CN110051715B - 菊苣酸、紫锥菊提取物及相应制剂用于制备缓解铅毒性药物的用途 - Google Patents
菊苣酸、紫锥菊提取物及相应制剂用于制备缓解铅毒性药物的用途 Download PDFInfo
- Publication number
- CN110051715B CN110051715B CN201910375415.XA CN201910375415A CN110051715B CN 110051715 B CN110051715 B CN 110051715B CN 201910375415 A CN201910375415 A CN 201910375415A CN 110051715 B CN110051715 B CN 110051715B
- Authority
- CN
- China
- Prior art keywords
- weight
- parts
- extract
- solid lipid
- echinacea purpurea
- 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.)
- Expired - Fee Related
Links
- 239000003814 drug Substances 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- YDDGKXBLOXEEMN-IABMMNSOSA-N chicoric acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C(O)=O)C(=O)\C=C\C1=CC=C(O)C(O)=C1 YDDGKXBLOXEEMN-IABMMNSOSA-N 0.000 title claims abstract description 36
- YDDGKXBLOXEEMN-UHFFFAOYSA-N Di-E-caffeoyl-meso-tartaric acid Natural products C=1C=C(O)C(O)=CC=1C=CC(=O)OC(C(O)=O)C(C(=O)O)OC(=O)C=CC1=CC=C(O)C(O)=C1 YDDGKXBLOXEEMN-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229930016920 cichoric acid Natural products 0.000 title claims abstract description 35
- YDDGKXBLOXEEMN-WOJBJXKFSA-N dicaffeoyl-L-tartaric acid Natural products O([C@@H](C(=O)O)[C@@H](OC(=O)C=CC=1C=C(O)C(O)=CC=1)C(O)=O)C(=O)C=CC1=CC=C(O)C(O)=C1 YDDGKXBLOXEEMN-WOJBJXKFSA-N 0.000 title claims abstract description 35
- YDDGKXBLOXEEMN-IABMMNSOSA-L Chicoric acid Natural products C1=C(O)C(O)=CC=C1\C=C\C(=O)O[C@@H](C([O-])=O)[C@H](C([O-])=O)OC(=O)\C=C\C1=CC=C(O)C(O)=C1 YDDGKXBLOXEEMN-IABMMNSOSA-L 0.000 title claims abstract description 34
- YDDGKXBLOXEEMN-PMACEKPBSA-N dicaffeoyl-D-tartaric acid Natural products O([C@H](C(=O)O)[C@H](OC(=O)C=CC=1C=C(O)C(O)=CC=1)C(O)=O)C(=O)C=CC1=CC=C(O)C(O)=C1 YDDGKXBLOXEEMN-PMACEKPBSA-N 0.000 title claims abstract description 34
- 229940079593 drug Drugs 0.000 title claims abstract description 32
- 230000001988 toxicity Effects 0.000 title claims abstract description 26
- 231100000419 toxicity Toxicity 0.000 title claims abstract description 26
- 229940045811 echinacea purpurea extract Drugs 0.000 title claims description 82
- 235000020694 echinacea extract Nutrition 0.000 claims abstract description 53
- 150000002632 lipids Chemical class 0.000 claims description 108
- 239000004005 microsphere Substances 0.000 claims description 108
- 239000007787 solid Substances 0.000 claims description 107
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 65
- 239000002994 raw material Substances 0.000 claims description 29
- 235000021355 Stearic acid Nutrition 0.000 claims description 28
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 28
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 28
- 239000008117 stearic acid Substances 0.000 claims description 28
- 229920001993 poloxamer 188 Polymers 0.000 claims description 20
- 229940044519 poloxamer 188 Drugs 0.000 claims description 20
- 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 15
- 239000000203 mixture Substances 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 239000002671 adjuvant Substances 0.000 claims description 6
- 239000002047 solid lipid nanoparticle Substances 0.000 claims description 6
- 229940083466 soybean lecithin Drugs 0.000 claims description 6
- 235000010469 Glycine max Nutrition 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 230000008961 swelling Effects 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 3
- 244000068988 Glycine max Species 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims 5
- 229920001983 poloxamer Polymers 0.000 claims 3
- 229960000502 poloxamer Drugs 0.000 claims 3
- 150000002500 ions Chemical class 0.000 abstract description 43
- 241000252212 Danio rerio Species 0.000 abstract description 19
- 210000004498 neuroglial cell Anatomy 0.000 abstract description 16
- 206010027439 Metal poisoning Diseases 0.000 abstract description 15
- 208000008127 lead poisoning Diseases 0.000 abstract description 15
- 238000011282 treatment Methods 0.000 abstract description 13
- 230000000366 juvenile effect Effects 0.000 abstract description 10
- 230000003013 cytotoxicity Effects 0.000 abstract description 9
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 9
- 206010061218 Inflammation Diseases 0.000 abstract description 7
- 230000004054 inflammatory process Effects 0.000 abstract description 7
- 238000001784 detoxification Methods 0.000 abstract description 5
