CN1771913A - Emulifying solvent diffusing process for preparing taste masked micro ball - Google Patents
Emulifying solvent diffusing process for preparing taste masked micro ball Download PDFInfo
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- CN1771913A CN1771913A CN 200510118384 CN200510118384A CN1771913A CN 1771913 A CN1771913 A CN 1771913A CN 200510118384 CN200510118384 CN 200510118384 CN 200510118384 A CN200510118384 A CN 200510118384A CN 1771913 A CN1771913 A CN 1771913A
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Abstract
The present invention is emulsifying solvent diffusing process for preparing taste masked micro ball. After proper high molecular material and medicine are dissolved in mixed solvent with good solvent and bridging agent, micro silica gel powder capable of improving the dispersive state of medicine is added and dispersed homogeneously and the mixture is dropped poor solvent containing certain amount of emulsifier; sub-stable emulsion is formed with medicine-high molecular material-micro silica gel powder-good solvent-bridging agent as internal phase and poor solvent as external phase; the medicine and high molecular material are separated out from the emulsion drop with the diffusion of good solvent to poor solvent and micro ball is formed; and through filtering and drying, taste masked micro ball is obtained. The taste masked micro ball is further into various orally taken preparations with masked bitter and raised compliance.
Description
Technical field
The present invention relates to medical technical field, exactly it is a kind of preparation method for preparing taste-masked microspheres with emulsion solvent diffusion method
Background technology
How effectively to cover the disagreeable taste of medicine, make " good medicine " no longer " earnestly ", be preparation scholars' research topic always.Many medicines itself have hard to bear bitterness, make it in the exploitation of novel form (as oral instant-dissolving tablet, oral cavity quick disintegrating slice, chewable tablet etc.) and clinical use, be subjected to great restriction, be subjected to increasing pharmacy circle personage attention so how effectively to cover bitter taste of drug, the study of pharmacy worker has done a large amount of work to this both at home and abroad.
The method of improving the adverse drug taste at present mainly contains: add correctives, aromatic, be prepared into capsule, tablet or granule are carried out coating, be prepared into microsphere or microcapsule, with enclose such as cyclodextrin, spent ion exchange resin absorption also can be carried out structure of modification to medicine by chemical means, is made into tasteless prodrug.
Summary of the invention
The present invention utilizes emulsion solvent diffusion method to make medicine and macromolecule form microsphere in liquid phase, and medicine bitterness behind the macromolecule parcel obviously improves, and again this microsphere is prepared into oral formulations as raw material by traditional handicraft.
Emulsion solvent diffusion method is a kind of of spherocrystal granulating technique.The spherocrystal pelletize is derived from the eighties in 20th century, and the Kawashima of Gifu, Japan pharmaceutical university has finished salicylic crystallization and separated out and coalescent granulating in a one-step process, has started in liquid phase a step and has finished and separate out crystallization and be gathered into the spherical particulate technology beginning.Because this method equipment simple (only needing the stirring paddle of a rotation rate-controllable), technology easy (step is realized the preparation of macromolecule packaging medicine microsphere in liquid phase), and receive domestic and international expert's concern.Emulsion solvent diffusion method generally needs three solvent systems: good solvent, poor solvent and bridging agent.Preparation during microsphere at first with medicine and macromolecule dissolution in the mixed solvent of good solvent and bridging agent, this mixture is slowly dropped in the poor solvent under the stirring, poor solvent is the aqueous solution that contains the finite concentration emulsifying agent.Because medicine and macromolecule are water insoluble, under the combined effect of emulsifying agent and stirring, are dissolved with medicine and high molecular good solvent in the moment of loose contact solvent, form small emulsion droplet immediately; Along with the solvent diffuse in the emulsion droplet to water, macromolecule and medicine are together separated out curing, under the effect of bridging agent, can keep spherical when the two is separated out, and in the certain proportion scope, macromolecule is packaging medicine fully, thereby effectively covers bitter taste of drug.
