CN100471527C

CN100471527C - Antioxidant wound dressing materials

Info

Publication number: CN100471527C
Application number: CNB2004800238156A
Authority: CN
Inventors: B·M·库伦; D·阿迪森; D·格林哈尔
Original assignee: Surgikos Ltd
Current assignee: Johnson and Johnson Medical Ltd; Johnson and Johnson Medical 2004 Ltd
Priority date: 2003-06-20
Filing date: 2004-06-21
Publication date: 2009-03-25
Anticipated expiration: 2024-06-21
Also published as: CN1838970A; GB2402882B; GB0314454D0; GB2402882A

Abstract

A wound dressing material comprising a solid bioabsorbable substrate dyed with an antioxidant dyestuff. The substrate may comprise collagen, chitosan or oxidized regenerated cellulose, and the dyestuff may for example be an aniline or acridine dye. The material preferably also comprises a silver salt, whereby the dyestuff stabilizes the silver salt. Also provided are methods of making such materials, and wound dressings comprising such materials.

Description

Antioxidant wound dressing materials

The present invention relates to antioxidant wound dressing materials, be suitable for preparing the method for this class material and the application of this class wound dressing materials.

Reactive oxygen species, such as hydroxyl radical free radical (OH), singlet oxygen ( ¹O ₂), hydroperoxy radical (OOH), superoxide radical anion (O ₂ ^-) and hydrogen peroxide (H ₂O ₂) concentration can in damaged tissues, raise, yet thereby produce the condition of reorganization oxidative stress. low-level reactive oxygen species exist by attract and activation engulf and kill and wound antibacterial and discharge cytokine and commitment that the macrophage of somatomedin cicatrizes a wound in be favourable., prolong and more serious oxidative stress can delayed healing, because it can produce chronic inflammatory disease, under the situation of loss tissue reconstruction, shift the available energy supply and increase the level that causes histolytic matrix metalloproteinase to the antioxidant defence. in even more serious situation, the reactive oxygen species of elevated levels can produce aging or the programmed cell death (being programmed cell death) or the tissue necrosis (being uncontrollable cell death and nonvolatil thus tissue injury) of hydrogen peroxide-induced.

Under mild oxidative stress, think hydrogen peroxide (H ₂O ₂) be the dominant species that exists, it is formed by superoxides fast by hemocuprein. and the disproportionation of this kind of enzyme mediation is also minimized the generation of singlet oxygen, described singlet oxygen can and have an opportunity in the too fast generation of superoxides not produce when having enzyme to assist spontaneous disproportionation thus. and the superoxides disproportionation of enzyme mediation is also with hydroperoxy radical fast, the level that is superoxides nonionic form is reduced to minimum. and the level of hydrogen peroxide is maintained by the effect of catalase and glutathion peroxidase thus. therefore, under the mild oxidative stress condition, when the hydrogen peroxide level slightly rises (10 ^-8-10 ^-4About mole) time, find that the cell proliferation rate in the fibroblast cell cultures is upset.

Therefore, can assist the chronic wounds healing by using antioxidant wound dressing, described antioxidant wound dressing special with excessive reactive oxygen species, such as above-mentioned those listed reactions, and reduce the level of oxidative stress thus.

The compositions of chemical modification polymer of chemical group that comprised grafting has been described among the US-A-5667501, described chemical group provide as the antioxidant activity of being measured in diphenylpicrylhydrazyl (DPPH) test and by with wound bed portion in the molecular oxygen reaction produce low-level hydrogen peroxide so that stimulate macrophage activity and fibroblast proliferation. these compositionss can be used to promote the chronic wounds healing.Preferred described polymer is the polysaccharide that has the polymer of hydroxyl, carbonyl or amide functional base or be lower than the hydroxyl-functional base, described functional group has been converted to the derivant of persistency free radical or persistency free radical precursor, and promptly they are for removing the free radical of antioxidant group.

The compositions that comprises polysaccharide has been described among the US-A-5612321, described polysaccharide at least one hydroxyl of this polysaccharide grafting antioxidant. these compositionss can be used to promote chronic wounds healing especially.Preferred described polysaccharide is that hyaluronic acid and described antioxidant group comprise phenolic group.

Above-mentioned antioxidant wound dressing materials, is made such as hydroquinones or benzimidizole derivatives and matrix material covalent bond so that the antioxidant part by the multistep chemical reaction.Still there is demand to obtaining the more easy and cheap approach of antioxidant wound dressing materials.

The wound dressing that contains the antibacterial that is used for the treatment of wound infection also is known.The preferred antimicrobial agents that is used for wound dressing at present is some antiseptic, give birth to such as chlorhexidine and three ammonia, and silver, no matter be form of film, nanoparticle, or collargol. the chemical compound of silver is also as antibacterial. and for example, following complex silver salts can be advantageously used in antiallergic perception and tolerant bacteria bacterial strain: silver sulfadiazine, norfloxacin silver (silver norfloxacinate), pipemidic acid silver, Kaolin silver, ethylenediaminetetraacetic acid silver, thiosalicylic acid silver and silver chloride imidazoline.

The application of alginic acid silver salt in wound dressing described among the WO91/11206.

