WO 2013/179310 Al 5 December 2013 (05.12.2013) P O P C T

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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/179310 Al 5 December 2013 (05.12.2013) P O P C T

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07C 69/76 (2006.01) C07C 69/95 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/IN20 13/000346 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, 3 1 May 2013 (3 1.05.2013) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (25) Filing Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 2186/CHE/2012 31 May 2012 (3 1.05.2012) IN (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: MYLAN LABORATORIES LIMITED [IN/ GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, —]; Plot No 564/A/22, Road No 92, Jubilee Hills, Hydera UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, bad 500 034 (IN). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (72) Inventors; and MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (71) Applicants : BHUSHAN, Indu; R & D Center, Plot No TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, 34A, Anrich Industrial Estate, Bollaram (PT), Jinnaram KM, ML, MR, NE, SN, TD, TG). (MD), Medak (DT), Hyderabad, A.P. -502 325 (IN). PANANCHUKUNNATH, Manoj; R & D Center, Plot No Declarations under Rule 4.17 : 34A, Anrich Industrial Estate, Bollaram (PT), Jinnaram — as to applicant's entitlement to apply for and be granted a (MD), Medak (DT), Hyderabad, A.P. -502 325 (IN). patent (Rule 4.1 7(H)) GORE, Subhash; R & D Center, Plot No 34A, Anrich In dustrial Estate, Bollaram (PT), Jinnaram (MD), Medak — as to the applicant's entitlement to claim the priority of the (DT), Hyderabad, A.P. -502 325 (IN). CHINNARI, Har- earlier application (Rule 4.1 7(in)) ish; R & D Center, Plot No 34A, Anrich Industrial Estate, — of inventorship (Rule 4.17(iv)) Bollaram (PT), Jinnaram (MD), Medak (DT), Hyderabad, A.P. -502 325 (IN). JADHAV, Sanjay; R & D Center, Published: Plot No 34A, Anrich Industrial Estate, Bollaram (PT), Jin — with international search report (Art. 21(3)) naram (MD), Medak (DT), Hyderabad, A.P. -502 325 (IN). — before the expiration of the time limit for amending the (74) Common Representative: MYLAN LABORATORIES claims and to be republished in the event of receipt of LIMITED; SANDEEP K. Rathod, Mylan Laboratories amendments (Rule 48.2(h)) Limited, R & D Center, Plot No: 34A, Anrich Industrial Estate, Bollaram Jinnaram (MD), Medak (DT) Hyderabad, A.P- 502 325 (IN).

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o (54) Title: STABLE AQUEOUS COMPOSITIONS OF PEMETREXED (57) Abstract: The present invention relates to storage stable, concentrated aqueous parenteral compositions comprising pemetrexed disodium and atleast one stability enhancing adjuvant such as cyclodextrin derivative, and method of preparing these compositions. "STABLE AQUEOUS COMPOSITIONS OF PEMETREXED"

This application claims priority to Indian Patent Applications 2186/CHE/2012 dated May 31, 2012.

FIELD OF INVENTION

The present invention relates to a storage stable, ready to use, liquid parenteral compositions of pemetrexed and their use in cancer therapy. More particularly, the invention relates to storage stable, concentrated aqueous parenteral compositions comprising pemetrexed disodium and atleast one stability enhancing adjuvant such as cyclodextrin derivative, and method of preparing these compositions.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

A series of 4-hydroxypyrrolo[2,3-d]pyrimidine-L-glutamic acid derivatives have been disclosed, for example in United States patent number 5,344,932.

Pemetrexed disodium salt is chemically known as N-[4-[2- (2-amino-4,7- dihydro-4-oxo- 1H-pyrrolo[2,3-d]pyrimidin-5-yl) ethyl]benzoyl]-L-glutamic acid, disodium salt. Pemetrexed disodium heptahydrate is marketed by Eli Lilly and Company under the trade name ALIMTA®, and is supplied as a sterile lyophilized powder for intravenous infusion available in single-dose vials.

Stress stability studies for pemetrexed have shown that there are two main degradation pathways. In solid state pemetrexed undergo oxidation while in solution it degrades via hydrolysis. This rapid degradation in solution state is one of the main factors that have prevented aqueous pemetrexed formulations having long-term stability from being commercially available. In solution state under acidic condition decarboxylation of glutamic acid is observed, while under alkaline condition degradation proceeds by side chain amide hydrolysis followed by deamination and in presence of oxygen pemetrexed undergoes oxidative degradation.

