used for the wound of surperficial tear, scratch, burn, stomatitis and other open surfaces.This adhesive of one class is 1,1-two substituted ethylene monomers, for example monomeric form of a-cyanoacrylate.
Use adhesive for wound healing with covering, developed the mixture of cyanoacrylate adhesive and medicament.For example, Greff etc. are at U.S. Patent number 5,684, disclose a kind of cyanoacrylate compositions in 042, and it comprises a kind of antimicrobial that contains iodine of antimicrobial effective dose.This antimicrobial that contains iodine can disperse in cyanoacrylate compositions, can not cause cyanoacrylate adhesive premature polymerization (that is, not initiated polymerization).
Coover etc. are at U.S. Patent number 3,483, disclose the purposes of Mecrilate as bone cement in 870.As long as antibiotic does not cause premature polymerization (that is, do not play polymerization initiator) or do not cause ill effect in agglutination, a-cyanoacrylate and antibiotic can be mixed.
The another kind of method of using binder cure or preventing relevant infection with wound relates to cyanoacrylate is coated on the medicine of injury.For example, Tighe etc. are at U.S. Patent number 5,580, disclose with a kind of external a-cyanoacrylate in 565 and have organized adhesive to form protective barrier on complete or the skin that breaks, and make the purposes that skin healing takes place.By contacting the polymerization that causes the a-cyanoacrylate adhesive with tissue protein with moisture of skin.Tighe etc. also disclose the purposes of a-cyanoacrylate as the medicament protective layer.Unique medicament of demonstrations such as Tighe is a cortisone, and it can not cause the polymerization of cyanoacrylate monomer compositions.
Other people also disclose cyanoacrylate adhesive as the obducent purposes of medicament.For example, Beasley etc. disclose antibiotic such as vancomycin powder or tetracycline have been used for wound, cover wound with isobutylcyanoacrylate then.This class treatment is disclosed as the hope that shows treatment bacterial infection tissue.(Beasley, J.D. etc., antibiotic and chemical adhesive to the effect of infected wound, Mil.Med.136 (6): 566-569,1971).Yet these antibiotic are not used for causing the polymerization of cyanoacrylate.
Also at the following purposes that discloses cyanoacrylate adhesive covering bioactivator: Miles etc., Oral Medicine, Oral Pathology, Vo1.75, No.3,397-402 (using triamcinolone acetone (Kenalog) or chlorhexidine digluconate (Peridex)) as bioactivator; And Kaufman, R.S., The Laryngoscope, 1974,793-804 (using dexamethasone sodium phosphate (Decadron)) as bioactivator.
Weisberg etc. are at U.S. Patent number 4,669, disclose the purposes of the antibacterial that protected property acrylic synthetic fingernail covers in 491.Antibacterial can be acid or phenol, but does not preferably influence treatment rate or glue-line bond strength those certainly.They comprise: the antibiotic of thymol, chlorothymol, benzoic acid, p-hydroxy benzoic acid Arrcostab, 4-and 6-phenyl-2-chlorobenzene, carvacrol, hexachlorophene, nitrofuran (nitroforans), allicin, 2-phenylphenol, boric acid, mercurial and for example bacitracin and griseofulvin, quaternary ammonium halide, brocide salt, 5-methyl-2-isopropyl-Hexalin, 2-Camphora, eucalyptole, safrol, bornyl chloride, 2-phenyl phenol, benzyl alcohol and ethanol such as chlorination n-alkyl dimethyl benzyl ammonium.Antibacterial is coated on the Concha, and the solution with the cyanoacrylate-containing adhesive covers then.Antibacterial is imposed on the natural nail with solution, allow the solution drying, active bactericide is stayed on the fingernail.With the fingernail grinding agent roughening that antibacterial is handled, coat the monomer cyanoacrylate solutions then and form the artificial nails.The polymethacrylates that contains benzoylperoxide catalyst by adding comes the polymerizable cyanoacrylate acrylate monomer.Not to selecting monomer and antibacterial to make antibacterial can cause polymeric suggestion.
Goodson etc. are at U.S. Patent number 4,764, disclose a kind of purposes that is used for the treatment of the therapeutic agent and the cyanoacrylate adhesive of periodontal disease in 337 and 4,892,736.Therapeutic agent is placed periodontal pocket, keep system's (it can be one deck adhesive thin film, for example the positive butyl ester of alpha-cyanoacrylate) with machinery then and cover, it is fixed on therapeutic agent in the periodontal pocket, and therapeutic agent is applied on the periodontal site.Goodson and colleague also as " periodontal disease research magazine ", 1990, Vol.25,243-249 and " periodontal learn latest developments ", Vol.11 discloses this type systematic among the 61-68.Therapeutic agent comprises: the antibacterial of iodine, sulfonamides, mercurial, two two guanidines or phenol for example; The antibiotic of tetracycline, neomycin, kanamycin, metronidazole or Semen Canavaliae mycin (canamycin) for example; The antiinflammatory of indomethacin, acetaminol or hydrocortisone for example; The for example immunosuppressant of 9-methylpteroylglutamic acid or levamisole or stimulant; The dental desensitizer of strontium chloride or sodium fluoride for example; Oleum menthae or chlorophyllously cover smelly dose for example; For example immunoglobulin or antigenic immunoreactant; The local anesthetic of lignocaine or benzocaine for example; For example aminoacid, elite fat and ascorbic nutrient; The antioxidant of alpha tocopherol and Yoshinox BHT for example; The lipopolysaccharide complexing agent of polymyxin for example; Or the peroxide of urea peroxide for example.Not to selecting monomer and antibacterial to make antibacterial can cause that polymerization advises.
Leung etc. are at U.S. Patent number 5,514, disclose in 371 and 5,624,669 to add therapeutic agent in cyanoacrylate compositions.Cyanoacrylate adhesive forms the substrate of therapeutic agent, and in the polymer biological degradation process, therapeutic agent discharges on substrate in vivo in time.Therapeutic agent is not used as polymerization initiator or rate of polymerization regulator.
Randen is at U.S. Patent number 4,940, discloses the compositions that comprises medicament and adhesive in 579.Transmit medicament with said composition to the non-mucosa district of body of mammals.Yet Randen is unexposed with the purposes of medicament as polymerization initiator and/or speed promoter.
Barley etc. are at U.S. Patent number 5,254, disclose the purposes of cyano group adhesive and antibiotic associating in 132.Antibiotic is added in the cyanoacrylate compositions, and is housed in the aseptic applicator, be used for single agent and be coated with usefulness.Compositions is kept in the sealed container, to avoid at the coating pre-polymerization; Therefore, antibiotic does not cause or quickens the polymerization of adhesive composition.
