FR2666507A1 - Pharmaceutical compositions for the topical administration of moxisylyte and of deacetylmoxisylyte and their uses in therapy - Google Patents

Abstract

Pharmaceutical composition for topical administration, containing an effective amount of moxisylyte or of one of its derivatives or metabolites, especially deacetylmoxisylyte, in combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants suitable for such an application.

Description

 The present invention relates to pharmaceutical compositions for the topical administration of Moxisylyte and its main metabolite deacetyl Moxisylyte.

 Moxisylyte is a known and already marketed product. It is an alphablocker whose use in humans is proposed in the treatment of psycho-behavioral disorders of senescence, circulatory disorders of the cerebrum or periphery, Raynaud's disease and urinary disorders related to prostatic adenoma.

 Moxisylyte is an active ingredient that is intensely metabolized. The half-life of the main metabolite deacetyl Moxisylyte is 1 hour after intravenous administration (VOLLMER-K-O. et al., J. Drug.

Metab. Pharmacokinet., 1985, 10, 1, 71-76). After oral administration, Moxisylyte gives rise to a strong first-pass hepatic effect (VOLLMER-K-O et al., Same reference). This short half-life and this hepatic first-pass effect require the administration of 3 to 4 doses per day to obtain the expected therapeutic effect.

 We have now discovered that Moxisylyte or deacetyl Moxisylyte can be administered externally in a topical and preferentially transdermal form such as lotion, cream, gel, plaster or bandage, in combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants. , suitable for such an administration.

 Topical application, externally, prolongs the duration of pharmacological action of Moxisylyte or deacetyl Moxisylyte by limiting the effect of first pass through the liver.

 The topical application of Moxisylyte makes it possible to treat once or twice a day, which improves the comfort of the patients.

Transcutaneous passage of Moxisylyte or desacetyl
Moxisylyte is not known in the scientific literature.

 These two substances have been shown in vitro to pass easily through the skin. This result is surprising because the chemical structure of Moxisylyte and desacetyl Moxisylyte did not predict a transcutaneous passage so important.

 The following study carried out in vitro makes it possible to better appreciate the transcutaneous passage of Moxisylyte and desacetyl Moxisylyte in comparison with that of known reference substances to pass easily through the skin.

1- Moxisylyte
In vitro permeability of Moxisylyte was determined using a so-called
Franz as described by FRANZ-TJ. (J. Investig.Dermatol., 1975, 64, 190-195).

 The in vitro permeability of Moxisylyte was determined through the skin of the rat hairless.

A dilution of Moxisylyte 14C was performed with
Moxisylyte unmarked. The resulting dilution is deposited pure on the skin.

 The amount of active ingredient that has passed through the skin and is found in the second compartment is measured.

 The results are expressed as a cumulative percentage of the amount of Moxisylyte having passed through the skin at time 0.5; 4; 8 and 24 hours.

We obtain the following results
Time to time 0.5 4 8 24
Cumulative percentage of the dose deposited 0.44 15.60 34.40 75.30
2- Désacétyl Moxisylyte
The transcutaneous passage of deacetyl Moxisylyte was determined as for the passage of Moxisylyte. A 10% solution of Moxisylyte deacetyl in Labrafac was used.

The results obtained are as follows
Hour to time 1 4 7 24
Cumulative percentage of the dose deposited 0.00 0.775 2.5 24.5
3- Reference substances
Transcutaneous passage of metoprolol was determined using a 15% solution of metoprolol in propylene glycol. The results are as follows
Hour to time 1 4 8 24
Cumulative percentage of the dose deposited 0.00 0.453 6.65 56.9
The transcutaneous passage of nicotine was determined using a 10% solution of metoprolol in mygliol 812.The results are as follows
Hour to time 1 4 8 24
Cumulative percentage of dose deposited 0.00 14.1 32.6 66.9
The transcutaneous passage of moxisylyte is more important than for the other active ingredients such as metoprolol and nicotine which have been presented in topical forms: metopolol (NISSAN chemical industry, Japanese patent number JO1308225, Pharmaceutical compositions, for external use, including propranolol or metoprolol Nicotin-SC and all in Clin Pharmacol Ther, 1990, 47, 331 Clinical and pharmacokinetics properties of a transdermal nicotine patch.