United States patent number 6,686,365 discloses ready to use (RTU) formulations of pemetrexed, which contain monothioglycerol, L-cysteine or thioglycolic acid as stabilizers to prevent degradation of pemetrexed. However, these formulations failed to demonstrate sufficient long term stability. The drug content during storage fell well below acceptable levels.

PCT patent applications No. WO2012/015810 discloses a long term, storage stable liquid pharmaceutical composition, comprising pemetrexed, antioxidants like lipoic acid, dihydrolipoic acid and methionine lactobionic acid, sodium citrate tribasic and pH adjusting/ modifying agents.

Cyclodextrins are known solubilizing agent and has the ability to complex with lipophilic materials and some proteins to form inclusion complexes and are increasingly used in pharmaceutical formulations. United States patent number 5,134,127 discloses use of sulfoalkyl ether cyclodextrins as solubilizing agents for insoluble or poorly soluble drugs. United States patent number 4,983,586 and 5,024,998 discuss the use of cyclodextrins (in concentrations of 20-50%) to solubilize (as inclusion complexes) lipophilic drugs for injection.

PCT patent applications No. WO2008/067027 discloses use of inclusion complexes of disubstituted urea compound capable of inhibiting Chkl and atleast one cyclodextrin; U.S. patent applications No. 20120065161 and PCT patent applications No. WO201 1/031865 discloses epothilone polymer conjugates including cyclodextrin-epothilone conjugate for the treatment cancer.

None of these prior arts teaches stable, aqueous parenteral compositions comprising pemetrexed and a stability enhancing adjuvants like cyclodextrin derivatives, which imparts long term storage stability to pemetrexed in aqueous solution state, without employing stabilizers such as monothioglycerol, L-cysteine, thioglycolic acid, antioxidants like lipoic acid, dihydrolipoic acid, methionine and lactobionic acid or sodium citrate tribasic.

Therefore, the present invention provides storage stable, ready to use, concentrated aqueous parenteral composition of pemetrexed comprising pemetrexed, a stability enhancing adjuvant, an aqueous vehicle and optional additives like pH modifiers and buffering agents, wherein pemetrexed exhibits long term storage stability in such aqueous solutions. OBJECT OF THE INVENTION

According to the invention, there is provided a stable, ready to use, concentrated, aqueous parenteral composition of pemetrexed or a pharmaceutically acceptable salt for use in cancer therapy.

It is an object of the present invention to provide ready to use, concentrated, aqueous parenteral composition of pemetrexed or a pharmaceutically acceptable salt, comprising pemetrexed and a stability enhancing adjuvant(s), wherein the pemetrexed in aqueous solution exhibits excellent stability.

Another object of the present invention to provide ready to use, concentrated, aqueous parenteral composition of pemetrexed, comprising pemetrexed disodium and a cyclodextrin derivative, wherein the pemetrexed in aqueous solution at pH 6.0± 0.2 to 8.0± 0.2 exhibits excellent stability.

Another object of the present invention is to provide stable, ready to use, concentrated, aqueous parenteral composition of pemetrexed, comprising pemetrexed disodium in an amount form about 1 mg/ml to about 100 mg/ml and hydroxypropyl- β-cyclodextrin, wherein the composition demonstrates long term storage stability.

Another object of the present invention is to provide stable, ready to use, concentrated, aqueous parenteral composition of pemetrexed, comprising pemetrexed disodium, hydroxypropyl- -cyclodextrin, water for injection, sodium hydroxide and hydrochloric acid, wherein the weight ratio of pemetrexed to hydroxypropyl-β- cyclodextrin is in between 1:1 to about 1:5. Another object of the present invention is to provide process for preparing a storage stable, ready to use, concentrated, aqueous parenteral composition of pemetrexed prepared by a process comprising - dissolving hydroxypropyl- β- cyclodextrin in water for injection, to this solution pemetrexed disodium is added and stirred to yield complex of pemetrexed-hydroxypropyl - -cyclodextriii, final volume and pH is then adjusted, the solution is subsequently subjected to aseptic filtration and packed in appropriate container and closure system.

