CN100362984C - Prepn. method of matrine magnetic micro-ball - Google Patents
Prepn. method of matrine magnetic micro-ball Download PDFInfo
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- CN100362984C CN100362984C CNB200610019300XA CN200610019300A CN100362984C CN 100362984 C CN100362984 C CN 100362984C CN B200610019300X A CNB200610019300X A CN B200610019300XA CN 200610019300 A CN200610019300 A CN 200610019300A CN 100362984 C CN100362984 C CN 100362984C
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Abstract
The present invention relates to a preparation method of a magnetic microsphere containing medicines for treating liver cancer, particularly to a preparation method of a matrine magnetic microsphere. The present invention is characterized in that the preparation method of the magnetic microsphere comprises the following steps: 1, the preparation of magnetic fluid, FeCl3 and FeCl2 are mixed according to 1 to 3:1 of molar ratio; distilled water is filled; NaOH solution or ammonia water is filled until the pH value of the solution system is no smaller than 8; then, oleic acid is filled, and after HCl solution or HAC solution is filled, the pH value is 7, and the magnetic fluid is obtained. 2, the preparation of the matrine magnetic microsphere, 1 to 10 mg/mL of chitosan solution is prepared by 0.5% to 5% of mass concentration of acetic acid solution; 0.5 to 10 mg/mL of polyphosphate is prepared with distilled water; chitosan solution is taken; the magnetic fluid which is 0.02 to 0.15 time of the volume of the chitosan solution and the matrine which is 0.2 to 2 times of the quality of the chitosan are respectively added, polyphosphate which is 0.2 to 1 time of the volume of the chitosan solution is filled into the chitosan solution, and after mixing, separation and dryness, the matrine magnetic microsphere is obtained. The matrine magnetic microsphere which has a magnetic positioning function and a medicine release function can be obtained by the method.
Description
Technical field
The present invention relates to a kind of preparation method that contains the magnetic microsphere for the treatment of liver-cancer medicine.
Background technology
The traditional medicine of China has formed the oncosis of comparatively system of own uniqueness for thousands of years because of, pathogenesis theory, and has accumulated the rich experiences that Chinese herbal medicine is anticancer, control cancer, and Chinese herbal medicine is being brought into play enormous function in the struggle of human and tumor.Matrine (matrine) is to separate the alkaloid that obtains from cassia leguminous plant Herba Sophorae alopecuroidis radix sophorae, and the anti-tumor activity with matrine in numerous alkaloid of sophora flavescens ait is the strongest.Studies show that matrine can suppress tumor cell proliferation, transfer, induce its apoptosis, reach to have the antineoplastic activity, experimental tumor is had inhibitory action to the normal cell differentiation.
The main pharmacological of matrine is as follows:
1), protect the liver, liver protection effect: matrine can reduce hepatocyte injury, and promote its regeneration, improve liver microcirculation, in order to bilirubinic picked-up, combination and drainage, thereby reach antiinflammatory, protect the liver and expand the effect that enzyme falls in liver and jaundice eliminating, finally make hepatopathy reason histology be improved significantly;
2), antiviral: matrine makes hepatitis suffer from the HBeAg negative conversion rate and reaches 51% the obvious suppression effect of having duplicated of HBV-DNA, and anti-HBc--lgM negative conversion rate reaches 50%;
3), anti-swollen fibrosis: mainly by the protection liver plasma membrane, suppress the release of the fibrosis factor, a plurality of links such as the function of regulation and control fat-storing cells (HSC) are brought into play the effect of anti-hepatic fibrosis;
4), the double regulation control immunity, effectively improve the pathologic tissue;
5), antitumor action: main by suppressing Na on the cell membrane, k-ATP enzyme and activated adenyl cyclase, and then the effect of inhibition growth of tumour cell; Simultaneously, matrine also can suppress the adhesion of tumor cell and endotheliocyte, thus the transfer of minimizing tumor etc.;
6), toxicological test confirms that matrine does not have obvious influence to animal breath system and cardiovascular system, acute toxicity LD50 is 64.4mg/kg.Long term toxicity test finds no the pathology damage of toxicity meaning, and mutagenicity test is all negative, shows that this product does not have overt toxicity.
