| 摘要: | 思覺失調症是一種連續或反復發作的精神病之一，於2019年全球估計有2000萬新案例，而台灣大約0.2 ~ 0.3% 的人被診斷出患有思覺失調症。其中Aripiprazole (APZ) 為治療思覺失調症廣泛使用之藥物，與其他治療思覺失調症藥物相比副作用較少，而目前APZ 長效針劑市售品需在投與藥物後十四天或二十一天搭配口服，因此，本研究目的希望可將速放及緩釋處方結合，以快速達到有效治療濃度，而取代或減少搭配口服次數，並且開發出一劑即可達到完整一個月之療效。
APZ 為弱鹼性藥物，其溶解度對pH具有依賴性，目前已成功設計出利用酸化劑改善藥物溶解度，並透過Top-down (High pressure homogenization) 與Bottom-up (anti-solvent) 製備懸浮液。由X射線繞射和傅立葉轉換紅外光譜結果表明HPMC和PVP添加量為150 mg，1N HCl酸含量為52、103 μL (H150-52、H150-103、P150-52及P150-103)與安立復美達持續性藥效肌肉注射用懸浮劑之市售品具有相似的晶型結構。由溶解度結果顯示，透過酸化劑及助溶劑皆可改善藥物溶解度，並且增加助溶劑比例可以減小粒徑，而有較快的藥物釋放速率，H150-103、P150-103溶解度為市售品兩倍，H150-52、P150-52則為市售品1.22倍和1.36倍，皆比市售品有較快的藥物釋放速率。
於藥物動力學結果顯示，劑量為50 mg/kg中HPMC之組別AUC0-10高於APZ product，並與口服市售品相比有較高的Cmax，且有相似T1/2，表示處方不需要初始服用口服錠片或可減少口服之次數，即可立即達到有效治療濃度，且可長達一個月之療效。綜上所述，基於酸鹼中和的沉澱/均質化有利於製備穩定的APZ懸浮液，並且成功開發速放與緩釋結合於同一處方，期許未來能減少口服之使用而改善思覺失調症患者依從性之問題。
Schizophrenia is a psychiatric diagnosis characterized by continuous or relapsing episodes of psychosis. About 0.3% to 0.7% of people are diagnosed with schizophrenia during their lifetime. In 2019, there were an estimated 20 million new cases globally. As the first line, Aripiprazole (APZ) is used as an antipsychotic drug for the patients with schizophrenia. For antipsychotic patients, this is such a widely used option since they have fewer side effects than other drugs based on the clinical results. However, patients are required to receive concomitant oral aripiprazole 10–20 mg/day for 14 days after the first injection.Therefore, the purpose of this study is to combined instant release and sustained release formulations, rapidly to achieve therapeutic APZ concentrations during initiation of therapy without co-administered the oral tablets.
APZ, a weakly basic drug with pH-dependent solubility, herein is feasibly prepared as micro-suspension using a microprecipitation/homogenization technique based on acid-base neutralization. The results of X-ray diffraction and differential scanning calorimetry demonstrate that the crystal structure of H150-52, H150-103, P150-52, P150-103 are similar to Abilify MAINTENA® (Commercial products) after the microprecipitation/homogenization processes. APZ microsuspensions are formulated by adding acidifiers and polymers to increase solubility. It also showed that the increase of polymer contents could reduce the particle size and exhibit a rapid release of the drug. In addition, 150 mg HPMC or PVP with 103 μL 1N HCl (H150-103、P150-103) increased the solubility of APZ products by about 2 times, and 150 mg HPMC or PVP with 52 μL 1N HCl (H150-52、P150-52 increased the solubility of APZ products by about 1.22 times and 1.36 times, respectively.
In terms of pharmacokinetics, a higher AUC0-7 was found in the groups of H52 and H103 with the dosage of 50 mg/kg compared with that of APZ commercial product.. While the T1/2 of the H52 and H103 is similar to the APZ commercial product. Meanwhile, the Cmax of H52 and H103 was higher than that of the APZ oral tablet. Taken together, a single dose of APZ from our formulation could provide a long-term effect. In addition, the prolonged-release effect of APZ microparticle injection might not require an initial administration of oral immediate-release tablets. Alternatively, a the frequency for the oral administration could be reduced during the monthly treatment.
In summary, the micro-precipitation/homogenization based on acid-base neutralization was successfully prepared to form a stable micro-suspension and a combination of instant and sustained drug release could be achieved.
Key words: Aripiprazole, schizophrenia, acidifiers, Long-acting injectable |
