WO2019215174A1

WO2019215174A1 - Composition for the prevention and treatment of skin aging

Info

Publication number: WO2019215174A1
Application number: PCT/EP2019/061715
Authority: WO
Inventors: Umberto DI MAIO
Original assignee: Neilos S.r.l.
Priority date: 2018-05-08
Filing date: 2019-05-07
Publication date: 2019-11-14
Also published as: IT201800005145A1

Abstract

A composition comprising an association of extract of at least a plant of the genus Carica and of extract of at least a plant of the genus Polypodium for use as antioxidant in the prevention or treatment of skin aging and of alterations related to it is described.

Description

“Composition for the prevention and treatment of skin aging”

DESCRIPTION

The present invention relates to a composition comprising an association of extract of at least a plant belonging to the genus Carica and extract of at least a plant belonging to the genus Polypodium for use as antioxidant in the prevention and/or treatment of skin aging and alterations related to it. Said composition is particularly effective thanks to the synergistic action of its components.

Background of the invention

The skin

The skin forms the outer coating of the human body and has a surface of about 2 m². It consists of a surface layer of epithelial nature, the epidermis, and a deep layer of connective nature, the dermis, which lies on an adipose connective layer, the hypodermis. The epidermis is a keratinized stratified pavement epithelium, 50 pm to 1 .5 mm thick, the outermost layer of which, made of dead keratinocytes, is called stratum corneum. The dermis, 0.3-4 mm thick, consists of two layers of connective tissue: deep reticular and superficial papillary. Being vascularized, it represents the diffusion pathway that metabolites and oxygen use to reach the epidermis. The hypodermis, whose function is to attach the skin to the underlying bones and muscles, is formed by loose connective tissue, adipose tissue and elastin. The skin also has cutaneous appendages such as nails, hairs, sebaceous and sweat glands, distributed with different density and development. Moreover, the skin is site of numerous nerve endings and, therefore, it also represents a very vast sense organ.

The skin in mammals has different functions:

Protective: as it represents an anatomical barrier against external aggressions and mechanical insults.

Immunological: since, thanks to the activity of different blood cells present in the dermis, of Langerhans cells and of keratinocytes, it is an integral part of the immune system.

Waterproofing: the stratum corneum cells and the intercellular lipids contribute to form an impermeable barrier that maintains the normal physiological conditions of the organism and controls the loss of liquids.

Thermoregulatory: the heat produced by our body is dispersed by irradiation and evaporation from the skin surface. When the ambient temperature is higher than the body temperature, sweating is the only heat dissipation mechanism subject to physiological control.

Sensory: the skin has numerous nerve endings that detect thermal variations (thermoreceptors), pressure (pressoreceptors) and painful sensations (nociceptors).

Supply: the skin is a reservoir of lipids and water and allows for the synthesis of some essential metabolites such as vitamin D3.

Most of the changes affecting the skin are due to skin aging.

Skin aging

Skin aging is a complex and multifactorial physiological phenomenon that involves the different layers of the skin and entails the progressive alteration of the functions and appearance of the skin.

Skin aging is due to a combination of changes that occur as a result of both time (intrinsic aging) and environmental factors (extrinsic aging). In particular, intrinsic skin aging, or chronoaging, represents the gradual process of cell senescence and is due to genetic factors and changes the body faces with age such as, for example, the change in hormone levels.

Extrinsic aging is instead caused by external factors such as pollution, smoking, incorrect nutrition and, above all, exposure to ultraviolet (UV) rays. In the latter case we also speak of photo-induced aging or photoaging.

The two types of aging cause different skin alterations.

Intrinsic skin aging is characterized by biological hypoactivity (slower cell regeneration) and entails dryness and skin dehydration, thinning of the skin, loss of elasticity, reduction of collagen, elastin and glycosaminoglycans and, therefore, the appearance of numerous and thin wrinkles.

The photoaging is instead characterized by biological hyperactivity and chronic inflammation leading to leathery skin, thickening of the stratum corneum, skin discoloration and telangiectasia. Furthermore, the photoaged skin is characterized by a statistically significant reduction in collagen, elastosis (accumulation of elastin in the surface layers), atypical keratinocytes and elongated and collapsed fibroblasts. Photoaging is mainly caused by the exposure to UV solar rays divided according to their wavelength in UVCs (200-290 nm), UVBs (290-320 nm) and UVAs (320-400 nm). Ozone absorbs 100% of UVC rays and 90% of UVB rays, but is not able to absorb UVAs. The UVBs/UVAs ratio reaching the ground is 20/120. UVB rays are absorbed by the epidermis, while UVAs penetrate deeper and can interact with fibroblasts, damaging them.

UVAs can inhibit the expression of TGF-b growth factor, a promoter of collagen synthesis. UVBs can upregulate the elastases in fibroblasts causing degradation of the elastic fibres and downregulate hyaluronic acid synthase (HAS1 , HAS2 and HAS3) causing a decrease in hyaluronic acid in the dermis.

UV rays are also able to induce immunosuppression and, by increasing the vascular endothelial growth factor (VEGF) and decreasing thrombospondin-1 , to promote angiogenesis.

Moreover, both UVAs and UVBs, through the formation of reactive oxygen species (ROS) such as, for example, the superoxide anion, the peroxide and the radical oxygen, can cause DNA alterations. ROS oxidize and inhibit tyrosine-phosphatase proteins which downregulate receptors such as the EGF, IL-1 and TNF-a receptor. Accordingly, in keratinocytes and fibroblasts, these receptors are upregulated, leading to the activation of the MAP-kinase signal cascade. The result is the activation of AP- 1 and NF-kB transcription factors: AP-1 stimulates the transcription of the extracellular matrix metalloproteinases (MMPs) and inhibits the formation of type 1 pro-collagen in fibroblasts; MMPs degrade the extracellular matrix with consequent degradation of collagen; and NF-kB stimulates the transcription of inflammatory cytokines which, in turn, lead to a further increase in ROS.

Finally, UV rays can also alter the levels of endogenous antioxidants such as superoxide dismutase, glutathione peroxidase and methionine sulfoxide reductase, thus leaving the organism devoid of an important defense mechanism.

To effectively counteract the action of UV rays on the skin, it is important to have products capable of blocking the activity of ROS which are the main compounds involved in the oxidative damage responsible for skin aging and the potential onset of cancer diseases.

Most of the products commercially available for the treatment of skin aging is based on active ingredients such as collagen, elastin and hyaluronic acid, that is they only aim to integrate the substances that, over time, have decreased. However, these products are not always effective. Furthermore, most commercially available products carry the active ingredients by means of topical formulations such as lotions, mousses, gels, creams and ointments. However, although ad hoc formulations have been developed to elude the skin barrier, skin aging entails major skin alterations, in particular to the stratum corneum, which unpredictably hinder the penetration of the formulation and the absorption of the carried active ingredients.

Therefore there is still the need of alternative compositions effective in the prevention and treatment of skin aging (both intrinsic and extrinsic) that are able, in particular, to counteract the activity of ROS and that do not present the disadvantages of currently available products.

Detailed Description of the Invention

The inventors of the present invention have now surprisingly found that the association of some plant extracts such as extract of at least a plant belonging to the genus Carica and extract of at least a plant belonging to the genus Polypodium represents a valuable alternative to commercially available products. In particular, the association of the present invention can comprise extract of Carica papaya and extract of Polypodium leucotomos.

Furthermore, the association of the present invention results in an unexpected synergistic effect of its components.

Carica Paoava

Papaya ( Carica papaya Linn.) belongs to the Cactaceae family and to the genus Carica which counts four species of which papaya is the most cultivated and known. This plant is probably native from Mexico and Costa Rica and was subsequently exported to several tropical and sub-tropical countries. The stem of the tree can grow up to ten meters high with broad palmate-lobate leaves from which the fruits, that can be green, yellow, orange or pink, sprout.

Papaya fruits have a remarkable nutritional value thanks to their high content in vitamins and minerals such as vitamin C, A, riboflavin, folate, calcium, thiamine, iron, niacin, potassium, fibers etc. The caloric content is very low (32 kcal/100 g of ripe fruit) so it is an ideal food for obese people or those who still want to control body weight. Compared to other fruits known to be used to prevent damage from free radicals, papaya has a higher content of carotene and, moreover, contains numerous enzymes such as papain, useful to help protein digestion in acid, alkaline or neutral environment.

