MXPA00010459A - Adhesive applicator with polymerization agents and/or bioactive material - Google Patents

Abstract

A method of applying a bioactive agent and/or a polymerization or cross-linking rate modifier and/or a polymerization initiator to an applicator tip includes dissolving or dispersing the rate modifier, the initiator, and/or the bioactive agent in a low boiling point solvent, applying the resulting solution or dispersion to the applicator tip, and drying the applicator tip. The initiator and/or rate modifier is preferably applied in a methanol solvent and distributed along a concentration gradient on the applicator tip.

Description

ADHESIVE APPLICATOR WITH AGENTS FOR POLYMERIZATION AND / OR BIOACTIVE MATERIAL BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to applicators for the application of biomedical adhesives and sealants, methods for making them, and methods for applying such adhesives and sealants- More particularly, this invention relates to methods for applying a bioactive agent, a modifier of the speed of the polymerization and / or a polymerization initiator for an applicator tip; applicators and applicator tips produced by these methods; and methods for using applicators in medical, surgical and other topical applications. 2. Description of Related Art The products in the primary use for wound closure are sutures and surgical staples. The sutures are recognized that provide adequate support of the wound. However, the sutures cause additional trauma to the site of the wound (for the reason that the needle and suture need to pass through Ref. 124254 through the tissue and the need to anesthetize the wound area by means of a puncture with a needle) and are time consuming at placement, and, at the level of. the skin, can cause unattractive marks of wound closure. Surgical staples have been developed to accelerate the apposition of wounds and to provide improved cosmetic results. However, surgical staples also impose additional wound trauma and require the use of ancillary and often expensive devices for the placement and application of 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 in their placement, and in geriatric cases where the skin tissue is weak and prone to tearing. As an alternative for sutures and surgical staples, adhesives have been proposed for use in wound closure. Similarly, adhesives have been proposed for use in wound coverage and protection in these topical applications such as superficial lacerations, abrasions, stomatitis and other superficial, open wounds, a group of these adhesives are the monomeric forms of -cyanoacrylates. .

Typically, for wound closure, the surgical cyanoacrylate adhesive is applied to one or both surfaces of a wound or incision, including the internal portions of the wound, with any excess adhesive that is rapidly removed from the bonding surfaces. Subsequently, the edges of the wound are held together until they adhere. For example, see U.S. Patent No. 3,559,652 issued to Coover, Jr. et al. An additional method of applying the surgical cyanoacrylate adhesive to wounds or incisions involves the formation of a bridge over the wound site. As described in U.S. Patent No. 3,667,472 issued to Halpern, the cut tissues are held together and held in a fixed relationship until a cyanoacrylate adhesive has been applied over the incision and the time necessary to develop a bond is left. A method for the application of a cyanoacrylate, topical tissue adhesive is described in the product literature accompanying Histoacril®, which is commercially available from B. Braun Melsungen AG of Germany. The manufacturer recommends the use of this adhesive only for the closure of minor skin wounds and not for internal use.

In addition, the manufacturer recommends that the adhesive be used economically or in thin films because the thick films do not increase the strength of the film and can lead to necrosis of the surrounding tissue due to the thermogenic polymerization of the cyanoacrylate adhesive. Typically, when used in medical applications, the cyanoacrylate adhesives are applied in monomeric form to the surfaces to be joined, sealed or otherwise treated. Typically, the anionic polymerization of the monomer occurs in itself, giving rise to the desired bond or coverage of the adhesive. In these examples, moisture and / or proteins naturally present in the treated fabrics initiate the polymerization of the adhesives. However, as is the case with Histoacril®, polymerization can proceed rapidly, with the generation of high levels of heat, which frequently damages the tissues at or near the application site. In an effort to overcome this type of tissue damage, first the fabric can be dried, for example by drying with a sponge, to essentially remove all fluids from the tissue of the site. In this method, there is essentially no water to start the polymerization. Therefore, the polymerization proceeds relatively slowly, often taking more than 150 seconds, for example. This system, while effective, does not provide a high level of convenience or utility to the user due to the extended time frequently required for polymerization. In view of the defects associated with the methods described above, an effort has been made to control the rate at which polymerization occurs such that the polymerization will occur fast enough to be convenient for the user, but not so quickly that damage to the product occurs. tissue due to the polymerization reaction. To control the rate at which the adhesives polymerize (and to improve the life span), additives have been included in the monomeric adhesive compositions. For example, inhibitors or stabilizers of cyanoacrylate polymerization including Lewis acids, such as sulfur dioxide, nitric oxide, boron trifluoride, and other acidic substances, including monomethyl ether of hydroquinone, hydroquinone, nitrohydroquinone, catechol and monoetilic ether of hydroquinone. Such inhibitors are described in, for example, U.S. Patent No. 3,559,652 issued to Banitt, the content of which is incorporated herein by reference. The addition of these inhibitors and stabilizers inhibits the premature polymerization of the monomer and decreases the speed of polymerization once the composition is in contact with the tissue to be treated. Another method for inhibiting the polymerization of monomeric adhesives is described in U.S. Patent No. 4,291,131 issued to Mclntire et al. Mclntire et al. Describes a nozzle for use in containers for containing the cyanoacrylate adhesives so that the cyanoacrylate compositions do not begin to polymerize upon exposure to moisture in the air. The nozzle comprises a moldable material having an organic acid dispersed therein which inhibits the polymerization of the cyanoacrylates while in the nozzle. The organic acids are incorporated into the moldable material prior to the formation of the die extrusion. Although it is known to add polymerization inhibitors and stabilizers to cyanoacrylate compositions to increase the stability and lifetime of the compositions, the addition of polymerization initiators or accelerators to the cyanoacrylate compositions is not widely performed. As discussed above, polymerization typically occurs in if t u without the need for an external initiator or accelerator. In situations where an initiator or accelerator is added to the composition, such as when the tissue fluids have been removed from the application site, the initiator or accelerator is not added immediately before the application of the adhesive. For example, U.S. Patent No. 4,042,442 issued to Dombroski et al. Describes the addition of a polymerization initiator (either caffeine or theobromine) to a cyanoacrylate adhesive composition. The caffeine or theobromine is added to the adhesive composition in one or two forms. In the first form, the caffeine or theobromine can be mixed with the cyanoacrylate adhesive composition by adding just before the application of the adhesive to the substrates to be joined. In the second form, 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 United. Both of these methods, while effective, are inconvenient for the user because two separate solutions or two separate applications are required. In an effort to address this inconvenience and lack of control over the polymerization process, the published PCT application, commonly assigned No. WO 96/40797, the description of which is incorporated by this action in its entirety, describes the incorporation of a polymerization initiator or a polymerization speed modifier in an applicator tip. The incorporation of the initiator or velocity modifier in the applicator tip provides convenience or utility because it requires only an individual composition, and allows a level of control over the speed of polymerization that can not be achieved through confidence. in the initiators or polymerization rate modifiers naturally present at the site of the wound (such as water). The initiators and / or polymerization rate modifiers are incorporated in the applicator tip by spraying, immersion treatment, or brush application to the applicator tip with a solvent (also referred to herein as a liquid medium). ) containing the initiator and / or speed modifier. Low-boiling solvents (such as acetone and ethanol, or mixtures thereof) are used to apply the initiator and / or speed modifier. The applicator tips described in this commonly assigned published PCT application allow for effective and convenient mixing of a cyanoacrylate composition with a polymerization initiator or a polymerization rate modifier during distribution. However, the resultant polymerization reaction can be highly exothermic, and, like other methods currently in use, it can cause tissue damage at the application site due to excessive generation of heat during polymerization. In addition to the addition of inhibitors, stabilizers and polymerization initiators to monomeric cyanoacrylate compositions, it is also known to add bioactive materials to these adhesive compositions. Frequently, these bioactive materials are medicaments which are added to the adhesive compositions to aid in the healing process when the cyanoacrylate adhesives are used to close the wounds. For example, U.S. Patent No. 5,684,042 issued to Greff et al. Describes a cyanoacrylate composition comprising an antimicrobially effective amount of an antimicrobial agent containing iodine. The iodine-containing antimicrobial agent is dispersible in the cyanoacrylate composition and does not cause premature polymerization of the cyanoacrylate adhesive (ie, does not initiate polymerization). Additionally, U.S. Patent Nos. 5,514,371 and 5,624,669 issued to Leung et al. Describe 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 of the matrix during the biodegradation of the polymer. U.S. Patent No. 4,940,579 issued to Randen discloses a composition comprising a medicament and a cyanoacrylate adhesive. The composition is used to deliver drugs to non-mucous areas of mammalian bodies. The American patent No. 5, 254,132 issued to Barley et al. Describes 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 dosage application. The composition is kept in a sealed container to prevent polymerization before application; therefore, the antibiotic does not initiate or accelerate the polymerization of the adhesive composition. While all of these methods include combining cyanoacrylate adhesives with bioactive materials, the described methods are disadvantageous for the application of the adhesive compositions because multiple solutions and / or applicators are required in order to mix the initiator and the adhesive composition or they fail to provide a way to control the speed at which the polymerization proceeds. In addition, the selection of bioactive materials has been limited in general by the desire to avoid interaction between adhesives and bioactive materials.

