Encyclopedia of
`Pharmaceutical Technology
`
`Second Edition
`
`Volume 2
`E—Pat
`
`Pages 1033-2044
`
`edited by
`
`James Swarbrick
`
`President
`PharmaceuTech, Inc., Pinehurst, North Carolina
`and
`
`Vice President for Scientific Afiairs, aaiPharma, Inc.
`Wilmington, North Carolina, U.S.A.
`
`and
`
`James C. Boylan
`
`Pharmaceutical Consultant
`
`Gurnee, Illinois, U.S.A.
`
`MARCEL
`
`‘ll
`
`DEKKER
`
`MAR(2EL DEKKER, INC.
`
`NEW YORK - BASEL
`
`Amgen Ex. 2004
`
`Complex Innovations v. Amgen
`
`|PR2016-00085
`
`Amgen Ex. 2004
`Complex Innovations v. Amgen
`IPR2016-00085
`
`

`
`Cover Art: Leigh A. Rondano, Boehringer angelheim Pharmaceuticals, Inc.
`
`ISBN: Volume 1:
`Volume 2:
`Volume 3:
`Prepack:
`
`0-8247-2822-X
`0-8247-2823-8
`0-8247-2824-6
`0-8247-2825-4
`
`ISBN: Online:
`
`0-8247-2820-3
`
`This book is printed on acid-free paper.
`
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`Copyright © 2002 by Marcel Dekker, Inc. except as occasionally
`
`noted on the opening page of each article. All Rights Reserved.
`
`Neither this book nor any part may be reproduced or transmitted in an
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`PRINTED IN THE UNITED STATES OF AMERICA
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`

`
`
`
`1138
`
`embedded. Depending on the release profile requirement,
`polymeric excipients are traditionally classified as
`hydrophilic or hydrophobic. Some representative coating
`materials include water~soluble resins (e.g, gelatin, starch,
`polyvinylpyrrolidone, water-soluble celluloses), water-
`insoluble resins (e.g., polymethacrylate, silicones, water-
`insoluble celluloses), waxes and lipids (e.g., paraffin,
`beeswax,
`stearic acid), enteric resins
`(e.g.,
`shellac,
`cellulose acetate phthalate)
`(63).
`(Further details on
`polymers for controlled release systems can be found
`under “Biopolymers for Controlled Drug Delivery” in the
`first edition of this encyclopedia series.) Here the focus is
`on some recent applications of excipients in biologicals.
`Live rotavirus vaccine was developed for oral delivery
`to prevent infections by the virus in young children (64).
`However,
`incorporation of
`live rotavirus into poly
`(DL—lactide—co-glycolide) microspheres or alginate micro-
`capsules was reported to result in a significant loss of
`rotavirus infectivity. The loss was reduced by stabilization
`of the rotavirus vaccine with an excipient blend of
`cellulose, starch, sucrose, and gelatin at a mass ratio of
`30:30:30:l0 in granules or tablets (64).
`Transforming growth factor (TGF)-betal, a cytoprotec—
`tant against
`the toxicity caused by cell cycle—specific
`drugs, was encapsulated in alginate beads as a potential
`oral delivery system to release TGF—betal
`in the
`gastrointestinal
`tract. However,
`the TGF—betal was
`interacting with alginate, which prevented the release of
`the protein. Polyacrylic acid, as a polyanion excipient, was
`used to shield the TGF—betal from interacting with the
`alginate (65).
`Glucose at concentrations >l0% was used to achieve
`
`freeze—dried biodegradable
`adequate reconstitution of
`poly—2—caprolactone nanoparticles with conservation of
`the encapsulated cyclosporin A (66). Glucose and
`trehalose were also found to be the most efficient
`
`cryoprotectors for the lyophilization process, whereas
`trehalose was used for spray—drying, in the production of
`solid lipid nanoparticles (67).
`Tetanus toxoid (the vaccine for tetanus) encapsulated in
`polyester microspheres was produced for single-injection
`immunization (68, 69). The entrapment efficiency of the
`protein vaccine was significantly improved by coencapsu—
`lation with excipients such as trehalose and (w/-Hydro-
`-Hydroxypropyl cyclodextrin. However, these excipients
`did not impart stabilizing effect on tetanus toxoid. In
`contrast, bovine serum albumin was found to be the most
`
`for protein in the body after
`prominent stabilizer
`administration by injection.
`It is important to point out that the stabilizing effects of
`excipients were sometimes reported for the formulations
`in vitro rather than in the in vivo conditions. However, the
`
`Excipients—Powders and Solid Dosage Forms
`
`degree of retention of the native protein structure in the
`dry state may not be a general indication of stability for the
`‘wetted’ solid within polymer controlled—release devices
`in the body. In the case of tetanus toxoid, it was shown that
`the extent of structural alternations in the presence of 1:5
`(gram excipient:gram protein) sodium chloride, sorbitol,
`or polyethylene glycol did not correlate with stability
`conferred toward moisture—induced aggregation (70).
`Surfactant and polyethylene glycols (PEG) excipients
`have been used in microencapsulation of macromolecules
`for various effects. For example, Tween 20, at the critical
`micelle concentration and at a molar concentration of
`proteinzsurfactant of 120.018 or larger, was found to
`increase the encapsulation efficiency of B-Lactoglobuline
`in poly (DL—Lactide—co-glycolide) microspheres (71). The
`initial burst release was reduced with increasing Tween
`20 concentration, and the effect was attributed to
`reduction of the number of pores and channels inside
`the microspheres. For gene therapy,
`the release of
`biologicals encapsulated in microspheres can be signifi-
`cantly improved by adding surfactant during micro-
`encapsulation, as recently exemplified by the enhancing
`effect of polyvinyl alcohol on the release of adenovirus
`from PLGA microspheres (72). PEG 400 has been used to
`improve the stability of the protein, nerve growth factor
`(NGF) during the microencapsulation by a double
`emulsion method. It stabilized the protein by reducing
`the contact with the organic solvent
`in the process.
`Furthermore, the presence of NaCl in the rr1icroencapsu—
`lation process has been shown to modify the microsphere
`structures, leading to a reduction of the initial release rate
`of NGF (73).
`
`EXCIPIENTS AND FORMULATION
`INCOMPATIBILITY
`
`During formulation design some excipients may be
`incompatible with the active ingredient or with other
`excipients. Excipient incompatibility problems are, in fact,
`widely published and date back to the mid—l950s. For
`example, as a tableting excipient, lactose could react via its
`aldehyde group with both primary (1) and secondary (74)
`amines by the Maillard—type condensation reaction.
`Sorbitol, another excipient sugar,
`is hygroscopic at
`relative humidity >65%, which should thus be avoided
`during manufacturing. Calcium salts are other widely used
`tableting excipients. However, calcium carbonate is
`incompatible with acids or acidic drugs because of the
`acid—base chemical
`reaction. Calcium salts are also
`
`incompatible with tetracyclines because of the formation
`
`

`
`1139
`
`crystallization will occur to expel the absorbed water from
`the crystal lattice. Before crystallization, these excipient
`materials will act as buffers or sorbents to hold the excess
`
`moisture which, depending on the water activity, may not
`be accessible to the active ingredient
`that
`is thus be
`protected from moisture—mediated decomposition. How-
`ever, when excipient crystallization occurs, the expelled
`water will become available to react, leading to instability
`of the drug.
`
`CONCLUSION
`
`Although excipients are the nonactive ingredients, they are
`indispensable for the successful production of acceptable
`solid dosage forms. The important
`roles played by
`excipients in tablets and capsules,
`freeze-dried, and
`spray-dried powders, as well as powder aerosol formu-
`lations, were discussed. Some recent applications of
`excipients in controlled, release formulations for biologi-
`cals were also highlighted. Finally,
`incompatibility
`problems attributable to excipients were considered with
`an emphasis on the indirect role of excipients through
`moisture distribution.
`
`REFERENCES
`
`1. Wade, A., Weller, P.J., Eds.; Handbook of Pharmaceutical
`Excipients, 2nd Ed.; American Pharmaceutical Association:
`Washington DC, 1994.
`2. Bandelin, F.J. Compressed Tablets by Wet Granulation.
`Pharmaceutical Dosage Forms: Tablets, 2nd Ed.; Lieber-
`man, H.A., Lachman, L., Schwartz, J.B.; Eds.; Marcel
`Dekker, Inc.: New York, 1989; 1.
`3. Pikal, M.J. Freeze-Drying of Proteins. Part 1: Process
`Design. BioPharmacology 1990, 18-27.
