Study of drug-macromolecule interactions for the development of new oral controlled delivery systems

The concept of drug-excipient interactions has gradually evolved in the past years, in particular concerning drug-polymer interactions. Rather than considering a detrimental occurrence during the pharmaceutical development, nowadays, polymer-polymer and drug-polymer interactions are considered a new promising tool to control drug delivery with advantages in terms of drug-sustained release, linear kinetics and reduced sensitivity to the external environment. Ionic interactions are the most investigated at the moment, whereas hydrogen bond and hydrophobic interactions are basically an unexplored field. However, the comprehensive understanding of the specific role of non-covalent interactions in controlled drug release is still an ongoing process. The aim of the present research work was the comprehensive investigation of the role of non covalent interactions between drugs and polymer in oral controlled drug delivery with the aim to present a more systematic approach for the prediction of desired release profile, depending on the chemical functions and the interactions involved. Non-covalent interactions between a model drug, presenting basic characteristics, such as atenolol, and polymer, carrying different functional groups, namely chondroitin sulfate, chitosan, sodium alginate and ?-carrageenan were characterized by ATR-FT-IR and H1-NMR. The desorption electrospray high resolution mass spectrometry was used as innovative and fast method to evaluate the interaction between the molecules selected. In vitro drug release studies, carried out on matrix tablets consisting of atenolol and each polymer selected, revealed that only the ionic interaction occurring between atenolol and ?-carrageenan was suitable for controlled drug delivery. Drug release from this system was highly influenced by the concentration of potassium dihydrogen phosphate in the dissolution medium, affording more prolonged zero-order release profiles at higher ionic strength and faster delivery rates with super Case II kinetics at lower ionic strength. The evaluation of the front position of ?-carrageenan-atenolol matrices, as well as the study of hydration properties of the polymer by DSC, showed that the overall mechanism of release was controlled by mutual interactions polymer-drug-salt. The addition of acidic potassium salt to the ?-carrageenan-atenolol mixture prior compression was effective in determining a prolonged drug release, independently of the external environmental conditions. ?-carrageenan-salt mixture were also evaluated to afford controlled release of different basic drugs, such as methyl L-dopa and buflomedil pyridoxal phosphate, showing distinct release behaviours, probably related to different strength of interaction. The last part of the research was conducted in Professor Duncan Craig's laboratory at UCL-School of Pharmacy. The subproject was aimed to investigate the hot melt extrusion as a technique to produce solid solutions, where oppositely charged drugs and polymers were electrostatically bonded.