CN102793674A - 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
- Publication number
- CN102793674A CN102793674A CN2011101390862A CN201110139086A CN102793674A CN 102793674 A CN102793674 A CN 102793674A CN 2011101390862 A CN2011101390862 A CN 2011101390862A CN 201110139086 A CN201110139086 A CN 201110139086A CN 102793674 A CN102793674 A CN 102793674A
- Authority
- CN
- China
- Prior art keywords
- emulsion
- oil
- particles
- triptolide
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- 239000002047 solid lipid nanoparticle Substances 0.000 title claims abstract description 127
- DFBIRQPKNDILPW-CIVMWXNOSA-N Triptolide Chemical compound O=C1OCC([C@@H]2C3)=C1CC[C@]2(C)[C@]12O[C@H]1[C@@H]1O[C@]1(C(C)C)[C@@H](O)[C@]21[C@H]3O1 DFBIRQPKNDILPW-CIVMWXNOSA-N 0.000 title claims abstract description 116
- YKUJZZHGTWVWHA-UHFFFAOYSA-N triptolide Natural products COC12CC3OC3(C(C)C)C(O)C14OC4CC5C6=C(CCC25C)C(=O)OC6 YKUJZZHGTWVWHA-UHFFFAOYSA-N 0.000 title claims abstract description 116
- 238000002360 preparation method Methods 0.000 title claims description 100
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 162
- 239000000839 emulsion Substances 0.000 claims abstract description 151
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 86
- 239000006185 dispersion Substances 0.000 claims abstract description 81
- 150000002632 lipids Chemical class 0.000 claims abstract description 75
- 239000003960 organic solvent Substances 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 47
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 43
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 25
- 239000008367 deionised water Substances 0.000 claims abstract description 23
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 92
- 239000003921 oil Substances 0.000 claims description 64
- 235000019198 oils Nutrition 0.000 claims description 64
- 239000012071 phase Substances 0.000 claims description 60
- 229960002668 sodium chloride Drugs 0.000 claims description 46
- 235000002639 sodium chloride Nutrition 0.000 claims description 46
- 239000011780 sodium chloride Substances 0.000 claims description 46
- 239000007788 liquid Substances 0.000 claims description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 239000008346 aqueous phase Substances 0.000 claims description 38
- 230000001804 emulsifying effect Effects 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 26
- 239000008187 granular material Substances 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- -1 polyoxyethylene Polymers 0.000 claims description 19
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 18
- 102000002322 Egg Proteins Human genes 0.000 claims description 18
- 108010000912 Egg Proteins Proteins 0.000 claims description 18
- 241000287828 Gallus gallus Species 0.000 claims description 18
- 239000000787 lecithin Substances 0.000 claims description 18
- 235000010445 lecithin Nutrition 0.000 claims description 18
- 229940067606 lecithin Drugs 0.000 claims description 18
- 210000004681 ovum Anatomy 0.000 claims description 18
- 230000002085 persistent effect Effects 0.000 claims description 16
- WECGLUPZRHILCT-GSNKCQISSA-N 1-linoleoyl-sn-glycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@@H](O)CO WECGLUPZRHILCT-GSNKCQISSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 12
- 239000003223 protective agent Substances 0.000 claims description 11
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 230000009467 reduction Effects 0.000 claims description 10
- 238000009834 vaporization Methods 0.000 claims description 10
- 230000008016 vaporization Effects 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 238000001694 spray drying Methods 0.000 claims description 8
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 7
- 238000004108 freeze drying Methods 0.000 claims description 7
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 7
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 claims description 7
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 239000005639 Lauric acid Substances 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
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- 238000013019 agitation Methods 0.000 claims description 6
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 6
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 5
- 235000021355 Stearic acid Nutrition 0.000 claims description 5
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 5
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 5
- 239000008117 stearic acid Substances 0.000 claims description 5
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 4
- 229930195729 fatty acid Natural products 0.000 claims description 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 150000004665 fatty acids Chemical class 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 4
- 229920000151 polyglycol Polymers 0.000 claims description 4
- 239000010695 polyglycol Substances 0.000 claims description 4
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 claims description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 3
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 3
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 3
- MRABAEUHTLLEML-UHFFFAOYSA-N Butyl lactate Chemical compound CCCCOC(=O)C(C)O MRABAEUHTLLEML-UHFFFAOYSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000005642 Oleic acid Substances 0.000 claims description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 3
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- 239000001191 butyl (2R)-2-hydroxypropanoate Substances 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 3
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 3
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 3
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- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 claims description 3
- 229940083466 soybean lecithin Drugs 0.000 claims description 3
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 3
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 claims description 2
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
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- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
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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 method for preparing of nanoparticle raw materials medicine, be specifically related to a kind of triptolide solid lipid nano-particles.
