Effect of Formulation Variables on the Nasal Permeability and Stability of Naloxone Intranasal Formulations.

ABSTRACT

Naloxone is an opioid antagonist with high affinity for µ-opioid receptor, and for this reason it is used for the emergency treatment of opioid overdose. Originally, it was available only as an injectable product. However, for the ease of administration, intranasal (IN) formulations have also become available. These IN formulations contain preservatives and stabilizers such as benzalkonium chloride (BKC), benzyl alcohol (BA), and ethylenediaminetetraacetic acid (EDTA). Some of these ingredients are known to affect permeability of drugs. This study focuses on investigating the effect of formulation variables including choice of preservatives, stabilizer, and pH on the permeability and stability of naloxone IN formulations. The in vitro permeability of naloxone was evaluated employing EpiAirway™ tissue-mounted Ussing chambers. BKC was found to enhance the apparent permeability (Papp) of naloxone significantly (p < 0.05) at very low concentration, while BA caused similar enhancement at a much higher concentration. EDTA was found to decrease Papp of naloxone by lowering the pH, and the Papp of naloxone was found to decrease approximately 51-fold with the decrease in formulation pH from 6.0 to 4.0. The product stability was, however, found optimal only below pH 5.0. Thus, selection of formulation ingredients, buffering agent, and pH of IN formulation is a balancing act for achieving desired permeability and optimal stability to achieve reasonable shelf life of naloxone IN formulation.