Comparison of pH and motility of the small intestine of healthy subjects and patients with symptomatic constipation using the wireless motility capsule.

Gastrointestinal luminal pH shows a rise from the duodenum to the terminal ileum in healthy individuals. Our objectives were to compare the pH in the proximal small intestine (SI) (first 60 min of small intestinal transit) lumen of human volunteers and patients with symptomatic constipation; to quantify contractile pressure profiles of the proximal SI, and to assess the relationship between luminally-recorded contractile pressure and small intestinal transit times (SITT) of a non-disintegrating capsule that measures pH and pressure activity (wireless motility capsule). We used previously acquired records from 39 healthy subjects and 41 patients with symptomatic constipation. Mean pH (±SD) of the proximal SI was similar in healthy subjects and patients with constipation at 6.2 (±0.6) and 6.3 (±0.4), respectively. In 13 of the healthy subjects, pH did not rise uniformly in the proximal SI though the pHmedian was 6.0 (5th, 95th percentiles 3.09, 7.06) and the pH fluctuated over a mean period of 28 min. Large inter-individual variability in frequency of pressure activity (Ct) and area under pressure curve (AUC) were observed in the proximal SI of healthy subjects and patients with constipation. Median AUC was 3996 mmHg s-1 (5th, 95th percentiles 948, 16866 mmHg s-1) in these two populations combined. Ct and AUC showed a strong direct linear correlation at r = 0.91, p < 1 × 10-6. An inverse correlation (suggesting longer SITT with lower pressure activity) was observed between Ct/AUC and SITT in both healthy subjects and patients with symptomatic constipation. The pooled results for both groups showed: AUC and SITT correlation at r = -0.49, p < 1 × 10-6. We concluded that both the frequency and amplitude of contractions in the proximal SI are important for the propagation of non-disintegrating capsules. The observed pH fluctuations in the proximal SI may impact supersaturation and precipitation of weakly basic drugs.

Effect of surfactants, gastric emptying, and dosage form on supersaturation of dipyridamole in an in vitro model simulating the stomach and duodenum.

The purpose of this study was to investigate the influence of gastric emptying patterns, surfactants, and dosage form on the supersaturation of a poorly soluble weakly basic drug, dipyridamole, using an in vitro model mimicking the dynamic environment of the upper gastrointestinal tract, and, furthermore, to evaluate the usefulness of this model in establishing correlations to in vivo bioavailability for drugs with solubility/dissolution limited absorption. A simulated stomach duodenum model comprising four compartments was used to assess supersaturation and precipitation kinetics as a function of time. It integrates physiologically relevant fluid volumes, fluid transfer rates, and pH changes of the upper GI tract. Monoexponential gastric emptying patterns simulating the fasted state were compared to linear gastric emptying patterns simulating the fed state. The effect of different surfactants commonly used in oral preparations, specifically, sodium lauryl sulfate (SLS), poloxamer-188, and polysorbate-80, on dipyridamole supersaturation was investigated while maintaining surface tension of the simulated gastric fluids at physiological levels and without obtaining artificial micellar solubilization of the drug. The supersaturation behavior of different dose strengths of dipyridamole was explored. Significant levels of dipyridamole supersaturation were observed in the duodenal compartment under all the different in vivo relevant conditions explored. Dipyridamole supersaturation ratios of up to 11-fold have been observed, and supersaturation has been maintained for up to 120 min. Lower duodenal concentrations of dipyridamole were observed under linear gastric emptying patterns compared to mononexponential gastric emptying. The mean duodenal area under concentration-time curves (AUC60min) for the dipyridamole concentration profile in the duodenal compartment is significantly different for all the surfactants explored (P < 0.05). Our investigations with the different surfactants and comparison of dosage form (solution versus suspension) on the precipitation of dipyridamole revealed that crystal growth, rather than nucleation, is the rate-limiting step for the precipitation of dipyridamole. A linear dose-response relationship was found for the mean in vitro duodenal area under concentration-time curves (AUC∞) in the dose range of 25 mg to 100 mg (R(2) = 0.886). This is in agreement with the pharmacokinetic data of dipyridamole reported in the literature. The simulated stomach duodenum model can provide a reliable and discriminative screening tool for exploring the effect of different physiological variables or formulations on the supersaturation/precipitation kinetics of weakly basic drugs with solubility limited absorption. The amount of drug in solution in the duodenal compartment of the SSD correlates to bioavailability for the weakly basic drug, dipyridamole, which has solubility limited absorption and undergoes supersaturation/precipitation.

The use of dynamic mechanical analysis (DMA) to evaluate plasticization of acrylic polymer films under simulated gastrointestinal conditions.

PURPOSE: Glass transition temperature (T(g)) measurements of polymers are conventionally conducted in the dry state with little attention to the environment they are designed to work in. Our aim was to develop the novel use of dynamic mechanical analysis (DMA) to measure the T(g) of enteric polymethacrylic acid methylmethacrylate (Eudragit L and S) polymer films formulated with a range of plasticizers in the dry and wet (while immersed in simulated gastric media) states. METHODS: Polymer films were fabricated with and without different plasticizers (triacetin, acetyl triethyl citrate, triethyl citrate, polyethylene glycol, propylene glycol, dibutyl phthalate, dibutyl sebacate). T(g) was measured by a dynamic oscillating force with simultaneous heating at 1 °C/min. This was conducted on films in the dry state and while immersed in 0.1M HCl to simulate the pH environment in the stomach. RESULTS: The T(g) of unplasticized Eudragit L and S films in the dry state was measured to be 150 and 120 °C, respectively. These values were drastically reduced in the wet state to 20 and 71 °C for Eudragit L and S films, respectively. The plasticized films showed similar falls in T(g) in the wet state. The fall in T(g) of Eudragit L films to below body temperature will have far-reaching implications on polymer functionality and drug release. CONCLUSIONS: Immersion DMA provides a robust method for measuring T(g) of polymer films in the wet state. This allows better prediction of polymer behaviour in vivo.

Drug solubility in luminal fluids from different regions of the small and large intestine of humans.

The purpose of this work was to study the solubility of two drugs with different physicochemical properties in luminal fluids obtained from various regions of the human gastrointestinal (GI) tract and to determine the most important luminal parameters influencing their solubility. Jejunal fluids were aspirated from healthy volunteers via an oral intubation tube. Ileal and colonic fluids were obtained from patients undergoing GI surgery. Stoma fluids were also retrieved from patients. pH and buffer capacity of all fluids were determined. Saturation solubility of prednisolone (unionisable) and mesalamine (5-aminosalicylic acid) (zwitterionic) was measured. Mean solubility of prednisolone in the different luminal fluids was 0.50 mg/mL (±0.05) and did not vary significantly between the different regions of the GI tract (ANOVA, p > 0.05). No correlation between prednisolone solubility and jejunal bile salt content was found. Mesalamine solubility increased down the GI tract: 1.97 (±0.25), 3.26 (±0.08), 6.24 (±1.13) and 7.95 (±0.21) mg/mL in jejunal, ileal, ascending and transverse/descending colonic fluids respectively. Buffer capacity also increased and in one patient was observed to range from 6.4 to 28.6 reaching 44.4 mM/L/pH unit in ileal, ascending and transverse/descending colon fluids respectively. Mesalamine solubility was found to be dependent on both buffer capacity and pH, with buffer capacity being the most important (standardized coefficient ß = 0.849, p < 0.0001) compared to pH (ß = 0.219, p < 0.05). For drugs delivered as modified release formulations it is important to consider solubility in different regions of the GI tract as significant differences can arise which will ultimately influence drug bioavailability.