EP2534187A1

EP2534187A1 - Active substance-releasing wound dressing

Info

Publication number: EP2534187A1
Application number: EP11702068A
Authority: EP
Inventors: Jan SCHÖNBERGER; Michael Mager; Heike Heckroth; Doris Klee; Mona Wambach; Christoph Suschek
Original assignee: Bayer Intellectual Property GmbH
Current assignee: Bayer Intellectual Property GmbH
Priority date: 2010-02-11
Filing date: 2011-02-08
Publication date: 2012-12-19
Also published as: US20130136785A1; WO2011098444A1

Abstract

The invention relates to a wound dressing, comprising a liquid-absorbing substrate having active substance depots contained therein, wherein the active substance depots comprise particles of at least one active substance which are encapsulated in a silicone shell. The invention further relates to a wound dressing according to the invention for use as a means for treating wounds and to the use of a wound dressing according to the invention for producing a means for treating wounds.

Description

Active agent Wound dressing

The invention relates to a drug-releasing wound dressing.

The use of wound dressings from foams for the treatment of weeping wounds is state of the art. Due to their high absorbency and good mechanical properties see especially polyurethane foams are used by reacting mixtures of diisocyanates and polyols or NCO-functional polyurethane prepolymers with water in the presence of certain catalysts and (foam) additives can be produced. Examples of such wound dressings are described, for example, in US Pat. Nos. 3,978,266, 3,975,567 and EP-A 0 059 048. Wound dressings containing an active ingredient are also known in the prior art. These active substances are, for example, compounds which promote wound healing. Also known is the use of antibacterial or analgesic agents. An active substance-containing wound dressing is described, for example, in WO 2007 068492 A1. The known wound dressings are impregnated with the respective active ingredients in most cases or impregnated therewith. This has the consequence that when they are used initially a large amount of the drug is released, but the discharge rate then drops quickly. It would be desirable, however, for the wound dressing to deliver the contained active ingredient continuously in an almost constant amount over the entire duration of use, as this would assist the healing process in an optimum manner. However, this is not possible with the known wound dressings, especially when using readily water-soluble active ingredients.

EP 0 436 729 A1 again discloses a bandage containing active ingredient-containing microcapsules. However, the microcapsules here consist of water-resistant, heat-cured resins. Release of the active substance can therefore only take place if the microcapsules are destroyed mechanically, for example by friction. Then the release takes place abruptly. A continuous release of the active ingredient is therefore not given.

The object of the invention was to provide a wound dressing which allows a continuous, quantitatively almost constant delivery of an optionally present, in particular water-soluble, active ingredient over the entire intended period of use. This object is achieved by a wound dressing comprising a liquid-absorbing substrate with active substance depots contained therein, wherein the active ingredient depots comprise particles of at least one active ingredient that are encapsulated in a silicone casing.

When used, the wound dressings according to the invention continuously release an almost uniformly large amount of the active substance contained in the active substance depot so that an optimal supply of the supplied wound to the active ingredient takes place.

According to a first preferred embodiment of the invention it is provided that the substrate is a foam. It is advantageous that the substrate on the one hand has a high absorption capacity for discharged from the wound fluids and on the other hand can adapt particularly well elastic to the wound.

The foam may in particular have a density of 0.5, preferably of 0.4, more preferably of> 0.01 to <0.3 and particularly preferably of> 0.05 to <0.3 g / cm ³ . Wound dressings which have such a foam as a substrate are characterized by a particularly high absorption capacity and particularly advantageous mechanical properties. The foam may be a polymer based foam, preferably a reactive foam or a blown foam.

According to a further preferred embodiment of the invention, the foam is based on polyurethanes.

Suitable polyurethanes are obtainable by reacting A) isocyanate-functional prepolymers having a weight fraction of low molecular weight, aliphatic diisocyanates having a molar mass of 140 to 278 g / mol of less than 1.0 wt .-%, based on the prepolymer, by reacting

Al) low molecular weight, aliphatic diisocyanates having a molecular weight of 140 to 278 g / mol

A2) di- to hexafunctional polyalkylene oxides having an OH number of 22.5 to 1 12 mg KOH / g, and an ethylene oxide content of 50 to 100 mol%, based on the total amount of oxyalkylene groups contained,

B) optionally heterocyclic, 4-ring or 6-membered oligomers of low molecular weight, aliphatic diisocyanates having a molar mass of 140 to 278 g / mol,

C) water

D) optionally catalysts,

E) C 1 - to C 22 -monocarboxylic acids or their ammonium or alkali salts or C 12 - to C 44 -dicarboxylic acids or their ammonium or alkali metal salts, F) optionally surfactants,

G) optionally monohydric or polyhydric alcohols and

H) optionally hydrophilic polyisocyanates obtainable by reaction of

Hl) low molecular weight, aliphatic diisocyanates having a molecular weight of 140 to 278 g / mol and / or polyisocyanates obtainable therefrom having an isocyanate functionality of 2 to 6 with

H2) monofunctional polyalkylene oxides having an OH number of 10 to 250 and an ethylene oxide content of 50 to 100 mol%, based on the total amount of oxyalkylene groups contained. available. With the aid of these polyurethanes, it is possible in particular to produce reactive foams which are particularly suitable for use as a substrate in the wound dressing according to the invention because of their high absorption capacity for liquids delivered by the wound.

The prepolymers used in A) preferably have a residual monomer content of less than 0.5% by weight, based on the prepolymer. This content can be achieved by appropriately selected amounts of Al) and A2). However, the use of isocyanate is preferred. Anats AI) in excess and subsequent, preferably distillative, separation of unreacted monomers.

The preparation of the isocyanate-functional prepolymers of component A) is typically carried out by reacting one equivalent of PolyoUcomponente A2), based on the hydroxyl function, with one to 20 mol, preferably one to 10 mol, particularly preferably 5 to 10 mol, of the low molecular weight aliphatic diisocyanate AI).

The reaction can be carried out in the presence of urethanization catalysts such as tin compounds, zinc compounds, amines, guanidines or amidines, or in the presence of allophanatization catalysts such as zinc compounds. The reaction is typically carried out at 25 to 140 ° C, preferably at 60 to 100 ° C.

Was worked with excess isocyanate, then the removal of the excess of low molecular weight, aliphatic diisocyanate is preferably carried out by thin film distillation.

Acidic or alkylating stabilizers such as benzoyl chloride, isophthaloyl chloride, methyl tosylate, chloropropionic acid, HCl or antioxidants such as di-tertiary-butyl-cresol or tocopherol may be added before, during and after the reaction or by distillation of the excess diisocyanate.

The NCO content of the isocyanate-functional prepolymers A) is preferably from 1.5 to 4.5% by weight, more preferably from 1.5 to 3.5% by weight and very particularly preferably from 1.5 to 3.0% by weight. %.

