CN1319637C - Chitose microsphere and microcapsule with uniform size and its preparation method - Google Patents
Chitose microsphere and microcapsule with uniform size and its preparation method Download PDFInfo
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Abstract
本研究针对蛋白质、多肽、抗癌剂、激素等亲水性药物和油溶性药物，提供尺寸均一、分散稳定的壳聚糖微球或微囊药物载体，以用于亲水性药物的控制释放和靶向性给药等。其特征是(1)将亲水性药物溶于壳聚糖的醋酸水溶液中，将该水相用压力通过微孔膜压入油相中，得到尺寸均一的乳滴，然后采用一定的固化方法使乳滴固化，得到尺寸均一、分散稳定的壳聚糖微球或微囊药物载体；(2)将油溶性药物溶于油性溶剂中，亲水性药物溶于壳聚糖的醋酸水溶液中，先用均相乳化器制备成O1/W初乳后，将该初乳用压力通过微孔膜压入油相中，得到尺寸均一的(O1/W)/O2复乳滴，然后采用一定的固化方法使乳滴固化，得到尺寸均一、分散稳定的壳聚糖微球或微囊药物载体。在优化条件下，微球和微囊的直径分布系数控制在11%以内，直径可在1-100微米内自由控制。该技术解决了传统搅拌乳化法制备的壳聚糖药物载体粒径不均一、包埋率低、分散性差的问题。可望利用粒径的均一性特性，达到稳定的释放药物、提高药物在体内利用率的关键问题。In this study, for hydrophilic drugs and oil-soluble drugs such as proteins, peptides, anticancer agents, hormones, etc., chitosan microspheres or microcapsule drug carriers with uniform size, dispersion and stability are provided for the controlled release of hydrophilic drugs and targeted drug delivery. Its characteristics are (1) dissolving the hydrophilic drug in the acetic acid aqueous solution of chitosan, pressing the water phase into the oil phase through the microporous membrane to obtain emulsion droplets with uniform size, and then adopting a certain curing method The emulsion droplets are solidified to obtain chitosan microspheres or microcapsule drug carriers with uniform size and stable dispersion; (2) the oil-soluble drug is dissolved in the oily solvent, and the hydrophilic drug is dissolved in the acetic acid aqueous solution of chitosan, After preparing O 1 /W colostrum with a homogeneous emulsifier, press the colostrum into the oil phase through the microporous membrane to obtain (O 1 /W)/O 2 double emulsion droplets with uniform size, and then A certain curing method is adopted to solidify the emulsion droplets to obtain chitosan microspheres or microcapsule drug carriers with uniform size and stable dispersion. Under optimized conditions, the diameter distribution coefficient of microspheres and microcapsules is controlled within 11%, and the diameter can be freely controlled within 1-100 microns. This technology solves the problems of non-uniform particle size, low embedding rate and poor dispersion of chitosan drug carriers prepared by traditional stirring emulsification method. It is expected to use the uniformity of the particle size to achieve the key issues of stable release of drugs and improvement of drug utilization in vivo.
