LU86547A1 - SUSPENSION FOR INDUCING AND STIMULATING HAIR GROWTH AND REDUCING FALL FROM PYRIMIDINE DERIVATIVES - Google Patents

Description

L'OREAL 380. -7 2.5344

.---- 86 5 4 / GRAND DUCHY OF LUXEMBOURG

Patent No *

Dear Minister "of 7.§ · 9.9..9. 1 ^ 56 of the Economy and the Middle Classes

Intellectual Property Service

...................- ÈfèS LUXEMBOURG

7?: Tg ^ a / .A ^. Patent Application

----------- --------------------------------------- ------------------------------------——-------— (U

.1. Request

The limited company known as: L'OREAL SA, 14, rue Royale, 75008 ^ 2) Paris, France, represented by Maître Alain RUKAVINA, lawyer-attorney, residing in Luxembourg, ÏOA, boulevard de la Foire, _ acting in his capacity as . _______________________________ (3) files (nt) this seven August 1900 eighty-six ______________________ (4) at hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a invention patent concerning: ............................................ ......... — ......... ~~~ ............................ ...........—-------------------------------------- -—--------—----------- (5) "Suspension to induce and stimulate the growth of _________ hair spray to decrease their fall based on derivatives of _______ pyrimidine" ... .................................................. ......................... _____ ______________ ______________________ 2. description in language ..............________________________________________ of the invention in triplicate; 3 ................................................. ......... drawing boards, in triplicate; 4. the receipt of the fees paid to the Luxembourg Registration Office, August 7, 1986 - 5. the delegation of power, dated from Paris ______________________....... _______________________ on__________6. August. .1986 ___________________; declare (s) assuming responsibility for this declaration, that the inventor (s) is (are): (6)

Monsieur ...... Jean-François GROLLIER, ........ 16bis, boulevard Morland, 75004 Paris, ........ France _............ .................................................. ........................... ........ _ _____ claims (s) for the above patent application priority d '' one (s) request (s) from (7) --------------------------- LL ......... .............................................. ”___________________________________________ filed ( s) in (8) ....................... DD .................... ...........................................- the (9) .. ............... LL .................................. .................................................. .................................................. .................................................. .................................................. ......................

under N ° (10) LL .......................................... ................................._................ .................................................. .................................................. .................................................. .........................

in the name of (11) ......... / .. / ............................... .................................................. .................................................. .................................................. .................................................. .................................................. ....

elect (elect) domicile for him / her and, if designated, for his / her representative, in Luxembourg ............................. ..............................

.IDA, ........ boulevard ...... de ....... la ..... Foire ................. .................................................. .................................................. .................................................. ........................ (12) requests (s) the grant of a patent for the invention for the subject described and represented in the appendices above, with postponement of this issue to ............................ 4ix-bui t nioi s ........ .................................................. .............month. (13)

The deposit ^ / n / ai / dataire: .... ________................................... .................................................. .............................. .................... .........- (14) if I iJUy J II. Deposit Minutes

The above patent application djrmentjm has been filed with the Ministry of the Economy and the Middle Classes, Servi ^ the Property Intdji ^ yifeî! a L ^ ttjghi ^ ourg, dated: August 7, 1986 I i '' · \ Pr- Ie Minister of Economy and Middle Classes, -QQ .hours l · '\?! j d.

The head of the service dej | intellectual property, Z '/ A 68007__ / / _

EXPLANATION OF THE DEPOSIT FORM. V

If 1 c'ïl v a li »n d» ivrtïfïeat H'iridttinn an hrvuM nrinriniil 1 la dntrifirU (ir »vpf nrinrtnil Kn du incmiV Ιικηητι nr» nnm ntnlMMn

• V

i JZ639f

1011./86 GD./DD

LU 380

Public limited company called: L'OREAL

"Suspension to induce and stimulate hair growth and reduce hair loss based on pyrimidine derivatives".

