Thermodynamics for the Stabilization of Amorphous Active Pharmaceutical Ingredients via Polymer-Based Formulations

通过聚合物配方稳定无定形活性药物成分的热力学

• 批准号: 290326182
• 负责人: Professorin Dr. Sabine Enders
• 金额: --
• 依托单位: Institut für Technische Thermodynamik und Kältetechnik (ITTK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290326182?language=en
• 关键词: Thermodynamics; Stabilization; Amorphous; Active; Pharmaceutical

Most active pharmaceutical ingredients (APIs) are very hydrophobic and show an extremely low solubility in aqueous media leading to a very low bioavailability. For that reason, more than 80% of the newly-developed, promising APIs never make it into a medicine. Moreover, most of them are crystalline solids exhibiting very slow dissolution kinetics and can therefore not be sufficiently absorbed by the body during their way through the intestinal tract. One possibility to improve both, solubility and dissolution kinetics is the amorphization of the APIs. This can e.g. be achieved via molecular dissolution of the API in a polymer matrix or adsorption of the API at a polymer matrix (leading to API/polymer formulations). Appropriate polymers are today found by trial-and-error procedures whereas the results are usually not transferable to other APIs. Moreover, it is known that amorphous APIs tend to re-crystallize in polymer formulations or to demix from the polymer when exposed to humidity, e.g. under storage conditions. This project focuses on the application of thermodynamic principles to systematically investigate the stabilization of amorphous APIs in polymer-based formulations. Since the chemistry of appropriate polymers is restricted by regulatory authorities (e.g. FDA), the project will investigate, how the stabilizing properties of the polymer can be influenced by changing its copolymer composition, conformation, or 3D-structure. Solubility and miscibility of APIs and polymers will be studied as function of these polymer properties. For the first time, amorphous miscibility of APIs and polymers will be measured quantitatively. Moreover, the influence of humidity on the API/polymer phase behavior will be studied by both, experiments and modeling. In cases, where thermodynamic stability cannot be achieved (e.g. at API concentrations higher than solubility), formulations might at least kinetically be stabilized at temperatures below the glass-transition temperature of the API/polymer formulation. Therefore, also the glass-transition temperature as well as the influence of humidity will be investigated. For that purpose, a model will be developed that will for the first time allow to predict the glass-transition temperature of branched polymers as function of polymer architecture, polymer semi flexibility, and in the presence of additives (APIs or modifiers). This model will also allow optimizing the manufacturing of 3D-polymer networks (aeorogels) used for API formulations. Based on systematic experiments and thermodynamic modeling of both, phase behavior and glass-transition temperature of API/polymer formulations, this project will provide a physically-sound basis to choose appropriate polymer properties which are best suitable to stabilize an amorphous API at given temperature, humidity and API concentration.

大多数活性药物成分（API）是非常疏水的，并且在水性介质中显示出极低的溶解度，导致非常低的生物利用度。因此，超过80%的新开发的有前途的API从未成为药物。此外，它们中的大多数是结晶固体，表现出非常缓慢的溶解动力学，因此在它们通过肠道的过程中不能被身体充分吸收。改善溶解度和溶解动力学的一种可能性是API的非晶化。这可以例如通过API在聚合物基质中的分子溶解或API在聚合物基质上的吸附（产生API/聚合物制剂）来实现。今天，通过试错程序发现了合适的聚合物，而结果通常不能转移到其他API。此外，已知无定形API倾向于在聚合物制剂中再结晶或在暴露于湿气时（例如在储存条件下）从聚合物中分层。该项目的重点是应用热力学原理系统地研究聚合物基制剂中无定形原料药的稳定性。由于适当聚合物的化学性质受到监管机构（例如FDA）的限制，因此该项目将研究如何通过改变其共聚物组成，构象或3D结构来影响聚合物的稳定特性。API和聚合物的溶解度和可溶解性将作为这些聚合物性质的函数进行研究。这是第一次定量测量原料药和聚合物的无定形可溶解性。此外，湿度对API/聚合物相行为的影响将通过实验和建模来研究。在不能实现热力学稳定性的情况下（例如，在高于溶解度的API浓度下），制剂可以在低于API/聚合物制剂的玻璃化转变温度的温度下至少动力学稳定。因此，还将研究玻璃化转变温度以及湿度的影响。为此，将开发一种模型，该模型将首次允许预测支化聚合物的玻璃化转变温度作为聚合物结构、聚合物半柔性和添加剂（API或改性剂）存在下的函数。该模型还将允许优化用于API制剂的3D聚合物网络（气凝胶）的制造。基于API/聚合物配方的相行为和玻璃化转变温度的系统实验和热力学建模，该项目将提供物理可靠的基础来选择最适合于在给定温度、湿度和API浓度下稳定无定形API的适当聚合物性质。