Abiraterone acetate(ABTA)was approved by the USFDA in 2011 for treating metastatic castrationresistant prostate cancer(mCRPC).ABTA exhibits poor aqueous solubility,inadequate dissolution,low oral bioavailability(<1...Abiraterone acetate(ABTA)was approved by the USFDA in 2011 for treating metastatic castrationresistant prostate cancer(mCRPC).ABTA exhibits poor aqueous solubility,inadequate dissolution,low oral bioavailability(<10%),and significant positive food effects.To overcome these limitations,in the present work,ABTA solid dispersions(SDs)were developed by using hot melt extrusion technology(HME)with various grades of hydroxypropyl methylcellulose HME(HPMC HME 15LV and 100LV)at different extrusion temperatures.HPMC HME demonstrated the ability to prevent drug precipitation for up to 120 min compared to the free drug(10 min),sustaining the supersaturation state of the drug in the solution phase and demonstrating the spring and parachute effect.The physical interactions of the ABTA SD’s were evaluated by Fourier transform infrared spectroscopy,powder X-ray diffraction,and differential scanning calorimetry confirming the conversion of ABTA into the amorphous state and the molecular interaction between HPMC and ABTA.The bio-relevant dissolution study of ABTA SD showed 2–5 times higher dissolution in fasted(FaSSIF)and fed(FeSSIF)conditions compared to free ABTA.Pharmacokinetic studies in Wistar rats revealed a 6.22 and 4.94-fold increase in Cmax and AUC0–t for the optimized ABTA SD formulation compared to free ABTA.Accelerated stability testing(40±2℃/75±5%RH,90 days)confirmed retained amorphous state,unchanged drug content and dissolution performance for the optimized formulations.The dissolution and bioavailability studies reflected that the prepared SD of ABTA may improve the therapeutic efficacy of ABTA in prostate cancer.The manufacturing technology is scalable and easy to commercialize,revealing the hope of a better treatment strategy for prostate cancer.展开更多
文摘Abiraterone acetate(ABTA)was approved by the USFDA in 2011 for treating metastatic castrationresistant prostate cancer(mCRPC).ABTA exhibits poor aqueous solubility,inadequate dissolution,low oral bioavailability(<10%),and significant positive food effects.To overcome these limitations,in the present work,ABTA solid dispersions(SDs)were developed by using hot melt extrusion technology(HME)with various grades of hydroxypropyl methylcellulose HME(HPMC HME 15LV and 100LV)at different extrusion temperatures.HPMC HME demonstrated the ability to prevent drug precipitation for up to 120 min compared to the free drug(10 min),sustaining the supersaturation state of the drug in the solution phase and demonstrating the spring and parachute effect.The physical interactions of the ABTA SD’s were evaluated by Fourier transform infrared spectroscopy,powder X-ray diffraction,and differential scanning calorimetry confirming the conversion of ABTA into the amorphous state and the molecular interaction between HPMC and ABTA.The bio-relevant dissolution study of ABTA SD showed 2–5 times higher dissolution in fasted(FaSSIF)and fed(FeSSIF)conditions compared to free ABTA.Pharmacokinetic studies in Wistar rats revealed a 6.22 and 4.94-fold increase in Cmax and AUC0–t for the optimized ABTA SD formulation compared to free ABTA.Accelerated stability testing(40±2℃/75±5%RH,90 days)confirmed retained amorphous state,unchanged drug content and dissolution performance for the optimized formulations.The dissolution and bioavailability studies reflected that the prepared SD of ABTA may improve the therapeutic efficacy of ABTA in prostate cancer.The manufacturing technology is scalable and easy to commercialize,revealing the hope of a better treatment strategy for prostate cancer.
