U.S. patent application number 10/243733 was filed with the patent office on 2003-04-17 for use of bradykinin antagonists for stimulating or inducing hair growth and/or arresting hair loss.
Invention is credited to Boyera, Nathalie, Duranton, Albert, Gautier, Brigitte, Pruche, Francis.
Application Number | 20030073616 10/243733 |
Document ID | / |
Family ID | 9483340 |
Filed Date | 2003-04-17 |
United States Patent
Application |
20030073616 |
Kind Code |
A1 |
Pruche, Francis ; et
al. |
April 17, 2003 |
Use of bradykinin antagonists for stimulating or inducing hair
growth and/or arresting 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.
Inventors: |
Pruche, Francis; (Paris,
FR) ; Duranton, Albert; (Paris, FR) ; Boyera,
Nathalie; (Paris, FR) ; Gautier, Brigitte;
(Les Ulis, FR) |
Correspondence
Address: |
Norman H. Stepno
BURNS, DOANE, SWECKER & MATHIS, L.L.P.
P.O. Box 1404
Alexandria
VA
22313-1404
US
|
Family ID: |
9483340 |
Appl. No.: |
10/243733 |
Filed: |
September 16, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10243733 |
Sep 16, 2002 |
|
|
|
08981279 |
Feb 11, 1998 |
|
|
|
6468972 |
|
|
|
|
08981279 |
Feb 11, 1998 |
|
|
|
PCT/FR96/01528 |
Oct 1, 1996 |
|
|
|
Current U.S.
Class: |
424/139.1 ;
424/143.1; 514/1; 514/12.5; 514/20.7; 514/44R |
Current CPC
Class: |
A61Q 7/00 20130101; A61P
17/00 20180101; A61K 8/64 20130101; Y10S 514/88 20130101; A61K
38/043 20130101 |
Class at
Publication: |
514/2 ; 514/44;
424/143.1; 514/1 |
International
Class: |
A61K 038/10; A61K
031/00; A61K 039/395 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 6, 1995 |
FR |
95/11809 |
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.
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.
EXAMPLE 1
[0064] Measurement of the Effect of Minoxidil and of Minoxidil
Sulphate on the Increase in Intracellular Calcium Concentration
Induced by Bradykinin:
[0065] a) Culturing Keratinocytes of the Outer Sheath of Human Hair
Follicles:
[0066] This procedure is a variant of that described by YANG et
al., J. Invest. Dermatol., 1993, 101 (5), 652-659.
[0067] After decontamination, a lifting scalp biopsy is treated
with dispase in a proportion of 2.4 units/ml for 20 hours at
4.degree. C.
[0068] The outer sheath of the hair follicles (ORS) is then
isolated by dissection, followed by treatment with 0.125% trypsin
for 30 minute at 37.degree. C.
[0069] The cells thus prepared are then cultured in Green medium
condition for 6 days.
[0070] The cells are then placed on glass slides 10 mm in diameter
and cultured in KGM medium.
[0071] b) Measurement of the Intracellular Calcium
Concentration:
[0072] The measurements are taken according to the procedures used
conventionally by those skilled in the art and which are found, for
example, in Cellular Calcium: A Practical Approach, published by J.
G. McCormack and P. H. Cobbold; IRL PRESS (1991).
[0073] The cells are incubated for 1 hour at 37.degree. C. in 10 mM
HEPES buffer, 5 mM KCl, 140 mM NaCl, 10 mM glucose, 1 mM
MgCl.sub.2, 2 mM CaCl.sub.2 with 5 AM FURA 2 acetomethyl ester and
Pluronic (5 mg/10 ml).
[0074] After rinsing in the buffer, the slides are placed in an
adapted support and the reading is taken using a PERKIN ELMER LS 50
B spectrofluorimeter at 37.degree. C.
[0075] The cells are preincubated with or without Minoxidil or
Minoxidil sulphate, for at least 120 seconds before the injection
of 1 AM bradykinin.
[0076] c) Results:
1 % Inhibition Product c.c.* in .mu.M (1 .mu.M bradykinin)
Minoxidil 10 0% 50 15% 100 25% 1000 31% Minoxidil sulphate 10 0% 50
31% 100 54% 1000 70% c.c.* = concentration of product in .mu.M used
in the test. Minoxidil and Minoxidil sulphate inhibit the increase
in intracellular calcium concentration induced by bradykinin, thus
acting as bradykinin antagonists.
EXAMPLE 2
[0077] Examples of compositions to be applied on the hair and/or
the scalp. These compositions can be prepared by simple mixing.
2 Composition 1: Spray: D-Arg, [Hyp3, Thi5, D-Tic7, Oic8]- 5
.times. 10.sup.-6 g bradykinin (HOE 140) Minoxidil 0.5 g 95.degree.
Ethanol 55.1 g Propylene glycol 22.8 g Fragrance qs Demineralized
water qs 100 g Composition 2: Daily lotion: D-Arg, [Hyp3,
D-Phe7]bradykinin 12.5 .times. 10.sup.-6 g (NPC5 67)
2,4-diaminopyrimidine 3-oxide 0.75 g 95.degree. Ethanol 30 g
Fragrance qs Dyes qs Demineralized water qs 100 g Composition 3:
Liposomal gel: Natipide II.sup.1 (i.e. 2 g of 10 g phospholipides)
D-Arg, [Hyp3, D-Phe7]bradykinin (NPC567) 3 .times. 10.sup.-4 g
Carbomer 0.25 g Triethanolamine qs pH = 7 Preserving agents qs
Demineralized water qs 100 g .sup.1Water/alcohol/lecithin mixture
from the company Natterman Composition 4: Liposomal gel: Natipide
II.sup.1 (i.e. 2 g of 10 g phospholipides) D-Arg, [Hyp3, Thi5,
D-Tic7, Oic8]- 5 .times. 10.sup.-5 g bradykinin (HOE 140) Carbomer
0.25 g Triethanolamine qs pH = 7 Preserving agents qs Demineralized
water qs 100 g .sup.1Water/alcohol/lecithin mixture from the
company Natterman Composition 5: Niosomal gel: Chimexane NS.sup.1
1.8 g Monosodium stearoylgiutamate 0.2 g des-Arg9, [Leu8]bradykinin
7.5 .times. 10.sup.-4 g Carbomer 0.2 g Triethanolamine qs pH = 7
Preserving agents qs Fragrances qs Demineralized water qs 100 g
.sup.1Nonionic surfactant sold by the company Chimex. Composition
6: Nisomal lotion: Chimexane NL.sup.1 0.475 g Cholesterol 0.475 g
Monosodium stearoylglutamate 0.05 g D-Arg, [Hyp3, Thi5,8, D-Phe7]-
10.sup.-3 g bradykinin Preserving agents qs Dyes qs Fragrance qs
Demineralized water qs 100 g .sup.1Nonionic surfactant sold by the
company Chimex. Composition 7: Care cream: O/W emulsion
Cetylstearyl alcohol/cetylstearyl 5 g alcohol oxyethylenated with
33 mol of oxyethylene (80/20) Glyceryl monostearate 1.5 g Cetyl
alcohol 0.75 g Liquid petroleum jelly 10 g Polydimethylsiloxane
0.75 g Glycerol 4 g Preserving agents qs D-Arg, [Hyp3, Thi5,
D-Tic7, Oic8]- 5 .times. 10.sup.-3 g bradykinin (HOE 140)
Demineralized water qs 100 g
* * * * *