CN1147206A - 含有药用粘土的x-射线造影组合物 - Google Patents
含有药用粘土的x-射线造影组合物 Download PDFInfo
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- CN1147206A CN1147206A CN95192622A CN95192622A CN1147206A CN 1147206 A CN1147206 A CN 1147206A CN 95192622 A CN95192622 A CN 95192622A CN 95192622 A CN95192622 A CN 95192622A CN 1147206 A CN1147206 A CN 1147206A
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- Prior art keywords
- alkyl
- halogen
- substituted
- ray contrast
- cycloalkyl
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- 239000000203 mixture Substances 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 22
- 210000001035 gastrointestinal tract Anatomy 0.000 claims abstract description 17
- 239000004927 clay Substances 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 82
- -1 hydroxy, carboxy Chemical group 0.000 claims description 77
- 239000002872 contrast media Substances 0.000 claims description 67
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 125000003545 alkoxy group Chemical group 0.000 claims description 28
- 125000003118 aryl group Chemical group 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
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- 239000002253 acid Substances 0.000 claims description 18
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 12
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 11
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 11
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 11
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
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- 125000003342 alkenyl group Chemical group 0.000 claims description 9
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- 238000009472 formulation Methods 0.000 claims description 7
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- YVPYQUNUQOZFHG-UHFFFAOYSA-N amidotrizoic acid Chemical compound CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I YVPYQUNUQOZFHG-UHFFFAOYSA-N 0.000 claims description 6
- 229960005223 diatrizoic acid Drugs 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 5
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- 125000002091 cationic group Chemical group 0.000 claims description 5
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000000129 anionic group Chemical group 0.000 claims description 4
- 229920001400 block copolymer Polymers 0.000 claims description 4
- OBISGMNJKBVZBT-UHFFFAOYSA-N ethyl 3,5-diacetamido-2,4,6-triiodobenzoate Chemical compound CCOC(=O)C1=C(I)C(NC(C)=O)=C(I)C(NC(C)=O)=C1I OBISGMNJKBVZBT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 claims description 3
- VNSBYDPZHCQWNB-UHFFFAOYSA-N calcium;aluminum;dioxido(oxo)silane;sodium;hydrate Chemical compound O.[Na].[Al].[Ca+2].[O-][Si]([O-])=O VNSBYDPZHCQWNB-UHFFFAOYSA-N 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
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- 239000003093 cationic surfactant Substances 0.000 claims description 3
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 claims description 3
- 229910052901 montmorillonite Inorganic materials 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 3
- BZHSRUIDLJDTTJ-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl) 3,5-diacetamido-2,4,6-triiodobenzoate Chemical compound CCOC(=O)COC(=O)C1=C(I)C(NC(C)=O)=C(I)C(NC(C)=O)=C1I BZHSRUIDLJDTTJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- INPWHIBRMNBPDX-UHFFFAOYSA-N 2,3,5,6-tetraiodoterephthalic acid Chemical compound OC(=O)C1=C(I)C(I)=C(C(O)=O)C(I)=C1I INPWHIBRMNBPDX-UHFFFAOYSA-N 0.000 claims description 2
- CJNZAXGUTKBIHP-UHFFFAOYSA-N 2-iodobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-N 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000440 bentonite Substances 0.000 claims description 2
- 229910000278 bentonite Inorganic materials 0.000 claims description 2
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- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 claims description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 229940070765 laurate Drugs 0.000 claims description 2
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 229940049964 oleate Drugs 0.000 claims description 2
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000002888 zwitterionic surfactant Substances 0.000 claims description 2
