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

由于其良好的生物相容性，磷酸钙骨水泥(CPC)被应用于骨缺损的修复。通过添加药物可以达到进一步的治疗效果。抗生素有助于遏制细菌感染。在活检切除肿瘤组织后，添加细胞抑制剂可以降低癌症复发的风险。抗骨质疏松剂，如双膦酸盐，在骨折时会进一步损害骨吸收。通过将这些助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，还可以减少系统性的不利影响。由于监管原因，这种复合材料作为医疗器械的批准实际上是不可能的，临床申请者应该有机会将获得批准的CP和医疗代理单独结合起来。药剂会对水泥的水化性能、流变性和凝结后的硬度等应用相关性能产生影响。相反，粘结剂可以影响药物的疗效，例如通过它们的pH值。因此，为了成功地应用这些配方，必须详细了解这些相互作用。因此，在拟议的研究中，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类似于临床上可用的CPC的不同型号的骨水泥。S对水泥水化影响的第一次评估将用等温量热法进行。用原位X-射线衍射法分析改性水泥中定量相组成的变化。为此，将采用外部标准方法，除了晶相的定量外，还可以对非晶态部分进行定量。初始和最终凝结时间将由配备吉尔莫尔针织仪器的Ieter确定。此外，还将研究水泥浆体的流变性和可注入性。细菌培养的分析将用于检查抗生素在选定的水泥系统中的有效性，而抗骨质疏松剂和细胞抑制剂的有效性将通过适当的细胞培养进行评估。药物的释放动力学将被定量测量。由于释放动力学预计与孔隙率相关，因此也将进行孔隙率测量。此外，还将研究SET水泥的力学性能。在研究结束时，应根据水泥成分和计划应用的医疗试剂的种类，向医疗申请者提供关于作为当地药物输送系统的适宜性和有效性的可靠信息。

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.