Spray-freeze-drying aprepitant with hydroxypropyl cellulose increases nasal bioavailability

Abstract

The design of free-flowing lyophilized powders by spray-freeze-drying (SFD) enables novel therapeutic applications, including nasal administration. In this study, a non-aqueous SFD approach using dimethyl sulfoxide (DMSO) as the spray solvent was investigated. Low-viscosity hydroxypropyl cellulose grades (HPC-SSL and HPC-UL) were employed as excipients to produce rapidly dissolving, porous, amorphous aprepitant powders at different drug-to-polymer ratios.

The resulting spherical particles contained amorphous aprepitant and exhibited sizes between 250 μm and 500 μm. In vitro dissolution at pH 7.0 showed rapid drug release, with maximum dissolution achieved after 3 min for aprepitant/HPC-UL at a 20/80 ratio, exceeding the corresponding physical mixture by 2- to 3-fold. Film-cast amorphous solid dispersions (ASDs) reached comparable drug concentrations but exhibited slower dissolution. Formulations containing HPC-SSL showed higher supersaturation levels but reduced dissolution rates. Increasing drug loading to a 40/60 ratio led to a marked delay in dissolution.

Nasal deposition in vitro exceeded 90% of the administered dose, attributed to the combination of low particle density (<0.1 g/cm³) and sufficient mechanical stability. Following nasal administration in rats, t_max ranged from 0.8 h to 4 h, C_max from 26.9 ng/ml to 64.0 ng/ml, and AUC_last from 125.4 ng·h/ml to 316.3 ng·h/ml, with no statistically significant differences between HPC-UL and HPC-SSL.

All SFD formulations demonstrated significantly increased nasal bioavailability compared to ASD controls. Despite similar t_max values, HPC-based SFD formulations enhanced aprepitant bioavailability by at least threefold. These findings underline the potential of SFD as a formulation platform for the nasal delivery of poorly water-soluble drugs.

Introduction

Aprepitant is an antiemetic agent used to prevent nausea and emesis associated with chemotherapy. It belongs to the class of neurokinin-1 (NK1) receptor antagonists, and its pharmacological activity consists of blocking substance P from binding to NK1 receptors (Curran and Robinson, 2009). Since the active pharmaceutical ingredient (API) is poorly water-soluble, its dissolution under physiological conditions is decisive for bioavailability. Consequently, aprepitant is currently marketed in the form of nanocrystals for oral administration to improve its dissolution rate and increase oral bioavailability (Hargreaves et al., 2011; Shono et al., 2010; Wu et al., 2004).

In recent years, many formulation approaches have been proposed for the oral administration of aprepitant. These include soft gelatin capsules, nanocrystals (Wu et al., 2004), and amorphous solid dispersions (ASDs) of the pure drug or in combination with various excipients. These ASDs have been prepared by melt processing (Penumetcha et al., 2016), spray drying (Punčochová et al., 2015), and deep eutectic solvent-based formulations (Palmelund et al., 2021). Furthermore, a spray-freeze-dried formulation has recently been reported to improve the oral bioavailability of aprepitant (Kožák et al., 2025).

Limited attention has been paid to alternative routes of administration. In particular, aprepitant could benefit from nasal administration in its antiemetic indications, as its current clinical use is preventive. Peroral administration leads to reduced drug absorption and limits its applicability in acute nausea. In this alternative clinical scenario, aprepitant could also be used in a broader, i.e., curative, therapeutic scheme. However, nasal administration of powders requires balancing two opposing parameters. On the one hand, particles must exceed a certain size threshold to avoid uncontrolled deposition in the lungs (Pozzoli et al., 2017). On the other hand, rapid drug dissolution is required to limit particle residence time on the nasal mucosa.

Spray-freeze-drying (SFD) can meet these requirements, as it produces freely flowable powders consisting of discrete, porous, spherical particles (Ali and Lamprecht, 2017; Rautenberg and Lamprecht, 2022; Wanning et al., 2015). These particles have demonstrated suitability for efficient nasal drug delivery in recent studies (Baldelli et al., 2024; Serim et al., 2021). While these results were based on aqueous SFD processes, a non-aqueous SFD technique was established to extend applicability to poorly water-soluble drugs. This approach uses tert-butanol (Kožák et al., 2026; Kožák et al., 2021; Lucas et al., 2022; Rautenberg and Lamprecht, 2024) and dimethyl sulfoxide (DMSO) as organic spray solvents (Kožák et al., 2022).

Tert-butanol and DMSO have been used as co-solvents in the freeze-drying of aqueous mixtures (Abla and Mehanna, 2025). Their use as pure solvents, providing improved solubility of the aforementioned compounds, introduces new formulation options. However, tert-butanol is flammable and has limitations for pharmaceutical use due to its toxicological profile. In contrast, DMSO has a more favorable solvent profile in terms of toxicity. It is classified as a Class 3 solvent in the ICH Q3C (R9) guideline, whereas tert-butanol is classified as Class 2 (ICH Harmonised Guideline – Impurities: Guideline for Residual Solvents Q3C(R8), 2021). In addition, a DMSO content of up to 50% is considered to be acceptable in certain pharmaceutical formulations (Yoshimura et al., 2021).

DMSO has a broad solubilizing spectrum, ranging from lipophilic to hydrophilic substances (Martin et al., 1967), and enables dissolution of a wide variety of poorly water-soluble drugs (Kožák et al., 2022). However, its low vapor pressure combined with a high boiling point of approximately 190 °C complicates processing during formulation. Consequently, only a few studies have reported the use of DMSO-based freeze-drying (Den Brok et al., 2005). The integration of a spray-freezing step instead of bulk-freezing increases the available interface for solvent sublimation and enables reasonable drying times (Kožák et al., 2022).

In previous studies, two low-viscosity hydroxypropyl cellulose (HPC) grades, HPC-SSL (MW 40.000 g/mol) and HPC-UL (MW 20.000 g/mol), have demonstrated the ability to form amorphous drug formulations for various oral dosage forms (Bachmaier et al., 2021; Pöstges et al., 2022), including SFD particles for oral delivery of aprepitant (Kožák et al., 2025).

Here, we report a proof-of-concept study for the design of aprepitant SFD particles composed of the two aforementioned HPC grades for nasal administration of the poorly water-soluble API. The spraying process was initially evaluated using tert-butanol and DMSO in a comparative screening step. Subsequently, SFD particles were designed by varying the solid content up to 10% and the drug-to-polymer ratio from 20/80 to 40/60 to identify mechanical suitability for nasal administration. Moreover, the influence of formulation variables on drug dissolution was investigated, particularly regarding the impact of porosity and the ability of HPC to generate supersaturated solutions. Finally, the study was complemented by initial pharmacokinetic data in rats following nasal administration, comparing HPC-based aprepitant SFDs with film-cast aprepitant ASDs of equivalent composition.

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Materials

Aprepitant was obtained from Piramal (India). Hydroxypropyl cellulose (HPC grades HPC-SSL (viscosity 2.0–2.9 mPa·s in 2% aqueous solution at 20 °C) and HPC-UL (viscosity 1.7 mPa·s in 2% aqueous solution at 20 °C) were provided by Nippon Soda Co., Ltd. (Tokyo, Japan). All other chemicals and solvents were of analytical or HPLC grade.

Annika Rautenberg, Paul Bühlbecker, Jan Kožák, Claire Chrétien, Yann Pellequer, Klaus Wunderling, Edmont Stoyanov, Alexander Pfeifer, Alf Lamprecht, Spray-freeze-drying aprepitant with hydroxypropyl cellulose increases nasal bioavailability, International Journal of Pharmaceutics: X, Volume 11, 2026, 100551, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2026.100551.

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