CN102793674B - Triptolide solid lipid nanoparticle as well as preparation method and application thereof - Google Patents
Triptolide solid lipid nanoparticle as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a method for preparing triptolide solid lipid nanoparticles by quick membrane emulsification. The method comprises the following steps of: dissolving triptolide and mixed lipid into an organic solvent to serve as an oil phase, and dispersing into deionized water with an emulsifying agent; performing high-speed shearing emulsification at temperature higher than a melting point of the mixed lipid to obtain O/W type pre-emulsion; circulating the pre-emulsion under nitrogen pressure by adopting quick membrane emulsification equipment, and obtaining O/W type emulsion; and removing the organic solvent, and solidifying the lipid particles to obtain a solid lipid nanoparticle dispersion solution, or centrifugally separating the dispersion solution to collect the nanoparticles, or performing spraying drying or freezing drying to obtain the triptolide solid lipid nanoparticles. The triptolide solid lipid nanoparticles are high in monodispersity, high in entrapment efficiency and stable in process.
Description
Technical field
The invention belongs to the preparation method of nanoparticle raw materials medicine, be specifically related to a kind of triptolide solid lipid nano-particles and its preparation method and application.
Background technology
Triptolide (Triptolide, TP), claim again Radix Tripterygii Wilfordii lactone alcohol, from Celastraceae Thunder God Calamus Radix Tripterygii Wilfordii (Tripterygium Wilfordii Hook.f, TWHf) a kind of diterpenic lactone that in, separation obtains, be one of main effective ingredient in Radix Tripterygii Wilfordii, molecular formula is C
20h
24o
6, molecular weight is 360.4, is insoluble in water, is dissolved in the organic solvents such as methanol, ethanol, propylene glycol, acetone, dimethyl sulfoxide, ultraviolet maximum absorption wavelength is 218nm.Its chemical structural formula as shown in Figure 1.
Triptolide has significant immunosuppressive action, can be used for treating the dermatosis such as rheumatoid arthritis, chronic nephritis and lupus erythematosus, psoriasis, has very strong resisting transplant rejection effect simultaneously.Yet triptolide toxicity is large, the LD of the quiet note of mice and lumbar injection first element
50be respectively 0.8mg/kg, 0.9mg/kg.See children Zheng orchid etc., " Triptolide some toxicity to mice and dog ", Acta Pharmacologica Sinica, 1981,2 (1): 70-72.Conventional formulation intravenous injection easily causes that vein festers, and oral have strong impulse effect to gastrointestinal tract.
The triptolide half-life is in vivo short, easily by metabolism.Oral Administration in Rats first element dosage 0.6,1.2 and 2.4mg/kg, peak reaching time of blood concentration is in 15min, and the elimination half-life is 16.81～21.70min.Intravenous injection first element, dosage 0.6mg/kg, after 48h, the medication amount in excrement, bile, urine is respectively 0.03%, 0.43% and 0.06% of dosage, shows that first element is drained with the form of metabolite.See Shao F, Wang GJ, Xie HT, et al. < < Pharmacokinetic study of triptolide, aconstituent of immunosuppressive Chinese herb medicine, in Rats > > .Biol.Pharm.Bull., 2007,30 (4): 702-707.
Solid lipid nano-particles (solid lipid nanoparticle, SLN) is the administration nano-drug administration system of new generation growing up the nineties in 20th century, is the colloidal particle forming by being at room temperature solid-state biodegradable lipid.SLN can improve the oral administration biaavailability of insoluble drug, thereby reduces using dosage, and this administration for toxic medicament triptolide is very significant.
Existing solid lipid nano-particles preparation method mainly contains high pressure homogenize, high speed shear and supersound process etc.These method energy expenditures are high, violent high pressure, at a high speed, the mechanism such as high shear may cause medicine degeneration and loss, causes envelop rate to reduce.
SLN can delay Slow release, the prolong drug half-life.The means that realize at present SLN slow release are mainly to select suitable lipid carrier and technique to make the kernel of more medicine in granule, or the release that delays medicine of covalent bond or electrostatic interaction by medicine and lipid carrier, and particle diameter and particle size distribution are paid close attention to less on the impact discharging.
Existing SLN preparation technology cannot accurately control particle diameter and particle size distribution, and stable preparation process is poor.And film emulsifying (Membrane emulsification) technology can, by the selection of film parameter and film emulsion process parameter, realize the accuracy controlling to the particle diameters such as Emulsion or microsphere/microcapsule and particle size distribution.Film emulsifying technology is the new method of preparing Emulsion (single breast, how newborn) and microsphere/microcapsule growing up on membrane technology basis.Its stable preparation process is good, and entrapment efficiency is high, and preparation condition is gentle, and energy expenditure is low, is easy to industry and amplifies, and in fields such as biological medicine, food, chemical industry, has represented good application prospect.A kind of fast film emulsifying technology that grows up again in recent years, claims again pre-emulsion film emulsifying (Premix membrane), first prepares pre-emulsion, then by pre-emulsion under elevated pressures by the fenestra of uniform particle diameter, obtain the emulsion of homogeneous.Because the preparation efficiency of the method emulsion is high, can prepare the emulsion droplet that particle diameter is less, therefore than direct film emulsifying technology, there is the scope of application widely.
