WO2004096167A1

WO2004096167A1 - Composition containing ethanolamine derivatives and citric acid

Info

Publication number: WO2004096167A1
Application number: PCT/EP2004/004502
Authority: WO
Inventors: Muriel Morelli; Carole Dupressoir; Stephanie David
Original assignee: Johnson & Johnson Consumer France S.A.S.
Priority date: 2003-04-25
Filing date: 2004-04-26
Publication date: 2004-11-11

Abstract

This invention relates to compositions comprising an ethanolamine derivative and citric acid. It further relates to the use of such compositions in topical formulations, in particular in anti-aging formulations. The invention further relates to the use of such compositions to combat the effects of skin aging.

Description

Composition containing Ethanolamine Derivatives and Citric Acid

Field of the invention

Background of the Invention

Skin is composed of three integrated layers: the epidermis, the dermis and the hypodermis. The thickness of the epidermis and the dermis varies over different parts of the body. The epidermis also grows into fingernails, toenails and hair. The epidermis is principally composed of three types of cells: keratinocytes (90% of epidermal cells), the melanocytes (2-8% of epidermal cells) and Langerhans' cells.

The dermis, or true skin, is thick, sturdy, rich in nerves and blood vessels and in perspiratory glands. It also functions to shield and repair injured tissue. The dermis consists mostly of collagen, which originates from cells called fibroblasts, elastin structural glycoproteins and proteoglycans. Collagen fibers, which represent 70% of the dry weight of the dermis, form a supporting mesh responsible for skin's mechanical characteristics such a strength, texture and resilience. Other cells such as macrophages and leukocytes are also present in the dermis layer.

The hypodermis, joined to the bottom of the dermis, is the deepest layer of the skin. It contains so-called 'adipocytes' which produce lipids that build the fatty layer in the subcutaneous tissue. This layer functions to protect muscles, bones and inner organs against shocks, and to act as an insulator and source of energy during lean times.

As a first sign of aging, skin becomes less elastic and develops fine lines and wrinkles, which are the direct result of deterioration of the supporting dermis layer. In fact the skin's ability to replace damaged collagen diminishes and more and more disconnections and irregularities develop in the collagen network. Further phenomena associated with skin aging are the appearance of pigment marks, skin thinning and skin sagging. Many factors contribute to accelerated collagen damage. These include sun exposure, the presence of free radicals, some age-related hormonal changes, and smoking.

Aging of the skin is attributed to two causal factors. On the one hand there is chronological or intrinsic aging while on the other there is extrinsic aging, or aging due to environmental factors. Amongst the latter there can be mentioned photo-aging, which is the damage caused to the skin due to direct or indirect effects of the ultraviolet spectrum of sunlight.

A number of treatments have been developed that have proved out to be more or less effective in combating the effects of skin aging. Cosmetic products have been introduced which contain vitamins or vitamin derivatives, in particular vitamin A or its derivatives (retinoids), vitamin C, alpha-hydroxy acids or plant extracts. These products, when applied regularly during longer periods of time, reduce the number of wrinkles and fine wrinkles. Collagen implants on the other hand can disguise expression lines around the eyes and mouth. Dermabrasion and chemical peels are applied to remove the top layer of damaged skin. Carbon dioxide laser resurfacing is applied to remove fine wrinkles and improve scars.

A particular pathway used in the treatment of the effects of skin aging is by stimulation of dermal human fibroblasts and collagen formation. Agents possessing these properties for example are L-ascorbic acid and in particular retinol. Other agents that have been described to be useful to treat the effects of skin aging are the ethanolamine derivatives. US 5,554,647 describes a method of treating aging skin and subcutaneous muscles comprising the use of an acetylcholine precursor such as dimethylaminoethanol (DMAE) in an amount effective to produce increased muscle tone.

US 5,643,586 describes the topical treatment of subcutaneous muscle and overlying cutaneous tissue by applying a composition comprising a catecholamine precursor which in particular is tyrosine, phenylalanine or a mixture thereof preferably in combination with an acetylcholine precursor such as dimethylaminoethanol.

EP-A-1219288 relates to a topical composition for the treatment of skin, in particular to improve skin firmness, comprising an effective amount of an ethanolamine salt which has a mixture of anionic counterions derived from at least two pharmaceutically acceptable acids and esters thereof; and a cosmetically acceptable carrier. This reference teaches that the ethanolamines of disclosed therein affect the biomechanicalproperties of the skin thus restoring youthful firmness resulting in improved facial contours.

