CA2064768A1 - Skin pigment composition containing a coleus extract - Google Patents
Skin pigment composition containing a coleus extractInfo
- Publication number
- CA2064768A1 CA2064768A1 CA002064768A CA2064768A CA2064768A1 CA 2064768 A1 CA2064768 A1 CA 2064768A1 CA 002064768 A CA002064768 A CA 002064768A CA 2064768 A CA2064768 A CA 2064768A CA 2064768 A1 CA2064768 A1 CA 2064768A1
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- extract
- coleus
- methyl
- derivatives
- alpha
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/04—Preparations for care of the skin for chemically tanning the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/67—Vitamins
- A61K8/673—Vitamin B group
- A61K8/675—Vitamin B3 or vitamin B3 active, e.g. nicotinamide, nicotinic acid, nicotinyl aldehyde
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9789—Magnoliopsida [dicotyledons]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9794—Liliopsida [monocotyledons]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
- A61Q5/10—Preparations for permanently dyeing the hair
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Birds (AREA)
- Microbiology (AREA)
- Engineering & Computer Science (AREA)
- Mycology (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Dermatology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Medical Informatics (AREA)
- Alternative & Traditional Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Cosmetics (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Entitled : Skin pigmentation composition containing a coleus extract in the names of : MEYBECK Alain BONTE Fr?d?ric DUMAS Marc ANDRE Patrice REDZINIAK G?rard Assignee: ? VMH RECHERCHE
ABSTRACT OF THE DISCLOSURE
A method of treating skin pigmentation is disclosed comprising applying a Coleus extract, in particular an extract of roots, on the skin to be pigmented.
ABSTRACT OF THE DISCLOSURE
A method of treating skin pigmentation is disclosed comprising applying a Coleus extract, in particular an extract of roots, on the skin to be pigmented.
Description
` 2064768 COMPOSITION CONTAINING AN EXTRACT OF COLEUS
FOR SKIN PIGMENTATION.
05 The present invention essentially relates to a cosmetic or pharmaceutical composition, particularly a dermatological composition, containing an extract of Coleus for skin pigmentation, or combined with various active principles for skin and hair pigmentation, and process for the preparation thereof.
It also relates to the use of an extract of Coleus for preparing said cosmetic or pharmaceutical composition for skin and/or hair pigmentation.
The different species of Coleus belong to the family of Labiaceae, in the same way as the Plectranthus which are very close thereto, and are often mistaken one for the other, since they are mainly originated from the same regions. Thus, the Coleus barbatus specie is generally designated under the name Plectranthus barbatus, and the Coleus aromaticus specie is also called Plectranthus aromaticus. However, L.H. CRAMER, in his article published in Kew Bull. 1978 volume 32 No. 3, pages 551-561, discusses the differences between these two groups of species.
There are nearly two hundred species of Coleus which are found in the tropical and subtropical regions of Asia, Africa, Australia and the Pacific Islands. About 9 species are catalogued in India. The ten principal varieties of Coleus are catalogued in various Indian dictionaries and in particular : "The Wealth of India, a dictionary of Indian Raw Materials and Industrial Products, Raw Materialsn, volume II, Dehli 1950, pages 308-309;
the book entitled ~Indian Materia Medica" by Dr. K.M. Nadkarni's, third edition revised and completed by A.K. Nadkarni in two volumes, volume I, page 372 ; the book entitled "the Flora of British Indian, by Sir J.D. Hooker, C.B., K.C., S.I. volume IV
entitled "Asclepiadae to Amarantaceae", pages 624 to 627.
More recently, the extracts of Coleus, in particular the " 2064768 Coleus forskohlii (syn. Coleus barbatus) have revealed substances having the carbon network of Labdanes, and more specifically, that of the 8,13-epoxylabd-14-en-11-one of the following formula :
05 ~ ~ R5 ~ (I) In particular, the 1~ ,6 ~,9~ -trihydro-7 ~ -acetoxy, or forskoline derivative whose extraction process was described in Hoechst patent application FR-2 336 138 was isolated. The 1c~,7~ ,9 ~ -trihydroxy-6 ~-acetoxy derivative, or coleforsine (HOECHST, FR-2 364 211) and the 1 ~ ,6 ~ dihydroxy-7p -acetoxy derivative, or 9-desoxyforskoline (HOECHST, EP-A1-0 243 646) were also described and isolated.
These documents describe a certain number of pharmacological properties of said substances, such as a hypotensive and calming activity on the central nervous system.
Document EP-A-O 293 837 also discloses a composition for treating hair comprising a combination of at least one coumpound selected from the group comprising forskoline and its derivatives and peptides having a structure of the basic network, alone or combined with a compound selected from the aliphatic acids, alcohols and derivatives having an uneven number of carbon atoms.
This composition is applied on hair in order to activate the melanocytes of the radix pili and to improve the melanine synthesis of said hair so as to prevent grey hair from appearing and to promote restoration of the natural color.
It should be noted that between the melanocytes present in the hair follicles and those present in the skin, there are significant differences, notably at the metabolic level.
Therefore, there is not necessarily any relationship as regards activity between a compound activating the melanocytes of 206~768 the hair follicles and a compound activating the melanocytes present in the skin. This is due in particular to the fact that to enable activation of the melanocytes in the skin, the compound must also be capable of going through the superficial layers of 05 the epidermis so as to penetrate through the level of the melanocytes.
The present invention is based on the discovery that the extracts of Coleus, in particular Coleus forskohlii, have interesting biological properties useful in the pharmaceutical and cosmetic ,fields by unexpectedly presenting a melanogenesis-promoting activity at the level of the melanocytes present in the skin, thus making it possible to promote skin pigmentation, as well as the carrying out of a treatment for treating the skin pigmentation disorders by promoting more particularly the melanine biosynthesis.
The object of the present invention is therefore to solve the new technical problem consisting in providing a new cosmetic or pharmaceutical composition, particularly a dermatological composition, intended to promote skin pigmentation.
2û Another object of the present invention is to solve the new technical problem consisting in the preparation of a novel formulation of a cosmetic or pharmaceutical composition presenting a good melanogenesis-promoting activity at the level of the melanocytes present in the skin.
Yet another object of the present invention is to provide a solution to the new technical problem consisting in providing a plant extract particularly easy to obtain, which presents in itself a good melanogenesis-promoting activity at the level of the melanocytes in the skin, without having to isolate any active substance, these isolation processes being in general long and expensive.
Yet another object of the present invention is to solve the new technical problem consisting in providing a novel formulation of a cosmetic or pharmaceutical composition presenting a good melanogenesis-promoting activity at the level of the 206~768 melanocytes present in the hair follicles, while promoting hair pigmentation.
All these new technical problems are solved for the first time by the present invention in a satisfactory way usable 05 on an industrial scale.
Thus, according to a first aspect, the present invention relates to the use of an extract of Coleus for preparing a cosmetic or pharmaceutical composition, particularly a dermatological composition, intended to promote skin pigmentation and/or to the treatment of skin pigmentation disorders.
According to a particular characteristic of the invention, the extract of Coleus is an extract of the Coleus forskohlii specie. It is preferably an extract of roots.
According to another characteristic, an organic extract of Coleus is used, preferably of rootC of Coleus, advantageously obtained by a process comprising at least one step of extraction with a solvent selected from the group constituted by ethyl acetate, methanol, ethanol and dichloromethane. In a general way, organic solvents, such as aromatic hydrocarbons, halogenated aliphatic or aromatic hydrocarbons, dialcoylic ethers, dialcoyl-Ketones, alcanols, carboxylic acids and their esters or other solvents, such as dimethylformamide, dioxane, tetrahydrofurane and dimethylsulfoxide can be used. Among the aforesaid solvents, preferred solvents are benzene, toluene or xylene, methylene chloride, chloroform, ethyl acetate, methanol or ethanol. The ratio of the plant matter to the extraction agent is not critical and is generally ranged between 1:5 and 1:20 parts by weight, and it is preferably about 1:10 parts by weight. The extraction is effected at temperatures included between ambient temperature and the boiling point of the solvent used for extraction. An advantageous technique of extraction is the technique known as the technique of extraction employing Soxhlet.
It may be advantageous, and in certain cases necessary, to evaporate the solvent, for example by lyophilization, and to take up the crude extracts for purification purposes. According to the 206~76~
s present invention, extraction by alcohol is particularly advantageous, notably at the end of the process for obtaining the extract due to the usually hardly toxic nature of the alcohols. A
particularly advantageous alcohol is, for example, ethanol.
05 Another particularly advantageous solvent is ethyl acetate because it provides an extract rich in labd-14-ene derivatives.
Particular variants of process are described in the litterature, in particular in the documents set forth in the preamble of the previous description.
Generally, the concentration of the extracts used according to the present invention, for preparing a cosmetic or pharmaceutical composition, expressed by dry weight is ranged between 0.001% and 2% by weight, preferably between 0.01% and 0.5%
by weight, with respect to the total weight of the composition.
