CN114786700A - Curcuminoid-free turmeric extract for inflammatory skin diseases - Google Patents
Curcuminoid-free turmeric extract for inflammatory skin diseases Download PDFInfo
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- CN114786700A CN114786700A CN202080085494.1A CN202080085494A CN114786700A CN 114786700 A CN114786700 A CN 114786700A CN 202080085494 A CN202080085494 A CN 202080085494A CN 114786700 A CN114786700 A CN 114786700A
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- A61K36/18—Magnoliophyta (angiosperms)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/37—Extraction at elevated pressure or temperature, e.g. pressurized solvent extraction [PSE], supercritical carbon dioxide extraction or subcritical water extraction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- Microbiology (AREA)
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- Epidemiology (AREA)
- Medicines Containing Plant Substances (AREA)
- Cosmetics (AREA)
Abstract
The present invention relates to a turmeric extract and a dermatological or dermo-cosmetic composition containing said turmeric extract, for the use thereof for the treatment and/or prophylaxis of inflammatory skin diseases, in particular psoriasis, atopic dermatitis or acne, said turmeric extract having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract.
Description
Technical Field
The field of the present invention relates to a turmeric (Curcuma longa) extract and to a dermatological or dermo-cosmetic composition containing said turmeric extract, for use in the treatment and/or prevention of inflammatory skin diseases, in particular psoriasis, atopic dermatitis or acne, said turmeric extract having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract.
Background
Skin disorders are diseases of the skin and mucous membranes characterized by unaesthetic signs, such as redness and scaly plaques. Various conditions are classified as inflammatory skin diseases. For example, psoriasis, atopic dermatitis, eczema, acne, rosacea, lichen planus, prurigo or seborrheic dermatitis may be mentioned. These skin diseases are often the result of inflammatory phenomena and/or immune disorders.
Psoriasis is a typical inflammatory disease characterized by the appearance of thick skin exfoliative plaques. These plaques may occur in different parts of the body, most commonly in the elbows, knees, and scalp. This chronic disease undergoes a cycle with a remission phase. Psoriasis can be most unpleasant and even painful when it occurs on the palms, soles or folds of the skin. There are several types of psoriasis, the most common form being plaque-like psoriasis or psoriasis vulgaris. Other forms are drip, erythrodermic and pustular psoriasis.
Atopic dermatitis is a skin manifestation of atopy and is a chronic inflammatory skin disease with a genetic predisposition. Which is now considered a major public health concern. Atopic dermatitis is often associated with other atopic diseases such as allergic rhinitis and asthma. This condition begins most often in childhood and is characterized by repeated outbreaks over the years. It progresses with sudden onset interrupted by spontaneous remission. Lesions are mainly characterized by dry skin and inflammatory lesions: erythema, papulosis, vesiculation, and squamous rash with intense pruritus. At the histological level, atopic dermatitis, like many skin diseases, is characterized by infiltration of lymphocytes, monocytes and eosinophils around small and capillary vessels. At the biochemical level, chemokines have been shown to be closely associated with skin diseases and chronic inflammatory diseases in general.
Acne is a common skin lesion caused by inflammation of the pilosebaceous glands, mainly due to colonization of the infundibulum by propionibacterium acnes (cutobacterium acnes) (Dr no et al, JEADV 2018,32(Suppl 2) 5-14).
For mild inflammatory skin conditions, emollients and keratolytics are suggested. The aim of these treatments is to allow the patient to tolerate the pathology and they usually have only a temporary effect. For more severe cases, anti-inflammatory drugs or corticosteroids that modulate skin inflammation have been used for many years. All of these treatments have serious side effects and are sometimes the most bothersome to the patient. In view of the above-mentioned serious side effects of the existing treatments for skin or scalp diseases, which are caused by the activation state of the innate immune response and the epidermal inflammatory skin reaction, there is a real need for new cosmetic or dermatological active substances and new cosmetic or dermatological compositions which can be used as a relay or concomitant treatment of said skin or scalp diseases.
