CN1732918A - Nanometer preparation of silybin and preparation method thereof - Google Patents
Nanometer preparation of silybin and preparation method thereof Download PDFInfo
- Publication number
- CN1732918A CN1732918A CN 200510094008 CN200510094008A CN1732918A CN 1732918 A CN1732918 A CN 1732918A CN 200510094008 CN200510094008 CN 200510094008 CN 200510094008 A CN200510094008 A CN 200510094008A CN 1732918 A CN1732918 A CN 1732918A
- Authority
- CN
- China
- Prior art keywords
- silybin
- preparation medicine
- silybin nanostructured
- nanostructured preparation
- gram
- 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.)
- Granted
Links
- SEBFKMXJBCUCAI-UHFFFAOYSA-N NSC 227190 Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-UHFFFAOYSA-N 0.000 title claims abstract description 81
- 235000014899 silybin Nutrition 0.000 title claims abstract description 80
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 title claims abstract description 77
- 238000002360 preparation method Methods 0.000 title claims abstract description 75
- FDQAOULAVFHKBX-UHFFFAOYSA-N Isosilybin A Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC(=CC=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-UHFFFAOYSA-N 0.000 title claims abstract description 61
- VLGROHBNWZUINI-UHFFFAOYSA-N Silybin Natural products COc1cc(ccc1O)C2OC3C=C(C=CC3OC2CO)C4Oc5cc(O)cc(O)c5C(=O)C4O VLGROHBNWZUINI-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 229940043175 silybin Drugs 0.000 title claims abstract description 61
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000002105 nanoparticle Substances 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 20
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 15
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims abstract description 15
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 15
- 229940046009 vitamin E Drugs 0.000 claims abstract description 15
- 239000011709 vitamin E Substances 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims description 73
- 239000000839 emulsion Substances 0.000 claims description 33
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000002245 particle Substances 0.000 claims description 22
- 239000008347 soybean phospholipid Substances 0.000 claims description 22
- 229950000628 silibinin Drugs 0.000 claims description 19
- 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 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 16
- 239000008176 lyophilized powder Substances 0.000 claims description 16
- 238000010008 shearing Methods 0.000 claims description 15
- 238000009472 formulation Methods 0.000 claims description 14
- 238000005303 weighing Methods 0.000 claims description 14
- 230000001804 emulsifying effect Effects 0.000 claims description 13
- 150000002333 glycines Chemical class 0.000 claims description 13
- 150000002632 lipids Chemical class 0.000 claims description 13
- 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 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 9
- 239000012071 phase Substances 0.000 claims description 9
- 238000004108 freeze drying Methods 0.000 claims description 8
- 150000003904 phospholipids Chemical class 0.000 claims description 8
- 239000008346 aqueous phase Substances 0.000 claims description 7
- 239000012153 distilled water Substances 0.000 claims description 7
- 239000011159 matrix material Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 238000002390 rotary evaporation Methods 0.000 claims description 7
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000000463 material Substances 0.000 abstract description 6
- 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 abstract description 2
- 235000010445 lecithin Nutrition 0.000 abstract description 2
- 239000000787 lecithin Substances 0.000 abstract description 2
- 229940067606 lecithin Drugs 0.000 abstract description 2
- 239000002502 liposome Substances 0.000 abstract 3
- 244000068988 Glycine max Species 0.000 abstract 2
- 235000010469 Glycine max Nutrition 0.000 abstract 2
- 229940079593 drug Drugs 0.000 description 12
- 238000004945 emulsification Methods 0.000 description 10
- 210000004185 liver Anatomy 0.000 description 10
- 238000009826 distribution Methods 0.000 description 9
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 238000000265 homogenisation Methods 0.000 description 7
- 230000008685 targeting Effects 0.000 description 7
- 229960000935 dehydrated alcohol Drugs 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 239000003995 emulsifying agent Substances 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 6
- -1 silibinin lipid Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 239000002047 solid lipid nanoparticle Substances 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 210000001835 viscera Anatomy 0.000 description 4
- 239000002077 nanosphere Substances 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000007962 solid dispersion Substances 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 241000581650 Ivesia Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229930003944 flavone Natural products 0.000 description 2
