Simulating the Postprandial Stomach: Physiological Considerations

Review pubs.acs.org/molecularpharmaceutics

Simulating the Postprandial Stomach: Physiological Considerations for Dissolution and Release Testing 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-Strasse 3, 17487 Greifswald, Germany ‡ Physiolution GmbH, Walther-Rathenau-Strasse 49a, 17489 Greifswald, Germany ABSTRACT: Food effects on drug release and absorption from solid oral dosage forms are a common biopharmaceutical problem. The fed state is characterized by different motility and secretory activity of the complete gastrointestinal (GI) tract compared to fasting conditions. Due to long gastric transit times, the postprandial stomach plays an essential role for drug release and the appearance of food effects. Therefore, a concise comprehension of the relationship between food intake and its effect on drug release from solid oral dosage forms is essential to understand their dissolution behavior under fed conditions. This review describes important aspects of stomach physiology occurring after meal ingestion with particular reference to the FDA standard breakfast. A brief overview of oral and gastric food processing and their potential influence on drug release is given. The key factors affecting the intragastric dissolution of solid oral dosage forms and their regional distribution in the stomach are discussed. Additionally, the effects of food properties on gastric emptying kinetics are presented. Mechanical aspects such as intragastric pressures and hydrodynamics caused by gastric peristalsis are defined. The initial state and the dynamic changes of the gastric content during digestion are characterized since the different physicochemical aspects such as pH value, buffer capacity, rheological properties or surface tension may be essential for the in vivo dissolution profiles of oral dosage forms. Possible effects of the discrete interplay of the physiological factors on the in vivo drug delivery behavior of solid oral dosage forms are discussed. KEYWORDS: dissolution, biorelevant dissolution, gastric content, oral drug delivery, physicochemical properties, gastric emptying, food effect, fed stomach, intragastric conditions, high-fat meal, standard breakfast, stomach physiology

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INTRODUCTION Where do all the tablets go in? More than 25 years later this question, title of a review by R. C. Spiller in 1986, has not been answered sufficiently.1 Our knowledge on the performance of solid dosage forms in the gastrointestinal (GI) tract, especially after food intake, still has many gaps. The present review includes literature data from the late 1960s up to the present and focuses on the processing of food in the oral cavity and the stomach based on the idea that dosage forms most probably underlie the same mechanisms. Furthermore, the initial gastric conditions are the result of these processes. Hence, the understanding of human GI physiology will help us to comprehend certain drug delivery characteristics of oral dosage forms as well as their pharmacokinetic profiles. Physiological aspects most relevant for dosage forms inside the oral cavity and the stomach that are changed by meal ingestion are described with particular reference to the highcalorie, high-fat FDA standard breakfast, which is recommended by the corresponding FDA guideline for the investigation of food effects in bioequivalence studies.2

changed by mastication and salivation leading to particles of different size, shape, surface area and mechanical resistance as well as to varying physicochemical properties of the surrounding medium including pH value, surface tension or viscosity. All of these parameters affect the dissolution behavior of solid oral dosage forms ingested together with a meal such as the FDA standard breakfast used for the clinical evaluation of dosage forms. Furthermore, mastication and salivation are the first steps of digestion and their interaction is essential to prepare the food for further processing.3 After food enters the oral cavity, the individual particles are grinded and simultaneously mixed with saliva for lubrication and cohesive binding in order to form a swallowable bolus, which is according to M. C. Bourne “a mixture of chewed food and saliva”.4,5 It was shown by Medicis and Hiiemae that the oral cavity is able to gain a volume of approximately 25 to 30 mL with differences caused by gender, age and food texture. Especially solid foods decrease the capacity due to the more complicated oral breakdown.6,7 It should be noted that solid foods are generally emptied from the oral cavity by multiple swallows.

PROCESSING OF FOOD IN THE ORAL CAVITY The knowledge of food processing inside the oral cavity is essential for defining and understanding the initial conditions in the postprandial stomach. The texture of food is significantly

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© 2013 American Chemical Society

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Molecular Pharmaceutics

Review

Typically, the bolus volume is highest for the first swallow and decreases for the following ones.8,9 Food Breakdown by Chewing. Although solid dosage forms such as tablets and capsules are usually not chewed, the chewing process should be elucidated, because it defines the initial particle characteristics of the gastric content and, thus, parameters such as the viscosity, the release of nutritional components, the abrasion of the dosage form or the gastric emptying.10,11 In contrast to former studies, Pera and coworkers demonstrated in a recent work that the gastric emptying rates of a test meal (250 kcal) composed of a cooked egg, ham cubes, crackers and 500 mL of water are affected by the number of chewing cycles. For 12 healthy subjects with full dentition, the gastric emptying times decrease from 62.5 ± 6 min to 49.1 ± 5.7 min by increasing the number of chewing strokes from 25 to 50.12 The test meal used in that study is quite similar to the FDA standard breakfast. Hence, it can be concluded that the performance of mastication may have an impact on dissolution behavior of solid dosage forms. Assuming full dentition, an adult has 32 teeth with 16 of them on each jaw forming the area of particle fragmentation, defined as the occlusal area. The teeth can be classified with respect to their function and biting forces: the main function of the incisors is the cutting of food, the canines are responsible for cutting and tearing while chewing and shearing is accomplished by the molars. The maximum bite forces increase from the incisors to the canines and further to the molars with maximum forces of up to 800 N. However, such high forces are applied only in exceptional cases.13−16 Regardless of the initial characteristics, the food is processed always in the same manner and a certain number of masticatory cycles are required to create a bolus that can be swallowed safely. In general, the oral food processing can be divided into three stages. After the food enters the mouth cavity, it is transported by the tongue and certain jaw movements from the front to the molar region (stage I transport), where the particles are processed by a series of chewing cycles in the occlusal area and mixed with saliva (food processing stage). Afterward the food, ready to be swallowed, is propelled into the oropharynx (stage II transport), where it accumulates until it is swallowed.17 Regarding the chewing cycles, Engelen and co-workers demonstrated that, for nonbuttered Melba toast for a group of 266 subjects, the number of cycles ranges from 20 to 90 indicating high interindividual differences, which can be explained by different individual factors (physiology, degree of hunger, certain habits).18 Additionally, the chewing performance is highly variable and depends on the volume and certain food properties like dryness, hardness or texture.19,20 Longer chewing times are found particularly for hard foods like peanuts or carrots, because breakdown of the particles takes longer. Table 1 shows that particle sizes are being decreased with an increased number of chewing strokes. Jalabert-Malbos et al. suggested that the individual particle sizes of the food bolus have to be below 2 mm to be swallowed safely except for soft particles, for which the individual particles can be bigger.21 Moreover, food volume and certain physicochemical properties influence the particle fragmentation.22 For instance, Agrawal and co-workers introduced the Food Fragmentation Index, which considers toughness and Young modulus of food particles. This index can be used to predict particle numbers and sizes after oral breakdown.23

Table 1. Particle Sizes (d50) of Peanuts and Carrots after Human Mastication peanuts

carrots

particle size (mm)

corresponding no. of chewing strokes

ref

0.82 1.18 2.49−1.39 1.90 6.74−2.78 8.7−3.4 9.0−3.8

27.2 ± 5.2 48.71 ± 5.8 10−26 33.6 ± 10.6 10−33 5−30 5−30

21 25 26 21 26 27 28

The fragmentation of particles was extensively examined in several studies. Mean particle sizes and the corresponding number of chewing cycles for frequently used model food (e.g., peanuts and carrots) are shown in Table 1. The high variability of the particle sizes depicts that the number of chewing strokes has a significant effect. In addition, the detection method or the food volume can lead to distinct results. Therefore, the particle size distribution is another commonly used parameter to describe the process of mastication.21,24 Salivation. In addition to the comminution of particles in the occlusal area, salivary flow is essential to moisten and lubricate the food in order to form a cohesive bolus ready for swallowing. The human saliva is a complex, heterogeneous fluid, which is mainly produced by three different pairs of glands, namely, the parotid, the sublingual and the submandibular glands. As depicted in Figure 1, the three major salivary glands are responsible for about 90% of the unstimulated salivary flow, whereas minor glands produce the remaining amounts.4,29,30

Figure 1. Saliva production by salivary glands in human oral cavity.

The total amount of saliva produced per day ranges from 1 up to 1.5 L and is excreted at different rates in the stimulated and unstimulated states. While the unstimulated salivary flow amounts to approximately 0.1 to 0.5 mL/min according to the literature, the stimulated flow can be up to 10 mL/min, especially for dry foods with a high surface area (e.g., toast or cake), because more saliva is needed to prepare a swallowable bolus. The parotid glands in particular contribute to this stimulated salivary flow, which is characterized by a hypoosmotic (110−220 mOsmol/kg), watery, amylase-rich fluid.4,18,31,32 A center in the medulla oblongata controls the salivation, which is triggered by mechanical (chewing), gustatory (e.g., acid or sweet) or olfactory stimuli. Further influences include age, pain, alcohol intake, administration of certain drugs (e.g., antidepressants, antihistaminics) and various disorders.29,30 Based on stimulated salivary flow rates described 1611

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Review

α-amylase.30,32,34 In contrast, Hoebler and co-workers reported that, during the short period (20−30 s) of oral digestion, 50% of the starch in bread and 25% of the starch in spaghetti are hydrolyzed.37 These observations indicate that oral digestion should not be underestimated and has to be taken into account for the in vitro simulation of postprandial conditions. For instance, the initial viscosity of the gastric content will be considerably decreased for polysaccharide-rich and dry foods because of the degradation of the thickening starch and the increased production of watery saliva. The simulation of the initial gastric conditions is a crucial point with parameters described above (e.g., salivary α-amylase, salivary flow) and should be considered for in vitro investigations. The simple shredding of a test meal will probably not fulfill the desired aims. Swallowing. The swallowing takes place after successful processing of the ingested food, which means that the particles are grinded to a certain size, moistened and lubricated with saliva. Okada and co-workers found that at least two swallows are needed for each bite, differentiating between interposed and isolated terminal swallowing.38 Different theories regarding the criteria that define the optimal moment of swallowing are still discussed in the literature.24,39−41 Generally, hard and dry foods are processed longer as more chewing cycles are required to break down the particles and more saliva is produced to provide a sufficient cohesiveness to the bolus, particularly for foods with a high surface area.42,43 Swallowing consists of three phases, namely, the oral phase (bolus formation), the pharyngeal phase defined as the time frame between the stimulation of the swallowing reflex and the closure of the upper esophageal sphincter and last the esophageal phase, in which the bolus is transported by primary and secondary peristalsis into the stomach.7 These peristaltic contractions in the esophagus are performed by striate and smooth muscle cells in the cervical (upper) and thoracal (lower) part respectively. Two sphincters border the hollow tubelike esophagus, the upper and lower esophageal sphincter. By the latter, the swallowed bolus is emptied directly into the stomach.44 High transport velocities are reported, and hence, the transit time is only a few seconds, but it is affected by body position, bolus properties, age and certain disorders.45,46 Especially gelatin capsules are known to remain in the esophagus unnoticed by the patient for hours, which could lead to severe problems in the case of irritant drugs as tetracycline or clindamycine.47 In general, the administration of solid dosage forms together with water in an upright position can avoid these difficulties.48,49

for foods that are similar to the single components of the FDA standard breakfast, it can be assumed that at least 100 mL of saliva will be secreted within the 30 min that is claimed for the intake duration in the respective FDA guidance. Therefore, the role of salivation is crucial for the composition and the physicochemical properties of the gastric content. Moreover, the knowledge of its composition is also essential to clarify and define the gastric milieu. Besides 99.5% of water, the human saliva contains 0.3% of proteins represented by immunoglobulins, enzymes, antimicrobial factors, proteins and mucosal glycoproteins as well as various electrolytes (sodium, potassium, calcium, magnesium, phosphate and bicarbonate). Further components are glucose and nitrogenous products such as urea.29 The mucins, large glycoproteins with a molecular weight of 0.5 to 20 MDa, are probably one of the most important components of saliva as they are responsible for the gel-like structure. A mucous layer is formed that covers and protects the oral cavity by lubrication, which means in terms of oral food processing the ability to reduce friction to oral surfaces and, thus, the protection against irritation and damage of oral tissues. Additionally, the non-Newtonian, shear-thinning behavior is also associated with the presence of the mucins.33−35 Table 2 summarizes the functions of selected saliva components.7,29,30,32 Table 2. Selected Saliva Components and Their Physiological Function component water electrolytes

proteins immunoglobulins (Ig A) salivary α-amylase (ptyalin) lysozyme, lactoferrin, IgA mucins urea

function lubrication, cleansing, taste mediation de- and remineralization buffering (H2CO3/HCO3−;H2PO4−/ HPO42−) immune defense starch digestion antibacterial effects lubrication, tissue protection buffering

The composition and properties as well as the flow rate of saliva produced under stimulation are variable due to an increased amount of saliva coming from the parotid glands.36 The pH value of unstimulated saliva is reported to be within pH 6 and pH 7.4. Approximately 5 min after food ingestion and thus stimulation of salivation, the pH is elevated to maximum values of around pH 7.4, but drops after another 10 min to its lowest level of about pH 6. The buffering capacity of the saliva is attributed to the presence of bicarbonate, phosphate, urea and proteins. As a result of the augmented bicarbonate release, the buffering capacity is enhanced for the stimulated flow.29,34 The salivary α-amylase (ptyalin) is one of the key enzymes in the oral digestion due to its central function in the hydrolysis of starch to maltose and related oligosaccharides by cleaving α-1,4 glycosidic bindings. It has a pH optimum at pH 7.4, and its activity is thus limited to the mouth cavity, because it is inactivated by the acid milieu and the proteolytic activity in the stomach. However, the inhomogeneous and slow gastric mixing as well as the elevated pH value in the fed stomach may lead to longer action times for the salivary α-amylase. However, it is regarded to be of minor significance compared to the pancreatic

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PHYSIOLOGY OF THE FED STOMACH After its ingestion, food is processed as described in Processing of Food in the Oral Cavity and transported via pharynx and esophagus into the stomach, which is the starting point of dissolution for most solid oral dosage forms. This section will give an overview of the physiological processes and physicochemical conditions inside the fed stomach to identify the aspects relevant for in vitro dissolution testing. Several studies demonstrated that the dissolution behavior of solid dosage forms can be influenced by the gastric state (i.e., fasted vs fed stomach).50−54 With respect to our experiences, we will highlight the most important parameters of the fed stomach. For further information on this topic, we recommend the excellent review “Imaging and modelling of digestion in the stomach and the duodenum” written by K. Schulze (2006).55 1612



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slightly hypoosmotic to the blood plasma.68,69 It should be kept in mind that, in consequence of the secretory activity of the stomach, the total volume of liquids available for the dosage form dissolution in the fed stomach is distinctly higher than the volume of liquids ingested with the meal. A recent MRI study by Sauter et al. showed that the gastric content volume decreases more slowly than the meal volume due to factors such as gastric secretion.70 This might be crucial for drug bioavailability and the dissolution behavior of solid oral dosage forms, which will be discussed in a subsequent section. Physicochemical Characteristics of Chyme. To gain insight into the composition of gastric contents is essential to understand the dissolution behavior of solid oral dosage forms in vivo. The nature of the gastric content is the result of salivary flow, gastric secretions and food properties. The main components of the gastric secretion are given in Table 3 together with the secreting cell type and their related function.71,72

Gastric Responses to Food Intake. The stomach is divided into three functional areas: the fundus as the gastric reservoir, the antrum as the site of particle trituration and gastric emptying and the corpus as the connective part between fundus and antrum (see Figure 2).

Figure 2. Schematic representation of stomach anatomy. Under moderate postprandial conditions the length of the stomach is about 25−30 cm.

Table 3. Gastric Juice and Its Main Components component

Volume and Secretion. The gastric content volume in the fasted state is relatively small and amounts to 10 to 50 mL.56−58 In contrast to the illustration in Figure 2, the empty stomach is collapsed like an empty bag except for the fundus, which can be expanded by gaseous phases such as swallowed air or carbon dioxide as the product of the bicarbonate degradation. Indeed, after meal boluses enter the stomach via the cardia, the unfolding takes place following a certain arrangement. The first boluses directly slide down the lesser curvature and accumulate in the sinus. The following boluses are layered above.55 Generally, the stomach is able to gather considerably more than 1 L of gastric content, whereas this maximum capacity depends on several factors such as food volume and individual physiology.59−61 After ingestion of a solid meal, the gastric volume arises to a maximum within the first minutes due to the food itself, salivary flow, gastric secretion and little gastric emptying (lag phase). With time, the gastric emptying exceeds the secretion and hence, the gastric volume falls back to its initial value. Burton and co-workers showed that, for a meal composed of two scrambled eggs and one slice of bran bread ingested together with 240 mL of skim milk, the gastric volume is equal to meal volume not until 3 h after meal intake.62 Therefore, it can be concluded that the volume of the gastric content is the sum of meal volume, fasting gastric volume, cumulative saliva and gastric secretion less gastric emptying.56,63 During digestion, gastric juice is secreted by the stomach wall into the lumen in order to provide functions such as protein and lipid digestion, preparation of micronutrients for absorption in duodenum, protection against microbial overgrowth, dilution of chyme and, related, the regulation of gastric emptying. The daily production of gastric juice ranges from 2 to 3 L with differences between unstimulated and stimulated state. Whereas for the unstimulated secretion rates of only 1 mL/min are reported, the gastric juice production under stimulation can be 10 to 50 mL/min.64 Sauter and co-workers reported that, 100 min after the intake of a test meal, nearly 50% of the gastric contents were gastric secretions.65 In line with this, other studies revealed a secretion volume of 800 mL corresponding to a 400 mL solid meal.66,67 By investigation of aspirates from the fasted human stomach, gastric contents were found to be

secreting cell type

function

hydrochloric acid (HCl)

parietal cells (mainly in fundus/corpus)

bicarbonate pepsinogen

mucous cells chief (peptic) cells, mucous neck cells chief cells mucous neck cells, surface mucous cells via duodenal reflux into gastric lumen

activation of pepsin denaturation of proteins support of duodenal micronutrient absorption (e.g., iron, calcium) protection against microbial overgrowth mucosa protection against acid protein digestion (after acid activation to pepsin) lipolysis mucosa protection lubrication

gastric lipase mucins bile salts

decrease of surface tension (surfactant) emulsification of lipids by creation of mixed micelles

Pepsin, secreted as the inactive precursor pepsinogen (zymogen), and gastric lipase are important enzymes for the intragastric digestion of proteins and lipids. Food intake is known to stimulate the secretion of the enzymes.73−75 Other enzymes acting in the stomach are the salivary α-amylase, which is swallowed together with the food bolus, and pancreatic enzymes (lipase, protease and amylase) entering the stomach by duodenal reflux.72 Renou and co-workers revealed that intragastric lipolysis of a liquid test meal (12.5 g of lipids, 11.3 g of triglycerides) accounts for around 25% of the overall lipolysis.76 Thereby, triglycerides are degraded by lipases mainly into diglycerides, fatty acids and some monoglycerides. Owing to the amphiphilic nature of free fatty acids and monoglycerides, they are capable of forming mixed micelles together with bile salts. These mixed micelles are later emptied into the duodenum. In this way, the action of pancreatic enzymes is supported by the increased surface area available for further degradation.77−79 Acid-labile emulsions in particular tend to break and as a consequence form fat layers that float on top of the gastric content.80 A further feature of the stomach is to separate the gastric content into certain phases. The fat phase floats on the aqueous phase due to the low density of fat compared to that of water. It is noteworthy that the subject posture and ingestion order influence the position of this lipid layer.81,82 The solid phase is 1613



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corpus, and the pyloric glands in the antral area. The pyloric glands possess no parietal cells, which are responsible for HCl secretion, and therefore cannot produce gastric acid. As a consequence, the pH values in fundus are generally lower especially near the stomach wall, while the antrum shows higher pH values and is less affected by gastric acid secretion. Simonian and co-workers described an acid pocket near the lower esophageal junction (LES) in the region of the cardia.85 Hila and co-workers observed the formation of acid layers in the stomach. A buffered food layer 3 to 8 cm below the LES is enclosed by a proximal and a distal acid layer with significantly lower pH values. Sauter and co-workers described a secretion layer on top of the gastric contents supporting the idea of an acid pocket near the cardia.70 Several food components such as proteins or ionic substances may also enhance the meal buffer capacity leading to the progression of action of salivary enzymes such as the salivary α-amylase, which are inactivated under acidic conditions.84 Certainly, food intake increases the gastric pH value and therefore may influence the dissolution of ionizable drugs especially if the pKa of the API is in the range of the physiological pH changes characteristic for the fed stomach (i.e., pH 1−7). The solubility of weak acids increases whereas weak bases usually become less soluble in the aqueous phase. Diminished drug dissolution was described for weak bases such as ketoconazole, dipyridamole or cefpodoxime.77,86−89 However, the in vivo data available are controversial. It is most probably caused by the complex composition, the emulsion-like character and the inhomogeneity of the gastric content. Additionally, it should be kept in mind that the performance of ionizable excipients such as disintegrants, coating materials, pore-forming substances or capsule shell materials may be also influenced.77 An overview of physicochemical parameters in fasted and fed states is depicted in Table 4. The parameters

separated by its higher gravity into the distal part, where the particles are ground by antral contractions. Between fat and solid phase, a watery phase with small suspended particles is present, which can be emptied quickly by a decanting-like process. The gastric anatomy accounts for this phenomenon as can be seen from Figure 3. However, considering the

Figure 3. Layering in fed stomach.

physiological circumstances and regular intake of foods and drinking scheme as well as the subject’s physical activity, the presence of such layers under everyday conditions is unclear. Gastric acid secretion is one of the main parameters affecting the dissolution profile of solid dosage forms, particularly for poorly water-soluble drugs or drugs with pH-dependent solubility.77 Basal acid output amounts to 2 to 4 mmol/h, but in stimulated state, rates of up to 20 to 30 mmol/h are reported. The gastric acid (HCl), which is produced by the parietal cells, has a maximum concentration of 160 mmol/L (pH 0.8).71 The acidic secretion is controlled by various hormones and neurotransmitters such as histamine, gastrin, acetylcholine or somatostatin. After meal ingestion, especially cholinergic neurons are stimulated.71,72 Under fasted conditions, the gastric pH value of healthy adults is reported to be within pH 1 to pH 3.83−85 Under such acidic conditions it is obvious that the dissolution of weak acids with higher pKa values than the pH value of the gastric milieu (e.g., ibuprofen, diclofenac, furosemide, valproic acid) is hampered, because they are primarily nonionized. In contrast, weak bases such as ketoconazole or dipyridamole are ionized to a high extent and, thus, their dissolution is enhanced.86 Nonetheless, fasted pH values can be elevated especially in elderly patients, under pathologic conditions (e.g., AIDS) or after the intake of antisecretory drugs such as antimuscarinic drugs, H2-receptor antagonists or proton-pump inhibitors.77 Additionally, meal intake also raises the pH values of the gastric content. Depending on meal composition and volume, values of up to pH 7 are reported in the literature and the return to baseline pH values takes several hours in particular for highcaloric meals. Dressman and co-workers investigated gastric pH values after intake of meals with composition similar to the FDA standard breakfast consisting of hamburger, toast, hashed brown potatoes and milk (caloric value: 1000 kcal). They observed that the maximum pH was reached within the first 5 min and pH decreased to values below pH 3 not after 56 ± 42 min.83 Interestingly, due to regional differences of the secretory activity and the specific mixing conditions in the postprandial stomach, the acid distribution is not homogeneous, leading to pH gradients in the stomach content. This is due to the presence of two distinct kinds of glands that consist of different cell types: the oxyntic glands, which are found in fundus and

Table 4. Physicochemical Characteristics of Fasted and Fed Stomach fasted stomach buffer capacity (mmol/ (L·ΔpH)) osmolality (mOsmol/ kg) surface tension (mN/m)

fed stomach

median

7−18a,73

14−28,b,73 25−30c,91

median mean

98−140a,73 221,69 19168

559−217,b,73 217,83 515−475c,91

median mean range

41.9−45.7a,73 33.669 35−4592

30−31b,73

a

Median values 20−210 min after administration of 250 mL of water via nasogastric tube. bMedian values 30−210 min after administration of 500 mL of Ensure Plus via nasogastric tube. cMedian values 30−120 min after administration of 500 mL of Ensure Plus.

chosen are considered as key factors affecting the intragastric dissolution of solid dosage forms according to Klein and coworkers.90 This table reveals that after meal ingestion the surface tension of the gastric content decreases. However, for both fasted and fed state, its value is below the surface tension of water (72 mN/m), indicating the presence of surfactants such as proteins, lipolysis products and carbohydrates. The latter are able to form quasi-emulsions by increasing the viscosity.73,88 On the other hand, osmolality and buffer capacity are increased by food intake, but their values are highly 1614



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dependent on meal composition and, in the fasted state, by the prior administration of water. The viscosity is another important physicochemical parameter of the gastric medium. However, viscosity measurements of the chyme are technically difficult due to its macroscopic inhomogeneity. Furthermore, the results are characterized by high variability. Due to the suspension-like character, the chyme can be separated into two components. Whereas the liquid phase has a density close to 1 g/cm3 (water) and nearly Newtonian fluid nature, the solid particles change the flow properties toward non-Newtonian, pseudoplastic flow behavior with shear thinning. Additionally, by rise of the inner friction caused by collision of solid particles the medium viscosity is increased in comparison to the individual liquid phase.93−97 Abrahamsson and co-workers estimated the viscosity of the gastric milieu to be within 10 to 2000 mPa·s.98 Marciani and co-workers demonstrated that although the viscosity of test meals differs by the factor 1000, the gastric emptying rates show only minor differences. In conclusion, gastric secretions and saliva must lead to a fast drop of the chyme viscosity.95 Due to secretions coming from the gastric wall and in line with the observations of Marciani and co-workers, the viscosity is not homogeneous in all areas of the stomach. For instance, outer areas are more diluted. Marciani and co-workers reported that a high viscous meal is not completely diluted even after 72 min.99,100 Further studies by the group of W. Schwizer confirmed these observations.65 Moreover, the viscosity is of interest owing to the fact that the diffusivity is inversely proportional to it, which further influences the intragastric digestion of nutrients and dissolution of drugs.88,90,101 Furthermore, the viscosity of the chyme and its rheological properties affect intragastric mixing and flow conditions in the postprandial stomach being the consequence of the gastric motility.102 Gastric Motility. Two different gastric motor patterns are known for the stomach, a fasted and a fed pattern. The fasted state is characterized by the interdigestive migrating motor complex (MMC), where the electric activity of the stomach wall serves as general cleansing allowing the emptying of nondigestible objects from the gastric lumen.103−105 A complete MMC cycle consists of four phases characterized by distinct intensity and duration. Regarding dissolution testing of solid dosage forms, especially MMC phase III is of interest, because powerful contractions enable the stomach to empty even large monolithic objects like tablets or capsules.106 Over 4 to 6 min, maximum pressures of up to 300 mbar are applied.107 As opposed to this, MMC I and IV are phases of motoric rest, whereas during MMC phase II (40 to 60 min) the amplitude of the contraction is approximately 50% of the maximum pressure. One MMC front moves from the proximal stomach to the ileum within 1 to 2 h and restarts afterward.108,109 Meal ingestion interrupts the MMC and induces the fed pattern (digestive motor activity). Caloric value and composition of the meal affect the duration of this interruption, which can be up to several hours.105,110,111 Moreover, lipids disrupt the MMC longer than carbohydrates or proteins due to prolonged gastric residence time that is caused by higher caloric density and the tendency to float on top of the gastric content as well as intestinal feedback mechanisms.112−114 Regarding the contractile activity, the fed pattern is comparable to MMC phase II, and thus, forces acting in the fed stomach are lower than in the fasted state.82,110

As discussed above, the proximal stomach serves as reservoir for gastric contents. Owing to the vagally mediated, reduced gastric tone, large volumes can be ingested without inducing any considerable increase of the intragastric pressure.63 This gastric accommodation is composed of different mechanisms (receptive, adaptive and feedback relaxation), and the fundic pressure gradient is further regarded as the driving force for liquid emptying.115−119 Slow fundic contractions contribute to the transport of gastric content to the antrum, where it is mixed and homogenized by antral contraction waves (ACW). Nguyen and co-workers observed a functional association between the fundic squeeze and the antral contraction waves for both the fasting and the fed stomach.120 The antral contraction waves originate from pacesetter cells (so-called interstitial cells of Cajal) at the greater curvature of the middle corpus. Within 60 s, peristaltic waves progress along the gastric wall toward the pylorus with velocities of around 2 to 3 mm/s and mean occlusion rates of 40% to 60%.121−123 The higher the occlusion, the higher the pressure exerted on intragastric objects. Manometric investigations revealed that the antral pressure is increasing toward the pylorus from 50 mmHg in upper antral regions to more than 200 mmHg at the pylorus.124,125 According to a consensus statement of the American Neurogastroenterology and Motility Society, motility is regarded as normal if antral contractility is greater than 40 mmHg in a manometric test.126 The frequency of the ACW has a constant level of around 3 min−1, but a certain initial pattern was found by Kwiatek and co-workers, who demonstrated lower frequencies of down to 1.5 min−1 just after the ingestion of a liquid test meal.127 Besides, food ingestion has several effects on ACW including the amplitude, the duration and the propagation length (i.e., start point shifted proximally for large meal volumes). Prö ve and co-workers demonstrated in experiments with dogs that low viscous meals induce deeper indentations of antral contractions compared to high viscous meals.128 In contrast, Marciani and co-workers demonstrated that frequency and velocity of the ACW are not affected by the physicochemical properties of the meal.121 Additionally, the occlusal diameter decreases toward the pylorus. Besides the central role in mixing and homogenization of gastric contents as well as in the emulsification of lipids, antral contractions have a key role in the trituration of particles in the stomach that is vividly described with the term “antral mill”.129,130 Thereby, particles are processed in a stereotypical manner. First, during propulsion, chyme consisting of liquids and suspended particles is transported toward the pylorus by single ACW. Whereas fluids and small particles are emptied into the duodenum through the pylorus, larger particles are retained in the sinus at the greater curvature.131 This discriminatory function of the stomach during gastric emptying is commonly described as “gastric sieving”. Shortly before a single ACW reaches the pylorus, the sphincter constricts. Thus, the hydrostatic pressure of the distal antrum increases and chyme together with bigger particles is forced back into the corpus leading to grinding of particles. Furthermore, a retrograde jet-like flow toward the proximal stomach arises as a result of the pressure gradient between antrum and corpus/fundus. This process is referred to as retropulsion and contributes to comminution and separation of particles (see Figure 4). As a second flow pattern, eddies emerge between the ACW located mainly at the stomach walls. These recirculating flow events transport secretions from the 1615



