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目的:制备pH敏感型魟鱼软骨多糖眼用原位凝胶剂(RCG凝胶)并考察其兔眼药动学和抑制角膜新生血管作用。方法:以卡波姆940和HPMC(1∶4,w/w)为辅料制得pH敏感型原位凝胶。取健康家兔30只,向兔眼中滴入50μL RCG凝胶,分别于给药10,30,60,120,180 min后处死家兔,收集兔眼玻璃体、房水、角膜和虹膜,并测定药物含量。取家兔20只,建立角膜新生血管模型并随机分为4组,分别给予生理盐水,25,50,100 mg·mL~(-1) RCG凝胶。观察给药后第3,6,9,12天新生血管面积及角膜病理切片。结果:魟鱼软骨多糖在玻璃体、房水、角膜和虹膜的药动学均符合二室模型,在玻璃体、房水、角膜和虹膜中的Cmax分别为(1.35±0.41),(9.31±0.39),(27.78±0.32),(15.97±0.13)μg·mL~(-1);AUC0-180分别为(80.54±9.65),(571.91±18.32),(1 763.72±48.66),(1 034.55±33.87)μg·mL~(-1)·min。对照组、低、中、高剂量组在第12天的新生血管面积分别为(30.00±3.45),(24.31±3.12),(5.36±1.24),(4.89±1.09)mm2。角膜病理切片中,对照组和低剂量组中有大量炎性细胞浸润,新生血管较多;而中剂量和高剂量组中角膜中炎性细胞和新生血管明显较少。结论:制备了一种pH敏感型魟鱼软骨多糖眼用原位凝胶,该凝胶给药后在角膜部位具有最大的药物浓度,其给药剂量高于50 mg·mL~(-1)时,具有显著的抑制新生血管生成的作用,该原位凝胶剂具有较好的临床应用价值。
OBJECTIVE: To prepare pH-sensitive cartilage polysaccharide ophthalmic in situ gel (RCG gel) and investigate its ophthalmic pharmacokinetics and inhibit corneal neovascularization. Methods: pH-sensitive in situ gels were prepared with Carbopol 940 and HPMC (1: 4, w / w) as excipients. Thirty healthy rabbits were dosed with 50μL RCG gel. Rabbits were sacrificed at 10, 30, 60, 120 and 180 min after administration. Vitreous humor, aqueous humor, cornea and iris were collected and the drug content was determined. Twenty rabbits were selected to establish corneal neovascularization model and were randomly divided into 4 groups. The rats were given physiological saline (25,50,100 mg · mL -1) RCG gel. The neovascularization area and corneal pathological section were observed on the 3rd, 6th, 9th and 12th day after administration. Results: The pharmacokinetics of cartilage polysaccharide in the vitreous body, aqueous humor, cornea and iris all accorded with two-compartment model. The Cmax in vitreous, aqueous humor, cornea and iris were (1.35 ± 0.41) and (9.31 ± 0.39) , (27.78 ± 0.32) and (15.97 ± 0.13) μg · mL -1, respectively; AUC0-180 were (80.54 ± 9.65), (571.91 ± 18.32), (763.72 ± 48.66), (1 034.55 ± 33.87 ) μg · mL -1 (-1) · min. The area of neovascularization on the 12th day in the control group was (30.00 ± 3.45), (24.31 ± 3.12), (5.36 ± 1.24) and (4.89 ± 1.09) mm2 respectively in the low, medium and high dose groups. In corneal biopsy, there were a large number of inflammatory cell infiltration in the control group and low dose group, more angiogenesis, while the number of corneal inflammatory cells and neovascularization was lower in middle and high dose group. CONCLUSION: A kind of pH-sensitive anchovy cartilage polysaccharide ophthalmic in situ gel is prepared. The gel has the highest drug concentration in the cornea after administration, and its dosage is higher than 50 mg · mL -1. , Has a significant inhibition of angiogenesis, the in situ gel has a good clinical value.