CN1743008A - 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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- CN1743008A CN1743008A CNA2005100151727A CN200510015172A CN1743008A CN 1743008 A CN1743008 A CN 1743008A CN A2005100151727 A CNA2005100151727 A CN A2005100151727A CN 200510015172 A CN200510015172 A CN 200510015172A CN 1743008 A CN1743008 A CN 1743008A
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Abstract
The preparation method includes the following steps: modifying hepatic target compound onto degradable polymer (chitosan, polylysine, glucosan, agar, polyglutamic acid-benzyl ester, polyalanine) with biological compatibility, and adopting ion exchange or ultrasonic emulsification process to obtain the invented nano hepatic target bio-degradable medicine carrier material. The hepatic target nano particle solution has good target performance for liver, the medicine enriched rate in the liver can be up to 75%, and its slowly-released administration can be up to above 15 days.
Description
Technical field
The invention belongs to biomedical materials field, particularly relate to a kind of preparation method of nano liver-target biodegradating medicine carrier material.
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 invention provides a kind of preparation method of nano liver-target biodegradating medicine carrier material.
The technology path that adopts is the liver target compound is modified degradable and to have on the polymer of biocompatibility, prepares nano liver-target biodegradating medicine carrier material by ionomer or ultrasonic emulsification method.
The liver target compound is any one in enoxolone, glycyrrhizic acid, the cholic acid, and the substitution value of targeting group is 0.5-1mmol/g.Polymer is any one in chitosan, polylysine, glucosan, agar, poly benzyl glutamate, the poly-alanine.The molecular weight of chitosan, agar, glucosan is 6000-20000, and the molecular weight of poly benzyl glutamate, poly-alanine, polylysine is 2000～40000.
With the ion crosslinking agent in the ionomer method is polymalic acid sodium, any one in polymalic acid or the sodium tripolyphosphate, and polymalic acid sodium, the molecular weight of polymalic acid are 2000～6000.
The preparation method of nano liver-target biodegradating medicine carrier material comprises the steps:
1 liver target compound is modified degradable and is had the preparation of the polymer of biocompatibility:
1.1 the preparation of liver target compound beautify chitosan:
In 2～10% chitosan aqueous solution, the N that adds liver target compound and EDC (1-ethyl-3-(3-dimethylamino isopropyl) carbodiimide), 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;
1.2 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;
1.3 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;
1.4 the liver target compound is modified the preparation of poly benzyl glutamate or poly-alanine:
The liver target compound is dissolved in the oxolane (THF), cooling adds N, N-dicyclohexylcarbodiimide (DCC), stir the back and add 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 to the solution of big excessive diamine (any one of ethylenediamine, hexamethylene diamine), and (ethylenediamine is made solvent with DMF, hexamethylene diamine is made solvent with dimethyl sulfoxide) middle reaction, in the derivant impouring water with cholic acid, 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, 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.
Described liver target compound is modified degradable and the material proportion that has in the preparation process of polymer of biocompatibility is:
In the preparation process of 1.1 liver target compound beautify chitosans, chitosan: liver target compound: EDC is 1: 0.2～0.4: 0.2～0.4, mol/mol;
Modify in the preparation process of polylysine at 1.2 liver target compounds, polylysine: liver target compound: EDC is 1: 0.1～0.7: 0.2～0.4, mol/mol;
Modify in the preparation process of agar or glucosan at 1.3 liver target compounds, agar (or glucosan): liver target compound: DMAP is 1: 0.5～2.0: 0.2～0.4, mol/mol;
Modify in the preparation process of poly benzyl glutamate or poly-alanine at 1.4 liver target compounds,
Liver target compound: DCC: SuOH is 1: 1.0～1.5: 1.0～1.5mol: mol;
Active ester: diamine is 1: 30～100, mol: mol;
The N-carboxylic acid anhydrides: the liver target compound that amido is modified is 50～300: 1mol: mol;
The preparation of 2 nano liver-target biodegradating medicine carrier materials:
2.1 the preparation of chitosan or polylysine based medicine carrier material nano particle:
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 nano liver-target biodegradating medicine carrier material;
2.2 the preparation of agar or glucosan based medicine carrier material nano particle:
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 nano liver-target biodegradating medicine carrier material;
2.3 the preparation of poly benzyl glutamate or poly-alaninyl drug carrier material nanoparticle:
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 nano liver-target biodegradating medicine carrier material.
