WO2002100450A1

WO2002100450A1 - Self-adhesive matrix plaster containing an active ingredient and based on polyurethane gels

Info

Publication number: WO2002100450A1
Application number: PCT/EP2002/006429
Authority: WO
Inventors: Holger Kartheus; Michael Schink; Jürgen-Christian Quandt; Peter Philipp
Original assignee: Beiersdorf Ag
Priority date: 2001-06-13
Filing date: 2002-06-12
Publication date: 2002-12-19
Also published as: EP1441775A1; DE10128685A1

Abstract

The invention relates to a self-adhesive matrix plaster containing an active ingredient and based on polyurethane gels, said plaster being used to release active ingredients into the skin in a controlled manner. The active ingredient is present in the matrix and penetration enhancers are added to said matrix.

Description

description

Self-adhesive, active ingredient-containing matrix plaster based on polyurethane gels

The invention relates to self-adhesive, active substance-containing matrix plasters based on polyurethane gels, in particular with active substances which promote blood circulation.

Active substance-containing plasters for transdermal application are often described in the literature and in patents.

The transdermal patch systems can be differentiated according to their structure, for example.

In the membrane-controlled transdermal therapeutic systems, there is a separate drug reservoir between an outer impermeable cover layer and a semi-permeable control membrane, which controls the release of the drug into the skin and is connected to an additional adhesive layer for skin fixation.

Since the individual components of these complex systems have to be carefully coordinated with one another, production is complex.

In the matrix-controlled systems, an inherent drug reservoir is built up by a homogeneous distribution of the drug in a polymer matrix or a gel matrix. Ideally, the polymer or gel matrix has self-adhesive properties, so that the matrix does not have to be fixed on the skin by additionally applying an adhesive layer. In the simplest case, the active substance-containing matrix is located between a cover layer firmly anchored with it and a removable separating layer. The active ingredient is usually homogeneously mixed into the polymer or gel matrix by dissolving, dispersing, suspending, extruding, kneading, mixing or similar processes, in some cases at elevated temperature. The use of polyurethanes for the controlled release of active substance has only been described in a few cases (Lamba, Woodhouse, Cooper, "Polyurethanes in Biomedical Applications", CRC Press, 1998, p. 240).

EP 0 057 839 A1 describes polyurethane gels into which various active substances can also be incorporated and their use as active substance carriers with a depot effect.

The hydrophilic, self-adhesive polyurethane gel compositions described in WO 97/43328 A1 are preferably used as active substance-free wound dressings for the treatment of chronic wounds. They are characterized, for example, by good skin friendliness, good adhesion, also over a long period of use and painless removability after use.

EP 0 016 652 A1 describes an active substance-containing composition which is produced by reacting a polyethylene oxide with polyfunctional isocyanates and which is a crystalline hydrogel in the dry form. A composition with controlled release is obtained by swelling a polymeric carrier produced in this way in a solution of an active substance and subsequent drying.

WO 96/31551 A1 is concerned with polyurethane microgels which contain active substances, for example proteins, swell in water and can thereby release the active ingredient.

WO 91/02763 A1 and WO 94/22934 A1 also deal with compositions for the controlled release of active substances from hydrogels based on polyurethane-ureas.

The known active ingredient-containing polyurethanes are also products that have no self-adhesive properties.

Circulation-enhancing active substance plasters are used to treat rheumatic complaints, muscle tension and pain in the area of the musculoskeletal system. Known heat-effective plaster systems contain an adhesive based Rubber, hydrocolloid or hydrogel, in which one or more active ingredients with blood circulation-promoting properties, such as benzyl nicotinate, capsaicin and nonivamide, are incorporated.

In addition to a controlled release of the active substance, active substance-containing patch systems also have certain requirements for the adhesive matrix, such as, for example, skin friendliness, good adhesion over a long period of use and painless removability. Self-adhesive, hydrophilic polyurethane gels, which are used in the field of chronic wound healing, meet the latter requirements particularly well. Although these systems are also described as active ingredient carriers, they only release the active ingredient to a small extent, for example, when active ingredients that promote circulation such as nonivamide, benzyl nicotinate and capsaicin are used. One reason for this is that the property profile of known, in particular hydrophilic, polyurethane gel products is tailored for moist wound healing, for example the ability to absorb liquid from the wound and not to release active substances into the intact skin.

The object of the invention is to provide an active substance-containing matrix plaster for the controlled delivery of active substances to the skin and / or in the wound, which is self-adhesive and which can be produced economically.

The problem is solved by a matrix plaster as set out in claim 1. The sub-claims comprise advantageous variants of the subject matter of the invention.

The present invention relates to self-adhesive, active substance-containing matrix plasters for the controlled delivery of active substances to the skin or into the wound with an absorbent, self-adhesive matrix based on polyurethane gels, the active substance being present in the matrix and penetration enhancers being added to the matrix.

Up to 30% by weight, in particular 5 to 15% by weight, is advantageously added to the matrix penetration enhancer. The penetration enhancers include, for example, lipophilic solubilizers / enhancers lipophilic solubilizers / enhancers such as oleic acid decyl ester, isopropyl myristate and palmitate (IPM and IPP), 2-octyldodecanol and / or other fatty acid esters.

Fatty acid esters C ₈ -C ₁₈ with short-chain alcohols or fatty alcohols are more preferably used as enhancers.

