臺灣博碩士論文加值系統

BCS class II、III、IV類的藥物各自因水溶解度及對細胞膜的滲透性的缺點而有其臨床應用的限制性，因此本研究欲開發一個以卵磷脂為基礎的自組裝型混合微胞藥物傳遞系統(saLMMs)作為載體平台，使其可以依活性成分的特性及適合其吸收之消化道黏膜部位，應用為不同的黏膜傳遞劑型，以改善既有應用方式之缺點。
在將微胞應用為口服液劑型以改善白藜蘆醇(t-Rev)（BCS class II）生體可用率的部分，優化後的微胞處方(t-Rev-loaded saLMPMs)其組成比例為t-Rev:Lec:PP123 = 5:2:20，在此比例下，微胞具有最佳的物理特性，包括: 平均微胞粒徑147 nm、藥物包覆率103.93% 及載藥量19.3%。
t-Rev-loaded saLMPMs在體外實驗中具有緩釋效果;在儲存安定性方面，其可在室溫儲存達56天以上，而在血漿中的安定性結果則顯示，在FBS中存在5小時後，其粒徑即會增加到大於200 nm，顯示微胞在血漿中比在PBS中更容易崩解造成析出。
在大鼠體內藥物動力學實驗的結果顯示，與IV給予t-Rev/HP-β-CD complex的組別相比，以IV給予t-Rev-loaded saLMPMs可促進t-Rev的絕對生體可用率為217%，但可維持高於預防癌症治療濃度的血中濃度仍較短(<15分鐘); 而以口服方式給予t-Rev-loaded PP123 saLMPMs則可提高絕對生體可用率至141%，且可維持高於預防癌症治療濃度的血中濃度達3小時，而若與口服給予t-Rev/HP-β-CD complex的組別(絕對生體可用率12%)相比，相對生體可用率則達到了11.4倍。上述口服生體可用率的提升代表能有更高比例的t-Rev經由腸胃道黏膜吸收並分佈到週邊組織，這使位於週邊組織的目的部位有機會達到治療濃度。
在將微胞應用為口溶膜劑型以改善Granisetron HCl (BCS Class III)生體可用率的部分，優化後的背襯層處方SGS512C具有最佳的物理特性，包括: 抗張力強度938.1mN，拉伸性438.7%，以此為基礎所建立的雙層膜GH-3310以及單層膜GH-F005系列處方，其厚度、重量均一度皆可控制在C.V.<10%內，在體外溶離試驗的結果顯示，市售對照樣品(Kytril® tablet)及單、雙層口溶膜處方皆在5分鐘內即釋出大部分藥物(>90%)並達到plateau，組別間並未顯示出顯著的溶離率差異。
在大白兔的體內試驗結果顯示，經由舌下黏膜給予單、雙層口溶膜及對照品之組別其相對生體利用率(378.21%、 252.14%、324.07%)皆比個別以口服給予經由腸胃道黏膜吸收高(276.44%、250.37%、100%)。在同為舌下黏膜給予組別的實驗結果顯示，雙層口溶膜GH-3310可能因有背襯層的存在，在一定時間內阻隔了唾液，使其生體可用率(252.14%)低於單層口溶膜(378.21%)及對照品(324.07%)的生體可用率，而在含有微胞的組別中，可能因藥物自身鹽類部位的親水性使其疏水性的化學結構部位未被緊密吸附嵌於微胞的介面上，而使得藥物未能因為微胞的助滲作用增加藥物對細胞膜的穿透能力及進一步提升生體可用率。
本研究提出的自組裝型卵磷脂混合微胞(saLMMs)是一個製程簡單、易於大量製備並具成本效益的處方，具有作為黏膜傳遞劑型平台的潛力，應用為t-Rev的口服液，可以改善t-Rev的口服生體可用率，因此具有潛力使t-Rev以口服經腸胃道黏膜吸收的方式，在體內達到治療有效性的濃度。而應用在Granisetron HCl的部分雖未更進一步增加口溶膜的生體可用率，但將藥物改為經口腔黏膜吸收的口溶膜劑型已大幅提高生體可用率，並且建立了結合載體概念的自乳化口溶膜模型，且可藉口溶膜的單、雙層設計調控藥物的釋放曲線，這對未來應用於其他不同藥物於口腔內黏膜吸收之研究，具有參考價值。

The low solubility or permeability to cell membrane limits the clinical application of BCS class II, III, IV drugs. The aim of this study is to develop a lecithin-based self-assembly mixed micellar drug delivery system(saLMMs) as vehicle platform, which can apply as various dosage types for transmucosal delivery of a target drug at different mucosal sites according to the properties and clinical limitations of the drug itself.
To improve the oral bioavailability of trans-resveratrol(t-Rev), a BCS class II drug, the saLMMs strategy was applied as oral solution dosage type. The optimized t-Rev-loaded saLMPMs are composed of　t-Rev: lecithin: PP123 at a 5:2:20 ratio and provides micelles with particle size 147nm, encapsulation efficiency(EE) 103.93% and drug loading(DL) 19.3%. t-Rev-loaded saLMPMs perform sustained release profile in in-vitro dissolution test. The stability results indicate that t-Rev-loaded saLMPMs are stable at room temperature or 4℃for 56 days, but are relatively easy to collapse in plasma because of the results of micelles’ particle size increasing to >200 nm in FBS after 5hrs.
Comparing to IV administration of t-Rev/HP-β-CD complex, IV and oral administration of t-Rev-loaded PP123 saLMPMs showed an increasing absolute bioavailability to 217% and 141% individually. Comparing to oral administration of t-Rev/HP-β-CD complex, oral administration of t-Rev-loaded PP123 saLMPMs showed an increase of 11.4 fold in relative bioavailability and furnished a 3h period of time when the plasma concentration of t-Rev remained above the desired plasma concentration for chemoprevention and potentially established a therapeutically effective level at the target site. The increase in oral bioavailability means a greater portion of t-Rev preferably distributed into the peripheral compartment, potentially establishing a therapeutic level at the targeted site via GI transmucosal delivery.
To improve the bioavailability of Granisetron HCL(GH), a BCS class III drug, the saLMMs strategy was applied as mouth dissolving film(MDF) dosage type. The backing film formulation SGS512C with optimized mechanic strength was used to establish bilayer MDFs(GH-3310 series) and one layer MDFs(GH-F005 series). The uniformity in thickness and weight of the MDFs can be controlled within C.V.<10%. The results of in-vitro dissolution showed most GH(>90%) in commercial kytril® tablets(as reference) and both one layer and bilayer MDFs are released in 5 minutes. There’s no significant difference in dissolution results between all groups.
The in vivo results of rabbits showed the relative bioavailability of both MDFs(GH-3310, GH-F005) and Kytril® tablet via sublingual absorption (378.21%, 252.14%, 324.07%) are higher than via GI mucosal absorption (276.44%, 250.37%, 100%), respectively. For the results of sublingual groups, the lower relative bioavailability of bilayer GH-3310(252.14%) than one layer GH-F005(378.21%) and kytril® tablet(324.07%) may be because of its backing film reducing the drug dissolution rate. Compared to GH-3310 and GH-F005, the micelle-containing MDFs showed no further bioavailability- enhancing effects, and the reason may be the hydrophobic moiety of the chemical structure of Granisetron HCl can not tightly absorb and incorporate on the micelle interface due to the hydrophilicity of Granisetron HCl salt itself.
It was concluded that saLMMs are a simple, reproducible, ease of preparation in large-scale and cost-effective formulation, and are potential as dosage type platform for transmucosal delivery. For t-Rev, the strategy can improve the oral bioavailability and potentiate in achieving therapeutic- effective concentration at targeted sites via GI transmucosal delivery. For Granisetron HCl, though the saLMMs strategy didn’t further increase the bioavailability, which already enhanced by designed as MDF dosage type. This study still established a self-microemulsifying mouth dissolving film dosage type(SMMDF) model which combined the advantages of both saLMMs and MDFs. Also, the releasing profile of drugs can be modulated by the design of one layer or bilayer MDFs. The results are valuable for study of intraoral transmucosal delivery of other target drugs in the future.

目錄 I
附圖目錄 IV
附表目錄 VII
中文摘要 X
Abstract XII
第壹章、緒論 1
第一節、研究背景介紹 1
一、 微胞 4
二、 兩性物質 17
三、 白藜蘆醇 30
四、 口腔給予 36
五、 口溶膜 40
六、 自微乳化口溶膜 48
七、 Granisetron HCl 50
第二節、研究目的 52
第貳章、自組裝型卵磷脂混合微胞應用於T-RESVERATROL腸胃道黏膜傳遞之研究 53
第一節、 實驗材料 53
第二節、 實驗方法 55
一、 Resveratrol之高效液相層析法分析方法 55
二、 血漿中Resveratrol之高效液相層析分析方法 56
三、 溶解度試驗 58
四、 自組裝型微胞體粒子製備與評估 58
五、 安定性 61
六、 體外藥物釋放實驗 61
七、 大鼠體內之藥物動力學實驗 62
第三節、實驗結果與討論 65
一、 Resveratrol之高效液相層析法分析方法 65
二、 溶解度試驗 68
三、 自組裝型微胞體粒子製備與評估 69
四、 穿透式電子顯微鏡 74
五、 安定性 75
六、 體外藥物釋放實驗 77
七、 大鼠體內之藥物動力學實驗 78
八、 討論 82
第參章、自組裝型卵磷脂混合微胞應用於GRANISETRON HCL口腔黏膜傳遞之研究 86
第一節、 實驗材料 86
第二節、 實驗方法 87
一、 Granisetron HCl之高效液相層析法分析方法 87
二、 血漿中Granisetron HCl之UPLC/MS/MS分析方法 88
三、 口溶膜之製備 90
四、 口溶膜物理特性評估 93
五、 含量分析及體外藥物溶離實驗 94
六、 家兔體內之藥物動力學實驗 95
第三節、結果與討論 96
一、 GRANISETRON HCL之高效液相層析法分析方法 96
二、 血漿中GRANISETRON HCL之UPLC/MS/MS分析方法 96
三、 口溶膜之製備 98
四、 口溶膜物理特性評估 99
五、 含量分析及體外藥物溶離實驗 102
六、 家兔體內之藥物動力學實驗 104
第肆章、結論 109
第伍章、參考文獻 110

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