WO2007059894A2 - Multi-cyclic compounds in pressure-sensitive adhesives - Google Patents

Abstract

The invention relates to a pressure-sensitive adhesive containing at least one type of multi-cyclic saturated or unsaturated hydrocarbon, which is substituted by at least one functional group selected from a group consisting of -(CH2)POH, -(CH2)POC1-6-AIkyl, -(CH2)POCO-C1-6-Alkyl, -(CH2)PSH, -(CH2)PCN, -(CH2)PN3, -(CH2)PNH2, -(CH2)PNHC1-6-Alkyl, -(CH2)PN(C1-6-Alkyl)2,-(CH2)PNHCO-C1-6-Alkyl, -(CH2)PCHO, -(CH2)PCOC1-6-Alkyl, -(CH2)PCO2H,-(CH2)PCO2C1-6-Alkyl, -(CH2)PCONHC1-6-Alkyl and -(CH2)PCON(C1-6-Alkyl)2, wherein p can be identical to or different from 0, 1, 2, 3, 4, 5 or 6. The inventive adhesive is particularly suitable for fastening objects such as plasters and transdermal therapeutic systems to the skin.

Description

 Multicyclic compounds in pressure-sensitive adhesives

The invention relates to a pressure-sensitive adhesive which has excellent adhesion properties on the skin, so that it can be used, for example, as a medical pressure-sensitive adhesive for transdermal therapeutic systems and other medical or cosmetic products.

Pressure-sensitive adhesives, for example those based on polyacrylates, polyisobutylenes, polysiloxanes or celulose derivatives, are widely used in the manufacture of medical plasters and transdermal therapeutic systems (TTSs).

With the help of TTS, certain drugs can be administered through the skin parenterally, systemically. In this case, the TTS are able to deliver the active ingredient transdermally at a certain rate for a fixed period of time continuously to the organism. In therapy, TTSs have proven to be effective as they allow a painless, convenient and simple administration of an active ingredient to the patient over a longer period of time. Usually, a TTS comprises at least a) a carrier layer impermeable to the active substance, b) an adhesive layer which at least partially covers the carrier layer, and c) optionally a protective film which at least partially covers the adhesive layer and can be stripped therefrom.

With regard to the structure and mode of operation of TTS, a distinction can be made between diaphragm-controlled systems (reservoir TTS) and matrix-controlled systems (matrix TTS).

A reservoir TTS typically comprises a skin self-adherent, flat pouch containing the active ingredients dissolved. Facing the skin side, the bag is equipped with a permeable membrane for the active substance, which controls the drug release. Adhesive layer and active substance-containing layer (reservoir) are usually spatially separate subunits of a reservoir TTS.

In a matrix TTS, the active ingredient is embedded in a matrix, whereby it can be dispersed in liquid, semi-solid or solid state or in dissolved form. If the matrix has adhesive properties at the same time, the adhesive layer is at the same time also the active substance-containing layer. However, it is also possible that the adhesive layer and the active substance-containing layer are separated from one another, as is the case with a reservoir TTS. In this case, the adhesive layer may be full-coverage or partial, e.g. may be annularly applied to the active substance-containing layer or the membrane of the reservoir.

By the composition and structuring of the matrix and / or the membrane, the release of the active ingredient can be regulated. For further details, see, for example, TK Gosh, Transdermal and Topical Drug Delivery Systems, Es Into Practice, CRC Press, 1997; RO Potts et al., Mechanisms of Transdermal Drug Delivery (Drugs and the Pharmaceutical Sciences), Marcel Dekker, 1997; and R. Gurny et al., Dermal and Transdermal Drug Delivery. New Insights and Perspectives, Scientific VG., Stuttgart, 1998. In order for a drug to be administered by TTS, it must sufficiently diffuse through the epidermis of the skin, particularly the stratum corneum, through the individual underlying layers of skin, and be absorbed by the bloodstream. A significant problem is often the low permeability of the skin for certain active ingredients. Depending on the chemical structure and lipophilicity of the active ingredient, it may therefore be necessary to improve the transcutaneous permeation of the active ingredient from the TTS by adding suitable auxiliaries.

In addition to the desired pharmacokinetic parameters, a TTS must have sufficient skin tolerance. The adhesion of the TTS to the skin is usually achieved by means of pressure-sensitive adhesives (medical pressure-sensitive adhesive). For the chemical and / or physical properties, e.g. To modify the consistency or stickiness of medical pressure-sensitive adhesives and to optimize them depending on the respective requirements, certain adjuvants or additives are added, in particular plasticizers or tackifiers. However, these auxiliaries or additives should be compatible with the other materials used. Thus, the said auxiliaries or additives should not adversely affect the chemical stability of the active substances contained in TTS or their release. Often it may also be advantageous if the polymer matrix of a pressure-sensitive adhesive contains predominantly lipophilic properties, so that it has a high loading capacity for lipophilic active ingredients.

In addition, the ingredients of such pressure-sensitive adhesives must not cause allergies or contact dermatitis, and in particular the repeated application to the skin and removal from the skin should also take place gently and should not cause any skin irritation.

The adhesion of the system to the skin should therefore be sufficient to ensure a lasting medication, but should not be too strong for removal after application without difficulty. Furthermore, a TTS that is often used by the patient for several days should have a have sufficient water resistance, so that it does not detach itself due to natural transpiration or showering. Finally, a TTS should also have sufficient mechanical resistance so that it is not damaged or unintentionally removed as a result of external influences.

The same requirements are in principle made of the adhesive layer of other systems, which, although not containing an active substance for transdermal administration, but to be applied to the human or animal skin. Examples of such applications are conventional dressings having a wound dressing, pressure site patches, medicated topical patch patches, adhesive bandages for dressing dressings, self-adhesive cosmetic products, e.g. for degreasing the skin, and self-adhesive labels for aesthetic purposes, e.g. for fixing garments or toupees on the skin.

The invention has for its object to provide pressure-sensitive adhesives available, which have advantages over the prior art. The pressure-sensitive adhesives should be suitable for use as medical pressure-sensitive adhesives on the skin, for example for patches or TTS, have sufficient resistance to water and a balance between adhesive strength on the one hand and removability on the other. The physical and chemical properties, in particular stickiness and plastic properties or coherence, should be able to be advantageously modified and improved, with all ingredients being compatible with one another and not impairing the stability and release of the transdermally administered active ingredient in the case of TTSs.

This object is solved by the subject matter of the claims. It has surprisingly been found that certain multicyclic hydrocarbons can be advantageously used in pressure-sensitive adhesives.

One aspect of the invention relates to a pressure-sensitive adhesive containing at least one multicyclic, saturated or unsaturated hydrocarbon which is substituted by at least one functional group, preferably with at least two identical or different functional groups selected from the group consisting of - (CH ₂ ) _P OH, - (CH ₂ ) p0C _1-6 alkyl, - (CH ₂ ) _P OCO-Ci. ₆ - alkyl, - (CH ₂ ) _P SH, - (CH ₂ ) _P CN, - (CH ₂ ) _P N _3> - (CH ₂ ) _P NH ₂ , - (CH ₂ ) _p NHC _1-6 alkyl , - (CH ₂ ) _p N (C _1-6 alkyl) ₂ , - (CH ₂ ) _P NHCO-C ₁ . _6- alkyl, - (CH ₂ ) _P CHO, - (CH ₂ ) _p COC _1-6- alkyl, - (CH ₂ ) _P CO ₂ H, - (CH ₂ ) _p CO ₂ C 1 _-6- alkyl, (CH ₂ ) _p CONHC _1-6 alkyl and - (CH ₂ ) _p CON (Ci _-6 -alkyl) _2l where p can be 0, 1, 2, 3, 4, 5 or 6, preferably 0 or 1 , particularly preferably 1. If the multicyclic hydrocarbon is substituted with two or more substituents of the same type, for example with two substituents of the type - (CH ₂ ) _P OH, then p may be different in each case.

The invention relates to a preferably hypoallergenic and hypoallergenic pressure-sensitive adhesive. Pressure-sensitive adhesives are known in principle to the person skilled in the art. In this connection can be made for example to I. Benedek, Pressure-Sensitive Adhesives and Applications, Marcel Dekker, 2 ^nd edition, of 2004.

The pressure-sensitive adhesive of the present invention contains a multicyclic hydrocarbon. In this context, "multicyclic" means that the hydrocarbon according to the invention is at least bicyclic. In this case, "bicyclic" preferably means that a correct name of the hydrocarbon according to IUPAC nomenclature (preferably as of 2005) contains the term "bicyclo". Preferably, the hydrocarbon is tricyclic. Correspondingly, "tricyclo" preferably means that a correct name of the hydrocarbon according to IUPAC nomenclature (preferably as of 2005) contains the term "tricyclo".

