WO2018127743A1 - Ready to infuse pemetrexed liquid compositions - Google Patents
Ready to infuse pemetrexed liquid compositions Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pemetrexed
- composition
- container
- pharmaceutically acceptable
- large volume
- Prior art date
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- WBXPDJSOTKVWSJ-ZDUSSCGKSA-L pemetrexed(2-) Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-L 0.000 description 91
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- 230000002496 gastric effect Effects 0.000 description 1
- 229940114119 gentisate Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000004688 heptahydrates Chemical class 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000011169 microbiological contamination Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 239000008381 oxidative degradant Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 1
- 238000009512 pharmaceutical packaging Methods 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920005678 polyethylene based resin Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005644 polyethylene terephthalate glycol copolymer Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000011519 second-line treatment Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229940100996 sodium bisulfate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002834 transmittance Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
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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Abstract
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.
Description
READY TO INFUSE PEMETREXED LIQUID COMPOSITIONS
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
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.
It is reported that, pemetrexed liquid formulation was discontinued and a lyophilized formulation was introduced during clinical development of
commercially available parenteral formulation of pemetrexed disodium
(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.
Annals of Pharmacotherapy article of 2006 discloses that pemetrexed in concentrations of 2, 10, and 20 mg/mL in dextrose 5% and NaCI 0.9% injection in polyvinyl chloride (PVC) containers are chemically stable for 90 days frozen at - 20 degrees C, however microparticulates were formed in pemetrexed diluted in the infusion solutions in PVC continers upon long-term frozen storage, thereby inferring physical instability.
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.
Though several liquid or ready to dilute compositions are published in the literature, administration intricacies and tedious procedures needs to be followed as these compositions need to be further reconstituted before administration and it requires qualified physicians to administer. However, it is a known fact that pemetrexed is prone to delamination in glass vials, therefore present
compositions are having pemetrexed at low concentration, hence chances of delamination is remote and this issue has been addressed in this invention.
Considering the Annals of Pharmacotherapy 2006 article, which disclose that pemetrexed when stored in PVC infusion containers at -20°C failed physical stability and above disclosed liquid compositions; this gives a challenge to develop a stable ready to infuse iso-osmolar pemetrexed liquid compositions. SUMMARY OF THE 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.
Another embodiment relates to the composition 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.
Another embodiment relates to composition, 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.
Another embodiment relates that the 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.
Another embodiment relates to a kit 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.
DETAILED DESCRIPTION OF THE INVENTION
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.
The term "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. 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
pharmaceutical use and veterinary use as well. The term includes one or more excipients or adjuvants.
The term "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,
complexation, or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions involving one or more of the ingredients.
The term "formulation" or "dosage form" or "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.
According to the present invention, 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.
The term 'stable', as used in the context of this application, means remaining in a state or condition that is suitable for administration to a patient. In particular, 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. The term "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.
The term 'sterile' solution dosage form, as used in the context of this application, 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
compromised. Sterile compositions are generally prepared by pharmaceutical manufacturers in accordance with current Good Manufacturing Practice
("cGMP") regulations.
The term "large volume parenteral" per invention 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.
The term "iso-osmolar" refers to a solution having the same osmotic pressure as blood.
Per invention any recitation of ranges of values set forth is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Furthermore, all references, including patents, patent applications, and publications, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
Per invention the terms "a" and "an" and "the," as used herein, are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing," as used herein, are to be construed as open ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted.
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.
In one embodiment 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.
In another embodiment container such as glass (USP Type-I, II, & III) 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.
In another embodiment 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), Polyvinyl chloride (PVC), oriented polyamide (OPA), 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. The laminate structure would primarily depend on moisture/light or gas barrier required by the drug or the composition. As the polyethylene-based resin, there can be enlisted but are not limited to linear low density polyethylene
(LLDPE), high density polyethylene (HDPE), low density polyethylene (LDPE), High Molecular High Density Polyethyene (HMHDPE) polypropylene,
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.
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.
In one of the embodiment of the present invention is to provide a vacuum sealed pack wherein the pack comprises three or more layers.
In another embodiment of the present invention is to provide with or without vacuum sealed pack wherein the innermost layer is a special plastic bag of (HMHDPE) high molecular high- density poly ethylene bag comprises oxygen absorber and vacuum sealed using heat induction.
In another embodiment of the present invention is to provide with or without vacuum sealed pack wherein the middle layer is a Triple Laminate Sunlight Barrier (TLSB) bag comprises oxygen absorber and vacuum sealed using heat induction.
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.
