Downloaded from Downloaded from journal.pda.org on March 18, 2015journal.pda.org on March 18, 2015
`
`
`
`
`
`
`
`
`
`
`
`Excipients and Their Use in Injectable Products
`Sandeep Nema, R. J. Washkuhn and R. J. Brendel
`
`
`
` 166-17151, 1997PDA J Pharm Sci and Tech
`
`
`
`
`
`
`
`Ex. 1020 - Page 1 of 8
`
`AMGEN INC.
`Exhibit 1020
`
` 
` 
`  
`

`

`
`
`Downloaded from on March 18, 2015journal.pda.org
`
`
`
`REVIEW ARTICLE
`
`Excipients and Their Use in Injectable Products
`
`SANDEEP NEMA*, R. J. WASHKUHN, and R. J.
`
` BRENDEL
`
`Mallinckrodt Medical, Incorporated, Saint Louis, Missouri
`
`ABSTRACT: Formulation of a 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 excipients. The
`information was consolidated into eight tables, categorizing excipients as I) 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. Excipients which are included in
`the 1996 FDA 'Inactive 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
`excipients available to the formulators.
`Generally, a knowledge of which excipients 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
`timeline of product development.
`The purpose of this paper is to present the various
`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 for publication May 16. 1997.
`*Author to whom correspondence should be addressed: P.O. Box 5840. St.
`Louis, MO, 63134
`
`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 was classified by Manufacturer, Trade name, Drag
`name. Route of Administration, SVP/LVP, pH 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(cid:173)
`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 VII and VIII. 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 Adriamycin RDF® formulation (Table VIII).
`The concentration of excipients 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-
`
`166
`
`
`
`PDA Journal of Pharmaceutical Science & Technology
`
`Ex. 1020 - Page 2 of 8
`
`

`

`
`
`Downloaded from on March 18, 2015journal.pda.org
`
`
`
`TABLE I
`Solvents and Co-solvents
`
`Excipient
`
`Frequency
`
`Benzyl Benzoate
`Cottonseed Oil
`N,N Dimethylacetamide
`Ethanol
`Glycerin (Glycerol)
`Peanut oil
`Polyethylene glycol
`PEG
`PEG 300
`PEG 400
`PEG 3350
`Poppyseed oil
`Propylene Glycol
`Safflower oil
`Seasme oil
`Soybean oil
`Vegetable oil
`
`* No data available.
`
`2
`1
`1
`24
`9
`1
`
`4
`2
`2
`5
`1
`25
`2
`6
`4
`2
`
`Range
`
`20% v/v
`73.6% w/v
`6% w/v
`0.6-80%
`1.6-70% w/v
`
`0.15-50%
`50-65%
