`
`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
`
`Hind Rajasthan’ Building
`DadarBombay 400 014
`1987 '
`
`AstraZeneca Exhibit 2134 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB
`IPR2017-00904
`
`
`
`Lea 8e Febiger
`600 Washington Square
`Philadelphia, PA 19106-4198
`U. SA.
`(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 & Febiger. Copyright under the
`International Copyright Union. All Rights Resenied. This book is
`protected by copyright. No part of it may be'repr'oduced in any
`manner or by any means without written permission from the
`publisher.
`
`FIRST INDIAN REPRINT, 1987
`SECOND INDIAN REPRINT, 1989
`THIRD INDIAN REPRINT, 1990
`FOURTH INDIAN REPRINT, 1991
`
`Reprinted in India by special arrangement with LEA & FEBIGER
`Philadelphia U S A.
`Indian Edition published by
`
`Varghese Publishing House, I-Iind Rajasthan Building, Dadar,
`Bombay 400 014.
`
`Reprinted by Akshar Pratiroop Pvt Ltd, Bombay 400 031
`
`AstraZeneca Exhibit 2134 p. 2
`
`
`
`
`
`Contents
`
`Section I.
`
`Principles of Pharmaceutical Processing
`
`3
`1. Mixing
`EDWARD G. RIPPIE
`
`21
`2. Milling
`EUGENE L. PARROT ,
`
`4'7
`3. Drying
`ALBERT s. RANKELL, HERBERT A. LIEBERMAN, ROBERT F. SCHIFFMANN
`
`4. Compression and Consolidation of Powdered Solids
`KEITH MARSHALL
`
`66
`
`rinciples (Related to Emulsion and Suspension
`5. Basic Chemical
`100
`a
`Dosage Forms
`STANLEY L. HEM, JOSEPH R. FELDKAMP, JOE L. WHITE
`
`6. Pharmaceutical Rheology
`JOHN H. WOOD
`
`7. Clarification and Filtration/
`‘s. CI—IBAI
`
`123
`
`146
`
`Section II. Pharmaceutical Dosage Form Design
`5S7 Preformulation
`171
`EUGENE-F. FIESE, TIMOTHY A. HAGEN
`
`197
`9. Biopharmaceutics .
`K.C: KWAN, M.R. DOBRINSKA, J.D. ROGERS, A.E. TILL, K.C. YEH
`10. Statistical Applications in the Pharmaceutical Sciences
`SANFORD BOLTON
`
`243
`
`Section III. Pharmaceutical Dosage Forms
`11. Tablets
`293
`GILBERT s. BANKER, NEIL R. ANDERSON
`
`346
`12. Tablet Coating
`JAMES A. SEITZ, SHASHI P. MEHTA, JAMES L. YEAGER
`
`ix
`
`AstraZeneca Exhibit 2134 p. 3
`
`
`
`-
`374
`13. Capsules
`Part One Hard Capsules
`'
`VAN B. HOSTETLER
`Part Two Soft Gelatin Capsules
`J.P. STANLEY
`
`374
`
`Part Three Microencapsulation
`J.A. BAKAN
`
`14. Sustained Release Dosage Forms
`‘ NICHOLAS c. LORDI
`15.” Liquids
`457
`J.C. BOYLAN
`
`398
`
`412
`
`430
`
`479
`16/Pharmaceutical Suspensions
`NAGIN K. PATEL, LLOYD KENNON*, R. SAUL LEVINSON
`17W 502
`MARTIN M. RIEGER
`
`18/ Semisolids
`
`534
`
`BERNARD IDSON, JACK LAZARUS*
`19. Suppositories
`564
`'
`LARRY J. COBEN, HERBERT A. LIEBERMAN
`Pharmaceutical Aerosols
`589
`
`JOHNJ SCIARRA, ANTHONYJ. CUTIE
`-
`121 Sterilization
`619
`KENNETH E. AVIS, MICHAEL J. AKERS
`22. Sterile Products
`639
`'
`KENNETH E. AVIS
`
`Section IV. Product Processing, Packaging, Evaluation, and
`Regulations
`
`23.‘ Pilot Plant Scale-Up Techniques
`SAMUEL HARDER, GLENN VAN BUSKIRK
`
`681
`
`711
`24? Packaging Materials Science
`CARLO P. CROCE, ARTHUR FISCHER, RALPH H. THOMAS
`
`733
`
`25.’ Production Management
`J.V. BATTISTA
`760'
`26. Kinetic Principles and Stability Testing
`, 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 Exhibit 2134 p. 4
`
`
`
` l4
`
`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 effect in the face of uncertain
`, fluctuations in the in, vivo environment
`in
`which drug releasetakes 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.1
`The pharmaceutical'industry prevides 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 rateand/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 redneed by formulation
`in an extended action form. The safety margin of
`
`430
`
`AstraZeneca Exhibit 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.2
`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-]
`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 Release'Forms
`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
`
`. Phenobarbital, digitoxin
`
`' Precise dosage titrated to
`individual is required.
`
`Anticoagulants, cardiac
`‘
`glycoside's
`
`No clear advantage for sus-
`tained release formulation.
`
`Griseofulvin
`
`didates for sustained release formulation. For
`some 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 ayerage
`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 — IeXp(—0.693'r/I‘:l))
`
`SUSTAINED RELEASE DOSAGE FORMS - 431
`
`AstraZeneca Exhibit 2134 p. 6
`
`
`
`\V
`
`\‘
`
`A /
`
`4
`
`
`
`BLOOD'LEVEL
`
`5
`
`1o
`TIME (HOURS)
`FIG. 14-1. Multiple patterns of dosage that characterize nonsustain’ed peroral administration of a drug with a biologic
`half-life of 3 hr and a half-life for absorption of20 min. Dosage intervals are: A, 8 hr,- B, 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 t; = 7, Di = 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 formis 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 form, one must have a thorough knowl-
`edge of the pharmacokinetics of the drug chosen
`for this formulation. Figure 14-2 shows a gen-
`eral phannacokinetic 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 (g = 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., . 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 Exhibit 2134 p. 7
`
`
`
`DOSAGE
`FORM
`
`MAINTENANCE
`
`LOADING
`
`"TISSUE"
`
`CENTRAL
`
`"BLOOD"
`
`ABSORPTION SITE PERIPHERAL
`
`BODY
`
`COMPARTMENT
`
`FIG. 14-2. A general pharmacokinetic model of an ideal peroral sustained release dosage form.
`
`form, which identifies the specific parameters
`that must be taken into accdunt in optimizing
`sustained release dosage form designs, is shown
`in Figure 14-2 at the absorption site. These‘are
`the loading Or immediately available pertion of
`the dose (Di), the maintenance or slowly avail-
`able portion of the dose (Din), the time (Tm) at
`which release of maintenance dose begins (i.e.,
`the delay time between release of Di and Dm),
`and the specific rate of release (kr) of the main-
`tenance dose.
`
`Figure 14—3 shows the form 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 former 'case, 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 procaina-
`
`SUSTAINED RELEASE DOSAGE FORMS . 4‘33
`
`AstraZeneca Exhibit 2134 p. 8
`
`
`
`
`
`BLOQDLEVEL
`
`MAXIMUM SAFE LEVEL
`
`
`
`
`
`
`\
`
`MAINTENANCE
`DOSE
`
`
`
`
`\
`
`
`
`
`\
`MINIMUM EFFECTIVE LEVEL
`LOADING \\
`DOSE
`
`
`
`FIG. 14-3. A blood-level time profile for an ideal peroral sustainedrrelease dosage form.
`
`Tn
`
`TIME
`
`mide, an important antiar'rhythmic agent, as an
`example.
`Table 14-3 lists the pharmacokinetic parame-
`ters characterizing the disposition of procaina—
`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 formulations 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
`
`Am = Cde
`
`kro = keAm
`
`Eq. (1)
`
`Eq. (2)
`
`Peak time
`Bioavailability factor
`
`J
`
`Tp = (2.3/(ka f ke))log(ka/ke)
`F = (AUC)oral/(AUC)iv
`
`Eq. (5)
`f— (31);?“
`Fraction of dose (Di) at '
`ke
`peak (F =—- 1)
`Eq. (6)
`Dm = kro(h - Tm)/F
`Maintenance dose
`Eq. (7)
`Di = Am/fF
`'
`’
`Loading dose (Tm = 1p)
`
`
`'Loading dose (rm ='0) Eq. (s) ' = (Di — kroTp)
`
`
`Eq. (3)
`Eq. (4)
`
`-
`
`‘
`
`434 - The Theory and Practice of/Industrial Pharmacy
`
`AstraZeneca Exhibit 2134 p. 9
`
`
`
`TABLE 14-3. Pharmacokinetic' Parameters for.
`Procaz'rzamide in an Average Subject (Weight:
`
`75 kg) ' ‘
`
`
`
`
` Parameter . Value Paranieter Value
`
`
`
`
`
`3.15 hr
`km
`0.21 hr
`[3
`1.4 hr
`k21
`3.4 hr
`t;
`59 L
`Vc
`0.97 hr
`ke
`205‘L
`Vd
`2.0 hr
`ka
`
`F 0.5 hr 0.83 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 rig/ml for 8 hours, i.e., Cp = 1 mg/L, and h —
`Tp é 8.'Tab1e 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-compartment
`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 Sits/tamed Release Design
`Parameters
`for Pro/cairtamide (Cp = 1 rig/ml,
`
`h Wimms) / .
`
`
` Parameter / , Case 1 Case 2 Case 3
`
`‘
`'
`
`59
`59‘
`, 205
`Am (mgf’
`57
`57
`43
`kro (mg/hr)" ’
`0
`0.5
`1.2
`Tm
`'
`549
`549
`414
`, Qm (mg)
`0.274
`0.274
`0.768
`f
`(Di) 224
`259
`322
`,
`Di (mg)
`2.45
`2.12
`1.28
`Dm/Di
`
`
`736Dm + Di (mg) 773 808
`
`
`~
`
`Vd, is used to calculate Am for the two—compart-
`ment model, i.e., Am = Cch. For example:
`
`Case 1:
`..
`
`Cases 2 and 3:
`
`kro = 0.21 X 1 X 205
`= 43 mg/hr
`
`kro = 0.97 X 1 X 59
`= 57 mg/hr
`
`2. Estimation of,‘Tm. 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 (0.21hr‘1) 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
`bioavailability factor,\F (equation 4), which is
`the fraction of the administered dose absorbed
`from a reference nonsustained release dosa e
`form. The F-value is estimated as the ratio of the
`area under the plasma level curve (AUG-val ’e)
`measured after oral administration to the A C-
`value observed after intravenous administratio
`.,
`of the same dose of drug. In the example/F <‘
`since procainamide is subject to the first-piss.
`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
`function/of the biological half—life, i.e., Dm ;
`0.693f(h — Tm) Diltb 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. For‘examme:
`
`'
`
`Case 1: Dm = 43 X 8/0.83 = 414 mg
`
`Cases 2 and 3: Dm = 57 X 8/083 = 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 Exhibit 2134 p. 10
`
`
`
`is doubled if the biologic half—life is halved. For
`case 1,
`'Dm would be 228 mg for g = 6 hr,
`-456 mg for t, = 3 hr, and 685 mg for t; = 2 hr.
`4. Estimation of Di. 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 = 59/(0274 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-
`compartment 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 [lg/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 ,ug/ml. Multiple units of a sus-
`tained release procainamide would have to be
`administered at each dosing interval to attain a
`therapeutic level.
`,
`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 byzod level profiles observed after administration of theoretic sustained release formulations of
`procainamide hydrocthride to an average patient. A, Case 2—loading dose; 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 Exhibit 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: k3. = 1.2, k6 = 0.47, kl2 = 0.8, kg] =
`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. Inmany instances,
`the rate of'
`appearance of drug at the absorption site can be
`approximated by anexp'onential or first-order
`process in which the rate of drug release is a
`‘ function only of the amount of drug remaining
`in the dosage fonn.. Table 14-5 lists the expres-
`sions that 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
`
`1 lists the parameters calcu1ated 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 the \desired 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.,
`krle = 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 Tp. For example:
`
`Ti= 9.2 —1.2=8hr
`
`krl = O.23exp(-O.23 x 8) = 0.055 hr
`Dm = 0173/0055 = 3.1
`
`Di = (075/075 x 1) — 0.173 x 1.2 =08
`
`. 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, krl 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 krlDM con-
`
`'
`
`h
`«‘TABLE 14-5. Expressions Useful for Estimation of Design Parameters for First—Order Sustained
`Release Dosage Form Models
`___________________________—.—._——————-———
`
`Method 3
`Method 2
`Method 1
`Parameter
`___________________._._.__.———————-———
`
`’ Tm
`
`o
`
`Ti
`krl
`
`Dm
`
`0! - TP)
`ke(exp(-—keTi))
`(Eq. 9)
`kro/kr1
`
`Tp (Eq. 3)
`
`-
`1/(h — Tp)
`
`krolkr,
`
`4.6/ka (Eq. 10)
`
`(h — Tp)/2
`E 11
`T' = 2.3log(kr1/ke)
`)
`( q‘
`‘
`(kn - ke)
`Dm = BdA—El—AR exp(kr,(2Ti - Tm)
`
`Dika
`. _
`_
`,
`A1 — (ka __ ke) exp( ke(T1 + Tm))
`
`(Eq. 12)
`*
`(Eq. 13)
`
`. Cde/fF
`Cde/fF
`Cde/fF — kroTp
`Di
`___________________________________.____———————
`
`SUSTAINED RELEASE DOSAGE FORMS - 437 '
`
`AstraZeneca Exhibit 2134 p. 12
`
`
`
`METH003
`
`».
`
`D E
`
`-—
`
`Map-1001
`~~-F~~~‘
`~~~-‘~
`
`.15LI. 4
`
`l
`I t
`O
`' 8
`<1,
`5
`t 8
`LI-
`
`.
`
`02 g
`
`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 (Cde/
`”FDz’).
`
`TIME (HOURS)
`
`stant. For example:
`
`Tm = Tp = 1.2 hr
`_
`_
`krl _ 1/(9'2 — 1'2) — 0‘125 hr
`Dm = 0.173/0.125 = 1.4
`. _
`_
`D1 — 0'75/0'75 X 1 _ 1
`.
`Since krle = 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. Delayed 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% of the 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 a .second peak at this
`time is the'maintenance dose, calculated from .
`equatlons (12’ 13)’ For example:
`/
`'
`
`Tm = 4.6/2.0 = 2.3 hr
`. __
`_
`__
`T1 _ (9'2
`1‘2)/2 _ 4 hr
`4 = 2.3 x log(kr1/0.23)/(kr1 — 0.23)
`
`'
`
`' TABLE 14-6. Estimated Design Parameters for a First-Order Sustained Release Model"
`
`Parameter
`Tm hr
`. Ti hr
`krl hr
`Dm/Di
`Di
`(Di + Dm)/Di
`
`_
`
`Zero-Order
`1.2
`—
`(kro = 0.173)
`1.4
`1.0
`2.4
`
`Method 1
`0
`8
`0.055
`3.1
`0.8
`3.9
`
`_
`
`Method 2
`1.2
`—
`0.125
`1.4
`1.0
`2.4
`
`'
`
`Method 3
`2.3
`4
`0.27
`1.45
`1.0
`2.45
`
`‘Drug Characteristics: One-Compartment Model
`
`t§=3hr
`Tp=1.2hr
`
`ka=2hr
`h=9.2hr
`
`ke=0.23hr
`F=l
`
`f=0.75
`Cde=0.75
`
`438 - The Theory and Practice of Industrial Pharmacy
`
`AstraZeneca Exhibit 2134 p. 13
`
`
`
`
`
`
`
`
`
`(Solve this expression iteratively by finding
`the value of krl that satisfies the equality: in this
`case, krl = 0.27.)
`
`Di = 0.75/0.75 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
`
`Dm = (0.23/0.27)(o.74 — 0.267)exp(0.27(2 x
`4 — 2.3)) = 1.45
`
`Methods 1 and 2 have the disadvantage that
`large maintenance doses are requir