Improving inhalation delivery of biologics with extra-large particles produced by spray freeze drying
Abstract
Inhalation delivery of biologics as dry powders offers a promising alternative to liquid formulations, eliminating the need for cold storage. However, controlling particle properties for efficient lung delivery is challenging. While spray drying (SD) has been successfully used, it often requires excipients not approved for inhalation. In this study, spray freeze drying (SFD) was explored as an alternative technology. Human immunoglobulin G (hIgG) was used as a model molecule and dried in a mannitol-based formulation, approved for inhalation delivery. The effect of nozzle diameter (50–100 μm) and solids’ concentration (5–10 %(w/w)) were investigated. Despite their large size (20–300 μm), SFD particles achieved fine particle doses over emitted doses (FPD/ED) up to 80 %, which was attributed to their low density (<0.52 g/cm3). The study highlights the SFD potential to enhance the aerodynamic performance of dry powder formulations for inhalation delivery, as demonstrated in comparative tests with SD.
Highlights
- Large SFD particles showed up to 80 % FPD/ED with excipients approved for inhalation.
- SFD particles’ rendered better FPF/ED compared to smaller SD counterparts.
- The high aerodynamic performance of SFD particles was linked to the low density.
Introduction
The inhalation delivery of biologics has attracted a growing interest as an alternative approach to address the challenges associated with intravenous administration [1]. Currently, the majority of inhaled protein drugs in clinical trials are developed as liquid formulations and administered through nebulization [2]. However, stability concerns tied to liquid biologics’ formulations, and the need for cold storage conditions to ensure shelf life have sparked interest in more stable dosage forms, such as dry powder inhalers (DPI) [[3], [4], [5]]. Nevertheless, such application is demanding for dry powders’ properties, and the stability and performance of drug products often depends on the selected manufacturing technology [6].
The particle size is a critical quality attribute (CQA) of inhaled biologics as it directly affects lung deposition efficiency [6]. In fact, this correlation is better described by the aerodynamic diameter, which corresponds to the diameter of a sphere with a density of 1 that presents the same terminal settling velocity in still air as the particle being considered [7]. The aerodynamic diameter increases with the particles’ geometric diameter and density (Eq. (1)), assuming the standard density is 1 and the particle is spherical (i.e., its dynamic shape factor is 1).
It is known that particles with an aerodynamic diameter above 5 μm are deposited in the oropharyngeal region, while particles below 1 μm are exhaled during tidal breathing [8,9]. Consequently, the powders’ fine particle dose (FPD), which represents the actual mass of particles that successfully reach the respiratory tract, is considered a key parameter in evaluating the aerodynamic performance of the formulations.
The fine particle dose is often expressed as a percentage of the emitted dose (ED), which represents the total mass released from the capsule and device after actuation. This metric, denoted as fine particle dose over the emitted dose (FPD/ED), represents the fraction of the emitted dose consisting of particles with an aerodynamic diameter between 1 and 5 μm [10].
Spray drying (SD) stands as a fundamental technology for producing dry powders of biologics for inhalation, although spray freeze drying (SFD) is emerging as a promising manufacturing alternative [6]. SFD combines the atomization feature of SD with the vacuum drying feature of freeze drying [6]. The SFD process comprises three different steps: the atomization of liquid solution to form droplets, flash-freezing in a cryogenic medium, and drying of the frozen particles by sublimation at low temperatures and under vacuum [6].
Four variants of the spray freeze-drying (SFD) process are described in the literature [11]. Among these, spray freezing into vapor over liquid (SFV/L) – where droplets begin freezing in a cold vapor gap above a cryogenic liquid and fully freeze upon reaching the cryogenic liquid – is the most commonly used at the laboratory scale due to its simplicity and ease of assembly [11]. On the other hand, spray freezing into vapor (SFV) – where droplets are frozen solely by exposure to a cold vapor – has the greatest potential for industrial scalability. This is evidenced by commercially available setups such as LYnfinity® and Meridion, both of which are based on the SFV variant [11].
To produce spray dried powders with good aerodynamic performance, formulation approaches that involve the use of dispersing agents, such leucine, are typically required [12]. Besides not having received approval for inhalation delivery, the need to tailor the formulation to achieve good aerodynamic performance may also present challenges in terms of limiting the drug load (DL) and solids’ concentration [13]. This a major drawback, potentially prolonging the time required to bring inhalation products to market [11].
Among inhalation-approved excipients, mannitol is a widely used option in dry powder inhalers (DPI) formulations [14]. Notable examples of inhaled products utilizing mannitol include BRONCHITOL®, a mannitol inhalation powder approved for the treatment of cystic fibrosis in adults, and Exubera®, an inhaled insulin product where mannitol was used as excipient [14,15].
SFD typically renders particles with low densities and high specific surface areas, which have been reported to result in good aerodynamic performances, even for less complex formulations [13,16,17]. With such enhanced aerodynamic performance, it is likely that larger SFD particles may be successfully delivered to the lungs as they present aerodynamic diameters similar to smaller nonporous spray dried particles [13,16,17].
The inhalation delivery of larger particles offers several benefits. Large particles typically result in enhanced aerosolization efficiency by aggregating less than smaller particles, which often deposit due to gravity and inertia before reaching airways. Larger particles can also avoid phagocytic clearance in the lungs but due to their high SSA, these particles are usually friable and easily fragmented [16,[18], [19]].The particles’ friability has been reported to impact the aerodynamic performance and to be dependent on the solids’ concentration, with lower concentrations resulting in more friable particles [19].
Large porous particles for inhalation delivery can be produced in SFD using an ultrasonic (US) monodisperse atomizer. Monodisperse atomizers, are a particular case of US which produce a stream of large monodisperse droplets and, consequently, a narrow PSD. US nozzles are also pointed as requiring lower shear stresses for atomization, compared to two-fluid nozzles (2FN), which are the most used technology for inhalation spray dried powders [[20], [21], [22], [23], [24]].
Beyond particle size, the dry powders’ residual water content also impacts DPI performance, and thus drug delivery efficiency. The dry powders’ residual water content can impact both the stability and performance of inhalation-based biopharmaceuticals [25,26].
It is important to notice that despite the potential of yielding better aerodynamic performance, there can be downsides in SFD. The fill weight with SFD powders may be limited when compared to standard SD powders as their lower density will reduce the mass allowable in the fixed volume of a given device or capsule [10,27]. Such limitation may have a direct impact in the FPD and may require an increase in the DL of the formulation, a higher number of actuations or a larger device/capsule [28].
Despite the advances in inhalation delivery of biologics, significant challenges remain that hinder their widespread clinical adoption. While SD is a well-established method for producing inhalable dry powders, it often requires complex formulation strategies and the use of non-approved excipients to enhance aerodynamic performance. However, SFD’s potential to produce particles with superior aerodynamic properties emerge as a promising alternative. Nonetheless, there is a need of comprehensive studies comparing the aerodynamic performance and stability of SFD-produced particles against those produced by SD, namely with large molecules. This paper addresses this critical gap by systematically evaluating the aerodynamic performance of large porous particles of a model immunoglobulin G (hIgG) produced with SFD, utilizing a Design of Experiments (DoE) approach to optimize key process variables. The selected formulation, featuring mannitol as an inhalation-approved excipient and devoid of dispersing agents, aimed to compare powder properties and aerodynamic performance of particles produced with SFD and SD.
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Materials
hIgG was obtained from Lee BioSolutions (Maryland Heights, Missouri, United States). PBS tablets were obtained from Sigma-Aldrich (Burlington, Massachusetts, United States). Mannitol was obtained from SPI Pharma (Wilmington, Delaware, United States). HCl 37 % was obtained from PanReac (Barcelona, Spain). TRIS was obtained from NZYtech (Lisbon, Portugal).
Susana Farinha, Marco Galésio, Joana Cristóvão, Paulo Lino, Miguel Ângelo Rodrigues, João Pires, Luís Marques,
Improving inhalation delivery of biologics with extra-large particles produced by spray freeze drying, Powder Technology, Volume 459, 2025, 121020, ISSN 0032-5910, https://doi.org/10.1016/j.powtec.2025.121020.
Read also our introduction article on Mannitol here:
