A kind of curcumin colon specific drug preparation and preparation method thereofTechnical field
The present invention relates to traditional Chinese medicine preparation or preparation method, specifically a kind of curcumin colon specific drug systemAgent and preparation method thereof.
Background technique
Colon cancer is one of main malignant tumour of the mankind, the 1970s so far, with the progress of Chinese society, lifeThe improvement of condition living and the increasingly westernization of people life style, incidence of the colon cancer in China rise rapidly, it has also become ChinaOne of most common 5 big malignant tumour, severely compromises the health of the mankind.Ulcerative colitis, clone disease etc. are inflammatoryIntestinal disease, the generation with colon cancer also have relationship, and the two is considered as the precancerous lesion of colon cancer.
Oral colon-specific drug delivery system is a kind of drug system by drug delivery to colon specific by oral routeAgent.Drug is not discharged in stomach and small enteral after administration, and when being transported to colon, just disintegration or corrosion, makes the drug of release in colonLesions position concentration, and colon is suitable for drug absorption because of its stable environment and highdensity enzymatic activity and close to neutral pH.Drug is longer in the residence time of colon, is also beneficial to depot drug product system and plays a role, can be used for treating colitis, colon cancerEtc. localities intestines problem, can also by postpone drug release method, for treating circadian rhythm disease.
Erodible materials mainly have 3 seed types: pH controlled release system, time controlled release system and enzyme triggering type control at presentRelease system (Bacterialtriggered controlled release system).
PH controlled release system is the characteristics of pH using gastrointestinal tract from stomach to colon gradually rises, with it is various at specific pH it is moltenThe enteric material of solution is coated, and drug positioning is made to be discharged into medicine-feeding part.Since small intestine and colon pH are very close, Er QiekeCan be because of colonic pathological change or bacterial action, pH is lower than small intestine, so the validity of pH controlled release system is lower, it is single-minded to lack positioningProperty.
Time controlled release system is to enter colon from stomach according to drug to generally require 3~4h, can be by with slightly solubility materialCoating makes drug reach colon site ability slow release.For time controlled release system, initial drug release position is mainly depended onPass through the time in gastrointestinal tract in drug delivery system.Although the small intestine passage time of the drug delivery system has relative uniformity, stomachResidence time is widely different, this allows for having uncertainty by the time of upper digestive tract.
The principle of enzyme triggering type controlled release system is: there are many unique bacteriums for colon, generate unique enzyme system, many heightMolecular material can be degraded as pharmaceutical carrier in colon by these enzymes, and in stomach and small enteral due to lacking corresponding enzyme, it cannotIt is degraded, to make drug in colon specific.Enzyme triggering type controlled release system is dependent on flora and related enzyme activity in colonSharply increase, and parenteral route is drunk by time and enteric cavity pH value, therefore compared with other colon-targeted delivery system systemsThe influences such as food, disease, individual difference are smaller, and it is a kind of ideal that having the advantages that release the drug, locus specificity is good, accurate positioningTargeted drug delivery system.Currently, the widely used degradable material of enzyme triggering type controlled release system has azo-compound and naturalPolysaccharide compound.Wherein azo-compound is the polymer that main chain, cross linked chain or side chain contain azo bond, can be existed by colonAzo reductase degradation, but azobenzene polymer biodegradation rate is slow, and may cause drug can not discharge completely, andWhether the catabolite of azobenzene polymer there is toxicity to need further to be assessed.And natural polysaecharides compound not only has colonEnzyme degradability, but also have the advantages that abundance, inexpensive, safe and stable and nontoxic, but usually as drugIt will appear that drug solubility is low when the carrier of colon targeting drug administration, the defects of cannot releasing the drug completely.
Curcumin is the phenol sulfonate extracted from zingiberaceous plant rhizome, is a kind of natural antioxidant, hasThe pharmacological actions such as cholagogue, reducing blood lipid, anti-oxidant, antibacterial, anti-inflammatory, anticancer, therefore it is widely used in field of medicaments, it is considered to be toolThere are one of the dual-purpose of drug and food natural prodcuts of Development volue.In recent years, some researches show that curcumins in treatment colitis and pre- anti-cakingIt is also had a certain effect in terms of intestinal cancer, and external curcumin has been reported for treating colon cancer II clinical trial phase result.But since curcumin water solubility is low, after preparation oral, since solubility of the curcumin in gastro-intestinal Fluid is low, through biomembraneAmount into blood circulation is few, so its oral administration biaavailability is very low, can only can just be played by increasing dosage in clinicCertain therapeutic effect；But the increase of dosage will certainly bring inconvenience to the medication of patient and preparation process.In addition, gingerThe stability of flavine is poor, sensitive to light and heat, is easy to happen decomposition during the preparation process.Therefore, we are highly desirable to grindThe curcumin peroral dosage form that a kind of property is stable, drug release is complete, targeting is strong is made, is mentioned with the treatment and prevention for clinical colon cancerIt is selected for more medications.
