AU667491B2 - Gel particle contrast media for improved diagnostic imaging - Google Patents
Gel particle contrast media for improved diagnostic imagingInfo
- Publication number
- AU667491B2 AU667491B2 AU28940/92A AU2894092A AU667491B2 AU 667491 B2 AU667491 B2 AU 667491B2 AU 28940/92 A AU28940/92 A AU 28940/92A AU 2894092 A AU2894092 A AU 2894092A AU 667491 B2 AU667491 B2 AU 667491B2
- Authority
- AU
- Australia
- Prior art keywords
- contrast medium
- polymer
- contrast
- metal
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 239000002872 contrast media Substances 0.000 title claims description 126
- 239000007863 gel particle Substances 0.000 title claims description 51
- 229940039231 contrast media Drugs 0.000 title description 29
- 238000002059 diagnostic imaging Methods 0.000 title description 3
- 229920000642 polymer Polymers 0.000 claims description 117
- 229910052751 metal Inorganic materials 0.000 claims description 90
- 239000002184 metal Substances 0.000 claims description 90
- 230000002708 enhancing effect Effects 0.000 claims description 57
- 239000011572 manganese Substances 0.000 claims description 56
- 229920002230 Pectic acid Polymers 0.000 claims description 53
- 239000010318 polygalacturonic acid Substances 0.000 claims description 50
- 238000003384 imaging method Methods 0.000 claims description 37
- 229920001277 pectin Polymers 0.000 claims description 37
- 239000001814 pectin Substances 0.000 claims description 37
- 235000010987 pectin Nutrition 0.000 claims description 37
- 150000002739 metals Chemical class 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 32
- 239000003349 gelling agent Substances 0.000 claims description 28
- -1 polyethylenes Polymers 0.000 claims description 22
- 238000002595 magnetic resonance imaging Methods 0.000 claims description 19
- 230000005298 paramagnetic effect Effects 0.000 claims description 16
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims description 14
- 150000001768 cations Chemical class 0.000 claims description 14
- 229920001282 polysaccharide Polymers 0.000 claims description 14
- 239000005017 polysaccharide Substances 0.000 claims description 14
- 150000004804 polysaccharides Chemical class 0.000 claims description 14
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 13
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 11
- 229910001385 heavy metal Inorganic materials 0.000 claims description 10
- 235000000346 sugar Nutrition 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 8
- 150000005846 sugar alcohols Polymers 0.000 claims description 8
- 150000008163 sugars Chemical class 0.000 claims description 8
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 7
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 6
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims description 6
- 229910052692 Dysprosium Inorganic materials 0.000 claims description 6
- 229910052688 Gadolinium Inorganic materials 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- 229910052769 Ytterbium Inorganic materials 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 claims description 6
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 claims description 6
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 6
- 238000006198 methoxylation reaction Methods 0.000 claims description 6
- 238000012285 ultrasound imaging Methods 0.000 claims description 6
- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 claims description 6
- 238000009007 Diagnostic Kit Methods 0.000 claims description 5
- 235000010443 alginic acid Nutrition 0.000 claims description 5
- 229920000615 alginic acid Polymers 0.000 claims description 5
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims description 5
- 229920002678 cellulose Polymers 0.000 claims description 5
- 229910052742 iron Inorganic materials 0.000 claims description 5
- 229920001983 poloxamer Polymers 0.000 claims description 5
- 229920000936 Agarose Polymers 0.000 claims description 4
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-IVMDWMLBSA-N D-allopyranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-IVMDWMLBSA-N 0.000 claims description 4
- 229930091371 Fructose Natural products 0.000 claims description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 4
- 239000005715 Fructose Substances 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-VSOAQEOCSA-N L-altropyranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-VSOAQEOCSA-N 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 4
- 239000003242 anti bacterial agent Substances 0.000 claims description 4
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 229930182830 galactose Natural products 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 229920000573 polyethylene Polymers 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 3
- OEANUJAFZLQYOD-CXAZCLJRSA-N (2r,3s,4r,5r,6r)-6-[(2r,3r,4r,5r,6r)-5-acetamido-3-hydroxy-2-(hydroxymethyl)-6-methoxyoxan-4-yl]oxy-4,5-dihydroxy-3-methoxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](OC)O[C@H](CO)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](OC)[C@H](C(O)=O)O1 OEANUJAFZLQYOD-CXAZCLJRSA-N 0.000 claims description 3
- ZFTFOHBYVDOAMH-XNOIKFDKSA-N (2r,3s,4s,5r)-5-[[(2r,3s,4s,5r)-5-[[(2r,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxymethyl]-3,4-dihydroxy-2-(hydroxymethyl)oxolan-2-yl]oxymethyl]-2-(hydroxymethyl)oxolane-2,3,4-triol Chemical class O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@@H]1[C@@H](O)[C@H](O)[C@](CO)(OC[C@@H]2[C@H]([C@H](O)[C@@](O)(CO)O2)O)O1 ZFTFOHBYVDOAMH-XNOIKFDKSA-N 0.000 claims description 3
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 claims description 3
- 229920000945 Amylopectin Polymers 0.000 claims description 3
- 229920000856 Amylose Polymers 0.000 claims description 3
- 229920002101 Chitin Polymers 0.000 claims description 3
- 229920002567 Chondroitin Polymers 0.000 claims description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- YTBSYETUWUMLBZ-UHFFFAOYSA-N D-Erythrose Natural products OCC(O)C(O)C=O YTBSYETUWUMLBZ-UHFFFAOYSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-CBPJZXOFSA-N D-Gulose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-CBPJZXOFSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-WHZQZERISA-N D-aldose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-WHZQZERISA-N 0.000 claims description 3
- LKDRXBCSQODPBY-JDJSBBGDSA-N D-allulose Chemical compound OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O LKDRXBCSQODPBY-JDJSBBGDSA-N 0.000 claims description 3
- YTBSYETUWUMLBZ-IUYQGCFVSA-N D-erythrose Chemical compound OC[C@@H](O)[C@@H](O)C=O YTBSYETUWUMLBZ-IUYQGCFVSA-N 0.000 claims description 3
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 claims description 3
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 3
- AEMOLEFTQBMNLQ-VANFPWTGSA-N D-mannopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H]1O AEMOLEFTQBMNLQ-VANFPWTGSA-N 0.000 claims description 3
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 3
- ZAQJHHRNXZUBTE-NQXXGFSBSA-N D-ribulose Chemical compound OC[C@@H](O)[C@@H](O)C(=O)CO ZAQJHHRNXZUBTE-NQXXGFSBSA-N 0.000 claims description 3
- ZAQJHHRNXZUBTE-UHFFFAOYSA-N D-threo-2-Pentulose Natural products OCC(O)C(O)C(=O)CO ZAQJHHRNXZUBTE-UHFFFAOYSA-N 0.000 claims description 3
- YTBSYETUWUMLBZ-QWWZWVQMSA-N D-threose Chemical compound OC[C@@H](O)[C@H](O)C=O YTBSYETUWUMLBZ-QWWZWVQMSA-N 0.000 claims description 3
- ZAQJHHRNXZUBTE-WUJLRWPWSA-N D-xylulose Chemical compound OC[C@@H](O)[C@H](O)C(=O)CO ZAQJHHRNXZUBTE-WUJLRWPWSA-N 0.000 claims description 3
- 229920000045 Dermatan sulfate Polymers 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- 229910052691 Erbium Inorganic materials 0.000 claims description 3
- 206010056474 Erythrosis Diseases 0.000 claims description 3
- 229910052693 Europium Inorganic materials 0.000 claims description 3
- 229920002670 Fructan Polymers 0.000 claims description 3
- 229920000855 Fucoidan Polymers 0.000 claims description 3
- BXEARCKJAZWJTJ-IJCVXDJZSA-N Galactocarolose Natural products OC[C@H](O)[C@@H]1O[C@@H](O[C@H](CO)[C@@H]2O[C@@H](O[C@H](CO)[C@@H]3O[C@@H](O)[C@H](O)[C@@H]3O)[C@H](O)[C@@H]2O)[C@H](O)[C@@H]1O BXEARCKJAZWJTJ-IJCVXDJZSA-N 0.000 claims description 3
- 229920001503 Glucan Polymers 0.000 claims description 3
- 229920002527 Glycogen Polymers 0.000 claims description 3
- 229910052689 Holmium Inorganic materials 0.000 claims description 3
- 102000011782 Keratins Human genes 0.000 claims description 3
- 108010076876 Keratins Proteins 0.000 claims description 3
- 208000007976 Ketosis Diseases 0.000 claims description 3
- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 claims description 3
- 229920000057 Mannan Polymers 0.000 claims description 3
- 239000004677 Nylon Substances 0.000 claims description 3
- 239000004743 Polypropylene Substances 0.000 claims description 3
- 239000004793 Polystyrene Substances 0.000 claims description 3
- 229920001218 Pullulan Polymers 0.000 claims description 3
- 239000004373 Pullulan Substances 0.000 claims description 3
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 3
- 229910052772 Samarium Inorganic materials 0.000 claims description 3
- 229920002125 Sokalan® Polymers 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 150000001323 aldoses Chemical group 0.000 claims description 3
- 239000000783 alginic acid Substances 0.000 claims description 3
- 229960001126 alginic acid Drugs 0.000 claims description 3
- 150000004781 alginic acids Chemical class 0.000 claims description 3
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 3
- SRBFZHDQGSBBOR-STGXQOJASA-N alpha-D-lyxopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-STGXQOJASA-N 0.000 claims description 3
- 150000001412 amines Chemical group 0.000 claims description 3
- 239000006172 buffering agent Substances 0.000 claims description 3
- 229920001525 carrageenan Polymers 0.000 claims description 3
- 239000000679 carrageenan Substances 0.000 claims description 3
- 235000010418 carrageenan Nutrition 0.000 claims description 3
- 229940113118 carrageenan Drugs 0.000 claims description 3
- 239000001913 cellulose Substances 0.000 claims description 3
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 claims description 3
- 229910052804 chromium Inorganic materials 0.000 claims description 3
- 239000011651 chromium Substances 0.000 claims description 3
- 229910017052 cobalt Inorganic materials 0.000 claims description 3
- 239000010941 cobalt Substances 0.000 claims description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- UYAHIZSMUZPPFV-UHFFFAOYSA-N erbium Chemical compound [Er] UYAHIZSMUZPPFV-UHFFFAOYSA-N 0.000 claims description 3
- UQPHVQVXLPRNCX-UHFFFAOYSA-N erythrulose Chemical compound OCC(O)C(=O)CO UQPHVQVXLPRNCX-UHFFFAOYSA-N 0.000 claims description 3
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 claims description 3
- 239000000174 gluconic acid Substances 0.000 claims description 3
- 235000012208 gluconic acid Nutrition 0.000 claims description 3
- 229940097043 glucuronic acid Drugs 0.000 claims description 3
- 229940096919 glycogen Drugs 0.000 claims description 3
- 229910052735 hafnium Inorganic materials 0.000 claims description 3
- VBJZVLUMGGDVMO-UHFFFAOYSA-N hafnium atom Chemical compound [Hf] VBJZVLUMGGDVMO-UHFFFAOYSA-N 0.000 claims description 3
- KJZYNXUDTRRSPN-UHFFFAOYSA-N holmium atom Chemical compound [Ho] KJZYNXUDTRRSPN-UHFFFAOYSA-N 0.000 claims description 3
- 229920002674 hyaluronan Polymers 0.000 claims description 3
- 229960003160 hyaluronic acid Drugs 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- 229920003063 hydroxymethyl cellulose Polymers 0.000 claims description 3
- 229940031574 hydroxymethyl cellulose Drugs 0.000 claims description 3
- 229910052738 indium Inorganic materials 0.000 claims description 3
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 claims description 3
- BJHIKXHVCXFQLS-PQLUHFTBSA-N keto-D-tagatose Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-PQLUHFTBSA-N 0.000 claims description 3
- 150000002584 ketoses Chemical group 0.000 claims description 3
- 229910052746 lanthanum Inorganic materials 0.000 claims description 3
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 claims description 3
- AIHDCSAXVMAMJH-GFBKWZILSA-N levan Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@@H]1[C@@H](O)[C@H](O)[C@](CO)(CO[C@@H]2[C@H]([C@H](O)[C@@](O)(CO)O2)O)O1 AIHDCSAXVMAMJH-GFBKWZILSA-N 0.000 claims description 3
- LUEWUZLMQUOBSB-GFVSVBBRSA-N mannan Chemical class O[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@H]3[C@H](O[C@@H](O)[C@@H](O)[C@H]3O)CO)[C@@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-GFVSVBBRSA-N 0.000 claims description 3
- CERZMXAJYMMUDR-UHFFFAOYSA-N neuraminic acid Natural products NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO CERZMXAJYMMUDR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- 229920001778 nylon Polymers 0.000 claims description 3
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 3
- 229920000058 polyacrylate Polymers 0.000 claims description 3
- 229920001155 polypropylene Polymers 0.000 claims description 3
- 229920002223 polystyrene Polymers 0.000 claims description 3
- 229920002635 polyurethane Polymers 0.000 claims description 3
- 239000004814 polyurethane Substances 0.000 claims description 3
- 235000019423 pullulan Nutrition 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- KZUNJOHGWZRPMI-UHFFFAOYSA-N samarium atom Chemical compound [Sm] KZUNJOHGWZRPMI-UHFFFAOYSA-N 0.000 claims description 3
- 229920001059 synthetic polymer Polymers 0.000 claims description 3
- 229910052713 technetium Inorganic materials 0.000 claims description 3
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052727 yttrium Inorganic materials 0.000 claims description 3
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 claims description 3
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 claims description 3
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229960002442 glucosamine Drugs 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- CERZMXAJYMMUDR-QBTAGHCHSA-N 5-amino-3,5-dideoxy-D-glycero-D-galacto-non-2-ulopyranosonic acid Chemical compound N[C@@H]1[C@@H](O)CC(O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO CERZMXAJYMMUDR-QBTAGHCHSA-N 0.000 claims 2
- AEMOLEFTQBMNLQ-YMDCURPLSA-N D-galactopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-YMDCURPLSA-N 0.000 claims 2
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 claims 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 2
- 125000002951 idosyl group Chemical class C1([C@@H](O)[C@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 229920002401 polyacrylamide Polymers 0.000 claims 2
- 229940032147 starch Drugs 0.000 claims 2
- 229920001285 xanthan gum Polymers 0.000 claims 2
- 239000000230 xanthan gum Substances 0.000 claims 2
- 235000010493 xanthan gum Nutrition 0.000 claims 2
- 229940082509 xanthan gum Drugs 0.000 claims 2
- 229920001221 xylan Polymers 0.000 claims 2
- 150000004823 xylans Chemical class 0.000 claims 2
- 239000000499 gel Substances 0.000 description 52
- 229910052748 manganese Inorganic materials 0.000 description 31
- 239000000243 solution Substances 0.000 description 31
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000011575 calcium Substances 0.000 description 12
- 238000001879 gelation Methods 0.000 description 12
- 230000014759 maintenance of location Effects 0.000 description 12
- 238000002604 ultrasonography Methods 0.000 description 12
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 11
- 229930006000 Sucrose Natural products 0.000 description 11
- 239000005720 sucrose Substances 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 229910052791 calcium Inorganic materials 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- 210000004185 liver Anatomy 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 7
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 7
- 238000004132 cross linking Methods 0.000 description 7
- 238000000502 dialysis Methods 0.000 description 7
- 230000002496 gastric effect Effects 0.000 description 7
- 239000011565 manganese chloride Substances 0.000 description 7
- 229910021645 metal ion Inorganic materials 0.000 description 7
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 6
- 230000026731 phosphorylation Effects 0.000 description 6
- 238000006366 phosphorylation reaction Methods 0.000 description 6
- 239000011148 porous material Substances 0.000 description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 description 5
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 229920002451 polyvinyl alcohol Polymers 0.000 description 5
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000013522 chelant Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 229920005615 natural polymer Polymers 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 210000005166 vasculature Anatomy 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical group [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000002591 computed tomography Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 230000005291 magnetic effect Effects 0.000 description 3
- 229910001437 manganese ion Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- FXYPGCIGRDZWNR-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-[[3-(2,5-dioxopyrrolidin-1-yl)oxy-3-oxopropyl]disulfanyl]propanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCSSCCC(=O)ON1C(=O)CCC1=O FXYPGCIGRDZWNR-UHFFFAOYSA-N 0.000 description 2
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000004971 Cross linker Substances 0.000 description 2
- ZFIVKAOQEXOYFY-UHFFFAOYSA-N Diepoxybutane Chemical compound C1OC1C1OC1 ZFIVKAOQEXOYFY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000012307 MRI technique Methods 0.000 description 2
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 150000001334 alicyclic compounds Chemical class 0.000 description 2
- 150000007824 aliphatic compounds Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229920006037 cross link polymer Polymers 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 150000002016 disaccharides Chemical class 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011503 in vivo imaging Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- QQHITEBEBQNARV-UHFFFAOYSA-N 3-[[2-carboxy-2-(2,5-dioxopyrrolidin-1-yl)-2-sulfoethyl]disulfanyl]-2-(2,5-dioxopyrrolidin-1-yl)-2-sulfopropanoic acid Chemical compound O=C1CCC(=O)N1C(S(O)(=O)=O)(C(=O)O)CSSCC(S(O)(=O)=O)(C(O)=O)N1C(=O)CCC1=O QQHITEBEBQNARV-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 0.000 description 1
- 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 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229920001202 Inulin Polymers 0.000 description 1
- 229910021577 Iron(II) chloride Inorganic materials 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229920006109 alicyclic polymer Polymers 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001735 carboxylic acids Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- LIKFHECYJZWXFJ-UHFFFAOYSA-N dimethyldichlorosilane Chemical compound C[Si](C)(Cl)Cl LIKFHECYJZWXFJ-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229920000140 heteropolymer Polymers 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 150000002454 idoses Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 1
- 229940029339 inulin Drugs 0.000 description 1
- 239000000193 iodinated contrast media Substances 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- BQINXKOTJQCISL-GRCPKETISA-N keto-neuraminic acid Chemical compound OC(=O)C(=O)C[C@H](O)[C@@H](N)[C@@H](O)[C@H](O)[C@H](O)CO BQINXKOTJQCISL-GRCPKETISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000002867 manganese chloride Nutrition 0.000 description 1
- 229940099607 manganese chloride Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000013365 molecular weight analysis method Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 238000001208 nuclear magnetic resonance pulse sequence Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002357 osmotic agent Substances 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920003226 polyurethane urea Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000007781 pre-processing Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
- G01R33/00—Arrangements or instruments for measuring magnetic variables
- G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
- G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
- G01R33/48—NMR imaging systems
- G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
- G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
- G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
-
- 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
- A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
- A61K49/0414—Particles, beads, capsules or spheres
-
- 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
- A61K49/1803—Semi-solid preparations, e.g. ointments, gels, hydrogels
-
- 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
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
- A61K49/1845—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule the small organic molecule being a carbohydrate (monosaccharides, discacharides)
-
- 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
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
- A61K49/1863—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
-
- 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
- A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
Description
TITLE
Gel Particle Contrast Media For Improved Diagnostic Imaging
REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of copending application Serial No. 507,125 filed April 10, 1990.
BACKGROUND OF THE INVENTION
Field of the Invention There are a .variety of imaging techniques that have been used to diagnose disease in humans. One of the first imaging techniques employed was X-rays. In X-rays, the images produced of the patients' body reflect the different densities of body structure. To improve the diagnostic utility of this imaging technique, contrast agents are employed to increase the density between various structures, such as between the gastrointestinal tract and its surrounding tissue. Barium and iodinated contrast media, for example, are used extensively for X-ray gastro- intestinal studies to visualize the esophagus, stomach, intestines and rectum.
Ultrasound is another imaging technique. In ultrasound, sound is transmitted into a patient via a transducer. When the sound waves propagate through the body, they encounter interfaces from tissues and fluids in the body, and the ultrasound sound waves are either reflected or absorbed. When sound waves are reflected by an interface they are detected by the receiver in the transducer and processed to form an image. The acoustic
properties of the tissues and fluids within the body determine the contrast which appears in the resultant image. Contrast agents have been sought which will increase the acoustic difference between the target area and the surrounding area. For example, heavy metals have been tested as contrast agents for ultrasound.
Magnetic resonance imaging (MRI) is a relatively new imaging technique which, unlike X-rays, does not utilize ionizing radiation. As in computed tomography, MRI can make cross-sectional images of the body, however, MRI has the additional advantage of being able to make images in any scan plane (i.e., axial, coronal, sagittal or orthogonal) . Unfortunately, the full utility of MRI as a diagnostic modality for the body is hampered by the lack of effective contrast agents. Contrast agents have been developed for MRI to improve detection of disease, but most of these efforts have been directed to using chelates of paramagnetic ions as contrast agents. Traditionally employed chelates have the disadvantage of decreasing the relaxivity of the chelate ion as well as potentially causing toxicity, should the metal ion escape from the chelate. Such chelates have the further disadvantage that they are rapidly cleared by the kidneys and do not work as effective contrast agents for imaging of the liver, for example. If better contrast agents were available, the overall usefulness of MRI as an imaging modality would improve.
New and/or better contrast agents for use in X-ray, ultrasound and MRI imaging, and in other imaging systems, are needed. The present invention is directed to these and other important ends.
SUMMARY OF THE INVENTION The present invention pertains to contrast media useful for diagnostic imaging. Specifically, in one aspect, the present invention is directed to contrast media comprising gel particles, preferably of less than about 90 μ in mean diameter, said gel particles comprising at least one polymer entrapping at least one contrast enhancing metal. Preferably the polymers employed are not cross- linked. The present invention also pertains to contrast media prepared by combining at least one polymer and at least one contrast enhancing metal, optionally in the presence of a gelling agent, to form a gel, and particularizing the mixture to form particles, as well as processes for preparing the same. The subject invention also pertains to methods for providing an image of an internal region of a patient, said methods comprising (i) administering to the patient one or more of the aforementioned contrast agents, and (ii) scanning the patient using magnetic resonance, ultrasound or X-ray imaging to obtain visible images of the region.
In addition, the present invention encompasses a method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient one or more of the foregoing contrast agents, and (ii) scanning the patient using magnetic resonance, ultrasound, or X-ray imaging to obtain visible images of any diseased tissue in the patient.
Further, kits comprising compounds of the present invention and conventional diagnostic kit components are provided.
These and other aspects of the invention will become more apparent from the following detailed description when taken in conjunction with the following drawing.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a schematic representation of a possible structural configuration for the gel particles of the invention. Specifically, Fig. la is a schematic representation showing the association of polymer chains by entrapment of metal ions according an "egg box" model. Fig. lb is a detail of the boxed region of Fig. la in which oxygen atoms are shown to coordinate with the divalent cation, Ca+2. Fig. lc is a schematic representation of a more complex structural configuration involving stacking of a number of polymer chains.
DETAILED DESCRIPTION OF THE INVENTION Contrast media comprising gel particles having one or more polymers entrapping one or more contrast enhancing metals are provided in the present invention.
These contrast media have been shown to be heat stable and stable in long term storage, both of obvious advantage in commercial use. They have also been shown to require a lower overall concentration of contrast enhancing metals, often to achieve the same or better imaging than some other metal-containing contrast media known heretofore. By minimizing the amount of metal, toxicity as well as cost may be reduced, since less of the often more expensive and potentially toxic metals are used. Contrast media of the invention have been found to be highly effective contrast agents, useful in many different applications.
Any of a wide variety of biocompatible polymers known in the art may be employed in preparing the media of the present invention. The term biocompatible, used herein in connection with the term polymer, is employed in its conventional sense, that is, to denote polymers that do not substantially interact with the tissues, fluids and other components of the body in an adverse fashion in the particular application of interest. As will be readily apparent to those skilled in the art, there are numerous types of such polymers available. For example, the
polymers useful in the present invention can be of natural, synthetic or semisynthetic origin. The term semisynthetic polymer, as employed herein, denotes a natural polymer that has been chemically modified in some fashion. Preferably, the polymer is natural or semisynthetic, most preferably natural. Further, as used herein, the term polymer denotes a compound comprised of two or more repeating monomeric units, preferably three or more repeating monomeric units, more preferably five or more repeating units, and most preferably ten or more repeating units.
Exemplary natural polymers suitable for use in the present invention may include naturally occurring polysaccharides such as, for example, arabinans, fructans, fucans, galactans, galacturonans, glucans, mannans, xylanε (such as, for example, inulin) , levan, fucoidan, carrageenan, galactocarolose, pectins, pectic acids, amylose, pullulan, glycogen, amylopectin, cellulose, dextran, pustulan, chitin, agarose, keratin, chondroitin, dermatan, hyaluronic acid, alginic acid, xanthin gum, starch, and various other natural homopolymers or heteropolymers such as those containing one or more of the following aldoses, ketoses, acids or amines: erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine and neuraminic acid; as well as naturally occurring derivatives thereof. Exemplary natural polymers may also include, for example, polypeptides and polyalcohols, as will be readily apparent to those skilled in the art. Exemplary semisynthetic polymers include such modified natural polymers as carboxymethylcellulose, hydroxymethylcellulose, hydroxypropyl ethylcellulose, methylcellulose and methoxycellulose. Exemplary synthetic polymers suitable for use in the present invention include polyethylenes (such as, for example, polyethylene glycol,
polyoxyethylene, polyoxyethylene glycol, and polyethylene terephthlate) , polypropylenes (such as, for example, polypropylene glycol) , polyurethanes (such as, for example, polyurethane ureas) , pluronic acids and alcohols, polyvinyls (such as, for example, polyvinyl alcohol, polyvinylchloride and polyvinylpyrrolidone) , nylon, polystyrene, polylactic acids, fluorinated hydrocarbons, fluorinated carbons (such as, for example, polytetrafluoroethylene) , polyacrylates (such as polymethylmethacrylate) , polyacrylic acids (such as polymethacrylic acid) and polyacryla ides, as well as derivatives thereof.
Such polymers may range in size, for example, from a molecular weight of about 500 to about 500,000. In some instances, the preferable molecular weight of the polymers is from about 100,000 to about 500,000. To suit other parameters, preferable molecular is from about 500 to about 100,000. Preferably, the polymer employed is one which has a relatively high water binding capacity, that is, a polymer which is capable of binding at least about 50% of its weight in water. When imaging of the gastrointestinal region is desired, preferably the polymer chosen is one which is not substantially absorbed from or degraded within the gastrointestinal region. Preferred polymers include polygalacturonic acid and pectins. As those skilled in the art are aware, pectins are generally methyl esters of polygalacturonic acid. Particularly preferred are low methoxy pectins. By the phrase "low methoxy", it is meant a pectin having less than about 40% methoxylation (that is, less than about 40% of the carboxylic acid groups are converted to methylesters) . As those skilled in the art will recognize, the degree of methoxylation of pectin may be measured by titrating the pectin with base. Numerous contrast enhancing metals which are suitable for use in the present invention are known to those skilled in the art and include, for example,
paramagnetic ions and/or heavy metal ions. Exemplary metals useful, for example, in magnetic resonance imaging include paramagnetic metal ions such as gadolinium, manganese (Mn+ and Mn+ ) , copper, chromium, iron (Fe* and Fe*3) , cobalt, erbium, nickel, europium, technetium, indium, samarium, dysprosium, ruthenium, ytterbium, yttrium, and holmium, most preferably manganese (Mn* ) . Exemplary metals useful, for example, in ultrasound or X-ray imaging are heavy metals such as hafnium, lanthanum, ytterbium, dysprosium and gadolinium. These and other contrast enhancer metals useful in magnetic resonance, ultrasound, and X-ray imaging will be readily apparent to those skilled in the art.
To prepare the contrast media of the present invention, an admixture is first formed between the polymers and the contrast enhancing metals. By admixture it is meant that the contrast enhancing metals are added to the polymer containing medium, and are not chemically bound to the polymer molecules by a covalent linkage. Partial or complete gelation of the polymers to entrap the contrast enhancing metals may occur spontaneously, simply upon adding these two components together. For example, agarose and high methoxy (greater than about 40%) pectin polymers will generally gel spontaneously and entrap the contrast enhancing metals merely upon addition of such metals to the polymers. In other embodiments of the present invention, partial or complete gelation of an admixture may occur as a result of, or be facilitated by, the addition of a gelling agent, thereby causing entrapment of the contrast enhancing metals by the polymers. By "entrap", or variations thereof, as used herein in connection with polymers entrapping contrast enhancing metals, it is meant that the polymers physically surround or enclose the metals. Such entrapment may occur through electrostatic interactions, hydrogen bonding, van der Waals forces, or the like.
Specifically, to cause gelation with polymers and metals which do not spontaneously gel, or to enhance
gelation, gelling agents such as polyvalent metal cations, sugars and polyalcohols may be employed. Exemplary polyvalent metal cations useful as gelling agents include calcium, zinc, manganese, iron and magnesium. Useful sugars include monosaccharides such as glucose, galactose, fructose, arabinose, allose and altrose, disaccharides such as maltose, sucrose, cellobiose and lactose, and polysaccharides such as starch. Preferably, the sugar is a single sugar, that is, monosaccharide or a disaccharide. Polyalcohol gelling agents useful in the present invention include, for example, glycidol, inositol, mannitol, sorbitol, pentaerythritol, galacitol and polyvinylalcohol. Most preferably, the gelling agent employed in the present invention is sucrose and/or calcium. The particular gelling agents which may be employed in the various formulations of the present invention will be readily apparent to one skilled in the art, once armed with the present disclosure. For example, sucrose is particularly useful for gelling admixtures of polygalacturonic acid and manganese. Similarly, low methoxy pectins gel especially quickly upon addition of calcium ions. It should be noted that some overlap exists between the polymers and contrast enhancing metals, and the gelling agents. Some agents are useful as polymers or contrast enhancing metals, as well as being additionally useful to cause gelation in mixtures of polymers and contrast enhancing metals which do not spontaneously gel. For example, sucrose is a useful polymer molecule, however, it may also be added to an admixture of, for example, polygalacturonic acid and manganese to effect gelation of the admixture. Further, iron may be effective as both a contrast enhancing metal and a gelling agent to cause gelation of an admixture which does not spontaneously gel.
Although not intending to be bound to any particular theory, it is believed that the polymer molecules and contrast enhancing metals of the present invention arrange during the gelation process in an "egg
box" type configuration such as that described in Figure 1 and in Grant, et al. FEBS Letters , Vol. 32, No. 1, pp. 195- 198 (1973), or in a tight coil-like aggregation such as that described in Vollmert, Polymer Chemistry, pp. 1-8, 541-561, Springer-Verlag, N.Y., New York (1973), the disclosures of each of which are hereby incorporated herein by reference in their entirety. Specifically, in a solution of polymers, the polymers are believed to be in random motion. Upon the addition of a contrast enhancing metal and, in some instances a gelling agent, however, the polymer chains are believed to be brought together by the interaction of the polymers with the contrast enhancing metals and/or gelling agents to "entrap" the contrast enhancing metals, thereby forming "egg boxes" or tight aggregation around the metals. Such phenomenon are discussed, in part, in Atkins, et al., Biopolymers , Vol. 12, pp. 1879-1887 (1973), the disclosures of which are hereby incorporated herein by reference in their entirety. In particular, it is believed that the contrast enhancing metals and/or the polyvalent metal cation gelling agents form bridges between two or more adjacent polymers, thereby effecting gelation. It is also believed that the sugars or polyalchohol polymers and/or gelling agents provide a lower energy state, thereby allowing the polymers and contrast enhancing metals to gel more effectively.
As those skilled in the art will recognize, admixtures of polymers, contrast enhancing metals, and optionally gelling agents, will form gels of different consistencies, depending upon the particular formulation employed. For example, calcium ions form relatively firm gels with various polymers, while manganese and ferrous ions form relatively weaker, somewhat watery, gels. In the context of the present invention, the term gel refers to a semisolid material, and includes both watery and firm gels. Preferably, the gel is firm. Firm gels are gels that have lost fluidity, as indicated by the inability of gas bubbles to rise in the gel. This phenomenon is described, for
example, in Odian, Principles of Polymerization, pp. 1-39, 96-112 and 611-614, McGraw-Hill Co., N.Y., New York (1970), the disclosures of which are hereby incorporated herein by reference in the entirety. For example, a watery gel will generally be formed by a combination of manganese and polygalacturonic acid, whereas a firm gel will generally be formed by a combination of manganese, polygalacturonic acid and calcium. As those skilled in the art would be aware, once armed with the present disclosure, the degree of gel firmness is related to the degree in which the polymer is capable of stabily retaining the contrast enhancing metal. Generally, firm gels are capable of retaining at least about 50% of the contrast enhancing metal in prolonged (greater than 24 hours) dialysis against physiological saline, preferably at least about 60% of the contrast enchancing metal, more preferably at least about 70% of the contrast enhancing metal, even more preferably at least about 80% of the contrast enchancing metal, and most preferably at least about 90% of the contrast enhancing metal.
In accordance with the invention, the resultant gel may then be treated to form gel particles. Such treatment may include any one of a variety of techniques, as will be readily apparent to those skilled in the art, such as blenderizing, microemulsification, microfluidization, extrusion, sonication, lyophilization, ball mixing, colloid mixing, etc. , as well as any and all combinations thereof. Blenderizing, for example, may be accomplished by using any of a number of commercial blenders, and may be followed, if desired, by extrusion with a commercial extruder device having a filter of a defined size. These and other processes are well known to those skilled in the art. The term particularizing, and variations thereof, as used herein, refers to the formation of small particles, preferably of relatively uniform size, by any of the aforementioned or other processes.
By employing the foregoing methods, gel particles of micrometer or nanometer size may be prepared. Preferably the particles have diameters of less than about 90 μ, more preferably, diameters ranging from about 5 nm to about 90 μ . The larger gel particles such as those ranging from about 1 μ to about 90 μ, are particularly useful for parenteral applications, and in gastrointestinal studies. The smaller gel particles such as those ranging in mean diameter from about 5 nm to about 400 nm, more preferably from about 10 nm to about 200 nm, are particularly useful contrast media for intravenous injections, for imaging the liver, and for controlling biodistribution. The terms nanogels and microgels, as used in connection with the present invention, denote gel particles ranging from about 1 nm to less than 1000 nm (less than 1 μ) (nanogels) and from 1 μ (1000 nm) to about 1000 μ (microgels) .
Gel particles prepared in accordance with the present invention are stable to heat and long term storage, characteristics which make these contrast media especially attractive as a diagnostic agent. The gel particles of the invention may be stored dried, or alternatively may be stored in an aqueous media.
Wide variations in the amounts of polymer, contrast enhancing metal, and gelling agent may be employed in the contrast medium of the present invention. Preferably, however, the polymer is present in a concentration of at least about 1%, by weight, more preferably, between about 5% and about 50%, by weight, and generally, most preferably at about 40% by weight. Of course as those skilled in the art will recognize, within these parameters the optimum polymer concentration will be influenced by various factors such as the particular polymer employed, the particular metal employed, the particular diagnostic use intended, etc. Preferably, in the case of paramagnetic metals for magnetic resonance imaging, the contrast enhancing metals may be present in a concentration of at least about 0.01% by weight, more
preferably between about 0.1% and about 5% by weight, and most preferably between about 0.5% and 0.7% by weight. A preferable concentration of heavy metals for ultrasound or X-ray imaging is at least about 0.1% by weight, more preferably between about 0.5% and about 30% by weight, most preferably between about 5% and about 25% by weight. A preferable concentration of gelling agent, where employed, is at least about 0.5% by weight, more preferably between about 0.5% and about 25% by weight, most preferably between about 5% and about 15% by weight.
The polymers employed in the present invention may, if desired, be phosphorylated such that when these phosphorylated polymers are mixed with contrast enhancing metals or gelling agents such as polyvalent metal cations (e.g., calcium), gels may form more rapidly. In general, higher degrees of polymer phosphorylation result in firmer gels that entrap the contrast enhancing metals more tightly.
Phosphorylation of the polymers may be carried out using conventional techniques which will be readily apparent to those skilled in the art. Specifically, starting with an aliphatic or alicyclic compound containing one or more hydrόxyl groups, for example, phosphorylation can be easily carried out by suspending the starting material in chloroform, then adding a phosphoric ester monochloride compound to the suspension, preferably dropwise. Suitable phosphoric ester monochloride compounds include C1P(0) (0R)2, wherein R is selected from C(0)CH3, C(0)H, CH3, C2I_5, C3H7, and C^. The resulting phosphorylated compound can then be treated with water to hydrolyze it to the corresponding phosphoric acid derivatives. Such hydrolyzed derivatives are included within the scope of the phrase phosphorylated compounds herein. Unbound phosphorus may be removed by passing the solution through a column filled anion exchanger. Polymers such as pectin, polygalacturonic acid or polyvinylalcohol
may be phosphorylated in such a manner to yield the corresponding phosphorylated derivatives.
In another method for preparing the phosphorylated aliphatic and alicyclic polymers which may be employed in the invention, urea catalyzed phosphoric acid (or phosphorous acid) phosphorylation procedures may be conveniently utilized. In this procedure, aliphatic or alicyclic compounds are soaked with mixtures of urea and phosphoric acid (or phosphorous acid) , then heated to at least 120°C.
In addition, phosphorylation of compounds such as polyvinyl alcohol can be carried out by dissolving polyvinyl alcohol in an organic solvent such as pyridine, dimethylformamide, or dimethylsulfoxide with triethylamine, and then adding dialkyloxyphosphoric monochloride
((R0)2P0C1, wherein R is a C|-C10 alkyl group) to the polymer solution. After phosphorylation, the polymer may then be hydrolyzed by adding water and acidifying with hydrochloric acid. Unbound phosphorous may be removed by passing the solution through a column filled anion exchanger.
Other methods of phosphorylating compounds to produce phosphorylated polymers within the scope of the present invention are disclosed, for example, in Sander et al., J. Macro ol . Sci . , Rev, Macromol . Chem . , Vol. 2, pp. 57-62 (1968), Leonard et al., J . App . Polymer Sci . , Vol. 55, pp. 799-810 (1961), Schroeder et al., J. of Polymer Sci . , Vol. 47, pp. 417-433 (1960), Kennedy et al., J . Appl . Chem . , Vol. 8, pp. 459-464 (1958), Marvel et al., J . of Polymer Sci . , Vol. 8, pp. 495-502 (1952), and U.S. Serial No. 649,437, filed February 1, 1991, the disclosures of each of which are hereby incorporated herein by reference, in their entireties.
If desired, the polymers employed in gel particles may be crosslinked using crosslinking agents known to those skilled in the art, either before or after particularization. Crosslinking may be accomplished by methods known to those skilled in the art. In particular,
polymers may be crosslinked by a linker moiety. The structure of such linkers may, for example, be of the following formula:
X-{(CHR)n-(CHR)n-(CHR)n- n}m-(L)0-X wherein: each R is, independently, H or X; L is a substituted or unsubstituted C,-C20 alkyl, cycloalkyl, or aryl group; each X is, independently, OH, NH2, NHR, COOH, COOR, SH, epoxide or Z; Y is O, S, CO, N or SiRR; Z is Cl, Br or I; each n is, independently, 0-10; m is 0-10,000; and o is 0-1,000. Linkers may be linked with COOH, OH or NH2 bearing groups on polymers by using condensation agents, for example, dicylohexylcarboimide (DCC) . For example, formaldehyde, glyoxal, epichlorhydrin, dimethyldichlorosilane, diepoxybutane and β ,β- dichloroethylsulfide may be used to crosslink gel particles of the present invention. Treatment with formaldehyde, for example, leads to crosslinkages between secondary hydroxyl groups to form mainly intermolecular methylene bridges. Crosslinking between carboxyl groups may be formed by agents such as diepoxybutane and j3,|8-dichloroethylsulfide. Sulfur containing cross-linkers may be used if desired, so as to be readily degradable within the body. Such cross- linkers include but are not limited to dithiobis(succinimidylpropionate) (DSP) and 3,3'- dithiobis(sulfosuccinimidylpropionate) (DTSSP) . Other procedures for cross-linking the polymers of the invention will be readily apparent to those skilled in the art, and include, for example, Staros, Biochemistry, Vol. 21, pp. 3950-3955 (1982), Lomant et al. , J. Hoi . Biol . , Vo. 104, pp. 243-261 (1976), Vollmert, Polymer Chemistry, pp. 1-8, 541-561, Springer-Verlag, New York, N.Y. (1973), and Odian, Principles of Polymerization, pp. 1-39, 96-112, and 611- 614, McGraw-Hill Co., N.Y., New York (1970), the disclosures of each of which are hereby incorporated herein by reference in their entirety. Crosslinking of the polymers is optionally employed, and is generally carried out for the purpose of increasing the stability of the gels
and prolonging the in vivo transit time. For example, such cross-linking may prolong the circulation or staying time of the gels within the patient in, for example, intravascular imaging or imaging of the gastrointestinal 5 tract. Such cross-linking is not preferred, however, since it has been found that the degree of tissue inflammation and patient discomfort tends to increase with the use of cross-linked polymers. Thus, for the purpose of the present invention it is preferable that the polymers are
10 not cross-linked, that is, are non-crosslinked polymers, although, of course, cross-linking may be employed, if desired, in accordance with the present invention.
Polymers may also, if desired, be modified prior or subsequent to gelation or particularization, such as by
15. the incorporation of targeting agents on their surface and in other ways that will be readily apparent to those skilled in the art. For example, agents such as antibodies, proteins, carbohydrates, and lectins may be incorporated on the polymeric surface of gel particles.
20 These targeting agents may be useful for example, for localizing gel particles to target regions or organs. For example, Fab ' 2 fragments of antibodies may be covalently bound to the surface of the gels, such as through amide linkages from amino groups of the antibodies to the
25 carboxylic acids groups on the polymers (e.g., polygalacturonic acid) . Similarly, other synthetic or natural peptides may be so attached. Alternatively, the carboxylic acid groups of proteins (e.g. , antibodies or peptides) may be attached to amide or thiol groups on the
30 polymers of the gels. The resulting labelled gel particles may then be used for imaging specific tissues. For example, fragments of antileukocyte antigen antibody covalently bound to gel contrast media may be used to detect metastases from colonic carcinoma. As one skilled
35 in the art would recognize, once armed with the tools of the present invention, there are numerous possibilities for using the subject gels for targeted site-specific imaging.
Also encompassed by the present invention are diagnostic kits comprising gel particles in combination with conventional diagnostic kit components such as buffering agents, antibacterial agents, stabilizing agents or excipients. Such components are well known in the art, and are discussed, for example, in The United States Pharmacopeia — The National Formulary. 22nd Revision, January 1, 1990, Mack Publishing Company, Easton, PA, Remington rs Pharmaceutical Sciences, Gennaro, A.R. , ed. , Mack Publishing Company, Easton, PA (1985) , the disclosures of each of which are hereby incorporated herein by reference in their entirety.
The present invention is useful in imaging a patient generally, and/or in specifically diagnosing the presence of diseased tissue in a patient. The imaging process of the present invention may be carried out by administering a contrast medium of the present invention to a patient, and then scanning the patient using ultrasound, X-ray or magnetic resonance imaging to obtain visible images of an internal region of a patient and/or of any diseased tissue in that region. By region of a patient, it is meant the whole patient or a particular area or portion of the patient. The contrast media of the invention are particularly useful in providing images of the liver. The subject contrast media are also particularly suited to imaging the gastrointestinal region and the vasculature. The phrase gastrointestinal tract, as used herein, includes the region of a patient defined by the esophagus, stomach, small and large intestines and rectum. The phrase vasculature, as used herein, denotes the blood vessels in the body or in an organ or part of the body. The patient can be any type of mammal, but most preferably is a human.
As those skilled in the art will recognize, administration may be carried out in various fashions, such as intravascularly, orally, rectally, etc., using a variety of dosage forms. When the region to be scanned is the gastrointestinal region, administration of the contrast
medium of the invention is preferably carried out orally or rectally. Alternatively, when the vasculature such as the vasculature of the liver is being scanned, the preferred mode of administration is intravascular administration. The useful dosage to be administered and the particular mode of administration will vary depending upon the age, weight and the particular mammal and region thereof to be scanned, the type of scanning and the particular medium of the invention to be employed. Typically, dosage is initiated at lower levels and increased until the desired contrast enhancement is achieved.
As those skilled in the art will recognize, various combinations of polymers, contrast enhancing metals, and gelling agents may be used, depending on such factors as the imaging modality employed, the type of mammal, the area to be imaged, and the particular diagnosis desired. In carrying out the method of the present invention, the contrast medium can be used alone, or in combination with other diagnostic, therapeutic or additional agents. Such additional agents include excipients such as flavoring, coloring, stabilizing agents, thickening materials, osmotic agents and antibacterial agents. Such agents may enhance the contrast media's use in vitro, the stability of the composition during storage, or other properties important to achieving optimal effectiveness. The contrast media of the present invention may also be sterilized prior to use by, for example, autoclaving, if desired.
The magnetic resonance imaging techniques which are employed are conventional and are described, for example, in Kean, D.M. , and M.A. Smith, Magnetic Resonance Imaging: Principles and Applications (William and Wilkins, Baltimore 1986) , the disclosures of which are hereby incorporated herein by reference in their entirety. Contemplated magnetic resonance imaging techniques include, but are not limited to, nuclear magnetic resonance (NMR) and electronic spin resonance (ESR) . Likewise, ultrasound
techniques are carried out by conventional procedures known to those skilled in the art, such as those disclosed in Brown, R. E. , Ultrasonography, Basic Principles and Clinical Applications (Warren H. Green, Inc., St. Louis, MO 1975) the disclosures of which are hereby incorporated herein by reference in their entirety. For example, with regard to ultrasound imaging, such imaging may be performed with an Acuson 128 Scanner (Milpitas, CA) using a 7.5 megahertz linear array transducer. The post processing function may be linear with pre-processing set at 0 and persistence at 2. Multifocal zones with a decreased frame rate can be used for most images. X-ray imaging is also conventional, and includes such X-ray imaging techniques as computed tomography (CT) , such as those described in Computed Body Tomography, Lee, J.K.T., Sagel, S.S., and
Stanley, R. . , eds., Ch. 1, pp. 1-7, (Raven Press, New York 1933) . These and other imaging techniques are also described in Squire, L. F., M.D. , Fundamentals of Radiology (Harvard University Press, Cambridge MA 1982) , the disclosures of which are hereby incorporated herein by reference in their entirety. Although any of a variety of imaging techniques may be employed, the preferred imaging modality is magnetic resonance imaging, specifically nuclear magnetic resonance imaging. As will be apparent to those skilled in the art, for magnetic resonance imaging purposes the gel particles may operate as Tl, T2 or proton density contrast medium, depending upon the type of polymer used, the molecular weight of the polymer, the concentration of the polymer, the type of metal ions mixed with the polymer, the type of MRI modality used, and the details of the pulse sequence employed for MRI imaging, and all such mechanisms of operation are considered to be within the ambit of" the present invention.
The gel particles of the present invention have been shown to be extremely useful as contrast enhancement media. By employing the gel particles in accordance with the present invention, lower overall concentration of the
contrast enhancing metals may be used to achieve the same, or in many cases a better degree of, contrast enhancement results. This has benefits not only in terms of toxicity, by avoiding the use of large amounts of the potentially toxic metal ions, but also in terms of cost, since less of the often more expensive conventional metal ions are used. Further, because of the entrapment of the contrast enhancing metals in the polymer matrix, the potentially toxic metal ions have less of an opportunity to be released and exhibit any toxic side effects. These and other advantages will be readily apparent to those skilled in the art, upon reading the present disclosure.
The present invention is further described in the following examples. In all of the examples, as well as throughout the present specification, all molecular weights are weight average molecular weights. The examples which follow are not to be construed as limiting the scope of the appended Claims.
Example l Preparation Of Polygalacturonic,
Manganese, And Calcium Gels
For preparation of the polygalacturonic acid, manganese and calcium gel contrast medium, 4.4 grams of polygalacturonic acid (poly-G) (Fluka, Ronkonkoma, N.Y.) was added to about 200 ml of deionized water, and the pH raised to a pH of 6.5 with sodium bicarbonate (30 ml 1 M sodium bicarbonate) at room temperature. The poly-G was then placed into a blender (commercial household blender) , after which 680 mg of Mn*2 was added as 24.5 ml of a 0.5 M MnCl2 stock solution. A clear inho ogeneous gel formed. The gel was blended on a liquify setting for 3 minutes after which time 250 mg Ca +2 was added by the addition of 9.2 ml of a CaCl2 solution. The resulting white gel was blended for 4 minutes on a liquify setting until homogenous and rather thin. The solution was then removed from the blender and the volume was brought up to 250 ml volumetrically with deionized water. The solution was returned to the blender and mixed on a liquify setting for
2 minutes to homogenize the solution. The solution was then extruded via an Extruder Device (Lipex Biomembranes,
Vancouver, B.C. Canada) through filters having pore sizes from 2000 nanometers to 15 nanometers (sequentially downsizing the filters) to produce nanogel contrast media of the present invention.
Example 2
Preparation Of Pectin, Manganese And Optionally Calcium Gels Two types of contrast media were prepared using purple and red low methoxy pectin: (1) 60 mg of Mn* with 1 gram of pectin (Spreda Corp. , Prospect KY) ; and (2) 60 mg Mn*2 with 1 gram of pectin and 10 mg Ca* . Purple and red pectin designate different types of low methoxy pectin sold by Spreda Corporation. Red pectin contains about 35 to about 40% methoxylation (esterification) , whereas purple pectin contains about 33 to about 38% methoxylation (esterification) .
1% Red Pectin and 0.6% Mn*2: One gram of pure red pectin was dissolved in 100 ml deionized water. Sixty mg of Mn* was added as 2.16 ml of a 500 mM MnCl2 stock solution. The solution was then blended on a liquify setting for thirty seconds and extruded through filters having pore sizes of 200, 100, 50, and 30 nm (sequentially downsizing the filters) to produce nanogel contrast media of present invention.
1% Red Pectin, 0.6% Mn*2 and 0.1% Ca*2: One gram of pure red pectin was dissolved in 100 ml deionized water. Sixty mg of Mn* was added as 2.16 ml of 500 mM MnCl2 stock solution. An inhomogeneous suspension resulted. To this suspension 10 mg of Ca* was added as 0.036 g of CaCl2. The gel was still inhomogeneous. The solution was then blended on a liquify setting for 1 minute. A thick, homogeneous gel resulted. The sample was extruded through filters having pore sizes of 200, 100, 50 and 15 nm (sequentially downsizing the filters) to produce nanogel contrast media of the present invention.
1% Purple Pectin, 0.6% Mn*2:
One gram of pure purple pectin was dissolved in 100 ml deionized water. Sixty mg of Mn* was added to the solution as 2.16 ml of 500 mM MnCl stock solution. The 5 resulting gel was then blended on a liquify setting for thirty seconds. A thick nonhomogeneous gel was formed. The gel was extruded through filters having pore sizes of 200, 100, 50, 30 and 15 nm (sequentially downsizing the filters) to produce nanogel contrast media of the present 10 invention.
1% Purple Pectin, 0.6% Mn*2, 0.1% Ca*2:
One gram of pure purple pectin was dissolved in 100 ml of water. Sixty milligrams of Mn*2 was added to the solution as 2.16 ml of a 500 Mm MnCl2 stock solution. The
15. resulting suspension was blended on a liquify setting for 30 seconds. 10 mg of Ca +2 was then added as 0.036 g of solid CaCl2. Subsequently, the solution was blended on a liquify setting for 1 minute. A thick tan gel resulted.
The gel was extruded through filters having pore sizes 200,
20 100, 50 and 15 n (sequentially downsizing the filters) to produce nanogel contrast media of the present invention.
Example 3
Preparation Of Polygalacturonic Acid And Ferrous Gels
25 The contrast medium was prepared by adding 3.3 g of polygalacturonic acid (poly-G) to 150 ml of deionized water and raised to a pH of 6.0 with sodium bicarbonate (30 ml of 1 M sodium bicarbonate) at room temperature. The poly-G was then put into a blender, after which 2.49 g of
30 ferrous iron (as solid FeCl2) was added. A yellow inhomogeneous gel formed. The gel was then blended on a liquify setting for 2 minutes until the resulting yellow/green gel was homogenous and rather thin. Next, the solution was brought up to 250 ml volumetrically with 5 deionized water, returned to the blender and mixed on a liquify setting for 2 minutes to homogenize the solution. The solution was then extruded via an Extruder Device
(Lipex Biomembranes, Vancouver, B.C., Canada) through filters having pore sizes of 200, 100, 50, 30 and 15 nanometers in mean diameter (sequentially downsizing the filters) to produce nanogel contrast media of the present invention.
Example 4
Preparation Of Polygalacturonic Acid, Manganese And Sucrose Gels
The gel was prepared by adding 1.5 grams of polygalacturonic acid to 150 ml of deionized water. Sodium bicarbonate was added to raise the pH to 6.0. Fifty grams of sucrose was then added and the solution was blended on a liquify setting for 20 seconds. Manganese ion (Mn* ) 680 mg was then added as 24.5 ml 0.5 M MnCl2 stock. The solution was blended on a liquify setting and brought up to 250 ml volumetrically by the addition of deionized water. The solution was returned to the blender and blended on a liquify setting for 20 seconds to homogenize the solution. The solution was extruded via the Extruder Device (Lipex Biomembranes, Vancouver, B.C., Canada) through filters having pore sizes of 200, 100, 50, 30 and 15 nanometers (sequentially downsizing the filters) to produce nanogel contrast media of the present invention. Example 5 Measurement Of Cation Concentration
Samples prepared substantially in accordance with Examples 1 through 4 were dialyzed for 24 hours in SPECTRA/POR Ce (cellulose ester) Membrane, molecular weight cutoff 100 (Spectrum Medical Industries Inc. , Los Angeles California) against 5% propylene glycol in normal saline. The samples were then spectrophotometrically analyzed for cation concentration (i.e., Mn* ) following dialysis, using a Milton Roy Spectronic 20D variable wavelength spectrophotometer (Rochester, N.Y.). Cation concentrations were as shown in Table 1. In Table 1, PG denotes polygalacturonic acid (Poly-G) .
TABLE 1
Example 6
Preparation of Low Molecular Height Poly-G from Low Methoxy Pectin
Preparation
Ten grams of D075-X Apple Pectin (Spreda Corp. , Prospect, KY) , a low methoxy pectin, was hydrolyzed in 100 ml of a 5% HC1 solution for 5 hours at a constant temperature of 85°C. The solution was then vacuum filtered, resulting in a dark brown precipitate and a yellow-colored solution. The dark brown precipitate (Sample 1) was set aside.
The solution was taken and subjected to a decolorization step by adding two grams of activated charcoal to the solution and heating the solution to 80°C for 30 minutes. The solution was then filtered, resulting in a clear colorless liquid. Next, the solution was evaporated to dryness, yielding a yellow-brown powder (Sample 2), which was low molecular weight polygalacturonic acid (Poly-G) , as shown in Table 2 (last entry) . The Poly-G is suitable for use in preparing a gel particle contrast medium of the invention.
Molecular Weight Analysis All HPLC analyses were done on a Binary Liquid Chromatography Pump, Model No. 250 (Perkin Elmer, Norwalk,
CT) , using the Diode Array Detector, Model No. 135 (Perkin Elmer) . The data were processed on a Personal Integrator, Model No. 1020 (Perkin Elmer) . Detector settings were lambda A 245 and lambda B 280. Run time was 20 minutes at a flow rate of 1 ml/minute. All samples were passed through a Biogel Sec 40 XL size exclusion chromatography column (Bio Rad Laboratories, Richmond, CA) . The resultant data is set forth in Table 2.
TABLE 2
High Pressure Liquid Chromatography Analysis of Molecular Weight
* Shows column retention time in minutes; shorter retention time indicates larger molecular weight polymer.
** Hydrolyzed from pectin (See "Preparation", above) .
As shown by Table 2, commercially available Poly-
G (Fluka, Ronkonknoma, N.Y.) which is known to be comprised of a mixture of polymers of Poly-G with molecular weights ranging from 25,000 to 50,000 has a retention time on the column of 5.33 minutes. Commercially available mono- galacturonic acid (molecular weight 194) , has the longest retention time, a retention time of 9.04 minutes. Deca galacturonic acid (prepared by the method described in Lakatos et al. , U.S. Patent No. 4,225,592 issued September 30, 1980, hereinafter referred to as Lakatos, the disclosures of which are hereby incorporated herein by
reference in their entirety) , has a molecular weight of approximately 2,200 and was found to have a retention time of 8.50 minutes. Comparing the retention times with that of commercial Poly-G, commercial galacturonic acid monomer and deca galacturonic acid described in Lakatos, reveals that the Poly-G hydrolyzed from pectin (Sample 2, as described in "Preparation" above) , is low molecular weight
Poly-G. Specifically, the Poly-G from Sample 2 has a retention time of 7.9 minutes, indicating a MW range near that of deca galacturonic acid («2,200 dalton) . Evaluation of the dark brown precipitate (Sample 1) showed a retention time of 5.53 minutes (data not shown) — almost identical to that of high molecular weight Poly-G.
Example 7 Relaxivity Of Various Polymers
And Manganese
Contrast media of the invention, prepared substantially in accordance with the procedures in Examples 1, 2, 3, 4 and 5, were analyzed for relaxivity and compared with the relaxivity of other samples. Samples A through D are provided for comparative purposes only. All samples were analyzed for relaxivity using a Toshiba 0.5 T clinical MR magnet. Samples E through J are gel particle contrast media within the scope of the invention. Samples A through D are provided for comparative purposes only. Table 3 below shows the relaxivity of the various samples.
TABLE 3
E. Pectin D-075X, Mn 16.53 ± 0.88 36.53 ± 0. 69
F. MnCl2, Algin 20. 3 ± 1.948 40. 20 ± 0.38
G. Poly-G, Mn 28.99 ± 0.562 55.31 ± 1. 11
H. 100% Deca Poly-G, 35.33 ± 0. 623 61.02 ± 0. 886 Mn
I. 40% Deca Poly-G, 42 . 62 ± 0.289 67 .28 ± 0.459 60% Normal Poly-G, Mn
J. Hydrolyzed Pectin 46.11 ± 0.347 67.98 ± 1.256 Mn
As shown by the data, manganese ion (Mn +2), as the free ion manganese chloride has an R, and R2 of about 8 and 39 per millimole/sec' respectively (Sample C) . In comparison with Sample C, the chelates (Samples A and B) showed reduce relaxivity. Specifically, the polymeric chelate Mh-Poly-EDTA-EOEA-DP has an R, and R2, respectively, of about 6 and 13 (Sample B) and the simple chelate Mn- EDTA-MEA has an R1 and R2, respectively, of about 3 and 8 (Sample A) . The monomer of galacturonate has no appreciable effect on the relaxivity of manganese (Sample D) . The contrast media of the invention, however, have a large effect on the relaxivity of manganese. For example, red pectin (D-075X, low methoxypectin, Spreda Corp., Prospect, KY) (Sample E) , and algin (Sample F) appreciably increase the relaxivity of manganese. As also shown by the
data in Table 3, different preparations of Poly-G within the scope of the invention show still greater relaxivity. Most effective are low molecular weight polygalacturonates. For example, hydrolyzed pectin prepared according to Example 5 had an R., and R2 relaxivity of 46 and 68, respectively (Sample J) . A mixture of 40% deca Poly-G prepared according to Example 5 and 60% normal Poly-G obtained from Fluka (MW 22,000 to 50,000) (Sample I) has relaxivity greater than pure deca Poly-G (Sample H) . These data show that optimal relaxivity is achieved for manganese in admixture with Poly-G below about 5,000 MW, Example 8
Stability Of Poly-G, Manganese And sucrose Gels The stability of gel particles in retaining manganese was tested by dialyzing the gel particles for 24 hours in a SPECTRA/POR Ce (cellulose ester) Membrane, molecular weight cut off 100 (Specturm Medical Industries, Inc., Los Angeles, CA) against various solutions.
The gel particles of the invention show retention of manganese upon prolonged dialysis, evidence of the good stability of compounds of the invention. Specifically, as Table 4 shows, between 22% and 52% of the manganese is retained after 24 hours, for gel particles prepared in accordance with Example 4. After the first 24 hours of dialysis where some unbound manganese is removed, the particles were found to retain the remaining manganese even after prolonged dialysis (e.g. greater than 72 hours of dialysis) (data not shown) .
TABLE 4
Example 9
Stability And Relaxivity Of Manganese In Polygalacturonic Acid Gels
Contrast media of the invention, prepared substantially in accordance with the procedures of Examples 1, 3 and 4, were analyzed for relaxivity and for stability on dialysis. Table 5 shows the percent retention and relaxivity of manganese by gel particles prepared in accordance with the invention. The gel comprising polygalacturonic acid (Poly-G; PG) , manganese, and sucrose exhibits the highest relaxivity and retention of manganese.
TABLE 5
Example 10
In Vivo Imaging Data
Shown in the Tables 6 through 9 are NMR imaging data from four rats injected intravenously with doses of 2.33 to 2.5 micromples/kg of manganese and polygalacturonic acid (Poly-G; PG) or pectin gel particles and scanned via NMR. Tables 6 and 7 are data from intravenous injections of contrast medium comprising gel particles prepared substantially in accordance with Example l. Table 8 is data from intravenous injections of contrast media comprising gel particles prepared substantially in accordance with Example 2. Table 9 is data from intravenous injections of contrast media comprising gel particles prepared substantially in accordance with Example 4. As shown by the data, enhancement by gel particles prepared by gelation of Poly-G and manganese with calcium showed some enhancement. Better enhancement was observed with red pectin and manganese gels. The greatest
enhancement is observed with the gel particles prepared by gelation of Poly-G and manganese with sucrose.
TABLE 6
* Percent enhancement = [(signal intensity post-contrast agent - signal intensity pre-contrast agent)/(signal intensity pre-contrast agent) ] x 100.
TABLE 7
* Percent enhancement = [(signal intensity post-contrast agent - signal intensity pre-contrast agent)/(signal intensity pre-contrast agent)] x 100.
TABLE 8
Red Pectin ++2Mn 2.Sμmoles Mn* /kg
Percent Λ
Liver Signal Enhancement of Intensity the Liver
Pre Contrast 157 ± 14
5 Min Post Contrast 169 ± 11 7.6% 15 Min Post Contrast 169 ± 10 7.6% 25 Min Post Contrast 205 ± 11 30.6% 60 Min Post Contrast 211 ± 13 34.4% * Percent enhancement = [ (signal intensity post-contrast agent - signal intensity pre-contrast agent) / (signal intensity pre-contrast agent)] x 100.
TABLE 9
* Percent enhancement = [ (signal intensity post-contrast agent - signal intensity pre-contrast agent) / (signal intensity pre-contrast agent)] x 100.
Example 11
In Vivo Imaging Data Table 10 represents enhancement of the liver using polygalacturonic acid manganese sucrose gel particles prepared substantially in accordance with Example 4 in
three studies. As the data indicates, enhancement is increased from 40 to 50% by the use of the gel particles.
TABLE 10
* Percent enhancement = [(signal intensity post-contrast agent - signal intensity pre-contrast agent)/(signal intensity pre-contrast agent)] x 100.
Example 12
In Vivo Liver to Tumor Contrast to Noise
Table 11 provides data of three tests of contrast to noise. Contrast to noise was approximately double in tests using poly-G manganese sucrose gels prepared substantially in accordance with Example 4. Contrast to noise was calculated by measuring the signal intensity of the liver, subtracting the signal intensity of the tumor, and dividing this by the standard deviation of the background noise.
TABLE 11
Example 13
Signal Intensity
Tables 12 and 13 provide data from tests of signal intensity in the heart, kidney/medulla and kidney/cortex. All tests show an increase in signal intensity in tests using gel particles prepared substantially in accordance with Example 4. Signal intensity increased only slightly in the heart, but increased more significantly in the kidney/medulla, and most substantially in the kidney/cortex.
TABLE 12
TABLE 13
Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended Claims.
Claims (1)
- CLAIMS What is Claimed is:1. A contrast medium comprising gel particles of less than about 90 μ in mean diameter, said gel particles comprising at least one polymer entrapping at least one contrast enhancing metal.2. A contrast medium of Claim 1 wherein said gel particles are from about 5 nm to about 90 μ in mean diameter.3. A contrast medium of Claim 2 wherein said gel particles are from about 1 μ to about 90 μ in mean diameter.4. A contrast medium of Claim 2 wherein said gel particles are from about 5 nm to about 400 nm in mean diameter.5. A contrast medium of Claim 4 wherein said gel particles are from about 10 nm to about 200 nm in mean diameter.6. A contrast medium of Claim 1 wherein said polymer is a synthetic polymer.7. A contrast medium of Claim 1 wherein said polymer is a natural or semisynthetic polymer.8. A contrast medium of Claim 6 wherein said polymer is selected from the group consisting of polyethylenes, polypropylenes, polyurethanes, pluronic acids, pluronic alcohols, polyvinylε, nylon, polystyrene, polylactic acids, fluorinated hydrocarbons, fluorinated carbons, polyacrylates, polyacrylic acids and polyacrylamides. 9. A contrast medium of Claim 7 wherein the polymer is a polysaccharide.10. A contrast medium of Claim 9 wherein said polysaccharide is selected from the group consisting of arabinans, fructans, fucans, galactans, galacturonans, glucans, mannans, xylans, levan, fucoidan, carrageenan, galactocarolose, pectins, pectic acids, amylose, pullulan, glycogen, amylopectin, cellulose, dextran, pustulan, chitin, agarose, keratin, chondroitin, dermatan, hyaluronic acid, alginic acid, xanthan gum, starch, carboxyl ethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, methylcellulos , methoxycellulose, and polysaccharides containing at least one aldose, ketose, acid or amine selected from the group consisting of erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine and neuraminic acid.11. A contrast medium of Claim 10 wherein said polysaccharide is pectin.12. A contrast medium of Claim 11 wherein said polysaccharide is a pectin which is a low methoxy pectin having less than about 30% methoxylation.13. A contrast medium of Claim 10 wherein said polysaccharide is polygalacturonic acid.14. A contrast medium of Claim 1 wherein said polymer is a phosphorylated polymer. 15. A contrast medium of Claim 1 wherein said contrast enhancing metal is selected from the group consisting of paramagnetic metals and heavy metals.16. A contrast medium of Claim 15 wherein said contrast enhancing metal is a paramagnetic metal.17. A contrast medium of Claim 16 wherein said paramagnetic metal is selected from the group consisting of gadolinium, manganese,•copper, chromium, iron, cobalt, erbium, nickel, europium, technetium, indium, samarium, dysprosium, ruthenium, ytterbium, yttrium, and holmium.18. A contrast medium of Claim 17 wherein said paramagnetic metal is Mn .19. A contrast medium of Claim 15 wherein said contrast enhancing metal is a heavy metal.20. A contrast medium of Claim 19 wherein said heavy metal is selected from the group consisting of hafnium, lanthanum, ytterbium, dysprosium and gadolinium.21. A contrast medium of Claim 1 wherein said contrast medium further comprises a gelling agent selected from the group consisting of polyvalent metal cations, sugars and polyalcohols.22. A contrast medium of Claim 21 wherein said gelling agent is a polyvalent metal cation which is a calcium cation.23. A contrast medium of Claim 1 wherein said polymer is crosslinked.24. A contrast medium of Claim 1 wherein said polymer is non-crosslinked. 25. A contrast medium prepared by the process of combining at least one polymer and at least one contrast enhancing metal to form a gel wherein said polymer entraps said contrast enhancing metal, and particularizing the gel to form particles of less than about 90 μ in mean diameter.26. A contrast medium of Claim 25 further comprising combining a gelling agent with said polymer and said contrast enhancing metal.27. A contrast medium of Claim 26 wherein said gelling agent is selected from the group consisting of polyvalent metal cations, sugars and polyalcohols.28. A contrast medium comprising gel particles, said gel particles comprising at least one polymer entrapping at least one contrast enhancing metal, wherein said polymer is non-crosslinked.29. A contrast medium of Claim 28 wherein said polymer is a synthetic polymer.30. A contrast medium of Claim 28 wherein said polymer is a natural or semisynthetic polymer.31. A contrast medium of Claim 29 wherein said polymer is selected from the group consisting of polyethylenes, polypropylenes, polyurethanes, pluronic acids, pluronic alcohols, polyvinyls, nylon, polystyrene, polylactic acids, fluorinated hydrocarbons, fluorinated carbons, polyacrylates, polyacrylic acids, and polyacrylamides.32. A contrast medium of Claim 30 wherein said polymer is a polysaccharide. 33. A contract medium of Claim 32 wherein said polysaccharide is selected from the group consisting of arabinans, fructans, fucans, galactans, galacturonans, glucans, mannans, xylans, levan, fucoidan, carrageenan,5 galactocarolose, pectins, pectic acids, amylose, pullulan, glycogen, amylopectin, cellulose, dextran, pustulan, chitin, agarose, keratin, chondroitin, dermatan, hyaluronic acid, alginic acid, xanthan gum, starch, carboxylmethylcellulose, hydroxymethylcellulose,10 hydroxypropylmethylcellulose, methylcellulose, methoxycellulose, and polysaccharides containing at least one aldose, ketose, acid or amine selected from the group consisting of erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose,15. idose, galactose, talose, erythrulose, ribulose, xylulose, psicose, fructose, sorbose, tagatose, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, glucosa ine, galactosamine and neuraminic acid.34. A contrast medium of Claim 33 wherein said 20 polysaccharide is pectin.35. A contrast medium of Claim 34 wherein said polysaccharide is a pectin which is a low methoxy pectin having less than about 30% methoxylation.36. A contrast medium of Claim 33 wherein said 5 polysaccharide is polygalacturonic acid.37. A contrast medium of Claim 28 wherein said polymer is a phosphorylated polymer.38. A contrast medium of Claim 28 wherein said contrast enhancing metal is selected from the group 0 consisting of paramagnetic metals, and heavy metals. 39. A contrast medium of Claim 38 wherein said contrast enhancing metal is a paramagnetic metal.40. A contrast medium of Claim 39 wherein said paramagnetic metal is selected from the group consisting of gadolinium, manganese, copper, chromium, iron, cobalt, erbium, nickel, europium, technetium, indium, samarium, dysprosium, ruthenium, ytterbium, yttrium, and holmium.41. A contrast medium of Claim 40 wherein said paramagnetic metal is Mn +2.42. A contrast medium of Claim 38 wherein said contrast enhancing metal is a heavy metal.43. A contrast medium of Claim 42 wherein said heavy metal is selected from the group consisting of hafnium, lanthanum, ytterbium, dysprosium and gadolinium.44. A contrast medium of Claim 28 wherein said gel particles are less than about 90 μ in mean diameter.45. A contrast medium of Claim 44 wherein said gel particles are from about 5 nm to about 90 μ in mean diameter.46. A contrast medium of Claim 45 which said gel particles are from about 1 μ to about 90 μ in mean diameter.47. A contrast medium of Claim 45 wherein said gel particles are from about 5 nm to about 400 nm in mean diameter.48. A contrast medium of Claim 47 wherein said gel particles are from about 10 nm to about 200 nm in mean diameter. 49. A contrast medium prepared by the process of combining at least one polymer and at least one contrast enhancing metal to form a gel wherein said polymer entraps said contrast enhancing metal, and particularizing the gel to form particles, wherein said polymer is non-cross- linked.50. A contrast medium of Claim 49 further comprising combining a gelling agent with said polymer and said contrast enhancing agent.51. A contrast medium of Claim 50 wherein said gelling agent is selected from the group consisting of polyvalent metal cations, sugars, and polyalcohols.52. A method of providing an image of an internal region of a patient comprising (i) administering to the patient a contrast medium of Claim 1, and (ii) scanning the patient using magnetic resonance imaging, ultrasound imaging or X-ray imaging to obtain visible images of the region.53. A method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient a contrast medium of Claim l, and (ii) scanning the patient using magnetic resonance imaging, ultrasound imaging or X-ray imaging to obtain visible images of any diseased tissue in the patient.54. A method of providing an image of an internal region of a patient comprising (i) administering to the patient a contrast medium of Claim 28, and (ii) scanning the patient using magnetic resonance imaging, ultrasound imaging or X-ray imaging to obtain visible images of the region. 55. A method for diagnosing the presence of diseased tissue in a patient comprising (i) administering to the patient a contrast medium of Claim 28, and (ii) scanning the patient using magnetic resonance imaging, ultrasound imaging or X-ray imaging to obtain visible images of any diseased tissue in the patient.56. A kit comprising a contrast medium of Claim 1 and conventional diagnostic kit components.57. A kit of Claim 56 wherein said kit components are selected from the group consisting of buffering agents, antibacterial agents and stabilizing agents.58. A kit comprising a contrast medium of Claim 28 and conventional diagnostic kit components.59. A kit of Claim 58 wherein said kit components are selected from the group consisting of buffering agents, antibacterial agents and stabilizing agents.60. A process for preparing a contrast medium comprising combining at least one polymer and at least one contrast enhancing metal to form a gel wherein said polymer entraps said contrast enhancing metal, and particularizing the gel to form particles of less than about 90 μ in mean diameter.61. A process of Claim 60 further comprising combining a gelling agent with said polymer and said contrast enhancing agent.62. A process of Claim 61 wherein said gelling agent is selected from the group consisting of polyvalent metal cations, sugars and polyalcohols. 63. A process for preparing a contrast medium comprising combining at least one polymer and at least one contrast enhancing metal to form a gel wherein said polymer entraps said contrast enhancing metal, and particularizing the gel to form particles, wherein said polymer is non- crossiinked.64. A process of Claim 63 further comprising combining a gelling agent with said polymer and said contrast enhancing agent.65. A process of Claim 64 wherein said gelling agent is selected from the group consisting of polyvalent metal cations, sugars and polyalcohols.66. The contrast medium of Claim 1 wherein said polymer is polygalacturonic acid and said contrast enhancing metal is the paramagnetic metal Mn* .67. The contrast medium of Claim 28 wherein said polymer is polygalacturonic acid and said contrast enhancing metal is the paramagnetic metal Mn* .68. The kit of Claim 56 wherein said polymer is polygalacturonic acid and said contrast enhancing metal is the paramagnetic metal Mn* .69. The kit of Claim 58 wherein said polymer is polygalacturonic acid and said contrast enhancing metal is the paramagnetic metal Mn +2.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US79443791A | 1991-11-19 | 1991-11-19 | |
US794437 | 1991-11-19 | ||
PCT/US1992/008948 WO1993010440A1 (en) | 1991-11-19 | 1992-10-20 | Gel particle contrast media for improved diagnostic imaging |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2894092A AU2894092A (en) | 1993-06-15 |
AU667491B2 true AU667491B2 (en) | 1996-03-28 |
Family
ID=25162622
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU28940/92A Ceased AU667491B2 (en) | 1991-11-19 | 1992-10-20 | Gel particle contrast media for improved diagnostic imaging |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0614527A4 (en) |
JP (1) | JPH07501331A (en) |
AU (1) | AU667491B2 (en) |
CA (1) | CA2121681A1 (en) |
WO (1) | WO1993010440A1 (en) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5885549A (en) * | 1991-02-01 | 1999-03-23 | Imarx Pharmaceutical Corp. | Phosphorylated materials as contrast agents for use in magnetic resonance imaging of the gastrointestinal region |
US5143716A (en) * | 1991-02-01 | 1992-09-01 | Unger Evan C | Phosphorylated sugar alcohols, Mono- and Di-Saccharides as contrast agents for use in magnetic resonance imaging of the gastrointestinal region |
DE69230885T3 (en) * | 1991-09-17 | 2008-01-24 | Ge Healthcare As | GASOUS ULTRASONIC CONTRASTING AGENTS |
MX9205298A (en) * | 1991-09-17 | 1993-05-01 | Steven Carl Quay | GASEOUS ULTRASOUND CONTRASTING MEDIA AND METHOD FOR SELECTING GASES TO BE USED AS ULTRASOUND CONTRASTING MEDIA |
US5409688A (en) * | 1991-09-17 | 1995-04-25 | Sonus Pharmaceuticals, Inc. | Gaseous ultrasound contrast media |
IL108416A (en) | 1993-01-25 | 1998-10-30 | Sonus Pharma Inc | Phase shift colloids as ultrasound contrast agents |
US5310537A (en) * | 1993-03-01 | 1994-05-10 | Sterling Winthrop Inc. | Compositions of iodoaniline derivatives for visualization of the gastrointestinal tract |
US5330740A (en) * | 1993-03-01 | 1994-07-19 | Sterling Winthrop Inc. | Compositions of iodoaniline derivatives in film-forming materials for visualization of the gastrointestinal tract |
US20030100830A1 (en) | 2001-11-27 | 2003-05-29 | Sheng-Ping Zhong | Implantable or insertable medical devices visible under magnetic resonance imaging |
US7090829B2 (en) | 2002-04-11 | 2006-08-15 | Carbomer, Inc. | Imaging probes |
DE10224352A1 (en) * | 2002-06-01 | 2003-12-11 | Mueller Schulte Detlef | Thermosensitive polymer carrier with changeable physical structure for biochemical analysis, diagnostics and therapy |
AU2003281270B2 (en) | 2002-07-02 | 2010-07-22 | Universitair Medisch Centrum Utrecht | Scanning suspension comprising a particle with a diameter of at least 1 micrometer |
US20050065434A1 (en) * | 2003-09-22 | 2005-03-24 | Bavaro Vincent P. | Polymeric marker with high radiopacity for use in medical devices |
US20050064223A1 (en) | 2003-09-22 | 2005-03-24 | Bavaro Vincent Peter | Polymeric marker with high radiopacity |
NO320691B1 (en) * | 2004-06-14 | 2006-01-16 | Ntnu Technology Transfer As | New contrast release system. |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1985233A (en) * | 1928-10-06 | 1934-12-25 | Petroleum Conversion Corp | Process and apparatus for converting hydrocarbon oils |
US4452773A (en) * | 1982-04-05 | 1984-06-05 | Canadian Patents And Development Limited | Magnetic iron-dextran microspheres |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4069306A (en) * | 1974-03-14 | 1978-01-17 | Pharmacia Aktiebolag | X-ray contrast preparation containing a hydrophilic polymer containing amino groups |
US4735796A (en) * | 1983-12-08 | 1988-04-05 | Gordon Robert T | Ferromagnetic, diamagnetic or paramagnetic particles useful in the diagnosis and treatment of disease |
GB8310038D0 (en) * | 1983-04-13 | 1983-05-18 | Amersham Int Plc | Technetium-99 labelled tin colloid |
EP0146583B1 (en) * | 1983-06-09 | 1991-04-03 | Field Group Chemicals Pty. Ltd. | Radiopaque medium |
GB8408127D0 (en) * | 1984-03-29 | 1984-05-10 | Nyegaard & Co As | Contrast agents |
US4749560A (en) * | 1984-08-13 | 1988-06-07 | Research Corporation | Metal organo phosphorous compounds for NMR analysis |
EP0184899B1 (en) * | 1984-11-01 | 1990-04-18 | Nycomed As | Paramagnetic contrast agents for use in "in vivo" diagnostic methods using nmr, and their preparation |
DE3619746A1 (en) * | 1986-06-12 | 1987-12-17 | Basf Ag | SUPER PARAMAGNETIC SOLID PARTICLES |
DE3709851A1 (en) * | 1987-03-24 | 1988-10-06 | Silica Gel Gmbh Adsorptions Te | NMR DIAGNOSTIC LIQUID COMPOSITIONS |
GB8808305D0 (en) * | 1988-04-08 | 1988-05-11 | Nycomed As | Compositions |
WO1990003803A1 (en) * | 1988-10-14 | 1990-04-19 | Mallinckrodt, Inc. | Radiolabelled particulate composition |
ATE153860T1 (en) * | 1990-04-10 | 1997-06-15 | Imarx Pharmaceutical Corp | POLYMERS AND THEIR USE AS CONTRAST AGENTS IN MAGNETIC RESONANCE IMAGING |
US5358702A (en) * | 1990-04-10 | 1994-10-25 | Unger Evan C | Methoxylated gel particle contrast media for improved diagnostic imaging |
-
1992
- 1992-10-20 CA CA 2121681 patent/CA2121681A1/en not_active Abandoned
- 1992-10-20 WO PCT/US1992/008948 patent/WO1993010440A1/en not_active Application Discontinuation
- 1992-10-20 JP JP5509251A patent/JPH07501331A/en active Pending
- 1992-10-20 EP EP92922870A patent/EP0614527A4/en not_active Withdrawn
- 1992-10-20 AU AU28940/92A patent/AU667491B2/en not_active Ceased
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1985233A (en) * | 1928-10-06 | 1934-12-25 | Petroleum Conversion Corp | Process and apparatus for converting hydrocarbon oils |
US4452773A (en) * | 1982-04-05 | 1984-06-05 | Canadian Patents And Development Limited | Magnetic iron-dextran microspheres |
Also Published As
Publication number | Publication date |
---|---|
EP0614527A4 (en) | 1998-06-03 |
AU2894092A (en) | 1993-06-15 |
CA2121681A1 (en) | 1993-05-27 |
EP0614527A1 (en) | 1994-09-14 |
JPH07501331A (en) | 1995-02-09 |
WO1993010440A1 (en) | 1993-05-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5358702A (en) | Methoxylated gel particle contrast media for improved diagnostic imaging | |
AU667491B2 (en) | Gel particle contrast media for improved diagnostic imaging | |
KR100278513B1 (en) | Iron-containing nanoparticles with double coatings and their use in diagnostics and treatment | |
US5658550A (en) | Non cross-linked synthetic polymers as contrast media for magnetic resonance imaging | |
US5512268A (en) | Polymeric shells for medical imaging prepared from synthetic polymers, and methods for the use thereof | |
JPH07110815B2 (en) | Polychelating agent for image and spectral enhancement (and spectral shift) | |
EP0693288B1 (en) | Polymers as contrast media for magnetic resonance | |
US8926947B2 (en) | Polyol and polyether iron oxide complexes as pharmacological and/or MRI contrast agents | |
US6372194B1 (en) | MRI contrast media recognizing minor environmental changes | |
US20030225033A1 (en) | Heat stable colloidal iron oxides coated with reduced carbohydrates and uses thereof | |
AU628403B2 (en) | Methods and compositions for magnetic resonance imaging | |
US20100260686A1 (en) | Nanoparticles for brain tumor imaging | |
KR101059285B1 (en) | Gadolinium complex, preparation method thereof, and MRI contrast agent containing the same | |
CN1249070C (en) | Paramagnetic metal-phthalocyanine complex compounds and contrast agent using the same | |
Stanicki et al. | Impact of the chain length on the biodistribution profiles of PEGylated iron oxide nanoparticles: A multimodal imaging study | |
JP2000507567A (en) | Methods of T-weighted nuclear magnetic resonance imaging of retinal system (RES) organs | |
JPH10120597A (en) | Highly accumulating colloidal particle of lymph node | |
WO2005065724A1 (en) | Formulations of paramagnetic ion complexes | |
EP3630203A1 (en) | Biogenic hemin-based mri contrast agents, and compositions and methods thereof | |
CN107802844B (en) | Preparation method of double-contrast-element-loaded hybrid sodium alginate nanogel | |
US20040022857A1 (en) | Synthesis of highly conjugated polymers | |
Ma et al. | Dextran-based Nanomicelle System with Directly Ester-bound Gadolinium Chelates as a Magnetic Resonance Imaging Contrast Agent for Tumor Detection | |
KR100448100B1 (en) | Paramagnetic metal-phthalocyanine complex compounds and contrast agent using the same | |
WO2004011036A1 (en) | Method for assessing capillary permeability | |
CN114949264A (en) | Bimodal magnetic resonance contrast agent with targeting function and preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |