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`WWII
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`b89052690158a
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`PDA Journal of
`
`Pharmaceutical
`
`Science and
`
`Technology
`
`—_
`M IVIIRNMIUNH Assouxnm lme
`PHANMAULIIL u S( Inn Aw “(mommy
`
`BEIDSEE'HEIJJBB
`
`l
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`llllHllll
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`1 997
`
`Julyi August
`
`Volume 51
`
`MAIA Exhibit 1017
`
`MAIA V. BRACCO
`
`IPR PETITION
`
`
`
`
`MAIA Exhibit 1017
`MAIA V. BRACCO
`IPR PETITION
`
`

`

`July—August 1997
`
`Vol. 51, No. 4
`
`FDA Journal of
`
`Pharmaceutical Science and Technology
`EDITOR: Joseph B. Schwartz
`
`
`
`Philadelphia College of Pharmacy & Science
`600 South 43rd Street
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`ADVISORY BOARD
`
`Michael Akers, Eli Lilly and C0.
`Frederick J. Carleton
`Patrick DeLuca, University ofKentucky
`Barry Garfinlde, Merck Sharp & Dohme
`Michael Groves, University afIIlinoir
`Joseph Robinson, University of Wisconsin
`Theodore Roseman, Baxter Healthcare
`
`1996 OFFICERS AND DIRECTORS
`
`Chairman:
`Chairman-Elect:
`Secretary:
`Treasurer:
`Immediate Past
`
`Raymond Shaw, Jr., Ph.D
`Joyce H. Aydlett
`Floyd Benjamin
`Raymond Gabler, Ph.D.
`
`Chairman:
`
`Clarence A. Kemper, Ph.D.
`
`James E. Akers, Ph.D.
`Jennie Allewell
`
`Peter T. Bigelow
`Joyce DeYoung, Ph.D.
`R. Michael Enzinger, Ph.D.
`John Geigert, Ph.D.
`Martin W. Henley
`Kunio Kawamura, Ph.D.
`Henry Kwan, Ph.D.
`Robert F. Mom'ssey, Ph.D.
`Terry E. Munson
`Robert B. Myers
`
`President: Edmund M. Fry
`
`PDA Journal of Pharmaceutical Science & Technology (ISSN
`1076-397X) is published bimonthly by the PDA, Inc., 7500 Old
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`Formerly the
`“Journal of Parenteral Science and Technology”
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`Copyright—PDA, Inc. 1997
`ISSN 1076-397X
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`The PDA, Inc. and its editor assume no responsibility for
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`

`

`
`
`RlZVIEVV14R77(TLE
`
`Excipients and Their Use in Injectable Products
`
`SANDEEP NEMA*, R. J. WASHKUHN, and R. J. BRENDEL
`
`Mallinckrodt Medical, Incorporated, Saint Louis, Missouri
`
`
`
`ABSTRACT: Formulation ofa new drug product with excipients, that have been previously added to an approved
`injectable product. may save pharmaceutical companies developmental time and cost. The Physicians’ Desk
`Reference (PDR) and Handbook on Injectable Drugs were reviewed. extracting all information on excipien/s. The
`information was consolidated into eight tables, categorizing excipients as 1) Solvents and Co-solvents, 2)
`Solubilizing, Wetting, Suspending, Emulsifving or Thickening agents, 3) Chelating Agents, 4) Antioxidants and
`Reducing Agents, 5) Antimicrobial Preservatives, 6) Bifiers and pH Adjusting Agents, 7) Bulking Agents,
`Protectants, and Tonicity Adjustors, and 8) Special Additives. Where applicable, tables list frequency of use,
`concentration, and an example ofa commercial product containing the excipient. Excipients which are included in
`the 1996 FDA ‘lnactive Ingredient Guide, 'but do not appear in the PDR or Handbook on Injectable Drugs, were
`included as a separate list.
`
`Introduction
`
`Injectable products require a unique formulation strategy.
`The formulated product has to be sterile, pyrogen free and.
`in the case of solutions, free of particulate matter. Preferably,
`the formulation will be isotonic, and depending on the route
`of administration (for instance, for intra—spinal or intra»
`cisternal routes), antioxidants and preservatives may not be
`allowed. For a given drug, the risk of adverse events is
`higher if it is administered as an injection versus a non-
`parenteral route. The requirement for sterility demands that
`the excipients be able to withstand autoclaving or other
`sterilization processes. These factors limit the choice of
`exeipients available to the formulators.
`Generally, a knowledge of which cxcipients have been
`deemed safe by the FDA or are already present in a marketed
`product provides increased assurance to the formulator that
`these excipients will probably be safe for their new drug
`product. However, there is no guarantee that the new drug
`product will be safe as excipients are combined with other
`additives and/or with a new drug, creating unforeseen
`potentiation or synergistic toxic effects. Regulatory bodies
`may View an excipient previously approved in an injectable
`dosage form favorably, and will frequently require less
`safety data. A new additive in a formulated product will
`always require additional studies adding to the cost and
`timelirre of product development.
