WO2016059238A1 - Pemetrexed formulations - Google Patents

Pemetrexed formulations Download PDF

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Publication number
WO2016059238A1
WO2016059238A1 PCT/EP2015/074065 EP2015074065W WO2016059238A1 WO 2016059238 A1 WO2016059238 A1 WO 2016059238A1 EP 2015074065 W EP2015074065 W EP 2015074065W WO 2016059238 A1 WO2016059238 A1 WO 2016059238A1
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Prior art keywords
pemetrexed
pharmaceutical composition
less
acid
composition according
Prior art date
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PCT/EP2015/074065
Other languages
French (fr)
Inventor
Jan BÖING
Wouter DEN DEKKER
Renata VARGA
Original Assignee
Teva Pharmaceutical Works Private Limited Company
Pharmachemie B.V.
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Priority claimed from GB1418555.7 external-priority
Application filed by Teva Pharmaceutical Works Private Limited Company, Pharmachemie B.V. filed Critical Teva Pharmaceutical Works Private Limited Company
Publication of WO2016059238A1 publication Critical patent/WO2016059238A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/243Platinum; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52Purines, e.g. adenine
    • A61K31/522Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids

Abstract

Disclosed are pharmaceutical formulations of pemetrexed or pemetrexed salts and processes for their preparation.

Description

PEMETREXED FORMULATIONS
FIELD OF THE INVENTION The present invention is directed to formulations of pemetrexed. In particular, the invention relates to stable formulations of pemetrexed and its salts. The invention is particularly useful for the preparation of liquid formulations, and preferably aqueous formulations of pemetrexed and its salts. The formulations may be prepared as solid formulations, or as liquid formulations in the form of a liquid concentrate or as a ready-to- use (RTU) liquid formulation.
BACKGROUND OF THE INVENTION
Pemetrexed, in its diacid form has the following formula:
Figure imgf000002_0001
The disodium salt of pemetrexed, i.e. pemetrexed di-sodium, is currently marketed by Eli Lilly and Company under the trade name ALIMTA® as a powder for concentrate for solution for infusion. The product is in the form of a white to either light yellow or green- yellow lyophilised powder. Pemetrexed disodium is a member of the folic acid family and is approved for treatment of malignant pleural mesothelioma and for treatment of non small cell lung cancer either as monotherapy or as combination therapy with cisplatin. The commercial product is reported to contain pemetrexed disodium heptahydrate, mannitol, sodium hydroxide, and hydrochloric acid.
Pemetrexed or pemetrexed disodium is currently not commercially available as a ready to use formulation. The preparation of a solution form of pemetrexed or its salts is particularly challenging because of the propensity of pemetrexed and it salts to degrade. This problem is especially exacerbated when pemetrexed or its salts are present in solution, as its degradation or discolouration by oxidation or hydrolysis occurs much more readily. The degradation or storage of pemetrexed or pemetrexed salts such as pemetrexed disodium can lead to a significant visible colour change. Typically, the pure product is colourless, and upon storage of the solution, the product can change in colour from yellow to green-yellow. Such a colour change is undesirable and may lead to acceptance problems for the clinician or patient. When present in solution,
pemetrexed/pemetrexed disodium typically develops a yellow or green-yellow
colouration. For example, solutions prepared by reconstitution of the lyophilised product are also prone to discolouration upon storage. Even in the absence of water, upon storage, pemetrexed/pemetrexed disodium API in solid form is also prone to oxidation and readily develops a yellow/green discolouration due to oxidation. Over time, the increased concentration of degradation products leads to a diminished activity and quality of the product.
Methods of stabilizing pemetrexed and pemetrexed salts are disclosed in the art.
EP2666463 discloses the use of a monothioglycerol as an antioxidant together with a co-stabilizer such as non-ionogenic water soluble polymer and /or an edetate.
WO2001056575 discloses the use of thioglycolic acid and at least one antioxidant selected from monothioglycerol, L-cysteine and thioglycolic acid.
WO2013144814 discloses the use of controlled oxygen and antimicrobial agents. The use of acetyl cysteine and sodium 2-mercaptoethanesulfonate is proposed in
WO2013178214.
Use of an organic amine, which is free from sodium ions and an inert gas is disclosed in WO2013179248.
Stability enhancing adjuvants such as cyclodextrins are proposed in WO2013179310. WO2012121523 discloses the use of antioxidant free solution, which involves controlling the dissolved oxygen concentration, and a closed system with an upper limit of oxygen partial pressure.
According to WO2012015810, antioxidants such as lipoic acid, dihydrolipoic acid, methionine, and a chelating agent can be used. WO2013165130 discloses the use of sodium sulfide and sodium sulfite as stabilising agents.
WO2014084651 discloses an injectable solution containing both an acetylcysteine (antioxidant) and citrate salt (as buffer). WO2014122460 proposes the use of pemetrexed or pemetrexed salt complexed with a co-former such as a carbohydate.
The prior art attempts to stabilise pemetrexed do not provide universally applicable methods to prepare stable formulations of pemetrexed and its salts. For example, reducing agents such as sodium sulfite, and cyclodextrins are not particularly desirable. None of these prior art disclosures provide a satisfactory solution to the problem of providing a simple formulation of pemetrexed or pemetrexed salts.
There is therefore a need to provide further stable formulations of pemetrexed or pemetrexed salts. It is therefore an object of the present invention to provide formulations of pemetrexed or its salts, that are stable and which can be easily manufactured without the need for special excipients.
SUMMARY OF THE INVENTION
The present invention provides stable pemetrexed formulations. Thus, in one aspect of the present invention, there is provided a pharmaceutical formulation comprising:
(a) at least one of the following:
(i) pemetrexed disodium,
(ii) pemetrexed diacid and sodium hydroxide,
(iii) pemetrexed tromethamine salt, or
(iv) pemetrexed diacid and tromethamine, and
(b) citric acid or a citrate,
wherein when (a) is (iii) or (iv), the composition further comprises a sugar alcohol.
The applicant has unexpectedly found that citric acid or a citrate such as sodium citrate e.g. trisodium citrate) can stabilise formulations of pemetrexed diacid, pemetrexed disodium and pemetrexed tromethamine salt. In particular, it has been found that citric acid alone is sufficient to stabilise the formulations, especially formulations containing tromethamine or pemetrexed tromethamine salt, thereby avoiding the need to use the expensive, and potentially undesirable, stabilising agents proposed in prior art compositions. A further aspect of the present invention provides a process for preparing a
pharmaceutical composition as defined above, wherein the process comprises:
(1 ) dissolving the following into water (preferably water for injection), in any order:
(A) pemetrexed diacid
(B) sodium hydroxide or tromethamine
(C) citric acid or a citrate and
(D) a sugar alcohol where necessary, and optionally
(2) adjusting the pH with an acid and/or base, preferably wherein the acid is selected from the group consisting of a mineral acid (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine.
Tromethamine is a particularly preferred base. A particularly preferred combination of acid and base for use to adjust the pH is hydrochloric acid and tromethamine. Other suitable acids include malic acid. The pH adjusting agent may also be a salt of a mineral or organic acid. Suitable such salts include: acetate, citrate, malonate, tartrate, maleate and phosphate. The invention further provides a pharmaceutical composition obtainable by such a process.
