CN106420604A - 一种番荔素类药物的纳米混悬剂及其制备方法 - Google Patents
一种番荔素类药物的纳米混悬剂及其制备方法 Download PDFInfo
- Publication number
- CN106420604A CN106420604A CN201610367608.7A CN201610367608A CN106420604A CN 106420604 A CN106420604 A CN 106420604A CN 201610367608 A CN201610367608 A CN 201610367608A CN 106420604 A CN106420604 A CN 106420604A
- Authority
- CN
- China
- Prior art keywords
- mpeg
- nano suspension
- medicine
- litchi element
- stabilizer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000006070 nanosuspension Substances 0.000 title claims abstract description 83
- 239000003814 drug Substances 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 241001629511 Litchi Species 0.000 title claims abstract 20
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 24
- 239000003381 stabilizer Substances 0.000 claims abstract description 23
- 238000002347 injection Methods 0.000 claims abstract description 16
- 239000007924 injection Substances 0.000 claims abstract description 16
- 150000002596 lactones Chemical class 0.000 claims abstract description 14
- 239000012530 fluid Substances 0.000 claims abstract description 11
- 239000002245 particle Substances 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 10
- 230000002496 gastric effect Effects 0.000 claims abstract description 9
- 238000000338 in vitro Methods 0.000 claims abstract description 9
- 238000001647 drug administration Methods 0.000 claims abstract description 8
- 210000002381 plasma Anatomy 0.000 claims abstract description 7
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 6
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 6
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 4
- 230000005764 inhibitory process Effects 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 14
- 238000004108 freeze drying Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 239000000178 monomer Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 229920000382 poly(ethylene glycol) methyl ether-block-poly(L-lactide-co-glycolide) Polymers 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 238000002604 ultrasonography Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000002504 physiological saline solution Substances 0.000 claims description 4
- 229960000502 poloxamer Drugs 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- MBABCNBNDNGODA-LTGLSHGVSA-N Bullatacin Natural products O=C1C(C[C@H](O)CCCCCCCCCC[C@@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 MBABCNBNDNGODA-LTGLSHGVSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- -1 HP- β- One of CD Chemical compound 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- MBABCNBNDNGODA-LUVUIASKSA-N bullatacin Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-LUVUIASKSA-N 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 238000010253 intravenous injection Methods 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- MBABCNBNDNGODA-WPZDJQSSSA-N rolliniastatin 1 Natural products O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@H]1[C@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-WPZDJQSSSA-N 0.000 claims description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 2
- 229920002582 Polyethylene Glycol 600 Polymers 0.000 claims description 2
- 229930195340 Squamostatin Natural products 0.000 claims description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 2
- 229930194900 annosquacin Natural products 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 238000000502 dialysis Methods 0.000 claims description 2
- 230000000968 intestinal effect Effects 0.000 claims description 2
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- 239000012296 anti-solvent Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
- 238000009826 distribution Methods 0.000 abstract description 8
- 239000002105 nanoparticle Substances 0.000 abstract description 7
- 238000002474 experimental method Methods 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 230000000857 drug effect Effects 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 229920001427 mPEG Polymers 0.000 abstract 5
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 abstract 1
- 239000008364 bulk solution Substances 0.000 abstract 1
- 230000008021 deposition Effects 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 69
- 244000183278 Nephelium litchi Species 0.000 description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 10
- 235000013339 cereals Nutrition 0.000 description 10
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- 239000012467 final product Substances 0.000 description 8
- 238000011534 incubation Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 206010018910 Haemolysis Diseases 0.000 description 5
- 230000008588 hemolysis Effects 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 4
- 238000012377 drug delivery Methods 0.000 description 4
- 238000003304 gavage Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- PAEZRCINULFAGO-OAQYLSRUSA-N (R)-homocamptothecin Chemical compound CC[C@@]1(O)CC(=O)OCC(C2=O)=C1C=C1N2CC2=CC3=CC=CC=C3N=C21 PAEZRCINULFAGO-OAQYLSRUSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 239000003182 parenteral nutrition solution Substances 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- 244000021317 Annona cherimola Species 0.000 description 1
- 241001081440 Annonaceae Species 0.000 description 1
- 208000031648 Body Weight Changes Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000221079 Euphorbia <genus> Species 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- IYPRWQPJYRBHIS-UHFFFAOYSA-N acetic acid;uranium Chemical compound [U].CC(O)=O IYPRWQPJYRBHIS-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004579 body weight change Effects 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000002318 cardia Anatomy 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 235000012547 cherimoya Nutrition 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000002114 nanocomposite Substances 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
-
- 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)
-
- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medical Informatics (AREA)
- Botany (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Dermatology (AREA)
- Biochemistry (AREA)
- Dispersion Chemistry (AREA)
- Alternative & Traditional Medicine (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域,具体涉及一种用mPEG‑PCL、mPEG‑PLA、mPEG‑PLGA、mPEG‑DSPE、mPEG‑Chol、SPC、Tween80、BSA、TPGS等两亲性稳定剂制备的番荔素类药物的纳米混悬剂,及其制备方法及应用。所述的番荔素总内酯纳米混悬剂采用溶剂沉淀‑超声注入法制备,其处方组成:番荔素类药物与稳定剂的组合比例为1∶0.02~10(重量比)。制备的番荔素纳米混悬剂,载药量最高达90%,粒径最小可达123.2nm,多分散性良好。在胃肠液中及血浆中均稳定,即可口服给药,也可以注射给药;体外具有良好的缓释效果,无突释;该纳米粒相比于原药溶液在体外对肿瘤细胞抑制率显著;体内组织分布表现出对肿瘤的被动靶向,有助于提高药效,降低毒副作用。体内药效实验同时表现出了卓越的抗肿瘤药效,具有广阔的开发前景。
Description
技术领域
本发明涉及药物制剂领域,具体涉及一种用mPEG-PCL、mPEG-PLA、mPEG-PLGA、mPEG-DSPE、mPEG-Chol、SPC、Tween80、BSA、TPGS等两亲性稳定剂制备的番荔素类药物的纳米混悬剂,及其制备方法及应用。
背景技术
番荔素包括番荔素内酯(简称ACGs)及其单体bullatacin、squamostatin、annosquacin等。番荔素是从番荔枝科植物种子中提取的一系列含有35或37个碳的长链脂肪酸,并含有0到3个四氢呋喃(THF)环类似的结构。番荔枝总内酯和单体大多数展示出来很强的抗肿瘤活性,其中活性最好的单体bullatacin对肺癌A549细胞、人肝癌HepG2细胞、人***HeLa细胞、人乳腺癌MCF-7细胞、人结肠癌Lovo细胞、肉瘤S180细胞等具有显著疗效。同时,ACGs对多药耐药的肿瘤细胞株也有较好活性。
ACGs水溶性差,小于1ug/mL,难于给药,导致体内研究大大受限。已有的体内研究多采用悬浮灌胃,或者分散在植物油中口服给药,由于生物利用度低导致其疗效难以最大程度发挥。并且ACGs毒副作用大,治疗窗口窄,对大鼠的肝和肾有一定毒性。
纳米粒是将药物通过不同的方法制备成纳米大小的颗粒,包括胶束、聚合物纳米粒、纳米混悬剂等。由于具有较大的表面积,药物溶出速度和程度均较高,纳米粒已成为解决难溶性药物的给药问题的主要方法之一。同时,药物多包封在纳米粒内部,进入体内之后可以在一定时间内与外界环境隔离,从而在一定程度上保护不稳定的药物,延缓代谢。如果纳米粒的粒径较小(如300nm以内),还可由于EPR(enhanced permeation and retention)效应而被动靶向肿瘤。因此,纳米给药***是解决难溶性药物,尤其是难溶性抗肿瘤药物的临床应用的有效手段。
