WO2015011311A1

WO2015011311A1 - Combination for reducing hyperpigmentation of the skin

Info

Publication number: WO2015011311A1
Application number: PCT/ES2014/070362
Authority: WO
Inventors: Carles Trullàs Cabanas
Original assignee: Isdin, S.A.
Priority date: 2013-07-26
Filing date: 2014-04-24
Publication date: 2015-01-29
Also published as: ES2530140B1; ES2530140A1

Abstract

Combination for reducing hyperpigmentation of the skin. The invention relates to the use of a combination comprising pine bark extract and grapeseed extract for preparing an oral composition for reducing hyperpigmentation of the skin, where said composition is administered sequentially or separately in combination with a topical composition comprising phenylethyl resorcinol, niacinamide and tetrapeptide-30 along with at least one excipient and/or carrier acceptable for topical use. The invention also relates to a kit comprising an oral composition and a topical composition with said components.

Description

Combination to reduce skin hyperpigmentation

This invention relates to the field of skin care compositions. More specifically, it refers to a method to reduce skin hyperpigmentation. In particular, the invention relates to the combined use of an oral composition and a topical composition for said use.

STATE OF THE TECHNIQUE Melanin in humans is primarily responsible for skin color. Melanin is produced by the melanocytes of the epidermis in response to environmental factors, such as sun exposure. Different environmental or physiological causes can cause disorders in the production of melanin. Non-homogeneous pigmentation of the skin is a cause of concern for its unwanted aesthetic effects, which causes cosmetics to be sought in order to mitigate these effects.

UV radiation is the main cause of pigment spots due to the sun. In particular, hyperpigmentation of the skin, such as melasma, is due to an excess of melanin in the skin. Melasma has a strong impact on the quality of life of affected individuals since injuries occur mainly on the face. These spots are easier to appear in certain situations, such as skins that have already had pigmentary disorders, pregnant women, people who are under the use of photosensitizing medications such as some contraceptives and compromised skin after a dermatological procedure. The main actions in melasma therapy are to provide protection against ultraviolet light, retard the proliferation of melanocytes, inhibit the formation of melanin and melanosomes and promote the degradation of melanin in melanosomes.

The use of topical formulations with color is an important part of the Treatment in subjects with hyperpigmentation of the skin. On the other hand, antioxidants play an important role in the treatment of hyperpigmentation as well as in the protection of the skin from the sun. Proanthocyanidins, and in particular Pycnogenol®, often give topical formulations a difficult color to mask, whose application on the skin is an additional aesthetic problem for the population suffering from skin hyperpigmentation. Thus, a topical formulation that included all the active ingredients of interest, including proanthocyanidins, would not allow the color of the formulation to be customized according to the needs of each skin phototype and, therefore, would not cover this aspect of the treatment of the subjects. In addition, the presence of certain antioxidant active ingredients in topical formulations does not allow the development of formulations with high protection factors and adequate cosmeticity, since it is not possible to incorporate a high concentration of sunscreens, to increase the effectiveness of the hyperpigmentation cosmetic treatment of the skin. On the other hand, the topical route of administration makes it difficult to include a large number of antioxidants, which are usually unstable by this route. The article by J. Yamakoshi J. et al. "Oral intake of proanthocyanidin-rich extract from grape seeds improves chloasma", Phytother Res. 2004, vol. 18, pp. 895-899, describes that oral administration of grape seed extract effectively reduces hyperpigmentation in women with chloasma. WO2005070383 describes an oral composition containing Pycnogenol (pine bark extract), vitamin C and vitamin E to inhibit the production of melanin in the skin.

To enable adequate action against hyperpigmentation of the skin, adequate action is needed between antioxidant agents and protective agents that act as a filter for solar radiation. Although numerous commercial products, both topical and oral administration, are known to mitigate skin hyperpigmentation, there is still no product that is fully effective for such use. Therefore, there is still a need to provide a safe and effective method to decrease skin hyperpigmentation.

