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WO2019011415A1 - Solubilisat comportant de la curcumine, du xanthohumol et de l'extrait de racine de réglisse - Google Patents

Solubilisat comportant de la curcumine, du xanthohumol et de l'extrait de racine de réglisse Download PDF

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Publication number
WO2019011415A1
WO2019011415A1 PCT/EP2017/067382 EP2017067382W WO2019011415A1 WO 2019011415 A1 WO2019011415 A1 WO 2019011415A1 EP 2017067382 W EP2017067382 W EP 2017067382W WO 2019011415 A1 WO2019011415 A1 WO 2019011415A1
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WO
WIPO (PCT)
Prior art keywords
range
curcumin
xanthohumol
solubilizate
temperature
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
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PCT/EP2017/067382
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German (de)
English (en)
Inventor
Dariush Behnam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aquanova AG
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Aquanova AG
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Filing date
Publication date
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Priority to PCT/EP2017/067382 priority Critical patent/WO2019011415A1/fr
Priority to JP2020501208A priority patent/JP2020529974A/ja
Priority to DK18738321.1T priority patent/DK3651805T3/da
Priority to EP18738321.1A priority patent/EP3651805B1/fr
Priority to US16/629,077 priority patent/US11344509B2/en
Priority to HRP20231160TT priority patent/HRP20231160T1/hr
Priority to HRP20231591TT priority patent/HRP20231591T1/hr
Priority to ES18738321T priority patent/ES2965739T3/es
Priority to PT187376231T priority patent/PT3651804T/pt
Priority to PT187383211T priority patent/PT3651805T/pt
Priority to ES18737623T priority patent/ES2960296T3/es
Priority to CA3148455A priority patent/CA3148455A1/fr
Priority to FIEP18737623.1T priority patent/FI3651804T3/en
Priority to EP18737623.1A priority patent/EP3651804B1/fr
Priority to CA3069621A priority patent/CA3069621C/fr
Priority to RU2020106042A priority patent/RU2752078C1/ru
Priority to KR1020237017168A priority patent/KR102573152B1/ko
Priority to HUE18738321A priority patent/HUE064518T2/hu
Priority to CN201880046608.4A priority patent/CN111201041A/zh
Priority to PCT/EP2018/068801 priority patent/WO2019011990A1/fr
Priority to DK18737623.1T priority patent/DK3651804T5/da
Priority to PCT/EP2018/068729 priority patent/WO2019011954A1/fr
Priority to RS20230894A priority patent/RS64650B1/sr
Priority to US16/629,155 priority patent/US11197834B2/en
Priority to HUE18737623A priority patent/HUE063380T2/hu
Priority to PL18738321.1T priority patent/PL3651805T3/pl
Priority to KR1020207004082A priority patent/KR20200029002A/ko
Priority to BR112020000398-0A priority patent/BR112020000398B1/pt
Priority to PL18737623.1T priority patent/PL3651804T3/pl
Priority to PCT/EP2018/068731 priority patent/WO2019011955A2/fr
Priority to CN201880046265.1A priority patent/CN111163806A/zh
Publication of WO2019011415A1 publication Critical patent/WO2019011415A1/fr
Priority to MX2021000339A priority patent/MX2021000339A/es
Priority to FIEP19736404.5T priority patent/FI3820528T3/en
Priority to HUE19736404A priority patent/HUE063768T2/hu
Priority to US17/258,397 priority patent/US20220133682A1/en
Priority to DK19736404.5T priority patent/DK3820528T3/da
Priority to RS20230897A priority patent/RS64642B1/sr
Priority to US17/258,363 priority patent/US20220133646A1/en
Priority to PL19736735.2T priority patent/PL3820529T3/pl
Priority to HUE19736735A priority patent/HUE063382T2/hu
Priority to RU2021103127A priority patent/RU2771527C1/ru
Priority to HRP20231135TT priority patent/HRP20231135T1/hr
Priority to ES19736735T priority patent/ES2960689T3/es
Priority to UAA202100177A priority patent/UA125552C2/uk
Priority to MX2021000385A priority patent/MX2021000385A/es
Priority to RS20230868A priority patent/RS64636B1/sr
Priority to MYPI2020007185A priority patent/MY200185A/en
Anticipated expiration legal-status Critical
Priority to US17/544,808 priority patent/US11931322B2/en
Priority to US17/730,356 priority patent/US20220249400A1/en
Priority to US18/600,907 priority patent/US12144784B2/en
Priority to US18/738,127 priority patent/US20240325318A1/en
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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)
    • 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)
    • A61K36/348—Cannabaceae
    • A61K36/3486—Humulus
    • 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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the invention relates to a solubilizate with curcumin
  • Xanthohumol and liquorice root extract according to claim 1. Furthermore, the invention relates to a fluid containing such a solubilizate, a capsule filled with such a solubilisate or fluid and a
  • Curcumin is discussed as an active ingredient based on various potential pharmacological properties.
  • Parkinson's for example Parkinson's, Alzheimer's, diabetes, colorectal tumors, pancreatic cancer and
  • liver dysfunction To enter the bloodstream after oral intake, the drug must pass through the intestinal wall, then into the liver
  • the remainder of the total ingested and released in the body active ingredient is either degraded microbially in the intestine or eliminated with the faeces or bile.
