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WO2024062470A1 - Compositions dermiques et cosmétiques - Google Patents

Compositions dermiques et cosmétiques Download PDF

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Publication number
WO2024062470A1
WO2024062470A1 PCT/IL2023/050989 IL2023050989W WO2024062470A1 WO 2024062470 A1 WO2024062470 A1 WO 2024062470A1 IL 2023050989 W IL2023050989 W IL 2023050989W WO 2024062470 A1 WO2024062470 A1 WO 2024062470A1
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WO
WIPO (PCT)
Prior art keywords
composition
skin
polygonum
disorder
extract
Prior art date
Application number
PCT/IL2023/050989
Other languages
English (en)
Inventor
Zeevi Maor
David PELED
Original Assignee
Moraz Medical Herbs (1989) Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Moraz Medical Herbs (1989) Ltd. filed Critical Moraz Medical Herbs (1989) Ltd.
Publication of WO2024062470A1 publication Critical patent/WO2024062470A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/733—Fructosans, e.g. inulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • A61K36/704—Polygonum, e.g. knotweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/99—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from microorganisms other than algae or fungi, e.g. protozoa or bacteria

Definitions

  • the invention generally pertains to the field of dermatological and cosmetic compositions using combinations of probiotic and herbal extracts, and specifically to compositions comprising live probiotics and prebiotics and Polygonum plant extracts.
  • the skin microbiome has been attracting increasing attention in recent years, from dermatologists and cosmetologists as one. It is now well established that a balanced skin microbiome in terms of preservation and maintenance of various commensal species composing the skin microbiota, i.e., bacteria, archaea, fungi, yeast, and viruses, is one of the key factors in protecting the skin against environmental and internal insults, and that an imbalance in the normal “healthy” diversity of skin microbiota (dysbiosis) is closely associated with various dermatological disorders and premature skin aging.
  • various commensal species composing the skin microbiota i.e., bacteria, archaea, fungi, yeast, and viruses
  • the skin is the largest organ with the outermost interface with the environment, whereby it creates multiple ecological niches for various commensal microorganisms.
  • Microbiome often referred to as “the hidden organ,” is a term denoting a functioning community of such commensal microorganisms at a specific body area of the host, in relation to the entire range of their phylogenetic, genetic, and biochemical components, their networking, and their interaction with the host.
  • Microbiome, and especially the skin microbiome is highly variable and dynamic structure that changes drastically in the same individual host and between individuals.
  • Probiotics are mixes of microorganisms with benefits for healthy microbiome (e.g., bacteria or yeast).
  • Prebio tics are compounds that stimulate microbial growth (e.g., carbohydrates)
  • Synbiotics are mixes of prebiotics and probiotics.
  • Postbio tics are additional components derived from live bacteria that contribute to probiotic activity (e.g., amino acids, antimicrobial peptides). In most countries probiotics are regulated under the umbrella of foods and supplements.
  • the main challenge remains in the ability to provide live and sustainable preparations of probiotics that could be incorporated into pharmaceutical and cosmetic formulations without compromising their viability and shelf-life and to ensure their successful delivery and activity in situ upon topical application onto the skin.
  • the existing cosmetic products for example, often use bacterial cell lysates and not live bacteria, and thus are essentially deprived of all the desired benefits of genuine probiotics.
  • compositions with probiotics were reported in patent literature, most of them using representatives of Lactobacillus and/or Bifidobacteria species (e.g., W02017063066A1, US10695386B2, US10238597B2, US20080107699A1, EP3727594A1, JP2009503042A, EP2704704B1, US11007137B2). While these two genera may have well documented benefits for the gut microbiome, their role in the skin microbiome is much less established as well as their use and delivery with topical applications. Another approach was suggested in EP3210612B 1 and EP0975227A1, describing cosmetic compositions with certain Bacillus strains in the form of spores and a prebiotic sugar, but without significant data on their safety and efficacy.
  • Polygonum is a flowering plant in the buckwheat-knotweed family Polygonaceae. It is being extensively used in traditional medicines for a variety of indications, including dizziness, soreness of back and knees, premature ejaculation, fatigues, atherosclerosis, high cholesterol, insomnia, menstrual problems, malaria, and many other conditions. It is widespread in temperate regions across many countries, with about 130 known species. A strain of Polygonum that is prevalent in Eurasia, Polygonum aviculare, proved to be particularly beneficial for skin conditions and atopic deficiencies.
  • Extracts of P. aviculare were shown to contain a particularly high content of active alkaloids and polyphenols, including flavonoids, terpenoids, phytoestrogens, quinones. Examples of such phytochemicals are shown in Table 1. Table 1. Active phytochemicals detected in the extracts of P. aviculare
  • the invention stems from more recent surprising findings by the inventors in a reconstructed skin in vitro model that was subjected to global transcriptome analysis with the assistance of bioinformatic tools, showing that a combination of Polygonum extract and Synbio® possesses new biological properties that are essentially distinct from the properties of the two components.
