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.

Recent Advances in Pharmaceutical Approaches of Antimicrobial Agents for Selective Delivery in Various Administration Routes.

Globally, the increase of pathogenic bacteria with antibiotic-resistant characteristics has become a critical challenge in medical treatment. The misuse of conventional antibiotics to treat an infectious disease often results in increased resistance and a scarcity of effective antimicrobials to be used in the future against the organisms. Here, we discuss the rise of antimicrobial resistance (AMR) and the need to combat it through the discovery of new synthetic or naturally occurring antibacterial compounds, as well as insights into the application of various drug delivery approaches delivered via various routes compared to conventional delivery systems. AMR-related infectious diseases are also discussed, as is the efficiency of various delivery systems. Future considerations in developing highly effective antimicrobial delivery devices to address antibiotic resistance are also presented here, especially on the smart delivery system of antibiotics.

Spatiotemporal tracking of gold nanorods after intranasal administration for brain targeting.

Intranasal administration is becoming increasingly more attractive as a fast delivery route to the brain for therapeutics circumventing the blood-brain barrier (BBB). Gold nanorods (AuNRs) demonstrate unique optical and biological properties compared to other gold nanostructures due to their high aspect ratio. In this study, we investigated for the first time the brain region-specific distribution of AuNRs and their potential as a drug delivery platform for central nervous system (CNS) therapy following intranasal administration to mice using a battery of analytical and imaging techniques. AuNRs were functionalized with a fluorescent dye (Cyanine5, Cy5) or a metal chelator (diethylenetriaminepentaacetic dianhydride, DTPA anhydride) to complex with Indium-111 via a PEG spacer for optical and nuclear imaging, respectively. Direct quantification of gold was achieved by inductively coupled plasma mass spectrometry. Rapid AuNRs uptake in mice brains was observed within 10 min following intranasal administration which gradually reduced over time. This was confirmed by the 3 imaging/analytical techniques. Autoradiography of sagittal brain sections suggested entry to the brain via the olfactory bulb followed by diffusion to other brain regions within 1 h of administration. The presence of AuNR in glioblastoma (GBM) tumors following intranasal administration was also proven which opens doors for AuNRs applications, as nose-to-brain drug delivery carriers, for treatment of a range of CNS diseases.

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.

Enhancement in Site-Specific Delivery of Chloramphenicol Using Bacterially Sensitive Microparticle Loaded Into Dissolving Microneedle: Potential For Enhanced Effectiveness Treatment of Cellulitis.

One of the biggest challenges in infectious disease treatment is the existence of bacterial infections in underskin wound tissue, such as cellulitis. Compared to other treatments, it is harder for antibacterial drugs to penetrate the physical barrier on the affected skin with a nonspecific target, making conventional therapy for cellulitis infection more difficult and considered. In this novel research, we pioneer a combined strategy of dissolving microneedles (MNs) and bacteria-sensitive microparticles (MPs) for enhanced penetration and targeted delivery of chloramphenicol (CHL) to the infection site specifically. The polycaprolactone polymer was used to make MPs because of its sensitivity to bacterial enzyme stimuli. The best microparticle formulation was discovered and optimized using the Design-Expert application. Furthermore, this study evaluated the antibacterial activity of MPs in vitro and in vivo on the mutant Drosophila larval infection model. This strategy shows improvement in the antibacterial activity of MPs and higher retention duration compared to conventional cream formulation, and the inclusion of these MPs into dissolving MNs was able to greatly improve the dermatokinetic characteristics of CHL in ex vivo evaluation. Importantly, the antimicrobial efficacy in an ex vivo infection model demonstrated that, following the use of this strategy, bacterial bioburdens decreased by up to 99.99% after 24 h. The findings offered a proof of concept for the enhancement of CHL dermatokinetic profiles and antimicrobial activities after its preparation into bacteria-sensitive MPs and distribution by MNs. Future research should investigate in vivo effectiveness in an appropriate animal model.

Marine Macrolides to Tackle Antimicrobial Resistance of Mycobacterium tuberculosis.

Tuberculosis has become a major health problem globally. This is worsened by the emergence of resistant strains of Mycobacterium tuberculosis showing ability to evade the effectiveness of the current antimycobacterial therapies. Therefore, the efforts carried out to explore new entities from many sources, including marine, are critical. This review summarizes several marine-derived macrolides that show promising activity against M. tuberculosis. We also provide information regarding the biosynthetic processes of marine macrolides, including the challenges that are usually experienced in this process. As most of the studies reporting the antimycobacterial activities of the listed marine macrolides are based on in vitro studies, the future direction should consider expanding the trials to in vivo and clinical trials. In addition, in silico studies should also be explored for a quick screening on marine macrolides with potent activities against mycobacterial infection. To sum up, macrolides derived from marine organisms might become therapeutical options for tackling antimycobacterial resistance of M. tuberculosis.

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.

Pharmaceutical Approaches on Antimicrobial Resistance: Prospects and Challenges.

The rapid increase in pathogenic microorganisms with antimicrobial resistant profiles has become a significant public health problem globally. The management of this issue using conventional antimicrobial preparations frequently results in an increase in pathogen resistance and a shortage of effective antimicrobials for future use against the same pathogens. In this review, we discuss the emergence of AMR and argue for the importance of addressing this issue by discovering novel synthetic or naturally occurring antibacterial compounds and providing insights into the application of various drug delivery approaches, delivered through numerous routes, in comparison with conventional delivery systems. In addition, we discuss the effectiveness of these delivery systems in different types of infectious diseases associated with antimicrobial resistance. Finally, future considerations in the development of highly effective antimicrobial delivery systems to combat antimicrobial resistance are presented.

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.

Phytosomal nanocarriers as platforms for improved delivery of natural antioxidant and photoprotective compounds in propolis: An approach for enhanced both dissolution behaviour in biorelevant media and skin retention profiles.

Propolis has been reported to possess rich content of antioxidant compounds and may provide health benefits through oxidative stress reduction. Presently, the formulation activities used to enhance the drug delivery have been hampered due to inherently low aqueous solubility and poor transdermal permeation of the bioactive phenols and flavonoids. Here, we show, the formulation of propolis extract (PE) into phytosome delivery systems. The optimum antioxidant activity was attained through extraction process using 75% v/v ethanol. The phytosome was prepared using thin-layer hydration technique with l-α-Phosphatidylcholine as a phospholipid. Fourier transform infrared (FTIR) was used to investigate the occurrence of molecular interactions between formulation components. This innovative approach could encapsulate >40% of bioactive compounds in PE, namely caffeic acid, quercetin, and kaempferol. FTIR spectroscopy indicated new hydrogen bond formation, supporting successful phytosome formulation. The phytosomes enhanced the dissolution up to 4-folds of bioactive compounds in bio-mimicked release media, as well as improved penetrability and skin retention up to 6-folds of the three main compounds of propolis, when compared to non-encapsulated PE formulation. Importantly, the hydrogel containing phytosome showed a potential for UVA and UVB radiation absorption, indicated by the SPF values of higher than 15. To conclude, this work shows promising novel delivery approaches for PE in the treatment of organ injured stress oxidative and skin aging.