`the various
`to present
`is
`The purpose of this paper
`excipients that have been included in the formulation of
`injectable products marketed in the USA. This information
`is not readily available. A literature search indicates that the
`last paper dealing with this was published in 1980 (1).
`Products approved outside the US are not covered in this
`
`Received October 1, 1996. Accepted lor publication May 16. [997.
`”‘Author to whom correspondence should be addressed: PO. Box 5840. St.
`Louis, MO, 63134
`
`166
`
`review. Also, sterile dosage forms not administered parenter-
`ally, such as solutions for irrigation. ophthalmic or otic
`drops, and oirrtments were excluded.
`
`Methodology
`
`Physicians’ Desk Reference published in 1994 & 1996 (2,
`3), and Handbook on Injectable Drugs (4) were used as the
`primary source of information. Entries on all
`injectable
`drugs were summarized in an Excel worksheet. Each
`product was classified by Manufacturer, Trade name, Drug
`name, Route of Administration, SVP/LVP, pll of Product,
`Solvent Used, Solubilizing/Suspending Agent, Preservative,
`Antioxidant, Chclator and Other Formulation Additives.
`The resulting Excel sheet had information on more than
`700 products. This information was condensed into easy—t0—
`read tables. Each table has been categorized based on the
`primary function of excipient
`in the formulation. For
`example, citrates are classified as buffers and not as chelat—
`ing agents, and ascorbates are categorized as antioxidants,
`although they can serve as buffers. This classification system
`was based on our experience in formulation development
`and on the published literature. Such simplification avoids
`duplication of entries and provides the audience with
`easy-to—read tables.
`Some duplication was unavoidable Tables VII and VIII
`contain some excipients which may have also been listed in
`the first six tables. Whenever the reference specifically
`designated a specific function to an ingredient
`it was
`re—listed in Tables Vll and Vlll. For example, glycine can be
`used as a buffer or as a stabilizing (protecting) agent.
`Therefore, glycine is listed in Tables VI and VII. Methyl
`paraben is a preservative (Table V) but also has a special
`function in Adr'iamycin RDF® formulation (Table VIII).
`The concentration of cxcipients is listed as percentages
`weight by volume (w/v) or volume by volume (v/v). If the
`product was listed as lyophilized or powder, these percent—
`
`PDA Journal of Pharmaceutical Science & Technology
`
`-166-
`
`-166-
`
`
`
`
`

`

`
`
`
`
` Exeipient Frequency Range Example
`
`TABLE I
`Solvents and Co-solvents
`
`Benzyl Benzoate
`2
`20% v/v
`DepoTestosterone® (Upjohn) 20% v/v
`Cottonseed Oil
`1
`73.6% w/v
`Depo-Tesloslel‘one‘m (Upjohn) 73.6% w/v
`N.N Dimetliylaeetamide
`1
`6% w/v
`Vumon® (Bristol Myers) 6% w/v
`Ethanol
`24
`0.6780%
`Prograf‘lD (Pujisawa) 80% v/v
`Glycerin (Glycerol)
`9
`1.640% w/v
`Multitest CMl® (Connaught) 70% w/v
`Peanut oil
`1
`*
`Bal in Oil® (Becton Dickinson)
`Polyethylene glycol
`Secobarbital sodium (Wyeth—Ayerst) 50%
`0.15*50%
`4
`PEG
`VePesid‘L” (Bristol Myers) 65% w/v
`50—65%
`2
`PEG 300
`Ativan‘fi" (Wyeth-Ayerst)
`*
`2
`PEG 400
`DepO—Medrol@ (Upjohn) 2.95% w/v
`0.3—3%
`5
`PEG 3350
`Ethiodol® (Savage) 1%
`1%
`1
`Poppyseed oil
`Terramycin Solution (Roerig) 75.2%
`0,2752%
`25
`Propylene Glycol
`Liposyn II® (Abbott) 10%
`5—10%
`2
`Safflower oil
`Solganal Inj.® (Schering)
`‘1‘
`6
`Seasme oil
`lntralipid® (Clintec) 20%
`5—20% w/v
`4
`Soybean oil
`
`Vegetable oil Virilon IM Inj.® (Star Pharmaceuticals) 2 '
`
`
`‘1‘ No data available.
`
`ages were derived based on the reconstitution volume
`commonly used. The tables list the range of concentration
`used. typical or most common concentration employed, and
`examples of products containing the excipient. specifically
`those which use extremely low or high concentrations.
`
`Dbcusfions
`
`Table I list solvents and co—solvents used in parenteral
`products. Water for injection is the most common solvent but
`may be combined or substituted with a eo—solvent
`to
`improve the solubility or stability of drugs. Oils like
`safflower and soybean are used in total parenteral nutrition
`products where they serve as a fat source and as carriers for
`fat—soluble vitamins. Ethanol and propylene glycol are used.
`either alone or in combination with other solvents, in more
`than 50% of parenteral co—solvent systems. It is surprising to
`see propylene glycol used more often than polyethylene
`
`in spite of its higher myotoxicity and
`glycols (PEGS)
`hemolyzing effects (5, 6). Probably, the presence or genera—
`tion of peroxides in PEGs is a major limitation.
`Table 11 includes a broad category of excipients whose
`function in formulation could be 7(1) Viscosity impatting or
`suspending agents like carboxy methyl cellulose, sodium
`carboxy methyl cellulose. sorbitol, acacia, Povidone, hydro-
`lyzed gelatin;
`(2) Solubilizing, wetting or emulsifying
`agents like Cremophore EL, sodium desoxycholate, PolysorV
`bate 20 01' 80, PEG 40 castor oil, PEG 60 castor oil, sodium
`dodecyl sulfate,
`lecithin or egg yolk phospholipid;
`(3)
`Aluminum monostearate which is added to fixed oil to form
`
`viscous or gel—like suspending medium. Polysorbate 80 is
`the most common and versatile solubilizing, wetting and
`emulsifying agent.
`Only a limited number of chelating agents are used in
`parenteral products (Table 111). They serve to complex heavy
`
`TABLE II
`
`Solubilizing, Wetting, Suspending. Emulsitying or Thickening Agents
`
`Excipient
`Frequency
`Range
`Example
`
`7%
`2
`Acacia
`2%
`1
`Aluminum mouostearate
`1%
`4
`Cai‘hoxy methyl cellulose
`0.1~0.75%
`9
`Carboxy methyl cellulose. sodium
`50—65% w/v
`3
`Cremophore EU‘
`0.4% w/v
`1
`Desoxycholate sodium
`1.2%
`3
`Egg yolk phospholipid
`16% w/v
`l
`Gelatin, Hydrolzyed
`04—12% w/v
`7
`Lecithin
`7% w/v
`1
`Polyoxyethylated fatty acid
`0.01—12%
`31
`POlySOI‘bale 80 (Tween 80)
`0.017051%
`5
`Polysorbate 20 (Tween 20)
`
`11.5% v/v
`1
`*
`PEG 40 caster oi
`
`20% w/v
`1
`PEG 60 castor oi
`0.570670 w/v
`6
`Povidone (Polyvinyl pyrrolidone)
`0.018% w/v
`1
`Sodium dodecyl sulfate (Na lauryl sulfate)
`25—50%
`3
`Sorbitol
`Cremophor El 1: Floods '15. polyethoxylated castor oil, polyoxyethyleue 35 custor oil.
`EG 40 Castor oil; polyoxyl 40 Castor oil. castor oil POE—40. Croduret 40, polyoxyethylene 40 castor oil, Protachem CAAAIO.
`
`PEG 60 hydrogenated castor oil: Cremophor RH 60, hydrogenated caster oil POE-60, Protuchem CAH-60
`
`Tuberculin Old Test® (Lederle) 7%
`Solganal lnj.® (Schering) 2%
`Bicillin® (Wyeth-Ayerst) 0.55%
`Lupron Depot® (TAP) 0.75% w/v
`Sandimmune® (Sandoz) 65% w/v
`Fungizone® (Bristol Myers) 0.41% w/v
`lntralipid® (Clintec) 1.2%
`Cortone® (Merck) 16% w/v
`Diprivan® (Zeneca) 1.2% w/v
`AquaMepliyton® (Merck) 7% w/v
`Cordarone X I,v.®. (WyethrAyerst) 10%
`Cnlcijex® (Abbott) 0.4% w/v
`Monistat® (Janssen) 11.5% v/v
`Prograf‘E (Fujisawa) 20% w/v
`Bicillin® (Wycth-Ayerst) 0.6% w/v
`Prolcukin® (Cetus) 0.018% w/v
`Aristrospan® (Fujisawa) 50% v/V
`
`Vol. 51, No.4 / July—August1997
`
`167
`
`-167-
`
`-167-
`
`
`
`
`

`

`TABLE III
`Chelating Agents
`
`
`Excipicnt
`Frequency
`Range
`Example
`Calcium disodium
`9
`0.01—0. 1 % Wydase® (Wyeth—
`EDTAil‘
`Aycrst) 0.1% w/v
`Disodium EDTA
`0.0140.1% Calcijcx® (Abbott)
`0.11% w/v
`Folvite® (Lederle)
`0.2%
`Magnevist® (Berlex)
`0.04%
`
`34
`
`1
`
`l
`
`0.20%
`
`0.04%
`
`Sodium EDTA
`
`DTPA””“
`
`toxicity (7, 8). Butylated hydroxy anisole, butylated hydroxy
`toluene and propyl gallate are primarily used in semi/non—
`aqueous vehicles because of their low aqueous solubility.
`Ascorbic acid/sodium ascorbate may serve as an antioxi-
`dant, buffer, and chelating agent in the same formulation.
`Benzyl alcohol was the most common antimicrobial
`preservative present in parenteral formulations (Table V).
`This is consistent with other surveys (9). Parabens are the
`next most common preservatives. Thirty-nine products had a
`combination of methyl and propyl parabens; eleven had only
`methyl, and one had only propyl paraben. Thimerosal was
`surprisingly common, especially in vaccines, even though
`some individuals have sensitivity to mercurics. Chlorocresol
`is purported to be a good preservative for parenterals, but
`our survey did not
`find any examples of commercial
`products containing Chlorocresol.
`Table VI lists buffers and chemicals used to adjust the pH
`of formulations. Phosphate, citrate. and acetate are the most
`common buffers used in parenteral products. Mono and
`diethanol amine are added to adjust pH and form correspond-
`ing salts. Hydrogen bromide, sulfuric acid, benzene sulfonic
`acid and methane sulfonic acids are added to drugs which
`are bromide (Scopolamine HBr, Hyoscine HBr, UDL),
`sulfate (Nebcin, Tobramycin sulfate, Lilly), besylate
`
`
`DTA : Ethlenediaminetetraacetic acid.
`“ DTPA = Diethylenetriamincpcntaacctic acid: Pentetic acid.
`
`metals and therefore can improve the efficacy of antioxi-
`dants or preservatives. In our opinion, calcium EDTA has an
`advantage over tetrasodium salt by not contributing sodium
`and not chelating calcium from the blood.
`An antioxidant as a class is defined as those compounds
`that can act as reducing agents or may serve as free radical
`scavengers. Table IV summarizes the antioxidants,
`their
`frequency of use, concentration range and examples of
`products containing them. Sulfite, bisulfite, and metabisul-
`fite constitute the majority of antioxidants used in parenteral
`products despite several reports of incompatibilities and
`
`TABLE IV
`Antioxidants and Reducing Agents
`
`
`Excipient
`Frequency
`Range
`Example
`Acetone sodium bisulfite
`4
`02—04% w/v
`Novocaine® (SanofiAWinthrop) 0.4% w/v
`Ascorbate (sodium/acid)
`7
`0.1—48% w/v
`Vibramycin‘m (Roerig) 4.8% w/v
`Bisulfite sodium
`28
`0.02—0.66% w/v
`Amikin® (Bristol Myers) 0.66% w/v
`Butylated hydroxy anisole (BHA)
`3
`0.00028—0.03% w/v
`Aquasol® (Astra) 0.03%
`Bntylated hydroxy toluene (BHT)
`3
`000116400370 w/v
`Aquasol® (Astra) 0.03%
`Cystein/Cysteinate HCl
`2
`0.07—0.10% w/v
`Acthar Gel® (Rhone—Poulanc) 0.1% w/v
`Dithionite sodium (Na hydrosulfite, Na sulf—
`1
`0.10%
`Numerphan® (DuPont) 0.10%
`oxylate)
`Gentisic acid
`OctreoScan® (Mallinckrodt)
`0.02% w/v
`1
`Gentisic acid etlianolamine
`M.V.I. 12® (Astra) 2%
`2%
`1
`Glutamate rnonosodiuni
`Varivas® (Merck) 0.1% w/v
`0.1 % w/v
`2
`Formaldehyde sulfoxylate sodium
`Teiramycin Solution (Roerig) 0.5% w/v
`0.075705% w/v
`9
`Metabisulfite potassium
`Vasoxy1® (Glaxo-We1lcome) 0.10%
`0.10%
`1
`Metabisulfite sodium
`Intropin® (DuPont) 1% w/v
`0.02 —1% w/v
`29
`Monothioglyccrol (Thioglycerol)
`Terramycin Solution (Roerig) 1%
`0.171%
`6
`Propyl gallate
`2
`0.02%
`Navarre® (Roerig)
`Sulfite sodium
`7
`ODS—0.2% w/V
`Enion® (Ohmeda) 0.2% w/v
`
`Thioglycolate sodium
`1
`0.66% w/v
`Sus-Phrine® (Forest) 0.66% w/v
`
`TABLE V
`Antimicrobial Preservatives
`
`Excipient
`
`Frequency
`
`Range
`
`Example
`
`Benzalkonium chloride
`Benzethonium chloride
`Benzyl alcohol
`Chlorobntanol
`erresol
`Myristyl gamma~picolininm Chloride
`Paraben methyl
`Paraben propyl
`Phenol
`2~Phenoxyethanol
`Plienyl mercuric nitrate
`Thimcrosal
`
`1
`4
`74
`17
`3
`2
`50
`40
`48
`3
`3
`46
`
`0.02% W/v
`0.01%
`0.75—5%
`025—05570
`0.140.3%
`0.019570.169% W/v
`0.054018%
`0.01 0.1%
`0.270.5%
`0.50%
`0.001%
`0.00340.Ol%
`
`Celestone Soluspan® (Schering) 0.02% w/v
`Bcnadryl‘i’ (Parke—Davis) 0.01% w/v
`Dimenhydrinatc® (Stcris) 5%
`Codine phosphate (Wyeth—Ayerst) 0.5%
`Humatrope® (Lilly) 0.30%
`Depo—Provera® (Upjohn) 0.169% w/v
`lnapsine® (Janssen) 0.18% w/v
`Xyiocaine w/Epinephrine (Astra) 0.1% w/v
`Ca1cimar® (Rhone Poulanc) 0.5% w/v
`Havrix® (SmithKline Beecham) 0.50% w/v
`Antivenin® (WyetheAyerst) 0.001%
`
`Atgam® (Upjohn) 0,01%
`
`168
`
`PDA Journal of Pharmaceutical Science & Technology
`
`-168-
`
`-168-
`
`
`
`
`

`

` Excipient Example
`
`TABLE VI
`Buffers and pH Adjusting Agents
`
`Acetate
`Sodium
`Acetic acid
`Glacial acetic acid
`Ammoniu m
`Ammonium hydroxide
`
`Miacalcin Injection“3 (Sandoz)
`Miacalcin lnjeclion® (Sandoz)
`Rrevibioc lnjection® (Ohmeda)
`Bumex Injection® (Roche)
`Triostat Injection® (SmithKline
`Beecham)
`'l‘racrium Injection® (GluXUchllCOlllB)
`Valium Injection® (Roche)
`Cct'otan lnjection® (Zeneca)
`HypoRho—D® (Bayer)
`
`DTIC-Dome® (Bayer)
`Ceredase® (Genzyme)
`Cerezyme® (Genzyme)
`Ceiezyme® (Genzyme)
`Bactrim IV® (Roche)
`Quinidine® (Lilly)
`dep—B Gammagee® (Merck)
`Amicar® (Immunex)
`Scopolamine (UDL)
`:entenyl citrate & Droperidol (Astra)
`Eminase Injection® (Roberts)
`Sibrium Injection® (Roche)
`DEE—45 Injection® (Sandoz)
`Terramycin Solution (Roerig)
`
`
`
`Benzene sulfonic acid
`Benzoate Sodium/acid
`Bicarbonate Sodium
`Carbonate Sodium
`Citrate
`Acid
`Sodium
`Disodium
`Trisodium
`Diethanolamine
`Glucono delta lactone
`Glycine
`Hydrochloric acid
`Hydrogen bromide
`Lactate acid/Sodium
`Lysine
`Maleic acid
`Methanesulfonic acid
`Mmioethanolamine
`Phosphate
`Acid (phosphoric)
`Monobasic potassium
`Monobasic sodium"‘
`Dibasic sodium“
`Tribasic sodium
`Sodium hydroxide
`Sulfuric acid
`Tartrate acid/sodium
`Tromethamine
`
`
`Humegon® ( Organon)
`Zantac InjectionTc (Glaxo—Wellcome)
`Pregnyl® (Organon)
`Prolastin‘fi‘ (Bayer)
`Synthroid® (Knoll)/
`Optiraym’ (Mallinckrodt)
`Nebcin® (Lilly)
`Methergine lnjecti0n® (Sandoz)
`Optiray® (Mallinckrodt)
`‘t Sodium biphosphate, Sodium diliydrogen phosphate or Na diliydrogen
`orthophospliale
`*‘5‘ Sodium phosphate. Disodium hydrogen phosphate
`
`(Tracrium Inj., Atracurium besylate) or mesylate (DHE 45
`Injection, Dihydroergotamine mesylate) salts. Glucono delta
`lactone is used to adjust the pH of Quinidine gluconate
`(Lilly). Benzoate buffer, at a concentration of 5%, is used in
`Valium Injection. Citrates are common buffers that can have
`a dual role as chelating agents. Lysine and glycine are amino
`acids which function as buffers and stabilize protein and
`peptide formulations. ’l‘hese amino acids zue also used as
`lyo-additives and may prevent cold denaturation. Lactate
`and tartrate are occasionally used as buffer systems.
`Table VII
`lists additives which are used to modify
`osmolality, and as bulking or lyo—cryo protective agents.
`Dextrose and sodium chloride are used to adjust tonicity in
`the majority of formulations. Some amino acids, glycine,
`alanine. histidine, imidazole, arginine, asparagine, aspartic
`acid, are used as bulking agents for lyophilization and may
`serve as stabilizers for proteins or peptides and as buffers.
`Monosaccharides (dextrose. glucose, lactose). disaccharide
`(sucrose), polyhydric alcohols (inositol, tnannitol, sorbitol),
`glycol (PEG 3350), Povidone (polyvinylpyrrolidone), and
`proteins (albumin, gelatin) are commonly used as lyo—
`additives.
`
`Vol.51, No.4 / July—August1997
`
`-169-
`
`TABLE VII
`Bulking Agents, Protectants, and Tonicity Adjustors
`
`Excipient
`Alanine
`Albumin
`Albumin human
`Amino acids
`L—Arginine
`Asparagine
`L-Aspartic acid
`Calcium chloride
`Citric acid
`Dextrose
`Gelatin hydrolyzed
`Glucose
`Glycerin
`Glycine
`Histidinc
`
`Imidazole
`Inositol
`Lactose
`Magnesium chloride
`Magnesium sulfate
`Mannitol
`Polyethylene glycol 3350
`Polysorbate 80
`Potassium chloride
`Povidone
`Sodium chloride
`Sodium succinat'e
`Sodium sulfate
`Sorbitol
`Sucrose
`
`Example
`
`Thrombate III® (Bayer)
`Biociate® (Arco)
`Botox® (Allei‘gan)
`Havrix® (SmithKline Beecham)
`Activase® (Genentech)
`Tice BCG® (Oganon)
`Pepcid® (Merck)
`Plienergan Injection® (Wyeth-[\yerst)
`Sensorcaine—MPF® (Astra)
`Betuseron® (Berlex)
`Acthar® (Rhone—Poulanc Rorer)
`Ivccgam® (immuno—US)
`Ticc BCG® (Oganon)
`Atgam Injection® (Upjohn)
`Antihcmophilic Factor. human
`(Am. Red Cross)
`Helixate® (Armour)
`OctreoScan® (Mallinckrodt)
`Caverject® (Upjohn)
`Terramycin Solution® (Roerig)
`Tice BCG® (Oganon)
`Elspar® (Merck)
`Bioclate® (Arco)
`Helixate® (Armour)
`Varivax® (Merck)
`Alkeran® (Glaxo—Wellcome)
`Wianio SD® (Univax)
`Actimmune® (Genentech)
`Depo-Provera® (Upjohn)
`Panhematin® (Abbott)
`Prolastinq') (Bayer)
`
`Special Additives
`
`These additives have been included in pharmaceutical
`formulation to serve specific functions (Table VIII). Below
`is a summary of the special additives along with their
`intended use——
`
`(1) Calcium gluconate injection (American Regent) is a
`saturated solution of 10% W/v; calcium d-saccharate
`tetrahydrate 0.46% w/v is added to prevent crystalli-
`zation during temperature fluctuations.
`(2) Cipro IV® (Ciproiloxacin. Bayer) contains lactic
`acid as a solubilizing agent for the antibiotic.
`(3) Premarin Injection® (Conjugated Estrogens, Wyeth—
`Ayerst Labs) is a lyophilized product that contains
`siinethicone to prevent formation of foam during
`reconstitution.
`(4) Dexamethasone acetate (Dalalone DP, Forest,
`DecadronLA, Merck, Dalalone DP Injection, UAD
`Labs) and Dexamethasone Na phosphate (Merck)
`are available as suspension or solution. These dexa—
`metbasone formulations contain creatine or creati-
`nine as an additive.
`
`(5) Adriainycin RDF® (Doxorubicin hydrochloride,
`Pharmacia) contains methyl parabcn, 0.2 mg/mL, to
`increase dissolution (10).
`(6) Ergotrate maleate (Ergonovine maleate, Lilly) con—
`tains 0.1% ethyl lactate as a solubilizing agent.
`(7) Estradurin Injection® (Polycstradiol phosphate,
`Wyeth-Ayerst Labs) uses Niacinamidc (12.5 mg/ml)
`
`169
`
`-169-
`
`
`
`
`

`

`
`
`TABLE Vlll
`Special Additives
`
`1
`
`Example
`Human Albumin (American Red
`Cross)
`Recombinant HB® (Merck)
`“etanus Toxoid Adsorbed®
`(Lederle)
`wD Adsorbed Adull‘IT
`(Couuaught)
`Eminase® (Roberts)
`Calcium Gluconate (American
`Regent)
`Human Albumin (American Red
`Cross)
`Dimenhydrinatc (Steris)
`Dalalone DP“m (Forest)
`Hydrocortone Phosphate
`(Merck)
`Conray (Mallinckrodt)
`Cardiotec (Squibb)
`Ergotrate maleate® (Lilly)
`Aminophylline® (Abbott)
`Kabikinase® (Pharmacia)
`Tice BCG® (Oganon)
`Cipro IV® (Bayer)
`Zoladex® (Zeneca)
`
`Excipient
`
`Acetyl tryptophanate
`
`Aluminum hydroxide
`Aluminum phosphate
`
`Aluminum potassium sulfate
`
`ErAminocaproic acid
`Calcium d -saccharate
`
`Caprylate sodium
`
`8~Chlorotheophylline
`Creatine
`Creatinine
`
`Diatrizoic acid
`Gamma Cyclodextrin
`Ethyl lactate
`Ethylenediamiue
`L-Glutamate sodium
`Iron ammonium citrate
`Lactic acid
`D.L-Lactic and Glycolie acid
`copolymer
`Maltose
`Meglumine
`Niacinamide
`Paraben methyl
`Protamine
`
`Gamimune® (Bayer)
`lVIagnevist® (Berlex)
`Estradurin® (Wyeth—Ayerst)
`Adriamycin RDF® (Pharmacia)
`lnsulatard NPH® (Novo
`Nordisk)
`Premarin Injection® (Wyeth—
`Ayerst)
`Compazine lnjection’m (Smith—
`Kline Beccham)
`Venoglobulin‘fi‘ (Apha Thera-
`petitic)
`von Willebrand factor
`Bioclate‘E (Arco)
`
`Zinc Lentc lnsulin® (Novo Nordisk)
`
`Simethicone
`
`Sodium saccharin
`
`Tri~n~butyl phosphate
`
`as a solubilizing agent. Hydeltrasol® (Merck) also
`contains niacinamide.
`
`(8) Aluminum in the form of aluminum hydroxide,
`aluminum phosphate or aluminum potassium sulfate
`is used as adjuvant in various vaccine formulations
`to elicit an increased immunogenic response.
`(9) Zoladex® (Goserelin acetate, Zeneca) is adminis—
`tered subcutaneously as mierospheres. These spheres
`are made of D,L-1actic and glycolic acid copolymer.
`Lupron Depot Injection® (TAP) are lyophilized ini-
`crospheres of gelatin and glycolic—lactie acid for
`intramuscular injection.
`(10) Gamma cyclodextrin is used as a stabilizer in
`Cardiotec® at a concentration of 50 mg/mL.
`(11) Sodium caprylate (sodium octoate) has antifungal
`properties, but it is also used to improve the stability
`of albumin solution against effects of heat. Albumin
`solution can be heat pasteurized by heating at 60”C
`for 10 hours in the presence of sodium caprylatc.
`Acetyl tryptophanate sodium is also added to albu—
`min formulations.
`
`(12) Meglumine (N-methylglucamine) is used as an ex—
`
`170
`
`-170-
`
`TABLE IX
`List of Excipient from 1996 FDA ‘Inactive Ingredient Guide‘
`Ammonium sulfate
`Benzyl chloride
`Butyl paraben
`Caldiamide sodium
`Caltcridol calcium
`Castor oil
`Cellulose (inicrocrystalline)
`Cholesterol
`Deoxycholic acid
`Diatrizoic acid
`Dicyclohexyl carhodiimide
`Dietliyl amine
`Dimyristoyl lecithin
`Dimyristoyl phosphatidyli
`glycerol
`Disofenin
`Docusate sodium
`Edamiue
`Exametaziine
`Gluceptate sodium
`Gluceptate calcium
`Glucuronic acid
`Guanidine HCl
`lofctaminc HCl
`Lactobionic acid
`Lecithin hydrogenated soy
`Lidofcnin
`Medrofenin
`Medronate disodium
`Medronic acid
`Methyl boronic acid
`Methyl cellulose
`Methylene blue
`Ne(carbnmoylemethoxy poly--
`etliyleneiglycol 2000)— l .2—
`distearoyl
`N72~hydroxyethyl piperazine
`N’-Z' ethane sulphonic acid
`Nioxime
`Nitric acid
`Oxyquinoline
`
`Pcntctate (DTPA) calcium
`trisodium
`Poloxamer 165
`PEG 4000
`PEG 600
`Polyglactin
`Polylactide
`Polyoxyethlene fatty acid
`esters
`Polyoxyethylene sorbitan
`monosterate
`Polyoxyl 35 Castor oil
`Polysorbate 40
`Polysorbate 85
`Potassium hydroxide
`Potassium phosphate, dibasic
`Sodium bisulfalc
`Sodium chlorate
`Sodium hypoehlon'de
`Sodium iodide
`Sodium pyrophosphate
`Sodium thiosulfate. anhydrous
`Sodium trimetaphosphate
`Sorbitan monopalmitate
`Stannous chloride
`Stannous fluoride
`Stannous tartrate
`Starch
`Succiiner
`Succinic acid
`Sulfurous acid
`Tetrakis (l isocyano—Zme
`thoxy—2,methyl-propante)
`copper (1) Te
`"hiazoximic acid
`"i‘ithiazoximic acid
`
`Urea
`Zinc acetate
`Zinc chloride
`Zinc oxide
`2-ethyl hexanoic acid
`PEG vegetable oil
`
`cipient and to form in—situ salt. For example, dia—
`trizoic acid, an X—ray contrast agent, is more stable
`when autoclaved as meglumine salt than as sodium
`salt (1 l). Meglumine is also added to Magnevist®, a
`magnetic resonance contrast agent, formulation.
`Sulprisingly, sodium saccharine is used in Stelazine®
`and CompazinefE formulations; our guess is that it
`serves as a stabilizer and tonicity adjuster.
`Triinebutyl phosphate is present as an cxcipient in
`human immune globulin solution (Veiioglohiiliii®).
`Its exact function in the formulation is not known,
`but it may serve as a scavenging agent.
`von Willebrand factor is used to stabilize recombi-
`nant antihemophilic factor (Bioclatel‘l).
`Maltose serves as a tonicity adjuster and stabilizer in
`immune globulin formulation (Gamimune N®).
`Epsilon amino caproic acid (6-amino hexanoie acid)
`is used as a stabilizer in anistreplase (Eminase injec—
`tion®).
`Zinc and protamine have been added to insulin to
`form complexes and control the duration of action.
`
`(13)
`
`(14)
`
`(15)
`
`(16)
`
`(17)
`
`(18)
`
`PDA Journal of Pharmaceutical Science & Technology
`
`-170-
`
`
`
`
`

`

`5
`
`6
`
`7
`
`9-
`10.
`
`11.
`
`. K. W. Reed and S. Yalkowsky. “Lysis of human red blood cells in the
`presence of various cosolvents." ./. Par-mam: Sci. Tech/ml, 39(2), 64
`(1985).
`. G. A. Bazeau and Ho-Leung Fang, "Use 01' an ll‘t'Vlll‘D model for the
`assessment of muscle damage from intramuscular injections: In—vitro-
`in-vivo correlation and predictability with mixed solvent systems,”
`P/mmi. R(‘.\'., 6(9), 766 ( l989).
`J. W. Munsori. A. lIussain. and R. Bilous. “Precautionary note for use
`of bistilfite in pharmaceutical formulation," J. P/mrm. Sci., 66(12).
`1775 (1977).
`. L. C. Schroeter, "Sulliirous acitl salts as pharmaceutical antioxidants,”
`J. P/mrm. Sci. 50(11), 891 (1961).
`R. Dabbali. “The use ofpi'eservatives in cinnpenilial articles.” P/ltll‘limA
`(-npci'ril Forum, 22(4), 2696 (1996).
`T. J. Baumami. M. A. Sniythe, K. Kaufmann, Z. Milolmszewski, J.
`O‘Malley, and R. P. Fudge, “Dissolution times of adriamycin and
`adriamycin RDF.”Am. J. Hosp. P/ILl/‘HI., 45, 1667 (1988).
`Y.
`.I. Wang, T. C. Dahl. G. D. Leesman, and D. C. Monkhouse,
`"Optimization of autoclave cycles and selection of formulation for
`parenteral product, Part II: El'l'ect of counter—ion on pH and stability of
`diatrizoic acid at autoclave temperatures,” J. Parental: Sci. Tee/iimL.
`38(2), 72 (1984).
`‘Inactive Ingredient Guide.’ Division of Drug Information Resources,
`FDA. CDER. January 1996.
`
`Recently, FDA has published “Inactive Ingredient Guide”
`which lists all
`the excipients in alphabetical order. Each
`ingredient is followed by the route of administration (for
`example, iv, oral) and, in some cases, the range of concentra—
`tion used in the approved drug product. However, this list
`does not provide the name of commercial product(s) COU‘Be
`spondingr to each excipient. Table IX is a summary of all the
`excipients which are included in the ‘Inactive Ingredient
`Guide,‘ but do not appear in PDR or Handbook on Injeciable
`Drugs,
`
`References
`
`1. Y. J. Wang and R. R. Kowal. “Review of excipients and pH’s for
`parenteral products used in the United States." J. Porcine): Sci. Tech-
`iioL, 34(6). 452 ( 1980).
`. Physicians" Desk Reference, ed. 48, 1994.
`. Physicians‘ Desk Reference, ed. 50, 1996.
`. L. A. Ti‘issel, “Handbook on [njectahle Drugs," ed, 8. American
`Society of Hospital Pharmacists. Inc.. 1994.
`
`Lwiq
`
`[2.
`
`Vol. 51, No. 4 / July—August1997
`
`171
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`-171-
`
`-171-
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`
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`
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