Chlorhexidine gluconate-containing solvent adhesive

0001This application claims the priority of US provisional application 61/434991 (filed on January 21, 2011), the entire contents of which are incorporated herein by reference.

0002The present invention particularly relates to a method of incorporating a chlorhexidine salt, which is chlorhexidine gluconate, into an adhesive, a chlorhexidine salt-containing adhesive, and a product using such an adhesive.

0003A wide range of medical products utilize adhesives to attach the product to the user's skin. It will be appreciated that it is desirable to prevent, or at least minimize, the growth of microorganisms at the contact between the adhesive and the skin, which can easily lead to infections and other unwanted situations.

0004Therefore, technicians have included a wide range of antibacterial agents in medical products or materials. Although some of such antibacterial agents have already been utilized in adhesives, their effective inclusion in adhesive compositions poses technical problems for many other antibacterial agents. It is difficult to effectively diffuse such antibacterial agents in the adhesive. In addition, certain antibacterial agents lose their efficacy as they are contained.

0005Chlorhexidine gluconate has a broad antibacterial spectrum, is safe and is well accepted on the market. However, chlorhexidine gluconate has never been used in solvent-based acrylic adhesives, which are standard for surgical use, due to their low cost and good adhesion to dry and wet skin.

0006Therefore, it would be desirable to provide a method of incorporating chlorhexidine gluconate into the adhesive composition so that the compound is efficiently diffused when present in the adhesive and retains its efficacy.

<p num="0007"> Difficulties and shortcomings associated with conventionally known compositions, products and utilization are addressed by the methods of the invention, adhesive compositions, products with such compositions and related uses.</p>

<p num="0008"> In one feature, the present invention provides a method for producing chlorhexidine in solid form. This method involves the step of preparing an aqueous solution of at least one chlorhexidine salt. The method also includes the step of positively drying the aqueous solution to obtain its at least one solid form of chlorhexidine salt.</p><p num="0009"> In another feature, the present invention provides a method of making an adhesive containing chlorhexidine. The method comprises the step of providing an aqueous solution of at least one chlorhexidine salt and the step of actively drying the aqueous solution to obtain the at least one solid form of the chlorhexidine salt. The method further comprises providing an adhesive component and providing a solvent compatible with the adhesive component. This method dissolves the solid form of chlorhexidine in its solvent to create a chlorhexidine solution. It includes more steps to solve. In addition, the method further comprises the step of creating an adhesive-containing chlorhexidine by combining the chlorhexidine solution with the adhesive component.</p><p num="0010"> In yet another feature, the present invention provides an adhesive formulation containing chlorhexidine. The adhesive formulation comprises an adhesive and at least one chlorhexidine salt.</p><p num="0011"> In yet another feature, the present invention provides a medical product having an adhesive with antibacterial properties. This medical product contains an adhesive formulation containing chlorhexidine.</p><p num="0012"> It will be appreciated that the present invention can also be practiced in other different embodiments, the details of which can be modified in various ways without departing from the scope of the invention. Therefore, the description of the present invention is exemplary and does not limit the present invention.</p>

0013<figref num="1">It is a graph which shows the antibacterial performance of the various adhesive samples explained here.</figref><figref num="2">It is a graph which shows the antibacterial property of various adhesive samples explained here.</figref>

0014The inclusion of chlorhexidine gluconate (CHG) in solvent-based adhesives is believed to have not been achieved due to the physical and chemical properties of chlorhexidine gluconate. For example, chlorhexidine gluconate is highly hydrophilic and can only be dissolved in methanol and acetone. More typically, chlorhexidine gluconate is commercially available in 20% or 40% by weight in aqueous formulations. The aqueous formulation cannot be easily combined with solvent-based adhesives. Chlorhexidine gluconate is sensitive to high temperatures, limiting subsequent treatment that would otherwise be required for inclusion in the adhesive. When further dried by evaporation, the compound cannot easily diffuse into the solvent. This presents another difficulty in attempting to include this compound in solvent-based adhesives.

