WO2002017928A2 - Systeme therapeutique transdermique destine a la delivrance d'exemestane - Google Patents

Systeme therapeutique transdermique destine a la delivrance d'exemestane Download PDF

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Publication number
WO2002017928A2
WO2002017928A2 PCT/EP2001/009530 EP0109530W WO0217928A2 WO 2002017928 A2 WO2002017928 A2 WO 2002017928A2 EP 0109530 W EP0109530 W EP 0109530W WO 0217928 A2 WO0217928 A2 WO 0217928A2
Authority
WO
WIPO (PCT)
Prior art keywords
active substance
transdermal therapeutic
therapeutic system
exemestane
matrix
Prior art date
Application number
PCT/EP2001/009530
Other languages
German (de)
English (en)
Other versions
WO2002017928A3 (fr
Inventor
Thorsten Selzer
Original Assignee
Lts Lohman Therapie-Systeme 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 Lts Lohman Therapie-Systeme Ag filed Critical Lts Lohman Therapie-Systeme Ag
Publication of WO2002017928A2 publication Critical patent/WO2002017928A2/fr
Publication of WO2002017928A3 publication Critical patent/WO2002017928A3/fr

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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
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide

Definitions

  • Transdermal therapeutic system for the delivery of exemestane.
  • the present invention relates to transdermal therapeutic systems with the active substance exemestane or another active substance from the group of the aromatase inhibitors, which enable the administration of this active substance through the skin.
  • the invention further includes the use of such systems for therapeutic treatment.
  • Exemestane is the first oral steroidal aromatase inhibitor to appear on the market after intravenous formestane. It is indicated for the treatment of advanced breast cancer in women with natural or induced postmenopause after progression under anti-estrogen treatment.
  • exemestane When administered orally, exemestane undergoes a pronounced and rapid metabolism during the first intestine-liver passage ("first pass") and has a short plasma half-life.
  • TTS Transdermal therapeutic systems
  • TTS consist of a drug-impermeable backing layer (also called a backing layer), a drug-containing reservoir layer and a pressure-sensitive adhesive layer for attachment to the skin.
  • the latter layer can also be identical to the drug-containing layer.
  • TTS usually point a backing which is also impermeable to the active ingredient and which is to be removed before the application.
  • other components may be present, such as. B. a control membrane limiting the active ingredient be.
  • the drug-containing reservoir layer mostly consists of polymeric basic substances; it can also contain various auxiliaries or additives.
  • the object of the present invention was to provide a dosage form for the active substance exemestane, the use of which avoids the disadvantages associated with the oral administration of exemestane, as described above.
  • Such a dosage form enables a sufficiently high active substance flux in vivo and can be produced inexpensively by means of common manufacturing processes.
  • the invention thus relates to TTS in plaster form for the administration of the active substance exemestane and / or another aromatase heater, which have an active substance-impermeable backing layer, an associated active substance reservoir containing the active substance exemestane, a skin-side pressure-sensitive adhesive layer and a protective layer which is removable before application and has an active substance-impermeable protective layer.
  • the TTS according to the invention enable a constant release of the active substance exemestane to and through the skin over a prolonged application period, which makes this active substance systemically available. That way the relatively rapid elimination of exemestane can be compensated for by constant supply from the drug reservoir of the TTS, and the therapeutic value of drug administration is increased. This is due to the fact that, in the case of transdermal administration, the metabolism of the active substance is prevented during the first intestinal-liver passage ("Fir . St-Pass" effect) and the plasma half-life is thus increased. It also avoids the problems of potentially low peroral availability or insufficient enteral absorption or gastrointestinal intolerance.
  • active ingredients from the aromatase inhibitor group are also suitable, preferably formestane, anasatrozole and letrozole. These active substances can be contained in the active substance reservoir either individually or in combination.
