WO2018083677A1 - Approche écologique de l'amélioration de la biodisponibilité d'huiles, de graisses et d'autres substances bioactives lipophiles et compositions associées - Google Patents

Approche écologique de l'amélioration de la biodisponibilité d'huiles, de graisses et d'autres substances bioactives lipophiles et compositions associées Download PDF

Info

Publication number
WO2018083677A1
WO2018083677A1 PCT/IB2017/056932 IB2017056932W WO2018083677A1 WO 2018083677 A1 WO2018083677 A1 WO 2018083677A1 IB 2017056932 W IB2017056932 W IB 2017056932W WO 2018083677 A1 WO2018083677 A1 WO 2018083677A1
Authority
WO
WIPO (PCT)
Prior art keywords
oil
powder
powder composition
fenugreek
fibre
Prior art date
Application number
PCT/IB2017/056932
Other languages
English (en)
Inventor
Krishnakumar ILLATHU MADHAVAMENON
Balu Paulose Maliakel
Original Assignee
Akay Flavours & Aromatics Pvt. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Akay Flavours & Aromatics Pvt. Ltd. filed Critical Akay Flavours & Aromatics Pvt. Ltd.
Publication of WO2018083677A1 publication Critical patent/WO2018083677A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/065—Diphenyl-substituted acyclic alcohols
    • 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
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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)
    • A61K36/185—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
    • 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)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to compositions for the delivery of bioactive oils, fats and other lipophilic substances, more particularly to a composition that enhances the bioavailability of said bioactive agents.
  • the bioactive substances are incorporated in to natural fenugreek dietary fiber to produce free flowing powders.
  • JP2004331539 discloses the hepatic disease preventing and treating agent in food or drink.
  • the hepatic disease preventing and treating agent is characterized by bisabolane type sesquiterpene compounds preferably originated from a plant of the genus curcuma, the family zingiberaceae.
  • the bisabolane type sesquiterpene compound is preferably at least one compound selected from ar-turmerone, a-turmerone, ⁇ -turmerone and their mixtures.
  • the main object of the present invention is to provide a powder composition for enhancing the bioavailability of lipophilic bioactive substances.
  • Another object of the present invention is to provide process for the preparation of powder compositions that has enhanced bioavailability of lipophilic bioactive substances.
  • the present invention provides a powder composition for enhancing the bioavailability of lipophilic bioactive substances comprising bioactive substance, fenugreek fibre matrix, an emulsifier and one or more of lecithin, or phosphatidyl choline.
  • fenugreek soluble dietary fibre act as a vehicle for the delivery of bioactive substances.
  • the fenugreek fibre has high loading of lipophilic bioactive substances of >50% (w/w), and still capable of forming water dispersible free flowing powder composition.
  • the powder composition enhance the in vivo bioavailability of in the range of 3-10 times compared to bioactive substance alone.
  • the invention provides a process for preparation of bioactive powder composition
  • a) lipophilic bioactive substance is mixed with lecithin or phosphatidylcholin containing glycerine or any emulsifier suitable for increasing the water solubility; b) subjecting the mixture of step (a) to sonication using ultrasound generator at 60 to 70°C in a closed vessel fitted with suitable condensing system for 30 to 120 min in pulses of duration 30 to 60 seconds; c) the mixture of step (b) is added to water solution containing the emulsifier and subjected to sonication as above to form micelle of less than ⁇ ⁇ size; d) Fenugreek fibre is dissolved in water and subjected to sonication to form homogeneous fibre solution; e) the mixture of step (c) is slowly added to the fibre solutions of step (d) and subjected to high pressure homogenization at 1000 to 1500 bars or sonication to form stable micelle of size about 1
  • FIG. 1 illustrates characterization of SBT-20: (a) FTIR chromatogram of Turmeric oil, F-GAL and SBT-20 (b) DSC of SBT-20 (c) SEM of Turmeric oil (d) SEM of SBT-20
  • FIG. 2 illustrates characterization of SBG-5: a) FTIR chromatogram of Ginger extract containing gingerols, F-GAL and SBG-5 (b) DSC of SBG-5 (c) SEM of Gingerols (d) SEM of SBG-5.
  • FIG. 3 illustrates characterization of SBB-20: (a) FTIR chromatogram of AKBA, F-GAL and SBB-20 (b) DSC of SBB-20 (c) SEM of AKBA (d) SEM of SBB-20 (e) Powder x-ray diffraction (PXRD) of SBB-20
  • FIG. 4 illustrates in vitro release data of (a) SBT-20 (b) SBG-5 (C) SBC-2
  • FIG. 5 Plasma concentration - time curve after oral administration of turmeric oil, SBT-20 (F- GAL formulation) and SBT-20 (F-GAL + excipients formulation).
  • FIG. 6 Plasma concentration - time curve after oral administration of ginger oil, SBG-5 (F- GAL formulation) and SBG-5 (F-GAL + excipients formulation).
  • FIG. 7 Plasma concentration - time curve after oral administration of unformulated Boswellia extract and SBB-20 (F-GAL + excipients formulation).
  • FIG 8. Plasma absorption comparison of turmerone rich turmeric oil with SBT-20 prepared by (a) fenugreek galactomannans, F-GAL (b) Psilium galactomannans, P-GAL and (c ) Guar gum galactomannans, G-GAL. DETAILED DESCRIPTION OF INVENTION
