IT201800006791A1 - Composition for the prevention and treatment of hyperpigmentation and skin aging - Google Patents

Description

Patent application for industrial invention entitled:

"Composition for the prevention and treatment of hyperpigmentation and skin aging"

DESCRIPTION

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

Background of the invention

The skin

The skin, or skin, forms the outer covering of the human body and has a surface area of about 2 m <2>. It consists of a superficial epithelial layer, the epidermis, and a deep connective layer, the dermis, which rests on a connective fatty layer, the hypodermis. The epidermis is a keratinized stratified pavement epithelium, 50 µm to 1.5 mm thick, whose outermost layer, made up of dead keratinocytes, is called the 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 made up of loose connective tissue, adipose tissue and elastin. The skin also has skin appendages such as nails, hair, sebaceous and sweat glands, distributed with different density and development. In addition, the skin is home to numerous nerve endings and, therefore, also represents a huge sense organ.

The skin in mammals performs several functions:

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

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

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

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

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

- Reserve: the skin constitutes a reservoir of lipids and water and allows the synthesis of some indispensable 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 involves the progressive alteration of the functions and appearance of the skin.

Skin aging is due to a combination of changes that occur both due to the effect of time (intrinsic aging) and environmental factors (extrinsic aging). In particular, intrinsic skin aging, or chrono-aging, represents the gradual process of cell aging and is due to genetic factors and changes that the body undergoes with age, such as, for example, the variation in hormonal levels. Extrinsic aging, on the other hand, is 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 changes.

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

Photoaging is instead characterized by biological hyperactivity and chronic inflammation that involve leathery skin, thickening of the stratum corneum, skin discolouration and telangiectasia. Furthermore, “photoaged” skin is characterized by a statistically significant decrease in collagen, elastosis (accumulation of elastin in the superficial layers), atypical keratinocytes and elongated and collapsed fibroblasts.

Photoaging is mainly caused by exposure to UV sun rays divided according to their wavelength into UVC (200-290 nm), UVB (290-320 nm) and UVA (320-400 nm). Ozone absorbs 100% of UVC rays and 90% of UVB rays, but is unable to absorb UVA. The UVB / UVA ratio that reaches the soil is 20/120. UVB rays are absorbed by the epidermis, while UVA penetrates deeper and can interact with fibroblasts, damaging them.

UVA can inhibit the expression of TGF-β growth factor, a promoter of collagen synthesis. UVBs can upregulate elastases in fibroblasts causing the degradation of elastic fibers and downregulate hyaluronic acid synthetase (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.

In addition, both UVA and UVB, through the formation of reactive oxygen species (ROS) such as, for example, the superoxide anion, peroxide and radical oxygen, can cause DNA alterations. ROS oxidize and inhibit tyrosine-phosphatase proteins that downregulate receptors such as the receptor for EGF, IL-1 and TNF-α. Consequently, in keratinocytes and fibroblasts, these receptors are upregulated, leading to the activation of the MAP-kinase signal cascade. The result is the activation of the transcription factors AP-1 and NF-kB: AP-1 stimulates the transcription of 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 body without 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.

Most of the products commercially available for the treatment of skin aging are based on active ingredients such as collagen, elastin and hyaluronic acid, which means that they only aim to integrate those substances that, over time, disappear. However, these products are not always effective. Furthermore, most of the commercially available products convey 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 evade the skin barrier, skin aging involves major alterations of the skin, in particular of the stratum corneum, which hinder the penetration of the formulation and the absorption of the active ingredients in an unpredictable way.

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

Detailed Description of the Invention

The inventors of the present invention have now surprisingly discovered that the association of some plant extracts such as extract of at least one plant belonging to the genus Carica and an extract of at least one plant belonging to the genus Polypodium represents a valid alternative to commercially available products. In particular, the association referred to in the present invention may include Carica papaya extract and Polypodium leucotomos extract.

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

Upload Papaya

Papaya (Carica papaya Linn.) Belongs to the Cactaceae family and to the Carica genus which has four species of which the papaya is the most widely cultivated and known.

This plant is probably native to 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 in height with broad palmate-lobed leaves from which the fruits that can be green, yellow, orange or pink are born.

