PDF(Pubmed)
Abstract：
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, i.e., 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 Candida albicans and Candida glabrata 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.
摘要：
克霉唑在水性介质中的溶解性差以及载药栓剂内容物的不受控制的去除限制了其治疗外阴阴道念珠菌病的有效性。我们在这里介绍非牛顿结构流体形式的克霉唑的水性制剂，即，由超支化聚缩水甘油构成的宾汉塑性或假塑性流体，HbPGL,具有带有芳基如苯基或联苯的疏水化核。通过用苯甲酰氯修饰含单羟基的线性单元获得两亲性构建体，苯基异氰酸酯,和联苯异氰酸酯，而壳中的末端1,2-二醇基团在改性步骤中受到保护，随之而来的是他们的保护。使用溶剂蒸发方法将克霉唑封装在内部疏水化的HbPGL中，然后添加水，导致形成结构化的流体。用克霉唑对芳基-HbPGL进行的详细傅里叶变换红外光谱（FTIR）和差示扫描量热法（DSC）分析揭示了聚合物之间药物相容性的差异。克霉唑在富含联苯的HbPGL中，与苯基衍生物不同，分子分布在干燥和水合状态，导致透明的配方。所获得的流体制剂的剪切稀化性质使其可注射并因此适用于阴道内应用。使用Franz扩散池进行的渗透性测试显示,与装载在市售的一次性片剂中的药物相比,克霉唑的渗透性常数增加了5倍,与克霉唑的水性悬浮液相比,渗透性增加了50倍。此外，基于联苯修饰的HbPGL的药物液体对白色念珠菌和光滑念珠菌均显示出增强的抗真菌活性，保留长达7天，与苯基-HbPGL衍生物和片剂相反。用他们简单的公式，方便的克霉唑/联苯-HbPGL配方策略，流变性能,和增强的抗真菌特性，这些系统是妇科应用的潜在抗真菌疗法。这项研究指出了提高水溶性差的富含芳基药物溶解度的合成方向。
