EP0967972A1 - Extendible transdermal therapeutic system - Google Patents

Extendible transdermal therapeutic system

Info

Publication number
EP0967972A1
EP0967972A1 EP98908021A EP98908021A EP0967972A1 EP 0967972 A1 EP0967972 A1 EP 0967972A1 EP 98908021 A EP98908021 A EP 98908021A EP 98908021 A EP98908021 A EP 98908021A EP 0967972 A1 EP0967972 A1 EP 0967972A1
Authority
EP
European Patent Office
Prior art keywords
layer
therapeutic system
transdermal therapeutic
skin
backing layer
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Withdrawn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
EP98908021A
Other languages
German (de)
French (fr)
Inventor
Michael Horstmann
Walter Müller
Wolfgang Laux
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.)
Horstmann Michael
Original Assignee
LTS Lohmann 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 Lohmann Therapie Systeme AG filed Critical LTS Lohmann Therapie Systeme AG
Publication of EP0967972A1 publication Critical patent/EP0967972A1/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Withdrawn legal-status Critical Current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
    • 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
    • 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
    • A61K9/7076—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/18—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing inorganic materials

Definitions

  • the invention relates to an active substance-containing transdermal therapeutic system with a non-sticky backing layer, a reservoir layer containing an active substance and a self-adhesive surface facing the skin, optionally with a releasable protective layer.
  • TTS Transdermal therapeutic systems
  • an essentially impermeable, non-adhesive backing layer is used.
  • transdermal therapeutic systems are intended to adhere to the skin, the layer facing the skin, sometimes only a part of the contour, is provided with a self-adhesive finish.
  • the backing layer usually consists of pharmaceutically common materials such as plastic films; but also paper, nonwovens, textiles and metal foils are mentioned.
  • the surface-stable active substance-impermeable back layer means that the patient is comfortable to wear: due to the "stiffness" or lack of elasticity of the foils used, there is practically a limitation to surface sizes of around 40 cm 2 .
  • the area-related transport rate through the skin is very low for most pharmaceutical active ingredients, a larger system area would be very desirable in order to be able to offer marketable TTS for such active ingredients.
  • Attempts have already been made to improve the wearing comfort by using elastic materials for the backing layer e.g. US Pat. No. 5,246,705), however, special attention has been paid to the impermeability of the material to the notified drug.
  • the object of the invention is to provide a transdermal therapeutic system with an elastic or plastically stretchable backing layer, which has an improved stabilization of the active ingredient against evaporation compared to the prior art.
  • TTS of the type mentioned at the outset, which is characterized by an elastic or plastically stretchable diffusible backing layer with a metal layer formed by layer growth, in particular metal vapor deposition layer, which acts as a passage barrier for auxiliaries and active substances of the reservoir layer.
  • the elastic and therefore active substance-permeable backing layer comprises a metal layer formed by layer growth (sputtering, cutting, etc.), in particular a zone of vapor-deposited metal, which acts as a barrier sufficient for auxiliaries and active ingredients without preventing the desired stretching behavior of the backing layer.
  • layer thicknesses of the metal layer in the range from 50 to 1500 ⁇ , in particular from 100 to 300 ⁇ .
  • desired area size of the TTS plays a certain role.
  • Aluminum vapor deposition layers, the production of which is generally well known per se, are particularly preferred.
  • WO 91-11752 describes an estradiol TTS, for the rear layer of which a large number of materials are specified, which also comprises flexible plastic films with Al vapor deposition.
  • this teaching in no way leads to the realization that the inclusion of a metal layer which is highly volatile as a barrier to loss of active ingredient and which allows the extensibility of the backing layer in the surface, in particular Al layer, in an elastic backing layer to achieve particularly suitable transdermal therapy systems.
  • the metal layer not only Prevents losses due to evaporation, but at the same time offers protection against the harmful effects of light on light-sensitive substances and components.
  • the metallization according to the invention in particular the aluminization of the backing layer, is not a self-contained, uniform, foil-like metal structure, but rather submicroscopic crystallites are inserted into the surface, which greatly restrict the incidence of light and diffusion, but a sufficient flexibility of the material in allow the area.
  • the backing layer is diffusible and contains at least one third of the amount of active substance contained in the preparation.
  • the backing layer has a dual function as part of the drug reservoir and at the same time as an element of mechanical strength and to avoid external jamming.
