發展柳氮磺吡啶之固化自微乳化藥物遞送系統

Abstract

自微乳化藥物遞送系統 （Self-microemulsifying drug delivery system, SMEDDS）是目前用來提高難溶解口服藥物生體可用率（Bioavailability）的一種方法。這種藥物載體是由油 (oil)、介面活性劑 (surfactant)和共溶劑 (cosolvent)所組成，在特定比例下，這三種成分可以順利混溶而不發生相分離。由於SMEDDS內部含有介面活性劑和共溶劑，可以提高水溶性差藥物的溶解度，當SMEDDS與人體腸道中的水接觸後，可以快速自乳化，形成微小的油滴，使藥物更容易被吸收，進一步提高藥物的生體可用率。柳氮磺吡啶 （Sulfasalazine）是一種合成藥物，目前在臨床上用於治療類風濕性關節炎、潰瘍性結腸炎和其他類似的炎症性腸道疾病。然而，由於其低水溶解度和高滲透性特性，若能提高磺胺嘧啶的水溶解度，即有提升其生體可用率的可能。 本研究的目的在於探討何種條件是最適合製備出穩定且含有最高藥物含量的固化SMEDDS。在SMEDDS的研究中，最終所篩選出的SMEDDS配方在溶離後粒徑約30 nm，PDI為0.181，最大的載藥量為12.5 mg/mL。為提高SMEDDS長時間儲存的穩定性我們進一步利用噴霧乾燥 (spray drying)技術，並使用親水性載體葡萄聚醣和疏水性載體矽酸鈣將SMEDDS製備成固化SMEDDS (solidified SMEDDS, s-SMEDDS)，來評估這兩種不同載體與SMEDDS的比例對於噴霧乾燥過程的影響。並透過實驗設計的方式優化s-SMEDDS，找出能乘載最高藥物含量的固化SMEDDS配方。最終確認的s-SMEDDS配方為SMEDDS 64.25 %、葡萄聚醣35.75 %，其製備後的產率為90 %，藥物回收率達到85 %，其藥物乘載劑量為10.5 mg/g。在藥物釋放率試驗中，SMEDDS及優化後固化SMEDDS在4小時內釋放80 %的藥物。安定性試驗中藥物含量在3個月內也維持在90 %之上。藥物動力學試驗中，SMEDDS和優化後的s-SMEDDS的血液中最高濃度 (Cmax)遠高於游離藥物，相對生體可用率分別增加2.3和2倍。綜合上述結果，SMEDDS及優化固化SMEDDS製劑皆成功製備，兩種製劑皆有表現出色的安定性和藥物釋放能力，同時在生體可用率上也有明顯提高。

Self-microemulsifying drug delivery system (SMEDDS) has been used to enhance thesolubility and bioavailability of poorly water soluble drugs for oral administration. This drug carrier consists of oil, surfactant, and cosolvent at specific ratios, which can dissolve drug without phase separation. In the gastrointestinal tract, SMEDDS spontaneously Self-emulsify and form small oil droplets, facilitating drug absorption and further enhancing drug bioavailability. Sulfasalazine is a synthetic drug currently used to treat rheumatoid arthritis, ulcerative colitis, and other similar inflammatory bowel diseases in clinic. In this study, the SMEDDS and solidified SMEDDS (s-SMEDDS) was developed to encapsulate sulfasalazine with the characteristics of low water solubility and high permeability. To identify the Self-emulsifying regions, a pseudoternary phase diagram was constructed by mixing the selected excipients at various ratios. An optimal SMEDDS incorporating sulfasalazine (SSZ SMEDDS) was generated in the formulation of peanut oil 20 %、TPGS 70%、Transcutol® P 10%. The particle size, PDI and drug content in the SSZ SMEDDS is about 30 nm, 0.181 and 12.5 mg/mL, respectively. Furthermore, spray drying technology is used to convert the SMEDDS into s-SMEDDS, aiming to enhance the long-term stability of SSZ SMEDDS. The formulation of SSZ s-SMEDDS was optimized by experimental design. The final SSZs-SMEDDS formulation was 64.25 % SMEDDS and 35.75 % dextran, capable of carrying 10.5 mg/g of drug. The fabricated SSZ SMEDDS and s-SMEDDS were well dispersed well in aqueous solutions without any problems of physical or chemical stability. The dissolution profiles of sulfasalazine in the SMEDDS and s-SMEDDS were similar with 80% of drug release within 4 hours. The in vivo pharmacokinetic study shows that the maximum concentration (Cmax) of optimized SMEDDS and s-viSMEDDS in the blood was significantly higher than that of free drugs, increasing the relative bioavailability by 2.3 and 2 times, respectively. These results demonstrated that the formulation of s-SMEDDS incorporating sulfasalazine can significantly increase drug solubility and stability, enhance drug absorption, leading to increased oral bioavailability