Drug Delivery for Ocular Allergy: Current Formulation Design Strategies and Future Perspectives.

The incidences of ocular allergy have been growing with the increase in pollution. Because of challenges in new drug development, there have been efforts to maximize the efficacy of existing drugs through drug delivery approaches. The effectiveness of drugs in ophthalmic conditions is primarily determined by permeability across the barrier, corneal retention, and sustained release. Thus, there have been widespread efforts to optimize these parameters to enhance efficacy through novel formulations. This review aims to analyze the approaches to drug delivery systems to encourage further research to optimize effectiveness. With this objective, research on drug delivery aspects of anti-allergy therapeutics was included and analyzed based on formulation/drug delivery technique, Food and Drug Administration approval limits, residence time, compatibility, pre-clinical efficacy, and potential for translational application. Conventional eye drops have concerns such as poor residence time and ocular bioavailability. The novel formulations have the potential to improve residence and bioavailability. However, the use of preservatives and the lack of regulatory approval for polymers limit the translational application. The review may assist readers in identifying novel drug delivery strategies and their limitations for the development of effective ophthalmic formulations for the treatment of ocular allergy.

Identification of core therapeutic targets for Monkeypox virus and repurposing potential of drugs against them: An in silico approach.

Monkeypox virus (mpox virus) outbreak has rapidly spread to 82 non-endemic countries. Although it primarily causes skin lesions, secondary complications and high mortality (1-10%) in vulnerable populations have made it an emerging threat. Since there is no specific vaccine/antiviral, it is desirable to repurpose existing drugs against mpox virus. With little knowledge about the lifecycle of mpox virus, identifying potential inhibitors is a challenge. Nevertheless, the available genomes of mpox virus in public databases represent a goldmine of untapped possibilities to identify druggable targets for the structure-based identification of inhibitors. Leveraging this resource, we combined genomics and subtractive proteomics to identify highly druggable core proteins of mpox virus. This was followed by virtual screening to identify inhibitors with affinities for multiple targets. 125 publicly available genomes of mpox virus were mined to identify 69 highly conserved proteins. These proteins were then curated manually. These curated proteins were funnelled through a subtractive proteomics pipeline to identify 4 highly druggable, non-host homologous targets namely; A20R, I7L, Top1B and VETFS. High-throughput virtual screening of 5893 highly curated approved/investigational drugs led to the identification of common as well as unique potential inhibitors with high binding affinities. The common inhibitors, i.e., batefenterol, burixafor and eluxadoline were further validated by molecular dynamics simulation to identify their best potential binding modes. The affinity of these inhibitors suggests their repurposing potential. This work can encourage further experimental validation for possible therapeutic management of mpox.

Ocular Delivery of Metformin for Sustained Release and in Vivo Efficacy.

Metformin is known to lower inflammation, independent of its anti-diabetic action. Thus, topical metformin can be a therapeutic strategy for managing ocular inflammation associated with diabetes. To achieve this and address the issues of ocular retention and controlled release an in situ gel of metformin was developed. The formulations were prepared using sodium hyaluronate, hypromellose, and gellan gum. The composition was optimized by monitoring gelling time/capacity, viscosity, and mucoadhesion. MF5 was selected as the optimized formulation. It showed both chemical and physiological compatibility. It was found to be sterile and stable. MF5 exhibited sustained release of metformin for 8h that fitted best with zero-order kinetics. Further, the release mode was found to be close to the Korsmeyer-Peppas model. Supported by an ex vivo permeation study, it showed potential for prolonged action. It showed a significant reduction in ocular inflammation that was comparable to that of the standard drug. MF5 shows translational potential as a safe alternative to steroids for managing ocular inflammation.

Quercetin against Emerging RNA Viral Diseases: Potential and Challenges for Translation.

