Kachi S, Terada M, Hashimoto H
Department of Parasitology, Hamamatsu University School of Medicine, Japan.
Jpn J Pharmacol. 1998 Jul;77(3):235-45. doi: 10.1254/jjp.77.235.
To enhance the bioavailability of PF1022A (cyclo(D-lactyl-L-N-methylleucyl-D-3-phenyllactyl-L-N-met hylleucyl-D-lactyl-L-N-methylleucyl-D-3-phenyllactyl-L-N- methylleucyl)), a newly developed antinematode drug, we examined whether the new drug has polymorphism or not. First, four forms of PF1022A, designated as form alpha, form I, form II and form III of PF1022A, were prepared. By examining physicochemical properties of these forms by various methods including X-ray powder diffractometry and differential scanning calorimetry, it became apparent that PF1022A had one amorphous (form alpha) and three crystalline polymorphic forms, form I, form II and form III. Secondly, a dissolution study was carried out, and form alpha and form III were found to have higher solubility than form I and form II. Thirdly, anti-larval effects of the 4 forms of PF1022A on tissue-dwelling nematode, Angiostrongylus costaricensis, in mice were compared when given orally for 5 successive days at 10 or 40 mg/kg/day. Significant effects were observed in almost all parameters in host mice and worms in the groups treated with form alpha or form III, each at 40 mg/kg, but form I and form II had little effect. The present results suggest that PF1022A has polymorphism and that the form alpha and form III were more effective against tissue-dwelling nematodes than the form I and form II when given orally.
为提高新开发的抗线虫药物PF1022A（环（D-丙氨酰-L-N-甲基亮氨酰-D-3-苯丙氨酰-L-N-甲基亮氨酰-D-丙氨酰-L-N-甲基亮氨酰-D-3-苯丙氨酰-L-N-甲基亮氨酰））的生物利用度，我们研究了该新药是否存在多晶型现象。首先，制备了四种形式的PF1022A，分别命名为PF1022A的α型、I型、II型和III型。通过包括X射线粉末衍射和差示扫描量热法在内的各种方法研究这些形式的物理化学性质，结果表明PF1022A有1种无定形形式（α型）和3种结晶多晶型形式，即I型、II型和III型。其次，进行了溶出度研究，发现α型和III型的溶解度高于I型和II型。第三，比较了连续5天以10或40mg/kg/天的剂量口服给药时，PF1022A的这4种形式对小鼠体内组织内寄生线虫哥斯达黎加血管圆线虫的抗幼虫效果。在以40mg/kg的剂量用α型或III型处理的组中，宿主小鼠和线虫的几乎所有参数均观察到显著效果，但I型和II型几乎没有效果。目前的结果表明PF1022A存在多晶型现象，口服给药时，α型和III型对组织内寄生线虫的效果比I型和II型更有效。