Described among the WO87/05517 can as or be used for the hyaluronic silver salt of antibacterial wound dressing. these materials trend towards instability having in the presence of the light. silver hair third contact of a total solar or lunar eclipse electronation and independent argent causes material deepening in a period of time.

The stable antibacterial wound dressing material of light has been described among the WO02/43743, wherein the light stabilizer that is selected from ammonium salt, thiosulfate, metal chloride and peroxide by interpolation is stablized silver salt and has been described the stable antibacterial wound dressing material of light among the .WO97/02038, wherein make silver salt stable by adding polyether polymer. this class light stabilizer has limited effect, and trends towards being extracted out from described dressing materials by the wound fluid.

Therefore, still there is demand in the improved antiseptic dressing that contains the stable silver compound of light.

Calcium alginate as wound dressing has been described among the GB-A-619165. antibacterial or Fungicidal compounds, can after they form, be administered on the silk such as acridine derivatives or eusol, maybe can join from wherein extracting out the solution of silk. calcium alginate is not biological absorbable.

Described chitosan films, rod, sheet, medicated bandage, patch etc. among the EP-A-0368253, they are made by the solution or the mixture of some chitosan derivative and antibacterial. still unexposedly can absorb wound dressing materials with antioxidant dyestuff dyeing biology.

The present invention provides wound dressing materials in aspect first, but comprises with the painted solid biologic absorption base of antioxidant dyestuff.

It is treated that the painted ＂ of term ＂ refers to the surface, but and using the solid-state solid material that makes this dyestuff and surface combination down of dyestuff. promptly after curing, carried out the solid material of post processing with dyestuff. have been found that biology absorption base material, such as oxidized regenerated cellulose to antioxidant dyestuff, having splendid affinity such as phenyl amines and acridine dye. this characteristic can make the fixing of dye of controlled amounts on host material according to simple and cheap staining procedure. find that further the painted material of gained has kept the antioxidant properties of this dyestuff, make them become the material standed for that treatment chronic wounds and further feature are the wound that the oxygen-derived free radicals level raises thus. these materials have useful antibacterial characteristics, particularly resisting gram-positive bacteria, and also anti-sometimes gram negative bacteria. bioabsorbable material progressively decomposes the slow release of having realized the effective dose antibacterial in wound.

The biological absorbable host material ＂ of term ＂ refers to the solid material of degrading fully and absorbing in mammalian body.This term does not comprise cellulose or textile material commonly used thus. this host material is water insoluble usually, but can be for water-swellable. in certain embodiments, substrate comprises (and mainly being grouped into by following one-tenth) solid biologic absorbable material, and this material is selected from following material: collagen protein; Chitosan; The plain derivant of bio-absorbable fibers is such as oxidized cellulose; Galactomannan is such as sugar/borate; Glycosaminoglycans is such as cross-linked-hyaluronic acid salt; Polylactide class/poly-Acetic acid, hydroxy-, bimol. cyclic ester class; The poly butyric esters; And composition thereof.

In certain embodiments, described substrate comprises that (and mainly being grouped into by following one-tenth) is selected from the solid biologic absorbable material of collagen protein, chitosan, oxidized regenerated cellulose and composition thereof.

For example, by producing oxidized cellulose with the dinitrogen tetroxide oxidized cellulose. this method changes into carboxylic moiety with the primary alconol base on the saccharide residue, thereby in cellulose chain, forming uronic acid residue. this oxidation is not carried out with complete selectivity, and the result is that 2 and 3 hydroxyls on the carbon are converted to the ketone group form sometimes. alkaline labile bond has been introduced in these ketone unit, and it separates the beginning decomposing copolymer by forming lactone and sugared ring crack when pH7 or pH7 are above.As a result of, oxidized cellulose is biodegradable and biological absorbable under physiological condition.

The preferred oxidized cellulose that is used for practical application is the cellulose by oxidation regeneration, such as the oxidized regenerated cellulose (ORC) of artificial silk preparation.Known for a period of time ORC has haemostatic properties and uses the degree that the ORC fabric can be used for alleviating the abdominal surgery tissue adhesion.

Can obtain oxidized regenerated cellulose (ORC) by method described in the US-A-3122479, the full content of the document is incorporated herein by reference. this material provides a large amount of advantages, comprising biocompatibility, biodegradable, non-immunogenic and the spy who is easy to be purchased. the ORC. that can obtain having different degree of oxidations and consequent degradation rate can use ORC with the form of insoluble fibre, comprise textile fabric, adhesive-bonded fabric and knitted fabric.

In certain embodiments; described oxidized cellulose is a particle form; such as fiber grain or powdered granule; they are scattered in suitable solid or the semi-solid topical medicament vehicle. especially; these materials preferably contain the ORC fiber; wherein the length that has of the fiber of at least 80% volume fraction is in the scope of 20 μ m-1000 μ m. for example; can be by grinding ORC cloth; subsequently the powder that grinds is sieved and obtain to treat size distribution to remove this extraneous fiber; average (volume averaging value) length of preferred ORC fiber is in the scope of 250 μ m-450 μ m. and in this scope, select the ORC fibre length to be easy to mix ORC and other composition; and it is compound with other composition more fully to produce highly uniform product .ORC, causes the treatment characteristic of sponge to strengthen.

