Van Nguyen Hien, Baek Namhyun, Lee Beom-Jin
College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea.
College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea; Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea.
Int J Pharm. 2017 May 15;523(1):189-202. doi: 10.1016/j.ijpharm.2017.03.047. Epub 2017 Mar 23.
Due to the instability of esomeprazole magnesium dihydrate (EPM), a proton pump inhibitor, in gastric fluid, enteric-coated dosage form is commonly used for therapeutic application. In this study, we prepared new gastric fluid resistant solid dispersions (SDs) containing alkalizers. Then, new mechanistic evidence regarding the effects of pharmaceutical alkalizers on the aqueous stability of EPM in simulated gastric fluid was investigated. The alkalizer-loaded SD were prepared by dissolving or dispersing EPM, hydroxypropyl methylcellulose (HPMC) 6 cps, and an alkalizer, in ethanol 50% (v/v) followed by spray drying. Nine different alkalizers were assessed for in vitro stability in two media, simulated gastric fluid (pH 1.2 buffer) and simulated intestinal fluid (pH 6.8 buffer). The microenvironmental pH (pH) was measured to evaluate the effect of the alkalizer on the pH of SDs. Drug crystallinity and morphology of the SDs were also examined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The interactions among EPM, the polymer, and the alkalizer were elucidated by Fourier transform infrared (FTIR) spectroscopy. The in vivo absorption studies of the optimized alkalizer-containing SD and the enteric-coated reference tablet Nexium were then conducted in beagle dogs. Among alkalizers, MgO loaded in SDs proved to be the best alkalizer to stabilize EPM in simulated gastric fluid. pH values of the alkalizer-containing SDs were significantly higher than that of the SD without alkalizer. The pH values decreased in the following order: MgO, NaCO, Ca(OH), and no alkalizer. DSC and PXRD data exhibited a change in the drug crystallinity of the SDs from crystalline to amorphous form. SEM data showed a relatively spherical shape of the MgO-loaded SD compared to the less-defined shape of pure drug. FTIR indicated a strong molecular interaction among EPM, alkalizer and polymer; in particular, MgO showed the strongest interaction with EPM. It was evident that alkalizer interacts with benzimidazole ring and/or sulfonyl group of EPM for enhancing EPM stability in gastric fluid. Regarding the in vivo absorption studies in beagle dogs, the optimized SD (C16) was bioequivalent to the reference Nexium and had a considerable greater absorption at the early stages. The current alkalizer-containing SD could provide a promising approach for aqueous stabilization of acid-labile drugs without using enteric coating method.
由于质子泵抑制剂埃索美拉唑镁二水合物（EPM）在胃液中不稳定，其肠溶制剂常用于治疗。在本研究中，我们制备了含碱化剂的新型耐胃液固体分散体（SDs）。然后，研究了药用碱化剂对EPM在模拟胃液中水解稳定性影响的新机制证据。通过将EPM、羟丙基甲基纤维素（HPMC）6 cps和碱化剂溶解或分散在50%（v/v）乙醇中，随后进行喷雾干燥来制备载碱化剂的SDs。评估了九种不同的碱化剂在两种介质（模拟胃液（pH 1.2缓冲液）和模拟肠液（pH 6.8缓冲液））中的体外稳定性。测量微环境pH值以评估碱化剂对SDs pH值的影响。还通过差示扫描量热法（DSC）、粉末X射线衍射（PXRD）和扫描电子显微镜（SEM）检查了SDs的药物结晶度和形态。通过傅里叶变换红外（FTIR）光谱阐明了EPM、聚合物和碱化剂之间的相互作用。然后在比格犬中进行了优化的含碱化剂SD和肠溶参比制剂耐信的体内吸收研究。在碱化剂中，载于SDs中的氧化镁被证明是在模拟胃液中稳定EPM的最佳碱化剂。含碱化剂的SDs的pH值显著高于不含碱化剂的SDs。pH值按以下顺序降低：氧化镁、碳酸钠、氢氧化钙和无碱化剂。DSC和PXRD数据显示SDs的药物结晶度从结晶形式变为无定形形式。SEM数据显示，与纯药物形状不太规则相比，载氧化镁的SDs形状相对呈球形。FTIR表明EPM、碱化剂和聚合物之间存在强烈的分子相互作用；特别是，氧化镁与EPM的相互作用最强。很明显，碱化剂与EPM的苯并咪唑环和/或磺酰基相互作用，以提高EPM在胃液中的稳定性。关于在比格犬中的体内吸收研究，优化的SD（C16）与参比制剂耐信生物等效，并且在早期阶段具有相当大的更高吸收。当前含碱化剂的SDs可为不使用肠溶包衣方法的酸不稳定药物的水相稳定化提供一种有前景的方法。