Given the transcutaneous passage of Moxisylyte and desacetyl Moxisylyte, the preparation of topical forms of these two active ingredients such as transdermal forms, lotions, gel, plaster or cream allows the administration of
Moxisylyte or deacetyl Moxisylyte.

 The concentration of the active ingredient in the various topical forms is between 40 and 0.1% relative to the excipients, and more particularly between 20 and 1%.

 The excipients used are solvents of moxisylyte or deacetyl moxisylyte such as esters (isopropyl myristate, dioctyl adipate, diisopropyl adipate, etc.), alcohols (benzyl alcohol, etc.), miglyol 812 (R), labrafac (R), polyethylene glycol PEG400, propylene glycol, dimethylformamide, or dimethyl isosorbide. They are also penetrating agents such as N-methyl pyrrolidinone-2, pyrrolidinone-2, N, N-dimethyl tolbutamide or azone, or auxiliary agents such as polyvinylpyrrolidone (PVP), carboxymethylcellulose, in particular. The excipients are used either alone or in combination.

 The present invention is described in the following examples without however that they limit its scope.

A -Preparation form ointment, qel and lotion
Example 1
Ointment: 50 g of glycerol monostearate and 850 g of petrolatum are melted at 700 ° C. It is cooled to 400 ° C. with stirring and 100 g of Moxisylyte base are incorporated. An ointment containing 10% of Moxisylyte is thus obtained.

Example 2
Gel: 200 g of Moxisylyte base are mixed with 500 g of Miglyol 812, 300 g of Miglyol gel are then added and the mixture is homogenized for 5 minutes using an ultraturax, thus obtaining a gel containing 20% of Moxisylyte.

Example 3
Lotion: 400 g of Moxisylyte base and 600 g of Miglyol 812 are mixed. A lotion containing 40% of
Moxisylyte.

B -Preparation of a plaster or dressing
The plasters or dressings are divided into 3 categories
1. The multilayer forms constituted by a layer
protective, a layer containing the active ingredient
and an adhesive layer.

2. The monolithic forms constituted by a layer
protective, an adhesive matrix containing the
active ingredient and controlling its release.

3. The reservoir forms formed by a layer
protective, a reservoir containing the principle
active, a membrane controlling the release of the
active ingredient and an adhesive layer.

 These forms are described in particular in: Transdermal drug delivrery, published by HADGRAFT-J and GUY-R-H, published by Dekker 1989, New York.

Example 4
100 g of Moxisylyte base are mixed with 832.5 g of an elastomer (silicone resin) and 62.5 g of crosslinking agent. This mixture is distributed on a support (polyamide gauze) using an automatic coating machine known to those skilled in the art. After heating to 1200C to obtain the polymerization, a self-adhesive dressing is obtained, the thickness of which can be easily adjusted and is between 0.5 and 0.05 mm. Dressings containing 4 to 0.4 mg of Moxisylyte per cm 2 are thus obtained which are cut in such a way as to obtain delivery units containing the desired amount of active ingredient.

Example 5
50 g of Moxisylyte base are mixed with 900 g of an elastomer (silicone resin) and 50 g of crosslinking agent.

This mixture is distributed on a support (polyamide gauze) using an automatic coating machine known to those skilled in the art. After heating to 1200C to obtain the polymerization, a self-adhesive dressing is obtained, the thickness of which can be easily adjusted and is between 0.5 and 0.125 mm. Dressings containing 2 to 0.5 mg of Moxisylyte per cm 2 are thus obtained, which are cut in such a way as to obtain delivery units containing the desired amount of active ingredient.

Example 6
Reservoir Form: Using one of the preparations of Examples 1, 2 or 3, reservoir system forms are prepared to provide delivery units containing the desired amount of active ingredient.

