CN1079391A - The preparation method that is used for the arsenic preparation of directly administering to cancer nidus - Google Patents
The preparation method that is used for the arsenic preparation of directly administering to cancer nidus Download PDFInfo
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- CN1079391A CN1079391A CN 92104358 CN92104358A CN1079391A CN 1079391 A CN1079391 A CN 1079391A CN 92104358 CN92104358 CN 92104358 CN 92104358 A CN92104358 A CN 92104358A CN 1079391 A CN1079391 A CN 1079391A
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- Prior art keywords
- preparation
- liposome
- arsenic
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- ratio
- Prior art date
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- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229910052785 arsenic Inorganic materials 0.000 title claims abstract description 13
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 10
- 201000011510 cancer Diseases 0.000 title claims abstract description 9
- 239000002502 liposome Substances 0.000 claims abstract description 24
- 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 description 22
- 239000003814 drug Substances 0.000 claims description 18
- IKWTVSLWAPBBKU-UHFFFAOYSA-N a1010_sial Chemical compound O=[As]O[As]=O IKWTVSLWAPBBKU-UHFFFAOYSA-N 0.000 claims description 13
- 229960002594 arsenic trioxide Drugs 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000003921 oil Substances 0.000 claims description 12
- 235000019198 oils Nutrition 0.000 claims description 12
- 235000012000 cholesterol Nutrition 0.000 claims description 11
- 210000000481 breast Anatomy 0.000 claims description 10
- 239000000839 emulsion Substances 0.000 claims description 9
- 239000012071 phase Substances 0.000 claims description 9
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 238000001694 spray drying Methods 0.000 claims description 8
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000000758 substrate Substances 0.000 claims description 7
- 239000000375 suspending agent Substances 0.000 claims description 7
- 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 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- -1 benzyl benzyl Chemical group 0.000 claims description 6
- 239000000872 buffer Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 239000000787 lecithin Substances 0.000 claims description 6
- 235000010445 lecithin Nutrition 0.000 claims description 6
- 229940067606 lecithin Drugs 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 229920000609 methyl cellulose Polymers 0.000 claims description 6
- 239000001923 methylcellulose Substances 0.000 claims description 6
- 235000010981 methylcellulose Nutrition 0.000 claims description 6
- 150000003904 phospholipids Chemical class 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 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
- 229920002472 Starch Polymers 0.000 claims description 4
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 claims description 4
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 4
- 229940093471 ethyl oleate Drugs 0.000 claims description 4
- 239000004531 microgranule Substances 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 239000010409 thin film Substances 0.000 claims description 4
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 4
- 239000008158 vegetable oil Substances 0.000 claims description 4
- 239000011787 zinc oxide Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 230000001804 emulsifying effect Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- 238000005507 spraying Methods 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- QYIXCDOBOSTCEI-QCYZZNICSA-N (5alpha)-cholestan-3beta-ol Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 QYIXCDOBOSTCEI-QCYZZNICSA-N 0.000 claims description 2
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 claims description 2
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 2
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical class 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 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- UIMGHSAOLFTOBF-DPAQBDIFSA-N 3beta-Hydroxycholest-4-ene Chemical compound C1CC2=C[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 UIMGHSAOLFTOBF-DPAQBDIFSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 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
- 239000002671 adjuvant Substances 0.000 claims description 2
- QYIXCDOBOSTCEI-UHFFFAOYSA-N alpha-cholestanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 QYIXCDOBOSTCEI-UHFFFAOYSA-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
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 229940099578 hydrogenated soybean lecithin Drugs 0.000 claims description 2
- 239000008384 inner phase 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
- 229920001296 polysiloxane Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229940084106 spermaceti Drugs 0.000 claims description 2
- 239000012177 spermaceti Substances 0.000 claims description 2
- 150000007970 thio esters Chemical class 0.000 claims description 2
- 235000004835 α-tocopherol Nutrition 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims 4
- 150000002632 lipids Chemical class 0.000 claims 3
- 239000000463 material Substances 0.000 claims 2
- 239000004094 surface-active agent Substances 0.000 claims 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 229940087168 alpha tocopherol Drugs 0.000 claims 1
- 239000008346 aqueous phase Substances 0.000 claims 1
- 210000002468 fat body Anatomy 0.000 claims 1
- 235000013336 milk Nutrition 0.000 claims 1
- 239000008267 milk Substances 0.000 claims 1
- 210000004080 milk Anatomy 0.000 claims 1
- 239000006072 paste Substances 0.000 claims 1
- 150000008105 phosphatidylcholines Chemical class 0.000 claims 1
- 229910000160 potassium phosphate Inorganic materials 0.000 claims 1
- 235000011009 potassium phosphates Nutrition 0.000 claims 1
- 238000001556 precipitation Methods 0.000 claims 1
- 239000007921 spray Substances 0.000 claims 1
- 229960000984 tocofersolan Drugs 0.000 claims 1