  • the aluminization is advantageously applied to the side of the backing layer facing the skin in order to avoid abrasion due to surface abrasion on the TTS. Since the active ingredient contained in the outermost surface of the backing layer decomposes particularly in the case of light influences Exposure to light may also make sense to limit the backing layer to an extremely thin polymer layer and to include a further zone that improves the tensile strength (supporting layer) between the now very thin backing layer and the remaining elements of the transdermal therapeutic system.
  • the invention can basically be used with all skin-active pharmaceutical ingredients. Of course, their use with volatile active substances and auxiliaries is particularly advantageous. Such substances are, for example, nicotine or nitroglycerin as examples of active pharmaceutical ingredients. Ethanol, propanediol and other low molecular weight alcohols, menthol, eucalyptol, limonene and many other terpenes, low molecular weight fatty acids such as B. capric acid, dimethyl sulfoxide may be mentioned as an example of typical additives in such preparations, which could migrate more or less strongly through the backing layer from the preparation.
  • transdermal therapeutic system Apart from the backing layer which is permeable to the active ingredient and which contains the active ingredient and which contains the protective layer of metal vapor deposition and any support layer which may be present, the further structure of the transdermal therapeutic system is not critical for achieving the purpose according to the invention. Any type of transdermal system can therefore be used, whether it is a single or multilayer matrix system, structures with single brought fibrous preparations containing active substance, real reservoir systems with a liquid active substance reservoir or systems of another type.
  • polyvinyl alcohol polyvinyl alcohol
  • styrene-diene block copolymers polyurethanes
  • polyvinyl chloride polymethacrylates
  • an additional adhesive layer that is adhesive, adhesive and removable after application, which can be removed after the system has been applied.
  • the mass is coated in a gap width of approx. 250 ⁇ on a polyester film which has been provided with a dehumidifier in such a way that, after drying for 4 hours at 35 ° C., a uniform layer with a weight per unit area of 50 g / m 2 is formed.
  • the mass is coated in a gap width of approximately 150 .mu.m on a polyester film which has been provided with a seal so that after half an hour of drying at 35.degree. C. and a further 15 minutes of drying at 60.degree. C., a uniform layer with a weight per unit area of 35 g / m 2 is formed.
  • phase A and phase B produced in this way are laminated together and spontaneously adhere to a manually non-detachable bond.
  • the dehumidified polyester film from phase B and the adhesive layer and the backing layer are punched out in a manner known to the person skilled in the art in a contour corresponding to the geometric shape of the preparation, and the residues lying outside are removed.
  • the dosage form is packaged individually in sealed bags. The user removes the drug from the packaging, removes the protective layer (release liner) for the adhesive layer, sticks the dosage form on a suitable skin area and finally removes the support layer (polyester film with adhesive).

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Dermatology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Botany (AREA)
  • Inorganic Chemistry (AREA)
  • Hematology (AREA)
  • Materials Engineering (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a transdermal therapeutic system containing active ingredients, comprising a non-adhesive back layer, a reservoir layer containing active ingredients and a self-adhesive surface layer facing the skin, which possibly has a detachable protective layer. Said therapeutic system is characterized in that it has an elastic, or plastically extendible, diffusible back layer with a metal coating, in particular one made of vaporized metal, formed by layer growth, which serves as a permeable barrier for active ingredients and additives contained in the reservoir layer.

Description

Dehnbares transdermales therapeutisches System Stretchy transdermal therapeutic system
Die Erfindung bezieht sich auf ein wirkstoffhaltiges transdermales therapeutisches System mit einer nicht klebrigen Rückschicht, einer irkstoffhaltigen Reservoirschicht und einer der Haut zugewandten selbstklebenden Oberfläche, gegebenenfalls mit wiederlösbarer Schutzschicht.The invention relates to an active substance-containing transdermal therapeutic system with a non-sticky backing layer, a reservoir layer containing an active substance and a self-adhesive surface facing the skin, optionally with a releasable protective layer.
