EP1194134A1 - Transdermal therapeutic system for the utilization of tolterodine - Google Patents

Transdermal therapeutic system for the utilization of tolterodine

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Publication number
EP1194134A1
EP1194134A1 EP00951373A EP00951373A EP1194134A1 EP 1194134 A1 EP1194134 A1 EP 1194134A1 EP 00951373 A EP00951373 A EP 00951373A EP 00951373 A EP00951373 A EP 00951373A EP 1194134 A1 EP1194134 A1 EP 1194134A1
Authority
EP
European Patent Office
Prior art keywords
transdermal therapeutic
polyethylene
mixture
therapeutic system
tolterodine
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00951373A
Other languages
German (de)
French (fr)
Inventor
Thomas Hexal AG STRÜNGMANN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hexal AG
Original Assignee
Hexal AG
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Filing date
Publication date
Application filed by Hexal AG filed Critical Hexal AG
Publication of EP1194134A1 publication Critical patent/EP1194134A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches

Definitions

  • the invention relates to a drug-containing transdermal therapeutic system for the use of tolterodine, 5-hydroxymethyltolterodine and / or their pharmaceutically acceptable salts.
  • Tolterodine [(R) -N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine] is a new, very effective and competitive muscarinic receptor antagonist (parasympatholytic agent). It has great affinity and specificity for the muscarinic receptor. Tolterodine is used to treat bladder incontinence and other conditions caused by an unstable bladder. When tolterodine is administered orally, the active ingredient is rapidly absorbed in the gastrointestinal tract and subsequently undergoes extensive first-pass metabolism in the liver. The metabolism takes place in two ways: the oxidation of the 5-methyl group and the dealkylation on nitrogen. The absolute Bioavailability is 30-40% and the usual and recommended oral dose is 1-2 mg twice a day because the side effects caused by the metabolites such as dry mouth, visual disturbances, gastrointestinal difficulties etc. remain tolerable for the patient.
  • parasympatholytic agent parasympatholytic agent
  • transdermal therapeutic systems The great advantage of transdermal therapeutic systems is that the active ingredient has a direct systemic effect after permeation through the skin.
  • the required therapeutically effective dose can thus be significantly reduced and a constant blood plasma level of the active substance can be guaranteed.
  • the bioavailability can be increased considerably, the liver can be relieved and the side effects caused by the metabolites such as dry mouth, gastrointestinal difficulties and visual disturbances can be reduced to a minimum.
  • the simple and convenient use of plasters which remain fully effective for several days is also a major advantage for the patient. Since the system is applied externally, it can fulfill its intended function for a very long time without changing. This is absolutely impossible with oral systems, since they leave the organism after a day at the most due to the digestive activity.
  • transdermal therapeutic system containing tolterodine, 5-hydroxymethyltolterodine, their pharmaceutically acceptable salts or a mixture of these.
  • compositions of tolterodine or 5-hydroxymethyltolterodine are understood to mean acid addition salts. This is obtained by the reaction of the active ingredient in the free base form with pharmaceutically acceptable acids.
  • Pharmaceutically acceptable acids are inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or organic acids (e.g.
  • solvates with the active ingredient.
  • Such solvates are, for example, hydrates, alcoholates and the like.
  • the preferred pharmaceutically acceptable salts can e.g. Tolterodine tartrate, especially tolterodine [(R, R) tartrate] and tolterodine hydrochloride
  • the transdermal therapeutic system of this invention can be a patch.
  • This plaster can be a matrix or membrane system which has an impermeable cover layer and a removable protective layer.
  • nylon come as an impermeable cover layer (Polyamide), nylon (polyamide) copolymer, polybutylene, polycarbonate, polyester, polyethylene terephthalate, thermoplastic polyester copolymer, polyethylene copolymer (high density), polyethylene (high-molecular-weight, high-density), polyethylene (intermediate-molecular-weight, high-density), polyethylene (linear low density), polyethylene (low density), polyethylene (medium density), polyethylene oxide, polyimide, polypropylene, polypropylene (coated
  • Polyester polyethylene, polypropylene, polysiloxane, polyacrylate, ethylene vinyl acetate, polyurethane, polyisobutene or paper, mostly coated with silicone and / or polyethylene, or a mixture of these, are suitable for the removable protective layer.
  • the amount of tolterodine, 5-hydroxymethyltolterodine, their pharmaceutically acceptable salts or a mixture thereof used in the transdermal therapeutic system according to the invention ranges from 0.5 to 80 mg.
  • the matrix patch consists of an impermeable cover layer, one or more self-adhesive matrix layer (s) containing the active ingredient and / or permeation promoter or one or more matrix layer (s) coated with a pressure sensitive adhesive and a removable protective layer.
  • the active ingredient contained in the matrix is tolterodine, 5-hydroxymethyltolterodine, their pharmaceutically acceptable salts or a mixture of these.
  • Medically customary matrix formers such as polyacrylate, silicone,
  • Polyisobutylene rubber, rubber-like synthetic homo-, co- or block polymers, butyl rubber, styrene / isoprene copolymer, polyurethanes, copolymers of ethylene,
  • Polysiloxanes, styrene / butadiene copolymer or a mixture of these, as provided in the prior art, are used.
  • Alkyl alcohol esters amine-resistant silicone in ethyl acetate or n-heptane, polyisobutylene / mineral oil or a mixture of these can be used.
  • a further embodiment according to the invention is a membrane system. This consists of an impermeable cover layer, an active substance-containing reservoir or a reservoir layer, a semipermeable membrane, an optional pressure-sensitive adhesive layer and a removable protective layer.
  • the reservoir contains tolterodine,
  • 5-hydroxymethyltolterodine its pharmaceutically acceptable salts or a mixture of these and / or permeation promoters, stabilizers, emulsifiers, thickeners and / or customary membrane system or reservoir plaster aids.
  • the reservoir or the reservoir layer lies between the cover layer and the membrane. If necessary, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,
  • Carboxyvinylpolymer sodium plyoxylate, carboxymethyl cellulose or a mixture of these can be used.
  • the membrane which usually consists of inert polymers, in particular based on polypropylene, polyvinyl acetate, polyamide, ethylene-vinyl acetate copolymers and / or silicone, can have an effect on the release of the active ingredient.
  • a pressure-sensitive adhesive for example based on polyurethane, polyisobutylene, polyvinyl ether, silicone, polyacrylate or a mixture of these, can be selected for the pressure-sensitive adhesive layer.
  • the silicone-based adhesive can be silicone adhesive that is based on two main components: a polymer or adhesive, in particular polysiloxane, and a tack-increasing resin.
  • the polysiloxane adhesive is usually with a crosslinker for the Adhesive, typically with a high molecular weight polydiorganosiloxane, and prepared with the resin to give a three-dimensional silicate structure using an appropriate organic solvent.
  • the admixture of the resin to the polymer is the most important factor in changing the physical properties of the polysiloxane adhesives; see.
  • Another example of a pressure sensitive silicone based adhesive is trimethylated silicon dioxide which has been treated with trimethylsiloxy terminated polydimethylsiloxane.
  • the acrylate-based adhesives can be any homopolymer, copolymer or terpolymer consisting of various acrylic acid derivatives.
  • the polyacrylate-based adhesives can be any homopolymer, copolymer or terpolymer consisting of various acrylic acid derivatives.
  • the polyacrylates can be polymers of one or more monomers of acrylic acids and other copolymerizable monomers.
  • the acrylate polymers can comprise copolymers of alkyl acrylates and / or methacrylates and / or copolymerizable secondary monomers or monomers with functional groups.
  • the acrylate polymer consists of at least 50% by weight of an acrylate, methacrylate, alkyl acrylate or alkyl methacrylate monomer, 0 to 20% of a functional monomer, copolymerizable with acrylate, and 0 to 50% of another monomer.
  • acrylate monomers such as e.g. Acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, isooctyl acrylate,
  • Tridecyl methacrylate listed, which can be polymerized alone or in a mixture.
  • acrylates such as, for example, acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert.-
  • Butylaminoethyl acrylate, ter.-butylaminoethyl methacrylate, methoxyethyl acrylate, vinyl acetate and methoxyethyl methacrylate can be used for the copolymerization.
  • pressure-sensitive acrylates which are suitable for the invention are, ed nd in Sata's Handbook of Pressure Sensitive Adhesive Technology "Acrylic Adhesives" 2., Pp. 396-456 (D. Sata, ed.), Van Nostrand Reinhold, New York (1989).
  • Mono- and / or polyhydric aliphatic, cycloaliphatic and / or aromatic-aliphatic alcohols each with up to eight C atoms, e.g. Ethanol, 1, 2-propanediol, dexpanthenol and / or polyethylene glycol; Alcohol / water mixtures; saturated and / or unsaturated fatty alcohols, each with 8-18 C atoms; terpenes; e.g. Cineol, Carveol, Menthon, Trepineol, Verbenon, Menthol, Limonen, Thymol, Cymen,
  • C atoms e.g. Ethanol, 1, 2-propanediol, dexpanthenol and / or polyethylene glycol
  • Alcohol / water mixtures saturated and / or unsaturated fatty alcohols, each with 8-18 C atoms
  • terpenes e.g. Cineol, Carveol, Menthon, Trepineo
  • Terpinen-4-ol, neomenthol, geraniol, fenchone Mixtures of terpenes and ethanol and / or propylene glycol; tea tree oil; saturated and / or unsaturated cyclic ketones; Alkyl methyl sulfoxides; saturated and / or unsaturated fatty acids, each with 8-18 C atoms; their esters and salts; natural vitamin E; synthetic vitamin E and / or vitamin E derivatives; Sorbitan fatty acid esters and ethoxylated sorbitan fatty acid esters; Azone (laurocapram); Azone mixed with alcohol; Urea; 1-alkylpyrrolidone; Block copolymers of polyethylene glycol and dimethylsiloxane with a cationic group at one end; Folate polyethylene glycol liposome, proliposome; Polyoxyethylene 10 stearyl ether; Mixture of polyoxyethylene 10 stearyl ether and glyceryl dilaurate;
  • 1st step 50 g of tolterodine are abs in 950 g of a mixture of ethanol. 65% (V / G), glycerin 20% (V / G), Copherol F1300 10% (V / G) and hydroxypropyl cellulose 1% (V / G) dissolved with stirring.
  • Step 2 an acrylate adhesive (ERA 1, Adhesives Research) is dissolved in sufficient ethyl acetate, depending on its dry weight, to produce an approx. 60% solution.
  • the coating solution is spread on a siliconized PET film and at
  • a microporous membrane eg CoTran 9711, 3 M Medica is then laminated onto the matrix.
  • step 3 The solution is supplied via a peristaltic pump.
  • the laminate from step 2 is welded to a filler opening with a heat-sealable protective film.
  • step 1 Filling with 400 ⁇ 5% mg of solution (step 1), the reservoir is sealed by sealing and the TTS is punched out. Amount of substances per TTS:
  • Copherol F1300 76 mg

