CN102240268B - Sustained/controlled release microsphere of biological extract Genipin cross-linked chitosan coated stilbene compound and preparation method thereof - Google Patents
Sustained/controlled release microsphere of biological extract Genipin cross-linked chitosan coated stilbene compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a sustained/controlled release microsphere of a chitosan coated stilbene compound using a biological extract Genipin as a cross-linking agent and a preparation method thereof. In the microsphere, a cross-linked condensation compound layer of the chitosan and the Genipin serves as a capsule shell and is used for coating a medicament 3,5-dihydroxyl-4-isopropyl stilbene, resveratrol, pterostilbene, oxidized resveratrol or piceatannol; the medicament stability of the product is improved; the sustained/controlled release of the medicament is realized; and the released Genipin after in vivo metabolism of the capsule shell has the characteristics of biocompatibility, no cytotoxicity and the like. The invention is applicable to the sustained/controlled release microspheres of Genipin cross-linked chitosan coated 3,5-dihydroxyl-4-isopropyl stilbene, resveratrol, pterostilbene, oxidized resveratrol, piceatannol and other stilbene compounds and a preparation method thereof. The preparation method is low in requirements on the control condition and easy to operate. In the microspheres, the quality is uniform; the grain size is 0.1 to 100 mu m; the surface of the microsphere has a multiporous structure; and the entrapment rate of the capsule shell to the medicament is 30 to 90 percent.
Description
Technical field
The invention belongs to the chemical and medicine industry preparation field, specifically a kind of bio-extract genipin cross-linked chitosan coats slow control-release microsphere of diphenylethylene compounds and preparation method thereof.
Background technology
Chitosan (Chitosan, CS) is to have bioadhesive and the poly-aminopolysaccharide of multiple bioactive natural polymer, enters in the body and can through the plurality of enzymes biodegradation, be absorbed fully by organism; Simultaneously, chitosan can also increase medicine to biomembranous permeability, is conducive to medicine and brings into play better drug effect in cell.It is a kind of novel form in the pharmaceutical preparation as a kind of good biological organic carrier coating medicine molecule that chitosan is prepared as slow control-release microsphere, the slow controlled release, tissue target that can realize medicine to, improve the satisfied effect such as medicine stability.
Present stage, the existing chitosan emulsification and cross linked solidification method that adopts prepared the technology of delaying control-release microsphere, the cross-linking agent that adopts is generally aldehyde compound, the electropositive of the carbonyl carbon of aldehyde is so that it is responsive especially to the attack of nucleopilic reagent, its characteristic reaction is the nucleophilic addition of the two keys of carbon oxygen, and in the chitosan molecule with amino can the Schiff reaction occur with the carbonyl carbon of aldehyde, chitosan and aldehyde are linked together, thereby form cross-linked network.Cross-linking agent commonly used had formaldehyde, Biformyl, glutaraldehyde etc. in the past, the active height of formaldehyde, but the formaldehyde toxicity that cross-linking agent discharges behind internal metabolism is larger, two aldehyde radicals of Biformyl directly link to each other, the cross-linking agent that forms with chitosan has more closely crystalline texture, the hardness of the microsphere that obtains is large, be not suitable for doing the coating of medicine, three methylene in interval between two aldehyde radicals of glutaraldehyde, crosslinked afterwards because constraint and the space steric effect of crosslinking points, the intensity of the cross-linking agent that forms is lower than the cross-linking agent of Biformyl and chitosan, is more suitable for doing the carrier of medicine.It is 200910075128.3 Chinese invention patent such as the applicant's the patent No., disclose a kind of " chitosan coating medicine slow release microsphere and preparation method thereof ", relate to take resveratrol as the core medicine, the sustained-release micro-spheres medicine take the condensation substance of chitosan and glutaraldehyde as softgel shell and preparation method thereof.Do the microsphere moderate strength of cross-linking agent preparation in this patent with glutaraldehyde, but because glutaraldehyde has human body cell toxicity, although in the preparation process microsphere has been carried out cleaning thoroughly to remove the residual glutaraldehyde of microsphere surface, but entering human body, microsphere behind enzymes metabolism, still can discharge glutaraldehyde, so harmful its application is subject to certain restrictions.
