Solid Dispersion Incorporated into Dissolving Microneedles for Improved Antifungal Activity of Amphotericin B: In Vivo Study in a Fungal Keratitis Model.

Fungal keratitis (FK) is a fungal infection of the cornea, which is part of the eye and causes corneal ulcers and an increased risk of permanent blindness, which is often found in Candida albicans species. Amphotericin B (AMB), which is a group of polyenes as the first-line treatment of FK, is effective in annihilating C. albicans. However, AMB preparations such as eye drops and ointments have major drawbacks, for instance, requiring more frequent administrations, loss of the drug by the drainage process, and rapid elimination in the precornea, which result in low bioavailability of the drug. An ocular dissolving microneedle containing the solid dispersion amphotericin B (DMN-SD-AMB) had been developed using a mixture of poly(vinyl alcohol) (PVA) and poly(vinylpyrrolidone) (PVP) polymers, while the solid dispersion AMB (SD-AMB) was contained in the needle as a drug. This study aims to determine the most optimal and safest DMN-SD-AMB formula for the treatment of FK in the eye as well as a solution to overcome the low bioavailability of AMB eye drops and ointment preparations. SD-AMB had been successfully developed, which was characterized by increased antifungal activity and drug release in vitro compared to other treatments. Furthermore, DMN-SD-AMB studies had also been successfully performed with the best formulation, which exhibited the best ex vivo corneal permeation profile and antifungal activity as well as being safe from eye irritation. In addition, an in vivo antifungal activity using a rabbit infection model shows that the number of fungal colonies was 0.98 ± 0.11 log10 CFU/mL (F3), 5.76 ± 0.32 log10 CFU/mL (AMB eye drops), 4.01 ± 0.28 log10 CFU/mL (AMB ointments), and 9.09 ± 0.65 log10 CFU/mL (control), which differed significantly (p < 0.05). All of these results evidence that DMN-SD-AMB is a new approach to developing intraocular preparations for the treatment of FK.

Incorporation of Inclusion Complexes in the Dissolvable Microneedle Ocular Patch System for the Efficiency of Fluconazole in the Therapy of Fungal Keratitis.

Fluconazole (FNL) is one of the first-line treatments for fungal keratitis as it is an effective broad-spectrum antimicrobial commonly administered orally or topically. However, FNL has a very low water solubility, limiting its drug formulation, therapeutic application, and bioavailability through tissues. To overcome these limitations, this study aimed to develop FNL inclusion complexes (FNL-IC) with cyclodextrin (α-cyclodextrin, sulfobutylether-ß-cyclodextrin, and hydroxypropyl-γ cyclodextrin) and incorporate it into a dissolvable microneedle (DMN) system to improve solubility and drug penetration. FNL-IC was evaluated for saturation solubility, Fourier transform infrared spectroscopy, differential scanning calorimetry, in vitro release, minimum inhibitory concentration, minimum fungicidal concentration, and time-killing assay. DMN-FNL-IC was evaluated for mechanical and insertion properties, surface pH, moisture absorption ability, water vapor transmission, and drug content recovery. Moreover, ocular kinetic, ex vivo antimicrobial, in vivo antifungal, and chorioallantoic membrane (HET-CAM) assays were conducted to assess the overall performance of the formulation. Mechanical strength and insertion properties revealed that DMN-FNL-IC has great mechanical and insertion properties. The in vitro release of FNL-IC was significantly improved, exhibiting a 9-fold increase compared to pure FNL. The ex vivo antifungal activity showed significant inhibition of Candida albicans from 6.54 to 0.73 log cfu/mL or 100-0.94%. In vivo numbers of colonies of 0.87 ± 0.13 log cfu/mL (F2), 4.76 ± 0.26 log cfu/mL (FNL eye drops), 3.89 ± 0.24 log cfu/mL (FNL ointments), and 8.04 ± 0.58 log cfu/mL (control) showed the effectiveness of DMN preparations against other standard commercial preparations. The HET-CAM assay showed that DMN-FNL-IC (F2) did not show any vascular damage. Finally, a combination of FNL-IC and DMN was developed appropriately for ocular delivery of FNL, which was safe and increased the effectiveness of treatments for fungal keratitis.

Enhancement of skin localization of ß-carotene from red fruit (Pandanus conoideus Lam.) using solid dispersion-thermoresponsive gel delivered via polymeric solid microneedles.

Red fruit (Pandanus conoideus Lam.) boasts high ß-carotene (BC) content, often consumed orally. However, absorption issues and low bioavailability due to food matrix interaction have led to transdermal delivery exploration. Nevertheless, BC has a short skin retention time. To address these limitations, this study formulates a ß-carotene solid dispersion (SD-BC) loaded thermoresponsive gel combined with polymeric solid microneedles (PSM) to enhance in vivo skin bioavailability. Characterization of SD-BC includes saturation solubility, X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and in vitro release. Characterization of SD-BC thermoresponsive gel includes gelation temperature, viscosity, rheological behaviour, pH, bio-adhesiveness, spreadability, and extrudability. PSM's mechanical properties and insertion capability were assessed. Ex vivo and in vivo dermato-pharmacokinetic studies, drug content, hemolysis, and skin irritation assessments were conducted to evaluate overall performance. Results confirm amorphous SD-BC formation, enhancing solubility. Both SD-BC thermoresponsive gel and PSM exhibit favourable characteristics, including rheological properties and mechanical strength. In vitro release studies showed a seven-fold increase in BC release compared to plain hydrogel. SD-BC thermoresponsive gel combined with PSM achieves superior ex vivo permeation (Cmax = 305.43 ± 32.07 µg.mL-1) and enhances in vivo dermato-pharmacokinetic parameters by 200-400 %. Drug content, hemolysis, and skin irritation studies confirmed its safety and non-toxicity.

Polymeric hydrogel forming microneedle-mediated transdermal delivery of sildenafil citrate from direct-compressed tablet reservoir for potential improvement of pulmonary hypertension therapy.

Pulmonary hypertension (PH) is a cardiovascular disease affecting patient's life. Sildenafil citrate (SC), the first-line treatment, is present in oral and injectable forms with some drawbacks, primarily poor patient's comfort and low oral bioavailability. To counter these limitations, stratum corneum-penetrating hydrogel-forming microneedles (HFM) was created, making it easier to distribute SC transdermally. HFM was fabricated using polyvinyl alcohol (PVA) and two variations of polyvinyl pyrrolidone's (PVP) concentration as polymers and citric acid (CA) as crosslinking agent. The crosslinking time was also variated. The assessment of swelling, insertion characteristics, and mechanical resistance revealed that it possessed swelling capacities up to 470 % and strong insertion capabilities. This HFM was integrated with a tablet reservoir prepared using several concentrations of sodium starch glycolate (SSG) as super disintegrant. The tablet reservoir's hardness, dissolution rate, XRD, and FTIR profiles were evaluated and the results showed that 4 % of SSG was the option for enhancing SC's solubility. According to ex vivo study, this system released 24.12 ± 0.92 % of SC. For the first time, SC was successfully incorporated into a system of HFM and tablet reservoir and was non-toxic, showing promise in terms of improving PAH therapy's efficacy following comprehensive in vivo studies in the future.

HPLC-UV method validation for quantification of ß-carotene in the development of sustained release supplement formulation containing solid dispersion-floating gel in situ.

Despite the health benefits of ß-carotene, its activity has been hampered by poor aqueous solubility and low oral bioavailability. Therefore, it is crucial to develop a new approach to overcome these problems. In this study, we developed a dry powder supplement comprising a combination approach of solid dispersion and floating gel in situ of ß-carotene to enhance the solubility and achieve sustained release behavior. Here, we validated an HPLC method to quantify ß-carotene as per the guidelines from ICH. The analytical method was validated in methanol and Fasted-State Simulated Gastric Fluid (FaSSGF) to determine ß-carotene in recovery and in vitro release studies, respectively. A simple HPLC method using Xselect CSH™ C18 column (Waters, 3.0 × 150 mm) with the particle size of 3.5 µm was validated with 100% acetonitrile as the mobile phase. The calibration curves were found to be linear with LLOQ values < 3 ng/mL. Importantly, the method was accurate and precise without a carry over effect and successfully applied to determine the ß-carotene concentration in the content analysis of the compound and in vitro drug release from floating gel in situ laden with solid dispersion formulations. The sensitivity of the method obtained here offers a wide potential use in various applications in drug delivery systems.