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to an active substance containing transdermal system for the utilization of tolterodine, 5-hydroxymethyl tolterodine, to their pharmaceutically acceptable salts or a mixture thereof.

Description

Transdermales therapeutisches System zur Anwendung von Tolterodin Transdermal therapeutic system for the application of tolterodine
Die Erfindung betrifft ein wirkstoffhaltiges transdermales therapeutisches System zur Anwendung von Tolterodin, 5-Hydroxymethyltolterodin und/ oder deren pharmazeutisch unbedenklichen Salzen.The invention relates to a drug-containing transdermal therapeutic system for the use of tolterodine, 5-hydroxymethyltolterodine and / or their pharmaceutically acceptable salts.
Tolterodin [(R )-N,N-Diisopropyl-3-(2-Hydroxy-5-Methylphenyl)-3-Phenylpropylamin] ist ein neuer, sehr wirksamer und kompetitiver Muscarinrezeptor-Antagonist (Parasympatholytika). Er besitzt eine große Affinität und Spezifität für den Muscarinrezeptor. Tolterodin wird zur Behandlung von Blaseninkontinenz und anderen Beschwerden, deren Ursache in einer instabilen Blase zu suchen sind, verwendet. Bei der oralen Verabreichung von Tolterodin erfolgt eine rasche Absorption des Wirkstoffes im Gastrointestinaltrakt und eine anschließende umfassende „First-Pass"-Metabolisierung in der Leber. Die Metabolisierung erfolgt über zwei Wege: die Oxidation der 5- Methylgruppe und die Dealkylierung am Stickstoff. Die absolute Bioverfügbarkeit beträgt 30-40 %. Die übliche und empfohlene orale Dosis beträgt 1-2 mg zweimal pro Tag, da somit die Nebenwirkungen, hervorgerufen durch die Metaboliten, wie Mundtrockenheit, Sehstörungen, Magen-Darm- Schwierigkeiten etc. für den Patienten erträglich bleiben.Tolterodine [(R) -N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropylamine] is a new, very effective and competitive muscarinic receptor antagonist (parasympatholytic agent). It has great affinity and specificity for the muscarinic receptor. Tolterodine is used to treat bladder incontinence and other conditions caused by an unstable bladder. When tolterodine is administered orally, the active ingredient is rapidly absorbed in the gastrointestinal tract and subsequently undergoes extensive first-pass metabolism in the liver. The metabolism takes place in two ways: the oxidation of the 5-methyl group and the dealkylation on nitrogen. The absolute Bioavailability is 30-40% and the usual and recommended oral dose is 1-2 mg twice a day because the side effects caused by the metabolites such as dry mouth, visual disturbances, gastrointestinal difficulties etc. remain tolerable for the patient.
Aufgabe der vorliegenden Erfindung ist es nun, eine Darreichungsform, enthaltend Tolterodin, 5-Hydroxymethyltolterodin und/ oder deren pharmazeutisch unbedenklichen Salze, bereitzustellen, bei der die Nachteile bisher angewandter oraler oder intravenöser Darreichungsformen vermieden werden können. Es wurde nun überraschenderweise gefunden, daß der Wirkstoff Tolterodin, dessen Derivat 5-Hydroxymethyltolterodin und deren Salze in einem Maße hautdurchgängig sind, daß mit ihnen wirksame, effektive transdermale therapeutische Systeme hergestellt werden können, was aufgrund der Molekülstruktur nicht zu erwarten war.It is an object of the present invention to provide a dosage form containing tolterodine, 5-hydroxymethyltolterodine and / or their pharmaceutically acceptable salts in which the disadvantages of previously used oral or intravenous dosage forms can be avoided. It has now surprisingly been found that the active ingredient tolterodine, its derivative 5-hydroxymethyltolterodine and its salts are permeable to the skin to an extent that effective, effective transdermal therapeutic systems can be produced with them, which was not to be expected due to the molecular structure.
Der große Vorteil von transdermalen therapeutischen Systemen besteht darin, daß der Wirkstoff nach der Permeation durch die Haut direkt systemisch zur Wirkung kommt. Die erforderliche therapeutisch wirksame Dosis kann somit deutlich verringert und ein konstanter Blutplasmaspiegel des Wirkstoffes garantiert werden. Durch Umgehung der, in diesem Fall stark ausgeprägten, hepatischen Metabolisierung des Wirkstoffes kann die Bioverfügbarkeit beträchtlich gesteigert, die Leber entlastet und die durch die Metaboliten hervorgerufenen Nebenwirkungen wie Mundtrockenheit, Magen-Darm- Schwierigkeiten und Sehstörungen auf ein Minimum reduziert werden. Die, im Gegensatz zur oralen Darreichung, einfache und bequeme Anwendung von Pflastern, die über mehrere Tage ihre volle Wirksamkeit beibehalten, ist ebenfalls ein wesentlicher Vorteil für den Patienten. Da das System extern appliziert wird, kann es ohne Wechsel sehr lange seine ihm zugedachte Funktion erfüllen. Dies ist mit oralen Systemen schlechterdings unmöglich, da sie durch die Verdauungstätigkeit nach längstens einem Tag den Organismus verlassen.The great advantage of transdermal therapeutic systems is that the active ingredient has a direct systemic effect after permeation through the skin. The required therapeutically effective dose can thus be significantly reduced and a constant blood plasma level of the active substance can be guaranteed. By bypassing the hepatic metabolism of the active ingredient, which is strongly pronounced in this case, the bioavailability can be increased considerably, the liver can be relieved and the side effects caused by the metabolites such as dry mouth, gastrointestinal difficulties and visual disturbances can be reduced to a minimum. In contrast to oral administration, the simple and convenient use of plasters which remain fully effective for several days is also a major advantage for the patient. Since the system is applied externally, it can fulfill its intended function for a very long time without changing. This is absolutely impossible with oral systems, since they leave the organism after a day at the most due to the digestive activity.
Die der Erfindung zugrundeliegende Aufgabe wird nun durch ein transdermales therapeutisches System mit einem Gehalt an Tolterodin, 5-Hydroxymethyltolterodin, deren pharmazeutisch unbedenklichen Salzen oder einem Gemisch von diesen gelöst.The object on which the invention is based is now achieved by a transdermal therapeutic system containing tolterodine, 5-hydroxymethyltolterodine, their pharmaceutically acceptable salts or a mixture of these.
Unter pharmazeutisch unbedenklichen Salzen von Tolterodin oder 5-Hydroxymethyltolterodin werden Säureadditionssalze verstanden. Diese erhält man durch die Reaktion des in der freien Basenform vorliegenden Wirkstoffes mit pharmazeutisch unbedenklichen Säuren. Pharmazeutisch unbedenkliche Säuren sind anorganische Säuren (z.B. Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Salpetersäure, Phosphorsäure) oder organische Säuren (z.B. Essig-, Propion-, Hydroxyessig-, Milch-, Brenztrauben-, Oxal-, Malein-, Malon-, Bernstein-, Fumar-, Äpfel-, Wein-, Citronen-, Methansulfon-, Ethansulfon-, Benzolsulfon-, p- Toluolsulfon-, Cyclohexansulfamin-, Salicyl-, p-Aminosalicyl- und Pamoasäure). Ebenso als Säureadditionssalze werden Solvate mit dem Wirkstoff bezeichnet. Derartige Solvate sind z.B. Hydrate, Alkoholate und dergleichen.Pharmaceutically acceptable salts of tolterodine or 5-hydroxymethyltolterodine are understood to mean acid addition salts. This is obtained by the reaction of the active ingredient in the free base form with pharmaceutically acceptable acids. Pharmaceutically acceptable acids are inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid) or organic acids (e.g. acetic, propionic, hydroxyacetic, milk, pyruvic, oxalic, maleic, malonic, amber, Fumaric, apple, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, p-aminosalicylic and pamoic acid). As well as Acid addition salts are called solvates with the active ingredient. Such solvates are, for example, hydrates, alcoholates and the like.