纳米混悬剂是纳米给药***的重要分支,是用合适的技术将药物直接制备成纳米大小的微粒,并借助于稳定剂对其进行稳定而得到的给药***,是纳米粒的一种。和使用了大量辅料的其他纳米给药***相比,纳米混悬剂具有许多优点:(1)理论上,纳米混悬剂是近乎纯药物的纳米粒,具有最大限度的载药量和药物传输效率,特别适合大剂量难溶性药物的口服和注射给药;(2)适用范围广,无论是难溶于水的药物,还是水、油都难溶的药物,都可利用一定的方法制得相应的纳米混悬剂,且可通过相应技术实现工业化大生产。纳米混悬剂处方组成简单、工艺简单、制备快速,干燥后所得粉末作为中间体进一步制备成口服、注射、外用等不同的剂型,方便携带,提高病人顺应性。
发明内容
本发明的目的之一在于提供一种制备方法简便、载药量高、稳定性高,能实现番荔素内酯或其单体的体内外缓释、改善其体内分布、增强抗癌疗效的纳米混悬剂。
一种番荔素类药物的纳米混悬剂,由番荔素类药物和稳定剂组成,药物与稳定剂的质量比为1∶0.02~10。
一种番荔素类药物的纳米混悬剂,选用的稳定剂为mPEG-PCL、mPEG-PLA、mPEG-PLGA、mPEG-DSPE、mPEG-Chol、SPC、Tween80、BSA、TPGS等两亲性稳定剂中的一种或多种联合运用。
本发明目的之二在于提供一种番荔素类药物的纳米混悬剂的制备方法,本发明采用的是溶剂沉淀-超声或搅拌注入的方法制备纳米混悬剂,技术方案如下:
(1)番荔素类药物和稳定剂溶于能与水混溶的有机溶剂中;
(2)超声或搅拌条件下将含有药物和稳定剂的有机溶剂加入到水中;
(3)减压旋转蒸发或透析法除去有机溶剂;
上述制备方法,其特征在于:步骤(1)所述的稳定剂选自mPEG-PCL、mPEG-PLA、mPEG-PLGA、mPEG-DSPE、mPEG-Chol、SPC、BSA、Tween80、TPGS等两亲性稳定剂中的一种或多种。其中mPEG-PCL、mPEG-PLA、mPEG-PLGA、mPEG-DSPE、mPEG-Chol中PEG嵌段的分子量的范围为500-20000。mPEG-PCL中PCL嵌段的分子量范围为500-20000;mPEG-PLA中PLA嵌段的分子量范围为500-20000;mPEG-PLGA中PLGA嵌段的分子量范围为500-20000。
上述制备方法,其特征在于步骤(1)所述的有机溶剂选自DMSO、DMF、甲醇、乙醇、丙醇、乙腈、异丙醇、PEG400、PEG600中的一种或两种或多种的混合体系;或者以上溶剂与乙酸乙酯、二氯甲烷、三氯甲烷等于水不相混溶的有机溶剂的混合体系,只要混合体系能和水混溶同时能很好滴溶解药物和辅料即可。药物在有机溶剂中的浓度为0.001%~20%(w/v),稳定剂的浓度为0.001%~50%(w/v);步骤(2)中有机溶剂与水相的体积比为1∶2~100(v/v);超声时间为1-60min;搅拌的条件为100~1000rpm,搅拌温度为0℃-60℃,搅拌时间1~60min。
步骤(3)还可以通过冷冻干燥等进一步固化,所用冻干保护剂可以是泊洛沙姆、甘露醇、HP-β-CD、海藻糖、麦芽糖、半乳糖中的一种或两种及两种以上的组合,优选泊洛沙姆或甘露醇为冻干保护剂;冻干保护剂的用量为0.1%-20%(g/100mL),优选的冻干保护剂用量为0.5-5%(g/100mL)。
本发明的目的之三在于提供一种番荔素纳米混悬剂在制备注射剂中的应用,所述的注射剂包括注射液和无菌粉针。本发明的番荔素纳米混悬剂水相分散介质可用高浓度的氯化钠或葡萄糖水溶液调成0.9%氯化钠或者5%葡萄糖生理等渗体系,适应临床应用。本发明的番荔素纳米混悬剂冻干粉可加入适量的无菌药用0.9%氯化钠或者5%葡萄糖水溶液稀释,重建成供静脉给药用的分散体系,适应临床使用。
本发明的纳米混悬剂的优点在于:(1)处方简单,最少可以只含有药物和稳定剂;(2)载药量可高达90%,同时平均粒径可小于200nm,具有非常高的药物传输效率,同时易实现对肿瘤的被动靶向;(3)体外释放没有突释,能缓慢释放;(4)在人工胃肠液和血浆中稳定,既可以口服给药,也可注射、外用或腔道给药;(5)载药量可根据需要再很宽的范围内(9-90%)调整,在低载药量时纳米混悬剂以胶束的形式存在。
本发明的番荔素纳米混悬剂经体外细胞毒实验表明,表现出较番荔素DMSO溶液有更高的肿瘤细胞抑制率。
本发明的番荔素纳米混悬剂经荷瘤小鼠实验证明,能改善药物的体内组织分布,很大程度实现了对肿瘤的被动靶向,有助于提高药效,降低毒副作用。
本发明的番荔素纳米混悬剂经荷瘤小鼠药效实验证明,表现出较市售喜树碱注射液(阳性药)以及传统油溶液灌胃的给药方式好得多的抗肿瘤药效,用于肿瘤治疗是一种很有前途的药物递送***。
本发明的纳米混悬剂工艺简单,辅料经济安全易得,有广阔的产业化前景。
附图说明
图1为实施例1中ACGs纳米混悬剂的平均粒径分布图
图2为实施例1中透射电镜照片(×19000)
图3为实施例1中ACGs纳米混悬剂在人工胃肠液中的稳定性考察(n=3)
图4为实施例1中ACGs纳米混悬剂的溶血考察(n=3)
图5为实施例1中ACGs纳米混悬剂在PBS中的体外释放曲线(n=3)
图6为实施例1中ACGs纳米混悬剂对MCF-7、Hela细胞毒考察(n=6)
图7为实施例1中ACGs纳米混悬剂在4T1荷瘤小鼠中的组织分布(n=5)
图8为实施例1中ACGs纳米混悬剂在离体组织脏器中的组织分布(n=5)
图9为实施例1中4T1荷瘤小鼠体重随时间变化曲线(n=10)
图10为实施例1中4T1荷瘤小鼠肿瘤体积随时间变化曲线(n=10)
具体实施方式
下面将描述本发明的几个实施例,但本发明的内容完全不局限于此。
实施例1
称取番荔素内酯9mg,mPEG2000-PCL2000 3mg溶于0.5mL丙酮中,常温,250HZ超声条件下将上述丙酮溶液缓慢滴注至4mL去离子水中。继续超声15min后,随后旋蒸除去丙酮,即得ACGs纳米混悬剂。平均粒径为123.2nm(图1),多分散性指数(PDI)为0.134,电位值-20.17mV。
实施例2
称取番荔素内酯9mg,mPEG2000-PCL1140 3mg溶于0.5mL丙酮中,常温,250HZ超声条件下将上述丙酮溶液缓慢滴注至4mL去离子水中。继续超声15min后,随后旋蒸除去丙酮,即得ACGs纳米混悬剂。平均粒径为136.4nm,多分散性指数(PDI)为0.06,电位值-19.9mV。
实施例3
称取番荔素内酯9mg,mPEG5000-PCL1000 3mg溶于0.5mL丙酮中,常温,250HZ超声条件下将上述丙酮溶液缓慢滴注至4mL去离子水中。继续超声15min后,随后旋蒸除去丙酮,即得ACGs纳米混悬剂。平均粒径为163.7nm,多分散性指数(PDI)为0.09,电位值-17mV。
实施例4
称取番荔素内酯9mg,mPEG5000-PCL2000 3mg溶于0.5mL丙酮中,常温,250HZ超声条件下将上述丙酮溶液缓慢滴注至4mL去离子水中。继续超声15min后,随后旋蒸除去丙酮,即得ACGs纳米混悬剂。平均粒径为148.3nm,多分散性指数(PDI)为0.101,电位值-20mV。
实施例5
称取番荔素内酯9mg溶于0.5mL丙酮中,常温,250HZ超声条件下将上述丙酮溶液缓慢滴注至含有9mg Tween80的4mL去离子水中。继续超声15min后,随后旋蒸除去丙酮,即得ACGs纳米混悬剂。平均粒径为145.3nm,电位值-17.5mV。
实施例6
称取番荔素内酯9mg,TPGS 9mg溶于0.5mL丙酮中,常温,250HZ超声条件下将上述丙酮溶液缓慢滴注至4mL去离子水中。继续超声15min后,随后旋蒸除去丙酮,即得ACGs纳米混悬剂。平均粒径为165.3nm,电位值-19.3mV。
实施例7
称取番荔素内酯9mg,SPC 9mg溶于0.5mL丙酮中,常温,250HZ超声条件下将上述丙酮溶液缓慢滴注至4mL去离子水中。继续超声15min后,随后旋蒸除去丙酮,即得ACGs纳米混悬剂。平均粒径为168.4nm,电位值-14.0mV。
实施例8
称取番荔素内酯9mg溶于0.5mL丙酮中,常温,250HZ超声条件下将上述丙酮溶液缓慢滴注至含有9mg BSA 3mg4mL去离子水中。继续超声15min后,随后旋蒸除去丙酮,即得ACGs纳米混悬剂。平均粒径为177.8nm,电位值-1.0mV。
实施例9
制备2mg/mL浓度的实例1中ACGs混悬剂,吸取6μL滴到300目的铜网上,空气中自然晾干,后用0.1%醋酸铀染色10min,透射电镜下观察粒子的形态(图2)。
实施例10
实例1中ACGs纳米混悬剂在0.9%NaCl、5%Glu、PBS中的稳定性考察
配置1.8%NaCl、10%Glu的溶液,随后将此溶液和PBS分别与实例一中的ACGs纳米混悬剂(2mg/mL)1∶1等体积混合,37℃孵育并在特定的时间点测其粒径的变化。
结果:ACGs纳米混悬剂在0.9%NaCl、5%Glu、PBS基本稳定,孵育12h之内未发现明显沉淀或粒径增大的现象(下表所示)。
实施例11
ACGs纳米混悬剂在人工胃肠液中的稳定性考察
人工胃液的配置:取浓度为1mol/L的稀盐酸16.4mL,加800mL蒸馏水,10g胃蛋白酶,混匀,加水稀释至1000mL。
人工肠液的配置:6.8g磷酸二氢钾,加水500mL,用0.1mol/L氢氧化钠调pH6.8,另取胰蛋白酶10g,加水溶解,两液混合后加水稀释至1000mL。
取0.5mL过膜后的配置好的人工胃肠液,与实例1中的ACGs纳米混悬剂等体积混合,37℃孵育,并在特定时间点测其粒径的变化。
结果:在人工胃肠液中,ACGs纳米混悬剂在12h之内粒径变化几乎不大(图3),说明ACGs纳米混悬剂在人工胃肠液中基本稳定,能够口服给药。
实施例12
ACGs纳米混悬剂在血浆中的稳定性考察
ACGs纳米混悬剂与大鼠血浆混合后(1∶4,v/v),37℃孵育并在特定的时间点测其粒径的变化。
结果:ACGs纳米混悬剂与血浆孵育后,24h之内并未发现沉淀或者粒径变化(下表所示),说明ACGs纳米混悬剂在血浆中基本稳定。
实施例13
ACGs纳米混悬剂的溶血考察
大鼠眼眶取血后,于5000rpm离心10min,收集沉淀。随后用0.9%的NaCl溶于洗涤几遍,直至上清无明显红色。随后血细胞沉淀用0.9%的NaCl的溶液稀释至4%红细胞悬浮液(v/v)。取此悬浮液0.5mL与0.5mL的已调等渗的纳米混悬剂混合,37℃孵育4h后,5000rpm离心10min,取上清于酶标仪540nm处测吸光值。同时将4%的红细胞悬浮液与0.9%的NaCl混合作为阴性对照,4%的红细胞悬浮液与去离子水混合作为阳性对照。
溶血率(%)=(OD样品-A阴性对照)/(A阳性对照-A阴性对照)×100
结果:ACGs纳米混悬剂的溶血率很降低,1mg/mL的ACGs纳米混悬剂溶血率约10%(图4),体内静脉给药时所需的浓度完全不溶血,满足静脉注射的条件。
实施例14
ACGs纳米混悬剂的体外释放实验
方案:取制备好的实例1中的ACGs纳米混悬剂4mL(1mg/mL,平行三份),于即用型透析袋(MWCO=20000,Spectra/Por,USA)中,分别置于1L释放介质PBS中,37℃下100rpm搅拌,定时从透析袋内吸取50μL释放内液,加950μL甲醇溶解纳米混悬剂和未释放的药物,HPLC测定ACGs的含量,计算累积释放率。
结果:ACGs纳米混悬剂能够缓慢释放96h(图5),整个过程无明显突释。
实施例15
ACGs纳米混悬剂对HepG2、Hela的体外细胞毒考察
方案:用含10%胎牛血清的1640培养液将Hela、MCF-7细胞配成单细胞悬液,以每孔5×103个细胞左右接种到96孔板。5%CO2、37℃细胞培养24h后,吸去培养液,用不含胎牛血清的培养基稀释ACGs纳米混悬剂至不同浓度梯度,加入200uL继续培养(同时以不含胎牛血清的培养基作为空白对照),每个浓度6个复孔。孵育24h后,吸去样品溶液,每孔加MTT溶液(5mg·mL-1,PBS配制)20μL;继续孵育4h后,终止孵育,吸去孔内培养上清液,每孔加200μLDMSO,振荡20min,使结晶物充分溶解。选择570nm波长,在酶联免疫荧光仪检测OD值。
