CN100428960C - Method for preparing nano liver-target biodegradating medicine carrier material - Google Patents
Method for preparing nano liver-target biodegradating medicine carrier material Download PDFInfo
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- CN100428960C CN100428960C CNB2005100151727A CN200510015172A CN100428960C CN 100428960 C CN100428960 C CN 100428960C CN B2005100151727 A CNB2005100151727 A CN B2005100151727A CN 200510015172 A CN200510015172 A CN 200510015172A CN 100428960 C CN100428960 C CN 100428960C
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Abstract
The present invention relates to a method for preparing nanometer liver target biodegradable medicinal carrier material, which belongs to the field of biological medicinal material. A liver target compound is modified onto a polymer which is biodegradable and has biocompatibility, such as chitosan, polylysine, dextran, agar, polyglutamic acid-benzyl ester and polyalanine, and the modified polymer is prepared into the nanometer liver target biodegradable medicinal carrier material by means of an ion crosslinked method or an ultrasonic emulsification method. A liver target nanometer particle solution has good target capacity to the liver, a medicine enriched rate in the liver is 75%, and slow-release administration can last for more than 15 days. A target substance is a small molecular compound which has clear liver target performance, and the target substance has no side effects on human bodies. Target material has good blood compatibility and can effectively realize the target slow-release treatment of liver diseases. Meanwhile, the target material has good liver target performance and has the function of slow-release administration, so curative effects and life quality are improved, and treatment cost is reduced.
Description
Technical field
The present invention relates to formation of a kind of biodegradation drug carrier material and medicine-carried nano particles and preparation method thereof, particularly relate to and the liver target compound modified degradable and have preparation biodegradation drug carrier material on the polymer of biocompatibility, and prepare the method for liver target drug-carrying nanoparticle by ionomer or ultrasonic emulsification method packaging medicine.
Background technology
Hepatocarcinoma, especially primary hepatocarcinoma are common clinical and frequently-occurring disease.The primary hepatocarcinoma mortality rate occupies the 3rd in malignant tumor, be only second to the gastric cancer and the esophageal carcinoma.China is the hotspot of hepatocarcinoma, and sickness rate accounts for more than 50% of the whole world.To the treatment of hepatocarcinoma, first-elected at present liver transplantation, but the donor difficulty is asked.Cancer drug therapy (cyclophosphamide, hydrochloric acid thymine arabinoside) is because the medicine whole body distributes, and big inadequately at the lesions position drug level, but bigger to other internal organs injuries, some patients often die from the injury of chemotherapeutics to other internal organs.
Hepatic-targeted delivery system (Hepatic targeted drug delivery System, HTDDS) be one of the focus of pharmaceutics research field, medicine can be delivered to effectively the diseased region of liver, improve the therapeutic effect of medicine, alleviate infringement to other internal organs, reduce dosage and administration number of times, therefore, HTDDS has positive impetus to the treatment of hepatic disease.In the research of liver targeting, often adopt two kinds of diverse ways: 1 passive target (passive targeting), the particle of 50～200 nm can be by macrophage phagocytic, and part is assembled at liver and pulmonary's reticuloendothelial system, and the part hepatic targeting is arranged; 2 targeting (active targeting) initiatively, nanoparticle is connected with specific part, can with receptors bind on the liver target cell, realize the liver targeted therapy, therefore initiatively the targeting of targeting is obvious, better effects if.
1978, Paul Ehrlich proposed, and antitumor drug and monoclonal antibody is covalently bound, can make the drug targeting tumor tissues.With the monoclonal antibody is the targeting group, connect medicine, radionuclide, immune molecule and enzyme and carry out the treatment of hepatic disease, and be the main method of studying liver targeting material at present in the world.Monoclonal antibody is that targeting is strong as the targeting substance biggest advantage, transhipment rate height, but present antibody mainly is the Mus endogenous antibody, safety becomes its matter of utmost importance.Humanized's antibody then owing to cost an arm and a leg, is difficult to large-scale application.
