WO2014122460A2 - Pemetrexed complexes and pharmaceutical compositions containing pemetrexed complexes - Google Patents

Pemetrexed complexes and pharmaceutical compositions containing pemetrexed complexes Download PDF

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Publication number
WO2014122460A2
WO2014122460A2 PCT/GB2014/050340 GB2014050340W WO2014122460A2 WO 2014122460 A2 WO2014122460 A2 WO 2014122460A2 GB 2014050340 W GB2014050340 W GB 2014050340W WO 2014122460 A2 WO2014122460 A2 WO 2014122460A2
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Prior art keywords
complex
pemetrexed
pharmaceutical composition
composition according
pharmaceutically acceptable
Prior art date
Application number
PCT/GB2014/050340
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French (fr)
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WO2014122460A3 (en
Inventor
Shrinivas Madhukar Purandare
Geena Malhotra
Dharmaraj Ramachandra Rao
Rajendra Narayanrao Kankan
Srinivas Laxminarayan Pathi
Ravikumar PUPPLA
Original Assignee
Cipla House
Turner, Craig Robert
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Publication date
Application filed by Cipla House, Turner, Craig Robert filed Critical Cipla House
Priority to US14/765,920 priority Critical patent/US20150359898A1/en
Priority to EP14709357.9A priority patent/EP2953616A2/en
Priority to CA2900088A priority patent/CA2900088A1/en
Publication of WO2014122460A2 publication Critical patent/WO2014122460A2/en
Publication of WO2014122460A3 publication Critical patent/WO2014122460A3/en
Priority to ZA2015/05678A priority patent/ZA201505678B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/18—Polyhydroxylic acyclic alcohols
    • C07C31/26—Hexahydroxylic alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/04—Disaccharides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to pharmaceutically acceptable complexes comprising pemetrexed and pharmaceutically acceptable compositions comprising said complexes, processes for preparation of the complexes and pharmaceutical compositions comprising said complexes, and their use in the treatment of cancer, pleural mesothelima and non- small cell lung cancer.
  • Pyrrolo[2,3-d]pyrimidine based antifolates are drugs that impair the function of folic acids. Many of them are used in cancer chemotherapy and some are used as antibiotics or antiprotozoal agents. These include pemetrexed, methotrexate, raltitrexed and pralatrexate.
  • Pemetrexed is an antifolate, antineoplastic agent.
  • Lily's anticancer drug Alimta ® (pemetrexed) is a sterilized lyophilized powder for intravenous administration and is approved for treatment of mesothelioma and non small cell lung cancer.
  • Pemetrexed was approved by the United States Food and Drug Administration in February 2004 in combination with cisplatin, a platinum-containing chemotherapeutic drug for the treatment of malignant pleural mesothelioma (MPM).
  • MPM malignant pleural mesothelioma
  • NSCLC metastatic non- small cell lung cancer
  • the drug is used as a single agent or in combination with other chemotherapeutic agents for the treatment of other types of cancer such as breast cancer, bladder cancer, colorectal carcinoma and cervical cancer.
  • Pemetrexed was first disclosed in US5344932 and is commercialized as Alimta ® sterile lyophilized powders for intravenous infusion, available in single-dose vials containing 100 mg or 500 mg equivalent of pemetrexed.
  • a crystalline form of pemetrexed disodium designated Disodium MTA Hydrate Form I has been described in WO200114379.
  • US7138521 describes a stable crystalline heptahydrate form of pemetrexed having a characteristic X-ray diffraction pattern, which comprises a peak corresponding to a d- spacing of 7.78 ⁇ 0.04 A when obtained at 22 ⁇ 2°C and at ambient relative humidity.
  • the patent also indicates that when the heptahydrate is subjected to elevated temperatures, low humidity, and/or a vacuum, it converts to the 2.5 hydrate crystal form by loss of water.
  • WO2008124485 discloses besides five crystalline forms of the diacid pemetrexed; an amorphous pemetrexed disodium as well as a crystalline Form III thereof including a composition containing a major amount of amorphous Form and a minor amount of crystalline Form III of pemetrexed disodium.
  • EP 1943252 discloses a process for the preparation of a lyophilized pharmaceutically acceptable di-base-addition salt of pemetrexed, in particular, a pemetrexed disodium salt, directly from pemetrexed diacid or an acid or base addition salt thereof, i.e. a di-base salt of pemetrexed which is not isolated prior to the lyophilization.
  • US2011201631A1 discloses a solid pharmaceutical formulation comprising amorphous pemetrexed, or a salt thereof, and at least one pharmaceutically acceptable excipient.
  • the crystalline, amorphous and hydrate forms of pemetrexed have been disclosed through different prior art patent, applications and literature.
  • the crystalline heptahydrate forms, 2.5 hydrate form have also been disclosed and pharmaceutical composition comprising these different forms of pemetrexed are known through prior art.
  • Prior art discloses various pharmaceutical compositions comprising different forms and salts of pemetrexed.
  • Each crystalline form of a drug candidate can have different solid-state (physical and chemical) properties which may be relevant for drug delivery.
  • Dissolution rates of an active ingredient in vivo may have therapeutic consequences since it affects the rate at which an orally administered active ingredient may reach the patient's bloodstream.
  • solubility a thermodynamic quantity, is a relevant property in evaluating drug delivery because a poorly soluble crystalline form of a drug will deliver less drug than a more soluble one in the same formulation.
  • An object of the present invention is to provide pharmaceutically acceptable complexes of pemetrexed.
  • Yet object of the invention is to provide process of preparation of pharmaceutical composition comprising complexes of pemetrexed along with one or more pharmaceutically acceptable excipients.
  • Another object of the invention is to provide a method of treating cancer, pleural mesothelima and non- small cell lung cancer by administering a pharmaceutical composition comprising complexes of pemetrexed along with one or more pharmaceutically acceptable excipients. .
  • Another object of the present invention is to provide a pharmaceutical composition comprising complexes of pemetrexed along with one or more pharmaceutically acceptable excipients for use in the treatment of cancer, pleural mesothelima and non- small cell lung cancer.
  • a complex of pemetrexed with a co-former there is provided a complex of pemetrexed with a co-former.
  • the use comprises the treatment of cancer, pleural mesothelima and/or non-small cell lung cancer.
  • a complex of the invention in the manufacture of a medicament for the treatment of cancer, pleural mesothelima and/or non-small cell lung cancer.
  • a method of treating a subject with cancer, pleural mesothelima and/or non-small cell lung cancer comprising administering a complex according to the present invention to a patient in need thereof.
  • a pharmaceutical composition comprising a complex of pemetrexed, and one or more pharmaceutically acceptable excipients.
  • a pharmaceutical composition of the invention for use in medicine comprises the treatment of cancer, pleural mesothelima and/or non-small cell lung cancer.
  • a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of cancer, pleural mesothelima and/or non-small cell lung cancer.
  • a method of treating a subject with cancer, pleural mesothelima and/or non-small cell lung cancer comprising administering a complex according to the present invention to a patient in need thereof.
  • a process of preparing a pharmaceutical composition according to the invention comprising dispersing a complex of pemetrexed optionally with at least one or more pharmaceutically acceptable excipients, adjusting the pH using a suitable pH adjusting agent; optionally filling the mixture into a container; and optionally lyophilising the mixture.
  • the present invention provides a complex comprising pemetrexed and at least one co-former and methods of preparing such complexes.
  • the present invention also provides pharmaceutical compositions comprising pemetrexed complexes with one or more pharmaceutically acceptable excipients.
  • pemetrexed is in the form of pemetrexed disodium or pemetrexed dipotassium or pemetrexed with any other metal salts. More preferably, pemetrexed is in the form of pemetrexed disodium.
  • Pemetrexed is used in broad sense to include not only “Pemetrexed” per se but also its pharmaceutically acceptable derivatives thereof. Suitable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes etc.
  • a “complex” according to the present invention is a single chemical entity comprising two or more different elements that have a unique and defined chemical structure. Complexes can be constructed through several modes of molecular recognition including hydrogen-bonding, z (pi)-stacking, guest-host complexation and Van Der Waals interactions. Of the interactions listed above, hydrogen-bonding is the dominant interaction in the formation of the pharmaceutical compounds, whereby a non-covalent bond is formed between a hydrogen bond donor of one of the moieties and a hydrogen bond acceptor of the other.
  • a complex of the present invention is considered to be one where hydrogen bonding occurs between pemetrexed and a co-former.
  • a co-crystal is a crystalline structure composed of at least two components, where the components may be atoms, ions or molecules. In the present disclosure, the co-crystal is a crystalline structure composed of at least two molecules; suitably two molecules.
  • the pharmaceutically acceptable complex of pemetrexed disodium or pemetrexed dipotassium used in the compositions of the present invention is a single chemical entity comprising two or more different elements that have a unique and defined chemical structure.
  • Pemetrexed Complex used in the pharmaceutical compositions of the present invention involves hydrogen bonding between pemetrexed and a co-former.
  • the complex of the present invention is a complex of pemetrexed and at least one co-former which is optionally a crystal co-forming agent.
  • the cofomer is a carbohydrate.
  • the complex of the invention is a complex of pemtrexed disodium or pemetrexed dipotassium and a carbohydrate.
  • the carbohydrate is a sugar and/or sugar alcohol.
  • the carbohydrate may be a sugar selected from the group comprising of glucose, dextrose, fructose, galactose, ribose, sucrose, xylose, trehalose, lactose, maltose, raffinose, melezitose, glycerol, mannitol, sorbitol, erythritol, xylitol, maltitol, lactitol, D series and L series of rare sugars.
  • the D series of rare sugars are selected from D-sorbose, D-psicose, D-tagatose, D-gulose, D- gulitol, D-idose, D-iditol, D-talose, D-talitol, D-galactitol, D-mannitol, D-glucitol, D-altrose, D-altritol, D-allose and D-allitol.
  • the L series of rare sugars are selected from L-sorbose, L-fructose, L-psicose, L-tagatose, L- gulose, L-gulitol, L-idose, L-iditol, L-talose, L-talitol, L-galactitol, L-galactose, L-mannitol, L-mannose, L-glucitol, L-glucose, L-altrose, L-altritol, L-allose and L-allitol.
  • the complex of the present invention is amorphous or crystalline in nature.
  • the complex is a co-crystal.
  • the components of the complex which are pemetrexed disodium or pemetrexed dipotassium and carbohydrate can be present in a substantially stoichiometric ratio.
