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Publication numberWO2016135038 A1
Publication typeApplication
Application numberPCT/EP2016/053463
Publication date1 Sep 2016
Filing date18 Feb 2016
Priority date23 Feb 2015
Publication numberPCT/2016/53463, PCT/EP/16/053463, PCT/EP/16/53463, PCT/EP/2016/053463, PCT/EP/2016/53463, PCT/EP16/053463, PCT/EP16/53463, PCT/EP16053463, PCT/EP1653463, PCT/EP2016/053463, PCT/EP2016/53463, PCT/EP2016053463, PCT/EP201653463, WO 2016/135038 A1, WO 2016135038 A1, WO 2016135038A1, WO-A1-2016135038, WO2016/135038A1, WO2016135038 A1, WO2016135038A1
InventorsVisscher Geofrey De, Mayu Takeiri
ApplicantNitto Denko Corporation
Export CitationBiBTeX, EndNote, RefMan
External Links: Patentscope, Espacenet
Wound dressing
WO 2016135038 A1
Abstract
The present invention relates to a wound dressing comprising: (i) a hacking layer; and (ii) a substrate layer comprising at least one compound according to Formula (1): wherein R1 and R2 may be the same or different and are selected from the group consisting of hydrogen, -SO3M and a physiologically hydrolyzable chemical group, wherein M is a cation, preferably a metal cation, and the physiologically hydrolyzable chemical group is selected from the group consisting of alkyl, alkylcarbonyl, alkenylcarbonyl arylcarbonyl, heteroarylearbonyl. alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylether, alkenylether, aryl ether, and heteroarylether groups wherein, the alkyl. group or moiety consists of unsubstituted or substituted, straight-chain or branched-chain or cyclic alkyl groups having 1-22 carbon atoms, wherein the alkenyl moiety consists of unsubstituted or substituted, straight-chain or branched-chain or cyclic alkenyl groups having 2-22 carbon atoms, wherein the aryl moiety consists of unsubstituted or substituted phenyl, or phenalkyl groups wherein the alkyl moiety contains 1-3 carbon atoms and the phenyl moiety is unsubstituted or substituted, and the heteroaryl moiety is an aromatic 5- or 6-membcred heterocyclic ring containing one or two heteroatonis selected from the group consisting of nitrogen, oxygen, and sulphur.
Claims  (OCR text may contain errors)
1. A wound dressing comprising:
(i) a backing layer; and
(ii) a substrate layer comprising at least one compound according to Formula (1):
Formula (1)
wherein and R; may be the same or different and are selected from the group consisting of hydrogen, -SO3M and a physiologically Jiydrolyzable chemical group, wherein M is a cation, preferably a metal cation, and. die physiologically hydrolyzable chemical group is selected from the group consisting of alkyl, alkylcarbonyl, alkenylcarbonyl arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylether, alkenylether, arylether, and heteroarylether groups wherein the alkyl group or moiety consists of unsubstituted or substituted, straight-chain or branched-chain or cyclic alkyl groups having 1 -22 carbon atoms, wherein the alkenyl moiety consists of unsubstituted. or substituted, straight-chain or branched-chain or cyclic alkenyl groups having 2-22 carbon atoms, wherein the aryl moiety consists of unsubstituted or substituted phenyl, or phenalkyl groups wherein the alkyl moiety contains 1 -3 carbon atoms and. the phenyl moiety is imsubstituted. or substituted, and the heteroaryl moiety is an aromatic 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected, from the .group consisting of nitrogen, oxygen, and sulphur.
2. The wound dressing according to claim 1, wherein, the substrate layer is an adhesive layer having an average thickness in the range of from 5 to 400 μιη.
3. The wound dressing according to claim 1 or 2, wherein the wound dressing is an adhesive patch, and wherein the backing layer comprises an ether-based ethane resin obtained from at least one member selected from the group consisting of polyoxytetramethylene glycol, butanediol, polyethylene glycol, and polypropylene glycol as a diol component, and methylene diphenyl-diisocyanate as an isocyanate component.
4. The wound dressing according to claim 3, wherein the ether-based urethane resin contains 5 to 60% by weight of the polyoxytetramethylene glycol and 10 to 50% by weight of the polyethylene glycol.
5. The wound dressing according to claim 3 or 4, wherein the substrate layer is pressure- sensitive adhesive layer, preferably an acrylic pressure-sensitive adhesive, a silicone pressure- sensitive adhesive, or a. urethane pressure-sensitive adhesive.
6. The wound dressing according to claim 1 or 2, wherein the backing layer comprises a laminated film comprising an elastomer film having provided on one side thereof a supporting film, and wherein the substrate layer is an adhesive layer, said adhesive layer being formed on the elastomer film side of the laminated film, wherein the adhesive layer mainly comprises an acrylic polymer and both the adhesive layer and the supporting film comprise a component that is liquid or aste at 20C.
7. The wound dressing according to claim 6, wherein the liquid or paste component is selected from the group consisting of propylene glycol dicaprylatc. propylene glycol dicaprate, propylene glycol diisoslearate, glyceryl monocaprylate, glyceryl tricaprylate, glyceryl tri-2- ethylhexanate, glyceryl tricaprate, glyceryl trilaurate, glyceryl triisostearate, glyceryl trioleate, trimethylolpropane tri-2-ethylhexanate and isopropyl myristate.
8. The wound dressing according to claim 1 or 2, wherein the substrate layer is an adhesive layer comprising a rubber-based adhesive, a polymer having a water-absorbing property and/or a water- swelling property, and a metal oxide and/or a metal salt, said polymer having the water- absorbing property and or the water-swelling property being a polymer containing a functional group having an ability to form a salt and/or to coordinate,
9. The wound dressing according to claim 8, which further comprises a nonwoven or woven fabric laminated with the backing on the side opposite the adhesive layer.
10. The wound dressing according to claim 8 or claim 9, wherein said rubber-based adhesive contains poiyisobutyiene as the base material and further contains at least one member selected from the group consisting of polyisoprene, natural rubber, polybutadiene. polyethylene, polypropylene, and an ethylene-propylene copolymer.
1 1. The wound dressing according to any one of claims 8 to 10, wherein said metal salt comprises a water-soluble metal salt, preferably an aluminum salt, calcium chloride or copper sulfate.
12. The wound dressing according to claim 1 or 2, wherein the substrate layer is an adhesive layer comprising a copolymer obtained by copolymerization of a monomer mixture containing an acrylic acid alkyl ester having C4 - C12 alkyl group, a (meth)acrylie acid, and a meihacrylie acid alkyl ester having CI - C4 alkyl group, which mixture is free of a multifunctional monomer having two or more unsaturated double bonds in a molecule, wherein the copolymer has a gel-sol. ratio of 35:65 to 55:45 and a weight average molecular weight of the sol portion of 300,000 to 500,000.
13. The wound dressing according to claim 1 or 2, wherein the substrate layer is an adhesive layer comprising a copolymer obtained by copolymerization of a monomer mixture containing an acrylic acid alkyl ester having C4 - CI 2 alkyl group, a (meth)acrylic acid, and a methacrylic acid alkyl ester having CI - C4 alkyl. group, which mixture is free of a multifunctional monomer having two or more unsaturated double bonds in a molecule, wherein the copolymer has a gel fraction of 35 to 55% and a swelling ratio of a gel portion of 50 to 90 times.
14. The wound dressing according to claims 12 or 13, wherein the monomer mixture comprises 1 to 5 parts by weight of the (meth)acrylie acid and 3 to 20 parts by weight of the methaerylic acid alkyl ester, per 100 parts by weight of the acrylic acid alkyl ester.
15. The wound dressing according to claim 1 or 2, wherein the substrate layer is an adhesive layer comprising an acrylic copolymer (100 parts by weight) obtained from a monomer mixture comprising a (meth)acrylic acid alkyl ester monomer (40-80 wt%), an alkoxy group-containing ethylenically unsaturated monomer (10-60 wt%) and a carboxy group-containing ethylenically unsaturated monomer ( 1- 10 wt%), and a carboxylic acid ester (20-120 parts by weight), which is liquid or paste at 20C, wherein the acrylic copolymer has a gel fraction of 30-80 wt%.
16. The wound dressing according to claim 1 or 2, wherein the substrate layer is an adhesive layer comprising a cross-linked polycondensate (A); and an oil additive (B); wherein the cross- linked polycondensate contains repeating units derived from a dicarboxylic acid (a) and a diol (b); wherein the weight average molecular weight of the polycondensate (A) before cross-linking is from 20,000 g/mol to 85,000 g mol; and wherein the content of oil additive (B) is 1 wt% to 150 wt% more preferably 80 wt% to 120 wt%, relative to the cross-linked polycondensate (A).
17. The wound dressing according to any one of claims 1 to 16, wherein the wound dressing is an adhesive patch in which the substrate layer is a pressure-sensitive adhesive layer coated on the backing layer, and wherein at least one compound according to Formula (1) is coated on the skin-facing surface of the adhesive layer.
Description  (OCR text may contain errors)

Wound dressing

1. Fl ELD OF THE INVENTION Compounds according to Formula (1) reduce scarring in wounds and exhibit biofilm inhibitory and eradicating effects. The present invention relates to a wound dressing comprising a compound according to Formula (1).

2, BACKGROUND OF THE INVENTION

Wound dressings are known, in the art. For example, EP 272 149 Bl describes a hydrocolloid- based medical dressing containing active components such as antiseptic and anti-inflammatory agents, US 8821916 B2 describes a dry medical dressing in the form of foam that is capable of releasing anti-bacterial agents to a wound bed. US 6312713 describes a thin-layered dressing for surface wounds which gradually releases drugs, such as analgesics. The drug is incorporated in a hydroph lic polymeric matrix and may be used topically. WO 2007/098772 Al describes a dressing for the local treatment of pain in a wound, said dressing comprising an absorbent element and an active pain relieving composition. US 2934066 A describes a wound covering coated with metals, especially silver, which is reported to have a disinfecting effect. US 7270721 B2 describes an antimicrobial composite which comprises a first, liquid permeable layer and a second layer arranged on the first layer. An antimicrobial metal in elemental form is present between the first and second layers. US 2010/01 6454 Al describes dressings comprising silicone elastomer cross-linked polymers that applied to closed wounds and cured at room temperature,

There is a need in the art for wound dressings that exhibit biofilm inhibitory and eradicating effects as well as reduce scarring in a healing wound. 3. SUMMARY OF THE INVENTION

The present invention relates to a wound dressing comprising:

(i) a backing layer; and

(ii) a substrate layer comprising at least one compound according to Formula (1):

wherein Ri and R2 may be the same or different and are selected from the group consisting of hydrogen, -SO3M and a physiologically hydrolyzable chemical group, wherein M is a cation, preferably a metal cation, and the physiologically hydrolyzable chemical group is selected from the group consisting of alkyl, alkylcarboiiyl, alkenylcarbonyl arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylether, alkenylether, arylether, and lieteroarylether groups wherein the alkyl group or moiety consists of unsubstituted or substituted, straight-chain or branched-chain or cyclic alkyl groups having 1 -22 carbon atoms, wherein the alkenyl moiety consists of unsubstituted or substituted, straight-chain or branched-chain or cyclic alkenyl groups having 2-22 carbon atoms, wherein the aryl moiety consists of unsubstituted or substituted phenyl, or phenalkyl groups wherein the alkyl moiety contains 1-3 carbon atoms and the phenyl moiety is unsubstituted or substituted, and. the heteroaryl moiety is an aromatic 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur.

The substrate can be an adhesive layer or a non-adhesive absorbent layer. The compound according to formula (1) can be uniformly mixed in the substrate layer and/or it can be coated on the wound-facing side of the substrate layer. The wound dressing of the invention is particularly suited as an adhesive patch for delivering compounds according to Formula (1) to treat wounds and inhibit or eradicate biofiims.

4. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts a wound dressing having a backing layer, an adhesive substrate layer that comprises at least one compound according to Formula (1), and a release liner (the protective layer). Figure 2 depicts a wound dressing having a backing layer, an adhesive layer, a non-adhesive substrate layer, and a release liner. In the depicted embodiment the non-adhesive substrate layer contains a compound according to Formula (1).

Figure 3 shows the release property of isosorbide from various wound dressings according to the invention.

Figure 4 shows the release amount of isosorbide from the wound dressing of example 1 ,

Figure 5 shows the release rate of isosorbide from various wound dressings according to the invention after 4h and 24 h.

Figure 6 shows the peel force of various wound dressings according to the invention.

5. D ESCRIPTION OF THE INVENTION

As used herein, the terms "comprises", "comprising", "includes", "including", "has", "having" or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a wound dressing that comprises a list of components is not necessarily limited to only those components but may include other components that are not expressly listed or inherent to such a composition. That said, the terms "comprises", "comprising", "includes", "including", " as", "having" or any other variation thereof also cover the disclosed embodiment having no further additional components (i.e. consisting of those components). By way of example, a wound dressing comprising a backing layer and a substrate layer comprising a compound according to Formula (1) discloses the wound dressing with just these components as well as wound dressings comprising these components along with other unmentioned components (e.g. a release liner).

Also, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be non-restrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular. By way of example, reference to a substrate comprising a compound according to Formula (1 ) should be understood to mean that the substrate comprises one or at least one compound according to Formula ( 1) unless specified otherwise.

Further, when an aspect of the invention is described as being 'preferred', it should be understood that this preferred aspect of the invention can be combined with other preferred aspects of the invention. As an example, if polyurethane is described in a list of preferred materials for the backing layer, and an acyrylate-based adhesive is described in a list of preferred materials for the an adhesive substrate, then the present disclosure should be taken as a disclosure of a wound dressing incorporating these preferred components.

That said, the present invention relates to wound dressings, in particular wound dressings that can be used in methods for treating wounds, methods of reducing scar formation, and methods of treating a biofilm hifection as well as for methods of inhibiting or eradicating tire formation of biofilms. The present invention also relates to wound dressings for use in cosmetic methods of treating wounds and cosmetic methods of reducing scar formation.

Wounds that can be treated with a wound dressing according to the invention may be acute or chronic. Acute wounds are wounds that proceed orderly through the three recognised stages of the healing process (i.e. the inflammatory stage, the proliferative stage and the remodelling phase) without a protracted time course. Chronic wounds, however, are those wounds that do not complete the ordered sequence of biochemical events because the wound has stalled in one of the healing stages. Viewed alternatively a chronic wound is a wound that has not healed within at least. 30 days, preferably at least 40 days, more preferably at least 50 days, most preferably at least 60 days. The wound to be treated may be a breach in, or demtdement of, the tissue for instance caused by surgical incision or trauma, e.g., mechanical, thermal, electrical, chemical or radiation trauma; a spontaneously forming lesion such as a skin ulcer (e.g. a venous, diabetic or pressure ulcer); a blister (e.g. a friction or thermal blister or a blister caused by pathogen infection such, as chicken pox); an anal fissure or a mouth, ulcer,

A "scar" in the sense of the present invention means normal scars, hypertrophic scars, keloid scars, contracture scars, atrophic scars and striae. Symptoms of scars include skin discolorations (including redness, changes in pigmentation, or other discolorations e.g. from blanching), erythema, dry, flaky, or itchy skin, raised area above the surrounding skin, keloid formation, hypertrophy, scar pain, decreased vascularisation of the scar and/or surrounding tissue, reduced pliability, and poor aesthetic appearance (including quality and texture of the sear tissue). Thus, for the purpose of the present invention, the reduction of scarring can also be considered as the treatment (prevention or amelioration) of these symptoms.

