CN105412046A - Curcumin colon-targeted medicine preparation and preparation method thereof - Google Patents
Curcumin colon-targeted medicine preparation and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a curcumin colon-targeted medicine preparation which comprises a curcumin cyclodextrin inclusion compound, a natural polysaccharide colon-targeted material and an enteric coating material according to a specific ratio. Meanwhile, the invention further discloses a preparation method of the preparation. The preparation method includes the steps that curcumin and cyclodextrin are prepared into the curcumin cyclodextrin inclusion compound according to a proportion; the curcumin cyclodextrin inclusion compound and the natural polysaccharide colon-targeted material are subjected to cross-linking and solidification according to a proportion and are filtered, washed and filtered, and curcumin colon-targeted micelles are obtained; the curcumin colon-targeted micelles are coated with the solution of the enteric coating material, and the curcumin colon-targeted medicine preparation is obtained. The curcumin colon-targeted medicine preparation is developed and prepared through the special method, the defect that curcumin is low in water solubility and poor in stability is overcome, the medicine can be released on colons in a positioning mode, the aim of colon targeting is achieved, and the preparation is simple in technology and easy to use and popularize.
Description
Technical field
The present invention relates to traditional Chinese medicine preparation or its preparation method, specifically a kind of curcumin colon specific drug preparation and preparation method thereof.
Background technology
Colon cancer is one of main malignant tumor of the mankind, 20 century 70s so far, along with the day by day westernization of the progress of Chinese society, the improvement of living condition and people life style, colon cancer rises rapidly in the incidence rate of China, become one of large malignant tumor of China modal 5, seriously endanger the health of the mankind.The inflammatory bowel disease such as ulcerative colitis, clone disease, also has relation with the generation of colon cancer, and both are considered to the precancerous lesion of colon cancer.
Oral colon-specific drug delivery system is that oral route is by the class pharmaceutical preparation of drug delivery to conlon targeting release.After administration, medicine does not discharge at stomach and little enteral, and when being transported to colon, just disintegrate or corrosion, makes the medicine of release concentrate at colon lesions position, and colon is because of its stable environment and highdensity enzymatic activity and close to neutral pH, is suitable for drug absorption.Medicine is longer at the residence time of colon, is also conducive to depot drug product system and plays a role, and can be used for intestinal tract disease such as locality such as treatment colitis, colon cancer etc., also by postponing release method, being used for the treatment of circadian rhythm disease.
Current erodible materials mainly contains 3 types: pH controlled release system, time controlled release system and enzyme flip-over type controlled release system (Bacterialtriggered controlled release system).
PH controlled release system is the feature that the pH utilizing gastrointestinal tract from stomach to colon raises gradually, carries out coating with the various enteric material dissolved under specific pH, medicine is located and is discharged into medicine-feeding part.Due to small intestinal and colon pH closely, and may because colonic pathological change or bacterial action, its pH is lower than small intestinal, so the effectiveness of pH controlled release system is lower, lacks location specificity.
Time controlled release system from stomach, enters colon according to medicine generally to need 3 ~ 4h, by with slightly solubility material coating, makes medicine at arrival colon site just slow releasing.For time controlled release system, initial drug release position depends primarily on drug-supplying system and pass through the time in gastrointestinal tract.Although the small bowel transit time of this drug-supplying system has relative uniformity, gastric retention time difference is very large, and this just makes to have uncertainty by the upper gastrointestinal time.
The principle of enzyme flip-over type controlled release system is: colonic has the antibacterial of many uniquenesses, produce unique enzyme system, many macromolecular materials can by these enzymatic degradation at colon as pharmaceutical carrier, and at the little enteral of harmonization of the stomach owing to lacking corresponding enzyme, can not be degraded, thus make medicine in conlon targeting release.Enzyme flip-over type controlled release system depends on the sharply increase of flora and related enzyme activity in colon, and parenteral route is by time and enteric cavity pH value, therefore compared with other colon-targeted delivery system systems, affect less by diet, disease, individual variation etc., having that release locus specificity is good, the advantage of accurate positioning, is a kind of ideal targeted drug delivery system.At present, the widely used degradable material of enzyme flip-over type controlled release system has azo-compound and natural polysaccharide compounds.Wherein azo-compound is main chain, cross linked chain or side chain contain the polymer of azo bond, can be degraded by the azo reductase that colon exists, but azobenzene polymer biodegradation rate is slow, medicine may be caused to discharge completely, and whether the catabolite of azobenzene polymer have toxicity and need further assessment.And natural polysaccharide compounds not only has colonic enzyme degradability, but also there is abundance, inexpensive, safe, stable and nontoxic advantage, but usually it can be used as that to there will be drug solubility during the carrier of the colon targeting drug administration of medicine low, can not the defect such as release completely.
Curcumin is the phenol sulfonate extracted from zingiberaceous plant rhizome, it is a kind of natural antioxidant, there is function of gallbladder promoting, blood fat reducing, antioxidation, antibacterial, antiinflammatory, the pharmacological action such as anticancer, therefore be widely used in field of medicaments, be considered to one of medicine-food two-purpose natural prodcuts with Development volue.In recent years, there are some researches show curcumin in treatment colitis with also there is certain effect in preventing colon cancer, and external curcumin is used for the treatment of colon cancer II clinical trial phase result and has been reported.But, because curcumin water solublity is low, after preparation oral, because the dissolubility of curcumin in gastro-intestinal Fluid is low, the amount entering blood circulation through biomembrane is few, so its oral administration biaavailability is very low, just can only can play certain therapeutic effect in clinical by increasing dosage; But the increase of dosage will certainly give taking medicine of patient and preparation process brings inconvenience.In addition, the less stable of curcumin, responsive to light and heat, easily decompose in preparation process.Therefore, we are necessary the curcumin peroral dosage form developing a kind of stable in properties, release is complete, targeting is strong very much, think that the treatment of clinical colon cancer and prevention provide more multiplex medicine to select.