Due to higher adaptability and mutability, there is always a possibility for RNA viral disease outbreaks. There are no approved antivirals for the majority of RNA viruses, including SARS-CoV-2, CHIKV, DENV, JEV, ZIKV, and EBOV. To treat these infections and prepare for future epidemics, it is necessary to identify effective therapeutic strategies with broad-spectrum actions against RNA viruses. Unregulated inflammation is the major cause of the severity associated with these viral diseases. Quercetin is a privileged molecule that is known to interfere at different levels of inflammatory response. Besides, it modulates pathways responsible for viral translation as well as the immune response of the host. It has also been found to inhibit replication by targeting critical targets of some of these viruses. Due to its abilities to inhibit viral targets, modulate host factors or a combination of both, quercetin has been demonstrated to help recover from some of these viral diseases in preclinical /clinical studies. Thus, it can be a drug candidate for application against a broad range of viral diseases. However, its translational value is limited by the lack of large-scale clinical studies. A major hurdle for oral application is poor solubility. Thus, developing a suitable form of quercetin can enable adequate bioavailability, leading to its translational application.

Effect of semicrystalline copolymers in solid dispersions of pioglitazone hydrochloride: in vitro-in vivo correlation.

OBJECTIVE: The study was aimed to improve the dissolution and bioavailability of developed stable amorphous solid dispersions (SDs) of pioglitazone hydrochloride (PGH), a poorly water-soluble drug. SIGNIFICANCE: Poor aqueous solubility of PGH was overcome by the design of SDs. Level A correlation demonstrated between in vitro release and bioavailability of PGH, suggest its biowaiver potential. METHODS: The effects of semicrystalline copolymers (poloxamer 407 and gelucire 50/13) and methods of preparations on dissolution behavior, in vivo performance, and stability of PGH SDs were investigated. All the SDs were characterized by FTIR, TGA, DSC, XRD, and SEM. RESULTS: FTIR and TGA showed the compatibility with the polymers. The significant change in melting pattern of the PGH observed in the DSC thermograms supported by XRD patterns & SEM indicated a change from a crystalline to an amorphous state. Gelucire 50/13 was observed to have greater ability to form SDs than poloxamer 407 in solvent evaporation method (SM). Prevention of recrystallization during storage suggested stability of the formulation. Gelucire 50/13 based SD, prepared by SM remarkably increased the dissolution within 15 min (87.27 ± 2.25%) and was supported by dissolution parameters (Q15, IDR, RDR, % DE, f1, f2). These SDs showed pH-dependent solubility. In vivo test showed significantly (p < .05) higher AUC0-t and Cmax, which were about 3.17 and 4.34 times that of the pure drug respectively. CONCLUSION: Gelucire 50/13 was found to be a suitable carrier for SM for preparation of SDs of PGH as evident from increased dissolution and bioavailability.

Effect of semicrystalline polymers on self-emulsifying solid dispersions of nateglinide: in vitro and in vivo evaluation.

This study was undertaken to improve solubility and bioavailability of nateglinide by preparation of stable self-emulsifying solid dispersions (SESDs). The influence of semicrystalline polymers (poloxamer 407, gelucire 50/13) and method of preparation on dissolution behavior, in vivo performance and stability of nateglinide SESDs were investigated. After optimization, SESDs were prepared at 1:5 weight ratio of nateglinide and polymer individually. All the SESDs were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. Aqueous solubility of nateglinide was enhanced by 91.82-fold. The SESDs (poloxamer 407-based solid dispersions) achieved rapid and complete drug release (∼100% within 45 min) at pH 2. The improved dissolution appeared to be well correlated with the enhanced bioavailability of nateglinide in rabbits. After oral administration of SESDs (poloxamer 407-based solid dispersions), Cmax and AUC of nateglinide were increased by ∼2.92 and 1.77-folds, respectively, signifying the effectiveness of solid dispersions to improve the bioavailability of nateglinide. Stability during storage was established to show prevention of recrystallization. In conclusion, SESDs with poloxamer 407 in solvent method appeared to be an economic and promising technique to improve the dissolution, bioavailability, and stability of nateglinide.