Examples of low molecular weight aliphatic diisocyanates of component AI) are hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), butylene diisocyanate (BDI), bis-isocyanatocyclohexylmethane (HMDI), 2,2,4-trimethylhexamethylene diisocyanate, bisisocyanato-methylcyclohexane, bisisocyanatomethyltricyclodecane, xylene diisocyanate, tetramethylxylylene - Diisocyanate, norbornane diisocyanate, cyclohexane diisocyanate or diisocyanatododecane, wherein

Hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), butylene diisocyanate (BDI) and bis (isocyanatocyclohexyl) methane (HMDI) are preferred. Particularly preferred are hexamethylene diisocyanate, isophorone diisocyanate, butylene diisocyanate, most preferably hexamethylene diisocyanate and isophorone diisocyanate. Polyalkylene oxides of component A2) are preferably copolymers of ethylene oxide and propylene oxide having an ethylene oxide content, based on the total amount of the oxyalkylene groups contained, of from 50 to 100 mol%, preferably from 60 to 85 mol%, started on polyols or amines. Suitable initiators of this type are glycerol, trimethylolpropane (TMP), sorbitol, pentaerythritol, triethanolamine, ammonia or ethylenediamine.

The polyalkylene oxides of component A2) typically have number-average molecular weights of from 1000 to 15000 g / mol, preferably from 3000 to 8500 g / mol.

In addition, the polyalkylene oxides of component A2) have OH functionalities of from 2 to 6, preferably from 3 to 6, more preferably from 3 to 4. Compounds of component B) which may be used are heterocyclic, 4-ring or 6-membered oligomers of low molecular weight, aliphatic diisocyanates having a molecular weight of 140 to 278 g / mol such as isocyanurates, Iminooxadiazindione or uretdiones of the aforementioned low molecular weight, aliphatic diisocyanates. Preference is given to heterocyclic 4-ring oligomers such as uretdiones. The increased content of isocyanate groups through the use of component B) ensures better foaming by more CO _{2 formed} from the isocyanate-water reaction.

The water to be used as component C) can be used as such, as the water of crystallization of a salt, as a solution in a dipolar aprotic solvent or else as an emulsion. The water is preferably used as such or in a dipolar aprotic solvent. Most preferably, the water is used as such.

To accelerate the urethane formation, catalysts can be used in component D). These are typically the compounds known to those skilled in polyurethane technology. Preference is given here to compounds of the group consisting of catalytically active metal salts, amines, amidines and guanidines. Exemplary are tin dibutyl dilaurate (DBTL), tin octoate (SO), tin acetate, zinc octoate (ZO), 1,8-

Diazabicyclo [5.4.0] undecene-7 (DBU), 1, 5-diazabicyclo [4.3.0] nonene-5 (DBN), 1, 4-diazabicyclo [3.3.0] octene-4 (DBO) , N-ethylmorpholine (NEM), triethylenediamine (DABCO), pentamethylguanidine (PMG), tetrametylguanidine (TMG), cyclotetramethylguanidm (TMGC), n-decyl-tetramethylguanidine (TMGD), n-dodecyltetramethylguanidine (TMGDO), dimethylaminoethyltetramethylguanidine (TMGN), 1 , 1,4,4,5,5-hexamethylisobiguanidine (HMIB), phenyltetramethylguanidine (TMGP) and hexamethylenoctamethylbiguanidine (HOBG).

Particularly preferred is the use of amines, amidines, guanidines or mixtures thereof as catalysts of component D). Very particular preference is given to using 1,8-diazabicyclo [5.4.0] undecene-7 (DBU).

As component E) are ammonium and alkali metal salts of C _& to C22 monocarboxylates or their free carboxylic acids or Cn to C44 dicarboxylates or their free dicarboxylic acids, preferably potassium or sodium salts of C _& to C22 monocarboxylates or Cn - C44-dicarboxylates, and more preferably sodium salts of C _& to C22 mono-carboxylates used.

Examples of suitable compounds of component E) are the ammonium, Na, Li or K salts of ethylhexanoic, octanoic, decanoic, dodecanoic, palmitic, stearic, octadecenoic, octadecadienoic, octadecatrienoic, isostearic, erucic and abietic acids and their hydrogenation products. Examples of C 1 - to C 44 -dicarboxylic acids or the ammonium and alkali salts derived therefrom are dodecanedioic acid, dodecenyl-, tetradecenyl-, hexadecenyl- and octadecenyl-succinic acid, C 36- and C 44 -dimer fatty acids and their hydrogenation products, and the corresponding ammonium, Na, Li or K salts of these dicarboxylic acids.

To improve the foaming, foam stability or the properties of a foam resulting from the polyurethanes, compounds of component F) can be used, wherein such additives may in principle be any anionic, cationic, amphoteric and nonionic surfactants known per se and mixtures thereof. Alkyl polyglycosides, EO / PO block copolymers, alkyl or aryl alkoxylates, siloxane alkoxylates, esters of sulfosuccinic acid and / or alkali metal or alkaline earth metal alkanoates are preferably used. Particular preference is given to using EO / PO block copolymers. Preferably, only the EO / PO block copolymers are used as component F).

In addition, compounds of component G) can be used to improve the foam properties of the resulting polyurethane foam. These are in principle all monohydric and polyhydric alcohols known to the person skilled in the art and mixtures thereof. These are mono- or polyhydric alcohols or polyols, such as ethanol, Propanol, butanol, decanol, tridecanol, hexadecanol, ethylene glycol, neopentyl glycol, butanediol, hexanediol, decanediol, trimethylolpropane, glycerol, pentaerythritol, monofunctional polyether alcohols and polyester alcohols, polyether diols and polyester diols.

In the preparation of the hydrophilic polyisocyanates H), the ratio of the monofunctional polyalkylene oxides H2) to the low molecular weight, aliphatic diisocyanates Hl is typically adjusted so that for 1 mol OH groups of monofunctional polyalkylene oxides 1, 25 to 15 mol, preferably 2 to 10 mol and more preferably 2 to 6 moles NCO groups of the low molecular weight, aliphatic diisocyanate Hl) come. This is followed by allophanatization or biurization and / or isocyanurate formation or uretdione formation. If the polyalkylene oxides H2) are bound to the aliphatic diisocyanates H1 via urethane groups, allophanatization preferably takes place subsequently. It is further preferred that isocyanurate structural units are formed.

An alternative preparation of the hydrophilic polyisocyanates H) is typically carried out by reacting 1 mol of OH groups of the monofunctional polyalkylene oxide component H2) with 1.25 to 15 mol, preferably 2 to 10 mol and more preferably 2 to 6 mol NCO groups of a polyisocyanate Hl). with an isocyanate functionality of 2 to 6 based on aliphatic diisocyanates. Exemplary of such polyisocyanates HI) are biuret structures, isocyanurates or uretdiones based on aliphatic diisocyanates. The polyisocyanates H1) and the polyalkylene oxides H2) are preferably linked to one another via a urethane group or a urea group, the linking via urethane groups in particular being preferred.

Was worked with excess low molecular weight diisocyanate, then the removal of the excess of low molecular weight, aliphatic diisocyanate is preferably carried out by thin film distillation.

Before, during and after the reaction or the distillative separation of the diisocyanate over shot, acidic or alkylating stabilizers, such as benzoyl chloride, isophthaloyl chloride, methyl tosylate, chloropropionic acid, HCl or antioxidants such as di-ferric butylcresol or tocopherol.

The NCO content (determined according to DIN-EN ISO 11909) of the hydrophilic polyisocyanates H) is preferably 0.3 to 20% by weight, more preferably 2 to 10% by weight and very particularly preferably 3 to 6% by weight. -%.

