JP2002505268A - Use of a sodium channel activity inhibiting compound in a composition for topical use - Google Patents

Abstract

  (57) [Summary] The present invention relates to calcium channels in cosmetic and / or pharmaceutical compositions for increasing the skin tolerance threshold of particularly sensitive or sensitive skin, especially for eliminating itching, pruritus, severe pain, stinging and / or erythema And the use of at least one compound that partially or totally inhibits the activity of sodium channels.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to skin, in particular sensitive or intolerant skin.
Cosmetic and / or pharmaceutical compositions for increasing the tolerance threshold of skins, especially for eliminating itching, pruritus, taughtness, stinging and / or erythema The use of at least one compound which partially or totally inhibits the activity of calcium and sodium channels, excluding lanthanum and lanthanides.

[0002] Skin is responsive to external aggression, and some skin is known to be more sensitive and more intolerant than others. The mechanism by which the skin responds to these attacks has not been previously known. Thus, no one knew exactly, for example, the processes associated with skin sensitivity and intolerance. Some consider hypersensitive skin to be skin that responds to cosmetics, but not necessarily to cosmetics, but to skin that responds to various external factors. Some are. Also, hypersensitive or intolerant skin was placed in the same category as allergic skin.

[0003] Because the mechanisms by which the skin responds to external attacks are not well known, it has hitherto been very difficult to prevent the skin from responding to these attacks, especially to treat sensitive or intolerant skin. It was difficult. Thus, skin has been indirectly treated, for example, by limiting the use of irritating products such as surfactants, preservatives or fragrances in cosmetic compositions.

[0004] Indeed, test methods have been developed to define hypersensitive skin, for example with DMSO or lactic acid, which are known to be irritants:
K. Lammintausta et al., Dermatoses, 1988, 36 , 45-
See pages 49 and T. Agner and J. Serup, Clinical and Experimental Dermatology, 1989, 14 , 214-217. I want to be. Unfortunately, however, it is not possible with these test methods to accurately characterize the mechanism by which the skin responds to external aggression, or to understand what governs sensitive or intolerant skin. Was.

[0005] Applicants have found that the responsiveness of the skin to an external attack is related to changes in skin excitability. In particular, the cell membrane of each nerve fiber and some skin cells, such as keratinocytes or melanocytes, contain many ion channels, especially sodium or calcium channels. The role of these ion channels is to allow passage of sodium or calcium ions on both sides of the cell membrane. These ion exchanges (active transfer of charged sodium or calcium) lead to electrical fluctuations that more or less excite sensory nerve fibers and skin cells such as keratinocytes or melanocytes.

[0006] As a result of a number of tests, Applicants have found that sensory nerve fibers present in the skin, as well as certain skin cells, such as keratinocytes or melanocytes, contain sodium or calcium channels. Was found. The Applicant has further found that there is a link between the activity of these channels and the excitability threshold of the skin, especially of sensitive or intolerant skin. They have also found that they can act on these channels to increase the skin tolerance threshold.

To the applicant's knowledge, to date, no one has established an association between the sodium or calcium channels of sensory nerve fibers of the cutaneous peripheral nervous system and the skin tolerance threshold, and the activity of these channels has been reduced. Nobody found that inhibition could increase the skin tolerance threshold. Substances that inhibit these channels and thus reduce the import of sodium or calcium ions into cells are called inhibitory compounds.

Thus, the use of compounds that partially or totally inhibit sodium or calcium channels present in skin tissue can increase the skin tolerance threshold. Thus, partially or totally inhibiting the transfer of sodium or calcium into cells will reduce the increase in skin tolerance threshold or excitability.

Accordingly, the present invention relates to a composition for increasing the tolerance threshold of the skin and / or
Or in the preparation thereof, except for lanthanum and lanthanides, which relates to the use of at least one compound which partially or totally inhibits the activity of at least one sodium or calcium channel.

[0010] The "skin tolerance threshold", above which the skin responds to external attacks with signs such as dysaesthetic sensations, ie a more or less painful sensation in the skin area, for example a puncture Pain, tingling, itching or pruritus, burning, sensations of heating, discomfort, severe pain (taughtn)
ess) and / or an excitability threshold of the skin that causes a reaction accompanied by redness or erythema.

“External attack” refers to, for example, irritating products such as surfactants, preservatives or fragrances and the environment, emotions, food, wind, friction, shaving, soaps, surfactants, calcium concentration, It means both high hard water, temperature change, wool and the like.

The subject of the present invention is also a topical use for preventing, treating or eliminating stinging, tingling, itching or pruritus, burning, warmth, discomfort, severe pain and / or redness or erythema. The use of at least one compound which partially or totally inhibits the activity of at least one sodium or calcium channel, excluding lanthanum and lanthanides, in the composition for use and / or in the preparation thereof.

The invention also relates to at least one cutaneous sensory nerve fiber and / or at least one keratinocyte, excluding lanthanum and lanthanide, in a composition for topical use for increasing the skin tolerance threshold and / or in its preparation. And / or the use of at least one compound that partially or totally inhibits the activity of at least one sodium or calcium channel of at least one melanocyte.

The present invention further provides a tingling tingling, tingling itch, itching or pruritus, burning sensation, warmth,
At least one cutaneous sensory nerve fiber and / or excluding lanthanum and lanthanide in a composition for topical use to prevent, treat or eliminate discomfort, severe pain and / or redness and / or erythema and / or in its preparation It relates to the use of at least one compound which partially or totally inhibits the activity of at least one sodium or calcium channel of at least one keratinocyte and / or at least one melanocyte.

Still further, to prevent, treat or eliminate tingling, tingling, itching or pruritus, burning, warmth, discomfort, severe pain and / or redness and / or erythema, or to set a skin tolerance threshold Topical cosmetics containing at least one compound that partially or totally inhibits the activity of at least one sodium or calcium channel, excluding lanthanum and lanthanide, present or absent in skin tissue to increase Cosmetic treatment comprising topically applying the composition to the skin, whether or not the channel is associated with cutaneous sensory nerve fibers and / or at least one keratinocyte and / or at least one melanocyte. In the way.

It has been mentioned hereinabove that certain skin responds more quickly to external aggression than normal skin and is more sensitive or intolerant. However, this hypersensitive or intolerant skin, which is not allergic skin because no immunological mechanisms are performed, responds to an external attack with the same signs as normal skin, but is more acute, and in some cases React more violently.

Thus, the mechanism by which normal skin responds to an external attack is, to a lesser extent, similar to that involving sensitive or intolerant skin that responds to a similar attack. . Thus, Applicants have found that hypersensitive or resistant outer skin is also associated with changes in skin excitability. Thus, the use of compounds that partially or totally inhibit the activity of sodium or calcium channels makes it possible to increase the tolerance threshold of sensitive or intolerant skin. Thus, partially or totally preventing the transfer of sodium or calcium into cells reduces the tolerance threshold or excitability of sensitive or intolerant skin.

The subject of the invention is especially for preventing, treating or eliminating stinging, tingling, itching, pruritus, burning, warmth, discomfort, severe pain, redness and / or erythema, or irritability At least partially or totally inhibit the activity of at least one sodium or calcium channel, excluding lanthanum and lanthanide, in a composition for increasing the tolerance threshold of sexual or intolerant skin and / or in the preparation thereof. Use of one compound, wherein the channel is at least one cutaneous sensory nerve fiber and / or at least one keratinocyte and / or at least one
One of which may or may not be the sodium or calcium channel of one melanocyte.

Similarly, a subject of the present invention is to prevent, treat or eliminate stinging, tingling, itching, pruritus, burning, warmth, discomfort, severe pain and / or redness and / or erythema. Contains at least one compound that partially or totally inhibits the activity of at least one sodium or calcium channel, excluding lanthanum and lanthanides, in order to increase the tolerance threshold of sensitive or intolerant skin A method of cosmetic treatment of sensitive or intolerant skin comprising topically applying a topical cosmetic composition to the skin, wherein the channel comprises at least one cutaneous sensory nerve fiber and / or at least one keratinocyte and / or Or one that may or may not be the sodium or calcium channel of at least one melanocyte is there.

[0020] Of course, the present invention relates to at least one calcium channel and at least one calcium channel.
It is possible to use inhibitors that are both inhibitors of one sodium channel, or to use inhibitors of calcium and sodium channels alone or as a mixture.

As the sodium or calcium channel, “Pharmacological Review”
(1992, Vol. 44, 3, 363-375), voltage-dependent calcium channels of the L, T, N, P, Q and R types, and the "International Review of Cytology"
(1993, Vol. 137c, 55-103) or "Annu. Rev. Biophys. Chem." (1991, Vol. 20,
65-78) or sodium channels described in "J. Gen. Physiol." (1993, Vol. 101, 153-182). In particular, one of the sodium channels may be the ASIC channel (Acid-Sensing Ionic Channel) disclosed by M. Lazdunski et al. In Nature, Vol. 386, pp. 173-177, March 1997. .

In the present invention, any substance that acts as an inhibitor of sodium channel or calcium channel activity can be used. In the present invention, in order for a substance to be recognized as an inhibitor of sodium or calcium channel activity, it must have the following properties: Calcium in the model described by JPGalizzi et al. (J. Biol. Chem. 1987, 262, p. 6947). -Reacts as a sodium antagonist in the model described by Y. Jacques et al. (J. Biol. Chem. 1987, 253, 7383);-HR Lee et al. (Life Sciences. 1984, 35 721). P.) And / or Schoemaker et al. (Eur.
J. Pharmacol. 1985, 111 p. 273) and / or IJ Reynolds et al. (J. Pharmacol. E
xp. Ther. 1986, 236 731) reacts as a substance that specifically binds in the L-type calcium channel binding model; described by JA Wagner et al. (J. Neuroscience. 1988, 8, 3354). Reacts as a substance that specifically binds in a model of N-type calcium channel binding;-WA Catterall et al. (J. Biol. Chem. 1979, 254, p. 11379) or GB Brown et al.
J. Neuroscience 1986, 6, 2064) reacts as a substance that specifically binds in the sodium channel binding model; described in Y. Okamiya et al. (Eur. J. Pharmacol. 1991, 205, 49). As a calcium antagonist in an isolated organ model such as the aorta constricted by the action of potassium chloride.

For example, inhibitors that can be used as calcium channel inhibitors in the present invention include: nicardipine, nitrendipine, nifedipine, nimodipine, niguldipine, amiloride, pimozide, quinidine, quinidine sulfate, ruthenium red, verapamil, N-acetylprocainamide , Apamin, cyproheptadine, diltiazem and loperamide. In the present invention, verapamil and / or amiloride are preferably used.

Of course, the amount of the inhibitor of at least one sodium channel or at least one calcium channel used in the present invention is related to the desired effect and can therefore be varied within a wide range. As a guide, the inhibitor should be present at 0.0001% to 1% based on the total weight of the composition.
It is in an amount of 0%, preferably in an amount of 0.001% to 5% based on the total weight of the composition.

Advantageously, in the present invention, at least one inhibitor of at least one sodium channel or at least one calcium channel is combined with a product having a stimulating effect commonly used in the cosmetic or pharmaceutical field. These products can also be active agents, possibly cosmetic or pharmaceutical.
Whether the product contains a product having an irritant effect, whether cosmetic or pharmaceutical,
The presence of inhibitors of sodium or calcium channels in such compositions can significantly reduce or even eliminate this stimulatory effect. In order to improve the effect, the amount of the active ingredient having the stimulating effect can be made larger than the amount of the active ingredient usually used.

In particular, the invention comprises in a cosmetically or pharmaceutically acceptable medium at least one inhibitor of at least one sodium channel or at least one calcium channel and a product having at least one stimulating effect. The present invention relates to a cosmetic or pharmaceutical composition characterized in that it is made at least.

Products having a stimulating effect include, for example, surfactants (ionic or non-ionic), preservatives, organic solvents or activators, for example α-hydroxy acids (citric acid, malic acid, glycolic acid, tartaric acid) , Mandelic acid, lactic acid), β-hydroxy acid (salicylic acid and its derivatives), α-keto acid, β-keto acid, retinoids (retinol, retinal, retinoic acid), anthralins (dioxyanthranol), anthranoids , Peracids (especially benzoyl peroxide), minoxidil, lithium salts, antimetabolites, vitamin D and its derivatives, hair coloring or dyes (para-phenylenediamine and its derivatives, aminophenols), aromatic alcohol solutions (Perfume, eau de toilette, after shaving, deodorant), antiperspirant (a kind of aluminum salt), hair removal or permanent clothing Activator (thiols) and depigmenting agent (hydroquinone)
Can be mentioned. Preferably, the inhibitor of a sodium channel or a calcium channel is an inhibitor described previously in the text.

Whatever the phenomena that lead to irritable or intolerant skin, all these mechanisms have in common that the final aspect is at least one inflammatory mediator by the mast cells of the skin, such as histamine, serotonin, Expressed by an inflammatory response, which can be measured by the release of heparin, leukotrienes, prostaglandins, cytokines, nitric oxide or reactive oxygen species. In some cases, for example, in hypersensitive skin, the entire mechanism is under the control of sensory nerve endings which release neuropeptides, especially substance P and CGRP.

The object sought in the present invention is to provide compositions that can treat the most widespread and beneficial effects of all these skin diseases and thus act on several factors of these diseases. To provide.

