JPS6131121B2 - - Google Patents
Info
- Publication number
- JPS6131121B2 JPS6131121B2 JP10285584A JP10285584A JPS6131121B2 JP S6131121 B2 JPS6131121 B2 JP S6131121B2 JP 10285584 A JP10285584 A JP 10285584A JP 10285584 A JP10285584 A JP 10285584A JP S6131121 B2 JPS6131121 B2 JP S6131121B2
- Authority
- JP
- Japan
- Prior art keywords
- dextrin
- ferric
- iron
- weight
- polynuclear
- 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.)
- Expired
Links
- 239000004375 Dextrin Substances 0.000 claims description 104
- 229920001353 Dextrin Polymers 0.000 claims description 104
- 235000019425 dextrin Nutrition 0.000 claims description 104
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 80
- 239000000243 solution Substances 0.000 claims description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 18
- 239000002244 precipitate Substances 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 238000009826 distribution Methods 0.000 claims description 10
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 238000001962 electrophoresis Methods 0.000 claims description 8
- 238000000862 absorption spectrum Methods 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 5
- 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 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 229910002588 FeOOH Inorganic materials 0.000 claims description 3
- 230000005856 abnormality Effects 0.000 claims description 3
- 230000009965 odorless effect Effects 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000001879 gelation Methods 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims 3
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- 239000002075 main ingredient Substances 0.000 claims 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 223
- 229910052742 iron Inorganic materials 0.000 description 111
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical class [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 26
- 229960004106 citric acid Drugs 0.000 description 21
- 235000015165 citric acid Nutrition 0.000 description 21
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 20
- 239000000523 sample Substances 0.000 description 20
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 11
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 11
- 239000002131 composite material Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 238000000691 measurement method Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 239000012488 sample solution Substances 0.000 description 7
- 238000013112 stability test Methods 0.000 description 7
- 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 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000005233 alkylalcohol group Chemical group 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 229910001447 ferric ion Inorganic materials 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 6
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 5
- 229920002307 Dextran Polymers 0.000 description 5
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 150000001447 alkali salts Chemical class 0.000 description 5
- 239000003708 ampul Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000174 gluconic acid Substances 0.000 description 5
- 235000012208 gluconic acid Nutrition 0.000 description 5
- 229940082629 iron antianemic preparations Drugs 0.000 description 5
- -1 iron complex compound Chemical class 0.000 description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 5
- 239000001509 sodium citrate Substances 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000012468 concentrated sample Substances 0.000 description 4
- 238000002523 gelfiltration Methods 0.000 description 4
- 239000001630 malic acid Substances 0.000 description 4
- 235000011090 malic acid Nutrition 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- 235000002906 tartaric acid Nutrition 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- 210000002700 urine Anatomy 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- 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 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003792 electrolyte Substances 0.000 description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 3
- 229910001448 ferrous ion Inorganic materials 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000001384 succinic acid Substances 0.000 description 3
- 235000011044 succinic acid Nutrition 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- FGJLAJMGHXGFDE-UHFFFAOYSA-L disodium;2,3-dihydroxybutanedioate;dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C(O)C(O)C([O-])=O FGJLAJMGHXGFDE-UHFFFAOYSA-L 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 238000003969 polarography Methods 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229940023144 sodium glycolate Drugs 0.000 description 2
- 229940092162 sodium tartrate dihydrate Drugs 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 1
- FPFSGDXIBUDDKZ-UHFFFAOYSA-N 3-decyl-2-hydroxycyclopent-2-en-1-one Chemical compound CCCCCCCCCCC1=C(O)C(=O)CC1 FPFSGDXIBUDDKZ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 239000004135 Bone phosphate Substances 0.000 description 1
- 238000006418 Brown reaction Methods 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 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
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010016807 Fluid retention Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 208000003455 anaphylaxis Diseases 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
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003922 charged colloid Substances 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical class Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- WPUMTJGUQUYPIV-JIZZDEOASA-L disodium (S)-malate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)CC([O-])=O WPUMTJGUQUYPIV-JIZZDEOASA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical group OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- WBJZTOZJJYAKHQ-UHFFFAOYSA-K iron(3+) phosphate Chemical compound [Fe+3].[O-]P([O-])([O-])=O WBJZTOZJJYAKHQ-UHFFFAOYSA-K 0.000 description 1
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 239000000276 potassium ferrocyanide Substances 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019265 sodium DL-malate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 239000001394 sodium malate Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- ZBTUYCUNQBRXOR-UHFFFAOYSA-L sodium succinate hexahydrate Chemical compound O.O.O.O.O.O.[Na+].[Na+].[O-]C(=O)CCC([O-])=O ZBTUYCUNQBRXOR-UHFFFAOYSA-L 0.000 description 1
- 229940074453 sodium succinate hexahydrate Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 238000004441 surface measurement Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000013076 target substance Substances 0.000 description 1
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Description
本発明は鉄欠乏性貧血の治療に有用な鉄錯化合
物に関し、さらに詳しくは、非経口投与可能なデ
キストリン・ヒドロキシカルボン酸・第二鉄多核
複合体及びその製造法に関する。
鉄欠乏性貧血症の治療法は主として経口による
鉄剤の投与に依存しているが、大量の鉄の投与を
必要とする場合、経口投与された鉄が適正に吸収
されない場合、副作用等のため患者が鉄の経口投
与に耐えられない場合、慢性持続性出血による鉄
喪失が鉄吸収より高く貯蔵鉄の喪失が見られる場
合等においては経口投与に代えて非経口による鉄
剤の投与が行われる。
鉄を経口投与する場合、腸管からの吸収速度は
遊離鉄濃度に依存するため鉄が遊離する方が治療
効果が高くなる結果、高濃度で遊離鉄として存在
しうる第一鉄が多く用いられている。
これに対し非経口用鉄剤の場合、遊離鉄はその
分量によつては投与された生体を極めて危険な状
態におとしいれることが知られているため、遊離
鉄の割合が少ない鉄剤の製造に努力が払われてお
り、又、非経口鉄剤においては、その分子量が適
度に高く尿中への排泄が少ないこと、鉄濃度が高
いこと、体液と等張の注射液を得やすいこと、中
性付近において溶液時安定であること及び溶液状
態での貯蔵安定性が高いことなどが要求され、経
口用鉄剤とは根本的に異なる課題を有し、製品の
