CN1485094A - Natural porous polymer beads, the preparation and application thereof - Google Patents
Natural porous polymer beads, the preparation and application thereof Download PDFInfo
- Publication number
- CN1485094A CN1485094A CNA021312753A CN02131275A CN1485094A CN 1485094 A CN1485094 A CN 1485094A CN A021312753 A CNA021312753 A CN A021312753A CN 02131275 A CN02131275 A CN 02131275A CN 1485094 A CN1485094 A CN 1485094A
- Authority
- CN
- China
- Prior art keywords
- microsphere
- polymer beads
- porous polymer
- cross
- natural porous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
A biodegradable porous microball of natural high molecular and its preparation method, treatment composition of the microballs and treating agents, the application of the microballs in a drug transmission system carrier floating in the gastral cavity, carrier attached to walls in the course of suspension cultivation of animal cells. The preparation method comprises: dispersing glutin and xanthogene glue into an oil phase, cooling and solidifying, cross-linking, separating, washing, drying and obtaining the natural high molecular porous microball.
Description
Technical field
The present invention relates to a kind of biodegradable natural porous polymer beads, the preparation method of this microsphere, the therapeutic combination that this microsphere and therapeutic agent are formed, and this microsphere is used for the adherent carrier in interior buoyant drug delivery system carrier of gastral cavity and the zooblast suspension culture process.
Background technology
For oral sustained and controlled release medicament transmission system, for the special pH environment that overcomes the gastric emptying time and utilize gastric, exploitation prolongation drug delivery system of the time of staying in gastral cavity is significant.On the one hand, it can prolong those medicines that need work at gastric and mainly in the gastric and the small intestinal upper end time of staying of absorbed medicine in stomach; In addition, for those unstable medicines that easily is decomposed in intestinal environment, and dissolubility is low and medicine that dissolubility is high in gastral cavity also needs to use this drug delivery system in intestinal environment.For example Verapamil HCl (isoptin, verapamil) is a kind of derivant of papaverine, and molecular weight is 491.08Da, and the dissolubility of this medicine and pH value dependency are very obvious.At pH value is 1.2,6.8 and 7.4 o'clock, dissolubility be respectively 150,2.71 and 0.75mg/ml (Streubelet al., 2000, Journal of controlled release 67,101-110).If adopt conventional controlled release form, drug release rate just might take place when medicine is in gastric enters into small intestinal descend, thereby cause the fluctuation of vivo medicine concentration and the problem of bioavailability.In order to guarantee more reliable curative effect of medication, the release time of prolong drug when the low pH value of gastric will be very ideal method.
At present, improve the drug delivery system of medicine and mainly comprise following several in the gastric time of staying: (i) bioadhesive delivery system, that is be attached on mucomembranous surface; (ii) large scale dosage form delivery system, the size that promptly improves dosage form has postponed the time of medicine by pylorus; (iii) density Controlled Release System is promptly controlled the density of pharmaceutical carrier, it can be swum in the stomach fluid (stomach gruel), thereby prolonged medicine passing through the time at gastric.The stagnant drug delivery system of overwhelming majority stomach all is individual unit device (as one floating tablets, a capsules floating etc.), owing to may or can not be drained by disposable emptying, usually all there is the probability (Hwang that too early lost efficacy, S.J.et.al.1998, Crit.Rev.Ther.Drug Carrier Syst.15,243-284).So floating system multiunit, that can all be dispersed in the stomach will be a kind of better selection.In general, the whole volume of individual unit device is bigger, and equivalent diameter reaches Centimeter Level, perhaps tens millimeters levels.And each microgranule or porous microsphere promptly are equivalent to a cell arrangement in the multiple unit system, but particle diameter is very little, have only the millimeter level, and perhaps micron order can be dispersed in the stomach.
Preparing low-density Loaded Microspheres Drug Delivery System, to come the time of staying of prolong drug in gastral cavity will be a kind of very effective method.What at present research was maximum mainly is some synthetic macromolecular material microspheres, as the polypropylene foam microgranule etc.The synthetic macromolecular material microsphere of this class must add reagent such as initiator, cross-linking agent, organic solvent in preparation process, and all there is bio-toxicity in these reagent major parts, and are residual bigger; These reagent and the polymer microsphere major part prepared can not biodegradations in addition, do not possess biocompatibility.
