Hair loss abstract
The use of an effective amount of at least one bradykinin antagonist
as the active principle in a physiologically acceptable medium in
a cosmetic composition or for preparing a drug is disclosed. The
antagonist or drug is intended to induce and/or stimulate hair growth,
and/or control hair loss.
Hair loss claims
1. Use, in a cosmetic composition or for the preparation of a medicinal
product, of an effective amount of at least one bradykinin antagonist,
this antagonist or the medicinal product being intended to induce
and/or stimulate hair growth and/or slow down hair loss.
2. Use according to the preceding claim, characterized in that
the bradykinin antagonist is chosen from compounds which inhibit
the synthesis and/or accelerate the catabolism of bradykinin, bradykinin
neutralizers, bradykinin receptor blockers such as those which interfere
with the effects of bradykinin by binding to its receptor (B1 or
B2), compounds which inhibit the synthesis of bradykinin receptors
or compounds involved in modulating the signal transduced by bradykinin.
3. Use according to either of the preceding claims, characterized
in that the bradykinin antagonist is chosen from optionally modified,
natural or synthetic peptides, natural or synthetic chemical molecules,
antisense nucleic acids, ribozymes, anti-bradykinin antibodies,
soluble bradykinin receptors, anti-bradykinin-receptor antibodies
or bradykinin receptor antagonists.
4. Use according to any one of the preceding claims, characterized
in that the bradykinin antagonist is chosen from compounds which
interfere with the effects of bradykinin by binding to its receptor
(B1 or B2) and preferably to the B2 receptor.
5. Use according to any one of the preceding claims, characterized
in that the bradykinin antagonist is chosen from D-Arg, [Hyp3, D-Phe7]bradykinin
(NPC567), [Thi5,8, D-Phe7]bradykinin, D-Arg, [Hyp3, Thi5,8, D-Phe7]bradykinin,
N-.alpha.-adamantaneacetyl-D-Arg, [Hyp3, Thi5,8, D-Phe7]-bradykinin,
des-Arg9, [Leu8]bradykinin, P-guanidobenzoyl, [Hyp3, Thi5, D-Tic7,
Oic8]bradykinin (S 16118), D-Arg, [Hyp3, Thi5, D-Tic7, Oic8]bradykinin
(HOE 140), D-Arg, [Hyp3, D-Hype (transpropyl)7, Oic8]bradykinin
(NPC 17731).
6. Use according to the preceding claim, characterized in that
the bradykinin antagonist is D-Arg, [Hyp3, Thi5, D-Tic7, Oic8]bradykinin
(HOE 140).
7. Process for the cosmetic treatment of the hair and/or the scalp,
characterized in that it consists in applying a cosmetic composition
as defined in any one of claims 1 to 6 to the hair and/or the scalp,
in leaving this composition in contact with the hair and/or the
scalp and optionally in carrying out a rinsing operation.
Hair loss description
[0001] The present invention relates to the use, as active principle,
in a physiologically acceptable medium, in a cosmetic composition
or for the preparation of a medicinal product, of an effective amount
of at least one bradykinin antagonist which is intended to induce
and/or stimulate hair growth and/or slow down hair loss.
[0002] In human beings, hair growth and its renewal are mainly
determined by the activity of the hair follicles. Their activity
is cyclical and comprises essentially three phases, namely the anagenic
phase, the catagenic phase and the telogenic phase.
[0003] The active anagenic phase or growth phase, which lasts 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 phase, known as the telegenic phase, which lasts
a few months.
[0004] At the end of the resting period, the hair falls out and
another cycle recommences. The head of hair is thus constantly renewed
and, of the approximately 150,000 hairs which a head of hair contains,
at each instant, approximately 10% of them are at rest and will
therefore be replaced in a few months.
[0005] In a significant number of cases, early hair loss takes
place in subjects who are genetically predisposed to it and it affects
men in particular. It is more particularly androgenetic or androgenic
alopecia or alternatively androgeno-genetic alopecia.
