Classifications

• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • 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)
  • A61K36/9068—Zingiber, e.g. garden ginger
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
  • A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
  • A23P10/00—Shaping or working of foodstuffs characterised by the products
  • A23P10/40—Shaping or working of foodstuffs characterised by the products free-flowing powder or instant powder, i.e. powder which is reconstituted rapidly when liquid is added
• • 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)
  • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • 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
• • 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
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
  • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

• the present invention relates to compositions comprising ginger or; in particular, compositions comprising ginger oleoresin that are highly water insoluble.
• Gingeroids are defined as the sum of gingerols, including but not limited to 6-gingerol, 8-gingerol and 10-gingerol, and shogaols, including but not limited to 6-shogaol, 8-shogaol and 10-shogaol.
• the present invention also relates to processes for providing such compositions and uses of such compositions.
• Ginger the rhizome of Zingiber officinale, is a member of the Zingberaceae family that has been used as a spice for many years. Ginger contains a wide variety of volatile and non-volatile compounds in varying concentrations depending on where the plant has been cultivated, and the methods used to harvest and process the plant.
• the major constituents in ginger comprise carbohydrates, lipids, terpenes and phenolic compounds.
• Phenolic compounds include gingerol, paradols and shogaol.
• the rhizomes have been used since antiquity in the various traditional systems of medicine to treat cold, fever, sore throats, infectious diseases, arthritis, rheumatism, sprains, muscular aches, pains, cramps, hypertension, dementia, migraine, nervous diseases, gingivitis, toothache, asthma, stroke, and diabetes and also used as home remedy in treating various gastric ailments like constipation, diarrhea, dyspepsia, belching, bloating, gastritis, epigastric discomfort, gastric ulcerations, indigestion, nausea, and vomiting (Giacosa, A., et al. (2015). Eur Rev Med Pharmacol Sci, 19(7), 1291-6.; Haniadka, R., et al. (2013).
• ginger has shown efficacy against numerous human disorders, it is also known to have limited bioavailability due to poor absorption, rapid metabolism, and rapid systemic elimination.
• Ginger extracts highly enriched in gingeroids such as oleoresins were found to be poorly soluble in water.
• the rapid metabolism, poor water solubility, and poor uptake by tissues drastically limits the potential utility of ginger, including the potential use of gingeroids (as used herein to refer to both gingerols and shogaols, in particular 6, 8 and 10 gingerol and 6, 8, and 10 shogaol) in the treatment of conditions such as gastrointestinal disorders.
• the present invention seeks to address the abovementioned problems associated with ginger’s poor solubility in water and provide a composition comprising ginger/gingeroids that is both highly soluble in water and stable at physiological pH.
• composition comprising ginger oleoresin or gingeroids, a gum (such as gum Arabic) and at least one saponin (such as an extract obtained from or obtainable from quillaja), provides a slow release of the gingeroids, is highly water soluble and stable at physiological pH and has an increased bioaccessibility, bioavailability, bio-efficacy, and/or bioactivity of said gingeroids.
• composition comprising:
• gum Arabic gum Arabic, guar gum, xantham gum, locust bean gum, gum tragacanth or mixtures thereof;
• a slow release composition comprising:
• gum Arabic gum Arabic, guar gum, xantham gum, locust bean gum, gum tragacanth or mixtures thereof;
• compositions of the invention may be referred to hereinafter as the “compositions of the invention”.
• slow-release is meant a delayed- and extended- release. This means that the active principle (gingeroids) are released after at least 30 minutes and then over a prolonged period of time of at least 1 , 4 or at least 8 hours.
• the inventors of the present invention have shown that in the present compositions of the invention, the actives (gingeroids) are released much slower that in the control ginger extracts.
• the slow release effect is shown on table 11 and 13 where it is seen similar maximum gingeroids level in blood at a similar Tmax between formulation while the composition of the invention provides a slower decrease in blood gingeroids concentration in any time points: 30 min, 1 , 2, 4 and 8 hours compared with both Ginger powder and Ginger 5%.
• the gingeroids used in the compositions of the invention may be obtained from any source. However, it is preferred that the gingeroids are obtained from a natural source, i.e. the gingeroids are not synthetic, but are plant based.
• Gingeroids are defined in the present invention as the sum of gingerols, including but limited to 6-gingerol, 8-gingerol and 10-gingerol and shogaols including but not limited to 6-shogaol, 8-shogaol and 10-shogaol.
• Other gingerols and shogaols may be present in the composition of the invention such as 12-gingerol.
• compositions may comprise at least about 5% gingeroids, such as at least about 7.5%, or at least about 10% or at least about 20% gingeroids by weight of the composition.
• the gingeroids may be present in an amount from about 5% to about 60%, such as from about 7.5% to about 50%, or from about 10% to about 40% by weight of the composition.
• the gingeroids may be obtained or obtainable from the root (rhizome) of ginger ( Zingiber officinale).
• the gingeroids may be provided by extraction and optionally purification from the root (rhizome) of ginger ( Zingiber officinale).
• Those ginger extracts in the present invention includes, without limitation, ginger oleoresin, defatted ginger oleoresin and mixtures thereof.
• the gingeroids may be in the form of an extract or purified extract of the root (rhizome) of ginger ( Zingiber officinale) (such as a ginger oleoresin, defatted ginger oleoresin and mixtures thereof), wherein the extract comprises from about 10% to about 100% gingeroids, such as from about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% to about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50% or 45% gingeroids by weight of the extract.
• the extract comprises from about 10% to about 100% gingeroids, such as from about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% to about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50% or 45% gingeroids by weight of the extract.
• gingeroids are provided as an extract of the root (rhizome) of ginger ( Zingiber officinale) (such as ginger oleoresin, defatted ginger oleoresin and mixtures thereof)
• the root (rhizome) of ginger ( Zingiber officinale) may be extracted using an organic solvent or a non-organic solvent or mixtures thereof.
• the root (rhizome) of ginger may be subjected to extraction with an organic solvent, at one or more temperatures ranging from 0 to 150 °C, depending on the solvent used.
• the organic solvent extract may be separated from the remaining root (rhizome) of ginger grounds by any method known in the art.
• the organic extract may be optionally concentrated using any suitable method known in the art.
• suitable organic solvents include, but are not limited to, hydrocarbons, such as pentane, petroleum ether, hexane, heptane or cyclohexane; alcohols such as methanol, 2- methoxyethanol, ethanol, n-propanol, isopropanol, all isomers of butyl alcohol, benzyl alcohol, 1,2,6-trihydroxyhexane, ethylene glycol, 1,2-propanediol, dipropylene glycol, 1,3-butanediol, 2-butoxyethanol, 1 ,3-butylene glycol, glycerol; esters, such as ethyl acetate, iso-propyl acetate, 2-butoxyethyl acetate, glycerol esters such as glyceryl diacetate, glyceryl triacetate, glyceryl tributyrate; ethers, such as diethyl ether, 2-ethoxyethanol;
• the root (rhizome) of ginger may be subjected to extraction with an alcoholic solvent or a hydro-alcoholic solvent, at one or more temperatures ranging from 0 to 150 °C, depending on the solvent used.
• the alcohol-based extraction solvent may be water/methanol (i.e. a mixture of water and methanol) or water/ethanol (i.e. a mixture of water and ethanol) or methanol or ethanol
• the organic solvent extract may be separated from the remaining root (rhizome) of ginger grounds by any method known in the art.
• the alcoholic or an hydro-alcoholic extract may be optionally concentrated using any suitable method known in the art.
• the ratio of water to alcohol may be from about 25:75 to about 1:99, such as from about 20:80 to about 5:95 or about 10:90.
• the extraction solvent may be water/ethanol in a ratio of from about 25:75 to about 1:99, such as from about 20:80 to about 5:95 or about 10:90.
• the root (rhizome) of ginger may be extracted using C02 extraction.
• the extract (such as an organic extract or C02 extract) may then be further purified to provide a purified extract of gingeroids comprising from about 10% to about 100% gingeroids, such as from about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% to about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50% or 45% gingeroids by weight of the extract.
• a purified extract of gingeroids comprising from about 10% to about 100% gingeroids, such as from about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% to about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50% or 45% gingeroids by weight of the extract.
• the purification of the extract may be performed using such techniques known in the art.
• the extract is purified using an alcohol-based solvent, such as 100% methanol or 100% ethanol.
• the extract may optionally be dried to remove any excess solvent.
• the gingeroids may be provided as a liquid or a powder, such as a powder.
• a powdered ginger extract for example, a powdered ginger extract.
• the gingeroids are provided as a oleoresin.
• gingeroids includes but is not limited to 6, 8 and 10 gingerol and 6, 8, and 10 shogaol.
• the composition may comprise the extract in an amount of at least 10% by weight of the composition, such as at least 15%, at least 20% at least 30% or at least 40%, or at least 50% by weight of the composition.
