KR101258046B1 - Matrix type antimicrobial vehicle and manufacturing method thereof - Google Patents

Abstract

The present invention is a matrix layer comprising an antimicrobial agent and an adhesive; It provides an antimicrobial agent release layer formed on one side of the matrix layer; and a release layer formed on the other side of the matrix layer and a method for producing the antimicrobial agent. Since the antimicrobial vehicle of the present invention is included in the package including the medical device, the antimicrobial agent can be continuously released to the surface of the medical device or the package, so that the concentration of the antimicrobial agent on the surface of the medical device or the package can be continuously maintained even during long-term storage. .

Description

Matrix type antibacterial vehicle and its manufacturing method {MATRIX TYPE ANTIMICROBIAL VEHICLE AND MANUFACTURING METHOD THEREOF}

The present invention relates to a matrix antimicrobial vehicle that is capable of minimizing the reduction of antimicrobial agents on the surface of a medical device when the medical device is stored as a source of antimicrobial agents that continuously release the antimicrobial agent to the surface of the medical device.

There is always a risk of infection when contacting patients with medical devices or medical devices. In particular, medical devices used to be put into the body are in direct contact with tissues or body fluids in the body, thereby greatly increasing the risk of infection. Efforts have been made to introduce infection inhibitors into medical devices to reduce the risk of such infections.

Products formulated with oral cleanser toothpaste using the antimicrobial activity of triclosan have been commercially available. In addition, various studies have been conducted to use as an antimicrobial agent to adhere to the surface of the medical device. US Pat. No. 7,513,093 describes an antimicrobial suture related technology prepared by coating triclosan on a suture used during surgery. Specifically, a technique of supplying triclosan antimicrobial has been described by mixing triclosan antimicrobial with a solvent and coating the suture surface.

However, sufficient antimicrobial agents should be introduced into the medical device in order to maintain the inhibitory effect for sufficient time of use of the medical device, which may adversely affect the surface properties of the medical device and simultaneously have cytotoxicity with antimicrobial properties. It may be. In addition, the inhibitory activity should be maintained at the desired level while medical devices containing infection inhibitors are used in the body.

Therefore, there is a need to develop a technique that maintains long-term antimicrobial properties while introducing an appropriate amount of antimicrobial agent that does not adversely affect the surface characteristics of the medical equipment or does not have cytotoxicity.

In order to solve the above problems, an object of the present invention is to provide a matrix-type antimicrobial vehicle that can minimize the reduction of antimicrobial agents during storage of medical devices by continuously releasing antimicrobial agents on the surface of the medical device.

In order to achieve the above object, the present invention is a matrix layer comprising an antimicrobial agent and an adhesive; An antimicrobial agent emitting layer formed on one side of the matrix layer; And a release layer formed on the other side of the matrix layer.

In addition, the present invention comprises the steps of applying an adhesive solution containing the antimicrobial agent and the adhesive on the antimicrobial agent release layer or release layer; Drying the applied adhesive solution to form a matrix layer; And it provides a matrix-type antimicrobial vehicle manufacturing method comprising the step of laminating a release layer or antimicrobial agent release layer on the matrix layer.

In addition, the present invention comprises the steps of exposing the implantable medical device to the matrix antibacterial vehicle; And subjecting the medical device and the matrix antimicrobial vehicle to a time, temperature and pressure condition sufficient to release an effective amount of the antimicrobial agent from the matrix vehicle to the medical device. .

In addition, the present invention comprises the steps of placing the implantable medical device and the matrix antimicrobial vehicle in a package; And applying the package, the medical device and the matrix antimicrobial vehicle to a time, temperature and pressure condition sufficient to release an effective amount of the antimicrobial agent from the matrix vehicle to the medical device or package. To provide.

Since the antimicrobial vehicle of the present invention is included in the package including the medical device, the antimicrobial agent can be continuously released to the surface of the medical device or the package, so that the concentration of the antimicrobial agent on the surface of the medical device or the package can be continuously maintained even during long-term storage. .

1 is a graph showing the triclosan content detected in the suture with storage days at 55 ° C. when the matrix vehicle of Examples 1-4 and Comparative Example 1 was applied to a medical suture.

