Giri Bhupendra Raj, Kwon Jaewook, Vo Anh Q, Bhagurkar Ajinkya M, Bandari Suresh, Kim Dong Wuk
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Vessel-Organ Interaction Research Center (VOICE, MRC), BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Kyungpook National University, Daegu 41566, Korea.
Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
Pharmaceuticals (Basel). 2021 Jan 18;14(1):73. doi: 10.3390/ph14010073.
Telmisartan (TEL, an antihypertensive drug) belongs to Class II of the Biopharmaceutical Classification System (BCS) because of its poor aqueous solubility. In this study, we enhanced the solubility, bioavailability, and stability of TEL through the fabrication of TEL-loaded pH-modulated solid dispersion (TEL pH-SD) using hot-melt extrusion (HME) technology. We prepared different TEL pH-SD formulations by varying the ratio of the drug (TEL, 10-60% /), the hydrophilic polymer (Soluplus, 30-90% ), and pH-modifier (sodium carbonate, 0-10% /). More so, the tablets prepared from an optimized formulation (F8) showed a strikingly improved in vitro dissolution profile (~30-fold) compared to the free drug tablets. The conversion of crystalline TEL to its amorphous state is observed through solid-state characterizations. During the stability study, F8 tablets had a better stability profile compared to the commercial product with F8, showing higher drug content, low moisture content, and negligible physical changes. Moreover, compared to the TEL powder, in vivo pharmacokinetic studies in rats showed superior pharmacokinetic parameters, with maximum serum concentration (C) and area under the drug concentration-time curve (AUC-) of the TEL pH-SD formulation increasing by 6.61- and 5.37-fold, respectively. Collectively, the results from the current study showed that the inclusion of a hydrophilic polymer, pH modulator, and the amorphization of crystalline drugs in solid dispersion prepared by HME can be an effective strategy to improve the solubility and bioavailability of hydrophobic drugs without compromising the drug's physical stability.
替米沙坦（TEL，一种抗高血压药物）因其水溶性差而属于生物药剂学分类系统（BCS）的II类药物。在本研究中，我们通过使用热熔挤出（HME）技术制备载有替米沙坦的pH调节固体分散体（TEL pH-SD）来提高替米沙坦的溶解度、生物利用度和稳定性。我们通过改变药物（替米沙坦，10 - 60% /）、亲水性聚合物（固体分散体载体，30 - 90% ）和pH调节剂（碳酸钠，0 - 10% /）的比例制备了不同的替米沙坦pH-SD制剂。此外，由优化制剂（F8）制备的片剂与游离药物片剂相比，体外溶出曲线有显著改善（约30倍）。通过固态表征观察到结晶态替米沙坦向非晶态的转变。在稳定性研究中，F8片剂与市售产品相比具有更好的稳定性，表现为药物含量更高、水分含量低且物理变化可忽略不计。此外，与替米沙坦粉末相比，在大鼠体内的药代动力学研究显示出更好的药代动力学参数，替米沙坦pH-SD制剂的最大血清浓度（C）和药物浓度-时间曲线下面积（AUC-）分别增加了6.61倍和5.37倍。总体而言，当前研究结果表明，在通过HME制备的固体分散体中加入亲水性聚合物、pH调节剂以及使结晶药物非晶化，是提高疏水药物溶解度和生物利用度而不影响药物物理稳定性的有效策略。