[0006] 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 takes
place by regression of the so-called "terminal" hairs
to the downy stage. Regions are preferentially affected, in particular
the temple or frontal bulbs in men and, in women, a diffuse alopecia
of the vertex is observed.
[0007] The term alopecia covers a whole family of complaints of
the hair follicle, whose final consequence is the partial or general
permanent loss of the hair. Mention may be made, for example, of
androgenic alopecia.
[0008] A search has been under way for many years in the cosmetic
or pharmaceutical industry for substances which make it possible
to suppress or reduce the effect of alopecia and in particular to
decrease hair loss or to induce or to stimulate its growth.
[0009] In this perspective, a large number of very diverse active
compounds have, admittedly, already been proposed, such as, for
example 2,4-diamino-6-piperidinopyrimidine 3-oxide or "Minoxidil"
described in U.S. Pat. No. 4,596,812, or alternatively the many
derivatives thereof such as those described, for example, in patent
applications EP 0,353,123, EP 0,356,271, EP 0,408,442, EP 0,522,964,
EP 0,420,707, EP 0,459,890 and EP 0,519,819.
[0010] Mention may also be made of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-
-piperidinopyrimidine and the derivatives thereof, which are described
more particularly in patent U.S. Pat. No. 4,139,619.
[0011] It generally remains that it would be advantageous and useful
to have available active compounds other than those already known,
that are potentially more active and/or less toxic.
[0012] Bradykinin is a peptide of plasma origin released from a
kininogen precursor by a plasma protease known as kallikrein (EC
3.4.21.24). This nanopeptide is one of the key mediators of inflammation
and has mitogenic properties. The receptors for this kinin are divided
into two main subtypes, B1 and B2. Bradykinin acts in particular
on the B2 receptor and causes the stimulation of many second messenger
production systems including the hydrolysis of inositol phosphates,
the metabolism of arachidonic acid, the phosphorylation of tyrosine
residues and the depolarization or hyperpolarization of the cell
membrane.
[0013] The activation of certain receptors causes the activation
of phospholipase C and thus the production of inositol 1,4,5-triphosphate
(IP3) and of diacylglycerol (DAG). IP3 is known to cause the release
of calcium from intercellular storage sites in cells, including
keratinocytes. Calcium is described as an activator and regulator
of many enzymes (proteases, phospholipases) and plays an important
part in regulating the differentiation and proliferation of keratinocytes.
[0014] Bradykinin is involved in a large number of physiopathological
disorders including: hypotension, contraction of the smooth muscles
in the digestive and respiratory tracts and in the uterus, pain,
the proliferation of connective tissue and the release of different
inflammation mediators: cytokins, leukotrienes and prostaglandins.
[0015] To date, to the Applicant's knowledge, it has neither been
envisaged or even suggested that bradykinin receptors exist in the
hair follicle, nor that bradykinin plays a part in the phenomena
resulting in hair loss and/or hair growth.
[0016] Surprisingly and unexpectedly, the Applicant has just discovered
that Minoxidil, which is known for its effects on regrowth of the
hair and on the storage and/or release of calcium by cells (Matsumoto
et al., Nippon Hifuka Gakkai Zasshi (1993), 103(2), 103-15), blocks
the increase in the calcium concentration of the intracellular medium
induced by bradykinin. The Applicant has also shown that this is
likewise the case for Minoxidil sulphate for which there is general
agreement in the prior art that this is probably the active derivative
of Minoxidil in regrowth of the hair in vivo.
[0017] Thus, Minoxidil or derivatives thereof can act as a bradykinin
antagonist.
[0018] The term bradykinin antagonist is understood to refer to
any compound which is capable of partially, or even totally, inhibiting
the biological effect of bradykinin, except for the compounds known
to have an effect on the storage and/or release of calcium in the
cell, such as Minoxidil and derivatives thereof.
