Essential considerations towards development of effective nasal antibiotic formulation: features, strategies, and future directions.

INTRODUCTION: Intranasal antibiotic products are gaining popularity as a promising method of administering antibiotics, which provide numerous benefits, e.g. enhancing drug bioavailability, reducing adverse effects, and potentially minimizing resistance threats. However, some issues related to the antibiotic substances and nasal route challenges must be addressed to prepare effective formulations. AREAS COVERED: This review focuses on the valuable points of nasal delivery as an alternative route for administering antibiotics, coupled with the challenges in the nasal cavity that might affect the formulations. Moreover, this review also highlights the application of nasal delivery to introduce antibiotics for local therapy, brain targeting, and systemic effects that have been conducted. In addition, this viewpoint provides strategies to maintain antibiotic stability and several crucial aspects to be considered for enabling effective nasal formulation. EXPERT OPINION: In-depth knowledge and understanding regarding various key considerations with respect to the antibiotic substances and nasal route delivery requirement in preparing effective nasal antibiotic formulation would greatly improve the development of nasally administered antibiotic products, enabling better therapeutic outcomes of antibiotic treatment and establishing appropriate use of antibiotics, which in turn might reduce the chance of antibiotic resistance and enhance patient comfort.

Preparation and Optimization of Bovine Serum Albumin Nanoparticles as a Promising Gelling System for Enhanced Nasal Drug Administration.

Bovine serum albumin (BSA) has been used extensively as a suitable carrier system for alternative drug delivery routes, such as nasal administration. However, the optimization of BSA nanoparticles with respect to their nasal applicability has not been widely studied. The present study focuses on the characterization of BSA nanoparticles prepared using the desolvation method, followed by a gelation process to facilitate intranasal drug delivery. The results demonstrated that the ratio of BSA and the desolvating agent, ethanol, played a critical role in the nanoparticle characteristics of the BSA nanogel matrices (BSA-NGs). Based on the gelling properties, the formulations of BSA-NG 2, BSA-NG 4, and BSA-NG 6 were selected for further investigation. The Raman spectra confirmed that there were no specific changes to the secondary structures of the BSA. The mucoadhesion studies revealed moderately high mucoadhesive properties, with a mucin binding efficiency (MBE) value of around 67%, allowing the dose to avoid elimination due to rapid mucociliary clearance of the nasal passage. Via studying the nexus of the carrier system, BSA-NGs loaded with dexamethasone as a model drug were prepared and evaluated by differential scanning calorimetry (DSC) and thermal gravimetry (TG), ascertaining that no ethanol remained in the samples after the freeze-drying process. Furthermore, the viscosity measurements exhibited moderate viscosity, which is suitable for nasal liquid preparations. The in vitro release studies performed with a simulated nasal electrolyte solution (SNES) medium showed 88.15-95.47% drug release within 4 h. In conclusion, BSA nanoparticle gelling matrices can offer potential, value-added drug delivery carriers for improved nasal drug administration.

Quality by design-based optimization of in situ ionic-sensitive gels of amoxicillin-loaded bovine serum albumin nanoparticles for enhanced local nasal delivery.

A recommended first-line acute bacterial rhinosinusitis (ABR) treatment regimen includes a high dose of orally administered amoxicillin, despite its frequent systemic adverse reactions coupled with poor oral bioavailability. Therefore, to overcome these issues, nasal administration of amoxicillin might become a potential approach for treating ABR locally. The present study aimed to develop a suitable carrier system for improved local nasal delivery of amoxicillin employing the combination of albumin nanoparticles and gellan gum, an ionic-sensitive polymer, under the Quality by Design methodology framework. The application of albumin nanocarrier for local nasal antibiotic therapy means a novel approach by hindering the nasal absorption of the drug through embedding into an in situ gelling matrix, further prolonging the drug release in the nasal cavity. The developed formulations were characterized, including mucoadhesive properties, in vitro drug release and antibacterial activities. Based on the results, 0.3 % w/v gellan gum concentration was selected as the optimal in situ gelling matrix. Essentially, each formulation adequately inhibited the growth of five common nasal pathogens in ABR. In conclusion, the preparation of albumin-based nanoparticles integrated with in situ ionic-sensitive polymer provides promising ability as nanocarrier systems for delivering amoxicillin intranasally for local antibiotic therapy.

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 Thermoresponsive-Gel-Matrix-Embedded Amoxicillin Trihydrate-Loaded Bovine Serum Albumin Nanoparticles for Local Intranasal Therapy.

