Polymers for -
`Controlled
`Drug Delivery
`
`Editor
`Peter J. Tarcba, Ph.D.
`Abbott Laboratories
`North Chicago, Illinois
`
`CRC Press
`Boca Raton Ann Arbor Boston
`
`Page 1 of 30
`
`KVK-TECH EXHIBIT 1024
`
`

`

`Library of Congress Cataloging-in-Publication Data
`
`Polymers for controlled drug delivery/editor, Peter J. Tarcha.
`p. cm.
`Includes bibliographical references.
`Includes index.
`ISBN 0-8493-5652-0
`I. Controlled release preparations. 2. Polymers. 3. Drugs(cid:173)
`I. Tarcha, Peter J.
`- Vehicles.
`I . Delayed-Action Preparation- administration & dosage.
`(DNLM:
`2. Drug Administration Routes. 3. Drug Carriers. 4. Polymers-
`administration & dosage.
`QV 785 P7836]
`RS201.C64P67 1990
`615'. !9-clc20
`DLC
`for Library of Congress
`
`90-2608
`CIP
`
`This book represents infonnation obtained from authentic and highly regarded sources. Reprinted material is
`quoted with permission, and sources are indicated. A wide variety of references are listed. Every reasonable effort
`has been made to give reliable data and information, but the author and the publisher cannot assume responsibility
`for the validity of all materials or for the consequences of their use.
`
`All rights reserved. This book, or any parts thereof, may not be reproduced in any form without written consent
`from the publisher.
`
`Direct all inquiries to CRC Press, Inc., 2000 Corporate Blvd. , N.W., Boca Raton, Florida 33431.
`
`c, 1991 by CRC Press, Inc.
`
`lntemational Standard Book Number 0-8493-5652-0
`
`Library of Congress Card Number 90-2608
`Printed in the United States
`
`Page 2 of 30
`
`

`

`Chapter 3
`
`39
`
`POLYMERS FOR ENTERIC COATING APPLICATIONS
`
`George A. Agyilirab and Gilbert S. Banker
`
`TABLE OF CONTENTS
`
`I.
`
`Definition and History ............... . ........................................ . .. 40
`
`II.
`
`Purpose of Enteric Coating .... . ......... . ... . ....... . ........................... 40
`
`III.
`
`Gastrointestinal Physiology Relative to Enteric Coating Functioning
`and Design Rationale ............................................................ 41
`A.
`pH ... . ... . ................................................................ 41
`B.
`Gastric Emptying ......................................................... 41
`C.
`Enzyme Activity ......................................................... 43
`
`IV.
`
`Requirements of an Ideal Enteric Coating ....................... . .... . ..... . . . .. . 43
`
`V.
`
`Theory of Enteric Polymer Performance .................................... : .... 43
`
`VI.
`
`B.
`
`C.
`
`Enteric Coating Materials ........................................................ .45
`A.
`Shellac ..................... . ............................................. 45
`l.
`Solubility ......................................................... 45
`2.
`Use of Shellac as an Enteric Coating Material ..... . ............. . 45
`Cellulose Acetate Phthalate (CAP) ..... . ... . ......................... . ... 46
`Solubility of CAP .................... . ............................ 46
`I.
`2.
`Properties of CAP as an Enteric Coating Material .... . ........... 47
`3.
`Preparation of CAP Coating Solution ............................. 48
`Polyvinyl Acetate Phthalate (PV AP) ................. . ........ . .......... 50
`I.
`Solubility ......................................................... 50
`2.
`Properties of PY AP as an Enteric Coating Material ............... 50
`3.
`Coating Preparation ............................................... 51
`Hydroxypropyl Methylcellulose Phthalate (HPMCP) .... . ................ 53
`1.
`Solubility .. . ......... . ...... . ....................... . .... . . . ...... 53
`Properties of HPMCP as an Enteric Coating Material ............. 54
`2.
`3.
`Coating Preparation ............................................. . . 55
`Hydroxypropyl Methylcellulose Acetate Succinate
`[(HPMCAS)AQOAT®] ................................................... 56
`I.
`Solubility ......................................................... 57
`Methacrylic Acid Copolymers (Eudragit) ................................. 58
`1.
`Solubility .................................................... . .... 58
`2.
`Application ..................... . ... ·.· . ......................... . . 59
`
`D.
`
`E.
`
`F.
`
`VII. Evaluation of Enteric Coatings ... . ............ . . . . .. ..... . ....................... 61
`In Vitro Methods . ................ . ...... . ... . .... . ....................... 61
`A.
`In Vivo Methods ............... . ... . .......................... . ........... 62
`B.
`
`VIII. Recent Advances and Future of Enteric Coatings ................................ 63
`
`References ........... . ................................................................... 64
`
`Page 3 of 30
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`

`

`40
`
`Polymers for Controlled Drug Delivery
`
`I. DEFINITION AND IDSTORY
`
`An enteric coating is one that resists disintegration or dissolution in gastric media, but
`disintegrates or dissolves in intestinal fluids.
`The notion that some coatings could delay the release of substances until they had
`emptied from the stomach was first noted in 1867, when it was reported that collodion(cid:173)
`protected pills did not dissolve in the stomach. 1 Unna is credited as being the first to use
`gastric insolubility as a basis for medication when he introduced keratin coated pills in
`4 Ceppi is reported to have introduced salol as an enteric coating a few years later. 4
`1884.2
`•5
`•
`The realization that certain medicaments needed to be protected against the gastric
`environment occurred after elucidation of the chemistry and mechanics of the process of
`digestion by Prout, Beaumont, and Pavlov .6·7 In 1889 Bourquelot listed four groups of
`medicaments that required gastric protection. 6· 8 The groups included drugs attacked by gastric
`contents, drugs influencing gastric performance, and drugs that irritate the stomach.
`As soon as it became clear that some types of drugs needed gastric protection, efforts
`were directed at finding substances that would do the job. Shroeter has listed a number of
`materials that have been tried or used as enteric coatings together with references to their
`investigations. 9 Among the older materials used were fonnalized gelatin, keratin, salol, steric
`acid, and sandarac. Most of the earlier materials are no longer used because they did not
`perform satisfactorily as enteric coatings, for one reason or another. Keratin, for example,
`did not withstand gastric digestion. 3 Formalized gelatin proved unreliable because poly(cid:173)
`merization of the gelatin on storage often resulted in failure of the coatings to release the
`drug contained in the coated product. 3•7•10 Salol-coated tablets were also found to go through
`the intestine without dissolving. 3 There were also instances when salol-coated tablets broke
`in the stomach. 3
`The search for better performing materials has continued through the years. We now
`have a variety of materials, including several new materials, available as enteric and delayed(cid:173)
`release coatings, which are discussed in later sections of this chapter. The search still
`continues for new enteric polymers and polymer forms.
`
`II. PURPOSE OF ENTERIC COATINGS
`
`The function of enteric coatings is primarily protective. This may be either to protect
`the stomach from the effect of the drug, or to protect the drug from the effect of the gastric
`contents. There are a number of drugs which, if directly exposed to gastric mucosa, will
`result in gastric irritation, and in some cases, actual corrosion of the gastric wall. Such drugs
`are enteric coated to protect the individuals taking them from their harmful side effects.
`Aspirin is an important example of such a drug. Several reports of gastric bleeding following
`aspirin medication can be found in the literature_l 1
`14 Other drugs that fall in this category
`•
`are strong electrolytes such as ammonium chloride and potassium chloride.
`Enteric coatings also protect drugs from degradation. For example, erythromycin and
`digoxin are unstable in gastric media. Other reasons for enteric coatings are
`
`1.
`
`2.
`3.
`
`to better deliver drugs that are absorbed from a region of the intestine, or that act in
`the intestine and require a high concentration of drug to be released there to be effective
`a (some anthelmintics);
`to provide a delayed component for repeat action dosage forms; and
`to prevent interaction of certain drugs with pepsin and peptones that would lead to a
`hindrance of gastric digestion.
`
`Page 4 of 30
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`

`

`41
`
`III. GASTROINTESTINAL PHYSIOLOGY RELATIVKTO
`ENTERIC COATING FUNCTIONING AND DESIGN RATIONALE
`
`Enteric coatings rely on the differences in environment between the stomach and intestine
`for their performance. Understanding the requirements of enteric coatings demands consid(cid:173)
`eration of gastrointestinal (GI) physiology and function.
`The most important GI physiological factors affecting the functioning of enteric coatings
`
`are
`
`The pH of the stomach and intestinal contents
`1.
`2. Gastric emptying
`3.
`Enzyme activity of the gastrointestinal tract
`
`Based on these regional differences in environment between the stomach and the intes(cid:173)
`tines, there are two mechanisms by which an enteric coating may be made to be resistant
`to dissolution or hydration in the stomach, yet release rapidly in the upper intestinal tract.
`These two mechanisms involve the pH change and the enzyme environment change between
`the stomach and the intestines.
`
`A. pH
`The pH of the stomach varies from about 1.0 to 3.5 depending on the presence or
`absence of food and reflux of intestinal contents into the stomach. 15
`19 The pH of the intestine
`-
`may range from about 3.8-6.620 in the small intestine to about 7 .5- 8.0 in the large
`intestine. 21 This range results from progressive dilution of acid chyme from the stomach by
`bicarbonate ions in the pancreatic secretion, which is delivered by the bile duct to the
`duodenum as well as from intestinal secretions. 16
`17
`•
`Based on the pH of the stomach and small intestine, enteric coatings must be designed
`to resist dissolution at pH values below 4 to avoid disintegration in the stomach, but to begin
`dissolving at pH 5 and above, and be readily soluble at pH 7. A number of earlier enteric
`formulations failed to release their contents appropriately because their design was based
`on the mistaken assumption that the pH of the small intestinal contents was alkaline.
`
`B. GASTRIC EMPTYING
`Gastric emptying of coated tablets have been reported to be highly variable, and may
`take anywhere from 30 min or less to 7 h or more depending on the presence and type of
`food in the stomach, in addition to other factors. 16•18•20
`Bukey and Brew18 reported an average gastric emptying time of about 6 h. There is
`general agreement, however, that because of the wide variability in emptying time, an
`arbitrary gastric emptying time of 1 or 2 b is not a reliable factor on which to base enteric
`performance. It might be reasonable to assume that any enteric polymer which can resist
`gastric contents for 6 his likely to give satisfactory performance in terms of gastric protection
`in most patients under most circumstances. Although some coatings may be able to resist
`gastric acid for l h, as specified by the compendia, these tablets may not be able to remain
`intact if held in the stomach for substantially longer periods.
`The fact that an enteric tablet has adequate protection against gastric acid does not
`guarantee that the tablet will be an effective dosage form/dn,lg delivery system, unless the
`enteric coating quickly dissolves/disintegrates on leaving the stomach, when it contacts a
`new environment.
`A general description of gastric motility and activity may be helpful in understanding
`the manner in which materials are handled by the stomach. The presence of food in the
`stomach, especially of fatty foods, reduces both the rate of emptying from the stomach and
`
`Page 5 of 30
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`

`

`42
`
`Polymers for Controlled Drug Delivery
`
`the level of peristaltic activity . This natural phenomena allows the stomach to undertake its
`work of food breakdown, in preparation for gastric emptying and intestinal absorption. As
`the stomach nears an empty stage, or operates in an essentially food emptied state, much
`more vigorous gastric activity occurs , which may be sensed by the individual as ''hunger
`pangs. " These more vigorous contractions of the stomach are described as "housekeeper"
`waves. It is for this reason that a solid dosage form which does not disintegrate in the
`stomach is much more likely to be expelled in a fasted state promptly than in a fed state.
`Thus, enteric dosage forms that are administered in the fed state have their greatest challenge
`as far as retaining their integrity in the stomach, due to the longer residence time and the
`more elevated gastric pH that exists in the fed state.
`As food is swallowed and enters the stomach, the fundus and body regions of the stomach
`relax to accommodate the volume of the meal. As food enters the stomach, it may form
`layers which are gradually mixed with the gastric secretions in the antrum by the more gentle
`contractions' of the stomach. Low-viscosity fluid that is swallowed may move into the antrum,
`and pass around and surround the more dense solid mass that may be present. The emptying ·
`of the stomach contents will typically begin only after a portion of the gastric contents have
`become fairly liquid and can readily pass through the pyloris. Peristaltic waves as contractions
`begin in the fundus region, travel down the stomach pre-pyloric area, and then become most
`intense as they reach the pyloris. The pyloris is not a valve, as some people may imagine,
`but is a sphincter. As the antrum leading into the pyloris, and the pyloric sphincter itself,
`contracts, the first segment or proximal region of the duodenum relaxes. A moment later,
`the antrum and pyloris relax, and the duodenum regains its tonicity. This type of movement
`"squeezes" the fluid gastric contents along as the contents move into the duodenum, and
`the pyloric sphincter recontracts momentarily to prevent regurgitation of intestinal contents
`back into the stomach. This gradual squeezing activity continues to move the contents along
`and into the further regions of the intestine. The gastric emptying process is influenced both
`by the rate of these antral and pyloric waves as well as by the strength of the contractions.
`These peristaltic waves are gentle, and the mixing activity is gentle with a filled stomach.
`The waves increase in frequency and strength in a more emptied gastric state. It has been
`reported that distention of the stomach is the only natural stimulus known to increase the
`emptying rate. Fat in any form has the greatest inhibitory effect on gastric emptying. This
`inhibitory influence permits more time for the digestion and processing of fat, which is the
`slowest of all foods to be digested. There may also be a hormonal mechanism which fats
`trigger to reduce gastric motility.
`Gastric emptying is generally regarded as occurring by an exponential (first-order) kinetic
`process. The rate of gastric emptyii:ig is probably not strictly linear if plotted first-order,
`especially at the earliest and latest times in the emptying process, but an overall approximation
`of first-order emptying will usually be fairly accurate.
`A few words are appropriate to describe intestinal transit. The rate at which materials
`move along the small intestine is important for both delayed and controlled release dosage
`forms, since drug absorption predominantly occurs in the small intestine. Knowledge of
`intestinal transit rates and ranges is important to understand the time frame in which the
`dosage form must operate to release drug and allow drug absorption to produce the intended
`propulsive and mixing movements.
`effect. There are two types of intestinal movements -
`The propulsive movements are generally regarded as synonymous with peristalsis, and the
`frequency and strength of the intestinal contractions will determine the transit rate along the
`intestine. Intestinal contents move along the intestinal tract at the rate of about I to 2 cm/
`sec. At this rate, material will transverse the small intestine in 3 to 10 h.
`The small intestine is approximately 7 m in length and is composed of three parts: the
`first being the duodenum; the second, the jejunum; and the third segment, the ileum, which
`joins the large intestine. The duodenum is the shortest segment, and is only about 25 cm
`
`Page 6 of 30
`
`

`

`43
`
`long. The common bile duct and the pancreatic duct enter the duodenum in the.first 33 to
`40% in organ length (in the first 7 to 10 cm) from the pyloris, where these ducts deliver
`their contents to substantially neutralize gastric acid that is conveyed with the gastric contents
`into the upper small intestine. The pH then quickly rises to about 4, even if the contents
`leaving the stomach were at a pH of about 1. The pH will then gradually increase as the
`contents move along into the jejunum, which is approximately 3 m long, and then to continue
`to rise as the material moves through the most lengthy segment of the intestine, the ileum.
`The colon or large intestine is about 1.5 m in length, and its principal function is to
`conduct indigestible materials from the small intestine to the exterior of the body as feces.
`During the process it removes a large amount of the water content of the materials. The
`mucosa of the colon is very smooth compared to the small intestine, which is covered with
`villi and micro-villi. Based on the greatly reduced surface area of the colon, it is not nearly
`as effective an absorption site as is the small intestine, although the longer residence of
`some materials in the colon may provide for some absorption of selected ingredients. An
`enteric dosage fonn that fails to disintegrate in the small intestine, and is delivered to. the
`colon, will almost certainly deliver no useful quantities of drug, unless the drug is being
`delivered to the colon for nonsystemic effects.
`
`C. ENZYME ACTIVITY
`There are a variety of enzymes in the intestine that help break down various substances.
`The enzymes which are part of the pancreatic juice are mainly hydrolytic, and include
`trypsin, chymotripsin, amylase, and lipase. Fats were used in the past as enteric coatings
`because they are not digested in the stomach due to the absence of lipase, but are digested
`in the intestine by intestinal lipase. Esterases are also thought to play a role in the disinte(cid:173)
`gration of some of the newer enteric coatings. Pepsin is the only primary enzyme of the
`stomach.
`
`IV. REQUIREMENTS OF AN IDEAL ENTERIC COATING
`
`Based on the GI physiology outlined above and the purpose of an enteric coating, an
`ideal enteric coating should possess the following properties:
`
`1. Must resist disintegration or dissolution in the stomach for as long as the dosage fonn
`remains there.
`2. Must be irnpenneable to gastric fluids and drug while in the stomach.
`3. Must dissolve or disintegrate rapidly in the small intestine.
`4. Must be physically and chemically stable during storage.
`5. Must be nontoxic.
`6. Must be easily applied as a coating.
`7. Must be economical, i.e., must not be too expensive.
`
`V. THEORY OF ENTERIC POLYMER PERFORMANCE
`
`A number of materials have been used as enteric coatings. The mode of action can be
`based on one mechanism or a combination of mechanisms. Some of the earlier coatings
`contained hydrophilic materials which swelled in the presence of moisture, causing the entire
`coating to break apart regardless of pH. 20 The idea behind this mechanism was that the
`coating material would start swelling in the stomach, but break up in the intestine. As Kanig6
`stated, "This type of system could disintegrate too early or too late due to the variability
`of gastric emptying and would not be reliable.''
`Other coatings such as Keratin, formalized gelatin, oils, and fats depended on enzymatic
`breakdown and/or emulsification, aided by bile salts and cholesterol. Coatings based solely
`
`Page 7 of 30
`
`

`

`44
`
`Polymers for Controlled Drug Delivery
`
`.,,
`on enzymatic breakdown have not been successful because enzyme breakdown is relatively
`slow.10.21
`Almost all the currently used enteric materials are synthetic or modified natural polymers
`containing ionizable carboxylic groups. In the low pH environments of the stomach, the
`carboxyJic groups remain un-ionized, and the polymer coatings remain insoluble. In the
`intestine, the pH increases to 5 and above, allowing the carboxylic groups on the polymeric
`coating materials to ionize, and the polymer coatings to disintegrate or dissolve, releasing
`their contents. The main factors influencing the ionization and subsequent disintegration of
`the coatings are the pKa of the polymeric acids and the pH of the surrounding medium. The
`relationship between the pH of the medium, the pKa, and extent of ionization of an acid is
`given, in general, by the Henderson-Hasselbach Equation
`
`concentration of on-ionized fonn
`p a-p = lo g - - - - - - - - - -(cid:173)
`K H
`concentration of ionized fonn
`
`(I)
`
`It is evident from the above equation that an enteric polymer with a pKa of 4 will be
`almost 99.9% on-ionized at pH 1, and 99.0% on-ionized at pH 2 conditions found in the
`stomach. This same polymer will be almost completely ionized at pH 6. In general, the
`polymer will be on-ionized and insoluble at pH values 2 units below its pKa, and completely
`ionized and soluble at pH values 2 units above its pKa. Based on the range of pH of 1.0
`to 3.519·21 in the stomach and 3.8 to 6.620 in the small intestine, the ideal pKa for enteric
`polymers that would prevent their gastric disintegration but help them disintegrate fairly
`rapidly in the intestine would be in the range of 3.5 to 5. As noted previously, no single
`enteric polymer can meet all enteric coating product needs according to the primary objectives
`for each product, or the needs of the drug(s).
`Other factors that influence the disintegration or dissolution of enteric coatings are
`
`1.
`
`3.
`4.
`
`The initial fraction of free carboxylic acid groups on the polymer molecule. Hiat22
`stated that for cellulose acetate phthalate, a free carboxylic group of 9 to 15% was
`best for enteric coating.
`2. Nature of the core material. Ozturk and others23 have shown that acidic core materials
`may lower the pH of the coating layer relative to that of the bulk, resulting in a delay
`in coating disintegration, whereas basic core materials increased the pH in the coating
`layer and could lead to premature disintegration in the stomach. These investigators
`suggested that the pH-lowering effect of acidic drugs may be offset by choosing a
`polymer with a lower pKa, whereas for a basic drug, a polymer with a higher pKa
`would be desirable to avoid dosage fonn disintegration during gastric residence. In
`addition, the water-drawing affinity of the core and its swelling properties on exposure
`to water can affect both the performance and reliability of the product. Clearly, the
`nature of the tablet core can greatly affect the performance and reliability of enteric
`coated products.
`The ionic strength of the dissolution medium also influences coating dissolution.23 •24
`The distance between various carboxyl groups on the polymer backbone also influences
`coating dissolution. Davis and others25 showed that the pKa of various enteric polymers
`increased as the distance between the phthalyl groups decreased, resulting in increasing
`disintegration times. Similar results were reported by Delporte using polyvinyl acetate
`phthalate (PV AP) batches of varying combined phthalyl contents as coatings. 16
`Coating thickness influences dissolution. The thicker the coating, the longer it will
`take for the polymer to dissolve.
`The presence or absence of plasticizers is another important factor that affects the
`performance of enteric coatings. 25-27 This factor will be discussed in later sections.
`
`5.
`
`6.
`
`Page 8 of 30
`
`

`

`45
`
`VI. ENTERIC COATING MATERIALS
`
`Due to the large number of materials used or proposed for enteric coating, it will not
`be possible to give an in-depth treatment of all the materials in one chapter. This discussion
`therefore, is limited to enteric materials that have been widely used, are compendia! materials,
`and have the potential for becoming widely used. The information provided here is largely
`drawn from technical literature obtained from the manufacturers of the various polymers as
`well as from the general literature.
`
`A. SHELLAC
`Shellac, also called purified Jae, is a refined product obtained from the resinous secretion
`of a tiny insect, Lace if er lacca Karr, which lives in the branches of various trees found in
`India an~ other countries in that region. 28
`29 Shellac is obtained through a series of purification
`•
`of the secretions. There are two grades of shellac. Orange shellac is produced by a process
`of filtration in the molten state or by a hot solvent extraction. Bleached or white shellac is
`prepared by dissolving lac in aqueous sodium carbonate, bleaching the solution with sodium
`hypochlorite, and precipitating the bleached shellac with 2N sulfuric acid. Refined bleached
`shellac is shellac with its wax content removed.
`On mild hydrolysis, shellac gives a mixture of aliphatic (about 50%) and alicyclic (5
`to 10%) hydroxy acids. The major component of the aliphatic acid fraction is aleuritic acid,
`and that of the alicyclic fraction is shellolic acid (Figure 1). Shellac also contains about 5
`to 6% wax and a small amount of lac pigment. 28
`
`1. Solubility
`Shellac is soluble in ethanol, propylene glycol, ammonia solution, and alkaline solutions.
`
`2. Use of Shellac as an Enteric Coating Material
`Shellac has been used extensively as an enteric coating alone or in combination with
`other materials since 1930, when Wruble30 reported on its use. He found that ammonia
`solutions of shellac provided the best enteric coatings, among a number of solutions inves(cid:173)
`tigated. Goorley and Lee3 stated that a mixture of shellac and castor oil gave a satisfactory
`enteric coating. Due to several reported disadvantages, shellac is no longer the material of
`choice when considering enteric coatings. Gorley and Lee3 pointed out that tackiness was
`a disadvantage of applying shellac as a coating. Also being of natural origin, there is the
`possibility of variation from batch to batch. Luce31 showed that tablets coated with shellac
`had substantially increased disintegration times after 6 months of storage, compared to freshly
`coated tablets. After 12 months storage some tablets failed to disintegrate in simulated
`intestinal fluid. The delayed disintegration and reduced solubility of shellac on storage is
`attributed to polymerization resulting from transesterification of the hydroxyl group of one
`shellolic or aleuritic acid molecule with the carboxyl group of another of the hydroxyl(cid:173)
`containing carboxylic acids. This esterification/aging process not only results in polymeri(cid:173)
`zation, but also reduces the number of carboxyl groups which provide the enteric solubility
`properties.
`· One other disadvantage of shellac as an enteric coating is that it does not dissolve below
`pH 7. 32 Since the pH in the small intestine, where most drug release is required, is between
`3.8 and 6.9, failure of shellac-coated tablets to disintegrate at .pH values below 7 is a major
`disadvantage. The requirement of a high pH for dissolution, coupled with delayed disinte(cid:173)
`gration due to aging, makes it a real possibility that shellac-coated tablets may occasionally
`go through the gastrointestinal tract without releasing their active ingredients. Even when
`the active ingredient is released, it is obvious that the onset of action following administration
`of shellac-coated dosage forms may be greatly delayed. The use of shellac in controlled- or
`
`Page 9 of 30
`
`

`

`46
`
`Polymers for . Controlled Drug Delivery
`
`0H-(CH
`
`CH
`2
`
`)
`
`2
`
`-(CH20H) 2-(cH2)
`5
`Alleuritic Acid
`
`- COOH
`7
`
`OH
`
`COOH
`
`HOOC
`
`Shellolic Acid
`
`AGURE I. Chemical structures of shellolic and alleuritic acids.
`
`sustained-release products is also risky due to reduced solubility resulting in altered-release
`profiles that are likely to occur on aging.
`On the positive side, shellac offers good protection against moisture permeation,2<>·33
`and has been widely used as a seal coat for various tablets, especially vitamin tablets, prior
`to coating with aqueous based compositions. It has also been recommended for incorporation
`in HPMCP coatings to reduce gastric fluid permeation. 33 Making reference to the use of
`shellac in wood finishing operations, Hicks2<> stated that "shellac in liquid form performs
`the task of a sealer, undercoat and finish as no other substance will." In World War II,
`shellac was used in India for gasproofing clothing and waterproofing ammunition. 2<>
`India and Thailand produce most of the commercial shellac of the world.
`
`B. CELLULOSE ACETATE PHTHALATE (CAP)
`Cellulose acetate phthalate was first described as an enteric coating by Hiatt in 1940.22
`The oldest of the phthalate-containing polymers used in enteric coating, it is prepared by
`reacting a partial acetate ester of cellulose with phthalic anhydride. Figure 2 shows the
`chemical structure of CAP.
`About half of the hydroxyl groups on the cellulose chain of this polymer are acetylated,
`and about one fourth is esterified with one of the two acid groups of phthalic acid. The
`other carboxyl group of phthalic acid is free to ionize. The degree of phthalyl substitution
`influences cellulose acetate phthalate solubility in both aqueous and organic solvents, and
`therefore its performance as an enteric coating. Aqueous solubility increases with increasing
`phthalyl content. 35 Because the degree of substitution can lead to changes in CAP properties,
`specifications for CAP composition have been established to ensure more uniform perfor(cid:173)
`mance, batch to batch. The NF specifications for CAP are shown below:
`
`Combined phthalyl as C8HsO3
`Combined Acetyl as CH3CO
`Free Acid as C8H60.
`Viscosity of a 15% solution in acetone with a moisture content of 0.4%
`
`30.0-36.0%
`19.0-23.5%
`"-6.0%
`50-90 cps at 25°C
`
`I. Solubility of CAP
`Cellulose Acetate Phthalate is insoluble in water, alcohols, hydrocarbons , and chlorinated
`hydrocarbons. It is soluble in ketones, ethers, alcohols, esters, and in certain solvent mixtures.
`
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`H
`
`H
`
`47
`
`n
`
`o-
`
`H
`
`OR
`
`0
`
`II o:::o,
`
`FIGURE 2. Chemical structure of cellulose acetate phthalate.
`
`Its supplier, Eastman Chemical Products, Inc., lists the following as useful solvents and
`solvent blends:
`
`Acetone
`I: I
`Acetone:ethanol
`I :3
`Acetone:methanol
`I :3
`Acetone:Methylene chloride
`Ethyl acetate:lsopropanol
`l: I
`
`Other solvents listed in the literature for CAP include methyl ethyl ketone, dioxane,
`methyl acetate, and ethyl acetate.
`
`2. Properties of CAP as an Enteric Coating Material
`There are several reports in the literature about the effectiveness of CAP as an enteric
`coating material. Hodge and others,37 after in vivo studies on the disintegration of CAP(cid:173)
`coated tablets and capsules, concluded that cellulose acetate phthalate-coated tablets and
`capsules possessed satisfactory enteric characteristics. Ellis and others38 stated that CAP
`comes very close to fulfilling the requirements of an ideal enteric coating material . There
`are also reports to the fact that CAP is a safe, nontoxic material. 36-40
`CAP is a polymeric acid, and behaves like other acidic materials which ionize and
`dissolve in regions of the gastrointestinal tract depending on the pH of the region and the
`pKa of the particular polymer samples. There are, however, a number of conflicting reports
`in the literature as to the mechanism of disintegration of CAP. Bauer and Masucci41 presented
`in vitro experimental results to show that CAP dissolution in the intestine is due mainly to
`the hydrolytic action of intestinal esterases, and not due to ion!zation. Hayashi and others,24
`however, stated that although enzyme action may play a role, it is so slow, and that the
`main effect on CAP disintegration is ionization. Wilken and others42 also presented results
`to show that pancreatin in simulated intestinal fluid had little effect upon the disintegration
`times of cellulose acetate succinate ~d cellulose acetate phthalate, and suggested that any
`effect by pancreatic enzymes was slow and overshadowed by th