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

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

 Drug formulation for topical use for the therapy and prophylaxis of hyperhidrosis

• 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.

It is known that glycopyrronium bromide (GPB) with the chemical formula 3- (cyclopentylhydroxyphenyl-acetoxy) -1, 1-dimethylpyrronium bromide is a spasmolytic, anticholinergic (parasympatholytic)

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 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.

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.

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.

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.

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.

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.

The glycopyrrolate, its salts and / or its derivatives are preferably used in a concentration of between 0.5 and 5% by weight.

Glycopyrronium bromide (GPB) is preferably used as the salt of the glycopyrrolate.

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

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.

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.

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:

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.

Investigations carried out

1. Dose finding study

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. Effectiveness study

In 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 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).

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.

Individual case observations in hyperhidrosis palmaris et plantaris and hyperhidrosis occipitalis

A 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

Treated hydroxyethyl cellulose gel 3 times a day for 3 months. Hyperhidrosis was deactivated using quantitative hidrometry. Mathematical model for biometric evaluation of the

Studies 1-3

The aim was to investigate whether statistically significant differences between the individual mean value groups under the influencing variable could be demonstrated.

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.

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 suffering from one of the following diseases: - Atopic dermatitis

- immunosuppression

- graft carriers (except auto grafts)

- Patients who were treated with systemic antiperspirant substances less than 4 weeks before the start of the test

- Patients who received botulinum toxin treatment less than 1 year ago

- Pregnant or nursing women

- Inadmissibility or lack of patient cooperation

c) packaging

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

Storage information:

The investigational medicinal products were not stored below + 2 ° C and not above 30 ° C. Methods to measure effectiveness:

Quantitative hydrometry (Heckmann gravimetry)

- Coffee filter bags 41 layers (Melitta) - Weighing on microbalance

- drying of the measuring points

- after 5 min placing the filter paper on the marked area

- Wait 60 seconds - Weigh out the microbalance

- Calculation of a factor sweat after measurement / sweat before measurement

Results:

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

1. Dose finding study: It turns out that only the 4% preparation has a significant effectiveness (FIG. 1).

2. Effectiveness study:

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. Optimization study: It was shown that only the application schemes of groups 3 and 4 had an effect (Fig. 3).

4. Individual observations in hyperhidrosis palmaris et plantaris and hyperhidrosos occipitalis:

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

claims 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. Pharmaceutical formulation according to claim 1, 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. Pharmaceutical formulation according to at least one of claims 1 or 2, characterized in that glycopyrronium bromide is contained as the salt of the glycopyrrolate. 4. Pharmaceutical formulation according to at least one of claims 1 to 3, characterized in that the gel-containing vehicle system contains hydroxyethyl cellulose gel. 5. Pharmaceutical formulation according to at least one of claims 1 to 4, characterized in that other active substances against hyperhidrosis, such as Sage extracts and / or metal salts are included. Pharmaceutical formulation according to at least one of claims 1 to 4, characterized in that further additives, e.g. Penetration enhancers, fragrances, are included. 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. Use according to claim 7, 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. 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. Use according to at least one of claims 7 to 9, 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. Use according to claim 10, characterized in that the gel-containing vehicle system contains hydroxyethyl cellulose gel. 12. Use according to at least one of claims 7 to 11, 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. Use according to at least one of claims 7 to 12, 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.