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WO2003011340A1 - Medicament formulation for topical application in the therapy and prophylaxis of hyperhidrosis - Google Patents

Medicament formulation for topical application in the therapy and prophylaxis of hyperhidrosis Download PDF

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Publication number
WO2003011340A1
WO2003011340A1 PCT/EP2002/008101 EP0208101W WO03011340A1 WO 2003011340 A1 WO2003011340 A1 WO 2003011340A1 EP 0208101 W EP0208101 W EP 0208101W WO 03011340 A1 WO03011340 A1 WO 03011340A1
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Prior art keywords
hyperhidrosis
glycopyrrolate
salts
derivatives
enantiomers
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PCT/EP2002/008101
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German (de)
French (fr)
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Johannes Wohlrab
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Johannes Wohlrab
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Publication of WO2003011340A1 publication Critical patent/WO2003011340A1/en

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • the invention relates to a pharmaceutical formulation for topical use for the therapy and prophylaxis of hyperhidrosis axillary, palmaris et plantaris and other forms of hyperhidrosis.
  • This pharmaceutical formulation is based on the use of glycopyrrolate, its salts and / or its derivatives.
  • glycopyrronium bromide with the chemical formula 3- (cyclopentylhydroxyphenyl-acetoxy) -1, 1-dimethylpyrronium bromide is a spasmolytic, anticholinergic (parasympatholytic)
  • GPB has an effect.
  • the mechanism of action is due to a blockade of the muscarinic receptors.
  • the strong hydrophilicity of GPB prevents passage through the blood-brain barrier and thus central effects.
  • the molar mass of the glycopyrronium bromide is 398.36 g / mol and the melting point of the compound is 193-198 ° C.
  • GPB is a white powder.
  • the stability of this compound is pH-dependent, the stability decreasing at a pH> 6.
  • GPB is a slightly water-soluble compound.
  • GPB has so far been used primarily as a secretion-inhibiting and spasmolytic substance in adjuvant therapy with special anesthetic or surgical procedures.
  • BTX botulinum toxin
  • a pharmaceutical formulation for topical use for the therapy and prophylaxis of hyperhidrosis axillary, palamaris et plantaris and / or other forms of hyperhidrosis is provided.
  • This pharmaceutical formulation contains a glycopyrrolate, its salts and / or its derivatives and / or its enantiomers in an amount between 0.05 and 20% by weight.
  • a gel and / or colloid-containing carrier system is used as the vehicle system.
  • the application is not locally restricted here; rather, these vehicle systems enable the pharmaceutical formulation according to the invention to can be easily applied in the armpit area, for example, and even with increased sweat secretion, the penetration of the active ingredient can be ensured over a longer period of time compared to aqueous solutions.
  • glycopyrrolate, its salts and / or its derivatives are preferably used in a concentration of between 0.5 and 5% by weight.
  • Glycopyrronium bromide is preferably used as the salt of the glycopyrrolate.
  • hydroxyethyl cellulose gel is preferably used.
  • glycopyrrolate, its salts and / or its derivatives and / or its enantiomers for the manufacture of a medicament for topical use for the therapy and prophylaxis of hyperhidrosis axillaris, palmaris et plantaris and / or other forms of hyperhidrosis is also used according to the invention taught.
  • the compound is used in a concentration between 0.05 to 20% by weight, preferably between 0.5 and 5% by weight.
  • Three concentrations were placebo-controlled with GPB (0.5; 2.0; 4.0%) in hydroxyethyl cellulose gel (hydroxyethyl cellulose 10000 2.5 parts; glycerol 85% 10.0 parts; water (cons.) 87, 5 parts) examined for their effectiveness.
  • the hyperhidrosis was objectified using quantitative hidroiuetry.
  • Group 1 1 week 3 times a day + 3 weeks 1 time a day
  • Group 2 2 weeks 2 times a day + 2 weeks 1 time a day
  • Group 3 1 week 3 times a day + 1 week 2 times a day + 2 weeks 1 time a day
  • Group 4 4 weeks 3 times a day
  • the hyperhidrosis was objectified using quantitative hydrometry.
  • the analysis of variance was used to analyze three and more samples (treatment groups) from normally distributed populations with the same variance. Since only one factor, the influence of the investigational medicinal product, was to be examined in the various mean value groups, the one-way analysis of variance (one-way ANOVA) was used. Here random samples with unknown common variance are examined. In addition, the differences between the individual groups will be examined using the Scheffe assessment of linear contrasts. For comparison of three or more independent groups, the Kruskal-Wallis-Test (H-Test) was offered, which tests the analog hypotheses of the one-way analysis of variance as a non-parametric test. The unpaired t-test was used to compare two samples with the same variance. Differences with an error probability of p ⁇ 0.05 were rated as statistically significant.
  • H-Test Kruskal-Wallis-Test
  • test preparations were stored in 75 ml glass jars with a ball attachment.
  • hydroxyethyl cellulose gel as a vehicle system is only suitable for the therapy of hyperhidrosis axillaris, but not for hyperhidrosis palmaris (FIG. 2).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Cosmetics (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a medicament formulation for topical application in the therapy and prophylaxis of hyperhidrosis axillaris, palmaris and plantaris in addition to other forms of hyperhidrosis. The inventive medicament formulation is based on the use of glycopyrrolate, the salts thereof and/or the derivatives thereof.