- 239000002076 α-tocopherol Substances 0.000 claims 1
- 201000009030 Carcinoma Diseases 0.000 abstract description 7
- 238000005516 engineering process Methods 0.000 abstract description 7
- 239000002552 dosage form Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000012545 processing Methods 0.000 abstract description 5
- 238000001914 filtration Methods 0.000 abstract description 3
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 230000001590 oxidative effect Effects 0.000 abstract 1
- 238000003860 storage Methods 0.000 abstract 1
- 229940079593 drug Drugs 0.000 description 8
- 239000012467 final product Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 3
- 229910052957 realgar Inorganic materials 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 150000002333 glycines Chemical class 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 230000035807 sensation Effects 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 201000008261 skin carcinoma Diseases 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- XIIAYQZJNBULGD-UHFFFAOYSA-N (5alpha)-cholestane Natural products C1CC2CCCCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XIIAYQZJNBULGD-UHFFFAOYSA-N 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 101100004286 Caenorhabditis elegans best-5 gene Proteins 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010018367 Glomerulonephritis chronic Diseases 0.000 description 1
- 241001057584 Myrrha Species 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000003555 analeptic effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 238000001354 calcination Methods 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- XIIAYQZJNBULGD-LDHZKLTISA-N cholestane Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 XIIAYQZJNBULGD-LDHZKLTISA-N 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 229910052956 cinnabar Inorganic materials 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 210000004905 finger nail Anatomy 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229940097322 potassium arsenite Drugs 0.000 description 1
- HEQWEGCSZXMIJQ-UHFFFAOYSA-M potassium;oxoarsinite Chemical compound [K+].[O-][As]=O HEQWEGCSZXMIJQ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 150000003772 α-tocopherols Chemical class 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The present invention is the preparation method of the arsenic preparation of directly administering to cancer nidus, belongs to anti-cancer drug preparation technology, and applicating modern times technology is made into particular dosage form.Purpose is above-mentioned arsenic preparation is introduced in the body the therapeutic effect of body surface, tract carcinoma, has also provided the preparation method of the arsenic preparation that can be used for body surface, the treatment of tract carcinoma simultaneously.And the preparation method of the liposome that the present invention is given owing to all taked the particular processing mode at liposome internal layer, middle level, skin, makes it not be only applicable to industrialized great production, and has solved the wet product guarantor storage phase weak point of liposome, easily unloads leakage; Need difficult problems such as press filtration, homogenize processing when easily rotten the and dry product liposome of oxidative rancidity redissolves behind the easy adhesion of dry product, moisture absorption, the deliquescence.
Description
The invention belongs to anti-cancer drug preparation technology.
The cmm of simple prescription of arsenic, the direct focus administration of compound preparation now have been widely used in body surface, tract etc. without the just directly treatment of the carcinoma of administration of special instrument.And obtained the curative effect that attracts people's attention.Folk prescription arsenicum sablimatum paste (two liang of arsenicum sablimatum two money, wheat flours) treatment skin carcinoma is recorded in Liaoning " Chinese herbal medicine new therapy that combines both Chinese and Western medical practices compilation of data ", can make tumor connect root and come off; County hospital Lee of Mengcunhui, Hebei autonomous region is long to cure 10 examples doubly with " five cigarette pellets " (cholelithiasis, Magnetitum, cinnabar, Alumen, Realgar wherein generate arsenic trioxide after the Realgar calcination) treatment skin carcinoma 16 examples, and 6 examples take a turn for the better effective percentage 100%.Chinese medicine " three products " such as the department of obstetrics and gynecology institute cervical cancer Yang Xue of research department of Jiangxi Province health care of women institute will, cake, bar (arsenicum sablimatum, Alumen, Realgar, Myrrha) treatment 190 routine cervical cancer patients, and whole patients have been carried out strict regular follow-up checked, late result: remove 1 example and after 3 years, die from chronic nephritis with uremia, 1 example was died from outside the cerebral hemorrhage in 4 1/2 years, all the other 188 examples all healthy (～nineteen eighty-two in 1972 different year repeatedly follow up a case by regular visits to) there is no recurrence, cure rate 100% and 1977 version " Henan Province's drug standard " include " canceroderm is clean " (arsenicum sablimatum, fingernail, hair, Fructus Jujubae, alkali fermentation～this side also can be considered the arsenicum sablimatum folk prescription, and other composition all can be considered slow releasing agent).Aforesaid single, compound arsenic preparation has reached justifiable degree on the curative effect of treatment body surface, tract cancer.But its range of application is narrower, still can not touch carcinoma in the body, simultaneously when body surface and tract medication, it also shows slightly weak on dosage form, the dosage form that has is unsuitable for industrialized great production, and the dosage form that has is very inconvenient on using, the difficult quality control between criticizing when the dosage form that has is produced and criticizing.