- 235000011949 flavones Nutrition 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001132 ultrasonic dispersion Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 235000008495 Chrysanthemum leucanthemum Nutrition 0.000 description 1
- 244000192528 Chrysanthemum parthenium Species 0.000 description 1
- 235000000604 Chrysanthemum parthenium Nutrition 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 239000008118 PEG 6000 Substances 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 241000320380 Silybum Species 0.000 description 1
- 244000272459 Silybum marianum Species 0.000 description 1
- 235000010841 Silybum marianum Nutrition 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- XAEMHHAVNYDWEO-CVEVMTCXSA-N [1-[(4e,9e,12e)-hexadeca-4,9,12-trienoyl]oxy-3-[(6e,10e,12e)-hexadeca-6,10,12-trienoyl]oxypropan-2-yl] 2-(trimethylazaniumyl)ethyl phosphate;(2r,3r)-3,5,7-trihydroxy-2-[3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2,3- Chemical compound C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1.CCC\C=C\C\C=C\CCC\C=C\CCC(=O)OCC(OP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCC\C=C\CC\C=C\C=C\CCC XAEMHHAVNYDWEO-CVEVMTCXSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000008384 feverfew Nutrition 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N n-hexadecanoic acid Natural products CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229960004245 silymarin Drugs 0.000 description 1
- 235000017700 silymarin Nutrition 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000004506 ultrasonic cleaning Methods 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a silybin nano medicinal preparation, which comprises liposome nano particles of silybin, the liposome material is the mixture of soya bean lecithin, vitamin E and soyabean oil by the mass ratio of 1:2.5:12.5-1:15:24, the mass ratio of silybin and lipsome material is 1:32-1:400, the grain diameter of the liposome nano particles is less than 500 nanometer. The invention also discloses the preparing process of the preparation.
Description
Technical field:
The present invention relates to a kind of preparation method of nanometer formulation medicine, particularly a kind of silibinin lipid nanometer preparation medicine and preparation method thereof.
Background technology:
Silibinin (Silybin; SLB) be the flavone compound that extraction separation obtains from feverfew Herba Silybi mariani (Silybum marianus) fruit; because of it has significant protection and the effect of stable hepatocyte; various hepatic disease all there is in various degree therapeutical effect; now become ideal hepatic injury repair medicine; be widely used in the treatment acute, chronic hepatitis clinically; hepatopathy such as hepatic fibrosis and early stage liver cirrhosis [referring to: Flora K; Hahn M; Rahn H; et al.Milk thisle (silybum marianum) for the therapy of live disease.Am JGastroenterol; 1998,93 (13): 139.].Because SLB is insoluble in water, the common oral preparation bioavailability is lower, in the recent period concentrate on the bioavailability that improves its oral formulations about SLB novel form and novel formulation research, as, make lecithin complex, solid dispersion, cyclodextrin clathrate etc. [referring to GiacomelliS, Gallo D, ApollonioP, et al.Silybin and its bioavailable phospholipid complex (IdB1016) potentiatein vitro and in vivo the activity of cisplatin.Life Sci, 2002,70 (12): 1447; Li Fengqian, Hu Jinhong, Zhu Quangang. the mensuration of total flavones in the silibinin solid dispersion. Chinese herbal medicine, 2002,33 (1): 31; Li Fengqian, Hu Jinhong, Wang Hui waits the .PEG6000 solid dispersion system to the solubilization of insoluble drug silymarin and the relation of lattice variations. Acta Pharmaceutica Sinica, 2002,37 (4): 294; Lirussi F, Beccarello A, Zanette G, et al.Silybin-beta-cyclodextrin in the treatment ofpatients with diabetes mellitus and alcoholic liver disease.Efficacy study ofa new preparation of an anti-oxidant agent.Diabets Nutr Metab, 2003,15 (4): 222.].
Lipid nanoparticle (lipid nanospheres, LN) as a kind of Performances of Novel Nano-Porous meter level pharmaceutical carrier, improve drug solubility, increase medicine stability, there is wide application prospect aspects such as slow controlled release drug administration, target administration [referring to Lawrence MJ, Rees GD.Microemulsion-based media as nonel drug delivery systems.Adv Drug Deliv Rev, 2000,45 (1): 89; Seki Junzo, Sonoke Satoru, Saheki Akira, et al.A nanometer lipid emulsion, lipid nano-sphere (LNS), as a parenteral drugcarrier for passive drug targeting.International Journal of Pharmaceutics, 2004,273 (1-2): 75.], because of LN enter in the body after mainly by the macrophage phagocytic in the histoorgans such as liver, spleen, demonstrate natural " targeting ".If pharmaceutical pack is wrapped in wherein, make corresponding dosage forms, medicine is concentrated at " target " organ camber, improve the therapeutic index of medicine, reduction therapeutic dose and toxicity [referring to: Simon Benita.Submicron Emulsions in Drug Targeting and Delivery.Harwood Academic Publishers.1998.205.].SLB is made the silibinin lipid nanoparticle, and (silybin lipid nanospheres, SLN), one of its remarkable advantage is the liver target effect that can realize SLB.
