IE65168B1 - Preparation comprising cavitate- or clathrate-forming host/guest complexes as contrast agent - Google Patents
Preparation comprising cavitate- or clathrate-forming host/guest complexes as contrast agentInfo
- Publication number
- IE65168B1 IE65168B1 IE268589A IE268589A IE65168B1 IE 65168 B1 IE65168 B1 IE 65168B1 IE 268589 A IE268589 A IE 268589A IE 268589 A IE268589 A IE 268589A IE 65168 B1 IE65168 B1 IE 65168B1
- Authority
- IE
- Ireland
- Prior art keywords
- derivatives
- solution
- crystals
- autoclave
- dissolved
- Prior art date
Links
- 239000002872 contrast media Substances 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title claims description 10
- 238000011835 investigation Methods 0.000 claims abstract description 10
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 49
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 24
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- KXYDGGNWZUHESZ-UHFFFAOYSA-N 4-(2,2,4-trimethyl-3h-chromen-4-yl)phenol Chemical compound C12=CC=CC=C2OC(C)(C)CC1(C)C1=CC=C(O)C=C1 KXYDGGNWZUHESZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000004202 carbamide Substances 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- -1 2,2,4-trimethylchroman-4-yl Chemical group 0.000 claims description 8
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- ZIKHLMVJGCYVAC-UHFFFAOYSA-N tri-o-thymotide Chemical compound O1C(=O)C2=C(C)C=CC(C(C)C)=C2OC(=O)C2=C(C)C=CC(C(C)C)=C2OC(=O)C2=C1C(C(C)C)=CC=C2C ZIKHLMVJGCYVAC-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- YECHEDVCXXVLIY-UHFFFAOYSA-N cyclotriveratrylene Chemical group C1C2=CC(OC)=C(OC)C=C2CC2=CC(OC)=C(OC)C=C2CC2=C1C=C(OC)C(OC)=C2 YECHEDVCXXVLIY-UHFFFAOYSA-N 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical class [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 150000004010 onium ions Chemical class 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- YDZNRNHKJQTGCG-UHFFFAOYSA-N 1,1'-binaphthyl-2,2'-dicarboxylic acid Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3C(=O)O)=C(C(O)=O)C=CC2=C1 YDZNRNHKJQTGCG-UHFFFAOYSA-N 0.000 claims description 2
- BOAQYZYOCBRFEV-UHFFFAOYSA-N 1,2,3,4,5,6-hexakis(phenylsulfanyl)benzene Chemical compound C=1C=CC=CC=1SC=1C(SC=2C=CC=CC=2)=C(SC=2C=CC=CC=2)C(SC=2C=CC=CC=2)=C(SC=2C=CC=CC=2)C=1SC1=CC=CC=C1 BOAQYZYOCBRFEV-UHFFFAOYSA-N 0.000 claims description 2
- 150000005208 1,4-dihydroxybenzenes Chemical class 0.000 claims description 2
- VTZDWVXUYPHSKJ-UHFFFAOYSA-N 4-(2,2,4,7-tetramethyl-3h-thiochromen-4-yl)phenol Chemical compound C=1C(C)=CC=C2C=1SC(C)(C)CC2(C)C1=CC=C(O)C=C1 VTZDWVXUYPHSKJ-UHFFFAOYSA-N 0.000 claims description 2
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 claims description 2
- KUQXWYPFKWLDRP-UHFFFAOYSA-N 9,9'-spirobi[fluorene]-2,2'-dicarboxylic acid Chemical compound C12=CC=CC=C2C2=CC=C(C(O)=O)C=C2C21C1=CC=CC=C1C1=CC=C(C(=O)O)C=C12 KUQXWYPFKWLDRP-UHFFFAOYSA-N 0.000 claims description 2
- CITFYDYEWQIEPX-UHFFFAOYSA-N Flavanol Natural products O1C2=CC(OCC=C(C)C)=CC(O)=C2C(=O)C(O)C1C1=CC=C(O)C=C1 CITFYDYEWQIEPX-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- KVDANDXXMLZEGA-UHFFFAOYSA-N N[Ni]C#N Chemical compound N[Ni]C#N KVDANDXXMLZEGA-UHFFFAOYSA-N 0.000 claims description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 229910052770 Uranium Inorganic materials 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 229940051879 analgesics and antipyretics salicylic acid and derivative Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229910002090 carbon oxide Inorganic materials 0.000 claims description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid 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](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 2
- 229960003964 deoxycholic acid Drugs 0.000 claims description 2
- 150000005205 dihydroxybenzenes Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 150000002206 flavan-3-ols Chemical class 0.000 claims description 2
- 235000011987 flavanols Nutrition 0.000 claims description 2
- 150000002211 flavins Chemical class 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 150000002989 phenols Chemical class 0.000 claims description 2
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical class S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 claims description 2
- BDLNCFCZHNKBGI-UHFFFAOYSA-N 1-nitro-4-(4-nitrophenyl)benzene Chemical group C1=CC([N+](=O)[O-])=CC=C1C1=CC=C([N+]([O-])=O)C=C1 BDLNCFCZHNKBGI-UHFFFAOYSA-N 0.000 claims 1
- XPGUQALNGZNWRM-UHFFFAOYSA-L 4-methylpyridine;nickel(2+);dithiocyanate Chemical class CC1=CC=NC=C1.CC1=CC=NC=C1.CC1=CC=NC=C1.CC1=CC=NC=C1.N#CS[Ni]SC#N XPGUQALNGZNWRM-UHFFFAOYSA-L 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 claims 1
- 229940039231 contrast media Drugs 0.000 abstract 1
- 239000013078 crystal Substances 0.000 description 60
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 40
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 238000001035 drying Methods 0.000 description 21
- 239000005968 1-Decanol Substances 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 12
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 12
- 239000003981 vehicle Substances 0.000 description 11
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000007789 gas Substances 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 8
- CRSOQBOWXPBRES-UHFFFAOYSA-N neopentane Chemical compound CC(C)(C)C CRSOQBOWXPBRES-UHFFFAOYSA-N 0.000 description 8
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 7
- 229910052724 xenon Inorganic materials 0.000 description 7
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 7
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 6
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 6
- 239000001282 iso-butane Substances 0.000 description 6
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 5
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 5
- 239000001273 butane Substances 0.000 description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 description 5
- 239000001569 carbon dioxide Substances 0.000 description 5
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 5
- 239000001294 propane Substances 0.000 description 5
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical compound FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 description 5
- 229960000909 sulfur hexafluoride Drugs 0.000 description 5
- 238000002604 ultrasonography Methods 0.000 description 5
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 229940102396 methyl bromide Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 238000000338 in vitro Methods 0.000 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 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 2
- 239000006163 transport media Substances 0.000 description 2
- BLIQUJLAJXRXSG-UHFFFAOYSA-N 1-benzyl-3-(trifluoromethyl)pyrrolidin-1-ium-3-carboxylate Chemical compound C1C(C(=O)O)(C(F)(F)F)CCN1CC1=CC=CC=C1 BLIQUJLAJXRXSG-UHFFFAOYSA-N 0.000 description 1
- NRZSTQWBQJYRAN-UHFFFAOYSA-N 4-(2,2,4-trimethyl-3h-thiochromen-4-yl)phenol Chemical compound C12=CC=CC=C2SC(C)(C)CC1(C)C1=CC=C(O)C=C1 NRZSTQWBQJYRAN-UHFFFAOYSA-N 0.000 description 1
- BNUBERJHAGFSPV-UHFFFAOYSA-N 4-methylpyridine;nickel(2+) Chemical compound [Ni+2].CC1=CC=NC=C1.CC1=CC=NC=C1.CC1=CC=NC=C1.CC1=CC=NC=C1 BNUBERJHAGFSPV-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- BMYPQOLESFVQPA-UHFFFAOYSA-N O=[Xe]=O Chemical compound O=[Xe]=O BMYPQOLESFVQPA-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- RBFQJDQYXXHULB-UHFFFAOYSA-N arsane Chemical compound [AsH3] RBFQJDQYXXHULB-UHFFFAOYSA-N 0.000 description 1
- 229910000070 arsenic hydride Inorganic materials 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004720 cerebrum Anatomy 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 150000001913 cyanates Chemical class 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 210000001214 frontal sinus Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910052743 krypton Inorganic materials 0.000 description 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000010297 mechanical methods and process Methods 0.000 description 1
- 230000005226 mechanical processes and functions Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 229910052704 radon Inorganic materials 0.000 description 1
- SYUHGPGVQRZVTB-UHFFFAOYSA-N radon atom Chemical compound [Rn] SYUHGPGVQRZVTB-UHFFFAOYSA-N 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 235000010269 sulphur dioxide Nutrition 0.000 description 1
- 239000004291 sulphur dioxide Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- SANRKQGLYCLAFE-UHFFFAOYSA-H uranium hexafluoride Chemical compound F[U](F)(F)(F)(F)F SANRKQGLYCLAFE-UHFFFAOYSA-H 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- ARUUTJKURHLAMI-UHFFFAOYSA-N xenon hexafluoride Chemical compound F[Xe](F)(F)(F)(F)F ARUUTJKURHLAMI-UHFFFAOYSA-N 0.000 description 1
- RPSSQXXJRBEGEE-UHFFFAOYSA-N xenon tetrafluoride Chemical compound F[Xe](F)(F)F RPSSQXXJRBEGEE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/189—Host-guest complexes, e.g. cyclodextrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/228—Host-guest complexes, clathrates, chelates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Landscapes
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Abstract
The invention relates to the use of cavity- or clathrate-forming host/guest complexes as contrast media in ultrasonic, X-ray or NMR investigations.
Description
The invention relates to a preparation comprising cavitate or clathrate host/guest complexes, the host molecules of which are dissolved in a fluid vehicle to release the guest, as contrast agents in ultrasonic, Xray or NMR investigations.
The manufacture of stoichiometric host-guest complexes comprising host molecules, essentially organic onium compounds and gases or gas formers as guest molecules, has been described in the literature (Angew. Chem. 97 (1985) 721). The use of the host/guest complexes as contrast agents has not been described.
The invention is based on the problem of providing for ultrasonic, X-ray or NMR investigations a preparation that can be used as a transport medium for contrast agents. In particular the invention is to provide host/guest complexes which store the largest possible guest volume in a minimal host mass.
It has surprisingly been found that the mentioned cavitate or clathrate host/guest complexes form a transport medium which can completely decompose and can be so selected that they do not exert any toxic influence on the biological substance in which the investigation is to be carried out.
Advantageously, the preparation used for ultrasonic investigation may comprise as host molecules: water, urea and derivatives thereof, thiourea and derivatives thereof, phenol and substituted phenols, dihydroxybenzenes and derivatives thereof, hydroquinone and substituted hydroquinones, salicylic acid and derivatives thereof, tri-o-thymotide and derivatives thereof, ascorbic acid, flavins and derivatives thereof, flavanols and derivatives thereof, cyclophanes and derivatives thereof, guaiacamin, naphthohydroguinones and derivatives thereof, cyclodextrin and derivatives thereof, especially dimethyl-l-cyclodextrin, methyl-β5 cyclodextrin, hydroxypropyl-fi-dextrin, chromans and derivatives thereof, especially 4-p-hydroxyphenyl-2,2,4trimethylchroman, 4-p-hydroxyphenyl-2,2,4-trimethylthiochroman, 4-p-hydroxyphenyl-2,2,4,7-tetramethylthiochroman, 4-p-hydroxyphenyl-2,2,4-trimethylselenium10 chroman, hexahost compounds, especially hexakis(phenylthio) benzene and derivatives thereof, cyclotriveratrylene and derivatives thereof, 1,1'-binaphthyl-2,2'dicarboxylic acid and derivatives thereof, onium compounds and derivatives thereof, acetylsalicylic acid, di15 , tri- and tetra-salicylides, 9,9'-spirobifluorene-2,2'dicarboxylic acid, choleinic acids, 4,4·-dinitrodiphenyl, bis-(N,N*-alkylene-benzidine), bis-(N,N*-tetramethylenebenzidine), deoxy cholic acid, monoaminonickel(II) cyanide, tetra(4-methylpyridine)-nickel(II) dithio20 cyanates and derivatives thereof, hexamethylisocyanidoferronchlorides, 2-phenyl-3-p( 2,2,4-trimethylchroman-4yl)-phenylquinazoline-4, cyclotriphosphazones, tris-1,2phenyldioxycyclotriphosphazones and as guest molecules: inert gases and inert gas compounds, sulphur halides, nitrogen and nitrogen oxides, carbon oxides, hydrogen and hydrogen oxides, sulphur oxides, hydrogen phosphides, hydrogen halides, uranium halides and oxygen as well as hydrocarbons and derivatives thereof, epoxides, ethers and halogenated hydrocarbons.
The preparation used for ultrasonic investigation may especially advantageously comprise as guest molecules helium, neon, argon, krypton, xenon, radon, sulphur hexafluoride, hydrogen, hydrogen peroxide, nitrogen monoxide, carbon monoxide, carbon dioxide, hydrogen iodide, xenon difluoride, xenon tetrafluoride, xenon hexafluoride, xenon dioxide, sulphur dioxide, sulphur trioxide, arsenic hydride, hydrogen phosphide, deuterium, uranium hexafluoride, methane, ethene, propane, cyclopropane, butane, pentane, ethylene oxide and methyl bromide.
The crystalline complexes can be influenced in their particle size especially by the crystallisation conditions and also by the mechanical processes of the particle breakdown (air jet milling).
The crystalline complexes may be coated with hydrophilic, lipophilic or amphiphilic excipients.
Suitable vehicles for applying the complexes are sterile aqueous systems with additives to adjust the viscosity, surface tension, pH value and osmotic pressure, in which vehicles the complexes are preferably dissolved, or alternatively suspended and optionally emulsified, prior to use.
The host/guest complexes are introduced into an aqueous vehicle. As the host molecules dissolve the complexes are broken down, releasing gas bubbles into the vehicle. The host molecules dissolved in the vehicle no longer have any complexing properties. The rate of the gas release and the size and duration of the gas bubbles can be adjusted within a wide range by means of the type of gas or gas-former enclosed, by means of the type of host molecule and the surface or particle size, as a function of the viscosity and surface tension of the vehicle.
It is thus surprisingly possible to obtain in a very simple manner injectable, gas-containing pharmaceutical preparations with excellent echogenic properties.
In particular it is possible to prepare the gas volume of about 150 μΐ required for the in vivo contrasting, for example, of the left ventricle of a human being, using very small amounts of active ingredient in the range from 2-10 mg/administration, as shown by the following composition: hydroquinone/N2 3:1 complex 1 mg 70 μΐ 10 hydroquinone/Xe 3:1 1 mg 53 μΐ dianin/SFg 3:1 ft 1 mg 26 μΐ dianin/argon 2:1 ft 1 mg 26 μΐ tri-o-thymotide/methane 2:1 tt 1 mg 23 μΐ tri-o-thymotide CI^Br 2:1 tt 1 mg 21 μΐ 15 dianin/N2 1 mg 103 μΐ 4-(4-hydroxyphenyl)-2,2,4-trimethyl-chroman) is designated dianin and is produced according to J. Russ Phys. Chem. Soc. 46, 1310 (1914) and Chem. Zentr. 1915, I, 1063.
It is thus possible to prepare a contrast agent for ultrasonic diagnostics which after intravenous administration is able to render visible for ultrasound the blood and its flow conditions on the right-hand side of the heart and, after passing through the pulmonary capillary bed, on the left-hand side of the heart.
Furthermore, it should also render possible the display of the circulation to other organs, such as the myocardium, liver, spleen and kidneys. It can similarly be used to display the efferent urinary ducts, gastro3q intestinal tract, joints, frontal sinus and eyes.
Especially when using gas molecules (e.g. xenon) that are able to overcome the blood/brain barrier, it is also possible to display the cerebrum and its physiological and pathological structures by means of ultrasound.
If the preparation according to the invention contains, for example, xenon, then it is possible to use that host/guest complex as an X-ray contrast agent. When using stable radicals (e.g. oxygen, nitroxyl) the preparations according to the invention can also be used as NMR contrast agents.
The invention is explained in the following by way of Examples. 1. Tri-o-thymotide/methyl bromide Tri-o-thymotide (25 g) was dissolved in 2,2,4-trimethylpentane (50 ml) at 100*C and the hot solution was introduced into a high-pressure autoclave. Methyl bromide was added to the autoclave until a pressure of 200 bar was reached. The high-pressure autoclave was kept at 110*C for 2 hours and the solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 3 times with cold 2,2,4-trimethylpentane; the crystals were then dried in a drying cabinet at 50*C. 2. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/ethylene oxide Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed ethylene oxide of 300 bar. The high-pressure autoclave was kept at 140*C for 2 hours and the solution was then cooled down to room temperature within 8 days.
The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml); the crystals were then dried in a drying cabinet at 100*C. 3. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/sulphur hexafluoride Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed sulphur hexafluoride of 300 bar. The highpressure autoclave was kept at 140’C for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100‘C. 4. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/ethane Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed ethane of 300 bar. The high-pressure autoclave was kept at 140’c for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100’C.
. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/propane Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to Ί compressed propane of 300 bar. The high-pressure autoclave was kept at 140*C for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100‘C. 6. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/carbon dioxide Dianin compound (25 g) was dissolved in 1-decanol (35 g) 10 at 125’C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed carbon dioxide of 300 bar. The high-pressure autoclave was kept at 140’C for 2 hours. The solution was then cooled down to room temperature within 8 days. 13 The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100‘c. 7. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/cyclopropane Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed cyclopropane of 300 bar. The high-pressure autoclave was kept at 140'c for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100’c. 8. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/methane Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed methane of 300 bar. The high-pressure autoclave was kept at 140*C for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100*C. 9. Dianin compound ( 4-p-hydroxyphenyl-2,2,4-trimethy 1chroman)/nitrogen Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed nitrogen of 300 bar. The high-pressure autoclave was kept at 140*C for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100*C.
Melting point: 162.88*C.
. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethylchroman)/xenon Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed xenon of 300 bar. The high-pressure autoclave was kept at 140*C for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100*C. 11. Dianin compound (4-p-hydroxyphenyl-2,2,4-trimethyl5 chroman)/argon Dianin compound (25 g) was dissolved in 1-decanol (35 g) at 125*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed argon of 300 bar. The high-pressure autoclave was kept at 140*C for 2 hours. The solution was then cooled down to room temperature within 8 days. The crystals were filtered off and washed 4 times with cold 1-decanol (5 ml). The crystals were then dried in a drying cabinet at 100*C. '5 Melting point: 160.84*C. 12. Hydroguinone/methane Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70’C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to 2o compressed methane of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a 25 drying cabinet at 70*C. 13. Hydroquinone/sulphur hexafluoride Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed sulphur hexafluoride of 300 bar. The high10 pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C. 14. Hydroquinone/propane Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed propane of 300 bar. The high-pressure autoclave was kept at 80’C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a 15 drying cabinet at 70*C.
. Hydroquinone/ethane Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed ethane of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C. 16. Hydroquinone/carbon dioxide Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed carbon dioxide of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C. 17. Hydroquinone/ethylene oxide Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70 *C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed ethylene oxide of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C. 18. Hydroquinone/cyclopropane Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed cyclopropane of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C. 19. Hydroquinone/nitrogen Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70*C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed nitrogen of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C.
Melting point: 176.92*C.
. Hydroquinone/xenon Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70’C. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed xenon of 300 bar. The high-pressure autoclave was kept at 80*C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C. 21. Hydroquinone/argon Hydroquinone (30 g) was dissolved in n-propanol (70 ml) at 70’c. The hot solution was introduced into a highpressure autoclave. The solution was subjected to compressed argon of 300 bar. The high-pressure autoclave was kept at 80C for 2 hours. The solution was then cooled down to room temperature within 5 days. The crystals were filtered off and washed 4 times with cold n-propanol (5 ml). The crystals were then dried in a drying cabinet at 70*C.
Melting point: 175.67*C. 22. Urea/butane g of urea were dissolved in 12 ml of ethanol at 60*C. The solution was then placed in a high-pressure auto13 clave and subjected to a butane pressure of 150 bar.
The solution was cooled from 60*C down to room temperature within 48 hours. The solution with h/g crystals was removed from the autoclave and filtered and the h/g crystals were washed with 10 ml of cold ethanol. The h/g complex crystals were dried in a vacuum cabinet at 60*C. 23. Urea/isobutane g of urea were dissolved in 12 ml of ethanol at 60*C. The solution was then placed in a high-pressure autoclave and subjected to an isobutane pressure of 150 bar. The solution was cooled from 60 ’C down to room temperature within 48 hours. The solution with h/g crystals was removed from the autoclave and filtered and the h/g crystals were washed with 10 ml of cold ethanol. The h/g complex crystals were dried in a vacuum cabinet at 60*C. Melting point: 138.50*C. 24. Urea/neopentane g of urea were dissolved in 12 ml of ethanol at 60‘C. The solution was then placed in a high-pressure autoclave and subjected to a neopentane pressure of 150 bar. The solution was cooled from 60*C down to room temperature within 48 hours. The solution with h/g crystals was removed from the autoclave and filtered and the h/g crystals were washed with 10 ml of cold ethanol. The h/g complex crystals were dried in a vacuum cabinet at 60 ’C. Melting point: 138.79*C.
. Thiourea/butane g of thiourea were dissolved in 12 ml of ethanol at 60*C. The solution was then placed in a high-pressure autoclave and subjected to a butane pressure of 150 bar.
The solution was cooled down to room temperature within 60 hours. The solution with h/g crystals was removed from the autoclave and filtered and the h/g crystals were washed with 10 ml of cold ethanol. The h/g complex crystals were dried in a vacuum cabinet at 60*C. 26. Thiourea/isobutane g of thiourea were dissolved in 20 ml of ethanol at 60*C. The solution was then placed in a high-pressure autoclave and subjected to an isobutane pressure of 150 bar. The solution was cooled down to room temperature within 60 hours. The solution with h/g crystals was removed from the autoclave and filtered and the h/g crystals were washed with 10 ml of cold ethanol. The h/g complex crystals were dried in a vacuum cabinet at 60*C. Melting point: 181.34’C. 27. Thiourea/neopentane g of thiourea were dissolved in 20 ml of ethanol at 60*C. The solution was then placed in a high-pressure autoclave and subjected to a neopentane pressure of 150 bar. The solution was cooled down to room temperature within 60 hours. The solution with h/g crystals was removed from the autoclave and filtered and the h/g crystals were washed with 10 ml of cold ethanol. The h/g complex crystals were dried in a vacuum cabinet at 60*C. 28. Vehicle A: The following solutions, for example, are suitable as a vehicle for hydroquinone, tri-O-thymotide, urea and thiourea h/g complexes: a) 1 % gelatine solution b) 1 % albumin solution c) 10 % glycerol solution d) 15 % propylene glycol solution e) mixtures of sodium cholate and phosphatidylcholine in water f) 0.01-1 % phosphatidylcholine dispersion (aqueous) g) 1 % methylcellulose h) 1-2 % dextran solution i) 1 % agar solution j) 2 % Tween solution (Tween 80/§) k) 1 % gum arabic B: The following vehicles are suitable dianin h/g complexes: a) 10-20 % 2-(2-methoxyethoxy)-ethanol b) mixtures of 2-(2-methoxyethoxy)-ethanol (20 %) and Tween 8<® (1 %) In vitro ultrasonic investigations The acoustic properties of the h/g complex-vehicle system were determined by in-vitro ultrasonic investigations.
For this, about 1-5 mg of the h/g complexes were mixed in 20 10-20 ml with one of the said vehicles and then examined using ultrasonic scanners.
The ultrasonic scanner Ekoline 20A/S was used in the frequency range 1-5 MHz for qualitative examinations.
Quantitative measurements of the acoustic properties were obtained in an apparatus with the ultrasonic scanner Kraut-Kraemer U.S.I. P-12 at 4 MHz. The results of four systems are detailed here by way of example (Figs. 1-4).
Fig. 1: Urea/isobutane (Example 23) in 2 % Tween 80 solution Fig. 2: Thiourea/isobutane (Example 26) in 1 % dextran solution 5 Fig. 3: Hydroquinone/argon (Example 21) in 1 % gelatine solution Fig. 4: Dianin/argon (Example 11) in 10 % 2-(2methoxyethoxy)-ethanol.
To explain the ultrasonic measuring apparatus and the diagrams obtained therefrom: The apparatus comprises an ultrasonic transmitter combined with a receiver and measuring bulb which contains the specimen. An ultrasonic pulse is transmitted to measure the acoustic properties of the speci15 men. Backscattered ultrasound is measured by the receiver and indicated by a change in the amplitude (see diagram). The diagrams each show only one amplitude change which results from the backscattering of the ultrasound at the front wall of the measuring bulb. A second amplitude change which results from backscattering at the back wall of the measuring bulb is obtained only with non-echogenic substances (for example water). In the case of echogenic substances a second backscattered signal is not obtained since the ultrasound is dissipated in the specimen or so changed that it can no longer be received.
Claims (3)
1. Preparation comprising cavitate or clathrate host/guest (h/g) complexes, the host molecules of which are dissolved in a fluid vehicle to release the guest, as contrast agents in ultrasonic, X-ray or NMR investigations.
2. Preparation according to claim 1 for ultrasonic investigation comprising as host molecules: water, urea and derivatives thereof, thiourea and derivatives thereof, phenol and substituted phenols, dihydroxybenzenes and derivatives thereof, hydroquinone and substituted hydroquinones, salicylic acid and derivatives thereof, tri-o-thymotide and derivatives thereof, ascorbic acid, flavins and derivatives thereof, flavanols and derivatives thereof, cyclophanes and derivatives thereof, guaiacamin, naphthohydroquinones and derivatives thereof, chromans and derivatives thereof, especially 4-p-hydroxyphenyl-2,2,4-trimethylchroman, 4-phydroxyphenyl-2,2,4-trimethylthiochroman, 4-p-hydroxyphenyl-2,2,4,7-tetramethylthiochroman, 4-p-hydroxyphenyl2,2,4-trimethylseleniumchroman, hexahost compounds, especially hexakis(phenylthio)benzene and derivatives thereof, cyclotriveratrylene and derivatives thereof, 1,1'-binaphthyl-2,2'-dicarboxylic acid and derivatives thereof, onium compounds and derivatives thereof, acetylsalicylic acid, di-, tri- and tetra-salicylides, 9,9'-spirobifluorene-2,2'-dicarboxylic acid, choleinic acids, 4,4'-dinitrodiphenyl, bis-(N,N'-alkylene-benzidine), bis-(N,N'-tetramethylene-benzidine), deoxycholic acid, monoaminonickel(II) cyanide, tetra(4-methylpyridine)-nickel(II) dithiocyanates and derivatives thereof, hexamethylisocyanidoferronchlorides, 2-phenyl-3p(2,2,4-trimethylchroman-4-yl)-phenylquinazoline-4, cyclotriphosphazones, tris-1,2-phenyldioxycyclotriphosphazones 5 and as guest molecules: inert gases and inert gas compounds, sulphur halides, nitrogen and nitrogen oxides, carbon oxides, hydrogen and hydrogen oxides, sulphur oxides, hydrogen phosphides, hydrogen halides, uranium halides and oxygen as well as 10 hydrocarbons and derivatives thereof, epoxides, ethers and halogenated hydrocarbons.
3. A preparation substantially as hereinbefore described with reference to the Examples and drawings.
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-
1988
- 1988-08-23 DE DE3828905A patent/DE3828905A1/en not_active Ceased
-
1989
- 1989-08-18 EP EP89250016A patent/EP0357163B1/en not_active Expired - Lifetime
- 1989-08-18 WO PCT/DE1989/000548 patent/WO1990001952A1/en unknown
- 1989-08-18 ES ES89250016T patent/ES2042986T3/en not_active Expired - Lifetime
- 1989-08-18 AT AT89250016T patent/ATE76758T1/en not_active IP Right Cessation
- 1989-08-18 AU AU40651/89A patent/AU641363B2/en not_active Ceased
- 1989-08-18 JP JP01508694A patent/JP3142539B2/en not_active Expired - Fee Related
- 1989-08-18 DE DE8989250016T patent/DE58901585D1/en not_active Expired - Lifetime
- 1989-08-18 IE IE268589A patent/IE65168B1/en not_active IP Right Cessation
- 1989-08-22 PT PT91501A patent/PT91501B/en not_active IP Right Cessation
-
1991
- 1991-02-21 DK DK030391A patent/DK30391D0/en not_active Application Discontinuation
- 1991-02-22 NO NO910711A patent/NO302101B1/en not_active IP Right Cessation
-
1992
- 1992-08-20 GR GR920401406T patent/GR3005457T3/el unknown
Also Published As
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AU4065189A (en) | 1990-03-23 |
JPH04501559A (en) | 1992-03-19 |
DK30391A (en) | 1991-02-21 |
DE58901585D1 (en) | 1992-07-09 |
DK30391D0 (en) | 1991-02-21 |
NO302101B1 (en) | 1998-01-26 |
PT91501B (en) | 1995-05-31 |
DE3828905A1 (en) | 1990-03-15 |
PT91501A (en) | 1990-03-08 |
AU641363B2 (en) | 1993-09-23 |
WO1990001952A1 (en) | 1990-03-08 |
NO910711L (en) | 1991-02-22 |
JP3142539B2 (en) | 2001-03-07 |
NO910711D0 (en) | 1991-02-22 |
ATE76758T1 (en) | 1992-06-15 |
GR3005457T3 (en) | 1993-05-24 |
ES2042986T3 (en) | 1993-12-16 |
EP0357163A1 (en) | 1990-03-07 |
IE892685L (en) | 1990-02-23 |
EP0357163B1 (en) | 1992-06-03 |
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MM4A | Patent lapsed |