CN107432874B - 柚皮素的用途、柚皮素纳米脂质体及其制备方法与应用 - Google Patents
柚皮素的用途、柚皮素纳米脂质体及其制备方法与应用 Download PDFInfo
- Publication number
- CN107432874B CN107432874B CN201610353469.2A CN201610353469A CN107432874B CN 107432874 B CN107432874 B CN 107432874B CN 201610353469 A CN201610353469 A CN 201610353469A CN 107432874 B CN107432874 B CN 107432874B
- Authority
- CN
- China
- Prior art keywords
- naringenin
- nano liposomes
- preparation
- phosphatide
- cholesterol
- 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
- FTVWIRXFELQLPI-ZDUSSCGKSA-N (S)-naringenin Chemical compound C1=CC(O)=CC=C1[C@H]1OC2=CC(O)=CC(O)=C2C(=O)C1 FTVWIRXFELQLPI-ZDUSSCGKSA-N 0.000 title claims abstract description 120
- 229940117954 naringenin Drugs 0.000 title claims abstract description 119
- WGEYAGZBLYNDFV-UHFFFAOYSA-N naringenin Natural products C1(=O)C2=C(O)C=C(O)C=C2OC(C1)C1=CC=C(CC1)O WGEYAGZBLYNDFV-UHFFFAOYSA-N 0.000 title claims abstract description 119
- 235000007625 naringenin Nutrition 0.000 title claims abstract description 119
- 239000002502 liposome Substances 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 19
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 17
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 16
- 239000000523 sample Substances 0.000 claims abstract description 14
- 239000000725 suspension Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 239000012736 aqueous medium Substances 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 20
- 239000008363 phosphate buffer Substances 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 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 6
- 235000005911 diet Nutrition 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 229940083466 soybean lecithin Drugs 0.000 claims description 6
- 230000037213 diet Effects 0.000 claims description 5
- 239000007853 buffer solution Substances 0.000 claims description 4
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 208000010706 fatty liver disease Diseases 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- 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 claims description 2
- 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 claims description 2
