Preparation and Evaluation of Self-emulsifying Drug Delivery System (SEDDS) of Cepharanthine

The aim of this article was to design a self-emulsifying drug delivery system (SEDDS) of loaded cepharanthine (CEP) to improve the oral bioavailability in rats. Based on the solubility determination and pseudo-ternary phase diagram, isopropyl palmitate (IPP) was chosen as the oil phase. Meanwhile, Cremophor RH40 and Macrogol 200 (PEG 200) were chosen as the emulsifier and co-emulsifier, respectively.

This prescription was further optimized by using central composite design of response surface methodology. The optimized condition was CEP:IPP:Cremophor RH40:PEG 200=3.6:30.0:55.3:11.1 in mass ratio with maximum drug loading (36.21 mg/mL) and the minimum particle size (36.70 nm). The constructed CEP-SEDDS was characterized by dynamic light scattering, transmission electron microscopy, in vitro release and stability studies. The dissolution level of CEP-SEDDS was nearly 100% after 30 min in phosphate-buffered saline (PBS, pH 6.8) which was higher than that of the pure CEP (approximately 20%).

In addition, in vivo pharmacokinetic study in rats showed that CEP-SEDDS dramatically improved bioavailability compared with active pharmaceutical ingredient (API) (the relative bioavailability was 203.46%). In this study, CEP-SEDDS was successfully prepared to enhance the oral bioavailability which might facilitate to increase its better clinical application.

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Introduction: Oral administration represents an attractive choice for systemic treatment which has advantages of less cost, convenience, and greater acceptability (1). With the gradual maturity and wide applications of computer-aided drug design, combinatorial chemistry, and high-throughput screening, the number of potential drug candidates with very low water solubility keeps increasing, as is known to all that dissolution is frequently the rate-limiting step in the gastrointestinal (GI) absorption, for the reason that the drug can only be absorbed from the GI tract if it is dissolved in the hydrous intestinal contents (2). Nevertheless, for many drugs that are insoluble in water, most of the dose is excreted after oral administration, resulting in low oral bioavailability.

Of the various physical and chemical factors that limit drug formation, low water solubility remains one of the most pervasive problems. For the sake of improving the solubility and oral bioavailability of insoluble drugs, many strategies have been adopted, such as solid dispersion (3), cyclodextrin complexation (4), lipid delivery (2), and micronization (5). Cyclosporin A (Sandimmune® and Nerol®), ritonavir (Kaletra®), sanquinavir (Fortovase®), and tipranavir (Aptivus®) have been marketed as lipid systems for oral pharmaceutical (6,7,8). In consequence, the study on lipid formulation has become a potential interest item for oral administration, especially for self-emulsifying drug delivery systems (SEDDS) (9,10,11,12). In SEDDS, drug molecules are thoroughly dissolved in the pre-concentrate consisting of the oil phase, emulsifier, and co-emulsifier. Once dispersed in the GI fluids, the O/W emulsion with a clear particle size of 10–500-nm emulsion is formed (13). In the fasting and feeding states, SEDDS tends to produce a reproducible drug concentration-time curve (AUC) after oral administration, and also plays a certain role in improving oral bioavailability (2,14). Relevant literature indicates that SEDDS is an effective method to improve the oral absorption, and bioavailability of insoluble drugs by improving their solubility and dissolution rate (15,16,17). In addition to drug solubility, gastrointestinal mucus barrier also plays a crucial role in oral absorption of drugs (18). Accordingly, there is an urgent need for innovative drug delivery systems to overcome that mucus barrier. SEDDS has attracted increasing attention because of its ability to conquer the mucous layer due to its small droplet size, charge, droplet surface, and shape deformation (19). Some studies have indicated that SEDDS can effectively overcome the mucus barrier and improve the oral bioavailability of the drug (20,21,22,23). By reason of the foregoing, SEDDS is effectively in improving oral bioavailability of insoluble drugs. Furthermore, SEDDS can be prepared in a simpler and more cost-efficient manner which is significant advantageous compared with other nanocarriers such as liposomes and nanoparticles (19).

