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    [0001] Formulations for oral administration or formulations for application to healthy or injured skin comprising active ingredients derived from the plant Murray a koenigii. Composition comprising at least one active ingredient derived from the Murraya koenigii plant, said active ingredient being metformin. [0002] Identification and quantification of metformin in Murraya koenigii and assignment of Murraya koenigii activity in the treatment of metabolic syndrome and cognitive disorders to the low-dose presence of metformin in Murraya koenigii.
    公开号:FR3064180A1
    申请号:FR1852453
    申请日:2018-03-21
    公开日:2018-09-28
    发明作者:Nicolas Wiernsperger；Alain Geloen；Claude Dalle；Franck Nordt
    申请人:Nicolas Wiernsperger；Alain Geloen；Claude Dalle；Franck Nordt；
    IPC主号:
    专利说明:

    Holder (s): WIERNSPERGER NICOLAS, GELOEN ALAIN, DALLE CLAUDE, NORDT FRANCK.
    Extension request (s)
    Agent (s): TRIPOZ CABINET.
    (54 / FORMULATIONS COMPRISING ACTIVE INGREDIENTS FROM THE PLANT MURRAYA KOENIGII.
    FR 3,064,180 - A1 (57) [0001] Formulations for oral administration or formulations for application to healthy or injured skin comprising active ingredients from the plant Murray a koenigii. Composition comprising at least one active ingredient from the Murraya koenigii plant, said active ingredient being metformin. [0002] Identification and quantification of metformin in Murraya koenigii and attribution of the activity of Murraya koenigii in the treatment of metabolic syndrome and cognitive disorders to the presence in low dose of metformin in Murraya koenigii.
    FORMULATIONS COMPRISING ACTIVE INGREDIENTS FROM THE PLANT MURRAYA KOENIGII.
    The present invention relates to formulations for oral administration or formulations for application to healthy or damaged skin comprising active ingredients from the plant Murraya koenigii.
    The virtues of Murraya koenigii leaves are known in traditional Ayurvedic medicine. Different applications have been described in the publication V. Jain et al., International Journal of aryurvedic and herbal medicine 2 (4) aug 2012, 607-627, and in particular its antioxidant, hypoglycemic, anti-obesity, antihyperlipidic and anti-amnesic activities .
    We know that Murraya koenigii contains biguanides (Ref: V. Perla et al., Food Chem 138, 1574-1580 (2013)). The properties of Murraya koenigii are a priori due to the presence of carbazole alkaloids such as girinimbine, ia murrayanine, ia mahanimbine, isomurayazoline, isomahanimbine, mahanine, ia koenimbidine, bismurrayafoline E, euchrestine B , ia murrayacine and ia koenoîine. (Maha E! Amin et al., Pak. J. Sci. Vol. 26 pp 359-65, Mar 2013; Jagtap S et al., Biofactors, 43 (2) 220231, Mar 2017; Pandey J. et al., J. Sci. Agric. 94: 2282-2288, 2014; Vasudevan M. et ai., Phytother 23: 308-316, 2009).
    Metformin is a molecule from the family of normoglycemic biguanides known under the name of Glucophage® or Stagid® for example and used in the treatment of type 2 diabetes. Metformin is administered in the form of tablets of 500, 700, 850 and 1000 mg. The recommended dosage for the treatment of type 2 diabetes is 500 to 1000 mg, three times a day. These dosages cause the appearance of undesirable effects more or less well tolerated by the patients in particular renal and / or hepatic insufficiency, digestive disorders and lactic acidosis.
    Surprisingly, the Applicant has been able to attribute the activity of Murraya koenigii in the treatment of metabolic syndrome and cognitive disorders to the presence at low dose of metformin in Murraya koenigii.
    Furthermore, the Applicant has demonstrated that a very low dose of metformin is effective in the treatment of metabolic syndrome and cognitive disorders.
    The invention relates to a composition comprising at least one active ingredient from the Murraya koenigii plant, said active ingredient being metformin.
    In one embodiment, said active ingredient is added to the composition in the form of ground dried leaves.
    In one embodiment, said active ingredient is added to the composition in the dry extract state.
    In one embodiment, said active ingredient is added to the composition in the form of an aqueous extract.
    In one embodiment, said active ingredient is provided in its composition in the form of alcoholic extract.
    In one embodiment, said active ingredient is provided in the composition in the form of standardized plant extract.
    In one embodiment, said standardized plant active ingredient is obtained by freeze-grinding the fresh frozen plant, leaching, alcoholic extraction and evaporation.