  • Licorice flavonoid oil consisting of hydrophobic polyphenols of licorice in medium-chain triglycerides has a weight-reducing effect, which with reduced body fat in
  • Licorice plant (Glycyrhizza glabra) extracted with ethanol, filtered, concentrated and treated with charcoal. After further filtration and concentration, the
  • Extracts ethanol extract further with medium-chain triglycerides (MCT), which have a fatty acid composition of C8: C10 99: 1. Then, the extract was concentrated and filtered to separate insoluble substances. The glabridin concentration was adjusted to 1% with MCT, the polyphenol content in the LFO was about 8%.
  • MCT medium-chain triglycerides
  • Control group significantly decreased after eight weeks of administration. 900 mg / day LFO administration resulted in a significant decrease in the visceral fat area, body weight, BMI and LDL cholesterol
  • Licorice flavonoid oil was prepared as described above and the glabridin concentration was adjusted to 3%. This solution has been named “LFO Concentrate Solution” and has the brand name "KANEKA GLAVONOID TM”. This LFO-concentrated solution contains 30% ethanolic
  • Triglycerides as a vehicle or vehicle respectively
  • Licorice prenyl flavonoids such as glabridin
  • glabridin which are active components of LFO.
  • the LFO-concentrated solution was adjusted to a glabridin concentration of 1% by dilution with further MCT and administered to the test persons via capsule.
  • ⁇ -oxidation is the biochemical degradation mechanism of fatty acids. The term refers to the oxidation occurring at the ⁇ -C atom of the fatty acid.
  • the ß-oxidation was formerly called fatty acid spiral
  • Glavonoid The manufacturer of the commercially available product "Kaneka Glavonoid TM", which is hereinafter referred to by the term “glavonoid”, is referred to in information sheets titled “Licorice extract: Body Shaping” and “Licorice extract: For a healthy liver” in particular pointed out that by a dual mechanism, glavonoid reduces body fat, especially visceral fat. On the one hand is activated by upregulation of genes, the beta-oxidation, on the other hand by
  • Glavonoid reduce next to the visceral
  • Fat and LDL cholesterol also glucose in the blood, triglycerides and oxidative stress.
  • Fat and LDL cholesterol also glucose in the blood, triglycerides and oxidative stress.
  • liver epithelial cells hepatocytes
  • Xanthohumol is a naturally occurring in hops flavonoid. This is a prenylated
  • xanthohumol can protect the nerve cells of the brain and thus possibly could help to slow down the disease in diseases such as Alzheimer's or Parkinson's.
  • PCSK9 a protein that plays an important role in cholesterol levels.
  • a decrease in PCSK9 levels could improve the breakdown of LDL cholesterol from the blood. Oregon State University scientists have demonstrated that
  • Xanthohumol occurs naturally in hops and beer.
  • the highest levels used in the study would be equivalent to a human dose of 350 milligrams per day for one person. However, this value clearly exceeds that which can be achieved by normal food intake. A taking over one Dietary supplements, however, would theoretically be easily possible.
  • the inventor therefore set himself the task of a
  • glavonoid accessible to the human or animal organism.
  • it is one
  • Object of the invention to allow the best possible bioavailability of curcumin, xanthohumol and licorice root extract, especially glavonoid.
  • Xanthohumol with a content of less than or equal to
  • Fluid containing licorice root extract in particular a hydrophobic solution of a liquorice root extract, preferably glavonoid and / or glabridin in an amount of less than or equal to 10% by weight, preferably less than or equal to
  • the solubilizate consists of
  • Xanthohumol with a content of less than or equal to
  • Fluid containing licorice root extract in particular a hydrophobic solution of a liquorice root extract, preferably glavonoid and / or glabridin in an amount of less than or equal to 10% by weight, preferably less than or equal to
  • Polysorbate 20 or a mixture of polysorbate 20 and polysorbate 80 are examples of polysorbate 20 and polysorbate 80.
  • Licorice root extract preferably glavonoid, and pure glabridin, for example, be used dissolved in a particular hydrophobic carrier fluid.
  • glavonoid enriched with glabridin can be used in order to increase the proportion of glabridin in the solubilizate.
  • ethanolic extract of hard resins from hops contains ethanolic extract of hard resins from hops, with xanthohumol in this extract in a concentration in the range between 65 wt .-% and 95 wt .-%, preferably to a concentration in the range of 80 wt .-% to 92 wt .-% is present. It turned out that depending on how much
  • Xanthohumol to be solubilized the mass ratio of emulsifier, in particular polysorbate 80, too
  • Xanthohumol in the range between 35: 1 and 10: 1, preferably in the range between 30: 1 and 12: 1, preferably in the range between 27.3: 1 to 15: 1 can be adjusted.
  • the invention offers the possibility of the mass ratio of emulsifier, in particular polysorbate 80, to curcumin in the range between 50: 1 and 5: 1, preferably in the range between 42: 1 and 10: 1 , preferably in the range between
  • the ratio of emulsifier With regard to the amount of liquorice root extract to be solubilized for the particular application, the ratio of emulsifier,
  • polysorbate 80 containing to fluid
  • Licorice root extract in particular a hydrophobic solution of a liquorice root extract, preferably glavonoid and / or glabridin in the range between 35: 1 and 3: 1, preferably in the range between 30: 1 and 5: 1, preferably in the range
  • Licorice root extract is to be solubilized as a whole, the mass ratio of emulsifier, in particular of
  • Polysorbate 80 to the total mass of curcumin, xanthohumol and Fluid containing licorice root extract in the range between 15: 1 and 3: 1, preferably in the range between 12: 1 and 4: 1, preferably in the range between 10: 1 to 4.3: 1.