BRIEF DESCRIPTION OF THE INVENTION It has been found that the use of methanol, alone or as a component of a low boiling point solvent mixture, to apply a material (such as an initiator or modifier of the polymerization rate and / or cross-linking) to an applicator tip used to distribute the monomer-containing adhesive compositions, provides an unexpectedly superior distribution profile of the material on, and within, the applicator tip. The upper distribution profile allows a reduction in time of the polymerization of the monomeric adhesive, distributed while avoiding the tapping to the tissue due to the highly exothermic polymerization reaction. It has also been discovered that bioactive materials, which can be initiators and / or polymerization rate modifiers can also be applied to such applicator tips, providing improved convenience when treating a fabric with a bioactive material. The present invention provides a method for applying at least one material to an applicator tip used to apply liquid compositions. In embodiments, the material can be applied to the applicator tip using a solvent comprising methanol and further comprising another low boiling solvent, such as a ketone or low molecular weight alcohol, or a mixture thereof. As used herein, ketones and low molecular weight alcohols are those which have three or fewer carbon atoms in their main chain. In preferred embodiments, the solvent consists essentially or entirely of methanol. In embodiments, the material is applied to an applicator tip such that the material is present at the tip in a gradient or anisotropically (i.e., in a pattern that is not identical in all directions within the tip). Preferably, the material is present at the tip in a gradient, where there is a greater amount of the material at the distal end of the tip (the end where the liquid composition leaves the applicator tip during application) compared to the proximal end (the end where the liquid composition enters the applicator tip during application). In the embodiments, the material is an initiator and / or a rate modifier for the polymerization and / or crosslinking of a polymerizable monomer. As used herein, a polymerization initiator is any material that causes a monomeric composition applied to a substantially dry fabric (i.e., substantially in the absence of similar plasma or tissue fluids) to polymerize in less than 300 seconds to a room temperature, for example, at about 21-25 ° C. Preferably, the initiator causes the monomeric composition to polymerize in less than 150 seconds at room temperature, more preferably within 130 seconds. As used herein, a polymerization rate modifier is any material that changes the rate at which a polymerizable monomer would polymerize in the absence of that material. Preferably, the speed modifier accelerates the speed of the polymerization reaction. In the modes, the initiator or the speed modifier is an accelerator or catalyst. In the modalities, the initiator and / or speed modifier is bioactive. In other embodiments, the material applied to the tip is bioactive, but not an initiator or a rate modifier for the polymerization and / or crosslinking of the polymerizable monomer. The present invention also provides a method for using an applicator tip that contains a polymerization and / or crosslinking initiator, a polymerization and / or crosslinking rate modifier, and / or a bioactive material for applying a monomer composition to a desired site, such as a wound, a surgical site or any other site of topical or deep tissue. In modalities, the method is used to treat wounds or to treat or protect topical sites, such as areas of skin prone to injury. The present invention also provides a method for delivering a bioactive material to a fabric. As used herein, the tissue includes any tissue of a human or animal, such as skin, mucous membranes, oral / nasal tissues, gastrointestinal tissues, organ tissues, tumors, non-keratinous tissues, etc. The present invention further provides an applicator tip having a polymerization or crosslinking initiator, a polymerization and / or crosslinking speed modifier, and / or a bioactive material applied thereto. The applicator tip according to the present invention provides various advantages, including the ability to: a) control the molecular weight distribution of the polymerized or crosslinked adhesive; b) controlling the curing time of the polymerized or crosslinked adhesive; c) provide precision and convenience in the application of the adhesive to a fabric; d) extending the lifetime of the monomer, e) reducing the amount of unreacted monomer at the termination of the polymerization reaction, to thereby avoid the odors of the associated monomers after the polymerization; f) control the flow properties of cyanoacrylate adhesives, applied; g) providing a bioactive material to a wound site while simultaneously providing closure, protection and / or wound coverage; and / or h) any combination thereof. In accordance with the embodiments of the present invention, there is provided a method for the application of at least one agent selected from the group consisting of bioactive materials, polymerization initiators and polymerization rate modifiers to an applicator tip for the adhesives. , which comprises: dissolving or dispersing the agent in a low-boiling solvent to form a solution; apply the solution to the applicator tip; and drying the applicator tip; wherein the low boiling point solvent comprises methanol at least when the agent does not comprise a bioactive material. That is, in these embodiments, when the agent is not a bioactive material, ie, when the agent is a polymerization initiator or a polymerization rate modifier, the low-boiling solvent comprises methanol. However, when the agent is a bioactive material, the low boiling solvent is not particularly limited, but may include methanol. In other embodiments, the present invention provides an applicator for a polymerizable adhesive, comprising: a conduit for a polymerizable, fluidizable adhesive material; an applicator tip operably connected to the conduit so that the fluid passes through the applicator tip; and at least one agent selected from the group consisting of bioactive materials, polymerization initiators, and polymerization rate modifiers on or at the applicator tip; wherein the applicator tip has a gradient of the agent at least when the agent does not comprise a bioactive material. That is, in these embodiments, when the agent does not comprise a bioactive material, ie, when the agent comprises a polymerization initiator or a polymerization rate modifier but is not a bioactive material, the applicator tip has a gradient. from the people. However, when the agent comprises a bioactive material, alone or in combination with a polymerization initiator or a polymerization rate modifier, the applicator tip may or may not have a gradient of the agent.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 represents an applicator of the invention, showing the distribution of a polymerization rate modifier or a polymerization initiator in a methanol applied applicator tip. Figure 2 is a cross section of the applicator of Figure 1, along line A-A. Figure 3 depicts an applicator showing the distribution of a polymerization rate modifier or a polymerization initiator in an applicator tip applied with acetone. Figure 4 is a cross section of the applier of Figure 3 along line A-A. Figure 5 shows the polymerization temperatures of a 2-octyl cyanoacrylate composition distributed through the applicator tips having an initiator applied with methanol and acetone. Figure 6 shows the relationship between the hardening time (time required for the polymerization) of a 2-octyl cyanoacrylate composition and the concentration of the initiator. The Figure also shows the time required for the polymerization of a 2-octyl cyanoacrylate composition applied through the tips having an initiator applied with methanol and acetone.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES As mentioned above, the commonly assigned PCT Application No. WO 96/40797, the description of which is incorporated by this act in its entirety, describes the use of low-boiling solvents, such as acetone, ethanol or mixtures thereof, to apply an initiator or a modifier of the speed of polymerization or crosslinking to an applicator tip. The cyanoacrylate adhesive compositions applied through these tips can show rapid polymerization, with concomitant heat production. If the compositions are applied to living tissues, this could, in some cases, cause tissue damage and necrosis of the underlying and / or adjacent living matter. The analysis of the tips produced by the methods of WO 96/40707 shows that the use of acetone to apply the initiator or the tip speed modifier results in the distribution of the material mainly on the outside, or near the outer surface, of the tip as well as in the proximal portion, or background. A distribution of this kind is shown in Figure 3. To improve the polymerization characteristics of the monomeric, polymerizable compositions delivered through applicator tips having a polymerization initiator and / or a polymerization rate modifier arranged in the same, the solvent used to apply the initiator or the speed modifier was changed. It was found that the use of methanol to apply the initiator or velocity modifier to an applicator tip provides polymerization characteristics unexpectedly superior to a monomeric, polymerizable composition compared to the compositions applied through the tips having an initiator and / or modifier, of the speed applied using acetone. The polymerizable cyanoacrylate monomer compositions disposed through these tips typically generate much less heat than the same compositions disposed through the tips prepared using acetone. It can be shown, using term analysis techniques such as differential scanning calorimetry, that the monomer compositions applied through such tips generate heat levels that can damage the tissues. For example, as shown in Figure 5, a composition comprising 2-octyl cyanoacrylate supplied through an applicator tip having an initiator (benzalkonium chloride) applied with acetone can generate sufficient heat in 200 seconds after initiation of the polymerization to raise the temperature of the composition to about 80 ° C. However, the same composition supplied through a tip having the same initiator applied using methanol shows a much lower level of heat generation (approximately 40 ° C). In addition, as shown in Figure 6, the curing time, or the amount of time required for the polymerization, of a 2-octyl cyanoacrylate composition is negligibly longer when the cyanoacrylate composition is supplied through a tip. having a benzalkonium chloride initiator disposed therein, making use of methanol compared to the use of acetone. Figures 1-4 show the effects of different solvents used to apply a polymerization initiator or a polymerization rate modifier to an applicator tip. The velocity initiator or modifier is applied to the tip when pumping a liquid medium comprising the initiator or the velocity modifier through a syringe and at the distal end of the tip. Figure 1 shows an applicator tip 2 of applicator 1 treated with a solution of an initiator or a speed modifier dissolved in 110 μL of methanol, and subsequently dried for about 30 minutes. Figure 2 shows a cross section of the applicator and the tip in Figure 1. The initiator or velocity modifier is present at the tip in a concentration gradient. The concentration of the initiator or the speed modifier is higher at the upper end, or distal, of the applicator tip and decreases toward the center and the bottom, or proximal, end of the applicator tip. In contrast, Figure 3 shows an applicator tip treated with a solution of an initiator or modifier of the dissolved speed in 110 μL of acetone, and subsequently dried for about 30 minutes. Figure 4 shows a cross-section of the applicator and the tip in Figure 3. The initiator or velocity modifier is present at the tip in a concentration gradient that increases from the upper (distal) end to the bottom end ( next) of the applicator tip. The distribution pattern of the material within the tip, when applied using a solvent comprising methanol, provides unexpectedly superior polymerization characteristics to the monomeric compositions disposed across the tip compared to the composition delivered through the tips prepared using other low-boiling point solvents, such as acetone. The monomeric compositions supplied through the tips prepared using solvents comprising methanol are polymerized sufficiently fast to make them convenient for the application; however, the polymerization that occurs does not result in the level of tissue damage frequently observed when using other cyanoacrylate delivery systems. In accordance with this aspect of the present invention, the solvent (also referred to herein as the liquid medium) for the application of the material comprises methanol. Methanol can be used as the sole solvent, or it can be present in mixtures of methanol with other low boiling point solvents, including low molecular weight ketones such as acetone. The mixture can be in any ratio. Preferably, the mixture is a ratio of methanol to another solvent of between 99: 1 to 1:99. For example, the ratio of methanol to another solvent may be about 80:20 to 20:80, or 60:40. at 40:60. A ratio of at least 70:30, such as 80:20 or 90:10 or greater, is desirable in the modalities. In preferred form, when the solvent comprises a different component of methanol, the other component is a solvent of low boiling point which has a vapor pressure of about 25-150 mm Hg at 20 ° C, such as about 30-125 mm Hg at 20 ° C, or approximately 40-100 mm Hg at 20 ° C, or mixtures thereof. In the modalities, low molecular weight solvents can be used. Ketones and low molecular weight alcohols are included. The material can be applied to the applicator tip by spraying, immersion treatment, injection, or brush application to the applicator tip with the liquid medium containing the material. Preferably, it is applied to the tip by the immersion or injection treatment. For example, it can be applied to the tip when pumping the liquid medium, for example, through a syringe, at the distal end of the tip. In exemplary embodiments, preparing an applicator for dispersing monomeric, polymerizable compositions includes applying a material to a tip of polyethylene, porous, which joins butyrate applicator tube. The use of solvents comprising methanol also provides for the proper bonding of the butyrate applicator tube to a polyethylene applicator tip. The solvent used to apply the material to the tip also helps to attach the polyethylene applicator tip to the butyrate applicator tube. When acetone is used, damage to the tube and / or tip can occur if too much acetone is used. Solvents comprising methanol, while still providing the union that is necessary to attach the tip to the tube, allow the use of a greater range of solvent quantities to apply the material to the tip. An anisotropic distribution or a concentration gradient of the material in the applicator tip can be obtained with the use of a solvent containing methanol. The distribution of the material can be varied depending on the solvent or the solvents used to apply it and the wetting characteristics of