The compositions of the present invention, when in the form of a liquid concentration, preferably an aqueous concentrate for dilution or a powder for reconstitution, may be diluted with water for injection or reconstituted in water for injection to provide an aqueous solution for injection or infusion. The dilution or reconstitution may also be done in saline for injection, preferably 0.9% aqueous sodium chloride (9 mg sodium chloride/ml water for injection) for injection. Preferably the dilution of the liquid or aqueous concentrate compositions, or the reconstitution of the powder is done in saline for injection, preferably 0.9% (9 mg/ml) for injection. The pharmaceutical compositions of the present invention particularly when in the form of an aqueous concentrate or a powder can be packaged into a vial or ampoule, which is preferably sealed with an inert gas such as nitrogen to provide a convenient product with good storage stability. A preferred pharmaceutical composition of the present invention is in the form of liquid concentrate, preferably an aqueous concentrate, for dilution. Preferably such a composition is packaged into a vial or ampoule, which is sealed with an inert gas such as nitrogen to provide a convenient, ready-to-dilute product having good storage stability.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the term De-Glu pemetrexed refers the following compound, which is a potential impurity of pemetrexed:
Figure imgf000006_0001
As used herein the term pemetrexed diethylester refers the following compound, which is a potential impurity of pemetrexed:
Figure imgf000006_0002
As used herein the term L-Glu pemetrexed refers to pemetrexed wherein the glutamic acid substituent has L-configuration, and which is a potential impurity of pemetrexed.
As used herein the term D-pemetrexed refers to the following compound, which is a potential impurity of pemetrexed (enantiomeric impurity):
Figure imgf000007_0001
The provision of stable pemetrexed formulations, particularly in the form of solutions (e.g. concentrate for dilution or ready-to-use aqueous solutions) presents a difficult challenge due to the tendency of pemetrexed and its salts to oxidise and/or hydrolyse and/or discolour. A particular concern is the speed at which aqueous pharmaceutical compositions of pemetrexed or its salts can discolour, including those formed by reconstitution of the marketed Alimta® lyophilised product, forming a yellow to green- yellow solution, which although acceptable from a regulatory view, is not desirable from a physician's or patient's perspective. Previous attempts to address the stability problem typically involve the use of a number of special antioxidants, complexing agents, reducing agents and other additives. However, not all of these are suitable for inclusion into concentrates or ready-to-use solutions. Moreover, many of the additives are expensive and their presence in infusion formulations are not especially desirable. In contrast, the stable formulations of the present invention contain simple and relatively inexpensive excipients which are well-tolerated and which do not require special manufacturing methods. In particular, the liquid formulations of the present invention provide a further advantage in that they do not require labour- and energy-intensive processes such as lyophilisation. Moreover, the ready-to-use formulations of the present invention do not require reconstitution, thus making these formulations particularly easy to use. For example, the ready-to-use formulations are liquid formulations, which may comprise an aqueous concentrate, which can be used without reconstitution (such as required in lyophilized products), but can be simply diluted with saline prior to use.
Accordingly, in a first aspect, there is provided a pharmaceutical formulation comprising: (a) at least one of the following:
(i) pemetrexed disodium,
(ii) pemetrexed diacid and sodium hydroxide,
(iii) pemetrexed tromethamine salt, or
(iv) pemetrexed diacid and tromethamine, and (b) citric acid or a citrate,
wherein when (a) is (iii) or (iv), the composition further comprises a sugar alcohol.
Preferably, the pharmaceutical formulation comprises:
(a) at least one of the following:
(i) pemetrexed tromethamine salt, or
(ii) pemetrexed diacid and tromethamine, and
(b) citric acid or a citrate, and
(c) a sugar alcohol.
More preferably, the pharmaceutical formulation comprises a combination of pemetrexed diacid and tromethamine, citric acid or a citrate and a sugar alcohol. Preferably, the weight ratio of tromethamine to pemetrexed diacid is from 0.6 to 1 .2, preferably 0.7 to 1 and more preferably 0.8 to 0.9. The composition may be in the form of a lyophilized powder, or a liquid concentrate or liquid solution. Preferably, the composition is an aqueous concentrate or an aqueous solution. In preferred embodiments, the compositions are in the form of a liquid concentrate or a liquid ready-to-use solution, more preferably the compositions are in the form of an aqueous concentrate or an aqueous ready-to-use solution. Preferably the compositions of any aspect or embodiment of the present invention are in the form of a liquid, preferably an aqueous concentrate. Preferably, the liquid compositions, more preferably an aqueous concentrate, is ready-to-use in that it does not require
reconstitution, and can simply be diluted with water before use. The liquid or aqueous concentrate may be diluted with saline (e.g. 0.9%, i.e. 9 mg/ml) for injection.
In one embodiment, the composition contains: (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide, or a mixture thereof. Preferably, the composition contains either: (i) pemetrexed disodium or (ii) pemetrexed diacid and sodium hydroxide. Preferably, the composition contains a combination of pemetrexed diacid with sodium hydroxide. Preferably, the composition is a liquid concentrate or a liquid ready-to-use solution, and more preferably, an aqueous concentrate or a ready-to- use aqueous solution. According to one embodiment, there is provided a pharmaceutical composition comprising:
(a) (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide,
(b) citric acid or a citrate,
and one or more pharmaceutically acceptable excipients, preferably selected from a tonicity adjusting agent, a pH adjusting agent (acid and/or base), an antioxidant and water for injection or infusion (preferably wherein the water is water for injection).
Suitable tonicity adjusting agents are selected from one or more of: a sugar (such as dextrose), arginine, glycerin, a sugar alcohol (such as mannitol), potassium chloride, or sodium chloride, preferably potassium chloride or sodium chloride, and more preferably sodium chloride. Preferably, suitable tonicity adjusting agents are selected from one or more of: a sugar (such as dextrose), glycerin, a sugar alcohol (such as mannitol) or sodium chloride, with sodium chloride being particularly preferred.
Suitable pH adjusting agents are an acid and/or base. Preferred acids include mineral acids (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine. Preferably, the pH adjusting agent comprises hydrochloric acid and/or sodium hydroxide, preferably both. Alternatively, the base is preferably tromethamine. A preferred acid and base combination for the pH adjusting agent may be tromethamine and citric acid, or tromethamine and hydrochloric acid. Particularly preferred is tromethamine and hydrochloric acid.
According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising:
- one of (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide,
- citric acid or a citrate
- a tonicity adjusting agent
- one or more pH adjusting agents and
- water for injection.
Preferably, the pharmaceutical composition comprises a combination of pemetrexed diacid and sodium hydroxide. Another embodiment of the present invention provides a pharmaceutical composition comprising:
- one of (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide,
- citric acid or a citrate
- sodium chloride
- one or more pH adjusting agents, preferably selected from sodium hydroxide and/or hydrochloric acid, and
- water for injection
in the form of a concentrate or a ready-to-use solution. Preferably, the pharmaceutical composition comprises a combination of pemetrexed diacid and sodium hydroxide, citric acid or a citrate, sodium chloride, and one or more pH adjusting agents, preferably selected from sodium hydroxide and/or hydrochloric acid, and water for injection.
Preferably in these embodiments of the present invention the weight ratio of the citric acid or citrate (based on citric acid) to pemetrexed diacid is from about 1 : 10 to about 1 : 40, preferably from about 1 : 15 to about 1 : 35, more preferably from about 1 : 20 to about 1 : 30, and preferably about 1 : 25.
It will be appreciated that depending on the final formulation and process, the
pemetrexed diacid may react with the sodium hydroxide to form the disodium salt of pemetrexed, i.e. a combination of pemetrexed diacid with sodium hydroxide may comprise pemetrexed disodium. Similarly, pemetrexed diacid may react with the tromethamine to form a tromethamine salt of pemetrexed, i.e. a combination of pemetrexed diacid with tromethamine may comprise pemetrexed tromethamine salt. The weight ratios and concentrations of pemetrexed used throughout refer to the weight ratios and concentrations relative to pemetrexed diacid.