Bereits seit dem Mittelalter ist es bekannt, daß pharmazeutische Wirkstoffe durch die menschliche Haut hindurchwan- dern können und somit durch Auflegen oder Aufstreichen von Zubereitungen aus pharmazeutischen Wirkstoffen auf die Haut arzneiliche Wirkungen erreichbar sind. Diese Wirkungen sind nicht auf die Haut und das darunterliegende Gewebe beschränkt, sondern können sich bei entsprechend geeigneten Substanzen auf fernliegende Organe erstrecken, da die Wirkstoffe nach der Aufnahme über den Blutkreislauf verteilt werden.It has been known since the Middle Ages that active pharmaceutical ingredients can migrate through human skin and thus medicinal effects can be achieved by placing or spreading preparations made from active pharmaceutical ingredients on the skin. These effects are not limited to the skin and the underlying tissue, but can extend to distant organs if the substances are suitable, since the active substances are distributed via the bloodstream after absorption.
Transdermale therapeutische Systeme (TTS), welche neben der angewandten Wirkstoffkonzentration auch die Applikations- fläche genau definieren, haben sich in der Vergangenheit als neue pharmazeutische Darreiσhungsformen etabliert, da sie die gewünschten Eigenschaften besonders anwendungs- freundlich bereitstellen. Zwischen den möglichen Ausführungsformen von TTS gibt es einige grundsäztliehe Gemeinsamkeiten:Transdermal therapeutic systems (TTS), which in addition to the active substance concentration also precisely define the application area, have established themselves in the past as new pharmaceutical forms of administration because they provide the desired properties in a particularly user-friendly manner. There are some basic similarities between the possible embodiments of TTS:
1. Zum Schutz vor der unerwünschten Abgabe von Wirkstoff oder auch Hautfeuchtigkeit durch das transdermale therapeutische System nach außen, des weiteren auch zum Schutz vor dem Ankleben an Textilien, wird eine im wesentlichen undurchlässige, nichtklebende Rückschicht verwendet.1. To protect against the unwanted release of active substance or skin moisture through the transdermal therapeutic system to the outside, and also to protect against sticking to textiles, an essentially impermeable, non-adhesive backing layer is used.
2. Da transdermale therapeutische Systeme auf der Haut haften sollen, wird die der Haut zugewandte Schicht, zuweilen auch nur ein Teil der Kontur, selbstklebend ausgerüstet.2. Since transdermal therapeutic systems are intended to adhere to the skin, the layer facing the skin, sometimes only a part of the contour, is provided with a self-adhesive finish.
3. Wegen der selbstklebenden Eigenschaften ist zur Lagerung vor Gebrauch eine wiederablösbare Schutzschicht aufgebracht .3. Because of the self-adhesive properties, a removable protective layer is applied for storage before use.
Die Rückschicht besteht in der Regel aus pharmazeutisch üblichen Materialien wie Kunststoffolien; aber auch Papier, Vliesstoffe, Textilien und Metallfolien werden genannt.The backing layer usually consists of pharmaceutically common materials such as plastic films; but also paper, nonwovens, textiles and metal foils are mentioned.
Solche TTS sind trotz des gewonnenen Fortschrittes dennoch auch mit einigen Nachteilen behaftet. So bedeutet die flächenstabile wirkstoffundurchlässige Rückschicht eine Einschränkung des Tragekomforts beim Patienten: Durch die "Steifheit" bzw. mangelnde Dehnbarkeit der verwendeten Folien resultiert praktisch eine Limitierung auf Flächengrößen um 40 cm2. Da nun jedoch die flächenbezogene Transportrate durch die Haut für die meisten pharmazeutischen Wirkstoffe sehr gering ist, wäre eine größere Systemfläche sehr wünschenswert, um auch für solche Wirkstoffe marktfähige TTS anbieten zu können. Es gab bereits Versuche, den Tragekomfort durch Verwendung elastischer Materialien für die Rückschicht zu verbessern (z. B. US-PS 5 246 705), jedoch wurde dabei ausdrücklich auf die Undurchlässigkeit des Materials für den avisierten Arzneistoff geachtet.Despite the progress made, such TTS still have some disadvantages. The surface-stable active substance-impermeable back layer means that the patient is comfortable to wear: due to the "stiffness" or lack of elasticity of the foils used, there is practically a limitation to surface sizes of around 40 cm 2 . However, since the area-related transport rate through the skin is very low for most pharmaceutical active ingredients, a larger system area would be very desirable in order to be able to offer marketable TTS for such active ingredients. Attempts have already been made to improve the wearing comfort by using elastic materials for the backing layer (e.g. US Pat. No. 5,246,705), however, special attention has been paid to the impermeability of the material to the notified drug.
