CN106466296B - A kind of camptothecine it is nanocrystalline and preparation method thereof - Google Patents
A kind of camptothecine it is nanocrystalline and preparation method thereof Download PDFInfo
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- CN106466296B CN106466296B CN201610195547.0A CN201610195547A CN106466296B CN 106466296 B CN106466296 B CN 106466296B CN 201610195547 A CN201610195547 A CN 201610195547A CN 106466296 B CN106466296 B CN 106466296B
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- camptothecine
- nanocrystalline
- added dropwise
- injection
- acid
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- 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 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000007924 injection Substances 0.000 claims abstract description 37
- 238000002347 injection Methods 0.000 claims abstract description 37
- 239000000243 solution Substances 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000004108 freeze drying Methods 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 13
- 239000000843 powder Substances 0.000 claims abstract description 9
- 238000000265 homogenisation Methods 0.000 claims abstract description 8
- 230000007423 decrease Effects 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 230000004087 circulation Effects 0.000 claims abstract description 3
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical group C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- 239000006228 supernatant Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000009938 salting Methods 0.000 claims description 8
- 230000001376 precipitating effect Effects 0.000 claims description 7
- 239000003381 stabilizer Substances 0.000 claims description 7
- 150000002596 lactones Chemical class 0.000 claims description 6
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 claims description 5
- 238000002604 ultrasonography Methods 0.000 claims description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- MYQKIWCVEPUPIL-QFIPXVFZSA-N 7-ethylcamptothecin Chemical compound C1=CC=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 MYQKIWCVEPUPIL-QFIPXVFZSA-N 0.000 claims 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 claims description 3
- 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 claims description 3
- 238000000703 high-speed centrifugation Methods 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 230000020477 pH reduction Effects 0.000 claims description 3
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 claims description 3
- 229950009213 rubitecan Drugs 0.000 claims description 3
- 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
- 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 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
- 229930195725 Mannitol Natural products 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 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
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000001694 spray drying Methods 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 238000007710 freezing Methods 0.000 claims 1
- 230000008014 freezing Effects 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 238000007711 solidification Methods 0.000 claims 1
- 230000008023 solidification Effects 0.000 claims 1
- 238000009826 distribution Methods 0.000 abstract description 10
- 238000005119 centrifugation Methods 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 239000003513 alkali Substances 0.000 abstract description 7
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 210000002381 plasma Anatomy 0.000 abstract description 5
- 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 abstract description 4
- 239000008103 glucose Substances 0.000 abstract description 4
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 abstract 1
- 229940127093 camptothecin Drugs 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 230000007774 longterm Effects 0.000 abstract 1
- 239000002159 nanocrystal Substances 0.000 abstract 1
- 238000005457 optimization Methods 0.000 abstract 1
- 229920001983 poloxamer Polymers 0.000 abstract 1
- 238000004321 preservation Methods 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 description 19
- 210000001519 tissue Anatomy 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 8
- 235000013339 cereals Nutrition 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 239000002105 nanoparticle Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 210000003462 vein Anatomy 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HAWSQZCWOQZXHI-UHFFFAOYSA-N CPT-OH Natural products C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 239000008213 purified water 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
- 238000010171 animal model Methods 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000013049 sediment Substances 0.000 description 3
- 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 2
- 241000233805 Phoenix Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- -1 galactolipin Chemical compound 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011435 rock Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000002485 urinary effect Effects 0.000 description 2
- 238000005303 weighing Methods 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
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000759909 Camptotheca Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 230000007018 DNA scission Effects 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 206010073069 Hepatic cancer Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 208000010932 epithelial neoplasm Diseases 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000003911 head and neck carcinoma Diseases 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000006070 nanosuspension Substances 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000003868 tissue accumulation Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K47/02—Inorganic compounds
-
- 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)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides nanocrystalline compositions of insoluble anti-tumor medicament camptothecin analogues and preparation method thereof.Using the alkali soluble acid of optimization it is heavy-high pressure homogenization: gradient speed acid adding after medicinal powder alkali soluble settles out nanocrystalline；Acid is heavy in two times and removes generated salt by centrifugation step；High pressure homogenization further decreases partial size.Gained camptothecin is nanocrystalline preferably with the average grain diameter of 100-150m; it is evenly distributed; only need to be added minute quantity PLURONICS F87 be freeze drying protectant can freeze-dried powder form long-term preservation, the shaking of 5% glucose solution, which is added, in when use can directly restore the state before freeze-drying.Method is easy, reproducible, is suitble to large-scale production.There is good slow release effect outside gained nanocrystal；More commercially available injection can improve the circulation time in blood plasma, improve drug organize in vivo in distribution, and have stronger antitumous effect, with wide development prospect.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to the camplotheca acuminata of a kind of no stabilizer and preparation process organic solvent-free
The nanocrystalline of bases drug, preparation method and application.