The preparation method of lipid nanoparticle mainly contains: and the even method of high pressure breast, emulsifying dispersion method, solvent emulsion method, thin film-ultrasonic dispersion, membrane emulsification method, high pressure homogenization method etc. [referring to: Xue Kechang, Zhang San is strange, Gu Yi, Deng. the liver targeting research of hexadecylic acid lamivudine ester solid lipid nanoparticle. PLA's Acta Pharmaceutica Sinica, 2004,20 (1): 1; PupoE, Padr ó n A, Santana E, et al.Preparation of plasmid DNA-containing liposomesusing a high-pressure homogenization--extrusion technique.J Control Release, 2005,104 (2): 379; Jenning V, Lippacher A, Gohla SH.Medium scale productionof solid lipid nanoparticles (SLN) by high pressure homogenization.JMicroencapsul, 2002,19 (1): 1.].The shortcoming of the even method of high pressure breast is directly under high pressure to carry out emulsifying, and emulsion process is insufficient, though particle diameter is less, and less stable; The shortcoming of emulsifying dispersion method and thin film-ultrasonic dispersion is that particle diameter is bigger, and stability is not good enough; The shortcoming of solvent emulsion method is that organic solvent residue is more in the preparation, though can adopt exsiccant method to be removed, has also increased the chance of destroying nanoparticle, causes the instability of preparation; Adopt the membrane emulsification legal system to be equipped with LN, emulsion process is very abundant, and stability better and can significantly improve the drug loading of insoluble drug, and method is easy, and the loss that can avoid the preparation process Chinese medicine is with rotten, and its major defect is that particle diameter is bigger; High pressure homogenization method is a kind ofly to reduce the nanoparticle particle diameter, increase its stable effective ways, and owing to adopt high pressure homogenizer to operate, the method favorable reproducibility is applicable to suitability for industrialized production, but this method is unsuitable for directly preparing nanoparticle.
Summary of the invention:
The present invention has drawn the advantage of membrane emulsification method and two kinds of methods of high pressure homogenization method, propose to adopt membrane emulsification-high pressure homogenization method to prepare the nanometer formulation medicine, provide that a kind of preparation method of new lipid nanoparticle and drug loading height, particle diameter are little, good stability, silybin nanostructured preparation medicine that hepatic targeting is good.
Technical scheme of the present invention is as follows:
A kind of silybin nanostructured preparation medicine, it is the lipid nanoparticle that comprises silibinin, matrix material is the mixture of soybean phospholipid, vitamin E and Oleum Glycines, mass ratio between them is: soybean phospholipid: vitamin E: Oleum Glycines=1: 2.5: 12.5～1: 15: 24, the mass ratio of silibinin and matrix material is 1: 32～1: 400, and the particle diameter of lipid nanoparticle is less than 500 nanometers.
Above-mentioned silybin nanostructured preparation medicine, the mean diameter of described lipid nanoparticle are 170～210 nanometers.
Above-mentioned silybin nanostructured preparation medicine can be emulsion or lyophilized powder.
A kind of method for preparing above-mentioned silybin nanostructured preparation medicine, it is made up of the following step basically:
Step 1. takes by weighing 1 gram silibinin and 2～10 gram soybean phospholipids, add 150～300 milliliters of anhydrous alcohol solutions, after the dissolving, system is the alcoholic solution of a clear, adds 5～150 gram natural Vitamin E again, and jolting makes its dissolving, rotary evaporation is removed ethanol, adding 25～240 gram Oleum Glycines also shake up, and place 60 ± 5 ℃ water-bath standby
Step 2. takes by weighing 20～80 gram soybean phospholipids, 2.5～15 gram glycerol and 10～50 gram mannitol, adds 40～80 milliliters distilled water, makes phospholipid be dispersed in aqueous phase with high-speed shearing machine, places 60 ± 5 ℃ water-bath standby,
Step 3. joins the water of step 2 gained in the oil phase of step 1 gained in 60 ± 5 ℃ of water-baths, with high-speed shearing machine emulsifying 8～10 minutes, obtains the crude product of silybin nanostructured preparation medicine emulsion behind the uniform mixing,
Step 4. through the high pressure homogenizer homogenizing, promptly gets silybin nanostructured preparation medicine emulsion with the silybin guest nanometer particle emulsion crude product that obtains in the step 3.
The preparation method of above-mentioned silybin nanostructured preparation medicine, it can be handled the silybin nanostructured preparation medicine emulsion that makes and make silybin nanostructured preparation medicine lyophilized powder through lyophilization.
The schematic flow sheet of preparation process of the present invention is seen Fig. 1.
Silybin nanostructured preparation medicine of the present invention, matrix material is selected soybean phospholipid for use, both can increase interior absorption of fat-soluble and body of medicine, has extremely strong emulsification again.Emulsifying agent can be selected soybean phospholipid, poloxamer F-68 or its mixture for use, and through screening, the independent result of use of soybean phospholipid is better.Oil phase can be selected vitamin E, soybean oil or its mixture for use, and through screening, the mixture of vitamin E and Oleum Glycines is as oil phase, and stability of formulation is better.Stabilizing agent is selected mannitol for use, helps to improve stability of formulation.
In the silybin nanostructured preparation medicine preparation method of the present invention, emulsifying can use one or more in mechanical agitation, magnetic agitation, high speed shear emulsifying, the high pressure homogenize, through experiment screening, this law has adopted the emulsification method of high speed shear emulsifying as crude product, its shear rate is 15000～20000 rev/mins, and emulsification times is 8～10 minutes; The following adopted high pressure homogenization method reduces the particle diameter of crude product, increases its stability, and pressure maintains about 1000bar, and the homogenizing number of times is 4-6 time.
Silybin nanostructured preparation medicine of the present invention, its form specifically is divided into: matrix material is to be the material of liquid phase under a kind of room temperature, and final prepared nanometer formulation is the nanoparticle emulsion; Matrix material is to be the material of solid phase under a kind of room temperature, and final prepared nanometer formulation is a solid lipid nanoparticle.Nanometer formulation can also can get lyophilized powder by oral or intravenous injection mode administration after lyophilization is handled.Lyophilized powder adds water and shakes up, and can revert to the nanoparticle emulsion, can oral or intravenous injection.
The invention has the beneficial effects as follows:
1. adopt membrane emulsification-high pressure homogenization method to prepare the nanometer formulation medicine, its advantage is that prepared lipid nanoparticle particle diameter is little, good stability, drug loading height, and method is simple, is convenient to suitability for industrialized production.The silybin nanostructured preparation medicine emulsion that adopts this law to make through its form of scanning electron microscopic observation, the results are shown in accompanying drawing 2, and as seen, distribution of particles is even among the figure, is spherical shape, and particle diameter is all less than 500nm; Photon correlation spectroscopy is measured its particle diameter and distribution, the results are shown in accompanying drawing 3, among the figure as seen, mean diameter is 148.9nm, polydispersity index is 0.17, and the narrower and rare macroparticle of particle size distribution range illustrates that the silybin nanostructured preparation medicine emulsion that adopts this law to make is stable system; Silybin nanostructured preparation medicine emulsion through lyophilizing handle lyophilized powder, lyophilized powder adds distillation and shakes up, photon correlation spectroscopy is measured its particle diameter and distribution, the results are shown in accompanying drawing 4, mean diameter is 296.4nm, polydispersity index is 0.348, and nanoparticle is evenly distributed, and silybin nanostructured preparation medicine lyophilized powder still is a nanometer formulation; Silibinin lipid nanoparticle drug loading measurement result is all greater than 0.9mg/ml.
2. SLB is made lipid nanoparticle, one of its remarkable advantage is the liver target effect that can realize medicine.Give mice oral silybin nanostructured preparation medicine emulsion of the present invention, the content of dispersion distribution results is seen Fig. 5 in blood that 30min records after the administration and the internal organs, among the figure as seen, compare with the commercial preparation, oral silybin nanostructured preparation medicine emulsion of the present invention can significantly reduce silibinin delay under one's belt, increase its distribution in liver and blood, the concentration of SLB in liver obviously improves, and its liver targeting index is 1.81; Give mouse tail vein injection with silybin nanostructured preparation medicine emulsion of the present invention, the content of dispersion distribution results is seen Fig. 6 in blood that records behind the administration 1h and the internal organs, among the figure as seen, compare with control formulation, injecting silybin nanostructured preparation medicine emulsion of the present invention can significantly increase the drug level of SLB in liver, and its liver targeting index is 2.72.No matter silybin nanostructured preparation medicine of the present invention is oral or drug administration by injection all demonstrates good liver target effect.
