CN104940942A - Preparation method of single-hole hollow arabinogalactan-chitosan composite microspheres - Google Patents
Preparation method of single-hole hollow arabinogalactan-chitosan composite microspheres Download PDFInfo
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- CN104940942A CN104940942A CN201410124349.6A CN201410124349A CN104940942A CN 104940942 A CN104940942 A CN 104940942A CN 201410124349 A CN201410124349 A CN 201410124349A CN 104940942 A CN104940942 A CN 104940942A
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Abstract
The invention discloses a preparation method of single-hole hollow arabinogalactan-chitosan composite microspheres. The preparation method comprises the following steps: dispersing arabinogalactan, chitosan and a water-soluble drug into an emulsifying agent or an organic solvent according with the emulsifying agent, preparing O/W/O type dispersion emulsion by adopting an ultrahigh-speed emulsification centrifugal technology, adding glutaraldehyde to perform crosslinking curing for 6 hours for forming, standing and then separating the organic solvent by using a separating funnel to obtain crude microspheres; and dialyzing the crude product in distilled water by using a dialysis membrane of which the cut-off molecular weight is 8000Da, and performing centrifugal separation at a rotating speed of 4000r/min, hot water washing and then lyophilization to obtain the single-hole hollow arabinogalactan-chitosan composite microspheres. The arabinogalactan used in the method disclosed by the invention comes from larch processing residues, so that the raw materials are low in price. The method is low in equipment requirement, simple in preparation process, and convenient for industrial production, and the used organic solvent can be repeatedly used. The preparation of the arabinogalactan-chitosan composite microspheres is chemical reaction; and a slow-release carrier of the microspheres also has good biocompatibility and organ targeting property, and has practical medical and medicinal values.
Description
Technical field
The present invention relates to a kind of preparation and medicament slow release application of medicine controlled release carrier, be specifically related to the hollow preparation method of poly-arabogalactan-chitosan compound microsphere of a kind of single hole and the application as drug release carrier.
Technical background
As far back as early 1970s, just start the research and development of slow releasing preparation abroad at field of medicaments, so far the development course of existing 40 years.Due to slow releasing preparation, to have the few and curative effect of administration number of times lasting, and blood concentration fluctuation is less, route of administration variation, zest and the advantage such as side effect is little and be subject to clinical attention gradually.The research and development of slow releasing preparation is in recent years very rapid, have developed the multiple dosage forms such as tablet, capsule, microspheres agent, liposome, nanosphere both at home and abroad.In view of the development trend in this field, the development of sustained release microsphere agents has wide market prospect and far-reaching clinical meaning.
Microsphere (microspheres) is a kind of spherical particle drug delivery system wrapping up with suitable macromolecular material for carrier or adsorb medicine and make.Can be used for injection (quiet note, intramuscular injection), oral, collunarium, subdermal implantation or articular cavity administration.Medicine dispersion in microsphere or embedding form spherical entity in the material.Microsphere diameter size is generally 1-300um, and different-grain diameter scope acts on different target cells pointedly.But the full particle that particle diameter is less than 2um is easy to by macrophage phagocytic, cannot realize administration.And tiny balloon can expand particle diameter, and provide the performance to privileged sites administration and medicine carrying.Natural macromolecular material albumin, gelatin, chitosan, starch etc. are had at present according to the microspherical carrier material that the development progress of slow-release material is conventional; Synthesized polymer material is as polylactide, polyvinyl alcohol, polylactic acid, ethyl cellulose and magnetic material etc.
In the research of medical controlled release carrier conventional microsphere supported be chitosan (chitosan).It is the natural alkaline polysaccharide of one that the chitin (chitin) extensively existed by nature obtains through deacetylation.Chitosan has multiple pharmacologically active, as antibacterial, antitumor, strengthening liver function, reduction blood glucose and cholesterol, acid suppression, has anticoagulant active, antithrombotic, immunologic enhancement etc. to pipe intestinal digesting system.These special natures make chitosan have broad application prospects in pharmaceutical carrier.Chitosan owing to having the features such as low toxicity, bioadhesive, histocompatibility, degradability, has become the excellent carrier of mucoadhesive delivery system as one.Chitosan has stronger mucosal adhesive properties can improve the permeability of film and prolong drug action time in the tissue, increase drug absorption with and the utilization ratio of target administration.
