CN108264546A - Succinyl casein-ferrous iron and its preparation method and application - Google Patents
Succinyl casein-ferrous iron and its preparation method and application Download PDFInfo
- Publication number
- CN108264546A CN108264546A CN201611257719.9A CN201611257719A CN108264546A CN 108264546 A CN108264546 A CN 108264546A CN 201611257719 A CN201611257719 A CN 201611257719A CN 108264546 A CN108264546 A CN 108264546A
- Authority
- CN
- China
- Prior art keywords
- ferrous
- casein
- succinyl
- iron
- 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.)
- Pending
Links
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 235000021240 caseins Nutrition 0.000 claims abstract description 61
- 239000005018 casein Substances 0.000 claims abstract description 57
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 claims abstract description 49
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims abstract description 24
- 208000007502 anemia Diseases 0.000 claims abstract description 19
- -1 succinyl casein Chemical compound 0.000 claims abstract description 15
- 206010022971 Iron Deficiencies Diseases 0.000 claims abstract description 8
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims abstract description 8
- 230000000536 complexating effect Effects 0.000 claims abstract description 5
- 208000024891 symptom Diseases 0.000 claims abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract 4
- 230000035322 succinylation Effects 0.000 claims abstract 3
- 238000010613 succinylation reaction Methods 0.000 claims abstract 3
- 239000000243 solution Substances 0.000 claims description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 238000001556 precipitation Methods 0.000 claims description 17
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 10
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical group ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 9
- 229940014800 succinic anhydride Drugs 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 229910001448 ferrous ion Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 4
- 239000011790 ferrous sulphate Substances 0.000 claims description 4
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 3
- DKKCQDROTDCQOR-UHFFFAOYSA-L Ferrous lactate Chemical compound [Fe+2].CC(O)C([O-])=O.CC(O)C([O-])=O DKKCQDROTDCQOR-UHFFFAOYSA-L 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 235000013924 ferrous gluconate Nutrition 0.000 claims description 2
- 239000004222 ferrous gluconate Substances 0.000 claims description 2
- 229960001645 ferrous gluconate Drugs 0.000 claims description 2
- 235000013925 ferrous lactate Nutrition 0.000 claims description 2
- 239000004225 ferrous lactate Substances 0.000 claims description 2
- 229940037907 ferrous lactate Drugs 0.000 claims description 2
- 229940062993 ferrous oxalate Drugs 0.000 claims description 2
- OWZIYWAUNZMLRT-UHFFFAOYSA-L iron(2+);oxalate Chemical compound [Fe+2].[O-]C(=O)C([O-])=O OWZIYWAUNZMLRT-UHFFFAOYSA-L 0.000 claims description 2
- VRIVJOXICYMTAG-IYEMJOQQSA-L iron(ii) gluconate Chemical compound [Fe+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O VRIVJOXICYMTAG-IYEMJOQQSA-L 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims 2
- 239000007864 aqueous solution Substances 0.000 claims 2
- 239000007900 aqueous suspension Substances 0.000 claims 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims 2
- 229910000000 metal hydroxide Inorganic materials 0.000 claims 2
- 150000004692 metal hydroxides Chemical class 0.000 claims 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims 1
- GIPOFCXYHMWROH-UHFFFAOYSA-L 2-aminoacetate;iron(2+) Chemical compound [Fe+2].NCC([O-])=O.NCC([O-])=O GIPOFCXYHMWROH-UHFFFAOYSA-L 0.000 claims 1
- JDTUPLBMGDDPJS-UHFFFAOYSA-N 2-methoxy-2-phenylethanol Chemical compound COC(CO)C1=CC=CC=C1 JDTUPLBMGDDPJS-UHFFFAOYSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims 1
- 239000013522 chelant Substances 0.000 claims 1
- 235000015165 citric acid Nutrition 0.000 claims 1
- 229940086413 ferrous bisglycinate Drugs 0.000 claims 1
- 239000011640 ferrous citrate Substances 0.000 claims 1
- 235000019850 ferrous citrate Nutrition 0.000 claims 1
- 239000001530 fumaric acid Substances 0.000 claims 1
- 235000011087 fumaric acid Nutrition 0.000 claims 1
- APVZWAOKZPNDNR-UHFFFAOYSA-L iron(ii) citrate Chemical compound [Fe+2].OC(=O)CC(O)(C([O-])=O)CC([O-])=O APVZWAOKZPNDNR-UHFFFAOYSA-L 0.000 claims 1
- 239000004310 lactic acid Substances 0.000 claims 1
- 235000014655 lactic acid Nutrition 0.000 claims 1
- 239000001630 malic acid Substances 0.000 claims 1
- 235000011090 malic acid Nutrition 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 150000002927 oxygen compounds Chemical class 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000011975 tartaric acid Substances 0.000 claims 1
- 235000002906 tartaric acid Nutrition 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 22
- 238000005917 acylation reaction Methods 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000005516 engineering process Methods 0.000 abstract description 4
- 230000009967 tasteless effect Effects 0.000 abstract description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 88
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 58
- 229910052742 iron Inorganic materials 0.000 description 45
- 102000011632 Caseins Human genes 0.000 description 44