Examples of low molecular weight, aliphatic diisocyanates of component HI) are hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), butylene diisocyanate (BDI), bis-isocyanatocyclohexylmethane (HMDI), 2,2,4-trimethylhexamethylene diisocyanate, bisisocyanato-methylcyclohexane, bisisocyanatomethyltricyclodecane, xylene diisocyanate , Tetramethylxylylene diisocyanate, norbornane diisocyanate, cyclohexane diisocyanate or diisocyanatododecane, wherein

Hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), butylene diisocyanate (BDI) and bis (isocyanatocyclohexyl) methane (HMDI) are preferred. Particularly preferred are hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), butylene diisocyanate (BDI), most preferably hexamethylene diisocyanate (HDI) and isophorone diisocyanate (IPDI). Examples of relatively high molecular weight polyisocyanates H1) are polyisocyanates having an isocyanate functionality of 2 to 6 with isocyanurate, urethane, allophanate, biuret, iminooxadiazinetrione, oxadiazinetrione and / or uretdione groups, based on the aliphatic and / or uretidione groups mentioned in the preceding section. or cycloaliphatic diisocyanates.

As component HI), relatively high molecular weight compounds having biuret, iminoxadiazinedione, isocyanurate and / or uretdione groups based on hexamethylene diisocyanate, isophorone diisocyanate and / or 4,4'-diisocyanatodicyclohexylmethane are preferably used. Further preferred are isocyanurates. Very particular preference is given to structures based on hexamethylene diisocyanate.

The preparation of polyalkylene oxides H2) by alkoxylation of suitable starter molecules is known from the literature (for example Ullmanns Encyclopadie der technischen Chemie, 4th Edition, Vol

19, Verlag Chemie, Weinheim pp. 31-38). Suitable starter molecules are in particular saturated monoalcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, diethylene glycol monobutyl ether and aromatic alcohols such as phenol or monoamines such as diethylamine. Preferred starter molecules are saturated monoalcohols Diethylenglykolmonobutylether or n-butanol are particularly preferably used as starter molecules.

By monofunctional polyalkylene oxides are meant here compounds which are only one isocyanate-reactive group, i. a group capable of reacting with an NCO group.

The monofunctional polyalkylene oxides H2) preferably have an OH group as the isocyanate-reactive group.

The monofunctional polyalkylene oxides H2) have an OH number of from 15 to 250, preferably from 28 to 112, and an ethylene oxide content of from 50 to 100 mol%, preferably from 60 to 100 mol%, based on the total amount of the oxyalkylene groups present.

The monofunctional polyalkylene oxides H2) typically have number-average molecular weights of from 220 to 3700 g / mol, preferably from 500 to 2800 g / mol.

The preparation of reactive foams from the aforementioned polyurethanes can by mixing the components A), C) and optionally B), D), E), F), G), H) in any order, foaming the mixture and curing, preferably by chemical crosslinking, done. The components A), B) and optionally H) are preferably premixed with one another. The components E) and optionally F) can be added to the reaction mixture in the form of their aqueous solutions.

The foaming can in principle be carried out by the carbon dioxide formed in the reaction of the isocyanate groups with water, but the use of further blowing agents is likewise possible. Thus, in principle, blowing agents from the class of hydrocarbons such as C3-C6 alkanes, for example, butane, pentane, zso-pentane, cyc7o-pentane, hexanes or the like. or halogenated hydrocarbons, such as dichloromethane, dichloromonofluoromethane, chlorodifluoroethanes, 1,1-dichloro-2,2,2-trifluoroethane, 2,2-dichloro-2-fluoroethane, in particular chlorine-free fluorohydrocarbons, such as difluoromethane, trifluoromethane, difluoroethane, 1, 1, 1, 2-tetrafluoroethane, tetrafluoroethane (R 134 or R 134a), 1,1,1,3,3-pentafluoropropane (R 245 fa), 1,1,1,3,3,3-hexafluoropropane (R 256), 1,1,1,3,3-pentafluorobutane (R 365 mfc), heptafluoropropane or sulfur hexafluoride can be used. It is also possible to use mixtures of these blowing agents. Subsequent curing is typically at room temperature.

Alternatively, polyurethanes can be used which are available by

I) isocyanate-functional prepolymers at least

11) organic polyisocyanates

12) polymeric polyols having number average molecular weights of 400 to 8000 g / mol and OH functionalities of 1.5 to 6 and

13) optionally hydroxy-functional compounds having molecular weights of 62 to 399 g / mol and

14) optionally isocyanate-reactive, anionic or potentially anionic and / or optionally nonionic hydrophilicizing agents,

getting produced,

J) whose free NCO groups then wholly or partly

Jl) optionally with amino functional compounds having molecular weights of 32 to 400 g / mol and / or

J2) isocyanate-reactive, preferably amino-functional, anionic or potentially anionic hydrophilicizing agents are reacted with chain extension and the prepolymers before, during or after step J) are dispersed in water, optionally containing potentially ionic groups by partial or complete reaction with a neutralizing agent in the ionic form be transferred.

These polyurethanes can be used in the form of aqueous dispersions, in particular for the production of blow foams, which are also distinguished by a high absorption capacity for fluids released from the wound when used as a substrate for the wound dressing according to the invention.

Suitable polyisocyanates of component II) are the aromatic, araliphatic, aliphatic or cycloaliphatic polyisocyanates of an NCO functionality of> 2 which are known per se to the person skilled in the art. Examples of such suitable polyisocyanates are 1,4-butylene diisocyanate, 1,6-hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), 2,2,4 and / or 2,4,4-trimethylhexamethylene diisocyanate, the isomeric bis (4 , 4'-isocyanatocyclohexyl) methanes or mixtures thereof of any isomer content, 1,4-cyclohexylene diisocyanate, 1,4-phenylenediisocyanate, 2,4- and / or 2,6-toluene diisocyanate, 1,5-naphthylene diisocyanate, 2,2 ' -and or

2,4'- and / or 4,4'-diphenylmethane diisocyanate, 1,3- and / or 1,4-bis (2-isocyanato-prop-2-yl) -benzene (TMXDI), 1, 3-bis (isocyanatomethyl) benzene (XDI), alkyl 2,6-diisocyanatohexanoate (lysine diisocyanates) with C l -C 8 -alkyl groups, and also 4-isocyanatomethyl-l, 8-octane diisocyanate (nonane triisocyanate) and triphenylmethane-4,4 ', 4 "- triisocyanate.

In addition to the abovementioned polyisocyanates, it is also possible proportionally to use modified diisocyanates or triisocyanates having uretdione, isocyanurate, urethane, allophanate, biuret, iminooxadiazinedione and / or oxadiazinetrione structures.

Preference is given to polyisocyanates or polyisocyanate mixtures of the abovementioned type having exclusively aliphatically and / or cycloaliphatically bonded isocyanate groups and an average NCO functionality of the mixture of 2 to 4, preferably 2 to 2.6 and particularly preferably 2 to 2.4 ,

It is particularly preferred in II) to use 1,6-hexamethylene diisocyanate, isophorone diisocyanate, the isomeric bis (4,4'-isocyanatocyclohexyl) methanes, and mixtures thereof. In 12), polymeric polyols having a number average molecular weight Mn of preferably from 400 to 6000 g / mol and more preferably from 600 to 3000 g / mol are used. These preferably have an OH functionality of from 1.8 to 3, particularly preferably from 1.9 to 2.1.

