Cosmetic uses of hyacinthus extracts

Abstract

The invention relates to a cosmetic use of an aqueous extract of Hyacinthus orientalis bulb as a skin neurosensorial agent, e.g. for improving skin perception, for rebalancing or improving the neurosensorial responsiveness of the skin to stimuli. The Invention also relates to a cosmetic composition comprising an aqueous extract from Hyacinthus bulbs, preferably from dormant Hyacinthus orientalis bulbs as an active cosmetic ingredient and at least one cosmetically acceptable excipient. The Invention also relates to a cosmetic ingredient comprising an aqueous extract from Hyacinthus bulbs in an appropriate carrier, to be incorporated in a cosmetic composition or product.

Description

[0001] COSMETIC USES OF HYACINTHUS EXTRACTS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the cosmetic field, in particular to cosmetic agents acting as skin neurosensorial agents, e.g. able to improve skin perception, decrease nociception and / or improve the skin wellness so that the skin appearance is more youthful, relaxed and radiant.

[0004] BACKGROUND OF THE INVENTION

[0005] The skin is a complex organ with a dense innervation that plays a crucial role in sensory perception and communication with the nervous system. The sensory nerve endings in the skin respond to various stimuli such as heat, cold, and touch. Certain fibers can even be activated by a variety of chemical substances including substances secreted by microorganisms e.g. present in the skin microbiome. Connections between the nerves and the skin are provided at the cellular level via neurotransmitters such as substance P, or calcitonin gene-related polypeptide (CGRP). These signaling molecules are released by the nerve endings but also by the skin or the immune cells in the skin. This communication between the skin cells and the sensory neurons influences numerous biological processes including healing, inflammation, immune response and the like, and is involved in the regulation the well-being and the homeostasis of the skin.

[0006] However, the sensory nerve endings located in the skin are highly exposed to environmental challenges and stress factors such as meteorological conditions, chemicals, pollution, certain lifestyle habits and the like. Such overexposure can alter the skin’s sensitivity and responsiveness to environmental insult and tactile stimuli. Similarly, certain physiological changes (e.g. ageing, menopause) can also have an impact on skin perception e.g. by impairing peripheral sensory function, or reducing the number of stimuli receptors in the skin. The alteration of skin detection and perception of external stimuli can result in impaired communication within the skinperipheral sensory system and thus inappropriate biological responses to stimuli e.g. an inappropriate immune response in the skin. The homeostasis of the skin can be altered, resulting in skin sensitivity and discomfort, and, eventually, changes in the skin’s visual appearance.

[0007] Thus, there is a need for cosmetic neurosensorial agents able to alleviate or prevent non- pathological skin perception alterations. SUMMARY OF THE INVENTION

[0008] The instant application relates to the cosmetic use of an aqueous extract of Hyacinthus bulb, preferably Hyacinthus orientalis as a skin neurosensorial agent. Preferably, the extract is obtained from dormant bulbs of Hyacinthus orientalis.

[0009] In some embodiments, the extract may be obtained by a process comprising the steps of:

[0010] (a) incubating peeled and crushed bulbs in water so as to obtain a slurry,

[0011] (b) recovering an aqueous phase from the slurry obtained in step (a)

[0012] (c) heating the aqueous phase obtained in step (b) at a temperature above 95 °C and then cooling so as to promote precipitation,

[0013] (d) recovering the aqueous phase from step (c), and

[0014] (e) optionally filtering and / or concentrating the aqueous phase obtained in step (d) whereby the aqueous extract is obtained.

[0015] By acting as a neurosensorial agent, the an aqueous extract of Hyacinthus bulb can be used for improving skin perception, and / or for rebalancing or improving the neurosensorial responsiveness of the skin to stimuli and / or for decreasing or preventing skin nociception.

[0016] In a particular embodiment, the Hyacinthus orientalis bulb extract is used for preventing or alleviating age-related impairment of skin perception, in particular skin sensitivity.

[0017] In an additional aspect, the Hyacinthus orientalis bulb extract acts as an agonist of OXT receptor, in particular those present on sensory nerve endings in the epidermidis.

[0018] The extract of the Invention may be further used for improving the visual appearance of the skin, in particular for attenuating, decreasing or treating one or more non-pathological alterations of the skin appearance such as roughness, redness, loss of radiance or glow, dull or non-uniform complexation, tired aspect and combination thereof. The extract of the invention may be also used for attenuating skin discomfort and / or skin sensitivity and / or for providing a comforting effect to the skin.

[0019] The extract of the Invention can be also used to attenuate the wrinkled aspect of the skin and / or to increase skin elasticity, in particular in a subject having a mature skin.

[0020] The extract of the invention may be also used for enhancing the skin’s receptivity to pleasant and / or gentle tactile stimuli when applied on the skin of a subject.

[0021] In a particular aspect, the present invention relates to the topical use of Hyacinthus orientalis bulb extract as a cosmetic agent for improving skin perception and / or for decreasing or preventing skin nociception and / or for alleviating skin discomfort. In some embodiments, the extract is topically applied on the skin of an intimate body area. Accordingly, the extract is used topically on the skin of an intimate body area to alleviate discomfort and / or to increase receptiveness (e.g. to affective touch or pleasant sensations) and / or increase wellbeing in the skin of the intimate body area.

[0022] In some embodiments, the extract is topically applied on hair scalp. Thus, the extract may be used to alleviate hair scalp discomfort.

[0023] The extract is topically applied on the skin, preferably on sensitive skin, and / or mature skin. The extract may be applied on the skin in the form of a cosmetic composition.

[0024] The cosmetic composition may be of any type. The cosmetic composition can be a skin care product, a skin hygiene product, a hair care product, an intimate care product or a make-up product such as a cream e.g. a night or a daily cream or a massage cream, a balm, an ointment, a serum, a gel, a mask, a foundation, a soap, a shower gel, a shampoo, a hair conditioner, or an aftershave.

[0025] In a further aspect, the application relates to a cosmetic composition for improving skin perception or for providing wellness in a subject comprising an aqueous extract from Hyacinthus bulbs, preferably from dormant Hyacinthus orientalis bulbs as an active cosmetic ingredient and at least one cosmetically acceptable excipient.

[0026] In a certain aspect, the application relates to a cosmetic method for improving skin perception, and / or for increasing skin receptiveness in particular to pleasant stimuli, and / or for decreasing skin discomfort, and / or for improving the visual aspect of the skin and / or for providing wellness in a subject, comprising topically applying an aqueous extract obtained from Hyacinthus bulbs preferably as defined herein, or a cosmetic composition as defined herein on the skin of the subject.

[0027] In some embodiments, the subject has mature skin and / or sensitive skin and / or the subject is a peri-menopausal or menopausal woman.

[0028] In a particular aspect, the application relates to a cosmetic ingredient comprising an aqueous extract from Hyacinthus bulbs, preferably from dormant Hyacinthus orientalis bulbs, as active cosmetic agent in a cosmetically acceptable carrier, preferably in a glycerin / water mixture.

[0029] The cosmetic ingredient may further comprise one or more cosmetically acceptable excipients selected from antioxidants, preservatives, and pH adjusting agents.

[0030] In a further aspect, the application relates to the use of an aqueous extract of Hyacinthus orientalis bulb as a skin neurosensorial agent for the manufacture of a composition for improving skin perception and / or for decreasing or preventing skin nociception and / or for alleviating skin discomfort. The composition may be a skin care product, an intimate care product or a hair care product.

[0031] FIGURES

[0032] Figure 1 shows that the extract of the Invention (right) effectively activates the OXTR receptor in a chimeric CHO model, reaching over 70% receptor activation at 0.2% Extract. Left: oxytocin positive control activation response curve.

[0033] Figure 2 shows the effect of the extract of the Invention at 0.1% (Hyacinth, o at 0.1%) on nociception signaling upon capsaicin stimulation, measured via quantification of CGRP release, in a neuron-keratinocyte coculture. The anti -nociceptive effect of the extract at 0.1% completely negated the signaling increase caused by capsaicin stimulation, reaching levels slightly lower than those observed with the two control legs: Oxytocin, and capsazepine 10 pM.

[0034] Figure 3A shows that the extract of the Invention at 0.1% (Hyacinth, o. at 0.1%) improves neuron survival in a neuron-keratinocyte coculture, while capsaicin reduces neuron survival, both as compared to the untreated control group.

[0035] Figure 3B shows that the extract of the Invention at 0.1% (Hyacinth, at 0.1%) improves neuron dendricity (shown here on a per-neuron basis) in a neuron-keratinocyte coculture, significantly compared to the untreated control group.

[0036] Figure 4 shows the effect of treatment with Hyacinthus orientalis bulb extract on electrical signaling in a neuron-keratinocyte multicompartment organ-on-a-chip coculture. HO = Hyacinthus orientalis bulb extract.

[0037] Figure 5A shows that the Ingredient of the Invention at 1% in formulation (Active) increases the EEG signal measured in the left frontal regions during a gentle feather touch stimulation, an effect associated with a pleasant or pleasurable sensation. This effect is noticeable when comparing the initial state (DO) with any of the subsequent time points shown: DO after product use, D7, and D28. In contrast, the placebo control group shows no appreciable change. Figure 5B shows the average alpha- wave activation at electrode AF3 (left frontal) at Day 0 (DO), (DO + 30 min after application), D7 and D28. Figure 5B confirms that the Ingredient of the Invention at 1% in formulation (Hyacinthus orientalis bulb extract) enhances skin touch sensorial receptivity 30 min after application and that this effect is present at D7 and D28 as compared to placebo cream.

[0038] Figure 6 shows that the Ingredient of the Invention at 1% in formulation decreases nociception in a clinical setting, as evaluated via a capsaicin stinging test, after 28 days of use, in a manner significantly more effective than recorded for the Placebo control group.

[0039] Figure 7 shows that the Ingredient of the Invention at 1% in formulation enhances the skin’s visible healthy glow, as evaluated by clinician grading (Left) and panelist self-assessment (Right), in a significantly stronger manner than observed in the Placebo control group, after 28 days of product use. In each case, D28 results are shown immediately before (‘D28’, center pair of bars) and immediately after product application (‘D28Timm’, right-hand pair of bars).

[0040] Figure 8 shows that the Ingredient of the Invention at 1% in formulation enhances the skin tone after 28 days’ treatment, in a manner significantly better than that observed in the Placebo control group, as observed via chromametry as a significant increase in luminance (L*) and a significant decrease in redness (a*).

[0041] Figure 9 shows that the Ingredient of the Invention at 1% in formulation enhances skin elasticity after 28 days’ treatment, in a manner significantly better than that observed in the Placebo control group.

[0042] Figure 10 shows that the Ingredient of the Invention at 1% in formulation reduces skin wrinkling, as evaluated by image analysis (Left) and clinician grading (Right), in a significantly stronger manner than observed in the Placebo control group, after 28 days of product use. In the clinician scoring case, D28 results are shown immediately before (‘D28’, center pair of bars) and immediately after product application (‘D28Timm’, right-hand pair of bars).

[0043] Figure 11 shows self-evaluation scoring of skin comfort and pleasantness immediately after application at Day 0 (DO) and at day 28 (D28). The skin application of the cream of the invention (Hyacinthus orientalis bulb extract) significantly improves skin comfort / pleasantness as compared to the placebo cream. The percentages of change were expressed as compared to DO scoring prior to application of the creams.

