(M1130-07-43) Formulation Development of Oral CBD-Loaded SEDDS with Optimized Dissolution and Digestive Performance

Purpose: Cannabidiol (CBD) is an FDA-approved non-psychoactive drug. CBD is a lipophilic drug with poor water solubility. It has low and variable oral bioavailability due to its significant metabolic elimination by first-pass metabolism and incomplete absorption. In addition, its bioavailability is highly food-dependent, and it can increase fourfold when co-administered with food (1). These limitations cause low oral bioavailability, high inter- and intra-subject variability, and a lack of dose proportionality. Lipid-Based Drug Delivery Systems (LBDDs) are designed to overcome oral administration limitations for lipophilic drugs with poor water solubility, which can affect their dissolution and absorption. LBDDs could enhance the drug bioavailability by keeping the drug in a solubilized form. In addition, it has potential absorption through the lymphatic system and avoids first-pass metabolism (2). Self-emulsifying Drug Delivery Systems (SEDDS) are one of the LBDDs that are considered an isotropic mixture of oil, surfactant, and co-surfactant. SEDDS provide numerous advantages, including great physical stability, simple manufacture, and the ability to accommodate high drug loads. Furthermore, they increase drug absorption and help decrease the impact of food and subject variability across individuals (3). The objective of this study is to develop stable CBD SEDDS formulations that achieve maximum drug loading and emulsification efficiency while minimizing susceptibility to digestion and the influence of food intake.

Methods: CBD SEDDS were formulated using Capryol® 90 (oil), Tween 20  (surfactant), and Transcutol® HP (cosurfactant) based on their selection in our previous study. Five CBD SEDDS formulations exhibiting the smallest particle size and lowest polydispersity index (PDI) were selected for drug release evaluation. The in vitro drug release studies were carried out using a USP dissolution apparatus 2 in phosphate buffer (pH 6.8) at 37 °C with a paddle speed of 50 rpm. The formulations demonstrating the highest drug release profiles were chosen for in vitro digestion studies using Fasted State Simulated Intestinal Fluid (FaSSIF) and Fed State Simulated Intestinal Fluid (FeSSIF). The digestive media were prepared using Biorelevant 3F Powder™, reconstituted in malic acid buffer (pH 6.5) for FaSSIF and acetate buffer (pH 5.0) for FeSSIF. Lipolytic enzymes were prepared by mixing 1 g of porcine pancreatin extract in 5 mL of digestion buffer without Biorelevant 3F Powder™, then the suspension was centrifuged (4000 rpm for 15 minutes). A volume of 1 mL of each selected CBD SEDDS formulation (in triplicate) was dispersed into 36 mL of the respective media and incubated for 10 minutes. Digestion was initiated by adding 4 mL of pancreatin extract, and the digestion was continued for 30 minutes under agitation at 100 rpm and 37 °C. Samples were collected at two key time points: (1) 10 minutes after the dispersion of the CBD-SEDDS formulation in the media, but before the addition of pancreatin enzymes, and (2) 30 minutes after digestion, and enzyme addition. The collected samples were filtered through a 0.45 μm PVDF syringe filter to remove undissolved CBD, then diluted with a chloroform/methanol mixture (1:2, v/v). The concentration of solubilized CBD was subsequently quantified using HPLC.

Results: CBD-SEDDS formulations using Capryol® 90, Tween 20, and Transcutol® can form an emulsion within 1 minute or less. Formulations containing 40% Tween 20 or more produced emulsions with a particle size of less than 200 nm and a polydispersity index (PDI) of less than 0.3 (Figure 1). In vitro drug release, all CBD-SEDDS formulations enhanced the CBD release by at least 40% within 5 minutes compared to pure drug, which was below the detection limit. Furthermore, the six SEDDS formulations kept the drug solubility without any precipitation for 120 minutes. The formulations that contain 65% or more of Tween 20 showed drug release of more than 90% within 5 minutes (Figure 2), and these formulations were selected to examine their ability to maintain CBD in solubilized form even after the SEDDS formulations were dispersed and digested in FaSSIF and FeSSIF. CBD-SEDDS formulations kept 90% of the drug solubilized after dispersion (without digestive enzymes). All three SEDDS formulations were affected by digestion in FaSSIF, and their solubilization capacity for CBD was decreased. The formulation (CTT1), which contains higher oil content (20%), was more sustainable for digestion in the fasted state; however, it maintained around 50% CBD soluble. In the fed state, the media contains a higher amount of endogenous emulsifiers (bile salts and lecithin) that help to enhance CBD solubility after digestion compared to its solubility in fasted media (food effect) (Figure 3). Increasing the amount of Tween 20 decreases the variation between the solubility of CBD in FaSSIF and FeSSIF, which could lead to minimizing CBD susceptibility to food effects.

Conclusion: The in vitro dissolution and digestion study results demonstrate the promise of using CBD-SEDDS formulations to enhance CBD bioavailability and control intra- and inter-subject variation.

References: 1. Perucca E, Bialer M. Critical aspects affecting cannabidiol oral bioavailability and metabolic elimination, and related clinical implications. CNS drugs. 2020 Aug;34(8):795-800.
2. Kalepu S, Manthina M, Padavala V. Oral lipid-based drug delivery systems–an overview. Acta Pharmaceutica Sinica B. 2013 Dec 1;3(6):361-72.
3. Chime SA, Onyishi IV. Lipid-based drug delivery systems (LDDS): Recent advances and applications of lipids in drug delivery. Afr. J. Pharm. Pharmacol. 2013 Dec 29;7(48):3034-59


Figure 1. Mean of particle size and PDI for CBD-SEDDS formulations.


Figure 2. In Vitro release profile of pure CBD and CBD-SEDDS formulations in phosphate buffer pH (6.8).


Figure 3. The percentage of CBD solubilized after dispersion for 10 minutes in the digestive media without the pancreatin enzymes, and after 30 minutes of adding the pancreatin enzymes in fasted and fed media.