Summary of the invention
Object of the present invention is just to provide a kind of curcumin colon specific drug preparation and preparation method thereof, solve that existing curcumin dosage form drug loading is little, medicine stability is low, targeting is poor and the problem such as release is incomplete, think that the treatment of clinical colon cancer and prevention provide more multiplex medicine to select.
The object of the invention is to be achieved through the following technical solutions: a kind of curcumin colon specific drug preparation, comprises curcumin cyclodextrin clathrate, natural polysaecharides Colontargeted materids and enteric-coating material; The mass ratio of described curcumin cyclodextrin clathrate and natural polysaecharides Colontargeted materids is 1:1-10, and the quality of described enteric-coating material is the 3-5% of described curcumin cyclodextrin clathrate and natural polysaecharides Colontargeted materids gross mass;
Described curcumin cyclodextrin clathrate forms primarily of the material of following weight part ratio: curcumin 1 part, cyclodextrin 2-5 part;
Described natural polysaecharides Colontargeted materids is the mixture of any one or two or more arbitrary proportion in chitosan, alginic acid and sodium salt thereof, pectin and derivant thereof, your natural gum, inulin, amylose, cyclodextrin and derivant thereof of melon, chondroitin sulfate, Konjac glucomannan, Rhizoma amorphophalli glucomannan and carob;
Described enteric-coating material comprises the material of following weight part ratio: enteric material 5-20 part, plasticizer 3-5 part, antitackiness agent 6-10 part.
Described cyclodextrin is the mixture of any one or two or more arbitrary proportion in alpha-cyclodextrin and derivant, beta-schardinger dextrin-and derivant thereof and gamma-cyclodextrin and derivant thereof; Described beta-cyclodextrin derivative is HP-β-CD, sulfobutyl ether-beta-cyclodextrin, dihydroxy group-beta-cyclodextrin, methyl-B-cyclodextrin, 2,6-DM-β-CD, 2, the compositions of one or more arbitrary proportions in 3,6-TM-β-CD, carboxymethyl-beta-cyclodextrin, glucosyl-ss-cyclodextrin, glucosulfone group-beta-cyclodextrin, malt sugar group-beta-cyclodextrin etc.
Described enteric material is crylic acid resin, CAP, polyvinyl alcohol phthalate ester, cellulose acetate benzenetricarboxylic acid ester, HP-55, HPMCAM, hypromellose succinate, succinic acid ethyl cellulose, HPMCAS, 1, the mixture of any one or two or more arbitrary proportion in 2,4-benzenetricarboxylic acid hydroxypropyl emthylcellulose, Opadry, Su Teli, Sulisi and Lac.
Described plasticizer is triethyl citrate (TEC), acetylation triethyl citrate, tributyl citrate (THC), glycerol, propylene glycol, polyethylene glycols (PEG), monoacetin, glyceryl diacetate, triacetin, dibutyl sebacate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, Oleum Ricini, Semen Maydis oil, the mixture of any one or two or more arbitrary proportion in fractionated coconut oil and liquid Paraffin.
Described antitackiness agent is the mixture of any one or two or more arbitrary proportion in Pulvis Talci, glyceryl monostearate (GMS), stearic acid, magnesium stearate, silicone, titanium dioxide and silicon dioxide.
The invention also discloses a kind of preparation method of curcumin colon specific drug preparation, it is characterized in that, comprise the following steps:
A 1 part of curcumin is equipped with 2-5 part cyclodextrin and makes curcumin cyclodextrin clathrate by ();
B curcumin cyclodextrin clathrate and natural polysaecharides Colontargeted materids are 1:1-10 crosslinking curing by () in mass ratio, filter, and washing is dry, obtains the segmented intestine targeted micelle of curcumin;
C () takes raw material by following weight part ratio: enteric material 5-20 part, plasticizer 3-5 part, antitackiness agent 6-10 part and solvent 65-86 part, and mixing, makes enteric-coating material solution; By segmented intestine targeted for described curcumin micelle enteric-coating material solution coating, coating weight gain reaches 3-5% and stops coating, obtains curcumin colon specific drug preparation.
In preparation method of the present invention, the described cyclodextrin of step (a) is the mixture of any one or two or more arbitrary proportion in alpha-cyclodextrin and derivant, beta-schardinger dextrin-and derivant thereof and gamma-cyclodextrin and derivant thereof; Described beta-cyclodextrin derivative is HP-β-CD, sulfobutyl ether-beta-cyclodextrin, dihydroxy group-beta-cyclodextrin, methyl-B-cyclodextrin, 2,6-DM-β-CD, 2, the compositions of one or more arbitrary proportions in 3,6-TM-β-CD, carboxymethyl-beta-cyclodextrin, glucosyl-ss-cyclodextrin, glucosulfone group-beta-cyclodextrin, malt sugar group-beta-cyclodextrin etc.
Curcumin cyclodextrin clathrate described in preparation method (a) step of the present invention by following 5 kinds of methods preparation, the organic solvent in preparation process be in methanol, ethanol, acetone, propylene glycol, chloroform and glacial acetic acid any one or any one and water be mixed in proportion after mixture.Concrete preparation method is as follows:
(1) saturated water solution method: cyclodextrin and derivant thereof are made saturated aqueous solution, be placed in constant temperature blender with magnetic force, add the organic solution containing curcumin, stir while adding, enclose 1.5-2.5h, puts refrigerator and cooled and hides rear sucking filtration, solid content absolute ethanol washing, drying under reduced pressure, obtains Powdered curcumin cyclodextrin clathrate.The mass ratio of wherein said curcumin, cyclodextrin and organic solvent is preferably 1:3:10.
