International Journal of Pharmaceutics 457 (2013) 446–460

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Review

Food, physiology and drug delivery

F.J.O. Varum 1 , G.B. Hatton, A.W. Basit ∗
Department of Pharmaceutics, UCL School of Pharmacy, University College London, WC1N 1AX, London, UK

a r t i c l e i n f o a b s t r a c t

Article history: Gastrointestinal physiology is dynamic and complex at the best of times, and a multitude of known vari-
Received 17 December 2012 ables can affect the overall bioavailability of drugs delivered via the oral route. Yet while the influences
Received in revised form 8 April 2013 of food and beverage intake as just two of these variables on oral drug delivery have been extensively
Accepted 12 April 2013
documented in the wider literature, specific information on their effects remains sporadic, and is not so
Available online 21 April 2013
much contextually reviewed. Food co-ingestion with oral dosage forms can mediate several changes to
drug bioavailability, yet the precise mechanisms underlying this have yet to be fully elucidated. Like-
Keywords:
wise, the often detrimental effects of alcohol (ethanol) on dosage form performance have been widely
Pharmacokinetics
Dose dumping
observed experimentally, but knowledge of which has only moderately impacted on clinical practice.
Controlled release Here, we attempt to piece together the available subject matter relating to the influences of both solid
Colonic drug delivery and liquid foodstuffs on the gastrointestinal milieu and the implications for oral drug delivery, with par-
Enteric coatings ticular emphasis on the behaviour of modified-release dosage forms, formulation robustness and drug
Biorelevant dynamic dissolution testing absorption. Providing better insight into these influences, and exemplifying cases where formulations
have been developed or modified to circumvent their associated problems, can help to appropriately
direct the design of future in vitro digestive modelling systems as well as oral dosage forms resilient to
these effects. Moreover, this will help to better our understanding of the impact of food and alcohol intake
on normal gut behaviour and function.
© 2013 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
2. The fate of food and beverages in the gastrointestinal tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
3. Effects of food on gastrointestinal physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
3.1. Gastrointestinal luminal changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
3.2. Gastrointestinal motility and transit time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
3.3. Effects of alcoholic beverages on gastrointestinal physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
4. Trends on the biopharmaceutical effects of food and alcohol on modified-release dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
4.1. Delayed release dosage forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
4.1.1. Food effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
4.1.2. Alcohol effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
4.2. Sustained release dosage forms (film coated and matrix formulations) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
4.2.1. Food effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
4.2.2. Alcohol effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
5. Formulation approaches to circumvent food and alcohol effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
6. In vitro simulation of food and alcohol effects on drug release from MR formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
6.1. Simulation of fed-state fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
6.2. Dynamic simulation of the gastrointestinal tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457

∗ Corresponding author. Tel.: +44 20 7753 5865; fax: +44 20 7753 5865.
E-mail addresses: abdul.basit@pharmacy.ac.uk, a.basit@ucl.ac.uk (A.W. Basit).
1
Present address: Tillotts Pharma AG, Baslerstrasse 15, CH-4310 Rheinfelden, Switzerland.

0378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2013.04.034
 F.J.O. Varum et al. / International Journal of Pharmaceutics 457 (2013) 446–460
1. Introduction
Peroral administration largely remains the most convenient
and popular means of providing both immediate- and modified-
release drug delivery. More often than not, however, this method
of administration occurs under conditions of food intake, and
usually several times a day. To this end, knowledge of the effects of
foods and fluids on the performance of oral formulations, includ-
ing modified-release systems, and on drug pharmacokinetics is
crucial to our continued understanding of factors influencing oral
bioavailability, and is of particular relevance to the frequently
poly-medicated geriatric population.
Indeed, the concomitant administration of oral dosage forms
with food has the potential to markedly affect oral drug bioavail-
ability, supplementary to parameters including lag time, rate and
extent of absorption (Fleisher et al., 1999; Yasuji et al., 2012). It is
also an issue which has gained increased attention in recent years,
posing several challenges to the design of drugs from developmen-
tal, clinical and regulatory perspectives: Often regarded as physical
barriers inasmuch as physicochemical ones, the complexity of
food effects on oral drug bioavailability results from the dynamic
interplay between the changing physiological environment of the
fed gut, the physicochemical properties of the drug, drug dosing,
and the characteristics of the formulations.
Food-mediated effects on oral drug bioavailability are already
well described and reviewed in the literature (Fleisher et al., 1999;
Schmidt and Dalhoff, 2002; Singh and Malhotra, 2004; Yasuji et al.,
2012), and it is not our intention to revisit these issues in great
detail. Briefly, a food-drug interaction can lead to five main different
outcomes (Welling, 1996):
No effect on oral bioavailability;
Positive food effect and consequent increase in bioavailability,
potentially compromising safety;
Negative food effect and consequent decrease in bioavailability,
potentially compromising efficacy;
Delayed absorption;
Accelerated absorption.
Particularly relevant to these potential effects are the
physicochemical characteristics of drugs, for which purpose
both the Biopharmaceutical Classification System (BCS) and the
Biopharmaceutical Drug Disposition Classification System (BDDCS)
- categorizing drugs according to their solubility, permeability and
metabolism - have contributed to the creation of a framework
used in food effect prediction (Amidon et al., 1995; Wu and Benet,
2005; Custodio et al., 2008). Overall, no food effect (high-fat meal)
in terms of extent of absorption would be expected for BDDCS
class I drugs (high solubility/high permeability/high metabolism),
though due to the delayed gastric emptying occurring after food
intake, a delayed Cmax is likely to occur (Fleisher et al., 1999;
Custodio et al., 2008). As for BDDCS class II drugs (low solubil-
ity/high permeability/high metabolism), higher drug exposure
can often be predicted due to the higher solubilizing capacity
of intestinal fluid following a meal. With BDDCS class III drugs
(high solubility/low permeability/low metabolism), on the other
hand, a negative food effect is expected due to the interaction of
food components with intestinal transporters, and largely in the
case of co-ingested high-fat meals: A general trend has not yet
been identified for BDDCS class IV drugs (Custodio et al., 2008).
The accuracy of this framework to predict food effects has been
recently estimated as 70% (Benet, 2013), whereas an additional
statistical model taking into consideration drug physicochemical
properties such as solubility, permeability and dose has also been
proposed to correctly predict food effects in 83%, 73% and 83%
447
of cases of positive, negative and no food effects, respectively
(Gu et al., 2007).
The very nature of both food and alcohol effects on oral drug
bioavailability is not, however, exclusive to the drug per se, and such
effects may also compromise the in vivo performance of modified-
release dosage forms. Modified-release dosage forms are predomi-
nantly designed to facilitate once- or twice- daily dosing regimens,
and to achieve sustained therapeutic plasmatic drug levels over a
prolonged period of time: In the latter case, they are referred to as
’sustained release’ dosage forms, whereas ’delayed’ drug release
systems by contrast deliver a drug to a specific site in the gut.