Thus, in another aspect, the subject of the present invention is the synthesis, release of at least one inhibitor of sodium or calcium channels and at least one inflammatory mediator in a cosmetically or pharmaceutically acceptable medium. And / or at least one compound which reduces the activity. A "cosmetically acceptable medium" is understood to be a medium that is compatible with the skin, mucous membranes, nails and hair.

Preferably, the compositions of the invention contain at least one compound that reduces the synthesis, release and / or activity of at least one inflammatory mediator of the skin in combination with an inhibitor of a sodium or calcium channel. . Preferably, the inhibitor of a sodium channel or a calcium channel is an inhibitor described previously in the text.

Compounds that reduce the synthesis, release and / or activity of at least one inflammatory mediator are preferably steroidal or non-steroidal anti-inflammatory agents, substance P and / or CGRP antagonists, NO-synthase inhibitors, bradykinin An antagonist, a cytokine antagonist, a histamine antagonist and an α-type tumor necrosis factor (TNFα) antagonist. If an antagonist is used, it is preferably a receptor antagonist.

Examples of steroidal anti-inflammatory agents include hydrocortisone, betamethasone valerate or clobetasol propionate. "Non-steroidal anti-inflammatory agents" are defined herein by Schorderet and Dayer et al. In pharmacology, "Des concepts fondamentaux aux applica
tions therapeutiques), 1992, Chapter 37, pp. 541-561, 2nd edition, Frison-Roche / Slat
Anti-inflammatory agent as described in the kine company version. They are arylcarboxylic acids, such as salicylic acid or anthranilic acid derivatives, arylalkanoic acids, such as arylacetic and heteroarylacetic acids or arylpropionic acids, enolic acids, such as pyrazolone derivatives or oxicams, and nonacid derivatives, such as bufet Kisamak (bufexamac) (Merck Index, 11th edition (MI) 14
62), benzydamine (MI 1136), epilizol (MI 3572), fluproquazone (MI 4120) or tiaramide (MI 935)
6).

[0034] Substance P antagonists are substances that reliably reduce retrograde neural stimulation or capsaicin-induced plasma transmigration through the vessel wall, and the inhibition of substance P-induced smooth muscle contraction. It is selected from the substances that give rise to it.

Substance P antagonists include plant or microbial extracts, spring water, salts of monovalent, divalent and trivalent cations, nitrogenous compounds having at least one benzene ring,
Non-peptidic compounds such as those having at least one heterocycle, peptides, and mixtures thereof.

For example, sendide and spantide II can be used as substance P antagonist peptides in the present invention.

Sendide is equivalent to the following formula: Tyr D-Phe Phe D-His Leu Met NH ₂ , wherein Tyr represents tyrosine, D-Phe represents D-phenylalanine, Phe Represents phenylalanine, D-His represents D-histidine, Leu represents leucine, and Met represents methionine.

Spantide II corresponds to the following formula: D-NicLys Pro 3-Pal Pro D-Cl ₂ Phe Asn D-Trp Phe D-Trp Leu Nle NH ₂ , wherein D-NicLys the D- lysine - represents nicotinate, Pro represents proline, 3-Pal represents 3-pyridyl alanine, D-Cl ₂ -Phe represents a D- dichloro-phenylalanine, Asn represents asparagine, D-Trp is Phe represents phenylalanine, Leu represents leucine, and Nle represents norleucine.

Also, US Pat. No. 4,472,305, US Pat. No. 4,839,465, European Patent Publication No. 101929, European Patent Publication No. 333174, and European Patent Publication No. 336.
No. 230, EP 394 1989, EP 443 132, EP 498 069, EP 515 681, EP 517 589, WO 92/22569 and UK Patent No. 22165
The peptides described in JP-A-29-29 can be used as a substance P antagonist peptide in the present invention.

The non-peptide substance P antagonists that can be used in the present invention are, in particular, compounds that contain a heteroatom contained in a heterocycle or directly or indirectly attached to a benzene ring. In particular, this heteroatom is an oxygen, nitrogen or sulfur atom.

Examples of the heterocyclic compound include the following publications: EP-A-360390, EP-A-429366, EP-A-430771, and EP-A-499.
313, EP-A-514273, EP-A-514274, EP-A-514275, EP-A-514276, EP-A-520555, EP-A-528495, EP-A-532456.
, EP-A-545478, EP-A-558156, WO-A-90 / 05525, WO-A-90 / 05729, WO-A-91 / 18.
No. 878, WO 91/18899, WO 92/12151, WO 92/15585, WO 92/17449, WO 92/92.
/ 20676, WO93 / 00330, WO93 / 00331
No., WO 93/01159, WO 93/01169, WO 93/01170, WO 93/06099, WO 93/09
No. 116 can be used particularly in the present invention.

In particular, compounds containing at least one nitrogenous heterocycle are 2-tricyclyl (tric
yclyl) -2-aminoethane derivative, spirolactam derivative, quinuclidine derivative,
An azacyclic derivative, an aminopyrrolidine derivative, a piperidine derivative, an aminoazaheterocycle or an isoindole derivative.

Other heterocyclic compounds include oxygen-containing or sulfur-containing heterocyclic compounds, for example, US Pat. No. 4,931,459, US Pat. No. 4,910,317 and European Patent Publication No. 2
Benzothiophene derivatives and thiophene derivatives, benzofuran derivatives and furan derivatives which may have a nitrogenous substituent, such as the heterocyclic compounds described in JP-A-99457, particularly alkoxy- and / or aryloxytetra. Zolylbenzofurancarboxamide or alkoxy- and / or aryloxytetrazolylbenzothiophenecarboxamide can be mentioned.

The compounds containing a nitrogen atom directly or indirectly bonded to the benzene ring include the following publications: EP-A-522808 and WO 93/0116.
No. 5 and WO93 / 10073.

The salts of the cations which can be used according to the invention are, in particular, strontium, magnesium,
Lanthanide, cobalt, nickel, manganese, barium, yttrium, copper, tin, rubidium, lithium and zinc salts having atomic numbers in the range of 57-71. These salts include, for example, carbonates, salicylates, bicarbonates, sulfates, glycerophosphates, borates, chlorides, nitrates, acetates, hydroxides or persulfates, and α-hydroxy acids ( Citric, tartaric, lactic or malic acid or fruit acid
s) or an amino acid salt [aspartate, alginate, glycocholate or fumarate] or a fatty acid salt [palmitate, oleate, caseinate or behenate]. Preferably, the salt is selected from strontium, manganese, yttrium or magnesium nitrate, strontium, manganese, yttrium or magnesium borate, strontium, manganese or magnesium chloride, or magnesium, manganese or strontium sulfate. . More preferably, these salts are strontium chloride or strontium nitrate.

The springs that can be used in the present invention include, in particular, those of Vichy basin, such as Celestins, Chomel, Grand-Gru.
Examples include those obtained from e-Grille, Opital, Lucas and Parc sources. Preferably, in the present invention, water from Luka spring is used.

Extracts prepared from plant material, such as extracts of the family Iridaceae, can be used in the present invention as substance P antagonists. The iris extract can be any extract prepared from plant material derived from an iris plant. Iris extract can be obtained from plant material derived from whole plants cultured in vivo, or from plant material derived from in vitro culture. For example, the extract in the present invention may be an extract of at least one organ or organ cell of an iris (root, stem, leaf), or an extract of at least one undifferentiated cell of the iris. Preferably, extracts obtained from undifferentiated cells obtained by in vivo or in vitro culture are used.

By selecting the pressure exerted by the physicochemical conditions during the growth of plant cells in vitro, we obtain standard plant material available year-round, unlike plants grown in vivo. be able to. "In vitro culture" can artificially obtain plants or plant parts,
Means techniques known to those skilled in the art. Thus, for example, in the present invention, an extract of at least one iris plant root cultured in vitro, or an extract of at least one iris plant undifferentiated cell can be used. Preferably, extracts obtained from plant material cultured in vitro, more preferably extracts obtained from undifferentiated cells cultured in vitro are used. By "undifferentiated plant cell" is meant any plant cell that does not exhibit any specific differentiated characteristics and is able to survive on its own, independent of other cells. These undifferentiated plant cells can undergo any differentiation according to their genome under the influence of induction.

With the chosen culture method, in particular the chosen culture medium, undifferentiated plant cells with different characteristics can be obtained from similar explants. About 750 species of irises are included. Iridaceae are used in particular because of their aromatic and decorative properties. Examples of species of the family Iridaceae that can be used in the present invention include, for example, the genus Romulea, the genus Crocus, the iris, the genus Gladiolus, the genus Sisyrinchium, and the genus Hermodactylus. Possible plant substances include German iris (Iris germanica),
(Iris florentina), Iris pallida, Crocus versicolor, Romulea bulbucodium or Gladiolus communis. In particular, in the present invention, a plant substance of the genus Iris, in particular, Iris pallida is used.

To prepare the extract contained in the composition of the present invention, any extraction method known to those skilled in the art can be used. In particular, alcohol extraction, especially ethanol extraction, or aqueous / alcohol extraction is mentioned. It is also possible to use an extract prepared by the method described in French Patent Application No. 95-02379 filed by the present applicant. For example, in the first step, the plant substance is pulverized in a low-temperature aqueous solution, in the second step, particles in the suspension are removed from the aqueous solution obtained in the first step, and in the third step, the second substance is removed. The aqueous solution obtained in the process is sterilized. This aqueous solution corresponds to the extract. Furthermore, the first step may advantageously be replaced by a single operation of freezing the plant tissue (e.g. -20 <0> C), followed by aqueous extraction, and the second and third steps described above are repeated. Of course, in the present invention, the substance P antagonists can be used alone or as a mixture.

In the present invention, “CGRP antagonist” means any compound that can completely or partially inhibit the biological effect of CGRP. In particular, certain substances are CG
To be considered an RP antagonist, the following tests: + Antagonist must reduce retrograde electrical stimulation (applied to afferent nerves) and / or vasodilation induced by capsaicin And / or + antagonists must inhibit CGRP release by sensory nerve fibers and / or + antagonists must inhibit CGRP-induced smooth muscle contraction of the vas deferens Must elicit an interfering pharmacological response (including or not including binding to the CGRP receptor) to one of the following.

Known CGRP antagonists include, for example, CGRP8-37 (CGRP
N-terminal 8 to 37 amino acid sequences), or an anti-CGRP antibody. Further, a plant substance obtained from an iris plant or a substance prepared from a microorganism such as an extract of a non-photosynthetic filamentous fungus can be used.

By “extract of a non-photosynthetic filamentous fungus” is meant equally the culture supernatant of the bacterium, the biomass obtained after culturing the bacterium, or the biomass extract obtained by treating this biomass. Things. The bacterial extract of the present invention can be used in a Bergey's Manual for bacterial phylogeny.
f Systematic Bacteriology) (Vol. 3, Sections 22 and 23, 9th edition, 1989), prepared from non-photosynthetic filamentous fungi, such as those belonging to the order Beggiatoales Bacteria, especially Beggiat
oa), Vitreoscilla, Flexithrix or bacteria belonging to the genus Leucothrix.

The defined bacteria, and some of those generally already described, live in aqueous environments and are found especially in seawater or spring water. Examples of bacteria used include: Vitreoscilla filiformis (ATCC 15551) Vitreoscilla beggiatoids (ATCC 43181) Beggiatoa alba (ATCC 33555) dorotheae) (ATCC 23163) Leucothrix mucor (ATCC 25107) Sphaerotilus natans (ATCC 13338). In the present invention, a strain of Vitreosilla filiformis is preferably used.

To prepare the extract according to the invention, the bacteria are cultured according to methods known to those skilled in the art and then separated from the resulting biomass, for example by filtration, centrifugation, coagulation and / or lyophilization. It is possible. In particular, it is possible to prepare an extract which can be used according to the invention according to the method described by the applicant in WO 93/00741.

For example, after culturing, the bacteria are concentrated by centrifugation. The biomass obtained is autoclaved. This biomass is lyophilized to form what is known as a lyophilized extract. Any lyophilization method known to those skilled in the art can be used to prepare this extract. The supernatant fraction of this biomass is filtered into a sterile container to remove particles in the suspension. In this way, an extract known in the text as an aqueous extract is obtained. Of course, in the present invention, the CGRP antagonist can be used alone or as a mixture.

In the present invention, the term NO-synthase actually covers a family of enzymes that specifically catalyze the enzyme catalysis from L-arginine to citrulline. Nitric oxide, or NO, is generated as a gaseous vehicle having the same. Nitric oxide has additional electrons due to its structure and can exhibit extremely high chemical reactivity. It is well known that such compounds are harmful and sought to limit their formation as much as possible. As a result, in the case of nitric oxide, NO-synthase inhibitors have been extensively studied.

Thus, in the present invention, a NO-synthase inhibitor is a product that can partially or completely inhibit the synthesis of nitric oxide (NO) in situ in humans. For example, they are selected from compounds that reduce the signal converted by NO-synthase, compounds that neutralize NO-synthase, or compounds that promote the catabolism of NO-synthase and / or inhibit synthesis. Compound. Accordingly, NO-synthase inhibitors can be selected from synthetic or natural peptides, which may be denatured, synthetic or natural chemical molecules, antisense nucleic acids, ribozymes and anti-NO-synthase antibodies.

