WO2016055702A1

WO2016055702A1 - Dermatological composition for the prevention and treatment of subcutaneous varicose veins

Info

Publication number: WO2016055702A1
Application number: PCT/FR2015/000193
Authority: WO
Inventors: Guillaume ISSARTEL
Original assignee: Laboratoires Urgo; Vivatech; Hcp Healthcare Asia Pte. Ltd.
Priority date: 2014-10-09
Filing date: 2015-10-01
Publication date: 2016-04-14
Also published as: FR3026949A1

Abstract

The invention relates to a novel topical dermatological composition, especially used in the prevention and/or treatment of subcutaneous varicose veins, comprising, in a physiologically acceptable support, at least one effective quantity of at least one synthetic polysulfated oligosaccharide having between 1 and 4 monosaccharide units, or one of the salts thereof.

Description

DERMATOLOGICAL COMPOSITION FOR PREVENTION AND

TREATMENT OF VARICE UNDER SKIN

The present invention relates to a new topical dermatological composition, particularly useful for preventing and / or treating subcutaneous varicose veins comprising, in a physiologically acceptable carrier, at least one effective amount of at least one synthetic polysulfated oligosaccharide having 1 to 4 units of daring, or one of its salts.

Varicose veins are permanent dilations of the veins that are most often located on the lower limb of the human body, also called pelvic limb, and preferably on the calf. These varices are generally described as subcutaneous varicose veins. They generally occur between the age of 30 and 70 and worsen chronologically gradually as soon as they appear. They are very frequently characterized by their sinuous trajectories and are the seat of a slow flow of blood. Indeed, the valves of the venous walls no longer provide their anti-reflux function thus disrupting the unidirectional flow of blood to the heart. The cause of subcutaneous varicose veins and in particular those of the pelvic limb responds to a vascular cause related to the physiological and natural wear of the endothelial walls of the varicose veins.

Sucrose octasulfate salts have long been known for use in all kinds of cosmetic, dermatological or medical applications. Thus, among all these uses, it is described through documents of Pierre Fabre Dermo-Cosmetic companies, or Urgo Laboratories, various salts of sucrose octasulfate for their benefits through healing actions, post-burn tissue remodeling actions or induced by aging, actions on stretch marks or pathological scars. Among them, the aluminum salt of sucrose octasulfate, more commonly referred to as sucralfate, is also known for its preventive action in the digestive tract, especially on so-called varices of the esophagus [Endoscopy]. Variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial, and hepatology. 2000 Sep; 32 (3): 461-5, Lo GH]. These varices of the esophagus, or more generally the gastric varices are to distinguish subcutaneous varices found on the surface of the human body. They have no symptoms, except in case of rupture where a blood emission is visualizable. These varices of the esophagus appear following a short circuit in the portal system, consequence of cirrhosis or cancer, forcing the blood to pass through other veins of lower caliber not supporting blood pressure new imposed. These varicose veins do not show signs of existence until their rupture, consequence of too much pressure inside these blood vessels of too small caliber. It is only then that an obligation of surgical treatment is required. This is not a problem of venous reflux. The pathophysiology of this type of varicose vein is therefore totally different from that of subcutaneous varicose veins.

Thus both oesophageal varices and subcutaneous varicose veins have specific causes, pathophysiology, and symptoms, and so the term gastric varices does not fit into the class as so-called varicose veins, let alone under the term of subcutaneous varices.

EP 0 391 905 describes a topical composition based on aluminum salt of a sucrose octasulfate salt useful for the prevention and treatment of hemorrhoids in addition to its healing action.

Hemorrhoids are often wrongly considered as a variety of varicose veins whose only location seems different. Indeed, many physiopathological hypotheses have been rejected, especially that of the anal "varix" in favor of mechanical and circulatory designs. In a first theory, the disease would be caused by the progressive alteration of the musculo-ligamentous structures (Parks ligament) maintaining in good position the pads of Thomson (cellulo-fibroelastic reinforcements of the submucous connective tissue ensuring complete obturation of light from the anal canal and containing hemorrhoids). This explains the possibility of hemorrhoidal procidence. In the other theory, the opening of arterio-venous shunts (cavernous structure) would cause an excessive arterial blood flow exceeding the drainage capacity of the hemorrhoidal tissue, thus causing congestion and haemorrhage of glowing blood. These vascular abnormalities could lead to venous dystrophy with formation of thrombosis and alteration of the supporting tissue, thus contributing to the gradual exteriorization of hemorrhoids. Finally, sphincter hypertonia is often present; it aggravates functional signs by decreasing the venous return which accentuates the haemorrhages [Faculty of Medicine of Marseille - DCEM 2 - Module n ° 12 "Hepato-Gastroenterology"].

The pathophysiology of hemorrhoids is therefore very far from that of subcutaneous varicose veins. Subcutaneous varicose veins therefore require appropriate, specific and different management of pathologies that may initially be considered as similar, such as gastric varices or hemorrhoids, the pathophysiology of each being very different.

There is currently no therapeutic treatment of the symptoms of subcutaneous varicose veins effective. There remains therefore a need in the manufacture of a novel composition for preventing and / or treating subcutaneous varicose veins, and preferably subcutaneous varicose veins of the pelvic limb.

Thus the subject of the invention lies in a topical dermatological composition for its use in the prevention and treatment of subcutaneous varicose veins, comprising, in a physiologically acceptable carrier, at least one effective amount of at least one synthetic polysulfated oligosaccharide having 1 to 4 units of oste, or a salt thereof and preferably a sucrose octasulfate salt.

