口服投藥對病患來說，是一最舒適且高接受度的給藥方式。然而口服疏水性藥物在腸道內由於容易自我聚集而無法被有效地分散和吸收，進而導致口服之生物可利用率普遍偏低。因此本研究建立一能於小腸內自我乳化脂質奈米油珠載體於口服難吸收之藥物，用以改善上述問題。此載體系統共包含四種材料: paclitaxel, capric acid, sodium bicarbonate, 與citric acid。paclitaxel為疏水性小分子抗癌藥物且應用於胰臟癌之第一線抗癌療程。脂質capric acid大量的存在於天然椰子油與動物乳奶中，而sodium bicarbonate與citric acid 為市面上泡騰片(effervescent tablet)之常見成分。這些材料，僅需在充分混合後，即可填充於一膠囊中，做成一創新的口服劑型。此一腸溶膠囊在口服後，通過食道、胃到了小腸後，膠囊外的腸溶衣在偏中性的環境下開始溶解，膠囊內的citric acid遇到腸液後隨即釋出質子(proton)產生一酸性環境。此酸性環境促使sodium bicarbonate裂解產生CO2氣泡，而腸道內之膽鹽(bile salt)具有界面活性劑的特性可隨之穩定CO2氣泡結構，並以其形成的氣泡載體攜帶脂質capric acid與疏水藥物paclitaxel。此載體在腸道內會由氣泡主動推散，當超過氣泡所能承受之表面張力時，氣泡會破裂進而自我乳化形成一脂質奈米油珠載體來裝載疏水藥物，使得疏水小分子藥物在此載體的幫助下能有效地分散在腸道之中減少疏水藥物的聚集現象，藉此大幅提升腸道吸收效率。於biodistribution實驗結果可推測疏水藥物可藉由腸淋巴系統運輸至胰臟。未來將利用此口服載體用以投遞藥物至胰臟以提升胰臟癌之治療效果，並在大鼠胰臟癌模型進一步探討此載體搭載paclitaxel治療胰臟癌之功效。

Oral therapeutic agents offer the advantages of greater convenience, ease of administration, and their associated complications and costs. Among all of the oral therapeutic agents, small molecule hydrophobic drugs have poor water solubility, and oral delivery of such drugs is limited by difficulties, including poor solubility, low permeability, instability, and rapid metabolism, all of which cause low oral bioavailability. To address these issues, we developed a self-emulsified lipid oil drops drug delivery system, the system including four compounds — sodium bicarbonate (SBC), citric acid, capric acid, together with hydrophobic drug (paclitaxel). The powder mixture can self-assembly undergo 3-stage structural transformations after encountering intestinal fluid: First, the test powder produces a CO2 bubble carrier system in aqueous phase where capric acid and paclitaxel encapsulated in the hydrophobic tail of bile salt. Next, these bubble carriers gradually float to the air-water interface due to their density with structural transition of which capric acid and paclitaxel is distributed from single layer to double layer once exposing to air. Finally, those of bubble carriers burst owing to their surface tension, and followed by a capric acid and paclitaxel loaded carriers with a particle size range around 200 nm mechanically emulsified in intestinal fluid. This carrier system can facilitate paclitaxel uptake through M-cellular endocytosis, which locate on the intestinal tract and can be visualized by CLSM. Afterward, the IVIS results suggested that those of delivered hydrophobic drug were underwent lymphocyte and then were specifically shipped into lymphatic system nearby pancreas tissue through the lymphatic drainage between intestinal and pancreas lymphatic channel. It is a niche to orally treat pancreas disease like pancreatic cancer.

【1】Vu Truong-Le, Phillip M. Lovalenti, Ahmad M. Abdul-Fattah, Stabilization Challenges and Formulation Strategies Associated with Oral Biologic Drug Delivery Systems, Advanced Drug Delivery Reviews, 2015, 93, 95-108.
【2】Craig L. Maynard, Charles O. Elson, Robin D. Hatton & Casey T. Weaver, Reciprocal interactions of the intestinal microbiota and immune system, Nature, 2012, 489, 231-241.