In addition, inflammatory skin diseases, in particular psoriasis or atopic dermatitis, have multifactorial origins and causes. The causes of these so-called autoimmune diseases have not been fully elucidated, but appear to be related to a dysregulation of the immune system, in particular at the level of cellular responses. Cellular responses can be divided into 3 classes: th1, Th2 and most recently Th 17. Although psoriasis and atopic dermatitis show differences in clinical signs, they appear to have similarities, particularly at the IL-17 and IL-22 levels, which is characteristic of Th17 responses (Miyagaki and Sugaya, j. dermatol sci.78(2)89-94,2015). IL-17 and IL-22 will then be interesting targets for the treatment of these diseases. Therefore, monoclonal antibodies against IL-17, IL-17R, IL-22, IL-23, TNFa have been developed to block the Th17 pathway (Lowes et al, Annu Rev Immunol 32, 227-. These molecules are effective in treating psoriasis, but have many side effects and require high treatment costs.
Furthermore, the Th17 pathway is also known to be strongly activated in lesions of acne patients (Kelhala et al, Plos One 9(8) e105238,2014).
Disclosure of Invention
The present invention aims to meet the above-mentioned need. In a completely unexpected manner, the inventors have demonstrated that turmeric extract exhibits interesting pharmacological activity for the treatment and prevention of inflammatory skin diseases, more particularly psoriasis, atopic dermatitis or acne, provided that the extract is free of curcumin, particularly of curcuminoids.
The curcuminoid content can be determined as described in the experimental section below, i.e. by reverse phase High Performance Liquid Chromatography (HPLC) with UV detection at a wavelength of 425 nm.
Accordingly, a first subject of the present invention relates to a turmeric extract having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract, for its use in the treatment and/or prevention of inflammatory skin diseases.
Another subject of the present invention relates to the use of a turmeric extract having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract, for the preparation of a dermatological or cosmetic composition intended for the treatment and/or prevention of inflammatory skin diseases.
Another subject of the present invention relates to the use of a turmeric extract having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract, for the treatment and/or prevention of inflammatory skin diseases.
Another subject of the present invention relates to a method for the treatment and/or prophylaxis of inflammatory skin diseases, comprising administering to a person in need thereof an effective amount of a turmeric extract having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract.
Definition of
In the meaning of the present invention, the term "prevention" refers to the prevention of the onset of a disease, disorder or one or more signs and/or symptoms.
The term "treating" or "treatment" of an inflammatory skin disease refers to reducing and/or inhibiting the development of an inflammatory skin disease and/or at least one symptom thereof.
In the present invention, "dermatologically or cosmetically acceptable" means useful for preparing dermatological or cosmetic compositions, are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and may be used for dermatological or cosmetic applications, particularly via topical application.
By "topical application" is meant application to the skin (including the scalp), mucous membranes, and/or skin appendages.
"turmeric extract" refers to an extract product obtained from the rhizome of a turmeric plant.
By "extracted product" is meant the product obtained after extraction of the rhizomes of the curcuma species with a solvent called extraction solvent (i.e. a liquid solution in the extraction solvent), optionally in concentrated or dried form after complete or partial evaporation of the extraction solvent. It may be a dry extract.
The term "dried extract" as used herein means an extract containing no extraction solvent or only a trace amount of extraction solvent. Thus, the dry extract contains only material from the rhizome of turmeric. It may also contain trace amounts of extraction solvent.
"curcuminoids"refers to curcumin (curcumine), demethoxycurcumin (dmethoxycurcumin), and bisdemethoxycurcumin (bisdemethoxycurcumin), which correspond to the following chemical formula 1, chemical formula 2, and chemical formula 3, respectively.