The cosmetic or pharmaceutical, particularly dermatological compositions, according to the present invention, may be applied by topical route to promote skin pigmentation, in particular in compositions in the form of creams, gels or lotions intended for application on the skin.
Thus, the cosmetic or pharmaceutical, particularly dermatological compositions, according to the invention, have various applications in cosmetology or dermatology, in particular when an increase in pigmentation is sought. For example, these compositions can be used as solar products for activating or intensifying the suntan which, in addition to the aesthetic advantage often sought, enables strengthening of the natural defenses ~against ultraviolet radiation by increasing the melanine rate in the epidermis. Moreover, in dermatology, the compositions according to the present invention can be used as therapeutical agents, alone or combined with other drugs, in particular in topical administration for treating melanogenesis disorders.
According to an advantageous embodiment, a cosmetic or pharmaceutical composition according to the invention comprises in addition a xanthine, such as in particular IBMX or theophylline, preferably at a weight concentration ranged between 0.01% and 2%, and still preferably between 0.01% and 0.5% with respect to the total weight of the composition.
According to another embodiment, a cosmetic or 05 pharmaceutical composition according to the invention further comprises tyrosine or one of its derivatives, preferably at a weight concentration ranged between 0.001% and 10%, with respect to the total weight of the composition.
According to yet another embodiment, a cosmetic or pharmaceutical composition according to the invention further comprises at least one other active substance, at an efficient concentration, selected from vitamins, in particular vitamins B, quinine or its derivatives, rubefacients, such as methyl nicotinate, a supernatant of culture of fibroblasts of papillae, as defined in document EP-A-272 920, keratin hydrolysates, oligo-elements such as zinc, selenium, copper, 5-C~-reductase inhibitors, such as progesterone, cyproterone acetate, minoxidil, azelaic acid and its~derivatives, a 4-methyl-4-azasteroid, in particular the 17- P -N,N-diethylcarbamoyl-4-methyl-4-aza-5-~ -androstan-3-one, or still an extract of Serenoa repens.
According to a second aspect, the present invention also relates to a process for the preparation of a cosmetic or pharmaceutical composition, particularly a dermatological composition, intended to promote skin pigmentation, characterized in that it comprises the incorporation of at least one extract of Coleus as described previously in a cosmetically or pharmaceutically acceptable excipient, vehicle or support.
According to a third aspect, the present invention further relates to a process for treating the skin so as to promote pigmentation, characterized in that it comprises the application in an efficient quantity to produce a pigmentation, of at least one extract of Coleus such as described previously, incorporated in a cosmetically or pharmaceutically acceptable excipient, vehicle or support.
According to a fourth aspect, the present invention also - 20~768 relates to the use of an extract of Coleus combined with an efficient quantity of at least another active substance, selected from xanthines, such as in particular IBMX or theophylline, quinine or its derivatives, rubefacients, such as methyl 05 nicotinate, a supernatant of culture of fibroblasts of papillae, keratin hydrolysates, oligo-elements such as zinc, selenium, copper, 5-d -reductase inhibitors, such as cyproterone acetate, minoxidil, azelaic acid and its derivatives, a 4-methyl-4-azaste-roid, in particular the 17-~ -N,N-diethylcarbamoyl-4-methyl-4-aza-5-C~-androstan-3-one, or else an extract of Serenoa repens, for the preparation of a cosmetic or pharmaceutical composition, intended to promote hair pigmentation.
According to particular variant embodiments, the preferred combinations relate to the combination of an extract of Coleus, in particular an extract of Coleus forskohlii, preferably of root, with a xanthine, such as in particular IBMX or theophylline.
According to a fifth aspect, the present invention also relates to a process for the preparation of a cosmetic or pharmaceutical composition, intended to promote hair pigmentation, characterized in that it comprises the incorporation of at least one extract of Coleus as described previously in combination with at least another active substance as defined above with regard to the use, in a cosmetically or pharmaceutically acceptable excipient, vehicle or support.
Finally, according to a last aspect, the present invention also relates to a process for treating hair so as to prevent gray hair from appearing and/or to restore the natural color of hair, characterized in that it comprises the application on hair of an efficient quantity in order to produce hair pigmentation, of at least one extract of Coleus as described previously in combination with at least one active substance as defined previously, incorporated to a cosmetically or pharmaceutically acceptable excipient, vehicle or support.
For each one of the preceding aspects intended to ` 2~64768 promote hair pigmentation, the concentration used is generally the same as that used to pigment the skin.
Other purposes, characteristics and advantages of the invention will appear more clearly from reading the following 05 explanatory description given with reference to several examples given solely by way of illustration and which consequently could not in any way limit the scope of the invention.
In the examples, the percentages are expressed by weight, unless otherwise indicated.
Preparation of an extract of Coleus from Coleus forskohlii 12 kg of dried and ground roots of Coleus forskohlii are extracted twice with each time 20 l of petroleum ether.
The roots are then repeatedly extracted with 15 l of methylene chloride till they are exhaustively extracted. 60 l of methylene chloride are used.
The extracts are combined with methylene chloride and are then filtered or centrifuged and concentrated under a reduced pressure.
The obtained residue is extracted twice each time with 3 1 of methanol.
The combined methalonic extracts are filtered and the methalonic filtrate is evaporated under reduced pressure, thus obtaining the extract of Coleus forskohlii called extract I1.
12 kg of dried and ground roots of Coleus forskohlii are extracted twice with 15 1 of petroleum ether.
3û The roots are taken up in order to proceed to repeated extractions with 25 1 of methanol until complete extraction. The combined methalonic extracts are filtered and are evaporated in vacuo.
An extract of Coleus forskohlii called extract I2 is thus obtained.
12 kg of dried and ground complete plants of Coleus forskohlii are repeatedly extracted and ground with a total of 100 l of methanol until the extraction is completed. The combined 05 methalonic extracts are filtered and evaporated in vacuo.
The obtainsd extract of Coleus can be used.
However, according to a variant embodiment, the residue (about 650 9) is partitioned by using a chloroform/water solvent mixture (2/1.5 v/v). Ths chloroformic layer is recovered after decanting. The aqueous layer is repeatedly extracted at the same time as the intermediate layer each time with 1.5 l of chloroform and the obtained chloroformic layer is recovered every time.
The combined chloroformic extracts are then filtered, dried over anhydrous sodium sulfate in order to eliminate the residual water and evaporated in vacuo. About 300 9 of an extract of Coleus called extract I3 is obtained.
Dried and finely ground roots of Coleus forskohlii (1 kg) are repeatedly extracted with benzene (3 x 5 l) preferably according to the extraction technique using Soxhlet at 70C for several hours. The obtained benzene extracts are filtered and concentrated in vacuo in order to eliminate the benzene. The obtained extract of Coleus is called I4.
60 9 of dried and ground roots of Coleus forskohlii are extracted with Soxhlet with 600 ml of solvent. Extraction is effected at the boiling temperature of the solvent with an ever-renewed solvent.
The mean yield of extraction is as follows, expressed in dry weight :
a) Ethanol/water mixture (80/20 v/v) : about 9.2 to 9.5 9, (Extract 5A) 206~7~8 b) Ethyl acetate : about 1.5 9, (Extract 5B) c) Dichloromethane : about 4 9, (Extract 5C) 05 Measurement of the activity of an extract of Coleus forskohlii according to the invention on cultured melanocvtes Protocol :
Murine melanocytes are conventionally cultured in an appropriate medium.
On day D = O, the product to be tested is introduced in the culture medium.
On day D = 5, cells are removed and isolated by centrifuging and the cellular residue is recovered and dissolved in soda 0.5 N.
A reading of the optical density is then effected on a spectrophotometer at 475 nm, which makes it possible to assess the quantity of melanine formed by comparison to the optical density of a melanine solution of known concentration.
Numbering of the cells is also e ff ected and the rate of melanine formed per cell is determined, with respect to a control culture without adding a product to be tested.
Test :
The extract Coleus 5B, according to example 5b is compared with the forskoline alone, used at an equivalent concentration with a positif control consisting in 10 8 mole of ~ -MSH. Forskoline at a concentration of 0.1 >g/ml is thus introduced on day D=O in the culture medium.
In another culture medium, the extract of Coleus is introduced at a determined concentration such that the forskoline rate is also of about û.1 ~g/ml.
Table I hereinafter shows the obtained results.
TABLE I
- i ¦ ¦ Control ¦ Extract ¦ Forskoline ¦ ~-MSH ¦
05 1 ¦ ¦ of Coleus l ¦ Melanine ¦ formed in >g ¦ for 106 ¦27 + 1 ¦116 + 2 192 + 3 ¦ 70 I cells ¦ A-activity ¦ in % ¦ 0 ¦207 1151 1 100 .1 1 1 1 1 1 The A-activity of the stimulation of the melanogenesis by the products according to the invention is determined by the following formula :
q - q A = x 100 q+ qo -in which the sizes q represent the quantities of melanine formed qp = culture medium receiving the product to be tested q+ = culture medium receiving the ~MSH
qO = control culture receiving no product.
