IPR PETITION
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`| bi Pi A EAG A a
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`July/August
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`Volume51
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`MAIA Exhibit 1017
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`MAIA V. BRACCO
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`PDAJournal of
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`Pharmaceutical
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`PHaRMACTUTICAL SCIENCE AND TECHNOLOGY
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`July-August 1997
`
`Vol. 51, No. 4
`
`PDAJournal of
`Pharmaceutical Science and Technology
`EDITOR:—Joseph B. Schwartz
`
`Philadelphia College of Pharmacy & Science
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`ADVISORY BOARD
`
`Michael Akers, Eli Lilly and Co.
`Frederick J. Carleton
`Patrick DeLuca, University ofKentucky
`Barry Garfinkle, Merck Sharp & Dohme
`Michael Groves, University of Illinois
`Joseph Robinson, University of Wisconsin
`Theodore Roseman, Baxter Healthcare
`
`1996 OFFICERS AND DIRECTORS
`
`Chairman:
`Chairman-Elect:
`Secretary:
`Treasurer:
`Immediate Past
`
`RaymondShaw,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. Morrissey, Ph.D.
`Terry E. Munson
`Robert B. Myers
`
`President: Edmund M.Fry
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`PDA Journal of Pharmaceutical Science & Technology (ISSN
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`Copyright—PDA,Inc. 1997
`ISSN 1076-397X
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`

`

`
`
`REVIEW ARTICLE
`
`Excipients and Their Use in Injectable Products
`
`SANDEEP NEMA’, R. J. WASHKURN, and R. J. BRENDEL
`
`Mallinckrodt Medical, Incorporated, Saint Louis, Missouri
`
`
`
`ABSTRACT: Formulation of anewdrug 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 HandbookonInjectable Drugs were reviewed, extracting all information onexcipients. The
`information was consolidated into eight tables, categorizing excipients as 1) Solvents and Co-solvents, 2)
`Solubilizing, Wetting, Suspending, Emulsifying or Thickening agents, 3) Chelating Agents, 4) Antioxidants and
`Reducing Agents, 5) Antimicrobial Preservatives, 6) Buffers 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 of a commercial product containing the excipient. Exciptents which are includedin
`the 1996 FDA ‘Inactive Ingredient Guide,’ but do net appearin the PDR or Handbook on Injectable Drugs, were
`included as a separatelist.
`
`Introduction
`
`Injectable products require a unique formulationstrategy.
`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 onthe 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 requirementforsterility demandsthat
`the excipients be able to withstand autoclaving or other
`sterilization processes. These factors limit the choice of
`excipients available to the formulators.
`Generally, a knowledge of which excipients have been
`deemed safe by the FDA orare already present in a marketed
`product provides increased assurance to the formulatorthat
`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 unforesccn
`potenUation 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 praduct will
`always require additional studies adding to the cost and
`timeline 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 forpublication May 16, 1997.
`* Author to whomcorrespondence should be addressed: P.O. 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 ointments 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 wasclassificd by Manufacturer, Trade name, Drug
`name, Route of Administration, SVP/LVP, pl of Product,
`Solvent Used, Solubilizing/Suspending Agent, Preservative,
`Antioxidant, Chelator and Other Formulation Additives.
`The resulting Excel sheet had information on more than
`700 products. This information was condensed into easy-to-
`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 VII
`contain some excipients which may havealso beenlisted in
`the first six tables. Whenever the reference specifically
`designated a specific function to an ingredient
`it was
`re-listed in Tables VIT and VIIT. 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 1s a preservative (Table VY) but also has a special
`function in Adriamycin RDF® formulation (Table VIID.