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 4
- 231100000783 metal toxicity Toxicity 0.000 abstract description 3
- 208000001608 teratocarcinoma Diseases 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 35
- 230000000052 comparative effect Effects 0.000 description 27
- 238000012360 testing method Methods 0.000 description 20
- 239000002245 particle Substances 0.000 description 19
- 239000008347 soybean phospholipid Substances 0.000 description 19
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 18
- RVPVRDXYQKGNMQ-UHFFFAOYSA-N lead(2+) Chemical compound [Pb+2] RVPVRDXYQKGNMQ-UHFFFAOYSA-N 0.000 description 18
- 235000011187 glycerol Nutrition 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000011068 loading method Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 239000000284 extract Substances 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 13
- 238000009826 distribution Methods 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 230000014509 gene expression Effects 0.000 description 11
- 241000251468 Actinopterygii Species 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 235000014134 echinacea Nutrition 0.000 description 10
- 240000004530 Echinacea purpurea Species 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 230000036542 oxidative stress Effects 0.000 description 9
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 9
- 108010018924 Heme Oxygenase-1 Proteins 0.000 description 7
- 238000005538 encapsulation Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000013270 controlled release Methods 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 6
- 239000003642 reactive oxygen metabolite Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 102100028006 Heme oxygenase 1 Human genes 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 5
- 230000006907 apoptotic process Effects 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 5
- 230000034994 death Effects 0.000 description 5
- 231100000517 death Toxicity 0.000 description 5
- 230000003203 everyday effect Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 150000003904 phospholipids Chemical class 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 206010072063 Exposure to lead Diseases 0.000 description 4
- 230000005526 G1 to G0 transition Effects 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000017531 blood circulation Effects 0.000 description 4
- 230000025084 cell cycle arrest Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 210000002257 embryonic structure Anatomy 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000002035 prolonged effect Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 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 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 208000031320 Teratogenesis Diseases 0.000 description 3
- 206010043275 Teratogenicity Diseases 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000004087 circulation Effects 0.000 description 3
- 239000007957 coemulsifier Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000287 crude extract Substances 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000004945 emulsification Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000001788 irregular Effects 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 230000009182 swimming Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 231100000211 teratogenicity Toxicity 0.000 description 3
- 230000003827 upregulation Effects 0.000 description 3
- 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 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 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 description 2
- 101150044653 HMOX1 gene Proteins 0.000 description 2
- 102000002737 Heme Oxygenase-1 Human genes 0.000 description 2
- 208000013038 Hypocalcemia Diseases 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000006286 aqueous extract Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000001201 calcium disodium ethylene diamine tetra-acetate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- SHWNNYZBHZIQQV-UHFFFAOYSA-L calcium;disodium;2-[2-[bis(carboxylatomethyl)azaniumyl]ethyl-(carboxylatomethyl)azaniumyl]acetate Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-L 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000008809 cell oxidative stress Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 238000002655 chelation therapy Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- -1 correctant Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 210000002969 egg yolk Anatomy 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000010262 high-speed countercurrent chromatography Methods 0.000 description 2
- 230000000705 hypocalcaemia Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000000116 mitigating effect Effects 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000003223 protective agent Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- FVVCFHXLWDDRHG-UPLOTWCNSA-N (2s,3r,4s,5r,6r)-2-[(2r,3s,4r,5r,6r)-6-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)[C@@H](CO)O1 FVVCFHXLWDDRHG-UPLOTWCNSA-N 0.000 description 1
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- 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 description 1
- DFJACSJACSDRSG-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;calcium;sodium Chemical compound [Na].[Na].[Ca].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O DFJACSJACSDRSG-UHFFFAOYSA-N 0.000 description 1
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- PVXPPJIGRGXGCY-TZLCEDOOSA-N 6-O-alpha-D-glucopyranosyl-D-fructofuranose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)C(O)(CO)O1 PVXPPJIGRGXGCY-TZLCEDOOSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 101150026888 84 gene Proteins 0.000 description 1
- 101150061183 AOX1 gene Proteins 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- 241000511582 Actinomyces meyeri Species 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 238000000035 BCA protein assay Methods 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 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 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 244000133098 Echinacea angustifolia Species 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- 230000004668 G2/M phase Effects 0.000 description 1
- 101150038307 Gclm gene Proteins 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 101000648740 Mus musculus Tumor necrosis factor Proteins 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000029726 Neurodevelopmental disease Diseases 0.000 description 1
- 208000011644 Neurologic Gait disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 101150097713 SCD1 gene Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000000875 Spinal Curvatures Diseases 0.000 description 1
- 206010058907 Spinal deformity Diseases 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 206010057362 Underdose Diseases 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- KQNKJJBFUFKYFX-UHFFFAOYSA-N acetic acid;trihydrate Chemical compound O.O.O.CC(O)=O KQNKJJBFUFKYFX-UHFFFAOYSA-N 0.000 description 1
- ADJBGWAVTYCZNA-UHFFFAOYSA-N acetonitrile;2-methoxy-2-methylpropane;hydrate Chemical compound O.CC#N.COC(C)(C)C ADJBGWAVTYCZNA-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 210000004712 air sac Anatomy 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000010598 annexinV-PE /7AAD assay Methods 0.000 description 1
- 230000006851 antioxidant defense Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 235000011188 calcium disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- JXRVKYBCWUJJBP-UHFFFAOYSA-L calcium;hydrogen sulfate Chemical compound [Ca+2].OS([O-])(=O)=O.OS([O-])(=O)=O JXRVKYBCWUJJBP-UHFFFAOYSA-L 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- DUEPRVBVGDRKAG-UHFFFAOYSA-N carbofuran Chemical compound CNC(=O)OC1=CC=CC2=C1OC(C)(C)C2 DUEPRVBVGDRKAG-UHFFFAOYSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000003783 cell cycle assay Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000006193 cichoric acid Nutrition 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 231100000415 developmental toxicity Toxicity 0.000 description 1
- 230000007673 developmental toxicity Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 238000001378 electrochemiluminescence detection Methods 0.000 description 1