It is clear from table I that the extract of Coleus according to the invention promotes the production of melanine in a significantly greater proportion than forskoline alone, which represents an unexpected result for the man skilled in the art.
Furthermore, extracts of Coleus 5A and 5C, respectively obtained by extraction by a ethanol-water mixture 80:20 and by dichloromethane were tested in similar conditions. However it should be noted that a culture medium receiving some ~-MSH at a 05 concentration of 2.10 8 M was taken as positive specimen.
The activity of these extracts, determined according to the aforesaid formula, is shown in table II hereinafter.
TABLE II
¦ Tested product Concentration ¦ Melanine formed in ¦ A -activity¦
¦ ¦ >9 for 106 cells ¦ in %
¦Extract 5A 1 >g/ml ¦ 121 + 3 ¦ 46 I n 2.5 n n ¦161 + 5 ¦ 83 I n 5 n n ¦188 + 9 ¦ 108 ¦ Extract 5B 1 n 1~ ¦ 89 + 3 ¦ 23 I n 2.5 n ~I 1114 + 7 ¦ 45 I n 5 ..... n ¦ 171 + 1 ¦ 95 I n 10 n n I 197 + 6 ¦ 118 ¦~ -MSH 2.10 8 M ¦ 179 + 4 ¦ 100 ¦ Cbntrol ¦ (no product) ¦ 71 1 3 ¦ 0 20~768 Measurement of the activity of a combination according to the invention of Coleus forskohlii with the 3-isobutyl-l-methylxanthine (IBMX), on cultured melanocytes.
05 The procedure is that of example 6. The combination IBMX
plus extract of Coleus is tested in comparison with the IBMX and the extract of Coleus alone, as well as with the ~ -MSH at a concentration of 2.10 8 M taken as positive specimen.
The results on day D = 4 and D = 5 are shown in table III hereinafter.
It is noted on day D = 4 and D = 5 for the combination IBMX + extract of Coleus a much more important activity, which is greater than the amount of activities corresponding to each of the two constituents tested separately.
This proves a very definite reinforcement of the activity of the extract of Coleus by the IBMX.
TABLE III
1 1 1 J = 4 J = 5 PRODUCT 1 Concen- 1 Melanine >9 1 A 1 Melanine >91 A
1 1 tration 1 for 106 1 1 for 106 1 1 >g/ml ¦ melanocytes ¦ ¦ melanocYtes¦
¦Ncne ¦(control) 1 0 1 29 + -3 1 0 1 51 + -l I ¦
1 ~-MSH
1 2.10 8 M 1 1ll9 + -7 1 + lûO 1 200 + -2 1 + lOO¦
1 l/ 1 lO 164 + -O 1 ~ 39 1 103 + -2 1 + 35 206~768 TABLE III (continued) .
l l I J = 4 J = 5 05 ¦ PRODUCT ¦ Concen- ¦ Melanine >g ¦ A ¦ Melanine >9¦ A
¦ ¦ tration ¦ for 106 1 ¦ for 106 ¦ >g/ml _ l melanocytes ¦ ¦ melanocytes¦
FOR SKIN PIGMENTATION.
05 The present invention essentially relates to a cosmetic or pharmaceutical composition, particularly a dermatological composition, containing an extract of Coleus for skin pigmentation, or combined with various active principles for skin and hair pigmentation, and process for the preparation thereof.
It also relates to the use of an extract of Coleus for preparing said cosmetic or pharmaceutical composition for skin and/or hair pigmentation.
The different species of Coleus belong to the family of Labiaceae, in the same way as the Plectranthus which are very close thereto, and are often mistaken one for the other, since they are mainly originated from the same regions. Thus, the Coleus barbatus specie is generally designated under the name Plectranthus barbatus, and the Coleus aromaticus specie is also called Plectranthus aromaticus. However, L.H. CRAMER, in his article published in Kew Bull. 1978 volume 32 No. 3, pages 551-561, discusses the differences between these two groups of species.
There are nearly two hundred species of Coleus which are found in the tropical and subtropical regions of Asia, Africa, Australia and the Pacific Islands. About 9 species are catalogued in India. The ten principal varieties of Coleus are catalogued in various Indian dictionaries and in particular : "The Wealth of India, a dictionary of Indian Raw Materials and Industrial Products, Raw Materialsn, volume II, Dehli 1950, pages 308-309;
the book entitled ~Indian Materia Medica" by Dr. K.M. Nadkarni's, third edition revised and completed by A.K. Nadkarni in two volumes, volume I, page 372 ; the book entitled "the Flora of British Indian, by Sir J.D. Hooker, C.B., K.C., S.I. volume IV
entitled "Asclepiadae to Amarantaceae", pages 624 to 627.
More recently, the extracts of Coleus, in particular the " 2064768 Coleus forskohlii (syn. Coleus barbatus) have revealed substances having the carbon network of Labdanes, and more specifically, that of the 8,13-epoxylabd-14-en-11-one of the following formula :
05 ~ ~ R5 ~ (I) In particular, the 1~ ,6 ~,9~ -trihydro-7 ~ -acetoxy, or forskoline derivative whose extraction process was described in Hoechst patent application FR-2 336 138 was isolated. The 1c~,7~ ,9 ~ -trihydroxy-6 ~-acetoxy derivative, or coleforsine (HOECHST, FR-2 364 211) and the 1 ~ ,6 ~ dihydroxy-7p -acetoxy derivative, or 9-desoxyforskoline (HOECHST, EP-A1-0 243 646) were also described and isolated.
These documents describe a certain number of pharmacological properties of said substances, such as a hypotensive and calming activity on the central nervous system.
Document EP-A-O 293 837 also discloses a composition for treating hair comprising a combination of at least one coumpound selected from the group comprising forskoline and its derivatives and peptides having a structure of the basic network, alone or combined with a compound selected from the aliphatic acids, alcohols and derivatives having an uneven number of carbon atoms.
This composition is applied on hair in order to activate the melanocytes of the radix pili and to improve the melanine synthesis of said hair so as to prevent grey hair from appearing and to promote restoration of the natural color.
It should be noted that between the melanocytes present in the hair follicles and those present in the skin, there are significant differences, notably at the metabolic level.
Therefore, there is not necessarily any relationship as regards activity between a compound activating the melanocytes of 206~768 the hair follicles and a compound activating the melanocytes present in the skin. This is due in particular to the fact that to enable activation of the melanocytes in the skin, the compound must also be capable of going through the superficial layers of 05 the epidermis so as to penetrate through the level of the melanocytes.
The present invention is based on the discovery that the extracts of Coleus, in particular Coleus forskohlii, have interesting biological properties useful in the pharmaceutical and cosmetic ,fields by unexpectedly presenting a melanogenesis-promoting activity at the level of the melanocytes present in the skin, thus making it possible to promote skin pigmentation, as well as the carrying out of a treatment for treating the skin pigmentation disorders by promoting more particularly the melanine biosynthesis.
The object of the present invention is therefore to solve the new technical problem consisting in providing a new cosmetic or pharmaceutical composition, particularly a dermatological composition, intended to promote skin pigmentation.
2û Another object of the present invention is to solve the new technical problem consisting in the preparation of a novel formulation of a cosmetic or pharmaceutical composition presenting a good melanogenesis-promoting activity at the level of the melanocytes present in the skin.
Yet another object of the present invention is to provide a solution to the new technical problem consisting in providing a plant extract particularly easy to obtain, which presents in itself a good melanogenesis-promoting activity at the level of the melanocytes in the skin, without having to isolate any active substance, these isolation processes being in general long and expensive.
Yet another object of the present invention is to solve the new technical problem consisting in providing a novel formulation of a cosmetic or pharmaceutical composition presenting a good melanogenesis-promoting activity at the level of the 206~768 melanocytes present in the hair follicles, while promoting hair pigmentation.
All these new technical problems are solved for the first time by the present invention in a satisfactory way usable 05 on an industrial scale.
Thus, according to a first aspect, the present invention relates to the use of an extract of Coleus for preparing a cosmetic or pharmaceutical composition, particularly a dermatological composition, intended to promote skin pigmentation and/or to the treatment of skin pigmentation disorders.
According to a particular characteristic of the invention, the extract of Coleus is an extract of the Coleus forskohlii specie. It is preferably an extract of roots.