There also exists the broader potential for use of modified-release
multiparticulates to improve pharmacokinetic reproducibility for
a particular drug candidate over their single-unit counterparts
(Varum et al., 2010). Especially relevant to these possible effects
the fed gut may have on modified-release dosage forms - namely,
sustained release formulations - is the concept of ’dose dumping’,
which may result in higher drug bioavailability and possible toxic-
ity (Schug et al., 2002b; Yasuji et al., 2012). This is also an issue when
alcoholic beverages are consumed simultaneously with sustained
release formulations, as highlighted recently (Lennerns̈, 2009). The
most notable reported case of an alcohol-dosage form interaction in
pharmacokinetic studies, however, is that of the product Palladone
XL® a once-daily, sustained release dosage form of hydromorphone
(Walden et al., 2007). An alcohol concentration-dependent effect
was noted as the Cmax increased 1.1-, 1.9- and 5.5-fold when alcohol
was ingested concomitantly with Palladone XL® at concentrations
of 4, 20 and 40%, respectively. Strikingly, a 16-fold increase in the
Cmax for one subject was observed following ingestion of 240 ml of
40% alcohol (Walden et al., 2007). These results ultimately lead to
the voluntary suspension of sales and marketing activities by the
manufacturer after a FDA request was made over concerns of safety
and lack of robustness of the formulation in the presence of alco-
hol. The incidenti has since driven the FDA and other regulatory
agencies to propose new requirements for the testing of modified-
release products which need to demonstrate robustness in media
containing up to 40% ethanol during in vitro testing.
The aim of this review is to provide deeper insights into the
role of food and alcohol intake on the in vivo performance of
modified-release systems, and the implications of their interac-
tions. A background of physiological changes occurring during food
intake will be elucidated, and selected case studies will be pre-
sented to highlight this phenomenon.
2. The fate of food and beverages in the gastrointestinal
tract
Solid food is first masticated in the mouth and passed by peri-
staltic contraction through the oesophagus to the stomach as a
bolus. The proximal stomach itself functions as a reservoir for undi-
gested food material and the emptying of liquids, with an expansion
capacity of around 4 l in volume; the distal stomach by contrast is
more critically involved in the processes of mechanical mixing and
gastric emptying of solid contents into the duodenum, per se con-
trolled by contractions of the pylorus. Various acidic and enzymatic
gastric, hepatic and pancreatic secretions released during the ear-
lier phases of digestion serve to homogenize food products into
their component parts, which are then readily absorbed along the
length of the small intestine. Any remaining waste is then propelled
into the colon prior to excretion.
The presence of insoluble food products such as fibre and guar
gum adding bulk to a peristaltic mass in the gut also contribute to
the mechanical influences on oral drug delivery through distension
of the stomach, duodenal and small intestinal spaces, and through
delaying gastric emptying (Schwartz et al., 1982; Sandhu et al.,
448 F.J.O. Varum et al. / International Journal of Pharmaceutics 457 (2013) 446–460
1987). Digestion time is dependent upon intra-individual variables
such as age and gender, though as will be discussed in the remit of
this review, food intake is a prominent influence on physiological
factors such as gastric emptying. Given that the majority of food and
drug absorption takes place at the level of the stomach and small
intestine, however, most in vitro models used for the simulation of
digestion often overlook the digestive phases of the colon.
Contrary to previous assumptions, only 10-20% of ingested
ethanol from alcoholic beverages is absorbed through the gastric
mucosa: The main site of alcohol absorption is instead that of
the small intestine (Cori et al., 1930; Elmslie and Harvey, 1968;
Persson, 1991). Furthermore, it has been demonstrated that fac-
tors known to delay gastric emptying - such as dietary fat and
certain drugs - may slow the rate of alcohol absorption (McFarlane
et al., 1986; Levitt, 2002), and potentially lead to deleterious effects
on modified-release dosage form performance. Though alcohol is
primarily metabolized in the liver by the action of alcohol dehy-
drogenases and aldehyde dehydrogenase enzymes, a small fraction
of this metabolism is also carried out by the gastric mucosa (Levitt
et al., 1997): If we take into account this reduced alcohol gastric
metabolism, and in combination with a limited gastric absorption,
the volume and concentration of alcohol in the stomach can be con-
siderable, and may compromise drug release from modified-release
dosage forms sensitive to ethanol. Additionally, the apparent solu-
bility of lipophilic drugs can be transiently increased, contributing
to increased bioavailability and possible toxicity (Fagerberg et al.,
2012).
3. Effects of food on gastrointestinal physiology
Food intake induces dynamic changes in the composition and
volumes of luminal fluids as well as in the patterns of gastrointesti-
nal motility, ultimately affecting the transit of dosage forms and
the mechanical stress applied during passage along the gastroin-
testinal tract. The main changes induced by food and beverages
consumption are represented in Fig. 1.
3.1. Gastrointestinal luminal changes
The pH in the stomach in the fasted state ranges from 0.8 and
2.0 due to hydrogen ion secretion, though ingestion of food causes
Fig. 1. Summary of gastrointestinal physiology changes upon food intake. Further details are provided in the manuscript.
the pH to rise between 4.0 and 5.0 thanks to buffering and dilution
effects (Evans et al., 1988; Fallingborg et al., 1989). No significant
changes in the small and large intestine pH have been reported after
meal consumption; however, this may be masked by inter- and
intra-individual variability, and slight changes occuring in differ-
ent stages of meal digestion (Bratten and Jones, 2009). Postprandial
duodenal pH has been reported to decrease, for instance, on emp-
tying of acidic contents from the stomach (Kalantzi et al., 2006).
Similarly, Diakidou and co-workers have shown that the pH (mea-
sured ex vivo) of colonic fluids decreases in the fed state (from pH
7.8 to 6.0) due to the fermentation of carbohydrates by bacteria and
production of short-chain fatty acids. However, it should be noted
that in both studies the pH was measured in aspirated fluids and
not with radiotelemetric capsules, which otherwise better reflect
the real in vivo pH dynamics (Diakidou et al., 2009b). Gastrointesti-
nal fluid also plays a key role in drug dissolution, and particularly
for poorly soluble molecules. The colon has been shown to hold
between 1 and 100ml of free fluid which may affect the behaviour
oral modified-release formulations, though free intestinal water
only represents a small proportion of the total water content, and
is not spread homogeneously throughout the gut lumen: Instead,
this water is formed as pockets of different volumes, and so it is
unlikely for oral dosage forms to be in continuous contact with fluid
(Schiller et al., 2005). Moreover, the composition of the gastroin-
testinal fluids determines the dissolution rate of ionizable drugs
and enteric coatings, and is affected by both the buffer capac-
ity and buffer species (Mooney et al., 1981; Aunins et al., 1985;
Ozturk et al., 1988). Additional other fluid components such as
bile salts, lipids and lipolysis products, which luminally increase
in response to a meal, can also influence bioavailability by affecting
drug dissolution and solubilization, and particularly for BCS class II
molecules (Charman et al., 1997; Dressman et al., 1998; Camilleri,
2006; Clarysse et al., 2009a; Diakidou et al., 2009a).
