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`
`
`MILO GIBALDI, PH.D.
`
`Dean, School of Pharmacy
`Associate Vice President,
`
`Health Sciences
`
`University of Washington
`Seattle, Washington
`
`FOURTH EDITION
`
`Biopharmaceatics and
`Clinical Pharmacokinetics
`
`p.
`
`
`
`LEA (gt FEBIGER °
`
`Philadelphia
`
`-
`
`London
`
`-
`
`1991
`
`p. 1
`
`SHIRE EX. 2025
`KVK v. SHIRE
`IPR2018-00290
`
`

`

`5 i %
`
`
`
`Lea &: Febiger
`200 Chester Field Parkway
`Malvern, Pennsylvania
`19355—9725
`U.S.A.
`.
`(215) 251—2230
`1—800-444—1785
`
`Lea 5: Febiger (UK) Ltd.
`145a Croydon Road
`Beckenham, Kent BR3 SRB
`UK.
`
`Library of Congress Cataloging-in-Publication Data
`
`Gibaldi, Milo.
`Biopharmaceutics and clinical pharmacokinetics I Milo Gibaldi.»~
`4th ed.
`cm.
`p.
`Inciudes bibliographical references.
`ISBN 0-8121w1346-2
`
`1. Biopharmaceutics. 2. Phannacoldnetics. I. Title
`{DNLM: 1. Biopharrnaceutics. 2. Pharmacokinetics. QV 38 G437b]
`RM301.4.G53
`1990
`615’.7%c20
`DNLMIDLC
`
`for Library of Congress
`
`90-5614
`CIP
`
`First Edition, 1971
`Reprinted 1973, 1974, 1975
`Second Edition, 1977
`
`Reprinted 1978, 1979, 1982
`Third Edition, 1984
`
`Reprinted 1988
`Fourth Edition, 1991
`First Spanish Edition, 1974
`First IapflflESE Edition, 1976
`Second Jflopdnese Edition, 1981
`Second Turkish Edition, 1981
`
`The use of portions of the text of USP XX—NF XV is by permission of the USP Convention. The Convention
`is not responsible for any inaccuracy of quotation or for false'or misleading implication that may'arise
`from separation of excerpts from the originai context or by obsolescence resulting from publication of a
`supplement.
`
`Reprints of chapters may be purchased from Lea & Febiger in quantifies of 100 or more.
`
`Copyright © 1991 by Lea & Febiger. Copyright under the international Copyright Union. All Rights Reserved. This
`book is protected by copyright. No part of it may be reproduced in any manner or by any means without written permission
`JFrom the publisher:
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`Printno.:
`
`4 3
`
`2
`
`1
`
`
`
`p. 2
`
`

`

`
`
`
`
`Gastrointestinal Absorption—m-
`Role of the Dosage Form
`
`
`
`Most of the drugs used today are potent and,
`increasingly, specific. However, finding a chemi-
`cal that selectively binds to an enzyme in the my—
`ocardiurn or inhibits the synthesis of a key element
`in blood clotting does not constitute drug discovery.
`Among the requirements for a drug, we must be
`able to administer it to the whole animal and it
`
`must find its way to the site of action. In this sense,
`the modern dosage form is a drug delivery system;
`its selection may be as important to the clinical
`outcome of a given course of therapy as is the
`selection of the drug. With virtuaily any drug, one
`can routinely produce a 2- to 5-fold difference in
`the rate or extent of gastrointestinal absorption,
`depending on the dosage form or its formulation.1
`In some cases, even greater differences may be
`observed. A difference of more than 60-fold has
`
`been found in the absorption rate of spironolactone
`from the worst formulation to the best formuia-
`
`tion.“ The peak concentration or" spironolactone
`metabolites in the plasma after a single dose of the
`drug in different dosage forms ranged from 0.06
`to 3.75 rig/L per mg of administered drug.
`From first principles, one would expect the bio-
`availability of a drug to decrease in the following
`order: solution > suspension > capsule > tablet
`> coated tablet. Although this ranking is not uni»
`versal, it provides a useful guideline. The results
`of bioavailability studies with pentobarbital in man
`are summarized in Figure Swl. The absorption rate
`of pentobarbitat after administration in various oral
`dosage forms decreased in the following order:
`aqueous solution > aqueous suspension of the free
`acid m capsule of the sodium salt > tablet of the
`free acid.5 These findings demonstrate how the dos-
`age form can influence drug absorption.
`
`Jig/ml
`N0|ch0:
`PENTOBARBITALCONCENTRATION.
`
`
`TIME, hr
`
`Pentobarbital concentrations in plasma after a
`Fig. 5—1.
`singte ZOO—mg dose in various oral dosage forms. .# aque-
`ous solution, 0——w aqueous suspension, 0—— capsule
`(sodium salt). Om e etabtet (acid). (Data from Sifigren, J.,
`solve", L, and Karlsson, LS)
`
`This chapter deals with the biopharmaceutic
`characteristics of dosage forms. The first section
`is an overview of the potential effects on absorption
`that may be observed with conventional oral dosage
`forms, including solutions, suspensions, capsules,
`tablets, and coated tablets. Special enteral dosage
`forms, like buccal or sublingual tablets and rectal
`preparations, are discussed in Chapter 6; pro-
`longed-release medication is considered in Chapter
`7. The second section deals with the correlation of
`
`
`
`p. 3
`
`

`

`62
`
`Biopharmaceutics and Clinical Pharmacokinetics
`
`drug absorption in man with in vitro parameters
`such as the disintegration time of the dosage form
`or the dissolution rate of the drug from the dosage
`form.
`
`DOSAGE FORMS
`
`Solutions
`
`The solution dosage form is widely used for
`cough and cold preparations and for many other
`drugs, particularly in pediatric and geriatric pa-
`tients. With rare exception, drugs are absorbed
`more rapidly when given as a solution than in any
`other oral dosage form. The rate-limiting step in
`the absorption of a drug from a solution dosage
`form is likely to be gastric emptying, particularly
`when the drug is given after a meal.
`When an acidic drug is given in solution in the
`form of a salt, there is the possibility of precipi-
`tation in gastric fluid. Experience suggests that
`these precipitates are usually finely subdivided and
`easily redissolved. However, with highly water-
`insoluble drugs,
`like phenytoin or warfarin,
`this
`may not be the case; one may find that the ab
`sorption rate or extent of absorption from a well—
`formulated suspension of the free acid is greater
`than from a solution of the sodium salt.
`
`Many drugs, unless converted to a water-soluble
`salt, are poorly soluble. Solutions of these drugs
`can be prepared by adding cosolvents, such as al- ,
`cohol, propylene glycol, polyethylene glycol 400,
`agents that form water-soluble complexes with the
`drug, or surfactants in sufficient quantity to exceed
`the critical micelle concentration and to effect sol-
`ubilization. After administration of such water-
`
`miscible preparations, dilution with gastrointesti-
`nal fluids may result in precipitation of the drug.
`Again experience suggests that in most cases rapid
`redissolution takes place. Reversible interactions
`that occur between the drug and solubilizing agent
`or other component of the formulation are unlikely
`to affect drug absorption if the interaction product
`is watensoluble.
`
`Serajuddin et al.6 studied the physical properties
`and bioavailability of a poorly water-soluble drug
`dissolved in polyethylene glycol (PEG) 400 or
`polysorbate 80. On dilution of the water—miscible
`solutions with simulated gastric fluid, the drug im-
`mediately formed saturated solutions and the ex»
`cess drug separated as finely divided emulsified
`oily globules with a high surface area. The average
`globule size of the oily form was 1.6 pm or less,
`
`as compared with a particle size of 5 to 10 nm for
`the solid drug,
`Absorption studies in the rat using labeled drug
`resulted in 54% of the radioactivity excreted in the
`urine when the PEG solution was given and 41%
`when the poiysorbate 80 solution was used, but
`only 19% of the radioactivity was found in the urine
`when an aqueous suspension of the drug was ad
`ministered. The large surface area of drug sepa-
`rating from water—miscible solvents on dilution
`with water facilitates its dissolution and absorption.
`Certain materials such as sorbitol or hydrophilic
`polymers are sometimes added to a solution dosage
`form,
`to improve pourability and paiatability by
`increasing the viscosity of the preparation. The
`higher the viscosity of the formulation, the slower
`are gastric emptying and absorption. Such effects,
`however, are unlikely to be clinically important.
`There has been some interest in giving drugs
`dissolved in oil. Rapid and complete absorption
`may be observed in some instances, particularly if
`the oil is administered in emulsified form. Early
`clinical studies with indoxole, a poorly water~sol»
`uble, investigational, nonsteroidal anti—inflamma-
`tory agent, suggested incomplete absorption of the
`drug from a suspension or capsule dosage form.
`Administration of indoxole dissolved in the oil
`
`phase of Lipomul-Oral, a commercially available
`oil-in-water emulsion, resulted in a threefold im-
`
`provement in the extent of absorption compared to
`that observed after administration of an aqueous
`
`suspension and a ninefold improvement compared
`to a hard gelatin capsule.7
`Serajuddin et al.6 found that a solution of a
`poorly water~soluble drug in peanut oil gave nearly
`75% greater bioavaiiability than an aqueous sus—
`pension of the drug when both dosage forms were
`studied in the rat. Bioavailabitity from the water-
`immiscible peanut oil solution, however, was not
`as great as that found when the drug was dissolved
`in PEG 400 or polysorbate 80 to form water-mis-
`cible solutions.
`
`Certain nontoxic but unpalatable solvents may
`be used for solubiiizing drugs if the solution can
`be encapsulated. This approach can, in some cases,
`dramatically improve the absorption of waten
`insoluble drugs. For example,
`the bioavailability
`of indoxoie after administration of a soft elastic
`
`capsule containing the drug dissolved in polysor—
`bate 30 was comparable to that found after admin
`istration of the drug dissolved in the oil phase of
`an oil—in—water emulsion.7
`
`
`
`
`sssssssssssgme.
`
`
`
`
`
`
`
`p. 4
`
`

`

`Gastrointestinal Absorption—Role of the Dosage Form
`
`63
`
`.
`Suspensions
`As a drug delivery system, the wellmformulated
`aqueous suspension is second in efficiencyonly to
`the solution dosage form. Usually, the absorption
`rate of a drug from a suspension is dissolution-rate
`limited; however, drug dissolution from a suspen«
`sion is often rapid because a large surface area is
`presented to the fluids at the absorption site. Drug
`contained in a capsule or tablet may never achieve
`the state of dispersion in the gastrointestinal tract
`that is attained with a finely subdivided, well—for—
`mulated suspension.
`Several studies have demenstrated the superior
`bioavailability characteristics of suspensions com-
`pared to those of solid dosage forms. For example,
`the blood levels of trimethoprim and sulfamethox-
`azole were compared in 24 healthy subjects fol—
`lowing oral administration of 3 forms (tablet, cap-
`sule,
`and suspension) of
`the antibacterial
`combination. The absorption rate of each drug was
`significantly greater with the suspension than with
`the tablet or capsule.a There were no significant
`differences between the preparations in the extent
`of absorption of either drug. Similar results have
`been found with pentobarbital5 and penicillin v.9
`Among the more important factors to consider
`in formulating suspension dosage forms for max-
`imum bioavailability are particle size, inclusion of
`wetting agents, formation of insoluble complexes,
`crystal form, and viscosity. Figure 5-2 compares
`the serum levels of phenytoin after a single 600“
`mg dose in the form of an aqueous suspension
`containing either micronized (Formulation G) or
`conventional (Formulation F) drug. Based on the
`total area under the drug concentration in serum
`versus time curve (AUC), almost twice as much
`phenytoin is absorbed after the micronized suspen~
`sion.‘°
`the
`The higher the viscosity of a suspension,
`slower is the dissolution rate of the drug. The in-
`clusion of methyicellulose in an aqueous suspen-
`sion of nitrofurantoin has been found to impair its
`rate and extent of absorption.“
`Merely shaking some drug powder in an aqueous
`solution of a gum such as acacia neither constitutes
`a well-formulated suspension nor guarantees good
`absorption. This extemporaneous approach to for—
`mulation is sometimes used in screening drugs for
`biologic activity and in the safety assessment of
`promising compounds in laboratory animals. More
`sophisticated methods than these are called for to
`
`mg/l
`‘2
`
`fa
`u
`
`10
`
`
`F =290’: 4o mgxh-cl“
`624303 66 -—ll
`G
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`B
`
`6
`
`4
`2
`
`\
`
`N-
`
`\ \-
`
`\
`
`5
`
`12
`
`24
`
`48
`
`72
`
`9'5
`Tlme
`
`120?)
`
`Phenytoin concentrations (mglt) in serum after
`Fig. 5—2.
`a EGO-mg oral dose in aqueous suspensions containing
`either micronized (G) or conventional (F) drug. The area
`under the serum levelttime curve is noted for each formu-
`lation. (From Neuvonen. P.J., Pentik'alinen. P.J., and
`Elfving, 3M1”)
`
`avoid costly mistakes regarding a drug’s safety or
`efficacy.
`Bioavailability studies with drugs suspended in
`oil-in—water emulsions have yielded some prom-
`ising results. One study compared the absorption
`of micronized gn'seofulvin after its administration
`to healthy subjects in a corn oil~in-water emulsion
`(in which the drug was suspended), an aqueous
`suspension, and two different commercial tablets.12
`Based on cumulative urinary excretion of griseo-
`fulvin metabolites, the extent of absorption of the
`drug after administration of the emulsion was about
`twice that observed after administration of the
`aqueous suspension or tablets. A mechanism based
`on the ability of fatty acids, liberated during the
`digestion of corn oil, to inhibit gastrointestinal mo—
`tility (which would increase the residence time of
`the drug in the small intestine) and to stimulate
`gallbladder evacuation and,
`thereby, elevate the
`concentrations of surface—active bile constituents
`in the intestine (which would promote dissolution
`of the drug) may explain the results.
`
`Capsules
`
`The capsule dosage form has the potential to be
`an efficient drug delivery system. The hard gelatin
`shell encapsulating the formulation should disrupt
`quickly, and expose the contents to the gastroin—
`
`
`
`
`
`twigseufia‘emyu.
`
`mmwma
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`Vixaxnssxsxssssrzsvwvsaauswnwu
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`alrwa'i‘t‘s'zwwbwm:e'zitaikwrzmw:
`
`
`
`p. 5
`
`

`

`64
`
`Biopharmaceutics and Clinical Pharmacokinetics
`
`testinal fluids. However, this will not be the case
`if the formulation or the method of manufacture
`imparts a hydrophobicnature to the shell.
`Drug particles in a capsule are not subjected to
`high compression forces that tend to compact the
`powder and to reduce the effective surface area.
`On disruption of the shell, the encapsulated powder
`mass should disperse rapidly to expose a large sur-
`face area to the gastrointestinal fluids. However,
`with some formulations the rate of dispersion has
`been found to be unacceptably slow. Thus,
`al—
`though one might expect better bioavailability char—
`acteristics of a drug from a capsule than from a
`compressed tablet, this is not always so. For ex—
`ample, tablets and capsules of a combination prod-
`uct containing triamterene and hydrochlorothiazide
`were compared in single—dose studies in normal
`subjects using cumulative urinary excretion of ap—
`parent drug as an index of the extent of absorp~
`tion.13 The capsule was a simple formulation con”
`taining the drugs, lactose, and a small amount of
`magnesium stearate. The tablet was a more com-
`plex formulation that included a large amount of
`glycine, used as a waterasolubie diluent. The ex-
`cretion of hydrochlorothiazide after the tablet was
`twice as much as that found after the capsule. A
`3—fold difference in the cumulative excretion of
`niamterene was observed. The tablets also consist-
`
`ently produced an earlier and a greater peak in-
`crease in sodium excretion.
`
`It is usually necessary to have a suitable diluent
`in a capsule dosage form, particularly when the
`drug is hydrophobic. Figure 5—3 shows the change
`in dissolution rate that can be effected by the in“
`corporation of hydrophilic diluents.14 The diluent
`serves to disperse the drug particles, minimize ag—
`gregation, and maximize the effective surface area
`and dissolution rate. The incorporation of a wetting
`agent in the formulation may also be advantageous.
`Other attempts to modify the wetting character—
`istics of poorly water-soluble drugs have included
`treating the drug with a solution of a hydrophilic
`polymer such as methylcellulose. Phenytoin was
`found to dissolve and be absorbed considerably
`
`faster from capsules containing drug treated with
`methylceilulose compared to capsules containing
`untreated drug.”
`Many pharmacologic and toxicologic studies
`with investigational drugs in dogs and monkeys
`use hand-packed, hard gelatin capsules of the drug
`alone as the delivery system. This practice may
`
` ll
`
`IOO
`90
`80
`TO
`80
`50
`4O
`
`30
`
`20
`
`l0
`
`
`
`PercentUndissolved
`
`
`
`. .__L
`IO
`
`.r._
`20
`
`.__I
`I
`4O
`30
`Time (min.}
`
`\
`I
`50
`
`.. _ 1
`60
`
`encapsulated liquid concentrate of digoxin is con-
`
`Fig. 5—3. Dissolution from hard gelatin capsules contain-
`ing drug alone (0) or drug plus diluents (O). The diluents
`serve to disperse the drug and enhance wetting and dis-
`solution. (Data from Paikoft. M., and Drumm. G94)
`
`lead to erratic and incomplete drug absorption, and
`should be strongly discouraged.
`The diluents of a capsule dosage form should
`have little tendency to adsorb or otherwise interact
`with the drug. The use of dicalcium phosphate as
`a diluent in tetracycline capsules has been found
`to significantly impair absorption, presumably be-
`cause a poorly soluble calcium-tetracycline com~
`. plex is formed in the powder mass or during dis-
`solution.16
`
`Factors that influence drug absorption from cap-
`sule dosage forms include particle size and crystal
`form of the drug, and selection of diluents and
`fillers.
`
`Attempts to improve the oral absorption of di-
`goxin has led to renewed interest in the use of soft
`elastic capsules as a solid oral dosage form. The
`soft elastic capsule has a gelatin shell somewhat
`thicker than that of hard gelatin capsules, but the
`shell is plasticized by the addition of glycerin, sor-
`bitol, or a similar material. Unlike the hard gelatin
`capsule, the soft elastic capsule may contain non—
`aqueous solutions of a drug, or drugs that are liq~
`uids (e.g.,
`the antitussive drug, benzonatate) or
`semisolids (e.g., certain vitamins).
`A formulation consisting of digoxin dissolved in
`a mixture of polyethylene glycol, ethanol, and pro-
`pylene glycol, prepared as a liquid concentrate in
`soft elastic capsules, has been developed and found
`to have good bioavailability characteristics. The
`
`p. 6
`
`

`

`Ei
`
`Gastrointestinal Absorption—410k: of the Dosage Form
`
`65
`
`modifying the physical characteristics of the ma—
`terial itself. For tablets in which the drug consti—
`tutes a major portion of the total tablet weight, the
`drug itself must have the physical attributes (crys-
`tallinity and cohesiveness) needed for the formu—
`lation to be compressed directly. Direct compres-
`sion can almost always be used for tablets
`containing 25% or less of the total weight as drug,
`by formulating with suitable diluents which act as
`a carrier or vehicle for the drug. These diluents
`include processed forms of common tablet mate-
`rials such as dicalcium phosphate dihydrate,
`tri-
`calcium phosphate, calcium sulfate, anhydrous lac-
`tose, and mannitol, as well as spray-dried lactose,
`pregelatinized starch, compressible sugar, and mi-
`crocrystalline cellulose.
`Most bioavailability problems with compressed
`tablets are related to the large reduction in effective
`surface area that results from the tablet manufac-
`turing process, as well as to the difficulty in re-
`generating well-dispersed primary drug particles in
`the gastrointestinal tract. After ingestion, the tablet
`first breaks down to granules and then to primary
`drug particles. Granules resulting from directly
`compressed tablets may be softer and more easily
`wetted than those produced by tablets prepared
`with the wet-granulation process, but it is difficult
`to generalize. The disintegration and dissolution
`processes that take place in the gastrointestinal flu—
`ids after oral administration of a tablet are presented
`in schematic form in Figure 5—4.
`The effective surface area of drug in an intact
`tablet is so limited that lo, the dissolution rate con—
`stant,
`is usually negligible, except for drugs that
`
`B
`A
`intact Tablet ————-—-—-* GranulesM Primary Drug Particles
`
`k1
`
`k2
`
`Drug in Solution in
`Gastrointestinal Fluids
`
`k3
`
`Drug Absorbed
`in Body
`
`Fig. 5—4. Schematic representation of disintegration (A, B) and dissolution (in, kg, k3) processes that precede drug
`absorption after administration of a tablet dosage form. The term ka is a first-order rate constant characterizing drug
`absorption from solution in the fluids of the gastrointestinal tract.
`
`sistently better absorbed than the standard fcom-
`mercial tablet of the drug”?
`A soft elastic capsule containing 0.4 mg of di—
`goxin is about equivalent to a tablet containing 0.5
`mg of the drug. In one study, mean absorption was
`75% of the dose from the tablet and 97% from the
`capsule.18 Surprisingly, some studies‘“-“ but not
`all22 suggest that the bioavailability of digoxin from
`the soft elastic capsule is greater than from an aque-
`ous solution of the drug. The superior bioavail-
`ability of the encapsulated liquid concentrate over
`an aqueous solution may result from less chemical
`breakdown in the stomach when the capsule is
`given. Whatever the mechanism, we can conclude
`that the absorption of digoxin from soft elastic cap-
`sules is clearly better than from conventional tab-
`lets and at least comparable to an aqueous solution
`of the drug.
`
`Tablets
`
`Compressed tablets are the most widely used
`dosage form. They are usually produced by either
`wet granulation or direct compression. Wet gran—
`ulation consists of mixing the drug with other pow—
`dered materials and wetting the mixture with an
`aqueous solution of a suitable binder such as gelatin
`or starch. The damp mass is forced through a 6-
`or 8~mesh screen and dried to produce cohesive
`granules. These granules usually flow easily
`through the tablet press and are easily compressed.
`Increasing attention is being given to manufac-
`turing tablets by direct compression. As its name
`implies, direct compression consists of compress—
`ing tablets directly from powdered material without
`
`
`
`p. 7
`
`

`

` i i
`
`
`
`wen.“
`
`Studies in the United Kingdom have shown that
`when commercial digoxin tabiets, from which the
`drug is incompletely absorbed, are crushed and
`given in a capsule, much higher digoxin levels are
`obtained.25
`
`Tabiet disintegration, although important, is un-
`likely to be the rate-iimiting step in the absorption
`of drugs administered as conventional tablets. In
`most instances, granule disintegration and drug dis~
`solution occur at a slower rate than tablet disinte-
`
`gration.
`Many factors related to the formulation or pro—
`duction of tablets may affect drug dissolution and
`absorption. Most formulations require the incor-
`poration of hydrophobic lubricants, such as mag-
`nesium stearate, to produce an acceptable tablet.
`in general, the larger the quantity of lubricant in a
`formulation, the slower is the dissolution rate.26
`Even seemingly modest changes in formulation
`may lead to significant effects on dissolution and
`availability. A classic example has been reported
`with tolbutamide.27 Two formulations of the drug
`were compared in healthy subjects with respect to
`bioavailability (serum totbutamide levels) and ther—
`apeutic efficacy (hypoglycemic response). One tab-
`let was the commercial product and the other was
`identical in all respects except for a halving of the
`amount of a disintegrant. Both tablets met United
`States Pharmacopeia (USP) specifications. Both
`tablets disintegrated in vitro within 10 min.
`Despite the similar specifications,
`the experi—
`mental formulation was inferior to the commercial
`product. The area under the average serum tolbu~
`tamide curve over an 8«hr observation period was
`more than 3 times greater with the commercial
`product than with the experimental formulation.
`The average cumulative reduction of serum glucose
`over the 8—hr period after administration of the
`commerciai tablet was twice that after administra
`tion of the experimental tablet (Fig. 5W6).
`Compression force may also be an important
`factor in drug bioavailability from compressed tab-
`lets. The in vitro disintegration time of tablets has
`been shown to be directly proportional
`to com—
`pression force and tablet hardness.“ High com
`pression forces may also increase the strength of
`the internal structure of the granules and retard
`dissoiution of drug from the granules and disinte—
`gration of the granules.
`The effect of particle size reduction on disso—
`lution and absorption may be reduced by com
`pression.29 Studies in man showed that a 33-fold
`
`Fig. 5—5. Dipyridamole concentrations in serum of indi-
`vidual subiects after a 25-mg oral dose as intact tablets (A)
`or crushed tablets (B). When the tablets are chewed before
`swallowing, the peak concentration tends to be higher and
`the peak time tends to be earlier. (Data from Mellinger, T.J ..
`and Bohorfoush, J.G.23)
`
`'L
`
`are extremely water~soluble. Tabiet disintegration
`(step A) greatly increases the effective surface area
`of the drug. A further increase in surface area is
`attained upon granule disintegration; accordingiy,
`it, >> k2 >> kl. The dissolution rate from the
`granules may be likened to that observed with a
`coarse, aggregated drug suspension, whereas the
`dissolution rate from the primary particles is prob-
`abiy comparable to that observed with a fine, welt-
`dispersed drug suspension. Poorly water—soluble
`drugs are likely to dissolve mainiy after granule
`disintegration.
`Tablet disintegration and granule disintegration
`are important steps in the absorption process. A
`tablet
`that fails to disintegrate 0r disintegrates
`slowly may result in incomplete absorption or an
`undue delay in the onset of clinical response. The
`importance of disintegration in drug absorption is
`evident from the results of clinical studies with
`dipyridamole.23 Curves of serum concentrations of
`dipyridamole versus time after administration are
`shown in Figure SAS. When the tablets were taken
`intact, the appearance of drug in blood was delayed
`and variable. When the tablets were chewed before
`swallowing, the drug appeared in the blood within
`5 or 6 min. In every patient, the peak drug con-
`centration was higher after the crushed tablet than
`after swallowing. the intact tablet. Similar results
`have been observed with thioridazine tablets.24
`
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`66
`
`Biopharmaceutics and Clinical Pharmacokinetics
`
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`‘c
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`F3 u:
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`bin
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`DIPYRIDAMOLECONCENTRATION.ng/ml 0 0|
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`TEME, hr
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`p. 8
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` process in drug absorption, since correlations have
`
`Gastrointestinal Absorption—Role of the Dosage Form
`
`67
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`:1) 0| GLUCOSE
`CONCENTRATION,mg/dl
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`TIME, hr
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`Fig. 5—6. Serum glucose levels after 0.5g tolbutamide
`in a commercial
`tablet (0} or an experimental
`tablet
`containing less disintegrating agent
`(0).
`(Data from
`Varley, A.B.27l
`
`increase in the specific surface area of griseofulvin
`led to a 23-fold increase in blood concentration
`after administration of a suspension, but only a 1.5—
`fold increase after administration of a tablet.
`A novel approach to enhance the availability of
`poorly water-soluble drugs from tablets has been
`used in a marketed griseofulvin product.30 A mo-
`lecular dispersion of the drug in polyethylene gly-
`col 6000, a water-soluble, waxy polymer that con-
`geals at about 60°C,
`is prepared and suitably
`modified for incorporation into a tablet dosage
`form. The absorption of griseofulvin from this
`product appears to be complete and about twice
`that observed from commercial tablets containing
`micronized drug.
`
`Coated Tablets
`
`Tablet coatings are used to mask unpleasant
`tastes and odors, to protect an ingredient from de-
`composition during storage, or simply to improve
`the appearance of a tablet. The most common
`coated medications are sugar-coated and film-
`coated tablets. Not only do these dosage forms
`present all the potential problems discussed earlier
`with respect to compressed tablets, but they also
`impose an additional barrier between the gastro-
`intestinal fluid and the drug. The coating rnust dis-
`solve or disrupt before tablet disintegration and
`drug dissolution can occur. The disintegration of
`certain coated tablets appears to be the rate-limiting
`
`been found between bioavailability and in vitro
`disintegration time.
`The venerable sugarwcoated tablet is still used
`today. The sugar coating formulation is complex;
`the coating process is time consuming and requires
`skill. The first step of the process is the application
`of a nonaqueous, sealing solution to protect the
`tablet and its ingredients from the aqueous solu»
`tions used in subsequent steps. A special grade
`shellac dissolved in alcohol is commonly used to
`seal tablets. Other materials that have been used
`
`include fatty glycerides, beeswax, and silicone res-
`ins. The other steps of the coating process add bulk
`and modify the shape of the tablets; Other ingre-
`dients of the coating formulation may include talc,
`acacia, flour, starch, and calcium carbonate, in ad-
`dition to sucrose.
`
`The application of the sealing coat and the de-
`velopment of a relatively dense crystalline barrier
`around the tablet retard the release of drug in the
`gastrointestinal tract. In general, we must assume
`that a sugar coating may affect the bioavailability
`of a drug. This dosage form should not be used
`when a prompt clinical response is desired.
`The basic disadvantages of sugar coating have
`stimulated a search for alternatives. These alter—
`
`natives include the film—coated tablet and the press-
`coated tablet. Film-coated tablets are compressed
`tablets that are coated with a thin layer or film of
`a material that is usually water soluble or dispers-
`ible. A number of polymeric substances with film-
`forming properties may be used including
`hydroxypropyl methyicellulose and carboxymeth-
`ylcellulose. Aqueous vehicles are preferred but a
`nonaqueous vehicle may be used when moisture is
`detrimental to the product being coated. A mixture
`of cellulose acetate phthalate and polyethylene gly~
`col can be applied from aqueous or nonaqueous
`solvents. Care should be taken when selecting coat«
`ing materials. Methylcellulose, for example, has
`been reported to retard drug dissolution.31
`The film coat masks objectionable tastes and pro-
`tects, to some degree, tablet ingredients from mois-
`ture during storage. The film coat should disrupt
`quickly in the fluids of the gastrointestinal tract,
`independent of pH. A wellnformulated product
`should show little difference in bioavailability com-
`
`pared with that of an uncoated tablet.
`Press-coated or dry-coated tablets are prepared
`by feeding previously compressed tablets into a
`special tableting machine and compressing another
`
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`p. 9
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`68
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`Biopharmaceutics and Clinical Pharmacokinetics
`
`granulation layer around the preformed tablet.
`Press—coated tablets appear to retain all the attrib-
`utes of compressed tablets bull-provide the advan-
`tages of sugar—coated tablets. Ideally, there should
`be little difference in disintegration time between
`press-coated and uncoated tablets.
`
`-
`
`Enteric-Caated Tablets
`
`An enteric coat is usually a special film coat
`designed to resist gastric fluids and to disrupt or
`dissolve in the small intestine. The enteric coat is
`used to protect a drug from degrading in the stom—
`ach (e.g., erythromycin), or to minimize gastric
`distress caused by some drugs (e.g., aspirin). En-
`teric-coated tablets must empty from the stomach
`before drug absorption can begin. The rate of ap-
`pearance of drug in the blood after giving an en-
`teric-coated tablet is, therefore, a function of gas—
`tric emptying. Differences in gastric emptying from
`one patient to another or in the same patient from
`one administration to another contribute to the large
`variability in drug absorption commonly found
`with this dosage form.
`The time course of an enteric coated aspirin tab-
`let from the stomach to the small intestine was
`monitored in dogs using radiotelemetry.32 A 500—
`mg enteric coated tablet was attached to a Heidel-
`berg capsule calibrated to pH 1 and pH 7. Gastric
`pH was about 1.5. As the tablet was emptied into
`the small intestine, the monitored pH rose to about
`7. This time interval was termed the gastric emp-
`tying time. The pH in the small intestine remained
`relatively constant until
`the enteric coating dis—
`solved and aspirin was released. At this time, the
`monitored pH dropped to about 3.8, close to the
`pKa of aspirin. This time interval was defined as
`the coating dissolution time.
`As a result of carrying out four replicates in each
`of 4 dogs both inter— and intrasubject variability
`could be evaluated. In 1 dog the gastric emptying
`time ranged from 7 to 40 min and in another from
`8 to 115 min. Mean gastric emptying times varied
`