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WO2019011414A1 - Solubilisat comprenant de la curcumine et de la boswellia - Google Patents

Solubilisat comprenant de la curcumine et de la boswellia Download PDF

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Publication number
WO2019011414A1
WO2019011414A1 PCT/EP2017/067381 EP2017067381W WO2019011414A1 WO 2019011414 A1 WO2019011414 A1 WO 2019011414A1 EP 2017067381 W EP2017067381 W EP 2017067381W WO 2019011414 A1 WO2019011414 A1 WO 2019011414A1
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WO
WIPO (PCT)
Prior art keywords
range
curcumin
solubilizate
temperature
polysorbate
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
Application number
PCT/EP2017/067381
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German (de)
English (en)
Inventor
Dariush Behnam
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Aquanova AG
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Aquanova AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Priority to PCT/EP2017/067381 priority Critical patent/WO2019011414A1/fr
Priority to HUE18737623A priority patent/HUE063380T2/hu
Priority to PCT/EP2018/068729 priority patent/WO2019011954A1/fr
Priority to EP18738321.1A priority patent/EP3651805B1/fr
Priority to DK18738321.1T priority patent/DK3651805T3/da
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 JP2020501208A priority patent/JP2020529974A/ja
Priority to PT187376231T priority patent/PT3651804T/pt
Priority to PT187383211T priority patent/PT3651805T/pt
Priority to EP18737623.1A priority patent/EP3651804B1/fr
Priority to CA3148455A priority patent/CA3148455A1/fr
Priority to FIEP18737623.1T priority patent/FI3651804T3/en
Priority to CA3069621A priority patent/CA3069621C/fr
Priority to KR1020237017168A priority patent/KR102573152B1/ko
Priority to PCT/EP2018/068801 priority patent/WO2019011990A1/fr
Priority to HUE18738321A priority patent/HUE064518T2/hu
Priority to US16/629,155 priority patent/US11197834B2/en
Priority to CN201880046608.4A priority patent/CN111201041A/zh
Priority to PL18738321.1T priority patent/PL3651805T3/pl
Priority to DK18737623.1T priority patent/DK3651804T5/da
Priority to ES18738321T priority patent/ES2965739T3/es
Priority to RS20230894A priority patent/RS64650B1/sr
Priority to CN201880046265.1A priority patent/CN111163806A/zh
Priority to RU2020106042A priority patent/RU2752078C1/ru
Priority to ES18737623T priority patent/ES2960296T3/es
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
Publication of WO2019011414A1 publication Critical patent/WO2019011414A1/fr
Priority to RU2021103127A priority patent/RU2771527C1/ru
Priority to MX2021000339A priority patent/MX2021000339A/es
Priority to DK19736404.5T priority patent/DK3820528T3/da
Priority to PL19736735.2T priority patent/PL3820529T3/pl
Priority to HUE19736735A priority patent/HUE063382T2/hu
Priority to UAA202100177A priority patent/UA125552C2/uk
Priority to US17/258,397 priority patent/US20220133682A1/en
Priority to US17/258,363 priority patent/US20220133646A1/en
Priority to ES19736735T priority patent/ES2960689T3/es
Priority to HUE19736404A priority patent/HUE063768T2/hu
Priority to RS20230897A priority patent/RS64642B1/sr
Priority to HRP20231135TT priority patent/HRP20231135T1/hr
Priority to MX2021000385A priority patent/MX2021000385A/es
Priority to FIEP19736404.5T priority patent/FI3820528T3/en
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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    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • 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)
    • A61K36/32—Burseraceae (Frankincense family)
    • A61K36/324—Boswellia, e.g. frankincense
    • 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
    • A61K47/26—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the invention relates to a solubilizate with curcumin and boswellia according to claim 1
  • 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
  • the drug In order to enter the bloodstream after oral intake, the drug must pass through the intestinal wall, is then metabolized in the liver and passes as
  • Active ingredient is either microbially degraded in the intestine or eliminated with the faeces or bile.
  • the extract from the resin of the frankincense tree, Boswellia serrata extract contains in particular the boswellic acids "CCBA” CC-boswellic acid and "ßBA” ß-boswellic acid and its derivatives "KBA” 11-keto-ß-boswellic acid (CAS 17019-92-0) and "AKBA” 3-O-acetyl-l 1-keto- ⁇ -boswellic acid (CAS 67416-16-9) and "A BA" 3-O-acetyl-CC-boswellic acid and "A ⁇ BA” 3-O-acetyl ß-boswellic acid.
