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EP1651215A1 - Transdermaltherapeutic system containing a pramipexol active agent - Google Patents

Transdermaltherapeutic system containing a pramipexol active agent

Info

Publication number
EP1651215A1
EP1651215A1 EP04740987A EP04740987A EP1651215A1 EP 1651215 A1 EP1651215 A1 EP 1651215A1 EP 04740987 A EP04740987 A EP 04740987A EP 04740987 A EP04740987 A EP 04740987A EP 1651215 A1 EP1651215 A1 EP 1651215A1
Authority
EP
European Patent Office
Prior art keywords
active ingredient
pramipexole
tts
tts according
patient
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Withdrawn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
EP04740987A
Other languages
German (de)
French (fr)
Inventor
Frank Theobald
Wolfgang Laux
Beatrix Platt
Regine Kaufmann
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
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
LTS Lohmann Therapie Systeme AG
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical LTS Lohmann Therapie Systeme AG
Publication of EP1651215A1 publication Critical patent/EP1651215A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a transdermal therapeutic system (TTS) for the administration of pramipexole.
  • TTS transdermal therapeutic system
  • a self-adhesive Pramipexol-TTS which is capable of continuously delivering the active ingredient Pramipexol as a base over a longer period of time, preferably 4 to 7 days, to a person who is dependent on a continuous supply with an effective amount of this active ingredient.
  • a transdermal therapeutic system is a layered pharmaceutical dosage form which consists of at least one polymer layer containing an active ingredient and a backing layer which is generally impermeable to the active ingredient.
  • the TTS can also contain other layers, often e.g. B. a membrane controlling the rate of release of the active ingredient, ensuring the adhesion of the TTS to the patient's skin
  • a TTS is capable of delivering the active ingredient continuously and in a controlled manner to the patient's skin. After passing through the various outer layers of the skin, the active pharmaceutical ingredient is absorbed by the underlying blood vessels. Due to the continuous release, particularly uniform plasma levels are obtained. Transdermal administration also has the advantage of bypassing the gastrointestinal tract.
  • the active ingredient pramipexole has the chemical name (S) -2-amino-4,5,6,7-tetrahydro-6- (propylamino) benzothiazole. Chemically speaking, the active substance is a base. He has the CAS registry number. [104632-26-0] and is considered the first non-ergotic, presynaptic dopamine D2 agonist.
  • the active ingredient is available in the form of the hydrochloride as a tablet under the brand names Sifrol ® and Mirapex ® . As such, it is used as a Parkinson's drug and to treat extrapyramidal disorders. Pramipexole is used in idiopathic (without identifiable cause, as it were self-developed) Parkinson's disease both in the early stage and in the advanced stage, here also in combination with levodopa.
  • the individual dose that is optimally matched to the effectiveness and tolerability must first be determined for each patient.
  • This dose titration is usually carried out at weekly intervals, with an amount of pramipexole hydrochloride corresponding to 0.088 mg of pramipexole base being administered three times a day for the first week.
  • an amount of pramipexole hydrochloride equivalent to 0.18 mg of pramipexole base is administered three times a day.
  • an amount of pramipexole hydrochloride equivalent to 0.36 mg of pramipexole base is administered three times a day.
  • the average daily dose generally corresponds to 1.5 mg of pramipexole hydrochloride, which means that 0.36 mg of pramipexole base is administered orally three times a day.
  • Parkinson's disease is a disease of the trunk ganglia that is mainly characterized by movement disorders.
  • pramipexole is also used to treat the so-called restless-Ieg syndrome; compare DE 197 01 619 A1, to which reference is made in full.
  • transdermal therapeutic systems with the active ingredient pramipexol, in particular its (-) enantiomer, and pharmaceutically acceptable acid addition salts.
  • TTS transdermal therapeutic systems
  • EP 428 038 A2 describes transdermal therapeutic systems with an active substance reservoir made from an emulsion-polymerized polyacrylate and 5 to 30% by weight of the active substance pramipexole.
  • Eudragit NE 30 D ® from Röhm GmbH Darmstadt is used as the preferred carrier material.
  • This product is available in the form of an aqueous dispersion of a copolymer with a neutral character based on ethyl acrylate and methyl methacrylate with a dry matter content of 30%. The average molecular weight is 800,000.
  • Films containing active ingredient can be produced from Eudragit NE 30 D ® , but these are not pressure-sensitive adhesives.
  • the active substance-containing reservoirs in special embodiments of these TTS have an area of 20 cm 2 , a thickness of 200 ⁇ m and an active substance content of 9% by weight.
  • the active substance-containing reservoirs provided with a covering plaster for attachment to the skin were able to deliver a daily dose of about 2.5 mg to two test subjects over a period of 3 or 4 days.
  • US Pat. No. 6,465,004 B1 discloses a transdermal therapeutic system which, in addition to the active pharmaceutical ingredient and one or more adhesives, contains cellulose acetate butyrate as a water-insoluble but soluble component. This is an esterified cellulose derivative, which is intended to prevent the crystallization of the active ingredient in the pressure sensitive adhesive.
  • Pramipexole is also considered as an active pharmaceutical ingredient. However, it is not disclosed whether a suitably structured pramipexole TTS is suitable for the continuous administration of the active ingredient over a longer period of time, preferably 4 to 7 days.
  • German patent application DE 10033 853 A1 discloses transdermal therapeutic systems which, in addition to the active pharmaceutical ingredient (including pramipexole) and a matrix material, contain highly disperse silicon dioxide as a further constituent.
  • a pramipexole TTS which is capable of continuously administering an effective amount of this active ingredient over a longer period of time, preferably 4 to 7 days, is not disclosed.
  • the object of the present invention is to provide a self-adhesive transdermal therapeutic system (TTS) which - after determining an individual daily dose - continuously releases the active ingredient pramipexole to the patient in the long-term phase of the therapy without the need for oral administration three times a day Tablet is necessary.
  • TTS self-adhesive transdermal therapeutic system
  • the active ingredient-containing polymer layer or the side of the TTS facing the skin should also be provided with a pressure-sensitive adhesive, so that the use of an additional pressure-sensitive adhesive plaster for fixing on the skin can be dispensed with.
  • the administration of a transdermal therapeutic system should preferably take place in a manner which provides the patient with sufficient active substance for a longer period, preferably for 4 to 7 days.
  • TTS transdermal therapeutic system
  • Such a TTS contains a - preferably active substance-impermeable - backing layer, at least one active substance-containing layer and a protective layer to be removed before use, the active substance-containing layer containing the active substance pramipexole.
  • the S - (-) enantiomer, as well as the? - (+) - enantiomer and a - preferably racemic - mixture of these two enantiomers, preferably the S - (-) enantiomer are referred to as pramipexole understand.
  • pramipexole can be used as the free base, as a hydrate, solvate or pharmaceutically acceptable salt (e.g. as a hydrochloride) in the at least one Active ingredient-containing layer may be included.
  • the use of pramipexole as the S - (-) enantiomer in the form of the free base is particularly preferred.
  • the active substance-containing layer also contains a pressure sensitive adhesive which is capable of securely attaching the TTS to a single point on the skin of the user during the entire application period, preferably from 4 to 7 days.
  • the TTS can also contain further layers, for example a membrane controlling the rate of release of the active ingredient, at least one additional active ingredient-containing layer, at least one support layer to increase the mechanical stability of the TTS and a pressure-sensitive adhesive layer on the side of the TTS facing the skin.
  • Pressure sensitive adhesives that are suitable for the layer containing the active substance and, if applicable, the pressure sensitive adhesive layer located on the side of the TTS facing the skin come from the group of silicones, polyisobutylenes and polyacrylates. Polyacrylates (acrylic pressure sensitive adhesives) without carboxyl groups have proven to be particularly suitable.
  • Silicone pressure sensitive adhesives e.g. Dow Corning Bio-PSA Q7-4301
  • pressure sensitive adhesives based on polyisobutylene / polybutene (PIB / PB) and combinations of styrene-isoprene-styrene block copolymers in combination with adhesive resins were also suitable.
