藥物釋放組合物、其製造方法及其用途

專利類型

發明

專利國別 (專利申請國家)

中華民國

專利申請案號

110106924

專利證號

I 781536

專利獲證名稱

藥物釋放組合物、其製造方法及其用途

專利所屬機關 (申請機關)

國立臺灣科技大學

獲證日期

2022/10/21

技術說明

我們先前開發置放超音波於外耳道來作用於中耳腔室內的微氣泡，用以提升藥物的內耳輸送，由於多數藥物的配方為水溶液，容易透過耳咽管、脈管系統和淋巴管途徑流失，導致中耳腔藥物後續擴散進入內耳的藥量與欲維持的濃度會隨時間的推移而下降。於是我們開發持續釋放且具有溫敏性的poloxamer407水凝膠與微氣泡結合，在超音波作用下，達到立即提升並可延長藥物緩釋的內耳藥物輸送新技術。 透由黏滯度量測顯示，12.5%的poloxamer407水凝膠與微氣泡結合最適合用於體外和體內的藥物遞送。以12.5%的poloxamer407-微氣泡水凝膠進行Franz體外擴散試驗，比較微氣泡水凝膠超音波作用組(USM)與微氣泡水凝膠靜置組(RWS)的釋放差異：以標示螢光的biotin-FITC做為釋放標的時，作用後6小時的差異為3.00倍; 若以類固醇藥物地塞米松（dexamethasone, DEX）做為釋放標的時，作用後3小時差異為1.52倍。 在天竺鼠的活體動物模型中，溫敏性微氣泡水凝膠透由耳膜穿刺注射於中耳腔內，在第1天和第7天的內耳DEX藥物含量測定，USM組與RWS組遞送效率的差異分別為100.68%和65.13%。USM組治療後的第28天，包括聽性腦幹反應之聽力閾值檢測、耳蝸結構完整性評估、聽小骨完整性以及中耳腔黏膜的切片鏡檢等安全性評估均顯示無異常變化及功能受損。上述結果支持12.5% 的微氣泡-poloxamer407水凝膠搭配超音波可有效促進內耳藥物輸送的應用。 Our previous study firstly investigated the feasibility of applying ultrasound (US) and microbubbles (MBs) via external auditory canal to facilitate drug delivery into inner ear. However, most drugs in solution formula loss through the Eustachian tube, via the vasculature and via the lymphatics can all contribute to the decline of middle ear concentration with time after drug application. In this study, the feasibility of a sustained release thermosensitive poloxamer 407 (P407) based MBs gel for US enhanced inner ear drug (dexamethasone, DEX) delivery was investigated. Recorded Tsol-gel shows that only 10% and 12.5% P407 in MBs and DEX solution can be used in the in vitro and in vivo drug delivery experiments. In Franz diffusion experiments performed in vitro, the release rates in the fluoresce model drug USM at 6 hours and DEX USM at 3 hrs groups resulted in 3.00 and 1.52 times than RWS groups. In vivo model of guinea pigs, by filling tympanic bulla with MB in DEX-poloxamer 407 gel, USM applied at day 1 and 7 induced 100.68% and 65.13% increases in DEX delivery efficiencies, respectively. On the 28th day after USM treatment, safety assessment showed no significant changes in the hearing thresholds and the integrity of cochlea. These are the first results to demonstrate the feasibility of US meidated liquid form DEX P407-MBs cavitation for round window membrane (RWM) permeation enhancements. Then, gel form DEX P407-MBs was generated and prolonged the release of DEX without traditonal perforations.

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