`The concentration of excipicnts is listed as percentages
`weight by volume (w/v) or volume by volume (v/v). If the
`product waslisted as lyophilized or powder, these percent-
`
`PDA Journal of Pharmaceutical Science & Technology
`
`-166-
`
`-166-
`
`
`
`
`

`

`TABLE|
`Solvents and Co-solvents
` Excipient Frequency Range Example
`
`
`
`Benzyl] Benzoate
`2
`20%viy
`Depo-Testosterone® (Upjohn) 20% v/v
`Cottonseed Oil
`1
`73.6% wiv
`Depo-Testosterone® (Upjohn) 73.6% w/v
`N.N Dimethylacctamide
`|
`6% wiv
`Vumon®(Bristol Myers) 6% w/v
`Ethanol
`24
`0.6-80%
`Prograf® (Fujisawa) 80% v/y
`Glycerin (Glycerol)
`9
`1.6-70% wiv
`Multitest CMI® (Connaught) 70% w/v
`Peanutoil
`1
`7
`Bal in Oil® (Becton Dickinson)
`Polyethylene glycol
`PEG
`PEG 300
`PEG 400
`PEG 3350
`Poppyseedoil
`Propylene Glycol
`Saffloweroil
`Seasmeoil
`Soybeanoil
`Vegetable oil
`* Nodata available.
`
`Secobarbital sodium (Wyeth-Ayerst) 50%
`VePesid® (Bristol Myers) 65% w/v
`Ativan® (Wyeth-Ayerst)
`Depo-Medrol® (Upjahn) 2.95% w/v
`Ethiodol® (Savage) 1%
`Terramycin Solution (Reerig) 75.2%
`Liposyn II® (Abbott) 10%
`Solganal Inj.® (Schering)
`Intralipid® (Clintec) 20%
`Virilon IM Inj.® (Star Pharmaccuticals)
`
`4
`2
`2
`5
`I
`25
`2
`6
`4
`2
`
`0.15-50%
`50-65 %
`*
`0.3-3%
`
`0.2~75.2%
`35-10%
`a
`5-20% wiv
`af
`
`ages were derived based on the reconstitution volume
`commonly used. The tables list the range of concentration
`used, typical or most commonconcentration employed, and
`examples of products containing the excipient, specifically
`those which use extremely low or high concentrations.
`
`Discussions
`
`Table I list solvents and co-solvents used in parentcral
`products. Waterfor injection is the most commonsolvent but
`may be combined or substituted with a co-solvent
`to
`improve the solubility or stability of drugs. Oils like
`safflower and soybean are used in total parcnteral nutrition
`products where they serve as a fat source and ascarriers for
`fat-soluble vitamins. Ethanol and propylene glycolare used,
`either alone or in combination with other solvents, in more
`than 50% of parentcral 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 1s a majorlimitation.
`Table IT includes a broad category of excipients whose
`function in formulation could be -(1) Viscosity imparting 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, Polysor-
`bate 20 or 80, PEG 40 castoroil, PEG 60 castoroil, sodium
`dodecyl sulfate,
`lecithin or egg yolk phospholipid;
`(3)
`Aluminum monostearate which is addedto fixed oil to form
`viscous or gel-like suspending medium. Polysorbate 80 is
`the most commonandversatile solubilizing, wetting and
`emulsifying agent.
`Only a limited numberof chelating agents are used in
`parenteral products (Table III). They serve to complex heavy
`
`TABLE1
`
`Solubilizing, Wetting, Suspending, Emulsifying or Thickening Agents
`
`Excipient
`
`Frequency
`
`Range
`
`Example
`
`1%
`2
`Acacia
`2%
`]
`Aluminum monoslearate
`1%
`4
`Carboxy methyl cellulose
`0.1-0.75%
`9
`Carboxy methyl cellulose, sodium
`50-65% wiv
`3
`Cremophore EL*
`0.4% wiv
`1
`Desoxycholate sodium
`1.2%
`3
`Egg yolk phospholipid
`16% wiv
`1
`Gelatin, Hydrolzyed
`0.4-1.2% wiv
`7
`Lecithin
`7% wiv
`1
`Polyoxyethylated fatty acid
`0.01-12%
`31
`Polysorbate 80 (Tween 80)
`0.01-0.4%
`5
`Polysorbate 20 (Tween 20)
`
`11.5% viv
`1
`PEG 40castoroil***
`
`20% wiv
`1
`PEG 60 castoroi
`0.5-0.6% wiv
`6
`Povidone (Polyvinyl pyrrolidone)
`0.018% wiv
`|
`Sodium dodecyl] sulfate (Na lauryl sulfate)
`25-50%
`3
`Sorhitol
`CremophorFI.: Ftacus 35, polyethoxylated castor oil, polyoxyethylene 35 castoroil.
`EG 40 castoroil; polyoxyl 40 castor oil, castor oi] POE-40, Croduret 40, polyoxyethylene 40 castoroil, Protachem CA-40.
`
`PEG 60 hydrogenatedcastor oil: Cremophor RH 60, hydrogenated castor oil POK-60, Protachem CAH-60.
`
`Tuberculin Old Test® (Lederle) 7%
`Solganal Inj.® (Schering) 2%
`Bicillin® (Wyeth-Ayerst) 0.55%
`Lupron Depot® (TAP) 0.75% w/v
`Sandimmune® (Sandoz) 65% w/v
`Fungizone® (Bristol Myers) 0.41% wiv
`Intralipid® (Clintec) 1.2%
`Cortone® (Merck) 16% wiv
`Diprivan® (Zeneca) 1.2% w/v
`AquaMephyton® (Merck) 7% w/v
`Cordarone X Lyv.©. (Wyeth-Ayerst) 10%
`Calcijex® (Abbott) 0.4% w/v
`Monistat® (Janssen) 11.5% v/v
`Prograf®(Fujisawa) 20% w/v
`Bicillin® (Wyeth-Ayerst) 0.6% w/v
`Proleukin® (Cetus) 0.018% w/v
`Aristrospan® (Fujisawa) 50% v/v
`
`Vol. 51, No. 4 / July-August 1997
`
`167
`
`-167-
`
`-167-
`
`
`
`
`

`

`TABLE Ill
`Chelating Agents
`
`Excipicnot
`Calcium disodium
`EDTA#*#
`Disodium EDTA
`
`Frequency
`9
`
`34
`
`
`
`
`
`toxicity(7, 8). Butylated hydroxy anisole, butylated hydroxy
`toluene and propyl gallate are primarily used in semi/non-
`aqucous vehicles because of their low aqueous solubility.
`Example
`Range
`Ascorbic acid/sodium ascorbate may serve as an antioxi-
`0.01-0.1% Wydase® (Wyeth-
`dant, buffer, and chelating agent in the same formulation.
`Aycrst) 0.1% wiv
`Benzyl alcohol was the most common antimicrobial
`0.01-0.1% Calcijex® (Abbott)
`0.11% w/v
`preservative present in parenteral formulations (Table V).
`Sodium EDTA 0.20%—Folvite® (Lederle)i
`This is consistent with other surveys (9). Parabens are the
`0.2%
`next most commonpreservatives. Thirty-nine products had a
`Magnevist® (Berlex)
`0.04%
`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
`diethanolamine are addedto 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
`
`DTPA**
`
`1
`
`0.04%
`
` DTA = Ethlenediaminetetraacetic acid,
`** DTPA = Diethylenetriamincpentaacctic acid; Pentetic acid.
`
`metals and therefore can improve the efficacy of antioxi-
`dants or preservatives. In our opinion, calcium EDTA has an
`advantage overtetrasodium 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 TV summarizes the antioxidants,
`their
`frequency of use, concentration range and examples of
`products containing them. Sulfite, bisulfite, and metabisul-
`tite constitute the majority of antioxidants used in parenteral
`products despite several reports of incompatibilities and
`
`TABLEIV
`Antioxidants and Reducing Agents
`
`
`Frequency
`4
`7
`28
`3
`3
`2
`1
`
`Range
`0.2-0.4% wiv
`0.1-4.8% wiv
`0.02-0.66% w/v
`0.00028-0.03 % wiv
`0.00116-0.03% w/v
`0.07-0.10% wiv
`0.10%
`
`Excipient
`Acetone sodium bisulfite
`Ascorbate (sodium/acid)
`Bisulfite sodium
`Butylated hydroxy anisole (BHA)
`Butylated hydroxy toluene (BHT)
`Cystein/Cysteinate HC]
`Dithionite sodium (Na hydrosulfite, Na sulf-
`oxylate)
`Gentisic acid
`0.02% wiv
`]
`Gentisic acid ethanolamine
`2%
`!
`Glutamate monosodium
`0.1% wiv
`2
`Formaldehyde sulfoxylate sodium
`0.075-0.5% wiv
`9
`Metabisulfilte potassium
`0.10%
`I
`Metabisulfite sodium
`0.02--1% wiv
`29
`Monothioglycerol (Thioglycerol)
`0.1-1%
`6
`Propyl gallate
`0.02%
`2
`Sulfite sodium
`7
`0.05-0.2% wiv
`
`Thioglycolate sodium
`l
`0.66% wiv
`
`TABLE V
`Antimicrobial Preservatives
`
`Example
`
`Novocaine® (Sanofi-Winthrop) 0.4% w/v
`Vibramycin® (Roerig) 4.8% w/v
`Amikin® (Bristol Myers) 0.66% w/v
`Aquasol®(Astra) 0.03%
`Aquasol® (Astra) 0.03%
`Acthar Gel® (Rhone-Poulanc) 0.1% w/v
`Numorphan® (DuPont) 0.10%
`
`OctreoScan® (Mallinckrodt)
`M.V.L 12® (Astra) 2%
`Varivas® (Merck) 0.1% w/v
`Terramycin Solution (Roerig) 0.5% w/v
`Vasoxyl® (Glaxo-Wellcome) 0.10%
`Intropin® (DuPont) 1% w/v
`Terramycin Solution (Roerig) 1%
`Navane® (Roerig)
`Enion® (Ohmeda) 0.2% w/v
`Sus-Phrine® (Forest) 0.66% w/v
`
`Example
`
`Excipient
`Benzalkoniumchloride
`Benzethonium chloride
`Benzyl alcohol
`Chlorobutanol
`m-Cresol]
`Myristyl gamma-picoliniumchloride
`Paraben methy]
`Paraben propyl
`Phenol
`2-Phenoxyethanol
`Phenyl mercuric nitrate
`Thimerosal
`
`Frequency
`l
`4
`74
`17
`3
`2
`30
`40
`48
`3
`3
`46
`
`Range
`0.02% wiv
`0.01%
`0.75-5%
`0.25-0.5%
`0.1-0.3%
`0.0195-0.169% w/v
`0.05-0.18%
`0.01 0.1%
`0.2-0.5%
`0.50%
`0.001 %
`0.003-0.01%
`
`Celestone Soluspan® (Schering) 0.02% wiv
`Benadry]®(Parke-Davis) 0.01% wiv
`Dimenhydrinate® (Steris) 5%
`Codine phosphate (Wyeth-Ayerst) 0.5%
`Humatrope® (Lilly) 0.30%
`Depo-Provera® (Upjohn) 0.169% w/v
`Inapsine® (Janssen) 0.18% w/v
`Xylocaine w/Epinephrine (Astra) 0.1% w/v
`Calcimar® (Rhone Poulanc) 0.5% w/v
`Havrix® (SmithKline Beecham) 0.50% wiv
`Antivenin® (Wyeth-Ayerst) 0.001%
`Algam® (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
`Ammonium
`Ammonium hydroxide
`
`Miacalcin Injection® (Sandoz)
`Miacalcin Injection® (Sandoz)
`Brevibioc Injection® (Ohmeda)
`Bumex Injection® (Reche)
`Triostat Injection® (SmithKline
`Beecham)
`‘Tracrium Injection® (Glaxo-Wellcome)
`ValiumInjection® (Roche)
`Cctotan Injection® (Zeneca)
`HypoRho-D®(Bayer)
`
`DTIC-Dome® (Bayer)
`Ceredase® (Genzyme)
`Cerezyme® (Genzyme)
`Cerezyme® (Genzyme)
`Bactrim IV® (Roche)
`Quinidine® (Lilly)
`Hep-B Gamimagee® (Merck)
`Amicar® (Immunex)
`Scopolamine (UDL)
`Fentenyl citrate & Droperidol (Astra)
`Eminase Injection® (Roberts)
`LibriumInjection® (Roche)
`DHE-45 Injection® (Sandoz)
`Terramycin Solution (Roerig)
`
`
`
`Benzenesulfonic 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
`Monvethanolamine
`Phosphate
`Acid (phosphoric)
`Monobasic polassium
`Monobasic sodium*
`Dibasic sodium**
`Tribasic sodium
`Sodiumhydroxide
`Sulfuric acid
`Tartrate acid/sodium
`
`Tromethamine
`
`Humegon® (Organon)
`Zanlac Injection® (Glaxo-Wellcome)
`Pregnyl® (Organon)
`Prolastin® (Bayer)
`Synthroid® (Knoll)/
`Optiray® (Mallinckrodt)
`Nebcin®(Lilly)
`Methergine Injection® (Sandoz)
`Optiray® (Mallinckrodt)
`* Sodiumbiphosphate, Sodiumdihydrogen phosphate or Na dihydrogen
`orthophosphate.
`* 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 dualrole as chelating agents. Lysine and glycine are amino
`acids which function as buffers and stabilize protein and
`peptide formulations. These amino acids are also used as
`lyo-additives and may prevent cold denaturation. Lactate
`andtartrate 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, mannitol, sorbitol),
`glycol (PEG 3350), Povidone (polyvinylpyrrolidone), and
`proteins (albumin, gelatin) are commonly used as lyo-
`additives.
`
`Vol. 51, No. 4 / July-August 1997
`
`-169-
`
`TABLEVII
`Bulking Agents, Protectants, and Tonicity Adjustors
`
`Excipient
`Alanine
`Albumin
`Albumin human
`Amino acids
`L-Arginine
`Asparagine
`L-Aspartic acid
`Calciumchloride
`Ciuic acid
`Dextrose
`Gelatin hydrolyzed
`Glucose
`Glycerin
`Glycine
`Histidine
`
`Imidazole
`Inositol
`Lactose
`Magnesiumchloride
`Magnesiumsulfate
`Mannitol
`Polyethylene glycol 3350
`Polysorbate 80
`Potassium chloride
`Povidone
`Sodium chloride
`Sodium succinate
`Sodium sulfate
`Sorbitol
`Sucrose
`
`Example
`
`Thrombate III® (Bayer)
`Biociate® (Arco)
`Botox® (Allergan)
`Havrix® (SmithKline Beecham)
`Activase® (Genentech)
`Tice BCG® (Oganon)
`Pepcid® (Merck)
`PhenerganInjection® (Wyeth-Ayerst)
`Sensorcaine-MPF®(Astra)
`Betuseron® (Berlex)
`Acthar® (Rhone-Poulanc Rorer)
`Ivecgam® (immuno-US)
`Tice BCG® (Oganon)
`AtgamInjection® (Upjohn)
`Antihemophilic 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)
`WinRho SD® (Univax)
`Actimmune® (Genentech)
`Depo-Provera® (Upjohn)
`Panhematin® (Abbott)
`Prolastin® (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—
`
`3 a
`
`(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 TV® (Ciprofloxacin, Bayer) contains lactic
`acid as a solubilizing agent for the antibiotic.
`Premarin Injection® (Conjugated Estrogens, Wyeth-
`Ayerst Labs) is a lyophilized product that contains
`simethicone to prevent formation of foam during
`reconstitution.
`Dexamethasone acetate (Dalalone DP, Forest,
`Decadron-LA, Merck, Dalalone DP Injection, UAD
`Labs) and Dexamethasone Na phosphate (Merck)
`are available as suspension or solution. These dexa-
`methasone formulations contain creatine or crcati-
`nine as an additive.
