CN1481782A - Emulsifying method for preparing emulsion and associated suspension and particles - Google Patents
Emulsifying method for preparing emulsion and associated suspension and particles Download PDFInfo
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- CN1481782A CN1481782A CNA031304486A CN03130448A CN1481782A CN 1481782 A CN1481782 A CN 1481782A CN A031304486 A CNA031304486 A CN A031304486A CN 03130448 A CN03130448 A CN 03130448A CN 1481782 A CN1481782 A CN 1481782A
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Abstract
The present invention is the emulsifying method of preparing emulsion, relevant suspension and grain. In the preparation of the present invention, water solution of PVA, etc. is used as water phase, and the mixture of dichloromethane, medicine and resin is used as the oil phase. The present invention features that after the oil phase is added into outer water phase to form initial homogeneous slurry, the initial slurry is added into water or water phase solution with emulsifier the same as that in the initial slurry to prepare emulsion; and when the oil phase of the emulsion contains resin and medicine, suspension system and micron level grain may be further prepared. The emulsion of the present invention has high stability, controllable liquid drop size, less adhesion and less damage; and the suspension and the separated solid phase grain has less adhesion and homogeneous and controllable grain size. The present invention is used in slow and controlled release of medicine.
Description
Technical field:
The present invention relates to a kind of preparation emulsion and relevant suspension and particulate emulsification method, belong to the preparation method of liquid liquid, liquid-solid mixed system and Related product thereof.
Background technology:
Based on emulsion preparation technology--the agent-in-water method of hydrophilic emulsifier, be meant a certain amount of emulsifying agent is soluble in the aqueous phase that then oil phase is added emulsifier aqueous solution, homogenate forms the method for emulsion.This method extensively applies to prepare oil-in-water and oil-in-water bag solid emulsification system, also is the important step that two-step emulsification method prepares the W/O/W multiple emulsion.The main deficiency of agent-in-water method is that the stability of emulsion of preparing is relatively poor, and is especially when the emulsifying agent that adopts between the polyvinyl alcohol equimolecular more easily by hydrogen bonded, inter-adhesive between the drop, causes emulsion that flocculation or coalescent and breakdown of emulsion finally takes place takes place; Simultaneously, because stability problem, also make the method prepare the emulsion that various drops are required size: to certain profit system with same profit system, when emulsion droplet is specific dimensions, keep emulsion-stabilizing to need in the suitable scope of being controlled at of emulsifier concentration and oil-water ratio, and the emulsion that the preparation emulsion droplet reaches this size also need be selected specific emulsifier concentration and oil-water ratio numerical value for use, and such oil-water ratio and emulsifier concentration may be unfavorable for the stable of emulsion; Prepare in the overall process of emulsion at agent-in-water method, emulsifier concentration of selecting for use and oil-water ratio can only be certain certain value, often can't not only satisfy emulsion droplet and reach required size but also satisfy the comparatively stable requirement of emulsion.Therefore, can't prepare multiple emulsion droplet is the simultaneously comparatively stable again emulsion of specific dimensions.
Adopt the emulsion of agent-in-water method preparation, also can further solidify the oil phase drop, preparation suspension system by solvent extraction method; This suspension by filtering or centrifugalize, can prepare fine particle again, is used for the fields such as Bao Zaiyu sustained release of medicine.The shortcoming of agent-in-water method supending and fine particle is that the grain diameter controllability is relatively poor, and adhesion is comparatively serious between granule.
Summary of the invention:
The object of the present invention is to provide a kind of preparation emulsion and relevant suspension and particulate emulsifying technology, the emulsion adhesion that this method makes, breakdown of emulsion not; By it can make further that particle diameter is controlled, adhesion, as the microgranule and the suspension system of controlled drug delivery system.
For achieving the above object, the present invention is achieved through the following technical solutions: to comprise polyvinyl alcohol, polyvinyl pyrrolidone, pluronic, tween, Pan, sodium lauryl sulphate, the aqueous solution of dodecyl sodium sulfate class hydrophilic emulsifier is a water, to comprise ethyl acetate, dichloromethane, normal hexane, vegetable oil, mineral oil, carbon tetrachloride, chloroform and they and medicine, the mixed system of resin is an oil phase, preparation oil-in-water phase system emulsion and relevant suspension and granule, it is characterized in that: the emulsifier aqueous solution that at first with concentration is 0.1%-20% is outer water, the homogenate of 500-18000rpm or 5-100W ultrasonic down, by 1: 2-1: 500 oil-water ratio adding oil phase system forms preliminary homogenate; Preliminary homogenate under the stirring of 100-2000rpm, is added in the entry or adds that (concentration of emulsifying agent is lower than the concentration of emulsifying agent in the preliminary homogenate in this aqueous solution) prepares drop adhesion, the controlled emulsion of particle diameter in the aqueous phase solution that is dissolved with the emulsifying agent identical with preliminary homogenate; When containing resin, medicine in the oil phase system of this emulsion, can adopt solvent extraction method to remove the oil phase solvent to the emulsion of gained, preparation particle adhesion, the controlled suspension system of particle diameter; This suspension is filtered or centrifugalize again, can obtain finely dispersed microgranule.
