MC200087A1 - Turmeric longa extract and its cosmetic or dermopharmaceutical applications - Google Patents

Description

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0 0 2 5 17

April 3, 2006

io PATENT D1 INVENTION

TITLE OF THE INVENTION:

TURMERIC LONGA EXTRACT AND ITS COSMETIC OR DERMOPHARMACEUTICAL APPLICATIONS 15

APPLICANT:

EXSYMOL S.A.M.

20 INVENTOR:

Mr. C. SEGUIN

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The invention relates to an extract obtained from the aerial parts of Curcuma longa, a cosmetic or dermopharmaceutical composition containing such an extract, and the use of such an extract or composition to regulate or inhibit androgen-dependent mechanisms at the level of the skin or scalp.

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Many people today are affected, to varying degrees, by one or more so-called androgen-dependent disorders, which share a common origin: a disruption in the metabolism of the androgen hormone testosterone (P. Vexiau, "Hormones et peau," Cosmétologie (1996), No. 10, pp. 43-47). These disruptions can be genetic or pathological in origin, but can also be linked to the aging process. At the level of the skin or scalp, the most common of these hormonal dysfunctions are the growth of unwanted hair on the body or face, including hirsutism in women, acne, seborrhea, and alopecia.

Another observation is that, nowadays, in Western societies, men, almost as much as women, seek to reduce their body hair. For both sexes, hairless skin has indeed become a symbol of beauty. To meet this growing desire, new hair removal techniques have been developed. However, they are most often cumbersome and expensive. One alternative today involves applying compounds to the skin that can locally interfere with the metabolism of testosterone, the main regulator of hair growth.

In general, there is a real demand to provide products or preparations that act on androgen-dependent mechanisms, both at the level of the skin and scalp.

Thus, in order to satisfy this need, the applicant discovered, curiously, unexpectedly, and this is the basis of the present invention, that extracts from the leaves or flowers of Curcuma longa exhibited remarkable activity in reducing or inhibiting the metabolism of testosterone, thus providing a new response for the treatment of androgen-dependent disorders, for aesthetic and dermatological needs.

Among the formulations on the market that claim a general "anti-androgenic" action, useful for

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In addition to the aforementioned applications, it is worth noting the presence of numerous preparations or combinations of plant origin in the prior art. For example, an ethanolic extract of the Majihto and/or Kachur plants is recommended for combating alopecia, seborrhea, and acne (patent JP4342535). A cosmetic or dermatological composition based on a myrrh extract (Commiphora myrrha) is intended to regulate sebaceous secretion in oily or acne-prone skin, as well as to treat acne, hirsutism, and slow facial hair growth (patent WO00/04872). Another topical composition, based in particular on an extract of cedarwood and cinnamon, is used to control seborrhea and treat acne (patent US2004/228822). Fifteen substances extracted from Japanese plants are attributed with an androgen receptor inhibition action, which is particularly relevant for acne and male pattern baldness (patents JP2000/001432 and JP8193094). For some of these preparations, characterized by a plant-based presence, an inhibitory effect on the 5-alpha reductase enzyme is sometimes clearly stated, as in international application W002/19974. This enzyme is of interest because it is responsible for converting testosterone into another, more potent androgen ion, dihydroxytestosterone, which is particularly active on the sebaceous glands of the skin and on the hair follicle.

The herbaceous plant Curcuma longa, of the ginger family (Zingiberaceae), has also been mentioned. Upon reading the monograph on this plant (Alternative Medicine Review (2001), 30 vol. 6, pp. S62-S66) and the following examples of preparations made available to the public, it appears that it is the rhizome, namely the underground stem, that constitutes the part of the plant traditionally used for medicinal purposes, particularly for the treatment of androgen-dependent disorders. The rhizome, once boiled, washed, and dried, yields a yellow powder (or "turmeric") rich in phenolic compounds called curcuminoids ("Turmeric," Nutranews, June 2002), such as curcumin, tetrahydrocurcumin, dimethoxycurcumin, etc. And it is attributed to this yellow powder iW