Cepharanthine (CEP) is a bis-benzylisoquinoline alkaloid isolated from plants of Stephania genus in 1934 (24). In 1937, the application of CEP enormously reduced the average mortality rate among patients with severe pulmonary tuberculosis from 41 to 22% at the Yokohama Sanatorium in Japan (25). But it has since been superseded by more effective drugs (26). Nonetheless, the initial successful clinical application of CEP in the treatment of tuberculosis has encouraged its utilization in other pathological indications, such as anti-inflammation, analgesia, anti-virus, and anti-tumor activity (27,28,29,30). In the last few years, CEP has attracted increasing attention in research due to its distinct 1-benzylisoquinoline moiety similarities with natural polypeptides, physiological properties, and long-established remarkable safety profile (31). In December 2019, the emergence of the 2019 novel coronavirus disease (labeled COVID-19), caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has posed an unprecedented challenge to global public health. In a large drug screen of 2406 clinically approved drugs, CEP was recently identified as the most effective drug against SARS-CoV-2-related pangolin coronavirus. CEP has become a drug of interest for treating COVID-19 (31,32,33). It is suggested that CEP is not a “one pill fits all” medication but certainly an under-explored drug which should be reconsidered (34). Increasing studies have indicated that CEP has a variety of pharmacological activities, implying that will play a crucial role in clinical trials. Nevertheless, CEP has the defect of low water solubility and low direct oral bioavailability which limit its pharmacological validity (35). The absolute bioavailability of CEP by oral route was only 5.65 ± 0.35% in rats (36). Therefore, it is urgent to explore effective means to boost oral bioavailability to meet the clinical needs of CEP.

In this work, we examined whether these shortcomings could be overcome by enacting CEP in SEDDS. The oil phase, emulsifier, and co-emulsifier were studied by single factor experiment, pseudo-ternary phase diagram, and central composite design, screening out the best prescription. CEP was dissolved in SEDDS pre-concentrate consisting of oil, emulsifier, and co-emulsifier. Upon dispersion of the pre-concentrate in aqueous media, the O/W emulsion was formed. The properties of CEP-SEDDS were characterized by particle size and size distribution, particle morphology, drug release, and stability experiments in vitro. This dosage form was applied to a pharmacokinetic study in rats to further elucidate the superiorities.

Materials: CEP was provided by Hubei Xingyinhe Chemical Co., Ltd. (Hubei, China). Transcutol P, Labrasol, and Labrafac Lipohile WL 1349 were obtained from Gattefossé Co. (Lyon, France). Cremophor EL, Primary Alcobol Ethoxylate (AEO-9), Kolliphor ELP, and Cremophor RH40 were kindly donated by BASF (Ludwigshafen, Germany). Castor oil and Capryliccapric triglyceride (GTCC) were purchased from Beijing FengliJingqiu Trading Co., Ltd. (Beijing, China). Macrogol 400 (PEG 400), Macrogol 200 (PEG 200), Polysorbate-80 (Tween-80), Isopropyl palmitate (IPP), and Isopropyl myristate (IPM) were purchased from Tianjin Komiou Chemical Reagent Co., Ltd. (Tianjin, China). Heparin sodium (>150 IU/mg) and isoflurane were received from the Dalian Meilun Biological Technology Co., Ltd. (Liaoning, China). Propranolol hydrochloride was obtained from Changzhou Yabang Pharmaceutical Co., Ltd. (Jiangsu, China). All other chemicals used in the experiments were analytical reagent grade and were obtained from local sources.

Article information: Yang, X., Gao, P., Jiang, Z. et al. Preparation and Evaluation of Self-emulsifying Drug Delivery System (SEDDS) of Cepharanthine. AAPS PharmSciTech 22, 245 (2021). https://doi.org/10.1208/s12249-021-02085-9