Genipin is one of active component of the Chinese medicine Cortex Eucommiae, it is the natural product that from geniposide, separates, purifies and obtain, belong to the iridoid heterocyclic compounds, often be used as a kind of antiphlogistic medicine invigorating gallbladder and be applied to treat various liver and gall diseases (can promote the secretion of bile) and infection symptoms.Genipin has a plurality of active function groups such as hydroxyl, carboxyl and acetal (hiding aldehyde radical), can form cross-linked network with chitosan generation condensation reaction under certain condition.Compare with traditional cross-linking agent, the slow control-release microsphere that natural biological extract genipin and chitosan form enters human body and discharges genipin and chitosan by enzymes metabolism, because both all have good biocompatibility and without any cytotoxicity, are conducive to the application of chitosan controlled release agent type in biomedical sector.
Summary of the invention
The technical problem to be solved in the present invention, slow control-release microsphere of a kind of bio-extract genipin cross-linked chitosan coating diphenylethylene compounds and preparation method thereof will be provided exactly, utilize chitosan to be base material, natural biological extract genipin is as cross-linking agent, coat diphenylethylene compounds 3, a kind of in 5-dihydroxy-4-isopropyl toluylene, resveratrol, Pterostilbene, oxidized resveratrol or the piceatannol.Use natural biological cross-linking agent genipin as cross-linking agent in the preparation process of microsphere, the slow control-release microsphere of the chitosan of formation is nontoxic to human body, has obviously improved the stability of the chemical compound that coats, and has realized simultaneously slow controlled release purpose; Preparation method controlled condition provided by the present invention requires low, easy operating, and prepared sustained-release micro-spheres quality homogeneous, softgel shell is 30%～90% to the envelop rate of diphenylethylene compounds.
The present invention is to realize by following technical scheme for solving above-mentioned technical problem:
A kind of bio-extract genipin cross-linked chitosan coats the slow control-release microsphere of diphenylethylene compounds, described microsphere is nucleocapsid structure, the diphenylethylene compounds of its center for being coated by shell, its special feature is that described shell is the crosslinked condensation substance layer of chitosan and natural natural extract genipin.
Described microsphere is spherical, and microspherulite diameter is 0.1～100 micron, and microsphere surface is the porous type structure.
As a kind of restriction of the present invention, described diphenylethylene compounds is a kind of in 3,5-dihydroxy-4-isopropyl toluylene, resveratrol, Pterostilbene, oxidized resveratrol or the piceatannol.
The raw material of making described slow control-release microsphere effective ingredient comprises that following quality or volume parts form:
Chitosan parts by weight 3-20,
Diphenylethylene compounds parts by weight 0.1-5,
Genipin parts by weight 1,
Disperse medium volume parts 1000-3000;
The proportionate relationship of above-mentioned parts by weight and volume parts is gram: milliliter.
The present invention also provides the preparation method of above-mentioned slow control-release microsphere, and this preparation method is carried out according to following step order:
(1) preparation of chitosan solution
2～36% acetic acid solution, chitosan mixing and stirring leave standstill and treat the bubble cancellation, and the specific concentration that makes chitosan weight and the liquor capacity of getting is that 1～6%(unit is g/mL, or kg/L) chitosan solution A;
(2) preparation of genipin solution
Get respectively distilled water and genipin, genipin is joined in the distilled water, 10～60 ℃ of lower 0.5～4 h that stir are down to room temperature, and making concentration is that 0.1～2%(unit is g/mL, or kg/L) genipin solution B;
(3) compound dissolution
Diphenylethylene compounds dissolves with alcohols solvent, then joins among the chitosan solution A, and mix homogeneously gets mixed solution C; Wherein the envelope-bulk to weight ratio of alcohols solvent and diphenylethylene compounds is 1～5:1, and unit is mL/g or L/kg;
(4) the slow control-release microsphere of emulsifying preparation
C is joined in the disperse medium that contains emulsifying agent, stir, regulate the temperature of mixture to obtain the mixed liquor D of mix homogeneously; Wherein the parts by weight of emulsifying agent are the 0-10% of disperse medium;
Other gets mentioned solution B and adds among the D, solidify 1～12 h after, centrifugalize, ethyl acetate is cleaned, sucking filtration, drying namely gets the slow control-release microsphere of Chitosan-coated diphenyl ethene compounds.
