EP1023053A1 - Transdermal, acetylsalicylic acid-containing therapeutic system with reinforced resorption - Google Patents

Transdermal, acetylsalicylic acid-containing therapeutic system with reinforced resorption

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Publication number
EP1023053A1
EP1023053A1 EP98902976A EP98902976A EP1023053A1 EP 1023053 A1 EP1023053 A1 EP 1023053A1 EP 98902976 A EP98902976 A EP 98902976A EP 98902976 A EP98902976 A EP 98902976A EP 1023053 A1 EP1023053 A1 EP 1023053A1
Authority
EP
European Patent Office
Prior art keywords
limonene
acetylsalicylic acid
therapeutic system
dimethyl isosorbide
transdermal therapeutic
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Withdrawn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
EP98902976A
Other languages
German (de)
French (fr)
Inventor
Michael Horstmann
Gerd Hoffmann
Heinrich Kindel
Theresa Maria Murphy
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.)
LTS Lohmann Therapie Systeme AG
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LTS Lohmann Therapie Systeme AG
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Publication date
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Publication of EP1023053A1 publication Critical patent/EP1023053A1/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Withdrawn legal-status Critical Current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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • 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
    • A61K9/7092—Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs

Definitions

  • the invention relates to a transdermal therapeutic system containing acetylsalicylic acid with an essentially active substance and moisture impermeable back layer, an active substance reservoir and optionally a removable protective layer.
  • TTS Transdermal therapeutic systems
  • Acetylsalicylic acid is a relatively safe drug with a high therapeutic index. It is used as an anti-inflammatory drug in very high doses (over one gram per day), as an antipyretic / analgesic in medium doses (250-500 mg) and as a platelet aggregation inhibitor in low doses (30 to 150 mg per day). Acetylsalicylic acid is a substance that melts at a low temperature (approx. 139 ° C) and is already noticeably volatile at this temperature.
  • Acetylsalicylic acid is susceptible to hydrolysis and transesterification due to the unstable ester grouping.
  • stabilization methods have already been considered, such as elimination of water, alcohols and esters as possible reaction partners for a transesterification or saponification; Add acetic acid or acetic anhydride or adjust pH 2-3.
  • dimethyl isosorbide is also mentioned as a stabilizing solvent.
  • a major obstacle to the development of pharmaceutically active transdermal therapeutic systems containing acetylsalicylic acid is, moreover, the low permeability of the active substance through the skin compared to the high required daily therapeutic dose.
  • Numerous permeation accelerators have therefore already been proposed as additives, such as azones, carboxylic acid esters and surface-active substances Etc.
  • US Pat. No. 5,164,416 also specifies limonene as a permeation-enhancing substance for acetylsalicylic acid, but its use is then restricted to the simultaneous addition of a possibly irritating alkaline additive. Furthermore, the permeation rates achievable for acetylsalicylic acid - following this teaching - are not yet sufficiently high.
  • the transdermal therapeutic system of the type mentioned at the outset is essentially characterized by a content of limonene and Dimethyl isosorbide in a mixing ratio of at least 50:50 (g / g) limonene to dimethyl isosorbide in the active substance range.
  • the principle according to the invention can be used both in matrix systems and in reservoir / membrane systems. It is also irrelevant which polymers, resins and possibly other additives are added, provided the formulation is only suitable for delivering the basic substances acetylsalicylic acid, limonene and dimethylisosorbide to the skin.
  • all three characteristic feedstocks can be dispersed or dissolved in a solution of base polymers, the mixture can be coated on a suitable base, usually a siliconized thermoplastic film, and, after evaporation of the solvent components, possibly reinforced by the addition of heat , are covered with another film, which makes up the back of the transdermal therapeutic system.
