不同來源之去乙醯幾丁質之壓錠特性與物化性質之解析

去乙醯幾丁質由於具有生體相容性與生體可降解性，故引起許多學者在研究上對其之關注。在藥劑方面已被當作賦型劑使用於直打劑型、錠劑崩散劑、控釋劑型及促進藥物溶解等方面，而分子量與去乙醯化程度為影響去乙醯幾丁質最重要之兩種物性。本實驗中旨在探討兩種來源不同，物性相異之去乙醯幾丁質做為調整藥物釋放之賦形劑之可能性。

選用五種不同物性之去乙醯幾丁質 (wako100 、 wako10 、 wako500 、 903 及 Sacchachitosan) 評估影響直壓成錠性之因素。製備以去乙醯幾丁質單純粉末及一系列與不同比例 acetaminophen 混合之處方進行直壓，測定其粉體流變性質，壓製曲線， Heckel plot 分析及在三種不同溶離環境下之藥物釋放現象 ( 模擬胃液，酸鹼值交換及模擬腸液 ) 。試驗結果顯示 Sacchachitosan 表現出不佳之成錠性，即使壓力增加之情況下亦無法有所改善。壓製曲線顯示不同去乙醯幾丁質在排錠壓力及有效做功上無顯著之差異。由 Heckel plot 計算之臨界成錠壓力亦無顯著之差異。壓力抗張強度上卻是明顯 wako100 與 wako10 高於 wako500 與 903 。彈性恢復程度之測定結果可說明 wako10 與 wako100為何有較好之抗張強度。

測定 wako 10 與 wako100 與 acetaminophen 混合之壓錠性質。各處方間測得之彈性恢復程度及有效做功並沒有顯著之差異。隨著去乙醯幾丁質之含量增高排錠壓力降低而抗張強則隨之增高。臨界成錠壓力隨著去乙醯幾丁質含量之增加一開始先下降，但去乙醯幾丁質含量超過 70% 後又開始上升。

在三種不同溶離環境下進行去乙醯幾丁質與 Acetaminophen 混合處方之溶離試驗。在模擬胃液的溶離環境下， wako10 含量超過 30% ， wako100 超過 10% 即可見到緩釋作用，推測可能與去乙醯幾丁質在酸中之凝膠化現象有關，因此使用黏度較高之去乙醯幾丁質只需較少之添加量即可達到緩釋的目的。而在酸鹼值交換之環境下，當轉換成模擬腸液 (pH=6.8) 後，可得到超過 24 小時之緩釋效果，其原因可能是錠片由酸性進入中性環境造成去乙醯幾丁質溶解度降低，錠片表面形成膠體層使得藥物之釋放較酸中來的緩慢。然而在模擬腸液之溶離環境下，各處方均迅速崩散，可能與去乙醯幾丁質在中性環境中溶解度低有關。

Physical and tabletting characterization of chitosan obtained from various sources

Chitosan is a biodegradable and biocompatible biopolymer leading to draw many research’s interests. It has been investigated as an excipient in the pharmaceutical field to be used in direct compression, as a disintegrant for the improvement of drug dissolution, as a matrix material for the production of controlled release solid dosage forms. The physical properties of chitosan is mainly characterized by two parameters: degree of acetylation and molecular weight. In this study, the possible use of chitosan from two different sources with variation in these two parameters as directly compressible excipient for modification of drug release were examined.

Five different chitosan products (wako10, wako100, wako500, and 903 from shell chitin, and sacchachitosan from sacchachitin) varied in physical properties were selected for evaluation of main factors influencing the success of direct compression. Powder only and a series ratio of binary mixture with acetaminophen were prepared for characterization with the measurement of powder rheology, compaction profiles, heckel plot analysis, and drug dissolution in three different conditions (simulated gastric fluid, pH-changing medium, and simulated intestinal fluid). Preliminary results demonstrated that the compressibility of sacchachitosan was so poor to form tablet even increasing compression force to a higher value. Compaction profiles showed that there was insignificant difference in profiling parameters including effective work and ejection force for all chitosan products compared. Yield pressure calculated from Heckel plot for each product also demonstrated to be insignificantly different. However, the tensile strength of tablets prepared with wako100 and wako10 was much higher than that with wako500 and 903. Degree of elastic recovery might be used to explain why wako100 and wako10 could make tablets stronger.

The compressibility for a series of binary mixture of acetaminophen and chitosan of wako100 and wako10 were determined. There also shows insignificant difference in degree of elastic recovery and effective work. With increasing the percentage of chitosan in the formulation, the ejection force of tablets decreased and the tensile strength of tablets increased correspondingly. The yield pressure of tablets decreased with increasing percentage up to 70% of chitosan in tablet formulation as well for all types of chitosan examined, and then increased afterward with increasing the percentage of chitosan.

The drug release of acetaminophen from binary mixture of acetaminophen and wako100 (or wako10) was examined in three different media. The drug release follows a sustained manner in simulated gastric fluid (pH=1.2) when the percentage of chitosan in tablet formulation is greater than 30% for wako10 and 10% for wako100. This is expectedly due to the gelling effect of chitosan in contact with acidic environment. Since that, the higher viscosity of chitosan is used, the less amount of chitosan is needed to achieve the sustained effect. Dissolution under pH-changing medium, the sustainability of drug release is even extended to be longer than 24 hours after changing to simulated intestinal fluid (pH=6.8). This might be ascribed to the insolubility of chitosan in neutral pH leading to the formation on the tablet surface of gel barrier with higher resistance than that formed in acidic medium. However, the dissolution of these tablets in the simulated intestinal fluid was faster as a result of disintegration effect of chitosan. This disintegration effect of chitosan might be explainable by its insolubility in neutral medium.