[0044] DETAILED DESCRIPTION OF THE INVENTION

[0045] Oxytocin (OT) is a nonapeptide that is released mainly into the central nervous system by the hypothalamic paraventricular and supraoptic nuclei.

[0046] This peptide is involved in different physiological functions such as: cardiovascular activity; breathing; feeding; social interactions. More recently, oxytocin was shown to be involved in nociception signaling as well.

[0047] Oxytocin acts through its receptor which is a seven-membrane spanning receptor that is coupled via various G-proteins isoforms to different signaling pathway.

[0048] Recent studies focus on the peripheral action of oxytocin in the skin. It was shown that oxytocin receptor (OXTR) is expressed on skin fibroblasts while oxytocin and its carrier protein neurophysin I are synthesized by keratinocytes.

[0049] Cho et al. (British Journal of Dermatology, 2019, 181, p 1216-1225) showed that oxytocin, though its binding to its receptor on fibroblasts, suppresses SASP (senescence-associated secretory phenotype)-induced senescence in normal human dermal fibroblasts (NHDFs), and that its effect depends on the age of the donor’s NHDFs. Cho et al. concluded that OT and OXTR agonists could be promising agents for the improvement of age-associated skin ageing. Additionally, Hayre (Journal of drugs in Dermatology, 2020, 19, 1146-1147) evidenced a correlation between the OT levels and the skin age score (SAS). High OT levels were correlated with more youthful skin and significantly lower SAS scores than expected. Hayre concluded that OT may provide a protective mechanism against photo aging, intrinsic aging, or both.

[0050] Grinevitch et al. (2017, www.painjournalonline.com) and Gonzalez-Hernandez et. Al (2017, www.painjournalonline.com) explain that oxytocin is secreted by keratinocytes while OXTR is expressed on nociceptive fibers in the skin, whereby peripheral oxytocin (e.g. released by keratinocytes) can inhibit the excitation of nociceptive fibers in the skin. In particular Gonzalez- Hernandez et al. showed that subcutaneous injection of OXT induced antinociception in an animal model, suggesting a new potential role for peripheral OT in pain modulation.

[0051] Furthermore, in the context of nervous system and nerve-skin interface, the literature suggests pleiotropic actions of OT, including in neurogenesis and neurite growth.

[0052] Taking into account the emerging evidence of OT involvement in skin homeostasis and perception, the Inventors hypothesized that compounds able to mimic the action of OT could act as cosmetic neurosensorial agents.

[0053] Surprisingly, the Inventors identified that an aqueous Hyacinthus bulb extract, namely an aqueous extract obtained from dormant Hyacinthus orientalis bulbs, was able to activate OXTR in vitro (Figure 1). Moreover, the Inventors showed that the aqueous Hyacinthus bulb extract was able to inhibit the nociception signaling upon capsaicin stimulation (via CGRP release quantification) in a neuron-keratinocyte coculture (Figure 2). Of note, the extract of the Invention at a concentration of 0.1% was more effective to decrease CGRP release induced by capsaicin challenge than Oxytocin at 10 pM. The Inventors further showed that the extract of the Invention was at least as effective as OT at 10 pM in improving neuron survival and dendricity upon capsaicin challenge. The Inventors further showed that the extract of the Invention was able to induce NHDF’s proliferation in vitro in a dose-dependent manner (Figures 3 A and 3B).

[0054] The Inventors conducted a placebo-controlled clinical study to confirm the in vitro results. This study indicated that a cream containing 1% of the ingredient of the Invention based on Hyacinthus orientalis bulb extract enhanced the skin’s pleasurable sensitivity to gentle skin touch, as evaluated via EEG readings taken while the skin was stimulated with a feather (Figures 5A and 5B). The cream of the Invention was also shown to reduce skin nociception, as modeled via a capsaicin stinging test. Self-evaluation with scale grading clearly shows a significant increase in skin pleasantness and comfort with the cream containing 1% of the ingredient of the Invention as compared to the placebo cream, illustrating an improvement in skin sensoriality and wellbeing.

[0055] Additionally, 28 days’ treatment with the cream of the Invention resulted in significant improvements in the skin’s appearance, as materialized in strong improvements in evaluation of the skin’s visible healthy glow by both study participants and trained clinicians; a significant reduction in skin redness and a lightening of the skin tone, both measured by Hunter L,a,b chromametry; a reduction in skin wrinkling, evaluated at the comer of the eye (crow’s feet area) both instrumentally (by PRIMOS image analysis) and through grading by trained clinicians; and, an improvement in skin elasticity, as measured by cutometer. Finally, panelist selfevaluation showed strong improvements in grades for perception parameters including: skin visible health, skin overall beauty, healthy glow, rosy / happy glow (Figures 5-10). In summary, this clinical trial demonstrates that the extract of the Invention acts as an effective sensorial agent. In particular, the extract of the Invention was shown to rebalance the neurosensorial responsiveness of the skin to external stimuli, alleviating skin discomfort and favoring pleasant touch stimuli.

[0056] The extract of the Invention was also shown to improve the youthful and healthy appearance of the skin, providing skin rejuvenation.

[0057] The extract of the invention was also shown to enhance positive skin touch sensations resulting in skin wellness and global wellbeing in the subject.

[0058] In summary, by activating the OXTR signaling cascade, the extract of the Invention acts as a safe agent to improve skin well-being. Among other applications, the extract of the Invention can be used as a cosmetic sensorial agent to improve skin perception (decrease in nociception and increase in receptiveness to pleasant stimuli), to alleviate skin discomfort and to promote the youthful appearance of the skin.

[0059] - The extract of the Invention and method of manufacture

[0060] In a first aspect, the invention relates to a Hyacinthus extract, in particular to an aqueous extract from Hyacinthus bulbs.

[0061] As used herein, the term “Hyacinthus” refers to any species belonging to the Hyacinthus plant genus. Hyacinthus plants are hardy, perennial, bulbous herbs also called hyacinths and known for their brightly colored and strongly fragrant flowers. These plants generally produce flowers in mid-spring for 2-3 weeks.

[0062] The three main species in Hyacinthus genus are Hyacinthus orientalis, Hyacinthus litwinovii and Hyacinthus transcaspicus. Hyacinthus orientalis (also known as common hyacinth, garden hyacinth or Dutch hyacinth) is the most common one. Hyacinthus orientalis is native to Southwestern Asia, Turkey, Syria, Lebanon and northern Israel and was introduced to Europe in the 16thcentury. Hyacinthus orientalis is widely cultivated in temperate regions. As of today, there are thousands of cultivars of Hyacinthus orientalis.

[0063] As used herein, the term “Hyacinthus orientalis ” includes any cultivar or variety belonging to “Hyacinthus orientalis” species. For instance, the extract may be prepared from Hyacinthus orientalis “White Pearl” cultivar.

[0064] In a preferred embodiment, the extract of the invention is obtained from Hyacinthus orientalis bulbs, preferably from dormant bulbs of Hyacinthus orientalis, preferably from fresh dormant bulbs ofH. orientalis.

[0065] For instance, the extract of the invention is obtained from dormant bulbs of Hyacinthus orientalis “White Pearl” cultivar.

[0066] As used herein, “dormancy” is a physiological state in which there is a marked decrease in the metabolic rate of cells or tissues and wherein the growth of a meristemic tissue is reversibly slowed or ceased. The dormancy can be obtained by providing particular environmental and / or physical conditions to the bulb.

[0067] As used herein, the term “aqueous extract” refers to an extract obtained by subjecting a plant material (e.g. Hyacinthus bulbs and any fractions thereof) to a water treatment enabling the extraction of compounds of interest from the plant material. Typically, the plant material is incubated in water. The incubation can be performed at room temperature or under heating. Ultrasonic treatment and / or stirring can be also applied. The incubation (which can be also called maceration) can last from several minutes to several hours. The plant material (herein the Hyacinthus bulb, preferably the Hyacinthus orientalis bulb) can be peeled, cut into pieces which can be of different sizes and shapes depending on the method used. For instance, the plant material can be cut, chopped, crushed, milled, cryo-milled and the like, and then put in water. As an alternative, the peeled bulb can be blended or crushed in water so as to form a slurry.

[0068] The weight ratio of water to the plant material is generally from 0.5 to 10 such as from 1 to 5. The plant material can be subjected to several steps of extraction with water at the same or at different temperatures. After the incubation, the plant material and the aqueous phase containing the compounds of interest are separated. This separation may be performed by any method known in the art, such as pressing, decantation, filtration, or centrifugation. A preferred method is centrifugation.

[0069] The recovered aqueous phase can be subjected to one or several additional steps such as filtration, ultrafiltration, or heat treatment followed by cooling e.g. so as to remove proteins and other unwanted materials.

[0070] In some embodiments, the Invention relates to a method for obtaining an aqueous extract of Hyacinthus bulbs, preferably Hyacinthus orientalis bulbs, comprising the steps of:

[0071] (a) incubating peeled and crushed bulbs in water so as to obtain a slurry,

[0072] (b) recovering an aqueous phase from the slurry obtained in step (a)

[0073] (c) heating the aqueous phase obtained in step (b) at a temperature above 95 °C and then cooling so as to promote precipitation,

[0074] (d) recovering the aqueous phase from step (c), and

[0075] (e) optionally filtering the aqueous phase obtained in step (d) whereby the aqueous extract is obtained.

[0076] The bulbs can be subjected to one or several treatments before step (a) such as washing, peeling, drying, grinding, cryo-grinding or cryo-milling, freezing, freeze-drying, thawing and combinations thereof.

[0077] In some embodiments, the aqueous extract of the invention is prepared from fresh, peeled bulbs. The bulbs can be crushed or milled by any appropriate way prior to, or during, step (a). For instance, the peeled bulbs can be directly crushed in water with a blender so as to obtain a slurry. The weight ratio of water to plant material is generally from 0.5 to 10. Once obtained, the slurry is allowed to stand, for instance from 5 to 120 min, e.g. from 10 to 60 min, preferably at room temperature to enable the extraction of compounds of interest from the crushed plant material. Ultrasonic treatment and / or stirring can be applied to promote the extraction.

[0078] In step (b), the slurry is separated into two phases, namely (i) the aqueous phase (containing the compounds of interest) and (ii) the solid particles initially present in the slurry. The separation can be performed by any methods known by the skilled artisan such as centrifugation.

[0079] Step (c) aims at removing at least a part of the proteins extracted from the plant material. The aqueous phase is heated to a temperature above 95°C, preferably from 100 °C to 130°C during at least 10 min, preferably from 15 min to 150 min, and then cooled, preferably to room temperature. Particles poorly soluble at room temperature are thus precipitated.

[0080] In step (d), the aqueous phase and the precipitate are separated, e.g. by centrifugation and / or filtration. Steps (c) and (d) can be repeated if needed.

[0081] The aqueous phase is recovered and generally can be used as an aqueous extract according to the invention.

[0082] The aqueous extract of the Invention generally contains dry matter from 20-160 mg / g, preferably from 40-85 mg / g such as from 45 to 70 mg / g.

