CN103169657A - Self-emulsifier containing breviscapine phosphatidylcholine complex, and preparation method and use thereof - Google Patents
Self-emulsifier containing breviscapine phosphatidylcholine complex, and preparation method and use thereof Download PDFInfo
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Abstract
The invention discloses a self-emulsifier containing a breviscapine phosphatidylcholine complex, and a preparation method and a use thereof. The self-emulsifier comprises the following components, by mass, 0.1-16% of breviscapine, 0.1-32% of phosphatidylcholine, 20-70% of an oily phase, 10-50% of a surfactant, and 0-40% of a cosurfactant. An insoluble dug breviscapine is processed to prepare a breviscapine phosphatidylcholine complex, and the breviscapine phosphatidylcholine complex is treated as an intermediate carrier to prepare the self-emulsifier containing the breviscapine phosphatidylcholine complex. The breviscapine phosphatidylcholine complex can effectively solve a bad fat solubility problem of breviscapine and substantially improve the drug loading capability of the self-emulsifier; and the self-emulsifier can increase the dissolution rate of breviscapine, promote breviscapine to penetrate epithelial cells, promote the lymphatic transport of drugs to a certain degree, reduce the hepatic first pass metabolism of the drugs and improve the oral bioavailability of breviscapine. Oral administration tests of rats show that the self-emulsifier containing the breviscapine phosphatidylcholine complex can substantially improve the absorption of breviscapine and improve the oral bioavailability of breviscapine.
Description
Technical field
The invention belongs to the biological medicine technology field, relate to a kind of self-emulsifier that breviscapine-phosphotide compound is intermediate carrier and its production and use of take, this self-emulsifier can significantly improve breviscapine oral administration and absorb, and improves the breviscapine oral administration bioavailability.
Background technology
Breviscapine is the Flavonoid substances extracted from the feverfew Herba Erigerontis, English name Breviscapine or Erigeron Breviscapus, and main effective ingredient is scutellarin (Fig. 1 is shown in chemical structural formula), its content accounts for more than 95% of total flavones.Breviscapine has significant curative effect for cardiovascular and cerebrovascular diseases such as cerebral infarction, atherosclerosis obliterans, myocardial infarctions.But, breviscapine oral administration absorbs non-constant, the oral absolute bioavailability of beasle dog is only 0.4%, the comprehensive literature analysis of report, possible reason comprises poorly water-soluble, a little less than lipotropy, easily by degradeds such as gastric acid, Intestinal Anaerobic Bacteria, liver drug enzymes, transform in body complicatedly, and protein called membrane transporters are to effluxing of medicine etc.In addition, breviscapine needs heavy dose of multiple dosing clinically, has blood drug level " peak valley " wave phenomenon, and curative effect is stable not.
Chinese patent literature (CN1593449A) discloses " a kind of self emulsifying soft capsule of breviscapine and preparation method thereof ", but, because breviscapine is fat-soluble poor, limited the drug loading of self-emulsifiable preparation, therefore, this self-emulsifiable preparation can't meet the high dose administration, and simultaneously, its stability has much room for improvement.Chinese patent literature (CN101862306A) discloses a kind of " new type slightly soluble oral medicine self-emulsification preparation and preparation method thereof ", add short supersaturation material in medicine self emulsifying system, can improve to a certain extent the drug loading of self-emulsifier.But short supersaturation material is to play a role after medicine disperses, solubilising power is limited, is difficult to solve the problem of the fat-soluble difference of breviscapine at all.In addition, the problem that after the self-emulsifier that relies on short supersaturation technology to prepare probably faces and disperses emphatically, medicine is separated out again.
Therefore, be necessary to research and develop Novel Drug Delivery Systems and improve the fat-soluble of breviscapine, improve the drug loading of breviscapine in preparation; Simultaneously, overcome the poor difficult problem of current Breviscapine oral absorption, effectively improve the breviscapine oral administration bioavailability, prolong drug effective acting time, improve curative effect of medication.
Summary of the invention
The purpose of this invention is to provide a kind of self-emulsifier containing breviscapine-phosphotide compound and its production and use, self-emulsifier can increase the dissolution of breviscapine, promote that breviscapine penetrates epithelial cell, and facilitate to a certain extent the lymph of medicine to transport, reduce the liver first pass metabolism of medicine, thereby improve the oral administration biaavailability of breviscapine.
A kind of self-emulsifier containing breviscapine-phosphotide compound provided by the invention, by percentage to the quality, each constituent content is: breviscapine 0.1～16%, phosphatidase 10 .1～32%, oil phase 20～70%, surfactant 10～50%, surplus is cosurfactant; The preferred content of each component is: breviscapine 1～12%, and phosphatidase 12～24%, oil phase 40～60%, surfactant 20～40%, surplus is cosurfactant.
The preparation method of the above-mentioned self-emulsifier containing breviscapine-phosphotide compound, the method comprises the steps:
(1) take breviscapine and the phospholipid of recipe quantity, add the organic solvent dispersion medicine, one or several in the optional ethyl acetate of described organic solvent, oxolane, dichloromethane, chloroform, normal hexane, cyclohexane extraction, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, acetone, preferably oxolane, methanol and ethanol; Adjust solution Chinese medicine concentration in 2～20mg/mL, preferably 5～10mg/mL; Reflux 0.5～3h in 40～60 ℃ of water-baths, rotary evaporation is removed organic solvent, obtains breviscapine-phosphotide compound; (2) get in the oil phase that appropriate breviscapine-phosphotide compound adds recipe quantity, 30～80 ℃ of stirring in water bath 0.5～5h, then add surfactant and the cosurfactant of recipe quantity, continue to stir until fully evenly, obtain.
Above-mentioned liquid self-emulsifiable preparation directly fill becomes the soft capsule application; Described solid-state self-emulsifier can further be made the application of powder, granule, micropill, tablet; The described self-emulsifier containing breviscapine-phosphotide compound can be used in the cardiovascular and cerebrovascular diseases such as treatment hypertension, treating myocardial ischemia damage, cerebral thrombosis clinically.