Technology of this preparation microsphere is simple, and equipment is not had specific (special) requirements, just can finish medicine and high molecular coprecipitated and coalescent balling-up in a one-step process, is the granulating technique of very valuable and an application prospect.80～nineties of 20th century, this method of usefulness such as Kawashima has successfully prepared the ibuprofen control-release microsphere; This method of employings such as Niwa has prepared the chlorpromazine hydrochloride microcapsule; Cui Fude etc. also are equipped with the solid dispersion slow-release micro-pill of nitrendipine and obtain effect preferably with this legal system.But above research all is to be applied to because granule is bigger, can only be loaded in the capsule in the preparation of slow control-release microsphere, can not tabletting.The grain diameter of the present invention's preparation is below 180 μ m, so can not influence the preparation of preparations such as follow-up tablet.
The present invention is further described below in conjunction with process chart.The medicine of selecting for use comprises that erythromycin, Roxithromycin, ketoprofen, ibuprofen etc. are insoluble in the chemical drugs that water and bitterness are difficult to tolerate.The preparation technology of microsphere as shown in Figure 1.Concrete operations are as follows: in the mixed solvent of good solvent dehydrated alcohol, bridging agent dichloromethane and acetone, the medicine that adds recipe quantity in this organic solvent stirs and makes its dissolving, adds micropowder silica gel again it is uniformly dispersed, as organic facies with macromolecule dissolution; Preparation finite concentration emulsifier aqueous solution is as poor solvent (as 3%PVA solution etc.), and (500-1000rpm) injects poor solvent with organic facies under stirring condition; Stirred for several hour treat the organic solvent diffusion in the microsphere basic fully after, filter, drying makes the medicine microspheres of macromolecule parcel.Prepare its oral formulations by traditional handicraft then.This oral formulations comprises oral cavity quick disintegrating slice, oral instant granule, oral cavity chewable tablet, oral suspensions etc.Microsphere Chinese medicine: macromolecule: micropowder silica gel=1～15: 0.5～60: 0～3); The ratio of all kinds of solvents is: good solvent: the liquid bridging agent: poor solvent=1～10: 0.5～10: 20～300; The scope of application of surfactant concentration is 0.2%～3.0%.Used macromolecular material is Eudragit E udragit E100, Eudragit L100-55, Eudragit L100, EudragitS100, Eudragit RS PO, Eudragit RL100, Eudragit RS100, homemade acrylic resin I～IV number, hydroxypropylmethyl cellulose phthalate HPMCP, ethyl cellulose EC etc., or several mixture arbitrarily wherein; Bridging agent comprises dichloromethane, chloroform, acetone, ethyl acetate, isopropyl acetate etc. or their mixed solvent; Good solvent comprises ethanol, acetone, ethyl acetate, isopropyl alcohol, isopropyl acetate etc. or their mixed solvent; Poor solvent is distilled water and other aqueous medium; Surfactant is poloxamer, tween 80, sucrose fatty acid ester, sodium lauryl sulphate, polyvinyl alcohol, gelatin, arabic gum etc.
After said preparation entered gastrointestinal tract, according to high molecular character, macromolecule corrosion or suction gradually formed the duct and discharges the medicine that wraps up in the microsphere, thereby reaches therapeutic effect.
Description of drawings
Figure 1 shows that the preparation technology of microsphere;
Figure 2 shows that the preparation technology of Roxithromycin granule;
Figure 3 shows that the preparation technology of ketoprofen enteric coated oral cavity disintegration tablet.
The specific embodiment
The preparation of embodiment 1 Roxithromycin granule
Preparation technology sees the Fig. 2 in " Figure of description ".
Eudragit S100 is dissolved in the mixed solvent of good solvent dehydrated alcohol, bridging agent dichloromethane and acetone, wherein Eudragot S100 concentration in dehydrated alcohol is 10～100mg/ml, and the volume ratio of dehydrated alcohol and dichloromethane and acetone is (5～20): (0～8): (0～5).(concentration in ethanol is 5～50mg/ml) to stir and make its dissolving, adds micropowder silica gel again it is uniformly dispersed, as organic facies to add the Roxithromycin of recipe quantity in this organic solvent; Preparation 1～5%PVA aqueous solution is as poor solvent; Under stirring condition (600～900rpm) inject poor solvent with organic facies, stirred for several hour treat the organic solvent diffusion in the microsphere basic fully after, filter, drying makes the Roxithromycin microsphere.Measure microsphere content.Roxithromycin microsphere, milk flavour, erythritol and the aspartame of recipe quantity are sieved and mix homogeneously, PVP (K-30) aqueous solution that adds an amount of concentration (3%～20%) is done binding agent and is prepared soft material, the granulation of sieving, the granulate that sieves after 40 ℃ of dryings gets final product.
