Advanced Drug Delivery Reviews 101 (2016) 75–88
`
`Contents lists available at ScienceDirect
`
`Advanced Drug Delivery Reviews
`
`j o u r na l h om e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / a d d r
`
`Navigating the human gastrointestinal tract for oral drug delivery:
`Uncharted waters and new frontiers☆
`Mirko Koziolek a,b, Michael Grimm a, Felix Schneider a, Philipp Jedamzik a, Maximilian Sager a, Jens-Peter Kühn c,
`Werner Siegmund d, Werner Weitschies a,⁎
`
`a Department of Pharmaceutical Technology and Biopharmacy, Center of Drug Absorption and Transport, Ernst-Moritz-Arndt-University, Felix-Hausdorff-Strasse 3, D-17487 Greifswald, Germany
`b Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
`c Department of Diagnostic Radiology and Neuroradiology, Ernst-Moritz-Arndt-University, Ferdinand-Sauerbruch-Strasse, Greifswald D-17475, Germany
`d Department of Clinical Pharmacology, Center of Drug Absorption and Transport, Ernst-Moritz-Arndt-University, Felix-Hausdorff-Strasse 3, D-17487 Greifswald, Germany
`
`a r t i c l e
`
`i n f o
`
`a b s t r a c t
`
`Many concepts of oral drug delivery are based on our comprehension of human gastrointestinal physiology. Un-
`fortunately, we tend to oversimplify the complex interplay between the various physiological factors in the
`human gut and, in particular, the dynamics of these transit conditions to which oral dosage forms are exposed.
`Recent advances in spatial and temporal resolution of medical instrumentation as well as improved access to
`these technologies have facilitated clinical trials to characterize the dynamic processes within the human gastro-
`intestinal tract. These studies have shown that highly relevant parameters such as fluid volumes, dosage form
`movement, and pH values in the lumen of the upper GI tract are very dynamic. As a result of these new insights
`into the human gastrointestinal environment, some common concepts and ideas of oral drug delivery are no
`longer valid and have to be reviewed in order to ensure efficacy and safety of oral drug therapy.
`© 2016 Elsevier B.V. All rights reserved.
`
`Article history:
`Received 1 February 2016
`Received in revised form 17 March 2016
`Accepted 20 March 2016
`Available online 29 March 2016
`
`Keywords:
`Drug absorption
`Oral drug delivery
`Gastrointestinal dynamics
`Gastrointestinal hydrodynamics
`Gastrointestinal motility
`Absorption window
`Food effect
`Biorelevant dissolution testing
`
`Contents
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`2.2.
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`2.3.
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`3.
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`Introduction .
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`Gastrointestinal (hydro)dynamics .
`Luminal fluid volumes .
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`2.1.
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`2.1.1.
`Fasted state
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`2.1.2.
`Fed state .
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`Transit of dosage forms through the GI tract
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`2.2.1.
`Fasted state
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`2.2.2.
`Fed state .
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`Luminal pH values
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`2.3.1.
`Fasted state
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`2.3.2.
`Fed state .
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`Implications for dissolution testing
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`Consequences and assumptions .
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`4.1.
`Are enteric coatings made for the dissolution tester? .
`Drug absorption from the small intestine—do we assume the right luminal concentrations?
`4.2.
`The common intake advice—are patients really fasted 2 h after a meal? .
`4.3.
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`Acknowledgment .
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`References .
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`☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Understanding the challenges of beyond-rule-of-5 compounds”.
`⁎ Corresponding author. Tel.: +49 3834 864813; fax: +49 3834 864886.
`E-mail address: werner.weitschies@uni-greifswald.de (W. Weitschies).
`
`http://dx.doi.org/10.1016/j.addr.2016.03.009
`0169-409X/© 2016 Elsevier B.V. All rights reserved.