- QMKYBPDZANOJGF-UHFFFAOYSA-N benzene-1,3,5-tricarboxylic acid Chemical compound OC(=O)C1=CC(C(O)=O)=CC(C(O)=O)=C1 QMKYBPDZANOJGF-UHFFFAOYSA-N 0.000 claims 2
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 claims 1
- 229960005280 isotretinoin Drugs 0.000 claims 1
- 229910000275 saponite Inorganic materials 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 14
- 239000003937 drug carrier Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 24
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 16
- 229920001213 Polysorbate 20 Polymers 0.000 description 15
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 15
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 15
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 13
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 13
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 10
- 239000000839 emulsion Substances 0.000 description 9
- 239000005711 Benzoic acid Substances 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 8
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical group [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 8
- 235000010233 benzoic acid Nutrition 0.000 description 8
- 229960004365 benzoic acid Drugs 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 229910052740 iodine Inorganic materials 0.000 description 8
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- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 7
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- 229940008099 dimethicone Drugs 0.000 description 7
- 239000004205 dimethyl polysiloxane Substances 0.000 description 7
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 7
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 6
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- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 5
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
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- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 2
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- LFYOKUYEEGKREO-UHFFFAOYSA-N 1,3,5-triiodo-2-oct-3-ynoxybenzene Chemical compound CCCCC#CCCOC1=C(I)C=C(I)C=C1I LFYOKUYEEGKREO-UHFFFAOYSA-N 0.000 description 2
- LWFOHWGWHJHQEZ-UHFFFAOYSA-N 1-cyclopentyloxy-2-iodobenzene Chemical compound IC1=CC=CC=C1OC1CCCC1 LWFOHWGWHJHQEZ-UHFFFAOYSA-N 0.000 description 2
- VHEGXFQQYZIMMF-UHFFFAOYSA-N 1-iodo-4-(4-iodophenoxy)benzene Chemical compound C1=CC(I)=CC=C1OC1=CC=C(I)C=C1 VHEGXFQQYZIMMF-UHFFFAOYSA-N 0.000 description 2
- FGZPFFOXFLTSSK-UHFFFAOYSA-N 1-iodo-4-pentadecan-2-yloxybenzene Chemical compound CCCCCCCCCCCCCC(C)OC1=CC=C(I)C=C1 FGZPFFOXFLTSSK-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 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
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 2
- YJPJRPDPNWHSRC-UHFFFAOYSA-N 4-iodo-n-octan-2-ylaniline Chemical compound CCCCCCC(C)NC1=CC=C(I)C=C1 YJPJRPDPNWHSRC-UHFFFAOYSA-N 0.000 description 2
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- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
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- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
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- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 2
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- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
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- 229910052749 magnesium Inorganic materials 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
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Abstract
本发明涉及的是用于口服或肠胃道退行性检查的X-射线造影组合物，该组合物包括一种X-射线造影剂，在一种药用载体中与一种药用粘土配合；也涉及该组合物在肠胃道的放射性诊断中的使用方法。
Description
本发明涉及一种用于哺乳动物口服或退行性给药的是X-射线造影组合物，该组合物含有一种X-射线造影剂和一种药用粘土。
对于骨折和与骨胳系统有关的其它病症所用的X-射线和计算机体层照相(以下称做CT)扫描的X-射线照相检查，常规上是在不使用造影剂的条件下实施的。但是含有软组织的器官，如肠胃(下面称做GI)道的X-射线显影则需要使用造影剂来减弱X-射线辐射作用。在医学上使用造影剂成像方面，D.P Swanson等人在“Pharmaceuticals In Medical Imaging”，1990，Macmillan Publishing Company中提供了很好的背景技术。
GI道的X-射线照相能够指出消化系统紊乱、肠内性能变化、腹痛、GI出血等的病情。放射检查之前，必须服用一种不透X-射线的造影介质使相应的体腔或软组织周围的粘膜表面适当显示出来。因此，用口服造影剂对口腔、咽喉、食道、胃、十二指肠和近侧小肠进行显影检查。该造影介质从直肠投药，用于检查远侧的小肠和结肠。
对GI道的显影最广泛使用的造影剂是硫酸钡，一种口服悬浮液，或者一种向直肠灌药的灌肠液。(例如，可参见美国专利：US 2,659,690；2680,089；3,216,900；3,235,462；4,038,379和4,120,946)。尽管它有相当好的造影特性，但是由于口服或直肠灌药后GI系统吸收极微并迅速地排出体外，所以硫酸钡有一定的缺点。在肠内流质存在下，它不能均匀分布并对粘膜的粘附性差，结果X-射线的成象性不好。灌肠时，在结肠内造影剂进行结絮形成不规则块状排泄物。
