Review pubs.acs.org/molecularpharmaceutics
Simulating the Postprandial Stomach: Biorelevant Test Methods for the Estimation of Intragastric Drug Dissolution Mirko Koziolek,† Grzegorz Garbacz,‡ Marco Neumann,† and Werner Weitschies*,† †
Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, University of Greifswald, Felix-Hausdorff-Str. 3, 17487 Greifswald, Germany ‡ Physiolution GmbH, Walther-Rathenau-Str. 49a, 17489 Greifswald, Germany ABSTRACT: Intragastric drug release from solid oral dosage forms can be affected by altered physicochemical and mechanical conditions in the upper gastrointestinal (GI) tract. Food effects may lead to changes of one or more pharmacokinetic parameters and, hence, influence drug plasma levels. This can result in severe consequences such as adverse drug reactions or even therapy failure. This review highlights different examples of drug performance under fed conditions. Various reasons such as delayed gastric emptying and pH-dependent solubility of the API as well as intragastric location and movement profiles of solid dosage forms can account for changed drug dissolution. Over the past years, several biorelevant media (e.g., fed state simulated gastric fluid) have been developed with the aim to approach the physiological situation regarding parameters such as pH, buffer capacity, surface tension, and osmolality. It was shown in different in vitro experiments that all of these factors can have an impact on drug dissolution. Besides the application of complex media such as milk or nutritional drinks, the dynamic changes of the gastric content were depicted in recent studies. The capabilities, limitations, and applicability of newly established test setups for the biorelevant simulation of intragastric drug delivery behavior are discussed. Simple test devices (e.g., rotating beaker or dissolution stress test) are mainly used for the biopharmaceutical evaluation of certain problems such as the impact of pressure or shear forces. On the other hand, complex biorelevant test devices (e.g., TNO TIM-1, Dynamic Gastric Model) have recently been introduced aiming at the simulation of multiple parameters characteristic for the postprandial upper GI tract. The different test methods are reviewed with respect to the spectrum of the simulated physiological factors and the degree of complexity. KEYWORDS: dissolution testing, biorelevant dissolution, dissolution media, dynamic dissolution, oral drug delivery, physicochemical properties, food effect, fed stomach, intragastric conditions, high-fat meal, standard breakfast
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INTRODUCTION Ingestion of food can lead to changes of one or more pharmacokinetic parameters of a drug (e.g., cmax, AUC0‑∞, or tmax). Food effects are classified into “positive”, “negative”, or no food effect in comparison to fasting conditions. Positive food effects refer to increased drug absorption and in a worst case scenario can result in dose-dumping (i.e., the release of large amounts of the drug within short time). In contrast, a decreased drug release is the result of negative food effects.1,2 Regarding the biopharmaceutical classification system (BCS), which was recently introduced by Amidon et al. and which classifies drugs with respect to their solubility and permeability into four groups, a rough assignment of the food effects is described in literature.3 Table 1 gives an overview of food effects on certain immediate release (IR) products.4−7 Chosen relevant examples of different food effects on the performance of solid dosage forms in vivo and in vitro are given in the following paragraph.
taken together with a lipid-rich meal. This circumstance is based on the prolonged gastric residence time, which is caused by delayed gastric emptying. Hence, intragastric dissolution was possible for a longer time. The solubilization effects of lipolysis products further contribute to the increased bioavailability of danazol.8 Weitschies and co-workers investigated the in vivo dissolution of felodipine extended release (ER) tablets with the use of magnetic marker monitoring (MMM) and came to a similar conclusion as for danazol. They reported that the intragastric location of the tablets affects plasma profiles. The residence of solid dosage forms in the fundus after food ingestion is characterized by low mixing, little movement, and only slight API release. Thus, prolonged residence in the proximal stomach leads to longer lag phases of the plasma profile as can be seen from Figure 1.9 On the other hand, dose-dumping can be the result of the accumulation of a drug in the fundus. Another MMM study by Goodman and co-workers revealed the differences between
DRUG DISSOLUTION IN THE POSTPRANDIAL STOMACH Sunesen and co-workers reported in a recent study that the bioavailability of danazol, a BCS class II drug, is increased if it is
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Table 1. Relationship between BCS Class and Predominant Food Effect for Immediate Release Drug Productsa
a
BCS class
S
P
predominant food effect
I II
high low
high high
AUC ↔, tmax ↑, cmax ↓ AUC ↑ (cmax ↑)
delayed gastric emptying increased solubility prolonged GRT
reason
III
high
low
AUC ↓
food−drug interaction on absorption likely variations of gastro-intestinal conditions prolonged GRT
IV
low
low
AUC ?