(2) polishing: after cyclodextrin and derivant thereof are added suitable quantity of water mix homogeneously, add the organic solution containing curcumin, fully grind to form pastel, 40-50 DEG C of drying, washing, drier, obtain Powdered curcumin cyclodextrin clathrate.The mass ratio of wherein said curcumin, cyclodextrin and organic solvent is preferably 1:3:10.
(3) supercritical ultrasonics technology: after cyclodextrin and derivant thereof are added suitable quantity of water mix homogeneously, add the organic solution containing curcumin, uses ultrasonic generator ultrasonic immediately after mixing, by the sedimentation and filtration of separating out, with absolute ethanol washing, dry, obtain Powdered curcumin cyclodextrin clathrate.
(4) freeze-drying: by curcumin and cyclodextrin and derivant enclose in suitable solution thereof, remove solvent with freeze-drying, obtain Powdered curcumin cyclodextrin clathrate.
(5) spray drying method: by curcumin and cyclodextrin and derivant enclose in suitable solution thereof, remove solvent with spray drying method, obtain Powdered curcumin cyclodextrin clathrate.
In preparation method of the present invention, step (b) described natural polysaecharides Colontargeted materids is the mixture of any one or two or more arbitrary proportion in chitosan, alginic acid and sodium salt thereof, pectin and derivant thereof, your natural gum, inulin, amylose, cyclodextrin and derivant thereof of melon, chondroitin sulfate, Konjac glucomannan, Rhizoma amorphophalli glucomannan and carob; Described pectin and derivant thereof are methyl pectin, methylolation pectin or amidated pectin.
In preparation method of the present invention, the crosslinking curing of step (b) to refer to curcumin cyclodextrin clathrate and natural polysaecharides Colontargeted materids at mass percent concentration is in 1-5% crosslinked fluid environment, crosslinking curing 0.5-2h, the solute of described crosslinked fluid is the mixture of one or more arbitrary proportions in the halogenide of calcium chloride, calcium oxalate, calcium acetate, calcium carbonate, calcium bicarbonate, calcium sulfate, calcium hydrogen phosphate, zinc acetate, zinc sulfate, copper sulfate, divalent metal.
In preparation method of the present invention, the described enteric material of step (c) is for being that crylic acid resin is (as EudragitL30D-55, EudragitL100, EudragitL100-55, EudragitS100, EudragitFS30D etc.), CAP (CAP), polyvinyl alcohol phthalate ester (PVAP), cellulose acetate benzenetricarboxylic acid ester (CAT), HP-55 (HPMCP), HPMCAM (HPMCAM), hypromellose succinate NF (HPMCAS), succinic acid ethyl cellulose (CAS), HPMCAS (HPMCAS), 1, 2, 4-benzenetricarboxylic acid hydroxypropyl emthylcellulose (HPMCr), Opadry (Opadry), Su Teli (Sureteric), Sulisi (Sureleasse), the mixture of any one or two or more arbitrary proportion in Lac etc.
In preparation method of the present invention, the described plasticizer of step (c) is triethyl citrate (TEC), acetylation triethyl citrate, tributyl citrate (THC), glycerol, propylene glycol, polyethylene glycols (PEG), monoacetin, glyceryl diacetate, triacetin, dibutyl sebacate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, Oleum Ricini, Semen Maydis oil, the mixture of any one or two or more arbitrary proportion in fractionated coconut oil and liquid Paraffin.
In preparation method of the present invention, the described antitackiness agent of step (c) is the mixture of any one or two or more arbitrary proportion in Pulvis Talci, glyceryl monostearate (GMS), stearic acid, magnesium stearate, silicone, titanium dioxide and silicon dioxide.
In preparation method of the present invention, the described solvent of step (c) is the mixture of any one or the two or more arbitrary proportion such as acetone, isopropyl alcohol, ethanol, ethyl acetate, dichloromethane, methanol, ammonia and water.
In preparation method of the present invention, the coating described in step (c) can carry out coating by following two kinds of methods:
(1) pan coating method: segmented intestine targeted for curcumin micelle is put into coating pan, by this area routine techniques means adjustment coating pan rotating speed, coating temperature, the atomisation pressure of coating material solution, hydrojet speed parameters, coating is carried out with enteric-coating material solution, after reaching predetermined coating weight gain, be drying to obtain.
(2) fluidized bed coating: segmented intestine targeted for curcumin micelle is put into fluid bed, by this area routine techniques means adjustment inlet temperature of fluid bed, air quantity, atomizing pressure and hydrojet speed parameters, coating is carried out with enteric-coating material solution, after reaching predetermined coating weight gain, be drying to obtain.