安全性および安定性を保つため比較にならぬ程高
度の製造技術が要求される。
第二鉄塩とモノ又はオリゴサツカリドおよびヒ
ドロキシカルボン酸類からなる複合体が鉄欠乏性
貧血症の治療に有効であることを開示した技術は
いくつかある。例えば、特公昭40−7296号、同40
−17782号には第二鉄塩、ヘキシトール及び１〜
３塩基性ヒドロキシカルボン酸を分散液安定剤の
存在下で反応せしめ鉄調合物を得る方法が示され
ている。しかしながら、この方法においては15〜
16重量％の比較的低い鉄含量の調合物しか得られ
ず、又急性毒性をハツカネズミに静注した場合、
LD5035mg/Kgという高い毒性を示す欠点を有す
る。又、特公昭46−3196号には水酸化第二鉄１モ
ルと、ソルビツト約1.5モル、グルコン酸約0.4モ
ル、平均分子量500〜1200のデキストリン、デキ
ストラン、水素化デキストリン又は水素化デキス
トラン0.5モル（グルコースとして）からなる錯
化合物形成剤の２モルとを反応させ鉄調合物を得
る方法が示されている。この方法においても、得
られた鉄調合物の鉄含量は21〜26重量％に過ぎ
ず、又、人体に投与した場合投与鉄量の10％が尿
中に排泄され、マウスにおけるLD50も筋肉内注
射で380mg/Kgと比較的高い毒性を示すなど改善さ
るべき欠点を有する。これらサツカリド・ヒドロ
キシカルボン酸・第二鉄複合体は上記の如き欠点
の他、分子量が比較的小さいため、血球、血管、
筋肉等を損傷するおそれがあり、その複合体溶液
は血液及び体液とかけ離れた高いPHにおいてのみ
安定であるなど非経口鉄剤として好ましくない点
を有する。
又、従来非経口用鉄剤として用いられているデ
キストラン・第二鉄複合体においてはデキストラ
ン自体が高価であり、又、体内での分解が極めて
遅く、蓄積性を有しており、デキストラン・第二
鉄複合体を非経口投与した場合、生体内の細網内
皮系への取込みが悪く、血中累積性が認められ、
抗原として作用し抗体を産生させ、又発癌性を有
するとの報告もあり非経口用鉄剤としては種々の
欠点を有する。
一方、デキストリン・第二鉄複合体において
は、その組成であるデキストリンは生体内に分解
酵素が存在するのでデキストランに見られるよう
な蓄積性はなく、有害な免疫抗体も産生しない。
又分子量の大きいデキストリン・第二鉄複合体に
おいては腎臓で濾過されず尿中への排泄が少ない
など有利な点が多い。しかしながらデキストリン
は還元基を有し第二鉄を第一鉄に還元して遊離の
第一鉄イオンを生ぜしめやすい。又デキストリ
ン・第二鉄複合体は水溶液状態において長期貯蔵
安定性、熱安定性が充分でないなどの欠点を有す
る。
そこで本発明者らは高分子量のデキストリンを
用いてこれら製剤の安定性の改善を試みたが、所
望の効果が得られず鉄含有率の低い治療効果の悪
いものしか得られなかつた。逆に鉄含有率を高め
ることにより治療効果を高め、デキストリンの還
元基の影響を少なくし、遊離の第一鉄イオンを生
じにくいデキストリン・第二鉄複合体の製造も試
みたが、かかる複合体では保水性が減少し不安定
なものしか得られなかつた。
本発明者らは適当な分子量を有するデキストリ
ンとクエン酸、グルコン酸、酒石酸、リンゴ酸、
コハク酸より選ばれたヒドロキシカルボン酸若し
くはそのアルカリ塩の少なくとも１種、好適には
クエン酸ナトリウム若しくはクエン酸カリウム
を、反応性を有する第二鉄多核オール化体に好ま
しい比率で配位結合せしめることによつて、かか
る要求を満たす鉄複合体をつくることに成功し本
発明を完成するに至つた。本発明は鉄含量35〜48
重量％で、投与された鉄は尿中にはほとんど排泄
されず実質的に遊離鉄を含まず、安定性・安全性
の極めて高い非経口鉄剤を提供する。
本発明によれば、第二鉄多核オール化体と、２
w/v%溶液を４℃で７日間放置するとき沈澱が生
じず、ソモジーネルソン法により測定される還元
末端数により求められる平均分子量が2500〜
10000、好ましくは3500〜6000のデキストリン
（以下単にデキストリンという）を鉄１モルに対
し0.75〜1.60モル（グルコール残基単位、以下同
様）及びクエン酸、グルコン酸、酒石酸、リンゴ
酸、コハク酸より選ばれたヒドロキシカルボン酸
（以下単にヒドロキシカルボン酸という）若しく
はそれらのアルカリ塩の少なくとも１種、好まし
くはクエン酸又はそのナトリウム塩もしくはカリ
ウム塩を鉄１モルに対し0.02〜0.20モル好ましく
は0.05〜0.16モルの範囲、及び炭酸ナトリウム又
は炭酸カリウムより選ばれる炭酸アルカリの少な
くとも１種を水と共に混合し、加熱撹拌可能な容
器中において、100℃〜130℃、好ましくは102℃
〜120℃の範囲で１〜５時間加熱撹拌することに
よつて粗製デキストリン・ヒドロキシカルボン
酸・第二鉄多核複合体溶液を得る。
他方、上記第二鉄多核オール化体とデキストリ
ン（鉄１モルに対し0.75〜1.60モル）を炭酸アル
カリの存在下100℃〜130℃の温度範囲で、好まし
くは102℃〜120℃の温度で１〜５時間加熱撹拌
し、得られた反応溶液に水を加えて希釈し、該溶
液を濾過し未反応物を除去する。次いで濾液にメ
チルアルコール・エチルアルコール及びイソプロ
ピルアルコールから選択された低級アルキルアル
コールの少なくとも１種を加え、デキストリン・
第二鉄多核複合体を沈澱させ、遠沈により分離す
る。好ましくは上記操作を繰り返し行うことによ
つてアルコール水を含む精製デキストリン・第二
鉄多核複合体を得ることができる。この工程で使
用される低級アルキルアルコールは少なくとも30
v/v%以上の濃度が必要であるが、アルコール濃
度を不必要に高くすることは精製効率を低くする
ので好ましくない。このようにして得られた精製
デキストリン・第二鉄多核複合体はアルコール水
を含むがこのまま、若しくはいつたん乾燥させた
のち、水と共に加熱溶解させる。低級アルキルア
ルコール水を含む精製デキストリン・第二鉄多核
複合体を用いた場合、適当な時間沸騰させて低級
アルキルアルコール分を留去させることが好まし
い。得られたデキストリン・第二鉄多核複合体溶
液にヒドロキシカルボン酸若しくはそのアルカリ
塩の少なくとも１種を鉄１モルに対し0.02〜0.2
モル、好ましくは0.05〜0.16モルの範囲で加え、
110〜130℃の温度で密閉容器中で１〜５時間加熱
撹拌することによつて粗製デキストリン・ヒドロ
キシカルボン酸・第二鉄多核複合体溶液を得る。
上記いずれかの方法によつて得られた粗製デキ
ストリン・ヒドロキシカルボン酸・第二鉄多核複
合体溶液を濾過し、メチルアルコール、エチルア
ルコール及びイソプロピルアルコールから選ばれ
た低級アルキルアルコールの少なくとも１種を加
えることによつて該複合体を沈澱せしめ、遠心分
離し、所望によりこれを繰り返し、精製デキスト
リン・ヒドロキシカルボン酸・第二鉄多核複合体
を得る。次いで低級アルキルアルコール水を含む
該複合体を温風又は減圧によつて乾燥し、所望に
より粉砕し、貯蔵することにより、用時非経口用
鉄剤として調製することができる。
本精製工程は未反応ヒドロキシカルボン酸アル
カリ塩、遊離鉄、低鉄含有量複合体及び低分子複
合体部分の除去に有効で本発明複合体の安定性、
安全性の向上に役立つ。
本発明において使用される第二鉄多核オール化
体は、例えば、塩化第二鉄水溶液を冷時ないし常
温においてよくかきまぜながら過剰量の炭酸アル
カリ水溶液をゆつくりと滴加し、生成する懸濁液
を蒸溜水または純水で洗滌・濾過ないし遠心分離
することによつて比較的簡単に調製される。この
ようにして得られた第二鉄多核オール化体におい
ては他の成分との配位結合を妨害し従つて鉄含有
率を低くする原因となる電解質が可及的に除かれ
ていることが好ましく、上記方法に従えば比較的
簡単にかつ、イオン交換、透析等を行うよりも経
済的に有利にかかる条件を達成できる。
又、本発明において使用されるヒドロキシカル
ボン酸若しくはそのアルカリ塩並びにその使用量
は重要な意味を有する。即ち、ヒドロキシカルボ
ン酸若しくはそのアルカリ塩を本発明複合体の構
成成分とすることにより、目的物質に負電荷を与
え、溶液時の安定性がデキストリン・第二鉄複合
体に比べ飛躍的に向上する。特にクエン酸アルカ
リ塩を鉄１モルに対し0.02〜0.20モル、好ましく
は0.05〜0.16モルの範囲の量で使用した場合最も
顕著な溶液時の安定性の向上が認められる。又ヒ
ドロキシカルボン酸アルカリ塩の反応量が増加す
るにつれ得られる複合体の分子量が低くなる傾向
があり、従つて該複合体の分子量を調節する意義
をも有している。
又、後記の実験より明らかな如く、本発明複合
体のデキストリン量は複合体の溶液時安定性に大
きく影響し、一般にデキストリン量が増加し、原
末鉄含量が低下する程遊離鉄の量が増え、総じて
安定性並びに安全性が低下するという結果が得ら
れている。
一方においてデキストリン量を極端に少なくす
ることは複合体の保水性が低下し溶液時の安定性
も低下するので好ましくない。そこで本発明にお
いては、デキストリン量は必要かつ最小限にとど
め、高鉄含量の複合体とし、複合体の親水性低下
をおぎなうためにヒドロキシカルボン酸を使用す
ることを特徴としている。従つて本発明複合体は
複合体の溶液時安定性を低下させることなく且つ
適度に高い分子量の複合体が得られる程度の範囲
の量のデキストリンを含んでいることが好まし
く、本発明の方法において鉄１モルに対し0.75〜
1.6モル（グルコース単位）のデキストリンを使
用することによつてかかる条件を満足する複合体
が得られる。
このようにして得られたデキストリン・ヒドロ
キシカルボン酸・第二鉄多核複合体は濃褐色無臭
の無定形粉末で、冷水には除々に溶け熱水には溶
けやすく、一旦溶解すると冷却しても析出しない
安定な溶液となる。またこの溶液は中性付近にお
いて充分安定である。エタノール・メタノール・
アセトン・エーテル等の有機溶媒にはほとんど溶
けない。又本複合体は負電荷を有し、浸透圧から
測定した数平均分子量は約14万の分子量分布を有
する高分子複合体である。
本発明によつて製造された鉄複合体は下記の特
徴を有する。
１ 鉄含有率が高いため製剤上、貯蔵上極めて有
利である。
２ 静脈中に投与された場合、すみやかに骨髄、
肝臓、脾臓等の内皮系細胞に取り込まれ、デキ
ストラン第二鉄の如き血中累積性を示さない。
３ 本複合体の水溶液は中性付近にて安定であ
り、従つて生体組織に損傷を与える心配はな
い。
４ 本複合体を構成している鉄成分以外はすべて
代謝性物質であるデキストリンとヒドロキシカ
ルボン酸であるため、投与時に蓄積性はなく、
その他重篤な副作用は見られない。
５ 溶液時の貯蔵並びに熱安定性が極めて高いた
め、製剤滅菌時並びに貯蔵、流通段階で極めて
有利である。
本発明複合体についての毒性及び薬理作用を調
べた。
１投与群８匹の雄マウスを用いて本発明のデキ
ストリン・クエン酸・第二鉄多核複合体の急性毒
性を調べたところ、静脈内投与によるLD50は約
460mgFe/Kg、皮下投与の場合2500mgFe/Kg以上を
示した。又、６匹の雄のモルモツトに前記複合体
の10mgFe/Kgを腹部皮下または後頚部皮下に隔日
に３回注射して感作し、３週間後に全身性アナフ
イラキシーを、又、同様に感作したモルモツトの
回腸を用いてSchltz−Dale反応等を調べ、抗原性
を調べたが、いずれの試験においても陰性であつ
た。
無胃性鉄欠乏性貧血症の患者に250mgの鉄を含
む59Feを用いた本発明のデキストリン・クエン
酸・第二鉄多核複合体を20w/v%ブドウ糖と混合
して静注し、鉄の動態を調べた。血中鉄消失曲線
より鉄半減期は約29分で、赤血球鉄利用曲線は14
日まで上昇を続け、鉄利用率は70％以上を示し
た。又、放射能の体表計測による59Feの体内分布
は、24時間後では肝が最も高く、次いで骨髄、脾
の順で、３日〜４日後には骨髄が最高となり、肝
では減少し始め、血中濃度を表わす心臓にカウン
ト数の増加が見られ、赤血球に利用されていく様
子が観察された。
又、婦人科疾患による鉄欠乏性貧血患者55例に
ついて症状に応じ１日１管〜２管（１管２ml中本
発明デキストリン・クエン酸・第二鉄多核複合体
110〜145mg（鉄として50mg）ソルビトール80mg、
注射用蒸留水適量）を１週間に２〜７回の割合で
静注若しくは筋注を行つた結果、血色素量の増加
が1.5ｇ/dl以上であつたもの38例、1.4〜1.0ｇ/dl
のもの12例、1.0ｇ/dl以下のもの５例であり、大
部分の例に貧血の有意な改善が認められた。全例
について副作用は見られず、急性鉄中毒症状、ア
レルギー症状、肝機能障害は見られなかつた。
本発明複合体は蒸留水に溶かしてそのまま、好
ましくは非還元性の等張化剤例えば食塩、ソルビ
ツト・マンニツト等のヘキシツト類若しくはグリ
セリン・エチレングリコール等の多価アルコール
類の少なくとも１種を適量加えることによつて注
射剤とすることができる。
実施例 １
新製の第二鉄多核オール化体を185ｇ（鉄原子
に換算して0.25モル）と、分子量5000のデキスト
リン34ｇ、クエン酸ナトリウム２水塩7.4ｇ及び
無水炭酸ナトリウム2.8ｇを少量の水と共にオー
トクレーブに充填し、よくかきまぜた後撹拌しつ
つ120℃で２時間反応させた。濃褐色を呈した粗
製のデキストリン・クエン酸・第二鉄多核複合体
溶液を得た。該溶液に500mlの水を加えて濾過
し、水不溶物を除去した。該濾液に水を加え全量
を1000mlとしたのち、メチルアルコール640mlを
加え生成物を沈澱させた。しばらく静置した後上
澄を捨て、沈澱部分を遠心分離し得られた沈澱に
水を350ml加え、沸騰浴で加熱溶解した。冷後パ
ルプ濾過を行い、濾液に水を加えて600mlとし
た。該溶液にエチルアルコール600mlを加え、暫
時静置した後上澄を除き遠心分離することによつ
て、エチルアルコール水を含むケーキ状の精製デ
キストリン・クエン酸・第二鉄多核複合体を得
た。該沈澱を室温下、塩化カルシウム上で減圧乾
燥後、乾燥物を粉砕し、濃茶褐色の粉末状デキス
トリン・クエン酸・第二鉄多核複合体26.3ｇを得
た。鉄含有率43.5重量％、収率（鉄を基準にし
て）81.4重量％。
実施例 ２
新製第二鉄多核オール化体78ｇ（鉄として5.6
ｇ）、分子量5100のデキストリン19.5ｇクエン酸
ナトリウム２水塩2.9ｇ（0.01モル）および無水
炭酸ナトリウム1.2ｇを少量の水と共にガラス性
簡易オートクレーブ中でかきまぜながら115℃で
３時間反応させデキストリン・クエン酸・第二鉄
多核複合体の濃厚溶液を得た。水200mlを加えた
後濾過し、濾液に水を加えて全量を400mlに調製
した。これにメチルアルコール285ml加えて複合
体を沈澱させ遠心分離した。分離後沈澱を水150
mlで加熱溶解させ冷却した後、精密にパルプ濾過
を行い、濾液に水を加えて全量を230mlに調製し
た。これにエチルアルコール250mlを加えて複合
体を沈澱させ、遠心分離した。得られた沈澱を減
圧下、塩化カルシウム上に乾燥してデキストリ
ン・クエン酸・第二鉄多核複合体10.4ｇを得た。
鉄含有率43.0重量％、収率（鉄を基準にして）
80.4重量％。
実施例 ３
実施例２で使用したクエン酸ナトリウム２水塩
の代わりにグリコール酸ナトリウム1.0ｇ（0.01
モル）を用い、実施例２と同様の方法で、デキス
トリン・グリコール酸・第二鉄多核複合体11.9ｇ
を得た。鉄含有率38.7重量％、収率（鉄を基準に
して）82.1重量％。
実施例 ４
実施例２のクエン酸ナトリウム２水塩のかわり
に、グルコン酸ナトリウム2.2ｇ（0.01モル）を
用い、実施例２と同様の方法でデキストリン・グ
ルコン酸・第二鉄多核複合体10.9ｇを得た。鉄含
有率42.8重量％、収率（鉄を基準にして）83.9重
量％。
実施例 ５
クエン酸ナトリウム２水塩のかわりに、酒石酸
ナトリウム２水塩2.3ｇ（0.01モル）を用いて、
実施例２と同様の方法でデキストリン・酒石酸・
第二鉄多核複合体11.0ｇを得た。鉄含有率42.1重
量％、収率（鉄を基準にして）82.1重量％。
実施例 ６
クエン酸ナトリウム２水塩のかわりに、リンゴ
酸ナトリウム1.8ｇ（0.01モル）を用いて、実施
例２と同様の方法でデキストリン・リンゴ酸・第
二鉄多核複合体10.8ｇを得た。鉄含有率39.3重量
％、収率（鉄を基準にして）75.0重量％。
熱安定性試験
実施例２で得られたデキストリン・クエン酸・
第二鉄多核複合体とクエン酸ナトリウム２水塩を
加えず、その他の条件はすべて実施例２に従つて
製造されたデキストリン・第二鉄多核複合体につ
いて、各々から鉄濃度25mg/mlの水溶液を調製
し、アンプルを充填し、該アンプルを100℃に加
熱して熱安定性試験を行つた。25時間毎に各試料
の外観及び電気泳動実験から熱安定性を比較判定
した。
上記試験の結果、デキストリン・クエン酸・第
二鉄多核複合体試料においては200時間経過して
もその外観に異常は認められず、電気泳動状態も
良好であつたが、クエン酸ナトリウムを加えない
デキストリン・第二鉄多核複合体試料では25時間
でゲル化がおこり、電気泳動においても原点残留
