Bioavailability enhancement of sildenafil citrate via hydrogel-forming microneedle strategy in combination with cyclodextrin complexation.

Sildenafil citrate (SIL) as a first-line treatment for erectile dysfunction is currently reported to have poor solubility and bioavailability. Moreover, SIL undergoes first-pass metabolism when taken orally and its injection can lead to discomfort. In this study, we introduce a novel transdermal delivery system that integrates hydrogel-forming microneedles with the inclusion complex tablet reservoir. The hydrogel-forming microneedle was prepared from a mixture of polymers and crosslinkers through a crosslinking process. Importantly, the formulations showed high swelling capacity (>400 %) and exhibited adequate mechanical and penetration properties (needle height reduction < 10 %), penetrating up to five layers of Parafilm® M (assessed to reach the dermis layer). Furthermore, to improve the solubility of SIL in the reservoir, the SIL was pre-complexed with ß-cyclodextrin. Molecular docking analysis showed that SIL was successfully encapsulated into the ß-cyclodextrin cavity and was the most suitable conformation compared to other CD derivatives. Moreover, to maximize SIL delivery, sodium starch glycolate was also added to the reservoir formulation. As a proof of concept, in vivo studies demonstrated the effectiveness of this concept, resulting in a significant increase in AUC (area under the curve) compared to that obtained after administration of pure SIL oral suspension, inclusion complex, and Viagra® with relative bioavailability > 100 %. Therefore, the approach developed in this study could potentially increase the efficacy of SIL in treating erectile dysfunction by being non-invasive, safe, avoiding first-pass metabolism, and increasing drug bioavailability.

Development of probiotic loaded multilayer microcapsules incorporated into dissolving microneedles for potential improvement treatment of vulvovaginal candidiasis: A proof of concept study.

Vulvovaginal candidiasis (VVC) is a vaginal infection caused by abnormal growth of Candida sp., especially Candida albicans, in the vaginal mucosa. A shift in vaginal microbiota is prominent in VVC. The presence of Lactobacillus plays a vital role in maintaining vaginal health. However, several studies have reported resistance of Candida sp. against azoles drugs, which is recommended as VVC treatment. The use of L. plantarum as a probiotic would be an alternative to treat VVC. In order to exert their therapeutic activity, the probiotics needed to remain viable. Multilayer double emulsion was formulated to obtain L. plantarum loaded microcapsules (MCs), thus improving its viability. Furthermore, a vaginal drug delivery system using dissolving microneedles (DMNs) for VVC treatment was developed for the first time. These DMNs showed sufficient mechanical and insertion properties, dissolved rapidly upon insertion, facilitating probiotic release. All formulations proved non-irritating, non-toxic, and safe to apply on the vaginal mucosa. Essentially, the DMNs could inhibit the growth of Candida albicans up to 3-fold than hydrogel and patch dosage forms in ex vivo infection model. Therefore, this study successfully developed the formulation of L. plantarum-loaded MCs with multilayer double emulsion and its combination in DMNs for vaginal delivery to treat VVC.

Validation of spectrophotometric method to quantify chloramphenicol in fluid and rat skin tissue mimicking infection environment: Application to in vitro release and ex vivo dermatokinetic studies from dissolving microneedle loaded microparticle sensitive bacteria.

Cellulitis is a common dermis/subcutaneous tissue skin infection and shared global disease burden, with a higher incidence for males and people aged 45-64 years. Application therapy of chloramphenicol (CHL) has been hindered because of its toxicity and limited penetration into the skin. In this research, CHL was developed into a bacterially sensitive microparticles which were further incorporated into a microneedle system to increase penetration. To support this formulation, in this study, UV-vis spectrophotometry method was validated in methanol, polyvinyl alcohol (PVA) 1%, phosphate buffered saline (PBS), tryptic soy broth (TSB) (fluid-mimicking infection), and skin tissue to quantify amount of CHL. The developed analytical method was subsequently validated according to ICH guidelines. The results obtained showed that the correlation coefficients were linear ≥0.9934. The values of LLOQ inside the methanol, PVA 1%, PBS, TSB, and skin tissue were 7.20 µg/mL, 4.40 µg/mL, 8.18 µg/mL, 387.48 µg/mL, and 7.27 µg/mL, respectively. The accuracy and precision of the developed method were prominent. These methods were successfully applied to quantify the amount of CHL in microparticle and microneedle system in fluid and tissue skin infection. The result showed the high drug release microparticle sensitive bacteria, and high drug retention in ex vivo dermatokinetic evaluation in rat skin tissue containing bacterial infection. This was due to the presence of Staphylococcus aureus bacteria culture that produced lipase enzymes, playing a role in lysing microparticle matrix to develop selectively delivery antimicrobials. A further analytical method needs to be matured to quantify CHL inside the in vivo studies.