3.2. Gastrointestinal motility and transit time
The mechanics of gastrointestinal transit are highly complex and
influenced by a multitude of factors, ranging from inter- and intra-
individual variability in gastrointestinal physiology (McConnell
et al., 2008; Freire et al., 2011) to the type and size of a formu-
lation (single units or multiple units), as well as the presence or
 F.J.O. Varum et al. / International Journal of Pharmaceutics 457 (2013) 446–460
absence of food. These issues have been extensively reviewed in
recent years (Newton, 2010; Varum et al., 2010; Wilson, 2010;
Yuen, 2010). Gastric retention and gastric emptying in the fasted
state are under the control of the migrating myoelectric complex
(MMC), whereas in the presence of food, the MMC is disrupted and
is replaced by fed state contractions. It should be noted that some
MMC cycles may bypass the stomach and originate in the small
intestine, thereby contributing to the prolonged gastric retention
of modified-release dosage forms, and mainly monolithics (Kellow
et al., 1986). Aside from mixing and milling the gastric contents,
these contraction cycles also exert mechanical pressure on dosage
forms, namely through the pyloric sphincter. Using a wireless
motility capsule (SmartPill(r) ), wave pressures above 100 mbar and
occasionally close to 300 mbar could be recorded during passage
residence in the distal antrum and passage through the pyloric
sphincter (Cassilly et al., 2008). However, during such experimental
proceedings, the size of the SmartPill needs to be taken into account
(13 mm x 26 mm), as smaller monolithic or multiparticulates may
not encounter such high motility pressures. A maximum gastric
emptying rate of 200 Kcal/h has been reported (Hunt, 1983), and the
complexity involved in the control of gastric emptying has already
been highlighted in the apt statement by Olsson and Holmgren
that älmost everything seems to affect gastric emptying(Olsson ¨
and Holmgren, 2001). This is another important issue where the
controlled and reproducible behaviour of modified-release dosage
forms is required in practice: Standardized fed state clinical stud-
ies are designed on the assumption that there is no further food
intake until 4 h after breakfast, though this situation is difficult to
replicate on a daily basis, and is further complicated by the changes
in meal composition. For instance, it has been shown that 10 mm
enteric coated tablets taken during breakfast, lunch and dinner did
not empty from the stomach for up to 12 h after the first tablet was
taken (unpublished data), whilst Katsuma and co-workers reported
that in one subject a 300 mg enteric coated tablet (CODES(tm) sys-
tem) given in the fasted state took 21 h to empty from the stomach
(Katsuma et al., 2004). Other small snacks consumed during the
day additionally contribute to delays in gastric emptying, and sim-
ilarly unpublished data brought to attention in a review article by
Newton revealed that the emptying of 1.0-1.4 mm pellets was fur-
ther delayed with subsequent meals (Newton, 2010). In this study,
two out of six volunteers were shown to have all pellets still resid-
ing in the stomach after 4 h (second meal given) and 8 h (third
meal given), delaying gastric emptying for at least 12 h (Newton,
2010). Equally, these influences should be considered in the case of
gastro-retentive dosage forms: An efficient gastro-retentive system
should be able to remain in the stomach for a prolonged period of
time when compared to standard formulations, and independent of
food consumption. However, significant advantages in dosage form
performance with these systems over single units given with a meal
have yet to be witnessed (Waterman, 2007). Small intestinal transit
time is frequently quoted at 3-4 h, and is reported to be similar for
tablets, pellets and liquid formulations (Davis et al., 1986), though
this figure hides the considerable inter- and intra-subject variabil-
ity for small intestinal transit times of multiple- and single-unit
systems, with values typically ranging from between 1 and 9.5 h
(Davis et al., 1986; Sugito et al., 1990; Coupe et al., 1991). Most oral
dosage forms also spend the majority of the total transit time at
rest in the small intestine (McConnell et al., 2008; Weitschies et al.,
2010). Feeding increases the motility in the terminal ileum/caecum,
triggering what is known as the gastro-colonic reflex, and therein
helping the luminal contents to move distally along the gastroin-
testinal tract whilst simultaneously accommodating food contents
emptying from the stomach (Price et al., 1993; Haggar et al., 2003;
Wilson, 2010). Interestingly, the stagnation of dosage forms in the
caecum was found to be affected by the type of ingested food as
well as the meal size (Khosla et al., 1989). This contrasts with the
449
outcome of a later study, revealing that meals with 70% fat, 70%
protein or 70% carbohydrate content had no influence on the stag-
nation of dosage forms or their movement to distal regions (Price
et al., 1993). Another crucial aspect to be considered is the passage
of dosage forms from the ileum to the caecum, as the sphincter in
the ileocaecal junction applies a mechanical stress that, depending
on the size and type of formulation, can result in premature disrup-
tion of the modified-release mechanism (Wilson, 2010). The basal
pressure (measured by intraluminal manometry) at the ileocaecal
junction increases to a value of 9.7 mmHg in the fasted state, and
up to 11.8 in the first 30 min in response to a meal (Dinning et al.,
1999).
3.3. Effects of alcoholic beverages on gastrointestinal physiology
It has been shown that pure ethanol and alcoholic beverages
can inhibit gastric emptying (Franke et al., 2005). Lennernas and
co-workers have since postulated that the inhibitory effect of alco-
hol on gastric emptying may be related to the caloric content of
the beverage, though somewhat interestingly these effects have
been shown to be independent of the caloric content of a meal
consumed at the same time (Lennerns̈, 2009). It has been shown
that both fat and alcohol are major dietary contributors to the
slowing of gastric emptying, along with reports that consump-
tion of fermented drinks which include high relative carbohydrate
contents - such as beer, red and white wine - leads to prolongation
of gastric emptying as compared to other ethanol-containing bev-
erages (Franke et al., 2005). It is moreover likely that the inhibitory
effect of alcohol on gastric emptying is reduced in the fully fed
state, characterised by distension of the stomach and dilution of
its contents.
Additionally, it has been shown that the ingestion of alcohol
may induce gastric acid secretion (Lenz et al., 1983), though such
results are conflicting, and may be again specific to the bever-
age consumed (Singer et al., 1983; Singer et al., 1991; Manabe
et al., 2003). Indeed, Lennerns̈ and co-workers have suggested
that it is more likely to be the non-alcoholic constituents of these
beverages stimulating gastric acid secretions (Lennerns̈, 2009).
Corroborating this observation of non-alcoholic constituents influ-
encing gastrin release are studies which have shown there to be a
negligible difference between a saline control and pure ethanol on
the stimulation of gastric acid secretion administered by intragas-
tric infusion (Singer et al., 1983; Peterson et al., 1986; Chari et al.,
1993), though problems related to the lack of standardized con-
trols have been reported. Nevertheless, as with alcohol-mediated
effects on gastric emptying, such phenomena may contribute to
affectation of oral modified-release dosage form performance at the
level of the stomach, potentially leading to dose dumping following
rapid dosage form disintegration along with drug dissolution and
absorption.
The study of the effects of moderate and chronic alcohol con-
sumption on gastrointestinal tissue functionality is beyond the
scope of this review, though it has been addressed in some detail
by various other researchers (Huppe et al., 1988; Bujanda, 2000;
Stermer, 2002; Taylor et al., 2005). For instance, it has been shown
that the permeability of the intestinal mucosa increases when
exposed to alcohol (Lavö et al., 1992). Therefore, higher drug dis-
solution in the stomach in combination with a higher permeability
can result in a higher Cmax , which can ultimately trigger patient
safety problems. It has also been shown in vitro that alcohol has
a direct dose-dependent effect on the activity of gastric and pan-
creatic lipases by decreasing their capacity to degrade the fat
components from food (Sternby et al., 1996), though this effect is
generally only observed in individuals in whom pancreatic function
is already compromised.
450 F.J.O. Varum et al. / International Journal of Pharmaceutics 457 (2013) 446–460
Fig. 2. Mean plasma concentration of salicylic acid after administration of acetyl-
salicylic acid as enteric coated tablets (top) or enteric coated granules (bottom) in
the fasted (open circles) and fed state (closed circles).
Source: Reprinted from Bogentoft et al. (1978) with permission.
