title: In vitro and in vivo evaluation of an oral multiple-unit formulation for colonic delivery of insulin.
abstract: A multiple-unit formulation for time-dependent colonic release of insulin was obtained by coating insulin and sodium glycocholate immediate-release minitablets with: (i) Methocel® E50, a low-viscosity hydroxypropyl methylcellulose (inner coating), (ii) 5:1 w/w Eudragit® NE/Explotab® V17, a mixture of a neutral polymethacrylate with a pore-forming superdisintegrant (intermediate coating), and (iii) Aqoat® AS, enteric-soluble hydroxypropyl methylcellulose acetate succinate (outer coating). Sodium glycocholate was added as a permeation enhancer while the inner, intermediate and outer coatings were aimed, respectively, at delaying the onset of release through swelling/erosion processes, extending the duration of the lag phase by slowing down water penetration into the underlying functional layer, and overcoming variable gastric residence time. In vitro studies showed that neither insulin nor sodium glycocholate were released from the three-layer system during 2h of testing in 0.1N HCl, while complete release of the protein and of the enhancer occurred in phosphate buffer, pH 6.8, after consistent lag phases. No significant changes were noticed in the release profiles following twelve-month storage at 4°C. Oral administration of the novel formulation to diabetic rats elicited a peak in the plasma insulin concentration after 6h, which was associated with a sharp decrease in the glycemic levels. The relative bioavailability and pharmacological availability of such a formulation, as determined vs. the uncoated tablets, were 2.2 and 10.3, respectively. Based on these results, the three-layer system presented was considered a potentially interesting tool for oral colonic delivery of insulin and adjuvant compounds.
authors: Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche, Sezione di Tecnologia e Legislazione Farmaceutiche "M.E. Sangalli", Via G. Colombo 71, 20133 Milano, Italy.
authors: Alessandra
authors: A
authors: Maroni
authors: Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche, Sezione di Tecnologia e Legislazione Farmaceutiche "M.E. Sangalli", Via G. Colombo 71, 20133 Milano, Italy.
authors: Maria Dorly
authors: MD
authors: Del Curto
authors: Università degli Studi di Padova, Dipartimento di Scienze del Farmaco, Via F. Marzolo 5, 35131 Padova, Italy.
authors: Stefano
authors: S
authors: Salmaso
authors: Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche, Sezione di Tecnologia e Legislazione Farmaceutiche "M.E. Sangalli", Via G. Colombo 71, 20133 Milano, Italy.
authors: Lucia
authors: L
authors: Zema
authors: Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche, Sezione di Tecnologia e Legislazione Farmaceutiche "M.E. Sangalli", Via G. Colombo 71, 20133 Milano, Italy.
authors: Alice
authors: A
authors: Melocchi
authors: Università degli Studi di Padova, Dipartimento di Scienze del Farmaco, Via F. Marzolo 5, 35131 Padova, Italy.
authors: Paolo
authors: P
authors: Caliceti
authors: Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche, Sezione di Tecnologia e Legislazione Farmaceutiche "M.E. Sangalli", Via G. Colombo 71, 20133 Milano, Italy. Electronic address: andrea.gazzaniga@unimi.it.
authors: Andrea
authors: A
authors: Gazzaniga
mesh_terms: D000277:Adjuvants, Pharmaceutic; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000737:chemistry; D002021:Buffers; D002417:Cattle; D003106:Colon / Q000187:drug effects*; D003692:Delayed-Action Preparations / Q000737:chemistry*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D006000:Glycocholic Acid / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000008:administration & dosage*; D008297:Male; D008747:Methylcellulose / Q000737:chemistry*; D008855:Microscopy, Electron, Scanning; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000737:chemistry; D013607:Tablets; D013696:Temperature; D014783:Viscosity
chemical_list: D000277:Adjuvants, Pharmaceutic; D001786:Blood Glucose; D002021:Buffers; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007328:Insulin; D013607:Tablets; D008747:Methylcellulose; D012964:Sodium; D006000:Glycocholic Acid
keywords: Colon delivery; Insulin; Oral drug delivery; Oral peptide delivery; Pulsatile release; Swellable/erodible coating