[0019] Particularly, for a substance to be recognized as a bradykinin
antagonist, it must induce a coherent pharmacological response which
may or may not include its binding to the bradykinin receptor.
[0020] Thus, any compound which can interfere with the effects
of bradykinin by binding to the bradykinin receptor (B1 or B2) and/or
any compound which, independently of binding to the receptor(s),
will induce by whatever mechanism an effect contrary to that known
for bradykinin (for example interfering with bradykinin synthesis)
falls within this definition.
[0021] The use of a bradykinin antagonist can thus be one of the
effective routes for controlling hair loss and/or for promoting
regrowth of the hair.
[0022] This discovery forms the basis of the present invention.
[0023] Thus, the invention relates to the use, in a cosmetic composition
or for the preparation of a medicinal product, of an effective amount
of at least one bradykinin antagonist, this antagonist or the medicinal
product being intended to induce and/or stimulate hair growth and/or
slow down hair loss.
[0024] According to the invention, it is possible to use a single
bradykinin antagonist or several together. For example, it is possible
to use a release antagonist and/or a synthesis antagonist in combination
with a B1 and/or B2 receptor antagonist, for example.
[0025] As has been pointed out above, according to the invention,
the term bradykinin antagonist is understood to refer to any compound
which is capable of partially, or even totally, inhibiting the biological
effect of bradykinin, except for the compounds known to have an
effect on the storage and/or release of calcium in the cell, such
as Minoxidil and derivatives thereof.
[0026] Among the bradykinin antagonists, it is preferred to use,
for example, compounds which inhibit the synthesis and/or accelerate
the catabolism of bradykinin, bradykinin neutralizers, bradykinin
receptor blockers such as those which interfere with the effects
of bradykinin by binding to its receptor (B1 or B2), compounds which
inhibit the synthesis of bradykinin receptors or compounds involved
in modulating the signal transduced by bradykinin. These compounds
can be of natural or synthetic origin.
[0027] Among the bradykinin antagonists, mention may be made-more
particularly of optionally modified, natural or synthetic peptides
such as D-Arg, [Hyp3, D-Phe7]bradykinin (NPC567), [Thi 5,8, D-Phe7]bradykinin,
D-Arg, [Hyp3, Thi5,8, D-Phe7]bradykinin, N-.alpha.-adamantaneacetyl-D-Arg-
, [Hyp3, Thi5,8, D-Phe7]-bradykinin, Arg9, [Leu8]bradykinin (which
are all sold by the company Sigma) or the compounds mentioned in
patents WO 95/08566, WO 95/07294, EP 0,623,350, EP 0,622,361, WO
94/11021, EP 0,596,406, WO 94/06453, WO 94/09001, EP 0,578,521,
EP 0,564,972, EP 0,552,106, WO 93/11789, U.S. Pat. No. 5,216,165,
U.S. Pat. No. 5,212,182, WO 92/17201, EP 0,496,369, EP 0,472,220,
EP 0,455,133, WO 91/09055, WO 91/02746, EP 0,413,277, EP 0,370,453,
EP 0,359,310, WO 90/03980, WO 89/09231, WO 89/09230, WO 89/01780,
EP 0,334,244, EP 0,596,406, WO 86/07263 or P-guanidobenzoyl, [Hyp3,
Thi5, D-Tic7, Oic8]bradykinin (S 16118) (Feletou M & al., Pharmacol.
Exp. Ther., June 1995, 273, 1078-84), D-Arg, [Hyp3, Thi5, D-Tic7,
Oic8]-bradykinin (HOE 140) (Feletou M & al., Eur. J. Pharmacol,
1995, 274, 57-64), D-Arg. [Hyp3, D-Hype (trans-propyl)7, Oic8]bradykinin
(NPC 17731) (Herzig M. C. S. and Leeb-Lundberg L. M. F., J. Biol.
