Diana Edwar Aziz

Background/Objectives: Cutaneous fungal infections remain a major therapeutic challenge due to poor skin penetration and emerging antifungal resistance of current treatments. Drug repurposing offers a promising strategy to expand antifungal therapy, with ketoprofen (KPN) recently demonstrating antifungal activity. Methods: In this study, KPN-cationic aspasomes (Ca-ASPMs) were developed using a Quality by Design (QbD) approach to enhance topical delivery and maximize the therapeutic potential of repurposed KPN. A D-optimal experimental design was implemented to investigate the influence of ascorbyl palmitate amount (X₁), ethanol concentration (X₂), and cationic SAA type (X₃) on the critical quality attributes of KPN-Ca-ASPMs, namely entrapment efficiency, particle size, and zeta potential. Results: Numerical optimization identified an optimum formulation comprising 10 mg ascorbyl palmitate, 5% ethanol, and didodecyldimethylammonium bromide (DDAB) as cationic SAA, with an overall desirability of 0.815. The optimal KPN-Ca-ASPM (F9) exhibited nanosized vesicles (213.24 ± 2.20 nm) and 91.30 ± 10.01% entrapment efficiency. TEM confirmed the spherical morphology of the vesicles, while DSC demonstrated successful incorporation of KPN within the aspasomal matrix. F9 exhibited enhanced in vitro drug release (68% after 6 h) and excellent storage stability. Confocal laser scanning microscopy demonstrated enhanced skin penetration of F9. In a murine cutaneous candidiasis model, F9 significantly enhanced the antifungal efficacy of KPN, producing a 2.989-log reduction in fungal burden compared with the untreated group and significantly outperforming the free drug (p = 0.0005). Histopathological examination confirmed restoration of normal skin architecture. Conclusions: Collectively, the QbD-guided development of KPN-Ca-ASPM provided a reproducible nanocarrier that significantly enhanced the topical antifungal efficacy of repurposed KPN, highlighting its potential for the treatment of cutaneous candidiasis.

Background/Objectives: This study aimed to repurpose aripiprazole (AR), an antipsychotic clinically approved by the FDA, as a novel antifungal drug and to potentiate its therapeutic efficacy through PEGylated terpesomes (PEG-TERs). Methods: PEG-TERs were prepared by thin-film hydration and optimized using a central composite design. The optimum PEG-TER formulation was characterized for entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP), and subsequently integrated into polylactic acid (PLA)-based 3D-printed ocuserts. Results: The optimized formulation exhibited spherical vesicles with high EE%, nanoscale PS, narrow PDI, and favorable ZP, alongside excellent stability and mucoadhesive properties. Ex vivo permeation demonstrated a sustained release profile of AR from PEG-TERs compared with an AR suspension, while confocal microscopy confirmed efficient corneal deposition of fluorescein-labeled PEG-TERs. In vivo, the optimum AR-loaded PEG-TERs ocusert exhibited a substantial therapeutic effect in a rabbit model of Candida albicans keratitis, while histopathological assessment confirmed its ocular safety and biocompatibility. Conclusions: In conclusion, AR-loaded PEG-TERs embedded in PLA-based 3D-printed ocuserts represent a promising, safe, and innovative therapeutic platform for the management of Candida albicans-induced corneal infections, offering both drug repurposing and emerging opportunities in advanced ocular drug delivery.

Agomelatine (AGO) is a dual action drug. Being serotonin receptor antagonist, AGO is orally administered for depression treatment. Here in, AGO was used for intraocular pressure management due to its agonistic activity on the melatonin receptors in the eyes. AGO is a BCS II drug, with low oral bioavailability and massive first-pass metabolism. Oleic acid enriched leciplexes were investigated as novel mucoadhesive cationic nanocarriers to improve AGO’s ocular bioavailability and prolong its pharmacological effect. Twenty-four AGO loaded leciplexes were fabricated by single-step procedure. AGO: lipid ratio, surfactant: phosphatidyl choline ratio, cationic surfactant type, permeation enhancer type were investigated. For optimization; in-vitro assessment of size, homogeneity, surface charge, drug entrapment and in-vitro release was conducted. The optimum system was further examined for crystallinity, compatibility, morphology, pH, refractive index, surface tension and stability. L20 developed at a drug: lipid ratio of 1: 20, cetyltrimethylammonium bromide and phosphatidyl choline at a ratio of 1:5 respectively and 0.25% w/v oleic acid was the optimum system with respect to shape and PS (spherical, 491 nm), PDI (0.29), ZP (31.1 mV), EE (81.8%), in-vitro release (Q _2h ; 34.9%, Q _8h ; 91.2%), crystallinity, pH (6.3), refractive index (1.24), surface tension (46.2 mN/m) and stability. AGO pharmacodynamic and histopathological studies were conducted in rabbits. Compared to AGO dispersion, elevated maximum IOP reduction (74.2%), prolonged mean residence time (12.88 h), enhanced bioavailability (3 folds) and normal histopathological micrographs proved the potential of L20 leciplex in improving and sustaining the ocular bioavailability of AGO and maintaining its safety. Graphical Abstract

