CN100352430C - Self microemulsifying preparation of curcumin and its preparing process - Google Patents
Self microemulsifying preparation of curcumin and its preparing process Download PDFInfo
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- CN100352430C CN100352430C CNB2005100425479A CN200510042547A CN100352430C CN 100352430 C CN100352430 C CN 100352430C CN B2005100425479 A CNB2005100425479 A CN B2005100425479A CN 200510042547 A CN200510042547 A CN 200510042547A CN 100352430 C CN100352430 C CN 100352430C
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Images
Abstract
The present invention relates to a self micro-emulsifying preparation of curcumin and a preparation technology thereof. The preparation is prepared from curcumin, a surface active agent, cosurfactant, an oil phase and solid sorbent. The preparation can be prepared into capsules or granules for oral administration. After the preparation enters a human body, under the action of gastrointestinal fluid, the preparation can be formed into liquid drops whose nanometer granule diameter is less than 100 nm in a self micro-emulsifying mode, the dissolvability of the curcumin is increased, the absorption of the curcumin in the gastrointestinal tract is promoted, and the biological availability is enhanced.
Description
(1) technical field
The present invention relates to a kind of self microemulsifying preparation of curcumin and preparation method thereof.
(2) background technology
Curcumin (curcumin) is a kind of natural constituent that extracts from rhizome such as Zingiberaceae Curcuma (curcuma L.) plant Rhizoma Curcumae Longae, Rhizoma Curcumae, Radix Curcumae, and molecular formula is C
21H
20O
6Pharmacological evaluation shows curcumin except that having antiinflammatory, anticancer, antioxidation; also have the protection kidney, suppress pulmonary fibrosis, suppress hepatic fibrosis, help the muscle injury reparation, treat multiple pharmacological effect such as cataract, parasiticide disease; and toxic and side effects is little; safe in utilization, good potential applicability in clinical practice is arranged.But curcumin is water-soluble hardly, and the dissolubility in multiple oil is also undesirable, and therefore few through gastrointestinal absorption, oral administration biaavailability is low, and drug administration by injection uses inconvenience, independently administration of patient, poor compliance.Therefore the oral absorption of improving curcumin at present is the bottleneck that enlarges the curcumin clinical practice, makes its further large-scale production.
Microemulsion is exactly stable, the liquid system of size droplet diameter between 10～100nm on homogeneous, the thermodynamics on the optics of being made up of water, oil and amphiphatic molecule, as the oral drugs carrier, microemulsion can increase the dissolubility of hydrophobic drug, improve bioavailability, preparation is simple, do not need the external force effect, only need gentle agitation that the component mix homogeneously can be formed; And good stability, placement, centrifugal all not stratified.The self-emulsifying microemulsion system is by oil, the microemulsion concentrated solution that forms of surfactant, or adds solid absorbent formation solid dispersion on the concentrated solution basis, places water or the gastro-intestinal Fluid can spontaneous formation microemulsion; Compare with microemulsion, self-microemulsion system volume is little, be easy to carry and can further improve stability of drug.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of self microemulsifying preparation of curcumin and preparation method thereof is provided.
Self microemulsifying preparation of curcumin of the present invention, as crude drug, the mixture that adopts surfactant, cosurfactant, oil phase and solid absorbent composition is as pharmaceutical carrier with curcumin, and the each component weight portion is as follows:
100 parts of curcumins, 1500～8000 parts in surfactant, 1500～8000 parts of cosurfactants, 300～6000 parts of oil phases, 3000～8000 parts of solid absorbents.
Above-mentioned surfactant is selected from one of following or their combination: lauric acid sucrose ester, Palmic acid sucrose ester, stearic acid sucrose ester, the fatty acid Pyrusussuriensis is smooth, Polysorbate, Myrj 52, Brij30, Brij35, polyoxyethylene castor oil glycerin ether (ethenoxy unit is 35～40), poloxamer 188, castor oil hydrogenated, lecithin, sodium lauryl sulphate, sodium stearyl sulfate, A Luosuo-OT or dodecylbenzene sodium sulfonate.
Above-mentioned fatty acid Pyrusussuriensis is smooth to be selected from one of following or their combination: the fatty acid Pyrusussuriensis is smooth 20, the fatty acid Pyrusussuriensis is smooth 40, the fatty acid Pyrusussuriensis is smooth 60, the fatty acid Pyrusussuriensis is smooth 65, fatty acid Pyrusussuriensis smooth 80 or fatty acid Pyrusussuriensis smooth 85.
Above-mentioned Polysorbate is selected from one of following or their combination: polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polyoxyethylene sorbitan monoleate or polysorbate 85.
Above-mentioned cosurfactant is selected from one of following or their combination: ethanol, isopropyl alcohol, 1,2-propylene glycol, n-butyl alcohol, n-octyl alcohol, n-heptanol, polyoxyethylene (400) monolaurate, polyoxyethylene (400) monostearate or PEG400.
Above-mentioned oil phase is selected from one of following or their combination: Oleum Arachidis hypogaeae semen, Oleum Glycines, Oleum Ricini, olive oil, Ethyl linoleate, ethyl oleate, medium chain (C
8～18) two caprylates of triglyceride, isopropyl laurate, isopropyl myristate, propyleneglycoles list caprylate, propyleneglycoles or Monooctamoin.
Above-mentioned solid adsorption material is selected from one of following or their combination: ethyl cellulose, Polyethylene Glycol (molecular weight 1000～20000), polyvidone (molecular weight 1000～360000), oxalic acid, lactose, mannitol, sorbitol, cellulose acetate phthalate ester, hypromellose phthalate ester, polyacrylic resin (E, RS, RL), micropowder silica gel or carboxylic first and second celluloses.With Macrogol 4000, polyethylene glycol 6000 and micropowder silica gel is good.
Above-mentioned self microemulsifying preparation of curcumin is granule or capsule.
The preparation method of self microemulsifying preparation of curcumin of the present invention is as follows:
Behind surfactant and cosurfactant mix homogeneously, add oil phase, with stirring, vibration, ultrasonic or vortex mode mixing, form blank microemulsion concentrated solution, add curcumin, fully dissolve curcumin microemulsion concentrated solution.The reuse solid absorbent is done carrier and is made granule, promptly gets self microemulsifying preparation of curcumin.
Above-mentioned make particulate method can be with the method for dissolving, solvent evaporation method, freeze-drying or direct prior art such as pelletize.
The above-mentioned granule branch of making is installed to must granule in the aluminium plastic bag.
With the above-mentioned granule branch of making pack in the capsule shells capsule.
Be the oral absorption and the formation stability of formulation that improve curcumin, the present invention selects the self-emulsifying microemulsion system as pharmaceutical carrier.The selected surfactant of the present invention, cosurfactant and oil phase are the pharmaceutic adjuvant of extensive use on the pharmaceutics, have nontoxic, non-irritating characteristic.By prescription screening and optimization, when three's proportioning was suitable, this mixture self-microemulsion under aqueous conditions formed microemulsion.
The dissolubility of curcumin in water very low (much smaller than 0.7 μ g/ml), the selected surfactant of the present invention, cosurfactant and oil phase, all can improve the dissolubility of curcumin, after preparation self-emulsifying microemulsion in water forms O/W type microemulsion, the dissolubility of curcumin in water brought up to 10～15mg/ml, increases more than 1000 times.The made oral interior back of the body self-microemulsion that enters of self microemulsifying preparation of the present invention forms the microemulsion of particle diameter between 10～100nm, because the microgranule below the particle diameter 100nm is very easily in gastrointestinal absorption, and O/W type microemulsion and gastrointestinal tract have good adhesiveness, so can effectively increase the absorption of medicine, improve bioavailability.
Rat is in the body test for intestinal absorption: the 50ml test liquid is added in the beaker of circulating device, test liquid (1): curcumin surfactant micella solution (the containing curcumin 100mg) 100ml+2mg of Krobs-Ringer test solution preparation is phenol red, test liquid (2): curcumin microemulsion (the containing curcumin 100mg) 100ml+2mg of Krobs-Ringer test solution preparation is phenol red.After the fasting male rat anesthesia at one night, open the abdominal cavity, respectively insert the glass tubing of diameter 0.5cm from duodenal cap and ileum bottom, after cleaning intestinal, open peristaltic pump, test liquid is circulated in intestinal, and timing sampling is also added phenol red solution (every ml Krobs-Ringer test solution contains phenol red 20 μ g).Measure the content of curcumin in the sample liquid, calculate the absorbtivity of curcumin.The result shows: curcumin polyoxyethylene nonylphenol ether micellar solution small intestinal absorbtivity is (32.4 ± 1.8) %, and curcumin microemulsion (prescription is as embodiment 1) small intestinal absorbtivity is (57.6 ± 2.3) %, and microemulsion absorbs and obviously is better than micellar solution.
Self microemulsifying preparation of curcumin preparation is simple, adopts modes such as stirring, vibration, ultrasonic, vortex with each component mixing, and medicine is fully dissolved, get final product curcumin microemulsion concentrated solution.With this concentrated solution and suitable solid absorbent by fusion method, solvent method, freeze-drying or directly be mixed with method such as granule, can make concentrated solution homodisperse in carrier material, can promote the dissolving and the absorption of medicine better, and have the effect that improves medicine stability.
(4) description of drawings
Fig. 1 is the embodiment of the invention 5 curcumin microemulsion electromicroscopic photographs, amplifies 72000 times.
(5) specific embodiment
Embodiment 1:
Take by weighing emulsifying agent-OP (polyoxyethylene nonyl 2, 2-Oxydiphenol, C
34H
62O
11, molecular weight 648.85) and 100g, add curcumin 2.5g, stir, medicine is dissolved fully, add PEG400 35g, ethyl oleate 10g, high-speed stirred makes mix homogeneously, gets curcumin self-emulsifying microemulsion concentrated solution.Got the micropowder silica gel 60g and the mannitol 20g of 100 mesh sieves, behind above-mentioned concentrated solution mix homogeneously, crossed 20 mesh sieves, made granule, 400 of dress hard capsules.
Embodiment 2:
Take by weighing tween 80 100g, add curcumin 3g, be heated to 40 ℃, medicine is dissolved fully, add glycerol 100g, ethyl oleate 10g, high-speed stirred, mix homogeneously gets curcumin self-emulsifying microemulsion concentrated solution.Taking polyethylene glycol 4000 200g, heating in water bath to 70 ℃ fusion is poured above-mentioned concentrated solution rapidly in the Macrogol 4000 behind the mix homogeneously, puts into ice-water bath cooling curing rapidly.The gained solid is pulverized, crossed 18 mesh sieves, make granule, after the drying, the aluminium plastic packaging bag of packing into gets granule 400 bags.
Embodiment 3:
Take by weighing tween 80 200g, PEG400 50g, Oleum Arachidis hypogaeae semen 25g, the high-speed stirred mix homogeneously adds curcumin 2.5g, stirs medicine is dissolved fully, gets curcumin self-emulsifying microemulsion concentrated solution, adds an amount of distilled water, makes to form curcumin microemulsion 1000ml.Got the lactose 200g and the PVP of 80 mesh sieves
K15200g behind above-mentioned microemulsion mix homogeneously, crosses 20 mesh sieves after the lyophilization, make granule.With the granule packing, promptly get granule.
Embodiment 4:
Take by weighing polyoxyethylene nonylphenol ether 100g, add curcumin 3g, the ultrasonic medicine dissolution that makes adds n-octyl alcohol 150g, olive oil 25g, and the high-speed stirred mix homogeneously gets curcumin self-emulsifying microemulsion concentrated solution.Taking polyethylene glycol 6000 400g, ethyl cellulose 100g behind above-mentioned concentrated solution mix homogeneously, crosses 18 mesh sieves, makes granule.
Embodiment 5:
Take by weighing tween 80 300g, dehydrated alcohol 45g, sunflower oil 25g, the high-speed stirred mix homogeneously adds curcumin 3g, stirs medicine is dissolved fully, gets curcumin self-emulsifying microemulsion concentrated solution.Taking polyethylene glycol 6000 400g got the micropowder silica gel 60g and the Macrogol 4000 15g of 100 mesh sieves, behind above-mentioned concentrated solution mix homogeneously, crossed 18 mesh sieves, made granule.
Getting above-mentioned granule, to add simulated intestinal fluid in right amount an amount of, makes principal agent curcumin content be about 3mg/ml, and slight vibration makes its self-emulsifying microemulsion form the microemulsion of clear.The curcumin microemulsion is dropped on the copper mesh phosphotungstic acid with 2% (pH4.47) negative staining, electron microscopic observation behind the natural drying.Microemulsion is spheroidal under Electronic Speculum, and inside is oil phase.Mean diameter is about 50nm, and is most below 100nm.According to the size of Emulsion dispersed phase drop, this Emulsion is microemulsion.
Claims (2)
1, a kind of self microemulsifying preparation of curcumin, as crude drug, the mixture that adopts surfactant, cosurfactant, oil phase and solid absorbent composition is characterized in that as pharmaceutical carrier component is as follows with curcumin:
Curcumin 2.5g,
Polyoxyethylene nonyl 2, 2-Oxydiphenol, C
34H
62O
11, molecular weight 648.85,100g,
PEG400 35g,
Ethyl oleate 10g,
Micropowder silica gel 60g,
Mannitol 20g.
2. self microemulsifying preparation of curcumin as claimed in claim 1 is characterized in that said preparation is granule or capsule.
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| EP2616053A2 (en) * | 2010-09-15 | 2013-07-24 | Cadila Pharmaceuticals Ltd. | Pharmaceutical compositions of curcumin |
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