(19)
(11)EP 2 665 363 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
25.12.2019 Bulletin 2019/52

(21)Application number: 12702693.8

(22)Date of filing:  23.01.2012
(51)Int. Cl.: 
A61K 9/14  (2006.01)
A61L 24/00  (2006.01)
A01N 47/44  (2006.01)
C09J 11/06  (2006.01)
A61L 24/04  (2006.01)
(86)International application number:
PCT/US2012/022162
(87)International publication number:
WO 2012/100244 (26.07.2012 Gazette  2012/30)

(54)

CHLORHEXIDINE GLUCONATE CONTAINING ADHESIVE

CHLORHEXIDINGLUCONAT ENTHALTENDER KLEBSTOFF

ADHESIF CONTENANT DU GLUCONATE DE CHLORHEXIDINE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 21.01.2011 US 201161434991 P

(43)Date of publication of application:
27.11.2013 Bulletin 2013/48

(73)Proprietor: Avery Dennison Corporation
Pasadena, CA 91103 (US)

(72)Inventors:
  • WIBAUX, Anne, Marie
    B-2018 Antwerpen (BE)
  • VAN DE POL, Vicky
    B-2300 Turnhout (BE)

(74)Representative: Müller-Boré & Partner Patentanwälte PartG mbB 
Friedenheimer Brücke 21
80639 München
80639 München (DE)


(56)References cited: : 
EP-A2- 1 203 531
WO-A1-00/61692
US-A- 5 382 451
US-A1- 2010 022 654
WO-A1-00/36353
WO-A1-93/00118
US-A1- 2002 018 814
  
  • GIUNCHEDI P ET AL: "Formulation and in vivo evaluation of chlorhexidine buccal tablets prepared using drug-loaded chitosan microspheres", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, NL, vol. 53, no. 2, 1 March 2002 (2002-03-01), pages 233-239, XP004342819, ISSN: 0939-6411, DOI: 10.1016/S0939-6411(01)00237-5
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description


[0001] The present invention relates to methods for incorporating chlorhexidine gluconate into an adhesive.

[0002] A wide array of medical products use adhesive for affixing the product onto a user's skin. As will be appreciated, it is desirable to prevent or at least minimize microbial growth or reproduction along the interface of adhesive and skin, as such can readily lead to infection and other undesirable conditions.

[0003] Accordingly, artisans have incorporated a wide range of antimicrobial agents into medical products or materials. Although a limited number of such agents have been incorporated into adhesives, effective incorporation into an adhesive composition presents a formidable technical challenge for numerous other antimicrobial agents. It is difficult to efficiently disperse such agents within the adhesive. Furthermore, certain antimicrobial agents undergo a loss in efficacy upon incorporation.

[0004] In this context, WO 93/00118 A1 describes chlorhexidine gluconate-containing adhesives and medical products comprising the same.

[0005] Chlorhexidine gluconate has a broad antimicrobial spectrum, is safe, and is well accepted in the market. However chlorhexidine gluconate has never been incorporated into solvent based acrylic adhesives which are the standard for surgical applications due to their low cost and good adhesion on skin in dry and wet conditions.

[0006] Accordingly, it would be desirable to provide a method for incorporating chlorhexidine gluconate into an adhesive formulation such that the compound is effectively dispersed and retains its efficacy when residing in the adhesive.

[0007] The present invention relates to the following items:
  1. 1. A method of forming an adhesive containing chlorhexidine digluconate, the method comprising:

    providing an aqueous solution of chlorhexidine digluconate;

    actively drying the aqueous solution to thereby obtain the chlorhexidine digluconate in solid form;

    providing an adhesive component;

    providing a solvent compatible with the adhesive component;

    solubilising the solid form chlorhexidine digluconate in the solvent to form a chlorhexidine digluconate solution;

    combining the chlorhexidine digluconate solution with the adhesive component to thereby form an adhesive containing chlorhexidine digluconate.

  2. 2. The method of item 1 wherein the aqueous solution contains the chlorhexidine digluconate in a total concentration by weight of from about 1% to the solubility limit of chlorhexidine digluconate.
  3. 3. The method of item 1 wherein the concentration of chlorhexidine digluconate in the aqueous solution is one of 20% and 40%.
  4. 4. The method of items 1 to 3 wherein actively drying includes at least one of freeze drying and spray drying.
  5. 5. The method of item 4 wherein freeze drying is performed at a temperature within a range of from about -80°C to about 10°C.
  6. 6. The method of item 4 wherein freeze drying is performed at a pressure within a range of from about 0.01 bars to about 0.95 bars.
  7. 7. The method of item 1 wherein the solid form is a layer form or a particulate form.
  8. 8. The method of item 4 wherein freeze drying includes spraying the aqueous solution of chlorhexidine digluconate.
  9. 9. The method of item 1 wherein the adhesive component is selected from the group consisting of (i) an adhesive ingredient, (ii) an adhesive premix, and (iii) an adhesive formulation.
  10. 10. The method of item 9 wherein the adhesive component is an adhesive formulation selected from the group consisting of acrylic adhesives, rubber adhesives, silicone adhesives, polyurethane adhesives, and combinations thereof.
  11. 11. The method of items 1 to 10 wherein the solvent is methanol.


[0008] The difficulties and drawbacks associated with previously known compositions, products, and practices are addressed in the present methods, adhesive compositions, products using such compositions and related methods of use.

