Dipyridamole 圓粒劑型之處方研究
Diphenidol 是一個合成之抗暈眩劑及止吐劑，具有很好的特異性與療效，上市至今三十多年，已經 成為抗暈眩藥物中之首選藥，臨床應用上非常普遍；然而，在代謝的研究上仍少有相關的研究報告。
本研究室曾以正相高效液相層析法 (normal phase HPLC) 分析其在家兔體內的動態，發現口服投與 後，血液檢品中並無 diphenidol 存在，僅劑量高達 150 mg/kg 時，於 diphenidol 之滯留時間前 0.7 分 鐘出現一巨大峰線，與人體藥效相比較，顯示 diphenidol 之代謝途徑在不同種生物中有相當的差異。
本實驗採逆相高效液相層析法，探討 diphenidol 與其代謝物之分析方法，進而以 LC/MS/MS 分析其 代謝物之質譜，期能解得 diphenidol 於家兔及人體之代謝途徑。
本實驗之分析方法是利用逆相高效液相層析管柱，配合波長 220 nm 之紫外光檢測生物檢體中 diphe nidol 及其代謝物。 Diphenidol 之最低檢測濃度為 100 ng/ml ，在血漿濃度範圍每毫升 100-4000 ng 內，呈現良好的線性關係， r>0.99 。同日內與異日間分析之變異系數均小於 15 % 。顯示所開發之 分析方法，能準確的定量生物檢體中之 diphenidol 。
靜脈注射投與 6 mg/kg 之 diphenidol 於家兔，其藥物動力學呈現二室性模式特性，與先前利用正相 層析法所得結果相符合；另外將二顆 25 mg diphenidol 糖衣錠口服投與於一名健康男性志願者，採 取其生物檢體分析，唯因定量之最低濃度 (100 ng/ml) 尚不足以偵測到人體口服 diphenidol 之最高血 中濃度，因此無法求得人體之藥物動力學參數。
探討 diphenidol 之代謝途徑，另以 120 mg/kg 之 diphenidol 口服投與於家兔，利用所開發之 LC 分析 條件，配合 LC/MS/MS 檢測，並將血液及尿液檢品以 b-glucuronidase 水解，檢測共軛結合型之代謝 物。 Diphenidol 之代謝行 hydroxylation 、 glucuronidation 及開環形成羧基化合物之途徑。以口服投 與 diphenidol 於人體，則 diphenidol 之代謝以氧化開環形成 N-(4,4-diphenyl-4-hydroxybutyl)-d-amino valeric acid 為主。
結果顯示 diphenidol 在家兔與人主要的代謝途徑不同。唯並未能取得 diphenidol 代謝物之標準品更 正確的加以比對及定量，僅能由生物檢品中微量藥物的分析，藉由質譜結果初步的說明 diphenidol 在家兔與人體中代謝的可能途徑。
The formulation study of dipyridamole pellet dosage form
Pellets as a drug delivery system offer not only therapeutic advantages such as less irritation of the gastro-intestinal tract and a lowered risk of side effects due to dose dumping but also technological advantages. The purpose of this research was to devel op a controlled release pellet dosage form for poorly water-soluble drug with high dose. Dipyridamole was selected as a mode l drug and the commercial product, Pertsantin® was marked as reference product. The release profile of dipyridamole from a commercial product, Persantin, was examined for reference.
There are two parts in this study. One is the preparation of pellets and the other is the coating of controlling film on the pellet.
In the preparation of pellets, microcrystalline cellulose (MCC), lactose anhydrate and low-substituted hydroxypropylcellulose (LHPC-LH21) were used as excipient. The production of pellets was done by means of the Extruder-Spheronizer. In order to i ncrease the dissolution of dipyridamole (pKa 6.4) in basic environment, simulated intestinal fluid containing 0.25% sodium la uryl sulfate was selected as a medium. The characteristics of pellets were evaluated by the yield and roundness of pellets. Wit h an increasing ratio of MCC to lactose anhydrate, the yield and roundness of pellets were gradually improved but the extent o f dipyridamole release was apparently decreased. The formulation 9 with the excipent mixtures (MCC : lactose anhydrate = 2 : 8) showed a similar dissoluton rate as that for Persantin. The yield of pellets prepared using lactose anhydrate and LHPC-LH 21 was increased with increasing stirring time and the amount of water added. With the addition of PEG 6000 as plasticizer an d Prmojel as disintegrant to pellets, the dissolution rate of drug from pellets was promoted and the yield of preparation was en hanced as well. The closeness of the dissolution profile to that of Persantin was demonstrated by the formulation with the pres ence of 7.5% Primojel and 1% PEG 6000 in the pellet containing MCC, lactose anhydrate, and LHPC-LH21 at a mixing ratio of 2 : 5 : 3. Besides that, the formulation with the presence of 5% Primojel and 0.5% PEG 6000 in the pellet containing MCC and lactose anhydrate at a mixing ratio of 3:7 also showed the similar dissolution profile.