In recent years, the scientific research has shown considerable interest in fermented papaya as a new raw material with potential immunomodulatory, antioxidant and anti- inflammatory activity. Fermentation preserves the beneficial properties of the fruit and significantly changes the composition of the extract resulting in an increase in carbohydrates, amino acids and oligosaccharides of different polymerization degrees, consisting of monomers with a structure similar to that of b 1-3 D-glucan.

Within the scope of the present invention, papaya extracts are of considerable interest due to their high antioxidant power. In fact, it has been described how the process of skin aging forces the cells of the skin to be continuously exposed to oxidative stress (both endogenous and exogenous). Normally the skin has an endogenous antioxidant system composed of both enzymatic antioxidants such as superoxide dismutase (SOD), glutathione peroxidase and catalase, and non-enzymatic antioxidants such as vitamin C, vitamin E, etc. During the aging process, both intrinsic and extrinsic, the endogenous antioxidant system can be compromised so that an oxidative damage is more likely to develop due to the accumulation of free radicals and proinflammatory cytokines that can lead to very serious skin diseases.

A clinical study in 2015 demonstrated the antioxidant efficacy of fermented papaya compared to a mixture of known antioxidants in increasing superoxide dismutase (SOD) levels, skin hydration and nitric oxide levels after 90 days of treatment. Furthermore, the oral intake of fermented papaya (9 g per day) could positively modulate the expression of genes involved in the expression of aquaporins, proteins expressed in keratinocytes and fibroblasts capable of regulating the movement of water through the plasma membranes, ensuring adequate skin health and hydration and optimal cell turnover. Finally, the fermented papaya extract was able to significantly reduce the expression of the CyPA and CD147 genes that are overexpressed in the genesis of skin cancer.

Given the high antioxidant power, papaya extracts can be considered as valid active ingredients for the realization of nutraceutical products able to counteract skin aging, in particular, extrinsic skin aging.

PolvDodium Leucotomos

Polypodium leucotomos (or Phlebodium aureum) is a fern belonging to the Polypodiaceae family and is native from Central and South America. In these areas it is also commonly known as "calaguala" and its extracts are called "anapsos". These extracts (mainly aerial parts and rhizomes) have always been used in South America and Spain for various skin diseases such as psoriasis, atopic dermatitis, vitiligo and, above all, for protecting the skin from ultraviolet radiation. The components probably responsible for these properties are phenolic compounds such as chlorogenic acid, coumaric acid, vanillic acid, caffeic acid and ferulic acid, all substances known for their antioxidant power.

In recent years, numerous in vitro, in vivo and human studies about calaguala extracts have been carried out to assess their potential beneficial action on the skin, especially for the protection against oxidative stress induced by ultraviolet radiations.

The extracts of Polypodium leucotomos are able to reduce the expression of COX-2, of nuclear transcription factors (such as NF-kB and AP-1 ) and therefore of proinflammatory cytokines, but also to reduce pro-inflammatory mechanisms induced by free radicals (like peroxidation) and therefore oxidative damage to DNA.

A study in mice has shown the efficacy of the extract (300 mg/kg per os), after a 10- day treatment period, in reducing the expression of COX-2 and the infiltration of cutaneous neutrophils following exposure to UV radiation.

Several in vitro studies, using human cell cultures, have demonstrated the photoprotective effect of Polypodium leucotomos extracts. Furthermore, the ability to reduce the formation of proinflammatory cytokines and to maintain unchanged the survival and the proliferative capacity against the oxidative damage caused by UV radiation has been demonstrated on keratinocytes and fibroblasts, respectively.

In other clinical studies the oral intake of Polypodium leucotomos extract was effective in reducing the harmful effects induced by the exposure to UV rays using dosages of about 500 mg per day in two administrations. Some data of scientific literature also show a promising activity for photoaging thanks to the ability of this extract to preserve the extracellular matrix by inhibiting metalloproteases and inducing the expression of elastin, TGF-b and different types of collagen thus promoting regeneration.

