摘要
氨基酸螯合铁是一种新型的和理想的铁营养强化剂,它具有良好的理化性质和生物活性,对预防和治疗缺铁症、改善缺铁性贫血有着重要的意义。但氨基酸螯合铁在强酸环境中不稳定、易于解离成无机铁盐,从而降低其生物利用率、影响其补铁效果。纳米脂质体作为一种新型的纳米运载系统是改善和增加氨基酸螯合铁稳定性并提高其口服生物利用率的可能途径。
本论文选用氨基酸螯合铁中的甘氨酸螯合铁为对象,系统地研究了甘氨酸螯合铁的合成、表征及其抗氧化能力和作为铁强化剂的透析性,探讨了不同工艺制得的甘氨酸螯合铁的存在状态；制备了甘氨酸螯合铁纳米脂质体,研究了脂质体的稳定性；以甘氨酸螯合铁纳米脂质体为铁源强化牛奶,研究了其对牛奶理化性质的影响；以缺铁性贫血大鼠为模型,研究了甘氨酸螯合铁纳米脂质体对缺铁性贫血的治疗作用。
以甘氨酸和无机铁盐为主要原料在水相体系中合成甘氨酸螯合铁,并采用有机溶剂沉淀法将甘氨酸螯合铁从反应液中分离出来。结果发现在制备过程中,将甘氨酸螯合铁从反应液分离后分别采用冷藏和冷冻两种方式处理,干燥所得产品的溶解性有明显差异,前者是具有良好溶解性的溶解型甘氨酸螯合铁,后者是溶解性较差的微溶型甘氨酸螯合铁。元素分析结果显示,两者具有一致的元素摩尔比,Fe(II):N:H2O的摩尔比为1：3：1。溶解型和微溶型甘氨酸螯合铁的摩尔电导率分别为22.00和27.80Ω-1cm2mol-1。红外光谱分析、X射线粉末衍射分析、热重分析结果显示,与游离甘氨酸配体相比,甘氨酸螯合铁的谱图发生了明显变化,氨基和羧基官能团的波段明显地红移或蓝移；α-氨基酸的特征吸收峰明显减弱或消失；甘氨酸螯合铁中不存在游离的甘氨酸,甘氨酸的羧基和氨基均与中心铁离子形成了配位键,生成了螯合物。Zeta电位分析结果显示,溶解型甘氨酸螯合铁水溶液的zeta电位很小,它在水相中是以真溶液存在的；微溶型甘氨酸螯合铁水溶液的zeta电位绝对值较大,它在水相中是以固体微粒的形式存在。
采用反相蒸发法制备甘氨酸螯合铁脂质体,以包封率为指标,优化了制备参数,结果显示,胆固醇／磷脂质量比1：8,吐温80/磷脂质量比1：2,甘氨酸螫合铁/磷脂质量比3：10,水合pH6.8,超声功率300 W,制备的甘氨酸螯合铁脂质体包封率较高,达84.80%。视频变焦显微镜图显示,甘氨酸螯合铁脂质体有良好的球形结构和较为均匀的粒径分布。平均粒径为559.2 nm, PDI指数为0.313,zeta电位为+9.6 mV。体外释放结果表明,在模拟胃液中前4h,芯材累积释放率约为5%；前5h,约为8%；至20h时,甘氨酸螯合铁的累积释放率约为55%；在不含胆酸盐的模拟肠液中放置20 h,几乎没有释放；在含有胆酸盐的模拟肠液中放置20 h,甘氨酸螯合铁的累积释放率约为5%。在模拟胃肠液中释放后脂质体的粒径测定结果显示,平均粒径略有增加,而视频变焦显微镜图显示,脂质体仍保持着良好的球形形态。因而甘氨酸螯合铁脂质体有良好的缓释效果。
采用反相蒸发法超声辅助制备了甘氨酸螯合铁纳米脂质体,所得脂质体的包封率可达76.2%。透射电镜图显示,甘氨酸螯合铁纳米脂质体具有良好的球形形态,一致的粒径分布和光滑的表面,绝大部分微粒粒径在100 nm以下。平均粒径为101.3 nm,PDI指数为0.361。在3个月的贮藏期内,脂质体有所泄露,但仍有较好的稳定性。经超声处理,甘氨酸螯合铁纳米脂质体发生了一定程度的泄露,粒子粒径明显降低,平均粒径由101.3 nm降低到86.8 nm, PDI指数由0.361降低到0.261。经加热处理,在前10 min脂质体有很好的稳定性,随后有较严重的泄露,粒子粒径没有发生明显变化,平均粒径由101.3 nm变为103.5 nm, PDI指数由0.361变为0.335。经金属离子的处理,甘氨酸螯合铁纳米脂质体在一价金属离子(Na+r和K+)溶液中发生明显泄露,脂质体粒径没有明显变化；在二价金属离子Mg+溶液中,脂质体泄露明显,粒子粒径明显增加；在Ca2+水溶液中,脂质体没有明显泄露,粒子粒径明显增加。体外释放结果显示,在模拟胃液中放置5 h,甘氨酸螯合铁累积释放率约为15%；在模拟肠液中放置5 h,其累积释放率约为20%,缓释效果明显。
甘氨酸螯合铁纳米脂质体作为铁源强化牛奶与硫酸亚铁、甘氨酸螯合铁相比对牛奶脂质氧化程度更小,引起的感官质量变化程度更弱,牛奶的组织状态更稳定。
缺铁性贫血大鼠的补铁效果和对贫血状况改善实验表明,与硫酸亚铁和甘氨酸螯合铁相比,甘氨酸螯合铁纳米脂质体可以更有效地改善大鼠的贫血状况,提高血红蛋白含量,增加体内的铁贮存。因而,甘氨酸螯合铁纳米脂质体的生物利用率得到了增加。纳米脂质体是一种能够增加甘氨酸螯合铁稳定性,提高其生物利用率的优良载体。