According to another characteristic, an organic extract of Coleus is used, preferably of rootC of Coleus, advantageously obtained by a process comprising at least one step of extraction with a solvent selected from the group constituted by ethyl acetate, methanol, ethanol and dichloromethane. In a general way, organic solvents, such as aromatic hydrocarbons, halogenated aliphatic or aromatic hydrocarbons, dialcoylic ethers, dialcoyl-Ketones, alcanols, carboxylic acids and their esters or other solvents, such as dimethylformamide, dioxane, tetrahydrofurane and dimethylsulfoxide can be used. Among the aforesaid solvents, preferred solvents are benzene, toluene or xylene, methylene chloride, chloroform, ethyl acetate, methanol or ethanol. The ratio of the plant matter to the extraction agent is not critical and is generally ranged between 1:5 and 1:20 parts by weight, and it is preferably about 1:10 parts by weight. The extraction is effected at temperatures included between ambient temperature and the boiling point of the solvent used for extraction. An advantageous technique of extraction is the technique known as the technique of extraction employing Soxhlet.
It may be advantageous, and in certain cases necessary, to evaporate the solvent, for example by lyophilization, and to take up the crude extracts for purification purposes. According to the 206~76~
s present invention, extraction by alcohol is particularly advantageous, notably at the end of the process for obtaining the extract due to the usually hardly toxic nature of the alcohols. A
particularly advantageous alcohol is, for example, ethanol.
05 Another particularly advantageous solvent is ethyl acetate because it provides an extract rich in labd-14-ene derivatives.
Particular variants of process are described in the litterature, in particular in the documents set forth in the preamble of the previous description.
Generally, the concentration of the extracts used according to the present invention, for preparing a cosmetic or pharmaceutical composition, expressed by dry weight is ranged between 0.001% and 2% by weight, preferably between 0.01% and 0.5%
by weight, with respect to the total weight of the composition.
The cosmetic or pharmaceutical, particularly dermatological compositions, according to the present invention, may be applied by topical route to promote skin pigmentation, in particular in compositions in the form of creams, gels or lotions intended for application on the skin.
Thus, the cosmetic or pharmaceutical, particularly dermatological compositions, according to the invention, have various applications in cosmetology or dermatology, in particular when an increase in pigmentation is sought. For example, these compositions can be used as solar products for activating or intensifying the suntan which, in addition to the aesthetic advantage often sought, enables strengthening of the natural defenses ~against ultraviolet radiation by increasing the melanine rate in the epidermis. Moreover, in dermatology, the compositions according to the present invention can be used as therapeutical agents, alone or combined with other drugs, in particular in topical administration for treating melanogenesis disorders.
According to an advantageous embodiment, a cosmetic or pharmaceutical composition according to the invention comprises in addition a xanthine, such as in particular IBMX or theophylline, preferably at a weight concentration ranged between 0.01% and 2%, and still preferably between 0.01% and 0.5% with respect to the total weight of the composition.
According to another embodiment, a cosmetic or 05 pharmaceutical composition according to the invention further comprises tyrosine or one of its derivatives, preferably at a weight concentration ranged between 0.001% and 10%, with respect to the total weight of the composition.
According to yet another embodiment, a cosmetic or pharmaceutical composition according to the invention further comprises at least one other active substance, at an efficient concentration, selected from vitamins, in particular vitamins B, quinine or its derivatives, rubefacients, such as methyl nicotinate, a supernatant of culture of fibroblasts of papillae, as defined in document EP-A-272 920, keratin hydrolysates, oligo-elements such as zinc, selenium, copper, 5-C~-reductase inhibitors, such as progesterone, cyproterone acetate, minoxidil, azelaic acid and its~derivatives, a 4-methyl-4-azasteroid, in particular the 17- P -N,N-diethylcarbamoyl-4-methyl-4-aza-5-~ -androstan-3-one, or still an extract of Serenoa repens.
According to a second aspect, the present invention also relates to a process for the preparation of a cosmetic or pharmaceutical composition, particularly a dermatological composition, intended to promote skin pigmentation, characterized in that it comprises the incorporation of at least one extract of Coleus as described previously in a cosmetically or pharmaceutically acceptable excipient, vehicle or support.
According to a third aspect, the present invention further relates to a process for treating the skin so as to promote pigmentation, characterized in that it comprises the application in an efficient quantity to produce a pigmentation, of at least one extract of Coleus such as described previously, incorporated in a cosmetically or pharmaceutically acceptable excipient, vehicle or support.
According to a fourth aspect, the present invention also - 20~768 relates to the use of an extract of Coleus combined with an efficient quantity of at least another active substance, selected from xanthines, such as in particular IBMX or theophylline, quinine or its derivatives, rubefacients, such as methyl 05 nicotinate, a supernatant of culture of fibroblasts of papillae, keratin hydrolysates, oligo-elements such as zinc, selenium, copper, 5-d -reductase inhibitors, such as cyproterone acetate, minoxidil, azelaic acid and its derivatives, a 4-methyl-4-azaste-roid, in particular the 17-~ -N,N-diethylcarbamoyl-4-methyl-4-aza-5-C~-androstan-3-one, or else an extract of Serenoa repens, for the preparation of a cosmetic or pharmaceutical composition, intended to promote hair pigmentation.
According to particular variant embodiments, the preferred combinations relate to the combination of an extract of Coleus, in particular an extract of Coleus forskohlii, preferably of root, with a xanthine, such as in particular IBMX or theophylline.
According to a fifth aspect, the present invention also relates to a process for the preparation of a cosmetic or pharmaceutical composition, intended to promote hair pigmentation, characterized in that it comprises the incorporation of at least one extract of Coleus as described previously in combination with at least another active substance as defined above with regard to the use, in a cosmetically or pharmaceutically acceptable excipient, vehicle or support.
Finally, according to a last aspect, the present invention also relates to a process for treating hair so as to prevent gray hair from appearing and/or to restore the natural color of hair, characterized in that it comprises the application on hair of an efficient quantity in order to produce hair pigmentation, of at least one extract of Coleus as described previously in combination with at least one active substance as defined previously, incorporated to a cosmetically or pharmaceutically acceptable excipient, vehicle or support.
For each one of the preceding aspects intended to ` 2~64768 promote hair pigmentation, the concentration used is generally the same as that used to pigment the skin.
Other purposes, characteristics and advantages of the invention will appear more clearly from reading the following 05 explanatory description given with reference to several examples given solely by way of illustration and which consequently could not in any way limit the scope of the invention.
In the examples, the percentages are expressed by weight, unless otherwise indicated.
Preparation of an extract of Coleus from Coleus forskohlii 12 kg of dried and ground roots of Coleus forskohlii are extracted twice with each time 20 l of petroleum ether.
The roots are then repeatedly extracted with 15 l of methylene chloride till they are exhaustively extracted. 60 l of methylene chloride are used.
The extracts are combined with methylene chloride and are then filtered or centrifuged and concentrated under a reduced pressure.
The obtained residue is extracted twice each time with 3 1 of methanol.
The combined methalonic extracts are filtered and the methalonic filtrate is evaporated under reduced pressure, thus obtaining the extract of Coleus forskohlii called extract I1.
12 kg of dried and ground roots of Coleus forskohlii are extracted twice with 15 1 of petroleum ether.
3û The roots are taken up in order to proceed to repeated extractions with 25 1 of methanol until complete extraction. The combined methalonic extracts are filtered and are evaporated in vacuo.
An extract of Coleus forskohlii called extract I2 is thus obtained.
12 kg of dried and ground complete plants of Coleus forskohlii are repeatedly extracted and ground with a total of 100 l of methanol until the extraction is completed. The combined 05 methalonic extracts are filtered and evaporated in vacuo.
The obtainsd extract of Coleus can be used.
However, according to a variant embodiment, the residue (about 650 9) is partitioned by using a chloroform/water solvent mixture (2/1.5 v/v). Ths chloroformic layer is recovered after decanting. The aqueous layer is repeatedly extracted at the same time as the intermediate layer each time with 1.5 l of chloroform and the obtained chloroformic layer is recovered every time.
The combined chloroformic extracts are then filtered, dried over anhydrous sodium sulfate in order to eliminate the residual water and evaporated in vacuo. About 300 9 of an extract of Coleus called extract I3 is obtained.
Dried and finely ground roots of Coleus forskohlii (1 kg) are repeatedly extracted with benzene (3 x 5 l) preferably according to the extraction technique using Soxhlet at 70C for several hours. The obtained benzene extracts are filtered and concentrated in vacuo in order to eliminate the benzene. The obtained extract of Coleus is called I4.
60 9 of dried and ground roots of Coleus forskohlii are extracted with Soxhlet with 600 ml of solvent. Extraction is effected at the boiling temperature of the solvent with an ever-renewed solvent.
The mean yield of extraction is as follows, expressed in dry weight :
a) Ethanol/water mixture (80/20 v/v) : about 9.2 to 9.5 9, (Extract 5A) 206~7~8 b) Ethyl acetate : about 1.5 9, (Extract 5B) c) Dichloromethane : about 4 9, (Extract 5C) 05 Measurement of the activity of an extract of Coleus forskohlii according to the invention on cultured melanocvtes Protocol :
Murine melanocytes are conventionally cultured in an appropriate medium.
On day D = O, the product to be tested is introduced in the culture medium.
On day D = 5, cells are removed and isolated by centrifuging and the cellular residue is recovered and dissolved in soda 0.5 N.