China starts to carry out the research of poly-arabogalactan preparation, modification and pathology toxicity in the beginning of this century.China larch in Xinanlin area is the Major Tree Species Planted of China Northeast Forest Areas, and timber reserves is enriched.But resinous in larch in Xinanlin area, therefore its utilization is made to receive serious restriction.The industrial wood waste that larch adds man-hour is very large in the residual quantity of forest zone processing factory, cause the significant wastage of biomass energy, and the content of poly-arabogalactan is very high.Recent years abroad scholar Chun H etc. has found the immunocompetence of AG and has applied AG and stimulate NK cytotoxicity that Patients with Viral Hepatitis is benefited; Tanaka etc. find that AG can be connected with the protein carrier of hepatocyte asialoglycoprotein, and AG can be used as by this carrier the carrier transmitting medicine, has 52.5% can reach liver after injection.Above-mentioned achievement makes poly-arabogalactan be subject to the common concern of field of medicaments researcher.Under the background that novel drugs new product emerges in an endless stream, urgently develop a kind of microsphere sustained-release preparation with the poly-arabogalactan of high popularization and high security.
Summary of the invention
The invention provides a kind of preparation method of poly-arabogalactan-chitosan compound microsphere, the object of the invention is to prepare a kind of single hole hollow compound microsphere slow-released carrier with biocompatibility and targeting.This microsphere diameter is controlled, and best molding scope is 50nm ~ 500um, and preferable range is 1um ~ 8um, and shell thickness is 0.9um.
Technical scheme of the present invention gathers arabogalactan and chitosan with glutaraldehyde cross-linking, prepared the hollow poly-arabogalactan-chitosan compound microsphere of single hole by ultrahigh speed emulsifying centrifugation technique.The method preparation technology is simple, cheap.
The hollow poly-arabogalactan-chitosan compound microsphere of the single hole that the present invention relates to comprises four steps, it is characterized in that:
(1) modulation of medicine carrying microballoons slurry: water soluble drug, poly-arabogalactan and chitosan are stirred into transparent mixture by the 1wt% acetum of fixed proportion and 10mL and vacuum outgas 2 hours, obtain medicine carrying microballoons slurry A;
(2) preparation of O/W emulsion: emulsifying agent, compound emulsifying agent are mixed with medicine carrying microballoons slurry A, adds a small amount of organic solvent in high-shear impeller, stirs 1 hour formation O/W emulsion B;
3) microsphere curing molding: add organic solvent in O/W emulsion B, and continue high-speed stirred 1 hour formation O/W/O emulsion C; Connect poly-arabogalactan and chitosan with cross-linking agent chemistry and after 6 hours, C emulsion be cooled to room temperature 40 DEG C of sizings;
4) microsphere is separated: divide upper strata organic solvent with separatory funnel after emulsion C is left standstill 24 hours, obtain rough microsphere D; Be that the dialyzer of 8000Da is dialysed thick product D in distilled water with molecular cut off, obtain the hollow poly-arabogalactan-chitosan compound microsphere E of single hole with lyophilization after the rotating speed centrifugalize of 4000r/min, hot wash.
The one of above-mentioned poly-arabogalactan employing larch in Xinanlin area, Yichun larch, larix sibirica or two kinds and the extraction of above mixed material; Chitosan adopts the chitosan of deacetylated process to be raw material.
Accompanying drawing explanation
The SEM electromicroscopic photograph of the hollow poly-arabogalactan-chitosan compound microsphere of Fig. 1 single hole
Specific embodiment
Embodiment 1
The 1wt% aqueous acetic acid of water soluble drug 5-Fu uracil 2.8mg, poly-arabogalactan 10mg and 1.075g chitosan and 10mL is stirred into transparent mixture and vacuum outgas 2 hours, obtain medicine carrying microballoons slurry A; Add 2.4g compound emulsifying agent (mass ratio of sodium lauryl sulphate and tween 80 is 1:1) and 10mL liquid paraffin high-speed stirred 1 hour formation O/W emulsion B; Under 1000r/min high velocity turbulent flow condition, add 190mL liquid paraffin and continue stirring 1 hour formation O/W/O emulsion C; Gather arabogalactan and chitosan with glutaraldehyde cross-linking and 40 DEG C of sizings 6 hours, after cooling curing, divide supernatant liquid paraffin to obtain rough microsphere D with separatory funnel; Molecular cut off is adopted to be that the dialyzer of 8000Da is dialysed thick product D in distilled water; Be the hollow poly-arabogalactan-chitosan compound microsphere E of 1um ~ 6um single hole with obtaining average diameter after the rotating speed centrifugalize of 4000r/min, hot wash 3 times, lyophilization.