Summary of the invention
It is an object of the invention to provide a kind of curcumin colon specific drug preparations and preparation method thereof, solve existingThe problems such as curcumin dosage form drugloading rate is small, medicine stability is low, targeting is poor and drug release is incomplete, for clinical colon cancerIt treats and prevents and more medication selections is provided.
The purpose of the present invention is what is be achieved through the following technical solutions: a kind of curcumin colon specific drug preparation, includingCurcumin cyclodextrin inclusion compound, natural polysaecharides Colontargeted materids and enteric-coating material；The curcumin cyclodextrin packetThe mass ratio for closing object and natural polysaecharides Colontargeted materids is 1:1-10, and the quality of the enteric-coating material is the turmericThe 3-5% of prime ring cyclodextrin inclusion compound and natural polysaecharides Colontargeted materids gross mass；
The curcumin cyclodextrin inclusion compound is mainly by the material composition of following weight part ratio: 1 part of curcumin, cyclodextrin 2-5 parts；
The natural polysaecharides Colontargeted materids are chitosan, alginic acid and its sodium salt, pectin and its derivative, GuarIn natural gum, inulin, amylose, cyclodextrin and its derivative, chondroitin sulfate, konjac glucomannan, konjaku glucomannan and carobAny one or two or more arbitrary proportions mixture；
The enteric-coating material includes the substance of following weight part ratio: 5-20 parts of enteric material, resists 3-5 parts of plasticizerIt is agent 6-10 parts glutinous.
The cyclodextrin is alpha-cyclodextrin and its derivative, beta-cyclodextrin and its derivative and gamma-cyclodextrin and its spreads outThe mixture of any one or two or more arbitrary proportions in biology；The beta-cyclodextrin derivative is hydroxy propyl-Beta-ring pasteEssence, sulfobutyl ether-beta-cyclodextrin, dihydroxy group-beta-cyclodextrin, methyl-B-cyclodextrin, 2,6- dimethyl-β-cyclodextrin, 2,3,6-Trimethyl-β-cyclodextrin, carboxymethyl-beta-cyclodextrin, glucosyl-ss-cyclodextrin, glucosulfone group-beta-cyclodextrin, maltoseThe composition of one or more of group-beta-cyclodextrin etc. arbitrary proportion.
The enteric material is crylic acid resin, cellulose acetate phthalate, polyvinyl alcohol phthalate ester, cellulose acetateBenzenetricarboxylic acid ester, hypromellose phthalate, hydroxypropyl methyl cellulose acetate maleate, hydroxypropyl methylcellulose amberAcid esters, succinic acid ethyl cellulose, succinic acid hydroxypropyl methylcellulose, 1,2,4 benzenetricarboxylic acid hydroxypropyl methyl fiberThe mixture of any one in element, Opadry, Su Teli, Sulisi and shellac or two or more arbitrary proportions.
The plasticizer is triethyl citrate (TEC), acetylation triethyl citrate, tributyl citrate (THC), sweetOil, propylene glycol, polyethylene glycols (PEG), monoacetin, glyceryl diacetate, triacetin, dibutyl decanedioic acidEster, repefral, diethyl phthalate, dibutyl phthalate, castor oil, corn oil, rectifying coconutThe mixture of any one or two or more arbitrary proportions in oil and liquid paraffin.
The antitackiness agent is talcum powder, single stearic acid glycerine lipoprotein (GMS), stearic acid, magnesium stearate, silicone, titanium dioxideWith the mixture of any one in silica or two or more arbitrary proportions.
The invention also discloses a kind of preparation methods of curcumin colon specific drug preparation, which is characterized in that including withLower step:
(a) 1 part of curcumin is equipped with 2-5 parts of cyclodextrin and curcumin cyclodextrin inclusion compound is made；
It (b) is in mass ratio that 1:1-10 crosslinking is solid by curcumin cyclodextrin inclusion compound and natural polysaecharides Colontargeted materidsChange, filter, washs, it is dry, obtain the segmented intestine targeted protomere of curcumin；
(c) weigh raw material by following weight part ratio: 5-20 parts of enteric material, 3-5 parts of plasticizer, 6-10 parts of antitackiness agent andIt 65-86 parts of solvent, mixes, enteric-coating material solution is made；By the curcumin segmented intestine targeted protomere enteric coating materialExpect solution coating, coating weight gain stops coating up to 3-5% to get curcumin colon specific drug preparation.
Step (a) cyclodextrin is alpha-cyclodextrin and its derivative, beta-cyclodextrin and its spreads out in preparation method of the present inventionThe mixture of any one or two or more arbitrary proportions in biology and gamma-cyclodextrin and its derivative；The β-ring pasteSmart derivative be hydroxypropyl-β-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, dihydroxy group-beta-cyclodextrin, methyl-B-cyclodextrin, 2,6- dimethyl-β-cyclodextrin, 2,3,6- trimethyl-β-cyclodextrin, carboxymethyl-beta-cyclodextrin, glucosyl-ss-cyclodextrin, twoThe composition of one or more of glucosyl-ss-cyclodextrin, malt sugar group-beta-cyclodextrin etc. arbitrary proportion.
