Hair loss abstract
Topically applicable hair growth-/hair loss-affecting cosmetic/pharmaceutical
compositions for treating mammalian subjects with hair or scalp
disorders, comprise an effective amount of at least one 2-amino-1,3-alkanediol
compound having the structural formula (I): ##STR1## formulated
into a physiologically topically acceptable carrier medium therefor.
Hair loss claims
What is claimed is:
1. A method for inducing or stimulating hair growth and/or retarding
hair loss on a mammalian subject in need of said treatment comprising
topically applying to the hair and/or skin an effective amount of
a cosmetic or pharmaceutical composition of matter, comprising a
hair growth stimulating and/or hair loss retarding effective amount
of at least one 2-amino-1,3-alkanediol compound having the structural
formula (I) which compound induces hair growth and/or retards hair
loss: ##STR5##
in which R.sub.1 is a saturated, and optionally is a hydroxylated,
linear or branched hydrocarbon radical having from 4 to 28 carbon
atoms; R.sub.2 is a hydrogen atom or the radical: ##STR6##
wherein R.sub.3 is a saturated or unsaturated, optionally hydroxylated,
linear or branched hydrocarbon radical having from 1 to 29 carbon
atoms, wherein the hydroxyl group thereof is optionally esterified
by a saturated or unsaturated, linear or branched acyl radical having
from 2 to 30 carbon atoms; and X is a hydrogen atom or the OH radical,
or at least one optical isomer or diastereoisomer thereof, in a
physiologically topically acceptable carrier medium therefor.
2. The method of claim 1 where, in the compound of formula (I),
R.sub.1 is a saturated hydrocarbon radical having from 11 to 23
carbon atoms.
3. The method of claim 1 where, in the compound of formula (I),
R.sub.1 has 14 carbon atoms.
4. The method of claim 1 where, in the compound of formula (I),
R.sub.1 is a saturated linear hydrocarbon radical.
5. The method of claim 1 where, in the compound of formula (I),
R.sub.2 is a radical: ##STR7##
6. The method of claim 5, wherein the R.sub.3 group in said compound
of formula (I) is a hydrocarbon radical having from 7 to 25 carbon
atoms.
7. The method of claim 1 wherein said at least one 2-amino-1,3-alkanediol
compound (I) comprises from 10.sup.-4 % to 20% by weight of said
topically administered composition.
8. The method of claim 7 wherein said at least one 2-amino-1,3-alkanediol
compound (I) comprises from 10.sup.-3 % to 10% by weight of said
topically administered composition.
9. The method of claim 1 wherein said at least one 2-amino-1,3-alkanediol
compound (I) is selected from the group consisting of 2-amino-1,3-octadecanediol,
2-acetylamino-1,3-octadecanediol, 2-octanoylamino-1,3-octadecanediol,
2-tetracosanoylamino-1,3-octadecanediol, 2-N-(2-hydroxyhexadecanoyl)amino-1,3-octadecanediol,
2-oleoylamino-1,3-octadecanediol, 2-hexadecanoylamino-1,3-octadecanediol,
2-N-(2-hydroxydocosanoyl)amino-1,3-octadecanediol, 2-amino-1,3,4-octadecanetriol,
2-hexadecanoylamino-1,3,4-octadecanetriol and 2-N-(2-hydroxyhexadecanoyl)amino-1,3,4-octadecanetriol.
10. The method as defined by claim 9, wherein said at least one
2-amino-1,3-alkanediol compound (I) is 2-N-(2-hydroxyhexadecanoyl)amino-1,3-octadecanediol.
11. The methbd as defined by claim 9, wherein said at least one
2-amino-1,3-alkanediol compound (I) is 2-oleoylamino-1,3-octadecanediol.
12. The method as defined by claim 1, wherein said topically administered
composition comprises an effective amount of at least one active
agent selected from the group consisting of an antibacterial agent,
an agent for combating parasites, an antifungal agent, an antiviral
agent, an anti-inflammatory agent, an antipruriginous agent, an
anaesthetic agent, keratolytic agent, an agent for combating free
radicals, a antiseborrhoeic agent, an antidandruff agent, an antiacne
agent, an agent which modulates at least one of cutaneous pigmentation,
proliferation and differentiation, a substance P antagonist, a calcitonin
gene related peptide antagonist, a bradykinin antagonist and nitric
oxide synthase inhibitor.
13. The method as defined by claim 12, wherein the topically administered
composition further comprises an effective amount of at least one
active agent selected from the group consisting of a substance P
antagonist, a calcitonin gene related peptide antagonist, a bradykinin
antagonists and a nitric oxide synthase inhibitor, in an amount
ranging from 0.000001% to 20% by weight thereof.
14. The method as defined by claim 1, wherein the topically administered
composition further comprises an agent selected from the group consisting
of a hydrophilic or lipophilic gelling agent, a hydrophilic or lipophilic
active agent, a preservative, an antioxidant, a solvent, a fragrance,
a filler, a sunscreen, an odor absorber and a colorant.
