REVIEW ARTICLE
`
`Parenteral Formulations of Small Molecules Therapeutics Marketed in
`the United States (1 999)—Part l
`
`ROBERT G. STFllCKl..E‘{
`
`Axys Plrarrrracerttlcals, Inc, Soutlt San Francisco, Coir‘ ornia
`
`Overview
`
`introduction
`
`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 iojectahle
`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 use-ful\t‘or those
`interested in knowing what additives are currentlfused in
`injcctable 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 Alters, discuss the various formula-
`tion approuches with detailed tables of examples. In a
`compendium of excipients for parenteral formulations (10)
`Gencntech scientists, Powell, Nguyrip and Baloian, list the
`acceptable excipients as well as their percent‘s within the
`formulations, route of administration and pH. The compila-
`tion hereln 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 fonnulations.
`
`Editor's Note: This review article on lnjectabic Products is being pub»
`lishcd in several parts, The next inst:tllment(s) will appear in subsequent
`issues of tltcrlonrnal.
`080.
`Cogrxespondencc address:
`
`I80 Kimball Way, South San Francisco. CA
`
`324
`
`The word “parentcral" is Latin for “other than intestine,”
`thus by definition the parenteral sciences not only includes
`injectable products but also transdermal, pulmonary, nasal,
`ophthalmic, and bacon! 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 forrnulations
`using microspheres. liposomes and polymeric gels. longer in
`viva ‘circulating times using PEGylated liposomes (also
`known as stealth liposomcs) and PEGylated proteins, and
`new excipients such as cyclodcxtrin 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 nccd1c—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 sufticlent shelf-life, which is generally considered to
`be the time for 10% degradation. The ideal
`injectable
`formulation, from an in viva tolerability point-of-view, is
`isotonic with physiological fluids and a neutral pli (i.e.,
`PBS: phosphate buffered saline, 0.01M sodium phosphate
`with 0.l35M 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 solttbilization techniques. If stability is
`insutiicient to provide :1 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. Solublllzatlon Techniques
`
`1. pl‘! Actgizrsrrtrerrrrnrrl Salts
`if the drug molecule is ionizahlc, 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
`
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`

`
`Functiona
`Grou - Name
`
`Sulfonic acid
`
`Phosphate ester
`
`Carboxylic acid
`
`4~l-Iydroxy
`coumarin
`
`Sulfonamide
`
`Barbituric acid
`
`Guanine
`
`Hydanloin
`
`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 on overall net neutral
`molecule) and are usually formulated at a pH in which the
`drug is ionic (Table lll). For example, both ciprolloxacin and
`sufentanil have a carboxylic acid and an amino. but are
`formulated as the cation at pil < 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.
`
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`Neutral
`
`Bethamethasone
`Dexamethasone
`Fludara a inc
`Pencillin
`Ketorolac
`
`Flurouracil
`
`Acetazolarmde
`Clorothiazide
`Diazoxidc
`
`Methohexital
`Pentobarbital
`Phenobarbital
`Secobarbital
`
`Acyclovir
`Gancyclovir
`
`Phcnytoin
`
`10.5
`emulsion
`organic
`oranic
`
`Liothyronine
`Propofil
`Etoposide
`Toni r oside
`
`The range in pH is quite broad and is between pH 2-12,
`and thus any molecule with a pKa bctwccn 3-11 can be
`potentially solubiiized by pH adjustment. However, when
`using extiemcs 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. 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,
`325
`
`

`
`
`
`
`
`
`Table II. Examples 0 Weak Base Chermca Functional Groups, Their - ppmximate pKa s
`and Formulation H's.
`
`Functional
`Grou Name
`
`Functional Group
`Structure
`
`Functional
`Grou Ka
`
`Formulation
`H
`
`Selected
`Examles
`
`
`
`
`lH-Imidazole
`
`Miconazole
`
`Ondansctroo
`
`
`
`
`Metoclopramidc
`Minocycline
`(Procaine
`Procainamide
`also have a
`tertiaty amine)
`
`~ 5
`
`2-6
`
`/’
`
`
`
` 4,5—Imidazoline
`Tolazoline
`
`§
`;
`’
`
`
`
`
`Ateno ol
`Codeine
`
`
`Daunombicin
`R---N
`
`
`Morphine
`\
`
`'1
`
`Vera . .
`R3
`
`R2
`
`/
`
`7—l0
`
`3~7
`
`Amine
`
`
`
`7.4
`
`< S
`
`Doxapram
`
`
`
`N-Alky
`morpholine
`
`
`
`
`Cimetidine
`\
`‘
`3-6.5
`~ 7
`/
`Dacarbazine
`\
`
`Phemolamine
`
`
`
`
`
`Pcntamidinc
`
`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, chlordiazcpoxide
`is administered intravenously or intramnscularly 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 and lo% ethanol. Subcutaneous fonnula-
`
`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 weal: acids,
`or hydrochloride salts of weak bases) utilize the same
`principle of ionization. and are often the marketed form of
`the drug (Table W). The most common cationic counterion
`is sodium which accounts for > 90% of the cations. and
`there are three megluminc salts, while only one salt each of
`
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`
`
`
`
`
`~ 5
`
`2-4
`
`Amrononc
`Milrinone
`
`
`
`Papaverinc
`Pyridoxine
`
`

`
`Selected
`Example
`
`Chemical Structure
`
`Ciprofloxacin
`
`Acidic
`Functional
`Group Name
`
`Basic
`Functional
`
`Group Name
`'
`
`Formulation
`
`pH
`(ionic state)
`
`Carboxylic
`acid
`- 4
`
`Aniline ~ 4
`Amine ~ 9
`
`3-4
`(Cationic)
`
`Sufentanil
`
`a,c\,fLN
`
`9COOH
`
`Ampicillin
`
`Cephapirin 0)
`
`°jx_,.
`
`S
`
`N
`
`H
`
`*9”!
`
`o
`
`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. tromcthnmine and calcium. There are
`many more anionic counterions and the most common is the
`hydrochloride salt followed by sulfate. rnesylatc, malcate
`and tartrate. When a salt is dissolved in non-buffered water.
`the resulting pH is generally ~2 pi(a 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 pll ~ 1!.
`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-ll and
`
`' ist of enter Ion in Salt Forms of Parenteral Dru
`Nuer 0 instances
`
` Hydrochloride
`......._\............_._......gq¢g:;;u.u.a\o{\)oo5“g
`
`Calcium .
`Tromcthamine
`
`Sulfate
`Mesylate
`Chloride
`Maleate
`Tmtratc
`Citrate
`Bromide
`Lactate
`Acetate
`Phosphate
`Besylate
`Hydrobromide
`Fumarate
`Gluceptate
`Gluconate
`Glucuronate
`Lactobionatc
`Salicylatc
`T05 late
`
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`
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`

`
`Buffer ( Ka’s)
`
`Malena acid
`(1.9, 6.2)
`Glycine
`
`Sodium lactate!
`Lactic acid
`3.8)
`Ascorbic acid
`4.2,
`1 1.6)
`Sodium citratesl
`Citric acid
`(3.1, 4.8, 6.4)
`0 mm acetate!
`Acetic acid
`
`Sodium
`bicarbonate!
`Carbonic acid
`
`succinatcf
`
`Succinic acid\
`(4.2, 5.6)
`
`‘~
`
`benzoatel
`Benzoic acid
`(4.2)
`O 0 mm
`
`phosphates
`(2.2. 7.2. 12.4)
`ris(hydroxy—
`methyl)amino-
`inethane
`\ (8.3)
`
`Concentration in
`Formulation.
`Molarit
`
`Concentration
`Administered,
`Moiari
`
`Route of
`Administration
`
`L
`
`IV infusion
`
`IV
`IV infusion,
`SC
`
`M, IV, IV
`infusion,
`
`IV, IV
`infusion
`
`IV infusion,
`SC
`
`IV infusion
`IM
`
`IV, ’ " in sion
`IM
`
`IM, IV infusion
`Intra-arteriaily.
`Intrathecal
`
`(Fomivcrsen)
`
`= intramuscu ar
`IV = intravenous
`SC == subcutaneous
`
`
`
`include citrznes. ncclnxes, histidine. phosphate. tris(hydroxy—
`rnc1Iiyl)aniinomethanc, and carbonates. The buffer concen-
`tration must be high enough to maintain the desired pH, but
`must be balanced by in vivo toierabiiity considerations, and
`thus it is good practice to minimize buffer capacity of the
`administered formulation.
`
`328
`
`2. Mixed Organic/Aqueous Fanzzzllaiiotzs
`
`If pH adjustment aione is insuflicient in achieving the
`desired solution concentration. than a combination of pH
`and organic soivent(s)
`is often employed. If the drug
`molecule is not ionimblc 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 (i.c.. a cosol-
`vent). The currently used organic solvents used in mixed
`orgnniclaqueous formulations are propylene glycol, ethanol,
`polyethylene glycol 300 or 400. cremophor EL, TWEEN 80,
`sorbitol. glycerin and dimethylccetamide (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 fonoldopam
`marketed formulation, but is diluted to <l% for IV infusion.
`However. propylene glycol is ~70% of the oxytetrncyclinc
`marketed formulation and is injected intramuscularly 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% (dihydroergutamine), glyc-
`erin 32% (epinephrine), and propylene glycol 10% (hydrolo-
`zlne). 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% (plugabarbitol). 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
`
`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
`rniconnzole marketed lonnulation, 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, cremopltor EL at l0
`or TWEEN 80 at 25% can
`be administered by IV infusion xtjsee section 1.3).
`3. Totally Organic Solrttion Forirtttlatiotts
`
`Molecules that are non-ionizabte (have pKa < 2, or
`pKa > ll) 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
`Vll). For example, busulfan is marketed in 33% dirnethyl-
`ncetamidc and 67% PEG 400, but is diluted l0-fold prior to
`IV infusion. The lorazepam marketed formulation is 80%
`propylene glycol, l8% ethanol and 2% benzyl alcohol. but is
`diluted 2-fold for lV bolus injection, but not diluted for
`intramuscular injection. Paclitaxcl is marketed with 5l%
`cremophor EL and 49% ethanol. but is diluted 5- to 20-fold
`for IV infusion. Docctaxel is marketed in 100% TWEEN 80,
`but is diluted to 25% for IV infusion.
`
`Vol. 53. No.6 I November~December1999
`
`4. Cyclnrlexlrins
`
`Some molecules can be solubilized by forming an inclu-
`sion complex with a cyclodextriu. Cyclorlcxtrins have a
`hydrophllic 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-
`otion with cyclodextrins has advantages over the cosolvent
`approach since upon dilution a l:l complex between cyclo-
`dcxtrln and drug will not precipitate, but a drug dissolved in
`n cosolvent often precipitates upon dilution. Two cyclodex—
`trins have been accepted for human injectable use with the
`approval of alprostidol alfadex and itraconazole. Alprostidol
`alfadcx is marketed as a lyophilized powder with ct-cyclodex-
`trio and is administered intracavernosally. ltraconnzole was
`approved in April 1999 as a solution with 40% hydroxyproo
`pyl-$3-cyciodextrin and is administered by intravenous infu-
`sion after a 2-fold dilution with saline (6). The next
`cycloclextrin likely to be approved is sulfobutylether-Ev
`cyclodextrin, which is in the clinical formulation of ziprasi-
`done for intramuscular injection (ll).
`
`5. Ertzttlsians
`
`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 solubilizc 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 pll 7—8, and is injected by
`either IV bolus or IV infusion. The only marketed emulsion
`formultuion 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. Pradntg:
`
`Molecules which contain an alcohol, phenol, catboxylic
`acid, amine, hydantoin functional group can potentially be
`derivatized as a prodrug. Once the prodrug is administered
`in vivo. the promoicty is hydrolyzed by either esterascs or
`phosphntases releasing the parent drug. Although prodrugs
`are nonnally 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 prod:-ugs that in design either increase or decrease
`water solubility. A water-soluble prodrug has an electroni-
`cally churged promoiety, while a water insoluble prodrug
`has been rlerivatized to be a neutral molecule (see section
`llfllb). 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 ctoposide (etoposicle
`phosphate) is dcrivatized as a water-soluble phosphate ester.
`Water~soluble phosphate esters are also prodrugs for alcohol-
`containing betarnethasonc, ctindamycin, dexamethasone,
`iludarabirtc, hydrocortisonc, and prednisolone. The hyclan-
`
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`

`
`i
`
`;
`
`‘
`
`Solvent
`
`Cromophor EL
`
`osolvents Used in Parenteral Formulations.
`Table VI. List 0
`%in Marketed
`'
`Route of
`olation dministered Anislration
`I
`V infusion
`l I
`0.02-0.08
`IV infusion
`20
`0.1-!
`IV infusion
`50
`18
`Intravesical
`50
`S I
`25-10
`IV infusion
`65
`0.65—3.3
`IV infusion
`IV infusion
`0. l 2-0.12
`3
`IV infusion
`
`Exam W
`Mzconazole
`Tacrolimus
`Tenoposide
`Valrubicin
`Paclitaxel
`C clos - orin
`Tenoposide
`Busulfan
`
`Medroxy-
`progesterone
`Dihydroergotamine
`Diazepam
`Digoxin
`Ketorolac
`Pentobarhital
`Phenobarbital
`Phenytoin
`Dooetaxel
`Paricalcitol
`Esrnolol
`
`Etoposide
`Cyclosporin
`Teniposide
`Paclitaxei
`Valrubicin
`Tacrolimus
`Carmustine
`
`Dihydroergotamine
`Idarubicin
`E u inc - hrine
`
`I xycyc me
`
`Oxytetracycline
`
`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
`
`Su ogingtva
`
`0.5
`
`61
`
`0
`25-10
`10
`10
`10
`I0
`
`10 (diluent)
`20
`1
`0.3-0.6
`0.35-1.7
`0.084—0.84
`25-10
`18
`0.08-0.32
`10
`
`I .
`25
`32
`
`100
`
`IV infusion
`
`Etoposide
`Lorazepam
`Lorazeparn
`Busulfan
`
`lmethy —
`acetamide
`(DMA)
`
`5 (diluent for
`LP)
`
`61
`
`0
`10
`10
`10
`10
`
`10
`13 (diluent)
`20
`25
`30
`35
`42
`49
`50 \~.
`80
`I00 (diluent for
`LP)
`15
`25
`32
`
`100 (diluent for
`LP)
`
`G ycerin
`
`—met yl-2-
`pyrrolidone
`(Pharmasolve)
`Monothio-
`l cerol
`
`5
`t
`’
`
`5
`‘
`
`g:
`
`toin-containing phcnytoin protlrug (fosphenytoin) is deriva-
`tized in a unique fashion as a water-soluble hydroxymethyl
`I phosphate ester, which after in viva enzymatic phosphate
`ester cleavage, the resulting hydroxymethyl
`intermediate
`quickly dissociates to phenytoin and formaldehyde (I2).
`Other water solubilizing prodrug approaches are a suecinate
`ester of the alcohol methylprcdnisolone. and a piperidine
`carbamate in irinotecan a prodrug for a phenol drug.
`Prodrugs can also be used for stability reasons. For
`example, alatrolioxacin is
`the alanineqdaninc dipcptide
`prodrng for the primary amine trovalloxttcin which is
`
`unstable in solution. The prodrng alatrofloxaciu is marketed
`as a solution at pH 3.4-4.3.
`
`ll. Sustained-Release Techniques
`
`The research in controlled release during the 19709 has in
`the l990s become a commercial realization with the ap~
`proval of liposomai, polymeric microsphcrc and polymeric
`gel formulations. However, traditional approaches are still in
`use such as suspensions, prodrugs and oil depots.
`
`330
`
`PDA.lournal of Pharmaceutical Science & Technology
`
`
`Supplied by The British Library - "The worid‘s knowledge"
`
`
`
`Astrazeneca Ex. 2112 p. 7
`
`

`
`Tab e VI (cont.). List of Cosolvents Used in Parenteral Formulations.
`% in Marketed
`%
`Route of
`
`Exam o les
`
`Hydralnzine
`Chlordiazepoxide
`
`Esmoloi
`Paricaicitol
`Etomidate
`
`Diazepam
`Digoxin
`Pentobarbital
`
`Phenytoin
`Dimenhydrinate
`Dimenhydrinate
`Fcnoldopam
`Meclroxy—
`progesterone
`Oxytetracycline
`Phenobarbital
`Lorazepam
`boraze . am
`
`itiet ylperazine
`Irinotecan
`
`Nicardipine
`Diltiazem
`Triamcinolone
`
`Dexamethasone
`Acetate '
`Calcittiol
`
`Chlordiazepoxide
`
`Etoposide
`Amiodarone
`Docetnxel
`
`lvent
`Propylene glycol
`(PG)
`
`Formulation Admin Administraon
`1M,
`10
`1M
`20 (diluent for
`
`IV infusion
`IV
`IV
`IM, IV
`IV
`IM, IV
`IM, IV
`IM
`IV infusion
`IV infusion
`IV infusion
`
`IM
`IM, IV
`
`IV infusion
`IV infusion
`IV
`Intra-articular,
`Intralesional
`IM
`
`IV bolus
`
`M N
`
`IV infusion
`IV infusion
`
`0.075
`
`0.4
`4
`
`0.08-0.16
`0.4
`25
`
`60 (diluent for
`LP)
`67-75
`68
`80
`80
`
`TWEEN 80
`
`0.075
`
`0.4
`4 (diluent for
`LP)
`
`8 1
`
`0
`100
`
`(Polysorbate 80)
`
`= intramuscu ar
`IV = intravenous
`LP = lyophilized powder
`PEG = polyethylencglycol
`SC == subcutaneous\.
`
`i
`7a. Sztspcttsiort Fommlmions '_
`
`Suspension fomiulations provide a sustained~t-eleasc 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 intraniuscularly.
`intralesionelly or intro-aniculorly. 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 (dmg in
`solution) and sustained activity (crystalline drug in suspen-
`sion). Thc only sesame oil suspension is the anti-rheumatic
`
`attrotltioglucose, which is administered intromuscularly ev-
`ery l—4 weeks.
`
`7!). Prodmgs in Sttspension Forumlrttians
`
`Most of the other suspension fonnulations are aqueous~
`based and contain water-insoluble prodrugs which are
`lipophilic esters of alcohols. For example. hydrocortisone
`acetate and dexametliasone acetate are acetate esters of their
`alcohol~containing parent drug, and are administered intra-
`muscularly, intralesionally or intra-anicularly once every
`l—-3 weeks. The contraceptive mcdroxyprogesterone acetate
`is administered intramuseularly once every 13 weeks. Aque-
`ous~bz1sed 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 i999
`
`331
`
`
`
`
`ll
`
`Supplied by The British Library — "The worlds knowledge"
`
`l
`
`Astrazeneca Ex. 2112 p. 8
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`A polymeric PLGA microsphere formulation of human
`growth hormone (Nutropin Depot) finished Phase III clinical
`trials in l999 (l3).
`In this Formulation, human growth
`hormone is made into an insoluble complex with zinc, and
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