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Antioxidant, hepatoprotective, anti-inflammatory, anticarcinogenic, and antimicrobial properties, which are also the reasons for the interest of Curcuma longa in traditional and Ayurvedic medicine ("Ayurvedic Medicine," 5 Nutranews, September 2003). Thus, as examples involving the turmeric rhizome itself or indirectly, when curcumin or its analog ion is highlighted, patent applications JP3176414, W003/088927, JP9255568, and US2003/105030 are noted. The first document mentions that acne and alopecia are the targets of a cosmetic agent based on Japanese and Chinese plants, notably turmeric rhizome. The following three disclose the use of curcumin or its analogues to counteract various androgen-dependent disorders.

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Despite these numerous findings, it should be noted that there has never been reported, or even suggested, a reducing or inhibitory effect on testosterone metabolism for extracts of Curcuma longa when these result exclusively from the aerial parts of the plant, nor has the use of this same type of extract, or compositions based on it, been described for the purpose of combating the growth of unwanted hair on the face or body, preventing or combating acne, seborrhea and male pattern baldness.

The previously mentioned term "aerial parts" refers to the flowers and leaves of the plant. While the leaves and flowers of Curcuma longa have been the subject of 30 studies, most of these studies almost exclusively focused on essential oils obtained by hydrodistillation. The literature reveals a high proportion of monoterpene derivatives, particularly terpinolenes, in these volatile oils from leaves or flowers (Chane-Ming J. et al., J. Essent. Oil Res. (2002), vol. 14, pp. 249-251). Specifically, an essential oil derived from turmeric leaves has been reported to have anti-inflammatory activity (Lyengar M. A. et al., Indian Drugs (1994), vol. 31, pp. 528-531).

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than an insecticidal action against beetles (Tripathi A.K. et al., J. Econ. Entomol. (2002), vol.95, pp.183-189).

According to a first aspect, the invention relates to a 5-extract of Curcuma longa, characterized in that:

It is obtained from the aerial parts of the plant, parts harvested at a specific time of year to guarantee maximum levels of active compounds, preferably in spring (March and April) when harvested at a latitude close to that of the Tropic of Cancer.

Capricorn,

It exhibits a reducing or inhibiting activity on testosterone metabolism.

Curcuma longa extract can be advantageously isolated from the aerial parts of the plant, dehydrated and ground.

Another characteristic of this extract is that it contains, in particular, phenylpropanoid derivatives and flavonoid derivatives, substances which are also used as tracers to standardize the extract. It is important to emphasize, however, the complete absence of curcumin and related compounds in the aerial parts of the plant. The properties exhibited by an extract obtained from these aerial parts are therefore not attributable to the presence of such substances, unlike the rhizome of Curcuma longa.

This extract, which is in itself a new product, contains phenylpropanoid and flavonoid derivatives, 30 in a mass content of between 0.05 and 3%.

The said extract can be obtained using a technique well known to those skilled in the art. First, the aerial parts of Curcuma longa are harvested, dehydrated, and coarsely ground. An extraction is then carried out using alcoholic, hydroalcoholic, or other polar solvents (DMF, DMSO, acetonitrile, etc.), under stirring and reflux. Once the extraction is complete, and after the plant material has been exhausted, the organic solvents are removed, and then the volume

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The extract is adjusted with water. It is also possible to add a water-miscible glycol to ensure the solubility of certain constituents of the extract.

5 According to an advantageous variant, in an extract containing 0.1% by weight of flavonoid derivatives, the extract contains from 0.01 to 0.5% by weight of phenylpropanoid-type derivatives, preferably from 0.01 to 0.1%.

10 According to an advantageous embodiment of the invention, in order to obtain a more active and stable extract, a controlled acid hydrolysis reaction is carried out on the extract in solution, notably allowing the production of flavonoid-type aglycone derivatives. The enhanced activity of this extract can 15 be partly explained by the formation of compounds that penetrate the epidermis more readily, such as aglycone flavonoids.

