Engineering Microparticles for Taste-Masking and Controlled Release of Pediatric

描述（由申请人提供）：需要新剂型来解决当前儿科人群用药实践的缺陷。具体而言，在缺乏儿科专用产品的情况下-既可口（以确保依从性）又可滴定（以满足体重/表面积-适当剂量）的制剂-提供者要么利用成人批准的液体制剂，要么操纵可用的产品以产生临时制剂（例如，通过压碎片剂）。液体悬浮液虽然是可滴定的并且在很大程度上比片剂和胶囊更受儿童的青睐，但通常适口性差，因此依从性差。特殊制剂也可能改变性能，并存在剂量不足或过量的可能性。Orbis Biosciences开发了一种自由流动的载药微胶囊粉末，可在摄入过程中掩盖苦味药物活性物质，并在胃肠道中显示出完全的剂型溶解。这种微胶囊平台是通过利用精密粒子 制造（PPF）在无水的单步过程中将pH响应性壳置于水溶性差的药物的固体分散核上。第一个使用Orbis的微胶囊方法来掩盖味道的产品将是ORB-101，一种载有泼尼松的微胶囊制剂。一旦成功获得FDA批准，ORB-101将与口服液体制剂或泼尼松和泼尼松龙竞争，这些产品的适口性较差。在第一阶段SBIR工作中，奥比斯成功开发了两种制剂，ORB-101和ORB-102，分别含有泼尼松和利托那韦。微胶囊粉末能够：（1）与这两种药物的RLD糖浆相比，在中性溶出介质中2分钟时泼尼松和利托那韦的存在分别减少55%和92%，和（2）当置于酸性介质中时，在30分钟时仍然表现出100%溶出。本II期提案的目的是将泼尼松制剂（ORB-101）优化为体外储存稳定的粉末（目标1），在人体味觉筛选中验证其与RLD相比的上级适口性（目标2），并在人体药代动力学研究中证明其与RLD的生物等效性（目标3）。该II期SBIR项目的完成将有助于向FDA高效、及时地提交IND申请（III期SBIR），并通过以下方式对治疗泼尼松反应性儿科疾病的最佳实践产生直接和持久的影响：（1）在第一次人体试验中建立改善的适口性或ORB-101，（2）准备ORB-101和它所基于的PPF平台，以达成共同开发协议或获得风险投资资金。

DESCRIPTION (provided by applicant): New dosage forms are needed to address the shortcomings of current practice with regard to administration of medications to pediatric populations. Specifically, in the absence of pediatric-specific products - formulations that are both palatable (to ensure compliance) and titratable (to meet the weight/surface area- appropriate dosage) - providers either utilize adult-approved liquid formulations or manipulate available products to create extemporaneous formulations (e.g., by crushing a tablet). Liquid suspensions, while titratable and largely preferred by children over tablets and capsules, are often poorly palatable and thus suffer from poor compliance. Ad-hoc formulations can also alter the performance and risk the likelihood of under or over-dosing. Orbis Biosciences's has developed a free-flowing drug-loaded microcapsule-based powder that will taste-mask bitter pharmaceutical actives during ingestion and exhibit complete dosage form dissolution in the gastrointestinal tract. This microcapsule platform is made possible by utilizing Precision Particle Fabrication (PPF) to place a pH-responsive shell over a solid-dispersed core of poorly water-soluble drug in a water-free, single step process. The first product to use Orbis's microcapsule approach to taste masking will be ORB-101, a prednisone-loaded microcapsule formulation. Upon successful FDA approval, ORB-101 will compete with oral liquid formulations or prednisone and prednisolone, products that suffer from poor palatability. Under the Phase I SBIR work, Orbis successfully developed two formulations, ORB-101 and ORB-102, containing prednisone and ritonavir, respectively. The microcapsule powders were able to: (1) reduce the presence of prednisone and ritonavir in neutral dissolution medium at 2 minutes by 55 and 92% respectively, compared to the RLD syrups for these two drugs, and (2) still exhibit 100% dissolution by 30 minutes when placed in acidic medium. The objective of this Phase II proposal is to optimize the prednisone formulation (ORB-101) into a shelf-stable powder in vitro (Aim 1), verify it's superior palatability compared to the RLD in a human taste screening (Aim 2), and demonstrate its bioequivalence to the RLD in a human pharmacokinetic study (Aim 3). The completion of this Phase II SBIR program will facilitate the efficient and timely submission of an IND filing to the FDA (Phase III SBIR) and have an immediate and lasting impact on the best practices for treating prednisone-responsive pediatric disorders by: (1) establishing the improved palatability or ORB-101 in the first human trials while, (2) readying ORB-101 and the PPF platform on which it is based for a co- development agreement or venture capital funding.