Single- and repeated-dose local toxicity in the nasal cavity of rabbits after intranasal administration of different glycols for formulations containing benzodiazepines

To furnish a systemic effect after intranasal administration, a formulation must contain the therapeutic dose in no more than 150 mu L, the maximum vo lume that can be applied as a single administration in one nostril in man. The objectives of these studies were to examine the local toxicity of formu lations containing benzodiazepines and to document the effects to support c linical trials in man. After stability, pharmacological and pharmacokinetic studies of several ben zodiazepine formulations, we studied nasal toxicity after single and repeat ed administration to rabbits of poly(ethylene glycol) 200, tetra(ethylene g lycol), glycofurolum and mixtures of these vehicles both with and without b enzodiazepines. Single-dose studies with examinations 5 or 10 min after app lication were undertaken with poly(ethylene glycol), tetra(ethylene glycol) , glycofurolum and tetra(ethylene glycol)-glycofurolum in the ratio 95:5; t he reactions were similar to that after physiological saline. A 14-day repe ated-dose study was conducted with diazepam, lorazepam and flunitrazepam fo rmulations in poly(ethylene glycol), and flunitrazepam in poly(ethylene gly col)-glycofurolum in the ratio 70:30; the two vehicles without any benzodia zepine were also examined. Microscopic study revealed mild changes only in the treated groups. A, final four-week study was conducted with repeated ad ministration of clonazepam formulated in tetra(ethylene glycol)-glycofurolu m in the ratio 95:5; microscopy revealed mild changes after three 150-mu L doses daily, but no abnormalities after one or three 100-mu L doses daily. It was concluded that these three solvents individually or as mixtures resu lted in only mild local toxicity and might be acceptable as vehicles in nas al preparations of benzodiazepines and other non-irritating drags for short -term use in man.