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英夫利昔单抗微囊化：一种在类风湿关节炎管理中关节内给予生物制剂的创新方法——体外评价。

Infliximab microencapsulation: an innovative approach for intra-articular administration of biologics in the management of rheumatoid arthritis-in vitro evaluation.

机构信息

Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Faculty of Sciences, Universidade de Santiago de Compostela, Campus Terra, 27002, Lugo, Spain.

Health Research Institute of Santiago de Compostela (IDIS), 15706, Santiago de Compostela, Spain.

出版信息

Drug Deliv Transl Res. 2023 Dec;13(12):3030-3058. doi: 10.1007/s13346-023-01372-1. Epub 2023 Jun 9.

DOI:10.1007/s13346-023-01372-1
PMID:37294425
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10624745/
Abstract

Microencapsulation of the therapeutical monoclonal antibody infliximab (INF) was investigated as an innovative approach to improve its stability and to achieve formulations with convenient features for intra-articular administration. Ultrasonic atomization (UA), a novel alternative to microencapsulate labile drugs, was compared with the conventional emulsion/evaporation method (Em/Ev) using biodegradable polymers, specifically Polyactive 1000PEOT70PBT30 [poly(ethylene-oxide-terephthalate)/poly(butylene-terephthalate); PEOT-PBT] and its polymeric blends with poly-(D, L-lactide-co-glycolide) (PLGA) RG502 and RG503 (PEOT-PBT:PLGA; 65:35). Six different formulations of spherical core-shell microcapsules were successfully developed and characterized. The UA method achieved a significantly higher encapsulation efficiency (69.7-80.25%) than Em/Ev (17.3-23.0%). Mean particle size, strongly determined by the microencapsulation method and to a lesser extent by polymeric composition, ranged from 26.6 to 49.9 µm for UA and 1.5-2.1 µm for Em/Ev. All formulations demonstrated sustained INF release in vitro for up to 24 days, with release rates modulated by polymeric composition and microencapsulation technique. Both methods preserved INF biological activity, with microencapsulated INF showing higher efficacy than commercial formulations at comparable doses regarding bioactive tumor necrosis factor-alpha (TNF-α) neutralization according to WEHI-13VAR bioassay. Microparticles' biocompatibility and extensive internalization by THP-1-derived macrophages was demonstrated. Furthermore, high in vitro anti-inflammatory activity was achieved after treatment of THP-1 cells with INF-loaded microcapsules, significatively reducing in vitro production of TNF-α and interleucine-6 (Il-6).

摘要

将治疗性单克隆抗体英夫利昔单抗 (INF) 微囊化，作为提高其稳定性的创新方法，并为关节内给药提供具有便利特性的制剂。超声雾化 (UA) 是一种替代不稳定药物微囊化的新方法，与使用可生物降解聚合物的常规乳液/蒸发方法 (Em/Ev) 进行了比较，具体使用的聚合物为 Polyactive 1000PEOT70PBT30 [聚（乙二醇-对苯二甲酸酯）/聚（丁二醇-对苯二甲酸酯）；PEOT-PBT] 和其与聚（D，L-丙交酯-共-乙交酯）（PLGA）RG502 和 RG503 的聚合物共混物 (PEOT-PBT:PLGA; 65:35)。成功开发并表征了六种不同的球形核壳微胶囊制剂。UA 方法实现了显著更高的包封效率（69.7-80.25%），而 Em/Ev 方法仅为 17.3-23.0%。平均粒径主要由微囊化方法决定，其次由聚合物组成决定，UA 范围为 26.6-49.9 µm，Em/Ev 为 1.5-2.1 µm。所有制剂在体外均表现出长达 24 天的持续 INF 释放，释放率可通过聚合物组成和微囊化技术进行调节。两种方法均保留了 INF 的生物学活性，与商业制剂相比，微囊化 INF 在可比剂量下显示出更高的功效，根据 WEHI-13VAR 生物测定法，对生物活性肿瘤坏死因子-α (TNF-α) 的中和作用更强。证明了微粒的生物相容性和 THP-1 衍生的巨噬细胞的广泛内化。此外，用负载 INF 的微胶囊处理 THP-1 细胞后，在体外实现了高抗炎活性，显著降低了 TNF-α 和白细胞介素-6 (Il-6) 的产生。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f13/10624745/0b4964cf56f7/13346_2023_1372_Fig13_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f13/10624745/4dd3d0efc1d7/13346_2023_1372_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f13/10624745/b5e9f5b776e4/13346_2023_1372_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f13/10624745/ef7f965e99a3/13346_2023_1372_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f13/10624745/6bf8bd45f0a8/13346_2023_1372_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f13/10624745/d6da468191d8/13346_2023_1372_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f13/10624745/55567561ccce/13346_2023_1372_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f13/10624745/1f6732672965/13346_2023_1372_Fig12_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4f13/10624745/0b4964cf56f7/13346_2023_1372_Fig13_HTML.jpg

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