CN100566708C - A kind of preparation method of hepatic targeting drug microcapsule - Google Patents
A kind of preparation method of hepatic targeting drug microcapsule Download PDFInfo
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- CN100566708C CN100566708C CNB2007100704086A CN200710070408A CN100566708C CN 100566708 C CN100566708 C CN 100566708C CN B2007100704086 A CNB2007100704086 A CN B2007100704086A CN 200710070408 A CN200710070408 A CN 200710070408A CN 100566708 C CN100566708 C CN 100566708C
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Abstract
The invention discloses a kind of preparation method of medicament sustained-release nano microcapsule of tool hepatic targeting.This method is carried out enzymatic reaction with the sugar monomer of liver targeting group-contain galactose residue with vinyl carboxylates and is combined, the vinyl acetate of the band glycosyl that makes again with unsaturated cation or anionic monomer copolymerization, obtain liver targeting polyelectrolyte.This polyelectrolyte by the electrostatic interaction layer assembly, obtains the drug microcapsule with hepatic targeting on the drug microparticles surface, and encapsulated drug release rate is controlled.Polymerization of the present invention is simply efficient, and synthetic polyelectrolyte does not have physiology toxicity.Method for coating efficient height, easy to operate, preparation technology's gentleness, polyelectrolyte can be repeatedly recycling, and the medicament capsule that makes is steady in a long-term to be stored.Encapsulated medicine can progressively discharge, and may accumulate at liver, can alleviate the poison of drug effect to other healthy organ when improving the lesions position drug effect greatly, has good application prospects.
Description
Technical field
The present invention relates to a kind of preparation method of drug microcapsule.
Technical background
The medicine of regular dosage form is behind vein, oral or local injection, and drug distribution is in whole body, and the real medication amount that arrives the treatment target area is the fraction of dosage only, and most of medicine does not only have therapeutical effect in the distribution of non-target area, also can bring toxic and side effects.At above problem, developed class novel pharmaceutical formulation a---targeting drug delivery system, medicine is concentrated be positioned in pathological tissues, organ, cell or the cell.Advantages such as targeting preparation has the curative effect height, drug dose is few, and toxic and side effects is little.Ideal target administration system can be in target organ or site of action release, and whole body picked-up simultaneously seldom like this, both can improve curative effect, had reduced the toxic and side effects of medicine again.Hepatic disease such as hepatocarcinoma, hepatitis is commonly encountered diseases and frequently-occurring disease, but medication effect is very undesirable at present, and its reason is except that the pharmacological action of medicine own is still not ideal enough, and the diseased region that medicine can not be delivered to effectively liver also is a major reason.In addition, most of Broadspectrum antiphlogistic cancer therapy drug is the very big toxicity of tool all, therefore, very necessary during administration blood drug level is controlled, and prevents to be lower than minimum drug effect concentration or surpass the maximum tolerance of human body, adopts the slow release method of medicine to adjust drug release behavior usually.
Conventional microcapsule preparation method mainly contains coacervation, interfacial polymerization and situ aggregation method, and which kind of method all at first will be entrapped emulsifying materials, dispersion.Wherein use a large amount of organic extractants and emulsifying agent, may cause certain pollution and toxicity.In addition, the permeability of this class microcapsule wall reaches can only be regulated and control from macro-scale usually the slow-releasing of medicine.The layer upon layer electrostatic self-assembly method prepares microcapsule, process is simple, system is an aqueous solution, solvent-free pollution, the capsule wall thickness is in the nanoscale inner control, by adjusting the inorganic salt concentration of polycation/polyanion assembling number of plies, assembling temperature, assembling material concentration, assembling medium, thickness and aperture and permeability that can the accuracy controlling microcapsule wall, thereby the drug release behavior of strict control medicine.Present domestic patent has been made certain report to it, is that the patent application disclosed method of CN1771917A and CN1562456A has been caught micromolecule such as medicine with pre-assembled capsule layer by layer as publication number in solution.But directly forming microcapsule in the layer assembly of solid drugs microparticle surfaces does not appear in the newspapers, and the general layer assembly microcapsule of having reported at present grafting targeting group not, do not have tissue (liver) targeting, still can produce and the similar toxic and side effects of conventional dose normal structure.And the medicine-carried system of reporting that contains the targeting group all be with the target base directly and medicine with the chemical method coupling, or form the simple composite thing with medicine, for example publication number is the Chinese patent application of CN1087093A, CN1733314A, though but this technology makes medicine have certain targeting, but can't accuracy controlling, and synthetic method more complicated to the slow release of medicine.Therefore, prepare a kind of environmental friendliness, release is accurately controlled, and has the pharmaceutical carrier of certain target function, is one and has challenging task.