Preferably, when the pharmaceutical composition is in the form of an aqueous solution, the concentration of citric acid or citrate (based on citric acid) in the solution may be from about 0.1 to about 4 mg/ml, preferably from about 0.1 to about 2 mg/ml, more preferably from about 0.5 to about 2 mg/ml or about 0.75 to about 1 .25 mg/ml, and most preferably about 1 mg/ml. It will be appreciated that depending on the final formulation and process, the citric acid may react with the sodium hydroxide to form the sodium citrate (e.g. trisodium citrate). The weight ratios and concentrations of citric acid or citrate throughout refer to the weight ratios and concentrations relative to citric acid.
Preferably, the concentration of pemetrexed acid in the solution is from about 10 to about 40 mg/ml, preferably from about 15 to about 35 mg/ml, more preferably from about 20 mg/ml to about 30 mg/ml, and most preferably about 25 mg/ml. In preferred embodiments of the present invention the pharmaceutical composition is in the form of an aqueous concentrate. The aqueous concentrate may be packaged into a pharmaceutical product, preferably the pharmaceutical product is packaged in a stoppered vial. In use, the aqueous concentrate may be diluted with saline (e.g. 0.9% saline - i.e. 0.9 mg/ml). The stopper can be a bromobutyl or chlorobutyl stopper.
In another embodiment of the present invention, the pharmaceutical composition comprises pemetrexed tromethamine salt, or pemetrexed diacid and tromethamine, or a mixture thereof. Preferably, the composition contains either pemetrexed tromethamine salt, or pemetrexed diacid and tromethamine,. More particularly, the composition contains a combination of pemetrexed diacid and tromethamine. In these embodiments, the composition may be in the form of a powder for reconstitution, a liquid concentrate or a liquid ready-to-use solution or an aqueous concentrate or a ready-to-use aqueous solution. Preferably, the composition may be in the form of a powder for reconstitution, such as a lyophilisate, or in the form of a liquid concentrate, preferably an aqueous concentrate. Most preferably, the composition is in the form of an aqueous concentrate.
A further embodiment of the present invention provides a pharmaceutical composition comprising:
(a) (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and
tromethamine,
(b) citric acid or a citrate,
(c) a sugar alcohol
and one or more pharmaceutically acceptable excipients, preferably selected from a tonicity adjusting agent, a pH adjusting agent (acid and/or base), a cryoprotectant and water for injection or infusion. Preferably the pharmaceutical composition comprises a combination of pemetrexed diacid and tromethamine. Suitable sugar alcohols include those selected from the group consisting of mannitol, sorbitol, and pentaerythritol, preferably mannitol. Suitable tonicity adjusting agent for use in formulations is selected from one or more of: a sugar (such as dextrose), arginine, glycerin, a sugar alcohol (such as mannitol), potassium chloride, or sodium chloride. Alternatively, the tonicity adjusting agent for use in the formulations is selected from one or more of: a sugar (such as dextrose), glycerin, a sugar alcohol (such as mannitol), or sodium chloride. More preferably, the tonicity adjusting agents are potassium chloride or sodium chloride, and most preferably sodium chloride.
Preferred pH adjusting agents for use in compositions containing (i) pemetrexed tromethamine salt, and/or (ii) pemetrexed diacid and tromethamine, are acids and/or bases. Preferably, the acid is selected from the group consisting of mineral acids (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid. Preferred bases are selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine. Preferred combinations of pH adjusting agent comprises sodium hydroxide and/or hydrochloric acid, preferably both or tromethamine and/or hydrochloric acid, preferably both.
In preferred embodiments, the composition containing at least one of (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and/or tromethamine, is in the form of a lyophilisate for reconstitution, and wherein the cryoprotectant is selected from the group consisting of sucrose, dextrose, mannitol, glucose, and preferably is mannitol.
Another embodiment of the present invention provides a pharmaceutical composition comprising:
- one of (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and tromethamine,
- citric acid or a citrate
- a tonicity adjusting agent
- a sugar alcohol
- one or more pH adjusting agents and optionally - water for injection.
A further embodiment provides a pharmaceutical composition comprising:
- one of (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and tromethamine,
- citric acid or a citrate
- a sugar alcohol, preferably mannitol
- pH adjusting agents, preferably selected from a combination of either: sodium hydroxide and hydrochloric acid; or tromethamine and hydrochloric acid, and optionally
- sodium chloride
in the form of a powder for reconstitution, preferably in the form of a lyophilisate.
Where the compositions contain (i) pemetrexed tromethamine salt, and/or (ii) pemetrexed diacid and tromethamine, the weight ratio of the citric acid or citrate (based on citric acid) to pemetrexed diacid is from about 1 : 10 to about 1 : 40, preferably from about 1 : 15 to about 1 : 35, more preferably from about 1 : 20 to about 1 : 30, and preferably about 1 : 25. The liquid or aqueous solution formulations, preferably aqueous solution formulations, of the present invention containing (i) pemetrexed tromethamine salt, and/or (ii) pemetrexed diacid and tromethamine preferably have a concentration of citric acid or citrate (based on citric acid) in the solution of from about 0.1 to about 4 mg/ml, preferably from about 0.1 to about 2 mg/ml, more preferably from about 0.5 to about 2 mg/ml and most preferably about 1 mg/ml.
The liquid or aqueous solution formulations, preferably aqueous solution formulations, of the present invention containing (i) pemetrexed tromethamine salt, and/or (ii) pemetrexed diacid and tromethamine preferably have a concentration of pemetrexed acid in the solution of from about 10 to about 40 mg/ml, preferably from about 15 to about 35 mg/ml, more preferably from about 20 mg/ml to about 30 mg/ml, and most preferably about 25 mg/ml.
Preferably these aqueous solutions are in the form of an aqueous concentrate. The citric acid employed in the compositions of the invention may preferably be anhydrous. The citrate component may be sodium citrate, preferably trisodium citrate or trisodium citrate dihydrate.
The pemetrexed disodium may preferably be in the form of the pemetrexed disodium heptahydrate.
According to a further aspect of the present invention, there is provided a process for preparing a pharmaceutical composition comprising
(a) at least one of the following:
(i) pemetrexed disodium,
(ii) pemetrexed diacid and sodium hydroxide,
(iii) pemetrexed tromethamine salt, or
(iv) pemetrexed diacid and tromethamine, and
(b) citric acid or a citrate,
wherein the process comprises:
(1 ) dissolving the following into water (preferably water for injection), in any order:
(A) pemetrexed diacid
(B) sodium hydroxide or tromethamine
(C) citric acid or a citrate and
(D) a sugar alcohol where necessary, and optionally .
(2) adjusting the pH with an acid and/or base, preferably wherein the acid is selected from the group consisting of a mineral acid (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine. Alternatively, the acid may also be selected from the group consisting of a mineral acid (preferably hydrochloric acid, acetic acid, citric acid, malonic acid, tartaric acid, or malic acid), or a salt of a mineral acid, such as acetate, citrate, malonate, tartrate, maleate or phosphate, and more preferably wherein the acid is hydrochloric acid
The step (1 ) of dissolving (A), (B), (C) and (D) can be carried out in any suitable order which enables the preparation of a solution of the four components. For example, the pemetrexed diacid (A) may be added to an aqueous solution containing at least a portion of component (B). Then the remaining (B), along with (C) and, where necessary, (D) can be added. Preferably, pemetrexed diacid is added to an aqueous solution containing (B), (C) and (D). Thus, preferably pemetrexed diacid is added to a solution of citric acid, mannitol and tromethamine.
In any embodiment of the process, the dissolution of pemetrexed is preferably carried out in an inert atmosphere. Preferably the inert atmosphere is one which minimizes the exposure of the pemetrexed to oxygen. More preferably, the dissolution of pemetrexed is carried out under a nitrogen atmosphere. In addition, it is also preferred that operations involving the handling of pemetrexed, such as weighing, mixing, filtration, filling (e.g. into vials or ampoules) and stoppering, are carried out under such an inert atmosphere, i.e. preferably under a nitrogen atmosphere.
