Can thiolation render a low molecular weight polymer of just 20-kDa mucoadhesive?

The objective was to investigate whether even low-molecular weight polymers (LMWPs) can be rendered mucoadhesive due to thiolation. Interceded by the double catalytic system carbodiimide/N-hydroxysuccinimide, cysteamine was covalently attached to a copolymer, poly(4-styrenesulfonic acid-co-maleic acid) (PSSA-MA) exhibiting a molecular weight of just 20 kDa. Depending on the amount of added N-hydroxysuccinimide and cysteamine, the resulting PSSA-MA-cysteamine (PC) conjugates exhibited increasing degree of thiolation, highest being "PC 2300" exhibiting 2300.16 ± 149.86 µmol thiol groups per gram of polymer (mean ± SD; n = 3). This newly developed thiolated polymer was evaluated regarding mucoadhesive, rheological and drug release properties as well from the toxicological point of view. Swelling behavior in 100 mM phosphate buffer pH 6.8 was improved up to 180-fold. Furthermore, due to thiolation, the mucoadhesive properties of the polymer were 240-fold improved. Rheological measurements of polymer/mucus mixtures confirmed results obtained by mucoadhesion studies. In comparison to unmodified polymer, PC 2300 showed 2.3-, 2.3- and 2.4-fold increase in dynamic viscosity, elastic modulus and viscous modulus, respectively. Sustained release of the model drug codeine HCl out of the thiomer was provided for 2.5 h (p < 0.05), whereas the drug was immediately released from the unmodified polymer. Moreover, the thiomer was found non-toxic over Caco-2 cells for a period of 6- and 24-h exposure. Findings of the present study provide evidence that due to thiolation LMWPs can be rendered highly mucoadhesive as well as cohesive and that a controlled drug release out of such polymers can be provided.

Chemical modification of hyaluronic acid for intraoral application.

This study was aimed to investigate chemical preactivated thiomers for their potential use in mucosal drug delivery. Thiomers--thiolated polymers--are mucoadhesive polymers with sulfhydryl group-bearing side chains. Thiomers are synthesized by covalent attachment of low molecular mass compounds bearing sulfhydryl group to the polymeric backbone of well-established polymers. Hyaluronic acid-cysteine ethyl ester-mercaptonicotinamide conjugates (HA-CYS-MNA) were synthesized by the oxidative S-S coupling of HA-CYS with 6-MNA. Conjugates were compressed into test discs to investigate cohesive properties, cytotoxicity assays, and mucoadhesion studies. Because of the immobilization of MNA, the HA-CYS-MNA conjugates exhibit comparatively higher swelling properties and cohesive properties corresponding unmodified HA. On the rotating cylinder, discs based on HA-CYS-MNA conjugates displayed fourfold improved mucoadhesion time compared with thiolated polymers. Tensile study results were found in good agreement with rotating cylinder results. Moreover, preactivated thiomers showed higher stability. All polymers were found nontoxic over Caco-2 cells. On the basis of achieved results, the preactivated thiomeric therapeutic agent seems to represent a promising generation of mucoadhesive polymers that are safe to use for a prolonged residence time to target the mucosa requested for intraoral application.

Suitability of Gelucire 50/13 for controlled release formulation of salbutamol sulphate.

Gelucire 50/13 (G50/13) was assessed to develop controlled release formulation of salbutamol sulphate (SBL) a highly water soluble drug by semisolid matrix filling capsule technique. Drug release profiles of SBL release by using G50/13 and its blends with other hydrophilic or hydrophobic materials were investigated. Lipid matrix formulations prepared with increasing amount of polymer showed a substantial decrease in release rate of the drug while increasing drug amount in fixed polymer concentration did not significantly affect the release profile. Polyethylene glycol 6000 caused an increased water uptake resulting in fast erosion of the matrix whereas cetostearyl alcohol and stearic acid caused retardation in drug release. These findings confirm that a considerable amount of Gelucire is required alone or in combination with hydrophobic substances in order to sustain the release profiles of water soluble drugs. More linear profile was obtained by using matrix comprising Gelucire/stearic acid blend in more than 85% that was comparable to standard, Ventolin SR tablet. The test formulation showed a significant decrease at pH 1.0 and the drug release rate increased at high stirring speed. Moreover, short term stability of controlled release test formulation indicated slight increase in dissolution rate at high temperature.