Pinto Juliana Munari Oliveira, Leão Aline Franciane, Bazzo Giovana Carolina, Mendes Cassiana, Madureira Letícia M P, Caramori Giovanni F, Parreira Renato L T, Stulzer Hellen Karine
Programa de Pós-Graduação em Farmácia, Federal University of Santa Catarina, Campus Trindade, 88040-970, Florianópolis, SC, Brazil.
Innovation Study Center in Pharmaceutical Technologies (NITFar), Pharmaceutical Sciences Department, Federal University of Santa Catarina, Campus Trindade, 88040-970, Florianópolis, SC, Brazil; Programa de Pós-Graduação em Farmácia, Federal University of Santa Catarina, Campus Trindade, 88040-970, Florianópolis, SC, Brazil.
Eur J Pharm Sci. 2021 Aug 1;163:105860. doi: 10.1016/j.ejps.2021.105860. Epub 2021 Apr 24.
The purpose of this study was to associate the poorly water-soluble antihypertensive drugs candesartan cilexetil (CC) and hydrochlorothiazide (HCTZ) as fixed-dose combination, in the form of ternary Amorphous Solid Dispersions (ASD), using hydroxypropylmethylcellulose acetate succinate (HPMCAS) type M as polymeric carrier. The potential of the system to generate and to maintain supersaturation of both drugs was also evaluated. The ASDs were prepared by ball milling technique and solid-state characterization was performed by differential scanning calorimetry (DSC), Fourier transformed infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). Interaction between drugs and polymer in solid-state was evaluated by molecular metadynamics simulations. In vitro supersaturation profiles were determined in biorelevant medium. Physicochemical stability of ASDs was also evaluated under different storage conditions. Amorphization of both drugs was confirmed by solid-state characterization techniques. Molecular metadynamics simulations indicated that CC has stronger interaction with HMPCAS than HCTZ. In vitro supersaturation studies have shown that ternary ASDs could generate and maintain supersaturation of both drugs in biorelevant medium. The polymer reduced the desupersaturation of both drugs. Ternary ASDs also showed physicochemical stability over a period of 90 days, demonstrating the potential of the polymer in reducing the drugs recrystallization over the time. Ternary ASDs of CC, HCTZ and HPMCAS can be considered a promising system to associate the drugs as fixed-dose combinations. Also, these systems generate and maintain supersaturation of both drugs in biorelevant medium, with great storage stability. HPMCAS M was a good carrier for reducing the desupersaturation of associated HCTZ and CC.
本研究的目的是将水溶性差的抗高血压药物坎地沙坦酯（CC）和氢氯噻嗪（HCTZ）以固定剂量组合的形式，制成三元无定形固体分散体（ASD），使用M型羟丙基甲基纤维素琥珀酸酯（HPMCAS）作为聚合物载体。还评估了该体系产生和维持两种药物过饱和的潜力。通过球磨技术制备ASD，并通过差示扫描量热法（DSC）、傅里叶变换红外光谱法（FTIR）和X射线粉末衍射（XRPD）进行固态表征。通过分子元动力学模拟评估药物与聚合物在固态下的相互作用。在生物相关介质中测定体外过饱和曲线。还在不同储存条件下评估了ASD的物理化学稳定性。通过固态表征技术证实了两种药物的非晶化。分子元动力学模拟表明，CC与HMPCAS的相互作用比HCTZ更强。体外过饱和研究表明，三元ASD可以在生物相关介质中产生并维持两种药物的过饱和。聚合物降低了两种药物的去饱和作用。三元ASD在90天内也显示出物理化学稳定性，证明了该聚合物在随时间减少药物重结晶方面的潜力。CC、HCTZ和HPMCAS的三元ASD可被认为是一种将药物制成固定剂量组合的有前景的体系。此外，这些体系在生物相关介质中产生并维持两种药物的过饱和，具有良好的储存稳定性。HPMCAS M是降低相关HCTZ和CC去饱和作用的良好载体。
