CA2023090A1 - Cosmetic composition - Google Patents
Cosmetic compositionInfo
- Publication number
- CA2023090A1 CA2023090A1 CA 2023090 CA2023090A CA2023090A1 CA 2023090 A1 CA2023090 A1 CA 2023090A1 CA 2023090 CA2023090 CA 2023090 CA 2023090 A CA2023090 A CA 2023090A CA 2023090 A1 CA2023090 A1 CA 2023090A1
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- CA
- Canada
- Prior art keywords
- hair
- acetyl
- hair growth
- composition according
- acid
- Prior art date
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Abstract
ABSTRACT
A composition suitable for topical application to mammalian skin and hair for inducing, maintaining or increasing hair growth comprises a hair growth promoter chosen from N-acylated amino-acids, in which the acyl group has from 2 to 20 carbon atoms, together with a cosmetically acceptable vehicle for the hair growth promoter.
A composition suitable for topical application to mammalian skin and hair for inducing, maintaining or increasing hair growth comprises a hair growth promoter chosen from N-acylated amino-acids, in which the acyl group has from 2 to 20 carbon atoms, together with a cosmetically acceptable vehicle for the hair growth promoter.
Description
COSMETIC COMPOSITION
FIELD OF THE INVENTION
The invention relates to cosmetic and pharmaceutical compositions for topical application to mammalian skin or hair, containing a hair growth promoter which is capable of increasing or maintaining hair growth, especially terminal hair growth on the human scalp.
BACKGROUND
The Hair Growth Cycle It should be explained that in most mammals, hair does not grow continuously, but undergoes a cycle of activity involving alternate periods of growth and rest.
The hair growth cycle can be divided into three main stages, namely ', .
tl~.
~ - 2 - 33121 (i) the growth phase known as anagen, during which the hair follicle penetrates deep into the dermis with the cells of the bulb dividing rapidly and differentiating to form the hair, s (ii) the transitional stage known a~ catagen, which is heralded by the cessation of mitosis, and during which the follicle regresses upward~s through the dermis and hair growth ceases, (iii) the resting stage known as telogen, in which the regressed follicle contains a small secondary germ with an underlying ball of tightly packed dermal papilla 1S cells.
~ he initiation of a new anagen phase is revealed by rapid proliferation in the germ, expansion of the dermal papilla and elaboration of basement membrane components.
The hair cycle is then repeated many times until, as a consequence of the onset of male pattern baldness, most of the hair follicles spend an increasing proportion of their time in the telogen stage, and the hairs produced become finer, shorter, and less visible; this is known as 2s terminal to vellus transformation.
PRIOR ART
Alleqed Baldness Cures Although there have been many claims in the scientific :Literature to the promotion or maintenance of hair growth by the topical application of hair ~onics and ~5 the like, w:ith the possible exception of minoxidil, none has been shown to be sufficiently ~ree from disadvantageous clinical side effects, whether : ' ' ' ,' ' ' ' - ~ . .
..
administered topically, orally or systemically, to warrant commercial exploitation as an ethical pharmaceutical, proprietary medicine, or as a cosmetic product. Possibly, the only means which has met with partial success for growing hair on the bald or ~alding human head is by transplantation of hair to the bald areas. This is, however, an elxtremely painful operation and is not always successful. Furthermore, it is immediately apparent to the casual observer that the subject has received a hair transplant and it may take many months or even years before hair ragrowth, following this operation, assumes an appearance which resembles that of the original naturally growing hair.
Among the many hair regrowth studies that have been reported in the literature, there is included the work of Bazzano as described in PCT International Publication No.
W0 85/04577. This publication describes a composition which is useful for increasing the rates of hair growth on mammalian skin, prolonging $he anagen phase of the hair growth cycle and for treating various types of alopecias. The composition in question comprises a pyrimidine carbamate.
It has also been reported in US patent no. 4 139 619 to Chidsey assigned to the Upjohn Company, that a topical composition comprising minoxidil as the free base or acid addition salt thereof, or certain epecified related iminopyrimidines, is useful in stimulating the conversion of vellus hair to growth as terminal hair, as well as - -increasing the rate of growth of terminal hair.
In spite of the apparent stimulation of hair growth ~5 or regrowth reported independently ~y Bazzano and Chidsey, following topical application of minoxidil or related compounds, there is general concern that systemic _ 4 _ J3121 side-effects can result, particularly following topical application of minoxidil. Thus it is generally recognised in the medical literature that the side effects of orally administered minoxidil are very serious, and include fluid rel:ention, tachycardia, dyspnea, gynecomastia, fatigue, nausea and cardiotoxicity. There is also evidence that certain side effects have been experienced following topical application of minoxidil.
It is also reported by Lion Corp., in JP 61151109 that compositions comprising mono-N-long chained acyl basic amino acid lower alkyl ester salt can, together with higher fatty acid having an odd number of carbon atoms, higher aliphatic alcohol having an odd number of carbon atoms, or their derivatives, can be used for regenerating and growth increasing effect on hair.
BACKGROUND TO THE_INVENTION
Our own search for effective compositions that could be applied topically to the human scalp in order to promote hair growth, was influenced by the need to 2s discover molecules which were not only effective but also completely safe in use and free from contra indications which would limit their appeal. Furthermore, we were anxious to identify relatively simple molecules in this respect which were easy to synthesis and inexpensive to deploy in a mass market affordable product which would appeal to a large number of potential consumers.
It was accordingly during in vivo studies into the effects on rat skin of N-acetyl glycine, that it was 3s observed unexpectedly that this substance may be capable of promoting hair growth. This was tested and evidence obtained to substantiate this surprising observation.
- . . , ~ . - . - . . .:
` - 5 - J3121 . ' DEFINITION OF THE INVENTION
.
Accordingly, the invention provides a composition suitable for topical application to mammalian skin or hair for inducing, maintaining or increasing hair growth, which comprises:
;
i. an effective amount of from 0.001 to 99% by weight - of a hair growth promoter chosen ~rom mono N-acylated amino acids or salts thereof, in which the acyl group has from 2 to 20 carbon atoms; and ii. from 1 to 99.999~ by weight of a cosmetically acceptable vehicle for the hair growth promoter.
DISCLOSURE_OF THE_INVENTION
The hair arowth promoter According to the invention, the composition comprises as a hair growth promoter, a mono N-acylated amino acid, in which the acyl group has from 2 to 20 carbon atoms.
2s Preferably the acyl group is chosen ~rom acetyl, hexanoyl, octanoyl, lauroyl, myristoyl, palmitoyl and stearoyl. The most preferred acyl group in acetyl.
io Examples of the amino acid moiety from which the mono N-acylated amino acid is derived include neutral -amino acids, such as:
- glycine S alaninle valine leucin~e ` ~ , : ., !
~ 6 - J3121 isoleucine phenylalanine tyrosine proline hydroxyproline serine threonine cysteine cystine methionine, and tryptophan.
Preferred mono N-acylated neutral amino acids include:
N-acetyl glycine N-acetyl hydroxyproline N-acetyl alanine N-acetyl valine N-acetyl leucine N-acetyl isoleucine N-acetyl phenylalanine N-acetyl tyrosine N-acetyl proline N-acetyl serine N-acetyl threonine N-acetyl cysteine N-acetyl cysteine N-acetyl methionine io N-acetyl tryptophan N-lauroyl glycine .-N-palmitoyl glycine N-myristoyl glycine N-lauroyl hydroxyproline ~5 N-octanoyl glycine N-octanoyl hydroxyproline, and N-hexanoyl glycine.
.,, ,, - , .
.
.
,', , , . ~:, .
r, r . ~
`:
Examples of the amino acid moiety from which the mono N-acylated amino acid is derived also include acidic amino acids, such as:
aspartic acid and glutamic acid.
Preferred mono N-acylated acidic amino acids include:
N-acetyl aspartic acid N-lauroyl aspartic acid N-palmitoyl aspartic acid N-octanoyl aspartic acid N-acetyl glutamic acid lS N-lauroyl glutamic acid N-palmitoyl glutamic acid, and N-octanoyl glutamic acid.
Examples of the amino acid moiety from which the mono N-acylated amino acid is derived also include basic amino acids, such as: !
arginine lysine histidine ornithine hydroxylysine, and citrulline.
Preferred mono N-acylated basic amino acids include:
N-acetyl arginine N~acetyl lysine N-acetyl histidine N-acetyl ornithine N-acetyl hydroxylysine N-acetyl citrulline .
- 8 - ~31~1 N-lauroyl lysine N-lauroyl citrulline N-myristoyl citrulline N-myristoyl ornithine N-octanoyl lysine, and N-oc anoyl citrulline.
The preferred N-acylated amino acids are those derived from neutral or acidic amino acids.
Particularly preferred mono N-acylated amino acids are those that contain no sulphur atoms in the molecule.
The mono N-acylated amino acids as herein defined can also be employed in the composition according to the invention as their corresponding salts, examples o~ which includes alkali metal salts, such as sodium and potassium and alkanolammonium salts such as triethanolammonium.
The composition can comprise two more mono N-acylated amino acid~, or salts thereof.
The total amount of the hair growth promoter present 2s in the composition according to the invention is preferably sufficient to increase hair growth in the rat, the model selected for this test, when said composition is appli~d topically thereto over a period o* no more than 3 months, by at least 10~ more than that obtainable using a control composition ~rom which the ~aid promoter has been omitted, in accordance with the Rat Hair ~rowth Test.
Preferably, the amount of promoter ~hould be sufficient to increase hair growth in the rat by at least 20%, more preferably by at least 30%, most preferably by at least 40% and ideally by at least 50%.
' ,: ',, , , . r, ~-~
_ g - J3121 The effective amount which is sufficient to induce, maintain or increase hair growth will depend on the effectiveness of the promoter ~ome being more effective than others, but in general, an amount of from 0.0001 to 99%, preferably from 0.01 to 20% by weight o~ the composition will provide an adequate dose to the skin after topical application.
Preservation of the Composition The composition according to the invention is preferably preserved in such a manner that it will enjoy an extended shelf life following manu~acture and prior to 1S sale and use. Ideally the composition will have an indefinite shelf life.
It is accordin~ly apparent that the haix growth promoter is likely to be prone to attack by bacteria, 2~ moulds and fungi and other microbial influences, particularly at p~ values near that of the skin that characterise the preferred composition. The shelf-life of the composition can therefore be unacceptahly short due to the biodegradation of the hair growth promoter 2s unless steps are taken to preserve the composition.
In order to be preserved, the composition should preferably be ~ree, or substantially ~ree, from viable microbial contaminants that are capable of resulting in o microbial spoilage of the composition, and/or biodegradation of the hair growth promoter prior to topical appl:ication of the composition to mammalian skin or hair. It is to be understood, however, that the invention is also concerned with compositions, as herein ~5 defined, which may contain viable but dormant microorganisms, such as bacterial spores, provided that the conditions of preservation do not result in - lO - J3121 substantial proliferation of the microorganisms prior to ` use of the composition.
':, Examples of methods that can be employed to achieve preservation of the composition, includes the following:
(i) Sterilisation The composition according to the invention can be preserved by sterilisation to remove or kill substantially all viable microbial contaminant~. This can be achieved for example by irradiation using a lethal dose of gamma rays, by heat sterilisation or by ultrafiltration using techniques that are well established in the pharmaceutical industry.
fii) Chemical_Preservative The composition according to the invention can also be preserved by including in it a chemical prPservative which functions to prevent the growth of or kill bacteria, fungi or other microorganisms.
2s Examples of chemical preservatives include ethanol, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, sodium propionate and the methyl, ethyl, propyl and butyl esters of p-hydroxybenzoic acid. The amount of chemical preservative that can be incorporated in the composition according to the invention will generally be from 0.05 to 5%, preferably from 0.1 to 2% by weight, the amount chosen being sufficient to arrest microbial proliferation.
~iii) Water activity depressants The composition according to the invention can also , .: . . .
be preserved by the inclusion of a water activity depressant such as glycerol, propylene glycol, sorbitol, sugars and salts, for examples~ alkali metal halides, sulphates and carboxylates. When employing a water activity depressant, sufficient should be lncorporated in the composition according to the invention to reduce the water activity (~ w) from 1 to < 0.9, preferably to <
0.85 and most preferably < 0.8, the lowest of these values bein~ that at which yeasts, moulds and fungi will not proliferate.
The hair growth promoter may be susceptable to hydrolysis, particularly when the pH value of the composition is alkaline. It is accordingly preferred that the composition, when aqueous, should have an acid pH valu~. The preferred pH value of the composition, when aqueous, is from 2 to <7, ideally from 4 to 6.5.
The Vehicle The composition according to the invention also 2s comprises a solid, semi-solid or liquid cosmetically and/or physiologically acceptable vehicle, ~o enable the hair growth promoter to be conveyed to the skin at an appropriate diluti.on. The nature of the vehicle will depend upon the method chosen for topical administration ~o of the composition. The vehîcle can itself be inert or it can possess physiological or pharmaceutical benefits of its own.
The sel~ection of a vehicle for this purpose presents a wide range of possibilities depending on the required f ~
~ 12 ~ J3121 product form of the composition. Suitable vehicles can be classified as described hereinafter.
It should be explained that vehicles are substances which can act as diluents, dis;persants, or solvents for the hair growth promoter which there~ore ensure that they can be applied to and distributed evenly over the hair and/or scalp at an appropriate concentration. The vehicle is preferably one which can aid penetration of the esters into the skin to reach the immediate environment of the hair follicle. Compositions according to this invention can include water as a vehicle, and/or at least one cosmetically acceptable vehicle other than water.
Vehicles other than water that can be used in compositions according to the invention can include solids or liquids such as emollients, solvents, humectants, thickeners and powders. Examples of each of these types of vehicles, which can be used singly or as mixtures o~ one or more vehicles, are as follows:
Emollients, such as stearyl alcohol, glyceryl 2s monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, ispropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, -isopropyl stearate, butyl stearate, polythylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, ~5 petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myxistyl myristate;
-, . ~
':
~J~ 2~
,, Propellants, such as trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, monochlorodifluoromethane, trichlorotrifluoroethane, propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide;
Solvents r such as ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran;
Humectants, such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin;
Powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal ~ilicon dioxide, sodium polyacrylate, tetra alkyl and/or trialkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate.
The amount of vehicle in the composition, including water if present, should preferably be su~ficient to carry at least a portion of a selected ester to the skin in an amount which is su~ficient effectively to enhance hair growth. The amount of the vehicle ~an comprise the balance of the composition, particularly where little or no other ingredients are present in the composition.
~ccordingly, the vehicle or vehicles can comprise ~rom 1 to 99.99~, preferably from 50 to 99.5% and ideally from 9o to 99% by weight of the composition.
~' -, b ' ,~ h ~3 .
Perfume The composition according to the invention can also optionally comprise a perfume in an amount sufficient to make the composition acceptable to the consumer and pleasant to use. Usually, th~e perfume will form from 0.01 to 10% by weight o~ the composition.
Activity Enhancer The composition according to the invention can also optionally comprise an activity enhancer.
The activity enhancer can be chosen from a wide variety of molecules which can function in different ways to enhance the hair growth effects of the hair growth promoter. Particular classes of activity enhancers include other hair growth stimulants, penetration enhancers and cationic polymer~, whose presence can further improve the delivery of the ester through the stratum corneum to its site of action in the immediate environment of the hair follicle.
Some activity enhancers can also function as vehicles for the ester.