examples paracetamol nifedipine danazol quetiapine felodipine bidisomide valsartan atenolol mebendazole
S − solubility, P − permeability.
with increased peak plasma concentrations (cmax) occurred. Long gastric emptying times (6.25 ± 2.47 h, n = 9) accompanied by high shear stresses arising in the fed stomach contribute to an increased erosion of the HPMC matrix. For the nine subjects observed, in seven of them the tablets were still in stomach at the moment of complete disintegration (10.09 ± 2.89 h).11 In only two subjects, the tablet was still intact at gastric emptying. Thus, the tablet’s mechanical robustness toward the high stresses acting in stomach was too low. Another mechanism of food effect on nondisintegrating ER dosage forms was described by Abrahamsson and co-workers. The existence of a film around the tablet, which slows down disintegration under fed conditions, was reported. This film is mainly formed by proteins coming from the nutrient drink used in the study. The proteins precipitate at the surface and form a film layer around the tablet. Consequently, no water penetration is possible and particles cannot leave the dosage form. Even the application of 100 rpm in USP apparatus II is not capable to remove this film. In vivo studies in dogs confirmed the in vitro results. However, the observations are only valid for nutritional drinks. Not even homogenized meals have the same effect.13 In a previous study by Abrahamsson and co-workers, it was shown that tablet erosion of hydrophilic gel matrix tablets is faster under fed conditions. The changed conditions of hydrodynamics and mechanical stresses are regarded to be the main reasons.14 Nifedipine is another drug, which was extensively investigated with respect to its food effects. Wonnemann and coworkers compared the nifedipine plasma concentration versus time profiles obtained after administration of OROS (Adalat) and hydrogel matrix tablets. It was demonstrated that the OROS formulation is not sensitive to fed conditions due to higher mechanical robustness, whereas the ER tablets lead to unpredictable and highly variable plasma profiles of nifedipine accompanied by higher risks of adverse events.15 The robustness of OROS against food effects was further demonstrated by Schug and co-workers.16 The difference in the pharmacokinetic (PK) profiles of the formulations may be explained by inhomogeneous mixing conditions in the fed stomach, by the lag-time of Adalat OROS, by the dependency of the dissolution characteristics of the tested nifedipine ER tablets on the pH, as well as by their lack of resistance toward mechanical stresses induced by gastric peristalsis. The impact of prandial state on drug absorption of an ER formulation containing amoxicillin and clavulanic acid (Augmentin XR) was demonstrated by Weitschies and coworkers in a magnetic marker monitoring study. Tablets are emptied significantly faster under fasted conditions leading to
Figure 1. Correlation (r2 = 0.9754) between the lag times (tlag) before felodipine appears in plasma and the tablets’ residence times in the proximal stomach (tfundus).9 Reprinted from Weitschies et al. (2005) with permission from Elsevier.
fasted and fed stomach with respect to intragastric velocity profiles. Peak velocities are missing during fed pattern indicating an overall reduced gastric motility. However, in one subject, an intragastric peak velocity of 12 cm/s was observed, which is likely to occur during retropulsive flow.10 It must be mentioned at this point that there still is a lack of information on relative velocities of solid dosage forms inside the stomach. Data obtained by MMM studies only give absolute velocities, but the movement of the dosage forms in relation to the surrounding medium was not taken into consideration yet. In our experience, the relative velocity of dosage forms is an important factor for the estimation of the drug distribution in gastric contents as well as realistic hydrodynamic shear forces acting directly on dosage forms during their gastric residence. Presumably solid dosage forms like tablets will behave like a pea in a soup. This means that the dosage forms are probably moved with the same velocity as the medium, which results in poor intragastric drug distribution. However, regions of different viscosities within the heterogeneous gastric content may also contribute to different velocities of solid dosage forms. The whole dilemma of food effects was demonstrated in two studies conducted for a α 1-adrenoceptor-antagonist.11,12 To minimize the risk of postural hypotension, which is associated with high plasma concentration of this drug, an oral controlled release formulation was developed to deliver the API continuously over 18 h. Whereas in vitro (USP apparatus I) and for the fasted state, the drug is released in the desired manner, after a high-fat FDA standard breakfast dose-dumping 2212
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earlier tmax. If the dosage forms are taken at the beginning of the meal, they are initially located in antral areas, because incoming food pushes the dosage form toward the pylorus. However, retrograde intragastric transport events that account for the deposition back into fundic regions 30−150 min after tablet administration were found in four of eight subjects. On the other hand, dosing 30 min after FDA standard breakfast leads to later gastric emptying and initial deposition of the tablets in the fundus. Afterward, tablets are moved only slowly into the antrum.17
Owing to ethic difficulties in terms of sampling, high interand intraindividual variability, low stability, and high costs of real human gastric fluids, several artificial media are proposed for the in vitro simulation of drug dissolution in fasted and fed stomachs. The most common ones are summarized in Table 2. Table 2. Artificial Media for Dissolution Studies Simulating Fasted or Fed Stomach fasted stomach
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0.1 N HCl simulated gastric fluid (SGF) USP SGFsp (sine pepsin) SGFSLS SGFTritonX fasted state simulated gastric fluid (FaSSGF)
BIORELEVANT MEDIA FOR THE IN VITRO SIMULATION OF POSTPRANDIAL GASTRIC CONDITIONS The in vitro dissolution of solid oral dosage forms often starts in the stomach owing to higher fluid volumes generated by secretion during digestion and longer residence times compared to the oral cavity and esophagus. Thorough understanding of the gastric milieu is a key factor for the successful development of dosage forms intended to be taken with meals or with prolonged gastric residence such as gastroretentive systems. Gastric content parameters generally regarded as critical for drug dissolution are pH value, buffer capacity, volume, surface tension, and osmolality.18−21 All of these parameters can affect disintegration, solubility, drug release, and thus, dissolution behavior. Chyme viscosity is another factor known to affect drug dissolution. Besides its effect on diffusivity, viscosity may influence tablet disintegration, decrease the water uptake and swelling, and therefore affect drug dissolution.13,19 Parojcic and co-workers investigated the dissolution behavior of paracetamol IR tablets in media of different viscosity and found that viscosity has no effect on solubility of paracetamol, but prolongs disintegration as well as dissolution of the formulations investigated in this study. Reasons assumed for this phenomenon are poor wetting in viscous media and, in addition, reduced shear stresses acting on dosage forms.22 However, it should be understood that the media used represent single phase model fluids of homogeneous viscosity. This circumstance does not reflect the complex nature of the gastric contents. Another question intensively discussed is the selection of surfactants. Surface tension in human gastric fluid is decreased by reflux of duodenal contents containing bile salts into the stomach as well as by surface tension lowering food components. Thus, surfactants such as sodium laurylsulfate (SLS) or Triton X are added to artificial media to enhance wetting, especially if poorly soluble drugs are tested. However, their application is controversial, because