Embodiment 2
The 1wt% aqueous acetic acid of water soluble drug 5-Fu uracil 2.8mg, poly-arabogalactan 10mg and 1.075g chitosan and 10mL is stirred into transparent mixture and vacuum outgas 2 hours, obtain medicine carrying microballoons slurry A; Add 2.4g tween 80 and 10mL liquid paraffin high-speed stirred 1 hour formation O/W emulsion B; Under 1000r/min high velocity turbulent flow condition, add 190mL liquid paraffin and continue stirring 1 hour formation O/W/O emulsion C; Gather arabogalactan and chitosan with glutaraldehyde cross-linking and 40 DEG C of sizings 6 hours, after cooling curing, divide supernatant liquid paraffin to obtain rough microsphere D with separatory funnel; Molecular cut off is adopted to be that the dialyzer of 8000Da is dialysed thick product D in distilled water; Be the hollow poly-arabogalactan-chitosan compound microsphere E of 1.293um single hole with obtaining average diameter after the rotating speed centrifugalize of 4000r/min, hot wash 3 times, lyophilization.
Embodiment 3
The 1wt% aqueous acetic acid of water soluble drug 5-Fu uracil 2.8mg, poly-arabogalactan 10mg and 1.075g chitosan and 10mL is stirred into transparent mixture and vacuum outgas 2 hours, obtain medicine carrying microballoons slurry A; Add 2.4g polyvinyl alcohol and 10mL liquid paraffin high-speed stirred 1 hour formation O/W emulsion B; Under 1000r/min high velocity turbulent flow condition, add 190mL liquid paraffin and continue stirring 1 hour formation O/W/O emulsion C; Gather arabogalactan and chitosan with glutaraldehyde cross-linking and 40 DEG C of sizings 6 hours, after cooling curing, divide supernatant liquid paraffin to obtain rough microsphere D with separatory funnel; Molecular cut off is adopted to be that the dialyzer of 8000Da is dialysed thick product D in distilled water; Be the hollow poly-arabogalactan-chitosan compound microsphere E of 1.513um single hole with obtaining average diameter after the rotating speed centrifugalize of 4000r/min, hot wash 3 times, lyophilization.
Embodiment 4
The 1wt% aqueous acetic acid of water soluble drug 5-Fu uracil 2.8mg, poly-arabogalactan 10mg and 1.075g chitosan and 10mL is stirred into transparent mixture and vacuum outgas 2 hours, obtain medicine carrying microballoons slurry A; Add 2.4g sodium lauryl sulphate and 10mL liquid paraffin high-speed stirred 1 hour formation O/W emulsion B; Under 1000r/min high velocity turbulent flow condition, add 190mL liquid paraffin and continue stirring 1 hour formation O/W/O emulsion C; Gather arabogalactan and chitosan with glutaraldehyde cross-linking and 40 DEG C of sizings 6 hours, after cooling curing, divide supernatant liquid paraffin to obtain rough microsphere D with separatory funnel; Molecular cut off is adopted to be that the dialyzer of 8000Da is dialysed thick product D in distilled water; Be the hollow poly-arabogalactan-chitosan compound microsphere E of 414um single hole with obtaining average diameter after the rotating speed centrifugalize of 4000r/min, hot wash 3 times, lyophilization.
Embodiment 5
The 1wt% aqueous acetic acid of water soluble drug 5-Fu uracil 2.8mg, poly-arabogalactan 10mg and 1.075g chitosan and 10mL is stirred into transparent mixture and vacuum outgas 2 hours, obtain medicine carrying microballoons slurry A; Add 2.4g tween 80 and 10mL liquid paraffin high-speed stirred 1 hour formation O/W emulsion B; Under 1000r/min high velocity turbulent flow condition, add 50mL liquid paraffin and continue stirring 1 hour formation O/W/O emulsion C; Gather arabogalactan and chitosan with glutaraldehyde cross-linking and 40 DEG C of sizings 6 hours, after cooling curing, divide supernatant liquid paraffin to obtain rough microsphere D with separatory funnel; Molecular cut off is adopted to be that the dialyzer of 8000Da is dialysed thick product D in distilled water; Be the hollow poly-arabogalactan-chitosan compound microsphere E of 20.82um single hole with obtaining average diameter after the rotating speed centrifugalize of 4000r/min, hot wash 3 times, lyophilization.