Summary of the invention
It is good to the invention provides a kind of targeting, and toxic and side effects is little, the preparation method of hepatic targeting drug microcapsule.
A kind of preparation method of hepatic targeting drug microcapsule comprises that it is 20nm～100 μ m drug microparticles surfaces that polyanion and polycation alternate group are contained in particle diameter.
The condition of assembling is: under 5～50 ℃, in the aqueous solution of the inorganic electrolyte of 0.2～5mol/L, add polycation or polyanion, the concentration of polycation or polyanion is 1～5mg/mL; Add drug microparticles again, the each adsorption time 10～30min of drug microparticles, the centrifugal supernatant of removing of each assembling back 5000rpm, washing, centrifugal 2～5 times, after polycation and polyanion are alternately assembled 1～20 time, obtain hepatic targeting drug microcapsule through centrifugal, washing.
Described inorganic electrolyte is NaCl, KCl, CaCl
2, CuCl
2, NaF, KBr, NaI, KI, NaNO
3, AgNO
3Or KNO
3, preferred NaCl, KCl or CaCl
2
Described drug microparticles is acyclovir, ganciclovir, cytosine arabinoside, fluorouracil, amycin, daunorubicin, ketoprofen, ibuprofen, dexamethasone or ribavirin C
4～C
12Serial anti-inflammatory and anticancer medicines such as the single vinyl acetate of chain length.
The preferred 0.5mol/L of the concentration of the aqueous solution of described inorganic electrolyte.
Described hepatic targeting drug microcapsule is stored in the water or the vacuum normal temperature drying is preserved.
It is sacchariferous having at least a kind of in described polyanion and the polycation, promptly has the glycosyl side chain in the molecular structure; Sacchariferous polyanion promptly contains sugared polyanion and makes by anionic monomer and the reaction of galactose vinyl acetate monomer; Sacchariferous polycation promptly contains sugared polycation and makes by cationic monomer and the reaction of galactose vinyl acetate monomer.
If when not having the glycosyl side chain in the molecular structure when described polyanion and polycation do not contain sugar, can adopt various polyanion of the prior art and polycation.
Described classes such as cationic monomer methylacryoyloxyethyl trimethyl ammonium chloride commonly used that contain sugared polycation contain the quaternary ammonium salt of unsaturated double-bond.Concrete as: the methylacryoyloxyethyl trimethyl ammonium chloride, the methylacryoyloxyethyl trimethylammonium bromide, dimethyl diallyl ammonium chloride, the dimethyl diallyl ammonium bromide, allyl amine and hydrochlorate thereof, vinyl imines and hydrochlorate thereof or sulfate, the 4-vinylpridine quaternary ammonium salt, N, the N-dimethyl, the N-benzyl, N-methylacryoyloxyethyl ammonium chloride, N, the N-dimethyl, the N-ethyl, N-methylacryoyloxyethyl ammonium bromide, N, the N-dimethyl, the N-butyl, N-methylacryoyloxyethyl ammonium bromide, N, N-dimethyl, N-cetyl or N-methylacryoyloxyethyl ammonium bromide.
The described synthetic method that contains sugared polycation is as follows:
Cationic monomer is mixed with the solution of water or dimethyl formamide (DMF); Mix with the galactose vinyl acetate monomer; Add the potassium peroxydisulfate of each monomer gross mass 0.1-10% or Ammonium persulfate. afterwards as initiator; under the nitrogen protection; in 20～100 ℃ of following copolyreaction 1～50h; add acetone precipitation and go out polymer; be placed in the bag filter that molecular cut off is 3500kD water dialysis 1-7 days with the 10mL water dissolution; with solution lyophilization in the bag, obtain containing sugared polycation.