(1996, Journal of controlledrelease 42 25-28) has developed a kind of generation CO to people such as macromolecular material microsphere such as Atyabi
2Multiunit, oral floating system, the ion-exchange resin particles surface that at first will be mounted with carbonate coats the last layer semipermeable membrane.In a single day this granule touches gastric juice, the ion exchange of carbanion and chloride ion will take place and causes CO
2Formation, and gas is covered by in the film, has so just caused the suspension of microgranule.But this effervescent system exists the shortcoming that can not suspend immediately usually, because produce CO
2Gas needs the regular hour.People such as Kawashima (1991,1992, Journal of PharmacySciences 81,135-140; Journal of controlled release 16 279-290) has developed a kind of hollow microsphere (micro-balloon) system.This microsphere surface is coated with one deck enteric polymer (polyacrylic resin), and medicine just is loaded in the outer field polymer shell.Polymer and medicine dissolution in ethanol/dichloromethane solution, are poured into this solution in the poly-vinyl alcohol solution that is stirring then.Ethanol is assigned to outer aqueous phase fast, and polymer is precipitation around the dichloromethane drop.Evaporate the dichloromethane that is included in inside and will form cavity at the micro polymer intragranular.But at this microgranule under stomach fluid pH condition, most of medicine can not fully discharge (Lee, J.H.Journal of Microcapsulation 16,715-729).
It is more to utilize natural polymer to prepare the research of controlled release drug delivery system carrier, be raw material mainly with alginate, starch and derivant thereof, cellulose and derivant thereof, arabic gum, guar gum, hyaluronic acid, chondroitin sulfate, heparin and chitosan etc., make microsphere or microcapsule as pharmaceutical carrier, perhaps make and contain gel medicine, that be used for embedding in vivo.(Chen，Jun?et.al.，Carbohydrate?Polymers?28(1)1995，69-76；Sinha，V.R.et.al.，International?Journal?of?Pharmaceutics224(1-2)，2001，19-38)。This class controlled-release medicament delivery system mainly utilizes polysaccharide carrier slowly corrosion in embedding position or the gastrointestinal tract, degraded in vivo, perhaps carrier is to the restriction of drug diffusion, influence the diffusion coefficient of medicine in carrier, thereby reach the medicine purpose of sustained release in vivo.But up to the present, utilizing natural polymer to prepare porous microsphere does not appear in the newspapers as the research of the pharmaceutical carrier of density Controlled Release System.
Summary of the invention
It is little to the purpose of this invention is to provide a kind of toxicity, biodegradable natural porous polymer beads.
Another object of the present invention provides a kind of method for preparing this natural porous polymer beads.
A further object of the present invention provides this natural porous polymer beads and is used for pharmaceutically suitable carrier as therapeutic agent, and this natural porous polymer beads is as the application of carrier in cell attachment is cultivated.
The objective of the invention is to realize by following mode:
The natural porous polymer beads that the present invention relates to has following characteristic: this microsphere comprises the gelatin of 30%-98% (w/w) and the xanthan gum of 2%-70% (w/w); The particle diameter of described microsphere is 0.1-3mm, and density is 0.2-1.0g/cm
3Density difference, each composition proportion are also different.
Described natural porous polymer beads, preferred gelatin accounts for 70%-95% (w/w), and xanthan gum accounts for 30%-5% (w/w), and surplus is a moisture content.
Described natural porous polymer beads comprises preferably the cross-linking agent of 0.01-5% (w/w), and cross-linking agent can be a kind of or several the share wherein in aldehydes cross-linking agent and the epoxychloropropane.
The preferred glutaraldehyde of aldehydes cross-linking agent, formaldehyde, acetaldehyde and glyceraldehyde.
The method for preparing natural porous polymer beads of the present invention comprises the steps:
(1) mixed solution of preparation gelatin and xanthan gum: a, get avirulent oil as oil phase, add
Heat is to 40 ℃-120 ℃; B, the limit heating edge adds by gelatin and xanthan gum in oil phase
The water of forming; The concentration of the gelatin solution of aqueous phase is 0.5-50% (w/v), Huang
The concentration of former sol solution is 0.1-2% (w/v); Gelatin solution and xanthan gum solution
Volume ratio be 1: 0.1-6; The volume of described oil phase is the volume 4-15 of water
Doubly; C, the temperature of the mixed liquor of oil phase and water is remained between 40-120 ℃,
Stir after 0.1-3 hour, be quickly cooled to again between 0 ℃-15 ℃, rapidly cooling
Make its curing;
(2) solidfied material that step (1) is obtained makes natural height behind-10 ℃～30 ℃ following vacuum dryings
The molecule porous microsphere.