  • the active substance-containing layer can consist of a single, preferably homogeneous, active substance-containing pressure-sensitive adhesive layer, but can also be composed of two or more layers which differ in the polymer and active substance composition.
  • the pressure sensitive adhesive layer can also be built up from a mixture of two or more different pressure sensitive adhesives.
  • Polyacrylates are generally produced by polymerizing various monomers (at least one monomer from the group comprising acrylic acid, methacrylic acid, acrylic acid esters and methacrylic acid esters, if appropriate together with vinyl acetate) and in particular from their mixtures.
  • Organic solvents in some cases also water, are preferably used as solvents in the polymerization to produce a suitable polyacrylate.
  • polyacrylates are obtained which may contain functional groups.
  • Polyacrylates with -OH groups (hydroxyl groups) and those with -COOH groups (carboxyl groups) as functional groups are widespread.
  • hydroxyl-containing polyacrylates are obtained as the only monomer or as a constituent in the monomer mixture.
  • Polyacrylates containing carboxyl groups are formed when acrylic acid and / or methacrylic acid are used as the monomer or in the monomer mixture.
  • Carboxyl group-free polyacrylates are therefore those which are prepared from a monomeric (meth) acrylic acid derivative or a corresponding monomer mixture without using acrylic acid or methacrylic acid.
  • the hydroxyl-containing polyacrylates include, for example, Durotak 2287, the monomer composition of which, according to WO 96/40087, is vinyl acetate, 2-ethylhexyl acrylate, hydroxyethyl acrylate and glycidyl acrylate and which is manufactured by National Starch.
  • This polyacrylate has proven to be a stable and well-tolerated pressure-sensitive polymer for the production of transdermal therapeutic systems.
  • pressure-sensitive adhesives from the group of polyacrylates are capable of absorbing pramipexole in a sufficient amount and of fulfilling the desired controlled release requirements over a longer period of preferably 4 to 7 days, which are free of carboxyl groups. It is not necessary to use additives to create pH-controlled conditions on the skin (e.g. a weak acid, a weak base or inorganic or organic salts that form a buffer system on the skin), crystallization inhibitors or highly disperse silicon dioxide in a penetration-promoting amount to add to the matrix.
  • These pressure-sensitive adhesives from the group of polyacrylates are produced exclusively by polymerization in an organic solvent or solvent mixture - not in water or an aqueous dispersion.
  • Polymers which can be prepared from monomers from the group comprising acrylic acid esters, methacrylic acid esters and mixtures thereof, optionally with additional vinyl acetate, are thus suitable as polyacrylates.
  • acrylic acid esters and methacrylic acid esters are those which carry linear, branched or cyclic aliphatic C Ci2 substituents without other functional groups.
  • This group includes in particular n-butyl acrylate, n-butyl methacrylate, ethyl acrylate, 2-ethylhexyl acrylate, ethyl methacrylate, methyl acrylate, methyl methacrylate, tert-butyl acrylate, sec-butyl acrylate, tert-butyl methacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate, 2-ethylhexyl methacrylate, Isopropyl acrylate and isopropyl methacrylate. 2-Ethylhexyl acrylate and methyl acrylate are particularly preferred.
  • acrylic acid esters and methacrylic acid esters which contain functional groups can also be contained in the monomer mixture used to prepare the polyacrylate. These are primarily to be understood as meaning esters containing hydroxyl groups, that is to say 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 3-hydroxypropyl acrylate and 3-hydroxypropyl methacrylate. However, substances such as acrylamide, dimethylaminoethyl acrylate, etc. can also be understood as functional groups-containing acrylic acid esters and methacrylic acid esters.
  • the proportion of acrylic acid esters and methacrylic acid esters containing such functional groups should be less than or equal to 10% by weight in the monomer mixture.
  • the proportion of acrylic acid esters containing functional groups and methacrylic acid esters containing functional groups in the monomer mixture is preferably less than 2% by weight.
  • the proportion of functional groups-containing acrylic acid esters and functional group-containing methacrylic acid esters in the monomer mixture is less than 0.2% by weight.
  • a monomer mixture which contains no functional groups-containing acrylic acid esters and methacrylic acid esters is particularly preferred.
  • vinyl acetate can also be used as a co-monomer together with at least one monomer from the group of acrylic acid esters and methacrylic acid esters for the preparation of the polyacrylate.
  • the proportion of vinyl acetate in the monomer mixture used to prepare this polyacrylate should be below 50% by weight, preferably below 25% by weight.
  • a vinyl acetate content between 0 and 5% by weight is particularly preferred.
  • the proportion of pramipexole in the form of the base in dissolved, emulsified or dispersed form in one of the above-mentioned pressure sensitive adhesives can be below 75% by weight. It is preferably in the range between 2 and 40% by weight, a range between 10 and 25% by weight is particularly preferred.
  • the optimal loading of the pressure sensitive adhesive with active ingredient also depends on the special requirements with regard to the release desired in time, the presence of further constituents in the active ingredient-containing pressure sensitive adhesive layer and the physico-chemical conditions that are present as a result. If the active ingredient pramipexole is dispersed in the active ingredient-containing layer, the solid particles of the active ingredient preferably have a size below 20 ⁇ m.
  • the transdermal therapeutic systems can contain one or more solvents for improved solution of the active ingredient in the polymer.
  • Propylene glycol, butanediol and lauryl lactate are particularly preferred.
  • the TTS may contain antioxidants to increase stability, e.g. As ascorbic acid, esters of ascorbic acid, sodium EDTA, bisulfite, etc., which can preferably be contained in a weight fraction up to 1% in the active ingredient-containing layer. Also, storing the TTS in an airtight manner
  • a particularly preferred transdermal therapeutic system is capable of delivering pramipexole over a period of 8 hours after application to 72 hours after application with a flux rate above 5 ⁇ g / cm 2 h.
  • Pramipexole can be used by means of the transdermal therapeutic system described here for therapeutic treatment or for reducing the symptoms of depression, tremor, ADHD (attention deficit hyperactivity disorder), anhedonia, HIV dementia, drug addiction and schizophrenia. It is preferred for the treatment of ALS (amyotrophic lateral scierosis), obesity (obesity), obesity and diabetes, as well as for its neuroprotective effect and its anticonvulsant effect.
  • the TTS containing pramipexole is particularly preferably used in the restless leg syndrome and in Parkinson's disease.
  • Example 1 A mixture is produced from 10% by weight of pramipexole (as base), 20% by weight of butanediol and 70% by weight of Durotak 2287, which is applied by means of a doctor blade to a backing film which serves as a backing layer after drying.
  • pressure-sensitive adhesive layer with a basis weight of 200 g / m 2 is spread. TTS patterns which can be used for in vitro investigations are punched out of the two-layer laminate of backing layer and active ingredient-containing PSA layer obtained in this way.
  • Example 2 A mixture is produced from 10% by weight of pramipexole (as base), 20% by weight of butanediol and 70% by weight of Durotak 2287, which is applied by means of a doctor blade to a backing film which serves as a backing layer after drying.
  • pressure-sensitive adhesive layer with a basis weight of 200 g / m 2 is spread. TTS patterns which can be used for in vitro investigations are punched out of the two-layer laminate of backing layer and active ingredient
  • a TTS consisting of a backing layer and two active substance layers is produced.
  • the first active substance-containing layer (reservoir layer) consists of 40% by weight of Pramipexol (base) and 60% by weight of Durotak 2287 and has a weight per unit area of 100 g / m 2 .
  • the second active substance-containing layer (pressure-sensitive adhesive layer) consists of 3% by weight of Pramipexol (base) and 97% by weight of Durotak 2287 and has a weight per unit area of 30 g / m 2 .
  • TTS patterns for the in vitro examinations are punched out of the laminate thus obtained, which consists of a backing layer, reservoir layer and pressure-sensitive adhesive layer.
  • Formulations which contain at least one active ingredient-containing layer with 10 to 40% by weight pramipexole in the form of the base are suitable for continuous transdermal administration of this active ingredient for up to 7 days.
  • Adhesives which have carboxyl functions as functional groups in the polymer e.g. Durotak 2051 or Durotak 2353
  • i.e. H. which were produced using acrylic acid or methacrylic acid.