碘化的有机化合物已被用作GI造影剂，因为碘原子是有效的X-射线吸收剂。它们最具有通用性，广泛用在多种造影方法中。它们对X-射线有很大的吸收能力，使X-射线与碘相互作用产生一种光电效应，从而使停留在含碘介质中的光子产生的造影有很大的放大作用。该造影的放大作用超过了由密度相对变化所预期的水平。由于这一放大作用，致使可以使用相当低浓度的造影剂。(对于碘化的造影剂，可以参见例如美国专利：US 2,786,055；3,795,698；3,360,436；3,574,718；3,733,397；4,735,795和5,047,228)。
对于理想的GI造影剂来说渴望得到的要求包括：良好的毒理学剖析；具有充满整个肠/腔的能力和均匀涂覆肠粘膜的能力，从而在不扩张肠腔情况下也能容易检测该肠的情况；可口性和不刺激肠粘膜；以及在通过GI道时不产生伪像或不刺激肠激烈地蠕动。
这些要求已被许多研究者提出，并经过他们多年的努力已有了很大的改进。造影剂均匀涂覆肠粘膜而有效地覆盖肠壁的要求，已证明这是相当困难的，不满足这些要求就不可能得到精确的X-射线照片。为此，曾提出使用某些聚合物添加剂，如下文所述。
美国专利US 4069306披露一种据说可粘附到体腔壁的X-射线造影制剂。该制剂包括一种细分散的水不溶的无机X-射线造影剂和一种不溶于水的但可被水溶胀的亲水性聚合物微细颗粒。用悬浮在水中的该制剂供于体腔。该X-射线造影剂是以与所说的聚合物细颗粒的混合物形式存在，或者是包覆在和/或粘附到该聚合物细颗粒上。
US 4,120,946披露一种用于使消化道的钡发生浑浊作用的药用组合物，它含有胶体硫酸钡和在含水载体中的聚丙烯酰胺。该聚丙烯酰胺形成一种低浓度的粘稠溶液，它可以维持硫酸钡的悬浮液状态并且同时使该制剂能很好粘附到需要照X光的器官壁上。
US 5,019,370公开一种可生物降解的X-光照相造影剂，它含有可生物降解的聚合物珠粒，该粒子带有一种对X-光不透光的元素，例如碘、溴、钐和铒。该造影介质以干态或液形式使用，并且可以静脉注射方式，口服方式和动脉内注射方式投药。
虽然这些聚合物材料大大提高了这里所用的造影剂对器官壁的附着性，使之有较好的显影，但还需要用一种改进的X-射线成像介质来均匀地涂覆那些受X-射线诊断检查的软组织。
现在我们发现，用某些天然粘土与产生X-射线的试剂复合能提高其在肠胃道上涂层均匀性和X-射线成像的质量。另外，这些粘土能掩蔽X-射线造影剂的令人讨厌的气味和味道，同时还能提高其物理稳定性。
本发明的目的是提供用于涂覆哺乳动物胃肠道的组合物，它能形成一种有效的不透X-射线的涂层，由此可实现GI系统的诊断上有价值的检查方法。为此，在用X-射线照射装置显影之前，通过食入一种含药用粘土和X-射线造影射的组合物而在GI系统的内表面形成一薄涂层。该组合物必须满足以下几项要求：X-射线造影剂和粘土两者都必须是无毒的；必须不含有对病人会产生有害的影响的可沥滤的或可消化的组分；和没有被肠内表面或通过肠内表面吸收的涂层组分。
本发明的目的是用这样的一种组合物来达到的，该组合物含有在含水药用载体中的X-射线造影剂和药用粘土。
本发明还提供一种用于GI道的X-射线诊断成象的方法，该方法包括：按口服或直肠投药方式给病人使用一种能产生有效造影量的上述X-射线造影组合物。
将上述的造影剂和药用粘土混入液体介质，用于哺乳动物需要X光透射的GI道。
本发明用的造影剂选自：
(1)通式(1)的化合物：
其中，
R是含有2～8碳原子的取代或未取代的烷基，其中所说的取代基选自C1-C6的烷基、羟基、和烷氧基；和
n是1～5
(2)下列通式表示的化合物或其药用可接受的盐：式中，Z是H、卤素、C1-C20的烷基、环烷基、低级烷氧基、烷氧羰基、氰基，这里的烷基和环烷基能够用卤素或卤代的低级烷基所取代；R是C1-C25的烷基、环烷基、或卤代低级烷基；它们中的每一种可以用卤、氟代低级烷基、芳基、低级烷氧基、羟基、羧基、低级烷氧羰基或低级烷氧羰氧基取代或不取代；或(CR1R2)p-(CR3＝CR4)mQ或(CR1R2)p-C≡C-Q；
R1、R2、R3和R4独立地代表H或低级烷基，可以用卤素取代或不取代；
x是1-4；
n是1-4；
m是1～15；
p是1～20；和
Q是H、低级烷基、低级链烯基，低级炔基、低级亚烷基、芳基或芳基低级烷基；
(3)下列通式所示的化合物或其药用可接受的盐：
其中
Z是H、卤素、C1-C20的烷基、环烷基、低级烷氧基、氰基，这里的烷基和环烷基能够被卤素或卤代的低级烷基所取代；
R1和R2独立地表示H、C1-C25的烷基、环烷基、乙酰基或卤代的低级烷基，其中所说的C1-C25的烷基，环烷基和卤代的低级烷基可以被氟代低级烷基、芳基、低级烷氧基、羟基、羧基、低级烷氧羰基或低级烷氧基羰氧基所取代或不取代，以及所说的乙酰基可以被氟代低级烷基、芳基、低级烷氧基、羟基、低级烷氧羰基或低级烷氧羰氧基所取代或不取代；
n是1-4
y是1-4；和
x是1或2
(4)下列通式表示的化合物：
式中，
Z是H、卤素、C1-C20的烷基、环烷基、低级烷氧基、氰基，这里的烷基和环烷基能够被卤素或卤代的低级烷基所取代；
R是C1-C25的烷基、环烷基、或卤代低级烷基，它们中的每一种可以被卤、氟代低级烷基、芳基、低级烷氧基、羟基、羧基、低级烷基羰基或低级烷氧羰氧基所取代或不取代；或(CR1R2)p-(CR3＝CR4)mQ或(CR1R2)p-C≡C-Q；
R1、R2、R3和R4独立地代表低级烷基、并可以用卤素取代或不取代；
x是1-3；
y是1-4；
n是1-5；
m是1-15；
p是1-10；和
Q是H、低级烷基、低级链烯基，低级炔基、低级亚烷基、芳基、或芳基低级烷基；
(5)下列通式所示的化合物或其药用可接受的盐：
其中，
Z是H、卤素、C1-C20的烷基、环烷基、低级烷氧基、氰基，其中的烷基和环烷基能够用卤素或卤代低级烷基所取代；
R是甲基、乙基、丙基、C9-C25的烷基、环烷基、或卤代低级烷基，可以用卤、氟代低级烷基、芳基、低级烷氧基、羟基、羧基、低级烷氧羰基或低烷氧羰氧基所取代或不取代；或(CR1R2)p-(CR3＝CR4)mQ、或(CR1R2)p-C≡C-Q；
R1、R2、R3和R4独立地代表低级烷基、并可以用卤素取代；
x是1～4；
n是1～5；
m是1～15；
p是1～10；和
Q是H、低级烷基、低级链烯基，低级炔基、低级亚烷基、芳基、或芳基低级烷基；
(6)下列通式表示的化合物：
其中，x是
或-SO2-；
Z是H、卤素、甲基、乙基、正-丙基、C4-C20的烷基、环烷基、低级烷氧基、氰基，这里的烷基和环烷基能够用卤素或卤代低级烷基所取代；
R是C1-C25的烷基、环烷基或芳基，它们中的每一种可以用卤素、氟代低级烷基低级烷氧基、羟基、羧基或低级烷氧基羰基、低级链烯基、低级炔基、低级亚烷基或低级烷氧羰氧基所取代或不取代；
n是1～5；
y是0～4；和
w是1～4；
(7)在表面上吸有表面改性剂的粒状结晶X-射线造影剂。
这里所使用的术语卤素(或卤代)指的是氟、氯、溴或碘。
这里所使用的术语环烷基指的是具有3-8个环碳原子的碳环的环，它们包括环丙基、环丁基、环戊基、环己基和环辛基，这些环烷基的任何一个环碳原子都可以被1个或多个低级烷基、低级烷氧基或卤素所取代。
这里所使用的术语低级烷基和低级烷氧基指的是具有1～10个碳原子的一价脂族基，包括支链基。因此，这些基团的低级烷基部分包括，例如，甲基、乙基、丙基、异丙基、正-丁基、仲-丁基、叔-丁基、正-戊基、2-甲基-3-丁基、1-甲基丁基、2-甲基丁基、新戊基、正-己基、1-甲基戊基、3-甲基戊基、1-乙基丁基、2-乙基丁基、2-己基、3-己基、1，1，3，3-四甲基戊基、1，1-二甲基辛基等。
这里所用术语低级链烯基和低级炔基指的是具3～10个碳原子的一价不饱和基(包括支链基)，因此包括1-乙烯基、1-(2-丙烯基)、1-(2-丁烯基)、1-(1-甲基-2-丙烯基)、1-(4-甲基-2-戊烯基)、4，4，6-三甲基-2-庚烯基、1-乙炔基、1-(2-丙炔基)、1-(2-丁炔基)、1-(1-甲基-2-丙炔基)、1-(4-甲基-2-戊炔基)等。
这里所用的术语亚烷基指的是具有2～10个碳原子的二价饱和基(包括支链基)，并且在不同的碳原子上含有它们的游离价，因此包括1，2-亚乙基、1，3-亚丙基、1，4-亚丁基、1-甲基-1、2-亚乙基、1，8-亚辛基等。
这里使用的术语芳基指的是具有6～10个碳原子的芳族烃基。优选的芳基是苯基、被1～3个取代基取代的取代苯基和萘基，这些取代基可以相同或不同，它们是低级烷基、卤素、羟基低级烷基、烷氧基低级烷基和羟基。
X-射线造影化合物可以在每个分子中含有1、2、3或更多的碘原子，优选的类型是每分子中含有至少两个碘原子，较优选的类型是每分子中至少含有3个碘原子。
实施本发明有用的粒状固体X-射线造影剂可以通过现有技术中的已知技术制备。采用常规的研磨方法，例如空气喷射或破碎研磨，将该固体造影剂研磨成所需要的粒度大小。我们已经发现，有效的平均粒度低于大约100μ的颗粒在GI道内可产生良好的分布和均匀的涂覆。其中所说的颗粒大小指的是用常规方法，例如沉积场流动分级法和盘式离心分离法测量的数均粒度。有效的平均粒度低于大约100μ指的是至少大约90％的颗粒重均粒度低于大约100μ(当使用公认的技术测量时)。
用固体X-射线造影剂的组合物可以是分散液或悬浮液，或者用油状X-射线造影剂的组合物，则可为乳液；我们优选用乳液作为优选的实施方案。
掺入本发明组合物中的天然粘土选自蒙脱土、贝得土、囊脱土、水辉土或滑石粉。
按照本发明对于医疗方法中使用的GI道的诊断成象方法，包括通过口服或直肠给药方式将可产生有效造影量的本发明的组合物投药给需要X-射线检查的哺乳类患者。投药以后，将含有所投组合物的至少一部分的GI道用X-射线照射，产生与该造影剂存在部位相应的X-射线成象图，然后用本领域的现有技术将该X-射线的图象显影和整理解释该检查结果。
上面定义的类型(1)的化合物在EP-A-568155中描述。其中有例如2，4，6-三碘代苯氧基-2-辛烷、2，4，6-三碘代苯氧基-2-丁烷、2，4，6-三碘代苯氧基-2-己烷和4-碘代苯氧基-2-辛烷。
优选的类型(1)的造影剂具有下列通式：
式中R为含有4～8个碳原子的仲烷基。
最优选的类型(1)的造影剂具有下列通式的2，4，6-三碘代酚的仲-辛基醚：
