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WO2018211380A1 - Compositions de curcuminoïdes - Google Patents

Compositions de curcuminoïdes Download PDF

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Publication number
WO2018211380A1
WO2018211380A1 PCT/IB2018/053285 IB2018053285W WO2018211380A1 WO 2018211380 A1 WO2018211380 A1 WO 2018211380A1 IB 2018053285 W IB2018053285 W IB 2018053285W WO 2018211380 A1 WO2018211380 A1 WO 2018211380A1
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Prior art keywords
composition
curcuminoids
compositions
curcuminoid
dissolution
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PCT/IB2018/053285
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English (en)
Inventor
Vaibhavi SHAH
Vijayendrakumar REDASANI
Vijaykumar SOMANI
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Inventia Healthcare Private Limited
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Publication of WO2018211380A1 publication Critical patent/WO2018211380A1/fr

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    • 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
    • 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
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to compositions comprising one or more curcuminoids, and at least one dissolution enhancer, exhibiting improved dissolution, and a process for the preparation thereof.
  • Curcuminoids are practically insoluble in water at acidic and neutral pH , and rapidly decompose at alkaline pH. Various attempts have been made in prior art to improve the solubility of curcuminoids.
  • US Patent 9,504,754 and US Patent Publication No. US 2018/0064821 provide curcuminoid formulations comprising: nanoparticles or microparticles loaded with curcuminoid-polymer complex, comprising at least one curcuminoid component; at least one polymer or co-polymer component having a backbone comprising polymethacrylate or methyl methacrylate; and a surfactant component, wherein the curcuminoid-polymer complex is formed by a process comprising: dissolving the curcuminoid component and the polymer or co-polymer component, in an organic solvent, to form a curcuminoid- polymer solution; adding the curcuminoid-polymer solution to an aqueous solution having the surfactant to precipitate the curcuminoid-polymer complex and form a dispersion of the complex; and removing the organic solvent from the dispersion to collect the curcuminoid-polymer complex.
  • US Patent Publication No. US 201 3/0303628 A1 provides a melt-processed solid dispersion product comprising one or more curcuminoids, a nutritionally acceptable thermoplastic polymer, and a phosphatide (like glycerophospholipids, phosphoglycerides, phosphatidylcholines, lecithin).
  • a phosphatide like glycerophospholipids, phosphoglycerides, phosphatidylcholines, lecithin.
  • US Patent Publication No. US 2010/0316631 A1 illustrates the design and synthesis of a novel class of water soluble curcumin-based compounds wherein the curcumin-based compound is chemically conjugated to at least one solubilizing agent selected from the group consisting of: poly(ethylene glycol) (PEG), derivatives of PEG, poly(substituted-2- oxazoline) (POZ), derivatives of POZ, an amino acid, a polypeptide and an antibody.
  • PEG poly(ethylene glycol)
  • POZ poly(substituted-2- oxazoline)
  • US Patent 8,568,815 B2 relates to methods of solubilizing curcumin by forming cyclodextrin complexes.
  • the patent discloses methods of manufacturing curcumin complexes using steps of contacting curcumin with cyclodextrin, in an aqueous phase at a pH of at least 1 1 to form a solution of curcumin and cyclodextrin, lowering the pH of said solution to below pH 8, and recovering the solution thus obtained containing the cyclodextrin complex of curcumin, said complex being dissolved in the aqueous phase.
  • Avinash et. al. disclose solid dispersions of curcumin using Eudragit EPO, prepared using the spray drying and the rota-evaporation technique, using organic solvents or aqueous solvents, and surfactants like CremophoreTM RH 40 and TweenTM 80 (Avinash B. Gangurde, Harish S. Kundaikar, Sharadchandra D. Javeer, Divakar R. Jaiswar, Mariam S. Degani, Purnima D. Amin, Journal of Drug Delivery Science and Technology 2015 29:226-237).
  • Jinglei et. al. disclose solid dispersions of curcumin with Eudragit EPO using the solution mixing technique wherein Eudragit® EPO is dissolved in pH 4.5 sodium acetate buffer solution, and curcumin acetone solution is dropped into the Eudragit® EPO solution under magnetic stirring. Acetone is removed by rotary evaporation and curcumin-Eudragit® EPO powder is retrieved after lyophilization.
