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: 8482952
• 负责人: Adam Jay Matzger
• 金额: $ 24.13万
• 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/8482952
• 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）：提供活性药物成分（API）的最常见和理想的方法是结晶形式。 API可以以纯形，盐或多组分（溶剂，共晶）固体形式配制，并且由于稳定性和处理优势而与其他配方的加工优势所致。这些形式之间的选择在很大程度上取决于药物分子的特定化学特性以及溶解性等因素。但是，要考虑的是晶体多态性的普遍问题：给定的组合物不受限制地以可预测的方式结晶，并且同一单元的多个填料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，更全面的技术，以控制生物活性有机分子的结晶，同时材料较少。 THI将使潜在药物的早期筛查能够确定哪种形式具有适当的溶解度和稳定性，可以将其配制为可生物利用剂量。 三个相互联系的目标旨在开发和部署更有效，更强大的多晶型物发现方法。 AIM 1适用于聚合物诱导的异核核酸（PIHN）方法对固体发现发现，以便它以适合多晶型物发现的高通量方式发挥作用。提出的两个关键进展是对技术的微型化和固体形式筛选的自动化，这将使Pihn方法更适合筛查临床前药物候选物。 AIM 2解决了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，盐和共晶人越来越成为进入诊所的药物的固体形式，因此在这种API中迫切需要理解固体形式的多样性。 AIM 1中提出的方法非常适合于溶剂，盐和共晶中的多晶型物发现，因为即使在多组分晶体形成中采用的相对狭窄的条件集中，它也可以产生固体形式多样性。最后，将引入AIM 3，一种用于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式，基于对Pihn如何加速成核的机械理解，重新部署以创建可溶性聚合物成核抑制剂。