Grundsätzlich sind leider alle elastischen und plastisch- dehnbaren, für die TTS-Rückschicht geeigneten Polymerrohstoffe für die meisten TTS-Wirkstoffe diffusibel, so daß damit hergestellte transdermale therapeutische Systeme generell das Problem potentieller Wirkstoffverluste (Verdampfung über die Außenfläche der Rückschicht) aufweisen, insbesondere, wenn sehr stark flüchtige Wirkstoffe eingesetzt werden.In principle, unfortunately, all elastic and plastically stretchable polymer raw materials suitable for the TTS backing layer are diffusible for most TTS active ingredients, so that transdermal therapeutic systems thus produced generally have the problem of potential loss of active ingredients (evaporation via the outer surface of the backing layer), especially if very volatile active ingredients are used.
Aufgabe der Erfindung ist die Bereitstellung eines trans- dermalen therapeutischen Systems mit elastischer bzw. plastisch dehnbarer Rückschicht, die eine gegenüber dem Stand der Technik verbesserte Stabilisierung des enthaltenen Wirkstoffs gegen Verdampfung aufweist.The object of the invention is to provide a transdermal therapeutic system with an elastic or plastically stretchable backing layer, which has an improved stabilization of the active ingredient against evaporation compared to the prior art.
Diese Aufgabe wird erfindungsgemäß bei einem TTS der eingangs genannten Art gelöst, das gekennzeichnet ist durch eine elastische bzw. plastisch dehnbare diffusible Rückschicht mit einer als Durchlaßbarriere für Hilfs- und Wirkstoffe der Reservoirschicht wirksamen, durch Schichtwachstum gebildeten Metallschicht, insbesondere Metallbedamp- fungsschicht. Weitere Besonderheiten ergeben sich aus den Unteransprüchen und der Beschreibung.This object is achieved according to the invention in a TTS of the type mentioned at the outset, which is characterized by an elastic or plastically stretchable diffusible backing layer with a metal layer formed by layer growth, in particular metal vapor deposition layer, which acts as a passage barrier for auxiliaries and active substances of the reservoir layer. Further special features result from the subclaims and the description.
Erfindungsgemäß umfaßt die elastische und mithin wirkstoffdurchlässige Rückschicht eine durch Schichtwachstum (Aufsputtern, Abschneiden etc.) gebildete Metallschicht, insbesondere Zone aufgedampften Metalls, die als Barriere für Hilfs- und Wirkstoffe ausreicht, ohne das angestrebte Dehnungsverhalten der Rückschicht zu unterbinden.According to the invention, the elastic and therefore active substance-permeable backing layer comprises a metal layer formed by layer growth (sputtering, cutting, etc.), in particular a zone of vapor-deposited metal, which acts as a barrier sufficient for auxiliaries and active ingredients without preventing the desired stretching behavior of the backing layer.
Diese Eigenschaften werden insbesondere mit Schichtdicken der Metallschicht im Bereich von 50 bis 1500 Ä, insbesondere von 100 bis 300 Ä erreicht. Dabei spielt selbstverständlich die gewünschte Flächengröße des TTS eine gewisse Rolle. Besonders bevorzugt werden Aluminium-Aufdampfschichten, deren Herstellung an sich allgemein gut bekannt ist.These properties are achieved in particular with layer thicknesses of the metal layer in the range from 50 to 1500 Å, in particular from 100 to 300 Å. Of course, the desired area size of the TTS plays a certain role. Aluminum vapor deposition layers, the production of which is generally well known per se, are particularly preferred.
Bekannt ist auch im TTS-Bereich die Abscheidung von sehr dünnen (8 Ä) AI-Schichten auf einem 25 μm LDPE-Film, der als Träger bzw. Rückschicht für eine arzneistoffhaltige Klebschicht mit Pflanzenextrakt-Wirkstoffen dienen soll ( P 53 10560 A) . Eine solche sehr dünne Abscheidung wäre jedoch für die erfindungsgemäß angestrebte Wirkung nicht ausreichend.It is also known in the TTS field to deposit very thin (8 Å) Al layers on a 25 μm LDPE film, which is to serve as a carrier or backing layer for a drug-containing adhesive layer with plant extract active ingredients (P 53 10560 A). Such a very thin deposition would, however, not be sufficient for the effect sought according to the invention.
