WO2005102312A1

WO2005102312A1 - Concentrated oxaliplatin solutions

Info

Publication number: WO2005102312A1
Application number: PCT/AU2005/000587
Authority: WO
Inventors: Darryl Vanstone Whittaker; Aikun Julie Liu; Marisa Ciampini; Allan Harvey Spencer
Original assignee: Mayne Pharma Limited
Priority date: 2004-04-27
Filing date: 2005-04-27
Publication date: 2005-11-03

Abstract

There is provided a pharmaceutical liquid formulation for parental administration comprising: (a) greater than 5 mg/mL oxaliplatin; (b) water; and (c) at least an effective solubilising amount of a cyclodextrin. The invention further provides use of a pharmaceutical formulation in the treatment of cancer and a method for treating cancer in a patient which comprises administrating a therapeutic amount of a pharmaceutical formulation. A method for preparing a pharmaceutical liquid formulation of oxaliplatin is also disclosed.

Description

CONCENTRATED OXALIPLATIN SOLUTIONS

FIELD OF THE INVENTION

The invention relates to formulations containing oxaliplatin.

BACKGROUND OF THE INVENTION

Oxaliplatin iβ an anti-car-ccr agent Oxaliplatin (CAS 61825-94-3), also known as L-OHP, is a third generation platinum complex. The term "oxaliplatin" as used herein includes mdividually ciι^oxalato(trans-l-l,2-diaιrιmocyclohexane) plat tum{II), its optical enantiomer cLs^xalato(trans-d-l,2-diamincκy ohexane) plat ram(II) or any racemic mixture thereof.

Oxaliplatin is currently approved and marketed for second-line treatment of colorectal cancer. Hospitals generally purchase oxaliplatin in a lyoptølised form (20 mg, 50 g or 100 mg vials). Just prior to administration, the lyophilised powdef is reconstituted using water for injection or 5% glucose injection solution to provide a solution containing 5 mg/mL oxaliplatin. The reconstituted solution is then further diluted in 250-500 mL of 5% glucose injection solution. The diluted oxaliplatin solution is then in used either by peripheral vein or central venous line over 2 to 6 hours.

Several ready-to-usc liquid oxaliplatin preparations have been proposed. Examples of previous attempts to provide a ready to use solution include:

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. According to this disclosure, oxaliplatin is not stable and soluble at concentrations greater than 5 mg/mL. An oxaliplatin in water solution at a concentration of 5 mg/mL was approved by the FDA in January 2005. 2. WO 99/43355 and US 6,306,902 disclose an oxaliplatin solution formulation containing 1 to 7 mg/mL oxaliplatin, a buffering agent and a pharmaceutically acceptable carrier. The buffering agent is defined to be any acidic or basic agent and the preferred buffering agent (and only example) is oxalic acid or an alkali metal salt thereof. The patent also reports that the presence of die anionic buffering agents citrate, acetate, and phosphate, and additionally buffers comprising glycine and TRIS result in unacceptable degradation of oxaliplatin in aqueous solutions. 3. WO 01/15691 discloses solutions of at least 7 mg/mL 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. It also teaches that alternative solubilisers such as cyclodextrins are inappropriate in oxaliplatin solutions as they cannot achieve the desired solubility.

4. US 6,476,068 discloses an oxaliplatin solution forniulation comprising 0.1 to 10 mg/mL oxaliplatin, an effective stabilising amount of lactic acid and a pharmaceutically acceptable carrier. However, fl c preferred range of oxaliplatin is 2 to 5 mg/mL

5. US Patent Application No.20030109515 discloses an oxaliplatin solution formulation containing a stabilising amount of malonic acid. The examples are directed to formulations having an oxaliplatin concentration of 2 mg/ml.

Issues associated with aqueous oxaliplatin solutions include: (1) solubility of the oxaliplatin; and (2) stability of the oxaliplatin.

Oxaliplatin is moderately soluble in water. The maximum solubility of the oxaliplatin in water at 37°C is reported to be 7.9 mg/mL and at 20^ώC is only 6.0 mg/mL As a consequence of this, aqueous solutions are about 5mg/ml in concentration to prevent any risk of formation of precipitates or crystalline matter.

