CN101885852B - Smooth-surfaced gelatin microsphere and preparation method - Google Patents
Smooth-surfaced gelatin microsphere and preparation method Download PDFInfo
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- CN101885852B CN101885852B CN2010102190695A CN201010219069A CN101885852B CN 101885852 B CN101885852 B CN 101885852B CN 2010102190695 A CN2010102190695 A CN 2010102190695A CN 201010219069 A CN201010219069 A CN 201010219069A CN 101885852 B CN101885852 B CN 101885852B
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Abstract
The invention relates to a smooth-surfaced gelatin microsphere and a preparation method. The preparation method comprises the following preparation steps of: under stirring, uniformly mixing a gelatin aqueous solution with liquid olefin at the temperature of 37-70 DEG C, emulsifying for 5-50 minutes, then mixing the mixed liquid with the liquid olefin at the temperature of minus10-0 DEG C, mechanically stirring, adding 75% (minus18-0 DEG C) of ethanol, stirring, settling for more than 10 minutes, and washing the gelatin microsphere three times through the ethanol (50-100% of ethanol) with gradient concentration to further dehydrate and wash out the liquid olefin remained on the surface of the microsphere; and finally carrying out air drying for a period of time to obtain the gelatin microsphere. The invention has the advantages that the gradient ethanol is used for dehydration after emulsification, and the smooth-surfaced gelatin microsphere is obtained under the condition of not using a surfactant. The invention has simple preparation process, no need of an organic solvent and fewer consumed oil phases, the smooth-surfaced gelatin microsphere can be obtained as long as the gradient ethanol is used for dehydration and other preparation parameters are changed, and a simple and easy method is supplied for efficiently preparing the smooth-surfaced gelatin microsphere.
Description
Technical field
The present invention relates to a kind of smooth-surfaced gelatin microsphere and preparation method.
Background technology
Oil-in-water-type (W/O) mon-galacta method can be used for preparing gelatin microsphere; Wherein water is the aqueous solution of gelatin; Oil phase is generally MO, olive wet goods, with the w/o type emulsion cooling that forms, again with the residual oil of water while eccysis microsphere surface in the displacement gelatin microspheres such as acetone.Gelatin is the hydrolysate of collagen; Its chemical constitution is very similar with collagen; Have excellent biological compatibility, the gelatin microsphere useful as drug carrier that makes also can be used as the pore-creating agent that tissue engineered porous scaffold prepares; The while gelatin microsphere also can carry out in-situ modified to rack surface, is with a wide range of applications in field of tissue engineering technology.
Generally; With emulsification/when solvent-extracted method prepares gelatin microsphere; Need to add tensio-active agent and come dispersion microsphere, be difficult to remove (Esposito E, Cortesi R yet tensio-active agent may residue in the surface of microballoon; Nastruzzi C. " Gelatin microspheres:influence of preparation parameters and thermal treatment on chemico-physical and biopharmaceutical properties "; Biomaterials, 1996,17 (20): 2009-2020).Research afterwards shows, does not add the gelatin microsphere that tensio-active agent also can be prepared better pattern, but in the process of preparation, needs to use a large amount of organic solvent such as acetone, 1; 4-DIOXANE, and mineral oils are in order to obtain ganoid microballoon; Also need further microballoon to be carried out solvent exchange and lyophilize, process is very complicated, little (the Liu XH of relative yield; Won YJ, Ma PX. " Porogen-induced surface modification of nano-fibrous poly (L-lactic acid) scaffolds for tissue engineering ", Biomaterials; 2006,27 (21): 3980-3987; Habraken WJEM; Boerman OC, Wolke JGC, Mikos AG; Et al. " In vitro growth factor release from injectable calcium phosphate cements containing gelatin microspheres "; Journal of biomedical materials research part A, 2009,91A (2): 614-622).
The aqueous solution with gelatin is water; With the whiteruss is oil phase; With acetone dehydration, with emulsification/when solvent-extracted method prepares gelatin microsphere, temperature, stirring velocity when adjusting ratio, the emulsification of concentration, water and the oil phase of gelatin solution respectively; Whether the adding of tensio-active agent Span80 waits parameter, explores the top condition of the ganoid gelatin microsphere of preparation.Under all identical condition of other conditions, explore and to add Span80 whether to the influence of microsphere surface.As shown in Figure 1, add and do not add Span80 and can both obtain the slick gelatin microsphere of part surface, there is the part of gelatin microsphere surface to demonstrate rough phenomenon, whether the adding of instruction card surface-active agent is not the key factor that influences microsphere features smooth surface property.