Description of drawings
Fig. 1 is the schematic flow sheet of preparation process of the present invention.
Fig. 2 is the sem photograph of silybin nanostructured preparation medicine emulsion of the present invention.
Fig. 3 is silybin nanostructured preparation medicine distribution of particle size of emulsion figure of the present invention.
Fig. 4 is the particle size distribution figure after silybin nanostructured preparation medicine lyophilized powder of the present invention adds water.
Fig. 5 is silybin nanostructured preparation medicine emulsion of the present invention content of dispersion scattergram in 30min blood and the internal organs behind the mice oral administration.
Fig. 6 is silybin nanostructured preparation medicine emulsion of the present invention content of dispersion scattergram in mouse tail vein injection administration 1h bleeding from anus and internal organs.
The specific embodiment
Following examples material therefor and instrument and equipment are:
Experiment material: soybean phospholipid (Shanghai Taiwei Pharmaceutical Co., Ltd.); glycerol (Wuxi just reaching medicinal hygienic article factory); mannitol (Shanghai chemical reagents corporation of Chinese Medicine group); dehydrated alcohol (Shanghai reagent head factory industrial and trading company); vitamin E (the paddy biological product company limited in Jiangsu spring), Oleum Glycines (Tieling Beiya Medical Oil Co., Ltd.).
Experimental apparatus: FA25 type high-speed shearing machine (Fluko company, Germany); Rotary Evaporators (Heidolph company, Germany); APV-2000 high pressure homogenizer (APV company, Denmark) H66025 ultrasonic cleaning machine (Wuxi Ultrasonic Electronic Equipment Factory).
Embodiment 1:
1, take by weighing soybean phospholipid 2g, glycerol 0.5g, mannitol 1g places beaker, adds distilled water 80ml, uses high-speed shearing machine to make phospholipid be dispersed in aqueous phase, places 60 ℃ of water-baths standby.
2, take by weighing silibinin 0.1g, soybean phospholipid 0.2g adds dehydrated alcohol 30ml, ultrasonicly makes its dissolving, adds the 0.5g natural Vitamin E again, and jolting makes its dissolving, and rotary evaporation is removed ethanol, adds Oleum Glycines 2.5g and also shakes up, and places 60 ℃ of water-baths standby.
The water that contains emulsifying agent that 3, will be made by step 1 in 60 ± 5 ℃ of water-baths adds in the oil phase that is made by step 2, uses high-speed shearing machine emulsifying 8～10 minutes behind the uniform mixing, obtains the crude product of silybin nanostructured preparation.
4, crude product is through high pressure homogenize 5 times, and pressure is 1000bar, silybin nanostructured preparation medicine emulsion.After measured, its mean diameter is 204nm, and maximum particle diameter is 351nm.
5, silybin nanostructured preparation medicine emulsion can also can get lyophilized powder for oral or injection after lyophilization is handled.
Embodiment 2:
1, take by weighing soybean phospholipid 8g, glycerol 1.5g, mannitol 5g places beaker, adds distilled water 80ml, uses high-speed shearing machine to make phospholipid be dispersed in aqueous phase, places 60 ℃ of water-baths standby.
2, take by weighing silibinin 0.1g, soybean phospholipid 1.0g.Add dehydrated alcohol 30ml, ultrasonicly make its dissolving, add the 15g natural Vitamin E again, jolting makes its dissolving, and rotary evaporation is removed ethanol, adds Oleum Glycines 24g and also shakes up, and places 60 ℃ of water-baths standby.
The water that contains emulsifying agent that 3, will be made by step 1 in 60 ± 5 ℃ of water-baths adds in the oil phase that is made by step 2, uses high-speed shearing machine emulsifying 8～10 minutes behind the uniform mixing, obtains the crude product of silybin nanostructured preparation.
4, crude product is through high pressure homogenize 5 times, and pressure is 1000bar, the nanometer formulation medicine emulsion of silibinin.After measured, its mean diameter is 191nm, and maximum particle diameter is 242nm.
5, silybin nanostructured preparation medicine emulsion can also can get lyophilized powder for oral or injection after lyophilization is handled.
Embodiment 3:
1, take by weighing soybean phospholipid 4g, glycerol 1.5g, mannitol 2g places beaker, adds distilled water 80ml, uses high-speed shearing machine to make phospholipid be dispersed in aqueous phase, places 60 ℃ of water-baths standby.