0015The present invention provides a unique approach for incorporating chlorhexidine gluconate into solvent-based adhesives such as solvent-based acrylic adhesives that are widely used in medical and surgical applications. In this novel method, chlorhexidine gluconate is preferably contained in a solvent-based adhesive by freeze-drying or spray-drying aggressive drying of chlorhexidine gluconate to obtain a powder. The powder is then dissolved in a solvent compatible with the target adhesive, such as an acrylic adhesive. One example of a suitable solvent for a typical acrylic adhesive is methanol.

0016Chlorhexidine Chlorhexidine is a chemical preservative and is commonly used as an antibacterial agent. Effective against both Gram-positive and Gram-negative bacteria, but less effective against some Gram-negative bacteria. It has a bactericidal action and a bacterial growth inhibitory function, and its mechanism of action is membrane disruption, not ATPase inactivation as previously thought. It is also available for fungi and enveloped viruses, but has not been studied in depth. Products containing high concentrations of chlorhexidine should be kept away from the eyes and ears due to the risk of injury. However, chlorhexidine is safely used at very low concentrations, for example in some contact lens solutions.

0017Chlorhexidine gluconate (also known as chlorhexidine digluconate) is a salt of chlorhexidine and gluconic acid. The structural formula of chlorhexidine gluconate is<chemistry num="1"><img id="000002" he="24" wi="112" file="JP2017036282A_D0001.tif" img-format="tif" img-content="drawing" /></chemistry>Is. This compound is actually a digluconate compound and is commonly referred to as chlorhexidine gluconate.

0018Thus, the term "chlorhexidine gluconate" used herein includes digluconate compounds. In addition, the terms "chlorhexidine gluconate" and "chlorhexidine digluconate" are used interchangeably here.

0019Pharmaceutically acceptable chlorhexidine salts that can be used as antibacterial agents by the present invention include, but are not limited to, chlorhexidine palmitate, chlorhexidine diphosphanite, chlorhexidine dihydrochloride, chlorhexidine diacetate, and chlorhexidine digluconate. The chlorhexidine free base is another example of an antibacterial agent.

0020As described above, the present invention provides a method for containing one or more chlorhexidine salts, which are chlorhexidine gluconate, in a solvent-based adhesive such as an acrylic adhesive. Although the present invention is specifically intended to contain chlorhexidine gluconate, the present invention can also be used for other chlorhexidine salts and related compounds. Any chlorhexidine salt, generally provided or produced in aqueous or liquid form, is a candidate for the various suitable forms of the invention described herein.

0021Aggressive drying method Water and / or other solvent or liquid is removed or separated from the chlorhexidine salt by one or more active drying methods. This "active drying method" refers to any method other than passive evaporation of the liquid that removes or separates the liquid, which is typically water, from the chlorhexidine salt. Passive evaporation refers to evaporation of a liquid component at atmospheric temperature without the use of an air stream or other fluid stream to assist in removing or separating the liquid component from the chlorhexidine salt.

0022As described above, the active drying used here is heat-accelerated evaporation, which utilizes an air flow on a liquid also known as an air action drying method or supplies heat energy to a liquid also known as a hot air drying method. It refers to, but is not limited to, a wide range of liquid removal techniques such as drying by exposure to electromagnetic waves such as electromagnetic energy, freeze-drying, and active evaporation such as spray-drying. A combination of these and other drying methods can also be used. Preferably, the active drying method is carried out by a freeze-drying method or a spray-drying method.

0023The freeze-drying method is a dehydration method typically used to store perishable materials or to make them more convenient for transportation. The freeze-drying method is typically carried out by freezing the material and directly sublimating the frozen moisture in the material from a solid to a gas by lowering the ambient air pressure and adding sufficient heat.

0024A suitable method according to the invention is freeze-drying a 20% (all percent is weight percent unless otherwise specified) solution of chlorhexidine gluconate. The freeze-drying process can be performed in almost any form. In one embodiment of the invention, 2 A solution of 0% chlorhexidine gluconate and 80% water is completely frozen by placing the solution at a temperature of about -20 ° C under a pressure of about 0.180 bar for about 24 hours. It will be understood that these temperatures, pressures and times are merely examples. The present invention includes a wide range of freeze-drying conditions. Typically, the temperature is from about -80 ° C (or less) to about 10 ° C (or higher), preferably from about -50 ° C to about 0 ° C. Atmospheric pressure typically ranges from about 0.01 bar to about 0.95 bar, preferably between about 0.10 bar and about 0.50 bar. Typical time is seconds to days.