In light of the numerous documented beneficial activities, Polypodium leucotomos extracts can be considered as valid functional ingredients for the development of new products able to counteract skin aging and protect the body from oxidative damage. Therefore, the association of the present invention allows to obtain at the same time antioxidant effect and anti-inflammatory effect.

In fact the extracts of papaya, in particular fermented papaya, are able to improve the health and hydration of the skin and to guarantee a complete antioxidant protection for the body, while Polypodium leucotomos extracts, endowed with a high antioxidant and anti-inflammatory power, are able to counteract the potential damages caused by the exposure to UV rays and therefore prevent the photoaging process and skin alterations.

An object of the present invention is a composition comprising the association of extract of at least one plant belonging to the genus Carica and extract of at least one plant belonging to the genus Polypodium in admixture with one or more suitable pharmaceutically acceptable carriers.

The extract of the plant belonging to the genus Carica can be present in an amount between 10 mg and 9000 mg, preferably between 100 mg and 7000 mg, still more preferably between 200 mg and 6000 mg.

The extract of the plant belonging to the genus Polypodium can be present in an amount between 1 mg and 5000 mg, preferably between 800 and 2000 mg, still more preferably between 100 and 1000 mg.

In a preferred embodiment, the composition object of the present invention comprises the association extract of Carica Papaya and extract of Polypodium leucotomos, optionally in admixture with one or more suitable pharmaceutically acceptable carriers.

Suitable acceptable carriers are those commonly known to the man skilled in the art for the preparation of pharmaceutical compositions for oral administration such as powders, granulates, capsules, tablets, solutions, suspensions, etc. By way of non- limiting example, said acceptable carriers can consist of diluents (for example dibasic calcium phosphate, lactose, microcrystalline cellulose and cellulose derivatives), thickeners (for example rubbers, hydroxypropyl methylcellulose and other cellulose derivatives), sweeteners (for example sorbitol, mannitol and other polyols, acesulfame K, aspartame, cyclamates, saccharin, sucralose), lubricants (for example magnesium stearate, stearic acid, waxes), dispersants, surfactants (for example sodium lauryl sulphate and polysorbates), flavoring agents, adsorbents (for example silica gel, talc, starch, bentonite, kaolin), glidants and non-sticking agents (for example talc, colloidal silica, corn starch, silicon dioxide), dyes (for example iron oxides), opacifiers (for example titanium oxide), antioxidants, binders (for example rubbers, starch, gelatin, cellulose derivatives, sucrose, sodium alginate), disintegrants (starch, microcrystalline cellulose, alginic acid, crospovidone), plasticizers (for example ethyl cellulose and other cellulose derivatives, acrylates and methacrylates, glycerol and sorbitol), preservatives (for example parabens, sulfur dioxide), thickening agents, emulsifiers, humectants, wetting agents, chelating agents and mixture thereof. The composition object of the present invention can be a medical device, a food supplement, a nutraceutical, dietetic and nutritional composition, a food product, a beverage, a nutraceutical product, a medicament, a medicated food, a pharmaceutical composition or a food for special medical purposes.

The composition object of the present invention is preferably a solid, semisolid or liquid composition for oral use.

In an embodiment, the composition object of the present invention is in the form of a powder, orodispersible powder, granulate, rigid capsule, soft-gel capsule, tablet or sachet. In another embodiment, the composition object of the present invention is in the form of a solution, suspension or emulsion.

The compositions of the present invention are particularly effective in counteracting skin aging thanks to the synergistic action of their components.

The composition object of the present invention exhibits a valid synergistic effect, in particular, when the extract of plant belonging to the genus Carica is in an amount between 10 mg and 9000 mg and the extract of plant belonging to the genus Polypodium is in an amount between 1 mg and 5000 mg.

More in particular, the composition object of the present invention shows a valid synergistic effect when the extract of Carica Papaya is in an amount between 10 mg and 9000 mg and the extract of Polypodium leucotomos is in an amount between 1 mg and 5000 mg.

Therefore, a further object of the present invention is a composition comprising the association extract of at least a plant belonging to the genus Carica and extract of at least a plant belonging to the genus Polypodium in admixture with one or more suitable acceptable carriers for use as antioxidant. In particular, an object of the present invention is a composition comprising the association extract of at least a plant belonging to the genus Carica and extract of at least a plant belonging to the genus Polypodium in admixture with one or more suitable acceptable carriers for use in the prevention and/or treatment of (intrinsic and/or extrinsic) skin aging and skin alterations related to it.

Moreover, a preferred object of the present invention is a composition comprising extract of Carica papaya and extract of Polypodium leucotomos in admixture with one or more suitable acceptable carriers for use as antioxidant. In particular, a preferred object of the present invention is a composition comprising extract of Carica papaya and extract of Polypodium leucotomos in admixture with one or more suitable acceptable carriers for use in the prevention and/or treatment of (intrinsic and/or extrinsic) skin aging and skin alterations related to it.

Without being bound to a specific theory, the inventors believe that the effect of the association extract of at least a plant belonging to the genus Carica and extract of at least a plant belonging to the genus Polypodium, according to the present invention, derives from the following activities of the components of the association.

Reduction of skin alterations by antioxidant activity

The effectiveness of the composition object of the present invention was evaluated according to experimental protocols known to the man skilled in the art.

In particular, for the evaluation of the antioxidant activity of the composition of the present invention, in vitro and/or in vivo tests known in the scientific literature can be used. More in particular, in order to demonstrate the antioxidant efficacy of the composition of the present invention, of particular interest for the prevention and/or treatment of skin aging, in vitro assays such as, for example: DPPH test, radical scavenging activity on nitric oxide or peroxynitrile radical, TEAC (Total radical- trapping antioxidant parameter) test, FRAP (Ferric reducing-antioxidant power), HORAC (Hydroxyl radical averting capacity), ORAC (Oxygen radical absorbance capacity) and the like are suitable.

In order to demonstrate the antioxidant efficacy of the composition of the present invention, in vivo tests are also suitable, which consist in determining in animals the levels of endogenous substances such as, for example, reduced glutathione, glutathione peroxidase, glutathione S-transferase, superoxide dismutase and catalase, after the administration of the active ingredients of interest. The measurement of lipid peroxidation is also a valid method for estimating the antioxidant activity of the present composition.

EXAMPLES

By way of example are now provided some non-binding examples of daily doses of the active components of the compositions object of the present invention. Daily doses are meant to be administrated in a suitable oral dosage form and divided in one or more dosage units, such as, for example, a capsule, a tablet or a sachet.

Changes or variations of the embodiments herein exemplified, obvious to a person skilled in the art, are encompassed by the appended claims. EXAMPLE 1 : orosoluble powder.

EXAMPLE 2: powder or granulate for oral solution or suspension.

EXAMPLE 3: powder or granulate for oral solution or suspension.

EXAMPLE 4: Tablet

Claims

1 ) A composition comprising an association of extract of at least a plant belonging to the genus Carica and extract of at least a plant belonging to the genus Polypodium in admixture with one or more suitable acceptable carriers.

2) Composition according to claim 1 , wherein the extract of plant belonging to the genus Carica is an extract of Carica papaya.

3) Composition according to claims 1 or 2, wherein the extract of plant belonging to the genus Polypodium is an extract of Polypodium leucotomos.

4) Composition according to any of the previous claims, wherein the extract of plant belonging to the genus Carica is present in an amount between 10 mg and 9000 mg.

5) Composition according to any of the previous claims, wherein the extract of plant belonging to the genus Polypodium is present in an amount between 1 mg and 5000 mg.

6) Composition according to any of the previous claims, wherein the composition is a medical device, a food supplement, a nutraceutical, dietetic and nutritional composition, a food product, a beverage, a nutraceutical product, a medicament, a medicated food, a pharmaceutical composition or a food for special medical purposes.

7) Composition according to any of the previous claims, in the form of a liquid, solid or semisolid composition for oral use.

8) Composition according to claim 7 in the form of powder, oral soluble powder, granulate, rigid capsule, softgel capsule, tablet, sachet, solution, suspension or emulsion.

9) Composition according to any of the previous claims for use as antioxidant.

10) Composition according to any of the previous claims for use in the prevention and/or treatment of skin aging.