A reading of the optical density is then effected on a spectrophotometer at 475 nm, which makes it possible to assess the quantity of melanine formed by comparison to the optical density of a melanine solution of known concentration.
Numbering of the cells is also e ff ected and the rate of melanine formed per cell is determined, with respect to a control culture without adding a product to be tested.
Test :
The extract Coleus 5B, according to example 5b is compared with the forskoline alone, used at an equivalent concentration with a positif control consisting in 10 8 mole of ~ -MSH. Forskoline at a concentration of 0.1 >g/ml is thus introduced on day D=O in the culture medium.
In another culture medium, the extract of Coleus is introduced at a determined concentration such that the forskoline rate is also of about û.1 ~g/ml.
Table I hereinafter shows the obtained results.
TABLE I
- i ¦ ¦ Control ¦ Extract ¦ Forskoline ¦ ~-MSH ¦
05 1 ¦ ¦ of Coleus l ¦ Melanine ¦ formed in >g ¦ for 106 ¦27 + 1 ¦116 + 2 192 + 3 ¦ 70 I cells ¦ A-activity ¦ in % ¦ 0 ¦207 1151 1 100 .1 1 1 1 1 1 The A-activity of the stimulation of the melanogenesis by the products according to the invention is determined by the following formula :
q - q A = x 100 q+ qo -in which the sizes q represent the quantities of melanine formed qp = culture medium receiving the product to be tested q+ = culture medium receiving the ~MSH
qO = control culture receiving no product.
It is clear from table I that the extract of Coleus according to the invention promotes the production of melanine in a significantly greater proportion than forskoline alone, which represents an unexpected result for the man skilled in the art.
Furthermore, extracts of Coleus 5A and 5C, respectively obtained by extraction by a ethanol-water mixture 80:20 and by dichloromethane were tested in similar conditions. However it should be noted that a culture medium receiving some ~-MSH at a 05 concentration of 2.10 8 M was taken as positive specimen.
The activity of these extracts, determined according to the aforesaid formula, is shown in table II hereinafter.
TABLE II
¦ Tested product Concentration ¦ Melanine formed in ¦ A -activity¦
¦ ¦ >9 for 106 cells ¦ in %
¦Extract 5A 1 >g/ml ¦ 121 + 3 ¦ 46 I n 2.5 n n ¦161 + 5 ¦ 83 I n 5 n n ¦188 + 9 ¦ 108 ¦ Extract 5B 1 n 1~ ¦ 89 + 3 ¦ 23 I n 2.5 n ~I 1114 + 7 ¦ 45 I n 5 ..... n ¦ 171 + 1 ¦ 95 I n 10 n n I 197 + 6 ¦ 118 ¦~ -MSH 2.10 8 M ¦ 179 + 4 ¦ 100 ¦ Cbntrol ¦ (no product) ¦ 71 1 3 ¦ 0 20~768 Measurement of the activity of a combination according to the invention of Coleus forskohlii with the 3-isobutyl-l-methylxanthine (IBMX), on cultured melanocytes.
05 The procedure is that of example 6. The combination IBMX
plus extract of Coleus is tested in comparison with the IBMX and the extract of Coleus alone, as well as with the ~ -MSH at a concentration of 2.10 8 M taken as positive specimen.
The results on day D = 4 and D = 5 are shown in table III hereinafter.
It is noted on day D = 4 and D = 5 for the combination IBMX + extract of Coleus a much more important activity, which is greater than the amount of activities corresponding to each of the two constituents tested separately.
This proves a very definite reinforcement of the activity of the extract of Coleus by the IBMX.
TABLE III
1 1 1 J = 4 J = 5 PRODUCT 1 Concen- 1 Melanine >9 1 A 1 Melanine >91 A
1 1 tration 1 for 106 1 1 for 106 1 1 >g/ml ¦ melanocytes ¦ ¦ melanocYtes¦
¦Ncne ¦(control) 1 0 1 29 + -3 1 0 1 51 + -l I ¦
1 ~-MSH
1 2.10 8 M 1 1ll9 + -7 1 + lûO 1 200 + -2 1 + lOO¦
1 l/ 1 lO 164 + -O 1 ~ 39 1 103 + -2 1 + 35 206~768 TABLE III (continued) .
l l I J = 4 J = 5 05 ¦ PRODUCT ¦ Concen- ¦ Melanine >g ¦ A ¦ Melanine >9¦ A
¦ ¦ tration ¦ for 106 1 ¦ for 106 ¦ >g/ml _ l melanocytes ¦ ¦ melanocytes¦
2/ 1 0.6 1 53 + -2 1 + 27 185 + -4 1 + 23 3/ 1 10 + 0.6 1 120 + -61 + 101 1 186 + -13l + 91 1.
1 : IBMX
2 : extract of Coleus 5B
3 : IBMX + extract of Coleus 5B
N.B. The A-activity of the tested products is determined as indicated in example 6.
Measurement of the activity of an extract of Coleus forskohlii according to the invention on thq cutaneous pigmentation in the guinea pig Protocole :
The study is made on a batch of 10 three-colored guinea pigs, Before and during the experimentation, the right and left flanks of the guinea pi98 are carefully shaved, every day for the first 5 days (period of exposure to U.V.), then every 2 days until the end of the study.
For each animal, comparably pigmented marks are found on each flank, mainly of light brown appearance. On one of the two flanks taken at random, about 0.5 9 of product to be tested or of control product, depending on the batch, is applied 10 mins.
before exposure to ultraviolet rays, the other flank being exposed "bare" by way of control.
The application of the products to be tested is effected as from the first day of exposure until the animal is sacrificed.
05 Exposure to ultraviolet radiation is effected by means of a solar simulator delivering 86% of U.V.A. and 14% of U.V.B.
during the first 5 days of the experiment, at a rate of 5 mins.
the first day, 10 mins. the second day, 15 mins. the third day and 20 mins. the fourth and fifth days.
The animals ars sacrificed 12 days after the last exposure, and a cutaneous biopsy is effected.
A fragment of skin is thus removed from the non-treated but exposed flank as well as from the other treated and exposed flank.
A histological examination is then made of the cutaneous fragments.
This examination comprises : on the one hand, the study of the melanogenesis by the Argentaffine de Fontana method on sections of 4 ~ m (Techniques d'histologie, Professor Chevreau, Ed.
Maloine, 1977, page 157), on the other hand, the assessment of the thickness of the epidermis on sections of 4~ m colored in accordance with the trichomic method of Masson.
The study of the thickness of the epidermis and of the intensity of the melanogenesis makes it possible to assess a suntan effect ~or more exactly the activation of the process of melanogenesis.
To study the melanogenesis, two zones taken at random from 8 pigmented mark are examined, in which zones 25 malpigian cells are noted and among these the "activated" melanocytes, i.e.
containing melanine in a cluster. The activation of the process of melanogenesis is then expressed in percentage of activated cells from the average of these two values.
On these same zones, the quantity of melanine in the other layers of the epidermis is examined and this quantity is assessed overall in a five value scale varying from O to 4 206476~
depending on whether the quantity of melanine formed is zero, low, average, large or very large.
Table IV shows the results of the histological study giving the percentage of activation and making it possible to 05 assess the variation in the quantity of melanine formed (average values on the scale defined hereinabove), of the thickness of the epidermis (expressed in ~ m).
The product to be tested is constituted by an extract of Coleus with ethyl acetate according to example 5b.
TABLE IV
¦ ¦ Control ¦ Flank treated with¦
I I flank I an extract Df l l ¦ Coleus I
1% Activation ¦ 31 ¦ 90 ¦Quantity of melanine ¦ 0.71 1 2.42 20¦Thickening of the epidermis in ~m ¦ 8.96 ¦ 9 From table IV it may be ascertained that the extract of Coleus is active on melanogenesis. A reading of the histological sections of the treated flanks shows a very high rate of activated melanocytes presenting rhizomic forms, and a considerable migration of the grains of melanines in the epidermis.
These results therefore clearly confirm the activity of the extracts of Coleus in accordance with the invention on melanogenesis in animal skin.
206476~
Measurement of the activity of an extract of Coleus forskohlii according to the invention on the cutaneous pigmentation in man.
The influence of the products according to the invention 05 were measured on the appearance and intensity of the suntan in man.
Protocol :
The experimentation was made on 12 subjects of the II or III skin type, which skin is not yet tanned.
The products to be tested were first of all applied twice a day (morning and evening) on the inside face of a forearm of each subject, during a first period of one week (7 days) ; the applied quantity being that conventionally used.
These products were then applied in the same quantities, i.e. only once a day (morning) during a second period of two weeks during which irradiation takes place.
The minimum erythemale dose (MED) was determined for each subject by irridiation of the arm opposite the one to which the products were applied.
The products to be tested were applied on four separate zones of the forearm. These four zones are exposed to U.V.
supplied by a solar simulator once a day (afternoon) at a daily dose which is lower than MED. When a slight tan appears, the radiation dose administered for 5 to lû seconds according to the skin type is increased while avoiding an occurence of an erytheme.