4. Trends on the biopharmaceutical effects of food and
alcohol on modified-release dosage forms
4.1. Delayed release dosage forms
4.1.1. Food effects
The susceptibility of a modified-release formulation to a food-
mediated interaction is frequently reduced for multiparticulates
(Varum et al., 2010). For instance, a lower variability and higher
bioavailability was shown for erythromycin enteric coated pellets
in comparison to enteric coated tablets after food intake (Graffner
et al., 1986). Similarly, the oral bioavailability of acetylsalicylic acid,
given as enteric coated granules, was shown to be higher, less vari-
able and not affected by the presence of food (Fig. 2), in contrast
to enteric coated tablets for which a significant delay in the onset
of absorption was noted (Bogentoft et al., 1978). Delayed gastric
emptying of the tablet formulation was also likely to have occurred
due to the presence of food and subsequent meals (lunch and snack)
further hindering gastric emptying. Generally speaking, the greater
the size of the formulation, the more prolonged the period of gas-
tric emptying, and mainly in the fed state (Davis et al., 1984; Sugito
et al., 1990; Abrahamsson et al., 1996). However, this may also
be an oversimplification: Faster emptying of multiple-unit dosage
forms from the fed stomach was not shown with 1 mm pellets,
for instance, when compared to 11 mm single-unit dosage forms
(Coupe et al., 1991) and, surprisingly, even 7 mm tablets have been
shown to readily empty from the stomach (Khosla et al., 1989). It
should also be noted that differences observed in drug absorption
from enteric coated delayed-release formulations may be due to
variability in gastrointestinal pH, rather than variability in tran-
sit itself (Fallingborg et al., 1989): Duodenal pH alone has been
shown to range between 5.17 and 6.10 during meals, and between
4.55 and 6.31 during the day time, increasing in the distal small
intestine to about pH 7.5 in the ileum (Bratten and Jones, 2009).
Furthermore, Kenyon and co-workers have shown that a delay
in gastric emptying arising from food intake did not compromise
the enteric properties of coated starch capsules, though disinte-
gration in the small intestine occurred earlier than for capsules
which emptied from the stomach quicker (Kenyon et al., 1994).
This may have been due to the elevated pH of the fed stomach,
which can contribute to softening of the enteric coating (Evans et al.,
1988). Also, a bioequivalence study (repeated dose) involving two
enteric coated formulations of omeprazole has shown that dose
administration after a high-fat meal reduced the rate and extent
of omeprazole bioavailability (Vaz-da-Silva et al., 2005). This may
again be related to the higher pH in the stomach and attributable to
the combined effect of repeated proton pump inhibitor administra-
tion and the high-fat meal, leading to premature drug release, drug
instability and decreasing bioavailability. Kamba and co-workers
proposed, through indirect measurements, that the fed stomach
also promotes a higher mechanical stress on dosage forms due to
the continuous milling of the food contents (Kamba et al., 2000),
though mechanical susceptibility in the small intestine did not
alter with food intake (Kamba et al., 2002). It is worth noting that
the mechanical strength of many oral solid dosage forms does,
however, drastically decrease on exposure to gastrointestinal fluid,
being more susceptible to damage by motility contractions during
passage along the gut (Sako et al., 1996).
Besides the traditional administration of oral dosage forms in
the fasted and fed states in standard clinical trial settings, other
options exist which allow for the demonstration of food effects on
oral drug delivery. For instance, Digenis and co-workers showed
that the administration of a multiple-unit formulation 30 min
before food (pre-feed regimen) resulted in faster gastric emptying
when compared to the fasted state (Digenis et al., 1990). This sug-
gests that food intake leads to an increase in gastric motility, and
consequently faster gastric emptying. Furthermore, small intestine
transit was accelerated, leading to a lower overall erythromycin
bioavailability - erythromycin being preferably absorbed in the
small intestine. Peristaltic activity and intestinal flow have also
been shown to increase after food intake, which may have con-
tributed to the results obtained (Matuchansky et al., 1972; Kerlin
et al., 1982). These findings were recently corroborated as a sim-
ilar acceleration of small intestinal transit, - in this case, with
tablets - was observed under the pre-feed regimen (Fig. 3). Here,
tablets spent a significantly shorter time in the small intestine
(100 min) than that observed for the standard fasted (204 min) and
fed regimens (210 min) (Fadda et al., 2009). Equally, it has also been
reported that a meal can induce a gastro-ileocaecal reflex, thereby
initiating the transport of fluids and solids from the distal small
intestine into the caecum, and providing room for further transport
along the small intestine (Schiller et al., 2005).
Liquids inasmuch as foodstuffs can also affect oral drug
bioavailability. For instance, the bioavailability of lansoprazole
enteric-coated granules following intake of different juices (orange
juice, tomato juice, or a small amount of strained pears) was sim-
ilar to that of the encapsulated material administered with water.
However, the onset of drug absorption was significantly delayed
with consumption of orange juice as compared to the other juices
and a control, resulting in a later tmax (3 h vs. 1.7 h in control) (Chun
et al., 2002). This may be related to differences in gastric emptying
 F.J.O. Varum et al. / International Journal of Pharmaceutics 457 (2013) 446–460
Fig. 3. Relationship between gastric emptying time and small intestinal transit time
in a pre-feed regimen. Open symbols: small intestinal transit of tablets which were
in the upper small intestine when a meal was given at 45 min after dosing. The
tablets had a rapid and statistically significant acceleration in small intestinal tran-
sit compared to the tablets which were in the stomach when food arrived (closed
symbols).
Source: Reprinted from Fadda et al. (2009) with permission.
of the liquids, as orange juice is known to have a slower rate of emp-
tying than that of tomato juice, and is possibly attributable to the
lower pH of orange juice itself (Haggard and Greenberg, 1941). Low
pH liquids are also known to have a slower rate of gastric clearance
(Rasmussen et al., 1999; Chaw et al., 2001), which in turn hinders
the rapid dissolution of enteric coatings.
It has been reported that the bioavailability of mesalazine
from delayed release MMX® systems (Lialda/Mezavant) increases
(91% higher Cmax and 16% higher AUC) when administered
with a high-fat meal (Yang and McCormack, 2011). This indi-
cates an earlier drug release taking place in the small intestine,
with a reduced amount of drug being available for the topi-
cal action in the colon. Similarly, the dosing instructions for a
new Eudragit S® coated mesalazine delayed release capsule prod-
uct (http://www.delzicol.com/index.jsp) indicate that it should be
taken 1 h prior to food or at least 2 h after a meal, hinting at a food
interaction. A gamma-scintigraphy study has also shown that in
three out of eight volunteers Eudragit S® coated tablets failed to
disintegrate when administered in the fed state or 30 min before
food, whereas in the fasted state only one subject was affected
(Ibekwe et al., 2008b). However, factors other than pH and tran-
sit time may have contributed to the overall outcome: Different
food effects were, for instance, observed in the case of two budes-
onide colonic delivery formulations. Budesonide modified-release
pellets (Entocort®) produced a significantly higher Cmax and a later
tmax when administered after food intake (Edsbc̈ker et al., 2003),
though a dissimilar effect on budesonide absorption was observed
when a high-fat and high caloric breakfast was taken before admin-
istration of a new colonic drug delivery system (tablet) using the
MMX® technology: In this case, food intake resulted in a lower
rate and extent of drug absorption. A food-drug interaction or
increased pre-systemic metabolism may, on the other hand, have
contributed to the lower bioavailability in the fed state (Brunner
et al., 2005). Other explanations can be related to activation of
the gastro-colonic reflex, which prompts a fast discharge of mate-
rial located at the ileo-caecal junction and further movement of
contents along the colon, therefore decreasing the time available
for drug release and dissolution in the colonic fluids. Hodges and co-
workers have shown that ingestion of food triggers the movement
of colonic release dosage forms distally along the colon in subjects
where arrival in the ascending colon occurred prior to or simulta-
neously with food administration (Fig. 4), though a late arrival in
the colon was also observed when the formulation was still residing
in the small intestine during feeding (Hodges et al., 2009). Diakidou
451
and co-workers reported a reduced water content for dissolution,
pH and surface tension in the fed state, though in contrast the buffer
capacity, osmolality, short-chain fatty acids, and bile salts (cholate
and chenodeoxycholate) were all higher in the fed state, and may
have contributed to the accelerated dissolution of modified-release
dosage forms arriving in the large intestine (Diakidou et al., 2009b).
