CN1141174C - Membrane emulsifying/internal gelatinizing coupled process for preparing gel beads of calcium alginate - Google Patents
Membrane emulsifying/internal gelatinizing coupled process for preparing gel beads of calcium alginate Download PDFInfo
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- CN1141174C CN1141174C CNB011043652A CN01104365A CN1141174C CN 1141174 C CN1141174 C CN 1141174C CN B011043652 A CNB011043652 A CN B011043652A CN 01104365 A CN01104365 A CN 01104365A CN 1141174 C CN1141174 C CN 1141174C
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Abstract
The present invention relates to a preparation method for gel beads of calcium alginate. In the method, a membrane emulsifying/internal gelatinizing coupling method is adopted; in the coupling method, a water solution of sodium alginate, which comprises insoluble calcium salt, is dispersed by an inorganic membrane to enter atoleine containing a surfactant to be emulsified; then a pH value of a system is decreased to make the insoluble calcium salt separated and release calcium ions, and gelatinization reaction is carried out to generate gel beads of calcium alginate. The gel beads of calcium alginate, which are prepared by the method, and microcapsules formed a covering membrane have controllable granularity within a range from 100 to 1 mum; in addition, the method has the advantages of mild conditions, low energy consumption and easy scale production.
Description
The present invention relates to a kind of method for preparing calcium alginate gel beads.Specifically, be to utilize membrane emulsifying/internal gelatinizing coupled process to prepare calcium alginate gel beads.
Calcium alginate gel beads is that cell commonly used is at present cultivated and the protein immobilization material, especially cover microcapsules that polymer material film (as polylysine and shitosan) forms outward as the immune isolating tool of cell transplantation and the control release vehicle of protein and polypeptide class bioactivator, in biomedical fields fine application prospect.But how to prepare the calcium alginate gel beads that particle diameter is little, particle diameter is controlled in certain limit, particle diameter is evenly distributed (being single dispersion); realize the large-scale production of single dispersion gel pearl; with in preparation process, protect the biological substance activity as far as possible, be still unsolved technical problem all the time.Up to now among Bao Dao the calcium alginate gel beads preparation method, electrostatic method (Hommel M, Sun A M, Goosen M F A.Canadian patent No.1241598,1988) be under electric field action, sodium alginate soln to be pressed through syringe needle to splash in the divalent calcium solion, the calcium alginate gel beads of formation is more even, but particle diameter is bigger, influence distribution in its body during as controlled release carrier, and gel beads productive rate lower (ml/h), can't realize large-scale production; Emulsion process (Wan L S C, Heng P W S, Chan L W.Drug J.Microencapsulation, 1992,9:309～316) second emulsifying in isooctane is prepared good sphericity by sodium alginate and calcium chloride solution, particle diameter is easy to realize large-scale production at the calcium alginate gel beads of 150 μ m, but stirs the activity maintenance that the high shear force that produces is unfavorable for the embedding biological substance; Emulsifying/internal gelling technique (Poncelet D, Lencki R, Beaulieu C et al.I.Methodology.Appl.Microbiol.Biotechnol., 1992,38:39～45, Poncelet D, Poncelet DeSmet B, Beaulieu C et al.II.Physicochemistry.Appl.Microbiol.Biotechnol., 1995,43:644～650) adopt the slightly solubility calcium salt to replace calcium chloride water, an emulsification can be prepared good sphericity, particle diameter is at the calcium alginate gel beads of 200～1000 μ m, but there is the high shear force destruction equally, and gel beads particle diameter wider distribution can't satisfy biomedical sector and keep in using material active and to the requirement of uniform particles.In sum, although existing method all can be prepared the calcium alginate gel beads of good sphericity, it is some or meet basic demand aspect certain two that they only can be in particle diameter, monodispersity and large-scale production.Film emulsifying technology (Muramatsu N, Nakauchi K.J.Microencapsulation, 1998,15 (6): 715～723) be based on the new emulsifying technology of microporous barrier, it can prepare emulsion droplet or the particulate with monodispersity, technical process gentleness, energy consumption is low, is easy to large-scale production.But, do not see the report that this film emulsifying technology is used to prepare calcium alginate gel beads so far as yet.
The purpose of this invention is to provide a kind of method for preparing calcium alginate gel beads, specifically adopt membrane emulsifying/internal gelatinizing coupled process to prepare calcium alginate gel beads.
To achieve these goals, the present invention introduces the calcium alginate gel beads preparation process with the film emulsifying technology, has realized the integrated of film emulsification and internal gelation technology; Select different inoranic membrane (nickel metal film, alumina ceramic membrane and stainless steel membrane etc.), and, realized having the large-scale production of certain particle diameter and the uniform calcium alginate gel beads of particle diameter by controlling diaphragm aperture and distribution and optimizing process operating parameter; Insoluble calcium salts evenly distributes in sodium alginate, has guaranteed calcium salt uniformity in the drop that film disperses to obtain, and can prepare even structure behind the gelation reaction, the calcium alginate gel beads that form is good; Whole technical process has taken into full account the maintenance to the biological substance activity, can satisfy the biomedical sector demands of applications; Microcapsules (as alginate/polylysine microcapsules and the alginate/chitosan microcapsules) particle diameter that calcium alginate gel beads and even overlay film form can be less than 100 μ m.