Usually, when being used for medical application, cyanoacrylate adhesive is coated onto the surface that will connect, seal or treat with monomeric form.Usually, monomer original position anionic polymerization taking place, produces required bonding combination or covering.The initiation of in-situ polymerization utilizes naturally occurring moisture and/or protein in by treated tissue usually.Therefore, in the application that has tissue fluid, need in cyanoacrylate compositions, not add polymerization initiator or speed promoter.Yet, need sometimes cyanoacrylate adhesive is coated on the dry tissue (that is, the tissue of basic inorganization liquid or analog).In addition, in order to prolong the storage life of the very strong cyanoacrylate monomer of these reactivities, they and stabilizing agent are prepared together, make them can premature polymerization.In these cases, the polymerization of cyanoacrylate adhesive is made slow progress, and causes the inconvenience of user.In order to overcome this inconvenience, polymerization initiator and/or speed promoter in the cyanoacrylate adhesive compositions, have been added.
In the time will adding initiator or promoter in compositions, they are up to being coated with add before the adhesive at once.For example, Dombroski etc. are at U.S. Patent number 4,042, disclose the adding of polymerization initiator in cyanoacrylate compositions (caffeine or theobromine) in 442.Caffeine or theobromine are added in the adhesive composition in one of two ways.In first kind of mode, caffeine or theobromine can be mixed by stirring and with the cyanoacrylate adhesive compositions before adhesive will being coated onto on the matrix that will connect.In the second way, caffeine or theobromine are dissolved in the volatile solvent, be coated onto on the surface that will connect, make the volatile solvent evaporation, then the cyanoacrylate adhesive compositions is coated onto the matrix surface that will connect.
Referring generally to be decided to be PCT application number WO 96/40797 (its disclosure is in these whole introducings) discloses polymerization initiator or rate of polymerization regulator has been incorporated into the applicator tip.The tip of mixing of initiator or rate adaptation agent makes the control level to rate of polymerization become possibility, and this control level is by relying on the natural polymerization initiator that is present in the injury inaccessiable.Mix initiator at the applicator tip and/or the rate adaptation agent provides convenience to user,, and do not need extra mixing because only need an applicator.Yet this application is unexposed with the purposes of medicament as polymeric initiator of monomer cyanoacrylate compositions or promoter.
Though known pharmaceutical agents and cyanoacrylate adhesive compositions unite use, and the purposes of known polymerization initiator and cyanoacrylate adhesive compositions, but still exist the demand of a kind of convenience, reliable and effective method is provided, this method can be delivered to the injury together with the medicament and the cyanoacrylate adhesive of materia medica effect level.In order to solve this needs, the medicament that the invention provides use materia medica effective dose is as the polymerization initiator of monomeric cement compositions or the method and composition of promoter.
The invention summary
According to the present invention, medicament has played the effect of the polymeric initiator of monomeric cement compositions and/or promoter and pharmacologic activity material simultaneously.Polymerization initiator used herein is that the cyanoacrylate compositions on any tissue that causes being coated in substantially dry (that is, do not have blood plasma or allied organization's liquid substantially) can be at ambient temperature, and (for example approximately 21-25 ℃) is being less than polymeric material in 300 seconds.Preferably, initiator causes cyanoacrylate compositions (for example about 21-25 ℃) polymerization in less than 150 seconds at ambient temperature, or preferred polymerization in less than 135 seconds.Polymerization accelerant used herein is the material that any acceleration cyanoacrylate compositions rate of polymerization is accelerated, making usually at ambient temperature, (for example about 21-25 ℃) needs the polymerization more than 300 seconds to take place in less than 300 seconds, preferably be less than in 150 seconds, be more preferably being less than in 135 seconds and take place.Initiator or speed promoter can be catalyst for example, but also may be to be consumed in polyreaction or the material of chemical modification.Medicament can be anyly the pharmacological effect that provided and polymerization initiation or speed are provided simultaneously accelerate active material, includes but not limited to antibiotic, antibiotics, antiseptic, bacillin, antibacterial, disinfectant, steroid, anesthetis, antifungal, antiinflammatory, antibacterial agent, antiviral agent, antitumor agent and tissue growth promoter.
The invention provides (with others) a kind of closure, sealing, covering and/or the protection degree of depth and/or superficial cut of being used for, for example because the method for operation or laceration, burn, ulcer, scratch and similar wound.This method is included in and applies a kind of medicament on wound and the ulcer, is coated with the compositions that one deck contains polymerisable monomer on medicament, and its polymerization is caused by this medicament or quickens.
In an embodiment, the present invention also provides the method that a kind of medicament part or general is passed to the human or animal, by medicament is coated in the tissue site, is coated with the compositions that one deck contains polymerisable monomer on this medicament, and its polymerization is caused by this medicament or quickens.Tissue used herein comprises the tissue of anyone or animal, comprises skin, mucosa, oral cavity/nasal cavity tissue, stomach intestinal tissue, organ-tissue, tumor, non-keratinocyte tissue etc.
The present invention also provides a kind of test kit, it comprises vendible packing, this packing contains the container of (ⅰ) a kind of polymerizable monomer composition as herein described and (ⅱ) container of a kind of medicament (preferably playing the polymerization initiator or the rate of polymerization modulator effect of described monomer composition).This container is the parts of applicator or applicator system preferably, and preferably sterilization.For example, packing and its content preferably can be sterilized simultaneously.
The present invention also provides a kind of and has comprised that polymerizable monomer composition and one pass to medicament the manufacture method of packing of patient's method explanation book list, and its method comprises:
With a kind of materia medica effective dose of medicament be coated onto described patient tissue and
A kind of polymerizable monomer composition is coated onto on the medicament,
Wherein this medicament is polymerization initiator or rate of polymerization promoter, and causes the polymerization of monomer composition, forms one deck adhesive covering that covers described tissue.
The invention provides the advantage of the multiple Wound healing and bone regeneration method that is better than using now, comprise energy:
A) molecular weight distribution (by using polymerization initiator and/or rate of polymerization promoter) of the polymeric or cross-linked material of control;
B) setting time of control polymerization and crosslinked cyanoacrylate adhesive;
C) flowability of control polymerizable cyanoacrylate compositions;
D) provide a kind of medicament that wound closure, protection and/or covering can be provided simultaneously to patient;
E) provide a kind of medicament by local dispenser to patient; And/or
F) combination of any top advantage.
Preference describes in detail
According to the present invention, be coated with coating medicament before containing monomer combination organizationally.This medicament plays the polymeric effect that causes and/or quicken monomer composition.Therefore, medicament not only provides biological action, and chemical action is provided.
The example of such medicament includes but not limited to: antibiotic, antibacterial, antiseptic, bacillin, antibacterial, disinfectant, steroid, anesthetis, antifungal, antiinflammatory, antibacterial agent, antiviral agent, antitumor agent, growth promotion thing and composition thereof.
Exemplary medicament is including but not limited to quaternary ammonium halide, for example: benzalkonium chloride and the Benzene Chloride first and second oxygen ammoniums; The sulphuric acid chlorhexidine; Gentamycin sulfate; Hydrogen peroxide; The thiourea quinolinones; Silver salt includes but not limited to: silver acetate, silver benzoate, Disilver carbonate, silver chloride, Itrol., silver iodide, silver nitrate and silver sulfate; Sodium hypochlorite; Sulfadiazine salt includes but not limited to: silver, sodium and zinc salt; And composition thereof.
Preferred agents is anion or promotion generation free radical or ion pair or itself is those medicaments of free radical.
In an embodiment, pharmacy optimization is a quaternary ammonium halide, for example has the alkyl benzyl dimethyl ammonium chloride (Benzalkonii Chloridum of the alkyl that contains 6-18 carbon atom; BAC), its pure component or its mixture, or the Benzene Chloride first and second oxygen ammoniums; Or sulfadiazine salt, for example silver, sodium or zinc salt.
Can move on to the initiating activity of testing medicament in the differential scanning calorimetric aluminum dish by an amount of liquid medicine suction that will prepare in volatile solvent.Make volatile solvent dry at ambient temperature.Perhaps an amount of medicament directly is assigned in the differential scanning calorimetric aluminum dish.With regard to two kinds of situations above-mentioned, the selected monomer solution suction of 25 microlitres is moved on in the dish.The time that monomer composition aggregates into gel point is exactly polymerization time.
In an embodiment, compositions may comprise other polymerization initiator and/or speed promoter except that medicament.The concrete additional initiator of concrete system can need not too much experiment by those skilled in the art and select easily.The suitable extra polymerization initiator of cyanoacrylate compositions is including but not limited to other medicament; Cleanser compositions; Surfactant, for example polysorbate 20 is (as Tween 20
TMICI Americas), polyoxyethylene sorbitan monoleate is (as Tween 80
TMICI Americas) and the pool non-ionic surface active agents such as Sha Mu that fall; Cationic surfactants such as bromination tetrabutylammonium and the Benzene Chloride first and second oxygen ammoniums or its pure component; Anion surfactants such as tin octoate (stannum (II) 2 ethyl hexanoic acid) and myristyl sodium sulfonate; With hydroxide dodecyl dimethyl (3-sulfopropyl) ammonium, both sexes or zwitterionic surfactants such as inner salt; Amine, imines and amide such as imidazoles, tryptamines, urea, arginine and polyvidon; Phosphine such as triphenylphosphine and NSC 5284, phosphite ester He phosphonium salt; Alcohol such as ethylene glycol; The gallic acid methyl ester; Ascorbic acid; Tannin and tannin; Inorganic base and salt such as sodium bisulfite, magnesium hydroxide, calcium sulfate and sodium silicate; Sulphur compound such as thiourea and polysulfide; Poly-cyclic ethers such as monensin, nonactin, crown ether, calixarenes and polyepoxide; Ring-type or non-annularity carbonic esters such as diethyl carbonate; Aliquat
TM336 (General Mills, Minneapolis, MN) phase transfer catalysts such as grade; Organo-metallic compound; Manganese acetylacetonate; And free radical and free-radical initiators such as di-tert-butyl peroxide and azodiisobutyronitrile.
Unless polymerizable and/or crosslinkable materials can also contain by catalyst or promoter (being included in term used herein " promoter " scope) activation, otherwise are the initiators of non-activity.These initiators can be by heat and/or light suitable thorn activations such as (for example ultraviolet light or visible lights).
The compositions that the present invention uses preferably can be sterilized.
The pharmaceutical quantities of using will be when mixing with monomer composition by contact with medicament, enough cause the amount of polymerization initiation or quickening rate of polymerization.Should also this medicine effectively be measured use with materia medica, and it should be selected with specific polymerisable monomer chemical compound, thereby make this medicine can play the function of selected monomeric specificity polymerization initiator and/or speed promoter.Such selection course can be easy to be undertaken by those skilled in the art.
Medicament can be only in the coating site (that is, be limited on its tissue that is coated with usefulness/among) pharmacological effect arranged, or it can have systemic effect (by whole body, represent that not only medicine has the effect whole to patient body, also be illustrated in the specific site that is coated with beyond the site and work).Be coated with showing among the embodiment of the active enough drug of systemic medication, medicine can be absorbed, betransported or be assigned to patient's drug disposition and learn active required site (as by cardiovascular or lymphsystem).
Concrete needs by user are decided, and medicament of the present invention and adhesive composition can be coated with usefulness by any appropriate device, and what medicament and adhesive composition were used can be identical or different.Example is including but not limited to glass paddle, aseptic brush or medical dropper.In many cases, preferably pump or pressure atomization are packed, and wherein adhesive composition and compatible anhydrous propellant are dissolved in the solution, and preferred device is to absorb swab or scraper.
Medicament can be a solid form, for example powder or solid film, or liquid form, for example water sample, mucoid or paste sample material.Medicament can and different additive, be mixed together as surfactant or emulsifying agent and carrier.
Method of the present invention can be used to two surfaces are linked together, and replenishes as the substitute of suture or its, uses relative wound surface by this compositions is coated with, and is fixed together when polymerization is carried out then.Method of the present invention also can be used to wrap by, protection or covering surfaces, shallow table or local wound or including but not limited to the pathology of shallow laceration, scratch, burn, ulcer and stomatitis.Method of the present invention can also be used in the tissue that does not show any tissue injury sign.For example, this method can be used to medicament is passed to patient by health tissues.They also can be used to, as with the medicament localized delivery to tissues such as tumor or organs.
In one embodiment, the invention provides the alternative of suture, comprise by forming the bio-compatible thin film medicament is passed to tissue on the adjacent tissue surface, comprise: (a) at least two place's tissue surfaces being fixed together forms the adjacent tissue surface, (b) will be coated onto the adjacent tissue surface for the medicament of polymerization initiator or rate of polymerization promoter, (c) on medicament and across the adjacent tissue surface, be coated with polymerizable adhesive monomer composition and (d) make the compositions polymerization come to form the bio-compatible thin film on the adjacent tissue surface.Also can be after being coated with preceding one deck coating immediately or pro-one deck coating be coated with the last layer additional coatings after the polymerization fully.Preferably, make the monomer composition that is coated in the adjacent tissue surface in coating subsequently or partially polymerized at least before being coated with the additional monomers compositions.Can be coated with usefulness as the second layer or back one deck coating with having the monomeric adhesive composition coating different with ground floor or preceding one deck.
