CN110551019A - 一种亚铁糖(ⅱ)复合物、制备方法及其应用 - Google Patents
一种亚铁糖(ⅱ)复合物、制备方法及其应用 Download PDFInfo
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- CN110551019A CN110551019A CN201910864166.0A CN201910864166A CN110551019A CN 110551019 A CN110551019 A CN 110551019A CN 201910864166 A CN201910864166 A CN 201910864166A CN 110551019 A CN110551019 A CN 110551019A
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- Prior art keywords
- sugar
- iron
- ferrous
- salt
- ferric
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- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 235000000346 sugar Nutrition 0.000 title claims abstract description 68
- 150000001875 compounds Chemical class 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 60
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical class [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000010438 heat treatment Methods 0.000 claims abstract description 17
- 125000003172 aldehyde group Chemical group 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910001868 water Inorganic materials 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 238000005303 weighing Methods 0.000 claims abstract description 7
- 239000000725 suspension Substances 0.000 claims abstract description 6
- 235000013402 health food Nutrition 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 43
- 229910052742 iron Inorganic materials 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 24
- 150000001413 amino acids Chemical class 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000003381 stabilizer Substances 0.000 claims description 10
- -1 ferrous sugars Chemical class 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 235000016709 nutrition Nutrition 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 150000002505 iron Chemical class 0.000 claims description 6
- 239000013589 supplement Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 150000004676 glycans Chemical class 0.000 claims description 4
- 239000013067 intermediate product Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 229920001282 polysaccharide Polymers 0.000 claims description 4
- 239000005017 polysaccharide Substances 0.000 claims description 4
- 238000006479 redox reaction Methods 0.000 claims description 4
- 239000002738 chelating agent Substances 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 150000002500 ions Chemical group 0.000 claims description 3
- 150000002772 monosaccharides Chemical group 0.000 claims description 3
- 150000005846 sugar alcohols Polymers 0.000 claims description 3
- 229920003169 water-soluble polymer Polymers 0.000 claims description 3
- 239000012634 fragment Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
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- 235000015097 nutrients Nutrition 0.000 abstract 1
- 235000001014 amino acid Nutrition 0.000 description 21
- 229940024606 amino acid Drugs 0.000 description 21
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 18
- 229930006000 Sucrose Natural products 0.000 description 18
- 239000005720 sucrose Substances 0.000 description 18
- 239000000047 product Substances 0.000 description 14
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 description 10
- 241000700157 Rattus norvegicus Species 0.000 description 9
- 229960004887 ferric hydroxide Drugs 0.000 description 9
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 9
- 239000003513 alkali Substances 0.000 description 8
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 8
- 239000004375 Dextrin Substances 0.000 description 7
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- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 229910021645 metal ion Inorganic materials 0.000 description 5
- 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 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 239000000174 gluconic acid Substances 0.000 description 4
- 235000012208 gluconic acid Nutrition 0.000 description 4