【3】Yuwei Duan, Baomei Zhang, Lianjun Chu, Henry HY Tong, Weidong Liu, Guangxi Zhai, Evaluation in vitro and in vivo of curcumin-loaded mPEG-PLA/TPGS mixed micelles for oral administration, Colloids and Surfaces B: Biointerfaces, 2016, 141, 345–354.
【4】Horwitz, S. B., Taxol (paclitaxel): mechanisms of action. Annals of oncology : official journal of the European Society for Medical Oncology, 1994, 5.
【5】Rowinsky EK, Chaudhry V, Cornblath DR, Donehower RC, Neurotoxicity of Taxol, J Natl Cancer Inst Monogr. 1993, 15, 107-15.
【6】H Gelderblom, J Verweij, KNooter, A Sparreboom, Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation, European Journal of Cancer, 2001, 13, 1590-1598.
【7】Sam Maher, Thomas W,.Leonard Jette, Jacobsen David, J.Brayden., Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic, Advanced Drug Delivery Reviews, 2009, 17,1427-49.
【8】Jacob S, Shirwaikar A, Nair A, Preparation and evaluation of fast-disintegrating effervescent tablets of glibenclamide, Drug Dev. Ind. Pharm., 2009, 35, 321-8.
【9】Sandeep Kalepu, Mohanvarma Manthina, Veerabhadhraswamy, Padavala, Oral lipid-based drug delivery systems – an overview, Acta Pharmaceutica Sinica B, 2013, 3, 361-372.
【10】Arshad Ali Khan, Jahanzeb Mudassir, Noratiqah Mohtar, Yusrida Darwis, Advanced drug delivery to the lymphatic system: lipid-based nanoformulations, International Journal of Nanomedicine, 201, 8, 2733–2744.
【11】Rucki, A. A., Zheng, L., Pancreatic cancer stroma: understanding biology leads to new therapeutic strategies, World journal of gastroenterology, 2014, 20, 2237-2246.
【12】Anastasios Dimou, Konstantinos N. Syrigos, Muhammad Wasif Saif, Overcoming the stromal barrier: technologies to optimize drug delivery in pancreatic cancer, Ther. Adv. Med. Oncol., 2012, 4, 271-79.
【13】Shery Jacob, Arun Shirwaikar, Anroop Nair, Encapsulation of Pancreatic Lipase in Hydrogel Beads with SelfRegulating Internal pH Microenvironments: Retention of Lipase Activity after Exposure to Gastric Conditions, Drug Development and Industrial Pharmacy, 2009, 35, 321–328.
【14】Yao HJ, Ju RJ, Wang XX, Zhang Y, Li RJ, Yu Y, Zhang L, Lu WL, The antitumor efficacy of functional paclitaxel nanomicelles in treating resistant breast cancers by oral delivery, Biomaterials, 2011, 32, 3285-302.
【15】He R, Yin C, Trimethyl chitosan based conjugates for oral and intravenous delivery of paclitaxel, Acta Biomater, 2017, 15, 355-366.
【16】Er-Yuan Chuang, Kun-Ju Lin, Tring-Yo Huang, Hsin-Lung Chen , Yang-Bao Miao, Po-Yen Lin, Chiung-Tong Chen, Jyuhn-Huarng Juang, Hsing-Wen Sung, An Intestinal “Transformers”-like Nanocarrier System for Enhancing the Oral Bioavailability of Poorly Water-Soluble Drugs, Acs nano, 2018.
【17】Rui He, Chunhua Yin, Trimethyl chitosan based conjugates for oral and intravenous delivery of paclitaxel, Acta Biomater, 2017, 53, 355-366.
【18】Suha Attili-Qadria, Nour Karraa, Alina Nemirovskia, Ouri Schwoba, Yeshayahu Talmonb, Taher Nassara, Simon Benitaa, Oral delivery system prolongs blood circulation of docetaxel nanocapsules via lymphatic absorption , Proc Natl Acad Sci U S A.,2013, 22, 110.
【19】Hubert G. Hotz, Howard A. Reber, Birgit Hotz, Thomas Foitzik, Heinz J. Buhr, Galen Cortina, O. Joe Hines, An Improved Clinical Model of Orthotopic Pancreatic Cancer in Immunocompetent Lewis Rats, Pancreas 2001, 22, 113–121.