4.1.2. Alcohol effects
The effects of alcohol on delayed-release dosage forms have
been scarcely explored. In these circumstances, premature drug
release due to an alcohol-mediated disruption of the delayed
release mechanism can significantly compromise oral drug
bioavailability. Many enteric coated formulations are produced
using polymers which are soluble in organic solvents, such as
ethanol, and therefore prolonged exposure to high alcohol con-
centration in the stomach can trigger premature dissolution of the
enteric coating and compromise overall drug bioavailability. In the
case of enteric coated dosage forms, a higher pH in the fed state
associated with intake of alcoholic beverages (even considering
possible dilution) can have deleterious effects on the enteric coat-
ing where gastric emptying is significantly delayed (Franke et al.,
2005). For instance, Fadda and co-workers evaluated the effect of
ethanol present in the dissolution medium on different mesalazine
modified-release formulations, observing that drug release was
generally accelerated for the different products but to differing
degrees depending on the formulation characteristics and the time
of exposure to alcohol (Fadda et al., 2008).
4.2. Sustained release dosage forms (film coated and matrix
formulations)
4.2.1. Food effects
As alluded to, the effects that food or alcohol may have on the
oral drug bioavailability of sustained release products can be com-
promising to their safety, especially given that these systems often
carry high drug loads to facilitate continuous drug release and allow
for once-daily dosing. It is therefore a requirement by regulatory
authorities that generic versions of a modified-release product for
single dose administration must be tested in the fasted and fed
state to allow for direct comparison with the reference product.
Often, the food effects on oral drug bioavailability from sustained
release dosage forms have been associated with the formulation
type and the engineered mechanism of release, as in the case of
sustained release tablets showing much higher inter-subject vari-
ability than sustained release multiparticulates in the fed state
(Delhotal-Landes et al., 1988; Cnota et al., 2005). This phenomenon
has been also linked to higher susceptibility to mechanical stress
during transit along the gut, particularly through the bottle-necked
pylorus and ileocaecal junction (Garbacz et al., 2008). It would seem
logical that single units would be more sensitive to mechanical
pressures along the gut, though it has been reported that sustained
release multiparticulates systems, with a reduced hardness after
soaking, can also suffer from premature drug release following
mechanical damage induced by food (Katori et al., 1996).
In one study, food intake resulted in a shorter tmax and
higher Cmax of verapamil when delivered as sustained release
ethylcellulose-coated pellets, with similar overall bioavailability
to that achieved in the fasted state. Arguably, this was due to the
increased residence time of pellets in the upper gastrointestinal
tract and consequent exposure to the fluid available (Marvola et al.,
1989). The fluid volume of the stomach in the fed state is, some-
what inevitably, significantly higher when compared to the fasted
state; however, this has been only reported as an increase in the
stomach volume (Schiller et al., 2005). In the small intestine, the
free fluid available is reduced in the fed state and with no signif-
icant differences in fluid volume in the large intestine, thought to
452 F.J.O. Varum et al. / International Journal of Pharmaceutics 457 (2013) 446–460

Fig. 4. Effects of dosage form localization when feeding takes palce on the moevement along the colon.
Source: Reprinted with permission from Hodges et al. (2009).

be predominantly due to the continuous absorption of water. The
changing environment of the stomach and proximal small intestine
in response to a meal - and particularly for fat-enriched meals - by
induction of pancreatic and biliary secretion and lipolysis has also
been investigated by gastric (Diakidou et al., 2009a) and duodenal
aspirates (Persson et al., 2006; Clarysse et al., 2009a; Clarysse et al.,
2009b). The solubilizing capacity of the fed intestinal fluid of poorly
soluble drugs is extensively affected by the rate of bile acid secre-
tion, the rate of lipolysis, and consequent generation of other lipidic
entities such as phospholipids, fatty acids and mono- and diglicery-
des (Fig. 5) (Persson et al., 2005; Persson et al., 2006). Notably, a
large inter-individual variability was observed in the composition
of the intestinal fluids after food intake: Lipid digestion products
after 30 min of food intake ranged from 0.0-5.5 mg/ml in the fasted
state to 3.1-22.4 mg/ml in the fat-enriched regimen, whereas the
bile salts varied between 2.0 and 9.0 in the fasted and 4.4 and
30.3 mM in the fat-enriched fed state (Clarysse et al., 2009b).
Further to this, a pharmacoscintigraphic study demonstrated
that a sustained release minitablets of diltiazem (Geomatrix) given
in the fasted state disintegrated completely in the large bowel,
providing sustained drug release and uniform absorption along
the entire gastrointestinal tract. In contrast, administration after
a high-fat breakfast resulted in prolongation of gastric retention
and tablet disintegration in the stomach in six out of eight volun-
teers - another important example of how food may compromise
drug formulation properties and result in dose dumping (Wilding
et al., 1995). In the fed state, the peristaltic activity in the distal
stomach promotes mixing and milling of solids, and controls the
 F.J.O. Varum et al. / International Journal of Pharmaceutics 457 (2013) 446–460
Fig. 5. Concentrations (mM) of (a) bile acids and (b) phospholipids from intestinal secretions and NuTRIflex in intestinal fluids after the starting the perfusion of a nutri-
tional drink. TCA, taurocholic acid; GCA, glycocholic acid; TCDCA, taurochenodeoxycholic acid; TDCA, taurodeoxycholic acid; GCDCA, glycochenodeoxycholic acid; GDCA,
glycodeoxycholic acid; PC, phosphatidylcholine; LPC, lysophoshatidylcholine.
Source: Reprinted with permission from Persson et al. (2006).
transfer of chyme into the duodenum. It is this activity which plays
a role in gastric emptying, responding to the osmotic pressure and
energy content of digestion products of food. Indeed, the greater
the caloric content of a meal, the lower the volume transferred to
the duodenum (Hunt and Stubbs, 1975; Hunt et al., 1978). It has
also been shown that dietary sugars and salt, available in high con-
tent in western diets (including soft drinks, sport drinks, fruit juices,
confectionary and many others), can accelerate drug release from
HPMC matrices, with the most popular being sustained release plat-
forms (Williams et al., 2009; Williams et al., 2010). Mechanistically,
the polymer hydration and gel layer formation is compromised in
the presence of high concentrations of dietary sugars, leading to a
higher mechanical susceptibility in the fed stomach (Williams et al.,
2009). In contrast, a delayed drug release from HPMC matrices was
seen in vitro in the presence of lipid emulsions - a key component
of high-fat diets and biorelevant media (Williams et al., 2011). In a
different study, an 800 mg ibuprofen sustained release formulation
took 15 h to empty from the stomach in 2 out of 11 subjects after a
heavy breakfast, with a mean emptying time of 8.8 h. In the fasted
state, a double peak in the pharmacokinetic profile was obtained
(Fig. 6), which was correlated with higher disintegration rate of
the formulation and likely due to the passage of the formulation
through the gastric pylorus and the ileocaecal junction (Garbacz
et al., 2008). However, a light breakfast intake abolished the double
peak profile, leading to a drug plateau between 4 and 12 h.