In a preferred embodiment, the structure of the multicyclic hydrocarbon derives from a tricyclo [abcd ^ef ] hydrocarbon, where a, b, c and d are natural numbers and have the meaning according to IUPAC nomenclature, and the sum of a, b , c and d are in the range of 6 to 16, more preferably in the range of 8 to 14. The structure of the multicyclic hydrocarbon is preferably derived from this hydrocarbon, ie in addition to the hydrocarbon as a backbone, in addition to the at least one substituent selected from the group consisting of - (CH ₂ ) _P OH, - (CH ₂ ) _p OCi _-6 alkyl , - (CH ₂ ) _p OCO-C _1-6 -alkyl, - (CH ₂ ) _P SH, - (CH ₂ ) _P CN, - (CH ₂ ) _P N ₃ , - (CH ₂ ) _P NH ₂ , - (CH ₂ ) _p NHC _1-6 -alkyl,

Alkyl) ₂ , - (CH ₂ ) _p NHCO-C _1-6 -alkyl, - (CH ₂ ) _P CHO, - (CH ₂ ) _p COC ₁ - ₆ -alkyl, - (CH ₂ ) _P CO ₂ H, - (CH _{2) p} CO ₂ C _1-6 alkyl, - (CH _{2) p} CONHC _1-6 alkyl and - (CH ₂₎ PCON (Ci _-6 alkyl) _2, wherein each p same or different 0 , 1, 2, 3, 4, 5 or 6, also further substituents may be present, in particular alkanyl, alkenyl or alkynyl radicals.

In a preferred embodiment, the structure of the multicyclic hydrocarbon derives from a

- tricyclo [ab1.0 ^{2 (a + 1)} ] hydrocarbon or - tricyclo [ab2.0 ^{2 (a + 1)} ] hydrocarbon

where a is 5, 6, 7 or 8 and b is 2, 3 or 4, respectively.

The multicyclic hydrocarbon is saturated or unsaturated. Unsaturated in this context means that the hydrocarbon contains one or more carbon-carbon double bonds and / or one or more carbon-carbon triple bonds. If there are several double or triple bonds, these can be conjugated. Preferably, however, the hydrocarbon is not aromatic and not polymeric. The hydrocarbon is in molecular form, i. solid or liquid, dissolved or suspended.

The hydrocarbon is preferably a compound of the general formula (I)

wherein n is 1, 2 or 3;

Ri and R _{2 are the} same or different selected from the group consisting of -CH ₂ OH, -CH ₂ NH ₂ and -CHO; and R ³ and R ^{4 are} each -H or together form a -Ci-4-alkylene bridge, wherein the -Ci- ₄ -alkylene bridge optionally substituted with one or two identical or different -d- ₆ alkyl radicals can be.

More preferably, the structure of the multicyclic hydrocarbon derives from a

- tricyclo [5.2.1.0 ^2l6 ] hydrocarbon,

- tricyclo [6.2.1.0 ^2l7 ] hydrocarbon,

- tricyclo [5.2.2.0 ^{2 | 6} ] hydrocarbon or

- tricyclo [6.2.2.0 ² ' ⁷ ] hydrocarbon,

where a tricyclo [5.2.1.0 ²ⁱ⁶ ] alkane, in particular a tricyclo [5.2.1.0 ²⁶ ] decane, is particularly preferred.

Preferably, the hydrocarbon is selected from the group consisting of

B / s (hydroxymethyl) tricyclo- [5.2.1.0 ^{2 6} ] decane ("TCD-alcohol DM"), eg 3 (4), 8 (9) -b / s- (hydroxymethyl) tricyclo- [5.2.1.0 ² - ⁶ ] decane, ie

3,8-ol / s (hydroxymethyl) tricyclo [5.2.1.0 ² ' ⁶ ] decane,

4,8-b / s (hydroxymethyl) tricyclo [5.2.1.0 ^{2 l6} ] decane,

- 3,9 - /? / S- (hydroxymethyl) -tricyclo [5.2.1.0 ^{2 l6} ] decane, or

4,9-b / s (hydroxymethyl) tricyclo- [5.2.1.0 ^{2 l6} ] decane;

• ö / s- (aminomethyl) -tricyclo- [5.2.1.0 ^2f6 ] decane, eg 3 (4), 8 (9) -ό / s- (aminomethyl) -tricyclo [5.2.1.0 ² ' ⁶ ] decane ie

3,8-ois / (aminomethyl) -tricyclo- [5.2.1.0 ^{2 l6} ] decane,

3,9-O / s (aminomethyl) -tricyclo [5.2.1.0 ^{2> 6} ] decane,

- 4,8-O / s- (aminomethyl) -tricyclo- [5.2.1.0 ^{2 | 6} ] decane, or

4,9-ö / s- (aminomethyl) -tricyclo [5.2.1.0 ^{2 l6} ] decane; and

• jb / s-formyl-tricyclo- [5.2.1.0 ^2t6 ] decane, eg 3 (4), 8 (9) -b / s-formyl-tricyclo- [5.2.1.0 ^{2 l6} ] decane, ie

3,8-b / s-formyltricyclo [5.2.1.0 ^{2 l6} ] decane,

3,9-b / s-formyltricyclo [5.2.1.0 ^{2> 6} ] decane,

4,8-b / s-formyltricyclo [5.2.1.0 ²ⁱ⁶ ] decane or

4,9-ol / s-formyl-tricyclo- [5.2.1.0 ² L ⁶ ] decane. Such tricyclic hydrocarbons can be prepared by conventional methods and sometimes also commercially available. Tricyclo- [5.2.1.0 ^2t6 ] -decane is obtained, for example, by hydrogenation of the Diels-Alder product of cyclopentadiene.

The present invention opens up new and advantageous applications of these and similar compounds in the medical field, especially in the field of medical pressure-sensitive adhesive products. This is possible because it has surprisingly been found that these multicyclic hydrocarbons are highly compatible with the polymers commonly used to make pressure-sensitive medical products.

In a preferred embodiment

- p = 0 or 1 and / or

the hydrocarbon is tricyclic, and / or

the hydrocarbon comprises 8 to 30, more preferably 9 to 29, even more preferably 10 to 28, most preferably 11 to 27 and especially 12 to 26 carbon atoms, and / or

the hydrocarbon is not aromatic and / or not polymeric.

The molecular weight of the multicyclic hydrocarbon is preferably in the range of 120 to 500 g mol ^"1 , more preferably 150 to 300 g mol ^{" 1} , still more preferably 160 to 250 g mol ^"1 , most preferably 170 to 220 g mol ^{" 1} and in particular from 180 to 200 g mol ^"1 .

The weight fraction of the multicyclic hydrocarbon, based on the total weight of the pressure-sensitive adhesive, is preferably in the range from 0.1 to 50% by weight, more preferably from 1.0 to 40% by weight, more preferably from 5.0 to 30% by weight. %, most preferably 10 to 25 wt .-% and in particular 12 to 22 wt .-%.

The multicyclic hydrocarbons of this invention are highly compatible with the polymers commonly used in pressure-sensitive adhesives (eg, poly (meth) acrylates or cellulose derivatives). Due to the good compatibility formulations are possible, which may have a relatively high content of low molecular weight compounds such as drugs, so that in these pressure-sensitive adhesives facilitated and accelerated diffusion of drugs is expected. Depending on the substitution pattern of the multicyclic hydrocarbons, the lipophilic character of these compounds can be varied, so that they are sometimes suitable for increasing the lipophilicity of the pressure-sensitive adhesive and thus also its capacity for lipophilic active ingredients.

Within the pressure-sensitive adhesive of the present invention, the multicyclic hydrocarbon preferably functions as a tackifier, and the pressure-sensitive adhesives of the invention may contain, in addition to the multicyclic hydrocarbons, other auxiliaries which also act as tackifiers.

In a preferred embodiment, the pressure-sensitive adhesive according to the invention contains, in addition to at least one multicyclic hydrocarbon, an at least partially esterified saccharide, preferably an at least partially esterified disaccharide. Sucrose octaesters, in particular sucrose octaacetate and sucrose-actetate isobutyrate (eg sucrose diacetate hexaisobutyrate), have proven to be particularly suitable. The addition of such esters to pressure-sensitive adhesives leads to plasticization of the polymers and to improved tack, ie the esters act both as plasticizers and as tackifiers. Esters of saccharides are understood as those esters in which one, two or more hydroxyl groups of the saccharide, preferably of the disaccharide, more preferably at least on average half of the hydroxyl groups, most preferably all hydroxyl groups, are esterified. Particularly suitable disaccharides are sucrose and maltose, with esters of sucrose, in particular sucrose octaester, being the most preferred. Fatty acids are primarily understood as meaning saturated acyclic monocarboxylic acids, which may also be branched monocarboxylic acids, for example isobutyric acid. Furthermore, the term "fatty acids" also includes unsaturated fatty acids. According to a particular embodiment, at least a part of the hydroxyl groups of the sugar molecule is unbranched or branched fatty acids having a chain length of at least 4, preferably from 6 to 12 carbon atoms. Atoms esterified; the remaining hydroxyl groups are esterified with shorter fatty acids, for example with acetic acid.

Usually, the application properties of a medical pressure-sensitive adhesive can not be determined on the basis of a single measurement with regard to its adhesion and skin compatibility. Rather, various test methods are required, with the properties of the pressure-sensitive adhesive then only resulting from the overall result of all measurements. These tests include sometimes a so-called "peel test", the measurement of the surface tension, adhesion work and elasticity, and the determination of the behavior upon contact with water or the determination of the water vapor permeability.