- 108010076119 Caseins Proteins 0.000 description 44
- 235000011044 succinic acid Nutrition 0.000 description 23
- 239000001384 succinic acid Substances 0.000 description 22
- 238000001914 filtration Methods 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 230000010933 acylation Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 239000006228 supernatant Substances 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 238000004108 freeze drying Methods 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 238000002835 absorbance Methods 0.000 description 6
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- MDXRFOWKIZPNTA-UHFFFAOYSA-L butanedioate;iron(2+) Chemical compound [Fe+2].[O-]C(=O)CCC([O-])=O MDXRFOWKIZPNTA-UHFFFAOYSA-L 0.000 description 5
- 229960001604 ferrous succinate Drugs 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 102000009027 Albumins Human genes 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- 229940021722 caseins Drugs 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 238000005057 refrigeration Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical class O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- 102000001554 Hemoglobins Human genes 0.000 description 3
- 108010054147 Hemoglobins Proteins 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 206010025476 Malabsorption Diseases 0.000 description 2
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000002505 iron Chemical class 0.000 description 2
- 150000004698 iron complex Chemical class 0.000 description 2
- 108010084684 iron protein succinylate Proteins 0.000 description 2
- 229940074442 iron protein succinylate Drugs 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000011573 trace mineral Substances 0.000 description 2
- 235000013619 trace mineral Nutrition 0.000 description 2
- OHZCFWMJMWFNFP-ZVGUSBNCSA-L (2r,3r)-2,3-dihydroxybutanedioate;iron(2+) Chemical compound [Fe+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O OHZCFWMJMWFNFP-ZVGUSBNCSA-L 0.000 description 1
- KWJPTZSGVFKSDH-UHFFFAOYSA-N 1-(3-nitrophenyl)piperazine;dihydrochloride Chemical compound Cl.Cl.[O-][N+](=O)C1=CC=CC(N2CCNCC2)=C1 KWJPTZSGVFKSDH-UHFFFAOYSA-N 0.000 description 1
- 206010002065 Anaemia megaloblastic Diseases 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PMVSDNDAUGGCCE-TYYBGVCCSA-L Ferrous fumarate Chemical compound [Fe+2].[O-]C(=O)\C=C\C([O-])=O PMVSDNDAUGGCCE-TYYBGVCCSA-L 0.000 description 1
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 208000000682 Megaloblastic Anemia Diseases 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- CHYQSXLXQCXPAA-UHFFFAOYSA-H butanedioate;iron(3+) Chemical compound [Fe+3].[Fe+3].[O-]C(=O)CCC([O-])=O.[O-]C(=O)CCC([O-])=O.[O-]C(=O)CCC([O-])=O CHYQSXLXQCXPAA-UHFFFAOYSA-H 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000000205 computational method Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 229960001459 ferrous ascorbate Drugs 0.000 description 1
- 235000002332 ferrous fumarate Nutrition 0.000 description 1
- 239000011773 ferrous fumarate Substances 0.000 description 1
- 229960000225 ferrous fumarate Drugs 0.000 description 1
- 229940057006 ferrous tartrate Drugs 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
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- 208000015181 infectious disease Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 235000014413 iron hydroxide Nutrition 0.000 description 1
- 235000020796 iron status Nutrition 0.000 description 1
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
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- 231100001016 megaloblastic anemia Toxicity 0.000 description 1
- 230000002175 menstrual effect Effects 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- JTEVUCQIVRGWHT-UHFFFAOYSA-N phosphoric acid;phthalic acid Chemical compound OP(O)(O)=O.OC(=O)C1=CC=CC=C1C(O)=O JTEVUCQIVRGWHT-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical class [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 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
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
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- 238000010998 test method Methods 0.000 description 1
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- 231100000397 ulcer Toxicity 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4732—Casein
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Abstract
The invention belongs to pharmaceutical technology fields; it is related to a kind of preparation method of succinyl casein ferrous iron; this method is using casein as raw material; it carries out acylation reaction under certain condition with succinylation reagent and succinyl casein is made, succinyl casein is complexed to obtain succinyl casein ferrous iron again with ferrous salt.Succinyl casein ferrous iron is in solid-state at normal temperatures,It is tasteless, it is water-soluble。The content of ferro element reaches more than 5% in succinyl casein ferrous iron of the present invention, and succinyl casein is not less than 98% with ferrous complexing rate, available for treating hypoferric anemia and having the patient of iron deficiency symptoms.
Description
Technical field
The invention belongs to pharmaceutical technology field, more particularly to a kind of albumen ferrous succinate and its preparation method and application.