the solvent and the tip. In general, the wetting characteristics of the solvent must be such that the surface tension is sufficiently close to that of the tip material to wet at least the surface of the tip. The material applied to the applicator tip can be any material, but is preferably an initiator that initiates the polymerization and / or crosslinking of the monomer; a polymerization speed modifier, which modifies the speed of polymerization of the monomer; or a bioactive material, such as a medicament. The material can be applied to a surface portion or to the entire surface of the applicator tip. Preferably, only a portion of the outside of the applicator tip is treated with the material. Initiators and particular speed modifiers for the particular monomers can be easily selected by one skilled in the art without undue experimentation. The control of the molecular weight distribution of the applied adhesive can be increased by selecting the concentration and functionality of the initiator or the speed modifier compared to the selected monomer. Initiators and polymerization rate modifiers, suitable for cyanoacrylate compositions include, but are not limited to, detergent compositions; surfactants, including nonionic surfactants such as polysorbate 20 (e.g., Tween 20MR; ICI Americas), polysorbate 80 (e.g. Tween 80MR; ICI Americas), and poloxamers; cationic surfactants such as tetrabutylammonium bromide; anionic surfactants, including quaternary ammonium halides such as benzalkonium chloride or its pure components, and benzenonium chloride; stannous octoate (tin 2-ethylhexanoate) (II)), and sodium tetradecyl sulfate; and amphoteric or positively and negatively charged surfactants such as inner salt of dodecyldimethyl (3-sulfopropyl) ammonium hydroxide; amines, imines and amides, such as imidazole, tryptamine, urea, arginine and povidin; phosphines, phosphites and phosphonium salts, such as triphenylphosphine and triethyl phosphite; alcohols such as ethylene glycol; methyl gallate; ascorbic acid; tannins and tannic acid; inorganic bases and salts, such as sodium bisulfite, magnesium hydroxide, calcium sulfate and sodium silicate; sulfur compounds such as thiourea and polysulfides; cyclic, polymeric ethers such as monensin, nonactin, crown ethers, calixarenes and polymeric epoxides; cyclic and acyclic carbonates, such as diethyl carbonate; phase transfer catalysts such as Aliquat ™ 336 (General Mills, Inc., Minneapolis, MN); organometallic, manganese acetylacetonate; initiators of radicals and radicals, such as di-t-butyl peroxide and azobisisobutyronitrile; and bioactive compounds or agents. In the preferred embodiments, the initiator can be a bioactive material, including quaternary ammonium halides such as alkylbenzyldimethylammonium chloride (benzalkonium chloride; BAC) its pure components or mixtures thereof, especially those with an alkyl containing 6-18 atoms of carbon; benzethonium chloride; and salts of sulfadiazine. Cobalt naphthenate can be used as an accelerator for peroxide. The polymerizable and / or crosslinkable material may also contain an initiator and / or a rate modifier which is inactive until activated by a catalyst or an accelerator (included within the scope of the term "initiator" as used herein). ) on the applicator tip. Initiators activated by stimulation such as with heat and / or light (e.g., ultraviolet or visible light) are also suitable if the tip and / or applicator is appropriately subjected to such stimulation. The initiator or speed modifier is dissolved or otherwise dispersed in the solvent and applied to the applicator tip in any effective amount. An effective amount is that amount of the initiator or rate modifier which effects the polymerization to a gel point in the dry tissue in less than 300 seconds, preferably within 150 seconds, and more preferably within 130 seconds, at room temperature, such as about 21-25 ° C. The coated applicator is then allowed to dry, due to which the solvent evaporates. In the embodiments, the applicator is allowed to dry for approximately 5 to 35 minutes. In the embodiments, the amount of the initiator or modifier dissolved or dispersed in the solvent may be about, or less than, 25% by weight, preferably less than 10% by weight and more preferably less than 1% by weight . The amount of the initiator or the speed modifier dissolved or dispersed in the solvent can be any effective amount. In the case where a quaternary ammonium halide is the initiator or speed modifier, the effective amount is preferably between 100 and 250 ppm or more in 110 μl. In the case of sulfadiazine salts, the effective amount is preferably about 50 ppm or more in 110 μ. The effective amount for each initiator and the combination of adhesive monomers can be readily determined by one of ordinary skill in the art. To determine the polymerization time, an appropriate volume of a solution of the initiator prepared in a volatile solvent is placed in a calorimetric differential scanning vessel. The volatile solvent is allowed to dry under ambient conditions. Alternatively, the appropriate amount of the initiator is delivered directly into the calorimetric differential scanning vessel. In any of the cases mentioned above, 25 μl of the selected monomer solution was pipetted into the container. The time taken for the monomeric composition to polymerize to the point of a gel is the time of polymerization. . 'In the modalities, the initiator and / or the velocity modifier can be, but does not have to be, bioactive. In embodiments where the initiator and / or the velocity modifier is bioactive, the method of the invention can be used to close, cover, or protect tissue and wounds while simultaneously providing a bioactive material to the tissue or tissue. wound. In embodiments where the initiator is also a bioactive material, the bioactive material is applied on the tip in an amount that is effective to initiate the polymerization and which is effective for the proposed biological activity (eg, in an amount sufficient to be antiseptic ). The bioactive material is selected in conjunction with the polymerizable monomer to be delivered such that the bioactive material functions as an initiator or a speed modifier for the monomer. During the delivery of the monomeric composition, the bioactive material is mixed with the monomeric composition. In embodiments, the bioactive material can be delivered to the tissue to be treated at a constant rate, or near constant, for a period of time while the polymerized composition is in contact with the wound site. As mentioned above, the bioactive material can, but is not necessary, be an initiator or a modifier of the polymerization rate. Where the bioactive material is not an initiator or a velocity modifier, an initiator or velocity modifier can also be applied to the tip along with the bioactive material. In this situation, it is not critical that the bioactive material be distributed anisotropically or in a gradient along the applicator tip. In embodiments where the bioactive material is not an initiator, it can be applied to the applicator tip in a solution comprising a low boiling point solvent, especially one comprising methanol. However, any suitable solvent (including aqueous solvents) can be used to apply the bioactive material. In embodiments where the applicator tip contains a bioactive material, the bioactive material is solubilized, dissolved or otherwise dispersed in the adhesive composition when the composition passes through the tip. In this way, the bioactive material similarly passes through the tip and is mixed with the adhesive composition before, and during, the application of the adhesive. The coelution of the bioactive material and the adhesive composition allows this mixing to occur. Additional mixing may occur once the adhesive composition / bioactive material has been delivered to the wound site. Such co-elution of the bioactive material and the adhesive composition provides an advantage not described in the prior art. Suitable bioactive materials include, but are not limited to, medicaments such as antibiotics, antimicrobials, antiseptics, antibiotics produced by bacteria, bacteriostats, disinfectants, steroids, anesthetics, fungicides, anti-inflammatory agents, antibacterial agents, antiviral agents, antitumor agents , growth promoting substances, or mixtures thereof. Such compounds include, but are not limited to, acetic acid, aluminum acetate, bacitracin, bacitracin zinc, benzalkonium chloride, benzethonium chloride, betadine, calcium chloroplatinate, certrimide, chloramine T, chlorhexidine phosphamylate, chlorhexidine, sulfate chlorhexidine, chloropenidine, chloroplatinatic acid, ciprofloxacin, clindamycin, clioquinol, cystetaphine, gentamicin sulfate, hydrogen peroxide, polyvinylidone iodine, iodine, iodofor, minocycline, mupirocin, neomycin, neomycin sulfate, nitrofurazone, no oninol 9, potassium permanganate, penicillin, polymycin, polymycin B, polymyxin, polymyxin B sulfate, polyvinyl pyrrolidone iodine, povidone iodine, 8-hydroxyquinoline, quinolone thioureas, rifampin, rifamycin , silver acetate, silver benzoate, silver carbonate, silver chloride, silver citrate, silver iodide, silver nitrate, silver oxide, silver sulphate, sodium chloroplatinate, sodium hypochlorite, sphingolipids, tetracycline, oxide of zinc, sulfadiazine salts (such as silver, sodium and zinc), and mixtures thereof. The preferable bioactive materials are USP approved, most preferably USP monographed. The present invention is also directed to a method for applying an adhesive composition using an applicator comprising a tip having a polymerization initiator, and a polymerization rate modifier and / or a bioactive material applied in the same In accordance with the invention, any appropriate design for the applicator can be used. These applicator designs include, but are not limited to, squeezable squeegee applicators, syringes, adhesive guns, pipettes, droppers, bottles, and the like with various nozzles or supply tips. For example, the applicator tip can be detachable from the applicator container containing the polymerizable and / or crosslinkable material. This applicator tip could be attached to the applicator container before use and could be separated from the applicator container subsequent to use in order to prevent polymerization or premature crosslinking of the non-applied material in the applicator container. At this point, the applicator tip can be discarded and a new applicator tip can be attached to the applicator container for subsequent use, or the applicator tip can be cleaned and reused. Additionally, the applicator tip according to the present invention can comprise multiple parts, with at least a part having the initiator, the velocity modifier, and / or the bioactive material. For example, the component containing the initiator, the velocity modifier, and / or the bioactive material can be manufactured separately from the other component (s) of the applicator tip and can be assembled prior to the union to the applicator container. The applicator tip may also be in the form of a nozzle to atomize the polymerizable and / or crosslinkable, liquid materials. Conical, flat spray or condensed current nozzles are suitable. The applicator tip and the applicator container can be an integral or even monolithic unit. The unit can be preformed as a single piece and can be loaded with the polymerizable and / or crosslinkable material. After application of the applicator container material, the unit can be discarded. Traditionally, this applicator tip unit / integral or monolithic applicator container can be adapted to provide the ability to recharge the unit with new material as an all-purpose device. The applicator tip may be composed of any of a variety of materials including polymerized materials such as plastics, foams, rubber, thermoset materials, films, or membranes. In embodiments, the applicator tip may be made of polyesters, polyolefins such as polyethylene or polyamides. In embodiments, the applicator may be made of polyethylene, such as that sold by Porex Technologies Corp. (Fairbum, GA) under the name LabPor®. Additionally, the applicator tip may be composed of materials such as' metal, glass, paper, ceramic and the like. The material of the applicator tip may be porous, absorbent, or adsorbent in nature to increase and facilitate loading of the initiator and / or the velocity modifier on or within the applicator tip. For example, the applicator tip may be composed of a material having random pores, capillaries, a honeycomb material, a material having a woven pattern, etc. The degree of porosity will depend on the materials that are used, and can be easily determined by one of ordinary skill in the art. Porosity is the open volume within the pores of an indicator tip divided by the total volume of the applicator tip. In the embodiments, the applicator tip may be porous and may have an average pore size of about 1 μm to about 500 μm. In general, according to the present invention, an applicator tip having an average pore size of about 20 μm is used with a polymerizable material having a viscosity of about 1-30 cPs, preferably about 2-18 cPs, and more preferably 7 cPs at 25 ° C. When the polymerizable and / or crosslinkable material has a viscosity higher than 7 cPs, the average pore size of the applicator tip in general is increased. For example, an applicator tip having an average pore size of about 140 μm is preferably used with a polymerizable material having a viscosity of about 30-500 cPs, preferably about 35-350 cPs, and more preferably preferable approximately 250 cPs at 25 ° C. In the modalities, an applicator tip has a porosity of less than or equal to 80 percent. In the embodiments, when a porous applicator is used, the amount of the initiator or the speed modifier necessary to initiate and / or modify the speed of polymerization and / or crosslinking increases as the pore size of the applicator tip increases. . The applicator tip according to the present invention, where it is connected to the applicator tube, can ^ "•? ^ * M» a »^ BM *.» A «« «. To * j (^ a? * I *? Fl ^^^ p ^ Sa5 ^ '" ^'? E'ra '"^ The polymerization and / or cross-linking material is ejected, and a portion of the applicator tip which is immediately downstream of the applicator tube is advantageously porous in order to avoid a severe pressure drop and to ensure a relationship profile. The structure can preferably trap fragments of any barrier or materials used to separate one or more components within the applicator container so that they do not interfere with the device or make contact with the patient. A porous applicator tip for applying the adhesive composition, the composition is preferably not directly expressed through the applicator tip in a continuous movement In accordance with the embodiments of the present invention, the adhesive composition is (1) expressed to the extreme or a far part to the extre m of the applicator tip, (2) the pressure is released to empty the composition to the applicator, and (3) the composition is subsequently expressed through the applicator tip in a continuous motion. This is called a suction method for the application of the adhesive composition of the present invention. As a result, the adhesive composition polymerizes more slowly than if it had been expressed directly through the tip.

