Luo Daoqi, Kim Joo Hee, Park Chulhun, Oh Euichaul, Park Jun-Bom, Cui Jing-Hao, Cao Qing-Ri, Lee Beom-Jin
College of Pharmacy, Ajou University, Suwon, 16499, Republic of Korea.
College of Pharmacy, The Catholic University, Bucheon, 420-743, Republic of Korea.
Int J Pharm. 2017 May 15;523(1):343-356. doi: 10.1016/j.ijpharm.2017.03.030. Epub 2017 Mar 19.
The aim of this study was to investigate a fixed dose combination (FDC) of telmisartan (TEL) and pravastatin sodium (PRA) in enteric-coated bilayer tablets, which was designed for once-daily bedtime dose in order to match circadian rhythmic variations of hypertension and cholesterol synthesis and optimize the patient friendly dosing treatment. Due to the poor aqueous solubility of TEL, ternary solid dispersions (SD) consisting of TEL, polyethylene glycol 6000 (PEG 6000) and magnesium oxide (MgO) were designed to enhance its dissolution rate in intestinal fluid. MgO was added as an effective alkalizer to maintain the high microenvironmental pH of the saturated solution in the immediate vicinity of TEL particles because TEL is known to be ionizable but poorly soluble in intestinal fluid. In contrast, PRA is known to be very unstable in low pH conditions. In the SD system, TEL was present in an amorphous structure and formed an intermolecular hydrogen bonding with MgO, giving complete drug release without precipitation in intestinal fluid. In addition, the amount of hydrophilic carrier (PEG 6000) was also a factor. In the design of tablet formulation, the diluents and superdisintegrants could play a key role in release profiles. Then, to fulfill the unmet needs of the two model drugs and match circadian rhythmic variations of hypertension and cholesterol synthesis, enteric-coated bilayer tablet consisting of TEL SD and PRA was finally prepared using Acryl-EZE as an enteric coating material. Prior to enteric coating, a seal coating layer (Opadry, 2% weight gains) was firstly introduced to separate the core bilayer tablet from the acidic enteric coating polymers to avoid premature degradation. Dissolution profiles of finished tablets revealed that enteric-coated bilayer tablets with 6% weight gains remained intact in acidic media (pH 1.0) for 2h and then released drugs completely within 45min after switching to the intestinal media (pH 6.8). It was observed that enteric-coated bilayer tablets were stable during 3 month under the accelerated condition of 40°C/75% RH. The delayed drug release and bedtime dosage regimen using enteric-coated bilayer tablet containing TEL and PRA, matching the circadian rhythms of hypertension and hyperlipidemia can provide therapeutic benefits for elderly patients in terms of maximizing the therapeutic effects.
本研究的目的是研究替米沙坦（TEL）和普伐他汀钠（PRA）的固定剂量复方（FDC）肠溶双层片，其设计为每日一次睡前服用，以匹配高血压和胆固醇合成的昼夜节律变化，并优化患者友好的给药治疗。由于替米沙坦的水溶性较差，设计了由替米沙坦、聚乙二醇6000（PEG 6000）和氧化镁（MgO）组成的三元固体分散体（SD），以提高其在肠液中的溶解速率。添加氧化镁作为有效的碱化剂，以维持替米沙坦颗粒附近饱和溶液的高微环境pH值，因为已知替米沙坦可离子化但在肠液中溶解度较差。相比之下，已知普伐他汀在低pH条件下非常不稳定。在固体分散体系统中，替米沙坦以无定形结构存在，并与氧化镁形成分子间氢键，在肠液中实现完全药物释放且无沉淀。此外，亲水性载体（PEG 6000）的用量也是一个因素。在片剂配方设计中，稀释剂和超级崩解剂对释放曲线可能起关键作用。然后，为了满足这两种模型药物未满足的需求，并匹配高血压和胆固醇合成的昼夜节律变化，最终使用Acryl-EZE作为肠溶包衣材料制备了由替米沙坦固体分散体和普伐他汀组成的肠溶双层片。在肠溶包衣之前，首先引入密封包衣层（欧巴代，增重2%），以将核心双层片与酸性肠溶包衣聚合物分开，避免过早降解。成品片剂的溶出曲线显示，增重6%的肠溶双层片在酸性介质（pH 1.0）中保持完整2小时，然后在切换到肠介质（pH 6.8）后45分钟内完全释放药物。观察到肠溶双层片在40°C/75%RH的加速条件下3个月内稳定。使用含有替米沙坦和普伐他汀的肠溶双层片延迟药物释放和睡前给药方案，与高血压和高脂血症的昼夜节律相匹配，可以在最大化治疗效果方面为老年患者提供治疗益处。