The adding of plasticiser and acid stabilizer can produce has abundant bond strength and elastic polymer coating, even thin film or coating have significant thickness.Suitable film thickness 0.1mm to 2.0mm or 3.0mm or more than, preferably 0.2mm is more preferably 0.4mm to 0.8mm to 1.5mm.
In an embodiment, the bio-compatibility thin film as the suture substitute that forms can have the film strength of inducing the required Hg of the 70mm at least vacuum pressure of wound healing in vivo, normally wound healing required from 70mmHg to 400mm Hg vacuum pressure, preferably wound healing required from 90mmHg to 400mm Hg vacuum pressure, and be more preferably wound healing required from 100mmHg to 400mm Hg vacuum pressure.
When repairing wounded tissue (as control over bleeding), the present invention includes and at first blot the site that to repair and remove shallow table or soma's liquid.Ideal tissue bond or hemostasis can also be when having blood with other body fluid as carrying out in that the drying tissue is good.The combination that forms has the proper motion that sufficient elasticity and intensity stand to organize.In addition, bond strength is kept in natural wound healing carries out.
In other embodiments, directed shallow table of a kind of treatment of the present invention or local pathological state include but not limited to the method as the skin wounds such as ulcer of shallow laceration, burn or scratch or mucomembranous surface.Method comprises that (a) is coated with being the medicament of polymerization initiator or speed promoter, (b) is coated with the compositions that contains polymerisable monomer with one deck on medicament on wounded tissue; (c) make the compositions polymerization; (d) optional, said composition of repaste at least on same loci.
The suitable film thickness of this local application is preferably between 1 and 10,000 micron, for example between 1 and 1000 micron.In an embodiment, so the bio-compatibility thin film that forms can have 5mm Hg at least, for example 5-400mm Hg, the preferably film strength of 50-400mm Hg.
In an embodiment, the invention provides the method that medicament is passed to tissue, comprise that (a) (for example, directly organizationally) is coated with a kind of medicament for polymerization initiator and/or rate of polymerization promoter in the site; (b) on medicament, be coated with the compositions that contains polymerisable monomer with one deck; (c) optional, said composition of repaste on same site.Suitable film thickness and intensity are preferably from disclosed those of other purposes of being used for above.
In an embodiment, medicament is discharged into tissue, it contacts in a period of time with the speed of wounded tissue with stable or almost stable at this place.
The present invention also provides the test kit that medicament is passed to patient.This test kit comprises and contains polymerizable monomer composition, as the container of cyanoacrylate adhesive.This test kit also comprises another container that contains medicament.Medicament is selected from it and common polymerizable monomer composition associating of packing can be played the trigger monomer polymerization or modification (for example accelerating) monomer forms the effect of the speed of polymer bonding agent.The appropriate combination of medicament and polymerisable monomer can be easy to determine by those skilled in the art.Medicament is coated with time spent materia medica effective dose with local (that is, directly organizationally) to be stored in the test kit.
Monomer composition among the embodiment is monomer (comprising prepolymerization) adhesive composition preferably.In an embodiment, monomer is 1,1-two substituted ethylene monomers, for example a-cyanoacrylate.The polymer of preferred monomers compositions of the present invention and formation thereof is as organizing adhesive, preventing sealer and other biomedical applications hemorrhage or the covering open wound.They can be used for for example merging tissue surgical incision or that wound is torn; Suppress wound bleeding; Drug delivery; Smear scald; Smear skin or other shallow table or superficial cut (as the scratch, by rub the stimulation or raw skin and/or stomatitis); With help living tissue reparation and regeneration.
It is polymerisable can be used for monomer of the present invention, as anionic property polymerizable or free radical polymerization, or forms polymer by amphion or ion pairing polymerization.These monomers comprise the monomer of those formation biodegradable (but not necessarily) polymer.For example, U.S. Patent No. 5,328 discloses these monomers in 687, all is incorporated herein by reference at this.
Useful 1,1-two substituted ethylene monomers are including but not limited to, the monomer of following molecular formula:
(I) HRC=CXY wherein X and Y is respectively a strong electron-withdrawing group group, and R is H ,-CH=CH
2Or if X and Y are cyano group, R is C
1-C
4Alkyl.
Examples of monomers in molecule formula I scope comprises: the C of a-cyanoacrylate, vinylidene cyanide, vinylidene cyanide
1-C
4Alkyl congener, methylene dialkyl malonate, acyl group acrylonitrile, molecular formula are CH
2(wherein X is-SO=CX ' Y '
2R ' or-SO
3R ' and Y ' is-CN ,-COOR ' ,-COCH
3,-SO
2R ' or-SO
3R ', and R ' is H or alkyl) ethylene sulfinic acid ester and vinyl sulfonic acid ester.
The preferred monomers of the molecule formula I that the present invention is used is an a-cyanoacrylate.This molecule has molecular formula known in the art
R wherein
2Be hydrogen and R
3It is the alkyl of alkyl or replacement; Has molecular formula-R
4-O-R
5-O-R
6Group, R wherein
4Be to have 1 of 2-4 carbon atom, 2-alkylidene, R
5Be alkylidene with 2-4 carbon atom, and R
6It is alkyl with 1-6 carbon atom; Or group with following molecular formula:
R wherein
7Be:
Wherein n is 1-10, preferably 1-5 carbon atom and R
8It is organic group.
The example of suitable alkyl and substituted hydrocarbon radical group comprises: the straight or branched alkyl with 1-16 carbon atom; By the straight or branched C of acyloxy, haloalkyl, alkoxyl, halogen atom, cyano group, haloalkyl replacement
1-C
16Alkyl; Straight or branched thiazolinyl with 2 to 16 carbon atoms; Straight or branched alkynyl with 2 to 12 carbon atoms; Cycloalkyl; Aralkyl; Alkylaryl; And aryl.
Organic group R
8Can be substituted or not be substituted, can be straight chain, side chain or ring-type, saturated, unsaturated or aromatics.The example of this organic group comprises: C
1-C
8Alkyl group, C
2-C
8Alkenyl group, C
2-C
8Alkynyl group, C
3-C
12Alicyclic group, aromatic yl group and aromatic alkyl groups such as benzyl, methyl-benzyl and phenylethyl such as phenyl and substituted-phenyl.Other organic group comprises the substituted hydrocarbon radical group, for example the hydrocarbyl group of halogen (as chloro-, fluorine and bromo-substituted hydrocarbon radical) and oxygen-(as the alkoxyl substituted hydrocarbon radical) replacement.Preferred organic group is to have 1 alkyl, thiazolinyl and alkynyl group and halo derivatives thereof to about 8 carbon atoms.Particularly preferably be the alkyl group of 4 to 6 carbon atoms.
