CN103315960A - Solid self-microemulsion based on spherical crystallization technique and preparation method thereof - Google Patents
Solid self-microemulsion based on spherical crystallization technique and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the medical technology field, and particularly relates to a solid self-microemulsion based on a spherical crystallization technique and a preparation method thereof. The solid self-microemulsion is characterized in that: with the use of the spherical crystallization technique, the solid self-microemulsifying micoparticles are prepared from poorly water soluble drugs in a liquid phase by one step. The solid self-microemulsion with the poorly water soluble drugs comprises the components, by weight: 0.1 to 1.5 g of the poorly water soluble drugs, 4.0 g of a polyoxyethylene hydrogenated castor oil, 2.0 g of capric caprylic triglyceride, 2.0 g of tpropylene glycol, 1.0 ml of ethanol, 4.0 ml of dichloromethane, 0.5 to 1.1 g of ethylcellulose (or Eudragit RS100, RL100), 0.05 g of PEG4000, and 0.5 g of colloidal silicon dioxide. The poorly water soluble drugs include cyclosporine A, fenofibrate, glimepiride, cilnidipine, isradipine, simvastatin, baicalein, neogambogic acid, puerarin, cyclovirobuxine D, silymarin and the like.
Description
One, technical field
The invention belongs to medical technical field, relate to a kind of preparation method of pharmaceutical preparation, exactly it is a kind of insoluble medicine solid self-microemulsion microgranule and preparation method thereof.Specifically a kind of in liquid phase a step make insoluble medicine solid self-microemulsion microgranule.
Two, background technology
Self-microemulsifying drug delivery system (self-microemulsifying drug delivery system, SMEDDS) be comprised of emulsifying agent, co-emulsifier and oil phase, basic feature is can the isotropic transparent or semitransparent o/w type dispersion of spontaneous formation particle diameter 10～100nm under gastrointestinal peristalsis or ambient temperature (being often referred to body temperature) and gentle agitation.The sandimmun neoral of Novartis company in 1994 (ciclosporin soft capsules/Sandimmun Neoral) successfully goes on the market, and has greatly promoted the research of self-microemulsion.SMEDDS has following advantage and 1. contains simultaneously oil phase, water in the system, can contain different fat-soluble medicines; 2. there is the exhibiting high surface activating agent to exist in the SEDDS system, can increases the dissolubility of some poorly water soluble drugs and some macromolecular drug; 3. the Dispersed Phase Size of microemulsion is tiny and even, is beneficial to medicine absorption in vivo, thereby improves the bioavailability of medicine; 4. some surfactants can suppress the effect that effluxes of p-glycoprotein, but the bioavailability of Effective Raise insoluble drug.But because dosage form is single, drug release is very fast behind the self-microemulsion capsule oral, lacks the dosage forms such as slow controlled release, enteric, is not suitable for that administration number of times is many, stomach irritation is large or under one's belt unsettled poorly water soluble drugs and protein medicaments.And self microemulsifying preparation all is liquid form, normally is encapsulated in soft capsule or the hard capsule, and there are consistency problem in preparation composition and softgel shell, and may reveal after the long term store.Therefore, be necessary to develop its solid system to meet clinical needs.