- 239000010793 electronic waste Substances 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 231100000613 environmental toxicology Toxicity 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- FTSSQIKWUOOEGC-RULYVFMPSA-N fructooligosaccharide Chemical compound OC[C@H]1O[C@@](CO)(OC[C@@]2(OC[C@@]3(OC[C@@]4(OC[C@@]5(OC[C@@]6(OC[C@@]7(OC[C@@]8(OC[C@@]9(OC[C@@]%10(OC[C@@]%11(O[C@H]%12O[C@H](CO)[C@@H](O)[C@H](O)[C@H]%12O)O[C@H](CO)[C@@H](O)[C@@H]%11O)O[C@H](CO)[C@@H](O)[C@@H]%10O)O[C@H](CO)[C@@H](O)[C@@H]9O)O[C@H](CO)[C@@H](O)[C@@H]8O)O[C@H](CO)[C@@H](O)[C@@H]7O)O[C@H](CO)[C@@H](O)[C@@H]6O)O[C@H](CO)[C@@H](O)[C@@H]5O)O[C@H](CO)[C@@H](O)[C@@H]4O)O[C@H](CO)[C@@H](O)[C@@H]3O)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@@H](O)[C@@H]1O FTSSQIKWUOOEGC-RULYVFMPSA-N 0.000 description 1
- 229940107187 fructooligosaccharide Drugs 0.000 description 1
- 239000008369 fruit flavor Substances 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005802 health problem Effects 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 1
- 229960000511 lactulose Drugs 0.000 description 1
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 229940046892 lead acetate Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001972 liquid chromatography-electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 238000010841 mRNA extraction Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000008722 morphological abnormality Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 101150075804 nqo1 gene Proteins 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000017448 oviposition Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000007965 phenolic acids Chemical class 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 230000000270 postfertilization Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000011506 response to oxidative stress Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 231100001055 skeletal defect Toxicity 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- ACTRVOBWPAIOHC-UHFFFAOYSA-N succimer Chemical compound OC(=O)C(S)C(S)C(O)=O ACTRVOBWPAIOHC-UHFFFAOYSA-N 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000013417 toxicology model Methods 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000003656 tris buffered saline Substances 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000002137 ultrasound extraction Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Alternative & Traditional Medicine (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Toxicology (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种菊苣酸、紫锥菊提取物及相应制剂用于制备缓解铅毒性药物的用途,该紫锥菊提取物系第一次被发现可以缓解重金属毒性,可以有效缓解铅离子对神经胶质细胞造成的细胞毒性和炎症反应,并可缓解铅离子造成的斑马鱼幼鱼的死亡率和畸形率;该发明能够为铅中毒的解毒治疗提供新途径和候选药物。
Description
技术领域
本发明属于制药技术领域,具体涉及一种紫锥菊提取物、制剂、相应制备方法以及菊苣酸或紫锥菊提取物及相应制剂用于制备缓解铅毒性药物的用途。
背景技术
2017年,全球共计生产了400多万吨铅金属,其中大量的铅已经通过电子废物,劣质燃料或废旧电池等形式进入到环境中(Joyce A Ober,US Geological Survey,2018)。铅可通过摄入污染的食物或吸入PM2.5颗粒等途径进入体内然后导致严重的健康问题,包括肝损伤,中枢神经系统损害以及炎症(Monica Shirley Mani et.al.,ToxicologyLetters,2018;Abjal Pasha Shaik et.al.,Journal of Hazardous Materials,2009)。最严重的是,铅可引起儿童不可逆的发育毒性,包括神经损伤和骨骼异常(Robyn M AmosKroohs et.al.,Neurotoxicology,2016; M et.al.,Toxicology,2016)。据世界卫生组织报告,仅2016年铅中毒事件导致54万人死亡。
目前对铅中毒的治疗主要基于螯合疗法,例如使用EDTA二钠钙或二巯基丁二酸。然而,它们的用途会引起严重的副作用,包括脱水,低血钙和肾脏损害。还可能出现更严重的问题,如低钙血症,神经发育障碍,甚至死亡(Guido Crisponi et.al.,CoordinationChemistry Reviews,2015;Mj Kosnett,Clinical Pharmacology&Therapeutics,2010)。并且对于长期暴露于低水平的铅,螯合疗法一般价值有限(Pamela A.Meyer et.al.,Mutation Research,2008)。此外,铅也很难从体内完全消除(Cássia Regina BrunoNascimento et.al.,Environmental Toxicology and Pharmacology,2016)。
发明内容
为了克服上述问题,本发明人进行了锐意研究,结果发现:紫锥菊提取物或菊苣酸系可以缓解重金属毒性,可以有效缓解铅离子对神经胶质细胞造成的细胞毒性和炎症反应,并可缓解铅离子造成的斑马鱼幼鱼的死亡率和畸形率,能够为铅中毒的解毒治疗提供新途径和候选药物,从而完成了本发明。
本发明的目的在于提供以下技术方案:
(1)紫锥菊提取物及其制剂用于制备缓解铅毒性药物的用途,其中,紫锥菊提取物中菊苣酸含量不低于95wt%。
(2)菊苣酸及其制剂用于制备缓解铅毒性药物的用途,其中,菊苣酸的含量不低于95wt%。
(3)根据上述(1)或(2)所述的用途,其特征在于,该菊苣酸或紫锥菊提取物缓解铅离子对神经胶质细胞的细胞毒性和炎症反应的有效摩尔浓度是5~40微摩尔每升;
该菊苣酸或紫锥菊提取物用于缓解铅离子造成的斑马鱼幼鱼的死亡率和畸形率的有效摩尔浓度是10~40微摩尔每升;
该菊苣酸或紫锥菊提取物用于缓解铅离子造成的小鼠铅毒性的有效剂量为20~100mg/kg。
(4)一种紫锥菊提取物固体脂质微球,其中,由包括以下重量配比组分的原料制成:
其中,紫锥菊提取物中菊苣酸含量不低于95wt%;
优选地,大豆磷脂与硬脂酸的重量比为(1.4~2.5):1;
甘油占原料总重的质量百分比不低于5%;
泊洛沙姆188占原料总重的质量百分比不低于8.5%。
(5)一种紫锥菊提取物固体脂质微球的制备方法,包括以下步骤:
步骤1,按照重量比例分别称取紫锥菊提取物、大豆磷脂和硬脂酸,加热熔融,搅拌均匀;
步骤2,向步骤1反应体系中加入相同温度的甘油和泊洛沙姆188水溶液,制备得到初乳;
步骤3,对初乳进行高压乳化处理,然后迅速冷却,形成固体脂质微球混悬液;
步骤4,冷冻干燥处理,得到紫锥菊提取物固体脂质微球。
(6)一种紫锥菊提取物固体脂质微球制剂,其由紫锥菊提取物固体脂质纳米粒和其他药用辅料制成;其中,紫锥菊提取物固体脂质纳米粒由包括以下重量配比的原料成分制成:
其中,紫锥菊提取物中菊苣酸含量不低于95wt%;
大豆磷脂与硬脂酸的重量比为(1.4~2.5):1;
甘油占原料总重的质量百分比不低于5%;
泊洛沙姆188占原料总重的质量百分比不低于8.5%;
药用辅料包括填充剂、崩解剂、粘合剂、溶胀辅料、润滑剂、矫味剂、或甜味剂及其组合。
(7)上述(4)所述的紫锥菊提取物固体脂质微球在用于制备缓解铅毒性药物的用途;
上述(6)所述的紫锥菊提取物固体脂质微球制剂在用于制备缓解铅毒性药物的用途;
上述(5)所述的紫锥菊提取物固体脂质微球的制备方法制备的到的紫锥菊提取物固体脂质微球在用于制备缓解铅毒性药物的用途。