The initiator, the velocity modifier, and / or the bioactive material 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 viscous or akin-like material. pasta. The tip may also include a variety of additives, such as surfactants or emulsifiers. Preferably, the initiator, the velocity modifier and / or the bioactive material are soluble or dispersible in the polymerizable and / or crosslinkable material, and / or comprise or are accompanied by at least one surfactant which helps them to coelute with the polymerizable and / or crosslinkable material. In embodiments, the surfactant can aid solubilization in the polymerizable and / or crosslinkable material. The initiator, the velocity modifier, and / or the bioactive agent are thus mixed with the adhesive composition when the mixture passes through the tip. The present invention provides a method for the treatment of wounds, including wound closure. The methods of this invention can be used as replacements for, or in addition to, sutures or staples to join together two surfaces when applying the present compositions to opposite surfaces of the wound which are then held together while the polymerization proceeds. The methods of this invention may also be used to coat, protect, or otherwise cover the surface of, superficial or otherwise topical wounds, including, but not limited to, surface lacerations, abrasions, burns, ulcers and stomatyses. . The methods of the invention can also be used in tissues that do not show any sign of tissue damage. For example, the methods can be used to deliver drugs to a patient through healthy tissue. These can also be used, for example, to deliver drugs locally to tissues such as tumors or organs. In embodiments, the present invention provides a replacement for sutures or staples and includes a method for joining two surfaces together in vivo, comprising: (a) holding the tissue surfaces of a wound or incision together to form a surface of adjacent tissue; (b) applying a composition of the present invention to the surface of the abutting tissue; and (c) keeping the surfaces in contact until the composition is polymerized. A subsequent coating can be immediately applied after the application of a precoating or after a precoating has been fully polymerized. Preferentially, the monomeric composition applied to the surface of the adjoining tissue is allowed to polymerize at least partially before the subsequent coatings or the applications of the monomeric, additional composition. A coating of an adhesive composition of the present invention having a monomer different from the monomer of the first or previous coating can be applied as the second or subsequent coating. The repair of injured tissues (for example, to control bleeding) comprises, in general, sponge-drying to remove surface fluids from the body, keeping the surfaces of the injured tissue together in an adjoining relationship and subsequent application to the surrounding tissue, exposed of the present adhesive composition. The composition is polymerized in a thin polymer film while in contact with the surface of the adjoining tissue. Tissues which are not bleeding or otherwise are not covered by necessary body fluids are not sponge-dried first. More than one coating or one application of the monomeric composition can be applied to the surface of the surrounding tissue. The desired union of tissues or haemostasis proceeds well in the presence of blood and other bodily fluids. The formed joints are of adequate flexibility and strength to withstand normal tissue movement. In addition, the strength of the joint is maintained as the natural healing of the wounds proceeds. In embodiments, the present invention is directed to a method of treating a superficial or topical wound, such as a wound in the skin or a wound in a mucous membrane which comprises (a) applying a composition of the present invention to the wound superficial; (b) allowing the composition to polymerize; and (c) optionally, applying the composition at least one more time to the surface, coated wound. The presence of a plasticizing agent and / or an acidic stabilizing agent can cause this coating to have sufficient bond strength and flexibility, even with significant thicknesses of film or coating. The thickness of the film suitable for wound closure in cases where the adhesive is replacing the sutures varies from 0.1 mm to 2.0 mm or 3.0 mm or greater, preferably 0.2 mm to 1.5 mm, and more preferably 0.4 mm to 0.8 mm. The adequate thickness of the film for other applications varies from 1 μm to 1000 μm.

