Purpose: With a significant rise in opioid overdoses in the US, due to an increased misuse of highly potent synthetic opioids such as fentanyl1, we set out to develop a rapid and more powerful rescue medication. The objective was to develop a stable high-dose powder-based nasal naloxone product with equivalent or superior pharmacokinetics compared to commercially available nasal liquid sprays2,3. Methods: Four compositions A, B, C, and D (Table 1.) all presented as an amorphous solid dispersion of naloxone in combination with various ingredients, were produced using spray drying. The powders were characterized by laser diffraction, XRPD, HPLC and the stability were followed for 12 months at long term storage (25°C/60%R.H.) and 6 months at accelerated storage conditions (40°C/75%R.H.)4. The stability studies were performed for the bulk powder and nasal devices filled with the formulation (UDS powder device, Aptar Pharma, France). The formulations were studied in a cross-over, comparative, bioavailability study in healthy volunteers using Narcan® Nasal Spray 4mg as reference. Results: The spray drying process yielded free flowing powders with a narrow particle size distribution, Dv,10 of 15-17 µm, Dv,90 of 44-58 µm and 0% < 5 µm, i.e. particle size distribution suitable for effective nasal deposition5. All four compositions were found chemically and physically stable at both long term and accelerated conditions (Table 2.). In the comparative bioavailability study, the powders were well tolerated and showed substantially higher plasma concentrations of naloxone, sustained duration of elevated plasma concentrations and equivalent or superior onset time when compared to Narcan® (Figure 1.). Conclusion: The combination of a remarkable stability with the rapid dissolution in minimal amounts of liquid, seen for all four naloxone powders, are ideal properties for a nasally administered emergency medication to reverse opioid overdoses. The powders provided for a higher exposure, faster onset and lower variability compared to the liquid naloxone reference, while still being both chemically and physically stable when stored in elevated temperatures. The powder-based technology, that is included in the naloxone powders, has subsequently demonstrated unexpectedly good stability results for several other APIs, including the highly unstable compound, epinephrine. This combination of positive results has led to the conclusion that the technology has great potential as a drug delivery platform (amorphOX®). References: 1. Volkow, N. D. (2021). The epidemic of fentanyl misuse and overdoses: challenges and strategies. World Psychiatry, 20(2), 195. 2. Trenkel, M., & Scherließ, R. (2021). Nasal Powder Formulations: In-Vitro characterisation of the impact of powders on nasal residence time and sensory effects. Pharmaceutics, 13(3), 385. 3. Wermeling, D. P. (2013). A response to the opioid overdose epidemic: naloxone nasal spray. Drug delivery and translational research, 3(1), 63-74. 4. ICH Harmonised Tripartite Guideline (2003). Stability testing of new drug substances and products Q1A(R2). ICH Guidelines, ICH Q1A (R2) 5. Henriques, P., Fortuna, A., & Doktorovová, S. (2022). Spray dried powders for nasal delivery: Process and formulation considerations. European Journal of Pharmaceutics and Biopharmaceutics. Table 1. Composition A, B,C and D.
Table 2. Physical and chemical stability data.
Figure 1. PK data from OX124-001 comparative n=20 clinical study.
.jpg)
.jpg)
.jpg)