The research of domestic present hepatic disease mainly concentrates on liposome and some other synthesized polymer material is prepared as nanoparticle packaging medicine or gene aspect.But nanoparticles such as liposome are lower to histiocytic specific recognition, and the transhipment rate is lower, and targeting is not strong, restricted to a great extent as the application of methods such as gene, radionuclide therapy in liver disease therapy.Domestic also have part seminar to adopt receptor-mediated method for designing, uses the galactose modified polymer, preparation liver targeting material.But because galactose is strong inadequately to liver surface receptor-specific recognition reaction, nanoparticle needs magnetisable material or antibody modification, makes the manufacturing of material and use bring a lot of inconvenience, and cost is also very high.
At present still untappedly go out hepatocarcinoma is had the gentle drug system of releasing drug treatment of specific target tropism simultaneously.By receptor-mediated, but chemotherapeutics or genetic stew are stated from the macromolecule carrier of vivo degradation, just medicine or genetic stew can be delivered to hepatocyte, realize the purpose of liver target slow-release drug treatment hepatocarcinoma.To have introducing degradables such as the small-molecule substance of high hepatic targeting such as enoxolone, glycyrrhizic acid, cholic acid and have the polysaccharide of good biocompatibility and the liver targeting material on the polyamino acid has not yet to see report.The objective of the invention is in order to solve above technical problem.
Summary of the invention
The object of the invention provides the preparation method of a kind of nano liver-target biodegradating medicine carrier material and medicine-carried nano particles.
Nano liver-target biodegradating medicine carrier material provided by the invention, its characteristics are that it comprises following ingredients:
The liver target compound,
Polymer;
The substitution value of targeting group is 0.5-1mmol/g;
Described liver target compound is any one in enoxolone, glycyrrhizic acid, the cholic acid,
Described polymer is a kind of in chitosan, polylysine, glucosan, agar, poly benzyl glutamate, the poly-alanine.
The molecular weight of chitosan, agar, glucosan is 6000-20000 in the polymer, and the molecular weight of poly benzyl glutamate, poly-alanine, polylysine is 2000～40000.
Liver target drug-carrying nanoparticle provided by the invention, its characteristics are that it comprises following ingredients:
Above-described nano liver-target biodegradating medicine carrier material,
Ion crosslinking agent,
The medicine of treatment hepatic disease;
Described ion crosslinking agent is a polymalic acid sodium, any one in polymalic acid, the sodium tripolyphosphate.
The molecular weight of polymalic acid, polymalic acid sodium is 2000～6000 in the ion crosslinking agent.
The preparation method of more than one described nano liver-target biodegradating medicine carrier materials, its characteristics are: the liver target compound is modified degradable and have on the polymer of biocompatibility, it comprises following preparation process:
1) preparation of liver target compound beautify chitosan:
In 2～10% chitosan aqueous solution, the N that adds liver target compound and 1-ethyl-3-(3-dimethylamino isopropyl) carbodiimide EDC, the solution of dinethylformamide DMF, 60～100 ℃ of reactions 4～6 hours, after the cooling, concentration of reaction solution, to precipitate in the concentrated solution impouring ethanol, filter, will precipitate drying, as the hepatic targeting drug carrier material;
2) the liver target compound is modified the preparation of polylysine:
In 2～10% polylysine aqueous solution, add the solution of the DMF of liver target compound and EDC, 60～100 ℃ of reactions 4～6 hours, after the cooling, concentration of reaction solution will precipitate in the concentrated solution impouring ethanol, filter, will precipitate drying, as the hepatic targeting drug carrier material;
3) the liver target compound is modified the preparation of agar or glucosan:
In the DMF aqueous solution of agar 2～10% or glucosan, the solution that adds the DMF of liver target compound and 4-dimethylamino naphthyridine DMAP, be heated to 40～80 ℃ of reactions 4～6 hours, after the cooling, concentration of reaction solution will precipitate in the concentrated solution impouring ethanol, filters, to precipitate drying, as the hepatic targeting drug carrier material;
4) the liver target compound is modified the preparation of poly benzyl glutamate or poly-alanine:
The liver target compound is dissolved in the tetrahydrofuran THF, cooling adds N, N-dicyclohexylcarbodiimide DCC, stir the back and add N-hydroxy-succinamide SuOH, at room temperature stirring reaction in gained solution impouring absolute ether behind the reactant mixture elimination 1,3-Dicyclohexylurea, is collected white solid, use a small amount of absolute ethanol washing, the washing of reuse absolute ether, vacuum drying gets active ester;
The DMF drips of solution of active ester is added in the solution of big excessive diamine and reacts, in the derivant impouring water with cholic acid or enoxolone, in the derivant impouring oxolane of glycyrrhizic acid, 3 ℃ of placements.With sedimentation and filtration, with small amount of ethanol, water, ether washing, drying, gained is deposited among the DMF dissolves, use ether sedimentation, vacuum drying obtains the liver target compound of amido modification; The liver target compound that takes by weighing N-carboxylic acid anhydrides-benzyl glutamate-N-carboxylic acid anhydrides or alanine-N-carboxylic acid anhydrides, amido modification is in reaction bulb; add DMF; stirring at room reaction under nitrogen protection then; reactant liquor is added drop-wise in the absolute ether under vigorous stirring and precipitates; sedimentation and filtration; with the ether washing, the dry white solid product that gets is as the target medicine carrier material.