[0059] These NO- synthase inhibitors, especially ^{N G} - monomethyl -L- arginine (L-NMMA), N G - nitro -L- arginine, N G ^- methyl ester of nitro -L- arginine, diphenylene Iodonium chloride, 7-nitroindazole, N (5)-(1-iminoethyl) -L-ornithine, ^NG , ^NG -dimethyl-L-arginine, ^NG , ^NG -dimethylarginine, 1-oxy-2 -(4-carboxyphenyl) -4,4,5,5-tetramethylimidazoline-3-oxide, aminoguanidine,
Mention may be made of canavanine, ebselen and α-type melanocyte stimulating hormone. Among the NO-synthase inhibitors, ^NG -monomethyl-L-arginine and α
The type of melanocyte stimulating hormone is preferably used. NO-synthase inhibitors can be used alone or as a mixture.

Bradykinin is a plasma-derived peptide released from kininogen precursors by a plasma protease called kallikrein (EC 3.4.21.24). This nanopeptide is one of the important mediators of inflammation and has cell division promoting properties. This kinin receptor can be classified into two major subtypes B1 and B2. Brachidinin acts particularly on the B2 receptor,
It stimulates many systems that produce second messengers, including hydrolysates of inositol phosphate, and is responsible for arachidonic acid metabolism, phosphorylation of tyrosine residues, and hyperpolarization or depolarization of cell membranes.

In the present invention, “bradykinin antagonist” means any compound capable of completely or partially inhibiting the biological effect of bradykinin. In particular, in order for a substance to be recognized as a bradykinin antagonist, it must elicit an interfering pharmacological response, with or without binding to the bradykinin receptor. Thus, included within this definition are those that can interfere with the effects of bradykinin by binding to the bradykinin receptor (B1 or B2) and / or independently of the effects known to bradykinin, independent of binding to the receptor. Is any compound that elicits the opposite effect by any mechanism (eg, interferes with the synthesis of bradykinin).

As the bradykinin antagonist, promotion of catabolism of bradykinin and / or
Or a compound that inhibits synthesis, a compound that neutralizes bradykinin, a compound that blocks a bradykinin receptor, such as those that interfere with the effect of bradykinin by binding to the receptor (B1 or B2), a compound that inhibits the synthesis of bradykinin receptor, Alternatively, a compound related to reduction of a signal converted by bradykinin is preferably used. These compounds may be of natural or synthetic origin.

[0063] Bradykinin antagonists include, in particular, optionally modified synthetic or natural peptides such as D-Arg, [Hyp3, D-Phe7] -bradykinin (NPC567), [Thi5,8, D-Phe7] -bradykinin, D -Arg, [Hyp3, Thi5,8, D-Phe7] -bradykinin, N-α-adamantaneacetyl-D-Arg, [Hyp3, Thi5,8, D-Phe7] -bradykinin, des-Arg9, [Leu8]- Bradykinin (all sold from Sigma), or WO 95/08566, WO 95/07294, EP 0623350, EP 0622361, WO 94/11021, European Patent 0596640
6, WO 94/06453, WO 94/09001, EP 0578521, EP 0564972, EP 055210.
6, WO 93/11789, US Pat. No. 5,216,165, US Pat. No. 5,212,182, WO 92/17201, EP 049636.
9, EP 0472220, EP 0455133, WO 91/09055, WO 91/02746, EP 041327.
7, EP 0370453, EP 0359310, WO 90/03980, WO 89/09231, WO 89/092
30, WO 89/01780, EP 0 334 244, EP 0 596 406, WO 86/07263, or compounds described in WO 86/07263, or P-guanidobenzoyl, [Hyp3, Thi5, D -Tic7, Oic8] -Bradykinin (S16118)
[Feletou M et al., Pharmacol. Exp. Ther., June 1995, No. 273.
1078-84], D-Arg, [Hyp3, Thi5, D-Tic7, Oic8] -bradykinin (HOE140) [Ferret-Em et al., Eur. J. Pharmacol, 1995, Vol. 274, 57- 64 pages], D-Arg, [
Hyp3, D-Hype (transpropyl) 7, Oic8] -Bradykinin (NPC17731) [Herzig MCS (Herzig MCS) and Lieb-Lundberg L.M.
F (Leeb-Lundberg LMF), J. Biol. Chem., 1995, Vol. 270, 20591-20598
Page] or "Bradykinin Antagonist: Development and Application (Bradykinin Antagonist
s: development and applications)] [Stewart J
M.), Biopolymers, 1995, Vol. 37, pp. 143-155], or natural or synthetic chemical molecules, such as Salvino et al., J. Med. Chem.
1993, Vol. 36, pp. 2583-2584.

In the present invention, a ribozyme or an antisense nucleic acid having the purpose of selectively inhibiting the synthesis of bradykinin can also be used. These antisense nucleic acids are known to those skilled in the art. These specifically prevent messenger RNA maturation, or prevent messenger RNA transfer from the nucleus to the cytoplasm, or cleave messenger RAN with RNase H, or block ribozyme progression or binding along the messenger RNA. By doing so, it can act on messenger RNA or DNA encoding bradykinin in various ways.

Further, in the present invention, an anti-bradykinin antibody or a soluble bradykinin receptor, an anti-bradykinin receptor antibody or an antagonist of a bradykinin receptor can also be used.

In the present invention, a compound that interferes with the effect of bradykinin by binding to the bradykinin receptor (B1 or B2), preferably the B2 receptor, is preferably used. More preferably, D-Arg, [Hyp3, D-Phe7] -bradykinin (NPC567), [Thi5,8, D-Phe7] -bradykinin, D-Arg, [Hyp3, Thi5,8, D-Phe7] -bradykinin N-α-adamantaneacetyl-D-Arg, [Hyp3, Thi5,8, D-Phe7] -bradykinin, des-Arg9, [Leu8] -bradykinin, P-guanidobenzoyl, [Hyp3, Thi5, D-Tic7 , Oic8] -Bradykinin (S16118) D-Arg, [Hyp3, Thi5, D-Tic7, Oic8] -Bradykinin (HOE140), D-Arg, [Hyp3, D-Hype (transpropyl) 7, Oic8] -Bradykinin ( NPC17731), used in the present invention. The modified peptide preferably used in the present invention is D-Arg, [Hyp3, Thi5, D-Tic7,
Oic8] -bradykinin (HOE140). Bradykinin antagonists can be used alone or as a mixture.

In the present invention, “histamine, cytokine and / or TNF-α antagonist” refers to a substance capable of inhibiting binding and / or synthesis and / or release of histamine, cytokine and / or TNF-α receptor, respectively. Means any substance. Antagonists that inhibit histamine receptor binding are agents specific for type 1 histamine receptor (H1).

In order for a substance to be recognized as a histamine, cytokine or TNF-α receptor antagonist, it has the following characteristics: it has an affinity for a receptor specific for these compounds; Has the pharmacological activity of a receptor antagonist of TNF-α, ie, the following test: + against a histamine receptor antagonist: inhibits smooth muscle contraction induced by administration of histamine; For: inhibits cytokine-induced superoxide anion release on neutrophils or inhibits cytokine-induced macrophage adhesion in endothelial cells; + For receptor antagonists of TNF-α: dermis On fibroblasts There inhibit the release of superoxide anions induced by TNF-alpha in inhibiting cell division activity of TNF-alpha, or neutrophils, or TNF in endothelial cells
Inhibit macrophage adhesion induced by -α; elicit an interfering pharmacological response to one of the following: must be satisfied.

In order for a substance to be recognized as an antagonist of the synthesis and / or release of histamine, cytokines or TNF-α, the following characteristics are:-stimulated with calcium ionophores (A23 187) or of compounds 40/80 Inhibits the release of histamine by mast cells stimulated by phorbol ester; inhibits the release of cytokines or TNF-α by monocytes (U937 cells) differentiated with phorbol ester (PMA); must not.

The histamine H1 receptor antagonists that can be used in the present invention are those conventionally used to treat allergic and anaphylactic symptoms, as well as against motion sickness. These compounds include, for example, diethylenediamine derivatives, such as cinnarizine or cyclidine; aminopropane derivatives,
For example, dexchloropheniramine or tripolizine (tri
prolidine); phenothiazine derivatives, such as promethazine or alimemazine, and the annual drug news of Joseph R. Prous (The Ye
ar's Drug News), the 1994 edition of Therapeutic Targets, a compound cited on pages 116-118 of Plaus Science Publishing Company, e.g., cetirizi
ne) hydrochloride, ebastin, loratadine or setastine hydrochloride.

Inhibitors of histamine release include, in particular, oxygen- or sulfur-containing heterocyclic compounds, such as benzothiophene derivatives, thiophene derivatives, benzofuran derivatives, furan derivatives, optionally having a nitrogenous substituent, for example US Patent No. 4931
No. 459, U.S. Pat. No. 4,910,317 and EP-A-299,457, especially alkoxy- and / or aryloxytetrazolylbenzofurancarboxamides, or alkoxy- and / or aryloxytetrazolyl. Benzothiophene carboxamide can be mentioned. As a specific example, 5-methoxy-3-phenoxy-N- (1H-tetrazol-5-yl) benzothiophen-2-carboxamide, 5-methoxy-3- (1-methylethoxy) -N-
(1H-tetrazol-5-yl) benzothiophen-2-carboxamide, 6-methoxy-3- (1-methylethoxy) -N- (1H-tetrazol-5-yl) benzothiophen-2-carboxamide, 5 -Methoxy-3- (1-methylethyl) -N- (1H-tetrazol-5-yl) benzothiophen-2-carboxyamide, 3-benzyloxy-5-methoxy-N- (1H-tetrazol-5-yl ) Benzothiophene-2-carboxamide, and 5-methoxy-3-phenoxy-N- (lH-tetrazol-5-yl) benzothiophene-2-carboxamide.

The cytokine antagonists include, for example, natural or synthetic peptides or peptide derivatives such as α-melanotropin or its derivatives, such as the tripeptide Lys-Pro-Val, or the synthesis of interleukin-1, which may be lactoferrin. Mention may be made of antagonists of the release of interleukin-1 that can be used according to the invention, which may be antagonists, or auranofin or SKF-105809.

Inhibitors of the synthesis and / or release of TNF-α and receptor antagonists of TNF-α that can be used according to the invention include, in particular, lisophylin, A80
2715 and sulfasalazine.

Histamine, cytokines and antagonists of TNF-α may be synthesized or extracted from natural substances (plant or animal substances). Of course, in the present invention, histamine, cytokines and TNF-α antagonists can be used individually or in combination, alone or in the form of a mixture.

Similarly, in the present invention, the synthesis, release and / or release of at least one inflammatory mediator
Alternatively, the compounds that reduce activation may be used separately or in combination, alone or in a mixture. Of course, the synthesis of at least one inflammatory mediator contained in the composition of the invention,
The amount of the compound that reduces release and / or activation is related to the desired effect and can therefore be varied over a wide range. As a guide, the composition of the present invention is 0.0001% based on the total weight of the composition.
It can contain a compound that reduces the synthesis, release and / or activation of at least one inflammatory mediator in an amount of ５5%, preferably in an amount of 0.001% to 2% relative to the total weight of the composition. is there.

Of course, whatever the form of the composition of the present invention, the amount of sodium or calcium channel inhibitor contained in the composition is related to the desired effect and can therefore be varied within a wide range. As a guide, inhibitors of sodium or calcium channels may be present in an amount of 0.0001% to 10%, preferably 0.001% to 5%, based on the total weight of the composition. Present in quantity.

The compositions according to the invention can be in any pharmaceutical form usually used, especially for topical application. The compositions of the present invention can be applied to the skin (any skin area of the body), scalp, nails or mucous membranes (buccal, cheekbone, gingival, genital or conjunctive). Depending on the method of administration, the compositions according to the invention can be in all commonly used pharmaceutical forms.

For topical application to the skin, the compositions may be prepared, in particular, as aqueous or oily solutions, or dispersions in the form of a lotion or serum, dispersing the oily phase in the aqueous phase (O / W) or vice versa (W / W O) a liquid or semi-liquid consistency emulsion in milk form or a thin consistency emulsion or suspension in aqueous or anhydrous gel form or cream, or microcapsules, or microparticles or ions obtained by O) It can be in the form of ionic and / or non-ionic vesicle dispersions. These compositions are prepared according to the usual methods. They can also be used on the scalp in the form of aqueous, alcoholic or aqueous / alcoholic solutions, or in the form of creams, gels, emulsions, foams or aerosol compositions which additionally contain a pressurized propellant. .

The amounts of the various components of the compositions according to the invention are those conventionally used in the ranges considered.

These compositions may be used as cleansing, protective, treatment or care creams (eg, day creams, night creams, make-ups), especially for the face, hands, legs, large anatomical skin folds or bodies. Removal cream, cream foundation or sun cream), liquid foundation, make-up removal milk, protective or care body milk, anti-sun milk, skin care lotion, gel or foam, e.g. cleansing lotion, Anti-sun lotion or artificial sun lotion, bathing composition, deodorizing composition containing bactericide, after shaving gel or lotion, depilatory cream, insect biting prevention composition, pain- control) composition, or certain skin diseases such as eczema, rosacea, It comprises a composition for treating psoriasis, moss or severe itching. The composition of the present invention can also consist of a solid preparation constituting a cleansing bar or a soap. In addition, the composition can be packaged in the form of an aerosol composition further containing a pressurized propellant.

