Modification of the In Vitro Release Profile of Cetrorelix by Complexation with Biophilic Partners

Thomas      Rattei; Jurgen      Engel; Wolfgang      Naumann; Alexander      Lang; Matthias      Rischer

doi:10.2174/156720108785915032

Abstract

Cetrorelix is a GnRH antagonist of the third generation. Its manifold therapeutic potential requires the adjustment of its resorption rates and effect profiles. The method of non-covalent complexation with suitable partner molecules enables the development of customized depot formulations. Investigating new partners and synthesis methods for Cetrorelix complexes we focused on maximal biocompatibility of the complexes. Compared to traditional depot forms the application of complexes aims at decreased aggregation of the peptide and increased biophily of the depots. The pharmacological properties of the new Cetrorelix complexes were analyzed by standardized dynamical in vitro liberation experiments. A new pharmacokinetic model has been developed and successfully applied for the quantitative analysis of the liberation profiles. With aromatic carboxylic acids and dipeptides we could synthesize stable complexes that have nearly linear release characteristics in aggregating environments close to in vivo conditions. The release rates were specific and very different for the complex partners. Thus several complexes have a great potential for a linear, characteristic release of the peptide in vivo and can be the basis for new depot forms for Cetrorelix.

Keywords: Cetrorelix, peptide hormone, complex, liberation, release, pharmacokinetics, aggregation

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