  • the emulsifier content, in particular the polysorbate content, according to the invention is at least 70% by weight, preferably in the range between 70% by weight and 95% by weight, more preferably in the range between 71% by weight and
  • the solubilizate contains up to 20% by weight, preferably up to 15% by weight, of ethanol.
  • the addition of ethanol can reduce the proportion of polysorbate, which is an advantage in terms of the ADI value for polysorbate.
  • solubilisate For the formation of stable micelles, depending on which active ingredients are to be solubilized in which amount, it can be helpful that the solubilisate reaches up to
  • Polysorbate can be reduced.
  • solubilizates according to the invention also have a narrow particle size distribution with a small mean in the physiological conditions of a gastric passage
  • the invention advantageously provides solubilisates having very good anti-inflammatory properties
  • CRP C-reactive protein
  • Solubilisats in a dosage of xanthohumol Solubilisats in a dosage of xanthohumol
  • CRP C-reactive protein
  • Body weight ranging from about 3200 pg / mL to about 3600 pg / mL.
  • the antiinflammatory effect measured as the concentration of myeloperoxidase (MPO) in the blood serum of arthritic rats after a single dose of the solubilisate in one
  • Dosage of xanthohumol and curcumin of 5 mg / kg body weight in the range of about 550 mU / mL to about 600 mU / mL is significantly lower than that
  • MPO myeloperoxidase
  • Xanthohumol and native curcumin at a dosage of 5 mg / kg body weight, respectively, ranging from about 1100 mU / mL to about 1300 mU / mL.
  • Xanthohumol and native curcumin at a dosage of 5 mg / kg body weight, respectively, ranging from about 1100 mU / mL to about 1300 mU / mL.
  • Licorice root extract especially a hydrophobic solution of licorice root extract, preferably glavonoid and / or glabridin, should further reduce these levels.
  • the enzyme unit (U) is a unit which has since been replaced by the catalysis to indicate the enzyme activity. Since the numerical values change when the catalysis is used, the enzyme unit (U) is still used in medicine and clinical chemistry.
  • An enzyme unit U corresponds to a micro-mole substrate turnover per minute.
  • compositions of xanthohumol with curcumin and licorice extract compared to non-inventive compositions
  • Bioavailability is the metrologically much easier to determine the turbidity of the solubilizate.
  • This turbidity of the solubilizate according to the invention is less than 5 FNU, preferably less than 2 FNU, measured by
  • the invention also provides a capsule filled with a solubilizate described above, wherein the capsule as
  • Soft gelatin capsule or hard gelatin capsule or as soft, gelatin-free capsule or as a hard, gelatin-free capsule is formed.
  • solubilizate according to the invention can be used in the context of
  • the invention also provides a fluid containing an above
  • solubilisate wherein the fluid is selected from the group consisting of foods
  • the fluid may comprise an aqueous dilution of the solubilizate.
  • the invention also enables the use of a solubilizate or fluid as described above
  • Medicaments for the treatment of inflammatory diseases, cancer, Alzheimer's, Parkinson's, obesity, high cholesterol, elevated blood sugar, metabolic syndrome and / or autoimmune diseases are included in the body.
  • the invention also provides a method for
  • the solubilisate is administered to the patient in a dose of xanthohumol in the range of 0.5 mg / kg
  • Body weight to 1 mg / kg body weight, preferably with a dose of 0.81 mg / kg body weight, especially once a day.
  • the solubilizate is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
  • Body weight preferably administered at a dose of 0.81 mg / kg body weight, especially once a day.
  • solubilizate according to the invention with the active ingredients curcumin, xanthohumol and glavonoid, either solubilisates prepared individually can be mixed with one another or a solubilizate containing curcumin, xanthohumol and glavonoid is prepared directly.
  • the invention further provides a method for producing a solubilizate described above
  • Licorice root extract in particular a hydrophobic solution of a liquorice root extract, preferably of glavonoid and / or glabridin, wherein in step a) heating to a temperature in the range of 40 ° C to 62 ° C, preferably to a
  • step b) heating to a temperature in the range of 60 ° C to 75 ° C, preferably to a
  • step c) heating to a temperature in the range of 70 ° C to 92 ° C, preferably to a
  • step d) heating to a temperature in the range of 80 ° C to 97 ° C, preferably to a
  • step b) a step
  • the invention also provides a further possibility for producing a solubilizate described above, namely by mixing a curcumin solubilisate and a
  • Xanthohumol solubilisate and a glavonoid solubilizate in particular in the ratio 1: 1: 1.
  • the curcumin product used was the product "Turmeric Oleoresin Curcumin Powder 95%” having product code EP-5001 from Green Leaf Extraction Pvt Limited, India, India
  • the curcumin powder is CAS No. 458-37-7 is a natural product, which by
  • Solvent extraction of rhizomes of Curcuma Longa is obtained.
  • the curcumin content of the powder is according to the manufacturer at least 95%. This curcumin content is determined by ASTA Method 18.0.
  • Greenleaf can also contain, for example, 95% curcumin extract from Neelam Phyto-extract s, Mumbai, India or curcumin BCM-95-SG or curcumin BCM-95-CG from eurochem GmbH, Gröbenzell, Germany or Curcuma Oleoresin 95% from Henry Lamotte OILS GmbH, Bremen,
  • Xanthohumol source used was the product "Xantho-Flav pur” of the brand “Hopsteiner” from Simon H. Steiner, Hopfen, GmbH, Mainburg, Germany.
  • “Xantho-Flav pure” is a natural product made from hops and the active ingredient is the hops polyphenol xanthohumol
  • Xanthohumol content according to manufacturer's instructions of at least 85%.