"Subcutaneous varicose veins" means any permanent dilatation of veins of any size, visible to the naked eye through any of the epithelial surfaces of the skin of the human or animal body, and having a cause Vascular related to the physiological and natural wear of the endothelial walls, especially at the level of the valves. Thus the term of varicosity is also included in this definition. Varicose veins located on the back of the hand or at the level of the arms are therefore in the same way included in this definition. On the other hand, the terms hemorrhoids or gastric varices are excluded from this definition.

"Subcutaneous varicose veins of the pelvic limb" means any permanent dilatation of the veins of any size, located on the lower limb of the human or animal body, that is to say from the top of the hip and to the foot through the thigh and calf and having a vascular cause related to the physiological and natural wear of the endothelial walls, particularly at the level of the valves. Thus varicose veins reticular, truncular and pelvic (vulvar and perineal) are also covered by this definition.

By "prevent and / or treat" is meant any therapeutic action at the level of the vascular endothelium of the varicose vein. For the purposes of the present application, the term "dermatological composition" is intended to mean a composition for topical application comprising a dermatologically acceptable medium, that is to say one which has a pleasant color, odor and feel and which does not generate dermal substances. unacceptable discomfort (tingling, tightness, redness), likely to divert consumers from the use of this composition. By "effective amount" is meant in the sense of the present invention an amount sufficient to achieve the expected effect.

By "physiologically acceptable carrier" means a non-toxic support and may be applied to at least one keratin material of human beings.

Synthetic polysulfated oligosaccharide having 1 to 4 ose units, or a salt thereof

The composition according to the invention comprises at least one synthetic polysulfated oligosaccharide having 1 to 4 units of oste, or one of its salts generally linked together by glycosidic linkage alpha or beta. In other words, it is mono, di, tri or tetrasaccharides, and preferably mono or disacharides. There is no particular limitation on the nature of the ose units of these polysaccharides. Preferably, it will be pentoses or hexoses. As an example of a monosaccharide, mention may be made of glucose, galactose or mannose. As an example of a disaccharide, mention may be made of maltose, lactose, sucrose or trehalose. As an example of a trisaccharide, mention may be made of melezitose. As an example of a tetrasaccharide, mention may be made of stachyose.

Preferably, the oligosaccharide is a disaccharide, and more preferably sucrose. For the purposes of the present application, the term "polysulfated oligosaccharide" is understood to mean an oligosaccharide of which at least two, and preferably all, hydroxyl groups of each monosaccharide have been substituted with a sulphate group.

For the purposes of the present invention, the potassium salt of sucrose octasulfate, which is a synthetic polymer formed from 2 units of osteosaccharide, generally bonded together by alpha or beta glycosidic bonding, is preferably used.

This potassium salt of sucrose octasulfate has a positive action on the prevention and treatment of subcutaneous varicose veins superior to those of other synthetic polysulfated oligosaccharides formed from 1 to 4 units of dares, or their salts. The latter, in the context of the present invention, may be in the form of a micronized powder or in solubilized form.

According to a particular embodiment of the invention, the potassium salt of sucrose octasulfate may be introduced into the compositions according to the invention, preferably alone but also as a mixture with other synthetic polysulfated oligosaccharides having 1 to 4 units of or their salts, such as sucralfate and / or with an active substance, preferably a healing active substance and / or restructuring of the skin, such as for example hyaluronic acid.

In the context of the present invention, the synthetic polysulfated oligosaccharide or oligosaccharides formed from 1 to 4 units of oste, or their salts, have a potentiating action of that of the potassium salt of sucrose octasulfate, that is to say which have a positive basic action for the prevention and treatment of subcutaneous varicose veins but which have a synergistic effect of the action of the potassium salt of sucrose octasulfate on said varicose veins. Among these synthetic polysulfated oligosaccharide salts formed from 1 to 4 units of risk can be used in general, the alkali metal salts such as sodium, calcium, magnesium salts, silver salts, salts aluminum, zinc salts; or the amino acid salts. Even more privileged, are used:

- the salt of calcium, zinc and magnesium;

the silver salt of sucrose octasulfate;

- the aluminum salt of sucrose octasulfate, more generally called sucralfate. According to a particular embodiment of the invention, the composition comprises at least one potassium salt of sucrose octasulfate in a content of between 0.1 and 50% by weight, relative to the total weight of the composition.

According to one particular embodiment of the invention, the composition comprises at least a quantity of potassium salt of sucrose octasulfate such that the quantity released on the varix is between 0.001 g / l and 50 g / l, and more preferably between 0.01 and 10 g / l.

Active substance

In addition to the presence of at least one synthetic polysulfated oligosaccharide having 1 to 4 units of osages, or its salts, and preferably the potassium salt of sucrose octasulfate, the composition according to the invention may comprise one (or more) other (s) active substance (s).

