Adhesive including medicament

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DESCRIPTION

Adhesive that includes a drug.

Invention sector

The present invention provides drug-containing cyanoacrylate adhesive formulations for wound closure.

Background and background of the invention

Wound closure technology continues to be involved with non-suture based alternatives, such as those consisting of staples, surgical tapes and, more recently, tissue adhesives, which have gained recognition and acceptance as effective surgical procedures. closed wounds. Two different forms of tissue-based adhesives for wound closure have been extensively studied: cyanoacrylate tissue adhesives, and fibrin-based sealants. Fibrin sealants have not gained acceptance due to the reduced tensile strength of the fibrin polymer, the long preparation time, and the risk of viral transmission. Cyanoacrylates are recognized as superior adhesives for skin wound closure and are undergoing continuous modification to improve technology.

A common property for all cyanoacrylates is the ability to bind and polymerize in the presence of water, to form a bond between the two sides of a wound, to hold it in position. When used for wound closure, cyanoacrylate polymerizes in the presence of water molecules on the surface of the skin, forming a bridge and bond, which holds tissue together, for wound healing purposes. The polymerized material is then gradually and slowly detached in flakes, after keeping the skin tissues in this position. The difficulties and risks associated with the use of cyanoacrylates are well known. Cyanoacrylates are toxic, and adverse reactions can occur, due to the fact of hypersensitivity to cyanoacrylates themselves or formaldehyde, one of the starting materials used for the preparation of cyanoacrylate adhesives.

The first cyanoacrylates used as adhesive fabrics included the short chain cyanoacrylates, commonly referred to as Super Glues.^®, (trademark of glues) and were associated with acute, severe and chronic inflammatory reactions. Subsequently, long chain cyanoacrylates, including butyl and octyl cyanoacrylates, gained acceptance. While butyl cyanoacrylates provide effective closure of simple superficial lacerations and incisions, they are toxic when introduced into vascular areas, and exhibit low tensile strength and high brittleness.

Octyl cyanoacrylates have proven to be superior wound closure adhesives, having demonstrated greater tensile strength than butyl cyanoacrylates, and are remarkably non-toxic when used for skin wound closure. Octyl Cyanoacrylate has been approved by the FDA for use as a fabric adhesive. However, there are problems associated with its use, including a higher incidence of wound infection, when compared to suturing as a wound closure procedure. Also, blood and body fluids trigger premature cyanoacrylate polymerization, resulting in an ugly-looking plasticized mass with very little skin bonding. It is also difficult to keep adhesive out of the wound. The polymerization reaction is exothermic and the heat generated can result in patient discomfort. Octyl cyanoacrylates can have a low viscosity, causing them to advance into unwanted areas or into the wound. Thus, for example, cyanoacrylates that penetrate the interior of the eye can result in tarsorrhaphy (fusion of the eyelids) or a lesion in the cornea.

International patent publication WO 99/42 535 discloses cyanoacrylate adhesive compositions for sealing wounds, which may comprise microencapsulating agents that reduce the concentration of formaldehyde, ie "formaldehyde sequestrants". The formaldehyde sequestrant is effective in reducing the levels of active formaldehyde concentration, a reduction that takes place during the in vivo biodegradation of the polymer. The adhesive can also optionally comprise a medicament.

US Patent Publication WO 96/00 760 discloses cyanoacrylate wound sealing adhesives which comprise an effective amount of pH modifier to modify the pH of an immediate, in vivo environmental environment of the adhesive, at which the biodegradation of the adhesive occurs, at a different rate than that corresponding to a physiological pH value. The pH modifier can be microencapsulated in order to control the biodegradation of the polymer.

International patent publication WO 96/10 374 discloses a biomedical implant comprising a biomedical matrix, a given example of cyanoacrylate, and a biodegradable porosifying agent. In addition to the matrix material and the porosifying agent, the implant may additionally include therapeutic agents. The porosifying agent forms pores in the matrix so that therapeutic agents can be released from the matrix.

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Summary of the invention

There is a need, in the specialized art of the wound closure technique, for an adhesive that can close wounds, with a reduced risk of infection, reduced bleeding, reduced pain, reduced tanning, and a improved cosmetic appearance.

Summary description of the drawings

Figure 1a provides a schematic illustrating the release of an encapsulated drug from a cyanoacrylate adhesive matrix. Figure 1a provides a cross-sectional diagram of an adhesive matrix containing microcapsules. Figure 1b provides a schematic of the release of the microcapsules from the adhesive matrix.

Figure 2 provides an IR spectrum for Penicillin G, gelatin, and Penicillin G gelatin microcapsules.

Figure 3 provides a UV spectrum for Penicillin G, gelatin, and Penicillin G gelatin microcapsules.

Figure 4 provides a UV spectrum of a Sulfanilamide microcapsule at 10, 50 and 105 minutes.

Figure 5a provides a release profile of gatifloxacin microcapsules prepared from an aqueous crosslinking solution (capture efficiency 2.3%, drug loading 0.7%); and Figure 5b provides a release profile of gatifloxacin microcapsules prepared from a formaldehyde-acetone solution (capture efficiency 53%, drug loading 0.7%).

Figure 6 provides a UV spectrum of encapsulated and unencapsulated Penicillin G extracts in solidified cyanoacrylate film.

Film 7 provides a UV spectrum of Sulfanilamide extracts on smooth and rough films of solidified cyanoacrylate.

Figure 8 provides a release curve (concentration versus time) of Sulfanilamidum, from two portions of an adhesive film sample with sodium chloride as a defect-forming agent.

Figure 9 provides the release curve (concentration versus time) of Sulfanilamidum, from two portions of a polyethylene glycol adhesive film sample.

Figure 10 provides a release curve (concentration versus time) of Gatifloxacin from two portions of an adhesive film sample with or without polyethylene glycol as a defect-forming agent.

Figures 11a and 11b are SEM images of the surface of a solidified adhesive containing 16% PEG 600, prior to extraction with aqueous solution.

Figures 12a and 12b are SEM images of the surface of a solidified adhesive containing 16% PEG 600, prior to extraction with aqueous solution.

Figure 13 shows the effect of a bacterial culture, after exposure to Gatifloxacin, on filter paper, and solidified adhesives that include only PEG, only microencapsulated Gatifloxacin, and microencapsulated Gatifloxacin with PEG.

Figure 14 provides the release curves (percent release versus time) of Gatifloxacin, of adhesive films containing 0, 5.6 and 19%, by weight, of polyethylene glycol.

Figure 15 provides the release curves (percent release versus time) of Gatifloxacin from adhesive films having a thickness of 1mm and 0.2mm.

Figure 16 provides a schematic illustrating a separate filler for cyanoacrylate antibiotic adhesive.

Figures 17a and 17b are optical microscopic images of sodium phosphate and dexamethasonagelatin microcapsules.

Figure 18 provides release curves (percent release versus time), for DST-gelatin microcapsules, with different DST-gelatin ratio factors and crosslinking times.

Figure 19 provides HPLC chromatograms for DST solutions and a solidified adhesive film extraction solution, containing DST microcapsules.

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Figure 20 provides the UV spectrum of a Vitamin C microcapsule extraction solution (VC-MC extract), an adhesive film extraction solution containing Vitamin C microcapsules (VC-MC-SG) and Vitamin C aqueous solution. (VC solution).

Detailed description of preferred forms of presentation

Introduction

The description and examples that follow illustrate a preferred embodiment of the present invention.

Minimally invasive surgery (MIS) has reduced the suffering of patients. Cyanoacrylate medical adhesives have been used effectively in the sealing or closing of wounds acquired during such surgery, as well as for the closure of other wounds such as lacerations. One form of presentation described herein provides a cyanoacrylate medical adhesive that contains a medicament that can be released and delivered to the wound in a controlled manner.

The drug can be delivered to a wound that has been closed with the disclosed adhesives. In a preferred form of presentation, the drug incorporated into the adhesive and delivered to the wound is encapsulated using known microencapsulation technologies. In other forms of presentation the medicine is added directly to the adhesive. The adhesives in a preferred form belong to the class of cyanoacrylate adhesives. In order to facilitate release of the drug from the adhesive matrix, a flaw or pore-forming agent is formulated in the adhesive. Figure 1a provides a schematic of microcapsules containing drugs within an adhesive matrix. The matrix may also include a defect or pore forming agent, typically a hydrophilic polymer or water soluble salt (Figure 1b). After contact with an aqueous solution (for example, blood or tissue fluid), the defect or pore-forming agent can solubilize, leaving behind passageways into the adhesive matrix (Figure 1c). The microencapsulated drug can then be released from the adhesive matrix through these defects or pores (Figure 1d).

Adhesives in preferred forms of presentation may possess various desirable properties, including, but not limited to, increased viscosity and increased cure rate. The use of adhesives in preferred forms of presentation can allow the achievement of several positive effects, including, but limited to these, infection control, pain control, easier application of the adhesive, facilitate the healing of the skin, and a reduced tanning.

