FR2753095A1 - Antiinflammatory use of melatonin or analogue - Google Patents

Abstract

The use of melatonin (I) (i.e. N-acetyl-5-methoxytryptamine) and its analogues is claimed (i) as antiinflammatory agent in a cosmetic composition or (ii) in the preparation of a pharmaceutical composition for the treatment of inflammation. Also claimed are: cosmetic or pharmaceutical compositions containing a carrier and (I) (or analogue) as antiinflammatory agent; and a product containing (I) (or analogue) and a second product (II) which tends to induce inflammation, for simultaneous, separate or sequential application, such that (I) inhibits inflammation caused by (II).

Description

 The present invention relates to the use of melatonin as an anti-inflammatory agent in a cosmetic or pharmaceutical composition.

 Inflammation (or inflammatory process) is a set of biological reactions found throughout the animal scale. In humans, two out of three patients have an inflammatory syndrome. The inflammation can be localized. It can be defined as the first response to any local aggression by a series of nonspecific reactions triggered regardless of the initial cause and taking place in three stages: vascular, cellulovascular and tissue fibrosis. Swelling, pain, redness, heat are the terms that can be used to describe localized inflammation. These are usually due to infiltration of the injured tissues by edema and / or vasodilatation of the capillaries. Signs of inflammation can include fever, general malaise and / or increased concentration of certain blood plasma proteins. It is also manifested by a change in blood flow with, at the site attacked, an increase in vascular permeability resulting in leakage of plasma proteins and cells to the extracellular fluid, as well as extravasation of leukocytes, mainly neutrophils. and macrophages to the inflammatory site.

Inflammatory phenomena are associated with many pathologies. Examples include rheumatic diseases such as rheumatic fever, rheumatoid arthritis, pulmonary diseases such as emphysema, joint disorders such as osteoarthritis, tendinitis, periarthritis, spondyloarthropathies, or rheumatoid arthritis. articular attacks of chronic enteropathies, allergies, inflammatory phases of alopecia, skin conditions such as sensitive skin, erythema, especially due to ultraviolet, pruritus, erythema nodosum,
Urticaria, systemic mastocytosis, psoriasis, insect bites, other dermatological conditions such as atrophic polychondritis, erythema, lipoic necrobiosis or systemic lupus erythematosus. Inflammation may also be related to an allergy when the final resultant of an allergic reaction results in an acute inflammatory reaction, usually associated with edema.

 Whatever the phenomenon envisaged, there is a point common to all these mechanisms that results in an inflammatory reaction whose terminal facet is measured by the release by the mast cells of the skin of at least one mediator of inflammation such as cytokines and other mediators such as substance P and CGRP, prostaglandins, leukotrienes, bradykinin, histamine or serotonin.

One of the precursors of many mediators of inflammation is arachidonic acid, which is transformed by different enzymatic pathways, the two main ones being the cyclooxygenase pathway and the lipoxygenase pathway. The cyclooxygenase pathway leads to the formation of prostaglandins or thromboxanes. For its part, the lipoxygenase pathway leads to the formation of leukotrienes (5-lipoxygenase), heoxilines and trioxilines (12-lipoxygenase) and lipoxins (15-lipoxygenase). The pathophysiology of inflammation is described by DAYER &
SHORDERET in "Pharmacology, From fundamental concepts to therapeutic applications", 1992, chapter 36, pages 529-540, 2nd edition,
Frison-Rock / Slatkin publishers.

 For many years, the pharmaceutical industry has been looking for substances to treat inflammation or allergy.

In this respect, many have already been described, known in the literature as steroidal or nonsteroidal anti-inflammatory drugs (AIS or NSAIDs) and described in, for example,
Schorderet and Dayer's book "Pharmacology, From fundamental concepts to therapeutic applications", 1992, chapter 37, pages 541-561, 2nd edition,
Frison-Rock / Slatkin publishers.

It is also sought to treat inflammation by specific inhibitors of the enzymes responsible for the formation of inflammatory mediators. Many compounds inhibiting the lipoxygenase pathway are currently under development (The Year's Drug News - 1995
Prous Science Edition). Several patent applications describe novel molecules capable of inhibiting the lipoxygenase pathway, and more particularly 5-lipoxygenase (EP 581,464, EP 586,229, EP 610,032, WO 94/22814, EP 623,614 and EP 94/27999). , WO 94/29297, WO 95/02402, WO 95/02575 and WO 95/05360).