Fatty alcohols are a collective name for the linear, saturated or unsaturated primary alcohols (1-alkanols) with 6 to 22 carbon atoms that can be obtained by reducing the triglycerides, fatty acids or fatty acid methyl esters.

Fatty alcohols are neutral, colorless, high-boiling, oily liquids or soft, colorless masses that are sparingly to insoluble in water, but easily soluble in alcohol and ether.

The following table shows physicochemical data of the fatty alcohols.

Table: Physico-chemical data of fatty alcohols.

Alcohol Formula M _R Mp Sdp.

° C ° C / kPa

1-hexanol C ₆ H ₁₄ 0 102.18 -51, 6 157.2

(Caproic)

1-heptanol C ₇ H ₁₆ 0 116.20 -30.0 177

(Önanthalkohol)

1-octanol C ₈ H ₁₈ 0 130.23 -16.3 194.5

(Caprylic)

1-nonanol C ₉ H ₂₀ O 144.26 212

(Pelargonic)

1-Decanol CιoH ₂₂ 0 158.28 -7.0 229

(Capric alcohol)

1-Undecanol C _U H _M O 172.31 16.3 131 / 2.0 10-Undecen-1-ol CnH ₂₂ 0 170.30 -2 133 / 2.1

1-Dodecanol Cι ₂ H ₂ 6θ 186.34 23.8 150 / 2.7

(Lauryl alcohol)

1-tridecanol Ci3H ₂₈ 0 200.36 155 / 2.0

1-Tetradecanol Cι ₄ H3oO 214.39 38.0 167 / 2.0

(Myristyl)

1-pentadecanol C-ιsH ₃₂ 0 228.42 44.0

1-hexadecanol C16H ₃ -4O 242.45 49.3 190 / 2.0

(Cetyl alcohol)

1-heptadecanol Cl H ₃ 6θ 256.47 54.0 308

1-octadecanol. Cι ₈ H3 ₈ 0 270.50 59.0 210 / 2.0

(Stearyl alcohol)

9-c / s-octadecen-1-ol CisHsßO 268.48 -7.5 209 / 2.0

(Oleyl alcohol)

9-rrans-octadecen-1-ol Cl ₈ H36θ 268.48 36.5 216 / 2.4

(Erucyl)

9-c / s-0ctadecen-1, 12-diol Cl ₈ H36θ ₂ 284.48 182 / 0.07

(Ricinol alcohol) all-cis-9, 12-octadecadien-1 -ol Cι ₈ H3 ₄ 0 266.47 -5 153 / 0.4

(Linoleyl alcohol) a // - c / s-9,12,15-octadecatrien-1-ol Cι ₈ H3 ₂ 0 264.45 133 / 0.3

(Linolenyl)

1-Nonadecanol C-ιgH ₄ oO 284.53 62 167 / 0.04

1-eicosanol C ₂ oH ₄₂ O 298.55 65.5 220 / 0.4

(Arachidyl alcohol)

9-c s-eicosen-1-ol C ₂ oH oO 296.54 209 / 2.0

(Gadoleyl)

5,8,11, 14-eicosatetraen-1 -ol C ₂ oH3 ₄ 0 290.49

1-heneicosanol C ι H ₄₄ 0 312.58 69.5

1-Docosanol C ₂₂ H ₄ 6θ 326.61 73.5 180 / 0.03

(Behenyl alcohol)

1-3-c / s-docosen-1-ol CH ₄₄ 0 324.59 34.5 241 / 1.3

(Erucyl)

1 -3-frans-docosen-1-ol C ₂₂ H ₄₄ O 324.59 53.5 241 / 1.1

(Brassidyl) Further preferred penetration enhancers are diesters and diethers of polyethylene glycol 6 to 12 with C ₈ -C ₁₈ fatty alcohols or C ₈ -C ₁₈ fatty acids.

Polyethylene glycols of the general formula belong to the class of polyethers under polyethylene glycols:

H-O-Chfe-Chfej-OH

Roger that.

Polyethylene glycols are produced industrially by a basic, catalyzed polyaddition of ethylene oxide (oxirane) in mostly small water-containing systems with ethylene glycol as the starting molecule. They have molar masses in the range from approx. 200 to 5,000,000 g / mol, corresponding to degrees of polymerization n of approx. 5 to> 100,000.

Propylene glycol di-esters with C ₈ -C ₁₈ fatty alcohols are more preferably used as enhancers.

Gylcerin, di- and triesters with C ₈ -C ₈ fatty alcohols are further preferably used as enhancers.

Suitable as a matrix are absorbent, self-adhesive polyurethanes, in foamed or non-foamed form, which can additionally contain fillers or auxiliaries, such as absorbent materials.

Suitable polyurethanes are the subject of DE 196 18 825 A1, in which hydrophilic, self-adhesive polyurethane gels are disclosed, which consist of a) 2 to 6 hydroxyl group-containing polyether polyols with OH numbers from 20 to 112 and an ethylene oxide (EO) content of > 10% by weight, b) antioxidants, c) bismuth (III) carboxylates based on carboxylic acids with 2 to 18 C atoms as catalysts and d) hexamethylene diisocyanate, soluble in the polyols, with a product of the functionalities of the polyurethane-forming components a) and d) of at least 5.2, the amount of catalyst c) being 0.005 to 0.25% by weight, based on the polyol a), the amount of antioxidants b) is in the range from 0.1 to 1.0% by weight, based on polyol a) and a ratio of free NCO groups of component d) to the free OH groups of component a) (isocyanate index) is in the range of 0 , 30 to 0.70 is selected.

