Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Efcacy of ketoconazole gel-fakes in treatment of vaginal candidiasis: Formulation, in vitro and clinical evaluation Noura H. Abd Ellah a,b, ⁎ , Jelan A. Abdel-Aleem c , Mariana N. Abdo d , Ola F. Abou-Ghadir e , Kamal M. Zahran f , Helal F. Hetta g,h a Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, Medical Sciences Building, University of Cincinnati, Cincinnati, OH 45267, USA b Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt c Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt d Department of Obstetrics and Gynecology, El_Ghanaium Hospital, MOH, 71742, Egypt e Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt f Department of Obstetrics and Gynecology, Assiut University, Egypt Women’s Health Hospital, Assiut 71511, Egypt g Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0595, USA h Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut 71526, Egypt ARTICLE INFO Keywords: Ketoconazole Candida albicans Vaginal candidiasis Gel-fakes Chitosan Gellan gum In situ gel ABSTRACT Candidaalbicans, as the main causative fungus of vaginal candidiasis, is currently a global issue of concern due to its high prevalence, bioflm formation and emergence of resistance. Ketoconazole (KTZ), an antifungal drug, which has poor water-solubility and penetration capacity, is inefective 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-fakes (threadlike and polygonal structures). Analytical studies revealed existence of electrostatic-derived complexes between negatively charged gellan gum and positively charged chitosan. Gel-fakes were then loaded in insitu gel of pluronic F-127 (PF-127). Based on gelation temperature (T gel ), viscosity and release studies; selected formulation was further evaluated, showing signifcant invitro anti-candida activity. Despite reduced dosage regimen (50 mg/daily/three days), KTZ fakes in situ gel was as efective as Gynoconazol vaginal cream® (80 mg terconazole/daily/three days) in im- proving patient complaints and Candida eradication. Multifunctionality of KTZ carrier was based on efcient spreading and coating of the vagina due to free-fowing properties during application, fakes entanglement within folded vaginal epithelia, sustained release and increased penetration capacity of KTZ to reach deep-seated infections. In conclusion, fakes in situ gel could be considered as a highly promising KTZ delivery option for treatment of vaginal candidiasis. 1. Introduction Vaginal candidiasis (Vulvovaginal candidiasis) is one of the most important mucosal infection of vagina caused by yeast, where 75% of women might be infected at least once in their life (Bernstein and Seidu, 2015). Candida albicans, which is a normal fora of the vagina, is the most common causative fungus of this disease. The imbalance between the naturally occurring organisms in the vagina leads to overgrowth of this fungus. This overgrowth is followed by adhesion and then migra- tion across vaginal epithelia, resulting in damage of the epithelium and many discomforting symptoms (Emeribe et al., 2015; Johal et al., 2016). Vaginal candidiasis is currently a global issue of concern due to the high prevalence, risk of bioflm formation and emergence of Candida resistance to the frequently used antifungal drugs such as azoles (Abd El-Baky et al., 2019; Beltrame et al., 2006; Bitew and Abebaw, 2018; Harriott et al., 2010). Additionally, wide spread of adverse drug reac- tions of the orally used azoles forced some drug control authorities to limit the use of some azoles to hospitals only (Chai et al., 2018). Ke- toconazole (KTZ) is an azole antifungal drug used against Candida al- bicans in a dose of 200 mg twice daily for 5 days (Kutzer et al., 1988). Its oral administration is associated with many adverse reactions (Chai https://doi.org/10.1016/j.ijpharm.2019.118472 Received 17 March 2019; Received in revised form 24 June 2019; Accepted 24 June 2019 ⁎ Corresponding author at: Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, Medical Sciences Building, University of Cincinnati, Cincinnati, OH 45267, USA. E-mail addresses: abdellna@ucmail.uc.edu, nora.1512@aun.edu.eg (N.H. Abd Ellah), Jelan.abdelrazik@pharm.aun.edu.eg (J.A. Abdel-Aleem), olaghadir@aun.edu.eg (O.F. Abou-Ghadir), helal.hetta@uc.edu, helalhetta@aun.edu.eg (H.F. Hetta). International Journal of Pharmaceutics 567 (2019) 118472 Available online 25 June 2019 0378-5173/ © 2019 Elsevier B.V. All rights reserved. T