Multi-composite system for the delivery of alendronate to bone tissue

Bakground The bisphosphonate (BPs) class drug, is widely employed for the treatment of a variety of bone disorders. In this work Sodium Alendronate (AL) was utilised as model Bisphosphonate drug. AL is often administered orally or via injection showing many side effects. Recently different release approaches have been evaluated in order to targeted AL delivery to bone. In particular calcium phosphate cements (CPCs) have been investigated as potential carries of BPs [1, 2]. The CPCs are bioactive and biodegradable grafting materials made of powders of suitable composition which, when mixed with a liquid phase, give a modulable paste which stiffens during the setting reaction and sets as primarily calcium-deficient hydroxyapatite. Unfortunately, the loading of AL interferes with the conversion of pristine powders (like alfa-tricalcium phosphate, alfa-TCP) into hydroxyapatite, increasing the setting times and worsening the mechanical properties. Therefore, the amount of AL that can be directly loaded is limited (1.8 mg / g) [1, 2]. Consequently, the drug encapsulation might overcome this drawback. The aim of this work was to develop an innovative drug delivery system potentially useful for the delivery of AL to bone tissue. In particular, we propose the use of Solid Lipid Microparticles (MPs), up to now mainly used for oral and topical drug delivery, as carrier for AL, due to the favourable biocompatibility and lower toxicity of the lipids compared with many polymers. Thus a multicomposite delivery platform consisted of a biomimetic-tricalcium phosphategelatin cement (CPCs) enriched with alendronate-loaded MPs (MPs-AL) was developed. Main results For the preparation of the MPs, the spray congealing technology was employed [3]. In particular six different excipient were considered: Stearic acid, Stearyl alcohol, Cutina® HR, Precirol® ATO 5 and Tristearin. In order to screen the effect of types, dimensions and amount of unloaded MPs on the CPCs most important mechanical properties a Design of Experiment (DoE) was employed. Then, MPs loaded with 10 % w/w of AL were produced using the different carriers. All MPs-AL exhibited a spherical shape, encapsulation efficiency higher than 90% and prevalent particle size ranging from 100-150 micron. Solid state characterization by means of DSC, HSM and X-ray powder diffraction demonstrated that encapsulation of the drug into MPs did not alter its crystal structure. MPs-AL addition to the cement provoked a modest lengthening of the setting times and of the hardening reaction leading to the complete transformation of alfa-TCP into calcium-deficient hydroxyapatite, without significantly affect the cement mechanical properties. Then MPs loaded with different concentration of AL (10%, 20% and 30%) were embedded into the CPC. The in vitro AL release studies from the multi-composite system (carried out in PB buffers at pH 7.4 at 37°C) showed that all the system allowed a controlled release of the drug over time. Therefore the results of this study demonstrated that it was possible to increase the amount of AL into the CPCs up to 10 time compared to the value previously reported [1,2]. Moreover, the use of MPs as carriers to enrich bone cement formulation with AL was a successful strategy to develop a system for the controlled local delivery of the drug. Future and prospective To value the effect of the AL release from CPCs-MPs system on cellular proliferation and differentiation, in vitro studies using osteoblasts and osteoclasts cell cultures are in progress. The obtain results suggest that this designed composite system could be useful for the delivery of other drugs (i.e. antibiotic, antiinflammatory agents and anticancer drugs) to bone tissue.