In general, the active ingredients are chosen from anti-bacterials, antiseptics, antifungals, anti-inflammatories, active agents promoting healing and / or restructuring of the skin, antipruritic agents, UV filters, soothing agents, moisturizing active agents, depigmenting agents, keratolytic agents, anti-virals, painkillers, anesthetics, vitamins, synthetic polysulfated oligosaccharides formed from 1 to 4 units of risk or their salt, with the exception of sucrose octasulfate potassium, and mixtures thereof. In general, the assets are chosen from:

anti-bacterials such as polymyxin B, penicillins (amoxycillin), clavulanic acid, tetracyclines, minocycline, chlorotetracycline, aminoglycosides, amikacin, gentamicin, neomycin, silver and its salts (Sulfadiazine argentic), probiotics; antiseptics such as sodium mercurothiolate, eosin, chlorhexidine, phenylmercury borate, hydrogen peroxide, Dakin liquor, triclosan, biguanide, hexamidine, thymol, Lugol, Povidone iodine, Merbromine, Benzalkonium and Benzethonium Chloride, ethanol, isopropanol, silver salts; anti fungal agents such as polyenes, Nystatin, Amphotericin B, Natamycin, imidazoles (Miconazole, Ketoconazole, Clotrimazole, Ecconazole, Bifonazole, Butoconazole, Fenticonazole, Isoconazole, Oxiconazole, Sertaconazole, Sulconazole, Tiabendazole, Tioconazole) triazoles (Fluconazole, Itraconazole, Ravuconazole, Posaconazole, Voriconazole), allylamines, Terbinafine, Amorolfine, Naftifine, Butenafine;

Flucytosine (antimetabolite), Griseofulvin, Caspofungin, Micafungin, Arginine;

anti-inflammatories such as glucocorticoids, nonsteroidal anti-inflammatory drugs, aspirin, ibuprofen, etoprofen, flurbiprofen, diclofenac, aceclofenac, ketorolac, meloxicam, piroxicam, tenoxicam, Naproxen, indomethacin, Naproxcinod, Nimesulide, Celecoxib, Etoricoxib, Parecoxib, Rofecoxib, Valdecoxib, Phenylbutazone, Niflumic acid, Mefenamic acid;

the active agents promoting healing and / or restructuring of the skin, such as retinol, water-soluble vitamins such as vitamin A or its derivatives, vitamin E or its derivatives, N-acetyl-hydroxyproline, extracts of CentellaAsiatica and of dill papain, silicones, essential oils of thyme, niaouli, rosemary and sage, hyaluronic acid, allantoin, Hema'tite (Gattefossé), Vitamin C, TEGO Pep 4-17 (Evonik ), Toniskin (Silab), CoUageneer (Expanscience), Timecode (Seppic), Gatuline skin repair (Gattefossé), Panthenol, PhytoCellTec Alp Rose (MibelleBiochemistry), Serilesine: Lipotec, Heterosides from Talapetraka (Beyer), Stoechiol (Codif), macarose (Sensient), Dermaveil (IchimaruPharcos), Phycosaccaride AI (Codif), metformin;

- depigmenting agents such as kojic acid (KojicAcid SL ^® - Quimasso (Sino Lion)) PArbutine (Olevatin ^® - Quimasso (Sino Lion)), sodium palmitoylpropyl mixture and extract of water lily (Sepicalm ^® - Seppic), undecylenoyl phenylalanine (Sepiwhite ^® - Seppic), licorice extract obtained by fermentation of Aspergillus and ethoxydiglycol (GatulineWhitening ^® - Gattefossé), octadecenedioic acid (ODA White ^® - Sederma), alpha -arbutin (Alpha-arbutin ^®, SACI-CFPA (Pentapharm)), leaves of the aqueous extract Arctophylos Uva Ursi (Melfade-J ^® - SACI-CFPA (Pentapharm)), the complex mixture of plant Gigawhite ^® (SACI-CFPA (Alpaflor)), diacetylboldine (Lumiskin ^® - Sederma), mandarin extract from Japan (Melaslow ^® - Sederma), lemon extract mixture enriched with citric acid and cucumber extract (Uninontan ^® U- 34 - Unipex), the mixture of extract of Rumex occidentalis and vitamin C (Tyrostat 11 - Unipex), oligopeptides (Melanostatin 5 ^® - Unipex), dipalmitatekoi (KAD-15 ^® - Quimasso (Sino Lion)), the complex of natural origin Vegewhite ^® from LCW, wheat germ extracts (Clariskin ^® II - Silab), ethyldiaminetriacetate (EDTA); - Antipruriginous agents such as hydrocotisone, enoxolone, diphenyhydramine, antihistamines with local anti H1 application;

UV filters such as Parsol MCX, Parsol 1789;

Soothing agents such as chamomile, bisabolol, xanthalene, glycyrrhenic acid, tanactin (CPN), Calmiskin (Silab);

- Moisturizing active ingredients such as xpermoist (Lipotec), hyaluronic acid, urea, fatty acids, glycerine, waxes, Exossine (Unipex);

keratolytic agents such as salicylic acid, zinc salicylate, ascorbic acid, alpha hydroxylated acids (glycolic acid, lactic acid, malic acid, citric acid, tartaric acid), extracts of silver maple, Griottier, tamarind , urea, topical retinoid

(Fi)

Keratinol (Sederma), the proteases obtained by fermentation of Bacillus Subtilis, the product

(Fi)

Linked-Papain (SACI-CFPA), papain (proteolytic enzyme derived from papaya fruit);

- Vitamins such as retinol (vitamin A) and its derivatives, tocopherol (vitamin E) and its derivatives.

- Veinotonics such as anthrocyanosides, citrofiavonoids and flavonoids in general, diosmin, rutosides, troxerutin, or extracts of ruscus.

- Analgesics such as morphine, buprenorphine, nalbuphine, sufentanil, remifentanil, fentanyl, alfentanil, codeine, hydromorphone, dextropropoxyphene, tramadol, nefopam, paracetamol or acetaminophen, ibuprofen, or nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin.