Preferred employing oil phase is mineral oil and vegetable oil, further preferred Oleum Helianthi, Oleum Brassicae campestris, soybean oil, the Semen arachidis hypogaeae wet goods of adopting.
Further preferably also comprise the steps: afterwards solidfied material is continued to stir 0.1-3 hour in step (1), add again that to account for water volume 1-10% (V/V), concentration be that aldehydes or the epoxychloropropane cross-linking agent of 0.01-2M carries out cross-linking reaction, its response time is 0.1-3 hour, then washs cross-linking products.Preferred volatile organic solvent and the deionized water thorough washing cross-linking products of adopting.The preferred petroleum ether of volatile organic solvent, ether, ethanol and isopropyl alcohol etc.
Aldehydes cross-linking agent in the preferred above-mentioned steps is glutaraldehyde, formaldehyde, acetaldehyde, glyceraldehyde.
Key technology of the present invention has these points: the one, and the selection of natural polymer raw material: gelatin is a kind of polymer of natural polypeptides, contains carboxyl and amino in the structure, has thermocoagulation, melts the characteristic of solidifying during cooling during heating.Xanthan gum is a kind of bacterial polysaccharides, contains carboxylic group.Carboxyl generation chemical action in amino on the gelatin chains and the xanthan gum strand, thus make microsphere be stablized.Two of key technology is to determine concentration and the two volume ratio each other of xanthan gum solution and gelatin solution: because this is the prerequisite of preparation porous microsphere.The concentration of the gelatin solution of selecting in the preparation method of the present invention is 0.5-50% (w/v).The concentration of xanthan gum solution is 0.1-2% (w/v), and the volume ratio of gelatin solution and xanthan gum solution is 1: 0.1-6.Three of key technology is to adopt the profit two phase process, and the solidified method of lowering the temperature again of heating up prepares porous microsphere, help the formation of porous microsphere like this, and particle size distribution is more even, has improved anti-poly-property.Four of key technology is the mol ratios by the use amount of regulating gelatin and xanthan gum, can realize the control to the density of the microsphere of preparation.Five of key technology is temperature controlling in preparation process, and temperature is too high during heating, can cause the irreversible denaturation of gelatin, crosses to hang down then can not melt, and is unfavorable for the formation of the chemical action between gelatin and the xanthan gum.The temperature that adopts among the present invention is 40-120 ℃.Six of key technology is to pass through the processing of steps such as cross-linking reaction in preparation process, and the aldehydes cross-linking agent can form schiff bases with the amido reaction on the gelatin chains; And epoxychloropropane can with hydroxyl generation cross-linking reaction, through after the cross-linking reaction, help improving the intensity of microsphere, thereby improve crushing resistance, and can improve the physicochemical properties of microsphere surface simultaneously or introduce new functional group, help further microsphere being carried out modification.In the present invention, the cross-linking agent use amount seldom and can further be removed residual cross-linking agent by last handling process; In preparation process, do not introduce virose organic solvent or reaction reagent in addition; Moreover gelatin and xanthan gum are natural polymer and have good biodegradability and biocompatibility, and have been applied to food, pharmaceuticals industry, so to compare advantage obvious with the carrier that synthesized polymer material is made.
The present invention also provides this natural porous polymer beads to be used for pharmaceutically suitable carrier as therapeutic agent.Therapeutic agent is meant chemical synthetic drug, biological engineering medicine, and the medicinal active ingredient that extracts from organism.As isoptin, theophylline etc.In preparation during medicine carrying microballoons, the two mixed solution of preparation gelatin solution and xanthan gum solution earlier, a certain amount of therapeutic agent of adding and stirring in mixed solution prepares the medicine carrying porous microsphere according to the method for preparing porous microsphere then again.With volatile organic solvent, deionized water thorough washing product, promptly get medicine carrying porous natural polymer microsphere after the drying.The density of medicine carrying microballoons is 0.20-1.0g/cm
3The amount that is encapsulated in the therapeutic agent in microsphere supported will change at the dissolubility of gastric with therapeutic purposes and this medicine that this medicine reaches.