 It has now been demonstrated that melatonin can specifically inhibit the activity of two key enzymes of inflammation, 5 and 15-lipoxygenases.

Melatonin, or N-acetyl-5-methoxytryptamine, best known for its circadian rhythm activity regulating the production of hormones, is also described for its antioxidant activity (Reiter RJ, Verhandung der
Deutschen Zoologischen Gesellschaft, 87 (2), 1994, 195-204; Reiter RJ & al.,
Neuroendocrinoll Leffer, 15 (1-3), 1993, 103-113; Reiter RJ et al., J. Pineal Res., 18 (1), 1995, 1-11), in particular its antiradical activity (Reiter RJ et al.,
Brazilian Journal of Medical and Biological Research, 26 (22), 1993, 1141-1155).

Most studies of the antioxidant properties of melatonin relate to oxidation phenomena related to aging of the brain (Poeggeler B & al.,
J. Pineal Res., 14 (4), 1993, 151-168; Cagnoii CM et al., J. Pineal Res., 18 (4), 1995, 222-226; Melchiorri D et al., FASEB J., 9 (12), 1995, 1205-1210;
Sewerynek E, et al., Neuroscience Leffers, 195 (3), 1995, 203-205.

 Melatonin has also been described for its use in dermocosmetics to improve the appearance of the skin (JP 61 221 104, WO 86/05093), or to protect the skin against the effect of irradiation with UV radiation (EP 0 438,856, E. Bangha et al., Dermatology 191, [2], 176, 1995).

However, no link has been made to date between melatonin and any anti-inflammatory activity.
The present invention therefore relates to the use of melatonin or its analogs as an anti-inflammatory agent in a cosmetic composition, or for the preparation of a pharmaceutical composition for the treatment of inflammation.

 Examples of melatonin analogs include derivatives such as 5-methoxytryptamine, 5-methoxytryptophan, 5-methoxytryptophol, 5-methoxyindole-3-acetic acid and 6-hydroxymelatonin.

Melatoninergic agonists, such as those described in patent applications WO 95/17405, EP 0 447 285, EP 0 527 687, EP 0 530 087 and EP 0 591 057, may also be mentioned. These compounds are of natural origin or synthetic.

 It is preferred to use melatonin itself.

 Melatonin or its analogs are used as inhibitors of the lipoxygenase pathway, more particularly as inhibitors of 5 and 15 lipoxygenases.

 Melatonin or its analogs are used in an appropriate amount.

By appropriate amount is preferably meant an amount sufficient to inhibit the lipoxygenase pathway.

 This appropriate amount is generally between 0.0001% and 10% by weight, relative to the total weight of the composition, in particular in an amount of between 0.0005% to 5% by weight, more particularly in a quantity less than 0.1%, of the order of 0.01%.

 Melatonin or its analogs may be used in a composition which must be ingested, injected or preferably applied to the skin (on any cutaneous zone of the body), the hair, the nails or the mucous membranes (oral, jugal, gingival, genital, anal, conjunctival). Depending on the mode of administration, this composition may be in any of the galenical forms normally used.

 The present invention also relates to a cosmetic or pharmaceutical composition comprising as anti-inflammatory agent at least a suitable amount of melatonin or its analogues and a suitable cosmetically or pharmaceutically acceptable carrier.

For a topical application to the skin, the composition may have the form in particular of an aqueous solution or oily suspension or of dispersion of the lotion or serum type, of emulsions of liquid or semi-liquid consistency of the milk type, obtained by dispersion of a fatty phase in an aqueous phase (O / W) or conversely (W / O), or suspensions or emulsions of soft consistency of the cream or gel type, aqueous or anhydrous, or microcapsules or microparticles, or vesicular dispersions of ionic type and / or nonionic.
These compositions are prepared according to the usual methods.

 They may also be used for hair in the form of aqueous, alcoholic or aqueous-alcoholic solutions, or in the form of creams, gels, emulsions, foams or in the form of aerosol compositions also comprising a propellant under pressure.