Still further, the compositions of the present invention may be in the form of a hair care composition, in particular a shampoo, a hair setting lotion, a treatment lotion, a hair styling cream or gel, a shampoo to enhance color tone, Products (especially oxidation dyes), hair regenerating lotions, permanent wave compositions (especially compositions for the first step of permanent wave treatment), hair loss preventing lotions or gels, deworming shampoos, etc. Is also good.

The composition may also be for a bucco-dental, for example a toothpaste. In this case, the composition is formulated with the customary adjuvants and additives of compositions used for dental cheeks, in particular surfactants, thickeners, wetting agents, abrasives, for example silica, various active ingredients, for example hydrofluoric acid. Chloride, especially sodium fluoride, and any sweeteners, such as sodium saccharinate.

When the composition is an emulsion, the proportion of the fatty phase ranges from 5% to 80% by weight, preferably from 5% to 50% by weight, based on the total weight of the composition. The oils, waxes, emulsifiers and coemulsifiers used in the composition in the form of an emulsion are selected from those conventionally used in the cosmetics field. The emulsifier and coemulsifier are present in the composition in a proportion ranging from 0.3% to 30% by weight, preferably from 0.5 to 20% by weight, based on the total weight of the composition. The emulsifier may further contain lipid vesicles.

When the composition is an oily gel or solution, the fatty phase can be more than 90% by weight relative to the total weight of the composition.

Also, in a known manner, cosmetic compositions can be formulated with adjuvants customary in the cosmetics field, for example hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives,
It may contain preservatives, antioxidants, solvents, fragrances, fillers, screening agents, odor absorbers and dyes. The amounts of these various adjuvants are those conventionally used in the cosmetics field, for example from 0.01% by weight to the total weight of the composition.
10% by weight. These adjuvants are, by their nature, incorporated into the fatty phase, the aqueous phase and / or the lipid globules.

The oil or wax that can be used in the present invention includes mineral oil (liquid Vaseline), vegetable oil
(Liquid fraction of carite butter, sunflower oil), animal oil (perhydrosqualene), synthetic oil (purcellin oil), silicone oil or wax (cyclomethicone)
) And fluorinated oils (perfluoropolyethers), beeswax, carnauba wax or paraffin wax. Fatty alcohols and fatty acids (stearic acid) can also be added to these oils.

Examples of emulsifiers that can be used in the present invention include glyceryl stearate, polysorbate 60, and PEG sold under the name Tefose 63 (registered trademark) by Gattefosse. -6 / PEG-32 / glycol stearate.

Solvents that can be used in the present invention include lower alcohols, especially ethanol and isopropanol, and propylene glycol.

The hydrophilic gelling agents that can be used in the present invention include carboxyvinyl polymers (carbomers), acrylic copolymers such as acrylate / alkyl acrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, Mention may be made of natural gums and clays, and lipophilic gelling agents include modified clays such as bentone, metal salts of fatty acids such as aluminum stearate and hydrophobic silica, ethyl cellulose and polyethylene. it can.

The composition may comprise other hydrophilic active agents such as proteins or protein hydrolysates, amino acids, polyhydric alcohols, urea, allantoin, saccharides and saccharide derivatives, water-soluble vitamins, plant extracts and It may contain a hydroxy acid.

As lipophilic active agents, retinol (vitamin A) and its derivatives, tocopherol (vitamin E) and its derivatives, essential fatty acids, ceramides, essential oils and salicylic acid and its derivatives can be used.

In the compositions of the present invention, it is possible to combine at least one inhibitor of sodium or calcium channels with other active agents, in particular intended for the treatment and / or prevention of skin diseases. These active agents include, for example: agents that regulate skin differentiation and / or proliferation and / or pigmentation, such as retinoic acid and its isomers, retinol and its esters, vitamin D and its derivatives, estrogens, Estradiol, kojic acid or hydroquinone; antimicrobial agents such as clindamycin phosphate, erythromycin or tetracycline class antibiotics;-anthelmintics, especially metronidazole, crotamiton or pyrethrinoids.
-antifungal agents, in particular compounds belonging to the imidazole class, such as econazole, ketoconazole or miconazole or salts thereof, polyene compounds such as amphotericin B, compounds of the allylamine group, such as terbinafine or octopirox; Steroidal anti-inflammatory agents such as hydrocortisone, betamethasone valerate or clobetasol propionate, or non-steroidal anti-inflammatory agents such as ibuprofen and its salts, diclofenac and its salts, acetylsalicylic acid, acetaminophen, Or glycyrrhetinic acid;-anesthetics, such as lidocaine hydrochloride and its derivatives;-antipruritics, such as tenaldine, trimeprazine or cyproheptadine;-keratolytics, such as α- and β-hydroxycarboxylic acids, or β-ketocarbonic acids, their salts, amides or esters, especially hydroxy acids such as glycolic acid, lactic acid, salicylic acid or citric acid and generally fruit acids, and 5- (n-octanoyl ) Salicylic acid;-anti-free radical agents such as α-tocopherol or its esters, superoxide-dismutase, certain metal chelators, or ascorbic acid and its esters;-antiseborrheic agents such as progesterone; Agents such as octopirox or zinc pyrithione; anti-acne agents such as retinoic acid or benzoyl peroxide.

Thus, in certain embodiments, the present invention relates to a method for treating at least one inhibitor of sodium or calcium channels, comprising an antibacterial, anthelmintic, antifungal, antiviral, anti-inflammatory, antipruritic, anesthetic, At least one selected from an agent, a keratolytic agent, an antifree radical agent, an antiseborrheic agent, an antidandruff agent, an antiacne agent, and / or an agent that regulates skin pigmentation and / or proliferation and / or differentiation. A composition containing two agents.

Of course, in the context of the present invention, inhibitors of sodium or calcium channels can be used for the preparation of cosmetic and / or pharmaceutical compositions, especially dermatological compositions.

A subject of the invention is also the prevention, treatment or elimination of stinging, tingling, itching or itching, burning, warmth, discomfort, severe pain and / or redness and / or erythema, or A cosmetic treatment method for skin, comprising topically applying the topical cosmetic composition of the present invention to the skin in order to increase the skin tolerance threshold. The method according to the invention is particularly suitable for sensitive or intolerant skin.

The cosmetic treatment method of the present invention can be implemented by applying these compositions according to the conventional techniques for using, in particular, hygiene or cosmetic compositions as described above. For example: application of creams, gels, serums, lotions, make-up removing milks or sunscreen compositions to skin or dry hair, application of hair lotions or shampoos to wet hair, or to gums of toothpaste. Application.

Next, the present invention is illustrated by examples and compositions, but is not limited in any way.
In the compositions, percentages are given by weight unless otherwise indicated.

Example 1 Functional Assay for In Vivo Neurogenic Inflammation Model : The in vivo functional assay is a cationic assay for nerve-induced inflammation induced by electrical stimulation that causes a phenomenon comparable to cellular hyperexcitability. This is performed by measuring the effect of a drug that inhibits ion conductivity. In vivo experiments were performed using the method described by Xu XJ et al. (Neuroscienc
es, 1991, 42, 731-737). The assay consists of retrograde stimulation of the saphenous vein nerve of the anesthetized animal, causing neurogenic inflammation. This nerve irritates the skin area of the hind legs. Neurogenic inflammation is quantified by measuring tissue permeability using Evans Blue, a marker of tissue extravasation of plasma albumin that occurs during inflammation. 5 μmol of the calcium channel inhibitor verapamil is injected intradermally 15 minutes before stimulation of the saphenous vein nerve. Vehicle is sterile water.

[0099] Spuntide II (0.03 μmol) is used as a positive reference. Beparamil reduced 66% of the statistically significant neurogenic inflammation.

Example 2: Example of the composition of the present invention. These compositions are obtained by conventional techniques commonly used in cosmetics or pharmaceuticals. Composition 1 : Body care cream Amiloride 0.10 Glycerol stearate 2.00 Polysorbate 60 [Tween 60] 1.00 sold by ICI 1.00 Stearic acid 1.40 5- (N-octanoyl) Salicylic acid 2.00 Triethanolamine 0.70 Carbomer 0.40 Water Amount to make the whole 100%

Composition 2 : Facial care cream (oil-in-water emulsion) Amiloride 0.10 Glycerol stearate 2.00 Polysorbate 60 (Tween 60 sold by ICI) 1.00 Stearic acid 1.405 -(N-octanoyl) salicylic acid 3.00 triethanolamine 0.70 carbomer 0.40 liquid fraction of karite butter 12.00 perhydrosqualene 12.00 antioxidant 0.05 fragrance 0.50 preservative 0.30 water Amount to make the whole 100%

Composition 3 : Facial care cream (oil-in-water emulsion) Nifedipinin 0.20 Glycerol stearate 2.00 Polysorbate 60 (Tween 60 sold by ICI) 1.00 Stearic acid 1.405 -(N-octanoyl) salicylic acid 3.00 triethanolamine 0.70 carbomer 0.40 liquid fraction of karite butter 12.00 perhydrosqualene 12.00 antioxidant 0.05 fragrance 0.50 preservative 0.30 water Amount to make the whole 100%

Composition 4 : Face care cream for sensitive skin (oil-in-water emulsion) Amiloride 0.30 Glycerol stearate 2.00 Polysorbate 60 (Tween 60 sold by ICI) 1.00 Stearic acid 1.40 Triethanolamine 0.70 Carbomer 0.40 Liquid fraction of carite butter 12.00 Perhydrosqualene 12.00 Antioxidant 0.05 Preservative 0.30 Water Amount to make the whole 100%

Composition 5 : Cream for facial care of sensitive skin (oil-in-water emulsion) Verapamil 0.20 Glycerol stearate 2.00 Polysorbate 60 (Tween 60 sold by ICI) 1.00 Stearic acid 1.40 Triethanolamine 0.70 Carbomer 0.40 Liquid fraction of carite butter 12.00 Perhydrosqualene 12.00 Antioxidant 0.05 Preservative 0.30 Water Amount to make the whole 100%

[Procedure amendment]

[Submission date] September 18, 2000 (2000.9.18)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Full text

[Correction method] Change

[Correction contents]

Title: Use of a sodium channel activity inhibiting compound in a composition for topical use

[Claims]

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to skin, in particular sensitive or intolerant skin.
Cosmetic and / or pharmaceutical composition for increasing the tolerance threshold of skins, especially for eliminating itching, pruritus, taughtness, stinging and / or erythema The use of at least one compound that partially or totally inhibits the activity of a sodium channel in a product.

[0002] Skin is responsive to external aggression, and some skin is known to be more sensitive and more intolerant than others. The mechanism by which the skin responds to these attacks has not been previously known. Thus, no one knew exactly, for example, the processes associated with skin sensitivity and intolerance. Some consider hypersensitive skin to be skin that responds to cosmetics, but not necessarily to cosmetics, but to skin that responds to various external factors. Some are. Also, hypersensitive or intolerant skin was placed in the same category as allergic skin.

[0003] Because the mechanisms by which the skin responds to external attacks are not well known, it has hitherto been very difficult to prevent the skin from responding to these attacks, especially to treat sensitive or intolerant skin. It was difficult. Thus, skin has been indirectly treated, for example, by limiting the use of irritating products such as surfactants, preservatives or fragrances in cosmetic compositions.

[0004] Indeed, test methods have been developed to define hypersensitive skin, for example with DMSO or lactic acid, which are known to be irritants:
K. Lammintausta et al., Dermatoses, 1988, 36 , 45-
See pages 49 and T. Agner and J. Serup, Clinical and Experimental Dermatology, 1989, 14 , 214-217. I want to be. Unfortunately, however, it is not possible with these test methods to accurately characterize the mechanism by which the skin responds to external aggression, or to understand what governs sensitive or intolerant skin. Was.

[0005] Applicants have found that the responsiveness of the skin to an external attack is related to changes in skin excitability. In particular, the cell membrane of each nerve fiber and some skin cells, such as keratinocytes or melanocytes, contain many ion channels, especially sodium channels. The role of these various channels is to allow passage of sodium or calcium ions on both sides of the cell membrane. These ion exchanges (active transfer of charged sodium or calcium) lead to electrical fluctuations that more or less excite sensory nerve fibers and skin cells such as keratinocytes or melanocytes.

As a result of a number of tests, the Applicant has found that sensory nerve fibers present in the skin, as well as certain skin cells, such as keratinocytes or melanocytes, contain sodium. . The Applicant has further found that there is a link between the activity of these channels and the excitability threshold of the skin, especially of sensitive or intolerant skin. They have also found that they can act on these channels to increase the skin tolerance threshold.

To the applicant's knowledge, to date, no one has established an association between sodium channels of sensory nerve fibers of the cutaneous peripheral nervous system and cutaneous tolerance thresholds and inhibits the activity of these channels As a result, no one found that the skin tolerance threshold could be increased. Substances that inhibit these channels and thus reduce the import of sodium ions into cells are called inhibitory compounds.

