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

磷酸钙骨水泥由于其良好的生物相容性，被广泛应用于骨缺损的修复。进一步的治疗效果可以通过添加药物来实现。抗生素有助于控制细菌感染。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。像双膦酸盐这样的抗骨质疏松剂在骨折的情况下会损害进一步的骨吸收。通过直接向水泥中添加这些药剂，它们可以在需要的地方发挥作用。此外，可以减少全身不良反应。由于监管原因，此类复合材料实际上不可能被批准为医疗器械，因此临床申请人应该有机会单独组合已批准的cpc和医疗制剂。药剂会影响水泥的水化性能、流变性能和固化后的硬度等与应用相关的性能。相反，水泥可以影响药物的功效，例如通过其ph值。因此，为了成功应用此类配方，详细了解相互作用至关重要。因此，在拟议的研究中，不同的模型水泥类似于临床可用的cpc，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。对药剂对水泥水化影响的首次评价将采用等温量热法进行。用原位x射线衍射分析了改性胶结物中定量相组成的发展。为此，将采用一种外部标准方法，该方法除了定量结晶相外，还允许定量非晶部分。初始和最终凝固时间将由配备吉尔莫针装置的液压计确定。此外，还研究了水泥浆体的流变性能和可注射性。细菌培养试验将用于检查选定水泥系统中抗生素的功效，而抗骨质疏松剂和细胞抑制剂的功效将通过适当的细胞培养来评估。将定量测量药物的释放动力学。由于预计释放动力学与孔隙度相关，因此也将进行孔隙度测量。此外，还将研究水泥的力学性能。在研究结束时，应根据水泥成分和计划应用的药物种类，向医疗申请人提供关于作为局部给药系统的适用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.