• the composition may comprise the extract from the root (rhizome) of ginger ( Zingiber officinale) (such as a ginger oleoresin, defatted ginger oleoresin and mixtures thereof) as previously defined in an amount of from about 10% to about 40% by weight of the composition, such as from about 15% to about 30% by weight of the composition.
• ginger such as a ginger oleoresin, defatted ginger oleoresin and mixtures thereof
• the composition may comprise from about 25% (i.e. 30%) to about 35% of the extract from the root (rhizome) of ginger (Zingiber officinale) (such as ginger oleoresin, defatted ginger oleoresin and mixtures thereof) by weight of the composition, where the extract from the root (rhizome) of ginger (Zingiber officinale), (such as ginger oleoresin, defatted ginger oleoresin and mixtures thereof) comprises from about 5%, 10%, 20%, 30%, 40% to about 50%, 60%, 70%, 80% or about 99%, such as from about 10% to 20%, such as 11% of gingeroids by weight of the extract from the root (rhizome) of ginger ( Zingiber officinale) (such as ginger oleoresin, defatted ginger oleoresin and mixtures thereof), providing a composition that comprises from about 5% to 30% gingeroids by weight of the composition.
• the gingeroids are provided in the form of ginger oleoresin.
• the present invention also provides a composition comprising:
• gum Arabic gum Arabic, guar gum, xantham gum, locust bean gum, gum tragacanth or mixtures thereof;
• the gum is gum Arabic.
• the ginger oleoresin may be obtained via super critical C02 extraction of ginger roots.
• the ginger oleoresin may be present in the composition in an amount of at least 10% by weight of the composition, such as at least 15%, at least 20% at least 30% or at least 40%, or at least 50% by weight of the composition.
• the composition may comprise ginger oleoresin in an amount of from about 10% to about 40% by weight of the composition, such as from about 15% to about 30% by weight of the composition.
• the final composition comprises at least 5% of gingeroids by weight of the composition, such as at least 10%, at least 15%, at least 20% at least 30% or at least 40%, or at least 50% gingeroids by weight of the composition.
• the composition may comprise from about 25% (i.e. 30%) to about 35% of ginger oleoresin by weight of the composition, where the ginger oleoresin comprises from about 11% of gingeroids by weight of the ginger oleoresin, providing a composition that comprises from about 5% to about 30% of gingeroids by weight of the composition.
• ginger oleoresins are liquid products that have a high content of lipids and fatty acids.
• the extract that are rich in gingeroids are also rich in lipids.
• Other natural components, like curcumin extracts from turmeric rich in curcuminoids are in form of powders that have low or very low quantities of fats. Those curcuminoids normally are present in the form of crystals.
• the ginger oleoresin, the defatted oleoresin and the mixtures thereof has a lipid content of at least 40%, such as of at least 50%, such as of at least 70%.
• the ginger oleoresin has a lipid content of at least 40%, such as of at least 50%, such as of at least 70%.
• the gingeroids are provided in the form of extracts such as an oleoresin and do not form crystals.
• the present invention also provides a composition comprising:
• gum Arabic guar gum, xantham gum, locust bean gum, gum tragacanth or mixtures thereof, preferably gum arabic; and (iii) at least one saponin, wherein the ginger oleoresin comprises at least 30 % of gingeroids and at least 50% of lipids, such as at least 70% of lipids.
• the present invention also provides a composition comprising:
• gum Arabic preferably gum arabic
• guar gum preferably gum Arabic
• xantham gum locust bean gum
• gum tragacanth preferably gum arabic
• the ginger oleoresin comprises at least 30 % of gingeroids and at least 50% of lipids, such as at least 70% of lipids, and optionally, wherein the composition is a dry composition comprising particles having a mean diameter of from 150 to 300 and a D90 of from 280 to 500.
• the present invention also provides a composition comprising:
• gum Arabic preferably gum arabic
• guar gum preferably gum Arabic
• xantham gum locust bean gum
• gum tragacanth preferably gum arabic
• the final composition comprises at least 5% of gingeroids by weight of the composition, such as at least 10%, at least 15%, at least 20% at least 30% or at least 40%, or at least 50% gingeroids by weight of the composition and, optionally, wherein the composition is a dry composition comprising particles having a mean diameter of from 150 to 300 and a D90 of from 280 to 500.
• the gum such as gum Arabic, guar gum, xantham gum, locust bean gum, gum tragacanth or mixtures thereof, may be present in the compositions of the invention an amount from about 20% to about 80% by weight of the composition, such as from about 50% to about 70% by weight of the composition or about 68% by weight of the composition.
• the gum (such as gum Arabic) may be present in the compositions of the invention in an amount from about 20% to about 80% by weight of the composition, such as from about 50% to about 70% by weight of the composition or about 68% by weight of the composition.
• Natural gums as defined before are normally commercially available and are highly purified.
• the gum (such as gum Arabic, guar gum, xantham gum, locust bean gum, gum tragacanth or mixtures thereof) is food grade.
• the gum is gum Arabic.
• composition comprising:
• gum Arabic gum Arabic, guar gum, xantham gum, locust bean gum, gum tragacanth or mixtures thereof;
• composition comprises at least 5% of gingeroids by weight of the composition, such as at least 10%, at least 15%, at least 20% at least 30% or at least 40%, or at least 50% gingeroids by weight of the composition, wherein the gum (such as gum Arabic) is present in an amount from about 20% to about 80% by weight of the composition, such as from about 50% to about 70% by weight of the composition or about 68% by weight of the composition, and optionally wherein the composition is a dry composition comprising particles having a mean diameter of from 150 to 300 and a D90 of from 280 to 500.
• the present invention also provides a composition comprising:
• gum Arabic preferably gum arabic
• guar gum preferably gum Arabic
• xantham gum locust bean gum
• gum tragacanth preferably gum arabic
• composition comprises at least 5% of gingeroids by weight of the composition, such as at least 10%, at least 15%, at least 20% at least 30% or at least 40%, or at least 50% gingeroids by weight of the composition, wherein the gum (such as gum Arabic) is present in an amount from about 20% to about 80% by weight of the composition, such as from about 50% to about 70% by weight of the composition or about 68% by weight of the composition, and optionally wherein the composition is a dry composition comprising particles having a mean diameter of from 150 to 300 and a D90 of from 280 to 500.
• Saponins are a group of naturally occurring glycosides, predominantly found in the plant kingdom. They comprise a non-carbohydrate aglycone coupled to sugar chain units. Sap-onins are divided in two groups: steroidal and triterpene saponins. Over 100 steroidal and an even higher number of triterpene saponins have been so far identified. (K. Hostettmann, & A. Marston, Saponins (Cambridge University Press 1995).
• the saponin of the present invention can be of natural origin or of synthetic origin. It may be one or more saponins from the same or different origin.
• the saponin(s) can be obtained or obtainable from plants such as soya, beans, peas, oat, Solanum and Allium species, tomato, asparagus, tea, peanut, spinach, sugar beet, yam, blackberry, liquorice root, primula root, senega root, tea, licorice, ginseng, Quillaja (such as Quillaja saponaria), Yucca (such as Yucca shidigera), and/or Gyposphila.
• the saponin is quillaja saponin(s).
• the saponin is not a ginger saponin.
• the one or more saponins used in the present invention can be highly purified or may be a natural extract.
• quillaja saponin(s) means one or more saponins that can be obtained or obtainable from any of the mem-bers of the quillaja family, or the yucca family or any of the plants that contains saponins such as the ones described before.
• the quillaja saponin or the mixture of quillaja saponins (or the yucca saponin or the mixture of yucca saponins) can be of synthetic or natural origin.
• the term “obtaina-ble from” means that the saponin(s) may be obtained from a plant or may be isolated from the plant, or may be obtained from an alternative source, for example by chemical synthesis or enzymatic production. Whereas the term “obtained” as used herein, means that the sapo- nin(s) is directly derived from the plant.
• the saponin(s) can be a “natural extract comprising saponin(s)”.
• the at least one saponin may be of natural or synthetic origin.
• a “purified saponin(s)” means one or more saponins of natural or synthetic origin that have a concentration of at least about 80%, at least about 90%, at least about 95%, at least about 99%, at least about 99.9% of one or more saponins as described before (such as quillaja saponin(s) and /or yucca saponin(s)).
• a “saponin(s) comprising extract” means any natural extract comprising at least one type of saponin as described before that may be derived from, e.g., but not limited to soya, beans, peas, oat, Solanum and Allium species, tomato, asparagus, tea, peanut, spinach, sugar beet, yam, blackberry, liquorice root, primula root, senega root, Quillaja (such as Quillaja saponaria), Yucca (such as Yucca shidigera), and/or Gyposphila.
• the at least one saponin may be derived from a single source or from multiple sources.
• the at least one saponin comprising extract may be derived from a single source or from multiple sources.