The exposures are effected every day until a definite tan is obtained, i.e. 8 days (twice 4 days separated by an interval of 2 days).
Measurements are effected on the skin which is not exposed to U.V. and on the treated zones.
A mark of 0 to 5 is given depending on the intensity of the tan. The more greatly tanned area is marked 5, the area without tan is marked 0, while the mark given to the other area is fixed between 0 and 5 depending on the intensity of the tan.
Several resdings are effected by different persons and the average 206~768 given mark is retained. The standard deviation is determined and a t test is effected in order to check if the results are significant.
Three products were tested :
û5 product A : extract of Coleus 5B, according to the invention, at 0.025% in a gelled excipient, product B : extract of Coleus 5B, according to the invention, at 0.05% in the same excipient, product C : the gelled excipient.
The results shown on table V respresent for the three products A, B and C the average marks of the intensity of the tan during 8 days of exposure to U.V.
TABLE V
¦ Product ¦ Reading average ¦ Significance with respect l l ¦ to the U.V. alone ¦ A 1 3.55 + 0.88 I S (~= 0.05) ¦ B ¦ 2.85 1 0.76 .I S ( n ¦ C ¦- 2.53 + 0.58 I NS ( n ¦ U.V. slone ¦ 2.14 + 0.67 ¦ S (with respect to the l l ¦ control without U.V. ¦
¦ control ¦ without U.V.¦ 0 + 0 206a~768 These results clearly show that an extract of Coleus in accordance with the invention makes it possible to intensify the cutaneous tan in man. This confirms the test results obtained on melanocyte in culture medium or in vivo on the aforementioned 05 guinea pigs.
Various examples of formulation of cosmetic or pharmaceutical composition, particularly a dermatological composition having an activity in the treatment of cutaneous pigmentation disorders will be given hereafter.
Tan gel for the face Extract of Coleus (dry weight) according to example 1 0.0284 9 Ethanol 40.- 9 Distilled water 2û.- 9 Carbopol 940 R gel at 1% qsf 100.- 9 Tan solar cream Extract of Coleus (dry weight) according to example 2 0.03 9 Isocetyl stearate 8.- 9 Hydrogenated peanut oil 10.- 9 Lanoline oil 3.5 9 Cetylic alcohol 5.- 9 Stearylic alcohol 2.5 9 Light paraffin oil 10.- 9 Phosphoric monoester of the neutralized OE cetylic alcohol 3.- 9 Cinnamate octylmethoxy 5.- 9 This phase is emulsified with an aqueous phase qsf 100 9 containing :
Pantothenol 0.1 9 Preserving agents 0.2 9 206~7~8 Lotion for strengthening the natur~l solar protection Alcohol 42.5 9 Propylene glycol 3.- 9 05 Menthol 0 05 9 Hydroxypropylmethylcellulose 1.5 9 Extract of Coleus (dry weight) according to example 5b 0.03 9 Perfumed aqueous excipients qsf 100 9 This lotion is applied locally, preferably twice a day, and daily for 3 to 8 days preceding prolonged exposures to the sun.
The daily applications can be continued during the exposure period.
Tonic hair lotion preventing gray hair from appearing Extract of Coleus according to example 5c û.02 9 IBMX 0.1 9 Alcohol 30,_ 9 Water 69.- 9 Perfumed excipients qsf 100 9 This lotion can be applied on the hair and on the scalp twice a day in a cure of 3 months.
Dermatological gel intended to promote skin pigmentation Extract of Coleus according to example 5b 0.03 9 Ethanol 30.- 9 30 Distilled water 20.- 9 Carbopol R gel qsf 100 9 This gel is used once or twice a day in local application on the zones of the skin to be treated.
206~768 Hair lotion preventing gray hair from appearing Extract of Coleus according to example 5b 0.03 9 L-tyrosine ethyl ester, HCl 1.- 9 05 Ethanol 40 _ 9 Perfume 0.5 9 Cremophor 0.2 9 Water qsf 100 9 This lotion, applied daily on the hair and on the scalp, makes it possible to retard the appearance of grey hair.
.
Tan gel for the skin Extract of Coleus 0.03 %
IBMX 0.1 %
Absolute ethanol 30 %
Water 19.86 %
Carbopol 940 R gel at 1.25% qsf 100 %
Application : once a day on the zones of the skin to be treated.
-" 20~768 Treating gel for preventing the appearance of grey hsir Extract of Coleus 0.025 % ) Absolute ethanol 30 % ) A
Bidistilled water 19.925 % ) Methyl nicotinate 0.05 % ) B
Carbopol 940 R gel at 1.25% qsf 100 %
After solubilization of the active principles in A and B, introduce A into B, stir 30 mins. at ambient temperature on the bar magnet. Add the gel, homogenize with Raynerie.
To be applied daily on the hair and on the scalp.
Gel promoting cutaneous pigmentation Extract of Coleus 0.01 % ) Absolute ethanol 28 % ) A
Theophylline 0.01 % ) Water qsf 100 % ) B
Carbopol 940 1 %
This gel is prepared according to the process of example 17 and is applied once or twice a day on the zones of the skin to be treated.
Naturally, the invention comprises all the means constituting technical equivalents of the described means as well as various combinations.
1 : IBMX
2 : extract of Coleus 5B
3 : IBMX + extract of Coleus 5B
N.B. The A-activity of the tested products is determined as indicated in example 6.
Measurement of the activity of an extract of Coleus forskohlii according to the invention on thq cutaneous pigmentation in the guinea pig Protocole :
The study is made on a batch of 10 three-colored guinea pigs, Before and during the experimentation, the right and left flanks of the guinea pi98 are carefully shaved, every day for the first 5 days (period of exposure to U.V.), then every 2 days until the end of the study.
For each animal, comparably pigmented marks are found on each flank, mainly of light brown appearance. On one of the two flanks taken at random, about 0.5 9 of product to be tested or of control product, depending on the batch, is applied 10 mins.
before exposure to ultraviolet rays, the other flank being exposed "bare" by way of control.
The application of the products to be tested is effected as from the first day of exposure until the animal is sacrificed.
05 Exposure to ultraviolet radiation is effected by means of a solar simulator delivering 86% of U.V.A. and 14% of U.V.B.
during the first 5 days of the experiment, at a rate of 5 mins.
the first day, 10 mins. the second day, 15 mins. the third day and 20 mins. the fourth and fifth days.
The animals ars sacrificed 12 days after the last exposure, and a cutaneous biopsy is effected.
A fragment of skin is thus removed from the non-treated but exposed flank as well as from the other treated and exposed flank.
A histological examination is then made of the cutaneous fragments.
This examination comprises : on the one hand, the study of the melanogenesis by the Argentaffine de Fontana method on sections of 4 ~ m (Techniques d'histologie, Professor Chevreau, Ed.
Maloine, 1977, page 157), on the other hand, the assessment of the thickness of the epidermis on sections of 4~ m colored in accordance with the trichomic method of Masson.
The study of the thickness of the epidermis and of the intensity of the melanogenesis makes it possible to assess a suntan effect ~or more exactly the activation of the process of melanogenesis.
To study the melanogenesis, two zones taken at random from 8 pigmented mark are examined, in which zones 25 malpigian cells are noted and among these the "activated" melanocytes, i.e.
containing melanine in a cluster. The activation of the process of melanogenesis is then expressed in percentage of activated cells from the average of these two values.
On these same zones, the quantity of melanine in the other layers of the epidermis is examined and this quantity is assessed overall in a five value scale varying from O to 4 206476~
depending on whether the quantity of melanine formed is zero, low, average, large or very large.
Table IV shows the results of the histological study giving the percentage of activation and making it possible to 05 assess the variation in the quantity of melanine formed (average values on the scale defined hereinabove), of the thickness of the epidermis (expressed in ~ m).
The product to be tested is constituted by an extract of Coleus with ethyl acetate according to example 5b.
TABLE IV
¦ ¦ Control ¦ Flank treated with¦
I I flank I an extract Df l l ¦ Coleus I
1% Activation ¦ 31 ¦ 90 ¦Quantity of melanine ¦ 0.71 1 2.42 20¦Thickening of the epidermis in ~m ¦ 8.96 ¦ 9 From table IV it may be ascertained that the extract of Coleus is active on melanogenesis. A reading of the histological sections of the treated flanks shows a very high rate of activated melanocytes presenting rhizomic forms, and a considerable migration of the grains of melanines in the epidermis.
These results therefore clearly confirm the activity of the extracts of Coleus in accordance with the invention on melanogenesis in animal skin.
206476~
Measurement of the activity of an extract of Coleus forskohlii according to the invention on the cutaneous pigmentation in man.
The influence of the products according to the invention 05 were measured on the appearance and intensity of the suntan in man.
Protocol :
The experimentation was made on 12 subjects of the II or III skin type, which skin is not yet tanned.