Example 7
50 g of Moxisylyte base are mixed with 950 g of an adhesive polymer (silicon 2920). This mixture is distributed on a support using an automatic coating machine known to those skilled in the art. After evaporation of the solvent and after cutting, a self-adhesive dressing containing the desired amount of active ingredient is obtained.

Example 8
50 g of desacetyl Moxisylyte base are mixed with 860 g of an elastomer (silicon 4210) and 90 g of crosslinking agent. This mixture is distributed on a support using an automatic coating machine known to those skilled in the art. After heating to 1400C for solidification, a non-adhesive dressing is obtained which is covered with an adhesive layer. After cutting, units of administration containing the desired amount of active ingredient are obtained.

Example 9
In vivo study demonstrating the pharmacodynamic activity of Moxisylyte administered transdermally.

 The transcutaneous passage of Moxisylyte was studied in vivo, by its antagonism, vis-à-vis the hypertensive effect of phenylephrine (alpha blocking activity).

 A comparative study was also performed with intradermal ID or subcutaneous injections of Moxisylyte SC in the same model.

Dressings prepared according to Example 4 comprising a placebo dressing and 4 dressings of different thicknesses containing Moxisylyte were used. The characteristics of the dressings are given below - placebo dressing (8 cm 2 thickness 0.5 mm, 0 mg / cm 2) - dressing 1 (8 cm 2 thickness 0.5 mm, 4 mg / cm 2) - dressing 2 (8 cm 2 thickness 0.25 mm, 2 mg / cm 2) - dressing 3 (8 cm 2 thickness 0.1 mm, 0.8 mg / cm 2) - dressing 4 (8 cm 2 thickness 0.05 mm, 0.4 mg / cm 2)
Methods and preparation of animals
Blood pressure and heart rate are measured continuously in the vigilant animal.

At least 24 hours before the experiment, the animals, rat hairless for transdermal passage and darlin rat spraque for intradermal and subcutaneous administration, are anesthetized with pentobarbital (Nembutal 60 mg / kg
IP) and catheterized at the level of the artery and the right femoral vein. The two catheters externalised behind the head respectively allow: the measurement of the arterial pressure and the intravenous administration of the substances.

The recording of the blood pressure is carried out continuously with the help of an external sensor STATHAM type P23id connected to a polygraph GOULD
ES1000.

 1 - Alpha-blocking activity of MOXISYLYTE transdermally (TD).

 In order to determine the transdermal efficacy (MD) of Moxisylyte against hypertension induced by 2.5 yg / kg IV phenylephrine, the effects of the dressings of Example 4 were investigated in vigilant rat (5 batches of 5 female rats) prepared as described in the paragraph preparation of the animals.

1.1 - Experimental Protocol
The various formulations of Example 4 are fixed on the back of the animals by a bandage and remain in contact with the skin for 24 hours.

 The dressings of constant surface (8 cm 2 of identical volume concentration, but of variable thickness of 0.5 to 0.05 mm, make it possible to apply on the skin of animals increasing doses of 3.2 to 32 mg of Moxisylyte.

Considering the weight of the animals, these dressings represent doses of 12.7 mg / kg, 25.7 mg / kg, 63.6 mg / kg and 114.8 mg / kg. A placebo dressing containing no Moxisylyte is applied to a control lot.

 On each animal, after obtaining 2 identical peaks of hypertension due to IV injection of 2.5 μg / kg phenylephrine, the dressing is applied as described above, the response of the agonist is measured every 30 minutes after installation, during the next 6 hours, then at 24 hours.

Expression of results
Mean inhibition of the hypertensive effect of phenylephrine is determined in each lot.

The significance of the results is calculated
(a) by analysis of variance between batches processed and
witness batch
b) time by time using a Duncan test.

1.2. Results
The average values of the increase in blood pressure due to the IV injection of 2.5 μg / kg of phenylephrine are significantly decreased in the groups treated with the dressings 1, 2, 3 which correspond to the application of doses of Moxisylyte of 114.8 mg / kg, 63.6 mg / kg and 25.7 mg / kg respectively. The effect of these dressings is significant after one hour of application.

 In the batch treated with dressing 4, which corresponds to the dose of 12.7 mg / kg, a significant effect appears only after 2.5 hours of application (see Table 1).

