Low Buffer Capacity and Alternating Motility along the Human Gastrointestinal Tract: Implications for in Vivo Dissolution and Absorption of Ionizable Drugs

Abstract

In this study, we determined the pH and buffer capacity of human gastrointestinal (GI) fluids (aspirated from the stomach, duodenum, proximal jejunum, and mid/distal jejunum) as a function of time, from 37 healthy subjects after oral administration of an 800 mg immediate-release tablet of ibuprofen (reference listed drug; RLD) under typical prescribed bioequivalence (BE) study protocol conditions in both fasted and fed states (simulated by ingestion of a liquid meal). Simultaneously, motility was continuously monitored using water-perfused manometry. The time to appearance of phase III contractions (i.e., housekeeper wave) was monitored following administration of the ibuprofen tablet. Our results clearly demonstrated the dynamic change in pH as a function of time and, most significantly, the extremely low buffer capacity along the GI tract. The buffer capacity on average was 2.26 μmol/mL/ΔpH in fasted state (range: 0.26 and 6.32 μmol/mL/ΔpH) and 2.66 μmol/mL/ΔpH in fed state (range: 0.78 and 5.98 μmol/mL/ΔpH) throughout the entire upper GI tract (stomach, duodenum, and proximal and mid/distal jejunum). The implication of this very low buffer capacity of the human GI tract is profound for the oral delivery of both acidic and basic active pharmaceutical ingredients (APIs). An in vivo predictive dissolution method would require not only a bicarbonate buffer but also, more significantly, a low buffer capacity of dissolution media to reflect in vivo dissolution conditions.

Application of the Gastrointestinal Simulator (GIS) Coupled with In Silico Modeling to Measure the Impact of Coca-Cola® on the Luminal and Systemic Behavior of Loratadine (BCS Class 2b)

“…The initial gastric conditions demonstrated having a significant impact on the outcome of the drug [36]. Fluctuations in intestinal pH are not uncommon as recently observed in the aspirated fluids of healthy subjects [37]. By applying physiologically-based pharmacokinetic (PBPK) modeling, Fotaki and Klein concluded that a possible increase in systemic exposure of itraconazole is not necessarily related to a dynamic change in GI pH but also caused by other variables (such as, for instance, prolonged gastric residence time) [38].…”

Assembly of lignin-based colloidal particles: effects of cationic surfactants, molecular weight, and solvent on morphology

“…Considering the fact that an oral drug passes from the stomach to the intestine in the human body, LS/CTAB@IBU-3 was rstly incubated in SGF for 2 h and then transferred to SIF for further incubation. [39][40][41] As shown in Fig. 8, only 1.77% IBU was released aer 2 h, while the release of IBU accelerated when LS/ CTAB@IBU-3 was transferred to SIF; subsequently, 75.76% IBU was released aer 24 h, reaching release saturation.…”

Integrating Drug- and Formulation-Related Properties With Gastrointestinal Tract Variability Using a Product-Specific Particle Size Approach: Case Example Ibuprofen

“…18,29 Considering that a strong correlation between ibuprofen plasma and duodenal T max has been observed, it appears that intraluminal pH acidification may slow down ibuprofen dissolution rate when larger doses are applied. 30 Improving the mechanistic understanding about the interplay between GI physiology and oral drug delivery is of paramount importance to anticipate the impact of extrinsic and intrinsic factors on oral drug absorption. Overall, the evidence suggests that GI variability (e.g., gastric emptying time, fluid volume, etc), self-buffering effect, dynamic intraluminal pH, and P-PSD should be taken into account when attempting to establish in vitro to in vivo relevance for drug products containing ionizable compounds such as ibuprofen.…”