The term "biofilm" is to be understood as having its ordinary meaning. A biolilm is a sessile community of microorganisms characterized by cells that are attached to a substratum or interface or to each other, that are embedded in a matrix of extracellular polymers (more specifically extracellular polymers that they have produced), and that exhibit an altered phenotype with respect to growth rate and gene transcription (for example as compared to their "non-biofilm" or free-floating or planktonic counterparts). The biofilms that may be treated in accordance with the invention, are not limited, in terms of the microorganisms that they contain. The biofilm may comprise any class, genus or species of microorganism, namely any microorganism that may form a biofilm. Such microorganisms typically include bacteria, including any genus or species of bacteria. Thus, the bacteria may be gram positive or gram negative, or gram test non-responsive. The bacteria may be aerobic or anaerobic. The bacteria may be pathogenic or non-pathogenic. It is particularly surprising that the molecules defined herein are able to kill bacteria in mature biofilms and the treatment of such biofilms is particularly preferred. Biofilms comprising or consisting of Gram positive bacteria are preferred targets. Biofilms comprising Staphylococcus are preferred targets, with biofilms comprising S. haemofyticus, S. aureus, and/or S. pidermidis being especially preferred. Biofilms may also contain fungi, algae and other organisms such as parasitic protozoa in addition to the bacteria. Such mixed colony biofilms are also treatable according to the methods described herein.

A "biofilm-associated infection" is a microbial infection of an. object or a subject where it is known or suspected that the microbes are present as a biofilm. As used herein, a subject refers to a human, or any non-human animal subject. Typically a biofilm-associated infection will be an infection where the existence of a biofilm is relevant to a particular clinical condition, e.g. to the diagnosis or prognosis, to the treatment regimen, to the severity of the infection, to the duration of the infection up to the point of treatment or anticipated in the future. Biofilms in chronic wounds are a preferred therapeutic target for the wound dressings of the present, invention. These chronic wounds include venous ulcers, diabetic ulcers, and pressure ulcers. Venous ulcers, for example, occur mostly in the legs, as a result of poor circulation (e.g., ischemia), malfunctioning valves of veins, or repeated physical trauma (e.g., repetitive injury). Pressure ulcers may be present when local pressure that is exerted at or around a wound site is greater than blood pressure, for ins tance, such that poor circulation, paralysis, and/or bed sores may contribute to, or exacerbate, the chronic wound. Diabetic ulcers may occur in individuals with diabetes mel tus. for example, persons in whom uncontrolled high blood sugar can contribute to a loss of feeling in the extremities, leading to repetitive injuries and/or neglect on the part of the individual to attend to injuries. Biofilms in chronic wounds that have resulted from acute wounds such as gunshot or shrapnel wounds, bums, punctures, or surgical wounds (e.g. postoperative wound infections) can also be treated with wound dressings according to the invention. Biofilms can be treated in other wounds such as those arising from radiation poisoning, malignancies, dermal infections, gangrene, nonhealing surgical wounds, pyoderma gangrenosum, traumatic wounds, acute arterial insufficiency, necrotizing fasciitis, and osteomyelitis (bone infection). "Treatment" of a biofilni includes prophylactic treatment and encompasses a reduction in size of the biofilm, a reduction in number of living microorganisms within the biofilni and prevention or reduction in the tendency of microorganisms within the biofilm to break free and form new biofilm colonies. The size, structure, integrity, and number of microbes in a biofilm can be analysed by any convenient method. For instance, scanning and transmission electronic microscopy is often used to assess the size, integrity and structure of a biofilm. When a subject is treated, treatment includes an improvement, observed by clinician or patient, in one or more of the symptoms associated with the infection, 5.1 Backing layer

The backing layer of the wound dressing serves to support the substrate layer when the wound dressing is applied to a wound and may be of any suitable layer known for use as a backing layer in wound dressings e.g. a foam layer, a woven or non- woven layer, or an elastomer film, Examples of the material that can be used as the backing layer include polyolefin such as polyethylene and polypropylene, polyester such as polyethylene terephthalate, polyamide such as nylon, polyvinyl chloride, and polyvinylidene chloride. The backing layer may be a composite film containing such a single film laminated with paper, non oven cloth, woven cloth, knitted cloth or metal foil in addition to such a single film. Elastomer films can provide strong support while maintaining flexibility and moisture penneability so as to exert an effect of fairly following the contour of the skin during sticking and lessening the irritation of the skin after placement. Examples of the elastomer employable herein include polyethylene, polyvinyl chloride, ethylene- vinyl acetate copolymer, polyamide, polyester, polyurethane, and acrylic polymer. Particularly preferred among these elastomers are polyamide, polyester, polyurethane and acrylic polymer, which have a high permeability to water vapour and so do not impede the perspiration from the skin. The thickness of the elastomer film is preferably predetermined to be from 10 pm to 150 pm, more preferably from 20 μηι. to 70 pm. When the thickness of the elastomer film falls below 10 pm, it is likely that the resulting film can break during peeling. On the contrary, when the thickness of the elastomer film exceeds 150 pm, it is likely that the resulting backing layer can less fairly follow the contour of the skin or exhibits deteriorated permeability to water vapor. Referring to the mechanical physical properties of the elastomer film, the modulus of the elastomer film, at 50% elongation is preferably predetermined to be from 0.2 to 15 N/imn2 as measured at ordinary temperature and humidity (23C and 60% RH) so as to provide suitable flexibility and allows the backing layer to follow the contour of the skin. The backing layer alone may have a moisture transmission rate of 500 to 14600 g/m2/24 hrs, preferably from 1000 to 2700 g/m2/24 hrs at 37C if measured according to DIN EN 13726-2. The backing layer may have a vapour transmission rate of 200 to 2000 L/m2/see5 preferably from 400 to 1000 L/m2/sec at 2 mbar if measured according to EN ISO 9073 -Tl 5. Higher values than those mentioned above can be advantageous in order to delay the saturation point of the wound dressing in strongly secreting wounds. Lower values can be beneficial in assuring a moist micro- environment around the wound in the case of low-secretion wounds. The backing layer can be transparent to allow the level of filling or moisture in the wound dressing or the status of the wound to be assessed without having to remove the dressing. The backing layer can be filled with colouring agents.

5.2 Substrate layer and active compound

In the present invention, one function of the substrate layer is to hold the compound according to Formula (1 ) until the wound dressing is applied to a wound. Upon application to a wound, the compound of Formula (1) migrates to the wound surface whereby it can exert its therapeutic effect. The substrate layer can be an adhesive layer or a non-adhesive layer as explained in more detail below.

Compounds for use in the present invention are those according to Formula (1):

wherein Ri and R2 may be the same or different and are selected from the group consisting of hydrogen, -SO3M and a physiologically hydrolyzable chemical group,

wherein M is a cation, and the physiologically hydrolyzable chemical group is selected from the group consisting of alkyl, alkenyl, alkylcarbonyl, alkenylcarbonyl arylcarboiiyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylether, alkenylether, arylether, and lieteroarylether groups, wherein the alkyl group or moiety consists of unsubstituted or substituted, straight-chain or branched-chain or cyclic alkyl groups having 1 -22 carbon atoms, wherein the alkenyl moiety consists of unsubstituted or substituted, straight-chain or branched-chain or cyclic alkenyl groups having 2-22 carbon atoms, wherein the aryl moiety consists of unsubstituted or substituted phenyl, or phenalkyl groups wherein the alkyl moiety contains 1-3 carbon atoms and the phenyl moiety is unsubstituted or substituted, and the heteroaryl moiety is an aromatic 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulphur. Suitable substituents, for all embodiments disclosed herein include: 3-12 member heterocycJe, C6-C 10 aryl, 5- 12 member heteroaryl, halogen (e.g. F, CI, Br), -NO:; NH2:S NR., -CN, -COR, - COOR, -CONR2, -OH, -OR, -OCOR, -SR, -SOR, -S02R, -SONR2, -SO2 R2, wherein each R in the substituent is independently selected from H, C I -C I 0 alkyl, 3-10 member heterocycie, C6- C10 aryl, 5-12 member heteroaryl.

M may be any suitable cation including, but not limited to, a hydrogen atom, a metal atom, or an ammonium or an alkylammonium ion. M is preferably a metal cation such as a cation of an alkali metal or an alkaline earth metal. Preferred metal cations are those selected from the metals Ag, Zn, AI, Li, Na, K, Mg and Ca, Metal cations based on Ag or Zn are useful because these metals can provide additional or complementaiy bactericidal or enzyme inhibiting properties. M may be a monovalent or polyvalent cation. When M is a polyvalent cation, two compounds according to Formula ( 1 ) may share M as a cation (e.g. dication bridging).

Exemplary alkyl .groups for the alkyl, alkylcarbonyl, alkoxycarbonyl, and alkylether, of Formula ( 1 ) include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyi, heptyl. octyl, nony , decyl, undecyl, dodecyl, tridecyl, as well as alkyl groups derived from fatty acids such valeric acid, isovaleric acid, caproic acid, enanthic acid, eapry!ic acid, peiargonie acid, capric acid, undecylic acid, lauric acid, tridecylie acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, and arachidic acid. Exemplary alkenyl groups for the alkenyl, alkenylcarbonyl, and alkenylether of Formula ( 1) include ethylene, propylene, butylene, pentylene, exylene, and octylene, including those derived from fatty acids such as myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaecenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, and arachidonic acid.

In preferred embodiments, Ri and R2 are selected from hydrogen, -SO3M, or a hydrocarbon group selected from alkyl, alkenyl, alkylcarbonyl, and alkenylcarbonyl, wherein the alkyl group or moiety consists of unsubstituted or substituted, straight-chain or branched-chain or cyclic alkyl groups having 1 -22 carbon atoms, and wherein the alkenyl moiety consists of unsubstituted or substituted, straight-chain or branched-chain or cyclic alkenyl groups having 2-22 carbon atoms. Ri and R2 may be the same or different. For example, Rj and R; may both be hydrogen, or one of Ri and R2 may be hydrogen and the other selected from the groups defined above. As another example, R] and i may both be methyl, or one of Ri and R2 may be methyl and the other selected from the groups defined above. As another example, Ri and R2 may both be -COMe, or one of R| and Ri may be -COMe and the other selected from the groups defined above. As a still further example, R i and Ri may both be -SO3M, or one of Rj and R2 may be -SO3M and the other selected from the groups defined above.

Preferred compounds according to Formula (1 ) are those where R| and R2 are the same or different and are selected from the group consisting of H, -SO3M, -R3 or -COR3, wherein R3 is a CI to C22 hydrocarbon group. More preferred are those compounds where i and 2 are the same and selected from the group consisting of H, -SO3M, -R3 or -COR3, wherein R3 is a linear

C I -C I 8 alkyl group, a branched C3-C18 alkyl group, a linear C2-C18 alkenyl group, or a branched C3-C18 alkenyl group. More preferred are those compounds where R i and R2 are the same and selected from the group consisting of H, -SO3M, -R3 or -CORj, wherein is a linear C I -C I 8 alkyl group, a branched. C3-C18 alkyl group, a linear C2-C 18 alkenyl group, or a branched C3-C18 alkenyl group. Also preferred are compounds according to Formula (1) where at least one of Ri and. R; is - SO3M. For example, preferred compounds include those where one of Ri and R; is -SO3M, and the other is H, -R3 or -COR3, wherein 3 is a linear CI -CI 8 alkyl group, a branched C3-C18 alkyl group, a linear C2-C18 alkenyl group, or a branched C3-C18 alkenyl group. Also preferred are those compounds where one of Ri and R2 is -SO3M, and the other is H, -R3 or -COR3, wherein R3 is a linear CI -CI O alkyl group, a branched C3-C10 alkyl group, a linear C2-C10 alkenyl group, or a branched C3-C10 alkenyl group. Also preferred are compounds according to Formula (1) where both R| and R are the same and are selected from either H, ~C, -C2H5, - COCH3, -COC2H5, or -SO3M.

Tlie compound according to Formula (1) may be any of the possible stereoisomers (e.g.

enaiitiomers or diastereoisomers). Thus, compounds according to Formula 1 having the same stereochemistry as isosorbide, isoidide or isomannide can be used in the present invention. Of these, compounds having the stereochemistry of isosorbide are most preferred. Thus, this disclosure should be taken to mean that, for all of the compounds according to Formula 1 , including all of the preferred embodiments described herein, the structure of the compound can have the same stereochemistry as isosorbide. It is to be understood that any disclosure herein with respect to the compounds of Formula (1) extends to the stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, and solvates thereof.

"Pharmaceutically acceptable salts", as used herein, are salts that retain the desired biological activity of the parent compound and do not impart undesircd toxicological effects.

Phannaceuticaliy acceptable salt forms include various crystalline polymorphs as well as the amorphous form of the different salts. The phannaceuticaliy acceptable salts can be formed with metal or organic counterions and include, but are not limited to, alkali metal salts such as sodium or potassium; alkaline earth metal salts such as magnesium or calcium; and ammonium or tetraalkyl ammonium, salts. The salts can be organic or inorganic in nature. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylmtrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N- methyiglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphospliate, polygalacturcmate, potassium, salicylate, sodium, stearate, subacetate, succinate, tannate. tartrate, teoclate, tosylale, triethiodide, trimethylammonium and valerate. "Solvates", as used herein, are addition complexes in which the compound is combined with an acceptable co-solvent in some fixed proportion. Co-solvents include, but are not limited to, ethyl acetate, lauryl lactate, myristyi lactate, cetyl lactate, isopropyl myristate, methanol, ethanol, 1 - propanol, isopropanol, 1 -butanol, isobutanol, tert-butanol. acetone, methyl ethyl ketone, acetonitriJe, benzene, toluene, xylene(s), ethylene glycol, dichloromethane, 1 ,2-diehloroethane, N-methylformamidc, Ν,Ν-dimethylformamide, N-methylacetamide, pyridine, dioxane, and diethyl ether. The term 'hydrate' is employed when the co-solvent is water.