According to a preferred embodiment, the composition according to the invention comprises at least one effective amount of another active substance that promotes healing and / or restructuring of the skin, preferably hyaluronic acid.

According to another preferred embodiment, the composition according to the invention comprises at least one effective amount of another active substance chosen from analgesics and / or venotonic agents. In addition, the active agents according to the invention may be combined with active agents intended in particular for the prevention and / or treatment of cutaneous affections.

galenic

The compositions according to the invention may be in any galenical form normally used by those skilled in the art.

When the compositions are intended for topical administration, they may be in the form of solutions (aqueous, hydroalcoholic or oily), dispersions (lotion or serum type), emulsions of liquid or semi-liquid consistency (milk type). , suspensions or emulsions (cream type), aqueous or lipophilic gel, microemulsions, microcapsules, microparticles, or vesicular dispersions of ionic and / or nonionic type. They may also be in the form of nonabsorbent interface dressings or compression band impregnated with said composition or comprising the potassium salt of sucrose octasulfate and / or any other associated active within the same fibers constituting said textile product. These compositions are prepared according to the usual methods.

They may in particular be in the form of treatment creams or skincare for the face, for large anatomical folds or for the body,

The compositions according to the invention may also consist of solid preparations such as soaps or cleaning bars. Of course, the amount of potassium salt sucrose octasulfate used in the galenic formulation according to the invention is adapted according to the desired kinetics as well as specific constraints related to its nature, solubility, heat resistance, etc.

Water and water soluble solvents

According to a preferred embodiment, the composition of the invention may also comprise water, and in particular a thermal and / or mineral water. The composition according to the invention may also comprise one or more water-miscible solvents, such as lower alcohols, especially rethanol and isopropanol, propylene glycol.

Fatty phase The composition according to the invention may also comprise a fatty phase.

When the composition of the invention is in the form of an emulsion, the proportion of the fatty phase can range from 5 to 80% by weight, and preferably from 5 to 50% by weight, relative to the total weight of the composition.

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

The oils used in the composition according to the invention are chosen from those conventionally used in the cosmetic and / or dermatological field.

As fats usable in the invention include, in addition to unsaturated fatty acids, mineral oils such as hydrogenated polyisobutene and petrolatum oil, vegetable oils such as a liquid fraction of shea butter, sunflower oil, almond and apricot oil, animal oils such as perhydrosqualene, synthetic oils including purcellin oil, isopropyl myristate and ethylhexyl palmitate, and fluorinated oils such as for example perfluoropolyethers. It is also possible to use fatty alcohols, fatty acids such as, for example, stearic acid and waxes, especially paraffin, carnauba and beeswax.

It is also possible to use silicone compounds such as silicone oils and, for example, cyclomethicones and dimethicones, waxes, resins and silicone gums.

Emulsifiers The composition according to the invention, when it is in the form of an emulsion, may also comprise one or more emulsifiers and / or co-emulsifiers. The emulsifiers and co-emulsifiers used in the composition are chosen from those conventionally used in the cosmetic and / or dermatological field.

As emulsifier that can be used in the invention, mention may be made, for example, of glycerol stearate, polysorbate 60, cetylstearyl alcohol / cetylstearyloxyethylene mixture with 33 moles of ethylene oxide sold under the name Sinnowax AO® by HENKEL, the mixture of PEG-6 / PEG-32 / glycol stearate sold under the name Tefose® 63 by Gattefosse, PPG-3 myristyl ether, silicone emulsifiers such as cetyldimethicone copolyol and sorbitan mono- or tristearate, PEG-40 stearate, oxyethylenated sorbitan monostearate (20OE).

The total content of emulsifiers and co-emulsifiers may especially range from 0.3 to 30% by weight, and preferably from 0.5 to 20% by weight, relative to the total weight of the composition.

Gelling agents The composition according to the invention may also comprise gelling agents.

As hydrophilic gelling agents, mention may be made of carboxylic polymers such as carbomers, acrylic copolymers such as copolymers of acrylates / alkyl acrylates, polyacrylamides and especially the mixture of polyacrylamide, C13-14-Isoparaffin and Laureth-7 sold under the name Sepigel 305® by the company SEPPIC, polysaccharides such as cellulose derivatives such as hydroxyalkylcelluloses and in particular hydroxypropylcellulose and hydroxyethylcellulose, natural gums such as guar, carob, xanthan gum and clays.

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, or else ethylcellulose and polyethylene.

admixtures

The dermatological composition of the invention may also contain adjuvants which are customary in the cosmetic, pharmaceutical and / or dermatological field, such as ^• preservatives, antioxidants, solvents, fragrances, fillers, odor absorbers and dyes. These adjuvants, depending on their nature, can be introduced into the fatty phase and / or into the aqueous phase of the composition.

The amounts of these various adjuvants are those conventionally used in the field under consideration, and for example from 0.01 to 20% of the total weight of the composition.

Movie

According to a preferred embodiment of the invention, the composition is in the form of a film, preferably a water-soluble polymeric filmogel® film.