Albumen ferrous succinate according to the present invention（iron(II) casein succinylate）(succinyl junket egg
In vain-ferrous), it is characterised in that more than 5%, the complexing rate of wherein succinyl casein and ferrous ion is not less than iron content
98%, available for prevention and treatment hypoferric anemia and with iron-deficient symptom patient.
Background technology
It is hemoglobin in blood of human body, myoglobins and more it is well known that iron is one of the essential trace elements of the human body
The important component of kind enzyme has important physiological action to human body.Anaemia (aniema) refers to red thin in blood circulation
Born of the same parents' number or hemoglobin are less than the pathological phenomenon of normal value for a long time.Usual anaemia is divided into three classes：Hypoferric anemia (iron
Deficiency aneima, IDA), megaloblastic anemia and alpastic anemia.Hypoferric anemia producing cause master
Caused by being blood loss or iron incomplete absorption, such as feminine menstrual is excessive, digestive system ulcer, hemorrhoid chronic blood loss are poor
Blood, the hypoferric anemias such as malnutrition, gestation, children growth phase.WHO report points out simultaneously, and iron deficiency is regardless of whether anaemia, to people
Health hazard it is very big.If pregnant woman's iron deficiency, very big hidden danger will be carried out to pregnant woman and fetal life safety belt；And children's iron deficiency is to it
Body and intellectual development have larger damage；Iron deficiency can also reduce the labour capacity and efficiency of physical labourer.Iron is human body requirements
Amount is maximum, and is easiest to occur the trace element of dysbolism.In 1,300,000,000 population of document report China, there are about 400,000,000 iron-deficients
Anaemia patient just has in annual 20000000 pregnant woman 66.3% needs to eat and mends iron drug, is sent out in 6 months to 2 years old baby's asiderosis
Sick rate is 75% ~ 82.5%, and 6 years old to 12 years old is 21.6%, and women incidence is 43.3%.Chalybeate is the specific drug for treating iron deficiency,
It is the secure unique for treating hypoferric anemia, effective and economic method, market potential is huge.
Iron derivative is widely used in drug, comprehensive for preventing and treating anaemia and gestational period asiderosis, malabsorption
Simulator sickness, nursing period asiderosis and growth period asiderosis；But when iron is taken in by human body and reaches duodenum, since intestinal juice is in alkali
Property, iron ion can often form the iron hydroxide being poorly soluble, so as to hinder being absorbed and utilized for iron, therefore the bioavailability of iron
It is relatively low.
The chalybeate clinically used both at home and abroad mainly has three classes.The first kind is oral inorganic molysite, and the most common are sulfuric acid
Ferrous iron, frerrous chloride.After these inorganic metal molysite are taken in by human body, part metals ion is not only not easy to be absorbed, and can also pierce
Swash stomach and intestine, cause diarrhea, tolerance is very poor.In addition, the antagonism between different metal element can also make to be absorbed into vivo
Metallic element utilization rate and deposition efficiency be restricted, cause its biological effectiveness reduction.
Second class is the organic molecule iron complex that organic acid or amino acid are formed with iron, such as such as ferrous oxalate, amber
Amber acid is ferrous；Ferrous tartrate, ferrous fumarate, ferrous ascorbate, ferrous lactate, ferrous gluconate, aspartic acid are sub-
Iron etc., for this kind of more inorganic chalybeate of chalybeate, side effect is reduced, and a degree of change has been obtained in terms of safety and tolerance
It is kind, but still it is not ideal enough.Third class is macromolecular iron complex, for example iron-dextrin, iron protein succinylate, polyferose are compound
Object etc., wherein iron protein succinylate and polyferose show its advantage in terms of safety and tolerance.
Document report, reduced iron, that is, ferrous iron are easily absorbed by the body compared with ferric iron, so the iron based on oral both at home and abroad
Agent either inorganic molysite or small molecule partner are based on ferrous salt.Therefore it will likely can improve the big of chalybeate tolerance
Molecule and the ferrous salt action generation macromolecular ferrous coordination compound for being more easy to absorption should be a new directions of chalybeate research, certainly,
Ferrous iron is easily oxidized to ferric iron, how to keep the stabilization of divalent iron salt and increases the site of macromolecular and ferrous ion
And need problem to be solved.In short, research macromolecular ferrous coordination compound, to more preferable, the absorptivity that obtains acquired tolerance
Better iron preparation is very necessary.
The research of albumen ferrous succinate has not been reported, and the technology of the present invention establishes for the first time utilizes casein combination amber
Acid anhydrides carries out the technique that complexing prepares succinyl casein-ferrous iron with iron again, and using bactard acid it is ferrous have iron-holder it is high,
The features such as bioavailability is high, tolerance is high, compliance is good, is developed into albumen ferrous succinate as novel benefit iron medicine
Object or quotation food, market potential are huge.