Accordingly, the use of a compound that partially or totally inhibits sodium channels present in skin tissue can increase the skin tolerance threshold. Thus, partially or totally inhibiting the transfer of sodium into cells suppresses an increase in skin tolerance threshold or excitability.

Accordingly, the present invention relates to a composition for increasing the tolerance threshold of the skin and / or
Or in the preparation thereof, the use of at least one compound which partially or totally inhibits the activity of at least one sodium channel.

[0010] The "skin tolerance threshold", above which the skin responds to external attacks with signs such as dysaesthetic sensations, ie a more or less painful sensation in the skin area, for example a puncture Pain, tingling, itching or pruritus, burning, sensations of heating, discomfort, severe pain (taughtn)
ess) and / or an excitability threshold of the skin that causes a reaction accompanied by redness or erythema.

“External attack” refers to, for example, irritating products such as surfactants, preservatives or fragrances and the environment, emotions, food, wind, friction, shaving, soaps, surfactants, calcium concentration, It means both high hard water, temperature change, wool and the like.

The subject of the present invention is also a topical use for preventing, treating or eliminating stinging, tingling, itching or pruritus, burning, warmth, discomfort, severe pain and / or redness or erythema. The use of at least one compound which partially or totally inhibits the activity of at least one sodium channel in a pharmaceutical composition and / or in its preparation.

The invention also relates to at least one cutaneous sensory nerve fiber and / or at least one keratinocyte and / or at least one dermal sensory nerve fiber and / or at least one keratinocyte in a composition for topical use for increasing the skin tolerance threshold and / or in its preparation. It relates to the use of at least one compound which partially or totally inhibits the activity of at least one sodium channel of melanocytes.

[0014] The present invention further provides a tingling, tingling, itching or pruritus, burning sensation, warmth sensation,
At least one cutaneous sensory nerve fiber and / or at least one keratinocyte in a composition for topical use to prevent, treat or eliminate discomfort, severe pain and / or redness and / or erythema; and / or And / or the use of at least one compound that partially or totally inhibits the activity of at least one sodium channel of at least one melanocyte.

Still further, to prevent, treat or eliminate tingling, tingling, itching or pruritus, burning, warmth, discomfort, severe pain and / or redness and / or erythema, or to set a skin tolerance threshold A topical cosmetic composition comprising at least one compound that partially or totally inhibits the activity of at least one sodium channel, which channel is present or absent in the skin tissue, to enhance the skin. A method for cosmetic treatment of skin comprising topical application to the skin, whether associated with sensory nerve fibers and / or at least one keratinocyte and / or at least one melanocyte.

It has been mentioned hereinabove that certain skin responds more quickly to external aggression than normal skin and is more sensitive or intolerant. However, this hypersensitive or intolerant skin, which is not allergic skin because no immunological mechanisms are performed, responds to an external attack with the same signs as normal skin, but is more acute, and in some cases React more violently.

Thus, the mechanism by which normal skin responds to an external attack is, to a lesser extent, similar to that involving sensitive or intolerant skin that responds to a similar attack. . Thus, Applicants have found that hypersensitive or resistant outer skin is also associated with changes in skin excitability. Thus, the use of compounds that partially or totally inhibit the activity of sodium channels makes it possible to increase the tolerance threshold of sensitive or intolerant skin. Thus, partially or totally preventing the transfer of sodium into cells reduces the tolerance threshold or excitability of sensitive or intolerant skin.

The subject of the invention is especially for preventing, treating or eliminating stinging, tingling, itching, pruritus, burning, warmth, discomfort, severe pain, redness and / or erythema, or irritability Use of at least one compound that partially or totally inhibits the activity of at least one sodium channel in a composition for increasing the tolerance threshold of sexual or intolerant skin and / or in the preparation thereof, The channel may or may not be the sodium channel of at least one cutaneous sensory nerve fiber and / or at least one keratinocyte and / or at least one melanocyte.

Similarly, a subject of the present invention is to prevent, treat or eliminate stinging, tingling, itching, pruritus, burning, warmth, discomfort, severe pain and / or redness and / or erythema. Or at least one that partially or totally inhibits the activity of at least one sodium channel to increase the tolerance threshold of sensitive or intolerant skin
A method of cosmetically treating sensitive or intolerant skin comprising topically applying a topical cosmetic composition containing two compounds to the skin, wherein the channel comprises at least one channel.
One may or may not be the sodium channel of one cutaneous sensory nerve fiber and / or at least one keratinocyte and / or at least one melanocyte.

Of course, the present invention can also use sodium channel inhibitors alone or as a mixture.

As sodium, "International Review of Cytology" (1993, Vol. 137c, 55-103) or "Annu. Rev. Biophys. Chem." (1991, Vol. 20, 65-78) or "J.
Gen. Physiol. "(1993, Vol. 101, 153-182). In particular, one of the sodium channels may be the ASIC channel (Acid-Sensing Ionic Channel) disclosed by M. Lazdunski et al. In Nature, Vol. 386, pp. 173-177, March 1997. .

In the present invention, any substance that acts as an inhibitor of sodium channel activity can be used. In the present invention, for a substance to be recognized as an inhibitor of sodium channel activity, it must have the following properties:-a sodium antagonist in the model described by Y. Jacques et al. (J. Biol. Chem. 1987, 253, p. 7383). -WA Catterall et al. (J. Biol. Chem. 1979, 254, p. 11379) or GB Brown et al.
J. Neuroscience 1986, 6, p. 2064) to react as a substance that specifically binds in the sodium channel binding model.

For example, inhibitors that can be used as cation channel inhibitors in the present invention are amiloride, quinidine, quinidine sulfate, N-acetylprocaineamide, and apamin. In the present invention, amiloride is preferably used.

Of course, the amount of the inhibitor of at least one sodium channel used in the present invention is related to the desired effect and can therefore be varied within wide limits. As a guide, the inhibitor should be present at 0.0001% to 1% based on the total weight of the composition.
It is in an amount of 0%, preferably in an amount of 0.001% to 5% based on the total weight of the composition.

Advantageously, in the present invention, at least one inhibitor of at least one sodium channel can also be combined with products having a stimulating effect commonly used in the cosmetic or pharmaceutical field, and their production The object is optionally a cosmetic or pharmaceutical active. Whether cosmetics or pharmaceuticals contain products with a stimulating effect, the presence of inhibitors of sodium channels in such compositions can significantly reduce or even eliminate this stimulating effect. . In order to improve the effect, the amount of the active ingredient having the stimulating effect can be made larger than the amount of the active ingredient usually used.

In particular, the invention is characterized in that the cosmetically or pharmaceutically acceptable medium comprises at least one inhibitor of at least one sodium channel and at least one stimulatory product. A cosmetic or pharmaceutical composition.

Products having a stimulating effect include, for example, surfactants (ionic or non-ionic), preservatives, organic solvents or activators, for example α-hydroxy acids (citric acid, malic acid, glycolic acid, tartaric acid) , Mandelic acid, lactic acid), β-hydroxy acid (salicylic acid and its derivatives), α-keto acid, β-keto acid, retinoids (retinol, retinal, retinoic acid), anthralins (dioxyanthranol), anthranoids , Peracids (especially benzoyl peroxide), minoxidil, lithium salts, antimetabolites, vitamin D and its derivatives, hair coloring or dyes (para-phenylenediamine and its derivatives, aminophenols), aromatic alcohol solutions (Perfume, eau de toilette, after shaving, deodorant), antiperspirant (a kind of aluminum salt), hair removal or permanent clothing Activator (thiols) and depigmenting agent (hydroquinone)
Can be mentioned. Preferably, the inhibitor of the sodium channel is an inhibitor described previously in the text.

Whatever the phenomena that lead to irritable or intolerant skin, all these mechanisms have in common that the final aspect is at least one inflammatory mediator by the mast cells of the skin, such as histamine, serotonin, Expressed by an inflammatory response, which can be measured by the release of heparin, leukotrienes, prostaglandins, cytokines, nitric oxide or reactive oxygen species. In some cases, for example, in hypersensitive skin, the entire mechanism is under the control of sensory nerve endings which release neuropeptides, especially substance P and CGRP.

The object sought in the present invention is to provide compositions that can treat the most widespread and beneficial effects of all these skin diseases and thus act on several factors of these diseases. To provide.

Thus, in another aspect, the present invention relates to the synthesis, release and / or synthesis of at least one inhibitor of a sodium channel and at least one inflammatory mediator in a cosmetically or pharmaceutically acceptable medium. A cosmetic or pharmaceutical composition characterized by containing at least one compound that reduces the activity. A "cosmetically acceptable medium" is understood to be a medium that is compatible with the skin, mucous membranes, nails and hair.

Preferably, the compositions of the present invention comprise at least one compound that reduces the synthesis, release and / or activity of at least one inflammatory mediator of the skin in combination with an inhibitor of a sodium channel. Preferably, the inhibitor of the sodium channel is an inhibitor described previously in the text.

Compounds that reduce the synthesis, release and / or activity of at least one inflammatory mediator are preferably steroidal or non-steroidal anti-inflammatory agents, substance P and / or CGRP antagonists, NO-synthase inhibitors, bradykinin An antagonist, a cytokine antagonist, a histamine antagonist and an α-type tumor necrosis factor (TNFα) antagonist. If an antagonist is used, it is preferably a receptor antagonist.

Examples of steroidal anti-inflammatory agents include hydrocortisone, betamethasone valerate or clobetasol propionate. "Non-steroidal anti-inflammatory agents" are defined herein by Schorderet and Dayer et al. In pharmacology, "Des concepts fondamentaux aux applica
tions therapeutiques), 1992, Chapter 37, pp. 541-561, 2nd edition, Frison-Roche / Slat
Anti-inflammatory agent as described in the kine company version. They are arylcarboxylic acids, such as salicylic acid or anthranilic acid derivatives, arylalkanoic acids, such as arylacetic and heteroarylacetic acids or arylpropionic acids, enolic acids, such as pyrazolone derivatives or oxicams, and nonacid derivatives, such as bufet Kisamak (bufexamac) (Merck Index, 11th edition (MI) 14
62), benzydamine (MI 1136), epilizol (MI 3572), fluproquazone (MI 4120) or tiaramide (MI 935)
6).

[0034] Substance P antagonists are substances that reliably reduce retrograde neural stimulation or capsaicin-induced plasma transmigration through the vessel wall, and the inhibition of substance P-induced smooth muscle contraction. It is selected from the substances that give rise to it.

Substance P antagonists include plant or microbial extracts, spring water, salts of monovalent, divalent and trivalent cations, nitrogenous compounds having at least one benzene ring,
Non-peptidic compounds such as those having at least one heterocycle, peptides, and mixtures thereof.

For example, sendide and spantide II can be used as substance P antagonist peptides in the present invention.

Sendide is equivalent to the following formula: Tyr D-Phe Phe D-His Leu Met NH ₂ , wherein Tyr represents tyrosine, D-Phe represents D-phenylalanine, Phe Represents phenylalanine, D-His represents D-histidine, Leu represents leucine, and Met represents methionine.

Spantide II corresponds to the following formula: D-NicLys Pro 3-Pal Pro D-Cl ₂ Phe Asn D-Trp Phe D-Trp Leu Nle NH ₂ , wherein D-NicLys the D- lysine - represents nicotinate, Pro represents proline, 3-Pal represents 3-pyridyl alanine, D-Cl ₂ -Phe represents a D- dichloro-phenylalanine, Asn represents asparagine, D-Trp is Phe represents phenylalanine, Leu represents leucine, and Nle represents norleucine.

Also, US Pat. No. 4,472,305, US Pat. No. 4,839,465, European Patent Publication No. 101929, European Patent Publication No. 333174, and European Patent Publication No. 336.
No. 230, EP 394 1989, EP 443 132, EP 498 069, EP 515 681, EP 517 589, WO 92/22569 and UK Patent No. 22165
The peptides described in JP-A-29-29 can be used as a substance P antagonist peptide in the present invention.

The non-peptide substance P antagonists that can be used in the present invention are, in particular, compounds that contain a heteroatom contained in a heterocycle or directly or indirectly attached to a benzene ring. In particular, this heteroatom is an oxygen, nitrogen or sulfur atom.

Examples of the heterocyclic compound include the following publications: EP-A-360390, EP-A-429366, EP-A-430771, and EP-A-499.
313, EP-A-514273, EP-A-514274, EP-A-514275, EP-A-514276, EP-A-520555, EP-A-528495, EP-A-532456.
, EP-A-545478, EP-A-558156, WO-A-90 / 05525, WO-A-90 / 05729, WO-A-91 / 18.
No. 878, WO 91/18899, WO 92/12151, WO 92/15585, WO 92/17449, WO 92/92.
/ 20676, WO93 / 00330, WO93 / 00331
No., WO 93/01159, WO 93/01169, WO 93/01170, WO 93/06099, WO 93/09
No. 116 can be used particularly in the present invention.

In particular, compounds containing at least one nitrogenous heterocycle are 2-tricyclyl (tric
yclyl) -2-aminoethane derivative, spirolactam derivative, quinuclidine derivative,
An azacyclic derivative, an aminopyrrolidine derivative, a piperidine derivative, an aminoazaheterocycle or an isoindole derivative.