Ferner wird in der WO 91-11752 ein Estradiol-TTS beschrieben, für dessen Rückschicht eine Vielzahl von Materialien angegeben wird, die auch flexible Kunststoff-Filme mit Al- Bedampfung umfaßt. Diese Lehre führt jedoch keineswegs zu der Erkenntnis, daß durch die Einbeziehung einer als Barriere für Wirkstoffverluste stark flüchtiger Substanzen wirksamen, die Dehnbarkeit der Rückschicht in der Fläche gestattenden Metallschicht, insbesondere Al-Schicht, in eine elastische Rückschicht besonders geeignete Transdermaltherapiessysteme erzielt werden können.Furthermore, WO 91-11752 describes an estradiol TTS, for the rear layer of which a large number of materials are specified, which also comprises flexible plastic films with Al vapor deposition. However, this teaching in no way leads to the realization that the inclusion of a metal layer which is highly volatile as a barrier to loss of active ingredient and which allows the extensibility of the backing layer in the surface, in particular Al layer, in an elastic backing layer to achieve particularly suitable transdermal therapy systems.
Erfindungsgemäß gelingt es tatsächlich und überraschend, die vorteilhafte Eigenschaft der größeren Nachgiebigkeit des transdermalen therapeutischen Systeme in der Fläche mit einer ausreichenden Stabilität auch bei problematischen Wirkstoffen zu verbinden, da die Metallschicht nicht nur Verluste durch Abdampfen verhindert, sondern gleichzeitig einen Schutz gegen schädliche Lichteinwirkung auf lichtempfindliche Wirkstoffe und Komponenten bietet.According to the invention, it is actually and surprisingly possible to combine the advantageous property of the greater flexibility of the transdermal therapeutic system in the area with sufficient stability even with problematic active substances, since the metal layer not only Prevents losses due to evaporation, but at the same time offers protection against the harmful effects of light on light-sensitive substances and components.
Der Schutz vor Lichteinflüssen ist bei klassischen transdermalen Systemen, welche eine wirkstoffundurchlässige dehnungssteife Rückschicht aufweisen, durch eine außenseitig aufgebrachte lichtundurchlässige pigmenthaltige Lackierung möglich. Dieses Verfahren ist jedoch bei elastischen Folien nicht einsetzbar, da die mechanisch starren Lacksysteme bei Dehnung abplatzen oder zumindest rissig werden. Bei der erfindungsgemäßen Metallisierung, insbesondere Alu- minisierung der Rückschicht handelt es sich nicht um einen in sich geschlossenen, einheitlichen, folienartigen Metallverband, sondern es werden submikroskopische Kristallite in die Oberfläche eingefügt, welche Lichteinfall und Diffusion stark einschränken, aber eine genügende Nachgiebigkeit des Materials in der Fläche zulassen.Protection against the effects of light is possible with classic transdermal systems, which have an active substance-impermeable, stretch-resistant backing layer, by means of an opaque pigment-containing coating applied on the outside. However, this method cannot be used with elastic films, since the mechanically rigid coating systems flake off or at least become cracked when stretched. The metallization according to the invention, in particular the aluminization of the backing layer, is not a self-contained, uniform, foil-like metal structure, but rather submicroscopic crystallites are inserted into the surface, which greatly restrict the incidence of light and diffusion, but a sufficient flexibility of the material in allow the area.
Damit erscheint die Erfindung auch nützlich für ein in der Zwischenzeit beschriebenes TTS, bei dem die Rückschicht diffusibel ist und mindestens ein Drittel der in der Zubereitung enthaltenen Wirkstoffmenge enthält. Bei diesen Systemen (deutsche Patentanmeldung P 195 46 024.3) übernimmt die Rückschicht eine Doppelfunktion als Teil des Arzneimittel-reservoirs und gleichzeitig als Element der mechanischen Festigkeit sowie zur Vermeidung von Verklβbungen nach außen.The invention thus also appears to be useful for a TTS described in the meantime, in which the backing layer is diffusible and contains at least one third of the amount of active substance contained in the preparation. In these systems (German patent application P 195 46 024.3), the backing layer has a dual function as part of the drug reservoir and at the same time as an element of mechanical strength and to avoid external jamming.