Summary of the invention
The invention provides a kind of preparation method of triptolide solid lipid nano-particles, solving existing solid lipid nano-particles preparation method cannot accurately control particle diameter and distribution thereof, and the problem of poor reproducibility, for Tripterygium Preparations provides, monodispersity is good, envelop rate is high, the crude drug of process stabilizing.
The preparation method of a kind of triptolide solid lipid nano-particles of the present invention, comprises the following steps:
(1) pre-emulsion preparation: triptolide is dissolved in organic solvent as oil phase with mixing lipid, and the mass ratio of triptolide and mixing lipid is 1: 10～1: 1000, and the mass volume ratio of mixing lipid and organic solvent is 1g: 5～10mL;
Oil phase is scattered in water, oil phase and water volume ratio are 1: 2～1: 20 again, adopt high-shear emulsifying to obtain oil-in-water type pre-emulsion;
Water is the deionized water that contains emulsifying agent, and the mass ratio of emulsifying agent and deionized water is 1: 10～1: 100;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, by the circulation of oil-in-water type pre-emulsion, prepare emulsion oil-in-water;
(3) dispersion liquid preparation: described emulsion oil-in-water is carried out to magnetic agitation 24h or reduction vaporization 1～2h, remove organic solvent, obtain solid lipid nano-particles aqueous dispersions; Or sodium-chloride water solution is added to described emulsion oil-in-water, organic solvent is diffused in sodium-chloride water solution, obtain solid lipid nano-particles sodium chloride dispersion liquid, the volume ratio of sodium-chloride water solution and emulsion oil-in-water is 2～6: 1, and the mass percentage concentration of sodium-chloride water solution is 0.88-0.92%;
(4) solid nano granule preparation: by solid lipid nano-particles aqueous dispersions or solid lipid nano-particles sodium chloride dispersion liquid or carry out centrifugalize, or spraying is dry or lyophilization, obtains triptolide solid lipid nano-particles.
Described preparation method, preferably, in described pre-emulsion preparation process, mix lipid and mix and form by lipoid and lipid carrier, the mass ratio of lipoid and lipid carrier is 1: 2～1: 5, and described lipoid is a kind of in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, phosphatidylcholine; Described lipid carrier is a kind of in satisfied fatty acid, saturated fatty acid glyceride, liquid oil or the mixture of two kinds wherein;
Described satisfied fatty acid is a kind of in stearic acid, Palmic acid, myristic acid, lauric acid, capric acid, behenic acid or the mixture of two kinds wherein;
Described saturated fatty acid glyceride class is the triglyceride of stearic acid, Palmic acid, myristic acid, lauric acid, capric acid, behenic acid, double glyceride, monoglyceride or two or three mixture wherein;
Described liquid oil be sad three sweet/a kind of in capric acid triglyceride, isopropyl myristate, isopropyl palmitate, the own fat of lauric acid, oleic acid, linoleic acid, Masine 35-1, soybean oil or the mixture of two kinds wherein.
Described preparation method, in described pre-emulsion preparation process, organic solvent is preferably a kind of in dichloromethane, chloroform, ethyl acetate, propyl acetate, toluene, ethanol, isopropyl alcohol, acetone, benzyl alcohol, butyl lactate or the mixture of two kinds wherein.
Described preparation method, in described pre-emulsion preparation process, described emulsifying agent is preferably polyvinyl alcohol, tween 80, tween 20, Tween-40, Arlacel-80, Arlacel-20, Myrij (Myrij) 52, Myrij (Myrij) 53, Brij (Brij) 30, Brij (Brij) 35, PLURONICS F87, poloxamer188, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, polyglycol distearate, dodecyl sodium sulfate (SDS), sodium cholate, NaTDC, sodium glycocholate, deoxidation natrii tauroglycocholas, glycerol, butanols, isoamyl alcohol, 1, a kind of in 2-propylene glycol or the wherein mixture of two kinds.
In described pre-emulsion preparation process, take high-shear emulsifying to obtain oil-in-water type pre-emulsion, rotating speed is 10,000r/min～30,000r/min, persistent period 1min～5min.
In described solid nano granule preparation process, when solid lipid nano-particles aqueous dispersions or solid lipid nano-particles sodium chloride dispersion liquid are carried out to centrifugalize, centrifugal speed is 1,000r/min～5,000r/min, persistent period 10min～30min.
