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系統識別號 U0026-2905201916175500
論文名稱(中文) 台灣藥品賦形劑管理現況與其可能的風險:以薄荷醇與硬脂酸鎂為例
論文名稱(英文) The Gap in Regulating Pharmaceutical Excipients and its Potential Risks in Taiwan: Using Menthol and Magnesium Stearate as Examples
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 107
學期 2
出版年 108
研究生(中文) 黃克理
研究生(英文) Kelly Huang
電子信箱 s68021032@mail.ncku.edu.tw
學號 S68021032
學位類別 博士
語文別 英文
論文頁數 104頁
口試委員 指導教授-高雅慧
召集委員-康照洲
口試委員-蔡瑞真
口試委員-高純琇
口試委員-李貽恆
口試委員-鄭靜蘭
中文關鍵字 賦形劑  薄荷醇  阿斯匹靈  硬脂酸鎂  缺血性中風 
英文關鍵字 excipient  menthol  aspirin  magnesium stearate  ischemic stroke 
學科別分類
中文摘要 由於賦形劑的品項眾多組合複雜,其重要性已漸受重視,但賦形劑實際造成的影響仍少有臨床證據。我們從文獻、仿單與配方上發現了一些可能的影響,包括賦形劑的致敏、錯誤標示、賦形劑和活性成分間的交互作用。本研究回顧台灣現有外用製劑中薄荷醇的定位與管理現況;並且以乙醯水楊酸與硬脂酸鎂的交互作用為研究標的,探討賦形劑對臨床療效上的影響。
薄荷醇的藥品活性濃度範圍很廣,但在台灣多數含薄荷醇之藥品標示其為賦形劑。含有薄荷醇的外用製劑在2018年十月底前仍有效的731張許可證中,其薄荷醇是否被列為活性成分與其薄荷醇濃度並不相關,但與該藥品的分類是否為成藥有高度相關性。薄荷醇未以活性成分管理亦有其他影響,例如應注意使用冷敷袋時可能接觸到的薄荷醇;一證多方藥品的薄荷香味劑型更可能影響藥品安全,而其衍生出的市場隔離更是落實醫藥分業的實質阻力。薄荷醇在台灣的定位仍非十分明確,而相關規定的落實也有待加強。
乙醯水楊酸俗名阿斯匹靈,是最普遍使用之血小板抑制劑,為次級預防缺血性中風與缺血性心臟病的首選藥品。硬脂酸鎂為廣泛用於固體製劑的賦形劑,但有文獻建議不應用於阿斯匹靈製劑,但此配伍禁忌僅限於製劑安定性研究而無臨床實證,我們假設含有硬脂酸鎂的配方可能會降低阿斯匹靈抑制血小板的藥效,並尋求其臨床實證。我們藉由次級資料中以回溯性世代研究來比較缺血性中風病人接受研究組(含有硬脂酸鎂成分)與對照組(不含硬脂酸鎂成分)阿斯匹靈後因缺血性中風復發住院的風險比值。
在2000-2013全民健保資料庫百萬抽樣歸人檔中尋找最近三年內首次發生因缺血性中風住院者,以其出院後首次回診並被處方阿斯匹靈為觀察起點,追蹤後續阿斯匹靈的處方情形。依所處方的阿斯匹靈配方將病人分為硬脂酸鎂組與非硬脂酸鎂組,以綜合心腦血管事件為觀察事件,比較研究組與對照組的缺血性中風復發的風險比值。
納入了10,051位缺血性中風病患中,其中60%為男性,平均年齡67歲。這些病患中有541人僅使用硬脂酸鎂組治療,9,510人僅使用非硬脂酸鎂組治療。綜合心腦血管事件的粗發生率為8.68/百人年,在非硬脂酸鎂組中為8.26/百人年而硬脂酸鎂組中為18.6/百人年。硬脂酸鎂組的心腦血管事件風險是非硬脂酸鎂組的2.12倍,95%信賴區間為1.72-2.56倍。此研究結果顯示阿斯匹靈用於缺血性中風的次級預防時,含有硬脂酸鎂成分比不含硬脂酸鎂的阿斯匹靈有更高的心腦血管事件風險。
英文摘要 The excipients in drugs are drawing more attention than before. Because the variety and the complex of the excipients, the clinical evidence of impact from excipients was rare. By reviewing the literature, the label information, and the formulations, we found some potential risk of excipients, including allergy, non-optimal labeling, and the interaction between the excipient and the active ingredient. In the study, we firstly focused on the menthol in external preparations to survey the label information of menthol, and related regulatory notes. Secondly, we explored the interaction between aspirin (acetylsalicylic acid, ASA) and magnesium stearate (MgSt) to estimate the impact of excipients on clinical effectiveness.
Menthol had pharmaceutical activity in a wide concentration range, but it was usually claimed as an excipient in Taiwan. In 731 external preparations containing menthol, menthol being labeled as an active pharmaceutical ingredient (API) or an excipient did not depend on the concentration, instead it had stronger correlation to the product classification being general sale list or prescription only medicines. The status of menthol in regulation was not clear enough in Taiwan. The exposure risk of menthol in cold packs shall be noticed. The impact of various menthol strengths in steroid ointments presented another regulatory loophole. It would be reasonable to define the menthol as an API or an excipients by their concentration in the product, and the compliance shall be improved.
Magnesium stearate (MgSt) is a widely used excipient in pharmaceutical formulations, which should be avoided in aspirin preparations since it hydrolyzes aspirin. We hypothesized that aspirin products containing MgSt (MgSt-ASA) would be less effective in preventing thrombosis in the clinical settings. A retrospective cohort study on Taiwan’s claims data from 1997 to 2013 was designed to evaluate the risk of all-cause mortality and recurrent ischemic stroke (IS) on patients treated with MgSt-ASA preparations as secondary stroke prevention.
Patients who were discharged after IS and administered with only MgSt-ASA or non-MgSt-ASA were enrolled. Composite events including all-cause mortality, ischemic stroke hospitalization, and myocardial infarction hospitalization follow-up period under therapy with MgSt-ASA or non-MgSt-ASA preparations was considered as the primary outcome. The hazard ratios (HR) were adjusted with the comorbidities, and baseline statin and antiplatelet prescriptions, by the Cox model.
A total of 10,051 patients with IS (60% males, average age 67) were identified, which included 541 patients receiving the MgSt-ASA treatment only, and 9,510 patients receiving non-MgSt-ASA preparation only. The crude incidence of composite events was 8.68 per hundred person-year, and 8.26 and 18.6 per hundred person-year for patients under non-MgSt-ASA and MgSt-ASA treatments, respectively. There was a higher risk of composite events in patients receiving MgSt-ASA preparations than those receiving non-MgSt-ASA formulations, with the adjusted HR being 2.12, at 95% confidence interval of 1.76-2.56. The use of MgSt-ASA preparations was associated with a higher risk of composite events compared with non-MgSt-ASA preparations. To review the aspirin formulations under a regulatory intervention is warranted.
論文目次 學位考試合格證明 i
中文摘要 ii
ABSTRACT iv
謝誌 vii
TABLES OF CONTENT viii
LIST OF TABLES x
LIST OF FIGURES xi
Chapter 1. Introduction 1
1.1. The regulation of excipients 2
1.1.1. The definition 2
1.1.2. Functions of excipients 3
1.1.3. Manufacture and regulation 3
1.1.4. Specification 5
1.1.5. Labeling of the excipient and the information accessibility 6
1.1.6. Box warning 7
1.1.7. Brief summary 8
1.2. Clinical concerns of excipients 10
1.2.1. Allergy of excipients 10
1.2.2. Dual use excipients 12
1.2.3. An API claimed as an excipient 16
1.2.4. Interaction between the active ingredient and the excipient 22
1.3. Objective and study hypothesis 25
Chapter 2. The Menthol in the External Preparations 26
2.1. Introduction 26
2.1.1. Background 26
2.1.2. The role of menthol 30
2.2. Methods 31
2.3. Menthol in other regulatory agencies 32
2.4. Current issues of menthol in Taiwan 34
2.4.1. As an inactive ingredient with an active concentration 35
2.4.2. The compliance of the box warning 37
2.4.3. Multiple flavors and the market segmentation 39
2.4.4. Menthol used in non-medical products 41
2.5. Conclusion 43
2.5.1. Recommendation 43
Chapter 3. The Magnesium Stearate in the Aspirin Products 45
3.1. Introduction 45
3.1.1. Equivalent generic drugs and excipients 45
3.1.2. Aspirin and magnesium stearate 46
3.1.3. The evaluation of aspirin containing magnesium stearate 47
3.2. Methods 49
3.2.1. Data source 49
3.2.2. Study population 50
3.2.3. Exposure to MgSt-ASA 50
3.2.4. Endpoint 52
3.2.5. Concomitant treatment and comorbidity 52
3.2.6. Statistical analyses 53
3.2.7. Sensitivity analyses 54
3.3. Results 56
3.3.1. Population 56
3.3.2. Follow-up 58
3.3.3. Incidence 60
3.3.4. Hazard ratio 61
3.3.5. Sensitivity analysis 63
3.4. Discussion 71
3.4.1. Design and results 71
3.4.2. Estimation 72
3.4.3. Policy implications 74
3.4.4. Strengths and limitations 76
3.4.5. Conclusion 78
Chapter 4. Summary 79
4.1. The study contribution 79
4.2. Recommendation 79
4.3. Research prospects 80
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APPENDIX XI
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