Cyclodextrin-based materials for pulmonary delivery: Insights and challenges

Abstract

Cyclodextrins (CDs) are cyclic oligosaccharides primarily used as excipients in the formulation of drugs, including those intended for pulmonary delivery. CDs have gained increased attention for their use as drug solubilizers. The beneficial role they play in the formulation of drugs intended for lung targeting has received particular attention in recent years, along with the potential benefits this route offers for achieving systemic effects. Hence, various CDs based materials have been considered in literature including CD/drug inclusion complexes, polymerized CDs and nanosponges, metal-organic frameworks, CDs in proliposomes, and others. The investigation of CDs as active agents is also considered in literature for the treatment of lungs diseases. The literature provides a large range of information on the manufacturing of CD-based materials for pulmonary delivery, the characterization of the obtained formulations, their suitability for lung deposition, the pharmacokinetics of the drugs when loaded in a particular formulation, and the resulting biological effects, yet the challenges of their clinical translation remain to be addressed.

Introduction

Pulmonary delivery has long been used in medicine, first by burning plants and herbs, then in anesthesia, and reached new heights with the invention of the pressurized metered-dose inhalers in 1956. The interest in this route has been constantly renewed (Cao et al., 2024; Wang et al., 2024). Indeed, it offers a large surface area of thin epithelial membranes allowing an easier exchange of molecules between the air and blood circulation and a high blood flow in the lung capillaries. Moreover, it allows drugs to bypass gastrointestinal degradation and first pass metabolism in the liver. Delivering drugs directly to the lungs represents a great advantage when it comes to treat pulmonary diseases, as administration is directly at the targeted injury, which could help minimize undesired side effects on distant tissues. Nonetheless, the respiratory system has a robust set of defense mechanisms, evidenced by the presence of mucus phagocytes and mucocilia which expel foreign bodies. In addition, lungs enzymes and transporters limit the lung deposition of drugs (Gaul et al., 2018; Kuzmov & Minko, 2015).

To effectively treat pulmonary diseases, pharmaceutical formulations should have certain physico-chemical properties, allowing them to reach the targeted alveoli without being retained in the upper respiratory tract (Laube et al., 2011; Qiao et al., 2021; Wang et al., 2024). Pathological states, however, complicate effective delivery. For example, microbial infection is usually coupled with increased macrophage activity and mucous production, which in itself creates an optimal medium for bacterial colonization (Costabile et al., 2020).

The administration of drugs via the pulmonary route is currently limited to some drug categories such as bronchodilators, corticosteroids, antibiotics, and mucolytic agents. This is mainly due to the inadequate deposition of drugs at the appropriate dose, and patient non-compliance. Therefore, even when treating local lung disease, treatment strategies often use other delivery routes. This prompts the need for refining drug technologies for intended pulmonary delivery.

Pulmo Sphere™ Technology pioneered in the engineering of porous particles that can load drugs of different physico-chemical properties for pulmonary delivery (Weers et al., 2019; Weers & Tarara, 2014). Depending on the physical properties of the drug, three different formats were proposed with distearylphosphatidylcholine and calcium chloride being the excipients at a molar ratio of 2:1. TOBI® Podhaler™, loading tobramycin, reached the market, and other drugs are in clinical development (Weers et al., 2019).

In parallel, several particles and systems are being investigated including lipid vesicles (Adel et al., 2021), polymers (Bonfield et al., 2024), lipid nanoparticles, gelatin-based particles (Dabbagh et al., 2018), metallic particles (Martín-Faivre et al., 2024) and mesoporous silica (Gaul et al., 2018; van der Zwaan et al., 2024). The bioavailability, biodegradability, drug release and effectiveness, and safety of the carrier materials are all required for a formulation to reach clinical investigation.