[0009] In one aspect, described herein is a method of forming chlorhexidine in solid form. The method comprises providing an aqueous solution of at least one chlorhexidine salt. The method also comprises actively drying the aqueous solution to thereby obtain the at least one chlorhexidine salt in solid form.

[0010] In another aspect, described herein is a method of forming an adhesive containing chlorhexidine. The method comprises providing an aqueous solution of at least one chlorhexidine salt and actively drying the aqueous solution to thereby obtain the at least one chlorhexidine salt in solid form. The method additionally comprises providing an adhesive component and providing a solvent compatible with the adhesive component. The method also comprises solubilizing the solid form chlorhexidine in the solvent to form a chlorhexidine solution. And, the method comprises combining the chlorhexidine solution with the adhesive component to thereby form an adhesive containing chlorhexidine.

[0011] In yet another aspect, described herein is an adhesive formulation including chlorhexidine. The adhesive formulation comprises an adhesive, and at least one chlorhexidine salt.

[0012] In still another aspect, described herein is a medical product having an adhesive with antimicrobial properties. The medical product comprises an adhesive formulation including chlorhexidine.

[0013] The figures show:

Figure 1 is a graph illustrating antimicrobial efficacy of various adhesive samples described herein.

Figure 2 is a graph illustrating antimicrobial efficacy of various adhesive samples described herein.



[0014] It is believed that the inclusion of chlorhexidine gluconate (CHG) into solvent based adhesives has not been achieved yet due to certain physical and chemical properties of chlorhexidine gluconate. For example, chlorhexidine gluconate is strongly hydrophilic and is only soluble in methanol and acetone. In addition, chlorhexidine gluconate is typically commercially available as a 20% or 40% by weight in water formulation. Aqueous compositions can not be readily combined with solvent based adhesives. Chlorhexidine gluconate is sensitive to high temperatures thereby limiting its subsequent processing as would otherwise likely be necessary in any adhesive incorporation. And, when dried by evaporation, the compound does not readily disperse in solvent. This presents another difficulty in attempting to incorporate this compound into a solvent based adhesive.

[0015] The present invention provides a unique strategy for incorporating chlorhexidine gluconate into a solvent based adhesive such as solvent based acrylic adhesives which are widely used in medical and surgical applications. The new method incorporates chlorhexidine gluconate into a solvent based adhesive by an active drying operation and preferably by freeze drying or spray drying, chlorhexidine gluconate to obtain a powder. The powder is then dissolved in a solvent that is compatible with the adhesive of interest such as an acrylic adhesive. An example of a suitable solvent for a typical acrylic adhesive is methanol.

Chlorhexidine



[0016] Chlorhexidine is a chemical antiseptic and generally used as an antimicrobial agent. It is effective on both Gram-positive and Gram-negative bacteria, although it is less effective with some Gram-negative bacteria. It has both bactericidal as well as bacteriostatic mechanisms of action, the mechanism of action being membrane disruption and not ATPase inactivation as previously thought. It is also useful against fungi and enveloped viruses, though this has not been extensively investigated. Products containing chlorhexidine in high concentrations should be kept away from eyes and the ears, due to the risk of damage to those organs. However, chlorhexidine is safely used in very low concentrations, for example in some contact lens solutions.

[0017] Chlorhexidine gluconate (also known as chlorhexidine digluconate) is a salt of chlorhexidine and gluconic acid. The structural formula of chlorhexidine gluconate is:



[0018] Although this compound is actually a digluconate compound, it is commonly referred to as chlorhexidine gluconate.

[0019] Thus, the term chlorhexidine gluconate as used herein encompasses the digluconate compound. Also, the terms "chlorhexidine gluconate" and "chlorhexidine digluconate" are used interchangeably herein.

[0020] Pharmaceutically acceptable chlorhexidine salts that may be used herein as antimicrobial agents include chlorhexidine palmitate, chlorhexidine diphosphanilate, chlorhexidine dihydrochloride, chlorhexidine diacetate, and chlorhexidine digluconate. Chlorhexidine free base is a further example of an antimicrobial agent.

[0021] Thus, described herein are methods for incorporating one or more chlorhexidine salts and particularly chlorhexidine gluconate in a solvent based adhesive such as an acrylic adhesive. Although the present invention is particularly directed to the incorporation of chlorhexidine gluconate, the present disclosure is applicable to other chlorhexidine salts and related compounds. Generally, any chlorhexidine salt that is generally provided or produced in an aqueous or liquid form is a candidate for the various preferred aspects described herein.

Active Drying



[0022] Water and/or any other solvents or liquids are removed and separated from the chlorhexidine salt(s) by one or more active drying operations. The term "active drying" refers to any operation in which liquid and typically water, is removed and separated from the chlorhexidine salt(s) besides passive evaporation of the liquid. Passive evaporation refers to evaporation of the liquid component(s) at ambient temperatures without any moving air streams or other flowing currents to aid in removal and separation of the liquid component(s) from the chlorhexidine salt(s).

[0023] Thus, the term active drying as used herein refers to a wide array of liquid removal techniques such as but not limited to aggressive evaporation using airflows over the liquid also known as pneumatic drying, heating promoted evaporation in which thermal energy is supplied to the liquid also known as hot air drying, drying by exposure to electromagnetic radiation such as microwave energy, freeze drying, and spray drying for example. Combinations of these and other drying strategies can be utilized. Preferably, active drying is performed by freeze drying or spray drying.

