Preactivated thiolated poly(methacrylic acid-co-ethyl acrylate): synthesis and evaluation of mucoadhesive potential.

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (2014-07-16)
Sabine Hauptstein, Sonja Bonengel, Julia Rohrer, Andreas Bernkop-Schnürch
RESUMEN

The study was aimed to developed and investigate a novel polymer for intestinal drug delivery with improved mucoadhesive properties. Therefore Eudragit® L 100-55 (poly(methacrylic acid-co-ethyl acrylate)) was thiolated by covalent attachment of L-cysteine. The immobilized thiol groups were preactivated by disulfide bond formation with 2-mercaptonicotinic acid. Resulting derivative (Eu-S-MNA) was investigated in terms of mucoadhesion via three different methods: tensile studies, rotating cylinder studies and rheological synergism method, as well as water-uptake capacity and cytotoxicity. Different derivatives were obtained with increasing amount of bound L-cysteine (60, 140 and 266 μmol/g polymer) and degree of preactivation (33, 45 and 51 μmol/g polymer). Tensile studies revealed a 30.5-, 35.3- and 52.2-fold rise of total work of adhesion for the preactivated polymers compared to the unmodified Eudragit. The adhesion time on the rotating cylinder was prolonged up to 17-fold in case of thiolated polymer and up to 34-fold prolonged in case of the preactivated polymer. Rheological synergism revealed remarkable interaction of all investigated modified derivatives with mucus. Further, water-uptake studies showed an over 7h continuing weight gain for the modified polymers whereat disintegration took place for the unmodified polymer within the first hour. Cell viability studies revealed no impact of modification. Accordingly, the novel preactivated thiolated Eudragit-derivative seems to be a promising excipient for intestinal drug delivery.

MATERIALES
Referencia del producto
Marca
Descripción del producto

Sigma-Aldrich
Hydrogen peroxide solution, 30 % (w/w) in H2O, contains stabilizer
Sigma-Aldrich
L-Glutathione reduced, ≥98.0%
Sigma-Aldrich
Hydrogen peroxide solution, contains inhibitor, 30 wt. % in H2O, ACS reagent
Sigma-Aldrich
Sodium chloride, BioXtra, ≥99.5% (AT)
Sigma-Aldrich
Sodium borohydride, powder, ≥98.0%
Sigma-Aldrich
Sodium chloride, for molecular biology, DNase, RNase, and protease, none detected, ≥99% (titration)
Sigma-Aldrich
Sodium phosphate monobasic, ReagentPlus®, ≥99.0%
Sigma-Aldrich
N-Hydroxysuccinimide, 98%
Sigma-Aldrich
5,5′-Dithiobis(2-nitrobenzoic acid), ≥98%, BioReagent, suitable for determination of sulfhydryl groups
Sigma-Aldrich
Sodium phosphate dibasic, ACS reagent, ≥99.0%
Sigma-Aldrich
Sodium chloride, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for plant cell culture, ≥99%
Sigma-Aldrich
Sodium chloride solution, 0.9% in water, BioXtra, suitable for cell culture
Sigma-Aldrich
Sodium borohydride, ReagentPlus®, 99%
Sigma-Aldrich
Sodium chloride solution, 5 M in H2O, BioReagent, for molecular biology, suitable for cell culture
Sigma-Aldrich
Sodium phosphate dibasic, ReagentPlus®, ≥99.0%
Sigma-Aldrich
Hydrogen peroxide solution, 50 wt. % in H2O, stabilized
Millipore
Hydrogen peroxide solution, 3%, suitable for microbiology
Supelco
Hydrogen peroxide solution, ≥30%, for trace analysis
Sigma-Aldrich
Sodium chloride solution, 5 M
Sigma-Aldrich
Sodium phosphate dibasic, BioXtra, ≥99.0%
SAFC
Sodium chloride solution, 5 M
Sigma-Aldrich
L-Glutathione reduced, suitable for cell culture, BioReagent, ≥98.0%, powder
Sigma-Aldrich
Sodium phosphate monobasic, BioReagent, for molecular biology, anhydrous, ≥98%
Sigma-Aldrich
Sodium phosphate dibasic, BioReagent, suitable for cell culture, suitable for insect cell culture, ≥99.0%
Sigma-Aldrich
Sodium phosphate dibasic, puriss. p.a., ACS reagent, anhydrous, ≥99.0% (T)
Sigma-Aldrich
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide, ≥97.0% (T)
Sigma-Aldrich
Sodium phosphate dibasic, for molecular biology, ≥98.5% (titration)
Sigma-Aldrich
Sodium chloride, meets analytical specification of Ph. Eur., BP, USP, 99.0-100.5%
Supelco
Phosphate Standard for IC, TraceCERT®, 1000 mg/L phosphate in water
Sigma-Aldrich
5,5′-Dithiobis(2-nitrobenzoic acid), ReagentPlus®, 99%