Sodium Stearate-Assisted Optimization of a Cannabidiol Dry Powder Inhaler for Enhanced Dissolution and Aerosol Performance

Abstract

Background/Objectives: Cannabidiol (CBD) has emerged as a potential therapeutic agent for respiratory disorders, including asthma and chronic obstructive pulmonary disease. However, its clinical translation via pulmonary delivery is limited by poor aqueous solubility, chemical instability, and low local bioavailability. This study aimed to develop and optimize a sodium stearate (NaSt)-based spray-dried dry powder inhaler (DPI) formulation to enhance the aerosol performance, dissolution, and storage stability of CBD.

Methods: CBD microparticles were prepared by spray drying using NaSt as the primary excipient. The feed preparation method, spray-drying parameters, and CBD:NaSt ratios were systematically optimized. The resulting powders were evaluated for aerodynamic properties using cascade impaction, dissolution behavior in simulated lung fluid, solid-state characteristics, and accelerated stability under stress conditions.

Results: The optimized formulation, SD-4, a spray-dried CBD:NaSt formulation prepared at a 20:80 weight ratio using Process B, demonstrated excellent aerosolization performance, with a fine particle fraction (FPF) exceeding 50% and a mass median aerodynamic diameter (MMAD) of 5.08 ± 0.1 μm. Dissolution testing revealed more than a three-fold increase in drug release compared with raw CBD, attributed to amorphous dispersion within the NaSt matrix and surfactant-induced micellization. Accelerated stability studies confirmed improved retention of the amorphous state and drug content, while antioxidant incorporation further reduced oxidative degradation.

Conclusions: The NaSt-based spray-dried formulation significantly improved aerosol deposition efficiency, dissolution rate, and physicochemical stability of CBD. This formulation strategy may provide a promising platform for pulmonary delivery of poorly water-soluble compounds.

Introduction

Cannabidiol (CBD), a hydrophobic and non-psychoactive constituent of Cannabis sativa, has attracted considerable interest because of its broad pharmacological potential, including anti-inflammatory and antioxidant activities [1,2]. Recent reviews have highlighted the therapeutic potential of CBD across a wide range of disorders and delivery contexts [1,2,3]. Recent reviews have further expanded the therapeutic scope of CBD, highlighting its potential in pain management, anxiety-related disorders, and immune modulation [4,5,6]. Collectively, these findings support the broad pharmacological relevance of CBD and strengthen its potential as a multifunctional therapeutic agent.

Recent studies have demonstrated that CBD exerts anti-inflammatory, antioxidant, and anti-fibrotic effects in multiple pulmonary disease models [7,8]. It has shown therapeutic efficacy against acute lung injury [8,9,10], pulmonary fibrosis [7,11,12], and asthma [13]. Mechanistically, CBD modulates pulmonary inflammation by suppressing pro-inflammatory cytokines and oxidative stress, leading to reduced leukocyte infiltration and fibrotic remodeling [7,13]. Taken together, these findings support the potential of CBD as a therapeutic option for respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis [7,13,14].

However, despite its therapeutic potential, the clinical translation of CBD remains limited by poor aqueous solubility, low and variable bioavailability, and chemical instability [15,16,17,18,19]. Following oral administration, CBD undergoes extensive first-pass hepatic metabolism and degradation in acidic gastric environments, resulting in an oral bioavailability of only 6–19%. Consequently, it is challenging to maintain consistent plasma concentrations. Pulmonary administration has been proposed as an alternative route to circumvent these limitations, bypassing gastrointestinal degradation and first-pass metabolism while enabling rapid absorption and improved systemic exposure [3,20].

Traditional inhalation approaches, such as smoking and vaporization, have demonstrated that cannabinoids can be efficiently absorbed through the lungs. However, these routes are limited by dose variability, dependence on individual inhalation patterns, and the possible generation of harmful by-products during high-temperature processing [21,22]. These limitations highlight the need for a safer, more reproducible, and pharmaceutically stable inhalable formulation of CBD.

Dry powder inhalers (DPIs) are a promising platform for pulmonary delivery of poorly water-soluble compounds such as CBD. Because DPIs deliver solid-state formulations directly to the lungs without propellants or large solvent volumes, they offer advantages in formulation stability, dose precision, portability, and patient compliance [23,24]. They can also be engineered to achieve efficient lung deposition for both local and systemic delivery [23,24,25,26,27]. In line with this potential, recent studies have demonstrated growing interest in inhalable CBD dry powders. Tai et al. developed spray freeze-dried CBD powders containing dipalmitoylphosphatidylcholine and demonstrated improved inhalation suitability together with enhanced solubility. Komal et al. reported inhalable CBD dry powders intended for chronic obstructive pulmonary disease treatment and evaluated their in vitro aerosol and formulation characteristics. Gomes et al. also developed a spray-dried inhalable CBD powder using hydroxypropyl-β-cyclodextrin and demonstrated the feasibility of producing CBD particles with favorable aerodynamic properties and modified morphology [14,28,29]. Collectively, these studies support the feasibility of pulmonary CBD delivery, but they have mainly focused on inhalation feasibility, carrier selection, or solubility-oriented formulation strategies.