  • a pilot study using this advanced molecular approach suggested that the effects of single components and the combination of both components differed strikingly by qualitative and quantitative parameters of the induced gene expression, which was not restricted to individual genes but rather reflected much broader changes in global gene expression (EXAMPLE 2).
  • the inventors could show that the induced changes in gene expression could be mapped to specific functional signaling pathways, and that the single and the combination preparations were further distinct by the up or down-regulation of specific molecular pathways.
  • the results suggested the involvement of pathways responsible for the regulation of cell cycle and pluripotency and differentiation of keratinocytes, and pathways regulating biosynthesis and metabolism of some important epidermal and dermal components, such as retinol, elastin and collagen, and mediators of radical scavenging (EXAMPLE 2).
  • the effectiveness of a probiotic preparation is highly dependent on the ability to preserve the probiotic bacteria in a specific formulation and the ability to evoke bacterial germination upon topical application onto the skin.
  • Synbiotic preparations, and particularly those including bacterial spores should in theory comply with both these requirements, assuming prolonged stability of spores and activation of bacterial germination by prebiotic sugar.
  • the question of effectiveness of the presently used synbiotics was addressed in a pilot study of healthy volunteers, daily applying a cream formulation with Synbio® over a 10-day period and testing bacterial viability in topicals samples of these individuals.
  • the invention provides a new line of products based on combinations of Polygonum extracts and Bacilli-based synbiotics that proved to be safe and efficient for cosmetic and dermatological uses.
  • the combinations of the invention can be formulated into gels, lotions, creams, sprayable liquids, ointments, powders, or semi-sold formulations. They can be further incorporated into various matrixes and films and provided in the form of dermal patches.
  • compositions and formulations of the invention can serve both for prevention and treatment. Relying on the present molecular data, they can be effective for alleviation of a wide range of temporary and chronic skin conditions, which in the most general terms can be referred to as clinical and preclinical conditions resulting from disruption of skin homeostasis, and more specifically conditions such as skin infections, skin inflammations, allergies, rashes, erythema, in promoting wound healing, protecting against photoinduced, oxidative and pollution damages, skin drying, discoloration, wrinkling, and skin aging in general.
  • GRAS generally safe
  • compositions and formulations of the invention can be articulated in terms of facilitators or inducers of a healthy complexion and rejuvenated appearance of the skin.
  • the products derived from the compositions and formulations of the invention meet the conditions of vegan cosmetics. Today, they are undergoing a process of registration under the trademark “PolyBiome”. BRIEF DESCRIPTION OF THE DRAWINGS
  • Fig. 1A illustrates the antiallergic effect of P. aviculare extract as revealed in the passive cutaneous anaphylaxis (PCA) model in mice, using anti-DNP-BSA specific IgE (0.5 pg) and DNP-BSA antigen with Evans blue (an indicator of mast cell reaction).
  • the extract was administered topically (100-1000 mg/kg) Ih before antigen exposure, diphenhydramine (DPH) was used as positive control.
  • Figure shows that Polygonum extract inhibited PCA in a dose dependent manner.
  • Fig. IB illustrates the antioxidant effect of P. aviculare extract by NBT assay (nitroblue tetrazolium assay) in vitro.
  • Cells were treated with the extract (2.5-100 pm/ml) (A) compared to cells treated with catechin as positive control ( ⁇ ), H2O2 measurements were obtained from five independent experiments.
  • Figure shows that Polygonum extract effectively inhibited free radical activity at the concentration as low as 2.5 pm/ml (60% inhibition), reaching a complete inhibition (100% inhibition) at concentrations of 5 pm/ml and higher.
  • Fig. 2A illustrates the dissimilarities of gene expression induced by single preparations of synbiotics (Syn, Synbio®) or P. aviculare extract (Poly) and combinations of Syn and Poly in various proportions (50_Syn_50_Poly and 33_Syn_67_Poly) as revealed in a reconstructed skin in vitro model by microarray analysis and computational comparisons.
  • Figure shows MDS plot (multidimensional scaling) of calculated dissimilarity (distance) for pairwise comparisons of individual signals on the arrays corresponding to treatments with single and combination preparations and combination preparations with different proportions of Syn and Poly, suggesting marked differences of gene expression in various treatments.
  • Fig. 2B shows MDS plot that further includes comparisons between treatments with combination preparations normalized to single preparations.
  • Figure shows that the changes in gene expression in combination preparations are distinct from changes in single preparations, and that the relative representation of single components (ratios 1:1 or 1:2) further contributes to these dissimilarities.
  • Fig. 3 illustrates the effect of the 50_Syn_50_Poly preparation (ratio 1:1) on changes in gene expression by the number of up- and down-regulated and unchanged genes, calculating the log fold change (log FC) of each gene in treated vs control groups and adjusted log FC relative to the median expression from the array. A two-fold change in the adjusted log FC was used as a cutoff for selection of up- and down-regulated genes.
  • Fig. 4 is another presentation of the same analysis by MA plot to illustrate the magnitude of changes (fold change vs no change) and the number of involved genes.
  • the invention provides a natural-based solution to problems of the skin stemming from impairments of skin homeostasis or disruption of skin barrier by reconstituting and reinforcing healthy skin homeostasis and healthy skin microbiome.