In embodiments, the biocompatible film formed for suture replacement may have an in vivo film strength of at least 70 mm Hg 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 90 mm Hg to 400 mm Hg vacuum pressure required to induce wound failure, and most preferably 100 mm Hg a 400 mm Hg. of pressure required to induce wound failure. In embodiments, the biocompatible film formed for other applications may have an in vivo film strength of 5-400 mm Hg vacuum pressure required to induce wound failure, most preferably 50-400 mm Hg. The present invention involves a polymerizable adhesive composition, such as a monomer composition comprising: A) at least one polymerizable monomer that forms a medically acceptable adhesive polymer; B) plasticizing agents, optional; C) stabilization agents, optional; and D) thickening agents, optional. In the embodiments, the composition preferably comprises a monomeric (or prepolymeric) adhesive. In the embodiments, the monomer is a 1, 1-disubstituted ethylene monomer, for example, an α-cyanoacrylate. In the embodiments, the monomeric composition comprises a bioactive material. Preferred compositions of the present invention and the polymers formed thereof are useful as fabric adhesives, sealants to prevent bleeding or to cover open wounds, and in other biomedical applications. They find use in, for example, the apposition of surgically cut or traumatically lacerated tissues; the delay of the blood flow of the wounds; the supply of drugs; the healing of burns; curing of the skin or other superficial or surface wounds (such as abrasions, excoriated or peeled skin, and / or stomatitis); the protection of damage-prone fabrics (for example, as artificial calluses); and help in the repair and growth of living tissue again. U.S. Patent No. 5,328,687 issued to Leung et al., U.S. Patent No. 3,527,841 issued to Wicker et al .; U.S. Patent No. 3,722,599 issued to Robertson et al .; U.S. Patent No. 3,995,641 issued to Kronenthal et al .; and U.S. Patent No. 3,940,362 issued to Overhults; and U.S. Patent Application Serial No. 08 / 266,647, describe materials that are useful as surgical adhesives. All the above references are incorporated by this act in their entirety by reference. The monomers that can be used in this invention are easily polymerizable, for example, they are anionically polymerizable or polymerizable with free radicals, or they are polymerizable by amphoteric ions or by ion pairs. Such monomers include those that form polymers that can, but are not necessarily, biodegrade. These monomers are described in, for example, U.S. Patent No. 5,328,687, which is hereby incorporated by reference in its entirety by reference herein. Useful 1, 1-disubstituted ethylene monomers include, but are not limited to, the monomers of the formula: (I) HRC = CXY wherein X and Y are each strong electron withdrawing groups, and R is H, -CH = CH2 or, provided that X and Y are both cyano groups, an alkyl group of 1 to 4 carbon atoms. Examples of monomers within the scope of formula (I) include α-cyanoacrylates, vinylidene cyanides, alkyl homologs of 1 to 4 carbon atoms of vinylidene cyanides, dialkyl methylene malonates, acrylacrylonitriles, vinyl sulphinates and sulfonates of vinyl of formula CH2 = CX'Y 'wherein X' is -S02R 'or -S03R' and Y 'is -CN, -COOR', -COCH3, -S02R 'or -S03R', and R 'is H or hydrocarbyl. The preferred monomers of the formula (I) for use in this invention are a-cyanoacrylates. These monomers are known in the art and have the formula CN (II) NRC = C \ COOR- wherein R2 is hydrogen and R3 is a hydrocarbyl or substituted hydrocarbyl group; a group having the formula -R4-0-R5-0-R6, wherein R4 is a 1,2-alkylene group having 2-4 carbon atoms, R5 is an alkylene group having 2-4 carbon atoms , and R6 is an alkyl group having 1-6 carbon atoms; or a group that has the formula CH3 or -C (CH3) 2- - (CH2) n -, - CH- where R is - R - C - 0 - R wherein n is 1-10, preferably 1-5 carbon atoms and R8 is an organic portion. Examples of suitable hydrocarbyl and substituted hydrocarbyl groups include straight chain or branched chain alkyl groups having 1-16 carbon atoms; alkyl groups of 1 to 16 carbon atoms, straight chain or branched chain 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 portion R8 may be substituted or unsubstituted and may be straight, branched or cyclic, saturated, unsaturated or aromatic chain. Examples of such organic portions include alkyl portions of 1 to 8 carbon atoms, alkenyl portions of 2 to 8 carbon atoms, alkylic portions of 2 to 8 carbon atoms, cycloaliphatic portions of 3 to 12 carbon atoms, aryl portions such as phenyl and substituted phenyl and aralkyl portions such as benzyl, methylbenzyl and phenylethyl. Other organic portions include portions of substituted hydrocarbon, such as halo (e.g., chloro, fluoro and bromo substituted hydrocarbons) and oxy- (e.g., alkoxy substituted hydrocarbons) portions of substituted hydrocarbon. Preferred organic radicals are alkyl, alkenyl and alkynyl portions having from 1 to about 8 carbon atoms, and halo substituted derivatives thereof. Alkyl portions of 4 to 6 carbon atoms are particularly preferred. In the cyanoacrylate monomer of the formula (II), R3 is preferably an alkyl group having 1-10 carbon atoms or a group having the formula -AOR9, wherein A is a straight chain alkylene or oxyalkylene portion or branched, divalent having 2-8 carbon atoms, R9 is a straight or branched alkyl portion having 1-8 carbon atoms. Examples of groups represented by the formula -AOR9 include l-methoxy-2-propyl, 2-butoxy ethyl, isopropoxy ethyl, 2-methoxy ethyl, and 2-ethoxy ethyl. Preferred a-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, cyanoacrylate. of 2-isopropoxyethyl or l-methoxy-2-propyl cyanoacrylate. The a-cyanoacrylates of the formula (II) can be prepared according to methods known in the art. U.S. Patent Nos. 2,721,858 and 3,254,111, each of which is hereby incorporated by reference herein, describe the methods for the preparation of α-cyanoacrylates. For example, a-cyanoacrylates can be prepared by reacting an alkyl cyanoacetate with formaldehyde in an organic, non-aqueous solvent and in the presence of a basic catalyst, followed by pyrolysis of the intermediate, anhydrous polymer in the presence of an inhibitor. of the polymerization. The a-cyanoacrylate monomers prepared with a low moisture content and essentially free of impurities are preferred for biomedical use. The a-cyanoacrylates of the formula (II) wherein R3 is a group having the formula R4-0-R5-0-R6 can be prepared according to the method described in U.S. Patent No. 4,364,876 issued to Kimura et al. , which is incorporated by this act by reference. In the method of Kimura et al., A-cyanoacrylates are prepared by the production of a cyanoacetate by esterifying cyanoacetic acid with an alcohol or by transesterifying an alkyl cyanoacetate and an alcohol; condensing the cyanoacetate and formaldehyde or paraformaldehyde in the presence of a catalyst in a molar ratio of 0.5-1.5: 1, preferably 0.8-1.2: 1, to obtain a condensed product; depolymerize the reaction mixture, condensation either directly or after removal of the condensation catalyst to produce crude cyanoacrylate; and distilling the crude cyanoacrylate to form a high purity cyanoacrylate. The a-cyanoacrylates of the formula (II) wherein R3 is a group having the formula they can be prepared according to the process described in U.S. Patent No. 3,995,641 issued to Kronenthal et al., which is incorporated by reference herein. In the method of Kronenthal et al., These α-cyanoarylate monomers are prepared by reacting an alkylic ester of an α-cyanoacrylic acid with a 1,3-cyclic diene to form a Diels-Alder adduct which is then subjected to alkaline hydrolysis followed by acidification to form the corresponding a-cyanoacrylic acid adduct. The a-cyanoacrylic acid adduct is preferably esterified by an alkyl bromoacetate to produce the corresponding carbalkoxymethyl a-cyanoacrylate adduct. Alternatively, the α-cyanoacrylic acid adduct can be converted to the α-cyanoacryloyl halide adduct by reaction with thionyl chloride. The a-cyanoacryloyl halide adduct is then reacted with an alkyl hydroxyacetate or an alkyl hydroxyacetate substituted with methyl to produce the corresponding carbalkoxymethyl a-cyanoacrylate adduct or an adduct of a carbalkoxy alkyl a-cyanoacrylate, respectively. The cyclic 1,3-diene blocking group is finally separated and the adduct of carbalkoxy methyl a-cyanoacrylate or the α-cyanoacrylate adduct of carbalkoxy alkyl is converted to the corresponding alkyl carbalkoxy a-cyanoacrylate by heating of the adduct in the presence of an insignificant deficit of maleic anhydride. Examples of monomers of the formula (II) include cyanopentadienoates and a-cyanoacrylates of the formula: CN / (III) NZC = C \ COOR3 wherein Z is -CH = CH2 and R is as defined above. The monomers of the formula (III) wherein R3 is an alkyl group of 1 to 10 carbon atoms, ie the esters of 2-cyanopenta-2,4-dienoic acid, can be prepared by reacting a 2-cyanoacetate suitable with acrolein in the presence of a catalyst such as zinc chloride. This method for preparing 2-cyanopenta-2,4-dienoic acid esters is described, for example, in U.S. Patent No. 3,554,990, which is incorporated herein by reference herein. Preferred monomers are alkyl α-cyanoacrylates and more preferably octyl cyanoacrylates, especially 2-octyl α-cyanoacrylate. The monomers used in the present application must be very pure and must contain very few impurities (eg, surgical grade). When present, component B) is at least one plasticizing agent imparting flexibility to the polymerized monomer formed in the wound, incision or abrasion. The plasticizing agent preferably contains little or no moisture and should not significantly affect the polymerization of the monomer. Examples of suitable plasticizing agents 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 myristate, butyl stearate, lauric acid, trioctyl trimellitate, dioctyl glutarate and mixtures thereof. Preferred plasticizers are tributyl citrate and acetyl tributyl citrate. In embodiments, suitable plasticizing agents include polymeric plasticizers such as polyethylene glycol (PEG) esters and capped PEG esters or ethers, polyester glutarates and polyester adipates. . When present, component C) is at least one stabilizing agent that inhibits polymerization. These stabilizing agents can also include mixtures of anionic stabilizing agents and radical stabilizing agents. Examples of suitable anionic stabilizing agents include, but are not limited to, sultones (e.g., α-chloro-α-hydroxy-o-toluenesulfonic acid ε-sultone), sulfur dioxide, sulfuric acid, sulfonic acid, lactone, boron trifluoride, organic acids, such as acetic acid or phosphoric acid, alkyl sulfate, alkyl sulfite, 2-sulfolene, alkylsulfone, alkyl sulfoxide, mercaptan and alkyl sulfide and mixtures thereof. Preferred anionic stabilizing agents are acidic stabilizing agents of organic acids such as acetic acid or phosphoric acid. In the embodiments, the amount of the sulfur dioxide stabilizer is less than 100 ppm, preferably 5-75 ppm, more preferably about 20-50 ppm. The amount of sulfone and / or trifluoroacetic acid is about 500-3000 ppm. Examples of suitable radical stabilizing agents include hydroquinone, hydroquinone monomethyl ether, catechol, pyrogallol, benzoquinone, 2-hydroxybenzoquinone, p-methoxy phenol, t-butyl catechol, butylated hydroxy anisole (BHA), butylated hydroxy toluene, and t-butyl hydroquinone. In the embodiments, the amount of BHA is approximately 1,000-5,000 ppm. Suitable stabilizing agents, acidic, include those having aqueous pKa ionization constants ranging from -12 to 7, about -5 to about 7, preferably from about -3.5 to about 6. For example, the agents of Suitable acid stabilizers include: hydrogen sulphide (pKa 7.0), carbonic acid (pKa 6.4), triacetylmethane (pKa 5.9), acetic acid (pKa 4.8), benzoic acid (pKa 4.2), 2,4-dinitrophenol (pKa 4.0) , formic acid (pKa 3.7), nitrous acid (pKa 3.3), flurhydric 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) (pKa 0.3), trifluoroacetic acid (pKa 0.2), sulfuric acid (pKa -3.0), sulfurous acid, and mixtures thereof. In the embodiments, the amount of trifluoroacetic acid is about 500-1,500 ppm. Combinations of the above stabilizers, such as sulfur dioxide and 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 can be used. and trifluoroacetic acid. When the aforementioned stabilizing agents, acidic, are added to the adhesive composition, the addition of the plasticizing agents in amounts ranging from about 0.5 wt% to about 16 wt%, preferably about 3 wt%, is added. to about 9% by weight and more preferably from about 5% by weight to about 7% by weight provides increased film strength (for example firmness) of the polymerized monomer on the polymerized monomers having amounts of plasticizing agents and stabilizing agents, acidic outside the above ranges. The concentration of the stabilizing agents, acidic, used may vary depending on the strength of the acid. For example, when acetic acid is used, a concentration of 80-200 ppm (w / w), preferably 90-180 ppm (w / w), and more preferably 100-150 ppm (weight) can be used. /weight) . When a stronger acid such as phosphoric acid is used, a concentration range of 20-80 ppm (w / w), preferably 30-70 ppm (w / w) and more preferably 40- 60 ppm (weight / weight). In the embodiments, the amount of trifluoroacetic acid is about 100 to 3000 ppm, preferably 500-1500 ppm. In other embodiments, the amount of phosphoric acid is about 10-200 ppm, preferably about 50-150 ppm, and more preferably about 75-125 ppm. The compositions of the present invention can also include at least one biocompatible agent effective to reduce the concentration levels of active formaldehyde produced during the in vivo biodegradation of the polymer (also referred to herein as "formaldehyde concentration reducing agents"). Preferably, this component is a formaldehyde scavenger compound. Examples of formaldehyde scavenging compounds useful in this invention include sulfites; bisulfites; mixtures of sulfites and bisulfites; Ammonium sulphite 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 the free heterocyclic ring compounds of a carbonyl group and containing an NH group, with the ring complete with nitrogen or carbon atoms, the ring being unsaturated or, when fused to a phenyl group, being unsaturated or saturated, and the NH group that binds to a carbon or nitrogen atom, the atom that is directly linked by a double bond to another carbon or nitrogen atom. The bisulfites and sulfites useful as the formaldehyde scavenging 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, bisulfite. of ammonium, sodium sulfite, potassium sulfite, lithium sulfite, ammonium sulfite and the like. Examples of amines useful in this invention include aliphatic and aromatic amines such as, for example, aniline, benzidine, aminopyrimidine, toluene diamine, triethylenediamine, diphenylamine, diaminodiphenylamine, hydrazines and hydrazide.

Suitable proteins include collagen, gelatin, casein, soy protein, vegetable protein, keratin and cola. 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. Examples of suitable compounds having a b-dicarbonyl group include malonic acid, acetylacetone, ethylacetone, acetate, malonamide, diethylmalonate or other malonic ester. Preferred cyclic ketones for use in this invention include cyclohexanone or cyclopentanone. Examples of heterocyclic compounds suitable for use as the formaldehyde scavenger in this invention are described, for example, in U.S. Patent No. 4,127,382 (Perry) which is incorporated by way of reference by reference herein. These heterocyclic 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. In the practice of the present invention, the formaldehyde concentration reducing agent, for example, the formaldehyde scavenging compound, is added in an effective amount to the cyanoacrylate. The "effective amount" is that amount sufficient to reduce the amount of formaldehyde generated during the subsequent in vivo biodegradation of the polymerized cyanoacrylate. This amount will depend on the type of active formaldehyde concentration reducing agent, and can be easily determined without undue experimentation by those skilled in the art. The formaldehyde concentration reducing agent can be used in this invention in any free form or in microencapsulated form. Other compositions are exemplified by US Patent Serial No. 08 / 714,288, incorporated by reference herein in its entirety. When microencapsulated, the formaldehyde concentration reducing agent is released from the microcapsule continuously for a period of time during in vivo biodegradation of the cyanoacrylate polymer.

