A Short Review on the Intranasal Delivery of Diazepam for Treating Acute Repetitive Seizures

Abstract

Benzodiazepines such as diazepam, lorazepam and midazolam remained the mainstay of treatment for acute repetitive seizures (ARS). The immediate care for ARS should often begin at home by a caregiver. This prevents the progression of ARS to prolonged seizures or status epilepticus. For a long time and despite social objections rectal diazepam gel remained only FDA-approved rescue medication. Intranasal administration of benzodiazepines is considered attractive and safe compared with rectal, buccal and sublingual routes. Intranasal delivery offers numerous advantages such as large absorptive surface area, bypass the first-pass metabolism and good patient acceptance as it is needle free and painless. Recent clinical studies have demonstrated that diazepam nasal spray (NRL-1; Valtoco®, Neurelis Inc.,San Diego, CA, USA) showed less pharmacokinetic variability and reliable bioavailability compared with the diazepam rectal gel. Diazepam nasal spray could be considered as a suitable alternative for treating seizure emergencies outside the hospital. This review summarizes the treatment options for ARS and findings from clinical studies involving intranasal diazepam for treating seizure emergencies.

A Physiologically Based Pharmacokinetic Model for Predicting Diazepam Pharmacokinetics after Intravenous, Oral, Intranasal, and Rectal Applications

“…Diazepam is considered effective for intranasal administration due to its physicochemical properties and provides extended action compared with other benzodiazepines [ 59 ]. This intranasal route for diazepam is more attractive for the user compared with some other formulations, i.e., rectal [ 11 ]. For intranasal PK profiles of diazepam, the abovementioned strategy of IV and oral formulations were implemented with additional parameters, i.e., f a and k a .…”

“…Ideally, the treatment option should be chosen based on disease type, rapid onset of action, easy administration, and extended duration with minimal adverse effects [ 11 ]. In terms of route of administration, diazepam has various pros and cons, where IV administration has a swift onset of action, but at the same time, it is not convenient in the ambulatory setting, and on the other hand, the oral route has slow absorption and administration issues, i.e., swallowing in seizure [ 16 ].…”

“…Diazepam is commonly employed as an anxiolytic and anticonvulsant in intravenous (IV), oral, intramuscular, intranasal, and rectal dosage forms [ 3 , 4 ]. It is administered through different routes of drug administration for the management of acute and chronic diseases [ 11 ]. Parenteral diazepam is preferred in hospitals because of its rapid action (especially to suppress seizures), but this route of administration is not convenient in ambulatory settings and is also associated with serious side effects, i.e., hypotension, dysrhythmias, etc.…”

Development of a Cyclodextrin-Based Mucoadhesive-Thermosensitive In Situ Gel for Clonazepam Intranasal Delivery

“…In particular, intranasal delivery was revealed to be an excellent strategy to delivery drugs directly to the central nervous system (CNS), through the olfactory and trigeminal nerve pathways, bypassing the blood–brain barrier (BBB) [ 10 ]. The nose-to-brain pathway seems to be especially beneficial for the treatment of different kinds of neurological brain disorders [ 10 , 11 ], and in particular in the treatment of epileptic seizure emergencies by benzodiazepines [ 12 , 13 ]. Commercial intranasal formulations of diazepam and midazolam have been recently approved [ 13 ].…”

“…The nose-to-brain pathway seems to be especially beneficial for the treatment of different kinds of neurological brain disorders [ 10 , 11 ], and in particular in the treatment of epileptic seizure emergencies by benzodiazepines [ 12 , 13 ]. Commercial intranasal formulations of diazepam and midazolam have been recently approved [ 13 ]. Numerous additional benefits, such as avoidance of first-pass metabolism, fast onset of action, reduced side-effects, ease of access and quick self-administration, as well as the possibility to be administered to patients in unconscious state, are associated to this administration route.…”