FR2732603A1 - Use of alkaline earth metal salt(s) - Google Patents

Abstract

The invention relates to the use of a strontium salt as an antagonist of substance P, in particular in a physiologically acceptable medium, to treat the pathological and / or physiological disorders associated with the release of substance P. The invention relates to in particular the use of a strontium salt to prevent and / or fight against skin conditions such as atopic dermatitis, psoriasis, eczema, acne, urticaria, neurodermatitis, prurigo, pilosebaceous diseases, bronchopulmonary diseases such as asthma, Allergic bronchitis, allergic rhinitis, headaches such as dental, ophthalmic, tympanic, rheumatic, post-traumatic and migraine headaches, gastrointestinal ailments, diseases of the central nervous system.

Description

The present invention relates to the use of strontium salts as a substance P antagonist in a physiologically acceptable medium for the treatment of pathological and / or physiological disorders associated with the release of substance P.

Substance P is a polypeptide chemical element elaborated and released by a nerve ending. It intervenes in particular in the transmission of pain and in diseases of the central nervous system such as anxiety, schizophrenia, in respiratory and inflammatory diseases, in gastrointestinal diseases, in rheumatic diseases and in certain dermatological diseases such as as eczema, atopic dermatitis, psoriasis and acne.

To treat the disorders associated with the release of the substance P, it is known to use substance P antagonists (see for example the application FR94 / 05537 filed May 5, 1994 in the name of the applicant). These substance P antagonists are substances of organic or mineral origin, capable of producing an inhibition of the substance P receptor binding or an inhibition of the synthesis of substance P release by the sensory nerve fibers.

A number of compounds are known as substance antagonists
P. It is most often peptides or non-peptide derivatives containing a heteroatom.

For a substance to be recognized as a substance P antagonist, it must meet in particular the following characteristic: - have a pharmacological substance P antagonistic activity, that is to say induce a pharmacological coherent response in at least l one of the following two tests:
the antagonist substance must decrease the extravasation of the plasma through the capsaicin-induced vascular wall or by antidromic nerve stimulation, or
the antagonistic substance must cause an inhibition of the smooth muscle contraction induced by the substance P administration.

On the other hand, the antagonist substance can have a selective affinity for the NK1 receptors of tachykinins.

The Applicant has surprisingly found that the strontium salts have the characteristic of producing an inhibition of the substance P receptor binding and could therefore be used as substance P antagonists.

The subject of the present invention is therefore the use of at least one strontium salt in a physiologically acceptable medium in eVou for the manufacture of a cosmetic, pharmaceutical eVou veterinary composition intended to treat the pathological and / or physiological disorders associated with the release of substance P.

The physiological disorders associated with substance P include skin disorders (atopic dermatitis, psoriasis, eczema, acne, urticaria, neurodermatitis, prurigo, sensitive skin, pruritus), bronchopulmonary conditions (asthma, allergic bronchitis, allergic rhinitis), pain (dental, ophthalmic, tympanic, rheumatic, post-traumatic, and migraine pains), gastrointestinal disorders, diseases of the central nervous system (depression, schizophrenia).

Also, the subject of the present invention is also the use of at least one strontium salt in a physiologically acceptable medium in eVou for the manufacture of a cosmetic, pharmaceutical and / or veterinary composition intended to treat cutaneous affections, bronchopulmonary affections, pain, gastrointestinal diseases and / or diseases of the central nervous system.

The present invention also relates to the use of at least one strontium salt in a physiologically acceptable medium and / or for the manufacture of a cosmetic, pharmaceutical and / or veterinary composition for treating atopic dermatitis, eczema, psoriasis , Acne.

As strontium salts that may be used in the invention, mention may be made of carbonate, bicarbonate, sulphate, glycerophosphate, borate, chloride, nitrate,
Acetate, hydroxyl, persulfate and the salts of α-hydroxy acids (citrate, tartrate, lactate, malate) or of fruit acids, or the salts of amino acids (aspartate, arginate, glycocholate, fumarate) or salts of fatty acids (palmitate, oleate, caseinate, behenate).

Advantageously, the strontium salt is strontium chloride or strontium nitrate.

In the compositions according to the invention, the strontium salt is preferably used in an amount representing from 0.001 to 30% of the total weight of the composition, and in particular in an amount representing from 0.1 to 15% of the total weight of the composition. the composition and better from 0.5 to 10%.

