LU84734A1 - NOVEL ANTI-ACNE COMPOSITION BASED ON TIOXOLONE AND AT LEAST ONE OTHER ACTIVE INGREDIENT - Google Patents

Description

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The subject of the present invention is a new anti-acne composition based on tioxolone (International Nonproprietary Name) in combination with at least one other active principle allowing the obtaining of a synergistic effect as well as complementarity in the treatment of 5 acne.

Acne, which manifests itself more particularly in young subjects between 14 and 30 years of age, is essentially caused by a hormonal disorder manifested by the appearance on the face, neck and possibly the back and chest of pimples, blackheads. or pus-10 tules, the sebaceous glands being under the direct control of the androgen hormonal system.

This manifestation of acne results from hyperkeratinization of the duct of the sebaceous glands causing a narrowing of the passage so that the sebum cannot freely flow and thus forms a medium conducive to bacterial proliferation.

Various therapeutic agents are recommended in the treatment of acne in order to prevent obstruction of the follicular duct or to act with respect to bacterial infections causing the phenomena of inflammation.

The therapeutic agents which make it possible to prevent obstruction of the follicular duct are known under the name of keratolytic agents and among these mention may be made of sulfur, resorcinol, salicylic acid, benzoyl peroxide and tioxolone .

In the treatment of acne, tioxolone has proven to be a powerful keratolytic agent also endowed with anti-seborrheic, anti-bacterial and anti-fungal properties but nevertheless has certain side effects such that its use cannot be prescribed in some subjects.

In fact, tioxolone is particularly irritating and causes sensations of cooking and itching phenomena even when it is applied at relatively low concentrations. In addition, the skin becomes dry and it is necessary to resort to the application of fatty products during treatment.

In order to avoid these drawbacks, in particular the phenomena of irritation, it has already been proposed to combine tioxolone with certain agents such as, for example, hydrocortisone, but such compositions, if they make it possible to reduce the treatment times. by synergistic effect, however, do not lead to completely satisfactory results in particular due to the side effects of the hydrocortisone such as thinning of the epidermis.

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The present invention proposes to provide a new com-

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anti-acne position containing, as anti-seborrheic and keratolytic agent, tioxolone as well as another active principle capable of imparting a synergistic as well as complementary effect in the treatment of acne.

The subject of the present invention is a new composition for the local treatment of acne based on tioxolone and at least one other active ingredient taken from the group consisting of palmitoyl col-lagenic acid, 183 glycyrrhetinic acid, allantoin, Ι'α-bisabolol, a lactalbumin hydrolyzate, mucopolysaccharide extracts and a * meristem extract.

These different active ingredients make it possible to act favorably on the irritant action of tioxolone so that the compositions according to the invention can be applied without special precautions and without it being necessary for the treatment to be carried out under medical supervision.

According to the invention the concentration of tioxolone is between 0.1 and 1% preferably between 0.4 and 0.6% and that of the active principle between 0.1 and 15% by weight depending on the nature of the active principle.

Tioxolone is a compound corresponding to the following formula: H0. , 0. 0 xa of nomenclature hydroxy-6 benzoxathiol-1,3 one-2 previously described erroneously as being the derivative hydroxy-4.

This compound of crude formula: C ^ H ^ O ^ S (molecular weight 168) is in the form of crystals, melting point ür 160 ° C, insoluble in water but soluble in ethanol, 1 ' isopropanol, propylene glycol and ether.

Palmitoyl collagenic acid is a substance obtained by association of palmitic acid with fractionations of collagen from animal skins and more particularly by the action of palmi-35 chloride on collagens previously hydrolysed by chemical or enzymatic means.

* ii - 3 - Palmitoyl collagenic acid is in the form of a waxy solid insoluble in water, partially soluble in the usual solvents, the melting point of which is between 65 and 75 ° C depending on the size of the peptides linked to the carbonyl group originating from the carboxyl group of the fatty acid.

5 The palmitoyl collagenic acid used according to the invention is more particularly described in French patent No. 1,431,698.