For purposes of this invention, the microencapsulated form of the formaldehyde concentration reducing agent is preferred because this mode prevents or substantially reduces the polymerization of the cyanoacrylate monomer by the formaldehyde concentration reducing agent, which increases the duration of life and facilitates the handling of the monomeric composition during use. Microencapsulation of the formaldehyde scavenger can be achieved by many known microencapsulation techniques. For example, microencapsulation can be carried out by dissolving a coating polymer in a volatile solvent, for example, methylene chloride, at 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 produce a scavenger concentration of 18% by weight; slowly add a solution of mineral oil containing surfactant to the polymer solution under rapid stirring; allow the volatile solvent to evaporate under agitation; remove the agitator; Separate the solids from the mineral oil; and wash and dry the microparticles.

The size of the microparticles will vary from about 0.001 to about 1000 microns. The coating polymer for the microencapsulation of the formaldehyde concentration reducing agent must be polymers which are subjected to the bioerosion in vivo, preferably at speeds similar to, or greater than, the cyanoacrylate polymer formed by the monomer, and have a low inherent moisture content. Such bioerosion can occur as a result of the physical or chemical disintegration of the microencapsulation material, for example, by the encapsulating material passing from the solid to the solute in the presence of bodily fluids, or by the biodegradation of the encapsulating material by the agents present in it. the body. Examples of coating materials which can be used to microencapsulate the formaldehyde concentration reducing agent include polyesters, such as polyglycolic acid, polylactic acid, poly-1,4-dioxa-2-one, polyoxalates, polycarbonates, copolymers of polyglycolic acid and polylactic acid, polycaprolactone, poly-b-hydroxybutyrate, epsilon-caprolactone and delta-valerolactone copolymers, epsilon-caprolactone and DL-didactic copolymers, and polyester hydrogels; polyvinyl pyrrolidone; polyamides; jelly; albumin; proteins; collagen; poly (orthoesters); poly (anhydrides); poly (alkyl-2-cyanoacrylates); poly (dihydropyrans); poly (acetals); poly (phosphazenes); poly (urethanes); poly (dioxinones); cellulose; and starches. Examples of the surfactant which can be added to the mineral oil include those commercially available under the designations Triton x-100.

, Tween 20 and Tween 80. When present, component D) is a 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-acid. -hydroxybutyrate, polyorthoesters, polyalkyl acrylates, copolymers of alkyl acrylate and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl and butadiene methacrylates. Examples of alkyl methacrylates and acrylates are poly (2-ethylhexyl methacrylate) and poly (2-ethylhexyl acrylate), also poly (butyl methacrylate) and poly (butyl acrylate) also the copolymers of various acrylate and methacrylate monomers , such as poly (butyl methacrylate-o-methylacrylate). To improve the cohesive strength of the adhesives formed from the compositions of this invention, the monomeric, difunctional crosslinking agents can be added to the monomer compositions of this invention. These crosslinking agents are well known. U.S. Patent No. 3,940,362 issued to Overhults, which is hereby incorporated by reference, describes these crosslinking agents. Examples of suitable regulating agents include alkyl bis (2-cyanoacrylates), triallyl isocyanurates, alkylene diacrylates, alkylene dimethacrylates, trimethylolpropane triacrylate and alkyl bis (2-cyanoacrylates). A catalytic amount of an amine-activated free radical initiator or amide modifier can be added to initiate the polymerization or to modify the rate of polymerization of the cyanoacrylate monomer / crosslinking agent mixture. The compositions of this invention may additionally contain fibrous reinforcements and colorants, i.e., dyes and pigments. Examples of suitable fibrous reinforcements include PEG microfibrils, collagen microfibrils, cellulosic microfibrils, and olefin microfibrils. Examples of suitable dyes 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. 6); 9- (o-carboxyphenyl) -6-hydroxy-2,4,5,7-tetraiodo-3H-xanthen-3-one, disodium salt monohydrate of 9- (o-carboxyphenyl) -6-hydroxy-2, 4, 5, 7-tetraiodo-3H-xanten-3-one (FD + C Red No. 3); disodium salt of 2- (1, 3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene) -2,3-dihydro-2-oxo-lH-indole-5-sulphonic acid (FD) + C Blue No. 2); and [phthalocyaninate (2-)] copper. Other compositions contemplated by the present invention are exemplified by U.S. Patent Nos. 5,624,669; 5,582,834; 5,575,997; 5,514,371; 5,514,372; and 5,259,835; the descriptions of which are incorporated by this act in their entirety by reference. The compositions, including polymerization initiators, speed modifiers, and / or bioactive materials, employed in the invention are preferably sterilizable such as by dry heat (for example above 100 ° C), electron beam, lightning irradiation. gamma, ethylene oxide vapor or hydrogen peroxide, and other methods.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following claims is claimed as property.