(a)_Other Hair_Growth Stimulants i. Examples of other substances which themselves possess the ability to stimulate or increase hair growth include, for example:
Benzalkonium chloride Benzethonium chloride Phenol .:
!. ~ , ' ,~ J ,' ~
' Estradiol : Diphenhydramine hydrochloride Chlorpheniramine maleate Chlorophyllin derivatives Cholesterol Salicylic acid Cystine ~ed pepper tincture Benzyl nicotinate dl-Menthol Peppermint oil Calcium pantothenate Panthenol Castor oil Hinokitiol Prednisolone Resorcinol Further substances which themselves possess the ability to increase the rate of terminal hair growth include:
ii.~ -1,4 esterified disaccharides described by Choay 2s S.A. in EP-A-0 064 012, having the structure (2):
o~ ~
~O~ ~OR
.
z olt ~s where Z represents a functional nitrogen group, such as an azide or a group having the structure -NHB, in which B represents -H or a functional - 16 - ~3121 group such as acetyl or sulphate as a salt with an organic or mineral ca ion;
M represents -H or S03M1, where M1 i5 an organic or metallic cation, particularly an alkali metal; or an acetyl group;
R represents a Cl to C4 alkyl radical, especially methyl; or an aryl radical;
A represents a functional group such as an acid or -COORl, wh~re R1 represents -H or a Cl to C4 alkyl radical, especially methyl; or a metal, especially an alkali metal;
esterified oligosaccharides as described by Unilever in EP-A-0 211 610, including at least one esterified 20 disaccharide unit consisting of a uronic acid residue having the structure (3):
ll~o , '''.
H.OR~'K~H.oR' ( 3 ) H R
and a hexosamine residue having the structure (4):
'1)~o ~-O Q~ .O R"
Il R~
.. : -. ' .. - ' ... . . : : . . -.' :' : ' :- , : .
,' . ' ~ . ~ -'.
- . .
j'jj`,',,'.,",'~' i5J
COOR"
where R' is -H, C3 to C10 alkyl or -CH~CH2)nCH3 R is -H, C1 to C4 alkyl, -CO(CH2)mCH3, -S03M, R is -H, -CO(CH2~nCH3, or -S03M, N is -H, or a metal:lic or organic cation n is o or an intege:r of from 1 to 7, and m is O or the integer 1 or 2;
the groups designated R" beinq the same or different, one R" group from each pyranose ring struckure being linked by a glycosidic linkage having the configuration d~-1,3, ~ -1,4, ~ -1,3 or ~-1,4; and the -COORI, -CH20R"
and -OR" groups being of either configuration with respect to the pyranose rings;
iii. Minoxidil glucuronides, as described ~y Unilever in /
EP-O 242 967, iv. Minoxidil sulphates, as described by The Upjohn Co.
in WO 86/04231, and v. Minoxidil, and other derivatives thereof as described by The Upjohn Co, in US patent 4 139 619.
2s Particularly preferred mixtures o~ minoxidil and a hair growth promoter according to the invention include the : following:
Minoxidil and N-acetyl glycine Minoxidil and N-acetyl methionine Minoxidil and N-acetyl aspartic acid and Minoxidil and N-lauroyl citrulline vi. Ethylenediaminetetraacetic acid or salts thereof, as described by Redken Laboratories, Inc. in US 4 814 351.
vii. Direct proteoglycanase inhibitors, such as 1,10-phenanthroline, a described by Unilever in EP-0 277 428.
viii.Glycosaminoglycanase inhibitors, as described by Unilever in EP-0 277 428, such as aldonolactones and esterified aldonolactones having the structure (16):
Al B - c2 _ H
B~ C3 - H (16) B - f4_ H
A
~D' OD
where Al and A2 are -H, CH3,-C = 0 or -C = p B is OD" or a lactone linkage to position 1 or 6, or -N~COCH3 and where D is -H or C2 to C8 alkyl, D' is the remainder of the molecule joined -through another C atom at positions 2 to 5 to form a lactone, 3~ V" is -H or C2 (ie acetyl) to C4 acyl of either configuration with respect to the backbone of this molecule;
' preferred examples of which include:
L-Galactono-1,4-lactone L-Arabino-1,5-lactone - D-Fucono-1,5-lackone D-Glucaro-1,4-lactone D-Glucurono-6,3-lactone Galactaric acid lactone 2-Acetamido-2-deoxygluconolactone 2-Acetamido-2-deoxygalactono-lactone D-Glucaro-1,4:6,3-dilactone L-Idaro-1,4-lactone 2,3,5-Tri-0-acetyl-~-glucaro-1,4-lackone 2,5-Di-0-acetyl-D-glucaro-1,4:6,3-dilackone, ix. Glycosaminoglycanase inhibitors, as described by Unilever in EP O ~77 428, such as monosaccharides and esterified monosaccharides having the structure (17):
CXO
H C - A
H -C -OG
(17 H - C OG
I
H - C ~ ~OG
C~2GI -where A is -OG or -NHCOCH3 3s G is ~H, -SO3M", C2 (ie acetyl) to C4 acyl : - 20 - J3121 G' is -H or -OG
~" is -H or a metal cation wherein the functional groups can be in either configuration with respect to the backbone of the above ; molecule;
preferred examples of which include:
N-Acetylglucosamine N-Acetylgalactosamine D-Galactosamine D-Glucosamine-3-sulpha-te N-Acetylmannosamine.
x. Glycosaminoglycan chain cellular uptake inhibitors, as described by Unilever in EP O 277 428, such as hexuronic acid and esters thereof which may be represented by the generic structure (18):
C~IO
: 25 H - C OG
I
~ _ C- 0~ (18) H - C - -OG
H - C - OG
where G is -H, -S03M", C2 (ie acetyl) to C4 acyl;
: , ,. . ..
! ,- ,, / ,,. ` J l.,s ~) D is -H or C2 to C~ alkyl M" is -H or a metal cation;
wherein the functional groups can be in either s configuration with respect to the backbone of the above molecule;
xi. Chemical inhibitors of glycosidase activity, as described by Unilever in EP 0 334 586, chosen from lactams having the structure (19):
Q - C - H
I
Q - C -H (19) Q C H
I
2s where A3 and A4 are -H, -CH3, -C-0, -CH2OT
or -C=0, A3 and A4 being the same or different, and at least one of which being the group:
-NH
~5 -C=0 , ~- "J .". , . " ~I
in a lactam ring;
and where Q is -OT', -NHT' or a lactam linkage ko A3 or A4;
the Q groups being the ~ame o;r different, and at least one of which is involved in a lactam linkage;
and wherP T is the same or different and is chosen from lo -H, -CpH2p+1 or a metal ion, , p is an integer of from 1 to 22;
provided that:
where any of the Q groups is -OT' or -NHT', then that group or groups can be of either stereochemical configuration with respect to the plane of the ring, preferred examples of which include:
D~glucaro-1,5-lactam, L-Galactono-1,4-lactam, L-Arabino-1,5-lactam, D-Fucono-1,5-lactam, D-Glucaro-1,4-lactam, - D-Glucurono--6,3-lactam, ~5 1,2,5-tri-0--acetyl-D-glucurono-6,3-lactam, 2-Acetamido--2-deoxygluconolactam, , .
; 2-Acetamido-2-deoxygalactonolactam, D-Glucaro-1,4:6,3-dilactam, L-Idaro-1,4-lactam, 2,3,5-Tri-O-acetyl-D-glucaro-1,4-lactam, 2,5-Di-O-acetyl-D-Glucaro-1,4:6,3-dilactam, D-glucaro~ -lactam ethyl ester;
xii. Chemical activators o~ protein kinase C enzymes, as described by Unilever in EP 0 334 585 chosen from diacylglycerols having the structure (20):
H -C-OH
:~ I
H -C-OX (20) H2-C-OX ' where X and X' are the same or different and is represented by the grouping:
~~-[(CH2)a, (CH=CH)b] CH3 where x is O or an integer of from 1 to 28, and y is 0 or an integer c>f Prom 1 to 5;
the X and X' groups being of either stereochem;cal configuration with respect to the carbon backbone of the glycerol molecule;
preferred examples of which include:
~5 1,2-Oibutanoyl-rac-glycerol 1,2-Dihexanoyl-sn-glycerol 1,2-Dioctanc)yl-rac-glycerol . " ~
.
1,2-Dioctanoyl-sn-glycerol 1,2-Didecanoyl-rac-glycerol l-Oleoyl-2-acetyl-rac-glycerol 1-Oleoyl-2-acetyl-sn-glycerol 1-Stearoyl-2-arachidonoyl-sn-glycerol 1,2-Distearoyl-rac-glycerol : 1,2-Dipentadecanoyl-sn-glycerol 1,2-dipentadecanoyl-rac-glycerol 1,2-Dipalmitoyl-rac-glycerol 1,2-Dipalmitoyl-sn-glycerol 1,2-Diseptadecanoyl-rac-glycerol 1,2-Dioleoyl-sn-glycerol 1,2-Dioleoyl-rac-glycerol 1,2-Diarachidonoyl-sn-glycerol 1,2-Dieicosanoyl-sn-glycerol 1,2-Didoeicosanoyl-rac-glycerol, and 1,2-Dioctaeicosanoyl-sn-glycerol.
xiii.Glycosaminoglycanase inhibitors, as described by Unilever in EP 0 348 184, chosen from aldonomonolactone or alduronomonolactone derivatives having the structure (21): .
2s A
Bl _ 12 ~ ~
B2 _ ~3_ H (21) B3 ~ C4 - H -~. ~ ., .
.
oR5 oR4 oR6 where A5 is -C=O, -C=O or -C-OQ;
oR5 oR4 A6 is -C=O, --C=O or CH20R6 B1, B2, B3 and B4 a~re each chosen from is oR
NHR6, NHR7 or a lac:tone linkage to position 1 or 6,and/or an ether linkage to Ql;
said substituents B being the same or different, and being in either configuration, with respect to the backbone of the above structure, on ,~
positions CG to C5 not involved in a lactone ring;
and where R4 is -H, C1 to C20 alkyl, a metal cation, or an alkanolamine cation;
R5 is the remainder of the molecule joined through another C atom at positions 2 to 5 to form a lactone;
R6 is -H, -CH3, benzyl or C2 to C~ acyl;
R7 is -H, -CH3, benzyl or C3 to C6 acyl;
Ql is the remainder of the molecule joined through an ether linkage to either C4 or C5, -forming either a pyranose or furanose ring;
. H oR5 provided that, when A5 is -C=o, then A6 is ~=O;
, .
provided also that, when A6 is CH20H, then one or more of the B substituents is -CH3, C2 to C4 acyl or NHR7;
oR5 provided also that, when A5 is -C=O, and all B1, B2, B3 and B4 substituents are -OH, then OR
lo A is -C=O or CH20R6, and R4 is Cl or Cg to C20 alkyl;
preferred examples of which aldonomonolactone ~erivatives : include:
6-acetyl-galactono-1,4-lactone 6-propionyl-galactono-1,4-lactone 6-butyryl-galactono-1,4-lactone 2-propionamido-2-deoxygluconolactone 2-butyramido-2-deoxygluconolactone 2-propionamido-2-deoxygalactonolactone 2-butyramido-2-deoxygalactonolactone 6-propionyl-2-acetamido-2-deoxygluconolactone diacetyl-6-propionyl-2-acetamido-2-deoxygluconolactone 6-butyryl-2-acetamido-2-deoxygalactonolactone diacetyl-6butyryl 2-acetamido-2-deoxygalactonolactone 2,3,5,6-tetraacetyl-galactono-1,4-lactone 2,3,5-triacetyl-6-propionylgalactono-1,4-lactone triacetyl-2-propionamido-2-deoxygalactonolactone ~o triacetyl-2-butyramido-2-deoxygluconolactone 6-methyl-glucaro-1,4-lactone 2,3,5,6-tetramethyl-glucarool,4-lactone 6-methyl-2,3,5-triacetyIglucaro-1,4-lactone 6-methyl-3-methyl-glucaro-1,4-lactone, and ~5 6-methyl-3-acetyl-glucaro-1,4-lactone;
: ., .,. ~, , , :
~ ~ .
- -.. . . .
- 27 - ~3121 and a preferred example of which alduronomonolactone derivative is:
1,2,5-triacetyl-glucurono 6,3-lactone.
: 5 xiv. Glycosaminoglycanase inhibitors, as describ~d by Unilever in EP O 348 18~, chosen from acylated monosaccharides having the st:ructure (22):
H c2 _ A7 H _ C3 oY
H - 14 B5 (22) where A7 is -OY or -NHR8 B5 and B6 are each chosen from is -OY, or an ether linkage to Dl, Dl is -CHOYI where x2 is an ether linkage xl either to C4 or C5 forming a pyranose or ~uranose ring;
Y is -H, -S03M, C2 to C4 acyl or C1 to C18 alkyl;
.
' ' :
.
- 28 - ~3121 ... .
said substituents A7, B5, B6 and -OY being the same or different, and being in either configuration, with respect to backbone o~
the above structure;
s and where zl is -H or -OY
R8 is ~H, _S03~2 or C3 or C4 acyl, M is -H, a metal cation, NH4+, or an alkanolamine cation;
provided that, when R8 is -H, then 1 or more of Y is chosen from -S03M2 or C2 to C4 acyl;
and mixtures therPof.
Preferred examples of which acylated monosaccharides include:
2-propionamido-2-deoxyglucose 1,3,4,6-tetraacetyl-2-propionamido-2-deoxyglucose 2-butyramido-2-deoxygalactose 1,3,4,6-tetraacetyl-2-butyramido-2-deoxygalactose 2-sulphamido-2-deoxygalactose 2-sulphamido-2-deoxyglucose 2-butyramido-2-deoxymannose 1,3,4,6-tetraacetyl-2-butyramido-2-deoxymannose 2-butyramido-2-deoxyglucose, and 1,3,4,6-tetraacetyl-2-butyramido-2-deoxyglucose.
xv. Esters of pyroglutamic acid, as described by ~ever : 30 Brothers CoDpany in US patent No. 4 774 255, having the structure ~23): -` ' ' ' ' .
.. . .
' .
~ ~ J-~, f ~ ,3 S ~
0~ N C-~-R1 (23) lo where R1 is Cl to C30 alkyl, or-CHCOOR"
and where R and R3 are the same or different and are each represented by H or the grouping (24):
[(CH ) , (CH2oH~v, (CH2)w, (CH3CH2)x, ~ y z (24) where u is z~ro or 1 v is zero, or the integer 1 or 2, w is zero, or an integer of from 1 to 21 x is zero, or an integer of from 1 to 4, y is zero, or the integer 1 or 2, z is zero, or an integer of ~rom 1 to 4, and u + v + w + x + y + z is an integer of from 1 to 22;
provided that when the subgrouping (CH=CH) is present, then the total number of carbon atoms in said grouping is from 10 to 22.
.
Examples of suitable esters of pyroglutamic acid where R1 in structure (23) is C1 to C30 alkyl are:
pyroglutamic acid methyl ester - pyroglutamic acid ethyl ester ~5 pyroglutamic acid n-propyl ester pyroglutamic acid n-butyl ester pyroglu1:amic acid n-hexyl ester : . , ~, ~ - , ' '. ~ , ' - . ~ .
. .
_ 30 _ ~3121 ;
pyroqlutamic acid n-heptyl ester pyroglutamic acid n-octyl ester pyroglutamic acid n~nonyl ester pyroglutamic acid n-decyl ester pyroglutamic acid n-undecyl ester : pyroglutamic acid n-dodecyl ester pyroglutamic acid n-tridlecyl ester pyroglutamic acid n-tetr,adcyl ester pyroglutamic acid n-hexadecyl ester pyroglutamic acid n-octadecyl ester pyroglutamic acid n-eicosyl ester pyroglutamic acid iso-propyl ester pyroglutamic acid 2-methylhexyl ester pyroglutamic acid 2-ethylhexyl ester pyroglutamic acid 3,7-dimethyloctyl ester pyroglutamic acid 2-hexyldecyl ester pyroglutamic acid 2-octyldodecyl ester pyroglutamic acid 2,4,4-trimetyl-1-pentane ester pyroglutamic acid methyloctyl ester Particularly preferred esters of this group are those where R1 in structure (23) is C1 to C14 alkyl, (linear or branched), especially C1 to C6 (linear.or branched).
