`
`Exhibit 1010
`
`S. S. Davis et al., Transit of Pharmaceutical
`Dosage Forms Through the Small Intestine,
`27 GUT 886 (1986) (“Davis 1986”)
`
`

`
`Gut, 1986, 27, 886-892
`Alimentary tract and pancreas
`Transit of pharmaceutical dosage forms through the
`small intestine
`S S DAVIS, J G HARDY, AND J W FARA
`From the Department ofPharmacy, University ofNottingham, University Park, Nottingham, Department of
`Medical Physics, Queen's Medical Centre, Nottingham, andAlza Corporation, PaloAlto, California, USA.
`
`SUMMARY The gastrointestinal transit of pharmaceutical dosage forms has been measured in 201
`studies in normal subjects using gamma scintigraphy. Solutions, small pellets, and single units
`(matrix tablets and osmotic pumps) were administered with different amounts of food in the
`stomach, ranging from fasted state to heavy breakfast. Gastric emptying was hiffected by the
`nature of the dosage form and the presence of food in the stomach. Solutions and pellets were
`emptied even when the stomach was in the digestive mode, while single units were retained for
`long periods of time, depending on the size of the meal. In contrast, measured intestinal transit
`times were independent of the dosage form and fed state. The small intestinal transit time of
`about three hours (mean ± 1 h SEM) has implications for the design of dosage forms for the
`sustained release of drugs in specific positions in the gastrointestinal tract.
`
`The main site for the absorption of drugs in man is
`considered to be the small intestine, with its high
`effective surface area.' Little, if any, drug absorp-
`tion occurs from the stomach, although some drugs
`are thought to be absorbed to a limited extent from
`the large intestine. As a general rule, therefore,
`drugs should be formulated so that they can be
`largely absorbed from the small intestine.
`Ho, Higuchi, and colleagues2 3 have introduced
`the concept of the 'reserve length' for drug absorp-
`tion. This is defined as the anatomical length over
`which absorption of drug can occur, less the length
`at which absorption is complete. The reserve length
`is dependent on physiological factors, however, such
`as bulk flow rate, spreading of the dosage form in
`the small intestine and the permeability of the drug
`through the intestinal mucosa.
`In the pharmaceutical field, the length of time a
`dosage form can remain in the small intestine tends
`to have been overestimated4; particularly when
`consideration is given to controlled release systems
`designed to provide 24 hour dosage. In some cases
`insufficient attention has been paid to the influence
`of gastric emptying, or to the implications of the
`studies on the nature and function of the migrating
`myoelectric complex,5 and the consequent differ-
`Address for correspondence: Professor S S Davis, Department of Pharmacy,
`University of Nottingham, University Park, Nottingham.
`Received for publication 4 November 1985.
`
`transit patterns in
`ence in the gastrointestinal
`digestive and interdigestive states. Based on recent
`physiological studies it could be predicted that a
`non-disintegrating single unit dosage form would
`remain in the stomach until the end of the fed phase
`and then be cleared from the stomach and through
`to the terminal ileum by the migrating myoelectric
`complex."7 Consequently, small intestinal transit
`would be expected to be of the order of 15-2 hours,
`provided the interdigestive, or non-fed state was
`maintained.6 Solutions of drugs, or pellet formula-
`tions of a size less than about 2 mm would be
`expected to empty from the stomach during the
`digestive phase and have similar small intestinal
`transit times to those Yeported for meals - about
`two to four hours.6 7
`Various reports have considered the gastric
`emptying of markers foodstuffs and a variety of
`dosage forms.7-10 Factors such as particle size,
`calorific values of meals, specific effects of fats,
`etc, have been well described.
`posture, stress
`Detailed studies on the transit from stomach to
`ileocaecal junction are fewer in number, however.6
`Read7 has commented recently that for the most
`part gastric emptying and small bowel transit are
`independent variables, each being controlled by its
`own regulatory mechanisms.