`
`Page 1
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`SHIRE EX. 2042
`KVK v. SHIRE
`IPR2018-00293
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`

`

`76
`
`1. Introduction
`
`M. Koziolek et al. / Advanced Drug Delivery Reviews 101 (2016) 75–88
`
`The oral administration is the most obvious, the most convenient,
`and, as a consequence, the prevalent route for drug therapy. Unfortu-
`nately, it is not as simple as it seems. The extent and rate of drug absorp-
`tion from the gastrointestinal (GI) tract depends on different factors
`that are either related with the drug itself, the formulation or the patient
`(Table 1) [1–10]. It is typically not known which of the numerous con-
`founding influences effectively affects drug absorption from the GI
`tract. Despite manifold attempts using animal models, in vitro, tissue
`or cell culture test systems as well as in silico calculations, reliable pre-
`dictions of the extent and rate of drug absorption in man – as well as in
`other species – are extremely difficult and often deficient. Obviously,
`there are still many “unknowns” that are determining drug absorption
`from the GI tract. Thus, the determination of oral bioavailability and the
`identification of parameters that might interfere with drug absorption,
`e.g., metabolizing enzymes, uptake, and efflux transporters or concomi-
`tant food, intake, are still a matter of human drug absorption studies.
`In the vast majority, the available absorption characteristics have
`been obtained in clinical studies on pharmacokinetics or bioequivalence
`with healthy volunteers under the strongly standardized phase I condi-
`tions that do not reflect the real life situation. Unfortunately, only a very
`few information is available for drug absorption under “real life” condi-
`tions or in patients with certain diseases. However, to understand the
`physiological rationale behind drug absorption from the GI tract, it is es-
`sential to characterize the conditions under which pharmacokinetic
`data are gathered.
`The present article was written to point out the often neglected im-
`portance of the dynamics of the gastrointestinal conditions for the
`in vivo performance of orally administered medications in both fasted
`and fed subjects. We will provide examples for dynamic processes in
`the human gut as recently explored using modern medical measure-
`ment technologies and explain how these processes may influence
`oral drug absorption. Particular attention is paid to the gastrointestinal
`conditions arising in clinical trials as they are the background of the
`pharmacokinetic data published in literature. Moreover, we will discuss
`adapted dissolution test methods capable of simulating critical dynamic
`conditions arising during the GI passage of oral dosage forms, as well as
`possible contributions of gastrointestinal dynamics to the variability in
`drug absorption of small and large molecules. It must be noted that
`this article expresses the authors' opinions and that it is specifically
`focused on selected physiological parameters in stomach and small
`intestine rather than on comprehensively reviewing the transit
`conditions in the human GI tract or the biopharmaceutical tools used
`to predict oral drug absorption. The interested reader is referred to
`reviews published by the European Innovative Medicines Initiative
`(IMI) on Oral Biopharmaceutics Tools (OrBiTo) and others [11–16].
`
`2. Gastrointestinal (hydro)dynamics
`
`The recent progress in non-invasive medical measurement tech-
`niques such as magnetic resonance imaging (MRI), magnetic marker
`
`monitoring (MMM) or telemetric capsules, and the rapidly advancing
`capabilities of medical imaging devices provided new fascinating in-
`sights into gastrointestinal physiology, but also into the fate of orally ad-
`ministered drugs and drug delivery systems within the human GI tract
`[17–19]. Furthermore, some groups even re-evaluated old knowledge
`on gastrointestinal physiology and came up with surprising results.
`For instance, Helander and Fändriks revealed that the surface of the
`human gut mucosa is not in the order of a tennis court (250–300 m2),
`but approximately half the size of a badminton court (approximately
`32 m2) [20].
`Apart from major improvements in image quality and spatial resolu-
`tion, modern medical measurement techniques provide essentially
`higher temporal resolution. The reduction of measurement duration
`and movement artifacts led to a turn of the acquired information from
`rather static to dynamic. As a result, a number of studies were conduct-
`ed in recent years, which aimed at the characterization of the dynamics
`of the gastrointestinal transit conditions. These studies showed that the
`common idea of a more or less continuous transport of drug delivery
`systems and drug substances through the GI tract was a misconception.
`Indeed, the opposite holds true as the gastrointestinal transport of solid
`oral dosage forms was found to be extremely discontinuous. In all major
`segments of the GI tract, i.e., stomach, small intestine, and colon, gastro-
`intestinal transport is characterized by phases of rest, slow propagation,
`and events of rapid transport of variable duration and range.
`In the following chapters, we will present the results of recent stud-
`ies, in which the dynamics in the upper GI tract were investigated with
`the aid of modern medical measurement technologies in both fasted
`and fed state. We will focus on luminal fluid volumes, pH values, and
`GI motility, and we will discuss how these parameters may affect the
`gastrointestinal transit behavior of solid oral dosage forms.