Compositions or formulations for topical use should have a pH that nears that of sldn. In particular the pH should not be too high, it should preferably be lower than pH 7, or too low, it should preferably be not lower than pH 4. Moreover, in order to be effective, any ethanolamine derivatives and in particular DMAE should be used as salt- forms and hence should be used in formulations having a pH lower than pH 7 since at higher pH values ethanolamine derivatives and in particular DMAE start occurring as free base. The latter has the additional disadvantage of having an unpleasant odor.

It now has been found that formulations containing a mixture of counterions as described in EP-A-1219288 tend not to be stable in terms of pH, when stored over prolonged periods of time. Stability, and in particular pH stability, is of paramount importance for topical formulations because of the need to deliver a product of stable and persistent quality to the consumer. It is therefore an object of this invention to provide compositions that contain an ethanolamine or a salt form thereof that effectively exert the beneficial properties of ethanolamines and more specifically of dimethylethanolamme, in particular in terms of effectiveness to combat the effects of skin aging. It is an additional object to provide compositions that are stable in particular in terms of pH, over prolonged periods of time.

These objects are attained by the compositions and formulations according to the present invention, which will be described hereinafter in more detail.

Summary of the invention

The present invention is directed to a composition comprising at least one ethanolamine derivative of formula (I), or a skin acceptable salt thereof:

R¹

\

N-CH₂-CH₂-OH (I), R^2/

and an amount of citric acid effective to provide the composition with a pH of from 4 to 7, and wherein the composition contains less than 10% of other hydroxy acids, relative to the total weight amount of citric acid in the composition.

In formula (I) R¹ and R² independently represent hydrogen, C_3-6 cycloalkyl or C_1-6 alkyl, optionally substituted with hydroxy, methoxy, oxo or formyl.

Preferably R¹ and R² independently represent C_1-4 alkyl.

The most preferred ethanolamine of formula (I) is dimethylaminoethanol (DMAE), also referred to as deanol. In a particular aspect, this invention is directed to a composition as described above wherein the molar ratio of the ethanolamine derivative of formula (I) to citric acid is in the range of from 3 : 1 to 1 : 1.

The invention further is concerned with a topical formulation comprising a composition as defined herein and further ingredients. The topical formulation can be for dermatological use but is in particular for cosmetic use.

In another aspect the invention provides the use of a composition as defined herein for manufacturing a topical or in particular a cosmetic formulation. The topical or cosmetic foπnulations in particular are useful for combating or treating the effects of skin aging.

In a further aspect the invention provides the use, and in particular the cosmetic use, of a composition as defined herein, or of a topical formulation as defined herein, for combating or treating the effects associated with the aging of skin.

Or, alternatively, the invention concerns a method, and in particular a cosmetic method, of combating or treating the effects of skin aging, which method or cosmetic method comprises applying to the affected skin area an amount of a composition or a topical formulation as defined herein, said amount being effective to treat said effects of skin aging.

Still another aspect of this invention comprises a cosmetic method for the improvement of the external appearance of an individual, said method comprising applying a composition or a topical composition as defined herein to affected skin areas.

Detailed description of the invention

The compositions of the present invention contain an ethanolamine of formula (I) as defined above. As used herein C_3-6 cycloalkyl refers to a cyclic cycloalkyl radical having from 3 to 6 carbon atoms and that preferably is saturated such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. C_1-6 alkyl refers to straight and branch chained hydrocarbon radicals which preferably are saturated and have from 1 to 6 carbon atoms such as, for example, methyl, ethyl, n.propyl, iso-propyl, n.butyl, iso-butyl, t.butyl, n. pentyl, iso-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2- dimethylbutyl and the like. C_1-4 alkyl refers to the same group of radicals with those having 5 or 6 carbon atoms being excluded.

A particularly preferred ethanolamine of formula (I) is dimethylaminoethanol DMAE (also referred to as dimethylathanolamine or deanol).

The ethanolamines of formula (I) can be prepared according to art-known procedures, e.g. by alkylating ethanolamine.

The pH of the compositions or formulations of the invention should be in the range of from pH 4 to pH 7, preferably in the range of from pH 5 to pH 7, more preferably in the range of from pH 5 to pH 6.5, still more preferably in the range of from pH 5 to pH 6. A particular preferred pH of the formulations of the present inventions is a pH of about 5.5.

The compositions or the formulations of the present invention contain an ethanolamine of formula (I), which in particular is DMAE, and citric acid. In certain embodiments of the invention, the molar ratio of the compounds of formula (I) (and in particular of DMAE) to citric acid is in the range of from 3 : 1 to 1 : 1. In particular embodiments said molar ratio is in the range of from 2.75 : 1 to 1.25 : 1 and in more particular embodiments said molar ratio is in the range of from 2.5 : 1 to 1.5 : 1. As used herein, the term molar ratio expresses the ratio of the number of moles of all compounds of formula (I) to the number of moles of citric acid present in a given composition or formulation in accordance with this invention.

In more preferred embodiments, the weight ratio of DMAE (base) to citric acid is in the range of from 1.4 : 1 to 0.45 : 1. In particular embodiments said weight ratio is in the range of from 1.25 : 1 to 0.60 : 1 and in more particular embodiments said weight ratio is in the range of from 1.15 : 1 to 0.70 : 1. As used herein, the term weight ratio expresses the ratio of the weight of DMAE (base) to the weight of citric acid present in a given composition or formulation in accordance with this invention.

The compositions and formulations may contain other acids to a limited extend. As used herein to a 'limited extend' means that the total amount of such acids does not exceed 10%, or preferably less than 5%, more preferably less than 2%, still more preferably less than 1%, all percentages in this paragraph being w/w of the total amount of other acids to the total amount of citric acid in the compositions or formulations. Of particular interest are compositions or formulations having no other acid than citric acid.

Examples of said other acids include any inorganic or, which is preferred, organic acid known to be useful in skin care compositions. These include acids such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; boric, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic (or glycolic), lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, ascorbic and the like acids. The said other acids do not include amphoteric compounds such as natural or non-natural amino acids.

Another compound, which may be advantageously present in the compositions of this invention, is tyrosine. Tyrosine may be present in the compositions of this invention in the amount of from about 0.01 to about 5%, more preferably from about 0.04 to about 3% by weight and most preferably about 0.5% by weight, based on the total composition.

The compositions of the invention are prepared by adding the ethanolamine component to citric acid or vice versa, preferably in aqueous solution. The compositions of the present invention therefore are mostly of aqueous nature.

This invention further relates to topical formulations containing a composition as defined herein. Topical formulations comprise dermatological formulations (or topical pharmaceutical formulations), and cosmetic formulations. Said topical formulations may further contain other ingredients or additives used in dermatological or in cosmetic formulations, including other active ingredients. Examples of further ingredients or additives are surfactants, emulsifiers, consistency factors, conditioners, emollients, skin caring ingredients, moisturizers, thickeners, lubricants, fillers, binding agents, anti- oxidants, preservatives, active ingredients, in particular dermatologically active ingredients, fragrances and the like. Active ingredients as mentioned herein comprise, for example, anti-inflammatories, anti-bacterials, anti-fungals and the like agents. Of particular interest are any active ingredients suited for topical applications.

The topical formulations according to the invention can further include one or more of a variety of optional ingredients, such as coloring agents, opacifying agents and the like.

The ethanolamine and more specifically dimehylethanolamine should be used in the formulations for topical application at concentrations from about 0.01% to about 10% , preferably from about 0.1% to about 5 %, more preferably from about 0.5% to about

2.5%.

Unless indicated otherwise, all percentages in the preceding and following paragraphs are w/w percentages, expressing the weight amount of an ingredient to the total weight of the composition of formulation.

The formulations according to the present invention can be prepared by adding the appropriate ingredients to a composition of the invention, or vice versa by adding the composition to an appropriate cosmetic or dermatological formulation base. It is also possible to mix all the ingredients individually, i.e. without making a separate composition as defined herein.

The compositions and topical formulations subject of the present invention are useful to combat or to treat the effects of skin aging. The effects of skin aging comprise those associated with the aging of the skin such as the appearance of fine lines, fine wrinkling, wrinkling, loss of skin firmness, sldn tightening, suppleness and skin smoothing effect. The effects of skin aging are due to aging as such, but also to aging of the skin caused by external factors such as exposure to environmental factors such as exposure to sunlight, wind, atmospheric pollutants and the like, or a combination of these factors.

