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
  • 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

• 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
• Active substance contains an ergoline derivative or its salt for the manufacture of a medicament for achieving and maintaining the circadian rhythm under dopaminergic therapy.
• 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 ingredient is not necessarily immobilized in an active ingredient reservoir, which is why the active ingredient 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 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 for different Indication, 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 ability to achieve circadian profiles (e.g. with low, possibly constant stimulation during the night or a break) are particularly important here and have 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 plasma concentration is not constant, but is subject to large fluctuations, and not only for kinetic reasons (very variable first-pass effect depending on the
• Metabolization type but also depending on the individual boundary conditions of the intake (type and time of food intake, effect of other pharmaceuticals on absorption and metabolism, etc.) Therefore, there is also the risk of a temporary overdose with the consequence of, for example, REM suppression and resulting sleep disorders or psychoses.
• a transdermal therapeutic system according to the invention described below can also achieve an individually metered, easily controllable and controlled duration of action (if necessary by removing the patch) without influencing the circadian rhythm, which is often the result of therapy for Parkinson's disease and is disturbed in other dopaminergic diseases.
• the invention is based on the technical problem of providing a means for achieving and maintaining the circadian rhythm which can be individually metered, easily controlled and the duration of action can be controlled well, and thus the circadian disorders which occur under dopaminergic therapy in the treatment of dopaminergic Diseases, especially in the treatment of Parkinson's patients, prevented.
• the ⁇ -adrenolytic effect of lisuride and the ergoline derivatives of the formula I has the further advantage in this form of use that nighttime urge to urinate and other bladder dysfunctions, as is not uncommon in Parkinson's patients (also due to prostate hyperplasia) be improved, which also contributes to the success of the therapy.
• the invention teaches 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 to the skin side of the active substance reservoir Diffusion barrier and as an active ingredient contains an ergoline derivative according to formula I or its physiologically compatible salt with an acid,
• TTS transdermal therapeutic system
• Double bond is in which 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 a means of achieving and maintaining the circadian rhythm under continuous dopaminergic therapy.
• Suitable salts of the active substances are, for example, sulfates, phosphates, maleates, citrates and succinates and, in particular, hydrogen maleate.
• the invention is based on the surprising finding that with an ergoline derivative of the formula I or its salt, which is highly effective and has a short half-life (0.5 to 4 hours, in particular 1 to 2 hours), circadian disorders under dopaminergic therapies are avoided.
• a particular advantage of the invention is that a continuous active substance flux is established and thus the plasma concentrations can be set in a defined manner and checked with regard to the course.
• Plasma for example depending on the type and time of food intake, can be practically eliminated with the invention.
• an overdose and consequently REM suppression and other sleep pattern disorders
• it can be discontinued comparatively quickly, namely simply by removing the TTS.
• the drop in the plasma concentration of active substance is additionally accelerated when the TTS decreases.
• the breakdown in the plasma is rapid and controlled, as a result of which "hang over" can also be avoided.
• an exact individual dosage is easily possible by selecting the Flux F and / or the effective area.
• F and effective area are preferably selected such that an effective dose in the range from 10 ⁇ g to 2 mg of active ingredient, preferably, is obtained on the second day of application 50 ⁇ g to 1 mg, (for example lisuride) in the body or 24 hours a day. It is preferred if the matrix and / or the diffusion barrier is selected with the proviso that the transdermal flux F through human skin, measured according to Example 1, in the range from 0.1 to 5.0 ⁇ g / cm * / h, in particular from 0.5 to 2.5 ⁇ g / cm 2 / h.
• a patch of this specification is particularly suitable for achieving continuous plasma concentrations in the range from 0.05 to 5.0 ng / ml, preferably from 0.1 to 0.5 ng / ml, with the active substance lisuride.
• the use of a TTS having a matrix and an ergoline derivative of the formula I or its salt as active ingredient is particularly preferred.
• 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-6-methyl-8 ⁇ -ergolinyl) -1, 1-diethylurea) or its physiologically compatible salt with an acid.
• lisuride and the other ergolines suitable according to the invention is 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 maleate.
• 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 his. This can be formed, for example, with films made of polyethylene or polyester. The thickness is typically 10 to 100 ⁇ m.
• Metallization is the application of a very thin layer (typically less than 1 ⁇ m, usually in the 10-100 nm 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 have a substance selected from the group consisting of "polyacrylate, polyurethane, cellulose ether, silicone, polyvinyl compounds, silicate and mixtures of these substances and copolymers of these polymer compounds", preferably hydrophilic polyacrylate with basic substituents, 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 here 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
• the thickness range of a matrix is typically in the range from 10 ⁇ m to 500 ⁇ m.
• a preferred polyacrylate adhesive as the main matrix component is commercially available under the name GELVA® multipolymer solution 7881, available from Monsanto Kunststoff GmbH,
• Eudragit ® E100 which is available from Röhm, Germany, is a particularly useful product, and is a copolymer of dimethylaminomethyl methacrylate with neutral methacrylic acid esters.
• the diffusion barrier can alternatively have a polymer selected from the group consisting of "cellulose esters, cellulose ethers, silicone, polyolefin and mixtures and copolymers of these substances" as the main barrier component.