[0083] If needed, in step (e), the retrieved aqueous phase may be concentrated e.g. under reduced pressure so as to obtain the aqueous extract of the invention in liquid form with the above cited dry matter or in dry form e.g. in the form of a powder.

[0084] In some embodiments, the extract of the Invention is in liquid form and has a dry matter from 20-160 mg / g, preferably from 40-85 mg / g such as from 45 to 70 mg / g.

[0085] In particular embodiments, the extract of the invention contains marker molecules such as carbohydrates, in particular sucrose and fructose, Iminosaccharides such as Homonojirimycin, Deoxynojirimycin, or Deoxymannojirimycin, and aminoacids such as aspartic acid and glutamic acid.

[0086] In a particular embodiment, the extract of the Invention is in liquid form, has a dry matter content from 20-160 mg / g, preferably from 40-85 mg / g and comprises

[0087] - at least 0.5%, preferably from 1% to 6% of carbohydrates as evaluated by GC-FID with preliminary acidic hydrolysis and derivatization

[0088] - at least 50 ppm, preferably from 60 to 1500 ppm of iminosaccharides as quantified by HPLC-UV using 1 -Deoxynojirimycin as standard and

[0089] - at least 0.02%, preferably from 0.04% to 2% of aminoacids as quantified by ninhydrin spectrophotometry, using aspartic acid as standard

[0090] In some embodiments, the extract of the Invention contains from 3 to 40 ppml- Deoxynojirimycin (DNJ), for instance from 5 to 30 ppm, e.g. from 9 to 25 ppm.

[0091] The aqueous extract of the invention obtained in step (e) can be subjected to additional steps such as filtration, ultrafiltration, sterilization e.g. by nanofiltration and / or formulation steps e.g. by mixing the aqueous extract with a cosmetically acceptable carrier.

[0092] For instance, the aqueous extract of the invention can be diluted or dissolved in a liquid cosmetically acceptable carrier such as triethyl citrate, a C2-C5 alkanediol such as propanediol, butylene glycol, pentylene glycol and isomers thereof, ketal esters such a methyl or ethyl levulinate, glycerin, water, and mixtures thereof. Alternatively, the aqueous extract of the invention can be adsorbed on a solid carrier such as maltodextrin. In some preferred embodiments, the aqueous extract of the invention is formulated in glycerin / water or in C2-C5 alkanediol / water, preferably in water / glycerin.

[0093] One or several cosmetically acceptable excipients such as antioxidant, preservative, or pH adjusting agents can be added.

[0094] Examples of antioxidants include, among others, tocopherol, ascorbic acid, salts thereof and combinations thereof.

[0095] Examples of preservatives include organic acids such as sorbic acid, benzoic acid, dehydroacetic acid and salts thereof, benzyl alcohol, methyl paraben, propyl paraben, carvacrol, caprylyl glycol, glycerol caprylate and combinations thereof.

[0096] Examples of pH-adjusting agents encompass organic acids such as citric acid, or acetic acid, phosphate buffer, TRIS-based buffer such as TRIS.HC1 or TRIS glycine and combinations thereof.

[0097] For illustration only, the extract of the Invention can be formulated in water / glycerin mixture so as to obtain a cosmetic ingredient that can be incorporated into topical compositions.

[0098] Cosmetic uses accordins to the Invention

[0099] The Invention also relates to the cosmetic, non-therapeutic, use of an aqueous Hyacinthus extract, preferably an aqueous extract of Hyacinthus orientalis bulbs as described herein as a neurosensorial agent on the skin.

[0100] As used herein “a skin sensorial agen ' or “a skin neurosensorial agent” refers to an active agent able to rebalance, normalize or improve the skin’s / sensorial perception (such as tactile perception) and / or the responsiveness of the skin neurosensory system to stimuli. It also refers to an active agent able to promote wellness or pleasant sensations in a subject. It also refers to an agent able to decrease skin nociception sensitivity and / or increase skin receptiveness to pleasant stimuli. Preferably, such an agent is applied topically, on the skin.

[0101] For instance, “a skin sensorial agent” can be an agent able to improve the sensations resulting from skin stimuli perception and / or to promote an overall wellbeing of the skin when applied topically.

[0102] As used herein, the term “stimuli” refer to any stimuli directly detected by the skin. The stimuli can be of any type, e.g. thermal, mechanical or chemical. This includes stimuli such as those resulted from meteorological conditions (wind, dryness, humidity, sunlight, temperature (cold, heat)), stimuli induced by other external factors (electromagnetic radiation e.g. blue light, pollution, chemicals, smoke, cosmetic treatments etc.), vibrations, hair movement and skin contact e.g. skin pressure or friction. In some embodiments, the stimulus is a skin contact.

[0103] In a particular embodiment, “skin perception" refers to “tactile or touch" skin perception.

[0104] The ability of a compound to act as a neurosensorial agent can be evidenced, and even objectively quantified, by any appropriate in-vitro or in-vivo assay well-known by the skilled artisan. For instance, the ability of a compound to decrease nociception can be assessed with capsaicin challenge in vitro as described in Example 3 or Example 4, or in vivo as described in Example 5. The ability of a compound to increase skin receptiveness to pleasant stimuli and / or promote skin wellbeing or skin comfort can be assessed in vivo as described in Example 5 through EEG recordings during gentle stimuli or through self-assessment of skin comfort using visual scoring scales before or after the application of the agent on the skin as described in Example 5.

[0105] As used herein, the term “skin" refers to any part of the skin of the human body, in particular the skin of the face, including the lips and eyelids, neck skin, hand skin and scalp.

[0106] The term “skin” as used herein also encompasses intimate external parts of the body such as external genitalia, buttocks, perineum area and breasts.

[0107] The extract of the invention is to be used topically, namely applied on the skin.

[0108] Preferably, the skin is healthy, which means that the skin does not show any wounds or skin disorders such as skin infection, eczema, or dermatitis.

[0109] In some embodiments, the skin is mature. Accordingly, the skin can show one or several signs of ageing such as wrinkles, fine lines, loss of elasticity and / or firmness, dull complexion, dark circles, and / or roughness.

[0110] In some other embodiments, the skin is sensitive skin, or atopy-prone skin.

[0111] As used herein, “sensitive skin" (also called reactive skin) is characterized by a disproportionate reactivity to external factors, resulting in skin discomfort. This increased reactivity may result from a non-pathological alteration in the skin's barrier function or a non-pathological alteration of the skin neurosensory system. Such alteration can lower the skin's tolerance threshold to stimuli.

[0112] This non-pathological alteration of the skin barrier or the skin neurosensory system can be caused by physiological changes (e.g. due to aging and / or hormonal changes e.g. during menopause or pregnancy), lifestyle habits (such as stress, lack of sleep, poor diet, alcohol, tabaco, jet lag, night work etc.), and / or external factors such as skin exposure to climatic conditions (e.g. wind, dryness, wet, cold, heat, sunlight), pollution (nanoparticles, ozone), and certain cosmetic treatments such as peeling, shaving, or hair removal. As used herein “ Atopy-prone skin" refers to skin in a subject who has an history of atopic dermatitis (e.g. in childhood or infancy), and / or has an allergic background, i.e. has a history of allergy and / or has a family history of allergy, and which overreacts to external stimuli.

[0113] As used herein, the term “cosmetic active ingredien or agent' refers to a compound exerting one or several cosmetic effects on the skin.

[0114] As used herein, “a cosmetic effect' refers to any non-therapeutic effect aiming at improving and / or modifying the appearance of the skin, the mechanical properties of the skin and / or the response / perception of the skin to stimuli.

[0115] A “cosmetic effect” includes preventing, slowing-down, delaying the onset and / or alleviating any non-pathological alterations of the skin due to aging, lifestyle (e.g. jet lag, lack of sleep, night work, poor diet such as high fat diet, consumption of alcohol and / or tabaco), or exposure to external stress such as climatic conditions (wind, cold, heat, sun, dryness), pollution, smoke, chemicals and the like.

[0116] The extract of the invention can be used in any human being. The subject can be of any gender or age.

[0117] In some embodiments, the subject is an adult. In some embodiments, the subject is at least 25 years old, in particular at least 40 years old.

[0118] In particular embodiments, the subject of the invention does not suffer from any neurological disorders or injuries, in particular those resulting in hyper- or hypoesthesia.

[0119] As mentioned above, the subject can have mature skin and / or sensitive skin.

[0120] In a particular embodiment, the subject is a woman having mature skin and / or sensitive skin.

[0121] In some embodiments, the subject is a woman, e.g. a peri-menopausal or menopausal woman.

[0122] In a particular aspect, the extract of the invention is used as a sensorial agent able to mimic the peripheral action of oxytocin in the skin. For instance, the extract of the invention is used to activate the OXT receptor expressed on sensory nerve endings in the epidermidis. Without wishing to be bound by any theory, the Inventors believe that such a peripheral activation may rebalance the skin neurosensory response to stimuli.

[0123] Accordingly, in a particular embodiment, the extract of the invention is used to rebalance or normalize the skin perception, in particular skin perception to tactile stimuli and / or to stimuli causing nociception.

[0124] As used herein, “a compound able to rebalance or normalize the skin perception” refers to a compound able to improve the skin detection of the stimuli and / or the skin neurosensory response to said stimuli. In particular, the compound may decrease and / or normalize the neurosensory response of the skin to a standard threshold corresponding to that of healthy, young and non-sensitive skin to the same stimuli.

[0125] For instance, the skin sensitivity in a subject can be increased due to the exposure of external stress or to lifestyle habits. In that case, the extract of the invention aims at decreasing the sensitivity of the skin to external stimuli, in particular those causing nociception.

[0126] As shown in the examples, the extract of the Invention is able to counteract the action of capsaicin, a well-known irritant and toxin acting on unmyelinated sensory C-fibers, notably those conveying nociceptive message. The Inventors also showed that the extract of invention improved neuronal survival and dendricity in an extent similar and even higher than OT at 10 pM in a neuron-keratinocyte co-culture model challenged by capsaicin.

[0127] Accordingly, in a particular aspect, the extract of the Invention can be used to decrease and / or prevent skin nociception. In other words, the Invention also relates to the use of the extract as described herein to reduce nociceptive nerve sensitivity.

[0128] In a particular embodiment, the invention relates to the use of the extract of the invention to increase receptiveness to affective touch and pleasant sensations.

[0129] In some embodiments, the invention relates to the use of the extract of the invention to increase skin receptiveness to affective touch and pleasant sensations while decreasing nociception nerve sensitivity.

[0130] Without being bound by any theory, the Applicant is of the opinion that this dual action specifically results from the ability of the extract to activate the OXT receptor, and thus the OXT signaling pathway in sensory nerve endings in the epidermidis.

[0131] In another particular aspect, the extract of the Invention can be used to decrease, alleviate, delay the onset and / or prevent skin discomfort sensations, in particular in a subject with sensitive skin or / and mature skin.

[0132] As used herein, “skin discomfort' or “skin discomfort sensation" encompasses a variety of unpleasant skin sensations such as sensations of stinging, itching, tingling, heating or burning sensations, redness, tightness or dryness. “Skin discomfort” can be observed in aged skin and / or in sensitive skin. The results of the clinical trial described in Example 5 also shows that the cream containing the extract of the Invention significantly increases skin comfort and pleasantness as compared to the placebo cream. Thus, the extract of the Invention can be used as an agent to provide skin comfort and more generally as an agent to enhance skin comfort.

