Rate Control
`in Drug Therapy
`
`Edited by
`
`L.F. Prescott
`W.S. Nimmo
`
`> H >
`HHH
`HHH
`l
`2
`CHURCHILL LIVINGSTONE
`EDINBURGH LONDON MELBOURNE AND NEW YORK 1985
`
`MYLAN EXHIBIT - 1070
`Mylan Pharmaceuticals, Inc. v. Bausch Health Ireland, Ltd.
`IPR2022-00722
`
`

`

`CHURCHILL LIVINGSTONE
`Medical Division of Longman Group Limited
`
`Distributed in the United States of America by
`Churchill Livingstone Inc., 1560 Broadway, New
`York, N.Y. 10036 and by associated companies,
`branches and representatives throughout the world.
`
`©Longman Group Limited 1985
`
`All rights reserved. No part of this publication may be
`reproduced, stored in a retrieval system, or
`transmitted in any form or by any means, electronic,
`mechanical, photocopying, recording or otherwise,
`without the prior permission of the publishers
`(Churchill Livingstone, Robert Stevenson House, 1-3
`Baxter's Place, Leith Walk, Edinburgh, EH1 3AF).
`
`First published 1985
`
`ISBN 0 443 02998 9
`
`British Library Cataloguing in Publication Data
`Rate control in drug therapy.
`1. Drugs—Dosage
`I. Prescott, L.F. II. Nimmo, W.S.
`615.5'8
`RS57
`
`Library of Congress Cataloging in Publication Data
`Rate control in drug therapy.
`"Proceedings of the Second International
`Conference on Drug Absorption which was held in
`Edinburgh"—Pref.
`Includes index.
`1. Drugs—Dosage forms—Congresses.
`2. Pharmacokinetics—Congresses. 3. Absorption
`(Physiology)—Congresses. I. Prescott, L.F.
`III. International Conference on
`II. Nimmo, W. S.
`Drug Absorption (2nd : 1983 : Edinburgh,
`Lothian) [DNLM: 1. Dosage
`Forms—congresses, 2. Drug—administration &
`dosage—congresses. QV 748 R233 1983]
`84-23894
`615.5'8
`RS200.R38 1985
`
`Printed in Great Britain by
`Butler & Tanner Ltd, Frome and London
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`15. Physiological limitations: gastric
`emptying and transit of dosage
`forms
`J. W. Fara
`
`Within recent years, a variety of oral dosage forms has been introduced to deliver
`their drug content over a specified period of time after administration. Because
`drug absorption from these forms may depend on where the delivery system
`resides in the gastrointestinal tract, gastrointestinal motility, gastric emptying,
`and intestinal transit became important considerations in the rational design of
`oral dosage forms.
`The general events that govern the emptying of food from the stomach have
`been known for some time. Indeed, over 150 years ago it was recognized that the
`stomach is a digestive vat, which not only contributes digestive secretions, but
`also performs the important function of reducing food to small particles by a
`vigorous grinding and mixing action.
`In addition, physiological studies have elucidated many of the mechanisms
`which control gastric emptying, and have given insight into gastric activity
`following a meal. At least three factors are recognized as influencing gastric
`emptying:
`
`1. Distension of the stomach, and various physiological influences such as
`emotional state.
`2. Physical characteristics of food: e.g. liquids empty faster than solids.
`3. Chemical composition of food: a light carbohydrate meal empties faster
`than a protein-rich meal, which empties faster than a fatty meal. Duodenal
`feedback mechanisms, involving hormone release and nerve reflexes, are
`triggered by components of the meal and by such factors as osmolality and pH.
`Also, a metering of calories delivered to the duodenum may be involved.
`
`These statements are at best incomplete descriptions of the multiple aspects of
`motility that govern and differentiate the emptying of solids and liquids from the
`stomach and their transit of the intestinal tract.
`
`MOTILITY MODES
`
`the disciplines of physiology and
`to eight years
`five
`the past
`Over
`gastroenterology have contributed to a clearer understanding of how food
`components and solid objects pass through the gastrointestinal tract. The
`
`144
`
`