Clinical practice: be mainly used to treat cancer, viral hepatitis, leukopenia etc.
The magnetic target preparation is that medicine and microgranule ferromagnetic material are wrapped in the high molecular polymer carrier jointly, and employing external magnetic field guide drugs orientation in vivo moves and locate the drug-supplying system that focuses on target site.Main carrier as cancer therapy drug.It is a kind of novel targeting preparation of studying energetically both at home and abroad in recent years, mainly contains magnetic microsphere, magnetic microcapsule, magnetic Emulsion, magnetic nano particle, magnetic liposome, magnetic lipid microsphere, magnetic tablet or capsule etc.
Magnetic fluid is by means of surfactant the ferromagnetism ultramicron to be distributed in the liquid phase resulting highly stablely and have the colloidal solution of magnetic, and it combines the rheological characteristic of solid ferromagnetism and liquid dexterously.Comparatively sophisticated at present magnetofluid making method comprises: chemical coprecipitation, mechanical milling method, thermal decomposition method, electrical discharge machining, reducing process, electroprecipitation method, vacuum vapour deposition etc.Chemical coprecipitation is easy and simple to handle because of having, cost is low, to equipment requirements advantages of higher not, be to prepare the magnetic fluid method of normal use at present.
Abroad propose first the beginning of the sixties cancer therapy drug and magnetisable material to be wrapped in altogether or to be scattered in carrier (skeleton) material, by being heating and curing or crosslinking curing forms the magnetic drug-carrying microsphere.Magnetic microsphere under enough externally-applied magnetic field effects, can guide carrying medicament in vivo orientation move, locate, concentrate.And microsphere adopts biodegradable polymer such as albumin, polylactic acid, chitosan, polylactic acid poly ethanol copolymer etc. as the carrier of target administration, with medicine parcel or embedding, prepares the microsphere or the microcapsule of medicine carrying.According to the diameter difference of microgranule, can be held back by lung, liver,kidney,spleen etc., thereby realize the biophysics targeting.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of matrine magnetic micro-ball, this method can obtain the matrine magnetic micro-ball of magnetic orientation and medicament slow release function.
To achieve these goals, technical scheme of the present invention is: a kind of preparation method of matrine magnetic micro-ball is characterized in that it comprises the steps:
1), the preparation of magnetic fluid: with FeCl
3, FeCl
21-3 in molar ratio: 1 mixes, and adds FeCl
3And FeCl
2Gross mass 30-100 distilled water doubly adds NaOH solution or ammonia to solution system pH 〉=8 under 40-80 ℃ of stirring, add FeCl behind the insulation reaction 0.5-2h
3And FeCl
2Gross mass 1-2 oleic acid doubly, behind the reaction 1-3h, adding HCl or HAC solution is 7 to pH, promptly gets magnetic fluid with distilled water wash behind the reaction 0.5-2h;
2), the preparation of matrine magnetic micro-ball: adopt the ion condensation legal system to be equipped with matrine magnetic micro-ball, with mass concentration is the chitosan solution of the acetum preparation 1-10mg/mL of 0.5%-5%, polyphosphate with distilled water preparation 0.5-10mg/mL, get chitosan solution, add chitosan solution volume 0.02-0.15 magnetic fluid and chitosan mass 0.2-2 matrine doubly doubly respectively, under high-speed stirred (500-1500r/min), chitosan solution volume 0.2-1 polyphosphate doubly is injected into chitosan solution, stir 5-30min, the centrifugalize microsphere is drying to obtain particle diameter little (500-1500nm), the matrine magnetic micro-ball that is evenly distributed.
The concentration of described NaOH solution is 0.5-3mol/L, and the concentration of ammonia is 1%-25%.
The present invention adopts the carrier of chitosan as target administration, chitosan is a cationic polymer, can interact with electronegative polymer (polyphosphate) and form compound polyelectrolyte, and pharmaceutical pack is embedded in the composite membrane, be prepared into sustained-release micro-spheres, this process is simple.The present invention adopts the ion condensation method, adopts static to cause physical crosslinking and avoid introducing deleterious reagent and unnecessary influence in the chemical crosslinking process.Polyphosphate (TPP) is a polyanion, can issue hair growth promoting at electrostatic interaction in cationic chitosan should, in the ion condensation method, polyphosphate soln is dropwise splashed into chitosan-acetic acid solution in the continuous stirring, chitosan and polyphosphate with opposite charges react, and chitosan promptly condenses and be precipitated out the formation microsphere from solution.