Invention of Jean-Erançois G-ROLLIER

Suspension to induce and stimulate hair growth and reduce hair loss based on pyrimidine derivatives.

The invention relates to new compositions in the form of a suspension for inducing and stimulating hair growth and reducing hair loss based on pyrimidine derivatives.

man has a capital of 100,000 to 150,000 hairs and it is normal to lose 50 to 10,100 hairs daily. The maintenance of this capital essentially results from the fact that the life of a hair is subjected to a cycle known as the hair cycle during which the hair is formed, grows and falls before being replaced by a new element which appears in the same 15 folicule.

Three phases are observed successively during a hair cycle: namely, the anagen phase, the catagen phase and the telogen phase.

During the first phase, called anagen, the hair goes through a period of active growth associated with intense metabolic activity at the level of the bulb.

The second phase, called catagen, is transient and is marked by a slowing down of mitotic activities. During this phase, the 2 hair undergoes an involution, the follicle atrophies and its dermal implantation appears higher and higher.

The so-called telogen terminal phase corresponds to a period of rest of the follicle and the hair ends up falling pushed by an incipient anagen hair.

This permanent physical renewal process undergoes a natural evolution during aging, the hair becomes thinner and its cycles shorter.

Alopecia occurs when this process of physical renewal is accelerated or disturbed, that is to say that the growth phases are shortened, the passage of the hair into the telogen phase is earlier and the hair falls in greater numbers. Successive growth cycles result in increasingly thinner and shorter hair, gradually transforming into an unpigmented down. This phenomenon can lead to baldness.

20 The hair cycle is dependent on many factors that can lead to more or less pronounced alopecia. Among these factors, mention may be made of dietary, endocrine, nervous factors, etc. The variations of the different hair categories can be determined by means of the trichogram.

For many years, research has been carried out in the cosmetic or pharmaceutical industry on compositions which make it possible to suppress or reduce the effect of alopecia and in particular to induce or stimulate hair growth.

With this in mind, compounds have already been proposed such as 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidino-pyrimidine and its derivatives. Such compounds are described in particular in patent 55 US-A-4,159,619.

3

It has also been proposed in patent WO-A-83 02 558 to associate retinoids with the above-mentioned compounds.

Preparations based on 6-amino 1,2-dihydro-5 hydroxy-1 imino-2 piperidino-4 pyrimidine generally comprise water, ethyl alcohol and propylene glycol or mixtures of these compounds taken two by two . Such compositions, however, have the disadvantage of sticking hair when loaded, making it greasy and sticky. This disadvantage becomes more pronounced after repeated topical applications. Such compositions, although having an effectiveness on the growth of the hair, do not however prove to be completely satisfactory at the cosmetic level.

Furthermore, the solvents used to present the active substance in solution are present in high proportions and they can be irritants.

The Applicant has discovered that it is possible to improve the effectiveness of pyrimidines having an effect on hair growth by using these compounds in micronized form in thickened aqueous suspension.

She found that this composition had an activity at the level of induction and stimulation of hair growth and action on the reduction of hair loss.

It noted in particular that the efficacy was greater than or at least equal to that of the previous compositions for lower doses of active substance and for lower application frequencies.

Furthermore, these compositions are particularly stable on storage. Finally, use in the form of a thickened suspension allows. i 4 also "good storage at the level of the stratum corneum and because of the size of the particles in suspension, a lower penetration in the pilosebaceous channel. The essentially aqueous compositions have, moreover, compared to the compositions of the art the advantage of not being irritating and oily and of not sticking the hair.

The subject of the invention is therefore a composition in the form of a thickened, stable suspension, based on 10 pyrimidine derivatives.

Other objects of the invention will appear on reading the description and the examples which follow.

The composition for inducing and stimulating hair growth and reducing hair loss, based on pyrimidine derivatives, is essentially characterized in that it is in the form of a thickened, stable suspension, containing a compound corresponding to the formula :

20 <j) H

H2N he JXK

YT

25 R3 in which R- | denotes a group in \ r4 in which R3 and R4 can be chosen from hydrogen, an alkyl group, preferably having 1 to 4 carbon atoms, alkenyl, lower alkylaryl or cycloalkyl, R3 and R4 can also form a heterocycle with l nitrogen atom to which they are linked chosen inter alia from the groups aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, hexahydro-35 azepinyl, heptamethyleneimine, octamethylineimine, S-5

V

morpholine and lower alkyl-4-piperazidinyl, the heterocyclic groups being able to be substituted on the carbon atoms by one to three lower alkyl, hydroxy or alkoxy groups; the group R2 is chosen from hydrogen, an alkyl, alkenyl, alkylalkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, alkylarylalkyl, alkoxyarylalkyl or lower haloarylalkyl group as well as cosmetically acceptable acid addition salts, in the form of 10 micronized particles having an average particle size less than 80 μm, preferably less than 20 μm and more particularly less than 5 μm, in a thickened, essentially aqueous medium. The term essentially aqueous medium, used in accordance with the invention, a medium containing less than $ 50 of solvent - chosen from lower alcohols and alkylene glycol alkyl ethers.

The active substance used in accordance with the invention is in the form of crystalline powder 20 obtained in particular by dry grinding in a mechanical mortar until particles are obtained having preferably an average diameter of less than 10 μm and preferably less than 5 yim or by micronization by air flow.

The compounds of formula (I) which are more particularly preferred are chosen from the compounds in which R2 denotes hydrogen and / “3

Ri represents a group in which R3 and R4 form a piperidinyl ring.

The particularly preferred compound is constituted by 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidino-pyrimidine also called "Minoxidil".

The aqueous suspension medium contains thickeners which do not cause agglomeration of the particles of active principle. These thickeners are preferably chosen from polyacrylic acids crosslinked with a polyfunctional agent such as more particularly the products sold under the name "CARB0P01" by the company GOODRICH or thickeners resulting from the ionic interaction of a cationic polymer constituted by a copolymer of cellulose or a cellulose derivative grafted with a salt of water-soluble quaternary ammonium monomer and a carhoxylic anionic polymer having an absolute capillary viscosity in dimethylformamide or methanol, at a concentration of $ 5 and at 30 ° C, less than or equal to 30 x 10-3 Pa.s, the thickener 15 itself having an Epprecht-Drage viscosity, module 3> in solution a \ $> in water at 25 ° C, higher or equal to 0.50 Pa.s.

the cationic polymer is preferably chosen from copolymers of hydroxyalkyl cellulose grafted by the radical route with a salt of water-soluble quaternary ammonium monomer chosen from the salts of methacryloylethyltrimethylammonium, of methacrylamidopropyltrimethylammonium, of dimethyl-diallylammonium. the anionic carboxylic polymer is preferably chosen from homopolymers of methacrylic acid having a molecular weight, determined by light scattering, greater than 20,000, copolymers of methacrylic acid with a monomer chosen from acrylates or methacrylates of C 1 -C 4 alkyl, acrylamide derivatives, maleic acid, a C 1 -C 4 alkyl monomaleate, vinyl pyrrolidone and copolymers of ethylene and maleic anhydride, weight ratio between the cationic polymer and the anionic carboxylic polymer is between 1./5 and 35 5./1 ·

V

»7 \

The particularly preferred thickeners are chosen from the products resulting from the ionic interaction of a hydroxyethyl-cellulose copolymer grafted by the radical route with diallyldimethylammonium chloride, such as the products sold under the name "CELQUAT L 200" or "H 100 "by the company NATIONAL STARCH with: - a copolymer of methacrylic acid and methyl methacrylate, having a capillary viscosity, 10 measured in solution in dimethylformamide at a concentration of $ 5 and at 30 ° C, around 15 x 10 “5 Pa.s; a copolymer of methacrylic acid with ethyl monomaleate having an absolute capillary viscosity, measured in solution in dimethylformamide at a concentration of $ 5 and at 30 ° C., of the order of 13 × 10 -3 Pa. s; - A copolymer of methacrylic acid with butyl methacrylate whose absolute capillary viscosity, measured in solution in methanol at a concentration of $ 5, is of the order of 10 × 10 -3 Pa.s; - a copolymer of methacrylic acid with maleic acid, the absolute capillary viscosity of which, measured in solution in dimethylformamide at the concentration of $ 5, is of the order of 16 × 10 -3 Pa.s.

