WO1996024327A1

WO1996024327A1 - Compositions having depigmenting activity, and uses thereof

Info

Publication number: WO1996024327A1
Application number: PCT/FR1996/000211
Authority: WO
Inventors: Raja Hanna
Original assignee: Hanna, Claude
Priority date: 1995-02-09
Filing date: 1996-02-08
Publication date: 1996-08-15
Also published as: FR2730408A1; AU4723296A; FR2730408B1

Abstract

Compositions and preparations having depigmenting activity, and the pharmaceutical and cosmetic uses thereof, are disclosed. Such plant-based compositions regulate skin pigmentation and essentially comprise a fruit extract selected from the group which consists of hydroalcoholic extracts of Punica granatum, Terminalia chebula, Terminalia belerica and Cydonia oblonga, aqueous extracts of Punica granatum, Terminalia belerica, Cydonia oblonga or Phyllanthus emblica, and extracts produced by pressing Punica granatum, Terminalia chebula, Terminalia belerica, Cydonia oblonga or Phyllanthus emblica, containing at least one α-hydroxyacid, ascorbic acid and at least one polyphenol as the active ingredients.

Description

COMPOSITIONS WITH DEPIGMENTING ACTIVITY AND APPLICATIONS THEREOF.

The present invention relates to new compositions and preparations with depigmenting activity as well as to their pharmaceutical, cosmetic or aesthetic applications.

The skin pigmentation of mammals, in general, and of humans, in particular, is based on the biosynthesis of a nitrogen pigment, melanin, from tyrosine, whose regulation is under the influence of several parameters:

- tyrosinase, produced by the pigment cell, - the melanocyte, which under the influence of ultraviolet light, catalyzes the oxidation of tyrosine to dihydroxyphenylalanine (DOPA), then to dihydroxyindole and finally to melanin,

- the melanin can then undergo oxidative polymerizations which will accentuate its coloring; this pigment is present in the form ^of organelles, the melanosomes in the dendrites of melanocytes and above these melanosomes are then transmitted to Keratinocytes, which will carry the melanin to the skin surface where it will be phased in natural flaking.

The color of the skin and its intensity therefore depend on the speed of melanin synthesis, its degree of polymerization, the speed of scaling and the thickness of the stratum corneum which is the layer containing the most pig¬ ment.

In general, to act effectively on skin pigmentation, it is necessary to reduce the synthesis of melanin by inhibiting tyrosinase, while reducing its polymerization and accelerating the desquamation of the horny layer.

Most of the depigmenting preparations available are based on substances of animal, mineral or plant origin. However, only a very small number of these substances actually have a depigmenting effect; most of these substances have bothersome and even harmful side effects. Mention may in particular be made of mercurial products which can cause serious poisoning; compounds based on hydroquinone which, although currently considered as the least irritating agents of the inhibitors of tyrosinase, nevertheless cause significant irritation and sensitization of the skin, incompatible with prolonged use as a depigmenting agent, both in dermatology and in cosmetology

Many active ingredients of plant origin or extracts of plants have also been attributed a depigmenting activity, such as Aleurites For st., Aleuntes fordu Hemsl, Mallotus Lotir., Mallotus japomcus Mite II. Arg., Sapium P. Br., Sapium sebiferum Roxb., Securmega comm. exjuss. (Japanese request on behalf of Nippon Shinyaku Co Ltd and Sunstar Chem Ind, n ° 5345720), or extracts of yarrow (Medical Gazette, 1988, 95, 15, 1-3) etc. A topical depigmenting must obey to three rules

- have a depigmenting effect on the only lesions to be treated,

- produce no irritation or post-inflammatory secondary pigmentation, and

- do not cause any allergy or systemic depigmenting effect, both mercurial products and hydroquinone-based products have side effects which contraindicate repeated local use of these products; on the other hand, among the substances of plant origin proposed in the prior art, their real depigmenting effect, for all of the recommended indications (normal skin pigmentation and its excess senile lentigo, chloasma, hyperpigmentation after use of products photosensitizing, brown scarring), has not been proven