It is preferred to use 3 to 4, very particularly preferably 4-hydroxyl group-containing polyether polyols having an OH number in the range from 20 to 112, preferably 30 to 56. The ethylene oxide content in the polyether polyols used according to the invention is preferably> 20% by weight.

The polyether polyols are known per se and are obtained, for example, by polymerizing epoxides, such as ethylene oxide, propylene oxide, butylene oxide or tetrahydrofuran, by themselves or by addition of these epoxides, preferably ethylene oxide and propylene oxide - optionally in a mixture with one another or separately in succession Starter components with at least two reactive hydrogen atoms, such as water, ethylene glycol, propylene glycol, diethylene glycol, dipropylene glycol, glycerin, trimethylolpropane, pentaerythritol, sorbitol or succrose. Representatives of the higher molecular weight polyhydroxyl compounds to be used are listed, for example, in High Polymers, Vol. XVI, "Polyurethanes, Chemistry and Technology" (Saunders-Frisch, Interscience Publishers, New York, Vol. 1, 1962, pp. 32-42).

The isocyanate component is monomeric or trimerized hexamethylene diisocyanate or by biuret, uretdione, allophanate groups or by prepolymerization with polyether polyols or mixtures of polyether polyols based on the known starter components with 2 or> 2 reactive H atoms and epoxides such as ethylene oxide or propylene oxide with an OH number from <850, preferably 100 to 600, modified hexamethylene diisocyanate. The use of modified hexamethylene diisocyanate is preferred, in particular by means of prepolymers with polyether diols with an OH number of 200 to 600 modified hexamethylene diisocyanate. Modifications of hexamethylene diisocyanate with polyether diols with an OH number of 200-600, the residual content of monomeric hexamethylene diisocyanate below 0.5% by weight, are very particularly preferred. Possible catalysts for the polyurethane gels according to the invention in the anhydrous polyether polyols a) are bismuth (III) carboxylates based on linear, branched, saturated or unsaturated carboxylic acids having 2 to 18, preferably 6 to 18, carbon atoms. Bi (III) salts of branched saturated carboxylic acids with tertiary carboxyl groups, such as 2,2-dimethyloctanoic acid (for example Versatic acids, Shell), are preferred. Preparations of these bi (III) salts in excess proportions of these carboxylic acids are very suitable. A solution of 1 mol of the Bi (III) salt of Versatic 10-acid (2,2-dimethyloctanoic acid) in an excess of 3 mol of this acid with a Bi content of approx. 17% has proven to be excellent.

The catalysts are preferably used in amounts of 0.03 to 0.1% by weight, based on the polyol a).

The antioxidants used for the polyurethane gels according to the invention are, in particular, sterically hindered phenolic stabilizers, such as BHT (2,6-di-tert-butyl-4-methylphenol), Vulkanox BKF (2.2 min -methylene-bis- (6-tert. -butyl-4-methyl phenol) (Bayer AG), Irganox 1010 (pentaerythrityl tetrakis [3- (3,5-ditert.-butyl-4-hydroxyphenyl) propionate]), Irganox 1076 (octadecyl-3- ( 3,5-ditert.-butyl-4-hydroxyphenyl) propionate) (Ciba-Geigy) or tocopherol (vitamin E), preferably those of the α-tocopherol type.

The antioxidants are preferably used in amounts of 0.15 to 0.5% by weight, based on the polyol a).

The isocyanate index (ratio of the free NCO groups used in the reaction to the free OH groups) of the polyurethane gel compositions according to the invention is in the range from 0.30 to 0.70, preferably in the range, depending on the functionality of the isocyanate and polyol components used from 0.45 to 0.60. The isocyanate index required for gel formation can be easily estimated using the following formula:

f (Poiyoi) * (f (ocyanat) ~) * key figure * 2

Key figure ■ ^■

J (polyol) * J (isocyanate) Functionality of the isocyanate or polyol component

Depending on the desired stickiness or elasticity of the gel, the actually used isocyanate index can deviate from the calculated value by up to + 20%. The polyurethane gel compositions according to the invention are produced by customary processes, as described, for example, in Becker / Braun, Kunststoff-Handbuch, Vol. 7, Polyurethane, p. 121 ff, Carl-Hauser, 1983.

Polyurethanes such as those disclosed in EP 0 665 856 B1 are more preferably used.

The hydrophilic polyurethane gel foams are therefore available from

1. a polyurethane gel, which

(A) 25-62% by weight, preferably 30-60% by weight, particularly preferably 40-57% by weight, based on the sum of (A) and (B), of a covalently cross-linked polyurethane as a high-molecular matrix and

(B) 75-38% by weight, preferably 70-40% by weight, particularly preferably 60-43% by weight, based on the sum of (A) and (B) of one or more in the matrix by secondary valence forces firmly bound polyhydroxyl compounds with an average molecular weight between 1000 and 12000, preferably between 1500 and 8000, particularly preferably between 2000 and 6000, and an average OH number between 20 and 112, preferably between 25 and 84, particularly preferably between 28 and 56, as liquid dispersant, the dispersant being essentially free of hydroxyl compounds with a molecular weight below 800, preferably below 1000, particularly preferably below 1500, and optionally

(C) 0 to 100% by weight, based on the sum of (A) and (B), of fillers and / or additives,

and which can be obtained by reacting a mixture of a) one or more polyisocyanates, b) one or more polyhydroxyl compounds with an average molecular weight between 1000 and 12000 and an average OH number between 20 and 112,

c) optionally catalysts or accelerators for the reaction between isocyanate and hydroxyl groups and optionally

d) fillers and additives known per se from polyurethane chemistry,

this mixture being essentially free of hydroxyl compounds with a molecular weight below 800, the average functionality of the polyisocyanates (F |) is between 2 and 4, the average functionality of the polyhydroxyl compound (F _p ) is between 3 and 6 and the isocyanate index (K) of the formula

κ = - 300 ± X

^■ + 7 (,. F _p ) - l

obeys, in which X <120, preferably X <100, particularly preferably X <90 and the characteristic number K lies between 15 and 70, the given average values of molecular weight and OH number being understood as number average,

2. a water absorbing material and

3. a non-aqueous foaming agent.

The polyurethane gels can be prepared from the starting compounds known per se from polyurethane chemistry by processes known per se, as are described, for example, in DE 31 03 499 A1, DE 31 03 500 A1 and EP 0 147 588 A1. It is essential, however, that the conditions defined above are observed when selecting the gel-forming components, since otherwise tack-free, elastic gels are obtained instead of self-adhesive gels.

Preferred polyhydroxyl compounds are polyether polyols, as are mentioned in detail in the above-mentioned laid-open publications. Both (cyclo) aliphatic and aromatic isocyanates are suitable as polyisocyanate components. Preferred (cyclo) aliphatic polyisocyanates are 1,6-hexamethylene diisocyanate and its biurets and trimehsates or hydrogenated diphenylmethane diisocyanate ("MDI") types. Preferred aromatic polyisocyanates are those obtained by distillation, such as MDI mixtures of 4,4'- and 2,4'-isomers or 4,4'-MDI, and tolylene diisocyanate ("TDI") types.

The diisocyanates can in particular be selected, for example, from the group of unmodified aromatic or aliphatic diisocyanates or from modified products formed by prepolymerization with amines, polyols or polyether polyols.

The polyurethane composition can be used without foaming, foaming, unfilling or with additional fillers such as superabsorbents, titanium dioxide, zinc oxide, plasticizers, dyes, etc. Hydrogels in semi-solid to solid form with active components for the central zone can also be used.

The polyurethane gels can optionally contain additives known per se from polyurethane chemistry, such as, for example, fillers and short fibers on an inorganic or organic basis, metal pigments, surface-active substances or liquid extenders such as substances with a boiling point above 150 ° C.

Examples of organic fillers are heavy spar, chalk, gypsum, kieserite, soda, titanium dioxide, cerium oxide, quartz sand, kaolin, carbon black and hollow microspheres.

For organic fillers, for example, powders based on polystyrene, polyvinyl chloride, urea formaldehyde and polyhydrazodicarbonamide can be used. The short fibers are, for example, glass fibers of 0.1 to 1 mm in length or fibers of organic origin, such as polyester or polyamide fibers. Metal powders, such as iron or copper powder, can also be used in the gel formation. In order to impart the desired coloring to the gels, the dyes or colored pigments known per se in the coloring of polyurethanes on an organic or inorganic basis, such as, for example, iron oxide or chromium oxide pigments, pigments based on phthalocyanine or monoazo, can be used. As Surface-active substances may be mentioned, for example, cellulose powder, activated carbon and silica preparations.

To modify the adhesive properties of the gels, additions of polymeric vinyl compounds, polyacrylates and other copolymers or adhesives based on natural materials up to a content of 10% by weight, based on the weight of the gel mass, which are customary in adhesive technology, can optionally be added.

Preferred water-absorbent materials are water-absorbent salts of polyacrylates and their copolymers known as superabsorbers, in particular the sodium or potassium salts. They can be uncrosslinked or networked and are also available as commercial products. Products such as those disclosed in DE 37 13 601 A1 are particularly suitable, and also superabsorbents of the new generation with only small proportions of dry water and high swelling capacity under pressure. Preferred products are weakly crosslinked polymers based on acrylic acid / sodium acrylate. Such sodium polyacrylates are available as Favor T (Chemische Fabrik Stockhausen GmbH, Germany).

Other absorbers, for example carboxymethyl cellulose and karaya, are also suitable.

The degree of foaming can be varied within wide limits by the amounts of foaming agent incorporated.

More preferably, the matrix has a thickness of 10 to 1000 μm, very particularly 30 to 300 μm.

A large number of substance groups which are free from hydroxyl, carboxyl or amine functionalities which are reactive toward the polyurethane crosslinking reaction are used as active substances, for example essential oils, skin-care cosmetic additives, pharmaceutically active substances or antiseptics.

Transdermal therapeutic systems which are doped with essential oils and their components (e.g. eucalyptus oil, peppermint oil, camphor, menthol) have a long-term therapeutic effect for colds,

Headache and other indications. Surprisingly, that bothers

Hydroxyl functionality in the menthol does not affect the polyurethane crosslinking reaction, which can be explained by the lower reactivity of the secondary OH group in the menthol molecule.

Essential oils are concentrates obtained from plants, which are used as natural raw materials mainly in the perfume and food industry and which consist more or less of volatile compounds, such as real essential oils, citrus oils, absolute, resinoids.