Hereinafter, the present invention will be described in detail.

The antimicrobial vehicle of the present invention is used for the purpose of adding an antimicrobial agent to a medical device or package in a package containing a medical device. The term "medical utensil" of the present invention includes medical utensils, medical devices, therapeutic and assistive devices used in surgery, and the like.

The matrix type antimicrobial vehicle according to the embodiment of the present invention includes an antimicrobial agent release layer, a matrix layer and a release layer sequentially stacked.

In one embodiment of the present invention, the antimicrobial agent may include, but is not limited to, halogenated hydroxyl ether, acyloxydiphenyl ether or mixtures thereof. For example, it may be described in US Pat. No. 3,629,477, specifically, halogenated 2-hydroxydiphenyl ether and / or halogenated 2-acyloxy diphenyl ether, more specifically 2,4,4'- called Triclosan. Trichloro-2'-hydroxydiphenyl ether can be used. Triclosan can exert antimicrobial activity against many microorganisms associated with post-operative or infection at the surgical site. Such microorganisms include, without limitation, staphylococci, epidermal staphylococci, staphylococcus aureus, methicillin-resistant epidermal staphylococci, methicillin-resistant staphylococci and combinations thereof.

In one embodiment of the invention, the antimicrobial agent may be included in 0.1 to 80% by weight, specifically 10-60% by weight based on the total weight of the matrix layer composition. When the content of the antimicrobial agent is less than 0.1% by weight, the concentration of the antimicrobial agent added to the medical device is reduced and it is difficult to impart antimicrobial properties to the medical device. When the antimicrobial agent is more than 80% by weight, the antimicrobial agent does not dissolve properly in the matrix layer and precipitates. Can be. In addition, when an appropriate amount of triclosan is added to the medical device, the medical device may be toxic by an excessive amount of triclosan.

In one embodiment of the present invention, the pressure-sensitive adhesive may include a water-insoluble acrylic polymer. The water-insoluble acrylic polymer is excellent in adhesive strength and also excellent in adhesion durability, compared to the water-soluble polymer used as an adhesive in a conventional platter or the like. In addition, since the antimicrobial agent of the present invention is almost insoluble in water and has a low melting temperature (55-57 ° C.), solubility is high in an organic solvent in which a water-insoluble acrylic polymer is dissolved, the concentration of the antimicrobial agent in the matrix layer is further increased. Can be released and slowly released while controlling the amount initially released. Accordingly, the antimicrobial vehicle of the present invention can exhibit excellent antimicrobial activity on the surface of a medical device or package for at least one year, preferably at least three years, without reducing the antimicrobial agent. In addition, by using a pressure-sensitive adhesive containing a water-insoluble acrylic polymer having excellent adhesion durability, the amount of the pressure-sensitive adhesive can be reduced, and the thickness of the vehicle can be reduced to, for example, 30-300 μm, preferably 100-200 μm, thereby providing medical equipment. The advantage of not having to change the design of the package.

In one embodiment of the present invention, the water-insoluble acrylic polymer is a homopolymer or a copolymer of two or more monomers polymerized one monomer selected from the group consisting of 2-ethylhexyl acrylate, vinyl acrylate and vinyl acrylic acid May be, but is not limited thereto.

In one embodiment of the present invention, the pressure-sensitive adhesive is included in 20 to 99.9% by weight, specifically 45-85% by weight relative to the total weight of the matrix layer composition. When the content of the pressure-sensitive adhesive is less than 20% by weight, the matrix layer and the matrix-type vehicle comprising the same are difficult to have adequate tackiness, and when the content of the pressure-sensitive adhesive exceeds 99.9% by weight, it is difficult to sufficiently support the antimicrobial agent in the matrix layer.

In one embodiment of the present invention, the matrix layer may further include a surfactant. The surfactant may include anionic, cationic, amphoteric and nonionic, and specifically may include a nonionic surfactant. The movement of the antimicrobial agent may be controlled by the nonionic surfactant to control the initial release amount of the antimicrobial agent of the present invention.

In one embodiment of the present invention, the surfactant may be further included in 0.1 to 30% by weight, specifically 1-15% by weight based on the total weight of the matrix layer composition. Surfactant can control the release of the antimicrobial component in proportion to this up to a certain amount, but the higher the content does not improve the ability to control the release.