Die bevorzugten pharmazeutisch unbedenklichen Salze können z.B. Tolterodintartrat, insbesondere Tolterodin[(R,R)-tartrat] und Tolterodin-Hydrochlorid seinThe preferred pharmaceutically acceptable salts can e.g. Tolterodine tartrate, especially tolterodine [(R, R) tartrate] and tolterodine hydrochloride
Das transdermale therapeutische System dieser Erfindung kann ein Pflaster darstellen. Bei diesem Pflaster kann es sich um ein Matrix- oder Membransystem handeln, welches eine undurchlässige Deckschicht und eine abziehbare Schutzschicht aufweist.The transdermal therapeutic system of this invention can be a patch. This plaster can be a matrix or membrane system which has an impermeable cover layer and a removable protective layer.
Als undurchlässige Deckschicht kommen Folien aus Acetal, Acrylat, Acrylonitril-Butadien- Styrol, Acrylonitril (Methyl Methacrylat) Copolymer, Acrylonitril Copolymer, Ethylen Ethyl Acrylat, Ethylen Methyl Acrylat, Ethylen Vinyl Acetat, Ethylen Vinyl Acetat Copolymer, Ethylen Vinylalkohol Polymer, Ionomere, Nylon (Polyamid), Nylon (Polyamid) Copolymer, Polybutylen, Polycarbonat , Polyester, Polyethylenterephthalat, thermoplastisches Polyester Copolymer, Polyethylen Copolymer (high density), Polyethylen (high-molecular-weight, high- density), Polyethylen (intermediate-molecular-weight, high-density), Polyethylen(linear low density), Polyethylen (low density), Polyethylen (medium density), Polyethylenoxid, Polyimid, Polypropylen, Polypropylen (coated), Polypropylen (oriented), Polystyrol, Polyurethan, Polyvinylacetat, Polyvinylchlorid, Polyvinylidenchlorid und/ oder Styrol- Acrylonitril in Frage, die bei Bedarf metallisiert oder pigmentiert werden können.Films made of acetal, acrylate, acrylonitrile-butadiene-styrene, acrylonitrile (methyl methacrylate) copolymer, acrylonitrile copolymer, ethylene-ethyl acrylate, ethylene-methyl acrylate, ethylene-vinyl acetate, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol polymer, ionomers, nylon come as an impermeable cover layer (Polyamide), nylon (polyamide) copolymer, polybutylene, polycarbonate, polyester, polyethylene terephthalate, thermoplastic polyester copolymer, polyethylene copolymer (high density), polyethylene (high-molecular-weight, high-density), polyethylene (intermediate-molecular-weight, high-density), polyethylene (linear low density), polyethylene (low density), polyethylene (medium density), polyethylene oxide, polyimide, polypropylene, polypropylene (coated), polypropylene (oriented), polystyrene, polyurethane, polyvinyl acetate, polyvinyl chloride, polyvinylidene chloride and / or styrene acrylonitrile in question, which can be metallized or pigmented if necessary.
Für die abziehbare Schutzschicht kommen Polyester, Polyethylen, Polypropylen, Polysiloxan, Polyacrylat, Ethylenvinylacetat, Polyurethan, Polyisobuten oder Papier, meistens mit Silikon- und /oder Polyethylen beschichtet, oder ein Gemisch aus diesen in Betracht.Polyester, polyethylene, polypropylene, polysiloxane, polyacrylate, ethylene vinyl acetate, polyurethane, polyisobutene or paper, mostly coated with silicone and / or polyethylene, or a mixture of these, are suitable for the removable protective layer.
Die in dem erfindungsgemäßen transdermalen therapeutischen System eingesetzte Menge an Tolterodin, 5-Hydroxymethyltolterodin, deren pharmazeutisch unbedenklichen Salzen oder einem Gemisch von diesen reicht von 0,5 bis 80 mg.The amount of tolterodine, 5-hydroxymethyltolterodine, their pharmaceutically acceptable salts or a mixture thereof used in the transdermal therapeutic system according to the invention ranges from 0.5 to 80 mg.
Das Matrixpflaster besteht aus einer undurchlässigen Deckschicht, aus einer oder mehreren den Wirkstoff und/ oder Permeationsförderer enthaltenden, selbstklebenden Matrixschicht(en) oder einer oder mehreren Matrixschicht(en), die mit einem Haftkleber beschichtet sind und einer abziehbaren Schutzschicht. Bei dem in der Matrix enthaltenen Wirkstoff handelt es sich um Tolterodin, 5-Hydroxymethyltolterodin, deren pharmazeutisch unbedenklichen Salze oder einem Gemisch von diesen.The matrix patch consists of an impermeable cover layer, one or more self-adhesive matrix layer (s) containing the active ingredient and / or permeation promoter or one or more matrix layer (s) coated with a pressure sensitive adhesive and a removable protective layer. The active ingredient contained in the matrix is tolterodine, 5-hydroxymethyltolterodine, their pharmaceutically acceptable salts or a mixture of these.
Für die Matrix werden die medizinisch üblichen Matrixbildner wie Polyacrylat, Silikon,Medically customary matrix formers such as polyacrylate, silicone,
Polyisobutylen, Kautschuk, kautschukähnliche synthetische Homo-, Co- oder Blockpolymere, Butylkautschuk, Styrol/ Isopren- Copolymerisat, Polyurethane, Copolymere des Ethylens,Polyisobutylene, rubber, rubber-like synthetic homo-, co- or block polymers, butyl rubber, styrene / isoprene copolymer, polyurethanes, copolymers of ethylene,
Polysiloxane, Styrol/ Butadien- Copolymerisat oder ein Gemisch aus diesen, wie sie im Stand der Technik vorgesehen werden, verwendet.Polysiloxanes, styrene / butadiene copolymer or a mixture of these, as provided in the prior art, are used.
Als Kleber kann Polydimethylsiloxan, Polyacrylate, Polyisobutylen, Polyacrylat mit C - C10 Polydimethylsiloxane, polyacrylates, polyisobutylene, polyacrylate with C - C 10
Alkylalkoholestern, amminrestistentes Silikon in Ethylacetat oder n-Heptan, Polyisobutylen/ Mineralöl oder ein Gemisch aus diesen verwendet werden.Alkyl alcohol esters, amine-resistant silicone in ethyl acetate or n-heptane, polyisobutylene / mineral oil or a mixture of these can be used.
Eine weitere erfindungsgemäße Ausführungsform stellt ein Membransystem dar. Dieses besteht aus einer undurchlässigen Deckschicht, einem wirkstoffhaltigen Reservoir oder einer Reservoirschicht, einer semipermeablen Membran, einer fakultativen Haftklebeschicht und einer abziehbaren Schutzschicht. Das Reservoir enthält Tolterodin,A further embodiment according to the invention is a membrane system. This consists of an impermeable cover layer, an active substance-containing reservoir or a reservoir layer, a semipermeable membrane, an optional pressure-sensitive adhesive layer and a removable protective layer. The reservoir contains tolterodine,
5-Hydroxymethyltolterodin, deren pharmazeutisch unbedenkliche Salze oder ein Gemisch von diesen und/ oder Permeationsförderer, Stabilisatoren, Emulgatoren, Verdickungsmittel und/ oder übliche Membransystem- bzw. Reservoirpflaster- Hilfsmittel. Das Reservoir bzw. die Reservoirschicht liegt zwischen der Deckschicht und der Membran. Als Gelbildner können bei Bedarf Methylcellulose, Hydroxypropylcellulose, Hydroxyethylcellulose,5-hydroxymethyltolterodine, its pharmaceutically acceptable salts or a mixture of these and / or permeation promoters, stabilizers, emulsifiers, thickeners and / or customary membrane system or reservoir plaster aids. The reservoir or the reservoir layer lies between the cover layer and the membrane. If necessary, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,
