CN102600076B - Ciclosporin A solid self-microemulsion particle and preparation method thereof - Google Patents
Ciclosporin A solid self-microemulsion particle and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to medical art, exactly it is a kind of ciclosporin A solid self-microemulsion particle and preparation method thereof.It is characterized in that: utilize spherocrystal granulating technique, ciclosporin A self-microemulsion is joined macromolecular material, dispersible carrier, porogen dissolve and form the even suspension solution of macromolecular material in a solvent, join in the poor solvent containing surfactant, a step obtains ciclosporin A solid self-microemulsion particle in the liquid phase.Ciclosporin A solid self-microemulsion weight consists of: ciclosporin A: 0.25 ~ 1.5, polyoxyethylene hydrogenated Oleum Ricini: 4.0, caprylic capric triglyceride: 2.0, propylene glycol: 2.0, ethanol: 1.0, dichloromethane 4.0, ethyl cellulose (or Eudragit? RS100, RS100) 0.5 ~ 1.1g, PEG4000? 0.05, micropowder silica gel 0.5.
Description
One, technical field
The invention belongs to medical art, relate to a kind of preparation method of pharmaceutical preparation, exactly it is a kind of ciclosporin A solid self-microemulsion particle and preparation method thereof.Specifically one in the liquid phase a step obtain ciclosporin A solid self-microemulsion particle.
Two, background technology
Ciclosporin A is a kind of potent immunosuppressant, has now been widely used in the anti-rejectiones of organ transplant patients such as liver, kidney, lung, bone marrow, pancreas and autoimmune disease as the treatment of the disease such as psoriasis, rheumatoid arthritis.Ciclosporin A has larger molecular weight (1202.6), strong lipotropy (lgP=2.92) and low aqueous solubility (37 DEG C, 1.73 μ g/ml), and highly rely on bile absorption, and there is gastrointestinal tract effect widely, thus oral absorption is poor, and bioavailability is low, individual variation is large, limits its extensive use clinically.The dosage form of current listing is soft capsule, oral liquid and injection, and medicine is met water generation self emulsifying in vivo and formed microemulsion, improves the problem that the bioavailability individual variation that is low and patient of medicine is large.After commercial preparation sandimmun neoral (Neoral) oral chance gastro-intestinal Fluid can automatic emulsified one-tenth about 30nm microemulsion, improve CyA oral administration biaavailability low, the shortcoming that pharmacokinetic variability is large, but a series of biology and physiology's side effect can be caused containing a large amount of solubilizing agent CremophorEL in self-microemulsion, as nephrotoxicity, anaphylaxis, hyperlipidemia, erythrocyte gathering etc., and the high and problem that later stage drug level is low of short-term drug level after confirming easily to occur taking medicine according to therapeutic drug monitoring.
Due to the oil phase that contains in self-microemulsion and surfactant viscosity large, spraying dry yield is low; Lyophilization rule has certain requirement to instrument and equipment, and cost is high, produces complicated; General carrier absorption method generally needs to add a large amount of vehicle excipients, and obtained pressed powder drug loading is lower and viscosity is comparatively large, is difficult to process etc.This seminar intends the new way that exploration spherocrystal granulating technique prepares Solid Self-microemulsion, is showed no the report relating to spherocrystal granulating technique and prepare Solid Self-microemulsion in current document and patent.
Ciclosporin A being made Solid Self-microemulsion preparation can make medicine steadily discharge slowly, and after avoiding taking medicine, blood drug level is too high and cause serious Liver and kidney toxicity, liquid alcohol also can be avoided the impact of soft capsule shell, improve oral administration biaavailability, improve curative effect.
Three, summary of the invention
The object of the invention is the deficiency for existing preparation, ciclosporin A being made Solid Self-microemulsion preparation can make medicine steadily discharge slowly, after avoiding taking medicine, blood drug level is too high and cause serious Liver and kidney toxicity, also liquid alcohol can be avoided the impact of soft capsule shell, improve oral administration biaavailability, improve curative effect, solidification self-microemulsion is conveniently stored and carries.