`
`0.3-3%
`1%
`0.2-75.2%
`5-10%
`*
`5-20% w/v
`*
`
`Example
`Depo-Testosterone® (Upjohn) 20% v/v
`Depo-Testosterone® (Upjohn) 73.6% w/v
`Vumon® (Bristol Myers) 6% w/v
`Prograf® (Fujisawa) 80% v/v
`Multitest CMI® (Connaught) 70% w/v
`Bal in Oil® (Becton Dickinson)
`
`Secobarbital sodium (Wyeth-Ayerst) 50%
`VePesid® (Bristol Myers) 65% w/v
`Ativan® (Wyeth-Ayerst)
`Depo-Medrol® (Upjohn) 2.95% w/v
`Ethiodol® (Savage) 1%
`Terramycin Solution (Roerig) 75.2%
`Liposyn II® (Abbott) 10%
`Solganal Inj.® (Schering)
`Intralipid® (Clintec) 20%
`Virilon IM Inj.® (Star Pharmaceuticals)
`
`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.
`
`Discussions
`
`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 co-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
`
`glycols (PEGs) in spite of its higher myotoxicity and
`hemolyzing effects (5, 6). Probably, the presence or genera(cid:173)
`tion of peroxides in PEGs is a major limitation.
`Table II 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 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 III). They serve to complex heavy
`
`TABLE II
`Solubilizing, Wetting, Suspending, Emulsifying or Thickening Agents
`
`Excipient
`
`Frequency
`
`Acacia
`Aluminum monostearate
`Carboxy methyl cellulose
`Carboxy methyl cellulose, sodium
`Cremophore EL*
`Desoxycholate sodium
`Egg yolk phospholipid
`Gelatin, Hydrolzyed
`Lecithin
`Polyoxyethylated fatty acid
`Polysorbate 80 (Tween 80)
`Polysorbate 20 (Tween 20)
`PEG 40 castor oil**
`PEG 60 castor oil***
`Povidone (Polyvinyl pyrrolidone)
`Sodium dodecyl sulfate (Na lauryl sulfate)
`Sorbitol
`
`2
`1
`4
`9
`3
`1
`3
`1
`7
`1
`31
`5
`1
`1
`6
`1
`3
`* Cremophor EL: Etocas 35, polyethoxylated castor oil, polyoxyethylene 35 castor oil.
`** PEG 40 castor oil; polyoxyl 40 castor oil, castor oil POE-40, Croduret 40, polyoxyethylene 40 castor oil, Protachem CA-40.
`*** PEG 60 hydrogenated castor oil; Cremophor RH 60, hydrogenated castor oil POE-60, Protachem CAH-60.
`
`Range
`7%
`2%
`1%
`0.1-0.75%
`50-65% w/v
`0.4% w/v
`1.2%
`16% w/v
`0.4-1.2% w/v
`7% w/v
`0.01-12%
`0.01-0.4%
`11.5% v/v
`20% w/v
`0.5-0.6% w/v
`0.018% w/v
`25-50%
`
`Example
`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% w/v
`Intralipid® (Clintec) 1.2%
`Cortone® (Merck) 16% w/v
`Diprivan® (Zeneca) 1.2% w/v
`AquaMephyton® (Merck) 7% w/v
`Cordarone X I.v.®. (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
`
`Ex. 1020 - Page 3 of 8
`
`

`

`
`
`Downloaded from on March 18, 2015journal.pda.org
`
`
`
`TABLE III
`Chelating Agents
`
`Excipient
`
`Frequency
`
`Range
`
`Calcium disodium
`EDTA*
`Disodium EDTA
`
`Sodium EDTA
`
`DTPA**
`
`9
`
`34
`
`1
`
`1
`
`0.01-0.1%
`
`0.01-0.1%
`
`0.20%
`
`0.04%
`
`Example
`Wydase® (Wyeth-
`Ayerst) 0.1 % w/v
`Calcijex® (Abbott)
`0.11% w/v
`Folvite® (Lederle)
`0.2%
`Magnevist® (Berlex)
`0.04%
`
`* EDTA = Ethlenediaminetetraacetic acid.
`** DTPA = Diethylenetriaminepentaacetic acid; Pentetic acid.
`
`metals and therefore can improve the efficacy of antioxi(cid:173)
`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
`
`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(cid:173)
`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
`diethanolamine are added to adjust pH and form correspond(cid:173)
`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
`
`TABLE IV
`Antioxidants and Reducing Agents
`
`Excipient
`
`Frequency
`
`Range
`
`Acetone sodium bisulfite
`Ascorbate (sodium/acid)
`Bisulfite sodium
`Butylated hydroxy anisole (BHA)
`Butylated hydroxy toluene (BHT)
`Cystein/Cysteinate HCl
`Dithionite sodium (Na hydrosulfite, Na sulf-
`oxylate)
`Gentisic acid
`Gentisic acid ethanolamine
`Glutamate monosodium
`Formaldehyde sulfoxylate sodium
`Metabisulfite potassium
`Metabisulfite sodium
`Monothioglycerol (Thioglycerol)
`Propyl gallate
`Sulfite sodium
`Thioglycolate sodium
`
`4
`7
`28
`3
`3
`2
`1
`
`1
`1
`2
`9
`1
`29
`6
`2
`7
`1
`
`0.2-0.4% w/v
`0.1-4.8% w/v
`0.02-0.66% w/v
`0.00028-0.03% w/v
`0.00116-0.03% w/v
`0.07-0.10% w/v
`0.10%
`
`0.02% w/v
`2%
`0.1 % w/v
`0.075-0.5% w/v
`0.10%
`0.02-1% w/v
`0.1-1%
`0.02%
`0.05-0.2% w/v
`0.66% w/v
`
`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.I. 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
`
`Excipient
`
`Frequency
`
`Range
`
`Benzalkonium chloride
`Benzethonium chloride
`Benzyl alcohol
`Chlorobutanol
`m-Cresol
`Myristyl gamma-picolinium chloride
`Paraben methyl
`Paraben propyl
`Phenol
`2-Phenoxyethanol
`Phenyl mercuric nitrate
`Thimerosal
`
`1
`4
`74
`17
`3
`2
`50
`40
`48
`3
`3
`46
`
`0.02% w/v
`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%
`
`Example
`Celestone Soluspan® (Schering) 0.02% w/v
`Benadryl® (Parke-Davis) 0.01% w/v
`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% w/v
`Antivenin® (Wyeth-Ayerst) 0.001%
`Atgam® (Upjohn) 0.01%
`
`168
`
`PDA Journal of Pharmaceutical Science & Technology
`
`Ex. 1020 - Page 4 of 8
`
`

`

`
`
`Downloaded from on March 18, 2015journal.pda.org
`
`
`
`TABLE VI
`Buffers and pH Adjusting Agents
`
`Excipient
`
`Example
`
`Miacalcin Injection® (Sandoz)
`Miacalcin Injection® (Sandoz)
`Brevibioc Injection® (Ohmeda)
`Bumex Injection® (Roche)
`Triostat Injection® (SmithKline
`Beecham)
`Tracrium Injection® (Glaxo-Wellcome)
`Valium Injection® (Roche)
`Cefotan Injection® (Zeneca)
`HypoRho-D® (Bayer)
`
`DTIC-Dome® (Bayer)
`Ceredase® (Genzyme)
`Cerezyme® (Genzyme)
`Cerezyme® (Genzyme)
`Bactrim IV® (Roche)
`Quinidine® (Lilly)
`Hep-B Gammagee® (Merck)
`Amicar® (Immunex)
`Scopolamine (UDL)
`Fentenyl citrate & Droperidol (Astra)
`Eminase Injection® (Roberts)
`Librium Injection® (Roche)
`DHE-45 Injection® (Sandoz)
`Terramycin Solution (Roerig)
`
`Acetate
`Sodium
`Acetic acid
`Glacial acetic acid
`Ammonium
`Ammonium hydroxide
`
`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
`Monoethanolamine
`Phosphate
`Acid (phosphoric)
`Monobasic potassium
`Monobasic sodium*
`Dibasic sodium**
`Tribasic sodium
`Sodium hydroxide
`Sulfuric acid
`Tartrate acid/sodium
`Tromethamine
`
`Humegon® (Organon)
`Zantac Injection® (Glaxo-Wellcome)
`Pregnyl® (Organon)
`Prolastin® (Bayer)
`Synthroid® (Knoll)/
`Optiray® (Mallinckrodt)
`Nebcin® (Lilly)
`Methergine Injection® (Sandoz)
`Optiray® (Mallinckrodt)
`* Sodium triphosphate, Sodium dihydrogen 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 dual role 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
`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, mannitol, sorbitol),
`glycol (PEG 3350), Povidone (polyvinylpyrrolidone), and
`proteins (albumin, gelatin) are commonly used as lyo-
`additives.
`
`TABLE VII
`Bulking Agents, Protectants, and Tonicity Adjusters
`
`Excipient
`
`Alanine
`Albumin
`Albumin human
`Amino acids
`L-Arginine
`Asparagine
`L-Aspartic acid
`Calcium chloride
`Citric acid
`Dextrose
`Gelatin hydrolyzed
`Glucose
`Glycerin
`Glycine
`Histidine
`
`Imidazole
`Inositol
`Lactose
`Magnesium chloride
`Magnesium sulfate
`Mannitol
`Polyethylene glycol 3350
`Polysorbate 80
`Potassium chloride
`Povidone
`Sodium chloride
`Sodium succinate
`Sodium sulfate
`Sorbitol
`Sucrose
`
`Special Additives
`
`Example
`Thrombate III® (Bayer)
`Biociate® (Arco)
`Botox® (Allergan)
`Havrix® (SmithKline Beecham)
`Activase® (Genentech)
`Tice BCG® (Oganon)
`Pepcid® (Merck)
`Phenergan Injection® (Wyeth-Ayerst)
`Sensorcaine-MPF® (Astra)
`Betaseron® (Berlex)
`Acthar® (Rhone-Poulanc Rorer)
`Iveegam® (immuno-US)
`Tice BCG® (Oganon)
`Atgam Injection® (Upjohn)
`Antihemophilic Factor, human
`(Am. Red Cross)
`Helixate® (Armour)
`OctreoScan® (Mallinckrodt)
`Caverject® (Upjohn)
`Terramycin Solution® (Roerig)
`Tice BCG® (Oganon)
`Elspar® (Merck)
`Biociate® (Arco)
`Helixate® (Armour)
`Varivax® (Merck)
`Alkeran® (Glaxo-Wellcome)
`WinRho SD® (Univax)
`Actimmune® (Genentech)
`Depo-Provera® (Upjohn)
`Panhematin® (Abbott)
`Prolastin® (Bayer)
`
`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(cid:173)
`zation during temperature fluctuations.
`(2) Cipro IV® (Ciprofloxacin, 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
`simethicone to prevent formation of foam during
`reconstitution.
`(4) 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(cid:173)
`methasone formulations contain creatine or creati(cid:173)
`nine as an additive.
`(5) Adriamycin RDF® (Doxorubicin hydrochloride,
`Pharmacia) contains methyl paraben, 0.2 mg/mL, to
`increase dissolution (10).
`(6) Ergotrate maleate (Ergonovine maleate, Lilly) con(cid:173)
`tains 0.1% ethyl lactate as a solubilizing agent.
`(7) Estradurin Injection® (Polyestradiol phosphate,
`Wyeth-Ayerst Labs) uses Niacinamide (12.5 mg/ml)
`
`Vol. 51, No. 4 / July-August 1997
`
`169
`
`Ex. 1020 - Page 5 of 8
`
`

`

`
`
`Downloaded from on March 18, 2015journal.pda.org
`
`
`
`TABLE VIII
`Special Additives
`
`TABLE IX
`List of Excipient from 1996 FDA 'Inactive Ingredient Guide'
`
`Excipient
`
`Acetyl tryptophanate
`
`Aluminum hydroxide
`Aluminum phosphate
`
`Aluminum potassium sulfate
`
`E-Aminocaproic acid
`Calcium d-saccharate
`
`Caprylate sodium
`
`8-Chlorotheophylline
`Creatine
`Creatinine
`
`Diatrizoic acid
`Gamma Cyclodextrin
`Ethyl lactate
`Ethylenediamine
`L-Glutamate sodium
`Iron ammonium citrate
`Lactic acid
`D,L-Lactic and Glycolic acid
`copolymer
`Maltose
`Meglumine
`Niacinamide
`Paraben methyl
`Protamine
`
`Simethicone
`
`Sodium saccharin
`
`Tri-n-butyl phosphate
`
`von Willebrand factor
`Zinc
`
`Example
`
`Human Albumin (American Red
`Cross)
`Recombinant HB® (Merck)
`Tetanus Toxoid Adsorbed®
`(Lederle)
`TD Adsorbed Adult®
`(Connaught)
`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)
`
`Gamimune® (Bayer)
`Magnevist® (Berlex)
`Estradurin® (Wyeth-Ayerst)
`Adriamycin RDF® (Pharmacia)
`Insulatard NPH® (Novo
`Nordisk)
`Premarin Injection® (Wyeth-
`Ayerst)
`Compazine Injection® (Smith-
`Kline Beecham)
`Venoglobulin® (Apha Thera(cid:173)
`peutic)
`Bioclate® (Arco)
`Lente Insulin® (Novo Nordisk)
`
`Ammonium sulfate
`Benzyl chloride
`Butyl paraben
`Caldiamide sodium
`Calteridol calcium
`Castor oil
`Cellulose (microcrystalline)
`Cholesterol
`Deoxycholic acid
`Diatrizoic acid
`Dicyclohexyl carbodiimide
`Diethyl amine
`Dimyristoyl lecithin
`Dimyristoyl phosphatidyl-
`glycerol
`Disofenin
`Docusate sodium
`Edamine
`Exametazime
`Gluceptate sodium
`Gluceptate calcium
`Glucuronic acid
`Guanidine HC1
`Iofetamine HC1
`Lactobionic acid
`Lecithin hydrogenated soy
`Lidofenin
`Medrofenin
`Medronate disodium
`Medronic acid
`Methyl boronic acid
`Methyl cellulose
`Methylene blue
`N-(carbamoyl-methoxy poly-
`ethylene-glycol 2000)-1,2-
`distearoyl
`N-2-hydroxyethyl 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
`Polyoxyl 35 Castor oil
`Polysorbate 40
`Polysorbate 85
`Potassium hydroxide
`Potassium phosphate, dibasic
`Sodium bisulfate
`Sodium chlorate
`Sodium hypochloride
`Sodium iodide
`Sodium pyrophosphate
`Sodium thiosulfate, anhydrous
`Sodium trimetaphosphate
`Sorbitan monopalmitate
`Stannous chloride
`Stannous fluoride
`Stannous tartrate
`Starch
`Succimer
`Succinic acid
`Sulfurous acid
`Tetrakis (l-isocyano-2-me-
`thoxy-2,methyl-propante)
`copper (I) Te
`Thiazoximic acid
`Trithiazoximic acid
`Urea
`Zinc acetate
`Zinc chloride
`Zinc oxide
`2-ethyl hexanoic acid
`PEG vegetable oil
`
`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(cid:173)
`tered subcutaneously as microspheres. These spheres
`are made of D,L-lactic and glycolic acid copolymer.
`Lupron Depot Injection®(TAP) are lyophilized mi(cid:173)
`crospheres of gelatin and glycolic-lactic 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 caprylate.
`Acetyl tryptophanate sodium is also added to albu(cid:173)
`min formulations.
`(12) Meglumine (N-methylglucamine) is used as an ex-
`
`cipient and to form in-situ salt. For example, dia(cid:173)
`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.
`(13) Surprisingly, sodium saccharine is used in Stelazine®
`and Compazine® formulations; our guess is that it
`serves as a stabilizer and tonicity adjuster.
`(14) Tri-n-butyl phosphate is present as an excipient in
`human immune globulin solution (Venoglobulin®).
`Its exact function in the formulation is not known,
`but it may serve as a scavenging agent.
`(15) von Willebrand factor is used to stabilize recombi(cid:173)
`nant antihemophilic factor (Bioclate®).
`(16) Maltose serves as a tonicity adjuster and stabilizer in
`immune globulin formulation (Gamimune N®).
`(17) Epsilon amino caproic acid (6-amino hexanoic acid)
`is used as a stabilizer in anistreplase (Eminase injec(cid:173)
`tion®).
`(18) Zinc and protamine have been added to insulin to
`form complexes and control the duration of action.
`
`170
`
`PDA Journal of
`
` Pharmaceutical Science & Technology
`
`Ex. 1020 - Page 6 of 8
`
`

`

`
`
`Downloaded from on March 18, 2015journal.pda.org
`
`
`
`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(cid:173)
`tion used in the approved drug product. However, this list
`does not provide the name of commercial product(s) corre(cid:173)
`sponding 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 Injectable
`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. Parenter. Sci. Tech(cid:173)
`nol., 34(6), 452 (1980).
`2. Physicians' Desk Reference, ed. 48, 1994.
`3. Physicians' Desk Reference, ed. 50, 1996.
`4. L. A. Trissel, "Handbook on Injectable Drugs," ed. 8, American
`Society of Hospital Pharmacists, Inc., 1994.
`
`5. K. W. Reed and S. Yalkowsky, "Lysis of human red blood cells in the
`presence of various cosolvents," J. Parenter. Sci. Technol, 39(2), 64
`(1985).
`6. G. A. Bazeau and Ho-Leung Fung, "Use of an in-vitro model for the
`assessment of muscle damage from intramuscular injections: In-vitro-
`in-vivo correlation and predictability with mixed solvent systems,"
`Pharm. Res., 6(9), 766 (1989).
`7. J. W. Munson, A. Hussain, and R. Bilous, "Precautionary note for use
`of bisulfite in pharmaceutical formulation," J. Pharm. Sci., 66(12),
`1775(1977).
`8. L. C. Schroeter, "Sulfurous acid salts as pharmaceutical antioxidants,"
`J. Pharm. Sci., 50(11), 891 (1961).
`9. R. Dabbah, "The use of preservatives in compendial articles," Pharma-
`copeial Forum, 22(4), 2696 (1996).
`10. T. J. Baumann, M. A. Smythe, K. Kaufmann, Z. Miloboszewski, J.
`O'Malley, and R. P. Fudge, "Dissolution times of adriamycin and
`adriamycin RDF," Am. J. Hosp. Pharm., 45, 1667 (1988).
`11. Y. J. Wang, T. C. Dahl, G. D. Leesman, and D. C. Monkhouse,
`"Optimization of autoclave cycles and selection of formulation for
`parenteral product, Part II: Effect of counter-ion on pH and stability of
`diatrizoic acid at autoclave temperatures," J. Parenter. Sci. Technol.,
`38(2), 72 (1984).
`12. 'Inactive Ingredient Guide,' Division of Drug Information Resources,
`FDA, CDER, January 1996.
`
`Vol. 51, No. 4 / July-August 1997
`
`171
`
`Ex. 1020 - Page 7 of 8
`
`

`

`
`
`Downloaded from on March 18, 2015journal.pda.org
`
`
`
`An Authorized User of the electronic PDA Journal of Pharmaceutical Science and
`Technology (the PDA Journal) is a PDA Member in good standing. Authorized Users are
`permitted to do the following:
`
`·Search and view the content of the PDA Journal
`·Download a single article for the individual use of an Authorized User
`·Assemble and distribute links that point to the PDA Journal
`·Print individual articles from the PDA Journal for the individual use of an Authorized User
`·Make a reasonable number of photocopies of a printed article for the individual use of an
`Authorized User or for the use by or distribution to other Authorized Users
`
`Authorized Users are not permitted to do the following:
`
`·Except as mentioned above, allow anyone other than an Authorized User to use or access the
`PDA Journal
`· Display or otherwise make any information from the PDA Journal available to anyone other
`than an Authorized User
`·Post articles from the PDA Journal on Web sites, either available on the Internet or an Intranet,
`or in any form of online publications
`·Transmit electronically, via e-mail or any other file transfer protocols, any portion of the PDA
`Journal
`·Create a searchable archive of any portion of the PDA Journal
`·Use robots or intelligent agents to access, search and/or systematically download any portion of
`the PDA Journal
`·Sell, re-sell, rent, lease, license, sublicense, assign or otherwise transfer the use of the PDA
`Journal or its content
`·Use or copy the PDA Journal for document delivery, fee-for-service use, or bulk reproduction or
`distribution of materials in any form, or any substantially similar commercial purpose
`·Alter, modify, repackage or adapt any portion of the PDA Journal
`·Make any edits or derivative works with respect to any portion of the PDA Journal including any
`text or graphics
`·Delete or remove in any form or format, including on a printed article or photocopy, any
`copyright information or notice contained in the PDA Journal
`
`Ex. 1020 - Page 8 of 8
`
`  
` 
`  
`