  • curcuminoids like solubilization, solid dispersions, conjugation, micelle formation, microencapsulation, nanoparticle formation, self- emulsifying delivery system (SMEDDS) formation, microemulsification, nanoemulsification and cyclodextrin complexation.
  • SMEDDS self- emulsifying delivery system
  • the techniques used in prior art use multi-step processes which are complex and long, use high molecular weight cyclodextrins, surfactants, lipids, fats, oils and/or organic/aqueous solvents. This reduces their practical and commercial utility.
  • the present invention provides curcuminoids compositions comprising at least one curcuminoid and at least one dissolution enhancer, the said compositions exhibiting improved dissolution.
  • the present invention provides a method of said compositions being with minimal excipients, and using a simple, yet effective process.
  • the object of the present invention is to provide compositions comprising one or more curcuminoids, and at least one dissolution enhancer.
  • Another object of the present invention is to provide compositions comprising one or more curcuminoids, and at least one dissolution enhancer, wherein the one or more curcuminoids exhibit improved dissolution.
  • Another object of the present invention is to provide orally bioavailable compositions comprising one or more curcuminoids, and at least one dissolution enhancer.
  • Another object of the present invention is to provide stable compositions comprising one or more curcuminoids, and at least one dissolution enhancer.
  • Yet another object of the invention is to provide compositions, comprising one or more curcuminoids, and at least one dissolution enhancer, the compositions being substantially free of surfactants.
  • Yet another object of the invention is to provide compositions, comprising one or more curcuminoids, and at least one dissolution enhancer, the compositions being free of oils, fats, lipids and/or the like.
  • Yet another object of the invention is to provide compositions comprising one or more curcuminoids and at least one dissolution enhancer, with a dissolution of at least 50% in 60 minutes when analyzed in 900 ml of purified water containing 1 % sodium lauryl sulphate at 37°C, using USP apparatus II (paddle), at 1 00 revolutions per minute.
  • Yet another object of the invention is to provide a process for preparation of said compositions comprising one or more curcuminoids, and at least one dissolution enhancer.
  • Another object of the invention is to provide a process for preparation of said compositions which does not use solvents.
  • Yet another object of the invention is to provide a process for preparation of said compositions which does not use surfactants.
  • Yet another object of the invention is to provide a process for preparation of said compositions which does not use oils, fats, lipids and/or the like.
  • Curcuminoids are diaryl heptanoid derivatives isolated from Turmeric, a member of the ginger family (Zingiberaceae). The three major curcuminoids present in Turmeric are: curcumin, desmethoxycurcumin, and bisdesmethoxycurcumin. Curcumin is the principal curcuminoid of Turmeric. Curcuminoids are polyphenols and are responsible for the yellow color of turmeric. Curcuminoids have been suggested for a variety of therapeutic and prophylactic applications.
  • curcuminoids have a variety of biological activities and pharmacological actions, such as anti-cancer, anti-viral, anti-arthritic, anti-amyloid, antioxidant, anti-inflammatory, anti-obesity, anti-depressant, improves symptoms of neurodegenerative diseases like Parkinson's, Alzheimer's, and Huntington's, improves brain function/health, improving mental health, lowers the risk of brain and heart diseases, regulates cholesterol, lowers the risk of atherosclerosis, improves cardiovascular function, prevents blood clots, improves symptoms of inflammatory bowel disease, improves symptoms of gastrointestinal conditions like constipation/dyspepsia/gastric ulcers/ulcerative colitis/pancreatitis, prevents cystic fibrosis, reduces pain and soreness in post-surgical recovery, relieves symptoms of menstruation, lowers the risk of diabetes, promotes liver health, delays aging, promotes skin and ocular health, and benefits sports nutrition by lowering oxidative stress in muscles, enhancing recovery
  • curcuminoids In spite of these wide span of activities, a major impediment in the development of curcumin formulations is its low bioavailability when administered orally.
  • the therapeutic efficiency of curcuminoids has been highly limited due to poor solubility in water (the maximum solubility was reported to be 1 1 ng/ml in plain aqueous buffer pH 5.0).
  • Low bioavailability of curcuminoids after oral delivery is attributed to poor aqueous solubility, poor absorption, high pre-systemic metabolism in gastrointestinal tract (GIT), low stability due to degradation in GIT at neutral and alkaline pH, and rapid systemic metabolism to sulfate and glucuronide conjugates leading to short half-life. It has been reported that serum levels in humans after an oral dose of 2g curcumin alone were either undetectable or very low.
