臺灣博碩士論文加值系統

本研究主要在發展以PF127為控釋成分之dexamethasone sodium phosphate及tobramycin sulfate之局部眼用複方製劑。
在分析方法上，使用高效率液相層析儀串聯紫外光可見光及螢光偵測器可同時定量分析dexamethasone sodium phosphate及tobramycin sulfate兩項藥品。
從安定性的實驗結果顯示：含1% dexamethason sodium phosphate、3% tobramycin sulfate、0.01% benzalkonium chloride、Sorensen's phosphate buffer(pH=7.4)及sodium chloride之溶液劑型，在70℃的溫度下不安定，但在8℃溫度下，經過120天，幾乎沒有分解；在34℃溫度下(接近人類角膜表面溫度)，則至少可維持24小時的安定性。
為了獲得較有效的眼用控釋劑型，在處方的研究上，於PF127控釋劑型中加入PEG4000、PEG2000、PVA、MC、HPMC 15cps及HPMC 100cps等聚合物，並使用無膜溶離模式來評估處方膠體之溶解速率及dexamethason sodium phosphate和tobramycin sulfate之釋出速率，實驗結果顯示：當PF127處方中加入PEG時，可加快膠體溶解速率及藥物釋出速率；但當PF127處方中加入之聚合物為HPMC時，則膠體溶解速率及藥物釋出速率為所有處方中最慢者。
在動物實驗上，1% PMA所引起的非侵入性之兔眼發炎反應，可應用於PF127控釋處方之動物實驗，實驗結果顯示：不論是含PEG或HPMC之PF127控釋處方的治療效果都比傳統的溶液劑型來的好。

The aim of this study is to develop a PF127-based controlled-release ocular dosage form for the combination of dexamethasone sodium phosphate and tobramycin sulfate.
Dexamethasone sodium phosphate and tobramycin sulfate could be assayed simultaneously using HPLC method by coupling a UV-VIS detector and a fluorescence detector.
It was found that the formulation, including：1% dexamethasone sodium phosphate, 3% Tobramycin sulfate, 0.01% benzalkonium chloride, sorensen's phosphate buffer(pH=7.4) and sodium chloride, was unstable at 70℃, but almost not decomposed at 8℃ for 120 days or at 34℃(ocular surface temperature) for 24 hours.
For getting potential ocular controlled-release dosage form, various polymers, PEG4000, PEG2000, PVA, MC, HPMC 15cps and HPMC 100cps, were added into the PF127-based controlled-release formulation. The in vitro dissolution of the dexamethasone sodium phosphate and tobramycin sulfate from various formulations were obtained simultaneously at 34℃ using a non-membrane model. It was observed that both drugs dissolved and released from PEG-containing PF127 formulation faster than from the control PF127 formulation. The combination drugs dissolving and releasing from the HPMC-containing PF127 formulation were the slowest of all the formulations.
The animal test revealed that 1% PMA induced a proper non-invasive inflammatory rabbit eye model. The HPMC- and PEG-containing PF127 formulations inhibited inflammation of rabbit eyes more effectively than the traditional solution dosage form.

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正文目錄………………………………………………………………Ⅰ
表目錄…………………………………………………………………Ⅵ
圖目錄…………………………………………………………………Ⅷ
中文摘要………………………………………………………………Ⅹ
英文摘要………………………………………………………………XI
第一章、緒言1
第一節、眼睛的構造……………………………………………..1
第二節、磷酸鈉迪皮質醇之介紹………………………………..4
壹、腎上腺皮質類固醇之藥理作用…………………………..4
貳、腎上腺皮質類固醇在眼科臨床上之應用…………………4
參、Dexamethasone sodium phosphate物化性質………………7
肆、市售dexamethasone局部眼用製劑現況之介紹……………7
第三節、硫酸泰百黴素之介紹………………………………9
壹、藥理作用……………………………………………………9
貳、抗菌活性及臨床用途………………………………………11
