KR20180094964A - Compositions comprising niacinamide and alpha-arbutin for skin lightening - Google Patents

Abstract

The present invention relates to a novel composition comprising niacinamide and alpha-arbutin and the use of said composition for skin lightening. More particularly, the present invention relates to the use of niacinamide to synergistically enhance skin lightening activity of alpha-arbutin.

Description

Compositions comprising niacinamide and alpha-arbutin for skin lightening

The present invention relates to a novel composition comprising niacinamide and alpha-arbutin and the use of said composition for skin lightening. More particularly, the present invention relates to the use of niacinamide to synergistically enhance skin lightening activity of alpha-arbutin.

There is an increasing demand in the industry for stable, safe and cost effective skin lightening products and the market needs are growing.

Synthetic dermal lightening agents, such as hydroquinone or kojic acid, are known as highly effective skin-lightening ingredients, but they can cause skin irritation or acute dermatitis and are no longer recognized in the cosmetics industry.

Alpha-arbutin (4-hydroxyphenylalpha-glucopyranoside; CAS: 84380-01-8) is currently used as a safer alternative to hydroquinone and kojic acid, but has been shown to exhibit appreciable whitening efficacy Should be applied at a concentration of 2% by weight or less. However, this dose regimen causes significant market limitations because alpha-arbutin is not very attractive for use costs.

The niacinamide (CAS 98-92-0) is an amazing component that reduces the appearance of fine lines and wrinkles, hyperpigmented spots, red blotchy, badly colored skin (yellowing) and inflammation and increases the elasticity, hydration and barrier function of the stratum corneum . However, its skin-lightening efficacy is very limited and can only be recognized at fairly high concentration levels.

Thus, there is a continuing need for improved skin lightening products that overcome the disadvantages of the prior art.

Surprisingly, it has been found that niacinamide synergistically enhances the skin-lightening efficacy of alpha-arbutin, resulting in similar efficacy to kojic acid. This finding enables the formulation of highly efficient and cost-effective skin-lightening compositions because only a small amount of alpha-arbutin should be used.

As used herein, the term "skin lightening" is intended to encompass skin relaxation, skin lightening / brightening, prevention of pigmentation and / or prevention of color material deposit, protection from sun or ultraviolet-induced skin darkening, Level.

A first object of the present invention is to provide a niacinamide composition wherein the amount of alpha-arbutin is selected in the range of 0.05 to 0.5% by weight based on the total weight of the topical composition and the weight ratio of niacinamide to alpha-arbutin is selected in the range of 50 to 5, And alpha-arbutin.

In a preferred embodiment, the amount of alpha-arbutin is selected in the range of 0.075 to 0.3% by weight, more preferably 0.1 to 0.25% by weight, based on the total weight of the topical composition, and the ratio of niacinamide to alpha- More preferably in the range of 25 to 5, most preferably in the range of 20 to 5, such as advantageously in the range of 15 to 6, more advantageously in the range of 12 to 8.

Thus, in certain advantageous embodiments, the amount of alpha-arbutin is selected in the range of 0.1 to 0.3 wt%, and the weight ratio of niacinamide to alpha-arbutin is selected in the range of 15 to 6. In an even more advantageous embodiment, the amount of alpha-arbutin is selected in the range of 0.15 to 0.25 wt%, and the weight ratio of niacinamide to alpha-arbutin is selected in the range of 12 to 8.

As used herein, the term "topical" is understood to mean external application to keratinous materials (especially skin, scalp, eyelashes, eyebrows, nails, mucous membranes and hair).

Preferably, the topical composition is a cosmetic or pharmaceutical composition. Most preferably, it is a cosmetic composition.

Because the compositions according to the invention are intended for topical application, they contain a physiologically acceptable medium, i.e. a medium compatible with keratinous substances such as skin, mucous and keratinous fibers. In particular, the physiologically acceptable medium is a carrier which is acceptable for cosmetics.

The term "cosmetically acceptable carrier" refers to all carriers and / or excipients and / or diluents conventionally used in cosmetic compositions.

Preferred cosmetic compositions according to the present invention are skin care preparations.

Examples of skin care preparations are in particular skin-lightening preparations, photo-aging treatment preparations, light protective preparations (sunscreens), anti-aging preparations, treatment creams, and BB and CC creams.

In certain embodiments, the topical compositions according to the present invention are skin care formulations such as milk, lotions, hydrodispersions, foundations, creams, cream gels, serums, toners, masks or gels.

The topical composition according to the invention may be in the form of a suspension or dispersion in a solvent or a fatty substance, or alternatively in the form of an emulsion or microemulsion (in particular water-in-oil (O / W) or oil- (W / Si) type, a PIT-emulsion, a multiple emulsion (e.g., oil-in-water-medium-oil (O / W / O) or In the form of a water-in-oil-in-oil-in-water (W / O / W) type, Pickering emulsions, hydrogels, alcoholic gels, lipogels, , A mask, or other useful form that can be applied as a spray.

In one embodiment, the topical composition according to the invention may be in the form of a water-in-oil (O / W) emulsion comprising an oily phase dispersed in an aqueous phase in the presence of an O / W emulsifier. Formulations of such O / W emulsions are well known to those skilled in the art.

When the topical composition according to the present invention is an O / W emulsion, it advantageously contains PEG-30 di-polyhydroxy stearate, PEG-4 dilaurate, PEG-8 dioleate, PEG-7 glyceryl cocoate, PEG-20 almond glyceride, PEG-25 hydrogenated castor oil, glyceryl stearate and PEG-100 stearate, PEG-7 olivate, PEG-8 oleate, PEG- PEG-60 almond glyceride, PEG-20 methyl glucose sesquistearate, PEG-40 stearate, PEG-100 stearate, PEG-80 sorbitan laurate, Steareth- Oleth-2, Ceteth-2, Laureth-4, Oleth-10, Oleth-10 / polyoxy 10 oleyl ether, Ceteth-10, 20, Cetareth-20, Cetareth-20, Oleeth-20, Steareth-20, Steareth-21, Ceteth-20, Ureth-23, Stearat-100, glyceryl stearate citrate, glyceryl stearate SE (self-emulsifying), stearic acid, salts of stearic acid, polyglyceryl- One or more O / W- or Si / W-emulsifiers selected from the list. Further suitable emulsifiers are phosphoric acid esters and salts thereof such as cetyl phosphate (Amphisol TM A), diethanolamine cetyl phosphate (Ampisol TM DEA), potassium cetyl phosphate (Ampisol TM ) K), sodium cetearyl sulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glyceride phosphate, and mixtures thereof. Further suitable emulsifying agents are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, ≪ / RTI > polycaprolactone, and polycaprolactone and hydrated polyisobutene. In addition, one or more synthetic polymers may be used as the emulsifier. For example, PVP eicosene copolymers, acrylate / C10-30 alkyl acrylate crosspolymer, acrylate / stearates-20 methacrylate copolymer, PEG-22 / dodecyl glycol copolymer, PEG- Dodecyl glycol copolymers and mixtures thereof.

Particularly suitable O / W emulsifiers for use in the topical compositions according to the present invention are potassium cetyl phosphate, such as, for example, ampicillin (commercially available from DSM Nutritional Products Ltd Kaiseraugst) K).

The at least one O / W, each Si / W emulsifier is preferably present in an amount ranging from 0.5 to 10% by weight, from 0.5 to 6% by weight, such as from 0.5 to 5% by weight, 4% by weight.

Further suitable O / W emulsifiers include polyethylene glycol (PEG) esters or diesters such as [INCI name] PEG-100 stearate, PEG-30 dipolyhydroxystearate, PEG-4 dilaurate, PEG- PEG-8 oleate, PEG-8 sorbitan peroleate, PEG-7 glyceryl cocoate, PEG-20 almond glyceride, PEG-25 hydrogenated castor oil, PEG-7 olivate, PEG-60 almond glyceride, PEG-20 methyl glucose sesquistearate, PEG-40 stearate, PEG-100 stearate and PEG-80 sorbitan laurate.

Particularly preferred according to the invention are PEG-100 stearates sold under the trade mark Arlacel (R) 165 (INCI glyceryl stearate and PEG-100 stearate) in Croda.

Another suitable class of O / W emulsifiers are non-ionic self-emulsifying systems derived from olive oil, such as cetearyl oleate (INCI name) sold under the trade name OLIVEM 1000 and sorbitan olivate (chemical composition: olive Sorbitan esters of fatty acids and cetearyl esters).

In certain embodiments, the present invention provides all definitions and / or limitations provided herein that are in the form of an O / W emulsion comprising an oil phase dispersed in an aqueous phase in the presence of an O / W emulsifier, wherein the O / W emulsifier is potassium cetyl phosphate (All definitions and preferences are provided herein).

The cosmetic compositions according to the invention can be prepared by conventional methods in the art, for example by combining niacinamide and alpha-arbutin with the cosmetically acceptable carrier in the respective amounts and ratios according to the invention.

The cosmetic composition (including the carrier) of the present invention may contain conventional cosmetic adjuvants and additives such as preservatives / antioxidants (e.g. sodium metabisulfite), fatty substances / oils, water, organic solvents, silicones, thickeners, An emulsifier, an antifoaming agent, an aesthetic component such as a perfume, a surfactant, a filler, an anionic, a cationic, a nonionic or amphoteric polymer or a mixture thereof, a propellant, an acidifying agent or a basicizing agent, a dye, a coloring agent, A chelating agent and / or a metal sequestering agent, an essential oil, a skin sensate, an astringent, a pigment, or any other ingredient generally formulated into such a composition.

According to the present invention, the cosmetic composition according to the present invention may further comprise a cosmetic active ingredient commonly used in cosmetic compositions. Exemplary active ingredients include ultraviolet filters, formulations for the treatment of hyperpigmentation; Agents for the prevention or reduction of inflammation; Firming agnet, a moisturizer, a sedative and / or an energizing agent, and an agent that improves elasticity and skin barrier.

Examples of excipients, diluents, adjuvants, additives and active ingredients for cosmetics commonly used in the skin care industry suitable for use in the cosmetic compositions of the present invention include, for example, BASE (http://online.personalcarecouncil.org/jsp/ But are not limited to, the International Cosmetic Ingredient Dictionary & Handbook by Personal Care Product Council (http://www.personalcarecouncil.org/).

The necessary amounts of active ingredients and excipients for cosmetics, diluents, adjuvants, additives and the like can be readily determined by those skilled in the art based on the intended product form and application. Additional ingredients may be added to the oil phase, to the water phase or to each other as needed.

The cosmetic active ingredients useful herein may in some cases provide more than one benefit or operate through more than one mode of operation.

Of course, those skilled in the art will appreciate that the optional additional ingredients, adjuvants, diluents and additives described above and / or the amounts thereof may be selected such that the beneficial properties inherently related to the combination according to the invention are not adversely affected or substantially unaffected by the anticipated addition You will be careful to choose.

The topical compositions according to the present invention generally have a pH in the range of 3 to 10, preferably in the range of 4 to 8, most preferably in the range of 4 to 7.5. The pH can be adjusted using a suitable acid such as citric acid or a base such as sodium hydroxide (e.g. aqueous solution), triethanolamine (TEA Care), Trizma Base and aminomethyl propanol (AMP-Ultra PC 2000) Can be readily and preferably adjusted according to standard methods in the art.

The amount of topical composition to be applied to the skin is not critical and can be readily controlled by those skilled in the art. Preferably, the amount is selected from the range of 0.1 to 3 mg / cm ² skin, for example, preferably 0.1 to 2 mg / cm ² , most preferably 0.5 to 2 mg / cm ² .

It is a further object of the present invention to provide a method for preventing skin lightening, such as, in particular, alleviating skin color unevenness, preventing smearing and / or preventing color deposits, protecting against sun or ultraviolet-induced skin darkening, and reducing melanin levels in human skin (Cosmetics) use of niacinamide and alpha-arbutin, wherein the weight ratio of niacinamide to alpha-arbutin ranges from 50 to 5, preferably from 30 to 5, more preferably from 25 to 5, most preferably from 20 To 5, such as advantageously in the range of from 15 to 6, more advantageously in the range of from 12 to 8.

In another embodiment, the present invention also relates to a pharmaceutical composition for the treatment or prevention of skin pigmentation disorders, wherein the niacinamide and alpha-arbutin for use in a topical pharmaceutical composition (all definitions and preferences are provided for the topical composition above) .

A further object of the present invention is to provide a pharmaceutical composition which is characterized in that the weight ratio of niacinamide to alpha-arbutin ranges from 50 to 5, preferably from 30 to 5, more preferably from 25 to 5, most preferably from 20 to 5, For example, advantageously from 15 to 6, more advantageously from 12 to 8, in order to improve the skin-lightening activity of alpha-arbutin.

The present invention also relates to a method of treating skin lightening, such as, in particular, alleviating skin color heterogeneity, comprising the step of locally administering an effective amount of a composition according to the present invention to a suitable skin area of a human in need of light, Prevention of burning and / or relaxation of color material deposits, protection from sun or ultraviolet-induced skin darkening, and reduction of the level of melanin in human skin (cosmetic).

It also relates to a method of treating or preventing a pigmentation disorder, comprising the step of topically applying an effective amount of a composition according to the present invention to a suitable skin area of a human in need of treatment of the pigmentation disorder, and optionally recognizing the effect .

The term " effective amount " refers to the amount necessary to obtain a physiological effect. The physiological effect can be achieved by a single application or repeated application. The dosage to be administered will of course vary according to known factors such as the physiological characteristics of the particular composition and its mode and route of administration; The age, health status and weight of the detainee; The nature and extent of symptoms; Types of Concurrent Therapy; Frequency of treatment; And the desired effect, and can be adjusted by those skilled in the art. Preferably, the amount of topical composition to be applied to the skin is in the range of 0.1 to 3 mg / cm ² skin, such as preferably 0.1 to 2 mg / cm ² skin area, most preferably 0.5 to 2 mg / cm ² skin Can be selected.

The present invention also relates to a method as described above wherein about 0.2 to about 200 [mu] g of niacinamide per skin of 1 cm < ² > per day and alpha-arbutin (calculated as the sum of the amounts of both compounds) will be.

The following examples are provided to further illustrate the compositions and effects of the present invention. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

Example : Methods and results of 3D epithelium model

Cell culture

Skin equivalents were provided on agarose plaque under sterile conditions. After arrival, they were transferred to 6-well plates according to the manufacturer's instructions and the maintenance culture (2 ml) was equilibrated by feeding at 37 ° C overnight. To start the test, a volume of 25 μL was applied to the top at a non-toxic concentration. The administration was performed every two days while changing the medium. Maintaining a skin model of a 6-well-well culture plate and cultured in an incubator at 37 ℃ for 9 days, and 5% CO ₂ atmosphere.

Determination of cytotoxicity

Briefly, MTT stock solution (5 mg / mL) was diluted to 1 mg / mL in PBS. Working solution (300 [mu] L) was added to each well of a new 24-well plate. The tissue was then transferred into the wells and the plates were incubated for 3 hours at 37 ° C and 5% CO ₂ humidified atmosphere. Then, 2-propanol (800 [mu] L) was charged into each well of a new 24-well plate and the tissue was transferred from the MTT-plate to a new plate. To completely cover the tissue with 2-propanol, 2-propanol (700 μL) was added into the insert. The plate was sealed with a parafilm and incubated with gentle stirring on a shaker at room temperature for 2 hours. The tissue was then punctured with a tip, and the solution was homogenized by pipetting up and down. This extraction solution (3 * 200 [mu] L) was then transferred into each well of a 96-well plate. 2-Propanol was used as a blank. The OD was read at a wavelength of 570 nm in the absorbance reader. Cytotoxicity was assessed as a single value using only one tissue insert compared to the vehicle control.