Description
Technical field
The invention belongs to the field of pharmaceutical preparations of pharmaceutical engineering
Background technology
The polysaccharide that shitosan is made up of aminoglucose and N-acetyl glucosamine copolymer is the product of chitin deacetylase base, and shitosan can be dissolved in dilute acid soln owing to have free amine group on the strand, therefore has purposes more widely than chitin.Shitosan is as a kind of cationic biopolymer, have bioadhesive, biocompatibility and biological degradability, and its catabolite is nontoxic, non-immunogenicity, non-carcinogenesis, and these uniquenesses of shitosan make it become the biological medicine carrier that has a extensive future
[1] [2] [3]
Shitosan mainly is to use with the form of microballoon or micro-capsule as the biological medicine carrier, can be used as the immobilization of the separating medium and the enzyme of protein as chitosan microball, owing to not only have hydroxyl but also have amino on the chitosan microball, can under the condition of gentleness, connect aglucon, be used as immobilization, immunity absorption and the Separation of Proteins medium of enzyme
[4]In addition by in chitosan solution, adding the chitosan microball that pore-foaming agent can be prepared macropore, this microballoon can be used as the carrier that cell is cultivated, nutrient and metabolite thereof can be by interconnective macropore input and output, this macroporous microsphere has two big major advantages as cell culture vector, can make cell avoid the influence of the shearing force of bioreactor in cell cultivation process, can improve the density that cell is cultivated on the other hand exactly greatly
[5]Chitosan microball mainly is because shitosan is a kind of cationic substance as genophore, its positive charge can form the compound microballoon with the negative electrical charge generation electrostatic interaction of DNA, can insert aglucon such as iron transfer protein, galactolipin etc. simultaneously and make it have better target on microballoon
[6]People such as Hai-Quan Mao adopt shitosan-DNA complex coacervation to prepare millimicro ball studies show that as genophore; shitosan can protect DNA to avoid the degraded of nuclease; the surface PEG (polyethylene glycol) of shitosan-DNA millimicro ball is changed; can improve the physical stability and the storage stability of microballoon; its freeze-drying prods good dispersion, adhesion, nor the transfection ability of reduction microballoon
[7]Chitosan microball or micro-capsule mainly concentrate on as slow releasing carrier of medication in the application of field of medicaments in recent years, and this mainly is based on chitosan microball or micro-capsule and has the toxic and side effect that strengthens drug absorption, sustained release performance, adhesiveness, immunostimulatory activity, anticoagulant property, antibiotic property, reduction medicine, prolongs advantages such as curative effect
[8]As as the consolidant of wound, it not only have sterilization and bacteriostasis, can accelerating wound healing, can also in gel, directly reach result of treatment efficiently by embedding medicinal at the wound slow releasing pharmaceutical
[8]Because shitosan has bioadhesive, put medicine by prolonging contained medicine at the gentle slow release of RT of affected part, can improve medicine bioavilability in vivo greatly, therefore become the ideal carrier of mucoadhesive delivery system
[9]Chitosan microball or micro-capsule can protected protein matter in addition, medicines such as polypeptide, nucleic acid exempt from digestive system and destroy, and make medicine can arrive the colon place smoothly and discharge medicine at this, reach optimum curative effect; Chitosan microball has many advantages as the vaccine slow-released carrier, and the firstth, shitosan dissolves in the aqueous acetic acid, has avoided with an organic solvent, and this provides advantageous conditions for the high activity that keeps antigen and protein; The secondth, because shitosan is a kind of cationic polyelectrolyte, it and electronegative cell surface have strong electrostatic interaction, vaccine or medicine are adsorbed on the epithelial membrane, improve medicine greatly cell and structural keeping, delay the release of medicine, compare with conventional medicament and can reduce medicine frequency
[10]The 3rd be shitosan as the carrier material of vaccine microballoon except possess improve penetrate with imbedibility and protection vaccine and slow releasing function; also has immunostimulatory activity; as increase the accumulation and the activity of macrophage and polymorphonuclear cell; improve opposing infected by microbes ability; the plain secretion of inducing cell improves cytotoxic T---lymphocytic immune response
[11], reduce medicine frequency simultaneously, overcome repeatedly in vivo the shortcoming that blood concentration fluctuation is big, side effect is big after the medication of traditional vaccine.Therefore shitosan is a kind of pharmaceutical grade protein carrier that has a extensive future.
