Eudragit S100 microspheres as a novel chronopharmaceutical for zaleplon delivery

Insomnia is one of most common sleep disorders affecting about 30% of adult population, while its prevalence is even higher among elderly and psychiatric patients. Therefore, the aim of this work was to develop pH-responsive microspheres of zaleplon (ZAL) with delayed drug release, as a novel chronopharmaceutical drug delivery system, suitable for treatment of a specific type of insomnia characterised by premature awaking and inability to fall asleep again. ZAL is rapidly cleared from the body (t1/2=1h), therefore it would be suitable for development of such formulation. Eudragit® S100 (ES100), a 1:2 methacrylatic acid and methylmethacrylate copolymer, with pH dependent solubility (pH>7) was used as the base of this formulation. Different microspheres were prepared by spray-drying the feed solution prepared in 0.96% aqueous NH4HCO3 medium, using Buchi mini spray drier at air flow of 400 NL/h, feed flow of 5 mL/min, inlet and outlet air temperature of 100 and 60°C, respectively. Prepared microspheres were further thermally treated at 85°C for 3.5 h to regenerate the ES100 insoluble form. Drug loading was assessed after extraction of ZAL with hydro-methanolic medium followed by spectrophotometrically drug determination at 335 nm. SEM micrographs were obtained by sputtering the samples with a thin layer of gold/palladium. FTIR spectra were obtained by the KBr method, while XRPD spectra were recorded using CuKα radiation and a graphite monochromator in the 5-40 2ϴ°. The in vitro dissolution studies were performed by introducing the sample containing 10 mg of ZAL in 250 mL of simulated gastric (pH 1.2) or intestinal (pH 6.8) medium thermostated at 37°C and stirred at 50 rpm. The withdrawn aliquots at predetermined time intervals were analyzed spectrophotometrically at 335 nm for the drug content. Microparticles were prepared by spray-drying of ZAL/ES100 dispersion from aqueous NH4HCO3 solution (MS1), transforming ES100 into soluble, thermolabile ammonium salt. After spray-drying procedure, ES100 was regenerated by thermal treatment at 85° for 3.5h, eliminating completely soluble ammonium salt from the microparticles, as confirmed by FTIR analysis (data not shown). In all preparations, high ZAL encapsulation efficiency (95.5-99.6%) into microspheres with mean particle diameter of 1.62-1.76 μm was achieved. However, in vitro dissolution profile of MS1 showed rather high drug leaking in the simulated gastric medium 24.7±0.5% of ZAL in 2h. XRPD analysis showed that this behaviour could be attributed to a thermally induced amorphization of ZAL into ES100 matrix. Therefore MS1 formulation was further optimised through addition of 10% of GMS (MS2), which sufficiently reduced unwanted drug release in simulated gastric medium to only 1.1±0.3% of encapsulated drug dose, but in the same time, reduced significantly the drug release rate in simulated intestinal medium (pH 6.8) to only 19.1 μg/min (Fig. 1). To overcome this obstacle, randomly methylated β-cyclodextrin (RAMEB) was added to the feed solution in quantities which would result in complexation of 25, 50 and 100% of the drug dose (MS3, MS4 and MS5, respectively).The optimal MS formulation contained 50% of the drug dose in form of an inclusion complex with RAMEB, resulting in an acceptable drug release level in the simulated gastric medium (pH 1.2) of about 10% of the ZAL doze after 2h and a zero-order release (r2>0.98, k=155.0 μg/min) in simulated intestinal medium (pH 6.8).