The Effect of Biorelevant Hydrodynamic Conditions on Drug Dissolution from Extended-Release Tablets in the Dynamic Colon Model

Abstract

The in vitro release of theophylline from an extended-release dosage form was studied under different hydrodynamic conditions in a United States Pharmacopoeial (USP) dissolution system II and a bespoke in vitro tubular model of the human colon, the Dynamic Colon Model (DCM). Five biorelevant motility patterns extracted from in vivo data were applied to the DCM, mimicking the human proximal colon under baseline conditions and following stimulation using polyethylene glycol or maltose; these represent the lower and upper bounds of motility normally expected in vivo. In the USPII, tablet dissolution was affected by changing hydrodynamic conditions at different agitation speeds of 25, 50 and 100 rpm. Applying different motility patterns in the DCM affected the dissolution profiles produced, with theophylline release at 24 h ranging from 56.74 ± 2.00% (baseline) to 96.74 ± 9.63% (maltose-stimulated). The concentration profiles of theophylline were markedly localized when measured at different segments of the DCM tube, highlighting the importance of a segmented lumen in intestine models and in generating spatial information to support simple temporal dissolution profiles. The results suggested that the shear stresses invoked by the unstimulated, healthy adult human colon may be lower than those in the USPII at 25 rpm and thus insufficient to achieve total release of a therapeutic compound from a hydroxyethyl cellulose matrix. When operated under stimulated conditions, drug release in the DCM was between that achieved at 25 and 50 rpm in the USPII.

Use of In Vitro Dynamic Colon Model (DCM) to Inform a Physiologically Based Biopharmaceutic Model (PBBM) to Predict the In Vivo Performance of a Modified-Release Formulation of Theophylline

“…Figure 3 shows the predictions of theophylline Cp–time profiles after administration of the Uniphyllin Continus ® 200 mg tablet bis in die (b.i.d) for 5 days, with a single dose on day 6 [ 41 ] using the USP II and DCM dissolution profiles as published by O’Farrell et al [ 36 ].…”

“…The simulations also showed that three different motility patterns (baseline, antegrade and retrograde) could explain the level of exposure of theophylline after oral administration of the Uniphyllin Continus ® tablet. However, O’Farrell et al [ 36 ] showed differences in the distribution of theophylline throughout the DCM after applying different motility patterns. The average dissolution profiles resulting from the baseline, antegrade and retrograde waves were similar.…”

“…O’Farrell et al [ 36 ] generated dissolution profiles of the Uniphyllin Continus ® tablet (200 mg) obtained from the USP II filled with 900 mL of pH 7.4 phosphate buffer at 25, 50 and 100 rpm and from the DCM filled with 900 mL of 0.25% ( w / v ) NaCMC solution buffered to pH 7.4, under six different motility patterns [ 36 ]. The authors showed that the formulation is sensitive to agitation speed and hence it was selected as a case study to assess the clinical relevance of the in vitro hydrodynamics of the DCM.…”

“… Average in vitro dissolution profiles of the Uniphyllin Continus ® tablet (200 mg) in the USP II ( a ) and DCM ( b ) and the corresponding predictions ( a’ , b’ ) of the plasma concentration of theophylline after administration of Uniphyllin Continus ® tablet (200 mg) twice daily (b.i.d) for 5 days, with a single dose (SD) on day 6 [ 41 ]. Dissolution testing applied agitation speeds of 25, 50 and 100 rpm were used in the USP II and four motility patterns were used in the DCM, as detailed in O’Farrell et al [ 36 ]. …”

“… Simulated fraction absorbed from regional GI segments after incorporation of the in vitro dissolution profiles of the Uniphyllin Continus ® tablet (200 mg) into the Advanced Dissolution Absorption Metabolism (ADAM) model. Dissolution profiles were obtained using agitation speeds of 25, 50 and 100 rpm in the USP II and four motility patterns in the DCM, as detailed in O’Farrell et al [ 36 ]. …”