Above-mentioned oil phase system is pure oil phase solvent, oil-phase solution, oil bag solid suspension system or invert emulsion system.
Above-mentioned macromolecule resin comprises abiotic degradation material such as polystyrene resins, polyacrylamide resinoid (as Eudragit), polyacrylic acid resinoid (as Carbopol), modified cellulose resinoid (as ethyl cellulose), methylmethacrylate and biodegradable resin comprise that poly-'alpha '-hydroxy acids is (as polylactic acid, polyglycolic acid, lactic acid-ethanol copolymer), poly-beta-hydroxy acid (as poly butyric and poly-hydroxypentanoic acid), the interlinkage polyester (is handed over fat as poly-third, poly-glycolide, glycolide-third is handed over resin copolymer, poly-own lactone), paracyanogen base acrylic acid alkyl fat, poly-ortho acid fat, polyanhydride, polyamino acid.
The invention has the advantages that and adopt this emulsifying technology to prepare emulsion, can obviously improve the stability that adopts the prepared emulsion of the numerous emulsifiers that comprises polyvinyl alcohol, reduce the adhesion of drop in a large number, the emulsion that flocculation causes is destroyed; Can obtain the different multiple stable emulsion of average droplet size with same profit system.The suspension system solid phase particles adhesion that the emulsion that obtains with said method further prepares is less, and particle size is controlled; In addition, adopt this emulsification method and cooperate certain removal of solvents method, can go out the granule and the suspension system thereof of large-size, be applied to the slow release and the sustained release field of medicine with the resins of lower molecular weight.
Description of drawings:
Accompanying drawing 1: the microphotograph of the polylactic acid microgranule that is loaded with Progesterone of the embodiment of the invention 2 preparations;
Accompanying drawing 2: the microphotograph that the bag of the embodiment of the invention 3 preparations carries salicylic lactic acid-ethanol copolymer resin medicine carrying microgranule;
Accompanying drawing 3: the bag of the embodiment of the invention 4 preparations carries the electromicroscopic photograph of the lactic acid-ethanol copolymer resin medicine carrying microgranule of bovine serum albumin.
The specific embodiment:
Embodiment 1: be continuous phase with water, the normal hexane drop is the preparation of the oil-in-water emulsion of decentralized photo
(1) oil water mixture is carried out homogenate, form colostrum: the 10mL normal hexane is added in the polyvinyl pyrrolidone solution of 100mL 1%, adopt ultrasonic generator to emulsion carry out homogenate (ultrasonic 3 times, each 60 seconds, ultrasonic power is 50W), form high oil-water ratio colostrum; (2) colostrum is stirred in dilution, forms stable emulsion: be under the mechanical agitation of 500rpm at rotating speed, the gained emulsion is slowly added in the 800mL deionized water that form the emulsion system of dilution, the emulsion drop size is 10-20 μ m, emulsion is comparatively stable.
Embodiment 2: the oil-in-water legal system is equipped with polylactic acid medicine carrying microgranule and the suspension system thereof that bag carries Progesterone
(1) preparation polylactic acid oil-phase solution: with 0.9g polylactic acid (M
w32,216) and the 0.1g Progesterone be dissolved in the 8mL dichloromethane and form the resin oil-phase solution comprise medicine; (2) prepare preliminary emulsion: this suspension is added 80mL 0.1% polyvinyl alcohol water solution.Adopt homogenizer that the gained mixture is carried out homogenate (mixing speed is 5,000rpm, the homogenize time is 1 minute), preparation oil-in-water emulsion (preliminary emulsion); (3) colostrum is stirred in dilution, and form stable oil-in-water bag solid emulsification system: at rotating speed is under the mechanical agitation of 200rpm, and the gained emulsion is slowly added 2, in the 000mL deionized water, forms the emulsion system of dilution; (4) continue to stir emulsion system, under reduced pressure (0.1atm), the volatile oil phase solvent, solidify the oil phase drop, obtain comprising the particulate suspension system of polylactic acid, gained suspension system is carried out centrifugalize (centrifugal force 400 * g power), isolate suspended particulates, mannitol solution with 50mg gained microgranule adding 25mL 1% carries out lyophilization to the gained system, obtains the microgranule lyophilized powder.