Preferably, the pH is adjusted to between about 6.0 to about 9.0, preferably about 6.0 to about 8.5, more preferably about 6.5 to about 8.0 and most preferably about 6.6 to about 7.8.
The order of dissolution is preferably (A), (B), (C) and where necessary, (D).
Alternatively, the order of dissolution may be (B), (A), and then, in either order, (C) or (D) (when present). Where the pharmaceutical composition is an aqueous concentrate or an aqueous ready- to-use solution, the process may further comprise a step of adding water to obtain the final volume/weight.
Where the pharmaceutical composition is a powder for reconstitution, the process may further comprise a step of removal of the water. For example, where the pharmaceutical composition is a lyophilizate for reconstitution, the process typically comprises: optionally adding a cryoprotectant (preferably selected from the group consisting of: sucrose, dextrose, mannitol, glucose, and more preferably mannitol) prior to removal of the water by lyophilization.
The invention further provides a pharmaceutical composition obtainable by any of the above described processes, as well as a pharmaceutical composition prepared by dilution or reconstitution of a liquid concentrate, an aqueous concentrate or a powder for reconstitution, more preferably, an aqueous concentrate or powder for reconstitution. A preferred pharmaceutical composition is one prepared by dilution of an aqueous concentrate of any embodiment or aspect of the present invention. Preferably, the dilution liquid is saline (e.g. 0.9%, i.e. 0.9 mg/ml).
Further provided is a pharmaceutical product comprising a pharmaceutical composition as defined herein packaged in a vial or ampoule, preferably under an inert gas, such as nitrogen. The pharmaceutical compositions and products of the present invention are stable, and preferably show no significant colour change, or in some cases may show no visible colour change, upon storage:
- at 2-8eC, for 3 months or
- at 2-8eC for 6 months.
The pharmaceutical compositions and products of the present invention are stable, and preferably show no significant colour change, or in some cases may show no visible colour change, upon storage:
- at 25eC, for 3 months, or
- at 25eC for 6 months.
The pharmaceutical compositions and products of the present invention are stable, and preferably show no significant colour change, or in some cases may show no visible colour change, upon storage:
- at 40eC, for 3 months, or
- at 40eC for 6 months.
The pharmaceutical compositions and products of the present invention are stable, and preferably the wt % of pemetrexed diacid is between 97-100%, preferably 98-100% and more preferably 99.5-100% relative to the initial amount before storage, following storage:
- at 2-8eC, for 3 months, or
- at 2-8eC for 6 months.
The pharmaceutical compositions and products of the present invention are stable, and preferably the wt % of pemetrexed diacid is between 97-100%, preferably 98-100% and more preferably 99.5-100% relative to the initial amount before storage, following storage:
- at 25eC, for 3 months, or
- at 25eC for 6 months.
The pharmaceutical compositions and products of the present invention are stable, and preferably the wt % of pemetrexed diacid is between 97-100%, preferably 98-100% and more preferably 99.5-100% relative to the initial amount before storage, following storage:
- at 40eC, for 3 months, or
- at 40eC for 6 months. Whilst the invention has been described herein with reference to specific and preferred embodiments, it will be appreciated that many variations, combinations, equivalents and modifications can be made while remaining within the spirit and scope of the invention. The invention is therefore not limited by the above described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention as claimed.
Examples of compositions according to the invention are set out below: Example 1
Figure imgf000018_0001
Osmolality adjusted with NaCI Example 2
Figure imgf000019_0001
Example 3
Figure imgf000019_0002
* present in headspace of the vials Example 4 - Preparation of pemetrexed concentrate for solution for infusion
A pemetrexed concentrate for solution for infusion containing: a combination of pemetrexed diacid, tromethamine, citric acid, mannitol and water for injection is prepared as follows (the process is carried out at 20 ± 5°C): 1 ) A portion (e.g. 25-90%, preferably 50-80%, more preferably 65-80%, or about
75%) of the total amount of water for injection is added to a vessel. The water for injection is preferably previously purged with nitrogen for a minimum of 10 minutes.
2) Tromethamine is dissolved into the water to form a solution 3) Citric acid anhydrous is dissolved into the Tromethamine solution
4) Mannitol is then dissolved into the tromethamine/citric acid solution
The following steps 4)-7) are preferably carried out in an inert atmosphere of nitrogen (target: 02≤ 1.5%; RH < 2.0), in the absence of UV light. For example, these steps may be conducted in red or yellow light. 5) Pemetrexed diacid is weighed and added to the solution of step 3) and the
solution is mixed until complete dissolution of the API
6) The pH is checked, and if necessary, adjusted to pH 6.0 to 8.5, preferably 6.5 to 8, more preferably 6.6 to 7.8, or about 7.2) using tromethamine solution (10 w/V% in water for injection) and/or 1 M hydrochloric acid solution in water for injection.
7) The solution is completed with water for injection to the final volume/final weight.
8) The solution is homogenized, filtered, filled into vials and stoppered.
Example 5 - Preparation of pemetrexed concentrate for solution for infusion
A pemetrexed concentrate for solution for infusion containing: a combination of pemetrexed diacid, tromethamine, citric acid, mannitol and water for injection is prepared as follows (the process is carried out at 20 ± 5°C): 1 ) A portion (e.g. 25-90%, preferably 50-80%, more preferably 65-80%, or about
75%) of the total amount of water for injection is added to a vessel. The water for injection is preferably previously purged with nitrogen for a minimum of 10 minutes. 2) Citric acid anhydrous and Mannitol is dissolved into the water to form a solution
3) Tromethamine is then dissolved into the Mannitol/citric acid solution
The following steps 4)-7) are preferably carried out in an inert atmosphere of nitrogen (target: 02≤ 1.5%; RH < 2.0%), in the absence of UV light. For example, these steps may be conducted in red or yellow light. 4) Pemetrexed diacid is weighed and added to the solution of step 3) and the
solution is mixed until complete dissolution of the API
5) The pH is checked, and if necessary, adjusted to pH 6.0 to 8.5, preferably 6.5 to 8, more preferably 6.6 to 7.8, or about 7.2) using tromethamine solution (10 w/V% in water for injection) and/or 1 M hydrochloric acid solution in water for injection.
6) The solution is completed with water for injection to the final volume/final weight.
7) The solution is homogenized, filtered with a 0.2 μηι sterilizing grade filter (PVDF Fluorodyne), filled into vials and stoppered.
Example 6 - Storage Stability The finished bulk solution was filled into two amber glass bottles and kept at 2-8 °C and room temperature for 168 hours. Samples were taken after 24, 48, 72, 96 and 168 hours. After storage the following parameters were tested: Tests Requirements
Clear solution,
Description practically free from
visible particles
Color > GY5 or Y5
PH 6.6 - 7.8
Assay of active ingredient 95.0 - 105.0 %
Any unknown impurity NMT 0.2 %
Impurities / Related substances
Total impurities NMT 1.0 %
* tested in accordance with European Pharmacopoeia 8.0, 2.2.2. "Degree of Coloration of Liquids"
GY = green-yellow
Y = yellow
Tests
Impurities/related Assay substances of Any
Temperature Description Color PH active unTotal ingreknown impdient impurit urities y
Initial Conforms GY7 7.1 101.0 % < 0.1 % < 0.1 % room temp. % < 0.1 %
After 24 CoHforms GY7 7.1 99.6 % < 0. l
hours 2 - 8 °C Conforms GY7 7.1 100.0 % < 0.1 % < 0.1 % room temp. %
After 48 Conforms GY? 7.1 101.2 % < 0.1 % < 0.1 hours 2 - 8 °C Conforms GY7 7.1 100.2 % < 0.1 % < 0.1 % room temp.