  • the complex of pemetrexed disodium or pemetrexed dipotassium and carbohydrates comprise carbohydrates in an amount of from about 5% to about 50% by weight of the complex.
  • the complex is pemetrexed disodium: mannitol complex, pemetrexed disodium: sorbitol complex, pemetrexed disodium: sucrose complex, pemetrexed disodium: glucose complex, or pemetrexed disodium: fructose complex.
  • the complex is pemetrexed dipotassium: mannitol complex, pemetrexed dipotassium: sorbitol complex, pemetrexed dipotassium: sucrose complex, pemetrexed dipotassium: glucose complex, or pemetrexed dipotassium: fructose complex.
  • the pemetrexed disodium: mannitol complex comprises pemetrexed disodium and mannitol in an almost stoichiometric ratio.
  • the pemetrexed dipotassium: mannitol complex comprises pemetrexed dipotassium and mannitol in an almost stoichiometric ratio.
  • the content of mannitol in the complex may be in the range of about 20% to about 50%, preferably from about 25%) to about 45% or more preferably from about 30% to about 40%.
  • the crystalline nature of pemetrexed disodium: mannitol complex has been analyzed, characterized and differentiated by X-ray powder diffraction, a technique which is well known per se.
  • the X-ray powder diffraction pattern was measured on a Rigaku Dmax 2200 advanced X-ray powder diffractometer with a copper- ⁇ - ⁇ radiation source.
  • the crystalline complex of pemetrexed disodium: mannitol has an XRD pattern comprising peaks at 9.619, 20.299 and 22.82 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the XRD pattern may further comprise peaks at 15.44, 20.98, 21.98, 23.8, 24.559, 25.16 and 36.00 2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the XRD pattern may comprise still further peaks at 4.66, 10.38, 14.12, 15.719, 17.14, 17.90, 18.559, 19.261, 25.861, 26.90, 27.78 and 28.82 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the complex of pemetrexed disodium: mannitol has an XRD pattern comprising peaks at 4.66, 9.619, 10.38, 14.12, 15.44, 15.719, 17.14, 17.90, 18.559, 19.261, 20.299, 20.98, 21.98, 22.82, 23.8, 24.559, 25.16, 25.861, 26.90, 27.78, 28.82 and 36 °2 ⁇ ⁇ 0.2 °2 ⁇ .
  • the complex is in a substantially pure form; preferably substantially free from other forms.
  • the X-ray diffraction pattern of the pure form does not show any diffraction peaks that allow calculation of a d-spacing of about 7.78 ⁇ 0.04 A, corresponding to 1 1.3 °2 ⁇ .
  • the pemetrexed disodium: mannitol complex is characterized by having an X-ray powder diffraction spectrum as shown in Figure 1.
  • the XRD peaks of the pemetrexed disodium: mannitol complex are identified in Table 1 below
  • the pemetrexed disodium: sorbitol complex is characterized by having an X-ray powder diffraction spectrum as shown in Figure 2.
  • the XRD peaks of the pemetrexed disodium: sorbitol complex are identified in Table 2 below.
  • the pemetrexed disodium: sucrose complex is characterized by having an X-ray powder diffraction spectrum as shown in Figure 3.
  • the XRD peaks of the pemetrexed disodium: sucrose complex are identified in Table 3 below.
  • the pH may be adjusted to 8 with aqueous sodium hydroxide solution.
  • the process may be carried out under an inert atmosphere, and may be carried out at a temperature ranging from 20°C to 30°C.
  • the pemetrexed used as a starting material may be in any form.
  • the pemetrexed may be a free acid or in a polymorphic form, in a mixture of polymorphic forms, crude or in anhydrous, hydrated or solvated form and the like.
  • the carbohydrate may be a sugar and/or sugar alcohol which may be selected from the sugars described hereinbefore.
  • the pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex may be precipitated by adding an antisolvent.
  • the antisolvent may be a water-miscible solvent.
  • the antisolvent may be selected form the group consisting of, but not limited to, acetone, CI -6 alcohols, and acetonitrile. In one embodiment, acetone is used as an anti- solvent and the like or mixtures thereof.
  • the CI -6 alcohols may include isopropyl alcohol.
  • the precipitated crystals are collected by filtration and may be dried at an elevated temperature ranging from about 30°C to about 60°C, and preferably ranging from about 40°C to about 50°C.
  • the process involves isolation of the complex in a solvent-free medium, thus producing a complex which is free of solvents or having a negligible solvent content.
  • a pharmaceutical composition comprising the complex of the present invention, with one or more pharmaceutically acceptable excipients.
  • the complexes used in the pharmaceutical compositions can be any of the complexes described herein.
  • compositions of the present invention can comprise pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients suitable for parenteral administration.
  • the pharmaceutical compositions for parenteral administration which are stable and bioavailable.
  • Further aspect of the present invention also includes administration of the pharmaceutical composition comprising pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients in the treatment of cancer, pleural mesothelima and non- small cell lung cancer.
  • the pharmaceutical composition of the present invention can contain a complex which may be amorphous or crystalline in nature.
  • the pharmaceutical composition comprises a complex is in a crystal form.
  • the present invention also provides the processes for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising a pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients which is suitable for parenteral administration.
  • pharmaceutical composition includes parenteral dosage forms, such as ready-to- use solutions; lyophilized forms and preparations thereof, like sterile lyophilized powders for intravenous infusion available in single or multi dose vials; aqueous solutions, colloidal nanosuspensions, emulsions, liposomal injections, injectable devices such as, but not limited to, pumps and autoinjectors; sterile powders for injection suitable for solubilization or suspension in liquid prior to injection, liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions, powders for reconstitution), gels, bolus, depots, implants (rods, capsules, rings) biodegradable or non-biodegradable microparticles/microspheres etc.
  • parenteral dosage forms such as ready-to- use solutions
  • lyophilized forms and preparations thereof like sterile lyophilized powders for intravenous infusion available in single or multi dose vials
  • the pharmaceutical composition comprising pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients which is suitable for parenteral administration can be in the form of a ready-to-use dosage form or can be in the form of a lyophilized preparation, which could be reconstituted by mixing with a carrier or a suspending agent before administration.
  • composition comprising pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients which is suitable for parenteral use may be administered via intramuscular route, intravenous route, subcutaneous route, intra dermal route, intra peritoneal route and the like.
  • the pharmaceutical composition comprising pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients is not only restricted for parenteral administration, but it may envisage other pharmaceutical dosage forms such as, but not limited to, tablets (single layer, bilayer, multilayer, tablet in tablet) which may be uncoated, film coated, carbohydrate coated, powder coated, enteric coated, seal coated; capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multi unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, microspheres and multiparticulates or combinations thereof), sachets (filled with powders, pellets, beads, mini- tablets, pills, micro-pellets, small tablet units, multi unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, microspheres, multiparticulates or combinations thereof) and sprinkles.
  • liquid dosage forms liquids, liquid dispersions, suspensions, solutions, emulsions, sprays, spot-on
  • gels aerosols, ointments, creams, controlled release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations etc.
  • controlled release formulations delayed release formulations
  • extended release formulations extended release formulations
  • pulsatile release formulations dual release formulations etc.
  • the pharmaceutical composition comprising the pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients can be prepared according to techniques known in the art using suitable pharmaceutically acceptable excipients such as, but not limited to bulking agents, pH adjusting agents, carriers or suspending agents, antibacterial preservatives, chelating agents, stabilizers, sequestering agents, antioxidants and tonicity adjusting agents or combinations thereof.
  • suitable pharmaceutically acceptable excipients such as, but not limited to bulking agents, pH adjusting agents, carriers or suspending agents, antibacterial preservatives, chelating agents, stabilizers, sequestering agents, antioxidants and tonicity adjusting agents or combinations thereof.
  • Bulking agents are excipients which are capable of making the pharmaceutical composition of the present invention isotonic with blood at the time of administration.
  • Suitable bulking agents or diluents that can be used, in the pharmaceutical composition of the present invention, include, but are not limited to, mannitol, sucrose, maltose, xylitol, glucose, starches, sorbitol, fructose, galactose, ribose, xylose, trehalose, lactose, raffinose, melezitose, glycerol, erythritol, maltitol, lactitol, D & L series of rare carbohydrates, their salts and the like or mixtures thereof.
  • the pharmaceutical composition of the present invention may further comprise a pH adjusting agent, which is used in an amount to adjust the pH from about 4 to about 10 before lyophilisation. It may be an acid or base depending upon whether the pH of the pharmaceutical composition needs to be raised or lowered to attain the desired value. Thus, when the pH needs to be lowered, an acidic pH adjusting agent, such as hydrochloric acid, tartaric acid, sulphuric acid, citric acid, phosphoric acid, benzoic acid or acetic acid and the like may be used.
  • a pH adjusting agent such as hydrochloric acid, tartaric acid, sulphuric acid, citric acid, phosphoric acid, benzoic acid or acetic acid and the like may be used.
  • a basic pH adjusting agent such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, magnesium carbonate, potassium carbonate, magnesium oxide, magnesium hydroxide, glutamic acid or histidine and the like may be used.
  • pH adjusting agents can either be used singly or in a combination.
  • the pharmaceutical composition of the present invention may further comprise carriers or suspending agents such as, but not limited to, water for injection, Ringer's solution, isotonic sodium chloride solution and the like or combinations thereof.
  • carriers or suspending agents may also include, fixed oils, fatty esters or polyols, sodium carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropylethyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, various polymers, low-molecular- weight oligomers, natural products, and surfactants (including nonionic and ionic surfactants), such as cetyl pyridinium chloride, gelatin, casein, phospholipids, lecithin (phosphatide), phophatidylcholines dextran.
  • surfactants including nonionic and ionic surfactants
  • glycerol gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters such as Tweens, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, hydroxypropyl celluloses, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, 4-(l , 1 ,3,3- tetramethylbutyl)-phenol polymer with ethylene oxide and formal
  • Suitable antibacterial preservatives that may be employed in the pharmaceutical composition of the present invention are phenylmercuric nitrate, thiomersal, benzalkonium chloride, benzethonium chloride, phenol, 4-amino benzoic acid (PABA), cresol and chlorobutanol; chelating agents such as ethylenediamine tetra acetic acid (EDTA) , their salts and the like or mixtures thereof.
