CN100340238C - Curcumin solid dispersion, and its preparing method and use - Google Patents
Curcumin solid dispersion, and its preparing method and use Download PDFInfo
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- CN100340238C CN100340238C CNB2005100350608A CN200510035060A CN100340238C CN 100340238 C CN100340238 C CN 100340238C CN B2005100350608 A CNB2005100350608 A CN B2005100350608A CN 200510035060 A CN200510035060 A CN 200510035060A CN 100340238 C CN100340238 C CN 100340238C
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Abstract
The present invention discloses solid dispersion of curcumin, a preparation method thereof and the application thereof. In the method, curcumin and polyvinylpyrrolidone are dissolved in an organic solvent (such as absolute ethyl alcohol, propyl alcohol, isopropyl alcohol, ethyl acetate, etc.) according to the mass ratio of 1:4 to 1:15, most of ethyl alcohol is removed to form paste under the condition of distillation at reduced pressure at the temperature of 55 to 95DEG C, and the paste is rapidly poured into a stainless steel disc, dried in a vacuum oven at the temperature of 60 to 90DEG C and pulverized by a pulverizer to obtain the solid dispersion of curcumin. The solid dispersion of curcumin of the present invention has the advantages of high water solubility and high bioavailability. The solid dispersion of curcumin is importantly applied in the preparation of medicines or health products for treating gastric ulcers, relieving cough, eliminating phlegm and resisting inflammation.
Description
Technical field
The present invention relates to field of medicinal compositions, relate to curcumin solid dispersion and preparation method thereof and application specifically.
Background technology
Modern pharmacological research shows in the Rhizoma Curcumae Longae that main effective ingredient is that (curcumin Cur), has many-sided pharmacological actions such as antiinflammatory, blood fat reducing, anticancer, antioxidation to curcumin.Though curcumin has pharmacotoxicological effect widely, the utmost point is insoluble in water, and bioavailability is extremely low simultaneously, has limited to it greatly and has been applied to experimentation and clinical development.Give the oral 1gkg of rat
-1Curcumin, about 75% from the feces discharge, and has only the curcumin of trace in the urine, and curcumin content and bile excretion result show that intestinal absorption is bad in the mensuration blood; The mode that the animal pharmacology experiment gives curcumin adopts lumbar injection, need the dissolving of 0.5% dmso solution, and the solution instability, show because the poorly water-soluble of curcumin and oral absorption is poor, bioavailability is low limits its rational Application in human patient.There is report that curcumin and macromolecular substances are formed complex to improve its water solublity, as gelatin, polysaccharide and albumen and HP-etc.But the complex preparation process is slow, and curcumin degraded easily in alkaline solution, in the phosphate buffer of pH7.4, and 25 μ molL
-1The very fast degraded of curcumin, be reduced to approximately 50% behind the absorption value 5min of its 426nm, only surplus 10% behind the 10min, last solution is colourless.So the present invention utilizes polyvinylpyrrolidone, adopt solid dispersion technology to disperse curcumin, to improve 880 times of its dissolubility (than using HP-to improve 150 times high), can improve external dissolution rate and bioavailability simultaneously.
Summary of the invention
The objective of the invention is low, the absorption difference problem of water solublity, provide a kind of good water solubility, the curcumin solid dispersion that bioavailability is high at above-mentioned curcumin.
Another object of the present invention provides the preparation method of above-mentioned curcumin solid dispersion.
Another object of the present invention provide above-mentioned curcumin solid dispersion be used for the treatment of gastric ulcer, antitussive in preparation, eliminate the phlegm and antiphlogistic medicine or health product in application.
The present invention adopts solid dispersion technology, utilizes polyvinylpyrrolidone (PVP-k30) as carrier, the preparation curcumin solid dispersion.Curcumin solid dispersion of the present invention, comprise curcumin and polyvinylpyrrolidone, mass ratio is 1: 4～1: 15, curcumin and polyvinylpyrrolidone are dissolved in organic solvent in proportion, under 55～95 ℃ of distilling under reduced pressure, remove most of organic solvent to becoming pasty state, fall rapidly as go in the stainless steel disc and dry, pulverize with pulverizer and obtain curcumin solid dispersion at 60～90 ℃ of following vacuum drying ovens.
Above-mentioned organic solvent is dehydrated alcohol, propanol, isopropyl alcohol or ethyl acetate.
The solid dispersion of Cur-PVPk30 is to form like this: in the solvent system of saturated Cur-PVPk30, evaporating solvent, Cur concentration reaches dissolubility gradually, and and then cross dissolubility and become supersaturated solution, degree of super saturation can strengthen gradually.In this course, certain density PVPk30 effectively suppresses the formation and crystalline the growing up of curcumin nucleus.Just obtained the formed solid dispersion of Cur-PVPk30 after volatilizing solvent.
The differential scanning calorimetric analysis results suggest, curcumin is not to exist with crystallization mode in the solid dispersion, but is dispersed in the PVP-k30 carrier with molecularity; The analysis of X-ray powder diffraction further specifies in solid dispersion, and the Cur crystal disappears, and is scattered among the unformed PVP-k30 with unformed or molecular forms, thereby reaches the high degree of dispersion state, and this dispersion is relevant with the amount of PVP-k30.The mass ratio of curcumin and PVP-k30 is generally (1: 4)～(1: 15) in the curcumin solid dispersion, and ratio commonly used is (1: 6)～(1: 12), and the most frequently used dosage is (1: 7)～(1: 10).
Solid dispersion method improves the stripping mechanism of curcumin: (1) curcumin exists with amorphous forms in solid dispersion, the surface area when having increased its dissolving greatly; (2) phenolic hydroxyl group in the Cur molecule and the carbonyl in the PVPk30 molecule form hydrogen bond, make less relatively curcumin molecule enter the PVP macromole on the one hand with unformed state, on the other hand, the formation of hydrogen bond does not change PVP character soluble in water, make its easily dissolving that becomes in the PVP macromole so that the curcumin molecule of indissoluble is scattered in by hydrogen bond.The bonded drug molecule quantity of each PVP molecular energy of PVP for certain molecular weight is certain, the curcumin of indissoluble often has certain crystal state, the consumption of PVP is not enough to make curcumin still based on crystalline state in conjunction with a certain amount of curcumin, and changes in solubility is little.Just can make medicine show as unformed dispersion so PVP must reach certain content, its dissolubility could obviously increase, and just can reach rapidly-soluble purpose.(3) curcumin in the solid dispersion is in upper state, is supersaturated solution, very easily reassembles into bulky grain, and centering on of PVPk30 effectively prevents this gathering.
Curcumin solid dispersion can cooperate with the medicament filler of normal conventional, makes through conventional method; Can make suitable dosage form as required, as injection, transfusion, tablet, powder, granule, capsule, syrup or suppository etc.Usually use with oral way, can certainly adopt other administering mode; Its, using dosage was generally about 0.001～200000 milligram every day, and adult's usual amounts is 0.002～80000 milligram of every day, and the most frequently used dosage is 0.01～30000 milligram.Once a day or divide for several times and use.The curcumin solid dispersion of the present invention preparation is used for the treatment of gastric ulcer, antitussive in preparation, eliminate the phlegm and antiphlogistic medicine or health product in important use is arranged.
Beneficial effect of the present invention: the present invention is carrier with PVP-k30, adopts solvent method to prepare curcumin consubstantiality dispersion and has significantly improved the dissolution rate of curcumin and dissolubility, bioavailability.When curcumin and PVP-k30 mass ratio were 1: 10, its dissolution was up to 90%, and dissolubility is 882 times of the former medicine of curcumin.Prepared curcumin solid dispersion is used for the treatment of gastric ulcer, antitussive in preparation, eliminate the phlegm and antiphlogistic medicine or health product in important use is arranged.Simultaneously, curcumin solid dispersion preparation method of the present invention is simple, and cost is low.
Description of drawings
Fig. 1 is the differential scanning calorimetric collection of illustrative plates of curcumin powder, PM and SD;
Fig. 2 is the X-ray powder diffraction collection of illustrative plates of curcumin powder and PM thereof;
Fig. 3 is the X-ray powder diffraction collection of illustrative plates of curcumin powder and SD;
Fig. 4 is the curcumin standard curve;
Fig. 5 is curcumin and PM dissolution in vitro curve chart thereof;
Fig. 6 is curcumin and SD dissolution in vitro curve chart thereof;
Fig. 7 is the HPLC chromatogram of curcumin in the rat plasma;
Fig. 8 is a curcumin blood plasma standard curve;
Curve when Fig. 9 is curcumin solid dispersion rat body giving drugs into nose.