Specifically, the preparation method of a kind of calcium alginate gel beads of the present invention, it is characterized in that it being to adopt membrane emulsifying/internal gelation coupling process, the sodium alginate aqueous solution that is about to contain the slightly solubility calcium salt disperses to enter emulsification in the atoleine that contains surfactant through film, reduce system pH then and the slightly solubility calcium salt is dissociated discharge calcium ion, the initiated gel reaction generates calcium alginate gel beads.
In the preparation method of the above, it is characterized in that emulsification system is; Sodium alginate 1～3% (w/v) aqueous solution that contains 0.1～2.0g/L slightly solubility calcium salt calcium carbonate is decentralized photo, and the atoleine that contains 0.5～5.0% (v/v) surfactant Span85 or Span80 is a decentralized medium.
Also have, in the preparation method of the above, it is characterized in that the gelation system is: with insoluble calcium salts calcium carbonate is that gelation calcium source is dispersed in the sodium alginate soln, reduces the reaction of emulsification system pH value initiated gel by adding 0.1～0.5% (v/v) glacial acetic acid.
Also have, in the preparation method of the above, it is characterized in that film is the tubular type inoranic membrane, the gel beads particle diameter is 2～10 times of film average pore size.
Also have,, it is characterized in that inoranic membrane is nickel metal film, copper metal film, stainless steel membrane or alumina ceramic membrane in the preparation method of the above.
Also have, in the preparation method of the above, it is characterized in that operating pressure at 0.05～0.30MPa, the decentralized medium flow velocity is in 200～2000ml/min. range regulation.
Preparation method by above-mentioned calcium alginate gel beads of the present invention has following characteristics:
One of 1. inorganic membrane assembly is the control emulsion droplet in the system of the present invention, even the critical component of calcium alginate gel beads quality.Decentralized photo and embedding thing by having the fenestra of certain diameter, had both been realized the preparation of small particle diameter and uniformity drop and gel beads under less pressure effect, avoided in the stirring and emulsifying process high shear force to the destruction of embedding thing again.
2. have agitator in the decentralized photo fluid reservoir in the system of the present invention.When containing embedding thing (as protein and polypeptide class bioactivator) in the decentralized photo, stirring at low speed can guarantee when not destroying the biological substance activity as far as possible that itself and slightly solubility calcium salt particle evenly disperse in sodium alginate soln, thereby reaches good embedding effect.
3. have thermostat in decentralized photo fluid reservoir and the emulsion fluid reservoir in the system of the present invention.According to embedding properties regulation thermostat, can be for keeping the biological substance activity that suitable temperature is provided in whole gel beads preparation process.
4. adopt peristaltic pump to keep the flow regime of decentralized medium in the system of the present invention.Under situation about the embedding microbic activity not being had than havoc, can be for water oil two-phase fully emulsified and drop stable existence suitable decentralized medium flow velocity is provided.
5. in the system of the present invention parameters such as membrane aperture, operating pressure and decentralized medium flow velocity are regulated, can realize the large-scale production of certain particle diameter under the temperate condition and the uniform calcium alginate gel beads of particle diameter.
Reach embodiment with reference to the accompanying drawings and give further instruction technology of the present invention.
Fig. 1 is a film emulsification internal gelation techniqueflow schematic diagram of the present invention;
Membrane emulsifying/internal gelation technique flow process as shown in Figure 1, in thermostat 1 with the sea The suspension of mosanom and slightly solubility calcium salt is decentralized photo, sees through under pressure inoranic membrane 3 holes Be separated into uniform small particle diameter drop, at once by from emulsifying tank 2 through containing that peristaltic pump pumped into Emulsification in the atoleine of surfactant forms water-in-oil type (w/o) emulsion, reduces then System pH is dissociated the slightly solubility calcium salt and is discharged calcium ion, thereby the initiated gel reaction generates the sea The calcium alginate gel pearl.
Embodiment 1
With internal diameter 5.2mm, external diameter 7.0mm, the metallic nickel film of film average pore size 5.3 μ m is installed in the membrane module of Fig. 1 flow process, connect pipeline, in the decentralized photo fluid reservoir, add 1.2% (w/v) sodium alginate soln and 1.5mg/ml calcium carbonate granule, start and mix and keep constant temperature, be forced into 0.05MPa, start peristaltic pump simultaneously, make the atoleine that contains 1.0% (v/v) surfactant Span85 in the decentralized medium fluid reservoir mobile with the speed of 400ml/min., when the decentralized photo volume accounts for emulsion volume 5%, in the emulsion that forms, add the reaction of 0.1% (v/v) glacial acetic acid initiated gel, can prepare particle diameter less (average diameter＜50 μ m) and even, the calcium alginate gel beads of good sphericity.