  • compositions and formulations these terms herein are interchangeable, comprising extracts of plants of the genus Polygonum and certain preparations of probiotics and prebiotics, the combination of these two latter is referred to herein as synbiotics.
  • synbiotics are distinct by the type of the probiotic component and the prebiotic component. The general advantage of synbiotics is in facilitating the germination or viability of the probiotic component upon application of the formulation onto the skin.
  • the prebiotic component can be a prebiotic sugar, which is an effective inducer of germination of bacteria and yeast.
  • the probiotic component can be a mix of live bacteria or yeast.
  • the prebiotic component or the prebiotic sugar can be an optional component since live probiotics, as opposed to spores, can easily move into a vegetative phase upon topical application of the formulation onto the skin.
  • the probiotic component can be a mix of bacterial or yeast spores, i.e., dormant probiotics.
  • the probiotic sugar is required for triggering the spores to move into a vegetative phase and for inducing their germination in situ. This type of synbiotics is advantageous in terms of preservation of the probiotic component.
  • compositions of the invention can be topical compositions, other words, can be formulated so as to permit direct application thereof onto the skin.
  • the methods of making topical formulations in terms of choice of excipients, stabilizers, skin absorption enhancers, etc., would be well known to a skilled practitioner in the field.
  • the invention uses extracts of plants belonging to the genus Polygonum (family Polygonaceae), which includes about 130 species that are distributed worldwide, predominantly in temperate climates.
  • Polygonum encompasses herein alternative names such as knotweed, knotgrass, bistort, tearthumb, mile-a-minute, all are perennial flowering plants of herbaceous or woody nature.
  • plant encompasses herein any part of a plant.
  • the plant can be of the species Polygonum aviculare, also known as prostrate knotweed, birdweed, pigweed and lowgrass, which encompasses herein all recognized morphological variations and different sub-species of these plants.
  • the plant extract can be prepared by various known procedures.
  • extraction methods that can be applicable to the invention are steam distillation, filtration, maceration, digestion, decoction, infusion, percolation, Soxhlet extraction using solvents such as acetone, hexane and dichloromethane (DCM), supercritical fluid extraction, supercritical CO2 extraction, ultrasound-assisted, microwave-assisted extractions, and combinations of the above methods, and also extraction by organic solvents such as ethanol, hexane, diethyl ether, chloroform and mixtures thereof in various proportions.
  • solvents such as acetone, hexane and dichloromethane (DCM)
  • supercritical fluid extraction supercritical CO2 extraction
  • ultrasound-assisted ultra-assisted
  • microwave-assisted extractions and combinations of the above methods
  • organic solvents such as ethanol, hexane, diethyl ether, chloroform and mixtures thereof in various proportions.
  • the Polygonum extracts can be prepared by immersion of the plant or a part thereof in a mixture of water, oil and Vaseline (an optional component), which is then boiled, soaked, infused and filtered to obtain a clear extract enriched with the original phytochemicals.
  • the Polygonum extracts of the invention can be obtained by boiling the Polygonum plant in a mixture comprising water and oil, soaking the boiled mixture, and filtering the mixture to obtain a clear extract.
  • the Polygonum extracts of the invention can be obtained by steam exposure of the Polygonum plant in a mixture comprising water and oil, soaking the mixture, and filtering the mixture to obtain a clear extract.
  • the Polygonum extracts of the invention can comprise substantial amounts of water, or more specifically up they can comprise up to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% and up to 99.99% water as measured by units of weight or volume (w/v, v/v or w/w).
  • the Polygonum extracts can comprise water in the range of 1-5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95% and 95- 99.99% as measured by units of weight or volume (w/v, v/v or w/w).
  • compositions of the invention can comprise more than one type of Polygonum extract or a mix of extracts obtained from more than one species of Polygonum plant.
  • the probiotic component can be yeast.
  • Yeast can exist in vegetative and dormant spore forms.
  • Some examples of yeasts that are used in cosmetic products are Saccharomyces cerevisiae and Torula yeast.
  • the probiotic component can be bacteria.
  • Bacillus strains for example, can exist in both vegetative and spore forms. They have been recognized as useful probiotics, predominantly in the context of gut, due to exceptionally high stability under various conditions, and additional benefits.
  • compositions of the invention can comprise bacterial spores of one or more Bacillus spp., e.g., 1, 2, 3 or 4 Bacillus spp or more.
  • Bacillus spp. can be one of the following Bacillus spp: B. subtilis, B. licheniformis, B. megaterium, B. amyloliquefaciens .
  • compositions can comprise one out of four Bacillus spp. as above, i.e., B. subtilis, B. licheniformis, B. megaterium or B. amyloliquefaciens.
  • they can comprise two out of four Bacillus spp. as above, in various combinations.
  • they can comprise three out of four Bacillus spp. as above, in various combinations.
  • they can comprise all four Bacillus spp. as above, i.e., B. subtilis, B. licheniformis, B. megaterium and B. amyloliquefaciens.