As said nonionic surfactant, For example, glycerol monolaurate, glycerol monooleate, glycerol mono linoleate, glycerol trilaurate, glycerol trioleate, glycerol tricaprylate, propylene glycol monolaurate, propylene Glycol dilaurate, caprylic / capric triglyceride, methyl laurate, methyl caprate, isopropyl myristate, isopropyl palmitate, ethyl oleate, oleyl oleate, sorbitan monolaurate, sorbitan mono Oleate, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene stearate, polyoxyethylene-9-nonylphenyl ether, polyethylene glycol-40 Hydrogenated Castor Oil, Polyethylene One or two or more substances selected from the group consisting of recall-35 castor oil, octocinol-11, fatty acid esters of tween and fatty acid esters of span, specifically, sorbitan monooleate, glycerol monolaurate, glycerol mono One or a mixture of two or more selected from the group consisting of oleate and sorbitan monolaurate can be used.

In one embodiment of the present invention, the matrix layer may further include an alcohol. Specifically, the alcohol may be an alcohol having a molecular weight of 600 Daltons or less. Since the antimicrobial agent of the present invention exhibits high solubility in alcohols having a low molecular weight of 600 Daltons or less, the antimicrobial agent is dissolved in a high solubility in the matrix layer containing the alcohol and then applied to a certain temperature, time and pressure. Is further promoted.

In one embodiment of the present invention, the alcohol having a molecular weight of 600 Daltons or less may be a C ₁ -C ₁₂ alcohol, for example, methanol, ethanol, isopropanol, butanol, benzyl alcohol, triacetin, transcutol, propylene One or two or more mixtures selected from the group consisting of glycol, glycerin and polyethyleneglycol having a molecular weight of 600 Daltons or less. Specifically, ethanol or isopropanol can be used.

In one embodiment of the present invention, the alcohol may further include 1 to 30% by weight, specifically 1-5% by weight, based on the total weight of the matrix layer composition. This is because the alcohol improves the solubility and solubility of the antimicrobial agent to a certain amount in proportion to it, but at higher contents, the concentration of the adhesive is reduced.

In one embodiment of the present invention, when the matrix layer further comprises a surfactant and an alcohol, the surfactant: alcohol in the matrix layer may be included in a weight ratio of 1: 1 to 1: 4. By including such a content ratio, it is possible to control the initial release of the antimicrobial component.

In one embodiment of the invention, the antimicrobial release layer may be in the form of a porous film or non-woven, it may be used one or more materials selected from the group consisting of polyester, polyurethane, polyethylene and rayon. The antimicrobial agent release layer covers the matrix layer containing the antimicrobial agent and serves to help the antimicrobial agent is volatilized from the matrix layer and added to the surface of the medical device or package.

In one embodiment of the present invention, the release layer is a layer that is protected before covering the matrix layer containing the antimicrobial agent is removed immediately before the attachment before the matrix vehicle is attached to the medical device package or the like. This release layer may comprise an antimicrobial impermeable film that is commonly applied.

One embodiment of the present invention comprises the steps of applying a pressure-sensitive adhesive solution containing an antimicrobial agent and a pressure-sensitive adhesive on the antimicrobial agent release layer or release layer; Drying the applied adhesive solution to form a matrix layer; And it provides a matrix-type antimicrobial vehicle manufacturing method comprising the step of laminating a release layer or antimicrobial agent release layer on the matrix layer.

In one embodiment of the present invention, the antimicrobial agent in the matrix layer includes a halogenated hydroxyl ether, acyloxydiphenyl ether or a mixture thereof, the pressure-sensitive adhesive may comprise a water-insoluble acrylic polymer.

In one embodiment of the present invention, the matrix layer may further include at least one of a nonionic surfactant and an alcohol having a molecular weight of 600 Daltons or less.

The type and weight of the material constituting the matrix layer are as described above. The type and weight of the material constituting the antimicrobial release layer are also as described above.

