Data di Pubblicazione:
2013
Citazione:
In vitro Evaluation of a Multiple-Unit Formulation for Oral Colonic Release of Insulin / M.D. Del Curto, A. Maroni, E. Macchi, G. Loreti, L. Palugan, M. Cerea, A. Gazzaniga - In: Proceedings of the 2013 CRS Annual Meeting and Exposition[s.l] : CRS (Controlled Release Society), 2013 Jul. (( Intervento presentato al 40. convegno Annual Meeting & Exposition of the Controlled Release Society tenutosi a Honolulu nel 2013.
Abstract:
SUMMARY
A multiple-unit formulation for time-dependent colonic release of insulin was prepared and evaluated. Minitablet cores containing the protein drug along with a permeation enhancer, sodium glycocholate, in a 1:10 ratio were in turn spray-coated with i) Methocel®E50, ii) blended Eudragit®NE / Explotab®V17 (5:1 as solids) and iii) Aqoat®AS, in order to obtain, respectively, a swellable/erodible layer, a flexible and moderately permeable coat able to slow down water penetration into the underlying functional layer and an enteric film intended to overcome the issue of variable gastric residence. As shown by release testing, the pursued performance was obtained in vitro. Indeed, no drug liberation took place in the acid stage, and a complete release of both compounds occurred, after consistent delay phases, in phosphate buffer. Three-month storage at 4°C did not result in significant changes in the release profiles.
INTRODUCTION
Oral colon delivery is under extensive investigation as a possible strategy to improve the oral bioavailability of peptide and protein drugs. Although the large bowel fails to be ideally suited for absorption, it may indeed offer a number of advantages over the small intestine, including a long transit time, lower levels of peptidases and a higher responsiveness to permeation enhancers [1,2]. A swellable/erodible delivery platform (Chronotopic™) based on a low-viscosity hydroxypropyl methylcellulose (HPMC) coating, which was demonstrated to provide the desired in vitro and in vivo release behaviour when conveying small molecules, was accordingly proposed for colonic release of insulin and selected adjuvants, such as protease inhibitor and absorption enhancer compounds [3-6]. For this purpose, the influence of all the involved manufacturing steps on the protein integrity was explored, thereby ruling out the occurrence of any significant degradation during the preparation of the delivery system. More recently, the design of the Chronotopic™ device, originally presented in single-unit configurations, was modified to comply with the size requirements of multiple-unit dosage forms in view of the relevant benefits in terms of consistent gastrointestinal transit and drug absorption patterns [7]. In particular, an insoluble, flexible film composed of the neutral polymethacrylate Eudragit®NE and the superdisintegrant sodium starch glycolate, added to act as a pore former, was applied to HPMC-coated minitablet cores in order to improve the efficiency of the hydrophilic layer in delaying the drug liberation without altering the typical release-controlling performance [8,9]. Such two-layer formulations were shown to give rise to a prompt in vitro release after lag phases of programmable duration and to the pursued in vivo behaviour. Moreover, they were proved physically stable while stored under ambient conditions for 3.5 years.
On the basis of these premises, the aim of the present work was to evaluate the above-described two-layer multiple-unit system as a possible colon delivery carrier for bovine insulin and the permeation enhancer sodium glycocholate.
EXPERIMENTAL METHODS
Materials: bovine insulin (Sigma-Aldrich, US-MO); copovidone (Kollidon®VA64, BASF, G); HPMC (Methocel®E50, Colorcon, I); hydroxypropyl methylcellulose acetate succinate (HPMCAS, Aqoat®AS-LG, Shin-Etsu, Tokio, J, a gift from Seppic Italia, I); magnesium stearate (Carlo Erba Reagenti, I); microcrystalline cellulose (Avicel®PH200, FMC Europe, B); poly(ethylacrylate, methylmethacrylate) aqueous dispersion (Eudragit®NE30D, Evonik Röhm, G, a gift from Rofarma, I); polyethylene glycol (PEG 400, ACEF, I); sodium glycocholate (NaGly, Sigma-Aldrich, US-MO); sodium starch glycolate (Explotab® and Explotab® V17, Mendell, UK
Tipologia IRIS:
03 - Contributo in volume
Elenco autori:
M.D. Del Curto, A. Maroni, E. Macchi, G. Loreti, L. Palugan, M. Cerea, A. Gazzaniga
Link alla scheda completa:
Titolo del libro:
Proceedings of the 2013 CRS Annual Meeting and Exposition