SUMMARY OF THE INVENTION The present invention provides a combination of compositions and an application method to decrease skin hyperpigmentation that provides a much greater effect than currently known formulations. The inventors have surprisingly found that a hyperpigmentation decrease effect, such as in melasma, can be achieved by combining oral administration of a composition comprising pine bark extract and grape seed extract with administration topically of a composition comprising phenylethylresorcinol, niacinamide and tetrapeptide-30. Said combination allows to increase the selectivity of action without producing a depigmenting effect in non-lesional or perilesional areas, so that a homogeneous effect of skin tone modulation occurs. According to the foregoing, one aspect of the present invention relates to the use of a combination comprising pine bark extract and grape seed extract for the preparation of an oral composition A to decrease the hyperpigmentation of the skin in a human, where said composition is administered sequentially or separately in combination with a topical composition B comprising phenylethylresorcinol, niacinamide and tetrapeptide-30 together with one or more pharmaceutically acceptable excipients and / or carriers for topical use. This aspect can be formulated as an oral composition A that comprises pine bark extract and grape seed extract together with one or more components acceptable for oral use to decrease hyperpigmentation of the skin in a human, where said composition is administered sequentially or separately in combination with a topical composition B comprising phenylethylresorcinol, niacinamide and tetrapeptide-30. This aspect can also be formulated as a method to decrease the hyperpigmentation of the skin in a subject, where the method comprises a) the administration to said subject of a safe and effective amount of an oral composition A comprising pine bark extract and extract of grape seed together with one or more components acceptable for oral use, in combination with b) administration in the hyperpigmented skin area of a safe and effective amount of a topical composition B comprising phenylethylresorcinol, niacinamide and tetrapeptide-30 together with one or more acceptable components for topical use.

The compositions of the invention are intended for use in reducing hyperpigmentation of certain areas of the skin, especially the skin of the face, in order to obtain a homogeneous hue of the skin and in accordance with the coloring of the areas of the skin that has not undergone hyperpigmentation and thus improve the appearance of the skin.

The combination of the active ingredients of the pine bark extract and the grape seed extract included in the oral administration composition allows a wider range of proanthocyanidins to be applied, which provides greater antioxidant protection.

The concomitant use of the aforementioned oral administration composition and the topical administration composition allows treating hyperpigmentation subjects with a combination of active ingredients that act directly on the skin spots, while protecting the skin from direct effects of sun exposure that worsen or cause skin hyperpigmentation. Oral intake of antioxidants allows improve the level of antioxidant activity of the cells, making them less susceptible to the action of the sun's rays.

As can be seen from the examples, said specific combination of active ingredients produces an unexpected effect in the hyperpigmented areas of the skin due to the synergistic effect produced by the joint action through two different routes of administration. In addition, the combined use of the two products allows a more constant treatment and a more uniform effect than in their separate application not combined. In this way the final action of the joint treatment is more effective than the non-combined application of the oral and topical products separately.

To act synergistically, the components of the combination of the invention must be in a safe and effective amount to produce the effect of diminishing the hyperpigmentation of the skin and homogenize its hue.

The person skilled in the art will understand that one of the compositions can be prescribed to be used in conjunction with the other composition to decrease skin hyperpigmentation.

Accordingly, one aspect of the invention provides the use of a combination comprising pine bark extract and grape seed extract for the preparation of an oral composition A to decrease the hyperpigmentation of the skin in a human, where said composition is to be administered in combination with a topical composition B comprising phenylethylresorcinol, niacinamide and tetrapeptide-30 together with one or more components acceptable for topical use. This aspect can also be formulated as a composition A which comprises a safe and effective amount of pine bark extract and grape seed extract together with one or more components acceptable for oral use to decrease skin hyperpigmentation in a human, where said composition is for be administered in combination with a composition B comprising a safe and effective amount of phenylethylresorcinol, niacinamide and tetrapeptide-30 together with one or more components acceptable for topical use. In another aspect, the invention provides the use of a combination comprising phenylethylresorcinol, niacinamide and tetrapeptide-30 for the preparation of a topical composition B to decrease hyperpigmentation of the skin in a human, wherein said composition is to be administered in combination with an oral composition A comprising pine bark extract and grape seed extract together with one or more components acceptable for oral use. This aspect can also be formulated as a composition B comprising a safe and effective amount of phenylethylresorcinol, niacinamide and tetrapeptide-30 together with one or more acceptable components for topical use to decrease skin hyperpigmentation in a human, where said composition is for be administered in combination with a composition A comprising a safe and effective amount of pine bark extract and grape seed extract together with one or more components acceptable for oral use. Another aspect of the invention relates to an oral composition comprising:

- from 1% to 30% by weight of pine bark extract with respect to the total weight of the composition, and

- from 1% to 30% by weight of grape seed extract with respect to the total weight of the composition,

together with one or more acceptable components for oral use.

Another aspect of the invention relates to a topical composition comprising:

- from 0.1% to 10% by weight of phenylethylresorcinol with respect to the total weight of the composition, - from 0.1% to 10% by weight of niacinamide with respect to the total weight of the composition, and

- 0.5 to 100 ppm (parts per million) of tetrapeptide-30,

together with one or more acceptable components for topical use.

Finally, yet another aspect of the invention provides a kit to decrease skin hyperpigmentation comprising:

a) a package containing an oral administration form of a composition A comprising pine bark extract and grape seed extract together with one or more components acceptable for oral use;

b) a package containing a topical composition B comprising phenylethylresorcinol, niacinamide and tetrapeptide-30 together with one or more components acceptable for topical use; Y

c) instructions to facilitate the joint use of the oral administration form and topical composition by a subject with skin hyperpigmentation problems.