Preferred described oxidized cellulose has greater than 50,000 mean molecule quantity. this class oxidized cellulose is insoluble to the wound fluid basically, but can resolve into biology very step by step under physiological pH can absorb fragment. described oxidized cellulose can be for neutral for its free acid form or it. for example, the present invention includes the partially or completely application of neutral material described in EP-A-0437095, the full content of the document is incorporated herein by reference. for example, as hereinafter more specifically as described in, ORC can partly be neutralized such as silver acetate by faintly acid silver salt.

In certain embodiments of the invention, described oxidized cellulose and collagen protein and/or chitosan are combined into the structure of type described in WO98/00180, WO98/00446, EP-A-1153622 or the WO2004/026200, full content with these documents is incorporated herein by reference especially. and for example, described oxidized cellulose can be for being scattered in the ORC fibers form of the grinding in the cryodesiccated collagen protein sponge.This situation provide because of with compound certain treatment and the synergism that produces of collagen protein.

If use, the collagen protein in the material so of the present invention can be collagen protein arbitrarily, comprises I type, II type or III collagen type; Natural fibrous collagen; Atelocollagen; The collagen protein of partial hydrolysis is such as gelatin; And combination. natural fibrous collagen, the natural fibrous collagen that for example derives from cattle is suitable. for example, the collagen protein that is prepared by Corii Bovis seu Bubali is the combination of type i collagen albumen (85%) and III collagen type (15%).

If use, chitosan in the material so of the present invention derives from chitin usually. and chitin is by natural biological copolymer that the N-acetyl group-the D-glucosamine units is formed. from the shell of shrimp and Eriocheir sinensis, extract chitin according to known way. then, for example make chitin partially deacetylated by handling with 5M-15M NaOH, thereby generation chitosan. chitinous deacetylated being practically impossible fully, but preferred chitosan is deacetylated at least 50%, more preferably at least 75% is deacetylated. and chitosan has been used for the Wound healing and bone regeneration of various physical form, for example as solution/gel; Film/membrane; Sponge; Powder or fiber.The chitosan of free alkali form is a swellable, but water insoluble basically under nearly neutral pH, but because of being dissolved in acid at ammonium on the chitosan chain.Can by for example with the dissolubility of the crosslinked reduction chitosan of chloropropylene oxide (epichlorhydrin). in general, be about 10 as the mean molecule quantity of the chitosan by gel permeation chromatography ⁵-Yue 10 ⁶

In specific embodiment, described substrate comprises following mixture of ingredients (and being made up of following mixture of ingredients basically): (a) collagen protein and/or chitosan; (b) oxidized regenerated cellulose, for example collagen protein/chitosan: the ORC dry weight than scope at the about 10:90 of about 90:10-, the about 25:75 of preferably about 75:25-, and the about 40:60. of particularly about 60:40-

Wound dressing materials of the present invention can also contain silver salt. and certain silver can be used as argent and exists, but there is the preferably colourless basically silver salt existence of conduct in the major part of preferred silver as silver salt.Silver in the preferred described material mainly is made up of silver salt, more preferably basically by forming as colourless basically silver salt. the amount (as silver ion and argent) of silver is at the about 5wt.% of about 0.01wt%-in the preferred material of the present invention, the about 2wt.% of 0.1wt%-more preferably from about, and the about 1wt.% of 0.1wt.%-most preferably from about, the most preferably from about more a spot of silver of the 0.3wt.%. antibiotic deficiency that is that can produce.Relatively large silver all wound healing cell produces antiproliferative effect.

For example, described in WO02/43743, can be by with silver salt or be dissolved in or be scattered in water or organic solvent, but silver introduced such as the compound treatment biology absorption base material in the ethanol. and suitable compound comprises silver oxide, siliver chromate, silver allantoinate, boric acid silver, glyceric acid silver (silver glycerolate), silver nitrate, silver acetate, silver chloride, silver sulfate, actol, Silver monobromide, silver iodide, Disilver carbonate, Itrol., lauric acid silver, deoxycholic acid silver, silver salicylate, para-amino benzoic acid silver and composition thereof. preferred described silver does not exist as silver sulfadiazine.

In preferred embodiments, silver can and host material compound. term ＂ complex ＂ refers to and is preferably having the ionic bond between silver and the polymer or an immixture of covalent bond on the molecular level. this complex preferably includes anionic polymer and Ag ⁺Between the silver that forms. suitable situation is that described anionic polymer is the polysaccharide of polycarboxylate or poly-Sulfation. suitable is that described anionic polymer comprises anion polysaccharide. suitable anion polysaccharide comprises: hyaluronate; Pectin; Carrageenan; Xanthan gum; The polysaccharide sulfate class; Such as dermatan sulfate or sulphation glucosan; And oxidized cellulose.

Can prepare the complex of anionic polymer and silver by a kind of method, this method comprises the step of handling anionic polymer with silver salt solution. and preferred described solution is aqueous solution. and preferred described anionic polymer is water insoluble basically and down described polymer is handled solid-state thus Ph 7 times.For example, this polymer can be solid fiber, sheet, sponge or form of fabric.In certain embodiments, described anionic polymer is salt and can regards processing as ion exchange thus. in other embodiments, described anionic polymer to small part is a free acid form, in this case, preferred silver salt is faintly acid salt, silver acetate for example, described thus anionic polymer to small part is neutralized by described silver salt.Similar approach is described among the EP-A-0437095, and the full content with the document is incorporated herein by reference especially.