Being prepared by following 5 kinds of methods for curcumin cyclodextrin inclusion compound described in preparation method (a) step of the present invention, is makingOrganic solvent during standby be in methanol, ethyl alcohol, acetone, propylene glycol, chloroform and glacial acetic acid any one or it is anyA kind of mixed mixture in proportion with water.It is specific the preparation method is as follows:
(1) saturated water solution method: saturated aqueous solution is made in cyclodextrin and its derivative, is placed in constant temperature blender with magnetic forceIn, the organic solution containing curcumin is added, stirs while adding, includes 1.5-2.5h, sets and is filtered after being refrigerated in refrigerator, solid contentIt is washed, is dried under reduced pressure with dehydrated alcohol, obtain powdered curcumin cyclodextrin inclusion compound.Wherein the curcumin, cyclodextrin and haveThe mass ratio of solvent is preferably 1:3:10.
(2) polishing: adding suitable quantity of water after mixing for cyclodextrin and its derivative, is added organic molten containing curcuminLiquid is fully ground into paste, and 40-50 DEG C of drying is washed, and re-dry obtains powdered curcumin cyclodextrin inclusion compound.Wherein instituteThe mass ratio for stating curcumin, cyclodextrin and organic solvent is preferably 1:3:10.
(3) supercritical ultrasonics technology: adding suitable quantity of water after mixing for cyclodextrin and its derivative, is added organic molten containing curcuminThe precipitating of precipitation is filtered, is washed with dehydrated alcohol with ultrasonic generator ultrasound immediately after mixing by liquid, dry, is obtained powderedCurcumin cyclodextrin inclusion compound.
(4) freeze-drying: curcumin and cyclodextrin and its derivative are included in appropriate solution, use freeze-dryingSolvent is removed, powdered curcumin cyclodextrin inclusion compound is obtained.
(5) spray drying process: curcumin and cyclodextrin and its derivative are included in appropriate solution, use spray drying processSolvent is removed, powdered curcumin cyclodextrin inclusion compound is obtained.
In preparation method of the present invention step (b) the natural polysaecharides Colontargeted materids be chitosan, alginic acid and itsSodium salt, pectin and its derivative, Guar natural gum, inulin, amylose, cyclodextrin and its derivative, chondroitin sulfate, konjakuThe mixture of any one or two or more arbitrary proportions in glue, konjaku glucomannan and carob；The pectin and its spread outBiology is methyl pectin, methylolation pectin or amidated pectin.
The crosslinking curing of step (b) refers to curcumin cyclodextrin inclusion compound and natural polysaecharides in preparation method of the present inventionColontargeted materids are crosslinking curing 0.5-2h in 1-5% crosslinked fluid environment in mass percent concentration, the crosslinked fluidSolute is calcium chloride, calcium oxalate, calcium acetate, calcium carbonate, calcium bicarbonate, calcium sulfate, calcium monohydrogen phosphate, zinc acetate, zinc sulfate, sulfuric acidCopper, divalent metal one or more of halide arbitrary proportion mixture.
In preparation method of the present invention step (c) enteric material be crylic acid resin (such as Eudragit L30D-55, Eudragit L100, Eudragit L100-55, Eudragit S100, Eudragit FS30D etc.), cellulose acetatePhthalate ester (CAP), polyvinyl alcohol phthalate ester (PVAP), cellulose acetate benzenetricarboxylic acid ester (CAT), hypromellose phthalate(HPMCP), hydroxypropyl methyl cellulose acetate maleate (HPMCAM), hydroxypropyl methylcellulose succinate NF(HPMCAS), succinic acid ethyl cellulose (CAS), succinic acid hydroxypropyl methylcellulose (HPMCAS), 1,2,4- benzene threeFormic acid hydroxypropyl methyl cellulose (HPMCr), Opadry (Opadry), Su Teli (Sureteric), Sulisi(Sureleasse), the mixture of any one or two or more arbitrary proportions in shellac etc..
Step (c) the plasticizer is triethyl citrate (TEC), acetylation lemon triethylenetetraminehexaacetic acid in preparation method of the present inventionIt is ester, tributyl citrate (THC), glycerol, propylene glycol, polyethylene glycols (PEG), monoacetin, glyceryl diacetate, sweetOily triacetate, dibutyl sebacate, repefral, diethyl phthalate, dibutyl phthalate,The mixture of any one or two or more arbitrary proportions in castor oil, corn oil, fractionated coconut oil and liquid paraffin.
In preparation method of the present invention step (c) antitackiness agent be talcum powder, single stearic acid glycerine lipoprotein (GMS), stearic acid,The mixture of any one in magnesium stearate, silicone, titanium dioxide and silica or two or more arbitrary proportions.
In preparation method of the present invention step (c) solvent be acetone, isopropanol, ethyl alcohol, ethyl acetate, methylene chloride,The mixture of any one or the two or more arbitrary proportions such as methanol, ammonium hydroxide and water.