  • concentrations of xanthohumol and isoxanthohumol in "Xantho-Flav pure” are quantified by the manufacturer according to the UV spectrophotometric analysis or HPLC EBC 7.8 using external calibration standard pure XN (370 nm) or IX (290 nm).
  • Xantho-Flav pur contains that
  • Glabridin is the product name of a composition of Kaneka Corporation, Osaka, Japan, which contains glabridin as an active ingredient. Glabridin is a flavonoid of the real Licorice (Glycyrrhiza glabra). The product "Kaneka
  • Glavonoid "contains 30% according to the manufacturer
  • Glabridin Licorice extract and 70% cooking oil. "Kaneka glavonoid” is standardized to 3% glabridin, which is the major component of the true licorice polyphenols, according to the manufacturer's instructions The Glabridin CAS # is 59870-68-7.
  • the source of polysorbate 80 was the material "TEGO SMO 80 V FOOD” with the specification code “K04 EU-FOOD” from Evonik Nutrition & Care GmbH, Essen, Germany.
  • Evonik's TEGO SMO 80 V can also be used as polysorbate 80 by TEGO SMO 80 V from InCoPA Gmbh, Illertissen, Germany.
  • glycerin was the product "Glycamed 99.7%” from Glaconchemie GmbH, Merseburg, Germany According to the manufacturer, the glycerol content of this product is at least 99.5%. ethanol
  • ethanol was purchased from Berkel Pbibzische Spritfabrik GmbH & Co. KG. According to the specification for "Neutral Alcohol 1411U taxed", the ethanol content of this product is approximately 94 +/- 1%.
  • NANOFLEX backscatter particle analyzer performed.
  • the measuring principle is based on dynamic light scattering (DLS) in a 180 ° heterodyne backscatter arrangement. With this geometry, the scattered light becomes part of the
  • Heterodyne technique Because of the low light path from 200 microns to 300 microns in the sample, backscattering is beneficial for absorbing and highly concentrated samples.
  • the heterodyne technique enhances the signal-to-noise ratio and the sensitivity of the sub-10 onm range.
  • the laser light is coupled into the Y-fork of an optical fiber. Come back in the same fiber on the
  • Saphir window of the sample chamber partially reflected laser light and the backward scattered from the sample light.
  • Detector in the second branch of the Y-fork receives the interfering signals.
  • Each frequency component represents a Brown 's diffusion constants and can therefore be assigned to a particle size
  • Particle size distribution uses the Stokes-Einstein formula:
  • a temperature sensor is located in the meter near the sapphire window close to the sample.
  • Turbidity meters calibrated with a standard suspension.
  • the display is thus not in the form of the measured light intensity, but as a concentration of
  • Suspension thus means the indication that the liquid in question causes the same light scattering as the standard suspension of the indicated concentration.
  • the internationally defined turbidity standard is Formazin.
  • FNU ie "Formazine Nephelometry Units”. This is the
  • Embodiment 1 For example, in the water treatment used unit for the measurement at 90 ° according to the provisions of the standard ISO 7072.
  • Polysorbate 80 and glycerol are mixed with stirring while heating to a temperature in the range of 48 to 52 ° C to homogenize the mixture well.
  • Ethanol is incorporated with such strong stirring in the polysorbate-glycerol mixture that forms a homogeneous solution.
  • the temperature is kept constant. Then xanthohumol is added to the solution of polysorbate,
  • curcumin powder is incorporated into the xanthohumol solubilizate.
  • the temperature is raised to a value in the range between 78 and 82 ° C.
  • glavonoid is stirred so vigorously that the newly added component of the solubilizate in the fluid introduced homogeneously combines to form the solubilized product.
  • the temperature is further increased to a value in the range between 85 and 98 ° C.
  • the product is a solubilizate with co-micellized
  • Curcumin, xanthohumo1 and glavonoid It is allowed to cool to a maximum of 45 ° C. with stirring and then bottled.
  • this solubilizate was first distilled in a ratio of 1: 500
  • Dilution of the solubilizate of 1.3 FNU which is an average of two measurements (2.5 FNU;
  • Active substances curcumin, xanthohumol and glavonoid, solubilisates according to the invention can also be obtained by mixing
  • Solubilisates of the individual active ingredients are produced.
  • glavonoid may be added to a solubilizate containing curcumin and xanthohumol.
  • Curcumin solubilizate prepared. To do this
  • the polysorbate is heated to a temperature in the range between 48 and 52 ° C, then the curcumin powder is incorporated with heating to a value in the range between 58 and 62 ° C. It is so strongly stirred that the
  • Curcumin powder is uniformly drawn into the polysorbate and forms a homogeneous solubilizate. At constant temperature, ethanol is released
  • Curcumin solubilisate dissolved This is followed by the addition of the Xantho Flav powder. It is stirred so strongly that the Xantho Flav powder is uniformly drawn into the ethanol-containing Curcuminsolubilisat and forms a homogeneous co-solubilizate. The temperature is increased with the addition of the Xantho Flav powder to a value in the range of 85 to 89 ° C.
  • the product is a solubilisate with curcumin
  • Xanthohumol and glavonoid The total amount is then 1075 g, resulting in a proportion of 4.68% with 50 g of xanthohumol and a proportion of 7.1% with 75 g of glavonoid and a proportion of 3.5% with 37.5 g of curcumin. It is allowed to cool to a maximum value of 45 ° C with stirring and then bottled.
  • a solubilizate with xanthohumol and glavonoid can also be prepared in the first step, and then curcumin can be added. At first one gets involved 7.5% glavonoid / 4.6% xanthohumol solubilisate. To do this
  • polysorbate 80 750 g polysorbate 80 used.
  • polysorbate 80 and glycerin are mixed and heated to a temperature in the range of 48 to 52 ° C with stirring. Ethanol is added to this fluid, it is so strongly stirred at a constant temperature that the fluids are homogeneous with each other
  • curcumin powder 95% incorporated with heating to a temperature in the range between 58 and 62 ° C. It is stirred so strongly that the curcumin powder is uniformly drawn into the co-solubilizate of xanthohumol and glavonoid and forms a homogeneous solubilizate. The total amount is then 1050 g, resulting in each case at 50 g of xanthohumol and
  • Curcumin a proportion of 4.8% and 75 g glavonoid gives a proportion of 7.1%.
  • the product is a solubilizate with curcumin, xanthohumol and glavonoid. It is allowed to cool to a maximum value of 45 ° C with stirring and then bottled.
  • a solubilizate according to the invention can also be obtained by mixing three individually prepared solubilisates of curcumin on the one hand and xanthohumol or
  • Glavonoid be made on the other hand.
  • polysorbate 80 900 g polysorbate 80 are used.
  • the glavonoid was added to polysorbate 80 with stirring
  • Polysorbate 80 incorporated. The powder is added at such a rate that it
  • Heating to 83 to 87 ° C is further homogenized. After a homogeneous solubilizate is reached, is cooled to a temperature below 60 °. The Xantho Flav solubilizate is then bottled and dark and cool, i. stored below 25 ° C.
  • the polysorbate 80 is heated to 48 to 52 ° C. With stirring, the curcumin powder is added to the polysorbate and further heated to a temperature in the range of 95 to 97 ° C. The addition of the powder takes place at such a rate that it is uniformly drawn into the emulsifier during stirring. After cooling to one
  • solubilisates (contains 50 g of glavonoid).
  • the solubilisates are optionally heated to a temperature in the range of 50 to 60 ° C to lower their viscosity, ie to improve the flowability.
  • Solubilisates are homogenized by stirring to a mixed solubilizate with curcumin, xanthohumol and glavonoid.
  • the product is cooled and bottled.
  • curcumin, xanthohumol and glavonoid in the individual solubilisates can also be set significantly higher than in the example shown, depending on the application.
  • glycerin glycerin
  • solubilisates may be added to the solubilisates.
  • Solubilisate according to the invention is irreversibly soluble in water and for these solubilized under
  • Such dispersions may be (nano) emulsions, but they are not solubilizates in which the active ingredient or agents are included in the very small micelles. But only the solubilizates allow after the Experiences of the inventor the significantly increased bioavailability of the active ingredient or the active ingredients according to the invention, even if an emulsion is a higher
  • the control is not carried out by sampling and thus outside the reaction vessel, but in the reaction vessel.
  • the laser beam is directed perpendicularly to the reaction vessel through a sight glass, which is located on the front of the reaction vessel. If only one point of light appears on the back inside of the reaction cube, completely free from scattering, these are
  • Reaction vessel smaller than the wavelength of visible light and thus a visual confirmation that the
  • micellization Process of micellization is completed.
  • the clarity of the solubilizate can also be represented by its low turbidity.
  • the clearer is an aqueous dilution of a solubilizate, in particular under physiological conditions of a gastric passage, ie at a pH of 1.1 and a temperature of 37 ° C., the better is its solubilization.
  • the better the solubilization the better the bioavailability of the active ingredient or the product containing it. This can already be read off from the particularly low turbidity of the solubilizate, which turns out to be a kind of
  • the turbidity of the solubilizate according to the invention is less than 50 FNU measured by scattered light measurement with infrared light according to the provisions of the standard ISO 7027.
  • the inventive transparent and completely stable water-soluble formulation has, without the above-mentioned adjuvants such as in soft and hard gelatin capsules, in gelatin-free capsules (hard and / or soft) and in
  • pH-independent liquid-based end products have a stable transparency and, in addition, a significantly improved bioavailability. Products with such transparency and water solubility, but also in particular so high bioavailability of the active ingredients curcumin,
  • Xanthohumol and glavonoid are urgently used by the relevant industry for innovative products
  • RCT data are the results of a randomized controlled trial (RCT), in which phytosomal curcumin was administered
  • RCT randomized controlled trial
  • curcumin may affect several health factors, including BMI (body mass index) and liver fat, and transaminase levels in people with non-alcoholic fatty liver (NAFLD).
  • BMI body mass index
  • NAFLD non-alcoholic fatty liver
  • curcumin has been associated with the lowering of serum total cholesterol, LDL cholesterol,
  • Triglycerides Non-HDL cholesterol and uric acid.
  • curcumin powder Jupiter Leys, Cochin, India. It contained 82% by weight of curcumin.
  • the curcumin micronisate was manufactured by RAPS GmbH & Co. KG, Kulmbach, Germany with the so-called "concentrated powder form technology"
  • Diacetyltartaric acid glyceride which in the EU as
  • Quantitative limit (quantum satis) is generally permitted for food.
  • the resulting solution is sprayed onto a porous support of silicon dioxide.
  • the resulting curcumin micronisate contains 17.2% by weight of curcumin powder, which corresponds to 14.1% by weight of curcumin.
  • Applicant's curcumin isolate consisted of 7% by weight of curcumin powder, which corresponds to 6% by weight of curcumin, and
  • AUC area under the curve
  • Curcumin micronisate and the curcumin solubilisate as for the native curcumin Averaged over all subjects, a 185-fold higher AUC value after taking the
  • Curcuminsolubilisats compared to the native form
  • Subjects measured a 453-fold higher maximum total plasma concentration C ma x.
  • the time T ma x, after which this higher maximum concentration in the plasma Cmax was detected, after taking the micellized curcumin from the solubilizate was significantly shorter than the native form.
  • the 185-fold higher AUC value is the
  • Curcuminsolubilisat the applicant according to their knowledge the formulation of curcumin, which of all hitherto
  • tested formulations have the highest bioavailability.
  • Solubilizat the applicant used with 9.2% xanthohumol This was prepared from 100 g of "Xantho-Flav Pur" corresponding to 92 g of xanthohumol, 150 g of 96% ethanol and 750 g of polysorbate 80. To adjust the concentration to 9 mg / mL, the solubilizate was treated with double-distilled water ("ddH20"). ) diluted.
  • mice of the strain C57BL / 6 at the age of 9 weeks either received usual diet or were prepared according to the "Western type diet" from 15% lard, 15%
  • the body weight of the control group remained nearly unchanged during the 4-week lead-time and 2-week randomized therapy, while the body weight of the Western type diet group ("WTD") was nearly randomized throughout this period increase linearly by at least 30% relative to baseline.
  • the WTD caused not only obesity, but also a significant increase in the mass of visceral fat. Photographs of the experimental animals showed that the gift of xanthohumol solubilisate to a
  • Photographs of the organs, which were taken from the animals at the end of the test series, as well as an increase in the weight of the liver shows.
  • a bright liver color also indicates fat accumulation in the liver (steatosis).
  • the administration of the solubilizate according to the invention in addition to the WTD caused that the increase in the liver weight was almost completely reversed, that is, it reached the starting value again.
  • Triglyceride content in the liver was also the histology of the liver confirmed the findings fatty liver (hepatic
  • liver inflammation mRNA expression of the pro ⁇ inflammatory chemokine MCP-1
  • marker of a liver inflammation mRNA expression of the pro ⁇ inflammatory chemokine MCP-1
  • Liver fibrosis (mRNA expression of collagen type I, which is the most common extracellular matrix protein in liver fibrosis) was significantly increased by WTD.
  • the solubilizate according to the invention is therefore suitable for returning an already developing liver inflammation and fibrosis.
  • solubilisate x 0.925 875.23 mg of polysorbate in the total amount of solubilisate.
  • solubilisate x 0.75 425.70 mg polysorbate in the total amount of solubilisate.
  • the total amount of polysorbate in the solubilisate with 5 mg curcumin and 5 mg xanthohumol is thus 1,300.93 mg.
  • Xanthohumol in each case in native or solubilized according to the invention form. Anti-inflammatory markers and antioxidant capacity were determined.
  • Female Wistar rats weighing between 150 and 200 g were prepared according to "Pearson et al. (1956) "the” adjuvant induced arthritis "exposed. The animals were subplanted
  • FCA Freund s e administered adjuvant
  • Group 1 formed the control group.
  • Group 2 received diclofenac as a reference drug at a dose of 3 mg / kg body weight.
  • Group 3 received native curcumin at a dosage of 5 mg / kg body weight.
  • Curcumin at a dosage of 5 mg / kg body weight Curcumin at a dosage of 5 mg / kg body weight.
  • Group 5 received native curcumin at a dose of 10 mg / kg body weight and
  • Group 6 curcumin solubilized in the same dosage.
  • Group 7 received native xanthohumol at a dose of 5 m / kg body weight and
  • Group 9 received a mixture of native curcumin at a dosage of 5 mg / kg body weight and native
  • Group 11 received a mixture of native curcumin at a dosage of 5 mg / kg body weight and native Xanthohumol in a dosage of 5 mg / kg body weight and
  • Curcumin and solubilized xanthohumol in each case the same dosage are identical.
  • MPO myeloperoxidase
  • CRP C-reactive protein
  • TAC total antioxidant capacity
  • TBARS thiobarbituric acid reactive substances
  • FIG. 2 effect of curcumin in native and solubilized form and of diclofenac on the serum content of MPO (mU / ml),
  • solubilized form on the serum content of MPO (mU / mL).
  • C-reactive protein is a specific marker for anti-inflammatory activity.
  • Both the native and solubilized forms of curcumin inhibited rat CRP serum levels in a dose-dependent manner, but the solubilized form was twice as effective as the native and significantly more potent than diclofenac at the selected dose (Figure la).
  • Xanthohumol showed a potentiating effect only in solubilized form
  • Xanthohumol alone has a comparable effect as Diclofenac and showed a better anti-inflammatory activity in solubilized form compared to the native form ( Figure lc).
  • MPO Myeloperoxidase
  • neutrophilic granulocytes in the affected tissue Its concentration is elevated in patients with rheumatoid arthritis and causes oxidative stress. In the
  • curcumin was efficiently reduced at both considered dosages in the same way and not significantly different from diclofenac.
  • native curcumin did not affect MPO levels
  • Oxidative stress is one of the major factors contributing to joint destruction in rheumatoid arthritis (RA).
  • An increase in the production of so-called “reactive oxigen species (ROS)” leads to a reduced intake of endogenous antioxidants and ultimately results in the destruction of cells .
  • ROS reactive oxigen species
  • the increase in antioxidant status which is represented by an increase in TAC, can be used as an indication of protection against the development of degenerative inflammatory processes.
  • TAC antioxidant capacity
  • the table contains data on the effect of curcumin and
  • Xanthohumol in native and solubilized form either alone or in combination with diclofenac at a dose of 3 mg / kg body weight once a day for 21 days on the antioxidant capacity TAC and the
  • the invention provides a solubilizate of curcumin, xanthohumol and a fluid containing licorice root extract, especially glavonoid, for use in the treatment of obesity, especially for lowering visceral fat, for lowering of
  • Cholesterol in particular LDL cholesterol, for lowering blood glucose, lowering triglycerides in the blood, reducing oxidative stress, and / or reducing the accumulation of fat in the hepatocytes, in particular for use as a medicament for the treatment of
  • Licorice root extract in particular glabridin, which a patient has to take orally daily.

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Abstract

L'objectif de cette invention est de produire une formulation permettant de faire bénéficier à l'organisme d'êtres humains ou d'animaux les propriétés favorables pour la santé voire curatives de la curcumine, du xanthohumol et de l'extrait de racine de réglisse, en particulier du Glavonoïd. A cet effet, l'invention se rapporte à un solubilisat renfermant du xanthohumol selon une proportion en % en poids de préférence inférieure ou égale à 6 % en poids, de préférence encore comprise entre 2,7 % en poids et 4,8 % en poids et de la curcumine selon une proportion inférieure ou égale à 10% en poids, de préférence inférieure ou égale à 6 % en poids, de préférence encore comprise entre 2,3 % en poids et 4,8 % en poids et un fluide contenant de l'extrait de racine de réglisse, en particulier une solution hydrophobe d'un extrait de racine de réglisse, de préférence du Glavonoïd et/ou de la glabridine selon une proportion inférieure ou égale à 10 % en poids, de préférence inférieure ou égale à 8 % en poids, de préférence encore comprise entre 3,3 % en poids et 5 % en poids, au moins un émulsifiant présentant une HLB comprise entre 13 et 18, en particulier du polysorbate 80 ou du polysorbate 20 ou un mélange de polysorbate 20 et de polysorbate 80.
PCT/EP2017/067382 2017-07-11 2017-07-11 Solubilisat comportant de la curcumine, du xanthohumol et de l'extrait de racine de réglisse Ceased WO2019011415A1 (fr)

Priority Applications (51)

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PCT/EP2017/067382 WO2019011415A1 (fr) 2017-07-11 2017-07-11 Solubilisat comportant de la curcumine, du xanthohumol et de l'extrait de racine de réglisse
JP2020501208A JP2020529974A (ja) 2017-07-11 2018-07-11 クルクミンと、任意選択で少なくとも１つの他の活性物質とを有する可溶化物
DK18738321.1T DK3651805T3 (da) 2017-07-11 2018-07-11 Solubilisat med curcumin og mindst ét yderligere aktivt stof
EP18738321.1A EP3651805B1 (fr) 2017-07-11 2018-07-11 Solubilisat contenant de la curcumine et au moins une autre substance active
US16/629,077 US11344509B2 (en) 2017-07-11 2018-07-11 Solubilizate with curcumin and boswellia and xanthohumol
HRP20231160TT HRP20231160T1 (hr) 2017-07-11 2018-07-11 Solubilizat s kurkuminom, bosvelijom i ksantohumolom
HRP20231591TT HRP20231591T1 (hr) 2017-07-11 2018-07-11 Solubilizat s kurkuminom i barem jednom drugom aktivnom tvari
ES18738321T ES2965739T3 (es) 2017-07-11 2018-07-11 Solubilizado con curcumina y al menos otro principio activo
PT187376231T PT3651804T (pt) 2017-07-11 2018-07-11 Solubilizado com curcumina e boswellia e xanthohumol
PT187383211T PT3651805T (pt) 2017-07-11 2018-07-11 Solubilizado com curcumina e, pelo menos, uma substância ativa adicional
ES18737623T ES2960296T3 (es) 2017-07-11 2018-07-11 Solubilizado con curcumina y boswelia y xantohumol
CA3148455A CA3148455A1 (fr) 2017-07-11 2018-07-11 Solubilisat contenant de la curcumine et optionnellement au moins une autre substance active
FIEP18737623.1T FI3651804T3 (en) 2017-07-11 2018-07-11 Solubilisate with curcumin, boswellia, and xanthohumol
EP18737623.1A EP3651804B1 (fr) 2017-07-11 2018-07-11 Solubilisat comprenant de la curcumine, du boswellia et du xanthohumol
CA3069621A CA3069621C (fr) 2017-07-11 2018-07-11 Solubilisat contenant de la curcumine et optionnellement au moins une autre substance active
RU2020106042A RU2752078C1 (ru) 2017-07-11 2018-07-11 Солюбилизат с куркумином и при необходимости по меньшей мере с одним другим активным веществом
KR1020237017168A KR102573152B1 (ko) 2017-07-11 2018-07-11 커큐민 및 선택적으로 적어도 1종의 다른 활성 물질을 갖는 가용화물
HUE18738321A HUE064518T2 (hu) 2017-07-11 2018-07-11 Kurkumint és legalább egy további hatóanyagot tartalmazó szolubilizátum
CN201880046608.4A CN111201041A (zh) 2017-07-11 2018-07-11 具有姜黄素和任选至少另一种活性物质的增溶物