After 72 Conforms GY7 7.1 100.6 % < 0.1 % < 0.1 % hours 2 - 8 °C Conforms GY7 7.1 100.5 % < 0.1 % < 0.1 % room temp.
After 96 Conforms GY7 7.1 101.2 % < 0.1 % < 0.1 % hours 2 - 8 °C Conforms GY7 7.1 100.6 % < 0.1 % < 0.1 % room temp.
After 168 Conforms GY7 7.1 101.2 % < !).1 % < 0.1 % hours 2 - 8 °C Conforms GY7 7.1 101.2 % < 0.1 % < 0.1 %
Example 7 - Stability under oxygen
After filling the filtered solution into vials, the headspace (i.e. the air in the vial between the product and the stopper) of the vials are set in the freeze-dryer to approx. 2 %, approx. 5 % and approx.10 % oxygen levels. Then the vials are stoppered by the freeze- dryer and capped with automatic capper. Headspace oxygen analyzer was measured using Lighthouse FMS-760. Then the vials are put on the different stability parameters:
Test methods and specifications: Tests Requirements
Color* > GY5 or Y5
Assay of active ingredient 95.0 - 105.0 %
Any unknown
Impurities / Related NMT 0.2 %
impurity
substances
Total impurities NMT 1.0 %
For monitoring
Headspace oxygen**
purpose
* tested in accordance with European Pharmacopoeia 8.0, 2.2.2. "Degree of Coloration of Liquids"
** tested from filled product at initial and stability time points
GY = green-yellow
Y = yellow
Storage conditions tested:
1 ) 5°C ± 3°C, not controlled relative humidity (NC RH)
2) 25°C ± 2°C, 60 ± 5% RH
3) 40°C ± 2°C, 60 ± 5% RH
Results:
Vials having about 2% or about 5% headspace oxygen content have all results conforming to the above requirements under all 3 storage conditions after 1 month. Vials having a headspace oxygen content of about 10% conformed to the above requirements under storage conditions 1 ) and 2), but the any unknown impurity and total impurities content were at 0.4% and 1 .1 % respectively
Example 8 - Storage Stability with different stoppers
Colour changes were observed and impurity/related substances were determined in vials having chlorobutyl and bromobutyl stoppers:
Chlorobutvl rubber stopper
Container: 6R Type I vial
20 mm Datwvler FM140/0 V9025 ISAF1
Closure: chlorobutvl rubber stopper, qrev
20 mm flip-off cap (red) Bromobutvl rubber stopper
Container: 6R Type 1 vial
20 mm Datwvler FM457/0 V9047
Closure: bromobutvl rubber stopper, FLCO, qrev
20 mm flip-off cap (dark qreen)
The vials were stored at 5 ± 3°C NC RH (i.e. uncontrolled relative humidity) ± 2°C and 60 ± 5% RH, for 3 months at upright and inverted positions. In the formulation comprising pemetrexed disodium (pemetrexed and sodium hydroxide), the stability was found to be dependent on the stopper used. In contrast all formulations comprising pemetrexed tromethamine (or pemetrexed and tromethamine) showed no colour change and met the impurity/related substances requirements independent of the stopper used.
Further aspects and embodiments of the present invention are set out in the following numbered paragraphs:
1 . A pharmaceutical formulation comprising:
(a) at least one of the following:
(i) pemetrexed disodium, or
(ii) pemetrexed diacid and sodium hydroxide,
(b) citric acid or a citrate.
2. A pharmaceutical composition according to paragraph 1 in the form of a lyophilized powder, an aqueous concentrate or an aqueous solution.
3. A pharmaceutical composition according to paragraphs 1 or 2 in the form of an aqueous concentrate or an aqueous ready-to-use solution, preferably wherein the composition is in the form of an aqueous concentrate.
4. A pharmaceutical composition according to any of paragraphs 1 to 3, wherein (a) is (i) or (ii) or a mixture thereof.
5. A pharmaceutical composition according to paragraph 4 wherein (a) is (i) or (ii).
6. A pharmaceutical composition according to any of paragraphs 1 -5 wherein the composition is an aqueous concentrate or a ready-to-use aqueous solution, preferably wherein the composition is in the form of an aqueous concentrate. 7. A pharmaceutical composition according to paragraph 6 comprising:
(a) (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide,
(b) citric acid or a citrate,
and one or more pharmaceutically acceptable excipients, preferably selected from a tonicity adjusting agent, a pH adjusting agent (acid and/or base), an antioxidant and water for injection or infusion.
8. A pharmaceutical composition according to paragraph 7 wherein the tonicity adjusting agent is selected from one or more of: a sugar (such as dextrose), arginine, glycerin, a sugar alcohol (such as mannitol), potassium chloride, or sodium chloride, preferably potassium chloride or sodium chloride, and more preferably sodium chloride.
9. A pharmaceutical composition according to any of paragraphs 7 and 8 wherein the pH adjusting agent is an acid and/or base, preferably wherein the acid is selected from the group consisting of a mineral acid (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine.
10. A pharmaceutical composition according to paragraph 9 wherein the pH adjusting agent comprises hydrochloric acid and/or sodium hydroxide, preferably both.
1 1 . A pharmaceutical composition according to any of paragraphs 1 -10 comprising: - one of (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide,
- citric acid or a citrate
- a tonicity adjusting agent
- one or more pH adjusting agents and
- water for injection.
12. A pharmaceutical composition according to paragraph 1 1 comprising:
- one of (i) pemetrexed disodium, or (ii) pemetrexed diacid and sodium hydroxide, - citric acid or a citrate
- sodium chloride
- one or more pH adjusting agents, preferably selected from sodium hydroxide and/or hydrochloric acid, and
- water for injection
in the form of a concentrate or a ready-to-use solution. 13. A pharmaceutical composition according to any of paragraphs 1 -12 wherein the weight ratio of the citric acid or citrate (based on citric acid) to pemetrexed diacid is from about 1 : 10 to about 1 : 40, preferably from about 1 : 15 to about 1 : 35, more preferably from about 1 : 20 to about 1 : 30, and preferably about 1 : 25. 14. A pharmaceutical composition according to any of paragraphs 1 -13 in the form of an aqueous solution wherein the concentration of citric acid or citrate (based on citric acid) in the solution is from about 0.1 to about 4 mg/ml, preferably from about 0.1 to about 2 mg/ml, more preferably from about 0.5 to about 2 mg/ml and most preferably about 1 mg/ml.
15. A pharmaceutical composition according to any of paragraphs 1 -14 in the form of an aqueous solution wherein the concentration of pemetrexed acid in the solution is from about 10 to about 40 mg/ml, preferably from about 15 to about 35 mg/ml, more preferably from about 20 mg/ml to about 30 mg/ml, and most preferably about 25 mg/ml.
16. A pharmaceutical composition according to any of paragraphs 13-15 in the form of an aqueous concentrate. 17. A pharmaceutical composition according to any of paragraphs 1 -16 wherein the pemetrexed disodium is in the form of the pemetrexed disodium heptahydrate.
18. A process for preparing a pharmaceutical composition comprising
(a) at least one of the following:
(i) pemetrexed disodium, or
(ii) pemetrexed diacid and sodium hydroxide,
and
(b) citric acid or a citrate,
wherein the process comprises:
(1 ) dissolving the following into water (preferably water for injection), in any order:
(A) pemetrexed diacid
(B) sodium hydroxide
(C) citric acid or a citrate and
(D) a sugar alcohol where necessary, and optionally:
(2) adjusting the pH with an acid and/or base, preferably wherein the acid is selected from the group consisting of a mineral acid (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine. 19. A process according to paragraph 18 wherein the pH is adjusted to between about 6.0 to about 9.0, preferably about 6.0 to about 8.5, more preferably about 6.5 to about 8.0 and most preferably about 6.6 to about 7.8.