The compositions according to the invention can be applied either locally, that is to say topically or by subcutaneous and "or intradermal injection, or systemically or generally, that is to say orally. eVou intramuscular injection.

Topically, it is intended to be applied on the skin, including the scalp, as well as on the mucous membranes, and for example on the nasal mucous membranes.

A physiologically acceptable medium is a medium compatible with the tissues of humans and animals.

The compositions according to the invention may be in any of the galenical forms normally used according to the route of use (topical, injectable or unmanageable application).

The injectable compositions may be in the form of an aqueous lotion, oily or in the form of serum.

The compositions used orally may be in the form of capsules, capsules, syrups or tablets.

For topical application, the compositions may be in the form of, in particular, aqueous, aqueous-alcoholic or oily solutions, lotion or serum-type dispersions, aqueous, anhydrous or lipophilic gels, liquid-type or semi-liquid-like emulsions of the milk type. , obtained by dispersion of a fatty phase in an aqueous phase (O / W) or conversely (ut), or of suspensions or emulsions of soft, semi-solid or solid consistency of the cream or gel type, or of microemulsions, of microcapsules, microparticles or vesicular dispersions of ionic type eVou nonionic.

These compositions are prepared according to the usual methods.

The amounts of the various constituents of the compositions according to the invention are those conventionally used in the fields under consideration.

When the composition of the invention is an emulsion, the proportion of the fatty phase may range from 5% to 80% by weight, and preferably from 5% to 50% by weight relative to the total weight of the composition. The oils, emulsifiers and coemulsifiers used in the emulsion composition are chosen from those conventionally used in the fields under consideration.

The emulsifier and the coemulsifier are present in the composition in a proportion ranging from 0.3% to 30% by weight, and preferably from 0.5% to 20% by weight relative to the total weight of the composition. The emulsion may further contain lipid vesicles.

When the composition of the invention is a solution or an oily gel, the fatty phase may represent more than 90% of the total weight of the composition.

In known manner, the composition of the invention may also contain adjuvants usual in the cosmetic, pharmaceutical and / or veterinary fields, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, complexing agents (EDTA ), solvents, fragrances, fillers, filters, bactericides, odor absorbers and coloring matter. The amounts of these various adjuvants are those conventionally used in the field under consideration, and for example from 0.01% to 20% of the total weight of the composition. These adjuvants, depending on their nature, can be introduced into the fatty phase, into the aqueous phase and into the lipid spherules.

As oils that can be used in the invention, mention may be made of mineral oils (hydrogenated polyisobutene, petroleum jelly), vegetable oils (liquid fraction of shea butter, apricot kernel oil), synthetic oils (vegetable oil). purcellin, isopropyl myristate, ethyl hexyl palmitate), silicone oils (volatile silicone oil) and fluorinated oils. It is also possible to use fatty alcohols (cetylstearyl alcohol, cetylstearyl alcohol, oxyethylenated with 33 mole EO, cetyl alcohol), fatty acids and waxes.

As emulsifiers that can be used in the invention, mention may be made, for example, of glycerol stearate, sorbitan mono- or tristearate, PEG40 stearate or oxyethylenated sorbitan monostearate (200E).

As solvents that can be used in the invention, mention may be made of lower alcohols, in particular ethanol and isopropanol, and propylene glycol.

As hydrophilic gelling agents, mention may be made of carboxyvinyl polymers (carbomer), acrylic copolymers such as copolymers of acrylates, alkyl acrylates, polyacrylamides and in particular the polyacrylamide, C13-14-lsoparaffin and Laureth-7 mixture sold under the name Sepigel 305. by the company Seppic, polysaccharides, natural gums and clays, and lipophilic gelling agents that may be mentioned modified clays such as bentones, metal salts of fatty acids, ethylcellulose or polyethylene.

As hydrophilic active agents, it is possible to use proteins or protein hydrolysates, amino acids, polyols (glycerine), urea, allantoin, sugars and sugar derivatives, water-soluble vitamins, starch, bacterial or plant extracts like those of Aloe Vera.

As lipophilic active agents, it is possible to use retinol (vitamin A) and its derivatives, tocopherol (vitamin E) and its derivatives, essential fatty acids, ceramides, essential oils.