细胞抑制率(%)=(空白对照组OD-实验组OD)/空白对照组OD×100%。
结果:结果显示,和番荔素DMSO溶液相比,纳米混悬剂对Hela、MCF-7均具有更强的抑制作用(图6)。孵育24h后,ACGs溶液和纳米混悬剂的1C50值如下表(n=6,mean±SD,**p<0.01vs.ACGs solution):
实施例16
ACGs纳米混悬剂在4T1荷瘤小鼠的组织分布
实验方案:将筛选出来的肿瘤大小相近的BALB/c-nu小鼠15只,随机分为3组,分别静脉注射给予共包载DiR的番荔素纳米混悬剂(药物与DiR重量比40∶1,药物剂量0.4mg·kg-1)、ACGs/DiR溶液(ACGs和DiR剂量同纳米混悬剂)、DiR对照“溶液”(DiR剂量同纳米混悬剂),在不同时间用小动物活体成像仪(IVIS Spectrum CT)拍照监测纳米混悬剂荧光物质在小鼠不同部位的分布。IVIS Spectra CT荧光探针的参数设置λEexcitation=748nm;λEmission=780nm,Binning factor:8;Exposure time:4s,Field of view:14cm。96h最后一次拍照后处死动物,取出脏器在同样条件下拍照,图片处理和数据分析用IVIS LivingImaging软件完成。
结果:由于纳米的EPR效应,番荔素纳米混悬剂在肿瘤部位有很明显的荧光累积(图7),表明其在肿瘤中分布比较多。体外离体组织成像的结果与体内基本一致(图8),表面番荔素纳米混悬剂能够在一定程度上实现被动靶向。
实施例17
ACGs纳米混悬剂在4T1荷瘤小鼠的抗肿瘤药效研究
给药方案:将筛选出来的荷瘤小鼠随机分为5组,每组10只,除正常饮食外,尾静脉注射ACGs纳米混悬剂(400ug/kg),ACGs溶液组(400ug/kg),灌胃给予ACGs油溶液(4mg/kg),同时设立阳性药对照组(尾静脉注射给予市售HCPT注射液5mg/kg),生理盐水阴性对照组。隔天给药,共实验18天。
考察指标:每日上午9点至10点,用电子秤称量小鼠体重;用游标卡尺测量肿瘤体积。实验结束后,脱颈椎处死小鼠,完整剥离腋下肿瘤组织称重,计算抑瘤率。
抑瘤率(%)=(1-治疗组平均瘤重/生理盐水组平均瘤重)×100%。
结果:ACGs纳米混悬剂给药组的体重变化与生理盐水组类似,有略微增加(图9),说明在给药剂量范围内无明显的严重毒性作用。ACGs纳米混悬剂静脉注射时表现出卓越的抗肿瘤治疗,400ug/kg尾静脉给药的肿瘤抑制率较HCPT市售注射剂5mg/kg(78.46%vs.49.32%,P<0.05)以及传统番荔素油溶液灌胃4mg/kg(78.46%vs.45.53%,P<0.05)有显着性增强。表明ACGs纳米混悬剂是一种很有前途的药物递送***。ACGs纳米混悬剂,ACGs油溶液及阳性药对4T1荷瘤小鼠的抑瘤率如下表(n=10,mean±SD):
Notes:#p<0.05vs blank control,##p<0.01vs blank control,*p<0.05vs HCPTinjections and &p<0.05vs ACGs oil solution.Δbased on four surviving mice,data limited for reference only.
Claims (10)
1.一种番荔素类药物的纳米混悬剂,其特征在于:所述的纳米混悬剂由番荔素内酯或其单体和稳定剂组成,药物与稳定剂的质量比为1∶0.02~10。
2.根据权利要求1所述的番荔素纳米混悬剂,其特征在于:所述的稳定剂为mPEG-PCL、mPEG-PLA、mPEG-PLGA、mPEG-DSPE、mPEG-Chol、SPC、Tween80、BSA、TPGS等两亲性稳定剂;其中mPEG-PCL、mPEG-PLA、mPEG-PLGA、mPEG-DSPE、mPEG-Chol中PEG嵌段的分子量的范围为500-20000,优选分子量1000-3000;mPEG-PCL中PCL嵌段的分子量范围为500-20000,优选分子量1000-3000;mPEG-PLA中PLA嵌段的分子量范围为500-20000,优选分子量1000-3000;mPEG-PLGA中PLGA嵌段的分子量范围为1000-20000,优选分子量1000-3000。
3.根据权利要求1至2所述的番荔素药物的纳米混悬剂,其特征在于:所述的稳定剂可为权利要求2中的一种或两种或多种稳定剂的组合物。
4.根据权利要求1至3所述的番荔素药物的纳米混悬剂,其特征在于:所述的番荔素药物,包括番荔素总内酯(ACGs)或者从中分离出来的单体,例如bullatacin、squamostatin、annosquacin等;或者总内酯与单体、不同单体的组合物。
5.如权利要求1至4所述的番荔素药物的纳米混悬剂,其特征在于,粒径10-1000nm,优选平均粒径在20-200nm,载药量最高可达90%。
6.如权利要求1至5所述的番荔素类药物的纳米混悬剂,其特征在于纳米混悬剂在5%葡萄糖溶液、0.9%生理盐水、PBS、人工胃液、人工肠液及血浆中能保持稳定,既不发生聚沉,粒径也无明显变化,从而既适合口服给药,也适合包括静脉注射在内的注射给药,以及外用和腔道给药。
7.根据权利要求1至6所述的番荔素类药物的纳米混悬剂,其特征在于:采用反溶剂法制备,包括搅拌注入或者超声注入或者二者结合来制备,制备方法包括以下步骤:
(1)番荔素类药物和稳定剂溶于能与水混溶的有机溶剂中;
(2)超声或搅拌条件下将含有药物和稳定剂的有机溶剂加入到水中;
(3)减压旋转蒸发或透析法除去有机溶剂。