Consequently, the Applicant has set itself the goal of providing compositions and preparations comprising substances

- effectively having a depigmenting effect on the only lesions to be treated and for all of the recommended indications,

- producing no irritation or secondary pigmentation, and

- causing neither systemic depigmenting effect, nor allergy

The subject of the present invention is compositions based on plants, regulating skin pigmentation, characterized in that they essentially comprise an extract of a fruit selected from the group consisting of hydroalcoholic extracts of Pumca granatum, Terminalia chebula , Terminalia belerica, Cydonia oblonga, aqueous extracts of Punica granatum, Terminalia belerica, Cydonia oblonga or Phyllanthus emblica and the extracts obtained by pressing Punica granatum, Terminalia chebula, Terminalia belerica, Cydonia oblonga or Phyllanthus emblica, containing as active substances at least one α-hydroxy acid, ascorbic acid and at least one polyphenol . Unexpectedly, such extracts, comprising the three aforementioned compounds, exhibit a depigmenting activity markedly greater than that of a composition comprising for example only polyphenols, on normal skin pigmentation and its excesses, senile lentigo, chloasma, hyperpigmentation after use of photo-sensitizers and brown scar spots. According to an advantageous embodiment of the invention, said extracts (both the extracts obtained by pressing and the extracts obtained by alcoholic maceration) are then concentrated at moderate temperature under reduced pressure, preferably less than 50 ° C., then optionally brought to dryness by freeze-drying or any other method under reduced pressure and temperature below 50 ° C., so as not to degrade the active principles of the fruits.

The present invention also relates to a process for the preparation of hydroalcoholic extracts used in the composition of said compositions according to the invention. This process is characterized in that it comprises:

the maceration of said fruits, in dry, fresh or lyophilized form, at a temperature between 20 ° C. and 50 ° C., in a solvent miscible with water, preferably ethanol, methanol, acetone, methyl ethyl ketone, more or less added with water and possibly

- The concentration of the extract obtained at moderate temperature, preferably less than 50 ° C and under reduced pressure and - the drying of the extract obtained, by freeze-drying or any other method under reduced pressure and temperature below 50 ° vs.

According to an advantageous embodiment of this process, said maceration is carried out by successive macerations with 80% ethanol.

The present invention also relates to a process for the preparation of extracts obtained by pressing used in the composition of said compositions in accordance with the invention. This process is characterized in that it comprises:

- pressing of said fruit, - filtration of said fruit and possibly

the concentration of the extract obtained at moderate temperature, preferably less than 50 ° C. and under reduced pressure, and

- drying of the extract obtained, by lyophilization or any other method under reduced pressure and temperature below 50 ° C.

The compositions based on extracts in accordance with the present invention or the combination of the abovementioned compounds are capable of being combined with vehicles suitable for obtaining pharmaceutical and / or cosmetic preparations, particularly effective in the treatment of hyperpigmentations undesirable melanin, in particular freckles (ephelids), pregnancy mask (chloasma), age spots or senile lentigo, post-traumatic or post-lesional hyperpigmentation, phototoxicity reactions due, in particular, to perfume.

The same preparations are also particularly useful for subjects who wish to lighten their complexion deemed too dark. The present invention also relates to cosmetic preparations with depigmenting effect, characterized in that they comprise between 1 and 20% of at least one composition based on extracts as defined above, associated with different excipients as well as possibly other active ingredients, to obtain preparations suitable for the intended purpose and for application to the skin, and in particular ointment, cream, milk, gel, lotion, paste, powder, tincture or aerosol .

The present invention also relates to pharmaceutical preparations, with a depigmenting effect, characterized in that they comprise between 1 and 20% of at least one composition based on extracts as defined above, associated with different excipients and possibly other active ingredients, to obtain preparations suitable for the intended purpose and for application to the skin, and in particular ointment, cream, milk, gel, lotion, paste, powder, tincture or aerosol.