  • F-GAL refers to soluble dietary fibre rich in galactomannans obtained from fenugreek.
  • P-Gal refers to soluble dietary fibre rich in galactomannans obtained from Psyllium.
  • G-Gal refers to soluble dietary fibre rich in galactomannans obtained from Guar gum.
  • SBT-20 refers to turmerones with 20% turmerone content.
  • SBG-5" refers to Ginger extract with 5% 6-gingerols content.
  • SBC-2 refers to Capsaicin extract with 2% capsaicin content.
  • SBB-20 refers to Boswellia extract with 20% total boswellic acids and 10% AKBA.
  • the present invention provides novel oral compositions for poorly bioavailable lipophilic bioactive substances when consumed orally.
  • the bioactive substances are converted to water soluble or water dispersible particles or amorphous particles of colloidal size for better intestinal absorption, thus enhancing the bio-availability.
  • the process involves loading of bioactive substances in a special grade fenugreek dietary fiber (galactomannans). Fenugreek dietary fibre compositions in powder form to enhance the bioavailability of lipophilic bioactive substances.
  • composition of present invention includes an effective amount of bioactive substance, b) dietary polysaccharide fenugreek powder in the range of 40 to 90%, one or more of lecithin, or phosphatidyl choline, and a pharmaceutically acceptable first emulsifier and second emulsifier.
  • the lipophilic bioactive substance is selected from the group consisting of essential oils, fixed oils, flavor oleoresins, polyunsaturated fatty acids rich oils like fish oil, carotenoids such as lutein, zeaxanthin, lycopene, astaxanthin, polyphenols, flavonoids, vitamins, and minerals.
  • the essential oils are selected from the group consisting of, but not limited to turmeric oil, clove oil, black cumin oil, pepper oil, ginger oil, cinnamon oil or any essential oils derived from plants containing pharmacologically active molecules such as terpenes, terpenoids, alkaloids, polyphenols, etc
  • the fixed oils are selected from the group consisting of, but not limited to fish oils or any edible oils rich in polyunsaturated fatty acids (Krill oil salmon oil, flax seed oil, saw palmito oil, evening prime rose oil, conjugated linolenic acid oil, gamma-linolenic acid oil, black cumin oil, Medium chain triglycerides (MCT) oil, Olive oil, coconut oil, Plam oil or sunflower oil or rice bran oil or annatto seed oil rich in vitamin E (tocophenrols and toco trienols).
  • the lipophilic bioactive substance is selected from the group consisting of turmeric oil, ginger oil, capsicum oleoresin
  • the lipophilic bioactive substance is a solid or liquid.
  • the dietary fenugreek fibre used in the present invention contains 90- 95% (w/w) of soluble fibre content as galactomannans, 5% protein derived from fenugreek and insoluble fibre content of ⁇ 1%.
  • the fenugreek fiber obtained by the said process has high oil loading capacity.
  • the novel combination of bioactive substances incorporated in fenugreek fiber composition enhances the overall bioavailability of the active substances incorporated in the fiber.
  • the fenugreek seeds are used as home spice is a rich source of galactomannans and are completely safe for human consumption.
  • the fiber matrix offer high loading capacity of oils to provide stable formulations.
  • the lipophilic bioactive molecule content is in the range of about 2 to 40% and the oil or lipid content in the range of about 10 to 60%.
  • the galactomannans are obtained from Psyllium and Guar.
  • the Psyllium and Guar also provides rich source of galactomannans however it has identified in the study they have poor oil holding and water binding capacity which makes them unsuitable for enhancing the bioavailability of the lipophilic bioactive substances.
  • the results are provided in Table-1.
  • the emulsifier used in the present invention is selected from the group consisting of, but not limited to gum acacia, cyclodextrin, modified starch, glycerine, modified starch, polysorbate, propylene glycol, quillaja saponaria extract.
  • one or more emulsifiers may be used to provide stable powder compositions.
  • the powder composition is hydrophilic in nature and dispersible in water with miscibility to the lipophilic substance.
  • the powder compositions consisting of bioactive substances encapsulated in fenugreek fibre matrix exhibits enhanced in vivo bioavailability in the range of 3-10 times compared to bioactive substance alone.
  • the powder composition exhibits enhanced absorption, systemic oral bioavailability and longer duration of existence in plasma when administered in the range of 250 to 500 mg.
  • the enhanced bioavailability of F-GAL based formulations can be dedicated to the high viscosity, gum-like character, film forming capacity, encapsulation effect and mucoadhesive character.
  • the unique chemical structure with 1 : 1 galactose to mannose ratio, high molecular weight of >100 KDa) and highly sterically hindered structure in the gel-phase contribute to its physical properties.
  • the ultrasound -aided or homogenization aided formulation allows the uniform distribution of the bioactive molecules in the gel-phase network and further drying produces amorphous and colloidal fibre encapsulated hydrophilic particles of the hydrophobic and lipophilic bioactives.
  • High mucoadhesive character of F-GAL helps the formulations to stick the endothelial membranes sustained delivery of the actives for enhanced elimination half- life as compared to the unformulated oils.