Task of the present invention be do not repel the middle prescription of arsenic, compound recipe is under the prerequisite of raw material, also can select purity higher arsenious oxide, salt and Organic substance separately for use is that raw material is made specific means such as dosage form, the therapeutic effect of above-mentioned arsenic preparation to body surface and tract carcinoma is incorporated in the body, also provided the preparation method of the preparation that is applicable to industrialized great production that is used for body surface and the treatment of tract carcinoma simultaneously.
Arsenic preparation of the present invention, be raw material mainly with arsenious oxide (being equivalent to the folk prescription arsenicum sablimatum), salt, organic compound and herbal mixture thereof, cooperate the ointment (I) that is used for body surface and tract carcinoma, the paste (II) that processes with specific support and be used for the suspension type injection (III) of cancer entity direct injection in the body, liposome (IV) etc.
Wherein the preparation method of (I), (II) is: after medicine (can select for use arsenious oxide, salt, Organic substance, herbal mixture among at least a) and substrate (can select for use in oils, lipoidis, hydro carbons, starch based, zinc oxide, the silicone at least a) are given processing respectively, various substrate are pressed fusing point order from high to low, successively add fusion, standby behind the mix homogeneously, with medicine and after the substrate of molten state is mixed on a small quantity, doubly measure dilution with other substrate again, be mixed, do not get final product to there being granular sensation.
Wherein the preparation method of (III) is: (can select medicine (can select for use arsenious oxide, salt, Organic substance, herbal mixture among at least a) solvent for use vegetable oil, benzyl benzyl formate, ethyl oleate etc.) after suspending agent (can select single, double, Aluminium Tristearate Micronized sterile for use) gives processing respectively, suspending agent is dissolved in forms oleogel in the solvent, with the medicine abundant mixing of factice therewith, the reuse colloid mill is levigate to qualified getting final product then.
Wherein the preparation method of (IV) is: (can select medicine for use arsenious oxide, salt, organic compound, at least a in the herbal mixture), the PH buffer agent of interior water (can be selected sodium carbonate for use, potassium bicarbonate, sodium hydroxide, dibastic sodium phosphate, sodium phosphate), oil phase (can be selected axunge for use, vegetable oil, the benzyl benzyl formate, ethyl oleate, at least a in the chloroform), suspending agent (can be selected list for use, two, Aluminium Tristearate Micronized sterile etc.), matrix material (can be selected phosphatidylcholine for use, phosphatidyl glycerol, the lecithin phatidylcholine, the hydrogenated soybean lecithin phatidylcholine, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dimyristoyl phosphatidyl choline, two spermaceti phospholipid, the fabaceous lecithin phatidylcholine, thioester, cholesterol, coprostenol, cholestane, Dihydrocholesterol, at least two kinds of alpha-tocopherols etc.), spray drying anticoagulant, entity injection slow releasing agent (can be selected sodium alginate for use, methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone etc.) above-mentioned raw materials, adjuvant is standby after giving processing.Medicine is dissolved in the internal layer water buffer, and transfers PH8～10 standby, suspending agent and 1/3 phospholipid, the cholesterol of measuring are dissolved in the oil phase respectively.Then above-mentioned pastille buffer is added in the oil phase under condition of stirring and carry out emulsifying, form w/o type Emulsion, again this W/O breast is removed most of organic solvent with the way of a gentleness, form a spissated W/O Emulsion, with this concentrate form the compound breast of W/O/W, homogenize in breast adds the phospholipid that contains total amount 2/3 and cholesterol under the state that stirs the aqueous solution after, this breast is carried out spray drying simultaneously with high viscosity copolymer solution, get final product the liposome microgranule of surperficial formation one layer of polymeric thin film.