In another embodiment of the present invention is to provide with or without vacuum sealed pack wherein the laminated container has one to five layers comprising of polypropylene and its co-polymer, overwrapped with silicium oxide laminate or aluminum barrier laminate.
In another embodiment of 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.
In another embodiment, 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.
In another embodiment, 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.
In another embodiment of the present invention is to provide with or without vacuum sealed pack wherein 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.
In one more embodiment the 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.
The 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.
The 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)bis[2-
(hydroxymethyl)propane-l, 3-diol], 2-[Bis(2-hydroxyethyl)imino]-2- (hydroxymethyl)-1 ,3-propanediol, 2- Amino ethanol, (2R,3R,4R,5S)-6- Methylaminohexane-l,2,3,4,5-pentol, 2,2',2"-Nitrilotriethanol. Examples of pharmaceutically acceptable organic amines are tromethamine and meglumine.
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.
The 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.
The 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.
The 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.
In another embodiment we found that, in the case of large volume parenteral compositions, by carefully purging a filled container with nitrogen or other inert gas, the formation of oxidative degradation products may be avoided. When the formulations are carefully purged of oxygen, the dissolved oxygen content may be less than 2 ppm, for example less than 1 ppm or lower.
In another specific embodiment the 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.
In another embodiment 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.
In another aspect the invention 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_. For example, the 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_.
In another aspect, 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.
In another aspect, 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.
In one embodiment, the large volume infusion dosage form of the present invention provides a recommended dose of 500 mg/m2 pemetrexed for nonsquamous non-small cell lung cancer or malignant pleural mesothelioma patients in combination with cisplatin. In order to provide this dose, 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. Similarly, the dosage form of the present invention provides 100 mg/m2 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. In contrast, pemetrexed makes hardly any
contribution to isotonization. It has surprisingly been found that, in the presence of this isotonicity agent concentration, pemetrexed dissolves in sufficient quantity and in stable form, so that such a formulation is suitable for use as a formulation for parenteral administration.
In an embodiment, 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.
In an embodiment, the aqueous liquid composition of pemetrexed of
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.
In an embodiment 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.
In another embodiment the 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 polymeric container covered with a secondary packaging system, wherein the solution is ready-to-be-infused.
In another embodiment, 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. In one embodiment, the secondary packaging may be an aluminum over-pouch. It can protect the solution from photolytic degradation. Furthermore, the container used is capable of withstanding heat sterilization in the filled and unfilled state, for example moist heat sterilization (counter pressure cycle).
In another specific embodiment of this invention, 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. In one embodiment, 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. In another embodiment, the concentration of pemetrexed or pharmaceutically acceptable salt thereof is 10 mg/mL. It may be noted that depending on the concentration of pemetrexed or pharmaceutically acceptable salt thereof, 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. For example, the 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.
For example, 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.
For example, 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.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, 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.
In another embodiment, 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.
In another specific embodiment, the invention relates to preparation of the large volume infusion dosage form, the process comprises:
1 ) dissolving of mannitol, antioxidant such as monothioglycerol, L- cysteine or thioglycolic acid, in water for injection which is nitrogen purged and adding pemetrexed to achieve a concentration of 6 mg to 12 mg of pemetrexed in one milliliter of the solution.
2) 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.
3) volume is made up and filtration is performed using suitable sterile grade filter.
4) 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 γ-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.
In one embodiment, the present invention provides a ready-to-be infused sterile solution dosage form which may be sterilized by γ-irradiation, e-Beam, natural light, filtration, microwave heat sterilization such as moist heat
sterilization. The present invention provides the use of terminal heat sterilization to destroy all viable microorganisms within the final, sealed container.
Advantageously 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 μιη to 0.45 μιη and the like.
The 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. Thus, there are also provided methods of treating a pemetrexed sensitive disease in mammals. The use or methods include administering therapeutically effective amount of a pemetrexed-containing pharmaceutical composition as described hereinabove to a mammal in need thereof. Further, 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. Examples of therapeutic agents that may be used in conjunction with the pharmaceutical compositions of the present invention include, but are not limited to vitamins, alkylating agents, antihistamines, hormonal agents, H2 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.
To further illustrate the invention, the following examples are provided. It is to be understood that these examples are provided for illustrative purposes and are not to be construed as limiting the scope of the invention. It is to be further understood that, in the examples the functions of individual ingredients are sometimes listed for illustration purposes.
Examples:
Pemetrexed liquid compositions were prepared to check the physical and chemical stability in different large volume containers.
Example 1 : Aqueous compositions
Considering the liquid injection composition results, as above said formulation with selected anti-oxidants were developed with different packing material to check the feasibility and stability of same.