they lead to an overestimation of drug dissolution in many cases.23,24 SLS has particular disadvantages such as the surface tension is lowered to below physiological level, hydrolysis in media with pH 160 min) physicochemical environment of the fed stomach. They can be used consecutively for dissolution tests. However, just the “middle” media is applied, which is also referred to as fed state simulated gastric fluid (FeSSGF). It shows good reflection of variations in postprandial stomach. Furthermore, FeSSGF has good physical stability and is easy to separate, and it considers the fact that in bioequivalence studies dosage forms are generally taken 30 min after food ingestion. The starting point of the media described is full-fat milk again. The composition of the snapshot media is given in Table 3.20,37
In a recent study by Klein, liquid meals (milk, Ensure, Ensure Plus) were compared with two homogenized standard meals (FDA standard breakfast and GSK standard breakfast), and it was concluded that Ensure Plus together with 0.45% pectin provides a good approximation of the physicochemical properties of the homogenized meal particularly with regard to viscosity and osmolality.40 However, this comparison does not incorporate the contribution of saliva and gastric secretions to the initial media compositions. In line with this, Diakidou et al. demonstrated that the composition of Ensure Plus itself is not sufficient to reflect initial conditions in the postprandial stomach after intake of 500 mL of Ensure Plus. Additionally, solubility profiles in Ensure Plus are distinct from Ensure Plus digested with pepsin.41 It was further concluded by the authors that it is essential to simulate vesicle/micellar as well as colloidal structures to approach the in vivo situation. Most common media and their physicochemical properties are summarized in Table 4. To date, an exact assessment of the most suitable artificial dissolution medium to predict intragastric dissolution after food intake is not feasible, because knowledge on the initial physicochemical situation in the fed stomach is poor. As long as these open questions cannot be answered sufficiently, appropriate media compositions can only be estimated. In addition, the initial composition of the gastric content was investigated only for liquid meals owing to technical difficulties regarding the performance of aspiration as well as for the measurement of solid meals such as the FDA standard breakfast. Due to its importance in bioequivalence studies, it is essential to investigate the dynamic digestion of the FDA standard breakfast with respect to its physicochemical parameters. Furthermore, the presence of solid particles leading to shear forces acting on the dosage form and increased viscosity as well as the contribution of saliva and gastric secretion to the composition of the gastric content (e.g., osmolality, surface tension, buffer capacity) have to be considered in alternative biorelevant media.
Table 3. “Snap-Shot” Media Reflecting the Fed Stomach Proposed by Jantratid et al. pH milk−buffer buffer NaCl (mM)
early
middle
late
6.4 1:0
5 1:1 acetate buffer 237.02
3 1:3 phosphate buffer 122.6
148
Owing to several disadvantages of milk such as batch-tobatch as well as brand variations and low calorie content, nutrition drinks or homogenized meals are proposed as alternatives.13,19,38,39
Table 4. Physicochemical Properties of Dissolution Media for the Fed Stomach medium human gastric fluid after 500 mL of Ensure Plus 30 min 60 min 120 min “snap shot” media early middle late milk partially digested milk pepsin (30 min) pepsin (60 min) pepsin (90−360 min) pepsin/lipase (30 min) pepsin/lipase (60 min) pepsin/lipase (90−360 min) Ensure Plus homogenized breakfast a
pH value
buffer capacity (mEq/(L ΔpH))
5.9 5.6 4.9
25 22.5 30
6.4 5 3 6.63; 6.5
21.3 25 25 19
4.7 3.8 2.6 5.1 4.5 4.0 6.45 5.12
32 25 38 49 55 69 21 47.2
surface tension (mN/m) osmolality (mOsmol/kg)
ref.a
515 513 475
41
49.7 52.3 58.1 49.8
559 400 300 285; 260
20, 37
35
47.8 45
338 378 462 475 557 540 375 715
35, 40
40 40
Ref. = reference. 2214
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tablet erosion and thus, drug release.52 Computer simulations based on in vivo MRI data showed that tablets experience different shear stresses in the stomach depending on their location.53 High shear stresses are observable in the antrum, especially if the dosage form is moved retrograde through the occlusion that is caused by gastric peristalsis. In order to evaluate the effect of intragastric surface shear stresses in a simple in vitro experiment, the rotating beaker device was developed by Abrahamsson and co-workers.47 A schematic of the test is shown in Figure 3. Due to the connection of the
IN VITRO DISSOLUTION TEST METHODS FOR THE FED STOMACH Within the last years, several static and dynamic biorelevant models of the upper GI tract were developed in order to investigate the dissolution behavior of oral solid dosage forms under fed conditions (see Table 5). Coming from food science Table 5. Overview of Simple and Complex Test Devices Designed To Model Fed Stomach Function simple devices