Curcumin and cyclodextrin and derivant thereof are made clathrate by the present invention first, overcome the shortcoming of the low and poor stability of curcumin water solublity, then the natural polysaecharides enzymatic degradable material such as curcumin clathrate and chitosan, pectin, sodium alginate are made segmented intestine targeted micelle, use enteric material coating again, be prepared into the segmented intestine targeted coating micelle of curcumin, make medicine in the release of colon site location, reach segmented intestine targeted object.Specifically innovative point of the present invention is:
(1) prepare curcumin cyclodextrin clathrate, improve dissolubility and the stability of curcumin, be conducive to dissolving and the absorption of medicine; Simultaneously cyclodextrin inherently enzyme touch type Colontargeted materids, can not be hydrolyzed and absorb at the little enteral of harmonization of the stomach, can be degraded by microorganisms in colon and discharge medicine;
(2) be used alone cyclodextrin clathrate, be subject to the impact of substance in vivo as lipoid, cholesterol etc., unstable in the gastrointestinal tract, do not reach desirable colon-targeted delivery system effect; Therefore curcumin cyclodextrin clathrate and enzyme are touched type Colontargeted materids such as chitosan, pectin, sodium alginate etc. and make segmented intestine targeted micelle further, and due to use in conjunction multiple material, by different enzymatic degradation in colon, can reach degraded fully, release is object completely;
(3) because polysaccharide Colontargeted materids has certain water solublity, in upper digestive tract easily swelling or dissolving, affect medicine to discharge in the location of colon, be made into insoluble micelle, Colontargeted materids can not be dissolved at upper digestive tract, reduce medicine and do not arrive the release of colon site;
(4) because the insoluble micelle of preparation belongs to matrix type structure, the medicine of micelle inside can be discharged by skeleton gap, the medicine of micelle surface adsorption also easily discharges, and therefore has some drug releases when not arriving colon site in digestive tract; Use enteric-coating material by the segmented intestine targeted micelle coating of preparation, can protect micelle smoothly by harmonization of the stomach small intestinal, after arriving colon site, coating material dissolves, exposes Colontargeted materids, is degraded by colonic enzyme, guarantees that medicine only discharges at colon;
(5) the micelle agent prepared of the present invention is except a small amount of coating material of skin, and all the other adjuvants are natural enzyme and touch type Colontargeted materids, can reduce volumes of formulation, increases enzymatic degradation efficiency;
(6) micelle belongs to multiple dose type preparation, can avoid because medicine local concentration is excessive and cause stimulation to colon; The destruction of indivedual pastille unit can not cause the change of overall drug release behavior, overcomes single-dose type preparation (as tablet) once preparation technology goes wrong, causes the shortcoming of whole preparation failure.
In sum, through studying for a long period of time and repetition test, curcumin and cyclodextrin are made clathrate according to specific proportioning by the present invention, and insoluble segmented intestine targeted micelle made by conbined usage multiple natural polysaecharides material, with enteric-coating material solution coating, make colon specific drug preparation.Shown by verification experimental verification, only have when above three steps be combined with each other, time indispensable, just significantly can increase water solublity and the stability of curcumin, guarantee that medicine only discharges at colon site, efficiently solve that colon targeting preparation polarization is poor, release is incomplete, drug solubility is low and cause absorbing the FAQs such as bad, thus completing the present invention.
Detailed description of the invention
Embodiment is for further describing the present invention below, but does not limit the present invention in any form.
Embodiment 1 curcumin-Benexate Hydrochloride preparation
Get the ethanol water (mass percent concentration is 50%) that 300g beta-schardinger dextrin-is dissolved in 1000g; Be placed in constant temperature blender with magnetic force, keep temperature 40 DEG C, add the ethanol solution (curcumin 100g, dehydrated alcohol 500g) that 600g contains curcumin, limit edged stirs, after enclose 2h, suspension containing clathrate is put refrigerator and cooled and hides 24h, then sucking filtration, solid content absolute ethanol washing, gained clathrate, at 40 DEG C of drying under reduced pressure, obtains yellow curcumin-Benexate Hydrochloride powder.
The preparation of embodiment 2 curcumins-hydroxypropylβ-cyclodextrin clathrate
By 300g hydroxypropylβ-cyclodextrin 1000mL water dissolution, be placed in constant temperature blender with magnetic force, 40 DEG C of acetone soln (curcumin 100g adding 1100g while stirring and contain curcumin, acetone is 1000g), stir 2h, with 0.45 μm of filtering with microporous membrane, filtrate spraying dry, obtain the yellow loose powder of curcumin-hydroxypropylβ-cyclodextrin clathrate.
The preparation of embodiment 3 curcumins-alpha-cyclodextrin clathrate
By the alpha-cyclodextrin of 200g 1500mL water dissolution, be placed in constant temperature blender with magnetic force, 40 DEG C of propylene glycol solution (curcumin 100g adding 900g while stirring and contain curcumin, propylene glycol is 800g), stir 2h, with 0.45 μm of filtering with microporous membrane, filtrate lyophilization 24h, obtains curcumin-loose freeze-dried powder of alpha-cyclodextrin clathrate yellow.
The preparation of embodiment 4 curcumins-gamma-cyclodextrin clathrate
By the gamma-cyclodextrin of 500g 2500mL water dissolution, be placed in constant temperature blender with magnetic force, 40 DEG C of propylene glycol solution (curcumin 100g adding 1600g while stirring and contain curcumin, propylene glycol is 1500g), stir 2h, 0.45 μm of filtering with microporous membrane, filtrate lyophilization 24h, obtains curcumin-loose freeze-dried powder of gamma-cyclodextrin clathrate yellow.
The preparation of the segmented intestine targeted micelle of embodiment 5 curcumin
Curcumin-Benexate Hydrochloride 100g prepared by Example 1, add the sodium alginate aqueous solution that 4000g mass percent concentration is 1.5%, mix homogeneously, obtains solution A; By 2000g mass percent concentration be 2% chitosan aqueous solution and 2000g mass percent concentration be 2% calcium chloride water mixing, by sodium hydroxide solution adjust ph to 5.5, obtain solution B; In solution B under solution A being stirred by the instillation of internal diameter 0.9mm syringe needle with constant flow pump, crosslinking curing 2h, filter, purification washes 3 times, and baking oven 40 DEG C of dry 24h, obtain the segmented intestine targeted micelle of curcumin, and particle diameter is 800 ~ 850 μm.
The preparation of the segmented intestine targeted micelle of embodiment 6 curcumin
Curcumin-hydroxypropylβ-cyclodextrin clathrate 100g prepared by Example 2, add the mixed solution (in mixed solution, the mass percent concentration of sodium alginate is 5%, the mass percent concentration of pectin is 5%) of 10000g sodium alginate and pectin, mix homogeneously, instilling 10000g mass percent concentration with constant flow pump by internal diameter 1.0mm syringe needle is in the calcium acetate aqueous solution of 4%, dropping limit, limit is stirred, crosslinking curing 1h, filter, purification washes 3 times, baking oven 40 DEG C of dry 24h, obtain the segmented intestine targeted micelle of curcumin, particle diameter is 900 ~ 950 μm.