The compounds in accordance with the invention are present in the suspension in proportions of between 0.1 and 10 $ by weight relative to the total weight of the composition, preferably between 0.1 and 5 $ 30 by weight and more particularly between $ 0.1 and $ 2 by weight.

The thickening agent is used in the compositions in proportions of between 0.5 and 2 $ and preferably between 0.7 and 1.5 $ by weight relative to the total weight of the composition.

] 8

V

V

These compositions may optionally contain, in addition to solvents in the proportions indicated above, preserving agents, complexing agents, dyes, alkali-5 or acidifying agents, perfumes.

The pïï of these compositions can vary between 4 and 9 and preferably between 7 and 8.5 ·

The particularly preferred composition comprises 0.5 to 5% of 6-amino-1,2-dihydro-1,10-hydroxy-2-imino-4 piperidino-pyrimidine in water containing from 0.5 to 2% of crosslinked polyacrylic acid having a molecular weight of 5,000,000 or a thickening agent consisting of the copolymer of hydroxyethylcellulose grafted by the radical route with diallyldimethylammonium chloride and the copolymer of methacrylic acid / methyl methacrylate and at most $ 10 by volume of ethyl alcohol.

The treatment method for combating hair loss consists mainly in applying to the alopecic areas of the scalp and the hair of an individual, a composition as defined above, for example after washing the scalp and the hair. using a shampoo or shortly after shampooing.

The process according to the invention has in particular characteristics of a cosmetic process insofar as it makes it possible to treat the hair or the scalp in the cosmetic sense of the term, that is to say to bring them the substances which it lacks and the 30 beautify.

It also has the characteristics of a therapeutic treatment insofar as it acts on biological functions and mechanisms. ' ! 9

The following examples are intended to illustrate the invention without, however, being limiting in nature.

EXAMPLE 1

The suspension medium of the following composition is prepared:

Crosslinked polyacrylic acid PM = 3 million, sold under the name "CARBOPOL 934" by the company GOODRICH 1.0 g

Butoxy-2 ethanol 4.5 g

2-amino-2-methyl-propanol-1 qs pH 8.5

Conservative qs

Water qs 100.0 g To this suspension medium is then added 3 g of 6-amino-1,2-dihydroxy-1 hydroxy-1 imino-2 piper-dino-4 micronized pyrimidine, with an average particle diameter of 4 μm and 1 'then homogenize with the three-cylinder.

The Epprecht-Drage viscosity of the composition at 25 ° C, module 4, is 7.2 Pa.s.

t 10 * * EXAMPLE 2

The suspension medium of the following composition is prepared:

Celquat L 200 0.7 g MA

Methacrylic acid / methacry- copolymer

methyl late 50/50 0.7 g MA

Ethyl alcohol $ 10 in Yol.

Ethylenediaminotetracetic acid 0.02 g

2-amino-2-methyl-propanol-1 qs pH 7.5

Water qs 100.0 g

Then added to this suspension medium 3 g of amino-6 dihydro-1,2-hydroxy-1 imino-2 piperi-dino-4 micronized pyrimidine, with an average particle diameter of 4 ^ m and homogenized with a three-cylinder.

The Epprecht-Drage viscosity of the composition at 25 ° C, module 3, is 2.15 Pa.s.

