DE10136404A1 - Topical medicament for treating or preventing hyperhidrosis, e.g. hyperhidrosis axillaris, comprises glycopyrrolate compound in gel and/or colloid-containing vehicle system - Google Patents

Abstract

Formulation (I) for topical use in the therapy and prophylaxis of hyperhidrosis contains: (A) a glycopyrrolate (or its salt, derivative and/or enantiomer) at 0.05-20 (preferably 0.5-5) wt. %; and (B) a gel and/or colloid-containing vehicle system. An Independent claim is included for the use of a glycopyrrolate (or its salt, derivative and/or enantiomer) at a concentration of 0.05-20 wt. % (preferably, but not necessarily, together with a gel and/or colloid-containing vehicle system) for the preparation of a medicament for use as above.

Description

The invention relates to a pharmaceutical formulation for topical application for therapy and prophylaxis from Hyperhidrosis axillaris, palmaris et plantaris as well as other forms of hyperhidrosis. This Drug formulation is based on the use of Glycopyrrolate, its salts and / or its derivatives.

It is known to use glycopyrronium bromide (GPB) the chemical formula 3- (Cyclopentylhydroxyphenylacetoxy) -1,1-dimethylpyrronium bromide spasmolytic, anticholinergic (parasympatholytic) Has an effect. The mechanism of action is open blockade of muscarinic receptors. Due to the strong hydrophilicity of GPB one Passage of the blood-brain barrier and thus the central one Effects prevented. As a result, it follows itself systematic application, according to the physiological distribution of muscarinic receptors, only to a reduction in the secretion of tears, saliva as well as sweat glands. The molar mass of the Glycopyrronium bromide is 398.36 g / mol and the melting point the connection is 193-198 ° C. at At room temperature, GPB is a white powder. The stability this compound is pH-dependent, the Stability decreases at a pH> 6. simultaneously GPB is a slightly water-soluble one Connection.

So far, GPB has mainly been used in human medicine as secretion-inhibiting and spasmolytic substance in the adjuvant therapy for special anesthetic or Surgical procedures used.

In US 5,962,505 the topical application of a Preparation containing GPB in case of seizures reddening of the face described. From LL Hays et al., The Frey syndrome: a simple effective treatment, Otolaryngol Head Neck Surg 90 (1982) 419-425 is the topical application of GPB in Frey syndrome, the so-called gustatory sweating. From HR Stegehuis et al., "Treatment of Frey's syndrome (gustadory sweating) with topical glycopyrrolate, N Z Med J 102 (1989) 479 is the application of a GPB containing cream for diabetic, gustatory Sweating, a special form of Frey syndrome, known. A 0.5% GPB was used standard preparation.

For the therapy of hyperhidrosis in the Medicine so far metal salt solutions, tap water Iontophoresis, tannins and sage extracts used. Most often, however, these therapy methods too little or no effectiveness. Farther is the intracutaneous injection of botulinum toxin (BTX) applied. However, this application is very painful and the therapy very expensive. There are also suggestions for operational Procedures that, however, have an increased potential for side effects include.

Based on these disadvantages of the prior art Technology was therefore an object of the present invention to provide a pharmaceutical formulation which is used in the Therapy and prophylaxis of various forms of Hyperhidrosis in addition to high effectiveness at the same time which is easy to apply.

This task is accomplished with the drug formulation the features of claim 1 and the use of glycopyrrolate for the manufacture of a medicinal product for topical application with the characteristics of Claim 7 solved.

According to the invention, a pharmaceutical formulation for topical application for the therapy and prophylaxis of Hyperhidrosis axillaris, palamaris et plantaris and / or other forms of hyperhidrosis provided. This pharmaceutical formulation contains a Glycopyrrolate, its salts and / or its derivatives in an amount between 0.05 and 20% by weight. As The vehicle system comes with a gel and / or colloid Carrier system for use. These vehicle systems have the advantage that the light Applicability is made possible. So here in Difference to the use of aqueous solution Application is not limited locally, but is rather limited by this Vehicle systems enable the invention Drug formulation, for example in the armpit area can be easily applied and also at increased sweat secretion the penetration of the active ingredient compared to aqueous solutions also over one longer period can be ensured.

