| 摘要: | Aripiprazole（APZ）是一種用於治療思覺失調症之藥物，在過去的研究指出其相較於其他藥品具有較少之副作用，因此成為治療思覺失調症有吸引力的藥物選擇。思覺失調症被National Institutes of Health（NIH）定義為一種慢性和嚴重的精神疾病，需要長期治療。目前治療思覺失調症面臨最大的問題是患者服藥時的不依從性。在過去研究指出，相較於口服錠片，長效注射針劑可以改善患者不依從行為，降低疾病復發率。然而，給予APZ長效注射針劑時，因其達到最低有效濃度的時間較緩慢，必須在起始治療前14天連續給予口服錠片，以達最低有效濃度。因此本研究目的為開發Aripiprazole速放及緩釋處方合併使用之注射針劑，以持續釋放藥物。
本研究使用HPMC-E3或Pluronic® F68透過固體分散體技術之溶劑揮發法製備APZ速放及緩釋處方。在X-ray分析結果中，APZ：HPMC-E3 =
1：5（w/w）時，沒有觀察到明顯的繞射峰，呈現Amorphous form的狀態。在DSC分析結果顯示APZ透過固體分散製備過程使藥物晶型結構改變。從體外溶離結果觀察到最佳的緩釋處方比例為（APZ：HPMC-E3 = 1：0.5, w/w），將其藥物釋放結果與市售品進行溶離比對，差異因子 (f1)為5.01，相似因子 (f2)為66.58，具有與市售品相似之藥物釋放行為，而最佳的速放處方比例為APZ：HPMC-E3：Pluronic® F68 = 1：1：1, w/w/w)，其體外溶離試驗結果顯示在三十分鐘藥物釋放達80%。從體外溶離試驗也觀察到，在處方中添加Pluronic® F68可以增加藥物釋放。
綜合以上研究結果，本研究成功使用固體分散體技術同時製備出速放及緩釋處方。未來也會進一步將速放及緩釋處方合併，進行體外體內評估。
Aripiprazole (APZ) is an antipsychotic drug indicated for the treatment of patients with schizophrenia. It is an attractive choice for antipsychotic patients, as they have fewer side effects than other drugs in previous studies. Schizophrenia is defined by the National Institutes of Health (NIH) as a chronic and severe mental disorder that requires continuous long-term treatment. However, poor adherence to drug treatments has been recognized as a problem worldwide and may be the most challenging aspect of treating patients with schizophrenia. In previous studies, long-acting injectable formulations have potential advantages over tablet in improving compliance and thus reducing relapse rates. However, the slow onset of long-acting injectable formulations is a limitation that 14 consecutive days of oral administration is necessary to achieve therapeutic APZ concentrations during initiation of therapy. Thus, the aim of this study is to develop an injectable APZ delivery system in combination of instant and prolonged release profiles.
In this study, APZ instant release and sustained release formulations were prepared by solid dispersion with HPMC-E3 or Pluronic® F68 using solvent-based methods. The results of X-ray diffractometry show the APZ:HPMC-E3 (1:5, w/w) did not have distinct diffraction peaks indicating its lacked crystalline characteristics. The differential scanning calorimetry experiments indicate the crystal structure of APZ has been changed after solid dispersion process.
In terms of drug release, the optimal sustained release pattern was obtained from the composition of APZ:HPMC-E3 (1:0.5, w/w). Compared with commercial product, the difference factor (f1) is 5.01 and similarity factor (f2) is 66.58 suggest a high correlation. For optimal instant release formulation- APZ:HPMC-E3:Pluronic® F68 (1:1:1, w/w/w), 80% of APZ was released within 30 mins. Base on the in vitro dissolution test, we found that adding Pluronic® F68 in the formulation can 1, w/w/w), 80% of APZ was released within 30 mins. Base on the in vitro dissolution test, we found that adding Pluronic® F68 in the formulation can effectively enhance the drug release.
In conclusion, solid dispersion formulations were successfully prepared and demonstrated both instant release and sustained release profile. Combined instant release and sustained release formulations will be further evaluated the in vitro and in vivo behavior in the near future. |