0025Preferably, the aqueous chlorhexidine gluconate solution is placed in a container that increases the surface area of the solution. It will be appreciated that increasing the surface area of the solution to promote heat conduction reduces the time required to freeze the aqueous chlorhexidine gluconate solution. The increase in surface area promotes the movement and sublimation of water from the frozen mass, thereby leaving a residual component of chlorhexidine gluconate.

0026It will be appreciated that the preferred method described herein utilizes a 20% chlorhexidine gluconate solution that is subsequently freeze-dried, but the invention is not limited thereto. As mentioned above, chlorhexidine gluconate is also typically available as a 40% aqueous solution and can be freeze-dried as described here. The use of an aqueous solution having a concentration from about 1% to the dissolution limit of the compound is expected. Typically, for many chlorhexidine salts, they are commercially available in the form of aqueous solutions at concentrations of about 1% to about 60%.

0027During the freeze-drying process, the aqueous solution is initially frozen to form a solid, after which at least part of the water is removed from the solid by sublimation. The present invention includes a step of partially removing water components by a technique or operation other than freeze-drying treatment. However, it is preferred that at least most and most preferably all water be removed by freeze-drying.

0028Another suitable active drying technique is the spray drying method. The spray-drying method is a method of producing a dry powder from a liquid or slurry by quickly drying it with a hot gas. This is a suitable method for drying thermally sensitive materials such as foods and chemicals. The dispersed state of a constant particle size is one of the reasons for spray-drying industrial products such as catalysts. Air is typically the heating and drying medium. However, nitrogen can be utilized if the liquid is a flammable solvent or if the product is sensitive to oxygen.

0029All spray dryers utilize a sprayer or spray nozzle to diffuse the liquid or slurry into a controlled drop size spray. The most common are rotary nozzles and single fluid pressure swirl nozzles. Alternatively, depending on the usage pattern, a two-fluid or ultrasonic nozzle is used. Depending on the treatment conditions, water droplet sizes from 10 micrometers to 500 micrometers can be achieved by selecting the appropriate nozzle. The most common water droplet sizes range in diameter from 100 micrometers to 200 micrometers. The resulting dry powder is often free-flowing.

0030The thermodry gas can pass in parallel or backflow in the direction of the atomizer. Parallel flow can reduce the time the particles stay in the system and allow the particle separator (typically a cyclone device) to work more efficiently. The backflow method can extend the residence time of particles in the chamber and is usually used with fluidized bed systems.

0031Additional techniques and / or other active drying methods can include, for example, a combination of spray-drying and freeze-drying methods. Inclusion of chlorhexidine in adhesives

0032After making a powder of chlorhexidine gluconate or other salt by one or more aggressive drying methods, optionally involving one or more size reduction steps, the powder is in particle form chlorhexidine gluconate in one or more suitable solvents such as methanol. It can be easily stabilized by adding to. Chlorhexidine gluconate is added in an amount that easily dissolves the compound in its solvent. For the use of methanol as a solvent, chlorhexidine gluconate concentrations have been found to be acceptable in the range of about 15% to about 20%. However, it will be understood that the present invention also includes the use of concentrations above or below these values.

0033After dissolving the powder of chlorhexidine gluconate (or other salt of chlorhexidine) in a suitable solvent, the chlorhexidine gluconate solution is contained in the solvent-based adhesive. Typically, this is done by adding the solution directly to the adhesive component or adhesive formulation, or by including it in some way.

0034The adhesive-containing chlorhexidine salt is then incorporated or used in the product as desired. Conventional coating and drying methods can be performed, for example, to form an adhesive layer on a medical product. Non-limiting examples of such medical products include incision films and device fixation products, wound treatment products and surgical products such as stoma pouches.

0035In some embodiments, the adhesive is preferably covered with a polyurethane membrane or other carrier of another material.

0036adhesive The methods of the invention can be used to include chlorhexidine salts, such as chlorhexidine gluconate, in a wide variety of adhesives, preferably solvent-based adhesives. Examples of non-limiting adhesives include acrylic adhesives, rubber adhesives, silicone adhesives, polyurethane adhesives and variants and combinations thereof. In general, the resulting chlorhexidine salt, preferably chlorhexidine gluconate, can be included in any non-aqueous base adhesive. Preferably the adhesive is a solvent-based adhesive. More preferably, the adhesive is a solvent-based acrylic adhesive.

0037The present invention also includes the step of combining the chlorhexidine powder produced by the methods described herein with an adhesive component and / or an adhesive such as an adhesive premix. This method provides another approach for the subsequent production of chlorhexidine-containing adhesives.

0038One or more chlorhexidine salts are contained in an adhesive in an adhesive formulation or adhesive intermediate by combining a solution, mixture or dispersion containing a chlorhexidine salt, and the resulting mixture is adhered by one or more drying methods. It is also envisioned to remove the liquid component from the mixture of agent and chlorhexidine salt.

0039In the embodiment where chlorhexidine is in the form of particles, another advantage is obtained when the particles are contained in the hydrophobic adhesive matrix. Due to this hydrophobic property, chlorhexidine, especially chlorhexidine gluconate, will be easily released from the hydrophobic adhesive matrix.

0040Additional additives One or more additional additives can be included in the adhesive and chlorhexidine formulation Wear. Preferably, this additional additive comprises a drug compound. Such drug compounds include bactericides, antibiotics, antibacterial agents, antiviral agents, anticoagulants, anesthetics, anti-inflammatory agents, analgesics, anticancer agents, vasodilators, wound remedies, vasculature. Includes, but is not limited to, forming agents, vasopressors, immunopotentiators, growth factors, and other biologics. Suitable fungicides include biguanide compounds, triclosan, penicillin, tetracycline, gentamicin and tobramycin.^TMAminoglucosides such as polymyxin, rifampicin, bacitracin, erythromycin, vancomycin, neomycin, chloramphenicol, myconazole, oxolinic acid, norfloxacin, nalidixic acid, pefoxacin, enoxacin, and quinolone antibacterial agents such as ciprofloxacin Includes, but is not limited to, amide, nonokinol 9, fujicinic acid, cephalosporin and combinations thereof and similar compounds. These additional fungicide compounds provide improved fungicidal activity.

0041Depending on the mode of use, the adhesive composition may contain one or more absorbents. One example of a suitable absorbent is a hydrophilic colloidal agent. The hydrophilic colloidal agent may be linear or crosslinkable. Suitable hydrophilic colloidal agents include synthetic hydrophilic colloidal agents such as sodium carboxymethyl cellulose and natural products such as gelatin, pectin, guar gum, locust bean rubber, tragacant rubber, rubber karaya, starch, rubber arabic, alginic acid and its sodium and / or calcium salts. Is included. In addition, synthetic hydrophilic colloidal agents such as polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, polyacrylic acid, polyhydroxyacrylic acrylate, polyacrylamide, high molecular weight polyethylene glycol and polypropylene glycol can be used. Other hydrophilic colloidal agents include crosslinked or crystalline sodium carboxymethyl cellulose, cross-linked dextran and starchy acrylonitrile graft copolymers.

