Klarić David, Soldin Željka, Vincze Anna, Szolláth Rita, Balogh György Tibor, Jug Mario, Galić Nives
Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, 10 000 Zagreb, Croatia.
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre u. 9., H-1092 Budapest, Hungary.
Pharmaceutics. 2024 Nov 21;16(12):1493. doi: 10.3390/pharmaceutics16121493.
Nabumetone (NAB) is a poorly soluble nonsteroidal anti-inflammatory prodrug (BCS class II drug) whose solubility is significantly improved by complexation with cyclodextrins (CDs). : The solid complexes, in a 1:1 molar ratio, were prepared by mechanochemical activation by grinding, using β-cyclodextrin (β-CD) and its derivatives, hydroxypropyl- and sulfobutylether-β-cyclodextrin (HP-β-CD and SBE-β-CD). The complexation was confirmed by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and attenuated total reflectance Fourier-transformed infrared spectroscopy (ATR-FTIR). Obtained products were further characterized regarding their solubility, in vitro dissolution, permeability and chemical stability. : Co-grinding with HP-β-CD and SBE-β-CD yielded products that showed in vitro dissolution profiles in hydrochloric acid medium (pH 1.2) that were substantially different from that of pure NAB, yielding dissolution efficiency enhancements of 34.86 ± 1.64 and 58.30 ± 0.28 times, respectively, for the optimized products. Their in vitro dissolution and gastrointestinal permeability were also studied in a low-volume environment at pH 6.8, corresponding to the intestinal environment. Both β-CD derivatives increased NAB dissolution rate and NAB mass transport across the biomimetic membrane. The effect of β-CD derivatives on NAB chemical stability was studied under the stress conditions by the developed and validated UHPLC-DAD-HRMS method. In acidic conditions, pure and complexed NAB was prone to hydrolytic degradation, yielding one degradation product-pharmacologically inactive NAB metabolite. However, under the oxidative conditions at elevated temperatures, 10 NAB degradation products were identified from co-ground samples. All systems were stable during photo- and long-term stability studies. : NAB complexes with HP-β-CD and SBE-β-CD are promising candidates for pharmaceutical product development.
萘丁美酮（NAB）是一种难溶性非甾体抗炎前体药物（BCS II类药物），与环糊精（CDs）络合后其溶解度显著提高。采用β-环糊精（β-CD）及其衍生物羟丙基-β-环糊精和磺丁基醚-β-环糊精（HP-β-CD和SBE-β-CD），通过研磨进行机械化学活化，制备了摩尔比为1:1的固体络合物。通过差示扫描量热法（DSC）、粉末X射线衍射（PXRD）和衰减全反射傅里叶变换红外光谱（ATR-FTIR）对络合作用进行了确认。对所得产物的溶解度、体外溶出度、渗透性和化学稳定性进行了进一步表征。与HP-β-CD和SBE-β-CD共研磨得到的产物在盐酸介质（pH 1.2）中的体外溶出曲线与纯NAB有显著差异，优化后的产物溶出效率分别提高了34.86±1.64倍和58.30±0.28倍。还在pH 6.8的低体积环境（相当于肠道环境）中研究了它们的体外溶出度和胃肠道渗透性。两种β-CD衍生物均提高了NAB的溶出速率和NAB跨仿生膜的质量传输。通过已建立并验证的超高效液相色谱-二极管阵列-高分辨质谱法（UHPLC-DAD-HRMS），研究了β-CD衍生物在应激条件下对NAB化学稳定性的影响。在酸性条件下，纯NAB和络合NAB均易于发生水解降解，产生一种降解产物——药理活性无的NAB代谢物。然而，在高温氧化条件下，从共研磨样品中鉴定出10种NAB降解产物。在光稳定性和长期稳定性研究中，所有体系均稳定。NAB与HP-β-CD和SBE-β-CD的络合物是药物产品开发的有前途的候选物。
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