Embodiment 2
With internal diameter 8.0mm, external diameter 10.0mm, the alumina ceramic membrane of film average pore size 0.6 μ m is installed in the membrane module of Fig. 1 flow process, connect pipeline, in the decentralized photo fluid reservoir, add 1.2% (w/v) sodium alginate soln and 1.5mg/ml calcium carbonate granule, start and mix and keep constant temperature, be forced into 0.15MPa, start peristaltic pump simultaneously, make the atoleine that contains 1.0% (v/v) surfactant Span85 in the decentralized medium fluid reservoir mobile with the speed of 400ml/min., when the decentralized photo volume accounts for emulsion volume 5%, in the emulsion that forms, add the reaction of 0.1% (v/v) glacial acetic acid initiated gel, can prepare particle diameter less (average diameter＜50 μ m) and even, the calcium alginate gel beads of good sphericity.
From the above, preparation method of the present invention has following outstanding advantage.
1. decentralized photo is in uniform suspension state all the time, the calcium alginate gel beads structure of formation Evenly, and guaranteed that the embedding thing is evenly distributed in gel beads.
2. decentralized photo is a gentle process through the inoranic membrane dispersion and emulsion, has avoided the stirring and emulsifying process The high shear force that produces is to the destruction of biological substance activity.
3. the calcium alginate gel beads particle diameter of the drop of film emulsification formation and internal gelation formation is equal One, and particle diameter＜50 μ m.
4. calcium alginate gel beads and even cover film formed Microcapsules Size at 100～1 mu m ranges Controlled.
5. process condition gentleness, energy consumption is low, is easy to large-scale production.
Claims (6)
1. the preparation method of a calcium alginate gel beads, it is characterized in that it being to adopt membrane emulsifying/internal gelation coupling process, the sodium alginate aqueous solution that will contain the slightly solubility calcium salt disperses to enter emulsification in the atoleine that contains surfactant through film, reduce system pH then and the slightly solubility calcium salt is dissociated discharge calcium ion, the initiated gel reaction generates calcium alginate gel beads.
2. according to the described preparation method of claim 1, it is characterized in that emulsification system is: sodium alginate 1～3% (w/v) aqueous solution that contains 0.1～2.0g/L slightly solubility calcium salt calcium carbonate is decentralized photo, and the atoleine that contains 0.5～5.0% (v/v) surfactant Span85 or Span80 is a decentralized medium.
3. according to the described preparation method of claim 1, it is characterized in that the gelation system is: with insoluble calcium salts calcium carbonate is that gelation calcium source is dispersed in the sodium alginate soln, reduces the reaction of emulsification system pH value initiated gel by adding 0.1～0.5% (v/v) glacial acetic acid.
4. according to the described preparation method of claim 1, it is characterized in that film is the tubular type inoranic membrane, the gel beads particle diameter is 2～10 times of film average pore size.
5. according to the described preparation method of claim 1, it is characterized in that inoranic membrane is nickel metal film, copper metal film, stainless steel membrane or alumina ceramic membrane.
6. according to the described preparation method of claim 1, it is characterized in that operating pressure at 0.05～0.30MPa, the decentralized medium flow velocity is in 200～2000ml/min. range regulation.
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| CNB011043652A CN1141174C (en) | 2001-02-28 | 2001-02-28 | Membrane emulsifying/internal gelatinizing coupled process for preparing gel beads of calcium alginate |
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| CN1310954C (en) * | 2003-04-15 | 2007-04-18 | 哈尔滨工程大学 | Preparation method of chromium alginate |
| US8221882B2 (en) * | 2003-06-18 | 2012-07-17 | Asahi Glass Company, Limited | Process and apparatus for producing inorganic spheres |
| CN1319637C (en) * | 2003-10-15 | 2007-06-06 | 中国科学院过程工程研究所 | Chitose microsphere and microcapsule with uniform size and its preparation method |
| CN101239052B (en) * | 2008-03-06 | 2010-10-13 | 浙江中医药大学 | Method for preparing sodium alginate/ chitosan sustained-release microcapsule by external gelation |
| CN103301762A (en) * | 2013-06-04 | 2013-09-18 | 北京中医药大学 | Emulsifying membrane component |
| CN105534951A (en) * | 2016-01-08 | 2016-05-04 | 魏永刚 | Synbiotic microcapsules and preparing method and application thereof |
| CN111481872A (en) * | 2020-05-08 | 2020-08-04 | 嘉兴宇鸣科技有限公司 | Formaldehyde scavenger with visual physical state and preparation method thereof |
| CN113616524B (en) * | 2021-06-07 | 2024-05-14 | 浙江圣兆药物科技股份有限公司 | Device and process for preparing reservoir foam liposome |
| CN116173294A (en) * | 2023-02-13 | 2023-05-30 | 深圳高性能医疗器械国家研究院有限公司 | Microsphere for injection filling and preparation method thereof |
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