  • the relevant prebiotic sugars are generally oligosaccharides, which are a type of carbohydrate composed of a relatively small number of monosaccharide units.
  • Nonlimiting examples of such sugars are fructo-oligosaccharides, galactooligosaccharides, and human milk oligosaccharides.
  • the general property of these compounds is that they stimulate the growth of the probiotic component, and specifically bacteria.
  • the compositions of the invention can comprise one or more probiotic sugars from natural sources.
  • compositions can comprise the least one probiotic sugar which is inulin.
  • Inulin is a naturally occurring oligosaccharide produced by certain plants. It belongs to the family of fructooligosaccharides, it is indigestible and non-absorbable.
  • compositions can comprise postbiotics, which are bioactive compounds that support the growth of probiotic bacteria such fatty acids, amino acids and nutrients.
  • compositions of the invention can comprise the Polygonum extracts and the synbiotics at a ratio in the range between about 10,000:1 and about 1 : 10,000, respectively, or more specifically at a ratio in the ranges of about 10,000: 1 to 1:10,000, about 9,000:1 to about 1:9,000, about 8,000:1 to about 1:8,000, about 7,000:1 to about 1:7,000, about 6,000:1 to about 1:6,000, about 5,000:1 to about 1:5,000, about 4,000:1 to about 1:4,000, about 3,000:1 to about 1:3,000, about 2,000:1 to about 1:2,000, about 1,000:1 to about 1:1,000, about 900:1 to about 1:900, about 800:1 to about 1:800, about 700:1 to about 1:700, about 600:1 to about 1:600, about 500:1 to about 1:
  • compositions can comprise the Polygonum extracts and the synbiotics at a ratio in the range between about 10,000:1 and about 1:1, respectively, or more specifically at a ratio in the ranges of about 10,000:1 to 1:1, about 9,000:1 to about 1:1, about 8,000:1 to about 1:1, about 7,000:1 to about 1:1, about 6,000:1 to about 1:1, about 5,000:1 to about 1:1, about 4,000:1 to about 1:1, about 3,000:1 to about 1:1, about 2,000:1 to about 1:1, about 1,000:1 to about 1:1, about 900:1 to about 1:1, about 800:1 to about 1:1, about 700:1 to about 1:1, about 600:1 to about 1:1, about 500:1 to about 1:1, about 400:1 to about 1:1, about 300:1 to about 1:1, about 200:1 to about 1:1, about 100:1 to about 1:1, about 90:1 to about 1:1, about 80:1 to about 1:1, about 70:1 to about 1:1, about 60:1 to about 1:1, about 50:1 to about 1:1, about 40:1 to
  • compositions can comprise the Polygonum extracts and the synbiotics at a ratio in the range between about 1,000:1 and about 1:1, respectively, as measured by units of weight or volume.
  • compositions can comprise the Polygonum extracts and the synbiotics at a ratio in the range between about 100:1 and about 1:1, respectively, as measured by units of weight or volume.
  • compositions can comprise the Polygonum extracts and the synbiotics at a ratio in the range between about 10:1 and about 1:1, respectively, as measured by units of weight or volume.
  • compositions can comprise the Polygonum extracts and the synbiotics at a ratio of about 7:3, 3:2, 3:1, 2:1 or 1:1, respectively, as measured by units of weight or volume.
  • compositions can comprise the Polygonum extracts and the synbiotics at a ratio of about 2.5:1, 2:1, 1.5:1 or 1:1, respectively, as measured by units of weight or volume.
  • compositions can comprise the Polygonum extracts and the synbiotics at a ratio of about 2:1 or 1:1, respectively, as measured by units of weight or volume.
  • the Polygonum extracts can comprise substantial amounts of water, in some embodiments the Polygonum extracts can constitute more than about 10% of the composition, or more specifically more than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% and 95% of the composition, as measured by units of weight or volume (w/v, v/v or w/w).
  • the Polygonum extracts can constitute more than about 10% of the composition (w/v), or more specifically more than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% and 95% of the composition (w/v).
  • the synbiotics can be diluted in a mixture of water and glycerin to the consistency of a liquid blend.
  • said liquid blend can comprise water at a concentration in the range between of about 0.1-5% of the liquid blend, or water at a concentration in the ranges of about 0.1-0.5%, 0.5-1%, 1-1.5%, 1.5-2%, 2-2.5%, 2.5-3%, 3-3.5%, 3.5-4%, 4- 4.5% and 4.5-5% of the liquid blend, and glycerin at a concentration in the range between about 1 %- 10%, or glycerin at a concentration in the ranges of about 1-2%, 2-3%, 3-4%, 4-5%, 5-6%, 6-7%, 7-8%, 8-9% and 9-10% of the liquid blend, as measured by units of weight or volume (w/v, v/v or w/w).
  • said liquid blend can comprise water at the concentration of about 0.5% and glycerin at the concentration of about 6%, as measured by units of weight or volume (w/v, v/v or w/w).
