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研究生:鄭欽華
研究生(外文):Chinhwa Cheng
論文名稱:市售未執行生體相等性試驗藥品之品質評估
論文名稱(外文):The Quality Assessment of Marketed Non-Surveillance Drugs
指導教授:許光陽許光陽引用關係
口試委員:陳繼明許秀蘊鄭慧文蔡義弘
口試日期:2013-07-29
學位類別:博士
校院名稱:臺北醫學大學
系所名稱:藥學系(碩博士班)
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:135
中文關鍵詞:Propranolol HCl 10毫克錠劑Calcium p-aminosalicylate 500毫克膜衣錠溶離試驗生體相等性試驗生物藥品分類系統(BCS)體外體內關聯性(IVIVC)
外文關鍵詞:PropranololDissolutionCalcium p-aminosalicylate (Ca PAS)Relative bioavailabilityin vitro-in vivo correlation (IVIVC)
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本研究係篩選健保局資料庫中使用量大,但未執行過生體相等性試驗評估之非監視學名藥市售品,來進行品質評估。挑選出屬於BCS class I 的Propranolol HCl 10毫克錠劑及治療肺結核的孤兒藥calcium p-aminosalicylate 500毫克膜衣錠來進行評估。
以8家Propranolol HCl 10毫克錠劑學名藥廠市售品,進行均一度與溶離試驗評估。試驗結果顯示所有檢品符合USP 之規範(Q30≧75 %)。以溶離試驗結果與原廠差異性最大之檢品T1,進一步執行12人之雙向交叉BE試驗。BE試驗結果顯示檢品T1的Tmax及半衰期與仿單刊載一致。雖然AUC0-t、 AUC0-∞及Cmax之90% 信賴區間分別為78.2 - 140.8 %、78.8 - 137.2 %及73.6 - 153.1 %,但經過統計推算,若將受試者增加至40人,將可達到BE。
PAS(calcium p-aminosalicylate)為治療肺結核常用的孤兒藥。採Ca PAS原料粉末調製之懸浮劑為對照品,與唯一的市售產品進行12位健康男性交叉試驗之生體可用率評估。試驗結果顯示試驗品相對於對照品之AUC0-t、 AUC0-∞及Cmax幾何平均數分別為0.873、0.874及0.569。以自然對數計算分析相關藥動學參數,90 %信賴區間數值分別是ln (AUC0-t) 為(74.0 - 103.0 %);ln (AUC0-∞)為(74.1 - 103.0 %);而ln (Cmax)為(38.4 - 4.3 %)。Ca PAS膜衣錠與懸浮劑之相對性生體可用為87.4 %。
Propranolol HCl 10毫克錠劑之生體相等性試驗比對評估結果顯示即使是溶離比對與原廠差異最大的Propranolol HCl 10毫克錠劑學名藥產品,若具有足夠的受試者人數,亦可達到生體相等性。因此BCS Class I藥品Propranolol HCl 10毫克錠劑可免除執行BE試驗之政策應可適用於我國。同時完成了孤兒藥Calcium p-aminosalicylate 500毫克膜衣錠之生體可用率評估,該產品具相當好的生體可用率,民眾使用該產品有保障。同時也顯示衛生署在確保民眾用藥安全性有效性把關之用心。
The purpose of the studies is to evaluate the quality of the registered products which are not mandatory required to conduct the bioequivalence studies. Two products were selected from the most prescribed non-mandatory BE required products. Content uniformity, dissolution test were performed as well as the bioequivalence studies.
A total of eight Propranolol HCl 10 mg marketed generic products from different manufacturers were sampled. All the samples complied with the dissolution acceptance criteria (Q30 ≧ 75 %) of the USP monograph. Seven out of eight products showed fast dissolving patterns, and more than 85 % of the active ingredient was dissolved in 15 minutes. The most deviated sample was then chosen for a two-way crossover bioequivalence evaluation with 12 subjects enrolled. The Tmax and the half-life of the most deviated sample (test) and reference products were consistent with the general information provided by the product insert. 90 % CI for AUC0-t, AUC0-∞ and Cmax were (78.2 - 140.8 %), (78.8 - 137.2 %), (73.6 - 153.1 %), respectively. Simulation was done to estimate the possibility of the BE for Propranolol HCl 10 mg tablets. It indicated that regardless the most deviation from the dissolution comparison, bioequivalence could be achieved when the subject number reached 40. This result suggests the biowaiver policy for BCS Class I drugs - Propranolol HCl 10 mg tablets can be applied.