- 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 claims description 2
- 208000004930 Fatty Liver Diseases 0.000 claims description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 2
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 claims description 2
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 2
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 2
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 2
- -1 cholesterol acetonyl ester Chemical class 0.000 claims description 2
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 2
- 239000005457 ice water Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 2
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 2
- 229940067626 phosphatidylinositols Drugs 0.000 claims description 2
- 239000002504 physiological saline solution Substances 0.000 claims description 2
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 claims description 2
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 238000004821 distillation Methods 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 238000003825 pressing Methods 0.000 claims 1
- 210000004185 liver Anatomy 0.000 description 25
- 150000002632 lipids Chemical class 0.000 description 19
- 241000699666 Mus <mouse, genus> Species 0.000 description 15
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 8
- 238000005538 encapsulation Methods 0.000 description 7
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000009825 accumulation Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 238000002604 ultrasonography Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 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 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000006193 liquid solution Substances 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 210000005228 liver tissue Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 210000002706 plastid Anatomy 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- LRYZPFWEZHSTHD-HEFFAWAOSA-O 2-[[(e,2s,3r)-2-formamido-3-hydroxyoctadec-4-enoxy]-hydroxyphosphoryl]oxyethyl-trimethylazanium Chemical class CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](NC=O)COP(O)(=O)OCC[N+](C)(C)C LRYZPFWEZHSTHD-HEFFAWAOSA-O 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 208000007082 Alcoholic Fatty Liver Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 235000001759 Citrus maxima Nutrition 0.000 description 1