Above-described preparation method is 1) in the preparation of step liver target compound beautify chitosan, its molar ratio of material is,
Chitosan: liver target compound: EDC is 1: 0.2～0.4: 0.2～0.4;
2) step liver target compound modifies in the preparation of polylysine, and its molar ratio of material is,
Polylysine: liver target compound: EDC is 1: 0.1～0.7: 0.2～0.4;
3) step liver target compound modifies in the preparation of agar or glucosan, and its molar ratio of material is,
Agar or glucosan: liver target compound: DMAP is 1: 0.5～2.0: 0.2～0.4;
4) step liver target compound modifies in the preparation of poly benzyl glutamate or poly-alanine, and its molar ratio of material is,
Liver target compound: DCC: SuOH is 1: 1.0～1.5: 1.0～1.5;
Active ester: diamine is 1: 30～100;
The N-carboxylic acid anhydrides: the liver target compound that amido is modified is 50～300: 1.
Described diamine is any one of ethylenediamine, hexamethylene diamine, and ethylenediamine is made solvent with DMF, and hexamethylene diamine is made solvent with dimethyl sulfoxide.
More than one described liver target drug-carrying nanometer particle process method, its characteristics are: by ionomer or ultrasonic emulsification method, come packaging medicine with the hepatic targeting drug carrier material, the preparation medicine-carried nano particles comprises following preparation process:
1) preparation of chitosan or polylysine base load medicine nanoparticle:
The aqueous solution of 5% hepatic targeting drug carrier material is added drop-wise to contain the medicine for the treatment of hepatic disease and ion crosslinking agent be that any one pH value in sodium tripolyphosphate, polymalic acid sodium, the polymalic acid is in 7.4 the phosphate buffer, sonic oscillation obtains finely dispersed liver target drug-carrying nanoparticle;
2) preparation of agar or glucosan based medicine carrier material drug-supplying system:
Dropping contains the pharmaceutical aqueous solution for the treatment of hepatic disease in the DMF solution that contains 5% hepatic targeting drug carrier material, and sonic oscillation obtains finely dispersed liver target drug-carrying nanoparticle;
3) preparation of poly benzyl glutamate or poly-alaninyl medicine-carried nano particles:
Dropping contains the pharmaceutical aqueous solution for the treatment of hepatic disease in any one alcoholic solution in the ethanol that contains 5% hepatic targeting drug carrier material, isopropyl alcohol, hexanol, and sonic oscillation obtains finely dispersed liver target drug-carrying nanoparticle.
Above-described preparation method,
1) in the preparation of step chitosan or polylysine base load medicine nanoparticle, its molar ratio of material is,
Chitosan: ion crosslinking agent is 100: 1～7;
2) in the preparation of step agar or glucosan base load medicine nanoparticle, its volume of material ratio is,
The DMF solution of agar or glucosan: pharmaceutical aqueous solution is 1: 1～10;
3) in the preparation of step poly benzyl glutamate or poly-alaninyl medicine-carried nano particles, its volume of material ratio is,
The alcoholic solution of target medicine carrier material: pharmaceutical aqueous solution is 1: 1～30.
