Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.
CiPharma-Post Graduation Course, School of Pharmacy, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
J Pharm Sci. 2017 Dec;106(12):3421-3430. doi: 10.1016/j.xphs.2017.08.007. Epub 2017 Aug 24.
This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate-release solid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the highest dose strength on the World Health Organization Essential Medicines List, the dose/solubility ratio calculated from solubility studies was higher than 250 mL, corresponding to a classification as "not highly soluble." Small, physiological doses of folic acid (≤320 μg) seem to be absorbed completely via active transport, but permeability data for higher doses of 1-5 mg are inconclusive. Following a conservative approach, folic acid is classified as a Biopharmaceutics Classification System class IV compound until more reliable data become available. Commensurate with its solubility characteristics, the results of dissolution studies indicated that none of the folic acid products evaluated showed rapid dissolution in media at pH 1.2 or 4.5. Therefore, according to the current criteria of the Biopharmaceutics Classification System, the biowaiver approval procedure cannot be recommended for immediate-release solid oral dosage forms containing folic acid.
这篇工作介绍了文献综述和实验数据，这些数据与免除含有叶酸作为单一活性药物成分的速释固体口服药物制剂在人体志愿者中进行药代动力学生物等效性研究以获得批准的可能性相关。对于含有 5 毫克叶酸的制剂，叶酸是世界卫生组织基本药物清单上的最高剂量强度，根据溶解度研究计算的剂量/溶解度比高于 250 毫升，这对应于“溶解度不高”的分类。小剂量、生理剂量的叶酸（≤320μg）似乎通过主动转运被完全吸收，但对于更高剂量（1-5 毫克）的通透性数据尚无定论。根据保守的方法，在获得更可靠的数据之前，叶酸被归类为生物药剂学分类系统第四类化合物。根据其溶解度特征，溶解研究的结果表明，在所评估的叶酸产品中，没有一种产品在 pH 值为 1.2 或 4.5 的介质中表现出快速溶解。因此，根据生物药剂学分类系统的现行标准，不能推荐含有叶酸的速释固体口服剂型采用生物豁免批准程序。