<p num="0042"> Tests were conducted to evaluate the processability of the adhesive containing the chlorhexidine agent and the bactericidal efficacy of the obtained compound. The adhesive composition contained adhesive components, absorbents and fungicides.</p><p num="0043"> A list of raw materials is shown in Table 1.</p><p num="0044"><tables num="1"><img id="000003" he="52" wi="169" file="JP2017036282A_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0045"> 1807 Adhesive is an acrylic adhesive commercially available from Avery Denison. AVC-12363 adhesive is also available from Avery Denison and is a solvent acrylic adhesive suitable for medical use such as adhesive coatings, fixing devices and incision membranes.</p><p num="0046"> A sample of the composition was prepared as follows. Freeze 20% chlorhexidine aqueous solution Rye processed. Wet adhesive was weighed and added to the breaker. A800 carboxymethyl cellulose (particle size less than 75 μm) was added directly to the adhesive under mixing at 800 rpm.</p><p num="0047"> The freeze-dried chlorhexidine gluconate powder was dissolved in methanol at a concentration of 15%. Chlorhexidine gluconate was then added to the adhesive under mixing at 800 rpm.</p><p num="0048"> An adhesive containing carboxymethyl cellulose and chlorhexidine gluconate was allowed to stay in a mixed state at 800 rpm for 30 minutes.</p><p num="0049"> The adhesive was then coated on the BG684 release liner with 100gsm. The coating speed was 4 m / min.</p><p num="0050"> The coating was dried in the oven at 95 ° C for 15 minutes.</p><p num="0051"> Using Med5575A as a carrier, it was manually laminated on the coating.</p><p num="0052"> As shown in Table 2, the following test methods were used for the evaluation multi-layer prototype.</p><p num="0053"><tables num="2"><img id="000004" he="51" wi="113" file="JP2017036282A_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0054"> For testing, T06 / 022 corresponds to EN13726. Details regarding T04 / 001 and T04 / 095 are as follows.</p><p num="0055">T04 / 001-Finat Tack on glass Definition: The tack property of a pressure-sensitive material is to separate loops of material that are in instant (or substantially instantaneous) contact with a specific area of the datum without the use of external pressure for more complete contact. It is a necessary force.</p><p num="0056"> Meaning: Tuck is a measure of the ability of a tape to bond instantly with minimal pressure.</p><p num="0057"> Test Specimen: The test specimen was 25 mm wide and 150 mm long. The test specimen was cut with a suitable cutter at right angles to the machine direction.</p><p num="0058"> Equipment: A flat "float process" glass plate with a minimum thickness of 3.0 mm was used. A metal peg was attached to the center of the plate. The dimensions of the pegs must be such that the pegs are tightened into the lower jaw of the adhesive tester. A 37 micron polyester film is used.</p><p num="0059"> Test method: The glass panel was cleaned before the test. To determine tack, the sides of the untested glass were covered with a 37 micron polyester film. The test piece was 25 mm wide and 150 mm long. The cut surface should be smooth and straight. The backing of each test piece was removed shortly before the test was performed. The test samples were arranged as follows. Both ends of the sample were held and formed in a loop, and the adhesive surface was directed outward by aligning the ends. The free ends were covered with polyester to protect the chin of the adhesive tester from the adhesive coating. The edges of the polyester-protected sample were placed between the jaws to form a 150 mm loop. The tester was started and the loop was brought into contact with the glass plate at a speed of 300 mm / min. When full contact with the glass plate (25 mm x 25 mm) was achieved, the direction of the tester was immediately reversed and separated at a rate of 300 mm per minute. It is important that the delay in the reverse direction is minimized. The maximum force required to completely separate the loop from the glass plate was recorded.</p><p num="0060"> Report: The tack report contains the tack value of Newton value (N / m) per meter width. If anything other than 25 mm wide is tested, the Newton value per meter is obtained by dividing the observed value by the width of the specimen. If it is reported which side of the tape the value represents (laminated side or mounting side) and the value is obtained from the test width deviation, then this sample width must also be recorded. Specimen stiffness affects results and must be taken into account when comparing different adhesives on different carriers. Report the tack value in Newton value per width (N / m).</p><p num="0061">T04 / 095-Peel adhesive to matt flex polyethylene in CD (4.5 lbs, 20 minutes), all products coated with acrylic adhesive were used Definition: Peel adhesion to polyethylene is the force (average) required to remove pressure-sensitive tape from a test panel at a particular angle and speed using a defined pressure that establishes contact.