Coating described in step (c) can be coated by following two method in preparation method of the present invention:
(1) pan coating method: the segmented intestine targeted protomere of curcumin is put into coating pan, conventional technical means in the art is passed throughCoating pan revolving speed, coating temperature, the atomisation pressure of coating material solution, hydrojet speed parameters are adjusted, with enteric coating materialMaterial solution is coated, and after reaching predetermined coating weight gain, is drying to obtain.
(2) fluidized bed coating: the segmented intestine targeted protomere of curcumin is put into fluidized bed, passes through this field routine techniques handInlet air temperature, air quantity, atomizing pressure and the hydrojet speed parameters of section adjustment fluidized bed, are carried out with enteric-coating material solutionCoating, after reaching predetermined coating weight gain, is drying to obtain.
For the first time inclusion compound is made in curcumin and cyclodextrin and its derivative by the present invention, overcomes curcumin water-soluble low and steadyThe disadvantage of qualitative difference, then by the natural polysaecharides enzymatic degradable material system such as curcumin inclusion compound and chitosan, pectin, sodium alginateIt is coated at segmented intestine targeted protomere, then with enteric material, is prepared into the segmented intestine targeted coating protomere of curcumin, makes drug in colonSpots localization release, reaches segmented intestine targeted purpose.Specifically the innovation of the invention consists in that:
(1) curcumin cyclodextrin inclusion compound is prepared, the solubility and stability of curcumin is improved, is conducive to the dissolution of drugAnd absorption；Cyclodextrin inherently enzyme touching type Colontargeted materids simultaneously, cannot be hydrolyzed and absorb in stomach and small enteral, tieIt can be degraded by microorganisms in intestines and discharge drug；
(2) cyclodextrin inclusion compound is used alone, vulnerable to the influence of substance in vivo such as lipoid, cholesterol etc., in the gastrointestinal tractIt is unstable, ideal colon-targeted delivery system effect is not achieved；Therefore curcumin cyclodextrin inclusion compound and enzyme touching type is segmented intestine targetedSegmented intestine targeted protomere is further made in material such as chitosan, pectin, sodium alginate etc., and due to a variety of materials of use in conjunctionMaterial is degraded in colon by different enzymes, can achieve degradation sufficiently, release the drug complete purpose；
(3) it since polysaccharide Colontargeted materids have certain water solubility, is easily swollen or dissolves in upper digestive tract, influenceDrug is discharged in the positioning of colon, is made into insoluble protomere, is prevented Colontargeted materids in upper digestive tract from dissolving,Drug is reduced in the release for not reaching colon site；
(4) since the insoluble protomere of preparation belongs to matrix type structure, the drug inside protomere can pass through skeletonGap release, the drug of protomere adsorption is also easy release, therefore has some drugs when not reaching colon site and releaseIt is put into alimentary canal；The segmented intestine targeted protomere of preparation is coated using enteric-coating material, protomere is can protect and smoothly leads toStomach and small intestine are crossed, after reaching colon site, coating material dissolution exposes Colontargeted materids, degraded by colonic enzyme, it is ensured that medicineObject is only discharged in colon；
(5) other than a small amount of coating material of outer layer, remaining auxiliary material is natural enzyme touching for protomere agent prepared by the present inventionType Colontargeted materids can reduce volumes of formulation, increase enzyme degradation efficiency；
(6) protomere belongs to multi-dose type preparation, can be avoided and causes to stimulate to colon because drug local concentration is excessive；The destruction of individual drug containing units not will cause the change of whole drug release behavior, overcome single-dose type preparation (such as tablet) once preparingThe shortcomings that technique goes wrong, and entire preparation is caused to fail.
In conclusion the present invention is by curcumin and cyclodextrin according to specific proportion by studying for a long period of time and repetition testInclusion compound is made, a variety of natural polysaecharides materials is used in combination, insoluble segmented intestine targeted protomere is made, use enteric-coating materialSolution coating, is made colon specific drug preparation.Show only to lack when three above step be combined with each other by verification experimental verificationOne can not when, can just dramatically increase the water solubility and stability of curcumin, it is ensured that drug only colon site discharge, effectivelySolve colon targeting preparation polarization it is poor, drug release not exclusively, drug solubility is low and leads to absorb the FAQs such as bad, fromAnd complete the present invention.
Specific embodiment
Following example is for present invention be described in more detail, but the invention is not limited in any way.
1 curcumin of embodiment-Benexate Hydrochloride preparation
300g beta-cyclodextrin is taken to be dissolved in the ethanol water (mass percent concentration 50%) of 1000g；It is placed in constant temperature magneticIt in power blender, is kept for 40 DEG C of temperature, ethanol solution (curcumin 100g, dehydrated alcohol that 600g contains curcumin is added500g), stirring while adding, after including 2h, the suspension containing inclusion compound is set and is refrigerated in refrigerator for 24 hours, is then filtered, solid content is usedDehydrated alcohol washing, gained inclusion compound are dried under reduced pressure at 40 DEG C, obtain yellow curcumin-Benexate Hydrochloride powder.
