Dipyridamole 圓粒劑型之處方研究

The formulation study of dipyridamole pellet dosage form

林泳村(Yeong-tseun Lin)

指導教授 ： 許 明 照 博士

臺北醫學大學/藥學院/藥學研究所/碩士(2000年)

摘要

中文摘要 圓粒劑型設計具多樣化，並具有改善藥物療效和提高安全性的特性。當口服後，可迅速分散於胃腸道，相較於一般儲體式的單體劑型，能減少胃腸道的局部傷害，避免藥物瞬間大量釋出，造成血中藥物濃度的大幅度變化，導致副作用的產生。本實驗目的是使高劑量的難溶性藥物能在胃腸道能完全吸收，並以開發其圓粒緩釋劑型為主要重點。本實驗選用Dipyridamole為模式藥，並以含 Dipyridamole的市售膠囊圓粒商品Persantin?為對照品。 本實驗分為二階段進行：一、圓粒的製備，二、控釋膜的包覆。在實驗圓粒之製備方面，採用擠出搓圓機（Extruder-Spheronizer）作為圓粒製造的機器，利用微晶纖維素（MCC）、無水乳糖（Lactose anhydrate）和低取代羥丙烷基纖維素（LHPC-LH21）為賦形劑進行圓粒的製造。為了增加dipyridamole（pka=6.4）藥物於鹼性環境下的溶離，溶離試驗以含0.25% 硫酸月桂酯鈉（Sodium Lauryl Sulfate）的擬人工腸液 (pH 6.8) 為溶離液，而評估圓粒的特質包括產率（% Yield ）及圓度（Roundness）。在以微晶纖維素與無水乳糖製備圓粒時，圓粒的產率與圓度會因微晶纖維素的添加量增加而提高，但少量微晶纖維素的添加，卻反而對Dipyridamole藥物的釋出造成明顯降低的效果；在利用微晶纖維素與無水乳糖製備圓粒處方中，含兩者比例為 2:8 的圓粒處方9 溶離速率較近似於原廠產品。以無水乳糖與低取代羥丙烷基纖維素 (LHPC-LH21)為賦型劑製備圓粒時，必須增加攪拌時間及使用水量，以減少細小圓粒的產生（小於篩網孔徑800微米），進而使產率增加。再者聚二乙醇6000 （PEG 6000）和崩散劑Sodium starch glycolate （Primojel）的添加對圓粒的製備，同樣地具有增加藥物釋出及提高產率的作用。而利用7.5％ Primojel和1％聚二乙醇6000添加於微晶纖維素:無水乳糖: 低取代羥丙烷基纖維素(2:5:3)之處方以及5％ Primojel和0.5％ PEG 6000添加於微晶纖維素:無水乳糖(3:7)之處方製備圓粒時，所得到圓粒的藥物溶離曲線與對照商品相似。 另一方面，在控釋膜的包覆上，選用聚甲基丙烯酸脂類（Methacrylate ester copolymers）腸溶性的膜衣材質Eudragit L30D-55和水不溶性的乙基纖維素(Ethylcellulose)，以流動床包覆機（Fluidized-bed coater）將上述兩種處方的圓粒進行不同厚度控釋膜之包覆；包覆後的圓粒，以pH 1.2 擬人工胃液之溶離液，進行溶離速率評估。實驗結果顯示，在pH 1.2的溶離液中與對照品具有相似的溶離曲線。

關鍵字

圓粒緩釋劑型 ； 擠出搓圓法 ； Dipyridamole ； 溶離 ； 流動床 ； 膜衣製備 ； Persantin

並列摘要

ABSTRACT 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 develop a controlled release pellet dosage form for poorly water-soluble drug with high dose. Dipyridamole was selected as a model 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 increase the dissolution of dipyridamole (pKa 6.4) in basic environment, simulated intestinal fluid containing 0.25% sodium lauryl sulfate was selected as a medium. The characteristics of pellets were evaluated by the yield and roundness of pellets. With an increasing ratio of MCC to lactose anhydrate, the yield and roundness of pellets were gradually improved but the extent of 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-LH21 was increased with increasing stirring time and the amount of water added. With the addition of PEG 6000 as plasticizer and Prmojel as disintegrant to pellets, the dissolution rate of drug from pellets was promoted and the yield of preparation was enhanced as well. The closeness of the dissolution profile to that of Persantin was demonstrated by the formulation with the presence 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. Two pellet formulations mentioned above were selected as core pellets to further coat with Eudragit 30D-55 and ethylcellulose using a fluidized-bed coating system. The dissolution profiles of dipyridamole from pellet coated with Eudragit 30D-55 and ethylcellulose were evaluated in the simulated gastric fluid. The results showed a release profile of dipyridamole in the medium of simulated gastric fluid was close to that for Persantin.

並列關鍵字

Pellet ； Extrusion/spheronization ； Dipyridamole ； Dissolution ； Fluidized-Bed coater ； Film coating ； Persantin

參考文獻

42.中華藥典，行政院衛生署，第四版，1994年。

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