- 244000276331 Citrus maxima Species 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010016262 Fatty liver alcoholic Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 241001093501 Rutaceae Species 0.000 description 1
- 239000004990 Smectic liquid crystal Substances 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 229960004308 acetylcysteine Drugs 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 208000026594 alcoholic fatty liver disease Diseases 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 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 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000002443 hepatoprotective effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000013441 quality evaluation Methods 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 235000014899 silybin Nutrition 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dispersion Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了柚皮素的用途、柚皮素纳米脂质体及其制备方法与应用。本发明柚皮素应用于制备治疗非酒精性脂肪肝药物中。本发明柚皮素纳米脂质体,包括柚皮素和纳米脂质体;纳米脂质体包括磷脂和胆固醇;柚皮素、磷脂和胆固醇的质量比为1:4~9:1~2。其制备方法,包括如下步骤:1)将柚皮素、磷脂和胆固醇溶于溶剂中,混合,然后除去溶剂,得到混合物;2)将步骤1)得到的混合物用水性介质水化,得到柚皮素纳米脂质体粗悬液;3)将步骤2)得到的柚皮素纳米脂质体粗悬液依次进行水浴超声和探头超声,即得到柚皮素纳米脂质体。本发明柚皮素纳米脂质体能提高柚皮素的口服的生物利用度,并提高柚皮素对非酒精性脂肪肝的防治效果。
Description
技术领域
本发明涉及柚皮素的用途、柚皮素纳米脂质体及其制备方法与应用,属于医药技术领域。
背景技术
非酒精性脂肪肝病(nonalcoholic fatty liver disease,NAFLD)是一种遗传-环境-代谢应激相关性疾病,是以肝细胞脂肪变性和脂肪过度蓄积为主要病理特征,但无过量饮酒史的临床综合征。近几年,随着我国生活水平的提高和生活方式与饮食结构的改变,这一过去在西方国家较为常见的肝脏疾病在中国的患病率呈逐年上升趋势,因此日益受到人们的关注。NAFLD的发病机制主要包括以胰岛素抵抗为主的“一次打击”和以氧化应激、肝细胞大量死亡和纤维化为主的“二次打击”。目前,临床上还没有治疗NAFLD的明确方案和药物,一般的治疗主要是以改变生活方式、调节饮食,合理运动等为主,而针对病因和发病机制的药物治疗主要有降脂药(他汀类)、降糖药(噻唑烷二酮类、二甲双胍等)、抗氧化剂(普罗布考、乙酰半胱氨酸、维生素E)等),此外还有一些保肝药如水飞蓟宾等也用于非酒精性脂肪肝的治疗。然而现有的这些治疗药物都不是针对非酒精性脂肪肝发病机制的特效制剂,且缺乏大样本多中心临床研究。因此,临床上急需寻找有效的药物来有效预防和治疗NAFLD。