Other heterocyclic compounds include oxygen-containing or sulfur-containing heterocyclic compounds, for example, US Pat. No. 4,931,459, US Pat. No. 4,910,317 and European Patent Publication No. 2
Benzothiophene derivatives and thiophene derivatives, benzofuran derivatives and furan derivatives which may have a nitrogenous substituent, such as the heterocyclic compounds described in JP-A-99457, particularly alkoxy- and / or aryloxytetra. Zolylbenzofurancarboxamide or alkoxy- and / or aryloxytetrazolylbenzothiophenecarboxamide can be mentioned.

The compounds containing a nitrogen atom directly or indirectly bonded to the benzene ring include the following publications: EP-A-522808 and WO 93/0116.
No. 5 and WO93 / 10073.

The salts of the cations which can be used according to the invention are, in particular, strontium, magnesium,
Lanthanide, cobalt, nickel, manganese, barium, yttrium, copper, tin, rubidium, lithium and zinc salts having atomic numbers in the range of 57-71. These salts include, for example, carbonates, salicylates, bicarbonates, sulfates, glycerophosphates, borates, chlorides, nitrates, acetates, hydroxides or persulfates, and α-hydroxy acids ( Citric, tartaric, lactic or malic acid or fruit acid
s) or an amino acid salt [aspartate, alginate, glycocholate or fumarate] or a fatty acid salt [palmitate, oleate, caseinate or behenate]. Preferably, the salt is selected from strontium, manganese, yttrium or magnesium nitrate, strontium, manganese, yttrium or magnesium borate, strontium, manganese or magnesium chloride, or magnesium, manganese or strontium sulfate. . More preferably, these salts are strontium chloride or strontium nitrate.

The springs that can be used in the present invention include, in particular, those of Vichy basin, such as Celestins, Chomel, Grand-Gru.
Examples include those obtained from e-Grille, Opital, Lucas and Parc sources. Preferably, in the present invention, water from Luka spring is used.

Extracts prepared from plant material, such as extracts of the family Iridaceae, can be used in the present invention as substance P antagonists. The iris extract can be any extract prepared from plant material derived from an iris plant. Iris extract can be obtained from plant material derived from whole plants cultured in vivo, or from plant material derived from in vitro culture. For example, the extract in the present invention may be an extract of at least one organ or organ cell of an iris (root, stem, leaf), or an extract of at least one undifferentiated cell of the iris. Preferably, extracts obtained from undifferentiated cells obtained by in vivo or in vitro culture are used.

By selecting the pressure exerted by the physicochemical conditions during the growth of plant cells in vitro, we obtain standard plant material available year-round, unlike plants grown in vivo. be able to. "In vitro culture" can artificially obtain plants or plant parts,
Means techniques known to those skilled in the art. Thus, for example, in the present invention, an extract of at least one iris plant root cultured in vitro, or an extract of at least one iris plant undifferentiated cell can be used. Preferably, extracts obtained from plant material cultured in vitro, more preferably extracts obtained from undifferentiated cells cultured in vitro are used. By "undifferentiated plant cell" is meant any plant cell that does not exhibit any specific differentiated characteristics and is able to survive on its own, independent of other cells. These undifferentiated plant cells can undergo any differentiation according to their genome under the influence of induction.

With the chosen culture method, in particular the chosen culture medium, undifferentiated plant cells with different characteristics can be obtained from similar explants. About 750 species of irises are included. Iridaceae are used in particular because of their aromatic and decorative properties. Examples of species of the family Iridaceae that can be used in the present invention include, for example, the genus Romulea, the genus Crocus, the iris, the genus Gladiolus, the genus Sisyrinchium, and the genus Hermodactylus. Possible plant substances include German iris (Iris germanica),
(Iris florentina), Iris pallida, Crocus versicolor, Romulea bulbucodium or Gladiolus communis. In particular, in the present invention, a plant substance of the genus Iris, in particular, Iris pallida is used.

To prepare the extract contained in the composition of the present invention, any extraction method known to those skilled in the art can be used. In particular, alcohol extraction, especially ethanol extraction, or aqueous / alcohol extraction is mentioned. It is also possible to use an extract prepared by the method described in French Patent Application No. 95-02379 filed by the present applicant. For example, in the first step, the plant substance is pulverized in a low-temperature aqueous solution, in the second step, particles in the suspension are removed from the aqueous solution obtained in the first step, and in the third step, the second substance is removed. The aqueous solution obtained in the process is sterilized. This aqueous solution corresponds to the extract. Furthermore, the first step may advantageously be replaced by a single operation of freezing the plant tissue (e.g. -20 <0> C), followed by aqueous extraction, and the second and third steps described above are repeated. Of course, in the present invention, the substance P antagonists can be used alone or as a mixture.

In the present invention, “CGRP antagonist” means any compound that can completely or partially inhibit the biological effect of CGRP. In particular, certain substances are CG
To be considered an RP antagonist, the following tests: + Antagonist must reduce retrograde electrical stimulation (applied to afferent nerves) and / or vasodilation induced by capsaicin And / or + antagonists must inhibit CGRP release by sensory nerve fibers and / or + antagonists must inhibit CGRP-induced smooth muscle contraction of the vas deferens Must elicit an interfering pharmacological response (including or not including binding to the CGRP receptor) to one of the following.

Known CGRP antagonists include, for example, CGRP8-37 (CGRP
N-terminal 8 to 37 amino acid sequences), or an anti-CGRP antibody. Further, a plant substance obtained from an iris plant or a substance prepared from a microorganism such as an extract of a non-photosynthetic filamentous fungus can be used.

By “extract of a non-photosynthetic filamentous fungus” is meant equally the culture supernatant of the bacterium, the biomass obtained after culturing the bacterium, or the biomass extract obtained by treating this biomass. Things. The bacterial extract of the present invention can be used in a Bergey's Manual for bacterial phylogeny.
f Systematic Bacteriology) (Vol. 3, Sections 22 and 23, 9th edition, 1989), prepared from non-photosynthetic filamentous fungi, such as those belonging to the order Beggiatoales Bacteria, especially Beggiat
oa), Vitreoscilla, Flexithrix or bacteria belonging to the genus Leucothrix.

The defined bacteria, and some of those generally already described, live in aqueous environments and are found especially in seawater or spring water. Examples of bacteria used include: Vitreoscilla filiformis (ATCC 15551) Vitreoscilla beggiatoids (ATCC 43181) Beggiatoa alba (ATCC 33555) dorotheae) (ATCC 23163) Leucothrix mucor (ATCC 25107) Sphaerotilus natans (ATCC 13338). In the present invention, a strain of Vitreosilla filiformis is preferably used.

To prepare the extract according to the invention, the bacteria are cultured according to methods known to those skilled in the art and then separated from the resulting biomass, for example by filtration, centrifugation, coagulation and / or lyophilization. It is possible. In particular, it is possible to prepare an extract which can be used according to the invention according to the method described by the applicant in WO 93/00741.

For example, after culturing, the bacteria are concentrated by centrifugation. The biomass obtained is autoclaved. This biomass is lyophilized to form what is known as a lyophilized extract. Any lyophilization method known to those skilled in the art can be used to prepare this extract. The supernatant fraction of this biomass is filtered into a sterile container to remove particles in the suspension. In this way, an extract known in the text as an aqueous extract is obtained. Of course, in the present invention, the CGRP antagonist can be used alone or as a mixture.

In the present invention, the term NO-synthase actually covers a family of enzymes that specifically catalyze the enzyme catalysis from L-arginine to citrulline. Nitric oxide, or NO, is generated as a gaseous vehicle having the same. Nitric oxide has additional electrons due to its structure and can exhibit extremely high chemical reactivity. It is well known that such compounds are harmful and sought to limit their formation as much as possible. As a result, in the case of nitric oxide, NO-synthase inhibitors have been extensively studied.

Thus, in the present invention, a NO-synthase inhibitor is a product that can partially or completely inhibit the synthesis of nitric oxide (NO) in situ in humans. For example, they are selected from compounds that reduce the signal converted by NO-synthase, compounds that neutralize NO-synthase, or compounds that promote the catabolism of NO-synthase and / or inhibit synthesis. Compound. Accordingly, NO-synthase inhibitors can be selected from synthetic or natural peptides, which may be denatured, synthetic or natural chemical molecules, antisense nucleic acids, ribozymes and anti-NO-synthase antibodies.

[0059] These NO- synthase inhibitors, especially ^{N G} - monomethyl -L- arginine (L-NMMA), N G - nitro -L- arginine, N G ^- methyl ester of nitro -L- arginine, diphenylene Iodonium chloride, 7-nitroindazole, N (5)-(1-iminoethyl) -L-ornithine, ^NG , ^NG -dimethyl-L-arginine, ^NG , ^NG -dimethylarginine, 1-oxy-2 -(4-carboxyphenyl) -4,4,5,5-tetramethylimidazoline-3-oxide, aminoguanidine,
Mention may be made of canavanine, ebselen and α-type melanocyte stimulating hormone. Among the NO-synthase inhibitors, ^NG -monomethyl-L-arginine and α
The type of melanocyte stimulating hormone is preferably used. NO-synthase inhibitors can be used alone or as a mixture.

Bradykinin is a plasma-derived peptide released from kininogen precursors by a plasma protease called kallikrein (EC 3.4.21.24). This nanopeptide is one of the important mediators of inflammation and has cell division promoting properties. This kinin receptor can be classified into two major subtypes B1 and B2. Brachidinin acts particularly on the B2 receptor,
It stimulates many systems that produce second messengers, including hydrolysates of inositol phosphate, and is responsible for arachidonic acid metabolism, phosphorylation of tyrosine residues, and hyperpolarization or depolarization of cell membranes.

In the present invention, “bradykinin antagonist” means any compound capable of completely or partially inhibiting the biological effect of bradykinin. In particular, in order for a substance to be recognized as a bradykinin antagonist, it must elicit an interfering pharmacological response, with or without binding to the bradykinin receptor. Thus, included within this definition are those that can interfere with the effects of bradykinin by binding to the bradykinin receptor (B1 or B2) and / or independently of the effects known to bradykinin, independent of binding to the receptor. Is any compound that elicits the opposite effect by any mechanism (eg, interferes with the synthesis of bradykinin).

As the bradykinin antagonist, promotion of catabolism of bradykinin and / or
Or a compound that inhibits synthesis, a compound that neutralizes bradykinin, a compound that blocks a bradykinin receptor, such as those that interfere with the effect of bradykinin by binding to the receptor (B1 or B2), a compound that inhibits the synthesis of bradykinin receptor, Alternatively, a compound related to reduction of a signal converted by bradykinin is preferably used. These compounds may be of natural or synthetic origin.

[0063] Bradykinin antagonists include, in particular, optionally modified synthetic or natural peptides such as D-Arg, [Hyp3, D-Phe7] -bradykinin (NPC567), [Thi5,8, D-Phe7] -bradykinin, D -Arg, [Hyp3, Thi5,8, D-Phe7] -bradykinin, N-α-adamantaneacetyl-D-Arg, [Hyp3, Thi5,8, D-Phe7] -bradykinin, des-Arg9, [Leu8]- Bradykinin (all sold from Sigma), or WO 95/08566, WO 95/07294, EP 0623350, EP 0622361, WO 94/11021, European Patent 0596640
6, WO 94/06453, WO 94/09001, EP 0578521, EP 0564972, EP 055210.
6, WO 93/11789, US Pat. No. 5,216,165, US Pat. No. 5,212,182, WO 92/17201, EP 049636.
9, EP 0472220, EP 0455133, WO 91/09055, WO 91/02746, EP 041327.
7, EP 0370453, EP 0359310, WO 90/03980, WO 89/09231, WO 89/092
30, WO 89/01780, EP 0 334 244, EP 0 596 406, WO 86/07263, or compounds described in WO 86/07263, or P-guanidobenzoyl, [Hyp3, Thi5, D -Tic7, Oic8] -Bradykinin (S16118)
[Feletou M et al., Pharmacol. Exp. Ther., June 1995, No. 273.
1078-84], D-Arg, [Hyp3, Thi5, D-Tic7, Oic8] -bradykinin (HOE140) [Ferret-Em et al., Eur. J. Pharmacol, 1995, Vol. 274, 57- 64 pages], D-Arg, [
Hyp3, D-Hype (transpropyl) 7, Oic8] -Bradykinin (NPC17731) [Herzig MCS (Herzig MCS) and Lieb-Lundberg L.M.
F (Leeb-Lundberg LMF), J. Biol. Chem., 1995, Vol. 270, 20591-20598
Page] or "Bradykinin Antagonist: Development and Application (Bradykinin Antagonist
s: development and applications)] [Stewart J
M.), Biopolymers, 1995, Vol. 37, pp. 143-155], or natural or synthetic chemical molecules, such as Salvino et al., J. Med. Chem.
1993, Vol. 36, pp. 2583-2584.

In the present invention, a ribozyme or an antisense nucleic acid having the purpose of selectively inhibiting the synthesis of bradykinin can also be used. These antisense nucleic acids are known to those skilled in the art. These specifically prevent messenger RNA maturation, or prevent messenger RNA transfer from the nucleus to the cytoplasm, or cleave messenger RAN with RNase H, or block ribozyme progression or binding along the messenger RNA. By doing so, it can act on messenger RNA or DNA encoding bradykinin in various ways.

