The first aim of this study was to evaluate the usefulness of optimized human fecal material in simulating sulforeductase activity in the lower intestine by assessing bacterial degradation of sulindac and sulfinpyrazone, two sulforeductase substrates. The second aim was to evaluate the usefulness of drug degradation half-life generated in simulated colonic bacteria (SCoB) in informing PBPK models. Degradation experiments of sulfinpyrazone and of sulindac in SCoB were performed under anaerobic conditions using recently described methods. For sulfinpyrazone, the abundance of clinical data allowed for construction of a physiologically based pharmacokinetic (PBPK) model and evaluation of luminal degradation clearance determined from SCoB data. For sulindac, the availability of sulindac sulfide and sulindac sulfone standards allowed for evaluating the formation of the main metabolite, sulindac sulfide, during the experiments in SCoB. Both model compounds degraded substantially in SCoB. The PBPK model was able to adequately capture exposure of sulfinpyrazone and its sulfide metabolite in healthy subjects, in ileostomy and/or colectomy subjects, and in healthy subjects pretreated with metoclopramide by implementing degradation half-lives in SCoB to calculate intrinsic colon clearance. Degradation rates of sulindac and formation rates of sulindac sulfide in SCoB were almost identical, in line with in vivo data suggesting the sulindac sulfide is the primary metabolite in the lower intestine. Experiments in SCoB were useful in simulating sulforeductase related bacterial degradation activity in the lower intestine. Degradation half-life calculated from experiments in SCoB is proven useful for informing a predictive PBPK model for sulfinpyrazone.

To develop a model linking in vitro and in vivo erosion of extended release tablets under fasting and postprandial status.A nonlinear mixed-effects model was developed from the in vitro erosion profiles of four hydroxypropyl methylcellulose (HPMC) matrix tablets studied under a range of experimental conditions. The model was used to predict in vivo erosion of the HPMC matrix tablets in different locations of the gastrointestinal tract, determined by magnetic marker monitoring. In each gastrointestinal segment the pH was set to physiological values and mechanical stress was estimated in USP2 apparatus rotation speed equivalent.Erosion was best described by a Michaelis-Menten type model. The maximal HPMC release rate (VMAX) was affected by pH, mechanical stress, HPMC and calcium hydrogen phosphate content. The amount of HPMC left at which the release rate is half of VMAX depended on pH and calcium hydrogen phosphate. Mechanical stress was estimated for stomach (39.5 rpm), proximal (93.3 rpm) and distal (31.1 rpm) small intestine and colon (9.99 rpm).The in silico model accurately predicted the erosion profiles of HPMC matrix tablets under fasting and postprandial status and can be used to facilitate future development of extended release tablets.

Purpose Lesogaberan, a γ-aminobutyric acid (GABA)B receptor agonist, was developed for the treatment of gastroesophageal reflux disease in patients with a partial response to proton pump inhibitor therapy. A high prevalence of paresthesia was observed in healthy individuals after dosing with lesogaberan in early-phase clinical trials. The aim of this review was to gain further insight into paresthesia caused by lesogaberan by summarizing the relevant preclinical and clinical data. Methods This study was a narrative review of the literature and unpublished data. Findings The occurrence of paresthesia may depend on the route or rate of drug administration; several studies were conducted to test this hypothesis, and formulations were developed to minimize the occurrence of paresthesia. Phase I clinical studies showed that, in healthy individuals, paresthesia occurred soon after administration of lesogaberan in a dose-dependent manner regardless of the route of administration. The occurrence of paresthesia could be decreased by fractionating the dose or reducing the rate of administration. These findings suggest that the initial rate of absorption plays an important part in the development of paresthesia. Modified-release formulations minimize the occurrence of paresthesia while retaining the anti-reflux activity of the drug, as measured by esophageal pH and the number of transient lower esophageal sphincter relaxations. Implications The development of lesogaberan was halted because the effect on gastroesophageal reflux disease symptoms observed in Phase II studies was not considered clinically meaningful in the target patient population. Nevertheless, it is an example of successful formulation development designed to minimize the occurrence of a compound’s adverse effect while retaining its pharmacodynamic action.

A clinical study was conducted to validate the in vivo drug release performance of IntelliCap® CR capsules. 12 healthy, male volunteers were administered IntelliCap® CR capsules, filled with metoprolol as a BCS 1 model drug, and programmed to release the drug with 3 different release profiles (2 linear profiles extending over 6h and 14h, respectively, and a pulsed profile with two equal pulses separated by 5h) using a cross-over design. An oral metoprolol solution was included as a reference. Standard bioavailability variables were determined. In vivo drug release-time profiles for the IntelliCap® CR capsules were calculated from the plasma drug concentrations by deconvolution, and they were subsequently compared with the in vitro drug release profiles including assessment of level A in vitro/in vivo correlation (IVIVC). The relative bioavailability for the linear, extended release profiles was about 85% which is similar to other extended release administrations of metoprolol. There was an excellent agreement between the predetermined release profiles and the in vivo release for these two administrations. For IntelliCap® CR capsules programmed to deliver 2 distinct and equal drug pulses, the first pulse was delivered as expected whereas only about half of the second dose was released. Thus, it is concluded that the IntelliCap® system is well suited for the fast and reliable generation of in vivo pharmacokinetic data for extended release drug profiles, e.g. in context of regional drug absorption investigations. For immediate release pulses delivered in the distal GI tract this version of the device appears however less suitable.

Four different hydrophilic matrix formulations based on hydroxypropyl methylcellulose (HPMC) were investigated for erosion properties in vivo. Three formulations contained a fixed amount of HPMC (40%) with varying proportions of two HPMC grades with different molecular weights (Methocel K100LV and K4M), and a fourth formulation contained a lower amount of the HPMC of lower molecular weight (20%). The effect of food on the in vivo erosion behavior was investigated on two formulations containing different contents of the same HPMC grade. The in vivo erosion behavior and gastrointestinal transit were investigated using magnetic marker monitoring (MMM). The in vitro and in vivo erosion–time profiles show that the erosion was strongly dependent on the composition of the formulation. The formulations containing a larger proportion of high molecular weight HPMC or higher content of HPMC exhibit relatively slower erosion rate and vice versa. In vivo erosion rates were significantly higher under postprandial administration as compared to fasted state administration. No rapid disintegration of any of the formulations (i.e. formulation failure that can potentially cause dose dumping) was observed.

To outline and test a new modeling approach for prospective predictions of absorption from newly developed modified release formulations based on in vivo studies of gastro intestinal (GI) transit, drug release and regional absorption for the investigational drug AZD0837.

To develop a semi-mechanistic model linking in vitro to in vivo drug release.

The purpose of this work is to evaluate the roles of lecithin and bile salts in a new generation of fasted simulated small intestinal fluid (FaSSIF-II), thus enhancing the closer mimic of simulated fluids to the real human intestinal fluids (HIF) in drug discovery and drug product development. To assess the effects of lecithin in FaSSIF-II, solubility studies were conducted at 37 °C using four media including first generation simulated intestinal fluid (FaSSIF-I), FaSSIF-II, phosphate pH 6.5 buffer, and HIF. A total of 24 model compounds representing a wide range of biopharmaceutic properties were included. The drug solubility values measured in the FaSSIF-II were compared with those in FaSSIF-I, pH 6.5 buffer and HIF. To assess the effects of bile acids, solubility was measured for 4 compounds in the FaSSIF-I containing five different bile acids of various concentrations. The lecithin concentration in the FaSSIF-II is lowered from 0.75 mM to 0.2 mM. The results suggested that the FaSSIF-II is a better medium to reflect HIF, compared with pH 6.5 phosphate buffer and FaSSIF-I. Solubility of neutral compounds including atovaquone, carbamazepine, cyclosporine, danazol, diethylstilbestrol, felodipine, griseofulvin and probucol in FaSSIF-II showed improvement in predicting the in vivo solubility. The relative standard deviation (SD) of solubility measurement in FaSSIF-II is comparable with FaSSIF-I. For the acidic and basic tested compounds, the FaSSIF-II performs similarly to the FaSSIF-I. Experimental results showed that the level of bile salts typically is less than 5 mM under fasted state. Among the five studied bile acids, the conjugation (glycine or taurine) has no impact on the drug solubilization, while there may be a minimal effect of the degree of hydroxylation of the steroid ring system on solubilization. The lecithin concentration of 0.2 mM in FaSSIF-II has been demonstrated to closely represent HIF, for both neutral and ionizable compounds. In the composition of simulated intestinal fluids, the structure of bile acids has minimal effect, providing the flexibility of choosing one bile salt to represent complex in vivo bile acids.

INTRODUCTION Oral modified-release (MR) formulation is designed to deliver the drug to the body at a predetermined rate or site in the gastrointestinal (GI) tract. Oral MR includes, for example, extended-, controlled-, prolonged-, sustained-, delayed-, and pulsatile-release formulations. The focus of this chapter is formulations providing a slower drug release compared with conventional immediate-release (IR) formulations and the term extended release (ER) will be used to refer to these formulations.

To develop media simulating human colonic fluids (HCFs), to evaluate their use in predicting intracolonic solubility of ketoconazole, danazol and felodipine and to compare solubilities in HCFs with previously determined solubilities in gastric (HGFs) and small intestinal (HIFs) fluids.

To characterize the fluid composition in ascending colon of fasted adults with ulcerative colitis in relapse and in remission with a view to predicting variations on dosage form performance in the lower inflamed gut.

Purpose: To compare the luminal contents of the ascending colon of adult patients with ulcerative colitis (UC) in relapse vs. remission, as defined by the Clinical and Endoscopic Rachmilewicz Indices (CRI and ERI). Methods: 12 patients participated in a two-phase, crossover study. Patients were administered 10mg bisacodyl 50h and 44h prior to colonoscopy. This procedure had been shown not to affect the colonic fluid composition [1]. Subjects consumed only liquid food from 48h to 16h prior to colonoscopy, then fasted for the last 16h before colonoscopy. Enrolment to the relapse phase was based on scores of 7≤CRI≤12 and 7≤ERI≤10, and to the remission phase on scores of 1≤CRI≤3 and 1≤ERI≤3. Samples were analyzed for pH and buffer capacity immediately upon collection. The sample was then ultracentrifuged (30,000g, 15 min, 25oC) and the supernatant kept at -70oC until analysis. Osmolality, surface tension, total protein and carbohydrate contents, levels of ten bile acids and of seven short chain fatty acids (SCFAs) were measured in all supernatants. Results. Mean±SD volume recovery from the ascending colon was 26.8 ± 13.6mL in relapse and 21.2 ± 8.8mL in remission, similar to volumes recovered from healthy adults [1]. Likewise, the aqueous fraction of the contents (64 ± 15% relapse vs. 57 ± 13% remission) and the surface tension (≈41mM/m) was similar to healthy adults. Median pH values were similar in relapse to remission (6.6 vs. 6.5), both significantly lower than in healthy adults (7.8 p=0.004). Buffer capacity was similar in relapse to remission (32.1 ± 18.1 vs. 38.0 ± 14.7mmol/L/ΔpH). Osmolality was 200 ± 127 in relapse vs. 288 ± 150mOsm/kg in remission, both significantly higher than in healthy adults (81mOsm/kg p=0.029). Total carbohydrate (≈6 mg/mL) was similar in both UC groups to values in healthy adults. However, mean total protein (≈19 mg/mL, both groups) was significantly higher than in healthy adults (9.7 mg/mL p=0.004). Total bile acids were 76 ± 43μM in relapse vs. 115 ± 100μM in remission, similar to healthy adults (115 μM). Unlike in healthy adults, though, conjugated bile acids were recovered in UC patients. SCFAs in relapse (23.2 ± 14.9 mM) were significantly lower than that in remission (45.3 ± 26.8 mM p=0.041), primarily due to lower acetate levels. Conclusion. In general, UC patients exhibit lower intracolonic pH, but higher osmolality and total protein than healthy adults, irrespective of whether they are in relapse or remission. SCFA recovery was significantly lower in relapse vs. remission. Furthermore, in UC patients, but not in healthy subjects, conjugated bile acids were recovered. (1) Diakidou et al. AAPS annual meeting Atlanta, GA, 15-19 Nov. 2008

Purpose To characterize the contents of the ascending colon in healthy adults under fasting and fed state conditions, with a view to designing in vitro studies to explain/predict dosage form performance in the lower gut. Methods Twelve healthy adults participated in a two-phase crossover study. In Phase A, subjects were fasted (water allowed) overnight plus 5 h in the morning prior to colonoscopy (fasted state). In Phase B, subjects were fasted overnight, consumed a standard breakfast (960 kcal) in the morning, and were offered a light lunch 4.5 h later. In this phase, colonoscopy was performed 1 h after lunch (fed state). Volume, pH, and buffer capacity of colonic contents were measured immediately upon collection. After ultracentrifugation, the supernatant was further characterized. Results Free water content, pH, surface tension, and isobutyrate levels were lower in fed than in fasted subjects. On the other hand, buffer capacity, osmolality, acetate, butyrate, cholate, and chenodeoxycholate levels were higher in fed subjects. Carbohydrate content; protein content; and levels of long chain fatty acids, phosphatidylcholine, and cholesterol were not affected significantly by prandial state. Conclusion Composition of fluids in the ascending colon is affected by feeding. This may affect the performance of products designed to deliver drug to the colon.

In order to improve the predictability of dissolution testing new apparatuses have been proposed that mimic hydrodynamic and mechanical conditions in the gastrointestinal tract. In this study tested were four different nifedipine extended release (ER) formulations using the paddle apparatus and the reciprocating cylinder as pharmacopoeial test devices as well as two newly developed test apparatuses: the rotating beaker apparatus and the dissolution stress test apparatus. Investigated were Adalat OROS in strengths of 30 and 60 mg, and two hydrophilic matrix formulations: 60 mg nifedipine Coral and Nifedipin Sandoz 40 mg retard. The results demonstrate that the dissolution characteristic of the ER tablets is strongly dependent on the applied test conditions. The dosage form related food effects for Coral 60 mg tablets that were previously observed in human bioequivalence studies could be predicted with the two non-compendial dissolution test devices. The dissolution of Sandoz 40 mg tablets was very sensitive to all applied test conditions. The stable drug delivery characteristics of Adalat OROS observed in numerous in vivo studies was also observed in all of the dissolution tests. In conclusion, the present study shows that besides pH dependency the aspect of the mechanical robustness may be an essential factor affecting the dissolution characteristic of hydrogel matrix formulations.

Magnetic marker monitoring (MMM) is a new technique for visualizing transit and disintegration of solid oral dosage forms through the gastrointestinal (GI) tract. The aim of this work was to develop a modeling approach for gaining information from MM studies using data from a food interaction study with felodipine extended-release (ER) formulation. The interrelationship between tablet location in the GI tract, in vivo drug release, and felodipine disposition was modeled. A Markov model was developed to describe the tablet's movement through the GI tract. Tablet location within the GI tract significantly affected drug release and absorption through the gut wall. Food intake decreased the probability of tablet transition from the stomach, decreased the rate with which released felodipine left the stomach, and increased the fraction absorbed across the gut wall. In conclusion, the combined information of tablet location in the GI tract, in vivo drug release, and plasma concentration can be utilized in a mechanistically informative way with integrated modeling of data from MM studies.

In a clinical crossover study the gastrointestinal transit and the in-vivo drug release of magnetically labeled extended release tablets containing felodipine were monitored under fasting and fed conditions in six healthy volunteers using Magnetic Marker Monitoring [4]. Observations from this study were of three kinds: GI location of the tablet, remaining non-disintegrated tablet and plasma concentration of felodipine. These data were combined with concentration data following i.v. infusion [1] to build an integrated population mixed effect model.

The haemolytic activity of a number of maltopyranoside surfactants was studied. The study included octyl, nonyl, decyl, dodecyl, tetradecyl, cyclohexyl-propyl, cyclohexyl-hexyl, and dimethyl-heptyl maltopyranoside. The in vitro haemolytic activity was determined by employing a static method in which surfactants are added to an erythrocyte suspension and the released haemoglobin is determined. It was found that alkyl maltopyranosides become more haemolytic the longer the alkyl chain. Branching or presence of cyclic groups clearly decreases haemolytic activity, but it also increases the critical micelle concentration. As a result, the cyclic or branched surfactants do not become better solubilizing excipients than the straight-chain surfactants. The most useful surfactant, for pharmaceutical applications appears to be tetradecyl maltopyranoside, which is the least haemolytic surfactant relative to its critical micelle concentration. (c) 2005 Elsevier B.V. All rights reserved.

Gastrointestinal motility and transport as well as concomitant food intake are factors that are known to influence pharmacokinetics derived after intake of extended release dosage forms. However, the mechanisms behind these influencing factors are mostly unknown. In this study the gastrointestinal transit and the in vivo drug release of magnetically labelled extended release tablets containing felodipine were monitored together with the drug absorption phase of pharmacokinetics under fasting and fed conditions in six healthy volunteers using Magnetic Marker Monitoring. It was found that the in vivo drug release profiles of the tablets compared well under fasting and fed conditions. However, the plasma concentration profiles were strongly influenced by concomitant food intake. This could be attributed to elongated residence of the tablets in proximal parts of the stomach, resulting in delayed drug absorption and the occurrence of late high plasma peak concentrations. The lag time until the first appearance of felodipine in plasma and the residence time of the tablets in the proximal stomach, were found to be directly correlated. The study shows that increased plasma peak drug concentrations after intake of extended release formulations together with food can be explained by poor mixing in the proximal part of the stomach and are not necessarily due to failure of the formulation to control drug release (dose dumping).