Described preparation method, in described solid nano granule preparation process, when solid lipid nano-particles aqueous dispersions or solid lipid nano-particles sodium chloride dispersion liquid are sprayed to dry or lyophilization, spraying is dried or cryodesiccated protective agent is selected from polyvinylpyrrolidone, hydroxypropyl emthylcellulose, maltose, lactose, mannitol, glucose, trehalose, arabic gum, xylitol, sorbitol, fructose, a kind of in sucrose, the mass volume ratio of protective agent and solid lipid nano-particles aqueous dispersions or solid lipid nano-particles sodium chloride dispersion liquid is 1g: 5～100mL.
Another object of the present invention is to provide a kind of triptolide solid lipid nano-particles and application thereof.
Concrete technical scheme is as follows:
The triptolide solid lipid nano-particles that method prepares from the above mentioned.
The application of described triptolide solid lipid nano-particles in preparing triptolide injection, oral or preparation capable of permeating skin.
Research shows, the monodispersed drug-loading system of particle diameter has good control for dosage and the release behavior of packaging medicine, has higher envelop rate.The size of drug-loading system and particle size distribution are one of key factors of the desirable Nano medication consideration of exploitation, and for maintaining, steadily effectively blood drug level is extremely important.
The present invention adopts pre-emulsification in conjunction with SPG film emulsifying technology, take and mixes lipid as carrier material, parcel triptolide.The characteristic of the advantage of binding film technology of the present invention and solid lipid nano-particles itself, preparation method is simple and quick, mild condition, process stabilizing, triptolide solid lipid nano-particles particle diameter is less than 500nm, polydispersity coefficient (PDI) 0.02～0.2, envelop rate 60%～90%.Described triptolide solid lipid nano-particles can be used for preparing triptolide injection, oral or preparation capable of permeating skin.
Accompanying drawing explanation
Fig. 1 is the chemical structural formula of triptolide.
Fig. 2 is triptolide solid lipid nano-particles particle diameter and scattergram thereof in embodiment 3.
Fig. 3 is triptolide solid lipid nano-particles particle diameter and scattergram thereof in embodiment 5.
Fig. 4 is triptolide solid lipid nano-particles particle diameter and scattergram thereof in embodiment 7.
Fig. 5 is triptolide solid lipid nano-particles particle diameter and scattergram thereof in embodiment 8.
The specific embodiment
The fast film emulsifying device adopting in the method for the invention, for Japan (SPG Technology Co., Ltd) company produces; Inorganic microporous glass (SPG, Shirasu porous glass) film is tubular film, external diameter 10mm, thickness 0.4mm～1mm, length 20mm, aperture 0.1 μ m～1 μ m.Under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 1～7 time, obtain emulsion oil-in-water, nitrogen pressure is 70～140psi (Pounds per square inch).
Below in conjunction with specific embodiment, the present invention is further described.
Embodiment 1
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 600mg, Ovum Gallus domesticus Flavus lecithin 2.0g, tripalmitin 3.2g, Masine 35-1 0.8g, be dissolved in 30mL dichloromethane as oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing polyoxyethylene hydrogenated Oleum Ricini 6.0g, is heated to 60 ℃, 30,000r/min, high shear 1min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 1 time, obtain emulsion oil-in-water, SPG film thickness 0.4mm, length 20mm, aperture 1 μ m, nitrogen pressure is 70psi;
(3) dispersion liquid preparation: to described emulsion oil-in-water reduction vaporization 2h, remove organic solvent, obtain solid lipid nano-particles aqueous dispersions;
(4) solid nano granule preparation: by the centrifugalize of solid lipid nano-particles aqueous dispersions, centrifugal speed is 1,000r/min, and persistent period 30min obtains triptolide solid lipid nano-particles.
This triptolide solid lipid nano-particles particle diameter 345.4nm, polydispersity coefficient (PDI) 0.081, envelop rate 70%.
Embodiment 2
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 600mg, Ovum Gallus domesticus Flavus lecithin 2.0g, tripalmitin 3.2g, Masine 35-1 0.8g, be dissolved in 30mL ethyl acetate as oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing polyoxyethylene hydrogenated Oleum Ricini 6.0g, is heated to 60 ℃, 30,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 2 times, obtain emulsion oil-in-water, SPG film thickness 0.4mm, length 20mm, aperture 1 μ m, nitrogen pressure is 70psi;
(3) dispersion liquid preparation: described emulsion oil-in-water is carried out to magnetic agitation 24h and remove organic solvent, obtain solid lipid nano-particles aqueous dispersions;
(4) solid nano granule preparation: by the lyophilization of solid lipid nano-particles aqueous dispersions, take trehalose as protective agent, consumption 0.6g, the amount ratio of 1g trehalose and solid lipid nano-particles aqueous dispersions is 100mL.
This triptolide solid lipid nano-particles particle diameter 332.4nm, polydispersity coefficient (PDI) 0.054, envelop rate 68%.