Beneficial effect of the present invention: be used for intravenous injection target slow-release treatment hepatic disease, hepatic-targeted nano-particle solution has good targeting ability to liver, and medicine liver accumulation rate reaches 75%, and sustained-release administration can reach more than 15 days; Targeting substance is the micromolecular compound with clear and definite hepatic targeting, and human body is free from side effects.The targeting material has good blood compatibility, and the target slow-release treatment of high efficiency realization hepatic disease has the function of high hepatic targeting and sustained-release administration simultaneously, improves therapeutic effect and life quality, has reduced the treatment cost.
Description of drawings
Fig. 1, nano liver-target biodegradating medicine carrier material preparation process sketch map,
Fig. 2, nanoparticle be at the intravital scattergram of rat,
The chitin nanometer of Fig. 3, modification enoxolone is sealed 5-fluorouracil release in vitro curve chart,
Among the figure
A chitin nanometer 30min detect the renal metabolism hepatic region detect less than
B GA-CTS nanoparticle 30min detects two kidney 14% livers and gathers 〉=and 76%.
The specific embodiment
Understand content of the present invention, characteristics and effect for further, and conjunction with figs. 1,2,3 is described in detail as follows:
Embodiment 1, the chitosan nano liver-target biodegradating medicine carrier material of modifying enoxolone and the preparation of nanoparticle:
1. the preparation of GA-CTS:
Take by weighing 2g enoxolone and 1g EDC and place in the 200mL beaker, in bottle, add 70mL DMF, the magnetic agitation dissolving.
In with the 500mL there-necked flask, add the 5g chitosan, add 100mL distilled water magnetic agitation to dissolving.The enoxolone solution that then top is prepared is poured in the chitosan solution, continues to stir, and is heated to 60 ℃ of reactions 6 hours.Reactant liquor is cooled to 40 ℃, is concentrated into about 50mL with Rotary Evaporators.The concentrated solution impouring filled in the alcoholic acid beaker of 800mL precipitate, filter, with 50mL ethanol, the washing of 50mL ether, (40 ℃, 5mmHg) 24 hours, product contained enoxolone 5% to vacuum drying to precipitation respectively.
2. the preparation of GA-CTS aqueous solution and ion crosslinking agent aqueous solution:
The chitosan of 1.0g being modified enoxolone is dissolved in the 50mL redistilled water, and is standby.0.3g ion crosslinking agent (polymalic acid sodium, polymalic acid, sodium tripolyphosphate) is dissolved in the 30mL redistilled water, standby.
The preparation of 3 GA-CTS hepatic-targeted nano-particles:
3.1 add 2mL polymalic acid sodium solution in 10mL modifies the chitosan solution of enoxolone, sonic oscillation 30min obtains containing the nanoparticle of targeting group.
3.2 add 2mL polymalic acid solution in 10mL modifies the chitosan solution of enoxolone, sonic oscillation 30min obtains containing the nanoparticle of targeting group.
3.3 add the 2mL sodium tripolyphosphate solution in 10mL modifies the chitosan solution of enoxolone, sonic oscillation 30min obtains containing the nanoparticle of targeting group.
1. enoxolone is modified the preparation of polylysine:
Take by weighing 2g enoxolone and 1 gEDC and place in the 200mL beaker, in bottle, add 70mLDMF, the magnetic agitation dissolving.
In with the 500mL there-necked flask, add the 5g polylysine, add 100mL distilled water magnetic agitation to dissolving.The enoxolone solution that then top is prepared is poured in the polylysine solution, continues to stir, and is heated to 60 ℃ of reactions 6 hours.Reactant liquor is cooled to 40 ℃, is concentrated into about 50mL with Rotary Evaporators.The concentrated solution impouring filled in the alcoholic acid beaker of 800mL precipitate, filter, with 50mL ethanol, the washing of 50mL ether, (40 ℃, 5mmHg) 24 hours, product contained enoxolone 8% to vacuum drying to precipitation respectively.
2. enoxolone is modified the preparation of polylysine aqueous solution and ion crosslinking agent aqueous solution:
The polylysine of 1.0g being modified enoxolone is dissolved in the 50mL redistilled water, and is standby.0.3g ion crosslinking agent (polymalic acid sodium, polymalic acid, sodium tripolyphosphate) is dissolved in the 30mL redistilled water, standby.
3. enoxolone is modified the preparation of polylysine hepatic-targeted nano-particle:
3.1 add 2mL polymalic acid sodium solution in 10mL modifies the polylysine solution of enoxolone, sonic oscillation 30min obtains containing the nanoparticle of targeting group.