• Examples of yucca include, but are not limited to, Yucca aloifolia, Yucca angustissima, Yucca arkansana, Yucca baccata, Yucca baileyi, Yucca brevifolia, Yucca campestris, Yucca capensis, Yucca carnerosana, Yucca cernua, Yucca coaeriensis, Yucca constricta, Yucca decipiens, Yucca declinata, Yucca desmetiana, Yucca data, Yuccalinguisticlinguisticiana, Yucca faxoniana, Yucca filamentosa, Yucca filifera, Yucca flaccida, Yucca gigantean, Yucca glauca, Yucca gloriosa, Yucca grandiflora, Yucca harrimaniae, Yucca intermedia, Yucca jaliscensis, Yucca lacandonica, Yucca linearifolia, Yucca luminosa, Yucca madrensis, Yucca mixtecana, Yucca necopina, Yucca n
• Y. schidigera stem/bark saponins are steroidal saponins. They differ in the structure of their aglycon, according to which, they are classified into spirostane- or furostane- type derivatives.
• Primary saponins are glycosides of three C-25 epimeric pairs of sapogenins: sarsapogenin and smilagenin, markogenin and samogenin, gitogenin and neogotogenin.
• the C-3 carbohydrate chains are typically branched oligosaccharides with pentapyranosyl and/or hexopyranosyl units.
• C-26 linked carbohydrate usually corre-sponds to a hexopyranose. It should be noted that derivatives of other sapogenins occur as minor compounds within Y. schidigera stem/bark.
• quillaja examples include, but are not limited to, Quillaja brasiliensis, Quillaja lanceolata, Quillaja lancifolia, Quillaja molinae, Quillaja petiolaris, Quillaja poeppigii, Quillaja saponaria, Quillaja sellowiana, or Quillaja smegmadermos.
• the quillaja is Quillaja saponaria.
• a plant name may refer to the plant as a whole, or to any part of the plant, such as the roots, stem or trunk, bark, leaves, flower, flower stems, or seeds or a combination thereof.
• These plant parts may be used fresh, or dried, and may be whole, pulverized, mashed, comminuted or ground up. Extracts from any part or parts of the plant are also contemplated.
• Saponins extracts can be obtained using similar extraction methods as described before for the ginger extracts.
• the solvent is a methanol/water (for example 70:30 v/v) and the incubation time is of 24 hours at ambient temperature.
• Another extraction solvent can be only water.
• the quillaja containing material is incubated with water at a temperature from 50 to 100°C (such as 50-60 °C or 100°C).
• the extraction may be performed using a soxhlet apparatus or by maceration and filtration.
• the incubation time may be from some hours (like 10 hours) to 24 hours or more.
• Saponin comprising extracts may include other compounds that are not saponins such as naturally occurring glicocomponents, polyphenols, salts and sugars.
• the purified saponin(s) or the “natural extract comprising sapo-nin(s)” are from Yucca schidigera and/or Quillaja saponaria.
• the at least one saponin or the saponin-comprising extract can be chosen from steroidal and triterpene saponins, and mixtures thereof.
• the at least one saponin (such as a purified saponin(s) or a saponin extract) is obtained or obtainable from Quillaja (such as Q. saponaria).
• the at least one saponin (such as a purified saponin(s) or a saponin extract) is obtained or obtainable from Yucca (such as Yucca schidigera).
• the at least one saponin (such as a purified saponin(s) or a saponin extract) is obtained or obtainable from Quillaja (such as Q. saponaria) and from Yucca (such as Yucca schidigera).
• This application concerns Yucca or Quillaja genus extracts, juice or any other product comprising saponins, more precisely saponins corresponding to any Yucca or Quillaja saponin structure.
• Y. schidigera or Q. Saponaria extract or spray dried extract in presence of inverted sugar or any other drying support that is well known in the art may be used in this application.
• the at least one saponin is a natural extract, such as a quillaja extract, tea extract, licorice extract, beet root extract, sugar beet extract, ginseng extract, oat extract, yucca extract or a mixture thereof that comprises (or consist essentially/consist of) at least 5% w/w, or at least 10% w/w, or at least 15% w/w, or at least 20% w/w, or at least 25% w/w, or at least 30% w/w, or at least 35% w/w, or at least 40% w/w, or at least 50% w/w, or at least 60% w/w, or at least 70% w/w, or at least 80% w/w, or at least 95% w/w, of saponins.
• the saponin component may be a quillaja extract with at least 60% saponins, such as at least 80% w/w, of saponins as defined before
• the at least one saponin (such as quillaja saponin(s)) may be present in the composition of the invention in an amount from about 0.1% to about 5% by weight of the composition (w/w), such as from about 0.5% to about 3% or about 2%, such as from 1.3 to about 1.5% by weight of the composition.
• the term “obtainable from” means that the extract (for example quillaja extract) may be obtained from a plant of the quillaja genus (such as Quillaja Saponaria Molina) or may be isolated from the plant of the quillaja genus, or may be obtained from an alternative source, for example by chemical synthesis or enzymatic production.
• the term “obtained” as used herein means that the extract is directly derived from the plant, for example a plant of the quillaja genus.
• the saponin is an extract obtained or obtainable from quillaja in the compositions may comprise at least 50% saponins, such as at least 60% saponins or at least 65% saponins by weight of the quilaja extract.
• the quillaja used in the compositions may comprise from about 50% to about 80% or from about 60% to about 75% saponins by weight of the quillaja extract.
• the saponin(s) used in the process of the invention may be in any form, such as a liquid or a solid.
• the saponin(s) (such as the quillaja extract) may be used in the form of a solid, such as a powder.
• water and/or other solvent such as alcohol
• the quillaja may be present in the compositions as an aqueous solution.
• composition comprising:
• gum Arabic gum Arabic, guar gum, xantham gum, locust bean gum, gum tragacanth or mixtures thereof;
• the final composition comprises at least 5% of gingeroids by weight of the composition, such as at least 10%, at least 15%, at least 20% at least 30% or at least 40%, or at least 50% gingeroids by weight of the composition, wherein the saponin (such as quillaja saponin(s)) is present in the composition in an amount from about 0.1% to about 5% by weight of the composition (w/w), such as from about 0.5% to about 3% or about 2%, such as from 1.3 to about 1.5% by weight of the composition and optionally, wherein the composition is a dry composition comprising particles having an mean diameter of from 150 to 300 and a D90 of from 280 to 500.
• the saponin such as quillaja saponin(s)
• the present invention also provides a composition comprising:
• gum Arabic preferably gum arabic
• guar gum preferably gum Arabic
• xantham gum locust bean gum
• gum tragacanth preferably gum arabic
• the final composition comprises at least 5% of gingeroids by weight of the composition, such as at least 10%, at least 15%, at least 20% at least 30% or at least 40%, or at least 50% gingeroids by weight of the composition, wherein the saponin (such as quillaja saponin(s)) is present in the composition in an amount from about 0.1% to about 5% by weight of the composition (w/w), such as from about 0.5% to about 3% or about 2%, such as from 1.3 to about 1.5% by weight of the composition and optionally, wherein the composition is a dry composition comprising particles having an mean diameter of from 150 to 300 and a D90 of from 280 to 500.
• the present invention also provides a composition comprising:
• gum Arabic preferably gum arabic
• guar gum preferably gum Arabic
• xantham gum locust bean gum
• gum tragacanth preferably gum arabic
• the final composition comprises at least 5% of gingeroids by weight of the composition, such as at least 10%, at least 15%, at least 20% at least 30% or at least 40%, or at least 50% gingeroids by weight of the composition, wherein the gum (such as gum arabic) is present in an amount from about 20% to about 80% by weight of the composition, such as from about 50% to about 70% by weight of the composition or about 68% by weight of the composition, wherein the saponin (such as quillaja saponin(s)) is present in an amount from about 0.1% to about 5% by weight of the composition (w/w), such as from about 0.5% to about 3% or about 2%, such as from 1.3 to about 1.5% by weight of the composition and optionally, wherein the composition is a dry composition comprising particles having a mean diameter of from 150 to 300 and a D90 of from 280 to 500.
• the gum such as gum arabic
• saponin such as quillaja saponin(s)
• the composition is a dry composition comprising particles having a mean
• compositions may optionally comprise a food acceptable alkali metal carbonate or alkali earth metal carbonate, such as calcium carbonate.
• the alkali metal carbonate or alkali earth metal carbonate may be present in the compositions in an amount of from about % to about 20% alkali metal carbonate or alkali earth metal carbonate, such as from about 2.5% to about 10% or about 5% by weight of the composition.
• the present invention also provides a process or method for the preparation of a compositions as previously defined (or process of preparation or method of preparation of the invention), wherein the process comprises the steps of:
• the gingeroids are provided as ginger oleoresin.
• the ginger oleoresin has a lipid content of at least 40%, such as of at least 50%, such as of at least 70%.
• natural gums may be used as described before (gum Arabic, guar gum, xantham gum, locust bean gum, gum tragacanth or mixtures thereof).
• the present invention provides a process for the preparation of a compositions as previously defined, wherein the process comprises the steps of:
• the gingeroids are provided as ginger oleoresin that is in form of a liquid.
• the ginger oleoresin has a lipid content of at least 40%, such as of at least 50%, such as of at least 70%.
• the mixture is homogenized.
• the emulsions obtained using the method of the invention may have droplets with an mean diameter of from 0.05 to 100 micron, such as from 0.1 to 100, such as from 0.1 to 90, from 0.1 to 50, such as from 0.1 to 10, such as from 0.05 to 10, from 0.05 to 9, from 0.05 to 8, 0.05 to 6, from 0.05 to 5, from 0.05 to 3, from 0.05 to 2, such as from 0.1 to 10, from 0.1 to 9, from 0.1 to 8, 0.1 to 6, from 0.1 to 5, from 0.1 to 3, from 0.1 to 2, 0.1 to 1, such as from 0.1 to 0.2, from 0,1 to 0.3, 0.1 to 0.4, from 0.1 to 0.5, from 0.1 to 0.7, from 0.1 to 0.9, from 0.2 to 0.6, from 0.2 to 0.5, from 0.2 to 0.8, from 0.2 to 0.9, from 0.3 to 0.9, from 0.3 to 1, such as from 0.9 to 10, such as from 10 to 80, such as from 10 to 70, such as from 10 to 50, such as from 20 to 50, such
• the droplets may have a mean diameter of about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40 or 45 microns.
• the droplet size of the emulsion form step (ii) may be also expressed as D90.
• D90 describes the diameter where ninety percent of the distribution has a smaller droplet size and ten percent has a larger droplet size.
• the emulsions obtained using the method of the invention may have droplets with an particle size with a D90 of from 0.05 to 500 micron, such as from 0.1 to 100, such as from 0.1 to 90, from 0.1 to 50, such as from 0.1 to 10, such as from 0.05 to 10, from 0.05 to 9, from 0.05 to 8, 0.05 to 6, from 0.05 to 5, from 0.05 to 3, from 0.05 to 2, such as from 0.1 to 10, from 0.1 to 9, from 0.1 to 8, 0.1 to 6, from 0.1 to 5, from 0.1 to 3, from 0.1 to 2, 0.1 to 1 , such as from 0.1 to 0.2, from 0,1 to 0.3, 0.1 to 0.4, from 0.1 to 0.5, from 0.1 to 0.7, from 0.1 to 0.9, from 0.2 to 0.6, from 0.2 to 0.8, from 0.2 to 0.9, from 0.3 to 0.9, from 0.3 to 1 , such as 0.5 to 1, such as from 0.9 to 10, such as from 10 to 80, such as from 10 to 70, such as from 10 to 50,
• the D90 is of about 0.05, 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40 or 45 microns.
• the process may optionally include a step of drying the product of (ii) to provide a composition comprising particles having a mean diameter of from about 5 microns to about 1000 micron, such as 100 to 500 micron, such as 200 to 450 micron.
• the drying of the product may be done using standard techniques known by the person skilled in the art such as spry drying,
• the dried product is free of nanoparticles or it contains less than 10% particles (number-based) with at least one dimension smaller than 500 nm.
• the particles of the dried product may have a mean diameter of from about 5 micron to about 1000 micron, such as from 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 450, 500, 600, 700, 800, 900 microns to about 800, 700, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 microns (this wording include all combinations from each of the increasing number to any one of the decreasing numbers), such as from 900 to 800 microns, from 500 to 600 microns, from 100 to 500 micron, such as from 200 to 500 micron, such as from 100 to 300 micron, such as from 100 to 250 micron, such as from 140 to 250 microns, such as from 150 to 250 microns.
• the particle size may be also expressed as D90.
• the particles of the dried product may have an D90 of from about 5 micron to about 1000 micron, such as from 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 450, 500, 600, 700, 800, 900 microns to about 800, 700, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 microns (this wording include all combinations from each of the increasing number to any one of the decreasing numbers), such as from 900 to 800 microns, from 500 to 600 microns, from 100 to 500 micron, such as from 200 to 500 micron, such as from 250 to 500 micron, such as from 250 to 450 micron, such as from 280 to 500 micron.
• the gingeroids are provided as ginger oleoresin.
• the ginger oleoresin has a lipid content of at least 40%, such as of at least 50%, such as of at least 70% and a gingeroids content of at least 10%, such as at least 17%, such as at least 30% w/w of gingeroids.
• the present invention may provide a process for the preparation of a compositions as previously defined, wherein the process comprises the steps of:
• the particles After drying, (such as spray drying) the particles may be blended, grounded, milled and /or compacted to provide a more uniform size.
• the gingeroids may have a purity of from about 5% to about 100% by weight of the gingeroids source, i.e. the ginger extract may comprise from about 5% to about 100% gingeroids, such as from about 5% w/w, 10% w/w, 20%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90% to about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50% or 45% w/w gingeroids based on the percentage of total weight of the extract.
• the gingeroids may have a purity of from 20% to 40%, such as of about 30% w/w.
• the ginger extract may have at least 5% w/w gingeroids, such as at least 10%, such as at least 20%, such as at least 30%w/w of gingeroids.
• the weight concentration of gingeroids or ginger oleoresin in the aqueous solution may be from about 1% to about 95%, such as from about 5% to about 80% or from about 7% to about 40% w/w.
• the aqueous gum solution (such as gum arabioc solution) may be prepared by mixing gum (such as gum arabic) with water.
• the aqueous gum (such as gum Arabic) solution may have a weight concentration of gum (such as gum arabic) of from about 20% to about 80%, such as from about 40% to about 60% w/w.
• the aqueous gingeroids or ginger oleoresin solution and aqueous gum arabic solution are mixed using agitation.
• the saponin(s) (such as an extract obtained from or obtainable from quillaja) may be as defined previously with respect to the compositions.
• the saponin(s) (such as an extract obtained from or obtainable from quillaja) used in the process of the invention may be in any form, such as a liquid or a solid.
• the saponin(s) (such as an extract obtained from or obtainable from quillaja) may be used in the form of a solid, such as a powder.
• the at least one saponin (such as quillaja saponin(s)) may be present in the final composition of the invention in an amount from about 0.1 % to about 5% by weight of the composition, such as from about 0.5% to about 3% or about 2%, such as from 1.3 to about 1.5% by weight of the composition.
• the saponin(s) may be mixed using agitation.
• aqueous solution comprising gum arabic and saponin(s) (such as quillaja) mixed with the gingeroids (such as ginger oleoresin) as defined above provide an emulsion.
• the process of the invention may optionally include a step of removing additional solvent as required in order to provide a substantially dry product, i.e. a product where at least 90%, such as at least 95% or 99% of the water present has been removed. Additionally, a pasteurisation step may be performed.
• compositions of the invention may be in the form of an emulsion or the compositions may be in the form a solid, for example, in the form of a powder.
• emulsion refers to a type of lipid dispersion that is formed by combining two liquids that do not usually mix. Typically, one of the liquids will contain a dispersion of the other liquid.
• emulsion when both phases of a mixture are liquids (ginger oleoresin as first liquid and the aqueous solution of saponins and gums as the second liquid).
• a colloidal solution is a mixture wherein solid particles are regularly suspended in a fluid.
• the product of step (ii) is not a colloidal solution but an emulsion.
• the droplets may have a mean diameter of from 0.05 to 100 micron, such as from 0.1 to 100, such as from 0.1 to 90, from 0.1 to 50, such as from 0.1 to 10, such as from 0.05 to 10, from 0.05 to 9, from 0.05 to 8, 0.05 to 6, from 0.05 to 5, from 0.05 to 3, from 0.05 to 2, such as from 0.1 to 10, from 0.1 to 9, from 0.1 to 8, 0.1 to 6, from 0.1 to 5, from 0.1 to 3, from 0.1 to 2, 0.1 to 1 , such as from 0.1 to 0.2, from 0,1 to 0.3, 0.1 to 0.4, from 0.1 to 0.5, from 0.1 to 0.7, from 0.1 to 0.9, from 0.2 to 0.6, from 0.2 to 0.5, from 0.2 to 0.8, from 0.2 to 0.9, from 0.3 to 0.9, from 0.3 to 1 , such as from 0.9 to 10, such as from 10 to 80, such as from 10 to
• the droplets may have a mean diameter of about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40 or 45 microns.
• the emulsions may have droplets with a D90 of from 0.05 to 500 micron, such as from 0.1 to 100, such as from 0.1 to 90, from 0.1 to 50, such as from 0.1 to 10, such as from 0.05 to 10, from 0.05 to 9, from 0.05 to 8, 0.05 to 6, from 0.05 to 5, from 0.05 to 3, from 0.05 to 2, such as from 0.1 to 10, from 0.1 to 9, from 0.1 to 8, 0.1 to 6, from 0.1 to 5, from 0.1 to 3, from 0.1 to 2, 0.1 to 1, such as from 0.1 to 0.2, from 0,1 to 0.3, 0.1 to 0.4, from 0.1 to 0.5, from 0.1 to 0.7, from 0.1 to 0.9, from 0.2 to 0.6, from 0.2 to 0.8, from 0.2 to 0.9, from 0.3 to 0.9, from 0.3 to 1, such as 0.5 to 1 , such as from 0.9 to 10, such as from 10 to 80, such as from 10 to 70, such as from 10 to 50, such as from 20 to 50, such as from 20 to 30
• the D90 is of about 0.05, 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40 or 45 microns.
• the emulsion may be subsequently dried so as to obtain a solid.
• the composition may, for example, comprise particles having a mean diameter of from about 5 micron to about 1000 micron, such as from 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 450, 500, 600, 700, 800, 900 microns to about 800, 700, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 microns (this wording include all combinations from each of the increasing number to any one of the decreasing numbers), such as from 900 to 800 microns, from 500 to 600 microns, from 100 to 500 micron, such as from 200 to 500 micron, such as from 100 to 300 micron, such as from 100 to 250 micron, such as from 140 to 250 microns, such as from 150 to 250 microns.
• particles having a mean diameter of from about 5 micron to about 1000 micron such as from 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150
• the particle size may be also expressed as D90.
• the particles of the dried product may have an D90 of from about 5 micron to about 1000 micron, such as from 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 400, 450, 500, 600, 700, 800, 900 microns to about 800, 700, 600, 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 microns (this wording include all combinations from each of the increasing number to any one of the decreasing numbers), such as from 900 to 800 microns, from 500 to 600 microns, from 100 to 500 micron, such as from 200 to 500 micron, such as from 250 to 500 micron, such as from 250 to 450 micron, such as from 280 to 500 micron.
• the particles in the compositions may be in the form of micelles.
• the particles may be ground and/or milled (such as ball milled) to provide a more uniform size.
• the size of the particles may be measured by method CQ-MO-304 (using a Mastersizer Malvern instrument).
• the droplet size may be measured using Mastersizer.
• compositions may be provided in a solid or liquid form, preferably a solid form, such as a powder.
• solid form it is included that the compound may be provided as an amorphous solid, or as a crystalline or part-crystalline solid.
• the compositions are typically highly water soluble and/or stable at a pH of 4 or more, such as a pH from about 4 to about 7.
• water soluble we mean that at least about 50%, such as at least about 60%, 70%, 80%, 90% or 95% of the composition will dissolve in water at room temperature, i.e. a temperature of about 25 °C.
• ⁇ 0.5% refers to variations of ⁇ 20%, ⁇ 10%, ⁇ 5%, ⁇ 1%, ⁇ 0.5%, or, particularly, ⁇ 0.1% relative to the specified amount.
• a variation of ⁇ 0.5% with regards to the percentage of a component in the compositions means a variation of 0.5% relative to the percentage given, i.e. ⁇ 0.5% of 10% would mean a variation from 9.5% to 10.5%.
• the compositions may be provided in the form of a nutraceutical formulation, a dietary or food product for humans or animals (such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a herbicide, a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation or may form a part of a nutraceutical formulation, a dietary or food product for humans or animals (such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation.
• a nutraceutical formulation such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements
• a herbicide such as functional food formulations, i.e. food, drink, feed or pet food or
• the present invention also refers to a nutraceutical formulation, a dietary or food product for humans or animals (such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation comprising a composition of the invention as previously defined.
• the present invention provides a nutraceutical formulation, a dietary or food product for humans or animals (such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation comprising the compositions of the invention, consisting of, or consisting essentially of (i.e. at least 90% w/w of the nutraceutical formulation, a dietary or food product for humans or animals a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation is the compositions, such as at least 95%, or 99% or 99.5% is the composition of the invention).
• the present invention also provides the use of the compositions of the invention in a nutraceutical formulation, a dietary or food product for humans or animals (such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation.
• compositions are in the form of a nutraceutical formulation, a dietary or food product for humans or animals (such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation or may form a part of a nutraceutical formulation, a dietary or food product for humans or animals (such as functional food formulations, i.e.
• nutraceutical formulation a dietary or food product for humans or animals (such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation may optionally further comprise a pharmaceutically/veterinary ingredients, such as excipients or carriers or (function) food acceptable ingredients and mixtures thereof as appropriate.
• references to pharmaceutically acceptable excipients may refer to pharmaceutically acceptable adjuvants, diluents and/or carriers as known to those skilled in the art.
• Food acceptable ingredients include those known in the art (including those also referred to herein as pharmaceutically acceptable excipients) and that can be natural or non-natural, i.e. their structure may occur in nature or not. In certain instances, they can originate from natural compounds and be later modified (e.g. maltodextrin).
• pharmaceutically/nutraceutically acceptable we mean that the additional components of the composition are sterile and pyrogen free. Such components must also be “acceptable” in the sense of being compatible with the compositions and not deleterious to the recipients thereof.
• pharmaceutically acceptable includes any compound(s) used in forming a part of the formulation that is intended to act merely as an excipient, i.e. not intended to have biological activity itself.
• the pharmaceutically acceptable excipient is generally safe, non toxic, and neither biologically nor otherwise undesirable.
• compositions forms part of a nutraceutical formulation, a dietary or food product for humans or animals (such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation
• the compositions may be present in the nutraceutical formulation, a dietary or food product for humans or animals, a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation in an amount from about 1 to about 99% by weight of the nutraceutical formulation, a dietary or food product for humans or a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation, such as from about 0.01 %, 0.1%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% to about 90%, 80%, 70%, 60%, 50%, 40%, 30%
• compositions either where the composition is in the form of nutraceutical formulation, a dietary or food product for humans or animals (such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation or where the nutraceutical formulation, a dietary or food product for humans or animals (such as functional food formulations, i.e.
• an oenological or cosmetic formulation comprises the compositions, the nutraceutical formulation, a dietary or food product for humans or animals (such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation may be administered to a patient or subject (e.g.
• a human or animal patient or subject by any suitable route, such as by the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal, intraperitoneal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
• suitable route such as by the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal, intraperitoneal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
• compositions of the invention and nutraceutical formulations may be administered orally.
• pharmaceutical compositions according to the present invention may be specifically formulated for administration by the oral route.
• compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings, or they can be formulated so as to provide controlled release of the active ingredient, such as sustained or prolonged release, according to methods well known in the art.
• Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily/oil based suspensions, syrups and elixirs.
• Nutraceutical formulations a dietary or food product for humans or animals (such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation described herein, such as those intended for oral administration, may be prepared according to methods known to those skilled in the art, such as by bringing the components of the composition into admixture.
• nutraceutical formulations a dietary or food product for humans or animals (such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulations as described herein may contain one or more additional components selected from the group consisting of food ingredients, such as sweetening agents, flavouring agents, colouring agents and preserving agents. Tablets may contain the active ingredient(s) in admixture with non-toxic pharmaceutically acceptable excipients (or ingredients) which are suitable for the manufacture of tablets.
• excipients may, for example, be: inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, maltodextrin or alginic acid; binding agents, for example, starch, gelatine or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
• Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
• solid carriers are lactose, terra alba, sucrose, cyclodextrin, maltodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid, arabic gum, modified starch and lower alkyl ethers of cellulose.
• liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
• the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
• compositions of the invention may be administered at varying doses (i.e. therapeutically effective doses, as administered to a patient in need thereof).
• doses i.e. therapeutically effective doses, as administered to a patient in need thereof.
• the skilled person will appreciate that the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe.
• the selection of the exact dose and formulation and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.
• compositions or the nutraceutical formulation, a dietary or food product for humans or animals such as functional food formulations, i.e. food, drink, feed or pet food or a food, drink, feed or pet food supplements), a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation as defined previously is administered to provide gingeroids in an amount of from about 10 mg gingeroids, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 70 mg, about 100 mg, about 200 mg, about 300 mg of gingeroids.
• compositions or the nutraceutical formulation, a dietary or food product for humans or animals such as functional food formulations, i.e.
• gingeroids in an amount of from about 5mg/day of gingeroids to about 400mg/day of gingeroids, such as about 5mg/day gingeroids, about 10 mg/day gingeroids, about 15 mg/day, about 20 mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, about 70 mg/day, about 100 mg/day, about 200 mg/day or about 300 mg/day of gingeroids.
• the composition or the nutraceutical formulation, a dietary or food product for humans or animals may provide gingeroids in an amount of from about 0.08 mg of gingeroids per kg body weight to about 6.5 mg of gingeroids per body weight, such as 1.5 mg of gingeroids per kg body weight , 0.2 mg of gingeroids per kg body weight, 0.5 mg of gingeroids per kg body weight, 1 mg of gingeroids per kg body weight, 2 mg of gingeroids per kg body weight, 3 mg of gingeroids per kg body weight or 5 mg of gingeroids per kg body weight.
• the composition may provide gingeroids in an amount of from 1.6 mg of gingeroids per kg body weight to 3.4 mg of gingeroids per kg body weight.
• the gingeroids per kg body weight is in a daily dose basis.
• the medical practitioner or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient.
• the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
• compositions can be used to improve bioaccessibility, bioavailability bioefficacy and/or bioactivity of gingeroids or ginger oleoresin in mammals.
• the improved bioaccessibility, bioavailability, bioefficacy and/or bioactivity of gingeroids or ginger oleoresin allows for the compositions to be used to prevent and/or treat diseases where in the past the poor aqueous solubility and stability of gingeroids or ginger oleoresin has been an issue.
• the present invention provides a method for improving bioaccessibility, bioavailability bioefficacy and/or bioactivity of gingeroids or ginger oleoresin in mammals comprising the administration of said gingeroids or ginger oleoresin in the form of a compositions as previously defined.
• the method maybe referred to hereinafter as the “method of the invention”.
• the present invention also provides the use of a composition as previously defined for improving the bioaccessibility, bioavailability bioefficacy and/or bioactivity of gingeroids or ginger oleoresin in mammals.
• the improvement in bioaccessibility, bioavailability, bioefficacy and/or bioactivity of gingeroids or ginger oleoresin in mammals may be due to the composition providing improved gastrointestinal resistance of the gingeroids or ginger oleoresin and/or improved absorption of gingeroids or ginger oleoresin by intestinal cells and/or improved blood circulation.
• the improvement in bioaccessibility, bioavailability bioefficacy and/or bioactivity of gingeroids or ginger oleoresin in mammals may be due to the composition providing improved water solubility and/or improved stability at a pH from about 4 to about 7.
• the present invention provides a method for improving the water solubility and/or pH stability of gingeroids or ginger oleoresin, wherein the method comprises the administration of said gingeroids or ginger oleoresin in the form of a composition as previously defined.
• the present invention also provides the use of a composition as previously defined for improving the water solubility and/or pH stability of gingeroids or ginger oleoresin.
• the present invention also provides a method for providing a slow release of gingeroids in the gut of mammals comprising the administration of said gingeroids or ginger oleoresin in the form of a composition of the invention or a nutraceutical formulation, dietary or food product for humans or animals, nutritional supplement, pharmaceutical or veterinary formulation comprising the compositions of the invention.
• the present invention also provides the use of a composition of the invention or a nutraceutical formulation, dietary or food product for humans or animals, nutritional supplement, pharmaceutical or veterinary formulation according to the invention for providing a slow release of gingeroids in the gut of a mammal.
• the gingeroids may be selected from the group consisting of 6-gingerol 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol, 10-shogaol or mixtures thereof
• the slow release and the improved bioaccessibility, bioavailability, bioefficacy and/or bioactivity of gingeroids or ginger oleoresin allows for the compositions to be used to prevent and/or treat diseases where in the past the poor aqueous solubility and stability of gingeroids or ginger oleoresin has been an issue.
• the present invention provides a composition as previously defined or a nutraceutical formulation, a dietary or food product for humans or animals, a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation as previously defined, for use in preventing or treating gastrointestinal disorders, metabolic disorders primary dysmenorrhea, heavy menstrual bleeding, metabolic disorders, sleep disorders (such as insomnia), neuropsychiatric disorders (such as depression and anxiety), neurodegenerative disease (such as schizophrenia, Alzheimer’s disease, Parkinson’s disease), and/or aged-induced cognitive declined attention, alertness and/or mood.
• gastrointestinal disorders metabolic disorders primary dysmenorrhea, heavy menstrual bleeding, metabolic disorders, sleep disorders (such as insomnia), neuropsychiatric disorders (such as depression and anxiety), neurodegenerative disease (such as schizophrenia, Alzheimer’s disease, Parkinson’s disease), and/or aged-induced cognitive declined attention, alertness and/or mood.
• metabolic disorders primary dysmenorrhea such as insomnia
• neuropsychiatric disorders such as depression
• the present invention also provides a method of preventing or treating gastrointestinal disorders, primary dysmenorrhea, heavy menstrual bleeding , metabolic disorders, sleep disorders (such as insomnia), neuropsychiatric disorders (such as depression and anxiety), neurodegenerative disease (such as schizophrenia, Alzheimer’s disease, Parkinson’s disease), and/or aged-induced cognitive declined attention, alertness and/or mood, wherein the method comprises the administration of a composition as previously defined or a nutraceutical formulation, a dietary or food product for humans or animals, a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation as previously defined to a patient in need thereof.
• the present invention also provides the use of a composition as previously defined in the manufacture of a medicament for treating or preventing gastrointestinal disorders, primary dysmenorrhea, heavy menstrual bleeding , metabolic disorders, sleep disorders (such as insomnia), neuropsychiatric disorders (such as depression and anxiety), neurodegenerative disease (such as schizophrenia, Alzheimer’s disease, Parkinson’s disease), and/or aged- induced cognitive declined attention, alertness and/or mood.
• the present invention also provides a method for supporting gastrointestinal health in a human or animal in need thereof, the method comprising administering to the human or animal an effective amount of a composition as previously defined or a nutraceutical formulation, a dietary or food product for humans or animals, a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation as previously defined.
• the present invention provides a composition as previously defined, a nutraceutical formulation, a dietary or food product for humans or animals, a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation as previously defined, for use in supporting gastrointestinal health.
• Gastrointestinal disorders comprises, without limitation, dyspepsia and other problems related to gastric emptying and dysrhythmia, Irritable Bowel Syndrome (IBS), constipation, hemorrhoids, anal fissures, perianal abscesses, anal fistulas, perianal infections, diverticular diseases, colitis, colon polyps, diarrhea, colorectal cancer, CINV in cancer patients, nausea or vomiting (such as chemotherapy induced nausea and vomiting, nausea and vomiting because of pregnancy, postoperative nausea and vomiting, hyperemesis gravidarum or motion sickness).
• IBS Irritable Bowel Syndrome
• the gastrointestinal disease is selected from dyspepsia, Irritable Bowel Syndrome (IBS), colorectal cancer, nausea or vomiting (such as chemotherapy induced nausea and vomiting, nausea and vomiting because of pregnancy, postoperative nausea and vomiting, hyperemesis gravidarum or motion sickness).
• IBS Irritable Bowel Syndrome
• nausea or vomiting such as chemotherapy induced nausea and vomiting, nausea and vomiting because of pregnancy, postoperative nausea and vomiting, hyperemesis gravidarum or motion sickness.
• the present invention provides a composition as previously defined, a nutraceutical formulation, a dietary or food product for humans or animals, a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation as previously defined, for use in supporting muscle health (such as reducing muscle pain, inflammation, and dysfunction induced by exercise or muscle damage delayed onset muscle soreness)
• the present invention provides a composition as previously defined or a nutraceutical formulation, a dietary or food product for humans or animals, a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation as previously defined, for use in preventing or treating muscle pain, inflammation, and dysfunction induced by exercise or muscle damage delayed onset muscle soreness.
• the present invention also provides a method of preventing or treating muscle pain, inflammation, and dysfunction induced by exercise or muscle damage delayed onset muscle soreness, wherein the method comprises the administration of a composition as previously defined or a nutraceutical formulation, a dietary or food product for humans or animals, a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation as previously defined to a patient in need thereof.
• the present invention also provides the use of a composition as previously defined in the manufacture of a medicament for preventing or treating muscle pain, inflammation, and dysfunction induced by exercise or muscle damage delayed onset muscle soreness.
• the present invention also provides a method for supporting muscle health in a human or animal in need thereof, the method comprising administering to the human or animal an effective amount of a composition as previously defined or a nutraceutical formulation, a dietary or food product for humans or animals, a nutritional supplement, a fragrance or flavouring, a pharmaceutical or veterinary formulation, an oenological or cosmetic formulation as previously defined.
• the mammal may be a human.
• bioavailability can be defined as the fraction of ingested component available at the site of action for utilization in normal physiological functions and is determined through in vivo assays (Guerra A, Etienne-Mesmin L, compassionlli V et al (2012) Relevance and challenges in modeling human gastric and small intestinal digestion. Trends Biotechnol 30:591-600). Bioavailability is the result of three main steps: digestibility and solubility of the element in the gastrointestinal tract; absorption of the element by the intestinal cells and transport into the circulation; and incorporation from the circulation to the functional entity or target (Wienk KJH, Marx JJM, Beynen AC (1999) The concept of iron bioavailability and its assessment.
• bioaccessibility can be defined as the fraction of a compound that is released from its food matrix within the gastrointestinal tract and thus becomes available for intestinal absorption (typically established from in vitro procedures). It includes the sequence of events that take place during food digestion for transformation into potentially bioaccessible material but excludes absorption/assimilation through epithelial tissue and pre-systemic metabolism (both intestinal and hepatic).
• bioactivity can be defined as how the nutrient or bioactive compound is transported and reaches the target tissue, how it interacts with biomolecules, the metabolism or biotransformation it may experience, and the generation of biomarkers and the physiological responses induced (Alegria A., Garcia-Llatas G., Cilia A. (2015) Static Digestion Models: General Introduction. In: Verhoeckx K. et al. (eds) The Impact of Food Bioactives on Health. Springer, Cham).
• Gastrointestinal disorders comprise, without limitation, dyspepsia and other problems related to gastric emptying and dysrhythmia, Irritable Bowel Syndrome (IBS), colorectal cancer, CINV in cancer patients, nausea or vomiting (such as chemotherapy induced nausea and vomiting, nausea and vomiting because of pregnancy, postoperative nausea and vomiting, hyperemesis gravidarum or motion sickness).
• IBS Irritable Bowel Syndrome
• CINV in cancer patients
• nausea or vomiting such as chemotherapy induced nausea and vomiting, nausea and vomiting because of pregnancy, postoperative nausea and vomiting, hyperemesis gravidarum or motion sickness.
• Metabolic disorders that can be treated with the composition of the invention includes without limitation: glucose control, insulin sensitivity, type 2 diabetes mellitus, insulin resistance, obesity related metabolic disorder reduction (such as diabetes), etc.
• a and “an” are defined as one or more unless expressly stated otherwise or constrained by other language herein.
• An element or feature proceeded by “a” or “an” may be interpreted as one of the recited element or feature, or more than one of the element or feature.
• a gum may be interpreted as one type of gum or as more than gums (for example gum Arabic and guar gum).
• Figure 1 Results of visual inspection of the samples.
• Figure 3 General scheme of the adapted SHIME system used to study the survival of probiotics in the gastro-intestinal tract.
• the system is composed of 1 reactor that is used to simulate first the stomach and then the small intestinal environment, both under fasted or fed conditions. In this experiment the system is coupled with Caco-2 transport assays.
• Figure 5 Gingeroid bioavailability calculated as %transport x %bioaccessibility with % transport defined as ([BL 4h]/20 or 10)*100, with 20 or 10 pg/mL being the theoretically added concentration of total gingeroids to the apical compartment at time point Oh.
• Figure 6 Gingeroid bioavailability calculated as %absorption x % bioaccessibility with %absorption defined as (([BL 4h]+[cells 4h])/20 or 10)*100, with 20 or 10 pg/mL being the theoretically added concentration of total gingeroids to the apical compartment at time point Oh.
• Figure 7 Microscopic view of the dried composition A.
• Example 1 Preparation of a Composition of the Invention
• composition A is prepared as follows:
• composition A The ingredients are mixed to create an emulsion and then dried using a spray drying equipment (Composition A).
• Table 1 Different compositions used in the examples Table 2: Particle size measurements of the dry powder.
• the dried product particles were measured with a Keyence VHX-700 digital microscope. Mastersizer equipment measures the particle size and particle size distribution by laser diffraction (laser light scattering) (CQ-MO-304 METHOD) It can be seen in Figure 7 that the Composition A particles show small spherical structures that are resulting from the dried emulsion.
• Table 4 Ginger extracts composition within the RTD
• composition A has a DE ⁇ 3.
• Example 3 Simulator of the Human Intestinal Microbial Ecosystem (SHIME ® ) The aim of this study was to evaluate the absorption of gingeroids from 4 test Formulations at the same level of gingeroids 20mg and 10mg for composition A, following passage through the human upper GIT under fasted condition.
• SHIME® Simulator of the Human Intestinal Microbial Ecosystem
• the reactor setup was adapted from the SHIME, representing the gastrointestinal tract (GIT) of the adult human, as described by Molly et al. (1993)1.
• the SHIME consists of a succession of five reactors simulating the different parts of the human gastrointestinal tract.
• the first two reactors are of the fill-and-draw principle to simulate different steps in food uptake and digestion, with peristaltic pumps adding a defined amount of SHIME feed and pancreatic and bile liquid, respectively to the stomach and small intestine compartment and emptying the respective reactors after specified intervals.
• pancreatic enzymes a raw animal pancreatic extract (pancreatin) containing all the relevant enzymes in a specific ratio is used.
• bovine bile extract is generally supplemented (bovine bile is a closer match to human than porcine in terms of tauro- and glycocholate)
• DMEM Modified Eagle Medium
• TEER transepithelial electrical resistance
• test formulations that were investigated in this phase of the project and their test doses are shown in Table 1. Formulations were added at the start of the stomach phase. All experiments were performed in biological triplicate to account for biological variability.
• composition A 20 mg
• Composition A 10 mg
• Bioaccessibility defined as accessible gingeroids after intestinal degradation, was highest from Ginger 5% and composition A compared to ginger powder and ginger oleoresin (Figure 4).
• Bioavailability defined as bioaccessibility when taking into account transport and absorption of total gingeroids was highest from composition A compared to any other formulations ( Figure 5 and 6).
• bioaccessibility of total gingeroids was highest from Composition A compared to the other formulation ( Figure 4). Moreover, bioaccessibility of total gingeroids from Composition A at a dose of 20 mg was significantly higher compared to all formulation. In contrast, bioaccessibility from Composition A at a lower dose of 10 mg was significantly not different from Oleo-resin and Ginger powder formulation at 20 mg. Composition A 10 mg was significantly lower versus Ginger 5% 20 mg but less significantly compared with Composition A 20 mg.
• Figure 4 shows the bioaccessibility of total gingeroids after passage through the upper gastro intestinal tract (GIT).
• GIT gastro intestinal tract
• Total gingeroids concentrations present in the apical samples at time point Oh were measured. Products were incubated under fasted upper gastro-intestinal tract (GIT) conditions at a concentration corresponding to an effective dose of either 20 mg or 10 mg gingeroids.
• (*) represents statistically significant differences between Composition A 20 mg and the other treatments.
• ($) represents statistically significant differences between Composition A 10 mg and the other treatments.
• composition A used at a lower dosage of 10 mg there was no difference of either bioaccessibility nor bioavailability compared to other formulation at 20 mg. This results demonstrate that by lowering the dosage by 2 of composition A, bioavailability and bioaccessibility are equivalent of a twice higher concentration of gingeroids within ginger 5%, ginger powder and ginger oleoresin.
• the aim of this study was to evaluate the absorption of gingeroids metabolites including free, glucuronide and sulfate metabolites of 6,8,10 gingerols and of 6, 8, 10 shogaols in their free, from 3 formulations: dry ginger powder, ginger 5% and Composition A (formulation the below table).
• mice were performed by intragastric administration using rigid dosing cannula at 6.3 mg/kg body weight in a single dose and tramadol (20mg/Kg of tramadol hydrochloride at 0.5mg/mL- Drag Pharma) was injected subcutaneously to avoid suffering during the administration.
• Blood samples were collected at different fixed times (0.25,0.5,1, 2, 4, 8 h) after gavage.
• ketamine/xylazine anesthesia was used as a procedure for euthanasia, and then blood samples were extracted from the celiac artery.
• Whole blood was collected in tube that contained EDTA and the plasma was obtained by centrifugation at 7500 rpm for 15 min at 4 °C. Then the samples were stored in aliquots and frozen at -80°C until the analysis.
• a calibration curve was prepared in the range 2-2500 ng/mL for each 6 gingeroids (Phytolab, Vestenbergsgreuth, Germany) adding 25 ng/mL of PAV (Perlagonic acid vanillylamide Merck, Darmstadt, Germany) as an internal standard to control retention time stability and correct system deviation. Methanol was used as the diluent for each stock standard solution.
• PAV Perlagonic acid vanillylamide Merck, Darmstadt, Germany
• Methanol was used as the diluent for each stock standard solution.
• For free gingeroids determination exactly 200pL of internal standard solution (31.25 ng/mL in methanol) was loaded over 50 pL of plasma sample into Captiva ND 96 wells plate (Agilent #A5969002). After mixing (30 s) and filtration (under vacuum), the eluate is ready to be injected into LC/MS system.
• the liquid chromatography system used was an Agilent Infinity 1290 system coupled with an Agilent 6420 Triple quadrupole mass spectrometer in electrospray ionization mode. Autosampler was kept at 15 °C.
• the metabolites were eluted from the Poroshell 120 EC-C8 column (50x3mm, 1.9pm; Agilent) at 25°C with a mobile phase consisting of 0.1% formic acid in water LC-MS grade (solvent A) and 0.1% formic acid in acetonitrile LC-MS grade (solvent B), at a flow rate of 0.8ml_/min.
• the elution was as follows: 0-1 min, 45-45%B; 1-2min, 50% B; 2-4min, 55% B; 4-8min, 90% B.
• the injection volume was 5pL for standards and samples.
• MRM transitions were optimized using direct infusion and Optimizer B.08.00 workstation software solution (Agilent technologies, Santa Clara, CA, USA). Two qualifiers were selected to validate the specificity of the detected peak (see Table 1).
• the mass spectrometer parameters were set as follows: ESI source in positive mode; drying gas (N2) flow rate, 10 L/min; gas temperature, 300°C; nebulizer, 40 psi; and capillary, 4.0kV.
• the MS system fully calibrated prior to running according to manufacturer’s guidelines. Datas analysis were post processed with Agilent MassHunter Quantitative/Qualitative analysis B.07.00 (Agilent technologies, Santa Clara, CA, USA).
• Table 9 Retention times (Tr), multiple reaction monitoring (MRM) transitions, and optimized tandem mass spectrometry (MS/MS) detection parameters for the 6 gingeroids and internal standard.
• Captiva ND protocol for the plasma treatment before injection. a) Add 50mI of plasma* into Capitiva ND b) Add 200mI of Methanol with Internal Standard c) Mix d) Pull vacuum until all volume is though cartridge for complete elution
• Beta-Glucuronidase Type HP-2 from Helix pomatia (Sigma, Ref. G7017)
• composition A had a significantly higher Area Under the Curve (AUC) compared with ginger powder or with ginger 5%.
• AUC Area Under the Curve
• the AUC increased is respectively of +53,08% and +26,26%.
• composition A induces a statistically significant shift of the half-life (t 1/2 (h) reported in table 9 and 11) with a 2,84-fold increase compared with Ginger powder and a 1,80 fold increase compared with Ginger 5%.
• This shift is due to statistically significant higher gingeroids plasmatic level at 30 min, 1 h, 4h and 8h after ingestion of composition compared A compared with ingestion of ginger powder and at 30min and 1h compared with ingestion of ginger 5% (Table 10 and 11 reported values at p ⁇ 0,05 in bold).
• composition A provide a gingeroids slow release effect characterised by longer Half-life and prolonged release in time up to 8h after ingestion.
• Table 10 Pharmacokinetic parameters on total metabolites of Ginger powder and Composition A.
• Table 11 Pharmacokinetic comparison of total gingeroids metabolites plasmatic level at any time points between Ginger powder and Composition A (mean+/-SEM).
• Table 12 Pharmacokinetic parameters on total metabolites of Ginger 5% and Composition A.
• Table 13 Pharmacokinetic comparison of total gingeroids metabolites plasmatic level at any time points between Ginger 5% and Composition A (mean+/-SEM).
• Table 14 AUC0-8h dose normalized of total gingeroids and relative bioavailability of Composition A compared to Ginger powder or Ginger 5%
• EXAMPLE 5 TESTING THE EFFECT OF THE COMPOSITION A TO ENHANCE THE BIOAVAILABILITY OF GINGEROIDS IN HEALTHY VOLUNTEERS THROUGH A COMPARATIVE PHARMACOKINETIC STUDY
• composition A is superior in terms of bioavailability in plasma as measured by the dose- normalized Area under the curve (AUC) compared to ginger root powder providing the same quantity of active substance (gingeroids).
• the primary objective of the study is to assess plasmatic concentration profile of total gingeroids (6-, 8-, 10-gingerol and 6-, 8-, 10-shogaol and their glucuronide and sulfate metabolites) on a 8-hour period after consumption of a single dose of 100 mg (16.7 mg/kg body weight assuming a 60kg human) of the Composition A compared to a single dose of ginger root powder that delivers the same amount of gingeroids.
• the pharmacokinetic study is a monocentric, randomized, crossover, pilot and open clinical trial.
• VO screening/inclusion visit
• V1 to V3 experimental sessions
• studied products are consumed by subjects (one different product at each session for each randomized subject).
• V1 visit take place 3 weeks maximum after VO, and can also constitute the randomization visit.
• Each experimental session (V1 to V3) is separated by 1 week minimum and 2 weeks maximum.
• subjects undergo blood samples kinetic during 8 hours.
• the last kinetic blood sample is realized after each experimental session, 8 hours after the beginning of the kinetic.
• Urine collection is also performed during these visits for biobanking.
• Subjects have to collect their first urination the morning of each experimental visit (totality of this first urination), and 0 to 8 hour urines during the kinetic on site.
• the end of study can be the day after the last experimental session V3.
• each subject consumes the three tested products in a random order during each experimental session (V1 to V3).
• the subjects (30 participants) consume each tested product one time, at each experimental session (V1 to V3), with a drink of water (strictly 240 ml).
• the tested products are consumed at TO time-point of the kinetic. Studied products are directly administered to subjects during experimental session (V1 to V3) according to random list of product attribution sequence.
• composition A 100mg, with a minimum of 10% gingeroids consumed as capsules (1 capsule; 100 mg per capsule),
• Standard Ginger root powder 700-800mg delivering the same quantity of gingeroids and consumed as capsules (2 capsules; 350-400 mg per capsule),
• Standard Ginger root extract 200 mg with a minimum of 5% gingeroids consumed as capsules (1 capsule; 200 mg per capsule).
• a blood sample is realized during VO visit for control record analysis and pregnancy test for non- menopausal women (bIiOQ dosage). Subject have to come at the clinical investigation center in a 12-hour fasting state. After realization of physical examination and verification of eligibility criteria the blood sampling is realized. Only one prick can be necessary and a maximum of 10 mL will be collected. Parameters are analyzed in serum and plasma, thus EDTA, fluor and dry tubes are used. Measurement of blood pressure are performed at each visit. It is performed during the physical examination with an electronic blood pressure monitor.
• Heart Rate HR, in bpm
• SBP Systolic Blood Pressure
• DBP Diastolic Blood Pressure
• a margin of ⁇ 30s is authorized for T15, ⁇ 1min for T30 and T45, ⁇ 2 min for T60, T75, T90, T105, ⁇ 5min for T120 to T480.
• TO time point correspond to study product consumption. Volunteer is allowed to consume his/her standard launch about 4 hours after study product consumption (just after at T240 time- point) and standard afternoon snack about 8 hours after study product consumption. Lunch will have to be consumed in 30 minutes maximum. Water is not permitted 1h before and 1h after product administration.
• 6-, 8-, 10- gingerol and 6-, 8-, 10-shogaol and their metabolites are analyzed using a LC/MS method as described in Example 4.
• AUC Area Under the Curve
• the dose normalized AUC is the AUC normalized according to gingeroids intake by dividing the observed AUC by the corresponding gingeroids dosage of each administration.
• the following time-points are considered: T15, T30, T45, T60, T75, T90, T105, T120, T150, T180, T240, T300, T360 and T480.
• T-5 can be considered as baseline value (TO) for AUC calculation.
• the primary comparison is Composition A 100 mg vs Standard Ginger root powder 700- 800mg.
• AUC of gingeroids separately (6-, 8-, 10- gingerol and 6-, 8-, 10-shogaol) and their metabolites plasmatic concentrations from 0 to 8 hours (AUC0-8h) (expressed in ng.h/mL);
• AUC0- AUC of gingeroids separately and their metabolites plasmatic concentrations from 0 to infinity
• Cmax/dose Peak of total gingeroids plasmatic concentration normalized according to gingeroids intake
• Tmax Time to peak of total gingeroids plasmatic concentration
• - Relative bioavailability defined as the ratio of the dose-normalized AUC0-8h of total gingeroids for the different tested formulation to the dose-normalized AUC0-8h obtained for the reference product (standard ginger root powder).
• T-5 can be considered as baseline value (TO) for AUC calculation.
• Gingeroids are defined as 6-, 8-, 10- gingerol and 6-, 8-, 10-shogaol and metabolites are defined as 6-gingerol glucuronide, 6-gingerol sulfate, 8-gingerol glucuronide, 8-gingerol sulfate, 10-gingerol glucuronide, 10-gingerol sulfate, 6-shogaol glucuronide, 6-shogaol sulfate, 8-shogaol glucuronide, 8-shogaol sulfate, 10-shogaol glucuronide, 10-shogaol sulfate.
• Total gingeroids can correspond to sum of 6-, 8-, 10- gingerol and 6-, 8-, 10-s
• ITT Intent-to-treat
• PP Per Protocol
• bioavailability is dose-normalized AUC between 0 and 8 hours. It is analyzed with a mixed model for repeated measurements (SAS® PROC MIXED, statistical model n°1):
• Results show an increase bioavailability of gingeroids when consumed in the form of the Composition A in comparison to the Standard Ginger root powder.
• Results show an increase bioavailability of gingeroids when consumed in the form of the Composition A in comparison to Standard Ginger root extract 5%.

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