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呋塞米(furosemide, FMD)是一种强效利尿剂，用于治疗高血压及由充血性心力衰竭、肝硬化和肾脏疾病引起的水肿。该研究旨在通过固体分散体技术改善其作为生物药剂学分类系统(biopharmaceutical classification system,BCS)Ⅳ类药物，因低溶解性和低渗透性导致的生物利用度受限问题，以介孔二氧化硅与聚乙烯吡咯烷酮K30(polyvinylpyrrolidone K30, PVP K30)为联合载体，制备呋塞米无定形固体分散体，并采用粉末直接压片工艺制备20 mg规格、片重125 mg的片剂。该研究经单因素和正交试验优化处方，确定最佳辅料组合为呋塞米固体分散体(48.00%)、微晶纤维素(14.07%)、乳糖(28.13%)、交联聚维酮(8.00%)、硬脂酸镁(0.80%)和阿斯巴甜(1.00%)。3批放大验证显示片剂溶出均一，工艺重现性良好。以比格犬为模型的体内药代动力学试验结果表明，与市售呋塞米片相比，固体分散体片的峰浓度(maximum plasma concentration, Cmax)和药时曲线下面积(area under the curve, AUC)显著增加，相对生物利用度达到172.6%，且表观分布容积(apparent volume of distribution, VZ/F)显著降低，研究结果证实固体分散体-粉末直压联合策略可显著提高BCS Ⅳ类药物的口服疗效，为难溶性药物的制剂开发提供了新的技术路线，也为改善呋塞米的临床疗效提供了新型制剂及理论支持。
Abstract：Furosemide(FMD) is a potent diuretic used for the treatment of hypertension and edema caused by congestive heart failure, liver cirrhosis, and renal diseases. This study aimed to improve its bioavailability limitation caused by low solubility and low permeability as a biopharmaceutical classification system(BCS) Class IV drug through solid dispersion technology. Using mesoporous silica and polyvinylpyrrolidone K30(PVP K30) as combined carriers, amorphous furosemide solid dispersions were prepared and formulated into tablets with a specification of 20 mg and tablet weight of 125 mg by direct powder compression. The formulation was optimized through single-factor and orthogonal experiments, and the optimal excipient combination was determined as furosemide solid dispersion(48.00%), microcrystalline cellulose(14.07%), lactose(28.13%), crospovidone(8.00%), magnesium stearate(0.80%), and aspartame(1.00%). Three-batch scale-up validation demonstrated uniform dissolution and good process reproducibility. In vivo pharmacokinetic studies in beagle dogs showed that compared with commercial furosemide tablets, the solid dispersion tablets exhibited significantly increased maximum plasma concentration(Cmax) and area under the curve(AUC), with relative bioavailability reached approximately 172.6%, and significantly reduced apparent volume of distribution(VZ/F). These results confirmed that the solid dispersion-direct compression combined strategy could significantly enhance the oral efficacy of BCS Class Ⅳ drugs, providing a new technical approach for the formulation development of poorly soluble drugs and offering new formulations and theoretical support for improving the clinical efficacy of furosemide.
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基本信息:
DOI：10.13478/j.cnki.jasyu.2026.02.010
中图分类号:R943
引用信息:
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2026-06-30
2026-06-30