  • AKBA 3-O-acetyl-l 1-keto- ⁇ -boswellic acid
  • a BA 3-O-acetyl-CC-boswellic acid and "A ⁇ BA” 3-O-acetyl ß-boswellic acid.
  • AKBA is said to have an anti-inflammatory effect.
  • biswellia is used, in particular in the term “boswellia solubilisate” in the sense that the term “boswellia” refers to the active ingredients from the resin of the
  • Boswellic acid refers.
  • the term "boswellic acid solubilisate" refers to a micellar formulation of at least one boswellic acid, which may also contain at least one boswellic acid derivative.
  • the inventor therefore set himself the task of a
  • Curcumin and Boswellia makes the human or animal organism accessible.
  • it is one Object of the invention to allow the best possible bioavailability of curcumin and boswellia.
  • solubilizate according to claim 1 contains curcumin in a proportion of less than or equal to 10 wt .-%, preferably less than or equal to 8 wt .-%,
  • one or more boswellic acids and / or one or more boswellic acid derivatives in a proportion of less than or equal to 10 wt .-%, preferably less than or equal to 8 wt .-%, particularly preferably 4.7 wt .-% to 6, 6 wt. -% and
  • Polysorbate 20 or a mixture of polysorbate 20 and polysorbate 80 are examples of polysorbate 20 and polysorbate 80.
  • the solubilizate consists of curcumin in an amount of less than or equal to 10% by weight, preferably less than or equal to
  • 8 wt .-% particularly preferably 3 wt .-% to 7 wt .-%, one or more boswellic acids and / or one or more boswellic acid derivatives with a proportion of less than or equal to 10 wt .-%, preferably less than or equal to 8 Wt .-%, particularly preferably 4.7 wt .-% to 6, 6 wt. -% and
  • Polysorbate 20 or a mixture of polysorbate 20 and polysorbate 80 Due to the high proportion of boswellia, the invention provides in an advantageous embodiment that the
  • Boswellia should be solubilized and, in particular, depending on the question of whether further active substances should be micellised in addition to boswellia, the
  • Emulsifier to curcumin in the range between 30: 1 and 3: 1, preferably in the range between 25: 1 and 9: 1, preferably in the range between 23: 1 to 12: 1 are selected.
  • the emulsifier content, in particular the polysorbate content, according to the invention is for this purpose at least 70% by weight, preferably in the range between 75% by weight and 95% by weight, more preferably in the range between 79% by weight and
  • the invention offers the possibility that the solubilizate contains up to 20 wt .-%, preferably up to 15 wt .-% ethanol.
  • the addition of ethanol can reduce the proportion of polysorbate, which is an advantage in terms of the ADI value for polysorbate.
  • the solubilizate contains up to 25% by weight, preferably up to 10% by weight, of glycerol.
  • solubilizates according to the invention also have a narrow particle size distribution with a small mean in the physiological conditions of a gastric passage
  • Particle sizes preferably the diameter distribution of the micelles in a dilution of the solubilisate with distilled water in the ratio 1: 500 at pH 1.1 and 37 ° C of about nm to about nm. These values were determined by volume distribution. Details of particle size analysis of the micelles of the solubilisates are discussed below.
  • CRP C-reactive protein
  • MPO myeloperoxidase
  • 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 with the use of the catalysis, the enzyme unit (U) becomes in medicine and clinical chemistry still used.
  • An enzyme unit U corresponds to a micro-mole substrate turnover per minute.
  • micellized compositions of boswellia with curcumin give improved bioavailability
  • the turbidity of the solubilizate is preferably less than 25 FNU, preferably less than 3 FNU, measured as a result of scattered light measurement with infrared light according to the invention
  • the invention also provides a capsule filled with a boswellic acid solubilizate described above or a corresponding one
  • the capsule is formed as a soft gelatin capsule or hard gelatin capsule or as a soft, gelatin-free capsule or as a hard, gelatin-free capsule.
  • solubilizate according to the invention can be used in the context of
  • the invention also provides a fluid containing the solubilizate described above, wherein the fluid is selected from the group consisting of foods, beverages, cosmetics and pharmaceutical products.