SUMMARY OF THE INVENTION

The present invention is directed to a liquid, parenteral composition comprising pemetrexed or a pharmaceutically acceptable salt, and a stability enhancing adjuvants like cyclodextrin derivatives. Further aspects of the invention include methods of treatment using pemetrexed-containing compositions and kits comprising the same.

Aqueous parenteral compositions according to the invention comprises solution stable complex of pemetrexed with a cyclodextrin derivative, wherein the amount of pemetrexed is from about 1 mg/ml to about 100 mg/ml, wherein the weight ratio of pemetrexed to hydroxypropyl-P-cyclodextrin is in between 1:1 to about 1:5. The composition according to the invention demonstrates long term storage stability and prevents degradation of pemetrexed during the shelf life, wherein the total impurities are not more than (NMT) 2% weight/weight (wt/wt), preferably NMT 1% wt/wt.

In accordance with an aspect of the invention, there is provided a long term storage stable, concentrated, aqueous parenteral composition of pemetrexed comprising: a) pemetrexed or a pharmaceutically acceptable salt thereof; b) hydroxypropyl-P-cyclodextrin; c) a pharmaceutically acceptable vehicle; and d) optional additives.

One of the advantages of the aqueous parenteral composition of the present invention is that the stability of pemetrexed is substantially improved in aqueous solutions. The inventive aqueous pemetrexed compositions are substantially free of impurities when storage at a temperature from about 2°C to about 8°C.

The aqueous parenteral compositions of the invention do not require use of i) monothioglycerol, L-cysteine or thioglycolic acid ; ii) lipoic acid, dihydrolipoic acid or methionine; and iii) lactobionic acid or sodium citrate tribasic as taught in the prior art to prevent degradation of pemetrexed in solution state. The compositions according to the invention are cost effective as they do not require use of techniques such as freeze drying whose operational cost is high. The inventive composition can advantageously be single dose or multi dose ready to use/ ready for further dilution before administration.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a storage stable, ready to use, aqueous parenteral compositions of pemetrexed or a pharmaceutically acceptable salt, for use in cancer therapy. More particularly, the invention relates to a storage stable, concentrated aqueous parenteral composition comprising pemetrexed disodium and atleast one stability enhancing adjuvant such as cyclodextrin derivative in the form of pemetrexed-adjuvant complex.

Attempts to make storage stable, ready to use, aqueous parenteral compositions of pemetrexed were not successful as pemetrexed in solution state tends to degrade very rapidly resulting into product having sub-therapeutic amount of pemetrexed in a very short period of time. It has been determined that pharmaceutically acceptable aqueous formulations of pemetrexed, or its pharmaceutically acceptable salts, in particular the sodium salt, can be prepared by combining pemetrexed, a atleast one stability enhancing adjuvant in aqueous medium to form pemetrexed-adjuvant complex according to the invention showing enhanced stability even in aqueous solution.

The aqueous parenteral compositions according to the invention demonstrate long term storage stability. The inventive complex of pemetrexed and cyclodextrin derivative in aqueous solution is stable and is substantially free of impurities when stored at a temperature of from about 2°C to about 8°C. The total impurity generated in said composition during storage will not be not more than (NMT) 2% weight/weight (wt/wt), preferably NMT 1% wt/wt.

The aqueous parenteral composition according to the invention utilizes cost effective sterilizing techniques such as aseptic filtration, which is easy to perform, efficient and cost effective in comparison to techniques such as freeze drying. The inventive composition can advantageously be single or multi dose ready to use or ready for further dilution before administration.

As used herein, the term "pemetrexed" refers to the free acid form of pemetrexed or its pharmaceutically acceptable salts and polymorphs thereof. Pharmaceutically acceptable salts of alkali metal, alkaline earth metal, non-toxic metal, ammonium, and substituted ammonium salts, such as for example, the sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, monoethanolammonium, triethanol ammonium, pyridinium, substituted pyridinium, and the like, preferably the disodium salt.

Pemetrexed disodium is present in an amount from about 1 mg/ml to about 100 mg/ml, preferably from about 10 mg/ml to about 50 mg/ml. More preferably, pemetrexed disodium concentration in the aqueous parenteral compositions according to the invention is from about 20 mg/ml to about 25 mg/ml. It will be understood that aqueous compositions containing any useful concentration within the ranges, i.e. 1, 10, 15, 20, 25, 30, 35, 40, 50, 75, 100 are contemplated.

Pharmaceutically acceptable stabilizing adjuvants that can be used to stabilize pemetrexed according to the invention includes but not limited to cyclodextrin derivative such as hydroxypropyl-P-cyclodextrin (HPPCD), sulfobutylether- β- cyclodextrin. Hydroxypropyl - -cyclodextrin is present in an amount from about 1 mg/ml to about 500 mg/ml, preferably from about 10 mg/ml to about 250 mg/ml. More

preferably, the concentration of hydroxypropyl - -cyclodextrin in the aqueous parenteral compositions according to the invention is from about 20 mg ml to about 60 mg/ml. The preferred weight ratio of pemetrexed disodium to hydroxypropyl- β- cyclodextrin is 1:3.

For purposes of the present invention, a pharmaceutically acceptable vehicle is a fluid capable of being included in sterile parenteral formulations/ solutions during manufacturing or during administration, and includes but not limited to water for injection, bacteriostatic water for injection, bacteriostatic sodium chloride, saline, 5% dextrose in water, propylene glycol (PG), etc., preferably 0.9% sodium chloride.

In one embodiment of the invention, the pharmaceutically acceptable vehicle is water for injection and/ or 0.9% sodium chloride, a mixture of propylene glycol (PG) and water for injection or a mixture of propylene glycol (PG) and 0.9% sodium chloride. Other vehicles that can be included are polyethylene glycols, alcohols, non aqueous ester solvents, vegetable oil, etc.

The pharmaceutically acceptable alcohol may consist of one alcohol or a mixture of two or more alcohols, preferably a mixture of two alcohols. Preferred pharmaceutically-acceptable alcohols for parenteral administration are ethanol, benzyl alcohol or a mixture of both ethanol and benzyl alcohol.

The pharmaceutically acceptable non-aqueous ester solvent may consist of one or a mixture of two or more pharmaceutically acceptable non-aqueous ester solvents, preferably just one. A preferred pharmaceutically acceptable non-aqueous ester solvent for parenteral administration is selected from benzyl benzoate, ethyl oleate, isopropyl myristate, isopropyl palmitate or a mixture of any thereof

The pharmaceutically acceptable vegetable oil may consist of one or a mixture of two or more vegetable oil, Preferred pharmaceutically acceptable vegetable oil for parenteral administration are castor oil, arachis oil and sesame oil.

Apart from pemetrexed, hydroxypropyl - -cyclodextrin and pharmaceutically acceptable vehicle, the aqueous parenteral compositions according to the invention may optionally contains additives such as chelating agents, buffers, pH/ tonicity modifiers, preservative, etc., which are commonly found as part of parenteral formulations.

The compositiOon according to the invention may optionally include one or more chelating agents like ethylenediaminetetraacetic acid (EDTA).

The buffer systems for sterile products consist of either a weak acid or the salt of weak acid and either weak base or salt of weak base. Buffer systems commonly used for sterile products are amino acids, acetates (1-2%), citrate (1-5%) and phosphates (0.8-2%).

As pH plays an important role in the stability of pemetrexed, the pH of the aqueous parenteral compositions according to the invention should be in between 6.0± 0.2 to about 8.0± 0.2. The pH of the solution can be adjusted using IN sodium hydroxide/ IN hydrochloric acid solution. The pH of the final solution according to the invention containing pemetrexed, hydroxypropyl - -cyclodextrin and water for injection should preferably be 7.0± 0.2.

The aqueous, parenteral compositions of pemetrexed according to the invention described herein may be administered by intravenous injection, by intravenous infusion, by intramuscular injection, by subcutaneous injection, by intracutaneous injection, by intrathecal injection or by intracranial injection. The preferred method of administration is by intravenous infusion.

The inventive aqueous, parenteral composition can advantageously be multi dose ready to use or ready for further dilution before administration, in such cases more than one dose of pemetrexed is packed and hence the compositions may additionally contains a suitable preservative commonly found as part of parenteral formulations.

It aqueous, parenteral compositions of the present invention can be administered in combination with one or more anti-neoplastic agents where the anti neoplastic agent is given prior to, concurrently with, or subsequent to the administration of the composition of the present invention. For sterile filtration, filter with pore size 0.2 µηι (microfiltration) that effectively remove microorganisms are commonly used. Nanofilter with smaller pore size of 20 -50 nm (nanofiltration) can also be employed. To achieve higher total throughput or avoid premature blockage, pre-filters might be used to protect small pore membrane filters.