`Several methods are available to measure small
`intestine transit times.6 These include radiography,
`intubation techniques, metabolisable markers (hyd-
`
`886
`
`

`
`887
`Transit of pharmaceutical dosage forms through the small intestine
`consisted of buttered toast, marmalade, and orange
`rogen breath test) and gamma scintigraphy. Each
`juice and a standard heavy breakfast (calorific value
`approach has its advantages and disadvantages and
`3600 kJ) consisted of sausages, bacon, eggs, and
`in some cases it has been shown that the nature of
`bread. On one occasion, subjects were allowed to
`the test - for example, intubation of the subject, or
`choose their own breakfast thereby providing a
`the use of high osmolarity preparation can alter the
`range of different meal sizes.18
`normal physiological processes.11 The non-invasive
`method of gamma scintigraphy now appears to be
`A cup of coffee, or orange juice was provided
`the method of choice. Recent studies by Caride et
`1-5-2 hours after dosing, a three course lunch at
`al,12 Read et al,13 14 Jian et al'5 and Malagelada et
`about three to four hours, a cup of tea, coffee, or
`al16 on foodstuffs and Davis et al on dosage
`orange juice at about seven hours and a dinner at
`forms17-20 have shown the usefulness of this techni-
`about 10 hours after dosing. The nature of the
`que, particularly when two radionuclides are used
`lunches and dinners varied in the different studies,
`simultaneously.
`but in general all volunteers in a given study
`consumed identical meals. The lunches had an
`During the last three years we have conducted a
`energy content of about 5000 kJ and the dinners
`number of scintigraphic studies on the gastrointes-
`4500 kJ.
`tinal transit of dosage forms, often with a view to
`relating pharmacokinetic parameters to transit be-
`haviour. Solutions, pellets, and single units (matrix
`MEASUREMENT OF GASTRIC EMPTYING AND
`tablets, osmotic pumps etc) have been tested in
`INTESTINAL TRANSIT
`The various formulations were labelled with gamma
`young adult male subjects and in some cases in
`(technetium 99m, tl/2=
`radionuclides
`emitting
`elderly women. The dosage forms have been admi-
`6-0 h, or indium-111, tl/2=2-8 days), so that their
`nistered with different amounts of food in the
`tract could
`transit through the gastrointestinal
`stomach; ranging from fasted state to heavy English
`contained
`formulations
`Solution
`followed.
`be
`studies have been
`these
`breakfast. Some of
`diethylenetriaminepentaagetic acid (DTPA) label-
`published17 20 or are in press, while others were
`led with technetium 99m. Pellets were ion-exchange
`conducted as part of work for submission to regula-
`beads (coated and uncoated) of size 0-3-1.2 mm, to
`tory authorities. In this paper we have brought
`which technetium 99m was firmly bound by ion
`together data from 201 investigations in human
`exchange mechanisms.1" None of these radiophar-
`subjects (representing 23 studies on solutions, 82 on
`maceuticals is absorbed from the gastrointestinal
`pellets and 96 on single units), in order to consider
`tract. Single unit dosage forms contained either
`gastric emptying and transit in the small intestine.
`DTPA powder labelled with radionuclide, or en-
`The results have implications for the design of
`trapped labelled ion-exchange resin. Some single
`pharmaceutical dosage forms, particularly those for
`units were formulated to travel the length of the
`controlled or timed release. Additionally, they also
`intestines without disintegrating while others were
`have relevance to the design of dosage forms to
`designed to release the labelled material at a rate
`release drugs at specific positions in the gastro-
`similar to that of the intended drug, so that in vivo
`intestinal tract.
`release and dissolution profiles could be evaluated
`and correlated with pharmacokinetic data.20 Details
`Methods
`of these formulations can be found elsewhere.17-20
`Some of the formulations contained active drug,
`SUBJECTS
`others were placebo. The solid dosage forms were
`Healthy male (aged 29-28 years) and female (aged
`swallowed with 100 ml water. The subjects were
`29-76 years) volunteers participated in the various
`imaged using a gamma camera having a 40 cm
`studies (Table) after giving informed consent. All
`diameter field of view, fitted with an appropriate
`protocols were approved by the University of
`Pairs of anterior and
`parallel hole collimator.
`Nottingham ethical committee. The subjects were
`posterior images of the abdomen were recorded at
`fasted overnight for at least nine hours before each
`suitable intervals with the subjects standing. From
`test. No alcohol was consumed for at least 24 hours
`the time of dosing and throughout the first day of
`before dosing. Smokers and those on any form of
`the study, subjects remained in upright positions
`medication were excluded.
`(sitting, standing, walking) and undertook a moder-
`ate amount of exercise. The images were recorded
`COMPOSITION OF MEALS
`by computer for analysis. Subsequently the images
`At about 900 am on the day of the study the subjects
`were displayed on a television monitor and regions
`were given a breakfast, or remained fasting before
`of interest were created around the stomach and the
`receiving a selected pharmaceutical formulation. A
`colon. The anatomical position of the tracer was
`standard light breakfast (calorific value 1500 kJ)
`
`

`
`888
`Table
`
`Davis, Hardy, and Fara
`
`Details of pharmaceutical formulations, subjects, and fed states
`Size
`(mm)
`
`Subjects
`M-5
`M-6
`M-6
`M-6
`M-4
`M-6
`F-5D
`F-SC
`M-6
`M-8
`M-4
`M-6
`M-8
`M-6
`M-8
`M-6
`M-4
`M-6
`M-6
`M-6
`F-SD
`F-6
`M-4
`F-SC
`M-4
`M-8
`M-6
`F-6
`M-6
`M-6
`M-6
`M-4
`M-8
`M-4
`M-6
`
`66
`
`Study
`Formulation
`Si
`Solution-DTPA
`S2
`Solution-DTPA
`S3
`Solution-DPTA
`S4
`Solution-DPTA
`P1
`0-31-2
`Pellets
`P2
`Pellets-resin
`0-S1-8
`P3
`Pellets-resin
`0-51-8
`Pellets-resin
`P4
`0-51-8
`PS
`0-81-2
`Pellets
`P6
`Pellets-coated
`0-7-1-0
`P7
`0-7-1-0
`Pellets-coated
`P8
`0-7-1-0
`Pellets
`P9
`Pellets
`0-6-08
`P1O
`0-81-2
`Pellets
`P11
`Pellets
`0-6-08
`P12
`Pellets
`0-81-2
`P13
`Pellets-coated
`0-7-1-0
`P14
`Pellets
`0-7-1-0
`Ti
`Tablet, slow release
`17x4
`T2
`Capsule, non-disintegr.
`25x9
`T3
`Capsule, non-disintger.
`25x9
`T4
`Tablet, slow release
`17x4
`TS
`24x7
`Osmotic pump
`T6
`Capsule, non-disintegr.
`25x9
`T7
`Tablet, slow release
`2-5 diam.
`T8
`Tablet, non-disintegr.
`12-0 diam.
`T9
`Osmotic pump
`24x7
`T10
`Tablet, slow release
`17x4
`Tll
`Tablet, slow release
`17x4
`T12
`Tablet, slow release
`10-5
`T13
`Tablet, non-disintegr.
`8-0 diam.
`T14
`Tablet, non-disintegr.
`8-0 diam.
`T15
`Tablet, non-disintegr.
`12-0 diam.
`T16
`Tablet, non-disintegr.
`17x4
`T17
`Osmotic pump
`24x7
`Solution and dietary fibre (data from
`Malagelada et al'7)
`99MTc
`Solution
`Fl
`No
`131 i
`No
`1-5
`Fibre-cellulose
`F2
`M-male, F-female, D-diarrhoea, C-constipation, FA-fasted, LB-light breakfast (-1500 kJ), HB-heavy breakfast (-3600 U),
`VA-variable meal, SM-standard meal (800 kJ).