`4. Oguchi, T.; Yamashita, J.; Yonemochi, E.; Yamamoto, K.;
`Nakai, Y. Effects of Saccharides on the Decomposition of
`Cephalothin Sodium and Benzylpenicillin Potassium in
`Freeze-Dried Preparations. Chem. Pharm. Bull. 1992, 40,
`1061-1063.
`
`J. Thermal Mechanical
`5. Williams, N.A.; Guglielmo,
`Analysis of Frozen Solutions of Mannitol and Some
`Related Stereoisomers: Evidence of Expansion During
`Warming and Correlation With Vial Breakage During
`Lyophilization.
`J. Parenteral Sci. Technol. 1993, 47,
`119-123.
`II:
`6. Pikal, M.J. Freeze -Drying of Proteins. Part
`Formulation Selection. BioPharmacology 1990 October,
`26-30.
`7. Crommelin, D.J.A., Sindelar, R.D., Eds.; Pharmaceutical
`Biotechnology
`Harwood Academic Publishers:
`The
`Netherlands, 1997; 72-74.
`
`Powders and Solid Dosage Forms
`. pient9"‘
`
`tetracycline complexes. Details of reactivities
`.
`.1" talc
`lumgatibilities of individual excipients are given
`d ll'lCOII1
`. ..
`-
`t
`‘
`ient
`'
`b 1t
`attributa e o excip
`s 1S
`-,"
`... Ref. 1. Incompati 11y
`1
`studied under accelerated testing conditions or
`"" mony
`lyses such as differential scanning
`1 ana
`_
`,
`.
`«rrlng therma
`r,
`the results of this rapid testing
`.
`-
`_ Howeve
`_
`_
`""' Gummy
`d thus of very limited value (75).
`-
`'s1eadiIlg 3“
`_
`.
`.
`' u1;dl.)(:eI:1dj1~ect excipient-drug interactions, excipients
`*
`esi
`____I
`lead to instability of the. active. ingredient by an
`.
`-
`, act role through moisture distribution. Residual water
`Fun t is known to affect the stability of solid dosage
`r:1t]:I1and powders (76). Decomposition of cephalothin
`‘dium and benzylpenicillin potassium decomposition in
`M eZe_dried preparation was believed to be partly
`zributed to the effect of water binding to excipients (4).
`3
`e degradation rate of cephalothin sodium increased with
`1 e water content of excipients corn starch and celluloses
`1:77), The results were correlated with the water mobility in
`_ e presence of the excipients (4, 77). A study of the effect
`1’ various excipients on the solid—state crystal ‘transform-
`'_ ion of the antimalarial compound mefloquine hydro-
`fihloride revealed that rnicrocrystalline cellulose promoted
`the transformation from form E into form D (78).
`.However, methylcellulose,
`hydroxyethylcellulose,
`£3-Cyclodextrin, crospovidone, and hydrous lactose had
`no effect. The effect was again explained by the difference
`in the water uptake behavior by the excipients. Aspirin was
`formulated with a sugar diluent containing approximately
`8% moisture, which did not cause instability problems
`(79). This was ascribed to the moisture present in the
`formulation being unavailable to react with the aspirin.
`The availability of moisture associated with excipients in a
`formulation can thus be manipulated to control
`the
`hydration rate of the active ingredient as in the case of
`flitrofurantoin, with crystalline lactose giving the fastest
`and microcrystalline cellulose giving the slowest rate (80).
`Thelrate of hydrolysis of methylprednisolone sodium
`'$_.llcc1nate was higher when cofreeze—dried with mannitol
`than with lactose (81). This correlated with the rate of
`crystallization of mannitol
`in the formulation and its
`subsequent effect on the water distribution in the solid.
`‘The stabilizing potency of excipients on recombinant
`Llglman albumin against aggregation also correlated with
`"t 6 water-sorbing capacity of the excipients (27).
`I
`_ Instability attributable to excipient—mediated water
`_‘ Slfilfution in solids and powders has been explained by
`;‘el’r1i:I11: ‘1’£'fi’S1Cal properties (21, 82-84). Crystalline
`Qim is reachetaotluptake moisture until the deliquescent
`sorb Water
`.
`contrast, amorphous excipients will
`M 1 below the elllnttl)‘
`their glass transition temperatures
`I. molecules 11111 ient temperature when the mobility of
`as
`increased so much that excipient
`
`
`
`y be
`other
`tfact,
`. For
`/ia its
`
`'(74)
`:tion.
`ic at
`aided
`used
`te is
`.f the
`also
`ation