[0024] Freeze drying is a dehydration process typically used to preserve a perishable material or render the material more convenient for transport. Freeze drying is typically performed by freezing the material and then reducing the surrounding pressure and adding sufficient heat to allow the frozen water in the material to sublime directly from the solid phase to the gas phase.

[0025] A preferred method in accordance with the present invention is to freeze dry a 20% (all percentages are percentages by weight unless noted otherwise) chlorhexidine gluconate solution. Freeze drying may be performed in nearly any manner. In one embodiment of the invention, the noted solution of 20% chlorhexidine gluconate and 80% water is fully frozen by subjecting the solution to a temperature of about -20°C and a pressure of about 0.180 bars, for a time period of about 24 hours. It will be appreciated that these temperature, pressure, and time values are merely representative. The invention includes a significantly broader range of freeze drying conditions. Typically, temperatures are within a range of from about -80°C (or less) to about 10°C (or more), and preferably from about -50°C to about 0°C. Typically, pressures are within a range of from about 0.01 bars to about 0.95 bars, and preferably from about 0.10 bars to about 0.50 bars. Typical time periods range from several seconds up to several days.

[0026] The aqueous chlorhexidine gluconate solution is preferably placed in a vessel that increases the surface area of the solution. As will be appreciated, increasing the solution surface area promotes heat transfer and thus reduces the time period necessary to freeze the aqueous chlorhexidine gluconate solution. Increasing the surface area also promotes migration and sublimation of water from the frozen mass to thereby leave a remaining component of chlorhexidine gluconate.

[0027] Although the preferred methods described herein utilize a 20% chlorhexidine gluconate solution which is then freeze dried, it will be understood that the invention is not limited to such. As previously noted, chlorhexidine gluconate is also typically available as a 40% aqueous solution and so such may be freeze dried as described herein. It is contemplated that a range of aqueous solutions having concentrations of from about 1% up to the solubility limit of the compound could be used. Typically for many chlorhexidine salts, they are commercially available in an aqueous solution and in a concentration of from about 1% to about 60%.

[0028] During freeze drying, after initially freezing the aqueous solution to form a solid, at least a portion of the water is removed from the solid by sublimation. The present invention includes operations in which the water component is partially removed by other techniques or practices besides freeze drying. However, preferably at least a majority and most preferably all of the water is removed via freeze drying.

[0029] Another preferred active drying technique is spray drying. Spray drying is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas. This is the preferred method of drying of many thermally sensitive materials such as foods and pharmaceuticals. A consistent particle size distribution is a reason for spray drying some industrial products such as catalysts. Air is typically the heated drying media. However, if the liquid is a flammable solvent or the product is oxygen-sensitive then nitrogen can be used.

[0030] All spray dryers use some type of atomizer or spray nozzle to disperse the liquid or slurry into a controlled drop size spray. The most common of these are rotary nozzles and single fluid pressure swirl nozzles. Alternatively, for some applications two-fluid or ultrasonic nozzles are used. Depending on the process requirements, drop sizes from 10 to 500 micrometers can be achieved with the appropriate nozzle selection. The most common drop sizes are in the 100 to 200 micrometer diameter range. The resulting dry powder is often free-flowing.

[0031] The hot drying gas can be passed as a co-current or counter-current flow to the atomizer direction. A co-current flow enables the particles to have a lower residence time within the system and the particle separator (typically a cyclone device) operates more efficiently. The counter-current flow method enables a greater residence time of the particles in the chamber and usually is paired with a fluidized bed system.

[0032] Additional techniques and/or alternative active drying operations can include for example combinations of spray drying and freeze drying.

Incorporation of Chlorhexidine in Adhesive



[0033] After forming a powder of chlorhexidine gluconate or other chlorhexidine salt by one or more active drying operations optionally including one or more size reducing operations, the powder can be readily solubilized by adding the chlorhexidine gluconate in particulate form to one or more suitable solvent(s) such as methanol. The chlorhexidine gluconate is added to the solvent in an amount such that the compound readily dissolves in the solvent. For using methanol as the solvent, a concentration of chlorhexidine gluconate in a range from about 15% to about 20% has been found acceptable. However, it will be appreciated that the invention includes the use of concentrations greater than and less than these values.

[0034] After dissolving the chlorhexidine gluconate powder (or other salt of chlorhexidine) into a suitable solvent, the chlorhexidine gluconate solution is incorporated into a solvent based adhesive. Typically, this is performed by adding or otherwise incorporating the solution directly into an adhesive component or adhesive formulation.

[0035] The adhesive containing chlorhexidine salt is then incorporated in a product or used as desired. For example, conventional coating and drying operations can be performed to form an adhesive layer on a medical product. Representative non-limiting examples of such medical products include surgical goods such as incise films, and device fixation products; wound care products; and ostomy pouches.

[0036] In certain embodiments, the adhesive can be covered with a carrier, preferably a polyurethane film or any alternative material.

Adhesives



[0037] The methods of the invention can be used to incorporate chlorhexidine salts such as chlorhexidine gluconate, into a wide array of adhesives, and preferably a solvent based adhesive. Non limiting adhesives include acrylic adhesives, rubber adhesives, silicone adhesives, polyurethane adhesives, and variants and combinations thereof. Generally, the resulting chlorhexidine salt which is preferably chlorhexidine gluconate, can be incorporated into nearly any non-aqueous based adhesive. Preferably, the adhesive is a solvent based adhesive. More preferably, the adhesive is a solvent based acrylic adhesive.

[0038] Also described herein is combining chlorhexidine powder produced by the methods described herein, with an adhesive component such as an adhesive ingredient and/or an adhesive premix. This strategy provides an alternative approach for subsequent formation of a chlorhexidine containing adhesive.

[0039] It is also contemplated that one or more chlorhexidine salts can be incorporated into an adhesive by combining a liquid solution, mixture or dispersion containing chlorhexidine salt(s) into an adhesive formulation or an adhesive intermediate and then subjecting the resulting mixture to one or more drying operations to thereby remove the liquid component(s) from the mixture of adhesive and chlorhexidine salt(s).

[0040] For embodiments in which the chlorhexidine is in a particle form, another advantage results when the particles are incorporated into a hydrophobic adhesive matrix. Due to its hydrophilic properties, chlorhexidine and particularly chlorhexidine gluconate, will easily release from a hydrophobic adhesive matrix.

Additional Additives



[0041] One or more additional additives can be incorporated into the adhesive and chlorhexidine formulation. Preferably the additional additives include medicinal compounds. Such medicinal compounds include, but are not limited to, antimicrobials, antibiotics, antifungal agents, antiviral agents, antithrombogenic agents, anesthetics, anti-inflammatory agents, analgesics, anticancer agents, vasodilation substances, wound healing agents, angiogenic agents, angiostatic agents, immune boosting agents, growth factors, and other biological agents. Suitable antimicrobial agents include, but are not limited to, biguanide compounds; triclosan; penicillins; tetracyclines; aminoglycosides, such as gentamicin and Tobramycin™; polymyxins; rifampicins; bacitracins; erythromycins; vancomycins; neomycins; chloramphenicols; miconazole; quinolones, such as oxolinic acid, norfloxacin, nalidixic acid, pefloxacin, enoxacin, and ciprofloxacin; sulfonamides; nonoxynol 9; fusidic acid; cephalosporins; and combinations of such compounds and similar compounds. The additional antimicrobial compounds provide for enhanced antimicrobial activity.

[0042] In certain applications, the adhesive composition may comprise one or more absorbents. An example of a suitable absorbent is a hydrocolloid agent. The hydrocolloid may be linear or crosslinked. Suitable hydrocolloids include synthetic hydrocolloids such as sodium carboxymethyl cellulose, and natural products such as gelatin, pectin, guar gum, locust bean gum, tragacanth gum, gum karaya, starches, gum arabic, alginic acid and its sodium and/or calcium salts. Other synthetic hydrocolloids such as polyvinyl alcohol, polyvinyl acetate, polyvinyl pyrollidone, polyacrylic acid, polyhydroxyalkyl acrylates, polyacrylamides, high molecular weight polyethylene glycols and polypropylene glycols are useful. Others hydrocolloids include crosslinked or crystalline sodium carboxymethyl cellulose, crosslinked dextran and starch-acrylonitrile graft copolymer.

Examples



[0043] A series of trials were conducted to evaluate adhesives containing chlorhexidine agents, their processability, and antimicrobial efficacy of the resulting compositions. The adhesive compositions included an adhesive component, an absorbent agent, and an antimicrobial agent.

[0044] A listing of the raw materials is set forth below in Table 1.
Table 1 - Raw Materials
ComponentDesignationSource
Adhesive I807 Avery Dennison
AVC-12363 Avery Dennison
Absorbent A800 (carboxymethyl cellulose) Aqualon
Antimicrobial CHG USP/EurPh Medichem
Liner BG684 Avery Dennison
Carrier Med5575A Avery Dennison


[0045] The 1807 adhesive is an acrylic adhesive commercially available from Avery Dennison. The AVC-12363 adhesive is also available from Avery Dennison and is a solvent acrylic adhesive suitable for medical applications such as for adhesive dressings, securement devices, incise films, etc.

[0046] Samples of the composition were prepared as follows. 20% chlorhexidine water based solution was freeze dried. Wet adhesive was weighted and added into a breaker. A800 carboxymethyl cellulose (particle size less than 75 µm) was added directly into the adhesive under mixing at 800 rpm.

[0047] The freeze dried chlorhexidine gluconate powder was dissolved in methanol at a concentration of 15%. The chlorhexidine gluconate solution was then added into the adhesive under mixing at 800 rpm.

[0048] The adhesive containing the carboxymethyl cellulose and chlorhexidine gluconate stayed under mixing for 30 minutes at 800 rpm.

[0049] Adhesives were then coated at 100 gsm onto a BG684 release liner. Coating speed used was 4 m/min.

[0050] Coatings were dried in an oven at 95°C for 15 minutes.

[0051] Med5575A was manually laminated on top of the coating as carrier.

[0052] The following test methods were used at evaluate multilayer prototypes as noted in Table 2 as follows:
Table 2 - Test Methods
TestStandard
90° Peel PE T04/095
Tack T04/001
Water Vapor Transmission T06/022
Static Absorption T06/022
Fluid Handling Capacity (FHC) T06/022
Antimicrobial Efficacy ASTM2180


[0053] Regarding the test procedures, the T06/022 procedure corresponds to EN13726. Details as to T04/001 and T04/095 are as follows:

T04/001 - Finat Tack onto Glass



[0054] Definition: The tack property of a pressure sensitive material is the force required to separate a loop of material which has been brought into contact with a specified area of a standard surface instantly (or substantially so), using no external pressure to secure more thorough contact.

[0055] Significance: Tack is a measure of a tape's ability to adhere instantly with a minimum of pressure.

[0056] Test specimen: The test specimens had a width of 25 mm and a length of 150 mm. The test specimen was cut with a suitable cutter, normally in the machine direction.

[0057] Equipment: A flat "Float Process" glass plate with a minimum thickness of 3.0 mm was used. A metal peg was attached at the center of the plate. The dimensions of the peg should be such that the peg can be clamped in the lower jaw of an adhesion tester. 37 micron polyester film is used.

[0058] Test method: Prior to testing, the glass panels were cleaned. To determine the tack, the side of the glass not to be tested was covered with 37 micron polyester film. The test strips were 25 mm wide and 150 mm long. The cuts should be clean and straight. The backing paper from each strip was removed immediately prior to the test being carried out. The test samples were positioned as follows. The two ends of the sample were held and formed into a loop, with the adhesive surface directed outward, by bringing the two ends together. The free ends were covered with polyester to protect the jaws of the adhesion tester from the adhesive coating. The polyester-protected ends of the sample were placed in between the jaws in such a way that a loop of 150 mm was formed. The tester was started and the loop was brought into contact with the glass plate at a speed of 300 mm per minute. When full contact over the glass plate was achieved (25 x 25 mm), the direction of the tester was immediately reversed thereby allowing separation to take place at a speed of 300 mm per minute. It is important that delay in reversing direction is kept to a minimum. The maximum force necessary to separate the loop completely from the glass plate was recorded.

[0059] Report: The tack report includes the tack value in Newton per meter width (N/m). If other than 25 mm widths are tested, Newton per meter values are obtained by dividing the observed value by the width of the specimen. Report which side of the tape the values represent (laminating or mounting), and if the value is obtained from a deviating test width, then this specific width should also be mentioned. The rigidity of the specimen affects the results and must be considered when comparing different adhesives on different carriers. Report the tack value in Newton per meter width (N/m).

[0060] T04/095 - 90° Peel Adhesion onto Mattflex Polyethylene in CD (4.5 pounds, 20 minutes dwell), Used for all Products Coated with Acrylic Adhesives

[0061] Definition: Peel adhesion onto polyethylene is the force (average) required to remove a pressure sensitive tape from a test panel at a specified angle and speed using a defined pressure to establish contact.

[0062] Equipment: The following equipment was used for this evaluation:

Adhesion Tester

Aluminum panel (15 cm x 15 cm)

DC tape

2050 g roller (4.5 pound) ASTM D1000

Polyethylene foil (25 µm) (standard PE testing side is typically an interior face of the roll) Supplier ACE

Ref 7660 Female side pre-treated

Paper strip 25 x 230 mm

Paper (no lacquering)



[0063] Preparation of Samples: Test material and polyethylene test substrates were conditioned for 24 hours at a temperature of 23 ± 2°C and at a relative humidity at that temperature of 50 ± 2%. A DC-tape was laminated onto the aluminum panel. The untreated side of the polyethylene foil was laminated onto the self-adhesive aluminum panel with a hard rubber roller. The polyethylene foil was protected with a clean unlacquered paper. The test specimens had a width of 25 mm and a length of approximately 150 mm. The test specimens were cut with a suitable cutter, in the machine direction. At the edge a paper strip was laminated with overlapping of ± 1 cm.

[0064] Measurement: The liner of test specimen was removed and the test specimen was laminated in cross direction onto the polyethylene foil. The sample was rolled with the ASTM roller with a constant speed of 150 cm/min. After waiting for 20 minutes, measurement with the adhesion tester was started. The end of the paper strip was clamped in the upper grip and the aluminum panel was clamped in the lower grip. The test angle between paper strip and the aluminum panel was 90°.

[0065] Reporting: 90° peel is the averaged force required to remove the test specimen from the test substrate (N/25 mm).

[0066] Prototypes were prepared based on two adhesives. I807 was chosen for its well known application in negative pressure wound therapy (NPWT) (long term application on skin). AVC12363 was selected for its polymer structure. AVC-12363 does not contain any -COOH functional groups.

[0067] Tables 3 and 4 summarize the performance and characteristics of multilayer assemblies formed using the adhesive compositions described herein. The designation "FD CHG" in the column "Antimicrobial" refers to freeze dried chlorhexidine gluconate as described herein. The term "AMX" refers to antimicrobial efficacy. The term "PAPE" refers to adhesion on polyethylene. The term "FHC" refers to fluid handling capacity. And, the reference "NT" refers to not nested.
Table 3 - Multilayer Assemblies Using I807 Adhesive
Sample IDCoat Weight (g/m2)Adhesive% A800 (w/w)AntimicrobialAMX Concentration % (w/w)PAPE T04/095 (N/25 mm)Tack T04/001 (N/25 mm)FHC T06/022 (g/m2/24 h)Static Absorption T06/022 (g/m2/24 h)MVTR T06/022 (g/m2/24 h)
1 85 I807 0 FD CHG 9 2.75 18.0 NT NT 324
2 85 I807 0 FD CHG 9 3.36 18.1 NT NT 334
3 85 I807 0 FD CHG 9 2.95 17.6 NT NT 347
4 96 I807 0 FD CHG 3 3.50 26.8 NT NT 315
5 96 I807 0 FD CHG 3 3.61 26.0 NT NT 327
6 96 I807 0 FD CHG 3 3.56 26.1 NT NT 330
7 96 I807 0 None 0 3.59 30.5 NT NT 308
8 96 I807 0 None 0 3.28 32.7 NT NT 321
9 96 I807 0 None 0 3.79 33.3 NT NT 306
10 100 I807 20 FD CHG 9 1.44 0.5 2090 1400 690
11 100 I807 20 FD CHG 9 1.50 1.7 2290 1600 690
12 100 I807 20 FD CHG 9 1.57 0.9 2820 2110 710
13 92 I807 20 None 0 1.45 / 2320 1160 1160
14 92 I807 20 None 0 1.48 12.7 2310 1140 1170
15 92 I807 20 None 0 1.19 13.7 2160 1040 1120
16 110 I807 40 FD CHG 3 0.62 0.7 3480 2800 680
17 110 I807 40 FD CHG 3 0.93 1.2 3150 2460 680
18 110 I807 40 FD CHG 3 0.63 0.6 3380 2550 830
19 106 I807 20 FD CHG 5 1.65 7.6 1640 900 740
20 106 I807 20 FD CHG 5 2.93 7.9 1850 1080 770
21 106 I807 20 FD CHG 5 1.86 10.1 1810 990 820
22 105 I807 20 FD CHG 3 2.16 13.5 1710 1040 670
23 105 I807 20 FD CHG 3 1.96 12.5 1510 870 640
24 105 I807 20 FD CHG 3 1.63 10.9 1690 950 740
25 116 I807 40 FD CHG 5 0.85 0.1 1470 750 720
26 116 I807 40 FD CHG 5 0.65 0.1 1550 840 710
27 116 1807 40 FD CHG 5 0.61 0.2 1740 840 900
28 112 1807 30 FD CHG 3 1.27 4.6 2130 1470 660
29 112 I807 30 FD CHG 3 8.85 4.0 2270 1590 680
30 112 1807 30 FD CHG 3 1.53 5.6 2260 1500 760
31 112 I807 20 None 0 1.94 17.5 1900 1300 600
32 112 I807 20 None 0 2.07 15.8 1860 1300 530
33 112 I807 20 None 0 1.88 14.3 2030 1320 710
34 104 I807 30 FD CHG 5 1.10 1.3 2710 2100 610
35 104 I807 30 FD CHG 5 1.25 2.2 2630 1990 640
36 104 I807 30 FD CHG 5 0.78 3.0 2690 1970 720
37 73 I807 0 FD CHG 5 3.03 20.0 590 160 430
38 73 I807 0 FD CHG 5 2.93 16.2 590 80 450
39 73 I807 0 FD CHG 5 2.91 14.8 510 80 430
40 84 I807 0 FD CHG 3 3.77 20.5 420 80 340
41 84 I807 0 FD CHG 3 2.92 21.8 490 110 380
42 84 I807 0 FD CHG 3 3.41 20.5 460 50 410
43 72 I807 0 FD CHG 5 3.64 20.2 550 90 460
44 72 I807 0 FD CHG 5 3.11 20.7 510 90 420
45 72 I807 0 FD CHG 5 2.94 19.6 600 70 530
46 95 I807 40 FD CHG 7 1.03 0.8 2250 1570 680
47 95 I807 40 FD CHG 7 1.18 0.8 2310 1520 790
48 95 I807 40 FD CHG 7 0.97 0.7 2270 1500 770
49 101 I807 30 FD CHG 2 0.74 3.2 2320 1550 770
50 101 I807 30 FD CHG 2 0.98 3.2 2310 1640 680
51 101 I807 30 FD CHG 2 0.96 3.0 2300 1190 1110
52 39 I807 0 FD CHG 2 2.58 32.6 620 130 490
53 39 I807 0 FD CHG 2 2.44 35.5 650 160 490
54 39 I807 0 FD CHG 2 2.82 32.9 720 220 500
55 96 I807 0 FD CHG 2 3.98 33.9 600 180 420
56 96 I807 0 FD CHG 2 3.92 40.3 450 90 360
57 96 I807 0 FD CHG 2 3.00 31.7 670 210 460
58 109 I807 30 FD CHG 2 0.76 10.9 1910 1230 680
59 109 I807 30 FD CHG 2 1.71 9.6 2480 1850 630
60 109 I807 30 FD CHG 2 1.13 11.3 2100 1440 660
Table 4 - Multilayer Assemblies Using AVC-12363 Adhesive
Sample IDCoat Weight (g/m2)Adhesive% A800 (w/w)AntimicrobialAMX Concent % (w/w)PAPE T04/095 (N/25 mm)Tack T04/001 (N/25 mm)FHC T06/022 (g/m2/24 h)Static Absorption T06/022 (g/m2/24 h)MVTR T06/022 (g/m2/24 h)
1 90 AVC-12363 0 FD CHG 9 5.29 22.5 NT NT 704
2 90 AVC-12363 0 FD CHG 9 4.95 21.8 NT NT 768
3 90 AVC-12363 0 FD CHG 9 5.42 23.2 NT NT  
4 97 AVC-12363 0 FD CHG 3 6.18 35.7 NT NT 717
5 97 AVC-12363 0 FD CHG 3 5.68 32.7 NT NT 800
6 97 AVC-12363 0 FD CHG 3 6.70 35.5 NT NT 733
7 91 AVC-12363 0 None 0 6.26 47.0 NT NT 684
8 91 AVC-12363 0 None 0 6.74 43.7 NT NT 742
9 91 AVC-12363 0 None 0 6.57 43.3 NT NT NT
10 106 AVC-12363 20 FD CHG 9 4.39 17.9 2060 610 1450
11 106 AVC-12363 20 FD CHG 9 4.37 17.6 1960 460 1500
12 106 AVC-12363 20 FD CHG 9 3.61 17.2 2010 550 1460
13 110 AVC-12363 20 None 0 3.28 17.0 1960 450 1510
14 110 AVC-12363 20 None 0 3.18 16.0 2020 520 1500
15 110 AVC-12363 20 None 0 2.98 16.2 2120 510 1610


[0068] It was determined that in all samples evaluated, the incorporation of chlorhexidine gluconate into the adhesive did not significantly impact the adhesive properties.

[0069] Evaluation of antimicrobial efficacy was also undertaken.

[0070] Antimicrobial efficacy evaluation was performed following ASTM 2180 initially on both adhesive samples with and without carboxymethyl cellulose. The rational for this choice was based upon the following. I807 with its high concentration of -COOH functional groups might inhibit the release of the positively charged chlorhexidine gluconate. And, carboxymethyl cellulose is an anionic polymer and could retain the chlorhexidine gluconate.

[0071] Two concentration levels of chlorhexidine were tested. High levels of chlorhexidine gluconate (9% CHG into 100 gsm adhesive) were evaluated. This high concentration was chosen to evaluate whether it would be possible to achieve antimicrobial efficacy. Medium levels of chlorhexidine base were also tested (5% chlorhexidine base in 45 gsm and 100 gsm). Chlorhexidine base exhibited a low solubility in water and represented therefore a worst case.

[0072] Antimicrobial efficacy of the various samples are illustrated in Figures 1 and 2. The data in the referenced figures was based upon all adhesives coated at 100 gsm. Figure 1 represents antimicrobial efficacy following ASTM2180 without re-inoculation. Figure 2 represents antimicrobial efficacy following ASTM2180.

[0073] In conclusion, antimicrobial efficacy of the prototypes made with I807 or AVC-12363 with or without carboxymethyl cellulose (A800) exhibited similar antimicrobial efficacy (see Figures 1 and 2) at high chlorhexidine gluconate concentration. Neither the carboxymethyl cellulose nor the - COOH functional group of the 1807 adhesive appeared to inhibit the antimicrobial efficacy.

[0074] Additional details and aspects of adhesives, agents for incorporation in the adhesives, arrangements and other components for multilayer structures are provided in US 2010/0322996.

[0075] Many other benefits will no doubt become apparent from future application and development of this technology.

[0076] It will be understood that any one or more feature or component of one embodiment described herein can be combined with one or more other features or components of another embodiment.

[0077] As described hereinabove, the present invention solves many problems associated with previous type products, adhesives and practices.


Claims

1. A method of forming an adhesive containing chlorhexidine digluconate, the method comprising:

providing an aqueous solution of chlorhexidine digluconate;

actively drying the aqueous solution to thereby obtain the chlorhexidine digluconate in solid form;

providing an adhesive component;

providing a solvent compatible with the adhesive component;

solubilising the solid form chlorhexidine digluconate in the solvent to form a chlorhexidine digluconate solution;

combining the chlorhexidine digluconate solution with the adhesive component to thereby form an adhesive containing chlorhexidine digluconate.


 
2. The method of claim 1 wherein the aqueous solution contains the chlorhexidine digluconate in a total concentration by weight of from about 1% to the solubility limit of chlorhexidine digluconate.
 
3. The method of claim 1 wherein the concentration of chlorhexidine digluconate in the aqueous solution is one of 20% and 40%.
 
4. The method of claims 1 to 3 wherein actively drying includes at least one of freeze drying and spray drying.
 
5. The method of claim 4 wherein freeze drying is performed at a temperature within a range of from about -80°C to about 10°C.
 
6. The method of claim 4 wherein freeze drying is performed at a pressure within a range of from about 0.01 bars to about 0.95 bars.
 
7. The method of claim 1 wherein the solid form is a layer form or a particulate form.
 
8. The method of claim 4 wherein freeze drying includes spraying the aqueous solution of chlorhexidine digluconate.
 
9. The method of claim 1 wherein the adhesive component is selected from the group consisting of (i) an adhesive ingredient, (ii) an adhesive premix, and (iii) an adhesive formulation.
 
10. The method of claim 9 wherein the adhesive component is an adhesive formulation selected from the group consisting of acrylic adhesives, rubber adhesives, silicone adhesives, polyurethane adhesives, and combinations thereof.
 
11. The method of claims 1 to 10 wherein the solvent is methanol.
 


Ansprüche

1. Verfahren zum Bilden eines Haftmittels, das Chlorhexidindiglukonat enthält, wobei das Verfahren umfasst:

Bereitstellen einer wässrigen Lösung von Chlorhexidindiglukonat;

aktives Trocknen der wässrigen Lösung, so dass das Chlorhexidindiglukonat in fester Form erhalten wird;

Bereitstellen einer Haftmittelkomponente;

Bereitstellen eines Lösungsmittels, das mit der Haftmittelkomponente verträglich ist;

Lösen der festen Form von Chlorhexidindiglukonat in dem Lösungsmittel zum Bilden einer Chlorhexidindiglukonatlösung;

Vereinigen der Chlorhexidindiglukonatlösung mit der Haftmittelkomponente, so dass dadurch ein Haftmittel gebildet wird, das Chlorhexidindiglukonat enthält.


 
2. Verfahren nach Anspruch 1, bei dem die wässrige Lösung das Chlorhexidindiglukonat in einer Gesamtkonzentration von etwa 1 %, bezogen auf das Gewicht, bis zur Löslichkeitsgrenze von Chlorhexidindiglukonat enthält.
 
3. Verfahren nach Anspruch 1, bei dem die Konzentration von Chlorhexidindiglukonat in der wässrigen Lösung eine von 20 % und 40 % ist.
 
4. Verfahren nach einem der Ansprüche 1 bis 3, bei dem das aktive Trocknen mindestens eine von einer Gefriertrocknung und einer Sprühtrocknung umfasst.
 
5. Verfahren nach Anspruch 4, bei dem die Gefriertrocknung bei einer Temperatur in einem Bereich von etwa -80 °C bis etwa 10 °C durchgeführt wird.
 
6. Verfahren nach Anspruch 4, bei dem die Gefriertrocknung bei einem Druck in einem Bereich von etwa 0,01 bar bis etwa 0,95 bar durchgeführt wird.
 
7. Verfahren nach Anspruch 1, bei dem die feste Form eine Schichtform oder eine Teilchenform ist.
 
8. Verfahren nach Anspruch 4, bei dem die Gefriertrocknung das Sprühen der wässrigen Lösung von Chlorhexidindiglukonat umfasst.
 
9. Verfahren nach Anspruch 1, bei dem die Haftmittelkomponente ausgewählt ist aus der Gruppe, bestehend aus (i) einem Haftmittelbestandteil, (ii) einer Haftmittelvormischung und (iii) einer Haftmittelformulierung.
 
10. Verfahren nach Anspruch 9, bei dem die Haftmittelkomponente eine Haftmittelformulierung ist, ausgewählt aus der Gruppe, bestehend aus Acrylhaftmitteln, Kautschukhaftmitteln, Silikonhaftmitteln, Polyurethanhaftmitteln und Kombinationen davon.
 
11. Verfahren nach einem der Ansprüche 1 bis 10, bei dem das Lösungsmittel Methanol ist.
 


Revendications

1. Procédé de formation d'un adhésif contenant du digluconate de chlorhexidine, le procédé comprenant les étapes consistant à :

fournir une solution aqueuse de digluconate de chlorhexidine ;

sécher activement la solution aqueuse pour obtenir ainsi le digluconate de chlorhexidine sous forme solide ;

fournir un composant adhésif;

fournir un solvant compatible avec le composant adhésif;

solubiliser le digluconate de chlorhexidine sous forme solide dans le solvant pour former une solution de digluconate de chlorhexidine ;

combiner la solution de digluconate de chlorhexidine avec le composant adhésif pour former ainsi un adhésif contenant du digluconate de chlorhexidine.


 
2. Procédé selon la revendication 1, dans lequel la solution aqueuse contient le digluconate de chlorhexidine à une concentration totale en poids d'environ 1% à la limite de solubilité du digluconate de chlorhexidine.
 
3. Procédé selon la revendication 1, dans lequel la concentration de digluconate de chlorhexidine dans la solution aqueuse est de 20 % et 40 %.
 
4. Procédé selon les revendications 1 à 3, dans lequel le séchage actif comprend au moins une étape parmi une étape de lyophilisation et une étape de séchage par pulvérisation.
 
5. Procédé selon la revendication 4, dans lequel la lyophilisation est effectuée à une température comprise entre environ -80°C et environ 10°C.
 
6. Procédé selon la revendication 4, dans lequel la lyophilisation est effectuée à une pression comprise entre environ 0,01 bar et environ 0,95 bar.
 
7. Procédé selon la revendication 1, dans lequel la forme solide est une forme en couche ou une forme particulaire.
 
8. Procédé selon la revendication 4, dans lequel la lyophilisation comprend une pulvérisation de la solution aqueuse de digluconate de chlorhexidine.
 
9. Procédé selon la revendication 1, dans lequel le composant adhésif est choisi dans le groupe constitué par (i) un ingrédient adhésif, (ii) un prémélange adhésif, et (iii) une formulation adhésive.
 
10. Procédé selon la revendication 9, dans lequel le composant adhésif est une formulation adhésive choisie dans le groupe constitué par les adhésifs acryliques, les adhésifs caoutchouc, les adhésifs silicone, les adhésifs polyuréthane et leurs combinaisons.
 
11. Procédé selon les revendications 1 à 10, dans lequel le solvant est le méthanol.
 




Drawing






REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description