Obtain particulate pattern of medicine carrying and size with observation by light microscope, taking pictures by the Polaroid microscopic camera obtains microphotograph (accompanying drawing 1).By accompanying drawing 1 as seen, freeze-drying particle is that particle diameter is the microsphere of 50-80 μ m, and adhesion is less between microgranule.
Embodiment 3: oil-in-water bag solid process preparation bag carries salicylic lactic acid-ethanol copolymer resin medicine carrying microgranule and suspension system thereof
(1) preparation oil bag solid suspension system: (lactic acid and glycolic segment mol ratio are 75: 25, M with 25.05g lactic acid-ethanol copolymer resin
w10,091) be dissolved in the 32mL dichloromethane and form the resin oil-phase solution, the 2.5g salicylic acid is added the resin oil-phase solution, to the gained mixture ultrasonic five times, each ultrasonic 50 seconds (the ultrasonic generator output is 20W) forms Water-In-Oil poplar acid solid suspension system; (2) homogenate mixture, form colostrum: this suspension is added 320mL 0.2% polyvinyl alcohol water solution, and (mixing speed is 5,000rpm to adopt homogenizer that the gained mixture is carried out homogenate, the homogenize time is 1 minute), preparation oil-in-water bag solid emulsion (preliminary emulsion); (3) colostrum is stirred in dilution, and form stable oil-in-water bag solid emulsion system: at rotating speed is under the mechanical agitation of 250rpm, and gained emulsion is slowly added 8, in the polyvinyl alcohol water solution of 000mL 0.05%, forms the emulsion system of dilution; (4) continue to stir emulsion system, under condition of normal pressure, the volatile oil phase solvent, solidify the oil phase drop, obtain comprising the suspension system of lactic acid-ethanol copolymer medicine carrying microgranule, gained suspension system is carried out centrifugalize (centrifugal force 400 * g power), isolate suspended particulates, mannitol solution with 50mg gained microgranule adding 25mL 1% carries out lyophilization to the gained system, obtains the microgranule lyophilized powder.
Obtain particulate pattern of medicine carrying and size with observation by light microscope, taking pictures by the Polaroid microscopic camera obtains microphotograph (accompanying drawing 2).By accompanying drawing 2 as seen, freeze-drying particle is that particle diameter is the microsphere (each grid is of a size of 12 * 12 μ m) of 30-60 μ m, and adhesion is less between microgranule.
Embodiment 4: the W/O/W legal system is equipped with lactic acid-ethanol copolymer resin medicine carrying microgranule and the suspension system thereof that bag carries bovine serum albumin
(1) preparation water-in-oil emulsion system: (lactic acid and glycolic segment mol ratio are 75: 25, M with lactic acid-ethanol copolymer
w10,091) 25.4312g is dissolved in and forms oil-phase resin solution in the 32mL dichloromethane solution.Bovine serum albumin 300mg is dissolved in the 3mL distilled water, and to the gained mixture ultrasonic five times, each ultrasonic 50 seconds (the ultrasonic generator output is 20W) forms O/w emulsion as oil phase; (2) homogenate mixture forms colostrum: this emulsion is added in 320mL 0.1% polyvinyl alcohol water solution, adopt homogenizer that the gained mixture is carried out homogenate (mixing speed is 5,000rpm, the homogenize time is 2 minutes), preparation W/O/W colostrum; (3) the profit mixed system is stirred in dilution, forms stable W/O/W emulsification system: be under the mechanical agitation of 150rpm at rotating speed, the gained emulsion is slowly added 8, the phosphate buffer solution of 000mL 0.2M pH3.0, the emulsion system of formation dilution; (4) volatile oil phase solvent, obtain medicine carrying microgranule and suspension system thereof: to the gained emulsion, continuation is carried out mechanical agitation with the rotating speed of 150rpm, slowly the volatile oil phase solvent is 3 hours, solidifies drop and forms the suspension system that comprises solid particle, and gained suspension system is carried out centrifugalize (centrifugal force 400 * g power), isolate the medicine carrying microgranule of suspension, mannitol solution with 50mg gained granule adding 25mL 1% carries out lyophilization to the gained system, obtains the microgranule lyophilized powder.
