`
`REVIEW ARTICLE
`
`Parenteral Formulations oi Small Molecules Therapeutics Marketed in
`the United States (1999)-—Part l
`
`ROBERT G. STRICKLEY
`
`Axys Plrarrrrocermlcals, Inc, San-llr San Francisco, Coir‘ amia
`
`0verviSW
`
`introduction
`
`The chemical structure of :1 molecule determines the
`potential successful formulation approaches available to the
`parenteral scientist. However, there is no comprehensive
`listing ofparcritcrnl products with the chemical structure and
`forrrtulatiun. A review of domestically marketed injectnble
`product
`fortnulatlons of small molecule therapeutics is
`presented herein with the intent of compiling a comprchem
`sive source of public infommtion for the formulation
`scientist. The compilation lists the drug name, marketed
`name. chemical structure of the drug. marketed irrjectable
`formulation, prendministration preparation, route of arlmin~
`istration, company and the clinical indication (l—'l).
`One purpose of this compilation is to assist the fomtulo-
`lion scientist in being able to look at u drug's chemical
`structure and then be able to detennine possible formtrlotion
`approaches. This compilation will also be use-l'ul\t‘or those
`interested in knowing what additives are cunentlfused in
`injectable products and at what concentrations they are
`administered in practice. This compilation only focuses on
`marketed formultrtions and does not delve into the subject of
`preclinical or drug discovery forrnulurions associated with
`early-stages pl-rarrnzrcokincties or proof-of-concept pharma-
`codynamies, where the formulation scientist is not bound by
`regulatory constraints.
`There are a few published reviews on parenteral feminis-
`tions (8) and in an excellent review article (9) Lilly
`scientists, Sweetrtna and Alters, discuss the various formula-
`tion appronchcs with detailed tables of examples. In a
`compendium of excipierns for parenteral formulations (10)
`Genontcch scientists, Powell, Nguyen and Boloian, list the
`acceptable excipients as well as their percent‘s within the
`formulations, route of ztdmirtistration nod pH. The compila-
`tion herein is an additional
`resource to the parenteral
`scientist by presenting the chemical structure and the
`fonmulution in :4 side-by—side fashion. An examination of
`this compilation reveals many examples of injectablc fortitu-
`lotion techniques to improve solubility or provide a sus-
`tained release. The next
`few sections highlight various
`forrnultttirm approaches with specific examples and tables,
`as well as general discussions ofpnrenternl fonnulations.
`
`Editor's Note: This review article on lnjcctablo Products is being pub»
`llshcd in several parts. Thenext inst:tllm<nI(s) will appear in suhsequeut
`issues or tltedormxal,
`Correspondence address: 180 Kimball Way. South San Francisco. CA
`94080.
`
`The word "parenteral" is Latin for “other than intestine,”
`thus by definition the parenteral sciences not only includes
`injectable products but also transdermnl, pulmonary, nasal,
`ophthalmic, and tween! routes of administration. However,
`in practice, parenteral usually refers to lujectable products.
`Recently we have seen the commercialization of previously
`academic pursuits such as controlled-release formulations
`using microspheres. liposomes and polymeric gels. longer in
`viva ‘circulating times using PECrylated liposorrres (also
`known as stealth liposomcs) and PEGylttted proteins. and
`new excipiertts such as eyclodextrin 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 reconstitw
`lion, and will
`likely soon see rteedle—frce injectors and
`\
`pocket—size infusion pumps.
`
`lnlectable Formulations
`
`Two key aspects of any successful injectable formulation
`are: l) to achieve the required drug concentration. and 2) the
`drug must be chemically and physically stable in order to
`have a sufficlent shelf-life, which is generally considered to
`be the time for
`l0% degradation. The ideal
`irtjectable
`fommlation, from an in viva tolerability point-of-view, is
`isotonic with physiological fluids and a neutral pli (i.c..
`PBS: phosphate buffered saline, 0.01M sodium phosphate
`with 0.l35M NaCl and 0.003M KCl, pH 7.4). However, in
`many inslmxces the drug does not have sufficient water
`solubility at pH 7.4, and thus the formulation scientist must
`use rt wide variety of soltrbilizatimt techniques. If stability is
`insufliciem to provide a two-year shell-life, then the formu-
`lation scientist must either change the solution conditions to
`achieve both the solubility and stability requirements or
`develop a lyopltilized product. This manuscript focuses on
`solubilization techniques for small molecules, and will not
`focus on stability or stabilization techniques.
`
`I. Soiulolllzatlon Techniques
`
`1. pH Acfjltslltlelllrfllll Srrirs
`lithe drug molecule is ioniztihlc, 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 arljustment and weak acids are normally formulated at
`
`324
`
`FDA Journal ot Pharmaceutical Science & Technology
`
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`
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`

