CN103550206B - A kind of resveratrol indirubin composition of medicine, slow-releasing microcapsule agent and application thereof - Google Patents
A kind of resveratrol indirubin composition of medicine, slow-releasing microcapsule agent and application thereof Download PDFInfo
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- CN103550206B CN103550206B CN201310502822.5A CN201310502822A CN103550206B CN 103550206 B CN103550206 B CN 103550206B CN 201310502822 A CN201310502822 A CN 201310502822A CN 103550206 B CN103550206 B CN 103550206B
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Abstract
The invention provides a kind of resveratrol indirubin composition of medicine, described is resveratrol and indirubin two kinds of medicine monomer mixing compositions; Described is using sodium alginate as carrier material, the slow-releasing microcapsule agent of making for active component with resveratrol and indirubin; A kind of resveratrol and indirubin composition of medicine and microcapsule formulation thereof, the composition of medicine of indirubin and resveratrol in activity due to the activity of arbitrary monomer under Isodose, while encapsulated form effectively can play the effect of slow release.
Description
Technical field
The present invention relates to a kind of plant amedica, relate to a kind of resveratrol indirubin composition of medicine, slow-releasing microcapsule agent and application thereof in particular.
Technical background
Cancer is the common chronic disease of serious harm human health and life.In recent years, affect by the factor such as ecological deterioration, job and life stress, cancer mortality oneself occupy first of all kinds of death of state.According to health ministry circular, since 70 years last century, China's cancer mortality is always in sustainable growth trend.The number that 20 century 70 China die from cancer is every year 700,000, and the nineties is 1,170,000, and 21 century then rises to 1,500,000.So numerous tumor patients, defines a huge antitumor drug market.According to the statistics of relevant department to 14 city 300 Duo Jia hospital anti-tumor drug amount of money such as Shanghai, Beijing, Guangzhou, Shenyang, 1999,2000, the amount of money of each hospital in calendar year 2001 above-mentioned city anti-tumor drug in lasting rising, annual amplification is more than 20%.Relevant research shows, China in 1999 antitumor drug market scale is 60.3 hundred million yuans, within 2000, is 70.2 hundred million yuan, and calendar year 2001 is 82.13 hundred million yuan, and market scale increases obviously.The good medicine of antitumor curative effect of generally acknowledging in the world at present have 50 ?60 kinds, wherein anti-tumor botanical is the main body of anti-tumor drug, account for the market share of 41%, this with such medicine in enhancing body self to the immunity of cancerous cell and promote the curative effect of uniqueness in cancer cell-apoptosis two relevant with lower toxic and side effects.Indirubin in resveratrol in Polygonum cuspidatum Sieb. et Zucc and Chinese medicine Folium Isatidis all has good activity for cancer.
But resveratrol and indirubin all have the problems such as dissolubility is low, poor stability, bioavailability are low, the half-life is shorter, affect its application clinically.
Summary of the invention
For solving the problem, the invention provides a kind of composition of medicine and the microcapsule formulation thereof that have indirubin and resveratrol combination, concrete summary of the invention is: described is resveratrol and indirubin two kinds of medicine monomer mixing compositions.
The weight ratio of described middle resveratrol and indirubin is 1-10:1-10.
The weight ratio of described middle resveratrol and indirubin is 2:3.
The slow-releasing microcapsule agent of described resveratrol indirubin composition of medicine, described in be using sodium alginate as carrier material, the slow-releasing microcapsule agent of making for active component with resveratrol and indirubin.
The preparation method of the slow-releasing microcapsule agent of described resveratrol indirubin composition of medicine, it is characterized in that: take resveratrol and indirubin according to ratio, add the sodium alginate aqueous solution that viscosity is 125mPa.s, mixing, draw with syringe the CaCl that suspension drops to low rate mixing
2in solution, solidification, filter, wash 3 times, 50 DEG C of dryings, obtain microcapsule.In order to the repeatability of guarantee test, regulation hardening time is 10min, and the volume of calcium chloride is 6 times of sodium alginate volume, drips apart from being 8cm; Sodium alginate viscosity is 380mPa.s, the combination quality of sodium alginate and resveratrol and indirubin than 0.5, sodium alginate mass fraction is 2.0%, calcium chloride mass fraction is 3.0%.
