Physiologic considerations in drug absorption
`from the gastrointestinal tract
`
`A. L. Golub, Ph.D., R. W. Frost, Pharm.D., C. J. Betlach, Pharm.D., Ph.D.,
`and M. A. Gonzalez, Ph.D. Miami, Fla.
`
`The dynamic interaction between variables within the gastrointestinal tract and the
`physicochemical properties of a drug in a delivery system determine the rate and extent of
`absorption of that drug. Among the major physiologic variables are pH, gastric emptying time,
`and intestinal transit time. Some physicochemical properties of interest include solubility,
`particle size, and chemical form of the drug. Attributes of the formulation such as controlled-
`release mechanism, pH sensitivity, and size, shape, and density of the product can also affect
`absorption. Food has also been reported to influence the absorption from some but not all
`controlled-release products. As a more thorough understanding of the many factors involved in
`drug absorption is developed, the formulation of more sophisticated oral drug delivery systems
`will be possible. (J ALLERGY CLIN IMMUNOL 1986;78:689-94 . )
`
`The interaction of the human gastrointestinal (GI)
`tract with the products of pharmaceutical development
`is highly complex and dynamic. During transit down
`the GI tract, drugs and dosage forms that have been
`formulated to control drug release and subsequent ab-
`sorption in a predictable manner are subject to a wide
`variety of physiologic factors, such as varying pH,
`enzymes, and bile salts, that can profoundly affect
`their therapeutic performance. Among the multiple
`variables involved in the drug absorption process are
`several that are not yet fully understood; this lack of
`understanding can lead to unanticipated and delete-
`rious results in clinical practice. Further, when drugs
`are administered in the presence of food, environ-
`mental conditions within the GI tract change relative
`to fasting, and the number of potential interfem'ng
`substances increases.
`
`The present objective is to identify and briefly dis-
`cuss the principal physiologic factors known to affect
`the absorption of drugs from the GI tract. While re-
`view of all the potential variables is beyond the scope
`of this discussion, a number of comprehensive treat-
`ments of the subject are available."5
`
`GASTRIC pH
`
`The principal variables affecting a drug or dosage
`form in the stomach are the gastric fluid volume, de-
`gree of digestive activity, rate of stomach emptying,
`and pH.
`
`Reprint requests: A. L. Golub, Ph.D., Key Pharmaceuticals, Inc.,
`50 NW. 176th St., Miami, FL 33169.
`
`It is generally considered that resting gastric pH is
`acidic, ranging from 1 to 3.5, or at most 1 to 5."‘8 In
`a study from the Netherlands, however, basal gastric
`pH of 366 normal middle-aged Dutch male and 198
`female subjects was measured by aspiration of the
`stomach contents after an overnight fast.9 Of these
`subjects, 129 had a basal pH higher than 6, and many
`values fell in the range between 7 and 9. Pentagastrin
`refractory achlorhydria was found in only 14 of the
`subjects; for the remainder, gastric pH fell to below
`6 after stimulation, indicating that there was no im-
`pairment of their acid secretory function. These ob-
`servations suggest that resting gastric pH may not
`reliably be in the acid range, and have obvious im-
`plications for drugs and formulations that may be sen-
`sitive to environmental pH.
`For absorption to occur, drugs must first undergo
`dissolution in the fluids of the GI tract:
`
`Dissolution
`
`Absorption
`
`Drug -——————> Drug in *9 Drug in
`solution
`circulation
`
`Dissolution from a dosage form is frequently the rate-
`limiting step in drug absorption and is the rationale
`for designing sustained-release products that control
`the rate at which a drug is solubilized and, hence, the
`rate at which it is absorbed. With the exception of
`enteric formulations (and poorly acid soluble com—
`pounds), lhe dissolution process for most drugs begins
`in the stomach. In simplist terms, the volume of gas-
`tric fluid must be large enough to initiate and achieve
`adequate drug dissolution. While absorption directly
`
`689
`
`MYLAN - EXHIBIT 1036
`
`MYLAN - EXHIBIT 1036
`
`

`

`690 Golub et al.
`
`J. ALLERGY CLlN. IMMUNOL.
`OCTOBER 1986
`
`
`In Vitro pH‘Depemceht
`
`1‘
`
`Dissolution (Measured)
`
`f
`
`/
`
`%
`
`SIF
`
`IO
`
`12
`
`14
`
`
`
`8
`(HOURS)
`
`a t
`
`o
`
`2
`
`4
`
`IONDTQQULVED
`
`FRACT
`
`FIG. 1. In vitro dissolution profile for a pH-dependent, sustained-release theophylline capsule.
`
`from the stomach is generally minimal, rapid passage
`of gastric fluid containing drug through the pylorus
`brings the solubilized drug into contact with the ab-
`sorptive surface of the duodenum and associated re-
`gions of the small intestine.
`
`GASTRIC EMPTYING AND GI MOTILITY
`
`GI motility is a function of digestive period. In the
`nonfasting state, the pattern of gastric and intestinal
`activity associated with the trituration, digestion, and
`absorption of food materials is a 9 to 12-hour process
`of consistent activity of the GI musculature. During
`this phase, gastric acid secretion is at its peak; exten-
`sively broken down food materials pass through the
`pylorus and, as chyme, are moved by peristalsis
`through the intestines, where absorption and, ulti-
`mately, fluid and electrolyte resorption take place.
`During the fasting period, gastric and intestinal mo-
`tility are very different, cycling through four identifi-
`able phases called the “migrating motor complex” or
`the “interdigestive myoelectric complex.’ ’ '0‘” Phase 1
`is a quiescent or resting phase of minimal activity,
`lasting approximately 1 hour. Phase 2 is a buildup
`period during which stomach contractions and peri-
`staltic activity in the GI tract are quite similar to those
`of the nonfasting period. Phase 3 involves a crescendo
`of strong muscular contractions known as “house-
`keeper waves” that cause the stomach to expel any
`remaining food or indigestible materials within it into
`the lumen of the intestines. Phase 4 is a short transition
`
`period between phase 3 and phase 1. The relative
`movement of drugs and dosage forms through the GI
`tract can be significantly influenced by these differing
`levels of GI activity, particularly with regard to gastric
`emptying.
`The results of several studies have demonstrated
`
`that water and homogenized food materials empty
`from the stomach quite rapidly, while larger solid
`foods, such as 1 cm cubes of liver, are retained for
`
`much longer periods.”“6 The reason for this delayed
`emptying has been shown to be a function of the size
`of the particles. When food material has been reduced
`by the stomach’s triturating action to particles less
`than 2 mm in diameter,
`it is free to pass into the
`intestines. Similarly, ding pellets or beads 2 mm in
`diameter or smaller are readily passed by the pylorus,
`while larger indigestible units such as tablets are re—
`tained in the stomach for extended periods.12 If not
`broken down in the stomach, the larger materials are
`evicted from the stomach by “housekeeping waves”
`during the interdigestive period.
`The rate of stomach emptying is also significantly
`influenced by the composition of the food material
`under digestion. The primary determinant of emptying
`is volume of liquid. Liquids empty exponentially; the
`larger the volume, the faster the rate of emptying.‘7
`The emptyng of neutral, iso—osmolar. and calorically
`inert solutions is rapid. ’8 Solutions that are hypertonic
`or contain acid, fats, or certain amino acids retard
`
`gastric emptying by action on specific small bowel
`
`

`

`VOLUME 78
`NUMBER 4. PART 2
`
`Physiologic considerations in drug absorption from GI tract
`
`691
`
`In V1VO pH~Depehdemt
`
`Absorption (Predicted)
`
`\
`
`25
`
`2C)
`
`15
`
`10
`
`5
`
`:3
`:3:\
`(D
`L)
`
`E4
`
`—)
`L.)
`
`O
`
`O
`
`4
`
`8
`
`l_._l____L__L___l—_l
`18
`20
`24
`
`12
`t(HOURS>
`
`FIG. 2. Plasma concentration-time profile predicted from dissolution data for a pH-dependent,
`sustained-release theophylline capsule.
`
`receptors.”20 It is also notable that stomach emptying
`can be accelerated or delayed by the local or systemic
`effects of various drugs and by the body’s physical
`orientation,21
`
`INTESTINAL TRANSIT
`
`For most drugs, the principal site of absorption is
`the proximal small intestine, particularly the duode—
`num. Here, the epithelial surface area through which
`absorption can take place is very large because villi
`and microvilli are present. These finger-like projec—
`tions, arising from and forming folds in the intestinal
`mucosa, increase the area available for absorption by
`more than 30 times that which would be present if the
`small intestine were a smooth tube.22
`
`In terms of their effect on drug absorption, many
`of the same considerations that apply to the stomach
`also apply to the intestines, for example, fluid volume,
`pH, and peristaltic activity related to the phase of the
`digestive process. Fluid volume must be adequate to
`continue the drug dissolution process. The pH of the
`duodenum approximates 5; jejunum, 6 to 7; ileum,
`7.6; and large intestine, 7.5 to 8.0.7 while this range
`is relatively narrow,
`the rate of drug release from
`enteric or pH-sensitive drug dosage forms can be sig—
`nificantly affected.
`In the intestines, other factors, such as the presence
`of a limited region for drug absorption known as an
`
`a
`
`can be very relevant to the
`“absorption window,’
`absorption of some drug compounds. If intestinal tran-
`sit moves the drug beyond that region, absorption and
`drug bioavailability will be incomplete. Splanchnic
`blood flow rate is also a relevant factor as this is the
`
`primary vehicle for the drug’s carriage from the site
`of absorption into the systemic circulation. Moreover,
`since blood drainage from the principal areas of GI
`absorption is portal and leads directly to the liver,
`the degree to which a compound is metabolized during
`its “first: pass” through the liver can significantly af-
`fect its apparent extent of absorption.
`
`PHYSIOCHEMICAL CONSIDERATIONS
`
`A general consideration of the drug itself is im-
`portant, as its interaction with the GI tract is largely
`a function of its physiocochemical properties, such as
`solubility, particle size, and chemical form. The pH-
`partition theory23 states that the gastrointestinal mem-
`branes act as a lipoid barrier; the nonionized form of
`a drug is preferentially absorbed. For instance, the-
`ophylline is stable and very weakly ionized within the
`range of physiologic pH. It is completely and rapidly
`absorbed from uncoated tablets and solution24 and is
`
`minimally metabolized on first pass through the liver.
`It has been shown, however,
`that the rate of drug
`
`absorption is slowed when an immediate-release the-
`ophylline preparation is administered concomitantly
`
`

`

`692 Golub et al.
`
`J. ALLERGY CLIN. IMMUNOL.
`OCTOBER 1986
`
`2C]
`
`16
`
`8
`
`(meg/ml)
`
`LP
`
`X=Fost 1 mg
`D=Non—Fost 1 mg
`
`W
`
`C)
`
`O
`
`10
`
`2C]
`
`30
`Time (hours)
`
`___A____L___A____L___J
`40
`50
`E30
`
`FIG. 3. Theophylline plasma concentration—time curve from a subject dosed in the fasting and
`nonfasting states with the pH-dependent product.
`
`with food. The extent of drug absorption is not af—
`fected.” 2"
`
`FORMULATION VARIABLES
`
`Just as the physicochemical characteristics of the
`drug influence its absorption kinetics from the GI tract,
`so also will the physicochemical attributes of its for-
`mulation. These include the particular pharmaceutical
`mechanism that is used to control drug release, the
`sensitivity of the release mechanism to influence by
`pH, and the size, shape, and density of the dosage
`form.” 23 For example, as noted above, the particle
`size of the dosage form can strongly influence the rate
`at which it is emptied from the stomach. Several recent
`studies have demonstrated that the formulation of the-
`
`ophylline into various sustained-release dosage forms
`can lead to significant effects on both the rate and
`extent of drug absorption.”32
`
`SPECIFIC EXAMPLES
`
`Drug dissolution from pH—dependent, pellet-filled
`capsules may be profoundly affected by changes in
`GI pH and stomach emptying time. The two fluids
`commonly used to test in vitro drug release kinetics
`from dosage forms are simulated gastric fluid with a
`pH of 1.2 and simulated intestinal fluid with a pH of
`7.5. When certain pH-dependent pellets are exposed
`to these media, the data illustrated in Fig.
`1 emerge.
`The formulation releases very slowly in simulated gas—
`tric fluid, releasing only a fraction of its total potency
`
`over several hours. In contrast, theophylline release
`is relatively rapid in simulated intestinal fluid, reach-
`ing completion in about 6 hours. Fig.
`1 demonstrates
`how such a dosage form reacts when a transition is
`made from a pH environment simulating the stomach
`to an environment simulating the intestine. This tran-
`sition is analogous to the stomach emptying process
`described earlier and is highly variable in vivo. A
`formulation that
`is affected by pH in this manner
`would be predicted to produce a blood level curve
`similar to that shown in Fig. 2. Indeed, an in vivo
`plasma concentration—time curve obtained with this
`preparation, shown in Fig. 3, is strikingly similar in
`appearance to that which can be predicted based on
`the product’s pH-sensitive drug release characteristics
`alone.
`
`This is not the case for other types of pellets such
`as those used for sprinkling on soft, moist food for
`administration to patients who have difficulty swal-
`lowing intact tablets or capsules. These pellets are
`small, in the range of 0.5 to 1 mm in diameter, and
`have drug release characteristics that are not affected
`by environmental pH. When administered with food,
`however, these pellets have been shown to have sub—
`stantially reduced bioavailability as compared to that
`after administration in the fasting state.31 The reason
`for this phenomenon is not known, but may be related
`to inadequate hydration and dissolution in the presence
`of food.
`
`One formulation whose drug release and absorption
`
`

`

`VOLUME 78
`NUMBER 4, PART 2
`
`Physiologic considerations in drug absorption from GI tract
`
`693
`
`
`
`
`.300m9
`. 200mg
`
`. 100mg
`
`~1.7mm
`
`FIG. 4. Cross section of the tablet dosage form cons sting of pellets within a matrix.
`
`kinetics have proved to be virtually immune to the
`influence of food or other GI variables is a two-phase
`tablet consisting of pellets compressed within a ma-
`trix.” 33' 34 This formulation is not pH sensitive and
`has constant-rate release kinetics that are little influ-
`
`enced by GI activity, whether fed or fasting. Because
`of the way that it is formulated, with individual pellets
`that are gradually released as the tablet matrix dis-
`integrates, the performance of this product has com-
`bined elements relating to both large and small units.
`A schematic diagram of this tablet is seen in Fig. 4.
`The matrix material contains theophylline, and as the
`tablet surface begins to slowly erode in the stomach,
`initial drug dissolution is from the matrix. Based on
`in vitro observations, it appears that the pellets closest
`to the eroding surface are the first to become wetted,
`and drug begins to be released from these smaller units
`through their coatings. Because of the tablet’s size,
`the bulk of the tablet is most likely retained in the
`stomach during this period. As erosion and dissolution
`proceed, pellets deeper in the tablet matrix are ex-
`posed and come into play sequentially, until tablet
`disintegration is complete, at which time, most, if not
`all,
`the particles should have passed into the small
`intestine. The hybrid structure of this type of for-
`mulation and its lack of pH sensitivity may largely
`account for its resistance to drug absorption variables
`in the GI tract.
`
`DISCUSSION
`
`The benefit-to-risk ratio of a drug like theophylline,
`which is rapidly absorbed and variably eliminated,
`
`and which has a narrow therapeutic range and poten—
`tially serious toxicity above that range, can be dra-
`matically improved by its formulation. Indeed,
`the
`successful clinical use of theophylline in the chronic
`therapy of bronchospastic disorders has been attrib-
`uted to the availability of reliable sustained-release
`formulations that slow down absorption and, thereby,
`provide circulating concentrations of the drug that are
`relatively constant over extended dosing intervals.
`However, the in vivo performance of some controlled-
`release theophylline dosage forms can be used to il-
`lustrate the deleterious effects that physiologic vari-
`ables can have on drug absorption from the GI tract.
`In the. case of pH—sensitive, pellet-filled capsules,
`exposure to a changing pH environment during GI
`transit can lead to erratic and unpredictable drug re-
`lease that can be attributed to the dosage form. The
`pH effect may be further magnified by other factors
`such as a delay in stomach emptying that is induced
`by the presence of a meal that is high in fats.
`While not affected by pH, another pellet-type for-
`mulation has been shown to have a decreased extent
`
`of absorption, i.e., low bioavailability, when admin-
`istered in the presence of food.
`In such a case, a
`decreased volume of GI fluid available for hydration
`and subsequent drug dissolution may be implicated.
`Finally, the existence of theophylline dosage forms
`that are resistant to the vagaries of GI transit, such as
`a two—phase compressed tablet preparation, suggests
`that the effects of GI physiologic variables on drug
`absorption can be minimized by appropriate appli-
`cation of available formulation procedures. In the last
`
`

`

`694 Golub et al.
`
`several years, significant advances have been made in
`“biopharmaceuticzs,” the area of pharmaceutical sci-
`ence that deals with the interaction between drug,
`dosage form, and the biologic system. Further un-
`derstanding of the multiple variables that are involved
`in the drug absorption process will, no doubt, lead to
`the formulation of more sophisticated and reliable
`drug dosage forms by the pharmaceutical
`industry
`and, as a result,
`to more effective drug therapy in
`clinical practice,
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