Maqui berry extracts for treatment of skin diseases

Abstract

To provide maqui berry for use in the treatment or prevention of skin diseases, wherein maqui berry may be the primary natural active ingredient.SOLUTION: Particular embodiments as disclosed herein find application in, inter alia, the prophylaxis and the treatment of skin diseases, in particular, dermatitis, atopic dermatitis (neurodermatitis), dermatitis solaris, eczema, hand eczema, lichen planus, lupus erythematosus, psoriasis, urticaria, itching, scabies, pigmentation, freckles, and dry / atopic skin of humans. In particular, the present invention relates to the use of maqui berry extract in the manufacture of a medicament or dietary supplement for use in treating or preventing the skin diseases or defects.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention generally relates to maqui berry, which may be a natural active ingredient, for use in the treatment or prevention of skin diseases.Specific embodiments disclosed herein are particularly used for the prevention and treatment of skin diseases, particularly human dermatitis, atopic dermatitis (neurodermatitis), photodermatitis, eczema, hand eczema, lichen planus, lupus erythematosus, psoriasis, urticaria, itch, scabies, age spots, freckles and dry / atopic skin.In particular, the present invention relates to the use of maqui berry extract in the manufacture of a pharmaceutical or nutritional supplement for use in the treatment or prevention of the above-mentioned skin diseases or skin defects. [Background technology]

[0002] As the largest human organ, the skin performs a variety of biological functions, including providing protection from cold, heat, radiation, chemical effects and pathogens. When the skin is no longer able to adequately perform this barrier function, local irritation and even systemic symptoms can result.

[0003] As a barrier organ of the human body, the skin, mainly the epidermis, is particularly exposed to external influences. This barrier function is maintained in particular by skin lipids. These epidermal lipids, such as glycosphingolipids, ceramides, sterols and sterol esters, fatty acids, triglycerides, n-alkanes or various polar lipids, are released during the keratinization process.

[0004] In the optimal state of skin, there is a balance between skin lipids and skin moisture. This balance plays a role in determining the main properties of skin, such as permeability, hydration, elasticity, regenerative capacity, or resistance to environmental influences and various toxins. Thus, skin lipids, especially surface lipids, are of great importance.

[0005] The outer lipid membrane of the skin is formed by an emulsion with a very complex composition of various lipids and secretions of the sweat glands such as urea, fatty acids, inorganic salts and water. The components of the oily phase are mainly secretions from the sebaceous glands, including inter alia squalene, cholesterol and cholesterol esters, wax esters, triglycerides and free fatty acids.

[0006] Maqui berry, also called Chilean wineberry (Aristotelia chilensis), is a natural berry that grows only in the virgin forests of Patagonia, located in Chile and Argentina. To date, there has been little industrial cultivation, and the majority of the berry is still collected from wild plants. The Patagonia region, close to the Andes, exhibits an extremely harsh climate with cold nights, hot days, and intense UV radiation. These conditions result in a unique phytochemical profile in the maqui berry. Known for its incredible health-promoting properties and valuable components, this small deep purple to black berry has been consumed for centuries by the indigenous Mapuche Indians. Today, the maqui berry is considered a "super fruit" after goji berry and açai berry due to its excellent antioxidant properties. In Chile, the berry is part of everyday life, used in jams, juices, ice creams, and liqueurs.

[0007] Increasing evidence suggests that natural compounds such as polyphenols found in fruits and vegetables have a wide range of biological and pharmacological effects. Summary of the Invention

[0008] In addition to providing skin care, it is an object of the present invention to provide compositions, particularly pharmaceuticals or dietary supplements, suitable for the treatment of skin disorders, particularly dermatitis, atopic dermatitis (neurodermatitis), photodermatitis, eczema, hand eczema, lichen planus, lupus erythematosus, psoriasis, urticaria, itch, scabies, age spots, freckles and dry / atopic skin in humans.

