開發泊洛沙姆溫敏感原位凝膠作為苯丁酸鈉和苯丁酸膽鹼鹽之眼部遞藥系統治療隅角開放性青光眼

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Title:	開發泊洛沙姆溫敏感原位凝膠作為苯丁酸鈉和苯丁酸膽鹼鹽之眼部遞藥系統治療隅角開放性青光眼 Development of thermosensitive in situ poloxamer gels as ocular drug delivery systems of phenylbutyrate sodium and choline salts for the treatment of open-angle glaucoma
Authors:	許宸瑄 HSU, CHEN-HSUAN
Contributors:	藥學系碩士班鄭幼文許明照
Keywords:	隅角開放性青光眼;苯丁酸鈉;苯丁酸膽鹼鹽;溫敏感性原位水凝膠 Open-angle glaucoma;thermosensitive in situ gel;sodium phenylbutyrate;choline phenylbutyrate
Date:	2023-06-12
Issue Date:	2024-01-22 15:34:54 (UTC+8)
Abstract:	隅角開放性青光眼 (Open-angle glaucoma, OAG) 是一種慢性疾病，他會導致高眼壓和視神經壓迫，可能引起永久性視力損害。目前，非侵入性眼藥水被已廣泛作為藥物給予的方式，但其生物利用率低，導致需頻繁給藥的缺點。本研究以苯丁酸鈉 (Sodium phenylbutyrate, SPB) 與苯丁酸膽鹼鹽 (Choline phenylbutyrate, CPB) 作為治療OAG的模式藥物，並搭載於以泊洛沙姆407 (Poloxamer 407, P407) 及羥丙基甲基纖維素 (Hydroxypropyl methylcellulose, HPMC)製備的溫敏感性原位水凝膠中。在後續配方中，將分別使用代號P表示poloxamer以及H表示HPMC各添加物。兩種藥物CPB及SPB添加至膠體處方後，分別選擇滯留效果最佳CPB1.63P13H3與SPB1.13P13H3處方。在溶液-凝膠轉換溫度測定及流變學研究中顯示，CPB1.63P13H3與SPB1.13P13H3溶液-凝膠轉換溫度為26.7 ± 0.6 °C與29.3 ± 0.8 °C，且均具有剪切稀化之流體特性，展現出適合應用於眼科治療之特性。離體穿透試驗顯示溶液製劑與凝膠製劑相比下，凝膠系統相較溶液系統展現出更長滯留時間並實現藥物控釋之效果。長期活體小鼠試驗中，使用了Dexamethasone acetate (DEX-acet) 誘導的青光眼動物模式實驗結果顯示，單獨處理DEX-acet可明顯誘發小鼠高眼壓、視神經功能下降以及平均血流速度減少等典型青光眼症狀。並於組織病理切片，以免疫螢光染色分析可觀察到小梁網 (Trabecular Meshwork, TM) 細胞上細胞外基質 (Extracellular Matrix, ECM) Collagen I與Fibronectin積累效果產生，與控制組相較之下顯著的增加。當同時以CPB與SPB凝膠處理後發現兩種藥物均顯著逆轉DEX-acet誘導小鼠之高眼壓、視神經損傷 (oscillatory potentials, Ops) 以及平均血流的下降。此外CPB與SPB凝膠亦顯著降低了DEX-acet誘發的 Collagen I與Fibronectin的堆積。綜合以上的活體小鼠試驗結果，我們發現CPB與SPB凝膠可有效的降低DEX-acet所誘導得青光眼相關症狀。同時我們也利用小鼠眼底攝影、螢光血管造影以及眼底雷射光學相干斷層掃描對所有試驗組別進行視網膜檢查，並發現無論是DEX-acet或是處理藥物 (CPB與SPB)，皆不會對視網膜結構產生損傷。這也進一步證實我們以DEX-acet誘發高眼壓疾病模式只會誘發小鼠眼睛功能性改變。此外同時驗證處理藥物 (CPB與SPB) 在此處理方式下亦不會對小鼠視網膜結構造成毒性傷害。我們的結果證實，CPB與SPB結合於凝膠系統後可以達到合適的溶液-凝膠轉換溫度，增加藥物在角膜上滯留時間，並有效地減輕青光眼誘發的高眼壓、視神經損傷與ECM堆積。我們希望此研究能夠提供新的青光眼治療選擇。 Open-angle glaucoma (OAG) is a chronic disease that causes elevated intraocular pressure and optic nerve compression, potentially leading to permanent vision damage. At present, non-invasive eye drops are widely used for drug delivery, but their relatively low bioavailability necessitates frequent administration. In this study, we used sodium phenylbutyrate (SPB) and choline phenylbutyrate (CPB) as model drugs for treating OAG. These drugs were loaded into thermosensitive in situ hydrogels prepared with poloxamer 407 (P407) and hydroxypropyl methylcellulose (HPMC). In the subsequent formulations, the additives will be referred to by the following codes: P for poloxamer and H for HPMC. After adding CPB and SPB to the gel formulations, we selected the one with the best retention effects, CPB1.63P13H3 and SPB1.13P13H3. The sol to gel transition temperatures for CPB1.63P13H3 and SPB1.13P13H3 were 26.7 ± 0.6 °C and 29.3 ± 0.8 °C, respectively. Both exhibited shear-thinning fluid characteristics, demonstrating their suitability for ophthalmic treatment. Ex vivo permeation tests showed that, compared with solution formulations, the gel systems exhibited longer retention times and achieved drug release control compared to solution systems. Long-term in vivo experiments on a dexamethasone acetate (DEX-acet) -induced glaucoma mouse model showed that treatment with DEX-acet alone significantly induced typical glaucoma symptoms in mice, such as elevated intraocular pressure, reduced optic nerve function, and decreased average blood flow rate. Furthermore, immunofluorescence staining of histopathological slices revealed a significant increase in Collagen I and Fibronectin accumulation in Trabecular meshwork (TM) cells compared to the control group. However, concurrent treatment with CPB and SPB gels significantly reversed these DEX-acet induced effects in mice, including high intraocular pressure, optic nerve damage (Oscillatory potentials, Ops) , and decreased average blood flow rate. In addition, CPB and SPB gels significantly reduced DEX-acet induced Collagen I and Fibronectin accumulation. Based on these in vivo mouse experiment results, we found that CPB and SPB gels can effectively alleviate DEX-acet induced glaucoma symptoms. Furthermore, using fundus photography, fluorescein angiography, and optical coherence tomography (OCT) for retinal examination of all test groups, we found that neither DEX-acet nor drug treatment (CPB and SPB) caused structural damage to the retina. This further confirms that our DEX-acet induced high intraocular pressure disease model only induced functional changes in the eyes of mice. In addition, it validated that the treatment drugs (CPB and SPB) do not cause toxic damage to the mouse retina under this treatment modality. Our research results confirm that when CPB and SPB are combined with the gel system, an appropriate solution-gel transition temperature can be achieved, increasing drug retention time on the cornea and effectively alleviating glaucoma-induced high intraocular pressure, optic nerve damage, and extracellular matrix (ECM) accumulation. We hope this research can provide a new option for treating glaucoma.
Description:	碩士指導教授:鄭幼文共同指導教授:許明照委員:鄭幼文委員:許明照委員:何秀娥委員:蕭哲志委員:邱士娟
Data Type:	thesis
Appears in Collections:	[School of Pharmacy] Dissertation/Thesis

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