The flavonoid-type aglycone derivatives that could be identified in the extract and that are used as tracers 20 to standardize the extract are quercetin and kaempferol, while the phenylpropanoid-type derivatives identified are ferulic acid and coumaric acid.

According to a second aspect, the present invention also extends to a cosmetic or dermopharmaceutical composition comprising, as a reducing or inhibiting agent for testosterone metabolism, an effective quantity of the extract as defined above. This extract is incorporated into the composition with any cosmetically or pharmaceutically acceptable excipient. Such a composition is substantially free of Curcuma longa rhizome extract.

Advantageously, the extract content in the above composition is between 1 and 10% by weight relative to the total weight of the composition, preferably between 1 and 5% by weight.

The said composition may also include another active ingredient selected from agents for which it is

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recognized an inhibitory effect on the activity of specific enzymes known to be involved in testosterone metabolism in the skin or scalp. These enzymes may include protein kinase C, ornithine decarboxylase, adenylosuccinate synthetase, aspartate transcarbamylase, gamma-glutamyl transpeptidase, S-adenosylmethionine decarboxylase, NO-synthase, serine protease, and 5-alpha-reductase. According to a preferred embodiment of the present invention, an agent capable of inhibiting the activity of the enzyme ornithine decarboxylase, such as efflornithine hydrochloride, or that of the enzyme NO-synthase, such as JX-nitro-L-arginine methyl ester, is selected.

15 According to a very particular embodiment of the invention aimed at an aesthetic benefit associated with a limitation of hair regrowth, said composition may also include, optionally, urea (up to a concentration of 20%) and IS^-nitro-L-arginine methylester.

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Cosmetic or dermopharmaceutical compositions are formulated to be applied topically to the skin in the form of, for example, milk, gel, cream, lotion, emulsion, etc. They can also be administered orally 25 (per os administration) in the form of tablets, capsules, ampoules, syrup, drops, etc.

By way of illustration, some examples of cosmetic or dermopharmaceutical composition formulations according to the invention, containing the aforementioned Curcuma longa extract, are mentioned below:

Formula A (topical application: anti-hair regrowth)

35 Turmeric extract (turmeric extract) 5%

Hydrogenated polydecene 5% Caprilic/Capric Triglycerides 2%

Ethoxydiglycol oleate (ethoxydiglycol oleate) 8%

Glyceryl stearate 3%

40 Dimethicone (dimethicone) 1% PEG-100 stearate (and) glyceryl stearate (polyethylene glycol-100 stearate and glyceryl stearate) 5%

Glycerin (glycerin) 3%

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Carbomer (acrylate/acrylamide copolymer & mineral oil) 0.2%

Sodium hydroxide (soda) 0.4%

Chlorphenesin (chlorphenesin) 0.2%

Phenonip (butyl, ethyl parabens (parahydroxybenzoate),

5 isobutyl, methyl, propyl and phenoxyethanol) 0.6%

Wheat germ oil (wheat germ oil) 1/5%

Sesamus indicum oil (sesame oil) 1.5%

PEG-8 & Tocopherol & Ascorbyl Palmitate & Ascorbic acid & Citric acid (polyethylene glycol-8 & tocopherol

10 (ascorbyl palmitate, ascorbic acid, and citric acid) 0.07%

Urea (urea) 5%

Efflornithine hydrochloride (efflornithine hydrochloride) 1% IS^-nitro-L-arginine methyl ester (methyl ester of

(ivf-nitro-L-arginine) 1%

15 Aqua (water) <3SP 100

Formula B (topical application: male pattern baldness)

20% Turmeric extract (turmeric extract) 3% Glyceryl stearate & stearyl alcohol (glyceryl stearate)