</p><p num="0062"> Equipment: The following equipment was used for this evaluation. Adhesive tester Aluminum panel (15 cm x 15 cm) DC tape 2050g roller (4.5 lbs) ASTM D1000 Polyetile Nfoiru (25 [mu] m) (reference PE testing side is typically the inner surface of the roll) Supplier ACE Pretreatment Ref7660 Female side Paper piece 25 x 230 mm Paper (without lacquer)</p><p num="0063"> Sample Preparation: The test material and polyethylene test substrate were prepared for 24 hours at a temperature of 23 ± 2 ° C and a relative humidity of 50 ± 2% at that temperature. The DC tape was laminated on the aluminum panel. The untreated side of the polyethylene foil was laminated on a self-adhesive aluminum panel with a hard rubber roller. The test specimen was 25 mm wide and about 150 mm long. The test specimen was machine oriented with a suitable cutter. The edges of the pieces of paper were laminated by overlapping ± 1 cm.</p><p num="0064"> Measurements: The liner (lining) of the test specimen was removed and the test specimen was transversely laminated on polyethylene foil. Samples were rolled on ASTM rollers at a constant speed of 150 cm / min. After waiting for 20 minutes, the measurement with the adhesive tester was started. The edges of the piece of paper were tightened with the upper grip and the aluminum panel was tightened with the lower grip. Pieces of paper and aluminum The test angle with the nium panel was 90 °.</p><p num="0065"> Report: 90 ° peel is the average value required to remove the test specimen from the test substrate (N / 25 mm).</p><p num="0066"> Prototypes were prepared based on two types of adhesives. 1807 was selected because it is a well-known form of use in negative wound treatment (NPWT) (long-term use on the skin). AVC-12363 was selected because of its polymer structure. AVC-12363 does not contain the -COOH functional group.</p><p num="0067"> Tables 3 and 4 outline the performance and characteristics of the multilayer structures formed using the adhesive compositions described herein. The name "FD CHG" in the "Antibacterial Agent" column is the freeze-dried chlorhexidine gluconate described here. "AXM" refers to antibacterial efficacy. "PAPE" is the adhesiveness to polyethylene. FHC is the fluid processing performance, and NT is the untested state.</p><p num="0068"><tables num="3"><img id="000005" he="244" wi="156" file="JP2017036282A_D0001.tif" img-format="tif" img-content="drawing" /></tables><img id="000006" he="249" wi="154" file="JP2017036282A_D0001.tif" img-format="tif" img-content="drawing" /><img id="000007" he="108" wi="166" file="JP2017036282A_D0001.tif" img-format="tif" img-content="drawing" /></p><p num="0069"><tables num="4"><img id="000008" he="190" wi="166" file="JP2017036282A_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0070"> In all the samples evaluated, the inclusion of chlorhexidine gluconate in the adhesive was found to have no significant effect on adhesion.</p><p num="0071"> The bactericidal efficacy was also evaluated.</p><p num="0072"> Initially, bactericidal efficacy assessments were performed according to ASTM 2180 in both samples containing and without carboxylmethyl cellulose. The reason for this choice is as follows. 1807 with a high concentration of -COOH functional groups would be able to suppress the release of positively charged chlorhexidine gluconate. In addition, carboxymethyl cellulose is an anionic polymer that can retain chlorhexidine gluconate. To.</p><p num="0073"> Two concentration levels of chlorhexidine were tested. High levels of chlorhexidine gluconate (9% CHG to 100gsm adhesive) were evaluated. This high concentration was selected to assess whether it is possible to achieve a bactericidal effect. Intermediate levels of chlorhexidine bases (5% chlorhexidine bases in 45gsm and 100gsm) were also tested. The chlorhexidine base showed low solubility in water, thus showing the worst case.</p><p num="0074"> Figures 1 and 2 show the antibacterial effects of various samples. The data in these figures were based on all 100gsm coated adhesives. Figure 1 shows the bactericidal effect of ASTM 2180 without reinoculation.</p><p num="0075"> In conclusion, the bactericidal effect of prototypes containing 1807 or AVC-12363 and containing or not containing carboxymethyl cellulose (A800) was similar to that of high concentrations of chlorhexidine gluconate (Figs. 1 and 2). reference). Neither carboxymethyl cellulose nor the -COOH functional group of the 1807 adhesive seemed to suppress its bactericidal effect.</p><p num="0076"> Adhesives, adhesive inclusions, structures and other ingredients for multi-layer structures are provided in US 2010/0322996.</p><p num="0077"> Other benefits will become apparent in future uses and research of this technology.</p><p num="0078"> The entire contents of all patents, gazettes and references cited herein are incorporated herein by reference.</p><p num="0079"> It will be appreciated that one or more features or elements of one embodiment described herein can be combined with one or more features or elements of another embodiment. Accordingly, the present invention includes all combinations of elements or features of the examples described herein.</p><p num="0080"> As mentioned above, the present invention solves many problems associated with existing products, adhesives and methods. However, those skilled in the art will appreciate the various changes in details, materials and ingredients and processes described herein to illustrate the features of the invention as described in the appended claims. And it will be understood that it can be carried out without departing from the scope.</p>