Bei der praktischen Realisierung wird die Aluminisierung vorteilhafterweise auf die der Haut zugewandte Seite der Rückschicht aufgebracht, um einen Abrieb durch Oberflächenabrasion am TTS zu vermeiden. Da insbesondere im Falle von Lichteinflüssen die in der äußersten Oberfläche der Rückschicht enthaltenen Wirkstoffanteile der Zersetzung durch Licht ausgesetzt sind, kann es weiterhin sinnvoll sein, die Rückschicht auf eine extrem dünne Polymerschicht zu begrenzen und zwischen der nunmehr sehr dünnen eigentlichen Rückschicht und den restlichen Elementen des transdermalen therpeutisehen Systems eine weitere, die Zugfestigkeit verbessernde Zone (Stützschicht) , einzubeziehen.In practical implementation, the aluminization is advantageously applied to the side of the backing layer facing the skin in order to avoid abrasion due to surface abrasion on the TTS. Since the active ingredient contained in the outermost surface of the backing layer decomposes particularly in the case of light influences Exposure to light may also make sense to limit the backing layer to an extremely thin polymer layer and to include a further zone that improves the tensile strength (supporting layer) between the now very thin backing layer and the remaining elements of the transdermal therapeutic system.
Die Erfindung ist grundsätzlich mit allen hautgängigen pharmazeutischen Wirkstoffen nutzbar. Besonders vorteilhaft ist selbstverständlich ihre Anwendung bei flüchtigen Wirkstoffen und Hilfsstoffen. Solche Stoffe sind zum Beispiel Nicotin oder Nitroglycerin als Beispiele für pharmazeutische Wirkstoffe. Ethanol, Propandiol und andere niedermolekulare Alkohole, Menthol, Eucalyptol, Limonen und viele andere Terpene, niedermolekulare Fettsäuren wie z. B. Caprin- säure, Dimethylsulfoxid seien exemplarisch für typische Zusatzstoffe in solchen Zubereitungen genannt, die mehr oder weniger stark durch die Rückschicht aus der Zubereitung herauswandern könnten.The invention can basically be used with all skin-active pharmaceutical ingredients. Of course, their use with volatile active substances and auxiliaries is particularly advantageous. Such substances are, for example, nicotine or nitroglycerin as examples of active pharmaceutical ingredients. Ethanol, propanediol and other low molecular weight alcohols, menthol, eucalyptol, limonene and many other terpenes, low molecular weight fatty acids such as B. capric acid, dimethyl sulfoxide may be mentioned as an example of typical additives in such preparations, which could migrate more or less strongly through the backing layer from the preparation.
Weiterhin ergeben sich besondere Vorteile bei Anwendung lichtempfindlicher Substanzen, die bei zahlreichen organisch-chemischen Wirkstoffgruppen auftreten, wie z. B. Phe- nothiazinen, bestimmten Peptiden, Dihydropyridinen ( z. B. Nifedipin) , Opioiden und zahlreichen anderen Wirkstoffgruppen.Furthermore, there are special advantages when using light-sensitive substances that occur in numerous organic chemical active ingredient groups, such as. B. phenothiazines, certain peptides, dihydropyridines (z. B. nifedipine), opioids and numerous other drug groups.
Von der wirkstoffdurchlässigen und den Wirkstoff enthaltenden Rückschicht abgesehen, welche die Schutzschicht aus Metallbedampfung enthält, und einer gegebenenfalls vorhandenen Stützschicht, ist der weitere Aufbau des transdermalen therapeutischen Systems nicht kritisch für die Erzielung des erfindungsgemäßen Zweckes. Es können daher transdermale Systeme jeglicher Bauart eingesetzt werden, mag es sich um ein- oder mehrschichtige MatrixsySterne, Aufbauten mit ein- gebrachten wirkstoffhaltigen faserförmigen Zubereitungen, echte Reservoirsysteme mit flüssigem wirkstoffhaltigem Reservoir oder um Systeme anderer Bauart handeln.Apart from the backing layer which is permeable to the active ingredient and which contains the active ingredient and which contains the protective layer of metal vapor deposition and any support layer which may be present, the further structure of the transdermal therapeutic system is not critical for achieving the purpose according to the invention. Any type of transdermal system can therefore be used, whether it is a single or multilayer matrix system, structures with single brought fibrous preparations containing active substance, real reservoir systems with a liquid active substance reservoir or systems of another type.