Yet the preparation method of chitosan microball or micro-capsule is very limited at present, mainly adopts emulsion-crosslinking method, spray drying process and complex coacervation
[12] [13]And these preparation methods adopt mechanical mixing method mostly, adopt this method in preparation emulsion process, because particle diameter heterogeneity, little emulsion droplet can be absorbed by big emulsion droplet, big emulsion droplet can destroy because of the effect of shearing force again simultaneously, and this can cause very heterogeneity of prepared chitosan microball or microcapsule diameter.And because the particle diameter heterogeneity of emulsion droplet, by big drop absorption, big drop is sheared into droplet again to droplet easily, thereby can form a lot of cross-linked cohesion things easily in cross-linking process.Simultaneously, in the merging and rupture process of drop, interior bag medicine escapes into the drop outside easily, causes the embedding rate of medicine to reduce.Even after microballoon forms,, in the washing of product and dry run, also form condensation product easily because minimicrosphere is easily by big microballoon absorption.The heterogeneity of microballoon and micro-capsule also can be brought many difficulties for the practical application of chitosan microball or micro-capsule.For example, as the immobilization and the Separation of Proteins medium of enzyme, because the particle diameter heterogeneity, little microballoon can gather in pillar in the space between the big microballoon, makes separating pressure increase, and can cause when serious separating and can't carry out; As cell culture vector, the particle diameter heterogeneity can cause the inhomogeneous of nutrient and cell density, thereby causes the inhomogeneous of cell growth; As slow releasing carrier of medication,, because microballoon or microcapsule diameter heterogeneity make the target of medicine poor in being administered systemically, cause medicine bioavilability in vivo to reduce greatly in addition because the emulsion instability can cause the embedding rate of medicine to reduce greatly.Therefore be necessary to study novel preparation method, prepare uniform particle diameter chitosan microball or micro-capsule, so as to overcome the not enough of traditional preparation process method and the application that brings thus on defective.
Summary of the invention
This research provides the chitosan microball or the microcapsule medicament carrier of size homogeneous, stably dispersing at hydrophilic medicament and oil-soluble medicines such as protein, polypeptide, anticancer, hormones, with the control release that is used for hydrophilic medicament and target administration etc.It is characterized in that (1) is dissolved in hydrophilic medicament in the aqueous acetic acid of shitosan, this water is pressed in the oil phase by microporous barrier with pressure, obtain the emulsion droplet of size homogeneous, adopt certain curing that emulsion droplet is solidified then, obtain the chitosan microball or the microcapsule medicament carrier of size homogeneous, stably dispersing; (2) oil-soluble medicine is dissolved in the oil-based solvent, hydrophilic medicament is dissolved in the aqueous acetic acid of shitosan, is prepared into O with the homogeneous phase emulsifier earlier
1Behind/W the colostrum, this colostrum is pressed in the oil phase by microporous barrier with pressure, obtains (the O of size homogeneous
1/ W)/O
2Emulsion drips, and adopts suitable curing that emulsion droplet is solidified then, obtains the chitosan microball or the microcapsule medicament carrier of size homogeneous, stably dispersing.Under optimal conditions, the diameter breadth coefficient of microballoon and micro-capsule is controlled in 11%, and diameter can freely be controlled in the 1-100 micron.
Chitin medicine carrier particle diameter heterogeneity, the embedding rate that this technology has solved traditional stirring and emulsifying method preparation is low, the problem of bad dispersibility.Be expected to utilize the homogeneity characteristic of particle diameter, reach stable release medicine, improve the medicine key issue of utilization rate in vivo.
The chitosan microball of size homogeneous provided by the invention or microcapsule medicament carrier and preparation method thereof can also bring down column effect:
(1) chitosan microball provided by the invention or microcapsule medicament carrier can be used for multiple hydrophily of embedding and oil-soluble medicine, as cancer therapy drug mitomycin, adriamycin, taxol etc.; The particle diameter of regulation and control microballoon or microcapsule carrier can be used it for hypodermic injection, intravenous injection, lumbar injection, arterial embolism, oral etc.
(2) chitosan microball provided by the invention or microcapsule medicament carrier because uniform particle diameter and controlled, use this pharmaceutical carrier can carry out relation research between particle diameter and different pharmaceutical and the result of treatment thereof.This is because particle diameter and its distributing position and time in vivo of carrier have bigger relation, as pharmaceutical carrier, the different medicines curative effect that diverse location produced in vivo may be different, the pharmaceutical carrier that different pharmaceutical is prepared a series of particle diameters, and medication respectively, can find out the medication effect of different pharmaceutical, thereby find out the required optimum grain-diameter scope of different pharmaceutical at different-grain diameter.If the size heterogeneity of pharmaceutical carrier then can't be carried out the research of this respect.