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

In recent years, 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 degrees of polymerization, consisting of monomers with a structure similar to that of β 1-3 D-glucan.

In the context of the present invention, papaya extracts are of considerable interest thanks to their high antioxidant power. In fact, it has been described how the skin aging process forces the skin cells 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 oxidative damage is more likely to develop due to the accumulation of free radicals and pro-inflammatory cytokines that can lead to very serious skin diseases. A 2015 clinical study 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 be able to positively modulate the expression of genes involved in the expression of aquaporins, proteins expressed in keratinocytes and fibroblasts able to regulate the movements of water through the plasma membranes, ensuring adequate skin health and hydration and optimal cell turnover. Finally, fermented papaya extract was found to be able to significantly reduce the expression of the CyPA and CD147 genes which are overexpressed in the genesis of skin cancer.

Given the high antioxidant power, papaya extracts can be considered as valid active ingredients for the creation of nutraceutical products capable of counteracting skin aging, in particular, extrinsic aging.

Polypodium Leucotomos

Polypodium leucotomos (or Phlebodium aureum) is a fern belonging to the Polypodiaceae family and is native to 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 conditions such as psoriasis, atopic dermatitis, vitiligo and, above all, for the protection of 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 have been carried out on calaguala extracts to evaluate their potential beneficial action on the skin, especially for protection from oxidative stress induced by ultraviolet radiation. Polypodium leucotomos extracts 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 proinflammatory mechanisms induced by free radicals ( such as peroxidation) and therefore oxidative damage to DNA.

A study in mice demonstrated the efficacy of the extract (300 mg / kg per os), after a treatment period of 10 days, in reducing the expression of COX-2 and the infiltration of neutrophils in the skin afterwards. 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 intact survival and proliferative capacity against 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 found to be effective in reducing the harmful effects induced by exposure to UV rays using dosages of about 500 mg per day in two doses. Some data from scientific literature also demonstrate a promising activity for "photoaging" thanks also to the ability of this extract to preserve the extracellular matrix by inhibiting metalloproteases and inducing the expression of elastin, TGF-β and different types of collagen in order to promote regeneration.

In light of the numerous documented beneficial activities, Polypodium leucotomos extracts can be considered valid functional ingredients for the development of new products capable of counteracting skin aging and protecting the body from oxidative damage.

Genus Malpighia

Plants of the Malpighia genus such as Malpighia glabra L., M. punicifolia L., M. emarginata D.C. they are widespread in the southern extremity of Texas, in Central America and throughout the Caribbean. The plants grow as a shrub or small tree and bloom from April to November. The fruit, which ripens in 3-4 weeks after flowering, is small and red cherry-like whose pulp is very juicy. These plants are mainly known for their high Vitamin C content; in fact, they represent some of the most important natural sources of this vitamin. They are also rich in proteins, phosphorus, calcium, iron, pyridoxine, riboflavin and thiamine.

In the study by Mezadri et al., The total content of ascorbic acid in the fruit of Malpighia emaginata, the main component with antioxidant activity, was found to be between 6.32 and 9.20 g kgˉ1 in the pulp and between 9.44 and 17.97 g Lˉ1 in the juice. Furthermore, the antioxidant activity of acerola fruit juice has been shown to be higher in vitro than other fruit juices particularly rich in phenols.

The Malpighia emarginata extract also has a high content of carotenoids and bioflavonoids, in particular the carotenoid content is between 3.2 and 406 mg kgˉ1. In reference to bioflavonoids, however, the fruits have a high content of anthocyanidins, quercetin and kaempferol.

In the study by Hanamura et al. 2008 the concentrated polyphenol extract of Malpighia emarginata was used both to examine the lightening / anti-pigmenting effect on the skin of guinea pigs subjected to UVB irradiation and the inhibition activity of the tyrosine kinase enzyme and of melanogenesis on mouse melanoma cells. The concentrated extract of polyphenols was administered orally at a concentration of 400 mg / kg per body weight per day for 8 weeks. After treatment, a visible reduction in skin pigmentation was demonstrated. The concentrated extract of polyphenols has been shown to inhibit the activity of the tyrosine kinase enzyme in a dose-dependent manner with an IC50 value of 15mg / ml, resulting in a decrease in the production of melanin in melanoma cancer cells. Therefore, the oral administration of plant polyphenols can be effective for the reduction of hyperpigmentation of the skin induced by UVB rays. The extracts of plants belonging to the Malpighia genus therefore exert an important antioxidant activity and are capable of acting on skin hyperpigmentation.

