.
`
`TBEATISE ON
`OONTBOLLEO
`OBIIO DELIVERY
`
`‘
`
`Fundarnentais - Optimizetien - Applications
`
`
`e e
`
`dited buy.
`E Agis Kydonieus
`ConvaTec
`A Bristol-Myers Squibb Company
`Princeton, New Jersey
`
`Marcel Dekker, Inc.
`
`New York ° Basel ° Hong Kong
`
`EN D0_OP_1333994
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`Lupin Exh. 1029
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`

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`Library of Congress Cataloging-in-Publication Data
`
`Treatise on controlled drug delivery: fundamentals, optimization,
`applications / edited by Agis Kydonieus.
`p.
`cm.
`'
`Includes bibliographical references and index.
`ISBN 0-8247-8519-3
`
`1. Drugs—-Controlled release. 2. Controlled release preparations.
`1. Kydonieus, Agis F.
`»
`[DNLM:
`l. Delayed-Action Preparations. 2. Dosage Forms. 3. Drug
`Carriers.
`QV 785 T784]
`RS20l.C64T74
`1991
`6l5’.6——dc20
`DNLM/DLC
`~>.
`_
`For Library of Congress 5
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`91-24646
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`This book is printed on acid~free paper.
`
`Copyright © 1992 by Marcel Dekker, Inc. All Rights Reserved.
`
`Neither this book not any part may be reproduced or transmitted in any
`form or by any means, electronic or mechanical, including photocopying,
`microfilming, and recording, or by any information storage and retrieval
`system, without permission in writing from the publisher.
`
`Marcel Dekker, Inc.
`270 Madison Avenue, New York, New York 10016
`
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`PRINTED IN THE UNITED STATES. OF AMERICA
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`ENDO_OP_1333995
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`.—.«-—~..i,—-r.-
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`6 O
`
`ral Controlled-Release Delivery
`
`Philadelphia College of Pharmacy and Science,
`Pardeep K. Gupta
`Philadelphia, Pennsylvania
`
`Joseph R. Robinson School of Pharmacy, University of Wisconsin,
`l\/ladison, Wisconsin
`
`INTRODUCTION
`
`Among all the routes of drug administration that have been explored for the development
`of controlled—release (CR) systems, the oral route has by far achieved the most attention
`and success. This is due, in part, to the ease of administration as well as to the fact that
`gastrointestinal physiology offers more flexibility in dosage-form design than most other
`routes. Development of an oral CR dosage form for a given drug involves optimization
`of the dosage-form characteristics within the inherent constraints of gastrointestinal (GI)
`physiology.
`,
`.
`Although significant clinical advantages have been obtained for CR formulations,
`most such dosage forms are still designed on an empirical basis. An understanding of
`varied disciplines, such as GI physiology, pharmacokinetics, and formulation techniques,
`is essential in order to achieve a systematic approach to the design of oral CR products.
`The scientific framework required for development of a successful oral controlled drug
`delivery dosage form consists of an understanding of three aspects of the system, namely,
`( l) the physicochemical characteristics of the drug, (2) relevant Gl anatomy and physiology,
`and (3) dosage-form characteristics. The anatomy and physiology includes insight into
`the basic physiology of the gut as well as the absorptive properties of the GI mucosa.
`Often one encounters additional factors, including the disease being treated, the patient,
`and the length of therapy. Given that it is usually not practical to alter the physicochemical
`characteristics of the drug, design of contro1led—delivery systems generally optimizes
`dosage~form characteristics relative to the GI environment.
`The objective of this chapter is to review oral CR systems, with a focus on dosage-
`form characteristics and GI physiology. Since an understandirig of the basic concepts of
`CR systems is vital for future development, particular emphasis will be on the rationale
`and mechanism of such delivery systems.
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`Gupta and Robinson
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`Definitions
`
`The term CR implies a system that provides continuous delivery of the drug for a pre-
`determined period with predictable and reproducible kinetics, and known mechanism of
`release. Also included in this term are systems that provide control over movement of
`the dosage form through the GI tract and/or deliver the drug to a specific area within the
`GI tract for either local or systemic effect. This chapter will deal only with dosage forms
`intended to be swallowed orally and will thus exclude buccal and rectal areas of delivery.
`
`Advantages/Disadvantages of Oral CR Dosage Forms
`
`The goal of oral CR products is to achieve better therapeutic success than with conventional
`dosage forms of the same drug. This goal is realized by improving the pharmacokinetic
`profile as well as patient convenience and compliance in therapy. Improvement is perhaps
`the major reason for so much attention being focused on drugs used in chronic therapy;
`e. g., diuretics, cardiovascular, and CNS agents. Some of the advantages of oral CR dosage
`forms are
`
`Reduced dosing frequency
`Better patient convenience and compliance
`Reduced GI side effects and other toxic effects
`
`Less fluctuating plasma drug levels
`More uniform drug effect
`Lesser total dose
`
`.‘3‘S":’*‘E'°!‘°’.“
`
`The ideal system possesses all of the above advantages. In most cases, however,
`there is little direct evidence of a more uniform drug effect, and success has to be based
`on circulating plasma drug levels. Also, a lesser total dose is based on the assumption
`that the drug shows linear pharmacokinetics, which in many cases, as will be discussed
`below, may not be achieved.
`On the other hand, oral CR formulations suffer from a number of potential disad-
`vantages. These include:
`
`S"‘.4**E*’!"
`
`I. Generally higher cost
`Relatively poor in-vitro/in—vivo correlation
`Sometimes unpredictable and often reduced bioavailability
`Possible dose dumping
`Reduced potential for dose change or withdrawal in the event of toxicity, allergy,
`or poisoning
`.
`Increased first-pass metabolism for certain drug
`
`6.
`
`Unpredictable and poor in—vitro/in—vivo correlations and bioavailability are often ob-
`served with such formulations, especially when the drug release rate is very -low or drug
`absorption from the colon is involved. Dose dumping is a phenomenon where a large
`amount of the drug is released in a short period of time, resulting in undesired high plasma
`drug levelsand potential toxicity.
`
`Drug Candidate Criteria
`
`A number of drug characteristics need to be considered in evaluating drug candidates for
`oral CR dosage forms. Some of these characteristics are discussed here.
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`Oral Control|ed—Release Delivery
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`273
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`In both first-order- and zero—order—release systems, the time required to achieve desired
`drug levels in the body depends on the elimination-rate constant. The slower the elimination ,
`the longer it takes to reach steady state.
`
`Bioavailability
`
`Factors affecting the bioavailability of a drug after its oral administration include incomplete
`absorption from the GI tract, presystemic clearance (gut metabolism and liver first-pass
`effect), and degradation of drug in the gut lumen. These factors may vary in their magnitude
`depending on whether a drug is given as a conventional dosage form or as a CR formulation.
`Incomplete drug release from a CR dosage form will constitute an additional factor
`contributing to the loss of drug prior to its absorption. Among these factors, first-pass
`liver metabolism is particularly susceptible to change when changing the drug input rate;
`
`First-Pass Liver Metabolism
`
`— After absorption from the GI tract, the drug must first pass through the liver before it
`reaches systemic circulation. This is because blood drainage from the entire GI tract, with
`the exception of thebuccal cavity and lower rectum, goes to the liver via the hepatic
`portal vein. Since the liver is the principal site of metabolism for a number of drugs, a
`fraction of the absorbed drug may be eliminated through metabolism by the liver before
`it reaches the general circulation. This fraction is a function of the susceptibility of the
`drug to liver microsomal enzymes for metabolism and is measured in terms of a parameter
`called extraction ratio. Because of this presystemic metabolism, which is also referred to
`as the “flrst—pass” effect, an oral dose of a drug may have incomplete bioavailability
`despite its complete absorption from the GI tract.
`A number of drugs have been identified as having a significant first-pass effect, and
`many of these have been shown to obey Michaelis—Menten kinetics in the therapeutic
`dose range [29]. Factors that affect first-pass metabolism are (1) liver enzyme activity
`(2) blood flow (3) plasma protein binding, and (4) plasma drug concentration. All of these
`factors can play important roles, depending on the nature of the drug and its interaction
`with liver enzymes.
`The major difference between conventional and CR oral dosage forms is the rate of
`drug input into the body. The amount of drug absorbed during any 24-h period is usually
`comparable. Therefore, if linear kinetics of drug metabolism are involved, one should
`expect no difference between the pharmacokinetic parameters of the two dosage forms.
`However, linear pharmacokinetics do not always apply in real situations. One such example
`is propranolol, which accumulates during repeated oral administration to a greater extent
`than predicted from its half—life and area under the curve after a single oral dose [30].
`This type of nonlinearity is commonly referred to as “dose—dependent kinetic.” Such
`nonlinearity may also arise from other saturable processes arising during the course of
`drug absorption and disposition [31]. In addition, certain disease conditions, such as renal
`insufficiency, can also lead to dose—dependent kinetics for certain compounds.
`Dose-dependent kinetics can be an important factor in considering the design and
`evaluation of CR systems. This is because the rate and pattern of drug delivery with a
`conventional dosage form are considerably different from those with a CR dosage form.
`- Most important among saturablc processes from an oral delivery standpoint is the saturable
`first pass liver metabolism effect. Experimental observations indicating dose~dependent
`and saturable first—pass metabolism include: (1) increase in dose—normalized bioavailability
`with increase in dose and (2) decreased clearance at steady state compared to a single
`dose. A consequence of dose-dependent kinetics is that bioavailability will decrease with
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`Gupta and Robinson
`
`a decrease in the rate of absorption after oral administration of the same dose. If one
`considers that a decreased rate of drug absorption from the GI tract is the primary goal _
`of most CR formulations, drugs showing saturable kinetics will need special attention,
`and indeed, they may be unsuitable for such formulations.
`Michaelis—Menten enzyme kinetics can be employed to better understand saturable
`liver metabolism. The equation describing the rate of drug metabolism is
`
`rate of metabolism =
`
`V maxc
`Eire
`
`where
`
`Vmax = maximum rate of metabolism
`
`C = drug concentration in plasma
`
`(8)
`
`Km = Michaelis-Menten constant measured as plasma drug concentration at
`metabolism rate of Vmax/2
`
`The Kmvalue is a measu1‘e;?f7 flmwapprainnatecwncertrtiiétnvuca-owe‘wtinbu"satarlaéhnjry
`becomes evident.
`
`For drugs like phenytoin, which show saturation of liver enzymes at relatively low
`concentrations (therapeutic concentration), increase in dose results in a disproportionate
`increase in bioavailability and circulating drug levels because both first—pass metabolism
`and systemic metabolism (clearance) are saturable. Propranolol and alprenolol show similar
`dose—dependent behavior [32,33].
`Therefore, bioavailability from an oral dose is an important parameter to consider
`when contemplating a CR dosage form for oral use. Generally, drugs with medium to
`high extraction ratio and -saturable first-pass metabolism make unsuitable candidates for
`CR. Alternatively, an appropriate change in the release rate may be incorporated into the
`dosage form to compensate for the increased loss due to first-pass effect. This approach
`may be possible for drugs with low to medium extraction ratios. Thus, dose-dependent
`nonlinearity can present a serious limitation for development of oral CR formulations.
`
`Pharmacokinetic Analysis
`
`An important consideration in oral CR formulations is the selection and use of appropriate
`models to assess in-vivo pharmacokinetic parameters. Most important in this regard is
`the measurement of the in-vivo release rate and its correlation with in—vitro dissolution
`
`profiles. Such information can help evaluate as well as refine oral delivery systems. One
`can use either a compartment model approach or a relatively recent “noncompar.tmental’ ’
`or “model~independent” approach in such studies. In both approaches, the kinetic pro-
`cesses are assumed to be first-order, linear, and irreversible.
`The compartment model methods assume that the drug concentration~time profile can
`be described by one of many pharmacokinetic models. The data are evaluated by using
`an equation consistent with the assumed model by using either the method of residuals
`or a nonlinear least-square regression analysis. Standard equations for one— or multicom—
`partment models are used to estimate pharmacolcinetic constants, including the absorption
`rate constant. The problem with model-based methods is that for drugs showing multi-
`compartment kinetics, one cannot be sure about the relative nature of the absorption and
`distribution rate constants. Additional factors such as drug degradation and metabolism
`in the gut, gastric emptying, and GI motility can further complicate the analysis.
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