  • the diluted synbiotics can constitute about 0.1% to about 10% of the composition, or more specifically in the ranges of about 0.1-0.5%, 0.5-1%, 1- 1.5%, 1.5-2%, 2-2.5%, 2.5-3%, 3-3.5%, 3.5-4%, 4-4.5%, 4.5-5%, 5-5.5%, 5.5-6%, 6- 6.5%, 6.5-7%, 7-7.5%, 7.5-8%, 8-9.5% and 9.5-10% of the composition, as measured by units of weight or volume (w/v, v/v or w/w).
  • the diluted synbiotics can constitute about 0.1% to about 5% of the composition, as measured by units of weight or volume (w/v, v/v or w/w).
  • compositions can be further formulated as a micro- or a nano-particulate matter or encapsulated into micro- or nanoparticles.
  • compositions can further comprise at least one additional therapeutic or cosmetic active, a mineral, a vitamin or a nutrient.
  • additional therapeutic or cosmetic active a mineral
  • a vitamin or a nutrient Non-limiting examples are vitamins A, D, E and K that are common in cosmetic compositions, and the conventional antiviral, antibacterial and anti-inflammatory drugs that included in many dermatological formulations.
  • compositions can further comprise various humectants, surfactants, solvents, emulsifiers, etc., to achieve desired consistency and texture.
  • compositions can comprise one or more agents from one or more of following groups: humectants, surfactants, emulsifiers, thickeners, preservatives, coloring agents, perfumes, or any combination thereof.
  • compositions can further comprise enzymes, phytochemicals, vitamins, antioxidants, fragrance substances and essential oils.
  • Stability of the Polygonum component can be evaluated by measuring the content or concentration of alkaloids and/or polyphenols at various time points using HPLC or analogous methods.
  • Stability of the synbiotics component in the course time can be evaluated by various bacterial viability assays (e.g., number of CFU (colony formation units) by plating or flow cytometry or MTT assay, and fluorescence staining methods).
  • compositions of the invention can have stability for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months and more at room temperature (RT).
  • RT room temperature
  • compositions can have stability for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, years and more at RT.
  • compositions can be provided in various forms, including but not limited to gels, lotions, creams, liquids and ointments, or more generally, liquid, semi-liquid, semisolid and solid formulations adapted for topical use.
  • One type of product is pharmaceutical or dermatological formulations comprising one or more of the presently disclosed compositions and a pharmaceutically acceptable carrier and/or excipient.
  • compositions comprising one or more of the presently disclosed compositions and a cosmetically acceptable carrier and/or excipient.
  • Still another type are dermal patches, matrixes or films comprising or impregnated with one or more of the presently disclosed compositions.
  • the dermatological and the cosmetic formulations of the invention can be a gel, a lotion, a cream, a serum, a sprayable liquid, an ointment, a powder, a mask, a shampoo or a liquid or semi-liquid soap.
  • compositions and formulations are revealed in their ability to provide prevention, treatment or alleviation of disorders or conditions resulting from disruption of skin homeostasis and/or skin microbiome.
  • the effects of the compositions of the invention are apparent at the molecular and cellular levels in cellular models closely mimicking the architecture and composition of the skin epidermis.
  • the effect of the compositions and formulations of the invention can be revealed by the detection of expression changes in at least one gene (i.e., biomarker), including over (up-regulated) and under (down-regulated) expression using various RNA-based and protein -based methods such quantitative PCR and proteomics.
  • the effect of the present compositions and formulations can be revealed by the detection of changes in expression of at least one gene (biomarker) related along specific molecular pathways, including but not limited to pathways related to TNF signaling, NF-KB signaling, WNT signaling, proteasome and cell cycle pathways, and pathways responsible for retinol, elastin and collagen metabolism.
  • biomarker a gene related along specific molecular pathways, including but not limited to pathways related to TNF signaling, NF-KB signaling, WNT signaling, proteasome and cell cycle pathways, and pathways responsible for retinol, elastin and collagen metabolism.
  • compositions and formulations of the invention can induce changes in the expression of one or more of the following biomarkers:
  • compositions and formulations can induce changes in the expression of biomarkers responsible for immunological response, such as cytokines TNFa, TNFp, and interleukins IL6, IL8, ILla, ILlp and IL17.
  • biomarkers responsible for immunological response such as cytokines TNFa, TNFp, and interleukins IL6, IL8, ILla, ILlp and IL17.
  • compositions and formulations can induce changes in the expression of one or more biomarkers of response to oxidative stress, such as superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), glutathione peroxidase (GPX3), thioredoxin (TRX2), cytochrome c peroxidase (CCP1), pentose phosphate pathway enzymes (GND1 and RPE1) and transcription factors for response to oxidative stress (YAP1 and SKN7).
  • SOD superoxide dismutase
  • GPX glutathione peroxidase
  • CAT catalase
  • TRX3 glutathione peroxidase
  • TRX2 thioredoxin
  • CCP1 cytochrome c peroxidase
  • GPD1 and RPE1 pentose phosphate pathway enzymes
  • transcription factors for response to oxidative stress YAP1 and SKN7
  • compositions and formulations can induce changes in the expression of one or more biomarkers of keratinocytes differentiation, such as keratin and filaggrin (FLG).