Whether the compound according to Formula (1 ) is present in an adhesive substrate or a non- adhesive substrate (see detailed discussion below), it is preferably that the sum amount of active compounds according to Formula (1 ) are formulated in the wound dressing in an amount suitable for release of 1 to 100,000 mg/m2 or preferably 10 to 10,000 mg/m2, more preferably 30 to 3,000 mg/m" and most preferably 50 to 1000 mg/m2 within the first 24 hours of administration. Typically the delivery is limited by a rest fraction remaining in the adhesive resulting in an effective .release of 10-80% of the active agent. Improved release times and release amounts of active compounds according to Formula (1) can be achieved by ensuring that the substrate is sufficiently thin, particualry when the substrate is an adhesive layer. 5.2.1. Adhesive substrate

The substrate layer that comprises a compound according to Formula (1) may be an adhesive layer, preferably a pressure-sensitive adhesive layer. The compound according to Formula (1) may be distributed (e.g. uniformly) throughout the adhesive layer. For example, a composition comprising a solvent, an adhesive, and a compound according to Formula (i), together with any other components such as a tackifier, an organic liquid component and the like, may be layered (e.g. by coating) and then dried to form an adhesive layer in which the compound according to Formula (1) is distributed throughout. The compound according to Formula (!) may be distributed on the wound-facing surface of the adhesive layer. The wound facing side of the substrate layer is the side Dearest the wound when the dressing is applied to a wound. For example, the adhesive layer can first be prepared without the compound according to

Formula ( 1 ), this compound being coated on the surface of the adhesive layer in a subsequent processing step. When the compound according to Formula (1) is coated on the surface of the adhesive layer (e.g. by spray coating, dispense coating) it is preferable that the compound covers 50% or less of the surface area so as to maintain sufficient adhesion properties. The compound according to Formula (1) may be coated in any regular or irregular pattern. In certain

embodiments the pattern has translational symmetry along at least one axis, for example along two or three axes, hi certain embodiments, the pattern is in the form of a network of compound coating, such as a mesh pattern or a honeycomb pattern. In other embodiments the pattern consists of a plurality of islands, dots, or patches of compound separated by compound- free regions of the adhesive substrate. The adhesive substrate layer may comprise a compound according to Formula (1) distributed throughout the adhesive layer as well as coated on the wound facing side as explained above.

The adhesive layer can be any adhesive known in the art of wound dressings (e.g. hydro colloid adhesive layer). In one embodiment the adhesive layer is preferably a hydrophilic adhesive layer. In view of providing a quick release of the compounds according to Formula (1), it is preferable that the adhesive layer contains as little water as possible. In this respect, the adhesive layer preferably comprises 0.5 wt.% or less of water (based, on the toai weight of the adhesive layer in the wound dressing), more preferably 0.1 wt.% or less of water, and even more preferably 0.01 wt.% or less of water. While the adhesive constituting the adhesive layer is not particularly limited, examples thereof include acrylic adhesives comprising acrylic polymer; styrene-diene- styrene block copolymers (e.g., styrene-isoprene-styrene block copolymer, styrene-butadiene- styreme block copolymer, etc.); rubber-based adhesives such as polyisoprene, polyisobutylene, polybutadiene and the like; silicone-based adhesives such as silicone rubber, dtmethylsiloxane- based, diphenylsiloxane-based and the like; vinyl ether-based adhesives such as polyvinyl methyl ether), polyvinyl ethyl ether), poly(vinyl isobutyl ether) and the like; vinyl ester-based adhesives such as vinyl acetate-ethylene copolymer and the like; polyester-based adhesives comprising carboxylate component such as dimethyl terephthalate, dimethyl isophthalate, dimethyl phthalate, etc., and polyvalent alcohol components such as ethylene glycol, etc. and the like. Suitable commercially available adhesives that can be used for the present invention include those sold under the trade name acResin (BASF). Other suitable adhesives for the present invention are those described in EP 0528 191 Al , JP1 189926, EP 1323437 A l , FP 1 184039 Al, and EP 1285670 Al, all of which are incorporated herein by reference.

The adhesive layer may be a cross-linked adhesive layer obtained by subjecting the

aforementioned adhesive layer to a cross-linking treatment, or a non-cross-linked adhesive layer obtained without a cross-linking treatment in the present invention. Here, the cross-linking treatment refers to a known treatment which can form bonds between molecules or in a molecule in an adhesive layer component constituting the adhesive layer. The crosslinking treatment simultaneously enables maintenance of sufficient skin adhesive force of an adhesive patch and reduction of skin irritation such as pulling feeling of the skin and physical scraping of the stratum coraeum of the skin during peeling off of the adhesive patch from the skin surface. Examples of the cross-linking treatment include a chemical crosslinking 'treatment using a crosslinking agent, a treatment for ion cross-linking, and a physical crosslinking treatment using electron beam, ultraviolet light and the like. Examples of the crosslinking agent include metal salts such as zinc acetate and the like, an epoxy compound, an amide compound, an amine compound, acid anhydride, peroxide, an isocyanate compound and the like. To confer an adequate adhesiveness to the adhesive layer, for example, a tackifier such as rosin- based resin, polyterpene resin, chroman-indene resin, petroleum-based resin, terpene-phenol resin, xylene resin and the like may be contained. These may be used alone or in a mixture of two or more kinds thereof. Examples of the aforementioned petroleum-based resin include aliphatic (C5-based) petroleum resin, aromatic (C9-based) petroleum resin, copolymer series (C5-C9- based) petroleum resin and alicyclic saturated hydrocarbon resin obtained by partially or completely hydrogenating aromatic (C9-based) petroleum resin. As the alicyclic saturated hydrocarbon resin, one having a. softening point by ring and ball method of 90 - 150C is preferable. While the amount of the tackifier is not particularly limited, it is, for example, 10 wt% to 40 wt% based on the adhesive formulation from the aspects of imparting of appropriate adhesiveness and cost-effectiveness.

When desired, the adhesive layer can contain an organic liquid component, An organic liquid component is not particularly limited as long as it is liquid at room temperature (25C). or is a mixture of two or more kinds which finally becomes liquid at room temperature (25C).

Examples of the organic liquid component include glycols such as ethylene glycol, propylene glycol, butylene glycol, di ethylene glycol, dipropylene glycol, triethylene glycol, tripropylene glycol, polyethylene glycol), poly(propylene glycol) and the like; vegetable fats and oils such as olive oil, castor oil and the like; animal fats and oils such as liquid lanolin; hydrocarbons such as squalane and liquid paraffin; various surfactants; ethoxylated stearyl alcohol; glycerol monoesters of fatty acids such as oleic acid monoglyceride, eaprylie acid monoglyceride and lauryl acid monoglyceride; dialkyl esters of polyalkylene glycol such as polyethylene glycol dilaurate, polyethylene glycol diisostearate, polypropylene glycol diisostearate, polypropylene glycol dioleate and the like; glycerol diesters such as glycerol diacetate and the like; glycerol triesters such as glyceroltriacetate and the like, or a mixture thereof; alkylesters of fatty acid such as triethyl citrate and the like; long chain alcohols such as isostearyl alcohol, oleyl alcohol and the like; higher fatty acids such as eaprylie acid, oleic acid, linoleic acid; alkylesters of higher fatty acid such as isopropyl myristate; pyrrolidones such as N-methylpyrrolidone, N- dodecylpyrrolidone; sulfoxides such as decylmethylsulfoxide; and the like. These can be used alone or in a mixture of two or more kinds thereof. The adhesive layer preferably has an average thickness of 5 μηι to 400 μπι, more preferably 10 μιη to 300 μηι, and even more preferably 20 μιη to 200 μηι. The average thickness of the adhesive layer can be measured on the wound dressing before it is applied to a wound. When an adhesive layer lias an average thickness within the aforementioned range, the substrate has a superior skin protection effect, can sufficiently contain and deliver the compound according to Formula (1), and is superior in the skin adhesion performance. The average thickness can be adjusted within these ranges to regulate the adhesiveness of the wound dressing to a patient. For instance, a thicker adhesive tends to lead to increased adhesiveness. The average thickness can also be adjusted to provide the optimum, release rate for a particular compound according to Formula (1). In the present invention, the peel force of the adhesive layer is preferably 1 N/25 mm or greater in view of providing a strong adhesion to the skin so as to effectively deliver a compound according to Formula (1). More preferably, the peel force is 1 .1 N/25 mm or greater, 1.2 N/25 mm or greater, and more preferably 1.3 N/25 mm or greater- The upper limit of the peel force is not particularly limited, and relatively high upper limits can be used, particuallry if the adhesive layer is composed of a debondable (or switchable) adhesive. Preferred upper limits of the peel force are 20 N/25 mm or less, more preferably 15 N/25 mm or less, more preferably 10 N/25 mm or less, more preferably 5 N/25 mm or less, and most preferably 3 N/25 mm. or less in view of reducing stress on the skin when the wound dressing is removed. .Any of the disclosed peel force lower limits can be combined with any of the disclosed peel force upper limits to define a suitable peel. force range for the purposes of this invention. Exemplary peel force ranges include 1-20

N/25mm, 1.1 -15 N 25mm, 1.2-10 N/25mm, 1.3-5 N/25mm, amd 1-3 N/25mm.

The peel forces recited above can be determined by Test Method A of the approved standard ASTM D3330M-04(2GT0) using the ear of a pig as the substrate. The ear should be clean so as to be free of debris or other agents that might affect the peel force measurement. For example, the ear can be cleaned, in water to remove relatively large debris and then, after drying, pre-stripped with an acrylic-based adhesive (e.g. Transpose, 3M, USA) to remove minor debris and any remaining agents that might affect the measurement. Obtaining a constant peel force (within experimental error) between two sequential pre-stripping applications can be used as an indication that the ear is sufficiently clean to determine the peel force in accordance with the invention. When, measuring peel forces, the adhesive layer whose peel force is to be measured should correspond to that (composition, thickness) which will be used in the wound dressing.

5.2.2 Absorbent substrate

The substrate layer that comprises a compound according to Formula (1 ) may be a non-adhesive layer. For instance, the substrate layer may be any of the layer types conventionally used for absorbing wound fluids, serum or blood in the wound healing art, including foams, sponges, gauzes, woven and nonwoven fabrics, and combinations thereof. Suitable materials for the substrate layer include natural and synthetic polymeric absorbents (e.g. polyacrylate),

hydrocolloid/polysaccharide absorbents, cellulosic absorbents, gum and resin absorbents, inorganic absorbents, gel-forming fluid-interactive adhesive dressings, wool, cotton, lint and superabsorbents (e.g. super absorbent particles (SAP) and/or super absorbent fibres (SAF)). Superabsorbents are water insoluble materials, typically in the form of fiber or flock material, which are capable of absorbing and retaining large amounts of water or other aqueous fluid in comparison to their own weight. Disposable goods manufactured using superabsorbents can be more comfortable, less bulky, and longer lasting than similar products made with traditional absorbents such as cellulose fibers. Unlike a sponge, liquid binds to the superabsorbent even under pressure (for example when a wound is in a position such that a patient may have occasion to sit on the dressing). A cellulose matrix containing a superabsorbent, e.g.,

carboxymethylcellulose, can be used. Sodium polyarcrylate is especially preferred, and particular in granular or powder form.

The compound according to Formula (1) may be distributed throughout the absorbent layer or may be coated on the wound-facing surface of the absorbent layer. The compound according to Formula (1) may be coated on the absorbent surface in any regular or irregular pattern. In certain embodiments the pattern has translational symmetry along at least one axis, for example along two or three axes. In certain embodiments, the pattern is in the form of a network of compound coating, such as a mesh pattern or a honeycomb pattern. In other embodiments the pattern consists of a plurality of islands, dots, or patches of compound separated by compound- free regions of tire absorbent substrate. The absorbent layer may comprise a stop layer on the skin-facing surface for preventing any speck or fluff from the absorbent layer to enter the wound. The stop layer may be of any suitable material known in the art being capable of retaining absorbent material, such as a cellulose tissue, non-woven or a perforated polymeric film, knits, PP, PE, polyester or lycra. The absorbent layer may further comprise a wound contacting layer at the wound-facing surface. This wound contacting layer may prevent adherence to the wound as well as in growth of the dressing. The layer may preferably be highly permeable to wound exudate. Preferably, the wound contacting layer is in the fon of a polymer net. The absorbent layer may be embossed or pre-cut in order to enhance flexibility of the dressing.

The basis weight of the absorbent layer may be in the range of 50-500g/m2, such as 100-400 g/m2. The uncompressed thickness of the absorbent layer may be in the range of from 0.5 mm to 10 mm, such as 1 mm to 4 mm. The free (uncompressed) liquid absorbency measured for physiological saline may be in the range of 5 to 30 g g at 25C.

When the substrate layer that comprises a compound according to Formula ( 1 ) is a non-adhesive absorbent layer, then the wound dressing may comprise an adhesive in addition to the absorbent layer so that the wound dressing can be securely attached to a patient. The adhesive may be on the substrate layer or on the backing layer on an area around the substrate layer. The pattern of the adhesive may be any regular or irregular pattern. In certain embodiments the pattern has translalional symmetry along at least one axis, for example along two or three axes. In certain embodiments, the pattern is in the fonn of a network of adhesive coating, such as a mesh pattern or a honeycomb pattern. In other embodiments the pattern consists of a plurality of islands, dots, or patches of adhesive separated by adhesive- free regions of the substrate. In yet other embodiments, the pattern may be in the form of an adhesive-coated margin or annulus

surrounding an absorbent substrate, for example for the production of adhesive-bordered dressings (see Figure 2 as an example). In any event, the adhesive pattern suitably covers from about 10% to about 90% of the area of the coated surface of the substrate, for example from about 20% to about 50% of said area. In addition to the absorbent substrate layer comprising a compound according to Formula (1), any adhesive that is included in the wound dressing may also comprise a compound according to Formula (1).

5.3 Release liner

If the wound dressing contains an adhesive layer, then a release liner may be laminated to the wound-facing adhesive surface to protect the adhesive layer prior to application of the dressing to a wound. Before use, the release liner, if present, is removed to expose the wound-facing side of the adhesive layer. The release liner is optional and may not be necessary. For instance, the wound dressing could be wound around on itself (e.g. in the form of a roll) such that the backing layer of the wound dressing provides suitable protection for the adhesive layer positioned immediately above it.

The release liner, if present, is not particularly limited, and examples of suitable materials are known in the field. Examples of such include plastic films of polyester-based resin film such as poly(ethylene terephthalate); vinyl-based, resin film such as poly( vinyl chloride), po!y(vinylidene chloride), polystyrene and the like; acrylic resin film such as various acrylic and niethacry!ic polymers; polycarbonate resin film; polyimide resin film; cellulose-based resin film, such as acetyl cellulose, regenerated cellulose (cellophane), celluloid and the like; a laminate film of high-quality paper, glassine paper and the like and polyolefin-based film and the like. For safety, economic efficiency and drug-transfer properties, a polyester-based resin film is preferably used. The thickness of the aforementioned release liner is generally 10 μιη to 200 pm, preferably 25 μηι to 100 m. The release liner is preferably treated for easy peeling on the interfacial surface side with an adhesive layer, so as to facilitate peeling from the adhesive layer. While the easy peeling treatment is not particularly limited, a known method can be applied. For example, a treatment method for forming a peeling-treated layer using a release agent containing a curable silicone resin as a main component by a coating method such as bar coating, gravure coating and the like can be mentioned. The thickness of the aforementioned peeling-treated layer is preferably 0,01 μηι to 5 μην to ensure releaseability and uniformity of the coating. The thickness of the release liner having a peeling-treated layer is generally 10 μηι to 200 μιη, preferably 50 μιη to 100 μιη. from the aspect of handling property.