Further, at these low concentrations, the required dose volume of oxaliplatin is such that the storage and handling of a large number of bottles or soft bags may be required, thus preventing the convenient use of containers such as pre-filled syringes or multi-dose bottles. For example, the recommended dose of 130 mg/m³ for an average person of 1.7 m² requires the use of at least 110 L of a 2 mg/mL solution.

Solutions of higher concentration obtained using conventional solubilization approaches, such as the use of organic solvents or a combination of organic solvent.., surfactants, or extreme pH conditions as taught in the prior art, would require large concentrations of co- solvent, or may render the solution viscous and/or difficult to handle during the reconstitution procedures. Further, such formulation additives often cause adverse reactions in patients, for example infusion-related pathologies and possible precipitation of the drug following dilution in the bloodstream. For oxaliplatin, these traditional methods are inadequate for solubilising a sufficient amount of oxaliplatin for use as a pharniaceutically acceptable intravenous pa renteral formulation.

Oxaliplatin is known to produce certain degradation products in aqueous solutions when other additives are present Ionic salts such as chloride, dtrate, acetate, phosphate and the additives glycine and TRJS, have all been reported to destabilise oxaliplatin in solution. Therefore, in any attempt to improve the solubility of oxaliplatin, care must be taken to ensure that the stability of the oxaliplatin in the solution is maintained so as to oid the formation of unwanted impurities such as diaqua oxaliplatin and diaqua oxaliplatin ditner.

It is known that cyclodextrins may be used as solubilising agents for improving the water solubility of certain poorly water soluble drugs.

Cyclodextrins are water-soluble cyclic sugar oligo ers (oligosaccharides) which differ from one another in the number of glucopyranose units. The most readily available cydαdextrins are composed of six, seven or eight alρha-D-glucose units (c , β and γ respectively).

The solubility of a drug may be increased by virtue of the inclusion of the drug in the relatively hydrophobic cavity of the cyclodextrin. For instance, US 4696918 discloses that α- cyclodextrin can be used to solubilisc l,l-<ydobutanedicaιboxylatedia--πmineplatinu (H) (carboplatin). However, it is by no means certain that cyclodextrins will improve the solubility of a particular drug. As stated above, WO 01 /15691 teaches that cyclodextrins are inappropriate as solubϋisers of oxaliplatin. It is stated that certain cyclodextrins have allowed the concentration of oxaliplatin to be increased only very slightly.

In addition to improving solubility, cyclodextrins may affect the stability of the drug. For example, destabilisation may result when the included drug is conf ormatiσnally constrained or when flic included drug Ls in close prox-mity to a substituent group on the cyclodextrin itself, which may lead to accelerated chemical degradation. For instance, it has been reported that the stability of certain β-lactam antibiotics is adversely affected by cyclodextrin, and the drugs indomethacin, chlorpromazine, acetylsalicylic acid and prostaglandin El are also destabilised by cydcκ3ex-rins. Further, the degradants so formed may be new degradants that might not ordinarily result in the absence of the cyclodextrin. For this reason, one cannot readily predict the effect dissolved cyclodextrin will have on the stability of a drug in solution. In particular, as oxaliplatin is prone to destabilisation in solution when additives are present, one might expect destabi-isation to occur in the presence of cyclodextrin, particularly if the cyclodextrin is in an ionic salt form. SUMMARY OF THE INVENTION

It has now unexpectedly been found that cyclcκkxtrins can increase the solubility of oxaliplatin in aqueous formulations to levels significantly greater than its intrinsic aqueous solubility without a significant decrease in stability, without the formation of significant amounts of new degradants, and without a significant increase in the viscosity of the formulations.

According to a first aspect of the invention, there is provided a pharmaceutical liquid formulation for parenteral administration comprising:

(a) greater than 5 mg/mL oxaliplatin, (b) water; and (c) a leas a efie<^v solubi--tein amountofa cydodextrin. •

According to a second aspect of the invention, there is provided the use of a pharmaceutical formulation according to the first aspect of the invention for the treatment of a cancer. According to a third aspect of the invention, there is provided the use of a pharmaceutical f rmulation according to the first aspect of the invention in the preparation of a medicament for the treatment of a cancer.

According to a fourth aspect of the invention, there is provided a method for treating a cancer which comprises aclministerlng a therapeutic amount of a pharmaceutical formulation according to the first aspect of the invention to the patient.

According to a fifth aspect of the invention there is provided a method of preparing a pharmaceutical liquid formulation of oxaliplatin according to the first aspect comprising the steps of: (i)

and oxaliplatin; and

(ii) optionally, adjusting the pH of the solution.

According to a sixth aspect of the invention, there is provided a phaimaccutical composition for the preparation of a liquid formulation according to the first aspect, the composition comprising:

(a) oxaliplatin; and (b) a cyclodextrin.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 depicts solubility isotherms obtained for oxaliplatin in sdertcd cydodcxtrin solutions. Concentration (M) of dissolved oxaliplatin vs cyclodextrin concentration (M) for the sulfobutyl ether substituted β-cyclodextrin • (Captisol®), two commercial hydroxypropyl substituted β-cyclodextrin grades having a degree of substitution of 4.1 - 5.1 ■ (Cavitron® 82003) and 5.0 - 8.0 A (Cavitron® 82004) and a methyl-β-cydodextrin O (Cavasol® W7 M Fharma). DETAILED DESCRIPTION OF THE INVENTION The prior art teaching of WO 01/15691 suggests that cyclodextrins arc unsuitable solubilising agents for oxaliplatin. Contrary to this teaching, the present inventors have found that cydodextrins can increase the solubility of oxaliplatin in aqueous formulations without a significant decrease in stability and without the formation of pharmaceutically significant amounts of new degradants. Further, the cyclodextrins of the present invention are appropriate for parenteral use and it has been found that even when high concentrations of the cydodcxtrin is present in solution, the viscosity of the oxaliplatin/ cyclαdextrin formulation is suffidently low for it to be suitable for 'parenteral administration,

(a) greater than 5 mg/mL oxaliplatin; (b) water; and (c) at least an effective solubilising amount of a cyclodextrin.

As used herein the term "effective solubilising amount of cyclodextrin" means an amount of cyclodextrin which is suffident to improve the solubility of oxaliplatin in water.

Preferably, the concentration of cydodextrin is at least 1% w/ .

It is pref rred mat the solution is clear, colourless and predpϊtate free for a pharmaceutically acceptable period of time. This will depend on the intended shelf life of the pharmaceutical formulation and the manipulation required prior to administration.

Preferably, the cyclodextrin is selected such that the solubility of the oxaliplatin is improved. The quantity of oxaliplatin in a pharmaceutical formulation according to the present invention will dictate the quantity of cyclodextrin required. The amount of oxaliplatin can range up to 15 mg/mL or higher provided that sufficient c clodexftrin is added. Preferably, the concentration of oxaliplatin is at least 7 mg/mL, more preferably at least 10 mg/mL, even more preferably at least 14 mg/mL. In another embodiment, the amount of oxaliplatin is in the range of from 9 mg/mL to 12 mg/mL, more preferably it is about 10 mg/mL.

The cydodextrin used may be an α-, β, or γ-cyclodextrin and may be substituted or unsubstituted. More preferably, the cydodextrin is substituted. Even more preferably, the cydodextrin is a substituted derivative of β^dodextrin selected from the group consisting of hydroxypropylatcd, methylated and sulphobutyl ether derivatives of β-cyclodextrin. Yet more preferably, the cydodextrin is a sulphobutyl ether substituted derivative of β- cyclodextrin.

Preferably, the cyclodextrin is a pharmaceutically acceptable derivative.

The formulation is preferably pharmaceutically stable. It has been found that the oxaliplatin in formulations according to the invention displays a level of stability that is within he limits appropriate for a pharmaceutical which is administered parenterally. The established limits are exempli ied by international guidelines issuing from International Conference on Harmonisation (ICH). A person skilled in the art will know what are the accepted limits for oxaliplatin stability at the time of preparing the pharmaceutical formulation. The relationship between oxaliplatin solubility and cydodextrin concentration in the concentration ranges studied has been found to be approximately linear (see Figure 1). As mentioned above and as can be seen from the examples, the concentration of cyclodextrin required to solubilise the oxaliplatin will vary depending on the type of cydodextrin used and the concentration of oxaliplatin desired. T e des edoxahplatmccacentrations aybe provided by cydodextrin concentrations in the preferred range of about 1 to 50% w/ v. For instance, concentrations of greater than 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% and 45% and ranges between any two of these values might be considered. For instance, from the solubility data provided, it can be inferred that for preparation of a solution containing 10 mg/mL of oxaliplatin the amount of the sulfobutyl substituted β-cylcodex-rin required will typically be at or above 20% w/v.

The pH of the pharmaceutical formulation according to the invention is preferably the pH of the resulting oxaliplatin solution obtained following complete dissolution of the drug and the cydodextrin. Typically this is a pH in the range from 3 to 7. The pH of the oxaliplatin formulation may be adjusted if necessary using known pharmaceutically- acceptable adds and bases which are compatible with oxaliplatin.

Accor ingly, the present invention further provides a pharmaceutical liquid formulation for parenteral administration comprising:

(a) greater than 5 mg/mL oxaliplatin; (b) water; (c) at least an effective solubilising amount of a cyclodextrin; and

(d) an additive selected from the group consisting of a pharmaceutically acceptable acid, a pharmaceutically acceptable salt of a pharmaceutically acceptable acid, a pharmaceutically derivative of a pharmaceutically acceptable acid, and mixtures thereof.

Preferably, the pharmaceutically acceptable add is an organic acid. More preferably, the acid is selected rom the group consisting of dtric add, maleic add, saccharic add, succinic acid, malic acid and mixtures thereof. Preferably, the pharmaceutically acceptable add is a dicarboxylic acid. More preferably, the acid is selected rom the group consisting of maleic add, saccharic add, succinic add, malic acid, tartaric add and mixtures thereof.

In a further preferred L^«mlxxumcnt, the pharmaceutically acceptable acid is selected from a dicarboxylic add of the formula H02CtC(Rl)(R2)InC02H wherein n « 2 to 6; and Rl and R2 are each independently selected from the group consisting of hydrogen, hydroxy, halo and methyl. Yet more preferably, the pharmaceutically acceptable add is selected from the group consisting of dtric add, maleic add, saccharic acid, sucdnic acid, malic acid and mixtures thereof. Even more preferably, the add is selected from, the group consisting of tartaric add, succinic acid and malic acid. Most preferably, the add is tartaric add. Preferably, the total concentration of the additive is from 0.01 mM to 2mM, more preferably from 0-lmM to ImM, even more preferably from O.l M to 0.6mM, and most preferably from 0.2mMto 0.6mM.

When the additive is a salt it is preferably a sodium salt _: Pharmaceutically acceptable derivatives of carboxylic acids indiide but are not limited to such derivatives as esters, amides, carbonates and carbamates of the acid. Further, as is known to the person skilled in the art, the pH of the formulation may be buffered by the use of a mixture of an add and its conjugate base which is typ aily, in the case of an organic acid, the salt of the add, Accordingly, the present invention further provides a pharmaceutical liquid formulation for parenteral administration comprising

(a) greater than 5 mg/ml. oxaliplatin, (b) water; and (c) at least an effective solubilising amount of a cydodextrin

(d) an additive selected from the group consisting of a pharmaceutically. acceptable add, a salt of the add and mixtures thereof.

The attainment of concentrated solutions of oxaliplatin makes it possible to produce low volume oxaliplatin parenteral products which are more convenient and safer to handle than the conventional products. Thus, in addition to improved product safety conferred by the rendition of a ready-to-use liquid format, the reduced product volume further improves safety in handling since the volumes to be transferred from container to infusion bag become smaller. Syringing is easier and more convenient and this, in turn, reduces the likelihood of accidental spillage or dilution error.

It would be understood by a person skilled in the art that a formulation according to the first aspect might be lyophilised for later reconstitution.

Preferably the pharmaceutical formulation of the invention is provided in a sterile, sealed container. For example, a neutral glass of type 1 and a stopper. Examples of the stopper include those made of an elastomer based on halogenated butyls, possibly coated with a fluorinatcd polymer.

According to a second aspect of this invention, there is provided the use of a pharmaceutical formulation according to the first aspect of the invention for the treatment of a cancer.

According to a third aspect of the invention, there is provided the use of a pharmaceutical formulation according to the first aspect of the invention in the preparation of a medicament for the treatment of a cancer.

According to a four h aspect of the invention, there is provided a method for treating a cancer which comprises administering a therapeutic amount of a pharmaceutical rmulation according to the first aspect of the invention to a patient in need thereof. The term "treating" as used herein, unless otherwise indicated_rmeans reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, refers to the act of treating, as "treating" is defined immediately above.

In the above methods, the therapeutic amount of the pharmaceutical formulation to be administered to a patient will typically provide an effective dosage of oxaliplatin which ranges from about 10 mg/m² to about 250 mg/m², more preferably from about 30 mg/m² to about 180 mg/m² and most preferably is about 85 mg/m¹. However, it will be understood that the therapeutic dosage administered will be determined by the physiάan in the light of the relevant ci-xurnstances 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 oxaliplatin will typically be according to best practice known to those skilled in the art at the time of administration.

According to a fifth aspect of the invention there is provided a method of preparing a pharmaceutical liquid formulation of oxaliplatin according to the first aspect comprising the steps of. (i) preparing an aqueous solution of a cydodextrin and oxaliplatin; and

(ϋ) optionally, adjusting the pH of the solution. In a preferred form, step (i) comprises the steps of:

(a) preparing an aqueous solution of cyclodextrin; and

(b) then adding oxaliplatin to the solution.

Preferably, the oxaliplatin is added as a solid and dissolved in the aqueous solution.

Preferably, the solution is made up to a desired final volume or weight with the addition of water for injection.

According to a sixth aspect of the invention, there is provided a pharmaceutical composition for the preparation of liquid formulation according to the first aspect, the composition comprising;

(a) oxaliplatin; and (b) a cydodextrin.

Preferably, the pharmaceutical composition is in a lycφhilised form. The preparation of lyophilised compositions is well known to those skilled in the art. This will enable the composition to be re-constituted by the addition of a suitable diluent and may confer added stability benefits. It is well known In the art that a lyophilised form will often need a bulking agent. Tn order that the nature of the present invention may be more clearly understood, preferred forms thereof will now be described with reference to the following non-limiting examples.

EXAMPLE 1

This example is a study of the effect of a sulphobutyl ether substituted cyclodextrin (SBECD) on the solubility of oxaliplatin in aqueous solution. The SBECD used is Captisol® (SBE7βCD) which is a sulfobutyl ether derivative of βκryclodt^trin (as the hepta-sodium salt), variably substituted on the 2-, 3- and 6- positions with an average total degree of substitution of 7.

A 40% w/v solution of Captisol® was prepared and then serially diluted to 20% w/v, 10% w/v, 5% w/v and 23% w/v. Excess oxaliplatin was added to a series of 2 mL clear glass vials and about 1 mL of the respective Captisol solutions were added to each vial. The vials ere capped and sealed. The sealed vials were placed on a tumbling roller mixer. Solutions were continuously mixed at room temperature for 48 hours. The resulting suspensions were filtered through 0-45μm nylon syringe filters. The filtrates were diluted and analysed for oxaliplatin content by HFLC.

The results of the oxaliplatin solubility study are shown in Table 1. The olubility of oxaliplatin -rignifteantly increased with increasing concentration of this substituted cydodextrin derivative.

The solubility of oxaliplatin in water at room temperature was determined to be 6.45 mg/mL. The solubility of oxaliplatin exceeded 10 mg/mL when the sulfobutyl derivative (Captisol®) concentration was 20 % w/v.

Tablel Solubility of oxaliplatin in different concentration of Captisol solutions.

As can be seen, the solubility of oxaliplatin was increased with addition of the sulfobutyl substituted cyclcdextrin Captisol to the solution. An oxaliplatin solubility of approximately 15 mg/mL was achieved using a cydodextrin concentration of 40% w/v.

The solubility isotherm obtained for oxaliplatin in Captisol solution is shown in Figure 1. EXAMFLE 2

This study investigated the influence of two dif erent grades of hydroxypropyl substituted β- cyctodextrin (HPBCD): Cavitron 82003 (having a degree of substitution 4.1 - 5,1 ) and Cavitron 82004 (having a degree of substitution 5.0 -8.0) on the solubility of oxaliplatin.

Aqueous solutions containing different concentrations of Cavitron solutions were prepared by dissolving known quantities of Cavitron 82003 or 82004 in 1 mL of WFI in 2 mL dear glass vials. Oxaliplatin in excess was added to each vial The vials were capped and sealed, and placed on a tumbling roller mixer. Solutions were mixed at room temperature for 24. hours. . The resulting suspensions were filtered through 0.45μm nylo syringe filters. The filtrates were diluted and analysed for oxaliplatin content by TTPLC. The solubility results are shown in Tables 2 and 3. The solubility data obtained with these two grades of hydroxypropyl-β-cyclodextrin are shown in Figure 1.

The solubility of oxaliplatin increased with increasing concentration of Cavitron 82003 and 82004. As shown in Figure 1, there is an apparent linear relationship between the solubility of oxaliplatin and the concentration of HPBCD in the concentration ranges studied.

Cavitron 82003 proved to be more effective in increasing the solubility of oxaliplatin than Cavitron 82004. The oxaliplatin solubility increased to values above 10 mg/mL with 20% (w/v) concentrations of Cavitron 82003 (Table 2), whereas the solubility was 9.30 mg/mL for the same concentration of Cavitron 82004 (Table 3). Table 2:

Solubility of oxaliplatin in dif erent concentration of Cavitron 82003 solutions.

Table 3

Solubility of oxaliplatin in different concentration of Cavitron 82004 solutions.

The oxaliplatin solubility was increased from 6.0 mg/mL to 12.0 mg/mL with the use of Cavitron 82003 at a concentration of 40% (w/v). The solubility isotherms obtained for oxaliplatin for the Cavitron 82003 and Cavitron 82004 solutions are shown in Figure 1.

EXAMPLE 3

This study investigated the effect of a methyl-β-cyclodextrin (trade name Cavasol W7 M Pharma®) on oxaliplatin in aqueous solution. Cavasol W7 M Pharma® is a statistically methylated β-cyclodextrin derivative variably substituted on the 2-, 3- and 6- positions with a degree of substitution ranging from 11.2 to 133.

(1) A 30% w/v of methyl-β-cydodextrin solution was prepared and then 15, 10, 5 and 2.5%w/v solutions were prepared by serial dilution.

(2) Excess oxaliplatin was added to each vial after which 2 L of cydodextrin solution was added. (3) The vials were capped and sealed and placed on a tumbling rotler mixer. Solutions were mixed at room temperature for 48 hours.

(4) The resulting suspensions were filtered through 0.22μm syringe filters.

(5) AH filtrates were diluted and analysed for oxaliplatin content by HPLC. Table 4 Solutions using Cavasol W7 M Pharma

The results of the oxaliplatin solubility study are sho n tn Table 5.

The solubility of oxaliplatin increased significantly in the presence of methyl-β-cyclodextrin. Increased solubility was noted as the amount of cyclodextrin increased. A maximum oxaliplatin solubility of 9.95 mg/mL was achieved using a methyl-β-cyclodextrin concenfration of 30% w/v. A higher concentration of methyl-β^clσdextrin (>30% w/v) could not be produced due to the limited water solubility of the cyclodextrin and the high solution viscosity. Table 5 Solubility of oxaliplatin in dif erent concentrations of Cavasol W7 M Pharma at room temperature

The solubility isotherm of oxaliplatin in the presence of mefhyl-β-cyclodextrin is shown in Figure 1. EXAMPLE 4

This study investigated the influence of added cyclodextrin on the stability of concentrated oxaliplatin solutions.

Known degradation products of oxaliplatin include:

(trans-.-l,2diaminocydohexane)trans-dihydroxo(oxalato) platinum (IV). This is an oxidative degradation product of oxaliplatin. This degradation product has been designated as Impurity C in this study. (SP-4-2)-diaqua-l(lR,2 )^yclθhexane ,2-diar-ύne-k-^,kN^,lρLιtinum, or diaqua DACH platinum. This is a hydrolysis degradation product of oxaliplatin. This degradation product has been designated as Impurity B in this study (SP^2)-di-μ-oxobis[(lR^)-cyclθhexane-l,2_'diaιnine- N,]d^^,]platinum, or diaqua DACH platinum dimer. This is a degradation produd resulting from further reaction of Impurity B. This degradation product has been designated as Dimer in this study. Table 6 shows the 10 mg/ml oxaliplatin solutions formulated using two different cyclodextrins, (1) Captisol, a sulfobutyl ether β cyclodextrin (SBECD), and (2) Cavitron 82003, a hydroxypropyl - -cyclodextrin (HPBCD) with an average degree of substitution of 4 .

Table 6 Formulation details of oxaliplatin solutions using cydodextrins as the solubilising agents

The oxaliplatin solutions were placed under accelerated conditions for six months. The following parameters were tested or the oxaliplatin formulation to determine the stability of oxahplatin foττnulations: pH Potency Platinum (TV) complex (impurity C) Dimer; and Diaqua (DACH) platinum (II) complex (impurity B) The test results for oxaliplatin formulations that contain cyclodextrins at temperatures of 8°C, 25 C and 40 C at the six month time point are shown in Table 7, 8 and 9- The formulations are compared with a control formulation containing 5mg/ml of oxaliplatin in Water for injection (WFI). Table 7 Test results for formulations stored at 8^βC or six months

Tableβ Test results for formulations stored at 25°C or si months

Table 9 Test results for formulations stored at 40°C for six months

These results show that these cyclodextrins enable the formation of solutions with 10 mg/mL of oxaliplatin with pharmaceutically acceptable stability. Further, analysis by HPLC indicated that no significant amounts of new degradants were formed.

EXAMPLES This study was directed towards the adjustment of the pH of an aqueous cyclodextrin/oxaliplatin solution using the pharmaceutically acceptable organic acid tartaric add. The cyclodextrin used was Captisol. An analysis of the stability of the solutions was also carried out using an accelerated protocol.

The components of oxaliplatm/Captisol/tεirtaric acid formulations at pH 4 and pH 7 are presented in Table 10, Table 10

Captisol Oxaliplatin Solutions containing Tartaric Acid

* The pH was adjusted to the required level using NaOH.

The formulations were prepared by dissolving Captisol in water for injection (WFI) at 45- 50°C, then dissolving the oxaliplatin in the solution. Tartaric acid was then added and, where necessary, the pH of the solution was adjusted to the desired level by the addition of NaOH. The solution was adjusted to the final volume or weight by the addition of WFI.

The concentration of tartaric add in the solution was 0.33 mM. The results of an accelerated study of the stability of the solutions is presented in Tables 11 and 12.

Table 11: Results for oxaliplatin solutions at 40°C for 4 weeks.

Throughout this specification the word "comprise'', or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, . or group of elements, integers or steps, but not the exclusion of any other element, integer oχ step, or group of elements, integers or steps. All publications mentioned in this spedficatiόn are herein incorporated by reference. Any discussion of documents, acts, materials, devices, artides or the Mice which has been induded in the present spedncatiσn 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 cotnmon general knowledge in the field relevant to the present invention as it existed any here before the priority date of each dai of this application. It will be appreciated by persons skilled in the art that numerous variations and/or modifications maybe made to the invention as shown in the specific embodiments without departing rom the spirit or scope of the invention as broadly described. The present embcK-Liments are, therefore, to be considered In all respects as illustrative arid not restrictive.

Claims

1. A pharmaceutical liquid formulation for parenteral adininistration comprising:

2. A formulation according to claim 1, wherein the concentration of cyclodextrin is at least 1% w/v.

3. A formulation according to any one of claims 1 or 2, wherein the cydc extrin is -mb_.titutcd.

4. A foπttulation according to any one of dairnsl to 3, wherein the cydodextrin is a substituted derivative of β-cydodcxtrin selected from the group cons-sting of hydroxypropylated, methylated and sulphobutyl ether derivatives of β-cydodextrin.

5. A formulation according to any one of claims 1 to 4, wherein the cydodextrin is a sulphobutyl ether substituted derivative of β-cyclodextrin.

6. A formuktion according to any one of claims 1 to 5, wherein the cydodextrin is about 5 to 40% w/v.

7. A formulation according to any one of claims 1 to 6, wherein the concentration of oxaliplatin is at least 7 mg/mL.

8. A formulation according to any one of claims 1 to 6, wherein the concentration of oxaliplatin is at least 10 mg/mL.

9. A formulation according to any one of claims 1 to 6, wherein the concentration of oxaliplatin is at least 14 mg/mL.

10. A formulation according to any one of daims 1 to 9 further comprising:

(d) an additive selected from the group consisting of a pharmaceutically acceptable acid, a pharmaceutically acceptable salt of a pharmaceutically acceptable add, a pharmaceutically derivative of a pharmaceutically acceptable add, and mixtures thereof.

11. A. formu tion accordin to claim 10, wherein the additive is selected from the group consisting of a pharmaceutically acceptable add, a pharmaceutically acceptable salt of the add and mixtures thereof.

12. A formulation according to claim 10 or claim 11, wherein the pharmaceutically . acceptable add is a dicarboxylic add.

13. A formulation according to claim 10 or daim 11, wherein the pharmaceutically acceptable add is selected from a dicarboxylic add of the formula H02C[C(Rl)(R2)jnC02H wherein n = 2 to 6; and Rl, R2 are each independently selected from the group coroisting of hydrogen, hydroxy, halo and methyl.

14. A formulation acςording to claim 10 or claim 11, wherein the pharmaceutically acceptable acid is selected from the group consisting of dtric acid, maleic add, saccharic add, malic acid, succinic add and tartaric acid.

15. A formulation according to claim 10 or daim 11, wherein the pharmaceutically acceptable add is selected from the group consisting of malic acid, succinic acid and tartaric add. .•

16. A formulation according to daim 10 or claim 11, wherein the pharmaceutically . , acceptable acid is tartaric acid.

17. A formulation according to any one of clain s 10 to 16, wherein the total concentration of the additive is from 0.01 mM to 2mM.

18. A rmulation according to claim 17, wherein the total concentration of the additive is from O.lmM to ImM.

19, A formulation according to claim 17, wherein the total concentration of the additive is from O.lmM to 0.6mM.

20. A formulation according to claim 17, wherein the total concentration of the additive is from 0.2mM to 0.6mM.

21. The use of a pharmaceutical formulation according to any one of claims 1 to 20 for the treatment of a cancer.

22. The use of a pharmaceutical formulation according to any one of claims 1 to 20 in the preparation of a medicament for the treatment of cancer.

23. A method for treating a cancer in a patient which comprises adrriir-istcring a therapeutic amount of a pharmaceutical formulation according to any one of daims 1 to 20 to the patient.

24. A method of preparing a pharmaceutical liquid formulation of oxaliplatin according to any one of claims 1 to 20 comprising the steps of:

(i) preparing an aqueous solution of a cydodextrin and oxaliplatin; and

(ϋ) optionally, adjusting the pH of the solution.

25. A method according to daim 24, wherein step (i) comprises the steps of: (a) foπr-ϊng an aqueous solution of a cyclodextrin; and

(b) then adding the oxaliplatin to the solution.

26. A pharmaceutical composition for the preparation of liquid formulation according to any one of daims 1 to 20 the composition comprising: ■,

(a) oxaliplatin; and (b) a cydodexirin.

27. A pharmaceutical composition according tro claim 26 wherein the composition is in a lyophilised form.