[0009] Surprisingly, the inventors have found that the maqui berry extract disclosed herein promotes skin healing and regeneration and prevents dermatitis, particularly inflammatory skin conditions.

[0010] Thus, disclosed herein is a method for treating an inflammatory skin condition in a subject, the method comprising administering to a subject in need thereof an effective amount of a maqui berry extract as described herein.

[0011] The subject may be suffering from a skin defect or disease, or may be susceptible or predisposed to such a defect or disease. The following terms define the above mentioned diseases according to the present invention: Dermatitis, also known as eczema, is a group of diseases that cause inflammation of the skin. These diseases are characterized by itching, redness and a rash.

[0012] In particular, atopic dermatitis (neurodermatitis) is a multifactorial inflammatory skin disease that arises from the interaction between genetic susceptibility and environmental factors.

[0013] Photodermatitis is caused by UV radiation, resulting in local inflammation and primary hyperalgesia.

[0014] The term dermatitis also refers to allergic contact dermatitis, irritant contact dermatitis and stasis dermatitis.

[0015] Lichen planus is a chronic inflammatory disease that affects the squamous cell layers that comprise the skin and mucous membranes.

[0016] Lupus erythematosus is a systemic autoimmune disease that originates from the collagen disease group. A special feature of SLE (systemic lupus erythematosus) is the so-called butterfly rash. In any case, inflammation is involved.

[0017] Psoriasis is a disease process driven by the overproduction of inflammatory mediators released by innate and adaptive immune cells.

[0018] Scabies is one of the three most common inflammatory skin disorders resulting from infection in children.

[0019] Urticaria is defined as a disease characterized by episodes of recurrent itchy wheals and / or angioedema lasting 6 weeks or more.

[0020] All mentioned diseases and defects are described in detail in Pschyrembel (e.g. https: / / www.pschyrembel.de / ).

[0021] The maqui berry extract may increase the rate or extent of healing of a condition. The extract or composition may promote healing or regeneration of the skin.

[0022] The defect or disease may be acute or chronic. Those skilled in the art will recognize that healing (whether injury or recovery) is The reader will readily appreciate the range of defects and disorders to which the embodiments disclosed herein relate, in which a skin irritation or inflammation (such as eczema, psoriasis, itch, psoriasis, rash, eczema, psoriasis, rash, rash or rash on the skin) is desirable or beneficial. In a preferred embodiment, the defects and disorders are preferably selected from the group of human dermatitis, atopic dermatitis (neurodermatitis), photodermatitis, eczema, hand eczema, lichen planus, lupus erythematosus, psoriasis, urticaria, itch, scabies, age spots, freckles and dry / atopic skin.

[0023] Therefore, the approach of the maqui berry extract, especially with regard to the antioxidant and anti-inflammatory defense, is important for the primary prevention of the skin, while it may also reduce the risk and improve the healing process of defects or diseases.Moreover, the maqui berry extract advantageously exhibits a specific anti-inflammatory effect, especially mediated by IL-8, as shown in this example.

[0024] Maqui berry extracts can be obtained by water / alcohol and other solvents based on the respective fractions obtained from the raw materials (fruit and berry). Such methods are well known in the state of the art.

[0025] Water / alcohol extractants are used in ratios of 40:60 (v / v) to 60:40 (v / v), especially 41:59 (v / v), or 50:50 (v / v).

[0026] As alcohol, in particular ethanol is used, in particular 96% ethanol (v / v).

[0027] In a preferred embodiment, the maqui berry extract is enriched with anthocyanins (containing sugars) as active ingredients, in particular delphinidin glycosides (so-called delphinidins), in particular delphinidin-3-sambubioside-5-glucoside, delphinidin-3,5-diglucoside, delphinidin-3-sambubioside or delphinidin-3-glucoside. Furthermore, delphinidin-3-O-galactoside, delphinidin 3-O-glucoside, cyanidin-3-O-galactoside, delphinidin-3-O-arabinoside, cyanidin-3-O-glucoside, petunidin-3-O-galactoside, petunidin-3-O-glucoside, cyanidin-3-O-arabinoside, peonidin-3-O-galactoside, petunidin-3-O-arabinoside, malvidin-3-O-galactoside, peonidin-3-O-glucoside, malvidin-3-O-glucoside, peonidin-3-O-arabinose, malvidin-3-O-arabinose are preferred compounds of maqui berry extract.