Chem. 1995, 270, 20591-20598) or those mentioned in Bradykinin Antagonists:
development and applications (Stewart J. M., Biopolymers, 1995,
37, 143-155), or alternatively natural or synthetic chemical molecules
such as, for example, those described in Salvino et al., J. Med.
Chem., 1993, 36,2583-2584.
[0028] According to the invention, it is also possible to use antisense
nucleic acids or ribozymes whose aim is to selectively inhibit bradykinin
synthesis. These antisense nucleic acids are known to those skilled
in the art. They can act in different ways on DNA or on messenger
RNA coding for bradykinin, in particular by blocking the binding
or the progression of the ribosomes along the messenger RNA, by
cleaving the messenger RNA with RNase H, or by preventing the transport
of the messenger RNA from the nucleus to the cytoplasm, or alternatively
by preventing maturation of the messenger RNA.
[0029] According to the invention, anti-bradykinin antibodies or
soluble bradykinin receptors, anti-bradykinin-receptor antibodies
or bradykinin receptor antagonists can also be used.
[0030] Preferably, according to the invention, a compound which
interferes with the effects of bradykinin by binding to its receptor
(B1 or B2), preferably to the B2 receptor, is used.
[0031] Even more preferably, a bradykinin antagonist chosen from:
[0032] D-Arg, [Hyp3, D-Phe7]bradykinin (NPC567),
[0033] [Thi5,8, D-Phe7]bradykinin,
[0034] D-Arg, [Hyp3, Thi5,8, D-Phe7]bradykinin,
[0035] N-.alpha.-adamantaneacetyl-D-Arg, [Hyp3, Thi5,8, D-Phe7]-bradykinin,
[0036] des-Arg9, [Leu8]bradykinin,
[0037] P-guanidobenzoyl, [Hyp3, Thi5, D-Tic7, Oic8]-bradykinin,
(S 16118),
[0038] D-Arg, [Hyp3, Thi5, D-Tic7, Oic8]bradykinin (HOE 140),
[0039] D-Arg, [Hyp3, D-Hype (transpropyl)7, Oic8]bradykinin (NPC
17731) is used according to the invention.
[0040] The modified peptide preferably used according to the invention
is D-Arg, [Hyp3, Thi5, D-Tic7, Oic8]bradykinin (HOE 140).
[0041] The effective amount of bradykinin antagonists to use corresponds,
needless to say, to the amount required to obtain the desired result.
A person skilled in the art is thus capable of evaluating this effective
amount, which depends on the nature of the antagonist used and on
the person thus treated.
[0042] In order to give an order of magnitude, according to the
invention, in a cosmetic composition, the antagonist can be present
at a concentration of between 10.sup.-12 M and 10.sup.-3 M, and
preferably between 10.sup.-9 M and 10.sup.-4 M. In the preparation
of medicinal products, the inhibitor can be present at a concentration
of between 10.sup.-12 M and 1 M, and preferably between 10.sup.--6
M and 10.sup.-1 M.
[0043] The medicinal product according to the invention can be
administered parenterally, enterally or topically. Preferably, the
medicinal product is administered topically.
[0044] The physiologically acceptable medium in which the active
agent is used according to the invention can be anhydrous or aqueous.
The term anhydrous medium is understood to refer to a solvent medium
containing less than 1% water. This medium can consist of a solvent
or a mixture of solvents chosen more particularly from C.sub.2-C.sub.4
lower alcohols such as ethyl alcohol, alkylene glycols such as propylene
glycol, and alkyl ethers of alkylene glycols or of dialkylene glycols,
in which the alkyl or alkylene radicals contain from 1 to 4 carbon
atoms. The term aqueous medium is understood to refer to a medium
consisting of water or of a mixture of water and another physiologically
acceptable solvent chosen, in particular, from the organic solvents
mentioned above. In the latter case, when they are present, these
other solvents represent 5 to 95% of the weight of the composition
approximately.
