高劑量圓粒緩釋劑型之開發研究
The study of preparation for high dose sustained-release pellets
中文摘要
以擠出-搓圓法（Extrusion-Spheronization）製得的圓粒，已被證實可得到較高的 圓粒密度。因此用此方法製造高劑量用藥的圓粒時，可以得到較小的劑型體積。
實驗所選擇的高劑量模式藥，etofibrate，其粉末的密度低、流動性及粒子之間的 結合性差，為了要克服其不佳的粉末性質，而得到理想的高劑量圓粒，因此實
驗將針對etofibrate 粉末的性質以及製程條件的因素，對圓粒性質的影響作評估。
並進一步包覆高分子材料形成緩釋圓粒後，觀察藥物釋放的情形。利用四種不同
的方式，處理etofibrate 原料粉末，結果發現能提高粉末的密度及流動性，其中
以經過熔融後於-80℃下固化的處理最顯著。而粉末性質改善的原因，是增加了 粉末粒子的緻密度與粉末平均粒徑的大小。由於粉末粒徑變大，總表面積會變小
，粉末粒子間的結合面積也減小，因此其圓粒的密度並沒有因為粉末密度的提 升而增加，並且造成圓粒的產值明顯降低。在處方因素及機器條件影響圓粒性質 的探討上，利用Central Composite Design 的實驗設計法配合迴歸分析及
Response Surface Method，對三種處方因素及二個搓圓條件進行影響圓粒性質的 評估。結果顯示，利用較小粒徑的粉末粒子製成圓粒，會得到較大密度的圓粒。
增加黏合劑或水份的用量，可明顯提高圓粒的產率，但是對圓粒的密度卻沒有 影響。在機器條件方面，搓圓時間比搓圓速度更能影響圓粒的密度，尤其延長搓 圓的時間，對實驗中大多數的處方，皆能有效地提高圓粒的密度，使一次劑量 的etofibrate 圓粒可完全充填在 0 號膠囊中。Etofibrate 圓粒經過高分子材料包覆 形成緩釋圓粒後，在加熱的情形下，再進行一次搓圓作用，觀察控釋圓粒性質 的變化，以及對緩釋膜衣熟化（curing）的實驗中發現，etofibrate 緩釋圓粒再經 過一次搓圓作用後，可提高緩釋圓粒的密度，但是當溫度增高或搓圓時間延長 時，會增加圓粒黏著在機器壁上的機會，而明顯減少緩釋圓粒的產量。另外，由 藥物溶離曲線的結果顯現，由於實驗中熱搓圓處理所使用的溫度必須低於 etofibrate 的熔點溫度（49℃），而以此溫度於短暫的搓圓時間下並不能對高分 子膜衣進行有效的熟化（curing）作用。以 ethylcellulose 作為 etofibrate 圓粒緩釋 的材料，可以明顯地延緩藥物的釋放。其中，包覆2.5% ethylcellulose 的緩釋圓 粒可與市售商（Lipo-Merz Retard(）的體外溶離曲線相同。而更高量（5%及 7.5%）的高分子材料可以使
etofibrate 圓粒的藥物溶離時間延長到 10 至 16 小時。
英文摘要
The object of this study was to develop a high dose pellet dosage form for a drug with poor powder characteristics and low density. The specific aims were to study the effects of the physical modification of powder and manufacturing process on the
physical characteristics of the treated powder and so obtained pellets, and their in vitro dissolution. Extrusion-spheronization technology was chosen as a basic method since it has been proved to be effective in the prodution of pellet with a higher density. Etofibrate was selected as a model drug due to its low bulk density andpoor flow characteristics. Etofibrate was subjected to four different methods to modify its physical characteristics. Among them, the processing method of melting and then solidifying at -80 ℃ significantly improved the density and flow characteristic of the powder. This was possible due to the increase of the mean size and the density of the powder. However, the increase of mean size leaded to the eecrease of total surface area resulting in the decrease of binding area of powder particles. Since that, the density of pellet did not increase with the increase of powder density. Furthermore, the yield of pellets decreased significantly. Anm experimental design of central composite was employed to quantitatively examine the influence of formulation factors and manufacturing conditions on the pellet properties. The results were analyzed by response surface methodology. Three formulation factors and two spheronization conditions were simultaneously examined. The results demonstrated that the use of powder with a smaller mean size to prepare pellet was able to obtain pellets with a higher density. Increasing the used amount of binder and water could significantly increase the yield of pellets, but they showed no influence on the density of pellets. Regarding the manufacturing conditions, the effect of spheronization time on the density of pellets was more profound than that of spheronization speed.
Especially, when the spheronization time was increased, the density of pellets could be effectively increased for most of formulations. As a result, one dose amount of etofibrate could be filled into a zero size of capsule by the simultaneous manipulation of powder characteristics and manufacturing conditions.A controlled release pellet dosage form of etofibrate was accomplished by coating etofibrate pellets with a polymeric material. Further spheronization of such a coated pellet under heating was conducted to examine its effect on the properties of pellets and the curing effect on the
controlling membrane. It was found that secondary spheronization could further improve the density of coated pellets. However, both increasing the temperature and extending the spheronization time tended to increase the chance for pellets to adhere to the wall of machine resulting in a significant decrease of the pellet yield.
Additionally, the results of in vitro dissolution showed that since the temperature could be employed was limited by the melting point of etofibrate at no more than 49
℃, the short residence time of spheronization employed was not able to effectively cure the coated polymeric membrane. Finally, the use of ethylcellulose as a
controlling material for etofibrate pellets to sustain the release of etofibrate was
demonstrated to be effective. Among them, the in vitro drug release profile for these pellets coated with 2.5% ethylcellulose was comparable to that for the commercial product of Lipo-Merz Retard(. With a higher coated amount (5.0 and 7.5%), the drug release time could be further prolonged to 10 and 16 hours respectively.
