ACID CONTAINING OXAUPLATIN FORMULATIONS
FIELD OF THE INVENTION
The invention relates to formulation containing oxaliplain.
BACKGROUND OF THE INVENTION
5 Oxallplatin is an anHcancer agent, Oxaliplain (CAS 61825-94-3),also known as L-OHP, is a
third gxxxtion piouinurn complex. The tunn "oxaliplatin" as used herein includes da-
nxalato(trans-/1,2-dtaminocyxxx) plahnum(11), its optic xxx cls-oxilato(trans-
d-l,2-diomincyclohexane) platinum(Il), and Any mixture thereof.
Oxllplalin is currently approved and marketed for second-line treatment of colorectel
10 cancer, Oxtiplatin is available in a lyophilised form (20 mg, 50 mg or 100 mg vlals). Just
prior to odministration the lyophitised powder is reconstiltuted using water for injection xxx
5% glocose Injection solution to provide a solution containing 5 mg/ml oxatiplatin.
Typically, the reconstituted solution is than further dilutcd in 250-500 ml of 5% glucose
Injection solution The diluted oxahiplatin solution is then infured elther by peripheral vain
15 nr central venous line over 2 to 6 hours.
Lyophilizcd oxaliplatin has some disadvantages as a phamaceutica1 form. The
manufacturing pincess for a lyophiliscd dasogc from is complicated and expensive. For
example, the risk of sterillty failure during manufacture of freeze dried forms is generally
higher than is the case for liquid solutions. In addition the reconstitution of freeze dried
20 preparations xxx both skill and cans as it involves several risks, inter alia, incomplete
dissolution of the powder, contamination through handling a highly toxic substrance as a
powder or cake, and maintaining the sturility of both the vial and the infusion Solution
during racostitutian and transfer to the infusion bag. Thus, to adminlster alyophilizcd
drug, multiple handling of "the drug is required - the lyophilised oxaltpatin is first
25 reconstituted then diluted with a 5% glucose solution and then administered by intravenous
infuslon.
Futher, following reconstitution oxallplain is prone to instabillity, particularly in solutions
containing certain nucleophilic agents. For example, some reconstitution solutions
containing chloride ions, such as 0.9% podium chloride solution are commonly used in
30 hospitals, The mistaken use of such a XXX solution in the case of the lyophilizcd
form of oxallplatin has the serious consequence of rapidly decomposing flm oxaliplatinum

WO 20D5/0M980 PCI7AU 2004/00116S
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metal complex, forming a precipitate (dilchloro-diminocycyclohaxane-platimum derivative)
with NaCI.
An a consequence of the limitations described above, sereval stabilised aqueous reacly-to-use
(RTU) liquid oxaliplatin preparations have been proposed:
5 1. US 5,716,988 and AU 731981 disclose a xxx formulation consisting of a 1
to 3 mg/mL solution of cocaliplntin in water having a pH range of 4.5 to 6. However,
subsequently, WO 99/43355 and US 6,476,068 report that simple aqueous solutions of
oxaliplatin prepared according to the methods taught In this specification are
insulfficiently stable.
10 2. WO 99/13355 and US 6,306,902 disclose an oxaliplatin solution formulation
containing 1 to 7 mg/ ml oxaliplatin, a buffering agcnt and a pharmaceutically
acceptable carrier. The preferred buffering agent (and only example) in oxalic add,or
an alkali metal ault thereof.
3. WO 01/15691 discloses solutiors of at least 7 mg/ml oxallplatin containing a solvcnt
15 containing a sufficeint amount of at least one hydroxylated derivative selected from.
1,2-prupane-diol, glyccrol, maltitol xxx and inositol. The speciflcation xxx that
these are the only suitable agents to use after consideration of several options.
Further, if buffering agents are used, the specification teaches that the buffcr should,
have an oxalic acid base.
20 4. US 6,476,068 discloses an oxaliplatin solution formulation comprising 0.I to 10
mg/ml oxaliplaitin an effective stabillzing amount of the monocarboxylic acicl, lactic
acid, and n pharmacecutically acceptable carrier. The prcfcrred concentration range of
oxalipalin is 2 to 5 mg/mL
5. US Patent Application No. 20030109515 discloses an oxaliplatin solution formulation
25 containing a stabillsing amount of malonic acid. The examples are directed to
formulations having an oxaliplatin concentration of 2 mg /mL In contrast to the
teaching of this application, and as is discussed below, the present inventors have
found that malonlc acid destabilises oxaliplatin in solution.
Buffering agents are used in liquid phamaceutical formulation to adjust the pH of the
30 formulation and to maintain the formulation within a desired pH range. As mentioned
above, the dicarboxylic acid, oxalic acid, and its salts have been proposed as a buffering and
stabilising agent for oxaliplatin. Oxalate ion is formed in equcous sohitions of oxaliplatin by
hydrolysis, thus conceivably this reation may be slowed (using Le Chateller's principle)

WO 2005/020980 PCT/AU2004/001168
3.
through purposeful addition of oxalate loa to solutions of oxalplatin. However, oxalic acid
has some disadvantages as a pharmaceutical buffering agent, notably it's toxlcity. Oxalic
acid is potentially nephrotoxic and alsn requlres special handling precnutions, which
complicate and limit its use In phamaceuitical products,
5 There is a need for agents that can be used with oxallplatin solutions as alternatives to the
prior art buffering agents (oxalic acid, lactic acid and malonic acid) and which do not have
the disadvantages xxx with the use of oxalic acid.
Idcally, the alternative agents would not destabilised oxliplatin in solution. In particular. It
would be useful if the alternative agents improvc the stabillty of oxaliplatin in aqucous
10 formulations in a manner that inirimies significant degredation of oxadiplatin and limits the
formulation of unwanted inpurities such as dinque DACH platinum and diaqua DACH
platinum dinner.
Partlicr, it would be proferable to limit the amount of unknown degradation products in the
aqueous formulation. Any unknown digradation product prcssent in an amount exccading
15 the thresholds act in the guldelines of the ICH (international Conference on Harrnanisation
of Technical Rcquirement for Rcgistration of Pharmaccuticuls for Humen Use) is requircd to
be identified. This impeses signficant ruquirement on the manufacturer of the formulation
as they are required to identify trace amounts of manufacturer degradation product. In
addition, the presence of unknown degradation products is an indication that there may be
20 additional risks of toxicity and unknown side effects as a consequence of the piresence of
these products. it is therefore of interest to manufactucer of a formulation to avoid
producing unknown degradation products.
Ideally, additional phamaceutically acceptable buffering agents should be non-toxic and be
present in the smallest possible quantity. Furthermore, during manufacture they should be
25 introduced in the safest and most convemient posiblc.
SUMMARY OF THE INVENTION
In a first aspect the present invention provides a pharamanceutcal liquid formulation of
oxcalipiatin for parcntaral admlnistration, said formulation comprising
(i) oxaliplatin;
30 (ii) water and
(iii) an acid

WO 2005/020980 PCT/AU2004/001168
4.
wherein the acid is stabilising and is not malonic acid, lactic add or oxalic acid.
In a second aspect the present invention provides a pharmaceutical liquid formulation of
oxatiplatin for parenteral administration, said furmulation comprising
(i) oxaliplatin;
5 (ii) water and
(iii) an acid comprsing at least a carbon atoms.
In a third aspect the present Invention provides a phamaceutical liquid formulation of
oxaliplatin for parenteral administration said formulation comprising
(i) oxliplatin
10 (ii) water; and
(iii) an additive selected from the group coneisting of a pharmaceutically acceptable
carboxylic add, a salt of a pharmaceutically acceptable carboxylic acid a pharrneccutically
acceptabic derivative of a pharmaceutically acceptable carboxylic acid and mixtures thereof;
wherein the additive is at a concentration of at least 0.01 rcM and wherein the acid, is not
15 malconic acid, lactic add or oxalic acid.
in a fourth aspect, the present invention provides a pharmaceutical liquid formulation of
oxaliplatin for parenteral administration, said formulation comprising
(i) oxaliplatin,
(ii) water and -
20 (iii) an additive selected from the group consisting of a pharmaceutically acceptable
carboxyik acid, a Salt of a phamaceutically acceptable carboxylic acid,a pharmaceutically
acceptable derivative of a pharmaceutically acceptable carboxylic acid and mixtures thereof;
wherein the additive is at concentration of at least 0.01 mM and wherein the carboxylic acid
is of the formula:
25 HO2C[C(RI)(R2)]nCO2H
wherein n - 2 to 6; andR1 and R2 are each independently selected from the group consisting
of H, OH, CO2H, halo and muthyl

WO 2005/020980 PCT/AU2004/001168
5.
In a fifth aspect, the present invcntion provides a pharmaceutical liquid formulation of
oxaplatin for parentanal administration, said formulation comprising
(i) axallplatin
(ii) water; and
5 (iii) an additive selected from the group consisting of turturic acid, a salt of Inrtaric acid, a
pharmaceutically acceptable derivative of tattaric acid and mixtures there of;
wherein the additive is at a concentration of at xxx 0.01 xxx.
In a sixth aspect, the present invention provides for the use of a pharmacetical formulation
according to the first to thrid aspects in the preporation of a medicament for the treatment of
10 a cancer.
In a seventh aspect the present Invention provides a method for treating a cancer which
comprises administering a pharamaceutical fonnulation according to the first to third nspects
to a patient in need thereof.
In a eight aspect there is provided a method for preparing phermaceutical formulation
15 according to the first to third acpects, the method comprising the steps of:
(i) dissolving oxaltiplatin in water to form a solution;
(ii) dissolving the additive in the solution;
(ii) optionally, adjusting the pH of the solution with, a pharrnaceutically acceptable base.
In a minth aspect the present Invention provides a pherxxx liquid formulation of
20 oxaliplatin for parenteral adminstration said formulation comptising
(i) about 5 mg/ml of oxaliplatiry,
(ii) water, and
(iii) an additive consisting of tartaric acid and the sodium salt of xxx acid,
wherein the concentration of the additive is about 0.2 mM and wherein the pH of the
25 solution is from about 4.7 to about 53.

WO 2005/020980 PCT/AU2004/001168
6.
In an teeth aspect the present invention provided for the use of a pharmuceutical
formulation according to the ninht aspect in the prepration of a mexdicument for the
treatment of a cancer.
In a eleventh aspect the present invention provides a method for treating a cancer which
5 comprises administuring a pharmaceutical formulation according to the seventh aspect to a
patient in need thereof.
In a twelfth aspect there is provided a method for preparing a pharmaoceutical formulation,
the meathrd comprising the stops of;
(i) dissolving oxaliplatin in water to form a solution;
10 (ii) dissolving tartaric acid in the solution;
(iii) adjusting the plf of the solution with solution hydroxide such it is in the range of
from 4.7 to 5.5
wherien the concentration of oxallplatin is oxallplatin is about 5 mg/ml and the concentration of tartaric
acid is about 0.2 mM.
15 BRIEF of DESCRIPT1O N OF THE FIGURES
Figure l(a) is a chromatogram showing stability of a solution of oxaliplatin in water stored at
40ºC for 12 weeks.
Figure 1(b) is a chromatogram showing stability of a solution of oxaliplatin and tartaric acid
in water stored at 40ºC lor 12 weeks.
20 Figure l(c) is a chromatogram showing stability of a solution of oxaliplatin, tartaric acid and
undium tartain in water stored at 400C for 12 weeks.
Figure 1(d) is a chomatogram showing stability of a solution of oxaliplatin and succinid acid
disodium salt in water stored at 40°C for 12 weeks.
Figure I(e) is a chromatogram showing stability of a solution of oxcaliplatin, maleic acid and
25 sodlum hydroxide in water stored at 40ºC for 12 weeks.
Figure 2(a) is a chrnmatogram showing stability of a solution of oxaliplatin in water stored at
400C for 8 weeks.

WO 2005/020980 PCT/AU2004/001168
7.
Figure 2(b) is a chromatogram showing stabillty of a solution of oxaliplatin and tartaric acid
in watcr stored at 40°C for 8 weeks.
Figure 2(c) is a chromatiogram showing stability of a solution of oxatiplatin, tartaric acid and
sodium turtrate In water stored nt 40ºC for 8 weeks.
5 Figure 2(d) is a chromatogram showing stabillty of a solution of oxaliplatin tartaric acid and
sodium tartrate in water at 40ºC for 8 weeks, the ratio of tartraic to tartaric acid being greater
than for the solution of Figure 2(c),
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect the present invention provides a pharmacceutical liquid formulation of
10 oxaliplatin for parenteral administration, xxx formulation comprising
(i) oxaliplatin;
(ii) water and
(iii) an acid
wherein the acid is stabillising and is not malonic acid, lactic acid or oxalic acid.
15 It is preferred that the acid a carboxylic acid preferably a dicarboxylic acid.
In a preferred embodiment the acid is selected from the group consisting of citric acid, maleic
acid, saccharic acid, surinic add, malic acid, tarmric acid and mixtures thcreof. It is
preferred that the acid is malic acid, succinic acid tartaric acid and mixture thereof of and is
most preferably tartaric acid.
20. In a second aspect, the present invention provides a pharmaceutical liquid formulation of
axaliplatin for parenteral administration, said formulation comprising
(i) oxliplatin;
(ii) water; and
(ii) an acid comprising at least 4 carbon atoms.
25 It is preferred that the acid is a dicarboxylic acid and preferably comprises 4 to 10 carbon
atoms, more preferably 4 to 6 carbon atoms,
In a further zmbodiment the acid comprises 1 to 2 hydroxyl groups.

WO 2005/020980 PCT/AU2004/001168
8.
In a preferred embodiment the acid is selected from the group consisting of citric acid, maleric
acid, xxx acid, succinic acid, malic acid, tartaric field and mixtures thereof. It is
preferred that the ocid is malic acid, sucinic acid, tartaric acid and mixtures thereof and is
most preferably butaric acid.
5 In a still further preferred embodiment of the first and second aspects of the invention the
acid is or a concentration of at least 0.01 mM.
In a third aspect, the present invention provides a pharmaceutical liquid formulation of
oxallplation for parentural administration, acid formulation comprising
(i) axallpiatin
10 (ii) water;and
(iii) an additive selectect from the group consisting of a pharmaotically arceptable
carboxylic acid, a salt of a pharamaceutically acceptable carboxylic acid, a pharmaculically
acceptable derivative of a pharmaccutically acceptable carboxylic acid and mixture thereof;
wherein the additive is at a conceptration of at least 0.01 mM and wherein the acid is not
15 molonic acid, lactic acid or oxalic acid
preferably, the ocid is a dicarboxy acid.
Preferably, the acid is selected from thc group consisting of citric acid, malcic and, saccharic
acid, succinic acid, malic acid, tartaric acid and mixtures thereof.
In a fourth, aspect, there in provided a pharmaceutical liquid formulation of oxsliplatin for
20 parenteral administration said formulation comprising
(i) oxaliplatin,
(ii) water; and
(iii) an additive selected from the group consisting of a pharmaceutically acceptable
carboxylic acid, a salt of a pharrnaceutically acceptable carboxylic acid, a pharmaceutically
25 acceptable derivetive of a phamaceutically acceptable carboxylic acid and mixtures thereof;
wherein the additive is at a concentration of at least 0.01 mM and wherein the carboxylic acid
is of the formulation:
HO2C[C(R1)(R2)]nCO2H

WO 2005/020980 PCT/AU2004/001168
9.
wherein n - 2 to 6; and RI and R2 are each independcntly selected from the groupe conslsting
of H, OH, CO2H halo and methyl.
Pharmoceutically acceptable adds include glutaric acid, citric acid, malic acid, succinic acid
tartaric acid and mixtures thereat preferably the pharmaceutically acceptable carboxylic
5 acid is selected from the group consisting of malic acid, succinic acid, tartaric acid and
mixtures thereof. More preferably, the pharmaceutically acceptable carboxylic acid is tartaric
ncid.
Preferably n=2 to 4; more preferably n = 2
Tartaric acid (HOOCCH(OH)CH(OH)COOH) is used in food and phanmaceutical
10 formulation as an acldu sequestering agent or antioxidant synergist In|pharmaceutical
formulation, it is widely used in combination with bicarbonates, as the acid component of
efferveacent granules powders and tablets. It displays none of thc toxicity associated with
the use of oxalic acid as a steblilsing agent, such as neplirotoxicity.
Succine acid. (HOOCCH2CH2COOH) is used as a food additive and in detergents and
15 cosmetics. It can be found naturally occurring in animal xxx and in vegetables or fruit.
Matic acid (HOOCCH(OH)CH2COOH) is used as a flavouring agent, flavour cxhancer and
acidulent in foods. If is frund naturally in apples and many other fruits.
Citdc acid is (2-hydroxy-1,2,3-propare-acid) is vridely distritruited in plants and
in animal tissues and fluids.
20 Malaic acid has the formula HOOCCH=CHCOOH.
Saccharic acid has the formula HOOC[CHOH]4COOH and is derived from struch.
In a fifth aspect, the present invention provides a pharmaccccutical liquid formulation of
oxallplatin for parenteral administratation said formulation comprisings
(i) oxaliplatin,
25 (ii) warter and
(iii) an additive selected from the group consisting of tartaric acid, a salt of tartaric acid,a
pharmceutically acceptable derivative of tartaric add and mixture thereof
wherein the addtive is a concentration of at least 0.01 mM.

WO 2005/020980 PCT/AU2004/001168
10.
Many of the carboxylic acids of the present invention are found as isomers. For trustance,
turtaric acid has many isomcric forms. The present invention contemplates the use of any of
the isomers of the carboxylic acid used as an additive. For Instance, where the carboxylic
acid is turtaric acid, the tartaric acid may be selected from any of the isomers of tartaric acid
5 including the group conaisting of (+)-tortaric acid, (-)-tartaric acid, mesoturtaric acid, and
mixtures thereof. Proferably, the tartaric acid is (+)-tartaric acid.
Where the additive is a mixture of a phamaceutically acceptable carboxylic acid and a salt of
a pharmaccutically acceptoble carboxylic acid, the concentration of the aditive is the sum of
the concentrations of the carboxylic acid and the salt. Preferably, where the additive is a
10 mixture of a phamaceutically acceptable carboxylic acid and a salt of a pharmaceutically
acceptable carbxoylic acid, the salt is the conjugate base of the carboxylic acid so as to form a
buffer solution.
when the additive incudes a selt of a xxx accoptable carboxylic acid, the salt of
may be formod in situ by the addition of a pharmaceutically acceptable base to an acid
15 solution. Alternatively, the salt may be added directly to the formulation.
preferably the concentration of the additive in the formulation of the first to third aspects of
the Invention is from about 0,01 mM to about 20 mM, more preferably from about 0.1 mM to
about 1.0 mM, even more preferably from about 0.1 mM to about 0.6 mM. yet more
preferably from about 0.2 mM to about 0.6 mM,
20 Preferably, when the additive comprises a salt of a pharmaceutically acceptable acid the salt
is a sodium salt.
Pharmaceutically acceptable derivatives of carboxylic acids include but are Hmibed to
such derivatives as esters, amides, carbonates and carbarmates of the acid.
The amount of oxaliplatin present in a pharmaceutical formulation according to the
25 invention is prefembly up to about 15 mg/ml, preferably about to about 7 mg/ml.
Preferably the amount of uxaliplatin is in the range of from 1 to 5 mg/ml and must
preferably is about 5 mg/ml.
As will be understood, the additive should be used at a concentration which does not
destabilise the oxallplatin and prefembly aids stebility of the oxaliplatin. The desired
30 stability of oxaliplatin will depend on the intended shelf the of the pharmaceutical
formulation and the manipulation prior to administration. More specifically, a stable
aqueous oxaliplatin formulation is one in which there them be no significant change in
oxaliplatin potency at the specified storage condition. The criteria for significant change"

WO 2005/020980 PCT/AU2004/001168
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are as defined in the lnternaltional Conference on Harmonisation (1CH) Culidelince Stability
Testing of New Drug Substances and Products QlA (82). Thus in the case of injucctable RTU
oxliplatin solution, potency of oxaliplatin should be at least 95% of initial conters and
solution remians clear, colourless and free of precipitation for a pharmaceutically acceptable
5 duration of time.
Preferably, the additive is at a concentration suffcient to buffer the formulation at a pH in
the rings of from about 3 to about 82 more preferably about 4 to about 7, even more
Preferably about 5.
As is known to a person skilled in the art a buffering system is a mixture of an acid with it
10 conjugate basc in a solution, the mixture being formulated so as to maintain the pH at a
desired lovel. As defined herrin “bufferting agent” refer to an acid or a base which may
form a component of a buffering system whether or not the ocid or base B associated with its
cunjugate base or conjugate acid, respectively.
Preferably the pharmaceutrical formulation of the invention is provided in a sterile, soated
15 container. For example, a neutral glass of type I and a stopper. Examples of the stopper
include those made of an elastomer bassed on hologemated bytyls, posibly coated with a
fluonneted polymer.
In a,sixth aspect of the present invention there is provided the use of the formulations of any
one of the first to third aspects in thc preparation of a mediciment for the treatment of a
20 cancer.
In a seventh aspect of the present Invention there is provided a method for treating a cancer
which comprises admintatering a pharmaceutical a pharmaceutical formulation according to the any one of the
frist to third aspects to a patient in need thereof.
The cancer can be any cancer that is emenable to treatment by oxalipletin, either alone or in
25 combination with other chernotherapeutic agent, and includes colurcectal cancer
The term "treating" as used hcrein unlees otherwise indicated, means reversing, allcviating,
truhibiting the progress of, or prevcnting thc disonlcr or condition to which such term
applies, or one or more symptums of such discorder or condition, The team "treatment", as
Used herein, refers to the act of treating, as treating is defined immediately above.
30 In the above methods, the effective dnsage of oxaliplatin to be administered to a patient
ranges from about 10 mg/m1/to about 250 mg/m1, more preferably from about 30 mg/m1 to
about 180 mg/m2 and most preferably is about 85 mg/m2. However, it will bc undcrstood

WO 2005/020980 PCT/AU2004/001168
12.
that the thempautie dosage administered will be detemined by the physician in the light of
the relevant cicumutances including the severity of the condition to be treated and the
chosen route of administration. Therefore, the above dosage ranges are not intended to limit
the scope of the invention in any way. Administration of oxallplatin will typically be
5 according to best practice known to those skilled in the art at the time of administration
The present invention also provides methods of preparing the formulations of the present
Invcntion, Accordingly, in a further aspect there is provided a method for preparing a
phermnceutical formulation,the method compriating the step of
(i) dissolving coaliplatin in water to form a solution;
10 (ii) dissolving in the solution an additive selected from the group Conslating of a
pharmaceutically acceptable carboxylic acid, a unit of a pharmaceutically acceptable
carboxylic acid, a pharmaceutically acceptable derivative of a phurmaceutically acceptable
carboxylic acid and mixtures thereof;
(iii) optionally, adjusting the pH of the solution with a pharmaceutically acceptablc base
15 wherein the acid is not malonic acid, lactic add or oxalic acid
In another aspect the present invention provides it method for preparing a pharmaceutically
formulation the method comprising the steps of
(i) dissolving oxaliplatin in water to form a solution;
(ii) dissolving in the solution an additive selected hom the group consisting of a
20 pharmaceutically acceptable carboxylic acid, n salt of a pharmccutically accoptable
carbonic acid a pharmaceutically acceptable derivation of a pharmaceutically acccptablic
carboxylic acid and mixtures thereof;
(iii) optionially adjusting the pH of the solution with a pharmaceutically acceptable bass
wherein the carboxylic acid is of the formular
25 HO2C[C(R1)(R2)]nCO2H
Wherein n = 2 to 6; and Kl and R2 are each indcpcndcntly selected from the group consisting
of H, OH CO2H, halo and methyl.
Preferably,n = 2 to 4. More preferably, n = 2.

WO 2005/020980 PCT/AU2004/001168
13.
In yet another aspect the present invention provide a method for preparing a
pharmaceutical formulation, the method comprising the steps of:
(i) dissoiving oxaliplatin in venter to form a solution;
(ii) dissolving in the solution an additive selected from the group consisting of a tartaric
5 acid a salt of tartaric acid, a pharmaccutically acceptable derivative of a phammcmtically
acceptable tartaric acid and mixtures thereof;
(iii) optionally, adjusting the pH of the the solution with a pharmaceutically acceptable bane,
pH ndjustment may be carried out with any pharmaceutically acceptable base. Prefarably
the pharmaceutically aceptablc base is a sodium hydroxid (NaOH) solution,
10 In a further aspect,the present provides a pharmaceutical liquid formulation of
oxaliplatin for parentcral administration said formulation comprising
(i) about 5 mg/ml of oxaliplatin
(ii) water, and
(iii) an additive consisting of tataric acid and the sodium salt of trutaric acid,
15 wherein the concentration of the additive is about 0.2 mM and wherein the pH of the
solution is from about 4.7 to about 55.
The present invention also provides for the use of the formulation of the present invention
in the preparation of a medicament for the treatment of a cancer and in tho treatment of
cancer in petients.
20 In a still further aspect the present invention provides a method for preparing a
pharmaceutically formulation, the method comprising the steps of:
(i) dissolving oxcaliplatin in water to form a solution;
(ii) dissolving tartaric acid in the solution;
(iii) adjusting this pH of the solution with sodium hydroxide such that it is in the
25 range of from 4.7 to 5.3
wherein thc concentration of oxaliplatin is about 5 mg/ml and the concentration of tartaric
acid is about 0.2 mM,

WO 2005/020980 PCT/AU2004/001168
14.
In order that the naturo of the present invention may be more clearly understood, preferred
forma thereof will now be described with reference to the following non-limiting examples.
EXPERIMENTAL
Mcatrurement of Stability of Oxallplatin formulation
5 The stability of an oxalliplatin formulation over a period of time can be measured by a
number of complemantary methods. Visual appearance and stability of the pH of the
formulation arc Important lndication and these can be measurred by techniquent well known
to those skilled in the art.
Stabilty can also be measured by high preasure liquid chrenatography (HPLC) techniquea.
10 HPLC is a technique that is widely used and well known in the nm. HPLC can be used to
measure the potency of the oxaliplatin where potency is defined as a percentage of the Initial
concentration of oxaliplatin HFLC can also be uscd to measure the relative prorportions of
known and unknown degradants in an oxaliplatin solution.
Known degradation products of oxaliplatin includes
15 • (trans-Al,2diaminocylohexane)trans-dihyplatinum (TV). This a
oxidative degradation product of oxaliplatin, This degradotion product has been
designated as Impurity C in the Examples.
• (SP-4-2)-diaquas-[(lK,2R)-cyclohexane-l,2-diaminc-KN,KNplatium, or diaqua
DACH platinnum. This is a hydrolysis degradiation. product of oxallplatin. This
20 degradation product has been designated as inpurity B in the Examples.
• (SP-4-2)-di-µ-oxobis (1R,2R)-clyclohexane-1,2-diamine-KN,KN]platium,or diaqua
DACH platinum dimer. This is a degradation product resulting from further reaction
of impurity b. This degradation product hAs been designated as Dimer in the
Example’
25 R,S-oxaliplatin is an isoneric form oxaliplation which is found at low levels as impurity
In oxaliplatin (le de-oxalato(trans-/-1,2-diaminocyclohexane) platinunm(II)).
Overview of the Examples
Example 1 details an indilat trial of oxliplatin formulations using a number of agents over a
pH range from3 to 7 in which the abilty of tartaric acid, xxx acid, succnic and mulic
30 acids to stabilise oxattptatin was compound to a control. Of the acids lested, tartaric acid was

WO 2005/020980 PCT/AU2004/001168
15.
found to give the most stable oxlipletin solutions and it was subsequently lested across a
wide pH and concentration range as reported in Examplc 2. This study confirmed the
advantages of tartaric acid and also indicated that there was a preferred concentration range
for improved stability. A further study, imported in Example 3, then reviewed a number of
5 other acids at a set concentration (03 mM) as buffering agents In solutions of oxaliplation,
This should that formulations containing malic and xxx acid had Impurity level which
were comparable to the mtaric acid formulation, Contrary to the teaching of the prior act, -
the malenic acid formulation contained a surprisingly and unacceptebly high level of
impurities relative to the tartaric acid formulation. Solution containing citric, maleic and
10 saccharic acid also showed reassonably low levels of Impurtiy. The stablisura of the prior
art, oxalic acid and lavtic acid, also displaycd reasonably low levels of impurity which is
unsuprising in the case of oxalic acid due to the operation of Le Chatilike's principle.
Example 4 provides details of a preferred formulation of an aqueous solution, of oxaliplatin
and tartaric acid.
15 Examplc 1
The siability of on array of oxnliptattn formulation in water for injection (WFI) having nn
oxcaliplatin concentration of Smg/ml was assered. Potential buffering agents of oxaliplntin
that were heated were turtaric acid, malic acid, succinic acid and maleic acid. The pH of the
formulation covered 4 ranget of values.
20 Comparative Example l(a)
Preparation of the Control solution
WFI (water for injection) was added to a suitable glass vessel to about 80% of the desired
qunntity of final volume and warrned to 45-50ºC. While stiring and flushing with nitrogen,
the desired quantity of oxaliplatin (calculated at 5 mg/mL at the final desired volume) was
25 added and dissolved. The solution was then made up to the desired final volume with WFL
Example l(b)
Prepatation of Dicarboxylic Acid Solution
For the formulations described below, WFI was added to a suitable glass vessel to about 80%
or the desired final volume; and warmed 10 45-30ºC, While stirring and fiushing with
30 nitrogen, the desired quantity of oxailplatin was added and dissolved.Trusrcufter the
proposed stabilising dicarboxylic acid or its akali salt was added to the oxaliplatin solution

WO 2005/020980 PCT/AU2004/001168
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until completely dissolved Where required, pH was adjusted through the addition of dilute
NaOH solution. Thc solution so formed was made up to the final volume with WPI.
Table 1 Oxallplatin formulation containing malelc and malic acid based agents


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Table 3 Oxallplatin formulation containing tartaric acid based agents

Thc pH values used to deslgrate different formulations are indications only and do not
nocossarily reflect the exact pH of each solution. The exact initial pH values are provided, in
5 the tables above,
Example 1(c)
Stability Study
In accordance with an auxelurated stablity protocol, the formulations were stored at 40°C
with 75% relative humidity for 12 weeks,
10 The potency of the formulation was examine by high performance liquid chromatography
(HPLC) at 4 week intervals over tin 12 week period. Potency is dcfined as a pcrcentage of
the initial conentration of oxaliplstin. Most formulations maintained at least 95% potency
over the 12 week period. The exception to this was Maleic pH 7 which had u potency of
41.9% after the 12 week period. Matric acid could cot therefore be conidered as a viable
15 stabiliser.
In respect of the use of malic acid as an stabiliscr, the study of Malic pH 7 was tcrminatcd
after 4 weeks due to significant precipitation find colour changes wiihim the formulation.
Accordingly mulic acid could not be considered as n vinble stabiliscr. As is dixcusscd below
this result may have been a consequence of the high concenirations of the malic acid disoxdiunt
20 salt in the formulation.

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Only very low levels of the oxidativc degradation product Impurity C [(trans-/-1,2
dismlnoyclolicxano)trans-dilhydroxo(oxalato) platinum (IV)] wem detected in the
formulations, This indicated that the formulations were substantially free of oxygen.
Example 1(d)
5 Study of the Degradation Products of Oxaliplatin at 12 weeks
Formulations Control, Tartaric pH 3, Tartaric pH7, Succinic and Maletc pH 7 were
analysed after 12 weeks at 40°C with 75% relative; humldity for the prcpance of major
degradation products of oxaliplatin [inpurly B( dloque DACH platinun) and Dimer
(dloque DACH dimer)] using HPLC.
10 The chromatograms of the formulations are presented in figure l(a) . (e). The impurity
peaks at above 0.01% are reported.
Figure 1(a)
Control 40ºC 12 weeks
This system displays art impurity peak at 5.945 minutes corresponding to Inpurity B (dlaque.
15 DACH platinum) and a further peak art 9.897 minutes corresponding to Dirner (diaque
DACH platinum dimer), A further three unknown Impurity peaks are present, One it
present 3.909 minutes at a level of 0,03% and has at 3.026 and 3.386 minutes at 0.01%.
Figure l(b)
Tartarlc pH3 40ºC l2 weeks
20 An impurity peak is present at 5.932 minutes which has been allocated to impurity 0 (diaque
DACH platinum). There is also present an inpurity at 3.906 minuter. There is no inpterity
peak corresponding to Dimer (diaqua DACM platinum dimer).
Figure 1(c)
Tartaric PH7 10ºC12 weeks
25 This system displays an impurity peak is present at 5.931 minutes which corresponds to
Impurity B (diaqua DACK platinum). There an also three unknown impurity peaks eluted
at 3.027 minutes,3.367 minutes and 3.906 minutes at the level of 0.01,0.01 and 0.03%

WO 2005/020980 PCT/AU2004/001168
19.
respectively. There is no impurity peak corresponding to Dinver (disque DACH platinum
dirner).
Figure 1(d)
Succinic pH7 400C12 weeks
5 This system display a large number of unknown impurity peaks. These are present at 3.075
mintes, 3.381 xxx, 4.007 minutes, 4.164 minutes, 4.368 minutes, 6512 minutes and 7,681
minutes, An Imptirlty peak is also present at 5.954 minutcs which corresponds to impurity 0
(dlaqua DACH platirium).
Figure l(e)
10 Maleic Add pH7 40º 12 weeks
The system displays a large number of unknown impurity peals present at 2.587 minutes,
2.751 minutes, 2.880 minutes, 3.012 minutes, 3378 minutes, 3.399 mintues, 3.963 minutes,
4,203 minutes and 5.539 minutes,
it is clear from visual compariacn of the xxx that the turtaric acid stabilised.
15 formulation are for more stable than the acid andxxx acid stablised
formulation. In addition, in compurision to the chronatogram of the control formulation,
the formation Dimer (disque DACH platinum-dimer) is suppressed in the tartaric acid
stablised formulation, furthcr, at least in the case of the Tartaric pH 7 formulation,
signicantly less Impurity B (diaqua DACH platinum), the principle degradant is formed.
20 ln addition the tartaric acid stabillcd formulations do not display as many unknown
impurity peaks as the control formulation.
Example1(e)
Study of the Degradaation Products of Oxaliplatin at 6 weeks
Formulation Control, Tartaric pH 3, Tartaric pH 5 and Tartaric pH7 werc anaiysed eftar 8
25 weeks at 40ºC with 75% relative humidily for the presunence
oxaliplatin using the HFLC protocol of Example 4.
The chromatograms are presented in Figure 2 (a)-(e)

WO 2005/020980 PCT/AU2004/00116820.
20
Figure 2(a)
Control 40º weeks
This system displays an Impurity peak at 6.301 minuted corresponding to Impurity B (dlaqua
DACH platinum) and a further peak at 10.145 minutes corresponding to Dinner (diaqua
5 DACH platinum dimer). An unknown impurity peak is present at 3,913 minutes.
Figure 2(b)
Tartaric pH 3 40ºC 8 weeks
This system displays on impitrity peak at 6.306 minutes corresponding to Impurity B (dinqua
DACH placuium). There is no peak corresponding to the prescnce of Dimer (diaqua DACH
10 plattrum dincr). An unknown Impurity peak is present at 3.91 minutes.
Figure 2(c)
Tartaric pH 5400C 8 weeks
This system displays an impuity peak at 6.306 minutes corresponding to impurity B (diaqua
DACH platinum). There is no significant peak corresponding to the presence of Dimer
15 (diaqua DACH platinum dimer). An unknown Impurity peak is present at 3.911 minutes.
Figure 2(c)
Tartaric pH 740ºC B weeks
This system displays an impurity peat at 6.306 minutes corresponding to impurity B (diaqua
DACH platinum). There is no significant peak corresponding to the presence of Dimer
20 (diaqua DACH platium dimer), An unknown impurity peak is present at 3.913 minutes
In composition to the chromatogram of the control formulation,Dinner(disquaDACH
platium dimer)formulation is suppressed in thc tartaric acid stabillsed formulation.
Summary
It is clear from a Visual comparison of the chromatograms of Figure 1 and 2 that the fartaric
25 acid stabilised fomulation of oxaliplatin are far more stable than the maleic acid and
succinic acid countaining formulation, In addition, In comparison to the chromatogram of
the control formulation the formulation of Dimer (disqua DACH platinum dimer) is

WO 2005/020980 PCT/AU2004/001168
21.
suppressed in the tartoric add stabilised farmulation and, In some cases, significantly lose
Impurity B (disqua DACH platinum), the principle degradant, is formed. Further, the
tartaric acid stabiliacd formulations do not display as many unknown Impurity peaks us the
control formulation which is of importance in meeting the guide lines of the lCH and also in
5 minimising any side effects due to the presence of unknown inpurities. The increased
wtabilty of the oxaliplatin formulations applies across a range of pH values.
Although malic acid and mucinic acid were considered as unsuitable agents following this
cxperiment, later lnvestigations, us detailed in Example 3, demonstratcd that malic acid
succinic acid and malic add can be used with oxaliplatin. A possible reason for the initial
10 finding that these formulations were unsuitable is because of the relatively high
concentrations of certain of the succinic And malic acid formulations used in Example 1. For
instance, the succinic pH 3 formulations has a concentration of succinic acid of about 1,10 mM
and the Succnic acid pH 7 formulations has a concentration of disodium salt of succlnic acid
of 633 mM. Similarly, the concentration of malic acid disodium salt in the malic pH 7
15 formulation is 8.42 mM The concentration of maleic acid in the Maleic pH 7 formulation is
about 6.1 mM. By contrast the tartaric acid corcentrations of the formulation of the
Example range from about 0.2 to about 0.3 mM.
Example 2
21 Background
20 This Example was conducted to further investigate the effect of different a amount of tartaric
acid and the effect of pH an the stability of oxaliptatin solution formulations. The tartaric
acid formulations were compared to a control formulation of oxaliplation water and to a
formulations of oxalipation in oxalic acid solution (according to US 6,306,902).
22 Preparation of formualtions for analysis
25 2.2.1 Mixing procedure for the formulations
• Add about 80%mL of desired amount of WFI into a 21 xxx vessel and heat to 45-
50ºC while stirring and flushing with nitrogen.
• Add oxaliplatin (total: 7.5g) and mix until solution becomes clear.
• Adjust to the volume with WFI to 1500 mL
30 • Divide the bulk solution to 100 mL each. Keep one l00mL solution as the control.

WO 2005/020980 PCT/AU2004/001168
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• Add the require amount of tartaric acid solution 5% w/y or oxalic acid and NaOH
(ION, 5N and/m 2N) attending to the formulation detail in Table 5 and 6,
• Cap the final solution and keep in the fridge untel filling.
222 filling and capping
5 • Filter each fomulilation using a 0.2 pm syringe filter.
• Fill 2.0 mL of each formulation filled into it Zml vinl and cap.
Table 5 and 6 indicated the quantities of reagents added for each different formulation.
Table 4 Formulation detain for the axollplatin solution a containing tataric add of
Example 2
10

Note: Molecular weight of tartaric acid -150.09
A = formulation containing tartaric acid at 0,0045% (03 mM)
B = formulation containing tartaric acid at 0,009% (06 mM)
15 C = formulation containing tartaric acid at 0,045% (03 mM)
D =formulation containing tartaric acid at 0.01% (6.7 mM)
E = Fomulation containing tartaric acid at 0.003% (02 mM)

WO 2005/020980 PCT/AU2004/001168
23.
Table 5; Quantity of oxaliplatin and exciplents required to be used for the
preparation of the oxaliplatin soutious containing tartaric acid of Example
2

5 Table 6 Formulation details for the oxallplatin control formulation and oxaplatin
Solution containing oxalic acid of Example 2.

Note: In the intial screening, live pH 3 tartaric formulation was formulated it pH 3.78.

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23 Stabilty Measurement at thc intial Time Point
All of the oxaliplatin formulation; at the Intial time point were clear, colourless solution
with no visible particles prcscnt in solution, The appearance of the solurtion are set out in
Table 7. Measurements of the pH results of the formulations are also shown in Table 7.
5 Table 7 Test Results for pH and Appearance of Oxaliplatin Solutions of example
at inltial Time point

24. Stabiltiy Measurements
10 The formulations were then stored at 25ºC and 40°C
The appearence of the formulations was assessed at the Intial 4 weak and 8 week time
points. Each fomulation remained clear and colouress.
The pH of the formulations was measured at the intial, 4 week and 12 weak time points for
25°C as shown in Table 8 and for 40ºC as shown in Table 9.

WO 2005/020980 PCT/AU2004/001168
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WO 2005/020980 PCT/AU2004/001168
26.
2.4.1 ponteney eassy
Formulations A4, A5, A7, B7, C7, E4, E7, Oxalic and the Control wcre maintained at 25°C and
40°C and were assayed for potency by HPLC after 12 weeks. Table 10 reports the impurity
profile deteimined from the potency assay for 25ºC Table 11 reports the impurity profils
5 deternimed from the potency assay for 4CºC
Table 10 Impurily profile from the potency assay for certain oxaliplatin formulations
of Example 2 at 12 weeks time point at 250C

10
Table 11 Impurily profile from the potency assay for certain oxaliplatin formulations
of Example 2 at 12 weeks time point at 400C


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27.
2.42 Impurity B Assay
The level of impurity b of the formulations maintained at 25ºC was assayed by HPLC after
12 weeks for A4, A5, A7,B7,C7,E4,E7,Oxalic and the Control. Table 12 reports the
impurity profile determined from that Impurity B assay for 25ºC. The level of impurity B of
5 the formulations maintained at 40ºC was assayed by HFLC after b weeks. Table 13 reports
the impurity profile dcterminied from that impurity B assay.
Table 12 The levels of Impurity B and other unknown impurities from lmparily B
assay in certain formulations of Example 2 at 12 weeks time point at 25ºC

10
Table 13 The levels of Impurity B and other unknown impurities from lmparily B
assay in certain formulations of Example 2 at 12 weeks time point at 40ºC


WO 2005/020980 PCT/AU2004/001168
28.
25 Stability Measurements at 9 months
Furmulations A40, A50, A7.0, E4.0 and E7,0 were stored at 25°C and 40ºC for 9 months and
then analysed for pH and lmpurities.
5 2.5.1 Results and Discussion
2.5.1.1 Appearance Results
Appearance was clear, colouricess with no viable particulate matter present in most of the
formulations (Table 14).
Table 14 Appearance of oxailplatin solutions at different time point at 25ºC
10

N = a clear, colourless solution with no particulate matter present in solution
N = a clear, colourless solution with few particulate matter present in solution
N = a clear, colourless solution with some particulate matter present in solution
N/t = not tested
15

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29.
2.5.1.2 Impurity B Assay
Lcvels of Impurity D and Dimer in formulations Control A4, A5, E4 and E7 at 9 months for
both 25ºC and 40ºC were assessed using HPLC. The results are shown in Table 15 and 16,
respectively
5 From the essay, the formulation A4, A5, E4 and E7 contained less total impurity then
control at 25ºC- M 40ºC formulations A4, A5 and EA containcd less total impurity than the
control. In all cases the Dimcr impurity was suppressed relative to the Control and Indeed
was not delected in formulations A5, A7 and E4.
Table 15 The % of impurity R and other unknown impurities from impurity B assay
10 in certain farmulailons of Examplc 2 at 25ºC for 9 months.

ND=not detected.
Table 16 The % of impurity R and other unknown impurities from impurity B assay
in certain farmulailons of Examplc 2 at 9 months time point at 400C.
15

ND=not detected.
2.6 Summary
The screening study indicated that tartaric acid is a suitable stabilising agent for oxaliplatin
at n range of concentration. In terms of the ability of tartaric acid to stablise the oxaliplatin
20 concentration of 0.2 mM and 03 m.M (formulations E and A respectively) are preferred,
although formulations at 0,6 mM (formulatiors B) also demonstrated some stabillsing effcet.

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formulation was then flushed with nitrogen until the dissolved oxygen content in solution
was below 0.05 ppm.
3.1.1.3 Filing and capping
Each fomulation was filtered using a O2.pm syringe flilter. Then 5 mL of the solution was
5 placed into a 10 mL vial, and capped and sealect for each formulation.
3.1.2 Formuation Details
Table 19, 30 and 21 show the formulation details and quantities of oxaliplation and excipients
Needed for each formulation.
Table 19 Formulation details for the oxaliplatin solutions of Example 3 (unit
10 formula)


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Example 3
As shown in Example 1, a formulation acrconing study showed that the presence of turtunic
add in an oxaliplatin solution can suppress thc formulation impurities relative to a control
solution and thereby stabilise the formulation. The studies discruseed in Example 2 Indicated
5 that the total concentration of tartaric acid in the formulation was of importance lit providing
a stabillising effect. The possibility existed that other carboxylic acids may have the xxx
stabilising effect. This study Involved the screening of a range of carboxylic acids (other than
tartaric acid) at a set concentration (0.3 mM) in oxaliplatin solution. The formulation were
placed at 40ºC for 5 weeks ond then evalunted for stability. Thc performance of the
10 formulation were compared to a solution of oxaliplatin containing tortaric acid at 0.3 mM.
31. Expermental
The following acid were used in the study:
Tartaric acid Malaic acid
Tactic acid D-Saocharic acid
15 Citric acid anhydrows Suodnic acid
Malonic acid Oxalic add
Malic acid
3.11 Procedure for making 1% acid solutions
Each acid was weighed separately into a 100mL volunrntric flask. The solutions were made
20 up to final volume after dissolving the acid completely.
3.1.2 Preparation of oxaliplatin formulations
About 80% mL of the desired amount of WFl was added into a clean glass beaker and heated
the WEI to 50ºC -55ºC, while stirring and flushing with nitrogen. The oxaliplatin was then
added to the beaker and mixed until clear Solution was obtained (about 50 minutes was
25 needed in achieve complete disolution of oxaliplatin), The solution was then made up to
volume with WFL The bulk solution was divided into 100 mL quantities and the requited
amount of add solution was added to each 100 mL quantity according to Table 20. Each

WO 2005/020980 PCT/AU2004/001168
32.
Table 20 Quentily required for oxaliplatin solution of Example 3

Table 21 Actual quanilty added for the oxaliplatin solutions of Example 3
5

Sacctraic acid was added as powder in 100 mL bulk solution to give 0.3 mM acid
concentration.

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3.2 Stability evaluation at Sweelon at 40ºC
The oxaliplatin solutions containing the various carboxylic acids were formulated and place
at 40ºC at 75% for stabilty evalution. The formulations was evaluated at the five weeks time
points and the results are reported below.
5 3.2.1 Results and Discussion.
3.2.1.1 pH and Appearance
The pH and apperance result for the formulations of Example 3 are shown in Table 22.
Table 22 Appearance and pH of oxaliplatin formulations of Example 3 for 5 weeks

10 N=clear colourless solution with no visoble particles.
N=clear colourless solution with few black particles.
N=clear colourless solution with many white particles.
N/t=not tested.

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3.2.1.2 Potency and Impurity Results
The potency of the formulations of Example 3 was measured by HPLC after 5 weeks at 40ºC
(Table 23). Each of the formulations maintained a polency above 95%.
Table 23 Potency results at initials and 5 weeks for the oxaliplatin solution of
5 Example 9 at 45ºC

The formulations of Examp1e 3 also assayed by HFLC for the presence of impurity b
and Dimer after 3 weekss 40ºC Table 24 reports the results of this assay.

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35.
Table 24 Test results at 40ºC of the formulations of Example 3 for
impunity B and the dimer Impurity.

ND:None delected
5 Table 25 summarises the impurity profile obtained from the assay for potency by HFLC
which was carried out by IIPLC at the 5 week time points.

WO 2005/020980 PCT/AU2004/001168
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Table 25 Impurity profile from potency assay for oxaliplatin solution formulations of
Example 3 at the 5 weeks time point at 40ºC

The total impurity levels for the Example 3 formulation From the HFLC assay for potency
5 and the HPLC assay for impurity B after 5 wceks at 40°C are shown Table 26.
Table 26 Total impurity for oxaliplatin solution formulations of example 3 at 5
weeks time point at 40ºC


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3.3 Summary
Formulation containing malic and succinic acid showed impurity levels which were
comparable to the tartaric arid formulation. Contrary to the teaching of the prior art, that
molinic add formulation contained a surprisingly and unacceptably high level of impurities
5 relative to the tartaric acid for formulations. Solutions containing citric, maleic and saccharic
acids also showed reascerably low levels of Impurity and would be considered to be sutable
buffering agent for oxaliplation. The stabillsers of the prier art, oxalic acid and lactic acid,
also displayed reasonably low levels of Impurity which is unsurprising in the case of oxalic
acid due to the operation of Le Chatalier's principle.
10 Example 1
The following formulation was prepared for the purpose of regulatory testing:
Oxaliplatin 5mg
Tdrtvkadd 0.03mg
NaOH (adjust to pH of approcdmately 5)
15 WFI qe mL
The pH is adjusted to pH 5 with a range of from 4.7 to 5.5 using NaOH. The concuntration of
tartaric acid is about 0-2 mM.
Throughout this spedfication, the word "canprise,* or variations such as "comprises" or
'comprising' will understood to Imply the inclusion a stated element, integer or step, or
20 groups of elements intogers or steps, but not the exclusion of any other element, integer or
step, or groups of elements, integers or steps.
Any discussion of documents, acts, materials devices, articles or the like which has been
included in the present specfication is solely for the purpose of providing a context for the
present invention. It is not to be taken as an admission that any or all of these matters form
25 part of the prior art base or were dumnon general knowledge in thc field relevant to the
present invention as it existed in Australla before the priority date of each claim of the
application.
It will be apptreciatcd by persons skilled in the art that numerous variations end/or
modifications may be made to the invention as shown in the spedcific embodiments without

WO 2005/020980 PCT/AU2004/001168
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deputing front the spirit or scope of the invention as broadly described. The present
embodiments are, therefore, 10 be considered in all respects as illuatrntive and not restrictive.

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CLAIMS
1. A pharmaceutical liquld formulation of oxaliplatin for parentoral administration,said
formulation comprising
(i) oxatiplatin;
5 (ii) water, and
(iii) an acid
wherein the acid is stabllising and is not malonic acid, lactic acid or oxalic acid.
2. A formulations according to claim 1 or claim 2 wherein the acid is a carboxylic acid.
3. A formulations according to claim 1 or claim 2 wherein the acid ln a discarboxylic acid.
10 4. A formulations according to any one of claim 1 to 3 wherein the acid is a selected from the
group consisting of citric acid, maleic acid, saccharic acid, succinic acid malic acid, totaric acid
and mixtures thereof.
5. A formulations according to any one of claims 1 to 4 wherein the acid, tartaric from, the
group consisting of malic acid, succinic acid, tartaric acid mixtures thereof.
15 6. A formulations according to any one of claims 1 to 5 Wherein the add is tartaric acid,
7. A formulations according to any one of claim l to 6 wherein the acid is at a concentration of
at least 0.01 mM.
8. A pharmeceutical liquid formulation of oxaliplation for parenteral administration, said
formulation comprising
20 (i) oxaliplatin;
(ii) water; and
(iii) an acid comprising at least 4 carbon atoms.
9. A formulations according to claim 8 wherein the acid is a dicarboxylic acid.
10. A formulations according to claim 8or claim 9 wherein the acid comprises 4 to 10 carbon
25 atoms.

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40.
11. A formulations according to any one of claims 8 to 10 whereien the acid comprises4 to 6
carbon atoms.
12. A formulation according to any one of claims b to 11 wherein the acid comprises 1 or 2
hydroxyl groups.
5 13. A formulation according to any one of claims 8 to 11 wherein the acid is selected from the
group consisting of citric acid malcic acid, saccharic acid, succinic acid malic acid, tartaric acid.
and mixtures thereof.
14. A formulation according to any one of claims 8 to 13 wherein the acid in selected from the
group consisting of malic acid, succinic acid, tartaric acid and mixtures thereof.
10 15. A formulation according to any one claim 8 to 13 wherein the acid is turturic acid.
16. A formulation according to any one claim 8 to 13 wherein the acid is at a comuatration
of at least 0.01 mM.
17. A pharmaccutical liquid formulation of oxaliplatin for parentaral administration, said
formulation comprising
15 (i) oxaliplatin,
(ii) water and
(iii) an additive selected from the group consisting of a pharmacetically acceptable carboxylic
acid, a salt of a phamaceutically acceptable carboxylic acid, a phormaceutically acccptable
derivative of a phamaceutically acceptable carboxylic acid and mixtures thereof;
20 wherein the additive is at a concentration of at least 0.01 mM and wheiein the acid is not malonic
acid, lactic acid or oxalic acid.
18. A formulation according to claim 17 wherein the acid is a discarboxylic acid.
19. A formulation according to claim 17 wherein the acid is selected from the group consisting
of citric acid, malcic acid xxx acid xxx acid, malic acid tartaric acid and mixtures
25 thereof.
20. A phamaceutical liquid formulation of oxaliplatin for parentenal administration, said
formulation comprising
(i) oxaliplatin,
(ii) water; and

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41.
(iii) on additive selected from the group consistring of a pharmaceutically acceptable carboxylic
acid, a self of a pharmacutically acceptable carboxylic acid, a pharmaceutically acceptable
derivative of a pharmaceutically acceptable carboxylic acid and mixtures thereof;
whenein the additive is at a concentration of at least 0.01 mM and whcrcin the carboxylic acid is of
5 the formula:
HO2C [C(RI)(R2)]nCO2H
whercin n = to 6; and Rl and R2 are each indepdently selected from the group consisting Of H,
OH,CO2H,inelo and methyl.
21. A formulation according to claim 20 wherein n=2 to 4.
10 22. A formulation according to claim 20 wherein the acid is selected from the group consisting
of citric acid, saccharic acid, succnic acid, malic acid. tartaric acid and mixtures thereof.
23. A formulation according to any one of claim of claims 17 to 22 wherein the carboxylic acid is
selected from the group consisting of malic acid, succinic tartaric acid and mixtures theereof
24. A pharmaceutical liquid formulation according to any one of claims 17 to 23 wherein the
15 pharmaceutical acceptable carboxylic acid is tartaric acid.
25. A pharmaceutical acceptable formulation of oxaliplatin for parenterul administration, said
formulation comprising
(i) oxaliplation,
(ii) water, and
20 (iii) an additive selected from the group consisting of tartaric acid, a salt of tartaric acid, a
pharmaceutically acceptable dcrivative of tartaric acid and mixtures thereof;
wherein the additive is at a concetration of st least 0.0l mM
26. A formulation according to any one of claims 17 to 25 wherein the concerrtration of the
additive is from about 0.01 mM to about 20mM.
25 27. A formulation according to any one of claim 17 to 26 wheiein the concentration of the
additive is from about 0.01 mM to about 20 mM.
28. A formulation according to any one of claims 17 to 27 wherein the concentration of the
adiditive is from about 0.1 mM to about 0.6 mM.

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29. A formulation according to any one of claims 17 to 28 wherein the wherein of the
additive is from about 0.2 mM to about 0.6 mM.
30. A formulation according to any one of claim 17 to 29 wherein the additive comprises a salt
of a pharamacontically acceptable acid and wherein the salt is to sodium salt.
5 31. A formulation according to any one of claim 1 to 30 wherein the concontration of
oxaplation up to about mg/mL.
32. A formulation according to any one of claims 1 to 31 wherein the concentration of
oxallplatin up to about 7mg/ml.
33. A formulation according to any one of claims 1 to 32 wherein pH of the formulation is
10 in the range of from about 3 to about 7.
34. The use of pharmaceutical formulation according to anyone of claims 1to 33 to the
preparation of a medicement for the treatment of a cancer.
35. A method/or treating a cancer which comprise administering a pharmaceutical
formulation according to any one of claims 1 to33 to a patient in need thereof.
15 36. A method for preparing a pharmaccutical formulation, the method comprising the steps of;
(i) dissolving oxaliplatin in water to forma solution from the group consisting carboxylic
(ii) dissolving in the solution an additive solected the group consistinf of a
pharmaceutically acceptable carboxylic acid, a salt of a pharmactutically acceptable carboxylic
acid, a pharmuceutically acccptable derivative of a pharmacountially acceptable carboxylic acid
20 and mixtures thereof;
(iii) optimally, adjusting the pH of the solution with a pharmasuutically acceptable base
wherein ihe acid is not maloric acid, lactic acid or oxalic acid.
37. A method according to claim 36 wherein the acid is a dicarboxylic acid.
38. A method according to claim 36 wherein the acid is selected from the group consisting of
25 citric acid, malcic acid, saccharic add, succinic acid, malic acid, tartaric acid and mixtures thereof,
39. A method for preparing a pharmacutical formulatical, the method comprising the steps of;
(i). dissolving oxaliplatin in water to form a solution;
(ii) dissolving in the solution an additive selected from the group consisting of a
pharmacutically acceptable Carbonylic acid, a salt of a pharmacutically acceptable carboxylic

WO 2005/020980 PCT/AU2004/001168
43.
acid, a pharmacutically acceptable derivative of a pharmacutically acceptable carboxy acid
and mixtures theceof;
(iii) optionally, adjusting the pH of the solution with a pharmacutically acceptable base
wherein the carboxylic acid is of the formula:
5 HO2C(C(RI)(R2)toCO2H
wherein n a 2 to 6; And Rl ond R2 are each indcpendcntly selected from the group conslating of H1
OH, CO2H, halo end methyl.
40. A method according to claim 39 wherein n 2 to 4.
41. A method according to claim 39 wherein the acid is selected from the group consisting of
10 citric acid saccharic acid miccinic acid mailc acid rartatic acid and mixtures thereof
42. A method according to any one of claim 36 to 41 wherein the carboxylic acid is selected
from the group consisting of malic add, succinic acid, tartaric acid. and mixtures thereof.
44. A method for preparing a pharmaceutical formulation, the method comprising the stupe of;
(1) dissolving oxaliplatin in water to form a solution;
15 (ii) dissolving tn the solution an additive selected from the group consisting of a tartoric acid, a
salr of tartaric acid, a pharmaceutically acceptable derivativc of a pharmaceutically acceptable
tartaric acid and mixtures thereof;
(iii) optionally, adjusting the pH of the solution with a phamacentically acceptubic baso.
45. A method according to any one of claims 36 to 44 wherein the concentration of the additive
20 is from about 0.01 mM to about 20. mM
46. A method according to any one of claims 36 to 45 wherein the concentration of the additive
is from about 0.I mM to about 1.0 mM.
47. A method according to any one of claims 36 to 46 wherein the concentration of the additive
is from about 0.l mM to about 0.6 mM.
25 48. A method according to any one of claims 36 to 46 wherein the concentration of the additive
is from about 0.2 mM to about 0.6 mM.
49. A method according to any one of claims 36 to 48 wherein the additive comprises a salt of a
pharmaceutically acceptable acid and salt is a sodium salt.

WO 2005/020980 PCT/AU2004/001168
44.
50. A method according to any one of claim 36 to 49 wherein the concentration of oxaliplatin
is up to aboul 15mg/ml.
51. A method according to any one of claims 36 to 49 wherein the concentration of oxaliplatin
is up to about 7 mg/mL
5 52. A method according to claim 51 wherein the concentration of oxallplatin
53. A method according to any one of claims 36 to 49 wherein the pharmaceutically acceptable
base is sodium hydroxide.
54, A formulation according to any one of claim 36 to 53 wherein the pH of the formulation is
adjusted to be in the range of from 3 to 7.
10 55. A pharmaceutical liquid formulation of oxaliplatin for parenteral administration, said
formulation comprising
(i) about 5mg/ml of oxaliplatin
(ii) water, and
(iii) an additive conslsting of tartaric acid and the sodium salt of tartaric acid,
15 whenein the concentration of the additive is about 0.2 mM and wherein the pH of the solution is
from about 4.7 to about 5.5.
56. This use of a pharmaceoeutical formulation according to claim 55 in the preparation of a
medicament for the treatment of a cancer.
57. A method for treating a cancer which comprises administrering a phermaceutical
20 formulation according to claim 55 to a patient in need thereof.
58. A method preparing a pharmaceutical formulation, the method comprises the steps of;
(i) dissolving oxaliplatin in water to form a solution;
(ii) dissolving tartaric acid in the solution;
(iii) adjusting the pH of the solution with sodium hydroidde such that it is in the range of from
25 4.7 to 5.5
wherein the concentration of oxaliplatin is about 5 mg/ml and the concentration, of tarteric acid is
about 0.2 mM.

The is provided a pharmacutical liquid formulation of oxaliplatin for parental xxx, said formulation
comprising (1) oxaliplatin; (ii) water, and (iii) an acid wherein the acid is xxx and is not malomic acid, tactic acid or oxalic
acid. Method of preparing the formulation are also disclosed. There is furture provided the use of the formulation in the preparation
of a modicament for the treatment of cancer and a method for treating cancer which comprises admintaring in therepentic amount
of a phamacontical formnulation.