CN105496971A - Controlled release microsphere of compound type biological cross-linking agent cross-linked chitosan and preparation method of controlled release microsphere - Google Patents
Controlled release microsphere of compound type biological cross-linking agent cross-linked chitosan and preparation method of controlled release microsphere Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
- C08J3/244—Stepwise homogeneous crosslinking of one polymer with one crosslinking system, e.g. partial curing
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
Abstract
The invention discloses a controlled release microsphere of compound type biological cross-linking agent cross-linked chitosan. The microsphere is spherical, the surface of the microsphere is in a porous structure, the microsphere is prepared from the raw materials of 3-20 parts of chitosan by weight, 0.1-1 part of genipin by weight, 0.01-25 parts of vanilline by weight, 20-30 parts of emulsifying agent by volume, 1,000-3,000 parts of dispersion medium by volume and the like; the preparation method of the controlled release microsphere comprises the steps of preparation of a chitosan liquid, preparation of a genipin solution, preparation of a vanilline solution, emulsion preparation of the controlled release microsphere and the like; the genipin and the vanilline are compounded as a cross-linking agent to be cross-linked with the chitosan to obtain the controlled release microsphere, the controlled release microsphere has biocompatibility and biodegradability, the disadvantages that the intensity of a genipin cross-linked microsphere is high, the release is slow, the swelling tolerance of a vanilline cross-linked microsphere is very low and the like are overcome, the release time of the microsphere is more suitable for the drug release requirement of a human body, and the microsphere release controllability is improved. The preparation method is suitable for preparation of the controlled release microsphere of the compound type biological cross-linking agent cross-linked chitosan.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of slow control-release microsphere and preparation method thereof, be specifically related to slow control-release microsphere of a kind of Compositional type Biological cross-linker cross-linked chitosan and preparation method thereof.
Background technology
At present, emulsion-crosslinking method is utilized to prepare in the field of slow control-release microsphere at chitosan, what major part cross-linking agent adopted is the cross-linking agent of chemosynthesis, as aldehyde compounds such as formaldehyde, glutaraldehyde, Biformyls, its characteristic reaction is the nucleophilic addition of C=O bond, and cross-bond is imine linkage, because cross-linking agent is all linear chain structure, therefore crosslinking ratio is easier to, and balling-up effect is better.The aldehyde crosslinking agent of these chemosynthesis is classified as toxic reagent, makes the chitosan microball that obtains there is certain safety problem in dispose procedure in vivo, its market is applied and is subject to great restriction.
Genipin is a kind of genipin, there is hydroxyl, multiple active function groups such as ester group and acetal, wherein mainly aminoly there is cross-linking reaction in the ester group of genipin and olefinic carbon atoms respectively with chitosan molecule, cross-bond is amido link mainly, therefore the microsphere network structure formed closely, hardness is larger, in vivo to the release of medicine mainly through the duct after microspheres swell, therefore, be not easy be degraded and make release too slow, as document ZhangY, YuY, ShiX, etal.Studyonthepreparationofgenipincrosslinkedchitosanmi crospheresofresveratrolandinvitrorelease [J] .JournalofPolymerResearch, 2013, the single crosslinked chitosan of genipin described in 20 (7): 1-10. delays control-release microsphere and discharges dose when pH7.4 and be about about 10%, discharge dose when pH3.6 and be about about 30%, can learn that the swellability of single genipin crosslinked chitosan microsphere is poor with this, microsphere discharges drug slow and burst size is low.Another kind of Biological cross-linker vanillin is also used to prepare in the slow control-release microsphere of chitosan.In the active group carbonyl of vanillin and chitosan molecule, the amino Schiff that occurs reacts and forms imines, hydrogen bond is formed between hydroxyl simultaneously in vanillin and chitosan, because the intensity of the hydrogen bond formed in this cross-linking process is low, very responsive to environmental condition, easily destroyed, rapid swelling degraded in time extremely short after making microsphere enter human body, by drug release, does not often reach the slow-release time of expection.Such as the slow control-release microsphere of single vanillin cross-linked chitosan joins in aqueous, and after 10 minutes, disintegrate becomes uneven liquid object completely, and therefore the sustained release performance of vanillin crosslinked chitosan microsphere is poor, is not suitable for the microsphere preparing coating medicine.From the above, genipin and vanillin are the natural biological extract that separation and purification in plant obtains, all low compared with the toxicity of chemical cross-linking agent, but be used alone genipin or be used alone the slow controlled-release effect of the slow control-release microsphere that vanillin is prepared poor, discharge too slow, release is too fast, therefore studies a kind of microsphere that can control slow controlled release release time and has great importance.
Summary of the invention
The technical problem to be solved in the present invention, be to provide slow control-release microsphere of a kind of Compositional type Biological cross-linker cross-linked chitosan and preparation method thereof, genipin and composite being jointly cross-linked as cross-linking agent and chitosan of vanillin is used to obtain slow control-release microsphere, its slow controlled release properties is between the slow controlled release properties of genipin or the single crosslinked chitosan microsphere of vanillin, the chitosan discharged through enzymes metabolism after the microsphere using composite cross-linking agent to prepare enters human body has biocompatibility and biodegradability, cross-linking agent genipin is without any cytotoxicity, the flavorant that vanillin allows as national regulation, there is the features such as nontoxic.Microsphere prepared by composite cross-linking agent is compared with the microsphere prepared by traditional single cross-linking agent, overcome the too high and release of genipin crosslinked microsphere intensity slowly and the shortcoming such as the extremely low swelling toleration of vanillin crosslinked microsphere, make to be more suitable for the release time of microsphere at the release request of human body to medicine, adjust the ratio of composite cross-linking agent simultaneously, improve the controllability of microsphere release, be conducive to the application of chitosan controlled release agent type in biomedical sector.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
A slow control-release microsphere for Compositional type Biological cross-linker cross-linked chitosan, described microsphere is spherical, and microsphere surface is porous structural, and the raw material making its effective ingredient comprises:
Chitosan 3 ~ 20 weight portion, genipin 0.1 ~ 1 weight portion,
Vanillin 0.01 ~ 25 weight portion, emulsifying agent 20 ~ 30 parts by volume,
Disperse medium 1000 ~ 3000 parts by volume;
The proportionate relationship of above-mentioned parts by weight and volume parts is gram: milliliter;
Described disperse medium is Oleum Perillae, or is the Compound disperse medium that Oleum Perillae and other disperse medium form; Other described disperse medium is the one in soybean oil, olive oil, Radix Oenotherae erythrosepalae oil or hazelnut oil, or the mixture of at least two kinds.
Limit as one of the present invention, described emulsifying agent is the one in Span-80, Span-85, Twen-80, Twen-85, Poloxamer, OP-10, or the mixture of at least two kinds.
Limit as another kind of the present invention, described Compound disperse medium is volume ratio is the Oleum Perillae of 1:1 ~ 25 and other disperse medium.
Present invention also offers a kind of preparation method that above-mentioned Compositional type Biological cross-linker cross-linked chitosan delays control-release microsphere, carry out according to following steps order:
(1) preparation of chitosan solution
Be acetic acid solution 60 ~ 1000ml and the chitosan mixing and stirring of 1 ~ 20% by mass concentration, leave standstill and treat bubble cancellation, obtain the chitosan solution A that bulking value specific concentration is 2 ~ 5%;
(2) preparation of genipin solution
Genipin is joined in distilled water, stir 0.5 ~ 3h at 25 ~ 60 DEG C, be down to room temperature, obtain the genipin solution B that bulking value specific concentration is 0.5 ~ 2%;
(3) preparation of vanillin solution
Vanillin is joined in acetone, stirred at ambient temperature, obtain the vanillin solution C that bulking value specific concentration is 1 ~ 5%;
(4) the slow control-release microsphere of emulsifying preparation
Chitosan solution A is joined prepare in advance containing in the disperse medium of emulsifying agent, stir, regulate the temperature of mixture, obtain the mixed liquor D of mix homogeneously;
Separately get above-mentioned genipin solution B and vanillin solution C adds in mixed liquor D, stir, be cured, control the temperature in solidification process and hardening time, centrifugalize, ethyl acetate is cleaned, sucking filtration, dry, obtain the slow control-release microsphere of Compositional type Biological cross-linker cross-linked chitosan.
Limit as one of the present invention, the temperature regulating mixture in described step (4) is 15 ~ 60 DEG C; Solidification temperature is 25 ~ 50 DEG C; Hardening time is 2 ~ 10h.
Limit as another kind of the present invention, the emulsifying agent in described step (4) is 1:50 ~ 100 with the volume parts ratio of disperse medium.
The present invention also has a kind of restriction, and the genipin solution B in described step (4) and the volume ratio of vanillin solution C are 1:0.05 ~ 10.