The preparation of the segmented intestine targeted micelle of embodiment 7 curcumin
Curcumin 100g embodiment 2 prepared-hydroxypropylβ-cyclodextrin clathrate joins in the calcium sulfate saturated solution of 500g, mix homogeneously, instilling 10000g mass percent concentration with constant flow pump by internal diameter 0.8mm syringe needle is in the sodium alginate soln of 3%, stir 30min, filter, solid washs, impregnated in 4000g mass percent concentration is again 10min in the 5% chitosan solution acetic acid of 5% (solvent to be mass percent concentration be), filter, purification washes 3 times, baking oven 40 DEG C of dry 24h, obtain the segmented intestine targeted micelle of curcumin, particle diameter is 700 ~ 750 μm.
The preparation of the segmented intestine targeted micelle of embodiment 8 curcumin
Curcumin-alpha-cyclodextrin clathrate 100g prepared by Example 3, add the sodium alginate aqueous solution that 4000g mass percent concentration is 1.5%, mix homogeneously, obtains solution A; By 2000g mass percent concentration be 2% chitosan aqueous solution and 2000g mass percent concentration be 2% calcium chloride water mixing, by sodium hydroxide solution adjust ph to 5.5, obtain solution B; In solution B under solution A being stirred by the instillation of internal diameter 0.9mm syringe needle with constant flow pump, crosslinking curing 2h, filter, purification washes 3 times, and baking oven 40 DEG C of dry 24h, obtain the segmented intestine targeted micelle of curcumin, and particle diameter is 800 ~ 850 μm.
The preparation of the segmented intestine targeted micelle of embodiment 9 curcumin
Curcumin-gamma-cyclodextrin clathrate 100g prepared by Example 4, add the mixed solution (in mixed solution, the mass percent concentration of sodium alginate is 5%, the mass percent concentration of pectin is 5%) of 10000g sodium alginate and pectin, mix homogeneously, instilling 10000g mass percent concentration with constant flow pump by internal diameter 1.0mm syringe needle is in the calcium acetate aqueous solution of 4%, dropping limit, limit is stirred, crosslinking curing 1h, filter, purification washes 3 times, baking oven 40 DEG C of dry 24h, obtain the segmented intestine targeted micelle of curcumin, particle diameter is 900 ~ 950 μm.
The preparation of embodiment 10 curcumin colon specific drug preparation
Take raw material by following mass percent: enteric material EudragitS100 is 50g, plasticizer triethyl citrate consumption is 30g, antitackiness agent amount of titanium is 60g, and ethanol is 860g, mixing, makes enteric-coating material solution; The segmented intestine targeted micelle of curcumin embodiment 5 prepared puts into fluid bed, and adopt end spray art for coating bag enteric layer, nozzle diameter is 1.0mm, and process conditions are: inlet temperature 40 DEG C, leaving air temp 35 DEG C, air quantity 130m
3/ h, atomizing pressure 0.4bar, hydrojet speed 1.0ml/min, coating weight gain is 4% stopping coating, obtains product.
The preparation of embodiment 11 curcumin colon specific drug preparation
Take raw material by following mass percent: enteric material EudragitL100100g, plasticizer polyethylene glycol 6000 consumption are 40g, antitackiness agent amount of talc is 80g, and solvent is isopropyl alcohol 780g, mixing, makes enteric-coating material solution; The segmented intestine targeted micelle of embodiment 6 curcumin is put into fluid bed, and adopt end spray art for coating bag enteric layer, nozzle diameter is 1.0mm, and process conditions are: inlet temperature 40 DEG C, leaving air temp 30 DEG C, air quantity 130m
3/ h, atomizing pressure 0.5bar, hydrojet speed 1.0ml/min; After coating weight gain reaches 4%, stop coating, obtain product.
The preparation of embodiment 12 curcumin colon specific drug preparation
Take raw material by following mass percent: enteric material CAP 50g, plasticizer phthalic acid dimethyl ester consumption are 50g, antitackiness agent silica content is 60g, and solvent is acetone 840g, mixing, makes enteric-coating material solution; The segmented intestine targeted micelle of embodiment 7 curcumin is put into centrifugal rotation seed-coating machine, and coating temperature is room temperature, and atomisation pressure is 0.1MPa, and hydrojet speed is 1.0ml/min, after coating weight gain reaches 3%, stops coating, obtains product.
The preparation of embodiment 13 curcumin colon specific drug preparation
Take raw material by following mass percent: enteric material Lac 200g, plasticizer triethyl citrate consumption are 50g, antitackiness agent stearic acid dosage is 100g, and solvent is ethanol 650g, mixing, makes enteric-coating material solution; The segmented intestine targeted micelle of embodiment 8 curcumin is put into centrifugal rotation seed-coating machine, and coating temperature is room temperature, and atomisation pressure is 0.1MPa, and hydrojet speed is 1.0ml/min; After coating weight gain reaches 5%, stop coating, obtain product.
Embodiment 14
Take raw material by following mass percent: enteric material EudragitFS30D consumption is 200g, plasticizer triethyl citrate consumption is 50g, and antitackiness agent amount of talc is 100g, and solvent is water 650g, and mixing, makes enteric-coating material solution; The segmented intestine targeted micelle of embodiment 9 curcumin is put into fluid bed, and adopt end spray art for coating bag enteric layer, nozzle diameter is 1.0mm, and process conditions are: inlet temperature 40 DEG C, leaving air temp 35 DEG C, air quantity 130m
3/ h, atomizing pressure 0.4bar, hydrojet speed 1.0ml/min; After coating weight gain reaches 4%, stop coating, obtain product.
