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WO2007059894A2 - Composes multicycliques dans des adhesifs sensibles a la pression - Google Patents

Composes multicycliques dans des adhesifs sensibles a la pression Download PDF

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Publication number
WO2007059894A2
WO2007059894A2 PCT/EP2006/011023 EP2006011023W WO2007059894A2 WO 2007059894 A2 WO2007059894 A2 WO 2007059894A2 EP 2006011023 W EP2006011023 W EP 2006011023W WO 2007059894 A2 WO2007059894 A2 WO 2007059894A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydrocarbon
skin
adhesive
pressure
Prior art date
Application number
PCT/EP2006/011023
Other languages
German (de)
English (en)
Other versions
WO2007059894A8 (fr
WO2007059894A3 (fr
Inventor
Heinrich Kugelmann
Original Assignee
Grünenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Grünenthal GmbH filed Critical Grünenthal GmbH
Publication of WO2007059894A2 publication Critical patent/WO2007059894A2/fr
Publication of WO2007059894A8 publication Critical patent/WO2007059894A8/fr
Publication of WO2007059894A3 publication Critical patent/WO2007059894A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J11/00—Features of adhesives not provided for in group C09J9/00, e.g. additives
    • C09J11/02—Non-macromolecular additives
    • C09J11/06—Non-macromolecular additives organic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/20—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing organic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/58—Adhesives
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J133/00—Adhesives based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Adhesives based on derivatives of such polymers
    • C09J133/02—Homopolymers or copolymers of acids; Metal or ammonium salts thereof

Definitions

  • 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).
  • 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.
  • TTS diaphragm-controlled systems
  • matrix TTS matrix-controlled systems
  • 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.
  • the active ingredient is embedded in a matrix, whereby it can be dispersed in liquid, semi-solid or solid state or in dissolved form.
  • the adhesive layer is at the same time also the active substance-containing layer.
  • the adhesive layer and the active substance-containing layer are separated from one another, as is the case with a reservoir TTS.
  • 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.
  • the release of the active ingredient can be regulated.
  • TTS Transdermal and Topical Drug Delivery Systems
  • RO Potts et al. Mechanisms of Transdermal Drug Delivery (Drugs and the Pharmaceutical Sciences), Marcel Dekker, 1997
  • R. Gurny et al. Dermal and Transdermal Drug Delivery. New Insights and Perspectives, Scientific VG., Stuttgart, 1998.
  • a drug 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.
  • a TTS 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).
  • pressure-sensitive adhesives medical pressure-sensitive adhesive
  • certain adjuvants or additives are added, in particular plasticizers or tackifiers.
  • these auxiliaries or additives should be compatible with the other materials used.
  • the said auxiliaries or additives should not adversely affect the chemical stability of the active substances contained in TTS or their release.
  • the polymer matrix of a pressure-sensitive adhesive contains predominantly lipophilic properties, so that it has a high loading capacity for lipophilic active ingredients.
  • 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.
  • 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.
  • a TTS should also have sufficient mechanical resistance so that it is not damaged or unintentionally removed as a result of external influences.
  • 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.
  • 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.
  • 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.
  • multicyclic means that the hydrocarbon according to the invention is at least bicyclic.
  • bicyclic preferably means that a correct name of the hydrocarbon according to IUPAC nomenclature (preferably as of 2005) contains the term "bicyclo”.
  • the hydrocarbon is tricyclic.
  • tricyclo preferably means that a correct name of the hydrocarbon according to IUPAC nomenclature (preferably as of 2005) contains the term "tricyclo".
  • 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
  • the structure of the multicyclic hydrocarbon derives from a
  • 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)
  • n 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.
  • the structure of the multicyclic hydrocarbon derives from a
  • a tricyclo [5.2.1.0 2i6 ] alkane in particular a tricyclo [5.2.1.0 26 ] decane, is particularly preferred.
  • the hydrocarbon is selected from the group consisting of
  • 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.
  • 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 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.
  • 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.
  • the lipophilic character of these compounds can be varied, so that they are sometimes suitable for increasing
  • the multicyclic hydrocarbon preferably functions as a tackifier
  • the pressure-sensitive adhesives of the invention may contain, in addition to the multicyclic hydrocarbons, other auxiliaries which also act as tackifiers.
  • 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.
  • 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.
  • the term "fatty acids" also includes unsaturated fatty acids.
  • 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.
  • 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.
  • 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.
  • 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.
  • the body temperature can play a role and on the other hand, the surface structure of the skin is not completely planar.
  • 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.
  • the adhesion properties of pressure sensitive adhesives on Artificial Skin Vitro Skin ®, Paraskin ®.
  • 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.
  • 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).
  • 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.
  • 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.
  • polyacrylates 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, rubber
  • 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.
  • (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.
  • 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.
  • (meth) acrylic acid esters can also be present in the monomer mixture used to prepare the polyacrylate which carry functional groups.
  • hydroxyl-containing esters such as 2-hydroxyethyl (meth) acrylate and 3-hydroxypropyl (meth) acrylate.
  • 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.
  • 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.
  • 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.
  • 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 Nachbar withe, 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.
  • the self-adhesive device prefferably, the self-adhesive device
  • 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
  • a pharmaceutically active substance e.g., a conventional patch with a dressing or a pressure site patch
  • 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.
  • an adhesive tape for attaching dressings
  • a self-adhesive cosmetic product such as for degreasing the skin
  • a self-adhesive label for aesthetic purposes, such as the fixation of garments or toupees on the skin
  • 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).
  • the drug to be administered transdermally is at least partially contained in the adhesive layer.
  • 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.
  • 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.
  • a barrier layer made of a suitable material between carrier layer and matrix.
  • the adhesive layer is preferably provided with a removable protective film.
  • 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.
  • 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
  • the TTS according to the invention is a so-called “monolithic drug-in-adhesive TTS".
  • the drug to be administered transdermally is contained in the adhesive layer (drfte in adhesive).
  • 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).
  • 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.
  • 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.
  • the TTS 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.
  • the TTS is a multilayer system in which the active substance to be transdermally administered is at least partly contained in the adhesive layer.
  • 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).
  • 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.
  • 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.
  • 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.
  • skin permeation-promoting substances compounds which enhance or facilitate the transdermal transport of the active ingredients
  • skin permeation-promoting substances known to the person skilled in the art for the particular active substance to be administered transdermally can be used.
  • 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; benzalkon
  • the drug-containing layer 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.
  • 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.
  • auxiliaries such as, for example, Solvents, solubilizers, emulsifiers, crosslinkers, stabilizers, preservatives, plasticizers, dyes, skin-smoothing agents, fragrances and / or thickeners.
  • adjuvants e.g. weak acids, weak bases or (on) organic salts which form a buffer system on the skin may be added.
  • crystallization inhibitors or fumed silica in a penetration-promoting amount is possible.
  • Stabilizers, emulsifiers and thickeners used are the auxiliaries known to the person skilled in the art.
  • 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.
  • 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 big
  • Preferred thickeners are gelatin, Vaseline, Olekladoleylester (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).
  • Vaseline eg Cetiol ®
  • Komplexemulgatorgele eg Lanettewachs ASS, Lanette ® N
  • semi-synthetic fats eg Softisan
  • fumed silica eg Aerosil ®
  • Bentonit eg Veegum ® , Volclay ® , Ben-A-Gel
  • 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.
  • 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.
  • plasticizers for example, phthalates such as dibutyl phthalates, mineral oils, esters of citric acid or esters of glycerol can be used.
  • 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, methylnon
  • TTS of the invention 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.
  • the fragrances are volatile. They are preferably used as oils.
  • a fragrance at least one naturally occurring mixture of fragrances can also be used.
  • 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.
  • the fragrance is initially present in microcapsules and / or cyclodextrins partially occluded.
  • 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.
  • 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.
  • 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.
  • 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
  • compounds effective as radical scavengers preferably N-acylethanolamine.
  • silicone derivatives are preferably optionally substituted polysiloxanes, which are optionally mixed with acrylate polymers.
  • compounds with anti-inflammatory or anti-inflammatory properties are preferably allantoin, dexpanthenol, bisabolol, chamazulen, aescin, bas.
  • 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.
  • 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 ⁇ -tocopherol acetate.
  • Suitable enzymes are preferably superoxide dismutase or catalase.
  • 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
  • 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.
  • this compound 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.
  • the skin irritant-reducing skin irritant-reducing compound 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.
  • 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.
  • 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.
  • 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 ⁇ m, more preferably 0.5-2 ⁇ m, between the removable protective film and adhesive layer.
  • 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 ⁇ m, preferably 5 to 90 ⁇ m and in particular 10 to 80 ⁇ m.
  • 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.
  • 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.
  • 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.
  • 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
  • the active ingredient is selected from the group consisting of narcotics, opioids (including opiates), tranquilizers, preferably benzodiazepines, stimulants and other anesthetics.
  • the active ingredient is an analgesic.
  • 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).
  • 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).
  • the active ingredient is an opioid.
  • opioids are ⁇ -, K- or ⁇ -opioid receptor agonists, very particularly preferably ⁇ -opioid receptor agonists.
  • 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, dextromor
  • the active compounds 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.
  • 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.
  • 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,
  • 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.
  • opioid buprenorphine 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.
  • 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 .
  • 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:
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • the protective layer is based on a polyester, for example, Hostaphan ® RNT.
  • the protective layer has a thickness of 10 to 100 ⁇ m, more preferably 25 to 50 ⁇ m.
  • the TTS 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.
  • 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).
  • the self-adhesive device is an active ingredient-containing patch, whereby the active substance develops its effect substantially only topically.
  • the active ingredient-containing patch is formulated in such a way that the active ingredient is administered only topically but not transdermally / systemically.
  • 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 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. %).
  • 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.
  • 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.
  • test persons determined the perceived adhesion on the human skin.
  • the value 4 means the strongest and the value 1 the weakest adhesion.
  • 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.
  • a comparison adhesive which contains no multicyclic hydrocarbon, but otherwise has the same composition.

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Abstract

L'invention concerne un adhésif sensible à la pression contenant au moins un hydrocarbure multicyclique saturé ou non saturé, qui est substitué par au moins un groupe fonctionnel sélectionné dans le groupe comprenant: -(CH2)POH, -(CH2)PO-alkyle C1-6, -(CH2)POCO-alkyle C1-6, -(CH2)PSH, -(CH2)PCN, -(CH2)PN3, -(CH2)PNH2, -(CH2)PNH-alkyle C1-6, -(CH2)PN(alkyle C1-6)2,-(CH2)PNHCO-alkyle C1-6, -(CH2)PCHO, -(CH2)PCO-alkyle C1-6, -(CH2)PCO2H,-(CH2)PCO2-alkyle C1-6, -(CH2)PCONH-alkyle C1-6 et -(CH2)PCON(alkyle C1-6)2, p, dans chaque cas identique ou différent, pouvant valoir 1, 2, 3, 4, 5 ou 6,. Ledit adhésif se prête particulièrement à la fixation d'articles sur la peau, tels que des emplâtres et des systèmes thérapeutiques transdermiques.
PCT/EP2006/011023 2005-11-24 2006-11-17 Composes multicycliques dans des adhesifs sensibles a la pression WO2007059894A2 (fr)

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DE200510056393 DE102005056393A1 (de) 2005-11-24 2005-11-24 Multicyclische Verbindungen in druckempfindlichen Klebstoffen

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DE102012210410B4 (de) * 2012-06-20 2016-11-24 Beiersdorf Ag Kosmetische und dermatologische Zubereitung enthaltend eine oder mehrere Substanz(en), die das Gen / Protein für den Rezeptor Endo180 modulieren
CN107530466A (zh) * 2015-01-30 2018-01-02 罗地亚聚酰胺特殊品公司 香料组合物及空气护理装置

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