Size and pattern with the sem observation medicine carrying microgranule: medicine carrying microgranule was stacked on the aluminum sample platform metal spraying 90 seconds, under scanning electron microscope, observes then, and photomicrograph.By the microphotograph of accompanying drawing 3 medicine carrying microgranules as seen, freeze-drying particle is that particle diameter is the microsphere of 40-70 μ m, and adhesion is less between microgranule.
Claims (3)
1, a kind of preparation emulsion and relevant suspension and particulate emulsification method, this method is to comprise polyvinyl alcohol, polyvinyl pyrrolidone, pluronic, tween, Pan, sodium lauryl sulphate, the aqueous solution of dodecyl sodium sulfate class hydrophilic emulsifier is a water, to comprise ethyl acetate, dichloromethane, normal hexane, vegetable oil, mineral oil, carbon tetrachloride, chloroform and they and medicine, the mixed system of resin is an oil phase, preparation oil-in-water phase system emulsion and relevant suspension and granule, it is characterized in that: the emulsifier aqueous solution that at first with concentration is 0.1%-20% is outer water, the homogenate of 500-18000rpm or 5-100w ultrasonic down, by 1: 2-1: 500 oil-water ratio adding oil phase system forms preliminary homogenate; Then with preliminary homogenate under the stirring of 100-2000rpm, add in the entry or add in the aqueous phase solution that is dissolved with the emulsifying agent identical (concentration of emulsifying agent is lower than the concentration of emulsifying agent in the preliminary homogenate in this aqueous solution), prepare drop adhesion, the controlled emulsion of particle diameter with preliminary homogenate; When containing resin, medicine in the oil phase system of this emulsion, can adopt solvent extraction method to remove the oil phase solvent to the emulsion of gained, preparation particle adhesion, the controlled suspension system of particle diameter; This suspension is filtered or centrifugal dispersion again, can obtain finely dispersed microgranule.
2, by the described preparation emulsion of claim 1 and relevant suspension and particulate emulsification method, it is characterized in that: the oil phase system is pure oil phase solvent, or oil-phase solution, oil bag solid suspension system or invert emulsion system.
3, by the described preparation emulsion of claim 1 and relevant suspension and particulate emulsification method, it is characterized in that: macromolecule resin comprises abiotic degradation material such as polystyrene resins, the polyacrylamide resinoid, the polyacrylic acid resinoid, the modified cellulose resinoid comprises ethyl cellulose, the poly-'alpha '-hydroxy acids of methylmethacrylate and biodegradable resin comprises as polylactic acid, polyglycolic acid, lactic acid-ethanol copolymer, poly-beta-hydroxy acid comprises poly butyric and poly-hydroxypentanoic acid, the interlinkage polyester comprises that poly-third hands over fat, poly-glycolide, glycolide-third is handed over resin copolymer, poly-own lactone, paracyanogen base acrylic acid alkyl fat, poly-ortho acid fat, polyanhydride, polyamino acid.
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| CN 03130448 CN1241547C (en) | 2003-07-24 | 2003-07-24 | Emulsifying method for preparing emulsion and associated suspension and particles |
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| CN1241547C CN1241547C (en) | 2006-02-15 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106731925A (en) * | 2017-01-06 | 2017-05-31 | 宁波大学 | Solid phase dispersion co-emulsifier method |
| CN109121392A (en) * | 2017-04-13 | 2019-01-01 | 株式会社Adhome | Utilize the preparation method of the vegetable oil lotion of ultrasonication |
| CN110799178A (en) * | 2017-04-19 | 2020-02-14 | 纳诺米有限公司 | Method and system for producing particles of a substantially monodisperse substance |
-
2003
- 2003-07-24 CN CN 03130448 patent/CN1241547C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106731925A (en) * | 2017-01-06 | 2017-05-31 | 宁波大学 | Solid phase dispersion co-emulsifier method |
| CN109121392A (en) * | 2017-04-13 | 2019-01-01 | 株式会社Adhome | Utilize the preparation method of the vegetable oil lotion of ultrasonication |
| CN109121392B (en) * | 2017-04-13 | 2021-08-24 | 株式会社Adhome | Method for preparing vegetable oil emulsion by ultrasonic treatment |
| CN110799178A (en) * | 2017-04-19 | 2020-02-14 | 纳诺米有限公司 | Method and system for producing particles of a substantially monodisperse substance |
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| CN1241547C (en) | 2006-02-15 |
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