title: Evaluating the Potential for Delivery of Irinotecan via the Buccal Route: Physicochemical Characterization and In Vitro Permeation Assessment Across Porcine Buccal Mucosa.
abstract: Irinotecan (CPT-11) is used to treat advanced colorectal cancer as an intravenous therapy. Depending on pH, CPT-11 exists in either a lactone (active) or carboxylate (inactive) form, or both. In this investigation, the feasibility for systemic delivery of CPT-11 through the buccal route was evaluated. Permeation of CPT-11 across porcine buccal mucosa was studied in vitro using side-by-side flow through diffusion cells at 37°C. Experiments were performed over a pH range from 4 to 9, and the permeability of both the lactone and carboxylate forms of CPT-11 was measured. CPT-11 steady state flux was determined over a range of donor concentrations at pH 4 (0.5, 1, 5, 10, 15, 20 mg/ml) and pH 6.8 (0.5, 5, 10 mg/ml). Steady state flux increased linearly with increasing donor concentration of CPT-11 at pH 4 (r2= 0.9935) and at pH 6.8 (r2= 0.9886). CPT-11 permeability was independent of pH, although the distribution coefficient increased with increasing pH. Estimates of permeability for the lactone and carboxylate forms were 4.16 × 10-5cm/s and 2.6 × 10-5cm/s, respectively. These calculated permeability values were in agreement with the in vitro experimental data. Overall, CPT-11 was found to permeate through porcine buccal mucosa via passive diffusion. CPT-11 permeability was independent of pH, suggesting that the compound was transported mainly via a paracellular route. Overall, the results of this research suggest that the buccal route is a potential extravascular mode of delivery for CPT-11.
authors.affiliation: Division of Pharmaceutical Sciences, Long Island University, Brooklyn, New York, 11201, USA. shahv@oregonstate.edu.|Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University/OHSU, Portland, Oregon, 97201, USA. shahv@oregonstate.edu.|College of Pharmacy, Oregon State University/OHSU, Collaborative Life Science Building, 2730 SW Moody Ave, Portland, Oregon, 97201, USA. shahv@oregonstate.edu.
authors.forename: Vidhi
authors.initials: V
authors.lastname: Shah
authors.affiliation: Division of Pharmaceutical Sciences, Long Island University, Brooklyn, New York, 11201, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Bellantone
authors.affiliation: Division of Pharmaceutical Sciences, Long Island University, Brooklyn, New York, 11201, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Taft
mesh_terms: D000278:Administration, Buccal; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004058:Diffusion; D016503:Drug Delivery Systems / Q000379:methods; D006863:Hydrogen-Ion Concentration; D000077146:Irinotecan; D009061:Mouth Mucosa / Q000378:metabolism*; D010539:Permeability; D013552:Swine
chemical_list: D000077146:Irinotecan; D002166:Camptothecin
keywords: buccal; diffusion; irinotecan; permeation; porcine