title: Thiolated chitosan: development and in vitro evaluation of an oral delivery system for acyclovir.
abstract: The aim of the study was to develop a novel oral delivery system for the efflux pump substrate acyclovir (ACY) utilizing thiolated chitosan as excipient which is capable of inhibiting P-glycoprotein (P-gp). Three chitosan-4-thiobutylamidine (Chito-TBA) conjugates with increasing molecular mass (Chito-9.4kDa-TBA, Chito-150kDa-TBA and Chito-600kDa-TBA) were synthesized and permeation studies on rat intestinal mucosa and Caco-2 monolayers were performed. Additionally, tablets comprising the conjugates and ACY were tested towards their drug release behaviour. The efflux ratio (secretory P(app)/absorptive P(app)) of ACY across Caco-2 monolayers was determined to be 2.5 and in presence of 100microM verapamil 1.1 which indicates ACY as P-gp substrate. In comparison to buffer only, the transport of ACY in presence of 0.5% (m/v) unmodified chitosan, 0.5% (m/v) Chito-150kDa-TBA and 0.5% (m/v) Chito-150kDa-TBA with 0.5% (m/v) reduced glutathione (GSH), was 1.3-, 1.6- and 2.1-fold improved, respectively. Transport studies across Caco-2 monolayers showed that P-gp inhibition is dependent on the average molecular mass of thiolated chitosan showing following rank order: 0.5% (m/v) Chito-150kDa-TBA/GSH>0.5% (m/v) Chito-9.4kDa-TBA/GSH>0.5% (m/v) Chito-600kDa-TBA/GSH. The higher the molecular mass of Chito-TBA was, the more sustained was the release of ACY. Chito-150kDa-TBA/GSH might be an appropriate sustained release drug delivery system for ACY, which is able to enhance ACY transport due to efflux pump inhibition.
authors: Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-Universität Innsbruck, Innrain 52, Josef Möller Haus, 6020 Innsbruck, Austria.
authors: Thomas F
authors: TF
authors: Palmberger
authors: Juliane
authors: J
authors: Hombach
authors: Andreas
authors: A
authors: Bernkop-Schnürch
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000212:Acyclovir / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D000277:Adjuvants, Pharmaceutic / Q000138:chemical synthesis / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002686:Chitin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D002927:Cimetidine / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D017097:Electric Impedance; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D011433:Propranolol / Q000378:metabolism; D051381:Rats; D013607:Tablets; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000277:Adjuvants, Pharmaceutic; D013607:Tablets; C493042:chitosan-4-thiobutylamidine; D002686:Chitin; D002927:Cimetidine; D011433:Propranolol; D014700:Verapamil; D005978:Glutathione; D000212:Acyclovir