The present invention is directed to fat-soluble poor, the problem such as oral administration biaavailability is low of breviscapine, a kind of self-emulsifier technical scheme containing breviscapine-phosphotide compound creatively is provided, at first the present invention is prepared as phosphatide complexes by the insoluble drug breviscapine, using breviscapine-phosphotide compound as intermediate carrier, and further preparation is containing the self-emulsifier of breviscapine-phosphotide compound.Phosphatide complexes can effectively solve the difficult problem of the fat-soluble difference of breviscapine, and significantly improves the drug loading of self-emulsifiable preparation.Compared with the prior art, demonstrate following technological progress:
(1) utilize the phosphatide complexes technology to efficiently solve the problem of the fat-soluble difference of breviscapine, improved the drug loading of breviscapine in self-emulsifier simultaneously.
(2) utilize the self-emulsifiable preparation technology, increase the dissolution of breviscapine, simultaneously, special adjuvant in self-emulsifier can suppress protein called membrane transporters effluxing medicine to a certain extent, promote the medicine permeable membrane to absorb, and facilitate to a certain extent the transhipment of medicine lymph, reduce the liver first pass metabolism of medicine, thereby effectively improve the oral administration biaavailability of breviscapine.
(3) the solid-state self-emulsifier that the present invention program provides has good sustained release performance, the intestinal holdup time that can prolong drug, is conducive to improve Oral drug absorption.
(4) technical scheme preparation technology provided by the invention is simple, and mild condition is suitable for suitability for industrialized production, has good development prospect.
In addition, the present invention finds in research process, and the catabolite scutellarin genin of scutellarin is close with the physicochemical property of scutellarin, may face same clinical application problem, although scutellarin genin is not yet granted clinical use so far, has larger DEVELOPMENT PROSPECT.
The accompanying drawing explanation
Fig. 1 is the scutellarin chemical structural formula.
Fig. 2 (a), (b), (c), (d) are respectively the physical mixed of the former medicine of breviscapine, soybean phospholipid, breviscapine and soybean phospholipid and the X-ray diffractogram of embodiment 1 gained breviscapine-phosphotide compound.
Fig. 3 is the transmission electron microscope picture after the liquid self-emulsifier aqueous dispersion of embodiment 2 gained.
Fig. 4 is the drug-eluting curve of the former medicine of breviscapine, embodiment 1 gained phosphatide complexes, embodiment 2 and the liquid self-emulsifier of embodiment 3 gained.
Fig. 5 is the drug-eluting curve of embodiment 2, the liquid self-emulsifier of embodiment 3 gained and embodiment 18, the solid-state self-emulsifier of embodiment 19 gained.
Fig. 6 is the medicine everted intestinal sac absorption curve of the former medicine of breviscapine, embodiment 1 gained phosphatide complexes, embodiment 2 and embodiment 3 gained self-emulsifiers.
Fig. 7 (a), (b), (c), (d) are curves during medicine after the rat oral gavage of the former medicine of breviscapine, embodiment 1 gained phosphatide complexes, embodiment 2 and embodiment 3 gained self-emulsifiers.
When Fig. 8 (a), (b), (c), (d) are the medicines of solid-state self-emulsifier of the liquid self-emulsifier of embodiment 2, embodiment 3 gained and embodiment 18, embodiment 19 gained, curve relatively.
The specific embodiment
Technical scheme provided by the invention is: a kind of self-emulsifier containing breviscapine-phosphotide compound, by percentage to the quality, each constituent content is: breviscapine 0.1～16%, phosphatidase 10 .1～32%, oil phase 20～70%, surfactant 10～50%, surplus is cosurfactant, in the present invention, the content of cosurfactant can be 0.
As better scheme of the present invention, above-mentioned each constituent mass percentage composition of self-emulsifier containing breviscapine-phosphotide compound is: breviscapine 1～12%, and phosphatidase 12～24%, oil phase 40～60%, surfactant 20～40%, surplus is cosurfactant.
Breviscapine-phosphotide compound of the present invention, is characterized in that phospholipid used is following one or more: soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, hydrogenated soya phosphatide, hydrogenated yolk lecithin.Wherein, preferred soybean phospholipid.
Breviscapine-phosphotide compound of the present invention, the mass ratio that it is characterized in that breviscapine and phospholipid is 1: 0.5～1: 5, preferably 1: 1～1: 3.
Oil phase of the present invention comprises that soybean oil, almond oil, Oleum Ricini, Semen Maydis oil, Oleum sesami, Oleum Arachidis hypogaeae semen, olive oil, rapeseed oil, Petiolus Trachycarpi oil, hydrogenated corn oil, oleic acid, linoleic acid, ethyl oleate, oleic acid polyethyleneglycol glyceride are (as Labrafil
tMseries, French Gattefosse company), glyceryl monooleate is (as Peceol
tMseries, French Gattefosse company), Masine 35-1 is (as Maisine
tMseries, French Gattefosse company), propylene glycol two caprylic/capric esters are (as Labrafac
tMseries, French Gattefosse company), Miglyol 812 is (as Labrafac
tMseries, French Gattefosse company) or above-mentioned mixture.The mixture of wherein preferred oil acetoacetic ester, or Masine 35-1 and Miglyol 812, the proportion optimization of mixture 1: 1～1: 2.
Surfactant of the present invention comprises that polysorbate20/60/80, Polyethylene Glycol 800/1000/1500/2000, polyoxyethylene castor oil are (as Cremophor EL series, Germany BASF AG), polyoxyethylene hydrogenated Oleum Ricini (as Cremophor RH series, German BASF AG), Labraso are (as Labrasol
tMseries, French Gattefosse company) or above-mentioned mixture.Preferred polyoxyethylene hydrogenated Oleum Ricini wherein.
Cosurfactant of the present invention comprises that propylene glycol, Macrogol 200/400/600, Capryol 90 are (as Capryol
tMseries, French Gattefosse company), PGML is (as Lauroglycol
tMseries, French Gattefosse company), ethylene glycol monomethyl ether is (as Transcutol
tMseries, French Gattefosse company), polyglyceryl fatty acid ester (as Plurol Oleique, French Gattefosse company) or above-mentioned mixture.Wherein, preferred propylene glycol or ethylene glycol monomethyl ether.
