Bunke A, Zerbe O, Schmid H, Burmeister G, Merkle H P, Gander B
Swiss Federal Institute of Technology Zurich (ETH), Department of Applied BioSciences, Institute of Pharmaceutical Sciences, Winterthurer Strasse 190, 8057 Zürich, Switzerland.
J Pharm Sci. 2000 Oct;89(10):1335-41. doi: 10.1002/1520-6017(200010)89:10<1335::aid-jps11>3.0.co;2-#.
The physiological substance and precursor of the heme synthesis 5-aminolevulinic acid (ALA) is a promising prodrug for photodiagnosis and photodynamic therapy of epithelial tumors, particularly in urological and gynecological tissues. For the clinical use of this substance, a chemically stable and sterile drug formulation is required. In the present study, degradation mechanism of ALA in aqueous solution and possibilities to improve its stability were examined. A capillary electrophoretic method was developed that was suitable for the quantification of ALA and of two degradation products. The intermediate degradation product was 2, 5-dicarboxyethyl-3,6-dihydropyrazine, which was further oxidized to 2,5-dicarboxyethylpyrazine. The structures of the degradation products were proven by (1)H and (13)C nuclear magnetic resonance spectroscopy. ALA degradation was very efficiently inhibited by adjusting the pH of the aqueous solution to a value <5 and by purging with nitrogen. Additives such as antioxidants did not improve the ALA stability. These results demonstrated that low pH ALA aqueous solution may be one possible dosage form to be considered for market introduction.
血红素合成的生理物质及前体5-氨基乙酰丙酸（ALA）是上皮肿瘤光诊断和光动力治疗的一种很有前景的前体药物，尤其适用于泌尿和妇科组织。对于该物质的临床应用，需要一种化学稳定且无菌的药物制剂。在本研究中，考察了ALA在水溶液中的降解机制以及提高其稳定性的可能性。开发了一种毛细管电泳方法，该方法适用于定量ALA及其两种降解产物。中间降解产物是2,5-二羧乙基-3,6-二氢吡嗪，其进一步氧化为2,5-二羧乙基吡嗪。降解产物的结构通过氢核磁共振（¹H NMR）和碳核磁共振（¹³C NMR）光谱得以证实。通过将水溶液的pH值调节至<5并通入氮气，可非常有效地抑制ALA的降解。抗氧化剂等添加剂并不能提高ALA的稳定性。这些结果表明，低pH值的ALA水溶液可能是一种可供考虑推向市场的剂型。