  • PABA 4-amino benzoic acid
  • EDTA ethylenediamine tetra acetic acid
  • Suitable tonicity adjusting agents that may be employed in the pharmaceutical composition of the present invention are sodium chloride, potassium chloride, dextrose, mannitol, sorbitol, sucrose and lactose; and alkaline substances including one or more of salts of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphates as well as organic amines such as meglumine and tromethamine, hydrochloric acid, tartaric acid, sulphuric acid, citric acid, phosphoric acid, benzoic acid or acetic acid, sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, magnesium carbonate, potassium carbonate, magnesium oxide, magnesium hydroxide, glycerine, propylene glycol, PEG, glutamic acid, histidine, their salts and the like or combinations thereof.
  • alkaline substances including one or more of salts of alkali and alkaline earth metals such as
  • the pharmaceutical composition of the invention can comprise a bulking agent, pH adjusting agent, a carrier or suspending agent, an antibacterial preservative, a chelating agent, a stabiliser, a sequestering agent, an antioxidant, a tonicity adjusting agent, or any mixtures thereof.
  • the pharmaceutical composition of the invention can comprise a bulking agent, a carrier, and a pH adjusting agent.
  • the pharmaceutical composition can comprise a bulking agent comprising sucrose, mannitol and/or sorbitol, and a pH adjusting agent comprising hydrochloric acid and/or sodium hydroxide.
  • a process for preparing the pharmaceutical composition suitable for parenteral administration is provided.
  • the process comprises dissolving the complex as well as bulking agent in a suitable carrier, adjusting the pH and lyophilizing it.
  • the process comprises dissolving the complex as well as bulking agent in a suitable carrier and adjusting the pH.
  • the process comprises formation of a sterile powder of the complex along with one or more pharmaceutically acceptable excipients.
  • the preferred pemetrexed disodiumxarbohydrate complexes in the formulation of the present invention are pemetrexed disodium: mannitol complex, pemetrexed disodium: sorbitol complex, pemetrexed disodium: sucrose complex, most preferred complex is pemetrexed disodium: mannitol complex.
  • the preferred pemetrexed dipotassium: carbohydrate complexes in the formulation of the present invention are pemetrexed dipotassium: mannitol complex, pemetrexed dipotassium: sorbitol complex, pemetrexed dipotassium: sucrose complex, most preferred complex is pemetrexed dipotassium: mannitol complex.
  • the present invention also provides methods of filling containers that contain a pharmaceutical composition of the present invention, comprising: a) pre sterilizing one or more containers, b) filling the containers with the pharmaceutical composition optionally in an aseptic environment, c) stoppering and sealing the filled containers and d) terminal sterilization.
  • the present invention also provides methods of filling containers that contain a pharmaceutical composition of the present invention, comprising: a) pre sterilizing one or more containers and closures, b) filling the containers with the pharmaceutical composition optionally in an aseptic environment, c) lyophilizing the filled containers, d) stoppering and sealing the filled containers and e) terminal sterilization.
  • the present invention also provides methods of filling containers that contain a pharmaceutical composition of the present invention, comprising: a) pre sterilizing the pharmaceutical composition, one or more containers and the closures, b) filling the containers with the pharmaceutical composition optionally in an aseptic environment, c) optionally lyophilizing the filled containers, and d) stoppering and sealing the filled containers.
  • Containers can be in the form of small glass vials that are sealed with a suitable stopper/seal and may also be replaced by other primary containers for example, but not limited to, pre- filled syringes.
  • Vials can be for single use or multi use and may include breakable and non- breakable glass containers, breakable plastic containers, miniature screw-top jars and any other type of container typically of a size capable of holding only unit or multi dose of the pharmaceutical composition of the present invention.
  • the present invention also provides packaging materials for containers and closures such as, but not limited to, high-density polyethylene (HDPE), low-density polyethylene (LDPE) and/or polypropylene and/or glass, glassine foil, polyvinyl chloride, polyvinylidene dichloride, and the like.
  • HDPE high-density polyethylene
  • LDPE low-density polyethylene
  • polypropylene and/or glass
  • glassine foil polyvinyl chloride
  • polyvinylidene dichloride polyvinylidene dichloride
  • stoppers may also be used to seal the vial containing the pharmaceutical composition of the present invention.
  • Some of the stopper materials include silicone rubber, coated stoppers, slotted bromobutyl rubber, and the like.
  • the present invention provides a method of treating patients with locally advanced or metastatic nonsquammous non-small cell lung cancer after prior chemotherapy or maintenance treatment of patients whose disease has not progressed after four cycles of platinum based first line chemotherapy by administering a pharmaceutical composition of the present invention.
  • the present invention also provides a method of initial treatment of patients with locally advanced or metastatic nonsquammous non-small cell lung cancer or mesothelioma by administering a pharmaceutical composition of the present invention in combination with cisplatin.
  • the present invention further provides the use of pharmaceutical compositions of the present invention for the treatment of patients with locally advanced or metastatic nonsquammous non-small cell lung cancer after prior chemotherapy or maintenance treatment of patients whose disease has not progressed after four cycles of platinum based first line chemotherapy.
  • the present invention further provides the use of pharmaceutical composition of the present invention for the treatment of locally advanced or metastatic nonsquammous non-small cell lung cancer or mesothelima by administering a pharmaceutical composition of the present invention in combination with cisplatin.
  • Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere.
  • the pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution.
  • the reaction mass was further stirred at 20-25°C for 10 minutes and filtered.
  • mannitol (22.5 g) at 25-30°C.
  • the reaction mass was further stirred at 25-30°C for 10 minutes.
  • the clear filtrate was added to acetone (1.14 1) over a period of 1 hour at 27 ⁇ 2°C. Stirring at 25-30°C was continued for about 2 hours.
  • the precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 47.5 g of a pharmaceutical compound of pemetrexed disodium: mannitol.
  • the content of the pemetrexed disodium is about 65% of the weight.
  • Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere.
  • the pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution.
  • the reaction mass was further stirred at 20-25°C for 10 minutes and filtered.
  • mannitol (22.5 g) at 25-30°C.
  • the reaction mass was further stirred at 25-30°C for 10 minutes.
  • the clear filtrate was added to methanol (1.1 1) over a period of 1 hour at 27 ⁇ 2°C. Stirring at 25-30°C was continued for about 2 hours.
  • the precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 45.0 g of a pharmaceutical compound of pemetrexed disodium: mannitol.
  • the content of the pemetrexed disodium is about 65% of the weight.
  • Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere.
  • the pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution.
  • the reaction mass was further stirred at 20-25°C for 10 minutes and filtered.
  • mannitol (22.5 g) at 25-30°C.
  • the reaction mass was further stirred at 25-30°C for 10 minutes.
  • the clear filtrate was added to isopropyl alcohol (1.1 1) over a period of 1 hour at 27 ⁇ 2°C. Stirring at 25-30°C was continued for about 2 hours.
  • the precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 45.0 g of a pharmaceutical compound of pemetrexed disodium: mannitol.
  • the content of the pemetrexed disodium is about 65% of the weight.
  • Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere.
  • the pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution.
  • the reaction mass was further stirred at 20-25°C for 10 minutes and filtered.
  • To the clear filtrate was added sorbitol (22.5 g) at 25-30°C.
  • the reaction mass was further stirred at 25-30°C for 10 minutes.
  • the clear filtrate was added to acetone (1.1 1) over a period of 1 hour at 27 ⁇ 2°C. Stirring at 25-30°C was continued for about 2 hours.
  • Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere. The pH of the reaction mass was adjusted to 8, with 10 % aqueous sodium hydroxide solution. The reaction mass was further stirred at 20-25°C for 10 minutes and filtered. To the clear filtrate was added sucrose (48 g) at 25-30°C. The reaction mass was further stirred at 25-30°C for 10 minutes. The clear filtrate was added to acetone (1.1 1) over a period of 1 hour at 27 ⁇ 2°C. Stirring at 25-30°C was continued for about 2 hours. The precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 47.5 g of pemetrexed disodium: sucrose complex. The content of the pemetrexed disodium is about 52%.
  • Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere. The pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution. The reaction mass was further stirred at 20-25°C for 10 minutes and filtered. To the clear filtrate was added glucose (22.5 g) at 25-30°C. The reaction mass was further stirred at 25-30°C for 10 minutes. The clear filtrate was added to acetone (1.1 1) over a period of 1 hour at 27 ⁇ 2°C. Stirring at 25-30°C was continued for about 2 hours. The precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 47.5 g of pemetrexed disodium: sorbitol complex. The content of the pemetrexed disodium is about 85%.
  • Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere. The pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution. The reaction mass was further stirred at 20-25°C for 10 minutes and filtered. To the clear filtrate was added fructose (22.5 g) at 25-30°C. The reaction mass was further stirred at 25-30°C for 10 minutes. The clear filtrate was added to acetone (1.1 1) over a period of 1 hour at 27 ⁇ 2°C. Stirring at 25-30°C was continued for about 2 hours. The precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 47.5 g of pemetrexed disodium: sorbitol complex. The content of the pemetrexed disodium is about 85%.
  • Pemetrexed diethyl ester ditosylate salt was added to purified water and sodium hydroxide, stirred for 3 hours at 20-25°C.
  • the reaction mass was filtered and isopropyl alcohol was added to the clear filtrate.
  • the pH was adjusted to 3.0-3.5 by using hydrochloric acid at 23 ⁇ 2°C.
  • the mixture was stirred at 23 ⁇ 2°C for 90 minutes, the contents were heated to 53 ⁇ 2°C and maintained for 30 minutes, and then further cooled to 25 ⁇ 2°C.
  • the material was filtered and dried at 48 ⁇ 2°C.
  • the solid was dissolved in dimethyl sulphoxide and precipitated in isopropyl alcohol, filtered and slurried in a mixture of isopropyl alcohol and water. The solid was filtered and dried at 43 ⁇ 2°C to obtain pemetrexed.
  • Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere. The pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution. The reaction mass was further stirred at 20-25°C for 10 minutes and filtered. To the clear filtrate was added mannitol (22.5 g) at 25-30°C. The reaction mass was further stirred at 25-30°C for 10 minutes. The clear filtrate was added to the acetone (1.14 1) over a period of 1 hour at 27 ⁇ 2°C. Stirring at 25-30°C was continued for about 2 hours. The precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 47.5 g of complex pemetrexed disodium: mannitol. The content of the pemetrexed disodium is about 60 % of the weight.
  • the quantity of Mannitol which is added separately in the formulation in the above example is based on the respective content of Mannitol present in the Pemetrexed Disodium complex.
  • the quantity of Mannitol which is added separately in the formulation in the above example is based on the respective content of Mannitol present in the Pemetrexed Disodium complex.