A high dose of amoxicillin is recommended as the first-line therapy for acute bacterial rhinosinusitis (ABR). However, oral administration of amoxicillin is connected to many adverse reactions coupled with moderate bioavailability (~60%). Therefore, this study aimed to develop a topical nasal preparation of amoxicillin, employing a thermoresponsive nanogel system to increase nasal residence time and prolong drug release. Rheological investigations revealed that formulations containing 21−23% w/w Poloxamer 407 (P407) were in accordance with the requirement of nasal administration (gelling temperature ~35 °C). The average hydrodynamic diameter (<200 nm), pH (6.7−6.9), and hypertonic osmolality (611−663 mOsmol/L) of the in situ gelling nasal nanogel appeared as suitable characteristics for local rhinosinusitis treatment. Moreover, taking into account the mucoadhesive strength and drug release studies, the 21% w/w P407 could be considered as an optimized concentration for effective nasal delivery. Antibacterial activity studies showed that the ability of amoxicillin-loaded in situ gelling nasal nanogel to inhibit bacterial growth (five common ABR pathogens) preserved its effectiveness in comparison to 1 mg/mL amoxicillin aqueous solution as a positive control. Altogether, the developed amoxicillin-loaded in situ gelling thermoresponsive nasal nanogel can be a potential candidate for local antibiotic therapy in the nasal cavity.

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.

Development of thermosensitive and mucoadhesive gels of cabotegravir for enhanced permeation and retention profiles in vaginal tissue: A proof of concept study.

As an effective anti-HIV drug, cabotegravir (CAB) is currently administered via oral and injection routes, leading to several drawbacks, such as poor oral bioavailability and problems in the injection application process, as well as low drug concentration in vaginal tissue of woman patients. To overcome these issues, for the first time, we formulated CAB into three types of vaginal gels, considering the benefits of vaginal tissue as a delivery route. Thermosensitive gel, mucoadhesive gel, and the combination of these gels were developed as suitable carriers for CAB. Pluronics®, hydroxy propyl methyl cellulose (HPMC), Carbomer and poly(ethylene glycol) (PEG) 400 were used as thermosensitive, mucoadhesive and permeation enhancer agents, respectively. The gels were evaluated for their thermosensitive and mucoadhesive properties, as well as their pH values, viscosities, gel erosions, drug content recovery, in vitro drug release, ex vivo permeation, ex vivo retention, hemolytic activities, Lactobacillus inhibition activities and in vivo irritation properties. The results showed that all formulations showed desired characteristics for vaginal administration. Importantly, all formulations did not show hemolytic activities and inhibitions to Lactobacillus as normal bacteria in the vagina. Furthermore, no irritation in the vaginal tissues of the rats was observed by histopathological studies. Considering the thermosensitive and mucoadhesive properties, the combination of Pluronic® F127, Pluronic F68, and HPMC in thermosensitive-mucoadhesive vaginal gels was selected as the optimum dosage form for CAB as this formulation was able to provide ease administration due to its liquid form at room temperature. The use of PEG in this formulation was able to increase the penetrability of CAB through vaginal tissue with 0.61 ± 0.05 mg and 17.28 ± 0.95 mg of CAB being able to penetrate and localize in the vagina, respectively. Essentially, the optimum formulation was retained in the vaginal mucosa for>8 h. To conclude, further extensive in vivo studies should now be conducted to evaluate the efficacy of this approach.

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.

Selective delivery of silver nanoparticles for improved treatment of biofilm skin infection using bacteria-responsive microparticles loaded into dissolving microneedles.

The treatment of infected chronic wounds has been hampered by development of bacterial biofilms and the low penetration of antibacterial compounds delivered by conventional dosage forms. Numerous bacterial biofilm formers have shown resistance to synthetic antibacterial agents. In this study, we explore the potential of silver nanoparticles (NPs) synthesized using green tea extract as antibiofilm agents against Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) biofilms. Due to the toxicity of silver NPs, for the first time, silver NPs were incorporated into bacteria-responsive microparticles (MPs) prepared from poly (Ɛ-caprolactone) decorated with chitosan. The in vitro release of silver NPs from MPs increased up to 9-times in the presence of SA and PA, showing the selectivity of this approach. Incorporation of the MPs into dissolving microneedles (DMNs) could enhance the dermatokinetic profiles of silver NPs compared to DMNs containing silver NPs without MP formulations and conventional cream formulations. Furthermore, 100% of bacterial bioburdens were eradicated on ex vivo biofilm model in rat skin following 60 h of the administration of this system. The findings revealed here confirmed the feasibility of the loading of silver NPs into responsive MPs for improved antibiofilm activities when delivered using DMNs. Following on from these promising results, toxicity and in vivo pharmacodynamic studies should now be carried out in an appropriate model.