[0045] It is possible for the physiologically acceptable medium
to contain other adjuvants commonly used in the cosmetic or pharmaceutical
field, such as surfactants, thickeners or gelling agents, cosmetic
agents, preserving agents, basifying or acidifying agents well known
in the prior art, and in sufficient amounts to obtain the desired
presentation form, in particular a relatively thickened lotion,
a gel, an emulsion or a cream. The use can optionally be in a form
pressurized as an aerosol or vaporized from a pump-dispenser bottle.
[0046] It is also possible to use, in combination with the active
agent, compounds which further improve the activity on hair regrowth
and/or on slowing down hair loss, and which have already been described
for this activity.
[0047] Among the latter compounds, mention may be made more particularly,
in a non-limiting manner, of:
[0048] nicotinic acid esters including, in particular, tocopheryl
nicotinate, benzyl nicotinate and C.sub.1-C.sub.6alkyl nicotinates
such as methyl or hexyl nicotinate;
[0049] pyrimidine derivatives such as 2,4-diamino-6-piperidinopyrimidine
3-oxide or "Minoxidil" described in U.S. Pat. No. 4,596,812
or alternatively the many derivatives thereof, or such as 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine
and the derivatives thereof as described in patent U.S. Pat. No.
4,139,619;
[0050] agents which promote hair regrowth such as those described
by the Applicant in the European patent application published under
the number 0648488;
[0051] antibacterial agents such as macrolides, pyranosides and
tetracyclines, and in particular "Erythromycin;
[0052] calcium antagonists such as Cinnarizine and Diltiazem;
[0053] hormones, such as oestriol or analogues, or thyroxine and
salts thereof;
[0054] steroidal anti-inflammatory agents, such as corticosteroids
(for example: hydrocortisone);
[0055] antiandrogenic agents such as oxendolone, spironolactone
and diethylstilbestrol;
[0056] 5-.alpha.-reductase antagonists;
[0057] OH-radical scavengers such as dimethyl sulphoxide.
[0058] Other compounds can also be added to the above list, namely,
for example, Diazoxide, Spiroxazone, phospholipids such as lecithin,
linoleic acid, linolenic acid, salicylic acid and the derivatives
thereof described in French patent FR 2,581,542, such as salicylic
acid derivatives bearing an alkanoyl group having from 2 to 12 carbon
atoms in position 5 of the benzene ring, hydroxycarboxylic acids
or ketocarboxylic acids and the esters thereof, lactones and the
corresponding salts thereof, anthralin, carotenoids, eicosatetraynoic
acid and eicosatriynoic acid or the esters and amides thereof, and
vitamin D and the derivative thereof.
[0059] It may also be envisaged that the composition comprising
at least one bradykinin antagonist is in liposomal form, as described
in particular in patent application WO 94/22468 filed on Oct. 13,
1994 by the company Anti Cancer Inc. Thus, the antagonist encapsulated
in the liposomes can be delivered selectively to the hair follicle.
[0060] The cosmetic composition according to the invention is to
be applied to alopecic areas of an individual's scalp and hair,
and is optionally left in contact for several hours and a rinsing
operation is optionally carried out. It is possible, for example,
to apply the composition containing an effective amount of at least
one bradykinin antagonist in the evening, to keep it in contact
throughout the night and optionally to shampoo the hair in the morning.
These applications can be repeated daily for one or more months
depending on the individual.
[0061] Thus, the subject of the present invention is also a process
for the cosmetic treatment of the hair and/or the scalp, characterized
in that it consists in applying a composition comprising an effective
amount of at least one bradykinin antagonist to the hair and/or
the scalp, in leaving this composition in contact with the hair
and/or the scalp and optionally in carrying out a rinsing operation.
[0062] The treatment process has the characteristics of a cosmetic
process insofar as it allows the aesthetic appeal of the hair to
be enhanced by making it more vigorous and improving its appearance.
[0063] Examples, which should not be considered as limiting the
scope of the invention in any way, will now be given by way of illustration.
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