pectins and 2-mercaptonicotinic-acid

The aim of this study was to evaluate the potential of preactivated thiolated pectin (Pec-Cys-MNA) for buccal drug delivery. Therefore, a gel formulation containing this novel polymer and the model drug lidocaine was prepared and investigated in vitro in terms of rheology, mucoadhesion, swelling behavior and drug release in comparison to formulations based on pectin (Pec) and thiolated pectin (Pec-Cys). Both pectin derivatives showed gel formation without addition of any other excipient due to self-crosslinking thiol groups. Under same conditions, pectin did not show gel formation. Viscosity of Pec-Cys-based formulation increased 92-fold and viscosity of Pec-Cys-MNA-based formulations by 4958-fold compared to pectin-based formulation. Gels did not dissolve in aqueous environment during several hours and were able to take up water. Mucoadhesion of pectin on buccal tissue could be improved significantly, value of total work of adhesion increased in the following rank order: Pec-Cys-MNA > Pec-Cys > Pec. The retention time of a model drug incorporated in gel formulations on buccal mucosa under continuous rinsing with phosphate-buffered saline was prolonged, after 1.5 h 3-fold higher amount of a model drug was to be found on tissue after application of Pec-Cys-MNA-based formulation compared to pectin-based and 2-fold compared to Pec-Cys-based formulation. The Pec-Cys-MNA-based gel showed a more sustained release of lidocaine than Pec-Cys-based gel, whereas pectin solution revealed an immediate release. According to these results, the self-crosslinking pectin-derivative is a promising tool for buccal application.

Topics: Anesthetics, Local; Animals; Cell Survival; Chemistry, Pharmaceutical; Cysteine; Drug Delivery Systems; Gels; Lidocaine; Mouth Mucosa; Nicotinic Acids; Pectins; Rheology; Sulfhydryl Compounds; Swine

The object of this study was to evaluate the potential of a recently developed preactivated thiolated pectin derivative as mucoadhesive excipient in drug delivery to the gastric cavity. Pectin (Pec) was chemically modified with L-cysteine (Cys). The free thiol groups of resulting thiomer were activated with 2-mercaptonicotinic acid (MNA) in order to improve stability and reactivity of attached thiol groups over a broad pH range. Multiunit dosage form properties of the resulting conjugate (Pec-Cys-MNA) were compared to unmodified pectin and the intermediate thiolated using rosuvastatin calcium as a model drug in loaded minitablets. Obtained results were compared with unmodified pectin and the intermediate thiolated pectin. Approximately half of attached thiol groups (507 μmol/g polymer) have been preactivated. Minitablets were evaluated regarding mucoadhesive properties, hardness, disintegration behavior, swelling characteristics and release of rosuvastatin calcium. Mediated by covalent bonds between the polymer and cysteine-rich subdomains in mucus, total work of adhesion increased more than 5-fold. The modification had no impact on hardness of compressed tablets but implementation of the aromatic ligand went along with reduction in hydrophilic properties. Disintegration time was prolonged more than 2-fold while water uptake capacity increased. Weight gain for Pec-Cys-MNA was at least 16-fold. Further, a sustained release of rosuvastatin calcium over 36 h was determined. Neither biodegradability nor CaCo-2 cell viability was affected. The study shows that Pec-Cys-MNA is a promising excipient for the development of mucoadhesive gastric dosage form.

Topics: Animals; Caco-2 Cells; Cell Survival; Cysteine; Delayed-Action Preparations; Drug Evaluation, Preclinical; Gastric Mucosa; Gastrointestinal Agents; Humans; Nicotinic Acids; Pectins; Sulfhydryl Compounds; Swine; Tablets

The study was aimed to synthesize a thiolated polymer (thiomer) that is resistant to oxidation in solutions above pH 5. In order to protect a pectin-cysteine conjugate against premature oxidation, the thiomer was S-protected by a disulfide connected leaving group. Therefore, 2-mercaptonicotinic acid was first coupled to L-cysteine by a disulfide exchange reaction and the purified product was subsequently attached to pectin by a carbodiimide mediated amid bond formation. The obtained fully S-protected thiolated pectin was in vitro characterized with respect to co- and mucoadhesive properties and stability toward oxidation. The results indicated a 1.8-fold and 2.3-fold enhanced disintegration time at pH 6.8 of the S-protected thiolated pectin (Pec-Cys-MNA) compared to thiolated pectin (Pec-Cys) and unmodified pectin (Pec). Moreover, rheological measurements of polymer/mucus mixtures showed a 1.6-fold (compared to Pec-Cys) and 6.7-fold (compared to Pec) increased dynamic viscosity of Pec-Cys-MNA. On the other hand, in the presence of a strong oxidizing agent such as H2O2 (0.3% v/v), no increase in viscosity of Pec-Cys-MNA could be observed. A 6-month experiment also demonstrated the long-term stability of a liquid formulation based on Pec-Cys-MNA. Further investigations proved that the first time all thiol groups on a thiolated polymer could be protected owing to the novel synthesis. Accordingly, these features may help to develop thiomer based liquid or gel formulations targeting mucosal surfaces such as nasal, ocular or vaginal drug delivery systems.

Topics: Animals; Caco-2 Cells; Chemistry, Pharmaceutical; Cysteine; Disulfides; Drug Delivery Systems; Gels; Humans; Hydrogen Bonding; Hydrogen-Ion Concentration; Ligands; Mucous Membrane; Nicotinic Acids; Oxazines; Oxygen; Pectins; Polymers; Rheology; Sulfhydryl Compounds; Swine; Tablets; Viscosity; Xanthenes