  • the lipophilic molecules can leach out of the fiber matrix in a colloidal form for better interaction with the lipid bilayers of the endothelial layer for better permeability and better absorption.
  • significant lymphatic absorption may also be predicted, which help to slow down the first will pass metabolism to produce free (unconjugated) active molecules.
  • the process of preparation of powder composition for enhancing the bioavailability of lipophilic bioactive substance comprising the steps of a) lipophilic bioactive substance is mixed with lecithin or phosphatidylcholin containing glycerine; b) subjecting the mixture of step (a) to sonication using ultrasound generator at 60 to 70°C in a closed vessel fitted with suitable condensing system for 30 to 120 min in pulses of duration 30 to 60 seconds; c) the mixture of step (b) is added to water solution containing the emulsifier and subjected to sonication as above to form micelle of less than ⁇ ⁇ size; d) Fenugreek fibre is dissolved in water and subjected to sonication to form homogeneous fibre solution; e) the mixture of step (c) is slowly added to the fibre solutions of step (d) and subjected to high pressure homogenization at 1000 to 1500 bars or sonication to form stable micelle of size about
  • the emulsion is converted into powder form by employing at least one of the drying techniques selected from spray drying, freeze drying, drum drying, pan drying, fluid bed drying or any other techniques suitable thereof.
  • the lipophilic bioactive substances are in solid of liquid form.
  • the solid bioactive substances are dissolved in neutral oil and powders are prepared by using the above process.
  • the powder compositions can be prepared without using any excipients or additives.
  • the fenugreek fibre acts as self-emulsifying agent to form a uniform solution.
  • the process of preparation of powder compositions without excipients comprising the steps of a) Fenugreek powder is dissolved in water and passed through homogenizer at 400 to 450 bar pressure to form homogeneous solutions; b) liquid bioactive substance is added to the solution of step (a) and passed through colloidal; then subjected to high pressure homogenization or sonication to form micelles; c) the homogeneous viscous solution of step (b) is kept stirring for 2h and spray dried to obtain powder composition.
  • the bioavailability of the various lipophilic substances preparing by using the above methods has been evaluated.
  • the powder compositions with additives have shown increase in bioavailability in the range of 3-10 times.
  • the highly stable powder is suitable to use in various targeted and sustained release dosage forms that including, but not limited to tablets, nutritional supplements, capsules, gels, beadlets, micro and nanoencapsulates, powder, granulates or any other pharmaceutically acceptable forms.
  • 100 Kg of fenugreek seeds are cut into small pieces of 1.5 ⁇ 0.2 mm particles and passed through a gravity separator to separate into lighter and heavy fractions.
  • the lighter fractions rich in endosperms were further passed through a hammer mill and coarse-grinded to 0.5 ⁇ 0.2 mm particles and again separated to lighter and heavy fractions.
  • the lighter fractions were then passed through a sieve of 20 mesh and collected the particles with greater than 20 mesh size. The process of milling and sieving continued until particles which are greater than 20 mesh was obtained.
  • the fraction of fiber above 20 mesh is collected and further subjected to fine milling and sieving through 80 mesh.
  • the 20 to 80 mesh particles were further grinded and sieved through 60 mesh. The process repeated until the particles of fenugreek fibre containing not less than 90% soluble dietary fibre with not more than 6% proteins. Yield of F-GaL 13.4 Kg (13.4%), with 92.8 % soluble dietary fibre as galactomannans and 5.2 % protein content upon Kjendhal's method with 25 to 32 mL/g water swelling capacity and 3.2 mL/g oil binding capacity. The insoluble fibre content was less than 1%.
  • Example 2 Physical properties of fenugreek- galactomannans (F-GAL) in comparison with psyllium seeds galactomannans (P-GAL) and Guar gum galactomannans (G-GAL).
  • F-GAL prepared in this invention is compared with commercially available purified galactomannans (>90%) of psyllium (P-GAL) and guar (G-GAL) as follows, employing standard methods. The results as shown in Table 1.
  • Turmerone-rich turmeric oil containing not less than 40% (w/w) of turmerones is prepared from dried rhizomes of turmeric ⁇ Curcuma Longa L) either by steam distillation or supercritical carbon dioxide extraction by employing the methods known in the prior art.
  • Ginger oleoresin and ginger oil containing >25% (w/w) of gingerols is prepared by supercritical carbon dioxide extraction by employing the methods known in the prior art.
  • Boswellia serrate extract containing not less than 30% Acetyl- 11-keto-beta-boswellic acid was commercially purchased. Fish oil rich in polyunsaturated fatty acids standardized for EPA and DHA was also purchased. All the extracts were miscible with oils and insoluble in water.
  • Turmerone, gingerol, AKBA and capsicinoids content in the respective oil or oleoresin or extract was analysed by GC -MS/MS, and FIPLC methods.
  • Analytical standards of turmerone (CAS Registry No. 532-65-0), 6-gingerol (CAS Registry No. (23513-14-6), AKBA (CAS Registry No. (67416-61-9) and capsaicin (CAS Registry No: 404-86-4) were purchased from Sigma-Aldrich, Bangalore, India.
