臺灣博碩士論文加值系統

本研究選擇一具高吸濕特性之藥品（pyridostigmine bromide；以下簡稱PB）為模式藥。在整個實驗過程，利用擠壓搓圓法、直接壓錠法及流動床包衣法將PB製成長效劑型（長效圓粒錠及長效圓粒）；並利用實驗設計法來篩選最佳處方及探討製備過程中最具有影響之因子。在體外試驗的部份，首先利用Taguchi實驗設計法來篩選以擠壓搓圓方法製備含藥之核心圓粒最佳處方；並探討於製程中最具有影響的因子。進一步再利用23複因子實驗設計法來篩選一組最佳之長效製劑處方進行動物體內體外相關性實驗。我們期許這組最佳處方能於溶離之特定時間點能釋出特定的藥量；並以零階次的模式來釋出藥品。（對於最佳的長效圓粒錠而言，藥品於1小時，6小時及12小時的溶離時間點分別釋出15.84%，58.56% 及93.10%；而對於最佳的長效圓粒來說，藥品於1小時，6小時，12小時及24小時的溶離時間點則分別釋出6.24%，33.48%，75.18% 及95.26%）。由卡式水分測定儀所得之結果得知，本實驗所製備的二組最佳長效製劑處方均有改善PB吸濕特性的缺點。
在體內試驗，由計算所得的藥物動力學數據顯示，本實驗中製備的兩組最佳長效製劑處方所達血中最高濃度之時間（Tmax）比市售速效錠長，且血中時間-濃度曲線下面積也比市售速效錠大，並具有良好的體內-體外相關性。最後，取最佳長效圓粒處方進行動物體內之微透析試驗。經投藥後，由體內乙醯膽鹼及游離藥品（蛋白未結合藥品）之釋出百分率得知，本實驗中自製之長效圓粒處方於體內釋出之速率比市售速效錠及注射劑慢；此種現象就代表自製之長效圓粒處方於體內作用時間比市售速效錠及注射劑長，能達長效持續釋出之作用。
我們期許本實驗自製之長效製劑處方，未來若運用於危險恐怖攻擊或戰爭時能改善一些事後解毒劑之限制，並減少投藥次數及增加藥品於體內作用的時間。

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. The PB sustained-release (SR) dosage forms (SR tableted-pellets and SR pellets) that were developed by extrusion-spheronization, direct compression and fluid-bed methods using Taguchi experimental and 23 full factorial design. Preceding in vitro studies, Taguchi experimental design was used to optimize formulations and process parameters for the extrusion-spheronization process to prepare drug-containing core pellets. Moreover, 23 full factorial design was utilized to search for the optimal PB-SR dosage forms with specific release rate at different time intervals (the released % of 1h, 6h and 12h were 15.84%, 58.56% and 93.10% for SR tableted-pellets and the release % of 2h, 6h, 12h and 24 h were 6.24 %, 33.48 %, 75.18 % and 95.26 % for SR pellets) and follow zero-order mechanism. The results of moisture absorption by Karl Fischer meter shown the optimal PB-SR dosage forms could improve the hygroscopic defect of pure drug (PB).
In the in vivo study, the results of the bioavailability data showed the Tmax and AUC0-t were prolonged and increased for optimal PB-SR dosage forms when compared with commercial immediate release (IR) tablets. Furthermore, a good linear regression relationship was observed between the fraction dissolution and fraction absorption for the optimal PB-SR dosage forms. Finally, the PB-SR pellets were chosen to proceed the microdialysis study. According to the results of microdialysis technique shown that the release of acetylcholine and the release of protein unbound drug for the PB-SR pellets were slower than IV-injection and commercial IR tablets; this phenomenon indicating that the occupancy time of drug efficacy in vivo of PB-SR pellet was longer than the others, that is to say, the PB-SR pellets provided with SR effect in vivo as well.
We believe that PB-SR dosage forms designed in our study would improve limitations of post-exposure antidotes, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo, for personnel exposed to contamination situations in wars or terrorist attacks in the future.