Description

Arzneiformulierung zur topischen Anwendung für die Therapie und Prophylaxe von Hyperhidrosis Drug formulation for topical use for the therapy and prophylaxis of hyperhidrosis
•Die Erfindung betrifft eine Arzneiformulierung zur topischen Anwendung für die Therapie und Prophylaxe von Hyperhidrosis axillaris, palmaris et plantaris sowie weitere Formen der Hyperhidrosis. Diese Arzneiformulierung basiert auf der Verwendung von Glycopyr- rolat, dessen Salzen und/oder dessen Derivaten.• The invention relates to a pharmaceutical formulation for topical use for the therapy and prophylaxis of hyperhidrosis axillary, palmaris et plantaris and other forms of hyperhidrosis. This pharmaceutical formulation is based on the use of glycopyrrolate, its salts and / or its derivatives.
Es ist bekannt, daß Glycopyrroniumbromid (GPB) mit der chemischen Formel 3- (Cyclopentylhydroxyphenyl- acetoxy) -1, 1-dimethylpyrroniumbromid einen spasmoly- tischen, anticholinergenen (parasympatholytischen)It is known that glycopyrronium bromide (GPB) with the chemical formula 3- (cyclopentylhydroxyphenyl-acetoxy) -1, 1-dimethylpyrronium bromide is a spasmolytic, anticholinergic (parasympatholytic)
Wirkeffekt besitzt. Der Wirkmechanismus ist dabei auf eine Blockade der Muskarinrezeptoren zurückzuführen. Durch die starke Hydrophilie von GPB werden eine Passage der Blut-Hirn-Schranke und damit zentrale Effek- te verhindert. Demzufolge kommt es selbst nach syste- matischer Applikation, entsprechend der physiologischen Verteilung der Muskarinrezeptoren, lediglich zu einer Reduktion der Sekretion der Tränen, Speichel- sowie Schweißdrüsen. Die molare Masse des Glycopyrro- niumbromids beträgt 398,36 g/mol und der Schmelzpunkt der Verbindung liegt bei 193-198 °C. Bei Raumtemperatur liegt GPB als weißes Pulver vor. Die Stabilität dieser Verbindung ist dabei pH-abhängig, wobei die Stabilität bei einem pH > 6 abnimmt. Gleichzeitig handelt es sich bei GPB um eine leicht wasserlösliche Verbindung.Has an effect. The mechanism of action is due to a blockade of the muscarinic receptors. The strong hydrophilicity of GPB prevents passage through the blood-brain barrier and thus central effects. As a result, even after system Matic application, according to the physiological distribution of the muscarinic receptors, only to reduce the secretion of tears, saliva and sweat glands. The molar mass of the glycopyrronium bromide is 398.36 g / mol and the melting point of the compound is 193-198 ° C. At room temperature, GPB is a white powder. The stability of this compound is pH-dependent, the stability decreasing at a pH> 6. At the same time, GPB is a slightly water-soluble compound.
In der Humanmedizin wird GPB bisher vor allem als se- kretionshemmende und spasmolytische Substanz bei der adjuvanten Therapie bei speziellen Narkose- bzw. Operationsverfahren eingesetzt.In human medicine, GPB has so far been used primarily as a secretion-inhibiting and spasmolytic substance in adjuvant therapy with special anesthetic or surgical procedures.
In der US 5,962,505 wird die topische Anwendung einer GPB-haltigen Präparation bei anfallsartig auftreten- der Rötung des Gesichtes beschrieben. Aus LL Hays et al. , The Frey syndrome: a simple effective treat- ment, Otolaryngol Head Neck Surg 90 (1982) 419-425 ist die topische Anwendung von GPB beim Frey-Syndrom, dem sogenannten gustatorischem Schwitzen, bekannt. Aus HR Stegehuis et al . , „Treatment of Frey' s syndrom (gustadory sweating ) with topical glycopyrrolate, N Z Med J 102 (1989) 479 ist die Anwendung einer GPB- haltigen Creme bei diabetischem, gustatorischem Schwitzen, einer Sonderform des Frey-Syndroms, be- kannt. Zur Anwendung kam dabei eine 0,5%ige GPB- haltige Standardzubereitung.US Pat. No. 5,962,505 describes the topical use of a preparation containing GPB in the event of reddening of the face, which may occur in seizures. From LL Hays et al. , The Frey syndrome: a simple effective treatment, Otolaryngol Head Neck Surg 90 (1982) 419-425, the topical application of GPB in Frey syndrome, the so-called gustatory sweating, is known. From HR Stegehuis et al. , "Treatment of Frey's syndrome (gustadory sweating) with topical glycopyrrolate, N Z Med J 102 (1989) 479, the use of a GPB-containing cream for diabetic, gustatory sweating, a special form of Frey syndrome, is known. A 0.5% GPB-containing standard preparation was used.