For the quantitative determination of the adhesion properties of pressure-sensitive adhesives, various methods are available, e.g. 180 ° peel test, 90 ° peel test, drum peel test, T peel test and lift-off test. These tests are based on standards from various industry associations of pressure sensitive adhesive manufacturers (AFERA, PCTC, FINAT, ASTM (e.g., ASTM D903-98)). However, the individual tests can yield quite different results for a given pressure-sensitive adhesive.

In the 90 ° or 180 ° peel test, peel force determines the force necessary to peel a strip of extensible sample from a mostly rigid substrate at 90 ° or 180 ° angles (see PSTC -1: Peel Adhesion for Single Coated Tapes 180 ° Angle 12, 23-24, Pressure Sensitive Tape Council, 1996, Illinois).

The 90 ° peel test often measures, as a measure of the adhesion properties of pressure sensitive adhesives, the force required to apply a 4 cm wide strip attached to a flat stainless steel surface over the pressure sensitive adhesive at a certain speed (eg, 50 mm / sec). min) orthogonally. A determination method which is preferred according to the invention is carried out on a testing machine from Zwick, particularly preferably as indicated in Example 4 a). Usually, values are measured that fluctuate within a certain range, so that the average bond strength as arithmetic Means of the measured maximum value and the measured minimum value can be specified.

However, the standard stainless steel surface to which the pressure-sensitive adhesives are applied in this method of determination is limited in their ability to simulate the adhesive properties of a pressure-sensitive adhesive on human or animal skin. Thus, on the one hand, for example, the body temperature can play a role and on the other hand, the surface structure of the skin is not completely planar. Furthermore, the skin has pores, hair, lipids, moisture and sometimes also keratin scales. Because of this complex structure, however, it is also difficult to find another standardized surface instead of stainless steel, which, because of its surface structure, is more similar to human or animal skin and ensures reproducible measured values. In the prior art methods are described for determining the adhesion properties of pressure sensitive adhesives on Artificial Skin (Vitro Skin ^®, Paraskin ^®). Although the results usually correlate better with the in vivo data, they are also not always completely satisfactory.

Also, in the pressure-sensitive adhesive of the present invention, the fact that the multicyclic hydrocarbon significantly improves the adhesion properties is poorly expressed in determining the adhesion properties by 90 ° peel (i.e., adhesion to a stainless steel surface). The improvement of the adhesion properties becomes clearer only when the human skin is used as the test surface, i. selects in vivo conditions. According to the invention, therefore, the determination of the adhesion properties of the pressure-sensitive adhesive is not carried out with a stainless steel surface as a substrate, preferably not on artificial skin, but particularly preferably as perceived adhesion on the human or animal skin, for example as described in Example 4 b).

However, if the adhesion properties are determined by conventional methods, for example in the 90 ° peel test, the determined average bond strength of the system according to the invention is preferably in the range from 0.1 to 2.0 N / cm, more preferably in the range from 0.2 to 1 , 8 N / cm, more preferably in the range of 0.4 to 1.6 N / cm, on most preferably in the range of 0.5 to 1.5 N / cm and in particular in the range of 0.6 to 1.4 N / cm.

In addition to the multicyclic hydrocarbon, the pressure-sensitive adhesive of the invention preferably contains at least one polymer, preferably selected from the group consisting of polyacrylates, polyvinyl ethers, polyvinyl alcohols, polyisobutylenes, acrylate copolymers, ethylene-vinyl acetate copolymers, polyurethanes, styrene-isoprene copolymers, styrene-butadiene - Copolymers, cellulose derivatives, silicones, rubbers, resins and optionally hydrogenated esters of rosin.

Suitable cellulose derivatives are e.g. Ethylcellulose, propylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose.

Suitable polyacrylates are e.g. (Co) polymers of acrylates, alkyl acrylates, methacrylates, and / or alkyl methacrylates, which are optionally copolymerized with further unsaturated monomers such as acrylamide, dimethylacrylamide, dimethylaminoethyl acrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, methoxyethyl acrylate, methoxyethyl methacrylate, acrylonitrile and / or vinyl acetate.

As used herein, "(meth) acrylic" means "acrylic" and / or "methacrylic".

Particularly suitable (meth) acrylic esters are those which carry linear, branched or cyclic aliphatic C ₁ -C ₂ substituents without other functional groups. In particular, this group includes methyl (meth) acrylate, ethyl (meth) acrylate, isopropyl (meth) acrylate, n-butyl (meth) acrylate, isobutyl (meth) acrylate, sec-butyl (meth) acrylate, tert-butyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, cyclohexyl (meth) acrylate and isobornyl (meth) acrylate.

However, (meth) acrylic acid esters can also be present in the monomer mixture used to prepare the polyacrylate which carry functional groups. These include hydroxyl-containing esters, such as 2-hydroxyethyl (meth) acrylate and 3-hydroxypropyl (meth) acrylate. But also substances such as acrylamide, dimethylaminoethyl acrylate, etc. may contain as functional groups (meth) - be understood acrylic acid ester. The proportion of (meth) acrylic acid esters which contain such functional groups should in the monomer mixture be less than or equal to 10% by weight, preferably less than 2% by weight, more preferably less than 0.2% by weight. Particularly preferred is a monomer mixture containing no (meth) acrylic acid ester containing functional groups.

However, it is also possible to use vinyl acetate as co-monomer together with at least one monomer from the group of the (meth) acrylic esters for the preparation of the polyacrylate. The proportion of vinyl acetate in the monomer mixture used to prepare this polyacrylate should be below 50% by weight, preferably below 25% by weight. Particularly preferred is a vinyl acetate content between 0 and 5.0 wt .-%. Particularly preferred are acrylate vinyl acetate copolymers, which are available, for example under the name DURO TAK ^® commercially. These copolymers are particularly preferred in combination with polyacrylates, such as Carbopol ^®, especially Carbopol ^® 980 used, or hydroxypropyl cellulose.

In the present invention, the weight ratio of the multicyclic hydrocarbon to the above-listed at least one polymer is preferably in the range of 10: 1 to 1: 100, more preferably 5: 1 to 1:50, still more preferably 1: 1 to 1:10, and most preferably 1: 1 to 1: 5.

The pressure-sensitive adhesive of the invention may contain other adjuvants which may make it particularly suitable for use on human skin. Examples of such auxiliaries are skin permeation-promoting substances, solvents, solubilizers, emulsifiers, crosslinkers, stabilizers, preservatives, dyes, skin-smoothing agents, fragrances, compounds which are transferable to the skin surface to reduce or prevent skin irritations, thickeners, plasticizers, tackifiers, etc. Adjuvants are known to the person skilled in the art. In this connection reference may be made, for example, to HP Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und Nachbargebiete, Editio Cantor Aulendorff, 2002; R. Niedner et al., Dermatics: Therapeutic Use, Pharmacology and Pharmacy, Wiss. Verl.-Ges. 1992. Concrete examples of the above Substance classes are also described below in connection with further aspects of the invention.

Another aspect of the invention relates to a self-adhesive skin fastening device comprising a tacky layer containing a pressure-sensitive adhesive as described above.

Preferably, the self-adhesive device

a Transdermal Therapeutic System,

a medicated plaster wherein the active ingredient is administered substantially only topically, but not transdermally / systemically,

a patch which does not contain a pharmaceutically active substance (e.g., a conventional patch with a dressing or a pressure site patch), or

- Another self-adhesive article, which is intended to be applied to the skin (eg an adhesive tape for attaching dressings, a self-adhesive cosmetic product, such as for degreasing the skin, and a self-adhesive label for aesthetic purposes, such as the fixation of garments or toupees on the skin) comprising a tacky layer based on a pressure-sensitive adhesive of the invention described above.

In a particularly preferred embodiment, this is a medicated plaster or a TTS, which is e.g. can be configured as a matrix TTS or as a reservoir TTS.

The TTS according to the invention preferably comprises at least one active substance-impermeable carrier layer, an adhesive layer which at least partially covers the carrier layer, and optionally a protective film which at least partially covers the adhesive-capable layer and can be stripped therefrom. The active substance can be contained in the adhesive-capable layer (drug-in-adhesive) and / or another layer, for example in a matrix isolated from the adhesive layer (drug-in-matrix). In a preferred embodiment, the drug to be administered transdermally is at least partially contained in the adhesive layer. In a preferred embodiment, the active substance to be transdermally administered is at least partially embedded in a matrix, wherein the matrix in turn may be part of the adhesive layer or form an independent layer.

In a preferred embodiment, the TTS according to the invention is a matrix TTS. The matrix TTS preferably comprises a carrier layer, of which a surface adjoins the matrix containing the active substance to be transdermally administered (active substance-containing layer), and an adhesive layer. The adhesive layer preferably covers the entire surface of the carrier layer. The intervening matrix preferably covers only a part of the surface of the carrier layer, so that an outer edge of the carrier layer remains, which is indeed covered with the adhesive layer but not with the matrix. In order to minimize the migration of the active ingredient into the carrier layer, it may be advantageous to insert a barrier layer made of a suitable material between carrier layer and matrix. The adhesive layer is preferably provided with a removable protective film.