The term is often used to refer to the volatile constituents still contained in the plants. In the real sense, however, essential oils are mixtures of volatile components that are produced from vegetable raw materials by steam distillation.

Real essential oils consist exclusively of volatile components, the boiling point of which is predominantly between 150 and 300 ° C. Unlike, for example, fatty oils, they do not leave a permanent, transparent grease stain when dabbed on filter paper. Essential oils mainly contain hydrocarbons or monofunctional compounds such as aldehydes, esters, ethers and ketones.

Parent compounds are mono- and sesquiterpenes, phenylpropane derivatives and longer-chain aliphatic compounds.

Some essential oils are dominated by one ingredient (e.g. eugenol in clove oil with more than 85%), others are extremely complex. The organoleptic properties are often shaped not by the main components, but by minor or trace components, such as the 1,3,5-undecatrienes and pyrazines in Galbanum oil. Many of the commercially important essential oils have hundreds of identified components. A large number of ingredients are chiral, with an enantiomer predominating or being present very often, such as (-) - menthol in peppermint oil or (-) - linalyl acetate in lavender oil.

In an advantageous embodiment, the matrix contains 0.1 to 20% by weight, in particular 1 to 10% by weight, of essential oils, in particular from the group consisting of eucalyptus oil, peppermint oil, chamomile oil, camphor, menthol, citrus oil, cinnamon oil, thyme oil, Lavender oil, clove oil, tea tree oil, cajeput oil, niaouli oil, kanuka oil, manuka oil, mountain pine oil are selected. Citrus oils are essential oils that come from the peels of citrus fruits (bergamot,

Grapefruit, lime, tangerine, orange, lemon), often also called agricultural oils.

Citrus oils largely consist of monoterpene hydrocarbons, mainly limonene (exception: bergamot oil, which only contains approx. 40%).

Camphor is understood to mean 2-bornanon, 1,7,7-trimethylbicyclo [2.2.1] heptan-2-one, see figure below.

(+) - camphor

Peppermint oils are essential oils obtained by steam distillation from leaves and inflorescences of various types of peppermint, occasionally also those from Mentha arvensis.

Menthol has three asymmetric carbon atoms and therefore occurs in four diastereomeric pairs of enantiomers (see the formula images, the other four enantiomers are the corresponding mirror images).

(-) - Menthol (+) - Neomenthol (+) - lsomenthol (+) - Neoisomenthol (1) (2) (3) (4)

The diastereomers that can be separated by distillation are called neoisomenthol, isomenthol, neonnenthol [(+) - form: component of Japanese peppermint oil] and menthol. The most important isomer is (-) - menthol (levomenthol), shiny, strongly peppermint-smelling prisms.

When rubbed on the skin (especially on the forehead and temples), menthol creates a pleasant feeling of cold due to surface anesthesia and irritation of the cold-sensitive nerves during migraines and the like; in fact, the areas in question show normal or elevated temperature. The other isomers of menthol do not have these effects.

Furthermore, cosmetic additives that care for the skin can advantageously be added to the matrix, in particular from 0.2 to 10% by weight, very particularly from 0.5 to 5% by weight.

According to the invention, the skin care cosmetic additives (one or more compounds) can be selected very advantageously from the group of lipophilic additives, in particular from the following group:

Azulene, vitamins, vitamin A palmitate, caffeine.

It is also advantageous to choose the additives from the group of refatting substances, for example Purcellin oil, Eucerit® and Neocerit.

The additives or additives are also particularly advantageously selected from the group of NO synthase inhibitors, in particular if the preparations according to the invention are used for treatment and prophylaxis of the symptoms of intrinsic and / or extrinsic skin aging and for the treatment and prophylaxis of the harmful effects of ultraviolet radiation on the skin.

The preferred NO synthase inhibitor is nitroarginine.

It is also advantageous to choose the additive (s) from the group of ubiquinones and plastoquinones.

Ubiquinones are characterized by the structural formula

and make the most widespread u. are the best studied bioquinones. Depending on the number of isoprene units linked in the side chain, ubiquinones are classified as Q-1, Q-2, Q-3 etc. or according to the number of C atoms as U-5, U-10 U-15 and so on. They preferably occur with certain chain lengths, for example in some microorganisms and the like. Yeast with n = 6. Q10 predominates in most mammals, including humans.

Coenzyme Q10, which is characterized by the following structural formula, is particularly advantageous:

Plastoquinones have the general structural formula

on. Plastoquinones differ in the number n of isoprene residues and are named accordingly, for example PQ-9 (n = 9). There are also other plastoquinones with different substituents on the quinone ring.

Creatine and / or creatine derivatives are also preferred additives for the purposes of the present invention. Creatine is characterized by the following structure:

Preferred derivatives are creatine phosphate and creatine sulfate, creatine acetate, creatine ascorbate and the derivatives esterified on the carboxyl group with mono- or polyfunctional alcohols.

The list of additives or combinations of additives mentioned which can be used in the preparations according to the invention is of course not intended to be limiting, apart from the criterion of the hydroxyl or carboxyl group reactive towards isocyanate. The additives can be used individually or in any combination with one another.