3.2 add 2mL polymalic acid solution in 10mL modifies the polylysine solution of enoxolone, sonic oscillation 30min obtains containing the nanoparticle of targeting group.
3.3 add the 2mL sodium tripolyphosphate solution in 10mL modifies the polylysine solution of enoxolone, sonic oscillation 30min obtains containing the nanoparticle of targeting group.
Embodiment 3, the agar nano liver-target biodegradating medicine carrier material of modifying enoxolone and the preparation of medicine-carried nano particles:
1. enoxolone is modified the preparation of agar:
Take by weighing 2g enoxolone and 1 gEDC and place in the 200mL beaker, in bottle, add 70mLDMF, the magnetic agitation dissolving.
In the 500mL there-necked flask, add 7g agar, add 100mL DMF magnetic agitation to dissolving.The enoxolone solution that then top is prepared is poured in the agar solution, continues to stir, and is heated to 60 ℃ of reactions 6 hours.Reactant liquor is cooled to 40 ℃, is concentrated into about 50mL with Rotary Evaporators.The concentrated solution impouring filled in the alcoholic acid beaker of 800mL precipitate, filter, with 50mL ethanol, the washing of 50mL ether, (40 ℃, 5mmHg) 24 hours, product contained enoxolone 4% to vacuum drying to precipitation respectively.
2. enoxolone is modified the preparation of agar liver target drug-carrying nanoparticle:
Dropping contains the pharmaceutical aqueous solution for the treatment of hepatic disease in the DMF solution that contains 5% target medicine carrier material, and sonic oscillation obtains finely dispersed liver target drug-carrying nanoparticle.
Embodiment 4, prepare nano liver-target biodegradating medicine carrier material and medicine-carried nano particles by the N-carboxylic acid anhydrides:
1. the 2mmol enoxolone is dissolved in the oxolane, is cooled to-10 ℃, add DCC 2.54g (12.3mmol), after stirring 30min, add SuOH 1.42g (12.3mmol), continue to stir 3 hours, at room temperature stir 8～18h, in gained solution impouring absolute ether behind the reactant mixture elimination 1,3-Dicyclohexylurea, collect white solid, use a small amount of absolute ethanol washing, the washing of reuse absolute ether, vacuum drying gets active ester.
2. the DMF drips of solution of active ester is added in the solution of ethylenediamine of 70mL, in 30～60 ℃ of reaction 5～10h.In the derivant impouring water with cholic acid and enoxolone (in the derivant impouring oxolane of glycyrrhizic acid), place 24h at 3 ℃.With sedimentation and filtration, use small amount of ethanol, water, ether washing, drying.Gained is deposited among the DMF dissolves, use ether sedimentation, vacuum drying obtains the liver target compound that amido is modified.
3. the liver target compound initiation benzyl glutamate-N-carboxylic acid anhydrides polymerization of amido modification prepares the targeting material:
The liver target compound 1mmol that takes by weighing benzyl glutamate-N-carboxylic acid anhydrides 100mmol, amido modification adds 80-100mL DMF in reaction bulb, stirring at room reaction 48h under the nitrogen protection.Under the vigorous stirring reactant liquor dropped in the excessive absolute ether and precipitate.Sedimentation and filtration, the ether washing, the dry white solid product that gets is as the hepatic targeting drug carrier material.
4. the preparation of poly benzyl glutamate medicine-carried nano particles:
Be added dropwise to the aqueous solution of the hydrochloric thymine arabinoside of 2mL in 10mL poly benzyl glutamate alcoholic solution, sonic oscillation 30min obtains containing the medicine-carried nano particles of targeting group.
The chitosan liver target nanoparticle that embodiment 5 the modifies enoxolone experiment that in the rat body, distributes:
Utilizing the radioelement labelling is a kind of quick and precisely quantitative analyzing detecting method in conjunction with the distribution in animal body of SPECT technology for detection nanoparticle.We adopt this method to study and modify the chitosan liver target nanoparticle of enoxolone in the intravital distribution of rat.
1. the preparation of nanoparticle:
The nano-particle solution of the chitosan of chitosan and modification enoxolone is prepared same 1-3.
