EP1194134A1 - Systeme therapeutique transdermal pour l'utilisation de tolterodine - Google Patents

Systeme therapeutique transdermal pour l'utilisation de tolterodine

Info

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Withdrawn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)
English (en)
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
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 Hexal AG filed Critical Hexal AG
Publication of EP1194134A1 publication Critical patent/EP1194134A1/fr
Withdrawn legal-status Critical Current

Links

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

Landscapes

  • 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

L'invention concerne un système transdermal contenant des agents actifs, destiné à l'utilisation de toltérodine, de 5-Hydroxyméthyltoltérodine, de ses sels pharmaceutiquement neutres, et d'un mélange de ces éléments.
EP00951373A 1999-07-13 2000-07-12 Systeme therapeutique transdermal pour l'utilisation de tolterodine Withdrawn EP1194134A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19932651 1999-07-13
DE1999132651 DE19932651A1 (de) 1999-07-13 1999-07-13 Transdermales therapeutisches System zur Anwendung von Tolterodin
PCT/EP2000/006605 WO2001003678A2 (fr) 1999-07-13 2000-07-12 Systeme therapeutique transdermal pour l'utilisation de tolterodine

Publications (1)

Publication Number Publication Date
EP1194134A1 true EP1194134A1 (fr) 2002-04-10

Family

ID=7914576

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00951373A Withdrawn EP1194134A1 (fr) 1999-07-13 2000-07-12 Systeme therapeutique transdermal pour l'utilisation de tolterodine

Country Status (4)

Country Link
EP (1) EP1194134A1 (fr)
AU (1) AU6434000A (fr)
DE (1) DE19932651A1 (fr)
WO (1) WO2001003678A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10114382A1 (de) * 2001-03-23 2002-09-26 Beiersdorf Ag Feuchtigkeitsaufnehmende Matrix auf Silikonbasis insbesondere zur Wundversorgung und/oder pharmazeutisch/kosmetischen Hautbehandlung
EP1424079A1 (fr) * 2002-11-27 2004-06-02 Boehringer Ingelheim International GmbH Combinaison d'un agoniste du beta-3-récepteur et d'un inhibiteur de recaptage de sérotonine et/ou norépinéphrine
KR20120014583A (ko) 2009-05-11 2012-02-17 라티오팜 게엠베하 타르타르산 염 형태의 데스페소테로딘
US20130195957A1 (en) * 2010-08-03 2013-08-01 Hisamitsu Pharmaceutical Co., Inc. Patch and method for enhancing adhesion force of the same
CN105536031B (zh) * 2016-02-03 2018-12-11 浙江康诚工业产品设计有限公司 一种茶树油脂质体抗炎抑菌医用敷料的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000515525A (ja) * 1996-07-19 2000-11-21 アベーグ，グンナー 尿と胃腸の疾患の治療におけるｓ（―）―トルテロジン
CZ302630B6 (cs) * 1998-08-27 2011-08-10 Pharmacia & Upjohn Ab Farmaceutický prostredek obsahující tolterodin nebo tolterodinu príbuznou slouceninu
SE9802864D0 (sv) * 1998-08-27 1998-08-27 Pharmacia & Upjohn Ab Transdermally administered tolterodine as antimuscarinic agent for the treatment of overactive bladder
DE19922662C1 (de) * 1999-05-18 2000-12-28 Sanol Arznei Schwarz Gmbh Transdermales therapeutisches System (TTS) Tolterodin enthaltend

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0103678A3 *

Also Published As

Publication number Publication date
AU6434000A (en) 2001-01-30
WO2001003678A3 (fr) 2001-05-25
WO2001003678A2 (fr) 2001-01-18
DE19932651A1 (de) 2001-01-18

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