Therefore, the association of the present invention allows to obtain at the same time an antioxidant effect, an anti-inflammatory effect and an effect of regulating skin pigmentation.

In fact, the extracts of papaya, in particular of fermented papaya, are able to improve the health and hydration of the skin and guarantee complete antioxidant protection for the body, the extracts of Polypodium leucotomos, with a high antioxidant power and anti-inflammatory, they are able to counteract the potential damage induced by exposure to UV rays and thus prevent the photoaging process and skin alterations. The extracts of plants of the Malpighia genus, thanks to the numerous bioactive constituents, have a strong antioxidant activity and are able to reduce skin hyperpigmentation.

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

The plant extract belonging to the Carica genus can be present in an amount between 10 mg and 9000 mg, preferably between 20 mg and 7000 mg, even more preferably between 100 mg and 6000 mg.

The plant extract belonging to the Polypodium genus can be present in an amount between 1 mg and 5000 mg, preferably between 20 and 3000 mg, even more preferably between 50 and 2000 mg.

The extract of a plant belonging to the Malpighia genus can be present in an amount between 1 and 5000 mg, preferably between 20 and 3000 mg, even more preferably between 50 and 2000 mg.

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

Suitable pharmaceutically acceptable carriers are those commonly known to those skilled in the art for the preparation of pharmaceutical compositions for oral administration (such as powders, granulates, capsules, tablets, solutions, suspensions, etc.) and for topical application (such as creams, emulsions, gels, creams , pastes, sprays, aerosols, sticks). By way of non-limiting example, these pharmaceutically acceptable carriers can consist of diluents (for example dibasic calcium phosphate, lactose, microcrystalline cellulose and cellulose derivatives), thickeners (for example gums, hydroxypropylmethylcellulose and other cellulose derivatives), sweeteners (for example e.g. sorbitols, mannitol and other polyols, acesulfame K, aspartame, cyclamates, saccharin, sucralose), lubricants (e.g. magnesium stearate, stearic acid, waxes), dispersants, surfactants (e.g. sodium lauryl sulfate and polysorbates), flavoring, adsorbents (e.g. e.g. silica gel, talc, starch, bentonite, kaolin), glidants and anti-adhesives (e.g. talc, colloidal silica, corn starch, silicon dioxide), dyes (e.g. iron oxides), opacifiers (e.g. oxide titanium), antioxidants, binders (e.g. gum, starch, gelatin, cellulose derivatives, sucrose, sodium alginate), breakdown agents (starch, cellulose microcrystalline, alginic acid, crospovidone), plasticizers (e.g. ethylcellulose and other cellulose derivatives, acrylates and methacrylates, glycerol and sorbitol), preservatives (e.g. parabens, sulfur dioxide), viscosifiers, emulsifiers, humectants, wetting agents, chelators and their mixtures .

The composition object of the present invention can be a medical device, a food supplement, a cosmetic, a nutraceutical, dietary and nutritional composition, a food product, a beverage, a nutraceutical, 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, semi-solid or liquid pharmaceutical composition for oral or topical use.

In one embodiment, the composition object of the present invention is in the form of powder, buccal powder, granulate, hard 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. In a further embodiment, the composition object of the present invention is in the form of spray, aerosol, stick, paste, gel, emulsion, cream for topical use.

The compositions referred to in the present invention are particularly effective in counteracting skin aging and skin hyperpigmentation 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 at least one plant belonging to the genus Carica is in an amount between 10 mg and 9000 mg, the extract of at least one plant belonging to the genus Polypodium it is in an amount between 1 mg and 5000 mg and, the extract of at least one plant belonging to the Malpighia genus is in an amount between 1 mg and 5000 mg.

More specifically, the composition object of the present invention exhibits a valid synergistic effect when the Carica Papaya extract is in an amount between 10 mg and 9000 mg, the Polypodium leucotomos extract is in an amount between 1 mg and 5000 mg and, the Malpighia glabra and / or Malpighia punicifolia and / or Malpighia emarginata extract is in an amount between 1 mg and 5000 mg.