Carboxyvinylpolymer, Natrium- Plyoxilat, Carboxymethylcellulose oder ein Gemisch aus diesen verwendet werden.Carboxyvinylpolymer, sodium plyoxylate, carboxymethyl cellulose or a mixture of these can be used.
Die Membran, die üblicherweise aus inerten Polymeren, insbesondere auf Basis von Polypropylen, Polyvinylacetat, Polyamid, Ethylen- Vinylacetat- Copolymeren und/ oder Silikon, besteht, kann je nach Porengröße eine die Wirkstoffreisetzung kontrollierende Wirkung haben.Depending on the pore size, the membrane, which usually consists of inert polymers, in particular based on polypropylene, polyvinyl acetate, polyamide, ethylene-vinyl acetate copolymers and / or silicone, can have an effect on the release of the active ingredient.
Für die Haftklebeschicht kann man ein druckempfindliches Klebemittel beispielsweise auf Polyurethanbasis, Polyisobutylenbasis, Polyvinyletherbasis, Siliconbasis, Polyacrylatbasis oder ein Gemisch aus diesen wählen.A pressure-sensitive adhesive, for example based on polyurethane, polyisobutylene, polyvinyl ether, silicone, polyacrylate or a mixture of these, can be selected for the pressure-sensitive adhesive layer.
Bei dem Klebemittel auf Silkonbasis kann es sich um Silikonkleber handeln, welche auf zwei Hauptbestandteilen basieren: Ein Polymer oder Klebstoff, insbesondere Polysiloxan, und ein tackerhöhendes Harz. Der Polysiloxankleber ist gewöhnlich mit einem Vernetzer für den Kleber, typischerweise mit einem hochmolekularen Polydiorganosiloxan, und mit dem Harz zubereitet, um über ein angemessenes organisches Lösungsmittel eine dreidimensionale Silikatstruktur zu ergeben. Die Zumischung des Harzes zu Polymer ist der wichtigste Faktor, um die physikalischen Eigenschaften der polysiloxanen Kleber zu ändern; vgl. beispielsweise Sobieski, et al., „Silicone Pressure Sensitive Adhesives", Handbook of Pressure Sensitive Adhesive Technology, 2nd ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New sive Technology, 2nd ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989).The silicone-based adhesive can be silicone adhesive that is based on two main components: a polymer or adhesive, in particular polysiloxane, and a tack-increasing resin. The polysiloxane adhesive is usually with a crosslinker for the Adhesive, typically with a high molecular weight polydiorganosiloxane, and prepared with the resin to give a three-dimensional silicate structure using an appropriate organic solvent. The admixture of the resin to the polymer is the most important factor in changing the physical properties of the polysiloxane adhesives; see. for example, Sobieski, et al., "Silicone Pressure Sensitive Adhesives", Handbook of Pressure Sensitive Adhesive Technology, 2 nd ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New sive Technology, 2 nd ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989).
Ein weiteres Beispiel für ein druckempfindliches Klebemittel auf Silikonbasis ist trimethyliertes Siliciumdioxid, das mit Polydimethylsiloxan mit endständigen Trimethylsiloxy- Gruppen behandelt worden ist.Another example of a pressure sensitive silicone based adhesive is trimethylated silicon dioxide which has been treated with trimethylsiloxy terminated polydimethylsiloxane.
Bei den Klebemitteln auf Acrylatbasis kann es sich um ein beliebiges Homopolymer, Copolymer oder Terpolymer, bestehend aus verschiedenen Acrylsäurederivaten handeln.The acrylate-based adhesives can be any homopolymer, copolymer or terpolymer consisting of various acrylic acid derivatives.
Bei den Klebemitteln auf Polyacrylatbasis kann es sich um ein beliebiges Homopolymer, Copolymer oder Terpolymer, bestehend aus verschiedenen Acrylsäurederivaten handeln.The polyacrylate-based adhesives can be any homopolymer, copolymer or terpolymer consisting of various acrylic acid derivatives.
So können die Polyacrylate Polymere eines oder mehrerer Monomere von Acrylsäuren und anderen copolymerisierbaren Monomeren sein. Außerdem können die Acrylatpolymere Copolymere von Alkylacrylaten und/ oder -methacrylaten und/ oder copolymerisierbaren sekundären Monomeren oder Monomeren mit funktioneilen Gruppen umfassen. Verändert man den Betrag jeder Sorte, die als Monomer hinzugefügt ist, können die kohäsiven Eigenschaften der daraus resultierenden Acrylatpolymere verändert werden. Im allgemeinen besteht das Acrylatpolymer aus mindestens 50 Gew.-% eines Acrylat-, Methacrylat-, Alkylacrylat- oder Alkylmethacrylat-Monomers, 0 bis 20 % eines funktionellen Monomers, copolymerisierbar mit Acrylat, und 0 bis 50 % eines anderen Monomeren.For example, the polyacrylates can be polymers of one or more monomers of acrylic acids and other copolymerizable monomers. In addition, the acrylate polymers can comprise copolymers of alkyl acrylates and / or methacrylates and / or copolymerizable secondary monomers or monomers with functional groups. By changing the amount of each grade added as a monomer, the cohesive properties of the resulting acrylate polymers can be changed. In general, the acrylate polymer consists of at least 50% by weight of an acrylate, methacrylate, alkyl acrylate or alkyl methacrylate monomer, 0 to 20% of a functional monomer, copolymerizable with acrylate, and 0 to 50% of another monomer.
Im folgenden sind verschiedene Acrylatmonomere, wie z.B. Acrylsäure, Methacrylsäure, Butylacrylat, Butylmethacrylat, Hexylacrylat, Hexylmethacrylat, Isooctylacrylat,The following are various acrylate monomers such as e.g. Acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, isooctyl acrylate,
Isooctylmethacrylat, Glycidylmethacrylat, 2-Hydroxyethylacrylat, Methylacrylat,Isooctyl methacrylate, glycidyl methacrylate, 2-hydroxyethyl acrylate, methyl acrylate,
Methylmethacrylat, 2-Ethylhexylacrylat, 2-Ethylhexylmethacrylat, Decylacrylat, Decylmethacrylat, Dodecylacrylat, Dodecylmethacrylat, Tridecylacrylat undMethyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, Decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate and
Tridecylmethacrylat, aufgeführt, die alleine oder in Mischung polymerisiert werden können.Tridecyl methacrylate, listed, which can be polymerized alone or in a mixture.
Zusätzlich können funktioneile Monomere, die mit den oben genannten Acrylaten copolymerisierbar sind, wie beispielsweise Acrylsäure, Methacrylsäure, Maleinsäure, Maleinanhydrid, Hydroxyethylacrylat, Hydroxypropylacrylat, Acrylamid, Dimethylacrylamid, Acrylnitril, Dimethylaminoethylacrylat, Dimethylaminoethylmethacrylat, tert.-In addition, functional monomers which are copolymerizable with the abovementioned acrylates, such as, for example, acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert.-
Butylaminoethylacrylat, ter.-Butylaminoethylmethacrylat, Methoxyethylacrylat, Vinylacetat und Methoxyethylmethacrylat, zur Copolymerisierung eingesetzt werden.Butylaminoethyl acrylate, ter.-butylaminoethyl methacrylate, methoxyethyl acrylate, vinyl acetate and methoxyethyl methacrylate can be used for the copolymerization.
