Preparation And In Vitro And In Vivo Evaluation Of Acetazolamide Extended-release Capsules

In recent years,as the number of builders and tourists entering the highlands increases,the demand for acute mountain sickness prevention drugs has grown.There are currently no chemical drugs available for the prevention of acute mountain sickness in China,and people usually choose supplements containing rhodiola and ginkgo for prevention.These drugs have longer periods of administration and their clinical effectiveness and safety are yet to be investigated.Therefore,it is imperative to develop safe and effective drugs for the prevention of acute mountain sickness.Acetazolamide is a carbonic anhydrase inhibitor that inhibits the activity of carbonic anhydrase,thereby reducing the amount of produced atrial aqueous humor,lowering intraocular and intracranial pressure,improving pulmonary and cerebral edema,increasing arterial oxygen concentration and improving oxygenation of arterial blood.It has been used clinically in recent years for the prevention of altitude sickness and is the drug of choice approved by the Food and Drug Administration（FDA）for acute altitude sickness.Although several acetazolamide tablets have been approved in China,their indications are all for the treatment of various types of glaucoma.Moreover,the extended-release capsules obtained in this study can effectively reduce side effects and improve patient compliance compared with immediate-release tablets,and have dosage form advantages.To address the above problems,this study prepared acetazolamide extended-release capsules based on the existing marketed dosage forms and conducted an in vivo and in vitro evaluation for rapid clinical application.In this study,analytical methods for the critical quality attributes of acetazolamide extended-release capsules were established and methodologically validated.The impurities were detected by HPLC and the assay and dissolution were determined by UV-Vis.The results of the raw and excipient studies show that the raw and excipients are safe,controllable and compatible.According to the Qb D analysis of reference drug,assay,impurities and dissolution are the critical quality attributes of acetazolamide extended-release capsules.The risk assessment of these critical quality attributes identified raw material particle size,raw material crystalline form and different excipient dosages as key prescription variables,mixing time,extrusion rounding parameters,drying temperature as key process parameters,which provided a basis for later studies.The optimal prescription of acetazolamide extended-release capsule was optimized and screened by single factor test method and factor analysis as acetazolamide 500.0 g,microcrystalline cellulose 92.5 g,talc 6.3 g,sodium lauryl sulfate 5.0 g,purified water170.0 g,ethanol 64.8 g.The key process parameters were also conducted and finally determined as extrusion speed 20 rpm,rolling speed600～1000 rpm,mixing time 10 minutes,drying temperature of 80°C.The critical quality attributes were used as an in vitro evaluation index and bioequivalence was used as an in vivo evaluation index to evaluate the quality and consistency of efficacy of the two drugs.In this study,the assay of the generic and the reference drugs were 99.9%,99.8%,respectively,with impurities of 0.1%,and the f₂ of87.3,98.4,84.2 and 94.3 in different dissolution media at p H 1.0,p H 4.5,p H 6.8 and water.A randomized,open,single-dose,two-drug,two-cycle crossover clinical bioequivalence study was conducted on 36 healthy adult volunteers.The 90%confidence intervals for C_max,AUC_0-t and AUC_0-∞geometric mean ratios in the fasting state ranged from 80.5%to 109.4%,92.7%to 111.6%and 91.0%to 114.7%.The 90%confidence intervals for the C_max,AUC_0-t and AUC_0-∞geometric mean ratios in the fed state were 97.1%to 108.4%,94.7%to 99.5%and 94.8%to 100.4%.In conclusion,the generic drug obtained in this study did not differ from the reference drug in terms of assay and impurities,and the f₂-factors were greater than80.0 in different dissolution media.Bioequivalence results showed that the geometric mean C_max,AUC_0-t and AUC_0-∞were within the acceptable limits（80.0%～125.0%）in90%confidence intervals,the results indicating that the generic drug of acetazolamide extended-release capsules is bioequivalent to the reference drug with quality consistency,and may provide a safe and effective clinically necessary drug for the treatment of acute mountain sickness.