  • the TTS according to the invention can be produced both in the form of matrix systems and in the form of bag reservoir or membrane systems.
  • matrix systems includes not only those systems in which the active ingredient is dissolved in a layered synthetic resin or plastic matrix and is released therefrom, but also those in which the active ingredient is based on fiber material, such as. B. cotton fabric or cotton fleece is adsorbed. This fiber material can be embedded in a plastic or synthetic resin matrix.
  • the active substance reservoir of the TTS according to the invention can also contain various auxiliaries or additives, for example from the group of solvents, solubilizers, plasticizers, permeation improvers, pH regulators, antioxidants and preservatives.
  • the preparation of the TTS according to the invention can be carried out by coarsely, colloidally or molecularly dispersing exemestane in a solution of matrix base polymers and coating the mixture on a suitable base, for example a thermoplastic film provided with a silicone layer.
  • a suitable base for example a thermoplastic film provided with a silicone layer.
  • the active substance-containing matrix layer is covered with another film, which represents the later back layer of the TTS.
  • TTS is produced from such a laminate by punching flat structures in the desired geometric shape and size.
  • Suitable base polymers for the active substance matrix and the pressure-sensitive adhesive layer are polyacrylates, poly (meth) acrylates, polyacrylic acid, cellulose derivatives, in particular methyl and ethyl celluloses, isobutylene, ethylene-vinyl acetate, natural and synthetic rubbers such as styrene-diene copolymers, styrene -Butadiene block copolymers, isoprene block copolymers, acrylonitrile-butadiene rubber, butyl rubber or neoprene rubber, and hot melt adhesive. Silicone-based adhesives can also be used. Suitable mixtures of the polymers mentioned can also advantageously be used.
  • hot melt adhesive includes all adhesives that are not melted by solvents but by melting when high temperatures, for example in the range of 60-200 ° C, can be liquefied.
  • hot melt adhesive z.
  • a particularly preferred embodiment of the invention is characterized in that the active substance exemestane is present in the TTS in combination with a solubilizer, preferably in the dissolved state; a mixture of different solubilizers can also be used.
  • solubilizers are polyhydric alcohols such as 1,2-propanediol, the various butanediols, glycerol, polyethylene glycol 400, tetrahydrofurfuryl alcohol, diethylene glycol monoethyl ether, diethyl toluamide and monoisopropylidene glycerol.
  • 1,2-Propanediol is particularly preferably used.
  • 1,2-propanediol can also promote performance. It has proven to be advantageous that the proportion of the solubilizer (s) is between 1 and 50% by weight, preferably between 5 and 35% by weight, based on the total TTS in the final state after production.
  • Suitable permeation-promoting substances are, in particular, substances from the groups of fatty alcohols, fatty acids, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, fatty alcohol esters and fatty acid esters, in particular sorbitan onolaurate or esters of long-chain fatty acids with methyl, ethyl or isopropyl alcohol, or esters of fatty alcohols with acetic acid or lactic acid. Substances such as oleic acid diethanolamine are also suitable. Polyoxylauryl ethers (Brij ® ) are particularly preferably used.
  • the active substance matrix of the TTS according to the invention can also have a two or more layers, ie. H. it can consist of two or more matrix layers.
  • the different matrix layers can differ in terms of their composition or the concentration of the constituents contained therein.
  • the different matrix layers can have a different polymer composition or consist of different pressure sensitive adhesives.
  • the individual matrix layers can contain different concentrations of active ingredient or additives such as permeation-promoting agents, solubilizers and plasticizers. Depending on the intended application, the concentrations of these ingredients, in particular the
  • Active ingredient concentration in these layers are adjusted so that they become smaller or larger from the inner layer to the layer on the skin side, depending on whether a particular long-term effect or a particularly strong initial effect is desired.