DETAILED DESCRIPTION OF THE INVENTION

All terms as used herein should be understood according to their ordinary meaning known in the art, unless otherwise indicated. Other more specific definitions for certain terms used herein are set forth below and are intended to apply uniformly throughout the description and claims unless another broader definition is expressly provided.

The term "percentage by weight", also referred to as% by weight, as used herein refers to the percentage of each ingredient of the composition in relation to the total weight. The term "relationship" as used herein is understood in the usual sense of the magnitude of relative amounts to each other. Specifically, the ratio of two quantities indicates how many times the first quantity (X) is contained in the second quantity (Y) and is expressed as X: Y.

The term "pharmaceutically acceptable" refers to excipients or carriers suitable for use in pharmaceutical technology for the preparation of compositions for medical use. The term "acceptable components for oral use" as used herein refers either to pharmaceutically acceptable excipients and / or carriers or to components acceptable for intake.

The term "acceptable for intake" as used herein refers to compounds that are, within the scope of medical judgment, suitable for oral administration without giving rise to toxicity or unwanted side effects.

The term "components acceptable for topical use" as used herein refers either to pharmaceutically acceptable excipients and / or carriers or to components acceptable to be applied to the skin. More specifically, it refers to excipients and / or carriers that are, within the scope of medical judgment, suitable for use in contact with human skin without giving rise to toxicity, incompatibility, instability or an allergic response, among other possibilities. Each excipient, and / or carrier "acceptable for topical use" must also be "acceptable" in the sense of being compatible with the other ingredients in the topical formulation.

The term "safe and effective amount" refers to the amount of active ingredients in each of the topical and oral compositions that is high enough to produce the desired effect after application, but low enough to avoid side effects at a ratio. reasonable benefit / risk.

The term "subject" as used herein refers to a human, particularly a woman.

The present invention relates to the use of a combination comprising pine bark extract and grape seed extract for the preparation of an oral composition A to decrease the hyperpigmentation of the skin in a human, where said composition is administered sequentially or separately. in combination with a topical composition B comprising phenylethylresorcinol, niacinamide and tetrapeptide-30, together with one or more components acceptable for topical use.

In a preferred embodiment, optionally in combination with one or more features of the various particular or preferred embodiments previously or subsequently defined, the oral and topical compositions are pharmaceutical compositions. Therefore, in addition to the active components, each of the pharmaceutical compositions comprises one or more pharmaceutically acceptable excipients and / or carriers.

Tetrapeptide-30 is a peptide with the amino acid sequence PKEK (proline-lysine-glutamic acid-lysine) that decreases post-inflammatory hyperpigmentation contributing to a homogeneous skin tone. All components of the combination of the invention are commercially available.

As described above, the combined use of an oral composition A and a topical composition B as defined above provides an improved effect on the depigmentation of the hyperpigmented areas of the skin due to the synergistic action exerted by both compositions. In a preferred embodiment, optionally in combination with one or more features of the various particular or preferred embodiments previously or subsequently defined, the pine bark extract is French marine pine bark extract (Pinus pinaster, Aitón, Atlantic Villar subsp. ), marketed under the name Pycnogenol® and manufactured by Horphag Research, Geneva, Switzerland. Pycnogenol is standardized to contain 65-75% of proanthocyanidins. The extraction procedure is carried out on the freshly crushed crust and uses ethanol and water in a patented equipment that allows a continuous and automated procedure (Rohdewald P. "A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology "Int J Clin Pharmacol Ther. 2002; 40 (4): 158-168; EP313441). The purified aqueous extract is spray dried to give a fine water soluble brown powder. The content of proanthocyanidins consists mainly of procyanidins (biopolymers of catechin and epicatechin subunits) and phenolic acids (p-hydroxybenzoic acid, protocatechic acid, gallic acid, vanillic acid, caffeic acid, ferulic acid, and p-cumaric acid).

Grapeseed extract (Vitis vinifera L.) is also a commercial product that contains 80-90% proanthocyanidins. The extract can be obtained, for example, by the procedure described in Yamaguchi F et al. "Free radical scavenging activity of grape seed extract and antioxidants by electron spin resonance spectrometry in an H ₂ 02 / NaOH / DMSO system", J. Agrie Food. Chem. Vol. 47, pp. 2544-2548, or that described in Koga T, et al. "Increase of antioxidative potential of rat plasma by oral administration of proanthocyanidin-rich extract from grape seeds" 1999, J. Agrie.

Food Chem. 1999, vol. 47, pp. 1892-1897.