• cellulose esters, cellulose ethers, silicone, polyolefin and mixtures and copolymers of these substances as the 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.
• auxiliary 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, fatty acid esters from C3 -19- Fatty acids and Cl-6-alkyl monools, dicarboxylic acid diesters from C4-8-dicarboxylic acids and Cl-6-alkyl monools, and mixtures of these substances.
• Penetration enhancing agents improve the flux of the active ingredient through the skin to which the TTS is applied.
• examples from the aforementioned 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 for example, are suitable as further auxiliaries. Crystallization inhibitors include highly disperse silicon dioxide or macromolecular substances such as polyvinylpyrrolidones, polyvinyl alcohols, dextrins, dextrans, sterols, bile acids and in particular
• Vinylpyrrolidone-vinyl acetate copolymers are suitable like Kollidon ® VA 64. It goes without saying that the penetration-enhancing agent must also diffuse sufficiently through the matrix or the diffusion barrier. If a matrix is used and the excipient lauryl alcohol, the lauryl alcohol preferably forms 10 to 30% by weight, most preferably 15 to 20% by weight, of the matrix.
• methionine is particularly desirable as a methyl donor, since the degradation of levodopa takes place particularly through O-methylation (COMT) and this results in an increase in homoserine at the required amounts of levodopa (up to a daily dose in the gram range), which is a risk factor for cardiac and cerebral Events applies.
• O-methylation O-methylation
• 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 TTS bearing In addition to the diffusion-related properties of the TTS, the human body also depends 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 .
• patient-specific dose variations 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.
• a TTS which has a (rather large) standard area, with 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.
• these substances can be dosed extremely low (in the case of lisuride: effective daily doses from 0.075 mg po, with a high first-pass effect) and can therefore be used with a TTS at very small application area very simply an effective and Achieve well-controlled active substance levels over the area over 24 hours and longer
• Active ingredients such as B. Cabergolin
• the transdermal dosing of lisuride and comparable active substances not only gives a much better dose (absence of the considerable and very variable first-pass effect after oral administration, e.g. of cabergoline), but the effects can also Need (e.g. if side effects occur) can be removed very quickly by removing the patch. After that, the very short terminal half-life of lisuride in the blood (approx. 2 h) comes into play - in contrast to the day-long side effects of oral dopamine agonists once taken.
• C A phase with reduced dopaminergic stimulation e.g. B. to reduce side-time-specific side effects, either by maintaining an interval between the patch removal and applying the new patch, or, more simply, by the simultaneous use of a new patch with very slow flooding (tmax »t / 2) at the time of the decrease.
• the invention also teaches a TTS set for the treatment of achieving and maintaining continuous receptor stimulation with a circadian rhythm, particularly in the case of
• the set containing a plurality of TTS elements the elements being set up to deliver different doses.
• the TTS elements can be separated from one another, the TTS elements being set up with a continuously increasing sequence for F in the range from 0.1 to 5 ⁇ g / cm 2 / h.
• the TTS elements can be equipped with different effective areas in a continuous sequence. In the latter case, it is possible to work with uniform F values. Then TTS elements can be formed by the markings to be applied on a large TTS construct. Of course, an already separated embodiment is also possible.
• the invention can also be used for other indications.
• One possible application is the use of a TTS according to the invention for producing an agent for the treatment or prevention of the premenstrual syndrome and its symptoms, where F is preferably from 0.1 to 0.5 ⁇ g / cm 2 / h, and the use for producing an agent for lactation inhibition, where F is preferably from 0.1 to 0.5 ⁇ g / cm 2 / h is.
• 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 Ola / Hsd, available from Harlan Olac, UK) are used, carefully removing subcutaneous adipose tissue.
• a 2 cm 2 TTS is applied to the skin used.
• the acceptor medium is arranged opposite. It is dilute HHBSS (Hepes Hanks Balanced Salt Solution) containing 5.96 g / 1 Hepes, 0.35 g / 1 NaHCO 3 and 0.1 ml / 1 lOx HBSS (available from Gibco, Eggenstein, DE).
• 1000 IU / ml Hepes Hanks Balanced Salt Solution
• Penicillin (benzylpenicillin potassium salt, available from Fluka, Neu-Ulm, DE).
• 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 becomes determined according to the following details using a radioimmunoassay.
• Ascorbic acid Ascorbic acid diluted in order to obtain lisuride free base concentrations in the range of 1000-3.9 pg / 0.1 ml.
• a drug-free sample Opg
• the calibration samples are analyzed in triplicate.
• the Lisurid 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 antiserum (rabbit) can be obtained by immunization with the immunogen lisurid-1-succinyl-BSA. The dilution of the antiserum in the assay is 1: 12500.
• Tracer 3 H-Lisuride hydrogen maleate with a specific activity of 4.3 GBq / mg is used. Incubation: 0.7 ml BSA buffer with active ingredient, 0.1 ml tracer solution (approx. 5000 cpm / 0.1 ml BSA buffer) and 0.1 ml diluted antiserum (1: 12500) and it is incubated at 4 ° C. for 18 h.
• 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.
• 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]
• RdenAcceptor medium flow [lml / h]
• A the measuring area [2cm 2 ]
• T the sampling time interval [h].
• 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 2 / h).
• dimethyl isosorbide 12.5 mg are suspended in 15 mg of isopropanol with 2 mg of lisuride.
• 80 mg of polyacrylate adhesive (Gelva 7881) are placed in a beaker and the above suspension is added with rinsing with 30 mg of isopropanol. After thorough mixing, the crystal-free wet mix obtained is extracted with a 500 ⁇ m doctor blade on a siliconized liner. Then at 60 ° C for 20 min. dried and finally a top layer was laminated on.
• Measurements of the flux according to Example 1 give F a day 1 value of 0.23 and a day 2 value of 0.28 and a maximum F of 0.50 (each 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 1.6 and a maximum F of 2.4 (each in ⁇ g / cm 2 / h).