Embodiment 3
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 600mg, Ovum Gallus domesticus Flavus lecithin 2.0g, tripalmitin 3.2g, Masine 35-1 0.8g, be dissolved in 30mL dichloromethane as oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing polyoxyethylene hydrogenated Oleum Ricini 6.0g, is heated to 60 ℃, 10,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 3 times, obtain emulsion oil-in-water, SPG film thickness 0.4mm, length 20mm, aperture 0.7 μ m, nitrogen pressure is 90psi;
(3) dispersion liquid preparation: described emulsion oil-in-water is carried out to magnetic agitation 24h and remove organic solvent, obtain solid lipid nano-particles aqueous dispersions;
(4) solid nano granule preparation: by the centrifugalize of solid lipid nano-particles aqueous dispersions, centrifugal speed is 5,000r/min, and persistent period 10min obtains triptolide solid lipid nano-particles.
This triptolide solid lipid nano-particles particle diameter 304.7nm, polydispersity coefficient (PDI) 0.023, envelop rate 74%, particle diameter and distribution thereof are as Fig. 2.
Embodiment 4
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 600mg, Ovum Gallus domesticus Flavus lecithin 2.0g, tripalmitin 2.0g, Masine 35-1 2.0g, be dissolved in 30mL dichloromethane as oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing polyoxyethylene hydrogenated Oleum Ricini 6.0g, is heated to 60 ℃, 10,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 3 times, obtain emulsion oil-in-water, SPG film thickness 0.4mm, length 20mm, aperture 0.7 μ m, nitrogen pressure is 90psi;
(3) dispersion liquid preparation: to described emulsion oil-in-water reduction vaporization 1h, remove organic solvent, obtain solid lipid nano-particles aqueous dispersions;
(4) solid nano granule preparation: by the centrifugalize of solid lipid nano-particles aqueous dispersions, centrifugal speed is 5,000r/min, and persistent period 30min obtains triptolide solid lipid nano-particles.
This triptolide solid lipid nano-particles particle diameter 315.3nm, polydispersity coefficient (PDI) 0.068, envelop rate 85%.
Embodiment 5
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation process: by triptolide 600mg, Ovum Gallus domesticus Flavus lecithin 2.0g, tripalmitin 2.0g, Masine 35-1 2.0g, be dissolved in 30mL dichloromethane as oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing polyoxyethylene hydrogenated Oleum Ricini 5.0g and sodium cholate 1.0g, is heated to 60 ℃, 10,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 4 times, obtain emulsion oil-in-water, SPG film thickness 1mm, length 20mm, aperture 0.7 μ m, nitrogen pressure is 100psi;
(3) dispersion liquid preparation: to described emulsion oil-in-water reduction vaporization 1h, remove organic solvent, obtain solid lipid nano-particles aqueous dispersions;
(4) solid nano granule preparation: by the lyophilization of solid lipid nano-particles aqueous dispersions, take trehalose as protective agent, consumption 12.0g, with solid lipid nano-particles aqueous dispersions amount ratio be 1g: 5mL.
This triptolide solid lipid nano-particles particle diameter 180.9nm, polydispersity coefficient (PDI) 0.097, envelop rate 83%, particle diameter and distribution thereof are as Fig. 3.
Embodiment 6
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 600mg, Ovum Gallus domesticus Flavus lecithin 2.0g, tripalmitin 2.0g, Masine 35-1 2.0g, be dissolved in 30mL dichloromethane as oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the consumption that mixes lipid summation and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing polyoxyethylene hydrogenated Oleum Ricini 5.0g and sodium cholate 1.0g, is heated to 60 ℃, 10,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 4 times, obtain emulsion oil-in-water, SPG film thickness 1mm, length 20mm, aperture 0.7 μ m, nitrogen pressure is 100psi;
(3) dispersion liquid preparation: be that 0.9% sodium-chloride water solution 540mL adds described emulsion oil-in-water by mass percentage concentration, organic solvent is diffused in sodium chloride solution, obtain solid lipid nano-particles sodium chloride dispersion liquid, the volume ratio of sodium-chloride water solution and emulsion oil-in-water is 6: 1;
(4) solid nano granule preparation: by the centrifugalize of solid lipid nano-particles sodium chloride dispersion liquid, centrifugal speed is 5,000r/min, and persistent period 30min obtains triptolide solid lipid nano-particles.
This triptolide solid lipid nano-particles particle diameter 190.5nm, polydispersity coefficient (PDI) 0.069, envelop rate 82%.
Embodiment 7
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 600mg, Ovum Gallus domesticus Flavus lecithin 2.0g, tripalmitin 2.0g, Masine 35-1 2.0g, be dissolved in 30mL dichloromethane as oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing polyoxyethylene hydrogenated Oleum Ricini 5.0g and sodium cholate 1.0g, is heated to 60 ℃, 10,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 4 times, obtain emulsion oil-in-water, SPG film thickness 1mm, length 20mm, aperture 0.1 μ m, nitrogen pressure is 130psi;
(3) dispersion liquid preparation: be that 0.9% sodium-chloride water solution 540mL adds described emulsion oil-in-water by mass percentage concentration, organic solvent is diffused in sodium-chloride water solution, obtain solid lipid nano-particles sodium chloride dispersion liquid, the volume ratio of sodium-chloride water solution and emulsion oil-in-water is 6: 1;
(4) solid nano granule preparation: by the centrifugalize of solid lipid nano-particles sodium chloride dispersion liquid, centrifugal speed is 5,000r/min, and persistent period 30min obtains triptolide solid lipid nano-particles.