The object of the invention is to realize according to following scheme
The preparation of ciclosporin A solid self-microemulsion utilizes spherocrystal granulating technique, by macromolecule blocker, porogen dissolves the even suspension solution forming macromolecular material in a solvent, under the condition stirred, add in the aqueous solutions such as the appropriate poor solvent containing certain surface activating agent, stir through appropriate time, supplement suitable quantity of water, continue to stir amount of time, good solvent and bridging agent be phase counterdiffusion in water, emulsion droplet solidifies, form microspheres with solid, dry under room temperature, collect, associating dispersible carrier is cured ciclosporin A self-microemulsion, thus prepare ciclosporin A solid self-microemulsion particle.
Wherein ciclosporin A solid self-microemulsion, it is characterized in that: utilize spherocrystal granulating technique, ciclosporin A self-microemulsion is joined macromolecular material, dispersible carrier, porogen dissolve and form the even suspension solution of macromolecular material in a solvent, join in the poor solvent containing surfactant, a step obtains ciclosporin A solid self-microemulsion particle in the liquid phase.
Preparation ciclosporin A solid self-microemulsion particle needs three solvent systems and surfactant to form.
Bridging agent: dichloromethane, chloroform;
Good solvent: ethanol, acetone etc. are separately or mixed solvent;
Poor solvent: water and aqueous medium thereof.
Surfactant: sodium lauryl sulphate, polyvinyl alcohol, poloxamer, tween 80 etc.
In ciclosporin A solid self-microemulsion, macromolecular material selection cellulose derivative class is selected from one or more in hypromellose titanate esters, Hydroxypropyl Methyl Cellulose Phthalate, hypromellose, hydroxypropyl cellulose phthalate, ethyl cellulose (10-40cp), preferred, ethyl (10-40cp); Crylic acid resin or cellulose derivative class, wherein crylic acid resin is selected from one or more in acrylic resin, EudragitRL, EudragitRS, EudragitE, EudragitL, EudragitS, preferred acrylic resins EudragitE100, EudragitRS100, EudragitRL100; Porogen selects one or more in PEG4000, PVP, HPMCK4M, lactose, mannitol powder; Dispersible carrier select micropowder silica gel, Pulvis Talci, calcium carbonate, calcium phosphate, magnesium stearate one or more.
Ciclosporin A solid self-microemulsion, it is characterized in that: said composition forms containing the weight of ciclosporin A self-microemulsion raw material: ciclosporin A: 5% ~ 20%, polyoxyethylene hydrogenated Oleum Ricini: 30% ~ 70%, caprylic capric triglyceride: 10% ~ 30%, propylene glycol: 10% ~ 30%, ethanol: 5% ~ 15%.
Ciclosporin A solid self-microemulsion, it is characterized in that: the weight of ciclosporin A solid self-microemulsion raw material consists of: ciclosporin A: 0.25 ~ 1.5, polyoxyethylene hydrogenated Oleum Ricini: 4, caprylic capric triglyceride: 2, propylene glycol: 2, ethanol: 1, dichloromethane 4.0, ethyl cellulose (10-40cp) 0.5g, PEG40000.05g, micropowder silica gel 0.5g.
The weight of ciclosporin A solid self-microemulsion raw material consists of: ciclosporin A: 1, polyoxyethylene hydrogenated Oleum Ricini: 4, caprylic capric triglyceride: 2, propylene glycol: 2, ethanol: 1, dichloromethane 4.0, ethyl cellulose (10cp) 0.5g, PEG40000.05g, micropowder silica gel 0.5g.
Spherocrystal granulating technique prepares ciclosporin A solid self-microemulsion, and its solidification temperature is 25 DEG C ~ 50 DEG C, and rotating speed is 400 ~ 600rpm.The mass fraction of ciclosporin A in Solid Self-microemulsion is 0.05 ~ 0.25.
Add adding of the object porogen of porogen in microsphere preparation process, make the microsphere of preparation with holes, thus better, more absorption ciclosporin A self-microemulsion, while guarantee improves drug loading, the microsphere obtained is had can the characteristic of vertical compression.