Used acetic acid solution concentration is 2%～36%, and the envelope-bulk to weight ratio of itself and chitosan is 16.5～100 milliliters: 1 gram.
Described emulsifying agent is one or more the mixture among Span-80 (Arlacel-80), Span-85 (Arlacel-85), Twen-80 (tween 80), Twen-85 (tween 85), Poloxamer (poloxamer), the OP-10 (alkylphenol polyoxyethylene).
Described disperse medium is one or more the mixture in soybean oil, olive oil, Oleum Arachidis hypogaeae semen, sunflower oil or the liquid paraffin.
Described alcohols solvent is one or more the mixture in methanol, ethanol, propanol, isopropyl alcohol or the n-butyl alcohol.
The reaction temperature of the slow control-release microsphere step (4) of emulsifying preparation is 0～60 ℃.
The curing reaction time is 1～12 h.(because in the process of preparation microsphere, if other factor (such as temperature, dosage of crosslinking agent etc.) is not simultaneously, have very large difference in the response time.If temperature is low, the response time will be elongated accordingly, otherwise then shorten, and the length of time connects each other with the other influences factor, and being defined as 1～12 h is reasonably, can guarantee the realization of goal of the invention.）
In proportioning raw materials of the present invention, be the core medicine with a kind of of 3,5-dihydroxy-4-isopropyl toluylene, resveratrol, Pterostilbene, piceatannol or oxidized resveratrol; Chitosan is the capsule material, plays the effect that coats the core medicine; The bio-extract genipin has played the effect of cross-linking agent, thereby cross-linking agent is by with chitosan generation chemical reaction chitosan molecule being coupled together, thereby makes microsphere more firm.
The present invention owing to adopted above-mentioned technical scheme, compared with prior art obtained technological progress is: substituted the larger glutaraldehyde of toxicity with nontoxic natural biological cross-linking agent genipin in the preparation process of microsphere, reduced largely the toxicity of metabolism deposits yields after the microsphere oral administration, make the microsphere of preparation be more suitable for pharmaceutical dosage form and health product, should delay the stability that control-release microsphere has improved the chemical compound that coats significantly, realize simultaneously slow controlled release purpose; The present invention is applicable to bio-extract genipin cross-linked chitosan and coats 3, slow control-release microsphere and the preparation thereof of the diphenylethylene compounds such as 5-dihydroxy-4-isopropyl toluylene, resveratrol, Pterostilbene, oxidized resveratrol, piceatannol, also be applicable to slow control-release microsphere and the preparation of other diphenylethylene compounds, preparation method controlled condition provided by the present invention requires low, easy operating, prepared sustained-release micro-spheres quality homogeneous, softgel shell is 30～90% to the envelop rate of diphenylethylene compounds.
The present invention is described in further detail below in conjunction with Figure of description and specific embodiment.
Description of drawings
Fig. 1 is the vertical profile structural representation of the slow control-release microsphere of the present invention.
Among the figure: 1-diphenylethylene compounds (nuclear); The inner duct that communicates with microsphere surface of 2-ball; The softgel shell that the condensation substance layer of 3-chitosan and genipin consists of.
The specific embodiment
Be illustrated in figure 1 as the slow control-release microsphere that a kind of bio-extract genipin cross-linked chitosan coats diphenyl ethene compounds, be nuclear-shell structure, its center is the diphenyl ethene compounds layer that coats, and softgel shell is the crosslinked condensation substance layer of chitosan and genipin.
Should delay the preparation method of control-release microsphere carries out according to following step order:
(1) preparation of chitosan solution
2～36% acetic acid solution, chitosan mixing and stirring leave standstill and treat the bubble cancellation, and making concentration is that 1～6%(unit is g/mL) chitosan solution A;
(2) preparation of genipin solution
Get respectively distilled water and genipin, genipin is joined in the distilled water, 10～60 ℃ of lower 0.5～4 h that stir are down to room temperature, and namely getting concentration is that 0.1～2%(unit is g/mL) genipin solution B;
(3) compound dissolution
Diphenylethylene compounds dissolves with alcohols solvent, then joins among the chitosan solution A, and mix homogeneously gets mixed solution C;
(4) the slow control-release microsphere of emulsifying preparation
C is joined in the disperse medium that contains emulsifying agent, stir, regulate the temperature of mixture to obtain the mixed liquor D of mix homogeneously;
Other gets mentioned solution B and adds among the D, solidify 1～12 h after, centrifugalize, ethyl acetate is cleaned, sucking filtration, drying namely gets the slow control-release microsphere of Chitosan-coated diphenyl ethene compounds.
The concrete proportioning raw materials of each embodiment and relevant parameter such as following table:
For example: embodiment 3 relates to the slow control-release microsphere that a kind of bio-extract genipin cross-linked chitosan coats the diphenyl ethene compounds Pterostilbene, and batching is with reference to shown in Figure 1, and its preparation method in accordance with the following steps order carries out:
(31) chitosan (CS) solution of configuration 3.0%
Get acetic acid solution 20 mL, chitosan 0.6 g of concentration 10%, mix, stir, leave standstill and treat the bubble cancellation, make w/v and be 3.0% (
W/V) chitosan solution A;
(32) genipin solution of configuration 1%
0.04 the g genipin joins in the 4 mL distilled water, 60 ℃ of lower 30 min that stir are down to the genipin solution B that room temperature namely gets 1% (W/V);
(33) medicine dissolution
Get 0.04 g Pterostilbene and dissolve with 0.12 g n-butyl alcohol, then join among the mentioned solution A, mix homogeneously gets mixed solution C; Then
(34) emulsifying prepares the slow control-release microsphere of chitosan coating medicine
With C join 120mL contain 5% (
W/
V) in the olive oil of Twen-80, stir, mix homogeneously gets mixed liquor D;
Solution B is added among the D, behind 35 ℃ of curing 6 h, centrifugalize, ethyl acetate is cleaned, sucking filtration, drying namely gets the slow control-release microsphere that the genipin cross-linked chitosan coats diphenylethylene compounds, envelop rate 90%.
The specific operation process of other examples only is from the difference of embodiment: related parameter is different, the respective substance kind different, and real data is with reference to as above shown in the table.
Claims (6)
1. a bio-extract genipin cross-linked chitosan coats the preparation method of the slow control-release microsphere of diphenylethylene compounds,
1. described microsphere is nucleocapsid structure, the diphenylethylene compounds of its center for being coated by shell, and described shell is the crosslinked condensation substance layer of chitosan and natural extract genipin;
2. described microsphere is spherical, and microspherulite diameter is 0.1～100 micron, and microsphere surface is the porous type structure;
3. described core medicine is a kind of in 3,5-dihydroxy-4-isopropyl toluylene, resveratrol, Pterostilbene, oxidized resveratrol or the piceatannol;
4. the raw material of making the required effective ingredient of described slow control-release microsphere comprises following composition:
Chitosan parts by weight 3-20,
Diphenylethylene compounds parts by weight 0.1-5,
Genipin parts by weight 1,
Disperse medium volume parts 1000-3000;
The proportionate relationship of above-mentioned parts by weight and volume parts is gram: milliliter;
It is characterized in thatThis preparation method is carried out according to the following steps order:
(1) preparation of chitosan solution
2～36% acetic acid solutions, chitosan mixing and stirring leave standstill and treat the bubble cancellation, make the bulking value specific concentration and be 1～6% chitosan solution A;
(2) preparation of genipin solution
Get respectively distilled water and genipin, genipin is joined in the distilled water, 10～60 ℃ of lower 0.5～4 h that stir are down to room temperature, namely get the bulking value specific concentration and be 0.1～2% genipin solution B;
(3) compound dissolution
Diphenylethylene compounds dissolves with alcohols solvent, then joins among the chitosan solution A, and mix homogeneously gets mixed solution C; Wherein the envelope-bulk to weight ratio of alcohols solvent and diphenylethylene compounds is 1～5 milliliter: 1 gram;
(4) the slow control-release microsphere of emulsifying preparation
C is joined in the disperse medium that contains emulsifying agent, stir, regulate the temperature of mixture to obtain the mixed liquor D of mix homogeneously; Wherein the volume parts of emulsifying agent is the 0-10% of disperse medium;
Other gets mentioned solution B and adds among the D, solidify 1～12h after, centrifugalize, ethyl acetate is cleaned, sucking filtration, drying namely gets the slow control-release microsphere of Chitosan-coated diphenyl ethene compounds.