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shear forces acting potentially on food particles or tablets in the occlusal region of the antropyloric region. These high shear forces correlate with the occurrence of the retropulsive jet and are about 10-fold higher than in the fundus.132 Three different mechanisms contribute to the digestion of particles: particle fragmentation, erosion and degradation. This classification is not strict, and for some foods, the mechanism changes within the processing time. The mechanism of fragmentation describes the breakage into smaller particulates. This process is only likely to be observed for food with low intrinsic cohesion (e.g., meat products), because forces applied in the stomach are low in comparison to the forces acting in the oral cavity. If the applied stresses are below cohesive forces, erosion is dominant. Depending on the food properties, erosion can be classified into surface and bulk erosion.139,140 Regarding solid oral dosage forms, it is hardly imaginable that the stomach walls will break tablets, but postprandial erosion is likely, for instance for hydrogel matrix tablets.141 Abrasion from the tablet is a result of friction between the tablet’s surface and the gastric wall as well as gastric contents. Furthermore, chemical degradation in saliva and gastric juice is primarily the result of enzymatic reactions (e.g., lipolysis, protein digestion) and, thus, related to the composition of these fluids. By use of their model stomach system, Kong and Singh proposed three different kinds of disintegration kinetics for particle size reduction: exponential, sigmoidal and delayedsigmoidal profile. The food texture during digestion is influenced by fluid absorption, gastric juice, oral processing, enzymatic reactions and heating to body temperature. Precise particle sizes for the gastric content cannot be given due to these highly individual processes.139,142 Nonetheless, there is no reason to assume that solid dosage forms are processed in another way than food particles. Gastric Emptying. As the result of propulsive intragastric forces and pyloric flow resistance, the emptying of chyme into the duodenum is the final step of food processing in the stomach. Hausken and co-workers demonstrated for a lowcaloric liquid meal that transpyloric flow is not continuous and rather follows a pulsatile pattern with alternating antegrade (emptying) and retrograde (reflux) flow. The latter enables pancreatobiliary secretions to act on the gastric content and is caused by duodenal contractions, which serve as a retroperistaltic pump. Flow events toward the duodenum are the consequence of an antroduodenal pressure and are classified into peristaltic-related flow (2−6 s) and longer non-peristaltic related flow (3−9 s). In contrast, the reflux periods are significantly shorter than emptying (2−3 s).143 Peak velocities of solid particles such as tablets or capsules during both emptying and reflux are reported to be 50 cm/s and higher.144,145 These high velocities and the pyloric geometry further contribute to the mixing of chyme as was recently shown by Dillard and co-workers.146 Generally, liquids and small suspended particles are able to pass the pyloric sphincter, whereas larger and hard particles as well as particles with deviant densities from water are retained in the stomach by gastric sieving. Subsequently, they are ground and hydrated until a sufficient state with respect to size and texture is obtained.147 Particle sizes of 1 to 2 mm are regarded as critical. However, it is impossible to give a clear cutoff dimension describing a particle size which allows solids to leave the pylorus together with the liquid, because of the diversity of the food parameters that have to be considered.103,148 This circumstance was highlighted in a review by Newton, who

Figure 4. Gastric peristalsis (ACW: antral contraction wave).

wall into the lumen and, thus, conduce to the hydration of the food boluses.102,132 Owing to the technically sophisticated in vivo examination of the gastric flow, only few studies describe intragastric flow velocities and flow patterns in the fed state. Boulby and coworkers determined peak velocities in humans of 2 to 8 cm/ s.114 Unpublished data of our group revealed retrograde velocities of 0.1 to 5 cm/s. More commonly, computer simulations based on computational fluid dynamics (CFD) are applied for the estimation of intragastric flow conditions.102,132−134 However, such models represent only a simplified picture of the physiological conditions. For instance, in the 3D model of Singh and co-workers, the gastric flow events are assumed to be laminar. This fact is arguable in particular for the distal antrum and not yet confirmed. Hence, the complex nature of the gastric content is not fully considered, and thus, more in vivo data are required to gain further insight into gastric flow events. Under assumption of certain predefined physiological aspects such as geometry or ACW frequency, Ferrua and co-workers investigated the effects of content viscosity, ACW propagation velocity and intragastric pressure on the gastric flow pattern. Their calculations revealed that the retrograde jet stream, which is generated near the occlusion caused by the ACW, can amount to maximum flow velocities of 2.8 cm/s. This value was calculated for water-like liquid chyme with Newtonian flow behavior and a viscosity of 1 mPa·s. On the other hand, it was demonstrated that, for fluids with higher viscosities, a decrease of the jet length combined with an increase of the jet velocity, which means that short, but intense, jet streams arise. In addition, the occurrence of eddies is diminished, indicating poor mixing of high-viscous meals.133,135 Moreover, the theoretical calculations of distribution of the flow velocities in the postprandial stomach led to the theory of a stomach road proposed by Pal et al. (“Magenstrasse”). This theory is based on a 2D computer simulation and describes the fast emptying of liquids and small particles by the occurrence of a passage short-cut between fundus and pylorus along the lesser curvature. According to the simulation results liquids can be emptied via stomach road within less than 10 min.136 Besides hydrodynamics, the intragastric mechanical conditions are studied intensively, but the results reported in the literature are highly variable due to the use of different evaluation techniques and different study objectives. In general, it was reported that the antral grinding forces represent the highest shear forces potentially acting on solid dosage forms in the fed stomach (0.2−1.89 N for grinding forces).137,138 Pal and co-workers calculated in a 2D computer model highest 1616



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(especially if digestible dosage forms are considered), and additionally, the gastric environment affects their dissolution behavior. It is still unanswered how dissolution processes of solid oral dosage forms are affected by the gastric physiology and to what extent this should be considered in the development of new oral dosage forms. It is well recognized that the mixing of gastric content is crucial to guarantee a consistent flow of nutrients and drug into the duodenum.164 Therefore, the understanding of the intragastric flow conditions as one of the factors determining the dissolution behavior of solid oral dosage forms is important for a rational dosage form development. Intragastric motility and in particular resulting flow events account for the mixing of gastric content with secretions and liquids. Pal and co-workers indicate in their study the antrum to be the site of intensive mixing, whereas in the fundus nearly no mixing occurs.132 Low viscous meals as soups are distributed quickly and emptied within a short time. For high viscous and/or solid meals, the situation is more complex. At first they are stored in the fundus, then processed in the antrum, maybe redistributed to proximal stomach and finally emptied but not until the chyme possesses certain properties including aspects like particle size and viscosity.157,165 According to distinct functional areas, the intragastric location of a solid dosage form is of importance. A food particle or a solid dosage form retained in the fundus is exposed to rather small shear forces, but is exposed to lower pH values and most probably to media of variable composition, which may affect dissolution. Owing to secretions coming from the stomach wall, there are further gradients between inner and outer regions of the gastric lumen with respect to pH value and viscosity. The latter is known to influence diffusivity and mixing and thereby causing a heterogeneous drug distribution.102 Faas and co-workers showed in an MRI study that the intragastric distribution volume of a contrast marker delivered in a hard gelatin capsule is lower in a high-viscous homogeneous meal than in a particulate heterogeneous meal, because for the latter the liquid is accessible more easily. In the same study it was further demonstrated that the intake of 300 mL of water in comparison to 100 mL of water does not increase the distribution volume, probably due to the fast emptying of noncaloric liquids along the lesser curvature.162 The FDA standard breakfast, which is recommended by the FDA for usage in clinical trials, is a high-fat, high-calorie meal.2 Consequently, gastric residence times of non-disintegrating monolithic solid dosage forms are expired by food intake in comparison to those ingested in the fasted state. Sarosiek and co-workers reported gastric residence times of more than 6 h for SmartPill and even longer gastric retention if further food is ingested.107 These long gastric residence times can lead to serious problems for the patient. For instance, if a drug has to be taken several times per day and the food intake follows common Western habits, which means three to four meals per day, it is likely that dosage forms are retained for longer times in the stomach and afterward are emptied all together. As a consequence, unwanted high plasma levels might result. In the case of enteric coated mesalazine tablets it has been shown that two or three consecutive doses separated by at least 7 h results in comparable plasma profiles to once daily dosing.162 Additionally, different forces act on the dosage forms during the fed pattern. MMC reappears soon after the complete meal is transferred into the duodenum. To empty even large non-

described different threshold values for the gastric emptying of pellets reported in the literature.149 This may have drastic consequences on pharmacotherapy, because particles are emptied in either fed or fasted state resulting in different gastric residence times (GRT) and, thus, distinct plasma profiles. The emptying of liquids can follow zero-order or first-order kinetics and is mainly affected by the gastro−duodenal pressure gradient.150−153 The emptying rate and kinetics depend on caloric content as well as composition, and the emptying rate ranges from 2 up to 4 mL/min, though, particularly for larger volumes, the emptying rates are initially higher (i.e., as far as 10−40 mL/min).63,123,154,155 Solid particles show a biphasic pattern. After a lag phase, during which the particles are triturated and softened in order to prepare them for the pyloric passage and only little emptying is observable, a zero-order emptying process is likely. The lag time, which can frequently be seen for viscous contents and solid meals, depends on certain factors such as meal composition, particle size and food texture and can be longer than one hour as was previously shown by Hellström and co-workers for an omelet.129,148,156 For instance, fat is known to increase the lag time and to decrease the emptying rate.157 On the other hand, nondigestible particles are retained in the stomach until the occurrence of MMC phase II or III, where the strong contractile activity of the gastric wall contributes to the emptying of even large objects.105,158 An example for such a large swallowable but indigestible object is the telemetric pH, temperature and pressure capsule sensor SmartPill (size of 13 mm × 26 mm).105 Willis and co-workers observed that, after ingestion of SmartPill with a test meal, the gastric emptying time (GET) is greater than 15 h in 7 out of 28 subjects.159 Thus, to use large objects is one of the approaches for the development of gastroretentive dosage forms. Whereas more than 50% of model fluid meals are emptied within 10 to 60 min, it is extremely difficult to examine a precise half-life for solid meals due to high interindividual differences in oral and gastric processing.64 Hence, gastric emptying is a highly variable process with certain factors registered by gastric and intestinal receptors involved.154 Several food characteristics influence the gastric processing and, thus, the gastric residence time. These are i.a. particle size, caloric value, certain nutrients, temperature and physicochemical aspects such as osmolality and viscosity that affect the GET.99,153,160,161 For example, viscous contents are emptied to slight extents owing to hampered flow properties.155 Faas and co-workers compared a homogeneous (mashed potatoes) and a heterogeneous (rice) meal with nearly the same caloric value and found no significant differences with respect to GET. Although the homogeneous meal contained no particles that have to be grinded, secretions are required to dilute the content owing to its dense consistency.162 By certain gastric and intestinal feedback mechanisms the stomach is able to control the gastric emptying rate with respect to the energy content of the meal. Values from 2 to 4 kcal/min are reported for the GET.65,113,154,162,163 Obviously, the stomach takes a sample of its content using feedback of several receptors and responds in an appropriate manner. Thus, gastric residence times especially for high-osmolar, high-fat and acid solid meals can be more than 4 h, whereas noncaloric liquids are emptied within a few minutes.72,107 Drug Dissolution in the Fed Stomach. In the fed stomach, solid dosage forms underlie similar processes as food 1617