Described anionic monomer Sodium styrene sulfonate commonly used or the acrylic acid that contains sugared polyanion.
The described synthetic method that contains sugared polyanion is as follows:
Anionic monomer is mixed with the solution of water or dimethyl formamide (DMF); Mix with the galactose vinyl acetate monomer; Add the potassium peroxydisulfate of each monomer gross mass 0.1-10% or Ammonium persulfate. afterwards as initiator; under the nitrogen protection; in 20～100 ℃ of following copolyreaction 1～50h; add acetone precipitation and go out polymer; placing molecular cut off with the 10mL water dissolution is that the bag filter of 3500kD was to water dialysis 1-7 days; with solution lyophilization in the bag, lyophilization obtains containing sugared polyanion.
Synthetic contain sugared polycation and contain sugared polyanion process in, galactose vinyl acetate monomer and cationic monomer or anionic monomer mol ratio are 10: 1～1: 10; Galactose vinyl acetate monomer and cationic monomer or anionic monomer gross mass percent concentration in reaction system is 10～80%; Preferred 30%.When going out polymer, use acetone volume 10-20 times as mixed solution cumulative volume in the polymerization reaction system with acetone precipitation.
The synthetic method of described galactose vinyl acetate monomer is as follows:
Galactose and divinyl ester were reacted 1-5 days in organic solvent in 10～80 ℃ under enzyme catalysis, and solids removed by filtration is separated crude product, and distilling under reduced pressure obtains double bond containing galactose vinyl acetate monomer.
The mol ratio of galactose and divinyl ester is 1: 1～10.
Described divinyl ester is adipic acid divinyl ester, decanedioic acid divinyl ester or Vinyl crotonate.
Described enzyme is bacillus alkaline protease, esterase, porcine pancreatic lipase, lipase from candida sp or immobilization miehei lipase, and every gram galactose uses enzyme 0.5～20g.
Described organic solvent is pyridine, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) or butyl alcohol-tert.Every gram galactose is 20-100mL with an organic solvent.
Preferred 50 ℃ of described reaction temperature, preferred 3 days of response time.
The medicament capsule that preparation method of the present invention is obtained places pH 1.4, pH 7.4 buffer systems of certain volume, and the medicine of capsule promptly can be discharged in the system lentamente.With glycosyl be outermost medicament capsule can with the peanut agglatinin specific recognition, and can with the HepG2 cell adhesion.
By adjusting the inorganic salt concentration of polycation/polyanion assembling number of plies, assembling temperature, assembling material concentration, assembling medium, thickness and aperture and permeability that can accuracy controlling microcapsule multilayer film, thus play the effect of controlled release drug.In addition, change temperature, pH value, ionic strength and the polarity size of extraneous release medium, or change the preserving type of microcapsule, also clearly the regulation and control of sustained drug release effect.
Galactose vinyl acetate monomer synthetic method provided by the present invention adopts enzymatic method, and selectivity is very high, and by-product is few, can keep the biological activity and the stability of glycosyl to greatest extent, and copolymerization process is simply efficient.Advantages such as used quaternary ammonium salt monomer has low toxicity, low irritant, has a broad antifungal spectrum, consumption is few, drug effect is high, pollute less, biological degradability is good.Thereby synthetic contain sugared liver targeting polyelectrolyte in vivo can be by progressively rupture ester bond degraded of hydrolytic enzyme effect, no physiology toxicity.The glycosyl very high biological activity of tool still in multilayer film that forms with polyanion and the microcapsule, can with the bonded lectin efficient identification of galactose specificity, and can adhere to human liver cancer cell (HepG2), because this cell surface is crossed expression asialoglycoprotein receptor (ASGPR), can discern the galactose group specially and combine closely, thereby prove the liver targeting function of microcapsule with it.The content of glycosyl can be regulated and control in the polycation, thereby also can be regulated and control the targeting degree.Method for coating efficient height provided by the present invention, easy to operate, preparation technology's gentleness, polyelectrolyte can be repeatedly recycling, and the medicament capsule that makes is steady in a long-term to be stored.Encapsulated medicine can progressively discharge, and may accumulate at liver, can alleviate the poison of drug effect to other healthy organ when improving the lesions position drug effect greatly.