Such polymeric polyols are the polyester polyols known per se in polyurethane coating technology, polyacrylate polyols, polyurethane polyols, polycarbonate polyols, polyether polyols, polyester polyacrylate oils, polyurethane polyacrylate polyols, polyurethane polyester polyols, polyurethane polyether polyols, polyurethane polycarbonate polyols and polyester polycarbonate polyols. These can be used in A2) individually or in any mixtures with each other. Polyester polyols are, for example, the known polycondensates of di- and optionally tri- and tetraols and di- and optionally tri- and tetracarboxylic acids or hydroxycarboxylic acids or lactones. Instead of the free polycarboxylic acids, it is also possible to use the corresponding polycarboxylic acid anhydrides or corresponding polycarboxylic acid esters of lower alcohols for the preparation of the polyesters.

Examples of suitable diols are ethylene glycol, butylene glycol, diethylene glycol, triethylene glycol, polyalkylene glycols such as polyethylene glycol, furthermore 1,2-propanediol, 1,3-propanediol, butanediol (1,3), butanediol (1,4), hexanediol (I, 6) and isomers, neopentyl glycol or hydroxypivalic acid neopentyl glycol esters, with hexanediol (1,6) and isomers, neopentyl glycol and hydroxypivalic acid neopentyl glycol ester being preferred. In addition, it is also possible to use polyols, such as trimethylolpropane, glycerol, erythritol, pentaerythritol, trimethylolbenzene or trishydroxyethyl isocyanurate.

Suitable dicarboxylic acids are phthalic acid, isophthalic acid, terephthalic acid, tetrahydrophthalic acid, hexahydrophthalic acid, cyclohexanedicarboxylic acid, adipic acid, azelaic acid, sebacic acid, glutaric acid, tetrachlorophthalic acid, maleic acid, fumaric acid, itaconic acid, malonic acid, suberic acid, 2-methylsuccinic acid, 3,3-diethylglutaric acid and / or 2,2-dimethylsuccinic acid. The acid source used may also be the corresponding anhydrides.

If the average functionality of the polyol to be esterified is greater than 2, it is additionally possible to use monocarboxylic acids, such as benzoic acid and hexanecarboxylic acid.

Preferred acids are aliphatic or aromatic acids of the abovementioned type. Particular preference is given to adipic acid, isophthalic acid and, if appropriate, trimellitic acid.

Hydroxycarboxylic acids which can be used as reactants in the preparation of a hydroxyl-terminated polyester polyol include hydroxycaproic acid, hydroxybutyric acid, hydroxydecanoic acid, hydroxystearic acid and the like. Suitable lactones are caprolactone, butyrolactone and homologs. Preference is given to caprolactone.

It is likewise possible in 12) to use hydroxyl-containing polycarbonates, preferably polycarbonatediols, having number-average molecular weights Mn of from 400 to 8000 g / mol, preferably from 600 to 3000 g / mol. These are by reaction of carbonic acid derivatives, such as diphenyl carbonate, dimethyl carbonate or phosgene, with polyols, preferably diols, available.

Examples of such diols are ethylene glycol, 1,2- and 1,3-propanediol, 1,3- and 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, neopentyl glycol, 1,4-bis-hydroxymethylcyclohexane, 2- Methyl-l, 3-propanediol, 2,2,4-Trimethylpentandiol-l, 3, dipropylene glycol, polypropylene glycols, dibutylene glycol, polybutylene glycols, bisphenol A and lactone-modified diols of the type mentioned above.

The polycarbonate diol preferably contains from 40 to 100% by weight of hexanediol, preferably 1,6-hexanediol and / or hexanediol derivatives, based on the diols which are the base. Such hexanediol derivatives are based on hexanediol and have ester or ether groups in addition to terminal OH groups. Such derivatives are obtainable by reaction of hexanediol with excess caprolactone or by etherification of hexanediol with itself to give di- or trihexylene glycol.

Instead of or in addition to pure polycarbonate diols, it is also possible to use polyether-polycarbonate diols in 12).

The hydroxyl-containing polycarbonates are preferably built linear.

Also in 12) polyether polyols can be used. Suitable examples are the polytetramethylene glycol polyethers known per se in polyurethane chemistry, such as are obtainable by polymerization of tetrahydrofuran by means of cationic ring opening. Also suitable polyether polyols are the per se known addition products of styrene oxide, ethylene oxide, propylene oxide, butylene oxides and / or epichlorohydrin to di- or polyfunctional starter molecules.

As suitable starter molecules, it is possible to use all compounds known from the prior art, for example water, butyl diglycol, glycerol, diethylene glycol, trimethylolpropane, propylene glycol, sorbitol, ethylenediamine, triethanolamine, 1,4-butanediol.

Preferred starter molecules are water, ethylene glycol, propylene glycol, 1,4-butanediol, diethylene glycol and butyl diglycol. Particularly preferably, the polyurethanes contain, as component 12), a mixture of polycarbonate polyols and polytetramethylene glycol polyols, the proportion of polycarbonate polyols in the mixture being from 20 to 80% by weight and the proportion of polytetra methylene glycol polyols from 80 to 20% by weight in this mixture. is. Preference is given to a proportion of 30 to 75 wt .-% of polytetramethylene glycol polyols and a content of 25 to 70 wt .-% of polycarbonate polyols. Particular preference is given to a proportion of 35 to 70% by weight of polytetra methylene glycol polyols and a proportion of 30 to 65% by weight of polycarbonate polyols, in each case with the proviso that the sum of the percentages by weight of the polycarbonate and polytetramethylene glycol polyols is 100%. and the proportion of the sum of the polycarbonate and Polytetramethylenglykolpolyetherpolyole to the component 12) is at least 50 wt .-%, preferably 60 wt .-% and particularly preferably at least 70 wt .-%.

In 13) polyols of said molecular weight range having up to 20 carbon atoms, such as ethylene glycol, diethylene glycol, triethylene glycol, 1, 2-propanediol, 1, 3-propanediol, 1, 4-butanediol, 1, 3-butylene glycol, cyclohexanediol, 1, 4 Cyclohexanedimethanol, 1,6-hexanediol, neopentyl glycol, hydroquinone dihydroxyethyl ether, bisphenol A (2,2-bis (4-hydroxyphenyl) propane), hydrogenated bisphenol A, (2,2-bis (4-hydroxycyclohexyl) propane), trimethylolpropane , Glycerin, pentaerythritol and any mixtures thereof.

Also suitable are ester diols of the stated molecular weight range, such as α-hydroxybutyl-ε-hydroxycaproic acid ester, co-hydroxyhexyl-γ-hydroxybutyric acid ester, adipic acid- (β-hydroxyethyl) ester or terephthalic acid bis (β-hydroxyethyl) ester.

Furthermore, monofunctional, hydroxyl-containing compounds can also be used in 13). Examples of such monofunctional compounds are ethanol, n-butanol, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, ethylene glycol monobutyl ether, propylene glycol monomethyl ether, dipropylene glycol monomethyl ether, tripropylene glycol monomethyl ether, dipropylene glycol monopropyl ether, propylene glycol monobutyl ether, dipropylene glycol monobutyl ether, tripropylene glycol monobutyl ether, 2-ethylhexanol, 1-octanol , 1-dodecanol, 1-hexadecanol.