Wherein, in Fig. 1, A: curcumin; B: polyvinylpyrrolidone k30; C: curcumin-polyvinylpyrrolidone-k30 solid dispersion (1: 2); D: curcumin-polyvinylpyrrolidone-k30SD (1: 4); E: curcumin-polyvinylpyrrolidone-k30SD (1: 6); F: curcumin-polyvinylpyrrolidone-k30SD (1: 8); G: curcumin-polyvinylpyrrolidone-k30SD (1: 10); H: curcumin-polyvinylpyrrolidone-k30PM (1: 8); I: curcumin-polyvinylpyrrolidone-k30PM (1: 10).
In Fig. 2, A: polyvinylpyrrolidone k30; B: curcumin-polyvinylpyrrolidone-k30PM (1: 2); C: curcumin-polyvinylpyrrolidone-k30PM (1: 4); D: curcumin-polyvinylpyrrolidone-k30PM (1: 6); E: curcumin-polyvinylpyrrolidone-k30PM (1: 8); F: curcumin-polyvinylpyrrolidone-k30PM (1: 10); G: curcumin.
In Fig. 3, A: polyvinylpyrrolidone k30; B: curcumin-polyvinylpyrrolidone-k30SD (1: 2); C: curcumin-polyvinylpyrrolidone-k30SD (1: 4); D: curcumin-polyvinylpyrrolidone-k30SD (1: 6); E: curcumin-polyvinylpyrrolidone-k30SD (1: 8); F: curcumin-polyvinylpyrrolidone-k30SD (1: 10); G: curcumin.
In Fig. 5,
Curcumin-polyvinylpyrrolidone-k30PM (1: 10);
In Fig. 6,
Curcumin-polyvinylpyrrolidone-k30SD (1: 10);
In Fig. 7, A: blank plasma; B: contain curcumin and interior target standard serum; C: the sample serum after the administration; 1: estradiol sample cutting edge of a knife or a sword; 2: curcumin sample peak.
The specific embodiment
The preparation of embodiment 1 solid dispersion and dissolubility thereof, determination of dissolution rate.
1.1 medicine, reagent and instrument curcumin (Tianjin recovery fine chemistry industry institute); Polyvinylpyrrolidone k30 (Polyvinylpyrrolidone k30, south, Hainan HANGYAO industry company limited); Dehydrated alcohol (Tianjin chemical industry all generations company limited); Above reagent is analytical pure.RCZ-8A intellectual drug digestion instrument (Precision Instrument Factory, Tianjin Univ.); UV-2102PC type ultraviolet spectrophotometer (UNICO Instr Ltd.); DSC-204 type differential scanning calorimeter (German Netzsch company); D/Max-IIIA type X-ray powder (polycrystalline) diffractometer (Japanese motor of science).
1.2 preparation physical mixture (the physical mixture of physical mixture and solid dispersion, PM): curcumin and PVP-k30 cross 80 mesh sieves respectively, accurate then title is fixed, be made into 1: 2 (w/w), 1: 4,1: 6,1: 8,1: 10 mixture, fully mixing promptly gets physical mixture.Solid dispersion (solid dispersion, SD): select for use dehydrated alcohol to make solvent, prepare with solvent method.A certain proportion of curcumin and PVP-k30 are dissolved in an amount of ethanol, under 65 ℃, remove most ethanol, fall rapidly as go in the stainless steel disc and dry, pulverize with pulverizer at 80 ℃ of following vacuum drying ovens to becoming pasty state.Make the curcumin solid dispersion that mass ratio is respectively 1: 2,1: 4,1: 6,1: 8,1: 10.
Differential scanning calorimetric experiment (DSC) working condition: with empty aluminum pincers pot is reference substance, puts into about 5mg sample in another aluminum pot, 10 ℃ of min of scanning speed
-1, 0～240 ℃ of sweep limits, the DSC curve chart of drafting curcumin material powder, PM and SD.
X-ray powder diffraction experimental work condition: copper target; High voltage intensity 40KV; Pipe flow 20mA; Disperse, scattering and accept 1 ° respectively of slit, 1 °, 0.3mm; 3 °～60 ° of the 4 °/min sweep limitss that tests the speed (2 θ).Draw the X-ray powder diffraction curve chart of curcumin material powder, PM and SD.
1.3 the mensuration of dissolution and dissolubility
The foundation of analytical method detects wavelength determination: take by weighing curcumin respectively and PVP-k30 is an amount of, be mixed with the solution of suitable concentration with the distilled water (representing) that contains 2% dense HCl (w/w), 10% ethanol (V/V) with solution A, and be blank with this solution, in 200～600nm scope, scan.The result shows that curcumin has maximum absorption band at the 428nm place; And PVP-k30 is noiseless to the mensuration of curcumin herein.Therefore, selected 428nm is as measuring wavelength.Standard curve: it is an amount of that precision takes by weighing curcumin, is mixed with the standard solution of series concentration with A solution, measures trap in the 428nm place, with concentration (C) trap (A) carried out linear regression.
PM and SD sample that PM and SD determination of dissolution rate get curcumin 368.4mg, contain curcumin 368.4mg carry out the dissolution test.5 parts of every group of sample parallel assays are undertaken by 2000 editions second methods of Chinese Pharmacopoeia.Dissolution medium is the A solution of 1000mL, 37 ± 0.5 ℃ of temperature, rotating speed 100 ± 1r/min.Respectively 5,10,15,30,45,60,90min sampling 5mL and mend the solution A of equal volume, sample is through 0.8 μ m filtering with microporous membrane.Get subsequent filtrate dilution back and measure trap in the 428nm place, calculate the dissolution of curcumin.Stripping curve is seen figure.Precision test: after the dissolution determination test was finished, replication discharged the trap 5 times of liquid, the RSD=0.383% of trap as a result with a 90min.Stability test: after the dissolution determination test was finished, the trap that discharges liquid with 90min was a starting point, measured 1 time its trap RSD=1.286% (n=3) every 1h.
The solubility test of PM and SD adds to excessive Cur, PM and SD in the tool plug conical flask that fills an amount of solution A, in 25 ℃, 100r/min jolting respectively.Equality of temperature leaves standstill, a sampling at regular intervals, the concentration of mensuration curcumin.
The result
The preparation of solid dispersion
Successfully prepared the PVP-Cur ratio and be 10: 1,8: 1,6: 1,4: 1,2: 1 solid dispersion.PVPk30 is an amorphous substance, fusing point height (decomposing more than 200 ℃), and the useable solvents method is made solid dispersion, and dry product is more easily pulverized.
Differential scanning calorimetric analysis
The DSC curve is seen Fig. 1, and PVP-k30 and curcumin have absworption peak at 74.6,187 ℃ respectively, and the crystalline endothermic peak reach of all purer adjuvant of its endothermic peak of the solid dispersion of making and Cur shows that carrier and Cur have formed eutectic.The Cur endothermic peak of the physical mixture of Cur and PVP-k30 (1: 8,1: 10) partly disappears, but not exclusively.The endothermic peak of Cur obviously moves forward (1: 2,1: 4) or complete obiteration (1: 6,1: 8,1: 10) on the DSC curve of Cur and PVP-k30 solid dispersion.
The X-ray powder diffraction is analyzed
Shown in Fig. 2,3.Cur has strong diffraction maximum between 3 °～60 °.PVP-k30 belongs to amorphous article, does not have the crystal diffraction peak.The crystal diffraction peak still appears in the X-ray diffractogram of the physical mixture of Cur and PVP-k30 (1: 10), but this diffraction maximum by the diffraction broadband cover of PVP-k30 with overlapping, may be less relevant with Cur proportion in the sample.Show in the X-ray diffractogram that the Cur-PVPk30 ratio is that the crystal diffraction peak of 1: 6 o'clock Cur is promptly not obvious, and along with the increasing of PVPK30 ratio, collection of illustrative plates is more and more near the PVP-k30 diffracting spectrum, the diffraction maximum of Cur disappears more obviously.
Solid dispersion system is to the influence of external stripping
As shown in Figure 4, standard curve equation C=0.2974A+0.0011, r=0.999, the range of linearity: 0.025～0.1667 * 10
-4Mol/L.
The dissolution in vitro result is shown in Fig. 5,6, and the dissolution of the solid dispersion of various ratios all is higher than raw material, and Cur and PVP-k30 ratio are that 1: 8,1: 10 SD promptly surpasses 80% at the dissolution of 5min; Ratio be 1: 6 the dissolution of SD in 90min not to 50%, and ratio is 1: 4 following SD, crosses 10% at the dissolution of 90min.The PM of each ratio Cur and PVP-k30 at the dissolution of 90min all not to 5%.As seen, solid dispersion system has increased the in-vitro release rate of medicine greatly, and along with the increase of carrier ratio among the SD, solubilization is more obvious.