The manufacturing procedure for the aqueous parenteral composition according the invention involves dissolving pemetrexed disodium salt and cyclodextrin derivative such as hydroxypropyl-p-cyclodextrin in water, adjusting the final volume and pH if required and filtering the solution using appropriate filter to get sterile, ready to use, storage stable aqueous solution of pemetrexed disodium, which is packaged in a suitable container and closure system.

The aqueous parenteral compositions of pemetrexed disodium according to invention can be packaged in any suitable sterile vial or container fit for the sterile storage for extended periods of time. Suitable containers can be glass vials, i.e. Schott treated vials, molded glass vials, and non-glass component vials such as CZ resin vials, polyolefins like polypropylene or polyethylene vials, cyclic olefins polymer (COP) vials and cyclic olefin copolymer (COC) like Schott TopPac vials or other special purpose bags or containers. Containers are of a size sufficient to hold one or more doses of pemetrexed. In accordance with current FDA requirements, vials containing the inventive formulations also have particulate matter well below the acceptable limits.

Preferably aqueous, parenteral compositions according to the invention can be packaged in glass vials, such as Schott treated vials, molded glass vials and non-glass component vials, which minimize delamination and pitting of the glass, as pemetrexed being a cytotoxic substance has a tendency to delaminate glass and due to this glass components leach out to the product resulting in particulate contamination of the product.

Typical long term storage includes time periods of, for example, about 30 days, about 90 days, about 180 days, about 365 days, and about 730 days (i.e. about 1 month, about 3 months, about 6 months, about 1 year and about 2 year). Preferred commercial storage conditions include temperatures of about 2°C to about 8°C, wherein the compositions according to the invention demonstrate long term storage stability.

An HPLC method was employed to identify the peaks for pemetrexed disodium and other related substances/ impurities. Various impurities that were identified during stability study are given below in Table I.

Table I;

Name of the Impurity Pemetrexed Oxidation impurity Pemetrexed Dimer impurity N-Methyl Pemetrexed Alanine derivative of Pemetrexed Dimethylformamide derivative of Pemetrexed Pemetrexed Acid Intermediate Pemetrexed Diethyl ester Single Maximum Unknown Impurity

In a typical preparation, the volume of the liquid formulation of the present invention needed for the required dose can be aseptically withdrawn and transferred to an infusion bag of 0.9% Sodium Chloride (or other pharmaceutically acceptable intravenous solution) for injection. After transfer, the contents of the infusion bag are thoroughly mixed. Administration by intravenous infusion is typically provided over a time period of from about 30 to about 60 minutes.

In one embodiment, the present invention provides stable, ready to use, concentrated, aqueous parenteral composition comprising pemetrexed disodium and hydroxypropyl-p-cyclodextrin containing 25 mg/ml of pemetrexed (2.5% wt/wt), 75 mg/ml of hydroxypropyl- -cyclodextrin (7.5% wt/wt), water for injection and optional additives, wherein the composition demonstrate long term storage stability.

In another embodiment, aqueous parenteral composition according to the invention can be prepared in the following manner; A stock solution of pemetrexed or pharmaceutically acceptable salt is prepared at the desired concentration in a suitable solvent, such as water. To that solution, a second stock solution of the cyclodextrin in a suitable solvent, such as water, is added. The resulting solution can be sonicated to ensure complete mixing of the components so that complex of pemetrexed-cyclodextrin derivative is formed. Final volume is adjusted using water. If required the pH of the mixture is adjusted using known techniques, such as the addition of suitable buffer or pH adjusting/ modifying agents. Sterilizing the solution using filtration and filing said final sterile solution in appropriate container and closure system to get composition according to the invention.

In one preferred embodiment of the invention, the aqueous parenteral composition is prepared by a process comprising the step of: a) A stock solution of hydroxypropyl-p-cyclodextrin is prepared in water for injection containing 1500 mg of pemetrexed; b) To the stock solution 500 mg pemetrexed disodium is added and mixed; c) Final volume and pH of the solution is adjusted and filtered using aseptic filtration; d) Filing the sterile solution containing pemetrexed disodium and hydroxypropyl - -cyclodextrin in suitable container and closure system.

