Single- and Repeated-dose Local Toxicity in the Nasal Cavity of Rabbits after Intranasal Administration of Different Glycols for Formulations Containing Benzodiazepines

Abstract

To furnish a systemic effect after intranasal administration, a formulation must contain the therapeutic dose in no more than 150 μL, the maximum volume 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 formulations containing benzodiazepines and to document the effects to support clinical trials in man. After stability, pharmacological and pharmacokinetic studies of several benzodiazepine formulations, we studied nasal toxicity after single and repeated administration to rabbits of poly(ethylene glycol) 200, tetra(ethylene glycol), glycofurolum and mixtures of these vehicles both with and without benzodiazepines. Single‐dose studies with examinations 5 or 10 min after application were undertaken with poly(ethylene glycol), tetra(ethylene glycol), glycofurolum and tetra(ethylene glycol)‐glycofurolum in the ratio 95:5; the reactions were similar to that after physiological saline. A 14‐day repeated‐dose study was conducted with diazepam, lorazepam and flunitrazepam formulations in poly(ethylene glycol), and flunitrazepam in poly(ethylene glycol)‐glycofurolum in the ratio 70:30; the two vehicles without any benzodiazepine were also examined. Microscopic study revealed mild changes only in the treated groups. A final four‐week study was conducted with repeated administration of clonazepam formulated in tetra(ethylene glycol)‐glycofurolum in the ratio 95:5; microscopy revealed mild changes after three 150‐μL doses daily, but no abnormalities after one or three 100‐μL doses daily. It was concluded that these three solvents individually or as mixtures resulted in only mild local toxicity and might be acceptable as vehicles in nasal preparations of benzodiazepines and other non‐irritating drugs for short‐term use in man.

Nasal administration of opioids for pain management in adults

“…Local toxicity of the formulation must also be considered. In general, penetration enhancers have a potential for toxicity, and might be expected to induce local irritation (45). The cost of possible local irritation or toxicity should be weighed against potential benefits.…”

Development of a Rapid Method for the PEGylation of Adenoviruses with Enhanced Transduction and Improved Stability under Harsh Storage Conditions

“…PEG is an uncharged, hydrophilic, linear polymer that is nonimm unogenic and has a low order of toxicity (Montaguti et al, 1994;Hjortkjaer et al, 1999). PEG is approved by the Food and Drug Administration (FDA) for use in drugs (parenterals, topicals, suppositories, nasal sprays), foods, and cosmetics.…”

Intracavernous application of diazepam: An alternative route of the seizure treatment − an experimental study in rabbits

“…More recently, the nasal route has received a great deal of attention as a convenient and reliable route, and it was investigated for the systemic administration of DZ 19−23 . One of the limitations of this method is that a small administration volume is required and applicable; it has been reported that it is not generally possible to administer a drug more than approximately 150 µL per each application; above this volume, the formulation can be drained out into the pharynx and swallowed 20 .…”