Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron

Literature data pertaining to the physicochemical, pharmaceutical, and pharmacokinetic properties of ondansetron hydrochloride dihydrate are reviewed to arrive at a decision on whether a marketing authorization of an immediate release (IR) solid oral dosage form can be approved based on a Biopharmaceutics Classification System (BCS)-based biowaiver. Ondansetron, a 5HT₃ receptor antagonist, is used at doses ranging from 4 mg to 24 mg in the management of nausea and vomiting associated with chemotherapy, radiotherapy, and postoperative treatment. It is a weak base and thus exhibits pH-dependent solubility. However, it is able to meet the criteria of “high solubility” as well as “high permeability” and can therefore be classified as a BCS class I drug. Furthermore, ondansetron hydrochloride 8 mg IR tablets (Zofran^® 8 mg) and multiples thereof (16 mg = Zofran^® 8 mg × 2 tablets and 24 mg = Zofran^® 8 mg × 3 tablets) meet the criteria of “rapidly dissolving” in dissolution testing. Ondansetron hydrochloride has a wide therapeutic window and is well-tolerated after oral administration. Based on its favorable physicochemical properties, pharmacokinetic data and the minimal risks associated with an incorrect bioequivalence decision, the BCS-based biowaiver procedure can be recommended for ondansetron hydrochloride dihydrate IR tablets.     

速释口服固体制剂人体生物等效性试验豁免药学研究的要求

随着科学认知的不断深入,为缩短药品的批准上市时间,不同药品监管机构相继出台了人体生物等效性豁免的相关法规及技术文件,旨在通过体外研究来替代体内试验。总结和比较国内外相关指导原则对速释口服固体剂型的仿制药药学研究的要求,重点关注存在的差异之处,探讨背后的科学原因,并在最终经国际人用药品注册技术协调委员会协调一致的过程中得到思考和启示,以期增加仿制药被豁免体内试验的成功率、进而降低仿制药的开发成本,但同时亦能保证其质量和疗效与参比制剂一致,真正实现其临床可替代性。     

一致性评价中部分品种BCS分类不明确问题的解决方案

基于生物药剂学分类系统（BCS）的生物等效性豁免旨在减少对体内生物等效性研究的需求,即可以提供一种体内生物等效性的替代方法。基于BCS分类的生物等效性豁免需提供药物的溶解性、渗透性和体外溶出数据。主要论述药物溶解性、渗透性和体外溶出度测定的方法,希望建立药物相关特性的标准化、规范化测定流程,以保证企业在申报生物等效性豁免时,所提供的数据是准确、可靠的。     

Evaluation of the losartan solubility in the biowaiver context by shake-flask method and intrinsic dissolution

This study aimed at evaluating the shake-flask use as a universal method to evaluate drug solubility in a biowaiver context as proposed by FDA, EMA and ANVISA. The solubility of losartan was determined in three buffers using the shake-flask method, intrinsic dissolution (ID) and Quantum Chemistry. Moreover, the evaluation of a losartan dissolution profile from coated tablets was conducted. The losartan low solubility in pH 1.2 and high solubility in pH 6.8 were observed using the shake-flask method. However, the solubility results using ID demonstrated its high solubility in pH 1.2 and 6.8. It was not possible to find conclusive results regarding the solubility of the drug in pH 4.5. The studies conducted by Quantum Chemistry provide molecular and electronic data that helped understand the losartan solvation in different pH values. Our experimental results defined that losartan can be classified as a low-solubility drug. In addition, this work shows that shake-flask cannot be a universal method of solubility studies in biowaiver context. Individual analysis will be necessary. The intrinsic dissolution should be considered as a complementary method.     

仿制药质量与疗效一致性评价的生物豁免原则及各国及国际组织的生物等效性豁免品种

目的 为我国仿制药质量与疗效一致性评价的生物等效性试验,提供可豁免药物品种的参考。方法 以《人体生物等效性试验豁免指导原则（征求意见稿）》为基础,以我国一致性评价的首批药物为前提,简要介绍和归纳美国食品药品管理局（FDA）、世界卫生组织（WHO）、欧洲药品局（EMA）的生物等效性试验豁免的标准和可申请豁免的药物品种。结果 对比FDA,289个一致性评价药物品种中可申请豁免的有59个,不可申请豁免的有19个;对比WHO,可豁免的药物有10个,EMA中有1个。结论 目前,我国生物等效性试验豁免的具体药物名单尚未公布,企业应该对比参考国内外的相关标准和具体药物,以加快一致性评价工作的进展。     

化学仿制药口服溶液剂的药学研究关注点

化学仿制药口服溶液剂是可能豁免人体生物等效性研究的口服给药剂型,其药学研究关注点与口服固体制剂、注射剂等剂型均有一定差异,但目前国内尚未出台相关药学研究技术指导原则。简要介绍了化学仿制药口服溶液剂药学研究中需要关注的问题,包括处方工艺、质量研究、稳定性研究等方面,重点关注了微生物控制方面的内容,结合审评实践提出了研究建议;同时在国内外相关法规要求的基础上,探讨了豁免人体生物等效性研究的相关要求。旨在为后续化学仿制药口服溶液剂的药学研究提供更多参考。     

Application of Gastrointestinal Simulation for Extensions for Biowaivers of Highly Permeable Compounds

The goal of this study was to apply gastrointestinal simulation technology and integration of physiological parameters to predict biopharmaceutical drug classification. GastroPlus was used with experimentally determined physicochemical and pharmacokinetic drug properties to simulate the absorption of several weak acid and weak base BCS class II compounds. Simulation of oral drug absorption given physicochemical drug properties and physicochemical parameters will aid justification of biowaivers for selected BCS class II compounds.     

益血生胶囊联合多糖铁复合物治疗妊娠期缺铁性贫血的临床研究

目的 探讨益血生胶囊联合多糖铁复合物胶囊治疗妊娠期缺铁性贫血的临床疗效.方法 选取2018年8月—2020年8月在南阳市中心医院进行治疗的158例妊娠期缺铁性贫血患者为研究对象,根据用药差别分为对照组(79例)和治疗组(79例).对照组口服多糖铁复合物胶囊,0.3 g/次,1次/d;治疗组在对照组基础上口服益血生胶囊,...     

Comparison of WHO and US FDA biowaiver dissolution test conditions using bioequivalent doxycycline hyclate drug products

Objectives The dissolution characteristics of immediate‐release doxycycline hyclate products with certified in‐vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver‐based approval. Methods Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin‐ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy‐Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.2, acetate buffer, pH 4.5, and simulated intestinal fluid without pancreatin, pH 6.8. Results were obtained at two paddle speeds recommended for biowaiver applications: 75 rpm (World Health Organization; WHO) and 50 rpm (US Food and Drug Administration; US FDA). Key findings The results for the tablets and hard gelatin capsules indicate that a paddle speed of 75 rpm is more representative than 50 rpm, since 75 rpm generates dissolution profiles corresponding more closely to the in‐vivo profiles than those at 50 rpm. For evaluating soft gelatin capsule formulations with lipid fill, both US FDA and WHO methods were found to be over‐discriminating. Conclusions Bioequivalence of immediate‐release doxycycline hyclate tablets and hard gelatin capsules, but not soft gelatin capsules, can be evaluated in vitro using the biowaiver dissolution test conditions specified by the WHO.     

药物制剂生物利用度和生物等效性试验指导原则（草案）

参考国际上的相关指导原则,对《中国药典》2015年版药物制剂生物利用度和生物等效性指导原则提出了修改草案。包括前言,常释制剂生物等效性试验的设计、实施和评价,调释制剂和透皮吸收制剂的生物等效性试验,试验报告,与生物等效性试验相关的体外溶出度检查,对不同剂型的生物等效性要求,以及基于生物药剂学分类系统的生物豁免。与现行药典指导原则相比,把生物样品定量分析方法的内容分离出去,对试验药品的规格、参比制剂选取、测试原形药物还是代谢物、高变异性药品生物等效性等提供了新的建议,强调溶出度实验的意义,并引入了生物试验豁免的相关内容。