Loading and release of doxycycline hyclate from strontium-substituted calcium phosphate cement M. Hamdan Alkhraisat a, * , C. Rueda a , J. Cabrejos-Azama a,b , J. Lucas-Aparicio a,b , F. Tamimi Mariño c , J. Torres García-Denche d , L. Blanco Jerez b , U. Gbureck e , E. Lopez Cabarcos a a Departamento de Química-Física II, Facultad de Farmacia, UCM, 28040 Madrid, Spain b Departamento de Estomatología III, Facultad de Odontología, UCM, 28040 Madrid, Spain c Faculty of Dentistry, McGill University, Montreal, QC, Canada d Departamento de Ciencias de la Salud III, Facultad de Ciencias de la Salud, URJC, Alcorcon-Madrid, Spain e Department of Functional Materials in Medicine and Dentistry, University of Würzburg, 97070 Würzburg, Germany article info Article history: Received 6 August 2009 Received in revised form 22 October 2009 Accepted 23 October 2009 Available online 30 October 2009 Keywords: Calcium phosphate cement Ionic substitution Strontium Drug release Doxycycline hyclate abstract Novel Sr-substituted calcium phosphate cement (CPC) loaded with doxycycline hyclate (DOXY-h) was employed to elucidate the effect of strontium substitution on antibiotic delivery. The cement was pre- pared using as reactants Sr-substituted b-tricalcium phosphate (Sr-b-TCP) and acidic monocalcium phos- phate monohydrate. Two different methods were used to load DOXY-h: (i) the adsorption on CPC by incubating the set cement in drug-containing solutions; and (ii) the use of antibiotic solution as the cement liquid phase. The results revealed that the Sr-substituted cement efficiently adsorbs the antibi- otic, which is attributed to an enhanced accessibility to the drug-binding sites within this CPC. DOXY- h desorption is influenced by the initial adsorbed amount and the cement matrix type. Furthermore, the fraction of drug released from CPCs set with DOXY-h solution was higher, and the release rate was faster for the CPC prepared with 26.7% Sr-b-TCP. The analysis of releasing profiles points to Fickian dif- fusion as the mechanism responsible for antibiotic delivery. We can conclude that Sr substitution in sec- ondary calcium phosphate cements improves their efficiency for DOXY-h adsorption and release. The antibiotic loading method provides a way to switch from rapid and complete to slower and prolonged drug release. Ó 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. 1. Introduction Osteotransductive calcium phosphate cements (CPCs) are suit- able materials for local delivery systems in osseous tissue since they can simultaneously promote bone regeneration and prevent infectious diseases by releasing therapeutic agents. Recent ad- vances in CPC technology have resulted in the enhancement of the handling, application and osteoconductive properties of these cements [1]. These improvements have permitted CPCs to be as- sayed as carriers for local delivery of drugs and biologically active substances such as growth factors [1]. Local drug delivery is espe- cially valuable in bone infection since it spares patients the adverse effects of systemically administered drugs, reduces the risks from resistant bacteria and enables high concentration of medicament at the infection site [2,3]. Most drug-delivery systems of clinical use are based either on polymers such as polymethylmethacrylate cement (PMMA) [4] and resorbable polylactic-co-glycolic acid (PLGA) [5], or on ceramic materials such as nanoporous alumina [6], silicon carbide [7] and calcium phosphates [8]. Many studies have investigated combina- tions of therapeutic agents with different calcium phosphates such as sintered hydroxyapatite (HA) [9], precipitated amorphous cal- cium phosphate [10], biphasic calcium phosphate [11] and calcium polyphosphates [12]. Otsuka et al. proved the efficiency of CPCs as vehicles for local delivery systems [13]. The success of this idea was favored by the easy incorporation of pharmaceutical and bio- logical substances into the cement solid or liquid phases, the inti- mate adaptation of the cement paste to bone defects and the high cement porosity which permits the release of the entrapped sub- stance to the local environment [14]. Furthermore, low-tempera- ture setting of CPCs allows the incorporation of heat-labile medicaments and substances into the cement matrix during its preparation. Secondary CPCs that set by the entanglement of brushite crys- tals (CaHPO 4 x2H 2 O) are gaining interest as drug-delivery systems [15–20] mainly due to their biodegradability [21]. Water forms part of the setting reaction of brushite cements, and enables adjustment of the cement porosity, a determinant factor for the release kinetics of the loaded drug [20]. Investigation of 1742-7061/$ - see front matter Ó 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.actbio.2009.10.043 * Corresponding author. Tel.: +34 91 3941751; fax: +34 91 3942032. E-mail address: mkhresat@farm.ucm.es (M.H. Alkhraisat). Acta Biomaterialia 6 (2010) 1522–1528 Contents lists available at ScienceDirect Acta Biomaterialia journal homepage: www.elsevier.com/locate/actabiomat