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(4) Gaviao, M. B.; Engelen, L.; van der Bilt, A. Chewing behavior and salivary secretion. Eur. J. Oral Sci. 2004, 112, 19−24. (5) Bourne, M. C. Food Texture and Viscosity, 2nd ed.; Academic Press: San Diego, 2002. (6) Medicis, S. W.; Hiiemae, K. M. Natural bite sizes for common foods. J. Dent. Res. 1998, 77, 295. (7) Chen, J. Food oral processingA review. Food Hydrocolloids 2009, 23, 1−25. (8) Hiiemae, K.; Heath, M. R.; Heath, G.; Kazazoglu, E.; Murray, J.; Sapper, D.; Hamblett, K. Natural bites, food consistency and feeding behaviour in man. Arch. Oral Biol. 1996, 41, 175−189. (9) Hiiemae, K. Mechanisms of food reduction, transport and deglutition: How the texture of food affects feeding behavior. J. Texture Stud. 2004, 35, 171−200. (10) Poitras, P.; Boivin, M.; Morais, J.; Picard, M.; Mercier, P. Gastric Emptying of Solid Food in Edentulous Patients. Digestion 1995, 56, 483−487. (11) Hattori, Y.; Mito, Y.; Watanabe, M. Gastric emptying rate in subjects with experimentally shortened dental arches: a pilot study. J. Oral Rehabil. 2008, 35, 402−407. (12) Pera, P.; Bucca, C.; Borro, R.; Bernocco, C.; De, L. A.; Carossa, S. Influence of mastication on gastric emptying. J. Dent. Res. 2002, 81, 179−181. (13) Paphangkorakit, J.; Osborn, J. W. The effect of pressure on a maximum incisal bite force in man. Arch. Oral Biol. 1997, 42, 11−17. (14) Miura, H.; Watanabe, S.; Isogai, E.; Miura, K. Comparison of maximum bite force and dentate status between healthy and frail elderly persons. J. Oral Rehabil. 2001, 28, 592−595. (15) Fontijn-Tekamp, F. A.; Slagter, A. P.; Van Der Bilt, A.; Van ’T Hof, M. A.; Witter, D. J.; Kalk, W.; Jansen, J. A. Biting and Chewing in Overdentures, Full Dentures, and Natural Dentitions. J. Dent. Res. 2000, 79, 1519−1524. (16) Mioche, L.; Peyron, M. A. Bite force displayed during assessment of hardness in various texture contexts. Arch. Oral Biol. 1995, 40, 415−423. (17) Hiiemae, K. M.; Palmer, J. B. Food Transport and Bolus Formation during Complete Feeding Sequences on Foods of Different Initial Consistency. Dysphagia 1999, 14, 31−42. (18) Engelen, L.; Fontijn-Tekamp, A.; van der Bilt, A. The influence of product and oral characteristics on swallowing. Arch. Oral Biol. 2005, 50, 739−746. (19) Fontijn-Tekamp, F. A.; van der Bilt, A.; Abbink, J. H.; Bosman, F. Swallowing threshold and masticatory performance in dentate adults. Physiol. Behav. 2004, 83, 431−436. (20) Helkimo, E.; Carlsson, G. E.; Helkimo, M. Chewing efficiency and state of dentition. Acta Odontol. Scand. 1978, 36, 33−41. (21) Jalabert-Malbos, M.-L.; Mishellany-Dutour, A.; Woda, A.; Peyron, M.-A. Particle size distribution in the food bolus after mastication of natural foods. Food Qual. Preference 2007, 18, 803−812. (22) Lucas, P. W.; Ow, R. K. K.; Ritchie, G. M.; Chew, C. L.; Keng, S. B. Relationship Between Jaw Movement and Food Breakdown in Human Mastication. J. Dent. Res. 1986, 65, 400−404. (23) Agrawal, K. R.; Lucas, P. W.; Prinz, J. F.; Bruce, I. C. Mechanical properties of foods responsible for resisting food breakdown in the human mouth. Arch. Oral Biol. 1997, 42, 1−9. (24) Peyron, M. A.; Mishellany, A.; Woda, A. Particle size distribution of food boluses after mastication of six natural foods. J. Dent. Res. 2004, 83, 578−582. (25) Jiffry, M. T. M. Analysis of particles produced at the end of mastication in subjects with normal dentition. J. Oral Rehabil. 1981, 8, 113−119. (26) Woda, A.; Mishellany-Dutour, A.; Batier, L.; Francois, O.; Meunier, J. P.; Reynaud, B.; Alric, M.; Peyron, M. A. Development and validation of a mastication simulator. J. Biomech. 2010, 43, 1667−1673. (27) Lucas, P. W.; Luke, D. A. Is food particle size a criterion for the initiation of swallowing? J. Oral Rehabil. 1986, 13, 127−136. (28) Lucas, P. W.; Luke, D. A.; Voon, F. C. T.; Chew, C. L.; Ow, R. Food breakdown patterns produced by human subjects possessing artificial and natural teeth. J. Oral Rehabil. 1986, 13, 205−214.

disintegrating objects such as matrix tablets during the so-called housekeeping wave, higher forces are applied by the stomach wall.166 During gastric emptying, pressures are acting on the capsule that are higher than 200 mmHg.105 These high pressures can also cause dose dumping of extended release (ER) formulations as was demonstrated by Garbacz and coworkers.167 Particularly the combination with long gastric residence times, during which the texture of solid dosage forms such as hydrogel matrix tablets is softened, must be considered. The pressures generated are the consequence of a circular occlusion. It can be assumed that large objects such as capsules or tablets experience higher pressures, whereas small objects such as pellets are less affected. In our interpretation this is one of the reasons why the risk of pellets to provide dose dumping is smaller than for monolithic dosage forms. In conclusion, the stomach was intensively investigated in the last decades. It was demonstrated that food intake leads to various changes of intragastric conditions regarding mechanical, enzymatic and physicochemical aspects. Thus, the postprandial drug release from solid oral dosage forms can be influenced by these physiological parameters, which may affect drug efficacy and toxicity profiles. The key factors are pH value, GET, motility (shear stresses, hydrodynamics and pressure), meal volume and composition, recurrence of the MMC and gastric content composition. Nonetheless, the factors affecting the in vivo performance of solid dosage forms need further characterization. This includes the quantification of fortitude and intensity of the pressure waves specific for particular gastric sections. Moreover, temperature distribution profiles after ingestion of food of different temperatures, viscosity gradients and flow conditions require consideration for the rational development of biorelevant dissolution test methods.

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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. M.K. and W.W. are participants in the FA1005 COST Action INFOGEST on food digestion.

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ACKNOWLEDGMENTS Financial support by the Federal Ministry of Education and Research (FKZ 13N11368-13N11370) is gratefully acknowledged.

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ABBREVIATIONS USED ACW, antral contraction wave; API, active pharmaceutical ingredient; CFD, computational fluid dynamics; ER, extended release; FDA, U.S. Food and Drug Administration; GET, gastric emptying time; GI, gastrointestinal; GRT, gastric residence time; LES, lower esophageal sphincter; MMC, migrating motor complex; MRI, magnetic resonance imaging

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REFERENCES

(1) Spiller, R. C. Where do all the tablets go in 1986? Gut 1986, 27, 879−885. (2) CDER. Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies; FDA: 2002. (3) van der Bilt, A.; Engelen, L.; Pereira, L. J.; van der Glas, H. W.; Abbink, J. H. Oral physiology and mastication. Physiol. Behav. 2006, 89, 22−27. 1618