  • Example 4 Formulation of turmerone rich turmeric oil using fenugreek- galactomannans (F- GAL) and SBT-20 (Super- Bio-Turmerones with 20% turmerone content)
  • Preparation of water dispersible and stable powder form of turmeric oil in fenugreek-soluble dietary fibre (F-GAL) matrix as microencapsulates can be prepared either by using fenugreek galactomannans alone or by using a combination of other excipients along with fenugreek galactomannans, as described below.
  • F-GAL fenugreek-soluble dietary fibre
  • Example 4A- With F-GAL Various percentage turmeric oil (20, 40, and 60% w/w) incorporated fenugreek dietary fibre powder is prepared by a self-emulsification procedure followed by spray drying or drum drying or freeze drying or by evaporation under controlled conditions of temperature and pressure. Briefly, 50g of fenugreek fibre prepared in example 2 is dissolved in 1500 mL water and passed through a homogenizer at 400 to 450 bar pressure. 50 g turmeric oil containing 52.4% turmerones is slowly added and passed through a colloidal mill.
  • the resulting solution was either passed through high pressure homogenizer (1200 -2000 bar) or subjected to sonication for 5 to 20 min, at 40°C, to form micelles of 1 ⁇ 0.5 ⁇ .
  • Sonication is performed using 1000 W ultrasound generator fitted with a sonotrode (Hieilscher, Germany).
  • the homogeneous viscous solution thus obtained is kept stirring for 2h and spray dried at inlet temperature of 90 ⁇ 5°C and outlet temperature of 160 ⁇ 5°C.
  • the spray drying conditions may change depending on the capacity and design of the equipment.
  • the powder collected was sieved to a uniform size of not more than 175 ⁇ 20 microns.
  • the powder is water dispersible and stable under conditions of less than 25°C for storage.
  • the powder contained 42.1% (w/w) oil content with a turmerone content of 19.2% (w/w).
  • Turmerone content is measured by a standard procedure employing gas chromatography - mass spectrometry (GC/MS).
  • Example 4B- With F-GAL and excipients Water dispersible powder of fats and oils (eg: turmeric oil) can also be prepared in the presence of excipients such as gum acacia, modified starch, cyclodextrin, and employing water miscible emulsifiers including but not limited to lecithin, phosphatydylcholin, glycerine, polysorbate etc.
  • Oil or fat or lipophilic substances impregnated soluble fiber (F-GAL) microencapsulates were prepared by an ultrasound mediated gel-phase dispersion followed by microemulsification and concentration.
  • turmeric oil containing 56% of turmerones is mixed with 80 g of lecithin or phosphatidyl cholin containing 20 g of glycerine. It is sonicated at 60 ⁇ 4°C using a 1000W ultrasound generator for 30 to 60 min, as pulses of duration 30 seconds to 2 min.
  • the homogeneous blend of turmeric oil and lecithin thus obtained was further added slowly to 600 mL water solution containing 10% (w/v) of cyclodextrin with sonication.
  • Example 5 Formulation of turmerone rich turmeric oil using Psyllium galactomannans (P- GAL) and guar galactomannans (G-GAL)
  • Example 6 Formulation of Gingerols rich Ginger oil or oleoresin (SBG-5) using fenugreek- galactomannans (F-GAL)
  • Preparation of water dispersible and stable powder form of gingerols in fenugreek-soluble dietary fibre (F-GAL) matrix as microencapsulates can be prepared either by using fenugreek galactomannans alone or by using a combination of other excipients along with fenugreek galactomannans, as described example 4A and 4B respectively.
  • Ginger oil or oleoresin containing more than 25% of gingerols was used for formulation.
  • SBG-5 containing not less than 5% (w/w) of 6-gingerol was prepared.
  • the powder was found to be water dispersible and stable under conditions of less than 25°C for storage.
  • the powder was found to contain6.8% (w/w) of total gingerols with 5% of 6-gingerol.
  • Example 7 Formulation of Capsaicinoids rich Capsicum oleoresin (SBC-2) using fenugreek- galactomannans (F-GAL)
  • the powder thus obtained was wet with water to form a dough and extruded to the form of noodles using an extruder. It was further processed with a spheroniser to form tiny 40 to 60 mesh spherical particles or pellets. It was further dried to a moisture content of not more than 5% and coated with commercially available enteric coating materials like polymethacrylate- methacrylic acid copolymers, cellulose derivatives, etc to completely mask the pungency and produce targeted and sustained colonic or intestinal delivery beadlets of capsaicinoids with not less than 2% (SBC-2).
  • Example 8 Formulation of Boswellic acids (AKBA)-rich boswellia extract (SBB-20) using fenugreek- galactomannans (F-GAL)
  • Boswellia serrata extract containing 35% (w/w) of Acetyl- 11-keto- beta-boswellic acid (AKBA) and 71% total boswellic acids was encapsulated in fibre matrix (F-GAL) as explained in above examples, particularly using the method of example 4B.
  • the final encapsulated form of boswellic acids were found to contain not less than 20% total boswellic acids and not less than 10% AKBA (SBB-20).
  • Example 9 Preparation of water dispersible powder of dietary oils enriched with omega-3 fatty acids (fish oil, algae derived oil rich in polyunsaturated fatty acids, flaxseed oil, linseed oil, evening prime rose oil, saw palmito oil, avocado oil etc) using fenugreek galactomannans
  • fenugreek fibre prepared in example 2 was dissolved in 2000 mL water and passed through a colloidal mill and further subjected to sonication to form uniform solution of less than 5 ⁇ particles.