Matrine magnetic micro-ball has magnetic orientation and medicament slow release function concurrently, its magnetic targeting positioning action has determined that drug main will assemble at lesions position, can make circulation time medicine microspheres arrive target site in vivo, realize targeting, reduce medicine Normocellular toxic and side effects; And have tangible slow-release function, but prolong drug action time in vivo; Matrine magnetic micro-ball also itself has good organism internal contact compatibility, and is very little for the toxicity of cell, and the growth of cell is subjected to the influence of magnetic microsphere little.
The invention has the beneficial effects as follows: preparation method is simple, preparing nanometer magnetofluid (ferriferrous oxide nano-particle) by nanotechnology examines as magnetic, carry matrine and magnetic fluid is prepared into microsphere with the chitosan bag, thereby prepare matrine targeted drug novel form, have targeting (magnetic orientation) and slow-releasing and controlled-releasing action preferably, can well bring into play the antitumor action of matrine, improve its anti-tumor activity, simultaneously reduce its toxic and side effects to greatest extent, make it become the real antineoplastic target drug-supplying system novel form that has future.Matrine magnetic micro-ball has the characteristics of magnetic responsiveness strong (Atomic Absorption result), particle diameter little (500-1500nm).
The present invention adopts the form of intravenous drip, and dosage and usage and dosage instil for add among the 10% glucose injection 500ml in 100mg (with matrine content) at every turn, and 1 time on the one, be 2 weeks the course of treatment.Drip velocity is advisable with about 60 of per minute.
The matrine magnetic micro-ball of the present invention's preparation is used for the treatment of hepatocarcinoma.
Description of drawings
Fig. 1 is an ion condensation method sketch map
Fig. 2 is the releasing curve diagram of matrine magnetic micro-ball
Fig. 3 is the grain-size graph of magnetic fluid
Fig. 4 is the grain-size graph of the matrine magnetic micro-ball of embodiment 1
Fig. 5 is the magnetic fluid microphotograph
Fig. 6 is the matrine magnetic micro-ball microphotograph
Fig. 7 is the X-ray diffracting spectrum of magnetic fluid
Fig. 8 is the grain-size graph of the matrine magnetic micro-ball of embodiment 2
Fig. 9 is the grain-size graph of the matrine magnetic micro-ball of embodiment 3
Among the figure: 1-polyphosphate soln, 2-agitator, 3-chitosan solution (containing magnetic fluid), 4-matrine magnetic micro-ball.
The specific embodiment
In order to understand the present invention better, further illustrate content of the present invention below in conjunction with embodiment, but content of the present invention not only is confined to the following examples.
Embodiment 1:
A kind of preparation method of matrine magnetic micro-ball, it comprises the steps:
1, the preparation of magnetic fluid
Prepare magnetic fluid with chemical coprecipitation.Take by weighing 2.703g FeCl
36H
2O and 0.994g FeCl
24H
2O is according to 1: 2mol fully is dissolved in the 200mL redistilled water, behind the ultrasonic degas 10min, is stirring and is being incubated under 40 ℃ the condition, drips the NaOH solution of 2mol/L.When the solution pH value was elevated to 6-7, iron salt hydrolysis produced a large amount of black Fe
3O
1Particle, continue to drip NaOH to pH about 11, at 40 ℃ of following ageing 30min, in 5min, splash into 5mL oleic acid with syringe, after continuing 2h again, be that 5% acetic acid is neutralized to pH=7, use the distilled water cyclic washing with mass concentration, and remove larger particles with the centrifugal 10min of the speed of 1000r/min, promptly obtain stable magnetic fluid.