The term "entrapment efficacy" as used herein, in conjunction with drugs, medicaments, or other microencapsulated substances, is a broad term and is used, in its ordinary sense, including, without limitation, weight of the drug, medicine, or other substances of the microcapsule, divided by the capsule of the microencapsule.

Medicines

The drugs are penicillins (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, peperacillin, piperacillin, ticarcillin).

Microencapsulated drugs

Certain drugs, pharmaceutical compositions, therapeutic agents, and other substances that are desired to be incorporated into a cyanoacrylate medical adhesive may contain reactive groups that activate the polymerization of cyanoacrylic esters, resulting in premature cure of the adhesive. Other substances may be sensitive to the components of the cyanoacrylate adhesive and, as a result, may undergo adverse chemical reactions or become less active or inactive. These effects can result in inactivity of medications and failure of adhesives, through solidification during storage. Microencapsulation is an effective technique to avoid unwanted chemical interaction between drugs and cyanoacrylates.

In a preferred form of presentation, penicillin antibiotics are entrapped in hydrophilic gelatin microcapsules and mixed with cyanoacrylic ester adhesives. Other preferred shell materials include water soluble alcohols and polyethylene oxides. The microcapsule shells block unwanted reactions, preventing direct contact of antibiotics and cyanoacrylates. Microencapsulation allows the use of a spectrum of antibiotics with appropriate sensitivity to different microorganisms. Microencapsulated antibiotics provide a controlled release of antibiotics from solidified adhesives at pre-selected concentrations.

Microencapsulation techniques involve coating solid particles of small solid particles, or gas bubbles, with a thin film of material, providing the material with a protective envelope for the contents of the microcapsule. Microcapsules suitable for use in preferred presentation forms can be of any appropriate size, typically from about 1 µm or less to about 4

ES 2 279 880 T3 at 1000 pm or more, preferably from about 2 pm to about 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800 or 900 pm and, more preferably, from about 3, 4, 5, 6, 7, 8, or 9 jum, to about 10, 15, 20, 25, 20, 35, 40, or 45 pm. In certain forms of presentation, it may be preferred to use microcapsules of sizes corresponding to the nanometer range. Such types of microcapsules can be of a size within the range of approximately 10 nm or less, to less than 1000 nm (1 pm), preferably from approximately 10, 15, 20, 25, 30. , 35, 40, 45, 50, 60, 70, 80, or 90 nm, up to about 100, 200, 300, 400, 500, 600, 700, 800, or 900 nm.

While in most presentation forms a drug or other substance is encapsulated in solid phase, in certain presentation forms it may be preferable to incorporate a liquid or gaseous substance. Microcapsules containing liquids or gases can be prepared using conventional procedures well known in the art of the art of microcapsule formation and such types of microcapsules can be incorporated into adhesives of preferred presentation forms.

Components of the microcapsules

Microcapsules are preferred forms of presentation, which contain a filler or filler material. The filler or filler material is typically one or more drugs or other pharmaceutical formulations, optionally in combination with substances other than drugs or pharmaceutical formulations. In certain presentation forms, it may be preferable that the microcapsules contain one or more substances that do not include drugs or pharmaceutical formulations. The filler or filler material is encapsulated within the microcapsule by means of a wrapping material.

Typical wrapping materials include, but are not limited to, gum arabic, gelatin, ethyl cellulose, polyurea, polyamide, aminoplast, maltodextrin, and hydrogenated vegetable oil. While any suitable material can be used, in preferred presentation forms, it is generally preferred to use an edible wrapping material approved for use in food or pharmaceutical applications. Such types of wrapping material include, but are not limited to, gum arabic, gelatin, diethyl cellulose, maltodextrin, and hydrogenated vegetable oils. Gelatin is especially preferred because of its low cost, its biocompatibility and the ease with which microcapsules can be prepared with gelatin shells. In certain forms of presentation, however, other wrapping materials may be preferred. The optimal wrapping material may depend on the particle size and particle size distribution of the starting material, the particle shape of the filler material, the compatibility with the filler material, the stability of the filler or filler material, and the release rate of the filler or filler material, from the microcapsule.

Microencapsulation procedure

A variety of encapsulation procedures can be used to prepare the microcapsules of preferred presentation forms. These processes include gas phase processes or vacuum processes, where the coating is sprayed in a spray form, or otherwise, is deposited on the filling material particles, such that an envelope is formed. or where a liquid is sprayed into a gas phase and subsequently solidifies to produce microcapsules. Appropriate processes also include emulsion and dispersion processes, where the microcapsules are formed in the liquid phase in a reactor.

Spray drying

Encapsulation by spray drying involves the spraying of a concentrated solution of wrapping material, which contains particles of filler or filler material or a dispersion of filler or filler material, liquid, immiscible, to the inside a heated chamber, where rapid desolvation occurs. Any suitable solvent can be used, however the procedure is most preferred for use with aqueous systems. Spray drying is commonly used to prepare microcapsules that include shell materials, including, for example, gelatin, hydrolyzed gelatin, acacia, modified starch, matodextrins, sucrose, or sorbitol. When an aqueous solution is used as the wrapping material, the filler material typically includes a hydrophobic liquid or a water immiscible oil. Dispersants and / or emulsifiers can be added to the concentrated solution of wrapping material. By spray drying processes, relatively small microcapsules can be prepared, for example, less than about 1 µm in size to greater than about 50 µm in size. The resulting particles can include individual particles, as well as aggregates of individual particles. The amount of filler or filler material that can be encapsulated using spray spray drying techniques is typically from less than about 20%, by weight, of the microcapsule, to no more than 60%, by weight. , of the microcapsule. The process is preferred due to the fact that it is low cost compared to other processes and has extensive utility in the preparation of edible microcapsules. The process may not be preferred for the preparation of heat sensitive materials.

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In another variety of spray drying, cooled air is used, rather than desolvation, to solidify a ground mixture of wrapping material containing filler or filler material, in particulate form or an immiscible liquid. Various types of fats, waxes, fatty alcohols and fatty acids are typically used as shell materials in such types of encapsulation processes. The process is generally preferred for the preparation of microcapsules having water insoluble shells.

Microencapsulation in fluidized bed

Encapsulation, in which fluidized bed technology is used, involves the spraying (spray) of a liquid envelope material, generally in the form of a solution or in a molten form, on solid particles suspended in a gas stream, of in a typical form, hot air and the particles thus encapsulated are subsequently cooled. Commonly used wrapping materials include, but are not limited to, colloids, solvent soluble polymers, and sugars. The envelope material can be applied to the particles from the top of the reactor, or it can be applied, as a spray, from the bottom of the reactor, for example, as in the Wurster process. The particles are kept in the reactor until a desired total coating thickness is achieved. Fluidized bed microencapsulation is commonly used for the preparation of water soluble food ingredients and pharmaceutical compositions. The process is particularly suitable for coating irregularly shaped particles. Fluidized bed encapsulation is typically used to prepare microcapsules larger than about 100 µm, however, smaller microparticles can also be prepared.

Complex coacervation

A pair of oppositely charged polyelectrolytes capable of forming a liquid complex coacervate (ie, a mass of colloidal particles that are held together by electrostatic attraction, can be used to form microcapsules by complex coacervation. A preferred polyanion is gelatin, which is capable of complexing with a variety of polyanions. Typical polyanions include gum arabic, polyphosphate, polyacrylic acid, and alginate. Complex coacervation is mainly used to encapsulate water-immiscible liquids or water-insoluble solids. The procedure is not suitable for use with water soluble substances, or substances sensitive to acidic conditions.

In complex coacervation of gelatin with gum arabic, a water-soluble material is dispersed in a hot emulsion of aqueous gelatin and then the gum arabic and water are added to this emulsion. The pH of the aqueous phase is adjusted to a slightly acidic pH, thereby forming the complex coacervate, which is absorbed onto the surface of the filler material. The system is cooled, and a crosslinking agent, such as gluuraldehyde, is added. The microcapsules can optionally be treated with urea and formaldehyde, at a low pH value, in such a way that the hydrophilic character of the shell is reduced, thereby facilitating drying, without excessive formation of aggregates. The resulting microcapsules can then be dried to form a powder. Polymer-polymer incompatibility

Microcapsules can be prepared using a solution containing two liquid polymers, which are incompatible, but soluble, in a common solvent. One of the polymers is preferentially absorbed by the filler or filler material. When the filler or filler material is dispersed in the solution, it is immediately covered by a thin film of the polymer that is preferentially absorbed. The microcapsules are obtained by either crosslinking the absorbed polymer or by adding a non-solvent for the polymer to the solution. The liquids are then removed to obtain the microcapsules, in the form of a dry, powdered matter.

Polymer-polymer incompatibility encapsulation can be carried out in an aqueous or nonaqueous medium.

This is typically used for the preparation of microcapsules containing polar solids with limited water solubility. Suitable wrapping materials include ethyl cellulose, polylactides, lactidoglycolide copolymers. Polymer-polymer incompatibility encapsulation is often preferred for the encapsulation of oral or parenteral pharmaceutical compositions, especially those containing proteins or polypeptides, due to the fact that biodegradable microcapsules can be easily prepared. Microcapsules prepared by polymer-polymer incompatibility encapsulation tend to be smaller than microcapsules prepared by other procedures and typically have diameters of 100 µm or less.

Interface polymerization

Microcapsules can be prepared by conducting polymerization reactions at interfaces in a liquid. In such a microencapsulation process, a dispersion of two immiscible liquids is prepared. The dispersed phase forms a filler or filler material. Each phase contains a separate reagent, the reagents being capable of undergoing a polymerization reaction to form an envelope. The reagent in the dispersed phase and the reagent in a continuous phase react at the interface, between the dispersed phase and the continuous phase, to form an envelope. The reagent, in the continuous phase, is typically led to the interface by a diffusion process. Once the reaction has started, the envelope eventually becomes a

ES 2 279 880 T3 diffusion barrier and thus limits the rate of the interface polymerization reaction. This can affect the morphology and uniformity of the envelope thickness. Dispersants can be added to the continuous phase. The dispersed phase can include an aqueous solvent or a nonaqueous solvent. The continuous phase is selected as being immiscible in the dispersed phase.

Typical polymerization reagents can include acid chlorides or isocyanates, which are capable of undergoing a polymerization reaction, with amines or alcohols. The amine or alcohol is solubilized in the aqueous phase, in a non-aqueous phase, capable of solubilizing the amine or alcohol. The acid chloride or isocyanate is then dissolved in the immiscible phase of water (or non-aqueous solvent). Similarly, solid particles containing reagents or having reagents as a coating on the surface can be dispersed in a liquid in which the solid particles are not substantially soluble. The reactants in the solid particles then react with reactants in the continuous phase to form an envelope.

In another type of microencapsulation, by interface polymerization, which is commonly referred to as encapsulation in situ, a filler or filler material, in the form of substantially insoluble particles, or in the form of a water-immiscible liquid, is dispersed in an aqueous phase. The aqueous phase contains urea, melamine, water-soluble urea-formaldehyde condensate, or water-soluble urea-melamine condensate. To form an envelope that encapsulates the filler or filler, formaldehyde is added to the aqueous phase, which is heated and acidified. Next, a condensation product is deposited on the surface of the dispersed core material as the polymerization reaction progresses. In a manner other than the interface polymerization reaction described above, the procedure may be appropriate for use with sensitive fillers or fillers, since the reactive agents do not have to dissolve in the filler or fillers. filling. In a related in situ process, a water-immiscible solid or liquid, containing a water-immiscible vinyl monomer and a vinyl monomer initiator, is dispersed in an aqueous phase. The polymerization begins, proceeding to heat, and a vinyl wrap is produced at the interface with the aqueous phase.

Gas phase polymerization

Microcapsules can be prepared by exposing filler or filler particles to a gas capable of undergoing polymerization on the surface of the particles. In such a process, the gas contains p-xylene dimers, which polymerize at the surface of the particles, to form a poly (pxylene) shell. Specialized coating equipment may be necessary to conduct such types of coating processes, making the process more expensive than certain liquid phase encapsulation processes. Also, the filler or filler material to be encapsulated is preferably not sensitive to reactants and reaction conditions.

Solvent evaporation

Microcapsules can be prepared by removing a volatile solvent from the emulsion of two water-miscible liquids, for example an oil-in-water type, oil-in-oil type, or water-in-oil type emulsion. The filler or filler material dissolves, disperses, or emulsifies in the solution. Appropriate solvents include methylene chloride and ethyl acetate. Solvent evaporation is a preferred procedure for encapsulation of water soluble materials, eg polypeptides. When such types of solvents must be encapsulated, typically a thickening agent is added to the aqueous phase and the solution is then cooled to gel the aqueous phase before removing the solvent. Dispersing agents may also be added to the emulsion prior to removal of the solvent. The solvent is typically removed by evaporation at atmospheric pressure or reduced pressure. Microcapsules less than 1 µm, or greater than 1000 µm, in diameter can be prepared using solvent evaporation procedures.

Centrifugal force encapsulation

Centrifugal encapsulation typically uses a perforated cup, which uses an emulsion of an envelope and a filler or filler material. The cup is immersed in an oil bath and rotates at a predetermined rate, thereby forming droplets including the wrapping and filler material in the oil outside of the rotating cup. The droplets gel by cooling to provide oil-laden particles, which can then be dried. The microcapsules produced in this way are generally relatively large. In another variation of centrifugal force encapsulation, referred to as rotary suspension separation, a mixture of filler or filler particles is introduced and either a ground shell or a solution of the shell is introduced. , on a rotating disk. The coated particles are thrown from the edges of the disk, where they gel or desolvate and are collected. Encapsulation by submerged injection nozzle

Microcencapsulation by means of a submerged injection nozzle involves, in a general way, the spraying (spray) of a liquid mixture of wrapping material and filler or filler, through a stream of carrier or support fluid. The resulting droplets gel and cool. The microcapsules produced in this way are generally relatively large.

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Desolvation

In desolvation or extractive drying, a dispersion of filler or filler material is atomized, in a concentrated solution or dispersion of wrapping material, in a desolvation solvent, typically, a water-miscible alcohol, where an aqueous dispersion is used. Water soluble casing materials are typically used, including maltodextrins, sugars and gums. Preferred solvation solvents include water soluble alcohols, such as 2-propanol or polyglycols. The resulting microcapsules do not have a clearly distinctive phase of the filler or filler material. The microcapsules thus produced typically contain less than about 15%, by weight, of filler material, but, in certain forms, may contain more filler or filler material.

Liposomes

Liposomes are microcapsules of a size that is comprised within ranges ranging from approximately less than 30 nm to a size greater than 1 mm. These consist of a phospholipid bilayer that encapsulates an aqueous space. The lipid molecules organize themselves by exposing their polar head groups to the aqueous phase and the hydrophobic hydrocarbon groups adhere together in the bilayer, forming compact, concentric lipid sheets that separate the aqueous regions. Medications can either be encapsulated in the aqueous space or entrapped between lipid bilayers. Whether a drug is encapsulated depends on its physicochemical characteristics and lipid composition. Liposomes can slowly release any drug through enzymatic lipid hydrolysis.

Various microencapsulation procedures

While, the microencapsulation procedures described above, are those that are generally preferred, to prepare the microcapsules in preferred forms of presentation, other appropriate microencapsulation procedures may also be used, as is known from the art. persons skilled in the specialized art of technique. Furthermore, in certain presentation forms, it may be desired to incorporate a microencapsulated drug or other substance, directly into a solid matrix of a carrier or support substance, as a vehicle. In such types of presentation forms, since the drug or other substance of the cyanoacrylate will come into contact, prior to curing of the adhesive, the drug or other substance is preferably not substantially sensitive to the cyanoacrylate, and does not cause a substantial premature curing of the adhesive prior to application. The microcapsules that are added to the adhesive may all be of the same type, and contain the same drugs or other substances, or they may include a variety of types and / or encapsulated drugs or other substances.

Preferred microencapsulated drugs

In preferred presentation forms, penicillin antibiotics are encapsulated in hydrophilic gelatin microcapsules, prior to incorporation into the cyanoacrylate adhesive, in such a way as to avoid unwanted reactions between the antibiotics and the cyanoacrylate.

Cyanoacrylate Adhesives

Adhesives in preferred forms of presentation include the 2-cyanoacrylic esters, commonly referred to as cyanoacrylates. Cyanoacrylates are hard crystalline resins, which exhibit excellent adhesion to high-energy surfaces, such as skin, but do not form strong bonds with low-energy materials, for example, polyolefins, polytetrafluoroethylene (commercially available with the Teflon® name), and polyvinyl chloride (often referred to as vinyl). Cyanoacrylate polymers form spontaneously when their liquid monomers are placed between two closely joined surfaces. The excellent adhesion properties of cyanoacrylate polymers come from the characteristics of the electrons that are adjacent to the polymerizable double bonds, which account for both the extremely high reactivity or cure rate, and their polar nature, which enable polymers to adhere tenaciously to many diverse substrates.

Chemistry of Cyanoacrylate Monomers

Some of the most common characteristics of monoacrylate monomers include, but are not limited to, ethyl, methyl, isopropyl, n-butyl, iso-butyl, methoxyethyl esters, ethoxyethyl, and octyl. Cyanoacrylate adhesives are manufactured and marketed worldwide by various companies, including Loctite, a Henkel Company, of Rocky Hill, CT, SAFE-T-LOC International Corporation of Lombard, IL , SUR-Lok Corporation of Walwoorth, WI, and Elmer Products, of Columbus, OH, the manufacturer of the well-known Krazy Glue®. Cyanoacrylates' ability to quickly heal and bond to the skin makes them particularly good for use as medical adhesives. Suitable medical adhesives for use as medical adhesives include octyl 2-cyanoacrylate, commercially available as Dermabond.^®, topical skin adhesive, manufactured by Ethicon, Inc., a Johnson &

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Johnson, of Somerville, NJ, and butyl cyanoacrylate, commercially available as Vetbond^®by World Precision Instruments, Inc. of Sarasota, FL.

The 2-cyanoacrylic ester monomers are all clear and thin aqueous liquids, with viscosities of 1-3 mPa. Only a few of the many esters that have been prepared and characterized are of significant commercial interest. Methyl and ethyl cyanoacrylates are the most commonly used for industrial adhesives. Cyanoacrylate adhesives for medical and veterinary uses generally include the longer chain alkyl cyanoacrylates, including butyl and octyl esters.

Base monomers are too thin for convenient use, and thus are generally formulated with stabilizers, thickeners, and property modifying additives. The viscosities of such types of adhesives can range from that of the base monomer to thixotropic gels. Alkyl esters are characterized by strong, tear-jerky, faintly sweet odors, while alkoxyalkyl esters are almost odorless, but less effective in adherence.

Link formation

Liquid cyanoacrylate monomers polymerize almost instantaneously, via an anionic mechanism, when brought into contact with a weakly basic or alkaline surface. Even the presence of a weakly basic substance, such as absorbed surface moisture, is appropriate to initiate the curing reaction. The curing reaction continues until all available monomers have reacted, or until it has been terminated with acidic species. The fixation time for cyanoacrylate occurs in a few seconds, on strongly catalytic surfaces, such as the skin, up to a few minutes, on non-catalytic surfaces. Surface accelerators or cure rate enhancing additives can be used to decrease setting time on non-catalytic surfaces. However, such types of accelerators and additives are generally not preferred for use in skin bonding due to the catalytic nature of the skin surface. The basic polymerization reaction includes the following initiation, propagation and termination steps:

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Cyanoacrylate Adhesive Formulations

Cyanoacrylate adhesives are soluble in N-methylpyrrolidone, N, N-dimethylformamide and nitromethane. Cyanoacrylates are hard, clear, glassy thermoplastic resins with high tensile strength values, but they tend to be brittle or brittle, and have only impact and peel strengths, ranging from low to low value. moderate. Elastomeric materials can be dissolved in cyanoacrylate adhesive formulations to provide a cured adhesive of greater flexibility and toughness. Long chain alkyl esters generally have longer cure rates, lower tensile strength, shear strength and hardness values ​​compared to short chain alkyl esters. Long chain alkyl esters also exhibit low gas transition temperatures (T_g), and adhesive bond service temperatures, when compared to short chain alkyl esters.

Although alkyl cyanoacrylate esters are the most common cyanoacrylate adhesives, in certain forms it may be preferable to use a cyanoacrylate ester adhesive, other than that for an alkyl ester. Thus, for example, allyl esters, which can be crosslinked by a free radical mechanism, via the alkyl group, can be used in applications where thermal resistance is desired.

ES 2 279 880 T3 increased. The alkoxyalkyl esters can be used in those applications where low odor is desirable, and where slightly reduced adhesive performance is acceptable.

Cyanoacrylate adhesives are prepared via the Knoevenagel condensation reaction, in which the corresponding alkyl cyanoacetate reacts with a formaldehyde, in the presence of a basic catalyst, to form a low molecular weight polymer. The polymer suspension is acidified and the water is removed. The polymer is cracked and redistilled at high temperature in an appropriate stabilizer combination to avoid premature repolymerization. Strong protonic or Lewis acids are normally used in combination with small amounts of a free radical stabilizer.

Adhesives formulated from 2-cyanoacrylic esters typically contain stabilizers and thickeners, and may also contain hardeners, colorants, and other special property-enhancing additives. Both types of stabilizers, anionic stabilizers and radical stabilizers, are required, since the monomer will polymerize via both mechanisms. Although the anionic polymerization mechanism depicted above is the predominant reaction, the monomer will undergo free radical polymerization under prolonged exposure to heat or light. In order to extend the shelf life of the cyanoacrylate adhesive formulations, free radical stabilizers, such as quinones or hindered phenols, are added to the formulations. Anionic inhibitors such as nitric oxide can also be added. Such types of inhibitors alter the viscosity and the rate of polymerization, thereby minimizing the risk of accidental spillage or overflow, and facilitating application.

Both liquid and cured cyanoacrylates support combustion, and a highly exothermic polymerization can occur, coming from the direct addition of catalytic substances, such as water, alcohols, and bases, such as amines, ammonia, caustic substances, or from contamination with surface activators. Cyanoacrylate Adhesives for Medical Purposes

Cyanoacrylate adhesives quickly bond to the skin, due to the presence of moisture and protein in the skin. Octyl cyanoacrylates are the most widely used cyanoacrylate adhesives for closing or sealing fabrics. When bound to tissue, octyl cyanoacrylates are four times stronger and less toxic than butyl cyanoacrylates. However, butyl cyanoacrylate is sometimes preferred for sealing deep lacerations, due to the fact that it disintegrates more easily, and can be absorbed by tissue, more rapidly than octyl cyanoacrylate.

2-cyanoacrylic esters have strong, pungent odors and are tear-jerky, even at very weak concentrations. These esters can be irritating to the nose, throat and eyes, at concentrations as low as those corresponding to 3 ppm. Good ventilation is desirable when using adhesives, and contact with the eyes, or other sensitive parts of the body, should be avoided when using cyanoacrylate adhesives for wound closure. Cured 2-cyanoacrylic ester polymers are relatively non-toxic, thus making them suitable for medical use. While slight skin irritation may be observed, there is no evidence of sensitization or absorption of cyanoacrylate adhesives through the skin.

Defect or pore forming additive for adhesives

Cyanoacrylic esters form a dense structure, after solidification, which inhibits the penetration of the drugs contained in the adhesive, in the blood or in the tissues. Controlled drug release from cyanoacrylate adhesives is typically achieved by one or two of the following routes: 1) biodegradation of cyanoacrylates, in the presence of enzymes from the blood or tissues around the wound, where antiseptic glues are applied; 2) roughness (unevenness) or voids, caused by uneven coating of adhesives to the wound; and 3) by artificially introduced defects in the adhesive matrix, proceeding to mix certain hydrophilic materials in the adhesive. When the water comes into contact with the hydrophilic materials, in the adhesive matrix, the materials dissolve in the water, leaving passages behind them. These passages facilitate the controlled release of drugs from microcapsules, allowing water to pass through the adhesive matrix.

In preferred forms of presentation, the controlled release of drugs, from the adhesive matrix, is achieved mainly through the use of artificially introduced defects or pores. Such types of defects can be introduced using water soluble salts, such as sodium chloride, in powder form. However, in particularly preferred presentation forms, polyethylene glycol (PEG) is added to the adhesive to form defects, which provide passage of the microencapsulated drugs into the adhesive matrix, thereby increasing the release rate of the drugs. , on the solidified adhesive film. In general, water is preferred over water-soluble salts, since it provides a more homogeneous mixture with cyanoacrylate adhesives, with respect to the way that water-soluble salts do, such as sodium chloride.

Defects or steps for the release of drugs from a solidified adhesive film or matrix are preferably provided by adding PEG, with a molecular weight of 600, to a cyanoacrylate adhesive. While polyethylene glycol is the preferred flaw-forming agent, flaws can

ES 2 279 880 T3 may also be formed by adding any appropriate hydrophilic material to the cyanoacrylate adhesive. Suitable hydrophilic materials include, but are not limited to, water-soluble polymers or water-miscible polymers, water-soluble salts, water-soluble small molecules, water-soluble natural products, mixtures and combinations of these, and like that.

Suitable water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), polyethylene glycolpropionaldehyde, ethylene glycol / propylene glycol copolymers, monomethoxy-polyethylene glycol, carboxymethylcellulose, dextran, polyvinyl-pyrrolyl alcohol (PVA), polyvinyl alcohol (PVA) , poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymer, polye- (amino acids) (including both homopolymers and random copolymers), poly (n-vinylpyrrolidone) polyethylene glycol, propylene glycol (PG) homopolymers, and other polyalkylene oxides, polypropylene oxide / ethylene oxide copolymers, polyoxyethylated (POG) polyols (e.g., glycerol) and other polyoxyethylated polyols, sorbitol, polyoxyethylated or polyoxyethylated glucose, colonic acids, and other carbohydrate polymers, Ficoll or dextran and mixtures of these. The water soluble polymer used is preferably approved for clinical use.

Water soluble polymers of any molecular weight can be used. However, it is preferred that the molecular weight is selected such that the polymer chain is approximately the same length as that of the cyanoacrylate adhesive in which it is mixed. A PEG with a molecular weight of 600 provides satisfactory technical performance when mixed with Super Glue.

The forms of presentation discussed above, above, refer to cyanoacrylate adhesives. The processes of the preferred forms of presentation, namely the formation of pores or defects by solvation of a hydrophilic component, in the adhesive matrix, can also be applied to adhesives of other chemical forms. Preferably, such types of adhesives form matrices similar to cured cyanoacrylates, that is, matrices that are substantially non-porous in the absence of additives, and substantially soluble in water. Such types of adhesives may include, but are not limited to, epoxies, resins, and the like, as is known in the art. Such types of adhesives may be useful in applications other than wound closure or other medical applications, that is, applications where a controlled release of a substance from the adhesive matrix is ​​desired under humid or wet conditions. .

It may also be desirable, in certain presentation forms, to provide an adhesive that does not contain any drugs, but which has a faster degradation or disintegration rate than a non-additive adhesive. For such types of applications, a flaw-forming agent may be added to the adhesive, as described above.

Anti-degradation agents

Water-soluble acidic materials can reduce the rates of polymerization and degradation of cyanoacrylates, thereby reducing, in a possible way, the toxicity of cyanoacrylate adhesives. Thus, therefore, in certain presentation forms, it may be preferable to incorporate one or more physiologically acceptable organic or inorganic acids into the adhesive formulation. Appropriate acids can be solid or liquid. Common basic, dibasic or higher organic acids are preferred, including, but not limited to, malonic acid, mandelic acid, oxalic acid, lactic acid, lactobionic acid, fumaric acid, maleic acid, tartaric acid, citric acid, ascorbic acid and acetic acid. Other suitable acids include dihydrogen phosphates and hydrogen sulfates, or the physiologically acceptable salts of phosphoric acids (eg, dihydrogen phosphate), sulfuric acids (eg, dihydrosulfuric acid), hydrohalic acids (eg, hydrochloric acids), and the like. .

Suitable acid salts include, but are not limited to, alkali or alkaline earth metal salts, especially sodium, potassium or calcium salts, as well as ammonium salts.

In addition to acting as antidegradation agents, soluble acid materials can also act as pore-forming agents. In certain embodiments, where the acidic material functions as a pore-forming agent, it may be preferred to have an additional pore-forming agent present, eg, ethylene glycol. Alternatively, in certain presentation forms, the acidic material can be added to a primary formulation, due to its anti-degradation activity, in order to provide an adhesive of reduced toxicity. In such presentation forms, the adhesive may or may not contain one or more pore-forming agents, drugs, or any other additive, as described above.

In order to provide anti-degradation activity, over an extended period of time, it may be preferable to add the acidic material to the adhesive, in encapsulated form. Appropriate encapsulation procedures may include those described above for the preparation of microencapsulated medicaments.

In preferred presentation forms, the water-soluble acidic materials include vitamin C (ascorbic acid), citric acid, and aspirin (salicylic acid). In particularly preferred presentation forms, these acidic materials are provided as gelatin microcapsules.

ES 2 279 880 T3

The acidic water-soluble material is preferably added to the cyanoacrylate, at a concentration corresponding to a percentage comprised within ranges from approximately 0%, by weight, to more than approximately 30%, in weight, more preferably, from about 1, 2, 3, 4, 5, 6, 7, 8, or 9% by weight, to about 21,22,23,24,25,26,27, 28 6 29%, by weight, a most preferably, from about 10%, by weight, up to about 11, 12, 13, 14, 15, 16, 17, 18, or 19%, by weight. The optimal concentration may depend on the chemical composition, solubility and acidity of the material, the chemical composition of the cyanoacrylate adhesive, whether the acid is present in encapsulated or non-encapsulated form, and the release rate. acid, if it is in encapsulated form. When the acidic substance is to be provided in encapsulated form, it is generally preferred that the microcapsules are of a size in the range from about 2 microns or less to about 100 microns or more, in a manner preferably, from about 5 microns to about 60, 70, 80, or about 90 microns and, most preferably, from about 10, 15, 20, or 25 microns, down to about 35, 40, 45 or 50 microns. Preferred trapping or trapping efficiencies are 20% by weight or more, preferably 35% by weight or more, and most preferably 50%. -80%, by weight, or greater. The drug loading is preferably a value corresponding to a percentage ranging from about 1%, by weight, or less, to about 50%, by weight, or more, and most preferably , from about 5%, by weight, to about 20%, by weight.

Adhesive formulation containing a microencapsulated drug

Microcapsules containing drugs or other substances are preferred, as described above. In order to ensure that premature curing of the adhesive does not occur, by adding the microcapsules, it is desirable to ensure that the microcapsules are thoroughly dried thoroughly. In preferred forms of presentation, the microcapsules are dried in the presence of a desiccant and, more preferably, under the action of vacuum. After drying, the microcapsules are preferably kept under an inert atmosphere of high purity, for example dry nitrogen or argon, until these are added to the cyanoacrylate. Due to the fact that basic compounds catalyze the polymerization of cyanoacrylate adhesives, it is desirable to control the microcapsule and adhesive preparations in such a way as to minimize the presence of such types of compounds.

The microcapsules and the defect-forming agent can be added to the cyanoacrylate adhesive in any convenient way, and in any convenient order. It is generally preferred to add the defect-forming agent to the uncured cyanoacrylate adhesive and then add the microcapsules to the resulting mixture. In order to form a homogeneous mixture of adhesive, flaw-forming agent, and microcapsules, any appropriate mixing procedure can be used, for example, mechanical stirring, vibration stirring, or sonification (sonication). The fact that the mixing procedure does not result in substantial damage to the microcapsules and premature release of drugs or other substances contained therein is preferred. Preferably, the components are mixed and stored under an inert atmosphere, or sealed in an airtight container, prior to application.

Preferably, the microcapsules are added to the adhesive to provide a concentration corresponding to values ​​within ranges of less than about 5% by weight to more than about 30% by weight. more preferably, from about 6, 7, 8, 9, or 10%, by weight, to about 21, 22, 23, 24, 25, 26, 27, 28, or 29%, by weight, and, most preferably, from about 10%, by weight, up to about 11, 12, 13, 14, 15, 16, 17, 18, or 19%, by weight. The optimal concentration may depend on the concentration of the filler or filler material in the microcapsules, the type of drug used, the desired release rate and the dosage level of the drug, the amount and type of defect-forming additive. added into the cyanoacrylate, and the encapsulation procedure used to prepare the drug microcapsules. It is generally preferred that the additive ingredient, whether it is incorporated into the microcapsule or added directly to the adhesive, is present in the adhesive, at a concentration ranging from approximately 5%, by weight, to more than about 30%, by weight, more preferably, from about 6, 7, 8 or 9%, by weight, to about 21, 22, 23, 24, 25, 26, 27, 28 or 29%, by weight, and most preferably, from about 10%, by weight, to about 11, 12, 13, 14, 15, 16, 17, 18, or 19%, by weight.

The water-soluble defect-forming material is added to the cyanoacrylate, preferably at concentration values ​​corresponding to percentages ranging from about 0% by weight to more than about 30% by weight. , more preferably, from about 1, 2, 3, 4, 5, 6, 7, 8, or 9%, by weight, to about 21, 22, 23, 24, 25, 26, 27, 28 or 29%, by weight and most preferably from about 10%, by weight, up to about 11, 12, 13, 14, 15, 16, 17, 18, or 19%, by weight. The optimal concentration may depend on the composition and molecular weight of the water-soluble material, the chemical composition of the cyanoacrylate adhesive, the encapsulation procedure used to prepare the microcapsules, and the release rate and dosage level of the drug. .

ES 2 279 880 T3

Generally, the greater the amount of defect-forming agent added, the greater the release rate of the drug contained in the adhesive. Likewise, the smaller the molecular size or molecular weight of the water-soluble defect-forming material, the higher the release rate.

In a preferred form of presentation, the medicament is an antibiotic, the defect-forming additive is PEG and the cyanoacrylate is octyl cyanoacrylate. The antibiotic is preferably encapsulated in a microcapsule having a gelatin shell and a mean diameter of about 4 µm.

In certain forms of presentation, it may be desirable to add additional components to the adhesive. These additional components may include additives commonly used in cyanoacrylate adhesives, eg, stabilizers and elastomers, as described above. Other materials may include fibers that improve the strength of the cured adhesive. Alternatively, after the adhesive has been applied to the wound, but before it has fully healed, a flexible fabric or non-woven may be compressed onto the adhesive surface. The fabric in this way bonded to the adhesive material improves the strength of the cured adhesive film.

Preferred presentation form adhesive formulations can be used in applications where a conventional cyanoacrylate medical adhesive is used. Adhesives can be used to seal (close) internal wounds (eg, arterial incision), as well as to seal or close external wounds (eg, skin cuts, punctures, and lacerations. When the adhesive is to be used in the closure of artery incisions, it is preferred that the adhesive has a burst strength not exceeding 250 mm Hg. However, in certain forms of presentation, strengths to burst rupture may be appropriate, corresponding to lower values.

Examples and comparative examples

Antibiotic encapsulation

The sadistic salt of Penicillin G (hereinafter referred to as "Penicillin G"), Sulfanilamidum Crystallinum Steril (hereinafter referred to herein document, such as "Sulfanilamide"), Cephalexin, and Gatifloxacin, were selected as sample drugs. Sulfanilamidum and Gatifloxacin were selected for testing, in part because their visible ultraviolet spectra are easily distinguishable from the background spectrum observed for aqueous saline, and because their aqueous solutions are stable. at room temperature.

The antiseptic microcapsules containing each of the antibiotics listed above, were obtained by preparing an aqueous dispersion of the antibiotic and gelatin in liquid wax, by vigorous stirring, at a temperature of 60 ° C. The dispersion was observed using visible microscopy to ensure that the desired particle size had been achieved. The dispersion was then cooled to a temperature of 5 ° C, while stirring was continued. The dispersion was then mixed with isopropanol and filtered, in order to obtain the microcapsules. The microcapsules were treated with formalin solution and then the solution was stored in a refrigerator for approximately 24 hours. The solution was filtered to separate the microcapsules, which were thoroughly dried. The resulting antibiotic microcapsules were pale yellow in color and spherical in shape, with a diameter of approximately 10 to 100μιη. Surfactants such as polyvinyl alcohol, or Pluronic® F68, can be used to stabilize the microcapsules and provide an appropriate particle size distribution. A narrow microcapsule size distribution, with a selected mean particle size, can be obtained using conventional sieving procedures. The stability of the dispersion of the microcapsules in the adhesive is largely dependent on the particle size.

Antibiotics trapped in gelatin microcapsules can be examined using infrared (IR) and ultraviolet (UV) spectroscopy. Potassium bromide wafers containing, respectively, Penicillin G, gelatin, and Penicillin G microcapsules were examined using IR spectroscopy. As shown in Figure 2, there are no obvious peaks indicating the existence of Penicillin G in the spectrum for Penicillin H microcapsules. However, Uv spectra for the aqueous extracts of, respectively, Penicillin G, gelatin, and Penicillin G gelatin microcapsules, provided a remarkable Penicillin G absorption peak for the Penicillin G gelatin microcapsule extract (Figure 3). Because the penetrating ability of infrared light inside opaque microcapsules is rather weak, this suggests the fact that Penicillin G can be trapped mainly in the nucleus rather than in the envelope, indicating, with it, a successful microencapsulation.

Antibiotic release from the particles was investigated by immersing either Penicillin G microcapsules or Sulfanilamide microcapsules, prepared in the manner described above, in a physiological saline solution, at body temperature. . Penicillin G was observed to break down during the release process. The aqueous extract of the sulfanilamide was stable at room temperature. Figure 4 provides UV spectra of the sulfanilamide extract, at 10, 50 and 105 minutes, demonstrating the controlled release of sulfanilamide from the microcapsules.

ES 2 279 880 T3

Optimization of the microcapsule preparation technique

It was observed that the microcapsules obtained by the initial procedure described in the previous section, had a relatively low capture or trapping efficiency (&lt;10%). Their release profile, provided in Figure 6a, did not follow a long-term release pattern. The release pattern indicates that approximately 80% of the total drug content was released within 2 minutes, thus suggesting the fact that the drug had been absorbed primarily in the surface of the gelatin particles, rather than being trapped inside the gelatin matrices.

While not wishing to limit it to any particular mechanism, the crosslinking step is believed to account, in part, for encapsulation efficiency. An acetone-formaldehyde solution was used as the crosslinking medium, due to the fact that gatifloxacin exhibits relatively weak solubility and gelatin does not swell in an acetone-formaldehyde solution. Microcapsules with a much higher trapping efficiency (50-80%) were obtained using the modified procedure and, the microcapsules, exhibited a long-term release profile (that is, of long duration in time), of the drug, such and as shown in figure 6b.

Microcapsules with high trapping or trapping efficiencies can be prepared by adding 1 volume of aqueous gatifloxacin solution (typically, about 1 to 10%, by weight), gelatin (typically, about 20%, by weight), and Pluronic F-68 (commercially available in the market, from Jinling Petroleum Chemical Co. Ltd. from China, typically present, at a rate of approximately 1%, by weight, as a stabilizer), in 8 volumes of liquid paraffin (commercially available in the market, from Hangzhou Chemical Reagent Co. of China), through a vigorous stirring, at a temperature of 60 ° C. The solution is stirred for approximately 15 minutes or until a whitish dispersion is formed. The dispersion is cooled to a temperature of approximately 5 ° C, and stirred for approximately 10 minutes, to induce complete gelation of droplets of gelatin solution. 30 ml of acetone-formaldehyde solution (10%, by weight) is added to the system, which is stirred for another 20 minutes, during which time the microcapsules crosslinking. The suspension is filtered and the filtered microcapsules are washed with cold acetone. The particles are dried under vacuum at a temperature of 40 ° C for 48 hours, providing spherical antibiotic microcapsules of a pale yellow hue, with a particle size of approximately 10-50 microns.

The effects of the degree of crosslinking, on the release profile of the microcapsules, was also studied, but no significant impact was observed. A crosslinking time of 20 minutes was observed, to obtain satisfactory encapsulation efficiencies.

Preparation of adhesives containing non-encapsulated drugs

Adhesive formulations that include unencapsulated antibiotics were investigated. The drugs were vacuum dried for 6 hours at room temperature in the presence of phosphorous pentoxide to remove residual water. The drugs were directly mixed with cyanoacrylic ester, which was conducted in a mixing chamber protected by a high purity nitrogen atmosphere. Agglomeration was observed, when Penicillin G was mixed with Super Glue, which may be due to the initiation of the cyanoacrylate curing reaction by penicillin. In contrast to Penicillin G, it was observed that the shelf life of cyanoacrylate adhesives, in the presence of Sulfanilamide, was more than 24 hours. This suggests the fact that uncured cyanoacrylate is more sensitive to Penicillin G than to Sulfanilamide.

Preparation of adhesives containing microcapsules

Adhesive formulations were prepared that included encapsulated antibiotics. The microcapsules loaded with antibiotics were dried completely, thoroughly, under the action of vacuum, and under conditions free of water, and then sealed. No agglomeration or solidification of the cyanoacrylic ester was observed after 24 hours, suggesting that microencapsulation effectively suppresses the unwanted chemical interaction between drugs and esters. cyanoacrylics.

Controlled release of antibiotics

Adhesive samples containing either encapsulated Penicillin G or non-encapsulated Penicillin G were prepared as described above. The solidification of the adhesives was carried out in humid air in order to provide an accelerated solidification rate. The solidified adhesives having a thickness of approximately 1 mm were cut into small pieces, which were immersed in physiological saline at room temperature. The aqueous extracts were examined using UV spectroscopy. As illustrated in Figure 6, no detectable release of Penicillin G (both encapsulated and non-encapsulated) was observed from the solidified adhesive film. The absence of release can be attributed to the dense mass of the cross-linked cyanoacrylic ester.

By reducing the solidified film, a greater surface unevenness and more voids are created, which can provide passageways for drug release. Adhesive samples were applied that

ES 2 279 880 T3 contained Sulfanilamide, on filter paper, infiltrated with ambient physiological serum. The spectroscopy of extracts of the solidified adhesives, provided the absorption characteristics of Sulfanilamide (figure 7). The uneven and porous surface of the paper filter is believed to result in more defects in the resulting solidified glue after contact with paper, which facilitates the release of antibiotics.

Artificially Formed Defects - Sodium Chloride Powder

Drug release passages were created in a solidified, dense glue film by using pore-forming or defect-forming agents.

The aqueous extracts of the solidified adhesive, using sodium chloride, exhibited a characteristic UV absorption spectrum for sulfanilamide. However, a large variation in release rate was observed for different parts of a solidified adhesive film. Figure 8 provides the release rate data from two different portions of the adhesive film. The data suggests the fact that the mixture is not uniform, due to the heterogeneous dispersion of sodium chloride in the adhesive.

In contrast to the results observed for sodium chloride, an adhesive prepared using PEG demonstrated a more uniform release rate. Figure 9 provides release rate data for extracts from two different portions of the adhesive film.

Adhesives were prepared using Gatifloxacin microcapsules, in both versions, with PEG and without PEG. Figure 10 shows the release characteristics of Gatifloxacin from solidified adhesive film. As observed in the experiments with Sulfanilamidum, the incorporation of PEG also increased the release rate in the solidified adhesive film.

While it is not intended to be limited to any particular mechanism, it is believed that when the solidified adhesive contacts an aqueous saline solution, the PEG found in the solid film dissolves in the aqueous solution, leaving a passage, behind him, consisting of pores and defects that give way. The microcapsules trapped in the glue are thereby directly exposed to water in the channels formed by the defect generator, that is, the PEG. This process accelerates the diffusion of the antibiotic in the saline solution. Figures 11a and 11b are SEM images of the surface of a solidified adhesive containing a percentage of 16.2% of PEG 600, before extraction with aqueous solution. Figures 12a and 12b are SEM images of the surface of the same adhesive, after extraction with aqueous solution. The modified adhesive, after extraction, exhibits cracks and fissures not represented before extraction.

Microbiological testing of antibiotics released from adhesives

The antibiotic activity of different solidified adhesives was measured, proceeding to place small pieces of solidified adhesive in a bacterial culture of S. aureus. Figure 13 shows the effect on the culture material, after exposure to Gatifloxacin, on filter paper (lower left corner of left hand) and solidified adhesives that include only PEG, only Gatifloxacin, and Gatifloxacin microencapsulated with PEG. (Clockwise from the left hand angle from the top of the image. The data demonstrates that a higher release capacity is observed for the PEG-containing antibiotic adhesive.

Release behavior of antibiotic adhesives containing Gatifloxacin microcapsules

The polymerized cyanoacrylate forms a compact film that can inhibit the penetration of water into the adhesive matrix. Thus, in this way, the release of antibiotics from a well-formed polycyanoacrylate film can be difficult. As discussed above, the introduction of PEG or defects into the adhesive matrix can greatly accelerate the release process.

The release percentage, for different polymerized cyanoacrylate films, containing gatifloxacin microcapsules, is illustrated in Figure 14 and Figure 15. The release percentage was calculated based on the total drug content of the gatifloxacin microcapsules (6 , 7%, by weight, drug loading), trapped in the solidified adhesive film. The microcapsule content (based on the total weight of the solidified adhesive) of the three films, in Figure 14 (containing percentages of 0%, by weight, 5.6%, by weight, and 19%, in weight, respectively), was 24%, by weight, 25%, by weight, and 26%, by weight, respectively. The microcapsule content of the films of FIG. 15 was 25%, by weight. The thickness of the solidified adhesive films, in Figure 15, and the thickness of the film, in Figure 15, was 1 ± 0.1 mm. The thickness of the film, in Figure 15, was approximately 0.2mm.

The data illustrated in Figure 14 suggests the fact that the presence of PEG in the adhesive matrix results in a more rapid release of antibiotic. The initial release rate increases significantly with increasing PEG concentration. Without wishing to limit it to any mechanism, it is believed that the PEG, in the solidified antibiotic adhesive, dissolves and leaves passages behind the film when the film contacts water. Thus, in this way, the microcapsules trapped in the dense film are exposed to water, through these passages left by the dissolved PEG. This process can accelerate the diffusion of water into the solidified adhesive and

ES 2 279 880 T3 accelerate drug release. It was noted that the adhesive containing 0% by weight PEG also exhibited a weak release. This is believed to be due to the presence of a small number of defects in the solidified adhesive film, which leads to drug release. The results of the experiment also demonstrate the fact that drug release can be greatly accelerated as the thickness of the adhesive film is reduced, as shown in figure 15. The data demonstrate the fact that, drug release from the thin film, which is approximately 0.2 mm thick, was much faster than from the thin film which is approximately 1.0 mm thick.

However, it was noted that the release percentages of the films of Figure 14 and Figure 15 are below a value corresponding to a percentage of 100%. It is believed that a number of microcapsules were firmly encapsulated by polycyanoacrylate, and were not able to provide access to water, until the outer polycyanoacrylate shell degraded.

Shelf life of the adhesive containing microcapsules

The direct mixing of methyl cyanoacrylate (Super Glue®) with dry gatifloxacin powder leads to solidification within approximately 3 hours at room temperature and the color of the cyanoacrylate changes to light green. indicating that some gatifloxacin has dissolved in the Super Glue^®. However, a mixture of microencapsulated gatifloxacin and Super Glue^®, exhibits greater stability. The shelf life (shelf life) of different cyanoacrylate adhesives containing 25%, by weight, of gatifloxacin microcapsules (6.7% of total load), is given in Table 1.

TABLE 1

<td>Cyanoacrylate</td><td>Methyl ester</td><td>Ethyl ester</td><td>Butyl ester</td>

<td></td><td>(Super Glue)</td><td>(Sticker 503</td><td>(Suncon Medical</td>

<td></td><td></td><td>from Beijing</td><td>Adhesive of</td>

<td></td><td></td><td>Chemical and</td><td>Beijing Suncon</td>

<td></td><td></td><td>Enginnering</td><td>Medical Adhesive</td>

<td></td><td></td><td>Company)</td><td>Co. Ltd.)</td>

<td>Time of life conservation (Temperature environment of about 25 ° C)</td><td>3 days</td><td>7 days</td><td>10 days</td>

<td>Time of life</td><td></td><td></td><td></td>

<td>conservation</td><td>&gt; 20 days</td><td>&gt; 30 days</td><td>&gt; 40 days</td>

<td>(4 ° C)</td><td></td><td></td><td></td>

The data show the fact that different cyanoacrylates have different reactivities and, thus, different shelf life times. Typically, higher alkyl ester cyanoacrylates have lower reactivity and longer shelf lives than lower alkyl ester cyanoacrylates. Storage temperature also has a significant effect on the shelf life of adhesives. With a reduced storage temperature, the shelf life was significantly extended. Thus, therefore, cold storage of antibiotic cyanoacrylate adhesives, containing gatifloxacin microcapsules, it is preferred that these be packaged in individual packages.

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In addition to the chemical composition of cyanoacrylate and storage temperature, the chemical composition or concentration of the pore-forming agent, or the packaging process and the packaging container, can have a significant effect on the shelf life of the products. adhesives containing microcapsules.

As illustrated in Figure 15, the addition of PEG can enhance the release of trapped drug. However, PEG can have adverse effects on the stability of the cyanoacrylate adhesive. Thus, therefore, it is preferred to use a small amount of PEG (typically about 5%, by weight, or less) if the adhesive is packaged in an individual package. However, PEG can be replaced by other pore-forming materials, in order to extend the shelf life of the adhesives. Acidic water-soluble materials, such as vitamin C, citric acid, or aspirin, are preferred pore-forming agents, due to the fact that acidic substances can reduce the degrees or rates of polymerization and degradation of cyanoacrylates, thereby possibly reducing the toxicity of cyanoacrylate adhesives.

Alternatively, a separate package can be used for adhesive antibiotics, thereby minimizing storage stability. A separate package is a package in which the cyanoacrylate adhesive and the microencapsulated pore-forming agent and / or drug are stored in different compartments and mixed shortly before use. When such packaging is used, the content of PEG (or other pore-forming materials) can be increased to provide a satisfactory release rate and a higher percentage of release.

The presence of trace amounts of basic substances, such as water and alcohol, may be sufficient to trigger the polymerization of cyanoacrylate adhesives (see, for this purpose, TM Brumit, “Cyanoacrylate adhesives-when should you use them?”, - Cyanoacrylate Adhesives - When Should You Use Them (Adhesives Age, February 1975, 17-22). It is therefore preferred that the amount of basic substances present is kept to a minimum in the mixture of cyanoacrylate and microcapsules. Thus, in this way, the packaging process can play an interpretive role in the resulting stability of antibiotic adhesives. Packaging procedures that can effectively remove basic substances, including water, are expected to provide products with longer shelf life. The type of container can also be a factor in the shelf life. Thus, for example, air-tight metal container containers can provide the best storage stability and polyethylene bottles or glass ampoules can also be satisfactory container containers.

Typically, it is quite difficult to achieve a satisfactory shelf life of antibiotic microcapsules containing cyanoacrylate, in an individual container. Thus, therefore, it is generally preferred to use a separate form of packaging, as represented schematically in Figure 16. The cyanoacrylate and microcapsules are separated into different container containers, which can be easily mixed, little time before use. Such type of container shape can provide satisfactory storage stability without loss of operational convenience. Cyanoacrylate is typically stored in a sealed ampoule. Dry microcapsules loaded with drugs, and appropriate additives, such as PEG and vitamin C, are stored in a capped syringe. In order to prepare the adhesive for use, the sealed cap on the syringe is removed, and the vial containing adhesive is opened. The cyanoacrylate is poured into the syringe, which is shaken to thoroughly mix the adhesive and the microcapsules. The mixture thus obtained can be extruded through an appropriately sized needle. If the sealing layer is put back into the syringe, the mixture is able to maintain its fluidity for a specified period of time, typically 4 hours or more. It is believed that a separate package will not only provide a much longer shelf life, but will also reduce production costs more extensively, due to the fact that pretreatment (especially , the drying process), of the microcapsules and containers, can be simplified.

Preparation of gelatin-sodium phosphate dexamethasone microcapsules and release of DSP from solidified adhesive microcapsules containing DSP

Gelatin-dexamethasone sodium phosphate (DSP) microcapsules were prepared in accordance with the optimized gelatin microcapsule procedure, using an acetone-formaldehyde solution, as described above. Figures 17a and 17b provide optical microscope images of Gelatin-DSP microcapsules. Preferably, the concentration of DSP, in the gelatin solution, does not exceed a percentage corresponding to 1%, by weight. If the concentration of DSP in the gelatin solution is greater than a percentage corresponding to 1%, by weight, the viscosity of the dispersion phase increases substantially, resulting in microcapsules of an undesired large size (&gt; 500 microns). See, to this effect, Arshady, “Microespheres and Microcapsules: A Survey of Manufacturing Techniques. Part 1: Suspension Cross-linking ”, -Microspheres and microcapsules: A Supervision of manufacturing techniques. Part 1: Crosslinking of suspensions-, Polym. Eng. And Sci., December 1989, Volume 29, No. 24, 1746-1758. At such low concentration values, the drug loading of the DSP microcapsule was low. However, the capture or trapping efficiency was satisfactory, as demonstrated by the data for four different batches of DSP microcapsules (DSP-MC1, DSP-MC2, DSP-MC3, and DSP-MC4), provided in Table 2. Additionally, the release profile of the DSP microcapsules exhibit a long-term controlled release character, as illustrated in Figure 18.

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TABLE 2

<td>Microcapsule</td><td>DSP-MC1</td><td>DSP-MC2</td><td>DSP-MC3</td><td>DSP-MC4</td>

<td>Crosslinking time</td><td> 210</td><td> 30</td><td> 210</td><td> 30</td>

<td>(minutes)</td><td></td><td></td><td></td><td></td>

<td>Ratio factor</td><td> 0,028</td><td> 0,028</td><td> 0,050</td><td> 0,050</td>

<td>introduction of DSP /</td><td></td><td></td><td></td><td></td>

<td>Gelatin (wt / wt)</td><td></td><td></td><td></td><td></td>

<td>Drug loading%</td><td> 1,86</td><td> 2,23</td><td> 3,46</td><td> 3,54</td>

<td>Trapping efficiency%</td><td> 65, 6</td><td> 79, 0</td><td> 61,2</td><td> 71,1</td>

Due to the fact that the spectra of DSP and the extractor solution of Super Glue® have overlapping absorptions, at 240 nm, the release behavior of cyanoacrylate adhesives containing microcapsules of DSP was studied by HPLC, instead of UV spectroscopy. It was found that the DSP microcapsules gradually decomposed in aqueous solution and, their characteristic peak, in the HPLC spectrum, at a retention time of 10.7 minutes, decreased, and the peak appeared and grew, at 14, 4 minutes, as the decomposition process progressed. Figure 19a shows the HPLC chromatogram of a DSP microcapsule solution, prepared just before performing the HPLC test, while Figure 19b shows the HPLC chromatogram of a DSP microcapsule solution, prepared one month before the HPLC test. The peak with a retention time of 14.4 minutes, in Figure 19b, is attributed to the decomposition product of DSP and its area varies with the storage time of the aqueous DSP solution.

The HPLC chromatogram of a Super Glue® film extractor solution containing DSP microcapsules is shown in Figure 19c. The peak is observable at 10.7 minutes, indicating the release of DSP. The peak at 14.4 minutes is also observable, which indicates the fact that a part of the DSP has decomposed, during the storage of the extraction solution.

Due note will be taken as to the fact that, if more effective dispersion procedures, such as ultrasonification (sonication), vortex mixing, and the like, are employed in the preparation of microcapsules, it will be expected that , the particle size is reduced, and the drug loading of DSP-gelatin microcapsules can be increased without an undesirable increase in size. A decrease in the size of the microcapsules can lead to a better mechanical strength of the cyanoacrylate adhesive containing solidified microcapsules.

Reduced degradation rates of 2-cyanoacrylate adhesives

When 2-cyanoacrylates are used in medical applications, their ability to biodegrade and the mechanism of degradation can play an interpretive role in their performance. The proposed mechanism of poly (2-cyanoacrylate) degradation includes two possible courses or trajectories, illustrated below, below. The first mechanism is the degradation of the skeleton, which follows a reverse Knoevenagel reaction, providing formaldehyde and alkyl cyanoacetate. The other path or course is the cleavage of the ester, by side chain hydrolysis, resulting in poly (2-cyanoacyl acid) and alcohol.

<img file="ES2279880T3_D0002.tif" />

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The second course, or trajectory, seems to be the main mechanism. The degradation rate depends on the temperature, the pH of the medium, the enzyme content and the length of the alkyl chains, and toxicity is largely related to the degradation rates. If the degradation rates of the solidified cyanoacrylate adhesive are decreased to such an extent that the degradation products are instantly metabolized, then the adhesive can satisfy the requirements for medical use.

It was observed that the degradation rate decreased with a decrease in the temperature and the pH value of the medium, and with an increase in the length of the ester side chain. Different types of enzymes and additives can accelerate or prohibit the degradation of poly (2-cyanoacrylate). Thus, for example, esterase can promote degradation and superoxide dismutase, indomethacin, and acetylsalicylic acid can retard degradation. Thus, in this way, butyl 2-cyanoacrylate and octyl adhesives can be selected for medical use and the toxicity of the adhesive can be reduced by the pH value and / or the enzyme content, and by the addition of certain additives.

Due to the fact that the degradation rate of poly (2-cyanoacrylate) is significantly reduced in a medium with a pH value &lt;7, it is preferred to add certain acidic, microencapsulated, physiologically acceptable materials to the cyanoacrylate adhesives, for a reduction in the degree of degradation and long-term toxicity. Gelatin microcapsules with ascorbic acid (Vitamin C) were prepared and the release behavior was studied qualitatively. The procedure for the preparation of ascorbico-gelatin acid microcapsules is in the same way as that described above, except for the fact that an atmosphere of N was used.₂In order to prevent the undesired oxidation of vitamin C. The release of Vitamin C was observed, from a solidified adhesive film containing vitamin C-gelatin microcapsules, by means of UV spectroscopy. The spectrum, provided in Figure 20, indicates that the acidic environmental environment of the solidified adhesive film can be obtained in this way.

Experimental data demonstrate the feasibility of a medical cyanoacrylate adhesive with an antibiotic function. The procedure for preparing such types of antibiotic microcapsules plays an interpretive role in the performance of the adhesive. In order to ensure high trapping efficiency, reasonable drug loading, and controllable microcapsule size, technical preparation can vary for different antibiotics. The Gatifloxacin-gelatin microcapsules, with a size comprised within the margins of 1050 microns, with a 50-80% trapping efficiency, and a 5-20% drug load, prepared by the preparation technique in the Using an acetone-formaldehyde crosslinking solution generally provides satisfactory performance.

The experimental data also demonstrate the fact that mixing an amount of PEG in a cyanoacrylate adhesive can increase the release rate of the drugs in the solid film. The mechanical strength of the solidified cyanoacrylate adhesive film containing microcapsules can be remarkably reduced if the PEG content exceeds an amount corresponding to 30% by weight, so that the fact of that the PEG is comprised in a concentration corresponding to a percentage of 30%, by weight, or less. The test of resistance to rupture by bursting, of microcapsules containing Super Glue® (20%, by weight) and PEG (20%, by weight), is satisfactory (resistance to rupture by bursting&gt; 350 mm Hg) . Typically, the mechanical strength of methyl cyanoacrylate (Super Glue^®, is greater than that of butyl or octyl cyanoacrylate.

When 2-cyanoacrylates are used in medical applications, their biodegradability and degradation mechanism can be significant for adhesive performance. The degradation rate is mainly dependent on the temperature, the pH value of the medium, the enzyme content, and the length of the alkyl chains. Toxicity is widely related to degradation rates. In general, if the degradation rate of solidified cyanoacrylate adhesive decreases to such an extent that the degradation products can be instantly metabolized, the adhesive may be suitable for internal use due to its low toxicity. Based on the fact that the degradation rate of poly (2-cyanoacrylate) is significantly reduced, in a medium having a pH value &lt;7, a cyanoacrylate adhesive containing gelatin-ascorbic acid microcapsules may be preferred. The addition of acidic substances (Vitamin C, citric acid and the like), in isocyanate adhesives, can delay their polymerization and degradation and, thus, their toxicity, in such a way that, cyanoacrylate adhesives butyl- or octyl, may be able to meet the requirements for internal medical use. The addition of acidic substances to the ethyl cyanoacrylate adhesive (Krazy Glue^®), can also make it suitable for medical purposes, such as bonding or closing wounds on the skin, which can lower the cost of drug adhesives, due to the fact that the cost of ethyl cyanoacrylate is much lower than that of butyl or octyl cyanoacrylate.

The shelf life of the cyanoacrylate adhesive mixed with antibiotic microcapsules in a single container may be limited and the addition of PEG may have adverse effects on the storage stability of the cyanoacrylate. A separate package for antibiotic adhesives can provide a low cost and effective solution to provide shelf life without losing operational convenience. And thus, in this way, greater flexibility can be achieved, since different combinations of cyanoacrylate and microcapsules loaded with drugs and / or additives can be used, in order to meet different practical demands.

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The description provided above herein discloses various methods and materials of the present invention. The invention is susceptible to being able to undergo modifications in the procedures and materials, as well as alterations in the manufacturing procedures and equipment. Such types of modifications will be apparent to those skilled in the art specialized in the art, from the considerations of this disclosure or practice of the invention disclosed herein. Accordingly, this invention is not intended to be limited to the specific forms of presentation disclosed herein, but rather to cover all modifications and alternatives that fall within the scope of the invention, as presented in the appended claims.