Physicochemical investigation of the influence of saccharide-based parenteral formulation excipients on L-p-boronphenylalanine solubilisation for boron neutron capture therapy.
Physicochemical investigation of the influence of saccharide-based parenteral formulation excipients on L-p-boronphenylalanine solubilisation for boron neutron capture therapy.
复制标题
硼中子俘获疗法中糖类肠胃外制剂赋形剂对 L-对硼苯丙氨酸溶解影响的物理化学研究。
DOI：
10.1002/jps.22761
复制
发表时间：
2012
影响因子：
3.8
通讯作者：
G. Halbert
中科院分区：
文献类型：
--
作者：
E. Schmidt;Neil Dooley;S. Ford;M. Elliott;G. Halbert
本文研究了目前用于硼中子俘获疗法的 L-对硼苯丙氨酸 (BPA)-果糖静脉注射制剂的可能药物替代品的理化特性。通过使用 Sirius T3 仪器测定 pKa 值、溶解度、沉淀和溶解，研究了在不存在和存在果糖、甘露醇、海藻糖和羟丙基-β-环糊精 (HPCD) 的情况下 BPA 的理化性质。还使用 (10) B-核磁共振 (NMR) 评估了复合物的形成。结果表明，果糖和甘露醇通过与硼酸基团的可逆相互作用与 BPA 形成复合物，具体取决于硼酸基团 pKa 的变化、紫外和核磁共振光谱以及动力学溶解度的增加。海藻糖和 HPCD 不会发生这种反应，因此不会影响硼苯丙氨酸的理化性质。尽管甘露醇与 BPA 复合的方式与果糖相同，但它的优越性在于它提供了更高的动力学溶解度。因此，在目前的临床 BPA 制剂中用甘露醇替代果糖是可行的，具有增加剂量并消除与果糖不耐受和热量负荷相关的问题的优点。结果还表明，重要的药物参数是复合物的溶解度和解离行为，而不是最初假设的复合物形成反应。
This paper investigates the physicochemical properties of possible pharmaceutical alternatives to L-p-boronphenylalanine (BPA)-fructose intravenous formulation currently employed in boron neutron capture therapy. The physicochemical properties of BPA in the absence and presence of fructose, mannitol, trehalose and hydroxypropyl-β-cyclodextrin (HPCD) was investigated by determination of pKa values, solubility, precipitation and dissolution using a Sirius T3 instrument. Complex formation was also assessed using (10) B-Nuclear magnetic resonance (NMR). The results indicate that fructose and mannitol form a complex with BPA through a reversible interaction with the boronic acid group, determined by changes in the pKa of the boronic acid group, the ultraviolet and NMR spectra, and increase in kinetic solubility. Trehalose and HPCD did not undergo this reaction and, consequently, did not affect boronphenylalanaine physicochemical properties. Although mannitol is complexed with BPA in an identical manner to fructose, it is superior because it provides increased kinetic solubility. Replacement of fructose by mannitol in the current clinical BPA formulation is, therefore, feasible with advantages of increased dosing and removal of issues related to fructose intolerance and calorific load. Results also indicated that important pharmaceutical parameters are the complex's solubility and dissociation behaviours rather than, as originally assumed, the complex formation reaction.
影响因子：
6.4
作者：
Nawashiro, Hiroshi;Otani, Naoki;Endou, Hitoshi
通讯作者：
Endou, Hitoshi