柚皮素(Naringenin,NRG)是一种广泛存在于芸香科等植物中的天然黄酮类化合物。但由于柚皮素属于难溶性药物,口服给药后在胃肠道中的溶出较低,导致药物损失与浪费,且易发生不良反应事件,影响柚皮素的临床疗效及应用。目前已有药学研究者致力于通过制剂技术提高柚皮素溶解度的研究。已经报道的剂型包括固体分散剂、多室脂质体、β-环糊精复合物、磷脂复合物、纳米自乳化给药体系、可降解纳米粒等。上述剂型都在一定程度上提高了NRG的溶解度和口服生物利用度,但依然存在很多问题有待解决。如:制备过程中的有机溶剂残留;液体制剂的储存稳定性;表面活性剂的口服安全性,粒径过大等。
纳米脂质体(nanoliposome)是目前最常用的一种纳米制剂,它是由排列有序的脂质双分子层组成的多层微囊,具有类似生物膜双分子层的近晶型液晶结构。在水中磷脂分子亲水头部插入水中,疏水尾部伸向空气,搅动后形成双层脂分子的球形脂质体,直径通常为几十纳米到几十微米不等。脂质体的主要成分为磷脂和胆固醇,具有较好的生物相容性和较低的体内外毒性。基于脂质体的优良特性,我们构建了柚皮素的纳米脂质体剂型(NRG-nanoliposome),以期改善柚皮素的溶解和吸收特性,减少药物使用剂量,在达到相同的治疗效果时降低药物的毒副作用。
发明内容
本发明的目的是提供柚皮素的用途、柚皮素纳米脂质体及其制备方法与应用。本发明柚皮素能用于制备治疗非酒精性脂肪肝药物,柚皮素纳米脂质体能提高柚皮素的口服的生物利用度,并提高柚皮素对非酒精性脂肪肝的防治效果。
本发明提供的柚皮素应用于制备治疗非酒精性脂肪肝药物中。
本发明还提供了一种柚皮素纳米脂质体,它包括柚皮素和纳米脂质体;
所述纳米脂质体包括磷脂和胆固醇;
所述磷脂为蛋磷脂、大豆磷脂、脑磷脂、氢化卵磷脂、1,2-二油酰氧丙基-N,N,N-三甲基溴化铵、磷脂酰肌醇、磷脂酰甘油、磷脂酰丝氨酸、磷脂酸、磷脂酰乙醇胺、磷脂酰胆碱、鞘磷脂、牛胆酸钠、β-谷甾醇和胆固醇乙酰酯中的至少一种;
所述柚皮素、所述磷脂和所述胆固醇的质量比为1:4~9:1~2。
本发明还提供了上述的柚皮素纳米脂质体的制备方法,包括如下步骤:1)将所述柚皮素、所述磷脂和所述胆固醇溶于溶剂中,混合,然后除去所述溶剂,得到混合物;
2)将步骤1)得到的所述混合物用水性介质进行水化,得到柚皮素纳米脂质体粗悬液;
3)将步骤2)得到的所述柚皮素纳米脂质体粗悬液依次进行水浴超声和探头超声,即得到柚皮素纳米脂质体。
上述的制备方法中,所述溶剂为氯仿、甲醇、无水乙醇、乙醚和石油醚中的至少一种;
所述柚皮素的质量与所述溶剂的体积比为1g:100~400mL,具体可为1g:238~313mL或1g:150~350mL。
本发明中,所述溶剂可为氯仿和甲醇的混合溶剂,所述氯仿和所述甲醇的体积比为1:0.5~2,具体可为2:1或1:2。
上述的制备方法中,步骤1)中除去所述溶剂采用减压蒸馏的方法,所述减压蒸馏的温度为35~50℃,具体可为37℃、40℃或37~40℃。
上述的制备方法中,所述水性介质是纯水或缓冲溶液,所述缓冲溶液包括磷酸盐缓冲液、生理盐水;
所述磷酸盐缓冲液的pH值为7.4,所述磷酸盐缓冲液的浓度为0.002~0.02mol/L,具体可为0.01mol/L;
所述柚皮素的质量与所述水性介质的体积比为1g:200~600mL,具体可为1g:313~476mL。
上述的制备方法中,所述水化的温度可为30~60℃,具体可为40℃或30~50℃;
所述水化的时间可为20~60min,具体可为30min、25~30min或25~50min。
上述的制备方法中,所述水浴超声的温度可为20~50℃,具体可为40℃、20~40℃、40~50℃或35~45℃;
所述水浴超声的时间可为20~40min,具体可为25min、30min或25~30min。
所述水浴超声功率可为50~100W,具体可为50W、80W或50~80W。
上述的制备方法中,所述探头超声在冰水浴中进行;
所述探头超声的时间可为10~20min,具体可为15min、20min或15~20min;
所述探头超声的振幅可为满输出功率振幅的50~100%;具体可为50%、80%或50~80%。
本发明所述柚皮素纳米脂质体在制备治疗非酒精性脂肪肝药物中的应用。
本发明具有以下优点:
本发明所涉及柚皮素纳米脂质体制备方法简便、易于控制和操作、清洁安全、无有毒有机溶剂残留,且可连续化批量生产;
本发明制得的柚皮素纳米脂质体平均粒度均一,包封率高,稳定性好;
本发明柚皮素纳米脂质体改善了柚皮素的溶解和吸收特性,能减少药物使用剂量,提高药物生物口服利用率,并提高柚皮素对非酒精性脂肪肝的防治效果,在达到相同的治疗效果时降低药物的毒副作用。
附图说明
图1为本发明柚皮素纳米脂质体的粒径分布图。
图2为本发明柚皮素纳米脂质体的体外释放曲线。
图3为柚皮素、柚皮素纳米脂质体在C57BL/6体内的血浆总柚皮素浓度-时间曲线图。
图4为小鼠血清ALT和AST水平,图4A为ALT水平,图4B为AST水平。其中,图4中平行试验次数n=5,*表示P<0.05,***表示P<0.001。
图5为小鼠肝脏形态学切片油红O染色结果图;图5A为对照组;图5B为MCD模型组;图5C为NRG组;图5D为NRG-Nanolipo组。
图6为小鼠肝脏脂质抽提结果,图6中平行试验次数n=5,**表示P<0.01,***表示P<0.001。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1、柚皮素纳米脂质体的制备
