LU86396A1 - COMPOSITIONS FOR THE TREATMENT OF Baldness and Alopecia - Google Patents

Description

1.

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The present invention relates to the field of preventive or curative treatment of baldness and alopecia.

It relates in particular to new compositions intended to prevent hair loss, or even to promote their regrowth.

. - The compositions according to the invention are also effective ^ in the treatment of diffuse alopecia, in particular androgenic alopecia, alopecia witness to a general pathology (hypothyroidism, anti-'10 pituitary insufficiency, diabetes mellitus, hypochromic anemia , systemic lupus erythematosus, nutritional deficiencies ...), stress alopecia (childbirth, surgery, psycho-emotional shock) and other similar ailments.

Androgenic alopecia called seborrheic alopecia. 15 are considered responsible for common baldness. They frequently affect humans between 25 and 40 years of age.

They begin with a clarification of the temporal gulfs and evolve in a few years towards hypocratic alopecia.

Much rarer in women, they present a diffuse appearance with the absence of completely bald areas.

Seborrhea is generally important.

The subject of the invention is cosmetic and pharmaceutical compositions presented for topical application and containing, as active agent, at least one of the 25 products known under the International Common Names (INNs) Phenytoin (or Phenytoine) and Diazoxide (or Diazoxy-.de) as well as their acceptable salts from the cosmetic or pharmaceutical point of view.

Diazoxide (see The Merck Index. 9th Edition, 30 1976, page 395, No. 2968) is a compound corresponding to the following formula ·.

AT.

CH 3

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't .2 -.- nomenclature 7-chloro-3-methyl-benzothiadiazine-1 / 2,4 dioxide-1,1.

This compound of crude formula Cg Cl N2 0 ^ S (MW: 230/70) is in the form of crystals / melting point close to 331 ° C / insoluble in water, soluble in alcohol " 'alkaline solutions. Diazoxide has already been proposed "" as an antihypertensive drug.

Phenytoine (see The Merck Index 9th Edition, 1976, page 952, n ° 7130), also called Diphenylhydan-10 toine, is a compound corresponding to the formula:

H

15 c H ^ 'C6H5

Y NH

0 of nomenclature 5,5-diphenyl imidazolidinedione-2,4. Phe-20 nytoxne has already been proposed as an anticonvulsant and antiepileptic drug.

This compound of crude formula C ^ g H12 N2 ° 2 (MW: 252.26) is in the form of powder with a melting point between 295 and 298 ° C, practically insoluble in water, soluble in alcohol (1 g / 60 ml) and in acetone (1 g / 30 ml).

The invention also relates to the salts of the above products, which are suitable for local application. Particularly known are the alkaline and alkaline earth salts of phenytoin, in particular the sodium and calcium salts. By way of illustration, sodium diphenylhydantonate is a compound corresponding to the formula:

- C, Hc NH ^ »ON

.6 / '-s. 3.

If

C-N

. /

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• .... 3.- • This salt is in the form of a white powder, slightly hygroscopic, slightly soluble in water, alcohol, soluble in medium, alkaline, insoluble in ether, chloroform.

: The new compositions are suitable for topical application to the scalp. Besides the active agent (s) (phenytoin and / or diazoxide), the composition contains an excipient which can be chosen by a person skilled in the art from traditional excipients and vehicles for this type of application. Thus, according to the invention, the composition can be presented in different forms, in particular in the form of a lotion, gel, emulsion, ointment.

The term "ointment" covers compressed formulations. nable absorbable oil bases, for example mud line, lanolin, polyethylene glycols and their derivatives and mixtures.

These ointments can be prepared by dispersing diazoxide, phenytoin or their salts or by dissolving said products using a third solvent.

The emulsions, whether of the oil in water or water in oil type, are prepared by dispersing the diazoxide in the aqueous phase and the phenytoin is dispersed according to its affinity, either in the fatty phase or in the phase aqueous before emulsification. Alternatively, the active agents can also be dissolved using a third solvent.