The granule of preparation is met the rapid dispersing and dissolving of water, and visible microsphere is dispersity and suspends in water.This granule taste is preferable, and flavor is fragrant, is fit to children taking, can not produce the problem that reduces that absorbs in human body.
The preparation of embodiment 2 ketoprofen enteric coated oral cavity disintegration tablets
Preparation technology sees the Fig. 3 in " Figure of description ".
Eudragit L100-55 is dissolved in the mixed solvent of 95% ethanol and bridging agent ethyl acetate, wherein Eudragit L100-55 concentration in ethanol is 50～200mg/ml, and the volume ratio of 95% ethanol and ethyl acetate is (5～15): (5～8).(concentration in ethanol is 30～100mg/ml) to stir and make its dissolving, as organic facies to add the ketoprofen of recipe quantity in this organic solvent; Preparation 0.1～1.5% aqueous gelatin solution is as poor solvent; Under stirring condition (600～900rpm) inject poor solvent with organic facies, stirred for several hour treat the organic solvent diffusion in the microsphere basic fully after, filter, drying makes ketoprofen enteric coated microsphere.Measure microsphere content.Behind the ketoprofen microsphere of recipe quantity, MCC PH102, crosslinked CMC-Na, lactose, fructose, Fructus Citri Limoniae essence, magnesium stearate mixing, direct compression.The gained tablet is disintegrate rapidly in the oral cavity, does not discharge medicine in simulated gastric fluid in two hours substantially, along with the dissolving of Eudragit L100-55, discharges medicine rapidly in simulated intestinal fluid.
Claims (6)
1, the preparation method for preparing taste-masked microspheres with emulsion solvent diffusion method, in liquid phase, adopt emulsion solvent diffusion method to prepare medicine and the coprecipitated taste-masked microspheres of suitable macromolecule, prepare various peroral dosage forms as crude drug, it is characterized in that: with suitable macromolecule and medicine dissolution in the mixed solvent of good solvent and bridging agent, add the micropowder silica gel that can improve the medicine dispersity again, after treating that it is uniformly dispersed, this mixture slowly is added dropwise in the poor solvent under the stirring, wherein contains certain density emulsifying agent; With medicine-macromolecule-micropowder silica gel-good solvent-bridging agent is inner phase, is that the foreign minister forms metastable Emulsion with the poor solvent; Along with good solvent in the emulsion droplet constantly diffuses in the poor solvent, medicine and macromolecule are together separated out in emulsion droplet, form microsphere together with micropowder silica gel under the bridging action of liquid bridging agent and stirring action, and the microsphere filtration drying is promptly got taste-masked microspheres.
2, according to claim 1ly prepare the preparation method of taste-masked microspheres, it is characterized in that: microsphere Chinese medicine: macromolecule: micropowder silica gel=1～15: 0.5～60: 0～3) with emulsion solvent diffusion method; The ratio of all kinds of solvents is: good solvent: the liquid bridging agent: poor solvent=1～10: 0.5～10: 20～300; The scope of application of surfactant concentration is 0.2%～3.0%.
3, according to claim 1ly prepare the preparation method of taste-masked microspheres with emulsion solvent diffusion method, it is characterized in that: described medicine comprises: erythromycin, Roxithromycin, ketoprofen, ibuprofen etc. are insoluble in water and have the medicine of disagreeable taste.
4, according to claim 1ly prepare the preparation method of taste-masked microspheres with emulsion solvent diffusion method, it is characterized in that: said oral formulations comprises oral cavity quick disintegrating slice, oral instant granule, oral cavity chewable tablet, oral suspensions.