The invention has the advantages that compare with traditional form of administration have wide range of applications, dosage is accurate, polarization good, more is applicable to industrialized great production; Compare with the whole body administration that overall dosage is little, focus entity drug level height, curative effect height, instant effect, side effect be little, and the method for preparing lipidosome that the present invention is given, be not only applicable to industrialized great production, and solved that the wet product preservation term of liposome lack, is easily unloaded with Louing, the easy adhesion of dry product, moisture absorption, the deliquescence rear oxidation becomes sour rotten and add during use the water redissolution need the press filtration homogenize etc. operation problem.
Prescription of the present invention, process example are:
Example 1-2
Component: (I) (II)
" three products " 100g 250g
White vaseline 800g 420g
Lanoline 50g 50g
Lecithin 30g 30g
Zinc oxide 20g 100g
Starch 150g
Technology: 200 mesh sieves are concocted, pulverized to " three products ", standby with zinc oxide and starch mix homogeneously, with vaseline, lanoline, lecithin according to fusing point order from high to low, successively add after the melting mixing standby, after grinding the said medicine mixture and the substrate of a small amount of molten state all, doubly to measure diluted mixture even with other residue substrate again, do not get final product to there being granular sensation.
Example 3 prescriptions:
Component: (III)
" three products " 50g
Aluminum monostearate 20g
Neuter flower oil generation adds to 1000ml
Technology is concocted " three products ", comminution by gas stream, to standby below the 5 μ m, learns from else's experience by filtration, the neuter flower oil generation of sterilization is made into 8% factice with the aluminum monostearate that steeps with oil immersion, and heats to 120 ℃, be incubated 1 hour, redilution becomes 2% oleogel, and mix homogeneously is standby.With drug powder therewith oleogel fully mix, the reuse colloid mill is levigate to qualified getting final product.
Example 4(IV) prescription: arsenic trioxide (arsenicum) 10g inner phase with distilled water 40g, potassium bicarbonate 7g, neutral Oleum Glycines 20g, aluminum monostearate 0.4g, chloroform 80g, internal layer with hydrogenated soya phosphatide/cholesterol 8g(1: 0.8 mole ratio), the foreign minister is with distilled water 400g, outer with hydrogenated soya phosphatide/cholesterol 16g(1: 0.6 mole ratio) spraying anti-freezing liquid water 500g, methylcellulose 5g.(IV) technology: arsenic trioxide is dissolved in the 40ml water that contains the potassium bicarbonate buffer, and it is standby to transfer PH to 8 to constitute water.Be dissolved in the chloroform phospholipid/cholesterol of 8g standby.Neutral Oleum Glycines and aluminum monostearate such as example 3 methods are made 2% oleogel, and be diluted in the above-mentioned chloroformic solution and constitute oil phase.Water is added in the oil phase, uses the homogenizer homogenize, get w/o type Emulsion, this Emulsion is evaporated 55～70% chloroforms under 40 ℃ of decompression situations, must concentrate w/o type Emulsion, this be concentrated breast under agitation adds in the aqueous solution that contains 16g phospholipid/cholesterol, emulsifying, form W/O/W type multiple emulsion.This moment with the compound breast of this W/O/W with contain the solution mix homogeneously of methylcellulose, spray drying immediately, get final product the liposome microgranule of surperficial formation one deck methylcellulose thin film.Packing promptly
Annotate: 1, add the oleogel of trace between the liposome bilayer, can effectively prevent unloading leakage of internal layer water soluble drug.
2, arsenic trioxide cancer entity injection.Owing to all added thickening agent, slow releasing agent in (III), (IV), can stop medicine from the cancer entity, to unload leakage, unload on a small quantity leakage, health is also had no adverse effects even have, because Fowler solution (potassium arsenite liquid) is low dose of as analeptic, also is the Oral preparation of using always.※
3, the redissolution method that has the liposome microgranule of methylcellulose thin film: quantitative distilled water is heated to 50 ℃ annotates in the peace bottle that liposome is housed, constantly jolting treats that temperature reduces to room temperature (best 5 ℃) particle suspension and be uniformly dispersed and get final product.
The ※ Chinese Medicine science and technology P30 of publishing house's in August, 1989 " medicines structure and preparation "
Claims (8)
1, the preparation method that is used for the arsenic preparation of directly administering to cancer nidus, it is characterized in that selecting arsenious oxide, salt for use, have the phase chemical compound and at least a in the prescription, compound recipe be raw material, combine with specific adjuvant, be processed into and contain arsenious ointment, paste, suspension type injection, liposome etc.