  • the quantity of Sorbitol which is added separately in the formulation in the above example is based on the respective content of Sorbitol present in the Pemetrexed Disodium complex.
  • the quantity of Sucrose which is added separately in the formulation in the above example is based on the respective content of Sucrose present in the Pemetrexed Disodium complex.
  • the quantity of Sucrose which is added separately in the formulation in the above example is based on the respective content of Sucrose present in the Pemetrexed Disodium complex.

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Abstract

A complex comprises pemetrexed and a coformer. A pharmaceutical composition comprises a complex of pemetrexed and a co-former and one or more pharmaceutically acceptable excipients.

Description

Pemetrexed complexes and pharmaceutical compositions containing pemetrexed complexes
The present invention relates to pharmaceutically acceptable complexes comprising pemetrexed and pharmaceutically acceptable compositions comprising said complexes, processes for preparation of the complexes and pharmaceutical compositions comprising said complexes, and their use in the treatment of cancer, pleural mesothelima and non- small cell lung cancer.
Background of the invention
Pyrrolo[2,3-d]pyrimidine based antifolates are drugs that impair the function of folic acids. Many of them are used in cancer chemotherapy and some are used as antibiotics or antiprotozoal agents. These include pemetrexed, methotrexate, raltitrexed and pralatrexate.
Pemetrexed is an antifolate, antineoplastic agent. Lily's anticancer drug Alimta® (pemetrexed) is a sterilized lyophilized powder for intravenous administration and is approved for treatment of mesothelioma and non small cell lung cancer.
Pemetrexed was approved by the United States Food and Drug Administration in February 2004 in combination with cisplatin, a platinum-containing chemotherapeutic drug for the treatment of malignant pleural mesothelioma (MPM). In July 2004, the drug was approved by the FDA as a second line agent for the initial treatment of advanced or metastatic non- small cell lung cancer (NSCLC). Currently, the drug is used as a single agent or in combination with other chemotherapeutic agents for the treatment of other types of cancer such as breast cancer, bladder cancer, colorectal carcinoma and cervical cancer.
Pemetrexed was first disclosed in US5344932 and is commercialized as Alimta® sterile lyophilized powders for intravenous infusion, available in single-dose vials containing 100 mg or 500 mg equivalent of pemetrexed. A crystalline form of pemetrexed disodium designated Disodium MTA Hydrate Form I has been described in WO200114379.
US7138521 describes a stable crystalline heptahydrate form of pemetrexed having a characteristic X-ray diffraction pattern, which comprises a peak corresponding to a d- spacing of 7.78±0.04 A when obtained at 22±2°C and at ambient relative humidity. The patent mentions that the heptahydrate form is much more stable than the previously known 2.5 hydrate and the primary advantage over the 2.5 hydrate crystal form is its stability and also with respect to the formation of related substances. The patent also indicates that when the heptahydrate is subjected to elevated temperatures, low humidity, and/or a vacuum, it converts to the 2.5 hydrate crystal form by loss of water.
WO2008124485 discloses besides five crystalline forms of the diacid pemetrexed; an amorphous pemetrexed disodium as well as a crystalline Form III thereof including a composition containing a major amount of amorphous Form and a minor amount of crystalline Form III of pemetrexed disodium.
EP 1943252 discloses a process for the preparation of a lyophilized pharmaceutically acceptable di-base-addition salt of pemetrexed, in particular, a pemetrexed disodium salt, directly from pemetrexed diacid or an acid or base addition salt thereof, i.e. a di-base salt of pemetrexed which is not isolated prior to the lyophilization.
US2011201631A1 discloses a solid pharmaceutical formulation comprising amorphous pemetrexed, or a salt thereof, and at least one pharmaceutically acceptable excipient.
The crystalline, amorphous and hydrate forms of pemetrexed have been disclosed through different prior art patent, applications and literature. The crystalline heptahydrate forms, 2.5 hydrate form have also been disclosed and pharmaceutical composition comprising these different forms of pemetrexed are known through prior art. Prior art discloses various pharmaceutical compositions comprising different forms and salts of pemetrexed.
Properties such as the solubility and stability and consequently the suitability for use and storage of each solid form may vary and is essential for providing pharmaceuticals with increased storage stability or predicable solubility profiles. Each crystalline form of a drug candidate can have different solid-state (physical and chemical) properties which may be relevant for drug delivery.
Dissolution rates of an active ingredient in vivo (e.g., gastric or intestinal fluid) may have therapeutic consequences since it affects the rate at which an orally administered active ingredient may reach the patient's bloodstream. In addition, solubility, a thermodynamic quantity, is a relevant property in evaluating drug delivery because a poorly soluble crystalline form of a drug will deliver less drug than a more soluble one in the same formulation.
Because these practical physical properties are influenced by the solid-state properties of the crystalline form of the drug, they can significantly impact the selection of a compound as a drug, the ultimate pharmaceutical dosage form, the optimization of manufacturing processes and absorption in the body. Moreover, finding the most adequate solid state form for further drug development can reduce the time and the cost of development.
However, the conversions between different polymorphic forms of pemetrexed when exposed to elevated temperatures, low humidity etc. may affect the formulation processes, resulting in a possibility that the stability of the final product may be affected. It is known that amorphous forms of active ingredients can be relatively more unstable, when compared to the crystalline form. Thus, stabilizing amorphous pemetrexed or its salts in formulations is considered difficult. Hence, formulating pemetrexed has not proven to be an easy task, due to its stability issues. Therefore, obtaining a suitable form of a drug is a necessary stage for many drug substances. Also, molecular and thermodynamic properties of the drug form contribute to the solubility and stability of a drug product for its pharmaceutical use.
Additionally, while designing any pharmaceutical composition it is important to lay emphasis on the API and excipients .The selection of the API type and excipients would ultimate decide the fate of bioavailability and robustness of the ultimate composition. The excipients API compatibility is of utmost importance to design a stable, bioavailable and robust composition. Secondly the form conversion of the API during the pharmaceutical composition processing due to change in temperature or humidity of the environment also needs to be considered.
The inventors of the present invention have appreciated that prior art forms of pemetrexed and pharmaceutical compositions comprising such forms of pemetrexed could be improved by tailoring physical properties such as stability of the API and solubility of the pharmaceutical compositions. However, there is a need to do this without affecting the chemical composition of the API. The inventors have appreciated that these problems could be solved by providing complexes formed by the pemetrexed API and a co- former or molecular complexes. These can be tailored to address formulation issues related to the physical properties such as solubility and stability without affecting the chemical composition of the API. These complexes can be further incorporated into the compositions to design stable and robust pharmaceutical compositions.
Objects of the invention
An object of the present invention is to provide pharmaceutically acceptable complexes of pemetrexed.
Another object of the present invention is to provide a pharmaceutical composition comprising complexes of pemetrexed along with one or more pharmaceutically acceptable excipients. Another aspect of the invention is to provide pharmaceutical composition comprising complexes of pemetrexed which are stable and bioavailable.
Yet object of the invention is to provide process of preparation of pharmaceutical composition comprising complexes of pemetrexed along with one or more pharmaceutically acceptable excipients.
Another object of the invention is to provide a method of treating cancer, pleural mesothelima and non- small cell lung cancer by administering a pharmaceutical composition comprising complexes of pemetrexed along with one or more pharmaceutically acceptable excipients. .
Another object of the present invention is to provide a pharmaceutical composition comprising complexes of pemetrexed along with one or more pharmaceutically acceptable excipients for use in the treatment of cancer, pleural mesothelima and non- small cell lung cancer.
Summary of the invention
According to an aspect of the invention, there is provided a complex of pemetrexed with a co-former.
According to another aspect of the invention, there is a provided a complex of the invention for use in medicine. Preferably, the use comprises the treatment of cancer, pleural mesothelima and/or non-small cell lung cancer.
According to another aspect of the invention, there is provided use of a complex of the invention in the manufacture of a medicament for the treatment of cancer, pleural mesothelima and/or non-small cell lung cancer. According to another aspect of the invention, there is provided a method of treating a subject with cancer, pleural mesothelima and/or non-small cell lung cancer, wherein the method comprises administering a complex according to the present invention to a patient in need thereof.
According to another aspect of the invention, there is provided a process for the preparation of a complex of the invention, wherein the process comprises;
(1) dispersing pemetrexed into an aqueous solvent to form a solution; and adjusting the pH of the solution ;
(2) optionally removing insolubles by filtration;
(3) adding a carbohydrate to the filtrate;
(4) precipitating and drying the complex from the solution.
According to another aspect of the invention, there is provided a pharmaceutical composition comprising a complex of pemetrexed, and one or more pharmaceutically acceptable excipients.
According to another aspect of the invention, there is provided a pharmaceutical composition of the invention for use in medicine. Preferably, the use comprises the treatment of cancer, pleural mesothelima and/or non-small cell lung cancer.
According to another aspect of the invention, there is provided use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of cancer, pleural mesothelima and/or non-small cell lung cancer.
According to another aspect of the invention, there is provided a method of treating a subject with cancer, pleural mesothelima and/or non-small cell lung cancer, wherein the method comprises administering a complex according to the present invention to a patient in need thereof. According to another aspect of the present invention, there is provided a process of preparing a pharmaceutical composition according to the invention, wherein the process comprises dispersing a complex of pemetrexed optionally with at least one or more pharmaceutically acceptable excipients, adjusting the pH using a suitable pH adjusting agent; optionally filling the mixture into a container; and optionally lyophilising the mixture.
Detailed Description
The present invention provides a complex comprising pemetrexed and at least one co-former and methods of preparing such complexes. The present invention also provides pharmaceutical compositions comprising pemetrexed complexes with one or more pharmaceutically acceptable excipients. Preferably, pemetrexed is in the form of pemetrexed disodium or pemetrexed dipotassium or pemetrexed with any other metal salts. More preferably, pemetrexed is in the form of pemetrexed disodium.
The term "Pemetrexed" is used in broad sense to include not only "Pemetrexed" per se but also its pharmaceutically acceptable derivatives thereof. Suitable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes etc.
A "complex" according to the present invention is a single chemical entity comprising two or more different elements that have a unique and defined chemical structure. Complexes can be constructed through several modes of molecular recognition including hydrogen-bonding, z (pi)-stacking, guest-host complexation and Van Der Waals interactions. Of the interactions listed above, hydrogen-bonding is the dominant interaction in the formation of the pharmaceutical compounds, whereby a non-covalent bond is formed between a hydrogen bond donor of one of the moieties and a hydrogen bond acceptor of the other. A complex of the present invention is considered to be one where hydrogen bonding occurs between pemetrexed and a co-former. A co-crystal is a crystalline structure composed of at least two components, where the components may be atoms, ions or molecules. In the present disclosure, the co-crystal is a crystalline structure composed of at least two molecules; suitably two molecules.