Further examples of preferred esters of pyroglutamic acid, where R1 in structure (23) is -CHCOOR , are those where R and/or R having the structure shown for grouping (24), include straight and branched chain, saturated or unsaturated aliphatic groups having from 1 to 22 carbon atoms, such as the alkyl groups:
'' '- . ' . ' :'. ~ : : : .
.. ::
.
-.. .
methyl ethyl propyl iso-propyl butyl iso-butyl n-valeryl iso-valeryl n-caproyl n-heptyl n-caprylyl n-capryl lauryl myristyl palmityl stearyl, and arachidyl.
20 and the C10 22 alkenyl groups:
linoleyl linolenyl . ~ -linolenyl arachidonyl, and columbinyl.
Further examples o~ the grouping (24) also include hydroxyalkyl groups having from 1 to 22 carbon atoms, 30 such as:
hydroxymethyl 2-hydroxyethyl 2-hydroxy-n-propyl 3s 3-hydroxy-n-propyl 2-hydroxy-n-butyl 3-:hydroxy-n-butyl , . . , . ~ , : . .
:
': ,, .: : .
.. . : . - . , . - - .
, - 4-hydroxy~n-butyl 5-hydroxy-n-valeryl 6-hydroxy-n caproyl 2,3-dihydroxy-n-propyl 2,3-dihydroxy-n-butyl 12-hydroxystearyl.
Further specific examples of esters of pyroglutamic : acid which are particularly suited ~or use as other hair growth stimulants are:
2-[pyroglutamoyloxy]-propionic acid methyl-2-[pyroglutamoyloxy]-acetate S ethyl-2-[pyroglutamoyloxy]-n-propionate ethyl-2-[pyroglutamoyloxy]-n-butyrate ethyl-2-[pyroylutamoyloxy]-iso-butyrate ethyl-2-[pyroglutamoyloxy]-n-valerate ethyl-2-[pyroglutamoyloxy]-n-caproate ethyl-2-[pyroglutamoyloxy]-n-heptylate ethyl-2-[pyroglutamoyloxy]-n-caprylate ethyl-2-~pyroglutamoyloxy]-n-pelargonate ethyl-2-[pyroglutamoyloxy]-3-hydroxybutyrate . iso-propyl-2-[pyroglutamoyloxy]-n-propionate 2 5 iso-propyl-2 - E pyroglutamoyloxy] -n-caprylate n-propyl-2-[pyroglutamoyloxy]-n-propionate n-propyl 2-[pyroglutamoyloxy~-n-caprylate stearyl-2-[pyroglutamoyloxy3-n-propio~ate 12-hydroxystearyl-2-[pyroglutamoyloxy]-n-propionate 3 0 stearyl-2-[pyroglutamoyloxy~-n-~tearate palmityl-2-~pyroglutamoylo~r]-n-prop~onate linoleyl-2-[pyroglutamoyloxy~-n-propionate linoleyl-2-[pyroglutamoyloxy]-n-caprylate lauryl-2-~pyroglutamoyloxy]-n-caprylate : ~S steary:L-2-~pyroglutamoyloxy] n-~aprylate glyceryl mono(2-[pyroglutamoyloxy]-n-propionate) glyceryl mono(2-tpyroglutamoyloxy]-n-caprylate), and .
' . - . ~
.. . .. . . .
, ....... -~ ;
. .
, _ 33 - J3121 glyceryl di(2-~pyroglutamoyloxy]-n-propionate).
xvi. hexosaccharic acids or an acylated hexosaccharic acids, or salts or esters thereof, having the structure (25):
COO
~HOY2 CHOY
lo IHoY4 XlnX m (~5) where Xl is chosen from H, alkalimetal, ammonium and substituted ammonium counterions;
X is chosen from an alkyl or hydroxyalkyl group having from 1 to 18 carbon atoms;
yl~ y2~ y3 and Y4 are each chosen from H, an alkyl group having from 1 to 12 carbon atoms, and an acyl group having from 1 to 2s 18 carbon atoms;
l is an integer of ~rom 1 to 3;
m and n are aach O or the integer 1 or 2; and m+n is l or 2.
Examples of hexosaccharic acids, in which Xl, yl~
y2~ y3 and Y4 in the above structure are -~, n is 2, and m is 0, include:
Allosaccharic acid - - . : . . . :
,. . : . ~ , . : .
., . : , ' _ 34 - J3121 Altrosaccharic acid ~lucosaccharic acid ~annosaccharic acid Gulosaccharic acid Idosaccharic acid Galactosaccharic acid, and Talosaccharic acid.
~ lo Examples where X1 s a cation, are the monovalent ; alkali metal cations Na and K .
Further examples where X1 is a cation are substituted ammonium cations, such as diethanolammonium and triethanolammonium cations.
Examples where x2 is an alkyl group are methyl, ethyl, n-propyl, n-butyl, n-octyl and lauryl.
Examples where yl~ y2~ y3 and Y4 are alkyl groups, are methyl and ethyl.
Examples where yl~ y2~ y3 and Y4 are acyl group, are acetyl and propionyl.
2s A particularly preferred hexosaccharic acid is glucosaccharic acid (also known as saccharic acid or ; glucaric acid, and hereinafter referred to as glucaric acid) having the structure (26):
COOH
H-C-OH
HO-C-H
H-C-OH (26) ~5 H-C-OH
COOH
. - , : : , ' ,:
: , : , .
': : . , '- . - ' ' - : "
~ ' ' . ' , - .. , ~ .. ..
_ 35 _ J3121 - A particularly stable salt of glucaric acid which is preferred, is the disodium salt.
xvii.aryl-substituted ethylenes having the structure ~27) s R ~7 R~
s (~7) R~ R~
where Rl, R2, R3, & R4 are the same or different, and are chosen from -H~ -OH, ~CnH2n+1, -N02, -Cl, -Br, -F
o and -CH;
and where R5 ~ R6 are the same or different, and are chosen from:
2r 0 0 S
11 ~
-H, -CN, -COH, -CNH2 and -CNH2;
and where R7 is chosen from -H and -OH
and where n is an integ~r o~ from 1 to 8.
The composition according to the invention can also comprise mixtures of said inhibitors.
Examples of the aryl-substituted ethylenes include ~5 1-carboxy-2--(4-hydroxyphenyl~ethylene , ~ . ,' ~' : '. ' , . ' '.
. . . ~ . ~ : .
,J ' ~ r 1 dicarboxy-2-(4-hydroxyphenyl)ethylene 1,1-dicyano-2-(4-hydroxyphenyl)ethylene 1-carboxy-2-(3,4-dihydroxyphenyl~ethylene 1,1-dicyano-2-(3-hydroxyphenyl)ethylene 1-cyano-1-carboxy-2-(2,5-dihydroxyphenyl)ethylene l-carboxy-1-cyano-2-(3,4-dihydroxphenyl)ethylene 1,1-dicyano-2-~3,4-dihydroxyphenyl)ethylene 1,1-dicyano-2-(3-methQxy-4,5-dihydroxyphenyl)ethylene 1,1-dicyano-2-(3,4,5-trihydroxyphenyl)ethylene 1-amido-1-cyano-2-~3,4-dihydroxyphenyl)ethylene l-thioamido-l-cyano-2-(3,4-dihydroxyphenyl)ethylene l-cyano-2-(4-hydroxyphenyl)ethylene 1,1-dicyano-2-(3-hydroxy-4-nitrophenyl)ethylene 1,1-dicyano-2-hydroxy-2-(4-hydroxyphenyl)ethylene 1,1-dicyano-2-(3-methoxy-4-hydroxyphenyl)ethylene 1,1-dicyano-2-(3,5-dihydroxyphenyl)ethylene 1,1-dicyano-2-hydroxy-2-(3,4,5-trihydroxyphenyl)ethylene 1-carboxy-1-cyano-2-(4-methoxyphenyl)ethylene 1-carboxy-1-cyano-2-(4-fluorophenyl)ethylene 1-carboxy-1-cyano-2-(3-methoxy-4-hydroxyphenyl)ethylene 1-carboxy-1-cyano-2-(3,5-dimethoxy-4-hydroxyphenyl)ethyl-ene 1-carboxy-1-cyano-2-(4-hydroxyphenyl)ethylene 1-carboxy-1-cyano-2-(4-phenylcarboxyaldehyde)ethylene s 1-cyano-1-carboxy-2-(2,5-dihydroxyphenyi)ethylene (b) Penetration Enhancers As has been stated earlier, the presence of a penetration enhancer can potentiate the benefit of the hair growth promoter by improving its delivery through the stratum corneum to its site of action in the immediatP environment of the hair follicle close to the ~5 dermal papilla.
.
.
.' ., ~ . . .
r3 - 37 - ~3121 The penetration enhancer can accordingly function in a variety of ways. It can *or example, improve the distribution of the hair growth promoter on the skin surface or, it can increase its partition into the skin from the composition when applied topically, so aiding : its passage to its site of action. Other mechanisms enhancing the benefit o~ the ~hair yrowth promoter may also be involved.
Examples of penetration enhancers include:
2-methyl propan-2-ol Propan-2-ol lS Ethyl-2-hydroxypropanoate Hexan-2,5-diol POE(2) ethyl ether Di(2-hydroxypropyl) ether Pentan-2,4-diol Acetone POE(2) methyl ether 2-hydroxypropionic acid 2-hydroxyoctanoic acid Propan-l-ol 2s 1,4 Dioxane Tetrahydrofuran Butan-1,4-diol Propylene glycol dipelargonate Polyoxypropylene 15 stearyl ether Octyl alcohol POE ester o~ oleyl alcohol Oleyl alcohol Lauryl alcohol Dioctyl adipate 3 5 Dicapryl adipate Diisopropyl adipate Diisopropyl sebacate .~ .
.
.
.'' '....... ' . "' :
.. . . . :
:
: : , :.
;' ~' I J , ~ , - 3~ ~J3121 - Dibutyl sebacate Diethyl sebacate Dimethyl sebacate Dioctyl sebacate Dibutyl suberate Dioctyl azelate Debenzyl sebacate Dibutyl phthalate lo Dibutyl azelate Ethyl myristate Dimethyl azelate Butyl myristate Dibutyl succinate lS Didecyl phthalate Decyl oleate Ethyl caproate Ethyl salicylate Isopropyl palmitate Ethyl laurate 2-ethyl-hexyl pelargonate Isopropyl isostearate Butyl laurate Benzyl ben20ate Butyl benzoate Hexyl laurate Ethyl caprate Ethyl caprylate Butyl stearate Benzyl salicylate 2-hydroxypropanoic acid 2-hyroxyoctanoic acid, Further examples of penetration enhancers include:-~S
Dimethyl sulphoxide .
.' ' ' ' .
, 7J ' ~
N,N-Dimethyl acetamide N,N-Dimethyl formamide 2-Pyrrolidone l-Methyl-2-pyrrolidone : 5-Methyl-2-pyrrolidone 1,5-Dimethyl-2-pyrrolidone l-Ethyl-2-pyrrolidone Phosphine oxides Sugar esters Tetrahydrofurfural alcohol Urea Diethyl-m-toluamide, and l-Dodecylazacyloheptan-2-one Further examples of penetration enhancers include surface active agents, preferred examples of which include:
(i) Anionic surface active agents, such as metallic or alkanolamine salts of fatty acids for example sodium laurate and triethanolamine oleate;
alkyl benzene sulphonates, for example triethanolamine dodecyl benzene sulphonate;
alkyl sulphates, for example sodium lauryl sulphate;
alkyl ether sulphates, for example sodium lauryl ether sulphate t2 to 8 EOJ;
sulphosuccinates, for example sodium dioctyl - sulphosuccinate;
3s monoglyceride sulphates, for example sodium glyceryl monostearate monosulphate;
: ' :
.
' , ' ' . .
s' )~J-3lJ JV
_ ~0 _ J3121 isethionates, for example sodium isethionate;
methyl taurides, for example Igepon T;
acylsarcosinates, for example sodium myristyl : sarcosinate;
acyl peptides, for example Maypons and Lamepons;
, 10 acyl lactylates, polyalkoxylated ether glycollates, for example trideceth-7 carboxylic acid;
phosphates, for example sodium dilauryl phosphate.
(ii) Cationic surface active agents, such as amine salts, for example sapamin hydrochloride;
quartenary ammonium salts, for example . Quaternium 5, Quaternium 31 and Quaternium 18;
2s (iii) Amphoteric suface active agents, ~uch as imidazol compounds, for example Miranol;
N-alkyl amino acids, such as sodium cocaminopropionate and asparagine derivatives;
betaines, for example cocoamidopropylbetaine (iv) Nonionic surface active agents, such as fatty acid alkanolamides, for example oleic ethanolamide;
.
' ~
-.
~; ~ J , ~ s, ~3 - 41 - ~3121 esters o~ polyalcohols, ~or example Span;
polyglycerol esters, for example that esterified with C12_18 fat~y acids and one or several OH groups;
polyalkoxylated derivatives, for example polyoxy:polyoxyethylene stearate, and octylphenoxy polyethoxyethanol (TRITON X~100) ethers, for example polyoxyethylene lauryl ether;
ester ethers, for example Tween;
amine oxides, ~or example coconut and dodecyl dimethyl amine oxides.
Mixtures of two or more of the above sur~ace active agents can be employed in the composition according to the invention.
(c) cationic polymers chosen from:
Guar Hydroxypropyltrimonium chloride Quaternium l9 Quat~rnium-23 Quaternium-40 3 O Quaternium-57 Poly~dipropyldiallylammonium chloride~ -Poly(methyl ~ -propaniodiallylammonium chloride) Poly(diallylpiperidinium chloride) Poly(vinyl pyridinium chloride~
Quaternised poly (vinyl alcohol) Quaternised poly ' . ', : . ' ' . ' . ' .:' ':
:...... '- ' ,, ' ' ~, ~' .
- \
- ~2 - J3121 (dimethylaminoethylmethacrylate); and mixtures thereof The amount of activity enhancer, when employed in accordance with the invention, will normally be from 0.1 to 50%, preferably from 0.5 to 25% and most preferably from 0.5 to 10% by weight of the composition.
Other hair qrowth promoter adiuncts The composition according to the invention can also contain adjuncts other than those already mentioned, depending on the form of the intended product. It is, for example, possible to include antiseptics, preservatives, antioxidants, emulsifiers and colouring agents, which can improve the stability and consumer appeal of the composition.
The composition according to the invention can also be employed as a vehicle ~or a wide variety of cosmetically or pharmaceutically active ingredients, particularly ingredients which have some beneficial 2s effect other than the promotion of hair growth when applied to the skin.
Process The invention also provides a process for the pr~paration of a composition suitable for topical application to mammalian skin or hair which comprises mixing a hair growth promoter as herein de~ined, with a suitable vehicle to provide a composition according to 3S the invention, in which the hair growth promoter ~orms from 0. 0001 to 99% by weight of the composition.
_ ~3 _ J3121 ;Product Form and Container The compositions of the invention can be formulated as liquids, for example as a lotion, shampoo, milk or cream for use in conjunction with an applicator such as a roll-ball applicator, or a spray device such as an aerosol can containing propellant, or a container fitted with a pump to dispense the liquid product. Alternatively, the compositions of the invention can be solid or semi-solid, for example sticks, creams or gels, ~or use in conjunction with a suitable applicator or simply a tube, bottle or lidded jar, or as a liquid-impregnated fabric, such as a tissue wipe.
The invention accordingly also provides a closed container containing a composition as herein defined.
Use of~the hair qrowth promoter_for Inducin~.
Maintaining_Qr Increasinq Hair Growth The invention also provides for the use of hair growth promoter as herein defined, for topical application to mammalian skin or hair for inducing~
maintaining or increasing hair growth.
The compositions according to the invention are primarily intended for topical application to the scalp of the human subject, particularly where the head is o already bald or balding, in order to promote the regrowth of terminal hair. The comp~sitions can also be applied -profilactically to the hair and hence the scalp to reduce or prevent the onset of baldness.