Both Pycnogenol and grape seed extract have a melanin biosynthesis suppression action, due to their strong action as inhibitors of tyrosinase, and a great antioxidant power.

The combination of the present invention is effective not only when both oral and topical compositions are administered sequentially, but also when administered separately.

Consequently, in a particular embodiment, optionally in combination with one or more features of the various particular or preferred embodiments previously or subsequently defined, oral composition A is administered sequentially with topical composition B.

In another particular embodiment, optionally in combination with one or more features of the various particular or preferred embodiments previously or subsequently defined, oral composition A is administered separately and in any order with topical composition B.

The oral composition of the combination of the invention comprises a safe and effective amount of the active components, pine bark extract and grape seed extract, together with one or more excipients and / or carriers acceptable for intake. Both extracts inhibit melanogenesis or even the proliferation of melanocytes only in the area where the hyperpigmentation problem manifests. Therefore, in a preferred embodiment the decrease in skin hyperpigmentation is achieved by inhibiting melanogenesis or melanocyte proliferation in the area where hyperpigmentation manifests.

Similarly, the topical composition of the combination of the invention comprises a safe and effective amount of the active components phenylethylresorcinol, niacinamide and tetrapeptide-30, together with one or more excipients and / or carriers acceptable for topical use, such as creams, emulsions, fluids, lotions, sprays, and gels, among others. The oral composition of the invention can be formulated in solid and liquid forms. The topical or oral compositions of the present invention can be prepared according to methods known in the state of the art. Those skilled in the art will be able to easily determine the appropriate excipients and / or carriers and their amounts according to the type of formulation to be prepared, its route of administration and the areas of skin to which said composition may be intended. Thus, the person skilled in the art will be able to select and / or avoid auxiliary substances that may or may not be suitable for oral use or in different regions of the skin, in particular in different areas of the face. The particular combination of components in the composition will be largely determined by their chemical compatibility. In particular, said selection will take into account that the components do not interfere with the effect of the active components of the oral or topical compositions.

In a preferred embodiment, optionally in combination with one or more characteristics of the various particular or preferred embodiments previously or subsequently defined, the oral composition is a solid form, more preferably contained in a gelatin capsule.

Solid forms may be prepared by conventional means with pharmaceutically acceptable excipients and / or carriers or components suitable for intake such as emulsifiers, thickeners or viscosity modifiers, anti-caking agents or anti-disintegrants, coating agents and humectants. Examples of oral dosage forms suitable for the present invention include forms such as tablets, powders and capsules, among others. Suitable excipients and / or carriers for use in the oral formulations described herein include, but are not limited to the same, diluents such as fillers, binders, lubricants, disintegrants, enhancers of the solubility, colorant, sweeteners and other components commonly used in oral formulations. The excipients used are well tolerated, stable, and used in an appropriate amount to provide the desired consistency and ease of administration.

In a particular embodiment, the oral composition A comprises from 3% to 30% by weight of pine bark extract, with respect to the total weight of the oral composition, and from 3 to 30% by weight of extract of grape seed, with respect to the total weight of the oral composition, together with one or more components acceptable for oral use. Generally, the combined amount of pine bark extract and grape seed extract in the oral composition of the invention is from 10% to 20% by weight with respect to the total weight of the oral composition, and preferably is of 17.6% by weight with respect to the total weight of the oral composition, the sum of components of the topical composition being 100%.

In a particular embodiment, optionally in combination with one or more features of the various particular or preferred embodiments previously or subsequently defined, the specific ratio of pine bark extract to grape seed extract in the oral composition is between 10: 1 and 1: 10. In another particular embodiment, the ratio of pine bark extract to grape seed extract is between 3: 1 and 1: 3. Non-limiting examples of appropriate ratios of both components in the oral composition are 2: 1, 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 3: 4, 3: 5, 4: 5, and 4: 10. In a particular embodiment, the ratio of pine bark extract to grape seed extract in the oral composition is 1: 1. In another particular embodiment the ratio of both components in the oral composition is 2: 1. Relationships are expressed as weight relationships.

The forms of the topical composition for application on the skin can be prepared by conventional means with excipients and / or carriers acceptable for topical use such as emulsifiers, emollients, thickeners or viscosity modifiers, stabilizers, humectants, pH regulators, suspending agents, antioxidants, solubilizers, colorants, perfumes and preservatives. Examples of topical dosage forms suitable for the present invention include solutions, aerosols, sprays, creams, lotions, gels, ointments, and emulsions, among others. The excipients and / or carriers used are well tolerated, stable, and are used in an appropriate amount to provide the desired consistency and ease in application.

In a preferred embodiment, optionally in combination with one or more features of the various particular or preferred embodiments previously or subsequently defined, the topical composition is a facial fluid.