Another purposes of the present invention is that this natural porous polymer beads is as the application of carrier in cell attachment is cultivated.Zooblast can not be cultivated at air agitation reactor inner suspension as microorganism owing to there is not the cell wall protection.Because when using stirred reactor, the shear stress between liquid is destroyed zooblast much larger than the ability to bear of zooblast, even the liquid shear stress of airlift reactor also surpasses and requires.In addition, most of zooblast needs could grow attached to solid or semi-solid surface, and cell is grown on carrier surface and is extended to a monolayer, i.e. adhere-wall culture.Close or the low carrier of density and culture medium so just must be arranged.And this natural porous polymer beads just in time can meet the demands, and on the one hand, density is lower, can satisfy the requirement of suspension; On the other hand, specific surface area is bigger, is fit to cell attachment and cultivates; Moreover microsphere is prepared from by natural polymer, has avoided using multiple organic reagent, the organic solvent of pair cell toxic side effect.The surface of this microsphere has many active groups, can carry out surface modifiedly, makes it meet the requirement of special cells adherent growth.Adopt the low-density microsphere supported cell attachment that carries out to cultivate and to compare, have better mass transfer, pass the performance of oxygen with traditional adhere-wall culture.
The natural porous polymer beads of the present invention's preparation is compared with existing common porous microsphere, and its tangible advantage is: preparation process economy is not high to equipment requirements; The microsphere of preparing has biocompatibility, can biodegradation; Active group is many on the microsphere, is easy to modification, can prepare the microsphere with different surfaces character; The inner porous of the microsphere of preparation, density is low, and according to different technological parameters, density can be regulated; Because microsphere has lower density, can be used as and microsphere supportedly be used for buoyant microsphere drug transmission system in gastral cavity, and the adherent suspension culture carrier of zooblast.
Description of drawings
Fig. 1 amplifies 30 times electromicroscopic photograph for natural porous polymer beads
This figure is an electromicroscopic photograph, and ball is the aperture minute bubbles of microsphere inside, and the scale among the figure is represented 1000 microns.
Fig. 2 amplifies 60 times electromicroscopic photograph for natural porous polymer beads
Fig. 2 is the partial enlarged drawing of Fig. 1, and the scale among the figure is represented 100 microns.
The specific embodiment
Embodiment 1
Get liquid paraffin 100ml, stirring (n=500rpm) heats simultaneously, when temperature rises to 80 ℃, add 10ml 15% (w/v) gelatin solution and the mutually mixed solution of 10ml 1% (w/v) xanthan gum solution, temperature remains between 80-90 ℃, stir after 10 minutes, be quickly cooled to 15 ℃, continue stirring and stop after 10 minutes.With petroleum ether, deionized water thorough washing product, promptly get porous natural polymer microsphere after 30 ℃ of dryings.Microspherulite diameter is 0.95-1.10mm (＞90%), and dispersibility is better, and density is 0.3g/cm
3, gelatin accounts for 93.0% (w/w) in the microsphere, and xanthan gum accounts for 7.0% (w/w).See accompanying drawing 1, Fig. 2.This figure is an electromicroscopic photograph, and ball is the aperture of microsphere inside.
Embodiment 2
Get Oleum Helianthi 400ml, stirring (n=1000rpm) heats simultaneously, when temperature rises to 40 ℃, add 10ml 5% (w/v) gelatin solution and the mutually mixed solution of 40ml 2% (w/v) xanthan gum solution, temperature remains on about 40 ℃, stirs after 80 minutes, is quickly cooled to 10 ℃, continue to stir the glutaraldehyde that adds 1ml 0.025M after 20 minutes, cross-linking reaction stopped after 1.5 hours.With ether, deionized water thorough washing product, after 20 ℃ of dryings, promptly get porous natural polymer microsphere.Recording microsphere density is 0.8g/cm
3, microspherulite diameter is 0.46-0.50mm (＞80%).Gelatin accounts for 38.3% (w/w) in the microsphere, and xanthan gum accounts for 61.5% (w/w), and cross-linking agent accounts for 0.2%.
Embodiment 3
Get Oleum Arachidis hypogaeae semen 300ml, stirring (n=300rpm) heats simultaneously, when temperature rises to 100 ℃, add 10ml 30% (w/v) gelatin solution and the mutually mixed solution of 5ml 1.5% (w/v) xanthan gum solution, temperature remains on about 100 ℃, stir after 40 minutes, be quickly cooled to 5 ℃, continue stirring and stop after 20 minutes.With volatile organic solvent (as petroleum ether, ether, ethanol and isopropyl alcohol etc.), deionized water thorough washing product, again with microsphere (pH=10) crosslinked 2 hours in the epoxychloropropane alkaline solution of 0.01M, use volatile organic solvent, deionized water wash then, after 15 ℃ of dryings, obtain crosslinked porous low-density natural polymer microsphere.Recording microsphere density is 0.5g/cm
3, microspherulite diameter is 2.52-2.84mm (＞95%).Gelatin accounts for 97.0% (w/w) in the microsphere, and xanthan gum accounts for 2.95% (w/w), and all the other are cross-linking agent.
Embodiment 4
Get liquid paraffin 800ml, stirring (n=1000rpm) heats simultaneously, when temperature rises to 60 ℃, add 20ml 20% (w/v) gelatin solution and the mutually mixed solution of 80ml 2% (w/v) xanthan gum solution, temperature remains on about 60 ℃, stirs after 120 minutes, is quickly cooled to 0 ℃, continue to stir the formaldehyde that adds 10ml 0.03M after 50 minutes, cross-linking reaction stopped after 0.2 hour.With volatile organic solvent ethanol, deionized water thorough washing product, promptly get porous natural polymer microsphere after 3 ℃ of dryings.Recording microsphere density is 0.7g/cm
3, microspherulite diameter is 0.15-0.33mm (＞80%).Gelatin accounts for 70.5% (w/w) in the microsphere, and xanthan gum accounts for 28.5% (w/w), and cross-linking agent is 1%.
Embodiment 5
Get Oleum Helianthi 1000ml, stirring (n=800rpm) heats simultaneously, when temperature rises to 90 ℃, add 10ml 40% (w/v) gelatin solution and the mutually mixed solution of 8ml 2% (w/v) xanthan gum solution, temperature remains on about 90 ℃, stir after 200 minutes, be quickly cooled to 2 ℃, continue stirring and stop after 100 minutes.With volatile organic solvent isopropyl alcohol, deionized water thorough washing product, again with microsphere (pH=10) crosslinked 1 hour in the epoxychloropropane alkaline solution of 0.5M, use volatile organic solvent, deionized water wash then, obtain crosslinked porous low-density natural polymer microsphere after 0 ℃ of drying.Recording microsphere density is 0.46g/cm
3, microspherulite diameter is 0.65-0.78mm (＞93%).Gelatin accounts for 94% (w/w) in the microsphere, and xanthan gum accounts for 4.2% (w/w), and all the other are cross-linking agent.
Embodiment 6
Get Oleum Helianthi 300ml, stirring (n=700rpm) heats simultaneously, when temperature rises to 70 ℃, add 10ml 0.5% (w/v) gelatin solution and the mutually mixed solution of 20ml 0.1% (w/v) xanthan gum solution, temperature remains on about 75 ℃, stirs after 60 minutes, is quickly cooled to 10 ℃, continue to stir the glyceraldehyde that adds 10ml 0.04M after 40 minutes, cross-linking reaction stopped after 2 hours.With volatile organic solvent, deionized water thorough washing product, promptly get porous natural polymer microsphere after 7 ℃ of dryings.Recording microsphere density is 0.78g/cm
3, microspherulite diameter is 0.84-0.92mm (＞80%).Gelatin accounts for 70.4% (w/w) in the microsphere, and xanthan gum accounts for 27.2% (w/w), and surplus is a cross-linking agent.
Embodiment 7
Get liquid paraffin 200ml, stirring (n=600rpm) heats simultaneously, when temperature rises to 60 ℃, add 20ml 0.5% (w/v) gelatin solution and the mutually mixed solution of 2ml 2% (w/v) xanthan gum solution, temperature remains on about 65 ℃, stirs after 60 minutes, is quickly cooled to 5 ℃, continue to stir the glutaraldehyde that adds 10ml 0.01M after 30 minutes, cross-linking reaction stopped after 3 hours.With volatile organic solvent, deionized water thorough washing product, promptly get porous natural polymer microsphere after-10 ℃ of dryings.Recording microsphere density is 0.46g/cm
3, microspherulite diameter is 0.58-0.70mm (＞80%).Gelatin accounts for 70.3% (w/w) in the microsphere, and xanthan gum accounts for 28.0% (w/w), and surplus is a cross-linking agent.