Background technology
(Triptolide TP), claims Radix Tripterygii Wilfordii lactone alcohol again to triptolide; Be from Celastraceae Thunder God Calamus Radix Tripterygii Wilfordii (Tripterygium Wilfordii Hook.f; TWHf) separating a kind of diterpenic lactone that obtains in, is one of main effective ingredient in the Radix Tripterygii Wilfordii, and molecular formula is C
20H
24O
6, molecular weight is 360.4, is insoluble in water, is dissolved in organic solvents such as methanol, ethanol, propylene glycol, acetone, dimethyl sulfoxide, ultraviolet maximum absorption wavelength is 218nm.Its chemical structural formula is as shown in Figure 1.
Triptolide has significant immunosuppressive action, can be used for treating dermatosis such as rheumatoid arthritis, chronic nephritis and lupus erythematosus, psoriasis, and very strong resisting transplant rejection effect is arranged simultaneously.Yet triptolide toxicity is big, the LD that quiet notes of mice and lumbar injection first are plain
50Be respectively 0.8mg/kg, 0.9mg/kg.See children Zheng orchid etc., " Triptolide is to some toxicity of mice and dog ", Acta Pharmacologica Sinica, 1981,2 (1): 70-72.The conventional formulation intravenous injection is prone to cause that vein festers, and oral have the strong impulse effect to gastrointestinal tract.
The triptolide half-life in vivo is short, is prone to by metabolism.Plain dosage 0.6,1.2 of the oral first of rat and 2.4mg/kg, peak reaching time of blood concentration is in 15min, and the elimination half-life is 16.81～21.70min.The intravenous injection first is plain, dosage 0.6mg/kg, and behind the 48h, the medication amount in excrement, bile, the urine is respectively 0.03%, 0.43% and 0.06% of a dosage, shows that the 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 nanoparticle is the administration nano-drug administration system of new generation that grows up the nineties in 20th century SLN) to solid lipid nano-particles, is by at room temperature being the colloidal particle that solid-state biodegradable lipid forms.SLN can improve the oral administration biaavailability of insoluble drug, thereby reduces using dosage, and this administration for the toxic medicament triptolide is very significant.
Existing solid lipid nano-particles method for preparing 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, mechanism such as high shear possibly cause medicine degeneration and loss, causes envelop rate to reduce.
SLN can slowly discharge medicine, prolong drug half-life.The means that realize the SLN slow release at present mainly are to select suitable lipid carrier and technology to make more medicine be in particulate kernel; Or the release that delays medicine of covalent bond or electrostatic interaction through medicine and lipid carrier, and particle diameter and particle size distribution are paid close attention to less to the influence that discharges.
Existing SLN preparation technology can't accurately control particle diameter and particle size distribution, and stable preparation process property is poor.And film emulsifying (Membrane emulsification) technology can be passed through film parameter and film emulsion process parameters of choice, realizes the accuracy controlling to particle diameter such as Emulsion or microsphere/microcapsule and particle size distribution.The film emulsifying technology is the new method of the preparation Emulsion that on the membrane technology basis, grows up (single breast, many breasts) and microsphere/microcapsule.Its stable preparation process property is good, and entrapment efficiency is high, and preparation condition is gentle, and energy expenditure is low, is easy to industry and amplifies, and has represented good application prospects in fields such as biological medicine, food, chemical industry.A kind of quick film emulsifying technology that grows up is again in recent years claimed pre-emulsion film emulsifying (Premix membrane) again, and promptly preparation pre-emulsion earlier with pre-emulsion fenestra through uniform particle diameter under elevated pressures, obtains homogenous emulsion then.Because the preparation efficiency of this method emulsion is high, can prepare the littler emulsion droplet of particle diameter, therefore the scope of application is widely arranged than direct film emulsifying technology.
Summary of the invention
The present invention provides a kind of method for preparing of triptolide solid lipid nano-particles; Solving existing solid lipid nano-particles method for preparing can't accurately control particle diameter and distribution thereof; And the problem of poor reproducibility, monodispersity is good, envelop rate is high, the crude drug of process stabilizing for the Radix Tripterygii Wilfordii preparation provides.
The method for preparing of a kind of triptolide solid lipid nano-particles of the present invention may further comprise the steps:
(1) pre-emulsion preparation: triptolide is dissolved in the organic solvent as oil phase with mixing lipid, and triptolide is 1: 10～1: 1000 with the mass ratio of mixing lipid, and the mass volume ratio of mixing lipid and organic solvent is 1g: 5～10mL;
Again oil phase is scattered in aqueous phase, oil phase and water volume ratio are 1: 2～1: 20, adopt high-shear emulsifying to obtain the 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 quick film emulsifying device, under nitrogen pressure, obtain emulsion oil-in-water through oil-in-water type pre-emulsion cycles prepare;
(3) dispersion liquid preparation: said emulsion oil-in-water is carried out magnetic agitation 24h or reduction vaporization 1～2h, remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions; Perhaps sodium-chloride water solution is added said emulsion oil-in-water; Organic solvent is diffused in the 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 preparation of granules: with solid lipid nano-particles aqueous dispersions or solid lipid nano-particles sodium chloride dispersion liquid or carry out centrifugalize, or spray drying or lyophilization, obtain the triptolide solid lipid nano-particles.
Described method for preparing; Preferably, in the said pre-emulsion preparation process, mix lipid and constitute by lipoid and lipid carrier mixing; The mass ratio of lipoid and lipid carrier is 1: 2～1: 5, and said lipoid is a kind of in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, the phosphatidylcholine; Said lipid carrier is a kind of in satisfied fatty acid, saturated fatty acid glyceride, the liquid oil or two kinds mixture wherein;
Said satisfied fatty acid is a kind of in stearic acid, Palmic acid, myristic acid, lauric acid, capric acid, the mountain Yu acid or two kinds mixture wherein;
Said saturated fatty acid glyceride class is the triglyceride of stearic acid, Palmic acid, myristic acid, lauric acid, capric acid, mountain Yu acid, double glyceride, monoglyceride or two or three mixture wherein;
Said liquid oil is a kind of in sad three sweet/capric acid triglyceride, isopropyl myristate, isopropyl palmitate, the own fat of lauric acid, oleic acid, linoleic acid, single glyceryl linoleate, the soybean oil or two kinds mixture wherein.
Described method for preparing, in the said 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, the butyl lactate or two kinds mixture wherein.
Described method for preparing; In the said pre-emulsion preparation process; Said 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, poloxamer 188, poloxamer 407, 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 the 2-propylene glycol or two kinds mixture wherein.
In the said pre-emulsion preparation process, take high-shear emulsifying to obtain the oil-in-water type pre-emulsion, rotating speed is 10,000r/min～30,000r/min, persistent period 1min～5min.
In the said solid nano preparation of granules step, when solid lipid nano-particles aqueous dispersions or solid lipid nano-particles sodium chloride dispersion liquid were carried out centrifugalize, centrifugal speed was 1,000r/min～5,000r/min, persistent period 10min～30min.
Described method for preparing; In the said solid nano preparation of granules step; When solid lipid nano-particles aqueous dispersions or solid lipid nano-particles sodium chloride dispersion liquid are carried out spray drying or lyophilization; Spray drying or cryodesiccated protective agent are selected from a kind of in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, maltose, lactose, mannitol, glucose, trehalose, arabic gum, xylitol, sorbitol, fructose, the sucrose, and 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 provides a kind of triptolide solid lipid nano-particles and application thereof.