`

`Sulfonic acid
`
`Phosphate ester
`
`Carboxylic acid
`
`4-Hydroxy
`coumarin
`
`Sulfonamidc
`
`Barbiiuric acid
`
`Guanine
`
`I-Iydanloin
`
`Neutral
`
`Bethamcthasone
`Dexamethasone
`Fludara a inc
`Pencillin
`Ketorolac
`
`Flurouracil
`
`Acetazolarmde
`Clorothiazide
`Diazoxidc
`
`Methohexital
`Pentobarbital
`Phenobarbital
`Secobarbital
`
`Acyclovir
`Gancyclovir
`
`Phcnytoin
`
`10.5
`emulsion
`organic
`'
`
`Liothyronine
`Propofil
`Etoposide.
`Toni o a side
`
`pH > 5 (Table 1). weak bases at pH < 7 (Table I1).
`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 lll). For example, both cipmlloxacin and
`sufentanil luv: a carboxylic acid and an amino. but are
`fomiulated as the cation at pH < 7. On the other hand, both
`ampicillin and cephapirin have :1 carboxylic acid and an
`amine or pyridine, but are formulated as the anion at pH > 5.
`
`Vol. 53, No.6 I November—December 1999
`
`The range in pH is quilt: broad and is between pH 2-12,
`and thus any molecule with at {Ma bclwccn 3-11 can be
`pozcmiolly solubilized by pH adjustment. However, when
`using exlfomcs in pH, care must be taken to minimize buffer
`capacity in order for the formulation to be in viva compat-
`ible. When given intravenously, the formulation components
`are quickly diluted by the flow of blood and neutralized by
`the buffer capacity of blood. Whcn given via intramuscular
`injection. the rate of dilution is rcduccd but rapid enough to
`still be able to inject in the range pH ~ 3—ll. However,
`325
`
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`
`

`

`Table II. Examples 0 Weak Base Chemtca Functtona
`and Formulation H's.
`Functional
`Functional Group
`
`Functional
`
`roups, Their - pproximate pKa s
`
`Formulation
`
`Selected
`
`lH—Imidazole
`
`4,5-Imidazoline
`
`Amidine
`
`Oztdansetrou
`
`Amrononc
`Milrinone
`Papaverine
`Pyridoxine
`
`Metoclopramidc
`Minocycline
`(Procaine
`Procainatnide
`also have a
`tertiary amine)
`
`Tolazoline
`
`Ateno ol
`Codeine
`Daunorubicin
`Morphine
`Vera - .
`'1
`
`Doxapram
`
`Cimetidine
`Dacmbazine
`Phentolamine
`
`Pcntamidine
`
`when given subcutaneously the rate of dilution is reduced
`further with more potential for irritation at the injcction site
`and thus the range is pH 3-6. For example, eliloxdiazepoxide
`is administered intravenously or intramusculnrly and formu-
`lated at pH 3 with 20% propylene glycol and 4% TWEEN
`20. Pltcnytoin sodium is administered either intravenously
`or intramuscularly and formulated at pH 10-32 with 40%
`propylene glycol nnd l0% ethanol. Subcutaneous fomtula-
`326
`
`tions are slightly acidic such as methadone at pH 3~6, and
`lcvorphanol 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 dmg (Table IV). The most common cationic counterion
`is sodium which accounts for > 90% of the cations. and
`there are three rnegluminc salts, while only one salt each of
`
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`
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`