2, ointment as claimed in claim 1, paste, it is characterized in that substrate can select in oils, lipoidis, hydro carbons, silicone, zinc oxide, the starch based at least two kinds for use, wherein a kind of phospholipid of selecting for use, to increase the affinity of medicine and focus, arsenic content should be controlled between 0.1%～10% in arsenic trioxide.
3, suspension type injection as claimed in claim 1, it is characterized in that solvent can select for use in vegetable oil, benzyl benzyl formate, the ethyl oleate at least a, suspending agent is selected for use in list, two, the Aluminium Tristearate Micronized sterile at least a, the amount ratio of suspending agent and solvent is 0.5: 100～5: 100, arsenic content calculates with arsenic trioxide, should be controlled between 0.01%～5%.
4, liposome as claimed in claim 1, it is characterized in that its preparation method is analogous to the preparation of W/O/W type multiple emulsion, be about to contain surfactant oily mixed with water be emulsified into w/o type Emulsion after, again this breast is added on the aqueous phase mixing and emulsifying that contains surfactant and forms the compound breast of W/O/W.Difference is in the preparation process of liposome, W/O Emulsion need evaporate makes the W/O/W breast after most of oil phase becomes ropy milk again, and, promptly get the liposome microgranule that dry surface forms the one layer of polymeric thin film with this W/O/W breast and high-viscosity polymer liquid simultaneous spray drying.
5, fat body inner phase aqueous solution as claimed in claim 4, it is characterized in that for prevent that medicine from forming water-fast arsenic trioxide precipitation and spilling from lipid layer, water is transferred PH8～10 with alkaline buffer, the applicable sodium carbonate of buffer agent, sodium hydroxide, potassium bicarbonate, dibastic sodium phosphate, potassium phosphate etc.
6, the preparation method of liposome as claimed in claim 4, it is characterized in that liposome bilayer material can select phosphatidylcholine for use, phosphatidyl glycerol, the lecithin phatidylcholine, the fabaceous lecithin phatidylcholine, the hydrogenated soybean lecithin phatidylcholine, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dimyristoyl phosphatidyl choline, two spermaceti phosphatidylcholines, thioester, cholesterol, coprostenol, Dihydrocholesterol, alpha-tocopherol, hemisuccinic acid cholesterol etc. are as for two kinds, its total consumption is equivalent to 0.5～15% of spray drying prelipid substance liquid, in, outer lipid ratio is about 1: 2, wherein the ratio of phospholipid and cholesterol should be between 1: 0.2～1: 1, and the ratio of cholesterol should be bigger than skin in the internal layer lipid layer.
7, the preparation method of liposome as claimed in claim 4, it is characterized in that having formed at last between the liposome bilayer oleogel phase, it can select axunge or vegetable oil, benzyl benzyl formate for use, the oleogel that one of ethyl oleate and suspensoid list, two, Aluminium Tristearate Micronized sterile form, the ratio of the amount of axunge or oleogel and liposome bilayer material should be between 0～500%.The ratio of suspending agent and oil phase should be between 0.5～5% in the oleogel.