Background technique
Camptothecine includes camptothecine, 10-hydroxycamptothecine, 7- ethyl-camptothecin, 7- ethyl -10- hydroxy-camptothecin
Alkali, 9-nitrocamptothecin etc. are insoluble drug, all have lactonic ring and preferable anti-tumor activity, and wherein 10- hydroxyl is liked
It is the most extensive to set alkali (10-HCPT) clinical application.
Camptothecine is that extract from Chinese camptotheca have the Alkaloid and its derivative of antitumaous effect, is belonged to
In cell cycle specific drugs, DNA synthesis phase (S- phase) is mainly acted on.HCPT is topoisomerase I (Topo I) special
Property inhibitor, by inhibit DNA superhelix relaxation in reconnection step, lead to single-stranded and double-strand DNA cleavage, touch
Send out cell death.Clinic is mainly used for primary carcinoma of liver, gastric cancer, head-neck carcinoma, gland originality epithelioma, leukaemia, bladder cancer etc.
The chemicotherapy of malignant tumour；Toxic reaction is mainly manifested in the inhibition etc. of urinary system, digestive system and hematopoiesis function, but its poison
Property be significantly lower than camptothecine, especially urinary system reaction is few, is clinically easily received.
Currently, using hydroxycamptothecin as the mainly application with injection clinically of the camptothecine of representative, injection
Liquid has in main problem present on clinical application: (1) half-life short (intravenous injection distribution half-life (t1/2a) be 4.5min,
Eliminate half-life period (t1/2 β) be 29min), need repetitively administered or extend the period for the treatment of, cause dose-limiting toxicity-bone marrow suppression and
Gastrointestinal toxicity is consequently increased.(2) gall-bladder is distributed mainly on after intravenously administrable, and cancer often sends out histoorgan such as liver, lung, stomach
The distribution of equal tissues is unsatisfactory.(3) the fat-soluble water solubility of hydroxycamptothecin is all bad, and the anticancer activity of water-soluble sodium salt is made
90% is reduced, toxic side effect increases；Stability is poor, and the lactonic ring of drug is sensitive to light, pH, and anti-tumor biological function is stronger
Closed loop lactones thaumatropy is the weaker open loop carboxylate structure of function, and pharmacological activity is greatly reduced.It hinders due to the above reasons,
Hydroxycamptothecin gives full play to antitumor action, limits its clinical application.
Have the method using solvent evaporation method preparation hydroxycamptothecin Fabaceous Lecithin nanometer lyophilized preparation both at home and abroad at present, it should
Though the hydroxycamptothecin Fabaceous Lecithin nanometer lyophilized preparation of method preparation can overcome the shortcomings of existing injection to a certain extent,
But this method need to use a large amount of low-boiling organic solvent, it is unfavorable to environmental protection, and easily lead to organic solvent in the formulation
Residual, influences the therapeutic effect of drug.
Alkali open ring can be added to be dissolved in water using camptothecine lactonic ring, the property that acid adding cyclization is precipitated can also be prepared
The nanocrystalline composition of camptothecine, but the technique is both needed to that auxiliary material stabilizer is added in preparation and final products, and
Nanometer particle size is also larger, and solubility is bad after freeze-drying, is unfavorable for clinical application.
Summary of the invention
That the purpose of the present invention is to provide a kind of preparation method simplicity is pollution-free, reproducible, is easily industrialized rule
Mould production, improves its distribution in vivo, enhancing anticancer at the inside and outside sustained release for being able to achieve hydroxycamptothecin and other camptothecines
Nanocrystalline composition of curative effect and its preparation method and application.
The present invention provides a kind of nanocrystalline compositions of camptothecine, it is characterised in that: described nanocrystalline group
It closes object to be only made of camptothecine, without any stabilizer.