Solid dispersion system is to the influence of dissolubility
As shown in table 1, because PVP-k30 is a water soluble polymer, dissolve each other fully with water, the dissolubility of curcumin SD and PM is actually the dissolubility of curcumin.The concentration that this paper records when no longer dissolving with curcumin SD, PM is its dissolubility.After in excessive Cur, SD, PM, adding an amount of solution A and shake well 30min, record under identical sample time, the curcumin dissolubility increases with the increase of PVPk30 ratio among SD, the PM, and comparing its dissolubility with the curcumin raw material significantly increases (P＜0.001).Under the identical prescription proportioning, the PM dissolubility is less than the SD dissolubility; The Cur dissolubility is stabilized in 0.006 to 0.007mgmL
-1, among the SD (1: 10) the curcumin dissolubility when 0.5h up to 6.088mgmL
-1, compare with curcumin dissolubility under the same time, improved more than 880 times.
The experiment of table 1 curcumin PM dissolution in vitro (x ± SD, n=5)
| Time (min) | Stripping percentage rate (%) | |||||
| Cur | PM(1∶2) | PM(1∶4) | PM(1∶6) | PM(1∶8) | PM(1∶10) | |
| 5 10 15 30 45 60 90 | 0.55±0.15 0.58±0.12 0.73±0.17 0.97±0.27 1.62±0.26 2.16±0.27 2.36±0.34 | 0.55±0.15 0.58±0.12 0.91±0.30 1.59±0.29 2.25±0.32 2.36±0.29 2.39±0.33 | 0.67±0.17 0.88±0.20 1.09±0.22 1.74±0.26 2.13±0.28 2.22±0.21 2.39±0.23 | 0.77±0.16 1.06±0.25 1.39±0.26 2.65±0.18 2.77±0.35 2.94±0.19 3.03±0.22 | 1.65±0.19 1.95±0.15 2.63±0.20 3.29±0.15 3.76±0.17 3.79±0.16 3.88±0.19 | 2.85±0.20 3.04±0.11 3.17±0.13 3.79±0.15 3.90±0.12 3.93±0.15 4.15±0.16 |
Table 2 curcumin and SD dissolution in vitro data thereof (x ± SD, n=5)
| Time (min) | Stripping percentage rate (%) | |||||
| Cur | SD(1∶2) | SD(1∶4) | SD(1∶6) | SD(1∶8) | SD(1∶10) | |
| 5 10 15 30 45 60 90 | 0.55±0.15 0.58±0.12 0.73±0.17 0.97±0.27 1.62±0.26 2.16±0.27 2.36±0.34 | 0.32±0.17 1.43±0.19 3.49±0.24 3.74±0.29 3.85±0.23 3.90±0.22 3.99±0.16 | 1.04±0.20 4.59±0.33 5.23±0.30 6.36±0.28 6.62±0.25 7.55±0.27 7.55±0.21 | 17.35±2.67 20.39±2.36 22.62±2.10 39.21±3.30 41.00±3.04 42.25±1.97 41.98±2.25 | 75.70±3.57 80.52±3.11 85.43±2.45 85.96±3.02 86.94±2.23 87.30±2.70 87.84±2.23 | 81.32±2.46 81.50±2.95 84.00±3.18 86.05±2.97 87.03±2.16 87.57±2.16 88.19±2.36 |
The differential scanning calorimetric analysis results suggest, curcumin is not to exist with crystallization mode in the solid dispersion, but is dispersed in the PVP-k30 carrier with molecularity; The analysis of X-ray powder diffraction further specifies in solid dispersion, and the Cur crystal disappears, and is scattered among the unformed PVP-k30 with unformed or molecular forms, thereby reaches the high degree of dispersion state, and this dispersion is relevant with the amount of PVP-k30.
Preparation situation from result of study and solid dispersion, we think that the solid dispersion of Cur-PVPk30 is to form like this: in the solvent system of saturated Cur-PVPk30, evaporating solvent, Cur concentration reaches dissolubility gradually, and and then cross dissolubility and become supersaturated solution, degree of super saturation can strengthen gradually.In this course, certain density PVPk30 effectively suppresses the formation and crystalline the growing up of curcumin nucleus.Just obtained the formed solid dispersion of Cur-PVPk30 after volatilizing solvent.
By comparative study, determine that the dissolution rate of curcumin solid dispersion, physical mixture and dissolubility and the former powder differences of medicine all have significance.The external rate of releasing drug and the dissolubility of curcumin solid dispersion and physical mixture thereof all are significantly increased than crude drug, but the two solubilizing mechanism difference.Physical mixture is accelerated the medicine stripping, is because water-solubility carrier has increased the event of the wettability of medicine; And solid dispersion method can significantly improve the mechanism of its stripping and comprises: (1) curcumin exists with amorphous forms in solid dispersion, the surface area when having increased its dissolving greatly; (2) phenolic hydroxyl group in the Cur molecule and the carbonyl in the PVPk30 molecule form hydrogen bond, make less relatively curcumin molecule enter the PVP macromole on the one hand with unformed state, on the other hand, the formation of hydrogen bond does not change PVP character soluble in water, make its easily dissolving that becomes in the PVP macromole so that the curcumin molecule of indissoluble is scattered in by hydrogen bond.The bonded drug molecule quantity of each PVP molecular energy of PVP for certain molecular weight is certain, the curcumin of indissoluble often has certain crystal state, the consumption of PVP is not enough to make curcumin still based on crystalline state in conjunction with a certain amount of curcumin, and changes in solubility is little.Just can make medicine show as unformed dispersion so PVP must reach certain content, its dissolubility could obviously increase, and just can reach rapidly-soluble purpose.(3) curcumin in the solid dispersion is in upper state, is supersaturated solution, very easily reassembles into bulky grain, and centering on of PVPk30 effectively prevents this gathering.
By table 1 as seen, the curcumin dissolubility descends along with the prolongation of standing time in curcumin PM and the SD solution, and dissolubility is constant substantially behind the 24h.This be since curcumin this as water-insoluble materials, it is unsettled supersaturated solution that its SD, PM join formed in the A liquid, along with the continuous precipitation of curcumin, its lowering of concentration is until reaching dissolution equilibrium.
Conclusion
With PVP-k30 is carrier, adopts solvent method to prepare dissolution rate and the dissolubility that the Cur solid dispersion has significantly improved Cur, and when Cur and PVP-k30 mass ratio were 1: 10, its dissolution was up to 90%; Dissolubility is 882 times of the former medicine of curcumin.
The dynamic (dynamical) research of generation of embodiment 2 curcumin solid dispersion rat body giving drugs into nose
2.1 medicine, reagent and instrument Wistar pure lines rat (SPF level) are provided by No.1 Military Medical Univ.'s Experimental Animal Center, the quality certification number: SCXK (Guangdong) 2002-009, word: 2004A068 checks and affirm in Guangdong, curcumin, analytical pure, Tianjin recovery fine chemistry industry institute; Curcumin solid dispersion and physical mixture (Cur and PVP-k30 mass ratio are 1: 8), this prepared in laboratory; Ethyl acetate, analytical pure, Guangzhou Chemical Reagent Factory; Estradiol, analytical pure, south, Hainan HANGYAO industry company limited; Acetonitrile, HPLC level, German Merk company; Methanol, HPLC level, U.S. Fisher company; Glacial acetic acid, analytical pure, Guangzhou Chemical Reagent Factory; Pure water; Nitrogen, high purity nitrogen, Guangzhou gas company limited.
2.2 the mensuration of curcumin blood drug level
2.2.1 the preparation of standard solution:
Prepare the curcumin standard stock solution of 100 μ g/mL with methanol; Interior mark estradiol is made into the methanol solution of 45 μ g/mL.Above solution all is stored in the brown bottle, 4 ℃ of cold preservations are standby.
2.2.2 test condition (chromatographic condition)
Selecting immobile phase is Kromasil C18 chromatographic column (4.6mm * 150mm, 5 μ m), mobile phase is methanol: water: acetonitrile: glacial acetic acid (23: 36: 41: 5, V/V), dual wavelength detects (curcumin and interior target detect wavelength and be respectively 428nm, 280nm), flow velocity is 1.0mL/nin, 35 ℃ of column temperatures.