Several particle engineering approaches have been used to prepare DPI formulations, including jet milling, carrier-based blending, freeze drying or spray freeze drying, supercritical fluid-based processing, and spray drying [30,31,32]. Although each approach has specific advantages, each also presents practical limitations. Jet milling is effective for particle size reduction but often provides limited control over particle morphology and surface properties and may increase interparticle cohesion because of irregular particle surfaces. Carrier-based blending is practical and widely used, but its performance can be strongly influenced by drug-carrier adhesion and blending uniformity. Freeze drying and spray freeze drying can be useful for thermally sensitive materials, although they are generally more complex and may be less suitable for routine large-scale powder production.

Supercritical fluid-based processing can generate fine particles with controlled properties, but it usually requires specialized equipment and more complicated operating conditions. In contrast, spray drying offers several formulation and manufacturing advantages, including simultaneous control of particle size, morphology, surface composition, and residual moisture content, all of which are critical determinants of aerosolization performance and storage stability in DPI systems [30,31,32]. In addition, spray drying enables one-step particle formation and facilitates the incorporation of functional excipients, making it particularly suitable for the development of inhalable formulations of poorly water-soluble drugs such as CBD.

Figure 1. Schematic illustration of feed preparation methods prior to spray drying.

Excipient selection is another key determinant of DPI performance. Depending on the intended formulation function, inhalation powders may contain lactose as a carrier in carrier-based systems, mannitol and trehalose as bulking or stabilizing agents, L-leucine as a dispersibility enhancer, and phospholipids or other amphiphilic materials to improve surface properties and dissolution behavior. In the present study, mannitol and L-leucine were selected as representative comparator excipients because they are widely used to improve powder handling, particle formation, and aerosol dispersion in DPI systems. In contrast, sodium stearate (NaSt), a fatty acid salt with amphiphilic and surface-active characteristics, has attracted attention as a multifunctional excipient for pulmonary drug delivery. During spray drying, NaSt preferentially migrates toward the droplet-air interface and forms a hydrophobic surface layer that can enhance powder flowability, reduce moisture-induced aggregation, and facilitate deagglomeration during aerosolization, thereby promoting efficient deposition of respirable particles [33,34,35,36]. After deposition in the pulmonary environment, NaSt can also behave as a mild anionic surfactant capable of forming micellar or vesicle-like assemblies upon contact with lung fluids [37,38].

These self-assembled structures may encapsulate hydrophobic molecules such as CBD, thereby improving wettability, dissolution, and apparent solubility while also helping to maintain CBD in an amorphous, bioavailable state [39]. Thus, unlike previously reported inhalable CBD powder systems that mainly emphasized inhalation feasibility or solubility enhancement, the present study investigated a NaSt-based spray-dried platform in which a single functional excipient could simultaneously contribute to aerosolization improvement, dissolution enhancement, and physicochemical stabilization.

Therefore, this study aimed to develop a sodium stearate-based spray-dried CBD DPI and evaluate its aerosolization performance, dissolution behavior, and stability. By systematically linking feed preparation strategy, NaSt-assisted matrix formation, hydration-induced nanostructure generation, and oxidative stability improvement, this study sought to establish a robust and scalable formulation strategy for the pulmonary delivery of highly hydrophobic cannabinoids such as CBD.

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Materials

CBD was purchased from Cayman Chemicals (Ann Arbor, MI, USA). NaSt, mannitol, and L-leucine were purchased from Dejung (Seoul, Republic of Korea). Ultrapure water was prepared using a laboratory purification system. High-performance liquid chromatography (HPLC)-grade solvents were used for analysis, with HPLC-grade acetonitrile purchased from Honeywell Burdick & Jackson (Muskegon, MI, USA). Unless otherwise specified, all other chemicals and solvents were of analytical grade and were purchased from Merck KGaA (Darmstadt, Germany) and used without further purification

Jeong, J.-H.; Jeong, J.S.; Moon, H.-S.; Son, J.W.; Min, K.H.; Kim, D.-W.; Han, C.-S.; Lee, W.; Park, C.-W.; Kang, J.-H. Sodium Stearate-Assisted Optimization of a Cannabidiol Dry Powder Inhaler for Enhanced Dissolution and Aerosol Performance. Pharmaceutics 2026, 18, 512. https://doi.org/10.3390/pharmaceutics18040512

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