In one specific embodiment the present invention provides a kit comprising a separate single dose/ multi dose container containing ready to use aqueous solution comprising 25 mg/ml of pemetrexed disodium and 75mg/ml of hydroxypropyl -P- cyclodextrin, prepared according to the invention and atleast one separate 100 ml pack of 0.9% sodium chloride injection.

The standard therapy of pemetrexed marketed formulation Alimta® involves administering pemetrexed as a solution via injection into a vein and is usually given once every 2 1 days as a 10-minute outpatient infusion.

During treatment with Alimta® a daily low-dose 350µg to 1000 g of folic acid orally is given as a pre-administration regimen to pemetrexed therapy. The method involve at least 5 daily doses must be taken during this 7-day period preceding the first dose of pemetrexed and continuing throughout treatment and for 2 1 days after the last dose of pemetrexed. Along with folic acid, 1000µg of vitamin B12 intramuscularly - every 3 cycles is also administered. The method involve mandatory administering one intramuscularly injection during the week preceding the first dose of pemetrexed and every 3 cycles thereafter. In one embodiment the present invention provides a pharmaceutical kit comprising single dose or multiple dose container comprising a complex of pemetrexed- hydroxypropyl - -cyclodextrin (1:3 ratio), a pack of 100 ml 0.9% sodium chloride injection or dextrose solution, a pack of 1000 g vitamin B12 injection and blister pack containing folic acid tablet each tablet containing 400 µg folic acid. The kit may contain optional materials for storing and/or administering the drug like infusion bag as well as instructions for storage and use.

The pre-administration of vitamin B12 and folic acid may be achieved by administering vitamin B12 via injection or orally in the form of vitamin B12 tablets/ capsules, folic acid in the form of tablets/ capsules or a combination tablet/ capsule comprising vitamin B12 and folic acid.

In another embodiment the present invention provides a method of administering compositions according to the invention in combination with about 1000 to about 2000 g/d of vitamin B12 administered intramuscularly atleast 1 to about 3 weeks prior to the administration of first dose of pemetrexed, which is repeated every 3 cycles and about 350 to about 1000µg/d of folic acid orally atleast 5 to about 7 days prior to the administration of first dose of pemetrexed, which is continued throughout treatment and for 2 1 days after the last dose of pemetrexed.

In another embodiment the present invention provides a method of administering composition according to the invention in combination with about 1000 to about 2000 µg/d of vitamin B12 administered orally atleast 1 to about 3 weeks prior to the administration of first dose of pemetrexed, and about 350 to about 1000µg/d of folic acid orally atleast 5 to about 7 days prior to the administration of first dose of pemetrexed, which is continued throughout treatment and for 2 1 days after the last dose of pemetrexed.

The aqueous parenteral compositions of the present invention are storage stable; ready to be used and do not require cost sensitive sterilization technique such as lyophilization/ freeze drying and are safer to handle and distribute. The invention also contemplates reducing the amount of pemetrexed impurities generated, especially in aqueous solution state when stored for extended periods. There is a concomitant reduction in unit cost, as the compositions are sterilized using cost effective aseptic filtration technique.

The following examples are intended to illustrate the benefits of the present invention, but not exemplify the full scope of the invention.

Example 1 - 7:

Manufacturing process: a) A stock solution of hydroxypropyl-P-cyclodextrin is prepared in water for injection; b) Pemetrexed disodium salt is added to the solution of hydroxypropyl-P- cyclodextrin and mixed to get a clear solution; c) Final volume of the solution of step b] is adjusted; d) The pH of the solution of step c] is adjusted to about 7.0± 0.2, by adding suitable buffer or pH modifying agent; e) The solution of step d] is subjected to aseptic filtration; f) The solution of step e] is filled in an appropriate container and closure system to get composition according to the invention. Stability Studies: Three composition of Example 1, 3 and 5 were assayed for initial total impurities, pH and drug content. Then these samples were stored at a temperature for about 2- 8°C for 24 weeks and then again by analytical testing total impurities, pH and drug content was measured. From the data on total impurity data as depicted in table II, it can be inferred that hydroxypropyl- -cyclodextrin improves the pemetrexed disodium stability in solution state.

Table II: We claim

1. A ready to use, stable, concentrated, liquid composition of pemetrexed for intravenous injection, comprising pemetrexed disodium, hydroxypropyl- -cyclodextrin and a pharmaceutically acceptable vehicle.