Material proportion in the preparation process of described hepatic targeting drug carrier material nanoparticle is:
In the preparation process of 2.1 chitosans or polylysine based medicine carrier material nano particle, chitosan: ion crosslinking agent is 100: 1～7, m/m;
In the preparation process of 2.2 agar or glucosan based medicine carrier material nano particle, agar (or glucosan) DMF solution: pharmaceutical aqueous solution is 1: 1～10, v/v;
In the preparation process of 2.3 poly benzyl glutamates or poly-alaninyl drug carrier material nanoparticle, the alcoholic solution of target medicine carrier material: pharmaceutical aqueous solution is 1: 1～30, v/v.
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 are at the intravital scattergram of rat
The chitin nanometer of Fig. 3, modification enoxolone is sealed 5-fluorouracil release in vitro curve chart
Description of reference numerals
Fig. 2:
A chitin nanometer 30 min detect the renal metabolism hepatic region detect less than
B GA-CTS nanoparticle 30 min detect two kidney 14% livers and gather 〉=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:
The preparation that embodiment 1 modifies the chitosan nano liver-target biodegradating medicine carrier material of enoxolone:
1.1 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.
1.2 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.
1.3 the preparation of GA-CTS hepatic-targeted nano-particle solution:
1.3.1 add 2mL polymalic acid sodium solution in 10mL modifies the chitosan solution of enoxolone, sonic oscillation 30min obtains containing the nano-particle solution of targeting group.
1.3.2 add 2mL polymalic acid solution in 10mL modifies the chitosan solution of enoxolone, sonic oscillation 30min obtains containing the nano-particle solution of targeting group.
1.3.3 add the 2mL sodium tripolyphosphate solution in 10mL modifies the chitosan solution of enoxolone, sonic oscillation 30min obtains containing the nano-particle solution of targeting group.
The preparation that embodiment 2 modifies the polylysine nano liver-target biodegradating medicine carrier material of enoxolone:
2.1 enoxolone is modified the preparation of polylysine:
Take by weighing 2g enoxolone and 1gEDC 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.
2.2 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.
2.3 enoxolone is modified the preparation of polylysine hepatic-targeted nano-particle solution:
2.3.1 add 2mL polymalic acid sodium solution in 10mL modifies the polylysine solution of enoxolone, sonic oscillation 30min obtains containing the nano-particle solution of targeting group.
2.3.2 add 2mL polymalic acid solution in 10mL modifies the polylysine solution of enoxolone, sonic oscillation 30min obtains containing the nano-particle solution of targeting group.
2.3.3 add the 2mL sodium tripolyphosphate solution in 10mL modifies the polylysine solution of enoxolone, sonic oscillation 30min obtains containing the nano-particle solution of targeting group.
The preparation that embodiment 3 modifies the agar nano liver-target biodegradating medicine carrier material of enoxolone:
3.1 enoxolone is modified the preparation of agar:
Take by weighing 2g enoxolone and 1gEDC and place in the 200mL beaker, in bottle, add 70mLDMF, the magnetic agitation dissolving.
In the 500mL there-necked flask, add 7g agar, add the 100mLDMF 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.
3.2 enoxolone is modified the preparation of agar hepatic-targeted nano-particle solution:
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 nano liver-target biodegradating medicine carrier material.
Embodiment 4 prepares nano liver-target biodegradating medicine carrier material by the N-carboxylic acid anhydrides:
4.1 the 2mmol enoxolone is dissolved in the oxolane, be cooled to-10 ℃, add DCC2.54g (12.3mmol), after stirring 30min, add SuOH1.42g (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.
4.2 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.
4.3 causing benzyl glutamate-N-carboxylic acid anhydrides polymerization, the liver target compound that amido is modified 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, then stirring at room reaction 48h under nitrogen protection.Reactant liquor is added drop-wise in the excessive absolute ether under vigorous stirring and precipitates.Sedimentation and filtration, with the ether washing, the dry white solid product that gets is as the hepatic targeting drug carrier material.