The pharmaceutically acceptable complex of pemetrexed disodium or pemetrexed dipotassium used in the compositions of the present invention is a single chemical entity comprising two or more different elements that have a unique and defined chemical structure. Pemetrexed Complex used in the pharmaceutical compositions of the present invention involves hydrogen bonding between pemetrexed and a co-former.
Preferably, the complex of the present invention is a complex of pemetrexed and at least one co-former which is optionally a crystal co-forming agent. Preferably, the cofomer is a carbohydrate.
Preferably, the complex of the invention is a complex of pemtrexed disodium or pemetrexed dipotassium and a carbohydrate. Preferably, the carbohydrate is a sugar and/or sugar alcohol.
The carbohydrate may be a sugar selected from the group comprising of glucose, dextrose, fructose, galactose, ribose, sucrose, xylose, trehalose, lactose, maltose, raffinose, melezitose, glycerol, mannitol, sorbitol, erythritol, xylitol, maltitol, lactitol, D series and L series of rare sugars.
The D series of rare sugars are selected from D-sorbose, D-psicose, D-tagatose, D-gulose, D- gulitol, D-idose, D-iditol, D-talose, D-talitol, D-galactitol, D-mannitol, D-glucitol, D-altrose, D-altritol, D-allose and D-allitol. The L series of rare sugars are selected from L-sorbose, L-fructose, L-psicose, L-tagatose, L- gulose, L-gulitol, L-idose, L-iditol, L-talose, L-talitol, L-galactitol, L-galactose, L-mannitol, L-mannose, L-glucitol, L-glucose, L-altrose, L-altritol, L-allose and L-allitol.
Preferably, the complex of the present invention is amorphous or crystalline in nature. Preferably, the complex is a co-crystal.
The components of the complex which are pemetrexed disodium or pemetrexed dipotassium and carbohydrate can be present in a substantially stoichiometric ratio. Preferably, the complex of pemetrexed disodium or pemetrexed dipotassium and carbohydrates comprise carbohydrates in an amount of from about 5% to about 50% by weight of the complex.
Preferably, the complex is pemetrexed disodium: mannitol complex, pemetrexed disodium: sorbitol complex, pemetrexed disodium: sucrose complex, pemetrexed disodium: glucose complex, or pemetrexed disodium: fructose complex.
Preferably, the complex is pemetrexed dipotassium: mannitol complex, pemetrexed dipotassium: sorbitol complex, pemetrexed dipotassium: sucrose complex, pemetrexed dipotassium: glucose complex, or pemetrexed dipotassium: fructose complex.
The pemetrexed disodium: mannitol complex comprises pemetrexed disodium and mannitol in an almost stoichiometric ratio. The pemetrexed dipotassium: mannitol complex comprises pemetrexed dipotassium and mannitol in an almost stoichiometric ratio. The content of mannitol in the complex may be in the range of about 20% to about 50%, preferably from about 25%) to about 45% or more preferably from about 30% to about 40%.
The crystalline nature of pemetrexed disodium: mannitol complex has been analyzed, characterized and differentiated by X-ray powder diffraction, a technique which is well known per se. The X-ray powder diffraction pattern was measured on a Rigaku Dmax 2200 advanced X-ray powder diffractometer with a copper-Κ-α radiation source.
In an embodiment, the crystalline complex of pemetrexed disodium: mannitol has an XRD pattern comprising peaks at 9.619, 20.299 and 22.82 °2Θ ± 0.2 °2Θ. The XRD pattern may further comprise peaks at 15.44, 20.98, 21.98, 23.8, 24.559, 25.16 and 36.00 2Θ ± 0.2 °2Θ. The XRD pattern may comprise still further peaks at 4.66, 10.38, 14.12, 15.719, 17.14, 17.90, 18.559, 19.261, 25.861, 26.90, 27.78 and 28.82 °2Θ ± 0.2 °2Θ. Thus, typically, the complex of pemetrexed disodium: mannitol has an XRD pattern comprising peaks at 4.66, 9.619, 10.38, 14.12, 15.44, 15.719, 17.14, 17.90, 18.559, 19.261, 20.299, 20.98, 21.98, 22.82, 23.8, 24.559, 25.16, 25.861, 26.90, 27.78, 28.82 and 36 °2Θ ± 0.2 °2Θ.
The complex is in a substantially pure form; preferably substantially free from other forms. The X-ray diffraction pattern of the pure form does not show any diffraction peaks that allow calculation of a d-spacing of about 7.78±0.04 A, corresponding to 1 1.3 °2Θ.
In an embodiment, the pemetrexed disodium: mannitol complex is characterized by having an X-ray powder diffraction spectrum as shown in Figure 1. The XRD peaks of the pemetrexed disodium: mannitol complex are identified in Table 1 below
Diffraction angle (20-values) Intensity (%)
4.660 14.6
7.700 7.1
9.619 100.0
10.380 1 1.2
14.120 1 1.1
14.879 8.9
15.440 43.6
15.719 1 1.8 17.140 15.8
17.900 29.8
18.559 19.7
19.261 25.5
19.716 2.7
20.299 94.1
20.980 51.0
21.980 38.2
22.820 63.8
23.800 31.6
24.559 37.1
25.160 52.4
25.861 15.5
26.900 1 1.8
27.780 12.0
28.820 18.6
30.160 9.8
32.040 8.1
33.938 1.6
34.840 9.0
35.180 3.3
36.000 36.7
36.400 12.0
37.262 1.7
39.359 10.5 In another embodiment, the pemetrexed disodium: sorbitol complex is characterized by having an X-ray powder diffraction spectrum as shown in Figure 2. The XRD peaks of the pemetrexed disodium: sorbitol complex are identified in Table 2 below.
Diffraction angle (20-values) Intensity (%)
4.720 25.0
7.760 13.1
9.459 24.7
10.140 8.9
10.460 18.6
14.200 18.0
14.939 16.2
15.520 66.7
15.800 16.0
17.221 20.9
17.980 50.4
18.620 33.6
19.040 18.9
19.299 30.2
20.839 17.9
22.920 100.0
23.362 2.6
23.860 55.1
25.481 4.4
25.960 28.3
26.580 5.6
26.981 18.2
27.500 4.6
28.681 21.3 28.920 26.1
29.793 1.3
30.240 14.0
In still another embodiment, the pemetrexed disodium: sucrose complex is characterized by having an X-ray powder diffraction spectrum as shown in Figure 3. The XRD peaks of the pemetrexed disodium: sucrose complex are identified in Table 3 below.
Diffraction angle (20-values) Intensity (%)
4.741 20.0
7.780 1 1.1
9.460 23.4
10.121 6.9
10.460 16.6
13.839 3.4
14.220 17.8
14.959 14.2
15.540 58.6
15.838 1 1.1
17.239 13.9
17.981 46.0
18.640 31.9
19.060 13.2
19.281 22.7
20.821 19.1
22.921 100.0
23.362 3.5
23.880 47.4
25.519 5.4 25.980 30.4
26.600 6.3
26.961 19.2
27.520 3.6
28.403 7.3
28.740 26.0
28.939 30.2
30.260 15.1
30.680 4.5
According to another aspect of the invention, there is provided a process for the preparation of a complex, wherein the process comprises;
(1) dispersing pemetrexed into an aqueous solvent to form a solution; and adjusting the pH of the solution ;
(2) optionally removing insolubles by filtration;
(3) adding a carbohydrate to the filtrate;
(4) precipitating and drying the complex from the solution.
The pH may be adjusted to 8 with aqueous sodium hydroxide solution.
After a carbohydrate is added to the filtrate, a clear solution may be obtained.
The process may be carried out under an inert atmosphere, and may be carried out at a temperature ranging from 20°C to 30°C.
The pemetrexed used as a starting material may be in any form. For example the pemetrexed may be a free acid or in a polymorphic form, in a mixture of polymorphic forms, crude or in anhydrous, hydrated or solvated form and the like. The carbohydrate may be a sugar and/or sugar alcohol which may be selected from the sugars described hereinbefore.
The pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex may be precipitated by adding an antisolvent. The antisolvent may be a water-miscible solvent. The antisolvent may be selected form the group consisting of, but not limited to, acetone, CI -6 alcohols, and acetonitrile. In one embodiment, acetone is used as an anti- solvent and the like or mixtures thereof. The CI -6 alcohols may include isopropyl alcohol.
The precipitated crystals are collected by filtration and may be dried at an elevated temperature ranging from about 30°C to about 60°C, and preferably ranging from about 40°C to about 50°C.
The process involves isolation of the complex in a solvent-free medium, thus producing a complex which is free of solvents or having a negligible solvent content.
According to the present invention, there is provided a pharmaceutical composition comprising the complex of the present invention, with one or more pharmaceutically acceptable excipients. The complexes used in the pharmaceutical compositions can be any of the complexes described herein.
According to the present invention, there is also provided a process of preparing the pharmaceutical composition comprising pemetrexed complex along with pharmaceutically acceptable excipients.
Pharmaceutical compositions of the present invention can comprise pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients suitable for parenteral administration. In one embodiment of the present invention, the pharmaceutical compositions for parenteral administration which are stable and bioavailable.
Further aspect of the present invention also includes administration of the pharmaceutical composition comprising pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients in the treatment of cancer, pleural mesothelima and non- small cell lung cancer.
The pharmaceutical composition of the present invention can contain a complex which may be amorphous or crystalline in nature. In a preferred embodiment the pharmaceutical composition comprises a complex is in a crystal form.
The present invention also provides the processes for preparing a pharmaceutical composition comprising a pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients which is suitable for parenteral administration.
The term "pharmaceutical composition" includes parenteral dosage forms, such as ready-to- use solutions; lyophilized forms and preparations thereof, like sterile lyophilized powders for intravenous infusion available in single or multi dose vials; aqueous solutions, colloidal nanosuspensions, emulsions, liposomal injections, injectable devices such as, but not limited to, pumps and autoinjectors; sterile powders for injection suitable for solubilization or suspension in liquid prior to injection, liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions, powders for reconstitution), gels, bolus, depots, implants (rods, capsules, rings) biodegradable or non-biodegradable microparticles/microspheres etc.