Generally, the amount of phenylethylresorcinol in the topical composition of the invention is 0.1 to 4% by weight, and preferably 0.5% by weight, based on the total weight of the topical composition. Generally, the amount of niacinamide in the topical composition of the combination of the invention can be comprised between 0.1 -6% by weight, and preferably is 5% by weight, based on the total weight of the topical composition. Generally, the amount of tetrapeptide-30 in the topical composition of the combination of the invention is 0.5 to 70 ppm and preferably is 40 ppm.

On the other hand, the oral composition of the present invention may further comprise other active ingredients commonly used in compositions for oral use, including, but not limited to, vitamins, such as vitamins C, E and B3 (niacinamide), and selenium, or one of its salts acceptable for intake, such as sodium selenite. Therefore, in a particular embodiment, optionally in combination with one or more characteristics of the various particular or preferred embodiments previously or subsequently defined, the oral composition further comprises vitamin C and vitamin E, preferably vitamin C and vitamin E and niacinamide (vitamin B3 ).

In another preferred embodiment, optionally in combination with one or more features of the various particular or preferred embodiments previously or subsequently defined, the composition of the invention further comprises vitamin C, vitamin E and L-cysteine or a precursor thereof, such as N-Acetylcysteine

In another particular embodiment, optionally in combination with one or more characteristics of the various particular or preferred embodiments previously or subsequently defined, the oral composition further comprises sodium selenite.

In a particular embodiment, optionally in combination with one or more features of the various particular or preferred embodiments previously or subsequently defined, the oral composition of the combination of the invention comprises or consists of the following components:

(i) pine bark extract,

(¡I) grape seed extract (Vitis vinifera L);

(iii) Vitamin C;

(iv) Vitamin E;

(v) Vitamin B3;

(vi) sodium selenite

(vü) one or more components acceptable for oral use.

In a particular embodiment, optionally in combination with one or more features of the various particular or preferred embodiments. previously or subsequently defined, the oral composition of the combination of the invention comprises or consists of the following components:

(i) pine bark extract,

(¡I) grape seed extract (Vitis vinifera L);

(iii) Vitamin C;

(iv) Vitamin E;

(v) L-cysteine

(vi) one or more components acceptable for oral use.

The topical composition of the present invention may also further comprise other active ingredients commonly used in topical compositions, including, but not limited to, at least one sunscreen agent; N-acetylglucosamine; at least one antioxidant such as vitamin C, derivatives of vitamin C, vitamin E, derivatives of vitamin E, coenzyme Q10 and lipoic acid; at least one retinoid, such as retinol (vitamin A), retinol palmitate, retinol aldehyde, retinol retinoate, tretinoin, isotretinoin, alitretinoin, alpha-14-hydroxy-retro-retinol, fenretinide, polyrenoic acid, etretinate, acitretin, isoacitretin, motretinide , poloprenoic acid, arotinoid ethyl ester, arotinoid carboxylic acid, arotinoid ethyl sulfone, arotinoid methyl sulfone. adapalene, tazarotene, bexarotene, tamibarotene and mafarotene; an alpha-hydroxy acid, such as glycolic acid, lactic acid, malic acid, citric acid, tartaric acid, mandelic acid and benzyl acid, a beta-hydroxy acid, such as salicylic acid, a polyhydroxy acid such as 2-hydroxyoctanoic acid, gluconolactone and glucoheptonolactone, a bionic polyhydroxy acid, such as lactobionic acid and maltobionic acid, and combinations thereof.

In a particular embodiment, optionally in combination with one or more characteristics of the various particular or preferred embodiments previously or subsequently defined, the topical composition of the combination of the invention comprises or consists of the following components:

(i) Vitamin B3 (niacinamide),

(I) phenylethylresorcinol;

(iii) tetrapeptide-30;

(iv) at least one sunscreen agent; Y

(v) one or more components acceptable for topical use, preferably at least one emulsifier, an emollient, a humectant and a preservative.