[ chemical formula 1]
[ chemical formula 2]
[ chemical formula 3]
Detailed Description
(Curcuma longa)
Curcuma longa (Curcuma longa) or Curcuma longa (Curcuma domestica) or Curcuma aromatica (Curcuma aromatica) belongs to Zingiberaceae (Zingifera). It is a herbaceous plant having rhizomes consisting of yellow and aromatic oval or cylindrical juxtaposed tubers. Alternate leaves have petioles up to 45cm in length. They have a cylindrical inflorescence of 20X 5cm, carried by a short inflorescence stalk at the base of the stem. In asia, the genus Curcuma (Curcuma) is well known. It is used locally in indonesia to treat urinary tract infections and refractory diarrhea. In india, it is used to treat scabies and other skin disorders. This rhizome also has choleretic activity, as it stimulates bile, pancreatic and gastric secretions. In china, japan and korea, the roots and stems of the plant are used to combat various diseases such as amenorrhea, abdominal pain. In eastern africa, rhizome powder is used to relieve headache and treat smallpox. In sang-gabar, women use it as an aphrodisiac, in mauritius, this powder is used as a menstruation stimulating agent for the treatment of menstrual disorders. In karilong, it is used to combat constipation. In morocco, it is used in endemic medicine against liver and blood diseases and even memory loss disorders.
Turmeric is a plant containing large amounts of starch and arabinogalactans (40% to 50%). However, the most active ingredient is curcuminoid (3% to 5%), mainly curcumin, an orange pigment. The roots and stems of this plant species, in addition to having culinary value, also have some medicinal properties related to the content of phellandrene, in particular zingiberene. The plant also contains essential oils (3 to 7%), polyphenolic compounds, minerals, vitamins (3.5%) and water-soluble peptides.
The rhizome of turmeric comprises the following main components:
curcuminoids, which impart a yellow colour and are the main active ingredient, including curcumin, demethoxycurcumin and bisdemethoxycurcumin;
-a quinone;
sesquiterpenes including alpha and gamma alantone, bisabolene, curcumol (bisacumol), bisabolol (bisacuone), caryophyllene, curcumene and curcumenone (curcumenone);
-steroids including cholesterol, campesterol or stigmasterol;
-monoterpenes including cineole, camphene or terpinenes;
-phenylpropanoids including caffeic acid, p-coumaric acid, or 4-hydroxycinnamoyl methane;
-lignans, including iso-curcumenol (iso-procucum é nol) or 4-hydroxy-cinnamoyl- (feruloyl) methane;
-benzenes, including guaiacol;
-carbohydrates including ukonane a;
-an alkaloid;
essential oils, including turmerone, dehydroturmerone, zingiberene, atlantone (atlantone), curcumenol (curcum é nol), borneol, camphor or terpinene.
Curcumin has a number of biological activities such as anti-inflammatory, antioxidant, anti-cancer, anti-viral, anti-microbial activity and liver protective properties. The non-toxic nature of this molecule makes it a potential target for the treatment of skin diseases such as psoriasis, scleroderma and skin cancer. Curcumin inhibits the inflammatory cascade by a variety of mechanisms, such as inhibition of NF-. kappa.B, downregulation of IL-1. beta., IL-6 and TNF-. alpha., and inactivation of the STAT3 pathway. The work of Varma et al (Eur J Pharmacol vol 813,33-41,2017) involved the use of imiquimod to develop an in vitro model of inflammation that mimics psoriasis; curcumin enables pharmacological validation of this model, further enhancing the fact that the anti-inflammatory properties of turmeric are produced by curcumin.
Furthermore, Bleu et al (phytoterrapie 9:7-17,2011) reported in one study the pharmacodynamic effects of hydroalcoholic extracts of turmeric. Dose-dependent hypotensive effects were reported in rabbits, which were accompanied by an increase in respiratory frequency and a decrease in respiratory amplitude. This same extract induced a strong dose-dependent reduction in the rhythmic contractions of the duodenum of the ex vivo rabbits. These negative effects of the hydroalcoholic extracts of turmeric are reminiscent of the well-known effects of calcium antagonists.
The present inventors have surprisingly shown that the turmeric extract of the present invention shows an antagonistic effect on cav1.4 calcium channels, which is associated with an anti-inflammatory effect via immunomodulation of psoriasis and atopic dermatitis.
Extracts of the invention
The turmeric extract of the present invention is an extract derived from the rhizome of a turmeric plant.