[0028] [ka]

[0029] [Table 1]

[0030] Formula 1 and Table 1 show some anthocyanidins (sugar-free).

[0031] In a preferred embodiment, the maqui berry extract comprises: a) obtaining a crude extract of a plant material; b) filtering the crude extract; c) contacting the crude extract with a polystyrene resin and adsorbing the anthocyanins onto the resin; d) washing the resin; e) eluting the anthocyanins from the polystyrene resin to obtain an anthocyanin-enriched composition; can be obtained by

[0032] Thus, the present invention refers to a maqui berry extract standardized to contain a minimum of 25% (w / w) delphinidin and a minimum of 35% (w / w) total anthocyanins.

[0033] In a preferred embodiment, maqui berry extract is the primary active ingredient.

[0034] "Major active ingredient" means that the active ingredient maqui berry extract is present in a major amount in the composition according to the invention in addition to other active ingredients.

[0035] As used herein, the terms "treat" and "treatment" or "prevent" and "prevention" refer to any and all uses for treating a condition or symptom, preventing the formation of a condition or disease, or otherwise preventing, hindering, slowing, or reversing the progression of a condition or disease or any other undesirable symptoms. Thus, the terms "treat" and "treatment" or "prevent" and "prevention" are considered in their broadest sense. For example, treatment does not necessarily mean that a subject is treated until complete recovery.

[0036] As used herein, the term "subject" includes humans and animals. Typically, a subject is a human or a patient.

[0037] Preferably, the maqui berry extract is formulated as a pharmaceutical composition further comprising one or more pharma- ceutically acceptable carriers or diluents.

[0038] The medical drug produced with the maqui berry extract of the present invention can be administered orally, preferably parenterally, topically, intramuscularly, periarticularly, intraarticularly, intravenously, intraperitoneally, subcutaneously or rectally. The present invention relates to a method for the preparation of a maqui berry extract of the present invention, comprising administering the extract to a patient in the presence of a medicament suitable and physiologically acceptable vehicle, and optionally further suitable active ingredients, additives or auxiliary substances. The present invention relates to a process for the manufacture of medical drugs, characterized by the function of providing a suitable dosage form of the drug for administration by adding the above-mentioned. Suitable solid or liquid galenic dosage form preparations or formulations include, for example, granules, powders, dragees, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injection solutions, as well as preparations that are used for the preparation of conventional auxiliary substances, such as preparations that release the active ingredient slowly (e.g. excipients), agents that bring about the disintegration of the preparation, binders, coating agents, bulking agents, glidants or lubricants, flavor improvers, sweeteners and solubilizers. The auxiliary substances may include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talcum, milk proteins, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol, and solvents, such as sterile water and mono- or polyhydric alcohols, such as glycerin.

[0039] When the maqui berry extract is used in pharmaceutical preparations, it may be administered in any dosage form advantageously used for oral or parenteral administration, such as injections (emulsifiable, suspendable, non-aqueous, etc.) or solid injections that are emulsified or suspended before use, infusions, powders, granules, tablets, capsules, enteric-coated tablets, troches, internal solutions, suspensions, emulsions, syrups, external solutions, poultices, nasal drops, inhalants, ointments, lotions, suppositories, enteral nutrition, etc. It may be used either alone or in combination, depending on the pathology. These may be prepared according to conventional methods of adding pharmacologically and pharma- ceutically acceptable adjuvants for manufacture to the main drug.