In the cyanoacrylate monomer of molecule formula II, R
3Preferably have the alkyl of 1-10 carbon atom or have formula-AOR
9Group, wherein A is bivalence straight or branched alkylidene or the oxyalkylene group with 2-8 carbon atom, and R
9It is straight or branched alkyl group with 1-8 carbon atom.
Formula-AOR
9The example of the group of representative comprises: 1-methoxyl group-2-propyl group, 2-butoxyethyl group, isopropoxy ethyl, 2-methoxy ethyl and 2-ethoxyethyl group.
Used preferred α-Qing Jibingxisuanzhidanti comprises alpha-cyanoacrylate 2-monooctyl ester among the present invention, the alpha-cyanoacrylate dodecyl ester, alpha-cyanoacrylate 2-Octyl Nitrite, Tisuacryl, methyl 2-cyanoacrylate, alpha-cyanoacrylate 3-methoxyl group butyl ester, alpha-cyanoacrylate 2-butoxy ethyl ester, alpha-cyanoacrylate 2-isopropyl ethyl ester, or 1-methoxyl group-2-propyl group cyanoacrylate.
The a-cyanoacrylate that can prepare the molecule formula II according to methods known in the art.U.S. Patent number 2,721,858 and 3,254,111 (all introducing for your guidance in this article respectively) disclose the method for preparing a-cyanoacrylate.For example, can by with alkyl cyanoacetates and formaldehyde in anhydrous organic solvent, exist under the condition of base catalyst and react, the anhydrous intermediate polymer of pyrolytic prepares a-cyanoacrylate in the presence of polymerization inhibitor then.The α-Qing Jibingxisuanzhidanti of low water content preparation and substantially free of impurities is biomedical the use preferably.
Can be according to Kimura etc. at U.S. Patent number 4,364, disclosed method (introducing for your guidance in full at this) prepares molecule formula II (R wherein in 876
3Be to have formula R
4-O-R
5-O-R
6) a-cyanoacrylate.In the method for Kimura etc., can be by producing cyan-acetic ester (by with cyanoacetic acid and pure esterification or by with alkyl cyanoacetates and pure ester exchange); There being mol ratio is 0.5-1.5: 1, and be preferably 0.8-1.2: condensation cyan-acetic ester and formaldehyde or paraformaldehyde under the condition of 1 catalyst obtain condensation substance; Directly or after removing condensation catalyst, separate the polycondensation reaction mixture and obtain thick cyanoacrylate; And distill thick cyanoacrylate and form the high-purity cyanoacrylate and prepare a-cyanoacrylate.
Can be according to Kronenthal etc. at U.S. Patent number 3,995, the program of describing in 641 (all introducing for your guidance) at this prepare the molecule formula II a-cyanoacrylate (wherein R3 has formula:
In the method for Kronenthal etc., can be by the Arrcostab and ring 1 that makes alpha-cyanoacrylate, the 3-diene forms the Diels-Alder adduct, then it is carried out basic hydrolysis, and acidify forms corresponding alpha-cyanoacrylate adduct and prepares this α-Qing Jibingxisuanzhidanti then.This alpha-cyanoacrylate adduct is preferably obtained corresponding alkoxycarbonyl methyl a-cyanoacrylate adduct by the esterification of bromoacetic acid Arrcostab.In addition, can be with the alpha-cyanoacrylate adduct by reaction is converted into alpha-cyano acryloyl halide adduct with thionyl chloride.Then alpha-cyano acryloyl halide adduct and hydroxyacetic acid Arrcostab or methyl substituted hydroxyacetic acid Arrcostab are obtained corresponding alkoxycarbonyl methyl a-cyanoacrylate adduct or alkoxycarbonyl alkyl a-cyanoacrylate adduct respectively.At last, remove cyclisation 1,3-diene blocking groups, existing down by maleic acid in shortage slightly, the heating adduct is converted into corresponding alkoxycarbonyl alkyl a-cyanoacrylate with alkoxycarbonyl methyl a-cyanoacrylate adduct or alkoxycarbonyl alkyl a-cyanoacrylate adduct.
The monomeric example of molecule formula II comprises the a-cyanoacrylate of cyano group pentadiene acid esters and following molecular formula:
Wherein Z is-CH=CH
2And R
3As above definition.Monomer that can be by the reaction under as the catalyst existence condition of zinc chloride of suitable 2-cyan-acetic ester and acrylic aldehyde being prepared the molecule formula III (R wherein
3Be the alkyl of 1-10 carbon atom), that is, 2-cyano group penta-2,4-diene acid esters.(introducing for your guidance in full at this) discloses preparation 2-cyano group penta-2, this method of 4-diene acid esters in U.S. Patent number 3,554,990 for example.
Preferred monomers is α-Qing Jibingxisuanwanjizhi and more preferably alpha-cyanoacrylate monooctyl ester, especially alpha-cyanoacrylate 2-monooctyl ester.The monomer that uses among the application should be very pure, and free from admixture (for example surgical grade) almost.
This compositions can be chosen wantonly comprises and at least aly authorizes wound, otch or scratch and go up the elastic plasticiser of polymerization single polymerization monomer that forms.This plasticiser does not preferably almost have or moisture-free, and does not answer the monomeric polymerization of appreciable impact.
The example of suitable plasticiser comprises: tributyl 2-acetylcitrate, dimethyl sebacate, triethyl phosphate, three (2-ethylhexyl) phosphate ester, three (p-tolyl) phosphate ester, glyceryl triacetate, tributyrin, ethyl sebacate, dioctyl adipate, isopropyl myristate, butyl stearate, lauric acid, benzenetricarboxylic acid three monooctyl esters, 1,3-propanedicarboxylic acid dioctyl ester and composition thereof.Preferred plasticiser is tributyl citrate and tributyl 2-acetylcitrate.In an embodiment, suitable plasticiser comprises polymeric plasticiser, for example Polyethylene Glycol (PEG) ester and end capped PEG ester or ether, 1,3-propanedicarboxylic acid polyester and adipate polyester.
The also optional polymeric stabilizing agent of at least a inhibition that comprises of compositions.This stabilizing agent also can comprise the mixture of anionic stabilizer and free radical stabilizing agent.