    In one embodiment, an addition of vegetable glycerin is carried out to stabilize the composition.
    The term “composition comprising active ingredients from Murraya koenigii” is understood to mean a composition comprising:
    - dried and ground leaves or stems,
    - dried and ground roots or bark,
    - essential oil,
    - extracts obtained by decoction or maceration of the leaves, stems, fruits and / or roots,
    - infusions of leaves, dried fruit and / or roots, or
    - metformin extracted from Murraya koenigii.
    In one embodiment, said extract of Murraya koenigii is concentrated.
    In one embodiment, said extract of Murraya koenigii is concentrated and the concentration of said active is multiplied by 2.
    In one embodiment, said Murraya koenigii extract is concentrated and the concentration of said active ingredient is multiplied by 5.
    In one embodiment, said Murraya koenigii extract is concentrated and the concentration of said active ingredient is multiplied by 10.
    Said active will be, depending on the intended applications, formulated for oral administration for example in the form of capsules, tablets, syrups, herbal teas, or granules.
    The oral dosage depends on the pathologies targeted but can vary between 1 to 6 doses per day of said composition.
    The composition according to the invention is administered one to six times a day. The oral dosage depends on the pathologies targeted but can vary between 1 mg and 3 g of said Murraya koenigii extract per day.
    The oral dosage depends on the pathologies targeted but can vary between 1 mg and 3 g of said Murraya koenigii extract per day, ie 0.003 mg to 15 mg of metformin per day.
    The oral dosage in the treatment of metabolic syndrome varies between 1 mg and 3 g of said Murraya koenigii extract per day, ie 0.003 mg to 15 mg of metformin per day.
    The oral dosage in the treatment of cognitive disorders varies between 1 mg and 3 g of said Murraya koenigii extract per day, ie 0.003 mg to 15 mg of metformin per day.
    The oral dosage depends on the pathologies targeted, but can vary between 1 mg and 3 g of said shredded Murraya koenigii leaves per day, ie 0.003 mg to 15 mg of metformin per day.
    The oral dosage in the treatment of metabolic syndrome varies between 1 mg and 3 g of said ground material of Murraya koenigii leaves per day, ie 0.003 mg to 15 mg of metformin per day.
    The oral dosage in the treatment of cognitive disorders varies between 1 mg and 3 g of said shredded leaf Murraya koenigii per day or 0.003 mg to 15 mg of metformin per day.
    Regarding skin applications, the formulations will be in the form of ointments, balms, or gels. The dosages will depend on the applications but the amounts of metformin used will be between 0.01 mg and 0.5 g per day.
    Said compositions can also comprise one or more additional active ingredients which will complement the pharmacological actions of the at least one active ingredient obtained from Murraya koenigii.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of proteinogenic amino acids, non-proteinogenic amino acids, alkaloids, inorganic compounds, coumarins , heterosides, isothiocyanates, phenols, polyphenols, phenylpropanoids, quinones and / or terpenes.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of proteinogenic amino acids.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of proteinogenic amino acids comprising Sa glutamine.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of non-proteinogenic amino acids.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of non-proteinogenic amino acids comprising ia citrulline.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of alkaloids.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of alkaloids comprising berberine and piperine.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of inorganic compounds.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemi-synthesis chosen from the group consisting of inorganic compounds comprising ie hydrogen disulfide.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of coumarins.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of coumarins comprising ia bergamottin and scopoletin.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of heterosides.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of heterosides comprising its naringin and narinenin.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of isothiocyanates.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of isothiocyanates comprising ie sulforaphane.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of phenols.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of phenols comprising thymol and hydroxytyrosol.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of polyphenols.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of polyphenols comprising ellagic acid, ellagitanine, urolithin, quercetin, curcumin, nobiletin, punicalin, fisetin and geraldol.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of phenylpropanoids.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of phenylpropanoids comprising ferulic acid.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of quinones.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of quinones comprising embellin.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of terpenes.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of terpenes comprising ursolic acid and Asian acid.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis chosen from the group consisting of glutamine, citrulline, berberine, piperine, hydrogen disulfide, bergamottin , scopoletin, naringin, naringenin, sulforaphane, thymol, hydroxytyrosol, ferulic acid, ellagic acid, ellagitanine, urolithin, quercetin, nobiletin, punicalin, fisetin, geraldol, embelline, ursolic acid and asian acid.