Embodiment 8
Get Oleum Arachidis hypogaeae semen 200ml, stirring (n=680rpm) heats simultaneously, when temperature rises to 75 ℃, add 10ml 25% (w/v) gelatin solution and the mutually mixed solution of 20ml 2% (w/v) xanthan gum solution, add theophylline 0.005g and stir in mixed solution, temperature remains on about 75 ℃, stirs after 20 minutes, be quickly cooled to 5 ℃, continue stirring and stop after 20 minutes.With volatile organic solvent, deionized water thorough washing product, promptly get medicine carrying porous natural polymer microsphere after the drying.Recording medicine carrying microballoons density is 0.84g/cm
3, microspherulite diameter is 0.80-0.92mm (＞80%).Gelatin accounts for 86.5% (w/w) in the microsphere, and xanthan gum accounts for 13.5% (w/w).
Embodiment 9
Get Oleum Helianthi 200ml, stirring (n=700rpm) heats simultaneously, preparation 10ml10% (w/v) gelatin solution and the mutually mixed solution of 10ml 2% (w/v) xanthan gum solution, in mixed solution, add Verapamil HCl (isoptin, verapamil) 1.5g and stir, when temperature rises to 70 ℃, add gelatin and the xanthan gum mixed solution that is mixed with medicine again, temperature remains on about 70 ℃, stirs after 50 minutes, is quickly cooled to 12 ℃; Continue to stir the glutaraldehyde that adds 1ml 0.025M after 20 minutes, cross-linking reaction stopped after 0.5 hour.With volatile organic solvent, deionized water thorough washing product, promptly get medicine carrying porous natural polymer microsphere after-5 ℃ of dryings.Recording medicine carrying microballoons density is 0.68g/cm
3, microspherulite diameter is 0.45-0.52mm (＞85%).
Embodiment 10
Get saxol 250ml, stirring (n=600rpm) heats simultaneously, preparation 15ml 20% (w/v) gelatin solution and the mutually mixed solution of 10ml 1.5% (w/v) xanthan gum solution, in mixed solution, add Verapamil HCl (isoptin, verapamil) 1.0g and stir, when temperature rises to 80 ℃, add gelatin and the xanthan gum mixed solution that is mixed with medicine again, temperature remains on about 80 ℃, stirs after 40 minutes, is quickly cooled to 5 ℃; Continue to stir the acetaldehyde that adds 1ml 0.02M after 20 minutes, cross-linking reaction stopped after 2 hours.With volatile organic solvent (as petroleum ether, ether, ethanol and isopropyl alcohol etc.), deionized water thorough washing product, promptly get medicine carrying porous natural polymer microsphere after-8 ℃ of dryings.Recording medicine carrying microballoons density is 0.75g/cm
3, microspherulite diameter is 0.98-1.32mm (＞85%).
Claims (10)
1, a kind of natural porous polymer beads, this microsphere comprise the gelatin of 30%-98% (w/w) and the xanthan gum of 2%-70% (w/w); The particle diameter of described microsphere is 0.1-3mm, and density is 0.2-1.0g/cm
3
2, natural porous polymer beads according to claim 1 is characterized in that: this microsphere comprises the gelatin of 70%-95% (w/w), the xanthan gum of 5%-30% (w/w).
3, natural porous polymer beads according to claim 1 is characterized in that: described microsphere also includes 0.01-5% (w/w) cross-linking agent that accounts for microsphere raw material total amount, and this cross-linking agent is a kind of in aldehydes cross-linking agent or the epoxychloropropane.
4, natural porous polymer beads according to claim 3 is characterized in that: described aldehydes cross-linking agent is selected from glutaraldehyde, formaldehyde, acetaldehyde or glyceraldehyde.
5, a kind of method for preparing the described natural porous polymer beads of claim 1 comprises the steps:
(1) mixed solution of preparation gelatin and xanthan gum: a, get avirulent oil as oil phase,
Be heated to 40 ℃-120 ℃; B, the limit heating edge adds by gelatin and xanthan gum group in oil phase
The water that becomes; The concentration of the gelatin solution of aqueous phase is 0.5-50% (w/v), the xanthan peptization
The concentration of liquid is 0.1-2% (w/v); The volume ratio of gelatin solution and xanthan gum solution
Be 1: 0.1-6; The volume of described oil phase is volume 4-15 a times of water; C, with oil
The temperature of the mixed liquor of phase and water remains between 40-120 ℃, and it is little to stir 0.1-3
The time after, be quickly cooled to again between 0 ℃-15 ℃, rapidly cooling makes its curing;
(2) cured product that step (1) is obtained makes behind-10 ℃～30 ℃ following vacuum dryings
Natural porous polymer beads.