Owing to have employed above-mentioned technical scheme, compared with prior art, acquired technological progress is in the present invention:
Microsphere provided by the present invention is obtained by vanillin and the composite cross-linked chitosan of genipin, its swellability is higher than the swellability of the single crosslinked chitosan microsphere of genipin, and do not occur that disintegrate becomes the phenomenon of uneven liquid state, achieve the slow controlled release properties of preparing microsphere between the slow controlled release properties of genipin or the single crosslinked chitosan microsphere of vanillin; And microsphere surface is porous structural, and microsphere quality is homogeneous, particle diameter is between 1 ~ 80 micron, and swelling ratio is 210 ~ 320%.To find in the selection course of Biological cross-linker and the Biological cross-linker of not all can both prepare particle diameter and all suitable microsphere of swelling ratio.
Operating condition ratio in course of reaction of the present invention is easier to control, vanillin and genipin is composite and occur between chitosan molecule crosslinked be many groups, multiple mechanism of crosslinking is cross-linked, in order to carrying out smoothly of ensureing to be cross-linked, realize the slow controlled release object that microsphere discharges medicine in vivo, whole preparation process needs the ratio adjusting genipin and the composite cross-linking agent of vanillin, and regulate the weight ratio of composite cross-linking agent and chitosan simultaneously, control intensity and the reaction temperature of stirring, genipin and the composite cross-linking agent of vanillin is regulated to add the speed of emulsion dispersion medium, the sequencing adjusting the ratio between genipin and vanillin simultaneously and join in emulsion dispersion medium, make chitosan delay the particle diameter of control-release microsphere and apparent condition controlled, realize chitosan and delay the swelling controllability of control-release microsphere, thus control medicine reaches more suitably slow releasing in vivo.
Compound disperse medium is employed in course of reaction of the present invention, thus make the more even of the slow control-release microsphere dispersion of preparation, in Oleum Perillae, the polybasic unsaturated fatty acid linolenic acid of high-load have adjusted the ratio of unsaturated fatty acid in original system, thus chitosan solution is distributed in disperse medium equably, this is also make microspherulite diameter little and one of finely dispersed reason.
The present invention is applicable to the preparation of the slow control-release microsphere of Compositional type Biological cross-linker cross-linked chitosan.
The present invention is described in further detail below in conjunction with specific embodiment.
Detailed description of the invention
Slow control-release microsphere of embodiment 1 one kinds of Compositional type Biological cross-linker cross-linked chitosans and preparation method thereof
A slow control-release microsphere for Compositional type Biological cross-linker cross-linked chitosan, described microsphere is spherical, and microsphere surface is porous structural, and the raw material making its effective ingredient comprises:
Chitosan 10g, genipin 0.5g, vanillin 6g, Twen-8020ml, Oleum Perillae 2000ml;
Prepare the method that above-mentioned Compositional type Biological cross-linker cross-linked chitosan delays control-release microsphere, carry out according to following steps order:
(1) preparation of chitosan solution
Be the chitosan mixing and stirring of acetic acid solution 200ml and 10g of 5% by mass concentration, leave standstill and treat bubble cancellation, the concentration of obtained w/v is the chitosan solution A of 5%;
(2) preparation of genipin solution
Joined by 0.5g genipin in 25ml distilled water, stir 2h at 40 DEG C, after stirring, be down to room temperature, the concentration obtaining w/v is 2%(g/ml) genipin solution B;
(3) preparation of vanillin solution
Joined by 6g vanillin in 200ml acetone, stirred at ambient temperature, obtaining bulking value specific concentration is 3%(g/ml) vanillin solution C;
(4) the slow control-release microsphere of emulsifying preparation
Joined by chitosan solution A in the Oleum Perillae (Twen-80 and Oleum Perillae prepare in advance) containing Twen-80, stir, the temperature regulating mixture is 40 DEG C, to obtain the mixed liquor D of mix homogeneously;
Isopyknicly get genipin solution B and vanillin solution C, join in mixed liquor D, carry out afterwards stirring and solidifying, the temperature controlled in solidification process is 30 DEG C and hardening time is 5h, centrifugalize after technology, ethyl acetate is cleaned, sucking filtration, dry, obtain the slow control-release microsphere of Compositional type Biological cross-linker cross-linked chitosan, the particle diameter of obtained microsphere is 30-50 micron, and swelling ratio is 300%.