根据本发明提供的菊苣酸、紫锥菊提取物及相应制剂用于制备缓解铅毒性药物的用途,具有的有益效果包括:
(1)紫锥菊提取物系第一次被发现可以缓解重金属毒性,可以有效缓解铅离子对神经胶质细胞造成的细胞毒性和炎症反应,并可缓解铅离子造成的斑马鱼幼鱼的死亡率和畸形率;该发明能够为铅中毒的解毒治疗提供新途径和候选药物。
(2)在本发明的紫锥菊提取物固体脂质微球中,对于要包载的活性药物成分紫锥菊提取物,通过甘油和泊洛沙姆188对由大豆磷脂和硬脂酸以设定量配比的组合脂质的协同调节促进作用,能形成载药量高、结构稳定性好、形状规则且粒径集中的紫锥菊提取物固体脂质微球,其生物利用度高、控释性好、药效稳定;
在固体脂质微球骨架中引入聚乙二醇6000,延长在血液循环中的时间,更利于对机体铅损伤的治疗。
附图说明
图1示出紫锥菊提取物保护神经胶质细胞抵抗铅离子毒性实验结果;
图2示出紫锥菊提取物缓解铅离子诱导的活性氧和肿瘤坏死因子α异常升高结果;
图3示出紫锥菊提取物对神经胶质细胞细胞周期和凋亡的缓解结果;
图4示出紫锥菊提取物影响的神经胶质细胞中氧化应激信号通路的相关基因和蛋白表达结果;
图5示出紫锥菊提取物缓解铅毒性的斑马鱼动物模型实验结果。
具体实施方式
下面通过优选实施方式和实施例对本发明进一步详细说明。通过这些说明,本发明的特点和优点将变得更为清楚明确。
为了改进和补充目前已知的铅中毒治疗药物的局限性,本发明的目的在于提供紫锥菊提取物用于制备缓解铅毒性药物的一种新用途。其中,紫锥菊提取物中主要的活性成分为菊苣酸,用于制备缓解铅毒性药物的菊苣酸提取物中的菊苣酸含量不低于95(重量)%(95wt%)。或者,
菊苣酸及其制剂用于制备缓解铅毒性药物的用途,其中,菊苣酸的含量不低于95wt%。
化合物菊苣酸的化学结构如式(I)所示:
菊苣酸是一种主要来源于紫锥菊的酚酸类天然化合物,CAS号6537-80-0。近年来的药理研究表明,菊苣酸具有抗氧化,免疫调节,抑制艾滋病病毒等活性和功能。但其应用于重金属解毒治疗未见报道。
本发明人采用,本实验采用大孔吸附树脂从紫锥菊水提物中得到粗提物,并以此粗提物进行高速逆流色谱(HSCCC)分离纯化,经一步分离得到菊苣酸含量大于95wt%的紫锥菊提取物。
本发明人经过研究发现,该紫锥菊提取物可以有效缓解铅离子对神经胶质细胞造成的细胞毒性和炎症反应,有效摩尔浓度是5~40微摩尔每升。
进一步地,该紫锥菊提取物还可以缓解铅离子造成的斑马鱼幼鱼的死亡率和畸形率,有效摩尔浓度是10~40微摩尔每升。
更进一步地,该紫锥菊提取物还可以缓解铅离子造成的小鼠铅毒性,有效剂量为20~100mg/kg,如40mg/kg。
本发明人发现,紫锥菊提取物将铅导致斑马鱼的61%畸形率降低至20%。从分子生物学机制上看,紫锥菊提取物可以显著降低铅诱导的活性氧和肿瘤坏死因子α,并通过调节一系列关键基因和蛋白活性,改善铅引起的氧化应激反应。
本发明人经过文献研究发现,人体内的铅在肝、肾、脾、肺、脑和骨骼中均有积累,以骨骼中蓄积量最大,软组织中铅蓄积约占总蓄积量的10%。人体内的铅处于一个微妙的动态平衡状态;血液中铅多了,会先在组织中存留一段时间,然后有一部分可能再回到血液中,最后沉积在骨骼内,而当血液中铅的浓度比较低的时候,骨骼中的铅也会少量释放到血液里。同时,职业性铅中毒患者为长期暴露于可吸入铅环境中,为慢性铅中毒,需要长期用药,结合铅的蓄积特点,用于治疗铅中毒的制剂倾向于长效性药物。由于药物对骨骼的靶向性和吸收性相较于软组织差,提高药物在血液中的半衰期,依靠血液循环整体降低人体内铅蓄积是较为可行的技术方案。
本发明中,紫锥菊提取物对缓解铅离子对神经胶质细胞造成的细胞毒性和炎症反应,以及缓解铅离子造成的斑马鱼幼鱼的死亡率和畸形率极为有效,且天然提取物毒副作用小,为铅中毒的解毒治疗提供了新途径和候选药物。本发明人对该药物进行试验发现,其对紫外线敏感,这可能是由于紫锥菊提取物中有效成分如菊苣酸在紫外线影响下,异构化成内消旋菊苣酸的原因。同时,若紫锥菊提取物作为口服制剂,则首过效应将会极大降低有效成分进入血液循环的量。
考虑到用于治疗铅中毒的药物倾向的治疗方案、以及紫锥菊提取物的敏感因素,本发明经过试验,最终确定以固体脂质微球作为紫锥菊提取物的载体,通过将固体脂质微球和其他药用辅料制成的固体脂质微球制剂,制备得到治疗铅中毒的制剂。
固体脂质微球是以多种类脂材料如脂肪酸、脂肪醇及磷脂等为载体将药物包裹制成的固体颗粒,其突出的优点是生理相容性好并可生物降解,可控制药物释放,长期稳定性强,在体循环中分布的时间较长,以及由于封闭性进而能够有效避免紫外线对有效成分的影响。固体脂质微球可以被制成胶体溶液或冻干粉针剂后静脉或肌肉注射给药,也可以被制成胶囊、片剂、散剂和颗粒剂口服给药,具有缓释、延长药物在循环系统或目标部位的停留时间等特点。固体脂质微球的上述特点,与用于治疗铅中毒的紫锥菊提取物及其药物形式所需要具备的特点相契合。
制备固体脂质微球的挑战在于选择适当的组成成分和制备方法。由于固体脂质微球的性质如载药量、稳定性、溶出性、控释性、生物利用度和毒副作用等与固体脂质微球的组成直接地密切相关,而固体脂质微球的组成与所要承载的药物性质密切相关,因此,选择什么样的成分形成具有良好品质(较高的载药量、骨架稳定性和较好的控释效果)的紫锥菊提取物固体脂质微球是需要进行大量研究和试验的问题。
为了实现上述目的,本发明提供了一种紫锥菊提取物固体脂质微球,由包括以下重量配比组分的原料制成:
优选地,大豆磷脂与硬脂酸的重量比为(1.4~2.5):1;
甘油占原料总重的质量百分比不低于5%;
泊洛沙姆188占原料总重的质量百分比不低于8.5%。
更优选地,所述紫锥菊提取物固体脂质微球由包括以下重量配比组分的原料制成:
在本发明中,大豆磷脂和硬脂酸是固体脂质微球的基质骨架的主要成分。本发明人经过研究发现,大豆磷脂与硬脂酸的重量比为(1.4~2.5):1,与助乳化剂组合使用时,对于水溶性紫锥菊提取物而言易于获得稳定膜体,由此获得的固体脂质微粒载药量高,骨架稳定性高。而当使用大豆磷脂和硬脂酸以其他重量比组合时,或者使用其他单一或组合的脂质时,水溶性紫锥菊提取物的载药量、控释性和稳定性不理想。大豆磷脂为含有卵磷脂、脑磷脂、肌醇磷脂、磷酯酰丝氨酸、磷脂酸及其他磷脂的多磷脂组合物,相较于单一磷脂,该天然多种组合物大小分子配合,对骨架的形成能够起到协同增效的作用。
对于紫锥菊提取物的固体脂质微球,相对于25重量份的紫锥菊提取物而言,大豆磷脂35~85重量份,硬脂酸25~34重量份。大量试验表明,如果大豆磷脂的用量低于35重量份,硬脂酸的用量低于25重量份,虽然紫锥菊提取物与大豆磷脂和硬脂酸乳化混合,但鉴于紫锥菊提取物的水溶性,使得反应体系由于固体脂质微球骨架量不足而会有大量游离的紫锥菊提取物未被包裹。如果大豆磷脂的用量高于85重量份,硬脂酸的用量高于34重量份,固体脂质微球的体积变大,但载药量较低。
在本发明中,甘油和泊洛沙姆188作为助乳化剂。助乳化剂对于固体脂质微球的形成以及载药量至关重要。本发明人研究发现,采用短链醇甘油和非离子表面活性剂泊洛沙姆188的组合,能够有效使紫锥菊提取物、大豆磷脂和硬脂酸制成纳米乳(或者称亚微乳),制成的固体脂质微球结构规则且粒径分布较为集中。采用其他乳化剂,如聚乙二醇2000等,虽然也可以形成固体脂质微球,但固体脂质微球载药量较低且规则性较差。
对于紫锥菊提取物的固体脂质微球,相对于25重量份的紫锥菊提取物而言,甘油用量为8~15重量份,泊洛沙姆188用量为10~16重量份,优选甘油占原料总重的质量百分比不低于5%;泊洛沙姆188占原料总重的质量百分比不低于8.5%。若甘油用量低于8重量份,泊洛沙姆188用量低于10重量份,会由于乳化剂的用量不足导致固体脂质微球载药量低、规则性差,影响药效;若甘油用量高于15重量份,泊洛沙姆188用量高于16重量份,则会由于乳化剂用量过高,结构稳定性和控释性受影响。
在本发明中,依据机体排铅机理,以及紫锥菊提取物固体脂质微球缓释性的特点,创造性的在固体脂质微球的骨架上引入聚乙二醇6000,发现相较于不引入聚乙二醇6000的固体脂质微球,具有聚乙二醇6000的固体脂质微球表现为使血液循环中的菊苣酸含量更高,更利于缓解机体内铅中毒症状。本发明人认为,原因可能在于聚乙二醇6000能够降低固体脂质微球易被肝脾巨噬细胞迅速清除的问题,使得固体脂质微球在血液中的循环时间延长。
对于紫锥菊提取物的固体脂质微球,相对于25重量份的紫锥菊提取物(或者35~85重量份大豆磷脂、25~34重量份的硬脂酸)而言,聚乙二醇6000的用量2~10重量份,不会影响固体脂质微球的结构稳定性,且能够较为有效的延长其在血液中的循环时间。
进一步地,本发明提供了上述紫锥菊提取物固体脂质微球的制备方法,包括以下步骤:
步骤1,按照重量比例分别称取紫锥菊提取物、大豆磷脂和硬脂酸,加热熔融,搅拌均匀;
步骤2,向步骤1反应体系中加入相同温度的甘油和泊洛沙姆188水溶液,制备得到初乳;
步骤3,对初乳进行高压乳化处理,然后迅速冷却,形成固体脂质微球混悬液;
步骤4,冷冻干燥处理,得到紫锥菊提取物固体脂质微球。
在本发明中,步骤1中,加热温度为70~80℃。
在本发明中,步骤2中,甘油和泊洛沙姆188在水溶液中的总浓度为10wt%~15wt%。
在本发明中,步骤1至步骤3的操作,均在通氮条件下进行。
在本发明中,步骤4中,为避免冷冻干燥后固体脂质微球聚聚和粒径变化,向体系中加入冻干保护局,所述冻干保护剂包括葡萄糖、甘露醇和乳糖等中的一种或多种,在冷冻时促进大量微小冰晶析生成,促使冻干品呈疏松状态,以利于固体脂质微球保持原形态并易于在水中再分散。
上述紫锥菊提取物固体脂质微球的制备方法中,采用适当的骨架原料和助乳化剂等,以高压乳化发制备得到固体脂质微球,粒径分布均匀,平均粒径小,该特点利于在体内停留时间延长,生物利用度增强。
进一步地,本发明还提供了上述紫锥菊提取物固体脂质微球制剂,其由紫锥菊提取物固体脂质纳米粒和其他药用辅料制成;其中,紫锥菊提取物固体脂质纳米粒由包括以下重量配比的原料成分制成:
优选地,大豆磷脂与硬脂酸的重量比为(1.4~2.5):1;
甘油占原料总重的质量百分比不低于5%;
泊洛沙姆188占原料总重的质量百分比不低于8.5%。
本发明提供的紫锥菊提取物固体脂质微球制剂形式为冻干粉注射剂、片剂、颗粒剂、胶囊剂或干混悬剂。
本发明中,药用辅料包括填充剂、崩解剂、粘合剂、溶胀辅料、润滑剂、矫味剂、或甜味剂及其组合。各种药用辅料的用量可以由本领域技术人员根据各辅料在相应制剂中的常规用量进行选择,这在本领域技术人员的能力范围内。
填充剂可以选自淀粉、预胶化淀粉、乳糖、蔗糖、甘露醇、山梨醇、微晶纤维素、硫酸钙、硫酸氢钙等中的一种或几种;
崩解剂可以选自羧甲基淀粉钠、低取代羟丙纤维素、交联聚乙烯吡咯烷酮、羧甲基纤维素钠、淀粉及其衍生物等中的一种或几种;
粘合剂可以选自羧甲基纤维素、聚乙烯吡咯烷酮、羟丙基甲基纤维素等中的一种或几种;
溶胀辅料可以选自苍耳胶、藻酸盐、葡萄糖、淀粉、亲水性纤维素及其衍生物如羧甲基纤维素钙等中的一种或几种;
润滑剂可以选自硬脂酸镁、硬脂酸锌、滑石粉、微粉硅胶、硬脂酸等中的一种或几种;
矫味剂选自薄荷油、薄荷醇、人造香草、肉桂、或各种果味等中的一种或几种;
甜味剂可以选自甘露醇、蔗糖、异麦芽酮糖、乳酮糖、棉子糖、大豆低聚糖、低聚果糖、低聚乳果糖、糖精钠、甜蜜素和安赛蜜等中的一种或几种。
上述制备得到的紫锥菊提取物固体脂质微球制剂形式为冻干粉注射剂、片剂、颗粒剂、胶囊剂或干混悬剂,允许注射、口服方式的选择。
实施例
以下通过具体实例进一步描述本发明,不过这些实例仅仅是范例性的,并不对本发明的保护范围构成任何限制。
实施例中,紫锥菊水提物购自西安天一生物技术有限公司,菊苣酸含量为2%;
大豆磷脂购自西安天正药用辅料有限公司;
硬脂酸购自西安悦来医药科技有限公司;
甘油购自西安天正药用辅料有限公司;
泊洛沙姆188购自西安天正药用辅料有限公司;
聚乙二醇6000购自西安天正药用辅料有限公司;
Pb2+通过三水合醋酸铅配置,购自北京百灵威科技有限公司;
活性氧诱导剂为Rosup试剂,购自北京碧云天生物技术有限公司;
阳性药物即螯合剂为乙二胺四乙酸二钠钙,购自北京百灵威科技有限公司;
细胞实验中神经胶质细胞BV-2细胞源自北京师范大学资源学院馈赠;
动物试验中的斑马鱼源自山东省科学院生物研究所;
动物试验中的昆明小鼠购自北京维通利华实验动物技术有限公司。
以下实施例1~3和对比例1~4中紫锥菊提取物通过实验例1中制备方法制备得到。
实施例1
(一)本实施例中紫锥菊提取物固体脂质微球的原料包括以下重量配比的组分:
(二)制备方法
称取50g紫锥菊提取物、110g大豆磷脂和54g硬脂酸,在通氮条件下加热至75℃熔融,搅拌均匀;
向上述反应体系中加入相同温度的18g甘油和30g泊洛沙姆188制得的水溶液,制备得到初乳;甘油和泊洛沙姆188在水溶液中的总浓度为10wt%;
在通氮条件下对初乳在40 MPa下高压乳化处理5次,然后迅速冷却,形成固体脂质微球混悬液;在-20℃、10 Pa压力下冷冻干燥60h,得到冻干的紫锥菊提取物固体脂质微球。
实施例2
本实施例中固体脂质微球和所用方法与实施例1相似,区别仅在于,紫锥菊提取物固体脂质微球的原料包括以下重量配比的组分:
实施例3
本实施例中固体脂质微球和所用方法与实施例1相似,区别仅在于,本实施例所用方法与实施例1相似,区别仅在于紫锥菊提取物固体脂质微球的原料包括以下重量配比的组分:
对比例
对比例1
本对比例中固体脂质微球和所用方法与实施例1相似,区别仅在于原料中,大豆磷脂的用量为55g,硬脂酸的重量为54g,大豆磷脂与硬脂酸的重量比为1.02:1。
对比例2
本实施例中固体脂质微球和所用方法与实施例1相似,区别仅在于原料中,大豆磷脂的用量为110g,硬脂酸的重量为22g,大豆磷脂与硬脂酸的重量比为5:1。
对比例3
本实施例中固体脂质微球和所用方法与实施例1相似,区别仅在于,泊洛沙姆188的用量为15g,占原料总重的5.8%。
对比例4
本实施例中固体脂质微球和所用方法与实施例1相似,区别仅在于原料中,原料中不添加聚乙二醇6000。
实验例
实验例1 药用紫锥菊提取物的制备
(1)紫锥菊粗提物制备:
称取紫锥菊水提物500g,加入50%乙醇1.5 L,超声提取30min,过滤,残渣再以相同的方法提取2次,合并提取液,减压蒸馏,回收乙醇,得浓缩液2 L,加到装有1100g预处理过的AB28型大孔吸附树脂的层析柱(120cm×5.2cm)上,静止吸附1.0h后,先用水洗脱除去糖类等杂质,然后再30%乙醇洗脱,接收30%乙醇洗脱物,减压浓缩除去乙醇后,真空冷冻干燥,得褐色粉末。
(2)紫锥菊粗提物的精制:高速逆流色谱(HSCCC)制备药用紫锥菊提取物:
使用的两相溶剂系统由甲基叔丁基醚-乙腈-水(4:1:5)组成。溶剂系统在分液漏斗中平衡,两相在使用前分离。用浓度为10mM的三氟乙酸使上层有机相呈酸性,并用作固定相。通过加入氨水使下层水相呈碱性,得到10mM的NH3溶液,用作流动相。
首先使用固定相灌满色谱分离柱,然后将样品溶解在固定相和水相的混合物中(比例为4:1,例如3.0g样本用20mL:5mL溶解)。然后将流动相以2mL/min泵入柱中,同时以组合的头对尾洗脱模式以800rpm旋转柱。在254nm连续监测洗脱液的吸光度,收集4mL级分。用pH计测量每个洗脱级分的pH。分离完成后,通过用加压氮气将柱的内容物从柱中取出,将柱内容物收集到量筒中来测量固定相的保留。收集的馏分在减压下使用旋转蒸发使其干燥,并通过HPLC和LC-ESI-MS分析。通过分析可知,最终获得的菊苣酸含量大于95wt%(95.6wt%)的紫锥菊提取物。
实验例2 紫锥菊提取物保护神经胶质细胞抵抗铅离子毒性实验
将BV-2细胞接种在6cm培养皿中(1×106个细胞,4mL DMEM培养基)。单独暴露铅离子或铅离子-紫锥菊提取物共暴露48h后,使用胰蛋白酶将细胞从培养皿底消化分散,将细胞悬液合并后,使用台盼蓝试剂染色,然后使用细胞计数器进行计数,计算各暴露组的活细胞数。
如图1所示,铅离子在10μM浓度下即可造成BV-2细胞活力显著下降超过40%,而如果同时与紫锥菊提取物(图1~5中以菊苣酸代表紫锥菊提取物)孵育,其细胞毒性得以显著缓解,BV-2的细胞活力显著上升。
实验例3 紫锥菊提取物对铅离子诱导的活性氧水平异常的缓解
将BV-2细胞接种在具有黑色壁和透明底部的96孔微量培养板中,单独暴露铅离子或铅离子/紫锥菊提取物共暴露48hh后,使用DCFH-DA活性氧测定试剂盒(碧云天生物试剂有限公司,北京)测定各个暴露组与活性氧水平成正比的的荧光强度。
文献报道,铅离子通过产生活性氧而导致的细胞氧化应激是其毒性的重要机制(Chan-Min Liu et.al.,Experimental and Toxicologic Pathology,2012;Ana CarolinaB Almeida Lopes et.al.,Springer,2016)。因此,我们测定了经处理的BV-2细胞中的活性氧水平。如图2A所示,铅离子显著增加了21%细胞中的活性氧水平,但与紫锥菊提取物共同孵育,紫锥菊提取物显著抑制了活性氧的增加,且具有浓度依赖性。这可能是紫锥菊提取物缓解铅离子毒性的分子机制之一。
实验例4 紫锥菊提取物对铅离子诱导的肿瘤坏死因子α(TNF-α)异常的缓解
将BV-2细胞接种在96孔微量培养板中,单独暴露铅离子或铅离子-紫锥菊提取物共暴露48h后,按照制造商的方案(Mouse TNF alpha Uncoated ELISA,Invitrogen,#lot88-7324),450nm下测定各个暴露组样品的吸光度,并使用TNF-α工作曲线计算对应的TNF-α的浓度。
BV-2细胞是一种位于中枢神经部位的巨噬细胞(即神经胶质细胞),过量的活性氧可以刺激BV-2细胞的免疫反应,防御细胞氧化应激。如图2B所示,铅离子诱导BV-2细胞中TNF-α浓度显著升高,而紫锥菊提取物显著抑制了这一炎症因子水平,结果表明,紫锥菊提取物可以缓解铅离子对BV-2细胞造成的炎症反应。
实验例5 神经胶质细胞细胞周期和凋亡测定实验
将BV-2细胞接种在6cm培养板中,并用单独的铅离子或铅离子和待测化合物(即铅离子-紫锥菊提取物)处理48h。收获细胞并用磷酸盐缓冲盐水洗涤两次。将细胞悬浮液分成两个管。一个用DAPI染色。另一个用Annexin V-PE/7-AAD染色,然后在BD流式细胞仪(BDBiosciences)上进行细胞周期和细胞凋亡分析。
如图3所示,当暴露于铅离子(10μM)48h后,BV-2细胞中发生明显的G1/S期细胞周期停滞(图3A)。而与紫锥菊提取物共孵育,可以部分缓解细胞周期的停滞,其中G2/M期细胞比例从5.6%恢复至12.3%。此外,铅离子(10μM)在48h后诱导8.5%的晚期凋亡/坏死(图3B)。紫锥菊提取物没有显著改善细胞凋亡/坏死的比例。因此,10μM铅离子对BV-2细胞的细胞毒性可能主要通过细胞周期停滞而诱导,部分通过暴露浓度下的细胞凋亡诱导。紫锥菊提取物减轻了BV-2细胞中铅离子造成的细胞周期停滞。
实验例6 紫锥菊提取物影响的神经胶质细胞中氧化应激信号通路的相关基因
BV-2神经胶质细胞单独暴露铅离子或铅离子-紫锥菊提取物共暴露48h后,用Trizol(Invitrogen)裂解BV-2细胞,然后进行mRNA提取。纯化后,通过Superscript III(Invitrogen)将约1.5μg的mRNA用于cDNA合成。然后将cDNA加入RT2 Profiler PCR Array微孔板(PAHS-084A,Qiagen)的孔中;每个孔含有氧化应激特异性基因引物混合物,其中5个孔含有管家基因作为对照。然后将PCR板进行两步RT2 PCR程序(95℃15秒,60℃60秒)。通过ΔΔCt方法定量84种氧化应激特异性基因的表达。
为了进一步验证紫锥菊提取物在帮助细胞存活中的作用,我们使用实时PCR阵列测定了涉及氧化应激和抗氧化防御的84个基因表达的变化。如图4A,铅离子显著影响了BV-2细胞的16个基因的表达(上调或下调倍数>2),反映了细胞对污染物(铅离子)暴露的反应。当BV-2细胞与10μM菊苣酸同时暴露于铅离子时,仅改变了9种基因的表达。具体而言,菊苣酸降低了铅离子诱导的Aox1,Gclm,Hmox1,Nqo1,Scd1和Srxn1的上调表达,这是参与细胞氧化应激诱导的关键基因。当螯合剂EDTA二钠钙与铅离子共同暴露时,有6个基因被改变。实验结果表明,菊苣酸缓解了铅离子引起的细胞氧化应激有关的基因表达上调。
实施例7 紫锥菊提取物影响的神经胶质细胞中氧化应激信号通路的HO-1蛋白表
达
将BV-2细胞(4mL培养基,1×10 6个细胞)接种在6cm培养皿中。BV-2神经胶质细胞单独暴露铅离子或铅离子-紫锥菊提取物共暴露48h后,PBS冲洗后收集细胞。以RIPA裂解缓冲液裂解细胞,制备细胞裂解物。使用BCA蛋白质测定法测定蛋白质浓度。将等量的总蛋白质加载到8%SDS-PAGE凝胶上并转移到PVDF上。用含有0.1%吐温20的Tris缓冲盐水中的5%脱脂奶封闭膜1h,然后用针对血红素加氧酶1(HO-1)和β-肌动蛋白的一抗进行印迹(Cell Signaling Technology,Danvers,MA,USA)在4℃下1:1,000稀释过夜。然后将膜与山羊抗小鼠或山羊抗兔二抗(1:5000,Santa Cruz Biotechnology)在室温下孵育1h。使用增强化学发光Western印迹系统(Millipore)来检测免疫反应条带。
为了验证实时PCR阵列的发现,我们通过蛋白质印迹检查了由Hmox1编码的血红素加氧酶1(HO-1)蛋白的表达。HO-1表达是公认的氧化应激的生物标志物。与基因表达结果一致,铅离子引起的HO-1蛋白表达上调被紫锥菊提取物抑制了57%(附图4B)。这些数据进一步支持了我们的发现,即紫锥菊提取物保护BV-2细胞免受铅离子诱导的细胞毒性。
实施例8 紫锥菊提取物缓解铅毒性的斑马鱼动物模型实验
将野生型(AB株)斑马鱼在光照/黑暗循环环境中28℃下封闭的流通系统中用木炭过滤的自来水维持。斑马鱼受精卵来自产卵成鱼。选择健康的受精卵并随机放入6孔板(每孔30个受精卵)中。在受精后2h(hpf),将胚胎暴露于DMSO(0.1%),铅离子(10μM),铅离子-紫锥菊提取物(10/5μM),铅离子-紫锥菊提取物(10/10μM),铅离子-紫锥菊提取物(10/20μM),或铅离子-EDTA二钠钙(10/40μM)溶于5mL鱼水中。每组有三个重复。每隔24h更换溶液,此时丢弃任何死胚。暴露持续时间为2hpf至120hpf。在72hpf时,检查并记录孵化率。在120hpf时,通过观测幼鱼心跳和未脱落的尾巴来鉴定死亡率。使用立体显微镜鉴定形态学异常。记录死亡率和畸形率。然后将来自每组的正常幼鱼放入行为记录装置中。在15分钟的适应期后,允许幼鱼自由地探索,并记录总游泳时间。
铅离子会导致严重的发育缺陷和神经系统疾病。同时,斑马鱼是胚胎发育过程中可接受的个体发育毒性模型,因此,我们使用斑马鱼胚胎来验证紫锥菊提取物在体内对铅离子的保护活性。结果显示,在72hpf,在测试化合物(包括铅离子)存在下,每组90只斑马鱼胚胎均成功孵化(图5A)。然而,在120hpf时,铅离子暴露导致了17%的斑马鱼幼鱼死亡和61%的发育畸形。紫锥菊提取物显著降低了铅离子的毒性至2%死亡率和20%畸形率(图5B和图5C)。同时,随机在铅离子单独或铅离子与待测化合物组挑选形态正常的6只斑马鱼幼鱼,其总游泳时间没有观察到显著差异(图5D)。形态学评估(图5E)显示在铅离子处理的斑马鱼中观察到严重的发育异常,包括脊柱弯曲,卵黄保留,鱼鳔缺失和尾部弯曲。与紫锥菊提取物共同孵育,可以部分缓解幼鱼的脊柱弯曲和卵黄保留,但并没有改善鱼鳔缺失情况。这些结果表明,紫锥菊提取物不仅在体外保护细胞免受铅离子的侵害,而且还在动物水平,可以缓解铅离子对斑马鱼的毒性。
实验例9 紫锥菊提取物固体脂质微球的粒径
使用扫描电镜和光镜对干燥的固体脂质微球的形态和表面特征进行观察。
在室温条件下,取实施例1~3和对比例1~4中制备得到的固体脂质微球混悬液,采用粒径测定以进行粒径及其分布的测定。结果示于下表1中。
表1粒径检测结果
实施例 | 外观 | 平均粒径 |
实施例1 | 大小分布均匀,球形 | 152.6±12.4nm |
实施例2 | 大小分布均匀,球形 | 193.5±15.8nm |
实施例3 | 大小分布均匀,球形 | 126.2±13.1nm |
对比例1 | 大小分布不均匀,不规整颗粒 | 122.8±21.5nm |
对比例2 | 大小分布不均匀,不规整颗粒 | 144.1±27.6nm |
对比例3 | 大小分布不均匀,不规整颗粒 | 171.4±32.0nm |
对比例4 | 大小分布均匀,球形 | 147.5±13.8nm |
由表1可知,本发明实施例1-3中所得固体脂质微球的外观相较于对比例1-3中所得固体脂质微球的外观更为均匀、规则性更好。这表明,紫锥菊提取物固体脂质微球的粒径与形态与用于形成脂质固体微球的骨架成分和用量直接相关。
对比例4中外观未劣化,这主要是因为聚乙二醇6000的主要作用不在于形成骨架结构上。
本发明的紫锥菊提取物固体脂质微球粒径分布均匀,利于提高药品的稳定性、控释性以及生物利用度。
实验例10载药量
载药量=(微球中所含药物的重量/微球的总重量)
取实施例1~3和对比例1~3中制备得到的固体脂质微球冻干剂,将冻干的固体脂质微球复溶,破乳,HPLC法测定紫锥菊提取物相较于微球的含量,结果如表2所示:
表2载药量
实施例 | 载药量 |
实施例1 | 8.3% |
实施例2 | 6.8% |
实施例3 | 7.4% |
对比例1 | 4.2% |
对比例2 | 4.7% |
对比例3 | 3.8% |
由表2可知,本发明实施例1~3中所得固体脂质微球的载药量相较于对比例1~3中所得固体脂质微球的载药量更高。这表明,紫锥菊提取物固体脂质微球的载药量与用于形成脂质固体微球的骨架成分和用量直接相关,本发明中成分和用量,能够得到较高载药量的固体脂质微球。
实验例11包封率
包封率=(微球中所含药物的重量/投入的总药量)
取实施例1~3和对比例1~3中制备得到的固体脂质微球冻干剂,将冻干的固体脂质微球复溶,破乳,HPLC法测定紫锥菊提取物相较于总投入量的比例,以菊苣酸作为指标化合物进行换算,,包封率结果如表3所示:
表3包封率
实施例 | 包封率 |
实施例1 | 99.5% |
实施例2 | 99.7% |
实施例3 | 98.4% |
对比例1 | 75.6% |
对比例2 | 82.8% |
对比例3 | 72.5% |
由表3可知,本发明实施例1~3中所得固体脂质微球的包封率相较于对比例1~4中所得固体脂质微球的包封率更高。这表明,紫锥菊提取物固体脂质微球的包封率与用于形成脂质固体微球的骨架成分和用量直接相关。
实验例12体外释放效果
以实施例1~3和对比例1~4中制备得到的固体脂质微球冻干剂作为测试样品。
根据漏槽条件,取0.15g的固体脂质微球放入透析袋中,加入2mL0.9%氯化钠溶液,两端扎好,放入加有0.9%氯化钠溶液50mL的具塞锥形瓶中进行摇床振荡,温度37±0.5℃,振荡频率100rpm;开始后在0.25h、0.5h、1h、2h、3h、4h、8h、12h、24h定时取样测定,取出3mL释放介质,同时补加等量的新鲜的0.9%氯化钠溶液,以后每24h取样,依次测定释放介质中紫锥菊提取物的量,依次累积计算,即可计算出微球的累计释放率。
第0.5h、24h和96h后,固体脂质微球的累计释放率如下表4所示:
表4
由表4可知,本发明固体脂质微球在0.9%氯化钠溶液中的突释得到抑制,在0.5h时的释放量在5%左右,后逐渐升高,相较于对比例1至对比例4,起到显著的抗突释和缓释作用,利于在血液中的循环,提高生物利用度。
实验例13 紫锥菊提取物缓解铅毒性的小鼠动物模型实验
以实验例1中药用紫锥菊提取物、实施例1和对比例4中制备得到的固体脂质微球冻干剂作为测试样品。
将50只体重相近的6周的雄性昆明小鼠(体重25±2.5g)分为5组,依次为:
溶剂对照组(1#试验组):每日灌胃0.9%氯化钠溶液200μL;24h/次,试验42天;
铅离子组(2#试验组):每日灌胃铅离子液5mg/kg,24h/次,试验42天;
铅离子-实验例1中药用紫锥菊提取物组(3#试验组):每日灌胃铅离子液5mg/kg+40mg/kg紫锥菊提取物,24h/次,试验42天;
铅离子-实施例1固体脂质微球组(4#试验组):每日灌胃铅离子液5mg/kg+500mg/kg紫锥菊提取物固体脂质微球,24h/次,试验42天;
铅离子-对比例4固体脂质微球组(5#试验组):每日灌胃铅离子液5mg/kg+500mg/kg紫锥菊提取物固体脂质微球,24h/次,试验42天。
在实验过程中,对各试验组小鼠的形态和体重特征进行评价,结果如下表5所示:
表5
试验组 | 皮毛稀疏率 | 动作迟缓、步态蹒跚 | 体重停止增加 | 死亡率 |
1# | 0/10 | 0/10 | 0/10 | 0/10 |
2# | 10/10 | 10/10 | 10/10 | 2/10 |
3# | 1/10 | 3/10 | 2/10 | 0/10 |
4# | 2/10 | 2/10 | 2/10 | 0/10 |
5# | 4/10 | 5/10 | 3/10 | 0/10 |
由表5可知,本发明中制备得到的紫锥菊提取物、紫锥菊提取物固体脂质微球对缓解铅中毒具有明显的效果,且以本发明中优选的骨架成分和含量制作的固体脂质微粒相较于其他成分组合,效果更佳(见试验组4#和试验组5#对比)。
以上结合具体实施方式和范例性实例对本发明进行了详细说明,不过这些说明并不能理解为对本发明的限制。本领域技术人员理解,在不偏离本发明精神和范围的情况下,可以对本发明技术方案及其实施方式进行多种等价替换、修饰或改进,这些均落入本发明的范围内。
Claims (5)
1.一种紫锥菊提取物固体脂质微球,其特征在于,由包括以下重量配比组分的原料制成:
紫锥菊提取物 25重量份
大豆磷脂 35~85重量份
硬脂酸 25~34重量份
甘油 8~15重量份
泊洛沙姆188 10~16重量份
聚乙二醇6000 2~10重量份;
其中,紫锥菊提取物中菊苣酸含量不低于95wt%;
大豆磷脂与硬脂酸的重量比为(1.4~2.5):1;
泊洛沙姆188占原料总重的质量百分比不低于8.5%。
2.根据权利要求1所述的紫锥菊提取物固体脂质微球,其特征在于,
甘油占原料总重的质量百分比不低于5%。
3.根据权利要求1所述的紫锥菊提取物固体脂质微球,其特征在于,其由包括以下重量配比组分的原料制成:
紫锥菊提取物 25重量份
大豆磷脂 55重量份
硬脂酸 27重量份
甘油 9重量份
泊洛沙姆188 15重量份
聚乙二醇6000 6重量份。
