State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China.
College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Int J Pharm. 2017 Oct 30;532(1):393-400. doi: 10.1016/j.ijpharm.2017.09.020. Epub 2017 Sep 8.
The development of poorly water-soluble drugs faces the risk of low bioavailability and therapeutic efficacy. The co-amorphous drug delivery system has recently gained considerable interest because it offers an alternative approach to modify properties of poorly water-soluble drugs. Herein, we developed a co-amorphous system of atenolol (ATE) and poorly water-soluble hydrochlorothiazide (HCT) by means of cryogenic milling. The co-administration of ATE and HCT has been reported to show therapeutic advantages for patients with uncomplicated hypertension. The co-amorphous ATE-HCT sample with 1:1 molar ratio showed excellent physical stability, which could be attributed to the formation of strong molecular interactions between ATE and HCT as evidenced by FT-IR spectra. Compared to the pure crystalline form, amorphous form and physical mixture, HCT in the co-amorphous form exhibited the significantly increased intrinsic dissolution rate, as well as the enhanced bioavailability in the pharmacokinetic study. It was found that the enhanced bioavailability of HCT in the co-amorphous formulation was achieved by the synergistic effect of amorphized HCT and the water-soluble coformer ATE. The present study provides an improved approach to implement the combination therapy of ATE and HCT for potential clinical treatments.
难溶性药物的开发面临着生物利用度和治疗效果低的风险。共无定形药物传递系统最近引起了相当大的兴趣，因为它提供了一种改变难溶性药物性质的替代方法。在此，我们通过低温粉碎法开发了阿替洛尔（ATE）和难溶性氢氯噻嗪（HCT）的共无定形系统。据报道，阿替洛尔和氢氯噻嗪的联合给药对患有单纯性高血压的患者具有治疗优势。摩尔比为 1:1 的共无定形 ATE-HCT 样品表现出优异的物理稳定性，这可归因于 ATE 和 HCT 之间形成了强分子相互作用，这可通过 FT-IR 光谱得到证明。与纯晶型、无定形态和物理混合物相比，共无定形中的 HCT 表现出显著提高的固有溶解速率，以及在药代动力学研究中提高的生物利用度。研究发现，共无定形制剂中 HCT 的生物利用度提高是通过增溶的 HCT 和水溶性共晶形成剂 ATE 的协同作用实现的。本研究为实施 ATE 和 HCT 的联合治疗提供了一种改进的方法，可能用于临床治疗。