`
`Label
`99mTc
`99WTC
`99mTc
`99mTc
`99mTc
`"'In
`"'In
`"'In
`99mTc
`99mTc
`99mTc
`99mTc
`99mTc
`99mTc
`99mTc
`"'In
`99mIn
`99mTc
`"'In
`99mTc
`99mTc
`"'In
`"'In
`99mTc
`"'In
`"'In
`"'In
`"'In
`"'In
`99MT
`"'lIn
`"'1In
`"'lIn
`"'lIn
`"'In
`
`Drug
`present
`No
`No
`Yes
`Yes
`No
`No
`No
`No
`No
`No
`No
`No
`No
`Yes
`No
`Yes
`No
`No
`Yes
`No
`No
`Yes
`No
`No
`Yes
`No
`No
`Yes
`Yes
`Yes
`No
`No
`No
`No
`No
`
`Fed
`state
`LB
`LB
`LB
`LB
`FA
`FA
`FA
`FA
`VA
`LB
`LB
`LB
`LB
`LB
`HB
`HB
`HB
`HB
`FA
`FA
`FA
`FA
`FA
`FA
`LB
`LB
`LB
`LB
`LB
`LB
`VA
`HB
`HB
`HB
`HB
`
`SM
`SM
`
`established by viewing the full sequence of images
`and by reference to a radiolabelled external marker
`taped to the skin overlying the liver to the right of
`the stomach. Many of the dosage forms provided
`good images of the various regions of the gastroin-
`testinal tract, because they were solutions or multi-
`particulates, or the dosage form itself released
`activity. Representative images have been presented
`previously. 7 18 20
`In some studies two dosage forms - for example,
`a single unit and pellets, labelled with different
`radionuclides were administered simultaneously, so
`that the stomach and colon images provided by the
`disperse sytem could be used to define the position
`
`of the non-dispersed single unit.18 19 Transit times
`for non-disintegrating single unit systems were
`obtained directly by viewing the images. For solu-
`tions and multiparticulate systems the radioactivity
`in a given region of interest was quantified, cor-
`rected for background counts and radioactive decay
`and then pairs of anterior and posterior count rates
`were used to calculate geometric mean count
`If two radionuclides were used simul-
`rates.2'
`taneously, then a correction was made for 'scatter-
`down' of the higher energy radiation (indium-111)
`into the energy window of the lower energy tracer
`(technetium 99m).18 19
`The transit behaviour of the solution and multi-
`
`

`
`889
`Transit of pharmaceutical dosage forms through the small intestine
`from the stomach quite rapidly and were not greatly
`particulate system has been expressed in terms of
`affected by the digestive state of the individual.
`the time for half of the tracer to leave the stomach,
`The emptying of the large single unit systems was
`or to arrive at the caecum. A small intestine transit
`greatly influenced by the presence of food in the
`time has been calculated as the difference between
`stomach. In a fasted state rapid emptying was often
`these two figures.
`observed, but even a light breakfast delayed
`emptying. A heavy breakfast resulted in greatly
`Results
`delayed empyting and in one study the units were
`The data from the various studies carried out with
`retained in the stomach in all six subjects for at least
`nine hours (study T17). When subjects were allowed
`the different pharmaceutical dosage forms are listed
`in the Table and summarised in graphical forms in
`to choose a varied breakfast gastric emptying ranged
`from rapid (no breakfast) to very slow (heavy
`Figures 1 and 2 for gastric emptying and small
`intestinal transit respectively. During studies 0 and
`breakfast). No difference has been found between
`old and young subjects (studies Ti, T4, T10 and Ti1
`W gastric emptying of the single unit had not
`respectively).
`occurred in all subjects at the times of recording the
`last image, and these last times have been used in
`the calculation of the mean values.
`SMALL INTESTINAL TRANSIT
`When the equivalent data for small intestine transit
`are examined a very different picture emerges (Fig.
`GASTRIC EMPTYING
`2). There were no differences that could be attri-
`The gastric emptying of different physical forms
`buted to dosage form, or stomach contents. Indeed
`varied according to the feeding conditions. Solutions
`and small pellets (less than 2 mm in size) emptied
`if the data for the three dosage forms are grouped
`
`Mecils
`
`IIIIIIIIIIIIIIiIIIIIIIII
`
`CM
`I=
`I
`
`Fl
`
`F2
`f
`
`I
`
`I! i0
`
`! !