In another particular embodiment, optionally in combination with one or more features of the various particular or preferred embodiments previously or subsequently defined, the topical composition of the combination of the invention comprises or consists of the following components:

(i) Vitamin B3 (niacinamide),

(I) phenylethylresorcinol;

(iii) tetrapeptide-30;

(iv) N-acetylglucosamine; Y

(i) Vitamin B3 (niacinamide),

(I) phenylethylresorcinol;

(iii) tetrapeptide-30;

(iv) a retinoid; Y (v) one or more components acceptable for topical use, preferably at least one emulsifier, an emollient, a humectant and a preservative. In another particular embodiment, optionally in combination with one or more features of the various particular or preferred embodiments previously or subsequently defined, the topical composition of the combination of the invention comprises or consists of the following components:

(i) Vitamin B3 (niacinamide),

(I) phenylethylresorcinol;

(iii) tetrapeptide-30;

(iv) an alpha-hydroxy acid, a beta-hydroxy acid, a polyhydroxy acid, a bionic polyhydroxy acid, or combinations thereof; Y

(v) one or more components acceptable for topical use, preferably at least one emulsifier, an emollient, a humectant and a preservative

In a more preferred embodiment, optionally in combination with one or more characteristics of the various particular or preferred embodiments previously or subsequently defined, in the topical composition the amount of phenylethylresorcinol is from 0.1% to 2% by weight with respect to the total weight of the topical composition, the amount of niacinamide is 0.5% to 6% by weight with respect to the total weight of the topical composition, and the amount of tetrapeptide-30 is 0.5 to 50 ppm, the sum of components of the topical composition being 100%.

As mentioned above, the invention also provides a kit to decrease skin hyperpigmentation. In a preferred embodiment, in said kit the amount of pine bark extract is from 1% to 30% by weight with respect to the total weight of the oral composition; the amount of grape seed extract is 1% to 30% by weight with with respect to the total weight of the oral composition; the amount of phenylethylresorcinol is 0.1 to 2% by weight with respect to the total weight of the topical composition; the amount of niacinamide is 0.5 to 6% by weight with respect to the total weight of the topical composition; and the amount of tetrapeptide-30 is 0.5 to 50 ppm.

In general, the different aspects of the invention defined as uses for the preparation of oral or topical compositions to decrease skin hyperpigmentation can also be formulated analogously as therapeutic treatment methods to decrease skin hyperpigmentation in a subject, where The method comprises administering to said subject a safe and effective amount of said oral or topical compositions. As mentioned above, the combination of compositions of the invention has an improved effect of decreasing skin hyperpigmentation against known formulations. Hyperpigmentation disorders include melasma (chloasma), post-inflammatory hyperpigmentation, sun lentigo, freckles, age spots (senile lentigo) or, in general, pigmentation spots that appear on the skin after sun exposure often in combination with drugs, such as contraceptives or other hormonal medication, or perfumes, or during pregnancy. In a preferred embodiment, the combination of the invention is useful for decreasing skin hyperpigmentation when it manifests as melasma.

The particular dose of the combination of the oral composition and the topical composition administered in accordance with this invention will be determined, as is apparent to a person skilled in the art, by the particular circumstances surrounding the case, including the condition involved with hyperpigmentation of the skin, duration of treatment, the nature of any concurrent treatment, excipients and / or Concrete carriers used and other factors known to the expert. In a particular embodiment the oral and topical compositions are administered daily. Preferably, the oral composition is administered once a day and the topical composition once or several times a day. More preferably, the topical composition is administered twice daily. Preferably, both compositions are administered daily for a period of between 3 and 12 months, more preferably for 6 months, more preferably even for 3 months. Surprisingly, the combination of the invention comprising a topical composition and an oral composition, as defined above, allows a shorter duration of the combined treatment than would be expected. Therefore, the combined administration of the two compositions provides greater efficacy than the currently available compositions for decreasing skin hyperpigmentation.

Throughout the description and the claims the word "comprises" and its vanes are not intended to exclude other technical characteristics, additives, components or steps. In addition, the word "comprises" includes the case "consists of". For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention. In addition, the present invention covers all possible combinations of particular and preferred embodiments indicated herein.

EXAMPLES

Example 1 . Oral formulation The following composition was prepared in a gelatin capsule (1): Quantity

Components (1)

(mg)

Pycnogenol® 37.50

Grape Extract (Vitis vinifera L.) 37.50

Vitamin C (Ascorbic Acid) 30

Vitamin E 50% (D-alpha tocopherol) 10

Vitamin B3 (Nicotinamide) 8

0.025 sodium selenite

Magnesium stearate 2

Microchstalin cellulose 299,975

(1) Capsule components: ge atina, titanium dioxide, red iron oxide and iron oxide ama ll

The preparation was carried out, first, by mixing and homogenization of the active components (Pycnogenol®, grape extract, vitamin C, 50% vitamin E, vitamin B3, sodium selenite, magnesium stearate and microchstalin cellulose) and later encapsulated in gelatin capsules.