By "film" is meant according to the present invention, a solid and thin film. By "end" is meant a solid having a thickness of at most 1000 μηι

This film is prehensible, that is to say, it is generally of adequate size to be easily manipulated by the user. It can have a shape of square, rectangle, disk or any other form. A film generally has a thickness of 10 μm to 1000 μm, preferably from 20 to 500 μm and better still from 50 to 300 μm. The term "water-soluble film" in the sense of the present invention, a film that dissolves in water. It is a film consisting of one or more water-soluble or water-dispersible polymers, that is to say polymers having a solubility in water measured at 25 ° C. of at least 0.1 g / Obtaining a macroscopically isotropic and transparent solution, colored or not). This solubility is preferably greater than or equal to 1 g / L. The film according to the invention is preferably an "anhydrous film", that is to say a film comprising a water content of less than 1% by weight, preferably less than 10% by weight and more preferably less than 5% by weight. % by weight, based on the total weight of the film. More preferably, the film according to the invention is free of water.

The polymers that can be used to form these films can be of synthetic or natural origin, and, where appropriate, modified by chemical reactions. They can be film-forming or non-film-forming. They are advantageously film-forming. These polymers must be physiologically acceptable, that is to say compatible with the skin, the mucous membranes, the hair and the scalp.

The composition in the form of a film comprises in particular at least one film-forming polymer. "Film-forming polymer" means a polymer capable of forming, by itself or in the presence of an auxiliary film-forming agent, a continuous film, and preferably a film whose cohesion and mechanical properties are such that said film may be isolated from a support.

These polymers are cataloged under the heading "Film Formers" in the cosmetic dictionary "International Cosmetic Ingredient Dictionary and Handbook" (see for example pages 2903-2906 of the ninth edition - 2002).

The film-forming polymers may be chosen for example from:

vinyl polymers such as polyvinyl acetate, polyvinylpyrrolidones, copolymers of methyl vinyl ether and maleic anhydride, copolymer of vinyl acetate and crotonic acid, copolymers of vinylpyrrolidone and polyvinylpyrrolidone; vinyl acetate, copolymers of vinylpyrrolidone and caprolactam, polyvinyl alcohols. Preferably, the vinyl polymer is polyvinyl acetate (PVA), which is especially prepared by radical polymerization of the vinyl acetate monomer and then hydrolyzed. In particular, it is possible to use 88% hydrolyzed polyvinyl acetate, such as that sold under the name CELVOL 540 PV ALCOHOL by the company Celanese Chemicals; cellulosic film-forming derivatives, such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose, and the quatemized derivatives of cellulose. Preferably, the cellulose derivatives are chosen from hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC). These polymers are soluble in water as well as in organic solvents. This makes it possible to increase the solubility field of the films containing them. The choice of the molecular weight of these cellulosic polymers must be done judiciously to increase the dissolution of the films. The HPCs used in a preferred manner are those marketed by the company Hercules under the name KlucelO MF whose molecular weight is 850,000 (viscosity 4000-6500 mPa). at 2% in water) - KlucelO EF whose molecular weight is 80,000 (viscosity 300-600 mPa at 10% in water). The HPMC preferably used is hydroxypropyl methylcellulose of viscosity 40-60 cps (40-60 mPa) at 2% in water at 20 ° C, sold by Sigma-Aldrich. starches and their derivatives;

polymers of natural origin, optionally modified, such as pullulan, pectin, mannan, galactomannans, glucomannans and their derivatives, gum arabic, guar gum, xanthan gum, karaya gum, alginates, carrageenans, ulvans and other algal colloids, hyaluronic acid and its derivatives, shellac, sandaraque gum, dammars, elemis, copals, deoxyribonucleic acid, mucopolysaccharides such as hyaluronic acid, chondroitin sulfate;

polymers derived from chitin or chitosan, anionic, cationic, amphoteric or nonionic; protein polymers, such as wheat or soy proteins; keratin and its derivatives, for example keratin hydrolysates and keratin sulfones, casein, albumin, collagen, glutelin, glucagon, gluten, zein, gelatins and their derivatives;

acrylic phosphorylcholine copolymers, such as poly-2- (methacryloyloxyethyl) phosphorylcholine sold under the name Lipidure HM by the company NOF Corporation (INCI name: Polyphosphorylcholine glycol acrylate);

anion-cation complexes of gum arabic / gelatin or gum arabic / chitosan or collagen / glycosaminoglycane type; and mixtures of these polymers. According to a preferred embodiment of the invention, the film-forming polymer is chosen from vinyl polymers, cellulose derivatives and mixtures thereof. Preferably, the film-forming polymer is chosen from polyvinyl acetate, hydroxypropylcellulose, hydroxypropylmethylcellulose, and mixtures thereof, polyurethanes, nitrocellulose, and carbomers.

In particular, the composition according to the invention comprises one or more film-forming polymer (s) in a content ranging from 10 to 95% by weight, preferably from 20 to 70% by weight, and more preferably from 30 to 60% by weight. % by weight, based on the total film ratio.