2, the preparation of matrine magnetic micro-ball:
As shown in Figure 1, ion condensation method.With mass concentration is the chitosan solution of 1.5% acetum preparation 4mg/mL, sodium polyphosphate with distilled water preparation 1mg/mL, get the chitosan solution of 10mL, add 0.5mL magnetic fluid and 40mg matrine respectively, under high-speed stirred (1000r/min), the polyphosphate of 5mL is injected into chitosan solution, stir 10min, centrifugalize microsphere (magnetic microsphere of preparation is separated) ,-80 ℃ of matrine magnetic micro-balls that lyophilization promptly gets particle diameter little (mean diameter is 682.4nm), is evenly distributed.
The release profiles of matrine magnetic micro-ball:
Measure down with reference to Chinese Pharmacopoeia version appendix in 2005 XIX D vitro drug release degree test item, get matrine magnetic micro-ball 0.1g, put in the drug dissolution instrument (RCZ-6C type, Shanghai), respectively at getting 5mL solution in 0.5,1,2,4,6,8,18 hour, and timely supplementing solvent; Measure matrine content at wavelength 215nm place with ultraviolet spectrophotometer (760 CRT, Shanghai), the results are shown in Table 1; And, see Fig. 2 according to measurement result drafting release profiles; The result shows that matrine magnetic micro-ball is slow release.
Table 1
| Time (h) | 0.5 | 1 | 2 | 4 | 6 | 8 | 18 |
| Accumulative total burst size (mg) | 0.929 | 1.402 | 2.419 | 3.395 | 4.105 | 4.954 | 6.114 |
Magnetic fluid and matrine magnetic micro-ball particle size distribution:
Magnetic fluid and matrine magnetic micro-ball are diluted to 50 times, (Britain Malvern) tests its particle size distribution with the Zetasizer3000HSA laser particle analyzer, as shown in Figure 3, Figure 4, the mean diameter of magnetic fluid is 152.2nm, be evenly distributed, the mean diameter of matrine magnetic micro-ball is 682.4nm, is evenly distributed.
The surface topography of magnetic fluid and matrine magnetic micro-ball:
Observe the surface topography of magnetic fluid and matrine magnetic micro-ball respectively with E200 type Nikon ECLIPSE biological microscope.Fig. 5 is the microphotograph of magnetic fluid, and as shown in Figure 5, magnetic fluid is evenly distributed, and does not reunite; Fig. 6 is the matrine magnetic micro-ball microphotograph, and as shown in Figure 6, matrine-loaded magnetic chitosan is spherical in shape, and shape is regular, is evenly distributed, and does not produce and reunites and flocculation.
The test of magnetic fluid X-ray diffraction:
Get the 100mL magnetic fluid, after the lyophilization, get powder and carry out the X-ray diffraction test, test condition is: Tianjin, island XRD-6000 type x-ray diffractometer; Scan mode: qualitative, step-scan; Voltage/current: 40kV/30mA; Scanning speed: 4.0000deg/min; Step-length: 0.02 ° (2 θ); Preset time: 0.3s; Target: Cu target; Sweep limits: (2 θ) 10-60 °.The result as shown in Figure 7, its characteristic peak and Fe
3O
1Mark card characteristic peak coincide.
The quantitative assay of iron content in the matrine magnetic micro-ball:
Adopt WFX-110 atomic absorption spectrophotometer (Beijing Rayleigh Analytical Instrument Co.,Ltd) to measure the content of ferrum in the matrine magnetic micro-ball.Analysis condition: element to be measured is carried out atomization with air acetylene mode of heating.Instrument working parameter: wavelength: 248.3nm; Spectral band-width is wide: 0.2nm; Lamp current 12mA; Air mass flow 10L/min; Acetylene flow 3L/min.
Content in the magnetic microsphere is 26.38% as can be seen from Table 2.
The Atomic Absorption testing result of table 2 matrine magnetic micro-ball
| The sample title | Color and luster | Content/mg.Kg -1 | Percentage rate % | The content % of ferrum |
| Matrine magnetic micro-ball | Brown | 191290.42 | 19.1％ | 26.38％ |
Matrine magnetic micro-ball strengthens the Graft Versus Tumor experimentation
1 experiment material
1.1 laboratory animal
Kunming mouse, body weight 20～25g, male and female have concurrently.Provide by Hubei Prov. Academy of Medical Sciences's animal center.Meet three grades of laboratory animal quality standards.
