纳米晶体药物制剂涉及几个关键的制造程序,导致复杂的结构,以提高药物的溶解度,溶出度,生物利用度,以及因此难溶性生物制药分类系统(BCS)II和IV药物的功效。由于活性药物成分(API)的物理性质的变化,已经批准的口服药物的纳米晶体制剂可能需要额外的免疫毒性评估。在这项研究中,我们选择了齐留顿,一种FDA批准的药物,属于BCS-II用于纳米晶体制剂。为了评估纳米晶体药物的疗效和粘膜免疫谱,使用含有单独的API或纳米晶体配制的Zileuton(NDZ)的胶囊对10周龄的大鼠进行给药,或使用柔性口腔灌胃注射器的物理混合物(PM)。对照组由未经治疗的,或安慰剂治疗的动物。以30mg/kg体重(bw)的剂量每天一次向大鼠施用测试制剂,持续15天。当与微米大小的API处理的大鼠相比时,用NDZ或PM处理的大鼠具有大约低4.0倍的API(7.5mg/kgbw)。在治疗结束时,测量粘膜(肠组织)和循环细胞因子。免疫反应表明,NDZ降低了回肠粘膜中的几种促炎细胞因子(白细胞介素-18,肿瘤坏死因子-α和RANTES[在激活时受到调节,正常T细胞表达和分泌])。对于微米大小的API和PM处理的大鼠,也观察到细胞因子谱中的类似模式。细胞因子的产生表明,在所有实验组中,雌性的IL-1β和IL-10的产生均显着增加。此外,NDZ对局部和全身的促炎细胞因子均有免疫抑制作用,这类似于微米大小的API处理的大鼠的反应。这些结果表明,NDZ显着降低了几种促炎细胞因子,并且其免疫毒性较小,可能是由于纳米晶体的配方。因此,纳米晶体制剂更适合口服药物递送,因为它表现出更好的功效,安全,减少毒性。
Nanocrystal drug formulation involves several critical manufacturing procedures that result in complex structures to improve drug solubility, dissolution, bioavailability, and consequently the efficacy of poorly soluble Biopharmaceutics Classification System (BCS) II and IV drugs. Nanocrystal formulation of an already approved oral drug may need additional immunotoxic assessment due to changes in the physical properties of the active pharmaceutical ingredient (API). In this study, we selected
Zileuton, an FDA-approved drug that belongs to BCS-II for nanocrystal formulation. To evaluate the efficacy and mucosal immune profile of the nanocrystal drug, 10-week-old rats were dosed using capsules containing either API alone or nanocrystal formulated
Zileuton (NDZ), or with a physical mixture (PM) using flexible oral gavage syringes. Control groups consisted of untreated, or placebo treated animals. Test formulations were administrated to rats at a dose of 30 mg/kg body weight (bw) once a day for 15 days. The rats treated with NDZ or PM had approximately 4.0 times lower (7.5 mg/kg bw) API when compared to the micron sized API treated rats. At the end of treatment, mucosal (intestinal tissue) and circulating cytokines were measured. The immunological response revealed that NDZ decreased several proinflammatory cytokines in the ileal mucosa (Interleukin-18, Tumor necrosis Factor-α and RANTES [regulated upon activation, normal T cell expressed and secreted]). A similar pattern in the cytokine profile was also observed for the micron sized API and PM treated rats. The cytokine production revealed that there was a significant increase in the production of IL-1β and IL-10 in the females in all experimental groups. Additionally, NDZ showed an immunosuppressive effect on proinflammatory cytokines both locally and systemically, which was similar to the response in micron sized API treated rats. These findings indicate that NDZ significantly decreased several proinflammatory cytokines and it displays less immunotoxicity, probably due to the nanocrystal formulation. Thus, the nanocrystal formulation is more suitable for oral drug delivery, as it exhibited better efficacy, safety, and reduced toxicity.