When it is in the form of an anhydrous film, the composition according to the invention may comprise at least one organic solvent which may be chosen from:

ketones such as methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone, isophorone, cyclohexanone, acetone;

alcohols which are liquid at room temperature, such as ethanol, isopropanol, diacetone alcohol, 2-butoxyethanol, cyclohexanol, n-propanol and n-butanol; propylene glycol ethers which are liquid at ambient temperature, such as propylene glycol monomethyl ether, propylene glycol monomethyl ether acetate or dipropylene glycol mono-butyl ether;

glycols such as ethylene glycol, propylene glycol, pentylene glycol, glycerol

cyclic ethers such as γ-butyrolactone;

short-chain esters (having from 3 to 8 carbon atoms in total) such as ethyl acetate, butyl acetate, methyl acetate, propyl acetate, isopropyl acetate isopentyl acetate, methoxypropyl acetate, butyl lactate;

ethers such as diethyl ether, dimethyl ether or dichlorodiethyl ether; alkanes which are liquid at ambient temperature, such as decane, heptane, dodecane or cyclohexane;

alkyl sulphoxides such as dimethyl sulphoxide;

aldehydes that are liquid at room temperature, such as benzaldehyde or acetaldehyde;

ethyl 3-ethoxypropionate;

carbonates, such as propylene carbonate and dimethyl carbonate,

acetals such as methylal;

and their mixtures. According to a preferred embodiment, the organic solvent is volatile.

By "volatile organic solvent" is meant an organic solvent capable of evaporating on contact with the skin in less than one hour, at room temperature and atmospheric pressure. The volatile organic solvent is liquid at ambient temperature, in particular having a non-zero vapor pressure at ambient temperature and atmospheric pressure, in particular it has a vapor pressure ranging from 0.13 Pa to 40 000 Pa (10 -3 300 mm Hg), and preferably ranging from 1.3 Pa to 8000 Pa (0.01 to 60 mm Hg).

According to a particularly preferred embodiment, the organic solvent is chosen from alcohols which are liquid at room temperature, such as ethanol, isopropanol, diacetone alcohol, 2-butoxyethanol and cyclohexanol, and mixtures thereof, and preferably ethanol and / or short chain esters (having 3 to 8 carbon atoms in total) such as ethyl acetate, butyl acetate, methyl acetate, propyl acetate, acetate isopropyl, isopentyl acetate, methoxypropyl acetate, butyl lactate.

According to a more preferred embodiment, the organic solvent used in the compositions according to the invention is chosen from ethanol, ethyl acetate or a mixture of these.

The organic solvent may represent from 60 to 95% by weight, preferably from 65 to 85% by weight, and preferably from 65 to 80% by weight, relative to the total weight of the composition.

It is also possible to use in the composition of the invention a polymer which is both a film-forming polymer and a thickening polymer, chosen, for example, from cellulose derivatives and polymers of natural origin which can be both film-forming and thickeners. .

According to a particular embodiment, the composition according to the invention, when it is in the form of a film, comprises, in addition to the film-forming polymer, at least one polysaccharide thickening agent.

The polysaccharide thickening agents used in the film according to the invention may be chosen from polysaccharides with gelling power. The term "gelling power" defines the fact that at a concentration greater than or equal to 0.5% by weight in water, the viscosity of the solutions thus obtained is greater than or equal to 0.01 Pa.s for a shear equal to 1 the measurements being carried out at 25 ° C using a Haake RheoStress R5150 rheometer in cone-plane configuration, the measurements of the measuring cone being as follows: diameter: 60 mm and angle: 2 °.

The polysaccharide thickening agents may be chosen in particular from gum arabic, ghatti gum, karaya gum, locust bean gum, guar gum, tamarind gum, xanthan gum, gellan, pectins, tragacanth, agar, alginates, carrageenan, furcelleran, konjac and cellulose derivatives, and mixtures thereof.

According to a preferred embodiment of the invention, the polysaccharide thickening agents are chosen from carrageenans which are linear polysaccharides extracted from certain red algae of the family Rhodophyceae. They consist of residues 1, 3-1,3 and a-1,4 galactoses alternately, many galactose residues can be sulfated.

There are three types of carrageenans, called kappacarraghenan, Iota-carrageenan and Lambda-carrageenan. This family of polysaccharides is described for example in Chapter 3 of the book "Food Gels" edited by Peter HARRIS, Elsevier 1989. It is possible in particular to use the carrageenan sold under the name SATIAGUM UTC 10 by the company Degussa.

The amount of thickening agent (s) in the composition according to the invention may range, for example, from 0.5 to 40% by weight, in particular from 1 to 20% by weight, and more particularly from 5 to 10% by weight. % by weight relative to its total weight.

In addition, according to an advantageous embodiment, the composition in the form of a film may incorporate, in combination with the polymer as defined above, at least one oxyalkylenated polydimethylsiloxane derivative.

As described in document FR0653343, such a derivative has the advantage of significantly increasing the dissolution kinetics of the water-soluble film incorporating it. The oxyalkylenated polydimethylsiloxanes (PDMS) used according to the invention are water-soluble or water-dispersible.

The term "water-soluble or water-dispersible" means PDMS having a solubility in water measured at 25 ° C at least equal to 0.1 g / L (obtaining a macroscopically isotropic solution and transparent, colored or not). This solubility is preferably greater than or equal to 1 g / l.

These PDMSs are preferably chosen from water-soluble silicones containing at least one terminal or pendant monovalent polyoxyalkylene group and which, introduced at 0.05% by weight in an aqueous solution, are capable of reducing the surface tension of the water to a minimum. value less than 35 mN / m, and preferably less than 30 mN / m.

Such oxyalkylenated PDMS are for example sold by the company OSI under the trade names Silwet, Silwet 1614, and Tegowet.

According to a particularly preferred embodiment, the composition according to the invention is in the form of a water-soluble anhydrous film comprising (i) at least one synthetic polysulfated oligosaccharide, (ii) at least one water-soluble or water-dispersible film-forming polymer and (iii) ) at least one oxyalkylenated polydimethylsiloxane derivative.