准确称取0.0126g柚皮素、0.1127g大豆磷脂、0.0124g胆固醇,加入2mL氯仿和1mL甲醇,充分溶解,37℃水浴条件下减压旋转蒸发除去溶剂,直至茄形瓶壁上形成一层均匀的脂质薄膜。加入3mL 0.01mol/L磷酸盐缓冲液(pH=7.4)在40℃水化30min,于80W,40℃水浴超声30min得到柚皮素纳米脂质体粗悬液。于冰浴下超声15min(满振幅的80%)得浅蓝色乳光的本发明柚皮素纳米脂质体。
实施例2、柚皮素纳米脂质体的制备
准确称取0.0056g柚皮素、0.0617g大豆磷脂、0.0143g胆固醇,加入1mL氯仿和2mL甲醇,充分溶解,37℃水浴条件下减压旋转蒸发除去溶剂,直至茄形瓶壁上形成一层均匀的脂质薄膜。加入3mL 0.01mol/L磷酸盐缓冲液(pH=7.4)在40℃水化30min,于50W,40℃水浴超声30min得到柚皮素纳米脂质体粗悬液。于冰浴下超声15min(满振幅的50%)得浅蓝色乳光的本发明柚皮素纳米脂质体。
实施例3、柚皮素纳米脂质体的制备
准确称取0.0096g柚皮素、0.0629g大豆磷脂、0.0146g胆固醇,加入2mL氯仿和1mL甲醇,充分溶解,40℃水浴条件下减压旋转蒸发除去溶剂,直至茄形瓶壁上形成一层均匀的脂质薄膜。加入3mL 0.01mol/L磷酸盐缓冲液(pH=7.4)在40℃水化25min,于80W,30℃水浴超声25min得到柚皮素纳米脂质体粗悬液。于冰浴下超声20min(满振幅的50%)得浅蓝色乳光的本发明柚皮素纳米脂质体。
实施例4、柚皮素纳米脂质体的制备
准确称取0.0249g柚皮素、0.2251g大豆磷脂、0.0250g胆固醇,加入2mL氯仿和1mL甲醇,充分溶解,37℃水浴条件下减压旋转蒸发除去溶剂,直至茄形瓶壁上形成一层均匀的脂质薄膜。加入6mL 0.01mol/L磷酸盐缓冲液(pH=7.4)在40℃水化30min,于80W,40℃水浴超声30min得到柚皮素纳米脂质体粗悬液。于冰浴下超声15min(满振幅的80%)得浅蓝色乳光的本发明柚皮素纳米脂质体。
实施例5、柚皮素纳米脂质体的应用试验
1、柚皮素纳米脂质体的质量评价
粒径测定:取本发明实施例1适量柚皮素纳米脂质体,采用Malvern Zeta电位仪测定其粒径,测得粒径为(98±5)nm,其粒径分布图如图1所示。
包封率EE(%)测定:
(1)HPLC法建立柚皮素标准曲线:
色谱条件:测定仪器:LC-15型高效液相色谱仪(日本岛津公司)(配有紫外检测器);色谱柱:C18(250mm×4.6mm,5μm);流动相:甲醇/0.2%磷酸水=71:29(V/V);体积流量为0.7mL/min;进样量为20μL,检测波长289nm。
建立标准曲线得到回归方程如下:
A=120766C+8544.7,R为0.9998,
上式中,A为峰面积,C为柚皮素浓度(μg/mL)。
(2)包封率和载药量的测定
取所制得的柚皮素纳米脂质体溶液100μL,置于10mL容量瓶中,用甲醇定容,超声(频率:40kHz,功率:100W)破乳10min。稀释一定倍数后于上述色谱条件下进样20μL,根据峰面积及标准曲线,计算脂质体总含药量。所制得的脂质体溶液200μL超速离心(30000r/min,2h,4℃)后,精密吸取上清液100μL,用流动相定容至一定浓度后,进样20μL,根据峰面积及标准曲线,计算脂质体处方中的游离药量。可以根据公式:包封率=(总药量-游离药物含量)/总药量×100%计算柚皮素脂质体包封率。根据公式:载药量=[脂质体中药物量/(脂质体中药物+载体总量)]×100%计算柚皮素脂质体的载药量。测得本发明实施例1中柚皮素纳米脂质体的包封率为97.85%,载药量为8.16%。
按照与上相同的方法,测得本发明实施例2、3、4中柚皮素纳米脂质体的包封率分别为76.43%,86.93%,97.40;载药量分别为3.99%,5.12%,8.95%。
2、柚皮素纳米脂质体体外释放考察
将本发明实施例1柚皮素纳米脂质体溶液0.5mL置于透析袋中,透析袋两端扎牢,置于37℃恒温的250mL释放介质中磁力搅拌(200r·min-1)。分别于0.5、1.0、2.0、4.0、8.0、12.0、24.0、48.0h取透析袋外释放介质1mL,同时补充等量相同温度下的新鲜释放介质。HPLC法检测各个时间点的释放介质中NRG的含量。以累积释放百分数为纵坐标,时间为横坐标绘制柚皮素纳米脂质体的体外释放曲线图,如图2所示。
由图2可知,本发明柚皮素纳米脂质体的体外释药结果表明NRG-nanoliposome在最初8h内释药率达到62.84±5.38%,随后缓慢释放,24h累计释放达到73.63±7.34%。
3、柚皮素纳米脂质体药代动力学研究
25±2g雄性C57BL/6小鼠20只,分两组,每组10只。给药前禁食12h,自由饮水。两组小鼠分别一次性腹腔注射相当于25mg·kg-1剂量的柚皮素或柚皮素纳米脂质体。两组小鼠于0.25、0.5、1、2、4、6、8、12和24h分别眼眶取血约0.1mL,置于肝素离心管中,4000r/min离心10min,分离上清液,测定血药浓度。药时曲线如图3所示,计算药动学参数,药动学参数结果如表1所示。