15. The method as defined by claim 1, wherein the topically administered
composition further comprises an effective amount of another compound
which stimulates hair growth and/or retards hair loss.
16. The method as defined by claim 1, wherein said topically administered
composition is selected from the group consisting of a solution,
dispersion, lotion, serum, emulsion, milk, suspension, foam, spray,
gel, cream, microcapsules, microparticles, an ionic vesicular dispersion
and a nonionic vesicular dispersion.
17. The method as defined by claim 1, wherein said topically administered
composition is selected from the group consisting of a hair care
formulation, shampoo, hair-setting lotion, styling cream or gel,
coloring formulation, hair-restructuring lotion, permanent-wave
formulation and parasite combatant.
18. The method as defined by claim 1, comprising topically applying
said composition to the hair and/or scalp of said mammalian subject,
to treat a disorder or affliction associated with hair loss.
19. The method as defined by claim 19, wherein said disorder or
affliction is an alopecia induced by chemotherapeutic anticancer
therapy.
20. A method for inducing or stimulalting hair growth and/or retarding
hair loss on a mammalian subject in need of said treatment comprising
topically applying an effective amount of a cosmetic or pharamaceutical
composition of matter, consisting essentially of a hair growth stimulating
and/or hair loss retarding effective amount of at least one 2-amino-1,3-alkanediol
compound having the structural formula (I) which compound induces
hair growth and/or retards hair loss: ##STR8##
in which R.sub.1 is a saturated, optionally hydroxylated, linear
or brached hydrocarbon radical having from 4 to 28 carbon atoms;
R.sub.2 is a hydrogen atom or the radical: ##STR9##
wherein R.sub.3 is a saturated or unsaturated, optionally hydroxylated,
linear or branched hydrocarbon radical having from 1 to 29 carbon
atoms, wherein the hydroxyl group thereof is optionally esterified
by a saturated or unsaturated, linear or branched acyl radical having
from 2 to 30 carbon atoms; and X is a hydrogen atom or is an OH
radical, or at least one optical isomer or diastereoisomer thereof,
in a physicologically topically acceptable carrier medicum therefor.
21. The method of claim 20 wherein said at least one 2-amino-1,3-alkanediol
compound (I) is selected from the group consisting of 2-amino-1,3-octadecanediol,
2-acetylamino-1,3-octadecanediol, 2-octanoylamino-1,3-octadecanediol,
2-tetracosanoylamino-1,3-octadecanediol, 2-N-(2-hydroxyhexadecanoyl)amino-1,3-octadecanediol,
2-oleoylamino-1,3-octadecanediol, 2-hexadecanoylamino-1,3-octadecanediol,
2-N-(2-hydroxydocosanoyl)amino-1,3-octadecanediol, 2-amino-1,3,4-octadecanetriol,
2-hexadecanoylamino-1,3,4-octadecanetriol and 2-N-(2-hydroxyhexadecanoyl)amino-1,3,4-octadecanetriol.
Hair loss description
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention
The present invention relates to novel cosmetic and/or pharmaceutical
compositions for topical application to the hair and/or scalp of
mammalian subjects, comprising an effective amount of at least one
2-amino-1,3-alkanediol, or derivative thereof, and to the use of
such novel compositions for inducing and/or stimulating hair growth
and/or retarding hair loss.
2. Description of the Prior Art
In human subjects, hair growth and its renewal are principally
determined by the activity of the hair follicles. This activity
is cyclical and essentially entails three phases, namely, the anagenic
phase, the catagenic phase and the telogenic phase.
The active anagenic phase, or growth phase, which lasts for several
years and during which the hair grows longer, is followed by a very
short and transitory catagenic phase, which lasts a few weeks, and
then by a resting or quiescent phase, designated the telogenic phase,
which lasts a few months.
At the end of the rest period, the hair falls out and another cycle
begins anew. The head of hair is thus constantly renewed and, of
the approximately 150,000 hairs on a human head, at any given instant
approximately 10% are at rest and will therefore be replaced in
a few months.
In a significant number of cases, early hair loss occurs in genetically
predisposed subjects and it affects men in particular. It is more
particularly androgenetic or androgenic alopecia or, alternatively,
androgeno-genetic alopecia.
This alopecia is essentially due to a disturbance in hair renewal
which results, at first, in an acceleration in the frequency of
the cycles at the expense of the quality of the hair and then of
its amount. A progressive thinning of the head of hair occurs by
regression of the so-called "terminal" hairs to the downy
stage. Certain regions are preferentially affected, in particular
the temple or frontal areas in men and, in women, a diffuse alopecia
of the vertex is observed.
Compositions that eliminate or reduce the effects of alopecia and,
in particular, that induce or stimulate hair growth or decrease
hair loss have long been considered desiderata in the cosmetic and
pharmaceutical industries.