Weiter Einzelheiten und Beispiele für druckempfindliche Acrylate, welche für die Erfindung geeignet sind, sind in Satas Handbook of Pressure Sensitive Adhesive Technology „Acrylic Adhesives", 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989) beschrieben.Further details and examples of pressure-sensitive acrylates, which are suitable for the invention are, ed nd in Sata's Handbook of Pressure Sensitive Adhesive Technology "Acrylic Adhesives" 2., Pp. 396-456 (D. Sata, ed.), Van Nostrand Reinhold, New York (1989).
Als Permeationsförderer lassen sich ein- und/oder mehrwertige aliphatische, cycloaliphatische und /oder aromatisch- aliphatische Alkohole mit jeweils bis zu acht C- Atomen, z.B. Ethanol, 1 ,2-Propandiol, Dexpanthenol und/ oder Polyethylenglykol; Alkohol/ Wasser- Gemische; gesättigte und/ oder ungesättigte Fettalkohole mit jeweils 8- 18 C- Atomen; Terpene; z.B. Cineol, Carveol, Menthon, Trepineol, Verbenon, Menthol, Limonen, Thymol, Cymen,Mono- and / or polyhydric aliphatic, cycloaliphatic and / or aromatic-aliphatic alcohols, each with up to eight C atoms, e.g. Ethanol, 1, 2-propanediol, dexpanthenol and / or polyethylene glycol; Alcohol / water mixtures; saturated and / or unsaturated fatty alcohols, each with 8-18 C atoms; terpenes; e.g. Cineol, Carveol, Menthon, Trepineol, Verbenon, Menthol, Limonen, Thymol, Cymen,
Terpinen-4-ol, Neomenthol, Geraniol, Fenchon; Gemische aus Terpenen und Etanol und/ oder Propylenglykol; Teebaumöl; gesättigte und/ oder ungesättigte cyclische Ketone; Alkyl- Methylsulfoxide; gesättigte und/ oder ungesättigte Fettsäuren mit jeweils 8- 18 C- Atomen; deren Ester und Salze; natürliches Vitamin E; synthetisches Vitamin E und/ oder Vitamin E- Derivate; Sorbitanfettsäureester und ethoxylierte Sorbitanfettsäureester; Azone (Laurocapram); Azone gemischt mit Alkoholen; Harnstoff; 1-Alkylpyrrolidon; Blockcopolymere von Polyethylenglykol und Dimethylsiloxan mit kationischer Gruppe an einem Ende; Folat-Polyethylenglykol-Liposom, Proliposom; Polyoxyethylen-10-stearylether; Gemisch aus Polyoxyethylen-10-stearylether und Glyceryldilaurat; Dodecyl-2-(N,N- dimethylamino)-propanoltetradecanoat und/ oder Dodecyl-2-(N,N-dimethylamino)-propianat; N-Acetylprolinatester mit > 8 C-Atomen; nichtionische Tenside, z.B. Laurylether, Ester von Polyoxyethylen; Ethosom (Phospholipidvesikel); Dimethyl(arylimino)sulfuran; Gemisch aus Ölsäureanaloga und Propylenglykol; Gemisch aus Padimat O, Oktylsalicylat, Oktylmethoxycinnimat, Laurocapram; Isopropylmyristat, Isopropylpalmitat oder ein Gemisch aus Einzelkomponenten verwenden.Terpinen-4-ol, neomenthol, geraniol, fenchone; Mixtures of terpenes and ethanol and / or propylene glycol; tea tree oil; saturated and / or unsaturated cyclic ketones; Alkyl methyl sulfoxides; saturated and / or unsaturated fatty acids, each with 8-18 C atoms; their esters and salts; natural vitamin E; synthetic vitamin E and / or vitamin E derivatives; Sorbitan fatty acid esters and ethoxylated sorbitan fatty acid esters; Azone (laurocapram); Azone mixed with alcohol; Urea; 1-alkylpyrrolidone; Block copolymers of polyethylene glycol and dimethylsiloxane with a cationic group at one end; Folate polyethylene glycol liposome, proliposome; Polyoxyethylene 10 stearyl ether; Mixture of polyoxyethylene 10 stearyl ether and glyceryl dilaurate; Dodecyl 2- (N, N-dimethylamino) propanol tetradecanoate and / or dodecyl 2- (N, N-dimethylamino) propianate; N-acetylprolinate esters with> 8 C atoms; nonionic surfactants, eg lauryl ether, esters of polyoxyethylene; Ethosome (phospholipid vesicle); Dimethyl (arylimino) sulfurane; Mixture of oleic acid analogues and propylene glycol; Mixture of Padimat O, octyl salicylate, Octyl methoxycinnimate, laurocapram; Use isopropyl myristate, isopropyl palmitate or a mixture of individual components.
Die Erfindung wird durch nachstehende Beispiele näher erläutert ohne aber den Erfindungsumfang damit einzuschränken.The invention is explained in more detail by the following examples, but without thereby restricting the scope of the invention.
Beispiel 1 (Matrix- Pflaster)Example 1 (matrix patch)
Es werden 1,6 g Tolterodin in 75 g Aceton gelöst und mit 8 g Copherol F1300 und 8 g Propylenglykol versetzt. Die klare Lösung wird zu 127,3 g eines ca. 49%igen Acrylat- Copolymeren (Duro- Tak 387-2287, Nat. Starch & Chemical B.V.) gegeben und gerührt. Die homogene Lösung wird auf einer silikonisierten Polyesterfolie (z.B. 75μm) oder auf silikonisiertem Papier ausgestrichen und bei 35 °C bis 85 °C getrocknet, so daß ein Matrix- Trockengewicht von 80 ± 10 % g/m2 erhalten wird. Auf die Matrixseite wird anschließend die abziehbare Schutzschicht (z.B. Polyester 15 μm) kaschiert. Es werden TTS mit einer Fläche von 10 cm2 ausgestanzt.1.6 g of tolterodine are dissolved in 75 g of acetone and 8 g of Copherol F1300 and 8 g of propylene glycol are added. The clear solution is added to 127.3 g of an approximately 49% acrylate copolymer (Durotak 387-2287, Nat. Starch & Chemical BV) and stirred. The homogeneous solution is spread on a siliconized polyester film (for example 75 μm) or on siliconized paper and dried at 35 ° C. to 85 ° C., so that a dry matrix weight of 80 ± 10% g / m 2 is obtained. The removable protective layer (eg polyester 15 μm) is then laminated onto the matrix side. TTS with an area of 10 cm 2 are punched out.
Beispiel 2 (Reservoir-Pflaster)Example 2 (reservoir patch)
1. Schritt: 50 g Tolterodin werden in 950 g einer Mischung aus Ethanol abs. 65% (V/G), Glycerin 20% (V/G), Copherol F1300 10% (V/G) und Hydroxypropylcellulose 1% (V/G) unter rühren gelöst.1st step: 50 g of tolterodine are abs in 950 g of a mixture of ethanol. 65% (V / G), glycerin 20% (V / G), Copherol F1300 10% (V / G) and hydroxypropyl cellulose 1% (V / G) dissolved with stirring.
2. Schritt: ein Acrylatkleber (ERA 1, Adhesives Research) wird in Abhängigkeit von seinem Trockengewichtsanteil in soviel Ethylacetat gelöst, daß eine ca. 60%ige Lösung entsteht. Die Beschichtungslösung wird auf einer silikonisierten PET- Folie ausgestrichen und beiStep 2: an acrylate adhesive (ERA 1, Adhesives Research) is dissolved in sufficient ethyl acetate, depending on its dry weight, to produce an approx. 60% solution. The coating solution is spread on a siliconized PET film and at
35 °C bis 85 °C getrocknet, so daß ein Matrix- Trockengewicht von 50 ± 10 % g/m2 erhalten wird. Auf die Matrix wird anschließend eine mikroporöse Membran (z.B. CoTran 9711, 3 M Medica) kaschiert.Dried 35 ° C to 85 ° C, so that a dry matrix weight of 50 ± 10% g / m 2 is obtained. A microporous membrane (eg CoTran 9711, 3 M Medica) is then laminated onto the matrix.
3. Über eine Schlauchpumpe wird die Verumlösung zugeführt. Das Laminat aus Schritt 2 wird mit einer heißsiegelfähigen Schutzfolie bis auf eine Einfüllöffhung verschweißt. Nach3. The solution is supplied via a peristaltic pump. The laminate from step 2 is welded to a filler opening with a heat-sealable protective film. To
Befüllen mit 400 ± 5% mg an Verumlösung (Schritt 1) wird das Reservoir durch Siegeln verschlossen und das TTS ausgestanzt. Menge der Substanzen je TTS:Filling with 400 ± 5% mg of solution (step 1), the reservoir is sealed by sealing and the TTS is punched out. Amount of substances per TTS:
Tolterodin: 20mgTolterodine: 20mg
Ethanol abs.: 220 mgAbs. Ethanol: 220 mg
Copherol F1300: 76 mgCopherol F1300: 76 mg
Glycerin: 80 mgGlycerin: 80 mg
Hydroxypropylcellulose : 4 mg Hydroxypropyl cellulose: 4 mg