2.2.3 plasma sample pretreatment
The accurate 0.2mL plasma sample of drawing is in the 5mL of tool plug glass centrifuge tube, add 10 μ L inner mark solutions (estradiol 45 μ g/mL), vortex concussion 30s adds 1.5mL ethyl acetate solution 2000r/min vortex oscillation extraction 90s, the centrifugal 10min of 3000rmp then.Get supernatant in another glass centrifuge tube; Precipitate merges supernatant with above-mentioned steps row extraction again, and nitrogen dries up, and residue dissolves with methanol 100 μ L, and centrifuging and taking 20 μ L supernatant are done the analysis of HPLC sample introduction.
2.2.4 the range of linearity
In 5mL glass centrifuge tube, add rat blank plasma 1mL, add the curcumin stock solution diluted again and make that the curcumin final concentration is respectively 30,50,200,400,600,800ng/mL, take out above-mentioned sample 0.2mL in another centrifuge tube and add and mark stock solution (estradiol 45 μ g/mL) in the 10 μ L, operate, measure by " 2.2.3 " sample treatment, each concentration determination 5 times, with curcumin and interior target peak area ratio (Y) curcumin plasma concentration (X) mapping, get the standard curve equation.
2.2.5 method is identified
2.2.5.1 method specificity
By more blank rat plasma, contain the specificity of relatively studying method of testing of the plasma sample of getting (containing interior mark) chromatogram after curcumin and interior target blank plasma and the curcumin administration.
2.2.5.2 method (application of sample) response rate
Make the curcumin plasma sample of basic, normal, high (150,300,600ng/mL) three concentration according to the method for preparation standard working curve, taking out above-mentioned sample 0.2mL operates, measures by sample treatment, each sample duplicate detection 5 times, the ratio of detected level and addition are the method response rate.
2.2.5.3 extraction recovery
Make the curcumin plasma sample of basic, normal, high (150,300,600ng/mL) three concentration according to the method for preparation standard working curve, take out above-mentioned sample 0.2mL and operate, measure by sample treatment; Other prepares the curcumin methanol solution 0.2mL of identical final concentration, directly measures each sample duplicate detection 5 times.Note extraction sample is A1 with the ratio of interior mark peak area, and standard sample is A2 with the ratio of interior mark peak area, and A1 is extraction recovery than A2.
2.2.5.4 precision
Make the curcumin plasma sample of basic, normal, high (150,300,600ng/mL) three concentration according to the method for preparation standard curve, operate, measure by " 2.2.3 " sample treatment.
Withinday precision: replication is 5 times in one day.
Day to day precision: measure once every day, METHOD FOR CONTINUOUS DETERMINATION 5 days.
2.2.5.5 sensitivity
Get signal to noise ratio and be 3 (being the curcumin peak height and the ratio of noise), record lowest detectable limit and minimal detectable concentration.
2.3 the medication design and the blood specimen collection of pharmacokinetics test
Choose health, male Wistar rat, body weight is 300 ± 10g, is divided into 9 groups at random, 3 every group.Fasting 12h, by containing curcumin 100,200,400mg/kg (does not have and specifies, following dosage is all represented the curcumin actual content) dosage to the curcumin of rat with the CMC-Na suspendible, physical mixture and solid dispersion are irritated stomach respectively, after the administration in 0.25,0.50,0.75,1.0,1.5,2,3,4,6,8, the arrogant rathole vena orbitalis posterior of 10h clump is got blood 0.5mL, be collected in the centrifuge tube that is added with heparin sodium, the centrifugal 10min of 3000r/min, separate blood plasma, get blood plasma 0.2mL, operate by " 2.2.3 " sample treatment, measure.With the administration time is abscissa, is that vertical coordinate prepares drug-time curve with the blood drug level of curcumin.
2.4 experimental result
2.4.1 method specificity
Under above-mentioned mobile phase and chromatographic condition, curcumin and interior mark separate well with the endogenous material in the blood plasma, and the free from admixture peak disturbs.The retention time of estradiol and curcumin is respectively 3.70min, 4.70min.
2.4.2 method (application of sample) response rate
As shown in table 3, the average recovery of high, medium and low three concentration is between 97% to 103%, and RSD is in 6.08, and is respond well, meets the requirement of biological sample analysis.
Table 3 curcumin method (application of sample) response rate
| Curcumin addition (ng/mL) | Detected level (ng/mL) | The response rate (%) | Average recovery rate (%) | RSD (％) |
| 150 | 150.57 156.99 159.42 154.11 148.36 | 100.38 104.66 106.28 102.74 98.91 | 102.59±2.70 | 2.63 |
| 300 | 300.81 339.53 304.57 294.39 285.10 | 100.27 113.18 101.52 98.13 95.03 | 101.63±6.18 | 6.08 |
| 600 | 568.31 580.70 626.94 556.80 582.47 | 94.72 96.78 104.49 92.80 97.08 | 97.17±3.97 | 4.09 |
2.4.3 absolute recovery
As shown in table 4, the extraction recovery of high, medium and low three concentration is respectively 77.38%, 80.13%, 84.89%, and RSD is respectively 8.0%, 9.95%, 9.65%, and is respond well all less than 10%, meets the requirement of biological sample analysis.
Absolute recovery in the table 4 curcumin blood plasma
| Curcumin addition (ng/mL) | Extraction sample and interior mark peak area ratio (A1) | Standard sample and interior mark peak area ratio (A2) | Absolute recovery (%) | Average recovery rate (%) | RSD (％) |
| 150 | 0.696 0.576 0.684 0.586 0.483 | 0.772 0.742 0.772 0.617 0.661 | 90.16 77.63 88.60 94.98 73.07 | 84.89±8.19 | 9.65 |
| 300 | 1.242 1.492 1.254 1.333 1.6 | 1.641 1.579 1.74 1.762 1.934 | 75.69 94.49 72.07 75.65 82.73 | 80.13±7.97 | 9.95 |
| 600 | 2.481 2.571 3.06 2.462 1.996 | 3.164 3.197 3.586 3.233 2.953 | 78.41 80.42 85.33 76.15 66.58 | 77.38±6.19 | 8.0 |
2.4.4 precision, sensitivity
In a few days precision in the daytime is as shown in table 5, and in a few days RSD value in the daytime is all less than 6.63%, and effect is taught, and meets the biological sample analysis requirement.Lowest detectable limit: 0.8ng, minimal detectable concentration: 20ng/mL.
Table 5 curcumin blood drug level in a few days, day differences (n=5)
| Curcumin addition (ng/mL) | Difference in a few days | Day differences | ||
| The amount of measuring | RSD(％) | The amount of measuring | RSD(％) | |
| 150 300 600 | 151.81±7.01 306.03±14.68 602.65±19.30 | 4.62 4.80 3.20 | 155.44±10.30 309.83±18.56 615.97±27.80 | 6.63 5.99 4.51 |
2.4.5 linear relationship
As shown in table 6, good in 30～800ng/mL concentration range internal linear relation, regression equation is: Y=221.26X+25.116 (r=0.9989), regression curve as shown in Figure 8.
The linear precision of table 6 curcumin blood plasma
| Concentration (ng/mL) | Detect number of times (n) | x±SD | RSD(％) |
| 30 50 200 400 600 800 | 5 5 5 5 5 5 | 0.08±0.013 0.1106±0.008 0.699±0.079 1.695±0.151 2.677±0.146 3.458±0.110 | 16.3 7.23 11.3 8.91 5.45 3.18 |
Adopt the analytical method of setting up to be used for detecting the concentration of curcumin in the rat plasma, specificity is strong, highly sensitive, after giving orally give CMC-Na curcumin suspension and curcumin physical mixture, the amount of curcumin is less than lowest detectable limit (20ng/mL) in the interior rat plasma of 0-4h; After giving curcumin solid dispersion, 0-10h can detect the existence of curcumin in the blood plasma, and curve is through the match of 3P97 program during medicine, and the result meets two-compartment model, during the medicine of three dosages (100,200,400mg/kg) curve as shown in Figure 9, parameter is respectively shown in table 7,8,9.Curcumin blood medicine peak time is all about 45min, and blood medicine peak value is respectively 74.558,110.174,193.665ng/mL.Bioavailability is respectively 514.646,609.111,1028.627ng/mLh.