Neutralization reaction can be carried out in independent water or alcohol, but preferably carries out in the mixture of water and alcohols.The application of water and alcohol mixture provides fine solubility by means of water for salt of weak acid, and alcohol has prevented that anionic polymer from excessive swelling, distortion and depletion taking place in N-process. therefore, the physical characteristic that has kept material. methanol is preferred alcohol, if because manyly in the above-mentioned salt in this alcohol and water, have fine solubility. preferred alcohols has the scope of about 4:1-1:4 with the ratio of water. and solution excessively is rich in alcohol, some salt may no longer dissolve so, if all the more so when particularly described alcohol is not methanol.If solution excessively is rich in water, so underway and the time polymer to a certain degree swelling can take place, and physical characteristic has to a certain degree loss such as the hot strength of polymer.Other useful alcohols comprises: for example ethanol, propanol and isopropyl alcohol.

Slight nertralizer, provide control such as the application of silver acetate to degree of neutralization. can not produce 100% neutral polymer to anionic polymer applied chemistry amount of calculation and stoichiometric nertralizer and carboxylic acid, because produce strong irreversible reaction, described alkali such as sodium hydroxide, sodium carbonate, sodium bicarbonate and ammonium hydroxide with alkali.

Anionic polymer works as ion-exchanger and the silver-colored cation of any silver salt by them is separated out from solution. and the by-product of this exchange is the acid from salt, and produce the weak organic acid that polymer is not had infringement by the salt that uses weak organic acid, such as acetic acid.The salt of strong acid has produced hydrochloric acid or sulfuric acid by-products respectively such as the application of sodium chloride or sodium sulfate, and these strong acid can produce infringement, such as making the polymer depolymerization.

When using faintly acid silver salt, the proton on the Ag ion exchange polymer and the part of salt are converted to weak acid. acid and the mixture of salt in solution have produced the buffer solution of keeping quite constant pH and controlling degree of neutralization. equilibrium establishment reaction makes silver ion combine with the acid moieties of polymer thus and combines with molecules of salt. the distribution of this silver ion prevented polymer neutralize carry out complete.

For example; use the silver acetate of stoichiometric amount to produce the degree of neutralization of hydroxy-acid group on the oxidized cellulose polymer of about 65-75%. this by generating the buffer solution control pH that the oneself produces and using the swollen method of methanol control material to produce the neutral material of part; physical characteristic wherein, for example hot strength and polysaccharide shape are protected.

The amount of used silver salt generally approximates the amount of acid content in the polymer or reaches its 2 times. perhaps, can use the silver salt of the stoichiometric amount that adds for the second time, condition is after interpolation reaches constant pH for the first time, give in the reaction system and add fresh solvent again. washing has the material of rising pH then, so that from wherein removing excessive silver salt and ion.

In certain embodiments, comprise and silver-colored compound collagen protein to the small part wound dressing materials.Can reach this purpose by handling collagen protein with silver salt solution. for example, silver salt can be about about 0.01 mole-Yue 1 mole silver acetate or silver nitrate for concentration. preferably under the pH of about 5-about 9, handles. and think that silver nitrogenous side chain main and collagen, amino acid is compound, described collagen, amino acid is lysine, oxylysine, agedoite, glutamine and arginine particularly.Silver can also combine (if existence) with the sulfydryl of methionine and cysteine and combines with the carboxyl of aspartic acid and glutamic acid.

The amount of silver accounts for about 30% weight of about 0.01-of collagen protein weight in the preferred collagen complex, and more preferably from about 0.1%-is about 20%, more preferably from about about 10% weight of 2%-.The preferred amount of silver-collagen complex in wound dressing materials is about the about 10wt.% of about 0.1-, more preferably from about the about 2wt.%. of 0.1-under any circumstance, silver-colored total amount in wound dressing materials is generally as above-mentioned appointment.

Will appreciate that and to prepare the silver with relative high silver content and the complex of above-mentioned host material, for example silver content is greater than 5wt.%, and use other host material (identical or different) dilution then and obtain required total silver content, be 0.01wt.%-5wt.%, the about 2wt% of preferably about 0.2wt.%-.

Material of the present invention can be made pearl, flakes, powder type, and the form of preferred film, fiber mat, net, textile fabric or adhesive-bonded fabric, cryodesiccated sponge, foam or its combination. in certain embodiments, but described solid biologic absorption base is selected from textile fabric, knitted fabric and adhesive-bonded fabric, they all can prepare according to conventional method. in other embodiments, for example, as mentioned above, but the solid biologic absorption base can comprise the sponge (or being made up of it basically) of cryodesiccated sponge or solvent seasoning.

But described solid biologic absorption base is generally sheet shape, for example has about 1cm ²-Yue 400cm ², particularly about 2cm ²-Yue 100cm ²The flaky material of area.The basis weight of this sheet generally is about 100g/m ²-Yue 5000g/m ², for example about 400g/m ²-Yue 2000g/m ²

But solid biologic absorption base material can account for wound dressing materials weight at least about 50%, for example at least about 75% weight or at least about 90% weight.