  • the fluid in the context of the invention comprise an aqueous dilution of the solubilizate.
  • the invention also makes it possible in a particularly simple manner to use a solubilizate or fluid as medicaments for the treatment of inflammation-associated diseases, cancer, Alzheimer's, Parkinson's, obesity, high cholesterol, elevated blood sugar, metabolic syndrome and / or
  • the invention also provides a method for
  • solubilizate according to the invention in particular in a capsule or as a fluid, is administered to the patient, in particular orally,
  • the solubilizate is the
  • a curcumin dose in the range of 0.5 mg / kg body weight to 1 mg / kg body weight, preferably at a dose of 0.81 mg / kg body weight, and in a boswellia dose in the range of 1 mg / kg body weight to 2 mg / kg body weight, preferably with a dose of
  • solubilisates prepared individually can be mixed with one another or a solubilizate containing curcumin and
  • Boswellia is made directly.
  • the invention further provides methods of making a solubilizate as described above. If a co-micellization of boswellia with curcumin is desired, the invention sets the following variant
  • step a) heating to a temperature in the range of 40 ° C to 62 ° C, preferably to a temperature in the range of 45 ° C to 57 ° C, more preferably to a temperature in the range of 48 ° C and 52 ° C, takes place
  • step b) heating to a temperature in the range of 60 ° C to 75 ° C, preferably to a temperature in the range of 61 ° C to 70 ° C, more preferably to a temperature in the range of 63 ° C and 67 ° C takes place
  • step c) heating to a temperature in the range of 82 ° C to 97 ° C, preferably to a temperature in the range of 83 ° C to 92 ° C, more preferably to a temperature in the range of 85 ° C and 89 ° C takes place.
  • Solubilisat produce which can form in aqueous dilution micelles, which are loaded with both curcumin and boswellic acids.
  • the two active ingredients even with a correspondingly adapted temperature control in a preparatory step
  • step b) a step
  • the invention also relates to solubilizates which show micelles diluted in aqueous dilution both with curcumin and with boswellic acids alone, at least immediately after their preparation. Therefore, the
  • Invention also a method for producing a solubilizate described above by mixing a
  • Curcuminsolubilisats and a Boswellia solubilizate in particular in the ratio 1: 1 available.
  • the invention also relates to a method for producing a boswellia solubilizate with the following steps,
  • step b) heating to a temperature in
  • Range of 82 ° C to 97 ° C preferably to a temperature in the range of 84 ° C to 95 ° C, more preferably carried out at a temperature in the range of 87 ° C and 93 ° C.
  • Boswellia is used in the context of the present application, in particular an extract from the resin of
  • Boswellic acids and / or derivatives of boswellic acids are used.
  • alpha-boswellic acid CAS No. 471-66-9
  • beta-boswellic acid CAS No. 631-69-6
  • their derivatives are included
  • 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.
  • curcumin powder from Greenleaf as curcumin
  • curcumin extract from Neelam Phyto-extracts, Mumbai, India or curcumin BCM-95-SG or curcumin BCM-95- CG of eurochem GmbH, Gröbenzell,
  • 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.
  • exemplary embodiments may also include TEGO SMO 80 V from InCoPA Gmbh, Illertissen, Germany or
  • the source of polysorbate 20 was the material "TEGO SML 20 V FOOD” with the specification code “K09 EU-FOOD” from Evonik Nutrition & Care GmbH, Essen, Germany,
  • Evonik's TEGO SML 20 can be used as part of the
  • polysorbate 20 also Crillet 1 / Tween 20-LQ (SG) from CRODA GmbH, Nettetal, Germany.
  • distilled water is used.
  • 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 Laser beam mixed (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 gets into the Y-fork of an optical fiber
  • 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 ' see diffusion constants and is thus attributable 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.
  • Solubilisates according to the invention are the following:
  • 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
  • solubilisates prepared individually can be mixed with one another or a solubilizate containing curcumin and
  • Boswellia is made directly.
  • the following is an example of the preparation using two solubilisates prepared individually beforehand
  • curcumin solubilizate is filled. This solubilizate was used for the preparation of a curcumin and boswellia solubilizate.