[0133] The results of the clinical trial described in Example 5 also showed that the cream containing the extract of the Invention is more effective to improve the appearance of the skin than the placebo cream. Skin treated with the test cream of the invention has an improved youthful and healthy aspect compared to skin treated with the placebo.

[0134] Without wishing to be bound by any theory, the Inventors are of the opinion that the improvement of the skin perception, and in particular the decrease of nociception and / or sensitivity, by the peripheral action of the extract of the Invention has a particular impact on the appearance of the skin: the skin appears more relaxed, radiant, healthy and / or young.

[0135] Thus, in a particular embodiment, the Invention relates to the use of an aqueous extract of Hyacinthus bulbs, in particular an aqueous extract of H. orientalis bulbs for improving the appearance of the skin, in particular in order to make the skin look and / or feel healthier and / or younger.

[0136] In a particular embodiment, the Invention relates to the use of an aqueous extract of Hyacinthus bulbs, in particular an aqueous extract of H. orientalis bulbs as an agent to provide skin rejuvenation.

[0137] In particular embodiments, the extract of the Invention is used as a cosmetic active agent to prevent (e.g. slow-down or delay), attenuate, decrease or treat one or more non-pathological alterations of the skin appearance, in particular in aged skin and / or a sensitive skin. Non- pathological alterations of the skin appearance encompass, without being limited to: roughness, redness, loss of radiance or glow, dull or non-uniform complexation, tired aspect and combinations thereof.

[0138] In another embodiment, the extract of the Invention may be used towards at least one (e.g. 1, 2, 3 or more) of the following cosmetic purposes:

[0139] - Prevent, treat, or reduce skin pigmentation irregularities, including pigment spots induced by fatigue or stress,

[0140] - Reduce signs of aging, including wrinkling and loss of tissue elasticity.

[0141] - Homogenize or unify the complexion of the face,

[0142] - Make the complexion of the face brighter and / or more radiant,

[0143] - Prevent or treat a dull complexion, a blurred complexion and / or drawn features,

[0144] - Make the skin, especially on the face, fresher and brighter,

[0145] - Soothe facial features,

[0146] - Make the appearance of the skin less tired, and more relaxed,

[0147] - Revitalize the skin, especially on the face,

[0148] - Improve the skin’s healthy glow,

[0149] - boost skin luminosity,

[0150] - Prevent, treat or attenuate, the appearance of redness, - Prevent, treat or attenuate skin discomfort, and / or

[0151] - Promote pleasant skin sensation.

[0152] As mentioned above, the extract of the invention is preferably topically used in subjects with sensitive skin or / and mature skin.

[0153] In a further aspect, the Invention relates to the use of an extract as described herein, in particular an aqueous extract from H. orientalis bulbs, as an active cosmetic ingredient for providing a cosmetic effect selected from the reduction of skin discomfort or oversensitivity, the improvement of skin tactile perception, and / or the improvement of the healthy and youthful appearance of the skin, in particular the radiance and the glow of the skin.

[0154] As illustrated in Example 5, the extract of the Invention also promotes positive perception of feather touch stimuli, resulting in pleasant sensations and thus experience of wellness.

[0155] In another aspect, the Invention relates to the use of an extract as described herein, in particular an aqueous extract of H. orientalis, to provide experience of wellness in a subject. In particular, the extract of the Invention can be used to promote or increase pleasant skin sensations in the subject.

[0156] In the uses and methods as described herein, the extract of the invention is administered topically, namely applied on the skin. Typically, the extract is applied by means of a cosmetic composition. In other words, the extract is present in a cosmetic composition which is applied on the skin of the subject. Cosmetic compositions of interest are described further below.

[0157] In certain embodiments, the extract of the Invention can be directly incorporated into a cosmetic composition.

[0158] In other embodiments, the extract of the Invention is pre-formulated into a cosmetic active ingredient before being incorporated into a cosmetic composition.

[0159] Cosmetic active ingredients of interest are described further below as well.

[0160] The aqueous extract of the Invention, preferably an aqueous extract of H. orientalis bulbs, is typically present in an amount from 0.005% to 10.0 % by weight, preferably from 0.01% to 5.0% e.g. such as 0. 5 % to 2.0 % by weight in the cosmetic composition.

[0161] An additional object of the present invention is a cosmetic method for providing one or more cosmetic effects as described herein., said method comprising applying an extract according to the invention, in particular an aqueous extract of H. orientalis bulbs on the skin of the subject. The extract is preferably applied in the form of a cosmetic composition as described herein. The cosmetic method of the invention is preferably performed for improving skin tactile perception and / or reducing skin discomfort, and / or improving the healthy and youthful appearance of the skin.

[0162] In a particular aspect, the cosmetic method of the invention can achieve one or several of the following effects in the subject:

[0163] - Prevent, treat, or reduce skin pigmentation irregularities, including pigment spots induced by fatigue or stress,

[0164] - Reduce signs of aging, including wrinkling and loss of tissue elasticity,

[0165] - Homogenize or unify the complexion of the face,

[0166] - Make the complexion of the face brighter and / or more radiant and / or clearer,

[0167] - Prevent or treat a dull complexion, a blurred complexion and / or drawn features,

[0168] - Make the skin, especially on the face, fresher, relaxed, and brighter,

[0169] - Soothe facial features,

[0170] - Make the appearance of the skin less tired, and more relaxed,

[0171] - Revitalize the skin, especially on the face,

[0172] - Promote a skin healthy glow effect,

[0173] - Prevent, treat, or attenuate, the appearance of redness,

[0174] - Prevent, treat, or attenuate skin discomfort,

[0175] - Promote pleasant skin sensations in the subject and / or

[0176] - Promote wellness in the subject.

[0177] As mentioned above, the subject is preferably an adult with sensitive skin and / or mature skin.

[0178] In the cosmetic methods and uses as described herein, the dose to be administered and the frequency of administration according to the invention vary according to the cosmetic effect sought, the characteristics of the individual, in particular his sex, age, and skin type. Typically, the extract of the invention, or the cosmetic composition comprising it, can be applied to a skin area to be treated once or twice daily, e.g. after skin cleaning, for several consecutive weeks or even months, for example for at least 3 months. For example, the subject can apply a dose of 1 g to 2 g of cosmetic composition on his face in the morning and / or in the evening. Preferably, the extract or the cosmetic composition of the invention is applied on the skin by massage. The application by massage may last from a few seconds to several minutes, e.g. from 1 min to 30 min. Without being bound by any theory, the Applicant is of the opinion that the results shown in Example 5 for skin area such as the face and the arms can be extrapolated to any skin area, including the scalp and intimate skin areas.

[0179] Thus, the present Invention also relates to the use of an aqueous extract obtained from H. orientalis bulbs, e.g. as described herein, as an active cosmetic ingredient in hair care products and in intimate care product.

[0180] In a particular aspect, the Invention relates to the use of an aqueous extract obtained from H. orientalis bulbs, e.g. as described herein, as a neurosensorial agent for hair scalp. In a particular embodiment, the aqueous extract obtained from H. orientalis bulbs, e.g. as described herein can be used to rebalance or normalize the neurosensorial perception of the hair scalp to external stimuli, in particular to stimuli causing nociception. In some embodiments, the Invention relates to the use of an aqueous extract obtained from H. orientalis bulbs for alleviating hair scalp discomfort and / or increasing hair scalp comfort.

[0181] Without being bound by any theory, the Applicant is of the opinion that rebalancing hair scalp neurosensorial perception, in particular by reducing nociceptive sensitivity, improves hair scalp comfort. Besides, the activation of OXT signaling pathway is likely to result in cell proliferation in the scalp and by the way in a possible enhancement in hair renewal and hair growth.

[0182] Accordingly, the Invention also relates to the use of an aqueous extract obtained from H. orientalis bulbs, e.g. as described herein, as an agent to promote hair growth and / or renewal. The extract of the invention can be applied as such on the scalp or incorporated into any hair care product such as hair shampoo, mask, conditioner, spray, serum, foam and the like.

[0183] In a particular aspect, the invention relates to a method for rebalancing or normalizing the neurosensorial perception of the hair scalp and / or for alleviating hair scalp discomfort and / or for promoting hair growth and / or hair renewal wherein an aqueous extract obtained from H. orientalis bulbs, e.g. as described herein is topically applied on the hair scalp.

[0184] Typically, the extract of the invention, or the cosmetic composition comprising it (e.g. a shampoo, a mask or a conditioner), can be applied to the scalp at least once a week for several consecutive weeks or even months, for example for at least 3 months. The extract or the cosmetic composition of the invention may be applied on the hair scalp by massage. The application by massage may last from a few seconds to several minutes, e.g. from 1 min to 5 min.

[0185] Without being bound by any theory, the Applicant is of the opinion that the extract of the invention can be beneficial as a neurosensorial agent for skin intimate areas, e.g. in women experimenting hormonal changes such as peri-menopausal women and menopausal women. For instance, with age and / or hormonal change, the sensorial skin perception in intimate parts of the body can be altered. One can observe discomfort, increased nociception, and / or decreased receptiveness to affective touch in intimate skin areas. Moreover, hair removal in intimate areas can also alter skin perception.

[0186] Thus, in a particular aspect, the invention relates to the use of an aqueous extract obtained from H. orientalis bulbs, e.g. as described herein, as a neurosensorial agent for intimate skin area. The aqueous extract of the invention can be incorporated in any kind of intimate care products, such as intimate hygiene care, intimate cream, intimate gel and the like.

[0187] In a particular aspect, the extract of the Invention is used to decrease intimate discomfort and / or increase skin responsiveness (e.g. to pleasant stimuli) in intimate areas and / or decrease sensitivity to nociception in intimate areas. In some embodiments, the extract of the Invention is used to decrease skin discomfort sensations such as stinging, itching, tingling, tightness, or dryness in the intimate area, in particular in external genitalia, buttocks, and / or the perineum area.

[0188] In a particular aspect, the invention relates to the use of an aqueous extract obtained from H. orientalis bulbs, e.g. as described herein, as an agent to increase receptiveness to affective touch and pleasant sensations in intimate skin areas. In a particular aspect, the aqueous extract obtained from H. orientalis bulbs, e.g. as described herein, can be used as a topical agent to increase intimate wellbeing and / or to increase sexual receptiveness.

[0189] In a particular aspect, the invention relates to a method for rebalancing or normalizing the neurosensorial perception of the skin in intimate areas, e.g. for decreasing intimate discomfort and / or increasing skin comfort in intimate areas and / or increasing receptiveness to affective touch and pleasant sensations in intimate skin areas wherein an aqueous extract obtained from H. orientalis bulbs, e.g. as described herein is topically applied on the intimate area, e.g. on external genitalia, buttocks, and / or the perineum area.

[0190] Typically, the extract of the invention can be routinely used, for instance daily, as intimate hygiene care or daily intimate care, or prior to or during sexual relations, e.g. being applied as a cream or a gel by massage.