The preparation of 2 curcumins of embodiment-hydroxypropylβ-cyclodextrin inclusion compound
300g hydroxypropylβ-cyclodextrin 1000mL water is dissolved, is placed in constant temperature blender with magnetic force, 40 DEG C while stirringThe acetone soln (curcumin 100g, acetone 1000g) that 1100g contains curcumin is added, 2h is stirred, with 0.45 μm of miillpore filterFiltering, filtrate are spray-dried to get curcumin-hydroxypropylβ-cyclodextrin inclusion compound yellow loose powder.
The preparation of 3 curcumins of embodiment-alpha-cyclodextrin inclusion compound
The alpha-cyclodextrin of 200g 1500mL water is dissolved, is placed in constant temperature blender with magnetic force, 40 DEG C are added while stirring900g contains the propylene glycol solution (curcumin 100g, propylene glycol 800g) of curcumin, 2h is stirred, with 0.45 μm of miillpore filter mistakeFilter, filtrate are freeze-dried for 24 hours to get curcumin-loose freeze-dried powder of alpha-cyclodextrin inclusion compound yellow.
The preparation of 4 curcumins of embodiment-gamma-cyclodextrin inclusion compound
The gamma-cyclodextrin of 500g 2500mL water is dissolved, is placed in constant temperature blender with magnetic force, 40 DEG C are added while stirring1600g contains the propylene glycol solution (curcumin 100g, propylene glycol 1500g) of curcumin, stirs 2h, 0.45 μm of miillpore filter mistakeFilter, filtrate are freeze-dried for 24 hours to get curcumin-loose freeze-dried powder of gamma-cyclodextrin inclusion compound yellow.
The preparation of the segmented intestine targeted protomere of 5 curcumin of embodiment
Curcumin-Benexate Hydrochloride 100g prepared by Example 1,4000g mass percent concentration, which is added, is1.5% sodium alginate aqueous solution is uniformly mixed, obtains solution A；The chitosan for being 2% by 2000g mass percent concentration is water-solubleThe calcium chloride water that liquid and 2000g mass percent concentration are 2% mixes, and adjusts pH value to 5.5 with sodium hydroxide solution, obtainsSolution B；Solution A is instilled in the solution B under stirring by internal diameter 0.9mm syringe needle with constant flow pump, crosslinking curing 2h, filtering is pureChange washing 3 times, for 40 DEG C of dryings of baking oven for 24 hours to get the segmented intestine targeted protomere of curcumin, partial size is 800~850 μm.
The preparation of the segmented intestine targeted protomere of 6 curcumin of embodiment
10000g sodium alginate and fruit is added in curcumin-hydroxypropylβ-cyclodextrin inclusion compound 100g prepared by Example 2(mass percent concentration of sodium alginate is 5% to the mixed solution of glue in mixed solution, the mass percent concentration of pectin is5%) it, is uniformly mixed, the calcium acetate that 10000g mass percent concentration is 4% is instilled by internal diameter 1.0mm syringe needle with constant flow pumpIt in aqueous solution, is stirred when being added dropwise, crosslinking curing 1h, filtering, purifying washing 3 times, 40 DEG C of dryings of baking oven are for 24 hours to get curcuminSegmented intestine targeted protomere, partial size are 900~950 μm.
The preparation of the segmented intestine targeted protomere of 7 curcumin of embodiment
Curcumin-hydroxypropylβ-cyclodextrin inclusion compound prepared by 100g embodiment 2 is added to the calcium sulfate saturation of 500gIt in solution, is uniformly mixed, the seaweed that 10000g mass percent concentration is 3% is instilled by internal diameter 0.8mm syringe needle with constant flow pumpIn acid sodium solution, 30min, filtering are stirred, solid is washed, then being impregnated in 4000g mass percent concentration is 5% chitosan10min in solution (solvent is the acetic acid that mass percent concentration is 5%), filtering, purifying washing 3 times, 40 DEG C of dryings of baking ovenFor 24 hours to get the segmented intestine targeted protomere of curcumin, partial size is 700~750 μm.
The preparation of the segmented intestine targeted protomere of 8 curcumin of embodiment
Curcumin-alpha-cyclodextrin inclusion compound 100g prepared by Example 3,4000g mass percent concentration, which is added, is1.5% sodium alginate aqueous solution is uniformly mixed, obtains solution A；The chitosan for being 2% by 2000g mass percent concentration is water-solubleThe calcium chloride water that liquid and 2000g mass percent concentration are 2% mixes, and adjusts pH value to 5.5 with sodium hydroxide solution, obtainsSolution B；Solution A is instilled in the solution B under stirring by internal diameter 0.9mm syringe needle with constant flow pump, crosslinking curing 2h, filtering is pureChange washing 3 times, for 40 DEG C of dryings of baking oven for 24 hours to get the segmented intestine targeted protomere of curcumin, partial size is 800~850 μm.
