Compositions and methods for improved retention of a pharmaceutical composition at a local administration site

A method for delivering a bioactive agent, comprising:

• injecting into the subject the following components:
• (a) a first biodegradable polymeric microparticle comprising a bioactive agent encapsulated therein;
• (b) a retention vehicle polymer;
• and
• (c) a controlled release cross-linking agent which comprises a cross-linking agent dissolved or dispersed in a second biodegradable polymeric microparticle,
• wherein the cross-linking agent cross-links the retention vehicle polymer in situ in the subject and wherein said cross-linking is achieved with ionic bonds wherein the controlled release of the cross-linking agent replenishes dissociated cross-linker and maintains the cross-linking of the retention vehicle polymer thereby prolonging the retention of the bioactive agent;
• and wherein (i) the cross-linking agent comprises a charged peptide or charged protein;
• or (ii) the cross-linking agent is a bioresorbable microparticle or nanoparticle with a charge on its surface;
• or (iii) the cross-linking agent is a multivalent ion,
• wherein the bioactive agent is selected from the group consisting of an anti-inflammatory agent, an analgesic, an anesthetic, an anti-infective agent, an anti-cancer agent, and a cardiovascular agent, and with the proviso that the bioactive agent is not a growth factor, a tissue growth agent, nor insulin.