(3) preparation method provided by the invention, mild condition is expected to keep the high activity of biologically active drug.
(4) microballoon provided by the invention and microcapsule diameter homogeneous are expected to realize that control stable, favorable reproducibility discharges.
Description of drawings
The preparation flow of Fig. 1 chitosan microball or microcapsule medicament carrier.
The light micrograph of the chitosan microball of Fig. 2 embodiment 1 preparation.
The light micrograph of the chitosan microball of Fig. 3 comparative example 1 preparation.
Fig. 4 embodiment 2 adopts the light micrograph of the chitosan microball of different membrane aperture preparations.
(chitosan microballs (A:4.7 μ m, B:5.7 μ m, C:13 μ m, D:19.6 μ m) of different membrane aperture preparations)
Graph of a relation between the chitosan microball particle diameter of the different membrane aperture of Fig. 5 embodiment 2 preparations and the membrane aperture.
The microphoto of the microballoon of the different chitosan concentrations of Fig. 6 embodiment 3 preparations.
(the microballoon microphoto of different chitosan concentrations (A:1.0wt%, B:1.5wt%, C:2.0wt%))
Fig. 7 drug bearing microsphere light micrograph.
The calibration curve of the model protein BSA (bovine serum albumin) of 4 embeddings of Fig. 8 embodiment.
Specific embodiments
The present invention includes the hydrophilic medicament chitosan microball of size homogeneous or microcapsule carrier and preparation method thereof.The chitosan microball of pharmaceutical grade protein or the preparation of microcapsule carrier are by step preparation shown in Figure 1, and concrete grammar and step are described as follows:
1) w/o type emulsion or (O
1/ W)/O
2The preparation of type emulsion
Hydrophilic medicament, shitosan, NaCl and other additive are dissolved in the certain density acetum, as water; More than one oil soluble emulsifying agent is dissolved in oil-based liquid, as oil phase.Water is pressed into oil phase by hydrophobic porous film, obtains the w/o type emulsion of size homogeneous.
When wanting the embedding oil-soluble medicine, oil-soluble medicine directly can be dispersed in the above-mentioned chitosan aqueous solution, maybe it can be dissolved in earlier in the oily matter, make interior oil phase (O
1) after, mix with above-mentioned chitosan aqueous solution with this oil phase, with homogeneous phase emulsifier or ultrasonic emulsator emulsification, make O
1Behind/W type the colostrum, colostrum is pressed into outer oil phase (O by hydrophobic porous film
2), obtain (the O of size homogeneous
1/ W)/O
2The type emulsion.
Hydrophilic medicament comprises anticancer, vaccine, nucleic acid, RNA and albumin, hemoglobin, colony stimulating factor, interferon, insulin and other each proteinoid and polypeptide drugs etc., in can being soluble in the aqueous phase together or separately as required; Interior water additive can comprise harmless water-soluble substanceses such as albumin, lecithin, glucose, sweet mellow wine.Oil-soluble medicine comprises hormone, anticancer and other various oil-soluble medicines.Oil phase is to be liquid under the normal temperature, with the immiscible oily matter of water, can use atoleine and benzinum, olive oil, cotton seed oil, soya-bean oil, sunflower oil, other alkanes hydrocarbon etc.Oil emulsifier must be dissolved in employed oily matter, can use polymer (as PO-500, PO-310), Crodaret, sorbitan trioleate (class of department 85), sorbitan monooleate (class of department 80), anhydrous sorbitol tristearate (class of department 65), the oleophylic-hydrophilic block copolymers of sorbitan sesquioleate (Arlace183), glycerin ether etc.The concentration of emulsifying agent is 0.5-10wt% in the oil phase.
The volume ratio of water and oil phase is 1: 1-1: 1000.
2) preparation of chitosan microball or micro-capsule
With above-mentioned steps 1) after the emulsion of gained adopts suitable emulsifying agent to be cured, washing, dry finished product chitosan microball or micro-capsule.Curing agent comprises the chemical cross-linking agent that can make chitosan molecule generation chemical crosslinking, makes the inorganic salt solution of shitosan dehydration, organic slat solution, alkaline solution and and the anionic polymer of shitosan generation ion complex (multiple cohesion).