Example 2. Topical formulation

A. Composition of the topical formulation:

A fluid emulsion was prepared with the following components:

Components% by weight

Niacinamide 5

Phenylethylresorcinol 0.5 Tetrapeptide-30 0.004

Emollients (1), sunscreen agents (2), 67.7

solvents (3), dyes (4), Emulsifiers

(5), humectants (6), stabilizers (7),

preservatives (8), opacifiers (9),

skin conditioners (10), agents

suspension (1 1), perfumes, chelating agents

(12), antioxidants (13), controller of the

viscosity (14) and pH regulator (15)

Water ^* csp 100

(1) dibutyl adipate, cyclopentasiloxane, cyclohexanesiloxane, dimethiconol; (2) octocrylene, titanium dioxide,

butylmethoxy dibenzoylmethane, bis-ethylhexyloxyphenol methoxyphenyl triazine;

(3) denatured alcohol, PEG-8; (4) titanium dioxide, iron oxides; (5) PEG-30 dipolyhydroxystearate, glyceryl stearate; (6) glycine; (7) sodium chloride; (8) phenoxyethanol; (9) Nylon-12, silica; (10) PEG-10 dimethicone, dimethicone, panthenol, tocopherol acetate, allantoin, ethylhexyl glyce na, sodium lauroyl glutamate, lysine; (1 1) hete ta of disteardimony; (12) disodium EDTA; (13) tocopherol, ascorbyl palmitate, ascorbic acid; (14) magnesium chloride; (15) citric acid.

^* "csp" means "sufficient quantity for". B. Procedure for preparing the fluid emulsion:

- Components of the different phases:

Phase (00) - PEG-30 dipolyhydroxystearate, dimethiconol, dibutyl adipate, glyceryl stearate, phenylethylresorcinol, Nylon-12, bis-ethylhexyloxyphenyl methoxyphenyl triazine, butylmethoxydibenzoylmethane, tocopherolic acid, palmitate, ascofercoric acid, palmitate, ascorbic acid, palmitate, ascorbic acid, palmitate

PEG-8

Phase (01) - ^" ΙΊΟ2, silica and dimethicone Phase (02) - tocopheryl acetate

Phase (03) - octocrylene, iron oxides, ΤΊΟ2, magnesium chloride, sodium lauroyl glutamate and lysine

Phase (04) - cyclomethicone and heterite of diesteardiamonium

Phase (05) - purified water, niacinamide, sodium chloride, sodium EDTA, tetrapeptide-30, phenoxyethanol, ethylhexyl glycerin, panthenol and allantoin

Phase (06) - denatured alcohol

Phase (07) perfume

- In the main reactor:

Phase (00) was heated to 70-80 ° C in the main reactor. Next, the components of Phase (01) on Phase (00) were added one by one and with stirring. Once well dispersed, the components of Phase (02) were added one by one and with stirring. They were stirred until fully incorporated and then the components of Phase (03) were added. Once Phase (03) was well dispersed, Phase (04) was added.

- In the fuser:

The components of Phase (05) were added one by one and with stirring until completely dissolved.

- In the reactor:

On the phases already incorporated in the reactor, the components of Phase (05) were added and the emulsion proceeded. Once the emulsion was obtained, Phase (06) was incorporated with stirring below 40 ° C. Then, below 30 ° C, Phase (07) was added with stirring of blades.

Example 3. Efficacy study on skin depigmentation

A trial was conducted in three groups of people to assess depigmenting efficacy after combined administration of the oral composition of the Example 1 and the topical composition of Example 2, in relation to the separate administration of said compositions.

For this, before, during and after treatment, the melanin index was measured in the hyperpigmented area and in the area adjacent to it; The MASI (Melasma Area and Severity Index), the number of spots and the area of involvement were determined with a visualization system, for example VISIA-CA®, which allowed to calculate the total surface area of the selected hyperpigmented area and, additionally, was performed a visual assessment of the degree of improvement by both the dermatologist and the treated subject.

The efficacy test was performed on a population sample of 30 people between 18 and 50 years of age, of all skin types and phototypes, with mild or moderate hyperpigmentation, considered adequate to check acceptability and evaluate the effectiveness of the product. The treatment was maintained for 3 months.

In one of the groups of people the composition of example 1 was administered, in another of the groups the composition of example 2 was administered and in the third group both compositions were administered.

The oral composition was administered at a dose of two capsules with breakfast with a glass of water. The topical composition was administered twice a day, in the morning and at noon, all over the face by a gentle digital massage until completely absorbed before sun exposure. .

According to the experimental conditions adopted and taking into account the evaluation parameters defined for the study and the subjective evaluation as additional data, the results obtained showed that the combination of the depigmenting oral composition of Example 1 co-administered with the topical composition of example 2 showed that surprisingly the depigmenting effect was visible in more than 80% of people in a shorter period of time than would be expected for such combination.

In addition, the combination showed a statistically significant depigmenting effect, reducing the number of spots and the area of the spots. A significant decrease in the area of melasma was also observed in a shorter period of time than would be expected for said combination.