PCT/EP2018/068801 WO2019011990A1 (fr) 2017-07-11 2018-07-11 Solubilisat d'extrait de réglisse
DK18737623.1T DK3651804T5 (da) 2017-07-11 2018-07-11 Solubilisat med curcumin, boswellia og xanthohumol
PCT/EP2018/068729 WO2019011954A1 (fr) 2017-07-11 2018-07-11 Solubilisat comprenant de la curcumine, du boswellia et du xanthohumol
RS20230894A RS64650B1 (sr) 2017-07-11 2018-07-11 Solubilizat sa kurkuminom i bosvelijom i ksantohumolom
US16/629,155 US11197834B2 (en) 2017-07-11 2018-07-11 Solubilizate with curcumin and optionally at least one other active substance
HUE18737623A HUE063380T2 (hu) 2017-07-11 2018-07-11 Szolubilizátum Kurkuminnal, Boswellia-val és Xantohumollal
PL18738321.1T PL3651805T3 (pl) 2017-07-11 2018-07-11 Solubilizator z kurkuminą i co najmniej jedną inną substancją czynną
KR1020207004082A KR20200029002A (ko) 2017-07-11 2018-07-11 커큐민 및 선택적으로 적어도 1종의 다른 활성 물질을 갖는 가용화물
BR112020000398-0A BR112020000398B1 (pt) 2017-07-11 2018-07-11 Solubilizado com curcumina e, opcionalmente, pelo menos umas outras substâncias ativas
PL18737623.1T PL3651804T3 (pl) 2017-07-11 2018-07-11 Solubilizator z kurkuminą i kadzidłowcem oraz ksantohumolem
PCT/EP2018/068731 WO2019011955A2 (fr) 2017-07-11 2018-07-11 Solubilisat contenant de la curcumine et optionnellement au moins une autre substance active
CN201880046265.1A CN111163806A (zh) 2017-07-11 2018-07-11 含有姜黄素，乳香和黄腐酚的增溶物
MX2021000339A MX2021000339A (es) 2017-07-11 2019-07-10 Solubilizado con curcumina y al menos un cannabinoide como sustancia activa adicional.
FIEP19736404.5T FI3820528T3 (en) 2017-07-11 2019-07-10 Solubilisate comprising curcumin and at least one cannabinoid as a further active agent
HUE19736404A HUE063768T2 (hu) 2017-07-11 2019-07-10 Kurkumint és további hatóanyagként legalább egy kannabinoidot tartalmazó szolubilizátum
US17/258,397 US20220133682A1 (en) 2017-07-11 2019-07-10 Solubilizate with curcumin and at least the cannabinoid thc as a further active substance
DK19736404.5T DK3820528T3 (da) 2017-07-11 2019-07-10 Solubilisat, der omfatter curcumin og mindst ét cannabinoid som et yderligere aktivt stof
RS20230897A RS64642B1 (sr) 2017-07-11 2019-07-10 Solubilizat sa kurkuminom i bar jednim kanabinoidom kao daljim aktivnim sastojkom
US17/258,363 US20220133646A1 (en) 2017-07-11 2019-07-10 Solubilizate with curcumin and at least one cannabinoid as a further active substance
PL19736735.2T PL3820529T3 (pl) 2017-07-11 2019-07-10 Solubilizator z kurkuminą i co najmniej kannabinoidem thc jako dodatkową substancją czynną
HUE19736735A HUE063382T2 (hu) 2017-07-11 2019-07-10 Szolubilizátum kurkuminnal és további hatóanyagként legalább a THC kannabinoiddal
RU2021103127A RU2771527C1 (ru) 2017-07-11 2019-07-10 Солюбилизат с куркумином и по меньшей мере одним каннабиноидом в качестве дополнительного активного вещества
HRP20231135TT HRP20231135T1 (hr) 2017-07-11 2019-07-10 Solubilizat s kurkuminom i najmanje kanabinoidom thc kao dodatnom aktivnom tvari
ES19736735T ES2960689T3 (es) 2017-07-11 2019-07-10 Solubilizado con curcumina y al menos el cannabinoide THC como una sustancia activa adicional
UAA202100177A UA125552C2 (uk) 2017-07-11 2019-07-10 Солюбілізат, що містить куркумін і щонайменше один канабіноїд як додаткову активну речовину
MX2021000385A MX2021000385A (es) 2017-07-11 2019-07-10 Solubilizado con curcumina y al menos el cannabinoide thc como una sustancia activa adicional.
RS20230868A RS64636B1 (sr) 2017-07-11 2019-07-10 Solubilizat sa kurkuminom i bar kanabinoidom thc-om kao daljim aktivnim sastojkom
MYPI2020007185A MY200185A (en) 2017-07-11 2019-07-10 Solubilizate with curcumin and at least one cannabinoid as a further active substance
US17/544,808 US11931322B2 (en) 2017-07-11 2021-12-07 Solubilizate with curcumin and optionally at least one other active substance
US17/730,356 US20220249400A1 (en) 2017-07-11 2022-04-27 Solubilizate with curcumin and boswellia and xanthohumol
US18/600,907 US12144784B2 (en) 2017-07-11 2024-03-11 Solubilizate with curcumin and optionally at least one other active substance
US18/738,127 US20240325318A1 (en) 2017-07-11 2024-06-10 Solubilizate with at least one cannabinoid

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11931322B2 (en) 2017-07-11 2024-03-19 Aquanova Ag Solubilizate with curcumin and optionally at least one other active substance
US12144784B2 (en) 2017-07-11 2024-11-19 Aquanova Ag Solubilizate with curcumin and optionally at least one other active substance
WO2020011402A1 (fr) * 2018-07-11 2020-01-16 Aquanova Ag Solubilisat de xanthohumol
US11786484B2 (en) 2018-07-11 2023-10-17 Aquanova Ag Xanthohumol solubilizate

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