DRUGS- MD THE WEN“: EUTICEL SCEHCE 5
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`‘a’ULUME 1C6
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`llral Drug Absurnlinn
`I
`I
`I
`Prediction and Assessment
`I
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`
`
`e iI~eu
`edited by
`i~er B
`J~
`Jemifer B. Dressman
`us e iem~c
`Hans Lennemés
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`KVK-TECH EXHIBIT 1038
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`KVK-TECH EXHIBIT 1038
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`

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`Oral Drug Absorption
`Prediction and Assessmeot
`
`edited by
`Jennifer B. Dressman
`Institute of Pharmaceutical Technology
`Johann Wolfgang Goethe University
`Frankfurt on Main, Germany
`
`Hans Lennernäs
`Biopharmaceutics Group
`Department of Pharmacy
`Uppsala University
`Uppsala, Sweden
`
`M A K C K L
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`K K K K F K
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`MARCEL DEKKER, INC.
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`NEW YORK. BASEL
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`Copyright © 2000 by Marcel Dekker, Inc. All Rights Reserved.
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`

`1G
`
`astrointestinal Transit and Drug
`Absorption
`
`Clive G. Wilson
`Strathclyde Institute for Biomedical Sciences, University of Strathclyde,
`Glasgow, Scotland, United Kingdom
`
`I.
`
`INTRODUCTION
`
`The human gut has evolved over many thousands of years to provide an
`efficient system for the extraction of nutrients from a varied diet. Functionally,
`the gut is divided into a preparative and primary storage region (mouth and
`stomach), a secretory and absorptive region (the midgut), a water reclamation
`system (ascending colon), and finally, a waste-product storage system (the
`descending and sigmoid colon regions and the rectum). The organization
`of the upper gut facilitates the controlled presentation of calories to the sys
`temic circulation allowing the replete person to perform physical work,
`to
`undergo social activities, and to go to sleep. In spite of this wondrous organiza
`tion it is still necessary, or at least desirable, in a modem lifestyle to take three
`meals a day. On the other hand, most of us wish to take our medications only
`once a day.
`Although the human race has relied on medicines for an indeterminate
`number of years, the physiology of the digestive process is less than conve
`nient for the efficient absorption of many of the modem therapeutic entities
`we wish to administer. The influence of feeding and temporal patterns on
`gastrointestinal transit, therefore, is of great relevance in attempting to opti
`mize drug absorption. In this chapter, we will consider how data from recent
`experiments might have an influence on how we think about dosing issues.
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`We will start with swallowing a medicine and finish with transit through the
`large intestine.
`
`II. ESOPHAGEAL TRANSIT
`
`After the dosage form leaves the buccal cavity, which is a relatively benign
`environment, transit through the esophagus is normally complete within 5—
`15 s, depending on posture. It has been known for many years that disorders
`of normal motility (dysphagia),
`left-sided heart enlargement, or stricture of
`the esophagus can result in impaired clearance of formulations. In some cases
`this can lead to damage of the esophageal wall. The elderly have a decreased
`ability to swallow large dosage forms, a phenomenon that may be related to
`the loss of secondary peristaltic mechanisms.
`Impairment of the ability to
`swallow with advancing age has been identified as a major health care problem
`in an aging population. Radiological studies of an asymptomatic group of 56
`patients, mean age 83 years, showed that a normal pattern of deglutition was
`present in only 16% of individuals (1). Oral abnormalities, which included
`difficulty in controlling and delivering a bolus to the esophagus following
`ingestion were noted in 63% of cases. Structural abnormalities capable of
`causing esophageal dysphagia include neoplasms, strictures, and diverticula,
`although several workers have commented that only minor changes of struc
`ture and function are associated with aging. The difficulty, therefore, appears
`to relate to neurological mechanisms associated with the coordination of
`tongue, oropharynx, and upper esophagus during a swallow.
`In scintigraphic studies of transit rates of hard gelatin capsules and tab
`lets, elderly subjects were frequently unable to clear the capsules (2,3). This
`appears to be due to the separation of the bolus of water and capsule in the
`oropharynx, resulting in a “dry” swallow. As a result, capsule adherence
`occurred in the lower third of the esophagus. In this region, adherence is not
`sensorially detected: subjects were unaware of sticking. The importance of
`buoyancy in capsule formulation has hitherto been ignored and may be an
`additional risk factor in dosing the elderly.
`
`III. GASTRIC RETENTION
`
`Our understanding of the behavior of dosage forms in the stomach has been
`gained largely from scintigraphic studies in which phases of a meal and formu
`lations are labeled with different radionuclides, particularly technetium-99m
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`Gastrointestinal Transit and Drug Absorption
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`3
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`and indium-i 11(4,5). Such studies have demonstrated that retention times of
`formulations in the stomach are dependent on the size of the formulation (6)
`and whether or not the formulation is taken with a meal (5). Enteric-coated
`or enteric matrix tablets may be retained for a considerable time if dosed with
`a heavy breakfast (7).
`Multiparticulate dosage forms will empty more slowly in the presence
`of food and, because the dosage forms mix evenly with the food, the entry
`into the small intestine will be strongly influenced by the calorific density and
`bulk of the ingested meal (8). The rate of gastric emptying, therefore, predicts
`the absorption behavior and is reasonably reproducible. In contrast, the absorp
`tion of drugs from small, soft gelatin capsules is sometimes less predictable,
`and other nonradionuclide measurements may aid in the understanding of dos
`age form behavior in this case. In recent studies in our laboratory, we noted
`erratic performance of a soft gel formulation containing a poorly soluble drug.
`Reduction of dose size increased the variability, and we were at some difficulty
`in explaining these results. Therefore, we had to look for other imaging possi
`bilities, including magnetic resonance imaging (MRI). The differences in pro
`ton shift of gut contents and tissues can be used to explore the behavior of
`formulations in the GI tract, provided that movement artifacts can be mini
`mized.
`It is well established that, after eating a meal, the shape of the stomach
`changes and the upper part (the fundus) relaxes to accommodate the extra
`volume. There is a short lag phase before the mixing movements in the lower
`part of the stomach, the pyloric antrum, increase. There is, therefore, a sharp
`contrast between the activity in the top and bottom halves of the stomach.
`This difference disappears when the subject lies prone in the MRI magnet:
`the pressure of the viscera causes mixing to abruptly cease and the liquid and
`solid phases separate in the stomach. This enabled us to perform studies to
`show previously unexplored mechanisms contributing to variability. Figure 1
`shows the semisolid fraction of a sandwich-based meal
`lying in the stom
`ach. Because the solid phase is not fully hydrated,
`it shows up as a bright
`doughnut-shaped solid against the liquid phase above it. Over a period of
`about 30 mill to an hour, the solids gradually hydrate and the two phases are
`no longer distinct. During the early phase of digestion, the center of the lumen
`is relatively immobile, and the secreted gastric juice flows around the food
`mass. The poor homogeneity of the lumenal contents prevents efficient mix
`ing. A small capsule given soon after the meal floats on the liquid above the
`solid mass, becoming stuck in the gastric rugae in the body of the stomach,
`or floats off ahead of the bulk of the gastric contents. The process is illustrated
`in Fig. 2.
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`4
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`Wilson
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`FIG. 1 MRI image showing a cross section through the upper abdomen: The semi
`solid fraction of a sandwich-based meal can be seen as a consolidated mass in
`the stomach. The stomach has squeezed the carbohydrate to an oblong mass.
`Image was taken within 10 mm of consumption.
`
`refornied into
`muss hi’ uciions of
`the p’vliiric ontruin
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`FIG. 2 Diagram showing how a small capsule given soon after the sandwich
`floats on the liquid above the solid mass.
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`Gastrointestinal Transit and Drug Absorption
`
`5
`
`IV.
`
`SMALL INTESTINE
`
`In the small intestine, contact time with the absorptive epithelium is limited,
`and a small-intestinal transit time of 3.5—4.5 h is typical in healthy volunteers.
`The Holy Grail of drug delivery would be to discover a mechanism that ex
`tended the period of contact with this area of the gastrointestinal tract. Various
`approaches have been suggested, although a universal solution is not evident,
`and data demonstrating phenomena which extend GI residence are often a
`subject of controversy. Florence (9) has argued that nanoparticulates show
`intercellular transport and increased residence in the GI tract, but other work
`ers have questioned the importance of this observation. Microparticulates are
`retained by the stomach, which may contribute to a prolongation of the absorp
`tive phase—their capacity is, however, limited (Thair and colleagues, unpub
`lished data). Prolonged stasis of pellets and tablets has been reported to occur
`at the ileocecal junction, but in our experience gastric emptying of subsequent
`meals causes movement of the material from terminal small bowel to cecum.
`Fat causes an extension of the small
`intestinal transit time, but the effect is
`modest (3 0—60 mm), and it does not appear that this mechanism is exploitable
`in drug delivery.
`
`V. COLONIC ABSORPTION
`
`For most formulations, colonic absorption represents the only real opportunity
`to increase the interval between doses. Transit through the lower part of the
`gut is quoted at about 24 h, but in reality only the ascending colonic environ
`ment has sufficient fluid to facilitate dissolution. In the cecum, the fermenta
`tion of soluble fiber will produce fatty acid and gas (largely carbon dioxide,
`but with small amounts of hydrogen and methane if the redox conditions are
`appropriate). The gas rises into the transverse colon and can form temporary
`pockets, restricting access of water to the formulation. Consequently, distal
`release of drug is associated with poor spreading, reduced surface area, and
`restricted absorption. In the colon, water availability is low past the hepatic
`flexure, as the ascending colon is extremely efficient at water absorption.
`Changing the water content of the human colon by coadministering 20 g lactu
`lose for 3 days markedly increases dispersion and dissolution in the transverse
`colon (Fig. 3). In the study shown in subjects were dosed with quinine sulfate
`in a colon-targeted device (Pulsincap) after receiving either lactulose for 3
`days or codeine 30 mg t.d.s. Fiber dosing, 20 g/day, was used as a control.
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`Wilson
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`—•—~—~ LaCtukan
`—.— ~od~ia~
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`Time (h)
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`Fio. 3 Graph illustrating the dispersion of colonic contents of a Pulsincap released
`in the ascending bowel.
`
`In comparison with either codeine or fiber control, lactulose treatment caused
`a marked increase in dispersion of the released contents (Hebden JM, et al.,
`unpublished data).
`
`VI.
`
`ROLE OF THE DISTAL COLON
`
`The anatomy of the distal colon, with its thick muscular walls, suggests a
`predominantly propulsive activity in this region. Studies with single adminis
`trations of pellets or Pulsincap devices suggested that this area is difficult to
`treat because the second half of the transverse colon and the descending colon
`function as a conduit. Steady-state measurements confirm this assertion (10).
`Subjects were dosed daily with indium-i 11-labeled Amberlite resin and im
`aged throughout the day. On the fourth day,
`the division of activity in the
`colon was 67% in the proximal half and 33% in the distal half. Subsequent
`experiments in patients with left-sided colitis have suggested that the division
`is even more exaggerated in colitis, which may provide an explanation for
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`Gastrointestinal Transit and Drug Absorption
`
`7
`
`poor therapeutic results often seen with orally administered medications in
`patients with active disease.
`Release at the ileocecal junction (i.e., before significant absorption of
`lumenal water has occurred) appears to provide satisfactory dispersion in the
`right colon. It has been suggested that there is a degree of stirring in the cecum,
`facilitated by the relatively liquid nature of the lumenal contents at this point.
`The cecum receives volumes of fluid sporadically, amounting to about iLl
`day, from meals and associated intestinal secretions.
`
`VII.
`
`THE IMPORTANCE OF TIME OF DOSING
`
`The time of dosing appears to be an important factor in maximizing colonic
`contact, particularly in the ascending colon. Morning dosing without fasting
`is a common regimen in clinical trials, and patterns of motility, at
`least in
`healthy volunteers, have been well-established using scintigraphy. Following
`early-morning dosing, a nondisintegrating unit clears the stomach in 1—2 h
`and has a small-intestinal transit time of 3—4 h. Thus, at about 1 PM, the unit
`will be expected to be at the ileocecal junction or will have just entered the
`colon. Colonic transit through the proximal colon of intact objects such as
`capsules is usually 5—7 h. For a nondisintegrating object, dosed in the morning,
`the unit will have arrived at the hepatic flexure by 7—8 PM. Thus, assuming
`the drug is absorbed in the colon, the maximum time window for absorption
`is 6—8 h following morning dosing with a monolith. Because the transit of a
`dispersed particulate phase through the proximal colon is longer, about 12 h
`(11,12) the maximum time window for absorption in this case is somewhat
`longer, 12—15 h. Further studies using the Pulsincap system (13) were carried
`out in our laboratories with the objective of targeting the distal colon using
`a pulsed delivery of a transcellular probe (quinine) and 51Cr-EDTA, a paracel
`lular probe (14).
`In these studies, subjects were dosed at 10 PM to ensure
`delivery to the descending colon by lunchtime the following day. The site of
`release was identified by incorporating HIn~labeled resin into the unit and
`the subjects were imaged with a gamma camera. A total of 39 subjects were
`investigated. Fifteen hours after nocturnal administration, the majority of the
`delivery systems were situated in the proximal colon at their predicted release
`time and had not advanced further than a similar set of systems viewed only 6
`h after dosing. This relative stagnation appears to reflect the lack of propulsive
`activity in response to by the intake of food and the effect of sleep in reducing
`colonic electrical and contractile activity (15—19). Delayed nocturnal gastric
`emptying (20) and reduced propagation velocity of the intestinal migrating
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`8
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`Wilson
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`motor complex (21) may also have been contributory, as supported by the
`finding that in two individuals the delivery system did not enter the colon until
`12.5 and 13.5 h after ingestion.
`If a delayed release formulation is taken close to 5 PM in the afternoon,
`it will have progressed through to the ascending colon by the time the patient
`goes to bed. Quiescence of propulsive movements in the large bowel during
`the night causes a relative stagnation, and units remain in the ascending colon.
`Potentially, this can increase the time of contact to 11—13 h even for a slowly
`dissolving matrix. On rising,
`the change in posture stimulates mass move
`ments, experienced by the subject as an urge to defecate, and contents move
`from the right to the left side of the colon.
`From the studies conducted using gamma scintigraphy and MRI, it ap
`pears that both temporal and dietary factors are important codeterminants of
`transit. For poorly soluble substances, the reserve time is an important determi
`nant of bioavailability. Moving away from the current practice of dosing sus
`tained-release formulations in the mornings might allow a reduction in the
`dosing frequency and increased efficacy of colon-targeted drugs, and would
`be especially suitable for formulations used to prevent acute disease episodes
`at night and in the early morning.
`
`ACKNOWLEDGMENTS
`
`Most of the work decribed in this chapter was carried out under the aegis of
`a MRC LINK award to the author and R. C. Spiller. I gratefully acknowledge
`the support of colleagues in the conduct of this work.
`
`REFERENCES
`
`1.
`
`2.
`
`3.
`
`Ekeberg 0, Feinberg MJ. Altered swallowing function in elderly patients without
`dysphagia: radiological findings in 56 cases. Am J Roentgenol 1991; 156:1181 —
`1184.
`Perkins AC, Wilson CG, Blackshaw PE, Vincent EM, Dansereau RJ, Juhlin KD,
`Bekker PJ, Spiller RC. Impaired oesophageal transit of capsule versus tablet for
`mulation in the elderly. Gut 1994; 35:1363—1367.
`Perkins AC, Wilson CG, Frier M, Vincent RM, Blackshaw PE, Dansereau RJ,
`Juhlin KD, Bekker PJ, Spiller RC. Esophageal transit of risedronate cellulose-
`coated tablet and gelatin capsule formulations. mt j Pharm 1999; 186:169—175.
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`Gastrointestinal Transit and Drug Absorption
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`9
`
`9.
`
`15.
`
`4. Hardy IG, Wilson CG. Radionuclide imaging in pharmaceutical, physiological
`and pharmacological research. Clin Phys Physiol Meas 1981; 2:71—121.
`5. Wilson CG, Washington N. Assessment of disintegration and dissolution of dos
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`6. Davis SS, Hardy JG, Taylor MJ, Whalley DR, Wilson CG. A comparative study
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`7. Wilson CG, Washington N, Greaves IL, Kamali F, Rees JA, Sempik AK, Lamp
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`Florence AT. The oral uptake of micro- and nanoparticulates; neither exceptional
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`10. Hebden 3M, Perkins AC, Frier M, Wilson CG, Spiller RC. Limited exposure
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`Frexinos I, Bueno L, Fioramonti I. Diurnal changes in myoelectric spiking activ
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`16. Narducci FG, Bassotti G, Gaburri M, Morrelli A. Twenty four hour manometric
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`Bassotti G, Betti C, Imbimbo BP, Pelli MA, Morelli A. Colonic motor response
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`Bassotti G, Betti C, Imbimbo BP, Pelli MA, Morelli A. Colonic high-amplitude
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`19. Soffer FE, Scalabrini P, Wingate D. Prolonged ambulant monitoring of human
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`20. Ghoo RH, Moore IG, Greenberg F, Alazraki NP. Circadian variation in gastric
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`17.
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`18.
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`C)
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