The release liner in the adhesive patch of the present invention may have an extended part outwardly extending over the adhesive patch main part. Since the extended part decreases the frequency of contact of the end of the adhesive patch main part against the inside of the package when the adhesive patch is contained in the package, even when an adhesive layer component oozes or protrudes from the end of the adhesive patch, main part, adhesion thereof to the inside of package which causes difficulty in taking the adhesive patch out from the package can be suppressed. To provide such effects, at least one part of the peripheral part of the adhesive patch main part preferably has a release liner with an extended part, and more preferably, the whole peripheral part of the adhesive patch main part has a release liner with an extended part. The length of the aforementioned extended part of the release liner is preferably about 0.5 mm to 10 mm, more preferably about 1 mm to 3 mm, so as to achieve the aforementioned effects and ensure smooth insertion into a package.

The release liner may also have a back split part. The aforementioned back split part is made by forming a broken line on the surface on the opposite side from the contact surface of the release liner with the adhesive layer. The shape of the aforementioned broken line may be linear or curve (e.g., wave shape), or a combination of these. The broken line may be a solid line or a dashed line, or a combination of these. Since a release liner has a back split part, the release liner can be easily removed when the adhesive patch is used.

5,4 Other active agents

In addition to the one or more compounds according to Formula (1), the substrate may comprise further agents capable of providing a therapeutic effect. For instance, the substrate may include one or more of an antimicrobial agents, antibiotic agents, anti-inflammatory agents,

antiproteolytic agents, anesthetic agents, nutritional agents, healing agents, coagulation agents, anticoagulation agents, oligodynamic metals, moisturizing agents, or angiogenesis stimulating agents.

Antimicrobial agent can. be a term for drugs, chemicals, or other substances that either kill or slow the growth of microbes. Among the antimicrobial agents are antibacterial drugs, including antibiotics, antiviral agents, antifungal agents, organometallic compounds such as silver carbenes, anti-parasitic drags, and oligodynamic metals to include silver and the like.

The antimicrobial agent can include an "Anti-microbial metal" which can be metals whose ions have an anti-microbial effect. "Metal" or '"metals" includes one or more metals whether in the form of substantially pure metals, alloys or compounds including oxides, and salts such as nitrides, borides, sulphides, lialides, carboxylates, or hydrides. The metal may also be biocompatible. Anti-microbial metals include Ag, An, Pt, Pd, Ir, Ga (i.e. the noble metals), Sn, Cu, Sb, Bi, Ce, and Zn. Atoms, ions, molecules or clusters of the anti-microbial metal (herein after "species" of the anti-microbial metal) can have "Anti-microbial effect" when they are released. When a compound according to Formula (1) is used where Rj and/or R; is ~S(M and M is Ag, then the wound dressing can provide multiple means for providing bactericidal effects (e.g. the dianhydroliexitol sulphate; the Ag cation; and the optional additional antimicrobial agent).

The antimicrobial, agent can be one or more of chloroxylenol (parachlorometaxylenol),

acedapsone; acetosulfone sodium; alamecin; alexidine; amdinocillin; amdinocillin; pivoxil; amicycline; amifloxacin; amifloxacinmesylate; amikacin; amikacin sulfate; aminosalicylic acid; aminosalicylate sodium; amoxicillin; amphoraycin; ampicillin; ampicillin sodium; apaicillin sodium; apramycin; aspartocin; astromicin sulfate; avilamycin; avoparcin; azithromycin;

azloeillin; azlocillin sodium; bacampicillin hydrochloride; bacitracin; bacitracin,

methylenedisalicyiate; bacitracin zinc; bambermycins; benzoylpas calcium; berythromycin; betamicin sulfate; biapenem; biniramycin; biphenaniine hydrochloride; bispvritbionemagsulfex; butikacin; butirosin sulfate; capreomycin sulfate; carbadox; carbenicillin disodium; carbeiiicillin, indanyl sodium; carbenicillin phenyl sodium; carbeiiicillin potassium; carumonam sodium; cefaclor; cefadroxil; cefamandole; cefamandolenafatc; cefamandole sodium; cefaparole; cefatrizine; cefazafiur sodium; cefazolin; cefazolin sodium; cefbuperazone; cefdinir; cefepime; cefepime liydrochloride; cefetecol; cefixime; cefinenoxime hydrochloride; cefinetazole;

cefinetazole sodium; cefonicid monosodium; cefonicid sodium.; cefoperazone sodium;

ceforariide; cefotaxime sodium; cefotetan; cefotetan disodium; cefotiam hydrochloride; cefoxitin; cefoxitin sodium; cefpimizole; eefpimizole sodium; cefpiramide; cefpiramide sodium; cefpirome sulfate; cefpodoxime; proxetil; cefprozil; celroxadine; cefsulodin sodium; ceftazidime;

ceftibuten; ceftizoxime sodium; ceftriaxone sodium; cefcroxime; cefuroximeaxetil;

cefuroximepivoxetil; cefuroxime sodium; cephacetrile sodium; cephalexin; cephalexin hydrochloride; cephaloglycin; cephaloridiiie; cephalothin sodium; cephapirin sodium;

cephradine; cetocycline hydrochloride; cetophenicol; chloramphenicol;

chloramphenicolpalmitate; chloramphemcolpantothenate complex; chloramphenicol sodiuni succinate; cnlorhexidinephosphanilate; chlorhexidinediacetate, chlorhexidinedihydrochloride, chlorhexidinediglucoiiate, chlortetracycline bisulfate; chlortetracycline hydrochloride; cinoxacin; ciprofloxacin; ciprofloxacin liydrochloride; cirolemycin; clarithromycin; clinafloxacin hydrochloride; clindamycin; clindamycin hydrochloride; clindamycinpalmitatc hydrochloride; clindamycin phosphate; clofazimine; cloxaciUinbenzathine; cloxacillin sodium; cloxyquin;

colistimethate sodium; colistin sulfate; coumermycin; coumermycin sodium; cyclacillin;

cycloserine; dalfopristin; dapsone; daptomycin; demeclocycline; demeclocycline hydrochloride; demecycline; denofiiiigin; diaveridine; dicloxacillin; dicloxacillin sodium; dihydrostreptomycin sulfate; dipyrithione; dirithromycin; doxycycline; doxycycline calcium; doxycyclinefosfatex; doxycyclinehyclate; droxacin sodium; enoxacin; epicillin; epitetracycline hydrochloride;

erythromycin; erythromycin acistrate; erythromycin estolate; erythromycin ethylsuccinate;

erythromycin gluceptate; erythromycin lactobionate; erythromycin propionate; erythromycin stearate; ethambutol hydrochloride; ethionamide; flerexacin; floxacillin; fludalanine; flumequiiie; fosfomycin; fosfomycintromethamine; fumoxieillin; furazoliuni chloride; furazoliumtartrate;

ftisidate sodium; fusidic acid; ganciclovir and ganciclovir sodium; gentamiciii sulfate;

gloximonam; gramicidin; haloprogin; hetacillin; hetacillin potassium; hexedine; ibaftoxaein; imipenem; isoconazole; isepamicin; isoniazid; josamycin; kanamycin sulfate; kitasaraycin;

levofuraltadone: levopropylcillin potassium; lexithromycin; lincomycin; lincomyci

hydrochloride; lomefloxacin; lomefloxacin hydrochloride; lomefloxacinmesylate; loracarbef; mafenide; meclocycline; meclocyclinesulfosalicylate; megalomicin potassium phosphate; mequidox; meropenem; methacycline; methacycline hydrochloride; methenainine; methenamine hippurate; methenamine mandelate; methicillin sodium; metioprim; metronidazole

hydrochloride; metronidazole phosphate; mezlocillin; mezlocillin sodium; minocycline;

minocycline hydrochloride; mirincamycin hydrochloride; monensin; moneosinsodiumr;

monovalent silver salts, nafcillin sodium; nalidixate sodium; nalidixic acid; natainycin;

nebramycin; neomycin palmitate; neomycin sulfate; neomycin undecylenate; netilmicin sulfate; neutramycin; nifuiradene; mfuraldezone; nifuratel; nif ratrone; nifurdazil; nifurimide;

nifiupirinol; nifurquinazol; nifurthiazole; nitroeycline; nitrofurantoin; nitromide; norfloxacin; novobiocin sodium; octenidinedihydrochloride, octenidinediacetate, octcnidinedigluconatc, ofloxacin; onnetoprim; oxacillin and oxacillin sodium; oximonam; oximonam sodium; oxolinic acid; oxytctracycline; oxytetracycline calcium; oxytetracycline hydrochloride; paldimycin; paracMorophenol; paulomycin; pefloxacin; pefloxaciiimesylate; penamecillin; penicillins such as penicillin g benzathine, penicillin g potassium, penicillin g procaine, penicillin g sodium, penicillin v, penicillin v benzathine, penicillin v hydrabarnine, and penicillin v potassium;

pentizidonc sodium; phenyl aminosalicylate; piperacillin sodium; pirbenicillin sodium;

piridicillin sodium.; pMlmycin hydrochloride; pivampicillin hydrochloride;

pivampicillinpamoate; pivampicillinprobenate; polyhexamethylenebiguanide (polyhexanide hydrochloride, PHMB); polym:yxin b sulfate; porfiromycin; propikacin; pyrazinamide; pyrithione zinc; quindecamine acetate; quinupristin; racephenicol; ramoplanin; raniniycin; relomycin; repromicin; rifabutin; rifametane; rifamexil; rifamide; rifampin; rifapentine; rifaximin;

rolitetracycline; rolitetracycliiie nitrate; rosaramicin; rosaramicin butyrate; rosaramicin propionate; rosaramicin sodium phosphate; rosaramicinstearate; rosoxacin; roxarsone;

roxithromycin; sancycline; sanfetrinem sodium; sarmoxicillin; sarpiciliin; scopafungin; silver acetate; silver nitrate, nanocrystalline silver, silver polystyrene sulfonate (cross-linked" and non- cross-linked); silver carboxymethyl cellulose, silver polysaccharides (such as silver chondroitin sulfate and the like), silver carbene compounds, sisomicin; sisomiein sulfate; sparfloxacin; spectinomycin hydrochloride; spiramycin; stallimycin hydrochloride; steffimycin; streptomycin sulfate; streptonicozid; sulfabenz; sulfabenzamide; sulfacetamide; sulfacetamide sodium;

sulfacytine; sulfadiazine; sulfadiazine sodium; sulfadiazine silver; sulfadoxine; sulfalene;

sulfamerazine; sulfameter; sulfamethazine; sulfamethizole; sulfamethoxazole;

sulfamonomethoxine; sulfamoxole; sulfamlate zinc; sulfanitran; sulfasalazine; sulfasomizole; siilfat azole; sulfazamet; sulfisoxazole; sulfisoxazole acetyl; sulfisboxazolediolamine;

sulfomyxin: sulopenem; sultamricillin; suncillin sodium; talampicillin hydrochloride; teicoplanin; temafloxacin hydrochloride; temocillin; tetracycline; tetracycline hydrochloride; tetracycline phosphate complex; tetroxopiim; thiamphenicol; thiphencillin potassium; ticarcillincresyl sodium; ticarcillin disodium; ticarcillin monosodium; ticlatone; tiodonium chloride; tobramycin; tobramycin sulfate; tosufloxacin; trimethoprim; trimethoprim sulfate; trisulfapyrimidines;

troleandomycin; trospectomycin sulfate; tyrothricin; vancomycin; vancomycin hydrochloride; virginiamycin and or zorbamycin. The anti-inflammatory agent can be one or more of hydrocortisone, hydroxy-triamcinolone, alphamethyldexamethasone, dexamethasone-sodium phosphate, dexamethasone; beclomethasone' dipropionate, clobetasolvalerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasonediacetate, diftucortolonevalerate, fluadrenolone, fluclaroloneacetonide, fludrocortisone, flu methasonepivalate, fluosinoloneacetonide.

fluocinoEide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene)acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate,

methylprednisolone, triamcinoloneacetonide, cortisone, cortodoxone, flucetonide,

fludrocortisone, difluorosonediacetate, fluradrenaloneacetonide, medrysone, amc, amcinafide, betamethasone and the balance of its esters, chlorprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide,

fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone

cyclopentylproprionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasonedipropionate, betamethasonedipropionate, triamcinolone

prostaglandin 11 synthetase inhibitors (Cox I or Cox II), flurbiprofen, ketorolac, suprofen, nepafenac, amfenac, indoniethacin, naproxen, ibuprofen, bromfenac, ketoprofen, mec!ofenamale, piroxicam, sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin, fenoprofen, benoxaprofen, nabumetome, etodolac, phenylbutazone, aspirin, oxyphenbutazone, NCX-4016, HCT-1026, NCX-284, NCX-456. tenoxicam, carprofen, cyclooxygenase type II selective inhibitors, vioxx, celecoxib, P54, etodolac, L-804600, S-33516; PAF antagonists, A- 1374 1. ABT-299, apafant, bepafant, minopafant, E-6123, BN-50727, nupafant, modipafauL PDE IV inhibitors, ariflo, torbafylline, rolipram, filaminast, piclamilast, cipamfylline, CG-1088, V-l 1294A, CT-2820, PD- 168787, CP-293121 , DWP-205297, CP-220629, SH-636. BAY- 19-8004, and/or roflumilast.

5.5 Other characteristics

The wound dressing may be any suitable shape or size, including a square, rectangle, circle, oval, triangle, strip or any other suitable shape in any desired size. The wound dressing can also be sterilized, if required, prior to packaging or application to a wound. The most preferred sterilization methods are X-ray irradiation and y-irradiation. Both of these sterilisation methods are compatible with the preferred adhesives of the present invention and did not affect the adhesion or release properties of the adhesives.