6, the preparation method of natural porous polymer beads according to claim 5, it is characterized in that afterwards in step (1), comprise the steps: that also solidfied material continues to stir 0.1-3 hour, add again that to account for water volume 1-10% (V/V), concentration be that aldehydes or the epoxychloropropane cross-linking agent of 0.01-2M carries out cross-linking reaction, its response time is 0.1-3 hour, then washs cross-linking products.
7, the preparation method of natural porous polymer beads according to claim 6 is characterized in that described aldehydes cross-linking agent is selected from glutaraldehyde, formaldehyde, acetaldehyde or glyceraldehyde.
8, the preparation method of natural porous polymer beads according to claim 5 is characterized in that described oil phase is mineral oil or vegetable oil.
9, the described natural porous polymer beads of a kind of claim 1 is used for the pharmaceutically suitable carrier as therapeutic agent.
10, the described natural porous polymer beads of a kind of claim 1 is as the application of carrier in cell attachment is cultivated.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021312753A CN1197624C (en) | 2002-09-24 | 2002-09-24 | Natural porous polymer beads, the preparation and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021312753A CN1197624C (en) | 2002-09-24 | 2002-09-24 | Natural porous polymer beads, the preparation and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1485094A true CN1485094A (en) | 2004-03-31 |
| CN1197624C CN1197624C (en) | 2005-04-20 |
Family
ID=34144869
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021312753A Expired - Fee Related CN1197624C (en) | 2002-09-24 | 2002-09-24 | Natural porous polymer beads, the preparation and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1197624C (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101879427A (en) * | 2010-06-29 | 2010-11-10 | 南京大学 | Doxorubicin hydrochloride-carrying natural polymer-poly(3-benzene acid acrylamide) composite nanospheres, manufacturing method and application thereof |
| CN104273169A (en) * | 2014-09-19 | 2015-01-14 | 中国检验检疫科学研究院 | Solid chlorine dioxide controlled-release disinfectant and preparation method thereof |
| CN105616348A (en) * | 2016-03-08 | 2016-06-01 | 南通大学附属医院 | Novel adriamycin-loaded nanoscopic drug carrier of collagen-poly (3-acrylamide benzene boric acid) and preparation method of nanoscopic drug carrier |
| CN106721618A (en) * | 2016-12-05 | 2017-05-31 | 陈庆功 | A kind of nutrition crucian carp feed in a balanced way |
| WO2020101461A1 (en) * | 2018-11-13 | 2020-05-22 | 한국화학연구원 | Organoid produced using carrier for cell culture, and method for evaluating drug toxicity using same |
| WO2020101460A1 (en) * | 2018-11-13 | 2020-05-22 | 한국화학연구원 | Carrier for cell culture comprising microcapsules containing natural oil |
| CN116270850A (en) * | 2023-04-20 | 2023-06-23 | 江西大自然制药有限公司 | Wuzi Yanzong oral liquid and preparation method thereof |
| CN116606485A (en) * | 2023-05-12 | 2023-08-18 | 大连工业大学 | Xanthan gum filler, preparation method and application |
-
2002
- 2002-09-24 CN CNB021312753A patent/CN1197624C/en not_active Expired - Fee Related
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101879427A (en) * | 2010-06-29 | 2010-11-10 | 南京大学 | Doxorubicin hydrochloride-carrying natural polymer-poly(3-benzene acid acrylamide) composite nanospheres, manufacturing method and application thereof |
| CN101879427B (en) * | 2010-06-29 | 2013-02-06 | 南京大学 | Doxorubicin hydrochloride-carrying natural polymer-poly(3-benzene acid acrylamide) composite nanospheres, manufacturing method and application thereof |
| CN104273169A (en) * | 2014-09-19 | 2015-01-14 | 中国检验检疫科学研究院 | Solid chlorine dioxide controlled-release disinfectant and preparation method thereof |
| CN105616348A (en) * | 2016-03-08 | 2016-06-01 | 南通大学附属医院 | Novel adriamycin-loaded nanoscopic drug carrier of collagen-poly (3-acrylamide benzene boric acid) and preparation method of nanoscopic drug carrier |
| CN106721618A (en) * | 2016-12-05 | 2017-05-31 | 陈庆功 | A kind of nutrition crucian carp feed in a balanced way |
| WO2020101460A1 (en) * | 2018-11-13 | 2020-05-22 | 한국화학연구원 | Carrier for cell culture comprising microcapsules containing natural oil |
| WO2020101461A1 (en) * | 2018-11-13 | 2020-05-22 | 한국화학연구원 | Organoid produced using carrier for cell culture, and method for evaluating drug toxicity using same |