In this regard, a large number of very diverse active compounds
or substances have already been suggested for such purposes, for
example vitamins, such as vitamin E, amino acids, such as serine
or methionine, vasodilators, such as acetylcholine and derivatives
thereof, female hormones, such as estradiol, keratolytic agents,
such as salicylic acid, or chemical compounds, such as 2,4-diamino-6-piperidinopyrimidine
3-oxide or "Minoxidil," described in U.S. Pat. No. 4,596,812
or, alternatively, its many derivatives, such as those described
in EP-353,123, EP-356,271, EP-408,442, EP-522,964, EP-420,707, EP-459,890
and EP-519,819.
Also exemplary thereof are 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine
and derivatives thereof, which are described, more particularly,
in U.S. Pat. No. 4,139,619.
Nonetheless, considerable research and development is continuing
in this art in quest of yet other such valuable active agents.
Minoxidil, while it remains the reference compound in the field,
exhibits not insignificant side effects which complicate the use
thereof.
SUMMARY OF THE INVENTION
Accordingly, a major object of the present invention is the provision
of compounds of the 2-amino-1,3-alkanediol type for efficaciously
inducing/stimulating hair growth and/or decreasing hair loss, without
exhibiting the disadvantages and drawbacks to date characterizing
the state of this art.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS
OF THE INVENTION
More particularly according to the present invention, the 2-amino-1,3-alkanediol
type compounds or derivatives thereof constitute active agents emanating
from tissues which are known to the art by the very general term
of "sphingolipids."
Among these sphingolipids, N-acylated derivatives based on sphinganine
[(2S,3R)-2-amino-1,3-octadecanediol] are ceramides mostly present
in the hair, whereas the analogous derivatives based on sphingenine
[(2S,3R,4E)-2-amino-4-octadecene-1,3-diol), other ceramides, constitute
a fraction of the lipids mostly present in the stratum corneum of
the skin.
The ceramides are formulated into cosmetics in the natural or synthetic
state, for example, to reinforce the barrier effect of the stratum
corneum in order to reduce water loss and thus dryness of the skin
(GB-2,178,312, GE-2,213,723, EP-227,994, EP-282,616 and EP-556,957).
They are also formulated into cosmetic compositions for their properties
which confer a better elasticity on the skin (EP-500,437) or into
compositions for hair use in order to reinforce the hair and/or
to repair the damage caused by the continual attacks to which the
latter is subjected.
Hitherto, to the knowledge of the assignee hereof, it has never
been described nor even suggested that 2-amino-1,3-alkanediols or
derivatives thereof exert an effect or influence on cell proliferation
and still less on keratinocyte proliferation.
It is on the basis of this new property of these aminodiols that
it has unexpectedly been shown that these compounds also exert an
effect on the survival of the hair follicle.
Thus, by increasing the survival time of the hair follicle, the
anagenic phase of the hair cycle is lengthened, which has the effect
of delaying hair loss.
Among the sphingolipids, compounds based on sphingenine induce
apoptosis, directly or through a series of events involving cellular
proteins. This phenomenon, which results in cell death, transposed
to the hair cycle, elicits a halt in the growth of the follicle
and in hair loss.
The synthesis of compounds based on sphingenine results from several
distinct mechanisms. Exemplary are the activation of cellular sphingomyelinase
by .alpha.-type tumor necrosis factor (TNF-.alpha.), by vitamin
D, by interleukin-1, by the FAS antigen or ionizing radiation. It
is also known that compounds based on sphingenine can also be generated
by activation of acyl-CoA: sphinganine (sphingosine) N-acyltransferase
(EC 2.3.1.24).
Thus, it has now unexpectedly been determined that the compounds
of formula (I) can interfere both during the synthesis of the compounds
based on sphingenine and during the events induced by these compounds.
The consequence of this is to prevent the apoptosis induced by the
compounds based on sphingenine and also to stimulate cell growth
and viability.
In chemotherapeutic anticancer treatments, the use of anticancer
agents causes cell death in the hair follicle, resulting in hair
loss. This induced alopecia is generally transitory, but can sometimes
be permanent (A. M. Hussein, South Med. J., 1993, 86, 489-496).
This side effect causes some patients to refuse this type of therapy
(K. O. Baxley et al., Cancer Nurs., 1984, 7, 499-503).
Doxorubicin, for example, induces such a hair loss. It is known
that doxorubicin activates ceramide synthase, an enzyme whose activation
results in an increase in the intracellular level of compounds based
on sphingenine which themselves induce the phenomenon of apoptosis
and of cell death.
It has now been determined that the compounds of formula (I) below
counteract the harmful side effects of anticancer agents, such as,
for example, doxorubicin, by increasing the cell viability of the
keratinocytes of the hair follicles.
The present invention features the formulation, into cosmetic/pharmaceutical
compositions, as active agents promoting hair survival and/or growth,
of at least one compound having the general formula (I): ##STR2##
in which R.sub.1 is a saturated or unsaturated, optionally hydroxylated,
linear or branched hydrocarbon radical having from 4 to 28 carbon
atoms; R.sub.2 is a hydrogen atom or the radical: ##STR3##
wherein R.sub.3 is a saturated or unsaturated, optionally hydroxylated,
linear or branched hydrocarbon radical having from 1 to 29 carbon
atoms, with the proviso that the hydroxyl group thereof may be esterified
by a saturated or unsaturated, linear or branched acyl radical having
from 2 to 30 carbon atoms; and X is a hydrogen atom or the OH radical,
or of at least one of its optical isomers or one of the diastereoisomers.
R.sub.1 preferably has from 11 to 23 carbon atoms and even more
preferably 14 carbon atoms.
R.sub.2 preferably is the radical: ##STR4##
wherein R.sub.3 preferably has from 7 to 25 carbon atoms.
R.sub.1 is preferably a saturated and/or linear hydrocarbon radical,
more particularly a saturated linear hydrocarbon radical.
R.sub.1 is more preferably a saturated hydrocarbon radical having
14 carbon atoms and even more preferably R.sub.1 is a saturated
linear hydrocarbon radical having 14 carbon atoms.
The active agent promoting hair survival and/or growth can be a
mixture of compounds of formula (I) for which R.sub.1 and/or R.sub.2
are radicals of different chain lengths.
These compounds can be employed in the form of a pure isomer or
of a mixture of isomers.
These compounds present the advantage of not inducing undesirable
side effects, which makes their use without risk for the user.
Exemplary compounds of formula (I) include:
2-Amino-1,3-octadecanediol;
2-Acetylamino-1,3-octadecanediol;
2-Octanoylamino-1,3-octadecanediol;
2-Tetracosanoylamino-1,3-octadecanediol;
2-N-(2-Hydroxyhexadecanoyl)amino-1,3-octadecanediol;
2-Oleoylamino-1,3-octadecanediol;
2-Hexadecanoylamino-1,3-octadecanediol;
2-N-(2-Hydroxydocosanoyl)amino-1,3-octadecanediol;
2-Amino-1,3,4-octadecanetriol;
2-Hexadecanoylamino-1,3,4-octadecanetriol; and
2-N-(2-Hydroxyhexadecanoyl)amino-1,3,4-octadecanetriol.
In a preferred embodiment according to the invention, 2-N-(2-hydroxyhexadecanoyl)amino-1,3-octadecanediol
and 2-oleoylamino-1,3-octadecanediol are employed.
The amount of the compounds of formula (I) which are advantageously
used according to the invention depends, of course, on the nature
of the compound itself, on its physicochemical properties and on
the technique for the application thereof. One skilled in this art
is cognizant how to adjust the amount of the at least one compound
of formula (I) according to the requirements thereof.
For example, the compounds of formula (I) can be formulated at
concentrations by weight of from 10.sup.-4 % to 20% and preferably
from 10.sup.-3 % to 10% in the composition.
The present invention also features the use of at least one compound
of formula (I) for combating an alopecia induced by an anticancer
treatment entailing chemotherapy.
When the compound of formula (I) is formulated into a composition
which must be topically applied onto the skin and particularly onto
the scalp, this composition can be provided in all of the pharmaceutical
dosage forms typically employed.
For topical application onto the skin, the composition can be in
the form, in particular, of an aqueous, alcoholic, aqueous/alcoholic
or oily solution, or of a dispersion of the lotion or serum type,
of an emulsion having a liquid or semi-liquid consistency of the
milk type, obtained by dispersion of a fatty phase in an aqueous
phase (O/W) or vice versa (W/O), or of a suspension or of an emulsion
with a soft consistency of the aqueous or anhydrous gel, foam or
cream type, or, alternatively, of microcapsules or microparticles,
or of a vesicular dispersion of ionic and/or nonionic type. It can
also be in the form of an aerosol composition also comprising a
pressurized propellent agent.
Whatever its form, this composition is formulated according to
the usual techniques.
The amounts of the different constituents of the compositions according
to the invention are those that are conventional in the fields under
consideration.
The compounds according to the invention can also be formulated
into various compositions for hair care and, in particular, shampoos,
hair-setting lotions, treating lotions, styling creams or gels,
dye compositions (in particular oxidation dyes), optionally in the
form of color-enhancing shampoos, hair-restructuring lotions, permanent-wave
compositions (in particular compositions for the first step of a
permanent wave), shampoos for combating parasites, and the like.
When the subject composition comprises an emulsion, the proportion
of the fatty phase advantageously ranges from 5% to 80% by weight,
and preferably from 5% to 50% by weight, with respect to the total
weight of the composition. The oils, the waxes, the emulsifiers
and the coemulsifiers comprising the composition in the emulsion
form are selected from among those conventionally used in the cosmetics
field. The emulsifier and the coemulsifier are present, in the composition,
in a proportion advantageously ranging from 0.3% to 30% by weight,
and preferably from 0.5% to 20% by weight, with respect to the total
weight of the composition. The emulsion can, in addition, contain
lipid vesicles.
When the composition is an oily gel or solution, the fatty phase
can constitute more than 90% of the total weight of the composition.
Also intended are compositions comprising at least one compound
of formula (I) as an active principle intended to induce and/or
to stimulate hair growth and/or to slow down or retard its loss
comprising liposomed form, such as, in particular, described in
WO-94/22468, filed Oct. 13, 1994 and assigned to Anti-Cancer Inc.
The compound encapsulated in the liposomes can thus be delivered
selectively to the hair follicle.
The subject compositions can also contain additives and adjuvants
which are conventional in the cosmetics field, such as hydrophilic
or lipophilic gelling agents, hydrophilic or lipophilic additives,
preservatives, antioxidants, solvents, fragrances, fillers, screening
agents, odor absorbers and colorants. The amounts of these different
additives and adjuvants are those typically employed in the cosmetics
field and range, for example, from 0.01% to 10% of the total weight
of the composition. These additives and adjuvants, depending on
the nature thereof, can be introduced into the fatty phase, into
the aqueous phase and/or into the lipid spherules.
Exemplary oils or waxes according to the invention include mineral
oils (liquid petrolatum), vegetable oils (liquid fraction of karite
butter, sunflower oil), animal oils (perhydrosqualene), synthetic
oils (purcellin oil), silicone oils or waxes (cyclomethicone) and
fluorinated oils (perfluoropolyethers), beeswax, carnauba wax or
paraffin wax. Fatty alcohols and fatty acids (stearic acid) can
be added to these oils.
Exemplary emulsifiers which are suitable per the invention include
glyceryl stearate, polysorbate 60 and the PEG-6/PEG-32/glycol stearate
mixture marketed under the trademark Tefose.RTM.63 by Gattefosse.
Exemplary solvents according to the invention include the lower
alcohols, in particular ethanol and isopropanol, or propylene glycol.
And exemplary hydrophilic gelling agents include carboxyvinyl polymers
(carbomer), acrylic copolymers such as acrylate/alkyl acrylate copolymers,
polyacrylamides, polysaccharides such as hydroxypropylcellulose,
natural gums and clays and representative lipophilic gelling agents
include the modified clays such as bentones, metal salts of fatty
acids such as aluminum stearates, and hydrophobic silica, ethylcellulose
or polyethylene.
The subject compositions can also contain other hydrophilic active
principles, such as proteins or protein hydrolysates, amino acids,
polyols, urea, allantoin, sugars and sugar derivatives, water-soluble
vitamins, plant extracts and hydroxy acids.
Exemplary such lipophilic active principles include those of retinol
(vitamin A) and derivatives thereof, tocopherol (vitamin E) and
derivatives thereof, essential fatty acids, ceramides other than
the compounds of formula (I), essential oils or salicylic acid and
derivatives thereof.
It is also envisaged to formulate, in combination with the compounds
of formula (I), compounds which further improve the activity with
respect to hair regrowth and/or with respect to slowing down or
retarding hair loss and which are already known to this art for
such activity.
Exemplary such compounds include, without limitation:
(a) nicotinic acid esters, including in particular tocopherol nicotinate,
benzyl nicotinate and C.sub.1 -C.sub.6 alkyl nicotinates, such as
methyl nicotinate or hexyl nicotinate;
(b) pyrimidine derivatives, such as 2,4-diamino-6-piperidinopyrimidine
3-oxide or "Minoxidil," described in U.S. Pat. No. 4,596,812
or, alternatively, its many derivatives, or compounds such as 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine
and derivatives thereof, as described in U.S. Pat. No. 4,139,619;
(c) agents promoting hair regrowth, such as those described in
published European patent application No. 0,648,488 assigned to
the assignee hereof;
(d) antibacterial agents, such as macrolides, pyranosides and tetracyclines,
and in particular erythromycin;
(e) calcium antagonists, such as cinnarizine and diltiazem;
(f) hormones, such as estriol or analogs thereof, or thyroxine
and its salts;
(g) steroidal anti-inflammatory agents, such as corticosteroids
(for example hydrocortisone);
(h) antiandrogen agents, such as oxendolone, spironolactone or
diethylstilbestrol;
(i) 5-.alpha.-reductase antagonists;
(j) OH-radical scavengers, such as dimethyl sulfoxide.
Other such compounds include, for example, diazoxide, spiroxazone,
phospholipids, such as lecithin, linoleic and linolenic acids, salicylic
acid and derivatives described in FR-2,581,542, such as the derivatives
of salicylic acid bearing an alkanoyl substituent having from 2
to 12 carbon atoms in the 5 position of the benzene ring, hydroxycarboxylic
or ketocarboxylic acids and esters thereof, lactones and their corresponding
salts, anthralin, carotenoids, eicosatetraenoic and eicosatrienoic
acids or the esters and amides thereof, or vitamin D and derivatives
thereof.
According to the invention, it is possible, inter alia, to combine
at least one compound of formula (I) with other active agents intended,
in particular, for the prevention and/or the treatment of cutaneous
conditions, particularly conditions of the scalp. Exemplary of such
active agents are:
(1) agents which modulate cutaneous pigmentation and/or proliferation
and/or differentiation, such as retinoic acid and its isomers, retinol
and its esters, vitamin D and its derivatives, estrogens, such as
estradiol, kojic acid or hydroquinone;
(2) antibacterials, such as clindamycin phosphate, erythromycin
or antibiotics from the tetracycline class;
(3) agents for combating parasites, in particular metronidazole,
crotamiton or pyrethroids;
(4) antifungals, in particular compounds belonging to the imidazole
class, such as econazole, ketoconazole or miconazole or their salts,
polyene compounds, such as amphotericin B, compounds of the allylamine
family, such as terbinafine, or alternatively octopirox;
(5) antiviral agents, such as acyclovir;
(6) steroidal anti-inflammatory agents, such as hydrocortisone,
betamethasone valerate or clobetasol propionate, or nonsteroidal
anti-inflammatory agents, such as ibuprofen and its salts, diclofenac
and its salts, acetylsalicylic acid, acetaminophen or glycyrrhetinic
acid;
(7) anaesthetic agents, such as lidocaine hydrochloride and derivatives
thereof;
(8) antipruriginous agents, such as thenaldine, trimeprazine or
cyproheptadine;
(9) keratolytic agents, such as .alpha.- and .beta.-hydroxycarboxylic
acids or .beta.-ketocarboxylic acids, their salts, amides or esters
and more particularly hydroxy acids, such as glycolic acid, lactic
acid, salicylic acid, citric acid and, generally, fruit acids, and
5-(n-octanoyl)salicylic acid;
(10) agents for combating free radicals, such as .alpha.-tocopherol
or its esters, superoxide dismutases, certain metal chelating agents
or ascorbic acid and its esters;
(11) antiseborrhoeics, such as progesterone;
(12) antidandruff agents, such as octopirox or zinc pyrithione;
(13) antiacne agents, such as retinoic acid or benzoyl peroxide;
(14) substances such as substance P, CGRP or bradykinin antagonists
or NO synthase inhibitors, which compounds are described as being
active for the treatment of sensitive skins and as exhibiting antiirritant
effects, in particular with respect to irritant compounds possibly
present in the compositions.
Thus, this invention also features compositions comprising an effective
amount of at least one compound of formula (I) and at least one
active agent selected from among antibacterial agents, agents for
combating parasites, antifungal agents, antiviral agents, anti-inflammatory
agents, antipruriginous agents, anaesthetic agents, keratolytic
agents, agents for combating free radicals, antiseborrhoeic agents,
antidandruff agents, antiacne agents, agents which modulate cutaneous
pigmentation and/or proliferation and/or differentiation, substance
P, CGRP (calcitonin gene related peptide) or bradykinin antagonists
or NO synthase inhibitors.
In the compositions according to the invention, the substance P,
CGRP or bradykinin antagonist or the NO synthase inhibitor is preferably
incorporated in an amount ranging from 0.000001% to 20% of the total
weight of the composition and in particular in an amount constituting
from 0.0001% to 15% of the total weight of the composition.
It is envisaged to employ at least one of the compounds corresponding
to the formula (I) for the formulation of a pharmaceutical, particularly
dermatological, composition intended to treat hair loss and/or to
promote hair regrowth.
In general, these pharmaceutical compositions are distinguished,
in particular, from cosmetic compositions by the amount of active
principle which they contain. One skilled in this art can readily
determine the amount of active principle which can be used as a
function of the result desired, but also taking account of the mode
of administration envisaged.
For example, the compound of formula (I) can be employed for the
preparation of a pharmaceutical composition at a concentration of
from 0.01% to 20% and preferably from 0.1% to 10% by weight with
respect to the weight of the composition.
The cosmetic or pharmaceutical compositions according to the invention
can be topically applied onto the alopecic areas of the scalp and
hair of an individual and optionally maintained in contact for a
number of hours and optionally rinsed. It is possible, for example,
to apply the composition containing an effective amount of at least
one compound of formula (I) in the evening, to retain the composition
in contact overnight and optionally to shampoo in the morning. These
applications can be repeated daily for one or a number of months,
depending on the particular individuals involved.
Thus, the present invention also features a regimen for the cosmetic
treatment of the hair and/or of the scalp, comprising topically
applying onto the hair and/or the scalp, a cosmetic composition
comprising an effective amount of at least one compound of formula
(I) in a physiologically topically acceptable carrier medium therefor,
maintaining this composition in contact with the hair and/or the
scalp, and optionally later rinsing the same therefrom.
In order to further illustrate the present invention and the advantages
thereof, the following specific examples are given, it being understood
that same are intended only as illustrative and in nowise limitative.
In said examples to follow, all parts and percentages are given
by weight, unless otherwise indicated.
EXAMPLE 1
Measurement of the Proliferative Influence of 2-amino-1,3-octadecanediol
and Derivatives Thereof on Cultured Keratinocytes
HaCat cells (Boukamp and coworkers, J. Cell Biol., vol. 106, March
1988, 761-771) were cultured in DMEM medium (marketed by Gibco)
containing amino acids (mixture of nonessential amino acids) at
a concentration of 0.1 mM, penicillin and streptomycin at respective
concentrations of 50 International Units per millimeter and of 50
.mu.g/ml, glutamine at a concentration of 2 mM, sodium pyruvate
at a concentration of 1 mM and 10% fetal calf serum. These cells
were inoculated at a density of 10,000 cells per well in the 24
wells of plates of the multiwell type (Costar, France). 24 hours
after inoculation, the cells were contacted with the various test
compounds in a KBM medium (marketed by Clonetics) containing 0.15
mM of calcium ion, insulin at 5 .mu.g/ml, hydrocortisone at 0.5
.mu.g/ml and lipid-free bovine serum albumin at 1 .mu.g/ml.
Cellular counting was carried out 5 days after the addition of
the various ceramides using a cell counter of the Coulter Counter
type.
The various compounds were tested at 0.5 nM, 5 nM, 50 nM and 500
nM.
The results, expressed as percentage, represent the increase in
the number of cells with respect to the control, namely, with respect
to a culture produced under the same conditions in the absence of
sphinganine.
The different compounds tested were:
A: 2-amino-1,3-octadecanediol,
B: 2-oleoylamino-1,3-octadecanediol,
C: 2-N-(2-hydroxyhexadecanoyl)amino-1,3- octadecanediol,
D: 2-tetracosanoylamino-1,3-octadecanediol,
E: 2-acetylamino-1,3-octadecanediol,
F: 2-octanoylamino-1,3-octadecanediol.
A B C D E F 0.5 nM 7 17 26 22 17 15 5 nM 15 24 36 27 34 18 50 nM
17 23 42 33 29 31 500 nM 30 14 22 42 35 27
These results evidence that 2-amino-1,3-octadecanediol and derivatives
thereof exhibit a proliferative activity with respect to cultured
keratinocytes.
EXAMPLE 2
Measurement of the Effect of 2-amino-1,3-octadecanediol and Derivatives
Thereof on Cell Viability
HaCat cells were cultured as in Example 1.
These were then inoculated at a density of 20,000 cells per well
in the 24 wells of plates of the multiwell type (Costar, France).
24 hours after inoculation, the cells were contacted with the various
test compounds in a KBM medium (marketed by Clonetics) containing
insulin at 5 .mu.g/ml and hydrocortisone at 0.5 .mu.g/ml.
Cell viability was evaluated 48 hours later by measuring the mitochondrial
respiration. This was carried out using an XTT kit, marketed by
Boehringer, according to the supplier's instructions.
The compounds A, B and C of the above Example 1 were tested at
a concentration of 50 nM, as well as a derivative based on sphingenine:
N-palmitoylsphingenine marketeed by Sigma (C16H).
The results, expressed as percentage, represent the increase in
the number of cells with respect to the control, namely, with respect
to a culture produced under the same conditions in the absence of
alkanediol compounds.
Control 0 A +17 B +23 C +20 C16H -25
The results evidence that 2-amino-1,3-octadecanediol (A), 2-oleoylamino-1,3-octadecanediol
(B) and 2-N-(2-hydroxyhexadecanoyl)amino-1,3-octadecanediol (C)
increased the viability of the cultured keratinocytes, whereas N-palmitoylsphingenine
(C16H) elicited a cytotoxic effect on the cultured cells.
This result indicates that compounds based on sphingenine cannot
be used for the treatment of hair follicles since they cause cell
death in culture.
EXAMPLE 3
Measurement of the Effect of 2-amino-1,3-octadecanediol and Derivatives
Thereof on the Cell Cycle
HaCat cells were cultured as above.
These were then inoculated at a density of 20,000 cells per well
in the 24 wells of plates of the multiwell type (Costar, France).
24 hours after inoculation, the cells were contacted with the various
test compounds in a KBM medium (marketed by Clonetics) containing
insulin at 5 .mu.g/ml and hydrocortisone at 0.5 .mu.g/ml and 5-bromo-2'-deoxyuridine
(BrdU) at 1 .mu.M.
The phase of the cell cycle was evaluated 48 hours later by measuring
the incorporation of BrdU in genomic deoxyribonucleic acid. This
was carried out using a BrdU fast kit, marketed by Boehringer, according
to the supplier's instructions.
The compounds A, B and C of the above example were tested at a
concentration of 50 nM.
The results, expressed as percentage, represent the increase in
the number of cells which have entered into the S phase with respect
to the control, namely, with respect to a culture produced under
the same conditions in the absence of alkanediol compounds.
72 hours 96 hours Control 0 0 A 36 41 B 43 51 C 17 43
The results evidence that 2-amino-1,3-octadecanediol (A), 2-oleoylamino-1,3-octadecanediol
(B) and 2-N-(2-hydroxyhexadecanoyl)amino-1,3-octadecanediol (C)
increase the number of keratinocytes which have entered into the
S phase, thus indicating stimulation of cell mitotic activity.
EXAMPLE 4
Measurement of the Effect of 2-amino-1,3-octadecanediol and Derivatives
Thereof on the Survival of the Hair Follicle in Vitro
Viable in vitro hair follicles were prepared according to the technique
described in FR-95/08,465, filed Jul. 12, 1995 and assigned to the
assignee hereof.
From a scalp biopsy, a rather fine strip of scalp was isolated
using a scalpel. The adipose tissue surrounding the follicles was
removed with microforceps while avoiding damage to the hair bulb.
The follicle was cut and removed with a scalpel under a microscope
in order to separate it from its epidermal and dermal surroundings.
The fragment obtained was maintained in culture in Williams E medium,
at 37.degree. C., in a humid atmosphere in the presence of CO.sub.2.
The survival of the follicles was evaluated each day by counting
the living follicles, according to their morphological appearance.
The results are reported as percentage of surviving follicles per
day.
The experiment was carried out employing the following compounds
at a concentration of 50 nM:
B: 2-amino-1,3-octadecanediol,
C: 2-oleoylamino-1,3-octadecanediol,
D: 2-N-(2-hydroxyhexadecanoyl)amino-1,3-octadecanediol,
in comparison with the culture medium without alkanediol (A).
Days 0 1 5 10 15 20 25 A n = 19 100 100 84 16 0 0 0 B n = 10 100
100 90 20 0 0 0 C n = 9 100 100 100 78 33 0 0 D n = 12 100 100 100
50 42 25 0 n = number of follicles tested in the experiment
This experiment evidenced that the alkanediols increased the survival
time of the cultured hair follicle.
EXAMPLE 5
Effect of 2-amino-1,3-octadecanediol and Derivatives Thereof on
Cell Viability in the Presence of Doxorubicin
HaCat cells were cultured as in Example 2.
24 hours after inoculation, the cells were contacted with the various
test compounds in a KBM medium (marketed by Clonetics) containing
insulin at 5 .mu.g/ml and hydrocortisone at 0.5 .mu.g/ml.
The cells were cultured in the presence of the 2-amino-1,3-octadecanediol
to be tested until evaluation of cell viability.
Doxorubicin at a concentration of 1 .mu.g/ml was added to the culture
medium for 2 hours at the beginning of the experiment.
Cell viability was evaluated 48 hours later by measuring the mitochondrial
respiration. This was carried out using an XTT kit, marketed by
Boehringer, according to the supplier's instructions.
The experiment was carried out with the following compounds at
a concentration of 50 nM:
C: 2-amino-1,3-octadecanediol,
D: 2-oleoylamino-1,3-octadecanediol,
E: 2-N-(2-hydroxyhexadecanoyl)amino-1,3-octadecanediol,
in comparison with the culture medium without alkanediol and without
doxorubicin (A) and with a medium containing only doxorubicin (B).
The results, expressed as percentage, represent the increase in
the number of cells with respect to the control (A), namely, with
respect to a culture produced under the same conditions in the absence
of alkanediol compounds and of doxorubicin.
A 0 B -20 C +25 D +28 E +23
Doxorubicin caused a decrease in cell viability. The presence in
the culture medium of a 2-amino-1,3-octadecanediol inhibited this
effect and increased cell viability.
EXAMPLE 6
Effect of 2-amino-1,3-octadecanediol and Derivatives Thereof on
Cell Viability in the Presence of a Compound Based on Sphingenine,
N-acetylsphingenine
The cells were cultured as in Example 5. N-Acetylsphingenine was
at a concentration of 10 .mu.M.
The experiment was carried out with the following compounds at
a concentration of 50 nM:
C: 2-amino-1,3-octadecanediol,
D: 2-oleoylamino-1,3-octadecanediol,
E: 2-N-(2-hydroxyhexadecanoyl)amino-1,3-octadecanediol,
in comparison with the culture medium without alkanediol and without
N-acetylsphingenine (A) and with a medium containing only N-acetylsphingenine
(B).
The results, expressed as percentage, represent the number of cells
with respect to the control (A), namely, with respect to a culture
produced under the same conditions in the absence of alkanediol
compounds and of N-acetylsphingenine.
A 100 B 57 C 72 D 76 E 78
N-Acetylsphingenine caused a decrease in cell viability. The presence
in the culture medium of a 2-amino-1,3-octadecanediol tended to
counteract this effect. |