Further, in the present invention, an anti-bradykinin antibody or a soluble bradykinin receptor, an anti-bradykinin receptor antibody or an antagonist of a bradykinin receptor can also be used.

In the present invention, a compound that interferes with the effect of bradykinin by binding to the bradykinin receptor (B1 or B2), preferably the B2 receptor, is preferably used. More preferably, D-Arg, [Hyp3, D-Phe7] -bradykinin (NPC567), [Thi5,8, D-Phe7] -bradykinin, D-Arg, [Hyp3, Thi5,8, D-Phe7] -bradykinin N-α-adamantaneacetyl-D-Arg, [Hyp3, Thi5,8, D-Phe7] -bradykinin, des-Arg9, [Leu8] -bradykinin, P-guanidobenzoyl, [Hyp3, Thi5, D-Tic7 , Oic8] -Bradykinin (S16118) D-Arg, [Hyp3, Thi5, D-Tic7, Oic8] -Bradykinin (HOE140), D-Arg, [Hyp3, D-Hype (transpropyl) 7, Oic8] -Bradykinin ( NPC17731), used in the present invention. The modified peptide preferably used in the present invention is D-Arg, [Hyp3, Thi5, D-Tic7,
Oic8] -bradykinin (HOE140). Bradykinin antagonists can be used alone or as a mixture.

In the present invention, “histamine, cytokine and / or TNF-α antagonist” refers to a substance capable of inhibiting binding and / or synthesis and / or release of histamine, cytokine and / or TNF-α receptor, respectively. Means any substance. Antagonists that inhibit histamine receptor binding are agents specific for type 1 histamine receptor (H1).

In order for a substance to be recognized as a histamine, cytokine or TNF-α receptor antagonist, it has the following characteristics: it has an affinity for a receptor specific for these compounds; Has the pharmacological activity of a receptor antagonist of TNF-α, ie, the following test: + against a histamine receptor antagonist: inhibits smooth muscle contraction induced by administration of histamine; For: inhibits cytokine-induced superoxide anion release on neutrophils or inhibits cytokine-induced macrophage adhesion in endothelial cells; + For receptor antagonists of TNF-α: dermis On fibroblasts There inhibit the release of superoxide anions induced by TNF-alpha in inhibiting cell division activity of TNF-alpha, or neutrophils, or TNF in endothelial cells
Inhibit macrophage adhesion induced by -α; elicit an interfering pharmacological response to one of the following: must be satisfied.

In order for a substance to be recognized as an antagonist of the synthesis and / or release of histamine, cytokines or TNF-α, the following characteristics are:-stimulated with calcium ionophores (A23 187) or of compounds 40/80 Inhibits the release of histamine by mast cells stimulated by phorbol ester; inhibits the release of cytokines or TNF-α by monocytes (U937 cells) differentiated with phorbol ester (PMA); must not.

The histamine H1 receptor antagonists that can be used in the present invention are those conventionally used to treat allergic and anaphylactic symptoms, as well as against motion sickness. These compounds include, for example, diethylenediamine derivatives, such as cinnarizine or cyclidine; aminopropane derivatives,
For example, dexchloropheniramine or tripolizine (tri
prolidine); phenothiazine derivatives, such as promethazine or alimemazine, and the annual drug news of Joseph R. Prous (The Ye
ar's Drug News), the 1994 edition of Therapeutic Targets, a compound cited on pages 116-118 of Plaus Science Publishing Company, e.g., cetirizi
ne) hydrochloride, ebastin, loratadine or setastine hydrochloride.

Inhibitors of histamine release include, in particular, oxygen- or sulfur-containing heterocyclic compounds, such as benzothiophene derivatives, thiophene derivatives, benzofuran derivatives, furan derivatives, optionally having a nitrogenous substituent, for example US Patent No. 4931
No. 459, U.S. Pat. No. 4,910,317 and EP-A-299,457, especially alkoxy- and / or aryloxytetrazolylbenzofurancarboxamides, or alkoxy- and / or aryloxytetrazolyl. Benzothiophene carboxamide can be mentioned. As a specific example, 5-methoxy-3-phenoxy-N- (1H-tetrazol-5-yl) benzothiophen-2-carboxamide, 5-methoxy-3- (1-methylethoxy) -N-
(1H-tetrazol-5-yl) benzothiophen-2-carboxamide, 6-methoxy-3- (1-methylethoxy) -N- (1H-tetrazol-5-yl) benzothiophen-2-carboxamide, 5 -Methoxy-3- (1-methylethyl) -N- (1H-tetrazol-5-yl) benzothiophen-2-carboxyamide, 3-benzyloxy-5-methoxy-N- (1H-tetrazol-5-yl ) Benzothiophene-2-carboxamide, and 5-methoxy-3-phenoxy-N- (lH-tetrazol-5-yl) benzothiophene-2-carboxamide.

The cytokine antagonists include, for example, natural or synthetic peptides or peptide derivatives such as α-melanotropin or its derivatives, such as the tripeptide Lys-Pro-Val, or the synthesis of interleukin-1, which may be lactoferrin. Mention may be made of antagonists of the release of interleukin-1 that can be used according to the invention, which may be antagonists, or auranofin or SKF-105809.

Inhibitors of the synthesis and / or release of TNF-α and receptor antagonists of TNF-α that can be used according to the invention include, in particular, lisophylin, A80
2715 and sulfasalazine.

Histamine, cytokines and antagonists of TNF-α may be synthesized or extracted from natural substances (plant or animal substances). Of course, in the present invention, histamine, cytokines and TNF-α antagonists can be used individually or in combination, alone or in the form of a mixture.

Similarly, in the present invention, the synthesis, release and / or release of at least one inflammatory mediator
Alternatively, the compounds that reduce activation may be used separately or in combination, alone or in a mixture. Of course, the synthesis of at least one inflammatory mediator contained in the composition of the invention,
The amount of the compound that reduces release and / or activation is related to the desired effect and can therefore be varied over a wide range. As a guide, the composition of the present invention is 0.0001% based on the total weight of the composition.
It can contain a compound that reduces the synthesis, release and / or activation of at least one inflammatory mediator in an amount of ５5%, preferably in an amount of 0.001% to 2% relative to the total weight of the composition. is there.

Of course, whatever the form of the composition of the present invention, the amount of sodium channel inhibitor contained in the composition is related to the desired effect and can therefore be varied within a wide range. As a guide, the inhibitor of the sodium channel should be present in an amount of 0.0001% to 10%, preferably 0.0%, based on the total weight of the composition.
It is present in an amount from 01% to 5%.

The compositions according to the invention can be in any pharmaceutical form usually used, especially for topical application. The compositions of the present invention can be applied to the skin (any skin area of the body), scalp, nails or mucous membranes (buccal, cheekbone, gingival, genital or conjunctive). Depending on the method of administration, the compositions according to the invention can be in all commonly used pharmaceutical forms.

For topical application to the skin, the compositions may be prepared, in particular, as aqueous or oily solutions, or dispersions in the form of a lotion or serum, dispersing the oily phase in the aqueous phase (O / W) or vice versa (W / W O) a liquid or semi-liquid consistency emulsion in milk form or a thin consistency emulsion or suspension in aqueous or anhydrous gel form or cream, or microcapsules, or microparticles or ions obtained by O) It can be in the form of ionic and / or non-ionic vesicle dispersions. These compositions are prepared according to the usual methods. They can also be used on the scalp in the form of aqueous, alcoholic or aqueous / alcoholic solutions, or in the form of creams, gels, emulsions, foams or aerosol compositions which additionally contain a pressurized propellant. .

The amounts of the various components of the compositions according to the invention are those conventionally used in the ranges considered.

These compositions may be used as cleansing, protective, treatment or care creams (eg, day creams, night creams, make-ups), especially for the face, hands, legs, large anatomical skin folds or bodies. Removal cream, cream foundation or sun cream), liquid foundation, make-up removal milk, protective or care body milk, anti-sun milk, skin care lotion, gel or foam, e.g. cleansing lotion, Anti-sun lotion or artificial sun lotion, bathing composition, deodorizing composition containing bactericide, after shaving gel or lotion, depilatory cream, insect biting prevention composition, pain- control) composition, or certain skin diseases such as eczema, rosacea, It comprises a composition for treating psoriasis, moss or severe itching. The composition of the present invention can also consist of a solid preparation constituting a cleansing bar or a soap. In addition, the composition can be packaged in the form of an aerosol composition further containing a pressurized propellant.

Still further, the compositions of the present invention may be in the form of a hair care composition, in particular a shampoo, a hair setting lotion, a treatment lotion, a hair styling cream or gel, a shampoo to enhance color tone, Products (especially oxidation dyes), hair regenerating lotions, permanent wave compositions (especially compositions for the first step of permanent wave treatment), hair loss preventing lotions or gels, deworming shampoos, etc. Is also good.

The composition may also be for a bucco-dental, for example a toothpaste. In this case, the composition is formulated with the customary adjuvants and additives of compositions used for dental cheeks, in particular surfactants, thickeners, wetting agents, abrasives, for example silica, various active ingredients, for example hydrofluoric acid. Chloride, especially sodium fluoride, and any sweeteners, such as sodium saccharinate.

When the composition is an emulsion, the proportion of the fatty phase ranges from 5% to 80% by weight, preferably from 5% to 50% by weight, based on the total weight of the composition. The oils, waxes, emulsifiers and coemulsifiers used in the composition in the form of an emulsion are selected from those conventionally used in the cosmetics field. The emulsifier and coemulsifier are present in the composition in a proportion ranging from 0.3% to 30% by weight, preferably from 0.5 to 20% by weight, based on the total weight of the composition. The emulsifier may further contain lipid vesicles.

When the composition is an oily gel or solution, the fatty phase can be more than 90% by weight relative to the total weight of the composition.

Also, in a known manner, cosmetic compositions can be formulated with adjuvants customary in the cosmetics field, for example hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives,
It may contain preservatives, antioxidants, solvents, fragrances, fillers, screening agents, odor absorbers and dyes. The amounts of these various adjuvants are those conventionally used in the cosmetics field, for example from 0.01% by weight to the total weight of the composition.
10% by weight. These adjuvants are, by their nature, incorporated into the fatty phase, the aqueous phase and / or the lipid globules.

The oil or wax that can be used in the present invention includes mineral oil (liquid Vaseline), vegetable oil
(Liquid fraction of carite butter, sunflower oil), animal oil (perhydrosqualene), synthetic oil (purcellin oil), silicone oil or wax (cyclomethicone)
) And fluorinated oils (perfluoropolyethers), beeswax, carnauba wax or paraffin wax. Fatty alcohols and fatty acids (stearic acid) can also be added to these oils.

Examples of emulsifiers that can be used in the present invention include glyceryl stearate, polysorbate 60, and PEG sold under the name Tefose 63 (registered trademark) by Gattefosse. -6 / PEG-32 / glycol stearate.

Solvents that can be used in the present invention include lower alcohols, especially ethanol and isopropanol, and propylene glycol.

The hydrophilic gelling agents that can be used in the present invention include carboxyvinyl polymers (carbomers), acrylic copolymers such as acrylate / alkyl acrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, Mention may be made of natural gums and clays, and lipophilic gelling agents include modified clays such as bentone, metal salts of fatty acids such as aluminum stearate and hydrophobic silica, ethyl cellulose and polyethylene. it can.

The composition may comprise other hydrophilic active agents such as proteins or protein hydrolysates, amino acids, polyhydric alcohols, urea, allantoin, saccharides and saccharide derivatives, water-soluble vitamins, plant extracts and It may contain a hydroxy acid.

As lipophilic active agents, retinol (vitamin A) and its derivatives, tocopherol (vitamin E) and its derivatives, essential fatty acids, ceramides, essential oils and salicylic acid and its derivatives can be used.

In the composition according to the invention, it is possible to combine the inhibitors of at least one sodium channel with other active agents which are intended especially for the treatment and / or prevention of skin diseases. These active agents include, for example: agents that regulate skin differentiation and / or proliferation and / or pigmentation, such as retinoic acid and its isomers, retinol and its esters, vitamin D and its derivatives, estrogens, Estradiol, kojic acid or hydroquinone; antimicrobial agents such as clindamycin phosphate, erythromycin or tetracycline class antibiotics;-anthelmintics, especially metronidazole, crotamiton or pyrethrinoids.
-antifungal agents, in particular compounds belonging to the imidazole class, such as econazole, ketoconazole or miconazole or salts thereof, polyene compounds such as amphotericin B, compounds of the allylamine group, such as terbinafine or octopirox; Steroidal anti-inflammatory agents such as hydrocortisone, betamethasone valerate or clobetasol propionate, or non-steroidal anti-inflammatory agents such as ibuprofen and its salts, diclofenac and its salts, acetylsalicylic acid, acetaminophen, Or glycyrrhetinic acid;-anesthetics, such as lidocaine hydrochloride and its derivatives;-antipruritics, such as tenaldine, trimeprazine or cyproheptadine;-keratolytics, such as α- and β-hydroxycarboxylic acids, or β-ketocarbonic acids, their salts, amides or esters, especially hydroxy acids such as glycolic acid, lactic acid, salicylic acid or citric acid and generally fruit acids, and 5- (n-octanoyl ) Salicylic acid;-anti-free radical agents such as α-tocopherol or its esters, superoxide-dismutase, certain metal chelators, or ascorbic acid and its esters;-antiseborrheic agents such as progesterone; Agents such as octopirox or zinc pyrithione; anti-acne agents such as retinoic acid or benzoyl peroxide.