Have widely application at drug release and tissue engineering bracket aspect preparing with the gelatin microsphere of emulsification/solvent-extracted method preparation.And be bad with the gelatin microsphere smooth surface degree of acetone dehydration method preparation usually, and need tensio-active agent in the process of preparation or need to consume a large amount of organic solvent and oil phase.Be different from and use acetone dehydration method, the present invention to propose a kind of method, and then need not tensio-active agent and further preparing ganoid gelatin microsphere under solvent exchange and the cryodesiccated situation with the gradient ethanol dehydration.
Summary of the invention
The object of the present invention is to provide a kind of smooth-surfaced gelatin microsphere and preparation method.The present invention is through the method with the gradient ethanol dehydration; Need not tensio-active agent and further preparing ganoid gelatin microsphere under solvent exchange and the cryodesiccated situation, for the ganoid gelatin microsphere of efficient production provides a kind of very simple method.
A kind of smooth-surfaced gelatin microsphere provided by the invention is to be feedstock production with gelatin and whiteruss; Concrete steps: stir down aqueous gelatin solution with whiteruss mixes, emulsification, mixed solution again with whiteruss thorough mixing below 0 ℃, adding ethanol; Stir dehydration; Leave standstill, with the washing with alcohol gelatin microsphere of gradient concentration, dry air.The quality of gelatin and whiteruss and volume ratio: 1～20: 50～300 (g/ml).
Said gelatin microsphere smooth surface, rounded, parameters such as the temperature when ratio, the emulsification of concentration, water and oil phase that particle diameter and size distribution can be through the adjustment gelatin solutions, stirring velocity are adjusted arbitrarily.
The step that the preparation method of a kind of smooth-surfaced gelatin microsphere provided by the invention comprises: stir down, 37～70 ℃ of aqueous gelatin solutions and whiteruss mix emulsification 5～50min; Mixed solution mixes with-10～0 ℃ whiteruss again; (500～3000r/min), the ethanol that adds 75%～85% (18 ℃) stirs dehydration to mechanical stirring, leaves standstill more than the 10min; Use the ethanol 50～100% (preferred 85% of gradient concentration respectively; 95%, 100% ethanol) washing gelatin microsphere is with further dehydration and the residual whiteruss of eccysis microsphere surface; After dry air obtains gelatin microsphere after for some time.
Use the gradient ethanol dehydration after the invention has the advantages that emulsification, obtain ganoid gelatin microsphere under the situation without tensio-active agent.The preparation process is simple; Need not organic solvent; And the oil phase that consumes seldom, according to exploring, as long as use the gradient ethanol dehydration; Temperature, stirring velocity when the ratio of concentration, water and the oil phase of change gelatin solution, emulsification, whether the adding of tensio-active agent Span80 waits parameter can obtain ganoid gelatin microsphere.For the ganoid gelatin microsphere of efficient production provides a kind of very simple method.
Description of drawings
(a. adds Span80 to the SEM photo of Fig. 1 gelatin microsphere; B. do not add Span80).
Fig. 2 embodiment 1 method prepares the SEM photo (a) and the size distribution figure (b) of gelatin microsphere.
Fig. 3 embodiment 2 methods prepare the SEM photo (a) and the size distribution figure (b) of gelatin microsphere.
Fig. 4 embodiment 3 methods prepare the SEM photo (a) and the size distribution figure (b) of gelatin microsphere.
Embodiment
Embodiment 1
The gelatin of 10g is dissolved in compound concentration is the solution of 0.4g/ml in 70 ℃ of zero(ppm) water of 25ml; The 150ml whiteruss is added in the 500ml round-bottomed flask, in 70 ℃ of water-baths, keep 60min, make its temperature reach 70 ℃; Under mechanical stirring (3000r/min), aqueous gelatin solution is poured in above-mentioned 70 ℃ of whiterusss into emulsification 15min; Above-mentioned mixing solutions is poured into immediately in the 100ml whiteruss of precooling (10～0 ℃ cryosel is bathed); Stirring is cooled to below 0 ℃ after (60min); To wherein adding 100ml 75% ethanol (18 ℃), stir dehydration 60min, stirring stops to leave standstill 10min and obtains gelatin microsphere in beaker bottom; Wash three times (15min/ time) to remove residual whiteruss through 85% ethanol, 95% ethanol, each 100ml of 100% ethanol; Dry air obtained gelatin microsphere after 3 days.The SEM photo (a) and the size distribution figure (b) of gained gelatin microsphere are as shown in Figure 2.