The preparation of the segmented intestine targeted protomere of 9 curcumin of embodiment
Curcumin-gamma-cyclodextrin inclusion compound 100g prepared by Example 4, addition 10000g sodium alginate and pectinMixed solution (mass percent concentration of sodium alginate is 5% in mixed solution, the mass percent concentration of pectin is 5%),It is uniformly mixed, the calcium acetate aqueous solution that 10000g mass percent concentration is 4% is instilled by internal diameter 1.0mm syringe needle with constant flow pumpIn, it is stirred when being added dropwise, crosslinking curing 1h, filtering, purifying washing 3 times, 40 DEG C of dryings of baking oven are for 24 hours to get curcumin colon targetTo protomere, partial size is 900~950 μm.
The preparation of 10 curcumin colon specific drug preparation of embodiment
Weigh raw material by following mass percent: enteric material Eudragit S100 is 50g, plasticizer lemon triethylenetetraminehexaacetic acidEster dosage is 30g, antitackiness agent amount of titanium is 60g, ethyl alcohol 860g, mixes, enteric-coating material solution is made；It will be realThe segmented intestine targeted protomere of curcumin for applying the preparation of example 5 is put into fluidized bed, sprays art for coating packet enteric layer, nozzle diameter the bottom of usingFor 1.0mm, process conditions are as follows: 40 DEG C of inlet air temperature, 35 DEG C of leaving air temp, air quantity 130m3/ h, atomizing pressure 0.4bar, hydrojetSpeed 1.0ml/min, coating weight gain are 4% stopping coating to get product.
The preparation of 11 curcumin colon specific drug preparation of embodiment
Raw material is weighed by following mass percent: enteric material Eudragit L100 100g, plasticizer polyethylene glycol6000 dosages are 40g, antitackiness agent amount of talc is 80g, and solvent is isopropanol 780g, mix, it is molten that enteric-coating material is madeLiquid；The segmented intestine targeted protomere of 6 curcumin of embodiment is put into fluidized bed, art for coating packet enteric layer is sprayed the bottom of using, nozzle is straightDiameter is 1.0mm, process conditions are as follows: 40 DEG C of inlet air temperature, 30 DEG C of leaving air temp, and air quantity 130m3/ h, atomizing pressure 0.5bar, sprayLiquid speed degree 1.0ml/min；After coating weight gain reaches 4%, stop coating to get product.
The preparation of 12 curcumin colon specific drug preparation of embodiment
Raw material is weighed by following mass percent: enteric material cellulose acetate phthalate 50g, plasticizer phthalic acidDimethyl ester dosage is 50g, antitackiness agent silica content is 60g, and solvent is acetone 840g, mixes, enteric-coating material is madeSolution；The segmented intestine targeted protomere of 7 curcumin of embodiment is put into centrifugation rotation seed-coating machine, coating temperature is room temperature, spraying pressurePower is 0.1MPa, and hydrojet speed is 1.0ml/min, after coating weight gain reaches 3%, stops coating to get product.
The preparation of 13 curcumin colon specific drug preparation of embodiment
Weigh raw material by following mass percent: enteric material shellac 200g, plasticizer triethyl citrate dosage are50g, antitackiness agent stearic acid dosage are 100g, and solvent is ethyl alcohol 650g, mix, enteric-coating material solution is made；By embodiment 8The segmented intestine targeted protomere of curcumin is put into centrifugation rotation seed-coating machine, and coating temperature is room temperature, atomisation pressure 0.1MPa, hydrojetSpeed is 1.0ml/min；After coating weight gain reaches 5%, stop coating to get product.
Embodiment 14
Weigh raw material by following mass percent: enteric material Eudragit FS30D dosage is 200g, plasticizer lemonTriethylenetetraminehexaacetic acid ester dosage is 50g, and antitackiness agent amount of talc is 100g, and solvent is water 650g, mixes, it is molten that enteric-coating material is madeLiquid；The segmented intestine targeted protomere of 9 curcumin of embodiment is put into fluidized bed, art for coating packet enteric layer is sprayed the bottom of using, nozzle is straightDiameter is 1.0mm, process conditions are as follows: 40 DEG C of inlet air temperature, 35 DEG C of leaving air temp, and air quantity 130m3/ h, atomizing pressure 0.4bar, sprayLiquid speed degree 1.0ml/min；After coating weight gain reaches 4%, stop coating to get product.
Comparative example 1 prepares the segmented intestine targeted coating protomere of curcumin
It is in 1.5% sodium alginate soln by the mass percent concentration that 4000g is added in 25g curcumin raw material, mixing is equalIt is even, obtain solution A；It is by the mass percent concentration of chitosan aqueous solution and 2000g that 2000g mass percent concentration is 2%2% calcium chloride water mixing adjusts pH value to 5.5 with sodium hydroxide solution, obtains solution B；Solution A is passed through with constant flow pumpInternal diameter 0.9mm syringe needle instills in the lower solution B of stirring, crosslinking curing 2h, filtering, and purifying is washed 3 times, 40 DEG C of dryings of baking oven for 24 hours,Up to the segmented intestine targeted protomere of curcumin, partial size is 800~850 μm；Then segmented intestine targeted to curcumin micro- according to embodiment 11Micelle is coated, and after coating weight gain reaches 4%, stops coating to get product.
