Improving drug bioavailability through solid form discovery

通过固体形式发现提高药物生物利用度

• 批准号: 8737297
• 负责人: Adam Jay Matzger
• 金额: $ 26.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737297
• 关键词: Address; Automation; Bioavailable; Biological Availability; Chemicals; Chemistry; Clinic; Complement; Crystal Formation; Crystallization; Drug Delivery Systems; Drug Formulations; Drug Stability; Event; Exercise; Genetic Polymorphism; Growth; Growth Inhibitors; Kinetics; Libraries; Measures; Methodology; Methods; Miniaturization; Modeling; Molecular; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Polymers; Process; Production; Property; Relative (related person); Reporting; Role; Route; Salts; Sampling; Signal Transduction; Solid; Solubility; Solutions; Solvents; Specificity; Spectrum Analysis; Staging; Techniques; Technology; Temperature; Therapeutic Effect; Thermodynamics; Time; Work; X ray diffraction analysis; X-Ray Diffraction; base; chemical property; density; design; dosage; drug candidate; drug discovery; improved; in vivo; inhibitor/antagonist; innovation; milligram; neutrophil; pre-clinical; programs; public health relevance; screening; tv watching

DESCRIPTION (provided by applicant): The most common and desirable way to deliver active pharmaceutical ingredients (APIs) is in the crystalline form. APIs can be formulated in pure form, as salts, or as multicomponent (solvate, cocrystal) solids and these offer due to stability and processing advantages over other formulations. The choice among these forms depends very much on the specific chemical properties of the drug molecule as well as factors such as solubility. However, there is the pervasive issue of crystal polymorphism to consider: a given composition is not constrained to crystallize in a predictable way and multiple packing motifs of the same unit possess different thermodynamic stabilities that can influence bioavailability. The proposed program will develop more rapid and comprehensive techniques to control the crystallization of bioactive organic molecules while being less material intensive. Thi will enable early stage screening of potential drugs to determine which form has the appropriate solubility and stability to be formulated into a bioavailable dosage. Three interconnected aims are designed to develop and deploy more efficient and robust polymorph discovery methodology. Aim 1 adapts the polymer-induced heteronucleation (PIHn) approach towards solid form discovery so that it functions in a high throughput manner suitable for polymorph discovery. Two of the key advances proposed are miniaturization of the technology and automation of the solid form screening, which together will make the PIHn method much better suited for the screening of preclinical drug candidates. Aim 2 addressed the issue of crystal polymorphism outside of the well-studied realm of neutral molecular compounds. Because solvates, salts, and cocrystals are increasingly the solid forms of choice for drugs entering the clinic, there is a pressing need for understanding solid form diversity in such APIs. The methodology proposed in Aim 1 is perfectly suited to polymorph discovery in solvates, salts, and cocrystals because it can generate solid form diversity even under the relatively narrow sets of conditions employed in multicomponent crystal formation. Finally, in Aim 3 a new strategy for identifying targeted inhibitors of crystal forms will be introduced. The approach involves a new paradigm, based on the mechanistic understanding of how PIHn accelerates nucleation, redeployed for creating soluble polymeric nucleation inhibitors.

描述（由申请人提供）：最常见和理想的递送活性药物成分（api）的方式是以晶体形式。原料药可以以纯形式配制，作为盐，或作为多组分（溶剂化物，共晶）固体，这些提供了由于稳定性和加工优于其他配方。这些形式的选择在很大程度上取决于药物分子的特定化学性质以及溶解度等因素。然而，有一个普遍存在的晶体多态性问题需要考虑：给定的组合物并不局限于以可预测的方式结晶，同一单元的多个包装基序具有不同的热力学稳定性，可以影响生物利用度。该计划将开发更快速和全面的技术来控制生物活性有机分子的结晶，同时减少材料密集。这将使潜在药物的早期筛选，以确定哪种形式具有适当的溶解度和稳定性，以配制成生物可利用剂量。三个相互关联的目标旨在开发和部署更有效和健壮的多晶发现方法。Aim 1将聚合物诱导异核（PIHn）方法应用于固体形态发现，使其以适合多晶发现的高通量方式发挥作用。提出的两个关键进展是技术的小型化和固体形式筛选的自动化，这将使PIHn方法更适合临床前候选药物的筛选。目的2解决了在中性分子化合物的研究领域之外的晶体多态性问题。由于溶剂化物、盐类和共晶体越来越多地成为进入临床的固体形式药物的选择，因此迫切需要了解这些原料药的固体形式多样性。Aim 1中提出的方法非常适合于溶剂化物、盐类和共晶中的多晶发现，因为即使在多组分晶体形成中采用的相对狭窄的条件下，它也可以产生固体形态的多样性。最后，在Aim 3中，将介绍一种识别晶体形式靶向抑制剂的新策略。该方法涉及一种新的范例，基于对PIHn如何加速成核的机制理解，重新部署用于创建可溶性聚合物成核抑制剂。