表1 小鼠单次腹腔注射柚皮素(25mg/kg)的药代动力学参数(Mean±SD,n=5)
由表1可知,本发明柚皮素纳米脂质体显著增加了柚皮素在体内的AUC及Cmax,表明本发明柚皮素纳米脂质体改善柚皮素体内生物利用度。
4、柚皮素(NRG)对蛋氨酸、胆碱缺乏(methionine choline deficient diet,MCD)饮食诱导小鼠非酒精性脂肪肝模型实验
(1)8周龄的雄性C57BL/6小鼠,体重平均23g,随机分成四组,对照组(control)给予普通繁殖饲喂饲7天,同时每天灌胃PBS 200μL;模型组给予单纯MCD饲料喂饲7天诱导非酒精性脂肪肝模型,同时每天PBS 200μL灌胃(MCD+PBS组);药物组给予单纯MCD饲料喂饲7天,同时每天分别给予25mg/kg NRG原料药(MCD+NRG组)或25mg/kg NRG-Nanolipo(MCD+NRG-Nanolipo)灌胃。所有动物7天后取材。
(2)动物处死取材
上述(1)中动物连续给药7天后,过夜禁食,称重,并用毛细管内眦取血,分离血清用于测定谷丙转氨酶(ALT),谷草转氨酶(AST)。小鼠麻醉致死,完整分离小鼠肝脏,称量肝脏总重。然后肝脏分别用于形态性分析、肝脏脂质抽提。
肝脏血清学检测结果显示(如图4所示),MCD饮食诱导下,血清的AST和ALT水平显著升高,预示小鼠肝脏收到严重损失。给予NRG对肝脏ALT、AST的升高有一定抑制作用,而本发明中NRG包载在纳米脂质体中,其保护肝脏的效果更显著。
(3)组织形态学实验方法
上述(2)中取材后小心取一部分新鲜肝组织放入4%多聚甲醛溶液中固定,固定2小时后取出,转移至20%蔗糖溶液中,过夜后包埋于OCT中,放入液氮中冷冻,进行冰冻切片,每片厚度7μm。对小鼠肝脏冰冻切片进行油红O染色,通过染色深浅判断肝细胞内脂质沉积多少。
(4)小鼠肝脏冰冻切片油红O染色
冰冻切片用PBS冲洗3分钟,2次;4%多聚甲醛固定10分钟;双蒸水浸泡2分钟,3次;60%异丙醇10分钟(脱水);油红O中染色30分钟;60%异丙醇中迅速过数次洗去浮色;双蒸水冲洗数次(保存在水中即可);苏木精染细胞核1分钟;双蒸水冲洗数次;90%甘油封片,显微镜下观察拍照。
油红O配制方法:0.5%储存液(母液)由1g油红O粉末加入200mL异丙醇制成。60%工作液是将母液(6份)加入双蒸水中(4份),激烈震荡,静置10分钟后过滤使用。(现用现配,2小时内用完)
4%多聚甲醛配制方法:称取4g多聚甲醛,加入0.01M 100mL的PBS,60℃水浴过夜,溶解。
如图5所示,肝脏切片油红O染色结果显示,对照组小鼠的肝脏无脂质蓄积,MCD模型组小鼠肝脏的脂质蓄积严重,柚皮素原料药对肝脏脂质蓄积有一定降低效果,柚皮素纳米脂质体增加了柚皮素对于肝脏脂质蓄积的抑制作用,而空白脂质体对肝脏脂质蓄积没有抑制作用,说明本发明柚皮素纳米脂质体对肝脏脂质蓄积的抑制作用是通过提高柚皮素本身的生物利用度实现的,而非脂质体本身的作用。
(5)小鼠肝脏脂质抽提
另取一块新鲜肝组织用作肝脏脂质抽提,称重,放入1mL预冷的PBS中匀浆,将匀浆液转移至10mL干净、干燥的玻璃管中,加入2:1的氯仿/甲醇4mL,充分涡旋30s后,4℃,2000转,离心30min。将上层水相转移至新玻璃管中称为水相管,转移下层有机相至另一套新玻璃管中称为有机管。往水相管中加入氯仿/甲醇3mL,充分涡旋30秒,4℃,2000转,离心30分钟。将下层有机相转移至有机管中,通风橱氮气吹干。加入3%TritonX-100(v-v)500μL溶解,反复吹打,恒温50℃摇床震荡30分钟,使脂质溶解,测总甘油三脂(TG)含量,以TG含量比上脂质抽提的肝脏重量,作为该样品肝细胞内脂质的含量。
如图6所示,小鼠肝脏脂质抽提结果显示,与油红O染色结果一致,模型组小鼠肝脏内TG水平显著升高,空白脂质体对TG含量没有降低作用,柚皮素原料药在所使用剂量下对TG含量没有显著降低作用,但本发明柚皮素纳米脂质体显著降低了肝脏内TG的蓄积(63%)。
Claims (10)
1.柚皮素在制备治疗非酒精性脂肪肝药物中的应用;
所述非酒精性脂肪肝为MCD饮食诱导的非酒精脂肪肝。
2.一种柚皮素纳米脂质体,其特征在于:它包括柚皮素和纳米脂质体;
所述纳米脂质体包括磷脂和胆固醇;
所述磷脂为蛋磷脂、大豆磷脂、脑磷脂、氢化卵磷脂、1,2-二油酰氧丙基-N,N,N-三甲基溴化铵、磷脂酰肌醇、磷脂酰甘油、磷脂酰丝氨酸、磷脂酸、磷脂酰乙醇胺、磷脂酰胆碱、鞘磷脂、牛胆酸钠、β-谷甾醇和胆固醇乙酰酯中的至少一种;
所述柚皮素、所述磷脂和所述胆固醇的质量比为1:4~9:1~2。
3.权利要求2所述的柚皮素纳米脂质体的制备方法,包括如下步骤:1)将所述柚皮素、所述磷脂和所述胆固醇溶于溶剂中,混合,然后除去所述溶剂,得到混合物;
2)将步骤1)得到的所述混合物用水性介质水化,得到柚皮素纳米脂质体粗悬液;
3)将步骤2)得到的所述柚皮素纳米脂质体粗悬液依次进行水浴超声和探头超声,即得到柚皮素纳米脂质体。