`
`(4 ar
`
`(6=
`
`(5) Adriamycin RDF® (Doxorubicin hydrochloride,
`Pharmacia) contains methyl paraben, 0.2 mg/mL, lo
`increase dissolution (10).
`Ergotrate maleate (Ergonovine maleate, Lilly) con-
`tains 0.1% ethyl lactate as a solubilizing agent.
`Estradurin Injection® (Polyestradiol phosphate,
`Wyeth-Ayerst Labs) uses Niacinamide (12.5 mg/ml)
`
`7 VS
`
`169
`
`-169-
`
`
`
`
`

`

`
`
`TABLEVIII
`Special Additives
`
`
`
`Example
`Human Albumin (American Red
`Cross)
`Recombinant HB® (Merck)
`Tetanus Toxoicd Adsorbed®
`(Lederle)
`TD Adsorbed Adult®
`(Connaugh0)
`Eminase® (Roberts)
`Calcium Gluconate (American
`Regent)
`Human Albumin (American Red
`Cross)
`Dimenhydrinate (Steris)
`Dalalone DP® (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
`Aluminumphosphate
`
`Aluminumpotassiumsulfate
`
`E-Aminocaproic acid
`Calciumd-saccharate
`
`Caprylate sodium
`
`8-Chlorotheophy line
`Creatine
`Creatinine
`
`Diatrizoic acid
`GammaCyclodextrin
`Ethyl lactate
`Ethylenediamine
`L-Glutamate sodium
`Tron ammoniumcitrate
`Lactic acid
`D,L-Lactic and Glycolic acid
`copolymer
`Maltose
`Meglumine
`Niacinamide
`Paraben methy!
`Protamine
`
`Gamimune® (Bayer)
`Magnevist® (Berlex)
`Estradurin® (Wyeth-Ayerst)
`Adriamycin RDF® (Pharmacia)
`Tnsulatard NPH® (Novo
`Nordisk)
`Premarin Injection® (Wyeth-
`Ayerst)
`Compazine Injection® (Smith-
`Kline Beecham)
`Venoglobulin® (Apha Thera-
`peutic)
`von Willebrand factor
`Bioclate® (Arco)
`
`Zine Lente Insulin® (Novo Nordisk)
`
`Simethicone
`
`Sodium saccharin
`
`Tri-n-butyl phosphate
`
`as a solubilizing agent. Hydeltrasol® (Merck) also
`contains niacinamide.
`
`(8a
`
`Aluminum in the form of aluminum hydroxide,
`aluminumphosphate or aluminum potassiumsulfate
`is used as adjuvant in various vaccine formulations
`to clicit an increased immunogenic response.
`9~— Zoladex® (Goserelin acetate, Zeneca) is adminis-
`tered subcutaneously as microspheres. These spheres
`are made of D,L-lactic and glycolic acid copolymer.
`Lupron Depot Injection® (TAP) are lyophilized mi-
`crospheres of gelatin and glycolic-lactic acid for
`intramuscularinjection.
`(10) Gamma cyclodextrin is used as a stabilizer in
`Cardiotec® at a concentration of 50 mg/mL.
`(11) Sedium caprylate (sodium octeate) has antifungal
`properties, but it is also used to improvethestability
`of albuminsolution against effects of heat. Albumin
`solution can be heat pasteurized by heating at GO°C
`for 10 hours in the presence of sodium caprylate.
`Acetyl (ryptophanate sodiumis 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’
`Ammoniumsulfate
`Benzyl chloride
`Butyl paraben
`Caldiamide sodium
`Caltcridol calcium
`Castoroil
`Cellulose (microcrystalline)
`Cholesterol
`Deoxycholic acid
`Diatrizoic acid
`Dicyclohexy] carbodiimide
`Diethyl amine
`Dimyristoyl lecithin
`Dimnyristoyl phosphatidyl-
`glycerol
`Disofenin
`Docusate sodium
`Edamine
`Exametazime
`Gluceplale sodium
`Gluceptate calcium
`Glucuronic acid
`Guanidine HC]
`lofetamine HCI
`Lactobionic acid
`Lecithin hydrogenated soy
`Lidofenin
`Medrofenin
`Medronate ‘disodium
`Medronic acid
`Methyl boronic acid
`Methyl cellulose
`Methylene blue
`N-(carbamoyl-methoxypoly-
`ethylene-glycal 2000)- 1,2-
`distearoy]
`N-2-hydroxyethy] piperazine
`N’-2' ethane sulphonic acid
`Nioxime
`Nitric acid
`Oxyquinoline
`
`Pentetate (DTPA) calcium
`trisodium
`Poloxamer 165
`PEG 4000
`PEG 600
`Polyglactin
`Polylactide
`Polyoxyethlene fatty acid
`esters
`Polyoxyethylene sorbitan
`monosterate
`Polyaxyl 35 Castoroil
`Polysorbate 40
`Polysorbate 85
`Potassiumhydroxide
`Polassium phosphate, dibasic
`Sodiumbisulfate
`Sodiumchlorate
`Sodiumhypochloride
`Sodiumiodide
`Sodium pyrophosphate
`Sodiumthiosulfate, anhydrous
`Sodiumtrimetaphosphate
`Sorbitan monopalmitate
`Stannous chloride
`Stannous fluoride
`Stannous tartrate
`Starch
`Succimer
`Succinic acid
`Sulfurous acid
`Tetrakis (1-isocyano-2-me-
`thoxy-2,methyl-propante)
`copper(I) Te
`Thiazoximic ucid
`
`Trithiazoximic acid
`Urea
`Zinc acetate
`Zinc chloride
`Zine oxide
`2-cthyl 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 (11). Meglumine is also added to Magnevist®, a
`magnetic resonance contrast agent, formulation.
`Surprisingly, sodium saccharine is used in Stelazine®
`and Compazine® formulations; our guess is that it
`serves as a stabilizer and tonicity adjuster.
`Tri-n-butyl phosphate is present as an cxcipient in
`human immune globulin solution (Venoglobulin®).
`Its exact function in the formulation is not known,
`but it may serve as a scavenging agent.
`von Willebrand factoris used to stabilize recombi-
`nant antihemophilic factor (Bioclate®).
`Maltoseserves as a tonicity adjusterandstabilizer in
`immune globulin formulation (Gamimune N®),
`Epsilon amino caproic acid (6-amino hexanoic acid)
`is used as a stabilizerin anistreplase (Eminase injec-
`tion®).
`Zine and protamine have been added to insulin to
`form complexes and control the duration of action,
`
`a3 a
`
`(4a
`
`(15)
`
`(16)
`
`(17)
`
`(18)
`
`PDAJournal of Pharmaceutical Science & Technology
`
`-170-
`
`
`
`
`

`

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`. G. A. Bazeau and Ho-Leung Fung, “Use ofan in-vitro model for the
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`‘Inactive Ingredient Guide.’ Division of Drug Information Resources,
`TDA, CDER,January 1996.
`
`.
`
`I.
`
`Recently, FDA has published ‘Inactive Ingredient Guide’
`which lists all
`the excipients in alphabetical order. Each
`in gredient is followed by the route of administration (for
`example, lv, 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) corre-
`sponding to each excipient. Table IX is a summaryofall the
`excipients which are included in the ‘Inactive Ingredient
`Guide,” but do not appear in PDR or HandbookonInjectable
`Drugs.
`
`References
`
`Y. J. Wang and R. R. Kowal, “Review of excipients and pH’s for
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`Physicians’ Desk Reference, ed. 48, 1994.
`Physicians’ Desk Reference, ed. 50, 1996.
`L. A. Trissel, “Handbook on Injectable Drugs,” ed. 8, American
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`
`w.
`I B
`
`Vol. 51, No.4 / July-August 1997
`
`171
`
`-171-
`
`-171-
`
`
`
`
`