Advantageously, the composition of the invention may also contain active agents capable of supplementing the effect of the strontium salt on the pathological and / or physiological disorders concerned. The composition may contain, for example, corticosteroids when it is intended for the treatment of cutaneous affections. It is known that corticosteroids are effective for the treatment of eczema, but that their use often leads to undesirable side effects. However, the combination with the strontium salt used according to the invention makes it possible to reduce or even eliminate the level of corticosteroid while allowing good efficacy on eczema.

In addition, the composition of the invention may advantageously contain a thermal and / or mineral water, chosen in particular from Vittel water, the waters of the Vichy basin, Uriage water, water from Roche Posay, the water of the Bourboule,
The water of Enghien-les-bains, the water of Saint-Gervais-les bains, the water of Néris-lesbains, the water of Allevard-les-bains, the water of Digne, the water Maizières, the water of
Neyrac-les-bains, the water of Lons le Saunier, the Good Waters, the Rochefort water,
The water of Saint Christau, the water of the Fumades and the water of Tercis-les-bains. It is preferably water Roche Posay.

Tests have demonstrated the activity of different strontium salts as substance P antagonists with reference to Span II, known as substance P antagonist, and compared to another alkaline earth metal salt, calcium nitrate.

The test consisted in determining the activity of the various compounds on the release of substance P, caused by antidromic stimulation of the sciatic nerve. This release is visualized by dye staining (Evans blue). The coloring is all the stronger as the quantity of substance P released is important. In other words, the more the substance P antagonist produces an inhibitory effect on this release, the lower the coloration.

The results are summarized in the tables below:
Table 1

<tb><SEP> Control <SEP> Span <SEP> II <SEP> Sr (NO3) 2 <SEP> SrCl2 <SEP> Ca (NO3) 2
<tb><SEP> vehicle <SEP> 30 <SEP> nmoles <SEP> 1 <SEP> pmole <SEP> 1 <SEP> Immune <SEP> 1 <SEP> pmole
<tb><SEP> pglmlde <SEP> 8,19 + 0,83 <SEP> 4,35 + 0,46 <SEP> 4,84i0,6 <SEP> 5,13 + 0.9 <SEP> 11, 25+
<tb> blue <SEP> Evans <SEP> 1.77
<tb><SEP> Inhibition <SEP> - <SEP> 47 <SEP>% <SEP> 41 <SEP>% <SEP> 37 <SEP>%
<tb><SEP> by <SEP> report
<tb><SEP> to the <SEP> control
<tb> Statistics <SEP> p <0.01 <SEP> p <0.05 <SEP> p <0.05 <SEP> no
<tb><SEP> meaningful
It appears from this table that the strontium salts have an important activity of inhibiting the release of the substance P while the calcium salt, at equal concentration rate, has no activity at all.

Table 2

<tb><SEP> Control <SEP> Span <SEP> II <SEP> Sr (NO3) 2 <SEP> SrCl2 <SEP> Ca (NO3) 2
<tb><SEP> vehicle <SEP> 30 <SEP> nmoles <SEP> 3 <SEP> pmoles <SEP> 1 <SEP> pmole <SEP> 10 <SEP> Immoles <SEP>
<tb><SEP> pglmlde <SEP> 626 + 1.09 <SEP> 3.63 <SEP> + <SEP> 0.69 <SEP> 1.80 <SEP>#<SEP> 0.68 <SEP><SEP> 2.71 <SEP>#<SEP> 0.67 <SEP><SEP> 8.45 + 1.55 <SEP>
<tb> blue <SEP> Evans
<tb><SEP> Inhibition <SEP> - <SEP> 42 <SEP>% <SEP> 71 <SEP>% <SEP> 57 <SEP>%
<tb><SEP> by <SEP> report
<tb><SEP> to the <SEP> control
<tb> Statistics <SEP> - <SEP> p <0.05 <SEP> p <0.001 <SEP> p <0.01 <SEP> no
<Tb>

<tb> significant <SEP>
<tb> It appears from this table that strontium salts have an important activity of inhibiting the release of substance P whereas the calcium salt has no activity at all, even at a higher concentration rate. important.

The following examples illustrate the invention. In these examples, the proportions indicated are percentages by weight.

