WO2002015889A1 - Transdermales therapeutisches system zur behandlung des restless-legs-syndroms - Google Patents

Transdermales therapeutisches system zur behandlung des restless-legs-syndroms Download PDF

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Publication number
WO2002015889A1
WO2002015889A1 PCT/EP2001/009823 EP0109823W WO0215889A1 WO 2002015889 A1 WO2002015889 A1 WO 2002015889A1 EP 0109823 W EP0109823 W EP 0109823W WO 0215889 A1 WO0215889 A1 WO 0215889A1
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WO
WIPO (PCT)
Prior art keywords
matrix
active substance
tts
diffusion barrier
skin
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.)
Ceased
Application number
PCT/EP2001/009823
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German (de)
English (en)
French (fr)
Inventor
Reinhard Horowski
Johannes Tack
Adalbert Engfer
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.)
NeuroBiotec GmbH
Bayer Pharma AG
Original Assignee
NeuroBiotec GmbH
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2002520810A priority Critical patent/JP2004530631A/ja
Priority to AU2002210462A priority patent/AU2002210462B2/en
Priority to DE50112452T priority patent/DE50112452D1/de
Priority to US10/362,183 priority patent/US20040028723A1/en
Priority to AU1046202A priority patent/AU1046202A/xx
Priority to EP01978305A priority patent/EP1311248B1/de
Application filed by NeuroBiotec GmbH, Schering AG filed Critical NeuroBiotec GmbH
Priority to DK01978305T priority patent/DK1311248T3/da
Publication of WO2002015889A1 publication Critical patent/WO2002015889A1/de
Anticipated expiration legal-status Critical
Priority to US11/087,754 priority patent/US20070243240A9/en
Priority to US11/116,279 priority patent/US20050220855A1/en
Priority to US11/116,278 priority patent/US20050214353A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A61P5/08—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

  • Transdermal therapeutic system for the treatment of restless legs syndrome
  • the invention relates to the use of a transdermal therapeutic system (TTS) comprising a medicament layer which contains at least one matrix containing an active substance and / or an active substance reservoir and an active substance-permeable diffusion barrier on the skin side of the active substance reservoir as well as an ergoline derivative or its salt as active substance a medicine to treat restless legs syndrome.
  • TTS transdermal therapeutic system
  • Restless Legs Syndro is a neurological disorder that occurs in all age groups, but more often in older age, and the symptoms of which mainly manifest themselves in the fact that cramps and leg pain occur as a result of dysesthesia and paraesthesia Trigger urge to move. Since these symptoms usually become noticeable at night or during periods of reduced activity such as sitting and resting, the urge to move leads to restlessness during the day and sleep disorders at night. This significantly affects the quality of life of those affected.
  • Medications such as Lisurid in the evening lead to an improvement in the symptoms and a general negative impact on the quality of life being affected.
  • Parkinson's therapy in which dopaminergic pharmaceuticals and their combinations are taken throughout the day, the development of a tolerance to the acute (flooding-related) dopaminergic side effects is impaired in the case of a single oral intake for the treatment of restless legs syndrome, ie Known side effects such as orthostasis, hypotension, dizziness, nausea and vomiting may occur with each effective dose.
  • Unpredictable and uncontrollable sleep attacks can also occur.
  • the plasma concentration is not constant, but is subject to large fluctuations, not only for kinetic reasons, but also depending on the individual boundary conditions of the intake (type and time of food intake, etc.). Therefore, there is also the risk of intermittent overdosing, with the result of, for example, REM suppression and the resulting problems and sleep disorders.
  • the invention is based on the technical problem of specifying an agent for the treatment of restless legs syndrome which is free of side effects, but at least shows significantly reduced side effects compared to oral administration, in particular allows the active ingredient to slowly flood in and the amount and duration of which can be controlled well.
  • a transdermal therapeutic system according to the invention described below can also achieve an individually desired controlled duration of action (possibly by removing the plaster).
  • the TTS increases bioavailability, which means that the total dose required to achieve the therapeutically desired effect can be reduced.
  • the ⁇ -adrenolytic effect of lisuride and its derivatives has the further advantage in this form of use that nocturnal urge to urinate and other bladder dysfunctions, as is not uncommon in restless leg and Parkinson's patients (also due to the prostate) -Hyperplasia), is significantly improved, which also contributes to the success of the therapy.
  • the invention relates to the use of a transdermal therapeutic system (TTS) comprising a medicament layer which has at least one matrix containing an active substance and / or an active substance reservoir and an active substance-permeable diffusion barrier on the skin side of the active substance reservoir, and as an active substance an ergoline derivative according to formula I or its physiologically tolerable salt with an acid,
  • TTS transdermal therapeutic system
  • Rl is an H atom or a halogen atom, in particular a bromine atom, and in which R2 is Cl-4-alkyl, in particular methyl, as an agent for the treatment of restless legs syndrome.
  • Diffusion barrier is selected with the proviso that the transdermal flux F through human skin, measured according to Example 1, is in the range from 0.1 to 2.0 ⁇ g / cm 2 / h.
  • ergoline derivatives examples include: bromoisuride (3- (2-bromo-9, 10-didehydro-6-methyl-8 ⁇ -ergolinyl) -1, 1-diethylurea), terguride (3- (6-methyl-8 ⁇ -ergolinyl) ) -1, 1-diethylurea) and proterguride (3- (6-propyl-8 ⁇ -ergolinyl) -1, 1-diethylurea).
  • the ergoline derivative is lisuride (3- (9, 10-didehydro- ⁇ -methyl- ⁇ -ergolinyl) -1, 1-diethylurea) or its physiologically compatible salt with an acid.
  • Lisurid and the others Ergolines suitable according to the invention are described for example in US 3,953,454, EP 056 358 and US 4,379,790.
  • Possible salts of the ergoline derivative are, for example, sulfates, phosphates, maleates, citrates and succinates and, in particular, hydrogen aleate.
  • TTS encompasses percutaneously acting systems, but also transmucosal systems.
  • a TTS is typically of a flat structure and is applied, for example, to the skin. Attachment to the skin can be carried out using an additional adhesive on the skin side (and permeable to the active ingredient).
  • the matrix and / or the diffusion barrier itself can be provided with adhesive properties.
  • a non-adhesive TTS can be brought into contact with the skin by means of further aids, for example adhesive tapes or bandages.
  • a matrix is a substance in which the active ingredient is immobilized. In contrast, the active substance is not necessarily immobilized in an active substance reservoir, which is why the active substance reservoir must be encased.
  • the part of the jacket on the skin side is formed by the diffusion barrier.