Its concentration in the anti-acne composition according to the invention is preferably between 2 and 15% by weight relative to the total weight of the composition.

10 Glycyrrhetinic acid (or enoxolone) in the form 18—3 is a natural acid extracted from licorice roots with the raw formula: 0., - 11,, 0.

30 46 4 (molecular weight 470) and melting point 296 ° C.

According to the invention, 18-3 glycyrrhetinic acid is preferably used at a concentration of between 0.1 and 5% by weight relative to the total weight of the composition.

Allantoin (or ureido-5 hydantoin) corresponds to the following formula:

H

20 / \ ί0 H0N-C - NH -

II

0 ^ -NH

25 Crude formula: C ^ HgN ^ O ^ (molecular weight: 158).

Allantoin is used in the anti-acne composition according to the invention at a concentration preferably of between 0.5 and 3% relative to the total weight of the composition.

Α-bisabolol is a monocylated unsaturated tertiary sesquiterpene alcohol of formula:

CH ^ 0H

ctx I) oh3

35 CIL

Crude formula: (molecular weight: 222).

- 4 - It is a viscous liquid, colorless to slightly yellowish, the essential oil of chamomile can contain up to 50% of the form (-) - a-bisabolol.

The anti-acne composition according to the invention preferably contains from 0.5 to 5% by weight of a-bisabolol relative to the total weight of the composition.

The lactalbumin hydrolyzate consists essentially of peptides whose molecular weight ranges between 200 and 5,000 and which are essentially present in free form and also in the form of soluble aggregates, this hydrolyzate containing only very low proportions of higher peptides and free amino acids.

This hydrolyzate is obtained by the action of an endopeptidase capable of cutting specific peptide bonds, in particular inside the polypeptide chains, such as for example enzymatically pure trypsin and / or chymotrypsin.

The composition of the hydrolyzate, depending on the starting lactalbumin, can vary within the following limits expressed in% by weight: - total nitrogen: 5 to 15 20 - lactose: 0.1 to 18 - ash: 2 to 7 - fat : 0.1 to 6 - water: 1 to 4.

The pH of the hydrolyzate is usually of the order of 6.5 to 25 8, preferably between 6.5 and 7.5.

The preparation of the lactalbumin hydrolyzate as defined above is described in French patent n ° 79.00952.

According to the invention, the anti-acne composition preferably contains from 0.5 to 5% by weight of lactalbumin hydrolyzate.

Mucopolysaccharides form part of the protoplasm, connective tissue and tissue or bacterial membranes alongside the proteins with which they are most often intimately associated in the form of glycoproteins or mucoids. The mucopolysaccha wrinkles used in the composition according to the invention result from the extraction of skins of different origins, in particular embryonic calf skin, shark fins, pyloric antrum of pigs, etc.

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These mucopolysaccharides are in the form of a whitish powder soluble in water, the molecular weights of which can vary between 500,000 and 1,250,000.

Among the mucopolysaccharides capable of being used according to the invention, mention may in particular be made of those obtained by the methods described in US Patent No. 3,887,703 and French Patent No. 76,35644.

The mucopolysaccharides in the form of dry extract are preferably present in the anti-acne composition according to the invention at a concentration of between 0.1 and 3.5% by weight relative to the total weight of the composition.

Meristem extract is a water-soluble extract from the tips of the roots of leafy trees (angiosperms) and is in the form of a dark brown liquid with a slight odor but characteristic.

According to the invention, the anti-acne composition contains from 1 to 10% by weight of the meristem extract in the form of an aqueous solution at 0.4% by weight of pure extract, this solution having a pH of between 6 and. 20 7 and a refractive index (n ^) of between 1.310 and 1.360.

The anti-acne composition according to the invention can be in various forms, in particular in the form of an ointment, an emulsion, a lotion or a gel.

The term "ointment" covers formulations comprising absorbable oil bases, for example petrolatum, lanolin, polyethylene glycols as well as their derivatives and mixtures.