Preferably the glycopyrrolate, its salts and / or its derivatives in a concentration between 0.5 and 5 wt .-% used.

The salt of glycopyrrolate is preferred Glycopyrronium bromide (GPB) used.

When using a gel-containing vehicle system Hydroxyethyl cellulose gel is preferably used.

It is also possible to add more to the drug formulation to add active ingredients against hyperhidrosis. These preferably include sage extracts and / or Metal salts. More can preferably also Additives, preferably penetration enhancers or Fragrances can be contained in the pharmaceutical formulation.

According to the use of Glycopyrrolate, its salts and / or its derivatives for Manufacture of a drug for topical Application for the therapy and prophylaxis of Hyperhidrosis axillaris, palmaris et plantaris and / or others Forms of hyperhidrosis taught. Here, the Compound in a concentration between 0.05 to 20% by weight, preferably between 0.5 and 5% by weight, used.

Using the example below, the subject according to the invention are explained in more detail without to limit this to this example.

example

The present results are based on the Carried out 3 pilot studies with GPB-containing Preparations and 10 individual case reports with further developed colloidal drug delivery systems, which meet optimized pharmaceutical requirements. The The auxiliary materials used were selected under dermatological aspects.

Investigations carried out 1. Dose finding study

In a pilot study on dose finding a total of 20 patients in 4 therapy groups (each n = 5) treated with axillary hyperhidrosis. there placebo-controlled three concentrations with GPB (0.5, 2.0, 4.0%) in Hydroxyethyl cellulose gel (hydroxyethyl cellulose 10,000 2.5 parts; Glycerol 85% 10.0 parts; Water (cons.) 87.5 parts) examined for their effectiveness. The Hyperhidrosis was assessed using quantitative hidrometry objectified.

2. Effectiveness study

In a pilot study to investigate the A total of 20 patients (10 × Hyperhidrosis axillaris, 10 × Hyperhidrosis palmaris) with a 4.0% GPB-containing Treated hydroxyethyl cellulose gel 3 times a day. The hyperhidrosis was objectified using quantitative hidrometry.

3. Optimization study in axillary hyperhidrosis

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 (each n = 5).
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 times 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 quantitative Objective hydrometry.

4. Individual case observations in hyperhidrosis palmaris et plantaris and hyperhidrosis occipitalis

A total of 10 patients were enrolled in one Attempted healing. Nine patients were in 3 therapy groups with 0.5 wt .-% GPB-containing colloidal drug delivery systems Hyperhidrosis palmaris et plantaris 2 times a day over 4 Weeks of therapy. A patient with hyperhidrosis occipitalis was with a 4.0% GPB-containing Hydroxyethyl cellulose gel 3 times a day over 3 Months. The hyperhidrosis was diagnosed using quantitative hidrometry objectified.

Mathematical model for biometric evaluation of the Studies 1-3

It was necessary to investigate whether statistical significant differences between the individual mean groups have it demonstrated under the influencing variable.

For analysis of three and more samples (Treatment groups) from normally distributed populations with analysis of variance was applied. Since only one factor, the influence of the Investigational product, in the different mean value groups the one-way analysis of variance came to be examined (one-way ANOVA) for use. Here are Random samples with unknown common variance examined. In addition, the differences between the individual groups with the assessment investigate linear contrasts according to Scheffe. To the Comparison of three or more independent groups offered the Kruskal-Wallis-Test (H-Test), which as nonparametric test independent of the distribution analog hypotheses of the one-way analysis of variance. To compare two samples with the same Variance, the unpaired t-test was applied. As Differences with one were statistically significant Error probability rated p <0.05.

Inclusion and exclusion criteria for studies 1-3

• a) Inclusion criteria:
  • - presence of the disease examined accordingly
  • - only voluntary participation
  • - 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) Exclusion criteria:
  • - Subjects with intolerance and / or hypersensitivity to one of the following substances:
  • - glycopyrronium bromide
  • - Hydroxyethyl cellulose gel
  • - subjects who suffer from one of the following diseases:
  • - Atopic dermatitis
  • - immunosuppression
  • - graft carriers (except auto grafts)
  • - Patients who were treated with systemic antiperspirant drugs less than 4 weeks before the start of the test
  • - Patients who received botulinum toxin treatment less than 1 year ago
  • - Pregnant or breastfeeding women
  • - Unreliability or lack of patient cooperation
• c) packaging

The test preparations were placed in 75 ml glass jars stored with ball attachment.

storage Information

The investigational medicinal products were not below + 2 ° C and not stored above 30 ° C.