Für die Therapie der Hyperhidrose werden in der Medizin bislang Metallsalzlösungen, Leitungswasser- Iontophoresen, Gerbstoffe sowie Salbeiextrakte eingesetzt. Meistens weisen diese Therapiemethoden jedoch zu geringe oder gar keine Wirksamkeit auf. Weiterhin wird die intrakutane Injektion von Botulinumtoxin (BTX) angewendet. Diese Applikation ist jedoch sehr schmerzhaft und die Therapie sehr kostenintensiv. Weiterhin bestehen Anregungen für operative Verfahren, die jedoch ein erhöhtes Nebenwirkungspotential beinhalten.Up to now, metal salt solutions, tap water iontophoreses, tannins and sage extracts have been used in medicine for the treatment of hyperhidrosis. Most often, however, these methods of therapy too little or no effectiveness. Intracutaneous injection of botulinum toxin (BTX) is also used. However, this application is very painful and the therapy is very expensive. There are also suggestions for surgical procedures, which, however, contain an increased potential for side effects.
Ausgehend von diesen Nachteilen des Standes der Tech- nik war es daher Aufgabe der vorliegenden Erfindung, eine Arzneiformulierung bereitzustellen, die bei der Therapie und Prophylaxe verschiedener Formen der Hy- perhidrose neben einer hohen Wirksamkeit gleichzeitig die leichte Applizierbarkeit aufweist.Based on these disadvantages of the prior art, it was therefore an object of the present invention to provide a medicament formulation which, in addition to being highly effective, is easy to apply in the therapy and prophylaxis of various forms of hyperhidrosis.
Diese Aufgabe wird durch die Arzneiformulierung mit den Merkmalen des Anspruchs 1 sowie die Verwendung von Glycopyrrolat zur Herstellung eines Arzneimittels zur topischen Anwendung mit den Merkmalen des An- spruchs 7 gelöst.This object is achieved by the pharmaceutical formulation with the features of claim 1 and the use of glycopyrrolate for the manufacture of a medicament for topical use with the features of claim 7.
Erfindungsgemäß wird eine Arzneiformulierung zur topischen Anwendung für die Therapie und Prophylaxe von Hyperhidrosis axillaris, palamaris et plantaris und/oder anderen Formen der Hyperhidrosis bereitgestellt. Diese Arzneiformulierung enthält ein Glycopyrrolat, dessen Salze und/oder dessen Derivate und/oder dessen Enantiomere in einer Menge zwischen 0,05 und 20 Gew.-%. Als Vehikelsystem kommt dabei ein gel- und/oder kolloidhaltiges Trägersystem zur Anwendung. Diese Vehikelsysteme weisen den Vorteil auf, daß hierdurch die leichte Applizierbarkeit ermöglicht wird. So ist hier im Unterschied zu der Verwendung wäßriger Lösung die Anwendung nicht lokal begrenzt, vielmehr wird durch diese Vehikelsysteme ermöglicht, daß die erfindungsgemäße Arzneiformulierung bei- spielsweise im Achselbereich leicht aufgetragen werden kann und auch bei verstärkter Schweißsekretion die Penetration des Wirkstoffs im Vergleich zu wäßrigen Lösungen auch über einen längeren Zeitraum sichergestellt werden kann.According to the invention, a pharmaceutical formulation for topical use for the therapy and prophylaxis of hyperhidrosis axillary, palamaris et plantaris and / or other forms of hyperhidrosis is provided. This pharmaceutical formulation contains a glycopyrrolate, its salts and / or its derivatives and / or its enantiomers in an amount between 0.05 and 20% by weight. A gel and / or colloid-containing carrier system is used as the vehicle system. These vehicle systems have the advantage that they are easy to apply. In contrast to the use of aqueous solution, the application is not locally restricted here; rather, these vehicle systems enable the pharmaceutical formulation according to the invention to can be easily applied in the armpit area, for example, and even with increased sweat secretion, the penetration of the active ingredient can be ensured over a longer period of time compared to aqueous solutions.
Vorzugsweise wird das Glycopyrrolat, dessen Salze und/oder dessen Derivate in einer Konzentration zwischen 0,5 und 5 Gew.-% eingesetzt.The glycopyrrolate, its salts and / or its derivatives are preferably used in a concentration of between 0.5 and 5% by weight.
Als Salz des Glycopyrrolats wird dabei bevorzugt Gly- copyrroniumbromid (GPB) eingesetzt.Glycopyrronium bromide (GPB) is preferably used as the salt of the glycopyrrolate.
Bei der Verwendung eines gelhaltigen Vehikelsystems findet bevorzugt Hydroxyethylcellulose-Gel Anwendung.When using a gel-containing vehicle system, hydroxyethyl cellulose gel is preferably used.
Ebenso ist es möglich, der Arzneiformulierung weitere aktive Wirkstoffe gegenüber Hyperhidrose zuzusetzen. Hierzu zählen bevorzugt Salbeiextrakte und/oder Me- tallsalze. Vorzugsweise können auch weitere Zusatzstoffe, bevorzugt Penetrationsenhancer oder Duftstoffe in der Arzneiformulierung enthalten sein.It is also possible to add other active substances to hyperhidrosis to the drug formulation. These preferably include sage extracts and / or metal salts. Further additives, preferably penetration enhancers or fragrances, can preferably also be contained in the pharmaceutical formulation.