Then pharmaceutically active substances can be added to the matrix of the active substance-containing matrix patch, preferably up to 40% by weight, particularly 0.01 to 25% by weight, very particularly 0.1 to 10% by weight. Typical active ingredients are - without claiming to be complete in the context of the present invention:

Indication: active ingredient

Antifungals naftifine ((E) -N-cinnamyl-N-methyl-l-naphthalene methanamine)

amorolfine

((±) -cis-2,6-dimethyl-4- [2-methyl-3- (4-tert-pentylphenyl) propyl] morpholine)

Tolnaftate, (0- (2-naphthyl) -N-methyl-N-m-tolyl-thiocarbamate)

Clotrimazole (1 - [(2-chlorophenyl) diphenylmethyl] -1 H-imidazole)

Antiseptics triclosan

ethacridine

chlorhexidine

hexetidine

Dodicin iodine

Nonsteroidal anti-inflammatory drugs methyl salicylate etofenamate

indomethacin

([1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1 H -indol-3-yl] acetic acid)

Antipuriginosa crotamiton

Local anesthetics benzocaine

antipsoriatics

Keratolytics urea Other active ingredients that are beneficial for wound healing, such as silver sulfadiazine, can also be used.

Hyperaemic active ingredients such as natural active ingredients of cayenne pepper or synthetic active ingredients such as nonivamide, nicotinic acid derivatives, preferably bencyl nicotinate or propyl nicotinate, or anti-inflammatory drugs and / or analgesics can also be mentioned particularly advantageously and within the meaning of the invention.

Capsaicin is an example

[8-methyl-trans-6-nonenoic acid (4-hydroxy-3-methoxybenzylamide)]

nonivamide

nicotinic acid

benzyl

called.

Of particular importance among the active ingredients are the disinfectants or antiseptics, so that their use in the matrix should be emphasized again.

Disinfectants are substances that are used for disinfection, i.e. h., are suitable for combating pathogenic microorganisms (e.g. bacteria, viruses, spores, small and mold fungi), generally by applying them to the surface of skin, clothing, equipment, rooms, but also drinking water, food, seeds ( Pickling) and as a floor disinfectant.

Disinfectants to be used particularly locally, for example for wound disinfection, are also referred to as antiseptics.

In particular, the lactic acid derivatives, such as esters and oligo- and polylactic acid, are to be used as antiseptics.

Lactic acid esters include the esters of the general formula which are often referred to as lactates of the respective alcohol component

OH R = CH ₃ : a

R = C ₂ H ₅ : b

H ₃ C-CH-COOR

R = CH (CH ₃ ) ₂ : c R = (CH ₂ ) ₃ CH ₃ : d are known, the majority of which are liquid or deep-melting products at 20 ° C. and which are only slightly soluble in water, with the exception of the lower alkyl esters, in alcohol and ether.

One differentiates

(a) Lactic acid methyl ester (methyl lactate), C4H803, M _R 104.10, boiling point 145 ° C

(b) Lactic acid ethyl ester (ethyl lactate), C5H10O3, M _R 118.13, D. 1, 03, boiling point 154 ° C

(c) Lactic acid isopropyl ester (isopropyl lactate), C6H12O3, M _R 132.15, D. 0.9980, boiling point 167 ° C

(d) Lactic acid butyl ester (butyl lactate), C7H1403, M _R 146.18, D. 0.9803, boiling point 187 ° C

Polylactic acid (polylactide) is a polyester based on lactic acid, from whose lactide it can be produced by ring-opening polymerization.

Then, in a further advantageous embodiment, the matrix contains, in particular, a hydrophilic filler based on cellulose and its derivatives, the average grain size of which is in the range from 20 to 60 μm, because it was surprisingly found in the selection of the fillers that fillers in particular were found on the Based on silicon dioxide or cellulose, the latter having an isotropic shape and do not tend to swell when in contact with water. Fillers with a particle size of less than or equal to 100 μm are particularly suitable.

The use of hydrophilic fillers in a non-polar matrix is known in the literature. They are described explicitly for use in transdermal therapeutic systems in EP 0 186 019 A1. Here, however, only up to a concentration of 3 to 30% by weight, without mentioning details of these fillers. Experience shows that systems with a filler content of more than 30% by weight clearly lose stickiness and become hard and brittle. As a result, they lose the basic requirement of a transdermal therapeutic system. Fillers based on microcrystalline or amorphous cellulose are preferably used in substantially higher concentrations without adversely affecting the adhesive properties, in particular if they have an isotropic shape with a particle size of no greater than 100 μm. Higher levels of fillers are desirable in order to improve the wearing properties, particularly after long and repeated use.

Furthermore, the matrix on the side facing away from the skin or the wound can be covered with a carrier material, for example consisting of foils (for example made of PUR, polyester, PE or PP), nonwovens, fabrics, foams, metallized foils, composites, cotton etc.

The occlusive foils are preferred from the group of suitable carrier materials.

For example, a metallocene polyethylene nonwoven is also suitable.

The metallocene polyethylene nonwoven preferably has the following properties:

• a weight per unit area of 40 to 200 g / m ² , in particular of 60 to 120 g / m ² , and / or

A thickness of 0.1 to 0.6 mm, in particular 0.2 to 0.5, and / or

• a maximum tensile force elongation of 400 to 700% and / or

• a maximum tensile strength stretch across 250 to 550%.

Known nonwovens, which are mechanically consolidated, can be used as carrier materials, namely by sewing over with separate threads or by

Meshing.

In the first case, the nonwoven thread sewing fabrics result. To make this a

Filed nonwoven, which can be cross-paneled, for example, and is sewn on using separate threads in fringed or tricot layers.

These nonwovens are known under the name "Maliwatt" (from the Malimo company) or Arachne. In the second type of consolidation, cross-paneling is also preferred

Fleece presented. During the consolidation process, needles are pulled from the fleece itself

Fibers and shape them into stitches, creating seams in fringe layers.

This nonwoven knitted fabric is known under the name "Malivlies", also from the Malimo company.

An overview of the different types of mechanically bonded nonwoven fabrics can be found in the article "Laminating car upholstery fabrics with nonwoven fabrics" by G. Schmidt, Melliand

Textile reports 6/1992, pages 479 to 486.

In summary, it can be stated that all rigid and elastic flat structures made of synthetic and natural raw materials are suitable as carrier materials. Carrier materials that can be used in such a way that they fulfill the properties of a functional dressing are preferred. Textiles such as woven fabrics, knitted fabrics, scrims, nonwovens, laminates, nets, foils, foams and papers are listed as examples. These materials can also be pretreated or post-treated. Common pretreatments are corona and hydrophobizing; Common post-treatments are calendering, tempering, laminating, punching and mounting.

In a preferred embodiment, the matrix is applied to a carrier material, preferably in such a way that the periphery of the carrier material is at least partially not covered by the matrix.

Furthermore, an adhesive can be coated between the matrix and the carrier material, specifically based on PUR, acrylates or rubber.

Finally, if the matrix is not completely present on the carrier material, the matrix and / or the carrier material coated with the adhesive can be covered with the customary release paper.

The matrix plaster according to the invention can have any shape, a regular shape such as rectangular, square, circular or oval being preferred. Preferred embodiments of the subject matter of the invention and several figures are described below by way of example without wishing to restrict the invention unnecessarily.

Examples 1 to 7

Production of the active ingredient-containing polyurethanes

The active ingredient nonivamide (NVA, Boehringer Ingelheim) is melted in a heating cabinet and homogeneously mixed with isopropyl palmitate (IPP, Pronova Oleochemicals) with stirring.

The Levagel (polyether polyol from Bayer, Leverkusen) and Desmodur (polyisocyanate based on hexamethylene diisocyanate from Bayer, Leverkusen) are weighed into a vessel and homogeneously mixed with the nonivamide / isopropyl palmitate mixture for a few minutes with stirring ,

After adding Coscat 83 (bismuth salt from CHErbslöh), the mixture is stirred homogeneously for one minute and then the still liquid mass is spread between a carrier film (polyurethane film, Beiersdorf, Hamburg or polyethylene film, company) using a coating bar with a defined gap width. BP Chemicals) and a silicone paper (or silicone film).

Quantities of the recipes for Examples 1 to 7:

Examples 1 to 7

release

To investigate the release behavior, samples are prepared on pig skin and the release is determined quantitatively after 24 hours.

Example 2

Release of NVA on pig skin over time

Figure 7 graphically represents the results of the above table.

FIG. 1 illustrates a preferred geometric shape of the matrix plaster. The plaster has a circular shape (diameter 100 mm) and consists of a polyurethane matrix 2 that is chamfered towards the edge. The polyurethane matrix 2 is initially beveled evenly and ends in a 20 mm wide ring, in which the thickness is kept constant. The polyurethane matrix 2 is essentially semi-convex in the middle and is accordingly comparable to a semi-convex lens.

The thickness of the polyurethane matrix 2 is 2.3 mm in the middle and 0.7 mm at the edge.

Finally, the polyurethane matrix 2 is covered with a siliconized paper 1 in order to avoid contamination or contamination of the matrix 2.

FIG. 2 illustrates another preferred geometric shape of the matrix patch.

The plaster has an ellipsoidal shape (length of the axes 42 mm or 68 mm) and consists of a polyurethane matrix 2 which is beveled towards the edge. The polyurethane matrix 2 is initially beveled evenly and ends in an approximately 11 mm wide ring in which the thickness is kept constant. The polyurethane matrix 2 is essentially semi-convex in the middle and is accordingly comparable to a semi-convex lens.

The PU matrix 2 is covered on the side facing away from the skin with a PE film 3.

The thickness of the polyurethane matrix 2 including PE film 3 is 1.6 mm in the middle and

Edge 0.3 mm. Finally, the polyurethane matrix 2 is covered with a siliconized paper 1 in order to avoid contamination or contamination of the matrix 2.

FIG. 3 illustrates a further preferred geometric shape of the matrix patch.

The patch has an ellipsoidal shape (length of the axes 110 mm or 65 mm) and consists of a polyurethane matrix 2 that is beveled towards the edge. The polyurethane matrix 2 is essentially semi-convex, and is accordingly comparable to a semi-convex lens with an axis length of 72 mm or 34 mm.

The PU matrix 2 is covered on the side facing away from the skin with a PE film 3, which is coated over the entire surface with the adhesive layer 4 based on polyurethane, which contains IPP. In the embodiment of the plaster shown here, the entire periphery of the adhesive layer 4 is not covered with the polyurethane matrix 2. In this way, two concentric zones of chemically different adhesive compositions 2, 4 result, which differ in terms of adhesion, absorption capacity and cushioning properties.

The thickness of the polyurethane matrix 2 together with PU film 3 and adhesive layer 4 is 1.3 mm in the middle and 0.15 mm at the edge.

FIG. 4 illustrates a further preferred geometric shape of the matrix patch.

The plaster has a circular shape (diameter 100 mm), consists of a foamed polyurethane matrix 2, which is beveled towards the edge. The polyurethane matrix 2 is essentially semi-convex, and is accordingly comparable to a semi-convex lens with a diameter of 60 mm. The PU matrix 2 is covered on the side facing away from the skin with a PU film 3 which is coated over the entire surface with the adhesive layer 6 based on acrylate. In the embodiment of the plaster shown here, the entire periphery of the adhesive layer 6 is not covered with the polyurethane matrix 2. In this way, two concentric zones of chemically different adhesive compositions 2, 6 result, which differ in terms of adhesion, absorption capacity and cushioning properties.

The thickness of the polyurethane matrix 2 together with PU film 3 and adhesive layer 6 is 1.5 mm in the middle and 0.1 mm at the edge.

FIG. 5 illustrates a further preferred geometric shape of the wound dressing.

The plaster has a square shape, the corners of the square are rounded (diameter of the square 50 mm), consists of a water-vapor-permeable foamed polyurethane matrix 2, which is beveled towards the edge. The polyurethane matrix 2 is essentially semi-convex and circular, and is accordingly comparable to a semi-convex lens with a diameter of 33 mm.

The PU matrix 2 is covered on the side facing away from the skin with a PU film 3 which is coated over the entire surface with the adhesive layer 6 based on rubber. In the embodiment of the plaster shown here, the entire periphery of the adhesive layer 6 is not covered with the polyurethane matrix 2. In this way, two concentric zones of chemically different adhesive compositions 2, 6 result, which differ in terms of adhesion, absorption capacity and cushioning properties.

Finally, the polyurethane matrix 2 is covered with a siliconized paper in order to avoid contamination or contamination of the matrix 2. FIG. 6 shows three further embodiments of a matrix plaster according to the invention, namely in cross section.

In the first embodiment of the three, the matrix patch consists of three individual layers. The doped wound dressing made of polyurethane 2, the matrix 2, is completely covered on the side facing away from the wound or the skin with a carrier material 8. The carrier material 8 is, for example, polymer films, nonwovens, fabrics and their combinations, and films or textile materials made from polymers such as polyethylene, polypropylene and polyurethane or natural fibers.

On the side facing the wound or skin, the self-adhesive matrix 2 is completely covered with a release paper 1.

In the second embodiment of the matrix plaster, the matrix 2 has a relatively high layer thickness in the center of the plaster, while they are thin in the edge region of the plaster.

In the third embodiment, between the matrix 2 and the carrier material 8 there is an additional adhesive coating 9 applied over the entire surface of the carrier material 8. In contrast to the matrix plasters according to the first and second embodiments, the matrix 2 does not extend over the entire surface of the carrier material 8 No matrix 2 is applied in the edge region of the carrier material 8.

The release of NVA on pig skin is documented in FIG. To investigate the release behavior, samples are prepared on pig skin and the release is determined quantitatively after 2, 4, 6, 8 and 24 hours. The graphic shows the amount of NVA released as a sum in the epidermis and dermis. A steady, linear increase over a period of 24 hours can be seen. This makes it clear that the active ingredient is released into the skin in a controlled and sustainable manner in order to develop its effectiveness there.

Claims

claims

1. Self-adhesive, active substance-containing matrix plaster for the controlled delivery of active substances to the skin based on polyurethane gels, the active substance being present in the matrix and penetration enhancers being added to the matrix.

2. Self-adhesive, active ingredient-containing matrix plaster according to claim 1, characterized in that the matrix penetration enhancer are added up to 30 wt .-%, in particular 5 to 15 wt .-%.

3. Self-adhesive, active ingredient-containing matrix plaster according to claims 1 and 2, characterized in that lipophilic solubilizers / enhancers such as oleic acid decyl ester, isopropyl myristate and palmitate (IPM and IPP), 2-octyl dodecanol and / or other fatty acid esters are used as penetration enhancers.

4. Self-adhesive, active ingredient-containing matrix plaster according to claims 1 to 3, characterized in that the matrix consists of polyurethane in foamed or non-foamed form.

5. Self-adhesive, active ingredient-containing matrix plaster according to claims 1 to 4, characterized in that ethereal oils, skin-care cosmetic additives, pharmaceutically active substances and / or antiseptics, in particular hyperemising active ingredients, are used as active ingredients.

6. Self-adhesive, active ingredient-containing matrix plaster according to claims 1 to 5, characterized in that the matrix contains 0.1 to 20% by weight, preferably 2 to 10% by weight, of an active ingredient.

7. Self-adhesive, active substance-containing matrix plaster according to claims 1 to 6, characterized in that the matrix has a thickness of 10 to 2000 microns, very particularly 100 to 1500 microns.

8. Self-adhesive, active substance-containing matrix plaster according to claims 1 to 7, characterized in that the matrix is applied to a carrier material, preferably such that the periphery of the carrier material is at least partially not covered by the matrix.

9. Self-adhesive, active substance-containing matrix plaster according to claim 8, characterized in that an adhesive layer is present between the matrix and the carrier material.

10. Self-adhesive, active ingredient-containing matrix plaster according to claims 8 and 9, characterized in that occlusive films, preferably made of polyethylene, polypropylene and / or polyester, are used as the carrier material.