Description of drawings
Before the polymerization of Fig. 1 galactose vinyl acetate monomer and with the quaternary ammonium salt monomer polymerization after infrared spectrogram;
Fig. 2 contain sugared polycation (a, b),
1H nuclear magnetic resonance, hydrogen spectrum;
Fig. 3 contains sugared polyanion
1H nuclear magnetic resonance, hydrogen spectrum;
Fig. 4 coats the acyclovir layer assembly and contains sugared microcapsule release finish capsulae vacuus transmission electron microscope (a) and sem photograph (b);
Fig. 5 coats the layer assembly of different number of plies acyclovir and contains sugared microcapsule cumulative release rate and drug release time graph of a relation;
The acyclovir layer assembly contains sugared microcapsule cumulative release rate and drug release time graph of a relation in the different pH release medium of Fig. 6;
Fig. 7 coats the layer assembly of different double-deck number dexamethasone and contains sugared microcapsule cumulative release amount and drug release time graph of a relation;
Fig. 8 coats 6 double-deck fluorouracil layer assemblies and contains different pH cumulative release amounts of sugared microcapsule and drug release time graph of a relation;
Fig. 9 coats 6 double-deck fluorouracil layer assemblies and contains the sugared microcapsule release capsulae vacuus transmission electron microscope picture that finishes;
Figure 10 coats the layer assembly of different double-deck number ribavirin vinyl caproate and contains different pH cumulative release amounts of sugared microcapsule and drug release time graph of a relation;
The wet degree acyclovir layer assembly of Figure 11 different dry contains sugared microcapsule cumulative release rate and drug release time graph of a relation;
The laser confocal microscope photo of microcapsule and fluorescein-labeled peanut agglatinin identification when Figure 12 contains sugared polycation as the medicament capsule outermost layer;
The laser confocal microscope photo of the not sacchariferous polyanion of Figure 13 microcapsule and fluorescein-labeled peanut agglatinin (PNA) identification during as the medicament capsule outermost layer;
The biological inverted microscope photo of microcapsule and hepatoma carcinoma cell (HepG2) cell absorption when Figure 14 contains sugared polycation as the medicament capsule outermost layer.
The specific embodiment
Embodiment 1 galactose vinyl acetate monomer is synthetic
16g adipic acid divinyl ester and 4g galactose, 1g subtilisin are placed the 250mL conical flask, add the 40mL pyridine, ultrasonic mixing, at 50 ℃ of shaking tables with 200rpm tachyphylaxis 3 days.Solids removed by filtration is separated crude product, and distilling under reduced pressure obtains double bond containing galactose vinyl acetate monomer.Galactose vinyl acetate monomer infrared spectrogram is seen Fig. 1 (upper curve), and two key feature cutting edges of a knife or a sword of vinyl acetate C=C and sugared C-O characteristic peak are obvious, illustrate that the galactose vinyl acetate monomer prepares successfully.
After galactose vinyl acetate monomer vacuum drying is placed in the exsiccator slowly dry 20 days, get 0.4g galactose vinyl acetate and 0.7g methylacryoyloxyethyl trimethyl ammonium chloride (DMC) in the little flask of 25mL, add the 1.4ml dissolved in distilled water, meanwhile add the potassium persulfate solution that 1ml concentration is 10mg/ml successively.The logical nitrogen of evacuation 3 times repeatedly; polymeric solution 70 ℃ of stirring reactions 24 hours under nitrogen protection; pour into and be settled out polymer in the acetone, be placed in the bag filter that molecular cut off is 3500kD water dialysis one day with the 10mL water dissolution; with solution lyophilization in the bag; gained contains sugared polycation infrared spectrum characterization and sees Fig. 1 (lower curve), and the two key characteristic peaks of C=C disappear, and the quaternary ammonium salt characteristic peak occurs; sugar C-O characteristic peak keeps, and two monomer copolymerization successes are described.Nucleus magnetic hydrogen spectrum characterizes sees Fig. 2 a, the sugar ring occurs on the galactose vinyl acetate monomer and goes up that the displacement of three methyl H characteristic peaks illustrates both copolymerization successes on displacement of H characteristic peak and the quaternary ammonium salt cationic monomer, grafting sugar mol ratio 20%.