Preferably, the pharmaceutical composition comprising pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients which is suitable for parenteral administration can be in the form of a ready-to-use dosage form or can be in the form of a lyophilized preparation, which could be reconstituted by mixing with a carrier or a suspending agent before administration.
Further, the pharmaceutical composition comprising pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients which is suitable for parenteral use may be administered via intramuscular route, intravenous route, subcutaneous route, intra dermal route, intra peritoneal route and the like.
The pharmaceutical composition comprising pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients is not only restricted for parenteral administration, but it may envisage other pharmaceutical dosage forms such as, but not limited to, tablets (single layer, bilayer, multilayer, tablet in tablet) which may be uncoated, film coated, carbohydrate coated, powder coated, enteric coated, seal coated; capsules (filled with powders, powders for reconstitution, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multi unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, microspheres and multiparticulates or combinations thereof), sachets (filled with powders, pellets, beads, mini- tablets, pills, micro-pellets, small tablet units, multi unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, microspheres, multiparticulates or combinations thereof) and sprinkles. Other dosage forms such as liquid dosage forms (liquids, liquid dispersions, suspensions, solutions, emulsions, sprays, spot-on), gels, aerosols, ointments, creams, controlled release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations etc. may also be envisaged under the ambit of the invention.
The pharmaceutical composition comprising the pemetrexed disodium: carbohydrate or pemetrexed dipotassium: carbohydrate complex along with one or more pharmaceutically acceptable excipients can be prepared according to techniques known in the art using suitable pharmaceutically acceptable excipients such as, but not limited to bulking agents, pH adjusting agents, carriers or suspending agents, antibacterial preservatives, chelating agents, stabilizers, sequestering agents, antioxidants and tonicity adjusting agents or combinations thereof.
Bulking agents (also called "cryoprotectant/lyoprotectant") are excipients which are capable of making the pharmaceutical composition of the present invention isotonic with blood at the time of administration.
Suitable bulking agents or diluents, that can be used, in the pharmaceutical composition of the present invention, include, but are not limited to, mannitol, sucrose, maltose, xylitol, glucose, starches, sorbitol, fructose, galactose, ribose, xylose, trehalose, lactose, raffinose, melezitose, glycerol, erythritol, maltitol, lactitol, D & L series of rare carbohydrates, their salts and the like or mixtures thereof.
The pharmaceutical composition of the present invention may further comprise a pH adjusting agent, which is used in an amount to adjust the pH from about 4 to about 10 before lyophilisation. It may be an acid or base depending upon whether the pH of the pharmaceutical composition needs to be raised or lowered to attain the desired value. Thus, when the pH needs to be lowered, an acidic pH adjusting agent, such as hydrochloric acid, tartaric acid, sulphuric acid, citric acid, phosphoric acid, benzoic acid or acetic acid and the like may be used. And when the pH needs to be raised, a basic pH adjusting agent, such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, magnesium carbonate, potassium carbonate, magnesium oxide, magnesium hydroxide, glutamic acid or histidine and the like may be used. Such pH adjusting agents can either be used singly or in a combination.
The pharmaceutical composition of the present invention may further comprise carriers or suspending agents such as, but not limited to, water for injection, Ringer's solution, isotonic sodium chloride solution and the like or combinations thereof. In addition to the aforementioned, carriers or suspending agents may also include, fixed oils, fatty esters or polyols, sodium carboxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropylethyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, various polymers, low-molecular- weight oligomers, natural products, and surfactants (including nonionic and ionic surfactants), such as cetyl pyridinium chloride, gelatin, casein, phospholipids, lecithin (phosphatide), phophatidylcholines dextran. glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters such as Tweens, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, hydroxypropyl celluloses, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, 4-(l , 1 ,3,3- tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers; poloxamines; charged phospholipids such as dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate; n-decyl-D-maltopyranoside; n-dodecyl-D-glucopyranoside; n- dodecyl-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-glucopyranoside; n-heptyl-D- thioglucoside; n-hexyl-D-glucopyranoside; nonanoyl-N-methylglucamide; n-nonyl-D- glucopyranoside; octanoyl-N-methylglucamide; n-octyl-glucopyranoside; octyl-D- thioglucopyranoside, their salts and the like or mixtures thereof.
Suitable antibacterial preservatives, that may be employed in the pharmaceutical composition of the present invention are phenylmercuric nitrate, thiomersal, benzalkonium chloride, benzethonium chloride, phenol, 4-amino benzoic acid (PABA), cresol and chlorobutanol; chelating agents such as ethylenediamine tetra acetic acid (EDTA) , their salts and the like or mixtures thereof.
Suitable tonicity adjusting agents, that may be employed in the pharmaceutical composition of the present invention are sodium chloride, potassium chloride, dextrose, mannitol, sorbitol, sucrose and lactose; and alkaline substances including one or more of salts of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and sodium phosphates as well as organic amines such as meglumine and tromethamine, hydrochloric acid, tartaric acid, sulphuric acid, citric acid, phosphoric acid, benzoic acid or acetic acid, sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, magnesium carbonate, potassium carbonate, magnesium oxide, magnesium hydroxide, glycerine, propylene glycol, PEG, glutamic acid, histidine, their salts and the like or combinations thereof.
The pharmaceutical composition of the invention can comprise a bulking agent, pH adjusting agent, a carrier or suspending agent, an antibacterial preservative, a chelating agent, a stabiliser, a sequestering agent, an antioxidant, a tonicity adjusting agent, or any mixtures thereof.
The pharmaceutical composition of the invention can comprise a bulking agent, a carrier, and a pH adjusting agent.
The pharmaceutical composition can comprise a bulking agent comprising sucrose, mannitol and/or sorbitol, and a pH adjusting agent comprising hydrochloric acid and/or sodium hydroxide. According to another aspect, the present invention provides a process for preparing the pharmaceutical composition suitable for parenteral administration.
In one embodiment, the process comprises dissolving the complex as well as bulking agent in a suitable carrier, adjusting the pH and lyophilizing it.
In another embodiment, the process comprises dissolving the complex as well as bulking agent in a suitable carrier and adjusting the pH.
In another embodiment, the process comprises formation of a sterile powder of the complex along with one or more pharmaceutically acceptable excipients. In an embodiment, the preferred pemetrexed disodiumxarbohydrate complexes in the formulation of the present invention are pemetrexed disodium: mannitol complex, pemetrexed disodium: sorbitol complex, pemetrexed disodium: sucrose complex, most preferred complex is pemetrexed disodium: mannitol complex.
In another embodiment, the preferred pemetrexed dipotassium: carbohydrate complexes in the formulation of the present invention are pemetrexed dipotassium: mannitol complex, pemetrexed dipotassium: sorbitol complex, pemetrexed dipotassium: sucrose complex, most preferred complex is pemetrexed dipotassium: mannitol complex.
The present invention also provides methods of filling containers that contain a pharmaceutical composition of the present invention, comprising: a) pre sterilizing one or more containers, b) filling the containers with the pharmaceutical composition optionally in an aseptic environment, c) stoppering and sealing the filled containers and d) terminal sterilization.
The present invention also provides methods of filling containers that contain a pharmaceutical composition of the present invention, comprising: a) pre sterilizing one or more containers and closures, b) filling the containers with the pharmaceutical composition optionally in an aseptic environment, c) lyophilizing the filled containers, d) stoppering and sealing the filled containers and e) terminal sterilization.
The present invention also provides methods of filling containers that contain a pharmaceutical composition of the present invention, comprising: a) pre sterilizing the pharmaceutical composition, one or more containers and the closures, b) filling the containers with the pharmaceutical composition optionally in an aseptic environment, c) optionally lyophilizing the filled containers, and d) stoppering and sealing the filled containers. Containers can be in the form of small glass vials that are sealed with a suitable stopper/seal and may also be replaced by other primary containers for example, but not limited to, pre- filled syringes. Vials can be for single use or multi use and may include breakable and non- breakable glass containers, breakable plastic containers, miniature screw-top jars and any other type of container typically of a size capable of holding only unit or multi dose of the pharmaceutical composition of the present invention.
The present invention also provides packaging materials for containers and closures such as, but not limited to, high-density polyethylene (HDPE), low-density polyethylene (LDPE) and/or polypropylene and/or glass, glassine foil, polyvinyl chloride, polyvinylidene dichloride, and the like.
Pharmaceutically acceptable stoppers may also be used to seal the vial containing the pharmaceutical composition of the present invention. Some of the stopper materials include silicone rubber, coated stoppers, slotted bromobutyl rubber, and the like.
The present invention provides a method of treating patients with locally advanced or metastatic nonsquammous non-small cell lung cancer after prior chemotherapy or maintenance treatment of patients whose disease has not progressed after four cycles of platinum based first line chemotherapy by administering a pharmaceutical composition of the present invention.
The present invention also provides a method of initial treatment of patients with locally advanced or metastatic nonsquammous non-small cell lung cancer or mesothelioma by administering a pharmaceutical composition of the present invention in combination with cisplatin.
The present invention further provides the use of pharmaceutical compositions of the present invention for the treatment of patients with locally advanced or metastatic nonsquammous non-small cell lung cancer after prior chemotherapy or maintenance treatment of patients whose disease has not progressed after four cycles of platinum based first line chemotherapy.
The present invention further provides the use of pharmaceutical composition of the present invention for the treatment of locally advanced or metastatic nonsquammous non-small cell lung cancer or mesothelima by administering a pharmaceutical composition of the present invention in combination with cisplatin.
The invention is further defined by reference to the following examples .The examples are for illustration purposes only and in no way would limit the scope of the invention.
Examples of preparing the complex of the present invention:-
Example 1- Preparation of pemetrexed disodium: mannitol complex
Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere. The pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution. The reaction mass was further stirred at 20-25°C for 10 minutes and filtered. To the clear filtrate was added mannitol (22.5 g) at 25-30°C. The reaction mass was further stirred at 25-30°C for 10 minutes. The clear filtrate was added to acetone (1.14 1) over a period of 1 hour at 27±2°C. Stirring at 25-30°C was continued for about 2 hours. The precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 47.5 g of a pharmaceutical compound of pemetrexed disodium: mannitol. The content of the pemetrexed disodium is about 65% of the weight.