 The maximum antagonist effect observed with respect to the hypertensive effect of phenylephrine is reached after 4 hours of application of the dressings 1, 2, 3 and 4 on the skin of the animals and are -46.7%, -36.3%, -35% and -32.5% at the respective doses of 114.8, 63.6, 25.7 and 12.7 mg / kg. After a contact time of 6 hours, this effect is respectively -47.7%, -30.9%, -25.1% and -29.1% (see Table 2).

After 24 hours of application, only the dressing 1 (114.8 mg / kg) still has an antagonistic activity (-34.6
%) with respect to phenylephrine. The results obtained are summarized in Table 1 and Figure 1.

2- MOXISYLYTE alpha-blocking activity
ID and SC
Alpha-blocking activity and the duration of the effect of
Moxisylyte intradermally (ID), or subcutaneously (SC), on hypertension induced by a dose of 2.5 Fg / kg of
Phenylephrine, were studied for a dose of 3 mg / kg in the conscious rat.

2.1 - Experimental Protocol
3 batches of 5 male Sprague-Dawley rats, prepared as above, were used
- 1 lot NaCl 0.9% treated control in SC
- 1 batch treated Moxisylyte 3 mg / kg in ID
- 1 batch treated Moxisylyte 3 mg / kg in SC
On each animal, after obtaining 2 identical peaks of hypertension due to IV injection of 2.5 zg / kg phenylephrine, the effect of a dose of Moxisylyte (3 mg / kg) or NaCl 0.9 % is studied on the response of the agonist every 10 minutes.

IV injections of phenylephrine are
carried out under a volume of 1 ml / kg
- the subcutaneous injections of Moxisylyte are
made in a volume of 0.5 ml / kg
- Intra-dermal injections of Moxisylyte
are performed by creating papules on the
back skin of animals by a volume of 0.5
ml / kg.

Phenylephrine solutions: 5 μg in 1 ml of NaCl 0.9%
Moxisylyte: 6 mg in 1 ml of NaCl 0.9%
2.2 - Results
In the control group, successive injections of 2.5 μg / kg IV phenylephrine, show that the hypertensive effect of the alpha adrenergic agonist is constant and reproducible for at least 2 hours.

Intra-dermal or subcutaneous administration of
Moxisylyte at the dose of 3 mg / kg, causes a significant decrease in the hypertensive effect of phenylephrine.

 This activity of Moxisylyte is maximal at time 15 minutes, respectively 52% and 59% in ID or SC, and decreases regularly to disappear 1.5 to 2 hours after administration.

In conclusion, the Moxisylyte antagonist activity, at the dose of 3 mg / kg vis-à-vis the hypertensive effect of phenylephrine, is identical intradermally or subcutaneously in the conscious rat. This activity disappears in 2 hours. The results are given in Table 3 and the
Figure 2

3 - Conclusions
Regardless of the doses used, the effectiveness of
Moxisylyte transdermally, compared to that of the intradermal or subcutaneous routes, is qualitatively identical, but significantly improved when comparing the duration of action.

Given the demonstration of the passage of
Moxisylyte from a topical form, the topical forms of Moxisylyte and decacetyl Moxisylyte can be used in human therapy for all therapeutic indications of Moxisylyte or Moxisylyte deacetyl.

TABLE 1
Mean values (mm Hg) of the hypertensive effect obtained by IV injection of 2.5 g / kg of phenylephrine before (TO) and after application of Placebo dressings or Moxisylyte dressings on female Hairless rats (n = 5).