    In one embodiment, the additional active agents are isolated molecules or active agents obtained by synthesis or hemisynthesis from plants chosen from the group consisting of Fragaria spp, Psidium guajava, Juglans regin, Terminalia chebuta, Solanum lycopersicum, Cynara cardunculus , Solanum melongena, Brassica oleracea, Citrus paradisi, Citrus sinensis, Musa paradisiaca, Angeiica sinensis, Cimicifuga foetida, Ligustricum chuangxiong, Salvia, Solidago gigantea, Ajuva iva, Rosmarinus officinalis, Salvia triloba, Nerium oleanunia i Vinca , Thymus vulgaris, Satureja montana, Centella asiatica, Syzygium claviflorum, Psiloxylon mauritianum, Schefflera octophyila, Schisandra grandiflora, Potentilla chinensis, Cucumis melo, Citrullus lanatus, Thymus vulgaris, Lippia, Alshifan Origan, Sushifan Origan, Sushifan origami, Elsholtan Origan, Sushifan Origan, Saffron Origan, Saffron Origan, , Aiiium sativum, Brassica oleracea, Berberis vulgaris, Hydrastis canade nsis, Berberis aristata, Argemone mexicana, Mahonia aquifolium, Coptis jamonica, Thalictrum fiavum, Thalictrum foliolosum, Oenothera biennis, Allium cepa, Podophyllum peltatum, Hypericum perforatum, Podophylium hexandrum, Cameiia sinensis, Phrcumauma, Currycuma x Olea europaea, Citrus aurantifoiia, Citrus limon, Citrus paradisi, Embelia ribes, Ardisia japonica, Citrus paradisi, Citrus sinesis, Lippia graveolens, Drynaria quercifolia, Drynaria fortunei, Citrus reticulata, Citrus tachibana, Citrus limon, Citrus depressa, Piper longum , Piper nigrum, Helianthuis annuus, Morinda citrifolia, Tertapleura tetraptera, Polygala sabuiosa, Brunsfelsai granoiflora, Artemisia iwayomogi, Pimpinelia anisum, Medicago sativa, Punica granatum, Terminalia cattapa, Terminalia chebuta, Artia macida. zeylanica, Moringa oleifera, Euterpe oleracea, Coffea arabica, Oryza sativa, Azadirachta indica, Garcinia cambogia, Trigonelia foenum-graecum, Trigonella caerulea, Allium sativum, Momordica charantia, Cocoa, Cornus, Safranus, liex paraguariensis, Gingko biloba, Betuia platyphylla, Cinnamomum verum, Origanum majoranaus Agrimus, Syzum officinalis, Cocos nucifera, Fragaria vesca, Terminalia chebuta, Terminalia arjuna, Terminalia cattapa, Saivia, Melissa officinalis, Rosmarinus, Rhus verniciflora, Cotinus coggygria, Acacia greggii, Acacia balandieri, Xantho cyparis nootkatensum, Proverbo, Nififuner, Prunipurus, Mangifucusis, Mangifucusis, Mangifunus, Nififunus, Mangifunus, Nififunus, Nififunus, Prunifucus, Nififunus, Nififera, Nififera, Nififera, , Malus, Petroselinum cirspum, Allium cepa, Cucumis sativus, Vitis vinifera, Viola tricolor, Sophora japonica, Eucalyptus macrorhuncha, Fagopyrum esculentum, Morus alba, Sambucus canadensis, Hydrangea paniculata, Melilotus officinalis, Causeaus Causea, Salvia Coccus Hypericum perforatum, Polygala tenuifloia, Nigella sativa, Cocoa, Bacopa monnieri, Boswellia serna ta, Rhodiola rosea, Capsicum annuum, Puncia granatum, Withonia somnifera, Zingiber officinalis, Griffonia simplicifolia, Apium graveolens, Mucuna pruriens, silybum marianum, Terminalia cattapa, Galega officinalis.
    Said compositions may also comprise at least one additional active agent chosen from the active agents obtained from plants chosen from the group consisting of plants of the Artemisia family, plants of the Cornus family, plants of its Saffron family, plants from the maté family, plants from the Pomegranate punica family, plants from the Fenugreek family, plants from the Garcinla family, plants from the garlic family and plants from the strawberry family.
    Said compositions can also comprise one or more additives.
    In one embodiment, the additives are chosen from the group consisting of coenzyme Q10, zinc, chromium, spermine, spermidine, salicylate, vitamin D, ie sodium propionate, sodium butyrate , sodium acetate, melatonin, biotin, anthocyanins, kaempferol and / or luteolin. The term "blue berry" means a fleshy fruit of blue, purple or black color which contains seeds or seeds such as, for example, blackberry, Elderberry, blueberry, sloe, black spurge, blackcurrant , orcette, juniper berry, blueberries, grapes, mauve and / or acai.