complex devices
rotating beaker apparatus paddle-bead method stress test device digestive cell model stomach system
artificial stomach duodenal model (ASD) dynamic gastric model (DGM) human gastric simulator TNO TIM-1
and industry, a number of devices characterized by different grades of complexity are reported in literature. Most of them aim at mimicking enzymical and/or physicochemical degradation processes of food (e.g., digestive cell by Chen or the model stomach system by Kong and Singh).42−45 In this review, we focus on devices that are already used or might be adapted for the evaluation of oral dosage forms with respect to simulation of the fed stomach. In comparison to compendial dissolution test methods known to oversimplify GI transit conditions, the superiority of new dissolution test methods was demonstrated in several studies.46−48 To investigate the impact of mechanical forces on the drug release of controlled-release formulations, Aoki et al. proposed a simple modification of the USP paddle apparatus. Polystyrene beads (d = 6.35 mm, ρ = 1.05 g/cm3) are filled together with certain volumes of medium as well as the dosage form into the vessel, and dissolution testing is performed at different rotational speeds (Figure 2). Collisions between beads and
Figure 3. Rotating beaker apparatus [adapted with permission from Abrahamsson et al. (2005). Copyright 2005 Springer Science+Business Media].47
beaker to the central rod, it is possible to generate controlled medium flow around the fixed tablet by beaker rotation (8−50 rpm). It could be demonstrated that the erosion rates of the investigated HPMC matrix tablets and the surface shear stresses were in close relationship. Thus, shear forces are able to alter drug release, because the latter correlates well with erosion rate. Moreover, it was demonstrated that shear stresses in USP apparatus I lead to lower erosion rates compared to the rotating beaker.47 The simple devices presented allow for the investigation of individual effects but oversimplify the complex gastric situation. The simulation of the interplay of different parameters important for the intragastric situation under fed conditions like realistic mechanic and hydrodynamic conditions, physiological media volumes, and media composition as well as their dynamic changes is not foreseen in these devices. The dissolution stress test device developed and first described by Garbacz and Weitschies in 2008 is intended to simulate biorelevant mechanical stresses as they may act on solid dosage forms during GI passage using a robust and simple test system that is close to conventional dissolution test systems.54 The apparatus aims to simulate the impact of physiologically based mechanical stress that may occur during the GI transit of a dosage form. Within an experiment, the dissolution stress test apparatus exposes a dosage form to sequences of agitation including movement and pressure fluctuations alternated with static phases as they typically occur in vivo. The schematic and photographic representation of the device is given in Figure 4.54 Briefly, the dissolution stress test device consists of a central axis with seven spheres made of steel wire netting (probe chamber), in which the dosage forms are located during the test. Furthermore, the central axis is connected with a pressure regulation module on one end and with a stepping motor on the other end. Pressure fluctuations can be generated by periodic inflation and deflation of the balloons inside the
Figure 2. Paddle-bead method. Adapted from Aoki et al. (1992) with permission from Elsevier.
tablets result in the generation of biorelevant mechanical stresses on the dosage form.49 It was assumed that the presence of beads causes erosion of the gel layer at the surface of the hydrogel matrix tablets. In vitro dissolution profiles are similar to in vivo data (fasted state) in beagle dogs if 2500 beads, a medium volume of 250 mL, and a paddle rotation speed of 25 rpm are applied.50 For the fed state, a good relationship is present up to 6 h.51 The paddle-bead method enables only the simulation of mechanical stresses and may be valuable in terms of tablets with low mechanical robustness. However, this model does not reflect the physiological situation. Mechanical stresses acting on the dosage forms are not caused by such hard particles but by gastric peristalsis and dosage form movement. In a study investigating postprandial effects, hydrodynamic mechanical stress was identified as a main parameter affecting 2215
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The digestive cell developed by Chen et al. is not used for dissolution testing to date, but the experimental setup would probably allow this application. Hence, we will describe its construction briefly (see Figure 5). The system consists of a