20. A process according to any of paragraphs 18 and 19 wherein the order of dissolution is (A), (B), (C) and where necessary, (D), or wherein the order of dissolution is (A) added to a solution containing (B), (C) and (D). 21 . A process according to any of paragraphs 18-20 wherein the pharmaceutical composition is an aqueous concentrate or an aqueous ready-to-use solution, the process further comprising a step of adding water to obtain the final volume.
22. A process according to any of paragraphs 18-20 or 21 wherein the
pharmaceutical composition is a powder for reconstitution, the process further comprising a step of removal of the water.
23. A process according to paragraph 22 wherein the pharmaceutical composition is a lyophilizate for reconstitution, wherein the process further comprises: optionally adding a cryoprotectant (preferably selected from the group consisting of: sucrose, dextrose, mannitol, glucose, and more preferably mannitol) prior to removal of the water by lyophilization.
24. A pharmaceutical composition obtainable by a process according to any of paragraphs 18-23.
25. A pharmaceutical composition prepared by reconstitution of an aqueous concentrate or powder for reconstitution according to any of paragraphs 1 -17. 26. A pharmaceutical product comprising a pharmaceutical composition according to any of paragraphs 1 -17 or 24 in a vial or ampoule.
27. A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-26 which shows no significant colour change, or no visible colour change, following storage at 2-8eC, for 3 months, and preferably no significant colour change, or no visible colour change following storage at 2-8eC for 6 months.
28. A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-27 which show no significant colour change, or no visible colour change, following storage at 25eC, for 3 months, and preferably no significant colour change, or no visible colour change following storage at 25eC for 6 months.
29. A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-28 which shows significant colour change, or no visible colour change, following storage at 40eC, for 3 months, and preferably no significant colour change, or no visible colour change following storage at 40eC for 6 months.
30. A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-29 wherein the wt % of pemetrexed diacid is between 97-100%, preferably 98-
100% and more preferably 99.5-100% relative to the initial amount before storage, following storage at 2-8eC, for 3 months, and preferably following storage at 2-8eC for 6 months. 31 . A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-30 wherein the wt % of pemetrexed diacid is between 97-100%, preferably 98- 100% and more preferably 99.5-100% relative to the initial amount before storage, following storage at 25eC, for 3 months, and preferably following storage at 25eC for 6 months.
32. A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-31 wherein the wt % of pemetrexed diacid is between 97-100%, preferably 98- 100% and more preferably 99.5-100% relative to the initial amount before storage, following storage at 40eC, for 3 months, and preferably following storage at 40eC for 6 months.
33. A pharmaceutical composition or product according to any of paragraphs 1 -17 and 24-32 for use as a medicament. 34. A pharmaceutical composition or product according to paragraph 33 for use in the treatment of malignant pleural mesothelioma or non-small cell lung cancer, optionally in combination with cisplatin.

Claims

1 . A pharmaceutical formulation comprising:
(a) at least one of the following:
(i) pemetrexed tromethamine salt, or
(ii) pemetrexed diacid and tromethamine, and
(b) citric acid or a citrate,
wherein the composition further comprises a sugar alcohol.
2. A pharmaceutical composition according to Claim 1 in the form of a lyophilized powder, an aqueous concentrate or an aqueous solution.
3. A pharmaceutical composition according any of Claims 1 or 2 in the form of an aqueous concentrate or an aqueous ready-to-use solution, preferably wherein the composition is in the form of an aqueous concentrate.
4. A pharmaceutical composition according to any preceding claim wherein the weight ratio of the citric acid or citrate (based on citric acid) to pemetrexed diacid is from about 1 : 10 to about 1 : 40, preferably from about 1 : 15 to about 1 : 35, more preferably from about 1 : 20 to about 1 : 30, and preferably about 1 : 25.
5. A pharmaceutical composition according to any preceding claim in the form of an aqueous solution wherein the concentration of citric acid or citrate (based on citric acid) in the solution is from about 0.1 to about 4 mg/ml, preferably from about 0.1 to about 2 mg/ml, more preferably from about 0.5 to about 2 mg/ml and most preferably about 1 mg/ml.
6. A pharmaceutical composition according to any preceding claim in the form of an aqueous solution wherein the concentration of pemetrexed acid in the solution is from about 10 to about 40 mg/ml, preferably from about 15 to about 35 mg/ml, more preferably from about 20 mg/ml to about 30 mg/ml, and most preferably about 25 mg/ml.
7. A pharmaceutical composition according to any of Claims 4-6 in the form of an aqueous concentrate.
8. A pharmaceutical composition according to any of Claims 1 -3 wherein (a) is (i) or (ii).
9. A pharmaceutical composition according to Claim 8 wherein the composition is in the form of a powder for reconstitution, an aqueous concentrate or a ready-to-use aqueous solution.
10. A pharmaceutical composition according to Claim 9 wherein the composition is in the form of a powder for reconstitution (such as a lyophilisate).
1 1 . A pharmaceutical composition according to any of Claims 9 or 10 comprising:
(a) (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and
tromethamine,
(b) citric acid or a citrate,
(c) a sugar alcohol
and one or more pharmaceutically acceptable excipients, preferably selected from a tonicity adjusting agent, a pH adjusting agent (acid and/or base), a cryoprotectant and water for injection or infusion.
12. A pharmaceutical composition according to any of Claims 8-1 1 wherein the sugar alcohol is selected from the group consisting of mannitol, sorbitol, and pentaerythritol, preferably mannitol.
13. A pharmaceutical composition according to any of Claims 1 1 -12 wherein the tonicity adjusting agent is selected from one or more of: a sugar (such as dextrose), arginine, glycerin, a sugar alcohol (such as mannitol), potassium chloride, or sodium chloride, preferably potassium chloride or sodium chloride, and more preferably sodium chloride.
14. A pharmaceutical composition according to any of Claims 1 1 -12 wherein the tonicity adjusting agent is selected from one or more of: a sugar (preferably dextrose), glycerin, a sugar alcohol (preferably mannitol) or sodium chloride, preferably sodium chloride.
15. A pharmaceutical composition according to any of Claims 1 1 -13 or 14 wherein the pH adjusting agent is an acid and/or base, preferably wherein the acid is selected from the group consisting of a mineral acid (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; , or alternatively, wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid, citric acid, malonic acid, tartaric acid, or malic acid), or a salt of a mineral acid, such as acetate, citrate, malonate, tartrate, maleate or phosphate, and more preferably wherein the acid is hydrochloric acid; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine
16. A pharmaceutical composition according to Claim 15 wherein the pH adjusting agent comprises sodium hydroxide and/or hydrochloric acid, preferably both.
17. A pharmaceutical composition according to Claim 15 wherein the pH adjusting agent comprises tromethamine and/or hydrochloric acid, preferably both.
18. A pharmaceutical composition according to any of Claims 1 1 -13, or 14, or 15-17, wherein the composition is a lyophilisate for reconstitution, and wherein the
cryoprotectant is selected from the group consisting of sucrose, dextrose, mannitol, glucose, and preferably is mannitol.
19. A pharmaceutical composition according to any of Claims 1 -3 and 8-1 1 comprising:
- one of (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and tromethamine,
- citric acid or a citrate
- a tonicity adjusting agent
- a sugar alcohol
- one or more pH adjusting agents and optionally
- water for injection.