Thus, in certain embodiments, the present invention relates to an inhibitor of at least one sodium channel and an antibacterial, anthelmintic, antifungal, antiviral, anti-inflammatory, antipruritic, anesthetic, keratin, Dissolving agents, anti-free radical agents, antiseborrheic agents, anti-dandruff agents,
It relates to a composition comprising at least one agent selected from anti-acne agents and / or agents that regulate skin pigmentation and / or proliferation and / or differentiation.

Of course, in the context of the present invention, inhibitors of sodium channels can be used for the preparation of cosmetic and / or pharmaceutical compositions, especially dermatological compositions.

A subject of the invention is also the prevention, treatment or elimination of stinging, tingling, itching or itching, burning, warmth, discomfort, severe pain and / or redness and / or erythema, or A cosmetic treatment method for skin, comprising topically applying the topical cosmetic composition of the present invention to the skin in order to increase the skin tolerance threshold. The method according to the invention is particularly suitable for sensitive or intolerant skin.

The cosmetic treatment method of the present invention can be implemented by applying these compositions according to the conventional techniques for using, in particular, hygiene or cosmetic compositions as described above. For example: application of creams, gels, serums, lotions, make-up removing milks or sunscreen compositions to skin or dry hair, application of hair lotions or shampoos to wet hair, or to gums of toothpaste. Application.

Next, the present invention is illustrated by examples and compositions, but is not limited in any way.
In the compositions, percentages are given by weight unless otherwise indicated.

Example 1: Example of the composition of the present invention. These compositions are obtained by conventional techniques commonly used in cosmetics or pharmaceuticals. Composition 1 : Body care cream Amiloride 0.10 Glycerol stearate 2.00 Polysorbate 60 [Tween 60] 1.00 sold by ICI 1.00 Stearic acid 1.40 5- (N-octanoyl) Salicylic acid 2.00 Triethanolamine 0.70 Carbomer 0.40 Water Amount to make the whole 100%

Composition 2 : Facial care cream (oil-in-water emulsion) Amiloride 0.10 Glycerol stearate 2.00 Polysorbate 60 (Tween 60 sold by ICI) 1.00 Stearic acid 1.405 -(N-octanoyl) salicylic acid 3.00 triethanolamine 0.70 carbomer 0.40 liquid fraction of karite butter 12.00 perhydrosqualene 12.00 antioxidant 0.05 fragrance 0.50 preservative 0.30 water Amount to make the whole 100%

Composition 3 : Facial care cream (oil-in-water emulsion) Quinidine 0.20 Glycerol stearate 2.00 Polysorbate 60 (Tween 60 sold by ICI) 1.00 Stearic acid 1.405 -(N-octanoyl) salicylic acid 3.00 triethanolamine 0.70 carbomer 0.40 liquid fraction of karite butter 12.00 perhydrosqualene 12.00 antioxidant 0.05 fragrance 0.50 preservative 0.30 water Amount to make the whole 100%

Composition 4 : Face care cream for sensitive skin (oil-in-water emulsion) Amiloride 0.30 Glycerol stearate 2.00 Polysorbate 60 (Tween 60 sold by ICI) 1.00 Stearic acid 1.40 Triethanolamine 0.70 Carbomer 0.40 Liquid fraction of carite butter 12.00 Perhydrosqualene 12.00 Antioxidant 0.05 Preservative 0.30 Water Amount to make the whole 100%

Composition 5 : Cream for the treatment of sensitive skin face (oil-in-water emulsion) Quinidine sulfate 0.20 Glycerol stearate 2.00 Polysorbate 60 (Tween 60 sold by ICI) 1.00 Stearin Acid 1.40 Triethanolamine 0.70 Carbomer 0.40 Liquid fraction of carite butter 12.00 Perhydrosqualene 12.00 Antioxidant 0.05 Preservative 0.30 Water Amount to make the whole 100%

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 7/00 A61K 7/00 NW (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI , GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US , UZ, VN, YU, ZW F term (reference) 4C083 AA031 AA111 AC012 AC242 AC312 AC522 AC542 AC641 AC851 AC852 AD042 AD092 AD411 CC05 DD32 EE12 EE13

Claims (34)

[Claims] 1. A composition for increasing the tolerance threshold of the skin and / or in the preparation thereof, excluding lanthanum and lanthanides, at least one partial or total of at least one sodium channel or at least one calcium channel. Use of inhibitors. 2. Itching, pruritus, tingling pain, warmth, tingling, severe pain and / or
Or in a composition for topical use for treating or removing erythema and / or in its preparation, excluding lanthanum and lanthanides, at least one present in skin tissue
Use of at least one partial or total inhibitor of one sodium channel or at least one calcium channel. 3. At least one of the compositions for topical use to increase the tolerance threshold of the skin and / or in the preparation thereof, excluding lanthanum and lanthanides.
Use of at least one partial or total inhibitor of at least one sodium channel or at least one calcium channel of at least one cutaneous sensory nerve fiber and / or at least one keratinocyte and / or at least one melanocyte. 4. Itching, pruritus, tingling pain, warmth, tingling, severe pain and / or
Or at least one cutaneous sensory nerve fiber and / or at least one keratinocyte and / or at least one melanin, excluding lanthanum and lanthanide, in a composition for topical use for treating or removing erythema and / or in its preparation Use of a partial or total inhibitor of at least one sodium channel or at least one calcium channel of a cell. 5. The inhibitor has the following properties:-reacts as a calcium antagonist;-reacts as a sodium antagonist;-reacts as a substance that specifically binds in an L-type calcium channel binding model;-N-type calcium. Reacts as a substance that specifically binds in the channel binding model;-Reacts as a substance that specifically binds in the sodium channel binding model;-Calcium in an isolated organ model (eg, an aorta contracted by the action of potassium chloride). The use according to any one of claims 1 to 4, wherein the substance satisfies at least one of the following: 6. The inhibitor is selected from nicardipine, nitrendipine, nifedipine, nimodipine, nigludipine, amiloride, pimozide, quinidine, quinidine sulfate, ruthenium red, verapamil, N-acetylprocainamide, apamin, cyproheptadine, diltiazem and loperamide. Use according to any one of claims 1 to 5, characterized in that: 7. The use according to claim 6, wherein the inhibitor is verapamil or amiloride. 8. The method according to claim 1, wherein the inhibitor is present in an amount of 0.0001% to 1% based on the total weight of the composition.
Use according to any one of the preceding claims, characterized in that it is used in an amount of 0%, preferably in an amount of 0.001% to 5% based on the total weight of the composition. 9. A cosmetically or pharmaceutically acceptable medium comprising at least one inhibitor of at least one sodium channel or at least one calcium channel and at least one product having a stimulating effect. A cosmetic or pharmaceutical composition, characterized in that: 10. The method of claim 1, wherein the at least one is in a cosmetically or pharmaceutically acceptable medium.
A cosmetic or a cosmetic composition comprising at least one inhibitor of at least one sodium channel or at least one calcium channel and at least one compound which reduces the synthesis, release and / or activity of at least one inflammatory mediator. Pharmaceutical composition. 11. The compound which reduces the synthesis, release and / or activity of at least one inflammatory mediator is a compound which reduces the synthesis, release and / or activity of at least one inflammatory mediator of the skin. The composition according to claim 10, wherein 12. A compound that reduces the synthesis, release and / or activity of at least one inflammatory mediator is a substance P and / or CGRP antagonist, NO
The composition according to claim 10 or 11, characterized in that it is selected from synthase inhibitors, bradykinin antagonists, cytokine antagonists, histamine antagonists and α-type tumor necrosis factor (TNFα) antagonists. 13. The composition according to claim 12, wherein the antagonist is a receptor antagonist. 14. A substance P antagonist which reliably reduces plasma extravasation through the vessel wall induced by retrograde neural stimulation or capsaicin and smooth muscle contraction induced by administration of substance P. 14. The composition according to claim 12, wherein the composition is selected from substances that cause inhibition. 15. The substance P antagonist, wherein the substance P antagonist is a plant extract, spring water, a salt of a monovalent, divalent or trivalent cation, a nitrogenous compound having at least one benzene ring, a compound having at least one heterocycle, The composition according to any one of claims 12 to 14, wherein the composition is selected from peptides and mixtures thereof. 16. The composition according to claim 15, wherein the peptide is Sendide or Spuntide II. 17. The compound having at least one heterocyclic ring is a 2-tricycl-2-aminoethane derivative, a spirolactam derivative, a quinuclidine derivative, an azacyclic derivative, an aminopyrrolidine derivative, a piperidine derivative, an aminoazaheterocycle, an isoindole. Derivative, furan derivative, benzofuran derivative, thiophene derivative and benzothiophene derivative, in particular, a nitrogenous, oxygen-containing or sulfur-containing heterocyclic compound selected from tetrazolylbenzofurancarboxamide or tetrazolylbenzothiophenecarboxamide. Claim 15 characterized by the above-mentioned.
A composition according to claim 1. 18. A fatty acid salt, amino acid salt of strontium, magnesium, a lanthanide, cobalt, nickel, manganese, barium, yttrium, copper, tin, rubidium, lithium and zinc having an atomic number in the range of 57 to 71. , Fruit salts, α-hydroxy salts, glycerophosphates, persulfates, sulfates, hydroxides, nitrates, borates, salicylates, bicarbonates, carbonates, acetates, chlorides 16. The composition according to claim 15, wherein the composition comprises: 19. The composition according to claim 15, wherein the spring water is water obtained from a Vichy basin spring. 20. The composition according to claim 15, wherein the plant extract is an extract of an iris plant. 21. A CGRP antagonist reliably reduces vasodilation induced by retrograde electrical stimulation (applied to afferent nerves) or capsaicin and / or inhibits CGRP release by sensory nerve fibers Substances and CGRP
14. A composition according to claim 12 or 13, characterized in that it is selected from substances which cause an inhibition of vas deferens smooth muscle contraction induced by. 22. The method according to claim 21, wherein the CGRP antagonist is selected from CGRP8-37 (amino acid sequence of 8-37 amino acids in the N-terminal part of CGRP), anti-CGRP antibody and plant or microorganism extract. A composition as described. 23. The composition according to claim 21, wherein the plant extract is an extract of an Iridaceae plant. 24. The composition according to claim 23, wherein the microbial extract is an extract of a non-fruiting filamentous fungus. 25. The method according to claim 12, wherein the NO-synthase inhibitor is selected from substances capable of partially or completely inhibiting the synthesis of nitric oxide (NO) in situ in humans. A composition according to claim 1. 26. A NO-synthase inhibitor which promotes a compound involved in reducing a signal converted by NO-synthase, a compound which neutralizes NO-synthase, a catabolism of NO-synthase and / or inhibits synthesis 26. The composition according to claim 25, wherein the composition is selected from the group consisting of: 27. A compound in which a bradykinin antagonist promotes and / or inhibits the catabolism of bradykinin, a compound that neutralizes bradykinin, binds to a bradykinin receptor (B1 or B2) and interferes with the effect of bradykinin. 14. The composition according to claim 12, wherein the composition is selected from a compound that blocks a bradykinin receptor, a compound that inhibits the synthesis of a bradykinin receptor, and a compound that reduces the signal converted by bradykinin. 28. A substance wherein the histamine, cytokine or TNF-α antagonist is selected from a histamine, cytokine or TNF-α receptor antagonist or an antagonist in the synthesis and / or release of histamine, cytokine or TNF-α. The composition according to claim 12, wherein the composition is: 29. The compound which reduces the synthesis, release and / or activity of at least one inflammatory mediator in an amount of 0.0001% to 5% relative to the total weight of the composition, preferably the total weight of the composition 29. The composition according to any one of claims 12 to 28, wherein the composition is present in an amount of 0.001% to 2% based on the weight of the composition. 30. at least one sodium channel or at least one
Inhibitor of one calcium channel is present in an amount of 0.00
30. Composition according to any of claims 12 to 29, characterized in that it is in an amount of from 01% to 10%, preferably in an amount of from 0.001% to 5% based on the total weight of the composition. 31. at least one sodium channel or at least one
A cosmetic treatment method for increasing the skin tolerance threshold, comprising topically applying to the skin a topical cosmetic composition containing at least one compound that partially or totally inhibits the activity of two calcium channels. 32. at least one sodium channel or at least one
To increase the tolerance threshold of sensitive or intolerant skin, including topically applying to the skin a topical cosmetic composition containing at least one compound that partially or totally inhibits the activity of two calcium channels Beauty treatment method. 33. at least one sodium channel or at least one
Treatment for reducing the irritating effect of a cosmetic composition, comprising topically applying to the skin a topical cosmetic composition containing at least one compound that partially or totally inhibits the activity of one calcium channel Method. 34. at least one sodium channel or at least one
Stinging, tingling, itching or pruritus, burning sensation, including topically applying to the skin a topical cosmetic composition containing at least one compound that partially or totally inhibits the activity of one calcium channel. A cosmetic treatment method for preventing, treating or removing warmth, discomfort, severe pain and / or redness or erythema.