Solubilising and Aerosolising Cannabidiol Using Methyl β-Cyclodextrin and Human Serum Albumin

Abstract

Pulmonary delivery can deliver cannabidiol (CBD) with high bioavailability and fast onset of action. One formulation obstacle is the low aqueous solubility of CBD, so solubilsers are necessary. This study aimed to develop inhalable CBD powders using excipients that help dissolving CBD. The solubilisation effects of human serum albumin (HSA), β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and methyl-β-cyclodextrin (mbCD) were investigated with phase solubility test. MbCD showed the highest CBD solubilisation ability at all tested concentrations, followed by HSA. Therefore, mbCD and HSA were co-spray freeze dried with CBD to obtain CBD + mbCD and CBD + HSA powders, respectively. Both powders were amorphous, had < 3% residual solvent, and contained CBD in complexes. CBD + mbCD maintained its amorphicity at < 70% relative humidity. On the other hand, CBD + HSA resisted recrystallisation even at 90% relative humidity. However, although both formulations emitted about 90% of CBD, CBD + HSA was less dispersible than CBD + mbCD (fine particle fraction < 5 µm: 30.2 ± 1.0% vs 53.5 ± 1.5%). The higher level of CBD solubility enhancement and better aerosol performance from mbCD indicated that it was an effective excipient to deliver CBD and potentially other cannabinoids in the future.

Introduction

The high therapeutic potential of cannabidiol (CBD) has attracted increasing research interest. However, the clinical translation of CBD is significantly hindered due to the lack of efficient delivery method. To date, the sole approved CBD-only product is Epidiolex®, an oral solution indicated for drug-resistant seizures in Dravet and Lennox Gastaut Syndromes and tuberous sclerosis complex. The high oral dose (5–25 mg/kg) is due to the low oral CBD bioavailability (4–20%) caused by extensive first pass metabolism and erratic gastrointestinal absorption [1, 2]. Therefore, an alternative route of administration with higher delivery efficiency could be used. A good choice to deliver CBD is by inhalation [3]. Compared to oral delivery, the absorption of inhaled drugs is more consistent and faster with less adverse effects, and hence the bioavailability is enhanced [4]. These benefits of inhaled CBD were evident in a Phase I clinical trial, which demonstrated a 9.1-fold increase in bioavailability with a higher and earlier maximum concentration than Epidiolex [2].

To formulate CBD for inhalation, three important aspects need to be considered, namely, chemical stability, aerosol performance, and aqueous solubility. CBD can easily be degraded by light, temperature, and oxygen [5]. It is also less stable in solution than as a solid [6]. Therefore, CBD could be formulated as a powder to maximise its stability. In addition, the formulation would need to be dispersible to deliver CBD to the lungs for systemic absorption. This requires suitable excipients that can maximise the aerosol performance and enhance the solubility of CBD to accelerate its absorption, thereby increasing its bioavailability. The requirements of being suitable for pulmonary delivery, having acceptable aerosol performance, and increasing aqueous drug solubility can only be fulfilled with limited types of excipients. Phosphatidylcholines, such as distearoylphosphatidylcholine (DSPC) and dipalmitoylphosphatidylcholine (DPPC), have previously been added in inhalable CBD formulations for enhancing aerosol performances and solubility [7]. However, since phosphatidylcholines are also hydrophobic, they may potentially reduce wetting and slow the dissolution rate. On the other hand, multiple polymers have been used to solubilise or aerosolise CBD [8,9,10]. But their safety is still uncertain as they may accumulate or degrade in the lungs, leading to potential toxicity [11]. This makes polymers less suitable for pulmonary delivery until further safety evidence is available.

Two other types of excipients that may help in dissolving and aerosolising CBD are cyclodextrins and albumin. Cyclodextrins are cyclic truncated-cone-like oligosaccharides that have long been used for drug solubility enhancement via formation of inclusion complexes inside their hydrophobic cavities [12]. The three native cyclodextrins consist of six, seven, and eight D-glucopyranose units, namely ɑ, β (bCD), and γ-cyclodextrins, respectively. Among these, bCD and its derivatives, such as those substituted with methyl- (methyl-β-cyclodextrin; mbCD) and hydroxypropyl- (2-hydroxypropyl-β-cyclodextrin; 2HPbCD) groups, were extensively explored as CBD solubilisers in multiple studies [8, 13,14,15,16,17,18,19,20,21,22,23,24]. However, only eight of them specified the target routes of administration, including oral [13, 14], topical [15, 16], sublingual [17], and nasal [18, 19], and only one focused on pulmonary delivery [25]. This gap is still unfilled, especially when cyclodextrins have been widely investigated as excellent aerosol carriers [26,27,28,29]. On the other hand, albumin is the most abundant carrier protein in human bodies [30]. Comprising of 585 amino acids, albumin is well-known for forming complexes with many molecules at its binding sites for transportation [30]. This characteristic makes albumin a good drug solubiliser. In vitro studies found that albumin increased the solubility of hydrophobic drugs such as prednisolone [31] and indomethacin [32]. At the same time, albumin has also been used as an excipient in Air® pulmonary delivery system [33] and as a carrier in a previous study [34]. However, no studies have investigated the solubility enhancement and aerosolisation of CBD by albumin.

In this study, bCDs and human serum albumin (HSA) were used as excipients to formulate CBD as inhalable powders. Phase solubility tests were first conducted to investigate the effect of bCD, mbCD, 2HPbCD, and HSA on improving CBD solubility. While no cyclodextrins were approved for pulmonary delivery, bCD and mbCD have been used in marketed intranasal products, which could be considered as inhalable products as they target the upper respiratory tract [35]. HPbCD is approved for oral and intravenous administration, and hence can also be regarded as safe [36]. The interactions between CBD and HSA or the cyclodextrin that achieved the highest CBD solubility were examined with Job’s plot. These two excipients were then co-spray freeze dried with CBD separately. Spray freeze drying was chosen over spray drying to avoid thermal degradation and oxidation of cannabinoids [37]. The large and porous spray freeze dried particles also benefits powder dispersibility (as they are less cohesive than the small dense spray dried particles) and drug dissolution (as they have a large surface area) [38]. The physicochemical properties and aerosol performance of the spray freeze dried CBD powders were also investigated in this study.

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Materials

CBD was bought from THC Pharm (Frankfurt, Germany). The supplier of tert-butanol, HSA, bCD, 2HPbCD, mbCD, and high-performance liquid chromatography (HPLC) grade methanol, and tetrahydrofuran was Sigma-Aldrich (St. Louis, United States). Phosphate buffered saline (pH 7.4) tablet was purchased from ThermoFisher Scientific (Waltham, United States). Ultrapure water (resistivity = 18.2 MΩ·cm) was obtained from a Milli-Q® Direct Water Purification System (Millipore, Massachusetts, United States).

Tai, W., Khanal, D., Arnold, J.C. et al. Solubilising and Aerosolising Cannabidiol Using Methyl β-Cyclodextrin and Human Serum Albumin. AAPS PharmSciTech 26, 120 (2025). https://doi.org/10.1208/s12249-025-03121-8

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