Comparative example 2 prepares the segmented intestine targeted coating protomere of curcumin
25g curcumin is added to 4000g mass percent concentration to be uniformly mixed in 1.5% sodium alginate soln, thenThe beta-cyclodextrin of 75g is added in above-mentioned solution and mixes to obtain solution A；The chitosan water for being 2% by 2000g mass percent concentrationThe calcium chloride water that the mass percent concentration of solution and 2000g are 2% mixes, and adjusts pH value to 5.5 with NaOH solution, isSolution B；Instill solution A in the solution B under stirring by internal diameter 0.9mm syringe needle with constant flow pump, crosslinking curing 2h is filtered, pureChange washing 3 times, for 40 DEG C of drying of baking oven for 24 hours to get the segmented intestine targeted protomere of curcumin, partial size is 800~850 μm, then according toEmbodiment 11 is coated protomere, after coating weight gain reaches 4%, stops coating to get product.
The preparation of the 3 segmented intestine targeted coating tablet of curcumin cyclodextrin inclusion compound of comparative example
Curcumin-Benexate Hydrochloride is prepared according to the method for embodiment 1, prepares tablet as follows；Take turmericPectin 100g, lactose 70g, microcrystalline cellulose 30g is added in element-Benexate Hydrochloride 100g, is uniformly mixed, with quality percentageThe HPMC K4M that specific concentration is 5% does binder softwood, the granulation of 20 meshes, 60 DEG C of dry 2h, 16 mesh sieves, addition 1%Magnesium stearate be uniformly mixed, select the stamping of 10mm scrobicula, slice weight 0.35g.Piece is placed in coating pan, with embodiment 11Coating material solution formula is coated, and coating temperature is room temperature, and atomisation pressure 0.1MPa, hydrojet speed is 1.0ml/min；After coating weight gain reaches 4%, stop coating to get product.
Preparation prepared by the embodiment of the present invention and comparative example is carried out performance detection by embodiment 15.
One, the stability test of curcumin bulk pharmaceutical chemicals and curcumin inclusion compound
By taking embodiment 1,2 as an example, curcumin-Benexate Hydrochloride and reality prepared by curcumin bulk pharmaceutical chemicals, embodiment 1Curcumin-hydroxypropylβ-cyclodextrin the inclusion compound for applying the preparation of example 2, which is respectively placed in 40 DEG C of insulating boxs, carries out heat stabilization test, fixedWhen sample, measure the content of curcumin, the results are shown in Table 1.
The assay result (%) of 1 curcumin bulk pharmaceutical chemicals of table and curcumin inclusion compound heat stabilization test
| Time (day) | Curcumin bulk pharmaceutical chemicals | Curcumin-Benexate Hydrochloride | Curcumin-hydroxypropylβ-cyclodextrin inclusion compound |
| 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 |
By curcumin-Benexate Hydrochloride prepared by curcumin bulk pharmaceutical chemicals, embodiment 1 and turmeric prepared by embodiment 2Element-hydroxypropylβ-cyclodextrin inclusion compound is respectively placed in the lighting box that illumination is 4500 ± 500lx and carries out photo-stability testing, fixedWhen sample, measure the content of curcumin, the results are shown in Table 2.
The assay result (%) of 2 curcumin bulk pharmaceutical chemicals of table and curcumin cyclodextrin inclusion compound photo-stability testing
| Time (day) | Curcumin bulk pharmaceutical chemicals | Curcumin-Benexate Hydrochloride | Curcumin-hydroxypropylβ-cyclodextrin inclusion compound |
| 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 |
By the stability test of Tables 1 and 2, the result shows that, the thermal stability of curcumin inclusion compound and anti-light solution property are compared with gingerFlavine bulk pharmaceutical chemicals are significantly improved；Illustrate that the unstable double bond structure of curcumin may be included in cyclodextrin tubular structure,Contacting for curcumin and ambient enviroment has been cut off in a way, to play a protective role, can guarantee that curcumin is producingWith the stability in storage process.
Two, the solubility test of curcumin bulk pharmaceutical chemicals and curcumin inclusion compound
By taking Examples 1 and 2 as an example, curcumin-beta-cyclodextrin packet prepared by excessive curcumin bulk pharmaceutical chemicals, embodiment 1Curcumin-hydroxypropylβ-cyclodextrin the inclusion compound for closing object and the preparation of embodiment 2 is separately added into 100ml distilled water, is placed in 25 DEG CIn constant-temperature table, 48h, sampling are shaken, 0.45 μm of filtering with microporous membrane measures the content of curcumin in filtrate, the results are shown in Table 3.