  • curcumin content can be further increased without negative consequences
  • a composition of 100 g of 95% curcumin powder and 900 g of polysorbate 80 results in a stable product as well as a composition of 95 g of 95% curcumin powder and 880 polysorbate 80
  • the 7% curcumin solubilizate has an average haze of 0.9 FNU.
  • Laser measurements Such a laser beam measurement, for example, by illuminating the sample using a commercial laser pointer, in particular with a
  • polysorbate 80 441 g of polysorbate 80 is used, which corresponds to a total of 943 g.
  • polysorbate 20 and polysorbate 80 are homogenized with stirring with each other while dissolved in each other.
  • Emulsifier mixture mixed with the water. It is stirred so much that the water evenly in the
  • Emulsifier solution is released.
  • the Boswellia serrata extract is incorporated with stirring in the water-diluted emulsifier.
  • the Boswellia serrata extract is added at such a slow rate that it is uniformly drawn into the dilute emulsifier solution with stirring.
  • Both solubilisates are optionally heated to a temperature in the range of 50 to 60 ° C to lower their viscosity, i. to improve the flowability.
  • Both solubilizates are homogenized by stirring to a mixed solubilizate with curcumin and boswellia. The product is cooled to a maximum temperature of 60 ° C and filled. This product is particularly suitable for
  • This solubilizate can be used, in particular, as an intermediate for the preparation of a co-solubilizate comprising boswellic acid and curcumin according to exemplary embodiment 6 be used.
  • a co-solubilizate comprising boswellic acid and curcumin according to exemplary embodiment 6 be used.
  • Boswellia solubilizate be for an amount of 953.5 g
  • polysorbate 20 and polysorbate 80 are homogenized with stirring with each other while dissolved in each other.
  • Emulsifier mixture mixed with the water. It is stirred so much that the water evenly in the
  • Emulsifier solution is released.
  • the Boswellia serrata extract is incorporated with stirring in the water-diluted emulsifier.
  • the Boswellia serrata extract is added at such a slow rate that it is uniformly drawn into the dilute emulsifier solution with stirring.
  • polysorbate 20 and polysorbate 80 are homogenized with stirring with each other while dissolved in each other. While maintaining the temperature, the
  • Emulsifier mixture mixed with the water. It is stirred so much that the water evenly in the
  • Emulsifier solution is dissolved.
  • the Boswellia serrata extract with stirring in the with Water diluted emulsifier incorporated.
  • the Boswellia serrata extract is added at such a slow rate that it is uniformly drawn into the dilute emulsifier solution with stirring.
  • Example 5 described Solubilisats this Solubilisat this first in the ratio 1: 500 diluted with distilled water and brought under constant stirring with a magnetic stirrer and with the aid of a hot plate to 37 ° C. Subsequently, the pH was adjusted to 1.1 with 32% hydrochloric acid. The samples were in the
  • Example to be set If higher loadings are set with active ingredient, this is limited by the fact that, when an individual active ingredient content that is individual for the respective composition is exceeded, no solubilisate is produced, but rather an emulsion. If the active ingredient content is increased, necessarily the corresponding proportions of the other components (in
  • solubilisates according to the invention irreversible in water is soluble and for these solubilisate 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. However, only the solubilizates allow according to the experience of the inventor significantly increased
  • RCT data which is 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.
  • Ch. Schiborr et al. "The oral bioavailability of curcumin from micronized powder and liquid micelles is significantly increased in healthy humans and differs between sexes", Molecular Nutrition & Food Research, 2014, 0, pages 1 to 12
  • Curcuminsolubilisat the applicant described.
  • the low systemic bioavailability has hitherto hindered the clinical application of curcumin. Due to the rapid conversion into the liver and intestinal wall, the concentrations of curcumin in the blood are low and the distribution in the tissue is limited after oral intake. Even after taking up to 12 g of curcumin, the maximum moves
  • 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.
  • Curcumin powder which corresponds to 14.1 wt .-% curcumin.
  • Applicant's curcumin isolate consisted of 7% by weight of curcumin powder, which corresponds to 6% by weight of curcumin, and
  • Curcumin administered in 50 g of woodruff syrup. Before intake of curcumin and after 0.5; 1; 1.5; 2; 4; Blood samples were taken 8 and 24 hours.
  • 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 total concentration was detected in the plasma C ma x, clearly after taking the micellized curcumin from the solubilisate, namely about 7 times, shorter than the native form.
