Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by chronic bronchitis and emphysema (Kim & Criner, 2013). In 2019, COPD ranked as the third foremost cause of mortality globally, resulting in 3.23 million deaths (WorldHealthOrganization, 2023). COPD pathophysiology is characterized by lung inflammation caused by key inflammatory mediators, including different cytokines such as tumour necrosis factor-alpha (TNF-α), interleukins (IL-1, IL-6, IL-8), reactive oxygen species, and proteases (King, 2015). Current treatments focus on alleviating symptoms. For example, bronchodilators are used in combination as an inhaler to relieve symptoms such as breathing difficulty and chest tightness, but do not relieve inflammation (Barnes, 2014). Corticosteroids are used as anti-inflammatory agents that have efficacy up to a limit, but high doses can have destructive effects on bones and may increase the risk of pneumonia (Barnes, 2000). Other anti-inflammatory drugs, such as roflumilast, a PDE4 inhibitor, has demonstrated efficacy in reducing exacerbation frequency and improving lung function, however its clinical utility is limited by adverse effects, including gastrointestinal disturbances, weight loss, and an increased risk of psychiatric symptoms at the standard 500  µg dose (Janjua et al., 2020, Li et al., 2018). These side effects contribute to poor patient adherence and restrict its use. There is an imperative need to develop a drug/treatment that is both safe and effective for the clinical management of COPD.

Cannabidiol (CBD) is a non-intoxicating, pharmacologically active compound of Cannabis sativa (Legare et al., 2022). CBD has shown anti-inflammatory properties, and some studies have demonstrated that CBD may be effective in treating COPD (Braun et al., 2011, Dudasova et al., 2013, Makwana et al., 2015, Robaina et al., 2021). The putative mechanism of CBD in treating COPD is its inhibition of proinflammatory cell activation and synthesis of proinflammatory mediators (e.g., IL-2, TNF-α, IFN-c, IL-6, IL-12, IL-17, MCP-1, eotaxin-1) and modulation of gene expression through several receptors and pathways (Chiba et al., 2011, de Filippis et al., 2011, Esposito et al., 2007, Kozela et al., 2010). Activity at adenosine A2A, TRPV1, CB2/5HT heterodimerization, and cannabinoid receptors (CB1 and CB2) may all contribute to reducing inflammation (Shebaby et al., 2021, Tran et al., 2023). Additionally, it inhibits the proliferation of Streptococcus pneumoniae, a common pathogen in COPD patients due to mucus build-up (Abichabki et al., 2022). Furthermore, CBD can help alleviate the pain often experienced by COPD patients (Schilling et al., 2021). Therefore, it is anticipated that a suitable formulation of CBD may be used to reduce lung inflammation in patients with COPD.

Although CBD demonstrates significant therapeutic promise, its clinical utility is limited when administered orally due to low water solubility, extensive first-pass metabolism, poor gastrointestinal absorption, and slow onset of action (Devinsky et al., 2021). For COPD patients, a rapid onset of action and localized delivery are required for effective symptom control and inflammation management. Therefore, pulmonary delivery via inhalation provides a direct route to the lungs, bypasses first-pass metabolism, offers a quicker onset of action, and improves local drug concentrations at the site of inflammation. Among the widely used inhalation devices- metered dose inhalers (MDIs), nebulizers, and dry powder inhalers (DPIs), DPIs are commonly preferred for inhaled delivery due to their superior product stability, ease of administration, and advantages in storage and transportation (Hickey, 2020, Lee et al., 2017). Therefore, delivering CBD directly to the lungs via a suitable dry powder formulation would be the most effective approach to ensure optimal concentration and maximize therapeutic efficacy. Inhaled CBD dry powders have been found effective in maintaining effective drug concentrations in the lungs. For instance, a phase I clinical study demonstrated that inhaled CBD dry powder with 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) and fumaryl diketopiperazine (FDKP) achieved a 9.1-fold more bioavailability and 71-fold higher maximum concentration compared to oral CBD solution, for treating seizures associated with epilepsy (Devinsky et al., 2021). Subsequently, several inhalable CBD formulations have been developed using spray-freeze drying, thin-film freezing and wet ball milling (Tai et al., 2024, Tai et al., 2025, Williams et al., 2021). These have incorporated excipients such as mannitol, trehalose, dipalmitoylphosphatidycholine (DPPC), human serum albumin, β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, L-leucine (LEC), lactose, and magnesium stearate (Tai et al., 2024, Tai et al., 2024, Tai et al., 2025, Williams et al., 2021). While these formulations have demonstrated improved physicochemical characteristics, none have explored the anti-inflammatory efficacy of inhaled CBD for COPD.

For effective lung deposition, dry powder formulations must produce particles with an aerodynamic diameter between 1–5 µm to ensure optimal delivery to the respiratory tract (Bosquillon et al., 2001, Kanig, 1963, Maloney et al., 2023). Spray drying is a robust and scalable technique widely employed for generating inhalable particles within this size range (Liu et al., 2015). It is a recognized method for preparing dry powder due to its reproducibility, cost-effectiveness and better control over particle properties compared to other techniques such as spray freeze drying, milling, and solvent-mediated precipitation (Alhajj et al., 2021, Momin et al., 2017). However, formulation of CBD via spray-drying is challenging due to its thermo-sensitive nature and tendency to agglomerate, requiring the use of excipients that can stabilize CBD and improve aerosolization performance (Kosović et al., 2021; Fraguas-Sánchez et al., 2020). To address these challenges, sugar-based excipients such as mannitol, trehalose, and inulin (INU) have been employed to protect thermolabile compounds (Drooge et al., 2004, Muntu et al., 2024). Among these, INU, a naturally occurring polysaccharide, offers several advantages, including a high glass transition temperature, low crystallization tendency, and enhanced dispersion of lipophilic drugs in dry powder formulations (Hinrichs et al., 2001, Van et al., 2004, Van Drooge et al., 2004). It provides thermal and oxidative protection by limiting molecular mobility and replacing water in hydrogen bonding networks (; Hinrichs et al., 2001, Ógáin et al., 2011). Previous studies have shown that INU is effectively used in thermolabile therapeutics, including proteins (e.g., alkaline phosphatase, DNase I, hemagglutinin), enzymes (e.g., AHL acylase), and cannabinoids such as tetrahydrocannabinol (THC) (Amorij et al., 2007, Ógáin et al., 2011, Rodriguez Furlán et al., 2011, Wahjudi et al., 2013, Zijlstra et al., 2009). Although INU is not approved for inhalation, it is generally recognized as safe (GRAS) by the United States Food and Drug Administration (FDA) for human consumption, and its established safety profile in parenteral and diagnostic applications supports its exploration for inhalation (Jansen et al., 2025, Wahjudi et al., 2013). Additionally, LEC, a hydrophobic amino acid, was included to enhance aerosolization performance by reducing interparticle cohesion and promoting favourable particle morphology (Chew et al., 2005, Li et al., 2016, Momin et al., 2017). LEC is an FDA-approved excipient and is widely used in DPI formulations (Dharmadhikari et al., 2013, Luinstra et al., 2019). This study aimed to develop a stable inhalable CBD dry powder formulation by a spray-drying technique using INU and LEC as excipients. The prepared dry powders were investigated for their physicochemical, aerosolization, cytotoxicity, and anti-inflammatory properties.