Preparation and in vitro evaluation of primaquine-conjugated gum arabic microspheres
Preparation and in vitro evaluation of primaquine-conjugated gum arabic microspheres
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DOI：
10.1021/bm0499435
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发表时间：
2004-07-01
影响因子：
6.2
通讯作者：
Jayakrishnan, A
中科院分区：
文献类型：
--
作者：
Nishi, KK;Jayakrishnan, A
阿拉伯树胶是一种支链多糖，用高碘酸盐氧化，在生物聚合物上生成活性醛。伯氨喹是一种8-氨基喹啉，通过亚胺键与氧化阿拉伯胶共价偶联，并在以山梨醇倍半油酸酯为表面活性剂的1:1轻石蜡油和甲苯的反相乳液中通过热变性制备成粒径小于2 μ m的微球。在pH为11的硼酸盐缓冲液的存在下，使用临床使用的磷酸伯氨喹的水溶性形式，实现了伯氨喹与多糖的共价结合。根据最初使用的药物浓度和多糖的氧化程度，高达35%的药物可以结合到聚合物主链上。有趣的是，我们发现伯氨喹的脂肪族和受阻族氨基都能通过席夫碱形成与醛功能发生反应，从而导致多糖与药物本身发生交联。体外37℃下将药物从微球中释放到磷酸盐缓冲盐水（PBS, pH 7.4, 0.1 M）中，结果表明，伯氨喹从基质中释放缓慢，但随着时间的推移逐渐增加。即使在10天后，最大释放量仍低于药物有效负荷的50%。与在PBS中的释放相比，释放到模拟胃液和肠液中的速度更快，这是由于胃液中的希夫键快速水解。希夫键水解敏感性差的一个可能原因是基于伯氨喹上的氨基不相等的反应性，以及它与这种聚合物-药物偶联物可能的治疗应用的相关性。
Gum arabic, a branched polysaccharide, was oxidized using periodate to generate reactive aldehyde groups on the biopolymer. Primaquine, an 8-aminoquinoline, was covalently coupled onto oxidized gum arabic via an imine bond and simultaneously fabricated into microspheres of less than 2 mum in size by heat denaturation in a reverse emulsion of 1: 1 light paraffin oil and toluene stabilized by sorbitan sesquioleate as the surfactant. The covalent binding of primaquine to the polysaccharide using the clinically used water-soluble form of the drug primaquine phosphate was achieved in the presence of borate buffer of pH 11. Up to 35% of the drug could be bound to the polymer backbone depending on the concentration of the drug employed initially and the degree of oxidation of the polysaccharide. Interestingly, both the aliphatic and the hindered aromatic amino groups of primaquine were found to react with the aldehyde functions through Schiff base formation leading to cross-linking of the polysaccharide with the drug itself. In vitro release of the drug from microspheres into phosphate buffered saline (PBS, pH 7.4, 0.1 M) at 37 degreesC showed that the release of primaquine from the matrix was slow, although gradually increased with time. The maximum released was below 50% of the drug payload even after 10 days. Release into simulated gastric and intestinal fluids was faster compared to the release in PBS due to rapid hydrolysis of the Schiff's linkage in the gastric fluid. A possible reason for the poor hydrolytic susceptibility of the Schiff's linkage is suggested based on the unequal reactivity of the amino groups on primaquine and its relevance in possible therapeutic application of this polymer-drug conjugate discussed.