Solid Self-microemulsion medicine-releasing system (solid self-microemulsifying drug delivery system, SSMEDDS) be that SMEDDS is combined with solid material, the solid preparation that is mixed with by medicine, oil phase, emulsifying agent, co-emulsifier and suitable solid material.Compare with SMEDDS and to have 1. that stability increases; Period of storage prolongs; 2. GI irritation minimizing; 3. can satisfy the advantages such as multiple demand such as slow controlled release, enteric
[2]Self-microemulsion curing technology commonly used mainly contains spray drying method, freeze-drying and carrier adsorption method at present.Such as (Tao Yi such as Tao Yi, Jiangling Wan, Huibi Xu, et al.A new solid self-microemulsifying formulation prepared by spray-drying to improve the oral bioavailability of poorly water soluble drugs[J] .European Journal of Pharmaceutics and Biopharmaceutics, 2008,70:439～444; [4] Tao Yi, Jiangling Wan, Huibi Xu, et al.Controlled poorly soluble drug release from solid self-microemulsifying formulations with high viscosity hydroxypropyl methyl cellulose[J] .European Journal of Pharmaceutical Sciences, 2008,34:274～280) use spray drying method to prepare the Nimodipine solid self-microemulsion, release in vitro shows: homemade Nimodipine solid self-microemulsion is faster than conventional tablet rate of release, use simultaneously HPMC as slow controlled-release material, not only can improve the oral availability of insoluble drug, can also control drug release.
(the Prabagar Balakrishnan such as Balakrishnan, Beom Jin Lee, Dong Hoon Oh, et al.Enhanced oral bioavailability of dexibuprofen by a novel solid Self-emulsifying drug delivery system (SEDDS) [J] .European Journal of Pharmaceutics and Biopharmaceutics, 2009,72:539～545) take Aerosil200 as inert solid carrier, adopt spray drying method to prepare the (S)-ibuprofen Solid Self-microemulsion, improved its bioavailability.The Solid Self-microemulsion internal structure of preparation is complete, is not destroyed in spray process.Spray drying prepares Solid Self-microemulsion as a kind of oil-laden powder preparation, and solid carrier that oil phase need to suit parcel, otherwise be easy to stick together disperses inhomogeneously, and redispersibility is poor.In addition, spray drying method is only applicable to the good medicine of chemical stability, and general yield is lower.
Jin Fang etc. (research [D] of golden side's oral insulin self-micro emulsifying medicament delivery system. Shanghai Institute of Pharmaceutical Industry 2005) adopt freeze-drying to prepare insulin self-emulsification solid powder, but this powder enters the Winsor I type nanoscale microemulsion that self emulsifying behind the intestinal becomes to be similar to o/w type or doubly-linked ideotype, and relative bioavailability is higher.Freeze-drying is applicable to the medicine of thermal instability, good stability, but instrument and equipment is had higher requirement, cost is higher, the production process more complicated.The solid carrier absorption method is fairly simple, such as (Pradeep Patil such as Patil, Prasad Joshi, Anant Paradkar.Effect of Formulation Variables on Preparation and Evaluation of Gelled Self-emulsifying Drug Delivery System (SEDDS) of Ketoprofen[J] .AAPSPharm Sci Tech, 2004,5 (3): 1～8) take silicon dioxide as carrier, by optimizing its use amount, prepared the ketoprofen Solid Self-microemulsion, made drug release rate very fast.The method need add a large amount of vehicle excipients, and the pressed powder drug loading that makes is lower and viscosity is larger, and making preparation also needs usually through granulation, drying.
Therefore, be necessary to study a kind of new curing technology and method, so as to construct good stability, cost is lower, drug loading is large, and can satisfy the multiple demand Solid Self-microemulsion medicine-releasing systems such as slow controlled release, enteric.
Spherocrystal technology (Spherical Crystallization Technique claims again spherical junctions to gather technology SphericalAgglomeratation Technique) is that medicine borrows the effect knot of bridging agent poly-in liquid phase in the crystallization, is stirring the technology that forms spheroidal particle under the shear action.This technology can prepare functional particles, can be made into the homogeneous powder body of Multiple components, and the physical property of improving product is easily controlled shape and the particle diameter of granule, improves the physical property of product, satisfies production technology demand (as improving porosity and specific surface area etc.).Form principle by its granule and can be divided into two classes: wet granulation (Wet SphericalAgglomeration method) and emulsion solvent diffusion method (Emulsion Solvent Diffusion method).Wherein its principle of emulsion solvent diffusion method is that drug solution at first forms emulsion droplet, and with the diffusion of solvent in the emulsion droplet, medicine is separated out, solidified, and keeps spherical.Compacting mechanism as shown in Figure 1
Say in a sense, emulsion solvent diffusion method also is the curing of Emulsion, is the diffusion with solvent in the emulsion droplet, and medicine is separated out, solidified, and keeps spherical a kind of method.