1.2 medicine
Matrine magnetic micro-ball (MCSM), self-control; Cyclophosphamide (Cyclophosphamide, CTX), Hualian Pharmaceutical Co., Ltd., Shanghai.
1.3 animal moves growing property tumor
Mice S180, Wuhan University China typical culture collection center.
2 methods and result
Get the good Kunming mouse S180 sarcoma ascites of growth, dilute with normal saline, adjustment concentration is 1 * 107/ml, expect blue dyeing through tire, confirmation obtains cell rate 95%, every mice axil subcutaneous injection 0.2ml, random packet is established normal saline (NS) matched group, cyclophosphamide (CTX) positive control, matrine magnetic micro-ball (MCSM) is established height, in, low three dosage groups, be respectively 100mg/kg, 50mg/kg, 25mg/kg, play intraperitoneal injection next day, the next day 1 time, continuous 16 days, the tumor body is got in dissection, thymus, spleen, weigh, calculate tumour inhibiting rate, according to following formula result of determination:
Tumor control rate (%)=(the average tumor of the average tumor weight-administration of matched group group is heavy)/average tumor of matched group heavy * 100%
Result of the test shows that the dosage group has tangible potentiation to the tumor-inhibiting action of mice S180 in the matrine magnetic micro-ball, and inhibitory rate 56.12% the results are shown in Table 3
Table 3 matrine magnetic micro-ball is to the effect of mice S180 (X ± S)
| Group | Dosage | Number of animals | Tumor heavy (g) | Thymus heavy (mg) | Spleen heavy (mg) | Tumour inhibiting rate (%) |
| NS | - | 10 | 2.14±0.59 | 28.43±6.49 | 39.57±6.34 | |
| CTX | 0.10 | 10 | 1.42±0.48 | 35.68±6.81 | 45.26±10.16 | 33.64 |
| MCSM | 0.10 | 10 | 1.18±0.52 | 39.34±5.76 | 48.51±9.28 | 44.86 |
| 0.05 | 10 | 1.40±0.43 | 36.58±6.23 | 46.72±10.41 | 34.58 | |
| 0.025 | 10 | 1.70±0.54 | 32.29±8.62 | 43.24±8.59 | 20.56 |
The result shows, the matrine magnetic micro-ball high dose has the anti-tumor effect of tangible enhancing, compares (p＜0.05) with CTX with dosage, and middle dosage is compared (p＞0.05) with CTX, it is not obvious that low dosage strengthens anti-tumor effect, compares with normal saline to still have anti-tumor effect (p＜0.05); Experiment simultaneously finds, tumor is heavy relevant with thymus, spleen heavy burden, and tumor is heavily more little, and thymus, spleen are big heavily more, otherwise tumor is big heavily more, and thymus, spleen are heavily more little.
Embodiment 2:
A kind of preparation method of matrine magnetic micro-ball, it comprises the steps:
1), the preparation of magnetic fluid: with FeCl
3, FeCl
2Mixed in 1: 1 in molar ratio, and added FeCl
3And FeCl
2The distilled water that gross mass is 30 times adds concentration and is 0.5mol/L NaOH solution to solution system pH=8 under 40 ℃ of stirrings, add FeCl behind the insulation reaction 0.5h
3And FeCl
2The oleic acid that gross mass is 1 times, behind the reaction 1h, adding HCl solution is 7 to pH, promptly gets magnetic fluid with distilled water wash behind the reaction 0.5h;
2), the preparation of matrine magnetic micro-ball: adopt the ion condensation legal system to be equipped with matrine magnetic micro-ball, with mass concentration is the chitosan solution of 0.5% acetum preparation 1mg/mL, polyphosphate with distilled water preparation 0.5mg/mL, get chitosan solution, the matrine that adds 0.2 times of the magnetic fluid of 0.02 times of chitosan solution volume and chitosan mass respectively, under high-speed stirred (500r/min), the polyphosphate of 0.2 times of chitosan solution volume is injected into chitosan solution, stir 5min, the centrifugalize microsphere, being drying to obtain particle diameter, little (mean diameter is 685.2, as shown in Figure 8), the matrine magnetic micro-ball that is evenly distributed.