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

Among the different oils capable of constituting the fatty phase, it is possible to use various products, such as: animal oils such as lanolin, perhy-drosqualene - vegetable oils such as sweet almond oil, oil avocado, castor oil, olive oil, 35 grape seed oil, flaxseed oil, rapeseed oil, peanut oil, corn / hazelnut oil, jojoba oil, safflower oil,

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4. '. wheat germ, shea butter and Shorea robusta fat, - mineral oils such as paraffin oil 5; - silicone oils soluble in other oils.

It is also possible to use certain synthetic products such as, for example, saturated esters, in particular isopropyl palmitate, isopropyl, butyl and cetyl myristate, hexadecyl stearate, the palm. ethyl tate as well as triglycerides of octanoic and decanoic acids and cetyl ricinoleate. ’Purcellin and hydrogenated polyisobutene.

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

Lotions are solutions or dispersions of diazoxide associated therewith in an appropriate carrier.

As suitable carrier, 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. this.

The gels are semi-solid preparations obtained by 25 gelation of a solution or. of a suspension of diazoxide, using gelling agents such as organophilic montmo-rillonites (Bentone), for a fatty phase, or cross-linked polyacrylic acid for an aqueous phase, cellulose derivatives., gums of natural or syn- origin.

30 thetic.

It is possible, if desired, to introduce a surfactant into the gel, which allows better dispersion and availability of the diazoxide. 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.

The formulations of the compositions of the invention

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can be diverse and their development for specific needs, belongs to the knowledge acquired by man. of career,

According to the invention, the concentration of the active ingredient (s) within the composition can vary quite widely, depending, in particular, on the form of presentation of the composition. In general, however, this concentration is between 0.1 and 15% by weight relative to the total weight of the composition, and in particular between 0.5 and 5% by weight. Illustrative examples of compositions in accordance with the invention are given below.

The activity of diazoxide, phenytoin or their salts is manifested by prevention of hair loss and regrowth when the hair bulb is not atrophied. The compositions according to the invention are therefore useful for the preventive or curative treatment of baldness and alopecia.

The compositions of the invention may contain a combination of diazoxide and phenytoin. Also, the subject of the invention is compositions in which the abovementioned active agents (diazoxide and / or phenytoline) are associated with one or more substances capable of potentiating their effect. The following are suitable categories of substances, with an indication (by weight, relative to the total of the composition) of their percentage range to obtain the desired potentiating effect. . ^ - Amino acid derivatives, such as octa-nucleus collagenic acid (lipoamino acid caprylyl collagen), which is the condensation product of octanoyl chloride on an alkaline hydrolyzate of collagen, or "Lipacid C ^ HP" (buty -ryl hydroxyproline), which is obtained by acylation of butyric anhydride on the amine function of hydroxyproline, these derivatives being usable in the range from 0.1% to 5%.

'- Nicotinic acid derivatives, such as benzyl nicotinate: 0.1 to 5% (see Merck Index, 10th Edition p. 935, n ° 6367) - Sulfur derivatives, such as carbocysteine (see

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Merck Index, 10th Edition, p. 249, n ° 1785), Lipoaminoacid - / caprylylcystinique: 0.1 to 5% - Enoxolone: 0.2 to 5% (See Merck index, lOème. Edition, p. 518, n ° 3545) .5 - Adjuvants favoring penetration of active principles such as: DMSO: 0.1 to 3% - Terpene derivatives such as Menthol: 0.005 to 0.5%, Thymol: 0.005 to 0.5% (See Merck Index, 10th Edition, p. 1347 , n ° 9246) 10 - Vitamin derivatives such as: panthothenic acid: 0.02 to 1% (See Merck Index, 10th Edition, p. 1007, • n ° 6877), vitamin E, B6 ...