  • biomarkers of keratinocytes differentiation such as keratin and filaggrin (FLG).
  • compositions and formulations can induce changes in the expression of one or more biomarkers of aging (senescence), such as collagen, elastin, P-galactosidase (P-GAL), Ki-67 nuclear protein, matrix metalloproteinases (MMPs), and pl 6 I K4a (pl 6) and cyclin-dependent kinase inhibitor (CKVp21) senescence biomarkers.
  • biomarkers of aging such as collagen, elastin, P-galactosidase (P-GAL), Ki-67 nuclear protein, matrix metalloproteinases (MMPs), and pl 6 I K4a (pl 6) and cyclin-dependent kinase inhibitor (CKVp21) senescence biomarkers.
  • biomarkers of aging such as collagen, elastin, P-galactosidase (P-GAL), Ki-67 nuclear protein, matrix metalloproteinases (MMPs), and pl 6 I K4a (pl
  • compositions and formulations can induce changes in the expression of one or more biomarkers which are growth factors, such as epidermal growth factor (EGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), transforming growth factor family (e.g., TGFP, HGNC, TGFpi-3) and growth factors receptors (e.g., EGFR, KGFR, HGFR, TGFR).
  • growth factors such as epidermal growth factor (EGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), transforming growth factor family (e.g., TGFP, HGNC, TGFpi-3) and growth factors receptors (e.g., EGFR, KGFR, HGFR, TGFR).
  • the compositions and formulations can induce changes in the expression of one or more biomarkers of apoptosis such as caspase 3/7 and caspase 8, for example.
  • compositions and formulations can induce changes in the expression of one or more collagen disrupters such as collagenase and/or elastin disrupters such as elastase.
  • the effect of the compositions and formulations of the invention can be revealed at the level of tissue functionality, such as processes involving neutralization of free radicals and effects of UV, control inflammation, keratinocyte differentiation, using perspective methods that are known in the art.
  • the effect of the compositions and formulations can be measured in vivo by measuring various physical, biochemical, cellular, immunological and morphological parameters of the skin, tissue and indices of skin homeostasis or skin barrier functionality.
  • skin homeostasis and “skin barrier” are closely related in the sense of preservation and maintenance of the intrinsic organization of the internal organic milieu as opposed to the erratic external environmental conditions.
  • the effect of the compositions and formulations can be measured by measuring changes in the diversity and composition of the skin microbiome.
  • compositions and formulations of the invention can be used for preventing, treating or alleviating disorders or clinical and preclinical conditions resulting from a disruption of skin homeostasis and/or skin microbiome.
  • disorders or clinical and preclinical conditions resulting from a disruption of skin homeostasis and/or skin microbiome encompass true dermatological disorders with a bona fide clinical manifestation and further common preclinical conditions such as rashes, minor skin inflammations or local infections, and other skin imperfections resulting from natural processes such as drying, discoloration, wrinkling and aging of the skin, and further changes in the diversity and composition of the skin microbiome.
  • such conditions can be temporary, chronic, or recurrent skin conditions, in terms of timeframe and length of the manifested of symptoms or changes.
  • such conditions can involve persistent, temporary, or recurrent inflammation of one or more regions of the skin.
  • such conditions can involve persistent, temporary, or recurrent viral, bacterial or fungal infection or an infection by macro-or micro-parasites, as primary or secondary infections.
  • Non-limiting examples are bacteria causing cellulitis, impetigo, and staphylococcal (staph) skin infections, viruses in shingles, warts, and herpes simplex, fungi in athlete's foot and yeast skin infections and parasites such as body lice, head lice, and scabies.
  • compositions and formulations of the invention can be for preventing, treating or alleviating symptoms or recurrence of acne, cold sore, blisters, hives, warts, ringworm, impetigo, actinic keratosis, rosacea, a skin allergy, an eczema, contact dermatitis, atopic dermatitis, psoriasis, cellulitis, keratosis pilaris.
  • compositions and formulations are particularly interesting applications in promoting wound healing and protecting against damages of pollution, irradiation and oxidative stress, and in restoring a healthy complexion and rejuvenated appearance of the skin.
  • they can be used for improving or promoting wound healing.
  • they can be used for protecting against photoinduced damage to the skin, including UV damage.
  • they can be used for protecting against oxidative stress or pollution damage to the skin.
  • inflammaging implies inflammatory processes related to skin aging.
  • they can be used for moisturizing, soothing, firming and maintaining a rejuvenated appearance of the skin.
  • compositions and formulations of the invention can be used for applications onto sensitive skin.
  • the invention can be further articulated in terms of analogous cosmetic and dermatological methods and uses. Of particular relevance in this context is the concept of an effective amount of the compositions and formulations.
  • effective amount implies herein an amount, a dose or a concentration of active(s) that induces a measurable effect on the molecular, cellular, or tissue levels, or on the level of whole organism.
  • One of the interesting application of the present compositions, formulations and methods is in the field of probiotic-based cosmetics, especially in view of present findings they probiotic component remains viable in situ for a substantial period without interfering or disrupting the normal healthy skin microbiome.