    By "red berry" is meant a fleshy fruit of red color which contains seeds or seeds such as, for example, arbutus, strawberry, Goji berry, red currant, raspberry, cranberry, lingonberry, jujube and / or cherry.
    In one embodiment, said anthocyanins come from fruits chosen from the group consisting of red berries and blue berries.
    In one embodiment, the mass proportion of said extract of Murraya koenigii in the composition is between 45 and 100%.
    In one embodiment, the mass proportion of said Murraya koenigii extract in the composition is between 50 and 98%.
    In one embodiment, the mass proportion of said extract of Murraya koenigii in the composition is 94%.
    In one embodiment, said extract of Murraya koenigii has a residual moisture level of less than 5%.
    In one embodiment, the mass proportion of said shredded dry leaves of Murraya koenigii in the composition is between 45 and 100%.
    In one embodiment, the mass proportion of said shredded dry Murraya koenigii leaves in the composition is between 50 and 98%. In one embodiment, the mass proportion of said shredded dry leaves of Murraya koenigii in the composition is 94%.
    In one embodiment, said shredded dry leaves of Murraya koenigii has a residual moisture content of less than 5%.
    In one embodiment, the composition according to the invention comprises an amount of Murraya koenigii extract allowing the administration of at least 0.0005 mg of metformin per tablet, capsule, unit of powder.
    In one embodiment, the composition according to the invention comprises an amount of comminuted dry leaves of Murraya koenigii allowing the administration of at least 0.0005 mg of metformin per tablet, capsule, unit of powder.
    In one embodiment, the composition according to the invention is in solid form.
    In one embodiment, the composition according to the invention is formulated in tablet, capsule or powder.
    In one embodiment, the composition according to the invention is formulated in a capsule.
    In one embodiment, the composition according to the invention is in liquid form.
    In one embodiment, the composition according to the invention in liquid form is formulated in the form of an ampoule and / or syrup.
    In one embodiment, the composition according to the invention is intended to be used as a medicament.
    In one embodiment, the composition according to the invention is intended to be used as a food supplement.
    In one embodiment, the composition according to the invention is intended to be used as a nutraceutical product.
    In one embodiment, the composition according to the invention is intended to be used as a dietetic product.
    In one embodiment, the composition according to the invention is intended to be used as a phytotherapeutic product.
    The invention also relates to the use of a composition according to the invention, in the applications chosen from the group consisting of:
    - Application in the treatment of polycystic ovary.
    - Application as antioxidant and anti-free radicals.
    - Application as hypoglycemic.
    - Application as a hepatoprotective.
    - Application as antimicrobial and antifungal.
    - Application as a pancreatic lipase inhibitor.
    - Application in the prevention of the development of dental caries.
    - Application as anticancer.
    - Application as an anti-inflammatory.
    - Application as an immunomodulator.
    - Application in the treatment of broncho-respiratory disorders.
    - Application as a cardio-protector.
    - Application as anti-osteoporotic.
    - Application in the treatment of Alzheimer's disease.
    - Application in the prevention of obesity and as an anti-hyperlipidic.
    - Application as anti-amnesic.
    - Application as a healing agent.
    - Application as a nephroprotector.
    - Application as antipyretic.
    - Application in the prevention of histological changes.
    - Application in radiation protection.
    - Application as an antiulcer.
    - Application as trichomonacid.
    - Application as antidiarrheal.
    - Application as a dewormer.
    - Application as an inhibitor of meianogenesis.
    - Application in cosmetic treatments.
    - Application in the treatment of cognitive disorders.
    - Application in the treatment of metabolic syndrome.
    The invention also relates to the use of a composition according to the invention for its application in the treatment of polycystic ovary.
    The invention also relates to the use of a composition according to the invention for its application in the prevention of obesity and as an antihyperlipidic.
    The invention also relates to the use of a composition according to the invention for its application as an anti-amnesic.
    The invention also relates to the use of a composition according to the invention for its application in the treatment of cognitive disorders.
    The invention also relates to the use of a composition according to the invention for its application in the treatment of metabolic syndrome.
    The invention also relates to the use of a composition according to the invention for its application in cosmetic treatments.
    With regard to skin applications, the formulations will be in the form of ointments, balms, or gels. The dosages will depend on the applications but the amounts of metformin used will be between 0.01 mg and 0.5 g per day.
    The invention also relates to a composition comprising at least one active ingredient from the Murraya koenigii plant, said active ingredient being metformin.
