Nanometer Layer Coating to Lactose Particles for Optimization of Dexamethasone Pulmonary Delivery

Abstract

Lactose (LA), the primary carrier in dry powder inhalers (DPIs), often exhibits excessive drug adhesion, which impairs aerosolization. In this study, four coating methods solid mixing, vapor deposition, suspension coating, and solution coating were evaluated to modify LA surfaces. Solution coating with leucine (Leu) proved optimal and was defined as Nanometer Layer Coating (NLC). When blended with jet-milled dexamethasone (DEX), NLC-LA increased the fine particle fraction from 20% to 50% and improved flowability, reducing Carr’s Index to 24%. Reduced adhesion forces and increased surface smoothness of NLC-LA were confirmed by scanning electron microscopy, synchrotron radiation micro computed tomography and atomic force microscope. Continuous Leu coverage at nanometer-scale thickness was verified using Raman imaging, focused ion beam–scanning electron microscopy, time-of-flight secondary ion mass spectrometry, and synchrotron radiation x-ray microdiffraction. In vivo studies demonstrated that DEX DPI formulated with NLC-LA enhanced bioavailability and allowed a 30-fold dose reduction while maintaining therapeutic efficacy against high-altitude acute lung injury. Collectively, the NLC strategy bridges fundamental surface engineering with translational DPI performance, advancing inhalation science and formulation development.

1 Introduction

Pulmonary drug delivery using dry powder inhalers (DPIs) has become a clinically mature and widely adopted platform for both local and systemic therapies, owing to its propellant-free design, formulation stability, portability, and patient-friendly operation [1-5]. Among DPI formulation design technologies, carrier-based formulations remain the most commercially established [6]. Coarse lactose (LA) particles are widely utilized as the dominant carrier excipient in marketed DPI products, serving as a functional “backbone” that enhances powder flow, supports dose uniformity, and enables dispersion of micronized drug particles during inhalation. Generally speaking, LA is cost-effective, widely available, chemically compatible with many active pharmaceutical ingredients, and supported by extensive regulatory and industrial experience [2, 6]. Therefore, LA-based carrier systems continue to define the mainstream formulation paradigm for DPIs, making LA carrier engineering a highly impactful route for improving DPI performance and manufacturability. Notably, the physicochemical attributes of LA carriers, including particle size distribution, surface morphology, surface roughness, surface chemistry, and surface energy heterogeneity, strongly influence aerosolization efficiency and lung deposition [5-8]. Because micronized drug particles rely on controlled detachment from carrier surfaces, LA is not merely an inert diluent but a performance-determining material that governs both dispersion dynamics and dose reproducibility.

In LA carrier-based DPI systems, micronized drug particles adhere to the surfaces of LA particles to form interactive mixtures [9]. During inhalation, the therapeutic fraction of the inhaled drug reaching the deep lung largely depends on drug detachment from the carrier under aerodynamic and inertial forces, making controlled de-adhesion a prerequisite for effective inhalation delivery [10]. Consequently, drug–carrier interactions must be carefully balanced: excessively strong adhesion hinders detachment and lowers the fine particle fraction (FPF), while overly weak interactions can compromise blend uniformity and dose consistency during handling and device actuation [11]. A useful conceptual framework for this dilemma is the cohesive–adhesive balance. Optimal aerosol performance often arises not from minimizing adhesion absolutely, but from tuning the relative magnitudes of drug–drug cohesion and drug–carrier adhesion to enable efficient detachment and deagglomeration under inhalation shear and turbulence [12, 13]. This implies that rational engineering of interfacial forces, rather than empirical adjustment, should be central to new DPI research and development.