There was no any bio-study data available for Calcium p-aminosalicylate (Ca PAS) 500 mg film coating tablet. An open - randomized, balanced, two-way crossover study was designed to evaluate the relative bioavailability (F) of a 500 mg Ca PAS F.C. tablet with a 500 mg Ca PAS suspension in 13 healthy subjects. Blood samples were collected at planned time schedule. The plasma concentrations of PAS were determined by LC/MS/MS. Pharmacokinetic parameters were determined by non-compartment methods. The mean geometric ratios of PK parameters including AUC0-t, AUC0-∞ and Cmax obtained were 0.873, 0.874 and 0.569, respectively. The 90 % CI of ln (AUC0-t), ln (AUC0-∞) and ln (Cmax) after being back natural log-transformed were (74.0 - 103.0 %), (74.1 - 103.0 %) and (38.4 - 4.3 %), respectively. The F of Ca PAS tablet was 87.4 %.
圖次 v
表次 viii
中文摘要 1
英文摘要 3
名詞解釋 5
第1章 緒論 6
1.1 研究動機 6
1.2 背景 7
1.3 品項之篩選 10
1.3.1 前言 10
1.3.2 進行方式 11
1.3.3 品項篩選結果 12
1.4 BCS分類系統及Biowaiver之沿革 14
1.5 Propranolol製劑簡介及法規現況 19
1.6 para-aminosalicylate製劑簡介及市售品現況 22
第2章 材料與方法 24
2.1 Propranolol HCl 10毫克錠劑市售品品質評估 24
2.1.1 試驗樣品的選擇 24
2.1.2 含量測定及均一度試驗 24
2.1.3 溶離試驗評估 25
2.1.4 Propranolol HCl 10毫克錠劑之生體相等性試驗評估 29
2.1.5 Propranolol 製劑體外體內關聯性(IVIVC)之探討 31
2.2 Propranolol 長效製劑體外體內關聯性(IVIVC)之研究 32
2.2.1 不同釋放速率的Propranolol 100毫克錠劑配方製備 32
2.2.2 體外溶離試驗 33
2.2.3 血中濃度試驗 34
2.2.4 Propranolol 長效配方IVIVC模式建立 36
2.3 para-aminosalicylate 500毫克膜衣錠之品質評估 37
2.3.1 試驗樣品的選擇 37
2.3.2 含量及含量均一度分析(Assay & Content Uniformity): 37
2.3.3 體外溶離試驗 38
2.3.4 生體可用率試驗評估 39
第3章 結果 43
3.1 Propranolol HCl 10毫克錠劑市售品品質評估 43
3.1.1 含量均一度評估及溶離試驗比對評估 43
3.1.2 Propranolol HCl 10毫克錠劑生體相等性試驗評估 47
3.1.3 Propranolol 製劑IVIVC探討 52
3.2 Propranolol 長效製劑體外體內關聯性(IVIVC)之研究 53
3.2.1 不同釋放速率的Propranolol 長效錠劑配方製備 53
3.2.2 Propranolol 製劑血中濃度試驗 54
3.2.3 Propranolol 長效錠劑配方體外體內關聯性 55
3.3 para- aminosalicylate 500毫克膜衣錠市售品之品質評估 57
3.3.1 para-aminosalicylate 500毫克膜衣錠之溶離試驗評估 57
3.3.2 para-aminosalicylate 500毫克膜衣錠之含量測定及含量均一度測定 58
3.3.3 para-aminosalicylate 500毫克膜衣錠之生體可用率評估 59
第4章 討論 67
4.1 Propranolol HCl 10毫克錠劑市售品品質評估 67
4.1.1 體外溶離試驗 67
4.1.2 Propranolol 生體相等性試驗 69
4.1.3 Propranolol 製劑IVIVC探討 72
4.2 Propranolol長效製劑之IVIVC研究 75
4.2.1 不同釋放速率之長效配方錠劑製備 75
4.2.2 IVIVC模式的確效 77
4.3 para-aminosalicylate 500毫克膜衣錠之生體可用率評估 79
4.3.1 para-aminosalicylate 500毫克膜衣錠體外試驗評估 79
4.3.2 para-aminosalicylate 500毫克膜衣錠之生體可用率評估 80
4.3.3 Calcium p-aminosalicylate(Ca PAS)製劑IVIVC之探討 86
第5章 結論 89
第6章 參考文獻 92
第7章 附錄 99
7.1 Propranolol HCl 10毫克錠劑之血中濃度曲線圖 99
7.2 Calcium p-aminosalicylate 500毫克膜衣錠之血中濃度曲線圖 111
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