Main pharmacokinetic parameter after the administration of table 7 curcumin solid dispersion rat (100mg/kg, n=3)
(100mg/kg，n＝3)
| Parameter/unit | Numerical value (x ± SD) |
| T max/h C max/ng/mL A/ng/mL B/ng/mL α/1h β/1/h V/F(c)/L/kg T 1/2α/h T 1/2β/h K21/1/h K10/1/h K12/1/h AUC/ng/mL·h CLs/L/(kg·h) | 0.718±0.069 74.588±2.287 33.704±44.240 56.782±46.571 1.362±1.481 0.152±0.045 1.165±0.044 0.862±2.390 4.837±1.396 1.315±1.513 0.173±0.045 0.026±0.045 514.646±101.163 0.200±0.044 |
Main pharmacokinetic parameter after the administration of table 8 curcumin solid dispersion rat (200mg/kg, n=3)
| Parameter/unit | Numerical value (x ± SD) |
| T max/h C max/ng/mL A/ng/mL B/ng/mL α/1/h β/1/h V/F(c)/L/kg T 1/2α/h T 1/2β/h K21/1/h K10/1/h K12/1/h AUC/ng/mL·h CLs/L/(kg·h) | 0.803±0.093 110.174±7.474 220.224±48.725 76.072±16.885 1.093±0.162 0.140±0.026 1.098±0.102 0.643±0.088 5.067±0.986 0.509±0.105 0.300±0.017 0.424±0.104 609.111±26.713 0.329±0.014 |
Main pharmacokinetic parameter after the administration of table 9 curcumin solid dispersion rat (400mg/kg, n=3)
| Parameter/unit | Numerical value (x ± SD) |
| T max/h C max/ng/mL A/ng/mL B/ng/mL α/1/h β/1/h V/F(c)/L/kg T 1/2α/h T 1/2β/h K21/1/h K10/1/h K12/1/h AUC/ng/mL·h CLs/L/(kg·h) | 0.678±0.217 193.665±10.400 985.771±124.109 84.890±28.815 1.554±0.746 0.104±0.041 1.023±0.038 0.498±0.187 7.658±3.767 0.428±0.280 0.386±0.061 0.861±0.449 1028.627±161.403 0.395±0.057 |
Irritate stomach and give curcumin CMC-Na suspension, all can't in blood plasma, measure curcumin original shape medicine in 0.25-4 hour behind the curcumin PVP-k30 physical mixture, its blood drug level is lower than lowest detectable limit (20ng/mL) in other words, may be because the CMC-Na suspension, curcumin PVP-k30 physical mixture absorption difference in the rat body, major part excretes with former medicine form.And have report to give the oral 1g/kg curcumin of rat, about 75% discharges from feces; These illustrate that all the curcumin absorption difference has limited its bioavailability.And after giving curcumin solid dispersion, learn that its bioavailability improves relatively by experimental result, belong to two-compartment model through check.The curcumin blood medicine peak time of basic, normal, high concentration is all about 45min, and blood medicine peak value is respectively 74.558,110.174,193.665ng/mL, and bioavailability is respectively 514.646,609.111,1028.627ng/mLh.Show that solid dispersion has improved the oral absorption and the bioavailability of curcumin.The oral administration biaavailability of medicine is determined that by multiple reason one of them is exactly that medicine decomposes at gastrointestinal, and the gastrointestinal of medicine decomposes by its dissolution and dissolubility decision.Curcumin PVP-k30 solid dispersion reaches the purpose that improves bioavailability by dissolution and the dissolubility that improves curcumin just.
3 curcumin solid dispersions are to the pharmacodynamic study of experimental gastric ulcer
3.1 medicine and reagent
Curcumin, analytical pure, Tianjin recovery fine chemistry industry institute; Curcumin solid dispersion (Cur and PVP-k30 mass ratio are 1: 8), unless otherwise noted, below used dosage all be actual curcumin content, preparation method is identical with embodiment 1; Ranitidine hydrochloride, middle promise pharmaceutcal corporation, Ltd, the accurate word of traditional Chinese medicines: H19994029, product batch number: 04075001; The reserpine injection, Guangdong Bangmin Pharmaceutical Co., Ltd., the accurate word of traditional Chinese medicines: H44021982 product batch number: 040620; Acetic acid, analytical pure, Guangzhou Chemical Reagent Factory; Formaldehyde, analytical pure, Guangzhou Chemical Reagent Factory; Sodium hydroxide, analytical pure, Shantou City's brilliance laboratory; Oxalic acid, analytical pure, Xing Ta chemical plant; Phenolphthalein, Guangzhou Chemical Reagent Factory; Endothelin immunoassay medicine box, the Fu Rui of Beijing bio-engineering corporation, product batch number: 20050401; The nitric oxide detection kit, product batch number: 20050325, bio-engineering research institute is built up in Nanjing; The pepsin detection kit, product batch number: 20050325, bio-engineering research institute is built up in Nanjing.
Sprague-Dawley (SD) rat is provided by Guangdong Medical Lab Animal Center, the quality certification number: SCXK (Guangdong) 2003-0002, word: 2004A021 checks and affirm in Guangdong.
The NIH mouse inbred lines is provided by Guangdong Medical Lab Animal Center, the quality certification number: SCXK (Guangdong) 2003-0002, word: 2004A018 checks and affirm in Guangdong.
3.2.1 curcumin solid dispersion burns the rat gastric ulcer model effect of inducing to acetic acid
Select 60 of healthy SD rats, male and female half and half, body weight 200 ± 10g, water 24h is can't help in the rat fasting before the experiment, wherein 50 30mg/kg pentobarbital sodium anesthesia (remain 10 and make the normal control group, male and female half and half), aseptic condition 2cm under xiphoid-process opens the abdominal cavity in the place, and the glass tubing of internal diameter 5mm, long 30mm vertically is put on the body of stomach serosal surface, in pipe, add acetic acid 0.02mL, dip in out acetic acid with cotton swab behind the 1min,, meet and close otch with physiological saline solution flushing twice.Be divided into 5 groups at random, every group 10 (male and female half and half), that is: model group, curcumin is low, in, high dose group, the ranitidine group, model group is irritated stomach and give PVP-k30 adjuvant 720mg/kg every day, curcumin is low, in, high dose group is irritated stomach respectively and contain curcumin 10 every day, 30, the solid dispersion of 90mg/kg (unless otherwise noted, below used dosage all be actual curcumin content), the ranitidine group is irritated stomach and give ranitidine 27mg/kg every day, the normal control group gives isopyknic normal saline every day, successive administration 14d, after water 24h was can't help in the 15d fasting, the eye socket venous plexus was got blood 3mL, and wherein 2mL injects and contains 10%EDTA-Na
2In the test tube of 30 μ L and aprotinin, mixing, 4 ℃, the centrifugal 10min of 3000rmp, separated plasma ,-20 ℃ of preservations are to be measured; Remaining 1mL injects glass tubing, and room temperature leaves standstill separation of serum after a period of time, and-20 ℃ of preservations are to be measured.Serum NO level and blood plasma ET measure the by specification operation.
Take off cervical vertebra and put to death rat, open abdominal cavity ligation pylorus cardia and get stomach, inject 4% formalin 5mL in stomach, fixedly 30min tailing edge greater gastric curvature is cut off, and stomach is turned up the flush away food debris.Ulcer is circular or oval, measures the major diameter and the minor axis at ulcer place, with their average as ulcer index
[79]Carry out statistical between each group, by formula 5-1 calculates ulcer inhibition rate.
3.2.2 curcumin solid dispersion is to the effect of rat pylorus ligation gastric ulcer model
Select 50 of healthy SD rats, male and female half and half, body weight 200 ± 10g is divided into 5 groups at random, 10 every group (male and female half and half), that is: model group, the basic, normal, high dosage group of curcumin, ranitidine group, model group are irritated stomach and give PVP-k30 adjuvant 720mg/kg every days, the basic, normal, high dosage group of curcumin is irritated the solid dispersion that stomach contains curcumin 10,30,90mg/kg every day respectively, and the ranitidine group is irritated stomach and give ranitidine 27mg/kg every day.3d begins administration before the experiment, and water 36h is can't help in the rat fasting before the experiment, and the anesthesia of 30mg/kg pentobarbital sodium is the sterile working down, executes pyloric ligation, and water is prohibited in the postoperative fasting, dissects behind the 16h, collects gastric juice, centrifugal measurement gastric juice content; Stomach, is observed the ulcer situation and is also write down ulcer index fixedly behind the 30min through 4% formalin, and the ulcer index scoring is revised slightly by methods such as Adami, is divided into six grades
[80-81]0 grade: no pathological changes; The I level: hemorrhage, rotten to the corn or take place rotten to the corn point (≤1mm); The II level: 1～5 aphtha (＞1mm ,≤3mm); The III level: 6 above aphthas or 1 big ulcer (＞3mm); The IV level: 11 above aphthas or 2 big ulcer (＞3mm); V level: big ulcer more than 2.Carry out statistical between each group, ulcer inhibition rate by formula 5-2 calculates.
