Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo 315201, PR China; Ningbo Cixi Institute of Biomedical Engineering, Cixi 315300, PR China.
Ningbo No. 2 Hospital, Ningbo 315010, PR China; Cixi Biomedical Research Institute, Wenzhou Medical University, Cixi 315300, PR China.
Int J Pharm. 2024 Dec 5;666:124789. doi: 10.1016/j.ijpharm.2024.124789. Epub 2024 Oct 2.
Berberine hydrochloride (BER), a promising candidate in treating tumors, diabetes and pain management, has relatively low oral absorption and bioavailability due to its low intestinal permeability. To address these challenges, we developed a BER and lornoxicam cocrystal (BLCC) by a solvent evaporation method and characterized it using X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis. Compared with BER, BLCC exhibited an instant release in pH 1.0 HCl and a sustained release up to 24 h in pH 6.8 buffer solutions and water. The Caco-2 permeability of BLCC has shown a remarkable increase compared to that of BER (i.e., P: 50.30 × 10vs 8.82 × 10 cm/s), which is attributed to the improved lipophilicity of BER (i.e., log P: 1.29 vs -1.83) and the reduced efflux amount of BER (i.e., ER: 1.71 vs 12.11). Furthermore, BLCC demonstrated a relative bioavailability of 410 % in comparison to the original BER, due to notably enhanced intestinal permeability of BLCC and its continuous dissolution in simulated intestinal fluid. BLCC has the potential to tailor the dissolution behavior, improve intestinal permeability, and boost the bioavailability of BER. This indicates that the cocrystal strategy holds promise as an effective approach to improving the oral absorption and bioavailability of active pharmaceutical molecules with low permeability during drug development.
盐酸小檗碱（BER）是一种有前途的治疗肿瘤、糖尿病和疼痛管理的候选药物，但由于其肠道通透性低，口服吸收和生物利用度相对较低。为了解决这些挑战，我们采用溶剂蒸发法制备了 BER 和洛索洛芬 cocrystal（BLCC），并通过 X 射线衍射、差示扫描量热法和热重分析对其进行了表征。与 BER 相比，BLCC 在 pH1.0 HCl 中即刻释放，在 pH6.8 缓冲溶液和水中可持续释放长达 24 小时。与 BER 相比，BLCC 的 Caco-2 渗透率显著增加（即 P：50.30×10-6cm/s 对 8.82×10-6cm/s），这归因于 BER 脂溶性的提高（即 log P：1.29 对-1.83）和 BER 外排量的减少（即 ER：1.71 对 12.11）。此外，与原药 BER 相比，BLCC 的相对生物利用度为 410%，这是由于 BLCC 的肠通透性显著增强，以及其在模拟肠液中的持续溶解。BLCC 有可能调整溶解行为、提高肠通透性并提高 BER 的生物利用度。这表明，在药物开发过程中，共晶策略有望成为提高低通透性活性药物分子口服吸收和生物利用度的有效方法。