  • the further part of the jacket should be as impermeable as possible, also with regard to diffusion paths, for the active substance.
  • immobilized means that no uncontrolled flow of active ingredients is possible.
  • diffusion of an active ingredient in a matrix and / or through a diffusion barrier is not only possible, but set up specifically.
  • the diffusion coefficients ultimately determine the flux of the active ingredient from the TTS in a patient's skin.
  • the dose delivered to a patient's skin is therefore, in a first approximation, a linear function of the effective area of the TTS.
  • the effective area is the contact area of areas of the TTS that are open to diffusion for active substances.
  • TTS can be used for both human and veterinary purposes.
  • a TTS of the structure mentioned at the outset is known in principle from the literature reference WO 92/20339. This particularly describes the effect of propylene glycol lauric acid on the flux, which achieves a considerable increase in flux.
  • the values given relate to solutions applied to skin samples and not to the actual TTS. No information regarding the flux is given for these. In a TTS, significantly lower flux values are achieved compared to values from a solution order.
  • a TTS containing lisuride is also known from literature reference WO 91/00746.
  • the flux values given therein for human skin samples are not readily transferable to achievable in vivo values.
  • TTS of the structure described are used for various indications, including Parkinson's.
  • Parkinson's In the case of treatment for Parkinson's disease, the highest possible doses are desirable.
  • a transdermal therapeutic system also improves compliance, which is of great importance for the combination therapies of this disease and its mostly old and multimorbid patients. Better controllability and the possibility of Achieving circadian profiles (e.g. with minimal, as constant as possible stimulation during the night or a break) is particularly cheap here and has not been achieved so far (e.g. to avoid psychosis and improve sleep quality).
  • their dopamine-partial agonistic or partial antagonistic effect also helps to prevent the development of psychoses or to improve existing psychoses and similar problems.
  • the TTS can be designed in detail as follows.
  • a cover layer can be arranged on the side of the matrix and / or the active substance reservoir facing away from the skin. This can be formed, for example, with films made of polyethylene or polyester. The thickness is typically 10 to 100 ⁇ m. It is possible to pigment and / or metallize the top layer to achieve adequate light protection.
  • Metallization is the application of a very thin layer (typically less than 1 ⁇ m, usually in the 10-100 ⁇ m range) of a metal, for example aluminum, to the top layer.
  • Pigments can be all pigments commonly used in the coating compositions, including effect pigments, provided that they are physiologically harmless.
  • a removable liner can be provided on the application side, for example a siliconized or fluoropolymer-coated polymeric protective film.
  • the matrix and / or diffusion barrier can be a substance selected from the group consisting of "polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, silicate and mixtures thereof Substances and copolymers of these polymer compounds ", preferably polyacrylate, as the main matrix component.
  • a main matrix component forms at least 50% by weight, for example at least 80-90% by weight, of the matrix (the term matrix refers to the finished layer, ie main matrix component (s) with auxiliary substance (s) and active substance (s))
  • the desired flux is set on the one hand by selecting the substance depending on the diffusion coefficient of the active substance therein and on the other hand and if necessary in coordination with this by selecting the layer thickness of the matrix in the orthogonal direction
  • the thickness range of a matrix is typically in the range from 10 ⁇ m to 500 ⁇ m.
  • a preferred polyacrylate adhesive as main matrix component is commercially available under the name GELVA ® multi polymer solution 7881, available from Monsanto Germany GmbH, Dusseldorf. In this context, express reference is made to the product sold under this name in accordance with the data sheet in the version dated April 23, 1996. Eudragit ® E100, also available from Röhm, Germany, can also be used well.
  • the diffusion barrier can alternatively be a polymer selected from the group consisting of "cellulose esters, cellulose ethers, silicone, polyolefin and mixtures and copolymers of these substances" as Have main barrier component.
  • the diffusion barrier can be designed as a film with a thickness of 10 ⁇ m to 300 ⁇ m, the thickness of the layer (in conjunction with the diffusion coefficient of the active ingredient in the polymer) being adjusted in accordance with the desired flux.
  • the matrix and / or the drug reservoir and / or the diffusion barrier can contain auxiliaries customary for TTS.
  • a penetration-enhancing agent which is preferably selected from the group consisting of "C1-C8 aliphatic, cycloaliphatic and aromatic alcohols, saturated and unsaturated C8-18 fatty alcohols, saturated and unsaturated C8-18 fatty acids, hydrocarbons and hydrocarbon mixtures, is preferably used as auxiliary. Fatty acid esters from C3-19 fatty acids and Cl-6 alkyl monools,
  • Penetration enhancing agents improve the flux of the active ingredient through the skin to which the TTS is applied. Examples from the above