`t0
`
`Gastric empty ng
`I
`
`I~~~~~~
`
`Single unit
`
`I
`
`4
`
`0
`
`II
`
`*
`
`I
`*I
`*
`: 11
`
`~~ ~~~0
`
`S
`
`0
`
`I
`0 1~~~
`1~~~~~~
`01~~~~~
`1 ~~~~0
`.3
`I00
`1 0 00
`I I.000
`
`Solution
`
`Pellets
`
`00
`
`Fil 0
`
`0-
`
`I
`
`I
`
`II I
`
`I>12
`
`I I II
`
`11I
`101
`91
`8
`*7
`zG6
`
`Ec
`
`-
`
`_
`
`_
`
`_
`
`43
`
`1
`21
`
`1 0
`
`Fig. 1
`
`00
`00
`S3
`S1
`T15
`P9 P11 P13
`Tll T13
`T17
`P5
`T10
`T12
`P10 P12 P14
`P8
`52
`T14 T16
`T6
`T8
`P2
`T2
`54
`P6
`P4
`T4
`Gastric emptying ofpharmaceutical dosageforms. Individual datapoints asfilled circles. Mean±SEM.
`
`P1
`
`P3
`
`P7
`
`Ti
`
`T3
`
`T5
`
`T7
`
`T9
`
`

`
`Solution
`
`Pellets
`
`Small intestine transit
`
`Single unit
`
`Meals
`
`Davis, Hardy, and Fara
`
`0
`
`Itj
`
`*Lw0
`
`0~~~~~~i~~~~~~
`
`I*\
`
`**
`
`*
`
`890
`
`9 8 7
`
`GPE
`.0ca10.1
`
`21
`1
`
`T5
`P1
`P9 P11
`P5
`53
`P7
`S1
`P3
`T7
`T3
`Ti
`P13
`S4
`S2
`PIO P12
`T6
`P8
`P6
`T2
`P14
`P2
`T4
`P4
`Small intestinal transit ofpharmaceutical dosageforms. Mean±SEM.
`
`Fig. 2
`
`Tl1
`T9
`T13 T15
`T1O T12 Ti4
`T16
`
`T8
`
`Fl
`
`F2
`
`(Fig. 3) then there is no statistical difference in
`transit behaviour for solutions, pellets and single
`units. Not only were the differences between the
`various studies small but also the variation of transit
`times within a study was reduced for the single units.
`Somewhat surprisingly, the mean intestinal transit
`values for fasted subjects were not statistically
`different from those where the subjects received
`meals. It is appreciated that fasted subjects received
`a meal about three hours into the study and this
`would then change their digestive state. Most
`subjects, however, had rapid gastric emptying (<
`one hour) in the fasted state.
`There was no difference that could be attributed
`to age in the small group of elderly subjects
`investigated.
`Discussion
`It has been shown that transit through the small
`intestine in healthy subjects is much more consistent
`than gastric emptying and it does not appear to be
`influenced by the physical state, or the size of the
`dosage form, nor by the presence of food in the
`stomach. The mean transit time of about three to
`
`Small intestinal transit
`n-23
`
`n=81
`
`n=l
`:84
`
`5 4
`
`.
`
`3
`
`2
`
`0 L
`I
`-4
`hmlmld.
`Solution
`Pellets
`Single unit
`Fig. 3
`Small intestinal transit ofpharmaceutical dosage
`forms. Mean values ±SD.
`
`

`
`Transit of pharmaceutical dosage forms through the small intestine
`
`891
`
`four hours agrees with the recent studies on the
`transit of food (mean transit solid food = 3-6±0-3 h,
`n=15)22 and water (4-0+0.8 h).23 This supports the
`proposal of Hofmann et at6 who suggested that
`'drugs, whether present as a particular dispersion, or
`as a micellar or molecular solution are considered to
`be propelled along the small intestine at the same
`net propulsive rate as food particles'. The recent
`work of Malagelada et al16 is also relevant. They
`found that a solution (labelled with 99mTc-DTPA).
`and a non-digestible solid particles of 131I-labelled
`fibre,
`gastric emptying was dependent on the
`physical nature of the test system, while small
`intestinal transit was not. They concluded that
`physiological discrimination between solids and
`liquids took place in the stomach, but not in the
`small bowel. Their mean values for small intestinal
`transit (3-0±0-28 h solution and 2.7±0-33 h solid)
`agree well with those given in the present report for
`a range of dosage forms.
`The shortest small intestinal transit time found in
`the present work is of the order of 1-3 h, while the
`longest is about six hours. One individual had a
`value of nine hours the reason for this slow transit is
`not known.
`IMPLICATIONS FOR DELIVERY THROUGH THE ORAL
`ROUTE
`The concept that a pharmaceutical dosage form has
`on average about eight hours for transit in the small
`intestine is clearly incorrect in young healthy male
`subjects. The 95% confidence limit for the small
`intestine transit time which is equal, or less than that
`of 95% of healthy volunteers (SITT95) applied to
`the data in Figure 3 indicates that SITT95 would be
`about one hour. If a drug is absorbed exclusively
`from the small intestine there is a good chance that
`the time the delivery system spends in that region
`could be as short as one to two hours. Thus efficient
`disintegration of the dosage form and dissolution of
`the drug in the stomach could be a considerable
`advantage, if the stability characteristics of the drug
`so permit. In contrast, an over effective delay of a
`drug release such as enteric coating, could result in
`markedly decreased biological availability. Thomp-
`son et al,24 however, have demonstrated variations
`in plasma glucose concentrations after oral dosing
`resulting from differences in motor activity in the
`upper gastrointestinal tract.
`A number of recently developed controlled, or
`sustained release products claim steady drug release
`characteristics in vitro of between 12 and 24 hours.
`The relevance of such release profiles in clinical use
`can be questioned if the drug is absorbed only from
`the small intestine,25 or is erratically absorbed from
`the large intestine,26 or suffers significant biotrans-
`
`formation by bacterial flora. If the delivery system
`reaches the caecum in three hours, then the greater
`proportion of the drug will be delivered not to the
`required site of the small intestine, but to the large
`intestine.
`Bioavailability data showing that the
`single dose controlled release system is equivalent to
`multiple doses of the drug over the same time scale
`and under fasted and non-fasted conditions, for
`subjects with long and short total transit times,
`would seem to be a sensible requirement for a
`satisfactory product to meet.
`The retention of the dosage form in the stomach
`(for example after a meal) would be expected to
`provide a greater opportunity for drug absorption.
`Indeed clear advantages would be gained if dosage
`forms could be held in the stomach by being of low
`density (floating capsules)27 or having so-called
`mucoadhesive properties.2' The limited data pre-
`sently available on these developments, however,
`suggest that these approaches are likely to have
`limited
`tablet
`sized,
`success.
`Taking a
`non-
`disintegrating single unit dosage form with a meal
`would have definite advantages. While the dosage
`form might remain in the stomach, the released drug
`would empty from the stomach with fluids and small
`food particles and be available for absorption from
`the intestine.10
`The predictable nature of intestinal transit for
`pellet and single unit dosage forms (approx 3±1 h,
`mean±SD) and the lack of an effect attributable to
`nutritional state means that it should be possible to
`design delivery systems for positioned release in the
`colon for the treatment of local conditions, such as
`ulcerative colitis.
`It should be remembered that majority of the data
`discussed above have been obtained in a large group
`of healthy male young subjects who were able to
`take moderate exercise during the studies. It is
`known that certain disease conditions, such as
`inflammatory lesions, or disorders of gut motility
`12 29 30
`can affect transit,
`as can the presence of
`administered drugs and unabsorbed food.12 Simi
`larly, in patients with partial obstruction or nar-
`rowed lumen, the passa e of a single unit formula-
`tion may be impeded.
`
`References
`1 Koch-Weser J, Schechter PJ. Slow release preparations
`in clinical perspective, In: Prescott LF, Nimmo, WS,
`eds. Drug absorption Lancaster: MTP Press, 1981:
`217-27.
`2 Ho NFH, Park JY, Morozowich W, Higuchi WI.
`Physical model approach to the design of drugs with
`improved intestinal absorption, In: Roche EB ed.
`Design of biopharmaceutical properties through prod-
`
`

`
`892
`
`rugs and analogs Washington: Am Pharm Ass, 1977:
`136-227.
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