ENDO - Ex. 2041
`
`Amneal v. Endo
`
`|PR2014-00360
`
`ENDO - Ex. 2041
`Amneal v. Endo
`IPR2014-00360
`
`

`
`EXtended—Release
`Dosage Forms
`
`Author
`
`Leszek Kréwczyriski, Phar. D., Ph.D.
`Professor
`Department of Pharmaceutical Technology and Biopharmaceutics
`Medical Academy
`Cracow, Poland
`
`Translator
`
`Dorota Porebska Brozyna, M. A.
`Lecturer
`
`Foreign Language Department
`Medical Academy
`Cracow, Poland
`
`C35 '.=
`
`CRC Press, Inc.
`Boca Raton, Florida
`
`

`
`Library of Congress Cataloging-in-Publication Data
`
`Krowczyiiski. Leszek.
`Extended—release dosage forms.
`
`Includes bibliographies and index.
`I. Drugs—Controlled release.
`I. Title.
`[DNLM:
`l. Delayed-Action Preparations. QV 785 K93e]
`RS20l.C64K76
`1987
`ol5’.l9l
`86-13683
`ISBN 0-8493-4307-0
`
`This book represents information 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, 3343l.
`
`© l987 by CRC Press, Inc.
`
`lntemational Standard Book Number 0-8493-4307-0
`
`Library of Congress Card Number 86-13683
`Printed in the United States
`
`

`
`Chapter 6
`
`ORAL EXTENDED-RELEASE DOSAGE FORMS:
`PRINCIPLES OF TECHNOLOGY
`
`I. GENERAL CONSIDERATIONS
`
`A. Types of Oral Extended-Release Dosage Forms
`A majority of the oral extended—release dosage forms are different types of tablets and
`capsules. Far less frequently liquid preparations, most often as suspensions, can also be
`found.
`
`Pharmaceutical companies produce a wide variety of such dosage forms giving them their
`own trade names. For better orientation in terminology, Tables 1, 2, and 3, based on
`literature, "4 contain a survey of trade names for extended—release dosage forms manufactured
`as tablets, capsules, and liquid preparations. The characteristics of particular dosage forms
`is, in many cases, very simplified, however it will be discussed in more detail below.
`
`B. Gastrointestinal Absorption
`Drug in oral dosage forms moves (Figure 1) from the oral cavity, through the esophagus,
`to the stomach, and then through the duodenum, small intestine, and large intestine.
`During passage through the GI tract, the transit time, the segment area, and the pH of
`the fluid in contact with the dosage form vary as is shown by the data in Table 4. Fluids
`excreted into the GI tract have various composition and pH (Table 5) which affect the release
`and absorption of drugs:‘ Both the differences in pH and the presence of some enzymes
`have been used in the design of extended—release oral dosage forms.""3
`While designing extended—release oral dosage form for a given drug, not only the release
`retardation, but the absorption site, should be taken into account. Wide variations in ab-
`sorption may be observed in the particular parts of the GI tract, for example when comparing
`rate of absorption from the stomach to that in the intestine, or from the small intestine to
`the large intestine. This is the result of the increased surface area for absorption of about
`4500 ml presented by the microvilli on the intestinal mucosa surface. The varying volume
`of blood passing through the intestinal (1000 m€/min)
`and gastric (150 mt’/min) capillaries
`affects the absorption rate. It is also concerned with the physical—chemical properties of the
`drugs themselves.
`Investigations of the absorption of propranolol in different regions of rat gastrointestinal
`tract in situ revealed that the transit rate declines with passage through the GI tract. Orally
`administered propranolol solution is absorbed, to the greatest extent, in the lower part of
`the small intestine.”
`
`The normal peristaltic movements of the gastrointestinal tract facilitate absorption by
`transfer of the material to contact with the surface where absorption takes place. The same
`movements facilitate dissolution of drugs, and therefore affect the release rate from solid
`dosage forms.
`In many constructions of solid oral extended—release dosage forms, considered as drug
`delivery systems, the transit time of the dosage form through the particular parts of GI tract
`is of great importance. It depends on the kind of food bulk. The rate of the stomach emptying
`is affected by the consistency and temperature of the food. Half of liquid food at room
`temperature leaves the stomach after 22 min, but if the food is 37°C, it leaves the stomach
`after 7 min. Ler '4 estimates transit time in the stomach for liquids at 0.2 to 0.5 hr, for
`well-chewed food, 0.5 hr; and for tablets, 0.5 to 3.0 hr. This time in the small intestine,
`
`

`
`
`
`"‘
`
`98
`
`Extended-Release Dosage Farms
`
`Table 1
`
`THE TRADE NAMES OF TABLET TYPE
`EXTENDED-RELEASE DOSAGE FORMS‘-3~“
`
`Definition
`
`Manufacturer
`
`Press—coated extended—release tablet
`Sustained-action tablet
`Extended—release tablet
`Time—release tablet
`Continuous-release tablet
`Two-layer tablet with the initial dose in
`the outer layer and an enteric-coating
`isolation of the maintenance dose in the
`core
`
`Like Dupletten
`Extended—release coated tablet containing
`drug—macromolecule complex
`Sustained—action coated tablet
`
`Extended-release plastic—matrix tablet
`Extended—release plastic-matrix tablet
`Extended—release plastic—matrix tablet
`Repeat—action tablet
`Press—coated prolonged-action tablet
`Extended-action tablet with a slow—re-
`lease core
`
`Long—release tablet with inert porous sol—
`ids as drug carriers
`Exchange resin extended—release tablet
`Time—release tablet for children with a
`special tasteless coating
`Extended—release tablets
`Tablet of mixed release-rate granules
`Extended—re1ease fat—eroding tablets
`Multi-layer dragee with different time of
`disintegration
`Press—coated long—acting inlay tablet with
`an enteric-coated slow-release core
`Oral osmotic therapeutic system
`Osmotic gastro—intestinal therapeutic
`system
`Tablet with a slow-release core
`Tablet in a capsule shape with slowly
`.
`disintegrating core
`Repeat-action enteric-coated tablet with
`the initial dose in sugar coat
`Bilayer tablet with one extended-release
`layer
`Original timed-enteric-coated tablet
`Continuous-release eroding-dosage form
`Time—release tablet
`Tablet of mixed release-rate granules
`Extended-release tablet
`Time-disintegration tablet
`Extended—release tablet
`Multi-layer press—coated extended—release
`tablet
`
`Wander (Switzerland)
`White Labs (U.S.)
`Napp (U.K.)
`Southern Drug Mfg. Co. (U.S.)
`Merrell (U.K.)
`Merck (W. Germany)
`
`Ciba (Switzerland)
`Neisler (U.S.)
`
`Wynn Pharrnacal. (U.S.)
`Cooper (U.S.)
`
`Hassle (Sweden)
`Astra (Sweden)
`Astra (Sweden)
`Premo Labs (U.S.)
`Geigy (U.S.)
`Robins (U.S.)
`
`Abbott (U.S.)
`
`Aspro—Nicholas (U.K.)
`Dorsey (U.S.)
`
`Wyeth (U.S.)
`Specia (France)
`
`Artesan (W. Germany)
`
`Ciba (U.S.)
`
`Alza Corp. (U.S.)
`Frosst Pharma (W. Germany)
`
`McNeil (U.S.)
`Schwarz (W. Germany)
`
`Schering (U.S.)
`
`Wamer Chicott (U.S.)
`
`Seal-lns. Labs. (U.S.)
`Pitman Moore (U.S.)
`Prime Labs. (U.S.)
`Sandoz (U.S.)
`Allen and Hanbury (U.K.)
`Smith, Kline & French (U.S.)
`Eastern Research (U.S.)
`Boehringer-Ingelheim (W. Germany)
`
`Special base-matrix tablet which allows
`for controlled, gradual drug release
`
`Ives Labs. (U.S.)
`
`Name
`
`Bitabs
`Chronotab
`Continus
`Delay Tab
`Dospan
`Dupletten
`
`Duplex
`Durabond
`
`Dura—Tab
`
`Durretter
`Duriles
`Durules
`Encore
`Enduret
`Extentab
`
`Gradumet
`
`lonexten
`Juvelet
`
`Latab
`Lenterule
`Lipetter
`Longoral
`
`Lontab
`
`Oros
`Osmogits
`
`Prestab
`Procaps
`
`Repetab
`
`S.A. tablet
`
`Seal-Ins
`Singlet
`Spacelet
`Spacetab
`Spandet
`Spantab
`Stedytab
`Tablonget
`
`Tembid
`
`

`
`99
`
`Table 1 (continued)
`THE TRADE NAMES OF TABLET TYPE
`EXTENDED-RELEASE DOSAGE FORMSZ~3~“
`
`Name
`
`Definition
`
`Tempo-tablet
`Tempotrol (T.T.)
`
`Ten~Tab
`Tenuate
`Timelet
`Timespan
`Timetab
`Ty—Med
`Tymtab
`
`Multilayer tablet designed for time disin—
`tegration over a period of 8 to 10 hrs
`Time-controlled therapy tablet with
`mixed release—rate granules
`Continuous—release tablet
`Extended—release tablet
`Sustained-release tablet
`Tablet with slow—release core
`Time—release tablet
`Timed—release tablet
`Timed—release tablet
`
`Manufacturer
`
`Penn Pharmacal. Co. (U.S.)
`Phillips—Roxane (U.S.)
`
`National Drug (U.S.)
`Merrell (U.K.)
`Rowell Labs. (U.S.)
`Roche (U.S.)
`Rocky Mt. Pharm. (U.S.)
`Lemmon Pharmacal (U.S.)
`Amfre-Grant (U.S.)
`
`units, have a duration of stay in the GI tract similar to the transit time of food. Dosage
`forms of the multiple—units dose type, e.g., spansule (gelatin capsules filled with pellets)
`behave in a totally different manner. It has been confirmed that pellets may move inde-
`pendently of chyme in the GI tract. They leave the stomach without being influenced by
`the stomach emptying rate. Transit time in the small intestine is affected by their density,
`and to a small extent, by their diameter in the range 0.3 to 1.7 mm. Pellets having a density
`of 1.0 g/m€ moved from the stomach to the large intestine within 7 hr, while those having
`a density of 1.6 g/m€, within 25 hr. By modification of pellet density, various transit times
`and periods of absorption can be obtained, and therefore they can provide a drug delivery
`system for a period of time longer than the transit time of food.
`Diazepam absorption is more desirable in the stomach, not in the intestine where it is
`poorly absorbed. For this reason the swimming—capsule, which remains on the surface of
`
`The fact that the stomach empties into the intestine and that many drugs will be absorbed
`from both the stomach and the intestines, although at different rates,
`is a very important
`factor that makes it difficult to gain a quantitative understanding of absorption since stomach
`emptying time is involved.
`The next factor which should be taken into account in the general consideration of ab-
`sorption from the GI tract is Brodie’s pH partition theory for drug absorption. ‘7 It states that
`drug absorbability is favored when it is present in the uncharged form at the site of absorption
`and possesses an intrinsic partition coefficient favoring oil in an oil—water system. Charged
`(ionized) molecules are,
`in general, oil insoluble and therefore the absorption of weakly
`
`Here acidic drugs appear in the ionized form as anions and are poorly absorbable while
`undissociated weakly basic drugs are well absorbed.
`Within one hr, 61% of salicylic acid (pk, = 3.0) is absorbed from a medium having a
`
`
`
`
`
`
`
`.»e~.»..w..~v<.-w-«-=«,.:-.«,-»:_a-t,¢.w.-:,«;.:'~*-:,v-reve-‘iv<-‘‘'''7‘'“'‘°''.‘.’'‘'"‘‘*7
`
`

`
`100
`
`Extended—Release Dosage Farms
`
`Table 2
`
`THE TRADE NAMES OF CAPSULE TYPE EXTENDED-RELEASE DOSAGE“-4
`FORMS
`
`Name
`
`Definition
`
`Manufacturer
`
`Chroncap
`Chronosule Capsule
`Chronsule
`Chronules
`Delacap
`Delaycap
`Diffucap
`Duracap
`' Gradual
`Gradule
`Granucap
`lntervule
`
`Keensule
`Longcap
`Medule
`Nyscap
`Pacap
`Palet
`Perlongetten
`Plateau Cap
`Prolcap
`Prolongsule
`Sequel
`Spansule
`
`Spancap
`Spascap
`Stankap
`Suscape
`Sustets
`Taysule
`
`Tembids
`Tempule
`
`Temsule
`
`Timcap
`Timecap
`Timed capsule
`Timeset
`Timesule
`Timkap
`Trisule
`Tymcap
`Unicelle
`
`Time—release capsule
`Capsule containing slow—release beads
`Extended-release capsule
`Capsule containing slow-release beads
`Delayed—action capsules
`Time-release capsule
`Extended-release capsule
`Sustained—release capsule
`Timed—disintegration capsule
`Gradual—release capsule
`Time-disintegrating capsule
`Delayed—action. time-disintegrating cap-
`sule released in 3 equal doses every 3
`— 4 hr
`
`Time—disintegt‘ating capsule
`Extended—action capsule
`Capsule with coated slow—release beads
`Extended-release capsule
`Extended—release capsule
`Timed—disintegrating capsule
`Extended-release capsule
`Sustained—release capsule
`Time—disintegrating capsule
`Time—disintegrating capsule
`Capsule containing slow—release beads
`Capsule containing mixture of colored
`pellets with different release rates
`Gradual-release capsule
`Time-disintegrating capsule
`Time-disintegration capsule
`Extended—release capsule
`Extended-release capsule
`Extended-release capsule for around—the-
`clock medication
`Extended-release capsule
`Proportionate—release capsule
`
`Time—disintegrating capsule
`Time-disintegrating hard—filled capsule
`Time-release capsule
`Capsule with slow—release beads
`Time—disintegrating capsule
`Capsule with coated slow—release beads
`Time-disintegrating capsule
`Extended-release capsule
`Timed-disintegration capsule
`Capsule containing pellets which disinte-
`grate at intervals giving uniform and
`prolonged release
`
`H.R. Cenci Pharrnacal (U.S.)
`Schering (U.S.)
`Louisons Pharmaceuticals (U.S.)
`Dexo (France)
`Sig. Labs. Inc. (U.S.)
`Southern Drugs and Mfg. Co. (U.S.)
`Globopharm. (Switzerland)
`Meyers Labs. (U.S.)
`Federal Pharmacal (U.S .)
`Jan Labs. (U.S.)
`SJ. Tutag (U.S.)
`Jan Labs. (U.S.)
`
`Keene Pharmacal (U.S.)
`v. l-leyden (W. Germany)
`Upjohn (U.S.)
`Nysco (U.S.)
`Servier (U.K.)
`Philadelphia Labs. (U.S.)
`Boehringer Ingelheim (W. Germany)
`Marion Labs. (U.S.)
`Gold Leaf Pharmacal (U.S.)
`Richlyn Labs. (U.S.)
`Lederle (U.S.)
`Smith. Kline & French (U.S.)
`
`Domed (U.S.)
`Prime Labs. (U.S.)
`Standex Labs. (U.S.)
`Mepha (Switzerland)
`Lederle (U.S.)
`Taylor Drug Co. (U.S.)
`
`Ayerst (U.K.)
`Armour Pharm (U.S.)
`Evron (U.S.)
`Veltex Co. (U.S.)
`Vitamix Corp. (U.S.)
`Leeds (U.S.)
`Fellows (U.S.A)
`Cabot Pharmacal (U.S.)
`Amar-Stone (U.S.)
`Betan Co. (U.S.)
`Chas. C. Haskell (U.S.)
`Amfre—Grant Inc. (U.S.)
`Hiss Pharmacal Co (U.S.)
`
`
`
`in
`
`

`
`101
`
`
`
`Schematic diagram of the gastrointestinal tract: (l) oral cav-
`FIGURE 1.
`ity. (2) esophagus. (3) stomach. (4) duodenum. (5) small intestine. and
`(6) large intestine.
`
`THE TRADE NAMES OF LONG-ACTING ORAL LIQUID
`PREPARATIONSL3“
`
`Table 3
`
`Name
`
`Definition
`
`Manufacturer
`
`Perlongit
`Spansion
`
`Oral suspension with extended release
`Oral suspension with extended release
`
`Boehringer-Ingelheim (W. Germany)
`Smith, Kline & French (U.S.)
`
`pH of 1.0, and 13% at pH 8. while 18% of quinine, which is a base (pku = 8.4) is absorbed
`from a medium having a pH of 8 within 1 hr. At pH 1,
`it
`is not absorbed at all (0%
`absorption).
`Acetylsalicylic acid, which has a pKa of about 3.4, exists in the stomach (assuming pH
`2) in the undissociated form. Only 4% is ionized. In the small intestine, at pH 7.0, more
`than 99.99% is in the ionic form. According to Brodie’s pH—partition theory, acetylsalicylic
`acid should be absorbed more rapidly from the stomach than from the intestine. This is
`because in the absorption process of this weak acid from the stomach to the blood (pH 7.4),
`the equilibrium ratio of the concentration in the stomach to the concentration in the blood
`is about I to 25,000. This means that in order to obtain equal concentrations of undissociated
`form on both sides of the lipid membrane separating stomach from the blood. acetylsalicylic
`acid will reach a blood concentration 25,000 times greater than in the stomach. Such a
`difference in concentration is the driving force which causes absorption.”
`With substances that are as soluble in blood as they are in gastric or intestinal fluids, a
`strong driving force to cause absorption exists because of the larger volume of blood and
`other fluids of distribution compared to the volume of either gastric or intestinal fluids.
`As mentioned in Chapter 2, dissolution rate is greatly influenced by the surface area
`exposed to the dissolution medium. This applies not only to the initial drug particle size or
`granule or pellet dimensions, but also to the possible change in the particle size in the
`stomach. In the case of the oral administration of solid drugs, various behaviors of the weak
`
`5,
`
`l i
`
`

`
`102
`
`Emmded-Release Dosage Farms
`
`‘
`Section
`
`Table 4
`CHARACTERISTICS OF THE GASTROINTESTINAL TRACT
`Liquids
`Transit time
`secretion
`of food
`(6/d)
`(hr)
`
`Reaction
`(pH)
`
`More important
`constituents
`
`Oral cavity
`
`0.5——2
`
`5.2—6.8
`
`E5°P““g“S
`Stomach
`
`.
`
`’
`
`Duodenum
`
`Small intestine
`Large intestine
`
`.
`
`.
`
`0.2
`About 0.2
`
`4.7——6.5
`7.5—8.0
`
`Short
`
`Very short
`
`0.25-3
`
`Amylase
`Ptyalin
`Mucins
`—
`
`Hydrochloric acid
`Pepsin
`Rennin
`Cathepsin
`Lipase
`Intrinsic factor
`Amylase
`Glucohydrolase
`Galactohydrolase
`Lipase
`Trypsin
`Chymotrypsin
`Bile acids
`I
`Like in duodenum
`Mucus
`Bacteriums
`
`'°
`
`T k‘
`'
`21 mg in
`
`testinal microvilli area into account, without them about 100 m2.
`Table 5
`ION AND ENZYME CONTENT IN GASTROINTESTINAL FLUIDS
`Saliva
`Gastric juice
`Bile
`Pancreatic juice
`
`in)
`
`Amylase (mg/mi“)
`Pepsin (U/24 hi")
`Chymotrypsin (mg/m
`Trypsin (mg/mi“)
`,
`“pas? (U/24 hm)
`Ch1°“‘_"‘ (“““° Om
`£0381-SS,:u:m(,l1nc:i]/6)
`0 111
`Calcium (mmol/O
`B“° “ids ‘gm
`glgfl
`( 6/min)
`ux m
`
`“ mt?/24 hr.
`
`0.38
`—
`-—
`—
`
`15.l——3l.6
`14-41
`5.2-24.4
`23:55
`5.8—7.1
`O.35——0.38
`
`—
`18.9—28.8
`—
`-
`-
`77.6-—l59
`6.4——l6.6
`l8.7——69.5
`20:48
`1.92-2.59
`13——2l7
`
`-
`-
`—
`—
`.-
`89-1 18
`2.6-12.0
`131-164
`3.3519
`6.2-8.5
`250-1100“
`
`0.29-1.30
`-
`l.22—7.60
`0.38-1.42
`0.78-3.50
`4-129
`6-9
`139-143
`2.2:-1.6
`7.5-8.8
`36
`
`sodium salts can be observed in the gastric fluid. The dissolution rate of
`free acid and its
`6 Sodium in gastric juice is about 800 times as fast as the free phenobarbitone
`.
`ph.enObarbu(§11e 6)_ This means that the gastric fluid will be almost instantaneously saturated
`ac_icr1l(s}ele T211)arbitone when the sodium salt is taken.
`wltofpcslilrcée the free phenobarbitone acid precipitates in this acidic medium, but this pre—
`. mfion presents a large surface area to the medium and 1S another factor helping to keep
`$11121 henobarbitone concentration high in the gastric juice, and hence to keep the absorption
`mtepat a maximum This sequence of events does not occur with acidic phenobarbitone, and
`therefore the absorption rate is much slower.
`
`

`
`Table 6
`THE DISSOLUTION RATE OF ACIDS AND
`THEIR SODIUM SALTS INTO ACIDIC
`AND NEUTRAL SOLUTIONS
`
`Dissolution rate
`(mg/100 min/cm‘)
`
`pH 1.5
`
`pH 6.8
`
`0.24
`200
`1.7
`1870
`Less than 0.1
`550
`
`l .2
`820
`27
`2500
`0.5
`810
`
`Phenobarbitone
`sodium salt
`Salicylic acid
`sodium salt
`Sulfathiazole
`sodium salt
`
`The design of an extended—release dosage form should also account for the possibility of
`an “absorption window” for a given drug. This means whether or not
`it
`is absorbed
`exclusively within a short part of the GI tract, or if there is a first-pass effect (the loss of
`drug as it passes through the gastrointestinal membranes and the liver for the first time
`during the absorption process). Such a situation makes the formulation of the oral extended-
`release dosage form impossible in most cases.
`
`C. Classification and Systematization of Oral Extended-Release Dosage Forms
`One of the first attempts at classification was undertaken by Cooper.” He differentiated
`the extended—release dosage forms according to their behavior within the GI tract: (1) tablets
`disintegrating into small particles, (2) tablets undergoing slow erosion, which keep the shape
`and diminish in dimension, (3) tablets which keep the shape and dimensions and from which
`a drug is released by leaching.
`Classification which accounted not only for the way of preparation, but also for the
`properties of excipients was provided by D€lp0I‘tC.2°
`
`l.
`
`Coated forms
`A. Of not continuous release
`
`1.
`
`Having coatings that prolong disintegration time (mixture of pellets having
`various release rates).
`Having enteric coatings
`2.
`B. Of continuous release
`
`Forms with drug embedded
`A.
`In a hydrophilic matrix
`B.
`In a hydrophobic matrix
`C.
`In a plastic matrix
`Forms with slightly soluble complexes
`A.
`Complexed with tannin, etc.
`B.
`Complexed with ion-exchange resins
`
`following
`the
`differentiated
`and Nelson3
`Ballard
`oral products depending on their type and construction:
`
`groups of
`
`extended—release
`
`Coated slow—release beads, granules, or pellets contained in hard gelatin capsules
`Tablets with slow—release cores
`
`Repeat-action tablets
`Tabletted mixed~release granules
`Multiple-layer tablets
`
`

`
`104
`
`Extended-Release Dosage Forms
`
`Porous inert carriers
`
`Ion—exchange resins
`Slightly soluble salts or complexes
`Liquid preparations
`
`Principally three basic technologies are applied to obtain oral extended-release dosage
`forms: chemical or physical—chemical binding, coating, and embedding. Table 7 contains
`basic information about the excipients used, the possibilities of release rate, and mechanism
`modification as well as the kinetics of release.
`
`II. DOSAGE FORMS WITH CHEMICAL OR PHYSlCAL—CHEMICAL
`BOUNDED DRUG
`
`A. Slightly Soluble Salts or Complexes
`Extended release can be obtained by tablet formulation in the conventional way but with
`preparation of a salt or complex of drug that is only slightly soluble in the gastrointestinal
`fluids.
`
`Drugs which are amines can form slightly soluble salts with tannic acid. The amine
`tannates were prepared by mixing methyl or ethyl alcohol solutions of the amine drug and
`tannic acid in 20% excess, and diluting the mixture with ice water to complete precipitation
`of the tannate. After the filtering of precipitate, it was washed with the ice water and dried
`in a vacuum.“
`
`Tablets were prepared by mixing tannate with standard excipients, and granulation with
`binder solution. The product of granulation was dried, and after mixing with lubricants, was
`pressed into tablets. Durabond® (Neisler) with amphetamine (Synatan®) tablets are prepared
`according to this principle. Phenylephyrine in the tannate form provides for a constant blood
`level within 12 hr after a single oral administration.’
`Another example of a slightly soluble salt is quinidine polygalacturonate. It is obtained
`by mixing stoichiometric quantities of polygalacturonic acid and quinidine base in hydroal—
`coholic solution and recovering the complex by evaporation of the solvent under reduced
`pressure. After pulverization, the product is pressed into tablets (Cardioquin®, Galaktoquin®).
`A complex of digitoxin and carboxymethylcellulose is also known. Extended release in
`the GI tract was also proved for the dye complexes with dextran, due to the slow fission
`by the dextranase enzyme.”
`Carbovinyl polymer (Carbopol 934®) interacts with antazoline hydrochloride forming an
`insoluble complex which can be used for the formulation of extended-dosage forms.”
`A polymer—drug interacted system can be also used in the physico-chemical design of
`extended—release dosage forms. The formation of polymer-drug salts, based on the example
`of the interaction of a therapeutically active amine with a cross—linked copolymer containing
`reactive carboxyl groups, was patented.“
`The hemi—esters of poly(methyl vinyl ether/maleic anhydride) with l.l2—dihydroxyocta-
`decane react with methapyrilene base to form hemi—ester salts, which have extended release
`from granular and tableted forms in vitro.“
`
`B. Drug Bound on Ion-Exchange Resin
`Polymers containing groups capable of exchanging ions (known since 1935, called ion-
`exchange resins) can be used to obtain extended—action preparations of ionizable drugs.
`These resins are built of molecules forming a skeleton: styrene, phenol and its derivatives
`together with cross—linking agents, divinyl-benzene or formaldehyde. They may contain
`acidic—reacting groups such as the phenolic, carboxylic, or sulphonic (cation ion~exchange
`resins). They may also contain basic groups such as amino or quaternary ammonium groups
`(anion ion—exchange resins) (Figure 2).
`
`

`
`105
`
`Reacting groups of ion—exchange resins can be used to bind drugs, basic drugs to acidic
`cation ion—exchangers, and acidic drugs to basic anion ion—exchangers. The attainment of
`extended release by means of ion—exchange resins was first described by Saunders.25'23
`The displacement reactions from drug resinate or drug resin salt in the GI tract are shown
`in Table 8.
`
`For example, the displacement reaction from drug-resin complex in the case of a sulfonic
`acid type cation-exchange resin combined with a basic (e.g., a primary amine) drug in
`contact with the intestinal fluid may be described by the simplified chemical equation:
`
`(R—SO;H3N*—R’) + (X*Y‘) 2 (R—SO;X+) + (H_,N*—R’Y‘)
`amine drug
`resinate
`
`where X" is H*, Na* or another cation, and Y‘ is C1" or another anion.
`Resins are available in the form of either globular particles (called by some authors ion
`exchange resins beads) or sharp-edged granules produced by crushing. The resins are char-
`acterized by
`
`].
`2.
`3.
`4.
`
`Cross—linkage (porosity) expressed in divinylbenzene percentage.
`Functional (reacting) group.
`Binding capacity (milimoles per g of dry resin).
`Particle size.”
`
`The drug content of a resin-drug complex may be expressed in g of drug per 100 g resin
`or in percentage of saturation (the percentage of the capacity of the resin that is utilized in
`binding the drug).
`Both Saunders” and Miinzelg stress the advantage of ion—exchange resins as drug carriers
`for extended—release dosage forms:
`
`1.
`2.
`
`Ion-exchange resins are not toxic and are easily excreted from the GI tract.
`Drug release, especially with strongly acidic groups,
`is primarily a function of the
`ionic strength of gastrointestinal fluids and pH has little effect.
`Formulation of a complex of ion exchange resins and drugs is very simple.
`Extended—release rate of drug is a result of a slow diffusion of drug molecules through
`resin particle structure. Release rate can be modified by alteration of the resin particle
`dimensions and chemical composition of the resin.
`
`The advantages of ion exchange resins as drug carriers providing for extended release
`were confirmed by in vivo experiments.3°'” After oral administration of resin—bound nos-
`capine, a considerable prolongation of the antitussive effect was observed in comparison to
`noscapine chloride.”
`The choice of an ion exchange resin for a particular drug should“ account for:
`
`How acidic or basic are the functional groups (Strongly acidic sulphonic groups release
`the drug slower in the stomach than less acidic carboxylic groups.)
`Exchange capacity size, which is a result of a number of functional groups (It should
`be as large as possible so that the greatest amount of a drug could be bound with the
`lowest possible amount of a resin.)
`Degree of Cross—linkage (The desirable range is 3 to 17%.)
`Particle diameter size (possibly uniform, optimal 320 to 450 um)
`
`

`
`106
`
`Extended-Release Dosage Forms
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`

`
`Extended—Release Dosage Forms
`
`+
`lll(CH3)3
`
`r
`NI (CH,)3
`
`c— c—
`
`c— c—c—
`
`fiéi
`<31
`
`—C—C
`
`C—
`
`‘i“=
`'f (CH3);
`
`FIGURE 2. Copolymers of styrene and divinylbenzene with acidic and basic
`reacting groups. To the left, the cation—exchange resin with sulphonic acid groups;
`to the right. the anion—exchange resin with quaternary ammonium groups.
`
`Table 8
`THE DISPLACEMENT REACTION FROM DRUG-RESIN COMPLEX IN
`GASTROINTESTINAL TRACT
`
`Substrate
`
`Product
`
`Stomach
`(HCI)
`
`Intestine
`(NaCl)
`
`Cation ion—exchange resin + Drug resinate
`basic drug
`Anion ion—exchange resin +
`acidic drug
`
`Resin salt
`
`Acidic resin + drug
`hydrochloride
`Resin chloride + free acidic
`drug
`
`Sodium resinate + drug
`hydrochloride
`Resin chloride + sodium
`salt of drug
`
`5.
`
`Purity of a resin (Remnants of the resin synthesis process, especially reducing sub-
`stances, can be a cause of drug instability.
`therefore a resin should undergo ion
`exchange twice and should be thorougly washed with water.)
`
`If the influence of these parameters on the release rate is known, then it is possible to
`produce a drug bound with ion—exchange resin with an elution characteristic determined in
`advance. Berg and Qstrup” proved that in the case of methylatropine, a low saturation is
`necessary to obtain a sufficiently slow elution. However, for diphenhydraminum—calcium
`resinate, the degree of saturation of diphenhydramine is less important. Many works3“‘37
`deal in detail with the problem of factors influencing drug release from resinate.
`The preparation of drug—ion-exchange complexes is very simple. A drug in solution in
`excess of, or less than, the amount required by stoichiometric considerations, is contacted
`with a suitable resin displacing the cation or anion, whatever the case may be, from the
`resin. Displacement can be conducted by mixing a drug solution and a resin in one vessel
`or by pouring a drug solution through a suitable glass column filled with a resin.
`Displacement is often conducted with a resin in the form of a salt and not the free acid,
`i.e., that the resin particles are swollen. When the displacement process is complete, the
`drug—ion-exchange complex is separated from the liquid by filtration, or centrifugation, and
`after washing with deionized water, is dried in a vacum at a temperature not exceeding 40
`to 50°C until its water content is about 25%.
`
`From drug-ion—exchange, resin capsules, tablets or liquid dosage froms are made.
`It should be borne in mind that the auxiliary substances chosen are nonionizable so they
`
`

`
`109
`
`cannot react with resins. Resins conglomerate easily under pressure and therefore the choice
`of suitable disintegrants is important. Resins containing more than 25% water and free acidic
`groups may cause erosion of the punch and matrix surface.
`Chwialkowska et al.-°’* prepared ephedrine—resinate tablets in the following way: the ion-
`exchange resin Amberlite IR-l20® was placed in a glass column and 10% hydrochloric acid
`was poured (50 times the theoretically calculated amount) at a rate of 2.5 m€/min. Then
`the cationite was washed with water until the reaction with Cl‘ ions stopped. Alkaloid
`binding was accomplished by pouring a solution of 0.12 mol/€
`ephedrine hydrochloride
`through the column until its presence was detected in the liquid flowing out of the column.
`The drug-ion-exchange complex was dried in a vacuum at 40°C. The amount of bound
`alkaloid was determined analytically. A displacement ability of 81% was obtained, i.e., 498
`mg ephedrine hydrochloride in 1 g of the complex.
`1
`tablet.
`Since the ephedrine hydrochloride dosage was established to be 100 mg in 1
`tablet contained 200 mg of the drug—ion—exchange complex (pulverized and sieved through
`a 0. 12 mm sieve) and 200 mg dextran (mean molecular mass 60,000). The mixed powders
`were granulated with a 50% solution of shellac-polyethylene glycol mixture in absolute
`ethanol. The granulated product was formed on a 0.75 mm sieve and after drying at a
`temperature of 40°C and the addition of lubricants (magnesium stearate and talc). tablets
`weighing 415 mg and 12 mm in diameter were pressed.
`Investigation of release revealed that, with the tablets containing lactos