Example 2- Preparation of pemetrexed disodium: mannitol complex
Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere. The pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution. The reaction mass was further stirred at 20-25°C for 10 minutes and filtered. To the clear filtrate was added mannitol (22.5 g) at 25-30°C. The reaction mass was further stirred at 25-30°C for 10 minutes. The clear filtrate was added to methanol (1.1 1) over a period of 1 hour at 27±2°C. Stirring at 25-30°C was continued for about 2 hours. The precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 45.0 g of a pharmaceutical compound of pemetrexed disodium: mannitol. The content of the pemetrexed disodium is about 65% of the weight.
Example 3- Preparation of pemetrexed disodium: mannitol complex
Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere. The pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution. The reaction mass was further stirred at 20-25°C for 10 minutes and filtered. To the clear filtrate was added mannitol (22.5 g) at 25-30°C. The reaction mass was further stirred at 25-30°C for 10 minutes. The clear filtrate was added to isopropyl alcohol (1.1 1) over a period of 1 hour at 27±2°C. Stirring at 25-30°C was continued for about 2 hours. The precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 45.0 g of a pharmaceutical compound of pemetrexed disodium: mannitol. The content of the pemetrexed disodium is about 65% of the weight.
Example 4- Preparation of pemetrexed disodium: sorbitol complex
Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere. The pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution. The reaction mass was further stirred at 20-25°C for 10 minutes and filtered. To the clear filtrate was added sorbitol (22.5 g) at 25-30°C. The reaction mass was further stirred at 25-30°C for 10 minutes. The clear filtrate was added to acetone (1.1 1) over a period of 1 hour at 27±2°C. Stirring at 25-30°C was continued for about 2 hours. The precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 47.5 g of pemetrexed disodium: sorbitol complex. The content of the pemetrexed disodium is about 85%. Example 5- Preparation of pemetrexed disodium: sucrose complex
Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere. The pH of the reaction mass was adjusted to 8, with 10 % aqueous sodium hydroxide solution. The reaction mass was further stirred at 20-25°C for 10 minutes and filtered. To the clear filtrate was added sucrose (48 g) at 25-30°C. The reaction mass was further stirred at 25-30°C for 10 minutes. The clear filtrate was added to acetone (1.1 1) over a period of 1 hour at 27±2°C. Stirring at 25-30°C was continued for about 2 hours. The precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 47.5 g of pemetrexed disodium: sucrose complex. The content of the pemetrexed disodium is about 52%.
Example 6- Preparation of pemetrexed disodium: glucose complex
Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere. The pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution. The reaction mass was further stirred at 20-25°C for 10 minutes and filtered. To the clear filtrate was added glucose (22.5 g) at 25-30°C. The reaction mass was further stirred at 25-30°C for 10 minutes. The clear filtrate was added to acetone (1.1 1) over a period of 1 hour at 27±2°C. Stirring at 25-30°C was continued for about 2 hours. The precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 47.5 g of pemetrexed disodium: sorbitol complex. The content of the pemetrexed disodium is about 85%.
Example 7- Preparation of pemetrexed disodium: fructose complex
Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere. The pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution. The reaction mass was further stirred at 20-25°C for 10 minutes and filtered. To the clear filtrate was added fructose (22.5 g) at 25-30°C. The reaction mass was further stirred at 25-30°C for 10 minutes. The clear filtrate was added to acetone (1.1 1) over a period of 1 hour at 27±2°C. Stirring at 25-30°C was continued for about 2 hours. The precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 47.5 g of pemetrexed disodium: sorbitol complex. The content of the pemetrexed disodium is about 85%.
Example 8- Preparation of pemetrexed disodium: mannitol complex
1) Pemetrexed diethyl ester ditosylate salt was added to purified water and sodium hydroxide, stirred for 3 hours at 20-25°C. The reaction mass was filtered and isopropyl alcohol was added to the clear filtrate. The pH was adjusted to 3.0-3.5 by using hydrochloric acid at 23±2°C. The mixture was stirred at 23±2°C for 90 minutes, the contents were heated to 53±2°C and maintained for 30 minutes, and then further cooled to 25±2°C. The material was filtered and dried at 48±2°C. The solid was dissolved in dimethyl sulphoxide and precipitated in isopropyl alcohol, filtered and slurried in a mixture of isopropyl alcohol and water. The solid was filtered and dried at 43±2°C to obtain pemetrexed.
2) Pemetrexed (30 g) was stirred in purified water (210 ml) at 20-25°C under a nitrogen atmosphere. The pH of the reaction mass was adjusted to 8, with 10% aqueous sodium hydroxide solution. The reaction mass was further stirred at 20-25°C for 10 minutes and filtered. To the clear filtrate was added mannitol (22.5 g) at 25-30°C. The reaction mass was further stirred at 25-30°C for 10 minutes. The clear filtrate was added to the acetone (1.14 1) over a period of 1 hour at 27±2°C. Stirring at 25-30°C was continued for about 2 hours. The precipitated product was collected by filtration and dried in vacuo for 8 hours to yield 47.5 g of complex pemetrexed disodium: mannitol. The content of the pemetrexed disodium is about 60 % of the weight.
Examples of preparing the pharmaceutical compositions of the present invention:-
Example 1- Lyophilized powder for infusion
Sr. No. Ingredients Strength
100 mg/vial
(Qty in mg)
1. Pemetrexed disodium: mannitol Equivalent to 100 mg complex Pemetrexed
2. Mannitol * 106.00
3. Hydrochloric acid q.s. to pH 6.6 to 7.8
4. Sodium Hydroxide
Process:
1) The pemetrexed disodium: mannitol complex was dissolved in water.
2) Mannitol was dissolved in the solution obtained in step (1).
3) The pH was adjusted with sodium hydroxide and/or hydrochloric acid.
4) The final volume of the solution was made up with water
5) The vials were filled with the solution obtained in step (4) and lyophilized.
* The quantity of Mannitol which is added separately in the formulation in the above example is based on the respective content of Mannitol present in the Pemetrexed Disodium complex.
Example 2- Lyophilized powder for infusion
Figure imgf000028_0001
Process: 1) The pemetrexed disodium: mannitol complex was dissolved in water.
2) Mannitol was dissolved in the solution obtained in step (1).
3) The pH was adjusted with sodium hydroxide and/or hydrochloric acid.
4) The final volume of the solution was made up with water
5) The vials were filled with the solution obtained in step (4) and lyophilized.
* The quantity of Mannitol which is added separately in the formulation in the above example is based on the respective content of Mannitol present in the Pemetrexed Disodium complex.
Example 3- Lyophilized powder for infusion
Figure imgf000029_0001
Process:
1) The pemetrexed disodium: sorbitol complex was dissolved in water.
2) Sorbitol was dissolved in the solution obtained in step (1).
3) The pH was adjusted with sodium hydroxide and/or hydrochloric acid.
4) The final volume of the solution was made up with water
5) The vials were filled with the solution obtained in step (4) and lyophilized. * The quantity of Sorbitol which is added separately in the formulation in the above example is based on the respective content of Sorbitol present in the Pemetrexed Disodium complex. Example 4- Lyophilized powder for infusion
Figure imgf000030_0001
Process:
1) The pemetrexed disodium: Sorbitol complex was dissolved in water.
2) Sorbitol was dissolved in the solution obtained in step (1).
3) The pH was adjusted with sodium hydroxide and/or hydrochloric acid.
4) The final volume of the solution was made up with water
5) The vials were filled with the solution obtained in step (4) and lyophilized.
* The quantity of Sorbitol which is added separately in the formulation in the above example is based on the respective content of Sorbitol present in the Pemetrexed Disodium complex.
Example 5- Lyophilized powder for infusion
Sr. No. Ingredients Strength
100 mg/vial
(Qty in mg) 1 Pemetrexed disodium: sucrose Equivalent to lOOmg
complex Pemetrexed
2. Sucrose * 195.00
3. Hydrochloric acid q.s. to pH 6.6 to 7.8
4. Sodium Hydroxide
Process:
1) The pemetrexed disodium: sucrose complex was dissolved in water.
2) Sucrose was dissolved in the solution obtained in step (1).
3) The pH was adjusted with sodium hydroxide and/or hydrochloric acid.
4) The final volume of the solution was made up with water
5) The vials were filled with the solution obtained in step (4) and lyophilized.
* The quantity of Sucrose which is added separately in the formulation in the above example is based on the respective content of Sucrose present in the Pemetrexed Disodium complex.
Example 6- Lyophilized powder for infusion
Sr. No. Ingredients Strength
500 mg/vial
(Qty in mg)
1 Pemetrexed disodium: sucrose Equivalent to 500mg
complex Pemetrexed
2. Sucrose * 920.00
3. Hydrochloric acid q.s. to pH 6.6 to 7.8
4. Sodium Hydroxide Process:
1) The pemetrexed disodium: sucrose complex was dissolved in water.
2) Sucrose was dissolved in the solution obtained in step (1).
3) The pH was adjusted with sodium hydroxide and/or hydrochloric acid.
4) The final volume of the solution was made up with water
5) The vials were filled with the solution obtained in step (4) and lyophilized.
* The quantity of Sucrose which is added separately in the formulation in the above example is based on the respective content of Sucrose present in the Pemetrexed Disodium complex.
It will be appreciated that the invention may be modified within the scope of the appended claims.
XRD measurements were made using the following settings:
SCAN: 3.0/40.0/0.02/0.6(sec), Cu (40kV, 30mA), I(max) = 2369.
PEAK: 15-pts/Parabohc Filter, Threshold =0.0, Cutoff = 0.1%, BG =1/0.7, Peak-Top = Summit.
NOTE: Intensity = Counts, 2T(0) = O.O(deg), Wavelength to compute d- spacing = 1.54056A (Cu/K-alphal).

Claims

Claims
1. A complex of pemetrexed with a co-former
2. A complex according to claim 1, wherein the pemetrexed is in the form of a pharmaceutically acceptable derivative, which optionally comprises pharmaceutically acceptable salts, solvates, hydrates, isomers, esters, tautomers, anhydrates, enantiomers, complexes, polymorphs or prodrugs.
3. A complex according to claim 2 or 3, wherein the pemetrexed is in the form of pemetrexed disodium or pemetrexed dipotassium.
4. A complex according to any one of claims 1 to 3, wherein the complex comprises pemetrexed disodium or pemetrexed dipotassium and a carbohydrate.
5. A complex according to claim 4, wherein the carbohydrate comprises a sugar and/or sugar alcohol.
6. A complex according to claim 4 or 5, wherein the carbohydrate comprises glucose, dextrose, fructose, galactose, ribose, sucrose, xylose, trehalose, lactose, maltose, raffinose, melezitose, glycerol, mannitol, sorbitol, erythritol, maltitol, lactitol, and/or D series or L series rare sugars.