2. The composition according to claim 1, wherein said composition contains 25 mg/ml to about 50 mg/ml of pemetrexed disodium.

3. The composition according to claim 1, wherein said composition contains 25 mg/ml to about 250 mg/ml of hydroxypropyl-P-cyclodextrin.

4. The composition according to claim 1, wherein said pharmaceutically acceptable vehicle is selected form water, water for injection, bacteriostatic water for injection, bacteriostatic sodium chloride, 0.9% sodium chloride solution, 5% dextrose in water, a mixture of propylene glycol and water for injection, a mixture of propylene glycol and 0.9% sodium chloride.

5. The composition according to claim 4, wherein said composition further contains additional vehicles such as polyethylene glycols, alcohols, , non-aqueous ester solvents, vegetable oil or mixtures thereof.

6. The composition according to claim 5, wherein said composition further contains additives such as chelating agents, buffers, pH/ tonicity modifiers, and preservatives.

7. The composition according to claim 6, wherein said pH modifier is selected from sodium hydroxide solution and hydrochloric acid solution.

8. The composition according to claim 7, wherein said composition has a pH from about 6.0 to about 8.0, preferably 7.0± 0.2. 9. A process of preparing ready to use, stable, concentrated, liquid composition of pemetrexed which comprises:

i) hydroxypropyl - -cyclodextrin is dissolved in water for injection to form a solution; ii) to said solution of step i) pemetrexed disodium is added and mixed; iii) final volume of said solution of step iii] is adjusted; iv) the pH of said solution of step iii] is adjusted to about 7.0± 0.2; v) said solution of step iv] is subjected to aseptic filtration; vi) said solution of step v] is filled in an appropriate container and closure system.

10 . A ready to use, stable, concentrated, liquid composition of pemetrexed for intravenous injection, comprising 25 mg/ml of pemetrexed disodium, 75 mg/ml of hydroxypropyl-p-cyclodextrin, water for injection, sodium hydroxide and/ or hydrochloric acid. INTERNATIONAL SEARCH REPORT International application No. PCT/I 13/00346

A. CLASSIFICATION O F SUBJECT MATTER IPC(8 ) - C07C 69/76, 69/95 (2013.01) USPC - 560/51; 514/265.1 According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC(8): C07C 69/76, 69/95 (2013.01) USPC: 560/51 ; 514/265.1; 544/280; 435/375

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) MicroPatent (US-G, US-A, EP-A, EP-B, WO, JP-bib, DE-C.B, DE-A, DE-T, DE-U, GB-A, FR-A); DialogPro; Google Scholar; IP.com; intraven*, IV, vein *, pemetrexed *, disodium*, hydroxypropyl* beta* cyclodextrin*, cyclodextrin*, pH, pharmaceutical *, accept *, vehicle *, water *, sodium *, chloride *, propylene * glycol *, additive*, preservative*

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

CN 10141 1710 B (DAI, J et al.) 15 June 201 1; abstract; paragraphs [0006], [0014], [0020] 1-10

CN 101969961 A (NISHIMURA, T et al.) 09 February 201 1; abstract; paragraphs [0013], [0029], 1-9 [0050]; claim 4

WO 2012/015810 A2 (PALEPU, NR et al.) 02 February 2012; abstract; claims 1, 4 2, 10

US 2005/0080046 A 1 (ARAMWIT, P et al.) 14 April 2005; abstract; claims.9, 12, 15 3, 10

US 201 1/0268658 A 1 (CRAWFORD, TC e t al.) 03 November 201 1; entire document 1-10

US 2009/0181990 A 1 (PATEL, NS et al.) 16 July 2009; entire document 1-10

I Further documents are listed in the continuation of Box C . | |

Special categories of cited documents: "T" later document published after the international filing date or priority document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other "Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art document published prior to the international filing date but later than "&" document member of the same patent family

Date of the actual completion o f the international search Date of mailing of the international search report

2 1 October 2013 (21 .10.2013) 0 5 NOV 2013

Name and mailing address of the ISA/US Authorized officer: Mail Stop PCT, Attn: ISA/US, Commissioner for Patents Shane Thomas P.O. Box 1450, Alexandria, Virginia 22313-1450 Facsimile No. 571-273-3201 Form PCT/ISA/210 (second sheet) (July 2009)