The camptothecine is camptothecine or the derivative with camptothecin backbone, is selected from 10- hydroxy-camptothecin
Alkali, 7- ethyl-camptothecin, 7-Ethyl-10-hydroxycamptothecin, 9-nitrocamptothecin.
The partial size of the nanocrystalline composition of the camptothecine is 100-500nm, and preferable particle size range is in 100-
150nm。
Wherein, camptothecine exists substantially in the form of lactone type；Drug has slow releasing function, no phenomenon of burst release.
The present invention also provides a kind of method for preparing the nanocrystalline composition of camptothecine, feature exists
In the preparation method comprises the following steps:
(1) camptothecine is dissolved in aqueous slkali, is prepared into camptothecine salting liquid；
(2) under ultrasound condition, acid solution is added dropwise in camptothecine salting liquid, carries out gradient acidification；
(3) high speed centrifugation removes salt produced during the preparation process until supernatant can't detect nanocrystalline presence, collects precipitating
Afterwards plus water is suspended；
(4) high pressure homogenization further decreases partial size when necessary；
Also, do not include the steps that adding stabilizer in the step.
Further, aqueous slkali described in step (1) can be sodium hydroxide, potassium hydroxide inorganic strong alkali solution, can also
To be sodium carbonate, sodium phosphate, potassium carbonate, potassium phosphate inorganic weak bases solution.
The pH of camptothecine salting liquid obtained by step (1) can be between 8-14, and preferred scope is in 9-12.
Step (1) drug in the concentration in aqueous slkali between 5-20mg/mL, preferred scope 10-15mg/mL.
Ultrasonic temperature is room temperature in step (2), and power 150-300W, acid solution can be dilute hydrochloric acid or acetic acid.
Step (2) camptothecine as pH=4 can be fully converted into lactone type, and at this moment the total volume of acid adding is V；It adopts
The method being added dropwise with gradient: being initially added dropwise 50%V with the speed of 2mL/min, and 25%V then is added dropwise with the speed of 1.0mL/min,
Then 15%V is added dropwise in the speed of 0.5mL/min, and 10000rpm is centrifuged 10min, takes out supernatant afterwards, continues with the speed of 0.5mL/min
10%V to pH=4 is added dropwise in degree.
Step (3) high speed centrifugal condition is that 10000-20000rpm is centrifuged 10~20min, and collecting precipitating is by two hypo acids
After precipitating after heavy is collected together plus water redissolves.
The homogeneous condition of step (4) mesohigh is 20~30 DEG C of temperature, pressure 500-4000bar, wherein ideal homogeneous condition
For 25 DEG C, 2000~2500bar, >=8 circulations.
It can also be further solid by freeze-drying, atomizing freeze drying or spray drying after step (3) or step (4)
Change, freeze drying protectant used can be one or more of P188, PVP, lactose, maltose, galactolipin, mannitol
Combination.Wherein, preferably P188 is freeze drying protectant；The dosage of freeze drying protectant is the 5-50% of nanocrystalline weight, preferably nanometer
The 25% of brilliant weight is freeze drying protectant.
The present invention also provides a kind of purposes, the nanocrystalline composition of the camptothecine is in preparing injection
Purposes, it is characterised in that the injection includes injection and aseptic powder injection.
Further, Aqueous dispersions medium can be tuned into the 5% isotonic body of glucose physiology with the glucose solution of high concentration
System adapts to clinical application.
Suitable sterile medicinal 5% glucose solution dilution can be added in hydroxycamptothecin nano crystalline substance freeze-dried powder, be reconstructed into
For the dispersion of intravenously administrable, clinical use is adapted to.
It is nanocrystalline to obtain better drug concentration, longer plasma half-life compared with conventional injection agent after drug administration by injection
With higher lower area of blood concentration-time curve (AUC), and in liver, lung, the higher drug distribution of tumor tissues (AUC).
It is nanocrystalline to obtain the better antitumous effect of more commercially available injection after administration.
Nanocrystalline composition of the invention is proved through tumor-bearing mice effect experiment, and it is good to show more commercially available camptothecine injection
Antitumor drug effect much is a kind of up-and-coming drug delivery system for oncotherapy.