The preparation method of the self-emulsifier containing breviscapine-phosphotide compound provided by the invention is:
(1) take breviscapine and the phospholipid of recipe quantity, add the organic solvent dispersion medicine, one or several in the optional ethyl acetate of described organic solvent, oxolane, dichloromethane, chloroform, normal hexane, cyclohexane extraction, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, acetone, preferably oxolane, methanol and ethanol; Adjust solution Chinese medicine concentration in 2～20mg/mL, preferably 5～10mg/mL; Reflux 0.5～3h in 40～60 ℃ of water-baths, rotary evaporation is removed organic solvent, obtains breviscapine-phosphotide compound; (2) get in the oil phase that appropriate breviscapine-phosphotide compound adds recipe quantity, 30～80 ℃ of stirring in water bath 0.5～5h, then add surfactant and the cosurfactant of recipe quantity, continue to stir until fully evenly, obtain.
Above-mentioned preparation method obtains is the liquid self-emulsifier containing breviscapine-phosphotide compound, this self-emulsifier by (v/v) aqueous dispersion in 1: 200 after particle diameter be 30～1000nm.Also can add firming agent and further be prepared as solid-state self-emulsifier, solid-state self-emulsifier by (w/w) aqueous dispersion in 1: 100 after particle diameter be 50～1300nm.
Described solid-state self-emulsifier, is characterized in that firming agent used comprises water-soluble saccharides, starch and modified starch, cellulose and derivant thereof, polyvinylpyrrolidone, poloxamer etc.The preferred hydroxypropyl methylcellulose (HPMC) of low viscosity specification (50cp～400cp) wherein.
Described solid-state self-emulsifier, the mass ratio of liquid self-emulsifier and firming agent is 1: 0.5～1: 5, preferably 1: 0.5～1: 2.
Described solid-state self-emulsifier, curing process comprises: directly adsorb, extrude round as a ball, spray drying, fluid bed drying/granulation, lyophilization etc.
In liquid self-emulsifier involved in the present invention, the quality percentage composition of each component in system just can reach technique effect of the present invention in above-mentioned scope, otherwise after emulsifying, the poor stability of self-emulsifier, medicine is lost self-emulsifier institute because separating out precipitation has superiority.
Described liquid self-emulsifiable preparation directly fill becomes the soft capsule application, and described solid-state self-emulsifier can further be made the application such as powder, granule, micropill, tablet.
Self-emulsifier containing breviscapine-phosphotide compound of the present invention can be used for treating the cardiovascular and cerebrovascular diseases such as hypertension, treating myocardial ischemia damage, cerebral thrombosis clinically.
Below in conjunction with example, the specific embodiment of the present invention is described further.It should be noted that at this, for the explanation of these embodiments, for helping to understand the present invention, but do not form limitation of the invention.In addition, below in each embodiment of described the present invention involved technical characterictic as long as form each other conflict, just can mutually not combine.
Proportioning in following each embodiment in the prescription composition all refers to mass percent.
Embodiment 1
(1) prescription forms:
(2) preparation technology:
The preparation of phosphatide complexes: take the former medicine 20g of breviscapine, soybean phospholipid 40g, be dissolved in the 2.0L dehydrated alcohol altogether, 60 ℃ of water-baths are reflux 2.0h in batches, and ethanol is removed in 60 ℃ of water-baths rotary evaporation in batches, obtains phosphatide complexes, be placed in the dry 12h of vacuum drying oven, sealed storage is standby.
The preparation of self-emulsifier: take phosphatide complexes and other self emulsifying components in above-mentioned prescription ratio, 30 ℃ of water-bath magnetic agitation 0.5h obtain liquid self-emulsifier.
(3) phosphatide complexes dissolubility test
Get appropriate alternative oil phase, surfactant and cosurfactant, add respectively the former medicine of excessive phosphatide complexes or breviscapine, vortex vibration 30min, 40 ℃ of shaking table balance 48h are fully to dissolve, centrifugal 10min under 8000rpm, get supernatant solution and dilute suitable multiple with methanol, determined by ultraviolet spectrophotometry breviscapine concentration.The dissolubility of the former medicine of the phosphatide complexes of gained and breviscapine in various oil phases, surfactant and cosurfactant be in Table 1, and result shows, after making phosphatide complexes, the dissolubility of breviscapine in each component all had raising in various degree.
Dissolubility (the unit: μ g/g) of the former medicine of table 1 phosphatide complexes and breviscapine in various oil, surfactant and cosurfactant.
(4) X-ray diffraction analysis of phosphatide complexes:
Adopt x-ray powder diffraction instrument (D8advance, German Bruker company) to survey phosphatide complexes Chinese medicine physical aspect.Test condition is: under room temperature, adjust voltage 40kV, electric current 40mA, control 5 °～65 ° of 2 θ angular scan ranges, 0.02 ° of step-length.Fig. 2 adopts x-ray powder diffraction instrument (D8advance, German Bruker company) test, and test condition is: under room temperature, adjust voltage 40kV, electric current 40mA, control 5 °～65 ° of 2 θ angular scan ranges, 0.02 ° of step-length.Test result shows: phosphatide complexes and soybean phospholipid are basically identical, do not have the characteristic peak of the former medicine crystal of breviscapine; In conjunction with the atlas analysis of physical mixed, the compound breviscapine of phospholipid may be to exist with unformed.
(5) sign of self-emulsifier:
Above-mentioned liquid self-emulsifier adds pure water by 1: 200 (v/v) and disperses, adopt laser particle analyzer (Zetasizer/Nano ZS90, Malvern company) recording particle diameter is 759 ± 21.6nm, and PDI is 0.391 ± 0.014, and Zeta potential is-21.2 ± 1.1mV.
Embodiment 2
(1) prescription forms:
(2) preparation technology:
Phosphatide complexes is embodiment 1 gained.
Take phosphatide complexes and other self emulsifying components in above-mentioned prescription ratio, 40 ℃ of water-bath magnetic agitation 1.5h obtain liquid self-emulsifier.
(3) relevant characterization:
Above-mentioned liquid self-emulsifier particle diameter is 287.4 ± 26.3nm, and PDI is 0.301 ± 0.019, and Zeta potential is-28.3 ± 1.4mV.Its tem observation result as shown in Figure 3, wherein, extension rate 1: 400 (v/v), TEM equipment (H-7000FA, Japanese Hitachi company).
Embodiment 3
(1) prescription forms:
(2) preparation technology:
Phosphatide complexes is embodiment 1 gained.
Form and take each component by prescription, first use the pre-dispersed phosphatide complexes of ethyl oleate, then add Cremophor RH40 and Transcutol
tMhP, 50 ℃ of water-bath magnetic agitation 2.5h obtain liquid self emulsifying system uniformly.
(3) relevant characterization:
Above-mentioned liquid self-emulsifier particle diameter is 123.7 ± 14.3nm, and PDI is 0.221 ± 0.015, and Zeta potential is-39.3 ± 5.4mV.
Embodiment 4
(1) prescription forms:
(2) preparation technology:
The preparation of phosphatide complexes: take the former medicine 1g of breviscapine, hydrogenated soya phosphatide 2g, be dissolved in 100mL acetone altogether, 60 ℃ of water-baths are reflux 2.0h in batches, and acetone is removed in 60 ℃ of water-baths rotary evaporation in batches, obtains phosphatide complexes, be placed in the dry 12h of vacuum drying oven, sealed storage is standby.
The preparation of self-emulsifier: form and take each component by above-mentioned prescription, first use the pre-dispersed phosphatide complexes of oleic acid, then add Cremophor EL and Transcutol HP, 60 ℃ of water-bath magnetic agitation 3.5h obtain liquid self-emulsifier.
(3) relevant characterization:
Above-mentioned liquid self-emulsifier particle diameter is 112.3 ± 12.2nm, and PDI is 0.278 ± 0.013, and Zeta potential is-33.1 ± 7.4mV.
Embodiment 5
(1) prescription forms:
(2) preparation technology:
Phosphatide complexes is embodiment 4 gained.
Form and take each component by above-mentioned prescription, first add Semen Maydis oil and Transcutol HP moistening phosphatide complexes, then add Cremophor RH40,80 ℃ of water-bath magnetic agitation 5h obtain liquid self-emulsifier.(3) relevant characterization:
Above-mentioned liquid self-emulsifier particle diameter is 109.3 ± 9.2nm, and PDI is 0.315 ± 0.033, and Zeta potential is-41.2 ± 7.4mV.
Embodiment 6
(1) prescription forms:
(2) preparation technology:
The preparation of phosphatide complexes: take the former medicine 5.0g of breviscapine, soybean phospholipid 5.0g, Ovum Gallus domesticus Flavus lecithin 5.0g, be dissolved in altogether in the 250mL oxolane, 40 ℃ of heating in water bath backflow 2.0h, 40 ℃ of water-bath rotary evaporations are removed oxolane, and the phosphatide complexes of gained is placed in vacuum drying oven 12h, collect product, sealed storage is standby.
The preparation of self-emulsifier: take phosphatide complexes and other self emulsifying components by above-mentioned prescription, 30 ℃ of water-bath magnetic agitation 0.5h obtain liquid self-emulsifier.
(3) relevant characterization:
Above-mentioned liquid self-emulsifier adds pure water by 1: 200 (v/v) and disperses, adopt laser particle analyzer (Zetasizer/Nano ZS90, Malvern company) recording particle diameter is 34.4 ± 1.3nm, and PDI is 0.212 ± 0.014, and Zeta potential is-5.8 ± 0.4mV.
Embodiment 7
(1) prescription forms:
(2) preparation technology:
The preparation of phosphatide complexes: take the former medicine 5.0g of breviscapine, Ovum Gallus domesticus Flavus lecithin 10.0g, be dissolved in altogether in 500mL oxolane/methanol (by 1: 1 volume mixture), 40 ℃ of heating in water bath backflow 2.0h, 40 ℃ of water-bath rotary evaporations are removed organic solvent, the phosphatide complexes of gained is placed in vacuum drying oven 12h, collects product, and sealed storage is standby.
The preparation of self-emulsifier: form and take each component by prescription, 40 ℃ of water-bath magnetic agitation 0.5h obtain liquid self-emulsifier.
(3) relevant characterization:
Recording particle diameter is 438.4 ± 15.2nm, and PDI is 0.321 ± 0.016, and Zeta potential is-23.3 ± 2.4mV.
Embodiment 8
(1) prescription forms:
(2) preparation technology:
Phosphatide complexes is embodiment 7 gained.
Form and take each component by prescription, 40 ℃ of water-bath magnetic agitation 1.5h obtain liquid self-emulsifier.
(3) relevant characterization:
Recording particle diameter is 383.4 ± 11.4nm, and PDI is 0.296 ± 0.022, and Zeta potential is-28.7 ± 2.1mV.
Embodiment 9
(1) prescription forms:
(2) preparation technology:
According to above-mentioned prescription ratio, take the former medicine 1.6g of breviscapine, Ovum Gallus domesticus Flavus lecithin 0.8g, be dissolved in altogether in 200mL methanol, 40 ℃ of heating in water bath backflow 2.0h, 40 ℃ of water-bath rotary evaporations are removed methanol, the gained phosphatide complexes is placed in vacuum drying oven 12h, and the taking-up sealed storage is stand-by.
Form and take above-mentioned phosphatide complexes and each component of self-emulsifier by prescription, 40 ℃ of water-bath magnetic agitation 1.5h obtain liquid self-emulsifier.
(3) relevant characterization:
Recording particle diameter is 534.4 ± 17.4nm, and PDI is 0.354 ± 0.027, and Zeta potential is-11.7 ± 1.3mV.
(1) prescription forms:
(2) preparation technology:
Phosphatide complexes is embodiment 7 gained.
Form and take each component by prescription, 60 ℃ of water-bath magnetic agitation 2.5h obtain liquid self-emulsifier.
(3) relevant characterization:
Recording particle diameter is 267.4 ± 13.8nm, and PDI is 0.214 ± 0.024, and Zeta potential is-35.8 ± 4.3mV.
Embodiment 11
(1) prescription forms:
(2) preparation technology:
Take the former medicine of breviscapine and each 0.1g of hydrogenated yolk lecithin, be dissolved in the 50mL chloroform, 40 ℃ of heating in water bath backflow 3h, 40 ℃ of water-bath rotary evaporations are removed chloroform, obtain phosphatide complexes, vacuum drying 12h, sealed storage is stand-by.
Take phosphatide complexes and self-emulsifier component in above-mentioned prescription ratio, 30 ℃ of water-bath lower magnetic forces stir 0.5h and obtain liquid self-emulsifier.
(3) relevant characterization:
Above-mentioned liquid self-emulsifier adds pure water by 1: 200 (v/v) and disperses, adopt laser particle analyzer (Zetasizer/Nano ZS90, Malvern company) recording particle diameter is 986.4 ± 29.3nm, and PDI is 0.487 ± 0.034, and Zeta potential is-15.8 ± 1.4mV.
Embodiment 12
(1) prescription forms:
(2) preparation technology:
Phosphatide complexes preparation: take the former medicine 1.0g of breviscapine, soybean phospholipid 2.0g, hydrogenated soya phosphatide 2.0g, be dissolved in altogether in the 100mL cyclohexane extraction, 50 ℃ of heating in water bath backflow 1.5h, 40 ℃ of water-bath rotary evaporations are removed cyclohexane extraction, are placed in vacuum drying oven 12h, collect product after bone dry, sealed storage is stand-by.
The self-emulsifier preparation: take phosphatide complexes and self-emulsifier component in above-mentioned prescription ratio, 40 ℃ of water-bath magnetic agitation 0.5h obtain liquid self-emulsifier.
(3) relevant characterization:
Above-mentioned liquid self-emulsifier adds pure water by 1: 200 (v/v) and disperses, and recording particle diameter is 32.4 ± 2.3nm, and PDI is 0.117 ± 0.014, and Zeta potential is-21.4 ± 2.1mV.
Embodiment 13
(1) prescription forms:
(2) preparation technology:
Phosphatide complexes is embodiment 11 gained.
Take phosphatide complexes and self-emulsifier component in above-mentioned prescription ratio, 30 ℃ of water-bath magnetic agitation 0.5h obtain liquid self-emulsifier.
(3) relevant characterization:
Above-mentioned liquid self-emulsifier adds pure water by 1: 200 (v/v) and disperses, and recording particle diameter is 775.2 ± 32.3nm, and PDI is 0.451 ± 0.024, and Zeta potential is-7.9 ± 0.6mV.
Embodiment 14
(1) prescription forms:
(2) preparation technology:
The phosphatide complexes preparation: take the former medicine 1.0g of breviscapine, hydrogenated yolk lecithin 3.0g, be dissolved in the 100mL ethyl acetate altogether, 50 ℃ of heating in water bath backflow 1.5h, 40 ℃ of water-bath rotary evaporations are removed ethyl acetate, obtain phosphatide complexes, be placed in vacuum drying oven 12h, collect product after bone dry
Sealed storage is stand-by.
The self-emulsifier preparation: take phosphatide complexes and self-emulsifier component in above-mentioned prescription ratio, 30 ℃ of water-bath magnetic agitation 0.5h obtain liquid self-emulsifier.
(3) relevant characterization:
Above-mentioned liquid self-emulsifier adds pure water by 1: 200 (v/v) and disperses, and recording particle diameter is 235.4 ± 12.3nm, and PDI is 0.342 ± 0.019, and Zeta potential is-32.6 ± 4.1mV.
(1) prescription forms:
(2) preparation technology:
Phosphatide complexes is embodiment 12 gained.
Take phosphatide complexes and self-emulsifier component in above-mentioned prescription ratio, in 40 ℃ of water-baths, magnetic agitation 2h is uniformly dispersed and get final product.
(3) relevant characterization:
Above-mentioned liquid self-emulsifier adds pure water by 1: 200 (v/v) and disperses, and recording particle diameter is 87.4 ± 4.3nm, and PDI is 0.107 ± 0.014, and Zeta potential is-13.5 ± 2.1mV.
Embodiment 16
(1) prescription forms:
(2) preparation technology:
Phosphatide complexes is embodiment 14 gained.
Take phosphatide complexes and self-emulsifier component in above-mentioned prescription ratio, in 40 ℃ of water-baths, magnetic agitation 1h is uniformly dispersed and get final product.
(3) relevant characterization:
Above-mentioned liquid self-emulsifier adds pure water by 1: 200 (v/v) and disperses, and recording particle diameter is 207.4 ± 20.3nm, and PDI is 0.298 ± 0.017, and Zeta potential is-27.4 ± 3.1mV.
Embodiment 17
(1) composition of liquid self-emulsifier:
(2) preparation and characterization of solid-state self-emulsifier:
The preparation method reference example 1 of liquid self-emulsifier.
Take liquid self-emulsifier and HPMC50cp in 2: 1 (w/w) ratios, HPMC is mixed with the aqueous solution of 20mg/mL, under the magnetic agitation condition, (500rpm) adds above-mentioned liquid self-emulsifier, fully after emulsifying, adopt Buchi B-290 spray drying to make solid-state self emulsifying powder, device parameter is INLET140 ℃, OUTLET70～75 ℃, ASPIRATION85%, PUMP20%.Gained solid state powder normal temperature drying storage is stand-by, or further granulation, tabletting etc.
Solid-state self-emulsifier adds pure water by 1: 100 (w/w) and disperses, adopt laser particle analyzer (Zetasizer/Nano ZS90, Malvern company) recording particle diameter is 1257.5 ± 43.5nm, and PDI is 0.564 ± 0.052, and Zeta potential is-11.2 ± 1.2mV.
Embodiment 18
(1) composition of liquid self-emulsifier:
(2) preparation and characterization of solid-state self-emulsifier:
The preparation method of liquid self-emulsifier is with embodiment 2.
Take liquid self-emulsifier and HPMC100cp in 1: 1 (w/w) ratio, HPMC is mixed with the aqueous solution of 20mg/mL, under the magnetic agitation condition, (500rpm) adds above-mentioned liquid self-emulsifier, fully after emulsifying, adopt Buchi B-290 spray drying to make solid-state self emulsifying powder, device parameter is INLET140 ℃, OUTLET70～75 ℃, ASPIRATION85%, PUMP20%.Gained solid state powder normal temperature drying storage is stand-by, or further granulation, tabletting etc.
Solid-state self-emulsifier adds pure water by 1:100 (w/w) and disperses, adopt laser particle analyzer (Zetasizer/Nano ZS90, Malvern company) recording particle diameter is 458.5 ± 33.1nm, and PDI is 0.321 ± 0.042, and Zeta potential is-13.2 ± 1.4mV.
Embodiment 19
(1) composition of liquid self-emulsifier:
(2) preparation and characterization of solid-state self-emulsifier:
The preparation method of liquid self-emulsifier is with embodiment 3.
Take liquid self-emulsifier and HPMC200cp in 1: 2 (w/w) ratio, HPMC is mixed with the aqueous solution of 20mg/mL, under the magnetic agitation condition, (500rpm) adds above-mentioned liquid self-emulsifier, fully after emulsifying, adopt Buchi B-290 spray drying to make solid-state self emulsifying powder, device parameter is INLET150 ℃, OUTLET70～75 ℃, ASPIRATION85%, PUMP20%.Gained solid state powder normal temperature drying storage is stand-by, or further granulation, tabletting etc.
Solid-state self-emulsifier adds pure water by 1: 100 (w/w) and disperses, and recording particle diameter is 386.5 ± 13.4nm, and PDI is 0.337 ± 0.032, and Zeta potential is-22.3 ± 2.2mV.
(1) liquid self-emulsifier forms:
(2) preparation technology:
The preparation of phosphatide complexes: take the former medicine 1g of breviscapine, soybean phospholipid 5g, be dissolved in the 100mL dichloromethane altogether, 60 ℃ of water-baths are reflux 2.0h in batches, and dichloromethane is removed in 60 ℃ of water-baths rotary evaporation in batches, obtains phosphatide complexes, be placed in the dry 12h of vacuum drying oven, sealed storage is standby.
The preparation of self-emulsifier: form and take each component by above-mentioned prescription, 60 ℃ of water-bath magnetic agitation 3.5h obtain liquid self-emulsifier.Take liquid self-emulsifier and HPMC400cp in 1: 2 (w/w) ratio, HPMC is mixed with the aqueous solution of 20mg/mL, under the magnetic agitation condition, (500rpm) adds above-mentioned liquid self-emulsifier, fully after emulsifying, adopt Buchi B-290 spray drying to make solid-state self emulsifying powder, device parameter is INLET150 ℃, OUTLET70～75 ℃, ASPIRATION85%, PUMP20%.Gained solid state powder normal temperature drying storage is stand-by, or further granulation, tabletting etc.
Solid-state self-emulsifier adds pure water by 1: 100 (w/w) and disperses, and recording particle diameter is 483.5 ± 23.4nm, and PDI is 0.367 ± 0.036, and Zeta potential is-26.3 ± 2.2mV.
Embodiment 21
(1) composition of liquid self-emulsifier:
(2) preparation and characterization of solid-state self-emulsifier:
The preparation method reference example 1 of liquid self-emulsifier.
Take liquid self-emulsifier and hetastarch in 1: 5 (w/w) ratio, hetastarch is mixed with the aqueous solution of 20mg/mL, under the magnetic agitation condition, (500rpm) adds above-mentioned liquid self-emulsifier, fully after emulsifying, adopt Buchi B-290 spray drying to make solid-state self emulsifying powder, device parameter is INLET130 ℃, OUTLET65～70 ℃, ASPIRATION85%, PUMP20%.Gained solid state powder normal temperature drying storage is stand-by, or further granulation, tabletting etc.
Solid-state self-emulsifier adds pure water by 1: 100 (w/w) and disperses, and records particle diameter and is: 533.5 ± 22.5nm, and PDI is 0.429 ± 0.021, Zeta potential is-35.5 ± 2.3mV.
Embodiment 22
(1) composition of liquid self-emulsifier:
(2) preparation and characterization of solid-state self-emulsifier:
Phosphatide complexes is by embodiment 9 gained.By the liquid self-emulsifier of above-mentioned formula preparation.Take liquid self-emulsifier and PLURONICS F87 in 1: 2 (w/w) ratio, poloxamer is mixed with the aqueous solution of 20mg/mL, under the magnetic agitation condition, (500rpm) adds above-mentioned liquid self-emulsifier, fully after emulsifying, adopt Buchi B-290 spray drying to make solid-state self emulsifying powder, device parameter is INLET130 ℃, OUTLET65～70 ℃, ASPIRATION85%, PUMP20%.Gained solid state powder normal temperature drying storage is stand-by, or further granulation, tabletting etc.
Solid-state self-emulsifier adds pure water by 1: 100 (w/w) and disperses, and recording particle diameter is 313.7 ± 14.5nm, and PDI is 0.389 ± 0.025, and Zeta potential is-38.5 ± 2.4mV.
Embodiment 23
(1) composition of liquid self-emulsifier:
(2) preparation and characterization of solid-state self-emulsifier:
The preparation of phosphatide complexes: take the 1.0g breviscapine, the 4.0g soybean phospholipid, use 200mL oxolane/isopropyl alcohol (1: 1v/v) mixed solvent disperses, 60 ℃ of heating in water bath backflow 2h, and rotary evaporation is removed organic solvent and be get final product.
The preparation of solid-state self-emulsifier: by above-mentioned prescription, form the liquid self-emulsifier of preparation, take liquid self-emulsifier and dextran in 1: 3 (w/w) ratio, dextran is mixed with the aqueous solution of 20mg/mL, under the magnetic agitation condition, (500rpm) adds above-mentioned liquid self-emulsifier, after emulsifying, adopts the BuchiB-290 spray drying to make solid-state self emulsifying powder fully, device parameter is INLET130 ℃, OUTLET65～70 ℃, ASPIRATION85%, PUMP20%.Gained solid state powder normal temperature drying storage is stand-by, or further granulation, tabletting etc.
Solid-state self-emulsifier adds pure water by 1: 100 (w/w) and disperses, and recording particle diameter is 217.5 ± 16.5nm, and PDI is 0.312 ± 0.018, and Zeta potential is-18.2 ± 2.1mV.
Embodiment 24
(1) prescription forms:
(2) preparation and characterization of solid-state self-emulsifier:
The preparation method of liquid self-emulsifier can be with reference to embodiment 9.
Take liquid self-emulsifier and trehalose in 1: 1 (w/w) ratio, trehalose is mixed with the aqueous solution of 20mg/mL, under the magnetic agitation condition, (500rpm) adds above-mentioned liquid self-emulsifier, fully after emulsifying, adopt Buchi B-290 spray drying to make solid-state self emulsifying powder, device parameter is INLET140 ℃, OUTLET70～75 ℃, ASPIRATION85%, PUMP20%.Gained solid state powder normal temperature drying storage is stand-by, or further granulation, tabletting etc.
Solid-state self-emulsifier adds pure water by 1: 100 (w/w) and disperses, and recording particle diameter is 975.7 ± 26.5nm, and PDI is 0.486 ± 0.027, and Zeta potential is-10.2 ± 0.4mV.
The dissolution test:
By " pertinent regulations in second appendix XC of Chinese pharmacopoeia version in 2010 adopt the oar method to carry out the dissolution test.The PBS buffer of pH6.8 of 900mL of take is dissolution medium, maintain 37 ± 0.5 ℃ of bath temperatures, adjust rotating speed of agitator 100rpm, respectively at 5,10,20,30,45,60,75,90,120,150,180min samples 5mL, 0.22 μ m filtering with microporous membrane, and supplementary 5mL blank medium, get subsequent filtrate and carry out ultraviolet spectrophotometry.Measure structure substitution standard curve equation, conversion accumulation dissolution.
First investigated the stripping behavior (seeing Fig. 4) of the former medicine of breviscapine, phosphatide complexes (embodiment 1), liquid self-emulsifier (embodiment 2) and liquid self-emulsifier (embodiment 3).The result demonstration, the phosphatide complexes dissolution rate of embodiment 1 gained is slow, but the accumulation stripping is higher than former medicine; And the liquid self-emulsifier of embodiment 2,3 gained discharges rapidly, fully, its drug loading does not have impact substantially on stripping.
Also compared liquid self-emulsifier (embodiment 2), liquid self-emulsifier (embodiment 3), the stripping behavior (seeing Fig. 5) of solid-state self-emulsifier (embodiment 18) and solid-state self-emulsifier (embodiment 19).Result shows, the liquid self-emulsifier stripping behavior zero difference of embodiment 2,3 gained, and the drug-eluting of liquid self-emulsifier is rapidly, fully; And the solid-state self-emulsifier of embodiment 18,19 gained, its drug-eluting wants much slow than corresponding liquid self-emulsifier (embodiment 2,3), simultaneously also thorough not; Embodiment 19 full-bodied HPMC400cp used makes drug-eluting slower.
Embodiment 26
The intestinal absorption experiment:
The sample of investigating is the former medicine of breviscapine, phosphatide complexes (embodiment 1), liquid self-emulsifier (embodiment 2 and embodiment 3).Each is organized sample and becomes respectively the pastille K-R liquid of certain solubility with the K-R compounding.Get 12 SD male rats (200～300g), be divided at random 4 groups, free diet.Before operation, chloral hydrate for rat (10%) is anaesthetized, open 2～3cm osculum in abdominal cavity, take out the jejunal segment of 8～10cm, the ligation upper end, at the auxiliary lower everted intestinal sac of small hose, clean small intestine contents, opening connects the 4cm plastic suction pipe, pour into the blank K-R liquid of 37 ℃ of preheatings, whole section intestinal capsule immerses in the blank K-R liquid of 37 ± 0.5 ℃ incubates 20min in advance, and logical medical oxygen is (containing 5%CO
2) to maintain the small intestinal activity.
Shift the intestinal capsule, immerse in the pastille K-R liquid of 37 ℃ of preheatings, continue logical oxygen, respectively at 15,30,45,60,90,120,150,180min gets 0.1mL sample determination drug level, final length and volume when measuring the intestinal capsule and filling, calculate the Heavy metal (ug/cm of each time point unit are
2), the intestinal absorption curve is as shown in Figure 6.Result shows, compared to former medicine form, with the form administration of phosphatide complexes, the intestinal absorption of breviscapine has had obvious improvement; And, with the form administration of self-emulsifier, Heavy metal has had again further must the raising, little on the impact of Heavy metal as for the drug loading of self-emulsifier.
Embodiment 27
Zoopery: need the sample of investigating to comprise: the former medicine of breviscapine, phosphatide complexes (embodiment 1), liquid self-emulsifier (embodiment 2, embodiment 3), solid-state self-emulsifier (embodiment 18, embodiment 19).30 male SD rats (200～300g) are divided into to 6 groups at random, and fasting 24h, freely drink water.Gastric infusion, dosage is 40mg/kg, the gavage volume below 3mL/kg, after administration respectively at 30min, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 36h time point eye socket is got the about 0.5ml of blood, and whole blood is centrifugal 10min under the 4000rpm condition, shifts supernatant blood plasma to be measured.Plasma treatment and detection, and the reference literature method (W.L.Lv, J.X.Guo, Q.N.Ping, et al.International Journal ofPharmaceutics, 2008,359:118-122.); It is as shown in table 2 that each organizes pharmacokinetic parameters, and during medicine, curve is shown in Fig. 7 and Fig. 8.Result shows, with the phosphatide complexes form administration, the oral absorption of breviscapine improves; On this basis, with the administration of phosphatide complexes self-emulsifier, further must the raising arranged again, and the better effects if of high concentration administration.The solid state oral disposition of self-emulsifier absorbs and does not make significant difference.
Table 2, the former medicine of breviscapine, phosphatide complexes (embodiment 1), liquid self-emulsifier (embodiment 2, embodiment 3), the pharmacokinetic parameters (number of samples n=5) of solid-state self-emulsifier (embodiment 18, embodiment 19).In table 2, C
maxmean blood Chinese medicine peak concentration, T
maxmean to reach blood Chinese medicine peak concentration C
maxtime, T
1/2zit is the elimination half-life of calculating by the statistical moment method, AUC (0-t) is the area under curve of calculating by the trapezoidal area method, these data of data representation that are labeled with " * " are compared with the corresponding data of the former medicine of breviscapine has significant difference (being p<0.05), these data of data representation that are labeled with " * * " are compared with the corresponding data of the former medicine of breviscapine has utmost point significant difference (being p<0.001), these data of data representation that are labeled with " # " are compared with the corresponding data of phosphatide complexes has significant difference (being p<0.05), these data of data representation that are labeled with " ## " are compared with the corresponding data of phosphatide complexes has utmost point significant difference (being p<0.001).
The above is preferred embodiment of the present invention, but the present invention should not be confined to the disclosed content of above-described embodiment.Do not break away from the equivalence completed under spirit disclosed in this invention so every or revise, all falling into the scope of protection of the invention.
Table 1
Table 2
Claims (10)
1. the self-emulsifier containing breviscapine-phosphotide compound, by percentage to the quality, each constituent content is: breviscapine 0.1～16%, phosphatidase 10 .1～32%, oil phase 20～70%, surfactant 10～50%, surplus is cosurfactant; The preferred content of each component is: breviscapine 1～12%, and phosphatidase 12～24%, oil phase 40～60%, surfactant 20～40%, surplus is cosurfactant.
2. according to claim 1 containing the self-emulsifier of breviscapine-phosphotide compound, it is characterized in that, in described breviscapine-phosphotide compound, the mass ratio of breviscapine and phospholipid is 1: 0.5～1: 5, and wherein preferred mass ratio is 1: 1～1: 3.
3. according to the described self-emulsifier containing breviscapine-phosphotide compound of claim 1 or 2, it is characterized in that, in described breviscapine-phosphotide compound, phospholipid is to comprise a kind of in soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, hydrogenated soya phosphatide, hydrogenated yolk lecithin or appoint severally, wherein is preferably soybean phospholipid.
4. according to the described self-emulsifier containing breviscapine-phosphotide compound of claim 1 or 2, it is characterized in that, described oil phase comprise in soybean oil, almond oil, Oleum Ricini, Semen Maydis oil, Oleum sesami, Oleum Arachidis hypogaeae semen, olive oil, rapeseed oil, Petiolus Trachycarpi oil, hydrogenated corn oil, oleic acid, linoleic acid, ethyl oleate, oleic acid polyethyleneglycol glyceride, glyceryl monooleate, Masine 35-1, propylene glycol two caprylic/capric esters and Miglyol 812 any or appoint several mixture.
5. according to the described self-emulsifier containing breviscapine-phosphotide compound of claim 1 or 2, it is characterized in that, described oil phase is ethyl oleate, or the mixture of Masine 35-1 and Miglyol 812, the mass ratio of mixture is preferably 1: 0.5～and 1: 2.
6. according to the described self-emulsifier containing breviscapine-phosphotide compound of claim 1 or 2, it is characterized in that, described surfactant comprise in polysorbate20/60/80, Polyethylene Glycol 800/1000/1500/2000, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, Labraso and Oleum Cocois polyethyleneglycol glyceride any or appoint several mixture, wherein, preferred polyoxyethylene hydrogenated Oleum Ricini.
7. according to the described self-emulsifier containing breviscapine-phosphotide compound of claim 1 or 2, it is characterized in that, described cosurfactant comprise in propylene glycol, Macrogol 200/400/600, Capryol 90, PGML, ethylene glycol monomethyl ether or polyglyceryl fatty acid ester any or appoint several mixture, wherein, preferred propylene glycol or ethylene glycol monomethyl ether.
8. the preparation method of the described self-emulsifier containing breviscapine-phosphotide compound of a claim 1, the method comprises the steps:
(1) take breviscapine and the phospholipid of recipe quantity, add the organic solvent dispersion medicine, one or several in the optional ethyl acetate of described organic solvent, oxolane, dichloromethane, chloroform, normal hexane, cyclohexane extraction, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, acetone, preferably oxolane, methanol and ethanol; Adjust solution Chinese medicine concentration in 2～20mg/mL, preferably 5～10mg/mL; Reflux 0.5～3h in 40～60 ℃ of water-baths, rotary evaporation is removed organic solvent, obtains breviscapine-phosphotide compound; (2) get in the oil phase that appropriate breviscapine-phosphotide compound adds recipe quantity, 30～80 ℃ of stirring in water bath 0.5～5h, then add surfactant and the cosurfactant of recipe quantity, continue to stir until fully evenly, obtain.
9. preparation method according to claim 8, is characterized in that,
What above-mentioned preparation method obtained is the liquid self-emulsifier containing breviscapine-phosphotide compound, and after this self-emulsifier aqueous dispersion, particle diameter is 30～1000nm; Perhaps add firming agent and further be prepared as solid-state self-emulsifier, after solid-state self-emulsifier aqueous dispersion, particle diameter is 50～1300nm
Described firming agent comprise in water-soluble saccharides, starch and modified starch, cellulose and derivant thereof, polyvinylpyrrolidone and poloxamer any or appoint several; The preferred hydroxypropyl methylcellulose (HPMC) of 50cp～400cp wherein;
Described solid-state self-emulsifier, the mass ratio of liquid self-emulsifier and firming agent is 1: 0.1～1: 5, preferably 1: 0.5～1: 2.
10. according to claim 1 containing the self-emulsifier of breviscapine-phosphotide compound, it is characterized in that, described liquid self-emulsifiable preparation directly fill becomes the soft capsule application; Described solid-state self-emulsifier can further be made the application of powder, granule, micropill, tablet; The described self-emulsifier containing breviscapine-phosphotide compound can be used in the cardiovascular and cerebrovascular diseases such as treatment hypertension, treating myocardial ischemia damage, cerebral thrombosis clinically.
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