Release mechanism of doxazosin from carrageenan matrix tablets: Effect of ionic strength and addition of sodium dodecyl sulphate.

The polyelectrolyte matrix tablets loaded with an oppositely charged drug exhibit complex drug-release mechanisms. In this study, the release mechanism of a cationic drug doxazosin mesylate (DM) from matrix tablets based on an anionic polyelectrolyte λ-carrageenan (λ-CARR) is investigated. The drug release rates from λ-CARR matrices are correlated with binding results based on potentiometric measurements using the DM ion-sensitive membrane electrode and with molecular characteristics of the DM-λ-CARR-complex particles through hydrodynamic size measurements. Experiments are performed in solutions with different ionic strength and with the addition of an anionic surfactant sodium dodecyl sulphate (SDS). It is demonstrated that in addition to swelling and erosion of tablets, the release rates depend strongly on cooperative interactions between DM and λ-CARR. Addition of SDS at concentrations below its critical micelle concentration (CMC) slows down the DM release through hydrophobic binding of SDS to the DM-λ-CARR complex. On the contrary, at concentrations above the CMC SDS pulls DM from the complex by forming mixed micelles with it and thus accelerates the release. Results involving SDS show that the concentration of surfactants that are naturally present in gastrointestinal environment may have a great impact on the drug release process.

Doxazosin-carrageenan interactions: a novel approach for studying drug-polymer interactions and relation to controlled drug release.

When a cationic drug like doxazosin mesylate (DM) is incorporated into matrix tablets made of anionic polyelectrolytes carrageenans (CARRs) of different types (κ-, ι-, λ-CARR), DM-CARR interactions have a strong impact on drug release. To investigate these interactions, special DM ion-selective membrane electrode was made and applied for construction of binding isotherms. Isotherms were treated by the Zimm-Bragg theory and cooperative binding model. It was demonstrated that binding of doxazosin cations, DH(+), to CARRs is cooperative. It starts at very low drug concentrations with strong electrostatic interactions followed by aggregation of DH(+) ions. Hydrophobic interactions between bound DH(+) substantially contribute to the extent of binding. The strength of interactions increases with increasing negative charge of CARRs. At saturation, the number of DM molecules bound per repeat unit depends on the charge and steric distribution of binding sites on CARRs. Drug release rates of DM from CARR matrices were in accordance with the cooperativity binding constants: the weakest binding resulted in the fastest release. However it was proven that prolonged drug release is possible only by several processes running simultaneously, i.e., by swelling and erosion of CARR matrices on one side and electrostatic interactions and cooperativity effects on the other.

Matrix tablets based on carrageenans with dual controlled release of doxazosin mesylate.

The use of polymeric polyelectrolytes as matrix-forming agents is far from optimally or fully understood. Polyelectrolyte carrageenan (CARR) matrices loaded with oppositely charged active substance doxazosin mesylate (DM) were investigated according to their water-uptake/erosion properties, in situ complexation ability of CARR with DM, and the possibility to achieve dual drug release control. Interactions between different CARR types (ι-, κ-, and λ-) and DM were confirmed by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and zeta potential measurements. Combination of water-uptake/erosion with in situ complexation prolonged DM release from CARR matrices for more than 24 h. The rate order of drug release was in accordance with the number of ester sulfate moieties per disaccharide unit of CARRs (κ (1)>ι (2)>λ (3)). The higher the charge on the CARR backbone, the higher the number of interactions with DM and the slower the drug release. Low pH, more vigorous hydrodynamics, and higher ionic strength resulted in faster drug release. Based on zeta potential measurements of DM and CARRs, proposed influence of counterion condensation and its effect on screening polyelectrolyte-drug interactions was confirmed to lower in situ DM-CARR complexation. Dual drug release control from polyelectrolyte matrices by water-uptake/erosion and in situ complexation offers many new approaches for designing controlled-release systems.

Effect of calcium ions on the gelling and drug release characteristics of xanthan matrix tablets.

Xanthan is a well-known biopolymer. It is an anionic polysaccharide, whose primary structure depends on the bacterial strain and fermentation conditions. Xanthan was extensively studied in combination with galactomannans, and over 90 patents cover the technology of this preparation. Our aim was to investigate the relation between the physical properties of a xanthan matrix in the absence or presence of calcium ions and its influence on the release of pentoxifylline. The release of pentoxifylline from xanthan tablets in purified water was shown to be very slow and governed by the process of polymer relaxation. The presence of calcium ions significantly increased the drug release, changing the release mechanism into a more diffusion controlled one. Xanthan matrices showed substantially faster and more extensive swelling in water than in the presence of Ca2+ ions. Surprisingly, negative correlation between drug release and degree of swelling was obtained for xanthan: the higher the swelling, the slower the drug release. Higher ionic strength led to lower erosion of xanthan tablets, and the gel layers formed were more rigid and of firmer texture, as shown by rheological experiments and textural profiling. The results indicate that the presence of Ca2+ ions in the solution or in matrices does not cause crosslinking of xanthan polymers, but causes charge screening of ionized groups on the trisaccharide side chains of xanthan, leading to lower inter-molecular repulsion and changing water arrangement. The understanding of the parameters influencing drug release leads to the conclusion that xanthan is suitable for controlled release formulations, especially with the incorporation of certain small counterions.