Currently, multiple approaches have been proposed to modulate drug–carrier interactions. Classic strategies include: (i) tailoring the particle size and size distributions of LA carrier; (ii) incorporating fine LA particles; (iii) altering the roughness and morphology of LA carrier; and (iv) adding force-controlling agents (FCAs) such as magnesium stearate (MgSt), leucine (Leu), or other surface-active excipients [13-17]. In general, these methods aim to reduce the strong adhesion of drug particles at the critical binding sites of LA, enhance deagglomeration, and improve detachment during inhalation. Among them, FCAs have received sustained attention because they can improve aerosolization performance at relatively low mass fractions, primarily by masking high-energy adhesion sites on carrier surfaces and reducing drug–carrier interfacial adhesion forces [12, 16, 17]. However, many FCA-based strategies comprise of simple physical blending that require high additive contents, often ranging from ∼1% up to 5% (w/w) or even higher in some formulations, to achieve consistent performance enhancement [18]. Such approaches frequently result in heterogeneous surface coverage, incomplete masking of high-energy sites, and poor reproducibility due to the stochastic nature of powder mixing [19]. In addition, the spatial distribution of FCAs on carrier surfaces is difficult to control, leading to batch-to-batch variability and formulation-dependent performance fluctuations [4, 20]. Moreover, owing to the intrinsic complexity of powder systems, improvements in FPF are often reported without sufficient mechanistic characterization linking surface chemistry, surface energy heterogeneity, and measurable interparticle forces to performance outcomes [21, 22]. Consequently, despite extensive empirical success, a gap remains between formulation practice and mechanistic understanding of how FCA distribution, interfacial interactions, and surface architecture collectively govern DPI performance.

In recent years, coating-based particle engineering has emerged as a promising alternative to conventional blending, offering improved control over LA surface properties through more uniform and reproducible surface coverage [23]. Compared with simple solid particle mixing, coating approaches allow the deliberate deposition of thin layers of lubricants, surfactants, or functional excipients onto carrier surfaces, resulting in better-defined interfacial modifications. Such controlled surface engineering can effectively tune drug–carrier adhesion and dispersion behavior while minimizing changes to the bulk composition, and preserving the intrinsic flow characteristics of coarse lactose carriers [16, 23, 24]. Representative examples include dry powder coating with magnesium stearate, fluid-bed or solvent-mediated coating of amino acids, and spray-assisted surface modification, all of which have demonstrated improved aerosolization performance compared with conventional physical blending [23-25]. Moreover, while numerous studies report improved aerosolization, systematic relationships between coating layer thickness, surface coverage intactness, interparticle force profiles, and macroscopic aerodynamic performance (FPF, emitted dose, dose uniformity, flow function) remain insufficiently mapped. Nevertheless, addressing this gap requires integration of advanced surface analysis, interfacial force quantification, and bulk powder rheology with aerosol performance evaluation, to establish a coherent mechanistic pathway from coating architecture to functional DPI outcomes.

In this study, a Nanometer Layer Coating (NLC) strategy was established to enable the simultaneous optimization of aerodynamic performance and rheological properties of DPI formulations. Various coatings were systematically evaluated and compared in terms of their impacts on LA surface roughness, drug-carrier adhesion, and aerosolization behaviors, using jet-milled dexamethasone (DEX) as a model drug to form DEX-NLC-LA particles, defined as DEX DPI. The underlying mechanisms were elucidated through multi-scale characterization, including scanning electron microscopy (SEM), atomic force microscope (AFM), synchrotron radiation micro computed tomography (SR-µCT), synchrotron radiation x-ray microdiffraction (SR-µXRD) and focused ion beam–scanning electron microscopy (FIB-SEM). Meanwhile, pharmacokinetic and high-altitude acute lung injury (HALI) evaluations of inhaling DEX DPI in rats were performed. Collectively, this study established NLC as a rational and versatile particle engineering strategy for DPI carriers and demonstrated that nanometer-scale surface modification of LA can markedly enhance both pulmonary deposition and powder flowability of DEX, thereby providing a simple yet effective approach for the development and optimization of carrier-based DPI formulations (Scheme 1).

2 Materials and Methods

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Nie, Q., Liu, J., Zhao, X., Yang, S., Sun, H., Jia, B., Ren, X., Chen, X., Sun, L., Wu, L., Wang, C., & Zhang, J. (2026). Nanometer Layer Coating to Lactose Particles for Optimization of Dexamethasone Pulmonary Delivery. Advanced science (Weinheim, Baden-Wurttemberg, Germany), e76929. Advance online publication.
https://doi.org/10.1002/advs.76929