Biomaterials 23 (2002) 3449–3454 A method to fabricate porous spherical hydroxyapatite granules intended for time-controlled drug release Vladimir S. Komlev a , Serguei M. Barinov a, *, Elena V. Koplik b a Institute for Physical Chemistry of Ceramics, Russian Academy of Sciences, Ozernaya 48, Moscow 119361, Russia b Institute of Normal Physiology, Russian Academy of Medicine Sciences, Bolshaja Nikitskaja 6-3, Moscow 109003, Russia Received 15 August 2001; accepted 31 January 2002 Abstract This study is aimed at the development of a method to fabricate porous spherical hydroxyapatite (HA) granules, which can be impregnated with a drug. These drug-loaded particles can be used as a system for targeted and time-controlled drug delivery, e.g. in bone surgery. The method to produce porous granules is based on liquids immiscibility effect. A suspension of HA powder in aqueous solution of gelatin and oil as a dispersion media were used. By stirring the mixtures of these immiscible liquids, granules of 50–2000 mm diameter can easily be produced. Dependence of the granules characteristics on the preparation route was studied. In vivo experiments were performed to simulate drug release kinetics from the granules to the blood of rats. r 2002 Elsevier Science Ltd. All rights reserved. Keywords: Hydroxyapatite; Granules; Drug delivery 1. Introduction Particulate systems for delivery and application of drugs are claimed to have enhanced bioavailability, predictable therapeutic response, greater efficacy and safety, and controlled and prolonged drug release time. Various particulate systems containing drugs distributed within a biocompatible matrix are under development [1–7]. For this purpose, encapsulation of drugs in a biodegradable matrix, as well as other, e.g. monolithic systems based on porous ceramics, have been proposed [1,7]. Ceramic-based systems have caused enhanced interest with particular attention focused on the use of hydroxyapatite as a ceramic constituent of the system. HA is widely used for bone reparation, being totally biocompatible with the human body, non-toxic and osteoconductive [8–11]. Therefore, the development of the particulate systems HA-drug, e.g. antibiotics, anti- microbial agent, growth factor, etc., with controlled drug release kinetics seems to be an important problem, in view of the rate of infection in bone surgery [2]. It is especially important in the case of poor drug distribu- tion at the site of infection due to limited blood circulation to the surrounding skeletal tissue [2,12]. Behavior of a particulate in the body depends on its morphology and microstructure. Irregular morphology of the particulate is known to cause inflammatory reactions [7], so the rounded granules with smooth geometry are preferable for tissue defect filling. Kinetics of drug release from the particulate is affected by pore size, content and distribution. An exponential equation to describe the release kinetics has been proposed by Krajewski [13]. A number of studies have reported the development of HA granulates by various techniques with irregular or spherical geometry [7]. In particular, porous spherical HA granules of 200–1000 mm diameter have been produced by the dispersion of well-mixed HA/chitosan slurry in a dispersion medium, the latter being a mixture of heavy and light liquid paraffins [7]. The dispersion has been stirred and gluteraldehyde was added to harden the spheres. After washing, drying and burning the chitosan, porous HA spheres have been obtained. The method seems to be a promising one, but possesses some inconveniences due to the use of paraffins. In this study, we propose a new method for preparing the porous HA granules, the method being simple, versatile and clean as compared to that described in [7]. In vivo *Corresponding author. Tel.: +7-95-4379892; fax: +7-95-4379893. E-mail address: mnctk@cityline.ru (S.M. Barinov). 0142-9612/02/$ - see front matter r 2002 Elsevier Science Ltd. All rights reserved. PII:S0142-9612(02)00049-2