4.一种紫锥菊提取物固体脂质微球制剂,其特征在于,其由紫锥菊提取物固体脂质纳米粒和其他药用辅料制成;其中,紫锥菊提取物固体脂质纳米粒由包括以下重量配比的原料成分制成:
紫锥菊提取物 25重量份
大豆磷脂 35~85重量份
硬脂酸 25~34重量份
甘油 8~15重量份
泊洛沙姆188 10~16重量份
聚乙二醇6000 2~10重量份
其中,紫锥菊提取物中菊苣酸含量不低于95wt%;
大豆磷脂与硬脂酸的重量比为(1.4~2.5):1;
甘油占原料总重的质量百分比不低于5%;
泊洛沙姆188占原料总重的质量百分比不低于8.5%;
药用辅料包括填充剂、崩解剂、粘合剂、溶胀辅料、润滑剂、矫味剂及其组合。
5.权利要求1至3之一所述的紫锥菊提取物固体脂质微球在用于制备缓解铅毒性药物的用途;
权利要求4所述的紫锥菊提取物固体脂质微球制剂在用于制备缓解铅毒性药物的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910375415.XA CN110051715B (zh) | 2019-05-07 | 2019-05-07 | 菊苣酸、紫锥菊提取物及相应制剂用于制备缓解铅毒性药物的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910375415.XA CN110051715B (zh) | 2019-05-07 | 2019-05-07 | 菊苣酸、紫锥菊提取物及相应制剂用于制备缓解铅毒性药物的用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110051715A CN110051715A (zh) | 2019-07-26 |
CN110051715B true CN110051715B (zh) | 2021-07-16 |
Family
ID=67322453
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910375415.XA Expired - Fee Related CN110051715B (zh) | 2019-05-07 | 2019-05-07 | 菊苣酸、紫锥菊提取物及相应制剂用于制备缓解铅毒性药物的用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110051715B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113826779B (zh) * | 2021-09-18 | 2023-12-26 | 中国水产科学研究院长江水产研究所 | 菊苣酸在制备预防和/或治疗鱼类脂肪肝的饲料中的应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108568278A (zh) * | 2017-03-13 | 2018-09-25 | 广州市芯检康生物科技有限公司 | 一种新型的即用型气凝胶微球及其制备方法 |
-
2019
- 2019-05-07 CN CN201910375415.XA patent/CN110051715B/zh not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108568278A (zh) * | 2017-03-13 | 2018-09-25 | 广州市芯检康生物科技有限公司 | 一种新型的即用型气凝胶微球及其制备方法 |
Non-Patent Citations (4)
Title |
---|
Ameliorative Effects of Caffeic Acid on Lead Accumulation and Oxidative Stress in Lead-Exposed Mice;Maryam Lotfi-Ghahramanloo等;《Zahedan J Res Med Sci.》;20160531;第18卷(第5期);全文 * |
Chlorogenic Acid Ameliorates Lead-Induced Renal Damage in Mice;Tongsen Zhang等;《Biological Trace Element Research》;20180909;全文 * |
Release of Polyphenols from Liposomes Loaded with Echinacea purpurea;RAMONA DANIELA PAVALOIU等;《REV.CHIM.(Bucharest)》;20181231;第69卷(第9期);第2315-2317页 * |
铅毒性拮抗剂的研究进展;刘洪娟等;《环境与职业医学》;20141130;第31卷(第11期);第882-886页 * |
Also Published As
Publication number | Publication date |
---|---|
CN110051715A (zh) | 2019-07-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2344920T3 (es) | Composicion farmaceutica para el tratamiento de patologias provocadas por la respuesta general del sistema inmutario. | |
US20150057342A1 (en) | Compositions for combined immediate and sustained release of cannabinoids, methods of manufacture and use thereof | |
EP3061452B1 (en) | Icaritin for use in preventing or treating hematocytopenia | |
CN111040006A (zh) | 一种越橘苷的提取方法及越橘苷的应用 | |
US20160151435A1 (en) | Pharmaceutical composition adjuvant to chemotherapy drugs and applications thereof | |
US20180092956A1 (en) | Composition for amelioration of peri- and post- menopausal symptoms and a process for producing the same | |
ES2880432T3 (es) | Uso del extracto de corteza de mangostán en la preparación de medicamentos para el tratamiento de enfermedades de la piel | |
CN104224885A (zh) | 一种缓解体力疲劳的中药组合物 | |
CN110051715B (zh) | 菊苣酸、紫锥菊提取物及相应制剂用于制备缓解铅毒性药物的用途 | |
CN104546809B (zh) | 3,3’,5,5’-四异丙基-4,4’-二联苯酚在预防及治疗缺血性脑卒中中的应用 | |
KR20010101616A (ko) | 진세노사이드 Rb₁을 함유하는 뇌혈관 재생ㆍ재구축촉진제 및 신경조직 이차변성 억제제 | |
CN110882278B (zh) | 五谷虫或其提取物在制备降低肾毒性的药物中的用途 | |
CN112370496A (zh) | 枸杞叶有效成分在制备预防或治疗肝纤维化药物中的应用 | |
CN102614182B (zh) | 一种复方氨酚肾素药物组合物脂质体固体制剂 | |
RU2504347C1 (ru) | Инъекционная лекарственная форма для лечения и профилактики заболеваний печени у животных | |
EP3200770B1 (en) | A formulation useful for delivery of neuro protecting agent | |
Yang et al. | Micelles of Licorice chalcone A for oral administration: preparation, in vitro, in vivo, and hepatoprotective activity evaluation | |
CN101843669B (zh) | 一种用于治疗冠心病的中药有效部位组合物 | |
AU2021105462A4 (en) | Use of fructus corni nano-powder in resisting type 2 diabetes mellitus | |
CN103800318B (zh) | 巴西苏木素在制备用于防治肝肾损伤的药物中的应用 | |
CN105106303B (zh) | 夏枯草水提物的医药用途 | |
CN104069062B (zh) | 一种防治缺血性心脑血管疾病的豆腐果苷注射剂及其制备方法与应用 | |
KR102628223B1 (ko) | 노르갈란타민을 포함하는 간 손상의 예방 또는 치료용 조성물 | |
Ansari et al. | Pre-treatment effects of walnut kernel (juglans regia) on brain edema, neuronal death and neurological scores in male rat after traumatic brain injury | |
CN109364069B (zh) | 棋盘花碱在制备变态反应性疾病治疗药物中的用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210716 |