The invention will be further illustrated, without being in any way limited, by the following examples, which describe various forms of presentation of the new compositions. EXAMPLE 1 Phenytoin anhydrous lotion 0.7 g 95% ethanol 70.0 g 20 'monopropylene glycol qs 100 g EXAMPLE 2

Phenytoin hydroalcoholic gel 0.5. g

Veegum R (gelling agent based on Al-Mg silicate) 1.2 g 'methylhydroxy propyl-eellulose (20,000 cps) 1.6 g ethanol. 20.0 g purified water qs 100 g, 30 EXAMPLE 3 '

Oil-in-water emulsion cream • phenytoin 2.0 g: polyethylene glycol mono- and di-palmitate 10.0 g • 35 stearic acid 3.0 g saturated C ^ to polyoxyethylenated glycerides 3.0 g

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palmitate. isopropyl 4.0 g monopropylene glycol 3.0 g preservatives purified water · qs 100 g ~; 5 EXAMPLE 4

Emulsion cream oil in water phenytoin- 2.0 g polyoxyethylenated fatty acid ester (HLB: 8.7) 6.0 g 10. cetyl alcohol 2.0 g stearic acid 5.0 g paraffin oil- 3.0 g 2-octyl dodecanol 6.0 g dimethicone 200 (silicone) 1.0 g 15 propylene glycol 10.0 g purified water preservatives qs 100 g EXAMPLE 5

Anhydrous lotion 20 benzyl nicotinate 0.2 g phenytoin 0.7 g ethanol 95% 70.0 g monopropylene glycol qs 100.0 g EXAMPLE 6 25. Hydroalcoholic phenytoin gel - 0.5 g butyryl hydroxyproline 1.0 g veegum R (gelling agent based on silicate Al-Mg) 1.2, g 30 methyl hydroxypropyl cellulose (20,000 cps) 1.6 g ethanol 20.0 g purified water 'qs 100.0 g. EXAMPLE 7' 35 'Cream emulsion oil in water phenytoin 2g

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. 8.

caprylyl-collagenic lipoamino acid 2.0 g polyethylene glycol mono di-palmitate 10.0 g. . 5 stearic acid 3.0 g saturated glycerides C ^ to C ^ g polyoxyethylenes 3.0 g isopropyl palmitate 4.0 g monopropylene glycol 3.0 g '10 preservatives purified water r qs 100.0 g • EXAMPLE 8

Oil-in-water emulsion cream phenytoin 2 g 15 caprylylcystinic lipoamino acid 2.0 g enoxolone 1.0 g polyoxyethylene fatty acid esters (HLB 8.7). 6.0 g 20 'cetyl alcohol 2.0 g stearic acid 5.0 g paraffin oil 3.0 g 2-octyl dodecanol 6.0 g dimethicone 200 (silicone) 1.0 g 25 propylene glycol 10.0 g. preservatives · purified water qs 100.0 g EXAMPLE 9 -

Alcoholic gel 30. sodium phenytoin 0.75 g DMSO 1.00 g ethanol 70.00 g methyl cellulose 0.5 g • _ monopropylene glycol qs 100.00 g 35 EXAMPLE 10

Phenytoin anhydrous lotion 1.5 g

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... · 9.

menthol 0.05 g thymol 0.05 g ethanol 95% 70.00 g propylene glycol qs 100.00 g 5 EXAMPLE 11 Anhydrous lotion •. · diazoxide 0.25 g • · DMSO '1.00 g ethanol · 70.00 g 10 monopropylene glycol qs 100.00 g EXAMPLE 12 Alcoholic gel 'diazoxide 0.25 g; ethanol 70.00 g 15 methyl cellulose 0.50 g pantothenic acid 0.10 g monopropylene glycol qs 100.00 g EXAMPLE 13 20 Oil in water diazoxide emulsion cream 1.00 g enoxolone 1.00 g polyoxyethylenated fatty acid ester 6 0.00 g 25 cetyl alcohol 5.00 g paraffin oil 5.00 g isostearyl isostearate 3.00 g propylene glycol 5.00 g preservatives 30 carbocysteine 1.50 g purified water qs 100.00 g

The compositions of Examples 1 and 11 were respectively used for the treatment of two groups of ten volunteers, men from 30 to 40 years old, having a marked tendency to hair loss, but not yet having reached stage of total baldness at the top of the scalp. Each volunteer applied the

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10 composition in the form of friction with light massage of the scalp. The total duration of treatment was two months.