The products to be tested were first of all applied twice a day (morning and evening) on the inside face of a forearm of each subject, during a first period of one week (7 days) ; the applied quantity being that conventionally used.
These products were then applied in the same quantities, i.e. only once a day (morning) during a second period of two weeks during which irradiation takes place.
The minimum erythemale dose (MED) was determined for each subject by irridiation of the arm opposite the one to which the products were applied.
The products to be tested were applied on four separate zones of the forearm. These four zones are exposed to U.V.
supplied by a solar simulator once a day (afternoon) at a daily dose which is lower than MED. When a slight tan appears, the radiation dose administered for 5 to lû seconds according to the skin type is increased while avoiding an occurence of an erytheme.
The exposures are effected every day until a definite tan is obtained, i.e. 8 days (twice 4 days separated by an interval of 2 days).
Measurements are effected on the skin which is not exposed to U.V. and on the treated zones.
A mark of 0 to 5 is given depending on the intensity of the tan. The more greatly tanned area is marked 5, the area without tan is marked 0, while the mark given to the other area is fixed between 0 and 5 depending on the intensity of the tan.
Several resdings are effected by different persons and the average 206~768 given mark is retained. The standard deviation is determined and a t test is effected in order to check if the results are significant.
Three products were tested :
û5 product A : extract of Coleus 5B, according to the invention, at 0.025% in a gelled excipient, product B : extract of Coleus 5B, according to the invention, at 0.05% in the same excipient, product C : the gelled excipient.
The results shown on table V respresent for the three products A, B and C the average marks of the intensity of the tan during 8 days of exposure to U.V.
TABLE V
¦ Product ¦ Reading average ¦ Significance with respect l l ¦ to the U.V. alone ¦ A 1 3.55 + 0.88 I S (~= 0.05) ¦ B ¦ 2.85 1 0.76 .I S ( n ¦ C ¦- 2.53 + 0.58 I NS ( n ¦ U.V. slone ¦ 2.14 + 0.67 ¦ S (with respect to the l l ¦ control without U.V. ¦
¦ control ¦ without U.V.¦ 0 + 0 206a~768 These results clearly show that an extract of Coleus in accordance with the invention makes it possible to intensify the cutaneous tan in man. This confirms the test results obtained on melanocyte in culture medium or in vivo on the aforementioned 05 guinea pigs.
Various examples of formulation of cosmetic or pharmaceutical composition, particularly a dermatological composition having an activity in the treatment of cutaneous pigmentation disorders will be given hereafter.
Tan gel for the face Extract of Coleus (dry weight) according to example 1 0.0284 9 Ethanol 40.- 9 Distilled water 2û.- 9 Carbopol 940 R gel at 1% qsf 100.- 9 Tan solar cream Extract of Coleus (dry weight) according to example 2 0.03 9 Isocetyl stearate 8.- 9 Hydrogenated peanut oil 10.- 9 Lanoline oil 3.5 9 Cetylic alcohol 5.- 9 Stearylic alcohol 2.5 9 Light paraffin oil 10.- 9 Phosphoric monoester of the neutralized OE cetylic alcohol 3.- 9 Cinnamate octylmethoxy 5.- 9 This phase is emulsified with an aqueous phase qsf 100 9 containing :
Pantothenol 0.1 9 Preserving agents 0.2 9 206~7~8 Lotion for strengthening the natur~l solar protection Alcohol 42.5 9 Propylene glycol 3.- 9 05 Menthol 0 05 9 Hydroxypropylmethylcellulose 1.5 9 Extract of Coleus (dry weight) according to example 5b 0.03 9 Perfumed aqueous excipients qsf 100 9 This lotion is applied locally, preferably twice a day, and daily for 3 to 8 days preceding prolonged exposures to the sun.
The daily applications can be continued during the exposure period.
Tonic hair lotion preventing gray hair from appearing Extract of Coleus according to example 5c û.02 9 IBMX 0.1 9 Alcohol 30,_ 9 Water 69.- 9 Perfumed excipients qsf 100 9 This lotion can be applied on the hair and on the scalp twice a day in a cure of 3 months.
Dermatological gel intended to promote skin pigmentation Extract of Coleus according to example 5b 0.03 9 Ethanol 30.- 9 30 Distilled water 20.- 9 Carbopol R gel qsf 100 9 This gel is used once or twice a day in local application on the zones of the skin to be treated.
206~768 Hair lotion preventing gray hair from appearing Extract of Coleus according to example 5b 0.03 9 L-tyrosine ethyl ester, HCl 1.- 9 05 Ethanol 40 _ 9 Perfume 0.5 9 Cremophor 0.2 9 Water qsf 100 9 This lotion, applied daily on the hair and on the scalp, makes it possible to retard the appearance of grey hair.
.
Tan gel for the skin Extract of Coleus 0.03 %
IBMX 0.1 %
Absolute ethanol 30 %
Water 19.86 %
Carbopol 940 R gel at 1.25% qsf 100 %
Application : once a day on the zones of the skin to be treated.
-" 20~768 Treating gel for preventing the appearance of grey hsir Extract of Coleus 0.025 % ) Absolute ethanol 30 % ) A
Bidistilled water 19.925 % ) Methyl nicotinate 0.05 % ) B
Carbopol 940 R gel at 1.25% qsf 100 %
After solubilization of the active principles in A and B, introduce A into B, stir 30 mins. at ambient temperature on the bar magnet. Add the gel, homogenize with Raynerie.
To be applied daily on the hair and on the scalp.
Gel promoting cutaneous pigmentation Extract of Coleus 0.01 % ) Absolute ethanol 28 % ) A
Theophylline 0.01 % ) Water qsf 100 % ) B
Carbopol 940 1 %
This gel is prepared according to the process of example 17 and is applied once or twice a day on the zones of the skin to be treated.
Naturally, the invention comprises all the means constituting technical equivalents of the described means as well as various combinations.
Claims (15)
1. Use of an extract of Coleus for preparing a cosmetic or pharmaceutical composition, intended to promote skin pigmentation and/or to the treatment of skin pigmentation disorders.
2. Use according to claim 1, characterized in that the aforesaid extract of Coleus is an extract of the Coleus forskohlii specie, preferably an extract of roots.
3. Use according to claim 1 or 2, characterized in that the aforesaid extract of Coleus is an organic extract of Coleus, preferably obtained by a process comprising at least one step of extraction with a solvent selected from the group constituted by ethyl acetate, methanol, ethanol and dichloromethane.
4. Use according to one of claims 1 to 3, characterized in that the concentration of the aforesaid extract of Coleus expressed by dry weight is comprised between 0.001% and 2% by weight, preferably between 0.01% and 0.5% by weight, with respect to the total weight of the composition.
5. Use according to one of the preceding claims, characterized in that it further comprises a xanthine, such as in particular IBMX or theophylline, preferably at a weight concentration ranging between 0.01% and 2%, and still preferably between 0.01% and 0.5% with respect to the total weight of the composition.
6. Use according to one of the preceding claims, characterized in that it further comprises tyrosine or one of its derivatives, preferably at a weight concentration ranging between 0.001% and 10%, with respect to the total weight of the composition.
7. Use according to one of the preceding claims, characterized in that it further comprises at least one other active substance, at an efficient concentration, selected from vitamins, in particular vitamins B, quinine or its derivatives, rubefacients, such as methyl nicotinate, a supernatant of culture of fibroblasts of papillae, keratin hydrolysates, oligo-elements such as zinc, selenium, copper, 5- .alpha. -reductase inhibitors, such as progesterone, cyproterone acetate, minoxidil, azelaic acid and its derivatives, a 4-methyl-4-azasteroid, in particular the 17-.beta.-N,N-diethylcarbamoyl-4-methyl-4-aza-5-.alpha.-androstan-3-one, or still an extract of Serenoa repens.
8. Use according to one of the preceding claims, characterized in that it is expressed in a form so that it may be applied by a topical route, in particular in the form of cream or gel intended for application on the skin.
9. Process for the preparation of a cosmetic or pharmaceutical composition, particularly a dermatological composition, intended to promote skin pigmentation, characterized in that it comprises the incorporation of at least one extract of Coleus in a cosmetically or pharmaceutically acceptable excipient, vehicle or support.
10. Process according to claim 9, characterized in that the aforesaid extract of Coleus is an extract of the Coleus forskohlii specie, preferably an extract of roots.
11. Process according to claim 9 or 10, characterized in that the aforesaid extract of Coleus is an organic extract of Coleus, preferably obtained by a process comprising at least one step of extraction with the ethyl acetate.