Chemical cross-linking agent can use the saturated toluene solution of glutaraldehyde (GST), the aqueous solution of glutaraldehyde, formalin, epoxide, and the amount ranges of chemical cross-linking agent is that the mol ratio of the amino of aldehyde radical or epoxy radicals and shitosan is 1: 1-1: 10; Crosslinking time is 0.5-5h, and crosslinked temperature is 18-50 ℃, and the oil phase revolution is 150-500rpm when crosslinked.
Inorganic and organic slat solution comprises Na
2SO
4, NaCl, tripolyphosphate, sodium acetate etc. can make the material of shitosan dehydration.
Alkaline solution comprises that NaOH, KOH, ammoniacal liquor, organic amino etc. make the material of shitosan dehydration with the chitosan-acetic acid solution neutralization.
Anionic polymer comprises alginic acid or alginate, carragheen, gelatin, casein, polyacrylic acid acid and copolymer, polymethylacrylic acid and copolymer thereof etc.
After curing reaction finished, successively with benzinum, acetone, ethanol, acetone washing, vacuum drying 48h got finished product chitosan microball or micro-capsule with thus obtained microsphere.
Embodiment 1
With the aperture is that the hydrophobic film of 4.7 μ m places oil loving material to soak into, and makes pore membrane fully moistening to guarantee the complete spread apart of hydrophobic chain on the film.The aqueous acetic acid of preparation 1wt% adds a certain amount of NaCl and under agitation to make its dissolving, its concentration be 1wt%, and adding certain amount of chitosan then, to make its concentration be 2wt%, treat that it dissolves fully after, solution is filtered standby.Oil soluble emulsifying agent is joined among the mixing oil phase 60ml of atoleine and benzinum, be stirred to fully and dissolve as oil phase.Under certain pressure, the hydrophobic microporous membrane by the aperture homogeneous is pressed in the oil phase, obtains the w/o type emulsion with the water of 6.0g; Slowly drip GST and carry out crosslinked (mol ratio amino and aldehyde radical is 1: 1) in the gained emulsion, crosslinkedly carry out at normal temperatures, the oil phase revolution is 300rpm when crosslinked, and crosslinking time is 2h; Crosslinked end is used benzinum, acetone, ethanol and acetone washing successively with the chitosan microball of gained, and vacuum drying 48h gets the finished product microballoon.The average grain diameter of emulsion adopts the microscope that has scale to measure, and surveys 200 and averages, and average diameter is 12.92 μ m, and the CV value is 19.70%.Optical microscope photograph as shown in Figure 2, particle diameter is homogeneous comparatively.
Comparative example 1 (mechanical mixing method)
Adopt the prescription identical with example 1, the aqueous acetic acid of preparation 1wt% adds a certain amount of NaCl and also under agitation makes its dissolving, its concentration is 1wt%, adding certain amount of chitosan then, to make its concentration be 2wt%, treat that it dissolves fully after, solution is filtered standby.Oil soluble emulsifying agent is joined among the mixing oil phase 60ml of atoleine and benzinum, be stirred to fully and dissolve as oil phase.The water of getting 6.0g mixes with oil phase, magnetic agitation 1000rpm, and 30min obtains the w/o type emulsion; Slowly drip GST and carry out crosslinked (mol ratio amino and aldehyde radical is 1: 1) in the gained emulsion, crosslinkedly carry out at normal temperatures, the oil phase revolution is 300rpm when crosslinked, and crosslinking time is 2h; Crosslinked end is used benzinum, acetone, ethanol and acetone washing successively with the chitosan microball of gained, and vacuum drying 48h gets the finished product microballoon.The average grain diameter of emulsion adopts the microscope that has scale to measure, and surveys 200 and averages, and average diameter is 117.60 μ m, and the CV value is up to 69.90%.Optical microscope photograph as shown in Figure 3, the particle diameter non-constant width that distributes.
