engleski

Preparation and characterisation of binary and ternary cyclodextrin complexes of zaleplon

Zaleplon (ZAL) is a non-benzodiazepine hypnotic agent which in 10 mg doses is indicated for the short-term treatment of insomnia. Unlike benzodiazepines, ZAL has a low potential for abuse and it does not cause rebound insomnia or other discontinuation effects. After oral administration the drug is extensively metabolised into pharmacologically inactive metabolites, resulting in an absolute oral bioavailability of only 30%. Furthermore, the ZAL absorption might be significantly impaired when compound is administrated with a high fat meal. In order to overcome such limitations, we have used a cyclodextrin technology. The aim of the work was to investigate the potential synergistic effect of water-soluble polymers (hypromellose, HPMC and polyvinylpyrrolidone, PVP) on zaleplon complexation with different cyclodextrin derivatives (β-cyclodextrin, βCD and randomly methylated β-cyclodextrin, RAMEB) in solution and in solid state. A further aim was to validate the applicability of prepared complexes in development of an immediate-release oral formulation of ZAL. Addition of HPMC to the complexation medium improved ZAL complexation and solubilization with RAMEB (KZAL/RAMEB=156±5 M-1 and KZAL/RAMEB/HPMC=189±8 M-1), while such effect was not observed for βCD (KZAL/βCD=112±2 M-1 and KZAL/βCD/HPMC=119±8 M-1). Although PVP increased the ZAL aqueous solubility for 18.5%, it did not show any synergistic effects on ZAL solubilization with cyclodextrins tested. Binary and ternary complexes of ZAL with βCD, RAMEB and HPMC were prepared by spray-drying. Solid-state NMR spectroscopy, supported by differential scanning calorimetry, X-ray powder diffraction and scanning electron microscopy confirmed inclusion complex formation in all binary and ternary samples. In vitro dissolution rate followed the rank ZAL/RAMEB/HPMC > ZAL/RAMEB = ZAL/βCD/HPMC > ZAL/βCD >>ZAL, clearly demonstrating the superior performance of RAMEB on ZAL complexation in the solid state and its synergistic effect with HPMC on the drug solubility. Surprisingly, when loaded into tablets made with insoluble microcrystalline cellulose, the positive effect of RAMEB complexes on drug dissolution was absent, because HPMC and RAMEB acted as a binders inside tablets, prolonging their disintegration. Contrariwise, the formulation with mannitol, a soluble excipient, containing ternary RAMEB complex released the complete drug-dose in only 5 min, clearly demonstrating its suitability in development of immediate-release oral formulation of ZAL.

zaleplon; cyclodextrin; solid-state analysis; immediate-release formulation

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