Certain ethanolamine derivatives and in particular DMAE are known to stimulate the proliferation of dermal cells and in particular the proliferation of fibroblasts and additionally show effects on collagen production (stimulation of collagen synthesis). The compositions of the invention possess beneficial effect on cell metabolism and on extracellular matrix synthesis in dermal fibroblasts.

Additionally certain ethanolamine derivatives and in particular DMAE are known to have skin-lifting and skin tightening effects and therefore improve the appearance of the skin.

The compositions and formulations of the present invention additionally have improved activity on the mechanical properties of the epidermis and are better suited for managing the effects of skin aging. They moreover have improved activity on skin appearance.

The topical formulations according to the invention may be in the form of a solution, a hydrophilic lotion, an ointment, a cream or a gel. The formulations may also be, for example, in the form of oil-in-water, water-in-oil or multiple emulsions, foaming products or in liposome form.

Preferred formulations are gel and cream based formulations. Of particular interest are formulations based on oil-in-water emulsions.

In the latter instance an oily phase, containing the oil-soluble components, is made separately which is added to any of the aqueous phases containing suitable emulsifiers. Preferably the first aqueous phase is made containing one or more suitable emulsifiers. The oily phase is made and added to the first phase while building an emulsion. Subsequently the second aqueous phase is added. In the instance where the first or oily phase contains solid or semi-solid components, it is recommendable to heat the phase or phases and to conduct the emulsifying process at elevated temperature.

The topical formulations according to the invention can further include one or more of a variety of additional ingredients commonly found in skin care compositions, such as for example, emollients, skin conditioning agents, emulsifying agents, humectants, preservatives, antioxidants, active ingredients, perfumes, chelating agents, dyes, opacifying agents, etc., provided that they are physically and chemically compatible with the other components of the composition. Notably useful is the incorporation of vitamin A and vitamin A derivatives, including but not restricted to retinol, retinyl palmitate, retinoic acid, retinal, and retinyl propionate.

Examples of other active agents which may be incorporated comprise anti-microbials, e.g. anti-bacterials and antifungals, anti-inflammatory agents, anti-irritating compounds, anti-itching agents, moisturising agents, skin caring ingredients, plant extracts, vitamins, and the like. Also included are sunscreen actives which may be inorganic or organic in nature.

Examples of suitable preservatives for use in the compositions or formulations of the invention include the Cι-C₄ alkyl parabens and phenoxyethanol. Generally, the preservative is present in an amount ranging from about 0.5 to about 2.0, preferably about 1.0 to about 1.5, weight percent based on the total composition. In a preferred embodiment, the preservative is mixture of from about 0.2 to about 0.5 weight percent methylparaben, from about 0.2 to about 5.0 weight percent propylparaben and from about 0.05 to about 0.10 weight percent butylparaben. A particularly preferred commercially available preservative that may be used in the skin care composition according to this invention is Phenonip which is a practically colorless, viscous, liquid mixture of phenoxyethanol, methylparaben, ethylparaben, propylparaben, and butylparaben available from Nipa Laboratories, Inc.

Preferably, antioxidants should be present in the compositions or formulations according to the invention. Suitable antioxidants include butylated hydroxy toluene (BHT), ascorbyl palmitate, butylated hydroanisole (BHA), phenyl-α-naphthylamine, hydroquinone, propyl gallate, nordihydroquiaretic acid, vitamin E or derivatives of vitamin E, vitamin C and derivatives thereof, calcium pantothenic, green tea extracts and mixed polyphenosls, and mixtures thereof of the above. When utilized the antioxidant can be present in an amount ranging from about 0.02 to about 0.5% by weight, more preferably from about 0.002 to about 0.1% by weight of the total composition.

Emollients which can be included in the compositions or formulations of the invention function by their ability to remain on the skin surface or in the stratum corneum to act as lubricants, to reduce flaking, and to improve the skin appearance. Typical emollients include fatty esters, fatty alcohols, mineral oil, polyether siloxane copolymers and the like. Examples of suitable emollients include, but are not limited to, polypropylene glycol ("PPG")-15 stearyl ether, PPG-10 cetyl ether, steareth-10, oleth-8, PPG-4 lauryl ether, vitamin E acetate, PEG-7 glyceryl cocoate, lanolin, cetyl alcohol, octyl hydroxystearate, dimethicone, and combinations thereof. Cetyl alcohol, octyl hydroxystearate, dimethicone, and combinations thereof are preferred. When utilized, the emollient can be present in an amount from about 0.01 to about 5, preferably from about 1 to about 4 percent by weight based on the total composition.