The viscosity adding oil phase caprylic capric triglyceride in the object ciclosporin A self-microemulsion of micropowder silica gel and surfactant polyoxyethylene hydrogenated castor oil in adsorption process is very large, and at high temperature easily there is melting, adding carrier material makes medicine better be adsorbed by porous microsphere, effectively improve solids flowability, can be used for directly filling or tabletting.
The ciclosporin A solid self-microemulsion of preparation can form microemulsion in the aqueous solution of 37 DEG C, presents blue-opalescent.
Advantage of the present invention a step can obtain ciclosporin A solidification self-microemulsion in the liquid phase.After said preparation enters gastrointestinal tract, medicine can slowly discharge stably, reduces the serious Liver and kidney toxicity that the quick releasing formulation such as oral liquid and soft capsule produces.Also to avoid in soft capsule alcohol-based liquid on the impact of softgel shell, and drug loading increases greatly, Solid Self-microemulsion, because its mobility is better, can directly incapsulate or direct compression, production cost is low, favorable reproducibility, and yield is high simultaneously.
Accompanying drawing explanation
Fig. 1 observes ciclosporin A solid self-microemulsion particle outward appearance, form taking pictures under being placed in transmission electron microscope
Fig. 2 laser particle size analyzer measures ciclosporin A solid self-microemulsion particle particle diameter and particle size distribution
Detailed description of the invention
Embodiment 1
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: take ciclosporin A 1.0g according to prescription, is dissolved in 1.0ml ethanol, then adds the caprylic capric triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol successively, stirs and obtains ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take 0.5 ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve completely or suspendible, add ciclosporin A self-microemulsion in small beaker, add appropriate micropowder silica gel, slowly be injected in the poor solvent containing 0.08%SDS aqueous solution, it is 25 DEG C that temperature controls, and rotating speed is 400rpm, adds appropriate distilled water after continuous stirring 1h, continue to stir 10min, until solidify completely.Do not occur sticky glutinous to aggregate particle, on sieve, natural drying 12h, sieves and weighs, and particle diameter concentrates on 100 ~ 400 μm.
Obtained ciclosporin A solid self-microemulsion is dissolved in the distilled water of a certain amount of 37 DEG C, after stirring a period of time, solution clear, and have obvious blue-opalescent.By drug release determination method (Chinese Pharmacopoeia version in 2010 two annex XD first methods), with 900ml distilled water for release medium, rotating speed is 50rpm, operates in accordance with the law.The scope of release is that 2h discharges more than 90% of 50% ~ 75%, 12h interior release labelled amount of 20% ~ ~ 50%, 6h interior release labelled amount of labelled amount.
Embodiment 2
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: root takes ciclosporin A 0.50g according to prescription, is dissolved in 1.0ml ethanol, then adds the caprylic capric triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol successively, stirs and obtains ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take 0.5g ethyl cellulose, 0.05gPEG4000 is in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve completely or suspendible, add above-mentioned ciclosporin A self-microemulsion in small beaker, add appropriate micropowder silica gel, slowly be injected in the poor solvent containing 0.08%SDS aqueous solution, it is 25 DEG C that temperature controls, rotating speed is 400rpm, appropriate distilled water is added after continuous stirring 1h, continue to stir 10min, do not occur sticky glutinous to aggregate particle, natural drying 12h on sieve, sieve and weigh, particle diameter concentrates on 100 ~ ~ 400 μm.
Obtained ciclosporin A solid self-microemulsion is dissolved in the distilled water of a certain amount of 37 DEG C, after stirring a period of time, solution clear, and have obvious blue-opalescent.By drug release determination method (Chinese Pharmacopoeia version in 2010 two annex XD first methods), with 900ml distilled water for release medium, rotating speed is 50rpm, operates in accordance with the law.The scope of release is that 2h discharges more than 90% of 50% ~ 75%, 12h interior release labelled amount of 20% ~ 50%, 6h interior release labelled amount of labelled amount.