Preferred compounds of component 13) are 1,6-hexanediol. 1, 4-butanediol, neopentyl glycol and trimethylolpropane. By anionically or potentially anionically hydrophilizing compounds of component 14) are meant all compounds which have at least one isocyanate-reactive group such as a hydroxyl group and at least one functionality such as -COO-M ⁺ , -S0 ₃ M ⁺ , -PO (O-M ⁺ ) ² with M ^+, for example, the same metal cation, H ⁺ , NH ₄ ⁺ , NHR ₃ ⁺ , where R may each be a C ₁ -C 12 -alkyl radical, C 5 -C ₆ -cycloalkyl radical and / or a C ₂ -C ₄ -hydroxyalkyl radical which may be present at Interaction with aqueous media enters a pH-dependent dissociation equilibrium and can be charged in this way negative or neutral. Suitable anionic or potentially anionic hydrophilizing compounds are mono- and dihydroxycarboxylic acids, mono- and dihydroxysulfonic acids, as well as mono- and dihydroxyphosphonic acids and their salts. Examples of such anionic or potentially anionic hydrophilicizing agents are dimethylolpropionic acid, dimethylolbutyric acid, hydroxypivalic acid, malic acid, citric acid, glycolic acid, lactic acid and the propoxylated adduct of 2-butenediol and NaHSO ₃ , as described in DE-A 2 446 440, page 5 - 9, formula I-III is described. Preferred anionic or potentially anionic hydrophilicizing agents of component 14) are those of the abovementioned type which have carboxylate or carboxylic acid groups and / or sulfonate groups.

Particularly preferred anionic or potentially anionic hydrophilicizing agents of component 14) are those which contain carboxylate or carboxylic acid groups as ionic or potentially ionic groups, such as dimethylolpropionic acid, dimethylolbutyric acid and hydroxypivalic acid or salts thereof.

Suitable nonionic hydrophilizing compounds of component 14) are e.g. Polyoxyalkylene ethers which contain at least one hydroxyl or amino group, preferably at least one hydroxyl group. Examples are the monohydroxy-functional, on average 5 to 70, preferably 7 to 55 ethylene oxide units per molecule having polyalkylene oxidpolyether alcohols, as they are accessible in a conventional manner by alkoxylation of suitable starter molecules (eg in Ullmann's Encyclopedia of Industrial Chemistry, 4th Edition, Volume 19, Verlag Chemie, Weinheim pp. 31-38).

These are either pure polyethylene oxide ethers or mixed polyalkylene oxide ethers, but they then contain at least 30 mol%, preferably at least 40 mol%, based on all contained alkylene oxide units of ethylene oxide units. Particularly preferred nonionic compounds are monofunctional mixed polyalkylene oxide polyethers which have 40 to 100 mol% of ethylene oxide and 0 to 60 mol% of propylene oxide units.

Suitable starter molecules for such nonionic hydrophilicizing agents are saturated monoalcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-

Butanol, the isomers pentanols, hexanols, octanols and nonanols, n-decanol, n-dodecanol, n-tetradecanol, n-hexadecanol, n-octadecanol, cyclohexanol, the isomeric methylcyclohexanols or hydroxymethylcyclohexane, 3-ethyl-3-hydroxymethyloxetane or Tetrahydrofurfuryl alcohol, diethylene glycol monoalkyl ethers, such as diethylene glycol monobutyl ether, unsaturated alcohols such as allyl alcohol, 1,1-dimethylallyl alcohol or oleic alcohol, aromatic alcohols such as phenol, the isomeric cresols or methoxyphenols, aliphatic alcohols such as benzyl alcohol, anisalcohol or cinnamyl alcohol, secondary Monoamines such as dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, bis (2-ethylhexyl) amine, N-methyl and N-ethylcyclohexylamine or dicyclohexylamine and heterocyclic secondary amines such as morpholine, pyrrolidine, piperidine or lH-pyrazole. Preferred starter molecules are saturated monoalcohols of the abovementioned type. Particular preference is given to using diethylene glycol monobutyl ether or n-butanol as starter molecules.

Alkylene oxides which are suitable for the alkoxylation reaction are, in particular, ethylene oxide and propylene oxide, which can be used in any desired order or even as a mixture in the alkoxylation reaction.

As component JI) can di- or polyamines such as 1, 2-ethylenediamine, 1,2- and 1, 3-diaminopropane, 1,4-diaminobutane, 1, 6-diaminohexane, isophoronediamine, isomer mixture of 2,2,4- and 2,4,4-trimethylhexamethylenediamine, 2-methylpentamethylenediamine, diethylenetriamine, triaminononane, 1,3- and 1,4-xylylenediamine, α, α, α ', α'-tetramethyl-1,3- and

1,4-diaminodicyclohexylmethane and / or dimethylethylenediamine. Also possible, but less preferred, is the use of hydrazine or hydrazides such as adipic dihydrazide.

In addition, as component JI), compounds which, in addition to a primary amino group, also have secondary amino groups or, in addition to an amino group (primary or secondary), also OH groups, can be used. Examples of this are primary secondary amines such as diethanolamine, 3-amino-1-methylaminopropane, 3-amino-1-ethylaminopropane, 3-amino-1-cyclohexylaminopropane, 3-amino-1-methylaminobutane, alkanolamines such as N-aminoethylethanolamine, ethanolamine , 3-aminopropanol, neopentanolamine. Also suitable as component J1) are also monofunctional isocyanate-reactive amine compounds, for example methylamine, ethylamine, propylamine, butylamine, octylamine, laurylamine, stearylamine, isononyloxypropylamine, dimethylamine, diethylamine, dipropylamine, dibutylamine, N-methylaminopropylamine, diethyl (methyl) aminopropylamine, morpholine, piperidine, or suitable substituted derivatives thereof, amide amines from diphenylamines and monocarboxylic acids, monoketime of diprimary amines, primary / tertiary amines such as N, N-dimethylaminopropylamine.

Preferred compounds of component JI) are 1, 2-ethylenediamine, 1, 4-diaminobutane and isophoronediamine.

By anionically or potentially anionically hydrophilizing compounds of component J2) are meant all compounds which have at least one isocyanate-reactive group, preferably an amino group, and at least one functionality such as -COO-M ⁺ , -S0 ₃ M ⁺ , -PO (0-M ⁺ ) ² with M +, for example, metal cation, Pf, NH ₄ ⁺ , NHR, where R may each be a C 1 -C 12 -alkyl radical, C 5 -C ₆ -cycloalkyl radical and / or a C ² -C ₄ -hydroxyalkyl radical which may be present at Interaction with aqueous media enters a pH-dependent dissociation equilibrium and can be charged in this way negative or neutral.

Suitable anionic or potentially anionic hydrophilizing compounds are mono- and diaminocarboxylic acids, mono- and diaminosulfonic acids and mono- and diaminophosphonic acids and their salts. Examples of such anionic or potentially anionic hydrophilicizing agents are N- (2-aminoethyl) -β-alanine, 2- (2-aminoethylamino) ethanesulfonic acid, ethylenediamine-propyl- or -butylsulfonic acid, 1, 2 or 1, 3 Propylene diamine β-ethylsulfonic acid, glycine, alanine, taurine, lysine, 3,5-diaminobenzoic acid and the addition product of IPDA and acrylic acid (EP-A 0 916 647, Example 1). Furthermore, cyclohexylaminopropanesulphonic acid (CAPS) from WO-A 01/88006 can be used as anionic or potentially anionic hydrophilizing agent. Preferred anionic or potentially anionic hydrophilicizing agents of component J2) are those of the abovementioned type which have carboxylate or carobonic acid groups and / or sulfonate groups such as the salts of N- (2-aminoethyl) -β-alanine, 2- (2 - Aminoethylamino) ethanesulfonic acid or the addition product of IPDA and acrylic acid (EP-A 0 916 647, Example 1).

For hydrophilization it is also possible to use mixtures of anionic or potentially anionic hydrophilicizing agents and nonionic hydrophilicizing agents.

It is furthermore particularly preferred if the active ingredient comprises a component which releases nitrogen monoxide under in vivo conditions, preferably L-arginine or an L-arginine-containing or an L-arginine-releasing component, particularly preferably L-arginine hydrochloride. Proline, ornithine and / or other biogenic intermediates such as biogenic polyamines (spermine, spermitine, putrescine or bioactive artificial polyamines) can also be used. Such components are known to assist wound healing, with their continuous quantitatively nearly uniform delivery of wound healing being particularly beneficial.

Further active substances which can be used according to the invention comprise at least one substance selected from the group of vitamins or provitamins, carotenoids, analgesics, antiseptics, hemostyptics, antihistamines, antimicrobial metals or their salts, plant wound healing substances or substance mixtures, plant extracts, enzymes, growth factors, enzyme inhibitors and combinations thereof.

As analgesics in particular, non-steroidal analgesics, in particular salicylic acid, acetylsalicylic acid and derivatives thereof such as Aspirin ^®, aniline and its derivatives, acetaminophen eg paracetamol ^®, anthranilic, and their derivatives such as mefenamic acid, pyrazole or its derivatives, for example, methimazole, Novalgin ^®, antipyrine, antipyrine ^® , Isopropylphenazone and very particularly preferably arylacetic acids and their derivatives, Heteroarylessigsäuren and their derivatives, arylpropionic acids and their derivatives and Herteroarylpropionsäuren and their derivatives such as Indometacin ^® , Diclophenac ^® , Ibuprofen ^® , Naxoprophen ^® , Indomethacin ^® , Ketoprofen ^® , Piroxicam ^® suitable.

Growth factors include: aFGF (Acidic Fibroplast Growth Factor), EGF (Epidermal Growth Factor), PDGF (Platelet Derived Growth Factor), rhPDGF-BB (becaplermin), PDECGF (Platelet Derived Endothelial Cell Growth Factor), bFGF (Basic Fibroplast growth factor), TGF a; (Transforming Growth Factor alpha), TGF (Transforming Growth Factor beta), KGF (Keratinocyte Growth Factor), IGF1 / IGF2 (Insulin-Like Growth Factor) and TNF (Tumor Necrosis Factor).

Vitamins or provitamins in particular are the fat-soluble or water-soluble vitamins vitamin A, group of retinoids, provitamin A, group of carotenoids, in particular β-carotene, vitamin E, group of tocopherols, in particular α-tocopherol, β-tocopherol, γ- Tocopherol, δ-tocopherol and α-tocotrienol, β-tocotrienol, γ-tocotrienol and δ-tocotrienol, vitamin K, phylloquinone, in particular phytomenadione or vegetable vitamin K, vitamin C, L-ascorbic acid, vitamin B 1, thiamine, vitamin B2, riboflavin , Vitamin G, vitamin B3, niacin, nicotinic acid and nicotinamide, vitamin B5, pantothenic acid, provitamin B5, panthenol or dexpanthenol, vitamin B6, vitamin B7, vitamin H, biotin, vitamin B9, folic acid and combinations thereof.

As an antiseptic, use must be made of such a composition that acts as a stain, bactericide, bacteriostatic, fungicidal, virucidal, virustatic and / or general microbiocidal agent.

In particular, those substances are suitable which are selected from the group resorcinol, iodine, iodine povidone, chlorhexidine, benzalkonium chloride, benzoic acid, benzoyl peroxide or Cethylpyridiniumchlorid. In addition, antiseptics in particular antimicrobial metals are to be used. In particular, silver, copper or zinc and their salts, oxides or complexes may be used in combination or alone as antimicrobial metals.

In the context of the present invention, extracts of chamomile, witch hazel extracts, for example, are used as herbal, wound healing promoting agents. Hamamelis virgina, calendula extract, aloe extract, e.g. Aloe vera, Aloe barbadensis, Aloe feroxoder or Aloe vulgaris, green tea extracts, seaweed extract, e.g. Red algae or green algae extract, avocado extract, myrrh extract, e.g. Commophora molmol, bamboo extracts as well

To call combinations of these.

The silicone encapsulation encapsulating the active substance particles may preferably consist of polydimethylsiloxane, polyvinylsiloxane, polyphenylsiloxane, polyalkylsiloxane, organo-modified silicones such as, for example, polyetherpolysiloxane copolymers, fluorosililicones or hydrosilicones, more preferably polydimethylsiloxane. In a further development of the invention, it is provided that the active substance depots are spherical and have a diameter of from 10 to 2,000, preferably from 100 to 1,000 and particularly preferably from 300 to 850 μm. The adjustment of the diameter can be done by screening. Such drug depots allow a particularly uniform release of the active ingredient contained over a period of 3 to 7 days.

The content of the active ingredient in the active substance depots can be in particular 2 to 60, preferably 2 to 50, more preferably 5 to 40 and particularly preferably 5 to 30% by weight. This active substance content represents an optimum from manufacturability of the particles, reservoir effect and release kinetics. It is furthermore advantageous if the substrate contains 0.1 to 20, preferably 0.5 to 15, more preferably 1 to 10 and particularly preferably 1 to 5% by weight. the drug depots, based on the total weight of the wound dressing contains. Thus, such wound dressings show comparable mechanical and haptic properties as corresponding active substance depot-free wound dressings, and the outer appearance of the wound dressing is not appreciably changed by the inked silicone particles.

Another object of the invention is a wound dressing according to the invention for use as a wound treatment agent.

Likewise provided by the invention is the use of a wound dressing according to the invention for the production of an agent for the treatment of wounds.

Examples

Unless otherwise indicated, all percentages are by weight.

The solids contents were determined according to DIN-EN ISO 3251.

NCO contents were determined volumetrically in accordance with DIN-EN ISO 11909, unless expressly stated otherwise.

The determination of the mean particle sizes (indicated by the number average) of the polyurethane dispersion 1 was carried out by means of laser correlation spectroscopy (apparatus: Malvern Zetasizer 1000, Malver Inst. Limited).

The indicated viscosities were determined by means of rotational viscometry according to DIN 53019 at 23 ° C. with a rotational viscometer from Anton Paar Germany GmbH, Ostfildern, DE.