Figure 5. Digestive cell [adapted from Chen et al. (2011) with permission of The Royal Society of Chemistry].42
glass vessel (168 mL) and a spherical Teflon probe attached to the load cell of a texture analyzer. The probe can be moved up and down thereby generating fluid flow of physiological magnitude. In a recent study, the intragastric digestion of peanut particles was investigated, and changes in pH value, particle size, and surface microstructure were monitored in response to varying levels of probe speed and pepsin concentration.42 The human postprandial stomach is a rapidly changing, dynamic system. Thus, the application of such simple, static models is not appropriate to simulate the drug release from solid oral dosage forms over several hours. The changing gastric environment must be considered. Particularly food scientists have a large share on novel complex models like TNO TIM-1 or DGM, which were introduced in the last two decades. Meanwhile, some of these devices are also applied in pharmaceutical research. Similar to a previous device reported by Vatier, Carino and co-workers proposed a simple computer-controlled dynamic system, the artificial stomach-duodenal model (ASD), which enables the simulation of different physicochemical conditions in the upper GI tract.58−61 It consists of two chambers arranged one above the other. The two compartment model allows gastric emptying from the stomach to the duodenum to be simulated. ASD is designed primarily for the determination of the bioavailability of pharmaceutical compounds in the duodenum. Each chamber is equipped with several sensors so that drug concentration, pH value, and volume can be monitored simultaneously. Mixing in the chamber is done by paddles connected with a stepping motor and secretion as well as emptying is controlled by a pump system. Mimicking the fed state is possible in a simple manner by adjusting pH value, secretion, and transit time. The application of other biorelevant parameters such as mechanical stresses or peristaltic activity as well as complex test media is not likely. The ASD intends for the simulation of the GI physiology of different species. Hitherto, only the canine physiology was depicted and compared with in vivo data. The Institute of Food Research (Norwich, UK) introduced the Dynamic Gastric Model (DGM) on the basis of magnetic resonance imaging (MRI) studies conducted by Marciani and
Figure 4. Schematic (A) and photograph (B) of dissolution stress test device [reproduced with permission from Garbacz and Weitschies, 2011. Physiolution GmbH (Greifswald, Germany)].54−56
chambers. The central axis is driven by a computer-controlled motor, which enables a controlled agitation. The dissolution medium (typical volume 1160−1200 mL) is mixed by a separate paddle stirrer during the entire test. To date, various experiments have been performed with this setup.55 To mimic the mechanical aspects of GI transit under fasting conditions, a whole set of test programs has been established. These are characterized by phases of agitation initiated by a rotational movement of the axis intended to simulate events of transport, followed by phases of pressure fluctuations mimicking GI tract motility events. Postprandial motility of the stomach has so far been simulated as a simple sequence of rotational movements and pressure fluctuations of biorelevant intensity. In order to clarify the reason for dosage form-related food effects of nifedipine ER formulations, dissolution studies were previously performed and compared with in vivo bioequivalence studies conducted with Coral 60 mg retard tablets.56 Test results from these studies denoted a lack of mechanical stability, and results obtained in different test media also indicated pHdependent dissolution behavior of Coral 60 mg retard tablets. These observations provide a likely explanation of the food effects that had been observed when comparing the in vivo plasma profiles resulting from Coral 60 mg retard tablets and Adalat OROS 60 mg tablet administration. The dissolution device described in a patent by Burke et al. is another test setup for the simulation of mechanical forces. It is a modification of the USP paddle apparatus, in which the dosage form is located in a small chamber. Physical stresses of different intensities and frequencies can act on the dosage form. However, literature data proving the applicability and utility of this device are lacking.57 2216
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co-workers.62 This computer-controlled stomach model intends for a dynamic physicochemical simulation (i.e., pH value, enzymes, shearing, mixing, and emptying) of intragastric processing and is to date the most realistic model for human gastric digestion. The DGM is composed of three different parts: main body (fundus), antrum, and valve assembly (Figure 6). The main body is a funnel with a maximum volume of 800
The DGM gives valuable data on how food is processed in the stomach, which is also essential for the understanding of drug release in stomach. However, at the moment the applicability of the DGM for pharmaceutical issues is not fully proved yet. The use of the model for routine dissolution testing is hampered by the high complexity. The artificial digestive system TIM-1 was developed at TNO (Zeist, Netherlands) to depict the in vivo processing of food ingredients in the upper GI tract.67,68 Over the last years, its field of application has been extended toward pharmaceutical issues. The computer-controlled model consists of four compartments representing stomach, duodenum, jejunum, and ileum (Figure 7). These are arranged one above the
Figure 6. Dynamic Gastric Model (DGM). Adapted with permission from Mackie et al. (2012) Institute of Food Research (Norwich, UK). Figure 7. Schematic of TNO TIM-1 (Ssecretion, pHpH electrode, Vvalve, Dhollow fiber membrane, Wwater absorption). Reproduced with permission from Verwei et al. (2003). Copyright 2003 American Society for Nutrition.67
mL, and hence, a large variety of meals can be used. The wall of the main body is flexible, which allows the generation of gentle contractions induced by water pressure changes of the surrounding water bath with a frequency of 3 min−1. Thus, inhomogeneous mixing of the meal in the fundus is simulated. Moreover, acid and enzymes are injected by feedback control at physiological rates. Intense shear stresses and mixing conditions in the antro-pyloric region are modeled by sliding of a piston in a barrel (piston pump). Thereby, antral contents are refluxed into the main body through an elastic annulus. At the same time, bigger particles fall down into a dead volume of the barrel. Consequently, preferential sieving as it is observed for gastric emptying in human is simulated. Sampling can be done via the valve assembly in order to mimic gastric emptying. This process is regulated by certain parameters of the meal such as volume or calorie value.62−64 So far, there are only few published studies regarding pharmaceutical application of the DGM. Vardakou et al. compared the breakdown of agar gel beads of different strengths in a high and a low viscous medium and compared the DGM results with USP apparatus II (50 and 100 rpm). It was found that higher shear forces are exerted by the DGM leading to the breakdown of the beads. These results are in accordance with observations made in vivo.63,65 In another study by the same author the disintegration and dissolution behavior of capsule shells made from HPMC (modified with gellan gum or carageenan) and gelatin are described under simulated fed and fasted conditions. Using the DGM, Mercuri et al. showed that the emulsification behavior of self-emulsifying drug delivery system (SEDDS) depends on enzymical and mechanical processing.66
other and are interconnected via peristaltic valves. By this construction, chyme transit can be controlled. Each compartment consists of two connected glass jackets with flexible inner walls. Water of 37 °C is pumped between inner and outer wall guaranteeing body temperature inside the lumen, which is enclosed by the inner silicone wall. Compression and relaxation of the lumen induced by water pressure changes alternate in the two units with specific frequencies, which contributes to mixing of the chyme and shall mimic peristaltic activity of the GI tract.69,70 The dosage form is hosted in between the two elements, thereby experiencing hydrodynamic shear forces.70 Main parameters affecting the dissolution behavior in TIM-1 are pH value regulated by secretion of gastric acid and bicarbonate, temperature, peristaltic mixing, transit times in the single compartments, site-specific secretions including digestive enzymes and bile salts as well as absorption processes. The latter can be obtained by two dialysis elements composed of hollow fiber membranes at simulated jejunum and simulated ileum that allow the evaluation of drug and nutrient absorption if passive diffusion is the dominant mechanism.69 Several studies on drug release of pharmaceutical compounds were conducted in recent years. The effect of food on jejunal absorption of paracetamol as free powder or sustained release formulation was demonstrated by Blanquet and co-workers.69 Furthermore, Souliman et al. revealed the benefit of TIM-1 in comparison to compendial methods and further investigated the IVIVC in two different studies.71,72 The TIM-1 system was 2217
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Table 6. Technical Possibilities of Test Devices Used for the Simulation of the Fed Stomacha test device paddle-bead method rotating beaker digestive cell stress test device ASD DGM TNO TIM-1 HGS a
control on dosage form movement
defined flow conditions
exposure of dosage form to biorelevant stresses
dynamic changes of GI environment
simulation of complex gastric chyme
−
−
−
−
−
− − + − − − −
− − + − (+) − +
+ + − − − (+) −
− (+) − + + + +
− + − − + (+) +
+ parameter can be simulated; − parameter cannot be simulated; brackets indicate limited performance or lack of information.