  • Substances are: 1, 2-propanediol, menthol, dexpanthenol, benzyl alcohol, lauryl alcohol, isocetyl alcohol, cetyl alcohol, mineral oil, lauric acid, isopalmitic acid, isostearic acid, oleic acid; Methyl ester, ethyl ester, 2-hydroxyethyl ester, glycerol ester, propyl ester, isopropyl ester, butyl ester, sec. -Butyl ester or isobutyl ester of lauric acid, myristic acid, stearic acid or palmitic acid.
  • Crystallization inhibitors include highly disperse silicon dioxide or macromolecular substances such as
  • Polyvinylpyrrolidones polyvinyl alcohols, dextrans, dextrans, sterols, bile acids and especially vinylpyrrolidone-vinyl acetate copolymers are suitable, such as Kollidon ® VA 64.
  • the penetration-enhancing agent must also diffuse sufficiently through the matrix or the diffusion barrier.
  • the lauryl alcohol preferably forms 10 to 30% by weight, most preferably 15 to 20% by weight, of the matrix.
  • the auxiliary substances can in principle form 0 to 50% by weight of the matrix.
  • the active ingredient can form 0.2 to 20% by weight, preferably 1 to 10% by weight, of the matrix.
  • the main matrix component, auxiliary substances and active substances always form 100% by weight.
  • the dose of the active ingredient in a human body carrying the TTS depends not only on the above diffusion-related properties of the TTS but also on its effective area with the skin. Effective area means the area with which the matrix or the diffusion barrier comes to rest against the skin.
  • the variation preferably takes place in accordance with the desired dose in a range from 1 to 100 cm 2 .
  • dose variations which are easy for the patient can be set up by a doctor, namely by choosing a suitable size. The treatment can thus be easily adjusted to different body weights, age groups, etc.
  • TTS which has a (rather large) standard area
  • division markings for partial doses so that a user can only separate and use a partial section corresponding to a specific dose.
  • Corresponding imprints can easily be attached to the top layer.
  • TTS for the production of an agent for the treatment or prevention of premenstrual syndrome or its symptoms
  • F being preferably from 0.1 to 0.5 ⁇ g / cm 2 / h
  • F is preferably from 0.1 to 0.5 ⁇ g / cm 2 / h
  • a FRANZ flow diffusion cell is used for the flux measurement.
  • the measuring area is 2 cm 2 . 4 cm 2 ventral and dorsal skin of a male hairless mouse (MFl hr / hr
  • Hsd Ola / Hsd, available from Harlan Olac, UK), carefully removing subcutaneous fat. A 2 cm 2 TTS is applied to the skin used. The acceptor medium is arranged opposite. It is diluted HHBSS (Hepes Hanks Balanced Salt
  • the measurement is carried out in detail as follows.
  • the TTS to be measured is first applied to the skin.
  • the skin is mounted in the diffusion cell.
  • 1 ml of acceptor medium are pumped through the diffusion cell per hour using a peristaltic pump.
  • the temperature of the acceptor medium is controlled by means of a circulating water bath and keeps the surface of the skin at a temperature of 31 ° C with 1 ° C Accuracy.
  • the drug concentration in the acceptor medium is determined according to the following details using a radioimmunoassay.
  • Calibration curves are constructed using two different methanol solutions of non-radioactive lisuride hydrogen maleate salt, each containing 1 mg / ml. These solutions are different with BSA buffer (0.041 M Na2HP ⁇ 2 * 2H2 ⁇ ,
  • BSA pH 7, supplemented with 0.05% (w / v) ascorbic acid) diluted in order to obtain lisuride free base concentrations in the range of 1000-3.9 pg / 0.1 ml.
  • an active ingredient-free sample Opg
  • the calibration samples are analyzed in triplicate.
  • the lisuride concentrations are calculated using the pharmacokinetic RIO PC software, 2.5 (other conventional software can also be used).
  • sample preparation Before the analysis, the acceptor medium is diluted with BSA buffer in order to set concentrations in the evaluable area of the calibration curve. 100 ⁇ l of diluted sample are directly subjected to radioimmunological analysis.
  • the antiseru (rabbit) is obtainable by immunization with the immunogen Lisurid-1 succinyl-BSA. The dilution of the antiserum in the assay is 1: 12500.
  • Antibody-bound lisuride is freed by adding 0.2 ml charcoal suspension (1.25% (w / v) and 0.125% (w / v) dextran in BSA buffer) and incubation for 30 min. separated at 0 ° C. The charcoal is centrifuged at 3000 g for 15 min. sedimented. The supernatant (containing antibody-bound active ingredient) is decanted and sent for radiometric analysis.
  • Radiometric analysis 4 ml of the Atomlight (NEN) scintillation cocktail are added to the supernatant. The counting is done with a WALLAC 1409 or 1410 ß scintillation counter without quench control.
  • the percutaneous skin flux is calculated as follows:
  • F is the percutaneous flux [ng / cm 2 / h]
  • C the active substance concentration in the acceptor medium [ng / ml]
  • R the acceptor medium flow [lml / h]
  • A the measuring area [2cm 2 ]
  • T the sampling time interval [h].
  • Maximum transdermal drug flux is taken directly from the data.
  • Measurements of the flux according to Example 1 give F a day 1 value of 0.43, a day 2 value of 0.44 and a maximum F of 0.85 (each in ⁇ g / cm / h).
  • Measurements of the flux according to Example 1 give F a day 1 value of 0.23, a day 2 value of 0.28 and a maximum F of 0.50 (in each case in ⁇ g / cm 2 / h).
  • Measurements of the flux according to Example 1 give F a day 1 value of 0.90, a day 2 value of 1.76 and a maximum F of 2.53 (each in ⁇ g / cm 2 / h).