5,6 Preferred embodiments In a first preferred embodiment, the invention relates to an adhesive skin patch comprising a backing layer and a pressure-sensitive adhesive layer comprising a compound according to Formula (I) on one side of the backing layer. In this embodiment the backing layer preferentially comprises an ether-based urcthanc resin obtained from at least one member selected from the group consisting of polyoxytetramethylene glycol, butanediol, polyethylene glycol, and polypropylene glycol as a diol component, and methylene diphenyl-diisocyanate as an isocyanate component. Such a layer exhibits excellent moisture permeability in contrast to conventional moisture permeable polyurethanc layers which can suffer a considerable decrease in strength due to absorption of a large amount of moisture or swell as a result of excessive moisture absorption. In this embodiment, the weight-average molecular weights of the polyoxytetramethylene glycol, polyethylene glycol, and polypropylene glycol used as the diol component are not particularly limited but are preferably in the range of 500 to 3,000. It is also preferable that,

polyoxytetramethylene glycol, and. polyethylene glycol and/or polypropylene glycol be used together, hi particular, it is preferable that the ether-based uretliane resin contains 5 to 60% by weight of the polyoxytetramethylene glycol and 10 to 50% by weight of the polyethylene glycol. More preferably, the ether-based uretliane resin contains 5 to 45% by weight of the

polyoxytetramethylene glycol and 20 to 45% by weight of the polyethylene glycol. Further, use of a random copolymer of, for example, polyoxytetramethylene glycol and polyethylene glycol as the diol component, ensures high moisture permeability while preventing water swellability. In this embodiment, a chain extender may also be used. Conventional chain extenders may be used. Examples thereof include diols such as ethylene glycol, propylene glycol, and butanediol, and diamines such as ethylenenediamine and triethylenediamine.

The backing layer for an adhesive skin patch in this embodiment has moisture permeability of a 30 μηι-thick layer of preferably 800 g 'n -24 hrs or more and 4,000 g m2-24 lirs or less, more preferably 1,000 g/rrf-24 hrs or more and 4,000 g/nt2-24 hrs or less, and particularly preferably 1,300 g/ni2-24 hrs or more and 4,000 g/m2-24 hrs or less. The moisture permeability is obtained by charging a predetermined amount of water in a vessel having a predetermined size of aperture, sealing the opening of the vessel with a layer, allowing the vessel to stand under the conditions of a temperature of 40C and a relative humidity of 30% RH for 24 hours, and measuring an amount of water decreased per unit nr. The higher the moisture permeability of a layer, the layer causes less non-breathing.

The backing layer for an adhesive skin patch in this embodiment, in a thickness of 10 μιη to 50 μηι, has a tensile strength in at least one direction of preferably 5 to 30 N/20 mm-width, an elongation in at least one direction of preferably 400% to 1 ,000%, and a tear strength in at least one direction of preferably 400 to 1 ,000 N/cm-thickness. This design allows the backing layer to achieve flexibility and conforniability to the skin. Further, the backing layer preferably has a tensile strength in at least one direction of 10 to 22 N/20 mm-width, an elongation in at least one direction of more preferably 600% to 900%, and a tear strength in at least one direction of more preferably 550 to 850 N/cm-thickness. The backing layer for an adhesive skin patch, of the present embodiment, in a thickness of 10 μιη to 50 μιη, has a 100% modulus in at least one direction of preferably 1 to 5 N/20 mm-width.

The pressure-sensitive adhesive layer that is on one side of the backing layer comprises a compound according to Formula (1). It is preferable that the pressure-sensitive adhesive layer is formed from at least one kind selected from the group consisting of an acrylic pressure-sensitive adhesive consisting mainly of an acrylic acid ester, a silicone pressure-sensitive adhesive consisting mainly of polyorganosiloxane, and a urethane pressure-sensitive adhesive consisting mainly of polyether polyurethane and/or polyester polyurethane.

When the pressure-sensitive adhesive layer is to be formed form an acrylic pressure-sensitive adhesive, for example, an acrylic acid ester-based polymer is mixed with a carboxylic acid ester that is compatible with the acrylic acid ester-based polymer and a crosslinking agent and the resulting mixture is subjected to crosslinking treatment to obtain, the objective pressure-sensitive adhesive layer. Note that the carboxylic acid ester has 16 or more carbon atoms and is liquid or paste at room temperature.

The acrylic acid ester-based polymer means a polymer that consists mainly of (meth)acrylic ester and is copolymerized with a monomer copolymerizable therewith as necessary. Preferable examples of the (meth)acrylic acid ester include (meth )acrylic acid alkyl esters in which the alkyl group has 2 or more carbon atoms and which has 2 or more and 18 or less carbon atoms. Specific examples thereof include ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodeeyl, etc. esters of (meth)acrylic acid. It is preferable that one or more from among these (meth)acrylic acid esters be used.. The alkyl ester chains may be either linear or branched.

The monomers that are copolymerizable with the (meth)acrylic acid ester include, for example, carboxyl group-containing monomers such as (meth)acrylic acid, itaconic acid, and maleie acid, hydroxyl group-containing monomers such as 2-hydroxyIethyl(meth)acrylate and 2- hydroxypropyl (meth)acrylate, alkoxy group-containing monomers such as

methoxyethyl(meth)acrylate, ethoxyethyl(meth)acrylate, butoxyethyl(meth)acrylate,

methoxypolyethylene glycol (meth)acrylate, and ethoxydiethylene glycol (meth)acrylale, styrene, styrene derivatives, vinyl monomers such as vinyl acetate and N-vinyl-2-pyrrolidone, and so on. One or more of these monomers may be used to copolymerize the (meth)acryiic acid esters therewith.

The acrylic acid ester-based polymer desirably has a glass transition temperature of 260 or less. By setting the glass transition temperature of the acrylic acid ester-based, polymer at 260K or less, adhesion to the skin can be sufficiently exhibited so 'that the resultant pressure-sensitive adhesive layer is desirable as one for a pressure-sensitive adhesive sheet for medical use or hygine materials.

In this embodiment, gel-like pressure-sensitive adhesive layer can. be obtained by mixing an acrylic acid ester-based polymer, a carboxylic acid ester, and a crosslinking agent and forming erossl inked moiety in at least a portion thereof. The pressure-sensitive adhesive layer thus obtained can have a decreased elastic modulus in minute deformed regions, so that adhesion (wetting) of the surface of the pressure-sensitive adhesive layer to the unevenness of the surface of skin increases and sufficient adhesion to the surface of skin can be exhibited. In addition, when the adhesive skin patch is peeled from the skin, stress applied to the surface of skin can be released or dispersed. As a result, advantageous effects can be obtained in that substantially no physical stimulations are given onto the surface of skin when the adhesive skin patch is peeled off, while causing substantially no peeling off of the stratum corneum of the surface of skin, or minimized damages to the skin. This is particularly beneficial when the patch is used to deliver compounds according to Formula ( 1 ) to healing wounds.

The carboxylic acid esters that can be preferably used in this embodiment include esters of various fatty acids such as phfhalic acid, maleic acid, adipic acid and stearic acid with alkyl alcohols, esters with polyhydnc alcohols such as ethylene glycol and glycerol, and soon. For example, esters obtained by using monohydric alcohols such as ethyl mynstate. isopropyl myristate, isopropyl palmitate, butyl stearate, isopropyl isostearate, hexyl laurate, cetyl lactate, myristyl lactate, diethyl phthalate, dioctyl phthalate, octyl dodecyl myristate, octyl dodecyl oleate, hexyl decyl dimetliyloctaiioate, cetyl 2-ethylhexanoate, isocetyl 2-ethylhexanoate, stearyl 2-ethylhexanoate, and dioctyl succinate, and esters obtained by using poiyhydric alcohols, that is, dihydric or more alcohols such as propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol diisostearate, glyceryl monocaprylate, glyceryl tricaprylate, glyceryl tii-2- ethylhexannoate, glyceryl tricaprinate, glyceryl trilaurate, glyceryl triisostearate, glyceryl trioleate, and trimethylolpropane tri-2-ehtylhexanoate.

The carboxylic acid esters used herein should have 16 or more carbon atoms. If the carboxylic acid esters have 15 or less carbon atoms, the backing layer tends to absorb liquid, components in large amounts so that swelling deformation of the backing layer occurs.

In this embodiment, when the above-mentioned carboxylic acid esters are blended, at least one kind from among them is dissolved in the acrylic acid ester-based polymer. A blending amount of the carboxylic acid is not particularly limited. For example, it is preferable that the carboxylic acid ester in the range of 30 to 100 mass parts be added to 100 mass parts of the acrylic acid ester-based polymer.

In this embodiment, when the acrylic acid ester-based polymer having dissolved therein the above-mentioned carboxylic acid ester is used, it is necessary that crosslinked moiety be formed in at least a portion of the polymer. To form crosslinked moiety, crosslinking treatment is performed. For example, chemical crossiinkmg treatment may be perfonned by using an organic peroxide compound, an isocyanate compound, an organic metal salt, a metal chelate, an epoxy compound or the like or physical crosslinking treatment may be performed by using ionizing radiation.

The resin composition (pressure-sensitive adhesive) that forms the pressure-sensitive adhesive layer may be blended with various additives, e.g., plasticizers such as glycerol and polyethylene glycol, water-soluble or water-absorbing resins such as polyacrylic acid and

polyvinylpyrrolidone, tackifiers such as rosin-based, lerpene-based, petroleum-based tackifiers, various types of softening agents, and various additives such as fillers, pigments. In particular, when carboxylic acid esters having unsaturated bonds are used as the carboxylic acid ester, it is feared that the physical properties will change due to oxidation deterioration caused by oxygen in the atmosphere, thus failing to exhibit desired characteristics, so that it is preferable that conventional antioxidants are blended in the resin composition (pressure-sensitive adhesive).

It is preferable that for this embodiment the thickness of the pressure-sensitive adhesive layer is set in the range of 10 μιη to 100 pm. If the thickness of the pressure-sensitive adhesive layer is less than 10 pm, it may happen that no sufficient adhesion is exhibited during application to the skin or wound. On the other hand, if the thickness of the pressure-sensitive adhesive layer is above 100 μηι, it may happen that permeability of water vapor on levels that are required for adhesive skin patches cannot be obtained.

In a second preferred embodiment, the invention relates to wound dressing that is a medical, patch in which the backing layer is a laminated film comprising an elastomer film having provided on one side thereof a supporting film, and the substrate layer is an adhesive layer, said adhesive layer being formed on the elastomer film side of the laminated film,, wherein the adhesive layer mainly comprises an acrylic polymer and both the adhesive layer and the supporting film comprise a component compatible with the acrylic polymer and that is liquid or paste at ordinary temperature. This embodiment provides a medical patch for application on skin excellent in workability and handleability which exhibits so high an adhesivity that the elastomer film and the supporting film cannot be easily peeled off each other during production (e.g. of an adhesive sheet to prepare the patch.) but shows a drop of adhesion, between, the elastomer film and the supporting film to allow the supporting film to be easily removed from the elastomer film during use. Furthermore, the elastomer film of the adhesive sheet exhibits flexibility and moisture permeability to exert an effect of fairly following the contour of the skin during sticking and lessening the irritation of the skin. This is particularly beneficial, when the wound dressing is used to deliver compounds according to Formula (1 ) to wounds. In this embodiment, the supporting film and/or the adhesive layer comprises a liquid or paste component (as determined at 20C). More preferably, the elastomer film has the liquid or paste component. Examples of the elastomer employable herein include polyethylene, polyvinyl chloride, ethylene- vinyl acetate copolymer, polyamide, polyester, polyurethane, and acrylic polymer. Particularly preferred among these elastomers are polyamide, polyester, polyurethane and acrylic polymer, which have a high permeability to water vapor, because they cannot impede the perspiration from the skin. The thickness of the elastomer film is preferably predetermined to be from 10 pm to 150 μιη, more preferably from 20 pm to 70 pm. When the thickness of the elastomer film falls below 10 μιη. it is likely that the resulting film can break during peeling. On the contrary, when the thickness of the elastomer film exceeds 150 pm, it is likely that the resulting adhesive sheet can less fairly follow the contour of the skin or exhibits deteriorated permeability to water vapor. Referring to the mechanical physical properties of the elastomer film, the modulus of the elastomer film at 50% elongation is preferably predetennined to be from 0.2 to 15 N/mm as measured at ordinary temperature and humidity by a tensile test from the standpoint of flexibility that allows the adhesive sheet to follow the contour of the skin. The supporting film of this embodiment is laminated on the elastomer film to reinforce the flexible elastomer, improving the producibility and handleability of the adhesive sheet. The supporting film is preferably transparent or semi-transparent taking into account visibility that allows the confirmation of sticking site in use. Further, the supporting film normally has a relatively high elastic modulus with respect to the elastomer film. The modulus of the supporting film at 50% elongation is preferably from 2 to 200 N/mm2, more preferably from 8 to 50 N/mm2 as measured at ordinary temperature and humidity by a tensile test. The elastic modulus of the supporting film is properly determined by the elastic modulus of the elastomer film but is normally from about 3 to 20 times that of the elastomer film. It is appropriate that the supporting film has been previously subjected to various treatments on the side thereof on which the elastomer film is to be laminated because it is necessary that the elastomer film be laminated properly kept adhesive to the supporting film. Examples of these treatments include corona discharge, plasma treatment, and ultraviolet treatment.

Examples of die material to be used as supporting film include polyolefin such as polyethylene and polypropylene, polyester such as polyethylene terephthalate, polyamide such as nylon, polyvinyl chloride, and polyvinylidene chloride. The supporting film may be a composite film containing such a. single film laminated with paper, nonwoven cloth, woven cloth, knitted cloth or metal foil in addition to such a single film. As the supporting film there is preferably used a polyolefin. or polyester film from the standpoint of visibility or cost.

As the adhesive layer to be fonned on the elastomer film side of the adhesive patch, any of those mentioned for the first embodiment above can be used. Preferred for this embodiment is an adhesive mainly containing an acrylic polymer having a low irritation against the skin and an excellent transparency, the water vapor permeability of which can be highly predetennined. Specific examples of these acrylic polymers include those obtained by the copolymerization of a monomer such as (meth)acrylic acid alkyl ester (e.g., ethyl (meth)acrylate, propyl (meth)acrylate. butyl (meth)acrylate, hexyl (meth)acrylate, octyl (meth)acrylate, nonyl (meth)acrylate, decyl (meth)acrylate) which is a main component with one or more of hydrophilic monomers such as (meth)acrylic acid, itaconic acid, maleic acid, hydroxyethyl (meth)acrylate, mcthoxyethyl (meth)acrylate, etlioxyethyl (meth)acrylate, butoxyethyl (meth)acrylate and ethylene glycol (meth)acrylate. ITie term "(tneth)acrylate" as used herein is meant to indicate both acrylate and methacrylate and the term "(meth)acrylic acid" as used herein is meant to indicate both acrylic acid and methacrylie acid. The thickness of the adhesive layer is preferably from 10 μιη to 100 μηι from the standpoint of adhesiveness to the skin, flexibility that allows the adhesive sheet to follow the contour of the skin and permeability to water vapor. The adhesive layer is preferably subjected to crosslink itig by treatment with a heat-crosslinking agent such as isocyanate compound, organic pero ide, epoxy group-containing compound and metal chelate compound or treatment by ultraviolet rays, gamma-rays, electron, rays or the like to improve the adhesiveness thereof. In the adhesive patch of this embodiment, the liquid or paste component to be incorporated in the adhesive layer plays an important role of adjusting the adhesion between the elastomer film and the supporting film. Referring further to an example, when the aforementioned adhesive containing a liquid or paste component is applied to the laminated film on the elastomer film side thereof during the preparation of the adhesive sheet that is used to prepare the patch, the liquid or paste component in the adhesive layer partly moves to the supporting film through the elastomer film, attaining substantial equilibrium, with the elapse of about 24 hours at ordinary temperature. This phenomenon causes the adhesion between the elastomer film and the supporting film to be deteriorated, making it possible for the elastomer film and the supporting film., which has been, stuck fast to each other during preparation, to be peelable off each other in use.