Comparative example 1 prepares the segmented intestine targeted coating micelle of curcumin
Mass percent concentration 25g curcumin raw material being added 4000g is in 1.5% sodium alginate soln, and mix homogeneously, obtains solution A; To be the chitosan aqueous solution of 2% and the mass percent concentration of 2000g by 2000g mass percent concentration be 2% calcium chloride water mixing, by sodium hydroxide solution adjust ph to 5.5, obtain solution B; In solution B under solution A being stirred by the instillation of internal diameter 0.9mm syringe needle with constant flow pump, crosslinking curing 2h, filter, purification washes 3 times, and baking oven 40 DEG C of dry 24h, obtain the segmented intestine targeted micelle of curcumin, and particle diameter is 800 ~ 850 μm; Then carry out coating according to embodiment 11 pairs of segmented intestine targeted micelles of curcumin, after coating weight gain reaches 4%, stop coating, obtain product.
Comparative example 2 prepares the segmented intestine targeted coating micelle of curcumin
25g curcumin being added to 4000g mass percent concentration is in 1.5% sodium alginate soln, mix homogeneously, then is added in above-mentioned solution by the beta-schardinger dextrin-of 75g and mix to obtain solution A; To be the chitosan aqueous solution of 2% and the mass percent concentration of 2000g by 2000g mass percent concentration be 2% calcium chloride water mixing, by NaOH solution adjust ph to 5.5, be solution B; In solution B solution A is stirred with constant flow pump by the instillation of internal diameter 0.9mm syringe needle under, crosslinking curing 2h, filter, purification washes 3 times, baking oven 40 DEG C of dry 24h, obtain the segmented intestine targeted micelle of curcumin, particle diameter is 800 ~ 850 μm, then carries out coating, after coating weight gain reaches 4% according to embodiment 11 pairs of micelles, stop coating, obtain product.
The preparation of the segmented intestine targeted coated tablet of comparative example 3 curcumin cyclodextrin clathrate
Prepare curcumin-Benexate Hydrochloride according to the method for embodiment 1, prepare tablet by following method; Get curcumin-Benexate Hydrochloride 100g, add pectin 100g, lactose 70g, microcrystalline Cellulose 30g, mix homogeneously, do adhesive soft material with the HPMCK4M that mass percent concentration is 5%, 20 mesh sieves are granulated, 60 DEG C of dry 2h, 16 mesh sieve granulate, add the magnesium stearate mix homogeneously of 1%, select the stamping of 10mm scrobicula, the heavy 0.35g of sheet.Be placed in by sheet in coating pan, carry out coating with the coating material solution formula of embodiment 11, coating temperature is room temperature, and atomisation pressure is 0.1MPa, and hydrojet speed is 1.0ml/min; After coating weight gain reaches 4%, stop coating, obtain product.
The preparation that embodiments of the invention and comparative example are prepared by embodiment 15 carries out Performance Detection.
One, the stability test of curcumin crude drug and curcumin clathrate
For embodiment 1,2, curcumin-hydroxypropylβ-cyclodextrin clathrate prepared by the curcumin-Benexate Hydrochloride prepare curcumin crude drug, embodiment 1 and embodiment 2 is placed in respectively in 40 DEG C of calorstats and carries out heat stabilization test, timing sampling, measure the content of curcumin, the results are shown in Table 1.
The assay result (%) of table 1 curcumin crude drug and curcumin clathrate heat stabilization test
| Time (my god) | Curcumin crude drug | Curcumin-Benexate Hydrochloride | Curcumin-hydroxypropylβ-cyclodextrin clathrate |
| 0 | 100.0 | 100.0 | 100.0 |
| 1 | 93.23 | 99.64 | 99.72 |
| 3 | 89.14 | 97.96 | 98.79 |
| 5 | 85.20 | 94.20 | 97.65 |
| 10 | 73.11 | 92.98 | 96.33 |
Curcumin-hydroxypropylβ-cyclodextrin clathrate prepared by the curcumin-Benexate Hydrochloride prepare curcumin crude drug, embodiment 1 and embodiment 2 is placed in respectively in lighting box that illumination is 4500 ± 500lx and carries out photo-stability testing, timing sampling, measure the content of curcumin, the results are shown in Table 2.
The assay result (%) of table 2 curcumin crude drug and curcumin cyclodextrin clathrate photo-stability testing
| Time (my god) | Curcumin crude drug | Curcumin-Benexate Hydrochloride | Curcumin-hydroxypropylβ-cyclodextrin clathrate |
| 0 | 100.0 | 100.0 | 100.0 |
| 1 | 94.89 | 97.65 | 98.45 |
| 3 | 77.63 | 90.98 | 94.91 |
| 5 | 65.10 | 85.44 | 89.95 |
| 10 | 37.89 | 81.66 | 85.77 |
Shown by the stability test result of table 1 and table 2, the heat stability of curcumin clathrate and anti-light solution all comparatively curcumin crude drug are significantly improved; Illustrate that the unstable double bond structure of curcumin may by enclose in cyclodextrin tubular structure, cut off contacting of curcumin and surrounding in a way, thus played a protective role, can ensure that curcumin is in the stability of producing and in storage process.
Two, the solubility test of curcumin crude drug and curcumin clathrate
For embodiment 1 and 2, curcumin-hydroxypropylβ-cyclodextrin clathrate prepared by the curcumin-Benexate Hydrochloride prepare excessive curcumin crude drug, embodiment 1 and embodiment 2 adds in 100ml distilled water respectively, be placed in 25 DEG C of constant-temperature tables, concussion 48h, sampling, 0.45 μm of filtering with microporous membrane, measures the content of curcumin in filtrate, the results are shown in Table 3.
Table 3 curcumin crude drug and curcumin cyclodextrin clathrate 25 DEG C of solubility test results (μ g/ml)
| Curcumin crude drug | Curcumin-Benexate Hydrochloride | Curcumin-hydroxypropylβ-cyclodextrin clathrate |
| 20.1 | 210.5 | 4020.7 |
From table 3 result, after curcumin makes cyclodextrin clathrate, its dissolubility can be significantly improved, make curcumin after colon site release, can solution absorption rapidly, play curative effect.