[0040] Medical drugs are preferably manufactured and administered in dosage units, each unit containing a defined amount of the maqui berry extract of the invention as active ingredient. In the case of solid dosage units such as tablets, capsules, dragees or suppositories, this dose can be 1-1000 mg, preferably 50-300 mg, and in the case of injections in ampoule form, this dose can be 0.3-300 mg, preferably 10-100 mg.

[0041] For the treatment of an adult patient weighing 50-100 kg, for example 70 kg, a daily dose of 20-1000 mg of active ingredient, preferably 100-500 mg of active ingredient, is required. However, under certain conditions, higher or lower daily doses can also be administered. The administration of the daily dose can be carried out in a single administration in individual dosage unit forms or in several smaller dosage unit forms, or in multiple administrations of subdivided amounts at defined intervals.

[0042] The present invention will be described in more detail below with reference to examples, which, however, do not limit the scope of protection of the present invention.

[0043] These Examples also refer to several figures, the legends of which are set forth below: Working Example Delphinol® (also known as maquisupreme®) is a highly water-soluble powdered extract of maqui berry manufactured under GMP conditions by Anklam Extrakt (Germany). Delphinol® is standardized to contain a minimum of 25% delphinidin and a minimum of 35% total anthocyanins. Example 1: Effect of Delphinol® on cellular glucose utilization.

[0044] Cultured keratinocytes (HaCaT cells; an aneuploid immortal keratinocyte cell line derived from adult human skin) were labeled with 2-NBDG (2-[N-(7-nitrobenzo-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose) and treated with Delphinol® or a positive control (rosiglitazone) for 24 hours. Fluorescence was measured and data were analyzed by the total integrated intensity of green objects. Fluorescence of rosiglitazone was set to 100% of the green object. The glucose uptake is considered as the radiolucent uptake and calculated as (% glucose uptake)=100(TB) / (PB), where T(treatment) is the fluorescence of Delphinol®-treated cells, B(basal) is the fluorescence of 2-NBDG cells, and P(positive control) is the fluorescence of cells treated with rosiglitazone. As a result, Delphinol® induced glucose uptake in keratinocytes at the highest concentration tested. Thus, the intake of Delphinol® increases the glucose uptake of skin-related cells, thereby nourishing the cells and enhancing their viability, leading to the maintenance of healthy skin (Figure 1). Example 2: Delphinol® exhibits potent TRPV1 antagonist activity.

[0045] Cultured 293T-VR1 were incubated with Delphinol® and then stimulated with the agonist capsaicin for 3 hours. Capsazepine was used as a positive control for TRPV-1 antagonism. Cell viability was measured by live cell imaging 3 hours after stimulation. The results revealed high viability of capsaicin-treated cells with Delphinol® treatment at higher concentrations, reflecting its strong agonist activity on TRPV1 receptors. TRPV1 receptors (capsaicin receptors) are known to enhance heat and pain sensations (nociception) and can also sense and control body temperature. Blocking TRPV1 receptors is an interesting approach for the treatment of skin. Thus, Delphinol® may exhibit anti-itch as well as anti-pain effects on sensitive skin (Figure 2). Example 3: Delphinol® exhibits anti-inflammatory properties.

[0046] Primary normal human dermal fibroblasts (NHDF) were incubated with IL-1β (cell stimulation) in the presence of Delphinol® for 24 hours. After 24 hours of cell stimulation, cell culture supernatants were examined for the inflammatory cytokines IL-6 and IL-8 by ELISA. Delphinol® showed an inhibitory effect on IL-1β-induced IL-6 release in NFIDF at 10 μg / ml and 100 μg / ml treatments. Furthermore, Delphinol® showed a strong dose-dependent suppression of IL-8 release in NFIDF (Figure 3). Example 4: Delphinol® exhibits an inhibitory effect on collagen decomposition enzyme MMP-1. HaCaT keratinocytes were cultured and stimulated with PolyIC in the presence of Delphinol® for 24 hours. After 24 hours, cell stimulation supernatants were removed and MMP-1 concentrations were examined by ELISA. Delphinol® showed a strong and dose-dependent inhibitory effect on MMP-1 enzyme in vitro. Thus, Delphinol® may potentially have beneficial effects on maintaining skin elasticity (Figure 4). Example 5: Delphinol® affects tyrosinase activity and reduces melanin production in vitro To measure tyrosinase activity in B16 melanoma cells, cells were treated with Delphinol® or kojic acid (as a positive control) for 72 hours. After cell lysis, the supernatant was incubated with L-dopa (a melanin precursor) for 2 hours and tyrosinase activity was measured photometrically at 485 nm. To examine melanin production, B16 cells were treated with Delphinol® for 3 days and then washed with phosphate-buffered saline at the end of treatment and dissolved in NaOH-containing 10% DMSO at 60°C for 1 hour. Melanin was measured photometrically at 405 nm. The results showed that Delphinol® It was possible to dose-dependently inhibit typrosinase activity and demonstrate a reduction in melanin production. Thus, Delphinol® may be useful in the treatment of age spots or freckles (Figure 5). [Brief description of the drawings]

[0047] [Figure 1] FIG. 1 is a graph showing that Delphinol® promotes glucose uptake in keratinocytes. [Diagram 2] FIG. 2 is a graph showing the beneficial effects of Delphinol® on sensitive skin conditions. [Diagram 3] FIG. 3 is a graph showing the anti-inflammatory effect of Delphinol® on immune stimulation of fibroblasts. [Figure 4]FIG. 4 is a graph showing that Delphinol® potently inhibits collagen fiber degrading enzyme MMP-1 in keratinocytes. [Diagram 5] FIG. 5 is a graph showing that Delphinol® dose-dependently inhibits tyrosinase activity and reduces melanin production in vitro.

Claims

1. 1. A pharmaceutical or nutritional supplement for use in the treatment or prevention of an inflammatory skin condition selected from the group consisting of lichen planus, lupus erythematosus, psoriasis, scabies, urticaria, comprising said pharmaceutical or nutritional supplement comprising a maqui berry extract; said maqui berry extract comprising a minimum of 25% (w / w) delphinidin and a minimum of 35% (w / w) total anthocyanins; The maqui berry extract is a) obtaining a crude extract of plant material comprising maqui berry; b) filtering the crude extract; c) contacting the crude extract with an adsorbent to adsorb the anthocyanins to the adsorbent; d) washing the adsorbent; e) eluting the anthocyanins from the adsorbent to obtain an anthocyanin-enriched composition.

2. 2. The pharmaceutical or nutritional supplement of claim 1, wherein the inflammatory skin condition is itch.

3. 3. A pharmaceutical or nutritional supplement according to claim 1 or 2, wherein the maqui berry extract is obtained with a water / alcohol extraction agent of 40:60 (v / v) to 60:40 (v / v), 41:59 (v / v) or 50:50 (v / v).

4. 4. The pharmaceutical or nutritional supplement of claim 3, wherein the alcoholic extractant is ethanol, in particular 96% ethanol.

5. 2. The pharmaceutical or nutritional supplement of claim 1, wherein step d) uses water and step e) uses ethanol.

6. 2. A pharmaceutical or nutritional supplement according to claim 1, wherein the adsorbent from steps c) to d) is a resin, in particular a polymeric resin or a polystyrene resin.

7. 7. The pharmaceutical or nutritional supplement of any one of claims 1 to 6, wherein the pharmaceutical or nutritional supplement is a formulation comprising a carrier material comprising the maqui berry extract in the form of dragees, tablets, film-coated tablets, powders, capsules or diluents, including drops, juices or syrups, ointments, emulsions, granules, powders, nasal sprays, liquid or solid inhalation preparations, compression dressings, wound and gum coverings, tamponades, tonsil linings, gargles, rinses, injections, infusions, granules, enteric coated tablets, troches, suspensions, poultices, nasal drops, inhalants, lotions, suppositories or enteral nutrients.

Images