Exploring gastrointestinal variables affecting drug and formulation behavior: methodologies, challenges and opportunities

Various gastrointestinal (GI) factors affect drug and formulation behavior after oral administration, including GI transfer, motility, pH and GI fluid volume and composition. An in-depth understanding of these physiological and anatomical variables is critical for a continued progress in oral drug development. In this review, different methodologies (invasive versus non-invasive) to explore the impact of physiological variables on formulation behavior in the human GI tract are presented, revealing their strengths and limitations. The techniques mentioned allow for an improved understanding of the role of following GI variables: gastric emptying (magnetic resonance imaging (MRI), scintigraphy, acetaminophen absorption technique, ultrasonography, breath test, intraluminal sampling and telemetry), motility (MRI, small intestinal/colonic manometry and telemetry), GI volume changes (MRI and ultrasonography), temperature (telemetry) and intraluminal pH (intraluminal sampling and telemetry)

Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted state

Previous imaging studies offered a snapshot of water distribution in fasted humans and showed that water in the small intestine is distributed in small pockets. This study aimed to quantify the volume and number of water pockets in the upper gut of fasted healthy humans following ingestion of a glass of water (240 mL, as recommended for bioavailability/bioequivalence (BA/BE) studies), using recently validated noninvasive magnetic resonance imaging (MRI) methods. Twelve healthy volunteers underwent upper and lower abdominal MRI scans before drinking 240 mL (8 fluid ounces) of water. After ingesting the water, they were scanned at intervals for 2 h. The drink volume, inclusion criteria, and fasting conditions matched the international standards for BA/BE testing in healthy volunteers. The images were processed for gastric and intestinal total water volumes and for the number and volume of separate intestinal water pockets larger than 0.5 mL. The fasted stomach contained 35 ± 7 mL (mean ± SEM) of resting water. Upon drinking, the gastric fluid rose to 242 ± 9 mL. The gastric water volume declined rapidly after that with a half emptying time (T50%) of 13 ± 1 min. The mean gastric volume returned back to baseline 45 min after the drink. The fasted small bowel contained a total volume of 43 ± 14 mL of resting water. Twelve minutes after ingestion of water, small bowel water content rose to a maximum value of 94 ± 24 mL contained within 15 ± 2 pockets of 6 ± 2 mL each. At 45 min, when the glass of water had emptied completely from the stomach, total intestinal water volume was 77 ± 15 mL distributed into 16 ± 3 pockets of 5 ± 1 mL each. MRI provided unprecedented insights into the time course, number, volume, and location of water pockets in the stomach and small intestine under conditions that represent standard BA/BE studies using validated techniques. These data add to our current understanding of gastrointestinal physiology and will help improve physiological relevance of in vitro testing methods and in silico transport analyses for prediction of bioperformance of oral solid dosage forms, particularly for low solubility Biopharmaceutics Classification System (BCS) Class 2 and Class 4 compounds

Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics : an UNGAP review

The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area

Ανθρώπινο κεφάλαιο, εμπορικές ροές και ισοζύγιο τεχνολογίας

This dissertation aims to evaluate the following topics and issues. Chapter 1 introduces thetopic of patents and knowledge spillovers. One of the most challenging issues in the recentliterature on innovation has been related to the “geography of innovation” or “spatialclustering of innovations”. The relationship between technology and geography is a topic ofgrowing interest in both economics and regional science. The main questions are the extentthat knowledge spillovers (knowledge externalities) are geographically localized and theirimpact on the innovative performance of regions. Chapter 2 shows that patents, industrial anduniversity research, and human capital in firms have similar patterns of spatial correlation.Actually, they suggest that research conducted by firms and universities has a strong effect onthe count of product patents observed in USA. This finding suggests local knowledgetransfers. In addition to searching for evidence of local knowledge effects, the spatial extentof these effects gets particular attention in this chapter. Chapter 3 examines how the spatialconcentration of innovation activity shapes the production of innovation in the US states. Weaugment the standard knowledge production function with a structure that allows for spatialeffects, income effects and trade effects. We account not only for bilateral influences, but alsofor effects from the rest of the states in technology production. In doing so, we avoidoverestimating the effect of local and external technological knowledge in producing localtechnological products. Chapter 4 summarizes the results.Αυτή η διατριβή στοχεύει στην αξιολόγηση των ακόλουθων θεμάτων και ζητημάτων. ΤοΚεφάλαιο 1 εισάγει το θέμα των διπλωμάτων ευρεσιτεχνίας και των διαχύσεων γνώσεων.Ένα από τα πιο σημαντικά ζητήματα στην πρόσφατη βιβλιογραφία για την καινοτομία έχεισχέση με τη «γεωγραφία της καινοτομίας» ή τη «χωρική ομαδοποίηση καινοτομιών». Ησχέση μεταξύ τεχνολογίας και γεωγραφίας είναι ένα θέμα αυξανόμενου ενδιαφέροντος τόσογια την οικονομία όσο και για την περιφερειακή επιστήμη. Τα κύρια ερωτήματα είναι ηέκταση που οι διαχύσεις γνώσης (εξωτερικές γνώσεις) εντοπίζονται γεωγραφικά και οαντίκτυπός τους στην καινοτόμο απόδοση των πολιτειών. Το κεφάλαιο 2 δείχνει ότι ταδιπλώματα ευρεσιτεχνίας, η βιομηχανική και πανεπιστημιακή έρευνα και το ανθρώπινοκεφάλαιο σε επιχειρήσεις έχουν παρόμοια πρότυπα χωρικής συσχέτισης. Στηνπραγματικότητα, προτείνουν ότι η έρευνα που πραγματοποιείται από εταιρείες καιπανεπιστήμια έχει ισχυρή επίδραση στον αριθμό των διπλωμάτων ευρεσιτεχνίας προϊόντωνπου παρατηρούνται στις ΗΠΑ. Αυτό το εύρημα υποδηλώνει τοπικές μεταφορές γνώσεων.Εκτός από την αναζήτηση αποδεικτικών στοιχείων σχετικά με τις τοπικές επιπτώσεις τηςγνώσης, η χωρική έκταση αυτών των αποτελεσμάτων περιγράφεται σε αυτό το κεφάλαιο. ΤοΚεφάλαιο 3 εξετάζει πώς η χωρική συγκέντρωση της καινοτόμου δραστηριότηταςδιαμορφώνει την παραγωγή καινοτομίας στις πολιτείες των ΗΠΑ. Η διατριβή μελετά όχιμόνο τις διμερείς επιρροές, αλλά και τις επιπτώσεις από τις υπόλοιπες πολιτείες στηνπαραγωγή τεχνολογίας. Με αυτόν τον τρόπο, αποφεύγουμε την υπερεκτίμηση της επίδρασηςτων τοπικών και εξωτερικών τεχνολογικών γνώσεων στην παραγωγή τοπικών τεχνολογικώνπροϊόντων. Το Κεφάλαιο 4 συνοψίζει τα αποτελέσματα

In vivo και in vitro εκτίμηση της καθίζησης λιπόφιλων ασθενών βάσεων και του υπερκορεσμού των περιεχομένων του αυλού του λεπτού εντέρου υγιών εν...

Purpose: To evaluate precipitation in and supersaturation of intestinal contents, after administration of pharmacologically relevant doses of dipyridamole and ketoconazole to twelve fasted healthy adults. Τo develop an in vitro methodology for prediction of concentrations and potential precipitation of highly permeable, lipophilic weak bases in fasted upper small intestine, based on luminal dipyridamole and ketoconazole data. To evaluate the usefulness of the in vitro methodology in predicting precipitation in fasted upper small intestine of two highly permeable, lipophilic weak bases under development, AZD0865 and SB705498, based on plasma data. Methods: On two separate days each subject was administered in stomach 240 mL aqueous solutions of two dipyridamole doses (30 mg and 90 mg) and two ketoconazole doses (100 mg and 300 mg). Physicochemical characteristics, total drug content, and drug concentration were measured in individual intestinal contents (≤7 mL) aspirated at specific times post-dosing. Drug concentration after incubation (37.C/48h) of the relevant supernatants and equilibrium solubility were also measured. For the in vitro experiments, a three-compartment setup was used. Depending on the dosage form administered in the human study, a solution or a suspension was placed in gastric compartment. A solution simulating the luminal environment (FaSSIF-V2plus) was initially placed in duodenal compartment. Concentrated FaSSIF-V2plus was placed in reservoir compartment in order to keep constant the physicochemical characteristics of the solution in the duodenal compartment during the experiment. Total drug content and drug concentration were measured in samples collected at specific time intervals. Also, drug concentration after incubation (37.C/48h) of the relevant filtrates and equilibrium solubility were measured. In both human and in vitro studies crystallinity of precipitates was evaluated with X-rays. Results: Intraluminal precipitated fraction was minimal (dipyridamole, ≤7 %) or limited (ketoconazole, ≤16 %). Ketoconazole precipitates were mostly amorphous. Depending on dose, intestinal contents with pH>3.6 were supersaturated with dipyridamole up to 10 min (low dose) and 30 min (high dose), and with ketoconazole up to 30 min (low dose) and 50 min (high dose) post-administration. Intestinal contents with pH>5 and concentration of micellar components 3,6 ήταν υπέρκορα ως προς τη διπυριδαμόλη μέχρι και 10 min (χαμηλή δόση) και 30 min (υψηλή δόση), και ως προς την κετοκοναζόλη μέχρι και 30 min (χαμηλή δόση) και 50 min (υψηλή δόση) μετά από τη χορήγηση. Τα ενδοαυλικά περιεχόμενα με pH>5 και συγκέντρωση μικκυλιακών συστατικών <5 mM ήταν υπέρκορα ως προς τη διπυριδαμόλη και την κετοκοναζόλη, αλλά το κλάσμα καθίζησης ήταν σημαντικό μόνο στην περίπτωση της κετοκοναζόλης. Μετά την επώαση, τα ιζήματα είχαν κρυσταλλική δομή σχεδόν σε όλα τα δείγματα. Πιθανόν, η αργή καθίζηση της βάσης ή/και η καθίζηση άλλων φάσεων αποτελούν δυο λόγους για αυτήν την παρατήρηση. Οι in vitro συγκεντρώσεις της διπυριδαμόλης και της κετοκοναζόλης και τα κλάσματα καθίζησης ήταν παρόμοια με τα αντίστοιχα ενδοαυλικά δεδομένα. Παρόλα αυτά, αντίθετα με τα ενδοαυλικά ιζήματα, τα ιζήματα κετοκοναζόλης, τα οποία συλλέχτηκαν στα in vitro πειράματα, ήταν κρυσταλλικά. Τα in vitro AZD0865 δεδομένα επιβεβαίωσαν τα ήδη δημοσιευμένα φαρμακοκινητικά δεδομένα κλινικών μελετών σε υγιείς εθελοντές, τα οποία καταδεικνύουν, ότι οι ρυθμοί απορρόφησης δεν επηρεάζονται από την ενδοαυλική καθίζηση. Τα in vitro SB705498 δεδομένα προέβλεψαν, ότι στατιστικά σημαντική καθίζηση συμβαίνει μετά τη χορήγηση δόσεων 100 mg και 400 mg, αλλά όχι μετά τη χορήγηση δόσης 10 mg, κάτι, το οποίο ήταν σύμφωνο με τα φαρμακοκινητικά δεδομένα κλινικών μελετών σε ανθρώπους. Συμπεράσματα: Η ενδοαυλική καθίζηση των λιπόφιλων, υψηλής διαπερατότητας δραστικών ουσιών με ασθενώς βασικές ιδιότητες, όταν χορηγούνται σε φαρμακολογικά δραστικές δόσεις, ίσως, να μην είναι τόσο σημαντική όσο θεωρείται μέχρι σήμερα. Η εκτίμηση του ενδοαυλικού υπερκορεσμού ως προς την ελεύθερη βάση είναι προβληματική, διότι είναι πιθανή η καθίζηση διαφόρων φάσεων. Αναπτύχθηκε μια in vitro μεθοδολογία για την πρόβλεψη των συγκεντρώσεων και της πιθανής καθίζησης στο ανώτερο τμήμα του λεπτού εντέρου κατά τη διαπεπτικήπερίοδο λιπόφιλων, υψηλής διαπερατότητας ασθενών βάσεων, η οποία αξιολογήθηκε ως προς τη δυνατότητά της να προβλέπει ενδοαυλική καθίζηση σε ανθρώπους με πολύ καλά αποτελέσματα

Estimation of intragastric solubility of drugs: In what medium?

Purpose. To measure the solubility of four drugs in human gastric aspirates, canine gastric aspirates (CGF) and simulated gastric fluids in order to propose a medium for estimating intragastric drug solubility relevant to a bioavailability study in the fasted state. Materials and Methods. Intragastric environment after administration of water to healthy fasted adults and to healthy fasted dogs (this study) was initially characterized. Solubilities were then measured with the shake-flask method in gastric fluid aspirated after the administration of water to healthy fasted adults and to healthy fasted dogs, in various simulated gastric fluids, i.e. SGFSLS, SGFTriton, FaSSGF, FaSSGFNaCl, and in various HCl solutions with pH values ranging from 1.2 to 2.9. Results. In all cases, FaSSGF performed better than canine aspirates, SGFSLS, SGFTriton, or FaSSGF NaCl in predicting solubility in HGF. However, its superiority over HCl pH 1.6 was not clear. For ketoconazole, dipyridamole, miconazole, and felodipine deviations of solubility data in FaSSGF from solubility data in HGF were non-significant, 34, -39 and 252%, respectively, whereas the corresponding deviations of data in HCl pH 1.6 from data in HGF were non-significant, 24, 70, and 130%, respectively. Conclusions. Combining data in FaSSGF and HCl pH 1.6 is comparatively the most efficient way to get an estimate of drug solubility in the fasting gastric contents during a bioavailability study. However, accurate estimation of intragastric solubility is limited by the changing environment during intragastric residence of solid particles and the degree of simulation of intragastric composition. © 2007 Springer Science+Business Media, LLC

Measuring pH and Buffer Capacity in Fluids Aspirated from the Fasted Upper Gastrointestinal Tract of Healthy Adults

Purpose: The design of biorelevant conditions for in vitro evaluation of orally administered drug products is contingent on obtaining accurate values for physiologically relevant parameters such as pH, buffer capacity and bile salt concentrations in upper gastrointestinal fluids. Methods: The impact of sample handling on the measurement of pH and buffer capacity of aspirates from the upper gastrointestinal tract was evaluated, with a focus on centrifugation and freeze-thaw cycling as factors that can influence results. Since bicarbonate is a key buffer system in the fasted state and is used to represent conditions in the upper intestine in vitro, variations on sample handling were also investigated for bicarbonate-based buffers prepared in the laboratory. Results: Centrifugation and freezing significantly increase pH and decrease buffer capacity in samples obtained by aspiration from the upper gastrointestinal tract in the fasted state and in bicarbonate buffers prepared in vitro. Comparison of data suggested that the buffer system in the small intestine does not derive exclusively from bicarbonates. Conclusions: Measurement of both pH and buffer capacity immediately after aspiration are strongly recommended as “best practice” and should be adopted as the standard procedure for measuring pH and buffer capacity in aspirates from the gastrointestinal tract. Only data obtained in this way provide a valid basis for setting the physiological parameters in physiologically based pharmacokinetic models. © 2020, Springer Science+Business Media, LLC, part of Springer Nature

Measuring pH and Buffer Capacity in Fluids Aspirated from the Fasted Upper Gastrointestinal Tract of Healthy Adults

Purpose: The design of biorelevant conditions for in vitro evaluation of orally administered drug products is contingent on obtaining accurate values for physiologically relevant parameters such as pH, buffer capacity and bile salt concentrations in upper gastrointestinal fluids. Methods: The impact of sample handling on the measurement of pH and buffer capacity of aspirates from the upper gastrointestinal tract was evaluated, with a focus on centrifugation and freeze-thaw cycling as factors that can influence results. Since bicarbonate is a key buffer system in the fasted state and is used to represent conditions in the upper intestine in vitro, variations on sample handling were also investigated for bicarbonate-based buffers prepared in the laboratory. Results: Centrifugation and freezing significantly increase pH and decrease buffer capacity in samples obtained by aspiration from the upper gastrointestinal tract in the fasted state and in bicarbonate buffers prepared in vitro. Comparison of data suggested that the buffer system in the small intestine does not derive exclusively from bicarbonates. Conclusions: Measurement of both pH and buffer capacity immediately after aspiration are strongly recommended as “best practice” and should be adopted as the standard procedure for measuring pH and buffer capacity in aspirates from the gastrointestinal tract. Only data obtained in this way provide a valid basis for setting the physiological parameters in physiologically based pharmacokinetic models

Structural features of colloidal species in the human fasted upper small intestine

Objectives This paper aims to study the features of colloidal species in the lumen of the upper small intestine of two healthy adults at fasted state by means of electron microscopy. Methods Samples were aspirated from a location near the ligament of Treitz 30 min (volunteer no. 1, Aspirate30min sample) and 60 min (volunteer no. 2, Aspirate60min sample), after administration of 240 ml of an aqueous solution in the fasted state. Key findings In the Aspirate30min sample micelles coexist with multi-, oligo- and unilamellar vesicles. Tubular structures and long structures were frequently visualised. In the Aspirate60min sample micelles, few unilamellar vesicles, long structures and tubular structures were the dominating structural features. In both samples, multivesicular structures and faceted vesicles (previously visualised at fed state) were absent. Structural features of both samples bear similarities with previously studied samples from the lower intestine in the fasted state. Micelles and unilamellar vesicles observed in both samples closely resemble morphological characteristics of those found in fluids simulating the colloidal species in fasted upper intestinal environment. Conclusions Features of colloidal species in contents of fasted small intestine have similarities with fluids simulating the contents in fasted upper small intestine and with contents of lower intestine in the fasted state. © 2015 Royal Pharmaceutical Society

Measuring pH and buffer capacity in fluids aspirated from the fasted upper gastrointestinal tract of healthy adults

Purpose: The design of biorelevant conditions for in vitro evaluation of orally administered drug products is contingent on obtaining accurate values for physiologically relevant parameters such as pH, buffer capacity and bile salt concentrations in upper gastrointestinal fluids. Methods: The impact of sample handling on the measurement of pH and buffer capacity of aspirates from the upper gastrointestinal tract was evaluated, with a focus on centrifugation and freeze-thaw cycling as factors that can influence results. Since bicarbonate is a key buffer system in the fasted state and is used to represent conditions in the upper intestine in vitro, variations on sample handling were also investigated for bicarbonate-based buffers prepared in the laboratory. Results: Centrifugation and freezing significantly increase pH and decrease buffer capacity in samples obtained by aspiration from the upper gastrointestinal tract in the fasted state and in bicarbonate buffers prepared in vitro. Comparison of data suggested that the buffer system in the small intestine does not derive exclusively from bicarbonates. Conclusions: Measurement of both pH and buffer capacity immediately after aspiration are strongly recommended as “best practice” and should be adopted as the standard procedure for measuring pH and buffer capacity in aspirates from the gastrointestinal tract. Only data obtained in this way provide a valid basis for setting the physiological parameters in physiologically based pharmacokinetic models