| CN112771150A (en) * | 2018-11-13 | 2021-05-07 | 韩国化学研究院 | Carrier for cell culture comprising microcapsules containing natural oil |
| CN112771151A (en) * | 2018-11-13 | 2021-05-07 | 韩国化学研究院 | Organoid prepared using cell culture carrier and method for evaluating drug toxicity using the same |
| US20210388313A1 (en) * | 2018-11-13 | 2021-12-16 | Korea Research Institute Of Chemical Technology | Organoid produced using carrier for cell culture, and methold for evaluating drug toxicity using same |
| CN112771150B (en) * | 2018-11-13 | 2023-12-26 | 韩国化学研究院 | Carrier for cell culture comprising natural oil-containing microcapsules |
| CN112771151B (en) * | 2018-11-13 | 2024-01-23 | 韩国化学研究院 | Organoids prepared using cell culture vectors and method for evaluating drug toxicity using the same |
| CN116270850A (en) * | 2023-04-20 | 2023-06-23 | 江西大自然制药有限公司 | Wuzi Yanzong oral liquid and preparation method thereof |
| CN116270850B (en) * | 2023-04-20 | 2024-06-04 | 江西大自然制药有限公司 | Wuzi Yanzong oral liquid and preparation method thereof |
| CN116606485A (en) * | 2023-05-12 | 2023-08-18 | 大连工业大学 | Xanthan gum filler, preparation method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1197624C (en) | 2005-04-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Reis et al. | Review and current status of emulsion/dispersion technology using an internal gelation process for the design of alginate particles | |
| Chakravarty et al. | Using supercritical fluid technology as a green alternative during the preparation of drug delivery systems | |
| Prajapati et al. | Current knowledge on biodegradable microspheres in drug delivery | |
| Matricardi et al. | Recent advances and perspectives on coated alginate microspheres for modified drug delivery | |
| Patil et al. | A review on ionotropic gelation method: novel approach for controlled gastroretentive gelispheres | |
| Malik et al. | Polymeric nanofibers: targeted gastro-retentive drug delivery systems | |
| Shi et al. | Preparation of chitosan/ethylcellulose complex microcapsule and its application in controlled release of Vitamin D2 | |
| Breslauer et al. | Generation of monodisperse silk microspheres prepared with microfluidics | |
| Srivastava et al. | Microsponges: a futuristic approach for oral drug delivery | |
| Della Porta et al. | Supercritical drying of alginate beads for the development of aerogel biomaterials: optimization of process parameters and exchange solvents | |
| CN101601986B (en) | Preparation method of chitosan-silicon dioxide compound hollow microballoon and application thereof | |
| CN107789332B (en) | Calcium carbonate/calcium alginate composite microspheres capable of adjusting drug release rate and prepared based on double-aqueous-phase biomineralization technology | |
| CN101249077A (en) | Preparation of degradable pollutant polyalcohol stephanoporate microballoons and uses thereof | |
| Mehregan Nikoo et al. | Controlling the morphology and material characteristics of electrospray generated calcium alginate microhydrogels | |
| CN107042082B (en) | Non-spherical microcapsule particle and preparation method thereof | |
| US6805879B2 (en) | Stable polymer aqueous/aqueous emulsion system and uses thereof | |
| WO2007144894A1 (en) | Hydrocolloid carrier beads with inert filler material | |
| Okhamafe et al. | Modulation of protein release from chitosan-alginate microcapsules using the pH-sensitive polymer hydroxypropyl methylcellulose acetate succinate | |
| Shilpi et al. | Colloidosomes: an emerging vesicular system in drug delivery | |
| Kunjukunju et al. | Cross-linked enzyme aggregates of alginate lyase: A systematic engineered approach to controlled degradation of alginate hydrogel | |
| Zhou et al. | A novel pulsed drug-delivery system: polyelectrolyte layer-by-layer coating of chitosan–alginate microgels | |
| CN1197624C (en) | Natural porous polymer beads, the preparation and application thereof | |
| CN108743545A (en) | A kind of alginate-drug-carrying nanometer particle-polycation microcapsules and its preparation and application | |
| CN110193007A (en) | A kind of preparation method and applications of pH response type hydrogel | |
| CN107714674A (en) | A kind of preparation method of PLGA microballoons |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050420 |