4.根据权利要求3所述的制备方法,其特征在于:所述溶剂为氯仿、甲醇、无水乙醇、乙醚和石油醚中的至少一种;
所述柚皮素的质量与所述溶剂的体积比为1g:100~400mL。
5.根据权利要求3或4中所述的制备方法,其特征在于:步骤1)中除去所述溶剂采用减压蒸馏的方法,所述减压蒸馏的温度为35~50℃。
6.根据权利要求3或4所述的制备方法,其特征在于:所述水性介质是纯水或缓冲溶液,所述缓冲溶液包括磷酸盐缓冲液、生理盐水;
所述磷酸盐缓冲液的pH值为7.4,所述磷酸盐缓冲液的浓度为0.002~0.02mol/L;
所述柚皮素的质量与所述水性介质的体积比为1g:200~600mL。
7.根据权利要求3或4所述的制备方法,其特征在于:所述水化的温度为30~60℃;
所述水化的时间为20~60min。
8.根据权利要求3或4所述的制备方法,其特征在于:所述水浴超声的温度为20~50℃;
所述水浴超声的时间为2~40min;
所述水浴超声功率为50~100W。
9.根据权利要求3或4所述的制备方法,其特征在于:所述探头超声在冰水浴中进行;
所述探头超声的时间为10~20min,
所述探头超声的振幅为满输出功率振幅的50~100%。
10.权利要求2所述的柚皮素纳米脂质体在制备治疗非酒精性脂肪肝药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610353469.2A CN107432874B (zh) | 2016-05-25 | 2016-05-25 | 柚皮素的用途、柚皮素纳米脂质体及其制备方法与应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610353469.2A CN107432874B (zh) | 2016-05-25 | 2016-05-25 | 柚皮素的用途、柚皮素纳米脂质体及其制备方法与应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107432874A CN107432874A (zh) | 2017-12-05 |
CN107432874B true CN107432874B (zh) | 2019-07-26 |
Family
ID=60453833
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610353469.2A Expired - Fee Related CN107432874B (zh) | 2016-05-25 | 2016-05-25 | 柚皮素的用途、柚皮素纳米脂质体及其制备方法与应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107432874B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111228220A (zh) * | 2020-01-14 | 2020-06-05 | 北京大学 | 柚皮素纳米脂质载体及其制备方法与应用 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108524364B (zh) * | 2018-06-14 | 2021-08-17 | 上海棠美生物科技有限公司 | 一种化妆品活性物纳米载体包裹及其制备方法 |
CN113041220B (zh) * | 2021-04-15 | 2022-09-30 | 中国医学科学院药用植物研究所 | 一种以tpgs为载体的柚皮素纳米混悬剂及其制备方法与应用 |
CN113893230B (zh) * | 2021-11-22 | 2022-09-27 | 南昌大学 | 一种抑制肺纤维化的脂质体纳米粒复合物及其制备方法和应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02160722A (ja) * | 1988-12-15 | 1990-06-20 | Nippon Oil & Fats Co Ltd | リポソーム製剤の製造法 |
EP0920870A1 (en) * | 1997-12-08 | 1999-06-09 | Director General of Shikoku National Agricultural Experiment Station, Ministry of Agriculture, Forestry and Fisheries | Flavanone-containing composition |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100472694B1 (ko) * | 2000-12-30 | 2005-03-07 | 한국생명공학연구원 | 플라바논 유도체 및 이를 포함하는 혈중 지질 농도 관련질환의 예방 및 치료용 조성물 |
-
2016