The present invention further relates to a preparation cos¬ métique or pharmaceutical depigmenting effect, characterized in that it comprises, in combination, the compounds present in the extracts according to ^the invention: at least one α-hydroxy acid, ascorbic acid and at least one polyphenol, preferably of plant origin, optionally combined with at least one vehicle acceptable for application to the skin. Among the hydroxy acids, mention may be made of citric acid, tartaric acid, malic acid or even lactic acid; among the polyphenols, mention may be made of polyphenols from the tannin family.

The present invention also relates to a method of aesthetic treatment of man, for modifying the pigmentation of the skin, comprising the topical administration of an appropriate amount of a composition or a prepa¬ ration with effect depigmenting agent, in accordance with the invention.

The pharmaceutical and / or cosmetic preparations according to the present invention do not cause significant irritation of the skin and do not sensitize it and can, therefore, be applied continuously for a long period of time.

As stated above, it is possible to use either the compositions based on extracts obtained from any of the abovementioned fruits, alone or as a mixture, in the preparations suitable for application to the skin. According to the invention, an extract selected from the hydroalcoholic extracts of Phyllanthus emblica, the aqueous extracts of Terminalia chebula and the mixture of aqueous extracts of Terminalia chebula, Terminalia belerica and Phyllanthus emblica, is used to regulate the pigmentation of the skin.

In addition to the foregoing provisions, the invention also comprises other provisions, which will emerge from the description which follows, which refers to examples of implementation of the method which is the subject of the present invention.

It should be understood, however, that these examples are given solely by way of illustration of the subject of the invention, of which they do not in any way constitute a limitation. EXAMPLE 1 Preparation of Freeze-Dried Juice of Fresh Punica Granatum Fruit

100 kg of freshly harvested fruits of Punica granatum are pressed in a wine type screw press. The collected juices, approximately 72 kg, are sieved through a stainless steel sieve with a porosity of 200 μm. It is then lyophilized for 85 hours. The amount of lyophilisate collected is 3.3 kg. EXAMPLE 2 Preparation of hydroalcoholic extract of dried fruits of Terminalia chebula.

100 kg of dried Terminalia chebula fruit are roughly ground in a hammer mill and then immersed in 800 liters of 80% ethanol. The fruits are macerated at 35 ° C with constant stirring for 24 hours

It is then roughly filtered to separate the fruits from the solvent and the same operation is repeated three times, replacing the quantity of solvent recovered each time exactly.

The four macerates, ie approximately 2,700 liters, are combined and filtered through a filter with a porosity of 100 μm, then the ethanol is removed by evaporation in a device continuously under reduced pressure and at a temperature of 45 ° C. A solution is then obtained aqueous extract representing approximately 150 liters The concentration is continued to up to 100 liters of extract, after having added to the previous 150 liters, 50 liters of monopropylene glycol to allow the dissolution of all the components of the extract to the final concentration.

This final concentration is 19%. EXAMPLE 3 Preparation of hydromethanolic extract of fresh fruits of Phyllantus emblica.

100 kg of freshly harvested fruits of Phyllantus emblica are immersed in 100 liters of pure methanol. The mixture is then passed through a homogenizer, in order to achieve crushing of the fruits at 35 ° C.

The mixture is then kept under constant stirring for 24 hours at the same temperature. The mixture is then pressed in a wine type screw press and coarsely filtered to separate the fruit from the solvent. The volume recovered is 168 liters.

It is then filtered through a filter with a porosity of 100 μm, then the methanol is removed by evaporation in a device, continuously under reduced pressure and at a temperature of 45 ° C. An aqueous solution of extract representing approximately 150 liters is then obtained. The concentration is continued up to 50 liters of extract. At this stage, all of the methanol has been evaporated. The aqueous solution is then dried by lyophilization for 72 hours.

The lyophilisate obtained represents 9.8 kg EXAMPLE 4 Preparation of hydroethanolic extract of fresh fruits of Cydonia oblonga.

100 kg of fresh Cydonia oblonga fruit (quince) are coarsely ground and their water content is evaluated by evaporation at 110 ° C. Let T be this content.