In one embodiment of the present invention, the manufacturing method is applied by applying a pressure-sensitive adhesive solution containing a nonionic surfactant, an alcohol having a molecular weight of 600 Daltons or less or a mixture thereof on at least one of the antimicrobial release layer and the release layer. The method may further include forming a layer.

In the step of preparing the adhesive solution, the adhesive solution obtained by dissolving the pressure-sensitive adhesive of the present invention in an organic solvent such as n-hexane, toluene or ethyl acetate can be used, it can be dissolved by adding an antimicrobial agent to the adhesive solution. In addition, the adhesive solution may further include one or more of the surfactant of the present invention and an alcohol having a molecular weight of 600 Daltons or less.

The applying step may be carried out by spraying a solution containing these volatile components in a spray method, or by applying a predetermined amount through a nozzle.

The coated adhesive solution may be dried at a high temperature of 80-120 ° C. for a short time of 1 to 10 minutes, and the organic solvent included in the adhesive solution may be removed by evaporation.

An embodiment of the present invention provides an antimicrobial medical device package comprising the implantable medical device and the matrix antibacterial vehicle.

Antimicrobial vehicles of the present invention include, but are not limited to, implantable medical devices, for example, surgical sutures such as multi or monofilaments, surgical meshes, suture clips, suture anchors, orthopedic absorbent pins and It can be applied to a package including the screw, the anti-adhesion mesh and the anti-adhesion film, the hernia fixing device, the stent, the catheter and the like. It also includes implantable medical devices that are absorbent and nonabsorbable. The medical device or package to which the antimicrobial vehicle to which the present invention is applied may or may not already include an antimicrobial agent.

The matrix-type antimicrobial vehicle produced by the present invention is attached to the package of the medical device serves as a source for supplying the antimicrobial agent to the medical device and the package.

One embodiment of the invention provides a time sufficient to expose an implantable medical device to the matrix antimicrobial vehicle and to release the medical device and the matrix antimicrobial vehicle an effective amount of antimicrobial agent from the matrix vehicle to the medical device. The present invention provides a method for producing an antimicrobial medical device comprising the step of applying to temperature and pressure conditions. Sufficient temperature, time and pressure conditions in the production method may be a condition of 30 ℃ ~ 80 ℃, 3 ~ 19 hours, atmospheric pressure or reduced pressure.

One embodiment of the present invention provides a method of disposing an implantable medical device and the matrix antimicrobial vehicle in a package, and placing the package, the medical device and the matrix antimicrobial vehicle in an effective amount from the matrix vehicle to the medical device or package. It provides a method for producing an antimicrobial medical device comprising the step of applying to a time, temperature and pressure conditions sufficient to be released. Sufficient temperature, time and pressure conditions in the production method may be a condition of 30 ℃ ~ 80 ℃, 3 ~ 19 hours, atmospheric pressure or reduced pressure.

Medical devices are sterilized or dried in a package. When the matrix type antimicrobial vehicle of the present invention is attached to a package of a medical device, the antimicrobial agent is added to the medical device or package by releasing the antimicrobial agent during sterilization or drying. Since the antimicrobial agent is continuously released from the antimicrobial vehicle, the amount of antimicrobial agent on the surface of the medical device can be kept constant. Placing the matrix antimicrobial vehicle of the present invention in a package containing a medical device and then sterilizing or drying the package and the medical device are sufficient to release an effective amount of the antimicrobial agent from the matrix vehicle into the medical device or package, eg For example, temperature, time and pressure conditions are 30 ° C. to 80 ° C., 3 to 19 hours, sterilized or dried under atmospheric or reduced pressure to allow the antimicrobial agent to adhere to the medical device and package surface.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Experimental Example  1) Matrix type antibacterial Vehicle  Manufacture and measurement of microbial growth inhibition area

In the following method, a matrix-type vehicle (Examples 1 to 4) was prepared by placing and laminating a matrix layer containing an antimicrobial agent between the antimicrobial agent release layer and the release layer, and the composition components of the matrix layer are shown in Table 2 below. .

An acrylate pressure sensitive adhesive (National Starch & Duro-Tak, 87-2196) was added to a 50 ml sample bottle, and triclosan, which is the antimicrobial agent in Table 2, was added thereto, followed by stirring at 200 rpm until the pressure-sensitive adhesive solution was completely uniform. . In order to remove the bubbles in the adhesive solution, the mixture was left for 10 minutes or more to prepare an adhesive solution.