  • the invention can provide a line of cosmetic leave-on products comprising formulations and compositions of the invention.
  • P. aviculare extract was prepared by chloroform extraction method. Previous analysis showed that P. aviculare extracts have a particularly high content of flavonoids, terpenoids, phytoestrogens, quinones and other alkaloids, polyphenols (Table 1 above). Total phenolic content of P. aviculare extract can be in the range of 677.4 ⁇ 62.7 mg/g, which is significantly higher than in extracts of aloe vera for example. This study tested several biological activities of the P. aviculare extract using in vivo and in vitro models.
  • Antiallergic activity of P. aviculare extract was tested in vivo by inducing local mast-cell mediated allergic reaction in mice.
  • Animals were exposed to anti-DNP-BSA (di-nitrophenol conjugated bovine serum albumin) specific IgE (0.5 pg) and further to DNP-BSA antigen containing Evans blue (an indicator of mast cell reaction).
  • the extract was administered topically (100-1000 mg/kg) before antigen exposure (1 h).
  • Diphenhydramine (DPH), an antihistamine drug was used as positive control. The results are shown in Fig. 1A.
  • Antimicrobial activity of P. aviculare extract was tested in vitro by antibiotic susceptibility testing (AST) by measuring the diameter of inhibition zone with various Gram-positive and Gram-negative bacteria. Plated bacteria were treated with increasing concentrations (0.4-400 mg/ml) of the extract. The results (mm inhibition zone) are shown in Table 2.
  • Antifungal activity of P. aviculare extract was tested in vitro by AST in different strains of pathogenic fungi (Aspergillus flavus and Aspergillus fumigatus), applying the extract (0.4-400 mg/ml) and measuring the diameter of inhibition zone. The results are shown in Table 3.
  • A. flavus is the second leading cause of invasive aspergillosis.
  • A. fumigatus causes a spectrum of diseases, e.g., allergic bronchopulmonary aspergillosis, chronic pulmonary aspergillosis and invasive aspergillosis.
  • the results show that Polygonum extract exerted effective antifungal activity on both types of fungi in a dose dependent manner.
  • the numbers of differentially expressed genes (DEG) detected are shown in Table 4.
  • Dissimilarities between groups were further evaluated using multidimensional scaling (MDS) plots, calculating dissimilarity (distance) for each pairwise comparison of gene signals on the respective arrays.
  • MDS multidimensional scaling
  • Figs. 2A-2B illustrating dissimilarities by the positions of groups on the plot.
  • Figures show clear distinctions between groups treated with the single and combination preparations, and also between groups treated with combination preparations with different proportions of Syn and Poly (SymPoly 1:1 or 1:2).
  • GSEA analysis gene set enrichment analysis of the microarray data, evaluating the data at the level of gene sets selected by affiliation to known molecular pathways from reference databases (KEGG and WIKI), suggested that the arrays derived from single and combination treatments were further distinct by specific molecular pathways that are relevant to the functionality of the skin.
  • TNF signaling The most significant changes in gene expression were mapped to pathways related to TNF signaling, NF-KB signaling, WNT signaling, proteasome and cell cycle pathways, and pathways responsible for retinol, elastin and collagen metabolism.
  • TNF, NF-KB and WNT signaling pathways in the context of skin may have consequences on the capacity of the skin to neutralize free radicals and effects of UV, control inflammation, keratinocyte differentiation, and on the overall capacity of the skin for self-renewal. More generally, these results suggest that the Polygonum extract and synbiotics combination induces significant changes in gene expression along multiple molecular pathways that are likely to impact on skin homeostasis.
  • a commercial cream formulation (an oil in water emulsion), containing 1% Synbio® and the following INCI ingredients: Water, Glycerol, Caprylic/capric triglyceride, Sodium polyacrylate, Ethyl hexyl stearate, Trideceth-6, Phenoxyethanol, Galacto-oligosaccharide, Ethyl hexyl glycerol, and Fragrance.
  • the cream was applied topically by 10 healthy volunteers, with daily applications over a 10-day period. Bacterial viability was tested in topicals samples obtained from these individuals before and after the initial application, and at various time points during the study and up to 10 days after the final application. The samples were further subjected to 16S rRNA sequencing and phylogenetic analysis of bacterial diversity.
  • the cosmetic listed formulations were further subjected to various dermatological tests for regulatory purposes, including microbial challenge testing, probiotic bacterial stability, clinical (human) skin sensitization testing and physico-chemical stability studies.

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Abstract

L'invention concerne des formulations dermatologiques et cosmétiques et des procédés utilisant des combinaisons de probiotiques vivants, de prébiotiques et d'extraits de plantes Polygonum, et concerne en outre des utilisations pharmaceutiques de telles formulations et des procédés pour traiter et soulager des états dermatologiques communs ainsi que leurs utilisations cosmétiques pour l'apaisement, l'hydratation et le maintien en continu de l'aspect rajeuni de la peau.