The present invention's emulsion solvent diffusion method in early-stage Study spherocrystal technology prepares on the basis of ball-type particle, by selecting suitable solvent system (good solvent-bridging agent-poor solvent), successfully prepared ciclosporin A solid self-microemulsion microsphere, and prove that this microspheres with solid can be with the release of self-microemulsion mode, and make at insoluble drugs such as fenofibrate, glimepiride, cilnidipine, isradipine, simvastatin, baicalin, neogambogic acid, puerarin, cyclovirobuxinum D, silymarin and to be adopted in the Solid Self-microemulsion preparation, very high practicality is arranged.Be showed no in the document at present and relate to the report that the spherocrystal technology prepares Solid Self-microemulsion or self-microemulsion curing.
Adopt the spherocrystal technology to prepare Solid Self-microemulsion, can be in liquid phase a step finish self-microemulsion solidified, by optimizing prescription and technological factor, make the microgranule that makes better mobile, avoided additive method to prepare Solid Self-microemulsion viscosity larger, later stage is difficult to the problems such as processing, be conducive to later stage capsule-filling or tabletting, avoided simultaneously necessary multistep processing step in the preparation solid preparation pelletization, be applicable to water, the heat sensitivity medicine, equipment needed thereby is simple, the energy-and time-economizing can have slow controlled release by selecting to add satisfied the preparing of different macromolecular materials in addition, the multiple demand Solid Self-microemulsion such as enteric medicine-releasing system.
Three, summary of the invention
The objective of the invention is the deficiency for existing preparation, insoluble drug is made the Solid Self-microemulsion preparation can make medicine steadily discharge slowly, the rear blood drug level of avoiding taking medicine is too high and cause serious Liver and kidney toxicity, also can avoid liquid alcohol on the impact of soft capsule shell, improve oral administration biaavailability, improve curative effect, solidify self-microemulsion and conveniently store and carry.
The objective of the invention is to realize according to following scheme
The preparation of insoluble medicine solid self-microemulsion utilizes the spherocrystal granulating technique, with the macromolecule blocker, porogen is dissolved in the even suspension solution that forms macromolecular material in the solvent, under the condition that stirs, add and contain in right amount in the aqueous solutions such as poor solvent of certain surface activating agent, stir through appropriate time, replenish suitable quantity of water, continue to stir an amount of time, good solvent and bridging agent phase counterdiffusion in water, emulsion droplet solidifies, and forms microspheres with solid, dry under the room temperature, collect, the associating dispersible carrier is cured the insoluble drug self-microemulsion, thereby prepares insoluble medicine solid self-microemulsion microgranule.
Insoluble medicine solid self-microemulsion wherein, it is characterized in that: utilize the spherocrystal granulating technique, the insoluble drug self-microemulsion is joined macromolecular material, dispersible carrier, porogen be dissolved in the even suspension solution that forms macromolecular material in the solvent, join in the poor solvent that contains surfactant, a step makes insoluble medicine solid self-microemulsion microgranule in liquid phase.
Preparation insoluble medicine solid self-microemulsion microgranule 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.
Macromolecular material selection cellulose derivative class is selected from one or more in hypromellose titanate esters, Hydroxypropyl Methyl Cellulose Phthalate, hypromellose, hydroxypropyl cellulose phthalate, the ethyl cellulose (10-40cp), preferred, ethyl (10-40cp) in the insoluble medicine solid self-microemulsion; Crylic acid resin or cellulose derivative class, wherein crylic acid resin is selected from one or more among acrylic resin, Eudragit RL, Eudragit RS, Eudragit E, Eudragit L, the Eudragit S, preferred acrylic resins Eudragit E100, Eudragit RS100, Eudragit RL100; Porogen is selected one or more in PEG4000, PVP, HPMC K4M, lactose, the mannitol powder; Dispersible carrier is selected one or more of micropowder silica gel, Pulvis Talci, calcium carbonate, calcium phosphate, magnesium stearate.
The insoluble medicine solid self-microemulsion, it is characterized in that: the weight that said composition contains insoluble drug self-microemulsion raw material forms: insoluble drug: 5%～20%, polyoxyethylene hydrogenated Oleum Ricini: 30%～70%, sad capric acid triglyceride: 10%～30%, propylene glycol: 10%～30%, ethanol: 5%～15%.
The insoluble medicine solid self-microemulsion, it is characterized in that: the weight of insoluble medicine solid self-microemulsion raw material consists of: insoluble drug: 0.25～1.5, polyoxyethylene hydrogenated Oleum Ricini: 4, sad capric acid triglyceride: 2, propylene glycol: 2, ethanol: 1, dichloromethane 4.0, ethyl cellulose (10-40cp) 0.5g, PE640000.05g, micropowder silica gel 0.5g.
The weight of insoluble medicine solid self-microemulsion raw material consists of: insoluble drug: 1, and polyoxyethylene hydrogenated Oleum Ricini: 4, sad capric acid triglyceride: 2, propylene glycol: 2, ethanol: 1, dichloromethane 4.0, ethyl cellulose (10cp) 0.5g, PEG40000.05g, micropowder silica gel 0.5g.
The spherocrystal granulating technique prepares the insoluble medicine solid self-microemulsion, and its solidification temperature is 25 ℃～50 ℃, and rotating speed is 400～600rpm.The mass fraction of insoluble drug in Solid Self-microemulsion is 0.05～0.25.
Add the adding of the purpose porogen of porogen in the microsphere preparation process, make the microsphere of preparation with holes, thereby better, more adsorb the insoluble drug self-microemulsion, when guaranteeing to improve drug loading, but make the microsphere that makes have the characteristic of vertical compression.
The sad capric acid triglyceride of oil phase in the adsorption process in the purpose insoluble drug self-microemulsion of adding micropowder silica gel and the viscosity of surfactant polyoxyethylene hydrogenation castor oil are very large, and melting at high temperature easily occurs, add carrier material so that medicine is better adsorbed by porous microsphere, effectively improve solids flowability, can be used for directly filling or tabletting.
The insoluble medicine solid self-microemulsion of preparation can form microemulsion in 37 ℃ aqueous solution, present blue-opalescent.
Advantage of the present invention be can be in liquid phase a step make insoluble drug and solidify self-microemulsion.Medicine can slowly discharge stably after said preparation entered gastrointestinal tract, reduced the serious Liver and kidney toxicity that the quick releasing formulations such as oral liquid and soft capsule produce.Also avoid simultaneously in the soft capsule pure class I liquid I on the impact of softgel shell, and drug loading increase greatly, Solid Self-microemulsion, better mobile because of it, can directly incapsulate or direct compression, production cost is low, favorable reproducibility, yield is high.Can be used for the Solid Self-microemulsion preparation of the insoluble drugs such as ciclosporin A, fenofibrate, glimepiride, cilnidipine, isradipine, simvastatin, baicalin, neogambogic acid, puerarin, cyclovirobuxinum D, silymarin, specifically see embodiment.
Description of drawings
Fig. 1 emulsion solvent diffusion method compacting mechanism figure
Fig. 2 places under the transmission electron microscope and to observe insoluble medicine solid self-microemulsion microgranule outward appearance, form and take pictures
Fig. 3 laser particle size analyzer is measured insoluble medicine solid self-microemulsion diameter of particle and particle size distribution
The specific embodiment
[prescription]
[preparation technology]
The preparation of fenofibrate self-microemulsion: take by weighing insoluble drug 1.0g according to prescription, be dissolved in the 1.0ml ethanol, add successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stir and namely get the fenofibrate self-microemulsion.
The preparation of fenofibrate Solid Self-microemulsion: take by weighing 0.5 ethyl cellulose, 0.05g PEG4000 in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible, add the fenofibrate self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, and rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continue to stir 10min, until solidify fully.Do not occur stickingly glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～400 μ m.
The fenofibrate Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 2
[prescription]
[preparation technology]
The preparation of fenofibrate self-microemulsion: root takes by weighing fenofibrate 2.50g according to prescription, is dissolved in the 1.0ml ethanol, adds successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stirs and namely gets the fenofibrate self-microemulsion.
The preparation of fenofibrate Solid Self-microemulsion: take by weighing the 0.5g ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve fully or suspendible, add above-mentioned fenofibrate self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～～400 μ m.
The fenofibrate Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 3
[prescription]
[preparation technology]
The preparation of glimepiride self-microemulsion: take by weighing glimepiride 1.0g according to prescription, be dissolved in the 1.0ml ethanol, add successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stir and namely get the glimepiride self-microemulsion.
The preparation of glimepiride Solid Self-microemulsion: take by weighing the 0.5mg ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible, add above-mentioned glimepiride self-microemulsion 1.0g in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 1%PVA aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～400 μ m.
The glimepiride solid microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 4
[prescription]
[preparation technology]
The preparation of glimepiride self-microemulsion: take by weighing glimepiride 2.0g according to prescription, be dissolved in the 1.0ml ethanol, add successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stir and namely get the glimepiride self-microemulsion.
The preparation of glimepiride Solid Self-microemulsion: take by weighing 1.0g Eudragit RS100,0.1gPEG4000 in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible, add the glimepiride self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～400 μ m.
The glimepiride Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 5
[prescription]
[preparation technology]
The preparation of cilnidipine self-microemulsion: take by weighing cilnidipine 0.5 according to prescription, be dissolved in the 1.0ml ethanol, add successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stir and namely get the cilnidipine self-microemulsion.
The preparation of cilnidipine Solid Self-microemulsion: take by weighing 0.5g Eudragit RL100,0.05g HPMC K4M is in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible, add above-mentioned cilnidipine self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～400 μ m.
The cilnidipine Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 6
[prescription]
[preparation technology]
The preparation of cilnidipine self-microemulsion: take by weighing cilnidipine 2.0g according to prescription, be dissolved in the 1.0ml ethanol, add successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stir evenly and namely get the cilnidipine self-microemulsion.
The preparation of cilnidipine Solid Self-microemulsion: take by weighing 1.1g Eudragit RS100,0.05g HPMC K4M is in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible, above-mentioned cilnidipine self-microemulsion is in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～400 μ m.
The cilnidipine solid microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 7
[prescription]
[preparation technology]
The preparation of isradipine self-microemulsion: take by weighing isradipine 0.5g according to prescription, be dissolved in the 1.0ml ethanol, add successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stir and namely get the isradipine self-microemulsion.
The preparation of isradipine Solid Self-microemulsion: take by weighing 0.5g Eudragit RL100,0.05g HPMC K4M is in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible, add above-mentioned isradipine self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～400 μ m.
The isradipine Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
[prescription]
[preparation technology]
The preparation of simvastatin self-microemulsion: take by weighing cilnidipine 2.0g according to prescription, be dissolved in the 1.0ml ethanol, add successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stir and namely get the simvastatin self-microemulsion.
The preparation of simvastatin Solid Self-microemulsion: take by weighing 1.1g Eudragit RS100,0.05g HPMC K4M is in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible, above-mentioned simvastatin self-microemulsion is in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～400 μ m.
The simvastatin solid microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 9
[prescription]
[preparation technology]
The preparation of simvastatin self-microemulsion: root takes by weighing simvastatin 2.0g according to prescription, is dissolved in the 1.0ml ethanol, adds successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stirs and namely gets the simvastatin self-microemulsion.
The preparation of simvastatin Solid Self-microemulsion: take by weighing the 0.5g ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve fully or suspendible, add above-mentioned simvastatin self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～～400 μ m.
The simvastatin Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: take by weighing ciclosporin A 1.0g according to prescription, be dissolved in the 1.0ml ethanol, add successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stir and namely get the ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take by weighing 0.5 ethyl cellulose, 0.05g PEG4000 in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible, add the ciclosporin A self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, and rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continue to stir 10min, until solidify fully.Do not occur stickingly glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～400 μ m.
The ciclosporin A solid self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 11
[prescription]
[preparation technology]
The preparation of ciclosporin A self-microemulsion: root takes by weighing ciclosporin A 0.50g according to prescription, is dissolved in the 1.0ml ethanol, adds successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stirs and namely gets the ciclosporin A self-microemulsion.
The preparation of ciclosporin A solid self-microemulsion: take by weighing the 0.5g ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve fully or suspendible, add above-mentioned ciclosporin A self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～～400 μ m.
The ciclosporin A solid self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.Embodiment 12
[prescription]
[preparation technology]
The preparation of neogambogic acid self-microemulsion: take by weighing neogambogic acid 1.0g according to prescription, be dissolved in the 1.0ml ethanol, add successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stir and namely get the neogambogic acid self-microemulsion.
The preparation of neogambogic acid Solid Self-microemulsion: take by weighing 0.5 ethyl cellulose, 0.05g PEG4000 in small beaker, add acetone 2ml and dichloromethane 4ml, make it to dissolve fully or suspendible, add the neogambogic acid self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, and rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continue to stir 10min, until solidify fully.Do not occur stickingly glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～400 μ m.
The neogambogic acid Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 13
[prescription]
[preparation technology]
The preparation of neogambogic acid self-microemulsion: root takes by weighing neogambogic acid 0.50g according to prescription, is dissolved in the 1.0ml ethanol, adds successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stirs and namely gets the neogambogic acid self-microemulsion.
The preparation of neogambogic acid Solid Self-microemulsion: take by weighing the 0.5g ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve fully or suspendible, add above-mentioned neogambogic acid self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～～400 μ m.
The neogambogic acid Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 14
[prescription]
[preparation technology]
The preparation of baicalin self-microemulsion: root takes by weighing baicalin 0.50g according to prescription, is dissolved in the 1.0ml ethanol, adds successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stirs and namely gets the baicalin self-microemulsion.
The preparation of baicalin Solid Self-microemulsion: take by weighing the 0.5g ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve fully or suspendible, add above-mentioned baicalin self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～～400 μ m.
The baicalin Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
[prescription]
[preparation technology]
The preparation of puerarin self-microemulsion: root takes by weighing puerarin 2.0g according to prescription, is dissolved in the 1.0ml ethanol, adds successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stirs namely to get puerarin self-microemulsion.
The preparation of Puerarin Solid Self-microemulsion: take by weighing the 0.5g ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve fully or suspendible, add above-mentioned puerarin self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～～400 μ m.
The Puerarin Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 16
[prescription]
[preparation technology]
The preparation of puerarin self-microemulsion: root takes by weighing puerarin 0.50g according to prescription, is dissolved in the 1.0ml ethanol, adds successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stirs namely to get puerarin self-microemulsion.
The preparation of Puerarin Solid Self-microemulsion: take by weighing the 0.5g ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve fully or suspendible, add above-mentioned puerarin self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～～400 μ m.
The Puerarin Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 17
[prescription]
[preparation technology]
The preparation of cyclovirobuxinum D self-microemulsion: root takes by weighing cyclovirobuxinum D 0.10g according to prescription, be dissolved in the 1.0ml ethanol, add successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stir and namely get the cyclovirobuxinum D self-microemulsion.
The preparation of cyclovirobuxinum D Solid Self-microemulsion: take by weighing the 0.5g ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve fully or suspendible, add above-mentioned cyclovirobuxinum D self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～～400 μ m.
The cyclovirobuxinum D Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 18
[prescription]
[preparation technology]
The preparation of cyclovirobuxinum D self-microemulsion: root takes by weighing cyclovirobuxinum D 0.2g according to prescription, be dissolved in the 1.0ml ethanol, add successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stir and namely get the cyclovirobuxinum D self-microemulsion.
The preparation of cyclovirobuxinum D Solid Self-microemulsion: take by weighing the 0.5g ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve fully or suspendible, add above-mentioned cyclovirobuxinum D self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～～400 μ m.
The cyclovirobuxinum D Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 19
[prescription]
[preparation technology]
The preparation of cyclovirobuxinum D self-microemulsion: root takes by weighing cyclovirobuxinum D 0.2g according to prescription, be dissolved in the 1.0ml ethanol, add successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, stir and namely get the cyclovirobuxinum D self-microemulsion.
The preparation of cyclovirobuxinum D Solid Self-microemulsion: take by weighing the 0.5g ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve fully or suspendible, add above-mentioned cyclovirobuxinum D self-microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～～400 μ m.
The cyclovirobuxinum D Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Embodiment 18
[prescription]
[preparation technology]
The preparation of Silymarin Self-emulsifying Microemulsion: root takes by weighing silymarin 0.50g according to prescription, is dissolved in the 1.0ml ethanol, adds successively the sadder capric acid triglyceride of recipe quantity, polyethylene glycol hydrogenated castor oil and propylene glycol, and stirring namely gets Silymarin Self-emulsifying Microemulsion.
The preparation of silymarin Solid Self-microemulsion: take by weighing the 0.5g ethyl cellulose, 0.05gPEG4000 in small beaker, add acetone 2ml and chloroform 4ml, make it to dissolve fully or suspendible, add above-mentioned Silymarin Self-emulsifying Microemulsion in small beaker, add an amount of micropowder silica gel, slowly be injected in the poor solvent that contains the 0.08%SDS aqueous solution, temperature is controlled to be 25 ℃, rotating speed is 400rpm, adds an amount of distilled water behind the continuous stirring 1h, continues to stir 10min, do not occur sticking glutinous to aggregate particle, natural drying 12h sieves and weighs on sieve, and particle diameter concentrates on 100～～400 μ m.
The silymarin Solid Self-microemulsion that makes is dissolved in a certain amount of 37 ℃ distilled water, after stirring a period of time, the solution clear, and obvious blue-opalescent is arranged.
Claims (8)
1. claim 1 is based on spherocrystal technology Solid Self-microemulsion, it is characterized in that: utilize the spherocrystal granulating technique, the insoluble drug self-microemulsion is joined macromolecular material, dispersible carrier, porogen be dissolved in the even suspension solution that forms macromolecular material in the solvent, join in the poor solvent that contains surfactant, a step makes insoluble medicine solid self-microemulsion microgranule in liquid phase.
2. Solid Self-microemulsion according to claim 1, it is characterized in that: the weight that said composition contains insoluble drug self-microemulsion raw material forms: insoluble drug: 5%～20%, polyoxyethylene hydrogenated Oleum Ricini: 30%～70%, sad capric acid triglyceride: 10%～30%, propylene glycol: 10%～30%, ethanol: 5%～15%.
3. according to claim 1,2 described a kind of insoluble medicine solid self-microemulsion, it is characterized in that: adopt based on the spherocrystal technology, used macromolecular material selection cellulose derivative class is selected from one or more in hypromellose titanate esters, Hydroxypropyl Methyl Cellulose Phthalate, hypromellose, hydroxypropyl cellulose phthalate, the 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 among acrylic resin, Eudragit RL, Eudragit RS, Eudragit E, Eudragit L, the Eudragit S, preferred acrylic resins Eudragit E100, Eudragit RS100, Eudragit RL100; Porogen is selected one or more in PEG4000, PVP, HPMC K4M, lactose, the mannitol powder; Dispersible carrier is selected one or more of micropowder silica gel, Pulvis Talci, calcium carbonate, calcium phosphate, magnesium stearate.
4. insoluble medicine solid self-microemulsion according to claim 2, it is characterized in that: the weight of insoluble medicine solid self-microemulsion raw material consists of: insoluble drug: 0.1～0.25, polyoxyethylene hydrogenated Oleum Ricini: 4.0, sad capric acid triglyceride: 2.0, propylene glycol: 2.0, ethanol: 1.0, dichloromethane 4.0, ethyl cellulose (10-40cp) (or Eudragit RS100, RS100) 0.5～1.1g, PEG40000.05, micropowder silica gel 0.5.
5. insoluble medicine solid self-microemulsion according to claim 2, it is characterized in that: the weight of insoluble medicine solid self-microemulsion raw material consists of: insoluble drug: 1.0, polyoxyethylene hydrogenated Oleum Ricini: 4.0, sad capric acid triglyceride: 2.0, propylene glycol: 2.0, ethanol: 1.0, dichloromethane 4.0, ethyl cellulose (10cp) 0.5g, PEG40000.05g, micropowder silica gel 0.5g.
6. preparation method according to claim 1, it is characterized in that: the mass fraction of insoluble drug in Solid Self-microemulsion is 0.1～0.25.
7. curing according to claim 1, it is characterized in that: the spherocrystal granulating technique prepares the insoluble medicine solid self-microemulsion, and its solidification temperature is 25 ℃～50 ℃, and rotating speed is 400～600rpm.
8. insoluble medicine solid self-microemulsion according to claim 1, insoluble drug comprises ciclosporin A, fenofibrate, glimepiride, cilnidipine, isradipine, simvastatin, baicalin, neogambogic acid, puerarin, cyclovirobuxinum D, silymarin etc.
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| CN103315961A (en) * | 2012-03-20 | 2013-09-25 | 安徽中医学院 | Neogambogic acid self-microemulsifying preparation and preparation method thereof |
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| CN110151730A (en) * | 2019-03-06 | 2019-08-23 | 安徽新华学院 | A kind of hesperetin Solid Self-microemulsion osmotic pumps capsule and preparation method thereof |
| CN110812326A (en) * | 2019-11-04 | 2020-02-21 | 黑龙江省农业科学院畜牧兽医分院 | Simvastatin suspension emulsion and preparation method and application thereof |
| CN111529572A (en) * | 2020-06-18 | 2020-08-14 | 山西中医药大学 | Scutellaria baicalensis extract self-microemulsion with biological antibacterial activity |
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| CN110151730A (en) * | 2019-03-06 | 2019-08-23 | 安徽新华学院 | A kind of hesperetin Solid Self-microemulsion osmotic pumps capsule and preparation method thereof |
| CN110812326A (en) * | 2019-11-04 | 2020-02-21 | 黑龙江省农业科学院畜牧兽医分院 | Simvastatin suspension emulsion and preparation method and application thereof |
| CN110812326B (en) * | 2019-11-04 | 2022-04-22 | 黑龙江省农业科学院畜牧兽医分院 | Simvastatin suspension emulsion and preparation method and application thereof |
| CN111529572A (en) * | 2020-06-18 | 2020-08-14 | 山西中医药大学 | Scutellaria baicalensis extract self-microemulsion with biological antibacterial activity |
| CN111529572B (en) * | 2020-06-18 | 2023-11-24 | 山西中医药大学 | A Scutellariae radix extract self-microemulsion with biological antibacterial effect |
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