  • Curcuminsolubilisat the applicant according to their knowledge the formulation of curcumin, which of all hitherto
  • tested formulations have the highest bioavailability.
  • Boswellia acids of 3.12% were added to 20 g of solubilisate with 80 mL of water. From the resulting solution was added 2 mL corresponding to a dose of 128 mg BSE / kg
  • Boswellia acids data in mg / kg body weight
  • the determined ratio was used to determine a consistent level of values for the dry extract and for the solubilizate for the determination of the Cmax, Tmax and AUC values.
  • Table 4 shows the values calculated with this correction. For each of the boswellia acids mentioned, the value of the blood plasma content in ng / mL, averaged over the respective number of animals, was investigated over a period of 8 hours.
  • Boswellia acids after a single dose of the dry extract of Boswellia serrata (BSE, 80%) or 10%
  • the dry extract equivalent level of AKBA resulted in a 23-fold increase in Cmax and a 53-fold increase in AUC compared to the dry extract.
  • inventive formulation is significantly increased over the dry extract.
  • solubilisate amount For the daily dose of a human results in the following solubilisate amount:
  • Curcumin solubilisate The following calculation was made for a 12% Boswellia solubilizate according to the invention.
  • Curcumin and 10 mg Boswellia is thus 1,626.92 mg.
  • the solubilisates described above are all within the recommended daily limits
  • 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
  • Curcumin and solubilized xanthohumol in each case the same dosage are identical.
  • TBARS thiobarbituratic acid reactive substances
  • FIG. 2 effect of curcumin in native and solubilized form and of diclofenac on the serum content of MPO (mU / ml), and
  • 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).
  • Boswellia xanthohumol is superior in potentiating the effect of curcumin at the doses considered.
  • MPO Myeloperoxidase
  • neutrophilic granulocytes in the affected tissue Its concentration is elevated in patients with rheumatoid arthritis and causes oxidative stress. In the
  • solubilized 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 ( Figure 2).
  • the use of boswellia with curcumin in both native and solubilized forms did not improve the effect of curcumin in reducing 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
  • the clarity of the solubilizate can also be represented by its low turbidity. This is the following
  • Solubilization the better the bioavailability of the active ingredients or of the product containing them.
  • the inventive transparent and completely stable water-soluble formulation has, without excipients as in soft and hard gelatin capsules, in gelatin-free capsules (hard and / or soft) and in liquid on water
  • the invention provides a solubilisate of curcumin with boswellia for use as a medicament, in particular for use as a medicament having an antiinflammatory effect.

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Abstract

L'invention vise à permettre une biodisponibilité la meilleure possible de curcumine et de boswellia. A cet effet, l'invention fournit un solubilisat contenant de la curcumine dans une proportion inférieure ou égale à 10 % en poids, de préférence inférieure ou égale à 8 % en poids, de manière particulièrement préférée de 3 à 7 % en poids, un ou plusieurs acides boswelliques et/ou un ou plusieurs dérivés d'acide boswellique dans une proportion totale inférieure ou égale à 10 % en poids, de préférence inférieure ou égale à 8 % en poids, de manière particulièrement préférée de 4,7 à 6,6 % en poids, et au moins un émulsifiant ayant un HLB compris entre 13 et 18, en particulier du polysorbate 80 ou du polysorbate 20 ou un mélange de polysorbate 20 et de polysorbate 80.