Review

(29) Humphrey, S. P.; Williamson, R. T. A review of saliva: normal composition, flow, and function. J. Prosthet. Dent. 2001, 85, 162−169. (30) de Almeida, V.; Gregio, A. M.; Machado, M. A.; de Lima, A. A.; Azevedo, L. R. Saliva composition and functions: a comprehensive review. J. Contemp. Dent. Pract. 2008, 9, 72−80. (31) Engelen, L.; de Wijk, R. A.; Prinz, J. F.; van der Bilt, A.; Bosman, F. The relation between saliva flow after different stimulations and the perception of flavor and texture attributes in custard desserts. Physiol. Behav. 2003, 78, 165−169. (32) Pedersen, A. M.; Bardow, A.; Jensen, S. B.; Nauntofte, B. Saliva and gastrointestinal functions of taste, mastication, swallowing and digestion. Oral Dis. 2002, 8, 117−129. (33) Schipper, R. G.; Silletti, E.; Vingerhoeds, M. H. Saliva as research material: biochemical, physicochemical and practical aspects. Arch. Oral Biol. 2007, 52, 1114−1135. (34) van Aken, G. A.; Vingerhoeds, M. H.; de Hoog, E. H. A. Food colloids under oral conditions. Curr. Opin. Colloid Interface Sci. 2007, 12, 251−262. (35) Schwarz, W. H. The rheology of saliva. J. Dent. Res. 1987, 66 (Spec. No.), 660−666. (36) Rantonen, P. J. F.; Meurman, J. H. Viscosity of whole saliva. Acta Odontol. Scand. 1998, 56, 210−214. (37) Hoebler, C.; Karinthi, A.; Devaux, M. F.; Guillon, F.; Gallant, D. J.; Bouchet, B.; Melegari, C.; Barry, J. L. Physical and chemical transformations of cereal food during oral digestion in human subjects. Br. J. Nutr. 1998, 80, 429−436. (38) Okada, A.; Honma, M.; Nomura, S.; Yamada, Y. Oral behavior from food intake until terminal swallow. Physiol. Behav. 2007, 90, 172− 179. (39) Hutchings, J. B.; Lillford, P. J. The Perception of Food TextureThe Philosophy of the Breakdown Path. J. Texture Stud. 1988, 19, 103−115. (40) Prinz, J. F.; Lucas, P. W. Swallow thresholds in human mastication. Arch. Oral Biol. 1995, 40, 401−403. (41) Peyron, M.-A.; Gierczynski, I.; Hartmann, C.; Loret, C.; Dardevet, D.; Martin, N.; Woda, A. Role of Physical Bolus Properties as Sensory Inputs in the Trigger of Swallowing. PLoS One 2011, 6, e21167. (42) Pereira, L. J.; Gavião, M. B. D.; Engelen, L.; Bilt, A. V. d. Mastication and swallowing: influence of fluid addition to foods. J. Appl. Oral Sci. 2007, 15, 55−60. (43) Pereira, L. J.; Duarte Gaviao, M. B.; Van Der Bilt, A. Influence of oral characteristics and food products on masticatory function. Acta Odontol. Scand. 2006, 64, 193−201. (44) Goyal, R. K.; Chaudhury, A. Physiology of normal esophageal motility. J. Clin. Gastroenterol. 2008, 42, 610−619. (45) Nguyen, H. N.; Silny, J.; Albers, D.; Roeb, E.; Gartung, C.; Rau, G.; Matern, S. Dynamics of esophageal bolus transport in healthy subjects studied using multiple intraluminal impedancometry. Am. J. Physiol. 1997, 273, G958−G964. (46) Osmanoglou, E.; Van Der Voort, I. R.; Fach, K.; Kosch, O.; Bach, D.; Hartmann, V.; Strenzke, A.; Weitschies, W.; Wiedenmann, B.; Trahms, L.; Monnikes, H. Oesophageal transport of solid dosage forms depends on body position, swallowing volume and pharyngeal propulsion velocity. Neurogastroenterol. Motil. 2004, 16, 547−556. (47) Jaspersen, D. Drug-Induced Oesophageal Disorders: Pathogenesis, Incidence, Prevention and Management. Drug Saf. 2000, 22, 237−249. (48) Fisher, R. S.; Malmud, L. S.; Applegate, G.; Rock, E.; Lorber, S. H. Effect of bolus composition on esophageal transit: concise communication. J. Nucl. Med. 1982, 23, 878−882. (49) Hey, H.; Jørgensen, F.; Sørensen, K.; Hasselbalch, H.; Wamberg, T. Oesophageal transit of six commonly used tablets and capsules. Br. Med. J. (Clin. Res. Ed.) 1982, 285, 1717−1719. (50) Fleisher, D.; Li, C.; Zhou, Y.; Pao, L.; Karim, A. Drug, Meal and Formulation Interactions Influencing Drug Absorption After Oral Administration: Clinical Implications. Clin. Pharmacokinet. 1999, 36, 233−254.

(51) Schöller-Gyüre, M.; Boffito, M.; Pozniak, A. L.; Leemans, R.; Kakuda, T. N.; Woodfall, B.; Vyncke, V.; Peeters, M.; Vandermeulen, K.; Hoetelmans, R. M. W. Effects of Different Meal Compositions and Fasted State on the Oral Bioavailability of Etravirine. Pharmacotherapy 2008, 28, 1215−1222. (52) Abrahamsson, B.; Albery, T.; Eriksson, A.; Gustafsson, I.; Sjoberg, M. Food effects on tablet disintegration. Eur. J. Pharm. Sci. 2004, 22, 165−172. (53) Wonnemann, M.; Schug, B.; Anschutz, M.; Brendel, E.; De Nucci, G.; Blume, H. Comparison of two marketed nifedipine modified-release formulations: an exploratory clinical food interaction study. Clin. Ther. 2008, 30, 48−58. (54) Schug, B. S.; Brendel, E.; Wonnemann, M.; Wolf, D.; Wargenau, M.; Dingler, A.; Blume, H. H. Dosage form-related food interaction observed in a marketed once-daily nifedipine formulation after a highfat American breakfast. Eur. J. Clin. Pharmacol. 2002, 58, 119−125. (55) Schulze, K. Imaging and modelling of digestion in the stomach and the duodenum. Neurogastroenterol. Motil. 2006, 18, 172−183. (56) Goetze, O.; Treier, R.; Fox, M.; Steingoetter, A.; Fried, M.; Boesiger, P.; Schwizer, W. The effect of gastric secretion on gastric physiology and emptying in the fasted and fed state assessed by magnetic resonance imaging. Neurogastroenterol. Motil. 2009, 21, 725− e742. (57) Fidler, J.; Bharucha, A. E.; Camilleri, M.; Camp, J.; Burton, D.; Grimm, R.; Riederer, S. J.; Robb, R. A.; Zinsmeister, A. R. Application of magnetic resonance imaging to measure fasting and postprandial volumes in humans. Neurogastroenterol. Motil. 2009, 21, 42−51. (58) Schiller, C.; Frohlich, C. P.; Giessmann, T.; Siegmund, W.; Monnikes, H.; Hosten, N.; Weitschies, W. Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Aliment. Pharmacol. Ther. 2005, 22, 971−979. (59) Geliebter, A.; Hashim, S. A. Gastric capacity in normal, obese, and bulimic women. Physiol. Behav. 2001, 74, 743−746. (60) Chial, H. J.; Camilleri, C.; Delgado-Aros, S.; Burton, D.; Thomforde, G.; Ferber, I.; Camilleri, M. A nutrient drink test to assess maximum tolerated volume and postprandial symptoms: effects of gender, body mass index and age in health. Neurogastroenterol. Motil. 2002, 14, 249−253. (61) Geliebter, A. Gastric distension and gastric capacity in relation to food intake in humans. Physiol. Behav. 1988, 44, 665−668. (62) Burton, D. D.; Kim, H. J.; Camilleri, M.; Stephens, D. A.; Mullan, B. P.; O’Connor, M. K.; Talley, N. J. Relationship of gastric emptying and volume changes after a solid meal in humans. Am. J. Physiol. 2005, 289, G261−G266. (63) Kwiatek, M. A.; Menne, D.; Steingoetter, A.; Goetze, O.; ForrasKaufman, Z.; Kaufman, E.; Fruehauf, H.; Boesiger, P.; Fried, M.; Schwizer, W.; Fox, M. R. Effect of meal volume and calorie load on postprandial gastric function and emptying: studies under physiological conditions by combined fiber-optic pressure measurement and MRI. Am. J. Physiol. 2009, 297, G894−G901. (64) Versantvoort, C. H. M.; van de Kamp, E.; Rompelberg, C. J. M., Development and applicability of an in vitro digestion model in assessing the bioaccessibility of contaminants from food. 2004. (65) Sauter, M. M.; Steingoetter, A.; Curcic, J.; Treier, R.; Kuyumcu, S.; Fried, M.; Boesiger, P.; Schwizer, W.; Goetze, O. Quantification of Meal Induced Gastric Secretion and Its Effect on Caloric Emptying by Magnetic Resonance Imaging (MRI). Gastroenterology 2011, 140, S− 297. (66) Malagelada, J. R.; Longstreth, G. F.; Summerskill, W. H.; Go, V. L. Measurement of gastric functions during digestion of ordinary solid meals in man. Gastroenterology 1976, 70, 203−210. (67) Malagelada, J. R.; Go, V. L.; Summerskill, W. H. Different gastric, pancreatic, and biliary responses to solid-liquid or homogenized meals. Dig. Dis. Sci. 1979, 24, 101−110. (68) Lindahl, A.; Ungell, A.-L.; Knutson, L.; Lennernäs, H. Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women. Pharm. Res. 1997, 14, 497−502. 1619



Review

(69) Pedersen, B. L.; Müllertz, A.; Brøndsted, H.; Kristensen, H. G. A Comparison of the Solubility of Danazol in Human and Simulated Gastrointestinal Fluids. Pharm. Res. 2000, 17, 891−894. (70) Sauter, M.; Curcic, J.; Menne, D.; Goetze, O.; Fried, M.; Schwizer, W.; Steingoetter, A. Measuring the interaction of meal and gastric secretion: a combined quantitative magnetic resonance imaging and pharmacokinetic modeling approach. Neurogastroenterol. Motil. 2012, 24, 632−e273. (71) Schubert, M. L.; Peura, D. A. Control of gastric acid secretion in health and disease. Gastroenterology 2008, 134, 1842−1860. (72) Camilleri, M. Integrated Upper Gastrointestinal Response to Food Intake. Gastroenterology 2006, 131, 640−658. (73) Kalantzi, L.; Goumas, K.; Kalioras, V.; Abrahamsson, B.; Dressman, J. B.; Reppas, C. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/ bioequivalence studies. Pharm. Res. 2006, 23, 165−176. (74) Carriere, F.; Barrowman, J. A.; Verger, R.; Laugier, R. Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans. Gastroenterology 1993, 105, 876−888. (75) Carrière, F.; Grandval, P.; Renou, C.; Palomba, A.; Priéri, F.; Giallo, J.; Henniges, F.; Sander-Struckmeier, S.; Laugier, R. Quantitative study of digestive enzyme secretion and gastrointestinal lipolysis in chronic pancreatitis. Clin. Gastroenterol. Hepatol. 2005, 3, 28−38. (76) Renou, C.; Carrière, F.; Ville, E.; Grandval, P.; Joubert-Collin, M.; Laugier, R. Effects of Lansoprazole on Human Gastric Lipase Secretion and Intragastric Lipolysis in Healthy Human Volunteers. Digestion 2001, 63, 207−213. (77) Charman, W. N.; Porter, C. J.; Mithani, S.; Dressman, J. B. Physiochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J. Pharm. Sci. 1997, 86, 269−282. (78) Hamosh, M.; Klaeveman, H. L.; Wolf, R. O.; Scow, R. O. Pharyngeal lipase and digestion of dietary triglyceride in man. J Clin Invest 1975, 55, 908−913. (79) Porter, C. J. H.; Trevaskis, N. L.; Charman, W. N. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat. Rev. Drug Discovery 2007, 6, 231−248. (80) Marciani, L.; Faulks, R.; Wickham, M. S.; Bush, D.; Pick, B.; Wright, J.; Cox, E. F.; Fillery-Travis, A.; Gowland, P. A.; Spiller, R. C. Effect of intragastric acid stability of fat emulsions on gastric emptying, plasma lipid profile and postprandial satiety. Br. J. Nutr. 2009, 101, 919−928. (81) Kunz, P.; Feinle-Bisset, C.; Faas, H.; Boesiger, P.; Fried, M.; Steingotter, A.; Schwizer, W. Effect of ingestion order of the fat component of a solid meal on intragastric fat distribution and gastric emptying assessed by MRI. J. Magn. Reson. Imaging 2005, 21, 383− 390. (82) Chang, C. A.; McKenna, R. D.; Beck, I. T. Gastric emptying rate of the water and fat phases of a mixed test meal in man. Gut 1968, 9, 420−424. (83) Dressman, J. B.; Berardi, R. R.; Dermentzoglou, L. C.; Russell, T. L.; Schmaltz, S. P.; Barnett, J. L.; Jarvenpaa, K. M. Upper gastrointestinal (GI) pH in young, healthy men and women. Pharm. Res. 1990, 7, 756−761. (84) Hila, A.; Bouali, H.; Xue, S.; Knuff, D.; Castell, D. O. Postprandial stomach contents have multiple acid layers. J. Clin. Gastroenterol. 2006, 40, 612−617. (85) Simonian, H. P.; Vo, L.; Doma, S.; Fisher, R. S.; Parkman, H. P. Regional postprandial differences in pH within the stomach and gastroesophageal junction. Dig. Dis. Sci. 2005, 50, 2276−2285. (86) Dressman, J. B.; Vertzoni, M.; Goumas, K.; Reppas, C. Estimating drug solubility in the gastrointestinal tract. Adv. Drug Delivery Rev. 2007, 59, 591−602. (87) Carlson, J. A.; Mann, H. J.; Canafax, D. M. Effect of pH on disintegration and dissolution of ketoconazole tablets. Am. J. Hosp. Pharm. 1983, 40, 1334−1336.