Für die Rückschicht sind mehrere, insbesondere für pharmazeutische Produkte akzeptable Materialien grundsätzlich geeignet: Polyvinylalkohol,Styrol-Dien-Blockcopolymere, Polyurethane, Polyvinylchlorid, Polymethacrylate, um nur einige Beispiele zu nennen.For the backing layer, several materials that are particularly acceptable for pharmaceutical products are basically suitable: polyvinyl alcohol, styrene-diene block copolymers, polyurethanes, polyvinyl chloride, polymethacrylates, to name just a few examples.
Es kann durchaus sinnvoll sein, zum Schütze und zur leichteren Applikation des transdermalen therapeutischen Systems auf die Haut eine dehäsiv ausgerüstete, haftende, nach Applikation wieder abnehmbare zusätzliche Stützschicht einzubringen, die nach Auflegen des Systems abgezogen werden kann.To protect and facilitate the application of the transdermal therapeutic system to the skin, it can make sense to apply an additional adhesive layer that is adhesive, adhesive and removable after application, which can be removed after the system has been applied.
Die Erfindung wird im folgenden durch Beispiele erläutert:The invention is illustrated below by examples:
Beispiel 1:Example 1:
A) 10 g Styrol-Isopren-Styrol-Copolymer (CariflexR TR 1107) werden in 20 g Benzin mit einem Siedebereich zwischen 80 und 100°C vollständig gelöst.A) 10 g of styrene-isoprene-styrene copolymer (Cariflex R TR 1107) are completely dissolved in 20 g of gasoline with a boiling range between 80 and 100 ° C.
Die Masse wird in einer Spaltbreite von ca. 250 μ so auf eine dehäsiv ausgerüstete Polyesterfolie beschichtet, daß nach 4-stündiger Trocknung bei 35°C eine gleichmäßige Schicht mit einem Flächengewicht von 50 g/m2 entsteht.The mass is coated in a gap width of approx. 250 μ on a polyester film which has been provided with a dehumidifier in such a way that, after drying for 4 hours at 35 ° C., a uniform layer with a weight per unit area of 50 g / m 2 is formed.
Nach 20-minütiger Nachtrocknung bei 80°C wird im Vakuum eine Aluminiumschicht von 80 mg/m2 aufgebracht. B) In einem getrennten Vorgang wird eine Lösung von 20 g hydriertem Kolophoniu -glycerolesterharz (Staybelite EsterR 5 E) und 7 g Styrol-Isopren-Styrol-Copolymer (CariflexR TR 1107) und 1 g dünnflüssigen Paraffins in 20 g Ethylacetat mit einem Siedebereich zwischen 80 und 100°C angefertigt, in die 0,5 g Nifedipin eingetragen werden, die sich bei Raumtemperatur vollständig auflösen. Die Masse wird in einer Spaltbreite von ca. 150 um so auf eine dehäsiv ausgerüstete Polyesterfolie beschichtet, daß nach halbstündiger Trocknung bei 35°C und 15-minütiger Nachtrocknung bei 60°C eine gleichmäßige Schicht mit einem Flächengewicht von 35 g/m2 entsteht.After drying for 20 minutes at 80 ° C., an aluminum layer of 80 mg / m 2 is applied in vacuo. B) In a separate process, a solution of 20 g of hydrogenated colophony glycerol ester resin (Staybelite Ester R 5 E) and 7 g of styrene-isoprene-styrene copolymer (Cariflex R TR 1107) and 1 g of low-viscosity paraffin in 20 g of ethyl acetate with a Boiling range between 80 and 100 ° C prepared in which 0.5 g of nifedipine are entered, which completely dissolve at room temperature. The mass is coated in a gap width of approximately 150 .mu.m on a polyester film which has been provided with a seal so that after half an hour of drying at 35.degree. C. and a further 15 minutes of drying at 60.degree. C., a uniform layer with a weight per unit area of 35 g / m 2 is formed.
Die so hergestellten Schichten aus Phase A und Phase B werden durch Kaschieren aufeinandergebracht und haften spontan zu einem manuell nicht lösbaren Verbund. Die dehäsiv ausgerüstete Polyesterfolie aus Phase B und die Klebschicht sowie die Rückschicht werden in dem Fachmann bekannter Weise in einer der geometrischen Form der Zubereitung entsprechenden Kontur gestanzt und die außenliegenden Reste entfernt .The layers of phase A and phase B produced in this way are laminated together and spontaneously adhere to a manually non-detachable bond. The dehumidified polyester film from phase B and the adhesive layer and the backing layer are punched out in a manner known to the person skilled in the art in a contour corresponding to the geometric shape of the preparation, and the residues lying outside are removed.