PCT/EP2017/067381 2017-07-11 2017-07-11 Solubilisat comprenant de la curcumine et de la boswellia Ceased WO2019011414A1 (fr)

Priority Applications (51)

Application Number Priority Date Filing Date Title
PCT/EP2017/067381 WO2019011414A1 (fr) 2017-07-11 2017-07-11 Solubilisat comprenant de la curcumine et de la boswellia
HUE18737623A HUE063380T2 (hu) 2017-07-11 2018-07-11 Szolubilizátum Kurkuminnal, Boswellia-val és Xantohumollal
PCT/EP2018/068729 WO2019011954A1 (fr) 2017-07-11 2018-07-11 Solubilisat comprenant de la curcumine, du boswellia et du xanthohumol
EP18738321.1A EP3651805B1 (fr) 2017-07-11 2018-07-11 Solubilisat contenant de la curcumine et au moins une autre substance active
DK18738321.1T DK3651805T3 (da) 2017-07-11 2018-07-11 Solubilisat med curcumin og mindst ét yderligere aktivt stof
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
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
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
EP18737623.1A EP3651804B1 (fr) 2017-07-11 2018-07-11 Solubilisat comprenant de la curcumine, du boswellia et du xanthohumol
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
CA3069621A CA3069621C (fr) 2017-07-11 2018-07-11 Solubilisat contenant de la curcumine et optionnellement au moins une autre substance active
KR1020237017168A KR102573152B1 (ko) 2017-07-11 2018-07-11 커큐민 및 선택적으로 적어도 1종의 다른 활성 물질을 갖는 가용화물
PCT/EP2018/068801 WO2019011990A1 (fr) 2017-07-11 2018-07-11 Solubilisat d'extrait de réglisse
HUE18738321A HUE064518T2 (hu) 2017-07-11 2018-07-11 Kurkumint és legalább egy további hatóanyagot tartalmazó szolubilizátum
US16/629,155 US11197834B2 (en) 2017-07-11 2018-07-11 Solubilizate with curcumin and optionally at least one other active substance
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
PL18738321.1T PL3651805T3 (pl) 2017-07-11 2018-07-11 Solubilizator z kurkuminą i co najmniej jedną inną substancją czynną
DK18737623.1T DK3651804T5 (da) 2017-07-11 2018-07-11 Solubilisat med curcumin, boswellia og xanthohumol
ES18738321T ES2965739T3 (es) 2017-07-11 2018-07-11 Solubilizado con curcumina y al menos otro principio activo
RS20230894A RS64650B1 (sr) 2017-07-11 2018-07-11 Solubilizat sa kurkuminom i bosvelijom i ksantohumolom
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
RU2020106042A RU2752078C1 (ru) 2017-07-11 2018-07-11 Солюбилизат с куркумином и при необходимости по меньшей мере с одним другим активным веществом
ES18737623T ES2960296T3 (es) 2017-07-11 2018-07-11 Solubilizado con curcumina y boswelia y xantohumol
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
RU2021103127A RU2771527C1 (ru) 2017-07-11 2019-07-10 Солюбилизат с куркумином и по меньшей мере одним каннабиноидом в качестве дополнительного активного вещества
MX2021000339A MX2021000339A (es) 2017-07-11 2019-07-10 Solubilizado con curcumina y al menos un cannabinoide como sustancia activa adicional.
DK19736404.5T DK3820528T3 (da) 2017-07-11 2019-07-10 Solubilisat, der omfatter curcumin og mindst ét cannabinoid som et yderligere aktivt stof
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
UAA202100177A UA125552C2 (uk) 2017-07-11 2019-07-10 Солюбілізат, що містить куркумін і щонайменше один канабіноїд як додаткову активну речовину
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
US17/258,363 US20220133646A1 (en) 2017-07-11 2019-07-10 Solubilizate with curcumin and at least one cannabinoid as a further active substance
ES19736735T ES2960689T3 (es) 2017-07-11 2019-07-10 Solubilizado con curcumina y al menos el cannabinoide THC como una sustancia activa adicional
HUE19736404A HUE063768T2 (hu) 2017-07-11 2019-07-10 Kurkumint és további hatóanyagként legalább egy kannabinoidot tartalmazó szolubilizátum
RS20230897A RS64642B1 (sr) 2017-07-11 2019-07-10 Solubilizat sa kurkuminom i bar jednim kanabinoidom kao daljim aktivnim sastojkom
HRP20231135TT HRP20231135T1 (hr) 2017-07-11 2019-07-10 Solubilizat s kurkuminom i najmanje kanabinoidom thc kao dodatnom aktivnom tvari
MX2021000385A MX2021000385A (es) 2017-07-11 2019-07-10 Solubilizado con curcumina y al menos el cannabinoide thc como una 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
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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US20230263728A1 (en) * 2022-02-22 2023-08-24 DGP Technology Limited Biologically active additive based on mesoporous silicon dioxide and on micellar solutions of active substrates and method for preparing same
KR20230129824A (ko) * 2022-03-02 2023-09-11 다미래 주식회사 수용화 커큐민과 보스웰리아 추출물을 이용한 인지 능력 개선용 조성물
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