Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1035
`
`Exh. 1035
`
`

`
`November-December 1999
`
`Vol. 53, No.6
`
`PD A Journal of
`Pharmaceutical Science and Technology
`EDITOR:
`Joseph B. Schwartz
`
`Philadelphia College of Pharmacy
`(University of the Sciences in Philadelphia)
`600 South 43rd Street
`Philadelphia, PA 19104-4495
`Phone: (215) 596-8590
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`
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`
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`Phone: (301) 986-0293 x128
`
`ADVISORY BOARD
`Michael Akers, Eli Lilly and Co.
`Frederick J. Carleton
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`Barry Garfinkle, Merck Shmp & Dohme
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`Joseph Robinson, University of Wisconsin
`Theodore Roseman, Baxter Healthcare
`
`1999 OFFICERS AND DIRECTORS
`Joyce H. Aydlett
`Robert B. Myers
`Floyd Benjamin
`R. Michael Enzinger, Ph.D.
`
`Raymond Shaw, Jr., Ph.D.
`
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`:Steoh2tnie R. Gray
`Gustafson
`K. Kwan, Ph.D.
`Levesque
`V. Levy, Ph.D.
`V. Mehringer
`F. Morrissey, Ph.D.
`RMunson
`B. Seamon, Ph.D.
`R Wright
`
`Edmund M. Fry
`
`PDA Joumal of Pharmaceutical Science & Technology (ISSN
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`
`Formerly the
`"J oumal of Parenteral Sciepce and Technology"
`Copyright-PDA, Inc. 1999
`ISSN 1079-7 440
`
`PDA and its editor assume no responsibility for the state-
`ments and opinions advanced by contributors. Views ex-
`pressed in the editorials are those of the author and do not
`necessarily represent the official position of PDA.
`
`Exh. 1035
`
`

`
`REVIEW ARTICLE
`
`Parenteral Formulations of Small Molecules Therapeutics Marketed in
`the United States (1999)-Part I
`
`ROBERT G. STRICKLEY
`
`Axys Pharmaceuticals, Inc., South San Francisco, California
`
`Overview
`The chemical structure of a molecule determines the
`potential successful formulation approaches available to the
`parenteral scientist. However, there is no· comprehensive
`listing of parenteral products with the chemical structure and
`formulation. A review of domestically marketed injectable
`product formulations of small molecule therapeutics is
`presented herein with the intent of compiling a comprehen-
`sive source of public information for the formulation
`scientist. The compilation lists the drug name, marketed
`name, chemical structure of the drug, marketed injectable
`formulation, preadministration preparation, route of admin-
`istration, company and the clinical indication (1-7).
`One purpose of this compilation is to assist the formula-
`tion scientist in being able to look at a drug's chemical
`structure and then be able to determine possible formulation
`approaches. This compilation will also be useful for those
`interested in knowing what additives are currently used in
`injectable products and at what concentrations they are
`administered in practice. This compilation only focuses on
`marketed formulations and does not delve into the subject of
`preclinical or drug discovery formulations associated with
`early-stages pharmacokinetics or proof-of-concept pharma-
`codynamics, where the formulation scientist is not bound by
`regulatory constraints.
`There are a few published reviews on parenteral formula-
`tions (8) and in an excellent review article (9) Lilly
`scientists, Sweetana and Akers, discuss the various formula-
`tion approaches with detailed tables of examples. In a
`compendium of excipients for parenteral formulations ( 1 0)
`Genentech scientists, Powell, Nguyen and Baloian, list the
`acceptable excipients as well as their percent's within the
`formulations, route of administration and pH. The compila-
`tion herein is an additional resource to the parenteral
`scientist by presenting the chemical structure and the
`formulation in a side-by-side fashion. An examination of
`this compilation reveals many examples of injectable formu-
`lation techniques to improve solubility or provide a sus-
`tained release. The next few sections highlight various
`formulation approaches with specific examples and tables,
`as well as general discussions of parenteral formulations.
`
`Editor's Note: This review article on Injectable Products is being pub-
`lished in several parts. The next installment(s) will appear in subsequent
`issues of the Journal.
`Correspondence address: 180 Kimball Way, South San Francisco, CA
`94080.
`
`Introduction
`The word "parenteral" is Latin for "other than intestine,"
`thus by definition the parenteral sciences not only includes
`injectable products but also transdermal, pulmonary, nasal,
`ophthalmic, and buccal routes of administration. However,
`in practice, parenteral usually refers to injectable products.
`Recently we have seen the commercialization of previously
`academic pursuits such as controlled-release formulations
`using microspheres, liposomes and polymeric gels, longer in
`vivo circulating times using PEGylated liposomes (also
`known as stealth liposomes) and PEGylated proteins, and
`new excipients such as cyclodextrin derivatives used as
`complexing agents for increasing water solubility of poorly
`soluble drugs. We have also seen the commercialization of
`injection devices such as prefilled syringes, dual chamber
`syringes containing solid drug and a liquid for reconstitu-
`tion, and will likely soon see needle-free injectors and
`pocket-size infusion pumps.