(and stearyl alcohol) 5%

Stearyl alcohol (stearyl alcohol) 2%

Hydrogenated polydecene 8%

25% Caprilic/Capric Triglyceride (capric/caprilic triglycerides) 5%

Cetearyl isononanoate (cetearyl isononanoate) 2%

Dicaprylyl carbonate (dicaprylyl carbonate) 1%

Cera alba (beeswax) 1%

Propylparaben (propyl paraben) 0.3%

30 Aqua (water) 10%

Ethylenediamine-tetraacetic acid disodium salt dihydrate (EDTA) 0.2%

Glycerin (glycerin) 3%

35 Xantha gum (xanthic gum) 0.4%

Macadamia Emulzome (hydrogenated polyisobutene, stearyl hepatanoate, macadamia oil, and methylparaben) 5%

Triethanolamine (triethanolamine) 0.35%

Aqua (water) qsp 100

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Formula C (topical application: acne)

Turmeric extract (turmeric extract) 2%

45% Hydrogenated polydecene (hydrogenated polyisobutene) 8% Caprilic/Capric Triglyceride (capric/caprilic triglycerides) 2%

Ethoxydiglycol Oleate (ethoxydiglycol oleate) 8%

Glyceryl stearate 2%

Dimethicone (dimethicone) 1% 50 PEG-100 stearate (and) glyceryl stearate (polyethylene glycol-100 stearate and glyceryl stearate) 5%

Propylparaben (propyl paraben) 0.3%

Stearyl alcohol (stearyl alcohol) 1%

Aqua (water) 10%

55 Ethylenediamine-tetraacetic acid disodium salt dihydrate (EDTA) 0.2%

Glycerin (glycerin) 2%

Xantha gum (xanthic gum) 0.4%

60 Wheat germ oil (wheat germ oil) 1%

Macadamia Ternifolia seed oil (Macadamia seed oil) 1% PEG-8 Se Tocopherol & Ascorbyl Palmitate &

Ascorbic acid & Citric acid (polyethylene glycol-8 & tocopherol)

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(Ascorbyl palmitate, ascorbic acid, and citric acid) 0.07%

Triethanolamine (triethanolamine) 0.35%

Aqua (water) qsp 100

5 ....

Formula D (application: hair regrowth inhibitor, oral administration)

Turmeric extract (turmeric extract) 4%

Excipients q.s. 1 gelatin capsule: soy lecithin, soybean oil, 10 fatty acid glycerides

According to a third aspect, the present invention relates to the use of a Curcuma longa extract, as defined above, as a cosmetic agent intended to reduce or inhibit the metabolism of testosterone, in particular to slow the growth of unwanted facial or body hair, or to combat or prevent seborrhea and male pattern baldness. Preferably, the aim with said extract is to slow the growth of unwanted facial or body hair.

According to another aspect of the invention, the present invention relates to the use of a Curcuma longa extract, as defined above, for the manufacture of a dermopharmaceutical composition 25 intended to reduce or inhibit the metabolism of testosterone, in particular to combat or prevent acne and hirsutism. It also relates to the use of a Curcuma longa extract, as defined above, for the manufacture of a cosmetic composition 30 intended to reduce or inhibit the metabolism of testosterone, in particular to slow the growth of unwanted facial or body hair, or to combat or prevent seborrhea and androgen-dependent alopecia. Preferably, the aim of this latter composition 35 is to slow the growth of unwanted facial or body hair.

Finally, the invention is illustrated, for purely indicative purposes, on the one hand, by the following in vitro test (test 1).

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Test 1: Demonstration of the effect of a Curcuma longa extract on the metabolism of testosterone in reconstructed human epidermis (supplier: SkinEthic®).

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These epidermis samples constitute a biological material exhibiting a high degree of homology with the human epidermis, and allowing for realistic testing of a product intended to be applied to the skin surface.

10 A glycolic extract of Curcuma longa leaves was therefore tested at different concentrations. Their action was also compared to that of a specific 5-alpha-reductase inhibitor, Finasteride® (reference molecule in this type of evaluation).