Embodiment 2
The gelatin of 20g is dissolved in compound concentration is the solution of 0.4g/ml in 70 ℃ of zero(ppm) water of 50ml; The 300ml whiteruss is added in the 500ml round-bottomed flask, in 70 ℃ of water-baths, keep 60min, make its temperature reach 70 ℃; Under mechanical stirring (3000r/min), aqueous gelatin solution is poured in above-mentioned 70 ℃ of whiterusss into emulsification 15min; Above-mentioned mixed solution is poured in the beaker that is put in advance in the cryosel bath (10～0 ℃); Stirring is cooled to below 0 ℃ after (60min); To wherein adding 200ml75% ethanol (18 ℃), stir dehydration 60min, stirring stops back 10min and obtains gelatin microsphere in beaker bottom; Wash three times (15min/ time) to remove residual whiteruss through 85% ethanol, 95% ethanol, each 200ml of 100% ethanol; Dry air obtained gelatin microsphere after 3 days.The SEM photo (a) and the size distribution figure (b) of gained gelatin microsphere are as shown in Figure 3.
Embodiment 3
The gelatin of 3g is dissolved in compound concentration is the solution of 0.15g/ml in 37 ℃ of zero(ppm) water of 20ml; The 200ml whiteruss is added in the 500ml round-bottomed flask, in 37 ℃ of water-baths, keep 60min, make its temperature reach 37 ℃; Under mechanical stirring (3000r/min), aqueous gelatin solution is added dropwise in 37 ℃ of whiterusss emulsification 15min; Pour in the above-mentioned mixing solutions 100ml whiteruss of precooling (10～0 ℃ cryosel is bathed) into solidified microsphere immediately; Be cooled to below 0 ℃ after (60min) etc. above-mentioned mixed solution, add 100ml 85% ethanol (18 ℃), stir the 60min dehydration, stir and stop back 10min and obtain gelatin microsphere in beaker bottom; Wash three times (15min/ time) to remove residual whiteruss through 90% ethanol, 95% ethanol, each 100ml of 100% ethanol; Dry air obtained gelatin microsphere after 3 days.The SEM photo (a) and the size distribution figure (b) of gained gelatin microsphere are as shown in Figure 4.
More than three kinds of methods can both obtain ganoid gelatin microsphere, adjust different preparation parameters, can obtain the gelatin microsphere of different-grain diameter and size distribution.The size distribution figure of microballoon obtains through the particle diameter with at least 200 microballoons in the SEM photo of Photoshop measurement gelatin microsphere.
Claims (3)
1. smooth-surfaced gelatin microsphere is characterized in that it is is feedstock production with gelatin and whiteruss, concrete steps: stir down; 37～70 ℃ of aqueous gelatin solutions and whiteruss mix, and emulsification 5～50min, mixed solution mix with-10～0 ℃ whiteruss again; Mechanical stirring, 75%～85% the ethanol that adds-18 ℃ stirs dehydration 60min, leaves standstill more than the 10min; Use the washing with alcohol gelatin microsphere of gradient concentration 50%～100% respectively, after dry air;
The quality of described gelatin and whiteruss and volume ratio: 1～20: 50～300, g/ml.
2. smooth-surfaced gelatin microsphere according to claim 1 is characterized in that the ethanol of described gradient concentration is: 85%, 95%, 100%.
3. smooth-surfaced gelatin microsphere according to claim 1 is characterized in that described stirring velocity is 500～3000r/min.
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| CN102475684B (en) * | 2010-11-23 | 2016-03-16 | 常州善美药物研究开发中心有限公司 | A kind of medicinal gelatin microspheres and preparation method thereof |
| CN105801899B (en) * | 2016-03-16 | 2019-02-22 | 杭州同净环境科技有限公司 | A kind of preparation method of porous gelatin nanosphere |
| CN107007875B (en) * | 2017-03-29 | 2020-09-22 | 中国人民解放军军事医学科学院野战输血研究所 | Enzyme and temperature dual-responsiveness drug-loaded hydrogel and preparation method and application thereof |
| CN107082893A (en) * | 2017-05-08 | 2017-08-22 | 广州赛莱拉干细胞科技股份有限公司 | A kind of gelatine microsphere and preparation method thereof |
| CN107296282A (en) * | 2017-06-08 | 2017-10-27 | 安徽全康药业有限公司 | A kind of preparation method of ferro-calcium-zinc-selenium multivitamin |
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