Detailed description of the invention
Fig. 1 is the high-pressure homogeneous front and back of hydroxycamptothecin nano grain and the average grain diameter being added after freeze drying protectant in example 1
Distribution map
Average particle size distribution figure of the Fig. 2 for hydroxycamptothecin nano grain in example 2 after high-pressure homogeneous
Average particle size distribution figure of the Fig. 3 for 7-Ethyl-10-hydroxycamptothecin nanoparticle in example 3 after high-pressure homogeneous
Fig. 4 is that the projection electromicroscopic photograph after freeze drying protectant is added in example 1
Fig. 5 is that X- powder diffraction spectrum in example 1 (is followed successively by hydroxycamptothecin nano crystalline substance, hydroxycamptothecin from top to bottom
The physical mixture of raw medicine and P188, hydroxycamptothecin raw medicine)
Fig. 6 is the In-vitro release curves (n=3) of hydroxycamptothecin in water in example 1
Fig. 7 is the relation curve (a schemes 0-24h, and b schemes 0-4h) (n=8) of serum level and time change in example 1
Fig. 8 is the nanocrystalline distribution (n=8) in tumor-bearing mice tumour in example 1
Specific embodiment
Several embodiments of the present invention are described below, but the contents of the present invention are completely not limited to this.
Example 1
25mg hydroxycamptothecin is weighed to be dissolved in 2mL sodium hydroxide solution (0.1molL-1), ultrasound condition (25 DEG C,
It is slowly added dropwise dilute hydrochloric acid solution (0.1molL-1) under 250W) with injection pump controller, controls speed: initial 2mL/min ×
0.5min, then 1.0mL/min × 0.5min, then 0.5mL/min × 0.6min (pH=5 at this time), centrifugation (centrifugation radius
5cm, 1000rpm are centrifuged 10min)；Supernatant is taken, continues that 0.2mL dilute hydrochloric acid solution is added dropwise with the speed of 0.5mL/min
Then (0.1molL-1) is centrifuged (1000rpm is centrifuged 10min) to pH=4 again.Merge the sediment after being centrifuged twice, adds
Enter the resuspension of 5mL purified water, high pressure homogenization (25 DEG C, 2 × 105KPa) 8 times.The nanocrystalline partial size of gained is 133.5 ± 0.3nm (figure
1), polydispersity index (PDI) is 0.13 ± 0.02.
It saves, is redissolved again after half a year, partial size is in 4 DEG C after the freeze drying protectant P188 freeze-drying for accounting for total weight 25% is added
140.6 ± 6.3nm, polydispersity index (PDI) are 0.20 ± 0.02, and long-time stability are good.
Example 2
It weighs 1000.0mg hydroxycamptothecin to be dissolved in 40.0mL sodium hydroxide solution (0.2molL-1), ultrasound condition
It is slowly added dropwise dilute hydrochloric acid solution (0.2molL-1) under (25 DEG C, 250W) with injection pump controller, controls speed: initial 2mL/
Min × 10min, then 1.0mL/min × 10min, then 0.5mL/min × 10min (pH=5 at this time), centrifugation (centrifugation radius
5cm, 1000rpm are centrifuged 10min)；Supernatant is taken, continues that 5.0mL dilute hydrochloric acid solution is added dropwise with the speed of 0.5mL/min
Then (0.2molL-1) is centrifuged (centrifugation radius 5cm, 1000rpm are centrifuged 10min) to pH=4 again.Merging is centrifuged twice
Sediment afterwards is added 80mL purified water and is resuspended, high pressure homogenization (25 DEG C, 2 × 105KPa) 8 times.It is measured with partial size/potentiometer
Partial size is (141.0 ± 0.4) nm (Fig. 2), and PDI value is 0.14 ± 0.02, and current potential is (- 26.0 ± 1.1) mV.
Example 3
It weighs 25mg 7-Ethyl-10 Hydroxycamptothecine to be dissolved in 2mL sodium hydroxide solution (0.1molL-1), ultrasonic item
It is slowly added dropwise dilute hydrochloric acid solution (0.1molL-1) under part (25 DEG C, 250W) with injection pump controller, controls speed: initially
2mL/min × 0.5min, then 1.0mL/min × 0.5min, then 0.5mL/min × 0.6min (pH=5 at this time), centrifugation
(centrifugation radius 5cm, 1000rpm are centrifuged 10min)；Supernatant is taken, is continued molten with the speed dropwise addition 0.2mL dilute hydrochloric acid of 0.5mL/min
Then liquid (0.1molL-1) is centrifuged (1000rpm is centrifuged 10min) to pH=4 again.Merge the sediment after being centrifuged twice,
5mL purified water is added to be resuspended, high pressure homogenization (25 DEG C, 2 × 105KPa) 8 times.The nanocrystalline partial size of gained is 106.7 ± 0.53nm
(Fig. 3), polydispersity index (PDI) are 0.185 ± 0.012, and current potential is (- 35.1 ± 1.0) mV.