The example of suitable anionic stabilizer includes but not limited to: organic acid or phosphoric acid, alkyl sulfate, sulfurous acid Arrcostab, 3-cyclobufene sultone, alkyl sulfone, alkyl sulfoxide, mercaptan and alkyl sulfur compounds and composition thereof such as sultone (as α-chloro-Alpha-hydroxy-o-toluenesulfonic acid-γ-sultone), sulfur dioxide, sulphuric acid, sulfonic acid, lactone, boron trifluoride, acetic acid.The preferred anionic surfactants stabilizing agent is organic acid acid stabilizer such as acetic acid or phosphoric acid.In an embodiment, the sulfur dioxide consistent dose is less than 100ppm, is preferably about 5-75ppm, more preferably 20-50ppm.Sultone and/or trifluoroacetic amount are about 500-3000ppm.
The example of suitable free radical stabilizing agent comprises: hydroquinone, hydroquinone methyl ether, catechol, pyrogallol, benzoquinone, 2-hydroxyl benzoquinone, p-methoxyphenol, t-butyl catechol, butylatedhydroxyanisole (BHA), Yoshinox BHT and t-butylhydroquinone.In an embodiment, the amount of BHA is about 1,000-5,000ppm.
Suitable acid stabilizer comprises those waters pKa ionization constant scope from-12 to 7, and approximately-5 to 7, preferably from-3.5 to 6 stabilizing agent approximately.For example, suitable acid stabilizer comprises: hydrogen sulfide (pKa 7.0), carbonic acid (pKa 6.4), triacetyl methane (pKa 5.9), acetic acid (pKa 4.8), benzoic acid (pKa 4.2), 2,2, 4-dinitrophenol (pKa 4.0), formic acid (pKa 3.7), nitrous acid (pKa 3.3), Fluohydric acid. (pKa 3.2), chloroacetic acid (pKa 2.9), phosphoric acid (pKa 2.2), dichloroacetic acid (pKa 1.3), trichloroacetic acid (pKa 0.7) 2,4,6-trinitrophenol (picric acid) (pK
a0.3), trifluoroacetic acid (pK
a0.2), sulphuric acid (pKa-3.0), sulfurous acid and composition thereof.In an embodiment, the trifluoroacetic acid amount is about 500-1,500ppm.Can use the combination of aforementioned stable agent, as sulfur dioxide and sulphuric acid, boron fluoride and sulphuric acid, sulfur dioxide and chloroacetic acid, boron trifluoride and monoxone, sulfur dioxide and trifluoroacetic acid and boron fluoride and trifluoroacetic acid.
When in adhesive composition, adding above-mentioned acid stabilizer, the plasticiser weight range is the about 16wt.% of about 0.5wt.%-, about 9 wt.% of preferably about 3 wt.%-, be more preferably about 7 wt.% of about 5 wt.%-, adding make the film strength (for example toughness) of polymerization single polymerization monomer strengthen (with containing above-mentioned extraneous plasticiser and comparing) with the polymerization single polymerization monomer of acid stable dosage.
The concentration of used acid stabilizer is decided by acid strength.For example when using acetic acid, available concentration is 80-200ppm (wt/wt), and preferably 90-180 ppm (wt/wt) is more preferably 100-150 ppm (wt/wt).When with strong acid such as phosphoric acid, available concentration range is 20-80 ppm (wt/wt), and preferably 30-70 ppm (wt/wt) is more preferably 40-60 ppm (wt/wt).In an embodiment, the trifluoroacetic acid amount is about 100-3000ppm, preferably 500-1500 ppm.In other embodiments, phosphoric acid amount is about 10-200 ppm, 50-150 ppm preferably, and be more preferably 75-125 ppm.
Compositions of the present invention can comprise at least a bio-compatible agent, and it has reduced the concentration level (also being cited as " concentration of formaldehyde depressant " in this article) of the active formaldehyde that produces during in vivo by biodegradation when polymer effectively.Preferably, this component is the formaldehyde removing immunomodulator compounds.The formaldehyde removing immunomodulator compounds that the present invention uses comprises sulphite; Bisulfites; The mixture of sulphite and bisulfites; The sulfurous acid ammonium salt; Amine; Amide; Imines; Nitrile; Carbaminate; Alcohol; Sulfur alcohol; Protein; Amine, amide and proteinic mixture; Activity methene compound such as cyclic ketones and α, the chemical compound of beta-dicarbonyl arranged; And do not have carbonyl and contain the heterocyclic compound of a NH group, its medium ring is made of nitrogen or carbon atom, and its ring is unsaturated, or when condensing with phenyl, be unsaturated or saturated, and the NH group is connected on carbon or the nitrogen-atoms, and this atom is connected with two keys with another carbon atom or nitrogen-atoms.
The bisulfites and the sulphite that are used as the formaldehyde removing immunomodulator compounds among the present invention comprise alkali metal salt and ammonium salts such as lithium, sodium and potassium salt, for example sodium sulfite, Potassium acid sulfite, bisulfite lithium, ammonium bisulfite, sodium sulfite, potassium sulfite, lithium sulfite, ammonium sulfite and analog.
The example of the available amine of the present invention comprises aliphatic and aromatic amine, for example aniline, benzidine, amino miaow pyridine, toluenediamine, triethylenediamine, diphenylamines, diamino-diphenylamine, hydrazine and hydrazides.
Suitable protein comprises collagen, gelatin, casein, soybean protein, vegetable protein, keratin and osseocolla.The used preferred protein of the present invention is a casein.
The used suitable amide of the present invention comprises carbamide, cyanamide, acrylamide, Benzoylamide and acetamide.Carbamide is preferred amide.
Suitable alcohol comprises phenol, 1,4-butanediol, d-Sorbitol and polyvinyl alcohol.
The suitable chemical compound with b-dicarbapentaborane comprises, malonic acid, acetylacetone,2,4-pentanedione, ethyl acetone, acetas, Malondiamide, diethyl malonate or other malonate.
The used preferred cyclic ketones of the present invention comprises Ketohexamethylene or Ketocyclopentane.
Be used as the example of the suitable heterocyclic compound of formaldehyde scavenger in the present invention, disclose as U.S. Patent number 4,127,382 (Perry) are incorporated herein with for referencial use.This heterocyclic compound for example comprises: benzimidazole, 5-tolimidazole, 2-tolimidazole, indole, pyrroles, 1,2,4-triazole, indoline, benzotriazole, indoline and analog.
Preferred formaldehyde scavenger used among the present invention is a sodium sulfite.
In the embodiment of this invention, the concentration of formaldehyde depressant joins in the cyanoacrylate with effective dose as the formaldehyde removing immunomodulator compounds.The dosage of the formaldehyde amount that " effective dose " produced when referring to enough to reduce the polymeric cyanoacrylate of biodegradation in the body.This dosage is decided by the type of active formaldehyde concentration depressant, and those skilled in the art need not, and too much experiment is just easy to be determined.
The concentration of formaldehyde depressant can be used with free form or microencapsulation form in the present invention.U.S. Patent application No.08/714,288 have enumerated other compositions, are incorporated herein with for referencial use.