2. bio-extract genipin cross-linked chitosan according to claim 1 coats the preparation method of the slow control-release microsphere of diphenylethylene compounds,
It is characterized in that:The concentration of used acetic acid solution is 2～36%, and the envelope-bulk to weight ratio of itself and chitosan is 16.5～100 milliliters: 1 gram.
3. bio-extract genipin cross-linked chitosan according to claim 1 coats the preparation method of the slow control-release microsphere of diphenylethylene compounds,
It is characterized in that:Described emulsifying agent is a kind of among Span-80, Span-85, Twen-80, Twen-85, Poloxamer, the OP-10, or at least two kinds mixture.
4. bio-extract genipin cross-linked chitosan according to claim 1 coats the preparation method of the slow control-release microsphere of diphenylethylene compounds,
It is characterized in that:Described disperse medium is a kind of in soybean oil, olive oil, Oleum Arachidis hypogaeae semen, sunflower oil or the liquid paraffin, or at least two kinds mixture.
5. bio-extract genipin cross-linked chitosan according to claim 1 coats the preparation method of the slow control-release microsphere of diphenylethylene compounds,
It is characterized in that:Described alcohols solvent is a kind of in methanol, ethanol, propanol, isopropyl alcohol or the n-butyl alcohol, or at least two kinds mixture.
6. bio-extract genipin cross-linked chitosan according to claim 1 coats the preparation method of the slow control-release microsphere of diphenylethylene compounds,
It is characterized in that:The reaction temperature of the slow control-release microsphere step (4) of emulsifying preparation is 0～60 ℃.
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| CN102579364B (en) * | 2012-03-05 | 2013-10-09 | 河北科技大学 | Sustained or controlled release microsphere of valnemulin/valnemulin salts and preparation method thereof |
| CN102989005A (en) * | 2012-12-05 | 2013-03-27 | 华侨大学 | Methotrexate-loaded magnetosome drug carrier and preparation method thereof |
| CN104689771B (en) * | 2015-03-05 | 2017-03-01 | 华南农业大学 | A kind of preparation method of oxidized resveratrol microcapsule and products thereof |
| CN104906047B (en) * | 2015-05-19 | 2017-12-12 | 南方医科大学 | A kind of preparation method of pravastatin sodium long-acting slow-release microballoon |
| CN106389386A (en) * | 2016-09-13 | 2017-02-15 | 温州生物材料与工程研究所 | Biocompatible cross-linking micro-nano material for drug encapsulation and sustained release and preparation technology of biocompatible cross-linking micro-nano material for drug encapsulation and sustained release |
| CN109316464B (en) * | 2018-11-01 | 2020-12-11 | 长春万成生物电子工程有限公司 | Preparation comprising islet-like cell mass |
| CN110448620A (en) * | 2019-09-20 | 2019-11-15 | 宁夏农林科学院枸杞工程技术研究所 | To the preparation method of lotion in a kind of fructus lycii luteole acid dipalmitate is high |
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| CN101618021A (en) * | 2009-08-12 | 2010-01-06 | 河北科技大学 | Chitosan coating medicine slow release microsphere and preparation method thereof |
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| CN101618021A (en) * | 2009-08-12 | 2010-01-06 | 河北科技大学 | Chitosan coating medicine slow release microsphere and preparation method thereof |
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