Three, the vitro release test of the segmented intestine targeted micelle of curcumin and segmented intestine targeted coating micelle
For embodiment 5,6,7 and embodiment 10,11, the curcumin colon specific drug preparation that the segmented intestine targeted micelle of curcumin prepare embodiment 5,6,7 and embodiment 10,11 are finally prepared carries out vitro release research.Micelle is placed in digestion instrument and turns basket, rotating speed 100r/min, first in pH1.2 hydrochloric acid solution, in 2h sampling and measuring; Then be transferred in pH4.5 acetate buffer solution, in 4h sampling and measuring; Then be transferred in pH5.5 phosphate buffered solution, in 6h sampling and measuring; Finally be transferred in pH6.5 phosphate buffer, in 8h sampling and measuring.Calculate cumulative release percentage rate, the results are shown in Table 4.
The cumulative in vitro medicine realeasing rate (%) of the segmented intestine targeted micelle of table 4 curcumin and segmented intestine targeted coating micelle
| Release liquid pH value | pH1.2 | pH4.5 | pH5.5 | pH6.5 |
| The cumulative release time | 2h | 4h | 6h | 8h |
| Embodiment 5 | 5.2 | 7.8 | 10.1 | 13.6 |
| Embodiment 6 | 4.4 | 8.3 | 11.2 | 15.7 |
| Embodiment 7 | 7.1 | 10.2 | 15.5 | 22.1 |
| Embodiment 10 | 0 | 0 | 0 | 0 |
| Embodiment 11 | 0 | 0 | 0 | 0 |
From table 4 result, the not enteric coated micelle of embodiment 5, embodiment 6 and embodiment 7 preparation all has certain drug release in simulated gastric fluid and simulated intestinal fluid, and the segmented intestine targeted micelle of curcumin that embodiment 10 and 11 is finally prepared does not have drug release.
Four, the vitro release test of the segmented intestine targeted coating micelle of curcumin
For embodiment 10,11, the segmented intestine targeted coating micelle of curcumin prepared by embodiment 10,11 is carried out vitro release research.Micelle is placed in digestion instrument and turns basket, rotating speed 100r/min, release medium is containing the pH7.0 phosphate buffer (A liquid) of 4% rat cecal content with not containing the pH7.0 phosphate buffer (B liquid) of rat cecal content respectively, in 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h sampling and measuring, calculate cumulative release percentage rate, the results are shown in Table 5.
The cumulative in vitro medicine realeasing rate (%) of the segmented intestine targeted coating micelle of table 5 curcumin
| The cumulative release time | 1h | 2h | 3h | 4h | 6h | 8h | 10h | 12h |
| Embodiment 10 (A liquid) | 40.1 | 60.6 | 85.7 | 92.3 | 93.2 | 94.6 | 95.6 | 96.9 |
| Embodiment 11 (A liquid) | 33.4 | 57.4 | 79.9 | 90.0 | 91.5 | 92.8 | 94.3 | 96.7 |
| Embodiment 10 (B liquid) | 7.4 | 11.6 | 19.1 | 21.5 | 22.3 | 25.3 | 26.9 | 28.8 |
| Embodiment 11 (B liquid) | 8.1 | 13.2 | 17.6 | 19.4 | 21.0 | 22.3 | 25.7 | 27.6 |
From table 5 result, in the release medium of pH7.0, enteric-coating material dissolves, and exposes micelle.The segmented intestine targeted coating micelle of curcumin can not release completely in not containing the release medium of rat cecal content, and release is rapid and complete in the medium containing rat cecal content, this is owing to containing multiple enzyme in rat cecal content, can to degrade the composition material of micelle, destroy the framing structure of micelle, make drug release out.
Five, the vitro release test of comparative example 1,2,3 in rat colon content release medium.
Curcumin colon targeting preparation prepared by comparative example 1,2,3 is carried out vitro release research.Use Rotating shaker, rotating speed 100r/min, release medium is the pH7.0 phosphate buffer containing 4% rat cecal content, in 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h sampling and measuring, calculates cumulative release percentage rate, the results are shown in Table 6.
The cumulative in vitro medicine realeasing rate (%) of curcumin colon targeting preparation prepared by table 6 comparative example
| The cumulative release time | 1h | 2h | 3h | 4h | 6h | 8h | 10h | 12h |
| Comparative example 1 | 5.3 | 8.9 | 10.2 | 15.0 | 15.6 | 16.3 | 16.2 | 16.5 |
| Comparative example 2 | 7.7 | 10.5 | 18.0 | 20.1 | 22.3 | 22.5 | 23.7 | 25.1 |
| Comparative example 3 | 6.8 | 14.6 | 20.1 | 28.9 | 37.2 | 49.7 | 58.4 | 75.3 |
As can be seen from Table 6, in comparative example 1 and 2, because curcumin does not form cyclodextrin clathrate, dissolubility is lower, can not release complete; Containing a large amount of non-colon degradable material in tablet prepared by comparative example 3, can not be degraded by colonic enzyme, therefore release is slower.
Six, the dissolution test of the segmented intestine targeted micelle of curcumin in different enzymatic solution
Curcumin colon specific drug preparation embodiment 10 prepared carries out vitro release research.Use Rotating shaker, rotating speed 100r/min, release medium is C liquid (the pH7.0 phosphate buffer containing 1% glycosidase), D liquid (the pH7.0 phosphate buffer containing 2% chitosanase), E liquid (the pH7.0 phosphate buffer containing 1% glycosidase and 2% chitosanase) respectively, in 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h sampling and measuring, calculate cumulative release percentage rate, the results are shown in Table 7.