Slow control-release microsphere of embodiment 2-6 Compositional type Biological cross-linker cross-linked chitosan and preparation method thereof
Embodiment 2-6 is respectively slow control-release microsphere of a kind of Compositional type Biological cross-linker cross-linked chitosan and preparation method thereof, it is similar to embodiment 1, difference part is only that the kind of raw material is different with technical parameter involved in consumption and preparation method, shown in specifically seeing the following form:
The particle diameter of microsphere obtained in embodiment 2-8 is all between 1-8-micron, and swelling ratio is all between 210-320%.
Microsphere effectiveness comparison obtained by the different cross-linking agent of embodiment 9
The method of preparing microsphere identical with embodiment 2-8 will be selected, but use different chemical cross-linking agents and Biological cross-linker, preparation method is: dropped to by chitosan solution in the disperse medium of stirring, to be emulsified be uniformly dispersed after drip cross-linking agent and be cured, reaction terminates rear centrifugal, and ethyl acetate is cleaned, dry, obtain crosslinked chitosan and delay control-release microsphere, result is as follows:
As seen from the above table, compared with chemical cross-linking agent, microsphere prepared by Biological cross-linker enters the cytotoxicity that after in body, metabolism produces and greatly reduces, this shows that Biological cross-linker is more suitable for preparing medicine carrying microballoons than chemical cross-linking agent, but microspherulite diameter prepared by Biological cross-linker oxidized sodium alginate and beta-schardinger dextrin-dialdehyde is larger and uneven, the crosslinked microsphere of preparing of vanillin enters degraded rapidly after in body, the microspheres swell that genipin is cross-linked preparation is too slow, but use genipin and vanillin to carry out the composite deficiency that can change single cross-linking agent, microspherulite diameter is evenly distributed, swelling toleration is better.
The selection of embodiment 10 Compositional type Biological cross-linker kind and consumption
Low compared with chemical cross-linking agent of the cytotoxicity of the microsphere that Biological cross-linker obtains can be found out by the result in embodiment 9, select different types of Biological cross-linker, result characterizes also different, obviously can find out that the particle diameter of the microsphere that Compositional type Biological cross-linker obtains is less and even, swelling ratio can reach comparatively ideal state, therefore the Biological cross-linker of Compositional type is carried out to the selection of kind and consumption, shown in table specific as follows:
As seen from the above table, vanillin and oxidized sodium alginate or beta-schardinger dextrin-dialdehyde is crosslinked can not prepare microsphere, the microspherulite diameter that genipin and oxidized sodium alginate or beta-schardinger dextrin-dialdehyde are cross-linked preparation more greatly and not easily swelling, the microspherulite diameter that oxidized sodium alginate and beta-schardinger dextrin-dialdehyde are cross-linked preparation is uneven, and the slow control-release microsphere swellability of genipin and the composite crosslinked preparation of vanillin is good, microspherulite diameter is little and be uniformly dispersed.Therefore, and the Biological cross-linker of not all carry out composite all can carry out microsphere preparation and can to obtain particle diameter comparatively even, swelling ratio is more suitable, the good microsphere of microsphere dispersibility.
The consumption of genipin and vanillin is selected, as shown in the table:
As seen from the above table, genipin and the composite crosslinked chitosan microsphere of vanillin all can form microsphere, and the particle diameter of microsphere is less, the mass ratio of genipin and vanillin is that microsphere prepared by 1:0.05 and 1:0.1 is not easily swelling, the microspheres swell toleration prepared during the mass ratio 1:3.0 of genipin and vanillin and 1:4.0 is poor, and the microspherulite diameter that the mass ratio of genipin and vanillin is prepared when 1:0.2 ~ 2 disperses more evenly and swelling behavior is better, be more suitable for the release request of medicine carrying microballoons in human body.
The selection of embodiment 11 disperse medium
The co-emulsifier of alcohols is often all added when using Biological cross-linker to prepare microsphere in prior art, but the also co-emulsifier of not all equal avirulence in the process introduced, therefore the use of co-emulsifier is reduced, the toxicity of obtained microsphere can be reduced, but do not use co-emulsifier easily to make prepared microsphere have adhesion in the process of preparation, the phenomenons such as particle size distribution is uneven, in order to prevent the generation of this phenomenon, disperse medium is selected, final discovery uses Oleum Perillae or uses composite Oleum Perillae can avoid the generation of above-mentioned phenomenon well as disperse medium, concrete selection course is as follows:
As seen from the above table, no matter be used alone Oleum Perillae, or undertaken composite by Oleum Perillae and a kind of, two or more other disperse medium, the result of particle diameter and swellability all comparatively uses the effect of other disperse medium better.Be used alone other disperse medium a kind of or two kinds, the two or more microspheres obtained by other disperse medium is all undesirable, therefore select Oleum Perillae or composite Oleum Perillae as disperse medium, can obtain and be uniformly dispersed, adhesion, and particle size range is more homogeneous, the microsphere that swelling ratio is more suitable.