Examples of the liquid or paste component for use in this embodiment include esters of phthalic acid, maleic acid, adipic acid, stearic acid or various aliphatic acids with alkyl. alcohol or polyhydric alcohol such as ethylene glycol and glycerin. Specific examples of these esters include esters of monohydric alcohol such as dibutyl phthalate, di-2-ethylhexyl phthalate. dibutyl adipate, di-2-ethylhe.xyl sebacate, dibutyl maleate, ethyl myristate, isopropyl. myristate, isopropyl palmitate, butyl stearate, isopropyl isostearate, hexyl laurate, cetyl lactate, myristyl lactate. diethyl phthalate, octyldodecyl myristatc, octyldodecyl oleate, hexyldodecyl dimethyloctanate, cetyl 2-efhylliexanate, isocetyl 2-ethylhexanate, stearyl 2-ethylhexanate and dioctyl succinate, and esters of dihydric or higher alcohol such as propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol diisostearate, glyceryl monocaprylate, glyceryl tricaprylate, glyceryl tri-2-ethylhexanate, glyceryl tricaprate, glyceryl trilauiate, glyceryl triisostearate, glyceryl trioleate and trimethyl lpropanc tri-2-ethylhexanate. These compounds may be used singly or in combination of two or more thereof. From the standpoint of the compatibility with the acrylic adhesive, carboxylic acid ester is preferably used, more preferably glycerin aliphatic acid ester. The content of the liquid or paste component varies with the kind of the adhesive and elastomer film but nonnally is from 20 to 200 parts by weight based on 100 parts by weight of the adhesive or from 5 to 30 g/m as basic weight.

In a third preferred embodiment the invention relates to a wound dressing comprising a backing layer and a substrate layer comprising a compound according to Formula (1), wherein the substrate layer is an adhesive layer comprising a rubber-based adhesive, a polymer having a water-absorbing property and/or a water-swelling property, and a metal oxide and/or a metal salt, said polymer having the water-absorbing property and/or the water-swelling property being a polymer containing a functional group having an ability to form a salt and/or to coordinate. When such dressing is applied to a wound, compounds according to Formula (1) can be delivered to the wound while at the same time the adhesive layer absorbs exudate from the wound. The polymer having the water-absorbing property and/or the water-swelling property forms ionic or coordinate bonds to metal ions generated from the metal oxide and/or metal salt, and the formation of such ionic or coordinate bonds serves to improve the adhesion of the adhesive composition, to maintain the shape retention property of the adhesive layer, to prevent the adhesive composition from dissolving into body fluid or flowing out, and to enable the adhesive layer to efficiently absorb an exudate and hold the absorbed liquids therein.

The backing layer is not particularly limited and can be any of the backing layers mentioned previous for the other embodiments. For this embodiment, the backing layer is preferably a film or sheet made of polyolefins, polyesters, polyurethanes, polybutadiene, polyamides, acrylic copolymers, or the like and nonwoven or woven fabrics made of polyesters, acetates, or the like. Of these, polyether polyurethanes, polyether-polyamide block polymers, and the like are advantageously used as stretchable materials. In order to impart, bacteria-barrier properties and virus impermeability to the dressing, use of a porous backing having no open cells is preferred. Further, it is preferred that the backing is in the form of a film having a thickness of about from 10 to 100 μιη. preferably about from 20 to 80 μηι. If the backing has a thickness below 10 μηι. the dressing has poor mechanical strength or handling properties, if the thickness of the backing exceeds 100 μηι, the dressing shows poor fitness and comfort to the body or has poor handling properties or moisture permeability. From the standpoint of attaining good handling properties and hand feeling, use of a multilayered backing is preferred which comprises a film or sheet of any of the above-described kinds and a nonwoven or woven fabric laminated therewith on the side opposite the side where an adhesive layer is to be formed.

It is preferred that the backing has a moisture permeability of from 300 to 5,000 g/m2-24hr, preferably from 500 to 2,000 g/m2-24hr. Moisture permeabilities as low as below 300 g/nr-24hr are not preferred in that, when the dressing is kept being applied to the body for a long time period, evaporation of the water that has absorbed, by the adhesive layer is diminished due to the low moisture permeability of the backing and, as a. result, the adhesive layer changes in

composition and part of the adhesive layer becomes more apt to flo out. On the other hand, moisture permeabilities exceeding 5,000 g/m2 24hr are not preferred in that the surface of the wounded part to which the dressing has been applied dries excessively due to the high moisture permeability of the backing and, as a. result, cure of the wound is retarded. In this embodiment, measured values of moisture permeability are obtained by the Payne cup method.

The adhesive layer in the dressing of this embodiment comprises an adhesive composition having the property of water-absorbing and/or the property of water-swelling. This adhesive composition comprises a rubber-based adhesive, a polymer having the water-absorbing property and/or the water-swelling propeity, and a metal oxide and/or a metal salt, and the polymer having the water- absorbing property and/or the water-swelling property contains a functional group having the ability to form a. salt and/or to coordinate.

In general, the adhesive layer is formed at a thickness of from. 10 to 4,000 μτη. It is preferable that the thickness of the adhesive layer is about from 10 to 1 ,000 μηι when the dressing is applied to a wound from which an exudate is oozing out in a relatively small amount, and is about from 1,000 to 4,000 μιη when the dressing is applied to a wound from which an exudate is oozing out in a relatively large amount. Small adhesive layer thicknesses are preferred in that the dressing of the preferred embodiment can have transparency and, hence, the wound to which the dressing lias been applied can be examined visually without the necessity of stripping off the dressing.

Examples of the rubber-based adhesive used in the adhesive layer include adhesives containing polyisobutylene, natural rubber, a polyurethane, a styrene-isoprene-styrene teleblock polymer, an acrylic polymer, polyvinyl acetate), an ethylene- vinyl acetate copolymer, or the like as a main component. It is necessary to use a rubber-based adhesive which has elasticity sufficient to fully relax a stress resulting from the water absorption and swelling of the polymer which is present in the adhesive layer along with the rubber-based adhesive and has the water-absorbing property and/or the water-swelling property. The rubber-based adhesive preferably is an adhesive which contains polyisobutylene as the base polymer for the adhesive, particularly an adhesive

containing a relatively low molecular weight polyisobutylene having a viscosity-average molecular weight of about from 30,000 to 300,000. From the standpoint of imparting cohesive force to the adhesive layer thereby to enable the adhesive layer to maintain the shape retention property and to be free from the problem, that part of the adhesive is squeezed out from a side of the adhesive layer, it is preferred that a high molecular weight polyisobutylene having a viscosity-average molecular weight of from 900,000 to 2,000,000 is added, along with the low molecular weight polyisobutylene described above, in an amount of from 5 to 20% by weight based on the weight of the rubber-based adhesive. The polymer having the water-absorbing property and/or the water-swelling property, which is added to the adhesive layer in the dressing of this embodiment, is a polymer containing a functional group having the ability to fonn a salt and/or to coordinate. As tMs polymer, a polymer which, when immersed in physiological saline, shows high saline penetrability and high saline- absorbing capacity is employed. Examples of the polymer include gelatin, pectin, carboxymelhyl cellulose (and its sodium salt), algiiiic acid (and its sodium salt), glucomannan, xanthine gum, locust bean gum, carrageenan, methyl vinyl ether- inaleic anhydride copolymers, and acrylic acid- vinyl alcohol copolymers. Examples thereof further include so-called highly water-absorbing polymers such as starch-acrylic acid graft polymers, acrylic acid-acrylamide copolymers, and crosslinked carboxymethyl cellulose. These polymers can be used alone or in combination of two or more thereof. It is a matter of course that a polymer which does not contain a functional group having the ability to form a salt or to coordinate, such as karaya gum, guar gum, poly( ethylene glycol), polyacrylaniide, polyvinyl alcohol), a starch-acrylonitrile graft polymer, or crosslinked dextrin, can be used in combination with the polymer containing a functional group having the ability to form a. salt and/or to coordinate. The metal oxide and/or metal salt contained in the adhesive composition is one which, when the adhesive layer of the dressing applied to a wound absorbs an exudate from the wound or body fluids, releases metal ions which form ionic or coordinate bonds to the polymer having the water- absorbing property and or (he water-swelling property, The metal salt consists of a water-soluble metal salt alone, a sparingly-water-soluble metal salt alone, or a combination thereof. Where the water-soluble metal salt is added, the adhesive composition quickly combines by absorption of exudates in the adhesive layer. On the other hand, where the sparingly-water-soluble metal salt is added, the adhesive composition gradually combines to maintain a sustained combined state. In the present invention, the term "water-soluble metal salt or metal oxide" is defined that 5 g or more of a metal salt or metal oxide dissolves in 100 g water, while the term "sparingly-water- soluble metal salt or metal oxide" is defined that less than 5 g of a metal salt or metal oxide dissolves in 100 g water.

Examples of the water-soluble metal salt include aluminum salts such as alum, burnt alum (anhydrous alum), aluminum sulfate, aluminum lactate, aluminum salicylate, and aluminum nitrate and other metal salts such as calcium chloride, iron chloride, copper sulfate, and barium chloride. These can be added alone or in combination of two or more thereof.

Examples of the sparingly- water-soluble metal salt or metal oxide include aluminum hydroxide, aluminum phosphate, aluminum citrate, aluminum benzoate, calcium hydroxide, calcium citrate, calcium carbonate, calcium hydroxide, calcium oxalate, calcium phosphate, calcium tartrate, zinc citrate, calcium oxide, aluminum oxide, zinc oxide, copper oxide, silver oxide, titanium oxide, silver chloride, barium sulfate, and calcium sulfite. These can be used alone or in combination of two or more thereof.

From the standpoint of attaining good absorption of exudates from, wounds, it is preferred that both the polymer having the water-absorbing property and/or the water-swelling property and the metal oxide and/or metal salt are added to the adhesive layer in the form, of a powder. In general,, an average particle diameter of those powders is from 1 to 1 ,000 μιη, preferably from 1 to 300 μιη. !f transparency of the dressing is required, an average particle diameter of the powders is 50 pm or less.

In the adhesive layer of this embodiment, the proportion of each component added, is specified below from the standpoints of the adhesion of the adhesive layer to the body, the rate of water absorption or swelling upon water absorption, die amount of water to be absorbed by the adhesive layer, and. the shape retention property of the adhesive layer. The relative amounts of the rubber-based adhesive (A), the polymer having the water-absorbing property and/or the water- swelling property (B), and the metal, oxide and/or metal salt (C) are such that the proportion of (A)/(B)/(C) is generally 30-80/20-65/0.5-20 by weight, preferably 40-60/30-60/2-10 by weight.

In a fourth preferred embodiment, the invention relates to an adhesive tape or sheet comprising a backing layer and a substrate comprising a. compound according to Formula (1), wherein the substrate is an adhesive composition comprising a copolymer obtained by copolymerization of a monomer mixture containing an acrylic acid alkyl ester having C4 - CI 2 alkyl group, a

(meth)aerylic acid, and a methacrylic acid alkyl ester having CI - C4 alkyl group, which mixture is "free of a. multifunctional monomer having two or more unsaturated double bonds in a molecule, wherein the copolymer has a. gel-sol ratio of 35:65 to 55:45 and a weight average molecular weight of the sol portion of 300,000 to 500,000.

As used herein, by the "gel-sol ratio" is meant a ratio of the weight of the gel portion, to the weight (weight of the sol portion) obtained by subtracting the weight of the gel portion from the initial weight of the copolymer. The weight of the gel portion is obtained by dissolving a predeteimined amount of the obtained copolymer in toluene, filtering and drying a solvent insoluble component (gel portion), and measuring the weight of this component.

When the copolymer to be used for the adhesive composition of this embodiment contains a gel portion of a lower level than that defined by the above-mentioned gel-sol ratio, adhesion to the skin is improved, but the cohesiveness decreases, which in turn causes inconvenience such as adhesive residue and the like after peeling of the adhesive tape or sheet In contrast, when the gel portion is contained at a higher level than that defined, by the above-mentioned gel-sol ratio, the problem of adhesive residue is resolved but the adhesive layer has a higher cohesive force, thus increasing the resilience of the adhesive layer to the skin, which in turn causes inconvenience in that an adhesive tape or sheet falls from the skin and the like. When the weight average molecular weight of the sol portion is lower than 300,000, the polymer having a low molecular weight is produced in a greater amount, as a result of which an adhesive composition containing such polymer may unpreferably contaminate the skin. In contrast, when the weight average molecular weight of the sol portion is greater than 500,000, the skin is free of contamination but the adhesive layer has an increased cohesive force, which in turn causes inconvenience in that an adhesive tape or sheet unpreferably falls from the skin and the like.

The gel-sol ratio of the above-mentioned copolymer and the weight average molecular weight of the sol portion can be adjusted to fall within the above-mentioned range by controlling the composition (monomer charge ratio) of the acrylic acid alkyl ester, niethacrylic acid alkyl ester and (meth)acrylic acid in the monomer mixture, or by changing the kind and amount of a chain transfer agent, polymerization temperature and the like. When the copolymerization is carried out by the emulsion polymerization to be mentioned later, the weight average molecular weight of the sol portion can be also controlled by adjusting the dripping speed of an emulsified monomer.

In a fifth preffered embodiment, the invention relates to an adhesive tape or sheet comprising a backing layer and a substrate comprising a compound according to Formula (1 ), wherein the substrate is an adhesive composition comprising 1 to 5 parts by weight of the (meth)acrylic acid and 3 to 20 parts by weight of the methacrylic acid alkyl ester, per 100 parts by weight of the acrylic acid alkyl ester. To afford an adhesive composition superior in the practical balance between adhesiveness and cohesiveness, the copolymer to be used for the adhesive composition is adjusted to have a gel fraction of 35 to 55%, and the swelling ratio of the gel portion adjusted to 50 to 90 times. As used herein, the "gel fraction" is calculated as a proportion (unit: %) of the weight of the gel portion relative to the initial weight of the copolymer (weight of the gel portion. + weight of the sol portion). The weight of the gel portion is obtained by dissolving a predetermined amount of the obtained copolymer in toluene, filtering, drying a solvent insoluble component {gel portion) and measuring the weight thereof.

