Development of Eudragit® S100 based pH-responsive microspheres of zaleplon by spray-drying: Tailoring the drug release properties

• pH-responsive microspheres were prepared by spray-drying of alkaline ES100/ZAL solution.
• Additional thermal treatment at 85 °C was used to regenerate the ES100 in the insoluble form.
• Unwanted ZAL release at pH 1.2 was reduced by the addition of 10% GMS.
• The ZAL release at pH 6.8 was modulated by cyclodextrin complexation of 50% of drug dose.
• The optimized formulation presented zero-order drug release kinetic (k0 = 155 μg min− 1).

The aim of this work was to develop Eudragit® S100 (ES100) based pH-responsive microspheres of zaleplon (ZAL) as a potential delivery system for treatment of an insomnia characterised by premature awaking and inability to fall asleep again. Microspheres were prepared by spray-drying of ZAL/ES100 dispersion from ethanolic (MS1) or 0.96% aqueous NH4HCO3 solution (MS2). In second case ES100 was first transformed into soluble, thermolabile ammonium salt and then regenerated by an additional thermal treatment at 85 °C for 3.5 h after spray-drying, as confirmed by FTIR. Preparation from ethanolic medium (MS1) resulted in higher preparation yield (75.14% vs. 56.55%; p < 0.05), while in both cases high encapsulation efficiency (91.1 and 95.5%) of drug into microspheres of 1.71–1.76 μm was achieved. However, MS1 were characterised by significant drug leaking in the simulated gastric medium (81.7 ± 2.2% of drug dose in 2 h), while MS2 formulation released about 24.7 ± 0.5% of ZAL (p < 0.01). DSC and XRPD analysis showed that this behaviour could be attributed to a thermally induced ZAL amorphization into ES100 matrix, but also to a sponge-like structure of MS1, while spherical MS2 offered better protection of encapsulated drug. Therefore MS2 were further optimized through addition of Eudragit® NE30D, glyceryl monostearate (GMS) and randomly methylated β-cyclodextrin (RAMEB). The optimal formulation contained ES100, 10% of GMS and 50% of the drug dose in form of inclusion complex with RAMEB, resulting in an acceptable drug release level at pH 1.2 of about 10% of the ZAL dose after 2 h and a zero-order release (r2 > 0.98, k = 155.0 μg/min) at pH 6.8.

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