Example 4
The hydroxycamptothecin nano crystalline substance prepared in example 1 is diluted to 100 μ g/mL, draws the copper mesh that 6 μ L drip to 300 mesh
On, naturally dry in air is rear to dye 10min with 0.1% phosphotungstic acid, and the form (Fig. 4) of particle is observed under transmission electron microscope.
Example 5
The X- powder x ray diffraction map of sample freeze-dried powder is shown in Fig. 5 in example 1, sample measurement parameter: the irradiation of Cu target pipe,Step width: 40kV, 100mA 0.01 °, scanning range: 3-70 °, as a result know hydroxycamptothecin in nanocrystalline freeze-dried powder
In still exist with crystalline forms.
Example 6
The extracorporeal releasing experiment of hydroxycamptothecin nano grain
Scheme: experiment carries out extracorporeal releasing experiment to hydroxycamptothecin nano grain using Bag filter method, while with commercially available
Carboxylic acid type alkyl camptothecine injection (Injections) and drug coarse powder compare.Take the above sample 2mL (100 μ g of drug containing)
It in bag filter (molecular cut off 8000-14000), is placed in 100mL dissolution medium, the constant temperature under the conditions of 37 DEG C, 100rpm
Stirring, each time point take 1mL release external solution HPLC to survey medicament contg therein, while supplementing the isometric release of isothermal and being situated between
Matter, calculate Accumulation dissolution, dissolution medium use purified water, 3 parts of same sample parallel laboratory test.
As a result: nanoparticle significantly enhances the slow release effect of drug, can be sustained in water 72h (Fig. 6)
7 hydroxycamptothecin nano grain pharmacokinetic of example
Experimental animal: healthy SD rat 16, male, 200~220g of weight.
Dosage regimen: two groups are randomly divided into.Fasting 12h, free water before being administered.With the dosage difference vein note of 5mg/kg
It penetrates and gives hydroxycamptothecin nano grain and commercially available injection.
Sample acquisition: 15min, 30min after administration, 1h, 2h, 4h, 8h, 12h, blood 0.5mL, 5000rpm are taken after eye socket for 24 hours
Centrifuging and taking supernatant blood plasma；Take the 200 μ L of blood plasma of collection in EP pipe, 20 μ L of acetic acid on the rocks, in dark place conversion 3h (by carboxylic acid type
It is converted to lactone type)；Add ethyl acetate 1mL, vortex oscillation 1min, 10000rpm are centrifuged 10min；Supernatant is taken, is dried with nitrogen；It is surplus
Excess adds 200 μ L ultrasonic dissolution of methanol, crosses 0.22 μm of syringe filter, 20 μ L is taken to detect with HPLC.
As a result: drug-time curve is shown in Fig. 7.Mean blood plasma concentration data are with Phoenix WinNonlin (version 6.1)
Fitting calculates pharmacokinetic parameter, pharmacokinetic parameter such as following table (n=8, mean ± SD；* P < 0.01, * * * P <
The commercially available injection of 0.001vs.):
Embodiment 8
Hydroxycamptothecin nano crystalline substance is distributed in H22 tumor-bearing mice body
The foundation of animal model:
In the non-fluorescence cell of incubator in vitro culture 4T1, the cell of exponential phase of growth is digested with pancreatin, with sterile PBS
Adjusting concentration of cell suspension is that 1 × 107/mL is spare.To injecting 0.2mL under the BALB/C female mice right axillary of 70 6 week old
4T1 cell (1 × 106/mL) PBS suspension, every other day observe tumour growth situation, until volume be greater than 100mm3, screen tumour
72 relatively uniform mouse of size are tested.