PCT/IL2023/050989 2022-09-21 2023-09-13 Compositions dermiques et cosmétiques WO2024062470A1 (fr)

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Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2178954A (en) * 1985-08-13 1987-02-25 Moraz Ltd Polygonum avicular extracts
EP0975227A1 (fr) 1997-04-18 2000-02-02 Ganeden Biotech, Inc. Utilisation topique de spores de bacilles probiotiques pour prevenir ou traiter les infections microbiennes
CN1923042A (zh) * 2005-08-29 2007-03-07 李伟 一种新型保健食品
US20080107699A1 (en) 2006-10-25 2008-05-08 Mark Spigelman Method of using topical probiotics for the inhibition of surface contamination by a pathogenic microorganism and composition therefor
JP2009503042A (ja) 2005-08-01 2009-01-29 ロレアル 敏感肌又は乾燥肌を予防及び／又は治療するための化粧料用及び／又は皮膚科用組成物
JP4587755B2 (ja) * 2004-09-17 2010-11-24 丸善製薬株式会社 抗炎症剤、美白剤、及び抗老化剤、並びに皮膚化粧料
WO2017063066A1 (fr) 2015-10-15 2017-04-20 Natura Cosméticos S.A. Composition cosmétique contenant des bactéries probiotiques
EP3210612A1 (fr) * 2016-02-26 2017-08-30 Chrisal NV Préparation synbiotique
EP2704704B1 (fr) 2011-05-03 2018-09-26 DuPont Nutrition Biosciences ApS Bacteries probiotiques pour le traitement topique des maladies cutanées.
US10238597B2 (en) 2015-11-19 2019-03-26 Beauty Biolabs Llc Probiotic treatment of skin diseases, disorders, and infections: formulations, methods and systems
EP2978503B1 (fr) * 2013-03-27 2019-08-07 BASF Beauty Care Solutions S.A.S. Utilisation cosmetique d'un extrait de polygonum bistorta
CN110404059A (zh) * 2019-07-04 2019-11-05 湖北真福医药有限公司 一种改善睡眠的功能性溶栓酶制品及其制备方法
US10695386B2 (en) 2017-05-11 2020-06-30 Shayne K. Morris Skin microbiome colonizer formulations and methods for use
EP3727594A1 (fr) 2017-12-22 2020-10-28 L V M H Recherche Composition cosmétique comprenant un extrait de caesalpinia spinosa, un extrait de kappaphycus alvarezii, au moins un prébiotique et un probiotique
US11007137B2 (en) 2018-02-12 2021-05-18 Genmont Biotech Incorporation Use of lactobacillus plantarum GMNL-6 composition for skin care

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2178954A (en) * 1985-08-13 1987-02-25 Moraz Ltd Polygonum avicular extracts
EP0975227A1 (fr) 1997-04-18 2000-02-02 Ganeden Biotech, Inc. Utilisation topique de spores de bacilles probiotiques pour prevenir ou traiter les infections microbiennes
JP4587755B2 (ja) * 2004-09-17 2010-11-24 丸善製薬株式会社 抗炎症剤、美白剤、及び抗老化剤、並びに皮膚化粧料
JP2009503042A (ja) 2005-08-01 2009-01-29 ロレアル 敏感肌又は乾燥肌を予防及び／又は治療するための化粧料用及び／又は皮膚科用組成物
CN1923042A (zh) * 2005-08-29 2007-03-07 李伟 一种新型保健食品
US20080107699A1 (en) 2006-10-25 2008-05-08 Mark Spigelman Method of using topical probiotics for the inhibition of surface contamination by a pathogenic microorganism and composition therefor
EP2704704B1 (fr) 2011-05-03 2018-09-26 DuPont Nutrition Biosciences ApS Bacteries probiotiques pour le traitement topique des maladies cutanées.
EP2978503B1 (fr) * 2013-03-27 2019-08-07 BASF Beauty Care Solutions S.A.S. Utilisation cosmetique d'un extrait de polygonum bistorta
WO2017063066A1 (fr) 2015-10-15 2017-04-20 Natura Cosméticos S.A. Composition cosmétique contenant des bactéries probiotiques
US10238597B2 (en) 2015-11-19 2019-03-26 Beauty Biolabs Llc Probiotic treatment of skin diseases, disorders, and infections: formulations, methods and systems
EP3210612A1 (fr) * 2016-02-26 2017-08-30 Chrisal NV Préparation synbiotique
EP3210612B1 (fr) 2016-02-26 2018-11-21 Chrisal NV Préparation synbiotique
US10695386B2 (en) 2017-05-11 2020-06-30 Shayne K. Morris Skin microbiome colonizer formulations and methods for use
EP3727594A1 (fr) 2017-12-22 2020-10-28 L V M H Recherche Composition cosmétique comprenant un extrait de caesalpinia spinosa, un extrait de kappaphycus alvarezii, au moins un prébiotique et un probiotique
US11007137B2 (en) 2018-02-12 2021-05-18 Genmont Biotech Incorporation Use of lactobacillus plantarum GMNL-6 composition for skin care
CN110404059A (zh) * 2019-07-04 2019-11-05 湖北真福医药有限公司 一种改善睡眠的功能性溶栓酶制品及其制备方法

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