Hair loss abstract
The present invention is directed to a method to promote, stimulate
and/or delay hair loss by administering an effective amount of at
least one bradykinin antagonists to promote, stimulate and/or delay
hair loss to an individual in need thereof.
Hair loss claims
What is claimed is:
1. A method to promote or stimulate hair growth and/or delay hair
loss, said method comprising administering an effective amount of
at least one bradykinin antagonist to promote or stimulate hair
growth and/or delay hair loss to an individual in need thereof,
wherein said bradykinin antagonist binds to a B1 and/or B2 bradykinin
receptor.
2. A method to promote or stimulate hair growth and/or delay hair
loss comprising administering an effective amount of at least one
bradykinin antagonist in an amount effective to promote, stimulate
and/or delay hair loss wherein said bradykinin antagonist is selected
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); and D-Arg,
(Hyp3, D-Hype (transpropyl)7, Oic8)-bradykinin (NPC 17731).
3. The method of claim 2 wherein said bradykinin antagonist is
D-Arg (Hyp3, Thi5, D-Tic7, Oic8)-bradykinin (HOE 140).
4. A process for the cosmetic treatment of the hair and/or scalp
comprising administering an effective amount of a cosmetic composition
wherein said composition comprises at least one bradykinin antagonist
in a physiologically acceptable medium, in an amount effective to
promote or stimulate hair growth and/or delay hair loss in said
subject wherein said bradykinin antagonist binds to a B1 and/or
B2 bradykinin receptor.
5. The process for cosmetic treatment of the hair and/or scalp
of claim 4 wherein said bradykinin antagonist is selected 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); and D-Arg,
(Hyp3, D-Hype (transpropyl)7, Oic8)-bradykinin (NPC 17731).
6. The process for cosmetic treatment of the hair and/or scalp
of claim 4 wherein said antagonist is D-Arg (Hyp3, Thi5, D-Tic7,
Oic8)-bradykinin (HOE 140).
7. The process of claim 4 wherein said cosmetic composition is
administered to the hair and/or scalp.
8. The process of claim 6 wherein said cosmetic composition is
left in contact with the hair and/or scalp.
Hair loss description
What is claimed is:
1. A method to promote or stimulate hair growth and/or delay hair
loss, said method comprising administering an effective amount of
at least one bradykinin antagonist to promote or stimulate hair
growth and/or delay hair loss to an individual in need thereof,
wherein said bradykinin antagonist binds to a B1 and/or B2 bradykinin
receptor.
2. A method to promote or stimulate hair growth and/or delay hair
loss comprising administering an effective amount of at least one
bradykinin antagonist in an amount effective to promote, stimulate
and/or delay hair loss wherein said bradykinin antagonist is selected
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); and D-Arg,
(Hyp3, D-Hype (transpropyl)7, Oic8)-bradykinin (NPC 17731).
3. The method of claim 2 wherein said bradykinin antagonist is
D-Arg (Hyp3, Thi5, D-Tic7, Oic8)-bradykinin (HOE 140).
4. A process for the cosmetic treatment of the hair and/or scalp
comprising administering an effective amount of a cosmetic composition
wherein said composition comprises at least one bradykinin antagonist
in a physiologically acceptable medium, in an amount effective to
promote or stimulate hair growth and/or delay hair loss in said
subject wherein said bradykinin antagonist binds to a B1 and/or
B2 bradykinin receptor.
5. The process for cosmetic treatment of the hair and/or scalp
of claim 4 wherein said bradykinin antagonist is selected 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); and D-Arg,
(Hyp3, D-Hype (transpropyl)7, Oic8)-bradykinin (NPC 17731).
6. The process for cosmetic treatment of the hair and/or scalp
of claim 4 wherein said antagonist is D-Arg (Hyp3, Thi5, D-Tic7,
Oic8)-bradykinin (HOE 140).
7. The process of claim 4 wherein said cosmetic composition is
administered to the hair and/or scalp.
8. The process of claim 6 wherein said cosmetic composition is
left in contact with the hair and/or scalp.
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Description
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FIELD OF THE INVENTION
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 delay hair loss.
BACKGROUND OF THE INVENTION
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.
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.
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.
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 in character
or is referred to as 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 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.
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.
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.
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.
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.
BRIEF DESCRIPTION OF THE INVENTION
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.
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.
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.
Bradykinin is involved in a large number of physiopathological
disorders including: hypotension, contraction of the smooth muscles
the digestive and respiratory tracts and in the uterus, pain, the
proliferation of connective tissue and the release of different
inflammation mediators: cytokines, leukotrienes and prostaglandins.
To date, to the Applicant's knowledge, it has neither been envisioned
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.
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.
Thus, Minoxidil or derivatives thereof can act as a bradykinin
antagonist.
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.
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.
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.
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.
This discovery forms the basis of the present invention.
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.
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.
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.
Among the bradykinin antagonists, it is preferred to use, for example,
compounds which inhibit the synthesis and/or accelerate the catabolism
of bradykinin, brady-kinin 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.
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, des-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 86107263 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. Phannacol,
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.
According to the invention, it is also possible to use antisense
nucleic acid 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.
According to the invention, anti-bradykinin antibodies or soluble
bradykinin receptors, anti-bradykinin-receptor antibodies or bradykinin
receptor antagonists can also be used.
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.
Even more preferably, a bradykinin antagonist 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)
is used according to the invention.
The modified peptide preferably used according to the invention
is D-Arg, [Hyp3, Thi5, D-Tic7, Oic8]bradykinin (HOE 140).
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.
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.
The medicinal product according to the invention can be administered
parenterally, enterally or topically. Preferably, the medicinal
product is administered topically.
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.
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.
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.
Among the latter compounds, mention may be made more particularly,
in a non-limiting manner, of: nicotinic acid esters including, in
particular, tocopheryl nicotinate, benzyl nicotinate and C.sub.1
-C.sub.6 alkyl nicotinates such as methyl or hexyl nicotinate; 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; agents which promote hair regrowth such as those described
by the Applicant in the European patent application published under
the number 0648488; antibacterial agents such as macrolides, pyranosides
and tetracyclines, and in particular Erythromycin; calcium antagonists
such as Cinnarizine and Diltiazem; hormones, such as oestriol or
analogues, or thyroxine and salts thereof; steroidal anti-inflammatory
agents, such as corticosteroids (for example: hydrocortisone); antiandrogenic
agents such as oxendolone, spironolactone and diethylstilbestrol;
5-.alpha.-reductase antagonists; OH-radical scavengers such as dimethyl
sulphoxide.
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 derivatives thereof.
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.
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.
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.
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.
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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