The above said formulation with selected anti-oxidants such as monothioglycerol were developed with different packing material to check the feasibility and stability of same.
Stability Details:
Table 1 - Stability details of compositions filled in PVC infusion container
CCS- Clear Colorless solution; PYS- Pale Yellow color solution; LPYS- Light Pale Yellow color solution
Considering the stability details of the solutions stored in vial labelled as control and polyvinyl chloride (PVC) infusion container, it is observed that the clarity of drug solution is affected changing from clear colorless solution to light pale yellow color solution, thereby inferring a physical instability of drug solutions stored in polyvinyl chloride infusion container versus the vial.
Further, considering the accelerated condition stability data of pemetrexed liquid injection, it is observed that the clarity of drug solution is affected changing from clear colorless solution to pale yellow color solution in the 2nd month and further there is an increase in the total impurities which is out of specification range.
Considering the room temperature condition stability data of pemetrexed liquid injection, it is observed that the clarity of drug solution is affected changing from clear colorless solution to light pale yellow color solution and further there is an increase in the total impurities which is out of specification range.
The physical stability of controlled condition stability data of pemetrexed liquid injection was better in comparison with accelerated and room temperature stability condition data as total impurities were in control, but the total impurities were increasing in trend when compared to first month data.
Considering both physical and chemical stability details of the aqueous compositions which were clear and colorless solution initially and slowly turned to
light pale yellow color solution; further the impurity profile was slightly increasing in trend thereby inferring the chemical instability, the reason is the PVC containers are permeable to oxygen and as pemetrexed is prone to oxidation, therefore the composition in the infusion container easily gets destabilized.
However, PVC containers as such were permeable to oxidation, hence to control the oxidation of pemetrexed, the compositions were protected using an aluminum wrap over the PVC containers and oxygen scavengers were used to control the oxidation.
Table 2: Comparison of composition as such in PVC container against PVC container protected with Aluminum pouch and oxygen scavengers.
#- Polyvinyl chloride infusion container wrapped with Aluminum pouch with oxygen scavengers
Considering above comparison observations with pemetrexed drug solution in PVC container wrapped over with aluminum pouch with oxygen scavengers there is a change in clarity of drug solution, the description of the solution changed from clear colorless solution to light pale yellow color solution thereby inferring physical instability. Further analytical study suggests there is
significant changes observed such as related substances increased in long term stability condition, however it reduced in the first month in the room temperature condition but showed an increasing trend in the 2nd month by 0.7%. Further controlled stability condition was also not very satisfactory. Therefore,
considering the above stability details and composition stored in polyvinylchloride containers it is inferred and confirmed that PVC containers were unsuitable for this drug solution, thereby further studies with PVC containers were discontinued. Further, to search a suitable packaging material for pemetrexed liquid
composition, few other containers were tested by storing the compositions in those containers.
Example 2: Aqueous compositions
Table 3: Stability details of compositions filled in Polypropylene infusion container
;" Control- Glass Vial
Considering the stability data at varying conditions, there were no significant changes physically as the description was intact inferring the physically stability; further total impurities was in the specified range when compared to the control sample stored in the glass vial. Further based on real time data, related substances are within the specification limit inferring that the polypropylene container seem to protect the drug solution from oxygen permeation thereby proving that polypropylene is impermeable to oxygen. Hence these compositions were continued for further stability studies.
Table 4: Compositions filled in Polypropylene infusion container wrapped with
Aluminum pouch with oxygen scavengers
2ΜΛ CCS 99.01 - 1 .572
25°C ± 2°C/
3ΜΛ CCS 98.486 97.1 1 .78
60% RH ±
1 ΜΛΛ CCS 100.628 - 0.62
5%RH
2ΜΛΛ CCS 99.292 - 1 .188
3ΜΛΛ CCS 98.836 99.0 1 .52
1 ΜΛ CCS 100.628 - 0.40
2ΜΛ CCS 98.320 - 0.483
3ΜΛ CCS 99.184 101 .7 0.36
2-8°C
1 ΜΛΛ CCS 100.306 - 0.34
2ΜΛΛ CCS 98.39 - 0.43
3ΜΛΛ CCS 98.668 102.4 0.58
Λ- Polypropylene infusion container wrapped with Aluminum pouch with oxygen scavengers; ΛΛ- Polypropylene infusion container
Considering the comparative study details of poly propylene infusion containers wrapped with Aluminum pouch with oxygen scavengers and poly propylene infusion containers as such at 3 month's stability data at varying conditions, there were no significant changes physically as the description was intact inferring the physically stability and total impurities were all in the specified ranges when compared to the control sample stored in the glass vial. Further based on real time data, related substances are within the specification limit inferring that the polypropylene container seem to protect from oxygen
permeation thereby proving that polypropylene is impermeable to oxygen and though polypropylene containers are wrapped with aluminum pouch with oxygen scavengers, both the containers are comparable and can be used for storage of pemetrexed liquid compositions. Hence these compositions were continued for further stability studies.
Table 5: Stability details of compositions filled in large volume glass container
%
Initial
To (Glass CCS 98.72 - 0.64
Vial)
40°C ± 1 M CCS 99.521 - 1 .147
2°C/75% RH 2M CCS 98.286 100.7 0.98
± 5%RH 3M CCS 98.752 99.1 1 .14
25°C ± 2°C/ 1 M CCS 98.976 - 1 .235
60% RH ± 2M CCS 98.875 100.5 1 .35
5%RH 3M CCS 98.726 99.2 0.63
1 M CCS 97.096 - 0.719
2-8°C 2M CCS 98.671 100.9 0.63
3M CCS 98.708 98.7 0.74
Considering the comparative study details of 50 ml_/ 32 mm clear molded infusion glass vials with 3 month's stability at varying conditions, there were no significant changes observed physically as the description was intact concluding the physically stability, light transmittance, assay and total impurities were all in the specified ranges. Further based on real time data, related substances are within the specification limit inferring that the molded glass vials also to be a suitable packing material along with other impermeable infusion containers. Hence these compositions were continued for further stability studies.
Further from the above examples it is concluded that 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. However, 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.
Claims
1 . 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.
2. The composition according to claim 1 , wherein the composition is available as large volume parenteral in infusion containers, glass vial or suitable parenteral containers, ready to be infused and composition further comprise of other pharmaceutically acceptable excipients.
3. The composition according to claim 2, wherein the pharmaceutically acceptable excipients include antioxidants, isotonicity agents, preservatives, chelating agent, amino acid, bulking agent, buffer, carrier, diluent, pH modifiers, solubilizer and the like or any mixtures thereof.
4. The composition according to claim 1 , wherein the composition has a pH of
about 7 to about 9.
5. The composition according to claim 1 , comprising pemetrexed or its
pharmaceutically acceptable salt thereof at concentration ranging from about 1 mg/mL to about 25mg/ml_.
6. A stable liquid composition, wherein the composition is stable at 2-8°C, 25°C, or room temperature and the like, for its shelf life when stored in a suitable parenteral container, wherein the container is impermeable to oxygen.
7. The liquid composition according to preceding claims, wherein the composition is stored in a large volume parenteral container such as glass vial, polypropylene container; polypropylene container comprising optionally the aluminum or suitable pouch with or without oxygen scavengers.
8. A kit comprising stable, iso-osmolar pemetrexed liquid composition, comprising pemetrexed or its pharmaceutically acceptable salt thereof and excipients 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.
A stable, iso-osmolar pemetrexed liquid composition, comprising pemetrexed its pharmaceutically acceptable salt thereof and excipients in an aqueous vehicle, wherein the composition is a large volume parenteral in a suitable parenteral container substantially as herein described.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019073482A1 (en) * | 2017-10-10 | 2019-04-18 | Sun Pharmaceutical Industries Limited | Intravenous infusion dosage form for pemetrexed |
| CN114642677A (en) * | 2020-12-21 | 2022-06-21 | 上海凯屹医药科技有限公司 | Stable liquid medicine composition containing ilexoside compound |
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|---|---|---|---|---|
| WO2013179310A1 (en) * | 2012-05-31 | 2013-12-05 | Mylan Laboratories Limited | Stable aqueous compositions of pemetrexed |
| WO2015092758A1 (en) * | 2013-12-19 | 2015-06-25 | Dr. Reddy' S Laboratories Ltd | Liquid pharmaceutical formulations of pemetrexed |
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2017
- 2017-08-22 WO PCT/IB2017/055059 patent/WO2018127743A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013179310A1 (en) * | 2012-05-31 | 2013-12-05 | Mylan Laboratories Limited | Stable aqueous compositions of pemetrexed |
| WO2015092758A1 (en) * | 2013-12-19 | 2015-06-25 | Dr. Reddy' S Laboratories Ltd | Liquid pharmaceutical formulations of pemetrexed |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019073482A1 (en) * | 2017-10-10 | 2019-04-18 | Sun Pharmaceutical Industries Limited | Intravenous infusion dosage form for pemetrexed |
| CN114642677A (en) * | 2020-12-21 | 2022-06-21 | 上海凯屹医药科技有限公司 | Stable liquid medicine composition containing ilexoside compound |
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