Efficacy of ketoconazole gel-flakes in treatment of vaginal candidiasis: Formulation, in vitro and clinical evaluation

• Published in: International journal of pharmaceutics 2019-08, Vol.567, p.118472-118472, Article 118472
• Main Authors: Abd Ellah, Noura H., Abdel-Aleem, Jelan A., Abdo, Mariana N., Abou-Ghadir, Ola F., Zahran, Kamal M., Hetta, Helal F.
• Format: Article
• Language: English
• Subjects: Adult; Antifungal Agents - administration & dosage; Antifungal Agents - chemistry; Candida albicans; Candida albicans - drug effects; Candida albicans - growth & development; Candidiasis, Vulvovaginal - drug therapy; Chitosan; Chitosan - administration & dosage; Chitosan - chemistry; Drug Compounding; Drug Delivery Systems; Drug Liberation; Female; Gel-flakes; Gellan gum; Gels; Humans; In situ gel; Ketoconazole; Ketoconazole - administration & dosage; Ketoconazole - chemistry; Middle Aged; Polysaccharides, Bacterial - administration & dosage; Polysaccharides, Bacterial - chemistry; Rheology; Vaginal candidiasis; Young Adult
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2019.118472

[Display omitted] Candida albicans, as the main causative fungus of vaginal candidiasis, is currently a global issue of concern due to its high prevalence, biofilm formation and emergence of resistance. Ketoconazole (KTZ), an antifungal drug, which has poor water-solubility and penetration capacity, is ineffective against deep-seated Candida infection. Considering these issues, this work aimed to develop a novel multifunctional carrier for KTZ via encapsulation of KTZ/β-cyclodextrin (β-CD) co-ground mixture into chitosan/gellan gum gel-flakes (threadlike and polygonal structures). Analytical studies revealed existence of electrostatic-derived complexes between negatively charged gellan gum and positively charged chitosan. Gel-flakes were then loaded in in situ gel of pluronic F-127 (PF-127). Based on gelation temperature (Tgel), viscosity and release studies; selected formulation was further evaluated, showing significant in vitro anti-candida activity. Despite reduced dosage regimen (50 mg/daily/three days), KTZ flakes in situ gel was as effective as Gynoconazol vaginal cream® (80 mg terconazole/daily/three days) in improving patient complaints and Candida eradication. Multifunctionality of KTZ carrier was based on efficient spreading and coating of the vagina due to free-flowing properties during application, flakes entanglement within folded vaginal epithelia, sustained release and increased penetration capacity of KTZ to reach deep-seated infections. In conclusion, flakes in situ gel could be considered as a highly promising KTZ delivery option for treatment of vaginal candidiasis.