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  • Engineering & Computer Science (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a transdermal therapeutic system (TTS) releasing an active pramipexol agent during a time ranging from 4 to 7 hours.

Description

Transdermales Therapeutisches System mit dem Wirkstoff ''Pramipexol Transdermal therapeutic system with the active ingredient '' Pramipexol

Die vorliegende Erfindung bezieht sich auf ein transdermales therapeutisches System (TTS) zur Verabreichung von Pramipexol. Sie bezieht sich insbesondere auf ein selbstklebendes Pramipexol-TTS, das befähigt ist, den Wirkstoff Pramipexol als Base kontinuierlich über einen längeren Zeitraum von vorzugsweise 4 bis 7 Tagen an eine Person abzugeben, die auf eine kontinuierliche Versorgung mit einer wirksamen Menge dieses Wirkstoffs angewiesen ist.The present invention relates to a transdermal therapeutic system (TTS) for the administration of pramipexole. In particular, it relates to a self-adhesive Pramipexol-TTS, which is capable of continuously delivering the active ingredient Pramipexol as a base over a longer period of time, preferably 4 to 7 days, to a person who is dependent on a continuous supply with an effective amount of this active ingredient.

Ein transdermales therapeutisches System (TTS) ist eine schichtförmig aufgebaute pharmazeutische Darreichungsform, die aus mindestens einer wirkstoffhaltigen Polymerschicht und einer für den Wirkstoff in der Regel undurchlässigen Rückschicht besteht. Wahlweise kann das TTS auch weitere Schichten enthalten, häufig z. B. eine die Geschwindigkeit der Freisetzung des Wirkstoffs kontrollierende Membran, eine die Haftung des TTS auf der Haut des Patienten gewährleistendeA transdermal therapeutic system (TTS) is a layered pharmaceutical dosage form which consists of at least one polymer layer containing an active ingredient and a backing layer which is generally impermeable to the active ingredient. Optionally, the TTS can also contain other layers, often e.g. B. a membrane controlling the rate of release of the active ingredient, ensuring the adhesion of the TTS to the patient's skin

Haftkleberschicht, eine Sperrschicht, und eine Schutzschicht, welche die den Wirkstoff abgebende Seite des TTS bis zur Anwendung bedeckt. In einem besonders einfach aufgebauten TTS ist die wirkstoffhaltige Polymerschicht selbst haftklebend ausgestattet, so daß auf eine zusätzliche Haftkleberschicht, einen z. B. ein kreisförmiges Reservoir einschließenden Klebering oder ein zusätzliches haftklebendes Überpflaster (Deckpflaster) verzichtet werden kann. Ein TTS ist aufgrund seiner Konstruktionselemente befähigt, den Wirkstoff kontinuierlich und kontrolliert an die Haut des Patienten abzugeben. Nach dem Durchgang durch die verschiedenen äußeren Schichten der Haut wird der pharmazeutische Wirkstoff von den darunter liegenden Blutgefäßen aufgenommen. Durch die kontinuierliche Abgabe erhält man besonders gleichmäßige Plasmaspiegel. Auch bringt die transdermale Verabreichung den Vorteil der Umgehung des Magen-Darm-Trakts mit sich.Pressure sensitive adhesive layer, a barrier layer, and a protective layer, which covers the active ingredient-dispensing side of the TTS until use. In a particularly simple TTS, the active ingredient-containing polymer layer itself is equipped with pressure-sensitive adhesive, so that an additional pressure-sensitive adhesive layer, e.g. B. a circular reservoir enclosing adhesive ring or an additional pressure-sensitive adhesive plaster (plaster) can be dispensed with. Thanks to its design elements, a TTS is capable of delivering the active ingredient continuously and in a controlled manner to the patient's skin. After passing through the various outer layers of the skin, the active pharmaceutical ingredient is absorbed by the underlying blood vessels. Due to the continuous release, particularly uniform plasma levels are obtained. Transdermal administration also has the advantage of bypassing the gastrointestinal tract.

Der Wirkstoff Pramipexol besitzt die chemische Bezeichnung (S)-2-Amino-4,5,6,7- tetrahydro-6-(propylamino)benzothiazol. Der Wirkstoff ist somit chemisch gesehen eine Base. Er besitzt die CAS Registry-Nr. [104632-26-0] und gilt als der erste nicht- ergotische, präsynaptische Dopamin-D2-Agonist. Der Wirkstoff ist in Form des Hydrochlorids als Tablette unter den Markennamen Sifrol® und Mirapex® erhältlich. Als solcher wird er als Parkinsonmittel und zur Behandlung von extrapyramidalen Störungen eingesetzt. Man verwendet Pramipexol bei idiopathischem (ohne erkennbare Ursache, gleichsam von selbst entstanden) Morbus Parkinson sowohl im frühen Stadium wie auch im fortgeschrittenen Stadium, hierbei auch in Kombination mit Levodopa.The active ingredient pramipexole has the chemical name (S) -2-amino-4,5,6,7-tetrahydro-6- (propylamino) benzothiazole. Chemically speaking, the active substance is a base. He has the CAS registry number. [104632-26-0] and is considered the first non-ergotic, presynaptic dopamine D2 agonist. The active ingredient is available in the form of the hydrochloride as a tablet under the brand names Sifrol ® and Mirapex ® . As such, it is used as a Parkinson's drug and to treat extrapyramidal disorders. Pramipexole is used in idiopathic (without identifiable cause, as it were self-developed) Parkinson's disease both in the early stage and in the advanced stage, here also in combination with levodopa.

Die chemische Formel von Pramipexol ist:The chemical formula of pramipexole is:

Bei der Behandlung von Parkinson'scher Krankheit mit oral applizierbarem Pramipexol muss zunächst für jeden Patienten die individuelle Dosis ermittelt werden, die optimal auf die Wirksamkeit und die Verträglichkeit abgestimmt ist. Diese Dosistitration erfolgt meistens in wöchentlichen Abständen, wobei man in der ersten Woche dreimal täglich eine Pramipexol-Hydrochlorid-Menge verabreicht, die 0,088 mg Pramipexol-Base entspricht. In der zweiten Woche wird dreimal täglich eine Pramipexol-Hydrochlorid-Menge verabreicht, die 0,18 mg Pramipexol-Base entspricht. In der dritten Woche wird schließlich dreimal täglich eine Pramipexol- Hydrochlorid-Menge verabreicht, die 0,36 mg Pramipexol-Base entspricht.When treating Parkinson's disease with pramipexole that can be administered orally, the individual dose that is optimally matched to the effectiveness and tolerability must first be determined for each patient. This dose titration is usually carried out at weekly intervals, with an amount of pramipexole hydrochloride corresponding to 0.088 mg of pramipexole base being administered three times a day for the first week. In the second week, an amount of pramipexole hydrochloride equivalent to 0.18 mg of pramipexole base is administered three times a day. Finally, in the third week, an amount of pramipexole hydrochloride equivalent to 0.36 mg of pramipexole base is administered three times a day.

Nachdem auf diese Weise die individuelle Dosis eingestellt ist, entspricht die durchschnittliche Tagesdosis im allgemeinen 1 ,5 mg Pramipexol-Hydrochlorid, was eine dreimal tägliche orale Verabreichung von 0,36 mg Pramipexol-Base bedeutet.After the individual dose has been set in this way, the average daily dose generally corresponds to 1.5 mg of pramipexole hydrochloride, which means that 0.36 mg of pramipexole base is administered orally three times a day.

Unter Morbus Parkinson versteht man eine Erkrankung der Stammganglien die vor allem durch Bewegungsstörungen gekennzeichnet ist. Neben der Behandlung des Morbus Parkinson wird Pramipexol auch zur Behandlung des sogenannten Restless-Ieg Syndroms eingesetzt; vergleiche DE 197 01 619 A1 , auf das vollinhaltlich Bezug genommen wird.Parkinson's disease is a disease of the trunk ganglia that is mainly characterized by movement disorders. In addition to the treatment of Parkinson's disease, pramipexole is also used to treat the so-called restless-Ieg syndrome; compare DE 197 01 619 A1, to which reference is made in full.

Zum Stand der Technik zählen transdermale therapeutische Systeme (TTS) mit dem Wirkstoff Pramipexol, insbesondere seinem (-)-Enantiomeren sowie pharmazeutisch verträglichen Säureadditionssalzen. So beschreibt EP 428 038 A2 transdermale therapeutische Systeme mit einem Wirkstoffreservoir aus einem emulsionspolymerisierten Polyacrylat und 5 bis 30 Gew.-% des Wirkstoffs Pramipexol. Als bevorzugtes Trägermaterial wird Eudragit NE 30 D® der Firma Röhm GmbH Darmstadt eingesetzt. Dieses Produkt ist in Form einer wäßrigen Dispersion eines Copolymehsats mit neutralem Charakter auf Basis von Ethylacrylat und Methylmethacrylat mit einem Trockensubstanzanteil von 30% erhältlich. Das mittlere Molekulargewicht liegt bei 800 000. Aus Eudragit NE 30 D® können Wirkstoff haltige Folien hergestellt werden, die jedoch nicht haftklebend sind. Die wirkstoffhaltigen Reservoire in besonderen Ausführungsformen dieser TTS besitzen eine Fläche von 20 cm2, eine Dicke von 200 μm und einen Wirkstoffgehalt von 9 Gew.-%. Die mit einem Deckpflaster zur Befestigung auf der Haut versehenen wirkstoffhaltigen Reservoire waren in der Lage, eine Tagesdosis von etwa 2,5 mg über einen Zeitraum von 3 bzw. 4 Tagen an zwei Probanden abzugeben. In-vitroThe prior art includes transdermal therapeutic systems (TTS) with the active ingredient pramipexol, in particular its (-) enantiomer, and pharmaceutically acceptable acid addition salts. For example, EP 428 038 A2 describes transdermal therapeutic systems with an active substance reservoir made from an emulsion-polymerized polyacrylate and 5 to 30% by weight of the active substance pramipexole. Eudragit NE 30 D ® from Röhm GmbH Darmstadt is used as the preferred carrier material. This product is available in the form of an aqueous dispersion of a copolymer with a neutral character based on ethyl acrylate and methyl methacrylate with a dry matter content of 30%. The average molecular weight is 800,000. Films containing active ingredient can be produced from Eudragit NE 30 D ® , but these are not pressure-sensitive adhesives. The active substance-containing reservoirs in special embodiments of these TTS have an area of 20 cm 2 , a thickness of 200 μm and an active substance content of 9% by weight. The active substance-containing reservoirs provided with a covering plaster for attachment to the skin were able to deliver a daily dose of about 2.5 mg to two test subjects over a period of 3 or 4 days. In vitro

Untersuchungen an Mustern dieser TTS zeigten, daß nach 4 Tagen bereits etwa 70 % der Wirkstoffmenge abgegeben war und daß in den nachfolgenden drei Tagen nur noch etwa weitere 10 % der ursprünglich im Reservoir vorhandenen Wirkstoff menge freigesetzt werden kann.Tests on samples of these TTS showed that after 4 days about 70% of the amount of active ingredient had already been released and that only about another 10% of the amount of active ingredient originally present in the reservoir could be released in the following three days.

