雙性聚多醣-矽膠奈米膠囊混成2-羥基乙基丙烯酸甲酯複合物水膠用於藥物傳輸之研究

Abstract

一般眼藥水會因眨眼，淚液稀釋、排出等反射動作而有所損失，以至於僅有5%的劑量可被眼睛吸收；此外，藥物停留至眼睛時間並不長，一旦藥物分子進入血液循環之中，可能會引發一些副作用。本實驗中藉由改質過後的兩性有機－無機幾丁聚醣混成分子與傳統水膠材料p(HEMA-MAA)合成出載體型複合性水膠材料。經由FT-IR與 13C-,29Si-固態核磁共振儀鑑定此兩性有機－無機幾丁聚醣混成分子之化學結構；此兩性有機－無機混成分子在水溶液中具有自組裝(self-assemble)的功能，可成為奈米級膠囊，作為包藥藥物的藥物載體。其自組裝形成的奈米載體之外觀形貌由掃描式電子顯微鏡(SEM)與穿透式電子顯微鏡(TEM)觀察；此外，粒徑分析由SEM、DLS偵測，發現其自組裝形成之粒徑與分子在水溶液中的濃度有關。在水膠材料分析上，經由SEM觀察到此載體型複合性水膠材料之表面型態；其光學特性則由紫外光/可見光光譜儀(UV-Vis spectrometer)分析，顯示此奈米載體於水膠材料中具有良好的分散性。在包覆藥物方法中，可由藥物分子本身對光敏感或水溶性不同，發展出兩種不同類型之包覆途徑：包覆型(encapsulation)，針對光穩定性良好或疏水性藥物；浸泡型(impregnation)則用於光敏感性或親水性藥物。在藥物釋放的探討上，分別採用抗生素藥物(AZM，疏水性藥物)及維生素藥物(Vitamin B12，親水性藥物)作為模擬藥物，皆可發現此複合性水膠具有兩階段式的藥物釋放：一開始為吸附在奈米載體表面及水膠間隙的藥物分子所造成之快速釋放，迅速使藥物濃度達到有效濃度；而後被包覆在奈米載體內部的藥物分子達到緩慢釋放，藉而維持眼睛中的藥物濃度，達到長時間療效。進一步發現藥物釋放情形受到此奈米載體/藥物濃度、環境溫度/酸鹼值之影響，亦與包覆藥物方法有關。此載體型複合性水膠材料進行細胞毒性檢測，本研究採用角膜內皮細胞(BCE)，結果與市售隱形眼鏡(ACUVUE)皆顯示相當好的存活率，代表此載體型複合性水膠材料具有優異的生物相容性。

Only about 5% of the dose delivered from an eye drop penetrates through the cornea to reach the intraocular tissue, while the rest is lost due to tear drainage. Besides, the dose has a short residence time in the film due to ocular barriers, and the presence of certain drugs in the bloodstream leads to undesirable side effects. In this study, incorporation of amphiphilic chitosan-crystalline silica hybrid macromolecule in a p(HEMA-MAA) hydrogel matrix prepared the particle-laden gels. The chemical structure of this hybrid molecule was characterized by FT-IR and 13C-, 29Si-nuclear magnetic resonance. Amphiphilic nature of the hybrid molecule rendered subsequent self-assembly forming nanocapsules in aqueous solutions. Structural morphology of the hybrid nanoparticles was investigated using scanning electron microscopy (SEM), transmission electron microscopy (TEM). And the mean size of the hybrid macromolecules was characterized by SEM and dynamic light scatter (DLS) measurements which demonstrated a concentration-dependent assembly size. On the other hand, structural morphology of the particle-laden gels was investigated using SEM. And the optical characterization of the particle-laden gels was measured by UV-Vis spectrometer which demonstrated the hybrid nanoparticles have great polydispersion in the polymerizing medium. In term of the drug loading method, according to photosensitivity or water solubility, developed two types of loading method: encapsulation, for non-photosensitive or hydrophobic drugs and impregnation, for photosensitive or hydrophilic drugs. A subsequent application to carry drugs of various degree toward water affinity (from water insoluble, azithromycin (AZM), to water soluble, Vitamin B12, following a controlled drug release in vitro has been systematically investigated. The experimental results indicated a long-term, sustained release profile for both types of drugs were monitored and release kinetics suggested a two-stage profile, suggesting a bimodal release pattern, and has been confirmed to be a result of drug distribution, i.e, within the nanocapsules and inter-capsule regions. Furthermore, the experimental results indicated the drug release behavior influences on hybrid/drug concentration, ambient temperature, pH-value medium, and drug loading method. And, the particle-laden gels showed an outstanding biocompatibility towards the BCE cell line, as well as the commercially lens, ACUVUE, suggest a promising vehicle for ocular drug delivery application.