Embodiment 3
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: take ciclosporin A 0.25g according to prescription, is dissolved in 1.0ml ethanol, then adds the caprylic capric triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol successively, stirs and obtains ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take 0.5mg ethyl cellulose, 0.05gPEG4000 is in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve completely or suspendible, add above-mentioned ciclosporin A self-microemulsion 1.0g in small beaker, add appropriate micropowder silica gel, slowly be injected in the poor solvent containing 1%PVA aqueous solution, it is 25 DEG C that temperature controls, rotating speed is 400rpm, appropriate distilled water is added after continuous stirring 1h, continue to stir 10min, do not occur sticky glutinous to aggregate particle, natural drying 12h on sieve, sieve and weigh, particle diameter concentrates on 100 ~ 400 μm.
Obtained ciclosporin A solid microemulsified slow-releasing preparation is dissolved in the distilled water of a certain amount of 37 DEG C, after stirring a period of time, solution clear, and have obvious blue-opalescent.By drug release determination method (Chinese Pharmacopoeia version in 2010 two annex XD first methods), with 900ml distilled water for release medium, rotating speed is 50rpm, operates in accordance with the law.The scope of release is that 2h discharges more than 90% of 50% ~ 75%, 12h interior release labelled amount of 20% ~ 50%, 6h interior release labelled amount of labelled amount.
Embodiment 4
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: take ciclosporin A 1.25g according to prescription, is dissolved in 1.0ml ethanol, then adds the caprylic capric triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol successively, stirs and obtains ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take 1.0gEudragitRS100, 0.1gPEG4000 is in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve completely or suspendible, add ciclosporin A self-microemulsion in small beaker, add appropriate micropowder silica gel, slowly be injected in the poor solvent containing 0.08%SDS aqueous solution, it is 25 DEG C that temperature controls, rotating speed is 400rpm, appropriate distilled water is added after continuous stirring 1h, continue to stir 10min, do not occur sticky glutinous to aggregate particle, natural drying 12h on sieve, sieve and weigh, particle diameter concentrates on 100 ~ 400 μm.
Obtained ciclosporin A solid self-microemulsion is dissolved in the distilled water of a certain amount of 37 DEG C, after stirring a period of time, solution clear, and have obvious blue-opalescent.By drug release determination method (Chinese Pharmacopoeia version in 2010 two annex XD first methods), with 900ml distilled water for release medium, rotating speed is 50rpm, operates in accordance with the law.The scope of release is that 2h discharges more than 90% of 50% ~ 75%, 12h interior release labelled amount of 20% ~ 50%, 6h interior release labelled amount of labelled amount.
Embodiment 5
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: take ciclosporin A 1.0g according to prescription, is dissolved in 1.0ml ethanol, then adds the caprylic capric triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol successively, stirs and obtains ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take 0.5gEudragitRL100, 0.05gHPMCK4M is in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve completely or suspendible, add above-mentioned ciclosporin A self-microemulsion in small beaker, add appropriate micropowder silica gel, slowly be injected in the poor solvent containing 0.08%SDS aqueous solution, it is 25 DEG C that temperature controls, rotating speed is 400rpm, appropriate distilled water is added after continuous stirring 1h, continue to stir 10min, do not occur sticky glutinous to aggregate particle, natural drying 12h on sieve, sieve and weigh, particle diameter concentrates on 100 ~ 400 μm.
Obtained ciclosporin A solid self-microemulsion is dissolved in the distilled water of a certain amount of 37 DEG C, after stirring a period of time, solution clear, and have obvious blue-opalescent.By drug release determination method (Chinese Pharmacopoeia version in 2010 two annex XD first methods), with 900ml distilled water for release medium, rotating speed is 50rpm, operates in accordance with the law.The scope of release is that 2h discharges more than 90% of 50% ~ 75%, 12h interior release labelled amount of 20% ~ 50%, 6h interior release labelled amount of labelled amount.