`
`2.1. Luminal fluid volumes
`
`2.1.1. Fasted state
`In the current guidelines for the determination of oral bioavailability
`or bioequivalence, investigations in fasted state are recommended after
`a fasting period of at least 8 h (EMA) or 10 h (FDA) prior to drug admin-
`istration together with at least 150 mL (EMA) or 240 mL of water (FDA)
`[21–23]. After such long overnight fasting period, the stomach is
`regarded as almost empty. However, a small volume of gastric content
`is always present in the gastric lumen. Recent MRI investigations that
`considered the conditions of the guidelines revealed that the fasted
`state volume of the stomach is typically below 50 mL but can vary con-
`siderably (Table 2). These data are in good accordance with published
`data for fasted state gastric content volumes determined with other
`tools under varying conditions [24,25].
`The (hydro)dynamic conditions in the fasted human upper GI tract
`mainly result from the distinct cyclic pattern of propagating myoelectric
`activation that typically starts in the stomach and ends in the distal
`small intestine, the so-called interdigestive migrating motor complex
`(IMMC) [32]. As can be seen in Fig. 1, the IMMC consists of three phases
`of different duration. Phase I is a longer phase of rest, whereas phases II
`and III are characterized by strong motility. In particular, during phase
`
`Table 1
`Different factors known to influence drug absorption from the gastrointestinal tract
`[1–10].
`
`Formulation-related
`factors
`Drug release profile
`Excipients
`
`Drug-related factors
`
`Molecular weight
`Water solubility
`Partition coefficient
`Stability toward gastrointestinal
`conditions, including digestive
`enzymes and pH values in the
`physiological range of pH 1–8
`
`Patient-related
`factors
`
`Intake condition
`Disease
`Age
`Ethnic group
`Genetic polymorphisms
`Gender
`Lifestyle and eating habit
`Co-medications
`
`Table 2
`Gastric content volumes after a fasting period of at least 8 h as determined by MRI
`(n/a—unreported data).
`
`MRI study
`
`No. of subjects
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`Gastric content volumes (mL)
`
`Schiller et al. [26]
`Goetze et al. [27]
`Goetze et al. [28]
`Babaei et al. [29]
`Koziolek et al. [30]
`Mudie et al. [31]
`Data on file
`
`n = 12
`n = 12
`n = 12
`n = 10
`n = 12
`n = 12
`n = 72
`
`Min
`
`Max
`
`Median
`
`Mean ± SD
`
`13
`n/a
`n/a
`n/a
`4
`n/a
`1
`
`72
`n/a
`n/a
`n/a
`64
`n/a
`95
`
`47
`n/a
`n/a
`n/a
`28
`n/a
`17
`
`45 ± 18
`65 ± 22
`40 ± 27
`85 ± 29
`31 ± 19
`35 ± 7
`21 ± 17
`
`Page 2
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`M. Koziolek et al. / Advanced Drug Delivery Reviews 101 (2016) 75–88
`
`77
`
`observed variability in residual gastric content volumes reflects the
`time that has passed since the last housekeeping wave. During the sub-
`sequent quiescent phase I of the IMMC, oral and gastric secretions are
`gathered within the lumen of the stomach, but not emptied into the
`small intestine. Assuming a typical basal gastric secretion rate of about
`1 mL/min and a saliva flow rate of 0.1–1 mL/min, about 75 mL of gastric
`juice may accumulate within 1 h after the last IMMC phase III [33].
`Under fasting conditions, the 240 mL of water co-ingested with the
`medication according to the guidelines is emptied from the stomach
`typically within 15–30 min, as shown by Mudie and co-workers
`(Fig. 2) [31]. It is believed that non-caloric liquids such as water are
`emptied from the stomach mainly by contractions of the distended
`stomach wall. Even though the volunteers are in supine position during
`the MRI investigations, gastric water emptying in fasted state is almost
`complete. Fig. 3 illustrates nicely how MRI can be used to visualize the
`process of gastric emptying of water.
`The small intestine is mostly empty in fasted subjects and, unlike the
`gas filled colon, the small intestinal walls are collapsed. Non-absorbed
`small intestinal fluid is segregated in a few “fluid pockets” of variable
`volume [26]. After overnight fasting, a mean total volume of about 50
`to 100 mL of fluid is present in the small intestine (Table 3).
`The largest pocket is typically found in the terminal ileum (see
`Fig. 4), where also non-absorbable material gathers. By contrast, free
`water is rarely observed in the colon [26], although the typical filling
`volumes of the colon are high [35].
`The 240 mL of water swallowed for drug administration obviously
`undergo rapid absorption from the small intestine. Thus, the total fluid
`volume in the small intestine remains nearly unchanged [31]. Water
`reaching the small intestine is immediately scattered over the jejunum
`and absorbed as illustrated in Fig. 5. The common idea of a water front
`traveling rather slowly down the small intestine is not supported by
`MRI data undertaken with high sampling rates.
`
`2.1.2. Fed state
`Food intake leads to numerous physiological changes in the upper
`GI tract and, therefore, can exert significant effects on drug absorption
`[33,36]. A classification of how food intake can influence drug absorp-
`tion from the human GI tract is given in Fig. 6.
`In order to investigate the impact of food on drug absorption, most
`food effect studies are performed according to the guidelines of FDA
`and EMA [21–23]
`. These studies follow a study protocol, which is equiv-
`alent to the one used for fasted state investigations, with the only differ-
`ence that the subjects receive a high-caloric (800–1000 kcal), high-fat
`(50% of the calories derived from fat) breakfast 30 min prior to drug in-
`take with 240 mL of water. This meal shall provoke a drastic effect on
`gastrointestinal physiology and, thus, on drug absorption. In a footnote
`of the FDA guideline, an example for a typical test meal is given,
`
`Fig. 1. Pressure–time profiles obtained by high-resolution manometry (36 pressure
`channels) illustrating the different phases (I–III) of the interdigestive migrating motor
`complex. LES—lower esophageal sphincter. Adapted by permission from Macmillan
`Publishers Ltd: Nat. Rev. Gastroenterol. Hepatol. (Deloose et al.), copyright (2012) [32].
`
`Fig. 2. Mean gastric content volumes after administration of 240 mL of water in fasted
`state investigated by MRI over a period of 120 min, n = 12. Reprinted from Mudie et al.
`[31]. Copyright (2014) American Chemical Society.
`
`III, strong peristaltic waves of variable amplitudes are generated in the
`stomach and propagate toward the terminal ileum (Fig. 1).
`It is very likely that the stomach is completely empty immediately
`after the occurrence of the strong peristaltic contractions of IMMC
`phase III (housekeeping waves). Therefore, to our understanding, the
`
`Fig. 3. MRI sequences demonstrating rapid gastric emptying of 240 mL water administered in the fasted state. Water inside the stomach is delineated by the red line. Left: 2 min—177 mL;
`middle: 10 min—120 mL; right: 20 min—4 mL.
`
`Page 3
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`78
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`M. Koziolek et al. / Advanced Drug Delivery Reviews 101 (2016) 75–88
`
`Table 3
`Comparison of total small intestinal water volumes observed by MRI in healthy volunteers after an overnight fast.
`
`MRI study
`
`Schiller et al. [26]
`Marciani et al. [34] (calculations based on digitized data)
`Mudie et al. [31]
`Data on file
`
`No. of subjects
`
`n = 12
`n = 16
`n = 12
`n = 48
`
`Small intestinal fluid volume (mL)
`
`Min
`
`45
`12
`5
`7
`
`Max
`
`319
`253
`159
`230
`
`Median
`
`Mean ± SD
`
`83
`81
`–
`52
`
`105 ± 72
`91 ± 68
`43 ± 14
`65 ± 51
`
`consisting of two toasts with butter, two eggs fried in butter, two strips
`of bacon, hash brown potatoes, and 240 mL milk. Thirty minutes after
`start of meal intake, i.e., typically 10–20 min after finishing the meal,
`the medication to be tested is administered together with 240 mL of
`water. After drug administration, water intake is prohibited for 1 h
`and food intake for at least 4 h, respectively.
`Food intake has a marked effect on the motility of the GI tract as the
`ingestion of caloric food or liquids causes an interruption of the IMMC
`and induces the digestive myoelectric motor activity [37,38]. The motil-
`ity pattern of the fed stomach is completely different from fasted state
`and characterized by constantly propagating antral contraction waves
`with a frequency of three waves per minute that are continued in the
`small intestine with an increased frequency of 12 waves per minute
`[37]. The gastric emptying rate is reduced in fed state. Thus, large vol-
`umes can gather in the gastric lumen, which serve as the dissolution
`medium of solid oral dosage forms administered after food intake. In
`Fig. 7, individual gastric content volumes over time are provided as
`measured in a recent MRI study that was performed considering the
`above mentioned FDA recommendations for fed state bioavailability/
`bioequivalence studies [30].
`After eating the fat-rich FDA meal and ingestion of 240 mL water, the
`mean gastric content amounted to about 580 mL. This volume was
`higher than the volume of the eaten meal, suggesting that there is
`additional oral and/or gastric secretion. The initial peak in volume was
`followed by a plateau phase, during which secretion and gastric
`
`Fig. 4. Distribution of water (red) in the gastrointestinal tract of a healthy volunteer after
`overnight fasting as observed by MRI (frontal view). In this example, water is present in
`the stomach (1: 27 mL) as well as in three “fluid pockets” located in duodenum (2:
`3 mL), proximal jejunum (3: 11 mL), and terminal ileum (4: 74 mL).
`
`emptying seemed to be more or less equally. Just 60–90 min after
`swallowing 240 mL water, gastric volume decreased with a rate of
`~1.7 mL/min. Even after more than 6 h, the gastric content exceeded
`the volumes assessed in fasting healthy subjects. These observations
`are in good accordance with emptying rates of 2–4 kcal/min reported
`in literature [39–41].
`In that study, moreover, it was also seen that swallowing of 240 ml
`water for virtual drug administration was not the reason behind persis-
`tent increase in gastric volume. Actually, water was rapidly emptied
`within 15–35 min (Fig. 8). This finding confirms old experience that
`there is a gastric route for rapid emptying of liquids from the postpran-
`dial stomach known as Magenstrasse (stomach road) or canalis gastricus
`[42,43]. In the original concept of the Magenstrasse, it was assumed that
`the pathway follows the lower curvature of the stomach. However, the
`present MRI data suggest that the water flows around the chyme in the
`lumen along the entire stomach wall. Similar observations were made
`in dogs by Scheunert and co-workers already in 1912 [44]. The authors
`demonstrated that fluids ingested after a meal can flow around the
`stomach contents and thereby, reach the small intestine rapidly. It
`was also observed in these dog experiments that, depending on the tex-
`ture of the food mass, certain amounts of the fluid can even flow
`through the matrix. In our understanding, it seems likely that the
`volume-induced relaxation of the fundus of the stomach creates a
`small gap between the viscous food mass and the fundus wall. Fluid
`that goes this way around the food mass gathers in the antrum of the
`stomach and is emptied from there into the duodenum within a few
`minutes (Fig. 8).
`Similar observations were made by Malagelada and co-workers
`[45,46]. In their studies, the water taken together with solid meals is
`emptied rapidly from the stomach. By contrast, the solid food is retained
`in the stomach, which enables sufficient time for digestive processes. As
`opposed to the rapid flow of water around the food mass in the fundus,
`the mass itself is astonishingly static. As already described in 1923
`by Groedel, food is segmented in different layers inside the stomach
`[47,48]. This has been confirmed for different meals by MRI [28,49].
`For instance, Wilson and co-workers demonstrated the formation of a
`dough ball in the stomach, which was surrounded by fluids [50].
`These data show that the mixing properties of the stomach for drugs
`taken after a solid meal are rather marginal. In a study by Faas and
`colleagues, this has been strikingly demonstrated for a liposomal
`preparation of an MRI contrast agent (Fig. 9) [51].
`Due to the poor mixing properties of the fundus, non-disintegrating
`solid dosage forms like extended release (ER) tablets can stay for several
`hours on top or within the gastric content [52,53]. In case of ER tablets,
`the static residence of the tablets in the food bolus may result in a local
`accumulation of the released drug substance. If such a bolus of accumu-
`lated drug is suddenly emptied into the small intestine, e.g., by postural
`changes, this may create a sharp rise in the drug plasma concentration.
`Notably, these plasma peaks can also be misinterpreted as dose dumping
`caused by failure of the drug delivery system [52].
`In the small intestine, food intake triggers the gastro-ileocecal reflex
`and, thus, causes the emptying of contents from the terminal ileum into
`the caecum [54,55]. Thereby, the small intestinal fluid volume decreases
`initially. Schiller et al. showed that the fluid volume decreases from
`105 ± 72 mL in fasted state to 54 ± 41 mL in fed state (1 h after a
`meal of 803 kcal) [26]. Interestingly, the number of fluid pockets
`
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`79
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`Fig. 5. Two examples of gastrointestinal water distribution directly before (−5 min) and after ingestion of 240 mL under fasting conditions. In these T2-weighted MR images only water is
`shown.
`
`increased. In a recent study, Marciani and colleagues investigated the
`dynamics of the small intestinal fluid volume after ingestion of low-
`caloric test meals over a period of more than 8 h [34]. They showed
`that the initial decrease of the small intestinal fluid volume is followed
`by a short plateau phase. Around 90 min after meal intake, the fluid vol-
`ume begins to rise again but reaches the original level not before 2–3 h
`post-meal. These data demonstrate that even after higher volumes of
`food, which typically cause considerable volumes of gastrointestinal se-
`cretions, the small intestine is not filled with large amounts of fluid and,
`thus, does not provide particularly favorable conditions for drug disso-
`lution. However, to the best of our knowledge, the small intestinal
`
`fluid dynamics after the FDA standard breakfast were not investigated
`so far.
`
`2.2. Transit of dosage forms through the GI tract
`
`2.2.1. Fasted state
`The physiological phenomenon of the IMMC is essential for the
`cleansing of the stomach from non-digestible material, but it has also
`particular importance for the gastric emptying of non-disintegrating
`dosage forms like enteric coated tablets or certain extended release
`(ER) tablets. Such big objects are emptied from the stomach mainly
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`Fig. 6. Classification of food effects on oral drug absorption.
`
`during phase III of the IMMC, in which the strongest contraction waves
`– the so-called housekeeping waves – sweep along the antral region.
`Therefore, the gastric residence times of large non-disintegrating solid
`oral dosage forms that are administered in the fasted state most likely
`depend on the IMMC phase present at the time of ingestion as well as
`the time until recurrence of the housekeeping waves. The mean cycle
`length was found to be about 120 min. This value marks the theoretical-
`ly maximum possible gastric residence time under fasting conditions.
`However, it could be seen that for some enteric coated and ER dosage
`forms, gastric residence times of almost 180 min are reported [17,56].
`These values are most likely the result of the high inter- and
`intraindividual variability of the IMMC duration. Some authors
`described values for the length of the IMMC of more than 200 min
`[57,58]. Furthermore, prolonged residence times in fasted state can
`also be the result of MMC phase III contractions that arise more distal
`in the human GI tract (i.e proximal small intestine) or of insufficient
`emptying by fasted state contractions. [32,59].
`In fasted state, non-disintegrating dosage forms pass the proximal
`small intestine typically very fast. We observed duodenal transit times
`of a few seconds to less than 5 min for large non-disintegrating tablets
`
`Fig. 7. Individual gastric content volume (GCV) profiles after intake of the high-caloric,
`high-fat standard breakfast over 375 min, n = 12. Immediately after t = 0 min, the
`subjects began with the intake of the breakfast, at t = 30 min they received 240 mL of
`water [30].
`
`and capsules as well as for small particles with a diameter of 1 mm
`[60,61]. The time needed to reach the terminal ileum is typically in the
`range of 1–3 h. At this region, non-digestible materials like non-
`disintegrating dosage forms gather until the transfer into the colon oc-
`curs. As already mentioned, a common trigger for the transport of mate-
`rial from the small intestine into the large intestine is meal intake. This
`mechanism is known as the gastro-ileocecal reflex [62]. In pharmacoki-
`netic studies with subjects having fasted overnight, the next meal is typ-
`ically served 4 h after drug administration. Therefore, the colon arrival
`of non-disintegrating dosage forms is usually identical to the scheduled
`time of meal, i.e., 2–4 h after gastric emptying [63,64].
`
`2.2.2. Fed state
`In the fed stomach, the situation is more complex as larger objects
`are retained by the process of gastric sieving [48]. There is contradictory
`information in literature about the maximum size of objects that still ex-
`perience gastric emptying under fed conditions [65]. In general, if a drug
`is not formulated in the form of small particles like pellets, disintegra-
`tion within the stomach is necessary for gastric emptying together
`with food. Large non-digestible dosage forms such as most ER tablets
`are typically only emptied in fasted state by the action of the IMMC.
`Therefore, the time until recurrence of the IMMC, and thus, the duration
`of the IMMC interruption by food, determines the gastric emptying time
`of such objects. Cassilly and colleagues showed that at least 90% of a
`meal has to be emptied until the IMMC returns [66]. After the high-
`caloric, high-fat meal, it takes at least 5 h until the gastric content
`volumes return to baseline levels [30]. However, it must be kept in
`mind that in food effect BA/BE studies, a next meal will already be
`served after 4–5 h according to the guidelines. It is therefore likely
`that during food effect studies the subjects are not at all or only for a
`short time period before dinner under fasting conditions during the
`first study day. This conclusion is supported by the observation that in
`food effect studies, which were performed with the high-fat breakfast,
`gastric emptying of non-disintegrating tablets is delayed for many
`hours [67–69].
`In a magnetic marker monitoring study, we revealed that even after
`a medium-fat breakfast of about 600 kcal, felodipine hydrogel matrix ER
`tablets are retained in the stomach for at least 3 h [52]. It could also be
`shown in this study that the plasma concentration time profiles of
`felodipine were strongly influenced by the gastric localization patterns.
`The specific shear and mixing conditions in fundus and antrum are
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`Fig. 8. Visualization of the Magenstrasse by use of maximum intensity projections (MIP) generated by MRI. In the underlying T2-weighted MR images it can be observed that water (bright
`areas) is flowing around the food mass in both, coronary and transversal view [30]. Copyright (2014) American Chemical Society.
`
`obviously the rationale behind different drug release profiles from the
`ER tablets [33]. Particularly in distal parts, solid oral dosage forms are
`exposed to high shear stresses, which can change the drug release be-
`havior. These forces are the result of the gastrointestinal motility of
`the fed stomach. In a worst-case scenario, this may lead to a burst re-
`lease of the drug also known as dose dumping [70]. Therefore, further
`research is needed to characterize the mechanical forces arising during
`gastrointestinal transit of solid oral dosage forms.
`In a recent study performed with the telemetric SmartPill® system,
`gastrointestinal pressures, pH, and temperature profiles were investi-
`gated under fed state intake conditions that strictly followed the FDA
`guidance for food effect BA/BE [67]. The SmartPill® is a telemetric motil-
`ity capsule (TMC) able to measure pH, temperature and pressure in high
`temporal resolution over a period of at least 5 days. As shape and di-
`mensions of this TMC (13 × 26 mm) resemble these of large solid oral
`dosage forms, this system enables the characterization of the physiolog-
`ical conditions, to which non-disintegrating oral drug delivery systems
`are exposed in the lumen of the human GI tract. The pressure profiles
`showed that the telemetric capsules experience only low pressures
`below 100 mbar during the first hours after intake. Assuming initial cap-
`sule deposition in the fundus, this confirms the hypothesis that little
`agitation is present in the proximal stomach. With ongoing gastric emp-
`tying, events of higher pressures of up to 200 mbar can be observed. As
`such high pressures can only be generated by antral contractions, it is
`likely that the TMC is located within distal parts of the stomach. The
`probability of capsule deposition in the antrum increases with the de-
`crease of the gastric content volume. However, the maximum pressures
`during the GI transit of the TMC are typically observed during or shortly
`before gastric emptying of the capsules. Thus, it can be assumed that
`these high pressures with a magnitude of 200–400 mbar are caused
`by strong antral contractions that only occur during phase II or phase
`III of the IMMC. Due to its size, the TMC is most likely retained in the
`
`stomach until recurrence of the IMMC, and thus, the measured pres-
`sures represent the maximum pressures arising under fasted state con-
`ditions. Interestingly, in a follow-up study, in which the fasted state