2, take by weighing silibinin 0.1g, soybean phospholipid 0.5g.Add dehydrated alcohol 30ml, ultrasonicly make its dissolving, add the 5g natural Vitamin E again, jolting makes its dissolving, and rotary evaporation is removed ethanol, adds Oleum Glycines 10g and also shakes up, and places 60 ℃ of water-baths standby.
The water that contains emulsifying agent that 3, will be made by step 1 in 60 ± 5 ℃ of water-baths adds in the oil phase that is made by step 2, uses high-speed shearing machine emulsifying 8～10 minutes behind the uniform mixing, obtains the crude product of silybin nanostructured preparation.
4, crude product is through high pressure homogenize 5 times, and pressure is 1000bar, silybin nanostructured preparation medicine emulsion.After measured, its mean diameter is 172.6nm, and maximum particle diameter is 307nm.
5, silybin nanostructured preparation medicine emulsion can also can get lyophilized powder for oral or injection after lyophilization is handled.
Embodiment 4:
1, take by weighing soybean phospholipid 6g, glycerol 1.7g, mannitol 3g places beaker, adds distilled water 80ml, uses high-speed shearing machine to make phospholipid be dispersed in aqueous phase, places 60 ℃ of water-baths standby.
2, take by weighing silibinin 0.2g, soybean phospholipid 0.4g.Add dehydrated alcohol 30ml, ultrasonicly make its dissolving, add the 2.5g natural Vitamin E again, jolting makes its dissolving, and rotary evaporation is removed ethanol, adds Oleum Glycines 10g and also shakes up, and places 60 ℃ of water-baths standby.
The water that contains emulsifying agent that 3, will be made by step 1 in 60 ± 5 ℃ of water-baths adds in the oil phase that is made by step 2, uses high-speed shearing machine emulsifying 8～10 minutes behind the uniform mixing, obtains the crude product of silybin nanostructured preparation medicine.
4, crude product is through high pressure homogenize 5 times, and pressure is 1000bar, silybin nanostructured preparation medicine emulsion.After measured, its mean diameter is 148.9nm, and maximum particle diameter is 500nm.
5, silybin nanostructured preparation medicine emulsion can also can get lyophilized powder for oral or injection after lyophilization is handled.
Embodiment 5:
L, take by weighing soybean phospholipid 4g, glycerol 0.5g, mannitol 5g places beaker, adds distilled water 80ml, uses high-speed shearing machine to make phospholipid be dispersed in aqueous phase, places 60 ℃ of water-baths standby.
2, take by weighing silibinin 0.2g, soybean phospholipid 0.4g.Add dehydrated alcohol 30ml, ultrasonicly make its dissolving.Add the 1g natural Vitamin E again, jolting makes its dissolving.Rotary evaporation is removed ethanol, and adding Oleum Glycines 6g also shakes up, and is standby in 60 ℃ of water-baths equally.
The water that contains emulsifying agent that 3, will be made by step 1 in 60 ± 5 ℃ of water-baths adds in the oil phase that is made by step 2, uses high-speed shearing machine emulsifying 8～10 minutes behind the uniform mixing, obtains silybin nanostructured preparation medicine crude product.
4, crude product is through high pressure homogenize 5 times, and pressure is 1000bar, silybin nanostructured preparation medicine emulsion.
5, silybin nanostructured preparation medicine emulsion gets silybin nanostructured preparation medicine lyophilized powder after lyophilization is handled, and lyophilized powder adding distil water again shakes up, and after measured, its mean diameter is 296.4nm, and maximum particle diameter is 1000nm, can use for oral or injection.
Claims (5)
1. silybin nanostructured preparation medicine, it is characterized in that: it is the lipid nanoparticle that comprises silibinin, matrix material is the mixture of soybean phospholipid, vitamin E and Oleum Glycines, mass ratio between them is: soybean phospholipid: vitamin E: Oleum Glycines=1: 2.5: 12.5～1: 15: 24, the mass ratio of silibinin and matrix material is 1: 32～1: 400, and the particle diameter of lipid nanoparticle is less than 500 nanometers.
2. according to the described silybin nanostructured preparation medicine of claim 1, it is characterized in that: the mean diameter of described lipid nanoparticle is 170～210 nanometers.
3. silybin nanostructured preparation medicine according to claim 1 is characterized in that: the nanometer formulation of silibinin is emulsion or lyophilized powder.