These ointments can be prepared by dispersing the tioxolone and the active compound associated with it in a suitable base such as petrolatum, lanolin, polyethylene glycols and their derivatives and mixtures thereof. The tioxolone and the active compound are finely divided by means of a colloid mill using, for example, light liquid petrolatum as a levigating agent before dispersing in the base for ointments.

The emulsions, whether of the oil-in-water or water-in-oil type, are prepared by dispersing tioxolone in the aqueous phase and the active compound associated with it is dispersed, depending of its affinity, either in the fatty phase or in the aqueous phase before the emulsification.

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The weight ratio of the fatty phase to the aqueous phase is generally between 95: 5 and 25:75.

Among the various oils capable of constituting the fatty phase, it is possible to use various products such as: 5 - animal oils such as lanolin, perhydrosqualene, - vegetable oils such as sweet almond oil, avocado oil, castor oil, olive oil, grape seed oil, flaxseed oil, rapeseed oil, peanut oil, corn oil, oil hazelnut, jojoba oil, safflower oil, oil of 10 wheat germs, shea butter and Shorea robusta fat, - mineral oils such as paraffin oil, - silicone oils soluble in other oils.

It is also possible to use certain synthetic products such as for example saturated esters and in particular isopropyl palmitate, isopropyl, butyl and cetyl myristate, hexa-decyl stearate, ethyl palmitate as well as octanoic and decanoic acid triglycerides and cetyl ricinoleate, purcellin oil and hydrogenated polyisobutene.

The fatty phase of the emulsions can also contain certain waxes and in particular carnauba wax, beeswax, ozo-kerite or candellila wax.

Lotions are solutions or dispersions of tioxolone and the active compound associated with it in a suitable carrier. As suitable support, there may be mentioned alcohols such as ethanol, polyols such as glycerin, (poly) alkylene glycols; organic solvents compatible with the skin, as well as water and mixtures thereof.

Gels are semi-solid preparations prepared by gelling a solution or suspension of tioxolone and the active compound associated with it, using gelling agents such as "ben-tone gel" , sold by the company NL INDUSTRIES, for a fatty phase, or crosslinked polyacrylic acid, for an aqueous phase, such as that sold by the company GOODRICH under the name of Carbopol 940 or 941 and used in neutralized form, the derivatives of cellulose, gums 35 of natural or synthetic origin.

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It is possible, if desired, to introduce a surfactant into the gel, which allows better dispersion and availability of the tioxolone. It is also possible to incorporate a lower aliphatic alcohol such as ethanol and optionally a silicone oil, glycols such as polypropylene or polyethylene glycols.

These anti-acne compositions can also contain other ingredients such as preservatives, pigments, humectants, fillers such as talc, nylon, starch, polyethylene powders, UV filters, etc.

In the treatment of acne, the compositions as defined. above are applied at least once a day to the lesions at a rate of 0.5 to 10 mg / cm 2, the duration of the treatment possibly being of the order of 2 to 4 weeks depending on the areas of skin affected.

Several examples of the anti-acne compositions according to the invention will now be given by way of illustration and without any limiting nature.

EXAMPLES OF COMPOSITIONS

EXAMPLE 1

Anhydrous lotion with glycyrrhetinic acid 20 - Tioxolone ........................ 0.5g - 18-3 Glycyrrhetinic acid ...... 1 , 0g - Ethanol .......................... 50,0g - Propylene glycol .......... qs .. 100g EXAMPLE 2 25 Allantoin gel - Tioxolone ........................ 0.6g - Allantoin ............ ........... 1.0g - Ethanol ........................ 40.0g - Propylene glycol ..... ............. 10,0g 50 - Carboxyvinyl polymer at 3% * active ingredient sold under the trade name of Carbopol 940 by the company GOODRICH Company .......... ....... 30.0g 35 - 20% Triëthanolamine ............ 2.0g - Water ................. ..... qs .. 100g '· - 8 - EXAMPLE 3

Ointment with palmitoyl-collagenic acid - Hydrogenated palm oil ....... 49.5g - Vaseline ......................... 20.0g 5 - Ethanol ....................... 20.0g - Tioxolone ................ ........ 0.5g - Palmitoyl-collagenic acid ..... 10.0g EXAMPLE 4