8, the preparation method of liposome as claimed in claim 4, it is characterized in that to select sodium alginate, methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone etc. for use with the high-viscosity polymer of liposome simultaneous spray drying, its consumption should be according to the different type of polymer and the back liposome required slow release degree and deciding in the cancer entity of redissolving, and its spray drying process can be selected for use and will carry out spray drying behind this high-viscosity polymer liquid and the liposome mix homogeneously.Also can select with two kinds of liquid by different spray guns the spraying simultaneously or the method for spraying at interval for use.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN92104358A CN1060935C (en) | 1992-05-31 | 1992-05-31 | Preparation method of arsenical capable of applying to cancer focus |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN92104358A CN1060935C (en) | 1992-05-31 | 1992-05-31 | Preparation method of arsenical capable of applying to cancer focus |
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| Publication Number | Publication Date |
|---|---|
| CN1079391A true CN1079391A (en) | 1993-12-15 |
| CN1060935C CN1060935C (en) | 2001-01-24 |
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| CN92104358A Expired - Fee Related CN1060935C (en) | 1992-05-31 | 1992-05-31 | Preparation method of arsenical capable of applying to cancer focus |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0955052A1 (en) * | 1998-05-08 | 1999-11-10 | Ill-Ju Bae | Arsenic hexaoxide (As4O6) for use in cancer therapy and its pharmaceutical composition |
| CN1057914C (en) * | 1994-08-17 | 2000-11-01 | 方敏轩 | Cancer treating pill and its preparing process |
| US6723351B2 (en) | 1997-11-10 | 2004-04-20 | Memorial Sloan-Kettering Cancer Center | Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol |
| US6733792B1 (en) | 1998-04-24 | 2004-05-11 | Daopei Lu | Arsenic sulfide compounds and derivatives thereof for the treatment of malignancies |
| US6875451B2 (en) | 1997-10-15 | 2005-04-05 | Polarx Biopharmaceuticals Inc. | Compositions and methods for the treatment of primary and metastatic neoplastic diseases using arsenic compounds |
| CN101347459B (en) * | 2008-09-10 | 2013-01-02 | 刘皇琼 | Medicine for treating cancer |
| CN107206022A (en) * | 2015-01-29 | 2017-09-26 | 益友制药私人有限公司 | Composition containing arsenic and its purposes in treatment method |
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1992
- 1992-05-31 CN CN92104358A patent/CN1060935C/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1057914C (en) * | 1994-08-17 | 2000-11-01 | 方敏轩 | Cancer treating pill and its preparing process |
| US6875451B2 (en) | 1997-10-15 | 2005-04-05 | Polarx Biopharmaceuticals Inc. | Compositions and methods for the treatment of primary and metastatic neoplastic diseases using arsenic compounds |
| US7205001B2 (en) | 1997-10-15 | 2007-04-17 | Polarx Biopharmaceuticals, Inc. | Compositions and methods for the treatment of primary and metastatic neoplastic diseases using arsenic compounds |
| US7179493B2 (en) | 1997-10-15 | 2007-02-20 | Polarx Biopharmaceuticals, Inc. | Compositions and methods for the treatment of primary and metastatic neoplastic diseases using arsenic compounds |
| US7163703B2 (en) | 1997-10-15 | 2007-01-16 | Polarx Biopharmaceuticals, Inc. | Compositions and methods for the treatment of primary and metastatic neoplastic diseases using arsenic compounds |
| US7132116B2 (en) | 1997-10-15 | 2006-11-07 | Polarx Biopharmaceuticals Inc. | Compositions and methods for the treatment of primary and metastatic neoplastic diseases using arsenic compounds |
| US6770304B2 (en) | 1997-11-10 | 2004-08-03 | Memorial Sloan-Kettering Cancer Center | Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol |
| US6861076B2 (en) | 1997-11-10 | 2005-03-01 | Memorial Sloan-Kettering Cancer Center | Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol |
| US6884439B2 (en) | 1997-11-10 | 2005-04-26 | Memorial Sloan-Kettering Cancer Center | Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol |
| US6982096B2 (en) | 1997-11-10 | 2006-01-03 | Memorial Sloan-Kettering Cancer Center | Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol |
| US6855339B2 (en) | 1997-11-10 | 2005-02-15 | Memorial Sloan-Kettering Cancer Center | Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol |
| US6723351B2 (en) | 1997-11-10 | 2004-04-20 | Memorial Sloan-Kettering Cancer Center | Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol |
| US7879364B2 (en) | 1997-11-10 | 2011-02-01 | Memorial Sloan-Kettering Cancer Center | Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol |
| US8273379B2 (en) | 1997-11-10 | 2012-09-25 | Memorial Sloan-Kettering Cancer Center | Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol |
| US7138147B2 (en) | 1998-04-24 | 2006-11-21 | Daopei Lu | Arsenic sulfide compounds and derivatives thereof for the treatment of malignancies |
| US6733792B1 (en) | 1998-04-24 | 2004-05-11 | Daopei Lu | Arsenic sulfide compounds and derivatives thereof for the treatment of malignancies |
| EP0955052A1 (en) * | 1998-05-08 | 1999-11-10 | Ill-Ju Bae | Arsenic hexaoxide (As4O6) for use in cancer therapy and its pharmaceutical composition |
| CN101347459B (en) * | 2008-09-10 | 2013-01-02 | 刘皇琼 | Medicine for treating cancer |
| CN107206022A (en) * | 2015-01-29 | 2017-09-26 | 益友制药私人有限公司 | Composition containing arsenic and its purposes in treatment method |
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| CN1060935C (en) | 2001-01-24 |
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