Bioadhesive-Thermosensitive In Situ Vaginal Gel of the Gel Flake-Solid Dispersion of Itraconazole for Enhanced Antifungal Activity in the Treatment of Vaginal Candidiasis

Abstract

The poor solubility of itraconazole (ITZ) has limited its efficacy in the treatment of vaginal candidiasis. Accordingly, the improvement of ITZ solubility using a solid dispersion technique was important to enhance its antifungal activity. Besides, as the purpose of this research was to develop local-targeting formulations, bioadhesivethermosensitive in situ vaginal gel combined with the gel-flake system was found to be the most suitable choice. To obtain optimum solubility, entrapment efficiency, and drug-loading capacity, optimization of solid dispersion (SD) and gel-flake formulations of ITZ was performed using a composite central design. The results showed that the optimized formulation of SD-ITZ was able to significantly enhance its solubility in both water and simulated vaginal fluid to reach the values of 4.211 ± 0.23 and 4.291 ± 0.21 mg/mL, respectively. Additionally, the optimized formulation of SD-ITZ gel flakes possessed desirable entrapment efficiency and drug-loading capacity. The in situ vaginal gel containing SD-ITZ gel flakes was prepared using PF-127 and PF-68, as the gelling agents, with the addition of hydroxypropyl methylcellulose (HPMC) as the mucoadhesive polymer. It was found that the obtained in situ vaginal gel provided desirable physicochemical properties and was able to retain an amount of more than 4 mg of ITZ in the vaginal tissue after 8 h. Importantly, according to the in vivo antifungal activity using infection animal models, the incorporation of the solid dispersion technique and gelflake system in the formulation of the bioadhesive-thermosensitive in situ vaginal gel led to the most significant decrease of the growth of Candida albicans reaching <1 log colony-forming units (CFU)/mL or equivalent to <10% of the total colony after 14 days, indicating the improvement of ITZ antifungal activity compared to other treated groups. Therefore, these studies confirmed a great potential to enhance the efficacy of ITZ in treating vaginal candidiasis. Following these findings, several further experiments need to be performed to ensure acceptability and usability before the research reaches the clinical stage.

The Expanded Role of Chitosan in Localized Antimicrobial Therapy

“…In a pilot study involving 100 vulvovaginal candidiasis patients, the efficacy of ketoconazole gel flakes formulation was equivalent to the marketed product, confirming the in vivo effect of the novel system [305]. A similar approach was developed by Permana et al comprising thermosensitive in situ vaginal gel combined with the gelflake system of itraconazole-containing solid dispersion powder [306]. In vivo antifungal activity was evaluated using a vulvovaginal candidiasis animal model.…”

“…The hydrogel containing amphotericin B-loaded chitosan microplatelets obtained a complete cure of infection in vivo [299] Fluconazole Chitosan-based vaginal inserts containing fluconazole showed improved antifungal activity both in vitro and in vivo compared to free drug [300] Curcumin Curcumin liquid crystal system containing chitosan increased the antifungal potency of curcumin in vitro [301] Curcumin liquid crystal system containing chitosan significantly decreased fungal burden in vivo and efficiently reduced the growth of biofilm in vitro [302] Fluconazole Chitosan-based vaginal tablets increased the antifungal activity of fluconazole [303] Chelidonii herba extract Chitosan-based vaginal tablets detained the in vitro antimicrobial activity of the extract [304] Ketoconazole Ketoconazole-containing chitosan and gellan gum gel flakes in thermosensitive gel expressed antifungal effect in vivo [305] Itraconazole Thermosensitive gel with a chitosan gel-flake system significantly improved the antifungal effect of itraconazole in vivo [306] Chlorhexidine Chitosan-based vaginal inserts increased the antifungal activity of chlorhexidine in vitro [307] Chitosan-based vaginal inserts increased the antifungal activity of chlorhexidine in vitro [308] Bacterial vaginosis -Chitosan-coated liposomes expressed in vitro antibacterial effect against S. epidermidis and S. aureus [8] Table 3. Cont.…”

“…In vivo antifungal activity was evaluated using a vulvovaginal candidiasis animal model. It was found that the combination of the solid dispersion, gel-flakes, and in situ gel significantly improved the anticandidal effect of itraconazole [306].…”

Photosensitizer‐Polypeptide Conjugate with Synergistic Antibacterial Efficacy

“…Furthermore, the antibacterial activities of PPa and PPa‐cP5 were evaluated through a diffusion agar method. [ 18 ] Briefly, bacterial solution (100 µL, 1 × 10 6 CFU mL −1 ) was spread on the Mueller–Hinton (MH) agar plates. PPa and PPa‐cP solutions were, respectively, dropped onto the paper discs and then gently placed on the agar surface.…”

Assessment of antifungal efficacy of itraconazole loaded aspasomal cream: comparative clinical study

“…ITZ offers felicitous options against superficial and cutaneous fungal infections including resistant types and is feasible currently in 200 and 400 mg/day doses in the form of capsules and cyclodextrin solution for oral administration (Martin, 1999 ; Permana et al., 2021 ). Despite being well tolerated, some unsatisfactory side effects might occur such as constipation, headache, liver damage, and cardiac disorders when administrated orally (Kumar & Goindi, 2021 ).…”