Iron amino acid chelates is promising iron fortifier used to combat iron-deficiency malnutrition, which is more stable and more bioavailable than the common iron fortifier such as ferrous sulfate. However, iron amino acid chelates are not stable under strong acid condition, and the complexes can be dissociated to inorganic iron salt, so the effect of combating iron-deficiency is decreased. As a nano-delivery system (NDS), nanoliposomes are a possible route that is helpful to improve and increase the stability of iron amino acid chelates, and to enhance oral bioavailability of the complexes.
Ferrous glycinate was selected as a representative of iron amino acid chelates. The preparation, characterization, antioxidant activity and iron availability of ferrous glycinate was systematically investigated; existence states of ferrous glyciante prepared from different methods was evaluated; preparation and stability of ferrous glycinate nanoliposomes was studied; effect of ferrous glycinate nanoliposomes as iron source on physical-chemistry property of milk-fortified was estimated; the feasibility of using nanoliposomes as an oral delivery system to improve the bioavailability of ferrous glycinate was examined using iron-deficiency anemia SD rats as the model.
Ferrous glycinate was prepared using glycine and ferrous chloride in aqueous system, and the product was separated from the reactive system using organic solvent-deposition method. The product was stored at low temperature 4℃or-18℃for 24 h, and then the product was dried in a vacuum drying oven to get soluble ferrous glycinate or in a freeze drier to get sparingly soluble ferrous glycinate. The results of element analysis showed that soluble and sparingly soluble ferrous glycinate have the same element composition, and the molar ratio of Fe(II):N:H2O was 1:3:1. Molar conductivities of soluble and sparingly soluble ferrous glycinate were 22.00 and 27.80Ω-1cm2mol-1, respectively. Fourier transform infrared (FT-IR) spectra, X-ray powder diffraction (XRD), thermogravimetric analysis (TGA) of soluble and sparingly soluble ferrous glycinate were significantly different from that of free glycine ligand. Coordination bonds were formed between Fe(II) and glycine, and iron-glycine chelate was produced. The results of zeta potentials showed that soluble ferrous glycinate solution was molecular solution, and the absolute value of zeta potential was small; sparingly soluble ferrous glycinate solution was pseudosolution, and the absolute value of zeta potential was bigger.