Turmeric rhizome may be fresh or dried, may be whole, cut or ground, and then subjected to an extraction step.
The method for preparing the extract of the present invention comprises the step of extracting rhizome of turmeric with an extraction solvent. The extraction may be carried out at ambient temperature (e.g. 15 to 30 ℃, especially 20 to 25 ℃) and/or at atmospheric or elevated pressure (e.g. 10 to 150 bar).
The extraction solvent may be one or a mixture of solvents selected from the group consisting of:
-water, which is water,
alcohols, such as ethanol, methanol, isopropanol,
ketones, including acetone and methyl ethyl ketone,
-an ethyl acetate, to which is added,
-methylene chloride in the presence of a catalyst,
-a mixture of diisopropyl ether and (II) diisopropyl ether,
-hexane, heptane or
-CO2More particularly supercritical CO2。
Preferably, the extraction solvent is supercritical CO2。
The extraction can be carried out using different techniquesIn particular, the so-called "green" techniques, such as those in which the extraction solvent is in a supercritical or subcritical state (e.g. CO) at atmospheric pressure (using ultrasound, microwaves, leaching, maceration, decoction … …) or at elevated pressure (e.g. 10 to 150 bar)2Or water) and/or at a temperature of from 20 ℃ to 250 ℃.
In a preferred embodiment of the present invention, supercritical CO of turmeric rhizome2The extraction enables to obtain turmeric oil, which is purified, in particular, by molecular distillation, to obtain a fraction enriched in turmerone (higher than or equal to 65% by weight with respect to the weight of the dry extract). The process (detailed in example 1) isolates the curcuminoid component, resulting in a significant reduction or even removal of the orange-yellow colour that is hardly suitable for cosmetic development.
In one embodiment of the invention, the extract has a content of curcumin, in particular curcuminoids, of less than 0.1% by weight relative to the weight of the dry extract. Preferably, the extract has a content of curcumin, in particular curcuminoids, of less than 0.08%, more preferably less than 0.06%, in particular less than 0.05%, more in particular less than 0.04%, even more in particular less than 0.03% by weight relative to the weight of dry extract.
Preferably, the turmeric extract of the present invention is obtained from EVONIK under the trade name EVONIKTurmerone, code CAS 84775-52-0.
Treatment and/or prevention of inflammatory skin diseases
Turmeric extract having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract, may be used for the treatment and/or prevention of inflammatory skin diseases.
Preferably, it is psoriasis, atopic dermatitis or acne. More preferably, it is psoriasis or atopic dermatitis. Further advantageously, it is psoriasis.
Advantageously, the extract is used in a form suitable for application via the topical route.
Dermatological or cosmetic composition
Another subject of the invention relates to a dermatological or cosmetic composition comprising, as active ingredient, at least one turmeric extract as defined above, having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract, and at least one dermatologically or cosmetically acceptable excipient, for the use in the treatment and/or prevention of inflammatory dermatological disorders.
Another subject of the present invention relates to the use of a dermatological or cosmetic composition comprising, as active ingredient, at least one turmeric extract as defined above, having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract, and at least one dermatologically or cosmetically acceptable excipient, for the treatment and/or prevention of inflammatory dermatological disorders.
Another subject of the invention relates to the use of a dermatological or cosmetic composition comprising, as active ingredient, at least one turmeric extract as defined above, having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract, and at least one dermatologically or cosmetically acceptable excipient, for the preparation of a pharmaceutical product intended for the treatment and/or the prevention of inflammatory dermatological disorders.
Another subject of the present invention relates to a method for the treatment and/or prevention of inflammatory skin diseases, comprising the application, to a human in need thereof, of a dermatological or cosmetic composition comprising, as active ingredient, at least one turmeric extract as defined above, having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract, and at least one dermatologically or cosmetically acceptable excipient.
In a particular embodiment, the composition of the invention is used for the treatment and/or prevention of an inflammatory skin disease selected from psoriasis, atopic dermatitis or acne.
Preferably, the composition of the invention is for use in the treatment and/or prevention of psoriasis or atopic dermatitis.