From eight to nine men in each group noted an improvement after this treatment, resulting in a marked slowdown in the amount of hair loss, which they observed by subjectively comparing the number of hairs retained by the comb. or brush, or fallen on clothes, before and after treatment.

. It goes without saying that the frequency of the applications and the duration of the treatment with the aid of the compositions of the invention will depend on the severity of the affection to be expected or cured. It should also be emphasized that hair regrowth is only possible if the hair bulbs are not irreversibly affected.

It will also be noted that the active products of the compositions of the invention have already been proposed as medicaments, but the corresponding pharmaceutical compositions have not been presented for topical application.

The invention therefore relates generally to the appli-20 cation of phenytoin, diazoxide or their salts, as products for the treatment of baldness and alopecia. It also relates to a process for obtaining said products when they are intended for such treatment.

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Claims (8)

1. Cosmetic and pharmaceutical compositions presented for topical application and containing, as active agent, at least one of the products known under the 5 International Nonproprietary Names (INNs) Phenytoin (or Phenytoin) and Diazoxide (or Diazoxide), as well as their V - salts acceptable from the cosmetic or pharmaceutical point of view 2. Compositions according to claim 1, character-ized, in that they contain, as active agent, at least one alkali or alkaline earth salt of phenyto'ine, in particular the sodium salt or calcium from it. 3. Compositions according to one of claims 1 or 2, presented in the form of lotions, gels, emulsions, ointments or other forms suitable for topical application, with the usual excipients for this type of application. 4. Composition according to any one of claims 1 to 3, characterized in that the concentration of the active agent is between 0.1 and 15% by weight relative to the total weight of the composition, and in particular between 0.5 and 5% by weight. 5. Compositions according to any one of claims 1 to 4, characterized in that the active agents, namely • diazoxide and / or phënytoïne or their salts are as-25 associated with one or more substances capable of 'potentiating their effect, chosen in particular from the following categories, in "respective amounts indicated in percent by weight, relative to the total weight of the composition: - Amino acid derivatives, such as oc ta- 'acid · 30 collagenic nucleus (collagenic lipominoacid caprylyl), which is the condensation product of octanoyl chloride on an alkaline hydrolyzate of collagen, or "Lipid C ^ HP" (butylyl hydroxyproline), which is obtained by acylation of butyric anhydride on the amine function of hydroxyproline, these derivatives being usable in the range of 0.1 to 5% - Nicotinic acid derivatives, such as benzyl nicotinate: 0.1 to 5 i, - 9755 LU. • f 5. 12. "- Sulfur derivatives, such as carbocysteine, Lipoami - caprylylcystinic acid: 0.1 to 5% - Enoxolone: 0.2 to 5% - Adjuvants promoting the penetration of the main active principles such as DMSO: 0.1 to 3%. ζ - Terpene derivatives such as Menthol s 0.005 to · 0.5%, Thymol: 0.005 to 0.5%. - Vitamin derivatives such as panthothenic acid: 0.02 to 1%., Vitamin E, B6 .... 10. '6. Compositions according to any one of claims 1 to 5, for the preventive or curative treatment of baldness and alopecia. 7 * Application of phenytoin, diazoxide or. • their salts, as products for the treatment of baldness and alopecia. 8. Process for obtaining phenytoin, diazoxide or their salts, as products intended for the treatment of baldness and alopecia. 9755 LU