Ferrous glycinate nanoliposomes were prepared using reverse phase evaporation method. Effects of CHOL, Tween 80, ferrous glycinate concentration, pH of hydrating media, and sonication strength on EE were investigated. The optimized technology parameters were CHOL/EPC 1:8, Tween 80/EPC 1:2, ferrous glycinate/EPC 3:10, hydrating media pH 6.8, and sonication power 300 W, and the EE was 84.80% under the condition. The results of VZM photo showed that ferrous glycinate liposomes were spheral shape, and size distribution was homogeneous. Mean diameter was 559.2 nm; polydispersity index (PDI) was 0.313; zeta potential was+9.6 mV. The release of ferrous glycinate liposomes in vitro showed that little core material was released from liposomes in the first 4 h in simulated gastrointestinal juice. The mean diameter of liposomes increased from 559.2 nm to 692.9 nm and 677.8 nm after incubation in simulated gastrointestinal juice of pH 1.3 and pH 7.5, respectively. VZM photo of ferrous glycinate liposomes showed that the liposomes were still spheral shape after incubation. The stability of ferrous glycinate in strong acid environment was greatly improved by encapsulation in liposomes.
Ferrous glycinate nanoliposomes with the EE of 76.2% were prepared by reverse phase evaporation method coupling sonication. The TEM micrographs showed that ferrous glycinate nanoliposomes were spherical-shaped vesicles, and most of they were less than 100 nm in diameter; the mean diameter and PDI index were 101.3 nm and 0.361, respectively. During 3 month storage period, some core material was leaked out from nanoliposome, but the stability of nanoliposomal vesicles was not significantly damaged. After sonication, some core material was leaked out from nanoliposomes, and the mean diameter was obviously reduced from 101.3 to 86.8 nm, and PDI value was reduced from 0.361 to 0.261. During heating period, nanoliposomes was stable in the first 10 min, and then ferrous glycinate was significantly released from nanoliposomes; the mean diameter was changed from 101.3 nm to 103.5 nm, and PDI value was changed from 0.361 to 0.335. The results of effect of metal ions showed that univalent metal ions (Na+and K+) caused obvious leakage of nanoliposomes, and the mean diameter was not significantly changed; Mg2+ obviously caused leakage of nanoliposomes and increase of mean diameter; Ca+ didn't cause leakage of nanoliposomes, and the mean diameter was significantly increased. Furthermore, the results of in vitro release of small ferrous glycinate glycinate liposomes showed that about 15% ferrous glycinate was released from liposomes in simulated gastric juice at 37℃for 5 h; about 20% ferrous glyciante was release from liposomes in simulated intestinal juice at 37℃for 5 h; ferrous glycinate nanoliposomes could effectively protect ferrous glycinate.
Compared with ferrous sulfate and ferrous glycinate, ferrous glycinate nanoliposomes (FGL) were more stable to fortify milk as iron source. Fat oxidation of FGL-fortified milk was weaker; sensory quality was better; organization structure was more stable.
The effectiveness of treatment of iron-deficiency anemia with ferrous glycinate nanoliposomes was investigated using SD rats, and compared with that of ferrous glycinate and ferrous sulfate. Hb, serum Fe, total iron binding capacity, iron contents of liver and spleen were measured at the end of the intervention. Significant treatment effects were observed for Hb, serum Fe, total iron binding capacity, and iron contents of liver and spleen (P<0.05) in ferrous glycinate nanoliposomes group. Ferrous glycinate nanoliposomes as an iron supplement performed better that ferrous glycinate and ferrous sulfate in groups of iron-deficient rats. Ferrous glycinate nanoliposomes may be the choice of iron for the treatment of iron-deficiency anemia because of its high effectiveness.
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