 For injection, the composition may be in the form of an aqueous lotion, oily suspension or in the form of serum. For the eyes, it can be in the form of drops or gels and for ingestion, it can be in the form of capsules, granules of syrups or tablets.

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

 These compositions comprise creams for cleaning, protection, treatment or care for the face, for the hands, for the feet, for large anatomical folds or for the body, (for example, day creams, night creams, make-up removing creams, foundation creams, sunscreen creams), fluid foundations, make-up removing milks, body care or protection milks, sunscreen lotions, lotions, gels or mousses for the care of the skin. skin, such as cleaning lotions, sunscreen lotions, artificial tanning lotions, bath compositions, deodorant compositions comprising a bactericidal agent, post-treatment gels or lotions, depilatory creams, anti-puncture compositions, insects, anti-pain compositions, compositions for treating certain skin diseases such as eczema, rosacea, psoriasis, lichens, severe pruritus.

 According to the invention, the compositions may also consist of solid preparations constituting soaps or cleaning loaves.

 The melatonin or its analogues used according to the invention may also be incorporated into various hair care compositions, and in particular shampoos, styling lotions, treatment lotions, creams or styling gels, dye compositions (especially oxidation dyes) optionally in the form of coloring shampoos, restructuring lotions for the hair, permanent compositions (especially compositions for the first time of a perm), anti-hair loss lotions or gels, antiparasitic shampoos, etc.

 The compositions may also be for oral use, for example a toothpaste. In this case, the compositions may contain adjuvants and additives customary for oral compositions and in particular surfactants, thickeners, humectants, polishing agents such as silica, various active ingredients such as fluorides, especially sodium fluoride, and optionally sweetening agents such as sodium saccharin.

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

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

 In a known manner, the cosmetic composition may also contain adjuvants customary in the cosmetic field, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic additives, preservatives, antioxidants, solvents, perfumes, fillers, and the like. filters, odor absorbers and dyestuffs. The amounts of these various adjuvants are those conventionally used in the cosmetics field, and for example from 0.01% to 10% of the total weight of the composition. These adjuvants, depending on their nature, can be introduced into the fatty phase, into the aqueous phase and / or into the lipid spherules.

 As oils or waxes that can be used in the invention, mention may be made of mineral oils (vaseline oil), vegetable oils (liquid fraction of shea butter, sunflower oil), animal oils (perhydrosqualene), synthetic oils ( Purcellin oil), silicone oils or waxes (cyclomethicone) and fluorinated oils (perfluoropolyethers), bees, carnauba or paraffin waxes. To these oils can be added fatty alcohols and fatty acids (stearic acid).

As emulsifiers that can be used in the invention, mention may be made, for example, of glycerol stearate, polysorbate 60 and the mixture of PEG-61PEG32 / glycol stearate sold under the name Tefoses 63 by the company
Gattefosse.

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

 As hydrophilic gelling agents that may be used in the invention, mention may be made of carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate / alkylacrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, natural gums and clays, and, as lipophilic gelling agents, mention may be made of modified clays such as bentones, metal salts of fatty acids such as aluminum stearates and hydrophobic silica, ethylcellulose and polyethylene.

 The composition may contain other hydrophilic active agents such as proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, water-soluble vitamins, plant extracts and the like. hydroxy acids.

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

 According to the invention, it is possible, inter alia, to associate melatonin or its analogs with other active agents intended in particular for the prevention and / or treatment of cutaneous affections.

 Among these active agents, agents that modulate differentiation and / or proliferation and / or cutaneous pigmentation may be mentioned; antibacterials; antiparasitic agents; antifungals, steroidal or non-steroidal anti-inflammatory agents, antipruritic agents; anti-free radical agents; antiseborrhoeics such as progesterone and anti-dandruff.

 Thus, according to a particular embodiment, the invention relates to the use of melatonin or its analogues in a composition comprising at least one agent chosen from antibacterial, antiparasitic, anti-fungal, antiviral anti-inflammatory, antipruritic, anesthetic and keratolytic agents. anti-free radicals, anti-seborrhoeic, anti-dandruff, anti-acne and / or agents modulating differentiation and / or proliferation and / or skin pigmentation. Melatonin or its analogs may also be combined with at least one substance P antagonist and / or a CGRP antagonist and / or a bradykinin antagonist. These compounds are described as being active also in the treatment of sensitive skin.