When by microencapsulation, the concentration of formaldehyde depressant is released out from microcapsule in a period of time when cyanoacrylate polymer is by biodegradation in vivo continuously.
For the purposes of the present invention, the microcapsule formalization of concentration of formaldehyde depressant is preferred, because this embodiment prevents with the concentration of formaldehyde depressant or fully reduced the monomeric polymerization of cyanoacrylate, prolonged the pot-life and when easy to use to the processing of monomer composition.
Can realize the microencapsulation of PARA FORMALDEHYDE PRILLS(91,95) scavenger by many known microencapsulation technology.For example, can obtain the polymer concentration of about 6% (weight) by dissolving coated polymeric in volatile solvent (as dichloromethane); Formaldehyde removing immunomodulator compounds with grain shape in vibration joins in coated polymeric/solvent solution, obtains the scavenger concentration of 18% (weight); In thermal agitation, the mineral oil solution that will contain surfactant slowly joins in the polymer solution; In vibration, evaporate volatile solvent; Remove agitator, separating solids from mineral oil; Washing and dry particles realize microencapsulation.The magnitude range of microgranule is from about 0.001 to about 1000 microns.
But the coated polymeric that is used for concentration of formaldehyde depressant microencapsulation should be the polymer of bioerosion in those bearing objects, and preferably, speed is similar to or forms the speed of cyanoacrylate polymer greater than monomer, and should have low inherent water content.This bioerosion be encapsulant by the result of physics or chemical depletion, for example, when body fluid exists, encapsulant from solid through the solute or body intrinsic factor biodegradation encapsulant cause.
The example that can be used for the coating material of microencapsulation concentration of formaldehyde depressant comprises: polyester such as polyglycolic acid ester (polyglycolic acid), polylactic acid, poly--1, copolymer, the hydrogel polyester of copolymer, 6-caprolactone and the DL-dilactide of the copolymer of 4-Er Evil-2-ketone, poly-oxalate (polyoxaltes), Merlon, polyglycolic acid and polylactic acid, polycaprolactone, poly--the b-hydroxy butyrate, 6-caprolactone and δ-Wu Neizhi; Polyvinylpyrrolidone; Polyamide; Gelatin; Albumin; Protein; Collagen; Poly-(ortho esters); Poly-(acid anhydride); Poly-(alkyl-2-cyanoacrylate); Poly-(dihydropyran); Poly-(acetal); Poly phosphazene (phosphazenes); Poly-(urethanes); Poly-oxine ketone (dioxinone); Cellulose; And starch.
The surfactant example that can join in the mineral oil comprises, the Triton x-100 that those can be buied
TM(Rohm and Haas), Tween 20
TM(ICI Americas) and Tween 80
TM(ICI Americas).
Compositions is also optional to comprise at least a thickening agent.Suitable thickening for example comprises: polybutylcyanoacrylate, polylactic acid, poly--1, the copolymer of 4-Er Evil-2-ketone, poly-oxalate (polyoxalates), Polyethylene Glycol acid, lactic acid-glycolic acid copolymer, polycaprolactone, lactic acid-caprolactone copolymer, poly--the 3-hydroxybutyric acid, poe, polyacrylic acid alkane ester, alkyl acrylate and vinyl acetate, the copolymer of polymethylacrylic acid alkane ester and alkyl methacrylate and butadiene.The example of alkylmethacrylate and acrylate is poly-(a 2-ethylhexyl butyl methacrylate) and poly-(2-ethylhexyl acrylate), also can be poly-(butyl methacrylate) and poly-(butyl methacrylate), also can be the copolymer of different acrylate and methacrylate, as poly-(butyl methacrylate-be total to-methacrylate).
In order to improve the bonding strength of the adhesive that the present composition forms, the bi-functional monomer cross-linking agent can be joined in the monomer composition of the present invention.Such cross-linking agent is known.Overhults is in U.S. Patent No. 3,940, and 362 (being hereby incorporated by) disclose this cross-linking agent.The example of suitable crosslinking agent comprises alkyl two (2-cyanoacrylate), triallyl isocyanurates, alkylidene diacrylate, alkylidene dimethyl allene acid butyl ester, trimethylolpropane triacrylate and alkyl two (2-cyanoacrylate).The activatory free-radical initiator of amine or the rate adaptation agent that can add catalytic amount cause the polymerization of cyanoacrylate monomer/cross-linking reagent mixture or regulate rate of polymerization.
Compositions of the present invention also can contain fiber enhancer and coloring agent, i.e. dyestuff and pigment.Suitable fiber enhancer comprises PGA microfibril, collagen microfibrils, cellulose microfibers and alkene class microfibre.The example of suitable coloring agent comprises, 1-hydroxyl-4-[4-aminomethyl phenyl-amino-9,10 amerantrone (the purple NO.2 of D+C); 6-hydroxyl-5-[(4-sulfophenyl) azo ］-2-naphthalene-sulfonic acid (6-hydroxy-5-[(4-sulfophenyl) axo]-2-naphthalene-sulfonic acid) disodium salt (FD+C yellow No.6); 9-(o-carboxyl phenyl)-6-hydroxyl-2,4,5, the 7-tetraiodo-3H-xanthene-3-ketone, disodium salt, sulfuric monohydrate (the red No.3 of FD+C); 2-(1, the inferior indole of 3-dihydro-3-oxygen-5-sulfo group-2H-dioxy-2-yl)-2,3-dihydro-3-oxygen-1H-indole-5-disodium sulfonate salt (the blue No.2 of FD+C); [phthalocyanine (2-) is closed] copper.
Other compositions that the present invention considers is in U.S. Patent No. 5,624,669; 5,582,834; 5,575,997; 5,514,371; 5,514,372; With 5,259, to enumerate in 835, the disclosure of all these all is incorporated herein by reference at this.
Embodiment
According to method mentioned above, 120 microlitre samples have been tested in the 1000ppm BAC solution that is dissolved in methanol to the induced of 2-octyl cyanoacrylate.Obtained following polymerization time: sample number setting time (second) 1 109 2 106 3 111 4 121 5 102 6 101 7 109 8 57 9 126
Claims (20)
1. one kind passes to patient's test kit with medicament, comprises a packing, it is characterized in that this packing contains:
Contain polymerizable monomer composition first container and
Second container that contains medicament.
2. test kit as claimed in claim 1 is characterized in that, described medicament is a kind of polymerization initiator or rate of polymerization promoter, and makes described monomer composition generation polymerization, forms polymer bonding agent.
3. test kit as claimed in claim 1 or 2 is characterized in that, described medicament exists with the materia medica effective dose that is used to tissue local application.