The above is only preferred embodiment of the present invention, is not restriction the present invention being made to other form, and any those skilled in the art may utilize above-mentioned technology contents to be changed or be modified as the Equivalent embodiments of equivalent variations as enlightenment.But everyly do not depart from technical solution of the present invention content, according to technical spirit of the present invention to the simple modification done by above embodiment, equivalent variations and remodeling, still belong to the protection domain of the claims in the present invention.
Claims (7)
1. a slow control-release microsphere for Compositional type Biological cross-linker cross-linked chitosan, described microsphere is spherical, and microsphere surface is porous structural, it is characterized in that: the raw material making its effective ingredient comprises:
Chitosan 3 ~ 20 weight portion, genipin 0.1 ~ 1 weight portion,
Vanillin 0.01 ~ 25 weight portion, emulsifying agent 20 ~ 30 parts by volume,
Disperse medium 1000 ~ 3000 parts by volume;
The proportionate relationship of above-mentioned parts by weight and volume parts is gram: milliliter;
Described disperse medium is Oleum Perillae, or is the Compound disperse medium that Oleum Perillae and other disperse medium form; Other described disperse medium is the one in soybean oil, olive oil, Radix Oenotherae erythrosepalae oil or hazelnut oil, or the mixture of at least two kinds.
2. the slow control-release microsphere of Compositional type Biological cross-linker cross-linked chitosan according to claim 1, it is characterized in that: described emulsifying agent is the one in Span-80, Span-85, Twen-80, Twen-85, Poloxamer, OP-10, or the mixture of at least two kinds.
3. the slow control-release microsphere of Compositional type Biological cross-linker cross-linked chitosan according to claim 1, is characterized in that: described Compound disperse medium is volume ratio is the Oleum Perillae of 1:1 ~ 25 and other disperse medium.
4. the Compositional type Biological cross-linker cross-linked chitosan according to any one of claim 1-3 delays a kind of preparation method of control-release microsphere, it is characterized in that it carries out according to following steps order:
(1) preparation of chitosan solution
Be acetic acid solution 60 ~ 1000ml and the chitosan mixing and stirring of 1 ~ 20% by mass concentration, leave standstill and treat bubble cancellation, obtained bulking value specific concentration is the chitosan solution A of 2 ~ 5%;
(2) preparation of genipin solution
Genipin is joined in distilled water, stir 0.5 ~ 3h at 25 ~ 60 DEG C, be down to room temperature, obtain the genipin solution B that bulking value specific concentration is 0.5 ~ 2%;
(3) preparation of vanillin solution
Vanillin is joined in acetone, stirred at ambient temperature, obtain the vanillin solution C that bulking value specific concentration is 1 ~ 5%;
(4) the slow control-release microsphere of emulsifying preparation
Chitosan solution A is joined in the disperse medium containing emulsifying agent, stir, regulate the temperature of mixture, obtain the mixed liquor D of mix homogeneously;
Genipin solution B and vanillin solution C add in mixed liquor D, stir, are cured, and control the temperature in solidification process and hardening time, centrifugalize, and ethyl acetate is cleaned, sucking filtration, dry, obtain the slow control-release microsphere of Compositional type Biological cross-linker cross-linked chitosan.
5. Compositional type Biological cross-linker cross-linked chitosan according to claim 4 delays a kind of preparation method of control-release microsphere, it is characterized in that: the temperature regulating mixture in described step (4) is 15 ~ 60 DEG C; Solidification temperature is 25 ~ 50 DEG C; Hardening time is 2 ~ 10h.
6. Compositional type Biological cross-linker cross-linked chitosan according to claim 4 delays the preparation method of control-release microsphere, it is characterized in that: the emulsifying agent in described step (4) is 1:50 ~ 100 with the volume parts ratio of disperse medium.
7. Compositional type Biological cross-linker cross-linked chitosan according to claim 4 delays the preparation method of control-release microsphere, it is characterized in that: the volume parts of the genipin solution B in described step (4) and vanillin solution C is than being 1:0.05 ~ 10.
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