The requirements for fed-state bioequivalence studies for new
sustained release generic formulations have emerged from these
observations that food intake can impact on drug integrity and
performance, despite bioequivalence often being observed in the
fasted state. For instance, administration of a generic nifedipine
60 mg erodible tablet (Coral(r) ) after a high-fat American breakfast
resulted in dose dumping and a consequent increase in nifedip-
ine plasma levels of 3-4-fold, though an osmotic driven system
(Adalat(r) , Oros) showed only a slight increase in bioavailability
when compared to the fasted state, revealing a clear lack of bio-
equivalence between both formulations in the fed state (Schug
et al., 2002b). Similarly, a 30 mg nifedipine generic formulation
(Nifedipine Merck, matrix monolayer tablet) has shown differences
in in vitro dissolution (pH-independent vs. pH-dependent assays
compared to the reference formulation (Adalat OROS, osmotic push
pull pump)). When administered with a high-fat meal, the generic
formulation led to a higher extent of absorption and correspond-
ing dose-dumping, as seen in Fig. 7 (Wonnemann et al., 2008). In a
453
different study where an osmotic pump formulation was compared
to a erodible enteric coated tablet formulation (Slofedipine XL), a
significant delay (15 h in 15 out of 24 subjects) in drug absorp-
tion was seen for the latter formulation following consumption of a
high-fat breakfast (Schug et al., 2002a) (Fig. 8). A number of generic
nifedipine sustained release products in turn demonstrated sus-
ceptibility to mechanical effects (Garbacz et al., 2009) simulated
using a novel dissolution apparatus, which may relate to the food
effects and lack of robustness observed in several prior bioequiv-
alence studies (Schug et al., 2002a; Schug et al., 2002b). From a
different angle, Weitschies and co-workers highlighted the impact
of the intragastric location of these sustained release preparations
and related food effects. They proposed that the so-called dose-
dumping effects observed for some sustained release nifedipine
and felodipine products may be due to poor mixing in the proximal
part of the stomach, leading to a delayed absorption as well as high
plasmatic levels after gastric emptying (Weitschies et al., 2005).
4.2.2. Alcohol effects
Observations of alcohol-induced effects on the oral bioavailabil-
ity of Palladone XL® and its consequential marketing withdrawal
(Walden et al., 2007) highlighted the major risks associated with
co-administration of certain medications and alcoholic beverages.
However, the influence of alcohol on the in vivo pharmacokinetic
profile of hydromorphone was much more modest when formu-
lated as an osmotic pump system (OROS) (Sathyan et al., 2008).
Studies conducted by Johnson and co-workers, on the other hand,
revealed that sustained release formulations of morphine sulphate
were not affected by simultaneous alcohol ingestion in both
the fasted and fed state, thereby demonstrating the potential of
certain formulation designs to overcome such problems (Johnson
et al., 2008). Equally, Henderson and co-workers have shown
that the pharmacokinetic parameters after administration of a
sustained release capsule of carvedilol were not affected by alcohol
intake (240 ml of 20% alcohol beverage) despite the dissolution
in vitro being clearly accelerated, and overestimating an alcohol
interaction (Henderson et al., 2007). These conflicting results
were subsequently explained on the basis of fed state behaviour
in the in vivo study: Here, the higher volume of fluid in the fed
stomach promotes a dilution effect, reducing a potential alcohol-
induced effect on modified-release formulations. In addition to
the various food-mediated effects on gastrointestinal physiology,
the ingestion of alcohol is also known to influence gastrointestinal
454 F.J.O. Varum et al. / International Journal of Pharmaceutics 457 (2013) 446–460
Fig. 6. Interplay between ibuprofen plasma concentration and rate of matrix disin-
tegration in the fasted state and after a light or heavy breakfast.
Source: Reprinted with permission from Wilson et al. (1989).
motor activity and fluid composition (Lenz et al., 1983; Franke
et al., 2005). Both Walden and co-workers and Lennernas and
co-workers have shown that the dissolution and drug release from
several sustained release dosage forms is markedly increased with
co-ingestion of alcohol (Walden et al., 2007; Lennerns̈, 2009), and
which can dramatically influence drug pharmacokinetics following
an increase in drug absorption rate from the gastrointestinal tract
if the drug solubility and/or permeability are positively affected
by alcohol intake. Furthermore, some formulation excipients
may be prone to exhibit higher solubility in aqueous solutions
with an increasing ethanol content, and so facilitate faster drug
release.
Several reports have also addressed the question of pos-
sible alcohol-induced changes influencing drug release from
modified-release dosage forms through in vitro dissolution stud-
ies. Leuner and co-workers, for instance, showed that marketed
sustained release dosage forms containing the opioids oxycodone
hydrochloride, hydromorphone hydrochloride and morphine sul-
phate differed in their susceptibility to alcohol in dissolution media
(Leuner et al., 2007). In this study, monolithic matrix systems
were not affected by alcohol, though multiparticulate formula-
tions coated with ethylcellulose exhibited a faster release profile
in the presence of low ethanol concentrations (5-10%), therein
highlighting the importance of dosage form design. Levina and
co-workers have shown that hydrophilic matrices (HPMC) incor-
porating felodipine, gliclazide or metformin hydrochloride were
insensitive in vitro on exposure to ethanol concentrations of
up to 40%, irrespective of HPMC viscosity grade (Levina et al.,
2007), though in a different study, aspirin hypromellose matri-
ces showed susceptibility to faster release in vitro, linked to
the slower hydration of the polymer in the presence of ethanol
(Roberts et al., 2007). Films of ethylcellulose blended with HPMC,
on the other hand, show greater potential for dosage form fail-
ure in the presence of ethanol (Larsson et al., 2010). In a more
extended study, 27 modified-release formulations (tablets or
beads/pellets in a capsule) were tested in dissolution media con-
taining different concentrations of ethanol. An accelerated release
was noted for 9 out of 10 capsule and 2 out of 17 tablet sus-
tained release preparations in the presence of 40% ethanol (Smith
et al., 2010). Therefore, during their early development it would
be advisable to test such dosage forms in dissolution media of
varying ethanol concentrations in order to assess robustness,
improve formulation design, and mitigate the likelihood of dose
dumping.
5. Formulation approaches to circumvent food and alcohol
effects
The formulation approach chosen to deliver a drug by the oral
route can significantly contribute to the enhancement or reduction
of food and alcohol effects on oral drug bioavailability, as discussed
in the case studies presented here. For instance, it has been shown
that targeting trientine to the middle or lower part of the small
intestine by means of an enteric coating abolished the negative
food effects observed when given as an oral solution in the fed state
(Tanno et al., 2008). This has been attributed to the delayed gastric
emptying of the enteric coated formulation and distal release of
the drug avoiding physicochemical drug-food interactions. Simi-
larly, the bioavailability of DX-9065 administered in a capsule was
shown to be limited in the fasted state and further reduced in the
fed state. The formulation of an enteric coated tablet, however,
increased oral drug bioavailability 5-fold and reduced food effects
by limiting interaction with bile salts (Fujii et al., 2011), which expo-
nentially increase in the duodenal fluid in the fed state (Schmidt and
Dalhoff, 2002). Recently, an enteric coated risedronate product has
 F.J.O. Varum et al. / International Journal of Pharmaceutics 457 (2013) 446–460
Fig. 7. Mean (SD) plasma concentration–time curves of nifedipine 30 mg after oral, single-dose administration of test* and reference† formulations in 12 healthy white male
volunteers following a high-fat breakfast.
Source: Reprinted from Wonnemann et al. (2008) with permission.
been launched which offers the possibility of being safely admin-
istered with food (http://www.atelvia.com/index.jsp) - a marked
improvement on the original uncoated product, which needed to
be taken on an empty stomach to prevent the from drug chelating
with food components. The tablet core contains drug and EDTA,
and the product is coated with a layer of enteric polymer, releasing
its contents in the small intestine. At this level, the EDTA acts as a
scavenger for food components (calcium ions), and so the drug is
free to be absorbed. This is an example of a coating overcoming a
food effect - although the main mechanism involves the EDTA, the
coating is still crucial to ensuring that both the drug and the EDTA
are released simultaneously at the same location in the intestine.