`

`Example
`
`Chemical Structure
`
`roximate o Ka’s and Formulation
`AC1dlC
`Basic
`Functional
`Functional
`Group Name
`and
`Ka
`
`Formulation
`
`ti}!
`(iom ate)
`
`Grou Name
`
`W V
`
`Ciprofioxacin
`
`Carboxylic
`acid
`~ 4
`
`Aniline ~ 4
`Amine ~ 9
`
`3-4
`(Cationic)
`
`Sufentanil
`
`\
`o
`N’\/©
`u,c\,lLN,©COOH
`
`: gm
`
`Carboxylic
`acid
`~ 4
`
`Carboxylic
`acid
`~4
`
`Carboxylic
`acid
`~ 3
`
`Amine - 8
`
`3.5-6
`(Cationic)
`
`Amine ~ 8
`
`Pyridine - 5
`
`8-10
`(Anionic)
`
`6-8
`(Anionic)
`
`the cations potassium. tromethnmine and caleium. There are
`many more anionic countcrions and the most common is the
`hydrochloride salt followed by sulfate. mesylatc, malcate
`and tanratc. 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 :1 weak
`
`base) or taken away from water (salt of a weak acid). For
`example, gancyclovir is a weak acid with pKa1 = 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 pl! adjustment also use buffers to control
`pH (Table V). Buffers span the range of pH 2.5-ll and
`
`Meglumine
`Potassium \
`Calcium ‘~,
`Tromcthamind
`
`Nuero mstances_
`--I|>—uéA—-on-at-—nt—I—-on-I-Ifi)fi){]1{)[L)xa\@’Hqm
`
`' ist of onter 1011 in Salt Forms of Parenteral Dru - s.
`‘ mon
`Number of instances i
`Hydrochloride
`Sulfate
`Mesylate
`Chloride
`Maleate
`Tomato
`Citrate
`Bromide
`Lactate
`Acetate
`Phosphate
`Besylate
`Hydrobromide
`Furnarate
`Gluccptate
`G1 neonate
`Glucuronate
`Lactobionate
`Salicylate
`Tos late
`
`Vol. 53, No.6 I November—December1999
`
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`
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`

`

`3.0-4.5
`
`Buffet‘ ( o Ka’s)
`Tattartic acid
`(2.9, 4.2)
`Malerc acid
`(1.9, 6.2)
`Glycine
`(2.3, 9.6)
`Sodium lactate!
`Lactic acid
`3.8)
`Ascorbic acid
`4.2.
`1 1.6)
`S - ium citratesl
`Citric acid
`(3.1, 4.8, 6.4)
`o o tum acetate}
`Acetic acid
`
`bicarbonatel
`Carbonic acid
`
`succinatc!
`
`Succinic acid
`(4.2, 5.6)
`
`‘~
`
`benzoatel
`Benzoic acid
`
`phosphates
`(2.2. 7.2. 12.4)
`ris(hydroxy-
`methyl)amino-
`methane
`
`Concentration in
`Formulation.
`Molarit
`
`Concentration
`Administered,
`Moiari M
`
`Route of
`Administration
`
`IV infusion
`
`IV
`IV infusion.
`SC
`
`M, IV, IV
`infusion,
`
`infusion
`
`IV infusion,
`SC
`
`IV infusion
`
`IM, IV infusion
`Intra-arterially.
`
`(Fomivcrscn)
`
`=intramuscu at
`IV -= intravenous
`SC = subcutaneous
`
`
`
`include citrales. acelules, histidinc. phosphate. tris(hydroxy-
`methyljaminomethanc. and carbonates. The buffer concen-
`tration must be high enough to maintain the desired pH, but
`must be balanced by in viva toierability consideralions, and
`thus it is good practice to minimize buffer capacity of the
`administered formulation.
`
`328
`
`2. Mixed Organic/Aqueous‘ Fannulrztiotls
`
`If pH adjustment atom: is insufficient in achieving the
`desired solution concentration. than Q combination of pH
`and organic soivent(s)
`is often employed. If the drug
`molecule is not ionimhlc then pH has no effect on solubility,
`
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`

`but solubility enhancement can often be accomplished by a
`combination of aqueous and organic solvents (its. a casel-
`went). The currently used organic solvents used in mixed
`orgrmiclaqueous fonnulntions are propylene glycol, ethanol,
`polyethylene glycol 300 or 400. crcmophcr 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 viva
`complications such as local irritation or precipitation at the
`injection site. Many cosolvent fonnulations 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 <l‘7: for N infusion.
`However. propylene glycol is ~70% of the oxytetracycline
`marketed fomtulntiozt and is injected intramusculztrly with-
`out dilution.
`Similar to formulations using pll 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% (dihydroergntamine), glyc-
`erin 32% (epinephrine), and propylene glycol 10% {hydratin-
`zine}. Whereas, the intravenous bolus route can use ethanol
`up to 20% (paricaleitrol), PE-JG 300 up to 50% (methocarbm
`mil), and propylene glycol up to 68% (phtyibnrbitol). The
`intramuscular route has similar in viva constraints to the
`intravenous route, but can tolerate even more organic
`solvent (see section 1.3, Totally Organic Solution Formula-
`tions).
`Surfactant formulations seem to be on the increase with
`exciplents 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, crernophor BL is 11% of the
`miconuzole marketed formulation, but is diluted to l% for
`IV infusion. Also, TWEEN 80 is 10% of the arniodaronc
`marketed formulation. but is diluted to 0.4% for IV infusion.
`However, crcmopltor EL at it)
`or TWEEN 80 at 25% can
`be administered by IV infusion \(see section 1.3).
`3. Totally Organic Scirrriort Forirttrlations
`
`Molecules that are non-ionizable (have pKa < 2, or
`pKa > ll) and non~polcr are water insoluble with no effect
`of pH on solubility, and thus are the most challenging for the
`formulation scientist. These xvatcr-insoluble molecules can
`be formulated in 100% organic solvent, which is then
`usually but not always diluted prior to administration (‘Table
`VII). For example, busulfao is marketed in 33% dimcthyl-
`acetamicle and 67% PEG 400, but is diluted l0-fold prior to
`IV infusion. The lorazepum marketed formulation is 80%
`propylene glycol, 18% ethanol and 2% benzyl alcohol. but is
`diluted 2-fold for W bolus injection, but not diluted for
`intramuscular injection. Paclitaxcl is marketed with 51%
`cremophor EL and 49% ethanol. but is diluted S~ to 20-fold
`for IV infusion. Docetaxel is marketed in 100% TWEEN 80,
`but is diluted to 25% for IV infusion.
`
`Vol.53, No. 6 I Novcmber-Decembert9Q9
`
`4. Cyclorlexlrirts
`
`Some molecules can be solubilized by forming an inclu-
`sion complex with a cyclodextrin. Cyclodcxtrins have a
`hydroplailic exterior and a itydmpltobic interior core of
`specific dimensions, and thus molecules with at norrpolar.
`aromatic or hcterocyclic ring can potentially fit inside the
`core. Increased water solubility through molecular complex-
`ution with cyclodextrins has advantages over the cosolvent
`approach since upon dilution a lzl complex between cyclo~
`dcxtrin and drug will not precipitate, but a drug dissolved in
`:1 cosolvent often precipitates upon dilution. Two cyclodex—
`trins have been accepted for human injectable use with the
`approval of alprostidol ulfadcx and itruconazole. Alprostidol
`alfadex is marketed as :1 lyophilized powder with rx-cyclodcx-
`trin and is administered intracavernosally. Itraconttzole was
`approved in April 1999 as it solution with 40% hydroxypro-
`pylllacyclodcxtrin and is administered by intravenous infu-
`sion after a 2-fold dilution with saline (6). The next
`cyclodextrin likely to be approved is sulfobutylcthcr-Ev
`cyclodextrin, which is in the clinical formulation of ziprasi-
`done for intramuscular injection (1 1).
`
`5. Errttrlsians
`
`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 is
`typical emulsion
`composed of 10% soybean oil containing 10 mglml. drug.
`The total parenteral nutrition (TPN) formulations are the
`lipid emulsions Intrnlipid and Liposyn, which are adrnirtis~
`tered by intravenous infusion as nutritional supplements.
`
`6. Pradmgs
`
`Molecules which contain an alcohol. phenol, carboxylic
`acid, amine, hydantoin functional group can potentially be
`derivalized as a prodrug. Once the prodrug is administered
`in vivo, the promoicty is hydrolyzed by either cstcrascs or
`phcsphatases releasing the parent drug. Although prodrugs
`are normally associated with orally administerert products
`for better oral bioavailability, many parenteral products are
`prodntgs (Table VIII).
`The versatility of the prodrog approach is demonstrated
`with prodrugs that in design either increase or decrease
`water solubility. A water-soluble prodrug has an electroni-
`cally charged prornoicty, while a water insoluble prodrug
`has heenrterivatized to be a neutral molecule (see section
`ll.7b). Recently, a few water-soluble phosphate ester pro-
`dnigs have been developed and marketed in order to replace
`the original formulations that contain high concentrations of
`organic solvent The phenol-containing ctoposide (etoposide
`phosphate) is ricrivatizcd as a water-soluble phosphate ester.
`Water-soluble phosphate esters are also prodrugs for alcohol-
`containing betamethasone, clindamycin, dexamcthasone,
`lludurabinc, hydroccrtisonc, and prednisolone. The hydran-
`329
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`

`

`l
`
`‘
`
`:
`’
`
`.
`
`:5
`'
`
`ll
`
`Solvent
`
`Crcmophor BL
`
`osolvents Used in Parenteral Formulations.
`Table VI. List 0
`% inM ctcd
`Route of
`
`ration dministered A
`V mfuston
`I
`0.02-0.08
`IV infusion
`IV infusion
`0.1-l
`Intravesical
`18
`25-10
`IV infusion
`065-33
`IV infusion
`IV infuston
`0. 12-0.12
`3
`IV infusion
`
`Exatnles _
`Mtconazole
`Tacrolimus
`
`Tenoposide
`
`Valrubicin
`Pacfitaxel
`clos - orin
`Tenopostde
`Busulfan
`
`5 (diluent for
`LP)
`6
`I0
`l0
`l0
`10
`10
`10
`13 (diluent)
`20
`25
`30
`35
`42
`49
`50 \~
`80
`I00 (diluent for
`LP)
`15
`25
`32
`I00 (diluent for
`LP)
`
`IO
`
`0
`so
`
`,
`
`0.5
`
`IV infusion
`
`6
`l0
`25-10
`I0
`IO
`10
`I0
`IO (diluent)
`20
`I
`0.3-0.6
`035- l .7
`0.0844184
`2.5- 1 0
`18
`0.08-0.32
`10
`
`l ‘
`25
`32
`100
`
`10
`
`1
`0.6-1.2
`18
`9
`5-7
`
`IM, SC, IV
`IM, IV
`IV
`IM, IV
`IM, IV
`IM, IV
`EM. IV
`IV infusion
`IV
`IV infusion
`IV
`IV infusion
`IV infusion
`IV infusion
`Intravesical
`IV infusion
`IV infusion
`
`IM, SC, IV
`IV infusion
`SC
`
`Su o gingtva
`
`IM
`
`[M ,
`
`IV infusion
`
`Medroxy-
`progesterone
`Dihydroergotamino
`Diazepam
`Digoxin
`Kctorolac
`Pentobarbital
`Phenobarbital
`Phenytoin
`Dooetaxel
`Paricalcitol
`Esmolol
`Etoposide
`Cyclosporin
`Teniposide
`Paclitaxel
`Valrubicin
`Tacrolimus
`Carmustinc
`
`Dihydroergotamine
`Idarubicin
`E inc 1 hrine
`I xycyc me
`
`Etoposidc
`Loraaopam
`Lorazepam
`Busulfan
`
`G ycerin
`
`—met yl-2-
`pyrrolidone
`(Pharmasolve)
`Monothio-
`;
`carol
`
`~
`
`loin-containing phcnytoin prodmg (fosphenytoirs) is deriva-
`tized in 3 unique fashion as a water-soluble hydroxymcthyl
`‘ phosphate ester, which after in viva enzymatic phosphate
`ester cleavage, the resulting hydroxymethyl
`intermediate
`quickly dissociates to pltcnytoin and fonnaldehydo (12).
`Other water solubilizing prodrug approachcs are a succinatc
`ester of the alcohol mcthylprcdnisolone. and a piperidine
`carbamate in irinotecan a prodrug for a phenol drug.
`Protlrugs can also be used for stability reasons. For
`example, alatrofioxacin is the alanine-alanine dipcptitle
`prodrug for the primary amine trovafloxztcin which is
`
`unstable in solution. The prodrng alatrolloxacin is marketed
`as rt solution at pH 34-43.
`
`ll. Sustained-Release Techniques
`
`The research in controlled release during the l970s has in
`the 1990s become a commercial realization with the ap
`proval of liposomal, polymeric microsphcrc and polymcxic
`get fonnulations. However, traditional approaches are still in
`use such as suspensions, prodrugs and oi! depots.
`
`330
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`

`

`Tab :3 VI (cont.). List of Cosolvents Used in Parenteral Formulations.
`Route of
`% in Marketed
`
`lvent
`Propylene glycol
`(PG)
`
`_ation
`10
`20 (diluent for
`
`Administer Adminison
`
`Exam 0133
`y ra aztne
`Chlordiazepoxide
`
`Esmolol
`Paricalcitol
`Etomidate
`Diazepam
`Digoxin
`Pentobarbital
`Phenytoin
`Dimenhydrinate
`Dimcnhydrinate
`Fenoldopam
`Mecit'oxy—
`progesterone
`Oxytetracycline
`Phenobarbital
`Lorazepam
`Lorazeam
`
`iet ylperazine
`Irinotecan
`Nicardipine
`Diltiazem
`Triamcinolone
`
`Dexamethasone
`Acetate '
`Caloitriol
`Chlordiazepoxide
`
`IV infusion
`IV
`IV
`IM, IV
`IV
`IM, IV
`IM, IV
`1M
`TV infusion
`IV infusion
`IV infusion
`
`IM
`IM, IV
`
`IV infusion
`IV infusion
`IV
`Intra—atticulnr.
`Intralesional
`IM
`
`IV bolus
`IM
`
`0.075
`
`0.4
`
`60 (diluent for
`L?)
`67-75
`68
`80
`80
`
`0.075
`
`0.4
`4 (diluent for
`LP)
`8
`10
`100
`
`TWEEN 80
`(Polysorbate 80)
`
`= intramuscu at
`IV = intravenous
`LP = lyophiiizcd powder
`PEG = polyethylcneglycol
`SC == subcutaneous
`\
`
`0.08-0. 16
`0.4
`25
`
`IV
`IV infusion
`IV infusion
`
`Etoposidc
`Amiodat-one
`Docetttxel
`
`7a. Suspension Fonnulaliolzs ',
`
`Suspension fomtulations provide a sustained-release de-
`pot at the injection site that releases prodmg 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 intrantuscuiarly.
`imrnlesionally orinlra~:1r1iouit1r1y. 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
`
`aurotltioglucosc, which is administered intramuscuiarly ev-
`ery 1-4 weeks.
`
`711. Pradmgs in Sumension Forumlmians
`
`Most of the other suspension fonnulations an: aqueous-
`based and contain water—insolulJle prodrugs which are
`lipophilic esters of alcohols. For example. hydrocortisonc
`acetate and dexamotliasone acetate are acetate esters of their
`alcol1ol~eontaining parent drug, and are administered intra-
`muscularly, intralesionally or intra-atticularly once every
`1-3 weeks. The contraceptive mcdroxyprogestcrone acetate
`is administered intramuscularly once every 13 weeks. Aque-
`ousbased 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
`
`
`
`Supplied by The British Library - “The worlds knowledge"
`
`
`
`Astrazeneca Ex. 2112 p. 8
`
`

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`Supplied by The British Library ~ "The world's knowledge"
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`Astrazeneca EX. 2112 p. 12
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`Vol. 53, No.6 I November—December1999
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`Suppiied by The British Library — "The world's knowledge"
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`Astrazeneca EX. 2112 p. 16
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`PDAJournal of Pharmaceutical Science & Technofogy
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`Supplied by The British Library — “The wcr1d’s knowledge“
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`Astrazeneca EX. 2112 p. 17
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`
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`

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`as sodium carhoxymethylcellulose at ~5 mg/ml, (i.e.,
`dcxamethasone acetate), PEG 3350 at 30 mg/ml. (i.c..
`metlrylptetlnisolonc acetate) or sorbltol at 50% (i.c., trium-
`cinolonc hexacetonide).
`
`8. Dr-pals
`
`Sesame oil formulations of oil-soluble drugs provide a
`sustained-release depot at the injection site that releases drug
`by dit'f'usion~likc uptake of oil. For example, the prodrugs
`halopcridol deconnte and testosterone enztnthate are formu-
`lated in l00% sesame oil and administered intrarnuscularly
`once 11 month.
`
`9. Lipasomcs
`
`An exciting new era of the parenteral sciences begun with
`the approval of liposomal products. A liposornc is u lipid
`bilayer and an aqueous-based multilayercd spherical drug
`delivery system where the drug is encapsulated inside the
`liposomc, and is released as the liposornc is eroded in vivo. A
`typical liposomc formulation contains water with lipid at ~5 ‘
`mgImL, an isotonicifier. 8 pH 5-8 buffer, and with o