Formulation Development for an Intramuscular Administer*

描述（由申请人提供）：炭疽杆菌是炭疽病的病原体，已被国防部确定为最优先生物战目标，并被疾病控制中心确定为A类制剂。据估计，在一个有50万人口的城市的上风处沿2公里长的一条线释放50公斤炭疽孢子沿着三天后，将发生125 000起感染，导致95 000人死亡。这种情况的经济影响估计为每100 000名接触炭疽的人262亿美元。一个主要的未满足的需求是用于治疗暴露于气溶胶化孢子后的炭疽的有效疗法。本文提出的研究将证明，单独或与抗生素联合使用Anthim IM制剂可有效治疗暴露后炭疽。长期目标。Elusys的长期目标是生产我们的候选药物Anthim的液体或冻干制剂，该制剂是治疗炭疽感染的有效产品，具有良好的保质期和生物战紧急情况下方便的IM给药途径。Elusys正在积极开发候选药物Anthim，这是一种针对炭疽毒素保护性抗原成分的超高亲和力单克隆抗体（MAb）。该抗体已在动物模型中进行了测试，并显示出有效保护动物受试者免于死亡。具体目标。我们假设这里提出的制剂研究将能够生产稳定的炭疽治疗剂，具有长的保质期，并且可以通过IM给药快速给药。具体目标#1：生产抗体以支持可比性试验、制剂开发和体内动物试验。里程碑#1：生产40克抗体。具体目标#2：开发Anthim的稳定制剂用于商业化。里程碑#2：Anthim稳定制剂生产工艺的开发。具体目标#3：使用相关动物模型通过体内动物试验显示疗效。里程碑#3：与参比标准品相比，重新配制的Anthim的结果相当。研究与开发方法。目前正在开发和检测生产细胞系的主细胞库（MCB）。将从该细胞系生产抗体用于制剂研究。将进行制剂研究，以开发稳定制剂，其中含有制剂前研究中确定的Anthim最大浓度和用于制备小批次的功能性冻干循环。处方开发后，将进行可比性计划以及体内和体外研究，以将新处方与先前的参比标准品进行比较。

DESCRIPTION (provided by applicant): Bacillus anthracis, the pathogen for Anthrax, has been identified as a top priority biowarfare target by the Department of Defense, and as a Category A agent by Centers for Disease Control. It is estimated that three days after the release of 50 kgs of anthrax spores along a 2 km line upwind of a city of 500,000 population, 125,000 infections would occur, leading to 95,000 deaths. The economic impact of such a scenario is estimated to be $26.2 billion per 100,000 exposed to Anthrax. A major unmet need is effective therapy for treatment of anthrax after exposure to aerosolized spores. The studies proposed herein will demonstrate that administration of Anthim with an IM formulation will be effective in treatment of post-exposure anthrax alone or in conjunction with antibiotics. Long term objectives. Elusys's long-term objective is to produce a liquid or lyophilized formulation of our drug candidate Anthim that is an effective product for the treatment of Anthrax infection and has a favorable shelf life and convenient IM route of administration for biowarfare emergency situations. Elusys is actively developing the drug candidate Anthim, an ultra high affinity monoclonal antibody (MAb) to the protective antigen component of the anthrax toxin. This antibody has been tested in animal models and shown to be efficacious in protecting animal subjects from death. Specific Aims. We hypothesize that the formulation studies proposed here will enable the production of an Anthrax therapeutic that is stable, has a long shelf-life and can be given rapidly via IM administration. Specific Aim #1: Produce antibody to support comparability testing, formulation development and in vivo animal testing. Milestone #1: Production of 40 grams of antibody. Specific Aim #2: Develop a stable formulation of Anthim for commercialization. Milestone #2: Development of process for production of a stable formulation of Anthim. Specific Aim #3: Show efficacy through vivo animal testing using a relevant animal model. Milestone #3: Comparable results of reformulated Anthim in comparison with the reference standard. Research & Development Methods. A Master Cell Bank (MCB) for the production cell line is currently being developed and tested. Antibody will be produced from this cell line for formulation studies. Formulation studies will be conducted to develop a stable formulation, containing the maximum concentration of Anthim determined in the pre-formulation study and a functional lyophilization cycle for making small batches. Following formulation development, a comparability program and both vivo and in vitro studies will be conducted to compare the new formulation to a previous reference standard.