  • a suitable base usually a siliconized thermoplastic film
  • another film which makes up the back of the transdermal therapeutic system.
  • a two-layer matrix is formed from a skin-side layer which contains the active ingredient in dispersed or dissolved form and a second skin-facing layer which contains limonene and dimethyl isosorbide in the desired mixing ratio.
  • these design variants are only the simplest of a number of possible system designs known to the person skilled in the art. Of course, matrix systems with more than two layers are possible and additional active ingredients can be provided if necessary.
  • Suitable base polymers for the system according to the invention are in particular acrylate copolymers, styrene / diene copolymers, silicone polymers, mixtures of polyisobutylene with suitable thermoplastic resins. This list is far from complete, but does show the broad applicability of the principle according to the invention.
  • the mixing ratio of limonene to dimethyl isosorbide is in particular in the range from 50:50 to 99: 1, preferably in the range from 85:15 to 95: 5 and especially in the range from 90:10.
  • a limonene fraction which is of the order of magnitude of the acetylsalicyl acid concentration can expediently be provided.
  • the mass is coated on a siliconized polyester film (100 ⁇ m thick) so that a layer of 150 g per m 2 basis weight is formed. Drying is gently achieved by storing in air for 10 hours at room temperature. A further film (polyester film 15 ⁇ m thick) is applied to this matrix by lamination and circular die-cuts of 20 cm 2 in size are produced with punch iron.
  • transdermal therapeutic systems were obtained which, after the siliconized polyester film had been detached, could be applied directly to the skin in order to produce the desired therapeutic effect.
  • a 2.54 cm 2 round fleece disc (cotton) is applied to the adhesive area of the laminate from (2). 8.5 mg of a mixture of 10% (g / g) dimethyl isosorbide and 90% (g / g) limonene, which had been saturated beforehand by stirring for 5 hours at room temperature and then filtering off with acetylsalicylic acid, are dripped onto the fleece disc.
  • Laminate of (1) and fleece disc are covered on the adhesive side with layer (2) so that a sandwich made of polyester film (15 ⁇ m), 52 g / m 2 polyacrylate with acetylsalicylic acid, doped fleece disc 2.54 cm 2 and 93 g / m 2 Polyacrylate with acetylsalicylic acid is formed, which is still covered on the adhesive side by a protective film made of siliconized polyester.
  • Example 3 (comparative example to example 2):
  • Layers 1 and 2 are made according to example 2.
  • a 2.54 cm 2 , round fleece disc (cotton) is applied to the adhesive area of the laminate from (2). 8.5 mg of pure dimethyl isosorbide, which had been saturated beforehand by stirring for 5 hours at room temperature and then filtering with acetylsalicylic acid, are dripped onto the nonwoven disk. Laminate from (1) and fleece disc are punched out in a pattern of 7.10 cm 2 analogously to Example 2. A permeation determination was also carried out on excised rat skin.
  • Example 4 (Comparative example to Example 2)
  • Layers 1 and 2 are made according to example 2.
  • a 2.54 cm 2 round fleece disc (cotton) is applied to the adhesive area of the laminate from (2). 8.5 mg of pure limonene, which had been saturated with acetylsalicylic acid by stirring for 5 hours at room temperature and then filtering off, are dripped onto the nonwoven disk.
  • Laminate from (1) and fleece disc are punched out in a pattern of 7.10 cm 2 analogously to Example 2.
  • a permeation determination was also carried out on excised rat skin. After 48 hours, an average permeation of 253.3 ⁇ g / cm 2 acetylsalicylic acid was found.
  • Example 5 (Comparative example to Example 2)
  • Layers 1 and 2 are made according to example 2.
  • a 2.54 cm 2 round fleece disc (cotton) is applied to the adhesive area of the laminate from (2). No medium is dripped on. Laminate from (1) and fleece disc are punched out in a pattern of 7.10 cm 2 analogously to Example 2. A permeation determination was also carried out on excised rat skin.