Embodiment 6
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: take ciclosporin A 2.0g according to prescription, is dissolved in 1.0ml ethanol, then adds the caprylic capric triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol successively, stirs and obtains ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take 1.1gEudragitRS100, 0.05gHPMCK4M is in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve completely or suspendible, above-mentioned ciclosporin A self-microemulsion is in small beaker, add appropriate micropowder silica gel, slowly be injected in the poor solvent containing 0.08%SDS aqueous solution, it is 25 DEG C that temperature controls, rotating speed is 400rpm, appropriate distilled water is added after continuous stirring 1h, continue to stir 10min, do not occur sticky glutinous to aggregate particle, natural drying 12h on sieve, sieve and weigh, particle diameter concentrates on 100 ~ 400 μm.
Obtained ciclosporin A solid microemulsified slow-releasing preparation is dissolved in the distilled water of a certain amount of 37 DEG C, after stirring a period of time, solution clear, and have obvious blue-opalescent.By drug release determination method (Chinese Pharmacopoeia version in 2010 two annex XD first methods), with 900ml distilled water for release medium, rotating speed is 50rpm, operates in accordance with the law.The scope of release is that 2h discharges more than 90% of 50% ~ 75%, 12h interior release labelled amount of 20% ~ 50%, 6h interior release labelled amount of labelled amount.
Claims (6)
1. a ciclosporin A solid self-microemulsion, its prescription: ciclosporin A 1.0g; Caprylic capric triglyceride 2.0g; Polyoxyethylene hydrogenated Oleum Ricini 4.0g; Ethanol 1.0ml; Propylene glycol 2.0g; Acetone 2.0ml; Dichloromethane 4.0ml; Ethyl cellulose 10cp0.5g; PEG40000.05g; Micropowder silica gel 0.05g; 0.08%SDS aqueous solution 125ml; Preparation technology is: the 1) preparation of ciclosporin A self-microemulsion: take ciclosporin A 1.0g according to prescription, be dissolved in 1.0ml ethanol, add the caprylic capric triglyceride of recipe quantity, polyoxyethylene hydrogenated Oleum Ricini and propylene glycol more successively, stir and obtain ciclosporin A self-microemulsion; 2) preparation of ciclosporin A solid self-microemulsion: take 0.5g ethyl cellulose 10cp, 0.05gPEG4000 in small beaker, add acetone 2.0ml and dichloromethane 4.0ml, make it to dissolve completely or suspendible, add ciclosporin A self-microemulsion in small beaker, add appropriate micropowder silica gel, slowly be injected in the poor solvent containing 0.08%SD8 aqueous solution, it is 25 DEG C that temperature controls, and rotating speed is 400rpm, adds appropriate distilled water after continuous stirring 1h, continue to stir 10min, until solidify completely; Do not occur sticky glutinous to aggregate particle, on sieve, natural drying 12h, sieves and weighs, and particle diameter concentrates on 100 ~ 400 μm.
2. a ciclosporin A solid self-microemulsion, its prescription: ciclosporin A 0.50g, caprylic capric triglyceride 2.0g, polyoxyethylene hydrogenated Oleum Ricini 4.0g, ethanol 1.0ml, propylene glycol 2.0g, acetone 2.0ml, chloroform 4.0ml, ethyl cellulose 20cp0.5g, PEG40000.05g, micropowder silica gel 0.5g, 0.08%SDS aqueous solution 125ml, preparation technology is: the 1) preparation of ciclosporin A self-microemulsion: take ciclosporin A 0.50g according to prescription, be dissolved in 1.0ml ethanol, add the caprylic capric triglyceride of recipe quantity, polyoxyethylene hydrogenated Oleum Ricini and propylene glycol more successively, stir and obtain ciclosporin A self-microemulsion, 2) preparation of ciclosporin A solid self-microemulsion: take 0.5g ethyl cellulose 20cp, 0.05gPEG4000 is in small beaker, add acetone 2.0ml and chloroform 4.0ml, make it to dissolve completely or suspendible, add above-mentioned ciclosporin A self-microemulsion in small beaker, add appropriate micropowder silica gel, slowly be injected in the poor solvent containing 0.08%SDS aqueous solution, it is 25 DEG C that temperature controls, rotating speed is 400rpm, appropriate distilled water is added after continuous stirring 1h, continue to stir 10min, do not occur sticky glutinous to aggregate particle, natural drying 12h on sieve, sieve and weigh, particle diameter concentrates on 100 ~ 400 μm.