- NCNCGGDMXMBVIA-UHFFFAOYSA-L iron(ii) hydroxide Chemical compound [OH-].[OH-].[Fe+2] NCNCGGDMXMBVIA-UHFFFAOYSA-L 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 206010022971 Iron Deficiencies Diseases 0.000 description 3
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- 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 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
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- 125000003277 amino group Chemical group 0.000 description 2
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
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- 150000001720 carbohydrates Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
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- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- 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 description 2
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- SZQUEWJRBJDHSM-UHFFFAOYSA-N iron(3+);trinitrate;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O SZQUEWJRBJDHSM-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/16—Inorganic salts, minerals or trace elements
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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Abstract
本发明提供了一种亚铁糖(Ⅱ)复合物、制备方法及其应用,利用还原性糖与三价铁盐在加热条件下直接反应制备得到稳定的亚铁糖(Ⅱ)复合物;制备过程为:按照化学计量比称取三价铁盐和还原性糖溶于水中,调节水溶液pH为2–10,搅拌条件下加热至50–120℃,反应至体系由悬浊液变为透明溶液;所述还原性糖与三价铁盐的比例以醛基和铁元素计,满足醛基与铁元素摩尔比为1:1–20:1;本发明可以补铁营养剂活补铁保健食品。
Description
技术领域
本发明涉及补铁营养剂生产工艺技术领域,具体涉及一种亚铁糖(Ⅱ)复合物、制备方法及其应用。
背景技术
缺铁性贫血(Iron-DeficiencyAnemia,IDA)是一种高发性贫血症,严重影响人类的健康和生活水平。据WHO报告,IDA发生率极为普遍,在婴幼儿及孕妇中更是分别高达48.1%和52.0%。令人担忧的是,IDA可影响婴幼儿智力与身体的发育,孕妇患IDA可影响胎儿的发育并导致分娩过程中母婴死亡率上升。
IDA可通过补铁治疗改善症状。以口服铁剂为例,成年人每日需补充铁元素100–200mg3。硫酸亚铁为最常见的IDA治疗药物。亚铁离子在溶液中易被氧化为不易吸收的三价铁离子。因此常加入各种有机酸或糖(氨基酸、延胡索酸、葡萄糖酸、蔗糖、糊精及其衍生物等)与铁盐形成复合物以增加亚铁离子稳定性或促进三价铁离子的吸收。静脉注射铁剂是另一种补铁手段。但成本较高,以蔗亚铁糖为例,静脉注射1000mg剂量的铁的花费约为45–251欧元。由于不发达国家的缺铁性贫血症的发病率显著高于发达国家,高昂的成本阻碍了补铁剂在不发达地区的应用。