Claims (10)

1. Composition for inducing and stimulating hair growth and reducing hair loss, based on pyrimidine derivatives, characterized in that it is in the form of a thickened aqueous suspension containing at least one compound corresponding to the formula: H2N A. NH II in which R-] denotes a group -N. in 15 ^ R4 which R3 and R4 may be chosen from hydrogen, an alkyl group, preferably having 1 to 4 carbon atoms, alkenyl, lower alkylaryl or cycloalkyl, R3 and R4 may also form a heterocycle with the atom of nitrogen to which they are linked chosen, inter alia, from the aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, hexahydro-azepinyl, heptamethyleneimine, octamethyleneimine, morpholine and lower alkyl-4-piperazidinyl groups, the heterocyclic groups being able to be substituted on the carbon atoms by one to three lower alkyl, hydroxy or alkoxy groups; the group R2 is chosen from hydrogen, an alkyl, alkenyl, alkylalkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, alkylarylalkyl, alkoxyarylalkyl and lower haloarylalkyl group as well as the addition salts of cosmetically or pharmaceutically acceptable acids, in the form of micronized particles having an average particle size of less than 80 yum in a t * 12 4! -% Μ essentially aqueous medium containing a thickening agent. 2. Composition according to Claim 1, characterized in that the compound of formula (i) 5 is 6-amino-1,2-dihydro-1,2-hydroxy-2-imino-4 piperidino-pyrimidine. 3. Composition according to claim 1 or 2, characterized in that the compound of formula (i) is present in the composition in the form of particles having an average particle size less than 20 µm and preferably less than 5 µm. 4- Composition according to any one of claims 1 to 3, characterized in that the thickening agent is chosen from polyacrylic acids crosslinked with a polyfunctional agent. 5 · Composition according to any one of claims 1 to 3> characterized in that the thickening agent consists of a product resulting from the ionic interaction of a cationic polymer consisting of a cellulose copolymer or of a cellulose derivative grafted with a water-soluble quaternary ammonium monomer salt and an anionic carboxylic polymer having absolute capillary viscosity in dimethylformamide or methanol, at a concentration of $ 5 and at 30 ° C, less than or equal to 30 x 10 "3 Pa.s, the thickener with Epprecht-Drage viscosity, module 3" in solution of $ 1 in water at 25 ° C greater than or equal to 0.5 Pa.s. 6. Composition according to claim 5, characterized in that the thickening agent is chosen from products resulting from the ionic interaction of copolymers of hydroxyalkylcellulose grafted by the radical route with a salt of water-soluble quaternary ammonium monomer chosen from the 35 salts of methacryloylethyltrimethylammonium, of metha-, v '- 13 \ vi crylamidopropyltrimethylammonium, of dimethyldiallyl ammonium and of an anionic carboxylic polymer chosen from homopolymers of methacrylic acid having a molecular weight, determined by diffusion of light, greater than 20,000, copolymers of methacrylic acid with a monomer chosen from acrylates or C1-C4 alkyl methacrylates, acrylamide derivatives, maleic acid, a C1- alkyl monomaleate C4, N-vinylpyrrolidone and the copolymers of ethylene and maleic anhydride. 7 · Composition according to any one of claims 1 to 6, characterized in that it contains less than $ 50 of solvent chosen from glycols and alcohols. 8. Composition according to any one of Claims 1 to 7, characterized in that the active substance is present in proportions of between 0.1 and 10 $ by weight relative to the total weight of the composition and preferably between 0.1 and 5 $ 20 by weight. 9 · Composition according to any one of claims 1 to 8, characterized in that the thickening agent is present in proportions of between 0.5 and 2 $ by weight relative to the total weight of the composition and preferably in proportions of between 0.7 and 1.5 $ by weight. 10. Cosmetic treatment method against hair loss, characterized in that at least one composition as defined in any one of claims 1 to 9 is applied to the scalp or the hair. _ ^ ..... pages of which ........ Λ ..... cover page ..... / 10 pages of description ......... claim pages .. .... descriptive abstract Luxembourg, te -7 AUGUST 1986 The agent: