suberoylbisphosphonic-acid and Calcinosis

Local implantation or injection of microspheres containing bisphosphonates for site-specific therapy may aid in treating several pathological conditions associated with bone destruction. Chitosan microspheres containing two antiresorption and anticalcification agents, pamidronate and suberoylbisphosphonate (SuBP), were prepared from a w/o emulsion. Various formulation variables were studied for their effect on the release rate profile of these bone-seeking agents. Polymer coating of micromatrices yielded microspheres with the most retarded release rate, and the drug delivery system was found biocompatible in endothelial cell culture. The microspheres were examined in vitro and in vivo for release kinetics and drug disposition. The release of bisphosphonate from the microspheres was faster in vitro than in vivo. Drug disposition following implantation of microspheres in the tibialis muscle resulted in a relatively increased disposition in the adjacent tibia while injection of drug solution in the tibialis muscle resulted in uniform disposition of the drug in the femorae and tibiae. Bisphosphonate released from chitosan microspheres effectively inhibited bioprosthetic tissue calcification in the rat subdermal model.

Topics: Animals; Biocompatible Materials; Bone and Bones; Bone Resorption; Calcinosis; Cattle; Chitin; Chitosan; Diphosphonates; In Vitro Techniques; Infusion Pumps, Implantable; Male; Microspheres; Pamidronate; Rats; Tissue Distribution

Some geminal bisphosphonates are used clinically for a number of important bone/calcium related diseases; however, side effects and lack of selectivity impede their wide use. This work reports the synthesis and evaluation of bisacylphosphonates (e.g., adipoyl- and suberoylbisphosphonate). These compounds were found to inhibit significantly hydroxyapatite formation and dissolution in vitro and the calcification of bioprosthetic tissue implanted subdermally in rats. These are the first instances of nongeminal bisphosphonates [P-(C)n-P, n greater than or equal to 2] that have been reported to be active in calcium-related disorders. The reported bisacylphosphonates possess apparent lower toxicity, and their calcium complexes/salts have improved solubility properties. Therefore, they are of potential importance for clinical applications.

Topics: Animals; Bioprosthesis; Calcinosis; Cardiomyopathies; Cattle; Diphosphonates; Heart Valve Prosthesis; Hydroxyapatites; Molecular Structure; Rats; Solubility