  • customary plasticizers are added to the active substance matrix, or individual layers of this matrix, in a concentration of up to 30% by weight, particularly preferably in a concentration of 5-20% by weight, based in each case on the active substance matrix.
  • Preferred plasticizers are those from the group of hydrocarbons, alcohols, carboxylic acids, derivatives of carboxylic acids, ethers, esters and amines.
  • the drug reservoir on the delivery side can also be provided with a control membrane which has a limited permeability for the drug and controls the delivery of the drug to the skin.
  • the pressure-sensitive adhesive attachment of the TTS according to the invention to the skin can be carried out in various ways.
  • the active substance-containing matrix can itself consist of a pressure-sensitive adhesive and thus establish the connection to the skin, or a separate pressure-sensitive adhesive layer is attached, which takes over this function.
  • a separate pressure-sensitive adhesive layer is attached, which takes over this function.
  • the invention further comprises embodiments in which the active substance reservoir containing exemestane is designed as a bag-shaped reservoir which is filled with a flowable, highly viscous, semi-solid or gel-like matrix which contains the active substance.
  • the active substance reservoir containing exemestane is designed as a bag-shaped reservoir which is filled with a flowable, highly viscous, semi-solid or gel-like matrix which contains the active substance.
  • it can be a polymer matrix, in particular a plastic matrix or a solution thereof. It is particularly advantageous if the active substance reservoir contains a gel former.
  • a drug-permeable membrane can control the drug release. Suitable materials for the production of the bag wall or the control membrane are known to the person skilled in the art.
  • the TTS according to the invention also have a backing layer which is impermeable to the active substance and a removable protective layer or release film which is likewise impermeable to the active substance.
  • Particularly suitable materials for the backing layer are polyesters, which are characterized by particular strength, such as. B. polyethylene terephthalate and polybutylene terephthalate, but also almost any other skin-compatible plastics, such as polyvinyl chloride, ethylene-vinyl acetate copolymers, polyvinyl acetate, polyethylene, polypropylene, polyurethanes, cellulose derivatives and many others.
  • the backing layer can be provided with an additional layer, e.g. B.
  • removable protective layer as for the backing layer, provided that they can be treated by a suitable surface treatment, such as. B. siliconization, is equipped removable.
  • a suitable surface treatment such as. B. siliconization
  • other removable protective layers such as e.g. B. treated with polytetrafluoroethylene
  • Paper or Cellophan ® (cellulose hydrate) can be used.
  • TTS according to the invention with the active ingredient exemestane are advantageously suitable for the treatment of advanced breast cancer in women with natural or induced postmenopause after progression under anti-estrogen treatment.
  • the active substance reservoir contains exemestane in combination with at least one further pharmaceutical active substance; it is preferably a drug with a tumor-inhibiting effect.
  • the invention is illustrated by the following example.
  • the TTS according to the invention can be produced, for example, as follows:
  • exemestane and 20 g of a suitable permeation-promoting substance are dissolved in 200 g of 1,2-propanediol.
  • This solution is introduced into a silicone adhesive (No. 4301; Dow Corning, USA) using a suitable stirring apparatus and dispersed, so that the most homogeneous liquid-liquid dispersion possible.
  • This dispersion is homogeneously applied to a carrier film, e.g. B. from polyethylene terephthalate coated.
  • the solvent of the silicone adhesive and any portions of the propanediol are then removed by controlled drying. Controlled drying means that the coated laminate has a very specific drying temperature,
  • Drying speed or drying time is suspended in order to adjust the intended content of volatile substances (e.g. solubilizers).
  • volatile substances e.g. solubilizers.
  • the laminate obtained in this way is then laminated with a further film of polyethylene terephthalate.
  • TTS are punched out with a certain area and packed in a suitable packaging.