Batches <SEP> witnesses <SEP> Treaties <SEP> Moxisylyte
<tb> Dressing <SEP> PLACEBO <SEP> 4 <SEP> 3 <SEP> 2 <SEP> 1
<tb> mg / yr <SEP> 0 <SEP> 3.2 <SEQ> 6.4 <SEP> 16 <SEP> 32
<tb> mg / kg <SEP> 0 <SEP> 12.7 <SEP> 25.7 <SE> 63.6 <SEP> 114.8
<tb><SEP> Time <SEP> m <SEP>#<SEP> se <SEP> m <SEP>#<SEP> se <SEP> m <SEP>#<SEP> se <SEP> m <SEP>#<SEP> se <SEP> m <SEP>#<SEP> se
<tb><SEP> to <SEP> 44.0 <SEP>#<SEP> 1.6 <SEP> 47.5 <SEP>#<SEP> 1.7 <SEP> 41.0 <SEP>#<SEP> 1.3 <SEP> 45.1 <SEP>#<SEP> 1.1 <SEP> 47.5 <SEP>#<SEP> 2.6
<tb><SEP> 30mn <SEP> 42.4 <SEP>#<SEP> 2.3 <SEP> 48.3 <SEP>#<SEP> 2.2 <SEP> 39.8 <SEP>#<SEP> 2.8 <SEP> 45.1 <SEP>#<SEP> 1.2 <SEP> 39.2 <SEP>#<SEP> 2.8
<tb><SEP> 1h <SEP> 45.1 <SEP>#<SEP> 2.6 <SEP> 41.3 <SEP>#<SEP> 2.7 <SEP> 33.3 <SEP>#<SEP> 2.9 * <SEP> 35.7 <SEP >#<SEP> 2.8 * <SEP> 32.5 <SEP>#<SEP> 3.1 *
<tb><SEP> 1.5h <SEP> 47.3 <SEP>#<SEP> 1.5 <SEP> 39.8 <SEP>#<SEP> 3.0 <SEP> 26.7 <SEP>#<SEP> 1.5 * <SEP> 37.1 <SEP>#<SEP> 2.1 * <SEP> 29.1 <SEP>#<SEP> 3.2 *
<tb><SEP> 2h <SEP> 44.0 <SEP>#<SEP> 2.1 <SEP> 37.9 <SEP>#<SEP> 2.6 <SEP> 25.1 <SEP>#<SEP> 2.8 * <SEP> 34.9 <SEP >#<SEP> 3.4 * <SEP> 32.0 <SEP>#<SEP> 3.8 *
<tb><SEP> 2.5h <SEP> 44.3 <SEP>#<SEP> 1.9 <SEP> 32.8 <SEP>#<SEP> 3.9 * <SEP> 26.5 <SEP>#<SEP> 2.4 * <SEP> 28.3 <SEP>#<SEP> 1.8 * <SEP> 25.9 <SEP>#<SEP> 2.1 *
<tb><SEP> 3h <SEP> 42.9 <SEP>#<SEP> 1.1 <SEP> 36.8 <SEP>#<SEP> 3.3 * <SEP> 26.9 <SEP>#<SEP> 2.4 * <SEP> 26.1 <SEP>#<SEP> 1.6 * <SEP> 26.7 <SEP>#<SEP> 2.6 *
<tb><SEP> 4h <SEP> 41.6 <SEP>#<SEP> 1.0 <SEP> 32.0 <SEP>#<SEP> 4.3 * <SEP> 26.7 <SEP>#<SEP> 1.4 * <SEP> 28.5 <SEP>#<SEP> 1.5 * <SEP> 25.6 <SEP>#<SEP> 3.5 *
<tb><SEP> 5h <SEP> 43.2 <SEP>#<SEP> 1.8 <SEP> 34.7 <SEP>#<SEP> 4.3 * <SEP> 27.5 <SEP>#<SEP> 2.7 * <SEP> 32.3 <SEP>#<SEP> 1.8 * <SEP> 27.5 <SEP>#<SEP> 4.0 *
<tb><SEP> 6h <SEP> 44.3 <SEP>#<SEP> 1.1 <SEP> 33.3 <SEP>#<SEP> 3.9 * <SEP> 30.7 <SEP>#<SEP> 1.6 * <SEP> 29.2 <SEP>#<SEP> 2.0 * <SEP> 25.1 <SEP>#<SEP> 2.9 *
<tb> 24h <SEP> 45.1 <SEP>#<SEP> 2.2 <SEP> 45.8 <SEP>#<SEP> 2.0 <SEP> 42.4 <SEP>#<SEP> 2.8 <SEP> 40.7 <SEP>#<SEP> 1.4 <SEP> 31.5 <SEP>#<SEP> 6.6 *
<tb> * = Duncan's significant test at <.05 TABLE 2
Mean change (%) in relation to the initial effect, hypertension obtained by IV injection of 2.5 phenylephrine after Placebo dressings or Moxisylyte dressings with gemella rats
Hairless (n = 5).