The cumulative in vitro medicine realeasing rate (%) of curcumin segmented intestine targeted coating micelle in different enzymatic solution prepared by table 7 embodiment 7
| The cumulative release time | 1h | 2h | 3h | 4h | 6h | 8h | 10h | 12h |
| C liquid | 15.3 | 22.8 | 30.5 | 44.0 | 62.4 | 85.3 | 90.7 | 91.5 |
| D liquid | 17.7 | 24.7 | 33.8 | 46.1 | 65.3 | 86.5 | 91.1 | 92.9 |
| E liquid | 30.2 | 54.9 | 78.3 | 86.7 | 90.5 | 91.4 | 93.1 | 96.6 |
From table 7 result, the release in single enzyme solution of the segmented intestine targeted coating micelle of curcumin is comparatively slow, and in composite enzyme solution, release is very fast.Illustrate that the multiple enzymatic degradable material of conbined usage prepares colon targeting preparation, in colon different enzyme effect under can be degraded rapidly, thus release medicine.
Claims (9)
1. a curcumin colon specific drug preparation, is characterized in that, comprises curcumin cyclodextrin clathrate, natural polysaecharides Colontargeted materids and enteric-coating material; The mass ratio of described curcumin cyclodextrin clathrate and natural polysaecharides Colontargeted materids is 1:1-10, and the quality of described enteric-coating material is the 3-5% of described curcumin cyclodextrin clathrate and natural polysaecharides Colontargeted materids gross mass;
Described curcumin cyclodextrin clathrate forms primarily of the material of following weight part ratio: curcumin 1 part, cyclodextrin 2-5 part;
Described natural polysaecharides Colontargeted materids is the mixture of any one or two or more arbitrary proportion in chitosan, alginic acid and sodium salt thereof, pectin and derivant thereof, your natural gum, inulin, amylose, cyclodextrin and derivant thereof of melon, chondroitin sulfate, Konjac glucomannan, Rhizoma amorphophalli glucomannan and carob;
Described enteric-coating material comprises the material of following weight part ratio: enteric material 5-20 part, plasticizer 3-5 part, antitackiness agent 6-10 part.
2. curcumin colon specific drug preparation according to claim 1, it is characterized in that, described cyclodextrin is the mixture of any one or two or more arbitrary proportion in alpha-cyclodextrin and derivant, beta-schardinger dextrin-and derivant thereof and gamma-cyclodextrin and derivant thereof.
3. the preparation method of curcumin colon specific drug preparation according to claim 1, it is characterized in that, described enteric material is crylic acid resin, CAP, polyvinyl alcohol phthalate ester, cellulose acetate benzenetricarboxylic acid ester, HP-55, HPMCAM, hypromellose succinate, succinic acid ethyl cellulose, HPMCAS, 1, 2, 4-benzenetricarboxylic acid hydroxypropyl emthylcellulose, Opadry, Su Teli, the mixture of any one or two or more arbitrary proportion in Sulisi and Lac.
4. a preparation method for curcumin colon specific drug preparation, is characterized in that, comprises the following steps:
A 1 part of curcumin is equipped with 2-5 part cyclodextrin and makes curcumin cyclodextrin clathrate by ();
B curcumin cyclodextrin clathrate and natural polysaecharides Colontargeted materids are 1:1-10 crosslinking curing by () in mass ratio, filter, and washing is dry, obtains the segmented intestine targeted micelle of curcumin;
C () takes raw material by following weight part ratio: enteric material 5-20 part, plasticizer 3-5 part, antitackiness agent 6-10 part and solvent 65-86 part, and mixing, makes enteric-coating material solution; By segmented intestine targeted for curcumin micelle enteric-coating material solution coating, coating weight gain reaches 3-5% and stops coating, obtains curcumin colon specific drug preparation.
5. the preparation method of curcumin colon specific drug preparation according to claim 4, it is characterized in that, the described cyclodextrin of step (a) is the mixture of any one or two or more arbitrary proportion in alpha-cyclodextrin and derivant, beta-schardinger dextrin-and derivant thereof and gamma-cyclodextrin and derivant thereof.
6. the preparation method of curcumin colon specific drug preparation according to claim 5, it is characterized in that, step (b) described natural polysaecharides Colontargeted materids is the mixture of any one or two or more arbitrary proportion in chitosan, alginic acid and sodium salt thereof, pectin and derivant thereof, your natural gum, inulin, amylose, cyclodextrin and derivant thereof of melon, chondroitin sulfate, Konjac glucomannan, Rhizoma amorphophalli glucomannan and carob.
7. the preparation method of curcumin colon specific drug preparation according to claim 6, it is characterized in that, the described enteric material of step (c) is crylic acid resin, CAP, polyvinyl alcohol phthalate ester, cellulose acetate benzenetricarboxylic acid ester, HP-55, HPMCAM, hypromellose succinate, succinic acid ethyl cellulose, HPMCAS, 1, 2, 4-benzenetricarboxylic acid hydroxypropyl emthylcellulose, Opadry, Su Teli, the mixture of any one or two or more arbitrary proportion in Sulisi and Lac.
8. the preparation method of curcumin colon specific drug preparation according to claim 7, it is characterized in that, the described plasticizer of step (c) is triethyl citrate, acetylation triethyl citrate, tributyl citrate, glycerol, propylene glycol, polyethylene glycols, monoacetin, glyceryl diacetate, triacetin, dibutyl sebacate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, Oleum Ricini, Semen Maydis oil, the mixture of any one or two or more arbitrary proportion in fractionated coconut oil and liquid Paraffin.
9. the preparation method of curcumin colon specific drug preparation according to claim 8, it is characterized in that, the described antitackiness agent of step (c) is the mixture of any one or two or more arbitrary proportion in Pulvis Talci, glyceryl monostearate, stearic acid, magnesium stearate, silicone, titanium dioxide and silicon dioxide.
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