Econazole nitrate (EC) is an active, imidazole antifungal agent. However, low aqueous solubility and dissolution rate of EC has discouraged its usage for the treatment of ophthalmic fungal infection. In this study, inclusion complexes of EC with cyclodextrins were prepared to enhance its solubility, dissolution, and ocular bioavailability. To achieve this goal, EC was complexed with β-CyD/HP-β-CyD using kneading, co-precipitation, and freeze-drying techniques. Phase-solubility studies were performed to investigate the complexes in the liquid form. Additionally, the complexes in the solid form were characterized with Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and transmission electron microscopy (TEM). Furthermore, different eye drops containing EC-CyD complexes were prepared using different polymers and then characterized regarding their drug contents, pH, viscosity, mucoadhesive strength, and in vitro release characteristics. The results showed that stable EC-CyD complexes were formed in 1:1 molar ratio as designated by B-type diagram. Econazole nitrate water solubility was significantly increased in about three- and fourfold for β-CyD and HP-β-CyD, respectively. The results showed that the prepared complexes were spherical in shape having an average particle diameter from 110 to 288.33 nm with entrapment efficiency ranging from 64.24 to 95.27%. DSC investigations showed the formation of real inclusion complexes obtained with co-precipitation technique. From the in vitro studies, all eye drops containing co-precipitate complexes exhibited higher release rate than that of other complexes and followed the diffusion-controlled mechanism. In vivo study proved that eye drops containing EC-CyD complexes showed higher ocular bioavailability than EC alone which indicated by higher AUC, C, and relative bioavailability values.

IntroductionThe first line of defence is the skin, preventing foreign things from entering the human body system and preventing water loss from the body via evaporation 1,2) . The stratum corneum is a complex outermost layer of the skin that acts as the initial physical barrier to any external elements, including medicines, entering the body, which also makes an obstacle in the drug penetration into the body 2) . However, owing to its simple and convenient accessibility, the skin remains an appealing route of drug administration,

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A PEGylated Tween 80–functionalized chitosan–lipidic (PEG-T-Chito-Lip) nano-vesicular hybrid was developed for intranasal administration as an alternative delivery route to help improve the poor oral bioavailability of BCS class-III model/antiemetic (metoclopramide hydrochloride; MTC). The influence of varying levels of chitosan, cholesterol, PEG 600, and Tween 80 on the stability/release parameters of the formulated nanovesicles was optimized using Draper-Lin Design. Two optimized formulations (Opti-Max and Opti-Min) with both maximized and minimized MTC-release goals, were predicted, characterized, and proved their vesicular outline via light/electron microscopy, along with the mutual prompt/extended in-vitro release patterns. The dual-optimized MTC–loaded PEG-T-Chito-Lip nanovesicles were loaded in intranasal in-situ gel (ISG) and further underwent in-vivo pharmacokinetics/nose-to-brain delivery valuation on Sprague-Dawley rats. The absorption profiles in plasma (plasma-AUC 0-∞ ) of the intranasal dual-optimized MTC–loaded nano-vesicular ISG formulation in pretreated rats were 2.95-fold and 1.64-fold more than rats pretreated with orally administered MTC and intranasally administered raw MTC-loaded ISG formulation, respectively. Interestingly, the brain-AUC 0-∞ of the intranasal dual-optimized MTC–loaded ISG was 10 and 3 times more than brain-AUC 0-∞ of the MTC-oral tablet and the intranasal raw MTC-loaded ISG, respectively. It was also revealed that the intranasal dual-optimized ISG significantly had the lowest liver-AUC 0-∞ (862.19 ng.g −1 .h −1 ) versus the MTC-oral tablet (5732.17 ng.g −1 .h −1 ) and the intranasal raw MTC-loaded ISG (1799.69 ng.g −1 .h −1 ). The brain/blood ratio profile for the intranasal dual-optimized ISG was significantly enhanced over all other MTC formulations (P < 0.05). Moreover, the 198.55% drug targeting efficiency, 75.26% nose-to-brain direct transport percentage, and 4.06 drug targeting index of the dual-optimized formulation were significantly higher than those of the raw MTC-loaded ISG formulation. The performance of the dual-optimized PEG-T-Chito-Lip nano-vesicular hybrids for intranasal administration evidenced MTC-improved bioavailability, circumvented hepatic metabolism, and enhanced brain targetability, with increased potentiality in heightening the convenience and compliance for patients.

For decades, the nasal route of administration is principally used for many therapeutic applications owing to the non-invasive nature of the nasal pathway. Besides, it circumvents blood-brain-barrier (BBB) and hepatic first-pass effect. Consequently, the nasal route is much preferred over other invasive approaches like intravenous, intracerebral, and transcranial for the systemic delivery of drugs and the treatment of central nervous systems (CNS) disorders such as depression, Alzheimer’s disease (AD), multiple sclerosis, and Parkinson’s disease (PD) via the nose-to-brain pathway. Drug applied via the nasal route displays some difficulty to reach the brain, like the dose limitation of the nasal pathway, mucociliary clearance, etc. The efficiency of the nasal route depends on the application delivery system. Lipidic-based drug delivery systems (liposomes, solid lipid nanoparticles …etc.) have been confirmed for their promising impact on the nasal delivery approach. Furthermore, the sensitivity of the nasal route and the touched-complications of clinical trials in CNS disorders assigns the necessity of consideration to the clinical trials and approval process of the niosomal-based nasal drug delivery approach. This review describes different approaches to nasal delivery, lipidic-based delivery systems with a focus on niosomes as a promising nasal delivery system, along with different formulation methodologies, and applications.