15 Seventeen-day reconstructed epidermis were precultured in 24-well plates for 24 hours. Then, 100 µL of labeled testosterone were deposited on the stratum corneum of each epidermis. After another 24 hours, the culture media were collected for analysis. The metabolism of testosterone was then examined by silica plate chromatography and by direct counting of the radioactivity of the different spots, using the "Optiquant version 3 (Packard)" software. Various metabolites, and in particular dihydrotestosterone (DHT), were identified using standards. Each point is the average of 3 measurements taken on different epidermis.

The results are summarized in the following table:

% inhibition of testosterone metabolism

% inhibition transformation into DHT

DHT/testosterone ratio.

Untreated witness

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2.2

Finasteride 10"4M

54

92

0.1

Glycolic extract 0.1%

38

4

1.5

Glycolic extract 0.5%

70

40

0.5

Glycolic extract 1%

85

51

0.2

30

10

15

20

25

30

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The glycolic extract exhibits strong anti-androgenic activity, revealed by a dose-dependent inhibition of testosterone metabolism (the percentage of inhibition is expressed relative to the untreated control). Comparison with finasteride, a specific inhibitor of the 5-alpha reductase enzyme, shows that the extract inhibits this enzyme, but also acts on other enzymes involved in testosterone metabolism (an effect revealed by chromatography).

Furthermore, and still by way of example, the invention is also illustrated by the three in vivo tests below (tests 2 to 4).

Test 2: demonstration of the effect, via topical application, of the aforementioned cosmetic composition on the growth of unwanted hair.

A statistical study was conducted on a panel of 25 men and women aged 20 to 50 with particularly vigorous underarm hair growth. A random selection was made to determine which subjects would receive treatment and which would not. The treated subjects included men and women who applied either the aforementioned Formula A lotion or a placebo lotion (without active ingredient) after shaving their underarms daily, morning and evening, for 20 days. The results are summarized in the following table:

% of subjects with reduced hair length

10 topics "covered": Formula A

80%

7 subjects "treated": placebo

14%

8 "unaddressed" topics

0%

After only 20 days of treatment, it was observed, in comparison to subjects who received no treatment, that 80% of the "treated" subjects who applied formula A, the subject of the present invention, saw the length of their underarm hair reduced by at least 39%.

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Test 3: Demonstration of the effect, via topical application, of a Curcuma longa extract on male seborrheic alopecia.

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In a preliminary study, a glycolic extract of Curcuma longa leaves, containing 0.25% active ingredients, was tested on eight men under 40 years of age with early signs of androgenetic alopecia. It should be noted that the activity of an extract/formulation, for the purpose of combating hair loss, can be assessed, as a first step, by monitoring the ratio of the number of hairs in the anagen phase to the number of hairs in the telogen phase. Thus, a ratio below 4 indicates a suspicious disturbance, which can be classified as pathological if it falls below 3 (P. Bouhanna, "Garder et retrouver ses cheveux", Ed. Springer-Verlag, 2000, and references cited).

This pre-clinical evaluation study was therefore conducted over 3 months on these eight volunteers, with two applications per day, morning and evening. The following results were noted (confirming the anti-alopecia potential of this active ingredient and very positive results in a developed formulation):

Five cases saw their initial ratio of "anagen phase hairs to telogen phase hairs" significantly increase, becoming clearly greater than 5, with the observation of visible partial coverage of some bare areas of the scalp.

Only one case showed no improvement. It should be noted that two cases were not classified as "positive", despite an increased ratio and a visible improvement in the quality of hair growth.

Test 4: Demonstration of the effect of the aforementioned composition, 35 administered orally, on the growth of unwanted hair.

Among women who frequented a beauty salon, 12 volunteers were selected, who regularly visited the salon (once a month) to undergo hair removal.