An amount of 96% ethanol is then added such that the final titer of the ethanol calculated relative to T, ie 60%.

The fruits are extracted by maceration for 24 hours in this mixture, then the solid material is sieved, the sieve is centrifuged and the total solid part is pressed in a screw press. The solid part is then taken up in a volume of alcohol to

70% corresponding to the volume of centrifugate collected. The mixture is macerated

24 hours, then the operation is repeated twice.

The liquid phases (about 450 liters) are combined, filtered and concentrated under reduced pressure at a temperature below 45 ° C up to a volume of 50 liters, then lyophilized. A lyophilizate weight of 22 kg is obtained.

EXAMPLE 5 Preparation of an aqueous extract of dried fruits of Terminalia belerica. 100 kg of dried Terminalia belerica fruit are roughly crushed in a hammer mill and then immersed in 1000 liters of distilled water to which 1 liter of chloroform is added, to avoid fungal contamination. The fruits are subjected to a maceration at 45 ° C. with constant stirring for 96 hours. It is then roughly filtered to separate the fruits from the solvent and the same operation is repeated three times, replacing the quantity of solvent recovered each time exactly.

The four macerates, approximately 3,100 liters, are combined and filtered through a filter with a porosity of 100 μm, then concentrated in a device, continuously under reduced pressure and at a temperature of 50 ° C. An aqueous solution of extract representing approximately 170 liters is then obtained. The concentration is continued up to 100 liters of extract after adding to the previous 150 liters, 50 liters of monopropylene glycol to allow the dissolution of all the components of the extract at the final concentration. This final concentration is 21%. EXAMPLE 6 In vitro evaluation of the inhibitory power of extracts of Phyllan¬ tus emblica on tyrosinase.

The tyrosinase used here is extracted from fungi and supplied by Sigma Laboratories (ref .: T-7755). * Reagents:

- Stock solution of tyrosinase: solution A tyrosinase: 5 mg phosphate buffer pH 6.5: 5 ml

- Enzyme solution: solution E solution A: 0.1 ml pH 6.5 buffer: 10 ml

- Stock extract solution: solution B extract: 5 mg buffer pH 6.5: 5 ml In the case of extract in solution, the amount of dry extract is reduced to its correspondence in solution.

- Inhibitor extract solution: solution I solution B: 0.1 ml buffer pH 6.5: 1 ml - Substrate solution: solution S

(L) Dopa (Sigma D.9628): 10 mg buffer pH 6.5: 10 ml

* Trial :

A solution is used serving as blank for the measurement of the control: buffer pH 6.5: 1.5 ml solution E: 0 ml solution S: 1 ml

A control solution: pH 6.5 buffer: 0.5 ml solution E: 1 ml solution S: 1 ml A solution used as a blank for the measurement of the test. buffer pH 6.5: 1.4 ml solution E: 0 ml solution S: 1 ml solution 1: 0, 1 ml

And a test solution proper: buffer pH 6.5: 0.4 ml solution E: 1 ml solution S: 1 ml solution I: 0.1 ml.

Thus, in double-beam reading, the evolution over time of the optical density of the witness at 450 nm is measured first, against its blank, then the evolution over time of the optical density of the test itself against its own white at the same wavelength. * Results:

The inhibition is calculated by determining the difference between the speed Vi of increase in the OD of the control and the speed V ₂ of increase in D O. of the test during the first 100 seconds when the evolution curve is comparable to a straight line. The inhibition expressed as a percentage is defined by: I = 100 (Vι-V ₂ ) / Vι.

Tested extracts Measured inhibition

Freeze-dried juice of fresh Phyllantus emblica 43

Hydroalcoholic extract of dried fruits of Phyllantus emblica 28

Hydromethanolic extract of fresh fruits of Phyllantus 34 emblica

Aqueous extract of dried fruits of Phyllantus emblica 22

EXAMPLE 7 In vivo evaluation of the inhibitory power of a cream based on various extracts of Terminalia chebula on the oxidative polymerization of melanin. Melanin is formed in a very complex way from tyrosine to Dopa and then to dopachrome, exclusively by the enzymatic route. However, the subsequent stages evolve in part without enzymatic intervention. This evolution is partly induced by ultraviolet A rays which cause a sudden increase in the pigmentation of the skin which is called instant pigmentation This pigmentation is in fact the result of the oxidative polymerization of the melanin already present in the horny layers of the epidermis which then sees its color intensified.

