`Volume 4, Issue 3 (1987)
`22.1
`
`GASTROINTESTINAL DYNAMICS AND PHARMACOLOGY FOR THE
`OPTIMUM DESIGN OF CONTROLLED-RELEASE ORAL DOSAGE FORMS
`
`Authors;
`
`N. W. Read
`
`Department of Physiology
`University of Sheffield and
`Royal Hallamshire Hospital
`Sheffield. England
`
`Keith Sugden
`Research and Development
`Pharmaceutical Division
`Reckitt & Colman
`
`Kingston upon Hull. England
`
`Rea-rec:
`
`'I'. 7.. (salt)-
`lkpartment of Pharmacology
`University of Missouri-Columbia School of Medicine
`Columbia. Missouri
`
`I. INTRODUCTION
`
`Oral administration ofa drug is perhaps the least predictable route of drug administration,
`yet
`it
`is the route that is used tnost frequently. Oral medications are relatively cheap to
`produce. and tablets and capsules offer the most convenient form of drug administration.
`However. these solid dosage forms have to disintegrate and dissolve at an appropriate rate
`in order to present the drug in a liquid state to the optimum site of absorption.
`The gut is a long tube: absorption rates vary widely from region to region within that
`tube. and the degree of absorption depends to a large extent on the length of time a drug
`remains in each of these regions. This will vary in response to such factors as the ingestion
`of food. physical exercise. mental stress. obesity, and the menstrual cycle. The colon contains
`bacteria which may degrade drugs to ineffective or even toxic compounds. and both the
`distribution and the metabolic activity of these bacteria may vary under differing conditions.
`The therapeutic activity of the majority of most. but not all. drugs is directly related to
`their concentration in the plasma.I If the plasma concentration is too high. this may give
`rise to toxic and unwanted side effects. It the plasma concentration is too low. then the drug
`may be ineffective. Between these boundaries there may be levels at which a drug exerts
`some but not all of its therapeutic actions. The ratio of the toxic level
`to the minimum
`effective level
`is known as the therapeutic concentration ratio (TCR), The TCR of many
`therapeutically important drugs is generally of the order of two to three2 but can vary
`Enormously according to the drug. disease, and patient. For example. highly susceptible
`bacterial infections can be treated with a wide range of antibiotic doses and a variety of
`dosage intervals: whereas in the maintenance of intraoperative hypotension with nitroprusr
`side.
`the range of desirable intensity of action is so narrow as to require treatment by
`intravenous infusion, the rate of which is continually titrated against arterial pressure.-‘
`Oral administration of a drug in a conventional dosage form results in fluctuations in
`plasma levels (Figure I). the size of which depends on the amount of the dose. the dosing
`interval. the rate of absorption. the volume of distribution. and the rate of elimination. The
`
`ENDO - Ex. 2042
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`CRC Critical Reviews in Therapeutic Drug Carrier Systems
`
`F'laEimaLevel
`
`Earn
`
`12am
`
`4pm
`
`8pm
`Time of Dose
`
`12pm
`
`darn
`
`Sam
`
`FIGURE |. A diagram illustrating the possible fluctualions in plasma level
`of a drug that might occur when the drug is administered orally in a conven-
`tional dosage form t—l and in a controlled—release form t- — .1.
`
`aim of chronic therapy is to attempt to maintain blood levels within the therapeutic range,
`avoiding peaks where toxic effects may occur and troughs where the drug is ineffective.
`This may be difficult
`if not impossible to achieve with drugs that have a short half-life
`unless doses are given at unacceptably frequent intervals.
`Less variable blood levels may in theory be achieved either by increasing the distribution
`volume or by reducing the rate of elimination (selection of an analog with a longer half-
`life) or by reducing the rate of absorption Reducing the rate of absorption is the most
`favored solution because absorption is normally the primary factor influencing drug levels
`and because absorption can be limited without altering the chemical structure of the drug
`or giving additional drugs.
`The aim of controlled-release oral administration is to minimize the frequency of dosage
`and the fluctuation in plasma drug levels by restricting the delivery of the drug into the
`gastrointestinal lumen to a rate which limits the rate of absorption.
`in this way, absorption
`is dominated by the rate of release of the drug from the formulation and this is more
`predictable and steady than the rate of epithelial transport.
`For the purposes of this review. we have taken the view that all dosage forms designed
`to limit release rate or to cause release to occur at a specific site could be termed controlled
`release. Others would reserve the term controlled release only for those products for which
`the rate of drug release can be accurately stated and is independent of environmental con-
`ditions within the gut. Forms that limit drug release in a variable and unpredictable manner
`are termed “slow release“, while those that only release their products when they reach the
`alkaline medium of the duodenum are termed “enteric coated".
`
`A. Advantages of Oral Controlled-Release Forms (Table I)
`Controlled-release oral dosage forms are designed to increase efficacy by avoiding sub-
`therapeutic concentrations and reduce the incidence of toxic side effects by smoothing out
`the peak blood levels. If different therapeutic effects are found at different drug levels, the
`stability of steady plasma concentrations allows the prescriber to select the effects he desires“5
`or to use drugs that otherwise might not be used because of a high incidence of side effects.
`Thus, the use of controlled-release forms gives greater precision in therapy.
`Less frequent dosage should lead to greater patient compliance. Even in the best hOSpitals.
`the proportion of patients who take their drugs as prescribed and who have serum concen—
`
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`Volume 4, Issue 3 (1987)
`
`223
`
`Table l
`
`POTENTIAL ADVANTAGES OF ORAL
`DOSE CONTROLLED-RELEASE
`FORMULATIONS
`
`Prolongation of drug action
`Greater therapeutic precision
`Decreased dosing frequency
`Greater patient compliance
`Absorption rates less dependent on lamina! conditions
`lncreased efficacy by abolishing suhtherapeulic troughs
`Reduced toxicity by flattening toxic peaks
`Allows drugs with very short action or low therapeutic ratio
`In be used
`
`Drugs with dangerously long half—lives can be avoided
`
`Table 2
`
`LIMITATIONS OF ORAL DOSE
`CONTROLLED-RELEASE THERAPY
`
`Missed doses lead to greater loss of efficacy than conven-
`tional forms
`
`Greater risk of toxicity if whole dose is released prematurely
`Reduced bioavailability if drug is rapidly degraded in the
`colon
`
`May be unsuitable for drugs —
`With very short elimination half—lives
`With very long elimination half-lives
`With extensive first—pass metabolism
`That are incompletely absorbed in small intestine
`That are rapidly degraded in the colon
`That are degraded in the colon to toxic metabolites
`
`trations within the therapeutic range is remarkably small" If controlled-release forms allow
`patients to take drugs once or twice a day when they are at home instead of three or four
`times a day, the chances of missed doses should be smaller.
`
`B. Disadvantages or Limitations of Oral Dose Controlled-Release Formulations
`(Table 2}
`The loss of therapeutic effect may well be greater if the patient were to miss a dose of a
`controlled-release formulation than if he were to omit a dose of a conventional form. The
`toxic effects of inadvertent release of the total dose from a controlled-release formulation
`are also much greater than from a conventional form because larger amounts of drug are
`often administered in the controlled-release forms. For this reason, it is recommended that
`drugs with a small TCR should not be given in a controlled-release form. The most important
`limitation of oral dosage controlled-release therapy, however. is that it could lead to a greater
`fraction of the dose escaping absorption and thus reduce the systemic availability of the drug
`in some patients.
`The systemic availability or bioavailability of a drug is that fraction of the close that reaches
`the systemic circulation and may be determined by comparing the plasma concentration
`profile after oral administration with that following intravenous administration.T The area
`under the plasma level vs. time curve (AUC) after a single dose is a measure of the amount
`of drug reaching the blood stream.
`
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`

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`CRC Critica! Reviews in Therapeutic Drug Carrier Systems
`
`Table 3
`SOME DRUGS WITH
`EXTENSIVE FIRST-PASS
`METABOLISM
`‘x
`
`Acctylsalicylic acid
`Aldosterone
`
`Alprenolol
`Bcclamcthasone
`Carbi mazole
`
`C hlorprom azine
`Imipramine
`Lignocaine
`Morphine
`Norlryptyl ine
`Pentazocine
`Pelhidine
`Pivampicillin
`Propoxyphene
`Salbutamol
`Terhuia] inc
`
`where D is the dose taken.
`
`Systemic availability depends on the rate and degree of absorption as well as the degree
`of metabolism during first pass through the gut wall and the liver. Controlled-release oral
`dosage forms may reduce systemic availability by slowing absorption so much that only a
`small proportion of the dose is released at its optimal absorption site in the small intestine.
`and much is released in the colon. where it may be absorbed very slowly or erratically or
`it may be rapidly broken down by bacterial action to metabolites that could be ineffective
`or toxic. Thus} controlled—release forms are unsuitable for drugs that are incompletely ab-
`sorbed when given in conventional formulations and for drugs that are rapidly degraded in
`the colon. particularly if the metabolites are toxic.
`Controlled-release forms may be a disadvantage for drugs that are extensively metabolized
`during first pass through the gut wall or the liver (Table 3). If the rate of absorption is
`slowed by a controlled—release formulation.
`then a higher proportion of the dose will be
`metabolized by the saturable enzyme systems and the amount reaching the systemic circu-
`lation may be considerably reduced. The common use of a slow—release formulation of
`propranolol (Inderal® SA]. which is rapidly metabolized in the liver. is explained by the
`probability that propranalol works through the active metabolite 4 hydroxy-propranolol.
`Slow—release forms are unnecessary and may be unsuitable for delivering drugs that take
`a long time to be eliminated from the body. Blood levels of such drugs are often quite stable
`even with conventional dosage, and sustained delivery could risk accumulation of the drug
`to toxic levels. Sustained—release forms are often used for such drugs in order to provide a
`less frequent dosing schedule and to improve the precision of therapeutic control.
`Controlled delivery may be dangerous for drugs with very short half-lives. This is because
`very large doses of controlled-release form may be required in order to achieve and maintain
`effective blood or tissue levels and toxic effects may occur if the dose is absorbed within a
`shorter time than anticipated or if elimination is prevented, by factors such as the inhibition
`of hepatic enzymes.
`
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`

`Volume 4, Issue 3 (1987)
`
`225
`
`Table 4
`RATE-LIMITING FACTORS DURING
`DRUG ABSORPTION
`
`Solubility in gastrointestinal contents
`Binding to food
`Gastric emptying
`Distribution in small intestine (contact area!
`Residence in small intestine (contact time)
`Release from dosage form
`Convection (mixing)
`Aqueous boundary layer tacid microclimate. unstirred
`layer]
`Panition in cell membrane
`Carrier-mediated transport (some drugs]
`Water flow through epithelium
`Metabolism in the intestinal epithelium
`Blood flow
`
`Lymphatic flow
`
`11. DRUG ABSORPTION
`
` The design of controlled-release oral dosage forms has to take into account the multiple
`
`A. Site of Absorption
`Although in principle the entire gastrointestinal tract is capable of drug absorption, the
`small intestine is the major site of absorption for most nutrients and drugs. The potential
`epithelial surface available for absorption in the small intestine has been estimated to be
`around the size of a basketball court (463 m2)?“ and is far greater than in the stomach or
`colon. Three morphological features increase the surface area of the small
`intestine: (I)
`mucosa] folds, (2) the myriad finger-like projections. termed villi, which are lined with
`absorbing cells or enterocytes, and (3) projections called microvilli on the mucosal membrane
`of each enterocyte.
`Thus, aspirin is absorbed predominantly in the small intestine even though 99.9% of the
`drug is ionized at the pH of the intestinal contents (around 7).” This is partly because of the
`greater intestinal surface area, partly because of the greater solubility of aspirin in neutral
`medium, and partly because there is an acid microclimate immediately adjacent to the
`intestinal epithelium,'0 which would result in a much greater concentration of un-ionized
`Species at the absorptive site than in the lumen. Similar results have been obtained for
`Warfarin” and digitoxin,12 and gastric absorption of hydrochlortliiazidel3 and metoprolol"
`is reported to be negligible.
`The colon has a flat epithelium, but material remains in the colonic lumen for a much
`longer time than it remains in the small intestine. Thus, the colon could be an important
`absorptive site for drugs that are poorly absorbed in the small intestine were it not for the
`fact that many drugs are degraded in the colon lumen by bacteria to inactive and occasionally
`toxic metabolites. '5-”‘
`
`factors that normally influence the rate and the degree of absorption from the gut. The aim
`of the following section is to discuss how these physiological factors will normally influence
`drug absorption and how this knowledge can be used for the optimum design of controlled-
`release oral dosage forms.
`
`B. Rate-Limiting Factors in Drug Absorption (Table 4)
`A drug administered in a solid form has to dissolve in gastrointestinal contents, pass out
`of the stomach into the small intestine, gain access to the epithelium by convection of the
`
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`Table 5
`POSSIBLE EFFECTS OF FOOD ON
`DRUG ABSORPTION
`
`Influences diseolution host drugs
`Some drugs bind to food constituents
`Increases flow of pancreatic enzymes that may de—
`grade some drugs
`Increases bile flow. which may enhance absorption of
`highly lipophilic drugs
`Slows gastric emptying
`Slows small bowel transit (increases Contact time)
`Enhances distribution of drug throughout the small in-
`testine [increases contact area}
`Reduces absorption due to increased viscosity
`Competes for absorption sites
`Enhances bIood and lymph flow
`increases bioaVailability of drugs with large first-pass
`effect
`
`luminal contents and by diffusion across the unstirred microclimate. and cross the epithelium
`either by partitioning into the lipid membrane or by passing through water-filled channels,
`or by combining with specific membrane-bound carriers. The residence of the drug in the
`small intestine has to be long enough for complete absorption to take place. and the drug
`should not bind excessively to food components. Once the drug has been absorbed. a
`proportion may be metabolized in the epithelial cells. The rest is cleared from the epithelium
`by the blood or the lymph. The blood draining the gut passes through the liver. and some
`drugs are extensively degraded by hepatic enzymes before they reach the systemic circulation.
`The rate and amount of absorption of drug reaching the systemic circulation may be
`modified by factors acting at each of these stages. The ingestion of food will also influence
`drug absorption by acting on all of these sites (Table 5).
`
`I. Solubility and Binding to Food Constituents
`Most drugs are weak acids or weak bases and are thought to cross the epithelium by
`dissolving in the lipid cell membrane. This requirement often means that their solubility in
`water is relatively poor and may be influenced by the volume and composition of gastroin-
`testinal contents. Absorption of poorly soluble amoxycillin is enhanced if the drug is ad-
`ministered with 250 mi? instead of 25 mt’ of water.” The presence of-gastric acid impairs
`the solution of weak acids such as aspirin“ or warfarin” and may slow their absorption
`because the insoluble drug is retained in the stomach. This would explain why an overdose
`of aspirin often collects in an insoluble ball in the stomach: toxicity may be avoided if this
`ball can be removed by gastric lavage. Aspirin is more rapidly absorbed in achlorhydric
`patients'8 than in normal subjects. In contrast, absorption of weak bases may be enhanced
`by gastric acid, which will increase the solution of these drugs. The lbw pH of the gastric
`contents may reduce or delay the absorption of drugs from enteric~coated formulations.
`formulations.
`
`the pH of the gastric contents are not
`Although the stomach can secrete HCI at pH 1.
`always highly acidic. Gastric acid is buffered by food and the pH remains above 3 for a!
`least
`1 hr after eating.'9 Under fasting conditions. the pH may fluctuate between about 1
`and 7. being low between meals and quite high for certain periods during sleep.""‘ [(una20
`measured gastric pH in 312 normal fasting subjects and found a pH below 3.5 in only 41%
`of his recordings. Thus. at certain times. the gastric pH may be high enough to allow the
`drug to be released into the stomach from enteric-coated preparations.. with an early rise in
`blood levels.
`
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`

`Volume 4, Issue 3 (1987)
`
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`
`The absorption of some very lipid-soluble drugs may be enhanced by bile acids, which
`effectively solubilize fats by formation of mixed micelles. This may explain why increasing
`the bile flow enhances the absorption of sulfadiazine by 50%“ and why griseofulvin and
`sulfadiazine are absorbed more rapidly when given with a fatty meal rather than a carbo-
`hydrate meal.22 Bile flow is normally increased by the entry of semidigested food into the
`duodenum and maintained for as long as a meal empties from the stomach. Brief periodic
`bursts of bile flow occur under fasting conditions. coincident with the passage of phase III
`of the migrating motor complex (MMC) through the duodenum.” Clearly. if the absorption
`of a drug is dependent upon micellization by bile acids, then the drug should be given as a
`conventional dosage form with a meal.
`Reducing agents in food, such as ascorbic acid. may increase iron absorption by main—
`taining iron salts in the intestinal lumen in the more soluble ferrous form.24 For this reason.
`ascorbic acid is usually incorporated into slow-release iron preparations.25 Tetracyclin binds
`to polyvalent metallic ions such as calcium. iron. aluminum. and magnesium in food forming
`poorly soluble chelates.2h Phytates, tannates. and phosphates in food also form insoluble
`complexes with iron and calcium?“ Thus, one could argue that the absorption of iron and
`calcium could be reduced if they were delivered in controlled-release formulations because
`there is greater opportunity for binding to food constituents.
`The absorption of isoniazid is reduced when given with a carbohydrate-rich breakfast,”
`probably because isoniazid may react with ketones or aldehydes present in the intestinal
`lumen to form inactive hydrazones.
`
`2. Gastric Emptying
`Most drugs are not absorbed in significant proportions until they reach the small intestine.
`Since intestinal absorption of many drugs occurs very rapidly, the rate of delivery from the
`stomach is often a major factor limiting the rate of absorption. Heading and colleagues-‘“
`observed highly significant correlations between blood levels of paracetamol and the rate of
`gastric emptying in convalescent hospital patients. In some subjects. the apparent first-order
`absorption rate constant for paracetamol was virtually identical to the first-order rate constant
`for gastric emptying of the drug.-‘I Ingestion of food delays the delivery of the drugs to the
`small intestine‘2 The degree of delay depends on the formulation; highly soluble drugs given
`in a conventional dosage form or drugs given as pellets disperse in the gastric contents and
`are gradually emptied with the meal. Nondispersible single units are retained in the stomach
`until the fasting motor pattern returns. Thus, after a meal.
`the pylorus appears to act as a
`sieve allowing small particles through but retaining larger particles. This sieving action does
`not occur under fasting conditions; drugs given as small pellets or as single units appear to
`leave the stomach together when administered under fasting conditions.32
`The stomach relaxes to receive food. stores it, mixes it with acid—pepsin, and grinds it
`up, emulsifying the fats and breaking large particles down to smaller ones, and finally
`delivers the semifluid chyme at a controlled rate into the small intestine.
`The rate of emptying of different components ofa meal may differ quite markedly. Liquids
`are emptied faster than solids,” which are gradually broken down by the turbulence induced
`by the contraction of the gastric antrum until they are sufficiently small to pass through the
`pylorus:‘3-34 Changing the physical state of the solid component of the meal to one that is
`less easily disrupted (fluffy pancake vs. a flat pancake) also prolongs the lag phase-‘4"
`Measurement of the size of particles aspirated from the canine duodenum after a meal of
`Chicken liver indicates that solids have to be broken down to a size of £2 mm before they
`
`can exit the stomach through the pyloric aperture.” However. nondestructible particles up
`to 5 mm in diameter have been shown to empty from the human stomach during the
`postprandial phase-‘5'" Perhaps the friable chicken [iver particles were further disrupted
`during passage through the pylorus or aspiration from the duodenum.
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`CRC Critical Reviews in Therapeutic Drug Carrier Systems
`
`‘00
`
`50
`
`
`
`PERCENTEMPTtED
`
`HOMOGENATE
`
`X
`
`CUBES
`
`
`
`
`
`t
`
`2
`TIME Ihr)
`
`SPHERES
`
`3
`
`.1
`
`FIGURE 2. The time course over which liquids. particles. and larger spheres
`empty from the stomach.
`
`Sal-460WW
`
`A recording of the intraluminal pressure in the lower esophageal
`FIGURE 3.
`sphincler (LES). gastric antrum. and small intestine at different distances (in
`cm) from the pylorus under fasting conditions. (From Bueno. 1.... Fioramonti.
`1.. and Ruckebusch. Y., Am. J. Dig. Dis. 33. 682. [978. With permission.)
`
`Particles that are resistant to gastric disruption and are larger than 5 mm do not usually
`leave the normal stomach together with digestible solids-“'3" but exit some hours later when
`the rest of the meal has emptied from the stomach (Figure 2). Fara“ incorporated a pellet,
`2 mm in diameter, a 4.5-mm bead, an 1 l-mm tablet. and the ALZET® drug delivery system
`in a meal, which he fed to dogs. The three larger objects remained in the stomach for as
`long as food was present. whereas the small pellets emptied quite rapidly with the meal.
`With continuous feeding, solid dosage forms greater than 2 mm in diameter could remain
`in the stomach for as long as 24 hr.“ Similar results were noted by Jonsson et al.. who
`compared pellets and solid tablets. 3 and 14 mm in diameter.“I The emptying of large inert
`particles. however, may depend on their deformability by antral contractions since Schlegel
`et al.” observed that hard nondeforrnable spheres empty more slowly than softer compliant
`spheres.
`It is generally assumed that large nondisrupted solids are expelled from the stomach by
`the return of phase III of the interdigestive MMC. which occurs when virtually all the meal
`has left the stomach-"‘43 The MMC is a recurrent motor pattern. usually observed in the
`interdigestive period and involving the stomach and small intestine. It consists in the small
`intestine of three distinct phases44 (Figure 3). These are a quiescent period (phase I), where
`
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`

`Volume 4. Issue 3 (1987}
`
`229
`
`
`
`there are few or no contractions; a period of intermittent contractile activity (phase II); and
`a short period of regular contractions (phase Ill). Phase [[1 is the most obvious feature of
`the interdigestive motor activity; it usually commences in the proximal duodenum and then
`migrates slowly down the small intestine to the ileum. A period of regular antral contractions
`often occars coincident with the development of phase III in the duodenum.“ This is often
`called antral phase [II and must be associated with an increased pyloric diameter since it
`appears to clear large particles from the stomach.“-”5
`The interdigestive motor pattern is disrupted by the presence of food in the stomach and
`small intestine and is replaced in the small intestine by an irregular pattern of motor activity
`resembling phase II. The postprandial motor activity in the stomach varies according to the
`nature of the food ingested. Hyperosmotic liquids or fatty foods suppress antral contractions,
`increase pyloric tone. and induce regular phasic increases in pyloric pressure."6 The emptying
`of solids, on the other hand. is associated with regular antral contractions.‘”-"‘ The pylorus
`must remain relatively narrow during postprandial antral contractions since these are unable
`to clear large particles from the stomach-““4"
`The dependence of the emptying of large particles from the stomach on the occurrence
`of phase III of the interdigestive MMC can result in great variability in the time of onset
`of drug absorption from enteric—coated forms, which only release their contents after they
`have entered the alkaline duodenum. Under fasting conditions, it may take anywhere from
`a few minutes to several hours before blood levels of an enteric-coated drug in tablet form
`start to rise. lf enteric—coated tablets are taken with a large meal, however, blood levels
`may not rise for up to [O brim-iso Antral phase 111 can be suppressed for a similar length of
`time after a heavy meals"I The variability in the time of absorption of enteric—coated forms
`may be avoided by administering the drug as enteric-coated granules or beads, small enough
`to pass out of the stomach with the food. Figure 4 shows the blood levels of aspirin
`administered as enteric-coated tablets and as emetic-coated granules.“q Administration as
`granules leads to more consistent blood levels under both fed and fasting conditions.50
`The delay in the emptying of large inert particles from the stomach has been utilized to
`design delivery forms that are large enough to be retained in the stomach for long periods
`of time. releasing the drug as a liquid into the gastric contents. from where it passes rapidly
`into the duodenum.52 This principle aims to deliver the drug at a steady rate to the site of
`maximal absorption in the upper small intestine.
`It
`is possible that the reduction in the
`volume of distribution as the meal empties from the stomach could increase the concentrations
`of the drug in the gastric effluent and lead to unstable blood levels. However,
`it is likely
`that for most controlled—release formulations the decrease in distribution volume is accom-
`panied by a decline in the release from the formulation so that the amount of drug entering
`the duodenum may well remain stable. Ideally. gastric retention devices should be given
`with food: if the delivery form is given to a fasting patient, phase 111 may propel it from
`the stomach and down the small intestine before it has released most of its contents.
`Some meals exist in the stomach in the form of discrete solid and liquid components
`which empty at different rates: others are rapidly converted to a viscous slurry, in which
`solids and liquids empty together. The addition of viscous polysaccharides. such as guar
`gum, to a meal slows the delivery of liquids from the stomach into the small intestine.53
`Increasing the viscosity of a glucose drink reduces postprandial glycemia-“Jl and would be
`expected to lower blood levels of soluble drugs. The emptying of small solid particles,
`however, may be accelerated by viscous polysaccharides because they are caught up in the
`viscous stream-“5“ Thus, increasing the viscosity of a meal reduces discrimination between
`liquids and small disruptible solids.
`Surprisingly. the incorporation of viscous agents in a meal containing glucose or other
`forms of available carbohydrate not only reduces the blood sugar profile following that meal
`but may also reduce the blood sugar profile following the next meal as well.57 The mechanism
`
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`

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`
`CRC Critical Reviews in Therapeutic Drug Carrier Systems
`
`ENTERIC-
`
`COATED
`
`TABLETS
`
`ENTERIC-
`
`COATED
`
`GRANULES
`
`mmol/l
`
`03
`
`02
`
`[ll
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`B
`
`10
`9
`Hours
`
`mmolrl
`
`D3
`
`02
`
`01
`
`0
`
`l
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`B
`
`ll]
`9
`Hours
`
`Plasma levels of salicylic acid in eight subjects after administration of l g
`FIGURE 4,
`acetylsalicylic acid as enteric-coated tablets and enteric—coated granules under lasting (0) and
`nonfasting conditions (-). Results are shown as mean : SEM. {From Bogentoft. C. . Carlsson.
`1.. Ekenved. G.. and Magnusson. A.. Eur. J. Pharmacol. I4. 35. 1978. With permission.)
`
`of the second meal phenomenon is not well understood. although slowing of absorption by
`viscous polysaccharides could result in the continued presence of unabsorbed nutrients in
`the small intestine by the time the seCond meal is ingested. This could in turn cause a reflex
`delay in gastric emptying and hence absorption-“‘5“ For example. Read and co-workers have
`recently shown that infusion of lipid into the small intestine reduces blood levels of alcoholm‘
`and glucose61 after drinks containing these substances.
`The presence of hyperosmotic liquids. lipids. and certain amino acids in a meal and a
`low pH of gastric effluent all delay gastric emptying by interacting with specific receptors
`in the small intestine."‘3-63 Not only will the interaction retard the emptying of liquids and
`solids, but ifthe active principle empties with the liquid phase. it will prolong the lag phase
`for disruptible solids which remain in the gastric fundus until most of the liquid has emptiedM
`without altering the slope of emptying of solids. The length of time from ingesting a meal
`to the return of phase III depends on the size and composition of the meal." Large meals
`and meals that contain fats take longer to empty from the stomach so that digestive activity
`is maintained for longer. To illustrate the effect this Would have on drug delivery. Davis
`and colleagues compared the gastrointestinal transit of entet‘ic-coated pellets and an enteric—
`coated osmotic pump device using gamma scintigraphy.“ Both preparations emptied from
`the stomachs of healthy volunteers quite rapidly when they were administered with a light
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`breakfast, but after a heavier meal. the osmotic device remained in the stomach for much
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`longer than the pellets. Perhaps a gastric retention device that slowly releases lipid as well
`as active drugs could be used to prolong the fed state and keep the delivery form in the
`stomach. The infusion of lipid into the small
`intestine has been shown to slow gastric
`emptying and reduce plasma ethanol levels“I following a drink of vodka and to reduce plasma
`glucose levels following a glucose drink or a meal of mashed potatoes.“I Incorporation of
`butter into the meal of mashed potatoes also reduces postprandial hyperglycemia, presumably
`by the same mechanism."1 If the subject is eating a meal in the seated posture, the lipids in
`the meal may not initially delay emptying because they tend to float on top of the gastric
`fluid level and leave the stomach after aqueous fluids.“
`Posture exerts other effects on gastric emptying. Bland liquids“? and pellet formulations“
`empty more rapidly from the stomach if the subject is standing or sitting upright than if he
`is supine. The absorption of paracetamol, which is limited by gastric emptying, is faster in
`ambulant compared with supine subjects.“l Gastric emptying of raft-forming alginate antacids
`is faster when subjects lie on their left sides?“ than when they are supine or lying on their
`right sides.
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`3. Access to the Epithelium
`The turbulence and mixing caused by contractions of the smooth muscle of the intestine
`must increase the contact between the dissolved drug and the epithelium. This effect of
`intestinal motility is inhibited by agents that increase the viscosity of luminal contents and
`may explain why viscous polysaccharides such as guar gum retard absorption.“5 In theory.
`co-administration of drugs that act directly on the small intestine to inhibit motor activity
`could be used to slow absorption.
`Convective forces can bring the drug close to the epithelium, but to gain access to the
`absorptive surface, the drug must diffuse through the layer of relatively unstirred water that
`coats the epithelial surface?I Diffusion through the unstin'ed water layer limits the rate of
`absorption of substances that normal