4. method for preparing the described silybin nanostructured preparation medicine of claim 1 is characterized in that it is made up of the following step basically:
Step 1. takes by weighing 1 gram silibinin and 2～10 gram soybean phospholipids, add 150～300 milliliters of anhydrous alcohol solutions, after the dissolving, system is the alcoholic solution of a clear, adds 5～150 gram natural Vitamin E again, and jolting makes its dissolving, rotary evaporation is removed ethanol, adding 25～240 gram Oleum Glycines also shake up, and place 60 ± 5 ℃ water-bath standby
Step 2. takes by weighing 20～80 gram soybean phospholipids, 2.5～15 gram glycerol and 10～50 gram mannitol, adds 40～80 milliliters distilled water, makes phospholipid be dispersed in aqueous phase with high-speed shearing machine, places 60 ± 5 ℃ water-bath standby,
Step 3. joins the water of step 2 gained in the oil phase of step 1 gained in 60 ± 5 ℃ of water-baths, with high-speed shearing machine emulsifying 8～10 minutes, obtains the crude product of silybin nanostructured preparation medicine emulsion behind the uniform mixing,
Step 4. through the high pressure homogenizer homogenizing, promptly gets silybin nanostructured preparation medicine emulsion with the crude product of the silybin nanostructured preparation that obtains in the step 3.
5. the preparation method of silybin nanostructured preparation medicine according to claim 4 is characterized in that: the silybin nanostructured preparation medicine emulsion that will make is handled through lyophilization and is made silybin nanostructured preparation medicine lyophilized powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510094008XA CN100356915C (en) | 2005-08-25 | 2005-08-25 | Nanometer preparation of silybin and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510094008XA CN100356915C (en) | 2005-08-25 | 2005-08-25 | Nanometer preparation of silybin and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1732918A true CN1732918A (en) | 2006-02-15 |
| CN100356915C CN100356915C (en) | 2007-12-26 |
Family
ID=36075674
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200510094008XA Expired - Fee Related CN100356915C (en) | 2005-08-25 | 2005-08-25 | Nanometer preparation of silybin and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100356915C (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829105A (en) * | 2010-05-25 | 2010-09-15 | 大理学院 | Application of benzoly-substituted silybin in preparing drugs for treating virus hepatitis |
| CN101317840B (en) * | 2007-06-06 | 2010-12-08 | 周亚伟 | Nano-composition, preparing method and application thereof |
| CN101953794A (en) * | 2009-07-21 | 2011-01-26 | 天津天士力制药股份有限公司 | Silibinin injection and preparation method thereof |
| CN101444503B (en) * | 2008-12-31 | 2011-02-02 | 江苏大学 | Efficient long-acting silibinin preparation and preparation method thereof |
| CN101224194B (en) * | 2007-01-18 | 2011-06-15 | 重庆太极医药研究院 | Silybin guest nanometer particle and preparing method thereof |
| CN105983015A (en) * | 2015-03-23 | 2016-10-05 | 天士力制药集团股份有限公司 | Medicine composition containing silibinin and VE |
| CN108524364A (en) * | 2018-06-14 | 2018-09-14 | 上海棠美生物科技有限公司 | A kind of cosmetic active object nano-carrier package and preparation method thereof |
| CN109223721A (en) * | 2018-09-28 | 2019-01-18 | 江苏天美健大自然生物工程有限公司 | Phosphatide milk thistle vitamin E composition and its preparation method and application |
| CN110123751A (en) * | 2018-06-14 | 2019-08-16 | 中国药科大学 | A kind of milk thistle class medicament nano cream dust composition and preparation method thereof |
| CN111714454A (en) * | 2020-07-22 | 2020-09-29 | 宿迁医美科技有限公司 | Perilla seed oil and silybum marianum seed oil compounded fat emulsion and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1463700A (en) * | 2002-06-21 | 2003-12-31 | 上海医药工业研究院 | Silymarin nano granular preparation and process for preparing the same |
-
2005
- 2005-08-25 CN CNB200510094008XA patent/CN100356915C/en not_active Expired - Fee Related
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101224194B (en) * | 2007-01-18 | 2011-06-15 | 重庆太极医药研究院 | Silybin guest nanometer particle and preparing method thereof |
| CN101317840B (en) * | 2007-06-06 | 2010-12-08 | 周亚伟 | Nano-composition, preparing method and application thereof |
| CN101444503B (en) * | 2008-12-31 | 2011-02-02 | 江苏大学 | Efficient long-acting silibinin preparation and preparation method thereof |
| CN101953794A (en) * | 2009-07-21 | 2011-01-26 | 天津天士力制药股份有限公司 | Silibinin injection and preparation method thereof |
| CN101953794B (en) * | 2009-07-21 | 2014-05-14 | 天士力制药集团股份有限公司 | Silibinin injection and preparation method thereof |
| CN101829105A (en) * | 2010-05-25 | 2010-09-15 | 大理学院 | Application of benzoly-substituted silybin in preparing drugs for treating virus hepatitis |
| CN105983015A (en) * | 2015-03-23 | 2016-10-05 | 天士力制药集团股份有限公司 | Medicine composition containing silibinin and VE |
| CN105983015B (en) * | 2015-03-23 | 2022-01-25 | 天士力医药集团股份有限公司 | A pharmaceutical composition containing silibinin and VE |
| CN108524364A (en) * | 2018-06-14 | 2018-09-14 | 上海棠美生物科技有限公司 | A kind of cosmetic active object nano-carrier package and preparation method thereof |
| CN110123751A (en) * | 2018-06-14 | 2019-08-16 | 中国药科大学 | A kind of milk thistle class medicament nano cream dust composition and preparation method thereof |
| CN109223721A (en) * | 2018-09-28 | 2019-01-18 | 江苏天美健大自然生物工程有限公司 | Phosphatide milk thistle vitamin E composition and its preparation method and application |
| CN111714454A (en) * | 2020-07-22 | 2020-09-29 | 宿迁医美科技有限公司 | Perilla seed oil and silybum marianum seed oil compounded fat emulsion and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100356915C (en) | 2007-12-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100356915C (en) | Nanometer preparation of silybin and preparation method thereof | |
| CN1840193A (en) | Nanometer capsule of anthracene nucleus anticancer antibiotic with polyethylene glycol-phospholipid | |
| CN101984958A (en) | Nanoscale albendazole micropowder and preparation method thereof | |
| Martínez-Muñoz et al. | Nanoprecipitation: Applications for entrapping active molecules of interest in pharmaceutics | |
| CN101028251A (en) | Camptothecine derivative phosphatide composite liposome nano-preparation and its making method | |
| CN100349565C (en) | Curcumenol solid lipid nanoparticle and preparation method thereof | |
| Xie et al. | Phytonanomaterials as therapeutic agents and drug delivery carriers | |
| CN109730966B (en) | Chitosan oligosaccharide modified self-carried carrier-free nasal cavity nano preparation brain targeting delivery system and preparation method thereof | |
| CN101062094B (en) | Total salvianolic acids long-cycle liposomes and the preparing method thereof | |
| CN1939315A (en) | Ganglioside solid lipid nano-particle of monosialic acid tetrahexose and its preparation | |
| CN101057831A (en) | Docetaxel liposome novel preparations and its preparation method | |
| CN110302160B (en) | Cabazitaxel prodrug liposome as well as preparation method and application thereof | |
| CN1883455A (en) | A long-circulating nanoliposome carrier of hydroxycamptothecine and preparation method thereof | |
| CN1686106A (en) | Rabdosia rubescens A microglobule medicinal agent and its preparation method | |
| CN1463700A (en) | Silymarin nano granular preparation and process for preparing the same | |
| CN108498485B (en) | Dihydroartemisinin modified drug delivery carrier and application thereof in pharmacy | |
| CN1823748A (en) | Medicinal preparation of coenzyme Q10 liposome and its preparation technology | |
| CN101310717A (en) | Tanshinone IIA polylactic acid nano particles and preparation method thereof | |
| CN1399958A (en) | Taxol nano magnetic target preparation and its preparation method | |
| CN1973843A (en) | Degradable polymer supported nanometer Daunorubicin microsphere and its prepn process | |
| CN102028655B (en) | Zanamivir solid lipid nanosphere oral preparation and preparation method thereof | |
| CN1215839C (en) | Nano granules of solid lipid of tanshinone and its preparation method | |
| CN110960491B (en) | Preparation method and application of tanshinone IIA-loaded water-soluble chitosan/gamma-polyglutamic acid nano-composite | |
| CN107412172A (en) | A kind of suspension freeze-dried powder of taxol albumin nano and its preparation technology | |
| CN1194683C (en) | Silymarin behenic acid glyceride lipid nano particle oral solution dosage and its preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20180726 Address after: 212400 No. 5 Xianlin East Road, Baohua Town, Jurong City, Zhenjiang, Jiangsu. Patentee after: Jurong Kenuo Health Science & Technology Co.,Ltd. Address before: No. 301 Dantu Road, Zhenjiang, Jiangsu Patentee before: Jiangsu University |
|
| TR01 | Transfer of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20071226 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |