The Theory
`
`and Practice of Industrial
`
`Pharmacy
`
`LEON LACHMAN, Ph.D.
`Lachman Consultant Services, Inc.
`Garden City, New York‘
`
`HERBERT A. LIEBERMAN, Ph.D.
`H. H. Lieberman Associates, Inc.
`Consultant Services
`
`Livingston, New Jersey
`
`JOSEPH L. KANIG, Ph.D.
`Kanig Consulting and Research Associates, Inc.»
`Ridgefield, Connecticut
`
`THIRD EDITION
`
`INDIAN EDITION
`
`VARGHESE PUBLISHING HOUSE
`
`asthan’ Building
`Hind
`DadarhBombay
`014
`1987 l
`
`I
`
`Astrazeneca Ex. 2134 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01326
`
`

`
`Lea 8: Fehiger
`600 Washington Square
`Philadelphia, PA 1910.6-4198
`U.S.A.
`
`(215) 922-1330
`
`Library of Congress Cataloging in Publication‘ Data
`Main entry under title:
`
`The Theory and practice of industrial pharmacy.
`
`Includes bibliographies and index.
`I. Laehman, Leon,
`1. Pharmacy.
`2. Drug trade.
`1929——
`II. Lieberman, Herbert A_., 1920.-
`III. Kanig. Joseph L., 1921 —
`[DNLM:,_1. Drug
`Industry.
`QV 704 T396]
`RSI92.L33 1985
`ISBN 0-8121-0977-5
`
`84-27806
`
`619.19
`
`First Edition, 1970
`Second Edition, 1976
`
`Copyright .© 1986 by" Lea 8: Fehiger. Copyrighpunder the
`International Copyright Union. All Rights Resenied. This book is
`protected by copyright. No part of it may béreproduced in any
`manner or by any means without written permission from the
`publisher.
`
`FIRST INDIAN RBPRINT, 1987
`SECOND INDIAN REPRINT, 1989
`THIRD INDIAN REPRINT, 1990
`FOURTH INDIAN REPRINT,'1991
`
`Reprinted in India by special arrangement with LEA & FEBIGER
`Philadelphia U SA.
`
`Indian Edition published by
`
`Varghese Publishing House, Hind Rajasthan Building, Dadar,
`Bombay 400-014.
`
`Reprinted by Akshar Pratiroop Pvt Ltd, Bombay 400 031
`
`Astrazeneca Ex. 2134 p. 2
`
`

`
`
`
`Contents
`
`Section I.
`
`Piinciples of Pharmaceutical Processing
`1.
`
`3
`Mixing
`EDWARD G. RIPPIE
`
`2.
`
`3.
`
`21
`Milling
`EUGENE L. PARROT .
`
`47
`Drying
`ALBERT s. RANKELL, HERBERT A. LIEBERMAN, ROBERT F. SCHIFFMANN
`Compression and Consolidation of Powdered Solids
`66
`KEITH MARSHALL
`
`rinciples [Related to Emulsion and Suspension
`. Basic “Chemical”
`100
`Dosage Forms
`.
`STANLEY L. HEM, JOSEPH R. FELDKAMP, JOE L. WHITE
`. Pharmaceutical Rheology
`123
`JOHN H. WOOD
`A
`
`. Clarification and Filtratioiy
`‘s. C-I-I_R.AI
`
`146
`
`Section II. Pharmaceutical Dosage Form Design
`Preformulation
`171
`EUGENE F. FIESE, TIMOTHYA. HAGEN
`Biopharmaceutics _
`197
`1<.c= KWAN, M.R. DOBRINSKA, J.D. ROGERS, A.E. TILL, K.C. YEH
`Statistical Applications in the Pharmaceutical "Sciences
`SANFORD BOLTON
`
`10.
`
`9.
`
`Section III. Pharmaceutical Dosage Forms
`11. Tablets
`
`293
`
`GILBERT S. BANKER, NEIL R. ANDERSON
`
`12.
`
`346
`Tablet Coating
`JAMES A. SEITZ, SHASHI P. MEHTA, JAMES L. YEAGER
`
`243
`
`ix
`
`Astrazeneca Ex. 2134 p. 3
`
`

`
`A
`374
`13. Capsules
`Part One Hard Capsules
`VAN B. HOSTETLER
`Part Two Soft Gelatin ‘Capsules
`1.19. STANLEY
`
`I
`V 374
`
`‘Part Three Microencapsulation
`,].A. BAKAN
`
`14. Sustained Release Dosage Forms
`‘ NICHOLAS C. LORDI
`15.’ Liquids
`457
`J .C. BOYLAN
`
`398
`
`412
`
`430
`
`479
`16/Pharmaceutical Suspensions
`N-ACIN K. PATEL, LLOYD KENNoN*, R. SAUL LEVIN-SON
`17 502
`MARTIN M. RIEGER
`
`18/ Semisolids
`
`534
`
`BERNARD IDSON, JACK LAzARUs’°‘
`19. Suppositories
`564
`'
`LARRY J. COBEN, HERBERT A. LIEBERMAN
`Pharmaceutical Aerosols
`589
`
`JOHN J. SCIARRA, ANTHONY J. CUTIE
`Sterilization
`619.
`P
`KENNETIH E. AVIS, MICHAEL J{A1_<ERs
`22. Sterile Products
`639
`'
`KENNETH E. AVIS
`
`__
`
`Section IV. Product Processing, Packaging, Evaluation, ancl
`Regulations
`-
`-
`
`23? Pilot Plant Scale-Up Techniques
`SAMUEL HARDER, GLENN VAN BUSKIRK
`24? Packaging Materials Science
`711
`CARLO P. CROCE, ARTHUR FISCHER, RALPH H. THOMAS
`
`681
`
`733
`
`25.’ Production Management
`_1.v. BATTISTA
`,
`760’
`26. ‘Kinetic Principles and Stability Testing
`I LEON LACHMAN, ‘PATRICK DELUCA, MICHAEL J. AKERS
`27. Quality Control and -Assurance
`‘ 804
`LEON LACHMAN, SAMIR A. HANNA, KARL LIN
`28. Drug Regulatory Affairs
`856
`WILLIAM R. PENDERGAST, RAYMOND D. MCMURRAY*
`
`INDEX
`
`883
`
`" Deceased.
`
`x 0 Contents
`
`Astrazeneca Ex. 2134 p. 4
`
`

`
`
`
`14
`
`Sustained Release
`Dosage Forms
`
`NICHOLAS G. LORDI
`
`With many drugs, the basic goal of therapy is to
`achieve a steady-state blood or tissue level that is
`therapeutically effective and nontoxic for an ex— _
`tended period of time. The design of proper dos‘-
`age regimens is an important element in accom-
`plishing this goal. A basic objective in dosage
`form design is to optimize the delivery of medi-
`cation so as to achieve a measure of control of
`the therapeutic efiect in the face of uncertain
`,fluctuations in the in, vivo environment
`in
`which drug _r_elease.takes place. This is usually
`accomplished by maximizing drug availability,
`i.e., by attempting to attain a maximum rate and
`extent of drug absorption; however, control of
`drug action through formulation also implies
`controlling bioavailability to reduce drug absorp-
`tion rates. In this chapter, approaches to the for-
`mulation of drug delivery systems, based on the
`deliberate control of drug availability, are consid-
`ered with emphasis on peroral dosage forms.
`
`The Sustained Release Concept
`Sustained release, sustained action, prolonged
`action, controlled release, extended action,
`timed release, depot, and repository dosage
`forms are terms used to identify drug delivery
`systems that are designed to achieve a prolonged
`therapeutic effect by continuously releasing
`medication over an extended period of time after
`administration of a single dose. In the case of
`injectable dosage forms, this period may vary
`from days to months. In the case of orally ad-
`ministered forms, however, this period is meas-
`ured in hours and critically depends on the resi-
`dence
`time of
`the dosage ,form in the
`gastrointestinal (GI) tract. The term “controlled
`release” has become associated with those sys-
`tems from which therapeutic agents may be au-
`tomatically delivered at predefined rates over a
`long period of time. Products of this type have
`
`been formulated for oral, injectable, and topical
`use, and include inserts for placement in body
`cavities as well.‘
`The phaimaceuticalindustry provides a vari-
`ety of dosage forms and dosage levels of particu-
`lar drugs, thus enabling the physician to control
`the onset and duration of drug therapy by alter-
`ing the dose and/or mode of administration. In
`some instances, control of drug therapy can be
`achieved by taking advantage of beneficial drug
`interactions that affect drug disposition and
`elimination, e.g,, the action of probenicid, which
`inhibits the excretion of penicillin, thus prolong-
`ingits blood level. Mixtures of drugs might be
`utilized to potentiate, synergize, or antagonize
`given drug actions. Alternately, drug mixtures
`might be formulated in which the ratepand/or
`extent of drug‘ absorption is modified. Sustained
`release dosage form design embodies this ap-
`proach to the control of drug action, i.e., through
`a process of either drug modification or dosage
`form modification, the absorption process, and
`subsequently drug action, can be controlled.
`Physicians can achieve several desirable ther-
`apeutic advantages by prescribing sustained re-
`lease forms-. Since the frequency of drug admin-
`istration is reduced, patient compliance can be
`improved, and drug administration can be made
`more convenient as well. The blood level oscilla-
`tion characteristic of multiple dosing of"conven-
`tional dosage forms is reduced, because a more
`even blood level is maintained. A less obvious
`advantage, implicit in the design of sustained
`release forms, is that the total amount of drug
`administered can be reduced, ‘thus maximizing"
`availability with a minimum dose. In addition,
`better control of drug absorption can be attained,
`since the high blood level peaks’ that may be ob-
`served after administration of a dose of a high-
`availability drug can be reduced by formulation
`in an extended action form. The safety margin of
`
`430
`
`Astrazeneca Ex. 2134 p. 5
`
`

`
`..
`
`‘high-potency drugs can be increased, and the
`incidence of both local and systemic adverse
`side effects can be reduced in sensitive patients.
`Overall, administration of sustained release
`forms enables increased reliability of therapy?
`In evaluating drugs as candidates for sus-
`tained release formulation, the disadvantages of
`such formulations that must be considered in-
`clude the following: (1) Administration of sus-
`tained release medication does not permit the
`prompt
`termination of
`therapy.
`Immediate
`-changes in drug need during therapy, such as
`might be encountered if significant adverse ef-
`‘ fects are noted, cannot be accommodated.
`(2) The physician has less flexibility in adjust-
`ing dosage regimens. This is fixed by the dosage
`form design. (3) Sustained release forms are
`designed for the normal population, i.e., on the
`basis of average drug biologic half-lives. Conse-
`quently, disease states that alter drug disposi-
`tion, significant patient variation, and so forth
`are not accommodated. (4) Economic factors
`must also be assessed, since more costly proc-
`esses and equipment are involved ‘in manufac-
`turing many sustained release forms.
`Not all drugs are suitable candidates for for-
`mulation as prolonged action medication. Table
`14-1 lists
`specific drug characteristics that
`- would preclude formulation in peroral sustained
`release forms. Drugs with long biologic half—lives
`(e.g., digoxin—34 hours) are inherently long-
`acting and thus are viewed as questionable can-
`
`TABLE 14-1. Characteristics of Drugs Unsuita-
`ble for Peroral Sustained ReleaseVForms
`
`Characteristics
`
`Drugs
`
`Not effectively absorbed in
`the lower intestine.
`
`‘
`
`Riboflavin, ferrous salts
`
`Absorbed and excreted rap-
`idly; short biologic half- .
`lives (<1 hr).
`
`Long biologic half-lives
`(>12 hr).
`
`Large doses required
`(>1 g).
`Cumulative action and
`undesirable side effects;
`drugs with low therapeutic
`indices.
`
`Penicillin G, furosemide
`
`Diazepam, phenytoin
`
`Sulfonamides
`
`V Phenobarbital, digitoxin
`
`' Precise dosage titrated to
`individual is required.
`
`Anticoagulants, cardiac
`glycosides
`
`No clear advantage for sus-
`tained release fonnulation.
`
`Griseofulvin
`
`didates for sustained release formulation._ For
`801116 drugs in this group, however, a properly
`designed sustained release formulation may be
`advantageous. Because single doses capable of
`producing equally prolonged effects often yield
`significant concentration peaks
`immediately
`after each dosing interval, control of drug release
`may be indicated if toxicity or local gastric irrita-.
`tion is a hazard. Drugs with narrow require-
`ments for absorption (e.g., drugs dependent on
`position in the GI tract for optimum absorption)
`are also poor candidates for oral sustained re-
`lease formulation, since absorption must occur
`throughout the length of the gut. Very insoluble
`drugs whose availability is controlled by dissolu-
`tion (e.g., griseofulvin) may not benefit from for-
`mulation in sustained release forms since the
`amount of drug available for absorption is lim-
`ited by the poor solubility of the compound.
`Before proceeding with the design of a sus-
`tained release form of an appropriate drug, the
`formulator should have an understanding of the.
`pharmacokinetics of the candidate, should be
`assured that pharmacologic effect can be corre-
`lated with drug blood levels, and should be
`knowledgeable about
`the therapeutic dosage
`range,
`including the minimum effective and
`maximum safe doses.
`
`_
`
`_
`
`-.
`
`Theory
`
`Design
`To establish a procedure for designing sus-
`tained release dosage forms, it is useful to exam-
`ine the properties of drug blood-level-time pro-
`files characteristic of multiple dosing therapy of
`immediate release forms. Figure 14-] shows
`typical profiles observed after administration of
`equal doses of a drug using differentl dosage
`schedules: every 8 hours (curve A), every, 3
`hours (curve B), and every 2 hours (curve C). As
`the dosage interval is shortened, the number of
`doses required to attain a steady-state drug level
`increases, the amplitude of the drug level oscil-
`lations diminishes, and the steady state average
`blood level is increased. As a first approximation,
`the optimum dosage interval can be taken to be »
`equal to the biologic half-life, in this case, 3
`hours. Curve D represents ‘a profile in which
`the first or loading dose is made twice that of
`all subsequent doses administered,
`i.e.,
`the
`maintenance doses. This dosing regimen allows
`the relation between the loading (Di) and main-
`tenance (Dm) doses to be determined as follows:
`
`Di = Dm(1 — 'exp(—o.s93r/_t,))
`
`SUSTAINED RELEASE DOSAGE FORMS - 431
`
`Astrazeneca Ex. 2134 p. 6
`
`

`
`\"
`
`V
`
`A /
`
`4
`
`.4
`u:
`
`>i
`
`n
`..n
`
`in
`
`OO.
`
`..|
`In
`
`5
`
`1o
`TIME (HOURS)
`FIG. 14-1. Multiple patterns of dosage that characterize nonsustained peroral administration of a drug with a biologic
`half-life of3 hr and a half-life for absorption of20 min. Dosage intervals are: A, 8 hr; 3, 3 hr; C, 2 hr; and D, 3 hr (loading
`dose is twice the maintenance dose). E, Constant rate intravenous infusion.
`‘
`
`15
`
`‘
`
`20
`
`where 1- is the dosing interval and t; is the bio-
`logic half-life. If ti = 7, D1 = 2Dm. Selection of
`the proper dose and dosage interval is a prereq-
`uisite to obtaining a drug level pattern that will
`remain in the therapeutic range.
`Elimination of drug level oscillations can be
`achieved by administration of drug through con-
`stant-rate intravenous infusion. Curve E in Fig-
`ure 14-1 represents an example whereby the in-
`fusion rate was chosen to achieve the same
`average drug level as a 3-hour dosage interval
`for the specific case illustrated. The objective in
`formulating a sustained release dosage forrnis to
`be able to provide a similar blood level pattern
`for up to 12 hours after oral administration of the
`drug.
`To design an efficacious sustained release .
`dosage fonn, one must have a thorough knowl-
`edge of the pharmacokinetics of the drug chosen
`for this formulation. Figure 14-2 shows a gen-
`eral pharmacokinetic model of an ideal sus-
`tained release dosage form. For the purposes of
`this discussion, measurements of drug blood
`level are assumed to correlate with therapeutic
`effect and drug kinetics are assumed to be ade-
`
`quately approximated by a one-body-compart-
`ment model. That is, drug distribution is suffi-
`ciently rapid so
`that
`a
`steady
`state
`is
`immediately attained between the central and
`peripheral compartments, i.e., the blood-tissue
`transfer rate constants, km and k2,, are large.
`Under the foregoing circumstances, the drug
`kinetics can be characterized by three parame-
`ters: the elimination rate constant (ke) or bio-
`logic half-life (Q = 0.693/ke), the absorption rate
`constant (ka), and the apparent distribution vol-
`ume (Vd), which defines the apparent body
`space in which drug is distributed. A large Vd
`value (e.g., y 100 L) means that drug is exten-
`sively distributed into extravascular space: a
`small Vd value (e.g., 10 L) means that drug is
`largely confined to the plasma. It is best inter-
`preted as a proportionality factor which when
`multiplied by the blood level gives the -total
`amount of drug in the body. For the two-body-
`compartment representation of drug kinetics, Vc
`is the volume of the central compartment, in-
`cluding both blood and any body water in which
`drug is rapidly perfused.
`A diagrammatic representation of a dosage
`
`432 - The Theory and Practice of Industrial Pharmacy
`
`Astrazeneca Ex. 2134 p. 7
`
`

`
`DOSAGE
`FORM
`
`ABSORPTION SITE
`
`PERIPHERAL
`
`"TISSUE"
`
`CENTRAL
`
`"BLOOD"
`
`FIG. 14-2. A general pharmacokinetic model of an ideal peroral sustained release dosage form.
`
`BODY
`
`COMPARTMENT
`
`form, which identifies the specific parameters
`that must be taken into account in optimizing
`sustained release dosage form designs, is shown
`in Figure 14-2 at the absorption site. These‘are
`the loading or immediately available portion of
`the dose (Di), the maintenance or slowly avail-
`able portion of the dose (Dm), the time (Tm) at
`which release of maintenance dose begins (i.e.,
`the delay time between release of D1 and Dm),
`and the specific rate of release (kr) of the main-
`tenance dose.
`Figure 14-3 shows the fonn of the body drug-
`level time profile that characterizes an ideal per-
`oral sustained release dosage form after a single
`administration. Tp is the peak time, and h is the
`total time after administration in which the drug
`is effectively absorbed. Cp is the average drug
`level to be maintained constantly for a period of
`time equal to (h — Tp) hours; it is also the peak
`blood level observed after administration of a
`loading dose. The portion of the area under the
`blood level curve contributed by the loading and
`maintenance doses is indicated on the diagram.
`To obtain a constant drug level, the rate of drug
`absorption must be made equal to its .rate of
`elimination. Consequently, drug must be pro-
`vided by the dosage form at a-rate such that the
`drug concentration becomes constant at the ab-
`sorption site.
`_
`Detailed theoretic treatments of a number of
`sustained release dosage form designs have
`been reported. These include systems in which
`
`drug is released for absorption by zero-order and
`first-order processes with and without loading
`doses. In the fonnercase, designs based on both
`immediate _and delayed release of maintenance
`dose have been described. The following general
`assumptions have been made in developing
`these designs: (1) Drug disposition can be de-
`scribed by a one-compartment open model.
`(2) Absorption is
`first-order and complete.
`(3) Release of drug from the dosage form, not
`absorption, is rate-determining, i.e., the effect of
`variation in absorption rate is minimized (ka >
`ke).
`
`Zero-Order Release
`
`Approximation
`The profile shown in Figure 14-3 can most
`nearly be approximated by a design consisting of
`a loading dose and a zero-order release mainte-
`nance dose, as described by Robinson and Erik-
`sen.3 If a zero-order release characteristic can be
`implemented in a practical formulation, the re-
`lease process becomes independent of the mag-
`nitude of the maintenance dose and does not
`change during the efiective maintenance pe-
`riod. Table 14-2 lists the expressions that can be
`used to estimate the design parameters for an
`optimized zero-order model, for both simultane-
`ous and delayed release of maintenance dose.
`Their application is illustrated using procaine-
`
`'
`
`SUSTAINED RELEASE DOSAGE FORMS - 4\33
`
`Astrazeneca Ex. 2134 p. 8
`
`

`
`
`
` BLOQDLEVEL
`DOSE
`
`LOADING \
`
`
`Tn
`
`TIME
`
`FIG. 14-3. A blood-level time profile for an ideal peroral sustainedrrelease dosage form.
`
`mide, an important antiarrhythmic agent, as an
`example.
`-
`Table 14-3 lists the pharmacokinetic parame-
`ters characterizing the disposition of procaine-
`mide, which is described by a two-body-
`compartment open model, in an average patient
`based on data reported by Manion et al. for 11
`subjects.4 Conventional fonnulations are admin-
`istered every 3 hours for maintenance of ther-
`apy, resulting in a maximum-to-minimum blood-
`
`level ratio >2 "at the steady state. Sustained re-
`lease formulations have been shown to have
`advantages as an alternate dosage form. A com-
`parison is -made between estimates based on
`three cases: (1) the one-compartment model as-
`sumption with delayed release of maintenance
`dose, (2) the actual two-compartment fit of pro-
`cainamide pharmacokinetic data‘ with delayed
`release of maintenance dose, and (3) the two-
`compartment model with simultaneous release
`
`TABLE 14-2. Expressions Useful for Estimation of Design Parameters for Zero-Order Sustained
`Release Dosage Form Models
`
`
`
` Parameter Equation
`
`‘\
`
`Maximum body drug content
`to be maintained
`
`Zero-order rate constant
`
`Peak time
`Bioavailability factor
`
`_
`
`Fraction of dose (Di) at '
`peak (F = 1)
`Maintenance dose
`
`Am = CpVd
`
`kro = keAm
`
`Tp = (2.3/(ka f ke))log(ka/ke)
`F = (AUC)ora.l/(AUC)iv
`
`J
`
`1, = (_1_<§_) ke':"ka
`ke
`Dm = kro(h - Tm)/F
`
`Eq. (1)
`
`Eq. (2)
`
`Eq. (3)
`Eq. (4)
`
`Eq. (5)
`Eq. (6)
`
`Loading dose (Tm = Tp)
`Di = Am/fF
`Eq. (7)
`
`Loading dose (rm =’ 0) Eq. (s) Di = (Di — kroTp)
`
`
`434 - The Theory and Practice of/Industrial Pharmacy
`
`Astrazeneca Ex. 2134 p. 9
`
`MAXIMUM SAFE LEVEL
`
` \
`
`
`MAINTENANCE
` DOSE
`
`
`\
`
`

`
`TABLE 14-3. Pharmacokinetio Parameters for: _
`Procainamide in an Average" ‘Subject (Weight:
`
`75 kg) ' ‘
`
`
`Parameter
`
`. Value
`
`Parameter
`
`Value
`
`3.15 hr
`km 7
`0.21 hr
`[3
`1.4 hr
`kg]
`3.4 hr
`ll;
`'59 L
`Vc
`0.97 hr
`ke
`205 ‘L
`Vd
`2.0 hr
`ka
`
`
`0.83F 0.5 hr Tp
`
`
`From Manion, C.-V., et al., J . Pharm. Sci., 66:98], 1977. He-
`produced with permission of the copyright owner, the American
`Pharmaceutical Association.
`
`_
`
`of loading and maintenance doses. In all cases,
`the blood level is assumed to be maintained at
`1 pg/ml for 8 hours, i.e., Cp = 1 mg/L, and h —
`Tp = 8.‘Table 14-4 summarizes the results of
`the calculation of sustained release design pa-
`rameters for procainamide, assuming zero-order
`release kinetics. The following steps are re-
`quired to estimate the design parameters listed
`in the table. (Equation numbers refer to equa-
`tions in Table 14-2.)
`1. Estimation of kro. Equation (2) is derived
`by considering that at the steady state the rate of
`absorption is constant and equal to the rate of
`elimination,
`that
`is: Rate Absorption = ka -
`Xa = Rate Elimination = ke - Xb where Xa is
`the amount of drug at the absorption site, and
`Xb is the body drug content, which is set equal
`to Vd - Cp, or Am in equation (1), the body drug
`content to be maintained constant. If absorption
`of the loading dose is effectively complete,
`kaXa = kro. For case 1 in Table 14-4, ke = 0.21
`(the beta disposition constant), since the bio-
`logic half-life is estimated from the terminal’ part
`of the blood level curve if a one-compartrnent
`model is used to approximate blood level data.
`For cases 2 and 3, ke = 0.97. The apparent vol-
`ume of the central compartment, Vc, rather than
`
`TABLE 14-4. Estimated Sugainéd Release Design
`Parameters
`for -Pr/o/caiertamide
`(Cp = 1 pg/ml,
`
`/h =-Tmf=/shame) -
`
` Parameter «’ , Case 1 Case 2 Case 3
`
`
`
`7
`
`"
`
`‘
`'
`
`59
`59‘
`(205
`Am (mg):’‘’
`57
`57
`43
`kro (mg/hr)" ’
`0
`0.5
`1.2
`Tm
`'
`549
`549
`414
`’ _D_m (mg)
`0.274
`0.274
`0.768
`f
`(Di) 224
`259
`322
`N
`Di (mg)
`2.45
`2.12
`1.28
`Dm/Di
`
`Dm + Di (mg) 773 736 808
`
`
`
`Vd, is used to calculate Am for the two-compart-
`ment model, i.e., Am = CpVc. For example:
`
`Case 1:
`_.
`
`-
`
`kro = 0.21 X 1 X 205
`= 43 mg/hr
`
`Cases 2 and 3: no = 0.97 x 1 x 59
`= 57 mg/hr
`
`2. Estimation ofTm. Release of maintenance
`dose is set at the peak time for the loading dose
`(cases 1 and 2). Equation (3) is used to calculate
`the peak time from known value absorption
`(2 hr”) and elimination (0.21 hr“) rate con-
`stants. Since equation (3) applies only to the
`one-compartment model, Tm, which is actually
`0.5 hours,
`is significantly overestimated. For
`example:
`‘
`
`Case 1:Tm=Tp(Eq.3)=
`= 1.2 hr
`
`2.3 X log(2/0.21)
`2_021
`
`Case 2: Tm = Tp (actual value) = 0.5 hr
`
`Case 3: Tm_= 0
`‘
`
`l
`
`3. Estimation of Dm. The maintenance dose
`is estimated as the product of release rate and
`maintenance time (equation 6), corrected for the
`bioavailabflity factor,\E (equation 4), which is
`the fraction of the administered dose absorbed
`from a reference nonsustained release dosage
`form. The F-value is estimated _as the ratio of the
`area under the plasma level curve (AUC-val 'e)
`measured after oral administration to the P7 C-
`value observed after intravenous adrniriistratih
`_,
`of the same dose of drug. In the example,/‘F /<7‘
`since procainamide is subject to the first-pa/ss.
`effect, in which a small portion of the absorbed
`dose is metabolized in the liver. Dm is also ‘a’
`function of the loading dose and an inverse
`functionaof the biological half—lJ'fe, i.e., Dm :
`0.693f(h - Tm) Di/t,, a relation obtained by
`combining equations (2), (6), and (7). Practi-
`cally, h is not likely to exceed 10 to ~12.hours,
`depending on the residence time in the small
`intestine. For drugs that are not efficiently ab-
`sorbed in the stomach, such as procainamide,
`the gastric emptying rate is an uncertain varia-
`ble that contributes to Tm. Forexample:
`
`7
`
`Case 1: Dm = 43 X 8/0.83 = 414 mg
`
`Cases 2 and 3: Dm = 57 X 8/0.83 = 549 mg
`
`Significant increases in dose size are required
`for drugs with short biologic. half-lives, e.g., Dm
`
`SUSTAINED RELEASE DOSAGE FORMS - 435
`
`Astrazeneca Ex. 2134 p. 10
`
`

`
`is doubled if the biologic half—life is halved. For
`case 1, ‘Dm would be 228 mg for Q = 6 hr,
`-456 mg for Q = 3 hr, and 685 mg for t; = 2 hr.
`4. Estimation of D1. The loading dose is that
`portion of the total dose that is initially released
`as a bolus and is therefore immediately available
`for absorption. It results in a peak blood level
`equal
`to the desired level
`to be maintained.
`Equation (7) allows estimation of Di if Dm is
`delayed (cases 1 and 2). If release of Dm is not
`delayed (case 3),
`the loading dose calculated
`using equation (7) is adjusted for the quantity of
`drug provided by the zero-order release process
`in time Tm as shown by equation (8). For exam-
`ple:
`
`‘
`
`Case 1: Di = 205/(0.768 X 0.83) = 327 mg ‘’
`
`Case 2: Di = 59l(O.274 X 0.83) = 259 mg
`
`Case 3: Di = (259 - 57 X 0.5) = 224 mg
`
`Figure 14-4 shows the simulated blood level
`profiles that result from administration of theo-
`retic sustained release dosage forms of procaina-
`mide to the average subject for the three cases
`
`listed in Table 14-4. Curve A is the profile ob-
`served after administration of the loading dose
`calculated for case 2. Calculations based on the
`assumption of a one-compartment model (curve
`B) fail to approximate the desired profile ade-
`quately. The procedure suggested for estimation
`of kro, however, based on the actual
`two-
`cornpartment model that fits procainamide data, '
`gives a reasonable approximation of the opti-
`mum profile (curve C). A formulation designed
`to release loading and maintenance doses simul-
`taneously (case 3) results in a profile (curve D)
`that does not significantly differ from case 2.
`The total dose required to maintain a blood level
`of 1 ,u.g/ml for 8 to 10 hours is about the maxi-
`mum (<1 g) that can be formulated in a reason-
`ably sized solid peroral dosage form. The usual
`minimum therapeutic level required for procain-
`amide is 3 to 4 pig/ml. Multiple units of a sus-
`tained release procainamide would have to be
`administered at each dosing interval to attain a
`therapeutic level.
`t_
`Computer simulation provides a valuable tool
`for evaluating the performance of sustained re-
`lease dosage form designs. Curve E‘ in Figure
`14-4 demonstrates another application of simu-
`
`1.0
`
`
`
`
`
`BLOODLEVEL(mg/ml) .001
`
`FIG. 14-4. Simulated b/good level profiles observed after administration of theoretic sustained release formulations of
`procainamide hydrochloride to an average patient. A, Case 2—loading close; B, Case 1; C, Case 2; D, Case 3; E, Case
`2—patient differs from average.
`
`TIME. (HOURS)
`
`436 - The Theory and Practice of Industrial Pharmacy
`
`Astrazeneca EX. 2134 p. 11
`
`

`
`lation, that is, to examine the performance of the
`dosage form in a patient in which the disposition
`of the drug (procainamide in the example) dif-
`fers significantly from the average. In this sub-
`ject, the pharmacokinetic parameters were as
`follows: ka = 1.2, ke = 0.47, km = 0.8, km =
`0.77, Vc = 101, and F = 0.7. Lower blood levels
`are observed initially, and higher blood levels are
`observed at the end of the maintenance period,
`since the absorption rate was lower and the bio-
`logic half-life higher (approximately 4 hours)
`than average in this patient. Overall, the differ-
`ence in response of this patient to the dosage
`form is not significant.
`
`First-Order Release
`
`Approximation
`The rate of release of drug from the mainte-
`nance portion of the dosage form should be zero-
`order if the amount of drug at the absorption site
`is toremain constant. Most currently marketed
`sustained release formulations, however, do not
`release drug at a constant
`rate-, and conse-
`quently do not maintain the relative constant
`activity implied by Figure 14-3‘. Observed blood
`levels decrease over time until the next dose is
`administered.
`In_ many instances,
`the rate of
`appearance of drug at the absorption site can be
`approximated by anexponential or first-order
`process in which the rate of drug release is a
`_ function only of the amount of drug remaining
`in the dosage form. Table 14-5 lists the expres-
`sionsthat can be used to estimate the design
`parameters for optimized first-order
`release
`models. Three different designs are considered:
`Dm not delayed. Dm delayed where Tm = Tp,
`and Dm delayed where Tm > Tp. Table 14-6
`
`H lists the parameters calculated for a drug fitted
`by a one-body-compartment model, and Figure
`14-5 shows the resulting profiles for each exam-
`ple considered. Doses listed in Table 14-6 are
`expressed as fractions of loading dose, using the
`calculation for a zero-order model (case 1, Table
`14-4) as a reference.
`Method 1. Simultaneous release of Dm
`and Di. The crossing time, Ti, is the time at
`which the blood level profiles produced by ad-
`ministration of separate loading and mainte-
`nance doses intersect. The closest approxima-
`tion to the ideal profile is obtained if the crossing
`point is made at least equal to theldesired main-
`tenance period (h — Tp). Equation (9) shown in
`Table 14-5, is an approximation of equation (11)
`where ke > krl. The maintenance dose is esti-
`mated from the initial
`release rate,
`i.e.,
`kr1Dm = keAm = kro. The loading dose is esti-
`mated by correcting the immediate release dose
`required to achieve the maintenance level for
`the quantity of drug delivered by the mainte-
`nance dose in the time 'I‘p. For example:
`
`Ti = 9.2 -1.2 = 8hr
`
`krl = O.23exp(—O.23 X 8) = 0.055 hr
`
`Dm = 0.173/0.055 = 3.1
`
`Di = (0.75/0.75 x 1) — 0.173 x 1.2 =_ 0.8
`
`. Method 2. Delayed release of Dm: Tm =
`Tp. If Dm is large and kr is made small, mainte-
`nance dose may be released as a pseudo-zero-
`order process. As a first approximation, lcrl may
`be estimated as the reciprocal of the mainte-
`nance time. Dm is then calculated as in method
`1. Better approximation of a-zero-order response
`can be obtained if Dm is. increased and krl is
`reduced to maintain the product kr1DM con-
`
`‘3
`- TABLE 14-5. Expressions Useful for Estimation of Design Parameters for First-Order Sustained
`Release Dosage Form Models?._
`
`
`
`Method 1 Method 2Parameter Method 3
`
`
`
`
`
`’ Tm
`
`o
`
`Ti
`kr,
`
`Dm
`
`(h — 1):)
`ke(exp(—keTi))
`(Eq. 9)
`kro/krl
`
`Tp (Eq. 3)
`
`-
`1/(h — Tp)
`
`kro/kr,
`
`4.6lka
`
`(Eq. 10)
`
`Ch - Tp)/2
`E . 11
`T. _ 2 31og(kr1/ke)
`)
`( q
`1
`(kn ~ ke)
`k A — '
`Dm — 3‘ E A‘) exp(kr1(2Ti- Tm)
`l
`.
`.
`D'ka
`,
`A1 = (ka‘_ ke) exp(-ke(T1 + Tm))
`
`(Eq. 12)
`~
`(Eq. 13)
`
`
`
`CpVdlfF — kro'I‘p CpVd/fFDi . CpVd/fF
`
`
`
`
`
`SUSTAINED RELEASE DOSAGE FORMS - 437 ‘
`
`Astrazeneca Ex. 2134 p. 12
`
`

`
`1.o
`
`\
`
`METHODS
`
`.
`
`-—...____ Map-I001
`333%“
`
`
`
`D 3
`
`;
`,,
`
`O "
`
`02 § 2
`
`5lul-
`
`7.
`‘x g
`IL
`
`4
`
`FIG. 14-5. Simulated blood level profiles observed after administration of a theoretic sustained release dosage form to an
`average patient based on different first-order release models. Blood level is plotted as the fraction of dose absorbed (CpVd/
`K_,.FDi).
`
`TIME (HOURS l
`
`stant. For example:
`
`Tm = Tp = 1.2 hr
`
`lcrl = 1/(9.2 — 1.2) = 0.125 hr
`
`Dm = 0.173/0.125 = 1.4
`
`Di = 0.75/0.75 X 1 = 1
`
`Since kr1Dm = 0.173, then krl should be re-
`duced to 0.86 if Dm is increased to 2.0, to main-
`tain this product constant.
`Method 3. Délayed release of Dm: Tm > Tp.
`Increasing the delay time, Tm, allows the use of
`faster release rates. A period equal to the time at
`
`which 99% ofythe loading dose has been‘ ab-
`sorbed is selected using equation (10) in Table
`14-5. The release rate constant is iteratively cal-
`culated from equation (11) such that a peak is
`obtained from the maintenance dose at the mid-
`point of the maintenance time. The amount of
`drug required to produce asecond peak at this
`time is themaintenance dose, calculated from
`equations (12, 13). For example:
`/ ‘
`
`Tm = 4.6/2.0 = 2.3 hr
`
`Ti = (9.2 — 1.2)/2 = 4 hr
`
`4 = 2.3 x 1og(kr1/0.23)/(krl — 0.23)
`
`' TABLE 14-6. Estimated Design Parameters for a First~0rder Sustained Release Model*
`
`Parameter
`
`Zero-Order
`
`_
`
`Method 1
`
`Method 2
`
`Method 3
`
`2.3
`1.2
`0
`1.2
`Tm hr
`4
`—
`8
`-
`V Ti hr
`0.27
`0.125
`0.055
`(kro = 0.173)
`k1‘1 hr
`1.45
`1.4
`3.1
`‘1.4
`Dm/Di
`Di
`1.0
`0.8
`1.0
`1.0
`
`(Di + Dm)/Di
`2.4
`3.9
`2.4
`2.45
`
`_
`
`'
`
`‘Drug Characteristics: One-Compartment Model
`
`g=3hr
`’I‘p= 1.g.hr
`
`ka=2hr
`h=9.2hr
`
`ke=0.23hr
`F=1
`
`f=.0.75
`CpVd =‘O.75
`
`438 - The Theory and Practice of Industrial Pharmacy
`
`Astrazeneca EX. 2134 p. 13
`
`

`
`(Solve this expression iteratively by finding
`the value of krl that satisfies the equality: in this
`case, krl = 0.27.)
`
`Di = 075/075 X l = 1
`
`Ai = (1 X 2)exp(—O.23(4 + 2.3))/(2.0 -
`0.23) = 0.267
`
`Am = kro/ke = 0.173/0.23 = 0.74
`
`Drn = (0.23/o.27)(o.74 — 0.267)exp(O.27(2 x
`4 — 2.3)) = 1.45‘
`
`Methods 1 and 2 have the disadvantage that
`large maintenance doses are required, resulting
`in a significant loss of drug available for absorp-
`tion. In the examples plotted in Figure 14-5,
`. 50% of the dose calculated using metho