Abstract

A transdermal, acetylsalicylic acid-containing therapeutic system has a substantially active substance- and humidity-impervious backing layer, an active substance reservoir and if required a detachable protecting layer. This transdermal therapeutic system is characterised by a limonene and dimethyl isosorbide content in a mixing ratio of at least 50 g limonene for 50 g dimethyl isosorbide in the area of the active substance.

Description

Acetylsalicylsäure enthaltendes transdermales therapeutisches System mit ResorptionsverstärkungTransdermal therapeutic system with absorption enhancement containing acetylsalicylic acid
Die Erfindung bezieht sich auf ein Acetylsalicylsäure enthaltendes transdermales therapeutisches System mit einer im wesentlichen Wirkstoff- und feuchtigkeitsundurchlässigen Rückschicht, einem Wirkstoffreservoir und gegebenenfalls einer wiederablösbaren Schutzschicht.The invention relates to a transdermal therapeutic system containing acetylsalicylic acid with an essentially active substance and moisture impermeable back layer, an active substance reservoir and optionally a removable protective layer.
Transdermale therapeutische Systeme (TTS) sind in der arzneilichen Therapie einer Reihe von Erkrankungen bereits im Markt eingeführt.Transdermal therapeutic systems (TTS) have already been introduced to the market in the medical therapy of a number of diseases.
Auch die grundsätzliche Permeationsfähigkeit des Wirkstoffes Acetylsalicylsäure durch die menschliche Haut und damit die Eignung als Bestandteil von transdermalen therapeutischen Systemen ist bekannt. So beschreiben Rougier et al. (J.Pharm. Sei. 176, 451-454, 1987) bereits die (eher geringe) Abhängigkeit der Acetylsalicylsäure- Aufnahmerate in die Haut vom ausgewählten Hautareal .The basic permeability of the active ingredient acetylsalicylic acid through human skin and thus its suitability as a component of transdermal therapeutic systems is also known. For example, Rougier et al. (J.Pharm. Sei. 176, 451-454, 1987) already show the (rather low) dependence of the rate of acetylsalicylic acid uptake on the skin on the selected area of the skin.
Acetylsalicylsäure ist ein verhältnismäßig sicherer Arzneistoff mit einem hohen therapeutischen Index. In sehr hohen Dosen (über ein Gramm pro Tag) ist es als Antirheu- matikum in Gebrauch, in mittleren Dosen (250-500 mg) als Antipyretikum/Analgetikum und in niedriger Dosierung (30 bis 150 mg pro Tag) als Thrombozytenaggregationshemmer. Acetylsalicylsäure ist eine bereits bei niedriger Temperatur (ca. 139°C) schmelzende Substanz, welche bei dieser Temperatur bereits merklich flüchtig ist.Acetylsalicylic acid is a relatively safe drug with a high therapeutic index. It is used as an anti-inflammatory drug in very high doses (over one gram per day), as an antipyretic / analgesic in medium doses (250-500 mg) and as a platelet aggregation inhibitor in low doses (30 to 150 mg per day). Acetylsalicylic acid is a substance that melts at a low temperature (approx. 139 ° C) and is already noticeably volatile at this temperature.
Acetylsalicylsäure ist wegen der instabilen Estergruppierung anfällig für Hydrolyse und Umesterung. Es wurden da- her bereits unterschiedliche Stabilisierungsmethoden in Erwägung gezogen, wie Elimination von Wasser, Alkoholen und Estern als möglichen Reaktionspartnern einer Umeste- rung oder Verseifung; Zusatz von Essigsäure oder Acetan- hydrid oder die Einstellung von pH 2-3. In der US-PS 4,228,162 wird auch Dimethylisosorbid als stabilisierendes Lösungsmittel genannt.Acetylsalicylic acid is susceptible to hydrolysis and transesterification due to the unstable ester grouping. There were Different stabilization methods have already been considered, such as elimination of water, alcohols and esters as possible reaction partners for a transesterification or saponification; Add acetic acid or acetic anhydride or adjust pH 2-3. In US Pat. No. 4,228,162, dimethyl isosorbide is also mentioned as a stabilizing solvent.
