| 摘要: | 口服投與因其使用之便利性，在藥物傳遞技術的領域中一直佔有優勢地位，但對於一些具良好溶解度但易大量於肝臟中代謝，容易被腸道上皮細胞排出（不良穿透率），或刺激胃黏膜者，例如分類於美國食品藥物管理局之生物藥劑學分類系統（BCS）的第III類藥物藥物而言，仍存在一些無法口服吸收的問題。現行之三元系相圖(Ternary phase diagram)平衡原理「自微乳化藥物輸送系統（SMEDDS）」技術，主要應用於增進親脂性藥物之口服生物可利用率。本研究以親水親油二相平衡 (Hydrophile-lipophile babance，HLB)原理進行口服自微乳化傳輸技術開發，以運用於增進親水性藥物的口服生體可用率及安定性。
親水性癌症化療用藥Gemcitabine因口服生體可用率低，現僅可以用靜脈輸注給藥，本研究以Gemcitabine為模式藥物進行親水性口服自微乳化傳輸系統配方開發，經評估其藥物之相容性、溶離率、穿透率及安定性後選定D07001-F4為Prototype配方進行各項相關研究。體外藥物rhCDA deamination試驗用來評估D07001-F4對CDA藥物代謝的影響，並以mice動物模式進行藥物動力學研究。另藉由比較D07001-F4 及Gemcitabine hydrochloride 對體外八種不同癌症細胞秼生長存活試驗研究及二種不同腫瘤之異位移植腫瘤試驗，以評估D07001-F4在抗腫瘤活性。
研究結果顯示，以INNO-4 oilless SMEDDS技術平台所得之最適化配方D07001-F4可獲得澄清的SMEDDS溶液配方，並具良好的配方相容性、體外溶離釋放速率及藥物安定性。另以6mg/mL藥物濃度進行SMEDDS配方與對照組Gemcitabine HCl Solution進行體外Caco-2 cells藥物穿透試驗，結果顯示經由SMEDDS設計之Gemcitabine配方具較佳之藥物穿透率。本研究亦進行體外D07001-F4及Gemcitabine HCl被rhCDA deamination的代謝速率之比較，結果顯示D07001-F4跟Gemcitabine HCl相比可減緩3.3倍CDA對Gemcitabine deamination的速率。另以八種不同的人類癌症細胞秼進行細胞存活率試驗結果顯示，D07001-F4相較於Gemcitabine HCl在其中七種細胞秼具更佳的細胞毒殺效果，其活性增進2-7750倍。在裸鼠異位移植腫瘤試驗(xenograft tumor model )結果，口服D07001-F4 可有效的抑制老鼠的胰臟癌及大腸癌之異位腫瘤生長。在口服D07001-F4藥物動力學試驗結果顯示，以mice為模式動物其生體可用率為34%及47%。
結論本研究所開發之親水性藥物自微乳化傳輸系統，在以Gemcitabine為模式藥所得的配方D07001-F4，能減低CDA酵素對藥物的代謝，進而增進藥物在胃腸道中之安定性而促進藥物之口服生體可用率。另無論在體外的腫瘤細胞存活試驗或異位移植腫瘤試驗中都顯示D07001-F4具抗腫瘤之效果。
Oral administration is a convenient and user-friendly mode of drug administration, which continues to dominate the area of drug delivery technologies. Even though many types of drugs could be administered orally with acceptable efficacy, there remains a problem for some classes of drugs, especially those which are known to have good solubility, but are extensively metabolized in the liver, easily degraded by enzyme of the gastrointestinal track , easily pumped out by the intestinal epithelium (poor permeability) or irritative to the gastric mucosa, such as class III drugs of Biopharmaceutics Classifictaion System (BCS) provided by the U.S. Food and Drug Administration. For these drugs, injection administration become the major option to achieve acceptable drug absorption and bioavailability.
Self-microemulsifying drug delivery system (SMEDDS) have been developed in the art which provides a good vehicle to improve bioavailability of hydrophobic drugs and make their oral delivery possible. However, for hydrophilic drugs, there are limitations to make them suitable in the SMEDDS. Other strategies, e.g. liposomes. Microparticles or prodrugs have been reported to enhance the bioavailability of hydrophilic drugs, Therefore, this study intended to develop an oral dosage form of hydrophilic drugs, especially an oral self-emulsifying pharmaceutical composition with good bioavailability and stability.
The chemotherapy agent Gemcitabine is currently administered intravenously because the drug has poor oral bioavailability. A novel SMEDDS oral formulation of Gemcitabine D07001-F4, was developed in this study. In order to assess the pharmacokinetics and antitumor activity of oral SMEDDS Gemcitabine formulation , this study also performed to compare the effect of D07001-F4 with administered Gemcitabine in vitro and in vivo. Methods D07001-F4 pharmacokinetics was examined by evaluation of in vitro deamination of D07001-F4 and Gemcitabine hydrochloride by recombinant human cytidine deaminase (rhCDA) and in vivo evaluation of D07001-F4 pharmacokinetics in mice and beagle dogs. Antitumor activity was evaluated by comparing the effect of D07001-F4 and Gemcitabine hydrochloride in inhibiting growth in nine cancer cell lines and by examining the effect of D07001-F4 and Gemcitabine in two xenograft tumor models in mice. The results showed that D07001-F4 formulation based on the oilless SMEDDS platform had good compatibility, dissolution rate and stability.
In vitro Caco-2 permeability study of D07001-F4 are presented at 6.0 mg/mL test concentration, the R960914-2 formulation showed better permeability than the drug substance solution. In vitro deamination of D07001-F4 by rhCDA was 3.3-fold slower than deamination of Gemcitabine hydrochloride. Growth inhibition by D07001-F4 of 7 of the 8 cancer cell lines was increased compared with that seen with Gemcitabine hydrochloride, and D07001-F4 inhibited the growth of pancreatic and colon cancer xenografts. In vivo pharmacokinetics showed the oral bioavailability of D07001-F4 to be 34-47 % in mice and over 70% in beagle dogs. Conclusions D07001-F4 was effective against several cancer types, was metabolized more slowly than Gemcitabine hydrochloride, and exhibited enhanced oral bioavailability. |