5, the preparation method for preparing taste-masked microspheres with emulsion solvent diffusion method according to claim 1, it is characterized in that: used macromolecular material is Eudragit E udragitE100, Eudragit L100-55, Eudragit L100, Eudragit S100, EudragitRS PO, Eudragit RL100, Eudragit RS100, homemade acrylic resin I～IV number, hydroxypropylmethyl cellulose phthalate HPMCP, ethyl cellulose EC etc., or several mixture arbitrarily wherein; Bridging agent comprises dichloromethane, chloroform, acetone, ethyl acetate, isopropyl acetate etc. or their mixed solvent; Good solvent comprises ethanol, acetone, ethyl acetate, isopropyl alcohol, isopropyl acetate etc. or their mixed solvent; Poor solvent is distilled water and other aqueous medium; Surfactant is poloxamer, tween 80, sucrose fatty acid ester, sodium lauryl sulphate, polyvinyl alcohol, gelatin, arabic gum etc.
6. the purposes for preparing taste-masked microspheres with emulsion solvent diffusion method,, it is characterized in that: the microsphere of emulsion solvent diffusion method preparation as medicine material, is added proper auxiliary materials and prepares various peroral dosage forms.
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| CN 200510118384 CN1771913B (en) | 2005-10-30 | 2005-10-30 | Emulifying solvent diffusing process for preparing taste masked micro ball |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101940554A (en) * | 2010-09-03 | 2011-01-12 | 四川大学 | Multi-core adhesive microspheres for loading water soluble low molecular medicament and preparation method thereof |
| CN102283806A (en) * | 2011-08-25 | 2011-12-21 | 西北农林科技大学 | Roxithromycin nanoemulsion antibacterial drug and preparation method thereof |
| CN103120647A (en) * | 2012-01-10 | 2013-05-29 | 安徽理工大学 | Method for preparing omeprazole sustained-release microspheres by emulsified solvent diffusion method |
| CN115501190A (en) * | 2022-11-10 | 2022-12-23 | 江南大学 | Spirolactone taste-masking dry suspension for children and preparation method thereof |
| CN116077450A (en) * | 2022-12-24 | 2023-05-09 | 东北农业大学 | Mirtazapine taste masking orally disintegrating tablet, and preparation method and application thereof |
| WO2024027794A1 (en) * | 2022-08-05 | 2024-02-08 | 哈尔滨市康隆药业有限责任公司 | Taste-masking microsphere, preparation process therefor, and use thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1159001C (en) * | 1997-10-06 | 2004-07-28 | 沈阳药科大学 | Method of preparing fast-releasing and slowly-releasing solid dispersion micropill in liquid phase |
| KR20100102749A (en) * | 2002-02-22 | 2010-09-24 | 산텐 세이야꾸 가부시키가이샤 | Drug delivery system for the subconjunctival administration of fine grains |
| CN1511510B (en) * | 2002-12-30 | 2010-04-28 | 沈阳药科大学 | High oil-coating type solid micro pill for preparing liquid oily medicine in liquid phase and is preparing method |
-
2005
- 2005-10-30 CN CN 200510118384 patent/CN1771913B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101940554A (en) * | 2010-09-03 | 2011-01-12 | 四川大学 | Multi-core adhesive microspheres for loading water soluble low molecular medicament and preparation method thereof |
| CN102283806A (en) * | 2011-08-25 | 2011-12-21 | 西北农林科技大学 | Roxithromycin nanoemulsion antibacterial drug and preparation method thereof |
| CN103120647A (en) * | 2012-01-10 | 2013-05-29 | 安徽理工大学 | Method for preparing omeprazole sustained-release microspheres by emulsified solvent diffusion method |
| WO2024027794A1 (en) * | 2022-08-05 | 2024-02-08 | 哈尔滨市康隆药业有限责任公司 | Taste-masking microsphere, preparation process therefor, and use thereof |
| CN115501190A (en) * | 2022-11-10 | 2022-12-23 | 江南大学 | Spirolactone taste-masking dry suspension for children and preparation method thereof |
| CN115501190B (en) * | 2022-11-10 | 2024-02-06 | 江南大学 | Spironolactone taste-masking dry suspension for children and preparation method thereof |
| CN116077450A (en) * | 2022-12-24 | 2023-05-09 | 东北农业大学 | Mirtazapine taste masking orally disintegrating tablet, and preparation method and application thereof |
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| CN1771913B (en) | 2011-07-20 |
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