`
`Injectable Formulations
`Two key aspects of any successful injectable formulation
`are: 1) to achieve the required drug concentration, and 2) the
`drug must be chemically and physically stable in order to
`have a sufficient shelf-life, which is generally considered to
`be the time for 10% degradation. The ideal injectable
`formulation, from an in vivo tolerability point-of-view, is
`isotonic with physiological fluids and a neutral pH (i.e.,
`PBS: phosphate buffered saline, 0.01M sodium phosphate
`with 0.135M NaCl and 0.003M KCl, pH 7.4). However, in
`many instances the drug does not have sufficient water
`solubility at pH 7 .4, and thus the formulation scientist must
`use a wide variety of solubilization techniques. If stability is
`insufficient to provide a two-year shelf-life, then the formu-
`lation scientist must either change the solution conditions to
`achieve both the solubility and stability requirements or
`develop a lyophilized product. This manuscript focuses on
`solubilization techniques for small molecules, and will not
`focus on stability or stabilization techniques.
`
`I. Solubilization Techniques
`
`1. pH Adjustm,ent and Salts
`If the drug molecule is ionizable, then pH adjustment can
`be utilized to increase water solubility since the ionized
`molecular species has higher water solubility than its neutral
`species. Indeed, the most common solubilization technique
`is pH adjustment and weak acids are normally formulated at
`
`324
`
`PDA Journal of Pharmaceutical Science & Technology
`
`Exh. 1035
`
`

`
`Formulation
`pH
`
`~Vn'e<
`L
`
`Selected
`Examples
`
`Neutral
`
`Aztreonam
`
`<1
`
`2
`
`2.5-5
`
`~8
`
`~8
`
`7-9
`
`Neutral
`
`5-8
`
`8.3
`
`9.2
`
`9-11.6
`
`Fosphenytoin
`Bethamethasone
`Dexamethasone
`Fludarapine
`Penicillin
`Ketorolac
`
`Warfarin
`
`Flurouracil
`
`Acetazolamide
`Clorothiazide
`Diazo xi de
`
`Methohexital
`Pentobarbital
`Phenobarbital
`Secobarbital
`
`Acyclovir
`Gancyclovir
`
`Functional
`Group Name
`
`Sulfonic acid
`
`Phosphate ester
`
`RJ-OH
`II 0
`R-0-~-0H
`
`0
`
`0
`0
`
`OH
`
`HN
`
`R---<H
`4-Hydroxy CXf
`!r
`
`Carboxy lie acid
`
`coumarin
`
`Uracil
`
`Sulfonamide
`
`Barbituric acid
`
`Guanine
`
`Hydantoin
`
`Phenol
`
`Table I. Examples of Weak Acid Chemical Functional Groups, Tho1r A
`· and Formulation pH's.
`... ...
`Functional Group
`Functional
`GrouppKa
`Structure
`
`R
`OAN
`H
`2
`0
`R
`R-M-~ 2
`II
`'H
`0
`HN~NH
`o)ylo
`XX>
`J
`R~H HN
`0 Q
`
`7-9
`
`9.5-11
`
`2.2, 9.4
`
`11
`
`R R2
`Q
`
`H2N
`
`0
`
`~ 10
`
`8-10
`
`10-12
`
`Phenytoin
`
`10.5
`emulsion
`organic
`organic
`
`Liothyronine
`Propofil
`Etoposide
`Teniposide
`
`OH
`
`pH > 5 (Table I), weak bases at pH < 7 (Table II).
`Zwitterionic molecules have multiple ionizable groups and
`can be either cationic, anionic or neutral (positive and
`negative charges cancel each other, for an overall net neutral
`molecule) and are usually formulated at a pH in which the
`drug is ionic (Table III). For example, both ciprofioxacin and
`sufentanil have a carboxylic acid and an amine, but are
`formulated as the cation at pH < 7. On the other hand, both
`ampicillin and cephapirin have a carboxylic acid and an
`amine or pyridine, but are formulated as the anion at pH > 5.
`
`The range in pH is quite broad and is between pH 2-12,
`and thus any molecule with a pKa between 3-11 can be
`potentially solubilized by pH adjustment. However, when
`using extremes in pH, care must be taken to minimize buffer
`capacity in order for the formulation to be in vivo compat-
`ible. When given intravenously, the formulation components
`are quickly diluted by the flow of blood and neutralized by
`the buffer capacity of blood. When given via intramuscular
`injection, the rate of dilution is reduced but rapid enough to
`still be able to inject in the range pH ~ 3-11. However,
`
`Vol. 53, No. 6 I November-December 1999
`
`325
`
`Exh. 1035
`
`

`
`Table II. Examples of Weak Base Chemical Functional Groups, Their Approximate pKa's
`and Formulation pH's.
`Functional
`Functional Group
`Group pKa
`Structure
`
`Functional
`Group Name
`
`1H-Imidazole
`
`Pyridine
`
`Aniline
`
`R2 I
`
`N erR
`()
`
`R
`1>-:: ~
`~
`
`Formulation
`pH
`
`Selected
`Examples
`
`-4-6
`
`<6
`
`Miconazole
`Ondansetron
`
`-5
`
`2-4
`
`-5
`
`2-6
`
`-6
`
`7-10
`
`3-4
`
`3-7
`
`Amronone
`Milrinone
`Papaverine
`Pyridoxine
`Metoclopramide
`Minocycline
`(Procaine
`Procainamide
`also have a
`tertiary amine)
`
`Tolazoline
`
`Atenolol
`Codeine
`Daunorubicin
`Morphine
`Verapamil
`
`7.4
`
`<5
`
`Doxapram
`
`-7
`
`3-6.5
`
`Cimetidine
`Dacarbazine
`Phentolamine
`
`-9-11
`
`<8
`
`Pentamidine
`
`N
`H/ "\.R
`H
`
`Amine
`
`/R2
`
`4,5-Imidazoline C)-A
`R-N " Rs
`N-Alky 1\
`\_;N-. R
`morpho line
`R):_~
`Ami dine RV(H
`t j
`NH2
`
`Imidazole
`
`R2
`
`when given subcutaneously the rate of dilution is reduced
`further with more potential for irritation at the injection site
`and thus the range is pH 3-6. For example, chlordiazepoxide
`is administered intravenously or intramuscularly and formu-
`lated at pH 3 with 20% propylene glycol and 4% TWEEN
`20. Phenytoin sodium is administered either intravenously
`or intramuscularly and formulated at pH 10-12 with 40%
`propylene glycol and 10% ethanol. Subcutaneous formula-
`
`tions are slightly acidic such as methadone at pH 3-6, and
`levorphanol at pH 4.3.
`Water-soluble salt forms (i.e., sodium salts of weak acids,
`or hydrochloride salts of weak bases) utilize the same
`principle of ionization, and are often the marketed form of
`the drug (Table IV). The most common cationic counterion
`is sodium which accounts for > 90% of the cations, and
`there are three meglumine salts, while only one salt each of
`
`326
`
`PDA Journal of Pharmaceutical Science & Technology
`
`Exh. 1035
`
`

`
`Table Ill. Examples of Zwitterionic Drugs, Approximate pKa' s and Formulation pH's.
`Acidic
`Basic
`Functional
`Functional
`Group Name Group Name
`andpKa
`andpKa
`
`Selected
`Example
`
`Chemical Structure
`
`HNl
`
`COOH
`
`0
`
`'~
`
`COOH
`
`Sufentanil
`
`Cephapirin
`
`-
`
`~
`
`H H
`
`N
`
`O
`
`N o
`COOH
`
`OI(CH3
`0
`
`y
`Ciprofloxacin ~NX)Ql
`I
`I
`F ~
`~ 09
`H3C~N . 6 COOH
`Ampicillin ~)-7~~~,
`NH2 J
`()' ~Jt~
`
`Formulation
`pH
`(ionic state)
`
`Aniline- 4
`Amine- 9
`
`3-4
`(Cationic)
`
`Amine- 8
`
`3.5-6
`(Cationic)
`
`Amine- 8
`
`8-10
`(Anionic)
`
`Pyridine- 5
`
`6-8
`(Anionic)
`
`Carboxylic
`acid
`-4
`
`Carboxylic
`acid
`-4
`
`Carboxylic
`acid
`-4
`
`Carboxylic
`acid
`-3
`
`the cations potassium, tromethamine and calcium. There are
`many more anionic counterions and the most common is the
`hydrochloride salt followed by sulfate, mesylate, maleate
`and tartrate. When a salt is dissolved in non-buffered water,
`the resulting pH is generally ~2 pKa units away from the
`pKa, because protons are either added to (salt of a weak
`
`base) or taken away from water (salt of a weak acid). For
`example, gancyclovir is a weak acid with pKa2 = 9.4 and
`dissolving its sodium salt in water results in pH ~ 11.
`In order to maintain a desirable pH range, many formula-
`tions that utilize pH adjustment also use buffers to control
`pH (Table V). Buffers span the range of pH 2.5-11 and
`
`Table IV. List of Counter Ion in Salt Forms of Parenteral Drugs.
`Anions
`Number of instances
`Number of instances
`Cation
`55
`64
`Hydrochloride
`Sodium
`16
`Sulfate
`3
`Meglumine
`1
`Mesylate
`Potassium
`8
`1
`Chloride
`Calcium
`7
`1
`6
`Maleate
`Tromethamine
`6
`Tartrate
`5
`Citrate
`5
`Bromide
`5
`Lactate
`Acetate
`2
`Phosphate
`2
`1
`Besylate
`1
`Hydrobromide
`1
`Fumarate
`1
`Gluceptate
`1
`Gluconate
`1
`Glucuronate
`1
`Lactobionate
`1
`Salicylate
`Tosylate
`1
`
`Vol. 53, No. 6 I November-December 1999
`
`327
`
`Exh. 1035
`
`

`
`Table V. List of Buffers Used in Parenteral Formulations
`Concentration in Concentration
`Formulation,
`Administered,
`Molarity
`Molarity
`0.04
`0.04
`
`0.14
`
`0.2
`
`0.17
`
`0.02
`0.02
`
`0.6
`
`0.1
`0.01
`
`0.08
`
`0.04
`
`0.005
`0.05
`0.5
`
`0.08
`
`0.01
`
`0.01
`
`0.14
`
`0.05
`
`0.17
`0.085
`0.02
`0.01
`0.02
`0.6
`
`0.1
`0.01
`
`0.08
`0.001
`
`0.005
`0.04
`
`0.0005
`0.05
`0.5
`
`0.08
`
`0.01
`
`0.01
`
`Route of
`Administration
`IM,IV
`
`IM
`
`IV infusion
`
`IV
`IV infusion,
`sc
`IM
`IV
`IM, IV, IV
`infusion,
`sc
`IV, SC
`
`IM
`IV, IV
`infusion
`
`IV infusion,
`sc
`
`IV infusion
`IM
`IV
`
`IV, IV infusion
`IM
`
`IM, IV infusion
`Intra-arterially,
`Intrathecal
`
`IV, IV infusion,
`Intravitreal
`(Fomiversen)
`
`pH
`2.5-4.0
`
`3
`
`3
`
`3.0-4.5
`
`3-5
`
`3.0-7
`
`4-6
`
`4-6.5
`
`4.2-6
`
`6
`
`6-7
`
`3-8
`
`7.4-9.0
`
`8.7-11
`
`Buffer (pKa's)
`Tartartic acid
`(2.9, 4.2)
`Maleic acid
`(1.9, 6.2)
`Glycine
`(2.3, 9.6)
`Sodium lactate/
`Lactic acid
`(3.8)
`Ascorbic acid
`(4.2, 11..6)
`Sodium citrates/
`Citric acid
`(3.1, 4.8, 6.4)
`Sodium acetate/
`Acetic acid
`(4.75)
`Sodium
`bicarbonate/
`Carbonic acid
`(6.3, 10.3)
`Sodium
`succinate/
`Succinic acid
`(4.2, 5.6)
`Histidine
`( 1.8, 6.0, 9 .2)
`Sodium
`benzoate/
`Benzoic acid
`(4.2)
`Sodium
`phosphates
`(2.2, 7 .2, 12.4)
`Tris(hydroxy-
`methyl)amino-
`methane
`(8.3)
`Sodium
`bicarbonate/
`Sodium
`carbonate
`(6.3, 10.3)
`
`1M = Intramuscular
`IV = intravenous
`SC = subcutaneous
`
`include citrates, acetates, histidine, phosphate, tris(hydroxy-
`methyl)aminomethane, and carbonates. The buffer concen-
`tration must be high enough to maintain the desired pH, but
`must be balanced by in vivo tolerability considerations, and
`thus it is good practice to minimize buffer capacity of the
`administered formulation.
`
`2. Mixed Organic/Aqueous Fonnulations
`
`If pH adjustment alone is insufficient in achieving the
`desired solution concentration, then a combination of pH
`and organic solvent(s) is often employed. If the drug
`molecule is not ionizable then pH has no effect on solubility,
`
`328
`
`PDA Journal of Pharmaceutical Science & Technology
`
`Exh. 1035
`
`

`
`but solubility enhancement can often be accomplished by a
`combination of aqueous and organic solvents (i.e., a casal-
`vent). The currently used organic solvents used in mixed
`organic/aqueous formulations are propylene glycol, ethanol,
`polyethylene glycol 300 or 400, cremophor EL, TWEEN 80,
`sorbitol, glycerin and dimethylacetamide (DMA) (Table VI).
`As with any formulation additive, the concentration that is
`administered should be minimized to avoid any in vivo
`complications such as local irritation or precipitation at the
`injection site. Many cosolv.ent formulations are marketed
`using rather high concentrations of organic solvent, and are
`usually but not always diluted prior to injection. For
`example, propylene glycol is 50% of the fenoldopam
`marketed formulation, but is diluted to < 1% for IV infusion.
`However, propylene glycol is ~70% of the oxytetracycline
`marketed formulation and is injected intramuscularly with-
`out dilution.
`Similar to formulations using pH adjustment, of the three
`main routes of administration (i.e., intravenous, intramuscu-
`lar and subcutaneous), the subcutaneous route has the most
`constraints when using cosolvent due to the reduced volume
`flow away from the injection site compared to intravenous
`and intramuscular. As a result, only three cosolvent products
`are administered subcutaneously and the amount of organic
`solvent is limited to ethanol 6% (dihydroergotamine), glyc-
`erin 32% (epinephrine), and propylene glycollO% (hydrala-
`zine). Whereas, the intravenous bolus route can use ethanol
`up to 20% (paricalcitrol), PEG 300 up to 50% (methocarba-
`mil), and propylene glycol up to 68% (phenobarbital). The
`intramuscular route has similar in vivo constraints to the
`intravenous route, but can tolerate even more organic
`solvent (se~ section I.3, Totally Organic Solution Formula-
`tions).
`Surfactant formulations seem to be on. the increase with
`excipients Cremophor EL and TWEEN 80 leading the way.
`These formulations, in general, are supersaturated upon
`dilution and must be used soon after dilution into IV
`compatible fluids. For example, cremophor EL is 11% of the
`miconazole marketed formulation, but is diluted to 1% for
`IV infusion. Also, TWEEN 80 is 10% of the amiodarone
`marketed formulation, but is diluted to 0.4% for IV infusion.
`However, cremophor EL at 10% or TWEEN 80 at 25% can
`be administered by IV infusion (see section I.3).
`
`3. Totally Organic Solution Formulations
`Molecules that are non-ionizable (have pKa < 2, or
`pKa > 11) and non-polar are water insoluble with no effect
`of pH on solubility, and thus are the most challenging for the
`formulation scientist. These water-insoluble molecules can
`be formulated in 100% organic solvent, which is then
`usually but not always diluted prior to administration (Table
`VII). For example, busulfan is marketed in 33% dimethyl-
`acetamide and 67% PEG 400, but is diluted 10-fold prior to
`IV infusion. The lorazepam marketed formulation is 80%
`propylene glycol, 18% ethanol and 2% benzyl alcohol, but is
`diluted 2-fold for IV bolus injection, but not diluted for
`intramuscular injection. Paclitaxel is marketed with 51%
`cremophor ELand 49% ethanol, but is diluted 5- to 20-fold
`for IV infusion. Docetaxel is marketed in 100% TWEEN 80,
`but is diluted to 25% for IV infusion.
`
`4. Cyclodextrins
`
`Some molecules can be solubilized by forming an inclu-
`sion complex with a cyclodextrin. Cyclodextrins have a
`hydrophilic exterior and a hydrophobic interior core of
`specific dimensions, and thus molecules with a non-polar,
`aromatic or heterocyclic ring can potentially fit inside the
`core. Increased water solubility through molecular complex-
`ation with cyclodextrins has advantages over the cosolvent
`approach since upon dilution a 1: 1 complex between cyclo-
`dextrin and drug will not precipitate, but a drug dissolved in
`a cosolvent often precipitates upon dilution. Two cyclodex-
`trins have been accepted for human injectable use with the
`approval of alprostidol alfadex and itraconazole. Alprostidol
`alfadex is marketed as a lyophilized powder with a-cyclodex-
`trin and is administered intracavernosally. Itraconazole .was
`approved in April 1999 as a solution with 40% hydroxypro-
`pyl-~-cyclodextrin and is administered by intravenous infu-
`sion after a 2-fold dilution with saline (6). The next
`cyclodextrin likely to be approved is sulfobutylether-~­
`cyclodextrin, which is in the clinical formulation of ziprasi-
`done for intramuscular injection (11).
`
`5. Emulsions
`
`Oil-soluble molecules are generally neutral uncharged
`and non-polar molecules, but can be formulated for intrave-
`nous administration by the use an oil-in-water emulsion.
`Emulsions can solubilize oil-soluble drugs since the drug
`partitions into the oil phase. A typical emulsion is composed
`of water with 10-20% soybean and/or safflower oil, 2%
`glycerol, 1% egg lecithin and pH 7-8, and is injected by
`either IV bolus or IV infusion. The only marketed emulsion
`formulation is propofol, which is in a typical emulsion
`composed of 10% soybean oil containing 10 mg/mL drug.
`The total parenteral nutrition (TPN) formulations are the
`lipid emulsions Intralipid and Liposyn, which are adminis-
`tered by intravenous infusion as nutritional supplements.
`
`6. Prodrugs
`
`Molecules which contain an alcohol, phenol, carboxylic
`acid, amine, hydantoin functional group can potentially be
`derivatized as a prodrug. Once the prodrug is administered
`in vivo, the promoiety is hydrolyzed by either esterases or
`phosphatases releasing the parent drug. Although prodrugs
`are normally associated with orally administered products
`for better oral bioavailability, many parenteral products are
`prodrugs (Table VIII).
`The versatility of the prodrug approach is demonstrated
`with prodrugs that in design either increase or decrease
`water solubility. A water-soluble prodrug has an electroni-
`cally charged promoiety, while a water insoluble prodrug
`has been derivatized to be a neutral molecule (see section
`II.7b). Recently, a few water-soluble phosphate ester pro-
`drugs have been developed and marketed in order to replace
`the original formulations that contain high concentrations of
`organic solvent. The phenol-containing etoposide (etoposide
`phosphate) is derivatized as a water-soluble phosphate ester.
`Water-soluble phosphate esters are also prodrugs for alcohol-
`containing betamethasone, clindamycin, dexamethasone,
`fludarabine, hydrocortisone, and prednisolone. The hydan-
`
`Vol. 53, No. 6 I November-December 1999
`
`329
`
`Exh. 1035
`
`

`
`Table VI. List of Cosolvents Used in Parenteral Formulations.
`Route of
`% in Marketed
`%
`Administered Administration
`Formulation
`IV infusion
`1
`11
`0.02-0.08
`IV infusion
`20
`0.1-1
`IV infusion
`50
`18
`Intravesical
`50
`2.5-10
`IV infusion
`51
`IV infusion
`65
`0.65-3.3
`IV infusion
`0.012-0.12
`6
`IV infusion
`33
`3
`
`Examples
`Miconazole
`Tacrolimus
`Tenoposide
`Valrubicin
`Paclitaxel
`Cyclosporin
`Tenoposide
`Busulfan
`
`Solvent
`Cremophor EL
`
`Dimethyl-
`acetamide
`(DMA)
`Ethanol
`
`5 (diluent for
`LP)
`6 '
`10
`10
`10
`10
`10
`10
`13 (diluent)
`20
`25
`30
`35
`42
`49
`50
`80
`100 (diluent for
`LP)
`15
`25
`32
`100 (diluent for
`LP)
`
`10
`
`50
`60
`18
`18
`67
`
`0.5
`
`6
`10
`2.5-10
`10
`10
`10
`10
`10 (diluent)
`20
`1
`0.3-0.6
`0.35-1.7
`0.084-0.84
`2.5-10
`18
`0.08-0.32
`10
`
`15
`25
`32
`100
`
`10
`
`50
`0.6-1.2
`18
`9
`6-7
`
`IV infusion
`
`IM, SC, IV
`IM,IV
`IV
`IM,IV
`IM,IV
`IM,IV
`IM,IV
`IV infusion
`IV
`IV infusion
`IV
`IV infusion
`IV infusion
`IV infusion
`Intravesical
`IV infusion
`IV infusion
`
`IM, SC, IV
`IV infusion
`sc
`Subgingival
`
`Medroxy-
`progesterone
`Dihydroergotamine
`Diazepam
`Digoxin
`Ketorolac
`Pentobarbital
`Phenobarbital
`Phenytoin
`Docetaxel
`Paricalcitol
`Esmolol
`Etoposide
`Cyclosporin
`Teniposide
`Paclitaxel
`Valrubicin
`Tacrolimus
`Carmustine
`
`Dihydroergotamine
`Idarubicin
`Epinephrine
`Doxycycline
`
`IM
`
`Oxytetracycline
`
`IM,IV
`IV
`IM
`IV
`IV infusion
`
`Methocarbamil
`Etoposide
`Lorazepam
`Lorazepam
`Busulfan
`
`Glycerin
`
`N-methyl-2-
`pyrrolidone
`(Pharmasolve)
`Monothio-
`glycerol
`PEG 300
`
`PEG400
`
`toin-containing phenytoin prodrug (fosphenytoin) is deriva-
`tized in a unique fashion as a water-soluble hydroxymethyl
`phosphate ester, which after in vivo enzymatic phosphate
`ester cleavage, the resulting hydroxymethyl intermediate
`quickly dissociates to phenytoin and formaldehyde (12).
`Other water solubilizing prodrug approaches are a succinate
`ester of the alcohol methylprednisolone, and a piperidine
`carbamate in irinotecan a prodrug for a phenol drug.
`Prodrugs can also be used for stability reasons. For
`example, alatrofloxacin is the alanine-alanine dipeptide
`prodrug for the primary amine trovafloxacin which is
`
`unstable in solution. The prodrug alatrofloxacin is marketed
`as a solution at pH 3.4-4.3.
`
`II. Sustained-Release Techniques
`The research in controlled release during the 1970s has in
`the 1990s become a commercial realization with the ap-
`proval of liposomal, polymeric microsphere and polymeric
`gel formulations. However, traditional approaches are still in
`use such as suspensions, prodrugs and oil depots.
`
`330
`
`PDA Journal of Pharmaceutical Science & Technology
`
`Exh. 1035
`
`

`
`Table VI {cont.). List of Cosolvents Used in Parenteral Formulations.
`% in Marketed
`Route of
`%
`Formulation
`Administered Administration
`10
`10
`IM, SC
`20 (diluent for
`20
`IM
`LP)
`25
`30
`35
`40
`40
`40
`40
`50
`50
`50
`60 (diluent for
`LP)
`67-75
`68
`80
`80
`2
`4.5
`5
`7
`50
`
`1
`30
`35
`40
`10-40
`40
`40
`50
`5
`0.2
`6
`
`67-75
`68
`80
`40
`2
`0.1
`0.2
`0.7-2
`50
`
`Examples
`Hydralazine
`Chlordiazepoxide
`
`Esmolol
`Paricalcitol
`Etomidate
`Diazepam
`Digoxin
`Pentobarbital
`Phenytoin
`Dimenhydrinate
`Dimenhydrinate
`Fenoldopam
`Medroxy-
`progesterone
`Oxytetracycline
`Phenobarbital
`Lorazepam
`Lorazepam
`Thiethylperazine
`Irinotecan
`Nicardipine
`Diltiazem
`Triamcinolone
`
`Dexamethasone
`Acetate
`Calcitriol
`Chlordiazepoxide
`
`Etoposide
`Amiodarone
`Docetaxel
`
`IV infusion
`IV
`IV
`IM,IV
`IV
`IM,IV
`IM,IV
`IM
`IV infusion
`IV infusion
`IV infusion
`
`IM
`IM,IV
`IM
`IV
`IM
`IV infusion
`IV infusion
`IV
`Intra -articular,
`Intralesional
`IM
`
`IV bolus
`IM
`
`IV
`IV infusion
`IV infusion
`
`Solvent
`Propylene glycol
`(PG)
`
`Sorbitol
`
`TWEEN80
`(Polysorbate 80)
`
`0.075
`
`0.4
`4 (diluent for
`LP)
`8
`10
`100
`
`0.075
`
`0.4
`4
`
`0.08-0.16
`0.4
`25
`
`IM =Intramuscular
`IV = intravenous
`LP = lyophilized powder
`PEG= polyethyleneglycol
`SC = subcutaneous
`
`7a. Suspension Fonnulations
`
`Suspension formulations provide a sustained-release de-
`pot at the injection site that releases prodrug by dissolution.
`Suspensions used for sustained delivery are composed of a
`drug dispersion in either an aqueous or oil-based suspension
`(Table IX).
`Almost all suspensions are administered intramuscularly,
`intralesionally or intra-articularly. The only subcutaneously
`administered suspension of a small molecule (many proteins
`are administered subcutaneous, e.g., human insulin) is
`epinephrine, which is administered every 6 hours and is
`formulated in 32% glycerin providing both rapid (drug in
`solution) and sustained activity (crystalline drug in suspen-
`sion). The only sesame oil suspension is the anti-rheumatic
`
`aurothioglucose, which is administered intramuscularly ev-
`ery 1-4 weeks.
`
`7b. Prodrugs in Suspension Formulations
`
`Most of the other suspension formulations are aqueous-
`based and contain water-insoluble prodrugs which are
`lipophilic esters of alcohols. For example, hydrocortisone
`acetate and dexamethasone acetate are acetate esters of their
`alcohol-containing parent drug, and are administered intra-
`muscularly, intralesionally or intra-articularly once every
`1-3 weeks. The contraceptive medroxyprogesterone acetate
`is administered intramuscularly once every 13 weeks. Aque-
`ous-based suspensions typically contain TWEEN 80 at
`~0.75-4 mg/mL (0.4%) along with a suspending agent such
`
`Vol. 53, No. 6 I November-December 1999
`
`331
`
`Exh. 1035
`
`

`
`CN
`CN
`1\)
`
`Drug Name/
`Marketed
`Name
`Busulfan/
`Busulfex
`
`Docetaxell
`Taxotere
`
`Etoposide/
`Etoposide
`injection
`and
`VePesid
`
`Haloperidol
`Decanoate/
`Hal dol
`decanoate
`
`-u
`0
`)>
`c....
`0 c:
`3
`~
`9.
`-u
`::::;
`~ 3 ~
`CD s. a·
`
`0
`
`~
`(f)
`0
`(i)"
`::J
`0
`CD
`Qo
`col 0
`
`::::;
`::J
`0
`0 co
`'<
`
`Structure
`Y.
`Hae-!Lo~ ~
`·~
`0-~-GHa
`
`Cyclosporin/
`Sandimmune
`
`Cyclic peptide ( 11
`amino acids), MW ~
`1200
`
`OH H
`0
`
`--}:: H
`"-H
`H3C ~
`0
`
`H
`
`" '
`
`_...H
`0
`
`¥ ~;c
`
`H,c-{
`
`:
`
`0
`
`OH
`
`Y.
`O~CH>)a-CH3
`
`.
`
`F
`
`...:?
`
`Table VII. List of Non-Aqueous Solution Formulations for Parenteral Administration.
`
`Formulation
`6mg/mL
`N, N-dimethylacetamide
`(DMA) 33%,
`PEG 400 at 67%
`50mg/mL
`Cremophor EL 65%,
`Ethanol 35%,
`blanketed with nitrogen
`
`TWEEN 80
`Provided diluent of Ethyl
`alcohol 13% in water
`
`20mg/mL
`PEG 300 60%,
`Ethyl alcohol 30%,
`TWEEN 80 at 8.0%,
`Benzyl alcohol 3.0 %,
`Citric acid 2 mg/mL
`pH= 3-4
`
`50-100 mg/mL
`
`Benzyl alcohol 1.2%
`
`Preadministrati on
`preparation
`Dilute with saline or
`dextrose 5% to 0. 6
`mg/mL.
`
`Dilute with saline or
`dextrose 5% to 1-2.5
`mg/mL ( 1 mL into 20-
`100mL)
`Dilute with provided
`diluent (13% ethyl
`alcohol) to 10 mg/mL.
`
`Route of
`Administration
`IV infusion
`
`Company and
`Indication
`Orphan Medical,
`Neoplastic
`
`IV infusion
`over 2-6 hours
`
`IV infusion
`over 1 hour
`
`Novartis,
`Immuno-
`suppressant
`
`Rhone-Poulenc
`Rorer,
`Antineoplastic
`
`Dilute with saline or
`dextrose 5% to 0.2-
`0.4 mg/mL.
`
`IV infusion
`over 30-60
`minutes
`
`None
`
`IM
`
`Astra
`and
`Bristol-Myers
`Squibb,
`Antineoplastic
`
`Ortho-McNeil,
`psychotic
`disorders,
`Tourette's
`Disorder
`
`="
`
`\.. p.,
`
`:~ 40mg/mL in
`0~e;.o
`--
`H~
`<iex<
`"'00¥~
`~~' in Sesame Oil
`
`Exh. 1035
`
`

`
`~
`01 _w
`z
`~
`(j)
`
`z 0 < CD
`
`3
`0'"
`CD
`I
`0
`CD
`0
`CD
`3
`0'"
`~
`
`-1. co co co
`
`(1.)
`(1.)
`(1.)
`
`Drug Name/
`Marketed
`Name
`Lorazepam/
`Ativan
`
`Paclitaxell
`Taxol
`
`Tacrolimus
`(FK 506)/
`Prograf
`
`Teniposide
`(VM-26)/
`Vumon
`
`Testosterone
`Enanthate/
`Delatestry 1
`
`Table VII (cont.). List of Non-Aqueous Solution Formulations for Parenteral Administration.
`
`Structure
`
`OH
`
`Ci/
`
`0
`
`S?
`~
`_..>'---0
`H3C
`H3C cr
`~o··~b 6}-c:
`u bH
`
`"-'::
`
`0
`
`I
`
`o
`
`0
`
`Paclitaxel
`Taxol
`
`Formulation
`2-4mg/mL
`PEG 400 at 18%,
`in Propylene glycol
`Benzyl alcohol2%
`
`Solution
`6mg/mL
`Cremophor EL 51%,
`Ethyl alcohol 49% (v/v)
`
`Preadministration
`preparation
`None for IM. For IV
`dilute with equal
`volume of saline,
`dextrose 5% or
`lactated Ringer's.
`Dilute with saline,
`dextrose 5% or
`lactated Ringer's to
`0.3-1.2 mg/mL.
`
`Route of
`Administration
`IMI
`IV bolus at ~ 2
`.mg/min
`
`IV infusion
`
`Company and
`Indication
`Wyeth-Ayerst,
`Anxiolytic;
`sedation;
`status epilepticus
`
`Bristol-Myers
`Squibb,
`Antineoplastic
`
`3
`
`5mg/mL
`Cremophor EL 20%,
`Ethyl alcohol 80%
`
`Dilute 250 or 1000-
`fold into saline or
`dextrose 5% to 0.004-
`0.02mg/mL
`
`IV infusion
`
`Fujisawa,
`Immuno-
`suppresent
`(transplant
`rejection)
`
`H,CO
`
`?H, OH
`
`O
`... /cH,
`
`:
`H3C
`Q-io
`N
`0 H3C,o
`\
`0
`0=\ OH H3C
`o.
`
`H3C
`
`OCH~H,
`(,'SY";O~O
`'LJ1 .0"0~0
`<JlN---~
`b
`11'1 OCH,
`H3coy
`OH
`~Hl
`
`0
`
`:
`
`50mg/mL
`Cremophor EL 50%,
`Ethyl alcohol 42%,
`Dimethylacetamide 6%,
`Benzyl alcohol30 mg/mL
`pH 5 (Maleic acid)
`
`200mg/mL
`Sesame oil,
`Chlorobutanol 5 mg/mL
`
`Dilute with saline or
`dextrose 5% to 0.1-1
`mg/mL
`
`IV infusion
`over 30-60
`minutes
`
`Bristol-Myers
`Squibb,
`Antineoplastic
`
`None
`
`1M
`
`BTG
`
`Exh. 1035
`
`

`
`Table VID. List of Prodru s for Parenteral Administration.
`
`Structure
`
`Fxir
`·Ar·~p Sr
`
`Formulation
`Solution
`5mg/mL
`pH 3.4-4.3
`
`Lyophilized powder
`500mg
`
`Phosphor-
`ylated thiol
`
`Preadministration
`re aration
`Dilute to 1-2
`mg/mL with 5%
`dextrose
`
`Reconstitute with
`saline to 50 mg/mL
`(stable at room
`temperature for 5
`hours).
`May be further
`diluted to 5 mg/mL
`with saline.
`None
`
`Route of
`Administration
`IV infusion over 60
`minutes
`
`IV infusion over 15-
`30 minutes
`
`IM
`
`(,)
`(,)
`,f::.
`
`Drug Name/
`Marketed
`Name
`Ala-
`trofloxacin
`mesylate/
`Trovan
`Amifostine/
`Ethyol
`
`CH
`
`0
`
`"""'
`I .
`
`I
`
`H
`
`fl
`H
`H2N~N~S/~""-..OH
`OH
`
`Betametha-
`sone
`Phosphate
`sodium and
`Betametha-
`sone Acetate/
`Celestone
`soluspan
`
`0
`
`0
`
`Suspension
`Betamethasone sodium
`phosphate 3 mg/mL,
`Betamethasone acetate 3
`mg/m