It is therefore possible to carry out a test on a preparation containing 5% of extract of Terminalia chebula applied to the skin of the back of voluntary subjects four times a day for three days before the test, an area being treated with the cream containing the extract and an area of the same subject being treated with the same cream containing no extract as a control

The subjects are then irradiated once with a dose of UVA such that the instant pigmentation is within easily measurable limits This measurement is carried out by a Minolta chromameter according to the only parameter L * Cream formula: Glycerol stearate 16

Polyoxyethylenated cetylstearyl alcohol 8

Octyldodecanol 12

Sweet almond oil 5

Glycerol 5 Terminalia chebula extract 5

Mixture of nipaesters in phenoxyethanol 0.5

Purified water 48.5

Let Li be the value found for the control zone and L ₂ the value of the test zone. The inhibition expressed as a percentage is defined by I = 100 (Lι-L) / Lι * Results -

Tested extracts Measured inhibition

Freeze-dried fresh fruit juice from Terminalia chebula 22

Hydroalcoholic extract of dried fruits of Terminalia 24 chebula

Hydromethanolic extract of fresh fruit from Terminalia 21 chebula

Aqueous extract of dried fruits of Terminalia chebula 19 EXAMPLE 8 In vivo study of a cream based on a mixture of extract of Phyllantus emblica and extract of Cydonia oblonga on the pigmentation of the skin of black subjects.

A test is carried out on a preparation containing 15% of extract of Phyllantus emblica applied to the skin of the forearm of 15 volunteer subjects four times a day for 21 days, an area being treated with the cream containing the extract and an area of the same subject being treated with the same cream containing no extract as a control. The intensity of the coloring of the skin is measured weekly by a Minolta chromameter according to the single parameter L. * Cream formula:

Glycerol stearate 12

Polyoxyethylenated cetylstearyl alcohol 10

Octyldodecanol 8

Sweet almond oil 5 Glycerol 1

Lyophilisate of Phyllantus emblica 10

Alcoholic extract of Cydonia oblonga 5

Mixture of nipaesters in phenoxyethanol 0.5

Purified water 48.5 * Results:

In 21 days, the color reduction of the area of skin treated with the cream containing the extract, compared to the area treated with cream without extract is on average 31%.

EXAMPLE 9 Clinical study of a cream based on Punica granatum extract on senile lentigo.

We chose 50 patient volunteers aged 46 to 78 years among which 34 women and all with marked senile lentigo. The patients are treated three times a day for 12 weeks by applying the cream used in Example 7. The hyperpigmentary tasks are recorded just before the test by photographs according to standardized conditions.

At the end of the treatment, the results of the treatment are evaluated qualitatively. * Results:

Of the 50 patients treated, 7 dropped out for reasons unrelated to the tolerance of the product and 1 for reasons of mild irritation causing discomfort in the second week. Of the 42 remaining at the end of the test, 4 saw their tasks completely disappear, 17 showed a very significant decrease, 7 a good decrease, 4 a slight and 6 had no results:

Results obtained Patients%

Total disappearance 8

Very significant decrease 34

Net decrease 14

Small decrease 8

No decrease 12

Abandonment 14

EXAMPLE 10: Formulations a) Cream:

Glycerol stearate 4

Palmito-stearic acid 8

Polyoxyethylenated cetostearyl alcohol

Octyldodecanol 15

Long chain fatty acid esters 2

Viscous paraffin oil 15

Hydroalcoholic extract of Terminalia Chebula 15

0.2 triethanolamine

Nipaesters 0.3

Perfume 0.3

Purified water 37.2 b. Emulsion for the body:

- •>

Glycerol stearate J

Cetostearyl alcohol 2

Polyoxyethylenated cetostearyl alcohol

Glycerol monooleate 0.5 Octyldodecanol 10

Dioctylcyclohexane 6

Freeze-dried Punica granatum fruit juice 1

Mixture of nipaesters in phenoxyethanol 0.5 Perfume 0.2

Purified water 73.8

Cross-linked polyacrylic acid 1.5

Aqueous extract of Terminalia belerica 20 NaOH 0.25

Perfume 0.3

Mixture of nipaesters in phenoxyethanol 0.5

Purified water 77.65 d) Lotion: Hydromethanolic extract of Phyllantus emblica 3

Monopropylene glycol 10

Glycerol 10

Perfume 0.2

Nipaesters 0.3 Purified water 76.5

As is apparent from the above, the invention is in no way limited to those of its modes of implementation, embodiment and application which have just been described more explicitly; on the contrary, it embraces all the variants which may come to the mind of the technician in the matter, without departing from the framework, or the scope, of the present invention.

Claims

1 °) Herbal compositions, regulating skin pigmentation, characterized in that they essentially comprise an extract of a fruit selected from the group consisting of hydroalcoholic extracts of Punica granatum, Terminalia chebula, Terminalia belerica, Cydonia oblonga , the aqueous extracts of Punica granatum, Terminalia belerica, Cydonia oblonga or Phyllanthus emblica and the extracts obtained by pressing of Punica granatum, Terminalia chebula, Terminalia belerica, Cydonia oblonga or Phyllanthus emblica, containing as active substances at least one α-hydroxy acid, ascorbic acid and at least one polyphenol.

2) Method for preparing the compositions according to claim 1, characterized in that it comprises:

- the maceration of said fruit, in dry, fresh or freeze-dried form, at a temperature between 20 ° C and 50 ° C, in a water-miscible solvent, preferably ethanol, methanol, acetone , methyl ethyl ketone, more or less added with water and possibly

3 °) Process according to claim 2, characterized in that said maceration is carried out by successive macerations with 80% ethanol

4 °) A process for preparing the compositions according to claim 1, characterized in that it comprises: - the pressing of said fruits,

- filtration of said fruit and possibly

- drying of the extract obtained, by lyophilization or any other method under reduced pressure and temperature below 50 ° C

5) Cosmetic preparations with depigmenting effect, characterized in that they comprise between 1 and 20% of at least one composition based on extracts according to claim 1, combined with different excipients as well as possibly with other active ingredients, to obtain preparations suitable for application to the skin, and in particular ointment, cream, milk, gel, lotion, paste, powder, tincture or aerosol. 6 °) Pharmaceutical preparations, with depigmenting effect, characterized in that they comprise between 1 and 20% of at least one composition based on extracts according to claim 1, combined with different excipients as well as possibly with others active ingredients, to obtain preparations suitable for application to the skin, and in particular ointment, cream, milk, gel, lotion, paste, powder, tincture or aerosol.

7 °) Preparation cosmetic depigmenting effect, characterized in that it comprises, in combination, the compounds present in the extracts according to claim 1: at least one α-hydroxy acid, ^ascorbic acid and at least one polyphenol, optionally associated with at least one acceptable vehicle, for application to the skin.

8 °) pharmaceutical preparation with depigmenting effect, characterized in that it comprises, in combination, the compounds present in the extracts according to claim 1: at least one α-hydroxy acid, ascorbic acid and at least one polyphenol, optionally associated with at least one acceptable vehicle, for application to the skin.

9 °) A method of aesthetic treatment of man, for modifying the pigmentation of the skin, comprising the topical administration of a suitable quantity of a preparation with depigmenting effect according to claim 5 or claim 7. 10 °) Use of an extract selected from the hydroalcoholic extracts of Phyllanthus emblica, the aqueous extracts of Terminalia chebula and the mixture of aqueous extracts of Terminalia chebula, Terminalia belerica and Phyllanthus emblica, to regulate the pigmentation of the skin.