A multiple-unit delivery system for time-based colonic release of insulin and an absorption enhancer

Purpose: To prepare and evaluate in vitro a multiple-unit erodible delivery system for time-based colonic release of insulin and the absorption enhancer sodium glycocholate (NaGly). Methods: Biconvex minitablets (2.5 mm) containing bovine insulin and NaGly (1:10) were manufactured by a rotary tableting machine and successively spray-coated with an aqueous solution of low-viscosity hydroxypropyl methylcellulose (Methocel®E50), an aqueous dispersion composed of Eudragit®NE30D and Explotab®V17 (5:1 as solids) and, lastly, a hydro-alcoholic solution of hydroxypropyl methylcellulose acetate succinate (Aqoat®AS). The release performance of the resulting system was evaluated by a disintegration apparatus under the following conditions: 2h in HCl 0.1M, 4h in phosphate buffer pH 6.8. The test was repeated throughout three-month storage at 4°C to preliminarily assess the physical stability of the formulation. Results: The delivery system prepared was a three-layer multiple-unit formulation. While the innermost Methocel®E50 coating was responsible for a programmable delay prior to the release of insulin and NaGly, the Eudragit®NE/Explotab®V17 interlayer was expected to slow down the penetration of water into the underlying coat thereby prolonging the duration of the delay phase. On the other hand, the external Aqoat®AS film was intended to protect the system during gastric residence thus overcoming the issue of the relevant variability and allowing colon delivery to be achieved according to the time-based strategy. The final formulation exhibited adequate gastroresistance properties during the acid stage of the test. In pH 6.8 phosphate buffer, a concurrent pulsatile release of insulin and NaGly was obtained. The duration of the lag phase before release of the protein, expressed as the time to 10% release (t10%), was not statistically different from that observed with a non-gastroresistant reference system (p>0.05). These findings implied that the enteric coating process would not impact on the functional characteristics of the inner coatings. Furthermore, t10% relevant to both the protein and the absorption enhancer was not altered after three-month storage at 4°C. Conclusion: The results obtained indicate that the proposed system could serve as a colon delivery carrier of insulin along with the absorption enhancer NaGly and would be worth undergoing in vivo testing.