Scientific Presentation – T1330

Amorphous Powder for Nasal Delivery:

Intranasal Naloxone Powder for Treating Opioid Overdose.

Purpose

The nasal route of administration has several benefits for systemic drug delivery, including non-invasive dosing, rapid absorption, and no first-pass metabolism. However, liquid nasal sprays have some limitations, e.g:

Poor chemical stability in aqueous solutions
Requirement for good solubility of the API
Suboptimal and variable absorption due to swallowing

We explored the possibility of developing a rapidly dissolving, spray-dried nasal powder formulation to overcome the limitations of liquid formulations while maintaining the advantages of the nasal route of administration.

Objectives

Development and characterization of spray-dried nasal powder formulations of naloxone compared with a commercially available liquid nasal spray
Comparison of pharmacokinetic properties of novel powder formulations with the liquid nasal spray

Methods

Four compositions (A, B, C, and D; see Table 1), all presented as amorphous solid dispersions (ASD) of naloxone in combination with various excipients, were spray-dried. The powders were characterized using laser diffraction, XRPD, and HPLC. Stability was monitored for 12 months under long-term conditions (25°C/60% RH) and for 6 months under accelerated conditions (40°C/75% RH).

Table 1

Compositions of Formulation A, B, C and D (per Dosage Unit)

Component	A (mg)	B (mg)	C (mg)	D (mg)
Naloxone HCl	4.00	4.00	4.00	8.00
Lactose	17.72	17.50	15.56	13.54
Sucrose Laurate	-	0.23	-	-
PVP	-	-	2.27	-
Residual Water	0.91	0.91	0.91	0.90

Pharmacokinetics of the novel powder formulations, administered as a single dose using an Aptar UDS powder device, were compared with a commercially available liquid nasal spray (Narcan^®) in a five-period crossover bioavailability study in healthy volunteers (n=20).

Results

Figure 1: Naloxone Plasma Concentration vs. Time

Comparative Bioavailability of Powder Formulations vs. Liquid Nasal Spray

Nasal powders showed significantly higher plasma concentrations of naloxone, a longer duration of elevated plasma levels, and more rapid absorption compared with Narcan®
Formulation B (containing sucrose laurate) demonstrated the highest bioavailability and the most rapid absorption, with approximately 84% higher total exposure and 175% higher peak exposure compared with Narcan®
All formulations were well tolerated

Powder Characterization and Stability

Spray drying produced free-flowing powders with a narrow particle size distribution suitable for nasal administration
All four compositions were chemically stable under both long-term and accelerated conditions, with related substances below 0.3% at study completion
All formulations remained physically stable and retained their amorphous state throughout the stability studies

Table 2: Physicochemical and Stability Data (Total Related Substances Shown)

Composition	Dv,10 (µm)	Dv,90 (µm)	XRPD	12M 25/60 (%RS)	6M 40/75 (%RS)
A	15	44	amorphous	0.11	0.10
B	15	55	amorphous	0.19	0.19
C	17	57	amorphous	0.14	0.28
D	17	58	amorphous	0.08	0.08

Table 3: Pharmacokinetic Parameters (Average Values, n=20, Geo.CV%)

PK Parameters	A	B	C	D	Narcan®
AUCt (h*ng/ml)	10.7 (24.8)	14.7 (18.5)	10.9 (27.6)	16.9 (35.9)	7.99 (44.1)
AUCinf (h*ng/ml)	10.8 (25.3)	14.8 (18.6)	11.1 (28.7)	17.1 (35.9)	8.06 (44.6)
Cmax (ng/ml)	8.43 (44.2)	15.6 (46.5)	8.94 (35.4)	12.1 (45.4)	5.67 (55.8)
Tmax (min)	20 (6.5, 40)	15 (7, 30)	15 (7, 30)	20 (10, 40)	20 (7, 30)
T½ (min)	74.6 (30.0)	76.1 (22.8)	88.3 (43.6)	85.5 (20.0)	84.2 (23.2)

Conclusions

Amorphous spray-dried naloxone nasal powders with appropriate particle size distribution for nasal delivery were successfully developed, with limited risk of lung exposure
All powders demonstrated excellent chemical and physical stability, even after 6 months under accelerated conditions (40°C/75% RH)
Naloxone nasal powders showed improved systemic absorption and reduced variability compared with a commercially available liquid nasal spray