Then, the adhesive solution is applied onto the peeling film (3; 3M Scotchpak 9744, 1022, 3M paper release liner 1361, 9743), using a lab coater and dryer (Mathis, Switzerland) at 80 to 120 ℃ It dried at high temperature for 8 to 12 minutes, and formed the peelable film and a matrix layer.

An antimicrobial release layer nonwoven fabric (Vilene nonwoven polyester, 3M nonwoven polyurethane 9905, 3M spunlaced nonwoven polyester 1538, 3M rayon nonwoven 1533, 3M rayon acetate) was placed on the matrix layer formed above and laminated to prepare a 2 cm x 2 cm matrix vehicle.

After attaching the matrix-type vehicle on a medical paper, neosorb suture (Samyang Co., Ltd.) was wound to an appropriate size, wrapped in paper, and placed in an aluminum package, and dried for about 5 hours by alternating nitrogen and reduced pressure at 20 to 60 ° C. Afterwards, sterilization was performed at 40-80 ° C. for about 2-8 hours while adding humidification and ethylene oxide gas (Ethylene oxide gas) so that the humidity was 10-60%. In order to remove residual ethylene oxide gas and dry moisture, the resultant was dried at 40 to 80 ° C. under reduced pressure for about 4 to 16 hours.

The suture was then removed from the package, and the antimicrobial content on the suture surface was measured according to the instrument operating conditions of Table 1 using HPLC and the results are shown in Table 2. In order to measure the antimicrobial content, the suture was chopped to 1 cm or less, and 500 mg was precisely taken and 10 mL of methanol was added and stirred at 150 rpm for 1 hour. The solution was filtered through a 0.45 um syringe filter, and 2 mL of the filtrate was used as a sample solution. The content of triclosan was measured.

In Comparative Example 1, kraft paper was immersed in a 5% by weight triclosan solution, dried and sterilized in the same manner as in Example, and the antimicrobial content was measured. In Comparative Example 2, the composition of the matrix layer was the same as that of Example 2, but the vehicle was prepared without the antimicrobial agent release layer, and the antimicrobial agent content was measured by the same method.

One) Device name : High Speed Liquid Chromatograph 2) column : Columns or similar columns packed with 5 µm octadecyl silylated silica gel in a 4.6 mm inner diameter and 150 mm length tube 3) Mobile phase : Dissolve 6.5 g of sodium phosphate in 1000 mL of water, mix with 1000 mL of isopropyl alcohol, and add 6 g of sodium lauryl sulfate. Phosphoric acid was added to this solution, which was adjusted to pH 3.0 as a mobile phase. 4) Flux : 1.0 mL / min 5) Temperature : 40 ℃ 6) Dose : 10 μl 7) Detector : UV Absorbance Spectrometer (239nm)

division Composition Components of the Matrix Layer (Weight%) Antibacterial amount of suture surface
(ug / g) Triclosan USP Acrylate adhesive ethanol Sorbitan monooleate Example 1 20 80 - - 150 Example 2 25 75 - - 250 Example 3 28 70 6 6 300 Example 4 28 70 3 9 300 Comparative Example 1 650 Comparative Example 2 25 75 - - 300

In addition, the suture was removed from the Examples and Comparative Examples package, and the microbial growth inhibition test area was measured by the disk diffusion method with reference to KISO20645. That is, Staphylococcus aureus grown in trypsin digested soybean broth at 37 ° C. for 24 hours was diluted with sterile 0.85% saline at a concentration of approximately 1 × 10 ⁶ to 10 ⁸ cfu (colony forming units) / ml. For the bacterium-free underlayer, 10 ml of agar was prepared, condensed in sterile Petri dishes. For the upper layer, 150 ml of agar was inoculated with 1 ml of Inoculum having a bacterial concentration of 1.5 x 10 ⁸ cfu / ml, and the mixture was stirred vigorously to mix well. 5 ml of agar was poured into each Petri dish and allowed to coagulate. The 5 cm long suture was in contact with the medium and incubated at 37 ° C. for 24 hours. After incubation, bacterial growth was confirmed and the inhibition zone (inhibition zone) was measured. The measurement was performed from the suture to the edge of the region in which proliferation was suppressed.

