Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland.
Department of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland.
ACS Appl Mater Interfaces. 2024 Apr 17;16(15):18434-18448. doi: 10.1021/acsami.3c19388. Epub 2024 Apr 5.
The poor solubility of clotrimazole in the aqueous medium and the uncontrolled removal of the drug-loaded suppository content limit its effectiveness in the treatment of vulvovaginal candidiasis. We present here the aqueous formulations of clotrimazole in the form of non-Newtonian structured fluids, , Bingham plastic or pseudoplastic fluids constructed of hyperbranched polyglycidol, HbPGL, with a hydrophobized core with aryl groups such as phenyl or biphenyl. The amphiphilic constructs were obtained by the modification of linear units containing monohydroxyl groups with benzoyl chloride, phenyl isocyanate, and biphenyl isocyanate, while the terminal 1,2-diol groups in the shell were protected during the modification step, followed by their deprotection. The encapsulation of clotrimazole within internally hydrophobized HbPGLs using a solvent evaporation method followed by water addition resulted in structured fluids formation. Detailed Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) analyses performed for aryl-HbPGLs with clotrimazole revealed the difference in drug compatibility among polymers. Clotrimazole in biphenyl-enriched HbPGL, unlike phenyl derivatives, was molecularly distributed in both the dry and the hydrated states, resulting in transparent formulations. The shear-thinning properties of the obtained fluid formulations make them injectable and thus suitable for the intravaginal application. Permeability tests performed with the usage of the Franz diffusion cell showed a 5-fold increase in the permeability constant of clotrimazole compared to drugs loaded in a commercially available disposable tablet and a 50-fold increase of permeability in comparison to the aqueous suspension of clotrimazole. Furthermore, the biphenyl-modified HbPGL-based drug liquid showed enhanced antifungal activity against both and that was retained for up to 7 days, in contrast to the phenyl-HbPGL derivatives and the tablet. With their simple formulation, convenient clotrimazole/biphenyl-HbPGL formulation strategy, rheological properties, and enhanced antifungal properties, these systems are potential antifungal therapeutics for gynecological applications. This study points in the synthetic direction of improving the solubility of poorly water-soluble aryl-enriched pharmaceuticals.
克霉唑在水介质中的溶解度低，以及载药栓剂内容物的不受控制的去除限制了其在治疗外阴阴道念珠菌病中的有效性。我们在这里介绍克霉唑的水性制剂，以非牛顿结构流体的形式出现，如宾汉塑性或假塑性流体，由具有芳基如苯基或联苯基的疏水性核的超支化聚缩水甘油（HbPGL）构建。两亲性结构通过用苯甲酰氯、苯异氰酸酯和联苯异氰酸酯修饰含有单羟基的线性单元来获得，而壳层中的末端 1,2-二醇基团在修饰步骤中被保护，然后再进行脱保护。克霉唑通过溶剂蒸发法包封在内部疏水性 HbPGL 中，然后加水，导致形成结构流体。对含克霉唑的芳基-HbPGL 进行详细的傅里叶变换红外光谱（FTIR）和差示扫描量热法（DSC）分析，揭示了药物与聚合物之间的相容性差异。与苯基衍生物不同，克霉唑在富含联苯的 HbPGL 中以分子形式分布在干燥和水合状态下，导致形成透明制剂。所得流体制剂的剪切稀化特性使它们可注射，因此适合阴道内应用。使用 Franz 扩散池进行的渗透测试显示，与商业上可获得的一次性片剂中负载的药物相比，克霉唑的渗透常数增加了 5 倍，与克霉唑的水性混悬液相比，渗透常数增加了 50 倍。此外，基于联苯修饰的 HbPGL 的药物液体显示出对 和 的增强抗真菌活性，与苯基-HbPGL 衍生物和片剂相比，该活性可保持长达 7 天。与苯基-HbPGL 衍生物和片剂相比，具有简单的配方、方便的克霉唑/联苯-HbPGL 制剂策略、流变特性和增强的抗真菌特性，这些系统是用于妇科应用的潜在抗真菌治疗药物。本研究指向改善疏水性芳基药物溶解度的合成方向。