Mebendazole (MBZ) is an anthelmintic drug that was repurposed as an anti-cancer agent. This study aimed at formulating MBZ into stearylamine tailored spanlastics dispersed in nanogel for enhancing MBZ anti-tumor efficacy against skin cancer. MBZ spanlastics were prepared by thin film hydration using 2¹ × 3¹ factorial design. The formulation variables were the total amount (mg) of Span 60 and Tween 80 in the formulations and the ratio between Span 60 and Tween 80. Optimal spanlastics formulation was composed of 400 mg of Span 60 and Tween 80 in a ratio of 2:1 and showed EE% of 78 ± 2.9% and PS of 284.00 ± 35.36 nm. Stearylamine (20 mg) was added to the optimized formulation and showed acceptable positive charge (zeta potential = 47.53 ± 1.50 mV). It was dispersed in 30% Tetronic^®1107 solution to form a nanogel. MBZ nanogel was assessed for their cytotoxic effect on cell proliferation against human malignant melanoma and epidermoid carcinoma cell lines and showed 38.70 ± 1.70% and 48.60 ± 0.50% (respectively) cell proliferation compared to the control group (100%). Finally, its permeation through Wistar rat skin was tested. SA-spanlastics nanogel holds potential as an effective nanocarrier for boosting MBZ anti-cancer efficacy.

Tolnaftate (TOL) is a thiocarbamate fungicidal drug used topically in the form of creams and ointments. No ocular formulations of TOL are available for fungal keratitis (FK) treatment due to its poor water solubility and unique ocular barriers. Therefore, this study aimed at developing novel modified spanlastics by modulating spanlastics composition using different glycols for enhancing TOL ocular delivery. To achieve this goal, TOL basic spanlastics were prepared by ethanol injection method using a full 3² factorial design. By applying the desirability function, the optimal formula (BS6) was selected and used as a nucleus for preparing and optimizing TOL-cosolvent spanlastics according to the full 3¹.2¹ factorial design. The optimal formula (MS6) was prepared using 30% propylene glycol and showed entrapment efficiency percent (EE%) of 66.10 ± 0.57%, particle size (PS) of 231.20 ± 0.141 nm, and zeta potential (ZP) of −32.15 ± 0.07 mV. MS6 was compared to BS6 and both nanovesicles significantly increased the corneal permeation potential of TOL than drug suspension. Additionally, in vivo histopathological experiment was accomplished and confirmed the tolerability of MS6 for ocular use. The fungal susceptibility testing using Aspergillus niger confirmed that MS6 displayed more durable growth inhibition than drug suspension. Therefore, MS6 can be a promising option for enhanced TOL ocular delivery.

Diacerein (DCN) is a hydrophobic osteoarthritis (OA) drug with short half-life and low oral bioavailability. Furthermore, DCN oral administration is associated with diarrhea which represents obstacle against its oral use. Hence, this article aimed at developing elastosomes (edge activator (EA)-based vesicular nanocarriers) as a novel transdermal system for delivering DCN efficiently and avoiding its oral problems. For achieving this goal, elastosomes were prepared according to 4¹.2¹ full factorial design using different EAs in varying amounts. The prepared formulae were characterized regarding their entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and deformability index (DI). Desirability function was employed using Design-Expert^® software to select the optimal elastosomes (E1) which showed EE% of 96.25 ± 2.19%, PS of 506.35 ± 44.61 nm, PDI of 0.46 ± 0.09, ZP of −38.65 ± 0.91 mV, and DI of 12.74 ± 2.63 g. In addition, E1 was compared to DCN-loaded bilosomes and both vesicles exhibited superior skin permeation potential and retention capacity compared to drug suspension. In-vivo histopathological study was performed which ensured the safety of E1 for topical application. Furthermore, the pharmacokinetic study conducted in albino rabbits demonstrated that there was no significant difference in the rate and extent of DCN absorption from topically applied E1 compared to oral suspension. Multiple level C in-vitro in-vivo correlation showed good correlation between in-vitro release and in-vivo drug performance for E1 and DCN oral suspension. Overall, results confirmed the admirable potential of E1 to be utilized as novel carrier for transdermal delivery of DCN and bypassing its oral side effects.