Objective: To establish a in vitro research method for consistency evaluation of aripiprazole oral disintegrating tablets by using computer modelling and parallel artificial membrane permeation model, to provide methods and data support for the screening of key process parameters in poorly-soluble drug preparations. Methods: In vitro dissolution methods for aripiprazole oral collapsing tablets was established. The model for in vivo absorption of aripiprazole oral collapsing tablets was established using GastroplusTM software. The in vitro/in vivo correlation of the dissolution methods was analyzed to find the physiological correlated dissolution method. The particle size range of the generic product was designed via the parameter sensitivity analysis of computer modelling. The dissolution curves of the generics product with different particle sizes and the reference preparation were compared to determine the particle size range. Parallel artificial membrane permeability assay was conducted to simulate the bioequivalence between the generic products and the reference product, thus to investigate the relationship between the particle size and the in vivo absorption of the drug. Bioequivalence prediction was validated through clinical trial results. Results: Aripiprazole is a poorly-soluble drug and shows a pH-relevant solubility. The dissolution profiles of aripiprazole oral collapsing tablets were different in pH 1.2, pH 4.0 and pH 4.5 media, with the fastest dissolution in pH 1.2 medium and the slowest dissolution in pH 4.5 medium. The dissolution in pH 4.5 medium showed the highest correlation coefficient with the simulated in vivo release curve (Y=0.005 3X2+0.404 1X-0.068 5, r=0.998 7). The dissolution curves of generic products meet the similarity requirement with the reference product(f2>50). A batch of generic products within the particle size range was used for clinical trials, and the results showed that it was bioequivalent with the reference product. Conclusion: A dissolution method with high in vitro and in vivo correlation was established by computer modelling combined with parallel artificial membrane permeation. This method successfully guided the drug particle size screening, and determined the drug particle size range in the process parameters. This method provides data support for the screening of generic drug prescription process quickly and effectively. It reduces the time spent in the research and development of generic products, reduces the cost and improves the success rate of bioequivalence of generic products.
GUO Zhiyuan, ZHOU Rui, FENG Wen, ZHU Qiang, XIE Hua, YANG Lei
. Appilcation of computer modelling and the parallel artificial membrane permeability assay in the study of aripiprazole oral collapsing tablets formulation process*[J]. Chinese Journal of Pharmaceutical Analysis, 2023
, 43(6)
: 982
-990
.
DOI: 10.16155/j.0254-1793.2023.06.09
[1] 瞿发林,王焕林. 抗精神病药阿立哌唑(aripiprazole)[J].世界临床药物,2003,24(9):571
QU FL WANG HL. Antipsychotic drug aripiprazole[J].World Clin Drugs, 2003, 24(9):571
[2] IBARRA M, VALIANTE C, SOPENA P, et al. Integration of invitro biorelevant dissolution and in silico PBPK model of carvedilol to predict bioequivalence of oral drug products[J].Eur J Pharm Sci,2018,118(3):176
[3] KESISOGLOU F. The role of physiologically based oral absorption modelling in formulation development under a quality by design paradigm[J].J Pharm Sci, 2017, 106(4):944
[4] KANSY M, AVDEEF A, FISCHER H. Advances in screening for membrane permeability:high-resolution PAMPA for medicinal chemists[J].Drug Discov Today Technol,2004,1(4):349
[5] 吴一凡,刘辉,倪京满.平行人工膜渗透模型及其应用进展[J].药学学报,2011,46(8):890
WU YF,LIU H,NI JM. Advances in parallel artificial membrane permeability assay and its applications[J].Acta Pharm Sin, 2011, 46(8):8905
[6] 关皓月,张广超,牛剑钊,等.平行人工膜体外渗透技术在药物一致性评价中的应用[J].中国药事,2020,34(8):891
GUAN HY, ZHANG GC, NIU JZ, et al. Application of PAMPA in drug evaluation of drug consistency[J].Chin Pharm Aff, 2020, 34(8):891
[7] BORBÁS E, BALOGH A, KATALIN B, et al. In vitro dissolution-permeation evaluation of an electrospuncyclodextrin-based formulation of aripiprazole using uFlux[J].Int J Pharm, 2015, 491:180
[8] MOUSTAPHA ME, MOTALEB MA, IBRAHIM IT, et al. Oxidative radioiodination of aripiprazole by chloramine-t as a route to a potential brain imaging agent:a mechanistic approach[J].Radiochemistry, 2013, 55(1):116
[9] New Zealand data sheet-abilifytab[DB]. 2019, 1(3):1
[10] 吴娟,沙先谊,方晓玲.阿立哌唑在 Caco-2 细胞单层模型中的跨膜转运[J].药学学报,2009, 44(2):188
WU J, SHA XY, FANG XL. Transport of aripiprazole across Caco-2 monolayer model[J].Acta Pharm Sin, 2009, 44(2):188
[11] DAVID WB, GEORGIA K, SURESH M, et al. Pharmacokinetics and tolerability of intramuscular, oral and intravenous aripiprazole in healthy subjects and in patients with Schizophrenia[J].Clin Pharmacokinet, 2008, 47(7):475
[12] 王洪允,沈凯,江骥,等. 阿立哌唑片在中国健康人体的单剂和多剂药动学研究[J].中国新药杂志, 2013,22(7):814
WANG HY, SHEN K, JIANG J, et al. Pharmacokinetics of aripiprazole after single and multiple dosing in Chinese healthy subjects[J].Chin J New Drugs, 2013, 22(7):814
[13] 王琳,吴斌,王铁松,等.基于孟鲁司特钠咀嚼片渗透速率分析初步预测制剂的生物等效性[J].中国药学杂志,2019,54(18):1511
WANG L,WU B,WANG TS, et al. Preliminary prediction of bioequivalence of montelukast sodium chewable tablets based on permeability analysis[J].Chin Pharm J, 2019, 54(18):1511
[14] 张斗胜,王晨,姚尚辰等,生理药动学模型结合体外相似性溶出实验预测国产口服苯唑西林钠溶出行为差异影响以及工艺合理性[J].中国新药杂志,2019,28(19):2347
ZHANG DS,WANG C,YAO SC, et al. Prediction of the difference in dissolution behavior of domestic oral oxacillin sodium and process rationality by physiological pharmacokinetic model combined with in vitro similarity dissolution generic[J].Chin J New Drugs, 2019, 28(19):2347
[15] 李丽,杨进波. 基于生理的口服吸收模型在仿制药研发中的应用和趋势[J].中国临床药理学与治疗学,2017,22(9):961
LI L,YANG JB. Applications and trends of physiologically-based absorption modeling in the research and development of generic drugs[J].Chin J Clin Pharmacol Ther, 2017, 22(9):961