2. the cDTPA coupling of nanoparticle:
Get chitosan (GA-CTS) nano-particle solution of 4mL0.1g/L chitosan (CTS) and modification enoxolone respectively and mix, at room temperature react 1h and finish coupling with 80mg diethylene triamine pentacetic acid (DTPA) two cyclic anhydrides (cDTPA).Mixed liquor is removed free diethylene triamine pentacetic acid (DTPA) (DTPA) with the conventional gel chromatography separation of Sephadex G75, and leacheate is a distilled water, and the content of ultraviolet detection enoxolone group obtains the nano-particle solution of CTS-DTPA and GA-CTS-DTPA.
3. the labelling of nanoparticle:
(Medronate pink salt (MDP-Sn) test kit adds the 1mL normal saline for CTS-DTPA and GA-CTS-DTPA, nano-particle solution 1mL 1mg/1mL), and each sample is got 100 μ L, adds 1mCi respectively to get above-claimed cpd
99mThe solution that Tc and 50 μ L MDP solution reaction 10min. labellings are good is diluted to 3mL with normal saline and uses for the experiment that distributes in the mice body.
4. distribution experimental result in the rat animal body is seen Fig. 2.
1. carry the preparation of 5-fluorouracil nanoparticle:
Drip 2.5mg/mL sodium tripolyphosphate solution 8mL under the room temperature magnetic agitation and modify among the chitosan solution 20mL of enoxolone, keep sonic oscillation 10min in the 5mg/mL that contains the variable concentrations 5-fluorouracil.
2. nanoparticle carries the calculating of 5-fluorouracil rate and envelop rate:
Under 4 ℃ of conditions, the 16000r/min high speed centrifugation separates a year 5-fluorouracil nanoparticle 30min, is detecting 5-fluorouracil content in the supernatant in wavelength 266nm place on the ultraviolet-uisible spectrophotometer.The nanoparticle lyophilization is weighed, and to be placed in the vacuum desiccator cryopreservation standby.Nanoparticle carries the computing formula of 5-fluorouracil rate (LC) and envelop rate (EE) respectively suc as formula (1), shown in the formula (2):
The chitin nanometer of modifying enoxolone carries 5-fluorouracil rate (LC) and reaches 37%, and envelop rate (EE) reaches 82%.
3. the external controlled release 5-fluorouracil of nanoparticle performance:
4mL carries the 5-fluorouracil nanoparticle suspension and places bag filter, and bag filter is put in 20mL PBS (pH=7.4) solution, and 37 ℃ of insulation magnetic stir.Get wherein 5-fluorouracil content of 2mL PBS liquor analysis at interval at regular intervals, add the fresh PBS solution of 2mL.
The 5-fluorouracil nanoparticle that carries of preparation does not have obviously prominent releasing, and external slow release can reach more than 15 days, and its experiment the results are shown in accompanying drawing 3.
Claims (9)
1. nano liver-target biodegradating medicine carrier material is characterized in that it comprises following ingredients:
The liver target compound,
Polymer;
The substitution value of targeting group is 0.5-1mmol/g;
Described liver target compound is any one in enoxolone, glycyrrhizic acid, the cholic acid,
Described polymer is a kind of in chitosan, polylysine, glucosan, agar, poly benzyl glutamate, the poly-alanine.
2. nano liver-target biodegradating medicine carrier material according to claim 1, it is characterized in that: the molecular weight of chitosan, agar, glucosan is 6000-20000 in the polymer, and the molecular weight of poly benzyl glutamate, poly-alanine, polylysine is 2000～40000.
3. liver target drug-carrying nanoparticle is characterized in that it comprises following ingredients:
The described nano liver-target biodegradating medicine carrier material of claim 1,
Ion crosslinking agent,
The medicine of treatment hepatic disease;
Described ion crosslinking agent is a polymalic acid sodium, any one in polymalic acid, the sodium tripolyphosphate.
4. liver target drug-carrying nanoparticle according to claim 3 is characterized in that: the molecular weight of polymalic acid, polymalic acid sodium is 2000～6000 in the ion crosslinking agent.
5. the preparation method of the described nano liver-target biodegradating medicine carrier material of claim 1 is characterized in that: the liver target compound is modified degradable and have on the polymer of biocompatibility, it comprises following preparation process:
1) preparation of liver target compound beautify chitosan:
In 2～10% chitosan aqueous solution, the N that adds liver target compound and 1-ethyl-3-(3-dimethylamino isopropyl) carbodiimide EDC, the solution of dinethylformamide DMF, 60～100 ℃ of reactions 4～6 hours, after the cooling, concentration of reaction solution, to precipitate in the concentrated solution impouring ethanol, filter, will precipitate drying, as the hepatic targeting drug carrier material;
2) the liver target compound is modified the preparation of polylysine:
In 2～10% polylysine aqueous solution, add the solution of the DMF of liver target compound and EDC, 60～100 ℃ of reactions 4～6 hours, after the cooling, concentration of reaction solution will precipitate in the concentrated solution impouring ethanol, filter, will precipitate drying, as the hepatic targeting drug carrier material;
3) the liver target compound is modified the preparation of agar or glucosan:
In the DMF aqueous solution of agar 2～10% or glucosan, the solution that adds the DMF of liver target compound and 4-dimethylamino naphthyridine DMAP, be heated to 40～80 ℃ of reactions 4～6 hours, after the cooling, concentration of reaction solution will precipitate in the concentrated solution impouring ethanol, filters, to precipitate drying, as the hepatic targeting drug carrier material;
4) the liver target compound is modified the preparation of poly benzyl glutamate or poly-alanine:
The liver target compound is dissolved in the tetrahydrofuran THF, cooling adds N, N-dicyclohexylcarbodiimide DCC, stir the back and add N-hydroxy-succinamide SuOH, at room temperature stirring reaction in gained solution impouring absolute ether behind the reactant mixture elimination 1,3-Dicyclohexylurea, is collected white solid, use a small amount of absolute ethanol washing, the washing of reuse absolute ether, vacuum drying gets active ester;
The DMF drips of solution of active ester is added in the solution of big excessive diamine and reacts, in the derivant impouring water with cholic acid or enoxolone, in the derivant impouring oxolane of glycyrrhizic acid, 3 ℃ of placements, with sedimentation and filtration, with small amount of ethanol, water, ether washing, drying is deposited in gained among the DMF and dissolves, and uses ether sedimentation, vacuum drying obtains the liver target compound that amido is modified; The liver target compound that takes by weighing N-carboxylic acid anhydrides-benzyl glutamate-N-carboxylic acid anhydrides or alanine-N-carboxylic acid anhydrides, amido modification is in reaction bulb; add DMF; stirring at room reaction under nitrogen protection then; reactant liquor is added drop-wise in the absolute ether under vigorous stirring and precipitates; sedimentation and filtration; with the ether washing, the dry white solid product that gets is as the target medicine carrier material.
6, the preparation method of nano liver-target biodegradating medicine carrier material according to claim 5 is characterized in that: 1) in the preparation of step liver target compound beautify chitosan, its molar ratio of material is,
Chitosan: liver target compound: EDC is 1: 0.2～0.4: 0.2～0.4;
2) step liver target compound modifies in the preparation of polylysine, and its molar ratio of material is,
Polylysine: liver target compound: EDC is 1: 0.1～0.7: 0.2～0.4;
3) step liver target compound modifies in the preparation of agar or glucosan, and its molar ratio of material is,
Agar or glucosan: liver target compound: DMAP is 1: 0.5～2.0: 0.2～0.4;
4) step liver target compound modifies in the preparation of poly benzyl glutamate or poly-alanine, and its molar ratio of material is,
Liver target compound: DCC: SuOH is 1: 1.0～1.5: 1.0～1.5;
Active ester: diamine is 1: 30～100;
The N-carboxylic acid anhydrides: the liver target compound that amido is modified is 50～300: 1.
7. nano liver-target biodegradating medicine carrier material according to claim 5 is characterized in that: diamine is any one of ethylenediamine, hexamethylene diamine, and ethylenediamine is made solvent with DMF, and hexamethylene diamine is made solvent with dimethyl sulfoxide.
8, the described liver target drug-carrying nanometer particle process method of a kind of claim 3 is characterized in that: by ionomer or ultrasonic emulsification method, come packaging medicine with the hepatic targeting drug carrier material, the preparation medicine-carried nano particles comprises following preparation process:
1) preparation of chitosan or polylysine based medicine carrier material drug carrier nanoparticle:
The aqueous solution of 5% hepatic targeting drug carrier material is added drop-wise to contain the medicine for the treatment of hepatic disease and ion crosslinking agent be that any one pH value in sodium tripolyphosphate, polymalic acid sodium, the polymalic acid is in 7.4 the phosphate buffer, sonic oscillation obtains finely dispersed liver target drug-carrying nanoparticle;
2) preparation of agar or glucosan based medicine carrier material drug carrier nanoparticle:
Dropping contains the pharmaceutical aqueous solution for the treatment of hepatic disease in the DMF solution that contains 5% hepatic targeting drug carrier material, and sonic oscillation obtains finely dispersed liver target drug-carrying nanoparticle;
3) preparation of poly benzyl glutamate or poly-alaninyl drug carrier material medicine-carried nano particles:
Dropping contains the pharmaceutical aqueous solution for the treatment of hepatic disease in any one alcoholic solution in the ethanol that contains 5% hepatic targeting drug carrier material, isopropyl alcohol, hexanol, and sonic oscillation obtains finely dispersed liver target drug-carrying nanoparticle.
9, liver target drug-carrying nanometer particle process method according to claim 8 is characterized in that:
1) go on foot in the preparation of chitosan or polylysine based medicine carrier material drug carrier nanoparticle, its molar ratio of material is chitosan: ion crosslinking agent is 100: 1～7;
2) go on foot in the preparation of agar or glucosan based medicine carrier material drug carrier nanoparticle, its volume of material ratio is the DMF solution of agar or glucosan: pharmaceutical aqueous solution is 1: 1～10;
3) go on foot in the preparation of poly benzyl glutamate or poly-alaninyl drug carrier material drug-supplying system, its volume of material ratio is the alcoholic solution of target medicine carrier material: pharmaceutical aqueous solution is 1: 1～30.
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| CN101249266B (en) * | 2008-04-08 | 2010-06-02 | 南开大学 | Nano liver target direction amphipathic nature block copolymers drug administration system and preparation |
| US9173852B2 (en) * | 2008-04-08 | 2015-11-03 | Tian Si Polymer Materials Technology Development Co. | Glycyrrhetinic acid-mediated nanoparticles of hepatic targeted drug delivery system, process for preparing the same and use thereof |
| CN102048694B (en) * | 2009-11-06 | 2013-03-13 | 复旦大学 | Polypeptide-modified liver tumor-targeted nano medicine delivery system and preparation method thereof |
| CN101757642A (en) * | 2010-03-03 | 2010-06-30 | 天津科技大学 | Method for preparing gadolinium-containing nano particles |
| CN102641495A (en) * | 2012-05-07 | 2012-08-22 | 苏州大学 | Liver targeting interleukin-12/chitosan nano drug feeding system for intravenous injection and preparation method thereof |
| CN103131006B (en) * | 2013-02-04 | 2016-01-20 | 中国科学院长春应用化学研究所 | A kind of graft copolymer, its preparation method and decorative material layer by layer |
| CN108148193B (en) * | 2015-08-03 | 2023-05-12 | 中国医学科学院药用植物研究所 | Cholic acid-containing high polymer material and liposome modified by same |
| CN111543637B (en) * | 2020-06-08 | 2022-07-22 | 浙江大学 | Construction method of targeting liver slow-release functional factor exosome based on brown algae |
| CN115558039B (en) * | 2021-07-02 | 2023-05-12 | 福建中医药大学 | Glycyrrhetinic acid-carboxymethyl chitosan-ketal-rhetinic acid conjugate, preparation method and application thereof |
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| WO1999001143A1 (en) * | 1997-07-03 | 1999-01-14 | Orquest, Inc. | Cross-linked polysaccharide drug carrier |
| CN1586488A (en) * | 2004-07-12 | 2005-03-02 | 复旦大学 | Chitosan glycyrrhizic acid nano particle and its preparing method |
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| WO1999001143A1 (en) * | 1997-07-03 | 1999-01-14 | Orquest, Inc. | Cross-linked polysaccharide drug carrier |
| CN1586488A (en) * | 2004-07-12 | 2005-03-02 | 复旦大学 | Chitosan glycyrrhizic acid nano particle and its preparing method |
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