This triptolide solid lipid nano-particles particle diameter 85.03nm, polydispersity coefficient (PDI) 0.100, envelop rate 75%, particle diameter and distribution thereof are as Fig. 4.
Embodiment 8
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 6.0mg, Ovum Gallus domesticus Flavus lecithin 1.0g, Glyceryl Behenate 3.0g, caprylic/capric triglyceride 2.0g, be dissolved in the mixed solvent of 60mL dichloromethane and ethyl acetate as oil phase, the mass ratio of lipoid and lipid carrier is 1: 5, the mass ratio of triptolide and mixing lipid is 1: 1000, and the amount ratio that mixes lipid and organic solvent is 1g: 10mL;
Again oil phase is scattered in 1200mL water, in water, containing polyvinyl alcohol 12.0g, is heated to 80 ℃, 30,000r/min, high shear 1min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 20, and the mass ratio of emulsifying agent and deionized water is 1: 100;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 2 times, obtain emulsion oil-in-water, SPG film thickness 1mm, length 20mm, aperture 0.7 μ m, nitrogen pressure is 100psi;
(3) dispersion liquid preparation: to described emulsion oil-in-water reduction vaporization 2h, remove organic solvent, obtain solid lipid nano-particles aqueous dispersions;
(4) solid nano granule preparation process: solid lipid nano-particles aqueous dispersions spraying is dry, take hydroxypropyl emthylcellulose as protective agent, consumption 12.0g, with solid lipid nano-particles aqueous dispersions amount ratio be 1g: 100mL.
This triptolide solid lipid nano-particles particle diameter 423.2nm, polydispersity coefficient (PDI) 0.022, envelop rate 85%, particle diameter and distribution thereof are as Fig. 5.
Embodiment 9
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 6.0mg, Ovum Gallus domesticus Flavus lecithin 1.0g, Glyceryl Behenate 2.0g, Masine 35-1 3.0g, be dissolved in the mixed solvent of 60mL dichloromethane and ethyl acetate as oil phase, the mass ratio of lipoid and lipid carrier is 1: 5, the mass ratio of triptolide and mixing lipid is 1: 1000, and the amount ratio that mixes lipid and organic solvent is 1g: 10mL;
Again oil phase is scattered in 1200mL water, in water, containing polyvinyl alcohol 10.0g and sodium cholate 2.0g, is heated to 80 ℃, 30,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 20, and the mass ratio of emulsifying agent and deionized water is 1: 100;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 3 times, obtain emulsion oil-in-water, SPG film thickness 1mm, length 20mm, aperture 0.7 μ m, nitrogen pressure is 120psi;
(3) dispersion liquid preparation: to described emulsion oil-in-water reduction vaporization 2h, remove organic solvent, obtain solid lipid nano-particles aqueous dispersions;
(4) solid nano granule preparation: the spraying of solid lipid nano-particles aqueous dispersions is dry, take hydroxypropyl emthylcellulose as protective agent, consumption 12.0g, with solid lipid nano-particles aqueous dispersions amount ratio be 1g: 100mL.
This triptolide solid lipid nano-particles particle diameter 310.6nm, polydispersity coefficient (PDI) 0.025, envelop rate 90%.
Embodiment 10
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 6.0mg, Ovum Gallus domesticus Flavus lecithin 1.0g, Glyceryl Behenate 2.0g, Masine 35-1 3.0g, be dissolved in the mixed solvent of 60mL dichloromethane and ethyl acetate as oil phase, the mass ratio of lipoid and lipid carrier is 1: 5, the mass ratio of triptolide and mixing lipid is 1: 1000, and the amount ratio that mixes lipid and organic solvent is 1g: 10mL;
Again oil phase is scattered in 1200mL water, in water, containing polyvinyl alcohol 10.0g and sodium cholate 2.0g, is heated to 80 ℃, 30,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 20, and the mass ratio of emulsifying agent and deionized water is 1: 100;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 3 times, obtain emulsion oil-in-water, SPG film thickness 1mm, length 20mm, aperture 0.5 μ m, nitrogen pressure is 140psi;
(3) dispersion liquid preparation: be that 0.9% sodium-chloride water solution 2520mL adds described emulsion oil-in-water by mass percentage concentration, organic solvent is diffused in sodium chloride solution, obtain solid lipid nano-particles sodium chloride dispersion liquid, the volume ratio of sodium-chloride water solution and emulsion oil-in-water is 2: 1;
(4) solid nano granule preparation: by the centrifugalize of solid lipid nano-particles sodium chloride dispersion liquid, centrifugal speed is 5,000r/min, and persistent period 10min obtains triptolide solid lipid nano-particles.