~5The amount of the composition and the frequency of application to the hair and/or scalp can vary widely, depending on personal needs, but it is suggested as an ',' :
,. '..... - - : , ~r~
_ .g4 ~ J3121 example that topical application of from 0.1 to 5g daily containing from 0.00001 to lg of a selected chemical inhibitor over the period of at least six months will in most cases result in an improvement in hair growth.
s , EVALUATION OF EFFICACY OF THE HAIR GROWTH PROMOTERS
ySING THE RAT MODEL
The Rat Hair Growth_~est The effect oE compounds on hair growth was assesced using male albino Wistar rats as an animal model. The rats were chosen from as few litters as possible and were each approximately 42 days of age at the start of the ; test. Each rat was housed individually to prevent licking.
In each comparison, 10 rats were used in each qroup and hair growth was assessed as ~ollows:
A small patch of normal skin (4cm x 4cm) on the upper back of each rat was clipped at the start and 0~3 ml of a hair growth stimulant composition (or a control) applied topically twice daily and once on Saturdays and Sundays to each clipped area. The concentration of test compound in the composition was chosen from 0.01 to 20 ~ by weight.
It is to be understood that the potency of each of the hair growth promoters in terms of its ability to induce, maintain or increase hair growth is unlikely to be uniform, some being more potent than others, and ~5 therefore the concentration of any promoter chosen fox - thorough evaluation must be carefully selected after preliminary testing to determine its potential as a hair f ~ ~ ~
- 45 - ~3121 growth promoter. In any case, this concentration will lie within the range of from 0.01 to 20% by weight as stipulated above.
Hair was clipped from the area of the patch twice weekly, collected and weighed at each time point over a standard period of 3 months, and cumulative hair weight calculated. From these data, it was possible to estimate lo the e~fect of a hair growth promoter acid as a hair growth stimulant (test compound) on the amount and duration of hair growth during the experiment. A
positive response, i.e. an increase of at least 10% by weight of hair after 3 months treatment, compared with a control indicates the potential of the test compound to prevent hair loss and/or reverse baldness in human subjects.
Accordingly, when the hair growth promoters as herein defined, are assessed either individually or in combination as test compound by the Rat Hair Growth Test, an increase of at least 10~ by weight oP hair after 3 months treatement will be obtained. Usually, the 10~ by weight minimum value will be attained well be~ore the end of this 3 months period Measurement of hair ~rowt ~ ical~a~plication of N-acetyl qlycine Topical treatment with a composition according to the invention was found to stimulate hair growth. In -this example, the effect o~ topical application of N-acetyl glycine is shown. The test solution in this experiment contained 10% (w/v) ~f the N-acetyl glycine in the form of a solution in distilled water adjusted to pH
4.2 with potassium hydroxide. The hair growth results are shown below in Table 1.
. ' ' ' ' "' " ''~ ' ' ~ ~
:' :
'. ' ,' ~ :
J
Table 1 ~ .... __ .~ _m ~ , . _.
Trea_ment Mean Cumulative SigniPicance Hair ~eight (mg) Level + sd, af.ter 58 days (vs control) _ _ . _ ._ ~
10% (w/v) N-acetyl glycine 622.8 1 101.11 p =0.02 Control (dis. water adjusted to pH 4.2) 505.9 + 103.1 , _ __ ............. .... __._ . _.
* statistically significant These results indicate that a statistically significant increase (23%) in hair growth was obtained in this experiment.
Examples The invention is illustrated by the following examples.
Example 1 2s This Example illustrates a lotion according to the invention which is suitable for topical application to the scalp in order to promote hair ~rowth.
.
The lotion has the following ~ormulation:
N-acetyl glycine 0.1 ethanol 99.995 perfume q.s.
3s _ 47 - J3121 Example 2 This Example illustrates a hair tonic which is suitable for application to h,air or scalp.
The hair tonic has the following formulation:
., % w/w N-acetyl alanine 0.8 ethanol 50 water 49 perfume . q-S-lS Example 3 This Example also illustrates a lotion which is suitable for topical application to the scalp.
The lotion has the following formulation:
% w/w N-acetyl valine 1.5 propan-2-ol 10 ethanol 88.5 perfume q~s.
~o . .
.' , ~ ' ' .
-- fj r~ r j 3 , ~ Example 4 `':.
This Example also illustrates a hair tonic which is suitable for application to hair or scalp.
s The hair tonic has the following formulation:
% w!W
N-acetyl leucine 0.2 .! 10 ethanol 40 water 59.80 perfume q.s.
., ExamPles 5 to 8 The followinq formulations represent lotions which can be used topically in the treatment of bald or balding male or female heads.
% wlw Hydroxyethyl cellulose 0O4 - 0.4 Absolute ethanol25 25 25 25 Propane-1,2-diol - - 38.4 38.4 Butane-1,3-diol38.4 38.8 - -Paramethyl benzoate 0.2 0.2 0.2 0.2 N-acetyl isoleucine 5 - - -N-acetyl phenylalanine - 1 - -N-acetyl tyrosine - - o.~ _ N-acetyl proline - - - 0.6 Perfume Water to 100 100 100 100 3s s, ~ r~ r.
~ 49 ~ ~3121 Examples 9 to 12 The following formulations represent creams which can be used in the treatment of baldness.
% wlw Cetyl alcohol lopolyoxyethylena (10) 4 4 4 4 Cetyl alcohol 4 4 4 4 Mineral oil 4 2 - -Paraffin wax - 2 4 Partial glyceride of palmitic and stearic acids - - - 4 N-acetyl hydroxyproline 2 N-acetyl serine - 1~5 N-acetyl threonine - - 2 N-acetyl cysteine Triethanolamine 0.75 0.75 0.75 0.75 Butane-1,3-diol 3 3 3 3 Xanthan gum 0.3 0.3 0.3 0.3 Preservative 0.4 0.4 0.4 0.4 Perfume q.s. q.s. q.s.
~.s.
Water to 100 100 100 100 . ~
.: . .
? ~ : -.
:
; _ 50 - J3121 ' Example 13 ~ his Example illustrates a water-in-oil high internal phase emulsion ~ontaining an ester according to the invention.
The emulsion consisted o~E 10% by volume oily phase and 90% by weight aqueous phase~
The oil~ phase and the aqueous phase had the following constitution: keel ~_w/w Oily phase Sorbitan monooleate 20 ~uaternium-18 hectorite 5 Liquid paraffin75 Aqueous phase N-acetyl cystine0.5 Xanthan gum Preservative 0.3 Perfume q.s.
25 Sodium chloride (1% w/w solution) to 100 The emulsion was prepared by taking 10 parts by volume of the oily phase and to it adding slowly with stirring 90 parts by volume of the agueous phase.
The high internal phase water-in-oil emulsion so formed can be applied topically to the scalp, to improve hair growth and regrowth.
.
The following examples 14 to 18 illustrate shampoos for use in washing the hair and scalp, and for promoting hair growth on the scalp.
ExamPle 14 % w/w Sodium lauryl ether sulphate (2 EO) [~1% AD~ 41.4 Lauryl dimethylamino acetic acid betaine: [30% AD] 4 Coconut fatty acid diethanolamine 1.5 Oleyl triethoxy phosphate (BRIPHOS 03D) Polyglycol-polyamine condensation resin (POLYQUART H) [50% active] 1.5 Preservative, colouring matter, salt 0.58 N-acetyl methionine 5 Perfume q.~.
Water to 100 . Example 15 % w~w Sodium lauryl ether sulphate (2 EO) [100% AD~ 12 BRIPHOS 03D 2.5 N-acetyl tryptophan 4 -Magnesium Sulphate 5 Perfume q. s .
Water to 100 3s ' - 52 - ~3121 Example 16 This Example also ill~strates a lotion which is suitable ~or topical applicati.on to the scalp.
The lotion has the ~ollowing formulation:
N-acetyl aspartic acid 1.5 propan-2-ol 10 athanol 88.5 perfume q.s.
Example 17 This Example also illustrates a hair tonic which is suitable for application to hair or scalp.
The hair tonic has the following formulation:
'' ~6 W/W
N-acetyl glutamic acid 0.2 ethanol 40 2s water 59.80 per~ume q.s.
~o . - 53 - J3121 . .
Example 18 % w/w Monoethanolamine lauryl sulphate :
[100% AD] 20 JAGUAR Cl3S 3 BRIPHOS 03D 1.7 Coconut diethanolamide 5 lo N-lauroyl glycine Zinc gluconate 3 Perfume q.s.
Water to 100 pH adjusted to 6.5 Example 19 % w/w 20 Sodium lauryl ether sulphate (3 EO) :
~100% AD] 12 JAGUAR C13S 0.3 N-palmitoyl glycine 2 Sodium chloride 4 Perfume q.s.
Water to 100 , pH adjusted to 6.5 ~5 , .
.
3 s ~ ~
_ 54 ~3121 .
~ Example 20 % w/w Sodium lauryl ether sulphate ( 2 EO) [100% AD] 12 Opacifier 9 N-myristoyl glycine 5 Perfume ~.s.
Water to 100 p~ adjusted to 6.5 Examples 21 This example illustrates a powder composition according to the invention which can be applied topically to the scalp.
% w/w Chemically modified starch 5 Chemically modified cellulose : 25 Boric acid 10 Zinc oxide 5 N-lauroyl hydroxyproline 3 Minoxidil glucuronide 5 Perfume q.s.
Chalk 10 Talc to 100 -~s ~3~ J~ 3 - 55 - ~3121 Example 22 The following example illustrates a lotion according to the invention which can be applied topically to the scalp to prevent hair loss and stimulate hair regrowth.
N-palmitoyl aspastic acid 7 Minoxidil 0.2 ethanol 16 citric acid 1.05 water to 100 pH adjusted to 4.2 with sodium hydroxide Examples 23 & 24 These examples illustrate hair tonics which are ~uitable for application to the hair and scalp.
The hair tonics had the following formulation:
% w/w N-octanoyl glycine 2 - -N-octanoyl hydroxyproline - 3 ethanol 50 50 water 48 47 perfume q.s. q.s.
: '.: . ' .
~ ,, , ' ~ ~ ~3~
;' Example 25 This example illustrates a microgel which is suitable for topical application to hair or scalp.
The gel had the following formulation-w A. Polyoxyethylene (10) oleyl ether 14.5 Polyoxyethylene fatty glyceride 14.5 Light liquid petroleum 13.7 Propylene glycol 7.6 50rbitol 5.9 N-hexanoyl glycine 4 B. Perfume q.s.
C. Water to 100 This microgel was prepared by heating part A to 90C
and part C to 95C and then adding part C to part A with stirring. Part B was then added at 70C and the final mixture cooled and poured into jars at 55C to 60C. On further cooling, a gel`was formed.
'I ~, .; ? , ~ 3 _ 57 _ ~3121 Example 26 This example illustrates a shampoo which is suitable for topical application to hair in order to cleanse it, at the same time delivering an inhibitor to the scalp to enhance hair growth or regro~th.
.:
The shampoo had the following formulation:
~_w/w Triethanolamine lauryl sulphate 16.8 Coconut diethanolamide 3.0 Hydroxypropylmethyl-cellulose (l) 0.25 Corn syrup (80% solids) (2) 20.5 Dimethylpolysiloxane (3) 1.0 Cationic cellulose (4~ 0.5 . .
Ethyl alcohol (SDA 40) 9.0 Vinyl carboxy polymer (5) 0.75 N-hexanoyl aspastic acid Perfume, colour, preservative q.s.
2s Water to 100 Acid or base to pH: 6.5 Methocel E4M (Dow Chemical~
` 2 - 42 Dextrose equivalent (Staley 1300) io 3 - 60,000 centistokes (Viscasil, GEC) 4 - Polymer JR 400 -5 - Carbopol 941 (BF Goodrich) :
' , :
The following formulations represent lotions which can be used topically in the treatment of bald or balding male or female heads.
.~ % w~w Hydroxyethyl cellulose 0.4 Absolute ethanol 25 25 ; Propane-1,2-diol - -Butane-1,3-diol 38.4 38.8 Paramethyl benzoate 0.2 0.2 N-acetyl glycine 5 N-acetyl hydroxyproline - 1 ~: Perfume Water to 100 100 .
,~ ~,q .,~." ,f ~
Exan!ple 29 This Example illustrates a lotion according to the invention which is suitable for topical application to the scalp in order to promote hair growth.
The lotion has the following formulation:
% W/w N-acetyl arginine 0.1 ethanol 99.995 perfume q.s.
lS Example 30 This Example illustrates a hair tonic which is suitable for application to hair or scalp.
The hair tonic has the following formulation:
.~,, wlw N-acetyl lysine 0.8 ethanol 50 2s water 49 perfume q.s.
, ' . .
.
~ r~
Example 31 Thîs Example also illustrates a lotion which is suitable for topical applicat.ion to the scalp.
The lotion has the ~ollowing formulation:
~ w/w N-acetyl histidine 1.5 propan-2-ol 10 ethanol 88.5 perfume q.s.
Example 32 This Example also illustrates a hair tonic which is suitable for application to hair or scalp.
The hair tonic has the following formulation:
% w/w N-acetyl ornithine 0.2 ethanol 40 2s water 59 ~0 perfume q.s.
,.~
Examples 33 to 36 The following formulations represent lotions which : can be used topically in the treatment of bald or balding male or female heads.
;` ~
Hydroxyethyl cellulose 0.4 - 0.4 Absolute ethanol 25 25 25 25 Propane-1,2-diol - - 38.4 38.4 Butane-1,3-diol 38.4 38.8 - -Paramethyl benzoate 0.2 0.2 0.2 0.2 N-acetyl hydroxylysine 5 - - -N-acetyl citrulline - 1 - -N-acetyl lysine - - 0.8 N-lauroyl citrulline - - - 0.6 Per~ume Water to 100 100 100 100 ~o .
, :
Examples 37 to 40 The following formulatio:ns represent creams which ; can be used in the treatment of baldness.
% w/w 37 38 ~9 ~o Cetyl alcohol polyoxyethylene (10) 4 4 4 4 Cetyl alcohol 4 4 4 4 Mineral oil 4 2 - -Paraffin wax - 2 4 Partial glyceride of palmitic and stearic acids - - - 4 N-acetyl hydroxyproline 2 - - -N-acetyl serine - 1.5 N-acetyl threonine - - 2 N-acetyl cysteine - - 1 Triethanolamine 0.75 0.75 0.75 0.75 Butane-1,3 diol 3 3 3 3 Xanthan gum 0.3 0.3 0.3 0.3 Preservative 0.4 0.~ 0.4 0.4 Perfume q.s. q.s. q.s.
~.s.
Water to 100 100 100 100 `
FIELD OF THE INVENTION
The invention relates to cosmetic and pharmaceutical compositions for topical application to mammalian skin or hair, containing a hair growth promoter which is capable of increasing or maintaining hair growth, especially terminal hair growth on the human scalp.
BACKGROUND
The Hair Growth Cycle It should be explained that in most mammals, hair does not grow continuously, but undergoes a cycle of activity involving alternate periods of growth and rest.
The hair growth cycle can be divided into three main stages, namely ', .
tl~.
~ - 2 - 33121 (i) the growth phase known as anagen, during which the hair follicle penetrates deep into the dermis with the cells of the bulb dividing rapidly and differentiating to form the hair, s (ii) the transitional stage known a~ catagen, which is heralded by the cessation of mitosis, and during which the follicle regresses upward~s through the dermis and hair growth ceases, (iii) the resting stage known as telogen, in which the regressed follicle contains a small secondary germ with an underlying ball of tightly packed dermal papilla 1S cells.
~ he initiation of a new anagen phase is revealed by rapid proliferation in the germ, expansion of the dermal papilla and elaboration of basement membrane components.
