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Combined formulations based on prodrugs and in situ gelling systems - Design and pharmaceutical chemical characterisation

Karsten Petersson

In situ forming drug delivery systems are in principle capable of releasing drug molecules in a sustained manner affording relatively constant plasma profiles. The concept has been investigated for various routes of administration including oral, ocular, rectal and parenteral administration. Compared to conventional controlled release formulations, in situ forming drug delivery systems possess potential advantages. Benefits embrace simpler manufacturing processes and ease of administration. The vast majority of the in situ forming drug delivery systems reported is based on polymeric materials which forms gel matrices upon administration. Polymers that have been investigated includes (1) polysaccharides like alginate, gellan and xyloglucan, (2) polyesters like PLA and PLGA, (3) polyethers like PEG-PPG-PEG or (4) mixed polyesters and polyethers such as PEG-PLGA-PEG. The gelation processes by which solutions of these polymers form drug depots are either pH-induced, ion-mediated, induced by solvent removal, or thermally-induced. Alternative systems like in situ formed crystal suspension have also been reported. These systems imply a highly concentrated solution of a poorly water-soluble drug salt in a biocompatible water-miscible solvent. Dilution of such relatively concentrated solutions with physiological fluids results in formation of crystals suspensions upon administration.

Drug release from in situ forming drug delivery systems may be altered by the employment of prodrug design. Compound characteristics suggested to influence the drug liberation include solubility, lipofilicity, molecular weight and chemical stability. More research needs to be done to elucidate in more detail the mechanisms for drug release from in situ forming drug delivery systems comprising relatively unstable prodrugs or macromolecular prodrugs.

The emergence of such new systems is to be considered as potential alternatives for the formulator and pharmacologist in the search for novel drug delivery systems.

Ingen Dansk version