8.根据权利要求7所述的番荔素类药物的纳米混悬剂的制备方法,其特征在于:步骤(1)和步骤(2)所述的有机溶剂选自DMSO、DMF、甲醇、乙醇、丙醇、乙腈、异丙醇、PEG400、PEG600中的一种或两种或多种的混合体系;或者以上溶剂与乙酸乙酯、二氯甲烷、三氯甲烷等于水不相混溶的有机溶剂的混合体系,只要混合体系能和水混溶同时能很好滴溶解药物和辅料即可;药物在有机溶剂中的浓度为0.001%~20%(w/v),稳定剂的浓度为0.001%~50%(w/v);步骤(2)中有机溶剂与水相的体积比为1∶2~100(v/v);步骤(2)中的超声条件为250HZ,超声温度为12℃-60℃,超声时间为1-60min;步骤(2)中的搅拌的条件为100~1000rpm,搅拌温度为12℃-60℃,搅拌时间1~60min。
9.根据权利要求10至12所述的番荔素类药物的纳米混悬剂的制备方法,其特征在于:步骤(3)还可以通过冷冻干燥进一步固化,所用冻干保护剂可以是泊洛沙姆、甘露醇、HP-β-CD、海藻糖、麦芽糖、半乳糖中的一种或两种及两种以上的组合,优选泊洛沙姆或甘露醇为冻干保护剂;冻干保护剂的用量为0.1%-20%(g/100mL),优选的冻干保护剂用量为0.5-5%(g/100mL)。
10.如权利要求1至9所述的番荔素类药物的纳米混悬剂,其特征在于体外表现出较番荔素DMSO溶液更高的肿瘤细胞抑制率,给药后能在与传统给药方法(如混悬剂、油溶液等)相近治疗效果(如抑瘤率)情况下降低用药剂量。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610367608.7A CN106420604B (zh) | 2016-05-31 | 2016-05-31 | 一种番荔素类药物的纳米混悬剂及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610367608.7A CN106420604B (zh) | 2016-05-31 | 2016-05-31 | 一种番荔素类药物的纳米混悬剂及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106420604A true CN106420604A (zh) | 2017-02-22 |
CN106420604B CN106420604B (zh) | 2019-11-12 |
Family
ID=58183081
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610367608.7A Expired - Fee Related CN106420604B (zh) | 2016-05-31 | 2016-05-31 | 一种番荔素类药物的纳米混悬剂及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106420604B (zh) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108079307A (zh) * | 2018-02-08 | 2018-05-29 | 中国药科大学 | 一种基于甲氧基聚乙二醇-聚乳酸的三元复合纳米体系及其应用 |
CN109223769A (zh) * | 2018-11-12 | 2019-01-18 | 中国医学科学院药用植物研究所 | 一种对番荔枝内酯类药物具有增效减毒作用的纳米粒及其制备方法和应用 |
CN109528785A (zh) * | 2019-01-31 | 2019-03-29 | 中国医学科学院药用植物研究所 | 一种对耐药肿瘤选择性杀伤或nM水平高效杀伤的药物组合物及其应用 |
CN112400892A (zh) * | 2020-12-30 | 2021-02-26 | 福建省农业科学院植物保护研究所 | 草地贪夜蛾性诱剂的纳米载药***及其应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106389385A (zh) * | 2016-05-19 | 2017-02-15 | 中国医学科学院药用植物研究所 | 一种基于环糊精及卵磷脂为载体的番荔素纳米粒及其制备方法和应用 |
-
2016
- 2016-05-31 CN CN201610367608.7A patent/CN106420604B/zh not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106389385A (zh) * | 2016-05-19 | 2017-02-15 | 中国医学科学院药用植物研究所 | 一种基于环糊精及卵磷脂为载体的番荔素纳米粒及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
JINGYI HONG等: "Annonaceous acetogenins (ACGs) nanosuspensions based on a self-assembly stabilizer and the significantly improved anti-tumor efficacy", 《COLLOIDS AND SURFACES B: BIOINTERFACES》 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108079307A (zh) * | 2018-02-08 | 2018-05-29 | 中国药科大学 | 一种基于甲氧基聚乙二醇-聚乳酸的三元复合纳米体系及其应用 |
CN109223769A (zh) * | 2018-11-12 | 2019-01-18 | 中国医学科学院药用植物研究所 | 一种对番荔枝内酯类药物具有增效减毒作用的纳米粒及其制备方法和应用 |