Term " dyestuff " refers to the material as the textile material coloring agent, promptly at the organic compound of the strong extinction of visible region of 400-700nm. in certain embodiments, described antioxidant dyestuff is selected from aniline dyes, acridine dye, thionine class dyestuff, two-naphthalocyanine dye, thiazin dyes, azo dyes, anthraquinone class and composition thereof.For example, described antioxidant dyestuff can be selected from gentian violet, aniline blue, methylene blue, crystal violet, acriflavine, 9-aminoacridine, acriflavinium chloride, acridine orange, proflavine, quinacrine, viride nitens, trypan blue, trypan red, peacock green, azepine atabrine, gentian violet, methyl orange, methyl yellow, ethyl violet, acid orange, Indian yellow, acid blue, Xylene Red, thioflavine, Alphazurine, indigo, methylene green and composition thereof.

These dyestuffs can also make the silver salt that is present in the described material keep stable with the decomposition of antagonism photochemistry by the light that absorbs near material surface, particularly resist photoreduction and become argent.The free radical that the further capture light chemistry of these dyestuffs produces, otherwise these free radicals just may be given birth to reaction with silver hair.In this manner, dyestuff can play photochemical desensitisers.Except that above-mentioned common dyes, but the organic desensitizer that is used for metal in the medical treatment of photography type can be suitable for the dyestuff as material of the present invention.

Described dyestuff may reside in the wound dressing materials of the present invention, and its consumption accounts for the about 5wt.% of about 0.05%-of material dry weight, generally is about the about 2wt.%. of 0.2-

Described wound dressing materials can also comprise and is up to 20% weight, preferably being lower than the water of 10% weight. this material can also contain 0-40% weight, the plasticizer of preferred 0-25% weight, preferred polyol, such as glycerol. this material can also comprise 0-10% weight, one or more therapeutic wound healing agent of preferred 0-5% weight are such as nonsteroid anti-inflammatory drugs (for example acetaminophen), steroid, antibiotic (for example penicillins or streptomycin class), antiseptic (for example silver sulfadiazine or chlorhexidine) or somatomedin (for example fibroblast growth factor or platelet-derived somatomedin).All above-mentioned percentage ratios are all with dry weight basis.

Wound dressing materials of the present invention preferably aseptic and be packaged in the microorganism impervious container.

The free radical activity that preferred material of the present invention has in diphenylpicrylhydrazyl (DPPH) test, promptly antioxidant activity is at least about 15%, and it is determined as polysaccharide 10 ^-4In the 0.5% w/v dispersion liquid among the MDPPH after 4 hours at the absorbance decline percentage ratio at 524nm place, as further described in the operation 1 hereinafter. preferably in DPPH test absorbance decline percentage ratio (with dyestuff to any absorbance calibration after) be at least about 25%, more preferably be at least about 50%, and most preferably be at least about 75%.

On the other hand or in addition, material of the present invention can show antioxidant activity, as determined by suppressing peroxidase to the ability of ABTS (2,2 '-azine group-two-[3-ethyl benzo thiazole phenanthroline sulphonic acid ester]) oxidation by it.

Preferred material of the present invention suction or wound fluid and become moistening, swelling thus or become gluey group, but can spontaneous dissolving therein or disperse.Be that it is hydrophilic, but the dissolubility in the water under 25 ℃ preferably is lower than about 1g/ liter. low solubility makes this class material be particularly suitable for as the wound dressing of removing reactive oxygen species from the wound fluid.

The antioxidant of material of the present invention and antibacterial characteristics have been pointed out the medical applications of certain limit, comprise ulcer and other chronic or gangrenosum acne wound and the inflammation infringement and the disease of treatment of acute surgical and traumatic wounds, burn, fistula, varicosis star ulcer, ulcer of artery, pressure ulcer (otherwise being called decubital ulcer), diabetic ulcer, mixed etiology.Material of the present invention is used for the treatment of the wound (promptly not showing the wound that infects sign) of infection and non-infection.

Therefore, the present invention provides in aspect second material of the present invention to be used for the treatment of application in the medicine of wound in preparation.Preferred described wound is a chronic wounds. and more preferably described chronic wounds is selected from ulcer, decubital ulcer or the diabetic ulcer of venous ulcer, ulcer of artery or mixed etiology. and preferred described material is used as the antioxidant that alleviates the oxidative stress in the wound environment and promote wound healing thus.

The present invention provides the method for treatment mammal wound in related aspect, comprise the material of the present invention to its administering therapeutic effective dose. and preferred described wound is a chronic wounds.

The present invention provides the wound dressing that comprises antioxidant wound dressing materials of the present invention in aspect the 3rd.

Described wound dressing is preferably sheet shape and comprises the active component layer of material of the present invention. and the active component layer is generally the wound contact layer in application, but in certain embodiments, it can separate from wound by the upper sheet that can see through liquid.The area of preferred active component layer is at about 1cm ²-Yue 400cm ², 4cm more preferably from about ²-Yue 100cm ².

Preferred described wound dressing further comprises and the mount backing layer of active component aspect to expanding on the relative active component layer in the side of wound. the preferred described backing layer of mounting is greater than the active component layer, make 1mm-50mm, the marginal zone of preferred 5mm-20mm thickness is expanded on the active component layer and is formed so-called dressing island.In this class situation, preferably be coated on the marginal zone at least of mounting backing layer with pressure sensitive medical grade adhesive.

The preferred described backing layer of mounting is can not see through liquid basically.This is mounted backing layer and is preferably semipermeable. promptly but this mounts the preferred permeate water steam of backing layer, but can not see through liquid water or wound fluid.Preferred this mounted backing layer and can not be seen through microorganism.Suitable uninterrupted concordance is mounted the moisture vapor transmission rate of mounting backing layer separately (MVTR) that backing layer preferably has and be 300-5000g/m under 37.5 ℃ and 100%-10% relative humidity difference ²/ 24 hours, preferred 500-2000g/m ²/ 24 hours. the thickness of mounting backing layer is preferably in the scope of 10-1000 micron, more preferably the 100-500 micron.Have been found that this class moisture vapor transmission rate makes the wound under the dressing heal under wet condition, and the skin of wound circumference is macerated.

Silver salt forms the suitable polymers mount backing layer and comprises polyurethanes and poly-alkoxyalkyl esters of acrylic acid and methyl acrylic ester, such as those disclosed among the GB-A-1280631. preferred describedly mount the uninterrupted layer that is mainly closed chamber that backing layer comprises the polyurethane foam of high-density block. and the suitable backsheet of mounting is that registered trade mark is the polyurethane film of ESTANE5714F.

Binding agent (if exist) layer should transmit dampness and/or form a fixed structure so that steam from wherein passing through. adhesive phase is preferably the pressure sensitive adhesive layer of the continual transmission dampness that is usually used in island type wound dressing, for example, based on for example contact adhesive of acrylate copolymer described in the GB-A-1280631, polyvinyl ethyl ether and polyurethanes. the basis weight of adhesive phase is preferably 20-250g/m ², and preferred 50-150g/m ². be preferably based on the contact adhesive of polyurethanes.

Can between active component layer and overcoat, set up other layer of multilayer absorbent article. for example, these layers comprise the absorbed layer between active component layer and the overcoat, if especially dressing is used ooze out make on the wound all the more so.Optionally absorbed layer can be for being usually used in absorbing the random layer of wound fluid, serum or blood in the wound healing field, comprising gauze, adhesive-bonded fabric, superabsorbents, hydrogel and composition thereof. preferred described absorbed layer comprises layer of absorbent foam, such as opening cell-type hydrophilic polyurethane foam according to EP-A-0541391 preparation, full content with the document is incorporated herein by reference especially. in other embodiments, absorbed layer can be nonwoven fiber mesh material, for example the carded net of viscose staple fibre.The basis weight of absorbed layer can be at 50-500g/m ²Scope, such as 100-400g/m ². unpressed absorber thickness can be in the scope of 0.5mm-10mm, such as 1mm-4mm.Freedom (unpressed) the Liquid Absorption energy of under 25 ° normal saline being measured can be in the scope of 5-30g/g. and preferred absorbed layer or many absorbed layers extend in time jointly with the active component layer basically.

Described dressing is preferably protected by removable cover layer towards the surface of wound. and this cover layer is formed by flexible thermoplastic usually. and suitable material comprises polyesters and TPO. and preferred cover layer face is a release surface to the surface of adhesive layer. promptly should the surface only so that help adhesive layer be peeled off from cover layer with mounting to adhere to a little less than active component layer on the backing layer and the adhesive layer. for example; cover layer can be by NA plastics; form such as fluoropolymer polymer; maybe can apply release coat, such as siloxanes or fluoropolymer polymer release coat to it.

In general, wound dressing of the present invention is sterile and packaged in the microorganism impervious container.

The present invention provides the method for preparing antioxidant wound dressing materials in one aspect of the method, but comprises the step with suitable dyeing biology absorption base material. and this method preferably further comprises with the silver salt that is dissolved in or is scattered in water or the organic solvent handles host material.

Method of the present invention can be used to prepare wound dressing of the present invention.

Method of the present invention can comprise: by the host material with sheet shape, for example the textile fabric of host material, adhesive-bonded fabric or knitted fabric or sponge are immersed dye bath it is dyeed, and be removing unconjugated dyestuff, and dry with after scouring.In other embodiments, can dye to host material, and it is fiber or particle form, make this material form sheet subsequently. for example, can handle the fiber of host material or particulate slurry and form painted sponge then with dyestuff. can after removing the step of combination dye not, carry out silver processing.

Be appreciated that any feature relevant with any one aspect of the present invention described herein or embodiment equally also go for any others of the present invention.

In the following example, further describe some specific embodiments of the present invention now.

Embodiment 1

Be prepared as follows antioxidant wound dressing materials based on the cryodesiccated wound dressing materials of collagen protein/ORC.

Following corium by cattle prepares the collagen protein composition. and peel off cattle corium from Corii Bovis seu Bubali, scraping is also immersed liquor natrii hypochloritis (0.03% w/v), so that be suppressed at the microbial activities in the further course of processing.Wash corium then with water and use the solution-treated that contains sodium hydroxide (0.2% w/v) and hydrogen peroxide (0.02% w/v), so that make corium swelling and sterilization at ambient temperature. make the corium overburden under greater than 12.2 pH, ambient temperature and containing in 10-14 days time limits in the solution of sodium hydroxide, calcium hydroxide and sodium bicarbonate (being respectively 0.4% w/v, 0.6% w/v and 0.05% w.v) and carry out alkali treatment subsequently, upset is lower than 0.24mmol/g up to the level that reaches amide nitrogen simultaneously.Under ambient temperature and pH 0.8-1.2, the corium overburden is carried out acid treatment step then with 1% hydrochloric acid. will handle with upset and continue to proceed to the corium overburden and adsorbed the acid of capacity and reached pH less than 2.5.Use then with overburden wash to the pH value of corium overburden reach 3.0-3.4. subsequently in the cartridge type chipper by slightly smashing to pieces for the first time the corium overburden with carefully smashing to pieces that ice is smashed to pieces and set then.Freezing and store the gained pastel, after this it be used for next procedure of processing by the composition of proportions of 650g corium overburden with 100g water (as ice). but, in next step with before ORC mixes with other composition, collagen protein is not carried out lyophilization.

Be prepared as follows the ORC composition of freeze-dried pad.Use rotary knife cutter to grind SURGICEL cloth (Johnson ﹠amp by sieve plate; Johnson Medical Arlington), is being lower than 60 ℃ with temperature maintenance.

Introduce dyestuff to reach final solid concentration be 1%. preparation samples by an amount of acid stain methylene blue being dissolved in 0.05M acetic acid and joining in the collagen paste that contains ground ORC powder, wherein dyestuff is introduced serosity: 0% (reference example), 1mg/ml, 0.5mg/ml and 0.1mg/ml with following concentration.

In the culture dish that gained serosity impouring 3mm is dark, place it on the shelf of cold closet, wherein temperature being set in advance in-40 ℃. the program that starts freeze dryer then is so that dry collagen protein and ORC and make device dehydrogenation heat cross-linking and form foam-rubber cushion. when circulation is finished, discharge vacuum, pack sponge sample then and use cobalt 60 γ irradiation sterilizations.

Embodiment 2

Operate according to embodiment 1, but replace MBD with basic stain crystal violet. with following concentration crystal violet is introduced serosity: 0% (reference example), 1mg/ml, 0.5mg/ml and 0.1mg/ml.

Embodiment 3

Operate according to embodiment 1, but with basic stain flavin 3,6-proflavin Hemisulphate replaces MBD.With following concentration flavin is introduced serosity: 0% (reference example), 1mg/ml, 0.5mg/ml and 0.1mg/ml.

Embodiment 4

Operate according to embodiment 1, but with basic stain flavin 3,6-proflavin Hemisulphate replaces MBD. with following concentration flavin is introduced serosity: 0% (reference example), 1mg/ml, 0.5mg/ml and 0.1mg/ml.

Embodiment 5

Operate according to embodiment 1, but with methylene blue and flavin 3, the mixture of 6-proflavin Hemisulphate replaces MBD, every kind of dyestuff is introduced serosity with the concentration of 0.5mg/ml.

Embodiment 6

Operate according to embodiment 1, but with crystal violet and flavin 3, the mixture of 6-proflavin Hemisulphate replaces MBD, every kind of dyestuff is introduced serosity with the concentration of 0.5mg/ml.

Embodiment 7

Operate according to embodiment 1, but replace MBD, every kind of dyestuff is introduced serosity with the concentration of 0.5mg/ml with the mixture of crystal violet and methylene blue.

Embodiment 8-14

Through the following steps silver is introduced the wound dressing materials for preparing described in embodiment 1-7: silver acetate is dissolved in 0.05M acetic acid also this solution is joined in the ORC/ collagen protein serosity, with the total solid is benchmark, and its introducing amount is enough to produce the final serosity that contains 1wt.% silver.

The sponge of the present invention that obtains among the embodiment 1-14 all shows the stable absorption to dyestuff. and the serum a couple of days under these sponges can being immersed 25 ℃ and they keep coloured from start to finish. and according to the difference of the dye strength that adds, excessive dyestuff begins to discharge and progressively discharge when sponge begins to degrade then.

Operation 1

By in the reaction of the test evaluation wound dressing materials of DPPH described in the WO94/13333 and oxygen radical and remove their ability, the full content with the document is incorporated herein by reference especially. this test employing from Blois M.S. " nature " ( Nature) 181:1199 (1958) and Banda P.W. etc. " analysis communication " ( Analytical Letters) test described in the 7:41 (1974).

Briefly, with the wound dressing materials (2.5mg in the test; 5mg; ﹠amp; The 25mg sample size) be suspended in 2.5ml 0.1M pH 7.0 phosphate buffers. adding consumption is the solution (10 of diphenylpicrylhydrazyl (DPPH) in methanol of 2.5ml ^-4M) and this mixture of jolting and being stored in 20 ℃ of following dark. assess sample through the following steps: in 6 hours, measure its absorbance at 524nm place and with the reference substance comparison, pay special attention to the figure after 4 hours.The absorbance of comparing with reference substance after 4 hours reduces percentage ratio and has drawn the DPPH test value, and repeatability is generally 5%. can represent this value expediently according to the simple minimizing of the absorbance unit of comparing with reference substance (AU).

Ascorbic acid is well-known antioxidant, and it provides useful positive control substance for the contrast purpose. the sponge of cryodesiccated chitin/chitosan and hydroxyethyl-cellulose is used as negative control.

