Interaction mechanisms of medical agents with calcium phosphate cements for the application as pharmacologically active bone substitutes

由于其优异的生物相容性，磷酸钙骨水泥（CPC）被应用于骨缺损的修复。通过添加药物可以实现进一步的治疗效果。抗生素有助于抑制细菌感染。活检去除肿瘤组织后，添加细胞抑制剂可以降低癌症复发的风险。双磷酸盐等抗骨质疏松药物会在骨折时损害进一步的骨吸收。通过将这些试剂直接添加到水泥中，它们可以在需要的地方发挥作用。此外，可以减少全身性副作用。由于出于监管原因，批准此类复合材料作为医疗器械实际上是不可能的，因此临床申请人应有机会单独组合批准的 CPC 和医疗制剂。药剂可以影响水泥的应用相关性能，例如水化性能、流变性能和凝固后达到的硬度。相反，水泥会影响药剂的功效，例如通过其 pH 值。因此，为了成功应用此类配方，必须详细了解相互作用。因此，在拟议的研究中，类似于临床可用的 CPC 的不同模型水泥将通过添加选定的抗生素、抗骨质疏松剂和细胞抑制剂来表征。该剂对水泥水化影响的首次评估将通过等温量热法进行。改性水泥中定量相组成的发展将通过原位 X 射线衍射进行分析。为此，将应用外部标准方法，该方法除了对结晶相进行定量外，还可以对非晶态部分进行定量。初始和最终凝固时间将由配备吉尔莫针装置的 Imeter 确定。此外，还将研究水泥浆的流变特性和可注射性。将应用细菌培养物检测来检查所选水泥系统中抗生素的功效，同时将通过适当的细胞培养物评估抗骨质疏松药和细胞抑制剂的功效。将定量测量药剂的释放动力学。由于预计释放动力学与孔隙率相关，因此还将进行孔隙率测量。此外，还将研究凝固水泥的机械​​性能。在研究结束时，应根据水泥成分和计划使用的药物种类，向医疗申请人提供有关局部药物输送系统的适用性和功效的可靠信息。

Due to their excellent biocompatibility, calcium phosphate cements (CPCs) are applied for the repair of bone defects. Further therapeutic effects can be achieved by the addition of medical agents. Antibiotics are helpful to contain bacterial infections. After biopsies to remove tumour tissue, the addition of cytostatics can reduce the risk of cancerrecurrence. Antiosteoporotic agents like bisphosphonates can impair further bone resorption in case of bone fracture. By direct addition of those agents to the cements, they can be efficient at the place there are needed. Furthermore, systemic adverse effects can be reduced. Since the approval of such composites as a medical device is practically impossible for regulatory reasons, clinical applicants should be given the opportunity to individually combine approved CPCs and medical agents. Medical agents can have an influence on applicationrelevant properties of the cements, like the hydration performance, rheological properties and the achieved hardness after setting. Conversely, the cements can affect the efficacy of the medical agents,for example via their pH. Hence, for a successful application of such formulations it is essential to understand the interactions in detail. Therefore, in the proposed study different model cements resembling clinically available CPCs will be characterized with the addition of selected antibiotics, antiosteoporotics and cytostatics. The first evaluation of the agent´s influence on cement hydration will be performed by isothermal calorimetry. The development of the quantitative phase composition in the modified cements will be analysed by in-situ X-ray diffraction. For this purpose, an external standard method will be applied, which besides the quantification of crystalline phases also allows quantification of the amorphous fraction. Initial and final setting times will be determined by an Imeter equipped with Gillmore Needle apparatus. Furthermore, rheological properties and injectability of the cement pastes will be investigated. Assays with bacterial cultures will be applied to check the efficacy of antibiotics in the selected cement systems, while the efficacy of antiosteoporotics and cytostatics will be assessed via appropriate cell cultures. The release kinetics of the agents will be quantitatively measured. Since release kinetics is expected to correlate with porosity, porosity measurements will also be performed. Additionally, mechanical properties of set cements will be investigated. At the end of the study, medical applicants should be provided reliable information about the suitability and efficacy as local drug delivery system, based on the cement composition and the kind of medical agent planned for application.