Gel fraction can be measured by weighing the adhesive (weight Wl), immersing the adhesive in toluene at 20C for 7 days, extracting the soluble components, filtering insoluble matters through a PTFE membrane (average pore size 0.2 μιτι, drying and weighing the insoluble matter [weight (W2)] and then, calculating the gel fraction from the following formula;

Gel fraction (%) = [W2/(W1 x A/B)] x 100

wherein

A= weight (g) of (acrylic copolymer + cross linking agent)

B= weight (g) of (acrylic copolymer + cross linking agent +

carboxylic acid ester + other additive)

The "swelling ratio of the gel portion" is calculated and expressed in a "swelling ratio" (unit: times) of the weight before drying (solvent + gel portion) to that after drying (gel portion), which is obtained by dissolving a predetermined amount of the obtained copolymer in toluene and filtering and measuring the weight, thereafter drying the gei and measuring the weight.

To be specific, the above-mentioned copolymer to be used for this preferred embodiment shows gel fraction of 35 to 55% and swelling ratio of the gel portion of 50 to 90 times, preferably a gel fraction of 40 to 50% and swelling ratio of the gel portion of 60 to 80 times. When the gel fraction is lower than 35% and the swelling ratio of the gel portion is higher than 90 times, the adhesive layer shows an improved skin adhesiveness but lower cohesiveness, which in practice causes inconvenience such as adhesive residue and the like. When the gel fraction is higher than 55% and the swelling ratio of the gel portion is lower than 50 times, the adhesive composition shows lower adhesiveness, which may possibly cause inconvenience in that the adhesive tape or sheet falls off from the skin and the like,

In. the adliesive composition of this embodiment, the gel fraction and the swelling ratio of the gel portion of the copolymer can be adjusted to fall within the above-mentioned ranges by changing the charge amount of monomers to be subjected to copolymerization of an acrylic acid alkyl ester, a methaerylic acid alkyl ester and a (nieth)acrylic acid, or by changing the amount of a chain transfer agent, polymerization temperature and the like. When the copolymerization is carried out by the emulsion polymerization to be mentioned later, the swelling ratio of the gel portion can be also controlled by adjusting the dripping speed of an emulsified monomer.

The adhesive composition of the fourth and fifth preferred embodiments (i.e. gel-sol embodiment or gel- fraction embodiment) can deliver compounds according to Formula (1) while at the same time exhibit superior balance between an adhesiveness that permits sufficient fixing on the skin and a cohesiveness free of adhesive residue upon peeling. This is particularly useful when, the adliesive tape or sheet is applied to a wound. In both embodiments, 3 to 20 parts by weight, preferably 7 to 15 parts by weight, of a

methaerylic acid alkyl ester, and 1 to 5 parts by weight, preferably 2 to 4 parts by weight, of a

(meth)acrylic aeid are charged in a. monomer mixture, per 100 parts by weight of the acrylic acid alkyl ester. When the methaerylic acid alkyl ester is charged in an amount of less than 3 parts by weight per 100 parts by weight of the acrylic acid alkyl ester, the obtained copolymer shows a. lower glass transition temperature and improved adhesiveness, but lower cohesiveness to possibly leave an adliesive residue upon peeling in practical use. When the methaerylic acid alkyl ester is charged in an amount exceeding 20 parts by weight per 100 parts by weight of the acrylic acid alkyl ester, the obtained copolymer shows an increased glass transition temperature and lower adhesiveness. However, because the cohesiveness is increased, an adhesive tape or sheet is free of an adhesive residue upon peeling from the skin, shows lower adhesion to the skin and possibly causes an increased pain upon peeling due to stick-slip phenomenon and the like.

When the amount of the (meth)acrylic acid in a monomer mixture is less than 1 part by weight per 100 parts by weight of the acrylic acid alkyl ester, the obtained copolymer shows insufficient adhesiveness, whereas when it exceeds 5 parts by weight, the copolymer used for an adhesive composition may cause lower adhesiveness to the skin.

For the production of the above-mentioned copolymer, for example, Iauryl mercaptan and the like are used as a chain, transfer agent. The chain transfer agent is generally added in an amount of 0.02-0.1 part by weight, preferably 0.04 to 0.07 part by weight, per 100 parts by weight of the monomer mixture.

In a sixth preferred embodiment, the present invention relates to a wound dressing comprising a backing layer and a substrate layer comprising a compound according to Formula (1), wherein the substrate layer is an adhesive layer, comprising an acrylic copolymer (100 parts by weight) obtained from a monomer mixture comprising a (meth)acrylic acid alkyl ester monomer (40-80 wt%), an alkoxy group-containing ethyienically unsaturated monomer (10-60 wt%) and a carboxy group-containing ethyienically unsaturated monomer (1 -10 wt%), and a carboxylic acid ester (20-120 parts by weight),, which is liquid or paste at 2()C, wherein the acrylic copolymer has a gel fraction of 30-80 wt%. The adhesive composition of tins embodiment is capable of delivering compounds according to Fomiula (1) to a wound surface while at the same time causes less steartiitiess of the skin surface and shows superior skin adhesion even daring perspiration. Gel fraction can be measured as described previously.

The substrate constituting the wound dressing of this embodiment is not subject to any particular limitation as long as it. can support the adhesive layer. To markedly improve steaminess of the skin surface when the adhesive tape or sheet is adhered to the skin surface and to prevent degraded adhesion to the skin during perspiration, the use of a moisture permeable substrate is preferable. The material of such substrate includes any of those listed previously. For this embodiment the substrate preferably comprises a urethane polymer {e.g., polyether polyurethane, polyester polyurethane and the like), amide polymer (e.g., polyether polyamide block copolymer and the like), acrylic polymer (e.g., polyacrylate and the like), polyolefin polymer (e.g., polyethylene, polypropylene, ethylene/vinyl acetate copolymer and the like), polyester polymer (e.g., polyether polyester copolymer and the like), cloth (e.g., nonwoven fabric) and the like. Of these, nonwoven fabric, urethane polymer and amide polymer are preferable, because they are particularly superior in water vapor permeation when prepared into an adhesive tape or sheet for application to skin and free of steaminess, whitening and the like when adhered to the skin surface. The substrate may be a monolayer film made of any one of the above-mentioned materials, or a laminate film consisting of plural films made of a single material or two or more kinds of materials. The above- mentioned substrate has a thickness of 10- 100 μιη, preferably 20-40 μιη, so that

uncom ibrtableness is not felt at the site where the adhesive tape or sheet for application to skin is adhered.

The acrylic copolymer to be used, for the adhesive composition of this embodiment is a copolymer obtained from a monomer mixture of a (mcth)acrylic acid alkyl ester monomer, an alkoxy group-containing ethylenically unsaturated monomer, and a carboxy group-containing ethylenically unsaturated monomer. The (meth)acrylic acid alkyl ester monomer imparts adhesiveness (or skin adhesion property) to an adhesive layer. The adhesive layer made from a (meth)acrylic acid alkyl ester monomer is advantageous in that it causes relatively less irritation to the skin, and adhesion to the skin is not easily degraded by use for a long time. Such

(meth)acrylic acid alkyl ester monomer is exemplified by linear or branched alkyl ester having 2 or more, preferably 6 to 15, carbon atoms. Examples thereof include ethyl ester, propyl ester, butyl ester, pentyl ester, hexyl ester, heptyl ester, octyt ester, nonyl ester, decyl ester and dodecyl ester of acrylic acid or methacrylic acid and the like. These esters may be used alone or in combination of two or more thereof. In this embodiment, it is preferable that 40-80 wt%, preferably 50-70 wt%, of the above- mentioned (meth)acrylic acid alkyl ester monomer be copolymerized with various ethylenically unsaturated monomers to be mentioned later. When the amount of the (meth)acrylic acid alkyl ester monomer to be copolynierized is less than 40 wt , the obtained acrylic copolymer does not show sufficient skin adhesion, whereas when it exceeds 80 wt%, the obtained acrylic copolymer shows decreased cohesion, which may result in an adhesive residue after peeling off thereof from the skin surface.

The alkoxy group-containing ethylenically unsaturated monomer imparts hydrophilicity to the acrylic copolymer to afford water vapor permeability and hygroscopicity of the adhesive layer. As the alkoxy group-containing ethylenically unsaturated monomer, preferred is alkoxy alkyl acrylate or alkoxy polyethyieneglycol acrylate containing alkoxy having 1 to 4 carbon atoms. Examples thereof include methoxyethyl acrylate, ethoxyethyl acrylate, butoxyethyl acrylate, methoxy polyethyieneglycol. acrylate, ethoxydiethyleneglycol acrylate, butoxydiethyleneglyeol acrylate and the like. The above-mentioned alkoxy group-containing ethylenically unsaturated monomer is desirably copolynierized and contained in the acrylic copolymer in a proportion of 10-60 wt%, preferably 20-50 wt%. When the amount of copotymerization is less than. 10 wt%, sufficient hydrophilicity and skin adhesion necessary for the adhesive layer during perspiration cannot be afforded. When it exceeds 60 wt%, the adhesive shows poor skin adhesion of an impractical level.

In the carboxy group-containing ethylenically unsaturated monomer, its carboxyl group acts as a reaction point in the cross linking treatment, and improves internal cohesion of the adhesive layer. This component is important for the preparation of an adhesive composition for application to skin according to the present embodiement. Typical examples of such monomer include acrylic acid, methacrylic acid, itaconic acid, crolonic acid, fumaric acid, maleic acid (anhydride) and the like. Of these monomers, acrylic acid and methacrylic acid are preferable from the aspects of copolymerization performance, handling property and the like. The above-mentioned carboxy group-containing ethylenically unsaturated monomer is copolynierized and contained in the acrylic copolymer in a proportion of about 1 -10 wt%, preferably 3-8 wt%. When the amount to be copolynierized exceeds 10 wt , the adhesive layer shows improved internal cohesion, but also shows unpreferably stronger irritation to the skin. The acrylic copolymer of this embodiment preferably has a weight-average molecular weight of not more than 1,000,000, preferably 500.000 - 900,000. The adhesive composition may be subjected to a chemical crosslinking treatment to adjust the gel fraction of the acrylic copolymer to a predetermined range. Alternatively, an adhesive composition after a chemical crosslinking treatment is processed to give an adhesive layer and the adhesive layer is subjected to ionization irradiation to adjust the gel fraction, to a predetermined range, thereby adjusting the internal cohesion of the adliesive layer. Therefore, the adhesive composition before chemical crosslinking treatment preferably has lower internal cohesion, and for this end, the weight-average molecular weight is preferably not more than 1 ,000,000. When die adhesive composition before chemical crosslinking treatment has a weight-average molecular weight of an acrylic copolymer of above 1 ,000,000, the internal cohesion of the adhesive layer thus formed may be increased too high to impair adhesion to the skin. The adhesive composition for application to skin according to the preferred embodiment contains carboxylic acid ester, which is liquid or paste at room temperature (25C). By dissolving such carboxyhc acid ester and the above-mentioned acrylic copolymer in an adhesive layer, the elastic modulus of the adhesive layer in a micro-deformation area is lowered and the adhesiveness (or wettability) of the surface of the adhesive layer to the irregularities on the skin surface to be adhered to is improved, whereby the adhesive layer shows superior adhesion to the skin. The addition of such carboxyhc acid ester also imparts superior perspiration resistant adhesiveness to the adhesive layer. The mechanism of this has not been elucidated, but it is postulated that, during perspiration, water present in the interface between the skin surface and the adhesive layer is absorbed into the adhesive layer by the surfactant- like action of the carboxylic acid ester, and combined with a plasticizing effect of the carboxylic acid ester, water can move easily in the adliesive layer and water that reached the substrate is easily dispersed to the outside in water vapor. As a result, adhesion to the skin can be maintained during perspiration. The addition of carboxylic acid ester to the adhesive layer reduces irritation and damage of corneum when the adhesive tape or sheet is peeled off from the skin surface, thereby decreasing the pain.

In the adliesive composition for application to skin according to this embodiment, the carboxylic acid ester needs to be liquid or paste at room temperature. Carboxylic acid ester, which is solid (e.g., wax) at room temperature, is hardly dispersed uniformly in an adhesive composition but shows low compatibility with the composition. Consequently, the adhesive layer may not permit adhesion to the skin or uniform adhesion to the skin, which is unpreferable in this embodiment.

The carboxylic acid ester, which is liquid or paste at room temperature (20C), preferably shows affinity for and compatibility with acrylic copolymer, as well as affinity for water produced during perspiration. Specific examples include esters of monoliydric alcohols such as ethyl myristate, isopropyl myristate, isopropyl palmitate, butyl stearate, isopropyl isostearate, hexyl laurate, cetyl lactate, myristyl lactate, diethyl phthalate, octyldodecyl myristate, octyldodecyl oleate, Iiexyldecy! dimethyloctanoate, cetyl 2-ethylhexanoate, isocetyl 2-ethylhexanoate, stearyl 2-ethylhexanoate, dioctyl succinate and the like with carboxylic acid, and esters of polyhydric alcohols such as propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol diisostearate, glyceryl monocaprylate, glyceryl tricaprylate, glyceryl tri( 2 -ethylhe anoate), glyceryl tricaprate, glyceryl tri laurate. glyceryl triisostearate, glyceryl trioleate,

trimethylolpropane tri(2-ethylhexanoate) and the like with carboxylic acid.

The above-mentioned carboxylic acid ester includes both saturated fatty acid ester and unsaturated fatty acid ester. For the prevention of oxidative degradation, saturated fatty acid ester is preferable, particularly saturated fatty acid ester having 8 to 10 carbon atoms is more preferable. Of the above-mentioned carboxylic acid esters, glycerine ester is preferable in view of small irritation to the skin and the economical aspects. Of the above-mentioned carboxylic acid esters, glycerine ester of saturated fatty acid having 8-10 carbon atoms is most preferable.

Specific examples include triglyceryl caprylate, tri glyceryl caprate and triglyceryl 2- ethylhexanoate.

In a seventh preferred embodiment, the wound dressing comprises a pressure-sensitive adhesive layer, wherein the adhesive comprises a mixture of a radiation-crosslinkable polymer (A) composed of at least 40% by weight of CI to C18 alkyl (meth)acrylates and a polymer (B) composed of at least 20% by weight of vinylpyrrolidone and of less than 40% by weight of C 1 to CI 8 alkyl (meth)acrylates. Preferably, the fraction of the polymer (B) in the mixture is less than 15% by weight, based on the sum of (A)+(B), The compound according to Formula (1) may be uniformly mixed in this adhesive composition or it may be coated on the surface of the adhesive layer. In an eigtlit preferred embodiment, the wound dressing comprises a pressure-sensitive adhesive layer, wherein the adhesive comprises a radiation-crosslinkabie polymer (C) composed of at least 40% by weight of CI to C 18 alkyl (meth)acrylates and comprising vinylpyrrolidone as

comonomer. Preferably, the amount of vinylpyrrolidone in the polymer (C) is less than 15% by weight. The compound according to Formula (1 ) may be uniformly mixed in this adhesive composition or it may be coated on the surface of the adhesive layer.