The gastric juice of measuring the gastric juice amount is got 1mL and is diluted to 10mL through centrifugal, with fixed its acidity of 0.01mol/L NaOH drop; The mensuration by specification operation of pepsin activity.
3.2.3 curcumin solid dispersion is to the effect of reserpine induction mouse gastric ulcer model
Select healthy NIH mice, male and female half and half, body weight 20 ± 1g is divided into 5 groups at random, 10 every group (male and female half and half), that is: model group, the basic, normal, high dosage group of curcumin, ranitidine group, model group are irritated stomach and give PVP-k30 adjuvant 720mg/kg every days, the basic, normal, high dosage group of curcumin is irritated the solid dispersion that stomach contains curcumin 10,30,90mg/kg every day respectively, and the ranitidine group is irritated stomach and give ranitidine 27mg/kg every day.3d begins administration before the experiment, beginning fasting 24h after the 4d administration, 1h after the 5d administration, subcutaneous injection of reserpine 10mg/kg; Take off cervical vertebra after 6 hours and put to death, get stomach, 4% formaldehyde fixed, the ulcer that counting glandular stomach portion occurs is counted as ulcer index.Ulcer inhibition rate by formula 5-2 calculates.The gastric mucosa injury assessment method: not damaged mucosa 0 minute, point-like damage 〉=1mm, 1 o'clock is 0.2 minute, 2 o'clock is 0.4 minute; 1 of strip damage is 1 minute, and 2 is 2 minutes, and the like.
3.3.1 curcumin solid dispersion burns the protective effect of gastric ulcer to acetic acid
3.3.1.1 curcumin solid dispersion is to the influence of ulcer index
The result is as shown in table 10, compares with model group, and middle and high dosage group of curcumin and ranitidine group ulcer index all reduce (p＜0.01), though curcumin low dosage administration group has reduction trend to the gastric ulcer index, p＞0.05.The result shows that the middle and high dosage of curcumin solid dispersion has significant inhibitory effect to this model gastric ulcer.
Table 10 curcumin SD to acetic acid burn gastric ulcer effect (x ± SD, n=10)
| Group | Dosage (mg/kg) | Ulcer index | Healing rate (%) |
| Dosage group curcumin high dose group ranitidine group in model group (giving adjuvant) the curcumin low dose group curcumin | 720 10 30 90 27 | 5.87±0.48 5.35±0.77 4.59±0.96 ** 3.33±0.93 ** 2.40±0.23 ** | 8.86 21.81 43.27 59.07 |
Compare with model group,
*P＜0.01
3.3.1.2 curcumin solid dispersion is to the influence of serum NO level and blood plasma ET content
The result is as shown in table 11, model group rat blood serum NO level obviously descends, and level of ET in plasma obviously raises, and compares with model group, the serum NO level level of curcumin high dose administration group and ranitidine group significantly raises (p＜0.01), and blood plasma ET significantly reduces (p＜0.05).
Table 11 curcumin SD to the influence of each group serum NO level and blood plasma ET content (x ± SD, n=10)
| Group | Dosage (mg/kg) | Serum NO level (μ mol/mL) | Blood plasma ET (pg/mL) |
| Dosage group curcumin high dose group ranitidine group in normal control group model group (giving adjuvant) the curcumin low dose group curcumin | - 720 10 30 90 27 | 54.75±15.54 23.63±5.73 26.63±7.17 29.75±5.90 * 39.63±12.73 ** 49.13±16.57 ** | 63.05±23.80 163.65±63.84 157.57±57.28 135.12±36.62 104.22±63.84 * 97.97±27.93 * |
Compare with model group,
*P＜0.05,
*P＜0.01
3.3.2 curcumin solid dispersion is to the protective effect of pylorus ligation gastric ulcer
3.3.2.1 curcumin solid dispersion is to the influence of ulcer index
The result is as shown in table 12, compare with model group, the ulcer index of curcumin high dose administration group and ranitidine group all reduces (p＜0.01), the dosed administration group also has reduction effect (p＜0.05) to the gastric ulcer index in the curcumin, but curcumin low dosage administration group does not have significant change to the gastric ulcer index.The result shows that curcumin solid dispersion has significant inhibitory effect to this model gastric ulcer.
Table 12 curcumin SD body to the effect of pylorus ligation gastric ulcer (x ± SD, n=10)
| Group | Dosage (mg/kg) | Ulcer index | Healing rate (%) |
| Dosage group curcumin high dose group ranitidine group in model group (giving adjuvant) the curcumin low dose group curcumin | 720 10 30 90 27 | 4.25±0.71 4.13±0.64 3.75±0.46 2.38±0.74 ** 1.63±0.52 ** | - 2.82 11.76 44.00 61.65 |
Compare with model group,
*P＜0.05,
*P＜0.01
3.3.2.2 curcumin solid dispersion is to gastric juice content, the influence of gastric acidity and pepsin activity
The result is as shown in table 13, compares with model group, and middle and high dosed administration group of curcumin and ranitidine group all have significant inhibitory effect (p＜0.05, p＜0.01) to gastric juice content, gastric acid secretion and pepsin activity; And curcumin low dosage administration group also has significant inhibitory effect (p＜0.05) to pepsin activity.
Table 13 curcumin SD organizes gastric juice content to each, and the influence of gastric acidity and pepsin activity (x ± SD, n=10)
| Group | Dosage (mg/kg) | Gastric juice amount (mL) | Gastric acidity (mmol/L) | Pepsin activity (U/mL) |
| Dosage group curcumin high dose group ranitidine group in model group (giving adjuvant) the curcumin low dose group curcumin | 720 10 30 90 27 | 14.61±1.80 13.70±1.26 12.68±1.46 * 9.99±0.79 ** 7.63±1.29 ** | 87.70±9.84 82.19±9.48 77.62±8.34 * 65.77±8.19 ** 55.66±10.46 ** | 408.63±41.75 ** 372.13±38.12 358.13±37.44 * 292.13±41.93 ** 254.88±42.37 ** |
Compare with model group,
*P＜0.05,
*P＜0.01
3.3.3.1 curcumin solid dispersion is to the influence of ulcer index
The result is as shown in table 14, compares with model group, and the ulcer index of middle and high dosed administration group of curcumin and ranitidine group all reduces (p＜0.01), and the result shows that curcumin solid dispersion has significant inhibitory effect to this model gastric ulcer.
Table 14 curcumin SD to the effect of the gastric ulcer of reserpine induction (x ± SD, n=10)
| Group | Dosage (mg/kg) | Ulcer index | Healing rate (%) |
| Dosage group curcumin high dose group ranitidine group in model group (giving adjuvant) the curcumin low dose group curcumin | 720 10 30 90 27 | 5.13±0.59 4.68±0.50 3.88±0.40 ** 3.03±0.64 ** 2.23±0.52 ** | - 8.77 24.37 40.94 56.53 |
Compare with model control group,
*P＜0.01
The antitussive of curcumin solid dispersion, eliminate the phlegm and antiinflammatory action
Experimental drug, reagent, animal
Sprague-Dawley, the SD rat, the SPF level is provided by Guangdong Medical Lab Animal Center, the quality certification number: SCXK (Guangdong) 2003-0002, word 2004A021 checks and affirm in Guangdong.The NIH mouse inbred lines, the SPF level is provided by Guangdong Medical Lab Animal Center, the quality certification number: SCXK (Guangdong) 2003-0002, word 2004A018 checks and affirm in Guangdong.Kunming mice, the SPF level is provided by Guangdong Medical Lab Animal Center, the quality certification number: SCXK (Guangdong) 2003-0002, word 2004A019 checks and affirm in Guangdong.
Positive control drug: dexamethasone tablet, Guangdong Huanan Pharmaceutical Factory, the accurate word of traditional Chinese medicines: H44024469, lot number: 040301.Positive control drug: capital of a country NIANCIAN MILIAN CHUANBEI PIPA GAO, capital of a country are read the total Co., Ltd., Factory of Ci An, and medical product number of registration: ZC2002010 (ZC2002009, ZC2002008), lot number: Y140495 (G240317, G341119).Curcumin, analytical pure, Tianjin recovery fine chemistry industry institute; Curcumin solid dispersion (Cur and PVP-k30 mass ratio are 1: 8), unless otherwise noted, below used curcumin solid dispersion dosage all be actual curcumin content, preparation method is identical with embodiment 1.
4.1.1 drawing, mice ammonia coughs experiment
Choose 70 of healthy NIH mices, body weight 18-22g, male, be divided into 7 groups at random, be respectively blank group, Dexamethasone group, read Ci An group, four dosage groups of curcumin solid dispersion (0.043,0.130,0.39 and 1.170gKg
-1), every group of 10 mices.Gastric infusion, once a day, successive administration 7d.30min after the last administration, every mice is placed the wide mouthed bottle of 250ml, add in advance in the wide mouthed bottle and inhale the cotton balls that 75 μ l ammonia are arranged, (it is that the mice abdominal muscle shrinks that the typical case coughs to observe and write down the cough latent period (by putting into bottle to producing the required time of coughing) of mice and the number of times of 2min mouse cough, magnify mouth simultaneously, cough sound).Experimental result is carried out statistical procedures and comparable group differences.
3.1.2 the phenol red drainage experiment of mice trachea
3.1.2.1 the making of phenol red standard curve
Accurately take by weighing phenol redly with analytical balance, add 5%NaHCO
3, being mixed with concentration is 100 μ gml
-1Storing solution, being diluted to concentration then in turn is 0.1,0.3,0.5,0.7,1,3,5 and 10 μ gml
-1Phenol red solution, with 5%NaHCO
3Solution is surveyed the OD value as blank down with the 546nm wavelength, is abscissa with phenol red concentration, and the OD value is a vertical coordinate, the production standard curve.
3.1.2.2 detection method
Choose 105 of healthy male mice in kunming, body weight 18～22g is divided into 7 groups at random, be respectively blank group, Dexamethasone group, read Ci An group, curcumin solid dispersion dosage group (43,130,390,1170mgKg
-1) every group of 15 mices.Gastric infusion, once a day, successive administration 7d.Behind the last administration 30min, lumbar injection 5% phenol red solution, 0.1ml/10g.Behind the injection 30min mice is put to death, back of the body position is fixing, separates trachea, gets one section trachea (long 1cm) and puts into the test tube that the 1ml normal saline is housed, and vibration 30min sucks flushing liquor in vitro, adds 1molL
-1NaOH, 0.1ml makes it be alkalescence, and phenol red standard pipe in 546nm place colorimetric, is converted out phenol red concentration (because part phenol red can by the respiratory mucus glandular secretion in tracheal glands) by phenol red standard curve.Experimental result is carried out statistical procedures and comparable group differences.
3.1.3 mice ear experiment
Choose 105 of healthy male mice in kunming, body weight 18～22g is divided into 7 groups at random, be respectively blank group, Dexamethasone group, read Ci An group, curcumin solid dispersion dosage group (43,130,390,1170mgKg
-1), every group of 15 mices.Gastric infusion, once a day, successive administration 7d.At the front and back of mouse right ear two sided coatings proinflammatory agent dimethylbenzene (concentration is 100%) 0.05ml/ only, left ear is left intact, and causes the mouse right ear inflammation behind last administration 30min.Put to death mice behind the 30min, cut ears and lay round auricle at same position respectively with 8mm diameter card punch, weigh, every Mus auris dextra sheet weight deducts left auricle weight and is the swelling degree, calculates the ear swelling degree and carries out statistical procedures and the comparable group differences.
Ear swelling degree=auris dextra sheet weight-left auricle weight
Inhibitory rate of intumesce=(the average swelling degree of the matched group-average swelling degree of administration group) the average swelling degree of ÷ matched group * 100%
3.1.4 rat paw edema experiment
Choose 70 of the male SD rats of body weight health, body weight 180-200g is divided into 7 groups at random, is respectively blank group, Dexamethasone group, reads the Ci An group, curcumin solid dispersion dosage group (30,90,270 and 810mgKg
-1), every group of 10 rats.Every day gastric infusion, once a day, continuous 7d.Measure the right sufficient volume of rat behind the last administration 0.5h once.Measure sufficient volume and adopt capillary tube measurement by magnification method: get one of three-way cock, an end links to each other with the 20ml glass syringe, and the other end and 5ml graduated pipette join, and the centre connects a catheter, in filled with and dripped phenol red aqueous solution.Make the graduation mark of labelling on liquid concave surface and the syringe equal by three-way cock, liquid is full of catheter and surpasses the minimum graduation mark of pipet, read this moment the scale on the pipet, around the rat hindlimb ankle joint, do mark line with marking pen, the experimenter is stretching with rat hindlimb, put into glass syringe, make the scale of labelling on rat ankle joint mark line and the syringe equal, by regulating three-way cock syringe is communicated with pipet, liquid flows into pipet by syringe, and liquid level raises in the pipet.With liquid level in the eye fixation syringe, the control three-way cock, swivel tee switch immediately when liquid level in the syringe is equal with the graduation mark of labelling makes the interior liquid of syringe and pipet no longer mobile.Read this moment the scale on the pipet, record, the difference of twice scale is the sufficient volume of rat when measuring.Except that normal group, all inject chondrus ocellatus Holmes for every group and cause inflammation.After the administration, the experimenter is stretching with rat hindlimb, and subcutaneous in the middle part of toes earlier upwards turning syringe needle then injects 0.05ml downwards with No. 26 needle applicators 1% carrageenin (accurately take by weighing 1.0g and be dissolved in the 100ml normal saline) of now joining before the experiment.Measure the volumetrical variation of rat ankle joint (being paw swelling) respectively at 0.5h, 1.0h, 2.0h, 4.0h, 6.0h behind the injection chondrus ocellatus Holmes, observe arriving rush hour and regression time, calculate paw swelling and carry out statistical procedures and the comparable group differences.
Right sufficient volume before the volume-experiment of the right foot in the scorching back of swelling degree (ml)=cause
3.1.5 the swollen experiment of rat granuloma
Choose 70 of the male SD rats of body weight health, body weight 180-200g is divided into 7 groups at random, is respectively blank group, Dexamethasone group, reads the Ci An group, curcumin solid dispersion dosage group (30,90,270 and 810mgKg
-1), every group of 10 rats.Rat is in ether light anaesthesia hypogastric region unhairing and with 75% ethanol and iodine disinfection.Do an otch in the abdominal part center, with two sterilization cotton balls (heavy 20mg of each cotton balls, autoclaving, each adds each 1mg/0.1ml of ampicillin, 50 ℃ of stove-dryings) implant rat both sides axillary fossa subcutaneous (or the both sides groin is subcutaneous) respectively, with behind the myometrial suture with 75% ethanol and iodine disinfection.Began gastric infusion the same day in the operation back, once a day, and continuous 14d.The dislocation of 15d cervical vertebra is put to death, and peels off and take out the cotton balls granulation tissue, claims dry weight behind the baking 12h then in 60 ℃ of baking ovens, compares and respectively organizes granulation swelling weight.Experimental result is carried out statistical procedures and comparable group differences.
4.1 the relievining asthma, eliminate the phlegm and the antiinflammatory experimental result of curcumin solid dispersion
4.1.1 drawing, mice ammonia coughs experiment
Curcumin solid dispersion 43,130,390,1170mgKg
-1The dosage group is compared with the blank group, the cough latent period of energy significant prolongation mice, the cough number of times is obviously reduced, compare with the blank group and to have significant difference (P＜0.05), and there was no significant difference (P＞0.05) is compared in the prolongation effect that dexamethasone is hidden to cough with the blank group, but the trend that prolongation is arranged, the cough number of times (P＜0.05) of minimizing mice that can significance.Curcumin solid dispersion 43,130,390,1170mgKg
-1Dosage group and Dexamethasone group and read the Ci An group and compare, cough suppressing effect there was no significant difference (P＞0.05), the antitussive effect difference between each dosage little (seeing Table 15).
Table 15 curcumin solid dispersion to ammonia cause the influence of coughing mice (x ± s, n=10)
| Group | Dosage (mgKg -1) | Cough latent period (s) | Cough number of times (n) |
| Blank group Dexamethasone group is read Ci An group curcumin solid dispersion group | - 1.55 5800 43 130 390 1170 | 26.8±7.9 31.2±20.3 38.8±16.5 * 38.4±10.5 *△■ 38.3±11.5 *△■ 39.7±14.3 *△■ 37.2±14.3 *△■ | 32.2±21.0 14.3±10.2 * 13.6±7.3 * 14.5±5.2 *△■ 12.4±7.6 *△■ 13.6±6.7 *△■ 15.6±5.3 *△■ |
Compare with the blank group,
*P＜0.05; Compare with Dexamethasone group,
△P＞0.05; Compare with reading the Ci An group,
■P＞0.05.