    The invention also relates to a composition characterized in that said active ingredient is provided in the composition in the form of ground dried leaves.
    The invention also relates to a composition characterized in that said active agent is provided in the composition in the form of dry extract.
    The invention also relates to a composition according to any one of the preceding claims, characterized in that it also comprises at least one additional active agent chosen from the group consisting of glutamine, citrulline, berberine, piperine, hydrogen disulfide, bergamottin, scopoletin, naringin, naringenin, sulforaphane, thymol, hydroxytyrosol, ferulic acid, ellagic acid, ellagitanine, urolithin, quercetin , nobiletin, punicalin, fisetin, geraldol, embellin, ursolic acid and / or asian acid.
    The invention also relates to a composition according to any one of the preceding claims, characterized in that it also comprises at least one additional active agent chosen from active agents obtained from plants chosen from the group consisting of plants of the artemisia family, the horned family plants, the saffron family plants, the mate family plants, the pomegranate punica family plants, the fenugreek family plants, the garcinia family plants, the plants from the garlic family and / or plants from the strawberry family.
    The invention also relates to a composition according to any one of the preceding claims, characterized in that it also comprises at least one or more additives chosen from the group consisting of coenzyme qlO, zinc, chromium , spermine, spermidine, salicylate, vitamin d, sodium propionate, sodium butyrate, sodium acetate, melatonin, biotin, anthocyanins, kaempferol, and / or luteolin.
    The invention also relates to a composition characterized in that the ground material of dry leaves comprises between 0.1 mg / g to 1.5 mg / g of metformin. The invention also relates to a composition characterized in that the dry extract comprises between 0.1 mg / g to 1.5 mg / g of metformin.
    The invention also relates to a pharmaceutical formulation comprising a composition as described above, characterized in that it comprises between 0.0005 mg to 2.5 mg metformin.
    The invention also relates to a galenical formulation comprising a composition as described above, characterized in that it comprises at most 500 mg of dry leaf mash and between 0.0005 mg and 2.5 mg of metformin. The invention also relates to a dosage formulation comprising a composition as described above, characterized in that it comprises at most 500 mg of dry extract and between 0.0005 mg and 2.5 mg of metformin .
    The invention also relates to a dosage formulation comprising a composition as described above intended for use in the treatment of metabolic syndrome, characterized in that it is administered one to six times a day.
    The invention also relates to a dosage formulation comprising a composition as described above intended for use in the treatment of metabolic syndrome, characterized in that the daily amount administered is between 1 mg and 3 g of said extract. Murraya koenigii is 0.003 mg to 15 mg of metformin.
    The invention also relates to a galenical formulation comprising a composition as described above intended for use in the treatment of cognitive disorders, characterized in that it is administered one to six times a day. The invention also relates to a galenical formulation comprising a composition as described above intended for use in the treatment of cognitive disorders, characterized in that the daily amount administered is between 1 mg and 3 g of said extract. Murraya koenigii is 0.003 mg to 15 mg of metformin.
    In one embodiment, the composition according to the invention is characterized in that the ground material of dry leaves comprises between 0.2 mg / g to 1.25 mg / g of metformin.
    In one embodiment, the composition according to the invention is characterized in that the ground material of dry leaves comprises between 0.5 mg / g to 1.00 mg / g of metformin.
    In one embodiment, the composition according to the invention is characterized in that the ground material of dry leaves comprises between 0.25 mg / g to 0.40 mg / g of metformin. In one embodiment, the composition according to the invention is characterized in that the ground material of dry leaves comprises between 0.5 mg / g to 0.7 mg / g of metformin.
    In one embodiment, the composition according to the invention is characterized in that the dry extract comprises between 0.1 mg / g to 1.5 mg / g of metformin.
    [000112] In a fashion of achievement, the composition according to the invention East characterized in this ; that the extract dry includes between 0.2 mg / g to 1.25 mg / g of metformin. [000113] In a fashion of achievement, the composition according to the invention East characterized in this : that the extract dry includes between 0.5 mg / g to 1.00 mg / g of metformin. [000114] In a fashion of achievement, the composition according to the invention East characterized in this that the extract dry includes between 0.25 mg / g to 0.40 mg / g of metformin. [000115] In a fashion of achievement, the composition according to the invention East
    characterized in that the dry extract comprises between 0.5 mg / g to 0.7 mg / g of metformin. In one embodiment, the invention is characterized in that the said composition is administered orally at least once a day so as to administer a daily dose of Murraya koenigii extract of between 1 mg and 3 g.
    In one embodiment, the invention is characterized in that said composition is administered orally at least once a day so as to administer a daily dose of metformin of between 0.003 mg and 15 mg.
