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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.(c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Hydroxypropyl-β-cyclodextrin (HP-β-CD) is known to enable absorption of the lipophilic drug itraconazole. Since the interaction between HP-β-CD and itraconazole is characterized by a non-lineair, AP-type phase-solubility diagram, the present study aimed to investigate the influence of intraluminal dilution (water intake) on the behavior and performance of an orally administered cyclodextrin-based solution of itraconazole. Subsequently, the in vivo behavior was simulated by combining in vitro dilution with permeation assessment. After the administration of a Sporanox® solution to healthy volunteers with or without a glass of water, gastrointestinal and systemic concentrations of itraconazole were simultaneously monitored. Independently of the intake of water, no gastric precipitation of itraconazole was observed. After transfer to the duodenum, precipitation occurred and was more pronounced in the condition with water, resulting in a 7.6-fold reduction in duodenal AUC0-3h compared to the condition without water. Nevertheless, plasma concentration-time profiles did not demonstrate any significant differences in AUC0-8h, Cmax and tmax. Application of freshly aspirated intestinal fluids on Caco-2 cells clearly confirmed that higher intestinal itraconazole concentrations after intake of Sporanox® without water do not generate a substantially increased itraconazole uptake. A two-stage in vitro dilution test was combined with a permeation compartment to capture this solubility-permeability interplay. In conclusion, this work demonstrates that variations in intraluminal dilution may have a drastic impact on the gastrointestinal behavior of lipophilic drugs in the presence of cyclodextrins. In the case of an AP-type interaction with cyclodextrins, the trade-off between solubility and permeability may be affected.

Following a previous study which aimed to determine the interlaboratory reproducibility of biorelevant dissolution testing in the USP 2 apparatus for commercial formulations of two weak acids (ibuprofen and zafirlukast), this study attempts to determine the interlaboratory reproducibility using a similar protocol for a commercially available formulation of a weak base, indinavir. Fourteen partners including twelve industrial and two academic partners participated in this study. To ensure uniformity, all partners were provided with a standardized protocol to perform (i) a single medium dissolution test in fasted state simulated gastric and intestinal fluids (FaSSGF and FaSSIF, respectively) and (ii) a two-stage dissolution experiment simulating gastrointestinal transfer. Optionally, partners could run a single-stage dissolution test in fed state simulated intestinal fluid (FeSSIF). For each dissolution test, one Crixivan® capsule (containing 400 mg indinavir as its sulfate salt) was added as dose of interest. For the single medium dissolution test in FaSSIF, all partners observed rapid release of indinavir resulting in supersaturated concentrations, followed by precipitation to equilibrium solubility. The degree and period of supersaturation varied among the participating laboratories. Average dissolution profiles in FeSSIF appeared to be highly reproducible with dissolved concentrations remaining lower than the thermodynamic solubility of indinavir in FeSSIF. For the two-stage dissolution test, most partners observed supersaturated concentrations in the intestinal compartment; two partners observed no supersaturation due to immediate precipitation. Given the fact that a high interlaboratory but low intralaboratory variability was observed when supersaturation/precipitation occurred, an undefined factor was hypothesized as a potential cause of the variability in precipitation. Hence, the impact of several experimental factors on the supersaturation and precipitation behavior of indinavir was investigated in a next step. The investigation indicated that variability is likely attributable to a combination of factors, especially, the time elapsed between sampling and dilution of the sample with the mobile phase. Therefore, when designing a test in which supersaturation and precipitation is anticipated, stringent control of the test methodology, especially regarding sampling and dilution, is needed. ispartof: EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS vol:140 pages:141-148 ispartof: location:Netherlands status: published

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. ispartof: EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS vol:136 pages:70-83 ispartof: location:Netherlands status: published

In a previously performed small-scale clinical study, healthy volunteers were asked to ingest an oral solution of itraconazole (Sporanox®) containing 40% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) (i) with or (ii) without a standardized volume of water (240 mL) after which gastrointestinal and blood samples were collected. Although omitting water during the administration of Sporanox® resulted in noticeably higher duodenal concentrations of itraconazole, systemic exposure was almost unaffected. It is assumed that this discrepancy can be explained by differences in the extent of entrapment of itraconazole in the duodenum caused by differential complexation depending on the concentration of cyclodextrins. To further substantiate this hypothesis, the quantification of HP-β-CD concentrations in the aspirated intestinal fluids was performed by LC-MS/MS. When comparing the intestinal concentrations of itraconazole and HP-β-CD for one single healthy volunteer (HV02) in both test conditions, an excellent correlation was observed (Spearman's rank coefficient of 0.96). Moreover, the data suggest that, similar to aqueous buffer media, also in human intestinal fluids a non-linear relationship exists between itraconazole solubility and HP-β-CD concentration (Ap-type profile; Spearman's rank coefficient of 0.78), indicating that higher order complexes are formed at higher concentrations of HP-β-CD. This difference in extent of entrapment in the inclusion complexes helps to understand the observed impact of water intake on precipitation and permeation behavior of itraconazole in man. Without water intake, higher HP-β-CD concentrations resulted in less precipitation and increased duodenal concentrations of itraconazole. On the other hand, the stronger interaction at higher HP-β-CD concentrations reduced the free fraction of the drug explaining that increased intraluminal concentrations of itraconazole were not translated into an enhanced uptake. In conclusion, quantifying the concentrations of the solubilizing agent HP-β-CD in human intestinal fluids appeared to be of crucial importance to interpret the intraluminal behavior of an orally administered cyclodextrin-based solution. ispartof: EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS vol:13 pages:231-236 ispartof: location:Netherlands status: published

Cell-free permeation systems are gaining interest in drug discovery and development as tools to obtain a reliable prediction of passive intestinal absorption without the disadvantages associated with cell- or tissue-based permeability profiling. Depending on the composition of the barrier, cell-free permeation systems are classified into two classes including (i) biomimetic barriers which are constructed from (phospho)lipids and (ii) non-biomimetic barriers containing dialysis membranes. This review provides an overview of the currently available cell-free permeation systems including Parallel Artificial Membrane Permeability Assay (PAMPA), Phospholipid Vesicle-based Permeation Assay (PVPA), Permeapad®, and artificial membrane based systems (e.g. the artificial membrane insert system (AMI-system)) in terms of their barrier composition as well as their predictive capacity in relation to well-characterized intestinal permeation systems. Given the potential loss of integrity of cell-based permeation barriers in the presence of food components or pharmaceutical excipients, the superior robustness of cell-free barriers makes them suitable for the combined dissolution/permeation evaluation of formulations. While cell-free permeation systems are mostly applied for exploring intestinal absorption, they can also be used to evaluate non-oral drug delivery by adjusting the composition of the membrane. ispartof: European Journal of Pharmaceutical Sciences vol:119 pages:219-233 ispartof: location:Netherlands status: published

In addition to its important role in preventing the interaction of toxic agents with the intestinal lining, the intestinal mucus layer can impede the permeation of drugs. The purpose of this study was to evaluate whether the presence of HP-β-CD in the intraluminal environment could influence the permeation of drugs through a layer of mucus. To this end, a new artificial membrane insert system incorporating a fixed mucus layer was developed to monitor the permeation of methylparaben (log P=1.96) and heptylparaben (log P=4.83). While the transport of methylparaben remained unaffected by the mucus layer, the transport of heptylparaben was significantly impeded by the mucus layer. In presence of relatively low concentrations of HP-β-CD, however, this negative effect of mucus on the permeation of heptylparaben disappeared. Importantly, the impact of the mucus layer was found to depend on the composition of the solvent system used. The colloidal structures present in simulated intestinal media were able to neutralize the impeding effect of mucus on heptylparaben permeation observed when using simple phosphate buffers. These findings advocate the use of biorelevant media when studying the impact of the mucus layer on drug permeation. ispartof: European Journal Of Pharmaceutical Sciences vol:114 pages:238-244 ispartof: location:Netherlands status: published

In view of the increasing interest of pharmaceutical companies for cell- and tissue-free models to implement permeation into formulation testing, this study explored the capability of an artificial membrane insert system (AMI-system) as predictive tool to evaluate the performance of absorption-enabling formulations. Firstly, to explore the usefulness of the AMI-system in supersaturation assessment, permeation was monitored after induction of different degrees of loviride supersaturation. Secondly, to explore the usefulness of the AMI-system in formulation evaluation, a two-stage dissolution test was performed prior to permeation assessment. Different case examples were selected based on the availability of in vivo (intraluminal and systemic) data: (i) a suspension of posaconazole (Noxafil®), (ii) a cyclodextrin-based formulation of itraconazole (Sporanox®), and (iii) a micronized (Lipanthyl®) and nanosized (Lipanthylnano®) formulation of fenofibrate. The obtained results demonstrate that the AMI-system is able to capture the impact of loviride supersaturation on permeation. Furthermore, the AMI-system correctly predicted the effects of (i) formulation pH on posaconazole absorption, (ii) dilution on cyclodextrin-based itraconazole absorption, and (iii) food intake on fenofibrate absorption. Based on the applied in vivo/in vitro approach, the AMI-system combined with simple dissolution testing appears to be a time- and cost-effective tool for the early-stage evaluation of absorption-enabling formulations. ispartof: International Journal of Pharmaceutics vol:537 issue:1-2 pages:22-29 ispartof: location:Netherlands status: published

Dissolution testing with biorelevant media has become widespread in the pharmaceutical industry as a means of better understanding how drugs and formulations behave in the gastrointestinal tract. Until now, however, there have been few attempts to gauge the reproducibility of results obtained with these methods. The aim of this study was to determine the interlaboratory reproducibility of biorelevant dissolution testing, using the paddle apparatus (USP 2). Thirteen industrial and three academic laboratories participated in this study. All laboratories were provided with standard protocols for running the tests: dissolution in FaSSGF to simulate release in the stomach, dissolution in a single intestinal medium, FaSSIF, to simulate release in the small intestine, and a "transfer" (two-stage) protocol to simulate the concentration profile when conditions are changed from the gastric to the intestinal environment. The test products chosen were commercially available ibuprofen tablets and zafirlukast tablets. The biorelevant dissolution tests showed a high degree of reproducibility among the participating laboratories, even though several different batches of the commercially available medium preparation powder were used. Likewise, results were almost identicalbetween the commercial biorelevant media and those produced in-house. Comparing results to previous ring studies, including those performed with USP calibrator tablets or commercially available pharmaceutical products in a single medium, the results for the biorelevant studies were highly reproducible on an interlaboratory basis. Interlaboratory reproducibility with the two-stage test was also acceptable, although the variability was somewhat greater than with the single medium tests. Biorelevant dissolution testing is highly reproducible among laboratories and can be relied upon for cross-laboratory comparisons.

Despite reasonable predictive power of current cell-based and cell-free absorption models for the assessment of intestinal drug permeability, high costs and lengthy preparation steps hamper their use. The use of a simple artificial membrane (without any lipids present) as intestinal barrier substitute would overcome these hurdles. In the present study, a set of 14 poorly water-soluble drugs, dissolved in 2 different media (fasted state simulated/human intestinal fluids [FaSSIF/FaHIF]), were applied to the donor compartment of an artificial membrane insert system (AMI-system) containing a regenerated cellulose membrane. Furthermore, to investigate the predictive capacity of the AMI-system as substitute for the well-established Caco-2 system to assess intestinal permeability, the same set of 14 drugs dissolved in FaHIF were applied to the donor compartment of a Caco-2 system. For 14 drugs, covering a broad range of physicochemical parameters, a reasonable correlation between both absorption systems was observed, characterized by a Pearson correlation coefficient r of 0.95 (FaHIF). Using the AMI-system, an excellent predictive capacity of FaSSIF as surrogate medium for FaHIF was demonstrated (r = 0.96). Based on the acquired data, the AMI-system appears to be a time- and cost-effective tool for the early-stage estimation of passive intestinal permeability for poorly water-soluble drugs. ispartof: Journal of Pharmaceutical Sciences vol:107 issue:1 pages:250-256 ispartof: location:United States status: published

MAGL is a potential therapeutic target for oncological and psychiatric diseases. Our objective was to develop a PET tracer for in vivo quantification of MAGL. We report [

MAGL is a potential therapeutic target for oncological and psychiatric diseases. Our objective was to develop a PET tracer for in vivo quantification of MAGL. We report [11C]MA-PB-1 as an irreversible MAGL inhibitor PET tracer. The in vitro inhibitory activity, ex vivo distribution, brain kinetics and specificity of [11C]MA-PB-1 binding were studied. Ex vivo biodistribution and microPET showed good brain uptake which could be blocked by pretreatment with both MA-PB-1 and a structurally non-related MAGL inhibitor MJN110. These initial results suggest that [11C]MA-PB-1 is a suitable tracer for in vivo imaging of MAGL., final draft, peerReviewed

Enteric-coated fixed-dose combinations of ezetimibe and lovastatin were prepared by fluid bed coating aiming to avoid the acidic conversion of lovastatin to its hydroxyacid derivative. In a two-step process, sucrose beads were layered with a glass solution of ezetimibe, lovastatin and Soluplus®, top-coated with an enteric layer. The impact of different bead size, enteric polymers (Eudragit L100® and Eudragit L100-55®) and coating time was investigated. Samples were evaluated by X-ray diffraction, scanning electron microscopy, laser diffraction and in vitro studies in 0.1M HCl and phosphate buffer pH 6.8. Results showed that smaller beads tend to agglomerate and release was jeopardized in acidic conditions, most likely due to irregular coating layer. Eudragit L100-55® required longer processing, but thinner coating layers provided lower drug release. Both polymers showed low drug release in acidic environment and fast release at pH 6.8. The off-line measurement of the coating thickness determined the ideal coating time as 15 and 30min for Eudragit L100-55® and Eudragit L100®-based samples, respectively. Both compounds were molecularly dispersed in Soluplus®, and Eudragit L100® formulations showed concave pores on the surface, presenting higher drug release in acidic conditions. Stability studies after 6 months showed unaltered physical properties and drug release. publisher: Elsevier articletitle: Development of enteric-coated fixed dose combinations of amorphous solid dispersions of ezetimibe and lovastatin: Investigation of formulation and process parameters journaltitle: International Journal of Pharmaceutics articlelink: http://dx.doi.org/10.1016/j.ijpharm.2017.01.053 content_type: article copyright: © 2017 Elsevier B.V. All rights reserved. ispartof: International Journal of Pharmaceutics vol:520 issue:1-2 pages:49-58 ispartof: location:Netherlands status: published