20. A pharmaceutical composition according to Claim 19 comprising:
- one of (i) pemetrexed tromethamine salt, or (ii) pemetrexed diacid and trometh amine,
- citric acid or a citrate
- a sugar alcohol, preferably mannitol
- pH adjusting agents, preferably selected from a combination of either: sodium hydroxide and hydrochloric acid; or tromethamine and hydrochloric acid, and optionally
- sodium chloride
in the form of a powder for reconstitution, preferably in the form of a lyophilisate.
21 . A pharmaceutical composition according to any of Claims 8-20 wherein the weight ratio of the citric acid or citrate (based on citric acid) to pemetrexed diacid is from about 1 : 10 to about 1 : 40, preferably from about 1 : 15 to about 1 : 35, more preferably from about 1 : 20 to about 1 : 30, and preferably about 1 : 25.
22. A pharmaceutical composition according to any of Claims 8-21 the form of an aqueous solution wherein the concentration of citric acid or citrate (based on citric acid) in the solution is from about 0.1 to about 4 mg/ml, preferably from about 0.1 to about 2 mg/ml, more preferably from about 0.5 to about 2 mg/ml and most preferably about 1 mg/ml.
23. A pharmaceutical composition according to any of Claims 8-22 in the form of an aqueous solution wherein the concentration of pemetrexed acid in the solution is from about 10 to about 40 mg/ml, preferably from about 15 to about 35 mg/ml, more preferably from about 20 mg/ml to about 30 mg/ml, and most preferably about 25 mg/ml.
24. A pharmaceutical composition according to any of Claims 22 or 23 in the form of an aqueous concentrate.
25. A pharmaceutical composition according to any preceding claim wherein the citric acid is anhydrous.
26. A pharmaceutical composition according to any of Claims 1 -24 wherein the citrate is sodium citrate, preferably trisodium citrate or trisodium citrate dihydrate.
27. A pharmaceutical composition according to any preceding claim wherein the pemetrexed disodium is in the form of the pemetrexed disodium heptahydrate.
28. A pharmaceutical composition according to any preceding claim wherein the concentration of tromethamine in the composition is from about 10 to about 25 mg/ml, preferably from about 12 to about 20 mg/ml, and preferably from about 1 6 to about 18 mg/ml.
29. A pharmaceutical composition according to any preceding claim wherein the weight ratio of tromethamine to pemetrexed diacid is from about 1 :1 to about 1 :3, preferably from about 1 :1 to about 1 :2, more preferably from about 1 :1 to about 1 :1 .75, and most preferably from about 1 :1 to about 1 :1 .6, or about 1 :1 .5;
or wherein the weight ratio of tromethamine to pemetrexed diacid is from 0.6 to 1 .2, preferably 0.7 to 1 and more preferably 0.8 to 0.9.
30. A pharmaceutical composition according to any preceding claim wherein the weight ratio of citric acid to tromethamine is from about 1 :10 to about 1 :25, preferably from about 1 : 10 to 1 :20, more preferably from about 1 :15 to about 1 :20, and most preferably from about 1 :17 to about 1 :18.
31 . A pharmaceutical composition according to any preceding claim wherein the concentration of the sugar alcohol, preferably wherein the sugar alcohol is mannitol, is from about 10 to about 30 mg/ml, or from about 10 to about 25 mg/ml, preferably from about 12 to about 20 mg/ml, and preferably from about 16 to about 18 mg/ml.
32. A pharmaceutical composition according to any preceding claim, wherein the pemetrexed in the composition contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% D- pemetrexed.
33. A pharmaceutical composition according to any preceding claim wherein the pemetrexed in the composition contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% De-Glu pemetrexed.
34. A pharmaceutical composition according to any preceding claim wherein the pemetrexed in the composition contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% pemetrexed diethyl ester.
35. A pharmaceutical composition according to any preceding claim wherein the pemetrexed in the composition contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% L-Glu pemetrexed.
36. A pharmaceutical composition according to any preceding claim wherein the pemetrexed in the composition contains less than 0.15 wt% D-pemetrexed, less than 0.15 wt% De-Glu pemetrexed, less than 0.15 wt% L-Glu pemetrexed and less than 0.15 wt% L-Glu pemetrexed.
37. A process for preparing a preparing a pharmaceutical composition comprising (a) at least one of the following:
(i) pemetrexed tromethamine salt, or
(ii) pemetrexed diacid and tromethamine, and
(b) citric acid or a citrate,
wherein the process comprises:
(1 ) dissolving the following into water (preferably water for injection), in any order:
(A) pemetrexed diacid
(B) sodium hydroxide or tromethamine, preferably tromethamine
(C) citric acid or a citrate and
(D) a sugar alcohol where necessary, and optionally .
(2) adjusting the pH with an acid and/or base, preferably wherein the acid is selected from the group consisting of a mineral acid (preferably hydrochloric acid), acetic acid, citric acid, malonic acid, tartaric acid and more preferably hydrochloric acid; or alternatively wherein the acid is selected from the group consisting of hydrochloric acid, acetic acid, citric acid, malonic acid, tartaric acid, or malic acid, or a salt of a mineral acid, such as acetate, citrate, malonate, tartrate, maleate or phosphate; and preferably wherein the base is selected from the group consisting of an alkali metal hydroxide (preferably potassium hydroxide or sodium hydroxide), or tromethamine, and more preferably wherein the base is tromethamine.
38. A process according to Claim 28 wherein the pH is adjusted to between about 6.0 to about 9.0, preferably about 6.0 to about 8.5, more preferably about 6.5 to about 8.0 and most preferably about 6.6 to about 7.8.
39. A process according to any of Claims 28 and 29 wherein the order of dissolution is (A), (B), (C) and where necessary, (D).
40. A process according to any of Claims 28-30 wherein the pharmaceutical composition is an aqueous concentrate or an aqueous ready-to-use solution, the process further comprising a step of adding water to obtain the final volume.
41 . A process according to Claim 31 wherein the pharmaceutical composition is a powder for reconstitution, the process further comprising a step of removal of the water.
42. A process according to Claim 32 wherein the pharmaceutical composition is a lyophilizate for reconstitution, wherein the process further comprises: optionally adding a cryoprotectant (preferably selected from the group consisting of: sucrose, dextrose, mannitol, glucose, and more preferably mannitol) prior to removal of the water by lyophilization.
43. A process according to any of Claims 37-42, wherein dissolution of the pemetrexed diacid is carried out in an inert atmosphere, preferably excluding oxygen, and more preferably wherein the dissolution is carried out under nitrogen.
44. A process according to any of Claims 37-43, wherein dissolution of the pemetrexed diacid is carried out in the absence of light, preferably in the absence of UV light.
45. A process according to any of Claims 37-44, wherein handling of pemetrexed is carried out in an inert atmosphere, and in the absence of light, preferably wherein the handling is carried out under nitrogen and in the absence of UV light.
46. A process according to any of Claims 37-45, wherein the pemetrexed diacid contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% D-pemetrexed.
47. A process according to any of Claims 37-46, wherein the pemetrexed diacid contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% De-Glu pemetrexed.
48. A process according to any of Claims 37-47, wherein the pemetrexed diacid contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% pemetrexed diethyl ester.
49. A process according to any of Claims 37-48, wherein the pemetrexed diacid contains less than 0.2 wt%, preferably less than 0.15 wt%, more preferably less than 0.1 wt%, and most preferably less than 0.05 wt% L-Glu pemetrexed.
50. A process according to any of Claims 37-49, wherein the pemetrexed diacid contains less than 0.15 wt% D-pemetrexed, less than 0.15 wt% De-Glu pemetrexed, less than 0.15 wt% L-Glu pemetrexed and less than 0.15 wt% L-Glu pemetrexed.
51 . A process according to any of Claims 37-50, further comprising a step of filling the pharmaceutical composition into a vial or ampoule.