4.4 the preparation of poly benzyl glutamate drug carrier material nanoparticle:
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 nano-particle solution of targeting group.
Embodiment 5 modifies the interior experiment that distributes of rat body of the chitosan nano liver-target biodegradating medicine carrier material of enoxolone:
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 nano liver-target biodegradating medicine carrier material of enoxolone in the intravital distribution of rat.
5.1 the preparation of nanoparticle:
The nano-particle solution of the chitosan of chitosan and modification enoxolone is prepared same 1-3.
5.2 the cDTPA coupling of nanoparticle:
Get chitosan (GA-CTS) nano-particle solution of 4mL 0.1g/L chitosan (CTS) and modification enoxolone respectively and mix, at room temperature react 1 h 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.
5.3 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
99mTc and 50 μ L MDP solution reaction 10min.The solution that labelling is good is diluted to 3mL with normal saline and uses for the experiment that distributes in the mice body.
5.4 distribution experimental result in the rat animal body is seen Fig. 2.
Embodiment 6 medicine release in vitro features
6.1 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.
6.2 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%.
6.3 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 2mLPBS 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, a kind of preparation method of nano liver-target biodegradating medicine carrier material, it is characterized in that the liver target compound being modified degradable and having on the polymer of biocompatibility, prepare nano liver-target biodegradating medicine carrier material by ionomer or ultrasonic emulsification method.
2, according to the preparation method of the described nano liver-target biodegradating medicine carrier material of claim 1, it is characterized in that described liver target compound is any one in enoxolone, glycyrrhizic acid, the cholic acid, the substitution value of targeting group is 0.5-1mmol/g.
3,, it is characterized in that described polymer is any one in chitosan, polylysine, glucosan, agar, poly benzyl glutamate, the poly-alanine according to the preparation method of the described nano liver-target biodegradating medicine carrier material of claim 1.
4, according to the preparation method of the described nano liver-target biodegradating medicine carrier material of claim 3, the molecular weight that it is characterized in that described chitosan, agar, glucosan is 6000-20000, and the molecular weight of poly benzyl glutamate, poly-alanine, polylysine is 2000～40000.
5, according to the preparation method of the described nano liver-target biodegradating medicine carrier material of claim 1, it is characterized in that the ion crosslinking agent in the described ionomer method is a polymalic acid sodium, in polymalic acid or the sodium tripolyphosphate any one, polymalic acid sodium, the molecular weight of polymalic acid are 2000～6000.
6, according to the preparation method of the described nano liver-target biodegradating medicine carrier material of claim 1, it is characterized in that the liver target compound modifies degradable and have the preparation of the polymer of biocompatibility, comprise following preparation process:
6.1 the preparation of liver target compound beautify chitosan:
In 2～10% chitosan aqueous solution, the N that adds liver target compound and EDC (1-ethyl-3-(3-dimethylamino isopropyl) carbodiimide), 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;
6.2 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;
6.3 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;
6.4 the liver target compound is modified the preparation of poly benzyl glutamate or poly-alanine:
The liver target compound is dissolved in the oxolane (THF), cooling adds N, N-dicyclohexylcarbodiimide (DCC), stir the back and add 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 to the solution of big excessive diamine (any one of ethylenediamine, hexamethylene diamine), and (ethylenediamine is made solvent with DMF, hexamethylene diamine is made solvent with dimethyl sulfoxide) middle reaction, in the derivant impouring water with cholic acid, 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, 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.
