Study On Calcium Phosphate Cement Containing Drug

Calcium phosphate cements (CPCs) present various advantages in the repair of hard tissues, such as in vivo self-setting and the perfect fit with the implantation bed, which ensures good bone-material contact even in geometrically complex defects. In the clinical setting, at different stages after the filling of bone defects drugs are often administered at the filled site for various purposes. Antibiotics are usually administered at sufficient concentrations to prevent potential infections. Osteogenic drugs may also be administered to accelerate bone repair. The low-temperature setting of CPC allows the incorporation of a variety of drugs and biologically active molecules without deactivation or denaturalization. Therefore, in addition to serving as bone substitutes, the possibilities of using CPC as carriers for local controlled release of drugs provides attractive opportunities in the treatment of skeletal disorders. In this work, three types of drug-containing CPCs designed for different clinical requirements were studied.The Biocement D composition was adapted for the work in this study. The solid phase contained a-tricalcium phosphate (a-TCP, a-Ca3(PO4)2), dicalcium phosphate dehydrate (DCPD, CaHPO4.2H2O), sintered hydroxyapatite (HA, Ca5(PO4)3OH) and calcium carbonate (CaCO3) in the ratio of 58/25/8.5/8.5 (w/w/w/w). The liquid phase contained equivalent volume of disodium hydrogen phosphate (0.2 mol/L Na2HPO4) and sodium dihydrogen phosphate (0.2 mol/L NaH2PO4).The incorporation of Xiangdan injection (Xiangdan), an accelerator of bone healing, was studied. Different incorporating techniques were compared. It was found that Xangdan could be mixed with DCPD and dried with denaturalization at 70℃. Then, the concentration of incorporated Xiangdan was extended to a relatively wide range. Xiangdan was mixed with DCPD at different ratios and dried into Xiangdan-loaded DCPD, which was then used as a raw material in the subsequent preparation of Xiangdan-loaded CPCs. The physicochemical properties of CPCs containing various Xiangdan concentrations were characterized, including the microstructures and in vitro drug release kinetics. The setting time increased with increasing Xiangdan concentration in CPC, and could meet the clinic requirement at a concentration of or below 0.2mL/g. The compressive strength also increased with increasing Xiangdan concentration. No difference in phase conversion degree was observed between hydrated CPCs with and without Xiangdan. SEM found that the morphology of crystals changed from particles to plates with the increase in Xiangdan concentration. In the first 4 h, the in vitro release of Xiangdan from CPCs with a Xiangdan concentration of 0.1-0.5ml/g could satisfy with the clinic requirement. It was concluded that both the setting time and in vitro Xiangdan release from CPC with Xiangdan concentrations of 0.1-0.2ml/g could meet the requirement of clinical applications in the initial stage. In addition, the effect of Xiangdan on the Zeta potential, pH and raw materials was studied to understand the mechanisms of the influence of Xiangdan on the properties of CPCs. The addition of Xiangdan was found to result in decreased Zeta potential, pH, and the ratio of calcium ions in the fragment ions. These findings suggested that the prolonged setting time was attributed to the coverage of reaction active center of CPC as well as the polar groups of Xiangdan, which resulted in increased CPC fluidity. The increased compressive strength was attributed to the change of microstructure of CPC and the bonding between calcium and Xiangdan.The long-retention of antibiotics in CPCs may induce the development of drug resistance. Fast-releasing CPC containing antibiotics (FRCPC) was proposed as a solution to this problem and studied in this work. The FRCPC containing different proportions of soluble component were prepared and characterized. The setting time, compressive strength, degree of the conversion, in vitro antibiotic release, and fractography of FRCPC were studied. The results showed that the setting time increased, the compressive strength decreased, the in vitro antibiotic release accelerated with increasing fraction of soluble component in FRCPC. SEM showed that the porosity and pore size increased with increasing fraction of soluble component. The setting time and compressive strength of FRCPCs containing 20 wt% soluble component were close to the requirements of clinic applications, and the in vitro release was completed within 7 d. The FRCPCs containing 20 wt% may be useful in clinical applications after appropriate modifications. The mechanisms of in vitro antibiotic release from these FRCPCs were studied. X-ray diffraction and titration revealed a rapid dissolution of the soluble component during the in vitro release, and SEM showed a higher porosity and larger pore size compared with the control CPC at the same time points. These findings explained an accelerated drug release. The release kinetics followed the Higuchi's diffusion-controlled model. These FRCPCs may prevent the development of drug resistance and may find applications in clinics.To address the different requirements of treatment at different clinical stages, gelatin /CPCs composite containing two drug components, paracetamol and chloromycetin, were prepared to realize the temporally-ordered release of two drugs. The drug intended to be released at the late stage was encapsulated in gelatin microspheres. The drug load in microspheres was enhanced by a modified emulsion crosslink method. The concentrations of released drugs were assayed by dual-wavelength spectrophotometry. The assay was confirmed to have a high recovery, ensuring an excellent accuracy. Gelatin/CPCs composite containing two drug components were prepared by mixing CPC, free chloromycetin, and paracetamol-containing microspheres. The optimum powder:liquid ratio for the formation of CPC was studied to prevent the disintegration of gelatin/CPCs composite. The result showed that the gelatin/CPCs composite design realized the temporally-ordered release of the two drugs. At the powder:liquid ratio of 0.85g/mL, gelatin/CPCs composite containing two drug components were readily formed and could resist disintegration in aqueous solution; the compressive strength obtained at this powder:liquid ratio was within the range of the clinic applications. The delayed release of drug was realized by encapsulation in microspheres, thus successfully achieving a temporally-ordered release of two drugs from gelatin/CPCs composite.