Embodiment 2
The hydrophobic film that the aperture is respectively 4.7 μ m, 5.7 μ m, 13 μ m, 19.6 μ m places oil loving material to soak into, and makes pore membrane fully moistening to guarantee the complete spread apart of hydrophobic chain on the film.The aqueous acetic acid of preparation 1wt% adds a certain amount of NaCl and under agitation to make its dissolving, its concentration be 1wt%, and adding certain amount of chitosan then, to make its concentration be 1.5wt%, treat that it dissolves fully after, solution is filtered standby.Oil soluble emulsifying agent is joined among the mixing oil phase 60ml of atoleine and benzinum, be stirred to fully and dissolve as oil phase.Under certain pressure, the hydrophobic microporous membrane by various apertures homogeneous is pressed in the oil phase respectively, obtains the w/o type emulsion with the water of 6.0g; Slowly drip GST and carry out crosslinked (mol ratio amino and aldehyde radical is 1: 1) in the gained emulsion, crosslinkedly carry out at normal temperatures, the oil phase revolution is 300rpm when crosslinked, and crosslinking time is 2h; Crosslinked end is used benzinum, acetone, ethanol and acetone washing successively with the chitosan microball of gained, and vacuum drying 48h gets the finished product microballoon.The average grain diameter of emulsion adopts the microscope that has scale to measure, surveying 200 averages, average diameter is respectively 13.81 μ m, 21.14 μ m, 32.11 μ m, 59.94 μ m, optical microscope photograph as shown in Figure 4, graph of a relation between microspherulite diameter and the membrane aperture as shown in Figure 5, by linear between the aperture of microspherulite diameter and film as can be seen on the figure, microspherulite diameter approximately is about 3 times of membrane aperture.
Embodiment 3
With the aperture is that the hydrophobic film of 4.7 μ m places oil loving material to soak into, and makes pore membrane fully moistening to guarantee the complete spread apart of hydrophobic chain on the film.The aqueous acetic acid of preparation 1wt%, adding a certain amount of NaCl and under agitation making its dissolving, its concentration is 1wt%, adds certain amount of chitosan then and makes its concentration be respectively 1.0wt%, 1.5wt% and 2.0wt%, after treating that it dissolves fully, solution is filtered standby.Oil soluble emulsifying agent is joined among the mixing oil phase 60ml of atoleine and benzinum, be stirred to fully and dissolve as oil phase.Under certain pressure, the hydrophobic microporous membrane by the aperture homogeneous is pressed in the oil phase, obtains the w/o type emulsion with the water of 6.0g; Slowly drip GST and carry out crosslinked (mol ratio amino and aldehyde radical is 1: 1) in the gained emulsion, crosslinkedly carry out at normal temperatures, the oil phase revolution is 300rpm when crosslinked, and crosslinking time is 2h; Crosslinked end is used benzinum, acetone, ethanol and acetone washing successively with the chitosan microball of gained, and vacuum drying 48h gets the finished product microballoon.The average grain diameter of emulsion adopts the microscope that has scale to measure, and surveys 200 and averages, and average diameter is respectively 17.40 μ m, 13.81 μ m and 12.92 μ m, and the CV value is respectively 21.94%, 13.35% and 19.70%.Optical microscope photograph as shown in Figure 6.
