Stable aqueous compositions of pemetrexed

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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.

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.

A series of 4-hydroxypyrrolo 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- 1 H-pyrrolo 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.

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-p-cyclodextrin, atleast one vehicle and optional additives, wherein the weight ratio of pemetrexed to hydroxypropyl-P-cyclodextrin is in between 1 : 1 to about 1 :5 and wherein said composition on storage exhibits total impurities which are not more than (NMT) 2% weight/weight (wt/wt), preferably NMT 1% wt/wt.

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-P-cyclodextriii, final volume and pH is then adjusted, the solution is subsequently subjected to aseptic filtration and packed in appropriate container and closure system.