Embodiment 3 contains sugared polycation synthetic (two)
Adopt embodiment 2 methods, get 0.1g galactose vinyl acetate monomer and 0.7g DMC copolymerization, finally obtain the sugared polycation that contains of grafting sugar mol ratio 5%, nucleus magnetic hydrogen spectrum characterizes sees Fig. 2 b.
Embodiment 4 contains sugared polycation synthetic (three)
Adopt embodiment 2 methods, change methylacryoyloxyethyl trimethyl ammonium chloride (DMC) into methylacryoyloxyethyl trimethylammonium bromide (DMBr), obtain the sugared polycation that contains of grafting sugar mol ratio 15%.
Embodiment 5 contains sugared polyanion synthetic ()
Adopt embodiment 2 methods, get 0.3g galactose vinyl acetate monomer and the copolymerization of 0.3g anionic monomer Sodium styrene sulfonate, finally obtain the sugared polyanion that contains of grafting sugar mol ratio 30%.
Embodiment 6 contains sugared polyanion synthetic (two)
Adopt embodiment 2 methods, get 0.3g galactose vinyl acetate monomer and the copolymerization of 0.3g anionic monomer acrylic acid, finally obtain the sugared polyanion that contains of grafting sugar mol ratio 25%, nucleus magnetic hydrogen spectrum characterizes sees Fig. 3.
Embodiment 7 acyclovir layer assemblies contain sugared microcapsule preparation ()
60mg acyclovir abrasive particles is placed centrifuge tube, add 2mL 2mg/mL, (the embodiment 2 preparations) solution that contains containing of 0.5M NaCl of sugared polycation, behind the ultra-sonic dispersion 5 minutes, in 200rpm, 25 ℃ of shaking tables, cultivate and took out 5000 in 10～15 minutes and leave the heart and remove supernatant (this solution can be recycled), add the aqueous dispersion washing and remove excessive polycation 3 times, contain sugared polycation thereby adsorbed one deck at medical surfaces.To contain sugared polycation and change kayexalate (PSS) into, continue at medical surfaces assembling one deck polyanion by above-mentioned assemble method; Repeat above process, assemble 4-10 the double-deck polycation and the polyanion self assembly layer by layer that will have positive electricity and negative electricity respectively, obtain coating the drug microcapsule of polyelectrolyte.Microcapsule is added low amounts of water preserve, or vacuum drying, grind slightly and disperse, directly preserve with powder type.
Embodiment 8 acyclovir layer assemblies contain sugared microcapsule preparation (two)
Adopt embodiment 7 methods, will contain sugared polycation and change embodiment 3 preparation gained into, finally obtain containing sugared microcapsule.
Embodiment 9 dexamethasone layer assemblies contain sugared microcapsule preparation
Adopt embodiment 7 methods, will contain sugared polycation and change embodiment 4 preparation gained into, change acyclovir into dexamethasone, finally obtain containing sugared microcapsule.
Adopt embodiment 7 methods, will contain the sugared polyanion that contains that sugared polycation changes embodiment 5 preparations into, change kayexalate into polyene bright propyl group amine hydrochlorate, change acyclovir into fluorouracil, finally obtain containing sugared microcapsule.
Embodiment 11 ribavirin vinyl caproate medicine layer assemblies contain sugared microcapsule preparation
Adopt embodiment 7 methods, change kayexalate the sugared polyanion that contains of embodiment 6 preparations into, just acyclovir changes the ribavirin vinyl caproate into, finally obtains containing sugared microcapsule.
Embodiment 12 acyclovir layer assemblies contain sugared microcapsule slow release in simulated gastric fluid
0.45 μ m aperture cellulose acetate membrane is fixed on the supply chamber of diffusion cell and accepts between the pond, receiving chamber's volume is 14.7mL, and acceptable solution is pH 1.4 HCl solution (simulated gastric fluid), and bath temperature is 25 ℃.Take by weighing the layer assembly of 10mg acyclovir and contain sugared drug microcapsule (embodiment 7 preparations) in supply chamber, under constant temperature continues to stir, at the fixed time acceptable solution is extracted out 100 μ L, and change with the fresh acceptable solution of equivalent, the acceptable solution of taking-up is measured acyclovir concentration with uv-vis spectra after diluting.Fig. 4 illustrates that for coating acyclovir microcapsule release finishing capsulae vacuus transmission electron microscope and sem photograph medicine can discharge fully from capsule.Fig. 5 illustrates that for coating different number of plies acyclovir microcapsule cumulative release rates and drug release time graph of a relation the coating number of plies is many more, and slow release effect is good more.
Embodiment 13 acyclovir layer assemblies contain sugared microcapsule slow release in simulated intestinal fluid
Acceptable solution is changed to pH 7.4 phosphate buffers, contains the release of sugared microcapsule (embodiment 7 preparations) in simulated intestinal fluid by embodiment 12 described method for releasing research acyclovir layer assemblies.Fig. 6 is acyclovir microcapsule cumulative release rate and a drug release time relation in the different pH release medium, and under the slant acidity condition, acyclovir microcapsule medicine realeasing rate is fast slightly.
Embodiment 14 dexamethasone layer assemblies contain sugared microcapsule slow release
Contain the release of sugared microcapsule (embodiment 9 preparations) in simulated intestinal fluid by embodiment 12 described method for releasing research dexamethasone layer assemblies.Fig. 7 is the release kinetic curve of this medicament capsule, coats the number of plies and reduces identical time release amount showed increased.
Contain the release of sugared microcapsule (embodiment 10 preparations) in simulated intestinal fluid and gastric juice by embodiment 12 described method for releasing research fluorouracil layer assemblies. Fig. 8 is different pH accumulative total burst size and drug release time relations down.Fig. 9 is for coating fluorouracil microcapsule release finishing capsulae vacuus transmission electron microscope picture, and it is empty that capsule becomes, and illustrates that medicine can be gone out by slow release from capsule.
Embodiment 16 ribavirin vinyl caproate layer assemblies contain sugared microcapsule slow release
Contain the release of sugared microcapsule (embodiment 11 preparations) in simulated intestinal fluid and gastric juice by embodiment 12 described method for releasing research ribavirin vinyl caproate layer assemblies.Figure 10 is the release kinetic curve of medicament capsule, and the coating number of plies is many more, and rate of release is slow more; PH partial neutral, rate of release are also slow more.
The acyclovir layer assembly of embodiment 17 dry and wet states contains sugared microcapsule slow release relatively
Press embodiment 12 described method for releasing, respectively dry and wet state is preserved acyclovir capsule (embodiment 8 preparations) and carry out releasing research, Figure 11 is wet degree acyclovir microcapsule cumulative release rate of different dry and a drug release time relation in the simulated gastric fluid, illustrates that dry run can delay the half-life of drug release.
Embodiment 18 acyclovir layer assemblies contain the agglutinin identification of sugared microcapsule
The acyclovir layer assembly of getting 100 μ L embodiment, 7 preparations contains sugared microcapsule suspensions and mixes with fluorescent labeling peanut agglatinin (FL-PNA) solution of 0.5mL 100 μ g/mL, after cultivating 2h, centrifugally remove excessive agglutinin solution, with phosphate buffer washing 3 times.Observe microcapsule and identification of fluorescein-labeled peanut agglatinin and apparent intense fluorescence when finding to contain sugared polycation (PGEDMC) under the laser confocal microscope, see Figure 12 as outermost layer; Not sacchariferous polyanion (PSS) is microcapsule and fluorescein-labeled peanut agglatinin nonrecognition during as outermost layer, fluorescence signal very a little less than, see Figure 13.Proof contains sugared PGEDMC and the effect of PNA tool specific adsorption, and glycosyl has kept its biological activity on the capsule.
