GB2441445A

GB2441445A - Acid containing oxaliplatin formulations

Info

Publication number: GB2441445A
Application number: GB0718274A
Authority: GB
Inventors: Darryl Vanstone Whittaker; Aikun Julie Liu
Original assignee: Mayne Pharma Pty Ltd
Current assignee: Mayne Pharma Pty Ltd
Priority date: 2003-08-28
Filing date: 2004-08-27
Publication date: 2008-03-05
Anticipated expiration: 2024-08-27
Also published as: GB2441445A8; GB0718274D0; GB2441445B

Abstract

There is provided a pharmaceutical liquid formulation of oxaliplatin for parenteral administration, said formulation comprising (i) oxaliplatin; (ii) water; and (iii) an acid wherein the acid is stabilising and is not malonic acid, lactic acid or oxalic acid. The acid may be citric, maleic, saccharic, succinic, malic or tartaric acids or mixtures thereof. Methods of preparing the formulation are also disclosed. There is further provided the use of the formulation in the preparation of a medicament as above for the treatment of cancer.

Description

ACID CONTAINING OXALIPLATIN FORMULATIONS

FIELD OF THE INVENTION

The invention relates to formulations containing oxaliplatin.

BACKGROUND OF THE INVENTION

Oxaliplatin is an anticancer agent. Oxaliplatin (CAS 61825-94-3), also known as L-OHP, is a third generation platinum complex. The term "oxaliplatin" as used herein includes cis-oxalato(trans-1-1,2-diaininocydohexane) platinum(ll), its optic enantiomer cis-oxalato(trans-d-1,2-diaminocyclohexane) platinum(ll), and any mixture thereof.

Oxaliplatin is currently approved and marketed for second-line treatment of colorectal cancer in combination with 5-FU and LV. Oxaliplatin is available in a lyophilised form (20 mg, 50 mg or 100 mg vials). Just prior to administration, the lyophilised powder is reconstituted using water for injection or 5% glucose injection solution to provide a solution containing 5 mg/mI oxaliplatin. Typically, the reconstituted solution is then further diluted in 250-500 mL of 5% glucose injection solution. The diluted oxaliplatin solution is then infused either by peripheral vein or central venous line over 2 to 6 hours.

Lyophilized oxaliplatin has some disadvantages as a pharmaceutical form. The manufacturing process for a lyophilised dosage form is complicated and expensive. For example, the risk of sterility failure during manufacture of freeze dried forms is generally higher than is the case for liquid solutions. In addition, the reconstitution of freeze dried preparations requires both skill and care as it involves several risks, inter alia, incomplete dissolution of the powder, contamination through handling a highly toxic substance as a powder or cake, and maintaining the sterility of both the vial and the infusion solution during reconstitution and transfer to the infusion bag. Thus, to administer a lyophilized drug, multiple handling of the drug is required -the lyophilised oxaliplatin is first reconstituted, then diluted with a 5% glucose solution and then administered by intravenous infusion.

Further, following reconstitution, oxalipla tin is prone to instability, particularly in solutions containing certain riucleophilic agents. For example, some reconstitution solutions containing chloride ions, such as 0.9% sodium chloride solution, are commonly used in hospitals. The mistaken use of such a reconstitution solution in the case of the lyophilized form of oxalipla tin has the serious consequence of rapidly decomposing the oxaliplatinurn 2.

metal complex, forming a precipitate (dichioro-diaminocyclohexane-platinum derivative) with NaC1.

As a consequence of the limitations described above, several stabilised aqueous ready-to-use (RTU) liquid oxaliplatin preparations have been proposed: 1. US 5,716,988 and AU 731981 disclose a pharmaceutical formulation consisting of a 1 to 5 mg/mL solution of oxaliplatin in water having a pH range of 4.5 to 6.

2. WO 99/43355 and US 6,306,902 disclose an oxaliplatin solution formulation containing 1 to 7 mg/mi oxaliplatin, a buffering agent and a pharmaceutically acceptable carrier. The preferred buffering agent (and only example) is oxalic acid or an alkali metal salt thereof.

3. WO01/15691 disdoses solutions of at least 7mg/mi oxaliplatin containing a solvent containing a sufficient amount of at least one hydroxylated derivative selected from 1,2-propane-diol, glycerol, maltitol, sucrose and inositol. The specification states 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 buffer should have an oxa]ic acid base.

4. US 6,476,068 discloses an oxalipla tin solution formulation comprising 0.1 to 10 mg/mi oxaliplatin, an effective stabilizing amount of the monocarboxylic acid, lactic acid, and a pharmaceutically acceptable carrier. The preferred concentration range of oxaliplatin is 2 to 5 mg/mi.

5. US Patent Application No. 20030109515 discloses an oxaiiplatin solution formulation containing a stabilising amount of malortic acid. The examples are directed to formulations having an oxaliplatin concentration of 2 mg/mI. In contrast to the teaching of this application, and as is discussed below, the present inventors have found that malonic acid destabilises oxaliplatin in solution.

Buffering agents are used in liquid pharmaceutical formulations to adjust the pH of the 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 aqueous solutions of oxaliplath by hydrolysis, thus conceivably this reaction may be slowed (using Le Chatelier's principle)

J 3.

through purposeful addition of ccalate Ion to solutions of ocaliplatln. However, oxalic acid has some disadvantages as a pharmaceutical buffering agent, notably It's toxicity. Oxalic add Is potentially nephTotoxlc and also requires special handling precautions, which complicate end limit Its use In pharmaceutical product& There is a need for agents that can be used with oxaliplatin solutions as alternatives to the prior art buffering agonts (oxalic acid, lactic acid and malonic acid) and which do not have the disadvantages associated with the use of oxalic acid.

Ideally, the alternative agonts would not dostabilisb uxaliplatin in solution. In particular, it * would be useful if the altvntativc agents improve the stability of oxaliplatin in aqueous * 10 funnulationa in a xnLmrlcr that mininisca thgui&ant degradation of oxaliplatht and limits the formation of unwanted impurities such as diaquo DACH platinum and diaquo DACH platinum dimcr.

Further, it would be preferable to limit the amount of unknown degradation products in the aqueous formulation. Any unknown degradation product present man amount exceeding the thresholds set in the guidelines of the ICH (International Conference on Harinoidsation of Technical Requirements for Registration of Pharmaceuticals for R'imn Usc) is required to be identified. This imposes significant requirements on the manufacturer of the formulatio as they axe required to identify trace amounts of an unimown degradation product In addition, the presence of wkrwwn degradation piuducts is an indication that there may be additional rzsl of toxicity and unknown side-ccb as a cwwcqucncc of the presence of these products. It is therefore of interest to a nriinufactuivr of a formulation to avoid producing unknown degradation products.

* Ideally, additional pharmaceutically acopl&ble buffering agunts should be non-toxic and be * present in the alleet possible quantity. Furthermore, during uranufacture they should be intiuduced in the safest and most convenient mamicrposslblc.

SUMMARY OF THE INVENTiON

In a first aspect the present invention provides a pharmaceutical liquid formulation of oxaliplatin for parenteral administration, said formulation comprising (I) oxaliplatin; (il wateiand (lii) wiadd wherein the acid Is stabilising and is xbt malonic acid, lactic acid or oxa]ic acid.

In a second aspect the present invention providc a pharmaceutical liquid fomtulatlon of * oxaliplatin for parenteral administration, said formulation comprising * (I) oxaliplatht; (ii) watnd (iii) an acid comprising at least 4 carbon atoms.

In a third aspcct the present invention provides a pharmaceutical liquid fonzmlation of oxaliplatin for paronteral administration, said forimlatlcit comprising " (ii) water; and (iii) an additive selected from the group consisting of a pharmaceutically acccpthblc carboxylic add, a salt of a pharmaceutically acceptable carbxylic add, a phannaccutically acceptable dcrjvative of a p1armaceutIca11y acceptable carboxylic acid and mixturca thereof; wherein the additive is at a concentration of at least DM1 mM and whcrcin the acid is not malcnic add, lactic acid or oxallc add.

in a fourth aspect, the present Invention provides a pharmaceutical liquid formulation of * oxaliplatin for parenteral administration, said fommiatlon comprising (I) oxallplatin, (ii) watmand (iii) an additivo selected from the group consisting of a pharmaceutically acceptable carboxylic acid, a salt of a pharmaceutically acceptable carboxylic acid, a pharmaceutically acceptable derivative of a phnrmaceutlea]ly acceptable cerboxylic acid and mixtures thereof; * wherein the additive is at a concentration of at least 0.01 mM and wherein the csrboxyllc acid is of the formula: HO2qqRl)(R2)]nco2H * wherein it = 2 to 6; and Ri and R2 e each Independently selected from the group consisting ofH,OH,CO2H,haloandmathyi. 5.

In a fifth aspect, the present invention provides a pharmaceutical liquid formulation of oxaliplatin for parenteral administration, said formulation comprising (i) oxaliplatin, (ii) water; and (iii) an additive selected from the group consisting of tartaric acid, a salt of tartar c acid, a pharmaceutically acceptable derivative of tartaric acid and mixtures thereof; wherein the additive is at a concentration of at least 0.01 mM.

In a sixth aspect, the present invention provides for the use of a pharmaceutical formulation according to the first to third aspects in the preparation of a medicament for the treatment of a cancer.

In a seventh aspect, the present invention provides a method for treating a cancer which comprises administering a pharmaceutical formulation according to the first to third aspects to a patient in need thereof.

In an eighth aspect, there is provided a method for preparing pharmaceutical formulations according to the first to third aspects, the method comprising the steps of: (i) dissolving oxaliplatin in water to form a solution; (ii) dissolving the additive in the solution; (iii) optionally, adjusting the pH of the solution with a pharmaceutically acceptable base.

In a ninth aspect, the present invention provides a pharmaceutical liquid formulation of oxaliplatin for parenteral administration, said formulation comprising (i) about 5 mg/mi of oxa]iplatin, (ii) water, and (iii) an additive consisting of tartaric acid and the sodium salt of tartaric acid, 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 5.5. 6.

In a tenth aspect, the present invention provides for the use of a pharmaceutical formulation according to the ninth aspect in the preparation of a medicament for the treatment of a cancer.

In an eleventh aspect, the present invention provides a method for treating a cancer which comprises adninistering a pharmaceutical formulation according to the seventh aspect to a patient in need thereof.

Jn a twelfth aspect, there is provided a method for preparing a pharmaceutical formulation, the method comprising 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 hydroxide such that it is in the range of from 4.7 to 5.5 wherein the concentration of oxaliplatin is about 5 mg/mi and the concentration of tartaric acid is about 0.2 mM.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1(a) is a chromatogram showing stability of a solution of oxa]iplatin in water stored at 40 C for 12 weeks.

Figure 1(b) is a chromatogram showing stability of a solution of oxaliplatin and tartaric acid in water stored at 40 C for 12 weeks.

Figure 1(c) is a chromatogram showing stability of a solution of oxaliplatin, tartaric acid and sodium tartrate in water stored at 40 C for 12 weeks.

Figure 1(d) is a chromatogram showing stability of a solution of oxaliplatin and succinic acid disodium salt in water stored at 40 C for 12 weeks.

Figure 1(e) is a chromatogram showing stability of a solution of oxaliplatin, maleic acid and sodium hydroxide in water stored at 40 C for 12 weeks.

Figure 2(a) is a chromatogram showing stability of a solution of oxaliplatin in water stored at 40 C for 8 weeks. 7.

PIgre 2(b) Is a cluvmatogram showing stability of a solution of oxaliplatin and tartaric acid In water stored a 40 C for 8 weeks.

Figure 2(c) is a chromatogram showing stability of a solution of oxailpiatin, tartaric acid and sodium taflrate In water stored at 40 C for 8 weeks.

Figure 2(d) Is a chromatograrn showing stability of a solution of oxalip1ath, tartaric acid and sodium tartratie In water at 40 C for 8 weeks, the ratio of tartnrtc 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 pharmaceutical liquid fonnulation of oxaliplatin for paienteral administration, said formulation comprising (1) oxaliplatiw (ii) water; and (iii) anacid wherein the acid is stablilsing and is not malanlc add, lactic acid or oxalic acid.

It is prefeued that the acId Is a carboxylic add, preferably a dicaxboxylic acid.

In a preferred embodiment the add Is selected from the group consisting of citric acid, maleic acid, saccharlc add, auccInk add, malic acid, tartark addend mixtures thonof. It is prefened that the acid Is malic acid, succinic add, tartaric acid and mixtures thereof and is most preferably tartaric acid.

21) In a second aspect, the precent Invention provides a pharmaceutical liquid fonnulation of oxaliplatin for parenteral dmlnlstraUon, said formulation comprising * (1) oxaliplatir (ii) water; and (1ff) an acid comprising at least 4 carbon atoms.

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 embodiment the add comprises I or 2 hydrcocy1 groups. 8.

In a preferred embodiment the acid Is selected from the group consisting of citric acid, maleic acid, saccharic acid, succlnic acid, malic acid, tartaric acid arid mixtures thereoL It Is preferred that the acid is n'iallc acid, euccinic acid, tartaric acid and nilxhues thereof and Is most preferably tartaric add.

In a still further pft.wd embodiment of the first and second aspects of the invention the add Is at a concentration of at icast 0.01 mM.

In a third aspect, the present mvcntion provides a pharmaccutical liquid formulation of oxaliplatin for parentaral administration, said formulation ccpzialng (i) axaliplatin, (ii) waler; and (111) an additive selected from the group consisting of a phazmaccuticaliy acccptablc carboxyllc add, a salt of a pharmaceutically acceptable caiboxylic add, a phaaccufics]y acceptable derivative of a pharmaceutically acceptable carbaxylic acid arid mixtures thereof; wherein the additive is at a concentration of at least 0.01 mM and whercin the add is not malonic acid, lactic acid or oxalic acid.

Preferably, the add is a dicaibàxylic acid.

Prefezably. the add is selected from the group consisting of citric acid, nwlcic acid, saccharic add, sucdnic add.. mAlic add, tartaric add and mixtures thereof.

In a fourth aspect, therv ispiuvided a ph nceutil liquid formulation of oxaliplatin for parenteral adm nistration, said formulation comprising (I) oxaliplatin, (ii) water; and (iii) an additive selected from the group consisting of phermaceutlailly acceptable carboxylic acid, a salt of a pharmaceutically acceptable carboxylic acid, a pharmaceutically acccptable derivative of a pharmaceutically acceptable carboxyllc acid and mixtures thereof; wherein the additive is at a concentration of at least 0.01 mM and wherein the caiboxylic acid is of the formuhe 1102C[C(R1)(R2)JnCO2H 9.

whereinxt = 2 to 6; and RI and R2 are oath independintly selected from the group canal sting of H. OH, CO2H, halo and methyL PharaiaceulicaBy acceptable acids include glutaric add, citric acid, m11c add, sucdrtlc acid, tartaric add and mixtures thereoL Preferably the pharmaceutically acceptable caiboxylic acid Is selected fromthe group consisting of malic acid, succinic acid, tartaric acid and mixtures thereoL More preferabIy, the pharmaceutically acceptable carboxylic add is tartaric add.

Preferablyn=2to4;morepreferablyn=2.

Tartarlc acid (HOOCCH(OH)CFI(OH)COOH) is used In food and pharmaceutical formulatIons as an acidulant, sequestering agent or antio,ddant syncrgiat. In pharmaceutical formulations, It Is widely used In combination with bicarbonatets, as the add compónentof effervescent granules, powders, and tablets. It displays none of the toxicity associated with the we of oxalic acid as a stablilsing agent, such as nepliroto,dcity.

Surclnlc add (HOOCCH2CHZCOOH) Is used as a food additive and in detergents and cosznetles. It can be found naturally occurring In animal tissues, and in vegetables or fruit.

Malic add (HOOCCH(OH)CH2COOH) Is used as a flavouring agent, flavour enhancer and acidulant in foods. It Is found naturally In apples and many other fruits.

Citric acid Is (2-hydroxy-1,2,3 ropane-tricaiboxylic acid) is widely distributed in plants and in animal tissuesand fluids.

MaleIc add has the formula HOOCCM=CFICOOH.

Saccharlc add has the formula HOOCICHOHI1COOH and is derived from starch.

In a fifth aspect, the present Invention provides a phannaccufical liquid formulation of oxaliplatin for parenteral administration, said formulation compriaing (I) oxaliplatin, (ii) wateiand (iii) an additive selected from the group consisting of tartaric acid, a salt of tartaric acid, a phaceutically acceptable derivative of taftarlc acid and U%ixturcs thereof wherein the additive I ta concentration of at least 0.01 mM-Many of the cazboxy& acids of thc present liwentlon are found as Isomers. Far inathnCe tartaric acid has many isomaric forms. The present invention contemplates the use of any of the isomers of the car'ooxyllc add used as an additive. For instance, where the carboxylic acid is tartaric acid, the tartaric acid may be selected from any of the isomers of tartaric add lndudixig the group consisting of (+)-tartaric acid, (-)-trtsxIc acid, niesotartaric acid end mixtures thereof. P*eferably, the tartaric acid is (+)-taztaric acid.

Where the additive Is a mixture of a pharmaceutically acceptable carboxyllc acid and a salt of a pharmacvuticafly acceptable carboxylic add, the concentration of the additive Is the sum of the concentrations of the catboxylic add and the salt. Piukbly, where the additive is a.

mIxture of a pharmaceutically acceptable carboxylic add and a salt of a pharmaceutically acceptable caibuxylic acid, the salt Is the conjugate base of the carboxylic acid so as to form a bulier solutic When the additive includes a salt of a pharmaceutically acceptable carboxylic acid, the salt of maybe fcnncdlnsltiiby the additionof a pharmiceuticafly acceptablebase teen add solution. Alternatively, the salt maybe added directly to the foimu]ation.

Preferably, the concentration of the additive In the formulations of the first to third aspecta of the Invention is from about 0.01 mM to about 2.0 mM, more preferably from about 0.1 mM to about 1.0 mM, even more preferably from about Di mM In about 0.6 inM. yet more preferably from about 02mM to about 0.6 mM.

Preferably, when the additive comprises a salt of a ph aceutically acceptable acid the salt Is a sodium salt.

Pharmacoutiea]ly accè,tab1e derivatives of carboxylic adds include but are not limited to such derivatives as esters, amides, carbonates and caibamates of the acid.

The anwunt of uxaliplatin present In a pharmaceutical formulation according to the Invention is preferably up to about 15 mg/mI, preferably about up Lu about 7mg/mi.

Preferably the amount of uxaliplatin Is In the range of Irvin 1 to 5mg/mi and moat preferal1y Is about 5mg/mi.

As will be understood, the additive should be used at a concentration which does not dcstablliae the oxallplatln and preferably aids stability of the oxaliplatin. The desired stability of oxaliplatin will depend on the Intended shelf life of the pharmaceutical formulation and the manipulation prior to administration. Muxe spedflcafly, a stable aqueous oxaliplatin formulation Is one In which there will be no significant change in oxaliplatin potency at the specified storage condition. The criteria for "significant change" 11.

are as defined In the International Conference on H monisation (1CR) Guideline: Stability Testing of New Drug Substances and Products QIA (R2). Thus in the case of injcctablc RIIJ oxaliplatin solution, potency of oxaliplatin should be at least 95% of ittitiol content, and.

solution remains clear, colourless and free of predpitatlon for a pharmaceutically acceptable duration of time.

Prekrably, the additive Is at a concentration sufficient to buffer the formulation at a pH In the range of from about 3 to about 8, more preferably about 4 to about 7, even more preferably about 5.

As is known to a person skilled in the eta buffering system Is a mixture of an acid with It conjugate base in a solution1, the mlxtuie being formulated so as to maintain the p1-I at a dvsiivd luvdL As definedherein, "bufferhg agent" refers to an acid or a base Which may form a component of a buffeting systn whether or not the acid or base is associated with Its conjugate baàe or conjugate add, respectively..

Pwkrably the pharmaceutical formulation of the Invention is provided hi a sterile, sealed container. For example, a neutral glass of type I and a stopper. Examples of the stopper include those made of an elastomer based on halogenated butyla, possibly coated with a fluorinated 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 the preparation of a medicanient for the treatment of a cancer.

In a seventh aspect of the present Invention there Is provided a method for treating a cancer which comprises administering a pharmaceutical formulation according to the any one of the first to third aspects to a patient In need thereof.

The cancer can be any cancer that Is amenable to treatment by oxaliplatin, either alone or in cumbhiatioi with other cheniotherapeutic agents and Includes colorectal cancer.

The term "treating" as icd herein, unless otherwise indicated, means revuiág, allcviating Inhibiting the progreas of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatznenf', as used herein, refexs to the act of treating, as "treating" Is defined Immediately above.

In the above methods, the effective dosage of oxaliplatin to be administered to a patient xangcs front about 10 mg/ni2 to about 250mg/rn2, trove preferably from about 30 mg/rn2 to.

about 120 mg/rn2 and ntostpieferably is about 85 mg/rn2. However, it will be undenstood 12.

that the therapeutic dosage administered will be determined by the physidan In the light of the relevant chun%stances inchading the severity of the condition to be treated and the chosen iuutc of adminlstmthn. Therefore, the above dosage ranges are not Intended to limit the ape of the invention in any way. Administration of oxaliplatin will typically be according to beat practice Jaiown to those skilled in the ert at the lime of administration.

The present invention also provides methods of prepaxing the formulations of tbe pxcsnt Invention. Accordingly, in a further aspect there is provided a method for preparing a * pharmaceutical fornwlaticn, the method comprising the steps of (I) dissoMng oxaliplatin in water to form a so1ulioi (IL) dlissolving in the solution en additive selected from the oup consisting of a pharmaceutically acceptable cazboxylic acid, a salt of a pharmaceutically acceptable carboxylic add, a pharmaceutically acceptable derivative of a ph nnaceutkally acceptable carboxylic acid and mixtures thereof; * (iii) optionally, adjusting the pH of the solution with a pharmaceutically acceptable base wherein the acid is not malonic acid, lactic acid or oxalic acid.

In another aspect the present invention provides a method for preparing a phannaceutical formulation, the method comprising the steps of: (I) dissolving oxaliplatin in water to form a solution (ii) dissolving in the solution an additive selected ftvm the group cunsisthtg of a 21) pharmaceutically acceptable carboxylic acid, a salt of a pharmaceutically acceptable carboxylic acid, a pharmacinitically acxcptable derivative of a pharmaceutically acceptable carboxylic acid and mixtures thezeof (lii) optionally, adjusting the p1-I of the solution with a pharmaceutically acceptable base wherein the carboxyllc acid is of the formula: HO2C[C(R1)(R2)JnCQ2H wherein 2 to 6; and Ri and R2 are each independimtly selected fivm the group consisting of H, OH, CO2H, halo and methyl Freferably,n 2 to 4. More preferably, n = 2. 13.

in yet another aspect the present invention provides a method for preparing a pharmaceutical formulation, 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 tartaric acid, a salt of tartaric acid, a pharmaceutically acceptable derivative of a pharmaceutically acceptable tartaric acid and mixtures thereof; (iii) optionally, adjusting the pH of the solution with a pharmaceutically acceptable base.

pH adjustment may be carried out with any pharmaceutically acceptable base. Preferably the pharmaceutically acceptable base is a sodium hydroxide (NaOH) solution.

In a further aspect, the present invention provides a pharmaceutical liquid formulation of oxaliplatin for parenteral administration, said formulation comprising (i) about 5 mg/mi of oxaliplatin, (ii) water, and (iii) an additive consisting of tartaric acid and the sodium salt of tartaric acid, 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 5.5.

The present invention also provides for the use of the formulations of the present invention in the preparation of a medicament for the treatment of a cancer and in the treatment of cancer in patients.

In a still further aspect, the present invention provides a method for preparing a pharmaceutical formulation, the method comprising 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 hydroxide such that it is in the range of from 4.7 to 5.3 wherein the concentration of oxaliplatin is about 5 mg/mi and the concentration of tartaric acid is about 02 mM.

In all of the aspects of the present invention, references to the concentration of the additive are references to the concentration of the additive in the pharmaceutical liquid formulation. 14.

In order that the nature of the prvsent invenilon mey be more clearly understood.. prcfcrred forms thereof will now be described with reference to the following non-)ixriiting cxamples.

EXPERIMENTAL

Measurement of Stability of Oxaliplatin formulations The stability of an oxaliplatin formulation over a period of time can be measured by a number of complementary methods. Visual appearance and stability of the pH of the formulation are Important indicators and these can be measured by techniques well known totheseskiliedintheart.

Stability can also be measured by high pressure liquidchroznatography (HPLC) technIq!es.

HFLC is a technique that Is widely vaed end wall known in the art.}J1'L.C can be used to measure the potency of the oxaftplatln where potency Is defined as a percentage of the frdtia] concentration of oxaliplatin. HPLC can also be used to measure the relative proportions of known and unknown degradants in an oxaliplatin solution.

Known degradation products of oxaliplatin Includc: 15. a (trans4l,2dlamlnocyclahexane)trana-dihydroxo(oxa]ato) platinum]V). This a o,ddntlve degradation pràduct of oxeliplatin. This degradation product lies been designated as Impurity C In the Exemplcs.

* (SP-4-Z)-diaqua-I(1R,2R)-cydobexane-1,2-dfainckN,kN'Jpladnum,or dlaqua DACH platinum. This Is a hydrolysis degradation product of oxaliplatin. This degradation product has been designated as Impurity B in the Examples.

* (SP42).di.i.oxobis[(1R..2R).cyc1ohexane1,2.diaxnizw.kN,kNnJpIatituun, or diaqul 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

Examples..

R,S-oxaliplatiri 1 an bomerk form of oxaliplath which Is found at low levels as an impurity In cixaliplatin (le cla-oxalato(fr ns../1,2'diainirucyclohexane) platinum(fl)).

Overview of the Examples Example 1 details an Initial trial of oxaliplatin forrenlatioris using a number of agents over a pH range from 3 to 7 In which the bility of tartaric add, inaleic acid, succinic and malic adds to stabilise oxaliplatin was compared to a control. 01 the acids tested, tartaric add was 15.

found to give the moat stable oxaliplatin aolutioris and it was subsequently tested across a wide pH and concentration range as reported in Example 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, reported In Example 3, then reviewed a number of other adds at a set concentration (O mM) as buffrIg agents in solutions of axallplatht This showed that fo u1atims containing malic and sucdnlc add bad impurity levels which were comparable to the tartaric acid formulation. Contrary to the teadthg of the prior art;.

the nialoric acid formulation contained a surprisingly and unacceptably high level of impurities relative to the tartaric acid Loruwlatlon. Solutions containing cihic, nialeic and sacchnrlc acids also showed reasonably low levels of Impurity. The thbIlisczs of the prior art, oxalic acid and lactic add, also displayed reasonably low levels of impurity which is unsurprising In the case of oxalic add due to The operation of Le Chatelier's principle.

Example 4 provide details of a preferred formulation of an aqueous solution of oxaliplatin and tartarlc acid.

Example I

The stability of an army of oxaliplatin formulations In water for Injection (WPI) having an oxailpiatin concentration of 5mg/ad was asseed. Potential buffering aglmts of oxaliplathi that were tasted were tartaric ad4 malic add, succinic acid and maleic acid. The pH of the formulations covered a range of values.

* * 20 Comparative Example 1(a) * Preparation of the Control solution WPI (water for injection) was added tO a suitable glass vessel to about 80 % of the desired * quantity of final volume and warmed to 45-50 C. While stirrIng and flushing with nitrogen, the desired quantity of oxaliplatin (calculated at 5 mg/mt at the final dircd vohune) was added and dissolved. The solution was then made upto the desired final volume with WFJ..

Example 1(b)

* Preparation of Dlcarboxyllc Acid Solutions Por the formulations described below, WFL was added to a suitable glass vessel to about 80% of the dashed &tal volume and warmed to 45-50 C. While stirrIng and flushing with nitrogen, the dashed quantity of oxaliplatin was added and dissolved. Thczvnfter the proposed etnbilising dicarboxyllc add or Its alkali salt was added to the oxaliiIath solution 16.

until completely dissolve& Where required. pH was adjusted tlwougb the addHion of dilute NaOH solution. The solution so formed was made up to the final volume with WFL Table I Oxailiplatin formulations containing naleic and inalic acid based agents F0nnulatlcn pH!1C pHI M1IQICpH 7 Maile pH? OxaIp1atin (m --5mg 6mg 5mg & mg MaJicacddPsd)um.afl4m) __________ N/a -P'Va 1.1mg Malola acid (mg 0.1 mg o.ce mg 0.71mg Nl POft 19N N( .OG7pL 1O.Di1. N/a * WHqs lmL imi. lmL imL t1al pH at the IIIWJ tannuisilon JO 5.35_-7.16 0.92 Table 2 Oxaliplatin formulations containing succink acid based agents FOM-JIII pH $ SuecinIc pH 5 Suochle pH? OxallpbIIn 0mg -5mg -5mg 5mg Sucalnlc acid dlicdlum eaR O.OlSmg -1.033mg Sueinf* add O13ng O.Oc -N/a WFIqs -lmL__-lniL lmL nldaIpHatth.flnaT formuletIc,, 3.si 6. e.st 17.

* TableS Oxaliplalin formulations containing tattarie add based agents FormulIon Thvtailc p113 Tta,tc p115 TaiIIe pHi - ____________________ 1.5mg Sing Sing NOH ION Wa -O.5 L --0.067 Id.

MIIPHCfIIIeInIJ ?cmiultloi, 3.56 4.5 7.06 MolaiftyetTalaIleAcjdfT. ,.1,Is 2.gxlq'M 2.2x104U 3.lxiO4U * The pH values used to designato the different formulations e indications only and do not necessarily teflect the exact pH of each solution. The exact Initial pH values axe provided in

the tables above.

Example 1(c)

Stability Study In accordance with an acceleratcd stability pyotocol, the formulations were stored at 40 C wIth 75% relative humidity for 12 weeks.

The potency of the fonnulations was examined by high performance liquid thomatngraphy (HPLC) at 4 week intervals over the 12 week period. Potency Is defined as a percentage of the initial concentration of oxaliplatin. Most formulations malntalncd at least 95% potency over the 12 week period. The exception to this was Maleic pH7 which had a potency of 41.9% after the 12 week period. Malcic acid could not therefore be considered as a viable stabiliser.

1nrspectorthenscofmalicacidosaflstabilisorthc5udyofM1jçpH7w5jJ after 4 weeks due to significant precipitation and colour changes within the formulation..

* Accordingly, malic acid could not beconsiclered as a vlab]c stabiliser. As is dLicuszced below this result may have been a conscquence of the high concentrations of the rnallc acid disodiuni salt in the formulation. 18.

Only vezy low levels of the wudative degradation productimpurity C [(trans-l-l,2-diaminocyclohozano)trans-dthydroxo(oxalato) platinum (IV)) were detected In the formu1alions This Indicated that the formulations were substantially free of oxygen.

Ecainp1e 1(d) S Study of the Degradation Products of Oxailpialin at 12 weeks Formulations Control, Tartaric pH 3. Tartaric pH7, Succinic pH7 and Maleic pl7 were analysed after 12 weeks at 40 C wIth 75% relative humidity for the presence of major degradation products of oxaliplatin [impurity B( dlaque DACH platinum) and Dinter (dIaua DACFI dimer)1 using 1IPLC.

The daromatograms of the formulations are presented In Figures 1(aXe). The putUy peaks at above 0.01% are aepoited FIgure 1(a) Control 40 C 12 weeks This system displays an Impurity peak at 5.945 mInutes corresponding to Impwtty B (dlaqua DACH platinum) and a further peak at 9.897 mInutes corresponding to Pfmer (dlaqua DACH platinum dimer). A further three unknown impurity peaks are present. One Is present at 3.909 mInutes at a level of 0.03% and two at 3.026 and 3.386 minutes at 0.01%.

Flguiel(b) Tartaric pH3 40 C 12 weeks -An impurity peak Is present at 5.932 mInutes which has been allocated to impuilty B (dliqva DACH platinum). There Is also present an Impurity at 3.906 mInutes, There is no impurity peak corresponding to Dimer (diaqua DAd-! platinum dimer).

FIgure 1(c) Tartarlc pH? 40 C 12 weeks This system displays an impurity peak is present at 5.931 mInutes which corresponds to impurity B (diaqua DACH platinum). There are also three unknown hnpvnty peaks elulad at 3.027 minutes, 3.387 mlnute and 3.9(16 minutes at the level of 0.01,0.01 and 0.03% 19.

respectively. There Is no Impurity peak corresponding to Dimer (diaqua DACH platinum dimer).

FIgure 1(d) SuccildcpH74O Cl2weeks ThIs system displays a large number of unIaown impurity peaks. These are present at 3.075 minutes, 3.581 minutes, 4.007 minutes, 4.164 nthmtcs, 4.368 mInutes, 6.512 mInutes and 7.684 inmutea. An Impurity peak Is also present at 5.956 minutes which corresponds to Impurity B (diaqus DACH platinum).

Plgujel(e) MaleicAddpj(740 Cl2wceka The system displays a large number of unkmvwzt impurity pcalca present at 2.587 minutes, 2751 mlnutac, 2.880 mInutes, 3.042 mimites, 3.378 minutes, 3.599 ntinute, 3.983 mInutes, 4.203 mInutes and 5.339 minutes.

It is clear from a visual comparison of the cbrcnatograms that the tartaric acid stablllsed formulatiozis are for more stable than the molcic add and succlnic add stabfllsed lormulatjons. In addition, In comparison to the cluvniatogram of the contixl Formulation, the formation of Dimer (diaqua DACH platinum dimer) is suppressed in the tattarlc acid stabilised fonnulations. Purthci at least in the vase of the TartnrkpH7 fonnulatlon, significantly less Impurity B (diaqua DACU platinum), the principle degradant, is formed.

21) In addition, the tartaric acid stabiliscd formulations do not display as many unknown impurity peaks as the control fommlation.

Example 1(e)

Study of the Degradation Products of Oxaliplafin at 8 weeks Pannulations Control, Tartarlc pH 3, Tartaric pH 5 and lartaric p147 were analysed after 8 weeks at 40 C wIth 75% relatIve humidity for the presence of degradation products of oxaliplatin iing the HPLC protocol of Example 4 The chromatogranis are presented in Figures 2(a)-(e) 20.

FIgure 2(a) Control 40 C 8 weeks This syst displays an Impurity peak at 6.304 minutes corresponding to Impurity B (dlaqua DACH platinum) and a furtheT peak at 10.145 mInutes conesponding to Dimer (diaqus S DACH platinum disnei. An unlcnown Impurity peak Is presertt at 3.913 minutes.

Figure 2(b) Tartarlc p}l3 413 C 8 weeks This system displays en impurity peak at 6.306 mInutes corresponding to ImpurIty B (diaqua DACH plalimmt). There Is no peak corresponding to the presence of Dlmer (diequa DACH platinum dimer). Art wluown impurity peak is present at 3.916 mInutes.

Figure 2(c) Tartaric pH 549 C 8 weeks This system displays an Impurity peak at 6.306 mInutes corr spending to unpunty B (diaqua * DACH plathnun). Thete Is no significant peak corresponding to the presence of Dirtier (dieque DACH platinum dlmer). An unknown Impurity peak Is present at 3.911 rtdnutus.

Figure 2(d) Tartark pH7 40 C 8 weeks This system displays an impurity peak at 6.306 minutes corresponding to impurity B (diaqua DACH platinum). There is no significant peak corresponding to the presence of Dimer (diaqua DACH platinum dfrner). An unknown Impurity peak is present at 3.913 minutca.

In comparison to the Uuimatogram of the control formulation, Dimer (dlaqua DAQ-i platixumt dimer) foimation is suppressed in the tartark acid stabilised formulations.

Snnunai,r It Is clear from a visual comparison of the chromatagrams of Figures 1 and 2 that the tartaric acid stabilised formulations of oxaUplatin are far more stable than the nialeic add and sucdnic acid containing formulations. In addition, In comparison to the chrontatogram of the control iulnticn, the formation of Pimer (dlaqua DACH platinum dimer) is 21.

suppressed in thc tartaric acid stabillsed formulations and, In some cases, significantly less Impurity B (diaqua DACH platinum), the principle dcgródant Ii formed. Further, the tartaric acid stabiliscd formulations do not display as many unknown Impurity peals as the control formulation which is of importance in meeting the guide lines of the ICH and also in nithirolslng any side effects due to the presence of unknown impurities. The Increased stability of the oxaliplatin formulations applies across a range of pH values.

Although malic acid and eucdnic acid were considered as unsuitable agents following this experiment, later investigations, as detailed In Example 3, demonstrated that maRc add, succink acid and nialeic add can be used with oxaliplatin. A possible reason for the Initial 11) finding that these formulations wcre unsuitable is because of the relatively high concx!nfrations of certain of the succinic and malic add formulations used in Example 1. For instance, the suvdnlc pH 3 formulation has a concenation of suocinic acid of about 1.10mM and the sucdrdc acid pH 7 formulation has a concentration of disodhun salt of succinlc acid of 6.38 mM Slmilariy, the concentration of niallc add dlsodlum salt in the malic pH 7 formulatIon Is U2 mM. The concentration of iualelc add in the Maleic pH? formulatIon Is about6.lmM. Bycontrastthctartaricacjdconcenfratjonsoftheforntnjatjoiijofthis Exaniple range from about 0.2 to about 0.3 mM.

Example 2

2.1 Background

This Example was conducted to further Investigate the effect of different amounts of tartaric acid and the affect of pH on the stability of oxallplatln solution fommlatIons The tartarle acid formulations were compared to a control formulation of oxaliplatin In water and to formulation of Oxaliplabn in oxelic acid solution (according to US 6,306,902).

2.2 PreparatIon of fornnialilons mr analysis 2.2.1 MixIng procedure for the formulations * Add about 80% mL of desired amomt of WFJ into a 2L mixing vessel and boat to 45- 50C, while stirring and flushing with nitrogen.

* Add oxa]iplatfn (total 7.5g) and mix until solution becomes clear.

* Adjust to the volurrie with WFI to 1500 niL.

* Dh'lde the bulk solution to 100 niL each. Keep one 100 niL solution as the control. 22.

* Addtherquiredamtoftacacidsolutlon5%w/i,oroxalicacldandNaOH (10N 5N and/or 2N) according to thc formulation details in Tables 5 and 6.

* Cap the final solution and keep In the fridge until filling.

2.2.2 Filling and capping * Fflte each formulation using a 02 m syringe filter.

* Fill 2.0 mL of each formulation filled Into a 2mL vial and cap.

Tables 5 and 6 Indicate the quantifies of reagenb added for each different formulation.

Table 4 Potmnlatlon details for the oxaliplatin solutions containing tartaric acid of

Example 2

__________ ________________________ ________ _________ _________ _________

Item Tartaric Tavtarc Tartaric I r$erlc Tztaiic ____ -_J0M -(0.000SM) (tLOO3OM) (O.006Thi) JQ002Ml Ponnulatlon A2.5 A4.0 A5.0 A74) A8.5 D4.0 D7.0 C4.O c7.0 D44) D7.0 E4.0 E7.0

ID

Oxallplatln.5 5 5 5 5 5 5 5 5 5 5 5 5 (mg) Tarlarkadc 0.05 0.05 0.05 0.05 04)5 0.09 0.09 0.45 0A5 1.0 1.0 0.03 0.03 (mg) ---WFIqS 1 1 1 1 1 1 1 1 1 2 1 1 1 * ____------Taiet pH 2.5 4.0 5.5 70 85 4.0 7.0 4.0 7.0 40 74) 4.0 7.0 * Note; Molecular wcight of taxtaiic acid = 150.09 * A = Formulation containing tartaric acid at 0.0045% (03 mM) * B = Formulation containing tartaric acid at 0.009% (0.6 mM) * C Formulation containing tartaxic acid at 0.045% (3mM) 0= FormulatIon containing tartartc add at 0.1% (6.7mM) * = pmta containing tartaric acid at 0.003% (02 mM) 23.

TableS: Quantity of oxal3platin and excipienls required to be used for the preparation of the oxailpiatin solutions contning tartarkacld of Eiiample Itent Tartaric (0.000SM) TrtarIc T.Ttark Tarta& Tadade __--__J3 L JL Pom%u1o$o M5 A4AJ A5.0 A7.0 A8.5 B4.0 B7.0 C4.0 7.0 P4.0 1)7.0 E4.0 E7.0

TO

Oxaliplatli 500 500 500 500 500 500 500 500 500 500 500 500 500 (mg) ---Tartarleac!' 4.5 4.5 43 4.5 4.5 9 9 45 45 100 100 3 3 ( --.------Tarterlc 90 90 90 90 90 180 180 900 900 2000 2000 60 60 odd 5%w/v (DL) WFI qs 100 100 100 100 100 100 100 100 100 100 1(X) 100 100 (lnL) Table 6 Formulation details for the oxaliplatin control formulation and oxaliplatin solutions containing oxalic acid of Exaniple 2.

Item. Control Oxalic add - ___________ _______ (0.OOIM) OxailpIalin 5 5 OxoUc odd N/s 0.126 (mg) _____ ______________ WPIqa(mL) 1 1 Target pH -5.5. 3.0 Note: In the initial screening, the pH3 tartaric formulation was formulated at pH 323. * 24.

2.3 Stability Measurements at the Initial Time Point All of the oxaliplatin formulations at the Initial time point were cleaç colowless solutions with no visible particles present In olutlon. The appearance of the solutions are set out in.

Table 7. Measurements of the pH results of the formulations ate also shown In Table?.

Table 7 Teat Results for ph and Appearance of Oxaliplatin Solutions of example 2 at Initial Time Point Formulation pH Inilial A1,pcaznce Control 5.77 N A3.5 3.56 N A4.0 96 N A5.0 5.22 N A7.O 7.44 N ASS 8.47 N B4.0 4.08 N 870 7.27 N C4.O 3.99 N C7.0 6.91 N D4.0 3.97 N D7.0. 7.37 N E4.0 5.99 ____________ B7.0 7.4 N_ -Oxalicadd 2.94 N N = a clear, coluurlcss bolubrn% with no visible particles present in solution * 2.4 Stabiflty Measurements The fonnulatic)ns were then stored at 25 C and 40 C.

The appearance of the formulations was assessed at the 1n1t144 week and 8 week time ponts Each formulation remained clear and colourless.

The pH of the formulations was measured at the initial, 4 week and 12 week thue points for 25 CasshvnjnTable8afldfor4o CasshownjnTable9. 25.

Table B Test Results for pH of Oxaliplalin Solutions of Exainple2 at 25 C Fonnulation pH InithI pff4wka pH l2wks Control 5.77 5. 80 5.73 A3.5 3.56 3.54 nfl A4 3.96 3.99 3.59.

As -5.22 5.03 5.1.5 A7 -7.44 5.54 5.54 MS 847 -6.26 n/t - ________ 4.08 4.52 n/t -87 727 543 -5.63 C4 3.99.4.03 nit C7 6.91 5.16 34.4 - _______ 3.97 _4.12 nit 07.7.37 -5.31 n/t 54 3.9 4.55 425 117.0 7.4 5.61 6.15 OxalIc add 2.94 3.42 3.31 Table9 Test Results for H of Oxaliplathi Solutions of Exainple2 at 40 C Foxmulotlon pH Initial pfl 4wks PH I2wlcs Ccmtrol 527 5.79 3.3(1 A33 336 3.57 -n/I A4 3.96 3.93 3.81 A5 5.22 5.06 5.01 V Aj 7.44 5.43 5.64 MS 8.47 6.17 n/t - 84 4.08 4.29 nft B7 7.27 541 5.95 c4. 3.99 4.17 __________ C7 6.91 V 5.25 5.43 D4 3.97 4.14 n/t. V 07 ______ 5.36 nit V 4. 3.99 4.24 V4.9 -V 7.4 4.23 6.20 Oxalkadd 2.94 3.25 V 26.

2.4.1 Potency assay Formulations A4, A5, A7, 07, C?, E4, E7, Oxallc nd the Control were maintained at 25 C and 40 C d were assayed for potency by HPLC after 12 weeks. Table 10 ivpoita the Impurity profile detemlined from the potency assay for 25 C, Table 11 reports the impurity profile 5' determined from the potency assay for 40 C.

Table 10 Impurity profile from the potency assay for certain oxalipiatin formulationa of Example 2 at 12 weeks lime point at 25 C impurity Control A4 AS A? B? C7 E4 E7 Oxidlc Total of unknown 0.10 0.05 0.05 0.07 0.08 0.17 0.10 0.11 0.1 impurities B,S.Oxaliplstin 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 OxaUplatln 99.87 99.89 99,89 99.89 99.88 99.72 99.86 99.85 99.76 Impurity C 0.01 0.01 0.01 0.01 0.01 -0.01 0.01 0.01 0.02 Total urity (%) _0i2 0.07 I 0.07 em 0.1 0.19 0.12 0.13 0. 18 Table 11 ImpurIty profile from the potency assay for certain oxaliplatht fwmulat3ons of Example 2 at 12 weeks time point at 40 C Impurity Control A4.0 A5.0 A7.0 07.0 C?'.O B4.0 E7.0 Oci1ic ____ __ __________ ____ add Total oF unknown 0.15 0.18 0.13 0,14 0.08 0.53 0.07 0.08 0.15 Impurities LS-OxaliplaUn 0.01 0.01 0.01 0.01 0.01 0.02 0.01 0.01 0.01 Oxaliplatin 99.73 99.81 99.27 99.77 99.77 99.66 hnpurityC 0.02 0.02 0.02 0.01 0.01 0.02 0.01 0.01 0.02 Total impurIty 0.18 0.21. 0.15).16 0.10 0.57 0.09 0. 10 0.18 27.

2.4.2 ImpurIty B Assay * The level of impurity B of the formulations maintained at 25 C was assayed by HFLC after 12 weeks for A4 AS, A7, 137, C7, E4, E7, Oxalic and the ControL Table 12 reports the impurity profile determined from that impurity B assay for 25 C. The level of inipwlty B of the formulations maintained at 40 C was assayed by HPLC after Ii weeks. Table 13 reports the impurity pmffle determined from that lmpimty B assay.

Table 12 The levels of Impurity B and other unlawwra Impurities from impurity B assay In certain formulations of Example 2 at 12 weeks time point at 25 C Impurity çqo1 A4 A5 -A? 137 C? -134 Oxalle Total of wiknown 0.07 0.05 0.06 0.06 0.04 0.06 0.02 0.06 0.06 Impurity Imp 13 0.24 0.29 0.12 0.10 0.13 0.06 0.21 0.18 0.38 Dimer 0.10 Nd Nd Nd 0.02 Nd Nd 0.05 Nd Tothflwpwlty(%) 0.41 034 0.18 0.16 0.19 0.12 02 0.29 0.44 Table 13 The levels of Impurity B and other unknown impurities from Impurity B assay in certain formulations of example 2 at the 8 weeks time point at 40 C Impurity COTthI,1 A4 AS A7 7 C7 E4 E7 Oxalic Tetalof unknown 0.15 0.06 0.09 0.10 0.09 0.11 0.06 0.07 0.05 hnpurities ImpS 0.26 0.24 0.09 0.09 0.11 0.06 0.19 0.19 036 Dimer 0.17 0.01 Nd Nd 0.03 0.01 Nd Nd Nd Total impurity (%) 0.58 0.31 0.18 0.19 0.23 0.18 0.25 0.26 CAl -28.

2.5 Stability Measurements at 9 months Pnnulations A4.O, A5,0, A7.0, E4.O and E'.O were stored at 25 C and 40 C for 9]xwnths and then anclysed for pfl and impuriticb.

2.5.1 Results and Discnssktn 2.S,11 Appearance Results Appearance was clear, olourJc with no visible particulate matter present In most of the formulations (Table 14).

Table 14 Appearance of oxailpiatin solutions at different time p&nt at 25 C

_______________ _________________________ _____________________

Formulations Appearance Appearance ______________ 9 numths (25 C) 9 months (40 C) Control N N' A4 N'

AS N N

A7 Nit N

N N

E7 N N N = a dear, colourless solution with no particulate matter present in solution N' = a clear, colourless solution with few particles prcscrt in solution N" a cleai, colourless solution with some black particles present In solution N/t=nottcsted 29.

2.5.1.2 ImpurIty B Assay Levels of Impurity ii and Dlmer In funnulatlons Control, A4, AS, E4 and E7 at 9 months for both 25 C and 40 C were assessed using HPLC. The results are shown In Table 15 and 16, respectively, Front the assay, the formulations A4, A5, E4 and E7 contained less total impurity than control at 25 C. At 40 C, fotmulath,ns A4, A5 and 4 contained less total impurity than the control, In all cases the Dimer impurity was suppressed telattve to the Control and Indeed was not detected in formulations AS, A? and EL Table 15 The % of Impurity B and other unknown impurities from Impurity B assay In certain formulations of Example 2 at 25 C for 9 months -Impurities Control Ad AS I B4 Total of unknown 0.07 0.05 0.06 0.03 010 Impithtics IMpB 0.22 0.27 0.11 0.18 0.15 dlnier 0.15 NI) ND Ni) 0.06 -Total impurity 0.44 I 032 I 0.17 I 021 I 0. 31 ND=notdetectvd.

Table 16 The % of Impurity B and other unknown Impurities front Impurity B assay In certain fonnulations of Example 2 at 9 months time point at 40 C

_________________ ____________________________________ _________________

Impurities Control A4 AS A? 4 7 Total of unknown 0.22 0.20 O.3 042 0.22 0.46 Impurities Imp B 0.26 021 0.09 008 0.23 0.12 dlmer 0.14 ND NI) ND ND 0.04 Total impurity -. 0.t2 0.41 I 0.40 I 0.50 0.45 I 0.62 ND = not detected

2.6 Summary

Thc screening study indicated that tartaric acid Is a auitable stabilising agent for oxalipiatin at a range of canventrations. In tcrms of the ability of rartaric aud to stabfllse the oxafiplatin, concentrations of 0.2mM and 0.3mM (formulations E and A respectively) ere preferred, although formulations at 0.6mM (formulations B) also demonstrated some stnbilkdng effect.

E*ainple 3 As shown In Example 1, & Lormulalion acenIng study showed that the piesence of tarteric acid In an oxaliplatin solution can suppr the formation of Impurities relative to a control solution and thereby stabilise the formulation. The studios discussed in Example 2 IndIcated that the total concentration of taitaric acid in the formulation was of importance In pioviding a stabllislng effect. Th. possibility edsted that other carboxylic acids may have the same stabilising effect. This study involved the screening of a range of carboxylic acids (other than tartaxic add) at a set concentration (0.3 mM) in oxaliplatin solutions. The formulations were placed at 40 C for S weeks and then evaluated for stability. The performance of the to fomuilations were compared to asolutlon of oxaliplatin containing tartarie acid at 0.3 mM.

3.1 Experimental The fo]lowing acids were used In the study Tartaric acid Maleic add Lactic add D-Saccbaric acid Civic acid anhydrous Succinic add Maloide acid Oxalic acid Maile acid 3.1.1 Procedure for naking 1% acid solutions Each acid was weighed separately Into a lOOzziL vchametdcflask. The aolutions were made up to final volume after dissolving the acid completely.

3.1.2 PreparatIon of oxallplatht fonm2latlons About 80% mL of the desired amount of WFI was added Into a dean glass beaker and hcated the WPI to 50 C -55 C, while et1rng and flushing with nitrogen. The oxaliplalin was then added to the beaker and mixcd imlil clear solution was obtained (about 50 mInutes was needed to achieve complete dissolutian.of uxalip]atin). The solution was then made up to volume with WFI. The bulk solution was dMdod into 100 mL quantities and the required amount of acid sohitlon was added to each 100 mL quantity acord1ng to Table 20. Each 31.

formulation wa tlen flushed with nitrogen until the dissolved oxygen content in solution.

was below 0.05 ppm.

31.I.3 Filling and capping Ead formulation was filtered using a 0.2 im syringe filter. Then 5 inL of the solution was placed into a 1OmL vial, and capped and sealed for each formulation.

3.12 Formulation Details Tables 19,20 and 21 show the formulation details and quantities of oxaliplatin and excipients * reded for cach formulation.

Table 29 Psrmulatlon details for the oxaliplatin sulutlon of Example 3 (unit formula) * Formulation Tartarle Lactic Citric MilonIc Mali Maleic Saxbaric Sucdruc Oxalie ID add add add acid ________ _____ acid add acid add _____ ______ _____ add xaliptatin 5mg 5mg 5mg 5mg 5mg 5mg 5 mg 5mg 5mg (mg) ___ __ ____ __ ___ ___ ___ ___ Add in nig 0.045 0.027 0.063 0.031 0.040 0.035 0.074 0.035 0.022 Addtninolur 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 a,ncnntTotOfl (mM) ____ ___ _____ ___ ____ ____ ____ ___ Molecular 150.09 90.08 210.14 104 134.09 116.01 248.02 118.09 72 weight ___ ___ ____ ___ ___ ____ ___ ___ WF1ç(mL) 2mL 1nL ImL izaL ImL. lmL intL lmL lint 32.

Table 20 QuantIty required for the ozaliplatin o1utIons of Example 3 Formulation Tartaric Lactic Citric fa1orik Mallc Malcic 5accharic Succlnlc Ozalic * U) acid add acid add acid odd acid acid add * Oxaliplatin 500mg 500mg 500mg 500mg 500mg 500mg 500mg 500mg 500mg mg) ___ ___ ___ ___ ___ ___ ___ --__ -Acid (mg) 4.50 2.70 630 3.12 4.02 348 744 334 2.16 1% acId In uL 450.1) VO.0 630.1 312.0 402.3 348.2 744.1 3543 216.0 WFL(mL) lOOmL lOOmL lOOtnL IQOniL lQQmL lQQmL lOOmL lOOmL IOOmL Table 21 Actual quantity added for the oxaliplatin solutions of Example 3

____ __ __ __ __ __ __ __ __

Formulation flrtaric Lactic Citric alan1c Molic Maleic.ar Succinic Oxalic ID acid acid add ___ add ____ Ic odd ____ acid Oxaliplatin 100 ml. lOOniL 100 ml. lOQmL 1(JQinL lOOtnL W0nL lOOuiL 100 bulk solution mL jmg/mL) __ __ __ __ __ __ __ __ 1% acid In ut 450.0 355 630 315 405 350 745 355 2163 WFI qa (nit) 100 ml. 100 ml. 100 ml. 100 ml. 100 mL lOOniL 100mL 100 niL 100 __ __ __ __ __ ml.

*SaCthal.IC acid was added as powder ii 100 mtbulkaolutlon to give 0.3 mM acid concentration. 33..

3.2 StabilIty evaluation at Sweelcs at 4ODC The oxaliplatin solutkmscontalning the various carboxylic adds were formulated and place at 40 C at 75%for stability evaluation. The formulations was evaluated at the five weels lim! points and the results are reported below.

3.2.1 Results and Discussion 3.2.2.1 pHandAppearance The pH andappearance results for the formulations of Example 3 are shown in Table 22.

Table 22 Appearance and pH of oxaliplathi formulations of Example 3 for 5 weeks Fouzsubtjon ID InitIal 5 weeks Appearance pH Appearance p14 ___________ _______ _______ 40C 40'C OxaUplatIn/tartarlc _N/t 3.65 N -C)xaliplalin/Iaetlc. Nit -3.94 N' 4.01 -QicaUpla&/thiie Nit 3.65 N. 3.61 Oxaliplathi/malonle N/t 3.69 N 3.64 Oxaliplatin/mollc N/t 3.81 N 3.91 -Oxoliplatln/na1eic -N/I 3.64 N 3.68 Oxaltplatlnfsaccharlc N/t 5.34 N" 4.75 Oxallplatin(wuccinlc N/t -4.03 N 4.09 OxaUpaUn/oxalk N/I 3. 76 N 5.89 I=desreoftnIrlesssaIilfio1I rD//h novLci/epamcis.

A' =cuiv colorless so/u/iou u'ii*fttc black j'izrlic/ea.

<p≥ dearcolor/ess soh#/o# with mauuy whzpaflides.

N/f =,ioI/esfrd. 34..

3.2.1.2 Potency and Impurity Results The potency of thc formulations of Example 3 was mesawed by HPLC after 5 wcek9 at 40 C (Fable 23). Each of the formulatlon.s maintained a potency above 95%.

Table 23 Potency results at initial and 5 weeks for the axaliplatln solutions of

Example3 at 40 C.

Formulation ID Initial (mglmt) wce1cs Gn&lmU % of Initial OxaMpaUn/taTtaI1l 5.19 5.17 99.6 -Oxallplallnf lactic 5.30 5.18 97.7 Oxalipk*Un/cltxlc 5.19 -5.15 99.2 - )xallplatln/rnoionl 5.21 5.18 99.4

C _________________

OxaflPlthifzna! 521 5.15 98.9 -Oxaliplatln/nialeic 520 -5.06 97.3 Dxa]ipladn/aacdiar 5.22 5.01 96.0 Dxa1pIatn/wuc&d 5.22 5.17 99.0

C

xahpLatinfoxallc 5.24 5.21 99.4 The formulations of Example 3 wcrc also assayed by IWLC for the prcscnce of inipurlty B and Dimer after 5 weeks at 400C. Table 24 reports the results of this nssuy. 35.

Table 24 Test results at S weeks at 409C uf the formulations of Example 3 for impurity B and the dimer Impurity.

muialioxt % Impurity B % Dlzner

ID _________________

flp]Min/farta'k 0.36 ND O,adiplatln/Iactlc 0.34 ND Oxallplatln/dtilc 0.26 ND -Oxaliplatht/malordc 0.27 ND Oxaliplatln/malle 0.31 ND OxatipIath/ma1c4c 0.18 ND Cria]ipIailn/saecharic 0.28 ND OxaUpatiu/9uuJnk 0.27 ND Oxaliplatin/oxatic 0.17 ND WD:Nonc dIecfrd Table25 surnmarises the impurity profile obtained from the essay for potency by HPLC wHch wa carded outby IU'LC at thc 5 week time points. 36.

Table 25 Impurity profile from potency assay for oxallplatln solution laimulations of Example 3 at the 5 weeks time point at 40 C.

Impurity Tartaric Lactic C1t1c htalonk iaIic MaleLc Sacc1tarl Sutn1c C)xalic ___________ add add add odd kdd add acid acid acid Totl of unknown 0.01 0.09 0.31 5.93 0.0 0.33 0.42 0.03 0.27 __nnnities -__ ___ __ -R.,S-Oxa1iplatl 0.01 001 0.01 0.2 0.01 0.02 0.01 001 Oxaliplati 99.91 99.71 99.59 93.20 9939 99.58 99.36 99.90 99.49.

ImpuittyC 0.01 0.03 0.02 0.20 O.02 0.05 0.01 Total impurity from 0.03 0.13 0.34 6.15 0.03 036 0.49 0.05 0.33 potancy aasa( _____ ______ -_______ ______ The total Impurity levels for the Exampic 3 fvzmulations from the HPLC assay for pattcy and the HPLC assay for Impurity B aftcr 5 wcels at 40 C ate shown In Table 26.

Table 26 Total Impurity for oxaliplatin solution Io,nuilations of example 3 at 5 weeks time point at 40 C

-

* Impurity Taflorlc Lactic Citric Matanic daliç Maleic Sac&iarlc Succinic Oxafic __________ add odd add acid add add add acid add Total ImpurIty 0.03 0.13 0.34 6.15 0.03 0.36 0.49 0.05 0.33 from potan oswy(%) ____ --____ ______ _____ TmpurllyB(%) 0.36 0.27 0.17 0.18 0.31 026 028 034 0.27 Dlmer(%) ND ND ND ND ND ND ND ND ND Total ImpurIty 0.39 0.40 0.51 6.33 0.34 0.62 0.77 0.39 0.60 (%) -________ --____________ __________ 37.

3.3 Sumntaiy Formulations containing nialic and succinlc acid showed impurity levels which were comparable to the tartarie add formulation. Contrary to the tcaching of the prior art, the malonlc acid formulation contained a surprisingly and imacceptably high level of Impurities relatIve to the tartaric acid formulation. Solutions containing citric, maleic and saecheric acids also showed reasonably low levels of impurity and would be considered to be suitable buffering agents for oxa].iplatln. The etabiftsere of the prior art, oxalic acid and lactic acid, also displayed reasonably low levels of impurity which is unsuzprLcing in the case of oxalic acid due to thc operation oft. Chateller's principle.

Example4

The following funnulation was prepared for the purpose olregulatoiy testing: Oxaliplatin 5mg Tartaric acid 0.03 mg NaOH (adjust to pH of approxImately 5) wvrqslmL The pH Is adjusted to pH 5 wIth a range of from 4.7 to 5.5 using NaOH. The cancimtration of tartaric add 1 about 0.2 mM.

Throughout this specification, the word "comprise", or variations such as "comprises" or "comprising" will be mdcrstood toply the inclusion of a stated element, Integer or step, or 21) groups of elements, intcgers or steps, but not the cxdusion of any other element, inlcger 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 specification 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 part of the prior art base or were common general knowledge in the geld relevant to the present Invention as It existed in Australia before the priority date of each claim of the application.

ft wifi be appreciated by persons skilled In the art that numerous variations and/or modificatkuw may be made to the irwerdicxn as shown In the specific embodime.nts without SR.

departing from the spirit or scope of the Invention as broadly described. The present cxnbodmmts axe, therefore, to be considered In all respects as illustrative and not restrictive. 39.

Claims

CLAIMS

1. A pharmaceutical liquid formulation of oxaliplatin for parenteral administration, said formulation comprising (1) oxaliplatln (ii) water and (iii) an add wherein the acid is stab'I]islng and Is not malonic acid, lactic acid or oxalic acid.

2. A formulation according to claim I wherein the add Is a carboxyllc acid.

3. A fonnulation according to claim 1 or claIm 2 wherein the add is a dicarboxylic acid..

4. A fonxuil&tion according to any one of claIms 1 to 3 wherein the add Is selected from the group consisting of citric acid, maleic acid, eaccharlc acid, aucdnlc add, malic acid, tartarc acid end mixtures thereof.

5. A formulation according to any one of claIms 1 to 4 wherein the acid is selected from the group consisting of maUc acid, succinic acid, tartaric acid and mixtures thereof.

6. A for ulalion according to any one of claims I to 5 whereIn the add Is tartoric acid, 7 A fomtulationaccordlngtoanyone of claims Ito bwhereln theaddls ara concentmtkmof aticast 0.01 mM.

8. A pharmaceutical liquid formulation of oxaliplatin for parenteral ad nlr%lshnlion, said formulation comprising (i) uxalip1ati (ii) water; and (fir) an acid comprising at least 4 carbon atoms.

9. A formulation according to claim S wherein the acid is a dicarboxylic acid.

ID. A fonmilatlon according to claIm 8 or claIm 9 whereIn the acid comprises 4 tolD carbon atoms.

ii. Afoxmulationaccordlngto anyonoclalzns8to l0whcreintheacid compzises4 to6 carbon atoms.

12. A formulation according to any one of claims 8 toll whezent thy acid comprises 1 or 2 hydroxyl groups.

-5 13. A formulation according to any one of claims S toll wherein the add is selected from the group consisting of citric acid, iiatyiv acid, saccharlc acid, succinlc add, malic add, tartaric add and niixtute (hereof.

14. A fo ulcnacco ngtoimyoncofclalms8 to 13wlere1ntheaddia selccbcfromthe group consisting o(rnallc add, succinic acid, tartaric acid and mixtures thereoL 15. A formulation according to any one of claims 8 to 14 whereIn the acid Is tartaric acid.

16. A formulation according to city one of claims 8 to 15 whereIn the acid Is at a canconfration of at Icat 0.01 mM.

17. A pharmaceutical liquid formulation of om]lpletin for parenteral adistratian, aaid formuIt1on comprising (1) oxallplatin, (ii) water and * (ii an additive selected from the group consisting of a pharmaceutically acceptable caiboxylic avid, a salt of a pharmarenP'rnl)y acceptable caboxyllc ac4 a ph miaceulically acceptable derivative of a phaxinaceutkaliy acceptable carboxyllc acid and mixtures theieof, whereIn The additive Is at a concentration of at least 0.01 mM and wherein the acid is not malonic adds, lactic acid or oxalic acid.

18. A formulation according to claim 17 wherein the acid is a dlcarboxylk acid.

:19. A formulation according to claIm 17 wherein the add is selected from the group consisting of citric acid, malcic add, sacehatic acid, succinic acid. ina& add, tartaxic acid and mixtures thereof.

20. A pharmaceutical liquid formulation of oxeftplatln for parenteral administration, said formulation comprising (i) oxa]iplatin, (U) water and 41.

(ill) an additive selected from the group consisting of a pharmaceutically acceptable corboxylic acid, a salt of a phannaceuticafly acceptable carboxylic acid, a pharmaceutically acceptable derivative of a pharmaceutically acceptable caiboxylic add and mixtures thereof; wherein the additive is at a concentration of at 1est 0.01 mM and wherein the carboxylic acid is of thefcrmula HQ2C[C(Kl)(R2))nCO2H wherein ii =2 to 6; and RI and R2 azv each independently selected from the group consisting of H, OH, CO2H, halo and methyL 21. A foimulatian according to dairn 20 wherein n = 2 to 4.

22. A formulation according to claim 20 wherein the acid Is selected from the group consisting of dide add, saccha& add, sucdxüc acid, malic acid, tartatc acid and mixtures thereof.

23. Afonu1atonaccord1ngtonyoneofclalms17to22whereInthecarbocylicaddia selected froni the group consisting of maJi add, succinic acid,, tartark acid and mixtures thereof.

24. A pharmaceutical liquid ulatlm according to any one of claIms 17 to 23 whcrdn the pharinaceutkally acceptable carboxylic add Is tartarlc add.

25. A pharmaceutical liquid fcnnulation of oxailpiatin for parenteral administration, said formulation comprising (1) oxaliplatln, (ii) watezand (iii) an additive selected from thc group consisting of tarlaric acid, a salt of tartaric acid, a pharmaceutically acceptable dcxivathrc of tartaric acid and mixtures thereof; wherein the additive Is aLa concentration of at least 0.01 mM.

26. A formulation according to any one of claims 17 to 25 whereIn the concentration of the additive Is from about 0.01 mM to about
2.0 mM.

27. A formulation according to any one of claIms 17 to 26 wherein the concentration of the additive Is from about 0.1 mM to about 1,0 mM.

28. A formulation according to any ac of clui 17to 27 whereIn the concentration of the additive is from about 0.1 mM to about 0.6 mM..

29. A formulation according to any one of claims 17 to 28 wherein the concentration of the additives is from about 0.2mM to about 0.6mM.

30. A formulation according to any one of claims 17 to 29 wherein the additive comprises a salt of a pharmaceutically acceptable acid and wherein the salt is a sodium salt.

31. A formulation according to any one of claims 1 to 30 wherein the concentration of oxaliplatin up to about 15 mg/mi.

32. A formulation according to any one of claims 1 to 31 wherein the concentration of oxaliplatin up to about 7mg/mi.

33. A formulation according to any one of claims 1 to 32 wherein the pH of the formulation is in the range of from about 3 to about 7.

34. The use of a pharmaceutical formulation according to anyone of claims 1 to 33 in the preparation of a medicament for the treatment of a cancer.

35. A method for preparing a pharmaceutical formulation, 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 pharmaceutically acceptable carboxylic acid, a salt of a pharmaceutically acceptable carboxylic acid, a pharmaceutically acceptable derivative of -42 -a pharmaceutically acceptable carboxylic acid and mixtures thereof: (iii) optionally, adjusting the pH of the solution with a pharmaceutically acceptable base wherein the acid is not malonic acid, lactic acid or oxalic acid.

36. A method according to claim 35 wherein the acid is a dicarboxylic acid.

37. A method according to claim 35 wherein the acid is selected from the group consisting of citric acid, maleic acid, saccharic acid, succinic acid, malic acid, tartaric acid and mixtures thereof.

38. A method for preparing a pharmaceutical formulation, the method comprising the steps of: (1) dissolving oxaliplatin in water to form a solution; (ii) dissolving in the solution an additive selected from the group consisting of a pharmaceutically acceptable carboxylic acid, a salt of a pharmaceutically acceptable carboxylic acid, a pharmaceutically acceptable derivative of a pharmaceutically acceptable carboxylic acid and mixtures thereof: (iii) optionally, adjusting the pH of the solution with a pharmaceutically acceptable base -43 -wherein the carboxylic acid is of the formula: HO2C(C(R1) (R2)]nCO2H S Wherein n=2 to 6; and Ri and R2 are each independently selected from the group consisting of H, OH, CO2H, halo and methyl.

39. A method according to claim 38 wherein n=2 to 4.

40. A method according to claim 38 wherein the acid is selected from the group consisting of citric acid, saccharic acid, succinic acid, malic acid, tartaric acid and mixtures thereof.

41. A method according to any one of claims 35 to 40 wherein the carboxylic acid is selected from the group consisting of malic acid, succinic acid, tartaric acid and mixtures thereof.

42. A method for preparing a pharmaceutical formulation, the method comprising the steps of: (1) dissolving oxaliplatin in water to form a solution; (ii) dissolving in the solution an additive selected from the group consisting of a tartaric acid, a salt of tartaric acid, a pharmaceutically acceptable derivative of a pharmaceutically acceptable tartaric acid and mixtures thereof; -44 - (iii) optionally, adjusting the pH of the solution with a pharmaceutically acceptable base.

43. A method according to any one of claims 35 to 42 wherein the concentration of the additive is from about 0.0]. mM to about 2.0mM.

44. A method according to any one of claims 35 to 43 wherein the concentration of the additive is from about 0.1 mM to about 1.0 mM.

45. A method according to any one of claims 35 to 44 wherein the concentration of the additive is from about 0.1 mM to about 0.6 mM.

46. A method according to any one of claims 35 to 45 wherein the concentration of the additive is from about 0.2 mM to about 0.6 mM.

47. A method according to any one of claims 35 to 46 wherein the additive comprises a salt of a pharmaceutically acceptable acid and wherein the salt is a sodium salt.

48. A method according to any one of claims 35 to 47 wherein the concentration of oxaliplatin is up to about 15 mg/mi.

49. A method according to any one of claims 35 to 48 wherein the concentration of oxaliplatin is up to about 7 mg/mi.

50. A method according to claim 49 wherein the concentration of oxaliplatin is about 5 mg/mi.

-45 - 51. A method according to any one of claims 35 to 50 wherein the pharmaceutically acceptable base is sodium hydroxide.

52. A formulation according to any one of claims 35 to 51 wherein the pH of the formulation is adjusted to be in the range of from 3 to 7.

53. A pharmaceutical liquid formulation of oxaliplatin for parenteral administration, said formulation comprising (i) about 5 mg/mi of oxalipiatin, (ii) water, and (iii) an additive consisting of tartaric acid and the sodium salt of tartaric acid, 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 5.5.

54. The use of a pharmaceutical formulation according to claim 53 in the preparation of a medicament for the treatment of a cancer.

55. A method for preparing a pharmaceutical formulation, the method comprising the steps of: (i) dissolving oxaliplatin in water to form a solution; -46 - (ii) dissolving tartaric acid in the solution; (iii) adjusting the pH of the solution with sodium hydroxide such that it is in the range of from 4.7 to 5.5.

S

wherein the concentration of oxaliplatin is about 5 mg/mi and the concentration of tartaric acid is about 0.2 inN.

-47 -