This triptolide solid lipid nano-particles particle diameter 180.2nm, polydispersity coefficient (PDI) 0.103, envelop rate 88%.
Embodiment 11
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 600mg, soybean lecithin 2.0g, stearic acid 3.2g, isopropyl myristate 0.8g, be dissolved in 30mL isopropyl alcohol as oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing polyglycol distearate 6.0g, is heated to 70 ℃, 30,000r/min, high shear 1min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 1 time, obtain emulsion oil-in-water, SPG film thickness 0.4mm, length 20mm, aperture 1 μ m, nitrogen pressure is 70psi;
(3) dispersion liquid preparation: to described emulsion oil-in-water reduction vaporization 2h, remove organic solvent, obtain solid lipid nano-particles aqueous dispersions;
(4) solid nano granule preparation: by the centrifugalize of solid lipid nano-particles aqueous dispersions, centrifugal speed is 1,000r/min, and persistent period 30min obtains triptolide solid lipid nano-particles.
Embodiment 12
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 600mg, phosphatidylcholine 2.0g, tripalmitin 3.2g, oleic acid 0.8g, be dissolved in 30mL propyl acetate as oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing polyoxyethylene castor oil 6.0g, is heated to 60 ℃, 30,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 2 times, obtain emulsion oil-in-water, SPG film thickness 0.4mm, length 20mm, aperture 1 μ m, nitrogen pressure is 70psi;
(3) dispersion liquid preparation: described emulsion oil-in-water is carried out to magnetic agitation 24h and remove organic solvent, obtain solid lipid nano-particles aqueous dispersions;
(4) solid nano granule preparation: by the lyophilization of solid lipid nano-particles aqueous dispersions, take mannitol as protective agent, consumption 0.6g, the amount ratio of 1g trehalose and solid lipid nano-particles aqueous dispersions is 100mL.
Embodiment 13
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 600mg, Ovum Gallus domesticus Flavus lecithin 2.0g, tristerin 3.2g, isopropyl palmitate 0.8g, be dissolved in 30mL chloroform as oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing tween 20 6.0g, is heated to 70 ℃, 10,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 3 times, obtain emulsion oil-in-water, SPG film thickness 0.4mm, length 20mm, aperture 0.7 μ m, nitrogen pressure is 90psi;
(3) dispersion liquid preparation: described emulsion oil-in-water is carried out to magnetic agitation 24h and remove organic solvent, obtain solid lipid nano-particles aqueous dispersions;
(4) solid nano granule preparation: by the centrifugalize of solid lipid nano-particles aqueous dispersions, centrifugal speed is 5,000r/min, and persistent period 10min obtains triptolide solid lipid nano-particles.
Embodiment 14
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 600mg, Ovum Gallus domesticus Flavus lecithin 2.0g, tripalmitin 2.0g, Masine 35-1 2.0g, being dissolved in 30mL butyl lactate is oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing PLURONICS F87 6.0g, is heated to 60 ℃, 10,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 3 times, obtain emulsion oil-in-water, SPG film thickness 0.4mm, length 20mm, aperture 0.7 μ m, nitrogen pressure is 90psi;
(3) dispersion liquid preparation: to described emulsion oil-in-water reduction vaporization 1h, remove organic solvent, obtain solid lipid nano-particles aqueous dispersions;
(4) solid nano granule preparation: by the centrifugalize of solid lipid nano-particles aqueous dispersions, centrifugal speed is 5,000r/min, and persistent period 30min obtains triptolide solid lipid nano-particles.
Embodiment 15
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 600mg, Ovum Gallus domesticus Flavus lecithin 2.0g, tripalmitin 2.0g, Masine 35-1 2.0g, be dissolved in 30mL benzyl alcohol as oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the consumption that mixes lipid summation and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing polyglycol distearate 5.0g and deoxidation natrii tauroglycocholas 1.0g, is heated to 60 ℃, 10,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 4 times, obtain emulsion oil-in-water, SPG film thickness 1mm, length 20mm, aperture 0.7 μ m, nitrogen pressure is 100psi;
(3) dispersion liquid preparation: be that 0.88% sodium-chloride water solution 540mL adds described emulsion oil-in-water by mass percentage concentration, organic solvent is diffused in sodium chloride solution, obtain solid lipid nano-particles sodium chloride dispersion liquid, the volume ratio of sodium-chloride water solution and emulsion oil-in-water is 6: 1;
(4) solid nano granule preparation: by the centrifugalize of solid lipid nano-particles sodium chloride dispersion liquid, centrifugal speed is 5,000r/min, and persistent period 30min obtains triptolide solid lipid nano-particles.
Embodiment 16
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 600mg, Ovum Gallus domesticus Flavus lecithin 2.0g, tripalmitin 2.0g, Masine 35-1 2.0g, be dissolved in 30mL dichloromethane as oil phase, the mass ratio of lipoid and lipid carrier is 1: 2, the mass ratio of triptolide and mixing lipid is 1: 10, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in 60mL water, in water, containing polyoxyethylene hydrogenated Oleum Ricini 5.0g and sodium glycocholate 1.0g, is heated to 60 ℃, 10,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 2, and the mass ratio of emulsifying agent and deionized water is 1: 10;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 4 times, obtain emulsion oil-in-water, SPG film thickness 1mm, length 20mm, aperture 0.1 μ m, nitrogen pressure is 130psi;
(3) dispersion liquid preparation: be that 0.92% sodium-chloride water solution 540mL adds described emulsion oil-in-water by mass percentage concentration, organic solvent is diffused in sodium chloride solution, obtain solid lipid nano-particles sodium chloride dispersion liquid, the volume ratio of sodium chloride solution and emulsion oil-in-water is 6: 1;
(4) solid nano granule preparation: by the centrifugalize of solid lipid nano-particles sodium chloride dispersion liquid, centrifugal speed is 5,000r/min, and persistent period 30min obtains triptolide solid lipid nano-particles.
Embodiment 17
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 6.0mg, Ovum Gallus domesticus Flavus lecithin 1.0g, Glyceryl Behenate 3.0g, linoleic acid 2.0g, be dissolved in the mixed solvent of 60mL chloroform and acetone as oil phase, the mass ratio of lipoid and lipid carrier is 1: 5, the mass ratio of triptolide and mixing lipid is 1: 1000, and the amount ratio that mixes lipid and organic solvent is 1g: 10mL;
Again oil phase is scattered in 1200mL water, in water, containing polyvinyl alcohol 12.0g, is heated to 80 ℃, 30,000r/min, high shear 1min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 20, and the mass ratio of emulsifying agent and deionized water is 1: 100;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 2 times, obtain emulsion oil-in-water, SPG film thickness 1mm, length 20mm, aperture 0.7 μ m, nitrogen pressure is 100psi;
(3) dispersion liquid preparation: to described emulsion oil-in-water reduction vaporization 2h, remove organic solvent, obtain solid lipid nano-particles aqueous dispersions;
(4) solid nano granule preparation process: solid lipid nano-particles aqueous dispersions spraying is dry, take glucose as protective agent, consumption 12.0g, with solid lipid nano-particles aqueous dispersions amount ratio be 1g: 100mL.
Embodiment 18
The preparation method of triptolide solid lipid nano-particles described in the present embodiment, comprises the following steps:
(1) pre-emulsion preparation: by triptolide 6.0mg, Ovum Gallus domesticus Flavus lecithin 1.0g, Glyceryl Behenate 2.0g, Masine 35-1 3.0g, be dissolved in the mixed solvent of 60mL dichloromethane and ethyl acetate as oil phase, the mass ratio of lipoid and lipid carrier is 1: 5, the mass ratio of triptolide and mixing lipid is 1: 1000, and the amount ratio that mixes lipid and organic solvent is 1g: 10mL;
Again oil phase is scattered in 1200mL water, in water, containing polyvinyl alcohol 10.0g and dodecyl sodium sulfate 2.0g, is heated to 80 ℃, 30,000r/min, high shear 5min obtains oil-in-water type pre-emulsion; Oil phase and water volume ratio are 1: 20, and the mass ratio of emulsifying agent and deionized water is 1: 100;
(2) emulsion preparation: utilize fast film emulsifying device, under nitrogen pressure, make oil-in-water type pre-emulsion cycle through SPG film 3 times, obtain emulsion oil-in-water, SPG film thickness 1mm, length 20mm, aperture 0.5 μ m, nitrogen pressure is 140psi;
(3) dispersion liquid preparation: be that 0.92% sodium-chloride water solution 2520mL adds described emulsion oil-in-water by mass percentage concentration, organic solvent is diffused in sodium chloride solution, obtain solid lipid nano-particles sodium chloride dispersion liquid, the volume ratio of sodium-chloride water solution and emulsion oil-in-water is 2: 1;
(4) solid nano granule preparation: by the centrifugalize of solid lipid nano-particles sodium chloride dispersion liquid, centrifugal speed is 5,000r/min, and persistent period 10min obtains triptolide solid lipid nano-particles.
Be more than for the illustrating of possible embodiments of the present invention, but this embodiment is not in order to limit the scope of the claims of the present invention, allly do not depart from the equivalence that skill spirit of the present invention does and implement or change, all should be contained in the scope of the claims of the present invention.