The hair cycle is then repeated many times until, as a consequence of the onset of male pattern baldness, most of the hair follicles spend an increasing proportion of their time in the telogen stage, and the hairs produced become finer, shorter, and less visible; this is known as 2s terminal to vellus transformation.
PRIOR ART
Alleqed Baldness Cures Although there have been many claims in the scientific :Literature to the promotion or maintenance of hair growth by the topical application of hair ~onics and ~5 the like, w:ith the possible exception of minoxidil, none has been shown to be sufficiently ~ree from disadvantageous clinical side effects, whether : ' ' ' ,' ' ' ' - ~ . .
..
administered topically, orally or systemically, to warrant commercial exploitation as an ethical pharmaceutical, proprietary medicine, or as a cosmetic product. Possibly, the only means which has met with partial success for growing hair on the bald or ~alding human head is by transplantation of hair to the bald areas. This is, however, an elxtremely painful operation and is not always successful. Furthermore, it is immediately apparent to the casual observer that the subject has received a hair transplant and it may take many months or even years before hair ragrowth, following this operation, assumes an appearance which resembles that of the original naturally growing hair.
Among the many hair regrowth studies that have been reported in the literature, there is included the work of Bazzano as described in PCT International Publication No.
W0 85/04577. This publication describes a composition which is useful for increasing the rates of hair growth on mammalian skin, prolonging $he anagen phase of the hair growth cycle and for treating various types of alopecias. The composition in question comprises a pyrimidine carbamate.
It has also been reported in US patent no. 4 139 619 to Chidsey assigned to the Upjohn Company, that a topical composition comprising minoxidil as the free base or acid addition salt thereof, or certain epecified related iminopyrimidines, is useful in stimulating the conversion of vellus hair to growth as terminal hair, as well as - -increasing the rate of growth of terminal hair.
In spite of the apparent stimulation of hair growth ~5 or regrowth reported independently ~y Bazzano and Chidsey, following topical application of minoxidil or related compounds, there is general concern that systemic _ 4 _ J3121 side-effects can result, particularly following topical application of minoxidil. Thus it is generally recognised in the medical literature that the side effects of orally administered minoxidil are very serious, and include fluid rel:ention, tachycardia, dyspnea, gynecomastia, fatigue, nausea and cardiotoxicity. There is also evidence that certain side effects have been experienced following topical application of minoxidil.
It is also reported by Lion Corp., in JP 61151109 that compositions comprising mono-N-long chained acyl basic amino acid lower alkyl ester salt can, together with higher fatty acid having an odd number of carbon atoms, higher aliphatic alcohol having an odd number of carbon atoms, or their derivatives, can be used for regenerating and growth increasing effect on hair.
BACKGROUND TO THE_INVENTION
Our own search for effective compositions that could be applied topically to the human scalp in order to promote hair growth, was influenced by the need to 2s discover molecules which were not only effective but also completely safe in use and free from contra indications which would limit their appeal. Furthermore, we were anxious to identify relatively simple molecules in this respect which were easy to synthesis and inexpensive to deploy in a mass market affordable product which would appeal to a large number of potential consumers.
It was accordingly during in vivo studies into the effects on rat skin of N-acetyl glycine, that it was 3s observed unexpectedly that this substance may be capable of promoting hair growth. This was tested and evidence obtained to substantiate this surprising observation.
- . . , ~ . - . - . . .:
` - 5 - J3121 . ' DEFINITION OF THE INVENTION
.
Accordingly, the invention provides a composition suitable for topical application to mammalian skin or hair for inducing, maintaining or increasing hair growth, which comprises:
;
i. an effective amount of from 0.001 to 99% by weight - of a hair growth promoter chosen ~rom mono N-acylated amino acids or salts thereof, in which the acyl group has from 2 to 20 carbon atoms; and ii. from 1 to 99.999~ by weight of a cosmetically acceptable vehicle for the hair growth promoter.
DISCLOSURE_OF THE_INVENTION
The hair arowth promoter According to the invention, the composition comprises as a hair growth promoter, a mono N-acylated amino acid, in which the acyl group has from 2 to 20 carbon atoms.
2s Preferably the acyl group is chosen ~rom acetyl, hexanoyl, octanoyl, lauroyl, myristoyl, palmitoyl and stearoyl. The most preferred acyl group in acetyl.
io Examples of the amino acid moiety from which the mono N-acylated amino acid is derived include neutral -amino acids, such as:
- glycine S alaninle valine leucin~e ` ~ , : ., !
~ 6 - J3121 isoleucine phenylalanine tyrosine proline hydroxyproline serine threonine cysteine cystine methionine, and tryptophan.
Preferred mono N-acylated neutral amino acids include:
N-acetyl glycine N-acetyl hydroxyproline N-acetyl alanine N-acetyl valine N-acetyl leucine N-acetyl isoleucine N-acetyl phenylalanine N-acetyl tyrosine N-acetyl proline N-acetyl serine N-acetyl threonine N-acetyl cysteine N-acetyl cysteine N-acetyl methionine io N-acetyl tryptophan N-lauroyl glycine .-N-palmitoyl glycine N-myristoyl glycine N-lauroyl hydroxyproline ~5 N-octanoyl glycine N-octanoyl hydroxyproline, and N-hexanoyl glycine.
.,, ,, - , .
.
.
,', , , . ~:, .
r, r . ~
`:
Examples of the amino acid moiety from which the mono N-acylated amino acid is derived also include acidic amino acids, such as:
aspartic acid and glutamic acid.
Preferred mono N-acylated acidic amino acids include:
N-acetyl aspartic acid N-lauroyl aspartic acid N-palmitoyl aspartic acid N-octanoyl aspartic acid N-acetyl glutamic acid lS N-lauroyl glutamic acid N-palmitoyl glutamic acid, and N-octanoyl glutamic acid.
Examples of the amino acid moiety from which the mono N-acylated amino acid is derived also include basic amino acids, such as: !
arginine lysine histidine ornithine hydroxylysine, and citrulline.
Preferred mono N-acylated basic amino acids include:
N-acetyl arginine N~acetyl lysine N-acetyl histidine N-acetyl ornithine N-acetyl hydroxylysine N-acetyl citrulline .
- 8 - ~31~1 N-lauroyl lysine N-lauroyl citrulline N-myristoyl citrulline N-myristoyl ornithine N-octanoyl lysine, and N-oc anoyl citrulline.
The preferred N-acylated amino acids are those derived from neutral or acidic amino acids.
Particularly preferred mono N-acylated amino acids are those that contain no sulphur atoms in the molecule.
The mono N-acylated amino acids as herein defined can also be employed in the composition according to the invention as their corresponding salts, examples o~ which includes alkali metal salts, such as sodium and potassium and alkanolammonium salts such as triethanolammonium.
The composition can comprise two more mono N-acylated amino acid~, or salts thereof.
The total amount of the hair growth promoter present 2s in the composition according to the invention is preferably sufficient to increase hair growth in the rat, the model selected for this test, when said composition is appli~d topically thereto over a period o* no more than 3 months, by at least 10~ more than that obtainable using a control composition ~rom which the ~aid promoter has been omitted, in accordance with the Rat Hair ~rowth Test.
Preferably, the amount of promoter ~hould be sufficient to increase hair growth in the rat by at least 20%, more preferably by at least 30%, most preferably by at least 40% and ideally by at least 50%.
' ,: ',, , , . r, ~-~
_ g - J3121 The effective amount which is sufficient to induce, maintain or increase hair growth will depend on the effectiveness of the promoter ~ome being more effective than others, but in general, an amount of from 0.0001 to 99%, preferably from 0.01 to 20% by weight o~ the composition will provide an adequate dose to the skin after topical application.
Preservation of the Composition The composition according to the invention is preferably preserved in such a manner that it will enjoy an extended shelf life following manu~acture and prior to 1S sale and use. Ideally the composition will have an indefinite shelf life.
It is accordin~ly apparent that the haix growth promoter is likely to be prone to attack by bacteria, 2~ moulds and fungi and other microbial influences, particularly at p~ values near that of the skin that characterise the preferred composition. The shelf-life of the composition can therefore be unacceptahly short due to the biodegradation of the hair growth promoter 2s unless steps are taken to preserve the composition.
In order to be preserved, the composition should preferably be ~ree, or substantially ~ree, from viable microbial contaminants that are capable of resulting in o microbial spoilage of the composition, and/or biodegradation of the hair growth promoter prior to topical appl:ication of the composition to mammalian skin or hair. It is to be understood, however, that the invention is also concerned with compositions, as herein ~5 defined, which may contain viable but dormant microorganisms, such as bacterial spores, provided that the conditions of preservation do not result in - lO - J3121 substantial proliferation of the microorganisms prior to ` use of the composition.
':, Examples of methods that can be employed to achieve preservation of the composition, includes the following:
(i) Sterilisation The composition according to the invention can be preserved by sterilisation to remove or kill substantially all viable microbial contaminant~. This can be achieved for example by irradiation using a lethal dose of gamma rays, by heat sterilisation or by ultrafiltration using techniques that are well established in the pharmaceutical industry.
fii) Chemical_Preservative The composition according to the invention can also be preserved by including in it a chemical prPservative which functions to prevent the growth of or kill bacteria, fungi or other microorganisms.
2s Examples of chemical preservatives include ethanol, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, sodium propionate and the methyl, ethyl, propyl and butyl esters of p-hydroxybenzoic acid. The amount of chemical preservative that can be incorporated in the composition according to the invention will generally be from 0.05 to 5%, preferably from 0.1 to 2% by weight, the amount chosen being sufficient to arrest microbial proliferation.
~iii) Water activity depressants The composition according to the invention can also , .: . . .
be preserved by the inclusion of a water activity depressant such as glycerol, propylene glycol, sorbitol, sugars and salts, for examples~ alkali metal halides, sulphates and carboxylates. When employing a water activity depressant, sufficient should be lncorporated in the composition according to the invention to reduce the water activity (~ w) from 1 to < 0.9, preferably to <
0.85 and most preferably < 0.8, the lowest of these values bein~ that at which yeasts, moulds and fungi will not proliferate.
The hair growth promoter may be susceptable to hydrolysis, particularly when the pH value of the composition is alkaline. It is accordingly preferred that the composition, when aqueous, should have an acid pH valu~. The preferred pH value of the composition, when aqueous, is from 2 to <7, ideally from 4 to 6.5.
The Vehicle The composition according to the invention also 2s comprises a solid, semi-solid or liquid cosmetically and/or physiologically acceptable vehicle, ~o enable the hair growth promoter to be conveyed to the skin at an appropriate diluti.on. The nature of the vehicle will depend upon the method chosen for topical administration ~o of the composition. The vehîcle can itself be inert or it can possess physiological or pharmaceutical benefits of its own.
The sel~ection of a vehicle for this purpose presents a wide range of possibilities depending on the required f ~
~ 12 ~ J3121 product form of the composition. Suitable vehicles can be classified as described hereinafter.
It should be explained that vehicles are substances which can act as diluents, dis;persants, or solvents for the hair growth promoter which there~ore ensure that they can be applied to and distributed evenly over the hair and/or scalp at an appropriate concentration. The vehicle is preferably one which can aid penetration of the esters into the skin to reach the immediate environment of the hair follicle. Compositions according to this invention can include water as a vehicle, and/or at least one cosmetically acceptable vehicle other than water.
Vehicles other than water that can be used in compositions according to the invention can include solids or liquids such as emollients, solvents, humectants, thickeners and powders. Examples of each of these types of vehicles, which can be used singly or as mixtures o~ one or more vehicles, are as follows:
Emollients, such as stearyl alcohol, glyceryl 2s monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, ispropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, -isopropyl stearate, butyl stearate, polythylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, ~5 petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myxistyl myristate;
-, . ~
':
~J~ 2~
,, Propellants, such as trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, monochlorodifluoromethane, trichlorotrifluoroethane, propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide;
Solvents r such as ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran;
Humectants, such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin;
Powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal ~ilicon dioxide, sodium polyacrylate, tetra alkyl and/or trialkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate.
The amount of vehicle in the composition, including water if present, should preferably be su~ficient to carry at least a portion of a selected ester to the skin in an amount which is su~ficient effectively to enhance hair growth. The amount of the vehicle ~an comprise the balance of the composition, particularly where little or no other ingredients are present in the composition.
~ccordingly, the vehicle or vehicles can comprise ~rom 1 to 99.99~, preferably from 50 to 99.5% and ideally from 9o to 99% by weight of the composition.
~' -, b ' ,~ h ~3 .
Perfume The composition according to the invention can also optionally comprise a perfume in an amount sufficient to make the composition acceptable to the consumer and pleasant to use. Usually, th~e perfume will form from 0.01 to 10% by weight o~ the composition.
Activity Enhancer The composition according to the invention can also optionally comprise an activity enhancer.
The activity enhancer can be chosen from a wide variety of molecules which can function in different ways to enhance the hair growth effects of the hair growth promoter. Particular classes of activity enhancers include other hair growth stimulants, penetration enhancers and cationic polymer~, whose presence can further improve the delivery of the ester through the stratum corneum to its site of action in the immediate environment of the hair follicle.
Some activity enhancers can also function as vehicles for the ester.
(a)_Other Hair_Growth Stimulants i. Examples of other substances which themselves possess the ability to stimulate or increase hair growth include, for example:
Benzalkonium chloride Benzethonium chloride Phenol .:
!. ~ , ' ,~ J ,' ~
' Estradiol : Diphenhydramine hydrochloride Chlorpheniramine maleate Chlorophyllin derivatives Cholesterol Salicylic acid Cystine ~ed pepper tincture Benzyl nicotinate dl-Menthol Peppermint oil Calcium pantothenate Panthenol Castor oil Hinokitiol Prednisolone Resorcinol Further substances which themselves possess the ability to increase the rate of terminal hair growth include:
ii.~ -1,4 esterified disaccharides described by Choay 2s S.A. in EP-A-0 064 012, having the structure (2):
o~ ~
~O~ ~OR
.
z olt ~s where Z represents a functional nitrogen group, such as an azide or a group having the structure -NHB, in which B represents -H or a functional - 16 - ~3121 group such as acetyl or sulphate as a salt with an organic or mineral ca ion;
M represents -H or S03M1, where M1 i5 an organic or metallic cation, particularly an alkali metal; or an acetyl group;
R represents a Cl to C4 alkyl radical, especially methyl; or an aryl radical;
A represents a functional group such as an acid or -COORl, wh~re R1 represents -H or a Cl to C4 alkyl radical, especially methyl; or a metal, especially an alkali metal;
esterified oligosaccharides as described by Unilever in EP-A-0 211 610, including at least one esterified 20 disaccharide unit consisting of a uronic acid residue having the structure (3):
ll~o , '''.
H.OR~'K~H.oR' ( 3 ) H R
and a hexosamine residue having the structure (4):
'1)~o ~-O Q~ .O R"
Il R~
.. : -. ' .. - ' ... . . : : . . -.' :' : ' :- , : .
,' . ' ~ . ~ -'.
- . .
j'jj`,',,'.,",'~' i5J
COOR"
where R' is -H, C3 to C10 alkyl or -CH~CH2)nCH3 R is -H, C1 to C4 alkyl, -CO(CH2)mCH3, -S03M, R is -H, -CO(CH2~nCH3, or -S03M, N is -H, or a metal:lic or organic cation n is o or an intege:r of from 1 to 7, and m is O or the integer 1 or 2;
the groups designated R" beinq the same or different, one R" group from each pyranose ring struckure being linked by a glycosidic linkage having the configuration d~-1,3, ~ -1,4, ~ -1,3 or ~-1,4; and the -COORI, -CH20R"
and -OR" groups being of either configuration with respect to the pyranose rings;
iii. Minoxidil glucuronides, as described ~y Unilever in /
EP-O 242 967, iv. Minoxidil sulphates, as described by The Upjohn Co.
in WO 86/04231, and v. Minoxidil, and other derivatives thereof as described by The Upjohn Co, in US patent 4 139 619.
2s Particularly preferred mixtures o~ minoxidil and a hair growth promoter according to the invention include the : following:
Minoxidil and N-acetyl glycine Minoxidil and N-acetyl methionine Minoxidil and N-acetyl aspartic acid and Minoxidil and N-lauroyl citrulline vi. Ethylenediaminetetraacetic acid or salts thereof, as described by Redken Laboratories, Inc. in US 4 814 351.
vii. Direct proteoglycanase inhibitors, such as 1,10-phenanthroline, a described by Unilever in EP-0 277 428.
viii.Glycosaminoglycanase inhibitors, as described by Unilever in EP-0 277 428, such as aldonolactones and esterified aldonolactones having the structure (16):
Al B - c2 _ H
B~ C3 - H (16) B - f4_ H
A
~D' OD
where Al and A2 are -H, CH3,-C = 0 or -C = p B is OD" or a lactone linkage to position 1 or 6, or -N~COCH3 and where D is -H or C2 to C8 alkyl, D' is the remainder of the molecule joined -through another C atom at positions 2 to 5 to form a lactone, 3~ V" is -H or C2 (ie acetyl) to C4 acyl of either configuration with respect to the backbone of this molecule;
' preferred examples of which include:
L-Galactono-1,4-lactone L-Arabino-1,5-lactone - D-Fucono-1,5-lackone D-Glucaro-1,4-lactone D-Glucurono-6,3-lactone Galactaric acid lactone 2-Acetamido-2-deoxygluconolactone 2-Acetamido-2-deoxygalactono-lactone D-Glucaro-1,4:6,3-dilactone L-Idaro-1,4-lactone 2,3,5-Tri-0-acetyl-~-glucaro-1,4-lackone 2,5-Di-0-acetyl-D-glucaro-1,4:6,3-dilackone, ix. Glycosaminoglycanase inhibitors, as described by Unilever in EP O ~77 428, such as monosaccharides and esterified monosaccharides having the structure (17):
CXO
H C - A
H -C -OG
(17 H - C OG
I
H - C ~ ~OG
C~2GI -where A is -OG or -NHCOCH3 3s G is ~H, -SO3M", C2 (ie acetyl) to C4 acyl : - 20 - J3121 G' is -H or -OG
~" is -H or a metal cation wherein the functional groups can be in either configuration with respect to the backbone of the above ; molecule;
preferred examples of which include:
N-Acetylglucosamine N-Acetylgalactosamine D-Galactosamine D-Glucosamine-3-sulpha-te N-Acetylmannosamine.
x. Glycosaminoglycan chain cellular uptake inhibitors, as described by Unilever in EP O 277 428, such as hexuronic acid and esters thereof which may be represented by the generic structure (18):
C~IO
: 25 H - C OG
I
~ _ C- 0~ (18) H - C - -OG
H - C - OG
where G is -H, -S03M", C2 (ie acetyl) to C4 acyl;
: , ,. . ..
! ,- ,, / ,,. ` J l.,s ~) D is -H or C2 to C~ alkyl M" is -H or a metal cation;
wherein the functional groups can be in either s configuration with respect to the backbone of the above molecule;
xi. Chemical inhibitors of glycosidase activity, as described by Unilever in EP 0 334 586, chosen from lactams having the structure (19):
Q - C - H
I
Q - C -H (19) Q C H
I
2s where A3 and A4 are -H, -CH3, -C-0, -CH2OT
or -C=0, A3 and A4 being the same or different, and at least one of which being the group:
-NH
~5 -C=0 , ~- "J .". , . " ~I
in a lactam ring;
and where Q is -OT', -NHT' or a lactam linkage ko A3 or A4;
the Q groups being the ~ame o;r different, and at least one of which is involved in a lactam linkage;
and wherP T is the same or different and is chosen from lo -H, -CpH2p+1 or a metal ion, , p is an integer of from 1 to 22;
provided that:
where any of the Q groups is -OT' or -NHT', then that group or groups can be of either stereochemical configuration with respect to the plane of the ring, preferred examples of which include:
D~glucaro-1,5-lactam, L-Galactono-1,4-lactam, L-Arabino-1,5-lactam, D-Fucono-1,5-lactam, D-Glucaro-1,4-lactam, - D-Glucurono--6,3-lactam, ~5 1,2,5-tri-0--acetyl-D-glucurono-6,3-lactam, 2-Acetamido--2-deoxygluconolactam, , .
; 2-Acetamido-2-deoxygalactonolactam, D-Glucaro-1,4:6,3-dilactam, L-Idaro-1,4-lactam, 2,3,5-Tri-O-acetyl-D-glucaro-1,4-lactam, 2,5-Di-O-acetyl-D-Glucaro-1,4:6,3-dilactam, D-glucaro~ -lactam ethyl ester;
xii. Chemical activators o~ protein kinase C enzymes, as described by Unilever in EP 0 334 585 chosen from diacylglycerols having the structure (20):
H -C-OH
:~ I
H -C-OX (20) H2-C-OX ' where X and X' are the same or different and is represented by the grouping:
~~-[(CH2)a, (CH=CH)b] CH3 where x is O or an integer of from 1 to 28, and y is 0 or an integer c>f Prom 1 to 5;
the X and X' groups being of either stereochem;cal configuration with respect to the carbon backbone of the glycerol molecule;
preferred examples of which include:
~5 1,2-Oibutanoyl-rac-glycerol 1,2-Dihexanoyl-sn-glycerol 1,2-Dioctanc)yl-rac-glycerol . " ~
.
1,2-Dioctanoyl-sn-glycerol 1,2-Didecanoyl-rac-glycerol l-Oleoyl-2-acetyl-rac-glycerol 1-Oleoyl-2-acetyl-sn-glycerol 1-Stearoyl-2-arachidonoyl-sn-glycerol 1,2-Distearoyl-rac-glycerol : 1,2-Dipentadecanoyl-sn-glycerol 1,2-dipentadecanoyl-rac-glycerol 1,2-Dipalmitoyl-rac-glycerol 1,2-Dipalmitoyl-sn-glycerol 1,2-Diseptadecanoyl-rac-glycerol 1,2-Dioleoyl-sn-glycerol 1,2-Dioleoyl-rac-glycerol 1,2-Diarachidonoyl-sn-glycerol 1,2-Dieicosanoyl-sn-glycerol 1,2-Didoeicosanoyl-rac-glycerol, and 1,2-Dioctaeicosanoyl-sn-glycerol.
xiii.Glycosaminoglycanase inhibitors, as described by Unilever in EP 0 348 184, chosen from aldonomonolactone or alduronomonolactone derivatives having the structure (21): .
2s A
Bl _ 12 ~ ~
B2 _ ~3_ H (21) B3 ~ C4 - H -~. ~ ., .
.
oR5 oR4 oR6 where A5 is -C=O, -C=O or -C-OQ;
oR5 oR4 A6 is -C=O, --C=O or CH20R6 B1, B2, B3 and B4 a~re each chosen from is oR
NHR6, NHR7 or a lac:tone linkage to position 1 or 6,and/or an ether linkage to Ql;
said substituents B being the same or different, and being in either configuration, with respect to the backbone of the above structure, on ,~
positions CG to C5 not involved in a lactone ring;
and where R4 is -H, C1 to C20 alkyl, a metal cation, or an alkanolamine cation;
R5 is the remainder of the molecule joined through another C atom at positions 2 to 5 to form a lactone;
R6 is -H, -CH3, benzyl or C2 to C~ acyl;
R7 is -H, -CH3, benzyl or C3 to C6 acyl;
Ql is the remainder of the molecule joined through an ether linkage to either C4 or C5, -forming either a pyranose or furanose ring;
. H oR5 provided that, when A5 is -C=o, then A6 is ~=O;
, .
provided also that, when A6 is CH20H, then one or more of the B substituents is -CH3, C2 to C4 acyl or NHR7;
oR5 provided also that, when A5 is -C=O, and all B1, B2, B3 and B4 substituents are -OH, then OR
lo A is -C=O or CH20R6, and R4 is Cl or Cg to C20 alkyl;
preferred examples of which aldonomonolactone ~erivatives : include:
6-acetyl-galactono-1,4-lactone 6-propionyl-galactono-1,4-lactone 6-butyryl-galactono-1,4-lactone 2-propionamido-2-deoxygluconolactone 2-butyramido-2-deoxygluconolactone 2-propionamido-2-deoxygalactonolactone 2-butyramido-2-deoxygalactonolactone 6-propionyl-2-acetamido-2-deoxygluconolactone diacetyl-6-propionyl-2-acetamido-2-deoxygluconolactone 6-butyryl-2-acetamido-2-deoxygalactonolactone diacetyl-6butyryl 2-acetamido-2-deoxygalactonolactone 2,3,5,6-tetraacetyl-galactono-1,4-lactone 2,3,5-triacetyl-6-propionylgalactono-1,4-lactone triacetyl-2-propionamido-2-deoxygalactonolactone ~o triacetyl-2-butyramido-2-deoxygluconolactone 6-methyl-glucaro-1,4-lactone 2,3,5,6-tetramethyl-glucarool,4-lactone 6-methyl-2,3,5-triacetyIglucaro-1,4-lactone 6-methyl-3-methyl-glucaro-1,4-lactone, and ~5 6-methyl-3-acetyl-glucaro-1,4-lactone;
: ., .,. ~, , , :
~ ~ .
- -.. . . .
- 27 - ~3121 and a preferred example of which alduronomonolactone derivative is:
1,2,5-triacetyl-glucurono 6,3-lactone.
: 5 xiv. Glycosaminoglycanase inhibitors, as describ~d by Unilever in EP O 348 18~, chosen from acylated monosaccharides having the st:ructure (22):
H c2 _ A7 H _ C3 oY
H - 14 B5 (22) where A7 is -OY or -NHR8 B5 and B6 are each chosen from is -OY, or an ether linkage to Dl, Dl is -CHOYI where x2 is an ether linkage xl either to C4 or C5 forming a pyranose or ~uranose ring;
Y is -H, -S03M, C2 to C4 acyl or C1 to C18 alkyl;
.
' ' :
.
- 28 - ~3121 ... .
said substituents A7, B5, B6 and -OY being the same or different, and being in either configuration, with respect to backbone o~
the above structure;
s and where zl is -H or -OY
R8 is ~H, _S03~2 or C3 or C4 acyl, M is -H, a metal cation, NH4+, or an alkanolamine cation;
provided that, when R8 is -H, then 1 or more of Y is chosen from -S03M2 or C2 to C4 acyl;
and mixtures therPof.
Preferred examples of which acylated monosaccharides include:
2-propionamido-2-deoxyglucose 1,3,4,6-tetraacetyl-2-propionamido-2-deoxyglucose 2-butyramido-2-deoxygalactose 1,3,4,6-tetraacetyl-2-butyramido-2-deoxygalactose 2-sulphamido-2-deoxygalactose 2-sulphamido-2-deoxyglucose 2-butyramido-2-deoxymannose 1,3,4,6-tetraacetyl-2-butyramido-2-deoxymannose 2-butyramido-2-deoxyglucose, and 1,3,4,6-tetraacetyl-2-butyramido-2-deoxyglucose.
xv. Esters of pyroglutamic acid, as described by ~ever : 30 Brothers CoDpany in US patent No. 4 774 255, having the structure ~23): -` ' ' ' ' .
.. . .
' .
~ ~ J-~, f ~ ,3 S ~
0~ N C-~-R1 (23) lo where R1 is Cl to C30 alkyl, or-CHCOOR"
and where R and R3 are the same or different and are each represented by H or the grouping (24):
[(CH ) , (CH2oH~v, (CH2)w, (CH3CH2)x, ~ y z (24) where u is z~ro or 1 v is zero, or the integer 1 or 2, w is zero, or an integer of from 1 to 21 x is zero, or an integer of from 1 to 4, y is zero, or the integer 1 or 2, z is zero, or an integer of ~rom 1 to 4, and u + v + w + x + y + z is an integer of from 1 to 22;
provided that when the subgrouping (CH=CH) is present, then the total number of carbon atoms in said grouping is from 10 to 22.
.
Examples of suitable esters of pyroglutamic acid where R1 in structure (23) is C1 to C30 alkyl are:
pyroglutamic acid methyl ester - pyroglutamic acid ethyl ester ~5 pyroglutamic acid n-propyl ester pyroglutamic acid n-butyl ester pyroglu1:amic acid n-hexyl ester : . , ~, ~ - , ' '. ~ , ' - . ~ .
. .
_ 30 _ ~3121 ;
pyroqlutamic acid n-heptyl ester pyroglutamic acid n-octyl ester pyroglutamic acid n~nonyl ester pyroglutamic acid n-decyl ester pyroglutamic acid n-undecyl ester : pyroglutamic acid n-dodecyl ester pyroglutamic acid n-tridlecyl ester pyroglutamic acid n-tetr,adcyl ester pyroglutamic acid n-hexadecyl ester pyroglutamic acid n-octadecyl ester pyroglutamic acid n-eicosyl ester pyroglutamic acid iso-propyl ester pyroglutamic acid 2-methylhexyl ester pyroglutamic acid 2-ethylhexyl ester pyroglutamic acid 3,7-dimethyloctyl ester pyroglutamic acid 2-hexyldecyl ester pyroglutamic acid 2-octyldodecyl ester pyroglutamic acid 2,4,4-trimetyl-1-pentane ester pyroglutamic acid methyloctyl ester Particularly preferred esters of this group are those where R1 in structure (23) is C1 to C14 alkyl, (linear or branched), especially C1 to C6 (linear.or branched).
Further examples of preferred esters of pyroglutamic acid, where R1 in structure (23) is -CHCOOR , are those where R and/or R having the structure shown for grouping (24), include straight and branched chain, saturated or unsaturated aliphatic groups having from 1 to 22 carbon atoms, such as the alkyl groups:
'' '- . ' . ' :'. ~ : : : .
.. ::
.
-.. .
methyl ethyl propyl iso-propyl butyl iso-butyl n-valeryl iso-valeryl n-caproyl n-heptyl n-caprylyl n-capryl lauryl myristyl palmityl stearyl, and arachidyl.
20 and the C10 22 alkenyl groups:
linoleyl linolenyl . ~ -linolenyl arachidonyl, and columbinyl.
Further examples o~ the grouping (24) also include hydroxyalkyl groups having from 1 to 22 carbon atoms, 30 such as:
hydroxymethyl 2-hydroxyethyl 2-hydroxy-n-propyl 3s 3-hydroxy-n-propyl 2-hydroxy-n-butyl 3-:hydroxy-n-butyl , . . , . ~ , : . .
:
': ,, .: : .
.. . : . - . , . - - .
, - 4-hydroxy~n-butyl 5-hydroxy-n-valeryl 6-hydroxy-n caproyl 2,3-dihydroxy-n-propyl 2,3-dihydroxy-n-butyl 12-hydroxystearyl.
Further specific examples of esters of pyroglutamic : acid which are particularly suited ~or use as other hair growth stimulants are:
2-[pyroglutamoyloxy]-propionic acid methyl-2-[pyroglutamoyloxy]-acetate S ethyl-2-[pyroglutamoyloxy]-n-propionate ethyl-2-[pyroglutamoyloxy]-n-butyrate ethyl-2-[pyroylutamoyloxy]-iso-butyrate ethyl-2-[pyroglutamoyloxy]-n-valerate ethyl-2-[pyroglutamoyloxy]-n-caproate ethyl-2-[pyroglutamoyloxy]-n-heptylate ethyl-2-[pyroglutamoyloxy]-n-caprylate ethyl-2-~pyroglutamoyloxy]-n-pelargonate ethyl-2-[pyroglutamoyloxy]-3-hydroxybutyrate . iso-propyl-2-[pyroglutamoyloxy]-n-propionate 2 5 iso-propyl-2 - E pyroglutamoyloxy] -n-caprylate n-propyl-2-[pyroglutamoyloxy]-n-propionate n-propyl 2-[pyroglutamoyloxy~-n-caprylate stearyl-2-[pyroglutamoyloxy3-n-propio~ate 12-hydroxystearyl-2-[pyroglutamoyloxy]-n-propionate 3 0 stearyl-2-[pyroglutamoyloxy~-n-~tearate palmityl-2-~pyroglutamoylo~r]-n-prop~onate linoleyl-2-[pyroglutamoyloxy~-n-propionate linoleyl-2-[pyroglutamoyloxy]-n-caprylate lauryl-2-~pyroglutamoyloxy]-n-caprylate : ~S steary:L-2-~pyroglutamoyloxy] n-~aprylate glyceryl mono(2-[pyroglutamoyloxy]-n-propionate) glyceryl mono(2-tpyroglutamoyloxy]-n-caprylate), and .
' . - . ~
.. . .. . . .
, ....... -~ ;
. .
, _ 33 - J3121 glyceryl di(2-~pyroglutamoyloxy]-n-propionate).
xvi. hexosaccharic acids or an acylated hexosaccharic acids, or salts or esters thereof, having the structure (25):
COO
~HOY2 CHOY
lo IHoY4 XlnX m (~5) where Xl is chosen from H, alkalimetal, ammonium and substituted ammonium counterions;
X is chosen from an alkyl or hydroxyalkyl group having from 1 to 18 carbon atoms;
yl~ y2~ y3 and Y4 are each chosen from H, an alkyl group having from 1 to 12 carbon atoms, and an acyl group having from 1 to 2s 18 carbon atoms;
l is an integer of ~rom 1 to 3;
m and n are aach O or the integer 1 or 2; and m+n is l or 2.
Examples of hexosaccharic acids, in which Xl, yl~
y2~ y3 and Y4 in the above structure are -~, n is 2, and m is 0, include:
Allosaccharic acid - - . : . . . :
,. . : . ~ , . : .
., . : , ' _ 34 - J3121 Altrosaccharic acid ~lucosaccharic acid ~annosaccharic acid Gulosaccharic acid Idosaccharic acid Galactosaccharic acid, and Talosaccharic acid.
~ lo Examples where X1 s a cation, are the monovalent ; alkali metal cations Na and K .
Further examples where X1 is a cation are substituted ammonium cations, such as diethanolammonium and triethanolammonium cations.
Examples where x2 is an alkyl group are methyl, ethyl, n-propyl, n-butyl, n-octyl and lauryl.
Examples where yl~ y2~ y3 and Y4 are alkyl groups, are methyl and ethyl.
Examples where yl~ y2~ y3 and Y4 are acyl group, are acetyl and propionyl.
2s A particularly preferred hexosaccharic acid is glucosaccharic acid (also known as saccharic acid or ; glucaric acid, and hereinafter referred to as glucaric acid) having the structure (26):
COOH
H-C-OH
HO-C-H
H-C-OH (26) ~5 H-C-OH
COOH
. - , : : , ' ,:
: , : , .
': : . , '- . - ' ' - : "
~ ' ' . ' , - .. , ~ .. ..
_ 35 _ J3121 - A particularly stable salt of glucaric acid which is preferred, is the disodium salt.
xvii.aryl-substituted ethylenes having the structure ~27) s R ~7 R~
s (~7) R~ R~
where Rl, R2, R3, & R4 are the same or different, and are chosen from -H~ -OH, ~CnH2n+1, -N02, -Cl, -Br, -F
o and -CH;
and where R5 ~ R6 are the same or different, and are chosen from:
2r 0 0 S
11 ~
-H, -CN, -COH, -CNH2 and -CNH2;
and where R7 is chosen from -H and -OH
and where n is an integ~r o~ from 1 to 8.
The composition according to the invention can also comprise mixtures of said inhibitors.
Examples of the aryl-substituted ethylenes include ~5 1-carboxy-2--(4-hydroxyphenyl~ethylene , ~ . ,' ~' : '. ' , . ' '.
. . . ~ . ~ : .
,J ' ~ r 1 dicarboxy-2-(4-hydroxyphenyl)ethylene 1,1-dicyano-2-(4-hydroxyphenyl)ethylene 1-carboxy-2-(3,4-dihydroxyphenyl~ethylene 1,1-dicyano-2-(3-hydroxyphenyl)ethylene 1-cyano-1-carboxy-2-(2,5-dihydroxyphenyl)ethylene l-carboxy-1-cyano-2-(3,4-dihydroxphenyl)ethylene 1,1-dicyano-2-~3,4-dihydroxyphenyl)ethylene 1,1-dicyano-2-(3-methQxy-4,5-dihydroxyphenyl)ethylene 1,1-dicyano-2-(3,4,5-trihydroxyphenyl)ethylene 1-amido-1-cyano-2-~3,4-dihydroxyphenyl)ethylene l-thioamido-l-cyano-2-(3,4-dihydroxyphenyl)ethylene l-cyano-2-(4-hydroxyphenyl)ethylene 1,1-dicyano-2-(3-hydroxy-4-nitrophenyl)ethylene 1,1-dicyano-2-hydroxy-2-(4-hydroxyphenyl)ethylene 1,1-dicyano-2-(3-methoxy-4-hydroxyphenyl)ethylene 1,1-dicyano-2-(3,5-dihydroxyphenyl)ethylene 1,1-dicyano-2-hydroxy-2-(3,4,5-trihydroxyphenyl)ethylene 1-carboxy-1-cyano-2-(4-methoxyphenyl)ethylene 1-carboxy-1-cyano-2-(4-fluorophenyl)ethylene 1-carboxy-1-cyano-2-(3-methoxy-4-hydroxyphenyl)ethylene 1-carboxy-1-cyano-2-(3,5-dimethoxy-4-hydroxyphenyl)ethyl-ene 1-carboxy-1-cyano-2-(4-hydroxyphenyl)ethylene 1-carboxy-1-cyano-2-(4-phenylcarboxyaldehyde)ethylene s 1-cyano-1-carboxy-2-(2,5-dihydroxyphenyi)ethylene (b) Penetration Enhancers As has been stated earlier, the presence of a penetration enhancer can potentiate the benefit of the hair growth promoter by improving its delivery through the stratum corneum to its site of action in the immediatP environment of the hair follicle close to the ~5 dermal papilla.
.
.
.' ., ~ . . .
r3 - 37 - ~3121 The penetration enhancer can accordingly function in a variety of ways. It can *or example, improve the distribution of the hair growth promoter on the skin surface or, it can increase its partition into the skin from the composition when applied topically, so aiding : its passage to its site of action. Other mechanisms enhancing the benefit o~ the ~hair yrowth promoter may also be involved.
Examples of penetration enhancers include:
2-methyl propan-2-ol Propan-2-ol lS Ethyl-2-hydroxypropanoate Hexan-2,5-diol POE(2) ethyl ether Di(2-hydroxypropyl) ether Pentan-2,4-diol Acetone POE(2) methyl ether 2-hydroxypropionic acid 2-hydroxyoctanoic acid Propan-l-ol 2s 1,4 Dioxane Tetrahydrofuran Butan-1,4-diol Propylene glycol dipelargonate Polyoxypropylene 15 stearyl ether Octyl alcohol POE ester o~ oleyl alcohol Oleyl alcohol Lauryl alcohol Dioctyl adipate 3 5 Dicapryl adipate Diisopropyl adipate Diisopropyl sebacate .~ .
.
.
.'' '....... ' . "' :
.. . . . :
:
: : , :.
;' ~' I J , ~ , - 3~ ~J3121 - Dibutyl sebacate Diethyl sebacate Dimethyl sebacate Dioctyl sebacate Dibutyl suberate Dioctyl azelate Debenzyl sebacate Dibutyl phthalate lo Dibutyl azelate Ethyl myristate Dimethyl azelate Butyl myristate Dibutyl succinate lS Didecyl phthalate Decyl oleate Ethyl caproate Ethyl salicylate Isopropyl palmitate Ethyl laurate 2-ethyl-hexyl pelargonate Isopropyl isostearate Butyl laurate Benzyl ben20ate Butyl benzoate Hexyl laurate Ethyl caprate Ethyl caprylate Butyl stearate Benzyl salicylate 2-hydroxypropanoic acid 2-hyroxyoctanoic acid, Further examples of penetration enhancers include:-~S
Dimethyl sulphoxide .
.' ' ' ' .
, 7J ' ~
N,N-Dimethyl acetamide N,N-Dimethyl formamide 2-Pyrrolidone l-Methyl-2-pyrrolidone : 5-Methyl-2-pyrrolidone 1,5-Dimethyl-2-pyrrolidone l-Ethyl-2-pyrrolidone Phosphine oxides Sugar esters Tetrahydrofurfural alcohol Urea Diethyl-m-toluamide, and l-Dodecylazacyloheptan-2-one Further examples of penetration enhancers include surface active agents, preferred examples of which include:
(i) Anionic surface active agents, such as metallic or alkanolamine salts of fatty acids for example sodium laurate and triethanolamine oleate;
alkyl benzene sulphonates, for example triethanolamine dodecyl benzene sulphonate;
alkyl sulphates, for example sodium lauryl sulphate;
alkyl ether sulphates, for example sodium lauryl ether sulphate t2 to 8 EOJ;
sulphosuccinates, for example sodium dioctyl - sulphosuccinate;
3s monoglyceride sulphates, for example sodium glyceryl monostearate monosulphate;
: ' :
.
' , ' ' . .
s' )~J-3lJ JV
_ ~0 _ J3121 isethionates, for example sodium isethionate;
methyl taurides, for example Igepon T;
acylsarcosinates, for example sodium myristyl : sarcosinate;
acyl peptides, for example Maypons and Lamepons;
, 10 acyl lactylates, polyalkoxylated ether glycollates, for example trideceth-7 carboxylic acid;
phosphates, for example sodium dilauryl phosphate.
(ii) Cationic surface active agents, such as amine salts, for example sapamin hydrochloride;
quartenary ammonium salts, for example . Quaternium 5, Quaternium 31 and Quaternium 18;
2s (iii) Amphoteric suface active agents, ~uch as imidazol compounds, for example Miranol;
N-alkyl amino acids, such as sodium cocaminopropionate and asparagine derivatives;
betaines, for example cocoamidopropylbetaine (iv) Nonionic surface active agents, such as fatty acid alkanolamides, for example oleic ethanolamide;
.
' ~
-.
~; ~ J , ~ s, ~3 - 41 - ~3121 esters o~ polyalcohols, ~or example Span;
polyglycerol esters, for example that esterified with C12_18 fat~y acids and one or several OH groups;
polyalkoxylated derivatives, for example polyoxy:polyoxyethylene stearate, and octylphenoxy polyethoxyethanol (TRITON X~100) ethers, for example polyoxyethylene lauryl ether;
ester ethers, for example Tween;
amine oxides, ~or example coconut and dodecyl dimethyl amine oxides.
Mixtures of two or more of the above sur~ace active agents can be employed in the composition according to the invention.
(c) cationic polymers chosen from:
Guar Hydroxypropyltrimonium chloride Quaternium l9 Quat~rnium-23 Quaternium-40 3 O Quaternium-57 Poly~dipropyldiallylammonium chloride~ -Poly(methyl ~ -propaniodiallylammonium chloride) Poly(diallylpiperidinium chloride) Poly(vinyl pyridinium chloride~
Quaternised poly (vinyl alcohol) Quaternised poly ' . ', : . ' ' . ' . ' .:' ':
:...... '- ' ,, ' ' ~, ~' .
- \
- ~2 - J3121 (dimethylaminoethylmethacrylate); and mixtures thereof The amount of activity enhancer, when employed in accordance with the invention, will normally be from 0.1 to 50%, preferably from 0.5 to 25% and most preferably from 0.5 to 10% by weight of the composition.
Other hair qrowth promoter adiuncts The composition according to the invention can also contain adjuncts other than those already mentioned, depending on the form of the intended product. It is, for example, possible to include antiseptics, preservatives, antioxidants, emulsifiers and colouring agents, which can improve the stability and consumer appeal of the composition.
The composition according to the invention can also be employed as a vehicle ~or a wide variety of cosmetically or pharmaceutically active ingredients, particularly ingredients which have some beneficial 2s effect other than the promotion of hair growth when applied to the skin.
Process The invention also provides a process for the pr~paration of a composition suitable for topical application to mammalian skin or hair which comprises mixing a hair growth promoter as herein de~ined, with a suitable vehicle to provide a composition according to 3S the invention, in which the hair growth promoter ~orms from 0. 0001 to 99% by weight of the composition.
_ ~3 _ J3121 ;Product Form and Container The compositions of the invention can be formulated as liquids, for example as a lotion, shampoo, milk or cream for use in conjunction with an applicator such as a roll-ball applicator, or a spray device such as an aerosol can containing propellant, or a container fitted with a pump to dispense the liquid product. Alternatively, the compositions of the invention can be solid or semi-solid, for example sticks, creams or gels, ~or use in conjunction with a suitable applicator or simply a tube, bottle or lidded jar, or as a liquid-impregnated fabric, such as a tissue wipe.
The invention accordingly also provides a closed container containing a composition as herein defined.
Use of~the hair qrowth promoter_for Inducin~.
Maintaining_Qr Increasinq Hair Growth The invention also provides for the use of hair growth promoter as herein defined, for topical application to mammalian skin or hair for inducing~
maintaining or increasing hair growth.
The compositions according to the invention are primarily intended for topical application to the scalp of the human subject, particularly where the head is o already bald or balding, in order to promote the regrowth of terminal hair. The comp~sitions can also be applied -profilactically to the hair and hence the scalp to reduce or prevent the onset of baldness.
~5The amount of the composition and the frequency of application to the hair and/or scalp can vary widely, depending on personal needs, but it is suggested as an ',' :
,. '..... - - : , ~r~
_ .g4 ~ J3121 example that topical application of from 0.1 to 5g daily containing from 0.00001 to lg of a selected chemical inhibitor over the period of at least six months will in most cases result in an improvement in hair growth.
s , EVALUATION OF EFFICACY OF THE HAIR GROWTH PROMOTERS
ySING THE RAT MODEL
The Rat Hair Growth_~est The effect oE compounds on hair growth was assesced using male albino Wistar rats as an animal model. The rats were chosen from as few litters as possible and were each approximately 42 days of age at the start of the ; test. Each rat was housed individually to prevent licking.
In each comparison, 10 rats were used in each qroup and hair growth was assessed as ~ollows:
A small patch of normal skin (4cm x 4cm) on the upper back of each rat was clipped at the start and 0~3 ml of a hair growth stimulant composition (or a control) applied topically twice daily and once on Saturdays and Sundays to each clipped area. The concentration of test compound in the composition was chosen from 0.01 to 20 ~ by weight.
It is to be understood that the potency of each of the hair growth promoters in terms of its ability to induce, maintain or increase hair growth is unlikely to be uniform, some being more potent than others, and ~5 therefore the concentration of any promoter chosen fox - thorough evaluation must be carefully selected after preliminary testing to determine its potential as a hair f ~ ~ ~
- 45 - ~3121 growth promoter. In any case, this concentration will lie within the range of from 0.01 to 20% by weight as stipulated above.
Hair was clipped from the area of the patch twice weekly, collected and weighed at each time point over a standard period of 3 months, and cumulative hair weight calculated. From these data, it was possible to estimate lo the e~fect of a hair growth promoter acid as a hair growth stimulant (test compound) on the amount and duration of hair growth during the experiment. A
positive response, i.e. an increase of at least 10% by weight of hair after 3 months treatment, compared with a control indicates the potential of the test compound to prevent hair loss and/or reverse baldness in human subjects.
Accordingly, when the hair growth promoters as herein defined, are assessed either individually or in combination as test compound by the Rat Hair Growth Test, an increase of at least 10~ by weight oP hair after 3 months treatement will be obtained. Usually, the 10~ by weight minimum value will be attained well be~ore the end of this 3 months period Measurement of hair ~rowt ~ ical~a~plication of N-acetyl qlycine Topical treatment with a composition according to the invention was found to stimulate hair growth. In -this example, the effect o~ topical application of N-acetyl glycine is shown. The test solution in this experiment contained 10% (w/v) ~f the N-acetyl glycine in the form of a solution in distilled water adjusted to pH
4.2 with potassium hydroxide. The hair growth results are shown below in Table 1.
. ' ' ' ' "' " ''~ ' ' ~ ~
:' :
'. ' ,' ~ :
J
Table 1 ~ .... __ .~ _m ~ , . _.
Trea_ment Mean Cumulative SigniPicance Hair ~eight (mg) Level + sd, af.ter 58 days (vs control) _ _ . _ ._ ~
10% (w/v) N-acetyl glycine 622.8 1 101.11 p =0.02 Control (dis. water adjusted to pH 4.2) 505.9 + 103.1 , _ __ ............. .... __._ . _.
* statistically significant These results indicate that a statistically significant increase (23%) in hair growth was obtained in this experiment.
Examples The invention is illustrated by the following examples.
Example 1 2s This Example illustrates a lotion according to the invention which is suitable for topical application to the scalp in order to promote hair ~rowth.
.
The lotion has the following ~ormulation:
N-acetyl glycine 0.1 ethanol 99.995 perfume q.s.
3s _ 47 - J3121 Example 2 This Example illustrates a hair tonic which is suitable for application to h,air or scalp.
The hair tonic has the following formulation:
., % w/w N-acetyl alanine 0.8 ethanol 50 water 49 perfume . q-S-lS Example 3 This Example also illustrates a lotion which is suitable for topical application to the scalp.
The lotion has the following formulation:
% w/w N-acetyl valine 1.5 propan-2-ol 10 ethanol 88.5 perfume q~s.
~o . .
.' , ~ ' ' .
-- fj r~ r j 3 , ~ Example 4 `':.
This Example also illustrates a hair tonic which is suitable for application to hair or scalp.
s The hair tonic has the following formulation:
% w!W
N-acetyl leucine 0.2 .! 10 ethanol 40 water 59.80 perfume q.s.
., ExamPles 5 to 8 The followinq formulations represent lotions which can be used topically in the treatment of bald or balding male or female heads.
% wlw Hydroxyethyl cellulose 0O4 - 0.4 Absolute ethanol25 25 25 25 Propane-1,2-diol - - 38.4 38.4 Butane-1,3-diol38.4 38.8 - -Paramethyl benzoate 0.2 0.2 0.2 0.2 N-acetyl isoleucine 5 - - -N-acetyl phenylalanine - 1 - -N-acetyl tyrosine - - o.~ _ N-acetyl proline - - - 0.6 Perfume Water to 100 100 100 100 3s s, ~ r~ r.
~ 49 ~ ~3121 Examples 9 to 12 The following formulations represent creams which can be used in the treatment of baldness.
% wlw Cetyl alcohol lopolyoxyethylena (10) 4 4 4 4 Cetyl alcohol 4 4 4 4 Mineral oil 4 2 - -Paraffin wax - 2 4 Partial glyceride of palmitic and stearic acids - - - 4 N-acetyl hydroxyproline 2 N-acetyl serine - 1~5 N-acetyl threonine - - 2 N-acetyl cysteine Triethanolamine 0.75 0.75 0.75 0.75 Butane-1,3-diol 3 3 3 3 Xanthan gum 0.3 0.3 0.3 0.3 Preservative 0.4 0.4 0.4 0.4 Perfume q.s. q.s. q.s.
~.s.
Water to 100 100 100 100 . ~
.: . .
? ~ : -.
:
; _ 50 - J3121 ' Example 13 ~ his Example illustrates a water-in-oil high internal phase emulsion ~ontaining an ester according to the invention.
The emulsion consisted o~E 10% by volume oily phase and 90% by weight aqueous phase~
The oil~ phase and the aqueous phase had the following constitution: keel ~_w/w Oily phase Sorbitan monooleate 20 ~uaternium-18 hectorite 5 Liquid paraffin75 Aqueous phase N-acetyl cystine0.5 Xanthan gum Preservative 0.3 Perfume q.s.
25 Sodium chloride (1% w/w solution) to 100 The emulsion was prepared by taking 10 parts by volume of the oily phase and to it adding slowly with stirring 90 parts by volume of the agueous phase.
The high internal phase water-in-oil emulsion so formed can be applied topically to the scalp, to improve hair growth and regrowth.
.
The following examples 14 to 18 illustrate shampoos for use in washing the hair and scalp, and for promoting hair growth on the scalp.
ExamPle 14 % w/w Sodium lauryl ether sulphate (2 EO) [~1% AD~ 41.4 Lauryl dimethylamino acetic acid betaine: [30% AD] 4 Coconut fatty acid diethanolamine 1.5 Oleyl triethoxy phosphate (BRIPHOS 03D) Polyglycol-polyamine condensation resin (POLYQUART H) [50% active] 1.5 Preservative, colouring matter, salt 0.58 N-acetyl methionine 5 Perfume q.~.
Water to 100 . Example 15 % w~w Sodium lauryl ether sulphate (2 EO) [100% AD~ 12 BRIPHOS 03D 2.5 N-acetyl tryptophan 4 -Magnesium Sulphate 5 Perfume q. s .
Water to 100 3s ' - 52 - ~3121 Example 16 This Example also ill~strates a lotion which is suitable ~or topical applicati.on to the scalp.
The lotion has the ~ollowing formulation:
N-acetyl aspartic acid 1.5 propan-2-ol 10 athanol 88.5 perfume q.s.
Example 17 This Example also illustrates a hair tonic which is suitable for application to hair or scalp.
The hair tonic has the following formulation:
'' ~6 W/W
N-acetyl glutamic acid 0.2 ethanol 40 2s water 59.80 per~ume q.s.
~o . - 53 - J3121 . .
Example 18 % w/w Monoethanolamine lauryl sulphate :
[100% AD] 20 JAGUAR Cl3S 3 BRIPHOS 03D 1.7 Coconut diethanolamide 5 lo N-lauroyl glycine Zinc gluconate 3 Perfume q.s.
Water to 100 pH adjusted to 6.5 Example 19 % w/w 20 Sodium lauryl ether sulphate (3 EO) :
~100% AD] 12 JAGUAR C13S 0.3 N-palmitoyl glycine 2 Sodium chloride 4 Perfume q.s.
Water to 100 , pH adjusted to 6.5 ~5 , .
.
3 s ~ ~
_ 54 ~3121 .
~ Example 20 % w/w Sodium lauryl ether sulphate ( 2 EO) [100% AD] 12 Opacifier 9 N-myristoyl glycine 5 Perfume ~.s.
Water to 100 p~ adjusted to 6.5 Examples 21 This example illustrates a powder composition according to the invention which can be applied topically to the scalp.
% w/w Chemically modified starch 5 Chemically modified cellulose : 25 Boric acid 10 Zinc oxide 5 N-lauroyl hydroxyproline 3 Minoxidil glucuronide 5 Perfume q.s.
Chalk 10 Talc to 100 -~s ~3~ J~ 3 - 55 - ~3121 Example 22 The following example illustrates a lotion according to the invention which can be applied topically to the scalp to prevent hair loss and stimulate hair regrowth.
N-palmitoyl aspastic acid 7 Minoxidil 0.2 ethanol 16 citric acid 1.05 water to 100 pH adjusted to 4.2 with sodium hydroxide Examples 23 & 24 These examples illustrate hair tonics which are ~uitable for application to the hair and scalp.
The hair tonics had the following formulation:
% w/w N-octanoyl glycine 2 - -N-octanoyl hydroxyproline - 3 ethanol 50 50 water 48 47 perfume q.s. q.s.
: '.: . ' .
~ ,, , ' ~ ~ ~3~
;' Example 25 This example illustrates a microgel which is suitable for topical application to hair or scalp.
The gel had the following formulation-w A. Polyoxyethylene (10) oleyl ether 14.5 Polyoxyethylene fatty glyceride 14.5 Light liquid petroleum 13.7 Propylene glycol 7.6 50rbitol 5.9 N-hexanoyl glycine 4 B. Perfume q.s.
C. Water to 100 This microgel was prepared by heating part A to 90C
and part C to 95C and then adding part C to part A with stirring. Part B was then added at 70C and the final mixture cooled and poured into jars at 55C to 60C. On further cooling, a gel`was formed.
'I ~, .; ? , ~ 3 _ 57 _ ~3121 Example 26 This example illustrates a shampoo which is suitable for topical application to hair in order to cleanse it, at the same time delivering an inhibitor to the scalp to enhance hair growth or regro~th.
.:
The shampoo had the following formulation:
~_w/w Triethanolamine lauryl sulphate 16.8 Coconut diethanolamide 3.0 Hydroxypropylmethyl-cellulose (l) 0.25 Corn syrup (80% solids) (2) 20.5 Dimethylpolysiloxane (3) 1.0 Cationic cellulose (4~ 0.5 . .
Ethyl alcohol (SDA 40) 9.0 Vinyl carboxy polymer (5) 0.75 N-hexanoyl aspastic acid Perfume, colour, preservative q.s.
2s Water to 100 Acid or base to pH: 6.5 Methocel E4M (Dow Chemical~
` 2 - 42 Dextrose equivalent (Staley 1300) io 3 - 60,000 centistokes (Viscasil, GEC) 4 - Polymer JR 400 -5 - Carbopol 941 (BF Goodrich) :
' , :
The following formulations represent lotions which can be used topically in the treatment of bald or balding male or female heads.
.~ % w~w Hydroxyethyl cellulose 0.4 Absolute ethanol 25 25 ; Propane-1,2-diol - -Butane-1,3-diol 38.4 38.8 Paramethyl benzoate 0.2 0.2 N-acetyl glycine 5 N-acetyl hydroxyproline - 1 ~: Perfume Water to 100 100 .
,~ ~,q .,~." ,f ~
Exan!ple 29 This Example illustrates a lotion according to the invention which is suitable for topical application to the scalp in order to promote hair growth.
The lotion has the following formulation:
% W/w N-acetyl arginine 0.1 ethanol 99.995 perfume q.s.
lS Example 30 This Example illustrates a hair tonic which is suitable for application to hair or scalp.
The hair tonic has the following formulation:
.~,, wlw N-acetyl lysine 0.8 ethanol 50 2s water 49 perfume q.s.
, ' . .
.
~ r~
Example 31 Thîs Example also illustrates a lotion which is suitable for topical applicat.ion to the scalp.
The lotion has the ~ollowing formulation:
~ w/w N-acetyl histidine 1.5 propan-2-ol 10 ethanol 88.5 perfume q.s.
Example 32 This Example also illustrates a hair tonic which is suitable for application to hair or scalp.
The hair tonic has the following formulation:
% w/w N-acetyl ornithine 0.2 ethanol 40 2s water 59 ~0 perfume q.s.
,.~
Examples 33 to 36 The following formulations represent lotions which : can be used topically in the treatment of bald or balding male or female heads.
;` ~
Hydroxyethyl cellulose 0.4 - 0.4 Absolute ethanol 25 25 25 25 Propane-1,2-diol - - 38.4 38.4 Butane-1,3-diol 38.4 38.8 - -Paramethyl benzoate 0.2 0.2 0.2 0.2 N-acetyl hydroxylysine 5 - - -N-acetyl citrulline - 1 - -N-acetyl lysine - - 0.8 N-lauroyl citrulline - - - 0.6 Per~ume Water to 100 100 100 100 ~o .
, :
Examples 37 to 40 The following formulatio:ns represent creams which ; can be used in the treatment of baldness.
% w/w 37 38 ~9 ~o Cetyl alcohol polyoxyethylene (10) 4 4 4 4 Cetyl alcohol 4 4 4 4 Mineral oil 4 2 - -Paraffin wax - 2 4 Partial glyceride of palmitic and stearic acids - - - 4 N-acetyl hydroxyproline 2 - - -N-acetyl serine - 1.5 N-acetyl threonine - - 2 N-acetyl cysteine - - 1 Triethanolamine 0.75 0.75 0.75 0.75 Butane-1,3 diol 3 3 3 3 Xanthan gum 0.3 0.3 0.3 0.3 Preservative 0.4 0.~ 0.4 0.4 Perfume q.s. q.s. q.s.
~.s.
Water to 100 100 100 100 `
Claims (12)
1. A composition suitable for topical application to mammalian skin and hair for inducing, maintaining or increasing hair growth, which comprises:
i. an effective amount of from 0.001 to 99% by weight of a hair growth promoter chosen from:
N-acylated amino acids, or salts thereof, in which the acyl group has from 2 to 20 carbon atoms; and ii. from 1 to 99.999% by weight of a cosmetically acceptable vehicle for the hair growth promoter;
i. an effective amount of from 0.001 to 99% by weight of a hair growth promoter chosen from:
N-acylated amino acids, or salts thereof, in which the acyl group has from 2 to 20 carbon atoms; and ii. from 1 to 99.999% by weight of a cosmetically acceptable vehicle for the hair growth promoter;
2. A composition according to claim 1, in which the hair growth promoter is chosen from:
N-acetyl glycine N-acetyl methionine N-acetyl aspartic acid N-acetyl citrulline, and mixtures thereof.
N-acetyl glycine N-acetyl methionine N-acetyl aspartic acid N-acetyl citrulline, and mixtures thereof.
3. A composition according to claim 1, in which the hair growth promoter forms from 0.01 to 20% by weight of the composition.
4. A composition according to claim 1, which further comprises an activity enhancer.
5. A composition according to Claim 4, in which the activity enhancer is another hair growth stimulant.
6. A composition according to claim 5, in which the other hair growth stimulant is minoxidil.
7. A composition according to Claim 4, in which the activity enhancer is a penetration enhancer.
8. A composition according to Claim 7, in which the penetration enhancer is a surface active agent.
9. A composition according to Claim 4, in which the activity enhancer is a cationic polymer.
10. A composition according to claim 1, 2 or 3, which is a shampoo or hair conditioner.
11. The use of a composition according to claim 1, 2 or 3, in inducing, maintaining or increasing hair growth following topical application to skin or hair.
12. The composition suitable for topical application as claimed in claim 1 and substantially as described herein.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2023090 CA2023090A1 (en) | 1989-08-16 | 1990-08-10 | Cosmetic composition |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8918709.0 | 1989-08-16 | ||
| CA 2023090 CA2023090A1 (en) | 1989-08-16 | 1990-08-10 | Cosmetic composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2023090A1 true CA2023090A1 (en) | 1991-02-17 |
Family
ID=4145710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2023090 Abandoned CA2023090A1 (en) | 1989-08-16 | 1990-08-10 | Cosmetic composition |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2023090A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018146051A1 (en) * | 2017-02-13 | 2018-08-16 | Unilever Plc | Method of strengthening oxidatively-treated hair |
| WO2018146054A1 (en) * | 2017-02-13 | 2018-08-16 | Unilever Plc | Method of strengthening hair |
-
1990
- 1990-08-10 CA CA 2023090 patent/CA2023090A1/en not_active Abandoned
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018146051A1 (en) * | 2017-02-13 | 2018-08-16 | Unilever Plc | Method of strengthening oxidatively-treated hair |
| WO2018146054A1 (en) * | 2017-02-13 | 2018-08-16 | Unilever Plc | Method of strengthening hair |
| EA038207B1 (en) * | 2017-02-13 | 2021-07-23 | ЮНИЛЕВЕР АйПи ХОЛДИНГС Б.В. | Method of strengthening hair |
| EA038216B1 (en) * | 2017-02-13 | 2021-07-26 | ЮНИЛЕВЕР АйПи ХОЛДИНГС Б.В. | Method of strengthening oxidatively-treated hair |
| US11219589B2 (en) | 2017-02-13 | 2022-01-11 | Conopco, Inc | Method of strengthening oxidatively-treated hair |
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