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PCT/EP2001/009823 2000-08-24 2001-08-24 Transdermales therapeutisches system zur behandlung des restless-legs-syndroms Ceased WO2002015889A1 (de)

Priority Applications (10)

Application Number Priority Date Filing Date Title
DK01978305T DK1311248T3 (da) 2000-08-24 2001-08-24 Transdermalt terapeutisk system til behandling af Restless Legs syndromet
AU2002210462A AU2002210462B2 (en) 2000-08-24 2001-08-24 Transdermal therapeutic system for treating restless-legs-syndrome
DE50112452T DE50112452D1 (de) 2000-08-24 2001-08-24 Transdermales therapeutisches system zur behandlung des restless-legs-syndroms
US10/362,183 US20040028723A1 (en) 2000-08-24 2001-08-24 Transdermal therapeutic system for treating restless-legs-syndrome
AU1046202A AU1046202A (en) 2000-08-24 2001-08-24 Transdermal therapeutic system for treating restless-legs-syndrome
JP2002520810A JP2004530631A (ja) 2000-08-24 2001-08-24 不穏下肢症候群治療用経皮治療系
EP01978305A EP1311248B1 (de) 2000-08-24 2001-08-24 Transdermales therapeutisches system zur behandlung des restless-legs-syndroms
US11/087,754 US20070243240A9 (en) 2000-08-24 2005-03-24 Transdermal therapeutic system
US11/116,278 US20050214353A1 (en) 2000-10-20 2005-04-28 Transdermal therapeutic system
US11/116,279 US20050220855A1 (en) 2000-08-24 2005-04-28 Transdermal therapeutic system

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10043321A DE10043321B4 (de) 2000-08-24 2000-08-24 Verwendung eines transdermalen therapeutischen Systems zur Behandlung der Parkinsonschen Krankheit, zur Behandlung und Prävention des prämenstruellen Syndroms und zur Lactationshemmung
DE10043321.9 2000-08-24

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/087,754 Continuation-In-Part US20070243240A9 (en) 2000-08-24 2005-03-24 Transdermal therapeutic system

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EP1311248B1 (de) 2007-05-02
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AU2002210463B2 (en) 2006-06-29
PT1311248E (pt) 2007-07-30
ES2286146T3 (es) 2007-12-01
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DE10066158B4 (de) 2007-08-09
EP1311249A1 (de) 2003-05-21
AU1046302A (en) 2002-03-04
US20040028723A1 (en) 2004-02-12
US20040101550A1 (en) 2004-05-27
US20050220855A1 (en) 2005-10-06
AU2002210462B2 (en) 2005-11-03
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EP1311248A1 (de) 2003-05-21
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DK1311248T3 (da) 2007-08-20
WO2002015890A1 (de) 2002-02-28
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ATE444742T1 (de) 2009-10-15
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