In the case of the matrix TTS according to the invention, the active substance to be administered transdermally is at least partially embedded in a matrix (active substance-containing layer). The matrix is preferably based on lipophilic or hydrophilic, preferably crosslinkable polymers. Hydrophilic matrix-forming layers can be hydrous, in which case they are preferably gels. Preferably, the matrix is based on at least one polymer selected from the group comprising cellulose derivatives, such as cellulose ethers, more preferably methylcellulose, ethylcellulose, propylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and / or carboxymethylcellulose; Polyethylene; chlorinated polyethylenes, such as polyvinyl chlorides or polyvinylidene chlorides; Polypropylene; polyurethanes; polycarbonates; polyacrylate; Polyacrylates; polymethacrylates; polyvinyl alcohols; polyvinylpyrrolidones; Polyethylene terephthalates; polytetrafluoroethylene; Ethylene-propylene copolymers; Ethylene-ethyl acrylate copolymers; Ethylene-vinyl acetate copolymers; Ethylene-vinyl alcohol copolymers; Ethylene-vinyloxyethanol copolymers; Vinyl chloride-vinyl acetate copolymers; Vinylpyrrolidone-ethylene-vinyl acetate copolymers; rubbers; synthetic homo-, co- or block polymers of butadiene and / or styrene, such as styrene-isoprene-styrene block copolymers; silicones; Silkon derivatives, particularly preferably siloxane-methacrylate copolymers, polyvinyl ethers, polyesters, and / or polysaccharides, or mixtures thereof. Particularly preferred are polyacrylates or acrylate copolymers, especially those as described above in connection with the polymers of the pressure-sensitive adhesive of the invention.

In a further preferred embodiment, the TTS according to the invention is a so-called "monolithic drug-in-adhesive TTS". In this case, the drug to be administered transdermally is contained in the adhesive layer (drfte in adhesive). Such a TTS preferably comprises a carrier layer, an adhesive layer containing the active substance, and optionally a removable protective film. The active substance-containing layer may additionally contain matrix-forming polymers, so that the active substance is embedded in a matrix (drug in matrix), which in turn is part of the adhesive layer of the TTS (drug in adhesive). To prepare such an adhesive layer, the components of the pressure-sensitive adhesive according to the invention can be mixed as stickable component with the matrix materials listed above in known amounts and a physiologically active substance can be added to produce the active substance-containing matrix region. After application, the matrix material can also be crosslinked if necessary. The active substance present in the matrix or the active substances present in the matrix can be liquid, semisolid or solid in the dispersed state or can be incorporated as an appropriate formulation with the addition of customary auxiliaries as active substance formulation.

If the TTS according to the invention does not have a full-surface adhesive layer, it may also be designed so that the pressure-sensitive adhesive is present only in the edge zones of the active substance-containing layer, these edge zones preferably containing no active ingredient. In a further preferred embodiment, the TTS is a multilayer system in which the active substance to be transdermally administered is at least partly contained in the adhesive layer. In this embodiment, at least one selectively permeable membrane is present between two adhesive layers, with both adhesive layers containing active ingredient (see TA Petersen et al., International Control, ReI, Bioact., Mater., 21: 477-478). , Suitable selectively permeable membranes are commercially available (see, for example, RE Kesting, Synthetic Polymer Membranes, McGraw Hill, JD Ferry, Ultrafiltration Membranes, Chemical Review, 18, 373).

In another preferred embodiment, the TTS according to the invention is a reservoir TTS. The reservoir TTS according to the invention preferably comprises a carrier layer and a reservoir which contains the active substance to be administered transdermally in dissolved or suspended form, wherein the reservoir is surrounded by a selectively permeable membrane at least on the side facing the application of the skin has. The carrier layer preferably has a certain mechanical resistance and possibly side walls. The capacity of the reservoir is dependent on the spatial extent of the cavity thus formed. The adhesive layer may extend over the entire surface of the reservoir TTS facing the application of the skin. But it is also possible that only parts of this surface are covered with the adhesive layer, such as only the skin-facing surface of the carrier layer, which is not covered with the reservoir or the selectively permeable membrane.

If it is a reservoir TTS, the transdermally administered drug is present in a reservoir. The reservoir is preferably enclosed by a selectively permeable membrane or bounded at least on one side thereof. Suitable membrane materials are the abovementioned polymers, which can also be used as matrix material. Preferably, the membrane is based on at least one polymer selected from the group consisting of polyethylenes, polypropylenes, polyvinyl acetates, polyamides, ethylene-vinyl acetate copolymers, polyethylene terephthalates and silicones. With help the reservoir membrane can be achieved from the reservoir controlled release of the drug.

The reservoir may preferably be arranged between a cover layer and the adhesive layer. If necessary, the reservoir can also be designed as a fleece, fabric or the like, which is impregnated with the active ingredient formulation.

The reservoir contains at least one active substance to be administered transdermally, preferably as a solution which can freely diffuse through the membrane surrounding the reservoir. The solution may have an increased viscosity, for example it may be a hydrogel or a lipogel. A hydrogel contains primarily hydrophilic substances, but not necessarily water. Suitable solvents are suitable solvents in which the active ingredient dissolves sufficiently, thereby precipitation of the active ingredients is avoided.

As customary adjuvants of TTS, compounds which enhance or facilitate the transdermal transport of the active ingredients (skin permeation-promoting substances) can be used. The skin permeation-promoting substances known to the person skilled in the art for the particular active substance to be administered transdermally can be used. In this connection, reference may be made, for example, to D.S. Hsieh, Drug Permeation Enhancement: Theory and Applications (Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs), Marcel Dekker, 1994 and E.W. Smith et al., Percutaneous Penetration Enhancers, CRC Press, 1995.

Examples of skin permeation promoting substances are selected from the group consisting of surfactants {eg nonionic surfactants, amphoteric surfactants, anionic surfactants, cationic surfactants, etc, including fatty acid esters, fatty alcohols, polyoxyethylene hardened castor oil (HCO), such as HCO-10, HCO-40, HCO-50, HCO-60; Polysolvate (Tween ^®), such as Tween ^® -60, Tween ^® -65, Tween ^® - 80; Sorbitan esters such as sorbitan trioleate, sorbitan monopalmitate, sorbitan monolaurate, sorbitan sesquioleate, polyoxyethylene / polyoxypropylene sorbitan mono-fatty acid esters, sorbitan-polyoxyethylene (160) -polyoxypropylene (30) glycol monostearate; Glycerinester such as glycerol monostearate, triacetin; benzalkonium chloride; Benzetonium chloride}; Amines {eg monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine}; inorganic bases {eg NaOH, KOH, Ca (OH) ₂ , NaHCO ₃ ); polyvinylpyrrolidone; long-chain alcohols {such as dodecanol, undecanol, octanol}; Propylene glycol; benzyl alcohol; Menthol; isosorbide; Dodecylazacycloheptan-2-one; Lactic acid; ethanol; Esters of carboxylic acids with polyethoxylated alcohols, diesters of aliphatic dicarboxylic acids such as adipic acid, and medium chain triglycerides of caprylic and / or capric acid, coconut oil, polyhydric alcohols such as 1, 2-propanediol, esters of polyhydric alcohols such as glycerol with levulinic acid or caprylic acid, and etherified polyhydric alcohols.

Further, the drug-containing layer (adhesive layer, matrix or reservoir) may contain at least one solvent, e.g. Water and / or optionally short chain alcohols, e.g. Ethanol, n-propanol, isopropanol, propylene glycol, glycerol or 1, 3-butanediol; Esters, e.g. Isopropyl myristate, ethyl oleate, lauryl lactate, glycerol monooleate, propylene glycol monocaprylate, sorbitan monooleate or sorbitan trioleate; Transcutol; solketal; Oleic acid; 1-methyl-pyrrolidone; triacetin; or surfactant compounds or mixtures thereof.

In addition, the active substance-containing layer-if appropriate in addition to matrix-forming polymers and / or skin permeation-improving substances-may comprise customary auxiliaries, such as, for example, Solvents, solubilizers, emulsifiers, crosslinkers, stabilizers, preservatives, plasticizers, dyes, skin-smoothing agents, fragrances and / or thickeners. For producing pH-controlled conditions on the skin, adjuvants, e.g. weak acids, weak bases or (on) organic salts which form a buffer system on the skin may be added. Further, the addition of crystallization inhibitors or fumed silica in a penetration-promoting amount is possible.

All materials that are used to build the transdermal systems, but especially those materials that come into contact with the skin, should be skin-friendly and physiologically safe.

Stabilizers, emulsifiers and thickeners used are the auxiliaries known to the person skilled in the art. As stabilizers antioxidants such as vitamin E, butylhydroxytoluene, butylated hydroxyanisole, parabens, ascorbic acid, ascorbyl palmitate, and / or chelating agents such as disodium ethylenediaminetetraacetic acid, potassium or sodium citrate may be used. Also suitable as preservatives are PHB esters, such as PHB methyl esters and PHB propyl esters, benzalkonium chloride, chlorhexidine, sorbic acid, benzoic acid, propionic acid, salicylic acid and its salts, formaldehyde and paraformaldehyde, hexachlorophene, o-phenylphenol, zinc pyrithione, inorganic sulfites, sodium iodate, Chlorobutole, dehydroacetic acid, formic acid, dibromohexamide, merthiolate, phenylmercuric salts (phenyl-Hg compounds), undecylenic acid, hexetidines, Bronidox, bronopol, 2,4-dichlorobenzyl alcohol, triclocarban, parachlorometacresol, triclosan, parachlorometaxylenol, imidazolydinyl-urea derivatives , Polyhexamethylene biguanidochlorohydrate, phenoxyethanol, methenamine, dowicil 200, 1-imidazolyl- (4-chlorophenoxy) -3,3'-dimethylbutan-2-one, dimethylhydantoin, benzyl alcohol, 1-hydroxy-4-methyl-6- (2, 4,4-trimethyl-pentyl) -2-pyridone, 1,2-dibromo-2,4-dicyanobutane, 3,3'-dibromo-5,5'-dichloro-2,2-dihydroxydiphenylmethane, isopropylmetacresol, Kathon, bisulfite Etc.

Preferred thickeners are gelatin, Vaseline, Olesäureoleylester (eg Cetiol ^® ), Komplexemulgatorgele (eg Lanettewachs ASS, Lanette ^® N), semi-synthetic fats (eg Softisan), fumed silica (eg Aerosil ^® ) and / or Bentonit (eg Veegum ^® , Volclay ^® , Ben-A-Gel). As a gelling agent and also thickeners can methylcellulose (eg Methocel ^®, Tylose ^® MW, Tylose ^® MB), hydroxypropyl cellulose (eg Klucel ^®), hydroxyethyl cellulose (eg Ethoxose ^®), hydroxypropyl methylcellulose (eg Methocel ^® E, Methocel ^® K), polyacrylic acid ( for example Carbopol ^®), carboxyvinyl polymer, carbomer copolymer, sodium Polyoxilat, carboxymethylcellulose or a mixture may be used of at least two of said compounds.

As solubilizers or emulsifiers N-methyl-2-pyrrolidone, lauryl pyrrolidone, triethanolamine, triacetin, diethylene glycol monoethyl ether, derivatives of fatty acids or fatty alcohols, low molecular weight, polyhydric alcohols such as propylene glycol or glycerol and / or surfactant compounds can be used. As plasticizers, for example, phthalates such as dibutyl phthalates, mineral oils, esters of citric acid or esters of glycerol can be used.

In a preferred embodiment, the TTS according to the invention contains at least one perfume. The system as fragrance preferably contains at least one natural or nature-identical compound selected from the group consisting of anethole, benzaldehyde, benzyl acetate, benzyl alcohol, benzyl formate, isoboronoacetate, camphene, neral, citronellal, citronellol, citronellyl acetate, para-cymene, decanal, Dihydrolinalool, dihydromyrcenol, dimethylphenylcarbinol, eucalyptol, geraniol, geranylacetate, geranylnitrile, cis-3-hexenylacetate, hydroxy-citronellal, limonene, linalool, linalooloxide, linalylacetate, linalylpropionate, methyl-anthranilate, alpha-methylionone, methylnonylacetaldehyde, methylphenylcarbinylacetate, menthone, iso- Menthone, myrcene, myrcenyl acetate, myrcenol, nerol, neryl acetate, nonyl acetate, phenylethyl alcohol, alpha-pinene, beta-pinene, gamma-terpinene, alpha-terpinol, beta-terpinol, terpinyl acetate, para-tert-butylcyclohexyl acetate, alpha-amylcinnamaldehyde, amylsalicylate, Caryophyllene, cedrene, cinnamyl alcohol, dimethylbenzylcarbinylacetate, ethylvanillin, eugenol, iso-Eugen ol, tricyclodecenyl acetate, piperonal, 3-cis-hexenyl salicylate, hexyl salicylate, lilial, gamma-methylionone, nerolidol, patchouli alcohol, phenylhexanol, beta-selenines, trichloromethylphenylcarbinylacetate, triethylcitrate, vanillin, dimethoxybenzaldehyde, benzophenone, ethylenebasylate, galaxolide, hexylcinnamaldehyde, lyral, methylcedrylon, Methyl beta-naphthyl ketone, musk ketone, phenylethyl phenylacetate, ambrettolide, cyclohexyl salicylate, delta nonalactone, delta undecalactone, dodecalactone, ethyl undecylenate, exaltolide, gamma-undecalactone, hexadecanolide, myristicin and musk xylene. Other perfumes that may comprise the TTS of the invention are disclosed in David J. Rowe, Chemistry and Technology of Flavors and Fragrances, Taylor & Francis Group, 2004; Michael Edwards, Fragrances of the World 2005, Crescent House Pub, 2004 and David Pybus, The Chemistry of Fragrances, Royal Society of Chemistry, 1999.

Preferably, the fragrances are volatile. They are preferably used as oils. As a fragrance, at least one naturally occurring mixture of fragrances can also be used. In particular, at least one perfume mixture is selected from the group comprising rosemary oil, Sandalwood oil, violet oil, lemongrass oil, lavender blossom oil, eucalyptus oil, peppermint oil, chamomile oil, clove leaf oil, cinnamon oil, thyme oil, tea tree oil, cajeput oil, niaouli oil, manuka oil, citrus oil, mountain pine oil, jasmine oil, geranium oil, caraway oil, pine oil, bergamot oil, turpentine oil, linalol oil, blood orange oil, Cypress oil, fir-tree oil, fennel oil, grapefruit oil, ginger oil, pine oil, lavandin oil, lemongrass oil, lime oil, tangerine oil, lemon balm oil, myrrh oil, patchouli oil, rosewood oil and thuja oil.

In a preferred embodiment, the fragrance is initially present in microcapsules and / or cyclodextrins partially occluded. Advantageously, these microcapsules or cyclodextrins release the perfume immediately upon use of the TTS when opening the package and / or by the application of the TTS to the skin, preferably by the slight contact pressure of the patient.

In a preferred embodiment, the TTS of the invention contains a compound transferable to the skin surface to reduce or prevent skin irritation. The compound transferable to the skin surface to reduce or prevent skin irritation is preferably a skin-friendly compound selected from the group comprising paraffins, camphor, silanols, silicones, silicone derivatives, mono-, di- or polyalcohols, natural or artificial lipids, ceramides, natural or artificial waxes, natural or artificial fats, saturated or unsaturated fatty acids and / or fatty alcohols, natural or artificial oils (eg evening primrose oil, borage oil, currant seed oil, fish oils, cod liver oil), natural or artificial polymers, starches, proteins, vitamins, compounds with anti-inflammatory or anti-inflammatory properties, compounds for preventing the growth of inflammatory microorganisms, compounds having anesthetic properties, compounds effective as radical scavengers, enzymes, plant extracts, preservatives and their mixtures of little at least two compounds of one class or at least two different classes of compounds. Particularly preferred is at least one skin-compatible compound selected from the group comprising polymers, preferably fluorinated polyethers, more preferably polyperfluoromethyl isopropyl ether, or silicone derivatives, compounds with anti-inflammatory or anti-inflammatory properties, preferably cortidoids or antihistamines, compounds for preventing the growth of inflammatory microorganisms, preferably antiseptics or anti-infective agents, and compounds effective as radical scavengers, preferably N-acylethanolamine.

As silicone derivatives are preferably optionally substituted polysiloxanes, which are optionally mixed with acrylate polymers.

As compounds with anti-inflammatory or anti-inflammatory properties are preferably allantoin, dexpanthenol, bisabolol, chamazulen, aescin, bas. Aluminum acetate tartrate, zinc oxide, tannins, melatonin, Peru balsam, bismuth gallate, their derivatives and / or salts. Suitable corticoids are preferably hydrocortisone, betamethasone, fluocinolone acetonide, fluocinonide, prednisolone, methylprednisolone, triamcinolone, flumetasone, clobetasol, flupredniden, alclometasone, prednicarbate, mometasone, fluticasone, halcinonide, clocortolone, diflucortolone, deoxymethasone and / or derivatives thereof. Diphenhydramine, dimetinden, isoprenaline, clemastine, bamipine, their derivatives and / or salts are preferably suitable as antihistamines.

As compounds for preventing the growth of inflammatory microorganisms, benzalkonium chloride such as benzalkonium chloride, e.g. Benzethonium chloride, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorhexidine, dequalinium chloride, clioquinol, sorbic acid, their derivatives and / or salts.

Povidone-iodine, iodoform, thymol, tyrothricin, chlorocresol, salicylic acid, ethacridine or polidocanol, their derivatives and / or salts are preferably suitable as antiseptics.

Suitable anti-infective agents are preferably framycetin, neomycin, gentamicin, nystatin, erythromycin, tetracycline, chlortetracycline, oxytetracycline, fusidic acid, Metronidazole, bacitracin-zinc, miconazole, amphotericin B, their derivatives and / or salts.

Benzocaine, lidocaine, tetracaine, prilocaine, mepivacaine, their derivatives and / or salts are preferably suitable as compounds with anesthetizing properties.

Vitamins are preferably liposoluble vitamins, vitamin A derivatives, preferably retinol acetate or palmitate, vitamin B derivatives, vitamin C derivatives, e.g. the corresponding palmitate, vitamin D derivatives, preferably colecalciferone or vitamin E derivatives, preferably α-tocopherol acetate.

Suitable enzymes are preferably superoxide dismutase or catalase.

As plant extracts are preferably extracts of plants such. Aloe vera, arnica, basil, blackthorn (Lat .: Prunus spinosa), large burdock (Lat .: Arctium lappa), marigold (Lat .: Calendula officinalis), camellia (Lat .: Camellia oleifera), clary sage (Lat .: Salvia clarea), chamomile (Lat .: Matricaria chamomilla), comfrey (Lat .: Symphytum officinale), coneflower (Lat .: Echinacea angustifolia), cucumber (Lat .: Cucumis sativus), eyebright (Lat .: Euphrasia officinalis), ginseng, green tea, lavender, chamomile (lat .: Chamomilla recutita and Matricaria chamomilla), peppermint (lat .: Mentha piperita), mugwort, nutmeg, oats (Lat .: Avena sativa), sandalwood, florsafran (lat .: Carthamus tinctorius), Soya, Tea Tree (Lat .: Melaleuca alternifolia), Vetiver Grass (Lat .: Vetiveria zizanioides), Violet, Licorice (Lat .: Glycyrrhiza glabra) and / or Witch Hazel (Lat .: Hamamelis).

Of the compounds mentioned, those compounds which also have a skin-smoothing property are preferably suitable. At least one skin-smoothing compound from the group comprising glycerol, chitosan, hydroxypropylmethylcellulose, cetearyl octanoate, vitamin E, coconut fat, peanut oil, soybean oil and Butyrospermum Parkii (shea butter) is also suitable as a skin irritation. The skin-compatible compound which is at least reducing skin irritations and can be transmitted to the skin surface is preferably present as a component in the adhesive layer and / or on the adhesive layer of the TTS according to the invention.

When present in the adhesive layer, this compound may be dissolved and / or dispersed therein. If the adhesive layer is at the same time also an active substance-containing layer, this compound can be dissolved and / or dispersed together with the active ingredient in the adhesive according to the invention. According to the arrangement of the adhesive layer in the TTS of the present invention, the arrangement of the skin irritation reducing compound is also preferable.

When the skin irritant-reducing skin irritant-reducing compound is adjacent to the adhesive layer, it lies between the adhesive layer and the protective film, leaving the bond on the adhesive layer when the protective film is peeled off. The arrangement of the skin-compatible compound on the adhesive layer preferably takes place in accordance with the arrangement of the adhesive layer in the plaster of the invention.

If the skin irritation at least reducing, skin-friendly compound is present on the adhesive layer adjacent to the skin surface, it may evenly distributed according to the arrangement of the adhesive layer, preferably distributed over the entire area in the form of a film or a layer, or selectively, for example in multiparticulate form be applied over the surface of the adhesive layer.

If the skin irritation at least reducing skin-compatible compound in multiparticulate form, which can be transmitted to the skin surface, is preferably present in micro- or nano-capsules, micro- or nano-particles or liposomes. The compound that at least reduces the reduction of skin irritations which can be transmitted to the skin surface is preferably a component of the adhesive layer, it being possible for this compound to be present only in a subsector of the adhesive layer. This subsector can also be designed as a reservoir for the skin-friendly compound. Alternatively, the skin irritation-reducing compound which is transferable to the skin surface may preferably also be in the form of a layer preferably having a thickness <5 μm, more preferably 0.5-2 μm, between the removable protective film and adhesive layer.

It is self-evident to a person skilled in the art that the skin irritation-reducing, skin irritation-reducing compound, whether this compound is in or on the adhesive layer, is present only in such an amount that the adhesive effect of the adhesive layer is not impaired, if at all.

The TTS according to the invention may contain other customary auxiliaries and additives. These adjuvants can be mixed with the active ingredients or present in a separate layer to the active ingredient-containing layer.

The layer thickness of the adhesive layer of the TTS is preferably 3 to 100 μm, preferably 5 to 90 μm and in particular 10 to 80 μm.

The TTS according to the invention is characterized by a good wearing comfort. Skin irritation during wear is avoided and the mechanical properties ensure sufficient resistance to external influences. Comfort and resistance to external mechanical influences are coordinated.

The TTS according to the invention, preferably the pressure-sensitive adhesive according to the invention, ie the adhesive layer of the TTS, can contain one or more transdermally administrable, physiologically active substances, for example pharmaceutical active substances (medicaments), but also food or dietary supplements. The physiologically active substance may be systemic or topically effective. The TTS according to the invention preferably contains at least one transdermally administrable substance which is systemically active. In the TTS according to the invention, the physiologically active substance may be present in various physical states, such as molecularly distributed, as crystals, in the form of clusters or encapsulated in liposomes.

Examples of transdermally administrable food or dietary supplements are proteins, saccharides, lipids, vitamins, provitamins, trace elements, saturated or unsaturated fatty acids and antioxidants.

The TTS according to the invention preferably contains one or more active substances, but preferably only a single transdermally administered active ingredient. The active ingredient is preferably at least partially embedded in a matrix, wherein the matrix is preferably at least partially formed by the pressure-sensitive adhesive according to the invention.

Basically all transdermally administered active ingredients are suitable as active ingredients. Preferably, the active ingredient is selected from the group consisting of antiallergic agents; antiarthritic; antiasthmatics; Antibiotics and other antimicrobials such as tetracyclines, oxytetracyclinics, chlortetracycline, sulfonamides; antidepressants; Antidiabetics, such as insulin; antiepileptic drugs; antihistamines; antihypertensives; Anti-convulsants, such as atropine, butylscopolamine bromide; Anti-migraine agents; antipyretics; anti-inflammatory drugs; antiviral agents; anxiolytics; cardiaca; cardiovascular compounds, such as nitroglycerin, cardiac glycosides; coronary dilators; corticosteroids; anti-inflammatory agents; enzymes; fungicides; Immunomodulators; vaccines; contraceptives; local anesthetics; Means for the treatment of alcohol and / or drug and / or drug dependence; Agents for the treatment of diseases of the central nervous system; Agents for the treatment of neurodegenerative diseases, in particular for the treatment of Parkinson's disease and / or Alzheimer's disease; Narcotics and analgesics, such as benzocaine, lidocaine, prilocaine; non-steroidal anti-inflammatory drugs or anti-inflammatory compounds, such as indomethacin, diclofenac; nicotine; Opioids (including opiates); Psychotropic drugs such as 3- (2-aminopropyl) indole acetate and 3- (2-aminobutyl) indole acetate; Sedatives such as sodium pentobarbiturate, phenobarbiturate, secobarbiturate sodium, codeine, carbromat; (Sexual) hormones, such as adrenocortico- Steroids, such as 6-α-methylprednisolone, androgenic steroids, such as methyltesto steroids, fluoxymesterone, estrogenic steroids, such as estrogen, 17-.beta.-estradiol, ethinylestradiol, progesterone, norethindrone, thyroxine; stimulants; Tranquillizers, such as reserpine, chlorpromazine hydrochloride; and vitamins.

In a preferred embodiment, the active ingredient is selected from the group consisting of narcotics, opioids (including opiates), tranquilizers, preferably benzodiazepines, stimulants and other anesthetics.

In a preferred embodiment, the active ingredient is an analgesic. According to the invention, the analgesic is preferably understood as meaning those pharmaceutical active ingredients which are assigned by the WHO to the ATC index N02 (preferably in the official German version of January 1, 2005). Preferred analgesics are opioids "(ATC code N02A)," other analgesics and antipyretics "(ATC code N02B) and" migraine agents "(ATC code N02C). Within the more preferred opioids, the" natural opium alkaloids "are particularly preferred (US Pat. ATC code N02AA), "phenylpiperidine derivatives" (ATC code N02AB), "diphenylpropylamine derivatives" (ATC code N02AC), "benzomorphan derivatives" (ATC code N02AD), "oripavine derivatives" (ATC code N02A) Code N02AE), "morphine derivatives" (ATC code N02AF), "opioids in combination with spasmolytics" (ATC code N02AG) and "other opioids" (ATC code N02AX).

In a particularly preferred embodiment, the active ingredient is an opioid. Particularly preferred opioids are μ-, K- or δ-opioid receptor agonists, very particularly preferably μ-opioid receptor agonists.