25 DEG C of solubility test results of 3 curcumin bulk pharmaceutical chemicals of table and curcumin cyclodextrin inclusion compound (μ g/ml)
| Curcumin bulk pharmaceutical chemicals | Curcumin-Benexate Hydrochloride | Curcumin-hydroxypropylβ-cyclodextrin inclusion compound |
| 20.1 | 210.5 | 4020.7 |
By 3 result of table as it can be seen that after cyclodextrin inclusion compound is made in curcumin its solubility can be significantly improved, so that turmericElement can dissolve and absorb rapidly after colon site drug release, play curative effect.
Three, the vitro release test of the segmented intestine targeted protomere of curcumin and segmented intestine targeted coating protomere
By taking embodiment 5,6,7 and embodiment 10,11 as an example, by the segmented intestine targeted micro- glue of curcumin of the preparation of embodiment 5,6,7The curcumin colon specific drug preparation that grain and embodiment 10,11 are finally prepared carries out vitro release research.Protomere is setTurn in basket in digestion instrument, revolving speed 100r/min, first in pH1.2 hydrochloric acid solution, is measured by sampling in 2h；It is then transferred to pH4.5In acetate buffer solution, it is measured by sampling in 4h；It is then transferred in pH5.5 phosphate buffer solution, is measured by sampling in 6h；MostAfter be transferred in pH6.5 phosphate buffer, in 8h be measured by sampling.Cumulative release percentage is calculated, the results are shown in Table 4.
The cumulative in vitro medicine realeasing rate (%) of the segmented intestine targeted protomere of 4 curcumin of table and segmented intestine targeted coating protomere
| 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 |
By 4 result of table as it can be seen that the not enteric coated protomere for preparing of embodiment 5, embodiment 6 and embodiment 7 is artificialThere is certain drug release in gastric juice and simulated intestinal fluid, and the segmented intestine targeted micro- glue of curcumin that embodiment 10 and 11 is finally preparedGrain does not have drug release.
Four, the vitro release test of the segmented intestine targeted coating protomere of curcumin
By taking embodiment 10,11 as an example, the segmented intestine targeted coating protomere of curcumin prepared by embodiment 10,11 carries out externalRelease research.Protomere is placed in digestion instrument and turns in basket, revolving speed 100r/min, and dissolution medium is containing in 4% rat cecal respectivelyTolerant pH7.0 phosphate buffer (A liquid) and the pH7.0 phosphate buffer (B liquid) without rat cecal content, in1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h are measured by sampling, and calculate cumulative release percentage, the results are shown in Table 5.
The cumulative in vitro medicine realeasing rate (%) of the segmented intestine targeted coating protomere of 5 curcumin of table
| 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 |
By 5 result of table as it can be seen that in the dissolution medium of pH7.0, enteric-coating material dissolution exposes protomere.TurmericThe segmented intestine targeted coating protomere of element cannot release the drug completely in the dissolution medium without rat cecal content, and contain ratIt releases the drug in the medium of cecal content quickly and completely, this is because containing in rat cecal content, there are many enzymes, can degradeThe composition material of protomere destroys the skeleton structure of protomere, comes out drug release.
Five, vitro release test of the comparative example 1,2,3 in rat colon content dissolution medium.
Curcumin colon targeting preparation prepared by comparative example 1,2,3 carries out vitro release research.Using Rotating shaker, turnFast 100r/min, dissolution medium be the pH7.0 phosphate buffer containing 4% rat cecal content, in 1h, 2h, 3h, 4h, 6h,8h, 10h and 12h are measured by sampling, and calculate cumulative release percentage, the results are shown in Table 6.
The cumulative in vitro medicine realeasing rate (%) of the curcumin colon targeting preparation of 6 comparative example of table preparation
| 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 inclusion compound, solubility is lower, noIt can release the drug complete；Containing a large amount of non-colon degradable materials in tablet prepared by comparative example 3, cannot be degraded by colonic enzyme, therefore releaseMedicine is slower.
Six, dissolution test of the segmented intestine targeted protomere of curcumin in different enzyme solutions
Curcumin colon specific drug preparation prepared by embodiment 10 carries out vitro release research.Using Rotating shaker,Revolving speed 100r/min, dissolution medium are that C liquid (the pH7.0 phosphate buffer containing 1% glycosidase), D liquid are (poly- containing 2% shell respectivelyThe pH7.0 phosphate buffer of carbohydrase), E liquid (the pH7.0 phosphate buffer containing 1% glycosidase and 2% chitosan enzyme), in1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h are measured by sampling, and calculate cumulative release percentage, the results are shown in Table 7.
Cumulative in vitro drug release of the segmented intestine targeted coating protomere of the curcumin of 7 embodiment 7 of table preparation in different enzyme solutionsRate (%)
| 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 |
By 7 result of watch as it can be seen that the segmented intestine targeted coating protomere of curcumin is released the drug in single enzyme solutions relatively slowly, in complex enzymeIt releases the drug in solution very fast.Illustrate that a variety of enzymatic degradable materials, which are used in combination, prepares colon targeting preparation, the work of different enzymes in colonIt can be degraded rapidly under, to discharge drug.