    In one embodiment, the invention is characterized in that the said composition is applied to the skin at least once a day so as to administer a daily dose of Murraya koenigii extract of between 0.01 mg and 0.5 g.
    In one embodiment, the invention is characterized in that said composition is applied to the skin at least once a day so as to administer a daily dose of metformin extract of between 0.00003 mg and 0 , 2 g.
    In one embodiment, said composition is administered for a period of between 10 and 30 days.
    Description of the Figures [000121] Figures 1 and 2: Metformin quantification spectrometer in Murraya koenigii by gas chromatography - single and triple quadrupole mass spectrometry (GCMS and GCMSMS, respectively, Agilent 7890 / 7000B). Extracts of Murraya koenigii (A) and metformin standards (C) produced the same characteristic fragments associated with metformin on the GCMS analysis (m / z 303, 288 and 274). A slight shift in retention times due to the Murraya koenigii matrix is observed. Diphenylamine (B and D) served as an internal standard.
    A: RT = 4.184 minutes / Extract from Murraya koenigii.
    B: RT = 5.519 minutes / Diphenyamine.
    C: RT = 3.786 minutes / standard Metformin.
    D: RT = 5.520 / Diphenyamine.
    The following examples illustrate, without limitation, the invention.
    Method for extracting its metformin from dry leaves of Murraya koenigii [000123] There was no method for extracting metformin from dried leaves of Murraya koenigii before the extraction method was developed described below. Methods of extracting metformin from blood plasma are known as that described in the publication by Uçatürk E; et al., Anal. Methods, 5: 4723-4730, 2013.
    Three 250 ml silicone Erlenmeyer flasks were filled respectively with 1.67 g, 1.67 g and 1.66 g of dry leaves of Murraya koenigii. The dry leaves of Murraya koenigii were put in an electric coffee grinder and pulverized into a very fine powder. The powder thus obtained was transferred equally to three flasks. To each flask, 15 ml of 20% NaCl (w / v) were added, the solutions thus obtained were then stirred by means of a magnetic stirring bar at 250 rpm at room temperature for 30 minutes. The resulting sludge was transferred to three large flasks. To each flask, 3.75 ml of 50% trichloroacetic acid (TCA) (w / v) was added to and then each flask was shaken (vortexed) for 10 minutes. The resulting sludge was transferred to three large flasks. In each bottle, 190 ml of chloroform: methanol (85:15, v: v) and 15.2 ml of 5N NaOH were added. The solutions thus obtained were stirred by means of a magnetic stirring bar at 350 rpm at room temperature for 25 minutes. The solutions were then transferred into 50 ml conical polypropylene centrifuge tubes (Sarstedt) and centrifuged at 6,500 rotations per minute (i.e. 1960 x g) for 10 minutes. The upper aqueous phase and the debris thus obtained were discarded. The remaining chloroform phases were combined into as few new 50 ml polypropylene tubes as possible and evaporated under N2 to approximately mi of total volume contained in a tube. The extract was then filtered using a polypropylene funnel through Whatman # 1 filter paper into a new polypropylene centrifuge tube. The filtrate was acidified with 0.4 ml of 2N HCl in 5 m! 95% ethanol and stirred (vortexing) for one minute and then evaporated to dryness under N2 gas. The resulting filter cake was dissolved in 10 ml of methanol and the suspension was again vigorously stirred (vortexing) before being filtered through Whatman No. 1 filter paper as described above, in a new tube. polypropylene centrifugation. A total volume of approximately 9 ml was recovered.
    Quantification of metformin in the leaves of Murraya koenigii [000125] The dry Murraya koenigii leaves were obtained from Mountain
    Rose Herbs (Eugene, Oregon). The leaves were pulverized and extracted essentially according to the method described above. The extracts were volatilized and analyzed to quantify metformin by gas chromatography single and triple quadrupole mass spectrometry (GCMS and GCMSMS, respectively,
    Agilent 7890 / 7000B). Extracts of Murraya koenigii (Figure 1) and metformin standards (LKT Laboratories) (Figure 2) produced the same characteristic fragments associated with metformin on the GCMS analysis (m / z 303, 288 and 274). A slight shift in retention times due to the Murraya koenigii matrix is observed. Diphenylamine (DPA) was used as an internal standard (Figures 1 and 2).
