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This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man. © 2021 The Authors

We evaluated the environment in TIM-1 luminal compartments using paracetamol and danazol solutions and suspensions and the fed state configuration. Data were compared with recently published data in healthy adults. TIM-1 experiments were performed with a 3-fold downscale. Volumes of secretions in gastric and duodenal compartments adequately reflected the luminal data in adults up to 3 h post drug dosing. pH values in duodenal and jejunal compartments adequately reflected average pH values in adults. In gastric compartment pH values where initially higher than average values in adults and reached baseline levels earlier than in adults. The environment in the TIM-1 gastric compartment and jejunal compartment adequately reflected the average total paracetamol and danazol amounts per volume of contents in the adult stomach and upper small intestine, respectively. Total bile acids concentrations in the micellar phase of contents in duodenal and jejunal compartments overestimated micellar concentrations in the upper small intestine of adults. Adjustments in gastric emptying/acid secretion rates and bile acids identities in the duodenal and jejunal compartments, and application of dynamic bile acids secretion rates are expected to further improve the relevance of luminal conditions in TIM-1 compartments with those in adults. © 2021 American Pharmacists Association

Objective: To investigate the usefulness of four in vitro methodologies in screening for product related differences in tacrolimus exposure after oral administration of amorphous solid dispersions with modified release characteristics in the fasted state. Methods: Initially, Advagraf® (5 mg tacrolimus/capsule), Envarsus® (4 mg tacrolimus/tablet) and a modified release Test Tablet (5 mg tacrolimus/tablet) were subjected to in vitro biorelevant performance testing simulating fasted state conditions using a small-scale two-stage biphasic system, a small-scale two-stage dissolution – permeation (D-P) system, the compendial apparatus IV (open loop mode) and the biorelevant gastrointestinal transfer (BioGIT) system. Early and total exposure, after single dose administrations of the three products to twelve healthy adults in the fasted state on a crossover basis, were then evaluated. Subsequently, the usefulness of in vitro data in qualitatively predicting product related differences in early exposure and in total exposure were assessed. Results: Product related differences in tacrolimus early exposure were successfully predicted by data collected with compendial apparatus IV. The two-stage biphasic system was useful for predicting differences in early exposure between the non-disintegrating Envarsus® and the disintegrating products (Advagraf® or Test Tablet). BioGIT data were useful only for discussing clinical data early after administration of the two disintegrating products. Prediction of product related differences in total exposure was successful only when the compendial apparatus IV was used for comparing the two disintegrating products. Conclusions: Biorelevant in vitro performance testing with compendial apparatus IV was useful for qualitatively predicting differences in tacrolimus early and total exposure after administration of disintegrating products with modified release characteristics in the fasted state. © 2021 Elsevier B.V.

A small-scale two-stage biphasic system, a small-scale two-stage dissolution-permeation system, the Erweka mini-paddle apparatus, and the BioGIT system were evaluated for their usefulness in assessing the intraluminal performance of two low solubility drugs in the fasted state, one with weakly acidic properties (tested in a salt form, diclofenac potassium) and one with weakly alkaline properties [ritonavir, tested as an amorphous solid dispersion (ASD) formulation]. In all in vitro methods, an immediate-release tablet and a powder formulation of diclofenac potassium were both rapidly dissolved in Level II biorelevant media simulating the conditions in the upper small intestine. Physiologically based biopharmaceutics (PBB) modelling for the tablet formulation resulted in a successful simulation of the average plasma profile in adults, whereas for the powder formulation modelling indicated that gastric emptying and transport through the intestinal epithelium limit the absorption rates. Detailed information on the behaviour of the ritonavir ASD formulation under both simulated gastric and upper small intestinal conditions were crucial for understanding the luminal performance. PBB modelling showed that the dissolution and precipitation parameters, estimated from the Erweka mini-paddle apparatus data and the small-scale two-stage biphasic system data, respectively, were necessary to adequately simulate the average plasma profile after administration of the ritonavir ASD formulation. Simulation of the gastrointestinal transfer process from the stomach to the small intestine was necessary to evaluate the effects of hypochlorhydric conditions on the luminal performance of the ritonavir ASD formulation. Based on this study, the selection of the appropriate in vitro method for evaluating the intraluminal performance of ionisable lipophilic drugs depends on the characteristics of the drug substance. The results suggest that for (salts of) acidic drugs (e.g., diclofenac potassium) it is only an issue of availability and ease of operation of the apparatus. For weakly alkaline substances (e.g., ritonavir), the results indicate that the dynamic dissolution process needs to be simulated, with the type of requested information (e.g., dissolution parameters, precipitation parameters, luminal concentrations) being key for selecting the most appropriate method. Regardless of the ionisation characteristics, early in the drug development process the use of small-scale systems may be inevitable, due to the limited quantities of drug substance available. © 2021

An important goal of the European Cooperation in Science and Technology (COST) Action UNGAP (UNderstanding Gastrointestinal Absorption-related Processes, www.ungap.eu) is to improve standardization of methods relating to the study of oral drug absorption. Solubility is a general term that refers to the maximum achievable concentration of a compound dissolved in a liquid medium. For orally administered drugs, relevant information on drug properties is crucial during drug (product) development and at the regulatory level. Collection of reliable and reproducible solubility data requires careful application and understanding of the limitations of the selected experimental method. In addition, the purity of a compound and its solid state form, as well as experimental parameters such as temperature of experimentation, media related factors, and sample handling procedures can affect data quality. In this paper, an international consensus developed by the COST UNGAP network on recommendations for collecting high quality solubility data for the development of orally administered drugs is proposed. © 2021

Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research. © 2021 The Authors

Objectives: To summarise key contributions of the Pharmaceutical Education and Research with Regulatory Links (PEARRL) project (2016-2020) to the optimisation of existing and the development of new biopharmaceutics tools for evaluating the in vivo performance of oral drug products during the development of new drugs and at the regulatory level. Key findings: Optimised biopharmaceutics tools: Based on new clinical data, the composition of biorelevant media for simulating the fed state conditions in the stomach was simplified. Strategies on how to incorporate biorelevant in vitro data of bio-enabling drug products into physiologically based pharmacokinetic (PBPK) modelling were proposed. Novel in vitro biopharmaceutics tools: Small-scale two-stage biphasic dissolution and dissolution-permeation setups were developed to facilitate understanding of the supersaturation effects and precipitation risks of orally administered drugs. A porcine fasted state simulated intestinal fluid was developed to improve predictions and interpretation of preclinical results using in vitro dissolution studies. Based on new clinical data, recommendations on the design of in vitro methodologies for evaluating the GI drug transfer process in the fed state were suggested. The optimized design of in vivo studies for investigating food effects: A food effect study protocol in the pig model was established which successfully predicted the food-dependent bioavailability of two model compounds. The effect of simulated infant fed state conditions in healthy adults on the oral absorption of model drugs was evaluated versus the fasted state and the fed state conditions, as defined by regulatory agencies for adults. Using PBPK modelling, the extrapolated fasted and infant fed conditions data appeared to be more useful to describe early drug exposure in infants, while extrapolation of data collected under fed state conditions, as defined by regulators for adults, failed to capture in vivo infant drug absorption. Summary: Substantial progress has been made in developing an advanced suite of biopharmaceutics tools for streamlining drug formulation screening and supporting regulatory applications. These advances in biopharmaceutics were achieved through networking opportunities and research collaborations provided under the H2020 funded PEARRL project. © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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. © 2021 The Authors

We characterized the contents of distal ileum and proximal colon of older people from a pharmaceutical product performance perspective, under two extreme situations, i.e. 5 h after a glass of water to fasted volunteers (fasted state) and 5 h after a high-calorie, high-fat meal to fasted volunteers (fed state). Five males and three females (65-70 y) participated in a two-phase crossover study. Contents were collected via colonoscopy. In distal ileum, luminal pH was lower and buffer capacity was higher than in young adults; differences reached significance for pH in the fed state. In proximal colon, differences reached significance for pH/fasted state and for buffer capacity/both fasted and fed states. Aqueous fraction of contents contained more short chain fatty acids than previously observed in young adults. In distal ileum, osmolality was significantly higher than in young adults. In proximal colon, aqueous fraction in the fasted state was significantly lower and long chain fatty acids 5 h after meal was significantly higher than in young adults. Characteristics of contents of lower intestine that are relevant to the performance of certain modified release products differ between individuals 65–74 years old and young adults, the typical age group employed in safety and efficacy studies of oral drug products. © 2020 American Pharmacists Association®

The importance of physiologically based pharmacokinetic (PBPK) model refinement with data acquired in adults using a pediatric formulation under age-relevant dosing conditions in order to extrapolate drug exposure to infants was recently demonstrated for paracetamol. In the present investigation, the aim was to evaluate the importance of similar PBPK model refinement for a low-solubility weak acid, ibuprofen, to simulate exposure across pediatric populations, i.e., infants, young children, and schoolchildren. After developing and evaluating adult disposition and oral absorption models for the aqueous suspension of ibuprofen, ibuprofen performance was extrapolated to pediatrics simulating exposure as a function of different prandial and dosing conditions: fasted conditions, reference-meal fed conditions (solid-liquid meal), and infant-formula fed conditions (homogeneous liquid). Successful predictions were achieved when employing the refined model for fasted state conditions or for fed state conditions relevant to specific age groups, i.e., infant formula for infants and reference meal for children. The present study suggested that ibuprofen performance was primarily guided by gastric emptying and showed sensitivity towards formulation characteristics and pH changes in the small intestine. Better understanding of luminal conditions in pediatrics and age-dependent ibuprofen post-absorptive processes could improve modeling confidence for ibuprofen, as well as other drugs with similar characteristics. © 2020, American Association of Pharmaceutical Scientists.

The main objective of this study was to investigate the mechanism of solifenacin release from a pH-responsive ion-complex oral resinate suspension under conditions simulating the environment in the upper gastrointestinal lumen. A secondary objective was to propose an appropriate in vitro methodology for evaluating the quality of orally administered solifenacin suspensions. The mechanism of solifenacin release from polacrilin potassium resin (Amberlite® IRP88) was investigated using biorelevant media and compendial setups (USP Apparatus 2 and USP Apparatus 4) and using newer, recently validated in vitro methodologies [biorelevant gastrointestinal transfer (BioGIT) system]. We evaluated the impact of particle size and concentration of the resin; thickener concentration (carbomer homopolymer, type B); and the impact of pH, cationic strength, agitation intensity and level of simulation of contents in the upper gastrointestinal lumen. Data suggested that solifenacin release from the resinate was determined by the resin particle size, the medium pH, cationic strength (when the conditions in the upper small intestine are simulated) and the level of simulation of contents in the upper small intestine. The interaction of solifenacin with taurocholic acid/lecithin aggregates was significant, but unlikely to affect the degree of solifenacin absorption, as a BCS Class I compound. Under acidic conditions, solifenacin was dissociated and released from the pH-responsive resin rapidly. Under conditions simulating the contents of the upper small intestine, solifenacin was replaced by cations from the testing media and diffused through the resin matrix. All three in vitro systems with or without a pH gradient are useful in distinguishing solifenacin release characteristics from resinate suspensions with different particle sizes. Because of this drug release mechanism, USP Apparatus 2 with fixed pH media demonstrated equivalent or slightly higher discriminative sensitivity than the other setups and appears to be appropriate for product quality control. © 2019 Elsevier B.V.

Objectives: To measure the pH, buffer capacity, lipid content, bile acid content, and viscosity in the upper gastrointestinal (GI) lumen after a standard high-calorie, high-fat meal as well as the osmolality, lipid content and bile acid content in the aqueous phase of the gastric contents and the micellar phase of contents of the upper small intestine. To evaluate the implications of these findings for the composition of biorelevant media employed in vitro oral drug product performance testing representing the upper GI conditions after ingestion of the standard meal. Methods: Eight healthy male adult volunteers participated in a two-phase, crossover study in which a homogenized standard meal was administered to the antrum via the gastric port of a naso-gastro-intestinal tube. A glass of tap water and single paracetamol and danazol doses were administered to the antrum of the stomach 30 min after the initiation of meal administration (Pentafragka et al., 2020). Samples were aspirated from the antrum and the upper small intestine over the next four hours. The pH and the buffer capacity of the samples were measured immediately upon aspiration, while viscosity, osmolality, and presence of solubilizing agents were measured after storage at -70 °C. Results: The composition of gastric contents over time fluctuated less after the homogenized standard meal than after liquid meals with similar composition. Intra-subject variability of pH and buffer capacity in the stomach and in the upper small intestine was low. Mean viscosity values in the stomach at 100 s−1 were 80–800 times higher than in the fasted state for more than 3 h after the standard meal. In the upper small intestine, mean viscosity values at 100 s−1 were at least 100 times higher than in the fasted state for 4 h after the standard meal. Conclusions: Based on data collected in this study, Level I and Level II biorelevant media simulating the intragastric conditions after ingestion of a standard meal could be simplified whereas FeSSIF-V2 composition was confirmed to be representative of the composition of contents in the upper small intestine. Representative values of viscosity in the stomach and the upper small intestine and Level II composition of the aqueous phase of gastric contents, after the standard meal, are proposed for first time. © 2020 Elsevier B.V.

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.

The absence of an intestinal absorption sink is a significant weakness of standard in vitro lipolysis methods, potentially leading to poor prediction of in vivo performance and an overestimation of drug precipitation. In addition, the majority of the described lipolysis methods only attempt to simulate intestinal conditions, thus overlooking any supersaturation or precipitation of ionizable drugs as they transition from the acidic gastric environment to the more neutral conditions of the intestine. The aim of this study was to develop a novel lipolysis method incorporating a two-stage gastric-to-intestinal transition and an absorptive compartment to reliably predict in vivo performance of lipid-based formulations (LBFs). Drug absorption was mimicked by in situ quantification of drug partitioning into a decanol layer. The method was used to characterize LBFs from four studies described in the literature, involving three model drugs (i.e., nilotinib, fenofibrate, and danazol) where in vivo bioavailability data have previously been reported. The results from the novel biphasic lipolysis method were compared to those of the standard pH-stat method in terms of reliability for predicting the in vivo performance. For three of the studies, the novel biphasic lipolysis method more reliably predicted the in vivo bioavailability compared to the standard pH-stat method. In contrast, the standard pH-stat method was found to produce more predictive results for one study involving a series of LBFs composed of the soybean oil, glyceryl monolinoleate (Maisine CC), Kolliphor EL, and ethanol. This result was surprising and could reflect that increasing concentrations of ethanol (as a cosolvent) in the formulations may have resulted in greater partitioning of the drug into the decanol absorptive compartment. In addition to the improved predictivity for most of the investigated systems, this biphasic lipolysis method also uses in situ analysis and avoids time- and resource-intensive sample analysis steps, thereby facilitating a higher throughput capacity and biorelevant approach for characterization of LBFs. © 2020 American Chemical Society.

Fluid sampling from the gastrointestinal (GI) tract has been applied as a valuable tool to gain more insight into the fluids present in the human GI tract and to explore the dynamic interplay of drug release, dissolution, precipitation and absorption after drug product administration to healthy subjects. In the last twenty years, collaborative initiatives have led to a plethora of clinical aspiration studies that aimed to unravel the luminal drug behavior of an orally administered drug product. The obtained drug concentration-time profiles from different segments in the GI tract were a valuable source of information to optimize and/or validate predictive in vitro and in silico tools, frequently applied in the non-clinical stage of drug product development. Sampling techniques are presently not only being considered as a stand-alone technique but are also used in combination with other in vivo techniques (e.g., gastric motility recording, magnetic resonance imaging (MRI)). By doing so, various physiological variables can be mapped simultaneously and evaluated for their impact on luminal drug and formulation behavior. This comprehensive review aims to describe the history, challenges and opportunities of the aspiration technique with a specific focus on how this technique can unravel the luminal behavior of drug products inside the human GI tract by providing a summary of studies performed over the last 20 years. A section ‘Best practices’ on how to perform the studies and how to treat the aspirated samples is described. In the conclusion, we focus on future perspectives concerning this technique. © 2020 The Author(s)

During the OrBiTo project, our knowledge on the gastrointestinal environment has improved substantially and biorelevant media composition have been refined. The aim of this study was to propose optimized biorelevant testing conditions for modified release products, to evaluate the reproducibility of the optimized compendial apparatus III (USP apparatus III) and compendial apparatus IV (USP apparatus IV, open-loop mode) dissolution methods and to evaluate the usefulness of these methods to forecast the direction of food effects, if any, based on the results of two «ring» studies and by using two model modified release (MR) products, Ciproxin / Cipro XR and COREG CR. Six OrBiTo partners participated in each of the ring studies. All laboratories were provided with standard protocols, pure drug substance, and dose units. For the USP apparatus III, the dissolution methods applied to Ciproxin / Cipro XR, a monolithic MR product of an active pharmaceutical ingredient (API) with moderate aqueous solubility, were robust with low intra- and inter-laboratory data variability. Data from all partners were in line on a qualitative basis with food effect data in humans. For the USP apparatus IV, the dissolution methods applied to COREG CR, a multiparticulate, pH dependent, MR product of an API with low and pH dependent solubility led to high intra- and inter- laboratory data variability. Data from all partners were in line, on a qualitative basis, with the previously observed food effects in humans. © 2020 Elsevier B.V.

We explored the potential impact of Crohn's disease on the intragastric environment of fasted adults with a view to potential effects on intragastric performance of orally administered drugs in the fasted state. Data were collected from 15 healthy individuals and 15 patients with Crohn's disease. All subjects remained fasted for at least 12h prior to gastroscopy. Intragastric resting volume and pH were measured upon aspiration. Osmolality, surface tension, pepsin activity, and content of six bile acids were measured within 4 months upon sample collection. Unlike intragastric volumes, intragastric osmolality was significantly increased by Crohn's disease. However, mean osmolality value in patients was only slightly higher than in healthy individuals (293 vs. 257 mOsmol/kg, respectively), therefore, unlikely to affect intragastric drug product performance. Primarily due to the high variability of data in healthy individuals, the potential effects on intragastric pH and surface activity could not be evaluated on a statistical basis. However, based on average (mean and median) values, even if they are statistically significant, it seems unlikely to be of clinical significance. Inter-subject variability of pepsin activity, and total bile acids content was high in both the healthy and the patients' groups. Statistical investigation of the potential impact of Crohn's disease on these parameters requires prior designation of the minimum differences to be detected; such differences will determine the minimum sample size required of relevant investigations. © 2020 by the authors.

This paper summarizes efforts to (i) better understand the behavior of amorphous solid dispersions (ASDs) under real-life dosing conditions and (ii) evaluate the capability of in vitro methodologies to capture gastro-intestinal drug disposition. In a first part of the study, five healthy volunteers participated in a two-way crossover trial in which one Norvir® tablet (100 mg ritonavir) was dosed under fasted and fasted + PPI conditions. Gastrointestinal aspirates were collected from both the stomach and duodenum as a function of time to map the gastrointestinal drug disposition of the ritonavir ASD formulation and to evaluate the impact of reduced gastric acid secretion on formulation performance. In both test conditions, ritonavir was shown to supersaturate in the upper GI tract illustrating the capacity of the formulation strategy itself to generate supersaturated drug content. In parallel, in vivo test conditions were closely mimicked in a multitude of in vitro methodologies (i.e., USP II dissolution apparatus, BioGIT and TIM-1 system) with the aim to evaluate their ability to predict in vivo gastrointestinal drug disposition. The selected in vitro methodologies were found capable of qualitatively and/or quantitatively picking up trends observed in the intraluminal sampling study. © 2020 Elsevier B.V.

In December 2019, The United States Pharmacopeia (USP) organized a 2-day workshop to explore new approaches to assess in vitro performance of drug products. Experts from around the globe presented processes, techniques, systems that can be used to evaluate and model in vitro performance of different pharmaceutical dosage forms. The following is a summary of most of the presentations and the highlights of the discussions that ensued. © 2020, Dissolution Technologies Inc. All rights reserved.

We evaluated the usefulness of quality control dissolution data collected with compendial Apparatus I and II, biorelevant dissolution data collected with compendial apparatus IV, and bioaccessibility data collected with the non-compendial tiny-TIM system in screening modified release formulations during the development of BCS Class I compounds using a Boehringer Ingelheim model experimental compound, A6197. Four products were investigated: an immediate release tablet, an extended release tablet, modified release mini-tablets, and extended release pellets. Data with modified release products collected with the compendial apparatus were evaluated vs. the average intraluminal dissolution estimated after deconvoluting clinical data collected in healthy adults. Data collected with the tiny-TIM system were evaluated vs. the average AUC and Cmax values estimated from the clinical data. Unlike with the quality control data collected with Apparatus I and II, data collected with Apparatus IV data and Level I biorelevant media adequately described the intraluminal dissolution process of the three modified release products. Data deviated less than 10% from the actual average deconvoluted intraluminal dissolution profiles, illustrating the usefulness of Apparatus IV biorelevant data in understanding the intraluminal dissolution process of BCS class I small molecules administered as modified release products in the fasted state. Total bioaccessibility data and maximum bioaccessibility data collected using the tiny-TIM and the immediate release tablet and the three modified release drug products correctly reproduced the ranking of A6197 AUC values (R2 = 0.989) and Cmax values (R2 = 0.962), respectively, illustrating tiny-TIM as a useful system for formulation selection of BCS class I small molecules administered in the fasted state. © 2020 Elsevier B.V.

Objectives: Using the type of meal and dosing conditions suggested by regulatory agencies as a basis, this review has two specific objectives: first, to summarize our understanding on the impact of food intake on luminal environment and drug product performance and second, to summarize the usefulness and limitations of available in vitro and in silico methodologies for the evaluation of drug product performance after food intake. Key findings: Characterization of the luminal environment and studies evaluating product performance in the lumen, under conditions suggested by regulatory agencies for simulating the fed state, are limited. Various in vitro methodologies have been proposed for evaluating drug product performance in the fed state, but systematic validation is lacking. Physiologically based pharmacokinetic (PBPK) modelling approaches require the use of in vitro biorelevant data and, to date, have been used primarily for investigating the mechanisms via which an already observed food effect is mediated. Summary: Better understanding of the impact of changes induced by the meal administration conditions suggested by regulatory agencies on the luminal fate of the drug product is needed. Relevant information will be useful for optimizing the in vitro test methods and increasing the usefulness of PBPK modelling methodologies. © 2018 Royal Pharmaceutical Society

Oregano essential oil (EO) was encapsulated by spray drying emulsions stabilized with polysaccharides. Both, emulsions and spray-dried powder (SDP) were characterized physicochemically and SDP was compressed into tablets with low (10% w/w) and high (20% w/w) EO content. Compression behavior, redispersibility and release of EO were studied. Antimicrobial activity of reconstituted emulsions was evaluated by disc diffusion and broth dilution. SDP showed good EO encapsulation efficiency and retained high carvacrol content. SDP with low EO content formed strong tablets, whereas SDP with high EO formed weaker tablets but with acceptable mechanical strength and friability. Oil leakage due to compression was negligible. Reconstitution of original emulsion was faster from the SDP than the tablets and the use of disintegrants did not show improvement. Interestingly, addition of croscarmellose sodium (CCS) greatly increased the release rate of EO from tablets despite lack of effect on redispersibility, possibly due to fast liquid uptake/swelling by the CCS fibres combined with repulsion between negatively charged carboxyl groups on CCS and gum Arabic resulting in opening of the microencapsulating wall. Sodium starch glycolate had small effect on release. The antimicrobial activity of reconstituted emulsions relative to neomycin ranked in the order: E coli < Klebsiella sp < S aureus < P mirabilis. © 2019 Elsevier B.V.

Amorphous solid dispersions (ASDs) represent an important formulation technique to achieve supersaturation in gastrointestinal fluids and to enhance absorption of poorly water-soluble drugs. Drug release from such systems is complex due to emergence of different colloidal structures and potential drug precipitation, which can occur in parallel to absorption. The latter drug uptake from the intestinal lumen can be simulated by an organic layer in a biphasic in vitro test, which was employed in this work to mechanistically study the release of ketoconazole from ASDs produced by hot melt extrusion using different HPMCAS grades. A particular aim was to introduce diffusing wave spectroscopy (DWS) to biopharmaceutical testing of solid dispersions. Results indicated that amorphous formulations prevented crystallization of the weakly basic drug upon transfer into the intestinal medium. Microrheological differences among polymer grades and plasticizers were revealed in the aqueous phase, which affected drug release and subsequently uptake into the organic layer. The results indicate that DWS can be employed as a new non-invasive tool to better understand drug release from solid dispersions. This novel light scattering technique is highly promising for future biopharmaceutical research on supersaturating systems such as solid dispersions. © 2019 Elsevier B.V.

Oral administration is the most common route of drug delivery. The absorption of a drug from the gut into the bloodstream involves disintegration of the solid dosage form, dissolution of the active pharmaceutical ingredient and its transport across the gut wall. The efficiency of these processes is determined by highly complex and dynamic interplay between the gastrointestinal tract, the dosage form and the API. The European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP)aims to improve our understanding of intestinal drug absorption by creating a multidisciplinary Network of researchers from academia and industry engaging in scientific discussions. As part of the basis for the UNGAP project, this review aims to summarize the current knowledge on anatomy and physiology of the human gastrointestinal tract with emphasis on human studies for the evaluation of the regional drug absorption and the prediction of oral dosage form performance. A range of factors and methods will be considered, including imaging methods, intraluminal sampling and, models for predicting segmental/regional absorption. In addition, in vitro and in silico methods to evaluate regional drug absorption will be discussed. This will provide the basis for further work on improving predictions for the in vivo behavior of drug products in the gastrointestinal tract. © 2019 The Authors

Solid dispersions provide a key technology to formulate poorly water-soluble drugs, and a main task of early development is appropriate selection of polymer. This study investigates the use of a novel rheology-based approach to evaluate miscibility and interactions of drugs with polymers regarding amorphous solid drug dispersions for oral administration. Tacrolimus was used as model drug and hydroxypropyl cellulose, ethylcellulose, Soluplus®, polyethyleneglycol 6000, Poloxamer-188 (Koliphor-188), and Eudragit® S100 were used as excipients. Solvent-based evaporation methods were used to prepare binary solid dispersions of drug and polymer. Data of the dilute solution viscosimetry were compared with in silico calculations of the Hansen solubility parameter (HSP), as well as phase separation/crystallization data obtained from X-ray diffraction and differential scanning calorimetry. HSP calculations in some cases led to false positive predictions of tacrolimus miscibility with the tested polymers. The novel rheology-based method provided valuable insights into drug-polymer interactions and likely miscibility with polymer. It is a rather fast, inexpensive, and robust analytical approach, which could be used complementary to in silico-based evaluation of polymers in early formulation development, especially in cases of rather large active pharmaceutical ingredients. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

The availability of in vitro tools that are constructed on the basis of a detailed knowledge of key aspects of gastrointestinal (GI) physiology and their impact on formulation performance and subsequent drug release behaviour is fundamental to the success and efficiency of oral drug product development. Over the last six years, the development and optimization of improved, biorelevant in vitro tools has been a cornerstone of the IMI OrBiTo (Oral Biopharmaceutics Tools) project. By bringing together key industry and academic partners, and by linking tool development and optimization to human studies to understand behaviour at the formulation/GI tract interface, the collaboration has enabled innovation, optimization and implementation of the requisite biorelevant in vitro tools. In this paper, we present an overview of the in vitro tools investigated during the collaboration and offer a perspective on their future use in enhancing the development of new oral drug products. © 2018 Elsevier B.V.

The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group “Food-Drug Interface”, the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives. © 2019 The Authors

The purpose of this study was to evaluate the usefulness of the in vitro biorelevant gastrointestinal transfer (BioGIT) system in assessing the impact of dose and formulation on early exposure by comparing in vitro data with previously collected human plasma data of low solubility active pharmaceutical ingredients. Eight model active pharmaceutical ingredients were tested; Lu 35-138C (salt of weak base in a HP-beta-CD solution, three doses), fenofibrate (solid dispersion, tablet, two doses), AZD2207 EQ (salt of weak base, capsule, three doses), posaconazole (Noxafil® suspension, two doses), SB705498 (weak base, tablets vs. capsules), cyclosporine A (Sandimmun® vs. Sandimmun® Neoral), nifedipine (Adalat® capsule vs. Macorel® tablet), and itraconazole (Sporanox® capsule vs. Sporanox® solution). AUC0–0.75h values were calculated from the apparent concentration versus time data in the duodenal compartment of the BioGIT system. Differences in AUC0–0.75h values were evaluated versus differences in AUC0–1h and in AUC0–2h values calculated from previously collected plasma data in healthy adults. Ratios of mean AUC0–0.75h, mean AUC0–1h, and mean AUC0–2h values were estimated using the lowest dose or the formulation with the lower AUC0–0.75h value as denominator. The BioGIT system qualitatively identified the impact of dose and of formulation on early exposure in all cases. Log-transformed mean BioGIT AUC0–0.75h ratios correlated significantly with log-transformed mean plasma AUC0–1h ratios. Based on this correlation, BioGIT AUC0–0.75h ratios between 0.3 and 10 directly reflect corresponding plasma AUC0–1h ratios. BioGIT system is a valuable tool for the assessment of the impact of dose and formulation on early exposure to low solubility drugs. © 2018, The Author(s).

Purpose: Optimize adult fecal material composition for evaluating the clinical importance of bacterial degradation of therapeutic agents in the lower intestine (distal small intestine, D-SI and proximal colon, P-COL). Evaluate the usefulness of optimized fecal material in the evaluation of bacterial degradation of five model highly permeable drugs: two nitroreductase substrates (nitrendipine and nimodipine), three drugs for which published data indicate no impact of bacterial degradation on in vivo performance (levodopa, budesonide and rivaroxaban) and one prodrug (sulfasalazine, an azoreductase substrate) from which a locally acting on the mucosa of the lower intestine drug is derived (mesalamine). Methods: 30 min and 95 min were used as point estimates of maximum bacterial degradation half-lives for bacterial degradation in D-SI or in P-COL, respectively, to be clinically important, i.e. for at least 20% reduction in absorption from D-SI or P-COL to occur. Optimization of fecal material was based on recently reported degradation profiles of metronidazole (a nitroreductase substrate) and olsalazine (an azoreductase substrate) in the lower intestine of healthy adults which are clinically important. Model compounds were tested in optimized fecal materials and data were evaluated vs. existing in vivo data in adults. Results: Simulated ileal bacteria (SIB) consisted of 5.5% (w/v) stools in normal saline and simulated colonic bacteria (SCoB) consisted of 8.3% (w/v) stools in normal saline. For all model compounds, data in SIB and SCoB were in line with available information in adults. [Degradation half-life in SIB/Degradation half-life in SCoB] ≈ [Stool content in SCoB/Stool content in SIB] ≈ 1.5, i.e. bacterial degradation in SIB could be predicted from bacterial degradation in SCoB. Conclusion: Data in SCoB only are useful for evaluating whether bacterial degradation in P-COL and in D-SI is likely to be clinically important for orally administered, highly permeable drugs or prodrugs which act locally after bacterial degradation. The usefulness of this approach in cases where enzymes other than nitroreductases or azoreductases are involved requires further confirmation. © 2018 Elsevier B.V.

Physiologically based absorption modeling has been attracting increased attention to study the interactions of weakly basic drug compounds with acid-reducing agents like proton-pump inhibitors and H2 blockers. Recently, standardized gastric and intestinal biorelevant media to simulate the achlorhydric and hypochlorhydric stomach were proposed and solubility and dissolution data for two model compounds were generated. In the current manuscript, for the first time, we report the utility of these recently proposed biorelevant media as input into physiologically based absorption modeling. Where needed, data collected with the biorelevant gastrointestinal transfer (BioGIT) system were used for informing the simulations in regard to the precipitation kinetics. Using two model compounds, a HCl salt and a semi-fumarate co-crystal which as expected dissolve to a greater extent in these media (and in gastric and intestinal human aspirates) compared to what the pH–solubility profile of the free form would suggest, we demonstrate successful description of the plasma concentration profiles and correctly predicted the lack of significant interaction after administration with pantoprazole or famotidine, respectively. Thus, the data reported in this manuscript represent an initial step towards defining biorelevant input for such simulations on interactions with acid-reducing agents. © 2018, American Association of Pharmaceutical Scientists.

Dissolution testing is an important physiochemical test for the development of solid oral dosage forms, tablets, and capsules. As a quality control test, the dissolution test is used for assessment of drug product quality and is specified for batch release and regulatory stability studies. In vitro dissolution test results can often be correlated with the biopharmaceutical behavior of a product.This article provides a summary of views from major global agencies (Europe, Japan, United States), pharmacopoeias, academia, and industry. Based on available guidance and literature, this article summarizes highlights for development and validation of a suitable dissolution method, setting appropriate specifications, in vitro–in vivo comparison, and how to obtain a biowaiver. © 2018 American Pharmacists Association®

Objectives. Drug precipitation in vivo poses a significant challenge for the pharmaceutical industry. During the drug development process, the impact of drug supersaturation or precipitation on the in vivo behaviour of drug products is evaluated with in vitro techniques. This review focuses on the small and full scale in vitro methods to assess drug precipitation in the fasted small intestine. Key findings. Many methods have been developed in an attempt to evaluate drug precipitation in the fasted state, with varying degrees of complexity and scale. In early stages of drug development, when drug quantities are typically limited, small‐scale tests facilitate an early evaluation of the potential precipitation risk in vivo and allow rapid screening of prototype formulations. At later stages of formulation development, full‐scale methods are necessary to predict the behaviour of formulations at clinically relevant doses. Multicompartment models allow the evaluation of drug precipitation after transfer from stomach to the upper small intestine. Optimisation of available biopharmaceutics tools for evaluating precipitation in the fasted small intestine is crucial for accelerating the development of novel breakthrough medicines and reducing the development costs. Summary. Despite the progress from compendial quality control dissolution methods, further work is required to validate the usefulness of proposed setups and to increase their biorelevance, particularly in simulating the absorption of drug along the intestinal lumen. Coupling results from in vitro testing with physiologically based pharmacokinetic modelling holds significant promise and requires further evaluation.

Purpose Evaluate ex vivo the bacterial metabolism induced degradation rates of mesalamine (negative control), metronidazole and olsalazine in distal ileum and in cecum. Methods The contents of distal ileum and cecum were collected during colonoscopy under anaerobic conditions from twelve healthy adults in the fasted and in the fed state. To eliminate potential effects of enzymes that may exist in the fluid of lower intestine, each sample was ultracentrifuged and the precipitate was diluted with a volume of normal saline equivalent to that of the supernatant, after ultracentrifugation of intestinal contents from which the specific precipitate had been obtained. Degradation of the three model drugs in individual materials was evaluated anaerobically. Results Mesalamine was stable in all cases. Degradation rates of metronidazole and olsalazine were higher in cecum than in distal ileum, only in the fasted state; no trend could be observed in the fed state. Degradation rates of metronidazole and olsalazine were decreased in the fed state in the cecum; no trend could be observed in distal ileum. Conclusions In the fasted state, bacterial activity is higher in cecum than in distal ileum. Food residues decrease bacterial metabolism degradation rates of drugs in cecum. © 2017 Elsevier B.V.

Objectives: To investigate at the ultrastructural level, the colloidal phases formed in the lumen of the distal ileum and caecum of healthy adults. Methods: Cryogenic transmission electron microscopy (Cryo-TEM) was employed to image the intermediate colloidal phases of human intestinal contents collected from distal ileum and caecum of two healthy volunteers under fasted and fed state conditions. Key findings: In samples collected both in the fasted and fed states, Cryo-TEM study revealed the presence of large spherical unilamellar and occasionally bi-lamellar and oligolamellar vesicles with diameters ranging from 50 to 200 nm for both volunteers in distal ileum and caecum. Bilayer fragments were frequently observed in caecal samples. Plate-like structures resembling the morphology of cholesterol plates were visualised in all samples. Elongated structures were observed in the fed state in distal ileum and caecum for both volunteers, whereas no micellar structures could be detected for all samples. Conclusions: This study provides a framework for understanding the structure of colloidal phases, and it may assist in elucidating the role of dosing conditions on drug absorption from the distal ileum and caecum. © 2017 Royal Pharmaceutical Society

Purpose To propose media for simulating the intragastric environment under reduced gastric acid secretion in the fasted state at three levels of simulation of the gastric environment and evaluate their usefulness in evaluating the intragastric dissolution of salts of weak bases. To evaluate the importance of bicarbonate buffer in biorelevant in vitro dissolution testing when using Level II biorelevant media simulating the environment in the fasted upper small intestine, regardless of gastric acid secretions. Methods Media for simulating the hypochlorhydric and achlorhydric conditions in stomach were proposed using phosphates, maleates and bicarbonates buffers. The impact of bicarbonates in Level II biorelevant media simulating the environment in upper small intestine was evaluated so that pH and bulk buffer capacity were maintained. Dissolution data were collected using two model compounds, pioglitazone hydrochloride and semifumarate cocrystal of Compound B, and the mini-paddle dissolution apparatus in biorelevant media and in human aspirates. Results Simulated gastric fluids proposed in this study were in line with pH, buffer capacity, pepsin content, total bile salt/lecithin content and osmolality of the fasted stomach under partial and under complete inhibition of gastric acid secretion. Fluids simulating the conditions under partial inhibition of acid secretion were useful in simulating concentrations of both model compounds in gastric aspirates. Bicarbonates in Level III biorelevant gastric media and in Level II biorelevant media simulating the composition in the upper intestinal lumen did not improve simulation of concentrations in human aspirates. Conclusions Level III biorelevant media for simulating the intragastric environment under hypochlorhydric conditions were proposed and their usefulness in the evaluation of concentrations of two model salts of weak bases in gastric aspirates was shown. Level II biorelevant media for simulating the environment in upper intestinal lumen led to underestimation of concentrations in aspirates, even when bicarbonate buffer was used. © 2017 Elsevier B.V.

The purpose of this article was two-fold: first, to optimize a recently proposed two-stage single-compartment in vitro test for the evaluation of dissolution in the lower intestine with the mini-paddle apparatus in the fasted and fed state using two model high dose, low solubility drugs [sulfasalazine (Azulfidine) and micronized aprepitant] and one mesalamine colon targeting product (Asacol, 400 mg/tablet); second, to evaluate the impact of passive absorption from the lower intestine on the overall absorption process using three model high dose, low solubility drugs [micronized aprepitant, SB705498, and albendazole (Zentel)]. The intensity of agitation and the physicochemical characteristics of fluids simulating the environment in the distal ileum and the proximal colon were optimized and the importance of solid particles was evaluated. Dissolution data collected under conditions simulating the upper and lower intestine were coupled with physiologically based oral absorption modeling to simulate the average plasma levels or the average absorption process. Reliability of the modeling approach was evaluated based on previously collected data in adults. The impact of solid particles on dissolution in the lower intestine was found to be clinically insignificant for Asacol tablets, as well as for sulfasalazine (Azulfidine) and micronized aprepitant. Average plasma levels (micronized aprepitant and SB705498) and cumulative amount absorbed (albendazole) could be adequately simulated by referring only to events in the upper gastrointestinal lumen, indicating that the impact of absorption from the lower intestine on actual plasma levels was minimal. Dissolution of Asacol tablets and immediate release formulations in the lower intestine can be adequately evaluated by employing Level II biorelevant media. However, simulation of actual drug particle dissolution in the lower intestine is not typically necessary for adequate prediction of oral absorption from immediate release formulations containing discrete, dispersed particles of lipophilic drugs. © 2017 American Chemical Society.