Propiverine undergoes extensive first pass metabolism by
intestinal CYP3A4 and efflux transporters. The lower metabolism
in the distal small intestine and colon contributes to a higher
oral bioavailability of propiverine when vehiculated through an
extended release formulation, as compared to the immediate
release dosage form which predisposes to a higher metabolism in
the proximal gut in both the fasted and fed state (Siegmund et al.,
2012). Interestingly, no food effect was observed for the extended
release formulation, as the drug itself could be absorbed more dis-
tally. However, in the case of the IR formulation, ingestion of a
Fig. 8. Geometric mean plasma concentration vs. time curves (n = 24) of nifedip-
ine determined after oral administration of Adalat OROS and Slofedipine XL under
fasting conditions and after a high-fat breakfast ( Adalat OROS, fasted administra-
tion; *Adalat OROS, fed administration; 䊉Slofedipine1 XL, fasted administration; 
Slofedipine1 XL, fed administration).
Source: Reprinted with permission from Shug et al. (2002).
455
fat-rich meal led to an increase in bioavailability, thus rendering the
differences between both IR and ER formulation profiles negligible.
One possible explanation may be the modulation of the metabolic
activity of intestinal CYP3A4 and inhibition of efflux transporters
by secreted bile salts and fatty components of the meal. Other com-
ponents of food may also be causative of such effects - grapefruit
juice, for instance, is a well-established inhibitor of intestinal CYP
enzymes as well as efflux transporters (Bailey et al., 2013). The list
of drugs administered by the oral route which act as substrates
for the CYP3A4 enzymes in the gut lining is extensive (McConnell
et al., 2009), and the interaction with grapefruit juice can also lead
to serious adverse effects due to a dramatic increase in bioavailabil-
ity (Ducharme et al., 1993; Lown et al., 1997; Kantola et al., 1998;
Lilja et al., 2000; Bailey et al., 2013).
Novel delayed release formulations designed to target the ileo-
colonic region and exploit gastrointestinal bacteria to trigger drug
release have been shown to be robust and effective independent of
the feeding regimen. In a study conducted by Basit and co-workers,
theophylline pellets coated with a mixture of ethylcellulose and
amylose exhibited similar bioavailability in the fasted and fed state
in a cross-over design despite the longer gastric retention in the fed
state, and also on higher exposure to pancreatic enzymes through-
out transit along the small intestine (Basit et al., 2009). Similarly,
a pH- and bacteria-combined triggered coating approach applied
on 8 mm tablets has been shown to produce a robust ileo-colonic
release platform, with accurate targeting of the colonic region in
the fasted, fed and pre-feed state (Ibekwe et al., 2008a). This shows
that the dynamic changes in the gastrointestinal physiology driven
by food intake did not influence these types of delayed release tech-
nologies, instead relying at least partially on the action of bacterial
enzymes to initiate drug release.
Roth and co-workers have shown that an innovative vera-
pamil hot-melt extrusion sustained release formulation (Verapamil
Meltrex) was not impaired in the presence of 40% ethanol in dis-
solution medium in vitro (Roth et al., 2009). In contrast, when
other marketed sustained release verapamil products were tested
in medium with 20-40% ethanol, a dose-dumping effect occurred,
and with 100% release achieved in 2 h. Recently, a new coating
material, Aquacoat® ARC (FMC Biopolymer), has been launched
with the purported benefit of providing robust sustained release in
the presence of ethanol. This product combines a polymer insoluble
in ethanol (guar gum) and ethylcellulose as a polymer insoluble in
ethanol-free media, with the combined properties of both poly-
mers contributing to overcome alcohol-induced dose-dumping
effects.
456 F.J.O. Varum et al. / International Journal of Pharmaceutics 457 (2013) 446–460
6. In vitro simulation of food and alcohol effects on drug
release from MR formulations
The clinical significance of food effects on oral drug bioavailabil-
ity is difficult to predict from traditional in vitro drug dissolution
studies. In vitro simulation of the environment in the fed gut (par-
ticularly in the stomach and small intestine) is limiting, as the
composition of a meal in everyday daily life is so widely variable
that a standard formula will never be able to accurately reflect the
in vivo situation. Equally, successful prediction of a food-induced
change in oral drug bioavailability is strongly dependent on the
characteristics of the drug and the design of the modified-release
system (Lentz, 2008; Yasuji et al., 2012).
6.1. Simulation of fed-state fluids
As previously described in this review, the changing gut envi-
ronment after meal consumption can affect the behaviour of
modified-release dosage forms and the solubility of the carried
drug. Therefore, close mimicry of the fed gut fluid is of critical
importance (Lentz, 2008; Klein, 2010). To this end, the use of milk or
milk-based products (Ensure Plus) has been proposed to simulate
the fed stomach fluid composition in vitro (Macheras et al., 1986;
Ashby et al., 1989; Galia et al., 1998; Klein et al., 2004; Diakidou
et al., 2009a). Ensure Plus was shown to have similar physico-
chemical properties to a homogenized FDA standard breakfast used
in bioavailability and bioequivalence studies (Klein et al., 2004),
whereas milk has been shown to improve solubility of lipophilic
drugs (Macheras et al., 1989), but also delays the disintegration of
formulations (Abrahamsson et al., 2004; Anwar et al., 2005). Dress-
man and co-workers introduced a Fed State Simulated Intestinal
fluid (FeSSIF) which includes bile salts and lecithin in the buffer
system to reflect bile secretions into the duodenum during a diges-
tion process (Dressman et al., 1998). However, these simulated
fluids per se are only able to provide a static resemblance of the
fed stomach and small intestine, and do not simulate the active
food digestion process characterised by physiological luminal com-
position changes due to the formation of lipid end-products (fatty
acid, monoglycerides) as well as variations in the rate of gastric and
intestinal secretions. Recently, “snap-shot” dissolution media were
proposed to simulate the dynamic changes in the fluid composi-
tion during digestion (Jantratid et al., 2008), and which correspond
to changes in the composition and physicochemical proper-
ties of gastrointestinal fluid in different phases of the digestive
process. The main changes observed were in pH, osmolality and the
milk/buffer ratio in simulated gastric fluid, and in the case of the
simulated intestinal fluid, bile salt, lecithin, monoglycerides, fatty
acid and pancreatin (facultative) concentrations were manipulated
to resemble the lipid digestion process in the duodenum (Porter
et al., 2007). Despite providing a better representation of the diges-
tion process, however, variability associated with food composition
in routine daily life and the timing of food ingestion and dosage
form administration cannot be effectively replicated. Another fac-
tor often neglected is the viscosity of the luminal contents in the
fed stomach, proposed to be in the range 200-2000 mPa s after
food ingestion (Marciani et al., 2001). Despite an initial increase
in the apparent viscosity of the gastric contents in response to vis-
cous foodstuffs, it is subsequently reduced by dilution effects and
motility. The viscosity of a homogenized standard meal (as recom-
mended by the FDA) was replicated in vitro using HPMC as viscosity
enhancing agent in standard buffers, and a good in vitro-in vivo cor-
relation was found for the negative food effect observed with the
BCS class III drug trospium chloride. The prolonged in vitro disin-
tegration time of commercial trospium chloride tablets and lower
dissolution rates as a result of reduced fluid ingress may explain its
lower bioavailability in the fed state, as the window of absorption
is limited to the upper small intestine (Radwan et al., 2012).
Equally, the luminal composition of the stomach and small
intestine following intake of alcohol beverages is not well under-
stood, and while it has been proposed that in vitro dissolution
testing of modified-release systems in the presence of 40% ethanol
for 2 h would provide a surrogate for alcohol-induced dose-duping
effects (Lennerns̈, 2009), gastric residence time may otherwise be
prolonged in the presence of alcohol. In this way, the exposure of
modified-release products would also be increased (Fraser et al.,
1995; Higaki et al., 2008).
6.2. Dynamic simulation of the gastrointestinal tract
The in vitro simulation of gastrointestinal compartments has
been historically limited to the use of USP dissolution apparatus
(I-IV). However, attempts to recreate events taking place in the
gut by these approaches have failed insofar as fluid composition
and hydrodynamic or mechanical changes in the gut lumen are
concerned (McCallister, 2010). The situation becomes even more
complicated if a prediction of food effects is warranted. For this rea-
son, the Dynamic Gastric Model (IFR, Norwich) was developed to
simulate the gastric digestion process, with gastric secretions and
patterns of mixing and motility intended to closely resemble the
in vivo situation (Wickham et al., 2009). The disintegration of cap-
sules under fasted conditions in this equipment generally matched
the in vivo observations. In the fed state, however, a delayed cap-
sule disintegration was observed (Vardakou et al., 2011) that was
significantly longer than for previous in vivo studies using gamma
scintigraphy (Cole et al., 2004; Tuleu et al., 2007; Jones et al., 2012).
This was attributed to the lower shear in the fundus as compared to
the antral regions, where most of the mixing and mechanical stress
on the wet contents occurs. The increasingly broad application of
such technology across the pharmaceutical field therefore offers
the possibility of assessing food effects on modified-release formu-
lations, and particularly for those more susceptible to mechanical
stress during gastric residence, enabling better prediction of poten-
tial dose-dumping effects.
Similarly, the gastrointestinal model TIM-1 is a dynamic mul-
ticompartimental system developed by TNO Nutrition and Food
Research that simulates both stomach and small intestinal phys-
iological processes, incorporating secretions, enzymatic reactions,
mixing and motility, pH changes, and the continuous removal of
digested compounds and small molecules through dialysis mem-
branes (Blanquet et al., 2004). The TIM-2 in turn is complementary
model which simulates the fermentation process and peristaltic
mixing of the large intestine (Minekus et al., 1999). These sys-
tems provide a more accurate representation of the exposure that
modified-release dosage forms experience during transit through
the gastrointestinal tract, and also allow for the assessment of
drug metabolism by colonic bacteria (Sousa et al., 2008). However,
the data available in the public domain is still scarce. Souliman
and co-workers have demonstrated a better in vitro/in vivo cor-
relation (IVIVC) in the fasted state when theophylline sustained
release tablets (hydrophilic matrix) were tested in TIM-1 as com-
pared to the USP II and IV apparatuses (Souliman et al., 2007).
Sustained release paracetamol tablets additionally showed a pro-
longed absorption in the TIM-1 model, closely replicating in vivo
data in the fasted state (Blanquet et al., 2004). In the fed state, a good
mimicry of the in vivo performance of immediate release paraceta-
mol tablets was also established, replicating the lower absorption
previously observed in the presence of food (Souliman et al., 2006).
Intake of a high-fat nutritional drink concomitantly with an imme-
diate release tablet of fosemprenavir led to a delay in disintegration
and a consequent shift of 2 h in the tmax (Brouwers et al., 2007).
The gastric and duodenal concentrations of fosemprenavir in the
 F.J.O. Varum et al. / International Journal of Pharmaceutics 457 (2013) 446–460
fed state could thus be closely predicted using the TIM-1 system,
in contrast to static dissolution which was shown to overestimate
the food effect (Brouwers et al., 2011). The impact of food effects
and gut physiology factors was also assessed in a delayed release
5-ASA product (Lialda, Shire) designed to target the colon. Through
coupling the TIM-1 and TIM-2 systems, it was demonstrated that
in both the fasted and fed state (high-fat breakfast), less than 1%
of drug was release after 6 h in TIM-1. After transition to the TIM-
2, complete drug release was observed over 20 h (Tenjarla et al.,
2007). However, in this study the gastric residence time was set
to 2 h, in both fasted and fed states, which may not resemble the
likelihood of prolonged gastric residence in the fed state, and in
particular for bigger dosage forms such as 1200 mg mesalamine
tablets. Indeed, it has been shown that gastric emptying can take
up to 12 h in the fed state, and can compromise the performance of
modified-release formulations (Newton, 2010). Overall, The TIM-
1 and TIM-2 systems provide a more dynamic and close mimicry
of the luminal environment and motility when compared to other
currently available gut modelling systems, though their associated
complexity and slow rate of data generation limit widespread use.
The magnitude of mechanical stress applied to modified-release
formulations during transit through the gut depends on the gas-
trointestinal location and prandial status (Garbacz and Klein, 2012).
Based on data collected from in vivo measurements of gastrointesti-
nal pressures, residence times, fluid volumes and fluid distribution
Fig. 9. Individual diclofenac plasma concentration profiles obtained after the
administration of ER formulations in the fasted state (n = 24). In the insets the means
and standard deviations are shown. (A) Voltaren retard ER tablets; (B) Diclofenac-
ratiopharm ER pellets.
Source: Reprinted with permission from Garbacz et al. (2008).
457
led to the development of a novel dissolution apparatus which
combines new features such as irregular mechanical pressure,
shear force and periods without exposure to fluid during tran-
sit through the gut (Garbacz et al., 2008). Using this system and
predetermined applied pressures, it was shown that changing the
applied pressure resulted in a different drug release profile from
a diclofenac extended-release tablet formulation (Voltaren 100 mg
Retard). In vivo in the fasted state, multiple peaks were noted in
the pharmacokinetic profile for individual subjects which was cor-
related with sensitivity to mechanical stress during transit through
the gastrointestinal tract, and namely during gastric emptying and
passage through the ileocaecal junction (Fig. 9). However, a pel-
let extended-release formulation did not exhibit multiple peaks,
suggesting that multiple units are less affected by the mechanical
pressure applied from the gut wall (Garbacz et al., 2008). Generic
versions of a diclofenac sustained release preparation also showed
variable susceptibility to mechanical stress, potentially leading to
variable oral drug bioavailability (Garbacz and Weitschies, 2010).
Abrahamsson and co-workers have otherwise proposed a new
approach to predict the shear stress applied on extended release
matrix formulations by the fed stomach which combines computer
simulations and in vitro dissolution able to provide a controlled
hydrodynamic and shear stress on a tablet surface (Abrahamsson
et al., 2005).
7. Conclusions
We know gastrointestinal functionality to be both highly com-
plex and variable, and with particular implications for peroral drug
delivery and bioavailability. However, it is insufficient to merely
consider the in vivo pharmacokinetic and pharmacodynamic effects
on oral dosage forms without taking into account the consequences
of food and alcohol co-ingestion. Food intake and the specific com-
ponents of consumable solid and liquids, such as fats, can influence
gastric emptying and transit times, and in doing so affect the
rate and extent of oral drug absorption. In the case of modified-
release dosage forms, this can lead to premature drug release or
’dumping’ with failure of the dosage form: ethanol, for instance,
has been repeatedly shown to affect parameters such as fluid pH
and composition, and can influence the disintegration and dis-
solution of various solid oral modified-release formulations both
in vitro and in vivo. Some dosage forms or drugs may also be more
sensitive or susceptible to the effects of ethanol than others, as
evidenced by the aforementioned market withdrawal of an opioid
formulation. The precise mechanisms through which both food and
alcohol interfere with the performance of oral dosage forms still
remain not completely understood. Some gaps in our knowledge
are limiting the effective design of in silico and in vitro meth-
ods able to precisely predict food and alcohol-induced changes.
Therefore, better in vivo data collected from well designed and
controlled studies need to be gathered for a more insightful under-
standing of the interplay between food-dosage form-drug and its
prediction, ultimately contributing to the appropriate design and
development of robust dosage forms resistant to food and alcohol
effects.
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