Substances used and abbreviations:

Diaminosulphonate: NH ₂ -CH ₂ CH ₂ -NH-CH ₂ CH ₂ -SO ₃ Na (45% in water)

Desmophen ^® C2200: polycarbonate polyol, OH number 56 mg KOH / g, number average molecular weight 2000 g / mol (Bayer Materials cience AG, Leverkusen, DE)

PolyTHF 2000: polytetramethylene glycol polyol, OH number 56 mg KOH / g, number average molecular weight 2000 g / mol (BASF AG, Ludwigshafen, DE)

PolyTHF 1000: polytetramethylene glycol polyol, OH number 1 12 mg KOH / g, number-average number average molecular weight 1000 g / mol (BASF AG, Ludwigshafen, DE)

Polyether LB 25: mono-functional polyether based on ethylene oxide / propylene oxide, number-average molecular weight 2250 g / mol, OH number 25 mg KOH / g (Bayer Materials Science AG, Leverkusen, DE)

Arg: L-arginine (BASF AG, Ludwigshafen, DE)

Arg-HCl: L-arginine hydrochloride (Sigma, Steinheim, DE) Sylgard ^® 184; Comp. A: dimethylvinyl-terminated dimethylsiloxane (Dow Corning SA, Seneffe, BE)

Sylgard ^® 184; Comp. B: hydrosilane (Dow Corning SA, Seneffe, BE)

Syl-Off ^® 4000: platinum Organic Catalyst (Dow Corning SA, Seneffe, BE) Pluronic ^® F127: EO / PO block copolymer (BASF, Ludwigshafen, DE)

Pluronic ^® PE6800: EO / PO block copolymer (BASF, Ludwigshafen, DE)

Desmodur ^® N 3400: Aliphatic polyisocyanate (HDI uretdione), NCO content 21.8%

(Bayer Materials Science AG, Leverkusen, DE) DBU: 1, 8-diazabicyclo (5.4.0) undec-7-ene (Sigma, Steinheim, DE)

Example 1 Preparation of the Polyurethane Dispersion 1

1077.2 g PolyTHF ^® 2000, 409.7 g of PolyTHF ^® 1000, 830.9 g Desmophen ^® C2200 and 48.3 g of polyether LB 25 were heated in a standard stirred apparatus at 70 ° C. Subsequently, at 70 ° C within 5 min, a mixture of 258.7 g of hexamethylene diisocyanate and

341.9 g of isophorone diisocyanate was added and stirred at 120 ° C until the theoretical NCO value was reached or slightly below. The finished prepolymer was dissolved with 4840 g of acetone while cooled to 50 ° C and then a solution of 27.4 g of ethylenediamine, 127.1 g of isophoronediamine, 67.3 g of diaminosulfonate and 1200 g of water was added within 10 min , The stirring time was 10 min. It was then dispersed by adding 654 g of water. This was followed by removal of the solvent by distillation in vacuo.

The resulting polyurethane dispersion had the following properties:

Solids content: 62.2%

Particle size (LKS): 528 nm

pH (23 ° C): 7.5 Example 2 Preparation of the Silicone Particles 1

The particular amount Arg- or Arg-HCl crystals (see Table 1) 184 and 0.34 g of Syl-Off * 4000 was homogeneously dispersed in 8.55 g of component A of Sylgard ^®. Any existing air bubbles were removed by means of ultrasound and evacuation. Subsequently, the wur- 0.85 g of component B of Sylgard 184 ^® and 3.125 ml of chloroform added.

After thorough mixing of the suspension, it was transferred by syringe and 15 G cannula within 6-10 minutes at 25 ° C in a saturated with Arg-HCl mixture of 300 mL of a 13.3% Pluronic ^® F127 solution in water and 700 mL Methanol was added dropwise (stirring speed of the methanolic solution: 350 rpm). When the addition was complete, the mixture was stirred for 2 hours at 25 ° C. at 300 rpm and for a further 30 minutes at 50 ° C. Finally, the silicone particles of the cooled suspension were separated with the aid of metal sieves into three fractions (0 <300 μm, 300 μm <0 <850 μm, 0> 850 μm) and washed with water and methanol. The particles were annealed overnight at 50 ° C under vacuum.

Table 1:

Arginine content based on the resulting total mass of the particle

Example 3 Production of Foams of Polyurethane Dispersion 1 and Silicone Particles 1

100 g of polyurethane dispersion 1, prepared according to Example 1, using a commercial hand mixer (bent wire stirrer) with 2.31 g of silicone particles 1 (300 μιη <0 <850 μιη, obtained by sieving), containing 20% Arg, mixed. After subsequent addition of 11.3 g of a 30% solution of Pluronic ^® PE 6800 in water volume of foam was beaten to 500 mL. Thereafter, the foams were using Film applicator (doctor blade) with gap height 5 mm mounted on non-sticky paper and dried at 100 ° C for 45 min in a convection oven.

It was obtained a pure white foam with homogeneously distributed silicone particles and good mechanical properties.

The release experiments were carried out with 1.5 g of this foam containing 3.4% silicone particles 1 or 0.7% Arg, at 20 ° C by means of diffusion cell (flow rate about 1, 1 ml / h, oriented on the usual lymph) with phosphate buffered Saline solution (pH 7.4) performed.

FIG. 1 shows the concentrations of the released arginine which are not cumulated: Within a few hours, the therapeutically necessary Arg concentration of 100 μmol / L is reached and maintained for about 3 days, which corresponds to the usual residence time of a wound dressing on a corresponding wound. The drug reservoir is not exhausted even after 5-7 days.

Example 4 Preparation of a Foamed Silicone Particle Composite Material from Polyurethane Dispersion 1 and Silicone Particles 1

100 g of polyurethane dispersion 1, prepared according to Example 1 were mixed with 9.9 g of a 30% solution of Pluronic ^® PE 6800 in water and opened using a commercially available hand stirrer (stirrer made of bent wire) to 400 mL of foam volume. Thereafter, the foam was applied by means of film applicator (squeegee) with gap height 2 mm on non-stick paper, while still wet with 6.37 g of silicone particles 1, prepared according to Example 2, sprinkled. Now, a further foam layer was applied by means of a film-drawing device to the first still moist foam layer such that the silicone particles were enclosed on both sides by polyurethane foam. The composite material was dried at 120 ° C for 20 minutes in a convection oven. There were pure white foam silicone particle composite materials with good mechanical

Properties (peel strength> 0.8 N / mm in the peel test) and a fine pore structure obtained. The silicone particles were located in the middle of the interface of the two foam layers. The peel strength, also called peel strength, was determined on a Zwick universal testing machine. For this purpose, the two foam layers were subtracted from each other at an angle of 180 ° at a crosshead speed of 100 mm / min.

Example 5 Production of a Foamed Silicone Particle Composite Material from Polyurethane Dispersion 1 and Silicone Particles 1

First, using a commercial hand mixer (bent wire stirrer) 100 g of polyurethane dispersion 1, prepared according to Example 1, mixed with 9.9 g of a 30% solution of Pluronic ^® PE 6800 in water and pitched to 400 mL foam volume. Thereafter, the foam was applied by means of a film applicator (doctor blade) with a gap height of 2 mm to non-sticking paper and dried at 140 ° C. for 15 minutes in a circulating air drying cabinet. The silicone particles 1 prepared according to Example 2 were then sprinkled like an island on this dried foam, covered with a further foam layer and the two foam layers at 160 ° C for 60 s to a thickness of 1 mm, ie 25% of the original thickness, pressed together, that the silicone particles in the resulting foam bag were enclosed on all sides in the foam.

Pure white foam-silicone-particle composite materials with good mechanical properties (peel strength> 0.8 N / mm in the peeling test) and a fine pore structure were obtained. The silicone particles were pocketed between the two foam layers.