The subjective evaluation of efficacy shows that the subjects mainly appreciated that with the continued use of both products in parallel, the skin acquires a more uniform appearance, produces a depigmenting effect, reduces the size of hyperpigmented spots, eliminates hyperpigmented spots, reduces appearance of new spots, improves the overall appearance of the skin, brings luminosity to the skin, gives the skin a younger look, the skin is firmer and softer and makes it appear more hydrated. REFERENCES CITED IN THE APPLICATION

1) J. Yamakoshi J. et al. "Oral intake of proanthocyanidin-rich extract from grape seeds improves chloasma", Phytother Res. 2004, vol. 18, pp. 895-899.

2) WO2005070383

3) Rohdewald P. "A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology", Int. J. Clin. Pharmacol Ther. 2002, vol. 40, pp. 158-168.

4) EP313441

5) Yamaguchi F et al. "Free radical scavenging activity of grape seed extract and antioxidants by electron spin resonance spectrometry in an

H ₂ O ₂ / NaOH / DMSO system ", J. Agrie Food. Chem. Vol. 47, pp. 2544-2548.

6) Koga T, et al. "Increase of antioxidative potential of rat plasma by oral administration of proanthocyanidin-rich extract from grape seeds "1999, J. Agrie.

Food Chem. 1999, vol. 47, pp. 1892-1897

Claims

1 . Use of a combination comprising pine bark extract and grape seed extract for the preparation of an oral composition A for decreasing skin hyperpigmentation in a human, wherein said composition is administered sequentially or separately in combination with a topical composition B comprising phenylethylresorcinol, niacinamide and tetrapeptide-30 together with one or more components acceptable for topical use.

2. Use according to claim 1, wherein oral composition A is administered sequentially with topical composition B.

3. Use according to claim 1, wherein oral composition A is administered separately and in any order with topical composition B.

4. Use of a combination comprising pine bark extract and grape seed extract for the preparation of an oral composition A to reduce hyperpigmentation of the skin in a human, wherein said composition is to be administered in combination with a composition topical B comprising phenylethylresorcinol, niacinamide and tetrapeptide-30 together with one or more components acceptable for topical use.

5. Use of a combination comprising phenylethylresorcinol, niacinamide and tetrapeptide-30 for the preparation of a topical composition B to reduce hyperpigmentation of the skin in a human, wherein said composition is to be administered in combination with an oral composition A comprising pine bark extract and grape seed extract together with one or more components acceptable for oral use.

6. Use according to any of claims 1-5, wherein the reduction of skin hyperpigmentation is achieved by inhibiting melanogenesis or the proliferation of melanocytes.

7 Use according to any of claims 1-5, wherein oral composition A further comprises vitamin C, vitamin E, niacinamide (vitamin B3).

8 Use according to any of claims 1-5, wherein oral composition A further comprises vitamin C, vitamin E and L-cysteine or a precursor thereof.

9. Use according to any of claims 7-8, wherein oral composition A further comprises sodium selenite.

10. Use according to any of claims 1 -9, wherein oral composition A comprises from 3% to 30% by weight of pine bark extract and from 3 to 30% by weight of grape seed extract , with respect to the total weight of the composition.

eleven . Use according to any of claims 1 -9, wherein the topical composition B comprises from 0.1% to 2% by weight of phenylethylresorcinol with respect to the total weight of the composition, from 0.5% to 6% by weight. weight of niacinamide with respect to the total weight of the composition, and from 0.5 to 50 ppm of tetrapeptide-30, the sum of components of the composition being 100%.

12. Use according to any of claims 1-1 1, wherein the hyperpigmentation of the skin manifests itself in the form of melasma.

13. Use according to any of claims 1-12, wherein the oral and topical compositions are administered daily.

14. Oral composition that includes:

- from 1% to 30% by weight of pine bark extract with respect to the total weight of the composition, and - from 1% to 30% by weight of grape seed extract with respect to the total weight of the composition,

together with one or more components acceptable for oral use.

15. Topical composition comprising:

- from 0.1% to 10% by weight of phenylethylresorcinol with respect to the total weight of the composition,

- from 0.1% to 10% by weight of niacinamide with respect to the total weight of the composition, and

- from 0.5 to 100 ppm (parts per million) of tetrapeptide-30,

together with one or more components acceptable for topical use.

16. A kit for reducing skin hyperpigmentation comprising: a) a container containing an oral administration form of a composition A comprising pine bark extract and grape seed extract together with one or more acceptable components for oral use;

b) a container containing a topical composition B comprising phenylethylresorcinol, niacinamide and tetrapeptide-30 together with one or more components acceptable for topical use; and

c) instructions to facilitate the joint use of the oral administration form and the topical composition by a subject with skin hyperpigmentation problems.