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

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

Without being tied to a specific theory, the inventors believe that the effect of the association with the extract of at least one plant belonging to the genus Carica, an extract of at least one plant belonging to the genus Polypodium and an extract of at least one plant belonging to the genus Malpighia according to the present invention, derives from the following activities of the members of the association.

Reduction of skin alterations through antioxidant action

The effectiveness of the composition object of the present invention was evaluated according to experimental protocols known to the 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 assays known in the scientific literature can be used. More specifically, 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 are suitable such as, for example: DPPH test, radical activity scavenging 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 similar.

In order to demonstrate the antioxidant efficacy of the composition according to the present invention, in vivo assays 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 administration of the active ingredients of interest. The measurement of lipid peroxidation is also a valid method for estimating the antioxidant activity of this composition.

EXAMPLES

Some examples of daily doses of the active components of the compositions object of the present invention are now provided for illustrative purposes. The daily doses are intended to be administered in suitable oral or topical dosage form and divided into one or more dosage units such as, for example, a capsule, a tablet or a sachet, a cream etc.

Modifications or variations of the embodiments exemplified here, obvious to one skilled in the art, are included in the appended claims.

EXAMPLE 1: buccal powder.

Active ingredient Daily dose Fermented Carica Papaya extract 3000 mg

Polypodium leucotomos extract 240 mg

Malpighia glabra 100 mg

EXAMPLE 2: powder or granules for solution or oral suspension. Active ingredient Daily dose Fermented Carica Papaya extract 6000 mg

Polypodium leucotomos extract 120 mg

Malpighia glabra 70 mg

EXAMPLE 3: Cream / gel / spray for external use.

Active ingredient Amount per 100 mL Fermented Carica Papaya Extract 500 mg

Polypodium leucotomos extract 500 mg

Malpighia glabra 500 mg

EXAMPLE 4: Cream / gel / spray for external use.

Active ingredient Daily dose Fermented Carica Papaya extract 100 mg

Polypodium leucotomos extract 100 mg

Malpighia glabra 100 mg

Claims (10)

CLAIMS 1) A composition comprising an association of extract of at least one plant belonging to the genus Carica, an extract of at least one plant belonging to the genus Polypodium and an extract of at least one plant belonging to the genus Malpighia in a mixture with one or more suitable pharmaceutically acceptable carriers. 2) Composition according to claim 1, in which the plant extract belonging to the Carica genus is an extract of Carica papaya. 3) Composition according to claims 1 or 2, in which the plant extract belonging to the Polypodium genus is an extract of Polypodium leucotomos. 4) Composition according to any of the preceding claims, in which the plant extract belonging to the Malpighia genus is an extract of Malpighia glabra and / or Malpighia punicifolia and / or Malpighia emarginata. 5) Composition according to any one of the preceding claims, in which the plant extract belonging to the Carica genus is present in an amount comprised between 10 mg and 9000 mg, preferably between 20 mg and 7000 mg, even more preferably between 100 mg and 6000 mg mg; the plant extract belonging to the Polypodium genus is present in an amount between 1 mg and 5000 mg, preferably between 20 and 3000 mg, even more preferably between 50 and 2000 mg; the plant extract belonging to the Malpighia genus is present in an amount between 1 mg and 5000 mg, preferably between 20 and 3000 mg, even more preferably between 50 and 2000 mg. 6) Composition according to any one of the preceding claims, wherein the composition is a medical device, a food supplement, a cosmetic, a nutraceutical, dietary and nutritional composition, a food product, a beverage, a nutraceutical, a medicament, a medicated food , a pharmaceutical composition or a food for special medical purposes. 7) Composition according to any one of the preceding claims in the form of liquid, solid or semi-solid composition for oral or topical use. 8) Composition according to claim 7 in the form of powder, buccal powder, granules, hard capsule, softgel capsule, tablet, sachet, solution, suspension, cream, emulsion, gel, paste, spray, aerosol, stick. 9) Composition according to any of the preceding claims for use as an antioxidant. 10) Composition according to any of the preceding claims for use in the prevention and / or treatment of skin hyperpigmentation and / or skin aging and related alterations.