Batches <SEP> witnesses <SEP> Treaties <SEP> Moxisylyte
<tb> Thoughtfully <SEP> Placebo <SEP> 4 <SEP> 3 <SEP> 2 <SEP> 1
<tb> mg / yr <SEP> 0 <SEP> 3.2 <SEQ> 6.4 <SEP> 16 <SEP> 32
<tb> mg / kg <SEP> 0 <SEP> 12.7 <SEP> 25.7 <SE> 63.6 <SEP> 114.8
<tb> Time <SEP> m <SEP>#<SEP> se <SEP> m <SEP>#<SEP> se <SEP> m <SEP>#<SEP> se <SEP> m <SEP>#<SEP> se <SEP> m <SEP>#<SEP> se
<tb> 30mn <SEP> -3.6 <SEP>#<SEP> 3.4 <SEP> 1.8 <SEP>#<SEP> 3.8 <SEP> -3.6 <SEP>#<SEP> 6.5 <SEP> 0.1 <SEP>#<SEP> 2.6 <SEP> -16.7 <SEP>#<SEP> 6.3
<tb> 1h <SEP> 2.8 <SEP>#<SEP> 5.9 <SEP> -12.4 <SEP>#<SEP> 6.6 <SEP> -18.7 <SEP>#<SEP> 7.0 <SEP> -20.5 <SEP>#<SEP> 6.5 <SEP> -31.1 <SEP>#<SEP> 6.9
<tb> 1.5h <SEP> 8.0 <SEP>#<SEP> 4.4 <SEP> -16.4 <SEP>#<SEP> 4.9 <SEP> -34.9 <SEP>#<SEP> 4.0 <SEP> -17.6 <SEP >#<SEP> 5.0 <SEP> -38.8 <SEP>#<SEP> 7.1
<tb> 2h <SEP> -0.2 <SEP>#<SEP> 2.2 <SEP> -20.6 <SEP>#<SEP> 3.1 <SEP> -39.2 <SEP>#<SEP> 6.3 <SEP> -21.8 <SEP >#<SEP> 8.8 <SEP> -33.3 <SEP>#<SEP> 8.6
<tb> 2.5h <SEP> 0.7 <SEP>#<SEP> 3.1 <SEP> -30.5 <SEP>#<SEP> 8.5 <SEP> -35.3 <SEP>#<SEP> 6.0 <SEP> -37.1 <SEP >#<SEP> 4.1 <SEP> -45.5 <SEP>#<SEP> 5.0
<tb> 3h <SEP> -2.1 <SEP>#<SEP> 2.8 <SEP> -22.8 <SEP>#<SEP> 5.6 <SEP> -34.6 <SEP>#<SEP> 4.7 <SEP> -41.9 <SEP >#<SEP> 3.6 <SEP> -44.2 <SEP>#<SEP> 5.7
<tb> 4h <SEP> -4.9 <SEP>#<SEP> 4.6 <SEP> -32.5 <SEP>#<SEP> 8.9 <SEP> -35.0 <SEP>#<SEP> 3.3 <SEP> -36.3 <SEP >#<SEP> 4.5 <SEP> -46.7 <SEP>#<SEP> 7.8
<tb> 5h <SEP> -0.8 <SEP>#<SEP> 7.0 <SEP> -26.8 <SEP>#<SEP> 9.1 <SEP> -33.6 <SEP>#<SEP> 4.9 <SEP> -28.0 <SEP >#<SEP> 5.2 <SEP> -42.9 <SEP>#<SEP> 8.9
<tb> 6h <SEP> 1.3 <SEP>#<SEP> 5.1 <SEP> -29.1 <SEP>#<SEP> 9.0 <SEP> -25.1 <SEP>#<SEP> 7.1 <SEP> -30.9 <SEP>#<SEP> 3.2 <SEP> -47.7 <SEP>#<SEP> 6.4
<tb> 24h <SEP> 3.1 <SEP>#<SEP> 5.0 <SEP> -3.5 <SEP>#<SEP> 6.5 <SEP> 3.7 <SEP>#<SEP> 7.2 <SEP> -9.62 <SEP>#<SEP> 2.9 <SEP> -34.6 <SEP>#<SEP> 15.3
<tb> TABLE 3
Mean change in mmHg blood pressure when injecting 2.5 g / kg phenylephrine before (TO) and after 3 mg / kg moxisylyte subcutaneously or intramermically in the conscious rat.