Aqueous lotion with Meristem 10 extract - Tioxolone ........................ 0.4g ~ - Meristem extract at 0.4%. ..... 10.0g - Ethanol .......................... 30.0g - Propanol ......... ............... 10,0g - Water ....................... qs. 100g 15 EXAMPLE 5

1'q-bisabolol gel - Tioxolone ........................ 0.3g - a-bisabolol .......... ............ 2.0g - Ethanol .......................... 35.0g 20 - Propylene glycol. ................. 15.0g - Carbopol 940 at 3% ................ 30.0g - Triethanolamine at 20% ............ 2.0g - Water ..................... qs ... 100g EXAMPLE 6 25 Ointment based on 'a lactalbumin hydrolyzate - Tioxolone ........................ 0.7g - Lactalbumin hydrolyzate ..... 2.0g - Mixture of fatty alcohols, oils and natural waxes (base sold by Henkel under the name CUTINA LM). 50.0g 1 - 2-octyldecanol ............ q.s.p .. 100g EXAMPLE 7

Mucopolysaccharide cream - Tioxolone ........................ 0.4g 35 - Mucopolysaccharide extract (dry matter weight) ....... .. 3.5g - Polyethylene glycol oxyethylenated stearate (20 moles) ........... 3.85g i * · - 9 - - Mixture of non-self-emulsifying glycerol mono- and di-stearate. 0.70g - Cetyl alcohol ................. 2.45g - Sweet almond oil .., .......... 5.0g 5 - Synthetic perhydrosqualene ...... 5.0g - Carboxyvinyl polymer sold under the trade name Carbopol 941 by the company GOODRICH Company ................. 0.2g 10 - Triethanolamine (20%) .......... 1.0g - Propylene glycol .................. 5.0g - Preservatives qs - Water ... .................. qs,., 100g

Claims (9)

1. Composition for the local treatment of acne based on tioxolone (or 6-hydroxy-benzoxathiol-1,3 one-2), characterized in that it contains tioxolone and at least one other active principle taken 5 in the group consisting of palmitoyl collagenic acid, 18-3 glycyrrhetinic acid, allantoin, Ι'α-bisabolol, a lactal-bumine hydrolyzate, mucopolysaccharide extracts and a meristem extract. 2. Composition according to claim 1, characterized in that the concentration of tioxolone is between 0.1 and 1% preferably between 0.4 and 0.6% and that of the active principle between 0.1 and 15% by weight relative to the total weight of the composition. 3. Composition according to any one of claims 1 and 2, characterized in that the palmitoyl collagenic acid is present at a concentration of between 2 and 15% by weight relative to the total weight of the composition. 4. Composition according to any one of claims 1 and 2, characterized in that the 18-3 glycyrrhetinic acid is present at a concentration between 0.1 and 5% by weight relative to the total weight of the composition. 5. Composition according to any one of claims 1 and 2, characterized in that 1 * allantoin is present at a concentration between 0.5 and 3% by weight relative to the total weight of the composition. 6. Composition according to any one of claims 1 and 2, characterized in that Ι'α-bisabolol is present at a concentration of between 0.5 and 5% by weight relative to the total weight of the composition. 7. Composition according to any one of claims 1 and 2, characterized in that the lactalbumin hydrolyzate is present at a concentration of between 0.5 and 5% by weight relative to the total weight of the composition. 8. Composition according to any one of claims 1 and 2, characterized in that the mucopolysaccharide extracts are present at a concentration of between 0.1 and 3.5% by weight. : 35 9. Composition according to any one of claims 1 and 2, characterized in that the meristem extract is present at a concentration between 1 and 10% by weight. * ... -ΠΙΟ. Composition according to any one of the preceding claims, characterized in that it is in the form of a, ointment, an emulsion, a lotion or a gel. 11. Composition according to any one of the preceding claims, characterized in that it also contains preservatives, pigments, humectants, fillers or filters Ü.V.