| 摘要: | 植物活性物質 (Phytochemicals) 對於促進健康、預防及治療疾病擁有極大的潛力，但由於低溶解度、低穩定度、低生體可用率及低標靶專一性的限制，無法廣泛地在臨床上應用。本實驗使用薄膜水合法製備自組型卵磷脂混合型微胞，結合卵磷脂與多種兩性物質 (如：TPGS, Pluronic®, Cremophor®, Sodium deoxycholate (NaDOC) ) 作為植物活性物質 (薑黃素、和厚朴酚/厚朴酚、白藜蘆醇) 載體，篩選最佳化之藥物傳遞系統及探討比較不同比例之卵磷脂與不同兩性物質對微胞形成之影響，以及改善植物活性物質溶解度及生體可用率。
本研究利用薄膜水合法製備混合型微胞，開發出兩個系統，一個為NaDOC與卵磷脂組成，利用此系統包覆薑黃素與和厚朴酚/厚朴酚，最佳處方比例為活性成分、卵磷脂與NaDOC分別為2:1:5與6:2:5，粒徑大小分別為111.6 ± 4.24 (PI = 0.327±0.021) 與147.1 ± 31.11 (PI = 0.052±2.137) nm，藥物負載率分別為26.3及44.4%，而藥物包覆率皆在95%以上。另一個系統則為Pluronic® P123與卵磷脂形成的混合型微胞，此系統可以包覆四種植物活性物質 (薑黃素、和厚朴酚/厚朴酚、白藜蘆醇)，活性成分、卵磷脂與Pluronic® P123最佳比例分別為5:2:20、1:1:10及5:2:20 ，粒徑大小為143.1 ± 1.72 (PI = 0.654±0.032)、177.5 ± 39.97 (PI = 1.118±0.063) 與132.2 ± 9.62 (PI = 1.297±0.255) nm，藥物負載率分別為16、9.8及19.3%，而藥物包覆率皆在85%以上。兩種藥物傳遞系統皆將植物活性物質的水溶解度提升至6 mg/ml。
其中使用NaDOC形成的微胞其藥物負載率較高且PI值較小，表示粒徑分布範圍會比較狹窄，在體外釋放實驗中顯示有速放的效果，而Pluronic® P123之包覆系統在體外實驗中具有緩釋效果，且適量增加卵磷脂的含量會促進其包覆率上升。在儲存安定性方面，除了薑黃素微胞僅能在室溫下儲存14天，在包覆和厚朴酚/厚朴酚與白藜蘆醇中皆可在室溫儲存長達56天以上。而在血漿中的穩定性則可以發現，雖然Pluronic® P123混合型微胞較容易受血漿蛋白影響，但其穩定性會優於NaDOC混合型微胞，證明高分子微胞穩定性比傳統界面活性劑微胞佳。在大鼠實驗中靜脈注射混合型微胞Curcumin、Honokiol-Magnolol，可將絕對生體可用率提高至573、323及499%，而口服給予時，絕對生體可用率分別提高至2、8及31.8%，由此可知將植物活性物質製備為自組裝型卵磷脂混合微胞可以成功改善其生體可用率。
Phytochemicals have great potential for maintaining and promoting health, as well as preventing and potentially treating some diseases. However, the low solubility, stability, bioavailability and target specificity generally have limited clinical application. In this study, the solubility of four phytochemicals (Curcumin/Resveratrol/Honokiol-Magnolol) was in an attempt to be enhanced by encapsulating in self-assembly lecithin-based mixed micelles composed of lecithin and several amphiphilic material (TPGS/Pluronic®/Cremophor®/Sodium deoxycholate).
Self-assembly lecithin-based mixed micelles for phytochemicals were prepared by using thin film hydration method. Two mixed polymeric micelles containing lecithin and either amphiphilic materials Sodium deoxycholate (NaDOC) or Pluronic® P123 were found to be optimal to encapsulate curcumin, honokiol/magnolol, and resveratrol. The optimized ratios of mixed micelles containing lecithin and NaDOC were 2:1:5 and 6:2:5 (phytochemicals:lecithin:NaDOC). The particle size of these micelles were 111.6 ± 4.24 (PI = 0.327±0.021) and 147.1 ± 31.11 (PI = 0.052±2.137) nm, drug loading were 26.3% and 44.4%, and the encapsulation efficacy (E.E.) were all above 95%. Another optimal mixed polymeric micelles containing lecithin and Pluronic® P123 could encapsulate four phytochemicals (Curcumin / Honokiol & Magnolol / Resveratrol), the optimized ratios of this system were separately 5:2:20, 1:1:10 and 5:2:20. The particle size of each phytochemicals were 143.1 ± 1.72 (PI = 0.654±0.032), 177.5 ± 39.97 (PI = 1.118±0.063) and 132.2 ± 9.62 (PI = 1.297±0.255) nm, drug loading were 16%, 9.8% and 19.3%, and the E.E. were all above 85%. The solubility of NaDOC and Pluronic® P123 systems were all up to 6 mg/mL.
The mixed micelles formed by NaDOC had higher E.E. and narrower particle distribution. In vitro study indicated immediate-release profile. The mixed polymeric micelles containing Pluronic® P123 could improve E.E. with increasing the amount of lecithin and sustained release profiles were observed correspondingly. Regarding storage stability, the mixed micelles of both systems could be maintained stable up to 56 days at room temperature except those containing curcumin. In the serum stability test indicated that although the integrity of Pluronic® P123 mixed micelles might be affected by serum protein, it demonstrated to be more stable than the NaDOC system. In pharmacokinetics study, intravenous administration of the mixed micelles containing curcumin and honokiol-magnolol was found to significantly increase the absolute bioavailability to 573%, 323% and 499%, and oral administration of the mixed micelles could increase absolute bioavailability to 2%, 8% and 31.8%. It seems that this novel phytochemicals-loaded self-assembly lecithin-based mixed micelles can be used to improve their absolute bioavailabilities. |