Tables……………………………………………………………i
Figures…………………………………………………………… iv

中文摘要…………………………………………………………. viii

Abstract………………………………………………………… x

1. Introduction………………………………………………… 1
1.1.Background………………………………………………… 1
1.2. Outlines of pyridostigmine bromide (PB)………… 4
1.2.1. Physicochemical properties………………………… 4
1.2.2. Pharmacology…………………………………………… 6
1.2.3. Pharmacokinetic (PK) and pharmacodynamic (PD) 7
1.2.3.1. Absorption…………………………………………… 7
1.2.3.2. Distribution………………………………………… 7
1.2.3.3. Metabolism ?t Elimination……………………… 7
1.2.4. Adverse reactions…………………………………… 9
1.3. Pellets…………………………………………………… 10
1.4. Modified oral drug release………………………… 14
1.4.1. Tableting……………………………………………… 16
1.4.2. Coating………………………………………………… 18
1.4.2.1. Fluid-bed equipment………………………………21
1.5. SR materials (polymers) ?t excipients…………… 26
1.5.1. Hydroxypropylmethyl cellulose (HPMC)…………… 26
1.5.2. Surelease?窗K………………………………………… 27
1.5.3. Opadry II ?t Opadry II HP…………29
1.6. Microdialysisstudy…………………………………… 31
1.6.1. A brief illustration………………………………… 31
1.6.2. Advantages of microdialysis technique………… 34
1.6.3. Disadvantages of microdialysis technique……… 35
1.6.4. Recovery of Microdialysis………………………… 36
1.7. In vitro/In vivo correlations (IVIVC)……………39
1.7.1. A brief illustration……………………………… 39
1.7.2. Categories of in vitro/in vivo correlations… 40
1.8. Experimental design…………………………………… 43
1.8.1. A brief introduction of experimental design… 43
1.8.2. The 23 full factorial design………………………45
1.8.3. The estimation of effects for 23 full factorial design…46
1.8.4. The Taguchi experimental design……………………50
1.9. Release mechanism of SR dosage forms……………52
2. The aim of this study………………………………………53
3. Materials and methods……………………………………56
3.1. Materials……………………………………………………56
3.1.1. Drug and excipients………………………………… 56
3.1.2. Analytical grade reagents……………………………56
3.1.3. Other chemical reagents…………………………… 57
3.2. Experimental methods…………………………………… 58
3.2.1. PB core pellets……………………………………… 58
3.2.1.1. Preparation of PB core pellets……………………58
3.2.1.2. Microscopic image analysis (determination of core
pellet shape) ……………………………58
3.2.1.3. Sieve analysis (determination of yield of core
pellet)……….59
3.2.2. PB-SR tableted-pellets……………………………… 61
3.2.2.1. Preparation of granules (external excipients)…61
3.2.2.2. Preparation of PB-SR……………………………… 61
3.2.3. PB-SR pellets………………………………………… 64
3.2.3.1. Preparation of PB-SR pellets…………………… 64
3.2.4. In-vitro study of PB………………………………… 68
3.2.4.1. Scanning electron microscopy……………………68
3.2.4.2. In vitro dissolution studies of PB-SR dosage
forms…68
3.2.4.3. High performance liquid chromatography (HPLC)
conditions……………………………………69
3.2.4.4. Exposure to stability conditions for estimating
the hygroscopic character of PB…………………71
3.2.5. In-vivo study of PB……………………………72
3.2.5.1. Animal treatment…………………………………72
3.2.5.2. Pretreatment (extraction method of blood sample)74
3.2.5.3. HPLC conditions………………………………… 74
3.2.5.4. Data analysis……………………………………… 77
3.2.6. Experimental design………………………………… 79
3.2.6.1. Taguchi experimental design………………………79
3.2.6.2. 23 full factorial design………………………… 80
3.2.7. Release mechanism of PB-SR dosage forms……… 81
3.2.8. Microdialysis study………………………………… 82
3.2.8.1. Animal treatment and dialysis technique…… 82
3.2.8.2. Data analysis……………………………………… 83
3.2.8.3. HPLC conditions of protein unbound drug (PB)88
3.2.8.4. HPLC conditions of ACh…………………………… 90
3.2.8.5. In vitro-in vivo Recovery……………………… 93
4. Results and discussion………………………………… 94
4.1. In-vitro study…………………………………………… 94
4.1.1. HPLC conditions……………………………………… 94
4.1.1.1. Determination of suitable wavelength………… 94
4.1.1.2. Chromatogram of PB…………………………………94
4.1.1.3. Calibration curve………………………………… 94
4.1.1.4. Assay validation (intra-day precision inter-day p recision)……………………………………………95
4.1.1.5. Accuracy……………………………………………… 95
4.1.2. Evaluation of preparation process variables of PB core pellets using Taguchi experimental design………100
4.1.3. In-vitro dissolution study of PB from SR dosage
forms……108
4.1.3.1. PB-SR tableted-pellets…………………………108
4.1.3.2. PB-SR pellets……………………………………114
4.1.4. The release mechanism of PB from PB-SR dosage
forms…………119
4.1.4.1. PB-SR tableted-pellets…………………………119
4.1.4.2. PB-SR pellets……………………………………119
4.1.5. Evaluation of drug release and release mechanism
from PB–SR dosage forms using 23 full factorial
design…………121
4.1.5.1. PB-SR tableted-pellets…………………………121
4.1.5.2. PB-SR pellets………………………………………121
4.1.6. Optimization of formulations using 23 full
factorial design…..125
4.1.7. Exposure to accelerated and long-term stability
conditions for estimating the hygroscopic character
of PB-SR dosage forms…………………………………129
4.2. In vivo absorption study……………………………… 134
4.2.1. HPLC conditions……………………………………… 134
4.2.1.1. Chromatogram of PB…………………………………134
4.2.1.2. Calibration curve of PB…………………………134
4.2.1.3. Assay validation (intra-day precision ?t inter-
day precision).……134
4.2.1.4. Accuracy……………………………………………… 135
4.2.1.5. Recovery……………………………………………… 135
4.2.1.6. Limits of detection (LOD) and limit of
quantification (LOQ).…………………………… 135
4.2.2. Pharmacokinetics………………………………………140
4.2.3. In vitro-In vivocorrelation………………………143
4.3. Microdialysis study……………………………………145
4.3.1. Protein unbound drug (PB)………………………145
4.3.1.1. Chromatogram……………………………………… 145
4.3.1.2. Calibration curve……………………………………145
4.3.1.3. Assay validation (intra-day precision inter-day
precision) 145
4.3.1.4. Accuracy……………………………………………… 150
4.3.1.5. In-vitro recovery In-vivo recovery…………… 150
4.3.1.6. Limit of detection (LOD) limit of quantification
(LOQ)……………150
4.3.1.7. In-vivo study (pharmacokinetics IVIVC)………150
4.3.2. Acetylcholine………………………………………… 155
4.3.2.1. Chromatogram……………………………………… 155
4.3.2.2. Calibration curve………………………………… 155
4.3.2.3. Assay validation (intra-day precision inter-day
precision)………155
4.3.2.4. Accuracy……………………………………………… 156
4.3.2.5. In-vitro recovery In-vivo recovery…………… 156
4.3.2.6. Limit of detection (LOD) limit of quantification
(LOQ)…156
4.3.2.7. In-vivo release of ACh in skeletalmuscle……161
4.3.2.8. Relationship between the release of ACh in
skeletal muscle and the release of protein
unbound drug (PB) in blood……162
4.3.2.9. Comprehensiveness………………………………… 166
5. Conclusion………………………………………………… 167
6. References...................................... 170
7. Publishing paper…………………………………………… 187
8. Suggestion for further study…………………………… 188

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