Bone substitute materials delivering zoledronic acid: Physicochemical characterization, drug load, and release properties

Abstract

Calcium phosphate-like bone substitute materials have a long history of successful orthopedic applications such as bone void filling and augmentation. Based on the clinical indications, these materials may be loaded with active agents by adsorption offering a perspective for providing innovative drug-delivery systems. The highly effective bisphosphonate zoledronic acid (ZOL) demonstrated a strong affinity to biominerals and is known to significantly reduce osteoclastic activity. Support of early bone formation and reduction of bone resorption can be promoted after implantation of bioceramics releasing ZOL. The aim of this study was to develop an easy to handle approach to combine ZOL with bone substitutes by use of a dipping technique. The properties of three different materials were investigated by using a number of physicochemical methods such as light microscopy, scanning electron microscopy (SEM), dynamic vapor sorption (DVS), true density, and surface area measurement to evaluate the feasibility of being potential drug carriers. Besides physicochemical characterization, the bone substitutes were evaluated by their ZOL-loading capacity in a time- and concentration-dependent manner. Additionally, the materials were assessed as release systems in an in vitro study. A controlled ZOL load in a range of 0.04-1.86 µg/mg material and a release of 0.02-0.18 µg/mg within 30 min is demonstrated. The findings support using the investigated bioceramics as carrier systems to release ZOL. Overall, the results create the base for further development of drug-delivery systems with controlled drug loading and prolonged release and need to be further analyzed in an in vivo study.

Preparation, characterization, release kinetics, and in vitro cytotoxicity of calcium silicate cement as a risedronate delivery system

“…These opposing results may be attributed to different inorganic phases and bisphosphonates loading methods used in these studies, and also to vastly different detection methods. The longer term cumulative release, however, was similar between these studies and our study—the drug release after one month had plateaued . Our long‐term fractional release curve [Fig…”

“…Fractional releases of RAC from CSC, however, were much lower compared to the previous results for CPC or other apatites, where more than 20% of alendronate was released within 3 weeks. In contrast, another study reported that the cumulative zoledronate release from commercial hydroxyapatites and CPC was in the 10 −6 M range . These opposing results may be attributed to different inorganic phases and bisphosphonates loading methods used in these studies, and also to vastly different detection methods.…”

“…[22][23][24][25][26]35 Among the clinically approved bisphosphonates, risedronate (RA) and zoledronate are third generation bisphosphonates with the highest potency to inhibit bone resorption. 35 There is currently a growing interest in using calcium phosphate (CaP) bioceramics as local bisphosphonate delivery devices, [36][37][38][39][40][41][42] as the strong apatite affinity of bisphosphonates will decrease the bisphosphonate release rate. For this work, we chose RA because of its lower binding affinity to bone (over zoledronate), leading thus potentially to higher expected release rates in the fractured area.…”

Development, in vitro and in vivo characterization of zoledronic acid functionalized hydroxyapatite nanoparticle based formulation for treatment of osteoporosis in animal model

“…HA has been proven to have an excellent bone repair properties, for example, stimulating tissue regeneration (Sun et al, 2008;Ooms et al, 2003;Apelt et al, 2004;Lin et al, 2009;Fox et al, 2012;Sorensen et al, 2013). These properties of HA are very important because bone tissue constantly undergoes remodeling, a process whereby bone tissue is simultaneously replaced and removed by the bone cells (osteoblasts and osteoclasts, respectively).…”

“…Recently, more efforts have been focused on the possibility of combining hydroxyapatite with other drugs and materials for multipurpose applications, such as antimicrobial treatments, osteoporosis treatments and magnetic manipulation (Fox et al, 2012). HA may be loaded with active agents by adsorption offering a perspective for providing innovative drug-delivery systems (McLeod et al, 2006;Sorensen et al, 2013).…”