Bioavailability of diazepam from aqueous-organic solution, submicron emulsion and solid lipid nanoparticles after rectal administration in rabbits

• Published in: European journal of pharmaceutics and biopharmaceutics 2001-09, Vol.52 (2), p.159-163
• Main Authors: SZNITOWSKA, Malgorzata, GAJEWSKA, Monika, JANICKI, Stanislaw, RADWANSKA, Aleksandra, LUKOWSKI, Gerold
• Format: Article
• Language: English
• Subjects: Administration, Rectal; Animals; Anticonvulsants - administration & dosage; Anticonvulsants - blood; Anticonvulsants - pharmacokinetics; Biological and medical sciences; Biological Availability; Capsules; Diazepam - administration & dosage; Diazepam - blood; Diazepam - pharmacokinetics; Emulsions; General pharmacology; Lipids - pharmacokinetics; Medical sciences; Neuropharmacology; Particle Size; Pharmaceutical Solutions - administration & dosage; Pharmaceutical Solutions - pharmacokinetics; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rabbits
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/S0939-6411(01)00157-6

The bioavailability of diazepam in rabbits after rectal administration of three formulations: organic-aqueous Relsed rectal solution (containing ethanol, benzyl alcohol and propylene glycol), submicron emulsion and solid lipid nanoparticles (SLN), was studied. Submicron emulsion contained MCT oil (20% w/w), egg lecithin and poloxamer; SLN were prepared with cetyl palmitate 10% w/v and non-ionic emulsifying agent, Plantacare. All formulations contained 4 mg/ml of diazepam and the dose administrated to rabbits was 2 mg/kg. In both submicron preparations nearly the same mean size of the dispersed particles (201-206 nm) and the fraction of the free drug in aqueous phase (0.9-1.5%) was determined. Besides very moderate prolongation of drug release, the submicron emulsion as a vehicle did not alter pharmacokinetics of diazepam when compared with the solution: the mean C(max) was 48.9+/-24.0 and 49.5+/-17.0 ng/ml, and area under the curve was 134.0+/-42.3 and 186.8+/-59.8 ng h/ml, for solution and emulsion, respectively. The low relative bioavailability, 47% compared to the solution, was observed after administration of SLN. Transmission electron microscopy pictures revealed that some of diazepam is present on the surface of the SLN and this fraction was immediately absorbed, while the diffusion of the drug in the solid core was not efficient enough to allow a complete release. It may be concluded that submicron emulsion may be a good choice of an ethanol-free drug formulation, but lipid matrix, which is solid at body temperature, is not advantageous system for diazepam rectal delivery, even if delivered as a submicron dispersion.