目的 制备一种用于溃疡性结肠炎（ulcerative colitis，UC）的直肠用靛蓝-靛玉红纳米泡沫气雾剂（indigo-indirubin nano-foam aerosol，Ind/INB-NFA），并对其进行体内外评价。方法 通过球磨技术制备靛蓝-靛玉红纳米混悬液（indigo-indirubin nanosuspensions，Ind/INB-NS），对其粒径、多分散度指数（polydispersity index，PDI）、ζ电位、稳定性、微观形貌、红外吸收、体外释放度等进行考察。以Ind/INB-NS为中间体，采用中心复合设计-效应面法（central composite design-response surface methodology，CCD-RSM）优化制备Ind/INB-NFA，并考察泡沫理化性能、黏膜渗透性；建立葡聚糖硫酸钠（dextran sulfate sodium，DSS）诱导的UC大鼠模型，以体质量、DAI评分、结直肠长度、肠质量系数、组织病理评分等指标考察该泡沫剂的药效。结果 Ind/INB-NS粒径为（117.5±0.8）nm，PDI为0.249±0.013，ζ电位为（−32.3±1.0）mV；60 d内稳定性良好；纳米化过程中傅里叶变换红外吸收光谱（Fourier transform infrared spectroscopy，FTIS）无明显变化；同原料药相比，纳米混悬液中靛蓝、靛玉红体外12 h的累积释放度分别提高了30.46%和21.39%。该泡沫剂泡沫基础液的最优处方为Ind/INB-NS 28.25%、月桂酰肌氨酸钠2.26%、Brij^® S10 1.00%、十六醇1.50%、十六十八醇1.26%、丙二醇与水用量比4.72∶5.28；制剂中抛射剂HFA-134a 20%。喷出物呈淡蓝色细密泡沫，发泡倍率达14.38±1.10，4 h内能稳定维持泡沫形态且仅流动（0.23±0.03）cm。同原料药相比，该泡沫剂中靛蓝、靛玉红24 h的黏膜透过率分别提高了60.05%和14.53%。所得泡沫剂能改善DSS诱导的UC模型大鼠腹泻、便血症状；降低DAI评分（P＜0.01）及肠质量系数（P＜0.01）；增加结直肠长度（P＜0.05）；减少炎症细胞浸润，降低结肠组织病理损伤评分（P＜0.01）。结论 成功制备了一种新型靛蓝-靛玉红纳米泡沫气雾剂，有利于充分发挥靛蓝、靛玉红治疗UC的疗效，具有良好的应用前景。

Objective To prepare a rectal indigo-indirubin nano-foam aerosol (Ind/INB-NFA) for ulcerative colitis (UC) and evaluate its performance through in vitro and in vivo studies. Methods Indigo-indirubin nanosuspensions (Ind/INB-NS) was prepared by ball milling technology and characterized for particle size, polydispersity index (PDI), ζ potential, stability, micromorphology, infrared absorption, and in vitro release. Ind/INB-NFA was optimized using central composite design-response surface methodology (CCD-RSM), with Ind/INB-NS as the intermediate. Its physicochemical properties and mucosal permeability were evaluated. A dextran sulfate sodium (DSS)-induced UC rat model was established to assess therapeutic effects through body weight, disease activity index (DAI) score, colorectal length, colon weight coefficient, and histopathological scoring. Results Ind/INB-NS had a particle size of (117.5 ± 0.8) nm, PDI of 0.249 ± 0.013, and ζ potential of (−32.3 ± 1.0) mV. It remained stable for 60 d. Fourier transform infrared spectroscopy (FTIS) showed no significant changes during the nanonization process. Compared with raw active pharmaceutical ingredients (APIs), the 12 h in vitro release of indigo and indirubin from nanosuspensions increased by 30.46% and 21.39%, respectively. The optimal formulation of the foam base solution contained 28.25% Ind/INB-NS, 2.26% sodium lauroyl sarcosinate, 1.00% Brij^® S10, 1.50% cetyl alcohol, 1.26% cetearyl alcohol, and a 4.72:5.28 propylene glycol/water ratio. The propellant HFA-134a content in this formulation was 20%. The ejecta formed light blue, finely textured foam with an expansion ratio of 14.38 ± 1.10, which maintained stable morphology with only (0.23 ± 0.03) cm of flow displacement over 4 h. Compared with raw APIs, mucosal permeation rates of indigo and indirubin increased by 60.05% and 14.53% at 24 h. The foam aerosol alleviated diarrhea and hematochezia in DSS-induced UC rats. It significantly reduced DAI scores (P < 0.01) and colon weight coefficients (P < 0.01), increased colorectal length (P < 0.05), diminished inflammatory infiltration (P < 0.01) ,and reduced the pathological injury score of colon tissue (P < 0.01). Conclusion The novel Ind/INB-NFA was successfully developed, which is conducive to giving full play to the therapeutic effect of indigo and indirubin in the treatment of UC and has a good application prospect.

R283.6

国家自然科学基金面上项目（82173976）