Embodiment 4
With the aperture is that the hydrophobic film of 4.7 μ m places oil loving material to soak into, and makes pore membrane fully moistening to guarantee the complete spread apart of hydrophobic chain on the film.The aqueous acetic acid of preparation 1wt%, add a certain amount of NaCl and under agitation make its dissolving, its concentration is 1wt%, adding certain amount of chitosan then, to make its concentration be 1.5wt%, after treating that it dissolves fully, solution is filtered, add the bovine serum albumin(BSA) (BSA, model drug) of the 20wt% of shitosan dry weight then and fully dissolve standby.Oil soluble emulsifying agent is joined among the mixing oil phase 60ml of atoleine and benzinum, be stirred to fully and dissolve as oil phase.Under certain pressure, the hydrophobic microporous membrane by the aperture homogeneous is pressed in the oil phase, obtains the w/o type emulsion with the water of 6.0g; Slowly drip GST and carry out crosslinked (mol ratio amino and aldehyde radical is 1: 1) in the gained emulsion, crosslinkedly carry out at normal temperatures, the oil phase revolution is 300rpm when crosslinked, and crosslinking time is 2h; Crosslinked end is used benzinum, acetone, ethanol and acetone washing successively with the chitosan microball of gained, and vacuum drying 48h gets the finished product microballoon.The average grain diameter of emulsion adopts the microscope that has scale to measure, surveying 200 averages, average diameter is 11.72 μ m, the CV value is 10.67%, gets dried microballoon 20mg and is scattered in the deionized water continuous stirring 48h, make the complete stripping of bovine serum albumin(BSA) of embedding, the centrifuging and taking supernatant adopts the Bradford method to measure protein content then, and by the embedding rate of calibration curve calculating BSA, the embedding rate of prepared after measured drug bearing microsphere is 90.05%.The optical microscope photograph of drug bearing microsphere as shown in Figure 7.The calibration curve of BSA as shown in Figure 8.
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Claims (10)
1, the preparation method of a kind of chitosan microball of size homogeneous or micro-capsule is characterized in that (1) water W is the shitosan aqueous acetic acid that has dissolved water soluble drug or disperseed oil-soluble medicine; (2) oil phase O be dissolved oil soluble emulsifying agent and with the immiscible oily matter of water; (3) water is pressed into oil phase with pressure by microporous barrier, obtains the w/o type emulsion droplet of size homogeneous; (4) in the w/o type emulsion of size homogeneous, add crosslinking agent, crosslinked chitosan microball or the micro-capsule of getting.
2, the preparation method of a kind of chitosan microball of size homogeneous or micro-capsule is characterized in that (1) interior oil phase O
1It is the oily matter that has dissolved oil-soluble medicine; (2) interior water W is the aqueous acetic acid that has dissolved water soluble drug and shitosan; (3) outer oil phase O
2Be dissolved oil soluble emulsifying agent, with the immiscible oily matter of water; (4) interior oil phase is mixed with water, be prepared into O with homogeneous phase emulsifier or ultrasonic emulsator
1Behind/W type the colostrum, with this O
1/ W type colostrum is pressed into outer water with pressure by microporous barrier, obtains (the O of size homogeneous
1/ W)/O
2The type emulsion; (5) at (O of size homogeneous
1/ W)/O
2Add crosslinking agent in the type emulsion, crosslinked chitosan microball or the micro-capsule of getting.
3, the preparation method of the chitosan microball of a kind of size homogeneous as claimed in claim 1 or 2 or micro-capsule is characterized in that, the concentration range of chitosan solution is 0.1wt%-10.0wt%.
4, the preparation method of the chitosan microball of a kind of size homogeneous as claimed in claim 3 or micro-capsule is characterized in that, the concentration range of chitosan solution is 0.5-5.0wt%.
5, the preparation method of the chitosan microball of a kind of size homogeneous as claimed in claim 1 or 2 or micro-capsule is characterized in that, water is 1 with the volume ratio of outer oil phase: 1-1: 1000.
6, the preparation method of the chitosan microball of a kind of size homogeneous as claimed in claim 5 or micro-capsule is characterized in that, water is 1 with the volume ratio of outer oil phase: 5-1: 100.
7, the preparation method of the chitosan microball of a kind of size homogeneous as claimed in claim 1 or 2 or micro-capsule is characterized in that, employed microporous barrier surface is a hydrophobicity.
8, the chitosan microball or the micro-capsule of the size homogeneous of method preparation as claimed in claim 1 or 2 is characterized in that, the size homogeneous of microballoon or micro-capsule, and the diameter breadth coefficient is in 20%.
9, the chitosan microball or the micro-capsule of the described a kind of size homogeneous of claim 8 is characterized in that, the embedding rate of hydrophilic medicament or oil-soluble medicine reaches more than 90%.
10, the chitosan microball of a kind of size homogeneous as claimed in claim 8 and micro-capsule is characterized in that, do not have phenomenon, microballoon or the micro-capsule good dispersion of merging between the microballoon.
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