Claims (8)
1. a preparation method for triptolide solid lipid nano-particles, is characterized in that, comprises the following steps:
(1) pre-emulsion preparation: triptolide is dissolved in organic solvent as oil phase with mixing lipid, and the mass ratio of triptolide and mixing lipid is 1:10～1000, and the amount ratio of mixing lipid and organic solvent is 1g:5～10mL;
Oil phase is scattered in water, oil phase and water volume ratio are 1:2～1:20 again, adopt high-shear emulsifying to obtain oil-in-water type pre-emulsion;
Described water is the deionized water that contains emulsifying agent, and the mass ratio of emulsifying agent and deionized water is 1:10～1:100;
Described mixing lipid is mixed and is formed by lipoid and lipid carrier, and the mass ratio of described lipoid and lipid carrier is 1:2～1:5, and described lipoid is a kind of in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, phosphatidylcholine; Described lipid carrier is a kind of in satisfied fatty acid, saturated fatty acid glyceride, liquid oil or the mixture of two kinds wherein;
Described satisfied fatty acid is a kind of in stearic acid, Palmic acid, myristic acid, lauric acid, capric acid, behenic acid or the mixture of two kinds wherein;
Described saturated fatty acid glyceride is the triglyceride, double glyceride, monoglyceride of stearic acid, Palmic acid, myristic acid, lauric acid, capric acid, behenic acid or two or three mixture wherein;
Described liquid oil is a kind of in caprylic/capric triglyceride, isopropyl myristate, isopropyl palmitate, the own fat of lauric acid, oleic acid, linoleic acid, Masine 35-1, soybean oil or the mixture of two kinds wherein;
(2) emulsion preparation: utilize fast film emulsifying device, make oil-in-water type pre-emulsion cycle through SPG film 1～7 time under nitrogen pressure, obtain emulsion oil-in-water, described nitrogen pressure is 70～140psi;
(3) dispersion liquid preparation: described emulsion oil-in-water is carried out to magnetic agitation or reduction vaporization, remove organic solvent, obtain solid lipid nano-particles aqueous dispersions; Or sodium-chloride water solution is added to described emulsion oil-in-water, organic solvent is diffused in sodium-chloride water solution, obtain solid lipid nano-particles sodium chloride dispersion liquid, the volume ratio of sodium-chloride water solution and emulsion oil-in-water is 2～6:1, and the mass percentage concentration of sodium-chloride water solution is 0.88-0.92%;
(4) solid nano granule preparation: by solid lipid nano-particles aqueous dispersions or solid lipid nano-particles sodium chloride dispersion liquid or carry out centrifugalize, or spraying is dry or lyophilization, obtains triptolide solid lipid nano-particles.
2. preparation method as claimed in claim 1, is characterized in that, described organic solvent is a kind of in dichloromethane, chloroform, ethyl acetate, propyl acetate, toluene, ethanol, isopropyl alcohol, acetone, benzyl alcohol, butyl lactate or the mixture of two kinds wherein.
3. preparation method as claimed in claim 1, it is characterized in that, described emulsifying agent is a kind of in polyvinyl alcohol, tween 80, tween 20, Tween-40, Arlacel-80, Arlacel-20, Myrj 52, Myrj 53, Brij30, Brij35, PLURONICS F87, poloxamer188, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, polyglycol distearate, dodecyl sodium sulfate, sodium cholate, NaTDC, sodium glycocholate, deoxidation natrii tauroglycocholas, glycerol, butanols, isoamyl alcohol, 1,2-PD or the mixture of two kinds wherein.
4. the preparation method as described in claim 1-3 any one, is characterized in that, adopts high-shear emulsifying to obtain oil-in-water type pre-emulsion in step (1), and rotating speed is 10,000r/min～30,000r/min, persistent period 1min～5min.
5. the preparation method as described in claim 1-3 any one, it is characterized in that, while solid lipid nano-particles aqueous dispersions or solid lipid nano-particles sodium chloride dispersion liquid being carried out to centrifugalize in step (4), centrifugal speed is 1,000r/min～5,000r/min, persistent period 10min～30min.
6. the preparation method as described in claim 1-3 any one; it is characterized in that; in step (4) middle spray dry or lyophilization, adopt protective agent; described protective agent is selected from a kind of in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, maltose, lactose, mannitol, glucose, trehalose, arabic gum, xylitol, sorbitol, fructose, sucrose, and the amount ratio of protective agent and solid lipid nano-particles dispersion liquid is 1g:5～100mL.
7. the triptolide solid lipid nano-particles being prepared by the preparation method described in claim 1-6 any one.
8. the application of triptolide solid lipid nano-particles claimed in claim 7 in preparing triptolide injection, oral or preparation capable of permeating skin.
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| SI3215133T1 (en) * | 2014-11-05 | 2021-07-30 | Selecta Biosciences, Inc. | Methods and compositions related to the use of low hlb surfactants in the production of synthetic nanocarriers comprising a rapalog |
| US10342797B2 (en) | 2016-03-13 | 2019-07-09 | LivePet, LLC | Solubility of therapeutic agents |
| CN107050037A (en) * | 2017-05-16 | 2017-08-18 | 广东艾时代生物科技有限责任公司 | Application and its pharmaceutical composition of the triptolide in anti-malaria medicaments are prepared |
| CN108635338B (en) * | 2018-05-15 | 2020-07-31 | 复旦大学附属肿瘤医院 | Triptolide lipid nanoparticle for external use and preparation method thereof |
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