物を認めた。クエン酸ナトリウム以外の本発明で
使用しうるヒドロキシカルボン酸アルカリ塩につ
いても同様の実験を行つた結果、クエン酸ナトリ
ウムに比較すれば若干劣るが、デキストリン・第
二鉄複合体に比べ熱安定性の有意な改善がみられ
た。
なお、以下において実施される熱安定性試験は
上記方法と同じ条件で行つた。
実施例 ７〜11
鉄成分に対し、各々0.01、0.02、0.10、0.15、
0.3のモル比を有するクエン酸ナトリウム２水塩
を、新製第二鉄多核オール化体146ｇ（鉄として
0.2モル）、分子量5600のデキストリン42ｇおよび
無水炭酸ナトリウム2.3ｇと共に同一条件で、実
質的に前記実施例１の方法に従い、反応させ、得
られたデキストリン・クエン酸・第二鉄多核複合
体について、収率・鉄含有率・熱安定性を調べ
た。結果を表１に示す。
The present invention relates to an iron complex compound useful for the treatment of iron deficiency anemia, and more particularly to a parenterally administrable dextrin/hydroxycarboxylic acid/ferric polynuclear complex and a method for producing the same. Treatment for iron deficiency anemia mainly relies on oral administration of iron, but in cases where large doses of iron are required, or when orally administered iron is not absorbed properly, or because of side effects, etc. Parenteral administration of iron is used instead of oral administration in cases where the patient cannot tolerate oral administration of iron, or in cases where iron loss due to chronic persistent bleeding is higher than iron absorption and loss of stored iron is observed. When iron is administered orally, the rate of absorption from the intestinal tract depends on the free iron concentration, so the therapeutic effect is higher when iron is released.As a result, ferrous iron, which can exist as free iron at high concentrations, is often used. There is. On the other hand, in the case of parenteral iron preparations, free iron is known to put the administered body in an extremely dangerous state depending on the amount, so efforts are being made to manufacture iron preparations with a low proportion of free iron. In addition, parenteral iron preparations have a moderately high molecular weight, are excreted little in the urine, have a high iron concentration, are easy to obtain an injection solution that is isotonic with body fluids, and are near neutral. In order to maintain the safety and stability of the product, iron preparations have fundamentally different issues than oral iron preparations, such as being stable in solution and having high storage stability in the solution state. Extremely sophisticated manufacturing technology is required. Several techniques have disclosed that complexes consisting of ferric salts, mono- or oligosaccharides, and hydroxycarboxylic acids are effective in treating iron deficiency anemia. For example, Special Publication No. 40-7296,
-17782 contains ferric salts, hexitol and
A method is presented for reacting tribasic hydroxycarboxylic acids in the presence of dispersion stabilizers to obtain iron formulations. However, in this method, 15~
A preparation with a relatively low iron content of 16% by weight was obtained and was acutely toxic when administered intravenously to mice.
It has the disadvantage of high toxicity with an LD 50 of 35mg/Kg. In addition, Japanese Patent Publication No. 46-3196 discloses 1 mole of ferric hydroxide, about 1.5 mole of sorbitol, about 0.4 mole of gluconic acid, and 0.5 mole of dextrin, dextran, hydrogenated dextrin, or hydrogenated dextran with an average molecular weight of 500 to 1200 ( (as glucose) to obtain an iron preparation. Even with this method, the iron content of the iron preparation obtained is only 21-26% by weight, and when administered to humans, 10% of the administered iron amount is excreted in the urine, and the LD 50 in mice is also low. It has drawbacks that need to be improved, such as relatively high toxicity of 380mg/Kg when intravenously injected. In addition to the drawbacks mentioned above, these saccharide/hydroxycarboxylic acid/ferric iron complexes have relatively small molecular weights, so they
There is a risk of damaging muscles, etc., and the complex solution is stable only at high pH, which is far from blood and body fluids, making it undesirable as a parenteral iron preparation. In addition, in the dextran/ferric iron complex conventionally used as a parenteral iron preparation, dextran itself is expensive, decomposes extremely slowly in the body, and has a tendency to accumulate. When iron complexes are administered parenterally, their uptake into the reticuloendothelial system in vivo is poor, and accumulation in the blood is observed.
It has various drawbacks as a parenteral iron preparation, as it acts as an antigen and produces antibodies, and is also reported to be carcinogenic. On the other hand, in the dextrin/ferric iron complex, the composition dextrin has degrading enzymes in the living body, so it does not accumulate like dextran does, and does not produce harmful immune antibodies.
Furthermore, the dextrin/ferric iron complex, which has a large molecular weight, has many advantages such as not being filtered by the kidneys and being excreted in the urine. However, dextrins have reducing groups and tend to reduce ferric iron to ferrous iron, producing free ferrous ions. Further, the dextrin/ferric iron complex has drawbacks such as insufficient long-term storage stability and insufficient thermal stability in an aqueous solution state. Therefore, the present inventors attempted to improve the stability of these preparations by using high-molecular-weight dextrins, but the desired effects could not be obtained and only products with low iron content and poor therapeutic effects were obtained. On the other hand, attempts were made to produce a dextrin/ferric iron complex that would enhance the therapeutic effect by increasing the iron content, reduce the influence of the reducing group of dextrin, and be less likely to generate free ferrous ions, but such a complex However, the water holding capacity decreased and only unstable products could be obtained. The present inventors used dextrins with appropriate molecular weights, citric acid, gluconic acid, tartaric acid, malic acid,
Coordinating at least one hydroxycarboxylic acid selected from succinic acid or an alkali salt thereof, preferably sodium citrate or potassium citrate, to a reactive polynuclear ferric iron compound in a preferred ratio. As a result, we succeeded in creating an iron composite that satisfies these requirements, and completed the present invention. The present invention has an iron content of 35-48
In terms of weight percent, the administered iron is hardly excreted in the urine and contains virtually no free iron, providing a parenteral iron preparation with extremely high stability and safety. According to the present invention, a ferric iron polynuclear olated product;
When the w/v% solution was left at 4℃ for 7 days, no precipitation occurred, and the average molecular weight determined by the number of reducing ends measured by Somogyi-Nelson method was 2500~
10,000, preferably 3,500 to 6,000 dextrin (hereinafter simply referred to as dextrin) is selected from 0.75 to 1.60 mol (glycol residue units, the same applies hereinafter) per 1 mol of iron, and citric acid, gluconic acid, tartaric acid, malic acid, and succinic acid. At least one type of hydroxycarboxylic acid (hereinafter simply referred to as hydroxycarboxylic acid) or an alkali salt thereof, preferably citric acid or its sodium salt or potassium salt, is added in an amount of 0.02 to 0.20 mol, preferably 0.05 to 0.16 mol, per mol of iron. and at least one alkali carbonate selected from sodium carbonate or potassium carbonate are mixed with water and heated to 100°C to 130°C, preferably 102°C in a container that can be heated and stirred.
A crude dextrin/hydroxycarboxylic acid/ferric polynuclear complex solution is obtained by heating and stirring at a temperature of ~120°C for 1 to 5 hours. On the other hand, the ferric polynuclear olate and dextrin (0.75 to 1.60 mol per 1 mol of iron) are mixed together in the presence of an alkali carbonate at a temperature of 100°C to 130°C, preferably at a temperature of 102°C to 120°C. After heating and stirring for ~5 hours, the resulting reaction solution is diluted with water, and the solution is filtered to remove unreacted substances. Next, at least one type of lower alkyl alcohol selected from methyl alcohol, ethyl alcohol, and isopropyl alcohol is added to the filtrate, and dextrin/
Ferric polynuclear complexes are precipitated and separated by centrifugation. Preferably, by repeating the above operations, a purified dextrin/ferric polynuclear complex containing alcoholic water can be obtained. The lower alkyl alcohol used in this step is at least 30%
Although a concentration of v/v% or higher is required, it is not preferable to increase the alcohol concentration unnecessarily because it lowers the purification efficiency. The purified dextrin/ferric polynuclear complex thus obtained, which contains alcoholic water, can be used as is or after being dried, it can be heated and dissolved together with water. When a purified dextrin/ferric polynuclear complex containing lower alkyl alcohol water is used, it is preferable to boil it for an appropriate period of time to distill off the lower alkyl alcohol content. At least one kind of hydroxycarboxylic acid or its alkali salt is added to the obtained dextrin/ferric polynuclear complex solution at a rate of 0.02 to 0.2 per mole of iron.
mol, preferably in the range of 0.05 to 0.16 mol,
A crude dextrin/hydroxycarboxylic acid/ferric polynuclear complex solution is obtained by heating and stirring for 1 to 5 hours in a closed container at a temperature of 110 to 130°C. The crude dextrin/hydroxycarboxylic acid/ferric polynuclear complex solution obtained by any of the above methods is filtered, and at least one lower alkyl alcohol selected from methyl alcohol, ethyl alcohol, and isopropyl alcohol is added. The complex is precipitated and centrifuged, optionally repeated, to obtain a purified dextrin-hydroxycarboxylic acid-ferric polynuclear complex. The complex containing the lower alkyl alcohol water is then dried with warm air or reduced pressure, crushed if desired, and stored to prepare a parenteral iron preparation at the time of use. This purification process is effective in removing unreacted hydroxycarboxylic acid alkali salts, free iron, low iron content complexes, and low-molecular complex parts, and improves the stability of the complexes of the present invention.
Helps improve safety. The polynuclear olated ferric iron used in the present invention is, for example, a suspension produced by slowly adding an excessive amount of an aqueous alkali carbonate solution dropwise to a ferric chloride aqueous solution while stirring well at cold or room temperature. It is relatively easily prepared by washing with distilled or pure water, filtering, or centrifuging. In the ferric polynuclear product thus obtained, electrolytes that interfere with coordination bonds with other components and cause the iron content to be lowered are removed as much as possible. Preferably, by following the above method, such conditions can be achieved relatively easily and more economically than by performing ion exchange, dialysis, etc. Furthermore, the hydroxycarboxylic acid or alkali salt thereof used in the present invention and the amount used have important meanings. That is, by using hydroxycarboxylic acid or its alkali salt as a component of the complex of the present invention, it imparts a negative charge to the target substance, and its stability in solution is dramatically improved compared to the dextrin/ferric iron complex. . In particular, when the alkali citrate salt is used in an amount ranging from 0.02 to 0.20 mol, preferably from 0.05 to 0.16 mol, per 1 mol of iron, the most remarkable improvement in stability in solution is observed. Furthermore, as the amount of the alkali hydroxycarboxylic acid salt reacted increases, the molecular weight of the resulting composite tends to decrease, and therefore, it has the significance of controlling the molecular weight of the composite. Furthermore, as is clear from the experiments described later, the amount of dextrin in the composite of the present invention greatly affects the stability of the composite in solution, and generally, as the amount of dextrin increases and the powder iron content decreases, the amount of free iron decreases. The result is that stability and safety generally decrease. On the other hand, it is not preferable to reduce the amount of dextrin to an extremely low level since this will reduce the water retention of the complex and its stability in solution. Therefore, the present invention is characterized in that the amount of dextrin is kept to the necessary and minimum amount, the complex has a high iron content, and hydroxycarboxylic acid is used to compensate for the decrease in hydrophilicity of the complex. Therefore, it is preferable that the complex of the present invention contains dextrin in an amount that does not reduce the stability of the complex in solution and that allows a complex with a suitably high molecular weight to be obtained. 0.75 to 1 mole of iron
By using 1.6 moles (glucose units) of dextrin, a complex satisfying these conditions is obtained. The dextrin/hydroxycarboxylic acid/ferric polynuclear complex thus obtained is a dark brown, odorless, amorphous powder that gradually dissolves in cold water and easily dissolves in hot water, and once dissolved, it precipitates even when cooled. The result is a stable solution. Moreover, this solution is sufficiently stable near neutrality. Ethanol/methanol/
Almost insoluble in organic solvents such as acetone and ether. Furthermore, this complex is a polymer complex that has a negative charge and a molecular weight distribution with a number average molecular weight of about 140,000 as measured from osmotic pressure. The iron composite produced according to the present invention has the following characteristics. 1. Due to its high iron content, it is extremely advantageous in terms of formulation and storage. 2. When administered intravenously, the bone marrow,
It is taken up by endothelial cells such as the liver and spleen, and does not exhibit cumulative effects in the blood like ferric dextran. 3. The aqueous solution of this complex is stable near neutrality, so there is no risk of damaging living tissue. 4. Since the components other than the iron component that make up this complex are all metabolizable substances, such as dextrin and hydroxycarboxylic acid, there is no accumulation during administration.
No other serious side effects were observed. 5. Since it has extremely high storage and thermal stability in the form of a solution, it is extremely advantageous during preparation sterilization and during storage and distribution stages. The toxicity and pharmacological effects of the complex of the present invention were investigated. When the acute toxicity of the dextrin-citrate-ferric polynuclear complex of the present invention was investigated using 8 male mice per administration group, the LD 50 after intravenous administration was approximately
It showed 460mgFe/Kg, and more than 2500mgFe/Kg when administered subcutaneously. In addition, six male guinea pigs were sensitized by injecting 10 mg Fe/Kg of the above complex into the abdomen subcutaneously or posterior cervical subcutaneously three times every other day, and 3 weeks later they developed systemic anaphylaxis and were similarly sensitized. Schltz-Dale reaction and other tests were performed using guinea pig ileum to determine antigenicity, but all tests were negative. The dextrin-citric acid-ferric polynuclear complex of the present invention using 59 Fe containing 250 mg of iron was mixed with 20 w/v% glucose and injected intravenously to patients with agastric iron deficiency anemia. We investigated the dynamics of According to the blood iron loss curve, the iron half-life is approximately 29 minutes, and the red blood cell iron utilization curve is 14 minutes.
It continued to rise until today, and the iron utilization rate was over 70%. In addition, the distribution of 59 Fe in the body, determined by body surface measurement of radioactivity, was highest in the liver after 24 hours, followed by the bone marrow and spleen, reaching the highest level in the bone marrow after 3 to 4 days, and began to decrease in the liver. An increase in the number of counts in the heart, which indicates blood concentration, was observed, and it was observed that the drug was being utilized by red blood cells. In addition, 55 patients with iron deficiency anemia due to gynecological diseases received 1 to 2 tubes per day (1 tube, 2 ml) of the dextrin/citric acid/ferric polynuclear complex of the present invention, depending on the symptoms.
110-145 mg (50 mg as iron) sorbitol 80 mg,
After intravenously or intramuscularly injecting an appropriate amount of distilled water for injection 2 to 7 times a week, 38 cases showed an increase in hemoglobin level of 1.5 g/dl or more, 1.4 to 1.0 g/dl.
There were 12 cases with anaemia, and 5 cases with 1.0 g/dl or less, and significant improvement in anemia was observed in most cases. No side effects were observed in all cases, and no symptoms of acute iron toxicity, allergic symptoms, or liver dysfunction were observed. The complex of the present invention is dissolved in distilled water, and an appropriate amount of at least one non-reducing tonicity agent, such as salt, hexites such as sorbitol and mannite, or polyhydric alcohols such as glycerin and ethylene glycol, is preferably added. It can also be made into an injection. Example 1 A small amount of 185 g of a newly produced polynuclear olated ferric iron (0.25 mol in terms of iron atoms), 34 g of dextrin with a molecular weight of 5000, 7.4 g of sodium citrate dihydrate, and 2.8 g of anhydrous sodium carbonate was added. The mixture was charged into an autoclave with water, stirred well, and reacted at 120°C for 2 hours with stirring. A crude dextrin/citric acid/ferric polynuclear complex solution with a dark brown color was obtained. 500 ml of water was added to the solution and filtered to remove water-insoluble matter. Water was added to the filtrate to bring the total volume to 1000 ml, and then 640 ml of methyl alcohol was added to precipitate the product. After standing for a while, the supernatant was discarded, the precipitate was centrifuged, 350 ml of water was added to the resulting precipitate, and the mixture was dissolved by heating in a boiling bath. After cooling, pulp filtration was performed, and water was added to the filtrate to make 600 ml. 600 ml of ethyl alcohol was added to the solution, and after allowing it to stand for a while, the supernatant was removed and centrifuged to obtain a purified dextrin/citric acid/ferric polynuclear complex containing ethyl alcohol water in the form of a cake. The precipitate was dried under reduced pressure over calcium chloride at room temperature, and the dried product was pulverized to obtain 26.3 g of a dark brown powdered dextrin/citric acid/ferric polynuclear complex. Iron content 43.5% by weight, yield (based on iron) 81.4% by weight. Example 2 78g of newly manufactured ferric iron polynuclear compound (5.6 as iron)
g), 19.5 g of dextrin with a molecular weight of 5100, 2.9 g (0.01 mol) of sodium citrate dihydrate, and 1.2 g of anhydrous sodium carbonate were stirred together with a small amount of water in a simple glass autoclave and reacted at 115°C for 3 hours to produce dextrin and citric acid. A concentrated solution of acid-ferric polynuclear complex was obtained. After adding 200 ml of water, it was filtered, and water was added to the filtrate to adjust the total volume to 400 ml. 285 ml of methyl alcohol was added to this to precipitate the complex, which was then centrifuged. After separation, add the precipitate to 150 ml of water.
After heating and dissolving in 1 ml of water and cooling, precise pulp filtration was performed, and water was added to the filtrate to adjust the total volume to 230 ml. 250 ml of ethyl alcohol was added to this to precipitate the complex, and the mixture was centrifuged. The obtained precipitate was dried on calcium chloride under reduced pressure to obtain 10.4 g of a dextrin/citric acid/ferric polynuclear complex.
Iron content 43.0% by weight, yield (based on iron)
80.4% by weight. Example 3 In place of the sodium citrate dihydrate used in Example 2, 1.0 g of sodium glycolate (0.01
11.9 g of dextrin/glycolic acid/ferric polynuclear complex in the same manner as in Example 2 using
I got it. Iron content 38.7% by weight, yield (based on iron) 82.1% by weight. Example 4 10.9 g of dextrin/gluconic acid/ferric polynuclear complex was prepared in the same manner as in Example 2, using 2.2 g (0.01 mol) of sodium gluconate instead of sodium citrate dihydrate in Example 2. I got it. Iron content 42.8% by weight, yield (based on iron) 83.9% by weight. Example 5 Using 2.3 g (0.01 mol) of sodium tartrate dihydrate instead of sodium citrate dihydrate,
Dextrin, tartaric acid,
11.0 g of ferric polynuclear complex was obtained. Iron content 42.1% by weight, yield (based on iron) 82.1% by weight. Example 6 10.8 g of dextrin/malic acid/ferric polynuclear complex was obtained in the same manner as in Example 2 using 1.8 g (0.01 mol) of sodium malate instead of sodium citrate dihydrate. . Iron content 39.3% by weight, yield (based on iron) 75.0% by weight. Thermal stability test Dextrin, citric acid, and
An aqueous solution with an iron concentration of 25 mg/ml was prepared from each dextrin/ferric polynuclear complex prepared according to Example 2 without adding the ferric polynuclear complex and sodium citrate dihydrate, but under all other conditions. A thermal stability test was conducted by preparing a sample, filling an ampoule, and heating the ampoule to 100°C. The thermal stability of each sample was compared and determined from the appearance and electrophoresis experiment every 25 hours. As a result of the above test, no abnormality was observed in the appearance of the dextrin-citric acid-ferric polynuclear complex sample even after 200 hours, and the electrophoretic condition was good, but sodium citrate was not added. In the dextrin/ferric polynuclear complex sample, gelation occurred in 25 hours, and origin residues were also observed in electrophoresis. Similar experiments were conducted with hydroxycarboxylic acid alkali salts that can be used in the present invention other than sodium citrate. Although they are slightly inferior to sodium citrate, they have better thermal stability than dextrin/ferric iron complexes. Significant improvement was seen. Note that the thermal stability test conducted below was conducted under the same conditions as the above method. Examples 7 to 11 0.01, 0.02, 0.10, 0.15, respectively for iron component
Sodium citrate dihydrate having a molar ratio of 0.3 was added to 146 g of a new ferric iron polynuclear product (as iron).
0.2 mol), 42 g of dextrin with a molecular weight of 5,600, and 2.3 g of anhydrous sodium carbonate under the same conditions, substantially according to the method of Example 1 above, and the obtained dextrin-citric acid-ferric polynuclear complex, The yield, iron content, and thermal stability were investigated. The results are shown in Table 1.
【表】
実施例 12
新製の第二鉄多核オール化体158ｇ（鉄として
0.2モル）と、分子量3800のデキストリン32.1ｇ
および無水炭酸ナトリウム2.0ｇを少量の水と共
にかきまぜながら油浴にて加熱した。内容物が静
かに還流するよう加熱すると約102℃に制御され
る。約２時間反応を続けると茶褐色の反応液は黒
褐色の均一な溶液に変化し、デキストリン・第二
鉄多核複合体の濃厚な溶液を得た。該溶液に水
400mlを加え希釈し冷却したのち濾過して少量の
不溶性の未反応物を除去した。得られた濾液に水
を加えて全量を800mlとしたのちメチルアルコー
ル520mlを加えて沈澱部分を分離した。得られた
沈澱部分に水600mlを加え沸騰浴中で加熱撹拌し
て溶かした。冷後該溶液をパルプ濾過し、濾液に
水を加えて全量700mlに調製したのちメチルアル
コール880mlを加えて、デキストリン・第二鉄多
核複合体を沈澱させた。しばらく静置させ上澄を
除き、沈澱部分を遠心分離し、メチルアルコール
水を含む精製されたケーキ状のデキストリン・第
二鉄多核複合体を得た。該複合体に水260mlを加
えて加熱しかきまぜて溶解し、含まれているメチ
ルアルコールを留去した。冷後濾過し水を加えて
400mlに調製した。この一部をとり鉄の定量試験
を行つた。収率は鉄を基準にして89.6重量％であ
つた。
該溶液を簡易型オートクレーブに充填し、クエ
ン酸ナトリウム２水塩0.95ｇを加え120℃で２時
間反応させた。冷後、該溶液を絹布で濾過し、濾
液に水を加えて全量を400mlとした。該溶液にエ
チルアルコール290mlを加えることによつて、デ
キストリン・クエン酸・第二鉄多核複合体の沈澱
を得た。得られたエチルアルコール水を含むデキ
ストリン・クエン酸・第二鉄多核複合体を室温で
塩化カルシウム存在下減圧乾燥し、乾燥物を粉砕
し濃茶褐色の粉末状デキストリン・クエン酸・第
二鉄多核複合体18.8ｇを得た。鉄含有率46.5重量
％、収率（鉄を基準にして）77.7重量％。
実施例 13
新製の第二鉄多核オール化体1072ｇ（鉄として
1.4モル）と分子量5300のデキストリン280ｇおよ
び無水炭酸ナトリウム15.7ｇを水120mlと共に還
流器を付した反応容器に加え、かきまぜつつ103
℃で４時間反応させてデキストリン・第二鉄多核
複合体の溶液を得た。これに水280mlを加え、パ
ルプ濾過し、濾液に水を加えて5600mlとした。該
溶液にメチルアルコール3800mlを加え複合体を沈
澱させ遠心分離した。該沈澱部分に水4200mlを加
え加熱溶解し、冷後再びパルプ濾過を行い、濾液
に水を加えて全量を5000mlとした。該溶液にメチ
ルアルコール6300mlを加え複合体を沈澱させた。
該沈澱を分離し水2100mlを加えて加熱溶解しメチ
ルアルコールを留去した。該溶液に水を加えデキ
ストリン・第二鉄多核複合体2800mlを得た。収率
（鉄を基準として）92.2重量％。
得られたデキストリン・第二鉄多核複合体溶液
400ml（鉄として10.3ｇ）とクエン酸ナトリウム
２水塩5.4ｇとから、実質的に前記実施例12と同
じ方法で、デキストリン・クエン酸・第二鉄多核
複合体23.7ｇを得た。鉄含有率39.6重量％、収率
（鉄を基準にして）83.9重量％。
実施例 14
前記実施例13で得たデキストリン・第二鉄多核
複合体溶液400ml（鉄として10.3ｇ）とグルコー
ル酸ナトリウム1.81ｇとから前記実施例12と実質
的に同一の方法でデキストリン・グルコール酸・
第二鉄多核複合体23.8ｇを得た。鉄含有率38.8重
量％、収率（鉄を基準にして）82.1重量％。
実施例 15
前記実施例13で得たデキストリン・第二鉄多核
複合体溶液400ml（鉄として10.3ｇ）とグルコン
酸ナトリウム4.0ｇとから前記実施例12と実質的
に同じ方法でデキストリン・グルコン酸・第二鉄
多核複合体24.0ｇを得た。鉄含有率39.8重量％。
収率（鉄を基準にして）85.7重量％。
実施例 16
前記実施例13で得たデキストリン・第二鉄多核
複合体溶液400ml（鉄として10.3ｇ）とコハク酸
ナトリウム６水塩5.0ｇとから前記実施例12と実
質的に同じ方法でデキストリン・コハク酸・第二
鉄多核複合体24.5ｇを得た。鉄含有率38.2重量
％。収率（鉄を基準にして）83.9重量％。
実施例 17
前記実施例13で得たデキストリン・第二鉄多核
複合体溶液400ml（鉄として10.3ｇ）と酒石酸ナ
トリウム２水塩4.2ｇとから前記実施例12と実質
的に同じ方法でデキストリン・酒石酸・第二鉄多
核複合体24.3ｇを得た。鉄含有率38.2重量％。収
率（鉄を基準にして）83.0重量％。
実施例 18
前記実施例13で得たデキストリン・第二鉄多核
複合体溶液400ml（鉄として10.3ｇ）とリンゴ酸
ナトリウム3.3ｇとから前記実施例12と実質的に
同じ方法でデキストリン・リンゴ酸・第二鉄多核
複合体24.2ｇを得た。鉄含有率39.0重量％。収率
（鉄を基準にして）83.9重量％。
熱安定性試験
実施例13で得られた中間体デキストリン・第二
鉄多核複合体溶液および最終生成物のデキストリ
ン・クエン酸・第二鉄多核複合体について熱安定
性試験を行つた。
クエン酸を加えないデキストリン・第二鉄多核
複合体アンプルは100℃で加熱を続けた場合25時
間でゲル化し、電気泳動実験においても原点残留
物を認めた。一方、デキストリン・クエン酸・第
二鉄多核複合体アンプルにおいては100℃で200時
間加熱を続けても外観に異常を認めず電気泳動実
験でも良好な泳動を示した。
実施例14〜18の化合物についても同様に熱安定
性試験を行つた結果、デキストリン・クエン酸・
第二鉄多核複合体に比べやや劣るが、デキストリ
ン・第二鉄複合体に比べて有意な熱安定性の向上
が認められた。
実施例 19〜23
新製第二鉄多核オール化体907ｇ（鉄として1.2
モル）、分子量5000のデキストリン240ｇおよび無
水炭酸ナトリウム13.5ｇから実施例13と同じ方法
でデキストリン・第二鉄多核複合体溶液2400mlを
得た。該溶液400ml（鉄として10.25ｇ）にクエン
酸ナトリウム２水塩を鉄１モルに対して各々
0.01、0.05、0.10、0.15、0.50のモル比で反応さ
せて得られたデキストリン・クエン酸・第二鉄多
核複合体について、それぞれ鉄含量、収率（鉄を
基準にして）及び熱安定性を調べた。結果を表２
に示す。[Table] Example 12 158g of newly manufactured ferric iron polynuclear compound (as iron
0.2 mol) and 32.1 g of dextrin with a molecular weight of 3800.
and 2.0 g of anhydrous sodium carbonate were heated in an oil bath while stirring with a small amount of water. The contents are heated to a controlled temperature of approximately 102°C to gently reflux. After continuing the reaction for about 2 hours, the brown reaction solution changed to a blackish brown homogeneous solution, yielding a concentrated solution of the dextrin/ferric polynuclear complex. Add water to the solution
400 ml was added to dilute, cool, and then filtered to remove a small amount of insoluble unreacted substances. Water was added to the obtained filtrate to bring the total volume to 800 ml, and 520 ml of methyl alcohol was added to separate the precipitate. 600 ml of water was added to the resulting precipitate and dissolved by heating and stirring in a boiling bath. After cooling, the solution was pulp-filtered, water was added to the filtrate to make a total volume of 700 ml, and 880 ml of methyl alcohol was added to precipitate the dextrin/ferric polynuclear complex. The mixture was allowed to stand for a while, the supernatant was removed, and the precipitate was centrifuged to obtain a purified cake-like dextrin/ferric polynuclear complex containing methyl alcohol water. 260 ml of water was added to the complex and dissolved by heating and stirring, and the methyl alcohol contained therein was distilled off. After cooling, filter and add water.
The volume was adjusted to 400ml. A portion of this was taken for a quantitative test of iron. The yield was 89.6% by weight based on iron. The solution was filled into a simple autoclave, 0.95 g of sodium citrate dihydrate was added, and the mixture was reacted at 120°C for 2 hours. After cooling, the solution was filtered through silk cloth, and water was added to the filtrate to make a total volume of 400 ml. By adding 290 ml of ethyl alcohol to the solution, a dextrin/citric acid/ferric polynuclear complex was precipitated. The obtained dextrin/citric acid/ferric polynuclear complex containing ethyl alcohol water was dried under reduced pressure at room temperature in the presence of calcium chloride, and the dried product was ground to obtain a dark brown powdered dextrin/citric acid/ferric polynuclear complex. 18.8 g of body was obtained. Iron content 46.5% by weight, yield (based on iron) 77.7% by weight. Example 13 1072g of newly manufactured ferric iron polynuclear compound (as iron)
1.4 mol), 280 g of dextrin with a molecular weight of 5300, and 15.7 g of anhydrous sodium carbonate were added to a reaction vessel equipped with a reflux device along with 120 ml of water, and the mixture was stirred to 103
The reaction was carried out at ℃ for 4 hours to obtain a solution of dextrin/ferric polynuclear complex. 280 ml of water was added to this, followed by pulp filtration, and water was added to the filtrate to make 5,600 ml. 3800 ml of methyl alcohol was added to the solution to precipitate the complex, which was then centrifuged. 4,200 ml of water was added to the precipitate and dissolved by heating, and after cooling, pulp filtration was performed again, and water was added to the filtrate to make a total volume of 5,000 ml. 6300 ml of methyl alcohol was added to the solution to precipitate the complex.
The precipitate was separated, 2100 ml of water was added, and the mixture was dissolved by heating, and the methyl alcohol was distilled off. Water was added to the solution to obtain 2800 ml of dextrin/ferric polynuclear complex. Yield (based on iron) 92.2% by weight. Obtained dextrin/ferric polynuclear complex solution
From 400 ml (10.3 g as iron) and 5.4 g of sodium citrate dihydrate, 23.7 g of a dextrin/citric acid/ferric polynuclear complex was obtained in substantially the same manner as in Example 12 above. Iron content 39.6% by weight, yield (based on iron) 83.9% by weight. Example 14 Dextrin/glycolic acid was prepared in substantially the same manner as in Example 12 from 400 ml of the dextrin/ferric polynuclear complex solution obtained in Example 13 (10.3 g as iron) and 1.81 g of sodium glycolate.・
23.8 g of ferric polynuclear complex was obtained. Iron content 38.8% by weight, yield (based on iron) 82.1% by weight. Example 15 Dextrin, gluconic acid, 24.0 g of ferric polynuclear complex was obtained. Iron content: 39.8% by weight.
Yield (based on iron) 85.7% by weight. Example 16 Dextrin/ferric polynuclear complex solution obtained in Example 13 above (10.3 g as iron) and 5.0 g of sodium succinate hexahydrate were used to produce dextrin/ferric polynuclear complex in substantially the same manner as in Example 12 above. 24.5 g of succinic acid/ferric polynuclear complex was obtained. Iron content 38.2% by weight. Yield (based on iron) 83.9% by weight. Example 17 Dextrin/tartaric acid was prepared in substantially the same manner as in Example 12 from 400 ml of the dextrin/ferric polynuclear complex solution obtained in Example 13 (10.3 g as iron) and 4.2 g of sodium tartrate dihydrate.・24.3g of ferric polynuclear complex was obtained. Iron content 38.2% by weight. Yield (based on iron) 83.0% by weight. Example 18 Dextrin, malic acid, 24.2 g of ferric polynuclear complex was obtained. Iron content: 39.0% by weight. Yield (based on iron) 83.9% by weight. Thermal Stability Test A thermal stability test was conducted on the intermediate dextrin/ferric polynuclear complex solution obtained in Example 13 and the final product dextrin/citric acid/ferric polynuclear complex. When the dextrin/ferric polynuclear complex ampoule without citric acid was heated continuously at 100°C, it gelled in 25 hours, and origin residues were also observed in electrophoresis experiments. On the other hand, the dextrin/citric acid/ferric polynuclear complex ampoule showed no abnormality in appearance even after being heated at 100°C for 200 hours and showed good migration in electrophoresis experiments. As a result of conducting the same thermal stability test for the compounds of Examples 14 to 18, it was found that dextrin, citric acid,
Although slightly inferior to the ferric polynuclear complex, a significant improvement in thermal stability was observed compared to the dextrin/ferric complex. Examples 19-23 907g of newly manufactured ferric iron polynuclear compound (1.2
mol), 240 g of dextrin with a molecular weight of 5000 and 13.5 g of anhydrous sodium carbonate were used in the same manner as in Example 13 to obtain 2400 ml of a dextrin/ferric polynuclear complex solution. Add sodium citrate dihydrate to 400 ml of the solution (10.25 g as iron) per mole of iron.
The iron content, yield (based on iron), and thermal stability of dextrin-citric acid-ferric polynuclear complexes obtained by reacting at molar ratios of 0.01, 0.05, 0.10, 0.15, and 0.50 were determined, respectively. Examined. Table 2 shows the results.
Shown below.
【表】
本発明複合体の構造は、疎水性の第二鉄多核連
鎖に親水性のデキストリンおよびヒドロキシカル
ボン酸が配位結合することにより、水に対し安定
に分散しうるデキストリン・ヒドロキシカルボン
酸・第二鉄多核複合体を形成しているものと推定
されるが、若干の遊離デキストリンを含み又分子
量的にも分布を有する高分子である。
本発明複合体について、その元素組成、残基組
成、赤外吸収スペクトル、分子量、粒子径分布、
電気泳動、薄層クロマトグラフ、極限粘度、ポー
ラログラフ、ゲル濾過等の測定実験の結果を以下
に示す。
ａ 元素組成
（測定方法）
Γ鉄含量分析：試料を塩酸で分解したのち、亜
鉛末で還元して第一鉄イオンとし、硫酸第二
セリウムアンモニウムでｏ−フエナントロリ
ン試液を指示薬として酸化還元滴定法で測定
した。
Γナトリウム含有分析：炎光光度計を用いて測
定した。
（結果）
上記方法により表３の測定結果を得た。[Table] The structure of the complex of the present invention consists of dextrin, hydroxycarboxylic acid, and hydroxycarboxylic acid, which can be stably dispersed in water, due to the coordination bond of hydrophilic dextrin and hydroxycarboxylic acid to hydrophobic ferric polynuclear chains. Although it is presumed to form a ferric iron polynuclear complex, it is a polymer that contains some free dextrin and has a molecular weight distribution. Regarding the complex of the present invention, its elemental composition, residue composition, infrared absorption spectrum, molecular weight, particle size distribution,
The results of measurement experiments such as electrophoresis, thin layer chromatography, intrinsic viscosity, polarography, and gel filtration are shown below. a Elemental composition (Measurement method) Γ iron content analysis: After decomposing the sample with hydrochloric acid, it is reduced with zinc dust to produce ferrous ions, and then redox titrated with ceric ammonium sulfate using o-phenanthroline test solution as an indicator. It was measured by the method. Analysis of Γ sodium content: Measured using a flame photometer. (Results) The measurement results shown in Table 3 were obtained by the above method.
【表】
ｂ 残基組成
（測定方法）
Γ第二鉄多核複合体残基〔FeOOH〕o：前記鉄
含量より計算で求めた。
Γデキストリン残基〔C6H10O5〕nおよび遊離デ
キストリン〔C6H10O5〕l：各試料を塩酸で加
水分解し、全デキストリンをグルコースとし
てベルトラン法により定量し、デキストリン
量に換算した。遊離デキストリン含量は、本
発明複合体の複合体部分が負電荷を有してい
る性質を利用し、正電荷を有するコロイド滴
定試薬メチルグライコールキトザン溶液の過
剰量で該複合体部分を共沈させ、過剰のメチ
ルグライコールキトザンを負電荷を有するコ
ロイド滴定試薬ポリビニル硫酸カリウム溶液
を加えて沈澱させた後、上澄液中に残された
遊離デキストリンを塩酸で加水分解してグル
コースとし、ベルトラン法で定量し、デキス
トリン量に換算した。全デキストリン含量と
遊離デキストリン含量の差をデキストリン残
基含量とした。
Γクエン酸残基〔C6H5O7〕：各試料を6N塩酸
で加水分解した後、強酸性イオン交換樹脂
（アンバーライトIR−120）を充填したカラ
ム中を流下させ測定を妨害する鉄を除去し、
通過液を濃縮乾固したものをエタノール水に
溶かし、電導度滴定用セルに移し、0.1N、
NaOH溶液で電導度滴定を行い、中和に要し
た0.1N NaOHの量からクエン酸残基量を求
めた。
（結果）
測定結果を表４に示す。[Table] b Residue composition (Measurement method) Γferric polynuclear complex residue [FeOOH] o : Calculated from the above iron content. Γ-dextrin residue [C 6 H 10 O 5 ] n and free dextrin [C 6 H 10 O 5 ] l : Each sample was hydrolyzed with hydrochloric acid, and the total dextrin was determined as glucose by the Bertrand method and converted to the amount of dextrin. did. The free dextrin content can be determined by coprecipitating the complex part with an excess amount of a positively charged colloid titration reagent methyl glycol chitozan solution, taking advantage of the fact that the complex part of the complex of the present invention has a negative charge. After precipitating the excess methyl glycol chitozan by adding a negatively charged colloidal titration reagent polyvinyl potassium sulfate solution, the free dextrin remaining in the supernatant was hydrolyzed with hydrochloric acid to produce glucose, and Bertrand The amount of dextrin was determined by the method and converted into the amount of dextrin. The difference between the total dextrin content and the free dextrin content was defined as the dextrin residue content. Γ Citric acid residue [C 6 H 5 O 7 ]: After hydrolyzing each sample with 6N hydrochloric acid, iron is allowed to flow down through a column packed with a strongly acidic ion exchange resin (Amberlite IR-120) and interferes with the measurement. remove the
The passed liquid was concentrated to dryness, dissolved in ethanol water, transferred to a conductivity titration cell, and 0.1N,
Conductivity titration was performed using a NaOH solution, and the amount of citric acid residue was determined from the amount of 0.1N NaOH required for neutralization. (Results) The measurement results are shown in Table 4.
【表】
ｃ 赤外スペクトル
（測定方法）
赤外分光光度計（日立製作所製EPI−G3型）
を用い、臭化カリウム錠剤法で測定した。
（結果）
測定を行つた各試料の赤外吸収スペクトルは
互いによく一致し、代表例として実施例１の複
合体についてその赤外吸収スペクトル図と特性
吸収の帰属を第１図および表５に示す。[Table] c Infrared spectrum (measurement method) Infrared spectrophotometer (Model EPI-G3 manufactured by Hitachi)
It was measured using the potassium bromide tablet method. (Results) The infrared absorption spectra of each sample measured were in good agreement with each other, and as a representative example, the infrared absorption spectra and characteristic absorption assignments of the composite of Example 1 are shown in Figure 1 and Table 5. .
【表】
第１図および表５の帰属結果は、第二鉄多核
体残基にデキストリンおよびクエン酸が配位結
合していると考えられる本発明複合体の構造を
支持するものである。
ｄ 数平均分子量
（測定方法）
実施例１及び21の複合体について高速膜浸透
圧計によつて試料濃度（Ｃ）と浸透圧（π）の
関係を求め、＝RT（π／Ｃ）c=0の関係式
から数平均分子量（）を求めた。（但し、Ｒ
＝84.7・cm水柱／deg・mol、Ｔ＝測定系の
絶対温度。）なお本発明複合体から限外濾過法
により遊離デキストリン部分を可及的に除いた
部分の分子量を参考の為求めたところ2.34×
105であつた。
（結果）
上記の測定結果を表６にまとめた。[Table] The assignment results shown in FIG. 1 and Table 5 support the structure of the complex of the present invention, in which dextrin and citric acid are thought to be coordinately bonded to ferric polynuclear residues. d Number average molecular weight (measurement method) For the complexes of Examples 1 and 21, the relationship between sample concentration (C) and osmotic pressure (π) was determined using a high-speed membrane osmometer, and = RT (π/C) c=0 The number average molecular weight () was determined from the relational expression. (However, R
= 84.7 cm water column/deg mol, T = absolute temperature of the measurement system. ) The molecular weight of the complex of the present invention after removing as much free dextrin as possible by ultrafiltration was determined to be 2.34× for reference.
It was 10 5 . (Results) The above measurement results are summarized in Table 6.
【表】
ｅ 粒子径分布
（測定方法）
実施例１、12及び21の各複合体の６w/v%水
溶液を各種孔径の限外濾過膜で濾過を行い、濾
液の鉄濃度をｏ−フエナントロリンによる比色
法により測定し、鉄成分濾過率より各試料の粒
子径分布を求めた。
（結果）
各試料の水溶液中での粒子径は約0.03〜0.1
μの分布を有し、その中の約90％は0.05〜0.08
μの範囲の粒子径を有していた。
ｆ 電気泳動
（測定方法）
セルロースアセテート膜（５×６cm）をそれ
ぞれのリン酸緩衝液（PH5.7、6.0、6.5、7.0、
7.5および8.0）に浸し、余分の緩衝液を濾紙で
軽くはさんで除去した後、同じPHのリン酸緩衝
液を入れた電気泳動セルに装着し、６w/v%試
料溶液をセルローズアセテート膜の中央線上に
付着させ、電圧90Vで40分間通電し、試料のか
つ色のスポツトの移動を観察した。
（結果）
各試料はすべて陽極に移動した。泳動距離を
表７に示す。[Table] e Particle size distribution (measurement method) A 6w/v% aqueous solution of each of the composites of Examples 1, 12, and 21 was filtered through ultrafiltration membranes with various pore sizes, and the iron concentration of the filtrate was determined by o-phenanthate. The particle size distribution of each sample was determined from the iron component filtration rate using the colorimetric method using Lorin. (Results) The particle size of each sample in aqueous solution is approximately 0.03 to 0.1
It has a distribution of μ, of which about 90% is 0.05~0.08
It had a particle size in the range of μ. f Electrophoresis (measurement method) Cellulose acetate membrane (5 x 6 cm) was soaked in each phosphate buffer solution (PH5.7, 6.0, 6.5, 7.0,
7.5 and 8.0), remove the excess buffer by gently sandwiching it with filter paper, place it in an electrophoresis cell containing phosphate buffer of the same pH, and apply the 6w/v% sample solution to the cellulose acetate membrane. It was attached to the center line, and the sample was energized for 40 minutes at a voltage of 90 V, and the movement of the colored spot on the sample was observed. (Results) All the samples moved to the anode. Table 7 shows the migration distance.
【表】
なお、本実験において、遊離の鉄イオンが存
在すればリン酸−ナトリウムにより淡黄色のリ
ン酸鉄（FePO4）を生成し原点に残留すると考
えられるが、それに相当するスポツトは認めら
れなかつた。
ｇ 薄層クロマトグラフ
（測定方法）
実施例１の複合体についてシリカゲル・ガラ
ス粉末を焼結した薄層板（５×20cm）にスポツ
トし、展開溶液（）ｎ−ブタノール・アセト
ン・水（４：５：１）、（）酢酸エチル・氷酢
酸・水（３：１：１）、（）エタノール・水・
アンモニア水（25：３：４）の各々で展開した
後、フエロシアン化カリウム試液および重クロ
ム酸カリウム・硫酸混合溶液で呈色しRfを測
定した。
（結果）
本発明複合体は高分子化合物であるため、ス
ポツトは原点より移動しなかつた。又、遊離の
クエン酸又はクエン酸ナトリウムおよび遊離の
ブドウ糖は検出されなかつた。
ｈ 極限粘度
（測定方法）
各試料より各種濃度の試料溶液を調製した。
該溶液および水について30±0.1℃でシユプレ
ンゲル・オストワルドピクノメーターによる方
法で比重を測定し、又、ウベローデ型毛細管粘
度計を用いて30±0.1℃で流下時間を測定し、
外挿法により極限粘度〔η〕＝〓〓〓ηsp／ｃ
を求めた。
（ηsp：比粘度、ｃ：試料濃度）。
（結果）
各試料の極限粘度〔η〕を表８に示す。[Table] In this experiment, if free iron ions exist, it is thought that pale yellow iron phosphate (FePO 4 ) is generated by sodium phosphate and remains at the origin, but no corresponding spots were observed. Nakatsuta. g Thin layer chromatography (measurement method) For the composite of Example 1, silica gel/glass powder was spotted on a sintered thin layer plate (5 x 20 cm), and a developing solution () n-butanol/acetone/water (4: 5:1), () ethyl acetate/glacial acetic acid/water (3:1:1), () ethanol/water/
After developing with aqueous ammonia (25:3:4), Rf was measured by coloring with a potassium ferrocyanide test solution and a mixed solution of potassium dichromate and sulfuric acid. (Results) Since the complex of the present invention is a polymer compound, the spot did not move from the origin. Also, free citric acid or sodium citrate and free glucose were not detected. h Intrinsic viscosity (measurement method) Sample solutions of various concentrations were prepared from each sample.
The specific gravity of the solution and water was measured at 30 ± 0.1°C using a Schuprengel-Ostwald pycnometer, and the flow time was measured at 30 ± 0.1°C using an Ubbelohde capillary viscometer.
By extrapolation, the limiting viscosity [η] = 〓〓〓ηsp/c
I asked for (ηsp: specific viscosity, c: sample concentration). (Results) Table 8 shows the intrinsic viscosity [η] of each sample.
【表】
ｉ ポーラグラフイー
（測定方法）
JIS−KO111記載の方法に基づき、支持塩溶
液（ワルホーレ緩衝液PH3.50、4.50、5.45）５
mlを電解びんに取り、試料溶液（60.0mg/ml、
Ca.25mgFe/ml）20μ若しくは第二鉄イオン
として硫酸第二鉄アンモニウム溶液（25mgFe/
ml）５μを加え、25℃の恒温槽に入れ溶存酸
素を除去するため約15分間窒素を通気し、電解
液を調製した。この電解液について水銀柱60
cm、電流感度30nA/mm、ダンピング５、飽和カ
ロメル電極基準（vsSCE）で直流ポーラログ
ラフを操作し、得られたポーラログラムから半
波電位（Ｅ1/2）および波高（ｉ）を測定し
た。
（結果）
実施例１の複合体および第二鉄イオンに関す
る半波電位・波高の測定値およびポーラログラ
ムの略図を各々表９および第２図に示す。[Table] i Polarography (Measurement method) Based on the method described in JIS-KO111, support salt solution (Walhole buffer PH3.50, 4.50, 5.45) 5
Transfer ml to an electrolysis bottle and add sample solution (60.0mg/ml,
Ca.25mgFe/ml) 20μ or ferric ammonium sulfate solution (25mgFe/ml) as ferric ion
ml) was added, and the solution was placed in a constant temperature bath at 25°C, and nitrogen was bubbled through it for about 15 minutes to remove dissolved oxygen, to prepare an electrolytic solution. About this electrolyte 60 mercury
cm, a current sensitivity of 30 nA/mm, a damping of 5, and a saturated calomel electrode reference (vsSCE).The DC polarograph was operated, and the half-wave potential (E1/2) and wave height (i) were measured from the obtained polarogram. (Results) Measured half-wave potentials and wave heights and schematic diagrams of polarograms for the complex of Example 1 and ferric ions are shown in Table 9 and FIG. 2, respectively.
【表】
この実験より本発明複合体の半波電位はいず
れのPHにおいても第二鉄イオンの半波電位より
負に移行しており、従つて本発明複合体が安定
な複合体を形成していると考えられる。波高は
電解液中の単位鉄濃度当りで比較するとき第二
鉄イオンの約1/4と小さく、これは分子量の大
きな複合体を形成しているためと考えられる。
又、この条件下では試料のポーラログラムには
第二鉄イオンの第一波に相当する半波電位には
波を認めず第二鉄イオンの存在は認められなか
つた。
ｊ ゲル濾過
実施例１および21の複合体について下記の条
件でゲル濾過を行い、各溶出分画について鉄お
よびデキストリンを定量した。
（条件）
試料添着量 6.00mg、ゲル セフアローズ6Bカ
ラム 40×2.5cm
緩衝液 0.05Mクエン酸緩衝液（PH6.0）分画
量 ５ml
（結果）
各々の測定結果を第３図１，２に示す。
ｋ 安定性試験
実施例１の複合体より鉄として５ｇ含む試料
量を量り、水80mlを加えて沸騰水浴中で加熱し
冷後水を加えて100mlとし、この液を濃厚試料
溶液（50mgFe/ml）とした。
濃厚試料溶液10mlを正確に量り水を加えて20
mlとし、この溶液を試料溶液とした。濃厚試
料溶液10mlを正確に量り、乾燥デキストリン
0.1ｇ、0.2ｇ、0.4ｇおよび0.8ｇをそれぞれ加
えて溶かし、水を加えて20mlとし試料溶液、
、およびとした。各試料溶液の全デキス
トリン濃度および複合体に換算した場合の鉄含
量を表10に示す。[Table] From this experiment, the half-wave potential of the complex of the present invention is more negative than the half-wave potential of ferric ion at any pH, which indicates that the complex of the present invention forms a stable complex. It is thought that The wave height is as small as about 1/4 of that of ferric ion when compared per unit iron concentration in the electrolyte, and this is thought to be due to the formation of a complex with a large molecular weight.
Furthermore, under these conditions, no wave was observed in the half-wave potential corresponding to the first wave of ferric ions in the polarogram of the sample, and the presence of ferric ions was not observed. j Gel filtration The complexes of Examples 1 and 21 were subjected to gel filtration under the following conditions, and iron and dextrin were quantified for each elution fraction. (Conditions) Sample loading amount 6.00 mg, gel Sepharose 6B column 40 x 2.5 cm Buffer solution 0.05M citrate buffer (PH6.0) Fraction volume 5 ml (Results) Each measurement result is shown in Figure 3 1 and 2. . k Stability test Weigh a sample containing 5g of iron from the composite of Example 1, add 80ml of water, heat in a boiling water bath, cool, add water to make 100ml, and convert this liquid into a concentrated sample solution (50mgFe/ml). ). Accurately measure 10 ml of the concentrated sample solution, add water, and add 20 ml of concentrated sample solution.
ml, and this solution was used as the sample solution. Accurately measure 10 ml of concentrated sample solution and add dry dextrin.
Add and dissolve 0.1g, 0.2g, 0.4g and 0.8g respectively, add water to make 20ml, sample solution,
, and. Table 10 shows the total dextrin concentration and iron content converted to complex in each sample solution.
【表】
各試料溶液をアンプルに密封し、沸騰水浴中
で０時間、１時間、３時間、６時間、10時間、
25時間および50時間加熱し、遊離鉄量の測定を
行つた。結果を第４図に示す。
ｌ デキストリン・クエン酸・第二鉄（限外濾
過）
実施例12の複合体の水溶液を限外濾過するこ
とによつて得られた試料の性状、鉄含量、デキ
ストリン含量、赤外吸収スペクトル、ゲル濾過
状態を調べた。結果を表11に示す。赤外吸収ス
ペクトル図、ゲル濾過曲線図を各々第５，６図
に示す。[Table] Each sample solution was sealed in an ampoule and placed in a boiling water bath for 0 hours, 1 hour, 3 hours, 6 hours, and 10 hours.
After heating for 25 and 50 hours, the amount of free iron was measured. The results are shown in Figure 4. l Dextrin/citric acid/ferric iron (ultrafiltration) Properties, iron content, dextrin content, infrared absorption spectrum, gel of the sample obtained by ultrafiltration of the aqueous solution of the complex of Example 12 The filtration condition was checked. The results are shown in Table 11. An infrared absorption spectrum diagram and a gel filtration curve diagram are shown in Figures 5 and 6, respectively.
【表】
強い吸収
[Table] Strong absorption
【表】
い吸収 核オール
化体残基
由来
[Table] Absorption nuclear all
converted residue
Origin
Claims (1)
配位結合した下記の特性を有するデキストリン・
クエン酸・第二鉄多核複合体。 性状：濃褐色無臭の無定形粉末 溶媒特性：冷水に除々に溶け、熱水には溶け易く
一旦溶解すると冷却しても析出しない安定な溶
液となる。エタノール、メタノール、アセト
ン、エーテル等の有機溶媒にほとんど溶けな
い。 元素組成：C12〜17％、H2〜３％、Fe35〜47％ 残基組成：第二鉄多核体残基〔FeOOH〕o55.7〜
74.8重量％、 デキストリン残基〔C6H10O5〕n13.0〜18.0重量
％、 クエン酸残基〔C6H5O7〕2.0〜14.0重量％、 遊離デキストリン〔C6H10O5〕l8.0〜11.0重量％ 数平均分子量：1.0×105〜1.60〜105 極限粘度：0.049〜0.054〔η〕 赤外吸収スペクトル（KBr）：3400cm-1（OH）、
2900cm-1（CH2）、1600cm-1（Ｏ〓Ｃ〓Ｏ）、
1380cm-1（CO、OH）、1150cm-1（Ｃ−Ｏ−
Ｃ）、1080cm-1（OH）、1020cm-1（OH）、700cm
-1（OH） 粒子径分布（溶液状態）：0.03〜0.1μ（90％は
0.05〜0.08μの範囲） ２ 25mgFe/mlの水溶液を100℃で200時間加熱し
てもゲル化を認めず且つ電気泳動においても異常
を認めない特許請求の範囲第１項記載のデキスト
リン・クエン酸・第二鉄多核複合体。 ３ 第二鉄多核体にデキストリン及びクエン酸が
配位結合した下記の特性を有するデキストリン・
クエン酸・第二鉄多核複合体を主成分とする非経
口用鉄欠乏性貧血治療剤。 性状：濃褐色無臭の無定形粉末 溶媒特性：冷水に除々に溶け、熱水には溶け易く
一旦溶解すると冷却しても析出しない安定な溶
液となる。エタノール、メタノール、アセト
ン、エーテル等の有機溶媒にほとんど溶けな
い。 元素組成：C12〜17％、H2〜３％、Fe35〜47％ 残基組成：第二鉄多核体残基〔FeOOH〕o55.7〜
74.8重量％、 デキストリン残基〔C6H10O5〕n13.0〜18.0重量
％、 クエン酸残基〔C6H5O7〕2.0〜14.0重量％、 遊離デキストリン〔C6H10O5〕l8.0〜11.0重量％ 数平均分子量：1.0×105〜1.60〜105 極限粘度：0.049〜0.054〔η〕 赤外吸収スペクトル（KBr）：3400cm-1（OH）、
2900cm-1（CH2）、1600cm-1（Ｏ〓Ｃ〓Ｏ）、
1380cm-1（CO、OH）、1150cm-1（Ｃ−Ｏ−
Ｃ）、1080cm-1（OH）、1020cm-1（OH）、700cm
-1（OH） 粒子径分布（溶液状態）：0.03〜0.1μ（90％は
0.05〜0.08μの範囲） ４ 注射剤形態にある特許請求の範囲第３項記載
の非経口用鉄欠乏性貧血治療剤。 ５ 等張化剤として非還元性物質を含有する特許
請求の範囲第４項記載の非経口用鉄欠乏性貧血治
療剤。 ６ 等張化剤としてソルビトールを含有する特許
請求の範囲第４項記載の非経口用鉄欠乏性貧血治
療剤。[Claims] 1. A dextrin having the following properties, in which dextrin and citric acid are coordinately bonded to a ferric polynuclear body.
Citric acid/ferric polynuclear complex. Properties: Dark brown odorless amorphous powder Solvent characteristics: Gradually dissolves in cold water, easily dissolves in hot water, and once dissolved, becomes a stable solution that does not precipitate even when cooled. Almost insoluble in organic solvents such as ethanol, methanol, acetone, and ether. Elemental composition: C12~17%, H2~3%, Fe35~47% Residue composition: Ferric polynuclear residue [FeOOH] o 55.7~
74.8% by weight, dextrin residue [C 6 H 10 O 5 ] n 13.0-18.0% by weight, citric acid residue [C 6 H 5 O 7 ] 2.0-14.0% by weight, free dextrin [C 6 H 10 O 5 ] l 8.0 ~ 11.0% by weight Number average molecular weight: 1.0 x 10 5 ~ 1.60 ~ 10 5 Intrinsic viscosity: 0.049 ~ 0.054 [η] Infrared absorption spectrum (KBr): 3400 cm -1 (OH),
2900cm -1 (CH 2 ), 1600cm -1 (O〓C〓O),
1380cm -1 (CO, OH), 1150cm -1 (C-O-
C), 1080cm -1 (OH), 1020cm -1 (OH), 700cm
-1 (OH) Particle size distribution (solution state): 0.03~0.1μ (90%
0.05 to 0.08μ) 2. Dextrin-citric acid according to claim 1, which does not show gelation even when a 25 mgFe/ml aqueous solution is heated at 100°C for 200 hours and shows no abnormality in electrophoresis. - Ferric polynuclear complex. 3 Dextrin and citric acid are coordinately bonded to a ferric polynuclear body, and have the following properties.
A parenteral iron deficiency anemia treatment whose main ingredient is a citric acid/ferric polynuclear complex. Properties: Dark brown odorless amorphous powder Solvent characteristics: Gradually dissolves in cold water, easily dissolves in hot water, and once dissolved, becomes a stable solution that does not precipitate even when cooled. Almost insoluble in organic solvents such as ethanol, methanol, acetone, and ether. Elemental composition: C12~17%, H2~3%, Fe35~47% Residue composition: Ferric polynuclear residue [FeOOH] o 55.7~
74.8% by weight, dextrin residue [C 6 H 10 O 5 ] n 13.0-18.0% by weight, citric acid residue [C 6 H 5 O 7 ] 2.0-14.0% by weight, free dextrin [C 6 H 10 O 5 ] l 8.0 ~ 11.0% by weight Number average molecular weight: 1.0 x 10 5 ~ 1.60 ~ 10 5 Intrinsic viscosity: 0.049 ~ 0.054 [η] Infrared absorption spectrum (KBr): 3400 cm -1 (OH),
2900cm -1 (CH 2 ), 1600cm -1 (O〓C〓O),
1380cm -1 (CO, OH), 1150cm -1 (C-O-
C), 1080cm -1 (OH), 1020cm -1 (OH), 700cm
-1 (OH) Particle size distribution (solution state): 0.03~0.1μ (90%
0.05-0.08μ) 4. The parenteral iron deficiency anemia therapeutic agent according to claim 3, which is in the form of an injection. 5. The parenteral iron deficiency anemia therapeutic agent according to claim 4, which contains a non-reducing substance as an isotonizing agent. 6. The parenteral iron deficiency anemia therapeutic agent according to claim 4, which contains sorbitol as an isotonizing agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10285584A JPS606701A (en) | 1984-05-21 | 1984-05-21 | Dextrin/hydroxycarboxylic acid/polynuclear ferric compound complex and its production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10285584A JPS606701A (en) | 1984-05-21 | 1984-05-21 | Dextrin/hydroxycarboxylic acid/polynuclear ferric compound complex and its production |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP51000256A Division JPS6039681B2 (en) | 1976-01-01 | 1976-01-01 | Dextrin-citric acid-ferric polynuclear complex and parenteral iron preparation containing the complex |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7312985A Division JPS6128501A (en) | 1985-04-06 | 1985-04-06 | Production of dextrin/hydroxycarboxylic acid/polynuclear ferric compound complex |
| JP7313085A Division JPS6128502A (en) | 1985-04-06 | 1985-04-06 | Production of dextrin/hydroxycarboxylic acid/polynuclear ferric compound complex |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS606701A JPS606701A (en) | 1985-01-14 |
| JPS6131121B2 true JPS6131121B2 (en) | 1986-07-18 |
Family
ID=14338536
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10285584A Granted JPS606701A (en) | 1984-05-21 | 1984-05-21 | Dextrin/hydroxycarboxylic acid/polynuclear ferric compound complex and its production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS606701A (en) |
-
1984
- 1984-05-21 JP JP10285584A patent/JPS606701A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS606701A (en) | 1985-01-14 |
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