Studies on optimization of the bioavailability of poor water-soluble drugs

高效、特异的药物通常是具有一个或多个手性中心的手性化合物。由于新的药物产品应仅含有活性对映体，因此非活性或甚至矛盾的有效对映体被认为是产品的污染。此外，此类化合物通常在水性介质中溶解性差且溶解缓慢。这类药物的特点是生物利用度低，因为水溶性差，因此溶出速率低，是限制其吸收和生物利用度的一个步骤，因此，本项目的目的是开发从外消旋溶液中选择性分离生物活性对映体的方法，该外消旋溶液直接与其在合适的多孔载体中的亚微米药物制剂结合。或者，将使用适当的吸附剂研究活性对映异构体的提取。对于这两种概念，活性成分的生物利用度通过pH依赖性和靶向释放来研究和评估。活性对映体的选择性富集包括选择和修饰合适的载体材料，以及它们对吸附和分离的特定要求的适应性。将使用的载体材料一方面是商业手性吸附剂，如环糊精和环果烷。另一方面，将使用基于非手性硅胶和AlO（OH）的无机载体，其用于表面改性将进一步用生物相容性手性选择剂衍生化。将通过化学键固定在颗粒表面上的氨基酸或手性醇旨在用作手性选择剂。适当的表征，如粒径和形态的研究，将有助于选择有前途的载体系统用于对映体的分离。预期的系统研究将能够确定最佳工艺条件，并更深入地了解工艺条件与产品特性之间的关系，例如优化的溶出行为。

Highly effective, specific drugs are often chiral compounds with one or more chiral centers. Since new pharmaceutical products should contain only the active enantiomer, non-active or even contradictory effective enantiomers are considered as contamination of the product. In addition, such compounds are often poor and slowly soluble in aqueous media. Such drugs are characterized by a low bioavailability since the poor water-solubility and therewith low dissolution rate is a limiting step for their absorption and biological availability.Therefore, the aim of this project is to develop methods for selective separation of the biologically active enantiomer from the racemate solution directly combined with its formulation as submicron drug in a suitable porous carrier. Alternatively, the extraction of the active enantiomer will be investigated using appropriate adsorbents. For both concepts, the bioavailability of the active ingredients is studied and evaluated by pH depended and thus targeted release.The selective enrichment of the active enantiomer covers the selection and modification of suitable carrier materials and their adaptation to the specific requirements for adsorption and separation. The carrier materials which will be used are on one hand commercial chiral adsorbents such as cyclodextrins and cyclofructanes. On the other hand inorganic carrier based on achiral silica gels and AlO(OH) will be used, which for surface modification will be further derivatised with biocompatible chiral selectors. Amino acids or chiral alcohols, which will be fixed by chemical bonds on the particle surfaces, are intended to serve as chiral selectors. A suitable characterization, e.g. studies on particle size and morphology, will help to make a selection of promising carrier systems for the separation of enantiomers. The intended systematic investigations will enable the identification of optimal process conditions and a deeper insight into the relationship between process conditions and product properties such as an optimized dissolution behavior.