Natural Oils Enhance the Topical Delivery of Ketoconazole by Nanoemulgel for Fungal Infections

Irfan Ahmad; Ms Farheen; Ashish Kukreti; Obaid Afzal; Md Habban Akhter; Havagiray Chitme; Sharad Visht; Abdulmalik Saleh Alfawaz Altamimi; Manal A Alossaimi; Ebtisam R Alsulami; Mariusz Jaremko; Abdul-Hamid Emwas

doi:10.1021/acsomega.3c01571

Natural Oils Enhance the Topical Delivery of Ketoconazole by Nanoemulgel for Fungal Infections

ACS Omega. 2023 Jul 26;8(31):28233-28248. doi: 10.1021/acsomega.3c01571. eCollection 2023 Aug 8.

Affiliations

¹ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha 62521, Saudi Arabia.
² School of Pharmaceutical and Population Health Informatics (SoPPHI), DIT University, Dehradun 248009, India.
³ Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
⁴ Nursing Department, Najran Armed Forces Hospital, Najran 66251, Saudi Arabia.
⁵ Smart-Health Initiative (SHI) and Red Sea Research Center (RSRC), Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudi Arabia.
⁶ Core Labs, King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudi Arabia.

Abstract

Nanoemulgel (NEG) pharmaceutical formulations are gaining popularity because of their ability to serve both as a nanoemulsion and as a gel. These products are well-known for their ease of use, spreadability, controlled release, and ability to hydrate dry skin. Natural essential oils have been shown to promote the cutaneous permeability of topical formulations, enhancing medication safety and efficacy. Herein, we developed NEG for the enhanced permeation of ketoconazole against candidiasis using clove oil (clove-oil-NEG) or eucalyptus oil (eucalyptus-oil-NEG), using the gelling agents carbopol 943 and hydroxypropyl methylcellulose (HPMC). We tested various excipients to increase the solubility of ketoconazole and formulate a nanoemulsion (NE). We measured the NE droplet particle size, shape, entrapment efficiency, and drug release. Furthermore, the physicochemical properties of the optimized nanoemulsion formulation were characterized by techniques such as Fourier transform infrared (FT-IR) spectroscopy and X-ray diffraction (XRD) analysis. The NEs were loaded into gels to form NEGs. NEGs were characterized for drug content, homogeneity, rheology, spreadability, and antifungal activity against Candida albicans, both in vitro and in vivo. Optimized ketoconazole NEG preparations consisted of either 15% clove oil or 20% eucalyptus oil. Droplet sizes in the optimized NEs were <100 nm, and the polydispersity indexes were 0.24 and 0.26. The percentages of ketoconazole released after 24 h from the clove-oil-NEG and eucalyptus-oil-NEGs were 91 ± 4.5 and 89 ± 7%, respectively. Scanning electron microscopy (SEM) showed that the NEGs had a smooth, uniform, and consistent shape and internal structural organization. The drug contents in the clove-oil-NEG and eucalyptus-oil-NEG were 98.5 ± 2.2 and 98.8 ± 3.4%, respectively. Permeation values of ketoconazole from clove-oil-NEG and eucalyptus-oil-NEG were 117 ± 7 and 108.34 ± 6 μg cm^-2, respectively. The ketoconazole NEG formulations also had higher levels of fungal growth inhibition than a marketed formulation. Finally, in vivo studies showed that the NEGs do not irritate the skin. Ketoconazole NEG with either 15% clove oil or 20% eucalyptus oil is stable with better efficacy than ketoconazole alone due to excellent dispersion, drug dissolution, and permeability and thus might be recommended for the effective and safe treatment of candidiasis.