Claims

Patentansprüche claims
1. Transdermales therapeutisches System mit einem Gehalt an Tolterodin, dessen pharmazeutisch unbedenklichen Salzen, Derivaten oder einem Gemisch aus diesen.1. Transdermal therapeutic system containing tolterodine, its pharmaceutically acceptable salts, derivatives or a mixture thereof.
2. Transdermales therapeutisches System nach Anspruch 1 , gekennzeichnet durch Tolterodin und/ oder Tolterodintartrat und/ oder Tolterodinhydrochlorid und/ oder 5- Hydroxymethyltolterodin als Wirkstoff.2. Transdermal therapeutic system according to claim 1, characterized by tolterodine and / or tolterodine tartrate and / or tolterodine hydrochloride and / or 5-hydroxymethyltolterodine as the active ingredient.
3. Transdermales therapeutisches System nach einem der vorhergehenden Ansprüche in Form eines Pflasters mit einer undurchlässigen Deckschicht und einer abziehbaren Schutzschicht, insbesondere in Form eines Matrix- oder Membransystems.3. Transdermal therapeutic system according to one of the preceding claims in the form of a plaster with an impermeable cover layer and a removable protective layer, in particular in the form of a matrix or membrane system.
4. Transdermales therapeutisches System nach Anspruch 3, gekennzeichnet durch eine Deckschicht auf Basis von Acetal, Acrylat, Acrylonitril-Butadien-Styrol, Acrylonitril4. Transdermal therapeutic system according to claim 3, characterized by a cover layer based on acetal, acrylate, acrylonitrile-butadiene-styrene, acrylonitrile
(Methyl Methacrylat) Copolymer, Acrylonitril Copolymer, Ethylen Ethyl Acrylat, Ethylen Methyl Acrylat, Ethylen Vinyl Acetat, Ethylen Vinyl Acetat Copolymer, Ethylen Vinylalkohol Polymer, Ionomere, Nylon (Polyamid), Nylon (Polyamid) Copolymer, Polybutylen, Polycarbonat , Polyester, Polyethylenterephthalat, thermoplastisches Polyester Copolymer, Polyethylen Copolymer (high density), Polyethylen (high-molecular-weight, high-density), Polyethylen (intermediate-molecular-weight, high-density), Polyethylen(linear low density), Polyethylen (low density), Polyethylen (medium density), Polyethylenoxid, Polyimid, Polypropylen, Polypropylen (coated), Polypropylen (oriented), Polystyrol, Polyurethan, Polyvinylacetat, Polyvinylchlorid, Polyvinylidenchlorid und/ oder Styrol- Acrylonitril in Frage, die gegebenenfalls metallisiert oder pigmentiert sein können.(Methyl methacrylate) copolymer, acrylonitrile copolymer, ethylene ethyl acrylate, ethylene methyl acrylate, ethylene vinyl acetate, ethylene vinyl acetate copolymer, ethylene vinyl alcohol polymer, ionomers, nylon (polyamide), nylon (polyamide) copolymer, polybutylene, polycarbonate, polyester, polyethylene terephthalate , thermoplastic polyester copolymer, polyethylene copolymer (high density), polyethylene (high-molecular-weight, high-density), polyethylene (intermediate-molecular-weight, high-density), polyethylene (linear low density), polyethylene (low density) , Polyethylene (medium density), polyethylene oxide, polyimide, polypropylene, polypropylene (coated), polypropylene (oriented), polystyrene, polyurethane, polyvinyl acetate, polyvinyl chloride, polyvinylidene chloride and / or styrene-acrylonitrile, which can optionally be metallized or pigmented.
5. Transdermales therapeutisches System nach Anspruch 3, gekennzeichnet durch eine abziehbare Schutzschicht auf Basis von Polyester, Polyethylen, Polypropylen, Polysiloxan, Polyacrylat, Ethylenvinylacetat, Polyurethan, Polyisobuten oder Papier, gegebenenfalls mit Silikon- und /oder Polyethylen beschichtet. 5. Transdermal therapeutic system according to claim 3, characterized by a removable protective layer based on polyester, polyethylene, polypropylene, polysiloxane, polyacrylate, ethylene vinyl acetate, polyurethane, polyisobutene or paper, optionally coated with silicone and / or polyethylene.
6. Transdermales therapeutisches System nach Anspruch 3, 4 oder 5, dadurch gekennzeichnet, daß es sich um ein Matrixsystem mit6. Transdermal therapeutic system according to claim 3, 4 or 5, characterized in that it is a matrix system with
■ einer undurchlässigen Deckschicht,An impermeable cover layer,
■ einer oder mehreren wirkstoffhaltigen selbstklebenden Matrixschicht(en) oder einer oder mehreren wirkstoffhaltigen Matrixschicht(en), die mit einem Haftkleber beschichtet sind,One or more self-adhesive matrix layer (s) containing active ingredient or one or more matrix layer (s) containing active ingredient which are coated with a pressure sensitive adhesive,
■ einer abziehbaren Schutzschicht und■ a removable protective layer and
■ Tolterodin, 5-Hydroxymethyltolterodin, deren pharmazeutisch verträglichen Salzen oder ein Gemisch aus diesen als Wirkstoff handelt.■ tolterodine, 5-hydroxymethyltolterodine, their pharmaceutically acceptable salts or a mixture of these acts as an active ingredient.
7. Transdermales therapeutisches System nach Anspruch 6, gekennzeichnet durch eine Matrixschicht auf Basis von Polyacrylat, Silikon, Polyisobutylen, Kautschuk, kautschukähnliche synthetische Homo-, Co- oder Blockpolymere, Butylkautschuk, Styrol/ Isopren- Copolymerisat, Polyurethane, Copolymere des Ethylens, Polysiloxane, Styrol/ Butadien- Copolymerisat oder ein Gemisch aus diesen.7. Transdermal therapeutic system according to claim 6, characterized by a matrix layer based on polyacrylate, silicone, polyisobutylene, rubber, rubber-like synthetic homo-, co- or block polymers, butyl rubber, styrene / isoprene copolymer, polyurethanes, copolymers of ethylene, polysiloxanes, Styrene / butadiene copolymer or a mixture of these.
