Mucus-penetrating budesonide nanosuspension enema for local treatment of inflammatory bowel disease.
Mucus-penetrating budesonide nanosuspension enema for local treatment of inflammatory bowel disease.
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粘液渗透的布德索尼纳米司令灌肠，用于局部治疗炎症性肠病。
DOI：
10.1016/j.biomaterials.2018.09.005
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发表时间：
2018-12
期刊：
影响因子：
14
通讯作者：
Ensign LM
中科院分区：
文献类型：
--
作者：
Date AA;Halpert G;Babu T;Ortiz J;Kanvinde P;Dimitrion P;Narayan J;Zierden H;Betageri K;Musmanno O;Wiegand H;Huang X;Gumber S;Hanes J;Ensign LM
炎症性肠病（IBD）是一种慢性炎症性胃肠道疾病，在美国影响超过100万人。局部治疗采用灌肠制剂，如微粉布地奈德（恩托考特®），是治疗远端活动性IBD患者的常用策略。然而，我们假设微颗粒太大，无法有效穿透结肠粘液，限制了药物在清除前递送到受影响组织的程度。在这里，我们描述了布地奈德纳米混悬液（NS）的发展，具有适当的表面涂层和尺寸，以增强结直肠粘液和溃疡性结直肠组织的渗透。我们发现，在三硝基苯磺酸（TNBS）诱导的IBD小鼠中，约200 nm大小的荧光聚苯乙烯（PS）模型与2µm大小的聚苯乙烯（PS）模型相比，具有黏膜惰性Pluronic F127涂层的荧光聚苯乙烯（PS）颗粒可以增强粘膜分布和组织渗透，而PVP是临床微细布地奈德配方中使用的稳定剂。然后，我们使用湿磨工艺开发了布地奈德NS配方，该配方采用粘惰性Pluronic F127涂层（粒径约230 nm），以及用PVP稳定的布地奈德微悬浮液（粒径约2µm）。使用急性TNBS IBD小鼠模型，我们发现，与未治疗的对照组或每天使用布地奈德MS灌肠的小鼠相比，每天使用布地奈德NS灌肠治疗可显著减少IBD的宏观（结肠重量减轻）和微观（组织学评分）症状。此外，我们发现，与未治疗的对照组或使用布地奈德MS灌肠的小鼠相比，布地奈德NS灌肠处理的小鼠结肠组织中炎性巨噬细胞和产生IL-β的CD11b+细胞的数量显著减少。我们得出的结论是，纳米尺寸和粘膜惰性涂层允许增强布地奈德的局部递送，因此，对局部结直肠组织炎症有更显著的影响。
Inflammatory bowel disease (IBD) is a chronic inflammatory gastrointestinal disorder that affects more than 1 million individuals in the USA. Local therapy with enema formulations, such as micronized budesonide (Entocort®), is a common strategy for treating patients with distally active IBD. However, we hypothesize that micronized particulates are too large to effectively penetrate colorectal mucus, limiting the extent of drug delivery to affected tissues prior to clearance. Here, we describe the development of a budesonide nanosuspension (NS) with the appropriate surface coating and size to enhance penetration of colorectal mucus and ulcerated colorectal tissues. We demonstrate that model fluorescent polystyrene (PS) particles ~200 nm in size with a muco-inert Pluronic F127 coating provide enhanced mucosal distribution and tissue penetration in mice with trinitrobenzenesulfonic acid (TNBS)-induced IBD compared to model 2 µm PS particles coated with polyvinylpyrollidone (PVP), the stabilizer used in the clinical micronized budesonide formulation. We then used a wet-milling process to develop a budesonide NS formulation with a muco-inert Pluronic F127 coating (particle size ~230 nm), as well as a budesonide microsuspension (MS) stabilized with PVP (particle size ~2 µm). Using an acute TNBS mouse model of IBD, we show that daily budesonide NS enema treatment resulted in a significant reduction in the macroscopic (decreased colon weight) and microscopic (histology score) symptoms of IBD compared to untreated controls or mice treated daily with the budesonide MS enema. Further, we show that the budesonide NS enema treated mice had a significantly reduced number of inflammatory macrophages and IL-β producing CD11b+ cells in colon tissue compared to untreated controls or mice treated with the budesonide MS enema. We conclude that the nano-size and muco-inert coating allowed for enhanced local delivery of budesonide, and thus, a more significant impact on local colorectal tissue inflammation.
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影响因子：
10.8
作者：
Ali, H.;Weigmann, B.;Lehr, C. -M.
通讯作者：
Lehr, C. -M.
DOI：
10.1152/ajpgi.2001.280.5.g922
发表时间：
2001-05-01
影响因子：
4.5
作者：
Atuma, C;Strugala, V;Holm, L
通讯作者：
Holm, L
影响因子：
3.7
作者：
Ali, Hussain;Weigmann, Benno;Lehr, Claus-Michael
通讯作者：
Lehr, Claus-Michael
影响因子：
16.1
作者：
Ensign, Laura M.;Cone, Richard;Hanes, Justin
通讯作者：
Hanes, Justin
影响因子：
24.5
作者：
Campieri, M;Ferguson, A;Weir, DG
通讯作者：
Weir, DG