  • curcuminoids is used herein to mean curcumin (diferuloylmethane), desmethoxycurcumin, or bisdesmethoxycurcumin, including their polymorphs, hydrates, solvates, derivatives and mixtures thereof.
  • Curcuminoids may be isolated from natural sources like the roots or rhizomes, of plants such as curcuma longa, curcuma amada, curcuma angustifolra, curcuma caesia, curcuma zedoaria, curcuma caulina, curcuma aromatics, curcuma wenyjuin, curcuma xanfhorrhiza roxb, or may be synthetic curcuminoids, or may be curcuminoid derivatives.
  • the one or more curcuminoids in the composition may be in their crystalline form or in the amorphous form or as mixtures of crystalline and amorphous forms.
  • the curcuminoid(s) may be present in concentrations from 5% to 85% by weight of the composition, preferably in concentrations from 10% to 60% by weight of the composition, more preferably in concentrations from 15% to 50% by weight of the composition, and most preferably in concentrations from 20% to 45% by weight of the composition.
  • the curcuminoid(s) is present in concentrations from 1 5% to 65% by weight of the composition.
  • compositions comprising one or more curcuminoids and at least one dissolution enhancer.
  • One embodiment provides compositions comprising one or more curcuminoids and at least one dissolution enhancer, exhibiting improved dissolution.
  • compositions comprising one or more curcuminoids and at least one dissolution enhancer, the said compositions being orally bioavailable.
  • compositions comprising one or more curcuminoids and at least one dissolution enhancer, the said compositions being stable.
  • compositions comprising one or more curcuminoids in an amorphous form.
  • Dissolution enhancers are selected from polymethacrylates like poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1 :2:1 ; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.2 ; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.1 , or mixtures thereof.
  • polymethacrylates like poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1 :2:1 ; poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.2 ; poly(ethyl acrylate, methyl methacrylate, tri
  • the polymethacrylate is poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1 :2:1 (commercially available as Eudraguard® Protect).
  • the dissolution enhancer is pre-treated with an acid.
  • the dissolution enhancer(s) may be present in concentrations from 15% to 95% by weight of the composition, preferably in concentrations from 40% to 90% by weight of the composition, more preferably in concentrations from 50% to 85% by weight of the composition, and most preferably in concentrations from 55% to 80% by weight of the composition.
  • the ratio of the curcuminoid(s) and the dissolution enhancer(s) may range from 1 :0.25 to 1 :10. Preferably the ratio of the curcuminoid(s) and the dissolution enhancer(s) may range from 1 :0.5 to 1 :5. More preferably the ratio of the curcuminoid(s) and the dissolution enhancer(s) may range from 1 :0.5 to 1 :1 .
  • the composition comprises at least one curcuminoid, at least one dissolution enhancer and at least one monosaccharide sugar alcohol.
  • Monosaccharide sugar alcohols are selected from mannitol, sorbitol, xylitol or ribitol.
  • Preferred monosaccharide sugar alcohol is mannitol.
  • Monosaccharide sugar alcohol (s) may be present from 5% to 75% by weight of the composition.
  • the ratio of the curcuminoid(s) and the monosaccharide sugar alcohol(s), may range from 1 0:1 to 1 :10, more preferably the ratio may range from 6:1 to 1 :6.
  • the ratio of the curcuminoid(s), the dissolution enhancer(s) and the monosaccharide sugar alcohol(s) ranges from 1 : 0.5: 0.25 to 1 : 5: 6.
  • the composition comprises at least one curcuminoid, at least one dissolution enhancer and at least one organic acid.
  • Organic acids are selected from citric acid, fumaric acid, ascorbic acid, lactic acid, malonic acid, succinic acid, gluconic acid, maleic acid, malic acid, tartaric acid, benzoic acid, and derivatives thereof.
  • organic acids are citric acid, tartaric acid, maleic acid, and/or ascorbic acid.
  • Organic acid(s) may be present from 1 % to 50% by weight of the composition. Preferably they may be present from 5% to 40% by weight of the composition.
  • the ratio of the curcuminoid(s) and the organic acid(s) may range from 5: 1 to 1 : 5, more preferably from 3: 1 to 1 : 3, and most preferably from 2: 1 to 1 : 2.
  • the ratio of the curcuminoid(s), the dissolution enhancer(s) and the organic acid(s) ranges from 1 : 0.5: 0.5 to 1 : 5: 1 .5.
  • the ratio of the curcuminoid(s), the dissolution enhancer(s), the monosaccharide sugar alcohol(s) and the organic acid(s) ranges from 1 : 0.5: 0.25: 0.5 to 1 : 5: 6: 1 .5.
  • the compositions comprise one or more curcuminoids, and at least one dissolution enhancer, the said compositions being substantially free of surfactants.
  • compositions comprising one or more curcuminoids, and at least one dissolution enhancer, the said compositions being free of oils, fats, lipids and/or the like.
  • compositions of the present invention may optionally comprise at least one excipient selected from the group of diluents, binders, disintegrants, lubricants, and glidants.
  • the diluents are selected from diluents known in the art, such as microcrystalline cellulose, silicified microcrystalline, cellulose, powdered cellulose, microfine cellulose, corn starch, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, or mixtures thereof.
  • the diluents may also be selected from glucose, lactose, sucrose, dextrose, fructose, compressible sugar, or mixtures thereof.
  • the diluents may be present in concentrations from 0.1 % to 70% by weight of the composition. Preferably, the diluents may be present in concentrations from 5% to 50% by weight of the composition.
  • the binders are selected from the group of cellulose derivatives such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), ethylcellulose, carboxymethylcellulose (CMC), sodium CMC, potassium CMC, calcium CMC, methylcellulose, hydroxyethyl cellulose (HEC), microcrystalline cellulose; polyvinylpyrrolidone (PVP), vinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, starch, carbomer, gums like xanthan gum, guar gum, acacia, locust bean gum, alginates, or mixtures thereof.
  • HPMC hydroxypropylmethyl cellulose
  • HPC hydroxypropyl cellulose
  • CMC carboxymethylcellulose
  • the binders may be present in concentrations from 1 % to 50% by weight of the composition. Preferably, the binders may be present in concentrations from 5% to 25% by weight of the composition.
  • the disintegrants are selected from sodium starch glycolate, crospovidone, croscarmellose sodium, croscarmellose calcium, croscarmellose potassium, sodium carbonate, sodium hydrogen carbonate, calcium carbonate, starch, starch 1500, modified starch, pregelatinized starch, crosslinked carboxymethyl starch, sodium hydrogen carbonate, hydroxypropyl cellulose, sodium carboxymethylcellulose or mixtures thereof.
  • the disintegrants may be present in concentrations from 1 % to 25% by weight of the composition. Preferably, the disintegrants may be present in concentrations from 5% to 20% by weight of the composition.
  • the lubricants are selected from magnesium stearate, calcium stearate, sodium benzoate, talc, or mixtures thereof.
  • the lubricants may be present in concentrations from 0.25% to 5% by weight of the composition.
  • the glidants are selected from suitable glidants known in the art.
  • An example of a suitable, acceptable glidant is colloidal silicon dioxide.
  • the glidants may be present in concentrations from 0.1 % to 10% by weight of the composition.
  • the acids may be selected from commonly used acids including hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, acetic acid, citric acid, formic acid, gluconic acid, lactic acid, oxalic acid, tartaric acid, ascorbic acid, maleic acid, malic acid, malonic acid, succinic acid, fumaric acid, benzoic acid, or their derivatives.
  • compositions of the invention preferably in the form of tablets, capsules, powders, granules, beads, pellets, lozenges, and pastilles, may optionally be coated with a film coating layer comprising film coating materials, and optionally comprising plasticizers, colorants, pigments, lubricants, and diluents.
  • the invention also provides a process for preparation of said compositions.
  • compositions comprise one or more curcuminoids, and at least one dissolution enhancer, the said compositions being prepared by a process that does not use surfactants.
  • compositions of the present invention comprise one or more curcuminoids, and at least one dissolution enhancer, the said compositions being prepared by a process that does not use oil, fats, lipids and/or the like.
  • the one or more processes that can be used to manufacture the compositions of the present invention include sifting, mixing, heating, melting, cooling, extruding, and milling. Processes like granulation, compression, compaction, spraying, coating, layering, and filling into capsules may further be used to manufacture the compositions.
  • a composition comprising one or more curcuminoids, and at least one dissolution enhancer, is prepared as follows: curcuminoid(s) is mixed with dissolution enhancer(s), and optionally with one or more monosaccharide sugar alcohols, and/or one or more organic acids, and optionally with one or more diluents, binders, disintegrants, lubricants, and/or glidants, to obtain a mixture.
  • the mixture is heated in a hot melt extruder to obtain a molten mass.
  • the molten mass is extruded to obtain extrudates.
  • the extrudates are cooled and milled to obtain the curcuminoid composition.
  • the cooled and milled extrudates may further be mixed with at least one monosaccharide sugar alcohol, and/or at least one organic acid to give curcuminoid compositions.
  • the cooled and milled extrudates may further be mixed with diluents, binders, disintegrants, lubricants, and/or glidants to give curcuminoid compositions.
  • the curcuminoid compositions may further be processed by granulation, compression, compaction, spraying, coating, layering, or filling to provide tablet or capsule dosage forms.
  • One embodiment of this invention provides curcuminoid compositions that are prepared by a process that does not use solvents. Another embodiment of this invention provides a process for preparation of curcuminoid compositions that does not use solvents.
  • Yet another embodiment of this invention provides a process for preparation of said compositions, comprising one or more curcuminoids that does not use organic solvents.
  • Yet another embodiment of this invention provides a process for preparation of said compositions, comprising one or more curcuminoids that does not use aqueous solvents.
  • the ratio of the curcuminoid(s) and the monosaccharide sugar alcohol(s), in the extrudates may range from 1 : 0.1 to 1 : 5, more preferably from 1 : 0.1 to 1 : 2.5, and most preferably from 1 : 0.2 to 1 : 1 .
  • the compositions of the present invention can be used in oral, topical or parenteral administration.
  • compositions can be used in the form of tablets, capsules, powders, granules, beads, pellets, lozenges, pastilles, syrups, elixirs, solutions, suspensions, dispersions, emulsions and the like.
  • compositions were analyzed for their dissolution in accordance with the recommendation of Dietary Supplements Compendium (DSC) 2015, United States pharmacopeia (USP) using the following conditions: 900 ml of purified water containing 1 % sodium lauryl sulphate, USP apparatus II (paddle) at 100 revolutions per minute, 37°C.
  • DSC Dietary Supplements Compendium
  • USP United States pharmacopeia
  • compositions of the present invention were formulated to exhibit a cumulative dissolution of:
  • curcuminoids • more preferably not less than 50% by weight of curcuminoids in 45 minutes
  • curcuminoids • more preferably not less than 50% by weight of curcuminoids in 30 minutes and
  • compositions of the present invention were formulated to exhibit a cumulative dissolution of:
  • curcuminoids • most preferably not less than 70% by weight of curcuminoids in 30 minutes.
  • compositions of the present invention were formulated to exhibit a cumulative dissolution of:
  • curcuminoids • preferably not less than 80% by weight of curcuminoids in 60 minutes
  • curcuminoids • more preferably not less than 80% by weight of curcuminoids in 45 minutes.
  • compositions of the present invention were formulated to exhibit a cumulative dissolution of:
  • curcuminoids • more preferably not less than 90% by weight of curcuminoids in 60 minutes.
  • Curcuminoid powder (containing not less than 95% curcuminoids) (21 .04%), poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) (21 .04%), citric acid monohydrate (28.84%) and mannitol (SD 200) (10.64%) were sifted through 30 mesh ASTM and mixed for 10 minutes to give a mixture. The mixture was hot melt extruded under the conditions mentioned in Table 1 .
  • the extrudates were cooled and milled in a co-mill (1 mm sieve) to give the extrudate powder.
  • the extrudate powder was sifted through 30 mesh ASTM. Mannitol 200 SD (10.64%) and anhydrous colloidal silica (7.8%) were sifted through 30 mesh ASTM.
  • the extrudate powder was blended with the sifted mannitol and anhydrous colloidal silica in a blender for 1 0 minutes to give the powder composition.
  • the powder composition equivalent to 50mg of curcuminoids was filled in HPMC capsules of size 00.
  • a Physical mixture of the ingredients used in example 1 was prepared by sifting the individual ingredients through 30 mesh ASTM and blending them for 10 minutes.
  • Curcuminoid powder (containing not less than 95% curcuminoids) (50%), and poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) (50%), were sifted through 30 mesh ASTM and blended for 10 minutes to give a mixture.
  • the mixture was hot melt extruded using conditions similar to example 1 .
  • the extrudates were cooled and milled in a co-mill (1 mm sieve) to give the extrudate powder.
  • the extrudate powder was sifted through 30 mesh ASTM to give the powder composition.
  • Curcuminoid powder (containing not less than 95% curcuminoids) (10.52%), poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) (10.52%), citric acid (1 2.02%) and Mannitol 200 SD (5.32%) were sifted through 30 mesh ASTM and mixed for 1 0 minutes to give a mixture.
  • the mixture was hot melt extruded using the conditions mentioned in table 2.
  • the extrudates were cooled and milled in a co-mill (1 mm sieve) to give the extrudate powder.
  • the extrudate powder was sifted through 30 mesh ASTM.
  • Curcuminoid powder (containing not less than 95% curcuminoids) (42.08%), poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) (21 .04%), citric acid (21 .04%) and mannitol 200 SD (14.00%) were sifted through 30 mesh ASTM and mixed for 1 0 minutes to give a mixture.
  • the mixture was hot melt extruded using the same conditions as example 3.
  • the extrudates were cooled and milled in a co-mill (1 mm sieve) to give the extrudate powder.
  • the extrudate powder was sifted through 30 mesh ASTM.
  • Anhydrous colloidal silica (1 .84%) was sifted through 30 mesh ASTM.
  • the extrudate powder was mixed with the sifted anhydrous colloidal silica in a blender for 10 minutes to give the powder composition.
  • the powder composition equivalent to 50mg of curcuminoids was filled in HPMC capsules of size 00.
  • Curcuminoid powder (containing not less than 95% curcuminoids) (1 2.34%) and mannitol 200 SD (12.34%) were sifted through 30 mesh ASTM, and mixed with the acid pre-treated poly(butyl methacrylate, (2- dimethylaminoethyl) methacrylate, methyl methacrylate) for 10 minutes to give a mixture.
  • the mixture was hot melt extruded similar to example 3.
  • the extrudates were cooled and milled in a co-mill (1 mm sieve) to give the extrudate powder.
  • the extrudate powder was sifted through 30 mesh ASTM.
  • Anhydrous colloidal silica (1 .23%) was sifted through 30 mesh ASTM.
  • the extrudate powder was mixed with the sifted anhydrous colloidal silica in a blender for 10 minutes to give the powder composition.
  • the powder composition equivalent to 50mg of curcuminoids was filled in HPMC capsules of size 00.
  • Curcuminoid powder (95%), the physical mixture of example 1 , the powder composition of examples 1 to 5, all equivalent to 50 mg of curcuminoids, were analyzed for dissolution of curcuminoids at conditions mentioned earlier. The results of the same are given in Table 4.
  • compositions of the present invention comprising curcuminoid powder 95% and at least one dissolution enhancer (examples 1 to 5), prepared through the hot melt technology, exhibit a significantly higher rate and extent of dissolution, when compared to either curcuminoid powder 95% alone or the physical mixture.
  • compositions of example 1 were subjected to stability studies.
  • the capsules of example 1 were packed in HDPE bottles with 1 g silica, and Alu-Alu blister. Both packs were subjected to storage conditions of 40°C and 75% relative humidity (RH) , and 25°C and 60% relative humidity (RH), for a period of six months.
  • RH relative humidity
  • RH 25°C and 60% relative humidity
  • the compositions were studied for their dissolution at 3 and 6 months, using the conditions mentioned in DSC 2015 (USP).
  • Table 6 and 7 shows the dissolution of the compositions at 60 minutes after storage for at 3 and 6 months.
  • a stable curcuminoid composition does not differ in its dissolution from the initial by more than 15%, preferably not more than 10% and more preferably not more than 5%, when stored at 40°C/75% RH for at least 6 months.
  • Table 6 Dissolution at 3 and 6 months after storage at 40°C/75% RH
  • the stability data in table 6 and 7 clearly illustrates that present invention provide stable curcuminoid compositions, the said compositions comprising one or more curcuminoids and at least one dissolution enhancer.
  • the initial dissolution (0 month) of the composition at 60 minutes and its dissolution at 60 minutes after storage at 40°C/75% RH and 25°C/60% RH storage conditions do not differ by more than 1 5%, at both 3 months and 6 months.
  • Dissolution of the composition of example 1 after storage at 40°C/75% RH and 25°C/60%RH , was found to be not less than 85% in 60 minutes, at both 3 months and 6 months.
  • example 1 of the present invention An open label, randomized, single oral dose, in-vivo study of example 1 of the present invention was conducted in normal, healthy, adult, human subjects under fasting conditions. The subjects were dosed with 6 x 250 mg capsules. Blood samples were collected from the subjects pre-dosing and at regular intervals of time post-dosing. The blood plasma were analyzed for free curcumin, total curcumin, total demethoxycurcumin, total bisdemethoxycurcumin and total tetrahydrocurcumin.
  • Tmax maximum plasma concentrations
  • Cmax maximum plasma concentrations
  • the curcuminoids from the compositions of the present invention exhibit rapid absorption, measured as the time to reach maximum plasma concentrations (Tmax) values.
  • Tmax maximum plasma concentrations
  • the present invention provides curcuminoid compositions with improved dissolution, said compositions being stable and orally bioavailable.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des compositions comprenant un ou plusieurs curcuminoïdes et au moins un activateur de dissolution. Lesdites compositions permettent une dissolution améliorée et sont sensiblement exemptes de tensioactifs. Lesdites compositions sont stables et biodisponibles par voie orale. La présente invention concerne également un procédé de préparation des compositions comprenant un ou plusieurs curcuminoïdes et au moins un activateur de dissolution. Ledit procédé n'utilise pas de solvants.
PCT/IB2018/053285 2017-05-17 2018-05-11 Compositions de curcuminoïdes WO2018211380A1 (fr)

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CN110075071A (zh) * 2019-05-22 2019-08-02 中北大学 一种姜黄素固体分散体的制备方法
WO2021111312A1 (fr) * 2019-12-03 2021-06-10 Omniactive Health Technologies Limited Compositions de curcumine pour l'ostéoarthrite et le bien-être articulaire
JP2022502418A (ja) * 2018-09-26 2022-01-11 インベンティア ヘルスケア リミテッド クルクミノイドコンポジット

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US20130029905A1 (en) * 2011-02-01 2013-01-31 M/S Akay Flavours & Aromatics Pvt Ltd Formulation containing curcuminoids exhibiting enhanced bioavailability
US20140010903A1 (en) * 2012-07-04 2014-01-09 Akay Flavours & Aromatics Pvt Ltd. Curcuminoid composition with enhanced bioavailability and a process for its preparation
EP3035947A1 (fr) * 2013-08-19 2016-06-29 Aurea Biolabs Private Limited Nouvelle composition de curcumine à biodisponibilité améliorée

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US20130029905A1 (en) * 2011-02-01 2013-01-31 M/S Akay Flavours & Aromatics Pvt Ltd Formulation containing curcuminoids exhibiting enhanced bioavailability
US20140010903A1 (en) * 2012-07-04 2014-01-09 Akay Flavours & Aromatics Pvt Ltd. Curcuminoid composition with enhanced bioavailability and a process for its preparation
EP3035947A1 (fr) * 2013-08-19 2016-06-29 Aurea Biolabs Private Limited Nouvelle composition de curcumine à biodisponibilité améliorée

Cited By (10)

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Publication number Priority date Publication date Assignee Title
JP2022502418A (ja) * 2018-09-26 2022-01-11 インベンティア ヘルスケア リミテッド クルクミノイドコンポジット
EP3856220A4 (fr) * 2018-09-26 2022-06-22 Inventia Healthcare Private Limited Composites curcuminoïdes
US11666535B2 (en) * 2018-09-26 2023-06-06 Inventia Healthcare Limited Curcuminoid composites
GB2591679B (en) * 2018-09-26 2023-06-07 Inventia Healthcare Ltd Curcuminoid composites
JP7547324B2 (ja) 2018-09-26 2024-09-09 ニュートリベンティア リミテッド クルクミノイドコンポジット
AU2019350611B2 (en) * 2018-09-26 2025-05-15 Nutriventia Limited Curcuminoid composites
CN110075071A (zh) * 2019-05-22 2019-08-02 中北大学 一种姜黄素固体分散体的制备方法
WO2021111312A1 (fr) * 2019-12-03 2021-06-10 Omniactive Health Technologies Limited Compositions de curcumine pour l'ostéoarthrite et le bien-être articulaire
CN114786699A (zh) * 2019-12-03 2022-07-22 奥米尼埃克蒂夫健康科技有限公司 用于骨关节炎和关节健康的姜黄素组合物
AU2020398079B2 (en) * 2019-12-03 2024-09-19 Omniactive Health Technologies Limited Curcumin compositions for osteoarthritis and joint wellness

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