7, modify degradable according to the described liver target compound of claim 6 and have the preparation of the polymer of biocompatibility, it is characterized in that material proportion is:
In the preparation claim of 6.1 liver target compound beautify chitosans, chitosan: liver target compound: EDC is 1: 0.2～0.4: 0.2～0.4, mol/mol;
Modify in the preparation claim of polylysine at 6.2 liver target compounds, polylysine: liver target compound: EDC is 1: 0.1～0.7: 0.2～0.4, mol/mol;
Modify in the preparation claim of agar or glucosan at 6.3 liver target compounds, agar (or glucosan): liver target compound: DMAP is 1: 0.5～2.0: 0.2～0.4, mol/mol;
Modify in the preparation claim of poly benzyl glutamate or poly-alanine at 6.4 liver target compounds,
Liver target compound: DCC: SuOH is 1: 1.0～1.5: 1.0～1.5mol: mol;
Active ester: diamine is 1: 30～100, mol: mol;
The N-carboxylic acid anhydrides: the liver target compound that amido is modified is 50～300: 1mol: mol.
8, according to the preparation method of the described nano liver-target biodegradating medicine carrier material of claim 1, it is characterized in that the preparation of hepatic targeting drug carrier material nanoparticle, comprise following preparation process:
8.1 the preparation of chitosan or polylysine based medicine carrier material nano particle:
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 nano liver-target biodegradating medicine carrier material;
8.2 the preparation of agar or glucosan based medicine carrier material nano particle:
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 nano liver-target biodegradating medicine carrier material;
8.3 the preparation of poly benzyl glutamate or poly-alaninyl drug carrier material nanoparticle:
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 nano liver-target biodegradating medicine carrier material.
9, described according to Claim 8 hepatic targeting drug carrier material nanometer particle process method is characterized in that material proportion is:
In the preparation claim of 8.1 chitosans or polylysine based medicine carrier material nano particle, chitosan: ion crosslinking agent is 100: 1～7, m/m;
In the preparation claim of 8.2 agar or glucosan based medicine carrier material nano particle, agar (or glucosan) DMF solution: pharmaceutical aqueous solution is 1: 1～10, v/v;
In the preparation claim of 8.3 poly benzyl glutamates or poly-alaninyl drug carrier material nanoparticle, the alcoholic solution of target medicine carrier material: pharmaceutical aqueous solution is 1: 1～30, v/v.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090252803A1 (en) * | 2008-04-08 | 2009-10-08 | Nankai University & Tian Si Polymer Materials Technology Development Co., Ltd. | Glycyrrhetinic acid-mediated nanoparticles of hepatic targeted drug delivery system, process for preparing the same and use thereof |
| 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 |
| 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 |
| 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 |
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| CN105131277A (en) * | 2015-08-03 | 2015-12-09 | 中国医学科学院药用植物研究所 | Polymer material containing cholic acid and liposome modified by same |
| CN111543637A (en) * | 2020-06-08 | 2020-08-18 | 浙江大学 | Construction method of targeting liver slow-release functional factor exosome based on brown algae |
| CN115558039A (en) * | 2021-07-02 | 2023-01-03 | 福建中医药大学 | Glycyrrhetinic acid-carboxymethyl chitosan-keto thiol-rhein conjugate, and preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1011690A4 (en) * | 1997-07-03 | 2006-08-23 | Depuy Spine Inc | Cross-linked polysaccharide drug carrier |
| CN1261101C (en) * | 2004-07-12 | 2006-06-28 | 复旦大学 | Chitosan glycyrrhizic acid nano particle and its preparing method |
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| 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 |
| 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 |
| US20090252803A1 (en) * | 2008-04-08 | 2009-10-08 | Nankai University & Tian Si Polymer Materials Technology Development Co., Ltd. | 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 |
| CN103131006A (en) * | 2013-02-04 | 2013-06-05 | 中国科学院长春应用化学研究所 | Grafted copolymer and preparation method thereof and layer-by-layer decorative materials |
| 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 |
| CN105131277A (en) * | 2015-08-03 | 2015-12-09 | 中国医学科学院药用植物研究所 | Polymer material containing cholic acid and liposome modified by same |
| CN111543637A (en) * | 2020-06-08 | 2020-08-18 | 浙江大学 | Construction method of targeting liver slow-release functional factor exosome based on brown algae |
| 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 |
| CN115558039A (en) * | 2021-07-02 | 2023-01-03 | 福建中医药大学 | Glycyrrhetinic acid-carboxymethyl chitosan-keto thiol-rhein conjugate, and preparation method and application thereof |
| 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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