Resveratrol indirubin composition of medicine described above is preparing the application in Therapeutic cancer medicine.
Advantageous Effects of the present invention is: the invention provides a kind of resveratrol and indirubin composition of medicine and microcapsule formulation thereof, the composition of medicine of indirubin and resveratrol is due to the activity of arbitrary monomer under Isodose in activity, and encapsulated form effectively can play the effect of slow release simultaneously.
Detailed description of the invention
Embodiment 1 adopts sodium alginate to be the technique investigation that carrier material prepares microcapsule
1, the research of blank sodium alginate micro-capsule preparation technology
Known through preliminary experiment, the factor of major effect sodium alginate micro-capsule comprises: sodium alginate viscosity; Calcification time and dripping technological parameter, as the size, a speed, a distance (distance that drop outlets is asked to liquid level) etc. of dripping syringe needle.Below these influence factors are carried out respectively to the single factor exploration of microcapsule mouldability.
The investigation of sodium alginate viscosity
Investigating 3 kinds of viscosity level is respectively 1.5% sodium alginate sample, on the impact of microcapsule molding.Be the syringe of sodium alginate No. 7 syringe needles of 1.5% by concentration, drop in 1.1% calcium chloride solution of low rate mixing with the speed of about 30/min, solidification 10min, filters, to obtain final product, to the results are shown in Table 1.
Table 1 sodium alginate viscosity
Experimental result shows, can not get complete spherical when sodium alginate viscosity is 30mPa.s.May be because viscosity is too little, part may dissolve in calcium chloride solution, independent spheroid can not be formed.Find that the viscosity of sodium alginate is higher, microcapsule hardness is larger simultaneously; But when being increased to 380mPa.s, its hardness is excessive.Therefore, optimum sodium alginate viscosity is 125mPa.s.
Drip the investigation of speed
Respectively get 5mL1.5% sodium alginate (viscosity 125mPa.s) solution and use (0.5 × 20RWLB), instill in 30mL1.1% calcium chloride solution with the speed of dripping of quick (52/min), middling speed (30/min), at a slow speed (17/min) respectively, solidification 10min, filter, obtain, the results are shown in Table 2.
Table 2 speed
Experimental result shows, drip speed and the particle diameter of microcapsule can be caused too soon to increase, and roundness is poor.Therefore drip speed in the preparation and be preferably less than or equal to 30/min.
Syringe needle size
5mL1.5% sodium alginate (viscosity 125mPa.s) drops in the 30mL1.1% calcium chloride of low rate mixing with the speed of about 30/min by the number of using 5,7 and No. 9 syringe needles respectively, and solidification 10min, filters, to obtain final product, to the results are shown in Table 3.
Table 3 syringe needle size
Experimental result shows, because microcapsule relies on extruding force to be formed by syringe needle dripping, therefore the size of syringe needle bore is the key determining size, and illustrate that syringe needle is less, microcapsule diameter is less.But when syringe needle is too small, because sodium alginate exists certain viscosity, dripping will become very difficult.
Drip the investigation of distance
With No. 5 syringe needles by 5mL1.5% sodium alginate (viscosity 125mPa.s) with the speed of about 30/min, drip apart from being respectively 0,5,10,20cm, drop in the 30mL1.1% calcium chloride of low rate mixing, solidification 10min, filters, to obtain final product, to the results are shown in Table 4.
Table 4 distance
Experimental result shows, drips apart from being that 5 ~ 10cm is more suitable, and dripping can not balling-up apart from being less than 5cm sodium alginate drop, drips and floats on calcium chloride solution face apart from being greater than 10cm microsphere, affect the further curing reaction of microsphere, cause roundness poor.
The investigation of mixing speed
With No. 5 syringe needles by 5mL1.5% sodium alginate (viscosity 125mPa.s) with the speed of about 30/min, dripping distance is 10cm, in the 30mL1.1% calcium chloride solution dropped to, wherein the mixing speed of calcium chloride solution be respectively without stirring, at a slow speed, middling speed, fast, solidification 10min, filter, to obtain final product, to the results are shown in Table 5.