affects the drug delivery behavior and associated PK profiles. Besides different biorelevant dissolution media for the fed state, different models were established within the last 20 years. Complex models such as TNO TIM-1 or DGM contributed to a better understanding of the effects of physical stresses of solid oral dosage forms in the human GI tract. They are of high value for bioavailability studies in both fasted and fed states, and they offer the chance to minimize the number of in vivo studies. However, there are still some drawbacks. These devices coming from food science were intended for simulation of food digestion and prediction of the bioavailability of nutrients. Therefore, their application for pharmaceutical dissolution testing is limited owing to partially distinct demands on in vitro methods. For dissolution test purposes, high reproducibility and low variability are the main requirements. Besides high efforts caused by high complexity, the reproducibility of complex test methods is frequently a critical factor, because the parameters acting on the dosage forms are either very variable or their impact is unknown. To improve reproducibility, a compromise between simple construction and complexity must be found to ensure both the applicability and the identification of key parameters during dissolution testing. Thus, the effect of every single parameter should be evaluated before it is introduced into a complex test system. Such a procedure might ensure the identification of parameters affecting drug release and the estimation of their impact. Nevertheless, the successful development of test systems that are intended to simulate the complex situation in the postprandial stomach shows that we are approaching biorelevant test devices that will be capable of predicting in vivo drug delivery behavior.
found to reflect the in vivo dissolution of paracetamol IR tablets better than USP apparatus II. In particular, for the fed state a high level A IVIVC is present. As is the case in vivo, lag time of absorption is decreased by food intake, and furthermore, plasma peaks of paracetamol are diminished and observable at later times.72 In a recent study, Brouwers and co-workers investigated the dissolution behavior of fosamprenavir IR tablets in both simulated fasted and fed state by the additional use of MRI.70 Although TIM-1 contributes much to the evaluation of food, transit times, and formulation properties on stability and bioavailability, it reveals some drawbacks. The valve system is not made for the passage of solid dosage forms, and thus, these must be transferred manually. Furthermore, the high variability of the results expresses the high complexity and reflects the in vivo situation according to the authors. However, it is questionable whether the high in vitro complexity reflects the complex in vivo situation. Usually, the TIM-1 experiments are performed according to one scenario, which does not reflect the edge parameters of the physiological variability regarding GET, GE kinetics, and differences in the acidification and processing of the stomach content. The application of TIM-1 as routine method for pharmaceutical dissolution testing is impeded also by high efforts regarding time and costs compared to simple in vitro methods. A further dynamic model, the Human Gastric Simulator (HGS), has been developed at the UC Davis by the group of Singh.73 Compared to DGM and TIM-1 a more realistic and continuous simulation of gastric peristalsis is performed. This is achieved by a motor-controlled set of rollers and belts that move along the outside of a latex lining chamber simulating the stomach. Furthermore, gastric secretions of acid and enzymes as well as emptying patterns are considered. A full technical description was given by Kong and co-workers.73 To date, the HGS has only been used for the investigation of solid foods, but a transfer to pharmaceutical issues as it has been done for other complex models like TIM-1 and DGM might be possible. In Table 6 simulation devices are presented with technical possibilities and limitations that might be important for dissolution testing under simulation of the fed stomach.
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AUTHOR INFORMATION
Corresponding Author
*Tel.: + 49 3834 864813. Fax: +49 3834 864886. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support by the Federal Ministry of Education and Research (FKZ 13N11368-13N11370) is gratefully acknowledged. M.K. and W.W. are participants in the FA1005 COST Action INFOGEST on food digestion.
CONCLUSION Solid oral dosage forms administered postprandially are processed in an analogous way as food particles. Since the stomach is usually the starting point of drug dissolution, the comprehension of food digestion in oral cavity and stomach is essential to identify relevant influences and to define the gastric conditions, which dosage forms are exposed to. The variability of physicochemical properties, hydrodynamics, and stresses
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ABBREVIATIONS ASD, Artificial stomach duodenal model; API, Active pharmaceutical ingredient; AUC, Area under the curve; BCS, 2218
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Biopharmaceutical classification system; CMC, Critical micelle concentration; DGM, Dynamic gastric model; ER, Extended release; FaSSGF, Fasted state simulated gastric fluid; FDA, U.S. Food and Drug Administration; FeSSGF, Fed state simulated gastric fluid; GE, gastric emptying; GET, gastric emptying time; GI, Gastrointestinal; GRT, Gastric residence time; HGS, Human gastric simulator; HPMC, Hypromellose; IR, Immediate release; IVIVC, In vitro−in vivo correlation; MMM, Magnetic marker monitoring; MRI, Magnetic resonance imaging; OROS, Osmotic-controlled release oral delivery system; PK, pharmacokinetics; SLS, Sodium lauryl sulfate; USP, United States Pharmacopeia
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