Development and in vivo pharmacokinetic evaluation of a phospholipid complex self-nanoemulsifying drug delivery system (PLC-SNEDDS) for enhanced oral bioavailability of cannabidiol

Abstract

Cannabidiol (CBD) exhibits poor oral bioavailability (approximately 6%) due to low solubility and excessive first-pass metabolism, limiting its therapeutic potential. This study introduces a novel phospholipid complex self-nanoemulsifying drug delivery system (CBD-PLC-SNEDDS) to enhance CBD delivery. CBD-PLC was integrated into an optimized SNEDDS via Design of Experiments (DoE), yielding nanoemulsions with 118.9 ± 0.77 nm particle size, 0.258 PDI, and −21.9 mV zeta potential. Physicochemical characterization (DSC, FTIR) confirmed amorphization and physical encapsulation without chemical alteration. In vitro dissolution showed 100% CBD release within 1 h for CBD-PLC-SNEDDS vs. 8 h for CBD-SNEDDS. Stability studies (ICH guidelines) retained 94.73% ± 0.62% CBD at 25 °C/60% RH and 80.21% ± 0.61% at 40 °C/75% RH after 4 months with preservatives. In vivo pharmacokinetics in Sprague–Dawley rats (n = 9, 20 mg/kg oral; 4 mg/kg IV) demonstrated that CBD-PLC-SNEDDS significantly enhanced systemic exposure, achieving a calculated absolute bioavailability (F) of 92%, compared to 47% for the oleic acid control. The formulation yielded a 5-fold higher C _max (593 ± 246 vs 118 ± 63 ng/mL) doubled AUC_0-∞ (88 vs. 45 h·kg·ng/mL/mg), faster T _max (2 ± 0.3 vs. 7.4 ± 2.3 h), and extended T _1/2 (3.7 ± 0.9 vs. 1.9 ± 0.6 h) versus control. CBD-PLC alone yielded only 39%. IVIVC modelling via Wagner–Nelson deconvolution established a strong correlation (R² > 0.7) between in vitro dissolution and in vivo absorption, validating the system’s predictive performance. This synergistic PLC-SNEDDS platform outperforms prior systems, offering a scalable template for lipophilic drugs and paving the way for clinical CBD therapeutics.

Introduction

Oral drug delivery remains the most preferred and patient-compliant route of administration (Tong et al., Citation2019); however, the poor aqueous solubility of many active pharmaceutical ingredients (APIs) continues to hinder their clinical translation. Recent data indicate that approximately 40% of marketed drugs and up to 90% of drug candidates under development exhibit poor water solubility, leading to low oral bioavailability, erratic pharmacokinetics, and suboptimal therapeutic efficacy (Ma et al., Citation2022; Kumari et al., Citation2023). Furthermore, over 67% of newly developed chemical entities are poorly water-soluble, and fewer than 8% possess both high solubility and high permeability (Ma et al., Citation2022).

Cannabidiol (CBD) is a BCS Class II compound with high lipophilicity (log P = 6.3) and extremely low aqueous solubility (~10 µg/mL) (Vlad et al., Citation2020). Although CBD demonstrates a broad spectrum of pharmacological activities – including analgesic, anti-inflammatory, anxiolytic, antitumor, and neuroprotective effects – it remains underutilized clinically due to its low and inconsistent oral bioavailability, typically estimated at ~6% (Mannila et al., Citation2007). This limitation is primarily attributed to poor solubility, extensive first-pass metabolism, and potentially physicochemical instability in gastric environments (Millar et al., Citation2020). While some in vitro studies suggest that CBD might be susceptible to degradation under simulated gastric fluid (Merrick et al., Citation2016), the physiological relevance still remains a topic of debate (Nahler et al., Citation2017). Furthermore, the extent to which significant CBD degradation occurs in human GI tract remains inconclusive, with recent literature suggesting that CBD conversion to psychoactive cannabinoids like THC doesn’t happen to a significant degree in vivo (Crippa et al., Citation2020). In addition, CBD is susceptible to degradation under conditions of heat, light, and oxidation, further complicating its formulation (Millar et al., Citation2020).

Recent advancements in drug delivery systems have improved CBD’s oral bioavailability. For instance, Nanostructured Lipid Carriers (NLCs) achieved a 4-fold bioavailability increase (27% in rats) via optimized lipid matrices (Taha et al., Citation2025). Similarly, micro-emulsifying capsules (CBDNEXT Supra Capsule) yielded a 5.7-fold higher C max in humans (Pisak et al., Citation2025), while camel milk-derived exosomes enhanced plasma concentrations by 5.75-fold (Aare et al., Citation2024). Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) and zein nanoparticles have also shown 2.3–2.7 fold bioavailability improvements (Nie et al., Citation2024; Hermush et al., Citation2025). These nanotechnology-based approaches highlight the potential to overcome CBD’s biopharmaceutical limitations, yet none have achieved near-IV bioavailability. Our novel CBD-PLC-SNEDDS formulation integrates phospholipid complexation with SNEDDS to maximize solubility, stability, and oral absorption, offering a superior platform for CBD delivery.