8. Transdermales therapeutisches System nach Anspruch 3, 4 oder 5, dadurch gekennzeichnet, daß es sich um ein Membransystem mit8. Transdermal therapeutic system according to claim 3, 4 or 5, characterized in that it is a membrane system with
■ einer undurchlässigen Deckschicht,An impermeable cover layer,
■ einem wirkstoffhaltigen Reservoir oder einer wirkstoffhaltigen Reservoirschicht, ■ einer mikroporösen oder semipermeablen Membran,An active substance-containing reservoir or an active substance-containing reservoir layer, a microporous or semipermeable membrane,
■ einer fakultativen Haftklebeschicht,An optional adhesive layer,
■ Tolterodin, 5-Hydroxymethyltolterodin, deren pharmazeutisch verträglichen Salzen oder ein Gemisch aus diesen als Wirkstoff handelt. 9. Transdermales therapeutisches System nach Anspruch 8, gekennzeichnet durch bekannte Emulgatoren, Verdickungsmittel und/ oder bekannte Membransystem- Hilfsmittel. 10. Transdermales therapeutisches System nach Anspruch 9, gekennzeichnet durch Methylcellulose, Hydroxyethylcellulose, Carboxyvinylpolymer, Natrium- Plyoxlat, Carboxymethylcellulose oder ein Gemisch aus diesen als Verdickungsmittel. 11. Transdermales therapeutisches System nach Anspruch 8, 9 oder 10, gekennzeichnet durch eine Membran auf Basis inerter Polymere, insbesondere Polypropylen, Polyvinylacetat, Polyamid, Ethylen- Vinylacetat- Copolymeren, Silikon oder ein Gemisch aus diesen. ■ tolterodine, 5-hydroxymethyltolterodine, their pharmaceutically acceptable salts or a mixture of these acts as an active ingredient. 9. Transdermal therapeutic system according to claim 8, characterized by known emulsifiers, thickeners and / or known membrane system aids. 10. Transdermal therapeutic system according to claim 9, characterized by methyl cellulose, hydroxyethyl cellulose, carboxy vinyl polymer, sodium plyoxlate, carboxymethyl cellulose or a mixture of these as thickeners. 11. Transdermal therapeutic system according to claim 8, 9 or 10, characterized by a membrane based on inert polymers, in particular polypropylene, polyvinyl acetate, polyamide, ethylene-vinyl acetate copolymers, silicone or a mixture of these.
2. Transdermales therapeutisches System nach einem der vorhergehenden Ansprüche, gekennzeichnet durch einen Permeationsförderer, insbesondere ein- und/oder mehrwertige aliphatische, cycloaliphatische und /oder aromatisch- aliphatische Alkohole mit jeweils bis zu acht C- Atomen; Alkohol/ Wasser- Gemische; gesättigte und/ oder ungesättigte Fettalkohole mit jeweils 8- 18 C- Atomen; Terpene; Gemische aus Terpenen und Etanol und/ oder Propylenglykol; Teebaumöl; gesättigte und/ oder ungesättigte cyclische Ketone; Alkyl- Methylsulfoxide; gesättigte und/ oder ungesättigte Fettsäuren mit jeweils 8- 18 C- Atomen; deren Ester und Salze; natürliches Vitamin E; synthetisches Vitamin E und/ oder Vitamin E- Derivate; Sorbitanfettsäureester und ethoxylierte Sorbitanfettsäureester; Azone (Laurocapram); Azone gemischt mit Alkoholen; Harnstoff; 1 -Alkylpyrrolidon;2. Transdermal therapeutic system according to one of the preceding claims, characterized by a permeation promoter, in particular mono- and / or polyvalent aliphatic, cycloaliphatic and / or aromatic-aliphatic alcohols, each with up to eight C atoms; Alcohol / water mixtures; saturated and / or unsaturated fatty alcohols, each with 8-18 C atoms; terpenes; Mixtures of terpenes and ethanol and / or propylene glycol; tea tree oil; saturated and / or unsaturated cyclic ketones; Alkyl methyl sulfoxides; saturated and / or unsaturated fatty acids, each with 8-18 C atoms; their esters and salts; natural vitamin E; synthetic vitamin E and / or vitamin E derivatives; Sorbitan fatty acid esters and ethoxylated sorbitan fatty acid esters; Azone (laurocapram); Azone mixed with alcohol; Urea; 1-alkyl pyrrolidone;
Blockcopolymere von Polyethylenglykol und Dimethylsiloxan mit kationischer Gruppe an einem Ende; Folat-Polyethylenglykol-Liposom, Proliposom; Polyoxyethylen-10- stearylether; Gemisch aus Polyoxyethylen-10-stearylether und Glyceryldilaurat; Dodecyl-2- (N,N-dimethylamino)-propanoltetradecanoat und/ oder Dodecyl-2-(N,N-dimethylamino)- propianat; N-Acetylprolinatester mit > 8 C-Atomen; nichtionische Tenside; Ester vonBlock copolymers of polyethylene glycol and dimethylsiloxane with a cationic group at one end; Folate polyethylene glycol liposome, proliposome; Polyoxyethylene 10 stearyl ether; Mixture of polyoxyethylene 10 stearyl ether and glyceryl dilaurate; Dodecyl 2- (N, N-dimethylamino) propanol tetradecanoate and / or dodecyl 2- (N, N-dimethylamino) propianate; N-acetylprolinate esters with> 8 C atoms; nonionic surfactants; Esters of
Polyoxyethylen; Ethosom (Phospholipidvesikel); Dimethyl(arylimino)sulfuran; Gemisch aus Ölsäureanaloga und Propylenglykol; Gemisch aus Padimat O, Oktylsalicylat, Oktylmethoxycinnimat, Laurocapram; Isopropylmyristat; Isopropylpalmitat oder ein Gemisch aus Einzelkomponenten. polyoxyethylene; Ethosome (phospholipid vesicle); Dimethyl (arylimino) sulfurane; Mixture of oleic acid analogues and propylene glycol; Mixture of Padimat O, octyl salicylate, octyl methoxycinnimate, laurocapram; isopropyl; Isopropyl palmitate or a mixture of individual components.
EP00951373A 1999-07-13 2000-07-12 Transdermal therapeutic system for the utilization of tolterodine Withdrawn EP1194134A1 (en)

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DE1999132651 DE19932651A1 (en) 1999-07-13 1999-07-13 Transdermal therapeutic system for the application of tolterodine
DE19932651 1999-07-13
PCT/EP2000/006605 WO2001003678A2 (en) 1999-07-13 2000-07-12 Transdermal therapeutic system for the utilization of tolterodine

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EP00951373A Withdrawn EP1194134A1 (en) 1999-07-13 2000-07-12 Transdermal therapeutic system for the utilization of tolterodine

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DE10114382A1 (en) * 2001-03-23 2002-09-26 Beiersdorf Ag Moisture-absorbing material used for plasters, medical fixings, wound coverings and bandages comprises adhesive matrix of silicon, gel former and optionally silicone resin
EP1424079A1 (en) * 2002-11-27 2004-06-02 Boehringer Ingelheim International GmbH Combination of a beta-3-receptor agonist and of a reuptake inhibitor of serotonin and/or norepinephrine
PL2416761T3 (en) 2009-05-11 2015-07-31 Ratiopharm Gmbh Desfesoterodin in the form of a tartaric acid salt
US20130195957A1 (en) * 2010-08-03 2013-08-01 Hisamitsu Pharmaceutical Co., Inc. Patch and method for enhancing adhesion force of the same
CN105536031B (en) * 2016-02-03 2018-12-11 浙江康诚工业产品设计有限公司 A kind of preparation method of the anti-inflammatory antibacterial medical dressing of tea tree oil liposome

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JP2000515525A (en) * 1996-07-19 2000-11-21 アベーグ，グンナー S (-)-tolterodine in the treatment of urinary and gastrointestinal disorders
OA11636A (en) * 1998-08-27 2004-09-03 Pharmacia Ab Therapeutic formulation for administering tolterodine with controlled release.
SE9802864D0 (en) * 1998-08-27 1998-08-27 Pharmacia & Upjohn Ab Transdermally administered tolterodine as an antimuscarinic agent for the treatment of overactive bladder
DE19922662C1 (en) * 1999-05-18 2000-12-28 Sanol Arznei Schwarz Gmbh Transdermal therapeutic system (TTS) containing tolterodine

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DE19932651A1 (en) 2001-01-18
WO2001003678A3 (en) 2001-05-25
WO2001003678A2 (en) 2001-01-18
AU6434000A (en) 2001-01-30

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