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采用薄膜冷冻干燥法开发含 AS01 的(可吸入)干粉制剂疫苗。

Development of (Inhalable) Dry Powder Formulations of AS01-Containing Vaccines Using Thin-Film Freeze-Drying.

机构信息

Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA; Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.

Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.

出版信息

Int J Pharm. 2022 Jun 25;622:121825. doi: 10.1016/j.ijpharm.2022.121825. Epub 2022 May 13.

Abstract

AS01 is a liposomal formulation of two immunostimulants namely 3-O-desacyl-4́-monophosphoryl lipid A (MPL) and QS-21. The liposomal formulation of AS01 reduces the endotoxicity of MPL and the lytic activity of QS-21. The AS01-adjuvanted Shingrix vaccine is marketed in a two-vial presentation, with the liquid AS01 liposomes in one vial and the antigen as a dry powder in another vial. In the present study, we tested the feasibility of applying thin-film freeze-drying (TFFD) to engineer dry powders of the AS01 liposomal adjuvant alone or vaccines containing AS01 as an adjuvant. Initially, we showed that after the AS01 liposomal adjuvant was subjected to TFFD using sucrose as a stabilizer at 4% w/v, the particle size distribution of AS01 liposomes reconstituted from the dry powder was identical to the liquid adjuvant before drying. We then showed using ovalbumin (OVA) as a model antigen adjuvanted with AS01 (AS01/OVA) that subjecting the AS01/OVA vaccine to TFFD and subsequent reconstitution did not negatively affect the AS01 liposome particle size, nor the immunogenicity of the vaccine. Importantly, the thin-film freeze-dried AS01/OVA vaccine, unlike its liquid counterpart, was not sensitive to repeated freezing-and-thawing. The developed AS01/OVA dry powder also showed the desirable aerosol properties (i.e., fine particle fraction of 66.3 ± 4.9% and mass median aerodynamic diameter of 2.4 ± 0.1 µm) for potential pulmonary administration. Finally, the feasibility of using TFFD to prepare dry powders of AS01-adjuvanted vaccines was further confirmed using AS01-adjuvanted Fluzone Quadrivalent and Shingrix, which contains AS01. It is concluded that the TFFD technology can enable the formulation of AS01-adjuvanted vaccines as freezing-insensitive, inhalable dry powders in a single-vial presentation.

摘要

AS01 是一种脂质体制剂,包含两种免疫佐剂:3-O-去酰基-4′-单磷酰脂质 A(MPL)和 QS-21。AS01 的脂质体制剂降低了 MPL 的内毒素毒性和 QS-21 的裂解活性。含 AS01 佐剂的 Shingrix 疫苗以两剂包装形式上市,其中一瓶装有液态 AS01 脂质体,另一瓶装有干粉抗原。在本研究中,我们测试了应用薄膜冷冻干燥(TFFD)技术来构建单独的 AS01 脂质体佐剂干粉或含有 AS01 作为佐剂的疫苗的可行性。最初,我们表明,在使用 4%w/v 的蔗糖作为稳定剂对 AS01 脂质体佐剂进行 TFFD 后,从干粉中重新配制的 AS01 脂质体的粒径分布与干燥前的液态佐剂相同。然后,我们使用卵清蛋白(OVA)作为模型抗原佐剂与 AS01(AS01/OVA)进行了实验,表明对 AS01/OVA 疫苗进行 TFFD 和随后的重构不会对 AS01 脂质体的粒径产生负面影响,也不会对疫苗的免疫原性产生负面影响。重要的是,与液态疫苗不同,薄膜冷冻干燥的 AS01/OVA 疫苗不易受到反复冻融的影响。所开发的 AS01/OVA 干粉也表现出了理想的气溶胶特性(即,细颗粒分数为 66.3±4.9%,质量中值空气动力学直径为 2.4±0.1μm),适用于肺部给药。最后,使用 TFFD 制备 AS01 佐剂疫苗干粉的可行性使用含有 AS01 的 AS01 佐剂 Fluzone 四价疫苗和 Shingrix 疫苗进一步得到了证实。总之,TFFD 技术可以使 AS01 佐剂疫苗以单剂形式配制为抗冷冻、可吸入的干粉。

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