Effect of polymer/basic drug interactions on the two-stage diffusion-controlled release from a poly(L-lactic acid) matrix

We investigated the effect of drug physico-chemical properties on the release of basic drugs from poly(L-lactic acid) (P(L)LA) cylindrical matrices (rods; 10 mm X 1 mm diameter). All the rods were revealed to exhibit two-stage diffusion-controlled release profiles resulting from the transformation of P(L)LA from an amorphous to a semicrystalline state in aqueous medium. On the assumption that interactions between polymer carboxyl residues and basic drugs control the drug release rate, we evaluated the strength of these interactions by the drug partition between the polymer and the aqueous medium. In the first release stage, the drugs diffused through the swollen polymer matrix. The polymer-drug interactions shielded the polymer terminal carboxyl residues, thereby resulting in a less hydrated matrix and consequent diminishment of drug diffusion. In the second release stage, the drugs diffused through the water-filled micropores which had developed as a result of polymer crystallization. The stronger polymer-basic drug interactions reduced the drug diffusion rate by decreasing not only the porosity of the matrix, but also the drug partition to the water-filled micropores. It was also found that the fractional drug release rate in the second stage increased with drug content of the rod at the pH where both the polymer carboxyl residues and the drugs were ionized. Since the polymer-drug interactions must be close to saturation with increasing drug content, we believe this result to be due to an increase in the ratio of the drug partition to the water-filled micropores. (C) 1999 Elsevier Science B.V. All rights reserved.