Erfindungsgemäß wird ebenso die Verwendung von Glyco- pyrrolat, dessen Salzen und/oder dessen Derivaten und/oder dessen Enantiomere zur Herstellung eines Arzneimittels zur topischen Anwendung für die Therapie und Prophylaxe von Hyperhidrosis axillaris, palmaris et plantaris und/oder anderen Formen der Hyper- hidrosis gelehrt. Hierbei wird die Verbindung in einer Konzentration zwischen 0,05 bis 20 Gew.-%, bevorzugt zwischen 0,5 und 5 Gew.-%, eingesetzt.The use of glycopyrrolate, its salts and / or its derivatives and / or its enantiomers for the manufacture of a medicament for topical use for the therapy and prophylaxis of hyperhidrosis axillaris, palmaris et plantaris and / or other forms of hyperhidrosis is also used according to the invention taught. Here, the compound is used in a concentration between 0.05 to 20% by weight, preferably between 0.5 and 5% by weight.
Anhand des nachfolgenden Beispiels soll der erfin- dungsgemäße Gegenstand näher erläutert werden, ohne diesen dadurch auf dieses Beispiel zu begrenzen. Beispiel:The subject according to the invention is to be explained in more detail with reference to the following example, without thereby restricting it to this example. Example:
Die vorliegenden Ergebnisse beruhen auf der Durchfüh- rung von 3 Pilotstudien mit GPB-haltigen Zubereitungen und 10 Einzelfallberichten mit weiterentwickelten kolloidalen Arzneistoffträgersystemen, welche optimierte galenische Voraussetzungen erfüllen. Die Auswahl der verwendeten Hilfsstoffe erfolgte unter der- matologischen Gesichtspunkten.The present results are based on the implementation of 3 pilot studies with GPB-containing preparations and 10 individual case reports with further developed colloidal drug delivery systems, which fulfill optimized galenic requirements. The auxiliaries used were selected from a dermatological point of view.
Durchgeführte UntersuchungenInvestigations carried out
1. Dosisfindungsstudie1. Dose finding study
In einer Pilotstudie zur Dosisfindung wurden insgesamt 20 Patienten in 4 Therapiegruppen (jeweils n=5) mit Hyperhidrosis axillaris behandelt. Dabei wurden placebokontrolliert drei Konzentrationen mit GPB (0,5; 2,0; 4,0%) in Hydroxyethylcellulose- gel (Hydroxyethylcellulose 10000 2,5 Teile; Gly- cerol 85% 10,0 Teile; Wasser (cons.) 87,5 Teile) hinsichtlich ihrer Wirksamkeit untersucht. Die Hy- perhidrose wurde mittels quantitativer Hidroiuetrie objektiviert.In a pilot study to determine the dose, a total of 20 patients in 4 therapy groups (each n = 5) were treated with axillary hyperhidrosis. Three concentrations were placebo-controlled with GPB (0.5; 2.0; 4.0%) in hydroxyethyl cellulose gel (hydroxyethyl cellulose 10000 2.5 parts; glycerol 85% 10.0 parts; water (cons.) 87, 5 parts) examined for their effectiveness. The hyperhidrosis was objectified using quantitative hidroiuetry.
2. Wirksamkeitsstudie2. Effectiveness study
In einer Pilotstudie zur Untersuchung der Wirksamkeit wurden insgesamt 20 Patienten (lOx Hyperhidrosis axillaris, lOx Hyperhidrosis palmaris) mit einem 4,0%igen GPB-haltigen Hydroxyethylcellulose- gel 3x täglich behandelt. Die Hyperhidrose wurde mittels quantitativer Hidrometrie objektiviert. Optimierungsstudie bei Hyperhidrosis axillarisIn a pilot study to investigate the efficacy, a total of 20 patients (lOx hyperhidrosis axillaris, lOx hyperhidrosis palmaris) were treated with a 4.0% GPB-containing hydroxyethyl cellulose gel 3 times a day. Hyperhidrosis was objectified using quantitative hidrometry. Optimization study in hyperhidrosis axillaris
In einer Optimierungsstudie zur Anwendung eines 4,0%igen GPB-haltigen Hydroxyethylcellulosegels wurde an 20 Patienten mit Hyperhidrosis azillaris in 4 Therapiegruppen (jeweils n=5) durchgeführt.In an optimization study on the use of a 4.0% GPB-containing hydroxyethyl cellulose gel, 20 patients with hyperhidrosis azillaris were carried out in 4 therapy groups (n = 5 each).
Gruppe 1 : 1 Woche 3 mal täglich + 3 Wochen 1 mal täglichGroup 1: 1 week 3 times a day + 3 weeks 1 time a day
Gruppe 2 : 2 Wochen 2 mal täglich + 2 Wochen 1 mal täglich Gruppe 3 : 1 Woche 3 mal täglich + 1 Woche 2 mal täglich + 2 Wochen 1 mal täglich Gruppe 4: 4 Wochen 3 mal täglichGroup 2: 2 weeks 2 times a day + 2 weeks 1 time a day Group 3: 1 week 3 times a day + 1 week 2 times a day + 2 weeks 1 time a day Group 4: 4 weeks 3 times a day
Die Hyperhidrose wurde mittels quantitativer Hi- drometrie objektiviert.The hyperhidrosis was objectified using quantitative hydrometry.
Einzelfallbeobachtungen bei Hyperhidrosis palmaris et plantaris und Hyperhidrosis occipitalisIndividual case observations in hyperhidrosis palmaris et plantaris and hyperhidrosis occipitalis
Es wurden insgesamt 10 Patienten im Rahmen eines Heilungsversuches behandelt . Neun Patienten wurden in 3 Therapiegruppen mit 0 , 5 Gew. -% GPB-haltigen kolloidalen Arzneistoffträgersystemen bei Hyperhidrosis palmaris et plantaris 2 mal täglich über 4 Wochen therapiert . Ein Patient mit Hyperhidrosis occipitalis wurde mit einem 4 , 0%igen GPB-haltigenA total of 10 patients were treated as part of a healing attempt. Nine patients were treated in 3 therapy groups with 0.5% by weight of GPB-containing colloidal drug carrier systems for hyperhidrosis palmaris et plantaris twice a day for 4 weeks. A patient with hyperhidrosis occipitalis was treated with a 4.0% GPB
Hydroxyethylcellulosegel 3 mal täglich über 3 Monate behandelt . Die Hyperhidrose wurde mittels quantitativer Hidrometrie obj ektiviert . Mathematisches Modell für biometrische Auswertung derTreated hydroxyethyl cellulose gel 3 times a day for 3 months. Hyperhidrosis was deactivated using quantitative hidrometry. Mathematical model for biometric evaluation of the
Studien 1-3Studies 1-3
Es galt zu untersuchen, ob sich statistisch signifikante Unterschiede der einzelnen Mittelwertgruppen unter der Einflußgröße nachweisen lassen.The aim was to investigate whether statistically significant differences between the individual mean value groups under the influencing variable could be demonstrated.
Zur Analyse von drei und mehr Stichproben (Behand- lungsgruppen) aus normalverteilten Populationen mit gleicher Varianz wurde die Varianzanalyse angewandt. Da lediglich ein Faktor, der Einfluß des Prüfpräparates, in den verschiedenen Mittelwertgruppen untersucht werden sollte, kam die Ein-Weg-Varianzanalyse (one-way-ANOVA) zur Anwendung. Hierbei werden Zu- fallsstichproben mit unbekannter gemeinsamer Varianz untersucht. Darüber hinaus werden die Unterschiede zwischen den einzelnen Gruppen mit der Beurteilung linearer Kontraste nach Scheffe untersuchen. Zum Ver- gleich von drei oder mehreren unabhängigen Gruppen bot sich der Kruskal-Wallis-Test (H-Test) an, der als nichtparametrischer Test verteilungsunabhängig die analogen Hypothesen der Ein-Weg-Varianzanalyse prüft. Zum Vergleich von zwei Stichproben mit gleicher Vari- anz wurde der ungepaarte T-Test angewandt. Als statistisch signifikant wurden Unterschiede mit einer Irrtumswahrscheinlichkeit p < 0,05 gewertet.The analysis of variance was used to analyze three and more samples (treatment groups) from normally distributed populations with the same variance. Since only one factor, the influence of the investigational medicinal product, was to be examined in the various mean value groups, the one-way analysis of variance (one-way ANOVA) was used. Here random samples with unknown common variance are examined. In addition, the differences between the individual groups will be examined using the Scheffe assessment of linear contrasts. For comparison of three or more independent groups, the Kruskal-Wallis-Test (H-Test) was offered, which tests the analog hypotheses of the one-way analysis of variance as a non-parametric test. The unpaired t-test was used to compare two samples with the same variance. Differences with an error probability of p <0.05 were rated as statistically significant.
Ein- und Ausschlußkriterien für die Studien 1-3:Inclusion and exclusion criteria for studies 1-3:
a) Einschlußkriterien:a) Inclusion criteria:
- Vorliegen der entsprechend untersuchten Erkrankung - nur freiwillige Teilnahme- Presence of the disease examined accordingly - only voluntary participation
- volljährige Patienten - Vorliegen der schriftlichen Einverständniserklärung zur Teilnahme an der Anwendungsbeobachtung, nach eingehender Aufklärung über Wesen, Risiken und Tragweite der klinischen Anwendungs- beobachtung- adult patients - A written declaration of consent for participation in the application observation is available after detailed information on the nature, risks and scope of the clinical application observation
b) Ausschlußkriterien:b) Exclusion criteria:
- Probanden mit Unverträglichkeit und/oder Überempfindlichkeit gegen eine der folgenden Sub- stanzen:- Subjects with intolerance and / or hypersensitivity to one of the following substances:
- Glycopyrroniumbromid- glycopyrronium bromide
- Hydroxyethylcellulose Gel- Hydroxyethyl cellulose gel
- Probanden, die an einer der folgenden Erkrankungen leiden: - atopische Dermatitis- Subjects suffering from one of the following diseases: - Atopic dermatitis
- Immunsuppression- immunosuppression
- Transplantatträger (außer Autotransplantate)- graft carriers (except auto grafts)
- Patienten, die vor weniger als 4 Wochen vor Testbeginn mit systemischen antihydrotisch wirk- samen Substanzen behandelt worden sind- Patients who were treated with systemic antiperspirant substances less than 4 weeks before the start of the test
- Patienten die vor weniger als 1 Jahr eine Bo- tulinumtoxin-Behandlung erhalten haben- Patients who received botulinum toxin treatment less than 1 year ago
- Schwangere oder Stillende- Pregnant or nursing women
- Unzuyerlässigkeit oder mangelnde Kooperation des Patienten- Inadmissibility or lack of patient cooperation
c) Verpackungc) packaging
Die Prüfpräparationen wurden in Glasgefäßen von 75 ml mit Kugelaufsatz aufbewahrt.The test preparations were stored in 75 ml glass jars with a ball attachment.
Lagerhinweis:Storage information:
Die Prüfpräparate wurden nicht unter +2°C und nicht über 30°C gelagert. Methoden zur Erfassung der Wirksamkeit:The investigational medicinal products were not stored below + 2 ° C and not above 30 ° C. Methods to measure effectiveness:
Quantitative Hidrometrie (Gravimetrie nach Heckmann)Quantitative hydrometry (Heckmann gravimetry)
- Kaffeefiltertüten 41agig (Melitta) - Einwaage auf Mikrowaage- Coffee filter bags 41 layers (Melitta) - Weighing on microbalance
- Abtrocknen der Meßstellen- drying of the measuring points
- nach 5 min Auflegen des Filterpapiers auf markier tes Areal- after 5 min placing the filter paper on the marked area
- 60 Sekunden warten - Einwaage auf Mikrowaage- Wait 60 seconds - Weigh out the microbalance
- Berechnung eines Faktors Schweiß nach Messung/Schweiß vor Messung- Calculation of a factor sweat after measurement / sweat before measurement
Ergebnisse:Results:
* bedeutet in den drei Figuren, daß ein statistisch signifikanter Unterschied zu beoabachten ist.* means in the three figures that there is a statistically significant difference.
1. Dosisfindungsstudie : Es zeigt sich, daß lediglich die 4%ige Präparation eine signifikante Wirksamkeit aufweist (Fig. 1) .1. Dose finding study: It turns out that only the 4% preparation has a significant effectiveness (FIG. 1).
2. Wirksamkeitsstudie:2. Effectiveness study:
Es zeigte sich, daß Hydroxyethylcellulose Gel als Vehikelsystem ledglich zur Therapie der Hyperhidrosis axillaris, nicht aber bei der Hyperhidrosis palmaris geeignet ist (Fig. 2) .It was shown that hydroxyethyl cellulose gel as a vehicle system is only suitable for the therapy of hyperhidrosis axillaris, but not for hyperhidrosis palmaris (FIG. 2).
3. Optimierungsstudie: Es zeigte sich, daß lediglich die Applikations- schemen der Gruppe 3 und 4 eine Wirkung erzielen (Fig. 3) .3. Optimization study: It was shown that only the application schemes of groups 3 and 4 had an effect (Fig. 3).
4. Einzelfallbeobachtungen bei Hyperhidrosis palmaris et plantaris und Hyperhidrosos occipitalis:4. Individual observations in hyperhidrosis palmaris et plantaris and hyperhidrosos occipitalis:
Es zeigt sich, daß durch die Anwendung eines optimierten Vehikelsystems auch bei der Hyperhidrosis palmaris et plantaris und der Hyperhidrosis occipitalis eine Wirksamkeit erzielt werden kann. It turns out that by using an optimized vehicle system also in hyperhidrosis palmaris et plantaris and the hyperhidrosis occipitalis effectiveness can be achieved.

Claims

Patentansprüche claims
1. Arzneiformulierung zur topischen Anwendung für die Therapie und Prophylaxe von Hyperhidrosis axillaris, palamaris et plantaris und/oder anderen Formen der Hyperhidrosis, enthaltend ein Glycopyrrolat, dessen Salze und/oder dessen Derivate und/oder dessen Enan- tiomere in einer Menge zwischen 0,05 bis 20 Gew.-% und ein gel- und/oder kolloid altiges Vehikelsystem.1. Pharmaceutical formulation for topical use for the therapy and prophylaxis of hyperhidrosis axillaris, palamaris et plantaris and / or other forms of hyperhidrosis, containing a glycopyrrolate, its salts and / or its derivatives and / or its enantiomers in an amount between 0, 05 to 20 wt .-% and a gel and / or colloidal old vehicle system.
2. Arzneiformulierung nach Anspruch 1,2. Pharmaceutical formulation according to claim 1,
dadurch gekennzeichnet, dass das Glycopyrrolat, dessen Salze und/oder dessen Derivate und/oder dessen Enantiomere in einer Menge zwischen 0,5 . bis 5 Gew.-% enthalten ist.characterized in that the glycopyrrolate, its salts and / or its derivatives and / or its enantiomers in an amount between 0.5. up to 5 wt .-% is included.
3. Arzneiformulierung nach mindestens einem der Ansprüche 1 oder 2,3. Pharmaceutical formulation according to at least one of claims 1 or 2,
dadurch gekennzeichnet, dass als Salz des Glycopyrrolats Glycopyrroniumbromid enthalten ist.characterized in that glycopyrronium bromide is contained as the salt of the glycopyrrolate.
4. Arzneiformulierung nach mindestens einem der Ansprüche 1 bis 3,4. Pharmaceutical formulation according to at least one of claims 1 to 3,
dadurch gekennzeichnet, dass als gelhaltiges Vehikelsystem Hydroxyethylcellulose-Gel enthalten ist. characterized in that the gel-containing vehicle system contains hydroxyethyl cellulose gel.
5. Arzneiformulierung nach mindestens einem der Ansprüche 1 bis 4,5. Pharmaceutical formulation according to at least one of claims 1 to 4,
dadurch gekennzeichnet, dass weitere gegen Hyperhidrosis aktive Wirkstoffe, wie z.B. Salbeiextrakte und/oder Metallsalze, enthalten sind.characterized in that other active substances against hyperhidrosis, such as Sage extracts and / or metal salts are included.
Arzneiformulierung nach mindestens einem der Ansprüche 1 bis 4,Pharmaceutical formulation according to at least one of claims 1 to 4,
dadurch gekennzeichnet, dass weitere Zusatzstoffe, z.B. Penetrationsenhancer, Duftstoffe, enthalten sind.characterized in that further additives, e.g. Penetration enhancers, fragrances, are included.
7. Verwendung von Glycopyrrolat, dessen Salzen und/oder dessen Derivaten und/oder dessen Enan- tiomere zur Herstellung eines Arzneimittels zur topischen Anwendung für die Therapie und Prophylaxe von Hyperhidrosis axillaris, palamaris et plantaris und/oder anderen Formen der Hyperhidrosis in einer Konzentration zwischen 0,05 bis 20 Gew.-%.7. Use of glycopyrrolate, its salts and / or its derivatives and / or its enantiomers for the manufacture of a medicament for topical use for the therapy and prophylaxis of hyperhidrosis axillaris, palamaris et plantaris and / or other forms of hyperhidrosis in a concentration between 0.05 to 20% by weight.
Verwendung nach Anspruch 7,Use according to claim 7,
dadurch gekennzeichnet, dass das Glycopyrrolat, dessen Salze und/oder dessen Derivate und/oder dessen Enantiomere in einer Konzentration zwischen 0,5 und 5 Gew.-% eingesetzt wird.characterized in that the glycopyrrolate, its salts and / or its derivatives and / or its enantiomers is used in a concentration between 0.5 and 5% by weight.
Verwendung nach mindestens einem der Ansprüche 7 oder 8, dadurch gekennzeichnet, dass als Salz des Glycopyrrolats Glycopyrroniumbromid eingesetzt wird.Use according to at least one of claims 7 or 8, characterized in that glycopyrronium bromide is used as the salt of the glycopyrrolate.
10. Verwendung nach mindestens einem der Ansprüche 7 bis 9,10. Use according to at least one of claims 7 to 9,
dadurch gekennzeichnet, dass das Glycopyrrolat, dessen Salze und/oder dessen Derivate und/oder dessen Enantiomere zusammen mit einem gel- und/oder kolloidhaltigem Vehikelsystem einge- setzt wird.characterized in that the glycopyrrolate, its salts and / or its derivatives and / or its enantiomers is used together with a gel and / or colloid-containing vehicle system.
11. Verwendung nach Anspruch 10,11. Use according to claim 10,
dadurch gekennzeichnet, dass als gelhaltiges Ve- hikelsystem Hydroxyethylcellulose-Gel enthalten ist.characterized in that the gel-containing vehicle system contains hydroxyethyl cellulose gel.
12. Verwendung nach mindestens einem der Ansprüche 7 bis 11,12. Use according to at least one of claims 7 to 11,
dadurch gekennzeichnet, dass das Glycopyrrolat, dessen Salze und/oder dessen Derivate und/oder dessen Enantiomere zusammen mit weiteren gegen Hyperhidrosis aktiven Wirkstoffen, wie z.B. Sal- beiextrakte und/oder Metallsalze, eingesetzt wird.characterized in that the glycopyrrolate, its salts and / or its derivatives and / or its enantiomers together with other active substances active against hyperhidrosis, such as e.g. Sage extracts and / or metal salts are used.
13. Verwendung nach mindestens einem der Ansprüche 7 bis 12,13. Use according to at least one of claims 7 to 12,
dadurch gekennzeichnet, dass das Glycopyrrolat, dessen Salze und/oder dessen Derivate und/oder dessen Enantiomere zusammen mit weiteren Zusatz- Stoffen, z.B. Penetrationsenhancer, Duftstoffe, eingesetzt wird. characterized in that the glycopyrrolate, its salts and / or its derivatives and / or its enantiomers together with further additives Substances, such as penetration enhancers, fragrances, is used.
PCT/EP2002/008101 2001-07-26 2002-07-19 Medicament formulation for topical application in the therapy and prophylaxis of hyperhidrosis WO2003011340A1 (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084905A3 (en) * 2003-03-24 2005-04-28 Univ Florida Use of 5-ht2c receptor activity affecting compounds for treating idiopathic hyperhidrosis and associated conditions
WO2006069998A2 (en) 2004-12-27 2006-07-06 Beiersdorf Ag Glycopyrrolate in cosmetic preparations
US8558008B2 (en) 2013-02-28 2013-10-15 Dermira, Inc. Crystalline glycopyrrolate tosylate
WO2014134510A1 (en) * 2013-02-28 2014-09-04 Dermira, Inc. Glycopyrrolate salts
US9006462B2 (en) 2013-02-28 2015-04-14 Dermira, Inc. Glycopyrrolate salts
MD4369C1 (en) * 2011-03-04 2016-04-30 Sosei R&D Ltd Use of glycopyrrolate for treating tachycardia, unit dose, delivery device, method of treatment and prophylaxis of tachycardia
KR20180091361A (en) 2017-02-06 2018-08-16 주식회사 퍼슨 UV blocking cosmetic composition having an antiperspirant function and preparing process for UV blocking agents using the same

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005029390A1 (en) * 2005-06-23 2007-01-04 Beiersdorf Ag Drug combinations of glycopyrronium bromide and polyols
DE102005029387B4 (en) 2005-06-23 2018-12-27 Beiersdorf Ag Drug combinations of glycopyrronium bromide and polyglyceryl (3) -methylglucose distearate
DE102005029388B4 (en) * 2005-06-23 2018-12-27 Beiersdorf Ag Active ingredient combinations of glycopyrronium bromide and one or more partially neutralized esters of monoglycerides and / or diglycerides of saturated fatty acids with citric acid
DE102005029389A1 (en) * 2005-06-23 2007-01-04 Beiersdorf Ag Combination, useful as cosmetic deodorant and antitranspirants, comprises glycopyrronium bromide and active materials e.g. boundary surface-active substances, polyols and hydrocolloids
DE102005029386A1 (en) * 2005-06-23 2007-01-11 Beiersdorf Ag Combination, useful as cosmetic deodorant and antitranspirants, comprises glycopyrronium bromide and active materials e.g. boundary surface-active substances, polyols and hydrocolloids
DE102004063726A1 (en) * 2004-12-27 2006-07-06 Beiersdorf Ag Combination, useful as cosmetic deodorant and antitranspirants, comprises glycopyrronium bromide and active materials e.g. boundary surface-active substances, polyols and hydrocolloids

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962505A (en) * 1998-08-31 1999-10-05 Bobrove; Arthur M. Method for treating hot flashes in humans
WO2000012087A1 (en) * 1998-08-31 2000-03-09 Bobrove Arthur M Method for treating hot flashes in humans
WO2001008681A1 (en) * 1999-08-02 2001-02-08 First Horizon Pharmaceutical Corporation Methods of administration of glycopyrrolate compositions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962505A (en) * 1998-08-31 1999-10-05 Bobrove; Arthur M. Method for treating hot flashes in humans
WO2000012087A1 (en) * 1998-08-31 2000-03-09 Bobrove Arthur M Method for treating hot flashes in humans
WO2001008681A1 (en) * 1999-08-02 2001-02-08 First Horizon Pharmaceutical Corporation Methods of administration of glycopyrrolate compositions

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MAY J S ET AL: "Frey's syndrome: treatment with topical glycopyrrolate.", HEAD & NECK. UNITED STATES 1989 JAN-FEB, vol. 11, no. 1, January 1989 (1989-01-01), pages 85 - 89, XP008009263, ISSN: 1043-3074 *
SEUKERAN D C ET AL: "The use of topical glycopyrrolate in the treatment of hyperhidrosis.", 1998, CLINICAL AND EXPERIMENTAL DERMATOLOGY, VOL. 23, NR. 5, PAGE(S) 204-205, ISSN: 0307-6938, XP001122802 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084905A3 (en) * 2003-03-24 2005-04-28 Univ Florida Use of 5-ht2c receptor activity affecting compounds for treating idiopathic hyperhidrosis and associated conditions
WO2006069998A2 (en) 2004-12-27 2006-07-06 Beiersdorf Ag Glycopyrrolate in cosmetic preparations
MD4369C1 (en) * 2011-03-04 2016-04-30 Sosei R&D Ltd Use of glycopyrrolate for treating tachycardia, unit dose, delivery device, method of treatment and prophylaxis of tachycardia
US8859610B2 (en) 2013-02-28 2014-10-14 Dermira, Inc. Crystalline glycopyrrolate tosylate
US10004717B2 (en) 2013-02-28 2018-06-26 Dermira, Inc. Glycopyrrolate salts
US9006462B2 (en) 2013-02-28 2015-04-14 Dermira, Inc. Glycopyrrolate salts
US9006461B2 (en) 2013-02-28 2015-04-14 Dermira, Inc. Crystalline glycopyrrolate tosylate
US9259414B2 (en) 2013-02-28 2016-02-16 Dermira, Inc. Glycopyrrolate salts
US8558008B2 (en) 2013-02-28 2013-10-15 Dermira, Inc. Crystalline glycopyrrolate tosylate
US9610278B2 (en) 2013-02-28 2017-04-04 Dermira, Inc. Glycopyrrolate salts
WO2014134510A1 (en) * 2013-02-28 2014-09-04 Dermira, Inc. Glycopyrrolate salts
US11291652B2 (en) 2013-02-28 2022-04-05 Journey Medical Corporation Glycopyrrolate salts
EP3473615A1 (en) * 2013-02-28 2019-04-24 Dermira, Inc. Glycopyrrolate salts
US10543192B2 (en) 2013-02-28 2020-01-28 Dermira, Inc. Glycopyrrolate salts
US10548875B2 (en) 2013-02-28 2020-02-04 Dermira, Inc. Glycopyrrolate salts
US11291651B2 (en) 2013-02-28 2022-04-05 Journey Medical Corporation Glycopyrrolate salts
KR20180091361A (en) 2017-02-06 2018-08-16 주식회사 퍼슨 UV blocking cosmetic composition having an antiperspirant function and preparing process for UV blocking agents using the same

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