Landscapes

• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Epidemiology (AREA)
• Dermatology (AREA)
• Urology & Nephrology (AREA)
• Pregnancy & Childbirth (AREA)
• Pain & Pain Management (AREA)
• Psychology (AREA)
• Diabetes (AREA)
• Gynecology & Obstetrics (AREA)
• Psychiatry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Electrotherapy Devices (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Materials For Medical Uses (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

Priority Applications (11)

Applications Claiming Priority (2)

Related Child Applications (1)

Publications (1)

Family

ID=7654783

Family Applications (2)

Family Applications After (1)

Country Status (10)

Cited By (5)

Families Citing this family (19)

Citations (8)

Family Cites Families (105)

• 2000
  • 2000-08-24 DE DE10066158A patent/DE10066158B4/de not_active Expired - Fee Related
  • 2000-08-24 DE DE10043321A patent/DE10043321B4/de not_active Expired - Fee Related
• 2001
  • 2001-08-24 PT PT01978305T patent/PT1311248E/pt unknown
  • 2001-08-24 JP JP2002520810A patent/JP2004530631A/ja active Pending
  • 2001-08-24 US US10/362,248 patent/US20040101550A1/en not_active Abandoned
  • 2001-08-24 EP EP01978306A patent/EP1311249B1/de not_active Expired - Lifetime
  • 2001-08-24 AT AT01978306T patent/ATE444742T1/de not_active IP Right Cessation
  • 2001-08-24 DK DK01978305T patent/DK1311248T3/da active
  • 2001-08-24 JP JP2002520811A patent/JP2004506682A/ja active Pending
  • 2001-08-24 DE DE50112452T patent/DE50112452D1/de not_active Expired - Lifetime
  • 2001-08-24 US US10/362,183 patent/US20040028723A1/en not_active Abandoned
  • 2001-08-24 DK DK01978306.7T patent/DK1311249T3/da active
  • 2001-08-24 AU AU1046202A patent/AU1046202A/xx active Pending
  • 2001-08-24 AT AT01978305T patent/ATE361062T1/de not_active IP Right Cessation
  • 2001-08-24 AU AU1046302A patent/AU1046302A/xx active Pending
  • 2001-08-24 DE DE50115161T patent/DE50115161D1/de not_active Expired - Lifetime
  • 2001-08-24 WO PCT/EP2001/009824 patent/WO2002015890A1/de not_active Ceased
  • 2001-08-24 WO PCT/EP2001/009823 patent/WO2002015889A1/de not_active Ceased
  • 2001-08-24 AU AU2002210462A patent/AU2002210462B2/en not_active Ceased
  • 2001-08-24 EP EP01978305A patent/EP1311248B1/de not_active Expired - Lifetime
  • 2001-08-24 ES ES01978305T patent/ES2286146T3/es not_active Expired - Lifetime
  • 2001-08-24 AU AU2002210463A patent/AU2002210463B2/en not_active Ceased
• 2005
  • 2005-04-28 US US11/116,279 patent/US20050220855A1/en not_active Abandoned

Patent Citations (11)

Also Published As

Similar Documents

Legal Events