More preferably, the composition of the invention is for use in the treatment and/or prevention of psoriasis.
In a particular embodiment, the dermatological or cosmetic composition of the invention comprises from 0.01 to 1%, preferably from 0.05 to 0.5%, more preferably from 0.08 to 0.2% by weight of the dry extract of turmeric of the invention, relative to the total weight of the composition.
Advantageously, the dermatological or cosmetic composition of the invention comprises 0.1% by weight of the dry extract of turmeric of the invention, relative to the total weight of the composition.
The compositions may be produced by methods well known to the skilled person.
The compositions of the invention are advantageously intended for topical application, in particular by application to the skin.
Thus, the composition of the invention may be in a form generally known for topical application, i.e. in particular a lotion, foam, gel, dispersion, emulsion, spray, essence, ointment, mask or cream.
Advantageously, it is a cream or ointment.
The invention therefore relates to dermatological or cosmetic compositions according to one of the embodiments of the invention, characterized in that they are in a suitable form for topical application.
These compositions generally comprise, in addition to the turmeric extract, a physiologically acceptable medium, generally a water-based or solvent-based medium, such as an alcohol, ether or glycol, said turmeric extract having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of the dry extract according to the present invention. They may also contain surfactants, complexing agents, preservatives, stabilizers, emulsifiers, thickeners, gelling agents, humectants, emollients, trace elements, essential oils, fragrances, colorants, delusterants, chemical or mineral filters, humectants, spa water, and the like.
The following examples illustrate but do not limit the scope of the invention.
Examples
Example 1: characterization of turmeric extract of the invention
The turmeric extract of the present invention was prepared according to the method described in US patent No. US 8420137. Briefly, turmeric rhizome is subjected to CO2Supercritical extraction, followed by separation of the curcuminoid-containing solid obtained by precipitation from the previously obtained extraction mixture, removal of the solvent contained in the extraction mixture obtained in the first two steps to obtain a concentrate, and finally distillation of the concentrate at a pressure lower than 1 bar to obtain a distillate of the extract.
The turmeric extract thus prepared contains at least 65% turmerone.
The turmeric extract of the present invention was analyzed by reverse phase High Performance Liquid Chromatography (HPLC) to determine the curcuminoid content. Quantification was performed by UV detection at a wavelength of 425 nm. The curcuminoid content of the extract was estimated to be below 0.03%, which corresponds to the limit of quantitation under these conditions.
Example 2: evaluation of turmeric extract of the present invention in Th17 lymphocyte model
It is now well known that the adaptive immune response plays a key role in the development of psoriatic lesions and that new therapies directed against IL-12, IL-23 or IL-17 show greater clinical efficacy in patients with moderate to severe plaque-like psoriasis. However, these systemic treatments still have limitations, and topical treatments always offer considerable advantages: fully limited treatment can protect healthy lesion-surrounding skin, better skin hydration and scratch prevention, better patient acceptability and better tolerability. In addition, topical treatment forms the basis of management of mild psoriasis, i.e. the condition is limited to patients with less than 10% of the body surface area.
The aim of this study was to evaluate the potential effect of the turmeric extract of the present invention on modulating the production of cytokines associated with conditions such as psoriasis, atopic dermatitis or acne. To this end, Th17 lymphocytes isolated and expanded from donor circulating blood were used as an in vitro immune pathogenesis model for psoriasis.
The scheme is as follows:
the turmeric extracts tested were prepared according to example 1 and dissolved in DMSO (dimethyl sulfoxide) at concentrations of 11, 33.3, and 100 μ g/ml. Curcumin was also evaluated in this model at the same three concentrations.
From the French national blood service EtablessmentT lymphocytes were sorted from blood cells recovered in blood bags provided by du Sang to obtain the following phenotypes: CD4+, CD45RA, CXCR3-CCR6 +. The number of Th17 lymphocytes obtained was increased by culturing these cells in the presence of a cytokine cocktail (IL-2, anti-TNF α and anti-INF γ) for two weeks.
The test was performed on human Th17 lymphocytes isolated and expanded in the absence (control condition) or presence (treated) of the test compound, and optionally stimulated by anti-CD 3/anti-CD 28 stimulating factors. The levels of pro-inflammatory cytokines (IL-17 and IL-22) of Th17 were quantified 24 hours after stimulation. Lymphocytes were treated with test compounds 30 minutes prior to stimulation and continued for 24 hours.
In the context of this study, the inventors sought to evaluate the ability of the turmeric extract of the present invention to inhibit cytokine secretion from Th17 lymphocytes via inhibition of the cav1.4 signaling pathway. For this purpose, the non-selective calcium channel blocker nicardipine (10. mu.g/ml), which is also dissolved in DMSO and used as a positive control, was tested.
Each experimental condition was performed in triplicate and repeated using blood from different donors.
The pro-inflammatory cytokines IL-17 and IL-22 of Th17 lymphocytes were measured using an ELISA kit according to the supplier's instructions.
Orthonormality and isovariance were verified using ANOVA (ANalysis Of Variance), followed by statistical ANalysis to determine percent inhibition, followed by Dunnett's test as a post test.
As a result:
table 1 below gives the IL-17 release (pg/ml) after treatment of Th17 lymphocytes with anti-CD 3/anti-CD 28 beads. These are coated beads to which the cited antibodies are attached to stimulate lymphocytes.
[ Table 1]
Exposure of Th17 lymphocytes to anti-CD 3/anti-CD 28 beads induced a clear and statistically significant increase in IL-17 release (table 1). Nicardipine (10. mu.g/ml) reduced this IL-17 production by 43%. This result demonstrates the good reactivity of the isolated and expanded Th17 lymphocyte model, which enables validation of the test.
Treatment of Th17 lymphocytes with curcumin showed severe inhibition of IL-17 release. At three tested concentrations (11, 33.3 and 100 μ g/ml), curcumin statistically inhibited the release of IL-17 (77%, 80% and 78% inhibition, respectively).
Treatment of Th17 lymphocytes with the turmeric extract of the present invention unexpectedly showed inhibition of IL-17 release. At a concentration of 100 μ g/ml, the turmeric extract of the present invention significantly reduced IL-17 production by 65%. At lower concentrations, the inhibitory effect did not reach statistical significance (NS ═ insignificant).
Table 2 below gives the release of IL-12 (pg/ml) after treatment of Th17 lymphocytes with anti-CD 3/anti-CD 28 beads.
[ Table 2]
Exposure of Th17 lymphocytes to anti-CD 3/anti-CD 28 beads induced a clear and statistically significant increase in IL-22 release (table 2). Nicardipine reduced IL-22 production, but inhibition did not reach the statistically significant threshold. Since nicardipine is a blocker of cav1.4 channel and does not significantly reduce IL-22 production, this release of IL-22 by stimulation of Th17 lymphocytes is likely independent of the type 1.4 calcium channel pathway.
Treatment of Th17 lymphocytes with the turmeric extract of the present invention was also shown to inhibit IL-22 release. At a concentration of 100 μ g/ml, the turmeric extract of the present invention significantly reduced IL-17 production by 68%. At lower concentrations, the inhibition did not reach statistical significance, although there appeared to be a concentration-dependent effect (40% inhibition at 11. mu.g/ml, 48% inhibition at 33.3. mu.g/ml, 68% inhibition at 100. mu.g/ml).
Thus, the inventors have shown that stimulated Th17 lymphocytes induce a large release of IL-17 and IL-22. In this model, the inventors show that the turmeric extract of the present invention is most effective in limiting the release of inflammatory interleukins (key markers in psoriasis and acne), demonstrating a protective effect in these conditions. Therefore, the turmeric extract of the present invention has anti-inflammatory activity and thus has a sedative effect.
Example 3: evaluation of turmeric extract of the present invention on Cav1.4 target
There is a number of arguments that suggest the clinical advantage of cav1.4 channel antagonists in the treatment of psoriasis. Studies have shown that by suppressing Cav1.4, the immune response will be greatly reduced (Omilusik et al, Immunity,35: 349-.