Fontana - Mason - Method (Fontana- Masson -Method) was used to detect melanin

Paraffin sections of 3-5 μm thickness on silane coated slides were deparaffinized and rehydrated and the slits were incubated in a humidified chamber at 56 ° C for 30 minutes using 5% ammonia-containing nitric acid silver solution. The wells were washed with several changes of distilled water. The sections were treated with 5% aqueous sodium thiosulfate for 1 minute and then washed with running tap water for 2-3 minutes. The nuclei were stained with hematoxylin for 5 minutes and the wells were washed with tap water for 5 minutes. The slides were dehydrated and fitted with cover slips in the presence of Entellan. Melanin content was quantified by measuring melanin area per tissue section of 1 [mu] m using cellSense software (Olympus).

Results of melanin staining and quantification compound Melanin content
[Optional units] Melanin content
[%] Vehicle 0.23 100% Alpha-arbutin 0.2% 0.23 100% Alpha-arbutin 0.4% 0.05 21% Niacinamide 1.8% 0.61 265% Alpha-arbutin 0.2% + niacinamide 1.8% 0.03 13% Kojic acid 0.4% 0.02 9% Significance (t-test):
Vehicle vs. alpha-arbutin 0.4%, p < 0.01
Vehicle vs Alpha-Arbutin 0.2% + Niacinamide 1.8%, p < 0.01
Alpha-arbutin 0.4% vs alpha-arbutin 0.2% + niacinamide 1.8%, p < 0.05

As can be seen from the data presented in Table 1, the combination of 9: 1 ratio of niacinamide and alpha-arbutin resulted in a significant improvement similar to the effect of kojic acid, while niacinamide itself did not cause skin lightening.

Claims (13)

Wherein the amount of alpha-arbutin is selected in the range of 0.1 to 0.3% by weight, and the weight ratio of niacinamide to alpha-arbutin is selected in the range of 15 to 6. The method according to claim 1,
Wherein the amount of alpha-arbutin is selected in the range of from 0.15 to 0.25 wt.%, And the weight ratio of niacinamide to alpha-arbutin is selected in the range of from 12 to 8. 3. The method according to claim 1 or 2,
A topical composition that is a cosmetic composition. The method of claim 3,
Wherein the cosmetic composition is a skin care formulation. The method according to claim 3 or 4,
Wherein the topical composition is in the form of a milk, lotion, hydrodispersion, foundation, cream, cream gel, serum, toner, mask or gel. The use of niacinamide and alpha-arbutin for skin lightening wherein the weight ratio of niacinamide to alpha-arbutin is selected in the range of from 15 to 6, more advantageously from 12 to 8. The method according to claim 6,
Use of niacinamide and alpha-arbutin for the relief of color heterogeneity, prevention of burning and / or prevention of color deposits, protection from sun or ultraviolet-induced skin darkening and reduction of melanin levels in human skin. Use of niacinamide for improving skin lightening activity of alpha-arbutin. Comprising topically administering an effective amount of a topical composition according to any one of claims 1 to 5 to a suitable skin area of a human in need of lightening. 10. The method of claim 9,
Wherein the method is for alleviating skin color unevenness, preventing smearing and / or preventing color deposits, protecting from sun or ultraviolet-induced skin darkening, and reducing melanin levels in human skin. A method for treating or preventing a pigmentation disorder, comprising the step of topically administering an effective amount of the topical composition of any one of claims 1 to 5 to a suitable skin area of a human in need of treatment for a pigmentation disorder. 12. The method according to any one of claims 9 to 11,
About 0.2 to about 200 [mu] g of niacinamide and alpha-arbutin per skin of 1 cm &lt; ² &gt; per day are applied. Claims 1. A niacinamide and alpha-arbutin for use in topical pharmaceutical compositions for the treatment and prevention of skin pigmentation disorders, wherein the amount of alpha-arbutin is selected in the range of 0.1 to 0.3% by weight based on the total weight of the topical composition, Niacinamide and alpha-arbutin, wherein the weight ratio of amide to alpha-arbutin is selected in the range of from 15 to 6.