(88) Horter, D.; Dressman, J. B. Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract. Adv. Drug Delivery Rev. 2001, 46, 75−87. (89) Li, S.; Wong, S.; Sethia, S.; Almoazen, H.; Joshi, Y. M.; Serajuddin, A. T. Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH. Pharm. Res. 2005, 22, 628−635. (90) Klein, S.; Butler, J.; Hempenstall, J. M.; Reppas, C.; Dressman, J. B. Media to simulate the postprandial stomach I. Matching the physicochemical characteristics of standard breakfasts. J. Pharm. Pharmacol. 2004, 56, 605−610. (91) Diakidou, A.; Vertzoni, M.; Dressman, J.; Reppas, C. Estimation of intragastric drug solubility in the fed state: comparison of various media with data in aspirates. Biopharm. Drug Dispos. 2009, 30, 318− 325. (92) Finholt, P.; Solvang, S. Dissolution kinetics of drugs in human gastric juicethe role of surface tension. J. Pharm. Sci. 1968, 57, 1322−1326. (93) Mudie, D. M.; Amidon, G. L.; Amidon, G. E. Physiological Parameters for Oral Delivery and in Vitro Testing. Mol. Pharmaceutics 2010, 7, 1388−1405. (94) Dikeman, C. L.; Murphy, M. R.; Fahey, G. C., Jr. Dietary fibers affect viscosity of solutions and simulated human gastric and small intestinal digesta. J. Nutr. 2006, 136, 913−919. (95) Marciani, L.; Gowland, P. A.; Spiller, R. C.; Manoj, P.; Moore, R. J.; Young, P.; Al-Sahab, S.; Bush, D.; Wright, J.; Fillery-Travis, A. J. Gastric response to increased meal viscosity assessed by echo-planar magnetic resonance imaging in humans. J. Nutr. 2000, 130, 122−127. (96) Takahashi, T.; Sakata, T. Large Particles Increase Viscosity and Yield Stress of Pig Cecal Contents without Changing Basic Viscoelastic Properties. J. Nutr. 2002, 132, 1026−1030. (97) Takahashi, T.; Sakata, T. Viscous properties of pig cecal contents and the contribution of solid particles to viscosity. Nutrition 2004, 20, 377−382. (98) Abrahamsson, B.; Pal, A.; Sjoberg, M.; Carlsson, M.; Laurell, E.; Brasseur, J. G. A novel in vitro and numerical analysis of shear-induced drug release from extended-release tablets in the fed stomach. Pharm. Res. 2005, 22, 1215−1226. (99) Marciani, L.; Gowland, P. A.; Spiller, R. C.; Manoj, P.; Moore, R. J.; Young, P.; Fillery-Travis, A. J. Effect of meal viscosity and nutrients on satiety, intragastric dilution, and emptying assessed by MRI. Am. J. Physiol. 2001, 280, G1227−G1233. (100) Hoad, C. L.; Rayment, P.; Spiller, R. C.; Marciani, L.; Alonso, B. d. C.; Traynor, C.; Mela, D. J.; Peters, H. P. F.; Gowland, P. A. In Vivo Imaging of Intragastric Gelation and Its Effect on Satiety in Humans. J. Nutr. 2004, 134, 2293−2300. (101) Braun, R. J.; Parrott, E. L. Influence of viscosity and solubilization on dissolution rate. J. Pharm. Sci. 1972, 61, 175−178. (102) Ferrua, M. J.; Singh, R. P. Modeling the Fluid Dynamics in a Human Stomach to Gain Insight of Food Digestion. J. Food Sci. 2010, 75, R151−R162. (103) Khosla, R.; Davis, S. S. The effect of tablet size on the gastric emptying of non-disintegrating tablets. Int. J. Pharm. 1990, 62, R9− R11. (104) Khosla, R.; Feely, L. C.; Davis, S. S. Gastrointestinal transit of non-disintegrating tablets in fed subjects. Int. J. Pharm. 1989, 53, 107− 117. (105) Cassilly, D.; Kantor, S.; Knight, L. C.; Maurer, A. H.; Fisher, R. S.; Semler, J.; Parkman, H. P. Gastric emptying of a non-digestible solid: assessment with simultaneous SmartPill pH and pressure capsule, antroduodenal manometry, gastric emptying scintigraphy. Neurogastroenterol. Motil. 2008, 20, 311−319. (106) Brun, R.; Michalek, W.; Surjanhata, B. C.; Parkman, H. P.; Semler, J. R.; Kuo, B. Comparative analysis of phase III migrating motor complexes in stomach and small bowel using wireless motility capsule and antroduodenal manometry. Neurogastroenterol. Motil. 2012, 24, 332−e165. (107) Sarosiek, I.; Selover, K. H.; Katz, L. A.; Semler, J. R.; Wilding, G. E.; Lackner, J. M.; Sitrin, M. D.; Kuo, B.; Chey, W. D.; Hasler, W. 1620



Review

L.; Koch, K. L.; Parkman, H. P.; Sarosiek, J.; McCallum, R. W. The assessment of regional gut transit times in healthy controls and patients with gastroparesis using wireless motility technology. Aliment. Pharmacol. Ther. 2010, 31, 313−322. (108) Vantrappen, G.; Janssens, J.; Hellemans, J.; Ghoos, Y. The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J. Clin. Invest. 1977, 59, 1158−1166. (109) Sarna, S. K. Cyclic motor activity; migrating motor complex: 1985. Gastroenterology 1985, 89, 894−913. (110) Ouyang, A.; Sunshine, A. G.; Reynolds, J. C. Caloric content of a meal affects duration but not contractile pattern of duodenal motility in man. Dig. Dis. Sci. 1989, 34, 528−536. (111) Madsen, J. L.; Dahl, K. Human migrating myoelectric complex in relation to gastrointestinal transit of a meal. Gut 1990, 31, 1003− 1005. (112) De Wever, I.; Eeckhout, C.; Vantrappen, G.; Hellemans, J. Disruptive effect of test meals on interdigestive motor complex in dogs. Am. J. Physiol. 1978, 235, E661−E665. (113) Hunt, J. N.; Stubbs, D. F. The volume and energy content of meals as determinants of gastric emptying. J. Physiol. 1975, 245, 209− 225. (114) Boulby; Moore; Gowland; Spiller. Fat delays emptying but increases forward and backward antral flow as assessed by flowsensitive magnetic resonance imaging. Neurogastroenterol. Motil. 1999, 11, 27−36. (115) Maurer, A. H. Advancing Gastric Emptying Studies: Standardization and New Parameters to Assess Gastric Motility and Function. Semin. Nucl. Med. 2012, 42, 101−112. (116) De Schepper, H. U.; Cremonini, F.; Chitkara, D.; Camilleri, M. Assessment of gastric accommodation: overview and evaluation of current methods. Neurogastroenterol. Motil. 2004, 16, 275−285. (117) Schwizer, W.; Steingötter, A.; Fox, M.; Zur, T.; Thumshirn, M.; Bö siger, P.; Fried, M. Non-invasive measurement of gastric accommodation in humans. Gut 2002, 51, i59−i62. (118) Patrick, A.; Epstein, O. Review article: gastroparesis. Aliment. Pharmacol. Ther. 2008, 27, 724−740. (119) Ehrlein, H. J.; Schemann, M. Gastrointestinal Motility; Technische Universität München: Munich, 2005. (120) Nguyen, N. Q.; Fraser, R. J.; Bryant, L. K.; Holloway, R. H. Functional association between proximal and distal gastric motility during fasting and duodenal nutrient stimulation in humans. Neurogastroenterol. Motil. 2007, 19, 638−645. (121) Marciani, L.; Young, P.; Wright, J.; Moore, R.; Coleman, N.; Gowland, P. A.; Spiller, R. C. Antral motility measurements by magnetic resonance imaging. Neurogastroenterol. Motil. 2001, 13, 511− 518. (122) Marciani, L. Assessment of gastrointestinal motor functions by MRI: a comprehensive review. Neurogastroenterol. Motil. 2011, 23, 399−407. (123) Faas, H.; Hebbard, G. S.; Feinle, C.; Kunz, P.; Brasseur, J. G.; Indireshkumar, K.; Dent, J.; Boesiger, P.; Thumshirn, M.; Fried, M.; Schwizer, W. Pressure-geometry relationship in the antroduodenal region in humans. Am. J. Physiol. 2001, 281, G1214−G1220. (124) Sun, W. M.; Smout, A.; Malbert, C.; Edelbroek, M. A.; Jones, K.; Dent, J.; Horowitz, M. Relationship between surface electrogastrography and antropyloric pressures. Am. J. Physiol. 1995, 268, G424−G430. (125) Savoye-Collet, C.; Savoye, G.; Smout, A. Determinants of transpyloric fluid transport: a study using combined real-time ultrasound, manometry, and impedance recording. Am. J. Physiol. 2003, 285, G1147−G1152. (126) Camilleri, M.; Bharucha, A. E.; Di Lorenzo, C.; Hasler, W. L.; Prather, C. M.; Rao, S. S.; Wald, A. American Neurogastroenterology and Motility Society consensus statement on intraluminal measurement of gastrointestinal and colonic motility in clinical practice. Neurogastroenterol. Motil. 2008, 20, 1269−1282. (127) Kwiatek, M. A.; Steingoetter, A.; Pal, A.; Menne, D.; Brasseur, J. G.; Hebbard, G. S.; Boesiger, P.; Thumshirn, M.; Fried, M.;