  • 50gof fish oil [EPA (Eicosapentanoic acid) -6% and DHA (Docosahexanoic acid) -38%] solution in cyclodextrin was then added slowly to the fibre emulsion and subjected to high pressure homogenization at 1200 to 1500 bar.
  • the solution was also subjected to sonication to form uniform micelles of 0.9 ⁇ 0.3 ⁇ .
  • the emulsion was the spray dried at outlet temperature of 90 ⁇ 5°C and inlet temperature of 160 ⁇ 5°C.
  • the spray drying conditions may change depending on the capacity and design of the equipment.
  • the powder collected was sieved to a uniform size of not more than 175 ⁇ 20 microns.
  • the powder was found to be water soluble and stable under conditions of less than 25°C for storage.
  • the powder was found to contain 46.8% (w/w) oil content with 2.8% EPA and 18%.
  • Example 10 Characterization of turmeric oil, ginger extract and capsicum extract encapsulated fenugreek dietary fibre Stability, crystallinity and bioactive molecule-fiber interactions were assessed by differential scanning calorimeter (DSC), Powder X-ray diffraction (PXRD), Nuclear magnetic resonance (NMR), Fourier-transformed infrared spectra (FTIR) and scanning electron microscopy (SEM) investigations. Thermogram was recorded using Q10 DSC, differential scanning calorimeter (DSC Metier Toledo 822e), Mettler-Toledo India Pvt Ltd, Mumbai, India. Samples (3- 5 mg) were sealed in the aluminum crimp pan, and heated at a rate of 10°C/min from 30 to 300°C under a nitrogen atmosphere.
  • FTIR and NMR studies of the oil extracts and fenugreek fibre formulations confirmed the presence of bioactive molecules (turmerone, gingerol, capsaicin, AKBA) in the fibre matrix.
  • DSC studies showed no sharp endotherm peaks in any of the formulations as similar to that of the soluble dietary fiber (galactomannans), indicating the absence of crystallinity. Neither the nature nor the shape of the peaks of fenugreek fibre or its formulations were changed upon formulation. However, a small endothermic shift around 95°C due to the residual moisture content in the fiber matrix was observed. The amorphous nature of the formulation was found to be increased with increase in the fibre content when various formulations with 10 to 60% fibre content was measured.
  • Example 11 Granulation of bioactive oil impregnated (microencapsulated) fenugreek dietary fibre powder
  • the powder is suitable for granulation or for making pellets of varying size from 20 to 100 mesh or even bigger particles by employing the techniques already known in the literature such as dry granulation (compact granulation), wet granulation (high shear granulation), or by extrusion - spheronisation techniques. Fluid-bed mediated granulation can also be performed using bottom-spray or top-spray methods.
  • fenugreek soluble fibre helps to produce stable particles or pellets without using additional excipients like polyvinyl pyrrolidone, gelatinized starch, hydroxypropylmethy cellulose etc.
  • the granules thus obtained can be further coated with functional coatings using Fluid-bed bottom spray coatings to produce multi-layered stable beadlets having a variety of functionalities such as controlled release, targeted delivery, pH-dependent enteric coatings, moisture barrier coatings, colour coatings etc.
  • the in vitro release profile of the loaded turmerone, 6-gingerol, capsaicin and AKBA from turmeric oil, ginger oleoresin, capsicum oleoresin and boswellia extract formulations with fenugreek galactomannans at pH 6.8 and pH 1.2 (to simulate stomach and colonic conditions) are illustrated in Fig. 4.
  • 50 mg of formulated powder is dispersed in 10 mL phosphate buffer at pH 6.8 and 0.1M HC1 at pH 1.2 for 24 hours and kept in a sealed thermostated water bath set at 37 ⁇ 0.5°C under constant shaking.
  • SBC-2 which is a taste masked formulation for the safe and comfortable delivery form of pungent capsaicin into the intestine and colon without stomach and abdominal pain, also investigated for in vitro release of capsaicin. It showed a percent release of only 5.1 ⁇ 1.2 at pH 6.8 and 3.7 ⁇ 0.9 at pH 1.2 in the initial 5 hour. On continuation of the release study, capsaicin release was prolonged and found to increase with time in a steady and sustained manner, such that 28.6 ⁇ 1.8 % was observed at pH 6.8 and 18.3 ⁇ 2.1 % at pH 1.2 by the end of 12 h and was nearly 60% and 85% by the end of 24 h, indicating the slow colonic delivery (Fig. 5d).
  • Example 13 Stability studies of the formulations SBT-20, SBG-5, SBC-2 and SBB-20
  • Table 2 Table (a), (b), (c), (d) illustrating the stability of the formulations SBT-20, SBG-5, SBC-2 and SBB-20 under accelerated conditions of storage.
  • each volunteer was first given one capsule of 500 mg (500 mg x l) of unformulated oil or extract and 2 mL each of blood samples were withdrawn at 0, 0.5, 1, 3, 5, 7 and 12 h post-dose; plasma was separated and frozen at -20°C till analysis. After 1 week, the subjects were given one capsules of 500 mg (500 mg ⁇ 1) containing formulations of oil or extracts (SBT-20, SBG-5, SBB-20) were given and the protocol was repeated exactly the same as above for collection of plasma samples at various time intervals.
  • Plasma was subjected to analysis for the respective molecules, (turmerones, 6-gingerol, and AKBA) using appropriate methods of HPLC (High performance liquid chromatography) or liquid chromatography tandem mass spectrometry (LC -MS/MS) or gas chromatography tandem mass spectrometry (GC -MS/MS).
  • HPLC High performance liquid chromatography
  • LC -MS/MS liquid chromatography tandem mass spectrometry
  • GC -MS/MS gas chromatography tandem mass spectrometry
  • Plasma concentration verses time plot was constructed for the detailed analysis of pharmacokinetics of each molecules and their respective formulations to deduce bioavailability or relative absorption. Extraction efficiency of bioactive molecules (turmerones, 6-gingerol, and AKBA) were confirmed by spiking 10 ⁇ g/mL of standard solution in 1 mL of rat plasma followed by analysis.
  • Retention time was confirmed by 10 repeated analyses at 20 ⁇ g/mL level on the same column under identical conditions. Measurement of the contents in plasma was validated by spiking standard the actives in plasma at 10 and 20 ⁇ g/mL concentrations. Extraction efficiency from plasma was 94% with a linear response of R 2 value of 0.999. The identity was established by analytical standards and by multiple reaction monitoring (MRM) of their MS/MS spectra in mass spectrometry.
  • MRM multiple reaction monitoring
  • Concentration of turmerones in plasma was measured by GC -MS/MS as follows.
  • Gas chromatograph (Agilent 7890B) coupled to a triple quadrupole mass spectrometer (Agilent G7010A) was used for ionization by electronic impact (70 eV).
  • the apparatus was fitted with a DB-WAX column (internal diameter: 0.25 mm, length: 30 m, film thickness: 0.25 ⁇ ).
  • the carrier gas was helium at a total flow of 36.082 mL/min.
  • the injector port temperature was 250°C and the transfer line temperature was 280°C, ion source heating was 230°C.
  • Interpretation and identification of the fragmentation mass spectrum was carried out by comparison with the NIST mass library data base.
  • Fig. 5 shows the plasma concentration-time plot of Ar-Turmerone after the oral administration of SBT-20 and unformulated Turmerone rich turmeric oil (SFT).
  • SBT-20 contained 100 mg of total turmerones (sum of Ar-turmerone, a-turmerone, and ⁇ - turmerone) (20% w/w) and that of 500 mg SFT contained 250 mg of turmerones (50% w/w; sum of Ar-turmerone, a-turmerone, and ⁇ -turmerone).
  • Plasma concentration-time plot clearly demonstrates enhanced absorption, bioavailability and improved pharmacokinetics (Area under curve, time taken for maximum absorption, longer duration of existence in plasma as clear from the elimination half-life ) of the formulation SBT- 20 as compared to the unformulated turmeric oil rich in turmerones. Bioavailability of SBG-5
  • UPLC analyses were carried out on a Shimadzu LC 20 AT system, with M20A Photo diode array (PDA) detector (Shimadzu Analytical Pvt ltd, Mumbai, India), fitted with a reverse phase C18 Phenomenex column (250 x 4.6 mm, 3 ⁇ ) using mobile phase as water with 1% acetic acid and acetonitrile at 35: 65 (v/v) and flow rate 1 mL/min and detection at 280 nm.
  • PDA Photo diode array
  • Plasma concentration - time plot clearly demonstrates enhanced absorption, bioavailability and improved pharmacokinetics (Area under curve, time taken for maximum absorption, longer duration of existence in plasma as clear from the elimination half-life) of the formulation SBT-20 as compared to the unformulated ginger extract rich in gingerols.
  • Fig. 6 shows the plasma concentration-time plot of 6-gingerol after the oral administration of SBG-5 and unformulated ginger oleoresin rich in 6-gingerol (SGO). It has to be noted that 500 mg of SBG-5 contained 25 mg of gingerol (5% w/w) and that of 500 mg SGO contained 125 mg of 6-gingerol (25 % w/w). It can be observed that the plasma concentrations of 6-gingerol was significantly higher for SBG-5 than the SGO, as evident from the area under curve (AUC) calculations of the plasma concentration-time plot (6.3- fold higher). Bioavailability of SBB-20
  • the absorption and bioavailability of the active molecule AKBA in Boswellia serrata extract was measured by an HPLC method as follows. HPLC analyses were carried out on a Shimadzu LC 20 AT system, with M20A Photo diode array (PDA) detector (Shimadzu Analytical Pvt ltd, Mumbai, India), fitted with a reverse phase C18 Phenomenex column (250 x 4.6 mm, 3 ⁇ ) using mobile phase as water/acetonitrile at (90: 10 v/v) acidified to pH 4 with glacial acetic acid. Flow rate 1 mL/min and detection at 280 nm.
  • PDA Photo diode array
  • Plasma concentration-time plot clearly demonstrates enhanced absorption, bioavailability and improved pharmacokinetics (Area under curve, time taken for maximum absorption, longer duration of existence in plasma as clear from the elimination half-life ) of the formulation SBB-20 as compared to the unformulated Boswellia extract rich in AKBA.
  • Fig. 7 shows the plasma concentration-time plot of AKBA after the oral administration of SBB- 20 and unformulated Boswellia serrata extract (BSE) rich in AKBA (BSE).
  • BSE Boswellia serrata extract
  • Example 15 Comparative bioavailability studies of SBT-20 prepared with F-GAL, P-GAL and G-GAL Water dispersible formulations of Turmerone rich turmeric oil was prepared as explained in example 4A and were investigated for bioavailability as mentioned in example 14. It was found that the relative enhancement in bioavailability with respect to the unformulated turmerone rich turmeric oil was highest for F-GAL based formulation (9.2 fold) as compared to P-GAL (3.1 fold) and G-Gal (1.7- fold). The data demonstrate the uniqueness of fenugreek galactomannans in enhancing the bioavailability of the lipophilic substances when converted to hydrophilic powders. The results as shown in Fig 8.

Landscapes

  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

Les compositions de la présente invention sont utilisées pour améliorer la biodisponibilité de substances bioactives lipophiles faiblement solubles ou faiblement biodisponibles. Les substances bioactives sont encapsulées dans des compositions de fibres de fenugrec pour former des compositions de poudre hydrophile. La fibre de fenugrec de qualité spéciale possède une capacité de rétention lipophile élevée et assure en outre la libération régulière de substances bioactives. La présente invention concerne en outre un procédé de préparation de substances bioactives lipophiles en poudre.
PCT/IB2017/056932 2016-11-07 2017-11-06 Approche écologique de l'amélioration de la biodisponibilité d'huiles, de graisses et d'autres substances bioactives lipophiles et compositions associées WO2018083677A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201641015898 2016-11-07
IN201641015898 2016-11-07

Publications (1)

Publication Number Publication Date
WO2018083677A1 true WO2018083677A1 (fr) 2018-05-11

Family

ID=62075930

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2017/056932 WO2018083677A1 (fr) 2016-11-07 2017-11-06 Approche écologique de l'amélioration de la biodisponibilité d'huiles, de graisses et d'autres substances bioactives lipophiles et compositions associées

Country Status (1)

Country Link
WO (1) WO2018083677A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110464815A (zh) * 2019-06-26 2019-11-19 广州市康伦生物技术有限公司 一种新型姜黄复合固体制剂及其制备方法
WO2020030612A1 (fr) * 2018-08-06 2020-02-13 Naturex S.A. Utilisations de compositions de curcuminoïdes
WO2020030611A1 (fr) * 2018-08-06 2020-02-13 Naturex S.A. Compositions de curcuminoïdes
WO2022055985A1 (fr) * 2020-09-08 2022-03-17 Nutrativa Llc Matrices solubles

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1993365A2 (fr) * 2006-03-06 2008-11-26 The Regents of the University of California Formulations de curcuminoïde biodisponibles pour traiter la maladie d'alzheimer et d'autres troubles associés à l'âge
US8785380B2 (en) * 2011-02-01 2014-07-22 M/S Akay Flavours & Aromatics Pvt Ltd. Formulation containing curcuminoids exhibiting enhanced bioavailability

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1993365A2 (fr) * 2006-03-06 2008-11-26 The Regents of the University of California Formulations de curcuminoïde biodisponibles pour traiter la maladie d'alzheimer et d'autres troubles associés à l'âge
US8785380B2 (en) * 2011-02-01 2014-07-22 M/S Akay Flavours & Aromatics Pvt Ltd. Formulation containing curcuminoids exhibiting enhanced bioavailability

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020030612A1 (fr) * 2018-08-06 2020-02-13 Naturex S.A. Utilisations de compositions de curcuminoïdes
WO2020030611A1 (fr) * 2018-08-06 2020-02-13 Naturex S.A. Compositions de curcuminoïdes
CN112566630A (zh) * 2018-08-06 2021-03-26 纳图瑞克斯有限公司 类姜黄色素组合物的用途
CN112566511A (zh) * 2018-08-06 2021-03-26 纳图瑞克斯有限公司 类姜黄色素组合物
JP2021533750A (ja) * 2018-08-06 2021-12-09 ナチュレックス エスアーNaturex Sa クルクミノイド組成物
CN110464815A (zh) * 2019-06-26 2019-11-19 广州市康伦生物技术有限公司 一种新型姜黄复合固体制剂及其制备方法
WO2022055985A1 (fr) * 2020-09-08 2022-03-17 Nutrativa Llc Matrices solubles

Similar Documents

Publication Publication Date Title
Choi et al. Nanoemulsions as delivery systems for lipophilic nutraceuticals: Strategies for improving their formulation, stability, functionality and bioavailability
Pinto et al. Design of multifunctional nanostructured lipid carriers enriched with α-tocopherol using vegetable oils
Hasan et al. Liposome encapsulation of curcumin: physico-chemical characterizations and effects on MCF7 cancer cell proliferation
WO2018083677A1 (fr) Approche écologique de l'amélioration de la biodisponibilité d'huiles, de graisses et d'autres substances bioactives lipophiles et compositions associées
Avachat et al. Self nanoemulsifying drug delivery system of stabilized ellagic acid–phospholipid complex with improved dissolution and permeability
Lammari et al. Plant oils: From chemical composition to encapsulated form use
Rodriguez et al. Enhanced bioactivity and efficient delivery of quercetin through nanoliposomal encapsulation using rice bran phospholipids
da Silva Stefani et al. Nanoencapsulation of linseed oil with chia mucilage as structuring material: Characterization, stability and enrichment of orange juice
Krishnakumar et al. An enhanced bioavailable formulation of curcumin using fenugreek-derived soluble dietary fibre
Comunian et al. Enhancing stability of echium seed oil and beta-sitosterol by their coencapsulation by complex coacervation using different combinations of wall materials and crosslinkers
US20160151440A1 (en) A Novel Composition of Curcumin with Enhanced Bioavailability
Hee et al. Production of virgin coconut oil microcapsules from oil-in-water emulsion with supercritical carbon dioxide spray drying
Istrati et al. Phyto-mediated nanostructured carriers based on dual vegetable actives involved in the prevention of cellular damage
WO2005067894A1 (fr) Billes stables de nutriments lipophiles
CN102405046A (zh) 表现出抗炎性质的药物组合物
Ahmad et al. Omega-3 fatty acids as adjunctive therapeutics: prospective of nanoparticles in its formulation development
US20240050381A1 (en) Complexes comprising collagen peptides and curcuminoids and compositions thereof
JP2013202005A (ja) クルクミン類含有油脂およびその製造方法
JP2022509463A (ja) 非クルクミノイドの水溶性粒子とクルクミノイドの水溶性粒子から構成される製剤
Abdullah et al. Recent advances in the extraction, chemical composition, therapeutic potential, and delivery of cardamom phytochemicals
WO2016077454A1 (fr) Composition à base de particules lipidiques solides stables permettant une meilleure biodisponibilité des composés lipophiles pour le traitement des maladies liées à l'âge
Gulzar et al. Nanoliposome powder containing shrimp oil increases free flowing behavior and storage stability
Ben-Othman et al. Phytochemical characterization of oil and protein fractions isolated from Japanese quince (Chaenomeles japonica) wine by-product
WO2015022454A1 (fr) Nouveau systeme solide instantane auto-emulsionnant a base de cyclodextrines et d'huile (s) pour l'administration orale
de Freitas Santos et al. Application of spray drying, spray chilling and the combination of both methods to produce tucumã oil microparticles: characterization, stability, and β-carotene bioaccessibility

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17867276

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17867276

Country of ref document: EP

Kind code of ref document: A1