The material of the present invention that this test is applied to embodiment 1-7 is 80-90% (10 to the DPPH test value that positive control produces ^-4M). opposite, negative control chitin/chitosan and hydroxyethyl-cellulose show the far away low DPPH value less than 15%.Collagen protein/ORC that cloth adds any dyestuff shows certain activity in the DPPH test, showing that ORC self has certain antioxidant properties. coloring material of the present invention shows apparently higher than the activity of independent collagen protein/ORC in the DPPH test, and this result is consistent with the antioxidant activity of described dyestuff.

Operation 2

By observing the bacteriostatic activity of inhibition zone to the sponge for preparing among Pseudomonas aeruginosa (pseudomonas Aeruginosa) and the routine 8-14 of staphylococcus aureus (staphylococcus Aureus) test implementation.

Under aseptic condition, downcut 6 2cm * 2cm square of every duplicate samples.When the 1st day of this experiment, the culture of Pseudomonas aeruginosa (ATCC 27853 and various PSI bacterial strain) and staphylococcus aureus (providing (Dept of ClinicalMicrobiology and Pathology) by the clinical microbiology and the pathology department of the Chinese Academy of Sciences) is being incubated 24 hours in aerobic mode down and on the diagnostic sensitivity agar (DSA) at 37 ℃.After 24 hours, specimen is placed on the DSA flat board separately and soaks with 0.5mls buffer solution at once. three squares of sample are placed on the flat board of having inoculated Pseudomonas aeruginosa and with three squares are placed on the flat board of having inoculated staphylococcus aureus.Then with flat board 37 ℃ of down insulations 24 hours. use subsequently and suppress the band of growth around the caliper measuring samples and specimen is placed on the DSA flat board of new inoculation. to carrying out swab test in the zone under the sample, so that it is, still germ-resistant by swab being smeared on the DSA flat board and it being incubated 24 hours and checking growing state to determine that sample is a bacteriostatic then.Sample is forwarded on the flat board of inoculation recently,, just carried out one time aforesaid operations, continue 72 hours every 24 hours as long as sample is kept perfectly.

As negative control, test does not contain the cryodesiccated 45%ORC/55% collagen protein sponge of any silver or dyestuff. with silver-containing antibacterial dressing (ACTICOAT, the Smith﹠amp that is purchased; The registered trade mark of Nephew) and silver nitrate solution (0.5%) as positive control and in duration of trial, both are observed the inhibition situation.

Discovery is observed remarkable bactericidal action to staphylococcus aureus and Pseudomonas aeruginosa to material of the present invention. and the performance of estimating to contain the performance of material of 1% silver medal and mentioned component and ACTICOAT dressing is suitable.

Only above-mentioned embodiment is described by embodiment. many other embodiments that belong in the claim scope that awaits the reply are apparent to those skilled in the art.

Claims

1. wound dressing materials, but it comprises with antioxidant dyestuff painted solid biologic absorption base, but wherein said solid biologic absorption base comprises oxidized cellulose and is selected from the sponge and the combination thereof of textile fabric, adhesive-bonded fabric, cryodesiccated sponge, solvent seasoning.

2. the wound dressing materials of claim 1, wherein said oxidized cellulose is an oxidized regenerated cellulose.

3. the wound dressing materials during arbitrary aforesaid right requires, wherein said antioxidant dyestuff are selected from aniline dyes, acridine dye, thionine class dyestuff, two-naphthalocyanine dye, thiazin dyes, azo dyes, anthraquinone class and composition thereof.

4. the wound dressing materials during arbitrary aforesaid right requires, wherein said antioxidant dyestuff are selected from gentian violet, aniline blue, methylene blue, crystal violet, acriflavine, 9-aminoacridine, acriflavinium chloride, acridine orange, proflavine, quinacrine, viride nitens, trypan blue, trypan red, peacock green, azepine atabrine, gentian violet, methyl orange, methyl yellow, ethyl violet, acid orange, Indian yellow, acid blue, Xylene Red, thioflavine, Alphazurine, indigo, methylene green and composition thereof.

5. the wound dressing materials during arbitrary aforesaid right requires, the amount of wherein said antioxidant dyestuff accounts for the about 2wt.%. of about 0.2-of this material dry weight

6. the wound dressing materials during arbitrary aforesaid right requires, wherein said material is a sheet shape.

Wound dressing materials during 7 arbitrary aforesaid rights require, wherein said material are aseptic and are packaged in the microorganism impervious container.

8. the wound dressing materials during arbitrary aforesaid right requires, the free radical activity that wherein said material has in diphenylpicrylhydrazyl (DPPH) test of as defined herein antioxidant activity is at least about 15%.

9. each material is used for the treatment of application in the medicine of wound in preparation among the claim 1-8.

10. the application of claim 9, wherein said wound is a chronic wounds, is preferably selected from the ulcer of varicose ulcer, decubital ulcer or diabetic ulcer.

11. the method for the antioxidant wound dressing materials of each of preparation claim 1-8, but comprise step with antioxidant dyestuff dyeing biology absorption base material.

12. wound dressing, it comprises among the claim 1-8 each antioxidant wound dressing materials.

13. the wound dressing of claim 12, wherein said material are aseptic and are packaged in the microorganism impervious container.