The composition according to the invention, in particular when it is in the form of a film, may further comprise one or more plasticizers chosen for example from castor oil, or polyols such as glycerin, sorbitol, mono- and / or di-saccharides, dipropylene glycol, butylene glycol, pentylene glycol, polyethylene glycols such as PEG-400.

The amount of plasticizer (s) may range, for example, from 1 to 40% by weight and better still from 2 to 15% by weight relative to the total weight of the composition. Compositions according to the invention

According to a preferred embodiment, the composition according to the invention is in the form of an oil-in-water emulsion, preferably in cream form, comprising:

0.1 to 5% potassium salt of sucrose octasulfate (= KSOS) _lg

40 to 60% by weight of water,

20 to 40% by weight of at least one oil,

1 to 10% by weight of at least one surfactant,

0 to 10% by weight of at least one wax,

0 to 20% by weight of another active substance,

0 to 2% by weight of preservatives,

0 to 5% by weight of thickeners.

According to another embodiment, the composition according to the invention is in the form of an oil-in-water emulsion, preferably in cream form, comprising:

0.1 to 5% potassium salt of sucrose octasulfate (= KSOS)

0.1 to 5% sucrose octasulfate aluminum salt (sucralfate)

40 to 60% by weight of water,

20 to 40% by weight of at least one oil,

1 to 10% by weight of at least one surfactant,

0 to 10% by weight of at least one wax,

0 to 20% by weight of another active substance,

0 to 2% by weight of preservatives,

0 to 5% by weight of thickeners.

0.1 to 5% potassium salt of sucrose octasulfate (= KSOS)

0.1 to 5% sucrose octasulfate aluminum salt (= sucralfate)

0.1 to 5% hyaluronic acid

40 to 60% by weight of water,

20 to 40% by weight of at least one oil,

1 to 10% by weight of at least one surfactant, 0 to 10% by weight of at least one wax,

0 to 20% by weight of another active substance,

0 to 2% by weight of preservatives,

0 to 5% by weight of thickeners.

0.1 to 5% of potassium salt of sucrose octasulfate (= KSOS)

0.1 to 5% sucrose octasulfate aluminum salt (= sucralfate)

- 0.1 to 5% ruscus extract

40 to 60% by weight of water,

20 to 40% by weight of at least one oil,

1 to 10% by weight of at least one surfactant,

0 to 10% by weight of at least one wax,

0 to 20% by weight of another active substance,

0 to 2% by weight of preservatives,

0 to 5% by weight of thickeners.

According to another preferred embodiment, the composition according to the invention is in the form of a water-based filmogel composition comprising:

0.1 to 5% potassium salt of sucrose octasulfate KSOS

70 to 99% by weight of water,

0 to 10% by weight of another active substance,

0 to 2% by weight of preservatives,

0 to 5% by weight of thickeners.

According to yet another preferred embodiment, the composition according to the invention is in the form of a solvent-based filmogel composition comprising:

- 0.01 to 5%) of potassium salt of sucrose octasulfate KSOS 15 to 50% by weight of ethanol,

40 to 60% of ethyl acetate,

5 to 20% by weight of film-forming polymer of the nitrocellulose type,

5 to 20% of plasticizer, preferably castor oil,

0 to 2% by weight of preservatives,

0 to 5% by weight of thickeners.

Use of the compositions of the invention

The use according to the invention may be such that the compositions or combinations defined above are implemented in a formulation intended for topical use.

In particular, the subject of the invention is a topical composition for therapeutic treatment of subcutaneous varicose veins, preferentially subcutaneous varicose veins of the pelvic limb, in a subject having a predisposition to the development of said varicose veins comprising, in a physiologically acceptable support, at least one effective amount of at least one potassium salt of synthetic sucrose octasulfate.

According to another of its aspects, the subject of the invention is the use of an effective amount of potassium salt of sucrose octasulfate in combination with an effective amount of at least one other active substance as defined above, for the manufacture of a dermatological composition intended to treat and / or prevent subcutaneous varicose veins, preferentially subcutaneous varicose veins of the pelvic limb.

The following examples are presented by way of illustration and not limitation of the field of the invention.

EXAMPLES Example 1

A formulation in the form of a cream (oil-in-water emulsion) comprising a potassium salt of sucrose octasulfate according to the invention having the following composition was prepared: Constituents%

Oil-in-water surfactant 5,000

Emulsifying wax 2,000

Stearic acid 1,000

Isodecyl isononanoate 6,000

Silicone oil (Decamethyl- 4,000

cyclopentasiloxane)

Emollient Ester (myristyl lactate) 5,000

Demineralized water 62,100

Thickener 0.300

Glycerin 5,000

Propylene glycol 5,000

Potassium salt of sucrose octasulfate (= 0.500

KSOS)

Conservative 1,500

NaOH 10% 0.600

Silicone Surfactant 2,000

The thickener was dispersed in the water. Glycerin, propylene glycol, KSOS and preservative were added and homogenized. It was heated to 70-75 ° C. When the mixture reached 70-75 ° C, the water level was adjusted and then neutralized with 10% sodium hydroxide and the temperature was reduced to 70-75 ° C. At the same time, the oil-in-water surfactant, the emulsifying wax, the stearic acid, the iodecyl isononanoate, the silicone oil (decamethylcyclopentasiloxane), the emollient ester (myristyl lactate) were mixed together. ) and heated to 70-75 ° C.

When the two mixtures reached 70-75 ° C, the second was added in the first with vigorous stirring and allowed to stir for 10 minutes.