Phospholipid complexes (PLCs) represent a promising strategy for enhancing the lipophilicity of such poorly water-soluble compounds through non-covalent interactions, including hydrogen bonding and Van der Waals forces, thereby improving their incorporation into lipid-based formulations like SNEDDS (Kuche et al., Citation2019). This integration facilitates superior drug loading, spontaneous formation of nanoemulsions with droplet sizes typically below 100 nm upon aqueous dispersion, enhanced gastrointestinal stability, membrane permeability via modulation of membrane fluidity and transient tight junction opening, ultimately maximizing systemic drug absorption and circumventing excessive hepatic first-pass metabolism (Zhou et al., Citation2013). Consequently, the synergistic combination of PLCs and SNEDDS can yield multifield improvements in oral bioavailability without altering the inherent permeability profile of BCS Class II drugs (Kazi et al., Citation2019).

Prior PLC-SNEDDS systems have demonstrated bioavailability enhancements for BCS II and III drugs. For example, silybin-PLC-SNEDDS (1:1 w/w) achieved an 18-fold increase in rats (Tong et al., Citation2019), paclitaxel-PLC-SNEDDS (1:1 w/w) a 3.42-fold improvement (Ding et al., Citation2019) and gentiopicroside-PLC-SNEDDS (1:2 molar) a 9.7-fold boost (Tong et al., Citation2023). Building on our prior CBD-PLC development (Muta et al., Citation2025), we successfully improved water solubility and permeability through amorphization. In the present study, we hypothesized that integrating this pre-formed complex into a SNEDDS would provide a harmonious effect: the PLC ensures molecular dispersion and improved hydrophilic-lipophilic balance, while the SNEDDS provides the lipidic environment necessary to maximize gastrointestinal absorption and systemic exposure. This two-step rationalization aims to push oral CBD bioavailability toward IV-equivalence, a goal that conventional single-platform delivery systems have yet to achieve. While recent literature reports that optimized SNEDDS can achieve a significant 12.9-fold increase in absolute bioavailability (from 0.3% to 4.4%) for lipophilic compounds, such values remain far below intravenous equivalence, highlighting the need for more advanced integrated platforms (Wang et al., Citation2020).

To our knowledge, this is the first study to develop and evaluate a CBD-PLC-SNEDDS formulation, including its pharmacokinetic (PK) performance in vivo, that has achieved near IV bioavailability through oral delivery. The integration of these two delivery platforms represents a novel approach to overcoming the biopharmaceutical limitations of CBD and could offer a versatile template for other poorly soluble, highly lipophilic drug candidates.

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Materials

CBD crystals (powder) were provided by Green Dispensary Compounding (Rx518926; Adelaide, Australia). HPLC-grade methanol (1.06018.4000) and acetonitrile (1.00030.2500) were from EMD Millipore® (Billerica, MA, USA). Ultra-pure water was generated using a Sartorius system (Goettingen, Germany). Other reagents: Ethanol (AJA214-10LPL; Thermo Fisher Scientific, Melbourne, Australia); L-α-Phosphatidylcholine (P5394-10G; egg yolk, ≥40%), formic acid (AC10760050), D-chloroform (570699), Tween 60 (P1629-500ML), Cremophor EL (C5135-500G), Kolliphor RH 40 (07076-1KG), Span 80 (S6760-250ML) (Merck Pty Ltd., Sydney, Australia); N-Octanol (OL001-500M), oleic acid (30-1299), Tween 80 (50259531) (ChemSupply, Adelaide, Australia); CBD-D3 (C-084-1ML; Novachem Pty Ltd., Melbourne, Australia); Butylated hydroxytoluene (30-1463), Miglyol 812 N (3093), almond oil (0975), acid-resistant CONI-SNAP #00 capsules (3100-09) (Medisca, Sydney, Australia); Polyethylene glycol 400 (GC0231) (Glentham Life Sciences Ltd., Corsham, UK); Captex® 300 (080228-6), Captex® 355 (14026UT14) (ABITEC Corp., Wisconsin, USA); Gelucire® 44/14 (3051PP1), Gelucire® 50/13 (3055), Maisine CC (3431), Transcutol P (3260), Labrasol® ALF (3405) (Gattefossé, Saint-Priest, France). Sorbic acid (30-5174), sesame oil (30-1436-480 ML), and tocopherol (30-1031-25 GM; PCCA, NSW, Australia). Design-Expert® 360 (v23.1.3; Stat-Ease, Minneapolis, MN, USA) was used for DoE; OriginLab Corporation, Northampton, MA, USA, software package were used for data visualization. Biorender (accessed on 6 September 2025) and Biorender Graph’s statistical analysis, which uses R (version 4.2.2), was utilized to compute all results of statistical analyses.

Muta, T., Mukhopadhyay, S., Noll, B., Song, Y., & Garg, S. (2026). Development and in vivo pharmacokinetic evaluation of a phospholipid complex self-nanoemulsifying drug delivery system (PLC-SNEDDS) for enhanced oral bioavailability of cannabidiol. Drug Delivery, 33(1). https://doi.org/10.1080/10717544.2026.2702143

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