How interactions between drugs and agarose-carrageenan hydrogels influence the simultaneous transport of drugs.

The diffusional transport of a series of small drug molecules (<400 Da) in agarose gel with and without kappa-carrageenan (a negatively charged polysaccharide) is studied. The drug molecules have amphiphile character, the hydrophilic part being a tertiary amine which is the same in all six drugs. The difference in structure resides in the hydrophobic part which give these molecules different properties such as a difference in CMC-values (critical micelle concentration). The transport studies show that the apparent diffusion coefficients (Dapp) of all the drugs in 1% (w/w) agarose gel are almost identical and with a value similar to that in water. These results were anticipated because of the small size of the drugs, the low concentration of agarose, and the lack of interaction between the diffusant and the polymer. In agarose gels also containing 0.02% (w/w) kappa-carrageenan, however, the Dapp-values are significantly decreased for all drugs, except for lidocaine. This lowering of the Dapp is ascribed to the interaction between the drug molecules and kappa-carrageenan. The Dapp-values of the drugs in the gel system containing kappa-carrageenan correlate well with the adsorption isotherms of the same drugs in the drug/kappa-carrageenan/water system obtained previously [1] and the Dapp-values follow the order: chlorpromazine

Release of PEGylated granulocyte-macrophage colony-stimulating factor from chitosan/glycerol films.

We have prepared a new formulation for mucosal delivery of GM-CSF or PEGylated GM-CSF based on a chitosan carrier plus added glycerol to control the rate of release of the protein. Thin dry films comprised of various weight ratios of chitosan to glycerol and containing either granulocyte-macrophage colony-stimulating factor (GM-CSF) or PEGylated GM-CSF, PEG-(GM-CSF), were prepared. The amount of GM-CSF or PEG-(GM-CSF) released from the chitosan/glycerol films was determined using size exclusion high performance liquid chromatography (HPLC-SEC). The amount of PEG-(GM-CSF) released from the films decreased with an increase in the amount of glycerol present in the film. In parallel with this, films with higher glycerol content exhibited a lower degree of equilibrium swelling when immersed in release media. pH measurements of the release media and analysis of the dried films by Fourier-transform infrared spectroscopy (FTIR) suggested that the amount of residual acetic acid in the dry films decreased as the glycerol content increased. This indicates that glycerol may act by displacing and releasing bound acetic acid from the chitosan molecules, resulting in chitosan--glycerol hydrogen bond formation as the film dries. Further, it was found that the release rate and the amount of PEG-(GM-CSF) released decreased with increasing molecular weight of the conjugated PEG. This effect was not observed with films containing physical mixtures of PEG and GM-CSF. The decrease in the fraction of PEG-(GM-CSF) released with increasing PEG molecular weight is believed to be due to the increased steric hindrance of the PEGylated protein molecule during its diffusion out of the swollen chitosan/glycerol film.

Polyelectrolyte/amphiphile interaction studied by surface tension measurements.

The interaction of kappa-carrageenan with three positively charged drug molecules with amphiphile character has been examined using surface tension measurements. The surface tension was measured by the pendant drop method which makes possible the determination at an apparent steady state which is important for polymeric systems. The results are compared with adsorption isotherms from dialysis equilibrium. The surface tension data, show that the presence of kappa-carrageenan in the amphiphile solutions leads to an increased and pronounced lowering of the surface tension in a low concentration range of amphiphile. It is also shown that not only the hydrophobicity of the amphiphile but also the structure of the polyelectrolyte (charge density and helix-coil structure) largely determine the extent of interaction.

Temperature and salt optimization of kappa-carrageenan fractionation by DEAE-cellulose.

Carrageenans play an important role in many medical and food technology applications. However, the study of their properties has been hampered by a lack of well-defined samples (fractions). In this paper, a new principle is presented by which well-defined fractions can be obtained. It is based on batch adsorption to DEAE-cellulose combined with careful control of temperature and salt content. The parameters have been pre-optimized in an analytical column.

Changes in the polyelectrolyte-amphiphile interaction due to helix-coil transition induced by specific counterions or variations in temperature.

For the system kappa-carrageenan/amitriptyline it is shown that the degree of binding of amitriptyline is closely related to the carrageenan conformation as regulated by the counterions (Na+ or K+). The adsorption becomes much more pronounced when the carrageenan molecule is in the helix form (counterion K+) than when it has a coil conformation (counterion Na+). Furthermore, for the helical state the adsorption becomes strongly cooperative. It is also shown experimentally that the release from the adsorbed state has a conversion temperature at about 42 degrees C (helix-coil transition). The effect is also related to the linear charge density. For iota-carrageenan with a higher charge density the adsorption is strong and cooperative both in the presence of Na+ and K+ ions.

The effect of hydrophobic character of drugs and helix-coil transition of kappa-carrageenan on the polyelectrolyte-drug interaction.

PURPOSE: The extent of adsorption of different drug molecules to kappa-carrageenan was investigated in order to evaluate the effect of drug hydrophobicity on the adsorption isotherm. METHOD: Dialysis experiments were used to determine the amount of drug adsorbed to the polyelectrolyte. The amount of drug on both sides of the membrane was determined spectrophotometrically after attaining equilibrium. CMC for the drugs were determined by the dye solubilisation method. RESULTS: It is shown that the small differences in structure between the drug molecules used in this study still leads to considerable difference in adsorption properties, especially the onset of adsorption. It was also found that the slope of the adsorption isotherms among the drug molecules followed the same pattern as the CMC values for drugs. The extent of adsorption of drugs to the helix from of kappa-carrageenan was much higher than to the coil form. CONCLUSIONS: These results suggest that the adsorption of charged drug molecules to an oppositely charged polymer is effected not only by the coulombic interactions, but also by the hydrophobicity of the drug. Furthermore, the adsorption of drug molecules to kappa-carrageenan in the helix form is higher than for the coil form because of the shorter distance between the charges and the thereby enhanced hydrophobic interaction between bound drug molecules.

Thermodynamics of kappa-Carrageenan-Amphiphilic Drug Interaction as Influenced by Specific Counterions and Temperature: A Microcalorimetric and Viscometric Study.

The adsorption of amphiphilic drug molecules to a polyelectrolyte, kappa-carrageenan, has been shown to be related to hydrophobicity of drug and the conformation of the polyanion which in turn can be regulated by choice of counterion. The binding is of a strongly cooperative nature and the degree of cooperativity has been found to be related to the self-aggregation tendency of the drug molecules. This system has been examined by titration microcalorimetry and capillary viscometry to determine the thermodynamics of the binding phenomenon. The titration calorimetry data confirms the trends and conclusions drawn regarding the factors that control the binding. Viscometry shows that although there is a change in size of the polymeric chains when the drug molecules are adsorbed, the effect is primarily due to charge neutralization and not a conformation change. This allows the microcalorimetry data to be analyzed to recover the enthalpy of binding of the drug molecules to the polymer. Earlier published equilibrium binding data has been analyzed to determine the binding constants and free energy changes in the process (-25 to -90 kJ/mol). A phenomenological model has been derived for the cooperative binding process for this purpose. The binding process is primarily enthalpy driven with the major part of enthalpy change (-10 to -40 kJ/mol) arising from the aggregation of bound drug molecules, i.e., from hydrophobic interactions; the process is also entropically favorable. The size of these aggregates in polymer-bound state is of the order of 2-5 molecules of drug, similar to the pre-micellar aggregates of the drugs in solution. Copyright 1998 Academic Press.