利用微乳液與反溶劑系統研究有機藥物之微粒化並探討系統組成對晶貌的影響

Abstract

針對難溶於水或生體利用率低的有機藥物而言，可以藉由微粒化這個直接又安全的方式，來增加藥物的表面積，以提高其在人體中的溶解速率，並達到提升生體利用率的功效。故本研究擬利用微乳液系統－改變溫度製程與溶劑擴散製程，來做有機藥物Mitotane、Glybenclamide (GBM)及Warfarin的微粒化作業。並進一步研究，在不同系統中，藉由系統組成的改變、操作條件與手法的改變或添加劑的加入等等，對於再結晶藥物晶貌與大小上的影響。 對於Mitotane而言，研究發現藉由water / butyl lactate / lecithin-ethanol / taurodeoxycholic acid sodium salt hydrate (TDC)，oil in water (O/W)微乳液－溶劑擴散製程使藥物再結晶時，可以得到大小在1*0.4-3*2微米之間的產物(原藥大小50*30-200*80微米)，經由溶解速率測試發現，在第五分鐘時，溶離比率比起原始藥物提升了4.81倍，同時溶解速率常數kW值也提高了7.54倍。此外也完成了water / benzyl alcohol / sodium dodecyl sulfate (SDS)三成分系統在不同溫度下(10oC-60oC)的三相圖，並同時發現利用此(O/W)微乳液－改變溫度製程或溶劑擴散製程使藥物再結晶時，可以藉由改變微乳液組成，提高界面活性劑SDS的濃度來使再結晶藥物的晶貌從柱狀轉變為塊狀。 對於Glybenclamide (GBM)而言，研究發現藉由cyclohexane / dimethyl sulfoxide (DMSO) / dioctyl sulfosuccinate sodium salt (AOT)，water in oil (W/O)逆微乳液－改變溫度製程使藥物再結晶時，可以得到0.3*0.2-1*1微米之間的產物(其中300nm-500nm的佔大多數)(原藥大小15*10-100*70微米)，經由溶解速率測試發現，在第五分鐘時，溶離比率比起原始藥物提升了6.51倍，同時溶解速率常數kW值也提高了10.01倍。此外也發現，在反溶劑製程中，藉由添加劑Tw80的加入，可以明顯提高微粒化的效果。 對於Warfarin而言，研究發現藉由water / benzyl alcohol / sodium dodecyl sulfate (SDS)，(O/W)微乳液－改變溫度製程使藥物再結晶時，可以得到大部分為0.8*0.7-4*3微米之間的塊狀產物(有少部分較大柱狀存在) (原藥大小20*5-100*30微米)，經由溶解速率測試發現，在第五分鐘時，溶離比率比起原始藥物提升了1.78倍，同時溶解速率常數kW值也提高了13.29倍。

For poor solubility in water or lower bioavailability organic drugs, micronization is one of the most direct and safe way to increase the surface area in order to enhance the dissolution rate and bioavailability of the drugs in body. So in this research, we want to us microemulsion system－temperature changing process and solvent diffusion process to micronize organic drugs of mitotane、Glybenclamide (GBM) and warfarin. Further, we want to research the effects of recrystalized drugs’ shape and size by changing system composition, operating conditions and adding extra addition. For mitotane, we can get 1*0.4-3*2micrometer products by water / butyl lactate / lecithin-ethanol / taurodeoxycholic acid sodium salt hydrate (TDC), oil in water (O/W) microemulsion－solvent diffusion process (original drug：50*30-200*80 micrometer). By dissolution rate test, we find the dissolution rate of products increase 4.81 times at 5 mins and the dissolution rate coefficient (kW) increase 7.54 times. In addition, we finish the phase diagram of water / benzyl alcohol / sodium dodecyl sulfate (SDS) system at 10oC-60oC. And we find that when we use this (O/W) microemulsion－temperature changing process or solvent diffusion process to recrystalize the drugs, we can make the products’ shape change from needlelike to lump by changing system composition－increasing the concentration of surfactant SDS. For Glybenclamide (GBM), we can get 0.3*0.2-1*1 micrometer products (mostly in 300-500nm) by cyclohexane / dimethyl sulfoxide (DMSO) / dioctyl sulfosuccinate sodium salt (AOT), water in oil (W/O) microemulsion－temperature changing process(original drug：15*10-100*70 micrometer). By dissolution rate test, we find the dissolution rate of products increase 6.51 times at 5 mins and the dissolution rate coefficient (kW) increase 10.01 times. Furthermore, we find that in antisolvent process we can effectively decrease the particle size by adding extra material－Tw80. For warfarin, we can get mostly 0.8*0.7-4*3 micrometer products by water / benzyl alcohol / sodium dodecyl sulfate (SDS), (O/W) microemulsion－temperature changing process (original drug：20*5-100*30 micrometer). By dissolution rate test, we find the dissolution rate of products increase 1.78 times at 5 mins and the dissolution rate coefficient (kW) increase 13.29 times.