Ein Haupthindernis für die Entwicklung Acetylsalicylsäure enthaltender pharmazeutisch wirksamer transdermaler therapeutischer Systeme stellt im übrigen die im Vergleich zur hohen erforderlichen therapeutischen Tagesdosis geringe Permeabilität des Wirkstoffes durch die Haut dar. Es wurden daher bereits zahlreiche Permeationsbeschleuni- ger als Zusätze vorgeschlagen wie Azone, Carbonsäureester, oberflächenaktive Stoffe etc.A major obstacle to the development of pharmaceutically active transdermal therapeutic systems containing acetylsalicylic acid is, moreover, the low permeability of the active substance through the skin compared to the high required daily therapeutic dose. Numerous permeation accelerators have therefore already been proposed as additives, such as azones, carboxylic acid esters and surface-active substances Etc.
In der US-PS 5,164,416 wird auch Limonen als permeations- verstärkender Stoff für Acetylsalicylsäure angegeben, seine Verwendung ist danach jedoch eingeschränkt auf den gleichzeitigen Zusatz eines möglicherweise irritierenden alkalischen Zusatzstoffes. Weiterhin sind die für Acetylsalicylsäure erreichbaren Permeationsraten - dieser Lehre folgend- noch nicht ausreichend hoch.US Pat. No. 5,164,416 also specifies limonene as a permeation-enhancing substance for acetylsalicylic acid, but its use is then restricted to the simultaneous addition of a possibly irritating alkaline additive. Furthermore, the permeation rates achievable for acetylsalicylic acid - following this teaching - are not yet sufficiently high.
Es wurde nun überraschenderweise festgestellt, daß der kombinierte Zusatz von Limonen und Dimethylisosorbid in bestimmten Mengenverhältnissen zu einer nicht vorhersehbaren erheblichen Verbesserung der Acetylsalicylsäure- Permeation durch die Haut ührt .It has now surprisingly been found that the combined addition of limonene and dimethyl isosorbide in certain proportions leads to an unforeseeable, considerable improvement in the permeation of acetylsalicylic acid through the skin.
Demgemäß ist das erfindungsgemäße transdermale therapeutische System der eingangs genannten Art im wesentlichen gekennzeichnet durch einen Gehalt an Limonen und Dimethylisosorbid im Mischungsverhältnis von zumindest 50 : 50 (g/g) Limonen zu Dimethylisosorbid im irkstoffaktiven Bereich.Accordingly, the transdermal therapeutic system of the type mentioned at the outset is essentially characterized by a content of limonene and Dimethyl isosorbide in a mixing ratio of at least 50:50 (g / g) limonene to dimethyl isosorbide in the active substance range.
Diese Lösung des Problems ist insofern überraschend, als für den Fachmann der Weg zu einer besser bioverfügbaren Arzneiform über gut lösende Grundstoffe führt, während Limonen eine äußere geringe Löslichkeit für Acetylsalicylsäure - selbst bei Zusatz von Dimethylisosorbid - zeigt.This solution to the problem is surprising in that for the person skilled in the art the path leads to a more bioavailable pharmaceutical form via well-dissolving base materials, while limonene shows an external low solubility for acetylsalicylic acid - even when dimethylisosorbide is added.
Besonderheiten der Erfindung ergeben sich aus den Patentansprüchen und der nachfolgenden Beschreibung.Special features of the invention result from the patent claims and the following description.
Das erfindungsgemäße Prinzip kann sowohl in Matrixsystemen wie auch in Reservoir-/Membransystemen genutzt werden. Auch ist es unerheblich, welche Polymere, Harze und eventuell weitere Zusatzstoffe zugesetzt werden, sofern die Formulierung nur geeignet ist, die Grundsubstanzen Acetylsalicylsäure, Limonen und Dimethylisosorbid an die Haut abzugeben.The principle according to the invention can be used both in matrix systems and in reservoir / membrane systems. It is also irrelevant which polymers, resins and possibly other additives are added, provided the formulation is only suitable for delivering the basic substances acetylsalicylic acid, limonene and dimethylisosorbide to the skin.
Im einfachsten Falle können alle drei kennzeichnenden Einsatzstoffe in einer Lösung von Grundpolymeren disper- giert oder aufgelöst werden, die Mischung auf eine geeignete Unterlage, in der Regel eine siliconisierte thermoplastische Folie, beschichtet werden und nach Abdampfen der Lösemittelanteile, unter Umständen durch Zufuhr von Wärme verstärkt, mit einer weiteren Folie abgedeckt werden, welche die spätere Rückseite des transdermalen therapeutischen Systems ausmacht. Durch Stanzung von flächigen Gebilden in der gewünschten geometrischen Form (Kreis, abgerundetes Rechteck etc.) werden transdermale therapeutische Systeme aus einem solchen Laminat erhalten.In the simplest case, all three characteristic feedstocks can be dispersed or dissolved in a solution of base polymers, the mixture can be coated on a suitable base, usually a siliconized thermoplastic film, and, after evaporation of the solvent components, possibly reinforced by the addition of heat , are covered with another film, which makes up the back of the transdermal therapeutic system. By punching flat structures in the desired geometric shape (circle, rounded rectangle etc.) they become transdermal receive therapeutic systems from such a laminate.
Weitere Ausgestaltungen können aber darin bestehen, daß eine zweischichtige Matrix gebildet wird aus einer haut- seitigen Schicht, welche den Wirkstoff in dispergierter oder gelöster Form enthält, und einer zweiten, hautabge- wandten Schicht, welche Limonen und Dimethylisosorbid in dem angestrebten Mischungsverhältnis enthält. Diese Gestaltungsvarianten sind aber nur die einfachsten aus einer Reihe von möglichen, dem Fachmann bekannten Systemkonzeptionen. So sind selbstverständlich Matrixsysteme mit mehr ab zwei Schichten möglich und gegebenfalls weitere Wirkstoffe vorsehbar.However, further refinements can consist in the fact that a two-layer matrix is formed from a skin-side layer which contains the active ingredient in dispersed or dissolved form and a second skin-facing layer which contains limonene and dimethyl isosorbide in the desired mixing ratio. However, these design variants are only the simplest of a number of possible system designs known to the person skilled in the art. Of course, matrix systems with more than two layers are possible and additional active ingredients can be provided if necessary.
Geeignete Grundpolymere für das erfindungsgemäße System sind insbesondere Acrylatcopolymere, Styrol/ Diencopolymere, Siliconpolymere, Mischungen von Polyiso- butylen mit geeigneten thermoplastischen Harzen. Diese Auflistung ist bei weitem nicht vollständig, läßt aber die breite Anwendungsfähigkeit des erfindungsgemäßen Prinzips erkennen.Suitable base polymers for the system according to the invention are in particular acrylate copolymers, styrene / diene copolymers, silicone polymers, mixtures of polyisobutylene with suitable thermoplastic resins. This list is far from complete, but does show the broad applicability of the principle according to the invention.
Das Mischungsverhältnis von Limonen zu Dimethylisosorbid liegt insbesondere im Bereich von 50:50 bis 99:1, vorzugsweise von 85:15 bis 95:5 und speziell im Bereich von 90:10. Dabei kann zweckmäßigerweise ein Limonenanteil vorgesehen werden, der in der Größenordnung der Acetylsa- licylsäurekonzentration liegt. Beispiel 1 :The mixing ratio of limonene to dimethyl isosorbide is in particular in the range from 50:50 to 99: 1, preferably in the range from 85:15 to 95: 5 and especially in the range from 90:10. A limonene fraction which is of the order of magnitude of the acetylsalicyl acid concentration can expediently be provided. Example 1 :
20 g mikronisierte Acetylsalicylsäure, 30 g Limonen und 1 g Dimethylisosorbid20 g micronized acetylsalicylic acid, 30 g limonene and 1 g dimethyl isosorbide
werden in 600 g einer Acrylatcopolymerlösung (Festkörperanteil: 50 % g/g) aufgelöst bzw. dispergiert.are dissolved or dispersed in 600 g of an acrylate copolymer solution (solids content: 50% g / g).
Die Masse wird auf eine siliconisierte Polyesterfolie (100 um Dicke) so beschichtet, daß eine Schicht von 150 g pro m2 Flächengewicht entsteht. Die Trocknung wird schonend durch 10-stündiges Lagern an der Luft bei Raumtemperatur erreicht. Auf diese so erhaltene Matrix wird eine weitere Folie (Polyesterfolie 15 μm dick) durch Laminie- ren aufgebracht und mit Locheisen kreisförmige Stanzlinge von 20 cm2 Größe erzeugt.The mass is coated on a siliconized polyester film (100 µm thick) so that a layer of 150 g per m 2 basis weight is formed. Drying is gently achieved by storing in air for 10 hours at room temperature. A further film (polyester film 15 μm thick) is applied to this matrix by lamination and circular die-cuts of 20 cm 2 in size are produced with punch iron.
Auf diese Weise wurden transdermale therapeutische Systeme erhalten, die nach Ablösung der siliconisierten Polyesterfolie direkt auf die Haut appliziert werden können, um den gewünschten therapeutischen Effekt zu erzeugen.In this way, transdermal therapeutic systems were obtained which, after the siliconized polyester film had been detached, could be applied directly to the skin in order to produce the desired therapeutic effect.
Beispiel 2:Example 2:
1.) 20 g mikronisierte Acetylsalicylsäure werden in 160 g einer Acrylatcopolymerlösung (Festkörperanteil: 50 % g/g) dispergiert. Die Masse wird auf eine siliconisierte Polyesterfolie (100 μm Dicke ) so beschichtet, daß eine Schicht von 52 g/m2 Flächengewicht entsteht. Die Trocknung wird durch 10-stündiges Lagern an der Luft bei Raumtemperatur erreicht. Auf diese so erhaltene Matrix wird eine weitere Folie (Polyesterfolie 15 μm dick) durch Laminieren aufgebracht. 2.) 20 g mikronisierte Acetylsalicylsäure werden in 160 g einer Acrylatcopolymerlösung (Festkörperanteil: 50 % g/g) dispergiert. Die Masse wird auf eine siliconisierte Polyesterfolie (100 μm Dicke ) so beschichtet, daß eine Schicht von 93 g/m2 Flächengewicht entsteht. Die Trocknung wird durch 10-stündiges Lagern an der Luft bei Raumtemperatur erreicht .1.) 20 g of micronized acetylsalicylic acid are dispersed in 160 g of an acrylate copolymer solution (solids content: 50% g / g). The mass is coated on a siliconized polyester film (100 μm thick) so that a layer of 52 g / m 2 basis weight is formed. Drying is achieved by storing in air at room temperature for 10 hours. A further film (polyester film 15 μm thick) is applied to this matrix by lamination. 2.) 20 g of micronized acetylsalicylic acid are dispersed in 160 g of an acrylate copolymer solution (solids content: 50% g / g). The mass is coated on a siliconized polyester film (100 μm thick) so that a layer of 93 g / m 2 basis weight is formed. Drying is achieved by storing in air at room temperature for 10 hours.
Auf den klebenden Bereich des Laminates aus (2) wird eine 2,54 cm2 große, runde Vliesscheibe (Baumwolle) appli- ziert. 8,5 mg eines Gemisches aus 10 % (g/g) Dimethylisosorbid und 90 % (g/g) Limonen, welches zuvor durch 5- stündiges Rühren bei Raumtemperatur und anschließendes Abfiltrieren mit Acetylsalicylsäure gesättigt wurde, werden auf die Vliesscheibe aufgetropft.A 2.54 cm 2 round fleece disc (cotton) is applied to the adhesive area of the laminate from (2). 8.5 mg of a mixture of 10% (g / g) dimethyl isosorbide and 90% (g / g) limonene, which had been saturated beforehand by stirring for 5 hours at room temperature and then filtering off with acetylsalicylic acid, are dripped onto the fleece disc.
Laminat aus (1) und Vliesscheibe werden klebseitig mit Schicht (2) so abgedeckt, daß ein Sandwich aus Polyester- folie (15 μm) , 52 g/m2 Polyacrylat mit Acetylsalicylsäure, dotierter Vliesscheibe 2,54 cm2 und 93 g/m2 Polyacrylat mit Acetylsalicylsäure entsteht, welches klebseitig noch durch eine dehäsiv wirkende Schutzfolie aus silico- nisiertem Polyester abgedeckt ist.Laminate of (1) and fleece disc are covered on the adhesive side with layer (2) so that a sandwich made of polyester film (15 μm), 52 g / m 2 polyacrylate with acetylsalicylic acid, doped fleece disc 2.54 cm 2 and 93 g / m 2 Polyacrylate with acetylsalicylic acid is formed, which is still covered on the adhesive side by a protective film made of siliconized polyester.
Es werden runde Stanzlinge dieses Laminates mit 7,10 cm2 so gefertigt, daß die Vliesscheibe mittig zu liegen kommt. Nach Aufkleben auf excidierter Rattenhaut wird die Permeation in vitro bestimmt.Round die cuts of this laminate with 7.10 cm 2 are manufactured in such a way that the fleece disc comes to rest in the center. After sticking on excised rat skin, the permeation is determined in vitro.
Es wurde nach 48 Stunden im Mittel eine Permeation von 632,6 μg/cm2 Acetylsalicylsäure festgestellt. Beispiel 3 (Verqleichsbeispiel zu Beispiel 2) :After 48 hours, an average permeation of 632.6 μg / cm 2 of acetylsalicylic acid was found. Example 3 (comparative example to example 2):
Schicht 1 und 2 werden entsprechend Beispiel 2 angefertigt.Layers 1 and 2 are made according to example 2.
Auf den klebenden Bereich des Laminates aus (2) wird eine 2,54 cm2 große, runde Vliesscheibe (Baumwolle) appli- ziert. 8,5 mg reines Dimethylisosorbid, welches zuvor durch 5-stündiges Rühren bei Raumtemperatur und anschließendes Filtrieren mit Acetylsalicylsäure gesättigt wurde, werden auf die Vliesscheibe aufgetropft. Laminat aus (1) und Vliesscheibe werden analog zu Beispiel 2 in Muster von 7,10 cm2 ausgestanzt. Ebenso wurde auch eine Permeationsbestimmung an excidierter Rattenhaut durchgeführt .A 2.54 cm 2 , round fleece disc (cotton) is applied to the adhesive area of the laminate from (2). 8.5 mg of pure dimethyl isosorbide, which had been saturated beforehand by stirring for 5 hours at room temperature and then filtering with acetylsalicylic acid, are dripped onto the nonwoven disk. Laminate from (1) and fleece disc are punched out in a pattern of 7.10 cm 2 analogously to Example 2. A permeation determination was also carried out on excised rat skin.
Es wurde nach 48 Stunden im Mittel eine Permeation von 130,4 μg/cm2 Acetylsalicylsäure festgestellt.After 48 hours, an average permeation of 130.4 μg / cm 2 acetylsalicylic acid was found.
Beispiel 4: (Vergleichsbeispiel zu Beispiel 2)Example 4: (Comparative example to Example 2)
Schicht 1 und 2 werden entsprechend Beispiel 2 angefertigt.Layers 1 and 2 are made according to example 2.
Auf den klebenden Bereich des Laminates aus (2) wird eine 2,54 cm2 große, runde Vliesscheibe (Baumwolle) appli- ziert. 8,5 mg reines Limonen, welches zuvor durch 5- stündiges Rühren bei Raumtemperatur und anschließendes Abfiltrieren mit Acetylsalicylsäure gesättigt wurde, werden auf die Vliesscheibe aufgetropft.A 2.54 cm 2 round fleece disc (cotton) is applied to the adhesive area of the laminate from (2). 8.5 mg of pure limonene, which had been saturated with acetylsalicylic acid by stirring for 5 hours at room temperature and then filtering off, are dripped onto the nonwoven disk.
Laminat aus (1) und Vliesscheibe werden analog zu Beispiel 2 in Muster von 7,10 cm2 ausgestanzt. Ebenso wurde auch eine Permeationsbestimmung an excidierter Rattenhaut durchgeführt . Es wurde nach 48 Stunden im Mittel eine Permeation von 253,3 μg/cm2 Acetylsalicylsäure festgestellt.Laminate from (1) and fleece disc are punched out in a pattern of 7.10 cm 2 analogously to Example 2. A permeation determination was also carried out on excised rat skin. After 48 hours, an average permeation of 253.3 μg / cm 2 acetylsalicylic acid was found.
Beispiel 5: (Verqleichsbeispiel zu Beispiel 2)Example 5: (Comparative example to Example 2)
Schicht 1 und 2 werden entsprechend Beispiel 2 angefertigt.Layers 1 and 2 are made according to example 2.
Auf den klebenden Bereich des Laminates aus (2) wird eine 2,54 cm2 große, runde Vliesscheibe (Baumwolle) appli- ziert. Es wird keinerlei Medium aufgetropft. Laminat aus (1) und Vliesscheibe werden analog zu Beispiel 2 in Muster von 7,10 cm2 ausgestanzt. Ebenso wurde auch eine Permeationsbestimmung an excidierter Rattenhaut durchgeführt.A 2.54 cm 2 round fleece disc (cotton) is applied to the adhesive area of the laminate from (2). No medium is dripped on. Laminate from (1) and fleece disc are punched out in a pattern of 7.10 cm 2 analogously to Example 2. A permeation determination was also carried out on excised rat skin.
Es wurde nach 48 Stunden im Mittel eine Permeation von 52,9 μg/cm2 Acetylsalicylsäure festgestellt.After 48 hours, an average permeation of 52.9 μg / cm 2 acetylsalicylic acid was found.
Ein Vergleich der Permeationsergebnisse der Beispiele 2 bis 5 zeigt deutlich die Überlegenheit des erfindungsgemäßen Systems. A comparison of the permeation results of Examples 2 to 5 clearly shows the superiority of the system according to the invention.

Claims

P A T E N T A N S P R Ü C H E PATENT CLAIMS
1. Acetylsalicylsäure enthaltendes transdermales therapeutisches System mit einer im wesentlichen wirkstoff- und feuchtigkeitsundurchlässigen Rückschicht, einem Wirk- stoffreservoir und gegebenenfalls einer wiederablösbaren Schutzschicht, gekennzeichnet durch einen Gehalt an Limonen und Dimethylisosorbid im Mischungsverhältnis von zumindest 50 : 50 (g/g) Limonen zu Dimethylisosorbid im Wirkstoffaktiven Bereich.1. Transdermal therapeutic system containing acetylsalicylic acid with an essentially active substance and moisture-impermeable back layer, an active substance reservoir and optionally a removable protective layer, characterized by a content of limonene and dimethyl isosorbide in a mixing ratio of at least 50:50 (g / g) limonene to dimethyl isosorbide in the active ingredient area.
2. Transdermales therapeutisches System nach Anspruch 1, gekennzeichnet durch eine ein- oder mehrschichtige Matrix als Wirkstoffreservoir, von der zumindest eine Schicht Limonen und Dimethylisosorbid in einem Mischungsverhältnis von 50:50 bis 99:1 (Limonen zu Dimethylisosorbid) enthält .2. Transdermal therapeutic system according to claim 1, characterized by a single- or multi-layer matrix as the active substance reservoir, of which at least one layer contains limonene and dimethylisosorbide in a mixing ratio of 50:50 to 99: 1 (limonene to dimethylisosorbide).
3. Transdermales therapeutisches System nach Anspruch 1 oder 2, gekennzeichnet durch ein Mischungsverhältnis von Limonen zu Dimethylisosorbid von 85:15 bis 95:5 (g/g), insbesondere 90:10.3. Transdermal therapeutic system according to claim 1 or 2, characterized by a mixing ratio of limonene to dimethyl isosorbide from 85:15 to 95: 5 (g / g), in particular 90:10.
4. Transdermales therapeutisches System nach einem der vorangehenden Ansprüche, dadurch gekennzeichnet, daß Acetylsalicylsäure, Limonen und Dimethylisosorbid im Grundpolymeren gelöst oder dispergiert vorliegen.4. Transdermal therapeutic system according to one of the preceding claims, characterized in that acetylsalicylic acid, limonene and dimethyl isosorbide are dissolved or dispersed in the base polymer.
5. Transdermales therapeutisches System nach einem der vorangehenden Ansprüche, gekennzeichnet durch eine zumindest zweischichtige Matrix, deren hautabgewandte Schicht Limonen und Dimethylisosorbid im genannten Mischungsverhältnis enthält. 5. Transdermal therapeutic system according to one of the preceding claims, characterized by an at least two-layer matrix, the skin-facing layer of which contains limonene and dimethyl isosorbide in the stated mixing ratio.
6. Transdermales therapeutisches System nach einem der vorangehenden Ansprüche, gekennzeichnet durch einen Li o- nenanteil in der Größenordnung der Acetylsalicylsäurekon- zentration. 6. Transdermal therapeutic system according to one of the preceding claims, characterized by a ion fraction in the order of magnitude of the acetylsalicylic acid concentration.
EP98902976A 1997-01-15 1998-01-03 Transdermal, acetylsalicylic acid-containing therapeutic system with reinforced resorption Withdrawn EP1023053A1 (en)

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DE19701059A DE19701059C2 (en) 1997-01-15 1997-01-15 Transdermal therapeutic system with absorption enhancement containing acetylsalicylic acid
DE19701059 1997-01-15
PCT/EP1998/000013 WO1998031348A1 (en) 1997-01-15 1998-01-03 Transdermal, acetylsalicylic acid-containing therapeutic system with reinforced resorption

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DE19949202A1 (en) * 1999-10-13 2001-05-03 Lohmann Therapie Syst Lts Transdermal therapeutic system for the delivery of acetylsalicylic acid and / or salicylic acid
DE19949252B4 (en) * 1999-10-13 2004-02-12 Lts Lohmann Therapie-Systeme Ag Use of a superficial therapeutic system for the topical application of acetylsalicylic acid for the treatment of acne disorders and process for its preparation
DE19959913A1 (en) * 1999-12-11 2001-06-28 Lohmann Therapie Syst Lts Transdermal system for the treatment of migraines containing acetylsalicylic acid
KR100448469B1 (en) * 2001-10-26 2004-09-13 신풍제약주식회사 Transdermal composition and device of anti-inflammatory agents
EP1446104B2 (en) 2001-11-01 2011-08-03 Novartis AG Spray drying methods
DE10338162B3 (en) † 2003-08-20 2005-06-02 Haldex Brake Products Gmbh Method for operating a compressed air procurement system of a motor vehicle and compressed air treatment device
DE102005033543A1 (en) * 2005-07-14 2007-01-18 Grünenthal GmbH A fragrance-containing transdermal therapeutic system
DE102005050431A1 (en) * 2005-10-21 2007-04-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system for the administration of lipophilic and / or less skin-permeable active ingredients
IT202000014578A1 (en) * 2020-06-18 2021-12-18 Poli Md S R L MEDICAL DEVICE INCLUDING ACETYL SALICYLIC ACID

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US4228162A (en) * 1979-07-09 1980-10-14 Research Corporation Dimethyl isosorbide in liquid formulation of aspirin
US5164416A (en) * 1989-02-03 1992-11-17 Lintec Corporation Transdermal therapeutic formulation containing a limonene
DE4332094C2 (en) * 1993-09-22 1995-09-07 Lohmann Therapie Syst Lts Active substance plaster which can be produced without solvent and process for its preparation
DE4332093C2 (en) * 1993-09-22 1995-07-13 Lohmann Therapie Syst Lts Transdermal therapeutic system with the active ingredient acetylsalicylic acid and process for its preparation

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WO1998031348A1 (en) 1998-07-23
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NO993435L (en) 1999-07-12

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