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

本文的目的是设计一个负载头氨酸（CEP）的自乳化药物输送系统（SEDD），以改善大鼠的口服生物利用度。根据溶解度测定和伪内相图，选择异丙酸酯（IPP）作为油相。同时，分别选择了Cremophor RH40和Macrogol 200（PEG 200）作为乳化剂和抗乳液。

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 vitrorelease 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%).

此外,in vivopharmacokinetic 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.

的各种物理和化学因素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).

头骨（CEP）是一种从植物中分离的双苯二唑喹啉生物碱Stephania genusin 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.

在这项工作中，我们检查了是否可以通过在SEDD中制定CEP来克服这些缺点。通过单因子实验，伪内图和中央复合材料设计研究了油相，乳化剂和共乳化剂，从而筛选出最佳的处方。将CEP溶解在由石油，乳化剂和共乳化剂组成的SEDDS预浓度中。在浓缩培养基中浓缩的浓度后，形成了O/W乳液。CEP-SEDD的特性以粒度和尺寸分布，颗粒形态，药物释放和稳定性实验为特征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).经烧醇p，，，，Labrasol，，，，andLabrafac Lipohile WL 1349从Gattefossé公司（法国里昂）。Cremophor EL，原代乙氧基甲氧基（AEO-9），Kolliphor ELP，，，，andCremophor RH40were kindly donated byBASF（德国路德维希芬（Ludwigshafen））。蓖麻油和磷酸甘油酸甘油三酸酯（GTCC）购自北京河口贸易公司（Fenglijingqiu）贸易有限公司（中国北京）。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.

文章信息：Yang，X.，Gao，P.，Jiang，Z。et al.Preparation and Evaluation of Self-emulsifying Drug Delivery System (SEDDS) of Cepharanthine.AAPS PharmSciTech22,245 (2021). https://doi.org/10.1208/s12249-021-02085-9