Stable Vaccines Delivered on Oral Thin Films

以口服薄膜形式提供的稳定疫苗

• 批准号: 8782199
• 负责人: Vu L. Truong
• 金额: $ 28.35万
• 依托单位: ARIDIS PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8782199
• 关键词: Air; Antibodies; Attenuated Vaccines; Biodistribution; Biological Assay; Biological Preservation; Biological Products; Blood; Case Study; Cessation of life; Child; Clinic; Combined Vaccines; Complex; Cost Savings; Cryopreservation; Data; Developing Countries; Development; Dosage Forms; Dose; Drug Formulations; Drug or chemical Tissue Distribution; Effectiveness; Ensure; Enzyme-Linked Immunosorbent Assay; Esophagus; Excipients; Feces; Film; Glass; Goals; Health; High temperature of physical object; Immunoglobulin A; Immunoglobulin G; Lead; Life; Liquid substance; Mass Vaccinations; Methods; Mus; Oral; Oral cavity; Pharmacologic Substance; Phase I Clinical Trials; Physicians; Plants; Preparation; Process; Proteins; Rotavirus; Rotavirus Infections; Rotavirus Vaccines; Serotyping; Serum; Small Intestines; Solutions; Stomach; Syringes; Technology; Temperature; Time; Tongue; Transportation; Vaccinated; Vaccines; Vial device; Virus; Weight; Work; compliance behavior; cost effective; design; dosage; immunogenicity; improved; in vivo; manufacturing process; mortality; oral vaccine; product development; reconstitution; response; scale up; stability testing; vaccine development

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.

描述(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，并将该疫苗纳入有效的剂量说明中，以便于储存、分发和大规模接种疫苗活动。目前能够稳定疫苗的制药工艺在发展中国家的实施成本通常很高，而剂型(主要是玻璃瓶、预填充的注射器)对于大规模疫苗接种活动相关的大规模储存、运输和分发通常成本效益不高。我们建议开发快速溶解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著的优势，包括紧凑的尺寸和重量(约为典型疫苗包装尺寸和重量的1/100)，高度可运输，使用简单，从而提高了患者的依从性。此外，没有确保剂量准确性的重构步骤，而且有完善的制造工艺(例如ListermintTM呼吸清新剂条)。为了达到最佳的技术解决方案，我们建议加入一种药物稳定配方，该配方不需要复杂的药物干燥过程来实现室温稳定性，同时与现有的薄膜制造工艺兼容。初步数据表明，阿里迪斯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，并在高温(45摄氏度)下完全保持了活性和储存稳定性。我们结合我们的液体疫苗稳定技术(21)和塑化玻璃稳定技术(10，22，23)，展示了一种成功包裹活轮状病毒疫苗的OTF(口服薄膜)配方，该配方完全保持了疫苗的效力，在45℃下的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，还因为它是一种重要的疫苗，已经显示出显著降低全球儿童轮状病毒感染造成的死亡率(每年约50万人死亡)的潜力(26)。拟议研究的成功示范将把这项技术推进到正式的生物制药产品开发中，并将提供可适用于其他口服疫苗和生物制品的概念验证数据。该项目的主要目标是开发不需要冷藏(即在室温和更高温度下稳定)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“一锅法”来稳定身体，而不需要药物干燥。初步数据表明，可以开发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配方。拟议的工作范围旨在进一步优化Lead配方，将演示扩展到单膜中的四价菌株混合物，并确定疫苗在接种小鼠体内的生物分布和体内免疫原性。最后，将启动中试工厂规模的工艺开发。这项技术不仅将简化疫苗的储存、分发和管理，还将为疫苗分销商和管理疫苗的医生或诊所节省成本。