Methods of measuring effectiveness Quantitative hydrometry (Heckmann gravimetry)

• - 41-ply coffee filter bags (Melitta)
• - Weighing on microbalance
• - drying of the measuring points
• - after 5 min placing the filter paper on the marked area
• - Wait 60 seconds
• - Weighing on microbalance
• - Calculation of a factor according to sweat Measurement / sweat before measurement

Results

• 1. Dosisfindungsstudie:
  Es zeigt sich, daß lediglich die 4%ige Präparation eine signifikante Wirksamkeit aufweist (Fig. 1).
• 2. Wirksamkeitsstudie:
  Es zeigte sich, daß Hydroxyethylcellulose Gel als Vehikelsystem ledglich zur Therapie der Hyperhidrosis axillaris, nicht aber bei der Hyperhidrosis palmaris geeignet ist (Fig. 2).
• 3. Optimierungsstudie:
  Es zeigte sich, daß lediglich die Applikationsschemen der Gruppe 3 und 4 eine Wirkung erzielen (Fig. 3).
• 4. Einzelfallbeobachtungen bei Hyperhidrosis palmaris et plantaris und Hyperhidrosos occipitalls:
  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.

* means in the three figures that there is a statistically significant difference.

• 1. Dose finding study:
  It can be seen that only the 4% preparation has a significant effectiveness ( FIG. 1).
• 2. Effectiveness study:
  It was found 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. Optimization study:
  It was found that only the application schemes in groups 3 and 4 had an effect ( FIG. 3).
• 4. Individual observations in hyperhidrosis palmaris et plantaris and hyperhidrosos occipitalls:
  It has been shown that the use of an optimized vehicle system can also be effective in hyperhidrosis palmaris et plantaris and hyperhidrosis occipitalis.

Claims (13)

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 in an amount between 0.05 to 20 wt .-% and a gel and / or colloidal vehicle system. 2. Pharmaceutical formulation according to claim 1, characterized in that the glycopyrrolate, its salts and / or its derivatives in one Amount between 0.5 to 5 wt .-% is included. 3. Drug formulation according to at least one of the Claims 1 or 2, characterized in that as the salt of Glycopyrrolate Glycopyrronium bromide is included. 4. Drug formulation according to at least one of the Claims 1 to 3, characterized in that as gelatinous Vehicle system contain hydroxyethyl cellulose gel is. 5. Drug formulation according to at least one of the Claims 1 to 4, characterized in that further against Hyperhidrosis active ingredients, such as. B. Sage extracts and / or metal salts are included. 6. Drug formulation according to at least one of the Claims 1 to 4, characterized in that more Additives, e.g. B. penetration enhancers, fragrances, are included. 7. Use of glycopyrrolate, its salts and / or its derivatives for the production of a Drug for topical use for the Therapy and prophylaxis of hyperhidrosis axillaris, palamaris et plantaris and / or others Forms of hyperhidrosis in a concentration between 0.05 to 20% by weight. 8. Use according to claim 7, characterized in that the glycopyrrolate, its salts and / or its derivatives in one Concentration between 0.5 and 5% by weight is used. 9. Use according to at least one of claims 7 or 8, characterized in that as the salt of Glycopyrrolats Glycopyrronium bromide is used. 10. Use according to at least one of claims 7 till 9, characterized in that the glycopyrrolate, its salts and / or its derivatives together with a gel and / or colloidal Vehicle system is used. 11. Use according to claim 10, characterized in that as gelatinous Vehicle system contain hydroxyethyl cellulose gel is. 12. Use according to at least one of claims 7 to 11. characterized in that the glycopyrrolate, its salts and / or its derivatives together with others active against hyperhidrosis Active ingredients, such as B. sage extracts and / or Metal salts is used. 13. Use according to at least one of claims 7 until 12, characterized in that the glycopyrrolate, its salts and / or its derivatives together with other additives, e.g. B. Penetration enhancer, fragrances, is used.