Dosage regimen: taking tumor-bearing mice 72, is randomly divided into commercially available injection and 2 groups of nanoparticle, fasting 12h before being administered,
Free water is administered according to 8mg/kg dosage tail vein injection.
Sample acquisition: after administration 0.5,1,4,8,12h, pluck eyeball for 24 hours cervical dislocation after blood taken to put to death mouse；Coring, liver,
Spleen, lung, kidney, brain and tumor tissues, physiological saline clean floating blood, and filter paper blots；Add 3 times of quality physiological saline after each tissue weighing
Tissue homogenate；Centrifugation takes each 200 μ L of tissue homogenate conversion 3h in 20 dark place μ L of acetic acid on the rocks, adds ethyl acetate 1mL, be vortexed vibration
1min is swung, 10000rpm is centrifuged 10min；Supernatant is taken, is dried with nitrogen, residue adds 200 μ L ultrasonic dissolution of methanol, crosses 0.22 μm of needle
Hair style filter takes 20 μ L to detect with HPLC.Each parameter Phoenix WinNonlin (version 6.1) the Fitting Calculation.
As a result: nanocrystalline group extends drug in the residence time of each tissue, such as the average residence time difference in liver, lung
It is 2.01 and 2.44 times of injection group.The extension of this residence time is conducive to drug in tissue accumulation, wherein the heart, liver,
Spleen, lung, the AUC0-24h in nephridial tissue are respectively the 6.71 of injection, 39.53,6.23,13.45,14.08 times.After administration, receive
The drug concentration of rice suspension group tumor tissues is significantly improved compared with injection group, and AUC0-24h is 7.25 times of the latter.In tumour
In distribution map see Fig. 8 (n=6, mean ± SD；The commercially available injection of * * P < 0.001vs.).
The distribution parameter of hydroxycamptothecin nano crystalline substance and commercially available injection in each tissue is as follows:
Ra=AUC (NSps)/AUC (Inj) Rb=MRT (NSps)/MRT (Inj) Rc=Cmax(NSps)/Cmax(Inj)
Example 9
Antitumor drug efficacy study of the hydroxycamptothecin nano crystalline substance in 4T1 tumor-bearing mice
The foundation of animal model: identical in embodiment 8.
Dosage regimen: being randomly divided into 6 groups for the tumor-bearing mice screened, and every group 10, in addition to normal diet, tail vein
Drug administration by injection is administered once for every 2 days, tests 18 days.Blank group gives normal saline solution, injection group according to 5mg/kg agent
Measure the commercially available HCPT injection (normal saline dilution) of tail vein injection, nano suspension group according to 5mg/kg, 2.5mg/kg,
The dosage tail vein injection HCPT of 1.5mg/kg is nanocrystalline.Inspection target: daily 9 points to 10 points of the morning, electronic scale weigh small
Mouse weight.After experiment, cervical dislocation puts to death mouse, completely strips the weighing of oxter tumor tissues, calculates tumour inhibiting rate (%)=(1-
Treatment group's average knurl weight/physiological saline group average knurl weight) × 100%.
As a result: under same dosage, nanoparticle shows brilliant antineoplaston, the more commercially available injection of tumor control rate
Agent (74.84%vs.37.93%) has significant property to enhance, P < 0.01.Show that the 10-HCPT of the method for the present invention preparation is nanocrystalline
It is a kind of up-and-coming drug delivery system for oncotherapy.The tumour inhibiting rate of nanoparticle and injection to 4T1 tumor-bearing mice
Such as following table (n=8, mean ± SD):
Note:###P < 0.001vs. physiological saline group；* p < 0.05, * * p < 0.01, * * * p < 0.001vs.10-HCPT note
Penetrate agent group.
The content of present invention merely illustrates claimed some specific embodiments, one of them or more skill
Documented technical characteristic can be combined with arbitrary one or more technical solutions in art scheme, these are combined and obtain
Technical solution also in the application protection scope, the technical solution just as obtained from these are combined is disclosed in the present invention
It is specifically recorded in content the same.
