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

Biopharm Drug Dispos. 2021 Jan;42(1):12-23. doi: 10.1002/bdd.2255. Epub 2021 Jan 2.


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.

Keywords: GABA; PLGA; anticonvulsant activity; formulation variables; nanoparticles; optimization; oral bioavailability; pharmacokinetics; zaleplon.

MeSH terms

  • Acetamides / chemistry*
  • Acetamides / pharmacokinetics
  • Acetamides / pharmacology
  • Animals
  • Anticonvulsants / chemistry*
  • Biological Availability
  • Hypnotics and Sedatives / pharmacology
  • Male
  • Nanoparticles / chemistry*
  • Polylactic Acid-Polyglycolic Acid Copolymer / chemistry*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology
  • Rabbits
  • Rats
  • gamma-Aminobutyric Acid / blood


  • Acetamides
  • Anticonvulsants
  • Hypnotics and Sedatives
  • Pyrimidines
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • gamma-Aminobutyric Acid
  • zaleplon

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