Concrete technical scheme is following:
The triptolide solid lipid nano-particles for preparing of method from the above mentioned.
The application of described triptolide solid lipid nano-particles in preparation triptolide injection, oral or preparation capable of permeating skin.
Research shows that the monodispersed drug-loading system of particle diameter has control preferably for the 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 steadily effectively blood drug level is extremely important for keeping.
The present invention adopts preparatory emulsifying to combine SPG film emulsifying technology, is carrier material to mix lipid, the parcel triptolide.The advantage of binding film technology of the present invention and the characteristic of solid lipid nano-particles itself; Method for preparing is simple fast, 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%.Said triptolide solid lipid nano-particles can be used for preparing triptolide injection, oral or preparation capable of permeating skin.
Description of drawings
Fig. 1 is the chemical structural formula of triptolide.
Fig. 2 is triptolide solid lipid nano-particles particle diameter and a scattergram thereof among the embodiment 3.
Fig. 3 is triptolide solid lipid nano-particles particle diameter and a scattergram thereof among the embodiment 5.
Fig. 4 is triptolide solid lipid nano-particles particle diameter and a scattergram thereof among the embodiment 7.
Fig. 5 is triptolide solid lipid nano-particles particle diameter and a scattergram thereof among the embodiment 8.
The specific embodiment
The quick film emulsifying device that adopts in the method for the invention is Japan (SPG Technology Co., Ltd) company's production; Inorganic micropore glass (SPG, Shirasu porous glass) film is a tubular film, external diameter 10mm, thickness 0.4mm～1mm, length 20mm, aperture 0.1 μ m～1 μ m.Under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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 specified.
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 600mg; Ovum Gallus domesticus Flavus lecithin 2.0g; Tripalmitin 3.2g, single glyceryl linoleate 0.8g are dissolved in the 30mL dichloromethane as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains polyoxyethylene hydrogenated Oleum Ricini 6.0g, is heated to 60 ℃, and 30,000r/min, high shear 1min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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 said emulsion oil-in-water reduction vaporization 2h, remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions;
(4) solid nano preparation of granules: with the centrifugalize of solid lipid nano-particles aqueous dispersions, centrifugal speed is 1,000r/min, and persistent period 30min obtains the 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 method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 600mg; Ovum Gallus domesticus Flavus lecithin 2.0g; Tripalmitin 3.2g, single glyceryl linoleate 0.8g are dissolved in the 30mL ethyl acetate as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains polyoxyethylene hydrogenated Oleum Ricini 6.0g, is heated to 60 ℃, and 30,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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: said emulsion oil-in-water is carried out magnetic agitation 24h remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions;
(4) solid nano preparation of granules: with the lyophilization of solid lipid nano-particles aqueous dispersions, be protective agent with the trehalose, 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 method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 600mg; Ovum Gallus domesticus Flavus lecithin 2.0g; Tripalmitin 3.2g, single glyceryl linoleate 0.8g are dissolved in the 30mL dichloromethane as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains polyoxyethylene hydrogenated Oleum Ricini 6.0g, is heated to 60 ℃, and 10,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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: said emulsion oil-in-water is carried out magnetic agitation 24h remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions;
(4) solid nano preparation of granules: with the centrifugalize of solid lipid nano-particles aqueous dispersions, centrifugal speed is 5,000r/min, and persistent period 10min obtains the 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 like Fig. 2.
Embodiment 4
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 600mg; Ovum Gallus domesticus Flavus lecithin 2.0g; Tripalmitin 2.0g, single glyceryl linoleate 2.0g are dissolved in the 30mL dichloromethane as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains polyoxyethylene hydrogenated Oleum Ricini 6.0g, is heated to 60 ℃, and 10,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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 said emulsion oil-in-water reduction vaporization 1h, remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions;
(4) solid nano preparation of granules: with the centrifugalize of solid lipid nano-particles aqueous dispersions, centrifugal speed is 5,000r/min, and persistent period 30min obtains the 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 method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation process: with triptolide 600mg; Ovum Gallus domesticus Flavus lecithin 2.0g; Tripalmitin 2.0g, single glyceryl linoleate 2.0g are dissolved in the 30mL dichloromethane as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains polyoxyethylene hydrogenated Oleum Ricini 5.0g and sodium cholate 1.0g, is heated to 60 ℃, and 10,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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 said emulsion oil-in-water reduction vaporization 1h, remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions;
(4) solid nano preparation of granules: with the lyophilization of solid lipid nano-particles aqueous dispersions, be protective agent with the trehalose, 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 like Fig. 3.
Embodiment 6
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 600mg; Ovum Gallus domesticus Flavus lecithin 2.0g; Tripalmitin 2.0g, single glyceryl linoleate 2.0g are dissolved in the 30mL dichloromethane as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the consumption that mixes lipid summation and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains polyoxyethylene hydrogenated Oleum Ricini 5.0g and sodium cholate 1.0g, is heated to 60 ℃, and 10,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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: with mass percentage concentration is that 0.9% sodium-chloride water solution 540mL adds said emulsion oil-in-water; Organic solvent is diffused in the 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 preparation of granules: with the centrifugalize of solid lipid nano-particles sodium chloride dispersion liquid, centrifugal speed is 5,000r/min, and persistent period 30min obtains the 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 method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 600mg; Ovum Gallus domesticus Flavus lecithin 2.0g; Tripalmitin 2.0g, single glyceryl linoleate 2.0g are dissolved in the 30mL dichloromethane as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains polyoxyethylene hydrogenated Oleum Ricini 5.0g and sodium cholate 1.0g, is heated to 60 ℃, and 10,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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: with mass percentage concentration is that 0.9% sodium-chloride water solution 540mL adds said emulsion oil-in-water; Organic solvent is diffused in the 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 preparation of granules: with the centrifugalize of solid lipid nano-particles sodium chloride dispersion liquid, centrifugal speed is 5,000r/min, and persistent period 30min obtains the 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 like Fig. 4.
Embodiment 8
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 6.0mg; Ovum Gallus domesticus Flavus lecithin 1.0g; Compritol 888 ATO 3.0g, caprylic/capric triglyceride 2.0g, the mixed solvent that is dissolved in 60mL dichloromethane and ethyl acetate are as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 5; Triptolide is 1: 1000 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 10mL;
Again oil phase is scattered in the 1200mL aqueous phase, aqueous phase contains polyvinyl alcohol 12.0g, is heated to 80 ℃, and 30,000r/min, high shear 1min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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 said emulsion oil-in-water reduction vaporization 2h, remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions;
(4) solid nano preparation of granules step: with solid lipid nano-particles aqueous dispersions spray drying, be protective agent with the hydroxypropyl emthylcellulose, 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 like Fig. 5.
Embodiment 9
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 6.0mg; Ovum Gallus domesticus Flavus lecithin 1.0g; Compritol 888 ATO 2.0g, single glyceryl linoleate 3.0g, the mixed solvent that is dissolved in 60mL dichloromethane and ethyl acetate are as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 5; Triptolide is 1: 1000 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 10mL;
Again oil phase is scattered in the 1200mL aqueous phase, aqueous phase contains polyvinyl alcohol 10.0g and sodium cholate 2.0g, is heated to 80 ℃, and 30,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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 said emulsion oil-in-water reduction vaporization 2h, remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions;
(4) solid nano preparation of granules: with solid lipid nano-particles aqueous dispersions spray drying, be protective agent with the hydroxypropyl emthylcellulose, 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%.
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 6.0mg; Ovum Gallus domesticus Flavus lecithin 1.0g; Compritol 888 ATO 2.0g, single glyceryl linoleate 3.0g, the mixed solvent that is dissolved in 60mL dichloromethane and ethyl acetate are as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 5; Triptolide is 1: 1000 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 10mL;
Again oil phase is scattered in the 1200mL aqueous phase, aqueous phase contains polyvinyl alcohol 10.0g and sodium cholate 2.0g, is heated to 80 ℃, and 30,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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: with mass percentage concentration is that 0.9% sodium-chloride water solution 2520mL adds said emulsion oil-in-water; Organic solvent is diffused in the 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 preparation of granules: with the centrifugalize of solid lipid nano-particles sodium chloride dispersion liquid, centrifugal speed is 5,000r/min, and persistent period 10min obtains the 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 method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 600mg; Soybean lecithin 2.0g; Stearic acid 3.2g, isopropyl myristate 0.8g are dissolved in the 30mL isopropyl alcohol as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains polyglycol distearate 6.0g, is heated to 70 ℃, and 30,000r/min, high shear 1min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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 said emulsion oil-in-water reduction vaporization 2h, remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions;
(4) solid nano preparation of granules: with the centrifugalize of solid lipid nano-particles aqueous dispersions, centrifugal speed is 1,000r/min, and persistent period 30min obtains the triptolide solid lipid nano-particles.
Embodiment 12
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 600mg; Phosphatidylcholine 2.0g; Tripalmitin 3.2g, oleic acid 0.8g are dissolved in the 30mL propyl acetate as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains polyoxyethylene castor oil 6.0g, is heated to 60 ℃, and 30,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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: said emulsion oil-in-water is carried out magnetic agitation 24h remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions;
(4) solid nano preparation of granules: with the lyophilization of solid lipid nano-particles aqueous dispersions, be protective agent with mannitol, consumption 0.6g, the amount ratio of 1g trehalose and solid lipid nano-particles aqueous dispersions is 100mL.
Embodiment 13
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 600mg; Ovum Gallus domesticus Flavus lecithin 2.0g; Tristerin 3.2g, isopropyl palmitate 0.8g are dissolved in the 30mL chloroform as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains tween 20 6.0g, is heated to 70 ℃, and 10,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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: said emulsion oil-in-water is carried out magnetic agitation 24h remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions;
(4) solid nano preparation of granules: with the centrifugalize of solid lipid nano-particles aqueous dispersions, centrifugal speed is 5,000r/min, and persistent period 10min obtains the triptolide solid lipid nano-particles.
Embodiment 14
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 600mg; Ovum Gallus domesticus Flavus lecithin 2.0g; Tripalmitin 2.0g, single glyceryl linoleate 2.0g, being dissolved in the 30mL butyl lactate is oil phase, the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains poloxamer 1886.0g, is heated to 60 ℃, and 10,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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 said emulsion oil-in-water reduction vaporization 1h, remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions;
(4) solid nano preparation of granules: with the centrifugalize of solid lipid nano-particles aqueous dispersions, centrifugal speed is 5,000r/min, and persistent period 30min obtains the triptolide solid lipid nano-particles.
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 600mg; Ovum Gallus domesticus Flavus lecithin 2.0g; Tripalmitin 2.0g, single glyceryl linoleate 2.0g are dissolved in the 30mL benzyl alcohol as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the consumption that mixes lipid summation and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains polyglycol distearate 5.0g and deoxidation natrii tauroglycocholas 1.0g, is heated to 60 ℃, and 10,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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: with mass percentage concentration is that 0.88% sodium-chloride water solution 540mL adds said emulsion oil-in-water; Organic solvent is diffused in the 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 preparation of granules: with the centrifugalize of solid lipid nano-particles sodium chloride dispersion liquid, centrifugal speed is 5,000r/min, and persistent period 30min obtains the triptolide solid lipid nano-particles.
Embodiment 16
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 600mg; Ovum Gallus domesticus Flavus lecithin 2.0g; Tripalmitin 2.0g, single glyceryl linoleate 2.0g are dissolved in the 30mL dichloromethane as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 2; Triptolide is 1: 10 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 5mL;
Again oil phase is scattered in the 60mL aqueous phase, aqueous phase contains polyoxyethylene hydrogenated Oleum Ricini 5.0g and sodium glycocholate 1.0g, is heated to 60 ℃, and 10,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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: with mass percentage concentration is that 0.92% sodium-chloride water solution 540mL adds said emulsion oil-in-water; Organic solvent is diffused in the 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 preparation of granules: with the centrifugalize of solid lipid nano-particles sodium chloride dispersion liquid, centrifugal speed is 5,000r/min, and persistent period 30min obtains the triptolide solid lipid nano-particles.
Embodiment 17
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 6.0mg; Ovum Gallus domesticus Flavus lecithin 1.0g; Compritol 888 ATO 3.0g, linoleic acid 2.0g, the mixed solvent that is dissolved in 60mL chloroform and acetone are as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 5; Triptolide is 1: 1000 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 10mL;
Again oil phase is scattered in the 1200mL aqueous phase, aqueous phase contains polyvinyl alcohol 12.0g, is heated to 80 ℃, and 30,000r/min, high shear 1min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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 said emulsion oil-in-water reduction vaporization 2h, remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions;
(4) solid nano preparation of granules step: with solid lipid nano-particles aqueous dispersions spray drying, be protective agent with the glucose, consumption 12.0g, with solid lipid nano-particles aqueous dispersions amount ratio be 1g: 100mL.
Embodiment 18
The method for preparing of the said triptolide solid lipid nano-particles of present embodiment may further comprise the steps:
(1) pre-emulsion preparation: with triptolide 6.0mg; Ovum Gallus domesticus Flavus lecithin 1.0g; Compritol 888 ATO 2.0g, single glyceryl linoleate 3.0g, the mixed solvent that is dissolved in 60mL dichloromethane and ethyl acetate are as oil phase, and the mass ratio of lipoid and lipid carrier is 1: 5; Triptolide is 1: 1000 with the mass ratio that mixes lipid, and the amount ratio that mixes lipid and organic solvent is 1g: 10mL;
Again oil phase is scattered in the 1200mL aqueous phase, aqueous phase contains polyvinyl alcohol 10.0g and dodecyl sodium sulfate 2.0g, is heated to 80 ℃, and 30,000r/min, high shear 5min obtains the 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 quick film emulsifying device, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the 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: with mass percentage concentration is that 0.92% sodium-chloride water solution 2520mL adds said emulsion oil-in-water; Organic solvent is diffused in the 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 preparation of granules: with the centrifugalize of solid lipid nano-particles sodium chloride dispersion liquid, centrifugal speed is 5,000r/min, and persistent period 10min obtains the triptolide solid lipid nano-particles.
More than be to the specifying of possible embodiments of the present invention, but this embodiment is not in order to limiting claim of the present invention, does not allly break away from the equivalence that skill spirit of the present invention does and implement or change, all should be contained in the claim of the present invention.
Claims (10)
1. a triptolide solid lipid nano-particles is characterized in that, may further comprise the steps:
(1) pre-emulsion preparation: triptolide is dissolved in the organic solvent as oil phase with mixing lipid, and triptolide is 1: 10～1000 with the mass ratio of mixing lipid, and the amount ratio of mixing lipid and organic solvent is 1g: 5～10mL;
Again oil phase is scattered in aqueous phase, oil phase and water volume ratio are 1: 2～1: 20, adopt high-shear emulsifying to obtain the oil-in-water type pre-emulsion;
Said 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 quick film emulsifying device, under nitrogen pressure, obtain emulsion oil-in-water through the circulation of oil-in-water type pre-emulsion;
(3) dispersion liquid preparation: said emulsion oil-in-water is carried out magnetic agitation or reduction vaporization, remove organic solvent, obtain the solid lipid nano-particles aqueous dispersions; Perhaps sodium-chloride water solution is added said emulsion oil-in-water; Organic solvent is diffused in the 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 preparation of granules: with solid lipid nano-particles aqueous dispersions or solid lipid nano-particles sodium chloride dispersion liquid or carry out centrifugalize, or spray drying or lyophilization, obtain the triptolide solid lipid nano-particles.
2. method for preparing as claimed in claim 1; It is characterized in that; Said mixing lipid is mixed by lipoid and lipid carrier and constitutes, and the mass ratio of said lipoid and lipid carrier is 1: 2～1: 5, and said lipoid is a kind of in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, the phosphatidylcholine; Said lipid carrier is a kind of in satisfied fatty acid, saturated fatty acid glyceride, the liquid oil or two kinds mixture wherein;
Said satisfied fatty acid is a kind of in stearic acid, Palmic acid, myristic acid, lauric acid, capric acid, the mountain Yu acid or two kinds mixture wherein;
Said saturated fatty acid glyceride class is the triglyceride of stearic acid, Palmic acid, myristic acid, lauric acid, capric acid, mountain Yu acid, double glyceride, monoglyceride or two or three mixture wherein;
Said liquid oil is a kind of in caprylic/capric triglyceride, isopropyl myristate, isopropyl palmitate, the own fat of lauric acid, oleic acid, linoleic acid, single glyceryl linoleate, the soybean oil or two kinds mixture wherein.
3. method for preparing as claimed in claim 1 is characterized in that, said organic solvent is a kind of in dichloromethane, chloroform, ethyl acetate, propyl acetate, toluene, ethanol, isopropyl alcohol, acetone, benzyl alcohol, the butyl lactate or two kinds mixture wherein.
4. method for preparing as claimed in claim 1; It is characterized in that; Said emulsifying agent is polyvinyl alcohol, tween 80, tween 20, Tween-40, Arlacel-80, Arlacel-20, Myrj 52, Myrj 53, Brij30, Brij35, poloxamer 188, poloxamer 407, 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, a kind of in the 2-propylene glycol or two kinds mixture wherein.
5. like each described method for preparing of claim 1-4, it is characterized in that adopt high-shear emulsifying to obtain the oil-in-water type pre-emulsion in the step (1), rotating speed is 10,000r/min～30,000r/min, persistent period 1min～5min.
6. like each described method for preparing of claim 1-4, it is characterized in that, under nitrogen pressure, make the oil-in-water type pre-emulsion cycle through the SPG film 1～7 time, obtain emulsion oil-in-water, nitrogen pressure is 70～140psi.
7. like each described method for preparing of claim 1-4; It is characterized in that; When in the step (4) solid lipid nano-particles aqueous dispersions or solid lipid nano-particles sodium chloride dispersion liquid being carried out centrifugalize, centrifugal speed is 1,000r/min～5; 000r/min, persistent period 10min～30min.
8. like each described method for preparing of claim 1-4; It is characterized in that; Adopt protective agent in spray drying or the lyophilization in the step (4); Said protective agent is selected from a kind of in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, maltose, lactose, mannitol, glucose, trehalose, arabic gum, xylitol, sorbitol, fructose, the sucrose, and the amount ratio of protective agent and solid lipid nano-particles dispersion liquid is 1g: 5～100mL.
9. the triptolide solid lipid nano-particles for preparing by each said method of claim 1-8.
10. the application of the described triptolide solid lipid nano-particles of claim 9 in preparation triptolide injection, oral or preparation capable of permeating skin.
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| 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 |
| CN108635338A (en) * | 2018-05-15 | 2018-10-12 | 复旦大学附属肿瘤医院 | A kind of external application triptolide lipid nano particle and preparation method |
| US10342797B2 (en) | 2016-03-13 | 2019-07-09 | LivePet, LLC | Solubility of therapeutic agents |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2016515530A (en) * | 2013-03-15 | 2016-05-30 | ファーマジェネシス， インコーポレイテッド | Intravenous emulsion of triptolide as an immunomodulator and anticancer agent |
| CN107072964A (en) * | 2014-11-05 | 2017-08-18 | 西莱克塔生物科技公司 | The method and composition related to purposes of the low HLB surfactants in synthesis nano particle of the production comprising 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 |
| CN108635338A (en) * | 2018-05-15 | 2018-10-12 | 复旦大学附属肿瘤医院 | A kind of external application triptolide lipid nano particle and preparation method |
| 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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