- 2016-05-25 CN CN201610353469.2A patent/CN107432874B/zh not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH02160722A (ja) * | 1988-12-15 | 1990-06-20 | Nippon Oil & Fats Co Ltd | リポソーム製剤の製造法 |
EP0920870A1 (en) * | 1997-12-08 | 1999-06-09 | Director General of Shikoku National Agricultural Experiment Station, Ministry of Agriculture, Forestry and Fisheries | Flavanone-containing composition |
Non-Patent Citations (1)
Title |
---|
3 种黄酮对脂肪肝细胞氧化应激的影响;谢丽阳等;《食品科学》;20111231;第32卷(第17期);全文 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111228220A (zh) * | 2020-01-14 | 2020-06-05 | 北京大学 | 柚皮素纳米脂质载体及其制备方法与应用 |
CN111228220B (zh) * | 2020-01-14 | 2020-12-18 | 北京大学 | 柚皮素纳米脂质载体及其制备方法与应用 |
Also Published As
Publication number | Publication date |
---|---|
CN107432874A (zh) | 2017-12-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107432874B (zh) | 柚皮素的用途、柚皮素纳米脂质体及其制备方法与应用 | |
CN107812197B (zh) | 一种炎症靶向的中性粒细胞递药系统及其应用 | |
CN110575448A (zh) | 大麻二酚组合物及其用途 | |
Veerareddy et al. | Formulation and evaluation of oil-in-water emulsions of piperine in visceral leishmaniasis | |
CN101879137B (zh) | 一种隐形脂质体的制备方法 | |
CN105708801A (zh) | 一种20(R)-人参皂苷Rg3/大豆卵磷脂/胆固醇/叶酸脂质体药物制备方法和应用 | |
CN104161745A (zh) | 一种制备纳米柠檬酸铁脂质体的方法 | |
CN105131277A (zh) | 一种含胆酸的高分子材料及其修饰的脂质体 | |
CN105287406B (zh) | 一种丙泊酚脂质体冻干制剂及其制备方法 | |
CN103191424A (zh) | 一种提高畜禽免疫功能的黄芪多糖纳米脂质体及其制备方法 | |
CN104324007B (zh) | 一种天然重组纳米脂质载体制备技术与应用 | |
CN111228220B (zh) | 柚皮素纳米脂质载体及其制备方法与应用 | |
CN104523591B (zh) | 无致敏性、无痛丙泊酚脂肪微乳冻干制剂配方和制备方法 | |
CN110898231A (zh) | 一种功能化拉洛他赛脂质体及其制备方法与应用 | |
CN113521006B (zh) | 蒿甲醚脂质体、红细胞膜包脂质体、靶向肽修饰仿生脂质体及其制备方法和治疗疟疾的应用 | |
AU2016250068B2 (en) | One-step method for production of Ultra-small Lipid Structures | |
CN111329838B (zh) | 一种紫杉醇脂质体药物组合物及其制备方法 | |
CN103877149A (zh) | 香青兰总黄酮磷脂复合物、香青兰总黄酮磷脂复合物自乳化剂及其制备方法 | |
CN106821984A (zh) | 一种阿仑膦酸钠固体脂质纳米粒及其制备方法 | |
CN109939071A (zh) | 一种红景天苷-维生素e双相前体脂质体及其制备方法和应用 | |
CN112641728A (zh) | 一种色胺酮纳米脂质体及其制备方法 | |
CN115177589B (zh) | 一种紫杉醇脑靶向脂质体和其制备方法及应用 | |
CN105395485B (zh) | 一种双环醇脂质体及其制备方法 | |
CN104771362B (zh) | 一种克拉霉素离子对脂质微球注射液及其制备方法 | |
CN105796496A (zh) | 一种非诺贝特纳米脂质体及其制备方法与应用 |
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: 20190726 |