Cyclodextrins (CDs) are cyclic oligosaccharides obtained from the enzymatic degradation of starch. They have a truncated cone shape with a hydrophilic outer surface and a hydrophobic inner cavity. Native CDs α, β, and γ are composed of six, seven and eight glucopyranose units, respectively (Szejtli, 2004). They represent an effective carrier system and are used in various domains as solubilizers of hydrophobic agents (Kfoury, Auezova, Greige-Gerges, Larsen and Fourmentin, 2016, Kfoury, Landy and Fourmentin, 2018). Due to the poor water solubility of native CDs, different derivatives are manufactured and used in pharmaceutical formulations such as sulfobutyl ether-β-CD and hydroxypropyl-β-CD (HP-β-CD) that are approved by the USFDA as pharmaceutical excipients in oral delivery (Fenyvesi, 2013). According to Loftsson et al. in 2005, CDs are considered as safe components for pulmonary delivery (Loftsson, Hreinsdóttir, & Másson, 2005; Loftsson, Jarho, et al., 2005). Since then, they are being investigated in pulmonary based formulations for various purposes, as excipients, solubilizers of poorly-soluble agents, stabilizers of some agents or formulations, and as active molecules able to treat lung diseases. CDs, either in solutions, suspensions, or dry powders are considered throughout literature.

Developing aerosols that have appropriate aerodynamic performance needed for effective pulmonary delivery is a challenge for most. Indeed, not only should the particulate be able to reach the alveoli but also escape lung defenses and adhere efficiently to the alveolar membrane to exert its effect (de Pablo et al., 2023; Lechanteur et al., 2023). To ensure alveolar deposition, various parameters should be considered including the device characteristics, inhalation flow, and particles characteristics.

For CD based pulmonary formulations, various devices are being used for administration including nebulizers, pressurized metered dose inhaler (p-MDI) and dry powder inhaler (DPI) and, with the latter being the most used (Laube et al., 2011). The aerodynamic diameter is used to evaluate the lung deposition of particles. The next generation impactor is used to examine the aerodynamic characteristics of the particles which are crucial for evaluating the behavior and efficacy of a formulation (de Castro et al., 2020). The parameters obtained include the aerodynamic particle size distribution (APSD), the mass median aerodynamic diameter (MMAD), the geometric standard deviation (GSD), and the fine particle fraction (FPF), referring to the distribution of the particle size, the median size of the aerosol particles, the particle size distribution, and the percentage of particles able to reach the lower respiratory tract, respectively. Ideally, particles with an aerodynamic diameter between 1 and 5 μm are desired for deep lung delivery. They exert their effects in the bronchi (Ibarra-Sánchez et al., 2022). Particles within this diameter range with non-spherical shapes, and a rough surface are more easily deposited in the lungs and have limited elimination by macrophages (Jyoti et al., 2015; McBride et al., 2017). Particles smaller than 0.5 μm could be expelled through Brownian diffusion. Particles smaller than 34 nm are removed to the surrounding lymph nodes and those below 5 nm are found in the bloodstream (Evrard et al., 2004; Ibarra-Sánchez et al., 2022).

In this review, we present an overview of the different formulations containing CDs and intended for pulmonary delivery. Emphasis will be placed on the role of these host molecules in the formulation, starting with their ability to encapsulate active compounds or to be used as excipients and lastly as active ingredients themselves. Finally, this review highlights a number of research gaps that could be addressed in the future to benefit from the properties of CDs in pulmonary delivery.

CDs as excipients

In the absence of any drug, HP-β-CD was examined for its effect on the physicochemical characteristics, physical stability and aerodynamic properties of particles composed of raffinose tetrahydrate and trehalose dehydrate (Amaro et al., 2014) (Table 3). Presenting the risk of recrystallization when exposed to approx. 75 % relative humidity, these sugars may lose their protective effects on biomolecules like proteins during spray drying.

Petra Gerges, Miriana Kfoury, David Landy, Sophie Fourmentin, Hélène Greige-Gerges, Cyclodextrin-based materials for pulmonary delivery: Insights and challenges, Carbohydrate Polymers, 2025, 123712, ISSN 0144-8617, https://doi.org/10.1016/j.carbpol.2025.123712.