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WO2018127743A1 - Compositions liquides de pémétrexed prêtes à infuser - Google Patents

Compositions liquides de pémétrexed prêtes à infuser Download PDF

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Publication number
WO2018127743A1
WO2018127743A1 PCT/IB2017/055059 IB2017055059W WO2018127743A1 WO 2018127743 A1 WO2018127743 A1 WO 2018127743A1 IB 2017055059 W IB2017055059 W IB 2017055059W WO 2018127743 A1 WO2018127743 A1 WO 2018127743A1
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WO
WIPO (PCT)
Prior art keywords
pemetrexed
composition
container
pharmaceutically acceptable
large volume
Prior art date
Application number
PCT/IB2017/055059
Other languages
English (en)
Inventor
Mohan MAILATUR SIVARAMAN
Hiren Patel
Bhaveshkumar Vallabhbhai PATEL
Raghu KANNEKANTI
Mahesh SANKA
Raheesh MOHAMMAD
Paramesh CHAKALI
Original Assignee
Orbicular Pharmaceutical Technologies Private Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Orbicular Pharmaceutical Technologies Private Limited filed Critical Orbicular Pharmaceutical Technologies Private Limited
Publication of WO2018127743A1 publication Critical patent/WO2018127743A1/fr

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Classifications

    • 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
    • A61K9/08—Solutions
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • 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

Definitions

  • the present invention relates to a stable, iso-osmolar pemetrexed liquid composition, comprising pemetrexed or its pharmaceutically acceptable salt thereof in an aqueous vehicle having a pH of about 5 to about 12, wherein the composition is a large volume parenteral, ready to infuse and the container is impermeable to oxygen.
  • Pemetrexed a folic acid antimetabolite is disclosed in US5344932 patent. This member of the folic acid family has been approved for treatment of malignant pleural mesothelioma and for second-line treatment of non small cell lung cancer.
  • Pemetrexed disodium is marketed by Eli Lilly and Company under the trade name ALIMTA® as a sterile lyophilized powder for intravenous administration. The commercial product is reported to be a lyophilized powder of heptahydrate pemetrexed disodium and mannitol.
  • Pemetrexed is prone for oxidative and hydrolytic degradations.
  • Pemetrexed is hydrolyzed both in acidic and basic conditions, resulting in decarboxylation of glutamic acid side chain. In presence of water and heat, same degradation products are formed, as in case of acidic and basic conditions. In presence of oxygen, two oxidative degradants are formed. Pemetrexed is also very prone for color change in aqueous solution formulation; color of the solution changes from colourless to yellow or green yellow. This colour change may be attributed to oxidative degradation of pemetrexed.
  • ALIMTA® in order to address oxidative and hydrolytic degradation and considerable glass delamination problem.
  • ALIMTA® the commercially available lyophilized product is approved as 100mg/vial and 500mg/vial strengths in most of the geographies. This product being lyophilized and need to be administered as IV infusion, it need two steps reconstitution procedure carried out by a trained staff, which is a tedious and time consuming process. Further the reconstituted solution does not have stability for more than 24 hours, when stored refrigerated. Considering these intricacies many have attempted to develop a ready to dilute liquid composition, which reduces one step of reconstitution in comparison with lyophilized product and are yet unsuccessful.
  • PVC polyvinyl chloride
  • WO0156575A1 disclose a pharmaceutical liquid composition comprising pemetrexed, at least one antioxidant selected from the group consisting of monothioglycerol, L-cysteine, and thioglycolic acid; and a pharmaceutically acceptable excipient.
  • EP2666463A1 publication details an aqueous pharmaceutical composition comprising pemetrexed or a pharmaceutically acceptable salt thereof and monothioglycerol, characterized in that it further comprises at least one non- ionogenic water soluble polymer such as polyethylene glycol, a
  • polyvinylpyrrolidone a polypropylene glycol or a polyvinylalcohol and or an edetate.
  • WO2015092758A1 publication discloses stable liquid pharmaceutical formulation ready to use or concentrate for further dilution of pemetrexed or pharmaceutically acceptable salts comprises at least one stabilizing agent selected from the group consisting of sodium formaldehyde sulfoxylate, EDTA and derivatives and mixtures thereof.
  • US20160310495A1 publication disclose a composition comprising pemetrexed diacid, tromethamine, and a pharmaceutically acceptable excipient, wherein the tromethamine is present in an amount of 40 to 90% by weight of the pemetrexed and the pharmaceutical composition is a ready-to-use liquid.
  • WO2016151365A1 discloses a liquid composition of pemetrexed comprising head space impurity level oxygen less than 5% with dissolved oxygen less than 2ppm and individual in the final product less than 0.5% and further composition comprises 5-100mg/ml_ of pemetrexed or its pharmaceutically acceptable salts, at least one antioxidant and pharmaceutically acceptable excipients.
  • Pemetrexed 25mg per ml_ concentrate for solution for infusion is approved in Europe and per pack insert instructions it must only be administered under the supervision of a qualified physician. Further it must only be diluted with 5% glucose solution, without preservative. The appropriate volume of pemetrexed concentrate must be diluted to 100ml with 5% glucose solution and administered as an intravenous infusion over 10 minutes.
  • compositions are having pemetrexed at low concentration, hence chances of delamination is remote and this issue has been addressed in this invention.
  • Embodiments of the present invention relate to a stable, iso-osmolar pemetrexed liquid composition, comprising pemetrexed or its pharmaceutically acceptable salt thereof in an aqueous vehicle having a pH of about 5 to about 12, wherein the composition is a large volume parenteral, ready to infuse and the container is impermeable to oxygen.
  • compositions which is available as large volume parenteral in infusion containers, glass vial or bottle or suitable parenteral containers, ready to be infused and composition further comprise of other pharmaceutically acceptable excipients.
  • compositions wherein the excipients include antioxidants, isotonicity agents, preservatives, chelating agent, amino acid, bulking agent, buffer, carrier, diluent, solubilizer and the like or any mixtures thereof.
  • composition according to previous embodiment has a pH of about 7 to about 9.
  • Another specific embodiment relates to a stable liquid composition, comprising pemetrexed or its pharmaceutically acceptable salt thereof at concentration ranging from about 1 mg/ml_ to about 25mg/ml_.
  • Another embodiment relates to a stable liquid composition, comprising pemetrexed or its pharmaceutically acceptable salt thereof wherein the
  • composition is stored in large volume glass vial with more than 20mm neck; a polypropylene container with or without aluminum pouch wrapped over polypropylene container, a polypropylene container with or without aluminum pouch and oxygen scavengers.
  • Another embodiment relates to a stable liquid composition, wherein the composition is stable when stored at temperature between 2°C to 37°C, and the like, or room temperature, for its shelf life when stored in a suitable parenteral container.
  • kits comprising stable iso-osmolar pemetrexed liquid composition, comprising pemetrexed or its pharmaceutically acceptable salt thereof in an aqueous vehicle having pH of about 5 to about 12, wherein the composition is a large volume parenteral which is ready to infuse and the container is impermeable to oxygen.
  • Another embodiment relates to a process of preparing the pemetrexed liquid composition.
  • the present invention relates to a stable, iso-osmolar pemetrexed liquid composition, comprising pemetrexed or its pharmaceutically acceptable salt thereof in an aqueous vehicle, having a pH of about 5 to about 12, wherein the composition is a large volume parenteral, ready to infuse and the container is impermeable to oxygen.
  • excipient or “pharmaceutically acceptable excipient” or “adjuvant” means a component of a pharmaceutical product that is not a pharmacologically active ingredient, such as diluent, bulking agent, carrier, acidifying agent, pH modifier, chelating agent, solvent, co-solvent, isotonicity agents, antioxidant, preservative, stabilizer and the like added to a drug to increase or aid its effect.
  • a pharmacologically active ingredient such as diluent, bulking agent, carrier, acidifying agent, pH modifier, chelating agent, solvent, co-solvent, isotonicity agents, antioxidant, preservative, stabilizer and the like added to a drug to increase or aid its effect.
  • the excipients or adjuvants that are useful in preparing pharmaceutical compositions are generally safe, non- toxic, and neither biologically nor otherwise undesirable, and are acceptable for human
  • the term includes one or more excipients or adjuvants.
  • composition is intended to encompass a combination including active ingredients and pharmaceutically acceptable excipients, as well as any product which results, directly or indirectly, from combination,
  • composition refers to finished pharmaceutical products that are suitable for administration, including, but not limited to, injections, infusions and the like.
  • “Pharmaceutically-acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified or unmodified by making acid or base salts, solvate, hydrate, ester, ether, conjugates, complexes and the like or mixtures thereof.
  • Pharmaceutically-acceptable salt forms of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • Pharmaceutically acceptable salts are those forms of compounds, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the pharmaceutical solution is referred to as a 'ready to infuse' solution or a 'ready-to-be-infused' solution, viz., the solution does not require any prior dilution or reconstitution or mixing before administration.
  • This attribute of the present invention makes the pharmaceutical solution extremely user friendly. It is envisaged that it will be possible to use the product of the invention to directly infuse, intravenously, the solution contained therein without the need for any intervening step of reconstitution or dilution or mixing.
  • stable' means remaining in a state or condition that is suitable for administration to a patient.
  • a “stable solution” is intended to refer to a solution which when stored at 2°C to 8°C, or 25°C or at room temperature, for a period of time, is physically stable, for example, it does not show the appearance of visible particulates and is also chemically stable.
  • chemically stable as used herein means that when the dosage form is stored at 2°C to 8°C or 25°C or room temperature, the impurities such as those resulting from chemical reaction in solution remains within acceptable limits over a long term storage. It is intended that the period of time over which the solution is stable for 12 months or 24 months or its shelf life.
  • 'sterile' solution dosage form means a dosage form that has been brought to a state of sterility and has not been subsequently exposed to microbiological contamination, i.e. the sterility of the container holding the sterile composition has not been
  • Sterile compositions are generally prepared by pharmaceutical manufacturers in accordance with current Good Manufacturing Practice
  • large volume parenteral refers to compositions stored or presented in glass vials or glass bottles, polypropylene container;
  • polypropylene container ethyl vinyl alcohol container or suitable parenteral containers comprising optionally the aluminum or suitable pouch with or without oxygen scavengers, wherein glass vials or glass bottles have neck configurations of 20 mm or more.
  • iso-osmolar refers to a solution having the same osmotic pressure as blood.
  • Intravenously administered solutions are solution for infusion that is rapidly and painlessly diluted by the blood, it is sufficient to adjust the tonicity to the physiological conditions in the best possible manner. By adjusting the rate of infusion appropriately, it is possible to make sure that these solutions are tolerated optimally.
  • the composition is available as large volume parenteral in infusion containers, glass vial or bottle or suitable parenteral containers, ready to be infused.
  • the parenteral containers are single or multiple compartment.
  • Example of single or multiple compartment containers include but not limited to, for example, glass or polymeric vials, ampoules, syringes, infusion containers or infusion bottles with sizes ranging from 5 ml_ to 500 ml_, for example 10ml_, 20ml_, 25ml_, 30ml_, 40ml_, 50ml_, 60ml_, 70ml_, 75ml_, 80ml_, 90ml_, l OOimL, 125ml_, 150ml_, 200ml_, 250ml_, 300ml_, 400ml_, 500ml_ or any permutation or combinations thereof.
  • the large volume parenteral presentations can be contained in infusion containers such as bags or bottles or the like thereof.
  • the large volume parenteral are packed in a package system refer to the substances for example glass, polyethylene (PE) and co-polymers, bi-axially oriented polypropylene (BOPP), polypropylene (PP) and co-polymer, polyethylene terephthalate (PET & PET-G) and co-polymer, polyvinyl chloride (PVC) and co-polymer, oriented polyamide (OPA) and co-polymer, cyclic olefin and co-polymer, butyl rubber and co-polymer, nylon and co-polymer, ethyl vinyl alcohol (EVOH) and co-polymer structures, silicium oxide and co-polymer, silicon and co-polymer, thermoplastic polyurethane (TPU) and copolymer, aluminum foil, resin, metal and the like or mixtures thereof used to manufacture the packaging component.
  • PE poly
  • container such as glass
  • vials include but not limited to vials, ampoules, glass bottles and the like or combinations thereof.
  • Vials include glass vials with fill volumes 5ml_ to 500ml_ and neck dimensions of about 13mm, 20mm, 28mm, 32mm + 0.3mm and the like.
  • vial adapter can be used as reconciliation of the drug products various sizes of adapters with single head or multi head adapters with filters or without filters and the like or any necessary modification available in the art shall be made use of, for this invention.
  • the packaging material for package system could comprise oxygen or air as well as moisture- impermeable material so that vacuum created during packaging is maintained throughout the shelf life of the drug. It can be chosen from Polyethylene (PE), bi-axially oriented polypropylene (BOPP), PET
  • polyethylene terephthalate Polyethylene terephthalate
  • PVC Polyvinyl chloride
  • OPA oriented polyamide
  • aluminum foil or a blend of these polymers or a laminated structure of these polymers.
  • Possible structures of the laminate are PET/aluminum foil/PE, or OPA/PET/PE, or Triple Laminate Sunlight Barrier (TLSB) or quad laminate ultra - barrier (QLUB) bag and various other permutations and combinations are possible.
  • TLSB Triple Laminate Sunlight Barrier
  • QLUB quad laminate ultra - barrier
  • the laminate structure would primarily depend on moisture/light or gas barrier required by the drug or the composition.
  • the polyethylene-based resin there can be enlisted but are not limited to linear low density polyethylene
  • LLDPE high density polyethylene
  • HDPE high density polyethylene
  • LDPE low density polyethylene
  • HMHDPE High Molecular High Density Polyethyene
  • acrylonitrile polyamide, polyvinylidinefluoride (PVDF), ethylene acrylic acid, ethylene/methacrylic acid (E/MAA) copolymer, polypropylene lacquer, polyacetal, laminations of desiccants and oxygen absorbers of any above polymer grades or mixtures and copolymers thereof.
  • PVDF polyvinylidinefluoride
  • E/MAA ethylene/methacrylic acid copolymer
  • polypropylene lacquer polyacetal
  • laminations of desiccants and oxygen absorbers of any above polymer grades or mixtures and copolymers thereof.
  • the rigid container as used herein include non-airtight/air-tight, plastic/ metal drums, corrugated shipper or fiberboard drum for drug packaging and HDPE (high density polyethylene), PP (polypropylene), LDPE (low density polyethylene), PET, PVC (polyvinyl chloride) bottle for composition packaging.
  • HDPE high density polyethylene
  • PP polypropylene
  • LDPE low density polyethylene
  • PET PET
  • PVC polyvinyl chloride
  • the pack comprises three or more layers.
  • HMHDPE high molecular high- density poly ethylene bag
  • TLSB Triple Laminate Sunlight Barrier
  • in another embodiment of the present invention is to provide with or without vacuum sealed pack wherein the outermost layer is triple laminated aluminum bag inside black coated or quad laminate ultra-barrier (QLUB) bag comprises oxygen absorber and vacuum sealed using heat induction.
  • QLUB quad laminate ultra-barrier
  • the laminated container has one to five layers comprising of polypropylene and its co-polymer, overwrapped with silicium oxide laminate or aluminum barrier laminate.
  • the present invention is to provide with or without vacuum sealed pack wherein the container is of one to five layers comprising of polypropylene and its co-polymer, overwrapped with silicium oxide laminate or aluminum barrier laminate wherein vacuum is removed from both bag as wells as well as the overwrap.
  • multilayer container comprises of different polymers such as polypropylene (PP), polyvinyl chloride (PVC), ethyl vinyl alcohol (EVOH), silicium oxide, aluminum, nylon, thermoplastic polyurethane (TPU), polyethylene terephthalate (PET), oriented polyamide (OPA) and its copolymers can be used to prepare single layer container with or without adhesive.
  • PP polypropylene
  • PVC polyvinyl chloride
  • EVOH ethyl vinyl alcohol
  • silicium oxide aluminum
  • nylon thermoplastic polyurethane
  • PET polyethylene terephthalate
  • OPA oriented polyamide
  • multilayer container comprises of different polymers such as polypropylene (PP), polyvinyl chloride (PVC), ethyl vinyl alcohol (EVOH), silicium oxide, aluminum, nylon, thermoplastic polyurethane (TPU), polyethylene terephthalate (PET), oriented polyamide (OPA) and its copolymers can be used to prepare single layer container as extrusion laminate or adhesive laminate.
  • polymers such as polypropylene (PP), polyvinyl chloride (PVC), ethyl vinyl alcohol (EVOH), silicium oxide, aluminum, nylon, thermoplastic polyurethane (TPU), polyethylene terephthalate (PET), oriented polyamide (OPA) and its copolymers can be used to prepare single layer container as extrusion laminate or adhesive laminate.
  • the oxygen absorber is selected from the group comprising of but not limited to canister desiccant, desiccant, activated carbon, silicas, zeolites, molecular sieves, hydrogels, calcium oxide and diatomaceous earth.
  • composition comprises pharmaceutically acceptable excipients include antioxidants, isotonicity agent, preservatives, chelating agent, amino acid, bulking agent, buffering agent, carrier, diluent, solubilizer, pH modifiers and the like or any mixtures thereof.
  • composition comprises of pemetrexed or its pharmaceutically acceptable salt thereof, isotonicity agent, optionally antioxidant or preservative, buffering agent, carrier or a solvent and pH modifiers.
  • composition comprises of pemetrexed or its pharmaceutically acceptable salt thereof; pemetrexed equivalent to pemetrexed base or its solvates, hydrates, esters, ethers and the like or any combinations thereof.
  • Isotonicity agent include but not limited to mannitol, sucrose, dextrose, glycerin, sodium chloride, potassium chloride and the like or any mixtures thereof.
  • Antioxidant or preservative include but not limited to monothioglycerol, L- cysteine, thioglycolic acid, sodium metabisulfite, ascorbic acid, sodium ethylenediaminetetraacetic acid, monoethanolamine gentisate, sodium formaldehyde sulfoxylate, sodium bisulfate, butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA), phenylmercuric nitrate, thiomersal,
  • benzalkonium chloride benzethonium chloride, phenol, cresol or chlorobutanol.
  • Buffering agent include but not limited to acetate, citrate, tartrate, phosphate, benzoate, bicarbonate, organic amines and the like or any mixtures thereof.
  • Organic amines include but not limited to Tris(hydroxymethyl) aminomethane, N- (2 - Acetamido) -2 -aminoethanesulfonic acid, N-(2- (Acetamido)imino)diacetic acid, 2-Amino-2- methyl-1 -propanol, 2-Amino-2- methyl-l,3-propanediol, N-(l,l-Dimethyl-2-hydroxyethyl)-3-amino-2- hydroxypropanesulfonic acid, N,N-Bis(2-hydroxyethyl)-2-aminoethanesulfonic acid, N,N-Bis(2-hydroxyethyl)glycine, 2,2'-(Propane-l,3-diyldiimino
  • Carrier or solvent or aqueous vehicle include but not limited to water, water for injection (WFI) and the like, wherein water or water for injection is free or substantially free of oxygen.
  • WFI water for injection
  • composition comprises of pemetrexed or its pharmaceutically acceptable salt or hydrate thereof, mannitol, mono-thioglycerol, optionally tromethamine, water for injection, and sodium hydroxide or hydrochloric acid.
  • composition comprises of pemetrexed or its pharmaceutically acceptable salt or hydrate thereof, mannitol, thioglycolic acid, optionally tromethamine, water for injection, and sodium hydroxide or hydrochloric acid.
  • composition comprises of pemetrexed or its pharmaceutically acceptable salt or hydrate thereof, mannitol, L-cysteine, optionally tromethamine, water for injection, and sodium hydroxide or hydrochloric acid.
  • the dissolved oxygen content may be less than 2 ppm, for example less than 1 ppm or lower.
  • composition has a pH of about 5 to about 12, example pH is between about 6 to about 10, for example pH is between such that there about 7 to about 9.
  • the pH of the composition is between about 7 to about 9 comprising in solution 1 mg to 25 mg pemetrexed or acceptable salt (expressed as free base) per ml of the solution.
  • the solution is storage-stable (both refrigerated and room temperature), capable of being aseptically-filled and heat-sterilized.
  • the infusion container contains pemetrexed solution at a concentration and in a volume, wherein there is no requirement of dilution before administration i.e. the solution can be directly infused from the large volume infusion container.
  • the invention in another aspect relates to a stable liquid composition, comprising pemetrexed or its pharmaceutically acceptable salt thereof at concentration ranging from about 1 mg/ml_ to about 25mg/ml_.
  • concentration is from about 2mg/ml_ to about 20mg/ml_, 4mg/ml_ to about 18mg/ml_; preferably from about 6mg/ml_ to about 12mg/ml_.
  • composition is stable when stored at temperature between about 2°C to about 37°C, and the like, or room temperature and the like, for its shelf life when stored in a suitable parenteral container.
  • composition is stable when stored at temperature between 2°C to 8°C, 25°C and the like, or room temperature and the like, for its shelf life when stored in a suitable parenteral container.
  • the large volume infusion dosage form of the present invention provides a recommended dose of 500 mg/m 2 pemetrexed for nonsquamous non-small cell lung cancer or malignant pleural mesothelioma patients in combination with cisplatin.
  • the infusion dosage form is tailored to contain corresponding volume of ready to be infused solution of pemetrexed at a concentration of 4 to 12 mg/mL in a large volume infusion container.
  • the dosage form of the present invention provides 100 mg/m 2 of, an approved dose for renally impaired patients.
  • An iso-osmolar solution is a solution which has an osmotic pressure of about 270 to 330 m Osmol.
  • pemetrexed makes hardly any
  • pemetrexed dissolves in sufficient quantity and in stable form, so that such a formulation is suitable for use as a formulation for parenteral administration.
  • the aqueous liquid composition of pemetrexed of 10mg/ml_ strength is stored in a large volume glass vial, polypropylene container, ethyl vinyl alcohol container with or without aluminum pouch wrapped over polypropylene container, a polypropylene container with or without aluminum pouch and oxygen scavengers.
  • 10mg/ml_ strength is stored in a large volume glass vial with neck dimensions of 20mm or more; polypropylene container, ethyl vinyl alcohol container with or without aluminum pouch wrapped over polypropylene container, a polypropylene container with or without aluminum pouch and oxygen scavengers.
  • present invention also provides a kit comprising a large volume infusion dosage form comprising a stable large volume solution of pemetrexed or its pharmaceutically acceptable salt in an aqueous vehicle filled in a large volume infusion triple laminated polymeric container covered with optional secondary packaging system, wherein the solution is ready-to-be-infused.
  • a large volume infusion dosage form comprising a stable large volume solution of pemetrexed or its pharmaceutically acceptable salt in an aqueous vehicle filled in a large volume infusion polymeric container covered with a secondary packaging system, wherein the solution is ready-to-be-infused.
  • the polymeric containers are provided with oxygen barrier as a secondary packaging system to prevent permeation of oxygen during storage and to further ensure the stability of the solution.
  • the secondary packaging not only provides oxygen barrier but it also provides additional protection which is important as pemetrexed is a cytotoxic agent.
  • the additional packaging also protects the infusion containers from being tampered or misused and can help to provide unique identity to the product.
  • the secondary packaging may be an aluminum over-pouch. It can protect the solution from photolytic degradation.
  • the container used is capable of withstanding heat sterilization in the filled and unfilled state, for example moist heat sterilization (counter pressure cycle).
  • the volume of the solution filled in the infusion container can be tailored to cater single dose of pemetrexed or pharmaceutically acceptable salt thereof as per the prescription.
  • pemetrexed or pharmaceutically acceptable salt thereof (expressed as free base) solution at a concentration of 10 mg/mL is dispensed into the infusion containers in variable volumes corresponding to a dose of 100 mg to 1000 mg per infusion container.
  • concentration of pemetrexed or pharmaceutically acceptable salt thereof is 10 mg/mL.
  • variable volumes of the solution can be filled in the infusion containers, in order to achieve the desired dose of pemetrexed or pharmaceutically acceptable salt thereof per container, which will correspond to a single dose.
  • concentration of pemetrexed or pharmaceutically acceptable salt thereof can range from 1 mg/mL to 25 mg/ mL, for example, 2 mg/mL to 20 mg/mL or 6mg/mL to 12 mg/mL.
  • a 10 mg per mL pemetrexed or pharmaceutically acceptable salt thereof (expressed as free base) solution can be provided in different volumes such as 5mL to 500mL; viz., 5mL, 10mL, 15mL, 20mL, 25mL, 30mL, 35mL, 40mL, 45mL, 50 mL, 55mL, 60mL, 65mL, 70mL, 75 mL, 80mL, 85mL, 90mL, 95mL, 100 mL and the like.
  • a 10 mg per mL pemetrexed or pharmaceutically acceptable salt thereof (expressed as free base) solution can be provided in different volumes such as 10 mL, 50 mL, 75 mL, 100 mL to provide 100 mg, 500 mg, 750 mg, or 1000 mg respectively.
  • the kit comprises a large volume infusion dosage form wherein the infusion container is filled with 10 mL of stable large volume solution of 10 mg/ml of pemetrexed or its pharmaceutically acceptable salt in an aqueous vehicle and provides a dose of 100 mg of pemetrexed per container.
  • the kit comprises a large volume infusion dosage form wherein the infusion container is filled with 50 mL of stable large volume solution of 10 mg/mL of pemetrexed or its pharmaceutically acceptable salt in an aqueous vehicle and provides a dose of 500 mg of pemetrexed per container.
  • the kit comprises a large volume infusion dosage form wherein the infusion container is filled with 75 ml_ of stable large volume solution of 10 mg/mL of pemetrexed or its pharmaceutically acceptable salt in an aqueous vehicle and provides a dose of 750 mg of pemetrexed per container.
  • the kit comprising a large volume infusion dosage form wherein the infusion container includes 100 ml_ of stable large volume solution of 10 mg/mL of pemetrexed or its salt in an aqueous vehicle which provides a dose of 1000 mg of pemetrexed per container.
  • the invention relates to preparation of the large volume infusion dosage form, the process comprises:
  • pH may be adjusted to about 7 to about 9 or above with the addition of a base and/or an acid and optionally buffering agent may be added to above solution, wherein the dissolved oxygen is less than 2 ppm.
  • volume is made up and filtration is performed using suitable sterile grade filter.
  • the filtered solution is then filled in a suitable container with pre and post nitrogen flush and filled container is optionally sterilized.
  • Stenlization can be achieved by ⁇ -irradiation, e-Beam, natural light, filtration, steam sterilization, heat sterilization such as microwave heat sterilization or moist heat sterilization.
  • the sterilization may be steam sterilization or may be heat sterilization or filtration sterilization or combination thereof.
  • the present invention provides a ready-to-be infused sterile solution dosage form which may be sterilized by ⁇ -irradiation, e-Beam, natural light, filtration, microwave heat sterilization such as moist heat
  • the present invention provides the use of terminal heat sterilization to destroy all viable microorganisms within the final, sealed container.
  • the heat sterilization is terminal heat sterilization or filtration sterilization.
  • An autoclave may be used to accomplish terminal heat-sterilization of drug products in their final packaging. Typical autoclave cycles in the pharmaceutical industry to achieve terminal sterilization of the final product are 121 ° C for 15 minutes. Filtration sterilization is done using suitable filters with different pore sizes such as 0.2 ⁇ to 0.45 ⁇ and the like.
  • compositions of the present invention comprising such compositions may be used as a medicament, particularly for treating a pemetrexed sensitive disease in mammals.
  • Pemetrexed sensitive diseases include, but are not limited to, cancers, such as malignant pleural mesothelioma and non-small cell lung cancer.
  • methods of treating a pemetrexed sensitive disease in mammals include administering therapeutically effective amount of a pemetrexed-containing pharmaceutical composition as described hereinabove to a mammal in need thereof.
  • the present compositions need to follow the precaution to take the prior administration therapy or therapies or agents as mentioned in the ALIMTA pack insert before administration of lyophilized compositions.
  • Pemetrexed with or without other therapeutically active agents may also be used in combination or prior to administering pemetrexed comprising composition without departing from the present invention or to prevent side effects (e.g., hypersensitivity reactions, gastrointestinal symptoms) associated with the administration of the inventive compositions. These agents may optionally be added to the compositions. Preferably the therapeutically active agents synergistically enhance the effect of pemetrexed.
  • therapeutic agents examples include, but are not limited to vitamins, alkylating agents, antihistamines, hormonal agents, H 2 antagonists, steroids, plant-derived agents, biologic agents, platinum containing anticancer agents, interleukins, interferons, cytokines, immuno-modulating agents, monoclonal antibodies, other anticancer agents and combinations thereof.
  • Pemetrexed liquid compositions were prepared to check the physical and chemical stability in different large volume containers.
  • Example 1 Aqueous compositions
  • Table 2 Comparison of composition as such in PVC container against PVC container protected with Aluminum pouch and oxygen scavengers.
  • composition few other containers were tested by storing the compositions in those containers.
  • Example 2 Aqueous compositions
  • Table 4 Compositions filled in Polypropylene infusion container wrapped with
  • pemetrexed liquid composition when stored in polyvinyl chloride containers are prone and permeable to oxygen, hence both physical and chemical tests were at higher side and hence discontinued from further studies.
  • pemetrexed liquid composition is stable, when stored in polypropylene infusion containers with or without aluminum pouch and/or oxygen scavengers and glass vials with neck configurations above 20mm. It is also observed that control of oxygen permeation to the container plays a major role in the stability and the same has been addressed.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
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  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition liquide de pémétrexed iso-osmolaire, stable, comprenant du pémétrexed ou son sel pharmaceutiquement acceptable dans un véhicule aqueux ayant un pH d'environ 5 à environ 12, la composition étant un grand volume parentéral, prête à infuser et le récipient étant imperméable à l'oxygène.
PCT/IB2017/055059 2017-01-05 2017-08-22 Compositions liquides de pémétrexed prêtes à infuser WO2018127743A1 (fr)

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IN201741000467 2017-01-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019073482A1 (fr) * 2017-10-10 2019-04-18 Sun Pharmaceutical Industries Limited Forme posologique de type perfusion intraveineuse pour le pémétrexed
CN114642677A (zh) * 2020-12-21 2022-06-21 上海凯屹医药科技有限公司 一种稳定的含有苦丁皂苷类化合物的液体药物组合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013179310A1 (fr) * 2012-05-31 2013-12-05 Mylan Laboratories Limited Compositions aqueuses stables de pémétrexed
WO2015092758A1 (fr) * 2013-12-19 2015-06-25 Dr. Reddy' S Laboratories Ltd Formulations pharmaceutiques liquides de pemetrexed

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013179310A1 (fr) * 2012-05-31 2013-12-05 Mylan Laboratories Limited Compositions aqueuses stables de pémétrexed
WO2015092758A1 (fr) * 2013-12-19 2015-06-25 Dr. Reddy' S Laboratories Ltd Formulations pharmaceutiques liquides de pemetrexed

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019073482A1 (fr) * 2017-10-10 2019-04-18 Sun Pharmaceutical Industries Limited Forme posologique de type perfusion intraveineuse pour le pémétrexed
CN114642677A (zh) * 2020-12-21 2022-06-21 上海凯屹医药科技有限公司 一种稳定的含有苦丁皂苷类化合物的液体药物组合物

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