Cancer Research UK Formulation Unit, Strathclyde Institute for Pharmacy and Biomedical Sciences, Robertson Wing, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, Scotland, UK.
Cancer Research UK Formulation Unit, Strathclyde Institute for Pharmacy and Biomedical Sciences, Robertson Wing, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, Scotland, UK.
Int J Pharm. 2012 Apr 15;426(1-2):67-75. doi: 10.1016/j.ijpharm.2012.01.024. Epub 2012 Jan 21.
The novel organoarsenical GSAO, 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid, has potential anti-angiogenic capability with application in cancer where tumour metastasis relies on neo-vascularisation. As GSAO arsenic is trivalent, the arsenoxide moiety reacts with appropriately spaced cysteine residues on adenine nucleotide translocase (ANT) mitochondrial membrane protein. Molecular oxidation of the arsenic to the pentavalent structure, as in the degradant GSAA (4-(N-(S-glutathionylacetyl)amino) phenylarsonic acid), prevents sulphydryl interaction and risks abolition of activity. We report here on formulation studies aiming to produce a parenteral product with the primary objective of restricting GSAA transformation from GSAO to protect maximal potency of the molecule. Successful anti-oxidant strategy primarily came from pH control. The presence of glycine was proposed to form a stabilising five-membered oxazarsolidinone ring with arsenoxide and this was investigated using potentiometric assays. We report on these tritration studies identifying a pK(a) of 8.2 associated with an As-OH, but not confirming ring presence. An original clinical trial pharmaceutical was successfully realised by lyophilisation of 50 mg/mL GSAO in 100 mM glycine solution, pH 7 to obtain a 48-month shelf life for the freeze-dried vials. The Phase I clinical study is ongoing in patients with solid tumours refractory to standard therapy.
新型有机胂化合物 GSAO，即 4-（N-（S-谷胱甘肽乙酰基）氨基）苯胂酸，具有潜在的抗血管生成能力，可应用于癌症治疗，因为肿瘤转移依赖于新血管生成。由于 GSAO 中的砷呈三价，砷氧化物部分与腺嘌呤核苷酸转位酶（ANT）线粒体膜蛋白上适当间隔的半胱氨酸残基反应。砷的分子氧化为五价结构，如降解产物 GSAA（4-（N-（S-谷胱甘肽乙酰基）氨基）苯胂酸），可防止巯基相互作用，并有可能使活性丧失。我们在此报告旨在制备一种可供注射的产品的配方研究，其主要目的是限制 GSAA 从 GSAO 转化，以保护分子的最大效力。成功的抗氧化策略主要来自 pH 值控制。据推测，甘氨酸的存在可以与砷氧化物形成一个稳定的五元噁唑烷酮环，并用电位测定法对此进行了研究。我们报告了这些滴定研究结果，确定了与 As-OH 相关的 pK(a)为 8.2，但未确认环的存在。通过将 50mg/mL GSAO 在 100mM 甘氨酸溶液（pH7）中冻干，成功地实现了原始的临床试验药物，冻干小瓶的保质期为 48 个月。正在对标准治疗耐药的实体瘤患者进行 I 期临床试验。