Then the silicone surfactant was added and heated again for 5 minutes.

Finally, the heating was stopped and allowed to cool to room temperature, maintaining sufficient agitation depending on the viscosity of the mixture. The mixture takes an inhomogeneous appearance towards 35 ° C, but the cream then becomes smooth and shiny.

Example 2

A formulation in cream form (oil-in-water emulsion) comprising an aluminum salt and a potassium salt of sucrose octasulfate according to the invention having the following composition:

Constituents%

Oil-in-water surfactant 5,000

Emulsifying wax 2,000

Stearic acid 1,000

Isodecyl isononanoate 6,000

Silicone oil (Decamethyl- 4,000

cyclopentasiloxane)

Emollient Ester (myristyl lactate) 5,000 Demineralized water 61,600

Thickener 0.300

Glycerin 5,000

Propylene glycol 5,000

Potassium salt of sucrose octasulfate (= 0.500

KSOS)

Sucrose octasulfate aluminum salt (= 0.500

sucralfate)

Conservative 1,500

NaOH 10% 0.600

Silicone Surfactant 2,000

The thickener was dispersed in the water. Glycerin, propylene glycol, KSOS, sucralfate and preservative were added and homogenized. It was heated to 70-75 ° C. When the mixture reached 70-75 ° C, the water level was adjusted and then neutralized with 10% sodium hydroxide and the temperature was reduced to 70-75 ° C.

At the same time, the oil-in-water surfactant, the emulsifying wax, the stearic acid, the iodecyl isononanoate, the silicone oil (decamethylcyclopentasiloxane), the emollient ester (myristyl lactate) were mixed together. ) and heated to 70-75 ° C.

Then the silicone surfactant was added and heated again for 5 minutes. Finally, the heating was stopped and allowed to cool to room temperature, maintaining sufficient agitation depending on the viscosity of the mixture. The mixture takes an inhomogeneous appearance towards 35 ° C, but the cream then becomes smooth and shiny.

Example 3

A solvent-based filmogel formulation comprising a synthetic polysulfated oligosaccharide according to the invention having the following composition was prepared:

The nitrocellulose was diluted in ethyl acetate absolute ethanol. Castor oil, UV filters and KSOS were then added until dissolution to obtain a filmogel composition.

Example 4

A water-based filmogel formulation was prepared comprising a synthetic polysulfated oligosaccharide according to the invention having the following composition Constituents%

Demineralized water 93,200

Thickener 0,500

Sorbitol 2,000

Dextran 1,000

Potassium salt of sucrose

1,000

octasulfate (= KSOS)

Methylparaben 0.050

Propylparaben 0.050

Phenoxyethanol 0.700

NaOH 10% 1,500

The thickener was dispersed in water with vigorous stirring, then sorbitol and dextran were added by heating at 40 ° C to obtain better solubility.

KSOS, parabens and phenoxyethanol were added and allowed to stir to homogenize. It was then allowed to cool to room temperature by stopping the heating, adjusting the water loss if necessary. Finally, it was neutralized with sodium hydroxide and allowed to stir for 10 minutes before stopping the stirring.

Claims

A topical dermatological composition comprising in a physiologically acceptable carrier at least one effective amount of at least one synthetic polysulfated oligosaccharide having 1 to 4 monosaccharides, or a salt thereof for use in the prevention and treatment of subcutaneous varicose veins .

2. Composition according to the preceding claim, characterized in that Γ synthetic polysulfated oligosaccharide having 1 to 4 ose units is a potassium salt of sucrose octasulfate.

3. Composition according to claim 2, characterized in that said potassium salt of synthetic sucrose octasulfate is present in a content of between 0.1 and 50% by weight, relative to the total weight of the composition.

4. Composition according to any one of the preceding claims 2 or 3, characterized in that it comprises one (or more) other active substance (s) selected from anti-bacterials, antiseptics, antifungal agents, anti-inflammatory agents, active agents promoting healing and / or restructuring of the skin, antipruritic agents, UV filters, soothing agents, moisturizing agents, depigmenting agents, keratolytic agents, anti-viral agents, painkillers, anesthetics, vitamins, analgesics, veinotonics, synthetic polysulfated oligosaccharides having 1 to 4 units, or salts thereof, and mixtures thereof.

5. Composition according to the preceding claim, characterized in that the other active substance is chosen from hyaluronic acid and / or sucralfate.

6. Composition according to Claim 4, characterized in that the other active substance is chosen from analgesics and / or venotonic agents.

7. Composition according to any one of the preceding claims, characterized in that it is in the form of solutions (aqueous, hydroalcoholic or oily), dispersions (lotion or serum type), emulsions of liquid or semi consistency liquid (milk type), suspensions or emulsions (cream type), aqueous or lipophilic gel, microemulsions, microcapsules, microparticles, vesicular dispersions of ionic and / or nonionic type, non-absorbent interface dressings, or still of impregnated compression article.

8. Composition according to any one of the preceding claims, characterized in that it is in the form of an oil-in-water emulsion, preferably in cream form, comprising:

0.1 to 5% potassium salt of sucrose octasulfate KSOS,

40 to 60% by weight of water,

20 to 40% by weight of at least one oil,

1 to 10% by weight of at least one surfactant,

0 to 10% by weight of at least one wax,

0 to 20% by weight of another active substance,

0 to 2% by weight of preservatives,

0 to 5% by weight of thickeners.