Abstract

L'invention concerne un système thérapeutique transdermique se présentant sous forme de pansement adhésif et destiné à l'administration du principe actif exemestane ou d'un autre principe actif du groupe des inhibiteurs de l'aromatase. Ce système présente une couche externe imperméable au principe actif, un réservoir de principe actif qui est raccordé à cette couche externe et qui contient le principe actif exemestane et/ou un autre principe actif du groupe des inhibiteurs de l'aromatase, une couche adhésive côté peau et une couche de protection qui est imperméable au principe actif et qui s'enlève avant l'application.
PCT/EP2001/009530 2000-08-30 2001-08-18 Systeme therapeutique transdermique destine a la delivrance d'exemestane WO2002017928A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10042411.2 2000-08-30
DE2000142411 DE10042411A1 (de) 2000-08-30 2000-08-30 Transdermales therapeutisches System zur Abgabe von Exemestan

Publications (2)

Publication Number Publication Date
WO2002017928A2 true WO2002017928A2 (fr) 2002-03-07
WO2002017928A3 WO2002017928A3 (fr) 2002-06-27

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DE (1) DE10042411A1 (fr)
WO (1) WO2002017928A2 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009007334A2 (fr) * 2007-07-10 2009-01-15 Braetter Christian Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol
DE102010046464A1 (de) 2009-03-19 2011-04-21 Amw Gmbh Transdermales System mit Aromatasehemmer
DE102010026883A1 (de) 2010-03-11 2011-12-15 Amw Gmbh Transdermales System mit Aromatasehemmer
US9775908B2 (en) 2007-07-10 2017-10-03 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Pharmaceutical preparations containing highly volatile silicones
US10045935B2 (en) 2012-07-31 2018-08-14 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
EP3725300A1 (fr) * 2019-04-18 2020-10-21 AMW GmbH Système d'administration transdermique comprenant des inhibiteurs de l'aromatase
EP3725301A1 (fr) * 2019-04-18 2020-10-21 AMW GmbH Système d'administration transdermique au moyen d'un inhibiteur d'aromatase dans une matrice sursaturée
US11154535B2 (en) 2012-07-31 2021-10-26 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102019201430A1 (de) 2019-02-05 2020-08-06 Lts Lohmann Therapie-Systeme Ag Transdermales Therapeutisches System (TTS) mit Transportmedium
DE102019201431A1 (de) 2019-02-05 2020-08-06 Lts Lohmann Therapie-Systeme Ag Transdermales Therapeutisches System (TTS) mit Feststoffreservoir

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019746A1 (fr) * 1992-04-03 1993-10-14 Orion-Yhtymä Oy Administration topique de toremifene et de ses metabolites
WO1997006788A1 (fr) * 1995-08-14 1997-02-27 Janssen Pharmaceutica N.V. Administration trans-cutanee de vorozole
WO1997029735A1 (fr) * 1996-02-19 1997-08-21 Monash University Promoteurs de penetration dermique et systeme d'administration de medicaments comprenant ces promoteurs
EP0943333A1 (fr) * 1998-03-18 1999-09-22 S.W. Patentverwertungs GmbH Médicament pour la prévention et/ou le traitement du cancer du sein contenant un inhibiteur de la synthèse d'estrogènes
WO2000043553A1 (fr) * 1999-01-26 2000-07-27 Pro-Duct Health, Inc. Identification, surveillance et traitement des femmes presentant un cancer du sein ou un etat precancereux

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9212833D0 (en) * 1992-06-17 1992-07-29 Glaxo Group Ltd Chemical compounds
US5567831A (en) * 1995-08-16 1996-10-22 Duguesne University Of The Holy Ghost Non-steroidal sulfatase inhibitor compounds and their method of use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993019746A1 (fr) * 1992-04-03 1993-10-14 Orion-Yhtymä Oy Administration topique de toremifene et de ses metabolites
WO1997006788A1 (fr) * 1995-08-14 1997-02-27 Janssen Pharmaceutica N.V. Administration trans-cutanee de vorozole
WO1997029735A1 (fr) * 1996-02-19 1997-08-21 Monash University Promoteurs de penetration dermique et systeme d'administration de medicaments comprenant ces promoteurs
EP0943333A1 (fr) * 1998-03-18 1999-09-22 S.W. Patentverwertungs GmbH Médicament pour la prévention et/ou le traitement du cancer du sein contenant un inhibiteur de la synthèse d'estrogènes
WO2000043553A1 (fr) * 1999-01-26 2000-07-27 Pro-Duct Health, Inc. Identification, surveillance et traitement des femmes presentant un cancer du sein ou un etat precancereux

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009007334A2 (fr) * 2007-07-10 2009-01-15 Braetter Christian Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol
WO2009007334A3 (fr) * 2007-07-10 2009-03-12 Christian Braetter Systèmes thérapeutiques transdermiques contenant le principe actif anastrozol
US9775908B2 (en) 2007-07-10 2017-10-03 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Pharmaceutical preparations containing highly volatile silicones
DE102010046464A1 (de) 2009-03-19 2011-04-21 Amw Gmbh Transdermales System mit Aromatasehemmer
DE102010026883A1 (de) 2010-03-11 2011-12-15 Amw Gmbh Transdermales System mit Aromatasehemmer
US10045935B2 (en) 2012-07-31 2018-08-14 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
US11154535B2 (en) 2012-07-31 2021-10-26 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
EP3725300A1 (fr) * 2019-04-18 2020-10-21 AMW GmbH Système d'administration transdermique comprenant des inhibiteurs de l'aromatase
EP3725301A1 (fr) * 2019-04-18 2020-10-21 AMW GmbH Système d'administration transdermique au moyen d'un inhibiteur d'aromatase dans une matrice sursaturée

Also Published As

Publication number Publication date
WO2002017928A3 (fr) 2002-06-27
DE10042411A1 (de) 2002-03-28

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