Polyhydric alcohols can be utilized as humectants in the compositions or formulations of the invention. The humectants aid in increasing the effectiveness of the emollient, reduce scaling, stimulate removal of built-up scale and improve skin feel. Suitable polyhydric alcohols include, but are not limited to, glycerol (also known as glycerine), polyalkylene glycols, alkylene polyols and their derivatives, including butylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol and derivatives thereof, sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-dibutylene glycol, 1,2,6,-hexanetriol, ethoxylated glycerol, propoxylated glycerol and mixtures thereof. Glycerin is preferred. When utilized, the humectant is present in an amount from about 0.1 to about 5, preferably from about 1 to about 3 percent by weight, based on the total weight of the composition.

The topical formulations of the invention have an improved effect on skin damage due to aging. The first results may be obtained after four weeks of treatment with the compositions and are exerted deep down. These effects comprise a reduction in the number and depth of wrinkles and small wrinkles, a firming and tightening of the skin and providing a more youthful and smooth aspect of the skin, in particular of facial skin.

The compositions or formulations of the invention show an excellent stability as concerns pH. Measured over periods of several weeks, for example up to 8 weeks, they show no relevant change of the pH (a formulation having a pH between 5.3 and 5.4 showed no pH change of more than about 0.1 pH unit), even when stored at higher temperatures, for example when stored at 50 °C. They therefore can be stored at sufficient long periods of time, e.g. during a standard shelf-life of a skin-care product, without relevant change of pH.

All the topical formulations as described above can be applied on the skin by means of wipes.

The topical formulations of the invention may be applied in the morning and/or evening. They may be applied on those parts of the body where skin aging is prominent, i.e. on the face, the body or the hands.

The following examples are meant to illustrate the invention and not to limit it thereto.

Examples

Formulation

Ingredients % (w/w)

Aqua 85.62

Sclerotium gum 0.75

Arachidyl alcohol

1.00 Behenyl Alcohol

Arachidyl glucoside Caprylyl glycol 0.50

Glycerin 2.00

Methylparaben 0.15

Dimethicone 2.00

Cyclopentasiloxane 2.00

Ammonium Acryloyldimethyltaurate /VP Copolymer 1.00

Citric acid 2.33

DiMethyl AE 2.50

Perfume 0.25

Total 100.00

The ingredients are mixed in ingredient groups as listed above (each group being separated by a blanc in the above table). Subsequently the groups are mixed together to the end formulation.

Claims

1. A composition comprising at least one ethanolamine derivative of formula (I), or a topically acceptable salt thereof:

^R\

N-CH₂-CH₂-OH (I),

R 2/

1 9 wherein in formula (I) R and R independently represent hydrogen, C_3-6 cycloalkyl or C_1-6 alkyl, optionally substituted with hydroxy, methoxy, oxo or formy, and and an amount of citric acid effective to provide the composition with a pH of from 4 to 7, and wherein the composition contains less than 10% of other hydroxy acids, relative to the total weight amount of citric acid in the composition.

2. A composition according to claim 1 wherein R¹ and R² independently represent C_1-4 alkyl.

3. A composition according to claim 1 or 2 wherein the ethanolamine of formula (I) is dimethylaminoethanol (DMAE).

4. A composition according to claims 1 to 3 wherein the molar ratio of the ethanolamine derivative of formula (I) to citric acid is in the range of from 3 : 1 to 1 : 1, or said molar ratio is in the range of from 2.75 : 1 to 1.25 : 1 or said molar ratio is in the range of from 2.5 : 1 to 1.5 : 1.

5. A composition according to claim 3 wherein the weight ratio of DMAE (base) to citric acid is in the range of from 1.4 : 1 to 0.45 : 1, or said weight ratio is in the range of from 1.25 : 1 to 0.60 : 1, or said weight ratio is in the range of from 1.15 : 1 to 0.70 : 1.

6. A topical formulation comprising a composition as claimed in claims 1-5 and further ingredients.

7. Use of a composition as claimed in claims 1-5 for manufacturing a topical or in particular a cosmetic formulation.

8. Use of a composition as claimed in claims 1-5 or of a formulation as claimed in claim 10 for combating or treating the effects associated with the aging of skin.