Example 1: Care cream for atopic dermatitis apart from eczematous flares - 3% ethyl hexyl palmitate - Liquid fraction of shea butter (Triglycerides of acid
2% - Glycerol 3% Stearate - Sorbitan Tristearate (Span 65 from ICI) 0.9% - Hydrogenated Polyisobutene 4.5% - Vitamin E 0.02% - Volatile Silicone Oil 5 % - PEG40 Stearate (Myrj 52) 2% - PCA Sodium 6% - Disodium EDTA 0.05% - Strontium Chloride 10% - Glycerin 3% - Preservative 0.3% -Sepigel 305 1% - Water qs 100%
Example 2: Care Cream for Atopic Dermatitis During Eczematous Flares - 3% Ethyl Hexyl Palmitate - Liquid Fraction of Shea Butter (Triglycerides of Acid
palmitic-stearic-oleic-linoleic) 2% - Glycerol stearate 3% - Sorbitan tristearate (Span 65 from ICI) 0.9% - Hydrogenated polyisobutene 4.5% Vitamin E 0.02% - Silicone oil volatile 5% - PEG40 Stearate (Myrj 52) 2% - PCA Sodium 6% - Disodium EDTA 0.05% - Strontium Chloride 5% - Beta-Methasone 17-valerate (Corticoid) 0.05% - Glycerin 3% - conservative 0.3% -Sepigel 305 1% -Water qs 100%
Example 3: Eczema care lotion
Strontium nitrate 5%
Glycerol stearate 1%
Cetylstearyl alcohol / cetylstearyl alcohol oxyethylenated to 33 mol O.sub.3 (Sinnowax AO sold by Henkel) 3%
Cetyl alcohol 1%
Volatile silicone oil 1%
Vaseline oil 6% Isopropyl myristate 3%
Glycerin 20%
Conservative 0.3%
Water qs 100%
Example 4: HIE emulsion for the treatment of acne
Fatty phase: - Apricot almond oil 14.5% - Liquid fraction of shea butter (Triglycerides of acid
palmitic-stearic-oleic-linoleic) 8% - Sorbitan mono-stearate (Span 60 from ICI) 2.5% - Purcellin oil 2%
Aqueous phase: - 0.5% preservatives - Disodium salt of ethylene di-amine tetracetic acid
2H2O (complexing agent) 0.05% - Neutralizer 0.5% - Gelling agent 0.7% - Glycerin 5% - Oxyethylenated sorbitan monostearate (200E)
(Tween 60 of ICI) (surfactant) 2,5% - Strontium chloride 1% - Roche-Posay water 60% - Demineralized or permuted water qs 100%

Claims (11)

 1. Use of at least one strontium salt in a physiologically acceptable medium in eVou for the manufacture of a cosmetic, pharmaceutical eVou veterinary composition for treating the physiological disorders eVou physiological associated with the release of substance P. 2. Use of at least one strontium salt in a physiologically acceptable medium in etlou for the manufacture of a cosmetic, pharmaceutical and / or veterinary composition intended to treat cutaneous affections, bronchopulmonary affections, pain, gastrointestinal disorders and / or diseases of the central nervous system. 3. Use of at least one strontium salt in a physiologically acceptable medium in or for the manufacture of a cosmetic, pharmaceutical and / or veterinary composition intended for treating atopic dermatitis, Eczema, psoriasis, acne. 4. Use according to one of claims 1 to 3, characterized in that the strontium salt is selected from chloride, carbonate, borate, nitrate, Acetate, hydroxide, sulfate, salts of fruit acids and salts of amino acids. 5. Use according to any one of the preceding claims, characterized in that the salt is a nitrate or a chloride. 6. Use according to any one of the preceding claims, characterized in that the strontium salt is used in an amount representing from 0.001 to 30% of the total weight of the composition. 7. Use according to any one of the preceding claims, characterized in that the strontium salt is used in an amount representing from 0.5 to 10% of the total weight of the composition. 8. Use according to any one of the preceding claims, characterized in that the composition further contains at least one corticoid. 9. Use according to any one of the preceding claims, characterized in that the composition further contains at least one mineral and / or thermal water. 10. Use according to any one of the preceding claims, characterized in that the composition is in a form suitable for topical application, injectable or unmanageable. 11. Use according to any one of the preceding claims, characterized in that the physiologically acceptable medium is an aqueous solution, oily or aqueous-alcoholic, a water-in-oil emulsion, an oil-in-water emulsion, a microemulsion, a gel aqueous, an anhydrous gel, a serum, a dispersion of vesicles.