In a preferred embodiment, the active ingredient is a transdermally administrable opioid, tranquilizer or other anesthetic selected from the group consisting of alfentanil, allobarbital, allylprodin, alphaprodine, alprazolam, amfepramone, amfetamine, amfetaminil, amobarbital, anileridine, apocodin, barbital, Benzylmorphine, Bezitramide, Bromazepam, Brotizolam, Buprenorphine, Butobarbital, Butorphanol, Camazepam, Cathin (D-Norpseudoephedrine), Chlordiazepoxide, Clobazam, Clonazepam, Clonitazen, Clorazepat, Clotiazepam, Cloxazolam, Cocaine, Codeine, Cyclobarbital, Cyclorphan, Cyprenorphine, delorazepam, desomorphine, dextromoramide, dextropropoxyphene, dextromethorphan, decocin, diampromide, diamorphone, diazepam, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, dronabinol, eptazocine, estazolam, ethoheptazine, ethylmethylthiambutene, ethyllellazepate, Ethylmorphine, etonitazene, etorphine, fencamfamine, fenetylline, fenproporex, fentanyl, fludiazepam, flunitrazepam, flurazepam, halazepam, haloxazolam, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, hydroxymethylmorphinan, ketazolam, ketobemidone, levacetylmethadol (LAAM)), levomethadone, Levorphanol, levophenacylmorphan, levoxemacin, lofentanil, loprazolam, lorazepam, lormetazepam, mazindol, medazepam, mefenorex, meperidine, meprobamate, meptazinol, metazocine, methylmorphine, metamfetamine, methadone, methaqualone, methylphenidate, methylphenobarbital, methyprylon, metopon, midazolam, modafinil, Morphine, myrophin, nabilone, nalbuphene, nalorphine, N arcein, nicomorphine, nimetazepam, nitrazepam, nordazepam, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxazepam, oxazolam, oxycodone, oxymorphone, papaver somniferum, papaveretum, pernoline, pentazocine, pentobarbital, pethidine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodin , Pholcodein, phenmetrazine, phenobarbital, phentermine, pinazepam, pipradrol, piritramide, prazepam, premethadione, profadol, proheptazine, promedol, propranidine, propoxyphene, remifentanil, secbutabarbital, secobarbital, sufentanil, temazepam, tetrazepam, tilidine (eis and trans), tramadol, Triazolam, vinylbital, (1R ^* , 2R *) - 3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (1R, 2R, 4S) -2- [dimethylamino) methyl-4 (p-fluorobenzyloxy) -1- (m-methoxyphenyl) cyclohexanol, (1R, 2R) -3- (2-dimethylaminomethylcyclohexyl) phenol, (1S, 2S) -3 (3-dimethylamino-1-ethyl) 2-methyl-propyl) -phenol, (2R, 3R) -1-dimethylamino-3 (3-methoxyphenyl) -2-methylpentan-3-ol, (1RS, 3RS, 6RS) -6-dimethylaminomethyl -1- (3 methoxy-phenyl) -cyclohexane-1,3-diol, 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) -phenyl 2- (4-isobutyl-phenyl) -propionate, 3- (2-dimethylaminomethyl-1-hydroxy -cyclohexyl) phenyl 2- (6-methoxynaphthalene-2-yl) propionate, 3- (2-dimethylaminomethylcyclohex-1-enyl) -phenyl 2- (4-isobutyl-phenyl) -propionate, 3 (2-dimethylaminomethylcyclohex-1-enyl) -phenyl 2- (6-methoxynaphthalene-2-yl) -propionate, (RR-SS) -2-acetoxy-4-trifluoromethylbenzoic acid 3- ( 2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl ester, (RR-SS) -2-hydroxy-4-trifluoromethylbenzoic acid 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl ester, (RR-SS ) -4-chloro-2- Hydroxy-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2-hydroxy-4-methylbenzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2-hydroxy-4-methoxybenzoic acid 3- (2-dimethylaminomethyl-1-hydroxycyclohexyl) phenyl ester, (RR-SS) -2-hydroxy-5-nitro benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2 ', 4'-difluoro-3-hydroxy-biphenyl-4-carboxylic acid 3- (2-dimethylaminomethyl-1 - Hydroxy-cyclohexyl) phenyl esters and their corresponding stereoisomeric compounds, in each case their corresponding derivatives, in particular amides, esters or ethers, and in each case their physiologically acceptable compounds, in particular their salts and solvates, particularly preferably their hydrochlorides.

The compounds (1R *, 2R *) - 3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol, (1R, 2R, 4S) -2- [dimethylamino] methyl-4- ( p-fluorobenzyloxy) -1- (m-methoxyphenyl) - cyclohexanol or their stereoisomeric compounds or their physiologically compatible compounds, in particular their hydrochlorides, their derivatives, such as esters, ethers or amides and processes for their preparation are, for example, from EP-A-693 475 and EP-A-780 369 known. The corresponding descriptions are hereby incorporated by reference and are considered part of the disclosure.

The active compounds, optionally in the form of their ether, ester or acid derivatives, can each be in the form of a pure stereoisomer, in particular enantiomer or diastereomer, racemate or in the form of a mixture of stereoisomers, in particular the enantiomers and / or diastereomers, in any desired mixing ratio, or each in the form of appropriate physiologically acceptable salts, or in each case in the form of corresponding solvates.

Examples of suitable physiologically tolerated salts are those which are prepared by reacting the free bases of the respective active substance with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, propionic acid, Oxalic, succinic, tartaric, mandelic, fumaric, maleic, lactic, malic, sebacic, citric, ascorbic, nicotinic, glutamic or aspartic acid salts. Other physiologically acceptable salts which may be mentioned by way of example are the salts obtained by reacting the free acids of the particular active substance with a suitable base. For example, the alkali metal salts, alkaline earth metal salts or ammonium salts [NH _{X R4-X]} are ⁺ mentioned, where x = 0, 1, 2, 3 or 4 and R represents a linear or branched C ₄ alkyl radical.

Particularly preferred is the opioid buprenorphine (ATC code N02AE01) as the free base or in the form of one of its pharmaceutically acceptable salts, preferably buprenorphine hydrochloride, buprenorphine saccharinate, buprenorphine formate, buprenorphine mesylate, buprenorphine hydrogen citrate, buprenorphine nicotinate or buprenorphine sebacinate.

It has surprisingly been found that the multicyclic hydrocarbon contained in the pressure-sensitive adhesive according to the invention is compatible with the above-mentioned, physiologically active substances without negatively influencing their stability and release behavior to a significant extent.

The TTS according to the invention preferably has a total area (contact area for H Haauutt when used as directed) of 0.5 to 200 cm ² , more preferably 20 to 150 cm ² .

In the case of the TTS according to the invention, the adhesive layer preferably directly adjoins a carrier layer.

The backing preferably comprises a flexible, stretchable, breathable, durable material and may be colored, for example, skin colored. The carrier layer preferably has such a thickness that the TTS has sufficient mechanical stability. The carrier layer is preferably impermeable to active substance, ie it is impermeable to the active ingredient, at least in the region in which the carrier layer adjoins an active substance-containing matrix or a drug reservoir. If the carrier layer as such is not impermeable to active substance, should be added between the active substance-containing layer, ie the matrix or the active ingredient reservoir, and the carrier layer can be arranged an active substance impermeable barrier layer. This barrier layer is then preferably the same or different based on one or more materials, as follows for the carrier layer:

As examples of suitable materials of the carrier layer may be mentioned in particular polyester or copolyester, preferably polyethylene terephthalate; Polyolefins or olefin copolymers, preferably polyethylenes, polypropylenes or polybutylenes; polycarbonates; Polyethylene oxides; polyurethanes; polystyrenes; Polyamides or copolyamides; polyimides; polyvinyl acetates; polyvinyl chlorides; polyvinylidene; Copolymers, preferably acrylonitrile-butadiene-styrene terpolymers or ethylene-vinyl acetate copolymers, paper, textiles and mixtures thereof. Particularly preferably, the backing layer is based on a polyester, in particular polyethylene terephthalate, for example Hostaphan ^® RN. The carrier layer can also be metallized and / or pigmented or as a layer sequence of the abovementioned materials and a metal foil, particularly preferably a foil made of aluminum.

In a preferred embodiment, the carrier layer is coated with an inorganic-organic hybrid polymer. Inorganic-organic hybrid polymers, so-called ormocers, are known in the prior art (cf., for example, EP-A 0 358 011, EP-A 0 373 451, EP-A 0 610 831, EP-B 0 644 908, EP-A 0 792846, EP-A 0 934 989).

In a preferred embodiment, the carrier layer of the TTS according to the invention has a layer thickness in the range of 5.0 to 125 .mu.m, more preferably 10 to 115 .mu.m, more preferably 25 to 100 .mu.m, most preferably 35 to 95 .mu.m and in particular 50 to 85 .mu.m.

Preferably, the carrier layer forms one of the two surface layers of the system according to the invention, ie, starting from the adhesive layer preferably immediately adjacent to the carrier layer, the TTS according to the invention preferably does not contain any further layer beyond the carrier layer. In a particularly preferred embodiment, the TTS according to the invention consists of a carrier layer, an adhesive layer and optionally a peelable protective layer.

The protective film preferably covers at least the drug-releasing region, preferably the entire adhesive layer. Before the application of TTS on the skin, the protective film is easily removable. The protective film is preferably silanized and / or fluoridated on at least the surface facing the adhesive layer and is removed prior to application of the system. This exposes the surface of the adhesive layer. The protective layer preferably directly adjoins the adhesive layer. The protective film may consist of polyethylene, polyester, polyethylene terephthalate, polypropylene, polysiloxane, polyvinyl chloride or polyurethane and optionally of treated paper fibers, such as cellophane, and may optionally have a silicone, fluorosilicone or fluorocarbon coating. Preferably, the protective layer is based on a polyester, for example, Hostaphan ^® RNT. Preferably, the protective layer has a thickness of 10 to 100 μm, more preferably 25 to 50 μm.