3. a ciclosporin A solid self-microemulsion, its prescription: ciclosporin A 0.25g, caprylic capric triglyceride 2.0g, polyoxyethylene hydrogenated Oleum Ricini 4.0g, ethanol 1.0ml, propylene glycol 2.0g, acetone 2.0ml, dichloromethane 4.0ml, ethyl cellulose 40cp0.5g, PEG40000.05g, micropowder silica gel 0.5g, 1%PVA aqueous solution 125ml, preparation technology: the 1) preparation of ciclosporin A self-microemulsion: take ciclosporin A 0.25g according to prescription, be dissolved in 1.0ml ethanol, add the caprylic capric triglyceride of recipe quantity, polyoxyethylene hydrogenated Oleum Ricini and propylene glycol more successively, stir and obtain ciclosporin A self-microemulsion, 2) preparation of ciclosporin A solid self-microemulsion: take 0.5g ethyl cellulose 40cp, 0.05gPEG4000 is in small beaker, add acetone 2.0ml and dichloromethane 4.0ml, make it to dissolve completely or suspendible, add above-mentioned ciclosporin A self-microemulsion 1.0g in small beaker, add appropriate micropowder silica gel, slowly be injected in the poor solvent containing 1%PVA aqueous solution, it is 25 DEG C that temperature controls, rotating speed is 400rpm, appropriate distilled water is added after continuous stirring 1h, continue to stir 10min, do not occur sticky glutinous to aggregate particle, natural drying 12h on sieve, sieve and weigh, particle diameter concentrates on 100 ~ 400 μm.
4. a ciclosporin A solid self-microemulsion, its prescription: ciclosporin A 1.25g, caprylic capric triglyceride 1.0g, polyoxyethylene hydrogenated Oleum Ricini 4.0g, ethanol 1.0ml, propylene glycol 2.0g, acetone 2.0ml, chloroform 4.0ml, EudragitRS1001.0g, PEG40000.1g, micropowder silica gel 0.5g, 0.08%SDS aqueous solution 200ml, preparation technology: the 1) preparation of ciclosporin A self-microemulsion: take ciclosporin A 1.25g according to prescription, be dissolved in 1.0ml ethanol, add the caprylic capric triglyceride of recipe quantity, polyoxyethylene hydrogenated Oleum Ricini and propylene glycol more successively, stir and obtain ciclosporin A self-microemulsion, 2) preparation of ciclosporin A solid self-microemulsion: take 1.0gEudragitRS100, 0.1gPEG4000 is in small beaker, add acetone 2.0ml and dichloromethane 4.0ml, make it to dissolve completely or suspendible, add ciclosporin A self-microemulsion in small beaker, add appropriate micropowder silica gel, slowly be injected in the poor solvent containing 0.08%SDS aqueous solution, it is 25 DEG C that temperature controls, rotating speed is 400rpm, appropriate distilled water is added after continuous stirring 1h, continue to stir 10min, do not occur sticky glutinous to aggregate particle, natural drying 12h on sieve, sieve and weigh, particle diameter concentrates on 100 ~ 400 μm.