上面定义的类型(2)的化合物在EP-A-614670中描述，例如其中描述的有聚乙二醇-400的双-(4-碘代苯基)醚、1，8-双-O-(2，4，6-三碘代苯基)-三丙二醇、1，11-双-(2，4，6-三碘代苯氧基)-3，6，9-三噁十一碳烷、1，2-双-(2，4，6-三碘代苯氧基)-乙烷、聚乙二醇400的双-O-(2，4，6-三碘代苯基)醚、1-(3-碘代苯氧基)-3，6，9-三噁癸烷、1，3-双-(2，4，6-三碘代苯氧基)-丁烷、1-(3-碘代苯氧基)-6-(2，4，6-三碘代苯氧基-己烷和1，12-双-(2，4，6-三碘代苯氧基)-十二碳烷。
上面定义的类型(3)化合物在EP-A-613689中描述。例如其中介绍了N-乙酰基-N-2-辛基-4-碘代苯胺和N-(4′-碘代苯基)-2-氨基辛烷。
上面定义的类型(4)的化合物在EP-A-614669中描述。例如，其中介绍的有2-辛基-2，3，5-三碘代苯甲酸酯、3，3，4，4，5，5，6，6，7，7，8，8-十二氟-2-辛基-2，3，5-三碘代苯甲酸酯、双(2-己基)-2，3，5，6-四碘代-对苯二酸酯、3-(2-辛氧基)-2，4，6-三碘代苯甲酸乙酯和双(2-辛基)-2，4，6-三碘代间苯二酸酯。
上面定义的类型(5)的化合物在EP-A-605987中有述，其中所说的例如有2-(4-碘代苯氧基)-癸烷、2-(2，4，6-三碘代苯氧基)-十五碳烷、2-(2，4，6-三碘代苯氧基)-癸烷、(2，4，6-三碘代苯氧基)-1H，1H，2H，2H-全氟辛烷、1-(2，4，6-三碘代-3-三氟代苯氧基)辛烷、2-(2，4，6-三碘代苯氧基)壬烷、2-乙基-1-(2，4，6-三碘代苯氧基)-己烷、3，3-二苯基-1-(2，4，6-三碘代苯氧基)丙烷、3-(2，4，6-三碘代苯氧基)-壬烷、2-(4-碘代苯氧基)-十一碳烷、2-碘代苯氧基环戊烷、3-碘代苯氧基环戊烷、(3，5-二甲基-2，4，6-三碘代苯氧基)环戊烷、2-(4-碘代苯氧基)-十五碳烷、4-碘代苯氧基环戊烷、2，4，6-三碘代苯氧基环戊烷、2，4，6-三碘代苯氧基甲基环戊烷、2-(2，4，6-三碘代苯氧基)乙基环戊烷、(E，E)-1-(2，4，6-三碘代苯氧基)-3，7，11-三甲基-2，6，10-十二碳三烯、1-(2，4，6-三碘代苯氧基)-3，7-二甲基-6-辛烯、(E)-1-(3，5-二甲基-2，4，6-三碘代苯氧基)-3，7-二甲基-2，6-辛二烯、(E)-1-(2，4，6-三碘代苯氧基)-3，7-二甲基-2，6-辛二烯、1-(2，4，6-三碘代苯氧基)-3-辛炔、2-(2，4，6-三碘代苯氧基)-4-辛炔、1-(2，4，6-三碘代苯氧基)-3-辛炔、2-(2，4，6-三碘代苯氧基)-1，3-丙二酸二乙酯、2-(2，4，6-三碘代苯氧基)-1，3-丙二酸二异丙酯、2，2-双-(3-碘代苯氧基)乙酸乙酯、5-(2，4，6-三碘代苯氧基)己酸乙酯、5-(2，4，6-三碘代苯氧基)-己-1-醇、10-(4-碘代苯氧基)-十一碳-1-醇、5-(2，4，6-三碘代苯氧基)己基碳酸乙酯和10-(3-碘代苯氧基)-十一碳酸乙酯。
上面定义的类型(6)的化合物在EP-A-617970中描述。例如其中有2-乙基-己酸2，4，6-三碘代苯基酯、2-甲基戊酸2，4，6-三碘代苯基酯、3-环戊基丙酸2，4，6-三碘代苯基酯、(2-丙基)戊酸2，4，6-三碘代苯基酯、全氟庚酸2，4，6-三碘代苯基酯、2，4，6-三碘代苯基-三-(2-乙基)-己酸酯、十二烷酸2，4，6-三碘代苯基酯、2-乙基己酸3-三氟甲基-2，4，6-三碘代苯基酯、2，4，6-三碘代苯基-双-(2-甲基戊酸酯)、己烷磺酸2，4，6-三碘代苯基酯、庚烷磺酸2，4，6-三碘代苯基酯和癸烷磺酸2，4，6-三碘代苯基酯。
上面定义的用于类型(7)组合物中的化合物是非放射性的和作为有机物质不连续的结晶相存在的。该结晶相不同于无定型或非结晶相，它是由例如US 4826689中所述的溶剂沉淀技术得到的。该有机物质能够以一种或多种合适的结晶相存在。可以用多种多样结晶的非放射性的X-射线造影剂来实施本发明。然而，该X-射线造影剂在至少一种液态介质中必须是劣溶的和分散的。“劣溶”指的是该造影剂在液态分散介质(例如水)中的溶解度大约低于10mg/ml，优选低于大约1mg/ml。优选的液体分散介质是水。另外，本发明也可用其它液体介质，该介质对选用的X-射线造影剂劣溶和分散性差，例如盐水溶液如磷酸盐缓冲水溶液(PBS)、原浆、含水或不含水的混合液如水和乙醇、以及适当的非水性溶剂如乙醇、甘油等。
X-射线造影剂可以是碘化的化合物。该碘的化合物可以是芳香族的或非芳香族的。但是优选芳香族的。该碘化化合物每一个分子中可以含有一个、两个、三个或多个碘原子。优选的类型是每分子中含有至少两个，更优选至少三个碳原子。所选用的碘化化合物可以含有不使该化合物增加溶解性的取代基，例如，烷基脲基、烷氧基酰胺基、羟基乙酰胺基、丁内酰胺基、琥珀酰亚胺基、三氟乙酰胺基、羧基、羰酰胺基(carboxamido)、羟基、烷氧基、酰氨基、如其它类似的取代基。
优选的一类造影剂包括，碘化芳香酸的各种酯类和酰胺类。该酯类优选烷基或取代烷基酯类。该酰胺类可以是伯或仲酰胺类，优选烷基或取代烷基酰胺类。例如，该造影剂可以是取代的三碘化苯甲酸(如酰基、氨基甲酰基和/或酰基甲基取代的三碘代苯甲酸)的酯或酰胺。可列举有代表性的碘化芳香酸的实例包括(但不限于)，泛影酸(diatrizoic acid)、甲基泛影酸(metrizoicacid)、异泛影酸(iothalamic acid)、苯均三酸(trimelsic acid)、醋碘苯甲酸(urokonicacid)、碘克酸[ioxaglic acid(碘克酸钠葡胺)]、甲醇异泛影酸(ioxitalamic acid)、四碘代对苯二甲酸、胆影酸(iodipamide)、碘卡酸(icarmic acid)、等等。
许多上述的碘化分子，如果以单体形式，也可以制成以二聚物(有时叫做双化合物)、三聚物(有时叫做三化合物)等形成存在，这些均可采用本技术领域的已知技术进行制备。可以预期本发明能够用劣溶的碘化化合物以单体形式、二聚体、三聚体形式和聚合物的形式来实现。
优选的造影剂类型具有下面的结构通式：泛影酸酯
异泛影酸酯[胆影酸]
在上述结构式中R可以是OR1、NR2R3、亚烷基、-CO·OR1或-O -亚烷基-CO·OR1，其中R1是烷基、R2和R3独立地代表H或烷基。
每个烷基分别可以含有1～20，优选1～8，和较优选1～4个碳原子。
该亚烷基优选含有1～4个碳原子，例如亚甲基、亚乙基、亚丙基等等。
特别优选的造影剂包括，泛影酸的乙基酯，即，3，5-二乙酰基胺-2，4，6-三碘代苯甲酸乙酯，也称做3，5-双(乙酰基氨基)-2，4，6-三碘代苯甲酸乙酸或泛影酸乙酯，它的结构式是上述的A其中R＝-OCH2CH3；泛影酸的乙基甘醇酸酯，即(3，5-双(乙酰基氨基)-2，4，6-三碘代苯甲酰氧基)乙酸乙酯、也叫做泛影酰氧基乙酸乙酯；以及2-(3，5-双(乙酰基氨基)-2，4，6-三碘代苯甲酰氧基)丁酸乙酯，也叫做2-泛影酰氧基丁酸乙酯。
另外，可以与PCT/EP90/00053中所述的水不溶的碘化碳酸酯一起实施本发明。
上述X-射线造影剂是已知的化合物和/或能用本技术领域已知的技术制备的化合物。例如，酸(如上述碘化芳香酸)的水不溶的酯和封端酰胺类能够通过本技术领域中已知的常规烷基化或酰胺化技术进行制备。可以用作原料的上述酸和其它酸是商业上可买到的和/或可从用本领域中的已知技术制备的。
用于上面定义的类型(7)造影剂的微粒包括表面改性剂。这里用的表面改性剂是物理粘附在X-射线造影剂的表面上而不是与该造影剂或它自身进行化学反应。该表面改性剂的各个被吸附分子基本上没有分子间的交联。适合的表面改性剂可以选自一些已知的有机和无机的药用赋形剂，例如各种聚合物、低分子量齐聚物、天然产物和表面活性剂。优选的表面改性剂包括非离子型和阴离子型的表面活性剂。表面改性剂的代表性实例包括明胶、酪蛋白、卵磷脂(磷脂)、阿拉伯胶、胆固醇、西黄蓍胶、硬脂酸、氯苄烷铵、硬脂酸钙、单硬脂酸甘油酯、十八醇十六醇混合物、聚西托醇乳化蜡、脱水山梨糖醇脂、聚氧乙烯烷基醚，例如，聚乙二醇醚如聚西托醇1000、聚氧乙烯蓖麻油衍生物、聚氧乙烯脱水山梨糖醇脂肪酸酯，例如，市场上可购到的各种吐温(Tweens)、聚乙二醇、聚氧乙烯硬脂酸酯、胶态二氧化硅、磷酸盐、十二烷基硫酸钠、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、非结晶纤维素、硅酸镁铝、三乙醇胺、聚乙烯醇、和聚乙烯基吡咯烷酮(PVP)。这些表面改性剂中的大多数是已知的药用赋形剂，并且在由美国医药协会和Great Britain的药学会联合发表的医药赋形剂手册上药品压片(1986)中已进行过详细地描述。
特别优选的表面改性剂包括聚乙烯基吡咯烷酮、泰洛沙泊、泊洛沙姆如普卢兰尼克F68和F108(Pluronic F68和F108)。(它是环氧乙烷和环氧丙烷的嵌段共聚物)、以及聚羟胺(Poloxamines)如特窗(Tetronic)908(。也称做聚羟胺908)(它是由环氧丙烷和环氧乙烷对乙二胺的顺序加成获得的四官能嵌段共聚物，得自BASF)、葡萄糖、卵磷脂、硫代琥珀酸钠的二烷基酯(例如气溶胶(Aerosol)OT，它是硫代珠珀酸钠的二辛酯，购自American Cyanamid，Duponolp，它是十二烷基硫酸钠，购自杜邦(Dupont))、特里顿X-200<非离子型表面活性，商品名>(Triton X-200)(它是烷基芳基聚醚磺酸酯，购自Rohm和Haas)、Tween80(它是聚氧乙烯脱水山梨糖醇脂肪酸酯，购自ICI SpecialtyChemicals)、以及Carbowax 3350和934(它们是聚乙二醇，购自UnionCarbide)。已发现特别有用的表面改性剂包括；Tetronic 908、Tween类、Pluronic F-68和聚乙烯基吡咯烷酮。
其它有用的表面改性剂包括：
癸酰基-N-甲基葡萄糖酰胺；
正-癸基β-D-吡喃葡萄糖苷；
正-癸基β-D-吡喃麦芽糖苷；
正-十二烷基β-D-吡喃葡萄糖苷；
正-十二烷基β-D-麦芽糖苷；
庚酰基-N-甲基葡萄糖酰胺；
正-庚基β-D-吡喃葡萄糖苷；
正-庚基β-D-硫代葡萄糖苷；
正-己基β-D-吡喃葡萄糖苷；
壬酰基-N-甲基葡萄糖酰胺；
正-壬基β-D-吡喃葡萄糖苷；
辛酰基-N-甲基葡萄糖酰胺；
正-辛基β-D-吡喃葡萄糖苷；
辛基β-D-硫代吡喃葡萄糖苷；等等。
特别优选的表面改性剂类型包括水可溶的或水可分散的化合物，其通式如下
其中
L′为化学键、-O-、-S-、-NH--CONH-或-SO2NH-；
R为疏水性的取代或未取代的烷基、取代或未取代的环烷基、或取代或未取代的芳基；
每个R1和R2独立地表示氢或具有1～4个碳原子的烷基；
每个a和b独立地表示O或1～3的整数，其条件是a与b之和不大于3；和
每个x和y分别是3～7的整数。
符合上述结构的这一类型中的优选化合物是其中R含有6～36个碳原子，例如，R为含有6～18个碳原子的正-烷基，每个R1和R2独立地为甲基、乙基、丙基或丁基以及a为0和b为0的化合物。这类表面改性剂已在1991年3月8日递交的U.K.专利申请9104957.7中叙述过，并可以通过相应的二羧酸酯与相应的单糖胺反应制得，优选在无溶剂条件下于140～200℃的温度下进行反应。
该表面改性剂是市面上购得的和/或可用本领域的已知技术制得的。可以将两种或多种表面改性剂混合起来使用。
上述的粒状组份可以按照US 5145684中所述的湿研磨法进行制备。该方法包括将劣溶性的X-射线造影剂在液态分散液介质中进行分散和在研磨介质存在下进行湿研磨，将造影剂的颗粒度减小到有效平均粒度为大约0.05μ～大约100μ，优选大约0.05μ-大约5μ，更优选大约0.1μ-大约1μ。该颗粒可在表面改性剂存在下减小其粒度。或者，可以在研磨之后使该颗粒与表面改性剂接触。
这里所用的粒度指的是数均粒度，是用本技术领域已知的测定粒度的普通技术，例如沉淀场流动分级、光子相关谱、或盘式离心分离的方法测定的。所说的“有效平均粒度大约0.05μ～大约100μ”指的是当用上述技术测定时，至少90％的颗粒具有重均粒度为大约0.05μ-大约100μ。这样的粒度范围使得由此涂覆GI道时有足够数量的颗粒分布在形成的组合物膜中，而且又能保证不通过肠壁吸收。
本发明组合物中天然的药用粘土含有硅酸铝。用纯的硅酸铝适合于病人服用。本发明的天然药用粘土一般是指绿土，其组成是二八面体(dioctohedral)绿土和三八面体(frioctahedral)绿土。
二八面体绿土包括：
蒙脱土，分子式为M+Al3y(FeMg)ySi4O10(OH)2·nH2O；
贝得土，分子式为M+Al2(Si4-xAlx)O10(OH)2·nH2O；
囊脱土，分子式为M+Fe2(Si4-xAlx)O10(OH)2·nH2O；
其中M+是Na、Ca、或Mg。
三八面体绿土包括：
滑石粉，分子式为M+(Mg3-y(AlFe)y)(Si4-xAlx)O10(OH)2·nH2O；
水辉石，分子式为M+(Fe3-yLiy)Si4O10(OH)2·nH2O；
其中M+是Na、Ca、或Mg。
这些粘土在一些化学品公司均有售，例如American Colloid Company，Arlington Heights，IL，商品名为：
MAGNABRITEHS；
HECTABRITEDP，
HECTABRITELT，
CARMARGOWhite，
POLARGELNF，
POLARGELHV，and
VOLCLAYNF-BC。
其它的供销商包括：Engelhard Corp.，Iselin，NJ；Ashland Chemical Inc.，Colombus，OH；RT Vanderbilt Co.，Inc.，Norwalk，CT和Whittaker Clark &Daniels，Inc.，S.Plainfield，NJ。
将造影剂和药用粘土用生理上可接受的载体和赋型剂按本领域的一般方法配制成服用制剂。可将造影剂加药用助剂(如表面活性剂和乳化剂)和赋型剂一起在含水介质中悬浮或乳化成悬浮液或乳液。
本发明的组合物含有下面的医药上可接受的各种组分(基于％w/v)：
组分 宽范围 较优选范围 最优选范围
造影剂 5～45 10～35 15～25
粘土 0.1～10 0.5～5 1～2
表面活性剂 1～20 2～10 3～5
赋形剂 0～15 0.5～5 1～2
水-足量至100％(按体积)
本发明用的赋型剂包括：消泡剂如二甲硅油、甲硅烷甲基亚烷基聚合物和聚氧烷基化的天然油；防腐剂如羟苯甲酸甲酯、羟苯甲酸丙酯、苯甲酸和山梨酸；香味/甜味剂如糖精钠；以及着色剂如色淀和染料。
用于本发明配方中的碘苯氧烷和医药上可接受的载体提供了较佳的X-射线图象，而在配方中加入粘土大大提高了X-射线图象的质量。用上述浓度范围的下限不能获得或很少获得好的图象，而超过该浓度范围的上限，乳液太粘不利于给药。
以下的配方实施例进一步说明本发明：
实施例1
组分 用量
2，4，6-三碘代苯氧基-2-丁烷 20.0g
HECTABRITER DP 1.45g
脱水山梨糖醇单硬脂酸酯 0.5g
聚山梨酯60 1.0g
Poloxamer338 5.0g
糖精钠 0.25g
苯甲酸 0.50g
山梨酸 0.05g
水足量至 100ml
实施例2
组分 用量
4-碘代苯氧基-2-辛烷 22.5g
POLARGELR NF 2.25g
脱水山梨糖醇单油酸酯 0.40g
聚山梨酯20 1.25g聚乙烯醇 4.50g糖精钠 0.25g二甲硅油乳液(食品级) 0.10g水足量至 100ml实施例3组分 用量2，4，6-三碘苯氧基-2-己烷 18.5gMAGNABRITER HS 1.25g脱水山梨糖醇棕榈酸酯 0.6g聚氧乙烯十四烷基醚 0.6g聚乙烯吡咯烷酮 3.5g香草调味剂(人造) 0.25g草莓调味剂(人造) 0.25g山梨醇 1.0g水足量至 100ml实施例4组分 用量(％w/v)聚乙二醇400的双-(4-碘代苯基)醚 17.50HECTABRITER DP 1.35聚山梨酯80(吐温80) 1.50脱水山梨糖醇单油酸酯(司盘80) 1.65用足量水至 100％(体积)实施例5组分 用量(％w/v)1，8-双-O-(2，4，6-三碘代苯基)-三丙二醇 25.00POLARGELR NF 2.30聚山梨酯60(吐温60) 1.00Poloxamer338 6.50苯甲酸 0.50山梨酸 0.05用足量水至 100％(体积)实施例6组分 用量(％w/v)1，11-双-(2，4，6-三碘代苯氧基)-3，6，9-三氧杂十一烷 17.50MAGNABRITER HS 1.25聚山梨酯20(吐温20) 1.50脱水山梨糖醇单月桂酸酯(司盘20) 2.00聚乙烯醇 4.00糖精钠 0.30用足量水至 100％(体积)实施例7组分 用量N-乙酰基-N-2-辛基-4-碘代苯胺 18.00gHECTABRITER DP 1.5g脱水山梨醇单硬脂酸酯 0.5g聚山梨酯60(吐温60) 1.2gPoloxamer338 4.0g糖精钠 0.3g苯甲酸 0.1g山梨酸 0.05g水足量至 100ml实施例8组分 用量N-(4′-碘代苯基)-2-氨基辛烷 25.00POLARGELR NF 2.0g脱水山梨糖醇单油酸酯 0.4g聚山梨酯20(吐温20) 1.2g聚乙烯醇 4.5g糖精钠 0.2g二甲硅油(食品级) 0.1g水足量至 100ml实施例9组分 用量2-辛基-2，3，5-三碘代苯甲酸酯 22.00gHECTABRITER DP 1.50g脱水山梨糖醇单硬脂酸酯 0.70g聚山梨酯60(吐温60) 1.20gPoloxamer338 4.00g糖精钠 0.30g苯甲酸 0.50g山梨酸 0.05g水足量至 100ml实施例10组分 用量3，3，4，4，5，5，6，6，7，7，8，8-十二氟代-2-辛基-2，3，5-三碘代苯甲酸酯 22.50gPOLARGELR NF 2.30g脱水山梨糖醇单油酸酯 0.45g聚山梨酯20(吐温20) 1.30g聚乙烯醇 4.50g糖精钠 0.25g二甲硅油乳液(食品级) 0.10g水足量至 100ml实施例11组分乙基-3-(2-乙酰氧)-2，4，6-三碘代苯甲酸酯 18.50gMAGNABRITER HS 1.25g脱水山梨糖醇棕榈酸酯 0.60g聚氧乙烯十四烷基醚 0.60g聚乙烯吡咯烷酮 3.50g香草调味剂(人造) 0.25g草莓调味剂(人造) 0.25g山梨醇 1.00g水足量至 100ml实施例12组分 用量2，4，6-三碘代苯氧基甲基环戊烷 22.00gHECTABRITER DP 1.50g脱水山梨醇单硬脂酸酯 0.70g聚山梨酯60(吐温60) 1.20gPoloxamer338 4.00g糖精钠 0.30g苯甲酸 0.50g山梨酸 0.05g水足量至 100ml实施例13组分 用量2-(4-碘代苯氧基)十五烷 22.50gPOLARGELRNF 2.30g脱水山梨糖醇单油酸酯 0.45g聚山梨酯20(吐温20) 1.30g聚乙烯醇 4.50g糖精钠 0.25g二甲硅油乳液(食品级) 0.10g水足量至 100ml实施例14组分 用量2-碘代苯氧基环戊烷 18.50gMAGNABRITER HS 1.25g脱水山梨糖醇棕榈酸酯 0.60g聚氧乙烯十四烷基醚 0.60g聚乙烯吡咯烷酮 3.50g香草调味剂(人造) 0.25g草莓调味剂(人造) 1.25g山梨醇 1.00g水足量至 100ml实施例15组分 用量2，4，6-三碘代苯基-2-乙基己酸酯 22.00gHECTABRITER DP 1.50g脱水山梨糖醇单硬脂酸酯 0.70g聚山梨酯60(吐温60) 1.20gPoloxamer338 4.00g糖精钠 0.30g苯甲酸 0.50g山梨酸 0.05g水足量至 100ml实施例16组分 用量2，4，6-三碘代苯基-三-(2-乙基乙酸酯) 22.50gPOLARGELR NF 2.30g脱水山梨糖醇单油酸酯 0.45g聚山梨酯20(吐温20) 1.30g聚乙烯醇 4.50g糖精钠 0.25g二甲硅油乳液(食品级) 0.10g水足量至 100ml实施例17组分 用量2，4，6-三碘代苯基磺酸己酯 18.50gMAGNABRITER HS 1.25g脱水山梨糖醇单棕榈酸酯 0.60g聚氧乙烯十四烷基醚 0.60g聚乙烯吡咯烷酮 3.50g香草调味剂(人造) 0.25g草莓调味剂(人造) 0.25g山梨醇 1.00g水足量至 100ml实施例18组分 用量乙基3，5-双(乙酰基氨基)-2，4，6-三碘代苯甲酸酯 22.00gHECTABRITER DP 1.50g脱水山梨糖醇单硬脂酸酯 0.70g聚山梨酯60(吐温60) 1.20gPoloxamer338 4.00g糖精钠 0.30g苯甲酸 0.50g山梨酸 0.05g水足量至 100ml实施例19组分 用量乙基(3，5-双(乙酰基氨基)-2，4，6-三碘代苯甲酰氧基乙酸酯 22.50gPOLARGELR NF 2.30g脱水山梨糖醇单油酸酯 0.45g聚山梨酯20(吐温20) 1.30g聚乙烯醇 4.50g糖精钠 0.25g二甲硅油乳液(食品级) 0.10g水足量至 100ml实施例20组分 用量乙基2-(3，5-双(乙酰基氨基)-2，4，6-三苯甲酰氧)丁酸酯 18.50g
MAGNABRITER HS 1.25g
脱水山梨糖醇棕榈酸酯 0.60g
聚氧乙烯十四烷基醚 0.60g
聚乙烯吡咯烷酮 3.50g
香草调味剂(人造) 0.25g
草莓调味剂(人造) 0.25g
山梨醇 1.00g
水足量至 100ml
本发明所用的表面活性剂可以是阳离子、阴离子、非离子或两性离子的。
合适的阳离子型表面活性包括十六烷基三甲基溴化铵、十六烷基氯化吡啶鎓、十四烷基γ甲基吡啶鎓氯化物和氯苄烷铵。合适的阴离子型表面活性包括十二烷基硫酸钠、十七烷基硫酸钠、烷基苯磺酸及其盐、丁基萘磺酸钠、和硫代琥珀酸盐。两性离子型表面活性剂是那些当溶于水时它们起着二元酸作用的物质，并且当它们离子化时又起着弱酸和弱碱的作用。又由于分子中两种电荷彼此抵消，所以它们起中性分子的作用。在两性离子浓度最大时的pH值叫做等电点。在本发明配方所要求的pH值下具有等电点的某些氨基酸等化合物可用来实施本发明。
在制备本发明制剂中我们优选使用非离子型乳化剂或表面活性剂，与非离子型造影剂相类似，与阴离子、阳离子或两性离子型剂相比具有极好的毒理剖析图。在非离子型乳化剂中亲水和疏水基的比例大约是对等的平衡。由于在分子中不存在电荷，不同于阴离子型和阳离子型表面活性剂，因此，通常它的刺激性比阳离子型或阴离子型表面活性剂的小。非离子型表面活性剂包括羧酸酯、羧酸酰胺、乙氧基化的烷基酚、乙氧基化的脂族醇、环氧乙烷聚合物或环氧乙烷/环氧丙烷共聚物、聚乙烯吡咯烷酮和聚乙烯醇。
一种具体类型的羧酸酯非离子型表面活性剂是偏酯，例如单酯，它是通过脂肪和树脂酸(具有8～18个碳原子)与多元醇反应形成的(该多元醇例如丙三醇、一、二、四和六甘醇等的乙二醇类、脱水山梨糖醇和其它类似物)；以及通过各种摩尔比的环氧乙烷对脂肪酸的羟基直接反应所形成的类似化合物。
另一类羧酸酯是脂肪与树脂偏酸(例如单酸)的缩合产物、氧化乙烯酯，例如聚氧乙烯脱水山梨糖醇和山梨糖醇的脂肪或树脂酸酯，例如聚氧乙烯脱水山梨糖醇、单妥尔油酯类。它们可以含有，例如每分子中大约3～大约80个氧化乙烯单元和具有约8～约18个碳原子的脂肪或树脂酸基。可以使用的自然界存在的脂肪酸混合物的例子是取自椰子油和动物脂的那些脂肪酸，而纯脂肪酸的例子是十二烷酸和油酸。
羧酸酰胺非离子型表面活性剂是大约8～大约18个碳原子的酰基链的脂肪酸的氨、单乙基胺和二乙基胺的酰胺类。
乙氧基化的烷基酚非离子型表面活性剂包括各种烷基酚的聚环氧乙烷缩合物，尤其是单烷基酚或二烷基酚(其中的烷基含有大约6～大约12个碳原子，并且可为支链或为直链构型，特别是直链构型，例如辛基甲苯酚、辛基苯酚或壬基苯酚)与环氧乙烷的缩合产物，所说的环氧乙烷的含量是，每摩尔烷基酚为大约5～大约25摩尔的环氧乙烷。
乙氧基化的脂族醇非离子型表面活性剂包括具有大约8～18个碳原子的直链或支链构型的脂族醇，例如油醇或十六碳醇，与环氧乙烷的缩合产物，所说的环氧乙烷对每摩尔醇的量为大约30～大约60摩尔的环氧乙烷。
优选的非离子型表面活性剂包括：
(a)具有下列结构通式的脱水山梨糖醇酯[出售的商品名称为司盘(Span)]
其中R1＝R2＝OH，R3＝R，对于脱水山梨糖醇单酯类；
R1＝OH，R2＝R3＝R，对于脱水山梨糖醇二酯类；
R1＝R2＝R3＝R，对于脱水山梨糖醇三酯类；其中R＝(C11H23)COO，对于月桂酸酯；
(C17H33)COO，对于油酸酯；
(C15H31)COO，对于棕榈酸酯；
(C17H35)COO，对于硬脂酸酯；(b)聚氧乙烯烷基醚(即Brijs)其结构通式如下：CH3(CH2)x(O-CH2-CH2)YOH
其中(x＋1)是烷基链上的碳原子数，通常：
12 月桂基 (十二碳烷基)
14 肉豆蔻基 (十四碳烷基)
16 鲸蜡基 (十六碳烷基)
18 硬脂基 (十八碳烷基)
Y是在亲水链中氧化乙烯基的数，通常为10～60；
(c)聚氧乙烯脱水山梨糖醇脂肪酸酯，市售的商品为聚山梨酯20、40、60、65、80和85，其结构通式为(1)和(2)。
式中
w＋x＋y＋z＝20(聚山梨酯20、40、60、65、80和85)
w＋x＋y＋z＝5(聚山梨酯81)
w＋x＋y＋z＝4(聚山梨酯21和61)
(d)聚氧乙烯硬脂酸酯，例如：
聚(氧-1，2-乙烷二基)，α-氢化-ω-羟基十八烷酸酯；聚乙二醇单硬脂酸酯；和
聚(氧-1，2-乙烷二基)-α-(1-氢化十八烷基)-ω-羟基-聚乙二醇单硬脂酸酯。
(e)环氧乙烷/环氧丙烷嵌段共聚物，商品名PLURONICTM，包括：
Poloxamer407(PLURONICTMF127)，Poloxamer188(PLURONICTMF68)，Poloxamer237(RLURONICTMF87)和Poloxamer338(PLURONICTMF108)。
(f)聚乙烯吡咯烷酮
(g)聚乙烯醇
本发明方法使用的造影剂的剂量将根据所用造影剂的明确性质而变化。但是优选的是应当保持能达到造影成象质量高的低剂量。通过使用尽可能小剂量的造影剂，使毒性的影响减至最小。对于本发明的大多数造影剂而言，其剂量范围应为大约0.1～大约16.0g碘/kg体重、优选大约0.5～大约6.0g碘/kg体重，最优选大约1.2～大约2.0g碘/kg体重，该范围适用于常规的GI道的X-射线显影。对于CT扫描而言，本发明的造影剂的用量范围应为大约1～大约600 mg碘/kg体重，优选大约20～大约200mg碘/kg体重，特别优选大约40～大约80mg碘/kg体重。
本发明的组合物用于哺乳动物时能产生优良的X-射线和CT图像。
Claims (10)
1.一种用于口服或肠胃道退行性检查的X-射线造影组合物，按每单位体积的％重量计包括：
(a)一种造影剂，选自：
(1)约5至4 5％以下通式的X-射线造影剂或其药用可接受的盐，
其中，
R是取代的或未取代的含有2～8个碳原子的烷基，其中所说的取代基选自C1-C6的烷基、羟基和烷氧基；并且n为1～5；
(2)约5至45％以下通式的X-射线造影剂或其药用可接受的盐，
其中Z是H、卤素、C1-C20的烷基、环烷基、低级烷氧基、烷氧羰基、氰基，这里的烷基和环烷基能够被卤素或卤代低级烷基所取代；
R是C1-C25的烷基、环烷基、或卤代低级烷基；它们中的每一个都可以被卤、氟代低级烷基、芳基、低级烷氧基、羟基、羧基、低级烷氧基羰基或低级烷氧基羰氧基取代或不取代；或(CR1R2)p-(CR3＝CR4)mQ或(CR1R2)p-C≡C-Q；
R1、R2、R3和R4独立地代表H、低级烷基，也可以被卤素取代或不取代；
x是1-4；
n是1-4；
m是1～15；
p是1～20；和
Q是H、低级烷基、低级链烯基，低级炔基、低级亚烷基、芳基或芳基低级烷基；
(3)约5至45％以下通式的X-射线造影剂或其药用可接受的盐，
式中
Z是H、卤素、C1-C20的烷基、环烷基、低级烷氧基、氰基，这里的烷基和环烷基可以用卤素或卤代低级烷基所取代；
R1和R2独立地表示H、C1-C25的烷基、环烷基、乙酰基或卤代的低级烷基，其中所说的C1-C25的烷基，环烷基和卤代的低级烷基可以用氟代低级烷基、芳基、低级烷氧基、羟基、羧基、低级烷氧羰基或低级烷氧基羰氧基取代或不取代，和所说的乙酰基可以用氟代低级烷基、芳基、低级烷氧基、羟基、低级烷氧羰基或低级烷氧基羰氧基取代或不取代；
n是1-4
y是1-4；和
x是1或2
(4)约5至45％以下通式的X-射线造影剂或其医药上可接受的盐，
其中，
Z是H、卤素、C1-C20的烷基、环烷基、低级烷氧基、氰基，这里的烷基和环烷基能被卤素或卤代低级烷基取代；
R是C1-C25的烷基、环烷基、或卤代低级烷，这其中的每一个可以被卤、氟低级烷基、芳基、低级烷氧基、羟基、羧基、低级烷氧基羰基或低级烷氧基羰氧基取代或不取代；或(CR1R2)p-(CR3＝CR4)mQ或(CR1R2)p-C≡C-Q；
R1、R2、R3和R4独立地代表低级烷基、并可以被卤素取代或不取代；
x是1-3；
y是1-4；
n是1-5；
m是1-15；
p是1-10；和
Q是H、低级烷基、低级链烯基，低级炔基、低级亚烷基、芳基、或芳基低级烷基；
(5)约5至45％以下通式的X-射线造影剂或其药用可接受的盐：
其中，
Z是H、卤素、C1-C20的烷基、环烷基、低级烷氧基、氰基，这里的烷基和环烷基能够用卤素或卤代低级烷基所取代；
R是甲基、乙基、丙基、C9-C25的烷基、环烷基、或卤代低级烷基，可以用卤、氟代低级烷基、芳基、低级烷氧基、羟基、羧基、低级烷氧基羰基或低烷氧基羰氧基所取代或不取代；或(CR1R2)p-(CR3＝CR4)mQ、或(CR1R2)p-C≡C-Q；
R1、R2、R3和R4独立地代表低级烷基、也可以用卤素取代或不取代；
x是1～4；
n是1～5；
m是1～15；
p是1～10；和
Q是H、低级烷基、低级链烯基，低级炔基、低级亚烷基、芳基、或芳基低级烷基；
(6)约5至45％以下通式的X-射线造影剂其药用可接受的盐：其中，x是或-SO2-；
Z是H、卤素、甲基、乙基、正丙基、C4-C20的烷基、环烷基、低级烷氧基、氰基，这里的烷基和环烷基能够被卤素或卤代低级烷基所取代；
R是C1-C25的烷基、环烷基或芳基，它们中的每一个可以用卤素、氟代低级烷基、低级烷氧基、羟基、羧基、或低级烷氧基羰基、低级链烯基、低级炔基、低级亚烷基或低级烷氧基羰氧基取代或不取代；
n是1～5；
y是0～4；和
w是1～4；
(7)约5至45％结晶造影剂选自泛影酸、甲基泛影酸、异泛影酸、苯均三酸、醋碘苯甲酸、甲醇异泛影酸、四碘代对苯二甲酸、碘克酸、胆影酸、乙基-3，5-二乙酰氨基-2，4，6-三碘代苯甲酸，乙基-2-(3，5-双(乙酰氨基)-2，4，6-三碘代-苯甲酸氧基)丁酸酯、和乙基-(3，5-双(乙酰氨基)-2，4，6-三碘代苯甲酰氧基)-乙酸酯，所说的结晶造影剂具有吸附在其表面上的表面改性剂，其用量足以维持有效平均粒度为大约0.5μ～大约100μ；和
所说的表面改性剂选自由环氧丙烷和环氧乙烷对乙二胺的顺序加成获得的四官能嵌段共聚物；
(b)约0.1至10％的药用可接受的粘土，选自蒙脱土、贝得土、囊脱土、水辉土和滑石粉；
(c)约1.0至20％的表面活性剂选自非离子型、阴离子型、阳离子型和两性离子型的表面活性剂；
(d)约0至15％的赋型剂；和
(e)水、至100％体积。
2、权利要求1的X-射线造影组合物，其中所说的X-射线造影剂的存在量为约10至35％。
3、权利要求1的X-射线造影组合物，其中所说药用可接受的粘土含量为组合物的0.5至5％。
4、按照权利要求1的X-射线造影组合物，其中所说的表面活性剂组分的含量为组合物2至10％。
5、权利要求1的X-射线造影组合物，其中所说的赋型剂含量为组合物的0.5至5％。
6、权利要求1的X-射线造影组合物，其中所说的非离子表面活性剂选自羧酸酯、羧酸酰胺、乙氧基化的烷基酚、乙氧基化的脂族醇、环氧乙烷聚合物、环氧乙烷/环氧丙烷共聚物、聚乙烯吡咯烷酮和聚乙烯醇。
7、权利要求1的X-射线造影组合物，其中所说的表面活性剂是脱水山梨糖醇酯，其结构式如下：
式中：
对于脱水山梨糖醇单酯类，R1＝R2＝OH，R3＝R；
对于脱水山梨糖醇二酯类，R1＝OH，R2＝R3＝R；
对于脱水梨糖醇三酯类，R1＝R2＝R3＝R；
其中R＝(C11H23)COO，对于月桂酸酯；
(C17H33)COO，对于油酸酯；
(C15H31)COO，对于棕榈酸酯；
(C17H35)COO，对于硬脂酸酯；
8、权利要求1的X-射线造影组合物，其中所说的表面活性剂是聚氧烯硬脂酸酯。
9、权利要求1的X-射线造影组合物，其中所说的表面活性剂是聚氧乙烯脱水山梨糖醇脂肪酸酯，其结构式如下式(1)和(2)表示：聚氧乙烯脱水山梨糖醇单酯
其中
w＋x＋y＋z＝20；
w＋x＋y＋z＝5；
w＋x＋y＋z＝4。
10、对患者肠胃道进行X-射线检查的方法，所说的方法包括将前面任何一项权利要求的一种X-射线造影制剂经口服或直肠给药于该患者。
Applications Claiming Priority (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/230,580 | 1994-04-21 | ||
| US08/230,580 US5476646A (en) | 1992-05-01 | 1994-04-21 | X-ray contrast compositions containing iodophenoxyalkanes and pharmaceutically acceptable clays |
| US08/236,287 | 1994-04-29 | ||
| US08/236,287 US5424056A (en) | 1993-03-01 | 1994-04-29 | X-ray contrast compositions containing iodoaniline derivatives and pharmaceutically acceptable clays |
| US08/237,502 US5492687A (en) | 1993-03-11 | 1994-05-03 | Compositions of iodophenoxy alkylene ethers and pharmaceutically acceptable clays for visualization of the gastrointestinal tract |
| US08/237,502 | 1994-05-03 | ||
| US08/239,090 US5484585A (en) | 1993-03-11 | 1994-05-05 | Compositions of iodobenzoic acid derivatives and pharmaceutically acceptable clays for visualization of the gastrointestinal tract |
| US08/239,090 | 1994-05-05 | ||
| US08/247,438 US5531979A (en) | 1993-02-02 | 1994-05-23 | Compositions of iodophenoxy alkanes and iodophenyl ethers and pharmaceutically acceptable clays for visualization of the gastrointestinal tract |
| US08/247,424 US5360604A (en) | 1994-04-14 | 1994-05-23 | X-ray contrast compositions containing an organic crystalline X-ray contrast agent in combination with pharmaceutically acceptable clays |
| US08/247,424 | 1994-05-23 | ||
| US08/247,438 | 1994-05-23 | ||
| US08/249,424 | 1994-05-26 | ||
| US08/249,424 US5472682A (en) | 1993-03-31 | 1994-05-26 | Compositions of iodophenyl esters and iodophenyl sulfonates and pharmaceutically acceptable clays for visualization of the gastrointestinal tract |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1147206A true CN1147206A (zh) | 1997-04-09 |
Family
ID=27569393
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95192622A Pending CN1147206A (zh) | 1994-04-21 | 1995-03-16 | 含有药用粘土的x-射线造影组合物 |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0756497A1 (zh) |
| JP (1) | JPH09512029A (zh) |
| CN (1) | CN1147206A (zh) |
| AU (1) | AU1897795A (zh) |
| CA (1) | CA2187019A1 (zh) |
| FI (1) | FI964212A0 (zh) |
| HU (1) | HUT76304A (zh) |
| NO (1) | NO964451L (zh) |
| WO (1) | WO1995028969A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330380C (zh) * | 2005-03-18 | 2007-08-08 | 山东师范大学 | 一种x－射线造影剂组合物 |
| CN106075476A (zh) * | 2016-07-30 | 2016-11-09 | 温州市人民医院 | 一种造影剂 |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5466440A (en) * | 1994-12-30 | 1995-11-14 | Eastman Kodak Company | Formulations of oral gastrointestinal diagnostic X-ray contrast agents in combination with pharmaceutically acceptable clays |
| JP4670229B2 (ja) * | 2003-06-10 | 2011-04-13 | 味の素株式会社 | Ｃｔコロノグラフィにおける消化管造影用組成物 |
| AP2006003700A0 (en) | 2004-02-13 | 2006-08-31 | Warner Lambert Co | Androgen receptor modulators |
| CA2563291A1 (en) | 2004-04-13 | 2005-10-27 | Warner-Lambert Company Llc | 4-cyano-phenoxy-alkyl carboxyl derivatives as androgen modulators |
| WO2005102990A1 (en) | 2004-04-22 | 2005-11-03 | Warner-Lambert Company Llc | Androgen modulators |
| BRPI0513020A (pt) | 2004-07-08 | 2008-04-22 | Warner Lambert Co | moduladores de andrÈgenio, seus usos, composição farmacêutica, formulação farmacêutica tópica e artigo de fabricação |
| TW200724139A (en) | 2005-05-05 | 2007-07-01 | Warner Lambert Co | Androgen modulators |
| WO2014145509A1 (en) | 2013-03-15 | 2014-09-18 | The Regents Of The University Of California | Enteric ct contrast material based on low-z atoms |
| WO2015024025A1 (en) | 2013-08-16 | 2015-02-19 | The Regents Of The University Of California | Silicone-based enteric ct contrast material |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB767788A (en) * | 1953-12-28 | 1957-02-06 | Schering Corp | Polyiodinated phenyl fatty acid compounds and process for their manufacture |
| CH338274A (fr) * | 1954-01-08 | 1959-05-15 | Schering Corp | Utilisation comme agents radio-opaques de phénoxy-acides gras polyiodés |
| CA985626A (en) * | 1970-03-10 | 1976-03-16 | E.R. Squibb And Sons | Coating composition for moist surface |
| CA2094893A1 (en) * | 1992-05-01 | 1993-11-02 | Carl R. Illig | X-ray contrast compositions containing film-forming materials |
| US5260049A (en) * | 1992-05-01 | 1993-11-09 | Sterling Winthrop Inc. | X-ray contrast compositions comprising alkoxyphenols |
| NZ250063A (en) * | 1992-12-14 | 1996-03-26 | Eastman Kodak Co | Iodinated aromatic acid ester derivatives; x-ray contrast compositions |
| US5322679A (en) * | 1992-12-16 | 1994-06-21 | Sterling Winthrop Inc. | Iodinated aroyloxy esters |
| US5316755A (en) * | 1993-02-02 | 1994-05-31 | Sterling Winthrop Inc. | Compositions of iodophenoxy alkanes and iodophenyl ethers for visualization of the gastrointestinal tract |
| US5326553A (en) * | 1993-02-02 | 1994-07-05 | Sterling Winthrop Inc. | Compositions of iodophenoxy alkanes and iodophenyl ethers in film-forming materials for visualization of the gastrointestinal tract |
| US5334370A (en) * | 1993-02-04 | 1994-08-02 | Sterling Winthrop Inc. | Compositions of alkylbenzenes in film-forming materials for visualization of the gastrointestinal tract |
| US5308607A (en) * | 1993-02-04 | 1994-05-03 | Sterling Winthrop Inc. | Compositions of alkylbenzenes for visualization of the gastrointestinal tract using X-ray contrast |
| US5310537A (en) * | 1993-03-01 | 1994-05-10 | Sterling Winthrop Inc. | Compositions of iodoaniline derivatives for visualization of the gastrointestinal tract |
| US5310538A (en) * | 1993-03-11 | 1994-05-10 | Sterling Winthrop Inc. | Compositions of iodophenoxy alkylene ethers in film-forming materials for visualization of the gastrointestinal tract |
| US5344638A (en) * | 1993-03-11 | 1994-09-06 | Sterling Winthrop Inc. | Compositions of iodobenzoic acid derivatives for visualization of the gastrointestinal tract |
| US5312616A (en) * | 1993-03-11 | 1994-05-17 | Sterling Winthrop Inc. | Compositions of iodobenzoic acid derivatives in film-forming materials for visualization of the gastrointestinal tract |
| US5318769A (en) * | 1993-03-31 | 1994-06-07 | Sterling Winthrop Inc. | Compositions of iodophenyl esters for X-ray visualization of the gastrointestinal tract |
| US5336484A (en) * | 1993-03-31 | 1994-08-09 | Sterling Winthrop Inc. | Compositions of iodophenyl esters and iodophenyl sulfonates in film-forming materials for visualization of the gastronintestinal tract |
| US5360604A (en) * | 1994-04-14 | 1994-11-01 | Sterling Winthrop Inc. | X-ray contrast compositions containing an organic crystalline X-ray contrast agent in combination with pharmaceutically acceptable clays |
-
1995
- 1995-03-16 JP JP7527425A patent/JPH09512029A/ja active Pending
- 1995-03-16 CA CA002187019A patent/CA2187019A1/en not_active Abandoned
- 1995-03-16 WO PCT/GB1995/000566 patent/WO1995028969A1/en not_active Application Discontinuation
- 1995-03-16 HU HU9602908A patent/HUT76304A/hu unknown
- 1995-03-16 EP EP95911399A patent/EP0756497A1/en not_active Withdrawn
- 1995-03-16 CN CN95192622A patent/CN1147206A/zh active Pending
- 1995-03-16 AU AU18977/95A patent/AU1897795A/en not_active Abandoned
-
1996
- 1996-10-18 FI FI964212A patent/FI964212A0/fi not_active Application Discontinuation
- 1996-10-18 NO NO964451A patent/NO964451L/no unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330380C (zh) * | 2005-03-18 | 2007-08-08 | 山东师范大学 | 一种x－射线造影剂组合物 |
| CN106075476A (zh) * | 2016-07-30 | 2016-11-09 | 温州市人民医院 | 一种造影剂 |
| CN106075476B (zh) * | 2016-07-30 | 2019-05-31 | 温州市人民医院 | 一种造影剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| NO964451D0 (no) | 1996-10-18 |
| EP0756497A1 (en) | 1997-02-05 |
| WO1995028969A1 (en) | 1995-11-02 |
| AU1897795A (en) | 1995-11-16 |
| HUT76304A (en) | 1997-07-28 |
| MX9604899A (es) | 1998-03-31 |
| FI964212A (fi) | 1996-10-18 |
| JPH09512029A (ja) | 1997-12-02 |
| FI964212A0 (fi) | 1996-10-18 |
| HU9602908D0 (en) | 1996-12-30 |
| NO964451L (no) | 1996-12-18 |
| CA2187019A1 (en) | 1995-11-02 |
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