In a nineth preferred embodiment, the wound dressing comprises a pressure-sensitive adhesive layer, wherein the adhesive comprises a polymer derived from monomes consisting essentially of: (a) from about 50 to 80% by weight of alkyl acrylate or mcthacrylate wherein the alkyl group contains from, about 4 to 12 carbon atoms; (b) from about 20 to 40% by weight of hydroxyalkyl acrylate or mcthacrylate wherein the alkyl group contains from about 2 to 4 carbon atoms; (c) from about 0 to 35% by weight of alkyl acrylate or methacrylate wherein the alkyl group contains from about 1 to 3 carbon atoms; (d) from about 0 to 10% by weight of glycidyl acrylate or mcthacrylate; and (e) from about 0 to 10% by weight of acrylic acid, the dressing laving a water vapor transmission rate of at least 1000 liters vapor/m2/24 hours at 40C and 80% relative humidity difference,

In a tenth preferred embodiment, the wound dressing comprises a pressure-sensitive adhesive layer, wherein the adhesive comprises a silicone pressure sensitive adhesive comprising (a) a silicone fluid; (b) a silicate resin; and (c) a cohesive strengthening agent selected from the group consisting of nonionic surfactants, fatty acid esters of glycerol and solid particulate materials, said solid particulate materials being selected from the group consisting of metallic salts of fatty acids, metallic salts of phosphoric acid, metallic salts of carbonic acid, polysaccharides, carboxvpolymethylene, polyvinylpyrrolidone, polyvinylalcohol, amorphous precipitated silicas having a surface area of between about 10 and 200 m2/g. In a eleventh prederred embodiment, the invention relates to an adhesive tape or sheet comprising a backing layer and a substrate comprising a compound according to Formula (1 ), wherein the substrate is an adhesive composition as described in EP Application No, 13 198 936.0 which is incorporated herein by reference. More specifically, the Adhesive composition comprises a cross- linked polycondensate (A); and an oil additive (B); wherein the cross-linked polycondensate contains repeating units derived froma dicarboxylic acid (a) and a diol (b); wherein the weight average molecular weight of the polycondensate (A) before cross-linking is from. 20,000 g/mol to 85,000 g/mol; and wherein the content of oil additive (B) is 1 wt% to 150 wt% more preferably 80 wt% to 120 wt%, relative to the cross-linked polycondensate (A). In this embodiment, the dicarboxylic acid (a) is preferably a dicarboxylic acid selected from general formula (I),

RaOOC-Rl-R2-R3-COORb (I)

wherein R l is absent or selected from C 1 - 15 alkylene, C2- 15 alkenylene, and C2- 15 alkynylene, wherein each of these groups is optionally substituted; R2 is selected from CI -12 alkylene, C2-12 alkenylene, and C2- 12 alkynylene, each of which may contain one or two 5-7-membered rings, which may optionally be condensed wherein each of these groups is optionally substituted; R3 is absent or selected from CI -15 alkylene, C2-15 alkenylene, and C2-1 5 alkynylene wherein each of these groups is optionally substituted; each of Ra and Rb is independently selected from hydrogen, alkyl groups having 1 to 24 carbon atoms, and glycerol. Even more preferably, the diol (b) is a diol selected from general formula (II),

HO-R4-R5-R6-OH (II)

wherein R4 is absent or selected from C I -15 alkylene, C2-15 alkenylene, and C2-15 alkynylene, wherein each of these groups is optionally substituted; R5 is selected from CI -12 alkylene, C2-12 alkenylene, and C2-1.2 alkynylene, each of which may contain one or two 5-7-membered rings, which may optionally be condensed, wherein each of these groups is optionally substituted; R6 is absent or selected from C 1 - 15 alkylene, C2- 15 alkenylene, and C2- 15 alkynylene, wherein each of these groups is optionally substituted.

The above dicarboxylic acid and diol are preferably ditner of fatty acids and dimer of fatty alcohols. And oil additive is selected from sorbitan mono- or di-esters of fatty acids, PEG diester, sesame oil, isosorbide diester, mixtures of isosorbide diesters, sorbitol mono- and diesters, oleate esters as well as vernonia oil or mixtures thereof. The oil additive for this embodiment, or indeed any of the preferred emobdiments disclosed herein, may be selected from any natural or synthetic, organic or mineral oil which is suitable for topical application to the human skin. The oil additive may also be selected from the group of softeners, and plasticizers employed in polymer industry, provided the softener or plastieizer is suitable for topical application to the human skin. In a preferred embodiment the oil additive is colorless, and its viscosity is lower than that of the polycondensate. It is also preferred that the polycondensale is fully soluble in the oil additive or in the mixture of the oil additive and an organic solvent. The oil additive can for instance be one or more oils selected from the following list, but it is not limited thereto; sorbitan mono- or di -esters of fatty acids such as sorbitan ester of oleic acid, oleate esters, soybean oil, citrate ester, vernonia oil, PEG (Mw 100-1000) and. PEG derivatives such as PEG ether (such as dimethyl PEG) or PEG esters such as PEG distearate. fatty acids such as myristic acid, palmitic acid, stearic acid, lauric acid, oleic acid, isostearic acid, neodecanoic acid, trimethylhexanoic acid and neoheplanoic acid; the esters of these fatty acids such as isopropyl myristate; fatty alcohols such as myristyl alcohol, cetyl alcohol, oleyl alcohol and lauryl alcohol; aliphatic pyrrolidon.es such as N-lauryl-2-pyrrohdoiie; terpen es such as 1 - menthol, d-limonene and cc-terpineol; alkanes such as heptane, octane, nonane and decane; and substances acting as solubilizers and transdermal absorption promoters of medicinal ingredients such as crotamiton and α-, β- and γ-cyclodextrin. Besides, mention may be made of substances for use as fragrant/refreshing materials such as L-menthol, camphor, thymol, mint oil, castor oil, fennel oil, star anise oil, cinnamon oil, oil of cloves, thiamine oil, turpentine oil, eucalyptus oil, lavender oil, lemon oil, orange oil, bergamot oil and rose oil. Additionally, fatty acid esters of monovalent alcohols such as cetyl octanoate, hexyl laurate, isopropyl myristate, isopropyl palmitate, butyl stearate, myristyl lactate, and the like; dibasic acid esters such as dioctyl adipate, diethyl sebacate, dioctyl sebacate, dioctyl succinate, and the like; fatty acid esters of polyvalent alcohols and the like such as propylene glycol dicaprate, glycerol trioctanoate, glycerol

tri(octanoate/decanoate), medium chain fatty acid triglyceride, and the like; and in particular, isopropyl myristate, isopropyl palmitate, diethyl sebacate, middle chain fatty acid, triglyceride, and the like are preferably used. Further examples of the oil additive include glycols such, as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, tripropylene glycol, methylene glycol, poly(propy!ene glycol) and the like; fats and oils such as olive oil, castor oil and the like; lanolin; hydrocarbons such as squalane and liquid paraffin; various surfactants; ethoxylated stearyl alcohol; glycerol monoesters such as oleic acid monoglyceride, caprylic acid monoglyceride and lauryl acid monoglyceride; dialkyl ester of polyalkylene glycol such as poly(propylene glycol); glycerol diester such as glycerol diacetate and the like, glycerol triester such as glycerol triacetate and the like, or a mixture thereof; fatty acid alkyl ester such as triethyl citrate and the like; long chain alcohol; higher fatty acid such as oleic acid and caprylic acid; alkyl ester of higher fatty acid such as isopropyl myristate; pyrrolidon.es such as N- m ethylpyrrol idone and -dodecylpyrrolidone; sulfoxides such as decyl methyl sulfoxide; 1 ,3 - butanediol and the like. All of the above oil additives can be used alone or in a mixture of two or more kinds thereof.

In the adhesive composition according to this embodiment, the cross-linked polycondensate has a gel content value between 60 % and 95%, preferably between 70 % and 80%, The preferred embodiements 1 to 1 1 as described above can be generalised or combined with any of the other preferred features disclosed herein. For instance, any of the preferred adhesives may comprise a. compound according to Formula (1) 'uniformly mixed therein or may comprise a compound according to Formula (1) coated on a surface thereof. For any of the embodiments dislcosed above, the wound dressing may be an adhesive patch.

Further examples of adhesive compositions and wound dressings that can be modified to include a compount according to Formula (1) are described for example, in EP 0524 776 A 1. US

6,262,329 Bl , US 2006/0173 124 Al, US 2003/0153642 A l , WO 2005/102403 Al , EP 0528 191 Al, JP1 189926, EP 1323437 Al , US 2005/0169975 Al, EP 1 184039 Al , and EP 1285670 Al, US2001/024699 Al, US2004/167262 Al , US20010024699 (Al), and US2014/0066539 (Al), each of which is incorporated herein by reference,

6. EXAMPLES In the following examples, adhesive compositions were prepared by mixing a polymer with the desired amount of compound according to Fomiula ( 1 ), plasticizer (optional), tackifier (optional) and solvent (optional). The obtained viscous paste was mixed homogeneously. The mixture was then coated onto a release liner or backing/carrier substrate and cured. Lastly, the sheet was laminated and sterilized. Example 1-1 Preparation of sterile hot-melt UV cured acrylate containing isosorbide

An adhesive comprising the acrylate acResin A 260UV (BASF) (10 g) and 0.6 wt% of ground isosorbide was coated on a release liner (SILPHAN S 1R1003; Siliconature) at 50 μιη thickness, cured by 350 mJ/cmf of UV-C, laminated by nonwoven substrate (BR6316; Ahlstrom) and sterilized at 25 kGy gamma.

Example 1-2 Preparation of sterile hot-melt UV cured acrylate containing isosorbide

The same procedure as Example 1-1 was followed except that 1.3 wt% of ground isosorbide was used.

Example 1-3 Preparation of sterile hot-melt UV cured acrylate containing isosorbide

The same procedure as Example 1-1 was followed except that 1.9 wt% of ground isosorbide was used.

Example 2 Preparation of hot-melt UV cured acrylate containing isosorbide

The same procedure as Example 1-2 was followed except that the wound dressing was not sterilized.

Example 3 Preparation of solvent acrylate containing isosorbide

An adhesive composition comprising the acrylate Duro-Tak 387-2516 (Henkel) (15 g) and 1.3 wt% of ground isosorbide was coated on release liner (SILPHAN S 1 1003; Siliconature) at 30 μπι thickness, cured at 130C / 5min and laminated by nonwoven substrate (M1573F;

Freudenberg).

Example 4 Preparation of silicone containing isosorbide

An adhesive comprising the silicone Silpuran 21 12 (Wacker Chemie) { 15 g) and 0.6 wt% of ground isosorbide was coated on release liner (SILFLU XR87001 ; Silieonature) at 120 μηι thickness, cured at 130C / 5min and laminated by nonwoven substrate (M1573F; Freudenberg).

Example 5 Preparation of acrylic copolymer containing isosorbide

An adhesive comprising an acrylic copolymer according to EP 1 184 039 and 1.9 wt% of ground isosorbide was prepared into a 50 μιη thick sheet. The sheet was laminated by nonwoven substrate (BR6316; Ahlstrom).

Example 6 Preparation of polyester containing isosorbide

An adhesive comprising polyester (10 g), 0.6 wt% of ground isosorbide, 2.5 wt% of

DESMODUR N3600 (Bayer) as crossliiiker and 100 wt% of Polysorb ID 37 (Roquette Freres, France) was coated on a release liner (SILPHAN S 1 1003; Silieonature) at 150 μιη thickness, cured, at 130 C for 5 min, and laminated by polyurethane substrate (EU50; Smith & Nephew). The polyester was obtained by polycondensation of a dimer diol with a dimer diacid as follows: 150.15 g of Pripol 1009 and 149.85 g of Pripol 2033 were loaded in a 500 mL reactor equipped with a vacuum adaptor and a mechanical stirring system (using an "anchor" shaped stirrer) and mixed at 150 - 220 rpm. Next 15 mg of Ti(OnBu)4 was added to the reaction mixture and the colorless viscous solution was heated at 180C under vacuum (pressure < 10 mbar) and kept under these conditions for 2h00 after which the heating temperature was set at 225C for 3h00 (pressure < 5 mbar). Subsequently the pale yellow reaction mixture was allowed to cool under vacuum; once its temperature reached 130-140C, the reaction vessel was vented and discharged, Example 7 Preparation of hot-melt UV cured acrylate coated by isosorbide on surface

An adhesive comprising the acrylate acResin A 260UV (BASF) was coated on a release liner at 50 pm thickness, cured by 350 mJ/cm2 of UV-C, laminated by nonwoven substrate (BR6316; AMstrom) and sterilized at 25 kGy gamma. Then, 5% of the adhesive surface was coated with 20 wt% isosorbide solution in isopropanol to a 15 pm target thickness.

Peel Test

The wound dressings prepared above were subject to a peel test. In this test, wound dressing samples were slit to a width of 10mm and length 60mm. Samples were placed on porcine skin. Sample materials were applied on substrate and pressed with a 2kg roller twice, 30 min setting time was allowed before testing. The samples were removed at 180 degrees at a rate of 300 mm/min. The peel force was measured with a load cell units of grams force.

Release Test

The wound dressings prepared above were subject to a release test, in this text, wound dressing samples were slit to a width of 25mm and length 25mm. The samples were placed in the middle of the Petri dishes (approximately 60mm diameter) with the adhesive surface as the upper surface After removing the release liner, 7 ml of phosphate-buffered saline solution was added. The samples with PBS solution were shaken gently (70 rpm) and PBS solution was collected at each samplmg time point (4hr, 24hr). The concentration of active component was measured by LCMS (UFLCXR-LCMS2020; Shimadzu) and total release amount was calculated.

Release amount fmg/mlj * 7 fmlf

Release amount [mg/m I =— _____ _______

0.000625 fm2J 24

Total release amount fmg/m J = ∑ ( if t [mg/m2J )

Ri ; Release amount at sampling point t [hr]

Total release amount

Release rate f%J = ( . ) *100

Total amount in sample

The data in Figures 3 to 6 demonstrate that wound dressings according to the present invention are capable of releasing a compound according to Formula 1 efficiently and in a controlled manner and are therefore useful for treating wounds or a biofdm-associated infections.

Patent Citations
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WO1994023713A1 *15 Apr 199427 Oct 1994Minnesota Mining And Manufacturing CompanyTransdermal antiinflammatory composition
EP0528191A1 *21 Jul 199224 Feb 1993Nitto Denko CorporationDressing
EP1184039A2 *31 Aug 20016 Mar 2002Nitto Denko CorporationAdhesive composition for skin and adhesive tape or sheet for skin comprising the composition
EP1285670A2 *17 Aug 200226 Feb 2003Nitto Denko CorporationMedical adhesive composition and adhesive tape or sheet using the composition
EP2886578A1 *20 Dec 201324 Jun 2015Nitto Denko CorporationHydrophilic skin adhesive
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Classifications
International ClassificationA61K9/70, A61L15/58, A61L15/44
Cooperative ClassificationA61L15/58, A61L2300/412, A61L15/44, A61K9/7069, A61K9/7061, A61L2300/404
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