title: Oral delivery system for two-pulse colonic release of protein drugs and protease inhibitor/absorption enhancer compounds.
abstract: It is well known that the intestinal stability and absorption of protein drugs are improved when enzyme inhibitors/permeation enhancers are coadministered. Recently, it was hypothesized that an increased effectiveness of these adjuvants might be achieved by timing their release prior to that of the protein, so that a more favorable environment would be established in advance. Therefore, an oral system was proposed for two-pulse colonic release of insulin and the protease inhibitor camostat mesilate/absorption enhancer sodium glycocholate. The device consisted of a drug-containing core, an inner swellable/erodible low-viscosity hydroxypropyl methylcellulose (HPMC) coating, an intermediate adjuvant layer, and an additional outer HPMC coating. HPMC coats and camostat mesilate/sodium glycocholate films with differing thicknesses were applied to immediate-release tablet cores by aqueous spray coating. The obtained units were characterized for weight, thickness, breaking force, and release performance. All systems showed satisfactory technological properties and the pursued pulsatile delivery behavior, with programmable delay phases preceding inhibitor/enhancer release and elapsing between inhibitor/enhancer and protein release, respectively. Indeed, both lag times linearly correlated with the relevant HPMC coating level. The system was thus proven suitable for yielding two-pulse release profiles, in which lag phases could be modulated to provide convenient concentration patterns for proteins and adjuvants.
authors.affiliation: Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche "P. Pratesi", 20133 Milan, Italy.
authors.forename: Maria Dorly
authors.initials: MD
authors.lastname: Del Curto
authors.affiliation: Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche "P. Pratesi", 20133 Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Maroni
authors.affiliation: Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche "P. Pratesi", 20133 Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Palugan
authors.affiliation: Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche "P. Pratesi", 20133 Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Zema
authors.affiliation: Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche "P. Pratesi", 20133 Milan, Italy. Electronic address: andrea.gazzaniga@unimi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gazzaniga
authors.affiliation: Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche "P. Pratesi", 20133 Milan, Italy.
authors.forename: Maria Edvige
authors.initials: ME
authors.lastname: Sangalli
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002417:Cattle; D003106:Colon / Q000201:enzymology* / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D004339:Drug Compounding; D016503:Drug Delivery Systems; D004355:Drug Stability; D004952:Esters; D016670:Gabexate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006000:Glycocholic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D065347:Hypromellose Derivatives; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D007408:Intestinal Absorption / Q000187:drug effects*; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013499:Surface Properties; D013608:Tablets, Enteric-Coated; D014783:Viscosity
chemical_list: D004337:Drug Carriers; D004952:Esters; D006146:Guanidines; D007004:Hypoglycemic Agents; D007328:Insulin; D011480:Protease Inhibitors; D013608:Tablets, Enteric-Coated; C034532:camostat; D065347:Hypromellose Derivatives; D016670:Gabexate; D008747:Methylcellulose; D006000:Glycocholic Acid