Stable Vaccines Delivered on Oral Thin Films

描述（由申请人提供）：我们的目标是开发一种在环境条件下稳定的疫苗，并将疫苗纳入有效的剂量表，以便于储存、分发和大规模疫苗接种运动。目前能够稳定疫苗的药品生产工艺在发展中国家实施起来通常成本高昂，剂型（主要是玻璃小瓶、预充式注射器）对于大规模疫苗接种运动相关的大规模储存、运输和分发通常不具有成本效益。我们建议发展快速溶解的口腔薄膜作为一种技术解决方案。这种剂型为疫苗应用提供了一系列显着的优势，包括紧凑的尺寸和重量（~<典型疫苗包装的尺寸和重量的1/100），便于运输，使用简单，从而提高了患者的依从性。此外，没有保证剂量准确性的重构步骤，并且有一个完善的制造工艺（例如，ListermintTM口气清新剂条）。为了实现最佳的技术解决方案，我们建议加入一种不需要复杂的药物干燥过程来实现室温稳定性的药物稳定配方，同时与现有的薄膜制造工艺兼容。初步数据表明，Aridis已经开发出一种薄膜配方和制造工艺，成功地包裹了一种热不稳定的活病毒疫苗，在高温（45℃）下完全保持活性和储存稳定性。我们将我们的液体疫苗稳定技术（21）和塑化玻璃稳定技术（10、22、23）结合起来，展示了一种OTF（口服薄膜）配方，该配方成功地包裹了轮状病毒活疫苗，在45°C下完全保存了疫苗效力和稳定性，从几天提高到几个月（见初步数据）。我们选择轮状病毒疫苗作为案例研究，不仅是为了证明OTF配方在稳定热不稳定的复杂活疫苗方面的有效性，也是因为它是一种重要的疫苗，已经证明有可能显著降低全世界儿童轮状病毒感染造成的死亡率（每年约50万人死亡）（26）。拟议研究的成功示范将推动这项技术进入正式的生物制药产品开发，并将提供可适用于其他口服疫苗和生物制剂的概念验证数据。该项目的主要目标是研制不需要冷藏（即在室温及以上温度下稳定）的轮状病毒疫苗的稳定配方，其剂型适合口服。我们的假设是，这种疫苗可以通过适当的配方选择和使用简单的“一锅”方法进行物理稳定，而不需要药物干燥。初步数据表明，可以研制出在高温下稳定几种轮状病毒血清型一个月或更长时间的制剂。拟开展的工作范围旨在进一步优化先导配方，将演示扩展到单膜中四价菌株混合物，并确定疫苗的生物分布和接种小鼠的体内免疫原性。最后，工艺开发将在中试工厂规模启动。这项技术不仅将简化疫苗的储存、分发和管理，而且还将为疫苗分销商和接种疫苗的医生或诊所节省成本。

DESCRIPTION (provided by applicant): Our goal is to develop a vaccine that is stable at ambient conditions, and to incorporate the vaccine into an effective dosage presentation that can facilitate storage, distribution, and mass vaccination campaigns. The current pharmaceutical manufacturing processes that are able to stabilize vaccines are generally expensive to implement in developing countries and the dosage forms (mainly glass vials, prefilled syringes) are generally not cost effective for large scale storage, transportation, and distribution associated with mass vaccination campaigns. We propose the development of quick dissolving oral thin films as a technology solution. This dosage form offers a remarkable array of advantages for vaccine applications including compact size and weight (~<1/100th of size and weight of typical vaccine package) that is highly transportable, and is simple to use, thus enhancing patient compliance. Furthermore, there is no reconstitution step ensuring dosage accuracy, and there is a well-established manufacturing process (e.g. ListermintTM breath freshener strips). To achieve an optimal technology solution, we propose to incorporate a pharmaceutical stabilization formulation which does not require complex pharmaceutical drying processes to achieve room temperature stability, which at the same time is compatible with existing thin film manufacturing processes. Preliminary data indicate that Aridis has developed a thin film formulation and manufacturing process that successfully encased a thermally labile live virus vaccine with complete preservation of activity and storage stability at high temperature (45o C). We combined our liquid vaccine stabilization technology (21) and plasticized glass stabilization technology (10,22,23) to demonstrate an OTF (oral thin film) formulation that successfully encased live rotavirus vaccine with complete preservation of vaccine potency and stability at 45°C improved from several days to several months (see preliminary data). We have chosen rotavirus vaccine as a case study not only to demonstrate the effectiveness of the OTF formulation in stabilizing a thermally labile, complex live vaccine, but also because it is an important vaccine that has already demonstrated the potential to significantly reduce mortality (~500,000 annual deaths) due to rotavirus infection in children worldwide (26). Successful demonstration of the proposed studies will advance this technology into formal biopharmaceutical product development and will provide proof-of- concept data that can be applicable to other oral vaccines and biologics. The primary goal of this project is to develop stable formulations of rotavirus vaccine that do not require cold storage (i.e., stable at room temperature and above) with dosage forms that are suitable for oral delivery. Our hypothesis is that this vaccine can be physically stabilized with the appropriate formulation selection and using a simple 'one-pot' method without the need for pharmaceutical drying. Preliminary data has shown that formulations can be developed that stabilize several rotavirus serotypes at high temperatures for a month or more. The proposed work scope is designed to further optimize the lead formulation, extend the demonstration to a quadrivalent mixture of strains in a single film, and determine the biodistribution of the vaccine and in vivo immunogenicity in vaccinated mice. Finally process development will be initiated at pilot plant scale. This technology will not only simplify vaccine storage, distribution and administration, but also provide cost savings to the vaccine distributor and the physician or clinic administering the vaccine.