Example 6 pH-Dependent Arginine Release from Silicone Particles

PU foams

In the course of the healing process, for example of a chronic wound, in many cases, the progress of wound healing also changes the pH value of the wound milieu. For this reason, release experiments according to Example 3 were carried out with PBS buffer solutions having different pH values. The resulting release profiles shown in FIG. 2 make it clear that the pH-in particular due to the pH-dependent Arg solubility-influences the release behavior of the active ingredient. The represented Arg concentrations of a measurement series are cumulative values. Example 7: Preparation of a Silicone Particle-Containing Polyurethane Reactive Foam

2880 g of a polyalkylene oxide having a molecular weight of 4680 g / mol was started at 80 ° C. over 2 hours on a mixture of 1440 g of HDI and 4 g of benzoyl chloride on glycerol, an ethylene oxide weight fraction of 72% and a propylene oxide weight fraction of 28%, previously at 100 ° C. during Was dried for 6 h at a pressure of 0.1 mbar, added dropwise and stirred for lh. The excess HDI was removed by thin film distillation at 130 ° C and 0.1 mbar. This gave a prepolymer having an NCO content of 2.1 1% and a viscosity of 3780 mPas.

20.0 g of this prepolymer and 2.2 g of Desmodur ^® N 3400 were added to 15 seconds at a stirrer speed of 1200 rev / min homogenized with 2.2 g of silicone particles 1, and again the mixture is homogenized at low speed. After addition of 0.08 g DBU and

11.1 g of a 1% solution of sodium oleate in water was stirred for a further 10 seconds and then the mixture was placed in a 500 ml beaker. After a

Start time of about 20 s, the mixture foams and results within a few minutes, a dimensionally stable, elastic foam of regularly fine cell structure with homogeneously distributed silicone particles inside.

The release experiments carried out corresponded to the results according to Example 3 both in terms of implementation and in terms of the resulting release profile.

Comparative Example 1: Arginine release from a polyurethane bumper

Using a commercially available hand stirrer (stirrer made of bent wire), 120 g of polyurethane dispersion 1, prepared according to Example 1, mixed with 12.4 g of a 30% solution of Pluronic ^® PE 6800 in water and 1.5 g of 50% Solution of Arg-HCl in

Water mixed and pitched to 500 mL foam volume. Thereafter, the foam was applied by means of film applicator (doctor blade) with gap height 6 mm on non-stick paper and dried at 140 ° C for 15 min in a convection oven. The result was a pure white foam with an Arg-HCl content of 0.95% based on the total mass, which corresponds to an arginine content of 0.78%.

The release experiments were carried out with 1.3 g of this foam, which at 22 ° C by Franz diffusion cell only in surface contact with 110 g of phosphate buffered saline (pH 7.4) was performed. Figure 3 shows the cumulative amount of arginine released: over the first 10 minutes, over 60% of arginine is already released; After 30 minutes, the drug reservoir is almost exhausted.

Comparative Example 2 Preparation of an Arginine-Containing Polyurethane Reactive Foam

20.0 g of the prepolymer prepared according to Example 6 and 2.2 g of Desmodur ^® N 3400 were added to 15 seconds at a stirrer speed of 1200 rev / min homogenized with 0.23 g of Arg-HCl and again the mixture is homogenized at low speed. After addition of 0.08 g DBU and 1 1, 1 g of a 1% sodium oleate in water was stirred for a further 10 seconds and the mixture then placed in a beaker of volume 500 ml. After a start time of about 30 s, the mixture foams up slowly, but is not fully cured even after 30 minutes; the introduced Arg-HCl consequently has a negative effect on the foaming reaction. The incompletely and inhomogeneously foamed mass was not subjected to release attempts because no suitable foam resulted.

Claims

claims

A wound insulation comprising a liquid-absorbent substrate having drug depots therein, wherein the drug depots comprise particles of at least one drug encapsulated in a silicone sheath and the substrate is a foam.

2. Wound dressing according to claim 1, characterized in that the foam has a density of <0.5, preferably of <0.4, more preferably of> 0.01 to <0.3 and particularly preferably of> 0.05 to < 0.3 g / cm ³ .

3. Wound dressing according to claim 1 or 2, characterized in that the foam is a polymer-based foam, preferably a reactive foam or a foaming foam.

4. Wound dressing according to one of claims 1 to 3, characterized in that the foam is based on polyurethanes.

5. Wound dressing according to claim 4, characterized in that the polyurethanes are obtainable by reaction of

A) isocyanate-functional prepolymers having a weight fraction of low molecular weight aliphatic diisocyanates having a molar mass of 140 to 278 g / mol of less than 1, 0 wt .-%, based on the prepolymer, obtainable by reaction of

A2) di- to hexafunctional polyalkylene oxides having an OH number of 22.5 to 12 mg KOH / g, and an ethylene oxide content of 50 to 100 mol%, based on the total amount of the oxyalkylene groups present, B) optionally heterocyclic, 4-ring or 6-membered oligomers of low molecular weight, aliphatic diisocyanates having a molar mass of 140 to 278 g / mol,

C) water D) if appropriate, catalysts, E) Cg- to C22-monocarboxylic acids or their ammonium or alkali metal salts or C 12- to C 44 -dicarboxylic acids or their ammonium or alkali metal salts,

F) optionally surfactants, G) optionally monohydric or polyhydric alcohols and H) optionally hydrophilic polyisocyanates obtainable by reaction of

H2) monofunctional polyalkylene oxides having an OH number of 10 to 250 and an ethylene oxide content of 50 to 100 mol%, based on the total amount of oxyalkylene groups contained.

6. Wound dressing according to claim 4, characterized in that the polyurethanes are obtainable by

I) isocyanate-functional prepolymers at least

11) organic polyisocyanates

13) optionally hydroxy-functional compounds having molecular weights of 62 to 399 g / mol and 14) optionally isocyanate-reactive, anionic or potentially anionic and / or optionally nonionic hydrophilicizing agents,

getting produced,

J) whose free NCO groups then wholly or partly

7. Wound dressing according to one of claims 1 to 6, characterized in that the active ingredient is a under in vivo conditions nitric oxide-releasing component, preferably L-arginine or an L-arginine-containing or an L-arginine releasing component, more preferably L -Arginine hydrochloride includes.

8. Wound dressing according to one of claims 1 to 7, characterized in that the silicone coating consists of polydimethylsiloxane.

9. Wound dressing according to one of claims 1 to 8, characterized in that the drug depots are spherical and have a diameter of 10 to 2000, preferably from 100 to 1000 and more preferably from 300 to 850 μιη.

10. Wound dressing according to one of claims 1 to 9, characterized in that the content of the active ingredient in the drug depots 2 to 60, preferably 2 to 50, more preferably 5 to 40 and particularly preferably 5 to 30 wt%.

11. Wound dressing according to one of claims 1 to 10, characterized in that the substrate 0.1 to 20, preferably 0.5 to 15, more preferably 1 to 10 and particularly preferably 1 to 5 wt .-% of the drug depots, based on contains the total weight of the wound dressing. A wound dressing according to any one of claims 1 to 11 for use as a wound treatment agent.

Use of a wound dressing according to any one of claims 1 to 11 for the preparation of an agent for the treatment of wounds.