Mechanistic analysis of Zein nanoparticles/PLGA triblock in situ forming implants for glimepiride

Abstract

Objectives The study aims at applying pharmaceutical nanotechnology and D-optimal fractional factorial design to screen and optimize the high-risk variables affecting the performance of a complex drug delivery system consisting of glimepiride–Zein nanoparticles and inclusion of the optimized formula with thermoresponsive triblock copolymers in in situ gel. Methods Sixteen nanoparticle formulations were prepared by liquid–liquid phase separation method according to the D-optimal fractional factorial design encompassing five variables at two levels. The responses investigated were glimepiride entrapment capacity (EC), particle size and size distribution, zeta potential, and in vitro drug release from the prepared nanoparticles. Furthermore, the feasibility of embedding the optimized Zein-based glimepiride nanoparticles within thermoresponsive triblock copolymers poly(lactide- co -glycolide)-block-poly(ethylene glycol)-block-poly(lactide- co -glycolide) in in situ gel was evaluated for controlling glimepiride release rate. Results Through the systematic optimization phase, improvement of glimepiride EC of 33.6%, nanoparticle size of 120.9 nm with a skewness value of 0.2, zeta potential of 11.1 mV, and sustained release features of 3.3% and 17.3% drug released after 2 and 24 hours, respectively, were obtained. These desirability functions were obtained at Zein and glimepiride loadings of 50 and 75 mg, respectively, utilizing didodecyldimethylammonium bromide as a stabilizer at 0.1% and 90% ethanol as a common solvent. Moreover, incorporating this optimized formulation in triblock copolymers-based in situ gel demonstrated pseudoplastic behavior with reduction of drug release rate as the concentration of polymer increased. Conclusion This approach to control the release of glimepiride using Zein nanoparticles/triblock copolymers-based in situ gel forming intramuscular implants could be useful for improving diabetes treatment effectiveness.

A PLGA-reinforced PEG in situ gel formulation for improved sustainability of hypoglycaemic activity of glimepiride in streptozotocin-induced diabetic rats

“…The major obstacle in the design of ISG formulations is the high initial burst of the drug after administration 6 , 13 – 16 . Accordingly, the goal was to sustain the release of GMD from the ISG formulation by controlling its initial burst from the designed formula.…”

“…At the same concentrations of both X 2 and X 3 , as the concentration of PLGA increased from 20 to 30%, Y 3 decreased from 2972.38 in F6 to 2517.45 µg in F7, from 2928.37 in F12 to 2181.8 µg in F10, and from 3039.05 in F11 to 2570.78 µg in F4. This observation can be attributed to the presence of PLGA at higher concentrations, which hastens the solidification of the formulation and subsequently reduces the leaching of GMD to the surrounding phase 6 , 15 , 17 , 18 . To a certain extent, the same finding was attained in the initial burst after 2 h in the previous formulations.…”

“…In vitro GMD release from the ISG formulations was investigated via the modified dialysis method, as described previously 6 . In brief, a GMD formula equivalent to 3 mg was injected into a dialysis tube (Sigma-Aldrich, St. Louis, MO.…”

“…Previous studies in our laboratory investigated the development of sustained-release formulations of GMD. These studies include the development of the triblock in situ gel (ISG) implant and self-nanoemulsifying, liposomal and ethosomal transdermal films 6 – 9 . In situ gel (ISG) formulations with biodegradable polymers are one of the applied methods for sustained delivery of drugs.…”

Preparation of Parenteral in situ Gel Formulation Based on smart PLGA polymer: Concepts to Decrease Initial Drug Burst and extend drug release

“…The authors reported 3.3 % and 17.3 % drug release after 2 and 24 h, respectively. This ISG system exhibited pseudoplastic behaviour with a reduction of glimepiride release rate as the concentration of the polymer was increased [57].…”