    Additional confirmation that the Murraya koenigii extract contains metformin was provided by subjecting both the metformin standard and the Murraya koenigii extract to a dynamic multiple reaction monitoring (MRM) analysis by GCMSMS. . Again, the same characteristic molecular fragments associated with pure metformin were observed in the extract of
    Murraya koenigii at characteristic retention times, providing for the first time, irrefutable proof that Murraya koenigii contains significant amounts of metformin.
    The concentration of metformin recovered in this way was approximately 0.34 ± 0.21 mg / g (0.34 ± 0.21 pg / mg) of dry Murraya koenigii leaves. The maximum yield obtained was 0.61 mg / g (0.61 pg / mg) of dry leaves of Murraya koenigii.
    Obtaining dry leaf grinds
    The fresh leaves are collected, cleaned and then dried in the open air or in the oven (gentle heat), they are then ground in a knife mill to obtain a fine powder. The powder thus obtained is a grind of dry leaves.
    Obtaining ground material from dry plant part (s)
    The dry aerial parts of the plants (leaves, flowers, fruit, bark, zest, bulb roots and / or stems) are ground in a knife mill to obtain a fine powder. The powder thus obtained is a ground material from the dry part (s) of the plant.
    Obtaining dry extracts
    The parts of the plant (leaves, flowers, fruit, bark, zest, bulb roots and / or stems), fresh or dry, are ground in a knife mill until a powder is obtained. A maceration step using this powder is carried out in a water: ethanol mixture for 24 hours. A step of leaching the macerate is carried out in a percolator with a water mixture (ethanol. The extract obtained is then washed using a non-polar organic solvent by evaporation at low temperature. The extract obtained can be concentrated before Evaporation A liquid extract is obtained which is then lyophilized according to the usual lyophilization methods The powder thus obtained is a dry extract of the part or parts of the plant.
    Examples of formulations according to the invention
    Formulation la for the treatment of metabolic syndrome:
    For a capsule:
    500 mg Murraya koenigii leaf crush
    Formulation lb for the treatment of metabolic syndrome:
    For a capsule:
    500 mg dry extract of Murraya koenigii leaves
    Formulation 2 for the treatment of metabolic syndrome:
    For a capsule:
    125 mg of shredded leaves of Murraya koenigii 125 mg of shredded leaves of Artemisia dracunculus 125 mg of shredded peels of Citrus reticulata 125 mg of shredded leaves of Houttuynia cordata
    Formulation 3 for the treatment of metabolic syndrome:
    For a capsule:
    166 mg dry leaf extract of Murraya koenigii
    167 mg of ground leaves of Artemisia dracunculus 167 mg of dry extract of zest of Citrus reticulata
    Formulation 4 for the treatment of metabolic syndrome:
    For a capsule:
    250 mg Murraya koenigii leaf crush
    125 mg dry extract of Artemisia dracunculus leaves
    125 mg of Citrus reticulata ground zest
    Formulation 5 for the treatment of metabolic syndrome:
    For a capsule:
    250 mg dry leaf extract of Murraya koenigii 100 mg dry leaf extract of Artemisia dracunculus 100 mg dry extract of zest of Citrus reticulata 50 mg dry leaf extract of Houttuynia cordata
    Formulation 6 for the treatment of cognitive disorders:
    For a capsule:
    500 mg dry leaf extract of Murraya koenigii
    Formulation 7 for the treatment of cognitive disorders:
    For a capsule:
    125 mg dry leaf extract of Murraya koenigii
    125 mg dry extract of Fragaria vesca leaves
    125 mg dry extract of Centelîa asiatica leaves
    125 mg of crushed bulbs of Allium sativum (aged garlic)
    Formulation 8 for the treatment of cognitive disorders:
    For a capsule:
    166 mg Murraya koenigii leaf crush
    167 mg of crushed leaves of Fragaria vesca 167 mg of crushed leaves of Centelia asiatica
    Formulation 9 for the treatment of cognitive disorders:
    For a capsule:
    250 mg dry extract of leaves of Murraya koenigii 125 mg of crushed leaves of Fragaria vesca 125 mg of dry extract of leaves of Centella asiatica
    Formulation 10 for the treatment of cognitive disorders:
    For a capsule:
    250 mg dry extract of Murraya koenigii leaves 100 mg dry extract of Fragaria vesca leaves 100 mg of ground mash of Centella asiatica 50 mg of ground mash of Allium sativum bulbs (aged garlic)
    Efficacy Studies of the Composition Formulations According to the Invention The compositions and formulations according to the invention were tested according to the protocol described in the publication Kawvised S. et a!., Oxid. Med. Cell. Longev. 2017: 2962316, to assess their effectiveness in the treatment of metabolic syndrome and cognitive disorders.