`

`stomach handles objects greater than 2 mm in diameter quite differently from the
`way it handles smaller particles and liquids. In fact, the gastric residence time of
`larger objects is quite predictable compared to that of small particles. This
`difference arises from the prevailing gastrointestinal motility pattern.
`Two distinct gastrointestinal motility patterns are fairly well characterized in
`animals and man (Code & Schlegel, 1974; Code & Marlett, 1975): a so-called
` mode', which begins after ingestion of food and
``fasting mode', and '
`continues until after food components are digested and emptied from the
`stomach (Table 15.1)
`
`Table 15.1 The gastrointestinal motility modes characterised in dogs
`
`Fed mode
`Fasting mode
`
`9-12 h
`2-h cycle
`
`Clamped in same pattern
`Cycles regularly through three
`recognizable patterns:
`quiescent: 56 ± 4 min
`build up: 40 ± 28 min
`(fed-like)
`housekeeper: 20 ± 6 min
`
`The fasting mode prevails during night-time rest and into the early morning
`hours. It consists of three phases of motility that recur every one to two hours.
`These interdigestive motor cycles are: a quiescent period (phase I), a period of
`gradual increase in motor activity (phase II), and a period of intense bursts of
`contractions (phase III). Phase III is known as the migrating motor complex or
`the `housekeeper' motility pattern. This pattern begins about mid-way down the
`stomach and continues uninterrupted down the intestinal tract to the distal ileum.
`After most of the meal has been emptied, these housekeeper waves clear the
`stomach of any remaining digested contents, and also of relatively large,
`indigestible solids.
`Ingestion of a meal replaces the fasting cyclic motor activity with a pattern of
`continuous activity, known as the fed mode. In the stomach, this fed mode
`consists of regular contractions at a frequency of 3-5 per minute. In the intestine,
`a somewhat more irregular pattern of contractions occurs. During this time, food
`is digested and ground into smaller and smaller particles such that an orderly flow
`of partially digested food leaves the stomach over the next several hours. Because
`of the heterogenity of the usual human diet, both within and between individuals,
`the duration of the fed mode is variable, but probably continues as long as
`nutrients remain in the stomach. In dogs, the fed mode lasts 9-12 hours. after
`ingestion of a large-protein fat meal (Table 15.1). When the stomach is
`completely empty, it enters the fasting mode.
`
`MOTILITY MODES AND GASTRIC EMPTYING
`
`Code and coworkers laid the groundwork for understanding how the stomach
`empties food and solid objects. These investigators used fluoroscopic observation
`of the intragastric transit of 1-cm-diameter radiopaque plastic spheres (Carlson et
`al, 1966). Subsequent experiments then defined the relationship between each
`
`145
`
`

`

`motility mode and the handling of food and solid objects (Code & Schlegel, 1974;
`Code & Marlett, 1975; Hinder & Kelly, 1977; Meyer et al, 1979). The stomach
`selectively empties solids according to particle size (Fig. 15.1). The studies were
`first done in dogs and were subsequently confirmed in humans (Hinder & Kelly,
`1977; Meyer et al, 1979; Meyer et al, 1981; Malagelada et al, 1976).
`Radiolabelled liver was fed as cubes of different sizes and as homogenate,
`together with 7 mm radiopaque plastic spheres, and a quantity of non-absorbable
`fluid labelled with another radionuclide. Transit of the respective radionuclide
`through the gastrointestinal tract was then followed. By sampling the duodenal
`contents, a profile of gastric emptying was constructed (Fig. 15.1).
`
`WATER
`
`HOMOGENATE
`
`CUBES
`
`100
`
`50
`
`PERCENT EMPTIED
`
`I
`1
`
`I
`2
`
`I
`3
`
`SPHERES
`
` •
`I
`4
`
`TIME (hr)
`Fig. 15.1 The time course over which liquids, particles, and larger spheres empty from the
`stomach
`
`Liquids emptied quite rapidly, followed by liver homogenate and then the liver
`cubes emptied substantially more slowly. Solid plastic spheres of 7 mm diameter,
`fed with the liver, remained in the stomach for over four hours; during that time
`the rest of the meal emptied completely. Significantly, examination of the
`duodenal contents showed that all the food particles present were less than 2 mm
`in diameter. Thus, digestible substances are ground into smaller and smaller
`particles until they approach 2 mm in diameter, when the are emptied from the
`stomach.
`After ingestion of a meal, gastric motility switches rapidly into the fed mode
`pattern. There is mixing, propulsion, and retropulsion of the food as particles are
`reduced in size, and the stomach gradually empties. Large, non-digested particles
`are selectively retained, however, as the semi-liquid, partially digested particles
`flow irregularly into the duodenum. Some time after the meal has emptied
`completely, the stomach enters the fasting mode. With the subsequent
`appearance of the housekeeper motility pattern, strong propulsive contractions
`clean out all that remains (including the 7 mm spheres).
`
`GASTROINTESTINAL TRANSIT OF DOSAGE FORMS
`
`As gastric emptying rates are demonstrably faster during phase III housekeeper
`146
`
`

`

`contractions than at other times, and since relatively large solids are evacuated
`only during phase III, it is apparent that the time of ingestion of drugs and the
`size of the dosage form will determine how long the agent resides in the upper
`gastrointestinal tract. This has obvious implications for drug delivery to intestine
`and hence bioavailability.
`Several reports provide evidence of shifts in plasma concentration time curves
`when patients take enteric coated dosage forms with food, illustrating the
`influence of motility modes and gastric emptying on drug absorption.
`For example, delays of 2-3 hours in peak plasma concentrations of
`acetylsalicyclic acid, erythromycin, and prednisolone were reported some years
`ago when these drugs were ingested as enteric coated formulations with a meal.
`Initial analysis suggested possible interaction between food and drug. Given the
`current insight into motility modes and gastric emptying, however, the delay was
`probably due to prolonged gastric retention of the enteric coated preparations.
`In our laboratories, fluoroscopy has been employed in animals to determine
`the gastric residence time of a pellet just under 2 mm in diameter, a 4.5 mm bead,
`an 11 mm tablet, and and ALZET® drug delivery system. When administered
`fasting, all objects left the stomach within 1-3 hours (Table 15.2). Given with a
`meal, however, the three larger objects remained in the stomach as long as food
`was present. In contrast, the small pellets under 2 mm in diameter emptied quite
`rapidly and randomly with the meal. With continuous feeding to maintain the fed
`mode, solid dosage forms greater than 2 mm diameter could remain in the
`stomach for 24 hours or longer, whereas the smaller pellets appeared in the stool
`within 6-18 hours.
`
`Table 15.2 Four objects, administered together to dogs which were either fasting or
`recently fed, are located at hourly intervals by fluoroscopy. After 8 hours, the
`location is identified either by an X in the chart below (when all four objects had
`transmited the stomach or intestine) or by a 2 mm designation (representing the
`1.5-2.0 mm pellet)
`
`Location of objects (+8 h)
`
`Procedure
`
`Fasting
`
`Fed
`
`Dog
`no.
`
`162
`170
`173
`181
`183
`
`162
`170
`181
`182
`183
`185
`
`stomach
`
`bowel
`
`xxx
`xxxx
`
`xx
`xxxx
`
`2 mm
`
`2 mm
`
`xxx
`xxx
`xxx
`xxxx
`xxx
`xxx
`
`stool
`
`2 mm
`
`xxx 2 mm
`x 2 mm
`
`2 mm
`
`2 mm
`
`2 mm
`
`Utilising an intragastric system to detect and record motility, as well as to
`infuse various agents, the phase III `housekeeper' patterns have been well
`characterised in fasting human subjects. Upon ingestion of continental breakfast,
`the fed mode begins and the occurrence of another `housekeeper' wave is delayed
`147
`
`

`

`2-3 hours. This delay depends on the type of meal and the time course over which
`its components are released.
`To study gastric residence time, enteric coated aspirin formulations have been
`used. Upon the arrival of this formulation in the duodenum, the dissolution and
`absorption of the drug and appearance of salicylate in plasma and saliva can be
`related to the time the dosage form resides in the stomach. Administration of
`Azulfidine-EN-tabs® (salicylazosulphapyridine) a formulation designed
`to
`remain intact in the stomach, gives an indication of mouth to colon transit time.
`Upon arrival in the colon, the drug is split into 5-aminosalicylic acid and
`sulphapyridine by bacteria. Sulphapyridine is rapidly absorbed and secreted into
`saliva, where its time of appearance can serve as an index of mouth-to-colon
`transit.
`In fasting subjects, enteric coated salicylazosulphapyridine reaches the colon in
`approximately 6 hours compared with 8 hours when given with a continental
`breakfast (Table 15.3). The 2 hour delay correlates with the recorded motility
`
`Table 15.3 Enteric coated salicyclazosulphapryridine transit
`time from mouth to colon in normal human volunteers
`
`Subject
`
`Fasting
`
`Fed
`
`01
`
`02
`
`04
`
`06
`
`07
`
`09
`
`10
`
`mean
`± SE
`
`7.3
`7.5
`
`2.8
`6.3
`
`5.0
`
`6.0
`
`5.0
`3.3
`
`7.0
`7.5
`5.5
`
`6.0
`7.0
`
`8.8
`7.5
`
`5.8
`6.5
`
`7.5
`7.5
`8.5
`7.8
`
`9.8
`10.1
`
`5.8
`
`8.3
`6.5
`
`8.0
`8.5
`
`5.9 7.79
`0.42 0.33
`
`mode; the next housekeeper pattern is also delayed approximately 2 hours by this
`meal. With other enteric coated agents, retention in the stomach accounts for this
`two hour delay (Table 15.4). Thus, only after the meal has left the stomach does
`an ensuing phase III housekeeper motility pattern sweep the solid dosage form
`from the stomach.
`
`148
`
`

`

`Table 15.4 Effect of a continental breakfast on delaying
`gastric residence and mouth to colon transit times in normal
`volunteers
`
`Delay in gastric residence time
`(determined with enteric coated aspirin)
`
`Delay in mouth to colon transit time
`(determined with enteric coated
`salieyhazosulphapyridine
`
`Time
`
`2.5 hours
`
`n = 13
`
`2.0 hours
`
`n = 13
`
`IMPLICATIONS FOR DOSAGE FORM DESIGN
`The prolonged-duration oral drug delivery systems developed in recent years can
`be classified as either single or multiple-unit types. From the foregoing discussion
`it is obvious that each will be handled quite differently by the stomach, and their
`gastrointestinal transit will be dependent on the prevailing motility mode. Small
`pellets of the multi-unit type behave more or less like liquids and digested
`particles and leave the stomach fairly soon after administration. A large single
`unit ingested with food, however, will remain in the stomach until the meal is
`emptied and either the unit disintegrates or a housekeeper motility wave sweeps it
`into the intestine.
`It has been suggested that multiple-unit systems, such as pellets or small
`granules, have an advantage over a single-unit system in that they will become
`dispersed or spread along the gastrointestinal tract after administration. Such
`suggestions are without proof. Indeed, studies in man indicate that these multiple
`unit formulations leave the stomach more or less together and move as a bolus
`through the gastrointestinal tract, much like that of a liquid (R. Davis, personal
`communication). Furthermore, pellets have been found to reaggregate in the
`distal ileum and/or ascending colon.
`Hunter and colleagues (Hunter et al, 1982) recently found rapid gastric
`emptying and lack of dispersion of a pellet formulation (Fig. 15.2). The slope of
`the emptying curve can be viewed as a `coefficient of dispersion' and complete
`emptying occurs over only 10-15 minutes. Once out of the stomach, the small,
`multiple units are swept rapidly along the intestine.
`Thus, evidence is accumulating that there is little dispersion of pellet
`formulations. Moreover, physiological motility patterns suggest that the small
`size of pellets offers little likelihood of altering their residence and transit times.
`In contrast, larger, tablet-sized solid dosage forms — ingested with a meal for
`example — will be retained selectively and predictably in the stomach with
`reduced variability in their gastric emptying. During prolonged residence in the
`upper gastrointestinal tract, the delivery system can release its content into the
`intestine where absorption is most favourable for the majority of drugs. This is
`particularly significant for the ALZA oral dosage form, OROS®, which delivers
`drug only in solution. Thus, while the antral sieving action of the stomach
`selectively retains this solid dosage form the drug solution rapidly leaves the
`stomach with other fluids for prompt absorption in the intestine. After the meal
`
`149
`
`

`

`106 cipmw MEI • AM
`
`80
`
`40
`
`20
`
`% radioactivity in stomach
`
`10
`0
`
`&
`10
`
`1
`20
`
`1
`30
`
`I
`40
`
`50
`
`I
`BJ
`
`Time (min)
`
`Fig. 15.2 Gastric emptying of pellet formulations in two human volunteers (Hunter et al, 1982)
`
`has left the stomach, the delivery system itself exits to begin its transit through the
`gastrointestinal tract, while continuously delivering drug in solution.
`Thus, a better understanding of human gastrointestinal motility patterns
`enables prediction of gastric retention and gastrointestinal transit of various
`dosage forms. In this way, one can also begin to understand and indeed to
`influence the duration of drug absorption from the dosage form.
`
`REFERENCES
`
`Carlson H C, Code C F, Nelson R A 1966 Motor action of the canine gastroduodenal function: A
`cineradiographic, pressure and electric study. Am J. Dig Dis 11: 155-172
`Code C F, Marlett J A 1975 The interdigestive myoelectric complex of the stomach and small
`bowel of dogs. J. Physiol (London) 246: 289-309
`Code C F, Schlegel J F 1974 The gastrointestinal interdigestive housekeeper: motor correlates of
`the interdigestive myoelectric complex of the dog. In: Proceedings of the fourth international
`symposium on gastrointestinal motility. Mitchell Press, Vancouver, 631-634
`Hinder R A, Kelly K A 1977 Canine gastric emptying of solids and liquids. Am J Physiol 133:
`E335-340
`Hunter E, Fell J Y, Sharma H 1982 The gastric emptying of pellets contained in hard gelatin
`capsules. Drug Dev Ind Pharm 8: 751-757
`Malagelda J R, Longstretch G F, Summerskill W H J et al 1976 Measurement of gastric functions
`during digestion of ordinary solid meals in man. Gastroenterology 70: 203-210
`Meyer J H, Thomson J B, Cohen M B et al 1979 Sieving of solid food by the canine stomach and
`sieving after gastric surgery. Gastroenterology 76: 804-813
`Meyer J H, Ohashi H, Jehn D, Thomson J B 1981 Size of liver particles emptied from the human
`stomach. Gastroenterology 80: 1489-1496
`
`150
`
`