52. A process according to any of Claim 37-51 , wherein the vial or ampoule is formed of clear glass, preferably wherein the vial is a 6R Type I vial.
53. A process according to any of Claim 37-52, wherein the vial or ampoule is sealed with a bromobutyl or chlorobutyl stopper, preferably a bromobutyl stopper.
54. A process according to Claim 37-53, wherein the filling is carried out in an inert atmosphere, preferably under nitrogen.
55. A process according to Claim 37-54, wherein the concentration of oxygen in the headspace of the vial or ampoule is less than 10%, preferably less than 5%, more preferably less than 2.5%, and most preferably 2% or less, or 1 .5% or less, relative to the volume of the headspace in the vial or ampoule.
56. A pharmaceutical composition obtainable by a process according to any of Claims 37-42, or 43-55.
57. A pharmaceutical composition prepared by reconstitution of an aqueous concentrate or powder for reconstitution according to any of Claims 1 -13, or Claim 14, or Claims 15-27, or Claims 28-36.
58. A pharmaceutical composition according to Claim 57 wherein the reconstitution is carried out with saline, preferably 0.9 w/v% saline for injection.
59. A pharmaceutical product comprising a pharmaceutical composition according to any of Claims 1 -13, or Claim 14 or Clams 15-27 or Claim 56 in a vial or ampoule.
60. A pharmaceutical composition or product according to any of Claims 1 -13, Claim 14, or Claims 15-27 or Claims 56-59, which shows no significant colour change, or no visible colour change, following storage at 2-8eC, for 3 months, and preferably no significant colour change, or no visible colour change following storage at 2-8eC for 6 months.
61 . A pharmaceutical composition or product according to any of Claims 1 -13, Claim 14, or Claims 15-27 or Claims 56-60, which shows no significant colour change, or no visible colour change, following storage at 25eC, for 3 months, and preferably no significant colour change, or no visible colour change following storage at 25eC for 6 months.
62. A pharmaceutical composition or product according to any of Claims 1 -13, Claim 14, or Claims 15-27 or Claims 56-61 , which shows no significant colour change, or no visible colour change, following storage at 40eC, for 3 months, and preferably no significant colour change, or no visible colour change following storage at 40eC for 6 months.
63. A pharmaceutical composition or product according to any of Claims 1 -13, Claim 14, or Claims 15-27 or Claims 56-62, wherein the wt % of pemetrexed diacid is between 97-100%, preferably 98-100% and more preferably 99.5-100% relative to the initial amount before storage, following storage at 2-8eC, for 1 -3 weeks, preferably following storage at 2-8eC, for 3 months, and more preferably following storage at 2-8eC for 6 months.
64. A pharmaceutical composition or product according to any of Claims 1 -13, Claim 14, or Claims 15-27 or Claims 56-63, wherein the wt % of pemetrexed diacid is between
97-100%, preferably 98-100% and more preferably 99.5-100% relative to the initial amount before storage, following storage at 25eC, for 1 -3 weeks, preferably following storage at 25eC, for 3 months, and more preferably following storage at 25eC for 6 months.
65. A pharmaceutical composition or product according to any of Claims 1 -13, Claim 14, or Claims 15-27 or Claims 56-64, wherein the wt % of pemetrexed diacid is between 97-100%, preferably 98-100% and more preferably 99.5-100% relative to the initial amount before storage, following storage at 40eC, for 1 -3 weeks, preferably following storage at 40eC, for 3 months, and more preferably following storage at 40eC for 6 months.
66. A pharmaceutical product according to 59-65, which is in a vial or ampoule.
67. A pharmaceutical composition or product according to any of Claim 66, wherein the vial or ampoule is formed of clear glass, preferably wherein the vial is a 6R Type I vial.
68. A pharmaceutical composition or product according to any of Claims 66 or 67 wherein the vial or ampoule is sealed with a bromobutyl or chlorobutyl stopper, preferably a bromobutyl stopper.
69. A pharmaceutical according to any of Claims 66-68, wherein the concentration of oxygen in the headspace of the vial or ampoule is less than 10%, preferably less than 5%, more preferably less than 2.5%, and most preferably 2% or less, or 1 .5% or less, relative to the volume of the headspace in the vial or ampoule.
70. A pharmaceutical composition or product according to any of Claims 1 -36 and 56-69, wherein the amount of De-Glu pemetrexed relative to pemetrexed diacid is less than 2 wt%, preferably less than 1 .5 wt%, more preferably less than 1 wt% or less than 0.5 wt%, and most preferably less than 0.2 or less than 0.1 wt% relative to the initial amount before storage, following storage at 2-8eC, for 1 -3 weeks, preferably following storage at 2-8eC, for 3 months, and more preferably following storage at 2-8eC for 6 months.
71 . A pharmaceutical composition or product according to any of Claims 1 -36 and 56-70, wherein the amount of De-Glu pemetrexed relative to pemetrexed diacid is less than 2 wt%, preferably less than 1 .5 wt%, more preferably less than 1 wt% or less than 0.5 wt%, and most preferably less than 0.2 or less than 0.1 wt% relative to the initial amount before storage, following storage at 25eC, for 1 -3 weeks, preferably following storage at 25eC, for 3 months, and more preferably following storage at 25eC for 6 months.
72. A pharmaceutical composition or product according to any of Claims 1 -36 and 56-71 , wherein the amount of De-Glu pemetrexed relative to pemetrexed diacid is less than 2 wt%, preferably less than 1 .5 wt%, more preferably less than 1 wt% or less than 0.5 wt%, and most preferably less than 0.2 or less than 0.1 wt% relative to the initial amount before storage, following storage at 40eC, for 1 -3 weeks, preferably following storage at 40eC, for 3 months, and more preferably following storage at 40eC for 6 months.
73. A pharmaceutical composition or product according to any of Claims 1 -36 and 56-72, for use as a medicament.
74. A pharmaceutical composition or product according to Claim 73 for use in the treatment of malignant pleural mesothelioma or non-small cell lung cancer, optionally combination with cisplatin.
PCT/EP2015/074065 2014-10-16 2015-10-16 Pemetrexed formulations WO2016059238A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010030598A2 (en) * 2008-09-11 2010-03-18 Dr. Reddy's Laboratories Limited Pharmaceutical formulations comprising pemetrexed
WO2013179248A1 (en) * 2012-05-30 2013-12-05 Fresenius Kabi Oncology Ltd. Pharmaceutical compositions of pemetrexed
WO2014084651A1 (en) * 2012-11-29 2014-06-05 Cj Healthcare Corporation A stabilized pemetrexed formulation
WO2014198337A1 (en) * 2013-06-14 2014-12-18 Synthon B.V. Stable and water soluble pharmaceutical compositions comprising pemetrexed
WO2015008221A1 (en) * 2013-07-16 2015-01-22 Dr. Reddy’S Laboratories Limited Novel crystalline forms of pemetrexed tromethamine salts

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010030598A2 (en) * 2008-09-11 2010-03-18 Dr. Reddy's Laboratories Limited Pharmaceutical formulations comprising pemetrexed
WO2013179248A1 (en) * 2012-05-30 2013-12-05 Fresenius Kabi Oncology Ltd. Pharmaceutical compositions of pemetrexed
WO2014084651A1 (en) * 2012-11-29 2014-06-05 Cj Healthcare Corporation A stabilized pemetrexed formulation
WO2014198337A1 (en) * 2013-06-14 2014-12-18 Synthon B.V. Stable and water soluble pharmaceutical compositions comprising pemetrexed
WO2015008221A1 (en) * 2013-07-16 2015-01-22 Dr. Reddy’S Laboratories Limited Novel crystalline forms of pemetrexed tromethamine salts

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