Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, 20993, USA.
Division of New Drug Product II, Office of New Drug Product, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20993, USA.
AAPS PharmSciTech. 2019 Jun 24;20(6):232. doi: 10.1208/s12249-019-1452-6.
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 (P) 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 P of naloxone by lowering the pH, and the P 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.
纳洛酮是一种具有高亲和力的阿片受体拮抗剂，正因为如此，它被用于阿片类药物过量的紧急治疗。最初，它只能作为注射产品使用。然而，为了便于给药，也出现了鼻内（IN）制剂。这些 IN 制剂含有防腐剂和稳定剂，如苯扎氯铵（BKC）、苯甲醇（BA）和乙二胺四乙酸（EDTA）。其中一些成分已知会影响药物的通透性。本研究专注于研究制剂变量（包括防腐剂、稳定剂和 pH 值的选择）对纳洛酮 IN 制剂渗透性和稳定性的影响。纳洛酮的体外渗透性通过 EpiAirway™组织安装的 Ussing 室进行评估。BKC 在非常低的浓度下显著提高了纳洛酮的表观渗透性（P）（p<0.05），而 BA 在更高的浓度下产生了类似的增强作用。EDTA 通过降低 pH 值降低了纳洛酮的 P 值，并且当制剂 pH 值从 6.0 降低至 4.0 时，纳洛酮的 P 值降低了约 51 倍。然而，产品稳定性仅在 pH 值低于 5.0 时才是最佳的。因此，对于 IN 制剂，选择制剂成分、缓冲剂和 pH 值是一个平衡行为，以实现所需的渗透性和最佳的稳定性，从而使纳洛酮 IN 制剂具有合理的保质期。