[0191] Cosmetic active ingredient and cosmetic composition according to the invention

[0192] In a particular aspect, the Invention relates to a cosmetic ingredient comprising (i) an extract of the Invention, preferably an aqueous extract of Hyacinthus orientalis bulbs, and (ii) a cosmetically acceptable carrier as described above. For instance, said carrier can be selected from triethyl citrate, a C2-C5 alkanediol such as propanediol, butylene glycol, pentylene glycol and isomers thereof, ketal esters such a methyl or ethyl levulinate, glycerin, water, and mixtures thereof. A preferred carrier is glycerin or glycerin / water mixtures. The weight ratio of glycerin / water is generally from 0.25 to 4.0, such as 0.5 to 2.0 or 0.75 to 1.25.

[0193] In some embodiments, the cosmetic ingredient of the Invention further comprises one or more cosmetically acceptable excipients, preferably selected from antioxidants, preservatives, pH adjusting agents and combinations thereof. Said antioxidants, preservatives, and pH adjusting agents can be as described above. The one or more cosmetically acceptable excipients account for 0.01% to 10.00%, preferably for 0.05% to 1.00% by weight of the total weight of the cosmetic ingredient of the Invention.

[0194] In a particular embodiment, the cosmetic ingredient comprises (i) an aqueous extract of the invention as cosmetic active ingredient, (ii) glycerin / water as a cosmetically acceptable support, (iii) citric acid as pH adjusting agent and (iv) benzoic salt and / or sorbate salt as preservatives. In a further aspect, the cosmetic ingredient of the invention consists of or consists essentially of (i) an aqueous extract of the invention as cosmetic active ingredient, (ii) citric acid as pH adjusting agent and (iii) benzoic salt and / or sorbate salt as preservatives in a mixture glycerin / water as cosmetically acceptable carrier.

[0195] In some embodiments, the active ingredient of the Invention may comprise one or several additional cosmetically active agents in addition to the extract of the Invention. Preferred additional cosmetic active agents are described further below. For instance, preferred additional cosmetic agents encompass pink flowering cistus extract, e.g. marketed under the brand name IBR-Chill™., liposoluble extract of Lavandula hybrid e.g. marketed under the tradename Immunight™ , liposoluble extract of Melaleuca alternifolia e.g. marketed under the tradename Regenight™, quinoa starch and derivatives thereof e.g. marketed under the tradename Pickmulse™ and combinations thereof.

[0196] In some embodiments, the extract of the Invention, preferably an aqueous extract of Hyacinthus orientalis bulbs, is the sole cosmetic active agent present in the cosmetic ingredient.

[0197] The cosmetic ingredient of the Invention is typically incorporated in a cosmetic composition at an amount from 0.1% to 10%, for instance from 0.5% to 5 % by weight of the total weight of the cosmetic composition.

[0198] In an additional aspect, the Invention further relates to a cosmetic composition comprising an extract of the invention or a cosmetic ingredient of the invention, as described herein.

[0199] Typically, the cosmetic composition of the Invention comprises (i) an extract of the Invention, in particular an aqueous extract of H. orientalis bulbs and (ii) one or more cosmetically acceptable excipients. The cosmetically acceptable excipients may be selected from standard excipients depending on the cosmetic composition to formulate.

[0200] Cosmetically acceptable excipients encompass, without being limited to, diluents, dispersing agents, gelling agents, emollients, vectorizing agents (such as polycationic polymers, phospholipids, liposomes, lamellar systems, lipid or polymeric vesicles, nanospheres, micro or nano-particles of natural or non-natural polymers, hydrogels), gums, resins, solvents, in particular water, C2-C6 alcohols or polyols including ethanol, isopropanol, dipropylene glycol, butylene glycol, propanediol, glycerin, sorbitol, propylene glycol and combinations thereof, fillers such as modified and polymerized starches, preservatives, pearlescent agents, odor absorbers, pH regulators, lubricating agents, thickening agents, surfactants including anionic, cationic, amphoteric or nonionic surfactants, humectants, wetting agents, stabilizing agents, bulking agents, dispersants, perfumes, dyes, organic or mineral pigments such as iron oxides, oily agents such as plant or animal oils or fats such as triglycerides, fatty alcohols, fatty acids or salts thereof, synthetic oils such as paraffins or isoparaffins, silicone oils (cyclomethicone), fatty alcohol esters, fluorinated oils, waxes, and / or other substances commonly used in cosmetic formulations.

[0201] In a particular embodiment, the cosmetic composition comprises from 0.005% to 10.0 % by weight, preferably from 0.01% to 0.5% e.g. such as 0.05 % to 2.0 % by weight of an aqueous Hyacinthus bulb extract as described herein, the percentage referring to the total weight of the cosmetic composition.

[0202] More particularly, said cosmetic composition may comprise:

[0203] - from 0.005% to 10.0 % by weight of an aqueous Hyacinthus bulb extract as described herein, in particular aqueous H. orientalis bulb extract and

[0204] - from 70 % to 99.995 % by weight of one or more cosmetically acceptable excipients.

[0205] In some embodiments, the cosmetic composition further comprises one or more active agents with additional cosmetic effect(s). Said one or more active agents can account for up to 29.995% by weight of the total weight of the composition. When present, the one or more additional cosmetic active ingredients account for 0.0001% to 29.995% of the total weight of the cosmetic composition.

[0206] The term "active agent with cosmetic effect or cosmetic active agent or ingredient" refers to an agent able to exert at least one cosmetic effect on the skin or its appendages. "Cosmetic effect" means any non-therapeutic effect aiming at modifying and / or improving the visual appearance and mechanical properties of the skin or mucous membranes such as the lips, protecting them from external aggressions (sun, wind, moisture, dryness, chemicals), preventing and / or correcting phenomena related to their aging, or preventing or treating the effects caused by stress or fatigue on the skin.

[0207] Examples of such agents are, among others, anti-wrinkle agents, anti-aging agents, antioxidant agents, moisturizing agents, soothing agents, anti-redness agents, exfoliating agents, seboregulating agents, lightening agents, concealers, anti-dark spot agents, anti-pollution agents, anti-stress agents, sunscreen agents, and combinations thereof.

[0208] In a particular embodiment, the cosmetic composition of the invention may comprise one or more additional cosmetic active agents selected from an anti-wrinkle agent, an anti-redness agent, an antioxidant agent, a moisturizing active, a soothing agent, a sebo-regulating agent, a lightening agent, an anti-stress agent, an anti-fatigue agent, an anti-pollution active, a concealer, a sunscreen agent, and combinations thereof.

[0209] Examples of anti-pollution agents include extracts of Chrysanthellum Indicum polysaccharides, especially marine from a fermentation medium of Alteromonas and salts of Nigari.

[0210] Examples of concealer agents include extracts of Chrysantellum Indicum or extracts and sulfated polysaccharides of algae, including Ascophyllum nodosum or Asparagopsis Armata.

[0211] Examples of moisturizing agents include urea, pidolic acid (PCA) and its derivatives in particular its salts such as arginine PCA, chitosan PCA, its copper salts (Copper PCA), magnesium (magnesium PCA), sodium (sodium PCA) or zinc, ethylhexyl PCA, calcium gluconate, hyaluronic acid and its salts and other glycosaminoglycans, trehalose, polydextrose, sucrose (Sucrose), maltitol, mannitol, sorbitol, xylitol and other carbohydrates and derivatives, polyethylene glycols such as PEG-7, PEG-8, PEG-10, PEG-12 or PEG-14, glycerin, propylene glycol, butylene glycol, betaine, citrulline, collagen and its derivatives, histidine, silk, keratin or soy hydrolysates, plant extracts rich in polysaccharides and / or polyphenols, for example extracts of aloe, blueberry (Centaurea cyanus), Burdock, allantoin, extracts rich in polysaccharides, especially from fermentation media of marine microorganisms such as Alteromonas or Porphyridium and combinations thereof.

[0212] Examples of anti-aging agents include ascorbic acid and its derivatives such as magnesium ascorbyl phosphate, glycosaminoglycans and their derivatives such as hyaluronic acid, retinoids such as retinol, Cyathea polysaccharides, collagen, flaxseed extracts (Linum usitatissimum), peptides such as Caprooyl-Tetrapeptide-3 and trifluoroacetyl tripeptide-2, extracts of Polygonum aviculare, extracts of brown algae, in particular Ascophyllum nodosum, extracts of Cyathea cumingii, extract of Anigozanthos flavidus marketed under the tradename Skinectura™. Examples of anti-stress agents include rose extracts such as Rosality™ which is a combination of rose water and rose essential oil and pink flowering cistus extract, for example marketed under the brand name IBR-Chill™.

[0213] Examples of anti-fatigue agents include liposoluble extract of Lavandula hybrid and liposoluble extract of Melaleuca alternifolia marketed under the tradename ImmunightTMand Regenight™. Examples of soothing agents include allantoin, extracts of aloe, birch (e.g. Betula alba), fireweed (e.g. Epilobium angustifolium), chestnut (e.g. Castenea sativa), blueberry (e.g. Centaurea cyanus), centella (e.g. Centella asiatica), horsetail (e.g. Equisetum arvense), fennel (e.g. Foeniculum vulgare ), witch hazel (e.g. Hamamelis virginiana), ivy (e.g. Hedera helix), Hibiscus sabdariffa, lily (e.g. Lilium candidum), mallow (e.g. Malva sylvestris), lemon balm (e.g. Melissa officinalis), skullcap (e.g. Scutellaria baicalensis), mimosa (e.g Mimosa tenuiflora), cinquefoil (e.g. Potentilla erecta , an extract of oligosaccharides or an oligosaccharide, for example flax, peptides such as palmitoyl tripeptide-8, extracts of polysaccharides, especially extracts of exopolysaccharides from the fermentation medium of Alteromonas or Porphyridium.

[0214] Examples of antioxidant agents include HMR (hydroxy methyl resorcinol), ascorbic acid and its derivatives, vitamin B9, histidine hydrochloride, or fireweed extract (Epilobium augustifolium), tocopherol, carotenoids and extracts containing carotenoids (e.g. extracts of Dunaliella salina), and the likes.

[0215] Examples of sebo-regulating agents include flax lignans, rice powder, zinc gluconate, sarcosine, an extract of Cinnamomum zeylanicum bark, an extract of avocado, an extract of Backhousia citriodora and combinations thereof.

[0216] Examples of anti-redness agents encompass saponins, flavonoids, ruscogenins, esculosides, and extracts containing them, for example extracts of Ruscus, as well as certain essential oils, for example lavender or rosemary.

[0217] Examples of anti-spot agents include extracts such as licorice (Glycyrrhyza glabra), jackfruit extract (Artocarpus heterophyllus), Rumex extract (R occidental is), plant extracts belonging to the genus citrus, resveratrol, peptides such as oligopeptide-68, nonapeptide- 1, kojic acid, magnesium ascorbyl phosphate and combinations thereof.

[0218] Preferred additional cosmetic agents encompass pink flowering cistus extract, for example marketed under the brand name IBR-Chill™., liposoluble extract of Lavandula hybrid e.g. marketed under the tradename Immunight™ , liposoluble extract of Melaleuca alternifolia e.g. marketed under the tradename Regenight™, quinoa starch and derivatives thereof e.g. marketed under the tradename Pickmulse™ and combinations thereof. It goes without saying that the additional active ingredients and the excipients to be used depend on the type of composition to formulate and the skin area on which the composition is to be applied.

