title: Preactivated thiomers: evaluation of gastroretentive minitablets.
abstract: 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.
authors.affiliation: Center for Chemistry and Biomedicine, Center for Molecular Biosciences (CMBI), Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hauptstein
authors.forename: Christiane
authors.initials: C
authors.lastname: Müller
authors.forename: Sarah
authors.initials: S
authors.lastname: Dünnhaupt
authors.forename: Flavia
authors.initials: F
authors.lastname: Laffleur
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003545:Cysteine / Q000737:chemistry* / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009539:Nicotinic Acids / Q000737:chemistry* / Q000494:pharmacology; D010368:Pectins / Q000737:chemistry* / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000494:pharmacology; D013552:Swine; D013607:Tablets
chemical_list: D003692:Delayed-Action Preparations; D005765:Gastrointestinal Agents; D009539:Nicotinic Acids; D013438:Sulfhydryl Compounds; D013607:Tablets; D010368:Pectins; C083470:2-mercaptonicotinic acid; D003545:Cysteine
keywords: 2-Mercaptonicotinic acid (CID 673681); Gastric; Mucoadhesive drug delivery system; Pectin (CID 441476); Preactivated thiomers; Rosuvastatin; Swellable polymer