Embodiment 3:
A kind of preparation method of matrine magnetic micro-ball, it comprises the steps:
1), the preparation of magnetic fluid: with FeCl
3, FeCl
2Mixed in 3: 1 in molar ratio, and added FeCl
3And FeCl
2The distilled water that gross mass is 100 times adds strong aqua ammonia to solution system pH=14 under 80 ℃ of stirrings, add FeCl behind the insulation reaction 2h
3And FeCl
2The oleic acid that gross mass is 2 times, behind the reaction 3h, adding HAC solution is 7 to pH, promptly gets magnetic fluid with distilled water wash behind the reaction 2h;
2), the preparation of matrine magnetic micro-ball: adopt the ion condensation legal system to be equipped with matrine magnetic micro-ball, with mass concentration is the chitosan solution of 5% acetum preparation 10mg/mL, polyphosphate with distilled water preparation 10mg/mL, get chitosan solution, the matrine that adds 2 times of the magnetic fluid of 0.15 times of chitosan solution volume and chitosan masses respectively, under high-speed stirred (1500r/min), the polyphosphate of 1 times of chitosan solution volume is injected into chitosan solution, stir 30min, the centrifugalize microsphere, being drying to obtain particle diameter, little (mean diameter is 1282.9nm, as shown in Figure 9), the matrine magnetic micro-ball that is evenly distributed.
Claims (1)
1. the preparation method of a matrine magnetic micro-ball is characterized in that it comprises the steps:
1), the preparation of magnetic fluid: with FeCl
3, FeCl
21-3 in molar ratio: 1 mixes, and adds FeCl
3And FeCl
2Gross mass 30-100 distilled water doubly adds NaOH solution or ammonia to solution system pH 〉=8 under 40-80 ℃ of stirring, add FeCl behind the insulation reaction 0.5-2h
3And FeCl
2Gross mass 1-2 oleic acid doubly, behind the reaction 1-3h, adding HCl or HAC solution is 7 to pH, promptly gets magnetic fluid with distilled water wash behind the reaction 0.5-2h;
2), the preparation of matrine magnetic micro-ball: adopt the ion condensation legal system to be equipped with matrine magnetic micro-ball, with mass concentration is the chitosan solution of the acetum preparation 1-10mg/mL of 0.5%-5%, polyphosphate with distilled water preparation 0.5-10mg/mL, get chitosan solution, add chitosan solution volume 0.02-0.15 magnetic fluid and chitosan mass 0.2-2 matrine doubly doubly respectively, under high-speed stirred, chitosan solution volume 0.2-1 polyphosphate doubly is injected into chitosan solution, stir 5-30min, the centrifugalize microsphere, being drying to obtain particle diameter is 500-1500nm, the matrine magnetic micro-ball that is evenly distributed.
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| CN101518258B (en) * | 2009-04-10 | 2012-06-06 | 暨南大学 | Method for preparing matrine/carboxymethyl chitosan/phosphonic chitosan pesticide nanoparticle aqueous dispersion preparation |
| CN104004744A (en) * | 2014-06-12 | 2014-08-27 | 江南大学 | Method for preparing immobilized glucose oxidase with slow-release effect |
| CN104213125B (en) * | 2014-09-05 | 2016-08-17 | 武汉理工大学 | A kind of anticorrosion magnetic Nano material with slow releasing function and preparation method thereof |
| CN104252106B (en) * | 2014-09-18 | 2018-07-31 | 南京理工大学 | A kind of color toner and its method using mini-emulsion polymerization and electrostatic coagulation preparation in situ |
| CN106962374A (en) * | 2017-03-24 | 2017-07-21 | 孙志廷 | A kind of biomass carbon particle for loading matrine chitosan sustained-release microsphere and preparation method thereof |
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| 磁性壳聚糖复合微球的制备和性能研究. 姜炜等.材料科学和工程学报，第22卷第5期. 2004 * |
| 磁性微球的制备及研究进展. 马秀玲等.广州化学，第28卷第3期. 2003 * |
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