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.

Development of samarium-doped phosphate glass microspheres for internal radiotheranostic applications.

Internal radiotherapy delivers radioactive sources inside the body, near to or into malignant tumours, which may be particularly effective when malignancies are not responding to external beam radiotherapy. A pure beta emitter, 90Y, is currently used for internal radiotherapy. However, theranostic radionuclide-doped microspheres can be developed by incorporating 153Sm, which emits therapeutic beta and diagnostic gamma energies. This study investigated the production of high concentrations of samarium-content doped phosphate-based glass microspheres. The glass P60 (i.e. 60P2O5-25CaO-15Na2O) was mixed with Sm2O3 at ratios of 75:25 (G75:Sm25), 50:50 (G50:Sm50) and 25:75 (G25:Sm75) and processed via flame spheroidisation. Scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) confirmed the microsphere uniformity with significantly high samarium content up to 44 % in G25:Sm75. Via X-ray diffraction (XRD) analysis, samarium-doped microspheres appeared to be glass-ceramic in nature. Mass-loss, size and pH changes were performed over 28 days, revealing a significant increase in samarium microsphere stability. After 15 min of neutron activation (neutron flux 3.01 × 1013 n.cm-2.s-1), the specific activity of the microspheres (G75:Sm25, G50:Sm50 and G25:Sm75) was 0.28, 0.54 and 0.58 GBq.g-1, respectively. Therefore, the samarium microspheres produced in this study provide great potential for improving internal radiotherapy treatment for liver cancer by avoiding complex procedures and using less microspheres with shorter irradiation time.

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.

Development of Thermoresponsive Hydrogels with Mucoadhesion Properties Loaded with Metronidazole Gel-Flakes for Improved Bacterial Vaginosis Treatment.

Bacterial vaginosis is an infectious disease that has significantly affected women's health. Metronidazole has been widely used as a drug for treating bacterial vaginosis. Nevertheless, the currently available therapies have been found to be inefficient and inconvenient. Here, we developed the combination approach of gel flake and thermoresponsive hydrogel systems. The gel flakes were prepared using gellan gum and chitosan, showing that the incorporation of metronidazole was able to provide a sustained release pattern for 24 h with an entrapment efficiency of >90%. Moreover, the gel flakes were incorporated into Pluronics-based thermoresponsive hydrogel using the combination of Pluronic F127 and F68. The hydrogels were found to exhibit the desired thermoresponsive properties, showing sol-gel transition at vaginal temperature. Following the addition of sodium alginate as a mucoadhesive agent, the hydrogel was retained in the vaginal tissue for more than 8 h, with more than 5 mg of metronidazole retained in the ex vivo evaluation. Finally, using the bacterial vaginosis infection model in rats, this approach could decrease the viability of Escherichia coli and Staphylococcus aureus with reduction percentages of more than 95% after 3 days of treatment, with the healing ability similar to normal vaginal tissue. In conclusion, this study offers an effective approach for the treatment of bacterial vaginosis.

Development of hydrogel-forming microneedles for transdermal delivery of albendazole from liquid reservoir.

Albendazole (ABZ) is an anthelmintic agent from the benzimidazole group, known as the broad-spectrum antiparasitic drug. ABZ is commonly used to treat human intestinal and systemic infections. Orally administered ABZ tends to have limited efficacy due to its poor solubility. In order to enhance its delivery to the therapeutic target, polyvinyl alcohol-based hydrogel-forming microneedles (HFMs) was developed. HFMs can effectively deliver drugs loaded in the reservoir through the transdermal route with fewer side effects and longer therapeutic duration. In addition, to enhance ABZ's solubility, the drug can be loaded as a liquid reservoir using water-miscible solvents, which will effectively enhance the solubility of ABZ, resulting in higher bioavailability. In this study, HFMs was successfully developed with high swelling abilities, more than 400%. Moreover, the penetration result showed HFMs could penetrate up to 63% into the skin with only a 7.14% of height decrease. The skin integrity test also showed HFMs permeation into the skin, causing no changes in skin integrity after 24 h of application. Incorporated with the liquid reservoir, the ex vivo permeation test showed that the cumulative amount of ABZ permeated through the skin was about 971.23 ± 11.77 µg/cm2. In conclusion, this innovation has a huge potential to overcome the limitations of ABZ in oral preparations and potentially enhance its therapeutic effect through the transdermal route.

A novel in vitro approach to investigate the effect of food intake on release profile of valsartan in solid dispersion-floating gel in-situ delivery system.

Valsartan (VAL) is a BCS class II drug with low solubility and high permeability and, thus, its formulations often encounter low bioavailability problems. Its low bioavailability can be improved through enhanced formulation, such as incorporating it into a solid dispersion system (SD). The absorption can be further enhanced through gastroretentive systems. Herein, we developed a novel combination delivery approach consisting of floating in-situ gel and SD. VAL was incorporated with polymer carrier PVP and PEG 6000 and its solubility was then evaluated. The study found that VAL-SD containing PVP K-30 as the carrier with drug:PVP K-30 ratio of 1:3 shown highest solubility in different media. Moreover, DSC and XRD evaluations exhibited the change of VAL from crystal to amorphous following SD formulation. The SD was then formulated into floating in-situ gel preparations using sodium alginate as gel forming compound and HPMC as the controlled release matrix. The prepared VAL-SD floating in-situ gels were evaluated for their physical properties and drug release profile. The results showed that all physical evaluation of the floating in-situ gel formula possessed desirable physical properties and the use of HPMC in floating in-situ gel was able to sustain the in vitro release of VAL for 24 h in biorelevant media. Importantly, the effect of food intake on VAL release was also investigated, for the first time, showing that the VAL release could be controlled in FaSSGF (Fasted-State Simulated Gastric Fluid) in 2 h and FeSSGF (Fed-State Simulated Gastric Fluid) onwards. Thus, in can be hypothesized that the food intake did not affect the VAL release after 2 h in an empty gastric environment. Leading on from these results, in vivo studies in an animal model should be carried out to further assess the potency of this system.

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

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, bioadhesive-thermosensitive 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 gel-flake 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.

Thermosensitive and mucoadhesive in situ ocular gel for effective local delivery and antifungal activity of itraconazole nanocrystal in the treatment of fungal keratitis.

Itraconazole is a lipophilic drug, which limits its absorption for ocular administration. This study focused on the incorporation of itraconazole into nanocrystalline carrier system with stabilizer Pluronic® F127 and was further formulated into thermosensitive in situ ocular gel. Itraconazole nanocrystals (ITZ-NCs) were fabricated using media milling method with ultra-small-scale device. The obtained nanocrystals were observed to have a better in vitro activity against C. albicans (CA) compared to free itraconazole suspension in water. Furthermore, the optimization of the thermosensitive ocular gel formula was carried out with a central composite design, using three types of polymers, namely Pluronic® F127, Pluronic® F68, and hydroxypropyl methylcellulose (HPMC). After being dispersed into the optimized thermosensitive gel base, ITZ-NCs did not alter in terms of physical characteristics. Ex vivo ocularkinetic studies on infected porcine eye models showed a better profile of the optimized formula of thermosensitive in situ ocular gel when compared to standard gel base. Importantly, the ex vivo antifungal activity of these preparations was also increased, with a 93% decrease in the CA population observed after 48 h in infected porcine eye model. Altogether, this work has provided evidence of a novel approach in developing more advanced treatments for fungal keratitis.