<SEP> WITNESSES <SEP> TRAITE <SEP> ID <SEP> TRAITE <SEP> SC
<Tb>

<SEP> NACL <SEP> 0.9% <SEP> MOXY <SEP> 3MG <SEP> / KG <SEP> MOXY <SEP> 3MG <SEP> / KG
<tb> TIME <SEP> N <SEP> AVERAGE <SEP>#<SEP> ECT <SEP> AVERAGE <SEP>#<SEP> ECT <SEP> AVERAGE <SEP>#<SEP> ECT
<tb> TO <SEP> 5 <SEP> 57.6 <SEP>#<SEP> 7.0 <SEP> 50.4 <SEP># 2.6 <SEP> 57.1 <SEP>#<SEP> 1.1
<tb> 15 <SEP> MN <SEP> 5 <SEP> 57.9 <SEP>#<SEP> 5.2 <SEP> 24.3 <SEP>#<SEP> 3.6 * <SEP> 56.4 <SEP>#<SEP> 1.2 *
<tb> 30 <SEP> MN <SEP> 5 <SEP> 57.7 <SEP>#<SEP> 7.1 <SEP> 27.7 <SEP>#<SEP> 3.7 * <SEP> 30: 4 <SEP>#<SEP> 6.7 *
<tb> 1H <SEP> 5 <SEP> 57.2 <SEP>#<SEP> 2.2 <SEP> 35.7 <SEP>#<SEP> 4.3 * <SEP> 42.1 <SEP>#<SEP> 2.9 *
<tb> 1.5H <SEP> 5 <SEP> 58.2 <SEP>#<SEP> 4.4 <SEP> 44.0 <SEP>#<SEP> 5.4 * <SEP> 50.1 <SEP>#<SEP> 4.4 *
<tb> 2H <SEP> 5 <SEP> 57.9 <SEP>#<SEP> 9.8 <SEP> 46.4 <SEP>#<SEP> 2.0 <SEP> 54.7 <SEP>#<SEP> 3.6
<tb> * = significant DUNCAN test at P <0.05

Claims (8)

 A pharmaceutical composition for topical administration containing an effective amount of Moxisylyte, or a derivative or metabolite thereof, particularly deacetyl moxisylyte, in combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants, suitable for such an application .  2. Pharmaceutical composition according to claim 1, characterized in that it is presented in trans-dermal form.  3. Pharmaceutical composition according to one of claims 1 or 2, characterized in that it is in the form of gel, ointment, cream or lotion.  4. Pharmaceutical composition according to one of claims 1 or 2, characterized in that it is in the form of a dressing or a plaster.  5. Pharmaceutical composition according to claim 4, characterized in that the dressing or plaster is monolithic, multilayer and / or comprises a reservoir.  6. Pharmaceutical composition according to one of claims 1 to 5, characterized in that the moxisylyte, one of its metabolites or one of its derivatives, is present between 40 and 0.1% by weight and preferably between 20 and and 1% by weight of the composition.  7. Pharmaceutical composition according to one of claims 1 to 6, characterized in that it is intended for therapeutic treatment in humans.  8. Pharmaceutical composition according to claim 7, characterized in that it is intended in particular for the treatment of psycho-behavioral disorders of senescence, cerebral or peripheral circulatory disorders, Raynaud's disease or urinary disorders related to the prostatic adenoma.