[0219] The cosmetic composition of the invention is typically applied on the skin. The cosmetic composition may be in any form suitable for such a topical administration. In a particular embodiment, the cosmetic composition of the invention is selected from the group consisting of aqueous solutions, hydroalcoholic solutions, oil-in-water emulsions (O / W) or water-in-oil (W / O) or multiple), including nanoemulsions, aqueous gels (also called hydrogels), emulgels, suspensions, preferably in aqueous or hydroalcoholic medium, liposome suspensions, oily compositions, serums, powders, lotions, milks, creams, ointments, gels, foams, balms, foams, and aerosols.

[0220] In some embodiments, the cosmetic composition according to the invention is selected from a cream, a balm, a serum, or a lotion.

[0221] More generally, the composition according to the Invention can also take the form of any cosmetic or dermocosmetic product. It may be a skin care product, a make-up product or a body hygiene product, for example a lotion, a milk, a serum, an aqueous or oily gel, an emulsion, a cream, a gel-cream, an ointment, a balm, foundation, spray, mascara, stick, lipstick, gloss, deodorant, nourishing mask, shower gel, an aftershave, cleansing oil, soap, shampoo or conditioner, hair mask or oil including massage oil. In some preferred embodiments, the composition of the Invention is a skin care product e.g. a cream, a balm, a serum, a gel cream or an ointment.

[0222] In some other embodiments, the composition of the Invention is a hair care product such as a shampoo, a conditioner, a hair mask or balm, a serum, a hair oil, or a hair form, the list being non exhaustive.

[0223] In some other embodiments, the composition of the Invention is an intimate care product such as an intimate hygiene (cleansing) care product (gel, soap), intimate wipes or an intimate cream or gel.

[0224] Other aspects and advantages of the present invention will become apparent from the following examples, which are to be regarded as illustrative and in no way limiting. EXAMPLES

[0225] EXAMPLE 1: Preparation of the extract and the cosmetic ingredient according to the

[0226] Invention

[0227] Preparation and characterization o f the extract

[0228] The aqueous extract of Hyacinthus orientalis bulb was prepared as follows:

[0229] Fresh, dormant Hyacinthus orientalis bulbs are peeled. Water is added to the peeled bulbs and the mixture is processed into a slurry (water / bulbs weight ratio: about 0.5-1.0). The resulting slurry as allowed to stand at least 20 minutes with intermittent stirring. The slurry was then centrifuged. The supernatant was recovered and heated at a temperature of about 100°C-125°C for at least 30 min. The supernatant was cooled at room temperature resulting in the formation of a precipitate and then centrifuged. The supernatant was heated at a temperature of about 100°C-125°C for at least 10 min and then cooled at room temperature. Following cooling, the mixture was centrifuged and filtered down to 0.45 pm, whereby the aqueous extract of the invention was obtained.

[0230] The dry matter content of the resulting extract was about 45-75 mg / g.

[0231] The resulting extract was directly formulated to obtain a cosmetic active ingredient according to the Invention.

[0232] Chemical characterization of the extract of the Invention

[0233] The composition of the resulting extract is characterized as follows:

[0234] Carbohydrate content (including sucrose and fructose) of about 1-2% in total, as evaluated by GC-FID with preliminary acidic hydrolysis and derivatization.

[0235] Presence of Iminosaccharides (such as Homonojirimycin, Deoxynojirimycin, Deoxymannojirimycin, etc.) at about 60-1200 ppm, as quantified by HPLC-UV using 1 -Deoxynojirimycin as standard (per Rodriguez- Sanchez, S.; Quintanilla-Lopez, J.E.; Soria, A.C.; Sanz, M.L. Evaluation of different hydrophilic stationary phases for the simultaneous determination of iminosugars and other low molecular weight carbohydrates in vegetable extracts by liquid chromatography tandem mass spectrometry, J. Chromatography A, 2014, 1372, 81-90.

[0236] Aminoacid content (including aspartic acid, glutamic acid) of 0.05-1%, as quantified by ninhydrin spectrophotometry, using aspartic acid as standard (per Michel, M.C. Dosage des acides amines et amines par la ninhydrine. Amelioration pratique. Ann. Biol. Anim. Bioch. Biophys. 1968, 8(4), 557-563).

[0237] Color: transparent to translucent, colorless to yellow. pH: 5.0-6.5.

[0238] Preparation of the cosmetic active ingredient of the Invention

[0239] The aqueous extract obtained as described above was formulated with glycerin and preservatives (potassium sorbate, sodium benzoate). The pH was adjusted to about pH 5.5 (with citric acid.

[0240] Composition of the cosmetic active ingredient of the Invention (% by weight) :

[0241] - aqueous extract of the Invention: 49%

[0242] - Glycerin: 50%

[0243] - Potassium sorbate, sodium benzoate and citric acid: 1.0%

[0244] - pH: 5.8.

[0245] EXAMPLE 2: The extract of the Invention activates the Oxytocin receptor

[0246] Protocol: The study employed CHO-K1 (hamster ovary) cells expressing the human Oxytocin receptor OXTR (accession CAA46097.1). Activity was evaluated using an IP-One HTRF assay at 1 h, i.e. at equilibrium (monitors a downstream product of the activation of the target receptor; in this case, detects the accumulation of inositol monophosphate, a stable downstream metabolite of IP3 induced by activation of a phospholipase C (PLC) cascade).

[0247] The extract of the Invention (as prepared in Example 1) was tested at 4 concentrations (0.025%, 0.05%, 0.1%, and 0.2%), with n=2. Oxytocin (Bachem H-2510, Bubendorf, Switzerland) itself was used as a positive control (10 concentrations, 0.01-1000 nM).

[0248] Results: The extract of the Invention was shown to activate OXTR at a concentration of 0.1% or 0.2% by weight. At 0.1% extract concentration, receptor activation was 53.14%; at 0.2%, activation was 71.49% (Figure 1).

[0249] EXAMPLE 3: Effects of the extract of the Invention on a coculture of human sensory neurons and human skin keratinocytes under capsaicin challenge

[0250] Materials and Method: a) Coculture of human sensory neurons and keratinocytes

[0251] Human sensory neurons were derived from hiPS cells (human induced Pluripotent Stem cells), obtained by transfecting human fibroblasts cells (foreskin fibroblasts, Coriell Institute AG08498, Camden, NJ, USA; cells were obtained from neonatal foreskin surgical residues from the Coriell Institute in full observance of local (NJ, USA) regulation and ethical guidelines, which did not require a specific ethical review or approval for cases such as this) with a lentivirus encoding for the KLF4, OCT4, SOX2, and c-MYC genes. Cells were plated in 96 wells plates coated by a thin layer of Matrigel (Corning 354277, New York, NY, USA) in a differentiation medium (DMEM / F12, Panbiotech P04-41450, Aidenbach. Germany + Knockout™ Serum Replacement synthetic serum, Fisher Scientific 10828010, Waltham, MA, USA+ SU-5402 fibroblast growth factor receptor inhibitor, Sigma Aldrich SML0443, St Louis, MO, USA + LDN193189 hydrochloride ALK2 / 3 (type I receptor serine-threonine kinases) inhibitor, Sigma Aldrich SML0559 + Retinoic Acid, Sigma Aldrich R4643), and incubated at 37°C and 5% CO2 for 6 days (during which the culture medium was changed every 2 days). After 9 days of differentiation, the medium was replaced by a human sensory neuron maturation medium (DMEM / F12 + N-2 supplement, Fisher Scientific 17502048 + PS (penicillin / streptomycin), Panbiotech P06-07100 + NGF (Nerve Growth Factor), Sigma Aldrich N1408). Cells were incubated at 37°C and 5% CO2. The culture medium was changed every 2 to 3 days.

[0252] Adult keratinocytes (PromoCell C 12013, Heidelberg, Germany) (from a donor ca. 30 years of age) were amplified in growth medium for keratinocytes (PromoCell C-20111), over one cycle before being dissociated by trypsination and frozen. These keratinocytes were then thawed and amplified again in growth medium for keratinocytes and dissociated by trypsination. Cell viability was established by cell counting.

[0253] After 14 days of culture, keratinocytes were combined with the above the sensory neurons, at an initial ratio of 5:1 (keratinocytes / neurons), by first seeding the hiPS differentiating cells, followed by seeding the keratinocytes above the hiPS layer in the same culture well. The coculture was maintained at 37°C and 5% CO2 in culture medium consisting of a mix of neuron maturation medium and keratinocyte growth medium. The culture medium was changed every 2 to 3 days. b) Coculture treatment for evaluation of extract activity on nociception

[0254] Sensory neurons and keratinocytes were cocultured as above. On day 17 of culture, the medium was removed and replaced with fresh medium. After 2 hours of incubation, the medium was removed, and replaced with fresh medium containing the extract of the Invention at a concentration of 0.1%, in addition to: an untreated control (medium only); a positive control (10 pM oxytocin); and a secondary control (10 pM capsazepine, Sigma C191-5MG - a capsaicin antagonist). After 24 h incubation, cells were activated using 10 pM capsaicin (Sigma M2028) for 30 min, in parallel with unstimulated control and media were recovered for ELISA dosage of CGRP and replaced by medium without capsaicin. After 24 hours of further incubation (in the absence of capsaicin), supernatants were collected and stored at -80°C. Cells were fixed in a 2% paraformaldehyde solution (Fisher Scientific J19943, Waltham, MA, USA) and stored at +4°C. One culture was performed, with 6 wells by condition. c) CGRP ELISA dosage

[0255] The culture supernatants recovered after 30 minutes of cell activation were thawed and the amount of CGRP released was dosed by ELISA (Antibodies online, Aachen, Germany, ABIN2542823; Multiskan FC plate reader, Thermofisher Scientific, Waltham, MA, USA).

[0256] Statistical analyses were performed using a one-way ANOVA test including Brown-Forsythe test and Bartlett’s test comparing all means with multiple comparison test option, with Dunnett correction and with a significance threshold of p < 0.05 for all tests. d) Immunofluorescence stainings (neuronal plasticity evaluations):

[0257] Cells were incubated with primary antibodies anti-P-tubulin (Abeam ab41489, Cambridge, UK), anti-OXTR (Abeam ab300443 -1004) and anti-synaptophysin (Abeam AB8049-1001). These antibodies were revealed by secondary antibodies coupled to fluorochromes (Fisher Scientific A21449, Al 1011 and Al 1001). 20 images by well were taken using an InCell 2200 automatized microscope (GE Healthcare, Piscataway, NJ, USA). Images were analyzed using the INCell Developer toolbox software, to automatically detect cellular bodies including neurons, neurites, and receptor expression. The number of sensory neurons, their neurite length and their dendricity were measured (via P-tubulin staining). The expression rate of OXTR receptors and synaptophysin were also determined.

[0258] Statistical analyses were performed using One-Way ANOVA with Dunnett’s multiple comparison test (using Prism 8.4.3, GraphPad, Boston, MA, USA), using p<0.05 as significance threshold.

[0259] Results:

[0260] Effect of the extract of the Invention on nociception signaling in vitro

[0261] The results are shown in Figure 2. The extract of the Invention was shown to reduce nociception signaling in a coculture of human keratinocytes and iPSC-derived neurons challenged with capsaicin (a widely recognized model of nociceptive stimulus, generating discomfort as a stinging, burning, or even painful sensation).