 It is also possible to use according to the invention melatonin or its analogues in combination with a second product capable of triggering an inflammatory process, more particularly by way of lipoxygenases. These are generally products with a specific therapeutic activity, but whose side effects result in triggering an inflammatory process.

 In this case, melatonin or its analogues and the second product likely to trigger an inflammatory process can be used together in the same composition, or in two distinct compositions.

In this second case, it is a combination product, for simultaneous use, separate or spread over time, to inhibit the inflammatory process may be triggered by the second product.

The activity of melatonin on the inhibition of lipoxygenases was studied according to the methods described by NAR UMiYA et al (J. Biol Chem, 256, 1981, 9588 - assay of 15-lipoxygenase) and COFFEY et al (J. Biol Chem., 267, 1992, 570 - assay for 5-lipoxygenase). The results are reported on the
Table below, the results are expressed in% inhibition of enzymatic activity

<tb><SEP> Concentration <SEP> 1 <SEP> 104M <SEP> -10-3M <SEP> M <SEP> 104 <SEP> M <SEP> 10-3 <SEP> M <SEP> 10M <SEP >
<tb> 5-lipoxygenase <SEP> 12 <SEP> 27 <SEP> 61 <SEP> 100
<tb> 15-lipoxygenase <SEP> 25 <SEP> 20 <SEP> 37 <SEP> 74
<Tb>
The following examples illustrate the invention without limiting it in any way.

In the compositions, the proportions indicated are percentages by weight.

The exemplified compositions are obtained by simple mixing of the constituents indicated.

EXAMPLE 1 Care Fluid for Sensitive Skins (Oil-in-Water Emulsion)
Melatonin 1.00
Calcium sulphate 3.00
Glycerol stearate 2.00
Polysorbate 60 (Tween 60 sold by the company ICI) 1.00
Stearic acid 1.40
Glycyrrhetinic acid 2.00
Triethanolamine 0.70
Carbomer 0.40
Liquid fraction of shea butter 12.00
Sunflower oil 10.00
0.05 Antioxidant
Conservative 0.30
Water qs 100%
Example 2: Shampoo
Melatonin 1.00
Sodium lauryl ether sulfate (2.2 EO) 12.00 Hydroxypropylcellulose (Klucel H sold by the company
Hercules) 1.00
Perfume 0,50
Conservative 0.30
Water qs 100%
Example 3: Anti-pain gel
Melatonin 0.5
Spantide It 0.02
Hydroxypropylcellulose (Klucel H sold by the company
Hercules) 1.00
0.05 Antioxidant
Lidocaine Hydrochloride 2.00
Isopropanol 40.00
Conservative 0.30
Water qs 100%

Claims (9)

 1. Use of melatonin or its analogs as an anti-inflammatory agent in a cosmetic composition.  2. Use of melatonin or its analogues for the preparation of a pharmaceutical composition for the treatment of inflammation.  3. Use according to one of claims 1 or 2, characterized in that melatonin or its analogues are used as inhibitors of the lipoxygenase pathway.  4. Use according to one of claims 1 to 3, characterized in that the amount of melatonin or its analogues is between 0.0001% to 10% by weight, relative to the total weight of the composition.  5. Use according to claim 4, characterized in that the amount is between 0.0005% to 5% by weight.  6. Use according to one of claims 1 to 5, characterized in that melatonin or its analogues are used in a composition that must be ingested, injected or preferably applied to the skin (on any cutaneous area of the body), hair, nails or mucous membranes (buccal, jugale, gingival, genital, anal, conjunctiva).  A cosmetic or pharmaceutical composition comprising as an anti-inflammatory agent at least a suitable amount of melatonin or its analogs and a suitable cosmetically or pharmaceutically acceptable carrier.  8. Composition according to claim 7, characterized in that it further comprises a product capable of triggering an inflammatory process.  9. A product containing melatonin or its analogues and a second product capable of initiating an inflammatory process as a combination product, for simultaneous, separate or spread use over time, to inhibit the inflammatory process likely to be triggered by the second product.