    [000129] 10 week old Wistar female rats were ovariectomized bilaterally. After 1 week of recovery, one group was fed standard food, another group was fed for 20 weeks on a diet rich in carbohydrates and fats. At the end of this period, animals with at least 25% overweight, a high HOMA (Homeostasis Mode! Accessment of insulin resistance) index and moderate hypertension were selected.
    In order to assess the effectiveness of the treatment against the metabolic syndrome, the selected animals were subjected to benchmark analyzes for monitoring the metabolic syndrome, comprising a biological assessment and clinical measures before and after 8 weeks of treatment with compositions and / or formulations according to the invention. In order to evaluate the effectiveness of the treatment against cognitive disorders, the selected animals were subjected to spatial memorization tests before and after 8 weeks of treatment with compositions and / or formulations according to the invention.
    The memorization test consists of an aquatic labyrinth where the animal is trained over 4 learning sessions. After this series, the latency between the placement of the rat in the labyrinth and the moment when it finds its platform is measured. A modification of this protocol by moving the platform makes it possible to measure the information retention time.
    The results obtained in the treatment of metabolic syndrome have shown an improvement in the biological balance and the clinical state of the animals treated, proving the effectiveness of the compositions and / or formulations according to the invention in the treatment of metabolic syndrome .
    The results obtained in the treatment of cognitive disorders have shown an improvement in the performance of the animals treated subjected to the memorization and information retention tests, proving the effectiveness of the formulations according to the invention in the treatment of cognitive disorders. .
    权利要求:
    Claims (3)
    [1" id="c-fr-0001]
    1. Composition comprising at least one active ingredient from the Murraya koenigii plant, said active ingredient 5 being metformin.
    [2" id="c-fr-0002]
    2. Composition according to claim 1, characterized in that said active agent is provided in the composition in the form of ground dried leaves.
    3. Composition according to Claim 1, characterized in that the said active ingredient is provided in the composition in the dry extract state.
    4. Composition according to any one of the preceding claims, characterized in that it also comprises at least one additional active agent chosen from the group consisting of
    15 glutamine, citrulline, berberine, piperine, hydrogen disulfide, bergamottin, scopoletin, naringin, naringenin, sulforaphane, thymol, hydroxytyrosol, ferulic acid, ellagic acid , ellagitanine, urolithin, quercetin, nobiletin, punicalin, fisetin, geraldol, embellin, ursolic acid and asian acid.
    5. Composition according to any one of the preceding claims, characterized in that it also comprises at least one additional active agent chosen from active agents obtained from plants chosen from the group consisting of plants of the Artemisia family, plants of the Cornus family, the plants of the Saffron family, the plants of the maté family, the plants of the Pomegranate punica family, the plants of the Fenugreek family, the plants of the family
    25 Garcinia, plants of the garlic family and plants of the strawberry family.
    6. Composition according to any one of the preceding claims, characterized in that it also comprises at least one or more additives chosen from the group consisting of coenzyme Q10, zinc, chromium, spermine, spermidine, salicylate, vitamin D,
    30 sodium propionate, sodium butyrate, sodium acetate, melatonin, biotin, anthocyanins, kaempferol, luteolin.
    7. Composition according to claim 2, characterized in that the ground material of dry leaves comprises between 0.1 mg / g to 1.5 mg / g of metformin.
    8. Composition according to claim 3, characterized in that the dry extract comprises between 0.1 mg / g to 1.5 mg / g of metformin.
    1/2 xW β
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    [3" id="c-fr-0003]
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    B.S)
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    同族专利:
    公开号 | 公开日
    WO2018172436A1|2018-09-27|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2009066303A2|2007-11-22|2009-05-28|Ganga Raju Gokaraju|New synergistic phytochemical composition for the treatment of obesity|AU2019449279A1|2019-06-06|2022-02-03|Sami-Sabinsa Group Limited|Composition for prostaglandin transporter inhibition and related therapeutic applications|
    FR3106755A1|2020-02-03|2021-08-06|Gattefosse Sas|MURRAYA KOENIGII EXTRACT AND ITS USE IN COSMETICS|
    法律状态:
    2020-03-31| PLFP| Fee payment|Year of fee payment: 3 |
    2021-02-20| PLFP| Fee payment|Year of fee payment: 4 |
    优先权:
    申请号 | 申请日 | 专利标题
    US201762474253P| true| 2017-03-21|2017-03-21|
    USUS62474253|2017-03-21|
    US201862637200P| true| 2018-03-01|2018-03-01|
    USUS62637200|2018-03-01|
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