In a further preferred embodiment of the TTS according to the invention, it comprises a plurality of isolable subunits, which in turn can be used in the form of an independent unit as transdermal therapeutic systems, wherein the individual subunits are connected to each other via preferably drug-free border areas, in which separation possibilities are provided, to form a coherent unit are. Preferably, there are linear perforations for separating the separable subunits from the contiguous unit. Further preferred are cutting marks on the carrier layer and / or the protective film, which predetermine the possibility of separating the separable subunits from the unit. The separation options are each preferably arranged so that they allow a separation of each contiguous subunit completely from the unit according to the invention. The individual subunits may be the same or different. If the subunits are different, they may contain, for example, the transdermally administered substance contained therein in various dosages or with different release rates. The preparation of the TTS according to the invention can be carried out by known production methods and include conventional process steps, such as lamination, coextrusion, stamping, delamination, unwinding, cutting, rewinding, mounting or dosing (Verpackungs-Rundschau 4/2002, 83-84).

In another preferred embodiment, the self-adhesive device is an active ingredient-containing patch, whereby the active substance develops its effect substantially only topically. The preferred embodiments described above in connection with the TTS according to the invention apply analogously to the active ingredient-containing patch according to the invention, with the only difference that the active ingredient-containing patch is formulated in such a way that the active ingredient is administered only topically but not transdermally / systemically.

The following examples serve to illustrate the invention in more detail, but are not to be construed as limiting their scope:

Example 1 :

160 g of DURO-TAK 387-2287 with a solids content of 51% and 40 g of TCD alcohol DM {3 (4), 8 (9) -bis (hydroxymethyl) -tricyclo [5.2.1.0 ^{2 l6} ] decane} mixed in a 500 ml round bottom flask and stirred for 30 minutes at 40 ⁰ C, then stirred for 30 minutes at room temperature until a homogeneous mixture appeared (weight fraction TCD-alcohol DM 20 wt .-%). With the help of an Erichsen film applicator "Coatmaster 509 / MC-1" an adhesive layer of 120 μm thickness was applied to a hostaphan film RN 75 as carrier layer at a speed of 5 mm / s. The coated film was dried for 2.5 hours at room temperature and covered with a RNT 36 Hostaphan film as a protective film (S). Example 2:

According to Example 1, a plaster was prepared, but DURO-TAK 387-2287 was used in an amount of 190 g and the TCD-alcohol DM in an amount of 10 g (weight fraction TCD-alcohol DM 5.0 wt .-%) ,

Example 3:

According to Example 1 and 2, a plaster was prepared, but DURO-TAK 387-2287 was used in an amount of 198 g and the TCD-alcohol DM in an amount of 2 g (weight fraction TCD-alcohol DM 1, 0 wt. %).

Example 4:

The bond strength of the patches obtained according to Examples 1 to 3 was measured in two different ways. For comparison, a plaster was prepared analogously to Examples 1 to 3, which, however, did not contain TCD-alcohol DM.

a) Determining the bond strength with a Zwick testing machine on a stainless steel surface

Equipment used: Material testing machine TestControl, type BTC FR2.5TH.D09, Zwick / Roell

A 4 cm wide piece of plaster was applied longitudinally to about 75% on the upper stainless steel plate of a mobile carriage. The carriage was positioned underneath the transducer and fastened. The non-glued remaining piece was clamped in the pneumatic jaws of the measuring device so that the plaster showed vertically upwards. Thereafter, the patch was peeled off the carriage at room temperature at a rate of 50 mm / min. When removing the sled was automatically tracked so that the plaster always was withdrawn vertically. The forces were recorded depending on the way.

b) In addition, 5 test persons determined the perceived adhesion on the human skin.

The results of both adhesion measurements are summarized in the following table:

For the perceived bond strength, the value 4 means the strongest and the value 1 the weakest adhesion.

As the measurements show, the pressure-sensitive adhesives according to the invention are characterized in that they adhere better to the skin than a comparison adhesive which contains no multicyclic hydrocarbon, but otherwise has the same composition. In the 90 ° peel test with a stainless steel surface as a substrate, however, the increased bond strength under the selected conditions is not expressed.

Claims

claims:

1. A pressure-sensitive adhesive comprising at least one multicyclic, saturated or unsaturated hydrocarbon ring substituted with at least one functional group selected from the group consisting of - (CH _{2) P} OH, - (CH ₂₎ p0Ci _-6 alkyl, - (CH ₂ ) _p OCO-C _1-6 alkyl, - (CH ₂ ) _P SH, - (CH ₂ ) _P CN, - (CH ₂ ) _P N ₃₎ - (CH ₂ ) pNH _2> - (CH ₂ ) _{p is} NHC _1-6 alkyl, - (CH ₂ ) _p N (C _1-6 alkyl) ₂ ,

- (CH ₂ ) _P CHO, - (CH ₂ ) _p COC _1-6 alkyl, - (CH ₂ ) _P CO ₂ H, - (CH ₂ ) _p CO ₂ C _1-6 alkyl - (CH ₂ ) _{p is} CONHCi _-6- alkyl and - (CH ₂ ) _{p is} CON (C _1-6 -alkyl) ₂ , wherein each p may be the same or different 0, 1, 2, 3, 4, 5 or 6.

2. An adhesive according to claim 1, characterized in that

p = 0 or 1 and / or

- The hydrocarbon is tricyclic, and / or

- The hydrocarbon comprises 8 to 30 carbon atoms, and / or

- The hydrocarbon is not aromatic.

3. The adhesive of claim 1 or 2, characterized in that the structure of the hydrocarbon from a tricyclo that [ab1.0 ^{2 (a + 1)]} hydrocarbon or a tricyclo [ab2.0 ^{2 (a + 1)]} Hydrocarbon is derived, where a is 5, 6, 7 or 8 and b is 2, 3 or 4, respectively.

4. Adhesive according to one of the preceding claims, characterized in that the hydrocarbon is a compound of general formula (I)

where n is 1, 2 or 3; R ₁ and R _{2 are} identically or differently selected from the group consisting of -CH ₂ OH, -CH ₂ NH ₂ and -CHO; and

R ³ and R ⁴ are each H or together form a -ci- ₄ -alkylene bridge, wherein the -ci- ₄ -alkylene bridge optionally substituted with one or two identical or different -ci- ₆ alkyl radicals substituted can be.

5. Adhesive according to one of the preceding claims, characterized in that the structure of the hydrocarbon of tricyclo [5.2.1.0 ²ⁱ⁶ ] decane derived.

6. An adhesive according to claim 5, characterized in that the hydrocarbon is selected from the group consisting of

3 (4), 8 (9) -6 / s (hydroxymethyl) tricyclo [5.2.1.0 ²⁶ ] decane, 3 (4), 8 (9) -b / s (aminomethyl) tricyclo [5.2 .1.0 ^2l6 ] decane and 3 (4), 8 (9) -O / s-formyltricyclo [5.2.1.0 ² ' ⁶ ] decane.

7. Adhesive according to one of the preceding claims, characterized in that the weight fraction of the multicyclic hydrocarbon in the range of 0.1 to 50 wt .-%, based on the total weight of the adhesive.

8. Adhesive according to one of the preceding claims, characterized in that it contains at least one polymer selected from the group consisting of polyacrylates, acrylate copolymers, ethylene-vinyl acetate copolymers, polyvinyl ethers, polyvinyl alcohols, polyisobutylenes, polyurethanes, styrene-isoprene copolymers, Styrene-butadiene copolymers, silicones, rubbers, resins and optionally hydrogenated esters of rosin.

9. Adhesive according to one of the preceding claims, characterized in that it contains at least one excipient selected from the group consisting of skin permeation-promoting substances, solvents, solubilizers, emulsifiers, crosslinkers, stabilizers, preservatives, dyes, skin-smoothing agents, perfumes, for reducing or preventing Skin irritations to the skin surface transferable compounds, thickeners and plasticizers.

A self-adhesive skin fastening device comprising an adhesive layer containing a pressure-sensitive adhesive according to any one of claims 1 to 9.

11. The device according to claim 10, characterized in that it is a Transdermal Therapeutic System or a patch.

12. Transdermal therapeutic system according to claim 11, characterized in that it contains a transdermally administered, physiologically active substance.

13. Transdermal therapeutic system according to claim 12, characterized in that the physiologically active substance is an active substance selected from the group consisting of antiallergic agents; antiarthritic; antiasthmatics; antibiotics; antidepressants; antidiabetics; antiepileptic drugs; antihistamines; antihypertensives; Anti-convulsants; Anti-migraine agents; antipyretics; anti-inflammatory drugs; antiviral agents; anxiolytics; cardiaca; cardiovascular compounds; coronary dilators; corticosteroids; anti-inflammatory agents; enzymes; fungicides; Immunomodulators; vaccines; contraceptives; local anesthetics; Means for the treatment of alcohol and / or drug and / or drug dependence; Agents for the treatment of diseases of the central nervous system; Agents for the treatment of neurodegenerative diseases; Narcotics and analgesics; nicotine; psychotropic drugs; sedatives; (Sexual) hormones; stimulants; tranquilizers; and vitamins.

14. Transdermal therapeutic system according to claim 12 or 13, characterized in that the physiologically active substance is at least partially embedded in the adhesive layer.

15. Transdermal therapeutic system according to one of claims 12 to 14, characterized in that the physiologically active substance is embedded in a matrix or is present in a reservoir.

Use of a multicyclic, saturated or unsaturated hydrocarbon as defined in any one of claims 1 to 6 as a tackifier in a pressure-sensitive adhesive.