Control of gentamicin release from a calcium phosphate cement by admixed poly(acrylic acid)

The aim of this work was to develop a calcium phosphate cement (CPC) provid ing controlled release of the antibiotic gentamicin sulfate (GS) over at le ast 1 week. The CPC was made of beta-tricalcium phosphate [beta-TCP; beta-C a-3(PO4)(2)], monocalcium phosphate monohydrate [MCPM; Ca(H2PO4)(2) . H2O] and water. Release of GS was controlled by admixture of poly(acrylic acid) (PAA). The effects on the GS release kinetics of the molecular weight of PA A, of the amount of admired PAA, and of the pH of the release medium were i nvestigated. A typical cement sample weighed 3.6 g and contained 100 mg of GS and between 0 and 150 mg of PAA. In the following, PAA content is expres sed as the weight ratio, lambda, with respect to GS. At a low PAA content i n the CPC (lambda < 0.7), GS was released over 1-2 days according to a squa re-root-of-time kinetics, but not all GS was released. The unreleased GS fr action increased from 0 to 58% with an increase of PAA content (up to lambd a = 0.7). At high PAA content; (lambda > 0.7), GS was released over a perio d of up to 8 days according to a combination of a square-root-of-time and a zero-order kinetics. The total GS fraction released increased again from 5 8 to 100% with an increase of the amount of PAA (up to lambda = 1.5). These observations were explained by molecular interaction between PAA and GS re sulting in gel formation. The maximum fraction of GS released from the ceme nt was indeed a function of the solubility of the PAA-GS (coacervate) compl ex in the release medium. Thus, GS release was controlled by two mechanisms : (1) diffusion of free CS molecules through the porous cement (square-root -of-time kinetics); and (2) dissociation of GS from the PAA-GS complex (zer o-order kinetics). The first mechanism was predominant at low lambda, where as the second mechanism became important at high lambda and later release t imes. As the solubility of the PAA-GS complex decreased with an increase in PAA molecular weight, the higher molecular weight PAA yielded more prolong ed release periods of up to 8 days. Interestingly, the use of 450 kDa PAA a t lambda = 1.00 provided an almost constant release profile over a period o f 7 days. Gel formation between PAA and GS was explained in terms of hydrog en bonding of PAA carboxyl groups with GS amino groups. The molar ratio bet ween carboxyl groups and amino groups in the gel was estimated to be simila r to 1.9. In conclusion, admixture of PAA into calcium phosphate cement app eared to be a very elegant tool to control the release of the antibiotic ov er a period of 7 to 8 days. (C) 2000 Wiley-Liss, Inc. and the American Phar maceutical Association.