5. a ciclosporin A solid self-microemulsion, its prescription: ciclosporin A 1.5g, caprylic capric triglyceride 2.0g, polyoxyethylene hydrogenated Oleum Ricini 4.0g, ethanol 1.0ml, propylene glycol 2.0g, acetone 2.0ml, dichloromethane 4.0ml, EudragitRL1000.5g, HPMCK4M0.05g, micropowder silica gel 0.5g, 0.08%SDS aqueous solution 125ml, preparation technology: the 1) preparation of ciclosporin A self-microemulsion: take ciclosporin A 1.5g according to prescription, be dissolved in 1.0ml ethanol, add the caprylic capric triglyceride of recipe quantity, polyoxyethylene hydrogenated Oleum Ricini and propylene glycol more successively, stir and obtain ciclosporin A self-microemulsion, 2) preparation of ciclosporin A solid self-microemulsion: take 0.5gEudragitRL100, 0.05gHPMCK4M is in small beaker, add acetone 2.0ml and dichloromethane 4.0ml, make it to dissolve completely or suspendible, add above-mentioned ciclosporin A self-microemulsion in small beaker, add appropriate micropowder silica gel, slowly be injected in the poor solvent containing 0.08%SDS aqueous solution, it is 25 DEG C that temperature controls, rotating speed is 400rpm, appropriate distilled water is added after continuous stirring 1h, continue to stir 10min, do not occur sticky glutinous to aggregate particle, natural drying 12h on sieve, sieve and weigh, particle diameter concentrates on 100 ~ 400 μm.
6. a ciclosporin A solid self-microemulsion, its prescription: ciclosporin A 2.0g, caprylic capric triglyceride 2.0g, polyoxyethylene hydrogenated Oleum Ricini 4.0g, ethanol 1.0ml, propylene glycol 2.0g, acetone 2.0ml, dichloromethane 4.0ml, EudragitRS1001.1g, HPMCK4M0.05g, micropowder silica gel 0.5g, 0.08%SDS aqueous solution 125ml, preparation technology: the 1) preparation of ciclosporin A self-microemulsion: take ciclosporin A 2.0g according to prescription, be dissolved in 1.0ml ethanol, add the caprylic capric triglyceride of recipe quantity, polyoxyethylene hydrogenated Oleum Ricini and propylene glycol more successively, stir and obtain ciclosporin A self-microemulsion, 2) preparation of ciclosporin A solid self-microemulsion: take 1.1gEudragitRS100, 0.05gHPMCK4M is in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve completely or suspendible, add above-mentioned ciclosporin A self-microemulsion in small beaker, add appropriate micropowder silica gel, slowly be injected in the poor solvent containing 0.08%SDS aqueous solution, it is 25 DEG C that temperature controls, rotating speed is 400rpm, appropriate distilled water is added after continuous stirring 1h, continue to stir 10min, do not occur sticky glutinous to aggregate particle, natural drying 12h on sieve, sieve and weigh, particle diameter concentrates on 100 ~ 400 μm.
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| KR101819310B1 (en) * | 2015-12-29 | 2018-01-18 | 단국대학교 천안캠퍼스 산학협력단 | Pharmaceutical composition comprising cyclosporine |
| JP2020511572A (en) * | 2017-03-17 | 2020-04-16 | ダウ グローバル テクノロジーズ エルエルシー | Method for recovering esterified cellulose ether from reaction product mixture |
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| CN100998864A (en) * | 2006-12-26 | 2007-07-18 | 沈阳药科大学 | Cyclosporin A semisolid skeleton capsule and its preparation method |
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| CN101199836A (en) * | 2007-11-07 | 2008-06-18 | 安徽省药物研究所 | Stage releasing CsA solid tiny milk agent and tiny milk curing method thereof |
| JP2011111429A (en) * | 2009-11-30 | 2011-06-09 | Hosokawa Micron Corp | Method for producing medicament-containing nano particle |
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| A novel formulation design about water-insoluble oily drug:preparation of zedoary turmeric oil microspheres with self-emulsifying ability and evaluation in rabbits;Jian You et al;《International Journal of Pharmaceutics》;20051231;第288卷;第315-323页，第315页摘要、第316-317页第2.2节、第322页第4节 * |
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Effective date of registration: 20200804 Address after: 230031 Mei mountain road, 103, Anhui, Hefei Patentee after: ANHUI University OF CHINESE MEDICINE Address before: 230038 School of traditional Chinese medicine, Anhui University of Traditional Chinese Medicine, 103 Mei Shan Road, Anhui, Hefei Patentee before: Hu Rongfeng |