Schwizer, W. Quantification of distal antral contractile motility in healthy human stomach with magnetic resonance imaging. J. Magn. Reson. Imaging 2006, 24, 1101−1109. (128) Pröve, J.; Ehrlein, H. J. Motor function of gastric antrum and pylorus for evacuation of low and high viscosity meals in dogs. Gut 1982, 23, 150−156. (129) Urbain, J.-L. C.; Siegel, J. A.; Charkes, N. D.; Maurer, A. H.; Malmud, L. S.; Fisher, R. S. The two-component stomach: effects of meal particle size on fundal and antral emptying. Eur. J. Nucl. Med. Mol. Imaging 1989, 15, 254−259. (130) Schwizer, W.; Steingoetter, A.; Fox, M. Magnetic resonance imaging for the assessment of gastrointestinal function. Scand. J. Gastroenterol. 2006, 41, 1245−1260. (131) Keinke, O.; Schemann, M.; Ehrlein, H.-J. Mechanical Factors Regulating Gastric Emptying of Viscous Nutrient Meals in Dogs. Exp. Physiol. 1984, 69, 781−795. (132) Pal, A.; Indireshkumar, K.; Schwizer, W.; Abrahamsson, B.; Fried, M.; Brasseur, J. G. Gastric flow and mixing studied using computer simulation. Proc. Biol. Sci. 2004, 271, 2587−2594. (133) Ferrua, M. J.; Kong, F.; Singh, R. P. Computational modeling of gastric digestion and the role of food material properties. Trends Food Sci. Technol. 2011, 22, 480−491. (134) Kozu, H.; Kobayashi, I.; Nakajima, M.; Uemura, K.; Sato, S.; Ichikawa, S. Analysis of Flow Phenomena in Gastric Contents Induced by Human Gastric Peristalsis Using CFD. Food Biophys. 2010, 5, 330− 336. (135) Singh, S.; Singh, R. P. Gastric Digestion of Foods: Mathematical Modeling of Flow Field in a Human Stomach. In Food Engineering Interfaces; Aguilera, J. M., Ed.; Springer Science +Business Media: New York, 2011; Chapter 5. (136) Pal, A.; Brasseur, J. G.; Abrahamsson, B. A stomach road or “Magenstrasse” for gastric emptying. J. Biomech. 2007, 40, 1202−1210. (137) Marciani, L.; Gowland, P. A.; Fillery-Travis, A.; Manoj, P.; Wright, J.; Smith, A.; Young, P.; Moore, R.; Spiller, R. C. Assessment of antral grinding of a model solid meal with echo-planar imaging. Am. J. Physiol. 2001, 280, G844−G849. (138) Kamba, M.; Seta, Y.; Kusai, A.; Ikeda, M.; Nishimura, K. A unique dosage form to evaluate the mechanical destructive force in the gastrointestinal tract. Int. J. Pharm. 2000, 208, 61−70. (139) Kong, F.; Singh, R. P. Modes of Disintegration of Solid Foods in Simulated Gastric Environment. Food Biophys. 2009, 4, 180−190. (140) Lentle, R. G.; Janssen, P. W. M. The Physical Processes of Digestion; Springer: New York: 2011; p 279. (141) Katori, N.; Aoyagi, N.; Terao, T. Estimation of agitation intensity in the GI tract in humans and dogs based on in vitro/in vivo correlation. Pharm. Res. 1995, 12, 237−243. (142) Kong, F.; Singh, R. P. A model stomach system to investigate disintegration kinetics of solid foods during gastric digestion. J. Food Sci. 2008, 73, E202−210. (143) Hausken, T.; Mundt, M.; Samsom, M. Low antroduodenal pressure gradients are responsible for gastric emptying of a low-caloric liquid meal in humans. Neurogastroenterol. Motil. 2002, 14, 97−105. (144) Berstad, A.; Hausken, T.; Gilja, O.; Thune, N.; Matre, K.; Ødegaard, S. Volume measurements of gastric antrum by 3-D ultrasonography and flow measurements through the pylorus by duplex technique. Dig. Dis. Sci. 1994, 39, 97S−100S. (145) Weitschies, W.; Cardini, D.; Karaus, M.; Trahms, L.; Semmler, W. Magnetic marker monitoring of esophageal, gastric and duodenal transit of non-disintegrating capsules. Pharmazie 1999, 54, 426−430. (146) Dillard, S.; Krishnan, S.; Udaykumar, H. S. Mechanics of flow and mixing at antroduodenal junction. World J. Gastroenterol. 2007, 13, 1365−1371. (147) Meyer, J. H.; Ohashi, H.; Jehn, D.; Thomson, J. B. Size of liver particles emptied from the human stomach. Gastroenterology 1981, 80, 1489−1496. (148) Siegel, J. A.; Urbain, J. L.; Adler, L. P.; Charkes, N. D.; Maurer, A. H.; Krevsky, B.; Knight, L. C.; Fisher, R. S.; Malmud, L. S. Biphasic nature of gastric emptying. Gut 1988, 29, 85−89. 1621



Review

(149) Newton, J. M. Gastric emptying of multi-particulate dosage forms. Int. J. Pharm. 2010, 395, 2−8. (150) McHugh, P. R.; Moran, T. H. Calories and gastric emptying: a regulatory capacity with implications for feeding. Am. J. Physiol. 1979, 236, R254−R260. (151) Brener, W.; Hendrix, T. R.; McHugh, P. R. Regulation of the gastric emptying of glucose. Gastroenterology 1983, 85, 76−82. (152) Hunt, J. N.; Smith, J. L.; Jiang, C. L. Effect of meal volume and energy density on the gastric emptying of carbohydrates. Gastroenterology 1985, 89, 1326−1330. (153) Moore, J. G.; Christian, P. E.; Brown, J. A.; Brophy, C.; Datz, F.; Taylor, A.; Alazraki, N. Influence of meal weight and caloric content on gastric emptying of meals in man. Dig. Dis. Sci. 1984, 29, 513−519. (154) Kong, F.; Singh, R. P. Disintegration of solid foods in human stomach. J. Food Sci. 2008, 73, R67−80. (155) Indireshkumar, K.; Brasseur, J. G.; Faas, H.; Hebbard, G. S.; Kunz, P.; Dent, J.; Feinle, C.; Li, M.; Boesiger, P.; Fried, M.; Schwizer, W. Relative contributions of “pressure pump” and “peristaltic pump” to gastric emptying. Am. J. Physiol. 2000, 278, G604−G616. (156) Hellström, P. M.; Grybäck, P.; Jacobsson, H. The physiology of gastric emptying. Best Pract. Res., Clin. Anaesthesiol. 2006, 20, 397−407. (157) Houghton, L. A.; Mangnall, Y. F.; Read, N. W. Effect of incorporating fat into a liquid test meal on the relation between intragastric distribution and gastric emptying in human volunteers. Gut 1990, 31, 1226−1229. (158) Coupe, A. J.; Davis, S. S.; Evans, D. F.; Wilding, I. R. Correlation of the Gastric Emptying of Nondisintegrating Tablets with Gastrointestinal Motility. Pharm. Res. 1991, 8, 1281−1285. (159) Willis, H. J.; Thomas, W.; Willis, D. J.; Slavin, J. L. Feasibility of measuring gastric emptying time, with a wireless motility device, after subjects consume fiber-matched liquid and solid breakfasts. Appetite 2011, 57, 38−44. (160) Sun, W. M.; Houghton, L. A.; Read, N. W.; Grundy, D. G.; Johnson, A. G. Effect of meal temperature on gastric emptying of liquids in man. Gut 1988, 29, 302−305. (161) Holt, S.; Reid, J.; Taylor, T. V.; Tothill, P.; Heading, R. C. Gastric emptying of solids in man. Gut 1982, 23, 292−296. (162) Faas, H.; Steingoetter, A.; Feinle, C.; Rades, T.; Lengsfeld, H.; Boesiger, P.; Fried, M.; Schwizer, W. Effects of meal consistency and ingested fluid volume on the intragastric distribution of a drug model in humans–a magnetic resonance imaging study. Aliment. Pharmacol. Ther. 2002, 16, 217−224. (163) Calbet, J. A.; MacLean, D. A. Role of caloric content on gastric emptying in humans. J. Physiol. 1997, 498, 553−559. (164) Abrahamsson, B.; Alpsten, M.; Hugosson, M.; Jonsson, U. E.; Sundgren, M.; Svenheden, A.; Tolli, J. Absorption, gastrointestinal transit, and tablet erosion of felodipine extended-release (ER) tablets. Pharm. Res. 1993, 10, 709−714. (165) Piessevaux, H. Intragastric distribution of a standardized meal in health and functional dyspepsia: correlation with specific symptoms. Neurogastroenterol. Motil. 2003, 15, 447. (166) Fadda, H.; McConnell, E.; Short, M.; Basit, A. Meal-Induced Acceleration of Tablet Transit Through the Human Small Intestine. Pharm. Res. 2009, 26, 356−360. (167) Garbacz, G.; Wedemeyer, R. S.; Nagel, S.; Giessmann, T.; Monnikes, H.; Wilson, C. G.; Siegmund, W.; Weitschies, W. Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses. Eur. J. Pharm. Biopharm. 2008, 70, 421−428.

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