12. Process according to one of claims 9 to 11, characterized in that an efficient quantity of at least one compound selected from xanthines, in particular IBMX or theophylline, tyrosine or one of its derivatives, vitamins, in particular vitamins B, quinine or its derivatives, rubefacients, such as methyl nicotinate, a supernatant of culture of fibroblasts of papillae, keratin hydrolysates, oligo-elements such as zinc, selenium, copper, 5-.alpha.-reductase inhibitors, such as progesterone, cyproterone acetate, minoxidil, azelaic acid and its derivatives, a 4-methyl-4-azasteroid, in particular the 17-.beta.-N,N-diethylcarba-moyl-4-methyl-4-aza-5.alpha.-androstan-3-one, or still an extract of Serenoa repens, is further incorporated.
13. Use of an extract of Coleus combined with an efficient quantity of at least one other active substance, selected from xanthines, in particular IBMX or theophylline, quinine or its derivatives, rubefacients, such as methyl nicotinate, a supernatant of culture of fibroblasts of papillae, keratin hydrolysates, oligo-elements such as zinc, selenium, copper, 5-.alpha.-reductase inhibitors, such as cyproterone acetate, minoxidil, azelaic acid and its derivatives, a 4-methyl-4-azasteroid, in particular the 17-.beta.-N,N-diethylcarba-moyl-4-methyl-4-aza-5-.alpha.-androstan-3-one, or still an extract of Serenoa repens, for the preparation of a cosmetic or pharmaceutical composition intended to promote hair pigmentation.
14. Use according to claim 13, characterized in that the aforesaid extract of Coleus is an extract of the Coleus forskohlii specie, preferably of roots.
15. Process for the preparation of a cosmetic or pharmaceutical composition, intended to promote hair pigmentation, characterized in that it comprises the incorporation of at least one extract of Coleus, particularly an extract of the Coleus forskohlii specie, preferably of roots, combined with an efficient quantity of at least one other active substance, selected from xanthines, in particular IBMX or theophylline, quinine or its derivatives, rubefacients, such as methyl nicotinate, a supernatant of culture of fibroblasts of papillae, keratin hydrolysates, oligo-elements such as zinc, selenium, copper, 5-.alpha.-reductase inhibitors, such as cyproterone acetate, minoxidil, azelaic acid and its derivatives, a 4-methyl-4-azasteroid, in particular the 17-.beta.-N,N-diethylcarba-moyl-4-methyl-4-aza-5-.alpha.-androstan-3-one, or still an extract of Serenoa repens, in a cosmetically or pharmaceutically acceptable excepient, vehicle or support for an application on the hair.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8910985 | 1989-08-17 | ||
FR898910985A FR2650952B1 (en) | 1989-08-17 | 1989-08-17 | COSMETIC OR PHARMACEUTICAL COMPOSITION, ESPECIALLY DERMATOLOGICAL, CONTAINING AN EXTRACT OF COLLEUS AND PROCESS FOR THE PREPARATION THEREOF |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2064768A1 true CA2064768A1 (en) | 1991-02-18 |
Family
ID=9384771
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002064768A Abandoned CA2064768A1 (en) | 1989-08-17 | 1990-08-14 | Skin pigment composition containing a coleus extract |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0486595B1 (en) |
JP (2) | JP3029866B2 (en) |
AT (1) | ATE118166T1 (en) |
CA (1) | CA2064768A1 (en) |
DE (1) | DE69016786T2 (en) |
ES (1) | ES2071112T3 (en) |
FR (1) | FR2650952B1 (en) |
WO (1) | WO1991002516A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5589161A (en) * | 1989-12-15 | 1996-12-31 | The Board Of Regents Of The University Oklahoma | Pigmentation enhancer and method |
US11052059B2 (en) | 2008-03-07 | 2021-07-06 | Lucolas - M.D. Ltd | Composition and uses for influencing hair growth |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2665637B1 (en) * | 1990-08-13 | 1993-08-06 | Lvmh Rech | COSMETIC OR PHARMACEUTICAL COMPOSITION CONTAINING AN EXTRACT OF ESQUIROLII COLEES, SCUTELLARIOIDE COLEES, COLEUS XANTHANTHUS OR A MIXTURE THEREOF. |
WO1995017161A1 (en) * | 1993-12-21 | 1995-06-29 | The Board Of Regents Of The University Of Oklahoma | Pigmentation enhancer and method |
JPH0826961A (en) * | 1994-07-12 | 1996-01-30 | Kao Corp | Skin external agent composition |
WO2002000240A2 (en) | 2000-06-27 | 2002-01-03 | Qualilife Pharmaceuticals Inc. | Compositions and methods for treating females sexual response |
FR2831434B1 (en) * | 2001-10-30 | 2004-04-02 | Oreal | COMPOSITIONS FOR ARTIFICIAL COLORING OF THE SKIN AND USES THEREOF |
FR2836630B1 (en) * | 2002-03-01 | 2004-07-09 | Lvmh Rech | COSMETIC USE OF PHYTOSPHINGOSINE AS A SLIMMING AGENT AND COSMETIC COMPOSITIONS CONTAINING PHYTOSPHINGOSINE |
KR101320151B1 (en) * | 2007-07-19 | 2013-10-22 | (주)아모레퍼시픽 | Method for screening anti-gray hair ingredient using stable cell lines and accelerated vitiligo mouse, and composition containing anti-gray hair ingredient detected thereby |
FR2946529B1 (en) | 2009-06-10 | 2011-09-09 | Lvmh Rech | USE OF A CEREAL EXTRACT AS A SLIMMING ACTIVE AGENT IN A SLIMMING COSMETIC COMPOSITION |
JP2017203012A (en) * | 2016-05-13 | 2017-11-16 | 株式会社Nil | Hair remedy |
WO2018179374A1 (en) * | 2017-03-31 | 2018-10-04 | 株式会社セルバンク | Cosmetic composition comprising culture supernatant of dermal fibroblasts and method for manufacturing same |
US20200155634A1 (en) * | 2017-07-14 | 2020-05-21 | Life Science Investments Ltd | Cosmetic composition comprising coleus forskohlii and cassia occidentalis and/or cassia alata, and compositions for use in treating vitiligo |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1083589A (en) * | 1975-09-06 | 1980-08-12 | Sujata V. Bhat | Effective substance from plants belonging to the labiatae family |
AU2717777A (en) * | 1976-07-21 | 1979-01-25 | Hoechst Ag | Pharmacologically effective substance from plants belonging to the family of labiatae |
JP2711549B2 (en) * | 1987-06-01 | 1998-02-10 | 圭吉 杉山 | Composition for preventing and improving white hair |
-
1989
- 1989-08-17 FR FR898910985A patent/FR2650952B1/en not_active Expired - Fee Related
-
1990
- 1990-08-14 CA CA002064768A patent/CA2064768A1/en not_active Abandoned
- 1990-08-14 WO PCT/FR1990/000610 patent/WO1991002516A1/en active IP Right Grant
- 1990-08-14 DE DE69016786T patent/DE69016786T2/en not_active Expired - Fee Related
- 1990-08-14 AT AT90912872T patent/ATE118166T1/en not_active IP Right Cessation
- 1990-08-14 EP EP90912872A patent/EP0486595B1/en not_active Expired - Lifetime
- 1990-08-14 JP JP2512021A patent/JP3029866B2/en not_active Expired - Fee Related
- 1990-08-14 ES ES90912872T patent/ES2071112T3/en not_active Expired - Lifetime
-
1999
- 1999-10-06 JP JP28605999A patent/JP3490357B2/en not_active Expired - Fee Related
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5589161A (en) * | 1989-12-15 | 1996-12-31 | The Board Of Regents Of The University Oklahoma | Pigmentation enhancer and method |
US5591423A (en) * | 1989-12-15 | 1997-01-07 | The Board Of Regents Of The University Of Oklahoma | Pigmentation enhancer and method |
US5628987A (en) * | 1989-12-15 | 1997-05-13 | The Board Of Regents Of The University Of Oklahoma | Pigmentation enhancer and method |
US11052059B2 (en) | 2008-03-07 | 2021-07-06 | Lucolas - M.D. Ltd | Composition and uses for influencing hair growth |
US11324711B2 (en) | 2008-03-07 | 2022-05-10 | S.W. Patentverwertungs Limited | Composition and uses for influencing hair growth |
US11974977B2 (en) | 2008-03-07 | 2024-05-07 | Lucolas—M.D. Ltd | Composition and uses for influencing hair growth |
Also Published As
Publication number | Publication date |
---|---|
JP3490357B2 (en) | 2004-01-26 |
DE69016786T2 (en) | 1995-09-21 |
EP0486595A1 (en) | 1992-05-27 |
DE69016786D1 (en) | 1995-03-23 |
JP3029866B2 (en) | 2000-04-10 |
FR2650952A1 (en) | 1991-02-22 |
EP0486595B1 (en) | 1995-02-08 |
JPH05501108A (en) | 1993-03-04 |
WO1991002516A1 (en) | 1991-03-07 |
ES2071112T3 (en) | 1995-06-16 |
FR2650952B1 (en) | 1994-10-14 |
JP2000095669A (en) | 2000-04-04 |
ATE118166T1 (en) | 1995-02-15 |
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Legal Events
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FZDE | Discontinued |