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wax on the legs. For this test, these women agreed to take, orally in capsule form, an oily extract of Curcuma longa (formula D mentioned above). One capsule was taken each morning on an empty stomach for a one-month treatment. At the end of this treatment, a survey of these 12 women showed that each of them had delayed their scheduled hair removal appointment at the aforementioned salon, thus demonstrating a significant anti-regrowth effect. The following was observed:

10 - that, for 5 of them, the delay was approximately 1 week; that, for 4 of them, the delay was 2 weeks; that, for the remaining 3, the delay was such that they were able to avoid a monthly session

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Claims (20)

DEMANDS 1. Extract of Curcuma longa, characterized in that it is obtained from the aerial parts of the plant and in that it exhibits an activity of reducing or inhibiting the metabolism of testosterone. 2. Extract according to claim 1, characterized in that it is 10 obtained from the aerial parts of the plant, dehydrated and crushed. 3. Extract according to claim 1 or 2, characterized in that it contains phenylpropanoid-type derivatives and 15 flavonoid-type derivatives. 4. Extract according to claim 3, characterized in that it contains phenylpropanoid and flavonoid derivatives, in a mass content of between 0.05 and 3%. 20 5. Extract according to any one of claims 1 to 4, characterized in that it contains, in an extract standardized to 0.1% by weight of flavonoid derivatives, 0.01 to 0.5% by weight of phenylpropanoid type derivatives. 25 6. Extract according to claim 5, characterized in that it contains from 0.01 to 0.1% by weight of phenylpropanoid-type derivatives. 30 7. Extract according to any one of claims 116, characterized in that the phenylpropanoid type aglycone derivatives are selected from the group consisting of ferulic acid and coumaric acid and in that the flavonoid type derivatives are selected from the group consisting of kaempferol and quercetin. 7fl/ 15 8. A cosmetic or dermopharmaceutical composition, characterized in that it comprises, as a reducing or inhibiting agent of testosterone metabolism, an effective amount of a Curcuma longa extract as defined in one of the 5 claims 1 to 7, and a cosmetically or pharmaceutically acceptable excipient. 9. Composition according to claim 8, characterized in that the extract content is between 1 and 10% by weight per 10 in relation to the total weight of the composition. 10. Composition according to claim 9, characterized in that the extract content is between 1 and 5% by weight relative to the total weight of the composition. 15 11. Composition according to any one of claims 8 to 10, characterized in that it further comprises another active element selected from the following enzyme inhibitors: protein kinase C, ornithine decarboxylase, adenylosuccinate synthetase, 20 aspartate transcarbamylase, gamma-glutamyl transpeptidase, S-adenosylmethionine decarboxylase, NO-synthase, serine protease and 5-alpha-reductase. 12. Composition according to any one of claims 8 to 11, 25 characterized in that it optionally comprises urea and IS^-nitro-L-arginine methylester. .13. Composition according to any one of claims 8 to 12, characterized in that it is formulated to be applied topically to the skin in the form of a milk, gel, cream, lotion, emulsion. 14. Composition according to any one of claims 8 to 12, characterized in that it is formulated for administration 35 orally in the form of tablets, capsules, ampoules, syrups, drops. 15. Use of a Curcuma longa extract as a cosmetic agent intended to reduce or inhibit the metabolism of 16 testosterone, in particular to slow the growth of unwanted facial or body hair, or to combat or prevent seborrhea and male pattern baldness. 5 16. Use according to claim 15, wherein the extract is used to slow the growth of unwanted facial or body hair. 17. Use of an extract of Curcuma longa for the manufacture of a dermopharmaceutical composition intended to reduce or inhibit the metabolism of testosterone, in particular to combat or prevent acne and hirsutism. 15 18. Use of an extract of Curcuma longa for the manufacture of a cosmetic composition intended to reduce or inhibit the metabolism of testosterone, in particular to slow the growth of unwanted facial or body hair, or to combat or prevent seborrhea and androgen-dependent alopecia. 19. Use according to claim 18, wherein the composition is used to slow down the growth of unwanted facial or body hair. 25 20. Use according to any one of claims 15 to 19, characterized in that the aforementioned extract of Curcuma longa is as defined in any one of claims 1 to 7. Tf \l