目前市场上主导的铁强化剂均为亚铁糖复合物。所用糖包括葡萄糖、蔗糖、糊精、低分子量糊精以及糖衍生物羧甲基糊精、葡萄糖酸等。在制备过程中多采用三价铁盐与糖类物质作用。U.S.Patent2820740,提供了一种制备低分子糊精铁复合物的方法。在该法中,将三价铁盐水溶液加入糊精的碱溶液中,加热一段时间后经纯化可得糊精铁复合物;U.S.Patent2885393,公开了一种糊精铁复合物的制备方法。首先将糊精与三价铁盐在酸性条件下络合,然后加入碱溶液处理得到糊精铁复合物;U.S.Patent3074297,公开了制备还原性糖与各种金属离子络合物的方法。在该法中,还原性糖与金属离子(摩尔比2:1)混合后用碱调价pH至8即可得到糖与各种金属的络合物。该法仅指出金属离子与还原性糖之间可形成稳定的络合物,但未探讨还原性糖与金属离子间发生氧化还原反应的可能性。U.S.Patent3821192,公开了一种亚铁糖复合物的制备方法。首先将糖与三价铁盐混合,之后加入碱调节pH至11,加热处理后可得产物;U.S.Patent7674780B2,将蔗糖与氢氧化铁按照2:1–50:1的比例混合,加热处理后得到蔗亚铁糖复合物。U.S.Patent8030480B2,三价铁与无机碱首先在弱酸性条件下生成氢氧化铁,然后加入蔗糖与并调节溶液pH至9–12,加热处理后即得到蔗亚铁糖复合物;U.S.Patent20080167266A1,向氢氧化铁与蔗糖的混合溶液中加入碱使溶液pH至10–12,然后加热至形成蔗亚铁糖复合物;USPatent20140303364A1,将经硼氢化钠将醛基还原为羟基的糖与铁盐混合,经碱化加热处理后得到稳定的亚铁糖复合物。CN104558064A,公开了一种蔗亚铁糖络合物的制备方法。首先将三价铁盐与无机碱反应制备氢氧化铁胶体,然后将该胶体与蔗糖在100–120℃条件下反应得到蔗亚铁糖复合物;CN104098616A,向碱化的蔗糖水溶液中同时滴加三价铁盐和碱的水溶液得到蔗亚铁糖产物,并利用微孔滤膜纯化产物的方法;U.S.Patent3014026,公开了一种单糖氨基酸铁螯合物的制备方法。在该法中,还原性单糖的半缩醛羟基首先与氨基酸的氨基在碱性条件下发生取代反应得到单糖氨基酸络合剂。该络合剂与铁盐在弱碱性条件下(pH8)反应得到单糖氨基酸螯合铁。在这些亚铁糖复合物的制备过程中,常利用无机碱调节反应体系pH,一般经过氢氧化铁的中间产物与糖类物质在加热的条件下生成稳定的复合物。
由于氢氧化铁并不稳定,可以将氢氧化铁生成的氢氧化铁与稳定剂反应后与糖继续反应。WO2009078037A2及WO2003098564A1分别将新制的氢氧化铁与醋酸和葡萄糖酸反应,然后将产物与蔗糖得到蔗亚铁糖复合物。在这些制备方法中,除了经历一个氢氧化铁的中间产物过程,三价铁在制备中价态没有改变,产物的主要形式也主要为三价铁。由于三价铁在胃肠道需转化为二价铁后才能被吸收,因此其口服生物利用度显著低于二价铁盐。
为了提高铁剂的吸收效率,可采用二价铁与糖类反应制备亚铁糖复合物。但由于二价铁极易被氧化,生产过程需要惰性气体保护,提高了工艺的复杂性。U.S.Patent2862920,公开了一种方法,在CO2气体的保护下,向羧甲基糊精溶液中加入亚铁盐或铁盐的水溶液,得到羧甲基糊精铁;CN1033622979A,描述了一种方法,利用蔗糖与二价铁盐制备蔗亚铁糖的方法。在该法中,分别将含有稳定剂的二价铁盐溶液碱化处理,之后将红棕色铁盐沉淀与经碱化处理的的蔗糖溶液络合,通过醇沉法纯化络合产物,得到其所声称的蔗糖亚铁复合物。该法也采用碱处理,并声称加入稳定剂可提高亚铁稳定性,但从碱处理后得到的红棕色沉淀结果看,稳定剂的加入对亚铁的保护效果并不明显(氢氧化亚铁为应为黑色,当三价铁与亚铁的摩尔比远大于2:1时产物才呈红棕色)。因此该专利与采用三价铁碱化制备蔗亚铁糖的工艺无本质区别。
考虑到亚铁的不稳定性,可加入络合剂以增加亚铁剂的抗氧化性。U.S.Patent2904573,公开了一种制备柠檬酸亚铁复合物的方法。在该法中,将铁粉与不同量的柠檬酸在加热和氮气的保护下反应,可得到含不同分子组成的柠檬酸亚铁复合物;CN1566087A,公开了一种利用甘氨酸及硫代氨基酸以固定的比例(2:3–6:1)作为配体与亚铁盐结合形成氨基酸螯合铁的方法。方法中需要加入硫代氨基酸(蛋氨酸、半胱氨酸等以调节铁盐比例和改善吸收);CN1491646A,公开了一种利用以亚铁盐、L-赖氨酸、L-天冬氨酸为原料,制备复合氨基酸亚铁的方法。在该法中,亚铁盐首先与碱性物质反应得到氢氧化亚铁,然后与复合氨基酸在加热条件下作用得到产物;CN101786962A,公开了一种利用角蛋白裂解液与氢氧化亚铁作用制备氨基酸亚铁络合物的方法;WO2007136727A2公开了一种方法,将亚铁源(亚铁盐、氧化亚铁、碳酸亚铁等)、氨基酸及还原剂(柠檬酸、抗坏血酸等)反应,得到稳定的氨基酸亚铁复合物;EP2717713B1,公开了一种制备混合氨基酸赖氨酸-谷氨酸(比例4:6–6:4)与多种微量元素(铁、锌、镁等)的复合物的方法。该复合物可利用谷氨酸的转运通路促进微量元素的吸收。这些方法相对简单,由于亚铁的易氧化性,制备过程中仍有部分铁元素被氧化为难以利用的三价铁。
USpatent4830716提供了多种制备氨基酸金属螯合物的方法,可用无机金属、金属盐、金属氧化物、氢氧化物、碳酸盐与氨基酸作用。得到的产物也有多种形式,氨基酸可与金属离子以多种形式结合;USPatent3002985,公开了一种氨基酸亚铁复合物的制备方法。在该法中,向氨基酸与亚铁盐的碱性溶液中加入小分子醛类化合物反应得到最终产物。反应中所用铁盐为亚铁盐,醛基主要与氨基酸的氨基作用生成席夫碱的形式;CN102992998A,公开了一种制备葡萄糖酸亚铁的方法。首先利用硫酸处理葡萄糖酸钙得到葡萄糖酸,然后与铁粉反应得到产物;CN101735089A,公开了一种利用五羰基铁与氨基酸反应制备氨基酸螯合铁(Ⅱ)的方法。在该法中所用为高活性的五羰基铁,价格较无机三价铁盐高,大量生产氨基酸铁的成本较高。同时为防止亚铁被氧化,反应需在惰性气体保护条件下进行。
基于现有技术的缺陷,亟需一种工艺简单、成本低的亚铁复合物的制备方法,并能够提供稳定的亚铁复合物,以满足IDA患者的日常需要。
发明内容
本发明提供了一种亚铁糖(Ⅱ)复合物、制备方法及其应用。其利用氧化还原反应一步法制备而得,工艺简单,产物中二价铁稳定性高。
为实现上述目的,本发明采用的技术方案如下:
作为本发明的一个方面,本发明提供了一种亚铁糖(Ⅱ)复合物的制备方法,其特征在于,以还原性糖与三价铁盐为原料,在水溶液中经过氧化还原反应直接制备得到亚铁糖复合物,所述亚铁糖复合物中铁元素为稳定的+2价。
此过程中的反应机理分两步:
1)糖将三价铁还原,生成葡萄糖酸亚铁:
C5H11O5CHO+Fe3++H2O→C5H11O5COOH+Fe2++H+
2)亚铁与葡糖糖酸或葡萄糖形成稳定的亚铁糖复合物;
进一步的,具体反应过程如下:按照化学计量比称取三价铁盐和还原性糖溶于水中,用盐酸或NaOH调节水溶液pH为2–10,搅拌条件下加热至50–120℃,反应至体系由悬浊液变为透明溶液;所述还原性糖与三价铁盐的比例以醛基和铁元素计,满足醛基与铁元素摩尔比为1:1–20:1。
进一步的,所述还原性糖为含有游离醛基,或在反应过程中生成含有游离醛基中间产物的单糖、多糖、多糖的酶解片段、糖衍生物或还原性糖与非还原性物质的混合物。
进一步的,所述三价铁盐为水溶性三价铁盐。
优选的,所述还原性糖与三价铁盐的比例以醛基与铁元素计,满足醛基与铁摩尔比为2:1–5:1。
进一步的,反应时间为1–36小时。反应产物可经冻干的方法得到干粉,或加入与水混溶的有机溶剂如(甲醇、异丙醇、乙醇等)沉淀的方法收集纯化。反应产物与药学上可接受辅料混合,可制备出临床上可用的药物用以治疗铁缺乏症。
进一步的,在制备过程中还加入稳定剂;所述稳定剂为离子螯合剂、氨基酸、多元醇或高分子水溶性聚合物。优选的,所述离子螯合剂为柠檬酸、EDTA及盐或琥珀酸;所述氨基酸为一种或多种氨基酸的混合物;所述多元醇为乙二醇、甘油或水溶性糖;所述高分子水溶性聚合物为PEG或肝素。
进一步的,所述稳定剂与铁盐比为1:10–10:1,优选1:2–1:5。
作为本发明的另一个方面,由上述方法制备的亚铁糖(Ⅱ)复合物。
作为本发明的第三个方面,所述亚铁糖(Ⅱ)复合物在补铁营养剂方面的应用,
所述补铁营养剂可以制备成片剂、口服液或注射剂。
作为本发明的第四个方面,所述亚铁糖(Ⅱ)复合物作为补铁保健食品的应用。
与现有技术相比,本发明具有如下技术效果:
本发明应用最少的原料制备出稳定的二价铁复合物。常规的方法多是以铁单质或亚铁剂为原料制备亚铁糖(Ⅱ)复合物,鉴于二价铁容易氧化的技术难题,往往需要增加过多的保护措施,导致工艺复杂,而本发明则是以三价铁盐为原料,通过与还原糖的氧化还原反应制备得到亚铁糖(Ⅱ)复合物,而由于还原糖的还原性较二价铁的还原性强,所以容易促使反应由三价铁还原为二价铁的方向进行,而且还原糖中的还原基团并未在反应中全部参与反应,因此导致形成的亚铁糖(Ⅱ)复合物中尚残存一部分还原基团,这是保证二价铁不被氧化的关键。本发明工艺简单,无需诸多的亚铁保护措施,无需繁琐的溶液碱化及脱盐过程。本发明为亚铁复合物的制备提供了一种可靠的技术手段。经过实验验证,本发明制备的亚铁糖(Ⅱ)复合物具有良好的补铁效果。
具体实施方式
下面将结合本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1:
称取无水氯化铁1.64kg,蔗糖10.8kg,水40L,搅拌条件下,80℃加热反应5小时,溶液由棕黄色悬浊液变为近无色透明溶液。经赤铁盐及黄铁盐显色反应显示溶液主要成分为亚铁,该溶液可在室温下稳定储存。与之相比,对照等浓度的氯化亚铁水溶液在开放的室温环境中可在10分钟内氧化变成黄色(经赤铁盐显色反应显示主要为Ⅲ价铁盐)。提示本发明中形成的二价铁与糖形成了稳定的复合物,有利于二价铁的稳定。其中赤铁盐及黄铁盐显色反应是鉴定亚铁离子的常规方法,属于本领域公知常识,且并非本发明的发明要点,在此不做赘述。
实施例2:
称取无水氯化铁1.64kg,葡萄糖7.2kg,天冬氨酸1.33kg,水40L,搅拌条件下,90℃加热反应8小时,溶液由棕黄色悬浊液变为褐色透明溶液。经喷雾干燥法得到干粉即为葡糖亚铁复合物粉末。
实施例3:
称取九水合硝酸铁4.04kg,糊精18kg,柠檬酸2.94kg,水40L,搅拌条件下90℃加热反应8小时,溶液由棕黄色悬浊液变为黄色透明溶液,加入120L乙醇沉淀产物,75%乙醇洗涤2次,干燥后即得亚铁糖(Ⅱ)复合物。
实施例4:
称取硫酸铁2kg,蔗糖7.2kg,透明质酸3kg,水40L,搅拌条件下90℃加热反应8小时,得近无色透明溶液。加入过量异丙醇沉淀产物,洗涤2次,干燥后即得亚铁糖(Ⅱ)复合物。
应用例:
以小白鼠为实验对象,对实施例1-4所得亚铁糖(Ⅱ)复合物的药理性进行检验,检验方法如下:
1、实验材料:
雌性Wistar大鼠12只;
低铁饲料:由奶粉、大豆油、玉米淀粉、NaCl配制而成;
清洁级饲料;去离子水;自来水。
2、实验方法:
筛选4组体重差小于0.01kg的成年雌性Wistar大鼠,分别记作A、B、C、D四组,每组3只,对每只Wistar大鼠进行血常规化验,记录Hb、RBC、WBC、PLT值,为初始值;对每组Wistar大鼠以低铁饲料喂养,饮用去离子水,三周后进行血常规化验,记录Hb、RBC、WBC、PLT值,为缺铁饲喂后初始值;对A、B、C、D四组性Wistar大鼠用常规清洁级饲料和自来水,每组Wistar大鼠常规清洁级饲料中分别加入等量的实施例1-4中所述的亚铁糖(Ⅱ)复合物,一日三次。每周测定并记录一次Hb、RBC、WBC、PLT值,四周之后停止实验。结果记录见表1.每个测定值均为每组小白鼠的平均值。
3、实验结果记录:
表1
3、结果分析:
Wistar大鼠的缺铁性贫血常以Hb(血红蛋白)、SI(血清铁)、TIBC(血清总铁结合力)作为判断指标。当)Hb≤100g/L;SI<10μmol/L;TIBC>60μmol/L时,可以判定为患有缺铁性贫血。在试验初期,四组Wistar大鼠的三大指标均处于正常水平,经过三周的缺铁饲喂,四组小白鼠的三大指标均出现异常,可以判定为患有缺铁性贫血症。当分别给四组Wistar大鼠补充实施例1-4产生的亚铁糖(Ⅱ)复合物后,三大指标逐渐趋于正常,四周之后三大指标均恢复正常水平,且未见其他不良反应,证明本发明所述的亚铁糖(Ⅱ)复合物可以用作补贴营养剂或补铁营养保健品。
以上所述的实施例仅是对本发明的优选方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案做出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (10)
1.一种亚铁糖(Ⅱ)复合物的制备方法,其特征在于,以还原性糖与三价铁盐为原料,在水溶液中经过氧化还原反应直接制备得到亚铁糖复合物,所述亚铁糖复合物中铁元素为稳定的+2价。
2.根据权利要求书1所述的一种亚铁糖(Ⅱ)复合物的制备方法,其特征在于,具体过程如下:按照化学计量比称取三价铁盐和还原性糖溶于水中,用盐酸或氢氧化钠调节水溶液pH为2-10,搅拌条件下加热至50-120℃,反应至体系由悬浊液变为透明溶液;所述还原性糖与三价铁盐的比例以醛基和铁元素计,满足醛基与铁元素摩尔比为1:1-20:1。
3.根据权利要求书1所述的一种亚铁糖(Ⅱ)复合物的制备方法,其特征在于,所述还原性糖为含有游离醛基,或在反应过程中生成含有游离醛基中间产物的单糖、多糖、多糖的酶解片段、糖衍生物或还原性糖与非还原性物质的混合物。
4.根据权利要求1所述的一种亚铁糖(Ⅱ)复合物的制备方法,其特征在于,所述三价铁盐为水溶性三价铁盐。
5.根据权利要求2所述的一种亚铁糖(Ⅱ)复合物的制备方法,其特征在于,反应时间为1–36小时。
6.根据权利要求2所述的一种亚铁糖(Ⅱ)复合物的制备方法,其特征在于,在制备过程中还加入稳定剂;所述稳定剂为离子螯合剂、氨基酸、多元醇或高分子水溶性聚合物。
7.根据权利要求书7所述的一种亚铁糖(Ⅱ)复合物的制备方法,其特征在于,所述稳定剂与铁盐摩尔比为1:10–10:1。
8.由权利要求书1-8任一项所述的方法制备的亚铁糖(Ⅱ)复合物。
9.根据权利要求书9所述的一种亚铁糖(Ⅱ)复合物作为补铁营养剂的应用,其特征在于,所述营养铁剂为片剂、口服液或注射剂。
10.根据权利要求书9所述的一种亚铁糖(Ⅱ)复合物作为补铁保健食品的应用。
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