Das US-Patent 6,465,004 B1 offenbart ein transdermales therapeutisches System, welches neben dem pharmazeutischen Wirkstoff und einem oder mehreren Klebern als wasserunlöslichen, aber im Kleber löslichen Bestandteil Celluloseacetatbutyrat enthält. Hierbei handelt es sich um ein verestertes Cellulosederivat, welches die Kristallisation des Wirkstoffs im Haftkleber verhindern soll. Auch Pramipexol wird als ein pharmazeutischer Wirkstoff in Betracht gezogen. Es ist jedoch nicht offenbart, ob ein entsprechend aufgebautes Pramipexol-TTS für die kontinuierliche Verabreichung des Wirkstoffs über einen längeren Zeitraum von vorzugsweise 4 bis 7 Tagen geeignet ist. Die deutsche Offenlegungsschrift DE 10033 853 A1 offenbart transdermale therapeutische Systeme, die neben dem pharmazeutischen Wirkstoff (darunter auch Pramipexol) und einem Matrixmaterial als weiteren Bestandteil hochdisperses Siliciumdioxid enthalten. Ein Pramipexol-TTS, welches befähigt ist, eine wirksame Menge dieses Wirkstoffs kontinuierlich über einen längeren Zeitraum von vorzugsweise 4 bis 7 Tagen zu verabreichen, ist nicht offenbart.US Pat. No. 6,465,004 B1 discloses a transdermal therapeutic system which, in addition to the active pharmaceutical ingredient and one or more adhesives, contains cellulose acetate butyrate as a water-insoluble but soluble component. This is an esterified cellulose derivative, which is intended to prevent the crystallization of the active ingredient in the pressure sensitive adhesive. Pramipexole is also considered as an active pharmaceutical ingredient. However, it is not disclosed whether a suitably structured pramipexole TTS is suitable for the continuous administration of the active ingredient over a longer period of time, preferably 4 to 7 days. The German patent application DE 10033 853 A1 discloses transdermal therapeutic systems which, in addition to the active pharmaceutical ingredient (including pramipexole) and a matrix material, contain highly disperse silicon dioxide as a further constituent. A pramipexole TTS which is capable of continuously administering an effective amount of this active ingredient over a longer period of time, preferably 4 to 7 days, is not disclosed.

Aufgabe der vorliegenden Erfindung ist es, ein selbstklebendes transdermales therapeutisches System (TTS) zur Verfügung zu stellen, das - nach Ermittlung einer individuellen Tagesdosis - den Wirkstoff Pramipexol in der Dauerphase der Therapie kontinuierlich an den Patienten abgibt, ohne daß eine dreimal tägliche Verabreichung einer oralen Tablette nötig ist. Auch soll die Wirkstoff haltige Polymerschicht bzw. die der Haut zugewandte Seite des TTS haftklebend ausgerüstet sein, so daß auf die Verwendung eines zusätzlichen haftklebenden Überpflasters zur Fixierung auf der Haut verzichtet werden kann. Vorzugsweise soll in dieser Dauerphase die Verabreichung eines transdermalen therapeutischen Systems in einer Weise erfolgen, die den Patienten für einen längeren Zeitraum, vorzugsweise für 4 bis 7 Tage ausreichend mit Wirkstoff versorgt.The object of the present invention is to provide a self-adhesive transdermal therapeutic system (TTS) which - after determining an individual daily dose - continuously releases the active ingredient pramipexole to the patient in the long-term phase of the therapy without the need for oral administration three times a day Tablet is necessary. The active ingredient-containing polymer layer or the side of the TTS facing the skin should also be provided with a pressure-sensitive adhesive, so that the use of an additional pressure-sensitive adhesive plaster for fixing on the skin can be dispensed with. In this permanent phase, the administration of a transdermal therapeutic system should preferably take place in a manner which provides the patient with sufficient active substance for a longer period, preferably for 4 to 7 days.

Gelöst wird die Aufgabe durch ein Transdermales Therapeutisches System (TTS) mit dem Wirkstoff Pramipexol, welches den Wirkstoff über einen längeren Zeitraum, der vorzugsweise 4 bis 7 Tage beträgt, kontinuierlich an eine Person, die den Wirkstoff Pramipexol benötigt, abgibt.The task is solved by a transdermal therapeutic system (TTS) with the active ingredient pramipexole, which continuously releases the active ingredient over a longer period of time, which is preferably 4 to 7 days, to a person who needs the active ingredient pramipexole.

Ein solches TTS enthält eine - vorzugsweise wirkstoffundurchlässige - Rückschicht, mindestens eine wirkstoffhaltige Schicht und eine vor Gebrauch zu entfernende Schutzschicht, wobei die wirkstoffhaltige Schicht den Wirkstoff Pramipexol enthält. Unter der Bezeichnung Pramipexol sind im Rahmen der vorliegenden Erfindung das S-(-)-Enantiomer, sowie das ?-(+)-Enantiomer und ein - vorzugsweise racemisches - Gemisch dieser beiden Enantiomere, vorzugsweise das S-(-)-Enantiomer, zu verstehen. In diesen Formen kann Pramipexol als freie Base, als Hydrat, Solvat oder pharmazeutisch akzeptables Salz (z. B. als Hydrochlorid) in der mindestens einen wirkstoffhaltigen Schicht enthalten sein. Besonders bevorzugt ist die Verwendung von Pramipexol als S-(-)-Enantiomer in Form der freien Base.Such a TTS contains a - preferably active substance-impermeable - backing layer, at least one active substance-containing layer and a protective layer to be removed before use, the active substance-containing layer containing the active substance pramipexole. Within the scope of the present invention, the S - (-) enantiomer, as well as the? - (+) - enantiomer and a - preferably racemic - mixture of these two enantiomers, preferably the S - (-) enantiomer, are referred to as pramipexole understand. In these forms, pramipexole can be used as the free base, as a hydrate, solvate or pharmaceutically acceptable salt (e.g. as a hydrochloride) in the at least one Active ingredient-containing layer may be included. The use of pramipexole as the S - (-) enantiomer in the form of the free base is particularly preferred.

Die wirkstoffhaltige Schicht enthält weiterhin einen Haftkleber, der befähigt ist, das TTS während der gesamten Applikationsdauer von vorzugsweise 4 bis 7 Tagen auf einer einzigen Stelle der Haut des Anwenders sicher zu befestigen. Das TTS kann auch weitere Schichten enthalten, zum Beispiel eine die Geschwindigkeit der Freisetzung des Wirkstoffs kontrollierende Membran, mindestens eine zusätzliche wirkstoffhaltige Schicht, mindestens eine Stützschicht zur Erhöhung der mechanischen Stabilität des TTS und eine auf der der Haut zugewandten Seite des TTS befindliche Haftkleberschicht.The active substance-containing layer also contains a pressure sensitive adhesive which is capable of securely attaching the TTS to a single point on the skin of the user during the entire application period, preferably from 4 to 7 days. The TTS can also contain further layers, for example a membrane controlling the rate of release of the active ingredient, at least one additional active ingredient-containing layer, at least one support layer to increase the mechanical stability of the TTS and a pressure-sensitive adhesive layer on the side of the TTS facing the skin.

Haftkleber, die für die wirkstoffhaltige Schicht und ggf. die auf der der Haut zugewandten Seite des TTS befindliche Haftkleberschicht geeignet sind, stammen aus der Gruppe der Silikone, Polyisobutylene und Polyacrylate. Als besonders geeignet erwiesen sich Polyacrylate (Acrylathaftkleber) ohne Carboxylgruppen.Pressure sensitive adhesives that are suitable for the layer containing the active substance and, if applicable, the pressure sensitive adhesive layer located on the side of the TTS facing the skin come from the group of silicones, polyisobutylenes and polyacrylates. Polyacrylates (acrylic pressure sensitive adhesives) without carboxyl groups have proven to be particularly suitable.

Ebenso waren Silikonhaftkleber (z. B. Dow Corning Bio-PSA Q7-4301), Haftkleber auf Basis von Polyisobutylen/Polybuten (PIB/PB) und Kombinationen von Styren- Isopren-Styren Block-Copolymeren in Kombination klebenden Harzen geeignet.Silicone pressure sensitive adhesives (e.g. Dow Corning Bio-PSA Q7-4301), pressure sensitive adhesives based on polyisobutylene / polybutene (PIB / PB) and combinations of styrene-isoprene-styrene block copolymers in combination with adhesive resins were also suitable.

Die wirkstoffhaltige Schicht kann aus einer einzigen, vorzugsweise homogenen, wirkstoffhaltigen Haftkleberschicht bestehen, aber auch aus zwei oder mehreren Schichten aufgebaut sein, die sich in der Polymer- und Wirkstoffzusammensetzung unterscheiden. Die Haftkleberschicht kann auch aus einer Mischung von zwei oder mehreren verschiedenen Haftklebern aufgebaut werden.The active substance-containing layer can consist of a single, preferably homogeneous, active substance-containing pressure-sensitive adhesive layer, but can also be composed of two or more layers which differ in the polymer and active substance composition. The pressure sensitive adhesive layer can also be built up from a mixture of two or more different pressure sensitive adhesives.

Polyacrylate werden generell durch Polymerisation verschiedener Monomere (mindestens ein Monomer aus der Gruppe umfassend Acrylsäure, Methacrylsäure, Acrylsäureestern und Methacrylsäureestem, ggf. zusammen mit Vinylacetat) und insbesondere aus deren Mischungen hergestellt. Als Lösungsmittel bei der Polymerisation zur Herstellung eines geeigneten Polyacrylats werden vorzugsweise organische Lösungsmittel, in manchen Fällen auch Wasser verwendet. In Abhängigkeit von der Struktur der bei der Polymerisation eingesetzten Monomere erhält man Polyacrylate, die funktioneile Gruppen enthalten können. Weit verbreitet sind Polyacrylate mit -OH-Gruppen (Hydroxylgruppen) und solche mit -COOH- Gruppen (Carboxylgruppen) als funktioneilen Gruppen. Hydroxylgruppenhaltige Polyacrylate erhält man bei der Verwendung von hydroxylgruppenhaltigen Acrylsäureestern und / oder hydroxylgruppenhaltigen Methacrylsäureestern als einzigem Monomer bzw. als Bestandteil im Monomerengemisch. Carboxylgruppenhaltige Polyacrylate entstehen, wenn Acrylsäure und / oder Methacrylsäure als Monomer oder im Monomerengemisch verwendet werden. Carboxylgruppenfreie Polyacrylate sind daher solche, die ohne Verwendung von Acrylsäure bzw. Methacrylsäure aus einem monomeren (Meth)acrylsäurederivat bzw. einem entsprechenden Monomerengemisch hergestellt werden.Polyacrylates are generally produced by polymerizing various monomers (at least one monomer from the group comprising acrylic acid, methacrylic acid, acrylic acid esters and methacrylic acid esters, if appropriate together with vinyl acetate) and in particular from their mixtures. Organic solvents, in some cases also water, are preferably used as solvents in the polymerization to produce a suitable polyacrylate. Depending on the structure of the monomers used in the polymerization, polyacrylates are obtained which may contain functional groups. Polyacrylates with -OH groups (hydroxyl groups) and those with -COOH groups (carboxyl groups) as functional groups are widespread. When using hydroxyl-containing acrylic acid esters and / or hydroxyl-containing methacrylic acid esters, hydroxyl-containing polyacrylates are obtained as the only monomer or as a constituent in the monomer mixture. Polyacrylates containing carboxyl groups are formed when acrylic acid and / or methacrylic acid are used as the monomer or in the monomer mixture. Carboxyl group-free polyacrylates are therefore those which are prepared from a monomeric (meth) acrylic acid derivative or a corresponding monomer mixture without using acrylic acid or methacrylic acid.

Zur den hydroxylgruppenhaltigen Polyacrylaten zählt beispielsweise Durotak 2287, dessen Monomerenzusammensetzung gemäß WO 96/40087 Vinylacetat, 2- Ethylhexylacrylat, Hydroxyethylacrylat und Glycidylacrylat ist und das von der Fa. National Starch hergestellt wird. Dieses Polyacrylat hat sich als stabiles und gut verträgliches haftklebendes Polymer für die Herstellung von transdermalen therapeutischen Systemen erwiesen.The hydroxyl-containing polyacrylates include, for example, Durotak 2287, the monomer composition of which, according to WO 96/40087, is vinyl acetate, 2-ethylhexyl acrylate, hydroxyethyl acrylate and glycidyl acrylate and which is manufactured by National Starch. This polyacrylate has proven to be a stable and well-tolerated pressure-sensitive polymer for the production of transdermal therapeutic systems.

Überraschend hat sich nun gezeigt, daß als Haftkleber aus der Gruppe der Polyacrylate insbesondere solche befähigt sind, Pramipexol in ausreichender Menge aufzunehmen und die gewünschten Erfordernisse der kontrollierten Freisetzung über einen längeren Zeitraum von vorzugsweise 4 bis 7 Tagen zu erfüllen, die frei sind von Carboxylgruppen. Es ist nicht erforderlich, Hilfsstoffe zur Erzeugung pH- kontrollierter Bedingungen auf der Haut (z. B. ein schwache Säure, eine schwache Base oder anorganische oder organische Salze, die ein Puffersystem auf der Haut bilden), Kristallisationsinhibitoren oder hochdisperses Siliciumdioxid in einer penetrationsfördernden Menge der Matrix zuzugeben. Die Herstellung dieser Haftkleber aus der Gruppe der Polyacrylate erfolgt dabei ausschließlich durch Polymerisation in einem organischen Lösungsmittel bzw. Lösungsmittelgemisch - nicht in Wasser oder einer wäßrigen Dispersion. Als Polyacrylate kommen somit Polymere (Homopolymere, Copolymere und Block- Copolymere) in Frage, die aus Monomeren der Gruppe umfassend Acrylsäureester, Methacrylsäureester und deren Mischungen, gegebenenfalls mit zusätzlichem Vinylacetat hergestellt werden können.Surprisingly, it has now been found that, as pressure-sensitive adhesives from the group of polyacrylates, in particular those are capable of absorbing pramipexole in a sufficient amount and of fulfilling the desired controlled release requirements over a longer period of preferably 4 to 7 days, which are free of carboxyl groups. It is not necessary to use additives to create pH-controlled conditions on the skin (e.g. a weak acid, a weak base or inorganic or organic salts that form a buffer system on the skin), crystallization inhibitors or highly disperse silicon dioxide in a penetration-promoting amount to add to the matrix. These pressure-sensitive adhesives from the group of polyacrylates are produced exclusively by polymerization in an organic solvent or solvent mixture - not in water or an aqueous dispersion. Polymers (homopolymers, copolymers and block copolymers) which can be prepared from monomers from the group comprising acrylic acid esters, methacrylic acid esters and mixtures thereof, optionally with additional vinyl acetate, are thus suitable as polyacrylates.

Die am besten geeigneten Acrylsäureester und Methacrylsäureester sind dabei solche, die lineare, verzweigte oder cyclische aliphatische C Ci2-Substituenten ohne sonstige funktioneile Gruppen tragen. Zu dieser Gruppe zählen insbesondere n- Butylacrylat, n-Butylmethacrylat, Ethylacrylat, 2-Ethylhexylacrylat, Ethylmethacrylat, Methylacrylat, Methylmethacrylat, tert.-Butylacrylat, sec.-Butylacrylat, tert.- Butylmethacrylat, Cyclohexylmethacrylat, 2-Ethylhexylmethacrylat, Isobornylmethacrylat, Isobutylmethacrylat, Isopropylacrylat und Isopropylmethacrylat. Besonders bevorzugt sind 2-Ethylhexylacrylat und Methylacrylat.The most suitable acrylic acid esters and methacrylic acid esters are those which carry linear, branched or cyclic aliphatic C Ci2 substituents without other functional groups. This group includes in particular n-butyl acrylate, n-butyl methacrylate, ethyl acrylate, 2-ethylhexyl acrylate, ethyl methacrylate, methyl acrylate, methyl methacrylate, tert-butyl acrylate, sec-butyl acrylate, tert-butyl methacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate, 2-ethylhexyl methacrylate, Isopropyl acrylate and isopropyl methacrylate. 2-Ethylhexyl acrylate and methyl acrylate are particularly preferred.

Doch können auch Acrylsäureester und Methacrylsäureester in dem zur Herstellung des Polyacrylats verwendeten Monomerengemisch enthalten sein, die funktionelle Gruppen tragen. Hierunter sind in erster Linie hydroxylgruppenhaltige Ester zu verstehen, also 2-Hydroxyethylacrylat, 2-Hydroxyethylmethacrylat, 3- Hydroxypropylacrylat und 3-Hydroxypropylmethacrylat. Aber auch Stoffe wie Acrylamid, Dimethylaminoethylacrylat etc. können im Sinne dieser Beschreibung als funktionelle Gruppen enthaltende Acrylsäureester und Methacrylsäureester verstanden werden.However, acrylic acid esters and methacrylic acid esters which contain functional groups can also be contained in the monomer mixture used to prepare the polyacrylate. These are primarily to be understood as meaning esters containing hydroxyl groups, that is to say 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 3-hydroxypropyl acrylate and 3-hydroxypropyl methacrylate. However, substances such as acrylamide, dimethylaminoethyl acrylate, etc. can also be understood as functional groups-containing acrylic acid esters and methacrylic acid esters.

Der Anteil von Acrylsäureestern und Methacrylsäureestern, die derartige funktionelle Gruppen enthalten, soll dabei im Monomerengemisch kleiner oder gleich 10 Gew.-% betragen. Vorzugsweise beträgt der Anteil von funktionelle Gruppen enthaltende Acrylsäureester und funktionelle Gruppen enthaltende Methacrylsäureester im Monomerengemisch weniger als 2 Gew.-%. In einer bevorzugten Ausführungsform beträgt der Anteil von funktionelle Gruppen enthaltende Acrylsäureester und funktionelle Gruppen enthaltende Methacrylsäureester im Monomerengemisch weniger als 0,2 Gew.-%. Besonders bevorzugt ist ein Monomerengemisch, das keine funktionelle Gruppen enthaltende Acrylsäureester und Methacrylsäureester enthält. Wie bereits erwähnt, kann jedoch auch Vinylacetat als Co-Monomer zusammen mit mindestens einem Monomeren aus der Gruppe der Acrylsäureester und Methacrylsäureester zur Herstellung des Polyacrylats verwendet werden. Der Anteil des Vinylacetats in dem zur Herstellung dieses Polyacrylats verwendeten Monomerengemisch sollte unterhalb von 50 Gew.-%, vorzugsweise unterhalb von 25 Gew.-% liegen. Besonders bevorzugt ist ein Vinylacetatgehalt zwischen 0 und 5 Gew.-%.The proportion of acrylic acid esters and methacrylic acid esters containing such functional groups should be less than or equal to 10% by weight in the monomer mixture. The proportion of acrylic acid esters containing functional groups and methacrylic acid esters containing functional groups in the monomer mixture is preferably less than 2% by weight. In a preferred embodiment, the proportion of functional groups-containing acrylic acid esters and functional group-containing methacrylic acid esters in the monomer mixture is less than 0.2% by weight. A monomer mixture which contains no functional groups-containing acrylic acid esters and methacrylic acid esters is particularly preferred. As already mentioned, however, vinyl acetate can also be used as a co-monomer together with at least one monomer from the group of acrylic acid esters and methacrylic acid esters for the preparation of the polyacrylate. The proportion of vinyl acetate in the monomer mixture used to prepare this polyacrylate should be below 50% by weight, preferably below 25% by weight. A vinyl acetate content between 0 and 5% by weight is particularly preferred.

Der Anteil von Pramipexol in Form der Base in gelöster, emulgierter oder dispergierter Form in einem der oben genannten Haftkleber kann unterhalb von 75 Gew.-% liegen. Vorzugsweise liegt er im Bereich zwischen 2 und 40 Gew.-%, besonders bevorzugt ist ein Bereich zwischen 10 und 25 Gew.-%. Allerdings hängt die optimale Beladung des Haftklebers mit Wirkstoff auch von den speziellen Anforderungen hinsichtlich der zeitlich gewünschten Freisetzung, dem Vorhandesein weiterer Bestandteile in der wirkstoffhaltigen Haftkleberschicht und den dadurch vorhandenen physikalisch-chemischen Bedingungen ab. Sofern der Wirkstoff Pramipexol in der wirkstoffhaltigen Schicht dispergiert vorliegt, besitzen die festen Partikel des Wirkstoffs vorzugsweise eine Größe unterhalb von 20 μm.The proportion of pramipexole in the form of the base in dissolved, emulsified or dispersed form in one of the above-mentioned pressure sensitive adhesives can be below 75% by weight. It is preferably in the range between 2 and 40% by weight, a range between 10 and 25% by weight is particularly preferred. However, the optimal loading of the pressure sensitive adhesive with active ingredient also depends on the special requirements with regard to the release desired in time, the presence of further constituents in the active ingredient-containing pressure sensitive adhesive layer and the physico-chemical conditions that are present as a result. If the active ingredient pramipexole is dispersed in the active ingredient-containing layer, the solid particles of the active ingredient preferably have a size below 20 μm.

Die transdermalen therapeutischen Systeme können zur verbesserten Lösung des Wirkstoffs im Polymer ein oder mehrere Lösungsmittel enthalten. Hierfür kommen Propylenglykol, Ethyloleat, 1 ,2-Propandiol, 1 ,3-Butandiol, Transcutol, Propylenglykolmonocaprylat, Solketal, Ölsäure, 1-Methyl-pyrrolidon, Glycerol, Lauryllactat, T acetin, Glycerolmonooleat, Sorbitanmonooleat und Sorbitantrioleat in Frage. Besonders bevorzugt sind Propylenglykol, Butandiol und Lauryllactat.The transdermal therapeutic systems can contain one or more solvents for improved solution of the active ingredient in the polymer. Propylene glycol, ethyl oleate, 1, 2-propanediol, 1, 3-butanediol, transcutol, propylene glycol monocaprylate, solketal, oleic acid, 1-methyl-pyrrolidone, glycerol, lauryl lactate, t acetin, glycerol monooleate, sorbitan monooleate and sorbitan trioleate are suitable for this. Propylene glycol, butanediol and lauryl lactate are particularly preferred.

Das TTS kann zur Erhöhung der Stabilität Antioxidantien enthalten, z. B. Ascorbinsäure, Ester der Ascorbinsäure, Natrium-EDTA, Bisulfit etc., die vorzugsweise in einem Gewichtsanteil bis zu 1% in der wirkstoffhaltigen Schicht enthalten sein können. Auch bewirkt das Lagern des TTS in einer luftdichtenThe TTS may contain antioxidants to increase stability, e.g. As ascorbic acid, esters of ascorbic acid, sodium EDTA, bisulfite, etc., which can preferably be contained in a weight fraction up to 1% in the active ingredient-containing layer. Also, storing the TTS in an airtight manner

Primärverpackung (Blisterpackung, Siegelrandbeutel) unter Schutzgasatmosphäre (N2, Ar, etc.) eine Erhöhung der Stabilität. Die zugelassenen maximale tägliche Dosis für Pramipexol, bezogen auf die Base des Pramipexols, im Rahmen der Therapie der Parkinson'schen Krankheit liegt bei 3,2mg pro Tag. Bezogen auf ein Transdermales Therapeutisches System, das eine den Wirkstoff Pramipexol an die Haut abgebende Fläche von 20 cm2 aufweisen soll, ergibt sich daraus eine erforderliche Fluxrate von 6,25 μg/cm2 h.Primary packaging (blister pack, sealed edge bag) under a protective gas atmosphere (N 2 , Ar, etc.) an increase in stability. The permitted maximum daily dose for pramipexole, based on the base of pramipexole, in the context of therapy for Parkinson's disease is 3.2 mg per day. In relation to a transdermal therapeutic system, which should have an area of 20 cm 2 that releases the active ingredient pramipexole to the skin, this results in a required flux rate of 6.25 μg / cm 2 h.

Ein besonders bevorzugtes Transdermales Therapeutisches System ist befähigt, Pramipexol über den Zeitraum von 8 Stunden nach Applikation bis 72 h nach Applikation mit einer Fluxrate oberhalb von 5 μg/cm2 h abzugeben.A particularly preferred transdermal therapeutic system is capable of delivering pramipexole over a period of 8 hours after application to 72 hours after application with a flux rate above 5 μg / cm 2 h.

Pramipexol kann mittels des hier beschriebenen Transdermalen Therapeutischen Systems zur therapeutischen Behandlung bzw. zur Minderung der Symptome von Depression, Tremor, ADHD (attention deficit hyperactivity disorder), Anhedonie, HIV- Demenz, Drogenabhängigkeit und Schizophrenie verwendet werden. Es wird bevorzugt zur Behandlung von ALS (amyotrophic lateral scierosis), Fettleibigkeit (Adipositas), Fettsucht (Obesity) und Diabetes sowie wegen seiner neuroprotektiven Wirkung und seiner antikonvulsiven Wirkung eingesetzt. Besonders bevorzugt wird das Pramipexol enthaltende TTS bei dem Restless Leg-Syndrom und bei der Parkinson'schen Krankheit eingesetzt.Pramipexole can be used by means of the transdermal therapeutic system described here for therapeutic treatment or for reducing the symptoms of depression, tremor, ADHD (attention deficit hyperactivity disorder), anhedonia, HIV dementia, drug addiction and schizophrenia. It is preferred for the treatment of ALS (amyotrophic lateral scierosis), obesity (obesity), obesity and diabetes, as well as for its neuroprotective effect and its anticonvulsant effect. The TTS containing pramipexole is particularly preferably used in the restless leg syndrome and in Parkinson's disease.

Die folgenden Beispiele sollten die vorliegende Erfindung näher erläutern, ohne daß sie als Einschränkung auf diese Fälle zu betrachten sind.The following examples are intended to explain the present invention in more detail without restricting it to these cases.

Beispiel 1 : Aus 10 Gew.-% Pramipexol (als Base), 20 Gew.-% Butandiol und 70 Gew.-% Durotak 2287 wird eine Mischung hergestellt, die mittels Rakelauftrag auf eine als spätere Rückschicht dienende Trägerfolie zu einer - nach Trocknung - haftklebenden Schicht mit einem Flächengewicht von 200 g/m2 ausgestrichen wird. Aus dem so erhaltenen zweischichtigen Laminat aus Rückschicht und Wirkstoff haltiger Haftkleberschicht werden TTS-Muster ausgestanzt, die für die in- vitro Untersuchungen einsetzbar sind. Beispiel 2Example 1: A mixture is produced from 10% by weight of pramipexole (as base), 20% by weight of butanediol and 70% by weight of Durotak 2287, which is applied by means of a doctor blade to a backing film which serves as a backing layer after drying. pressure-sensitive adhesive layer with a basis weight of 200 g / m 2 is spread. TTS patterns which can be used for in vitro investigations are punched out of the two-layer laminate of backing layer and active ingredient-containing PSA layer obtained in this way. Example 2

Ein aus Rückschicht und zwei wirkstoffhaltigen Schichten bestehendes TTS wird hergestellt. Die erste wirkstoffhaltige Schicht (Reservoirschicht) besteht aus 40 Gew.- % Pramipexol (Base) und 60 Gew.-% Durotak 2287 und besitzt ein Flächengewicht von 100 g/m2. Die zweite wirkstoffhaltige Schicht (Haftkleberschicht) besteht aus 3 Gew.-% Pramipexol (Base) und 97 Gew.-% Durotak 2287 und besitzt ein Flächengewicht von 30 g/m2. Aus dem so erhaltenen, aus Rückschicht, Reservoirschicht und Haftkleberschicht bestehenden Laminat werden TTS-Muster für die in-vitro Untersuchungen ausgestanzt.A TTS consisting of a backing layer and two active substance layers is produced. The first active substance-containing layer (reservoir layer) consists of 40% by weight of Pramipexol (base) and 60% by weight of Durotak 2287 and has a weight per unit area of 100 g / m 2 . The second active substance-containing layer (pressure-sensitive adhesive layer) consists of 3% by weight of Pramipexol (base) and 97% by weight of Durotak 2287 and has a weight per unit area of 30 g / m 2 . TTS patterns for the in vitro examinations are punched out of the laminate thus obtained, which consists of a backing layer, reservoir layer and pressure-sensitive adhesive layer.

Beispiel 3Example 3

Für die beiden TTS-Muster der Beispiele 1 und 2 wurden der Flux an Pramipexol über die humane Vollhaut in-vitro bestimmt.For the two TTS patterns of Examples 1 and 2, the flux of pramipexole was determined in vitro via the human whole skin.

Die in-vitro Untersuchungen wurden mit einer modifizierten Franz-Zelle durchgeführt. Als Membran diente Humanvollhaut, die aus plastischen Operationen stammt. Die TTS Fläche betrug 1 ,54 cm2. Als Akzeptorlösung diente eine Phosphatpufferlösung pH 7,4 die mit 0,1% Natiumazid versetzt war. Das Akzeptorvolumen betrug 9 ml und wurde nach 24, 32, 48, 56 und 72 Stunden komplett entnommen und durch neue Pufferlösung ersetzt. Die Franz-Zellen befanden sich in einem Wasserbad, dessen Temperatur auf 32°C eingestellt war. Der Gehalt an Pramipexol in der Phosphatpufferlösung wurde mittels einer geeigneten HPLC Analytik bestimmt.The in vitro investigations were carried out with a modified Franz cell. Full human skin, which comes from plastic surgery, served as the membrane. The TTS area was 1.54 cm 2 . A phosphate buffer solution pH 7.4, which was mixed with 0.1% sodium azide, served as the acceptor solution. The acceptor volume was 9 ml and was completely removed after 24, 32, 48, 56 and 72 hours and replaced with new buffer solution. The Franz cells were in a water bath, the temperature of which was set at 32 ° C. The content of pramipexole in the phosphate buffer solution was determined using a suitable HPLC analysis.

Die Ergebnisse sind in den Abbildungen 1 und 2 aufgeführt. Es konnte mittels dieser in-vitro Untersuchungen an humaner Vollhaut gezeigt werden, daß TTS-The results are shown in Figures 1 and 2. Using these in vitro studies on human whole skin, it could be shown that TTS

Formulierungen, die mindestens eine wirkstoffhaltige Schicht mit 10 bis 40 Gew.-% Pramipexol in Form der Base enthalten, für eine kontinuierliche transdermale Verabreichung dieses Wirkstoffs von bis zu 7 Tagen geeignet sind.Formulations which contain at least one active ingredient-containing layer with 10 to 40% by weight pramipexole in the form of the base are suitable for continuous transdermal administration of this active ingredient for up to 7 days.

Als ungeeignet zur Herstellung erwiesen sich solche Kleber, die Carboxylfunktionen als funktionelle Gruppen im Polymer aufweisen (z.B. Durotak 2051 oder Durotak 2353), d. h. die unter Verwendung von Acrylsäure bzw. Methacrylsäure hergestellt wurden. Adhesives which have carboxyl functions as functional groups in the polymer (e.g. Durotak 2051 or Durotak 2353), i.e. H. which were produced using acrylic acid or methacrylic acid.

Claims

Patentansprüche claims 1 . Transdermales therapeutisches System (TTS) zur kontinuierlichen Verabreichung von Pramipexol, umfassend eine Rückschicht und mindestens eine wirkstoffhaltige Polymerschicht, die den Wirkstoff Pramipexol enthält, dadurch gekennzeichnet, daß die wirkstoffhaltige Polymerschicht mindestens ein haftklebendes Polymer aus der Gruppe der Silicone (Polydimethylsiloxane), der Polyisobutylene, der Polybutene, der Styrol- Isopren-Styrol-Block-Copolymere in Kombination mit Harzen, und der carboxylgruppenfreien Polyacrylate enthält.1 . Transdermal therapeutic system (TTS) for the continuous administration of pramipexole, comprising a backing layer and at least one active ingredient-containing polymer layer which contains the active ingredient pramipexole, characterized in that the active ingredient-containing polymer layer comprises at least one pressure-sensitive adhesive polymer from the group of silicones (polydimethylsiloxanes), polyisobutylenes, the polybutenes, the styrene-isoprene-styrene block copolymers in combination with resins, and the carboxyl-free polyacrylates. 2. TTS nach Anspruch 1 , dadurch gekennzeichnet, daß es eine weitere Haftkleberschicht, eine zusätzliche, die Geschwindigkeit der Freisetzung von Pramipexol kontrollierende Membran, eine zusätzliche wirkstoffhaltige Schicht oder eine zusätzliche Stützschicht enthält.2. TTS according to claim 1, characterized in that it contains a further pressure-sensitive adhesive layer, an additional membrane controlling the rate of release of pramipexole, an additional active substance-containing layer or an additional support layer. 3. TTS nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß das haftklebende Polymer ein carboxylgruppenfreies Polyacrylat ist, welches durch Polymerisation eines Monomerengemisches von mindestens einem Acrylsäureester oder Methacrylsäureester herstellbar ist. 3. TTS according to claim 1 or 2, characterized in that the pressure-sensitive adhesive polymer is a carboxyl-free polyacrylate, which can be prepared by polymerizing a monomer mixture of at least one acrylic acid ester or methacrylic acid ester. 4. TTS nach Anspruch 3, dadurch gekennzeichnet, daß das Monomerengemisch mindestens ein Acrylsäureester oder Methacrylsäureester mit linearen, verzweigten oder cyclischen aliphatischen CrCi2-Substituenten ohne sonstige funktionelle Gruppen enthält.4. TTS according to claim 3, characterized in that the monomer mixture contains at least one acrylic acid ester or methacrylic acid ester with linear, branched or cyclic aliphatic CrCi 2 substituents without other functional groups. 5. TTS nach Anspruch 3 oder 4, dadurch gekennzeichnet, daß das Monomerengemisch zusätzlich mindestens einen hydroxylgruppenhaltigen Acrylsäureester oder einen hydroxylgruppenhaltigen Methacrylsäureester in einem Gewichtsanteil unterhalb von 10% enthält.5. TTS according to claim 3 or 4, characterized in that the monomer mixture additionally contains at least one hydroxyl group-containing acrylic acid ester or one hydroxyl group-containing methacrylic acid ester in a weight fraction below 10%. 6. TTS nach einem oder mehreren der Ansprüche 3 bis 5, dadurch gekennzeichnet, daß das Monomerengemisch zusätzlich Vinylacetat in einem Gewichtsanteil unterhalb von 50%, vorzugsweise unterhalb von 25% und besonders bevorzugt zwischen 0 und 5% enthält. 6. TTS according to one or more of claims 3 to 5, characterized in that the monomer mixture additionally contains vinyl acetate in a proportion by weight below 50%, preferably below 25% and particularly preferably between 0 and 5%. 7. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß der Wirkstoff Pramipexol in der wirkstoffhaltigen Polymerschicht in gelöster, emulgierter und / oder dispergierter Form vorliegt.7. TTS according to one or more of the preceding claims, characterized in that the active ingredient pramipexole is present in the active ingredient-containing polymer layer in dissolved, emulsified and / or dispersed form. 8. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß der Wirkstoff Pramipexol als S-(— )-Enantiomer, /?-(+)- Enantiomer oder racemisches Gemisch dieser beiden Enantiomere in der wirkstoffhaltigen Polymerschicht enthalten ist.8. TTS according to one or more of the preceding claims, characterized in that the active ingredient pramipexole as S - (-) enantiomer, /? - (+) - enantiomer or racemic mixture of these two enantiomers is contained in the active ingredient-containing polymer layer. 9. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß der Wirkstoff Pramipexol als freie Base, als Hydrat, Solvat und / oder pharmazeutisch akzeptables Salz in der wirkstoffhaltigen Polymerschicht enthalten ist.9. TTS according to one or more of the preceding claims, characterized in that the active ingredient pramipexole is contained as a free base, as a hydrate, solvate and / or pharmaceutically acceptable salt in the active ingredient-containing polymer layer. 10. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß der Wirkstoff Pramipexol als S-(-)-Enantiomer in Form der freien Base in der wirkstoffhaltigen Polymerschicht enthalten ist. 10. TTS according to one or more of the preceding claims, characterized in that the active ingredient pramipexole as S - (-) - enantiomer in the form of the free base is contained in the active ingredient-containing polymer layer. 11. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß es befähigt ist, den Wirkstoff Pramipexol über einen Zeitraum von 4 bis 7 Tagen kontinuierlich an die Haut eines Patienten abzugeben.11. TTS according to one or more of the preceding claims, characterized in that it is capable of continuously delivering the active ingredient pramipexole to the skin of a patient over a period of 4 to 7 days. 12. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß es befähigt ist, den Wirkstoff Pramipexol über den Zeitraum zwischen 24 Stunden ab Verabreichung bis 168 h ab Verabreichung mit einer Fluxrate oberhalb von 5 μg/cm2 h freizusetzen.12. TTS according to one or more of the preceding claims, characterized in that it is capable of releasing the active ingredient pramipexole over a period of between 24 hours from administration to 168 h from administration at a flux rate above 5 μg / cm 2 h. 13. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß es befähigt ist, den Wirkstoff Pramipexol über den Zeitraum zwischen 24 Stunden ab Verabreichung bis 72 h ab Verabreichung mit einer Fluxrate oberhalb von 5 μg/cm2 h freizusetzen13. TTS according to one or more of the preceding claims, characterized in that it is capable of releasing the active ingredient pramipexole over a period of between 24 hours from administration to 72 hours from administration at a flux rate above 5 μg / cm 2 h 14. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß der Wirkstoff Pramipexol in einem Anteil unterhalb von 75 Gew.-%, vorzugsweise zwischen 2 und 40 Gew.-% und besonders bevorzugt zwischen 10 und 25 Gew.-% darin vorliegt.14. TTS according to one or more of the preceding claims, characterized in that the active ingredient pramipexole in a proportion below 75 wt .-%, preferably between 2 and 40 wt .-% and particularly preferably between 10 and 25 wt .-% therein is present. 15. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß die tägliche Abgaberate von Pramipexol zwischen 0J - 10 mg, vorzugsweise zwischen 0,5 - 4,5 mg liegt. 15. TTS according to one or more of the preceding claims, characterized in that the daily delivery rate of pramipexole is between 0J - 10 mg, preferably between 0.5 - 4.5 mg. 16. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß die wirkstoffhaltige Polymerschicht den Wirkstoff Pramipexol in einer Konzentration unterhalb der Sättigungslöslichkeit enthält.16. TTS according to one or more of the preceding claims, characterized in that the active ingredient-containing polymer layer contains the active ingredient pramipexole in a concentration below the saturation solubility. 17. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß es zwischen 5-40 Gew.-%, vorzugsweise zwischen 10- 20 Gew.-% Butandiol, 1 ,2-Propandiol, Propylenglykol und / oder Lauryllactat enthält.17. TTS according to one or more of the preceding claims, characterized in that it contains between 5-40 wt .-%, preferably between 10- 20 wt .-% butanediol, 1, 2-propanediol, propylene glycol and / or lauryl lactate. 18. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß bis zu 1 % Antioxidantien und / oder Stabilisatoren enthält.18. TTS according to one or more of the preceding claims, characterized in that up to 1% contains antioxidants and / or stabilizers. 19. TTS nach einem oder mehreren der vorangehenden Ansprüche, dadurch gekennzeichnet, daß es zur therapeutischen Behandlung des Krankheitszustands eines Patienten eingesetzt wird, bei dem die Verabreichung von Pramipexol zur Linderung der Symptome und / oder Wiederherstellung der körperlichen Leistungsfähigkeit beiträgt.19. TTS according to one or more of the preceding claims, characterized in that it is used for the therapeutic treatment of the disease state of a patient, in which the administration of pramipexole contributes to the relief of symptoms and / or restoration of physical performance. 20. TTS nach Anspruch 19, dadurch gekennzeichnet, daß der Krankheitszustand des Patienten durch Depression, Tremor, ADHD (attention deficit hyperactivity disorder), Anhedonie, HIV-Demenz, Drogenabhängigkeit, Schizophrenie, ALS (amyotrophic lateral scierosis), Fettleibigkeit (Adipositas), Fettsucht (Obesity) und / oder Diabetes hervorgerufen wird.20. TTS according to claim 19, characterized in that the disease state of the patient through depression, tremor, ADHD (attention deficit hyperactivity disorder), anhedonia, HIV dementia, drug addiction, schizophrenia, ALS (amyotrophic lateral scierosis), obesity (obesity), Obesity and / or diabetes is caused. 21. TTS nach Anspruch 19, dadurch gekennzeichnet, daß der Krankheitszustand des Patienten aufgrund der neuroprotektiven Wirkung und / oder der antikonvulsiven Wirkung von Pramipexol behandelbar ist.21. TTS according to claim 19, characterized in that the disease state of the patient can be treated due to the neuroprotective effect and / or the anticonvulsive effect of pramipexole. 22. TTS nach Anspruch 19, dadurch gekennzeichnet, daß der Krankheitszustand das Restless Leg-Syndrom und / oder die Parkinson'sche Krankheit ist.22. TTS according to claim 19, characterized in that the disease state is the restless leg syndrome and / or Parkinson's disease. 23. Verwendung von Pramipexol zur Herstellung eines selbstklebenden Transdermalen Therapeutischen Systems zur therapeutischen Behandlung des Krankheitszustands eines Patienten, bei dem die Verabreichung von Pramipexol zur Linderung der Symptome und / oder Wiederherstellung der körperlichen Leistungsfähigkeit beiträgt.23. Use of pramipexole for the manufacture of a self-adhesive transdermal therapeutic system for the therapeutic treatment of a patient's disease state, in which the administration of pramipexole helps to alleviate symptoms and / or restore physical performance. 24. Verwendung nach Anspruch 23, dadurch gekennzeichnet, daß der Krankheitszustand des Patienten durch Depression, Tremor, ADHD (attention deficit hyperactivity disorder), Anhedonie, HIV-Demenz, Drogenabhängigkeit, Schizophrenie, ALS (amyotrophic lateral scierosis), Fettleibigkeit (Adipositas), Fettsucht (Obesity) und / oder Diabetes hervorgerufen wird.24. Use according to claim 23, characterized in that the patient's disease state due to depression, tremor, ADHD (attention deficit hyperactivity disorder), anhedonia, HIV dementia, drug addiction, Schizophrenia, ALS (amyotrophic lateral scierosis), obesity (obesity), obesity (obesity) and / or diabetes. 25. Verwendung nach Anspruch 23, dadurch gekennzeichnet, daß der Krankheitszustand des Pateinten aufgrund der neuroprotektiven Wirkung und / oder der antikonvulsiven Wirkung von Pramipexol behandelbar ist.25. Use according to claim 23, characterized in that the disease state of the patient can be treated due to the neuroprotective effect and / or the anticonvulsive effect of pramipexole. 26. Verwendung nach Anspruch 23, dadurch gekennzeichnet, daß der Krankheitszustand das Restless-Ieg Syndrom und / oder die Parkinson'sche Krankheit ist.26. Use according to claim 23, characterized in that the disease state is the Restless-Ieg syndrome and / or Parkinson's disease. 27. Verfahren zur Behandlung zur therapeutischen Behandlung des Krankheitszustands eines Patienten, bei dem die Verabreichung von Pramipexol zur Linderung der Symptome und / oder Wiederherstellung der körperlichen Leistungsfähigkeit beiträgt, umfassend die Schritte: a) Befestigen eines transdermalen therapeutischen Systems (TTS), welches eine Rückschicht und mindestens eine wirkstoffhaltige Polymerschicht mit dem Wirkstoff Pramipexol enthält auf einer unverletzten Stelle der Haut eines Patienten, und b) kontinuierliches Verabreichen des Wirkstoffs Pramipexol an die Haut des Patienten über einen längeren Zeitraum, dadurch gekennzeichnet, daß das Befestigen mittels einer wirkstoffhaltigen Polymerschicht erfolgt, die mindestens ein haftklebendes Polymer aus der Gruppe der Silicone (Polydimethylsiloxane), der Polyisobutylene, der Polybutene, der Styrol-Isopren-Styrol-Block-Copolymere in Kombination mit Harzen, und der carboxylgruppenfreien Polyacrylate enthält.27. A method of treatment for the therapeutic treatment of a patient's disease state, in which the administration of pramipexole helps to relieve symptoms and / or restore physical performance, comprising the steps of: a) attaching a transdermal therapeutic system (TTS) which comprises a backing layer and at least one active ingredient-containing polymer layer with the active ingredient pramipexol contains on an uninjured area of the skin of a patient, and b) continuous administration of the active ingredient pramipexol to the patient's skin over a longer period of time, characterized in that the attachment is carried out by means of an active ingredient-containing polymer layer which contains at least one pressure-sensitive adhesive polymer from the group of silicones (polydimethylsiloxanes), polyisobutylenes, polybutenes, styrene-isoprene-styrene block copolymers in combination with resins, and carboxyl-free polyacrylates. 28. Verfahren nach Anspruch 27, dadurch gekennzeichnet, daß der Krankheitszustand des Patienten durch Depression, Tremor, ADHD (attention deficit hyperactivity disorder), Anhedonie, HIV-Demenz, Drogenabhängigkeit, Schizophrenie, ALS (amyotrophic lateral scierosis), Fettleibigkeit (Adipositas), Fettsucht (Obesity) und / oder Diabetes hervorgerufen wird.28. The method according to claim 27, characterized in that the patient's disease state due to depression, tremor, ADHD (attention deficit hyperactivity disorder), anhedonia, HIV dementia, drug addiction, schizophrenia, ALS (amyotrophic lateral scierosis), obesity (obesity), Obesity and / or diabetes is caused. 29. Verfahren nach Anspruch 27, dadurch gekennzeichnet, daß der Krankheitszustand des Patienten aufgrund der neuroprotektiven Wirkung und / oder der antikonvulsiven Wirkung von Pramipexol behandelbar ist.29. The method according to claim 27, characterized in that the disease state of the patient is treatable due to the neuroprotective effect and / or the anticonvulsant effect of pramipexole. 30. Verfahren nach Anspruch 27, dadurch gekennzeichnet, daß der Krankheitszustand das Restless Leg-Syndrom und / oder die Parkinson'sche Krankheit ist. 30. The method according to claim 27, characterized in that the disease state is the restless leg syndrome and / or Parkinson's disease.
EP04740987A 2003-07-23 2004-07-14 Transdermaltherapeutic system containing a pramipexol active agent Withdrawn EP1651215A1 (en)

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