參、市售Tobramycin局部眼用製劑現況介紹………………..13
肆、物化性質……………………………………………………13
第四節、併用類固醇及抗生素於眼科疾病治療之現況…………15
壹、併用類固醇及抗生素治療之時機及適應症………………15
貳、類固醇及抗生素複方製劑之優點…………………………15
第五節、眼用藥物輸藥系統之發展現況…………………………16
壹、理想眼用製劑應具備之條件………………………………16
貳、近年來局部眼用製劑的發展及其優缺點…………………16
第六節、Pluronic F127之介紹……………………………………18
壹、Pluronics系列產品之介紹…………………………………18
貳、Pluronic copolymer的毒性………………………………..18
參、微膠粒及膠體的形成………………………………………18
第七節、PF127應用於局部眼用製劑之文獻回顧………………22
第八節、研究動機…………………………………………………22
第九節、研究目的…………………………………………………23
第二章、材料與方法24
第一節、儀器與材料………………………………………………24
第二節、Dexamethasone sodium phosphate及Tobramycin sulfate 的分析方法………………………………………………26
壹、原理…………………………………………………………26
貳、溶液劑型處方的設計………………………………………28
參、分析方法的建立……………………………………………29
一、儀器的連接………………………………………………29
二、移動相溶液的配製及濃度梯度之設定…………………29
三、高效率液相層析儀系統條件的設定……………………32
四、OPT試劑的配製………………………………………… 32
五、檢品的配製………………………………………………32
六、紫外光偶極陣列檢測……………………………………34
七、標準曲線的建立、同日間精密度及準確度的考驗及 靈敏度的測量……………………………………………34
八、異日間精密度及準確度的考驗………………………… 35
第三節、分析方法的驗證………………………………………….35
壹、證明分析方法可用於本研究處方溶液之分析……………35
貳、證明分析方法可用於其它溶液劑型處方之分析…………36
第四節、複方溶液劑型安定性的研究……………………………37
壹、複方溶液劑型在高溫下的安定性………………………….37
貳、複方溶液劑型在低溫下的安定性………………………….38
參、複方溶液劑型在34℃的安定性…………………………..38
第五節、Dexamethasone sodium phosphate及Tobramycin sulfate 複方眼用製劑之PF127控釋處方的研究………………39
壹、處方設計………………………………………………..….39
貳、控釋處方配製步驟…………………………………………39
參、控釋處方體外溶離試驗……………………………………39
一、體外無膜溶離試驗裝置…………………………………40
二、膠體溶解試驗……………………………………………42
三、藥物溶離試驗……………………………………………42
四、硬度的測量………………………………………………42
第六節、動物實驗…………………………………………………44
壹、兔眼發炎模式的建立………………………………………44
貳、藥品配製……………………………………………………44
參、以控釋劑型及市售溶液劑型治療兔眼炎之比較…………45
肆、發炎程度之評估…………………………………………….45
伍、實驗分組及取樣時間……………………………………….45
第三章、結果與討論46
第一節、分析方法的建立…………………………………………46
壹、紫外光偶極陣列檢測結果………………………………..47
貳、標準曲線的建立、同日間精密度及準確度的考驗及靈 敏度測量…………………………………………………47
一、標準曲線的建立…………………………………………47
二、同日間精密度及準確度的考驗…………………………53
三、靈敏度的測定……………………………………………56
四、異日間精密度及準確度的考驗…………………………56
第二節、分析方法的驗證60
壹、證明分析方法可用於本研究處方溶液之分析…………….60
貳、證明分析方法可用於市售dexamethasone sodium phosphate製劑的分析……………………………………... 60
參、證明分析方法可用於市售tobramycin sulfate製劑的分 析…………………………………….…………………………60
第三節、複方溶液劑型安定性的研究……………………………63
壹、複方溶液劑型在高溫下的安定性…………………………63
貳、複方溶液劑型在低溫下的安定性…………………………66
參、複方溶液劑型在34℃的安定性…………………………..66
第四節、Dexamethasone sodium phosphate及Tobramycin sulfate 複方眼用製劑之PF127控釋處方的研究……………...73
壹、膠體溶解實驗結果…………………………………………73
貳、藥物溶離實驗結果…………………………………………75
一、Dexamethasone sodium phosphate的溶離結果…………75
二、Tobramycin sulfate的溶離結果…………………………79
參、硬度測量之結果……………………………………………79
第五節、動物實驗…………………………………………………89
壹、眼睛發炎模式之建立………………………………………89
貳、動物實驗處方的選擇………………………………………91
參、實驗結果……………………………………………………91
一、外觀症狀…………………………………………………91
二、房水中血液成分分析……………………………………91
第四章、結論…………………………………………………………96
第五章、參考文獻……………………………………………………98
表 目 錄
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表1、醣皮質固醇作用強度比較表………………………………6
表2、Aminoglycosides抑菌強度比較表…………………………12
表3、Pluronics類聚合物分子結構關係圖………………………19
表4、Dexamethasone sodium phosphate及Tobramycin sulfate複方溶液劑型處方…………………………………………30
表5、移動相濃度梯度之設定……………………………………33
表6、Dexamethasone sodium phosphate分析方法同日間精確度及準確度的評估……………………………………………54
表7、Tobramycin sulfate分析方法同日間精確度及準確度的評估……………………………………………………………55
表8、分析方法靈敏度的測定……………………………………57
表9、Dexamethasone sodium phosphate分析方法異日間精確度及準確度的評估……………………………………………58
表10、Tobramycin sulfate分析方法異日間精確度及準確度的評估……………………………………………………………59
表11、溶液劑型之HPLC分析結果………………………………61
表12、市售藥品之HPLC分析結果………………………………62
表13、Dexamethasone sodium phosphate及Tobramycin sulfate之複方及單方溶液劑型在70℃溫度下，隨時間變化之活性藥物殘留百分比……………………………………...65
表14、Dexamethasone sodium phosphate及Tobramycin sulfate之複方溶液劑型在8℃溫度下隨時間變化之活性藥物殘留百分比……………………………………………………69
表15、Dexamethasone sodium phosphate及Tobramycin sulfate之複方溶液劑型在34℃溫度下隨時間變化之活性藥物殘留百分比…………………………………………………72
表16、控釋處方結構強度(硬度)的測量………………………….83
表17、以PMA引起發炎而未治療兔眼之房水中血液成分分析..93
表18、經溶液劑型及控釋處方治療兔眼之房水中血液成分分析95
圖 目 錄
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圖1、眼球橫切面解剖圖…………………………………………2
圖2、Corticosteroids之藥理作用………………………………..5
圖3、Dexamethasone sodium phosphate之化學結構式…………8
圖4、Aminoglycosides類抗生素之藥理作用…………………..10
圖5、Tobramycin之結構式………………………………………14
圖6、在37℃之環境下Pluronic copolymer型成微膠粒之大小.21
圖7、Tobramycin與OPA的反應………………………………..27
圖8、紫外光偵測器及螢光偵測器串聯之高效率液相層析系統儀器連接圖…………………………………………………31
圖9、體外無膜溶離試驗裝置……………………………………41
圖10、落球高度之測量方法圖示…………………………………43
圖11、Dexamethasone sodium phosphate偶極陣列檢測圖………48
圖12、Dexamethasone sodium phosphate標準曲線………………49
圖13、Tobramycin sulfate標準曲線………………………………50
圖14、Dexamethasone sodium phosphate以UV檢測器偵測之HPLC圖譜51
圖15、Tobramycin sulfate以螢光檢測器偵測之HPLC圖譜……52
圖16、Dexamethasone sodium phosphate及Tobramycin sulfate複方及單方溶液劑型在70℃環境下之安定性64
圖17、Dexamethasone sodium phosphate於8℃溫度下之安定性67
圖18、Tobramycin sulfate於8℃溫度下之安定性……………….68
圖19、Dexamethasone sodium phosphate於34℃溫度下之安定性70
圖20、Tobramycin sulfate於34℃溫度下之安定性……………….71
圖21、在34℃溫度下，dexamethasone sodium phosphate及tobramycin sulfate之PF127複方控釋劑型加入同比例不同種類聚合物之膠體溶解圖…………………………………..74
圖22、在34℃溫度下，dexamethasone sodium phosphate及tobramycin sulfate之PF127複方控釋劑型加入同比例同種類但不同分子量聚合物之膠體溶解圖……………………..76
圖23、在34℃溫度下，加入同比例不同種類聚合物處方之dexamethasone sodium phosphate溶離圖…………………..77
圖24、在34℃溫度下，加入同比例同種類但不同分子量或黏度聚合物處方之dexamethasone sodium phosphate溶離圖….78
圖25、在34℃溫度下，加入同比例不同種類聚合物處方之tobramycin sulfate溶離圖…………………………………..80
圖26、在34℃溫度下，加入同比例同種類但不同分子量或黏度聚合物處方之tobramycin sulfate溶離圖………………….81
圖27、不同聚合物處方間，膠體溶解與dexamethasone sodium phosphate釋出的關係………………………………………..85
圖28、不同聚合物處方間，膠體溶解與tobramycin sulfate釋出的關係………………………………………………………..86
圖29、不同分子量或黏度聚合物處方間，膠體溶解與dexamethasone sodium phosphate釋出的關係……………..87
圖30、不同分子量或黏度聚合物處方間，膠體溶解與tobramycin sulfate釋出的關係…………………………………………..88
圖31、眼睛發炎模式的建立。(A)正常眼睛。(B)給予1%PMA之兔眼變化圖。（C）給予10%PMA之兔眼變化圖…………90
圖32、控釋處方及溶液劑型治療之兔眼圖………………………..92

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