DEVELOPMENT OF AN ORAL-DRUG FORMULATION FOR DICHLOROACETATE AND THIAMINE
DEVELOPMENT OF AN ORAL-DRUG FORMULATION FOR DICHLOROACETATE AND THIAMINE
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DOI：
10.3109/03639049409042647
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发表时间：
1994-01-01
影响因子：
3.4
通讯作者：
STACPOOLE, PW
中科院分区：
文献类型：
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作者：
HENDERSON, GN;WHALEN, PO;STACPOOLE, PW
二氯乙酸 (DCA) 是一种用于治疗多种代谢和心血管疾病的研究药物。迄今为止，它主要用于静脉注射、短期治疗方案。长期服用该药物可能有毒，部分原因是组织硫胺素储备耗尽。因此，我们开发了一种稳定的 DCA 钠盐和硫胺素.HC1 液体制剂，适合长期口服给药。 DCA-硫胺素混合物被配制为在pH 3.5的磷酸盐缓冲液中含有甘油、苯甲酸钠和阿斯巴甜的可口溶液。口服 DCA 制剂的热加速分解研究显示，4℃ 下的保质期约为 5 年，25℃ 下的保质期约为 156 天。稳定性在 4℃ 的储存条件下也进行了 1 年的跟踪，结果发现至少可稳定 1 年，这是其目前推荐的储存时间。开发了一种新的高效液相色谱方法来定量处方中的 DCA、硫胺素、阿斯巴甜和苯甲酸钠。 DCA-硫胺素制剂味道鲜美，儿童耐受性良好，其中一些儿童已连续服用三年多。在长期治疗下，以 12.5 mg/Kg 或 25 mg/Kg 的剂量，DCA 在患有先天性乳酸性酸中毒的儿童中的平均血浆半衰期为 7.9 小时。
Dichloroacetate (DCA) is an investigational drug for the treatment of several metabolic and cardiovascular disorders. Hitherto, it has been used mostly in intravenous, short term treatment regimens. Chronic administration of the drug may be toxic, due in part to the depletion of tissue thiamine stores. We therefore developed a stable liquid preparation of the sodium salt of DCA and thiamine.HC1 suitable for chronic oral administration. The DCA-thiamine mixture is formulated as a palatable solution containing glycerol, sodium benzoate and aspartame in phosphate buffer at pH 3.5. A thermally accelerated decomposition study of the oral DCA formulation revealed a shelf-life of about 5 years at 4 degrees C and about 156 days at 25 degrees C. The stability was also followed for 1 year at its storage condition of 4 degrees C and it was found to be stable at least for 1 year, which is its current recommended storage time. A new high performance liquid chromatographic method was developed to quantitate DCA, thiamine, aspartame and sodium benzoate in the formulation. The DCA-thiamine formulation is palatable and well tolerated by children, some of whom have received it continuously for over three years. Under chronic treatment, at a dose of 12.5 mg/Kg or 25 mg/Kg, DCA has a mean plasma half life of 7.9 hrs in children with congenital lactic acidosis.