Polymeric nanoencapsulation of zaleplon into PLGA nanoparticles for enhanced pharmacokinetics and pharmacological activity.

Yusuf A Haggag,Ahmed Kh Abosalha,Murtaza M Tambuwala,Ebtessam A Essa,Sanaa A El‐Gizawy,Enass Y Osman,Ahmed A Donia

doi:10.1002/bdd.2255

Yusuf A Haggag, Ahmed Kh Abosalha + Show 5 more

Open Access

https://doi.org/10.1002/bdd.2255

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Abstract

Zaleplon (ZP) is a sedative and hypnotic drug used for the treatment of insomnia. Despite its potent anticonvulsant activity, ZP is not commonly used for the treatment of convulsion since ZP is characterized by its low oral bioavailability as a result of poor solubility and extensive liver metabolism. The following study aimed to formulate specifically controlled release nano‐vehicles for oral and parenteral delivery of ZP to enhance its oral bioavailability and biological activity. A modified single emulsification–solvent evaporation method of sonication force was adopted to optimize the inclusion of ZP into biodegradable nanoparticles (NPs) using poly (dl‐lactic‐co‐glycolic acid) (PLGA). The impacts of various formulation variables on the physicochemical characteristics of the ZP‐PLGA‐NPs and drug release profiles were investigated. Pharmacokinetics and pharmacological activity of ZP‐PLGA‐NPs were studied using experimental animals and were compared with generic ZP tablets. Assessment of gamma‐aminobutyric acid (GABA) level in plasma after oral administration was conducted using enzyme‐linked immunosorbent assay. The maximal electroshock‐induced seizures model evaluated anticonvulsant activity after the parenteral administration of ZP‐loaded NPs. The prepared ZP‐PLGA NPs were negatively charged spherical particles with an average size of 120–300 nm. Optimized ZP‐PLGA NPs showed higher plasma GABA levels, longer sedative, hypnotic effects, and a 3.42‐fold augmentation in oral drug bioavailability in comparison to ZP‐marketed products. Moreover, parenteral administration of ZP‐NPs showed higher anticonvulsant activity compared to free drug. Oral administration of ZP‐PLGA NPs achieved a significant improvement in the drug bioavailability, and parenteral administration showed a pronounced anticonvulsant activity.

Highlights

Zaleplon (ZP) is commonly used as a sedative and hypnotic drug with potent anticonvulsant activity
The current study was conducted to investigate the impact of different formulation variables on the various characteristics of the ZP nanoparticles, such as nanoparticles size, surface morphology, and entrapment efficiency
In vitro release to optimize the fabrication of ZP‐PLGA NPs having an appropriate size and high drug loading for controlled pharmacological action was investigated

Summary

| INTRODUCTION

Zaleplon (ZP) is commonly used as a sedative and hypnotic drug with potent anticonvulsant activity. PNP drug delivery systems can improve the oral bioavailability of poorly soluble drugs, sustain its biological activity, and improve drug stability (Haggag et al, 2020a). Polymeric nanocarriers are more stable in vivo, with high drug loading capacities, as well as controlled or triggered release of drugs (Kamaly et al, 2012) According to these unique properties, polymeric nanomaterials are well positioned in our study to provide a novel solution for ZP oral and parenteral delivery. The current study is the first to adopt the formulation of PLGA NPs encapsulating ZP to investigate the bioavailability and pharmacological activity of ZP‐PLGA NPs in vivo following oral or parenteral administration. The effect of various formulation variables, such as the polymer amount, stabilizer concentration, and sonication time, on the characteristics of the nanoparticles, release profiles, in vivo pharmacokinetic behavior, and in vivo biological activity of encapsulated ZP were investigated in this study.

| MATERIALS AND METHODS

| Evaluation of anticonvulsant activity

| RESULTS AND DISCUSSION

| CONCLUSIONS