Embodiment 19 5-fluorouracil layer assemblies contain the absorption of sugared microcapsule to human liver cancer cell
The 5-fluorouracil layer assembly of getting 100 μ L embodiment 10 preparation contains sugared microcapsule suspensions (containing sugared polycation is outermost layer) and is added to cultivate and has on 6 orifice plates of human liver cancer cell (HepG2), wash 3 times with phosphate buffer after cultivating 3h, go not adsorbent particles.Inverted microscope is observed the proof large quantity of micro-capsule down and is attracted to the HepG2 cell surface, because this cell surface expression can be discerned the receptor of galactose group specially, microcapsule combines with the hepatoma carcinoma cell surface receptor is effective by the galactose group of self, promptly has been targeted to hepatocyte, sees Figure 14.
Claims (9)
1, a kind of preparation method of hepatic targeting drug microcapsule comprises that it is 20nm～100 μ m drug microparticles surfaces that polyanion and polycation alternate group are contained in particle diameter;
The condition of assembling is: under 5～50 ℃, in the aqueous solution of the inorganic electrolyte of 0.2～5mol/L, add polycation or polyanion, the concentration of polycation or polyanion is 1～5mg/mL; Add drug microparticles again, the each adsorption time 10～30min of drug microparticles, the centrifugal supernatant of removing of each assembling back 5000rpm, washing, centrifugal 2～5 times, after polycation and polyanion are alternately assembled 1～20 time, obtain hepatic targeting drug microcapsule through centrifugal, washing;
It is sacchariferous having at least a kind of in described polyanion and the polycation, promptly has the glycosyl side chain in the molecular structure; Sacchariferous polyanion promptly contains sugared polyanion and makes by anionic monomer and the reaction of galactose vinyl acetate monomer; Sacchariferous polycation promptly contains sugared polycation and makes by cationic monomer and the reaction of galactose vinyl acetate monomer;
Described inorganic electrolyte is NaCl, KCl, CaCl
2, CuCl
2, NaF, KBr, NaI, KI, NaNO
3, AgNO
3Or KNO
3
2, preparation method according to claim 1 is characterized in that: described inorganic electrolyte is NaCl, KCl or CaCl
2
3, preparation method according to claim 1 is characterized in that: described drug microparticles is the C of acyclovir, ganciclovir, cytosine arabinoside, fluorouracil, amycin, daunorubicin, ketoprofen, ibuprofen, dexamethasone or ribavirin
4～C
12The single vinyl acetate of chain length.
4, preparation method according to claim 1 is characterized in that: the described synthetic method that contains sugared polycation is as follows:
Cationic monomer is mixed with the solution of water or dimethyl formamide (DMF); Mix with the galactose vinyl acetate monomer; Add the potassium peroxydisulfate of each monomer gross mass 0.1-10% or Ammonium persulfate. afterwards as initiator, under the nitrogen protection, in 20～100 ℃ of following copolyreaction 1～50h, add acetone precipitation and go out polymer, be placed in the bag filter that molecular cut off is 3500kD water dialysis 1-7 days with the 10mL water dissolution, with solution lyophilization in the bag, obtain containing sugared polycation;
Described cationic monomer is the methylacryoyloxyethyl trimethyl ammonium chloride, the methylacryoyloxyethyl trimethylammonium bromide, dimethyl diallyl ammonium chloride, the dimethyl diallyl ammonium bromide, allyl amine and hydrochlorate thereof, vinyl imines and hydrochlorate thereof or sulfate, the 4-vinylpridine quaternary ammonium salt, N, the N-dimethyl, the N-benzyl, N-methylacryoyloxyethyl ammonium chloride, N, the N-dimethyl, the N-ethyl, N-methylacryoyloxyethyl ammonium bromide, N, the N-dimethyl, the N-butyl, N-methylacryoyloxyethyl ammonium bromide, N, N-dimethyl, N-cetyl or N-methylacryoyloxyethyl ammonium bromide.