CN109528785A (zh) * | 2019-01-31 | 2019-03-29 | 中国医学科学院药用植物研究所 | 一种对耐药肿瘤选择性杀伤或nM水平高效杀伤的药物组合物及其应用 |
CN112400892A (zh) * | 2020-12-30 | 2021-02-26 | 福建省农业科学院植物保护研究所 | 草地贪夜蛾性诱剂的纳米载药***及其应用 |
CN112400892B (zh) * | 2020-12-30 | 2021-11-09 | 福建省农业科学院植物保护研究所 | 草地贪夜蛾性诱剂的纳米载药***及其应用 |
Also Published As
Publication number | Publication date |
---|---|
CN106420604B (zh) | 2019-11-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Hou et al. | Phytosomes loaded with mitomycin C–soybean phosphatidylcholine complex developed for drug delivery | |
CN102218027B (zh) | 一种包载难溶性抗肿瘤药物的聚合物胶束冻干制剂 | |
Jing et al. | A novel polyethylene glycol mediated lipid nanoemulsion as drug delivery carrier for paclitaxel | |
Yang et al. | Targeted delivery of ginsenoside compound K using TPGS/PEG-PCL mixed micelles for effective treatment of lung cancer | |
CN105853403B (zh) | 一种紫杉醇棕榈酸酯脂质体及其制备方法 | |
Zhang et al. | Folate-conjugated beta-cyclodextrin-based polymeric micelles with enhanced doxorubicin antitumor efficacy | |
CN103705469B (zh) | 一种和厚朴酚纳米粒及其制备方法 | |
CN106420604B (zh) | 一种番荔素类药物的纳米混悬剂及其制备方法 | |
Zhou et al. | Polymeric micelles loading with ursolic acid enhancing anti-tumor effect on hepatocellular carcinoma | |
Zhang et al. | Sodium cholate-enhanced polymeric micelle system for tumor-targeting delivery of paclitaxel | |
CN104523597B (zh) | 一种鬼臼毒素类药物的靶向给药制剂 | |
CN108186605A (zh) | 一种基于单宁酸的载药纳米颗粒及其制备方法和应用 | |
CN109276544A (zh) | 一种水合淫羊藿素纳米粒及其制备方法和应用 | |
Öztürk et al. | Preparation and in vitro characterization of lamivudine loaded nanoparticles prepared by acid and/or ester terminated PLGA for effective oral anti-retroviral therapy | |
Ma et al. | Multi-functionalized dendrimers for targeted co-delivery of sorafenib and paclitaxel in liver cancers | |
CN107049944B (zh) | 一种可实现索拉非尼和姜黄素同时给药的聚合物胶束及其制备方法 | |
Wang et al. | A tumor-targeted delivery of oral isoliquiritigenin through encapsulated zein phosphatidylcholine hybrid nanoparticles prevents triple-negative breast cancer | |
CN105131277A (zh) | 一种含胆酸的高分子材料及其修饰的脂质体 | |
CN105919935B (zh) | 索拉非尼药物脂质纳米混悬剂及其制备方法 | |
CN104225612A (zh) | 一种基于天然p-糖蛋白抑制剂构建的口服吸收促进剂的制备及其应用 | |
CN106389385A (zh) | 一种基于环糊精及卵磷脂为载体的番荔素纳米粒及其制备方法和应用 | |
Liu et al. | Efficient intracellular delivery makes cancer cells sensitive to nanoemulsive chemodrugs | |
CN105879051A (zh) | 一种自组装的核壳结构纳米药物的制备及应用 | |
CN106860874B (zh) | 羧甲基壳聚糖-大黄酸偶联物及其合成工艺 | |
CN109223769B (zh) | 一种对番荔枝内酯类药物具有增效减毒作用的纳米粒及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into 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: 20191112 |