Injectable sustained-release hydrogel for high-concentration antibody delivery†

Talia Zheng and Patrick S. Doyle
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Abstract

There is an increasing interest in subcutaneous (SC) delivery as an alternative to the traditional intravenous (IV) for immunotherapies and other advanced therapies. High-concentration formulations of antibodies are needed to meet the limited-volume requirements of subcutaneous SC delivery. Despite this need, there remain challenges in delivering stable and injectable antibodies in these high concentrations. Hydrogel encapsulation of amorphous solid antibodies has been proven to improve the stability and injectability of high-concentration antibody formulations. However, the antibody is quickly released from the hydrogel due to the material's porosity, leading to rapid, uncontrolled drug release kinetics undesirable for the drug's efficacy and safety. In this paper, we propose a dual-network composite hydrogel which leverages interactions between the two polymer networks to achieve controlled release of the antibody. We load the solid form of the antibody at high concentrations within alginate hydrogel microparticles which are then suspended in thermogelling methylcellulose solution to formulate the in situ gelling composite hydrogel. By facile chemical modification of the alginate to tune the microparticles’ gel properties and alginate–methylcellulose interactions, we demonstrate how the composite system can delay release of the drug in a tunable manner and achieve a near-zero order release profile for improved therapeutic efficacy. We show acceptable injectability properties of the composite hydrogel at high antibody concentrations, highlighting the functionalities of dualnetwork encapsulation. We imagine this composite system to be applicable for the sustained delivery of various therapeutic protein forms, especially for high-loading SC formulations.

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可注射的缓释水凝胶用于高浓度抗体递送†
人们对皮下(SC)给药作为传统静脉(IV)免疫疗法和其他先进疗法的替代方案越来越感兴趣。需要高浓度的抗体制剂来满足皮下SC递送的有限体积要求。尽管有这样的需求,但在提供这些高浓度的稳定的可注射抗体方面仍然存在挑战。水凝胶包封无定形固体抗体已被证明可以提高高浓度抗体制剂的稳定性和可注射性。然而,由于材料的多孔性,抗体很快从水凝胶中释放出来,导致快速,不受控制的药物释放动力学,这对药物的有效性和安全性是不利的。在本文中,我们提出了一种双网络复合水凝胶,它利用两种聚合物网络之间的相互作用来实现抗体的控制释放。我们将抗体的固体形式以高浓度加载在海藻酸盐水凝胶微颗粒中,然后悬浮在热凝胶甲基纤维素溶液中,形成原位凝胶复合水凝胶。通过对海藻酸盐进行简单的化学修饰来调节微颗粒的凝胶特性和海藻酸盐-甲基纤维素的相互作用,我们展示了复合系统如何以可调的方式延迟药物的释放,并实现近零级释放,从而提高治疗效果。我们展示了复合水凝胶在高抗体浓度下可接受的注射特性,突出了双网络封装的功能。我们设想这种复合系统适用于各种治疗蛋白形式的持续递送,特别是高负荷SC制剂。
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Back cover Injectable sustained-release hydrogel for high-concentration antibody delivery† Strategies for beating the bitter taste of pharmaceutical formulations towards better therapeutic outcomes Back cover Dual-action antimicrobial surface coatings: methylene blue and quaternary ammonium cation conjugated silica nanoparticles†
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