Embodiment 6
The 1wt% aqueous acetic acid of water soluble drug 5-Fu uracil 2.8mg, poly-arabogalactan 10mg and 1.075g chitosan and 10mL is stirred into transparent mixture and vacuum outgas 2 hours, obtain medicine carrying microballoons slurry A; Add 2.4g tween 80 and 10mL liquid paraffin high-speed stirred 1 hour formation O/W emulsion B; Under 1500r/min high velocity turbulent flow condition, add 50mL liquid paraffin and continue stirring 1 hour formation O/W/O emulsion C; Gather arabogalactan and chitosan with glutaraldehyde cross-linking and 40 DEG C of sizings 6 hours, after cooling curing, divide supernatant liquid paraffin to obtain rough microsphere D with separatory funnel; Molecular cut off is adopted to be that the dialyzer of 8000Da is dialysed thick product D in distilled water; Be the hollow poly-arabogalactan-chitosan compound microsphere E of 3.067um single hole with obtaining average diameter after the rotating speed centrifugalize of 4000r/min, hot wash 3 times, lyophilization.
Embodiment 7
The 1wt% aqueous acetic acid of water soluble drug 5-Fu uracil 2.8mg, poly-arabogalactan 10mg and 1.075g chitosan and 10mL is stirred into transparent mixture and vacuum outgas 2 hours, obtain medicine carrying microballoons slurry A; Add 2.4g tween 80 and 10mL liquid paraffin high-speed stirred 1 hour formation O/W emulsion B; Under 750r/min high velocity turbulent flow condition, add 50mL liquid paraffin and continue stirring 1 hour formation O/W/O emulsion C; Gather arabogalactan and chitosan with glutaraldehyde cross-linking and 40 DEG C of sizings 6 hours, after cooling curing, divide supernatant liquid paraffin to obtain rough microsphere D with separatory funnel; Molecular cut off is adopted to be that the dialyzer of 8000Da is dialysed thick product D in distilled water; Be the hollow poly-arabogalactan-chitosan compound microsphere E of 1.367um single hole with obtaining average diameter after the rotating speed centrifugalize of 4000r/min, hot wash 3 times, lyophilization.
Embodiment 8
The 1wt% aqueous acetic acid of water soluble drug 5-Fu uracil 2.8mg, poly-arabogalactan 10mg and 1.075g chitosan and 10mL is stirred into transparent mixture and vacuum outgas 2 hours, obtain medicine carrying microballoons slurry A; Add 2.4g tween 80 and 10mL liquid paraffin high-speed stirred 1 hour formation O/W emulsion B; Under 500r/min high velocity turbulent flow condition, add 50mL liquid paraffin and continue stirring 1 hour formation O/W/O emulsion C; Gather arabogalactan and chitosan with glutaraldehyde cross-linking and 40 DEG C of sizings 6 hours, after cooling curing, divide supernatant liquid paraffin to obtain rough microsphere D with separatory funnel; Molecular cut off is adopted to be that the dialyzer of 8000Da is dialysed thick product D in distilled water; Be the hollow poly-arabogalactan-chitosan compound microsphere E of 194.2um single hole with obtaining average diameter after the rotating speed centrifugalize of 4000r/min, hot wash 3 times, lyophilization.
Embodiment 9
According to the hollow poly-arabogalactan-chitosan compound microsphere of the single hole preparing load 5-Fu uracil described in embodiment 1, utilize bovine serum albumin in vitro the hollow poly-arabogalactan-chitosan compound microsphere of simulate blood environmental testing single hole to the sustained release performance of 5-Fu uracil.Be converted into sample concentration value according to standard curve after adopting ultraviolet-uisible spectrophotometer to measure absorbance, calculate the hollow poly-arabogalactan-chitosan compound microsphere of single hole to the envelop rate of 5-Fu uracil and slow release data.Concrete data are in table 1.
The 5-Fu uracil slow release data of the hollow poly-arabogalactan-chitosan compound microsphere of table 1 single hole
Claims (8)
1. the preparation method of poly-arabogalactan-chitosan compound microsphere, it is characterized in that comprising the following steps: water soluble drug, poly-arabogalactan and chitosan are stirred into transparent mixture by 1% acetum of fixed proportion and 10mL and vacuum outgas 2 hours, obtain medicine carrying microballoons slurry A; Medicine carrying microballoons slurry A is mixed with emulsifying agent or compound emulsifying agent, adds a small amount of organic solvent in high-shear impeller, stir 1 hour formation O/W emulsion B; Continue to be added with machine solvent in O/W emulsion B, and high-speed stirred forms O/W/O emulsion C in 1 hour; Connect poly-arabogalactan and chitosan with cross-linking agent and after 6 hours, C emulsion be cooled to room temperature 40 DEG C of sizings; Divide upper strata organic solvent with separatory funnel after emulsion C is left standstill 24 hours, obtain rough microsphere D; Be that the dialyzer of 8000Da is dialysed thick product D in distilled water with molecular cut off, obtain the hollow poly-arabogalactan-chitosan compound microsphere E of single hole with the rotating speed centrifugalize of 4000r/min, hot wash, lyophilization.
2. the preparation method of complex microsphere E according to claim 1, it is characterized in that: poly-arabogalactan and chitosan and acetum are stirred into transparent mixture, adopt and add organic solvent high-speed stirred formation O/W/O emulsion step by step, with cross-linking agent, microsphere slurries dispersant liquid drop is fixed to complex microsphere E.
3. the preparation method of complex microsphere E according to claim 1, is characterized in that: poly-arabogalactan used is larch in Xinanlin area, Yichun larch, larix sibirica a kind of or two kinds and two or more composition mixed material extract; Chitosan adopts the chitosan of deacetylated process to be raw material.
4. the preparation method of complex microsphere E according to claim 1, is characterized in that: organic solvent used is the mixed organic solvents of kerosene, transformer oil, pump oil, gasoline, liquid paraffin a kind of or two kinds and two or more composition.
5. the preparation method of complex microsphere E according to claim 1, is characterized in that: emulsifying agent used or its volume of compound emulsifying agent are 1 ~ 10% of organic solvent.
6. the preparation method of complex microsphere E according to claim 1, is characterized in that: emulsifying agent used or compound emulsifying agent are the compound emulsifying agent of Twin-80, Span-80, oleic acid, dodecyl sodium sulfate, potassium oleate, polyvinyl alcohol, Polyethylene Glycol, cetyl trimethyl ammonium bromide a kind of or two kinds and two or more composition.
7. the preparation method of complex microsphere E according to claim 1, is characterized in that: mixing speed is at 500 ~ 4000r/min.
8. the preparation method of complex microsphere E according to claim 1, it is characterized in that: complex microsphere E is single hole tiny balloon, complex microsphere E particle diameter is 50nm ~ 500um.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114849604A (en) * | 2022-04-12 | 2022-08-05 | 中怡(深圳)医疗科技集团有限公司 | Preparation method of single-hole microspheres |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102641245A (en) * | 2011-11-02 | 2012-08-22 | 中国科学院过程工程研究所 | Chitosan-chitosan derivative nanosphere for loading indissoluble medicament, preparation method of nanosphere, and application of nanosphere serving as oral prepration |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102641245A (en) * | 2011-11-02 | 2012-08-22 | 中国科学院过程工程研究所 | Chitosan-chitosan derivative nanosphere for loading indissoluble medicament, preparation method of nanosphere, and application of nanosphere serving as oral prepration |
Non-Patent Citations (2)
| Title |
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| 杨建平等: "单分散壳聚糖微囊的制备与表征", 《化学研究与应用》 * |
| 王玮等: "不同方法制备壳聚糖微囊形成机理初探", 《河南大学学报（医学版）》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114849604A (en) * | 2022-04-12 | 2022-08-05 | 中怡(深圳)医疗科技集团有限公司 | Preparation method of single-hole microspheres |
| CN114849604B (en) * | 2022-04-12 | 2023-08-18 | 中怡(深圳)医疗科技集团有限公司 | Preparation method of single-hole microsphere |
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