7. A complex according to any preceding claim, wherein the pemetrexed complex comprises at least one or more of the following complexes: pemetrexed disodium: mannitol complex, pemetrexed disodium: sorbitol complex, pemetrexed disodium: sucrose complex, pemetrexed disodium: glucose complex, or pemetrexed disodium: fructose complex.
8. A complex according to any preceding claim, wherein the pemetrexed complex comprises at least one or more of the following complexes: pemetrexed dipotassium: mannitol complex, pemetrexed dipotassium: sorbitol complex, pemetrexed dipotassium: sucrose complex, pemetrexed dipotassium: glucose complex, or pemetrexed dipotassium: fructose complex.
9. A complex according to any preceding claim, wherein the pemetrexed complex is in crystal form.
10. A complex according to any one of claims 4 to 9, wherein the pemetrexed disodium or dipotassium and carbohydrate present in the complex are present in a stoichiometric ratio.
11. A complex according to claim 1, wherein the complex comprises pemetrexed disodium or dipotassium and mannitol, wherein mannitol is present in the complex in an amount from about 20% to about 50% by weight of the complex, optionally from about 30% to about 40% by weight of the complex.
12. A complex according to claim 1, wherein the complex comprises pemetrexed disodium and mannitol in a crystalline form with an XRD pattern comprising peaks at 9.619, 20.299 and 22.82 °2Θ ± 0.2°2Θ, optionally further comprising peaks at 15.44, 20.98, 21.98, 23.8, 24.559, 25.16 and 36.00 2Θ ± 0.2 °2Θ, and optionally further comprising peaks at 4.66, 10.38, 14.12, 15. 719, 17.14, 17.90, 18.559, 19.261, 25.861, 26.90, 27.78 and 28.82 °2Θ ± 0.2 °2Θ.
13. A complex according to any one of claims 1 to 3, wherein the complex comprises pemetrexed disodium and mannitol characterised by an X-ray powder diffraction spectrum as shown in figure 1.
14. A process for the preparation of a complex according to any one of claims 1 to 13, wherein the process comprises;
(1) dispersing pemetrexed into an aqueous solvent to form a solution; and adjusting the pH of the solution ;
(2) optionally removing insolubles by filtration;
(3) adding a carbohydrate to the filtrate;
(4) precipitating and drying the complex from the solution.
15. A process according to claim 14, wherein the pemetrexed starting material is in the form of a salt, a free acid, any polymorphic form or a mixture of any polymorphic forms, in crude form, in anhydrous form, or in a hydrated or solvated form.
16. A process according to claim 14 or 15, wherein the process comprises adjusting the pH of the solution to from 7.8 to 8.3.
17. A process according to any one of claims 14 to 16, wherein the process comprises adjusting the pH with sodium hydroxide.
18. A process according to any one of claims 14 to 17, wherein the reaction is carried out at a temperature ranging from about 20°C to about 30°C.
19. A process according to any one of claims 14 to 18, wherein the step of precipitation comprises the addition of an antisolvent.
20. A process according to any one of claims 14 to 19, wherein the anti-solvent is selected from the group consisting of acetone, CI -6 alcohols and acetonitrile.
21. A complex according to any one of claims 1 to 20 for use in medicine.
22. A complex according to claim 21, wherein the use comprises the treatment of cancer, pleural mesothelima and/or non-small cell lung cancer.
23. Use of a complex according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment of cancer, pleural mesothelima and/or non-small cell lung cancer.
24. A method of treating a subject with cancer, pleural mesothelima and/or non-small cell lung cancer, wherein the method comprises administering a complex according to any one of claims 1 to 13 to a patient in need thereof.
25. A pharmaceutical composition comprising a complex of pemetrexed with a co- former, and one or more pharmaceutically acceptable excipients.
26. A pharmaceutical composition according to claim 25, wherein the pemetrexed is in the form of a pharmaceutically acceptable derivative, which optionally comprises pharmaceutically acceptable salts, solvates, hydrates, isomers, esters, tautomers, anhydrates, enantiomers, complexes, polymorphs or prodrugs.
27. A pharmaceutical composition according to any one of claims 25 and 26, wherein the pemetrexed complex comprises pemetrexed disodium or pemetrexed dipotassium.
28. A pharmaceutical composition according to any one of claims 25 to 27, wherein the pemetrexed complex comprises pemetrexed disodium or pemetrexed dipotassium and a co-crystal forming agent.
29. A pharmaceutical composition according to any one of claims 25 to 28, wherein the pemetrexed complex comprises pemetrexed disodium or pemetrexed dipotassium and a carbohydrate.
30. A pharmaceutical composition according to claim 29, wherein the carbohydrate comprises a sugar and/or sugar alcohol.
31. A pharmaceutical composition according to claim 29 or 30, wherein the carbohydrate comprises glucose, dextrose, fructose, galactose, ribose, sucrose, xylose, trehalose, lactose, maltose, raffinose, melezitose, glycerol, mannitol, sorbitol, erythritol, maltitol, lactitol, and/or D series or L series rare sugars.
32. A pharmaceutical composition according to any one of claims 25 to 31, wherein the pemetrexed complex comprises at least one or more of the following combinations: pemetrexed disodium: mannitol complex, pemetrexed disodium: sorbitol complex, pemetrexed disodium: sucrose complex, pemetrexed disodium: glucose complex, pemetrexed disodium: fructose complex; most preferred combination is pemetrexed disodium: mannitol complex.
33. A pharmaceutical composition according to any one of claims 25 to 32, wherein the pemetrexed complex comprises at least one or more of the following combinations: pemetrexed dipotassium: mannitol complex, pemetrexed dipotassium: sorbitol complex, pemetrexed dipotassium: sucrose complex, pemetrexed dipotassium: glucose complex, pemetrexed dipotassium: fructose complex; most preferred combination is pemetrexed dipotassium: mannitol complex.
34. A pharmaceutical composition comprising according to any one of claims 25 to 33, wherein the pemetrexed complex is in crystal form.
35. A pharmaceutical composition according to any one of claims 29 to 34, wherein the pemetrexed disodium or pemetrexed dipotassium and carbohydrate present in the complex are present in a stoichiometric ratio.
36. A pharmaceutical composition according to any one of claims 25 to 35, wherein the composition is suitable for parenteral administration
37. A pharmaceutical composition according to any one of claims 25 to 36, wherein the composition is in the form of ready-to-use solutions; lyophilized forms and preparations thereof, sterile lyophilized powders for intravenous infusion available in single or multi dose vials; aqueous solutions, liquid dispersions, suspensions, colloidal nanosuspensions, emulsions, liposomal injections, gels, bolus, depots, implants (rods, capsules, rings), injectable devices such as pumps and autoinjectors; and sterile powders for injection suitable for solubilization or suspension in liquid prior to injection.
38. A pharmaceutical composition according to any one of claims 25 to 37, wherein the at least one or more pharmaceutically acceptable excipients comprise a bulking agent.
39. A pharmaceutical composition according to any one of claims 25 to 38, wherein the at least one or more pharmaceutically acceptable excipients comprise a pH adjusting agent.
40. A pharmaceutical composition according to any one of claims 25 to 39, wherein the at least one or more pharmaceutically acceptable excipients comprise a carrier or suspending agent.
41. A pharmaceutical composition according to any one of claims 25 to 40, wherein the at least one or more pharmaceutically acceptable excipients comprise an antibacterial preservative.
42. A pharmaceutical composition according to any one of claims 25 to 41, wherein the at least one or more pharmaceutically acceptable excipients comprise a chelating agent.
43. A pharmaceutical composition according to any one of claims 25 to 42, wherein the at least one or more pharmaceutically acceptable excipients comprise a stabiliser.
44. A pharmaceutical composition according to any one of claims 25 to 43, wherein the at least one or more pharmaceutically acceptable excipients comprise a sequestering agent.
45. A pharmaceutical composition according to any one of claims 25 to 44, wherein the at least one or more pharmaceutically acceptable excipients comprise an antioxidant.
46. A pharmaceutical composition according to any one of claims 25 to 45, wherein the at least one or more pharmaceutically acceptable excipients comprise a tonicity adjusting agent.
47. A pharmaceutical composition according to any one of claims 25 to 46, wherein the at least one or more pharmaceutically acceptable excipients comprise a bulking agent, a carrier, and a pH adjusting agent.
48. A pharmaceutical composition according to any one of claim 38 to 47, wherein the bulking agent comprises sucrose, mannitol and/or sorbitol, and the pH adjusting agent comprises hydrochloric acid and/or sodium hydroxide.
49. A pharmaceutical composition according to any one of claims 25 to 48, wherein the at least one or more pharmaceutically acceptable excipients comprise a bulking agent, pH adjusting agent, a carrier or suspending agent, an antibacterial preservative, a chelating agent, a stabiliser, a sequestering agent, an antioxidant, a tonicity adjusting agent, or any combination thereof .
50. A pharmaceutical composition according to any one of claims 25 to 49, wherein the composition has a pH from 4 to 10, preferably from 6 to 8.5.
51. A pharmaceutical composition according to any one of claims 25 to 50 for use in medicine.
52. A pharmaceutical composition according to claim 51, for the treatment of cancer, pleural mesothelima and/or non-small cell lung cancer.
53. Use of a pharmaceutical composition according to any one of claims 25 to 50 in the manufacture of a medicament for the treatment of cancer, pleural mesothelima and/or non-small cell lung cancer, optionally in combination with cisplatin.
54. A method of treating a subject with cancer, pleural mesothelima and/or non-small cell lung cancer, wherein the method comprises administering a pharmaceutical composition according to any one of claims 25 to 50, optionally in combination with cisplatin to a patient in need thereof.
55. A container comprising a pharmaceutical composition according to any one of claims 25 to 50.
56. A process of preparing a pharmaceutical composition according to any one of claims 25 to 50, wherein the process comprises dispersing a complex of pemetrexed optionally with at least one or more pharmaceutically acceptable excipients, adjusting the pH using a suitable pH adjusting agent; optionally filling the mixture into a container; and optionally lyophilising the mixture.
57. A complex substantially as described herein with reference to the description and examples.
58. A pharmaceutical composition substantially as described herein with reference to the description and examples.
PCT/GB2014/050340 2013-02-06 2014-02-06 Pemetrexed complexes and pharmaceutical compositions containing pemetrexed complexes WO2014122460A2 (en)

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