Mouse and human Th17 express cav1.4 calcium channels, and pharmacological inhibitors of these channels reduce the production of Th17 cytokines. Thus, at least partial blockade of the Cav1.4 channel by modulation of the Th17 pathway would be beneficial for conditions such as psoriasis, atopic dermatitis or acne.
Topical application of cav1.4 channel antagonist (nicardipine) in a psoriasis mouse model, a model induced via topical application of imiquimod, significantly reduced skin disorders.
The L-type ion current is a long-charge calcium current. It slowly deactivates itself. It involves the generation of action potentials and synaptic transmission in dendrites. The channel proteins involved are 4: cav1.1 (skeletal muscle), cav1.2 (cardiac muscle, smooth muscle), cav1.3 (neuron, endocrine cell), cav1.4 (first found in retina).
The aim of this study was to evaluate the potential antagonistic activity of the turmeric extract of the present invention on human cav1.4 channels stably expressed in HEK293 cells by direct measurement of free calcium.
Turmeric extracts were prepared as in example 1 and tested at 7 concentrations of 0.3 to 300 μ g/ml. Curcumin was also evaluated at 7 concentrations (0.1 to 100 μ g/ml). Control compounds were evaluated in this study: the Cav1 channel (Cav1.1, Cav1.2, Cav1.3, and Cav1.4) non-specific activator FPL 64176(CAS number 120934-96-5) was tested at 3nM to 50 μ M; the cav1.4 specific blocker nifedipine was tested at 1nM to 0.1 mM; the Cav1.4 non-specific blocker nicardipine was tested at 0.1nM to 10. mu.M. All these products were dissolved in DMSO.
Studies were performed in a stable HEK293 cell line expressing the human cav1.4 channel.
The scheme is as follows:
cells were trypsinized, i.e., the culture medium was removed, cells were detached with trypsin solution, then counted, seeded at a density of 50000 cells per well in a volume of 100 μ l in a 96-well black/clear bottom plate, and incubated overnight. The culture medium was removed, the cells were washed twice with Phosphate Buffered Saline (PBS), and 70. mu.l of the compound to be assayed for antagonist activity dissolved in assay buffer (20mM HEPES-HBSS pH 7.4) was added. Cells were loaded with calcium fluorescent marker 5. The dye was concentrated 10-fold in water and diluted 1:10 in buffer. The dye solution was added to the wells and incubated at ambient temperature for 1 hour. For antagonist assays, test compounds are added to the wells and incubated at ambient temperature for 10 minutes. The plate was placed in a fluorescence imaging plate reader (FLIPR) and fluorescence was recorded at excitation/emission wavelengths 488nm/510-570 nm. After 20 seconds, agonist (FPL 64176) (80. mu.l, dissolved in assay buffer-20 mM HEPES-HBSS pH 7.4) was added and fluorescence was recorded at the same wavelength. For agonist assays, the protocol was similar except that no antagonist was added.
For all these assays, 3 different measurements were performed within 3 separate days.
In the first series of experiments, compounds were evaluated as agonists (CE)50Measurement of (2). In a second series of experiments, compounds were evaluated as antagonists against a reference agonist (FLP 64176) to enable determination of their CI50The value is obtained. To determine CE50And CI50Two strategies are used.
For each series, the CE was determined by adjusting the concentration-response curves to data using GraphPad Prism software50And CI503 values (one for each experiment). The 3 values are then averaged. Thus obtaining an average CE50And CI50The value is obtained.
Raw data were normalized by defining the highest RFU value (relative fluorescence units) as 100%. Normalized RFU means were calculated for each concentration of test compound to plot a curve with the normalized summary data from 3 experiments. CE for each compound was determined by adjusting the concentration-response curve using GraphPad Prism software50And CI50A single value of (a). CE50And CI50The values are referred to as summarized values.
Average summary values of the same order of magnitude are considered robust and reliable.
As a result:
CE50the determination of the values is summarized in table 3 below.
[ Table 3]
Exp: performing an experiment; moy: averaging; N/A: not analyzed.
Average CE50Values are expressed as values ± SEM (standard error of mean).
FLP64176 is robust, so the study was fully validated because the calculated mean and normalized aggregate values (CE)501.5 μ M) were strictly identical.
Curcumin showed agonist effects on cav1.4, CE50The value was 17.8. + -. 5.3. mu.g/ml. Due to the CE50Values are at the top of the concentration range studied, and therefore curcumin cannot be studied as an antagonist of cav 1.4.
The turmeric extract of the present invention does not exhibit any agonist activity at the tested concentrations on the human cav1.4 channel because concentration-response curves cannot be plotted.
CI50The determination of the values is summarized in table 4 below.
[ Table 4]
Exp: performing an experiment; moy: average
CI for the Cav1.4-specific reference antagonist nifedipine50The value determination was robust and the test was validated because the calculated mean value and the normalized sum value (CI) were501.3 μ M) were strictly identical. The non-specific reference antagonist nicardipine showed activity on cav1.4, calculated CI50The value was 256. + -.48 nM.
The turmeric extracts of the present invention show reproducible concentration-response curves between experiments, enabling the same order of magnitude of calculated CI as normalized summary data50The value is obtained. Thus, the turmeric extract of the present invention has antagonist activity against cav1.4, calculated CI50The value was 17.4. + -. 2.5. mu.g/ml.
And (4) conclusion:
the turmeric extract of the present invention is effective in blocking Cav1.4 calcium channels (low CI)50Value), which means that it is a disease state associated with Th17 activity (such as psoriasis, a disease state associated with the activity of Th17, a disease associated with the activity of Th17, a cell growth factor for example, a cell growth factor for the cell, a cell growth hormone receptor, a cell growth factor for the cell growth factor and a cell growth factor for the like a cell,Atopic dermatitis or acne).
Claims (9)
1. Turmeric (Curcuma longa) extract having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract, capable of passing supercritical CO, for use in the treatment and/or prevention of an inflammatory skin disease selected from psoriasis, atopic dermatitis and acne2And (4) extracting.
2. Turmeric extract for use according to claim 1, characterised in that the extract is derived from the rhizome of turmeric.
3. Turmeric extract for use according to any one of claims 1 and 2, characterized in that the extract comprises less than 0.05% by weight of curcumin, in particular less than 0.05% by weight of curcuminoids, relative to the total weight of the dry extract.
4. Turmeric extract for use according to any one of claims 1 to 3, characterized in that the extract is in a form suitable for application via the topical route.
5. Dermatological or cosmetic composition comprising at least one turmeric extract having less than 0.1% by weight of curcumin, in particular less than 0.1% by weight of curcuminoids, relative to the weight of dry extract, capable of passing supercritical CO, and at least one dermatologically or cosmetically acceptable excipient, for use in the treatment and/or prevention of an inflammatory skin disease selected from psoriasis, atopic dermatitis and acne2And (4) extracting.
6. The dermatological or cosmetic composition for use according to claim 5, characterized in that the turmeric extract is an extract of turmeric rhizomes.
7. The dermatological or cosmetic composition for use according to any one of claims 5 and 6, characterized in that the turmeric extract comprises less than 0.05% by weight of curcumin, in particular less than 0.05% by weight of curcuminoids, relative to the total weight of dry extract.
8. The dermatological or cosmetic composition for use according to any one of claims 5 to 7, characterized in that it comprises from 0.01 to 1%, preferably from 0.05 to 0.5%, more preferably from 0.08 to 0.2% of turmeric extract by weight of dry extract relative to the total weight of the composition.
9. The dermatological or cosmetic composition for use according to any one of claims 5 to 8, characterized in that it is suitable for application via the topical route.
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PCT/FR2020/052528 WO2021123660A1 (en) | 2019-12-18 | 2020-12-18 | Curcuminoid-free extract of curcuma longa in inflammatory dermatoses |
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张洪英: ""姜黄油对角朊细胞体外增殖分化的影响的研究"" * |
李晋杰等: ""天然调味香料姜黄挥发油的研究进展"" * |
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