4. test kit as claimed in claim 2 is characterized in that described superficial tissue is a skin.
5. as the arbitrary described test kit of claim 1-3, it is characterized in that described medicament is selected from antibiotic, antibiotics, antiseptic, bacillin, antibacterial, disinfectant, steroid, antifungal, antiinflammatory, antibacterial agent, antiviral agent, antitumor agent, growth promoter and composition thereof.
6. test kit as claimed in claim 1 or 2 is characterized in that described polymerisable monomer is 1,1-two substituted ethylene monomers.
7. as the described test kit of claim 1,2 or 6, it is characterized in that described polymerisable monomer is a cyanoacrylate.
8. as claim 1-3 or 5 arbitrary described test kits, it is characterized in that described medicament is selected from quaternary ammonium halide, sulfadiazine salt and silver salt.
9. as claim 1-3,5 or 8 arbitrary described test kits is characterized in that described medicament is a quaternary ammonium halide, is selected from: have the alkyl benzyl dimethyl ammonium chloride of the alkyl that contains 6-18 carbon atom, its pure component, or its mixture; And or the Benzene Chloride first and second oxygen ammoniums.
10. as claim 1-3,5 or the described test kit of 8-9, it is characterized in that described medicament is a sulfadiazine salt, is selected from: silver salt, sodium salt and zinc salt.
11. test kit as claimed in claim 7 is characterized in that, this test kit is sterilized.
12. test kit as claimed in claim 2 is characterized in that, described patient is an animal.
13. one kind comprises that polymerizable monomer composition and one pass to medicament the manufacture method of packing of patient's method explanation book list, is characterized in that this method comprises:
With the medicament of materia medica effective dose be coated onto described patient tissue and
Polymerizable monomer composition is coated onto on the medicament,
Wherein said medicament is polymerization initiator or rate of polymerization promoter, and causes the polymerization of monomer composition, forms the adhesive covering that covers described tissue.
14. manufacture method as claimed in claim 13 is characterized in that, this medicament has topical remedy's effect at its tissue that is coated with usefulness.
15., it is characterized in that this medicament has the systemic medication effect to described patient as claim 13 or 14 described manufacture methods.
16. as the arbitrary described manufacture method of claim 13-15, it is characterized in that described polymerisable monomer is 1,1-two substituted ethylene monomers.
17., it is characterized in that described polymerisable monomer is a cyanoacrylate as the arbitrary described manufacture method of claim 13-15.
18., it is characterized in that described medicament is to participate in the anion that free radical produces, and is ion pair, or free radical as the arbitrary described manufacture method of claim 13-17.
19., it is characterized in that described medicament can be by spraying, brush, wipe away, drip, sweep or loose powder being coated with usefulness as the arbitrary described manufacture method of claim 13-18.
20. as the arbitrary described manufacture method of claim 13-19, it is characterized in that described medicament is selected from antibiotic, antibiotics, antiseptic, bacillin, antibacterial, disinfectant, steroid, antifungal, antiinflammatory, antibacterial agent, antiviral agent, antitumor agent, growth promoter and composition thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6987598A | 1998-04-30 | 1998-04-30 | |
| US09/069,875 | 1998-04-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1299289A true CN1299289A (en) | 2001-06-13 |
Family
ID=22091751
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 99805653 Pending CN1299289A (en) | 1998-04-30 | 1999-04-30 | Use of an adhesive composition over a bioactive polymerization initiator or accelerator |
Country Status (7)
| Country | Link |
|---|---|
| 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 (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Families Citing this family (15)
| 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 |
| AU3638001A (en) * | 1999-10-29 | 2001-05-14 | Closure Medical Corporation | Adhesive applicator tip with a polymerization initiator, polymerization rate modifier, and/or bioactive material |
| EP1272231A1 (en) | 2000-04-06 | 2003-01-08 | University Technology Corporation | Compositions and methods for promoting wound healing |
| 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 |
| US7238828B2 (en) * | 2005-03-24 | 2007-07-03 | Ethicon, Inc. | Absorbable α-cyanoacrylate compositions |
| EP3391965B1 (en) * | 2015-12-18 | 2023-08-30 | Acenet Inc. | Use of a radical generating catalyst 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 |
| 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 |
| USD848624S1 (en) | 2016-09-29 | 2019-05-14 | Ethicon, Inc. | Release paper for wound treatment devices |
| US10687986B2 (en) | 2016-09-29 | 2020-06-23 | Ethicon, Inc. | Methods and devices for skin closure |
| US10470935B2 (en) | 2017-03-23 | 2019-11-12 | Ethicon, Inc. | Skin closure systems and devices of improved flexibility and stretchability for bendable joints |
| US10993708B2 (en) | 2018-07-31 | 2021-05-04 | Ethicon, Inc. | Skin closure devices with interrupted closure |
| CA3140217A1 (en) * | 2019-06-11 | 2020-12-17 | Animal Ethics Pty Ltd | Pain relieving method |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3513938A1 (en) * | 1985-04-18 | 1986-10-23 | Merck Patent Gmbh, 6100 Darmstadt | CYTOSTATIC-CONTAINING PHARMACADEPOT |
| CN1056973C (en) * | 1993-10-04 | 2000-10-04 | 毛里齐奥·托内蒂 | Pharmaceutical composition to enhance tissue healing and regeneration and application kit comprising it |
| US5928611A (en) * | 1995-06-07 | 1999-07-27 | Closure Medical Corporation | Impregnated applicator tip |
| US5684042A (en) * | 1997-01-10 | 1997-11-04 | Medlogic Global Corporation | Cyanoacrylate compositions comprising an antimicrobial agent |
| FR2760971B1 (en) * | 1997-03-20 | 1999-12-10 | Dow Corning Sa | PROCESS FOR PRODUCING A CONTROLLED RELEASE COMPOSITION |
-
1999
- 1999-04-30 WO PCT/US1999/009374 patent/WO1999055374A1/en active IP Right Grant
- 1999-04-30 CA CA002330479A patent/CA2330479A1/en not_active Abandoned
- 1999-04-30 AU AU38730/99A patent/AU759076B2/en not_active Expired
- 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 EP EP99921545A patent/EP1073468A1/en not_active Withdrawn
- 1999-04-30 CN CN 99805653 patent/CN1299289A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU3873099A (en) | 1999-11-16 |
| WO1999055374A1 (en) | 1999-11-04 |
| AU759076B2 (en) | 2003-04-03 |
| CA2330479A1 (en) | 1999-11-04 |
| BR9910063A (en) | 2000-12-26 |
| JP2002512980A (en) | 2002-05-08 |
| EP1073468A1 (en) | 2001-02-07 |
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