Claims (10)
1. a kind of nanocrystalline composition of camptothecine, it is characterised in that: the nanocrystalline composition is only by camptothecine
Class drug composition, without any stabilizer；The wherein camptothecine, is camptothecine or the derivative with camptothecin backbone
Object is selected from 10-hydroxycamptothecine, 7- ethyl-camptothecin, 7-Ethyl-10-hydroxycamptothecin, 9-nitrocamptothecin, and substantially
Exist in the form of lactone type；
The preparation method of the nanocrystalline composition of the camptothecine comprises the steps of:
(1) camptothecine is dissolved in aqueous slkali, is prepared into camptothecine salting liquid；It is molten that the aqueous slkali is selected from sodium hydroxide
Liquid, potassium hydroxide solution, sodium carbonate liquor, sodium radio-phosphate,P-32 solution, solution of potassium carbonate, potassium phosphate solution；
(2) under ultrasound condition, acid solution is added dropwise in camptothecine salting liquid, carries out gradient acidification；The acid solution is selected from dilute
Hydrochloric acid or acetic acid；
(3) high speed centrifugation removes salt produced during the preparation process until supernatant can't detect nanocrystalline presence, adds after collecting precipitating
Water is suspended；
(4) optional high pressure homogenization further decreases partial size；Also, do not include the steps that adding stabilizer in the step.
2. the nanocrystalline composition of camptothecine according to claim 1, it is characterised in that partial size 100-
500nm。
3. the nanocrystalline composition of camptothecine according to claim 1 or 2, it is characterised in that drug tool therein
There are slow releasing function, no phenomenon of burst release.
4. a kind of method for preparing the nanocrystalline composition of camptothecine described in claims 1 to 3 any one, feature
It is, the preparation method comprises the steps of:
(1) camptothecine is dissolved in aqueous slkali, is prepared into camptothecine salting liquid；
(2) under ultrasound condition, acid solution is added dropwise in camptothecine salting liquid, carries out gradient acidification；
(3) high speed centrifugation removes salt produced during the preparation process until supernatant can't detect nanocrystalline presence, adds after collecting precipitating
Water is suspended；
(4) optional high pressure homogenization further decreases partial size；Also, do not include the steps that adding stabilizer in the step.
5. according to the method described in claim 4, it is characterized by: drug is in the concentration in aqueous slkali between 5-20mg/mL；
The pH of camptothecine salting liquid is between 8-14.
6. according to the method described in claim 4, it is characterized by: ultrasonic temperature is room temperature, power 150- in step (2)
300W, as pH=4, camptothecine can be fully converted into lactone type, and at this moment the total volume of acid adding is V；It is added dropwise using gradient
Method: 50%V is initially added dropwise with the speed of 2mL/min, 25%V is then added dropwise with the speed of 1.0mL/min, then 0.5mL/
15%V is added dropwise in the speed of min, and 10000rpm is centrifuged 10min, takes out supernatant afterwards, continues to be added dropwise 10% with the speed of 0.5mL/min
V to pH=4.
7. according to the method described in claim 4, it is characterized by: step (3) high speed centrifugal condition is 10000-
20000rpm is centrifuged 10~20min, and collecting precipitating is to add water to redissolve after collecting precipitating of two hypo acids after heavy together, step (4)
The homogeneous condition of mesohigh is 20~30 DEG C of temperature, pressure 500-4000bar, dry by freezing after step (3) or step (4)
Dry, atomizing freeze drying or spray drying further solidification, freeze drying protectant used are selected from P188, PVP, lactose, maltose, half
The combination of one or more of lactose, mannitol.
8. according to the method described in claim 7, it is characterized by: ideal homogeneous condition be 25 DEG C, it is 2000~2500bar, big
In or equal to 8 circulations.
9. according to the method described in claim 7, it is characterized by: P188 is freeze drying protectant；The dosage of freeze drying protectant is
The 5-50% of nanocrystalline weight.
10. according to claim 1 to the nanocrystalline composition of camptothecine described in 9 any one in preparing injection
Purposes, it is characterised in that the injection be injection and aseptic powder injection.
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| CN102091041B (en) * | 2009-12-10 | 2013-08-21 | 中国科学院过程工程研究所 | Novel nanoparticle of camptothecin drug and preparation method thereof |
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| CN102091041B (en) * | 2009-12-10 | 2013-08-21 | 中国科学院过程工程研究所 | Novel nanoparticle of camptothecin drug and preparation method thereof |
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| "Preparation and cytotoxic activity of hydroxycamptothecin nanosuspensions";Yong-Xing Zhao et al.;《International Journal of Pharmaceutics》;20100317(第392期);第64-71页 * |
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