title: Degradation of raw or film-incorporated beta-cyclodextrin by enzymes and colonic bacteria.
abstract: beta-cyclodextrin (beta-CD) is a suitable excipient for peroral use, which improves the solubility of lipophilic drugs, as well as for colon-specific drug release when it is mixed with coating polymers. The first aim of this work was to examine the suitability of various enzymes as a simple in vitro model for the glycolytic activity in the human colon. alpha-Amylase (source Aspergillus oryzae) and taka diastase (source A. oryzae) showed remarkable degradation capacity of free beta-CD, whereas other alpha-amylases (sources Bacillus subtilis or Hog pancreas) were found to be unsuitable. The next aim was to find out if film-incorporated beta-CD is also degraded by these enzymes. Therefore, diffusion studies of 5-aminosalicylic acid (5-ASA) through Eudragit RS or Eudragit NE films containing beta-CD were performed with taka diastase present in the buffer medium. Pronounced diffusion of the drug through the Eudragit RS film was found only when swelling excipients like crosslinked sodium carboxymethylcellulose (CMC-CL sodium) or polyvinylpyrrolidone (PVP 25) were present in the film, indicating enhanced accessibility of beta-CD by the enzyme. Films containing CMC-CL without beta-CD showed even higher permeability, which also points to enzymatic degradation of CMC-CL. Permeabilization by taka diastase of Eudragit NE films without swelling agents correlated with the beta-CD content, whereas control films containing talcum remained impermeable upon enzyme action. Furthermore, the beta-CD degradation capacity of colonic bacteria like Escherichia fergusonii, Serratia odorifera or Proteus mirabilis was examined with beta-CD coatings on tablets, which contained bisoprolol as a model drug. Tablets with beta-CD-containing Eudragit RS coatings showed the highest drug release upon incubation with P. mirabilis. The moderate drug release by E. fergusonii could be increased almost to the same level when the bacteria were pre-incubated for 24 h in medium containing 2.5 mg/ml beta-CD, indicating the induction of glycolytic enzymes by beta-CD in this colonic bacteria strain.
authors.affiliation: Merck KGaA, Department of Pharmaceutical Development, Darmstadt, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Fetzner
authors.forename: Stefan
authors.initials: S
authors.lastname: Böhm
authors.forename: Sven
authors.initials: S
authors.lastname: Schreder
authors.forename: Rolf
authors.initials: R
authors.lastname: Schubert
mesh_terms: D000180:Acrylic Resins / Q000378:metabolism; D000818:Animals; D003106:Colon / Q000201:enzymology* / Q000382:microbiology*; D004058:Diffusion; D004337:Drug Carriers / Q000378:metabolism*; D013552:Swine; D047392:beta-Cyclodextrins / Q000378:metabolism*
chemical_list: D000180:Acrylic Resins; D004337:Drug Carriers; D047392:beta-Cyclodextrins; C050528:Eudragit RS; C031215:betadex