Invention content
The purpose of the present invention is to provide a kind of method for being used to prepare succinyl casein-ferrous iron, prepared by the method
Succinyl casein-ferrous iron have that acylation degree is high, amount of iron load is big, dissolubility is good, stable quality, impurity content is low and curative effect is shown
The advantages that work, described method includes following steps：
(a) casein and the water of 8 ~ 100 times of volumes are added in reaction kettle, 10min ~ 30min is stirred at 25 DEG C ~ 45 DEG C；It adds in
4mol/L sodium hydroxide solutions adjust pH values dissolves casein 7.0 ~ 9.0, into casein solution by weight junket egg
It is white: succinic anhydride 1: 1 ~ 10: 1 is continuous or is slowly added to succinic anhydride (time interval is 30 ~ 300 seconds), side edged several times
4mol/L sodium hydroxide solutions adjust pH values 7.0 ~ 9.0, the reaction was continued after succinic anhydride adds 10 ~ 25min, centrifuge
Filter, takes supernatant or filtrate；Supernatant or filtrate adjust pH values to 1.0 ~ 4.6 with 3mol/L hydrochloric acid solutions, make casein amber
Amber acid anhydrides precipitates, and precipitation is washed with water in centrifugal filtration, and centrifugal filtration obtains casein succinic acid.
(b) above-mentioned casein succinic acid is placed in reaction kettle, add in 8 ~ 15 times of volumes water, by the use of nitrogen as protect
Gas is full of entire reaction kettle, and 4mol/L sodium hydroxide solutions is added to adjust pH values dissolves precipitation 7.0 ~ 9.0, is contained using iron
It measures 4% ~ 10% and is configured to 12% solution to add frerrous chloride or ferrous sulfate, be stirred to react under the conditions of 25 DEG C ~ 45 DEG C
10min ~ 20min simultaneously adds 4mol/L sodium hydroxide solution adjusting control pH value that it is molten to obtain succinyl casein-ferrous iron 6.0 ~ 7.0
Liquid.
(c) by above-mentioned casein ferric succinate solution with 3mol/L hydrochloric acid solutions adjust pH value to 1.0 ~ 4.6,25 DEG C ~
45 DEG C are stirred to react 10 ~ 30min, and precipitation is washed with water in centrifugal filtration, and centrifugal filtration obtains succinyl casein-ferrous iron.
(d) above-mentioned precipitation is put into drying in vacuum drying chamber (40 DEG C ~ 50 DEG C) or freeze drying box (- 40 DEG C), obtains powder
Succinyl casein-ferrous iron of shape.
In step (a) of the present invention, casein: the volume ratio of water preferably 1:8~1:15
In step (a) of the present invention, preferably 25 DEG C ~ 30 DEG C of the temperature of reaction.
In step (a) of the present invention, the time being stirred to react is preferably 20min ~ 30min.
In step (a) of the present invention, it is preferably 8.0 ~ 9.0 that 4mol/L sodium hydroxide solutions, which adjust pH value,.
In step (a) of the present invention, casein: the weight ratio of succinic anhydride is preferably 1:1~5:1.
In step (a) of the present invention, the time that succinic anhydride interval adds in is preferably 300 seconds.
In step (a) of the present invention, the time of succinic anhydride reaction is preferably 15 ~ 20min.
In step (a) of the present invention, it is preferably 3.8 ~ 4.6 that 3mol/L hydrochloric acid solutions, which adjust pH value,.
In step (b) of the present invention, casein: the volume ratio of water preferably 1:8~1:15.
In step (b) of the present invention, it is preferably 8.0 ~ 9.0 that 4mol/L sodium hydroxide solutions, which adjust pH values,.
In step (b) of the present invention, iron content preferably 4% ~ 7%.
In step (b) of the present invention, preferably 25 DEG C ~ 30 DEG C of the temperature of reaction.
In step (b) of the present invention, the time being stirred to react is preferably 15min ~ 20min.
In step (c) of the present invention, it is preferably 3.8 ~ 4.6 that 3mol/L hydrochloric acid solutions, which adjust pH values,.
In step (c) of the present invention, preferably 25 DEG C ~ 30 DEG C of the temperature of reaction.
In step (c) of the present invention, the time being stirred to react is preferably 20min ~ 30min.
The preparation method of succinyl casein-ferrous iron of the present invention is raw material directly with casein, and reaction yield is high,
Good product purity.The impurity such as casein that may be present, succinic acid, sodium chloride can be removed by refining repeatedly.Using freeze-drying,
Obtained succinyl casein-ferrous iron is fluffy, easily crushes, color is uniform, white, tasteless, water-soluble.Amber after freeze-drying
Amber acyl casein-ferrous iron character is good, other indexs meet the requirements.
The complexing rate of casein succinic acid and iron of the present invention is up to 98%, the content of ferro element in succinyl casein-ferrous iron
Up to more than 5%.
It is yet another object of the invention to provide the succinyl casein-ferrous iron in the drug for preparing treatment disease
Using, which is characterized in that the disease is absolute and relative hypoferric anemia, since iron intake is insufficient or malabsorption causes
It is acute or chronic lose blood and the infection of various age patients caused by recessive or dominant hypoferric anemia and gestation with feed
Newborn phase anaemia.
A further object of the present invention provides the purposes that the succinyl casein-ferrous iron is used to prepare medicament, wherein should
Dosage form is commonly used in taking orally, such as capsule, granule and oral liquid.
Specific embodiment
Following embodiment is used to illustrate and the present invention be explained further, but be never limited in the present invention.
If be not specifically stated, heretofore described percentage refers both to weight percent.
First, the preparation of embodiment succinyl casein-ferrous iron
Embodiment 1
(a) casein succinic acid is prepared
Under the conditions of 25 DEG C, 5g caseins are suspended in 40ml water, are stirred to react 30min.Add in the NaOH solution of 4mol/l
PH value is adjusted to 8.5.1g succinic anhydrides are taken, are added in solution in three times（The time interval added in every time is 300s）, and
PH is maintained 8.5, is stirred to react 20min.Centrifugal filtration takes supernatant or filtrate.The HCl tune pH to 3.8 of 3mol/l is added in,
Precipitate casein succinic acid, precipitation is washed with water in centrifugal filtration separation.
(b) iron reaction is carried
Again plus about 105ml water, the NaOH solution for adding in 4mol/l adjust pH value to 8.5 acquisition casein succinic acid solutions,
Under nitrogen protective condition, 1.136gFeCl is taken212% solution is configured to, is slowly added into casein succinic acid solution, is stirred
15min is reacted, and pH is controlled 6.0 ~ 7.0.
(c) it refines
The HCl tune pH to 3.8 of 3mol/l is added in, is stirred to react 30min, precipitation is washed with water in centrifugal filtration.
(d) it is freeze-dried
Precipitation after deionized water is washed is put in freeze drying box, closes chamber door, booting refrigeration, for sample at -40 DEG C, holding 4 is small
When；Vacuum system is opened, vacuum degree is kept to be warming up to -20 DEG C to increase 2 DEG C per hour in 10Pa, is kept for about 8 hours；Again
30 DEG C are warming up to increase 2 DEG C per hour, is kept for 6 hours, breaking vacuum, outlet obtains succinyl casein-ferrous iron 4.45g.
Embodiment 2
(a) casein succinic acid is prepared
Under the conditions of 25 DEG C, 5g caseins are suspended in 45ml water, are stirred to react 30min.Add in the NaOH solution of 4mol/l
PH value is adjusted to 9.0.5g succinic anhydrides are taken, are added in solution in three times（The time interval added in every time is 300s）, and
PH is maintained 9.0, is stirred to react 20min.Centrifugal filtration takes supernatant or filtrate.The HCl tune pH to 4.6 of 3mol/l is added in,
Precipitate casein succinic acid, precipitation is washed with water in centrifugal filtration separation.
(b) iron reaction is carried
Again plus about 110ml water, the NaOH solution for adding in 4mol/l adjust pH value to 9.0 acquisition casein succinic acid solutions,
Under nitrogen protective condition, 1.79gFeCl is taken212% solution is configured to, is slowly added into casein succinic acid solution, is stirred
15min is reacted, and pH is controlled 6.0 ~ 7.0.
(c) it refines
The HCl tune pH to 4.6 of 3mol/l is added in, is stirred to react 30min, precipitation is washed with water in centrifugal filtration.
(d) it is freeze-dried
Precipitation after deionized water is washed is put in freeze drying box, closes chamber door, booting refrigeration, for sample at -40 DEG C, holding 4 is small
When；Vacuum system is opened, vacuum degree is kept to be warming up to -20 DEG C to increase 2 DEG C per hour in 10Pa, is kept for about 8 hours；Again
30 DEG C are warming up to increase 2 DEG C per hour, is kept for 6 hours, breaking vacuum, outlet obtains succinyl casein-ferrous iron 4.12g.
Embodiment 3
(a) casein succinic acid is prepared
Under the conditions of 30 DEG C, 5g caseins are suspended in 75ml water, are stirred to react 20min.Add in the NaHCO of 4mol/l3It is molten
Liquid adjusts pH value to 8.0.5g succinic anhydrides are taken, are added in solution in three times（The time interval added in every time is 300s）,
And pH is maintained 8.0, it is stirred to react 20min.Centrifugal filtration takes supernatant or filtrate.Add in the HCl tune pH of 3mol/l extremely
4.6, precipitate casein succinic acid, precipitation is washed with water in centrifugal filtration separation.
(b) iron reaction is carried
Again plus about 110ml water, the NaOH solution for adding in 4mol/l adjust pH value to 8.0 acquisition casein succinic acid solutions,
Under nitrogen protective condition, 1.63gFeCl is taken212% solution is configured to, is slowly added into casein succinic acid solution, is stirred
15min is reacted, and pH is controlled 6.0 ~ 7.0.
(c) it refines
The HCl tune pH to 4.6 of 3mol/l is added in, is stirred to react 30min, precipitation is washed with water in centrifugal filtration.
(d) it is freeze-dried
Precipitation after deionized water is washed is put in freeze drying box, closes chamber door, booting refrigeration, for sample at -40 DEG C, holding 4 is small
When；Vacuum system is opened, vacuum degree is kept to be warming up to -20 DEG C to increase 2 DEG C per hour in 10Pa, is kept for about 8 hours；Again
30 DEG C are warming up to increase 2 DEG C per hour, is kept for 6 hours, breaking vacuum, outlet obtains succinyl casein-ferrous iron 4.06g.
Embodiment 4
(a) casein succinic acid is prepared
Under the conditions of 30 DEG C, 5g caseins are suspended in 75ml water, are stirred to react 30min.Add in the NaHCO of 4mol/l3It is molten
Liquid adjusts pH value to 8.5.1g succinic anhydrides are taken, are added in solution in three times（The time interval added in every time is 300s）,
And pH is maintained 8.5, it is stirred to react 30min.Centrifugal filtration takes supernatant or filtrate.Add in the HCl tune pH of 3mol/l extremely
4.0, precipitate casein succinic acid, precipitation is washed with water in centrifugal filtration separation.
(b) iron reaction is carried
Again plus about 110ml water, the NaOH solution for adding in 4mol/l adjust pH value to 8.5 acquisition casein succinic acid solutions,
Under nitrogen protective condition, 1.136gFeCl is taken25% solution is configured to, is slowly added into casein succinic acid solution, is stirred
15min is reacted, and pH is controlled 6.0 ~ 7.0.
(c) it refines
The HCl tune pH to 4.0 of 3mol/l is added in, is stirred to react 25min, precipitation is washed with water in centrifugal filtration.
(d) it is freeze-dried
Precipitation after deionized water is washed is put in freeze drying box, closes chamber door, booting refrigeration, for sample at -40 DEG C, holding 4 is small
When；Vacuum system is opened, vacuum degree is kept to be warming up to -20 DEG C to increase 2 DEG C per hour in 10Pa, is kept for about 8 hours；Again
30 DEG C are warming up to increase 2 DEG C per hour, is kept for 6 hours, breaking vacuum, outlet obtains succinyl casein-ferrous iron 4.17g.
2nd, test example
Succinyl casein-ferrous iron and the quality and stability of intermediate prepared by the preparation method of 1 embodiment 1-4 of test example
Research is studied using succinyl casein-ferrous iron sample prepared by embodiment 1-4.
(1) acylation degree of intermediate casein succinyl measures
In two steps, key intermediate is casein succinyl to the method for the invention, and the detection of acylation degree is to check acylation
Degree, acylation degree height be conducive to carry iron reaction progress and sample viscosity, solution uniformity.So acylation degree is in control
One important indicator of mesosome amber acid albumin has vital influence to the quality of final product amber acid albumin iron.
We conducted the research of acylation degree method for measuring, and establish Quality control of intermediates index (acylation degree is more than 94%).
Method：The classical way of amino acid content is surveyed with reference to ninhydrin.Ninhydrin solution and protein heat altogether, ninhydrin with
The amino reaction generation ammonia to dissociate in protein, ammonia and ninhydrin and reproducibility ninhydrin reaction, generate violet compound.
The depth of the compound colors is directly proportional to the content of free amine group, can be measured by measuring the absorbance at 570nm wavelength
The content of free amine group.
Instrument：TU-1810 type UV, visible light spectrophotometrics Beijing Puxi General Instrument Co., Ltd
Measuring method and computational methods：Precision measures casein contrast solution and each 2ml of test solution, puts 2 10ml examinations respectively
Pipe, respectively plus 1ml color developing agents, water-bath 15min are cooled to room temperature in cold water, respectively plus 40% ethyl alcohol 5ml, then use water constant volume respectively
To 10ml measuring bottles, 20min is placed, absorbance is measured at 570nm wavelength, while do blank correction.
Calculation formula：
In formula：Asp is the absorbance of amber acid albumin test solution
Ap is the absorbance of casein contrast solution
Csp is the concentration of amber acid albumin test solution
Cp is the concentration of casein contrast solution
Casein succinyl acylation degree in the preparation process of embodiment 1-4 is tested, the result is shown in tables 1.
Intermediate acylated degree result prepared by 1 embodiment 1-4 of table
(2) iron content and impurity determination of succinyl casein-ferrous iron prepared by the preparation method of embodiment 1-4
2.1 chloride
This product raw material is in the synthesis process due to the use of hydrochloric acid, last inevitable introducing chloride.Therefore it is coped in raw material
Middle content is controlled.To detect raw material chloride content, using two annex of Chinese Pharmacopoeia version in 2010, VIII A turbidimetrys into
Row measures.
Method：This product 0.25g is taken, phosphorate phthalate buffer（pH7.6）Then about 30ml, stirring and dissolving add in
0.05mol/L sulfuric acid solution tune pH value makes it precipitate completely to 2.5~3.0, filters, and with appropriate water washing and precipitating, merging filtrate,
500ml measuring bottles are put, are diluted with water to scale, are shaken up, precision measures 5ml, checks in accordance with the law（Chinese Pharmacopoeia two annex of version in 2010
ⅧA）, respectively compared with comparison liquid made of standard chlorination sodium solution 1.0ml, 2.5ml.
Succinyl casein-the ferrous iron prepared to the preparation method of embodiment 1-4 has carried out chloride test, test result
It is shown in Table 2.The result shows that：Succinyl casein prepared by the preparation method of embodiment 1-4-ferrous iron solution colour developing is shallower than 2.5ml
The colour developing of comparison liquid made of standard chlorination sodium solution, i.e. chloride in sample are below 0.5%
2 chloride determination result of table
2.2 sulfate
This product raw material is in the synthesis process due to the use of ferrous sulfate, last inevitable introducing sulfate.Therefore cope with its
Content is controlled in raw material.To detect raw material sulphuric acid salt content, using side in two VIII B of annex of Chinese Pharmacopoeia version in 2010
Method is measured.Method is as follows：This product 0.25g is taken, adds 0.1mol/L sodium hydroxides（pH7.6）About 30ml, stirring and dissolving, then
Adding in 0.1mol/L hydrochloric acid solution tune pH value makes it precipitate completely to 2.5~3.0, filters, and uses appropriate water washing and precipitating, merges and filters
Liquid puts 500ml measuring bottles, is diluted with water to scale, shakes up, and precision measures 5ml, checks in accordance with the law（Chinese Pharmacopoeia version two in 2010
VIII B of annex）, must not be denseer compared with comparison liquid made of standard potassium sulfate solution 1.0ml（0.2%）.To the system of embodiment 1-4
Sulfate is tested in succinyl casein-ferrous iron prepared by Preparation Method, and test result is shown in Table 3.The result shows that it is respectively less than
0.2%。
The measurement result of 3 sulfate of table
2.3 succinic acid
The preparation method of the present invention has used succinic anhydride in preparation process, and form in water is succinic acid, although refined
A large amount of remaining succinic acids can be removed in the process, but may still have a little residual, for the safety ensured drug quality, adopted
Remaining succinic acid in raw material is detected with high performance liquid chromatography, method is as follows：Chromatograph：Agilent 1100Series
HPLC instrument, Agilent chem workstation chromatographic columns：AichromBond-AQ C18250mm × 4.6mm, 5 μm.With
0.025mol/L potassium dihydrogen phosphates (phosphorus acid for adjusting pH value to 3.0) are mobile phase；Detection wavelength is 210nm, flow velocity
1.0ml/min, 30 DEG C of column temperature.Number of theoretical plate is calculated by succinic acid should be not less than 2000.By the use of high performance liquid chromatography as amber
Acid residual Limit Test method, precision is high, linear relationship is good, and sample measures the processing method rate of recovery and also complies with requirement, energy
Enough science, the quality for rationally, effectively controlling this product.
Succinic acid is tested in the succinyl casein-ferrous iron prepared to the preparation method of embodiment 1-4, is as a result seen
Table 4, the experimental results showed that its succinic acid content is below 0.05%.
4 succinic acid content Limit Test result of table
The measure of 2.4 total iron
Using Shimadzu GFA6880 atomic absorption spectrophotometers, the sample of digestion process is measured with flame method.Mode determination is
Integral mode, lamp current 5mA, Detection wavelength 248.3nm, narrow peak width are 0.2mm.To the preparation method of embodiment 1-4
Total iron is tested in succinyl casein-ferrous iron of preparation, the results are shown in Table 5, the results showed that its total iron content 5% ~
In the range of 6%, iron content is higher.
5 iron content determination data of table
2.5 free iron
Succinyl casein-ferrous iron should be a kind of ferrous complex compound of no ionic condition, and there may be inherent drops for product
Solution is impure with itself, can all lead to the presence of free iron, its presence can influence the accuracy and product matter of iron content measure
Amount, so the measure of free iron and limit value are critically important.With standard iron solution (two annex VIII G of Chinese Pharmacopoeia version in 2010)
Manufactured comparison liquid compares, and the absorbance of test solution is considered as less than the absorbance (0.1%) of comparison liquid not to be detected.
10ml, 5% succinyl casein-ferrous iron solution are taken, 15min is centrifuged under 3000r/min, pours out supernatant,
Add people's 10ml deionized waters, centrifuged under similarity condition, washing twice, collects supernatant, is settled to 50ml, with adjacent phenanthrene
Sieve quinoline method surveys iron ion content in water lotion, as free iron.The succinyl junket prepared to the preparation method of embodiment 1-4
Free iron is tested in albumen-ferrous iron, the results are shown in Table 6, the results showed that its free iron content is respectively less than 0.1%.
6 free iron measurement result of table
（3）The long term test of succinyl casein-ferrous iron prepared by the preparation method of embodiment 1-4
Succinyl casein-the ferrous iron prepared to the preparation method of embodiment 1-4 has carried out long term test, the results are shown in Table 7, experiment
The result shows that：Intend the albumen ferrous succinate raw material of listing packaging, at 25 DEG C ± 2 DEG C, under conditions of relative humidity 60% ± 10%
Long-term investigation 24 months, the inspection targets such as shape, clarity of solution, loss on drying, free iron, iron content become without apparent
Change, the content of succinic acid has increase, but also drafting within standard.
7 long-term experiment test result of table
Succinyl casein-ferrous iron prepared by the preparation method of 2 embodiment 1 of test example imitates the intervention of animal hypoferric anemia
Fruit
Method：40 SD rats, which are made according to Liao Shi methods after Anemia model, is randomly divided into blank group and experimental group, and blank group is given
The physiological saline of equivalent is given, experimental group is given the solution 10ml (10mg/kg) of succinyl casein-ferrous iron, measured after one month
Hemoglobin (Hb) and red blood cell (RBC).
8 are the results are shown in Table, experimental group increases compared with blank group Hb, SF, RBC content conspicuousness.Succinyl prepared by embodiment 1
Casein-ferrous iron can obviously improve Induced By Iron Deficiency Anemia In Rats Iron status, and be substantially better than blank group.
8 succinyl casein of table-ferrous iron is to the intervention effect of animal hypoferric anemia
* P ＜ 0.01
Although the present invention has obtained understanding explanation by above example, however without departing substantially from of the invention spiritual and its essence
In the case of, person of ordinary skill in the field makes various corresponding variations and modifications, but these phases in accordance with the present invention
The variations and modifications answered should all belong to the scope of the claims of the present invention.
Claims (11)
1. a kind of succinyl casein-ferrous complex is complexed by succinyl casein with ferrous ion.
2. succinyl casein-ferrous complex according to claim 1, wherein succinyl casein and ferrous ion
Complexing rate is not less than 98%.
3. succinyl casein-ferrous complex according to claim 1, the wherein content of complex compound ferrous ions are not
Less than 5%.
4. a kind of preparation method of complex compound according to any succinyl casein-ferrous iron of claim 1 ~ 3, feature
It is, includes the following steps：
(a) suspension casein forms casein suspension in water；With
(b) if desired, casein suspension is made to react to form caseic aqueous solution at least one alkali；With
(c) caseic aqueous solution is made to react the aqueous suspension solution to form succinyl casein at least one succinylation reagent；With
(d) the aqueous suspension solution and at least one ferrous reactant salt for making the succinyl casein obtained in step (c) form amber
Amber acyl casein-ferrous iron suspension；With
(f) make the casein of the succinyl obtained in step (d)-ferrous iron suspension that succinyl junket be obtained by the reaction at least one acid
Albumen-ferrous precipitation.
5. the preparation method of succinyl casein-ferrous complex according to claim 4, it is characterized in that in step (a)
The casein：Water volume ratio is 1：1~1：100, preferably 1：8~1：15.
6. the preparation method of succinyl casein-ferrous complex according to claim 4, it is characterized in that in step (b)
The alkali is the mixture of one or more alkali, selected from alkali or alkaline earth metal salt, preferably metal hydroxides, metal oxygen
Compound and/or metal carbonate, further preferred alkali are metal hydroxides, more preferably NaOH, KOH, most preferably NaOH,
It is 7.0 ~ 9.0, preferably 8.0 ~ 9.0 that the alkali, which adjusts pH,.
7. the preparation method of succinyl casein-ferrous complex according to claim 4, it is characterized in that in step (c)
The succinylation reagent is succinic anhydride, succinyl chloride, preferably succinic anhydride；Preferably, the casein and succinyl
The weight ratio for changing reagent is 1：1~20：1, preferably 1：1~5：1.
8. the preparation method of succinyl casein-ferrous complex according to claim 4, it is characterized in that in step (d)
The ferrous salt is frerrous chloride, ferrous sulfate, asparatate ferrous iron, ferrous citrate, ferrous gluconate, fumaric acid
Ferrous iron, ferrous bisglycinate chelate, ferrous lactate or ferrous oxalate, preferably frerrous chloride or ferrous sulfate.
9. the preparation method of succinyl casein-ferrous complex according to claim 4, it is characterized in that in step (f)
The acid is hydrochloric acid, sulfuric acid, acetic acid, malonic acid, malic acid, citric acid, tartaric acid or lactic acid, preferably hydrochloric acid；Preferably,
The acid-conditioning solution pH is 3.0 ~ 5.0.
10. one kind suitable carrier comprising any succinyl casein-ferrous complex of claim 1 ~ 3 and its pharmaceutically
Pharmaceutical composition.
11. any succinyl casein-ferrous complex of claim 1 ~ 3 is preparing treatment hypoferric anemia and iron deficiency
Purposes in property symptom drug.
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