microbe NO. sample water at least maximum Average Staphylococcus aureus Example 1 3 10 12 11 Example 2 3 14 16 15 Example 3 3 22 26 24 Example 4 3 20 25 23 Comparative Example 1 3 30 40 35 Comparative Example 2 3 18 24 21 Epidermal Staphylococcus Example 1 3 11 12 12 Example 2 3 16 18 17 Example 3 3 25 27 26 Example 4 3 24 26 25 Comparative Example 1 3 35 37 36 Comparative Example 2 3 20 25 23

Experimental Example  2) Comparison of antimicrobial content detected in suture

The suture of the present invention was stored at 55 ° C. and the triclosan content detected in the suture was compared and shown in FIG. 1.

In Comparative Example 1, the triclosan content was drastically decreased as the storage time elapsed, but the vehicle of the present invention suggested that the suture surface was kept constant by supplying an antimicrobial agent to the suture to provide a stable suture. . In Comparative Example 2, the content of the antimicrobial agent in the suture was maintained for a period of time compared with the embodiment of the present invention, but it was found that the extent of the antimicrobial reduction was large at the beginning. It was found that the antimicrobial agent release layer initially serves to prevent the antimicrobial agent from being released in excess and to maintain the antimicrobial content uniformly.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (3)

Implantable medical supplies,
An antimicrobial agent comprising halogenated hydroxyl ether, acyloxydiphenyl ether, or mixtures thereof, based on the total weight of the matrix layer composition; Pressure-sensitive adhesive comprising a water-insoluble acrylic polymer which is one homopolymer or two or more copolymers selected from the group consisting of 2-ethylhexyl acrylate, vinyl acrylate and vinyl acrylic acid, which is 20 to 85% by weight based on the total weight of the matrix layer composition; Nonionic surfactant is 0.1 to 30% by weight based on the total weight of the matrix layer composition; And an alcohol having a molecular weight of 600 Daltons or less that is 1 to 30% by weight based on the total weight of the matrix layer composition.
An antimicrobial agent emitting layer formed on one side of the matrix layer and composed of a porous film or a nonwoven fabric made of at least one material selected from the group consisting of polyester, polyurethane, polyethylene, and rayon; And
Exposing to a matrix antimicrobial vehicle comprising a release layer formed on the other side of the matrix layer; And
Method for producing an antimicrobial medical device comprising the step of applying the medical device and the matrix antibacterial vehicle at 30 ℃ ~ 80 ℃, 3 ~ 19 hours, atmospheric pressure or reduced pressure. Implantable medical supplies,
An antimicrobial agent comprising halogenated hydroxyl ether, acyloxydiphenyl ether, or mixtures thereof, based on the total weight of the matrix layer composition; Pressure-sensitive adhesive comprising a water-insoluble acrylic polymer which is one homopolymer or two or more copolymers selected from the group consisting of 2-ethylhexyl acrylate, vinyl acrylate and vinyl acrylic acid, which is 20 to 85% by weight based on the total weight of the matrix layer composition; Nonionic surfactant is 0.1 to 30% by weight based on the total weight of the matrix layer composition; And an alcohol having a molecular weight of 600 Daltons or less that is 1 to 30% by weight based on the total weight of the matrix layer composition.
An antimicrobial agent emitting layer formed on one side of the matrix layer and composed of a porous film or a nonwoven fabric made of at least one material selected from the group consisting of polyester, polyurethane, polyethylene, and rayon; And
Positioning a matrix type antimicrobial vehicle in a package, the release layer formed on the other side of the matrix layer; And
A method of manufacturing an antimicrobial medical device comprising the step of applying a package, a medical device and the matrix antimicrobial vehicle at 30 ° C. to 80 ° C., for 3 to 19 hours, at atmospheric pressure or under reduced pressure. 3. The method according to claim 1 or 2,
The surfactant and the alcohol is a method of producing an antimicrobial medical device will be included in a weight ratio of 1: 1 to 1: 4.

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