Table 5 mixing speed
Experimental result shows, mixing speed should be not too fast because too fast time can cause microcapsule not yet molding time be stirred, cause the size of microcapsule uneven, roundness is bad.
The investigation of hardening time
With No. 5 syringe needles by 5mL1.5% sodium alginate (viscosity 125mPa.s) with the speed of about 30/min, drip apart from being 10cm, drop in the 30mL1.1% calcium chloride of low rate mixing, be respectively 5 hardening time, 10,30,60min, filter, to obtain final product, to the results are shown in Table 6.
Table 6 hardening time
From the results of view, the microcapsule no significant difference that different hardening time obtains, and size is even, roundness is good, illustrates that hardening time, the mouldability to microcapsule did not make significant difference.Can prove that sodium alginate soln is react instantaneously to form alginic acid acid calcium microcapsule when instilling calcium chloride solution.
The investigation of the volume of calcium chloride
With No. 5 syringe needles by 5mL1.5% sodium alginate (viscosity 125mPa.s) with the speed of about 30/min, drip apart from being 10cm, drop to 5 of low rate mixing, 10,20,30, in 40mL1.1% calcium chloride, solidification 10min, filter, to obtain final product, to the results are shown in Table 7.
The volume of table 7 calcium chloride
The microcapsule no significant difference that the calcium chloride of different volumes obtains, and size is even, roundness is good, the mouldability of volume to microcapsule of visible calcium chloride does not make significant difference.But when the volume of calcium chloride is too small, the microcapsule of formation is once increase, and microcapsule can be attached on together, cannot stir.Therefore the volume of calcium chloride should be equal to or greater than the sodium alginate soln volume of 2 times.
2, the preparation of resveratrol microcapsule
According to the single factor test result of study of blank sodium alginate micro-capsule preparation technology, carry out the Study on Preparation of resveratrol slow-releasing microcapsule.Take appropriate resveratrol, add sodium alginate (viscosity is 125mPa.s) aqueous solution, mixing, draws with syringe (No. 9 syringe needles) CaCl that suspension drops to low rate mixing
2in solution, solidification, filter, wash 3 times, 50 DEG C of dryings, obtain microcapsule.In order to the repeatability of guarantee test, regulation hardening time is 10min, and the volume of calcium chloride is 6 times of sodium alginate volume, drips apart from being 8cm.
The mensuration of microencapsulation productive rate and drug loading
Take dry microcapsule appropriate, grinding, with dehydrated alcohol extraction medicine several, be settled to 50ml after filtration, according to standard curve Equation for Calculating drug quality concentration, and be calculated as follows drug loading and Yield of Mitoxantrone.
Drug loading=microcapsules medicine thing amount/microcapsule gross weight × 100%
Yield of Mitoxantrone=microcapsules medicine thing amount/dosage × 100%
Microcapsule influence factor tests
The viscosity of sodium alginate
Take indirubin and resveratrol by weight 1:1, obtain the combination of resveratrol and indirubin; Under 1.5% sodium alginate, 3.0% calcium chloride, sodium alginate are 1.0 conditions with resveratrol and the combination quality ratio of indirubin, sodium alginate viscosity is respectively 30mPa.s, 125mPa.s, 380mPa.s, prepare a series of microcapsule, observe its form, measure its drug loading and envelop rate, the results are shown in Table 8.Test shows, the viscosity of sodium alginate does not make significant difference to the drug loading of microcapsule and envelop rate.And have appreciable impact to roundness and hardness.The viscosity of sodium alginate is larger, and roundness is better, and hardness is stronger.The optimum viscosity of sodium alginate is 380mPa.s as can be seen here.
The impact (n=3) of table 8 sodium alginate viscosity
Sodium alginate and composition of medicine mass ratio
Under 1.5% sodium alginate (380mPa.s), 3.0% calcium chloride condition, sodium alginate is respectively 0.5,1.0,2.0 with resveratrol with the combination quality ratio of indirubin and prepares a series of microcapsule, observe its form, measure its drug loading and envelop rate, the results are shown in Table 9.Test shows, the combination quality comparison roundness of sodium alginate and resveratrol and indirubin, hardness and envelop rate all do not make significant difference, and have appreciable impact to the drug loading of microcapsule.The mass ratio of the combination of sodium alginate and resveratrol and indirubin is larger, and drug loading is then less.And when sodium alginate is less than 0.5 with resveratrol with the combination quality ratio of indirubin, after the combination of resveratrol and indirubin and sodium alginate soln mix, solution is thickness too, causes easily blocking syringe needle during dripping.The optimum quality ratio of the combination of sodium alginate and resveratrol and indirubin is 0.5 as can be seen here.
The different sodium alginate of table 9 and the impact (n=3) of resveratrol with the combination quality ratio of indirubin
Sodium alginate mass fraction
Under 3.0% calcium chloride, sodium alginate (380mPa.s) are 0.5 condition with resveratrol and the combination quality ratio of indirubin, sodium alginate mass fraction is respectively 1.0%, 1.5%, 2.0%, prepare a series of microcapsule, observe its form, measure its drug loading and envelop rate, the results are shown in Table 10.Test shows, along with the increase of sodium alginate mass fraction, the roundness of microcapsule improves gradually, and hardness strengthens, and envelop rate is without significant change, but drug loading reduces gradually.When sodium alginate mass fraction is less than 2.0%, although the drug loading of microcapsule is higher, its roundness and hardness undesirable; When the mass fraction of sodium alginate is greater than 2.5% dripping difficulty, need special pressue device.Therefore the best in quality mark of sodium alginate is 2.0%.
The impact (n=3) of table 10 sodium alginate mass fraction
Calcium chloride mass fraction
Under 2.0% sodium alginate (380mPa.s), sodium alginate are 0.5 condition with resveratrol and the combination quality ratio of indirubin, calcium chloride mass fraction is respectively 2.0%, 3.0%, 4.0%, 5.0%, prepare a series of microcapsule, observe its form, measure its drug loading and envelop rate, the results are shown in Table 11.Result of the test shows, although calcium chloride mass fraction is lower, the drug loading of microcapsule is higher, when calcium chloride mass fraction is 3.0% or 4.0%, and the roundness of microcapsule and hardness optimal.Therefore consider drug loading, roundness and hardness, the best in quality mark of calcium chloride is 3.0%.
The impact (n=3) of table 11 calcium chloride mass fraction
The checking of optimization formulation
The optimum process drawn according to experiment of single factor and prescription condition, prepare resveratrol indirubin composition of medicine combination microcapsule 3 batches, record and the results are shown in Table 12.
Table 12 confirmatory experiment result table (n=3)
Result shows, the optimum process of this preparation technology and prescription condition are sodium alginate viscosity is 380mPa.s, the combination quality of sodium alginate and resveratrol and indirubin than 0.5, sodium alginate mass fraction is 2.0%, calcium chloride mass fraction is 3.0%.Demonstration test shows that this process stabilizing is reliable, drug loading and envelop rate higher.
The preparation of embodiment 2 laboratory sample
Take medicine monomer in the ratio of resveratrol and indirubin 1:10 and mix, by the preparation method of embodiment 1 optimum, preparing group I.
Take medicine monomer in the ratio of resveratrol and indirubin 10:1 and mix, by the preparation method of embodiment 1 optimum, preparing experimental group II.
Take medicine monomer in the ratio of resveratrol and indirubin 8:1 and mix, by the preparation method of embodiment 1 optimum, preparing experimental group III.
Take medicine monomer in the ratio of resveratrol and indirubin 1:7 and mix, by the preparation method of embodiment 1 optimum, preparing experimental group IV.
Take medicine monomer in the ratio of resveratrol and indirubin 2:3 and mix, by the preparation method of embodiment 1 optimum, preparing experimental group V.
Take resveratrol monomer, by the preparation method of embodiment 1 optimum, prepare resveratrol group.
Take indirubin alcohol monomer, by the preparation method of embodiment 1 optimum, prepare indirubin group.
Embodiment 3 resveratrol indirubin composition of medicine combination microcapsule is to animal transplanting tumor inhibitory action
Getting female KM mice, 18 ~ 22g, rat, 60 ~ 80g, under aseptic condition, get the inoculation ascites tumor of 7 days (H22 hepatocarcinoma), make suspension, is 10 by 1:10 dilution counting, adjustment oncocyte number
7individual/ml, is inoculated in the right axil of mice subcutaneous, and only, every mouse inoculation oncocyte number is 2 × 10 to 0.2ml/
6, divide 9 groups at random after weighing next day, often organize 10; The each sample group of preparation in administration embodiment 2 respectively, blank group, group I-V group, resveratrol group, indirubin group and cyclophosphamide group.Group I-V group, resveratrol group and indirubin group gastric infusion every day (ig) secondary (dosage calculates with active component content), successive administration 10 days, cyclophosphamide group subcutaneous administration (sc), be administered once every day successive administration 10 days.Blank group then gives respective volume distilled water, drug withdrawal one day after last administration, and de-neck puts to death animal, weigh, cut open tumor weighs.Press formulae discovery tumor control rate and check the significant difference between comparable group with t.
, successive administration 10 days is to H
22hepatocarcinoma has obvious inhibitory action.The results are shown in Table 13.
Table 13 resveratrol indirubin composition of medicine combination microcapsule is to H
22the inhibitory action of hepatocarcinoma transplantability tumor strain
Note: compare with matched group, * P<0.05, * * P<0.01
Take the logarithm the H of trophophase respectively
22tumor cells of hepatocellular carcinoma, after trypsinization, being made into concentration with the culture fluid containing 10% calf serum is 1 × 10
4individual mL
-1cell suspension, be seeded in 96 well culture plates, every hole 190 μ L, puts containing 5%CO
237 DEG C of cell culture incubators in, cultivate after 24h, until attached cell adherent completely after, every hole adds different medicine 10 μ L, empirically designs group I-V group, resveratrol group and the indirubin group that add preparation in embodiment 2 respectively; Positive control Cytoxan 10 μ L, separately establishes the matched group of not dosing.Cultivate 48h in incubator after, every hole adds the MTT (1mgmL of 10 μ L subsequently
-1) solution, latter 37 DEG C of vibration mixing continues to cultivate 4h, careful abandoning supernatant, add 200 μ LDMSO to dissolve, Oscillating Flat instrument vibration 10min, microplate reader is used wavelength 492nm, and reference wavelength is measure each hole absorbance (OD) value under the condition of 570nm, calculates suppression ratio [tumour inhibiting rate (%)=(1-experimental group OD value/matched group OD value) × 100%].The results are shown in Table 14.
Table 14 resveratrol indirubin composition of medicine combination microcapsule is outer to H
22the inhibitory action of tumor cells of hepatocellular carcinoma strain
Note: compare * <0.05 with matched group, * * P<0.01.
From table 14; Resveratrol indirubin composition of medicine combination microcapsule all can suppress the propagation of H22 tumor cells of hepatocellular carcinoma strain; In table 14, prompting resveratrol indirubin composition of medicine combination microcapsule has certain direct killing In vitro culture H
22the effect of tumor cells of hepatocellular carcinoma strain; The compositions of resveratrol and indirubin, to the activity of the active function of cancer due to the monomer of Isodose, has the effect of synergy.
Claims (3)
1. the slow-releasing microcapsule agent of a resveratrol indirubin composition of medicine, using sodium alginate as carrier material, with the slow-releasing microcapsule agent that resveratrol and indirubin are active component, it is characterized in that: in described slow-releasing microcapsule agent, the weight ratio of resveratrol and indirubin is 1-10:1-10.
2. the slow-releasing microcapsule agent of resveratrol indirubin composition of medicine according to claim 1, is characterized in that: the weight ratio of described middle resveratrol and indirubin is 2:3.
3. the application in Therapeutic cancer medicine is being prepared in the slow-releasing microcapsule agent of the resveratrol indirubin composition of medicine described in any one of claim 1-2.
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| CN1947765A (en) * | 2005-10-10 | 2007-04-18 | 黄振华 | Traditional Chinese medicine composition contg. isatis root and rhizoma belamcandae, and its prepn. method and use |
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