[0262] Neuronal output (representing the signal resulting from the stimulus) was evaluated via measurement of CGRP release. In the presence of 0.1% the extract, the nociceptive signal was significantly reduced (- 22% vs. capsaicin-stimulated control, p = 0.0005), restoring signaling to values just below that of the unchallenged, untreated control and representing a somewhat stronger effect than the 10 pM OXT or 10 pM capsazepine (a capsaicin antagonist) control groups.

[0263] Effect of the Extract on neuronal survival and dendricity of neuron in co-culture with keratinocytes after capsaicin challenge.

[0264] The results are shown in Figures 3 A and 3B.

[0265] In the same coculture model described above, the extract of the Invention also provided the following benefits:

[0266] The extract of the Invention significantly improved neuron survival under capsaicin challenge while treated with 0.1% extract: +44% vs. unchallenged, untreated control (p<0.01); +89% vs. capsaicin-challenged, untreated control (p<0.01); slightly better vs. capsaicin-challenged, 10 pM oxytocin-treated reference leg (+20%, p = 0.2).

[0267] The Extract of the Invention increased neuron dendricity in neurons under capsaicin challenge: treatment with the extract at 0.1% resulted in an improvement of +25% vs. unchallenged, untreated control (p<0.05). A positive trend (+12%, p<0.20) was observed in culture under capsaicin challenge while treated with 0.1% extract, vs. capsaicin- challenged, untreated control.

[0268] Thus, the extract of Invention provides protective effects against capsaicin challenge: it increases the survival and the dendricity of neurons in coculture with keratinocytes under capsaicin to an extent similar and even higher than oxytocin at 10 pM.

[0269] EXAMPLE 4 : Organ-on-a-chip nerve-skin interface model

[0270] This study was carried out as two successive identical runs.

[0271] Culture : This study employed Netri (Lyon, France) Neurofluidics™ MEA organ culture chips, consisting of two parallel channels, with neurons seeded in the left-hand channel, and keratinocytes in the right-hand channel; these two channels are connected by two hundred

[0272] 125x6x3-pm microchannels (Length x Width x Height), spaced 20 pm apart (large enough to allow the growth of axons, but not cell migration, from one compartment to the next). This layout is overlaid by 42 electrodes (15 in each cell compartment, 10 in the microchannel zone, and 2 central reference electrodes) to measure electrical activity.

[0273] Culture chips were coated with 0.1 mg / mL poly-D-lysine (Thermofisher A38904, Waltham, MA, USA), and incubated overnight at 37°C, then triple-washed with PBS. The chips were then coated with SureBond-XF solution (Axol Bioscience ax0053, Easter Bush, UK) diluted by a factor of 200, and incubated for 4 hours at 37°C. The SureBond-XF solution was removed from the chips prior to cell seeding.

[0274] Thawed AxoCells sensory neurons (Axol Bioscience ax0055) were seeded in the neuron compartment at a density of 2000 cells / mm2. On days 1 and 3, medium was completely replaced with enhanced sensory neuron maintenance medium supplemented with 0.25% 1 :200 Surebond-XF; on day 3, 75% of the medium was replaced with enhanced sensory neuron maintenance medium supplemented with 2.5 pg / mL mitomycin C (Sigma M4287, St Louis, MO, USA); on day 6, 75% of the medium was replaced with enhanced sensory neuron maintenance medium supplemented with 0.25% 1 :200 Surebond-XF; and on days 9, 13, 16, 20, and 23, 50% of the medium was replaced with enhanced sensory neuron maintenance medium. Enhanced sensory neuron maintenance medium consists of sensory neuron maintenance medium (Axol Bioscience ax0060) + 1% sensory maturation maximizer (Axol Bioscience ax0058) + 25 ng / mL Recombinant human Glial -Derived Neurotrophic Factor (Axol Bioscience axl39855) + 25 ng / mL Recombinant human Nerve Growth Factor (Axol Bioscience axl39789) + 10 ng / mL Recombinant human Brain-Derived Neurotrophic Factor (Axol Bioscience axl39800) + 10 ng / mL Recombinant human Neurotrophin-3 (Axol Bioscience axl39811).

[0275] On day 20, keratinocytes (PromoCell C12005, Heidelberg, Germany) were seeded at 25000 cells / channel. Medium was completely replaced at 24h, and then three times a week. The medium consisted of keratinocyte growth medium (Promocell C-20011B) supplemented with 2.5% of a keratinocyte supplement mix (Promocell C-39016), and 0.012% 0.5 M calcium chloride (Promocell C-34005).

[0276] Incubation was carried out at 37°C and 5% CO2.

[0277] Treatment and measurement of electrical signaling Treatments were applied on day 21 in four groups of four chips each, each group treated with one of: 10 pM capsaicin; 10 pM oxytocin; 0.1% or 0.2% HO extract. This was done in parallel with recording the immediate effects of the treatments on electrical signaling, with a Maestro Pro (Axion Biosystems, Atlanta, GA, USA). Following 3 minutes’ basal recording, 20 pL of the respective sample vehicle was added via the keratinocyte channel inlet. Electrical activity was recorded for a further 3 minutes, following which the medium was removed from the keratinocyte channel inlet, and treatments were added in 20 pL volumes to the keratinocyte channel inlet (mimicking exposure through the stratum comeum and viable epidermis in the real-life situation). After a further 55 minutes incubation, electrical signaling was recorded over 10 minutes. Recordings were extracted from the AxIS Navigator 3.7.4 software (Axion Biosystems) using the spike count output with a 3 second binning. For each chip, the mean firing rate (MFR) over the three first minutes of the fast-acting recording was used to normalize all the data points. The activity fold change was obtained by normalizing the MFR over the entire length of the longterm recording.

[0278] Effects were assessed using a 1-way Anova analysis with Sidak’s post-hoc test, following normality and variance homogeneity checks; for non-normal data, a Kurskal Wallis analysis with Dun’s post hoc test was used instead. Outliers were excluded.

[0279] Immunofluorescent staining for DAPI (marker of nuclei) and peripherin (axon marker): Once the recording of electrical activity was complete, cell culture media were removed, and cell culture channels were washed with D-PBS. A 4% formaldehyde solution in D-PBS (diluted from Thermofisher 28908) was added, followed by 30 minutes’ incubation at room temperature. Channels were then triple-washed with D-PBS. A 0.1% Triton X100 (Sigma Aldrich X100) permeabilization solution was added, followed by 10 minutes’ incubation at room temperature and triple-washing with D-PBS. A 1% BSA blocking solution (Thermofisher 14190250) was added, followed by 30 minutes’ incubation at room temperature and removal of the blocking solution. A primary antibody solution (Anti-PRPH (Rabbit), diluted 1 / 50, Abeam ab4666, Cambridge, UK) was added to the neuron compartment, followed by incubation overnight at 4°C. After triple-washing with D-PBS, a secondary antibody solution (Anti-Rabbit AF647, diluted 1 / 1000, Abeam abl50075) was added in the dark, followed by 2 hours’ incubation in the dark at room temperature, and triple-washing with D-PBS. Finally, a 3 pM DAPI solution (Sigma D8417) was added, followed by 10 minutes’ incubation at room temperature and triplewashing with D-PBS.

[0280] Images were acquired with an Axio observer 7 microscope (Zeiss, Oberkochen, Germany). Images were reconstituted with the instrument’s software (Zeiss Zen 3.3.89).

[0281] Image analysis:

[0282] Image analysis was carried out using Fiji and Cellpose, as implemented in the BIOP Fiji plugin

[0283] Neuron nucleus segmentation: Raw DAPI images of the neuron compartment were also corrected for noise using a 2D-Gaussian blur filter (1x1 kernel value). To reduce the blurring effect observed in the DAPI-neuron staining and improve nucleus segmentation, a Fast Fourier Transform (FFT) was applied, including only high-frequency information (corresponding to nucleus staining). An unsharp masking (radius=15, mask=0.9) was performed, subtracting a blurred copy of the image and sharpening the DAPI-nucleus staining. Automatic nucleus segmentation was carried out using the stardist model, as implemented in Fiji, and the corresponding output segmentation maps were used to calculate the total number of neurons in the neuron compartment. analysis Peripherin staining was measured in the neuron compartment.

[0284] Raw images were corrected for Gaussian noise using a 2D-Gaussian blur filter (1x1 kernel value). A background correction was then performed using a rolling ball algorithm , determining local background value by averaging all values in a large ROI around each pixel, and subtracting this average value from the original image. The Tubeness Fiji-plugin was then used to produce a score for how "tube-like" each point in an image is, making it possible to focus specifically on peripherin staining corresponding to neuronal axons. Finally, a kmeans clustering algorithm (k=4) was applied to delimit these neuronal axons in the neuron compartment. This neuronal axon ROI was used to quantify peripherin density, defined as the ratio between the neuronal axon area and the image area in the neuron compartment.

[0285] Statistical analyses were performed using Prism 10.2.3 (GraphPad, Boston, MA, USA), using a one-way ANOVA test with post hoc Dunnett test or Sidak test for parametric tests and Kruskal-Wallis test with post hoc Dunn's test was used for non-parametric tests. A significance threshold of p < 0.05 was used for all analyses.

[0286] Results:

[0287] In an organ-on-a-chip model equipped with separate compartments for neurons and keratinocytes, electrical signaling data (Figure 4) showed a slight signaling increase vs. baseline with capsaicin (+19%), and a decrease after oxytocin treatment (-34% vs. capsaicin, p = 0.0147). Treatment with Hyacinthus orientalis extract at 0.1% and 0.2% decreased signaling activity to similar extents, by 41% at 0.1% ( / ?=0.0036) and 43% at 0.2% (p = 0.0043) vs. capsaicin treatment).

[0288] EXAMPLE 5: Clinical trial

[0289] Protocol :

[0290] This study was run following a double-blind, randomized placebo-controlled design, in two groups (Active vs. Placebo). Product application was to take place to the face and forearms twice a day for 28 days. So as to capture immediate, short-term, and longer-term effects, measurements were carried out at DO and D28 before and immediately (ca.30 min or Ih) after product application, as well as at D7. 60 subjects were recruited (in 2 groups of 30), aged 18 to 65 years, of both sexes (50% of each in each group); all types of skin were included; a phototype (Fitzpatrick) range of I to IV was selected. Menopausal status was recorded.

[0291] All evaluations were performed in one of two time periods (9h00-13h00 and 13h00-19h00) to as to minimize circadian variations, in a climate-controlled room and after at least 15 min acclimatization of at least (T = 21°C ± 2°C; RH = 55% ± 10%).

[0292] The following assessments were carried out:

[0293] • The subjects’ sensorial response to a gentle tactile stimulation of skin was assessed by Electroencephalography (EEG) (using a 32- channel Neuroelectrics Enobio-32 device, iMotions, Copenhagen, Denmark). A gentle touch on the forearm using a feather was used as model stimulus. Measurements were taken at DO before and after product application, at D7 (without product application), and at D28 before and after product application. A Power Spectral Decomposition of the EEG signals was performed in the following steps using the instrument software: Pre-processing of the signal: bandpass filtering and notch filtering (using a zero phase-lag band-pass Butterworth filter); rereferencing; artifact rejection; Fast Fourier Transform (FFT).