Claims (32)

1. A method for applying at least one agent to an applicator tip for adhesives, characterized in that it comprises: dissolving or dispersing the agent in a low boiling point solvent to form a solution; apply the solution to the applicator tip; and drying the applicator tip; wherein at least one agent is selected from the group consisting of (a) a bioactive material that is also not a polymerization initiator or a polymerization rate modifier, (b) a bioactive material that is also an initiator of the polymerization. polymerization or a polymerization rate modifier, (c) a polymerization initiator that is also not a bioactive material, and (d) a polymerization rate modifier that is also not a bioactive material, and wherein the solvent of low boiling point comprises methanol at least when the agent is (b), (c) or (d).

2. The method according to claim 1, characterized in that the agent is dissolved in the low boiling point solvent.

3. The method according to claim 1 or 2, characterized in that the agent is selected from the group consisting of polysorbate 20, polysorbate 80, poloxamers, tetrabutylammonium bromide, alkylbenzylalkonium chloride, stannous octoate (tin (2) -ethylhexanoate) , sodium tetradecyl sulfate and dodecyldimethyl (3-sulfopropyl) ammonium hydroxide.

4. The method according to claim 1 or 2, characterized in that the agent is selected from the group consisting of imidazole, tryptamine, urea, arginine, povidin, triphenylphosphine, triethyl phosphite, ethylene glycol, methyl gallate, ascorbic acid, tannins, tannic acid, sodium bisulfite, magnesium hydroxide, calcium sulfate, sodium silicate, thiourea, monensin, nonactin, crown ethers, calixarenes, polymeric epoxides, diethyl carbonate, di-t-butyl peroxide, and azobisisobutyronitrile.

5. The method according to claim 1 or 2, characterized in that the agent is alkylbenzyldimethylammonium chloride with an alkyl containing 6-18 carbon atoms, its pure components or mixtures thereof.

6. The method according to claim 1 or 2, characterized in that the agent is a bioactive material.

7. The method according to claim 1 or 2, characterized in that the agent comprises at least one member selected from the group consisting of antibiotics, antimicrobials, antiseptics, antibiotics produced by bacteria, bacteriostats, disinfectants, steroids, anesthetics, fungicides, anti-aging agents. inflammatory, antiviral agents, antitumor and antibacterial agents.

8. The method according to any of claims 1-7, characterized in that the agent comprises a mixture of (i) at least one member selected from the group consisting of polymerization initiators and modifiers of the polymerization rate, and (ii) ) bioactive materials.

9. The method according to any of claims 1-8, characterized in that the agent comprises at least one compound that is a bioactive material that is also a polymerization initiator or a polymerization rate modifier.

10. The method according to claim 8 or 9, characterized in that the agent is selected from the group consisting of antibiotics, antimicrobials, antiseptics, antibiotics produced by bacteria, bacteriostats, disinfectants, steroids, anesthetics, fungicides, anti-inflammatory and antibacterial agents.

11. The method according to any of claims 1-10, characterized in that the solvent is methanol.

12. The method according to any of claims 1-11, characterized in that the solvent further comprises a ketone or a low boiling alcohol other than methanol.

13. The method according to any of claims 1-12, characterized in that the solvent also comprises acetone.

14. The method according to any of claims 1-13, characterized in that it comprises applying the solution to a distal end of the applicator tip and forming a concentration gradient of the agent decreasing from the distal end of the applicator tip towards a center and an end next to the applicator tip.

15. The method according to any of claims 1-14, characterized in that it comprises fixing the applicator tip to an applicator tube before applying the solution to the applicator tip.

16. The method according to any of claims 1-14, characterized in that it comprises placing the applicator tip on or in an applicator tube after applying the solution to the applicator tip.

17. The method according to any of claims 1-16, characterized in that the applicator tip comprises a porous polyolefin, polyester or polyamide.

18. The method according to any of claims 1-17, characterized in that the applicator tip comprises porous polyethylene.

19. The method according to any of claims 1-18, characterized in that the applicator tip has an average pore size of about 1 μm to about 500 μm.

20. An applicator tip, characterized in that it is made by the method according to any of claims 1-19.

21. An applicator for a polymerizable adhesive, characterized in that it comprises: a conduit for an adhesive material, polymerizable, fluid; an applicator tip operably connected to the conduit so that fluid flowing through the conduit also runs through the applicator tip; and at least one agent selected from the group consisting of (a) a bioactive material that is also not a polymerization initiator or a polymerization rate modifier, (b) a bioactive material that is also a polymerization initiator or a polymerization rate modifier, (c) a polymerization initiator that is also not a bioactive material, and (d) a polymerization rate modifier that is also not a bioactive material; wherein the applicator tip has an agent gradient at least when the agent is (b), (c) or (d).

22. The applicator according to claim 21, characterized in that the agent is a bioactive material that is also a polymerization initiator or a polymerization rate modifier.

23. The applicator according to claim 21 or 22, characterized in that the agent is a bioactive material selected from the group consisting of antibiotics, antimicrobials, antiseptics, antibiotics produced by bacteria, bacteriostats, disinfectants, steroids, anesthetics, fungicides, anti-inflammatory, antibacterial agents , antiviral agents, antitumor agents, and mixtures thereof.

24. The applicator according to any of claims 21-23, characterized in that the agent is a bioactive material selected from the group consisting of acetic acid, aluminum acetate, bacitracin, bacitracin zinc, benzalkonium chloride, betadine, calcium chloroplatinate, certimide, chloramine T, chlorhexidine phosphamylate, chlorhexidine, chlorhexidine sulfate, chloropenidine, chloroplatinatic acid, ciprofloxacin, clindamycin, clioquinol, cystetaphine, gentamicin sulfate, hydrogen peroxide, polyvidone iodine, iodine, iodophor, minocycline, mupirocin, neomycin, sulfate of neomycin, nitrofurazone, non-oninol-9, potassium permanganate, penicillin, polymycin, polymycin B, polymyxin, polymyxin B sulfate, polyvinylpyrrolidone iodine, povidone iodine, 8-hydroxyquinoline, quinolone thioureas, rifampin, rifamycin, acetate silver, silver benzoate, silver carbonate, silver chloride, silver citrate, silver iodide, nitrate silver, silver oxide, silver sulfadiazine, silver sulphate, sodium chloroplatinate, sodium hypochlorite, sodium sulfadiazine, sphingolipids, tetracycline, zinc oxide and zinc sulfadiazine.

25. The applicator according to any of claims 21-24, characterized in that it further comprises a container of polymerizable adhesive physically separated from the applicator tip.

26. The applicator according to any of claims 21-25, characterized in that the polymerizable adhesive comprises a 1, 1-disubstituted ethylene monomer.

27. The applicator according to claim 26, characterized in that the monomer is a cyanoacrylate.

28. An applicator for a polymerizable adhesive, characterized in that it comprises: a conduit for an adhesive material, polymerizable, fluid; and an applicator tip according to claim 20.

29. The applicator according to any of claims 21-28, characterized in that the applicator contains the adhesive, polymerizable material.

30. The applicator according to any of claims 21-29, characterized in that the polymerizable adhesive composition, upon passing through the applicator tip, is solubilized or dispersed and mixed with the agent, to thereby produce a Adhesive composition, medical.

31. The applicator according to claim 21, characterized in that the gradient shows a decrease in the concentration of the agent from one end distal to a proximal end of the applicator tip.

32. The applicator according to any of claims 21-31, characterized in that the applicator is sterilized.