The kinetics of pentoxifylline release in vivo from drug-loaded hydroxyapatite implants

Porous hydroxyapatite implants were evaluated as potential skeletal delivery systems for sustained delivery of drugs. Pentoxifylline (PTX) was employed as a model agent and 50 mg of PTX powder was loaded into hollow cylindrical implants. The kinetics of PTX release from the implants was studied both in vitro, employing phosphate buffer (pH 7.35) at the temperature of 37°C, and in vivo, implanting drug-containing cylinders into rabbit iliac bones. For the sake of comparison rabbits were also administered a single i.v. or i.m. dose of 50 mg PTX. Serum PTX concentration levels were measured using the HPLC method. Results of analyses carried out employing the mercury porosimetry method and the hydrostatic weighing method showed that the investigated biomaterial was characterized by a large number of pores ranging in size from 0.4 to 6 μm and with open and total porosity values of 31.8 and 35.6%, respectively. Studies in vitro revealed typical sigmoid-type drug release patterns with a lag time. After 40 h, the amount of released PTX reached a plateau and equaled 78% of the total amount of drug loaded into an implant. Studies in vivo demonstrated that due to decelerated PTX release from cylinders implanted in rabbit iliac bones, its serum concentration values were maintained at measurable levels almost eight times longer than following the systemic administration of PTX. The serum half-life following PTX administration via implants was significantly higher than the value calculated after systemic administration and equaled 6.3 h. The authors also showed that despite differences in the temporal distribution of PTX concentration values, its bioavailability was similar after i.m. injections and administration via implants. As it follows from the investigations, hydroxyapatite implants manifest positive drug-release patterns both in vitro and in vivo.