[0294] • Nociception and skin sensitivity were assessed using a Capsaicin stinging test, where cotton impregnated with a 3.16x10-5% Capsaicin solution (Sigma-Aldrich 1003366230, St Louis, MO, USA) is applied to the nasogenian fold. The stinging sensation is assessed at 2 min, 5 min and 10 min, on a 7-point scale from ‘absent’ to ‘significant’. The final stinging score is the mean of the three assessments. This assessment was made at DO and at D28, each time before and after product application.

[0295] • The visible healthy glow aspect of the skin was assessed by study participants and by trained clinicians, on a scale from Score 0: Absence of skin glow to Score 4: Very healthy skin glow. Grading was carried out on the whole face, at DO and D28 (each time, both before and after product application). Half-points were allowed to increase resolution.

[0296] • Skin color was evaluated using a tristimulus color analyzer measuring reflected light (Chromameter CR-400, Minolta, Japan), and expressing light in the three-parameter Hunter color space: Luminance (L*), a* (red-green) and b*(blue-yellow). The measurement was carried out in the periocular area, at DO and D28 (without product application). • Skin elasticity was evaluated using a Cutometer® dual MPA 580 (Courage & Khazaka, Germany) with a 2-mm probe, at DO and D28 (without product application). This method measures the elasticity of the upper skin layers using negative pressure (suction), which deforms the skin mechanically. The penetration depth of tissue into the probe (indicating the extent of skin deformation) is determined by an optical measurement system. Elasticity is evaluated as the skin’s ability to return into its original position following deformation.

[0297] • Skin wrinkling was assessed by image analysis using a Visia-CR with PRIMOS (VISIA- CR, Canfield, USA), taking standardized photographic images of the participants’ face at DO, D7 and D28 (without product application) with normal, cross-polarized, and parallel-polarized lighting. This instrument assesses wrinkle counts through deviation analysis of fringe projection images. Additionally, skin wrinkling was graded at DO and D28 (before and after product application each time), by trained clinicians, based on Bazin’s scale (Bazin, R. and Doublet, E., 2007. Skin aging atlas. Med'com.).

[0298] • Self-evaluation of skin comfort / pleasantness (skin sensoriality): quantification of skin comfort / pleasantness feeling was assessed by self-grading using a visual five-point scale (from very unpleasant (0) to very pleasant (5)) prior to and after application of the placebo cream or the cream of the invention on the skin. The percentage of change was expressed as compared to DO scoring prior application of the creams.

[0299] For the purposes of the clinical trial, the Ingredient of the Invention was formulated at 1% in a cream-gel chassis, alongside a corresponding placebo product, as detailed in the following Table.

[0300] Results :

[0301] The main results of the clinical trial are shown in Figures 5-10 and can be summarized as follows :

[0302] • EEG during feather touch stimulation: Selective left-side frontal activation of alpha waves was observed with 1% Hyacinthus orientalis bulb extract in formulation; the same was not observed with the Placebo product. This effect is apparent when comparing visualizations of EEG signal at DO before product application to those recorded on DO after product application, on D7, and on D28. This indicates that the extract exerts both short-term and long-term effects, and promotes positive affect and wellbeing sensations in the user via the enhancement of pleasurable skin touch perception (Figure 5A). These results were confirmed by the recording of alpha-wave activation at electrode AF3 (left frontal) at Day 0 (DO), (DO + 30 min after application), D7 and D28. In the literature, this kind of alpha wave activation is associated with positive affect and wellbeing, and indicates a positive emotional state advantage. As evidenced by Figure 5B, the Ingredient of the Invention at 1% in formulation (Hyacinthus orientalis bulb extract) enhances cerebral activity at AF3 and thus enhances skin touch sensorial receptivity 30 min after application. This effect is also present at D7 and D28 as compared to placebo. These results can be interpreted as indicating a pleasant or pleasurable sensation during the feather touch, more pronounced with the cream of the Invention than the placebo cream. One can conclude that the extract of the Invention grants both short-term and long-term increased receptiveness to gentle, pleasant tactile stimulation (represented by a feather touch), as evaluated by EEG. The extract of the Invention can thus promote positive affect and wellbeing sensations in the subject via the enhancement of pleasurable skin touch perception. Capsaicin stinging test: After 28 days, 1% Hyacinthus orientalis bulb extract in formulation shows a significant reduction (-24%, p < 0.01) in the capsaicin-induced stinging sensation compared to placebo. This indicates that the extract reduces skin nociception, confirming the in-vitro indications detailed above in Example 3 (Figure 6). Of note, similar results were obtained for nociception trigged by heat (data not shown).

[0303] • Self-evaluation of skin comfort / pleasantness (skin sensoriality): Self-evaluation confirmed that the cream of the invention enables significantly increased skin comfort in short and long terms as compared to the placebo cream.

[0304] • Healthy skin glow aspect grading: Clinician grading and self-assessments both show strong and statistically significant advantages in healthy glow with 1% Hyacinthus orientalis bulb extract in formulation, compared to placebo. At D28 compared to DO, before product application, +19% (p < 0.05) clinician grades and +32% (p < 0.05) self-assessment grades; after product application, +30% (p < 0.01) clinician grades and +36% (p < 0.05) selfassessment grades (Figure 7).

[0305] • Skin tone: After 28 days of treatment, Chromameter data show a significant reduction in skin redness (a*) (-9%, / ? < 0.01) with 1% Hyacinthus orientalis bulb extract in formulation, compared to placebo, supporting reduction in skin sensitivity. A small but significant lightening effect (L*) is also shown (+2%, / ? < 0.01) (Figure 8).

[0306] • Skin elasticity: Cutometer data at D28 showed an improvement in skin elasticity for 1% Hyacinthus orientalis bulb extract in formulation, compared to placebo (+13%, / ? < 0.05) (Figure 9).

[0307] • Skin wrinkling: Image analysis shows an advantage in wrinkle counts for 1% Hyacinthus orientalis bulb extract in formulation vs. placebo, at D28 compared to DO, of -18% (p < 0.05). This is borne out by clinician grading, which shows a decrease of -5% (p < 0.05) in wrinkle grading for 1% Hyacinthus orientalis bulb extract in formulation vs. placebo at D28 before product application compared to DO, and -7% (p < 0.05) at D28 after product application compared to DO.

Claims

Claims1. Cosmetic use of an aqueous extract of Hyacinthus orientalis bulb as a skin neurosensorial agent.

2. The cosmetic use of Claim 1 wherein the extract is obtained from dormant bulbs of Hyacinthus orientalis.

3. The cosmetic use of Claim 1 or 2, wherein the extract is obtained by a process comprising the steps of:(a) incubating peeled and crushed bulbs in water so as to obtain a slurry,(b) recovering an aqueous phase from the slurry obtained in step (a)(c) heating the aqueous phase obtained in step (b) at a temperature above 95 °C and then cooling so as to promote precipitation,(d) recovering the aqueous phase from step (c), and(e) optionally filtering and / or concentrating the aqueous phase obtained in step (d) whereby the aqueous extract is obtained.

4. The Cosmetic use of any one of Claims 1 to 3, wherein the extract is used for improving skin perception.

5. The Cosmetic use of any one of Claims 1 to 4, wherein the extract is used for rebalancing or improving the neurosensorial responsiveness of the skin to stimuli.

6. The Cosmetic use of any one of Claims 1 to 5, wherein the extract is used for decreasing or preventing skin nociception.

7. The Cosmetic use of any one of Claims 1 to 6, wherein the extract is used for enhancing the skin’s receptiveness to pleasant and / or gentle tactile stimuli.

8. The Cosmetic use of any one of Claims 1 to 7, wherein the extract is used for attenuating skin discomfort and / or for providing comforting effect to the skin.

9. The Cosmetic use of any one of Claims 1 to 8, wherein the Hyacinthus orientalis bulb extract is used for preventing or alleviating age-related impairment of skin perception, in particular skin sensitivity.

10. The Cosmetic use of any one of Claims 1 to 9, wherein the extract is further used for improving the visual appearance of the skin, in particular for attenuating, decreasing or treating one or more non-pathological alterations of the skin appearance such as roughness, redness, loss of radiance or glow, dull or non-uniform complexation, tired aspect and combination thereof.

11. The Cosmetic use of any one of Claims 1 to 10, wherein the extract is topically applied on a skin, e.g. on sensitive skin, and / or mature skin.

12. The Cosmetic use of any one of Claims 1 to 9, wherein the extract is topically applied on a skin of the intimate body area.

13. The Cosmetic use of claim 12, wherein the extract is used topically in the skin of the intimate body area to alleviate discomfort and / or to increase receptiveness and / or increase wellbeing in the intimate skin area14. The Cosmetic use of any one of Claims 1 to 9, wherein the extract is topically applied on hair scalp.

15. The Cosmetic use of Claim 14, wherein the extract is used to alleviate hair scalp discomfort.

16. The cosmetic use of any one of Claims 1 to 15 wherein the extract is present as an active cosmetic ingredient in a cosmetic composition which is applied on the skin.

17. The cosmetic use of Claim 16, wherein the cosmetic composition is selected from a skin care product, a skin hygiene product, a make-up product, a hair care product, or an intimate care product such as a cream e.g. a night or a daily cream or a massage cream, a balm, an ointment, a serum, a gel, a mask, a foundation, a soap, a shower gel, a shampoo, a hair conditioner, or an aftershave.

18. A cosmetic composition for improving skin perception, for improving the visual aspect of the skin, and / or for increasing skin receptiveness, and / or for decreasing skin discomfort and / or for providing wellness in a subject comprising an aqueous extract obtained from Hyacinthus orientalis bulbs and at least one cosmetically acceptable excipient.

19. The cosmetic composition of Claim 18 wherein the aqueous extract is as defined in any one of claims 2 to 3.

20. The cosmetic composition of Claim 18 or 19 wherein the aqueous extract is formulated into glycerin before being incorporated in the cosmetic composition.21 A cosmetic method for improving skin perception, and / or for increasing skin receptiveness, and / or for decreasing skin discomfort, and / or for improving the visual aspect of the skin and / or for providing wellness in a subject, comprising topically applying an aqueous extract obtained from Hyacinthus orientalis bulbs preferably as defined in Claims 2 or 3, or a cosmetic composition as defined in Claim 18 on the skin of the subject.

22. The method of Claim 21 wherein the subject has mature and / or sensitive skin and / or the subject is a peri-menopausal or menopausal woman.

23. A cosmetic ingredient comprising an aqueous extract from Hyacinthus orientalis bulbs, preferably from dormant Hyacinthus orientalis bulbs, as active cosmetic agent in a cosmetically acceptable carrier, preferably in a glycerin / water mixture.

24. The cosmetic ingredient of Claim 23 which further comprises one or more cosmetically acceptable excipients selected from antioxidants, preservatives and pH adjusting agents.

25. Use of an aqueous extract of Hyacinthus orientalis bulb as a skin neurosensorial agent for the manufacture of a composition for improving skin perception and / or for decreasing or preventing skin nociception and / or for alleviating skin discomfort.

26. The use of Claim 25 wherein the composition is a skin care product, an intimate care product or a hair care product.

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