4.1.2 the phenol red drainage experiment of mice trachea
Phenol red standard curve is: y=0.1306x-0.0061, (r=0.9995).With blank group ratio, curcumin solid dispersion 130,390,1170gKg
-1Group and Dexamethasone group, read Ci An group and all can increase the phenol red excretion (P＜0.05) of mice trachea in significance ground, and read that Ci An organizes, Dexamethasone group is compared curcumin solid dispersion 130,390,1170mgKg
-1Group is to the phenol red excretion there was no significant difference of mice trachea (P＞0.05), wherein curcumin solid dispersion 1170mgKg
-1Group best results (seeing Table 16).
Table 16 curcumin solid dispersion to the influence of phenol red excretion (x ± s, n=15)
| Group | Dosage (mgKg -1) | Phenol red concentration (ugml -1) |
| Blank group Dexamethasone group is read Ci An group curcumin solid dispersion group | - 1.55 5800 43 130 390 1170 | 0.21±0.10 0.33±0.11 0.26±0.06 * 0.28±0.12 △■ 0.29±0.07 *△■ 0.33±0.09 **△■ 0.38±0.13 **△■ |
Compare with the blank group,
*P＜0.05,
*P＜0.01: compare with Dexamethasone group,
△P＞0.05; Compare with reading the Ci An group,
■P＞0.05.
4.1.3 mice ear experiment
Curcumin solid dispersion 390,1170mgKg
-1Dosage and positive control drug all can alleviate the mice ear degree (P＜0.05) that dimethylbenzene causes, wherein Dexamethasone group and 1170mgKg by significance
-1Curcumin solid dispersion group effect best (P＜0.01); Compare 1170mgKg with Dexamethasone group
-1Curcumin solid dispersion group there was no significant difference (P＜0.05); Compare 42,130,390mgKg with reading Ci An group
-1Curcumin solid dispersion group there was no significant difference (P＞0.05), and 1170mgKg
-1The curcumin solid dispersion group with read Ci An group and compare (P＜0.05) (the seeing Table 17) that have significant difference.
Table 17 flavin solid dispersion to the influence of mice ear (x ± s, n=15)
| Group | Dosage (mgKg -1) | Swelling degree (mg) |
| Blank group Dexamethasone group is read Ci An group curcumin solid dispersion group | - 1.55 5800 43 130 390 1170 | 19.7±4.0 10.9±4.2 *** 15.7±4.3 * 17.9±4.5 ▲■ 16.6±4.3 ▲■ 15.6±5.4 *▲■ 11.7±5.6 ***△□ |
Compare with the blank group,
*P＜0.05,
* *P＜0.001; Compare with Dexamethasone group,
▲P＜0.05; Compare with reading the Ci An group,
P＜0.05,
■P＞0.05.
4.1.4 rat paw edema experiment
Behind the injection carrageenin, the rat toes begin swelling behind 20min, and the swelling degree is the most obvious behind 4h.30,90,270,810mgKg
-1Curcumin solid dispersion and positive control drug cause the degree (P＜0.05) of rat paw edema, the wherein antiphlogistic effects of dexamethasone best (P＜0.01) at the inhibition carrageenin of different time significance.Curcumin solid dispersion 8.1gKg
-1Compare with reading the Ci An group, there was no significant difference (P＞0.05) (sees Table 18.
Table 18 curcumin solid dispersion to the influence of rat paw edema (x ± s, n=10)
| Group | Dosage (mgKg -1) | Different time foot swelling degree (ml) | ||||
| 0.5h | 1.0h | 2.0h | 4.0h | 6.0h | ||
| Blank group Dexamethasone group is read Ci An group curcumin solid dispersion group | - 1.05 5400 30 90 210 810 | 0.39±0.21 0.14±0.12 *** 0.15±0.13 **△ 0.22±0.18 * 0.14±0.11 **△ 0.15±0.06 **△ 0.18±0.09 **△ | 0.47±0.26 0.18±0.10 *** 0.23±0.15 * 0.25±0.23 0.37±0.14 0.35±0.16 0.38±0.16 | 0.67±0.33 0.16±0.09 *** 0.43±23 0.37±0.23 * 0.40±0.22 * 0.43±0.22 0.49±0.17 ■ | 0.81±0.34 0.15±0.10 *** 0.43±0.26 ** 0.40±22 ** 0.56±0.14 0.53±0.29 0.56±0.18 *■ | 0.72±0.36 0.18±0.10 *** 0.41±0.26 * 0.26±0.19 *** 0.38±0.22 * 0.25±0.17 ** 0.33±0.16 ** |
Compare with the blank group,
*P＜0.05,
*P＜0.01,
* *P＜0.001; Compare with Dexamethasone group
△P＞0.05; With read Ci An group and compare
■P＞0.05.
4.1.5 the swollen experiment of rat granuloma
After implanting cotton balls, the rat wound healing is good.Behind the successive administration 14d, blank group rat oxter granuloma is very obvious, gives 30,90,270,810mgKg
-1Curcumin solid dispersion can obviously suppress the hypertrophy (P＜0.01) of granuloma induced by implantation of cotton pellets, and the inhibition effect is read Ci An with positive drug, Dexamethasone group is compared there was no significant difference (P＞0.05).Illustrate that each dosage group of curcumin solid dispersion all can effectively suppress granulomatous formation, have the effect (seeing Table 19) of anti-chronic inflammatory disease.
Table 19 curcumin solid dispersion is to the bullate influence of rat granuloma (x ± s)
| Group | Dosage (mgKg -1) | Number of animals (n) | Granuloma weight (mg) |
| Blank group Dexamethasone group is read Ci An group curcumin solid dispersion group | - 1.05 5400 30 90 210 810 | 10 10 10 10 10 10 10 | 105.3±39.2 43.3±5.2 ** 48.2±5.3 ** 51.0±6.0 **△■ 50.2±6.3 **△■ 46.9±3.6 **△■ 45.4±6.3 **△■ |
Compare with the blank group,
*P＜0.01; Compare with Dexamethasone group,
△P＞0.05; Compare with reading the Ci An group,
■P＞0.05.
Claims (5)
1, a kind of preparation method of curcumin solid dispersion, it is characterized in that curcumin and polyvinylpyrrolidone were dissolved in organic solvent in 1: 4～1: 15 by mass ratio, remove most of organic solvent to becoming pasty state in 55～95 ℃ of following distilling under reduced pressure, then 60～90 ℃ of following vacuum drying oven oven dry, pulverize, obtain curcumin solid dispersion.
2, preparation method as claimed in claim 1, the mass ratio that it is characterized in that curcumin and polyvinylpyrrolidone is 1: 6～1: 12.
3, preparation method as claimed in claim 2, the mass ratio that it is characterized in that curcumin and polyvinylpyrrolidone is 1: 7～1: 10.
4,, it is characterized in that described organic solvent is dehydrated alcohol, propanol, isopropyl alcohol or ethyl acetate as claim 1 or 2 or 3 described preparation methoies.
5, a kind of curcumin solid dispersion is characterized in that being prepared from by the described preparation method of claim 1.
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| CN101081213B (en) * | 2007-06-26 | 2010-10-06 | 中山大学 | Butane diacid(5-androstene-17-ketone- 3beta -hydroxyl group ) diester solid dispersoid and method for making same and applications thereof |
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| CN102652741A (en) * | 2012-05-15 | 2012-09-05 | 中国人民解放军总医院 | Application of curcumin to preparation of drugs for treating cerebral ischemia/reperfusion injuries |
| CN103054006A (en) * | 2012-12-25 | 2013-04-24 | 上海染料研究所有限公司 | Preparation method of high concentration water-solubility curcumine |
| CN103271393B (en) * | 2013-04-09 | 2014-08-13 | 广东工业大学 | Health care curcumin-sea-buckthorn beverage and preparation method thereof |
| CN104739751B (en) * | 2013-12-26 | 2018-11-20 | 四川省中医药科学院 | A kind of tetrahydro curcumin solid dispersions and preparation method thereof |
| CN109481689B (en) * | 2018-12-25 | 2021-12-03 | 广州白云山汉方现代药业有限公司 | Composition for enhancing water solubility of curcumin and preparation method thereof |
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| CN109771379A (en) * | 2019-03-06 | 2019-05-21 | 常州大学 | A kind of calcium carbonate solid dispersion of curcumin and preparation method thereof |
| CN110075071A (en) * | 2019-05-22 | 2019-08-02 | 中北大学 | A kind of preparation method of curcumin solid dispersion |
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