5, preparation method according to claim 1 is characterized in that: the described synthetic method that contains sugared polyanion is as follows:
Anionic monomer is mixed with the solution of water or dimethyl formamide (DMF); Mix with the galactose vinyl acetate monomer; Add the potassium peroxydisulfate of each monomer gross mass 0.1-10% or Ammonium persulfate. afterwards as initiator, under the nitrogen protection, in 20～100 ℃ of following copolyreaction 1～50h, add acetone precipitation and go out polymer, placing molecular cut off with the 10mL water dissolution is that the bag filter of 3500kD was to water dialysis 1-7 days, with solution lyophilization in the bag, lyophilization obtains containing sugared polyanion;
Described anionic monomer is Sodium styrene sulfonate or acrylic acid.
6, according to claim 4 or 5 described preparation methoies, it is characterized in that: described galactose vinyl acetate monomer and cationic monomer or anionic monomer mol ratio are 10: 1～1: 10; Galactose vinyl acetate monomer and cationic monomer or anionic monomer gross mass percent concentration in reaction system is 10～80%;
7, preparation method according to claim 6 is characterized in that: the synthetic method of described galactose vinyl acetate monomer is as follows:
Galactose and divinyl ester were reacted 1-5 days in organic solvent in 10～80 ℃ under enzyme catalysis, and solids removed by filtration is separated crude product, and distilling under reduced pressure obtains double bond containing galactose vinyl acetate monomer;
The mol ratio of described galactose and divinyl ester is 1: 1～10;
Described enzyme is bacillus alkaline protease, esterase, porcine pancreatic lipase, lipase from candida sp or immobilization miehei lipase, and every gram galactose uses enzyme 0.5～20g.
8, preparation method according to claim 7 is characterized in that: described divinyl ester is adipic acid divinyl ester, decanedioic acid divinyl ester or Vinyl crotonate.
9, preparation method according to claim 7 is characterized in that: described organic solvent is pyridine, dimethyl formamide, dimethyl sulfoxide or butyl alcohol-tert.
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| CN102813937A (en) * | 2012-06-12 | 2012-12-12 | 天津大学 | Hydrophobic drug containing polyelectrolyte complex, its preparation method and application thereof |
| CN109395678A (en) * | 2013-03-01 | 2019-03-01 | 国立研究开发法人科学技术振兴机构 | Substance encapsulation micro-capsule and preparation method thereof |
| CN103341169B (en) * | 2013-07-04 | 2015-10-07 | 张峰 | A kind of packaging method for micromolecule hydrophilic drugs controlled release |
| JP6510497B2 (en) * | 2014-04-17 | 2019-05-08 | 株式会社シード | Anionic drug-containing medical device |
| CN104293859A (en) * | 2014-07-10 | 2015-01-21 | 程怡 | Enzymatic synthesis method of galactose ligand molecule |
| CN110028681B (en) * | 2019-04-19 | 2020-06-16 | 西南交通大学 | Preparation method and use method of triple shape memory polyampholyte hydrogel |
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| Bioactive Galactose-Branched Polyelectrolyte Multilayersand Microcapsules:Self-Assembly,Characterization,andBiospecificLectin Adsorption. Fu Zhang et al.Langmuir,Vol.22 No.20. 2006 * |
| Chemo-enzymatic synthesis of disaccharide-branchedcopolymers with high molecular weight. Xu Wang et al.Carbohydrate Polymers,Vol.60 . 2005 |
| Chemo-enzymatic synthesis of disaccharide-branchedcopolymers with high molecular weight. Xu Wang et al.Carbohydrate Polymers,Vol.60. 2005 * |
| Controlled Release of Dexamethasone from MicrocapsulesProduced by Polyelectrolyte Layer-by-Layer Nanoassembly. Nikhil Pargaonkar et al.Pharmaceutical Research,Vol.22 No.5. 2005 |
| Fabrication of drug-loaded biodegradable microcapsules forcontrolled release by combination of solvent evaporation andlayer-by-layer self-assembly. Chaoyang Wang et al.International Journal of Pharmaceutics,Vol.338 . 2007 |
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