Die Arzneiform wird einzeln in Siegelbeutel verpackt . Der Anwender entnimmt das Arzneimittel aus der Verpackung, entfernt die Schutzschicht (Release Liner) für die Klebschicht, klebt die Arzneiform auf eine geeignete Hautstelle und entfernt zuletzt die Stützschicht (dehäsiv ausgerüstete Polyesterfolie) . The dosage form is packaged individually in sealed bags. The user removes the drug from the packaging, removes the protective layer (release liner) for the adhesive layer, sticks the dosage form on a suitable skin area and finally removes the support layer (polyester film with adhesive).

Claims

P A T E N T A N S P R Ü C H E PATENT CLAIMS
1. Wirkstoffhaltiges transdermales therapeutisches System mit einer nicht klebrigen Rückschicht, einer wirkstoffhaltigen Reservoirschicht und einer der Haut zugewandten selbstklebendenOberfläche, ggf. mit wiederablösbarer Schutzschicht, gekennzeichnet durch eine elastische bzw. plastisch dehnbare diffusible Rückschicht mit einer als Durchlaßbarriere für Hilfs- und Wirkstoffe der Reservoirschicht wirksamen, durch Schichtwachstum gebildeten Metall- schicht, insbesondere MetallbedampfungsSchicht.1. Transdermal therapeutic system containing an active substance with a non-sticky backing layer, an active substance-containing reservoir layer and a self-adhesive surface facing the skin, optionally with a removable protective layer, characterized by an elastic or plastically stretchable diffusible backing layer with an effective layer as a passage barrier for auxiliary and active substances of the reservoir layer , metal layer formed by layer growth, in particular metal vapor deposition layer.
2. Transdermales therapeutisches System nach Anspruch 1, σekennzeichnet durch eine Dicke der Metallschicht von 50 - 1500 Ä, insbesondere von 100-300 Ä.2. Transdermal therapeutic system according to claim 1, σ characterized by a thickness of the metal layer of 50 - 1500 Å, in particular 100-300 Ä.
3. Transdermales therapeutisches System nach Anspruch 1 oder 2, gekennzeichnet durch eine Aluminiumschicht als Metallschicht.3. Transdermal therapeutic system according to claim 1 or 2, characterized by an aluminum layer as a metal layer.
4. Transdermales therapeutisches System nach einem der vorangehenden Ansprüche, dadurch gekennzeichnet, daß die Metallschicht auf der hautzugewandten Seite der Rückschicht vorgesehen ist.4. Transdermal therapeutic system according to one of the preceding claims, characterized in that the metal layer is provided on the side of the back layer facing the skin.
5. Transdermales therapeutisches System nach einem der vorangehenden Ansprüche, gekennzeichnet durch eine Gesamt- dicke ("Applikationsdicke" ohne Schutzschicht) von 50-250 um, insbesondere um 100 um.5. Transdermal therapeutic system according to one of the preceding claims, characterized by a total thickness (“application thickness” without protective layer) of 50-250 μm, in particular around 100 μm.
6. Transdermales therapeutisches System nach einem der vorangehenden Ansprüche, dadurch gekennzeichnet, daß die metallisierte Rückschicht auf der hautzugewandten Seite mit einer Stützschicht versehen ist. 6. Transdermal therapeutic system according to one of the preceding claims, characterized in that the metallized back layer is provided on the side facing the skin with a support layer.
EP98908021A 1997-02-11 1998-01-30 Extendible transdermal therapeutic system Withdrawn EP0967972A1 (en)

Applications Claiming Priority (3)

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DE19705138 1997-02-11
DE19705138A DE19705138A1 (en) 1997-02-11 1997-02-11 Stretchy transdermal therapeutic system
PCT/EP1998/000496 WO1998034600A1 (en) 1997-02-11 1998-01-30 Extendible transdermal therapeutic system

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EP (1) EP0967972A1 (en)
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DE19705138A1 (en) 1998-08-13
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CA2279994A1 (en) 1998-08-13
AU6617798A (en) 1998-08-26
JP2001512428A (en) 2001-08-21
US6277400B1 (en) 2001-08-21
WO1998034600A1 (en) 1998-08-13
NO993855D0 (en) 1999-08-10
NO993855L (en) 1999-08-10

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