WO2014060962A1 - Formulations à base de dipotassium de pémétrexed - Google Patents

Formulations à base de dipotassium de pémétrexed Download PDF

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Publication number
WO2014060962A1
WO2014060962A1 PCT/IB2013/059388 IB2013059388W WO2014060962A1 WO 2014060962 A1 WO2014060962 A1 WO 2014060962A1 IB 2013059388 W IB2013059388 W IB 2013059388W WO 2014060962 A1 WO2014060962 A1 WO 2014060962A1
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WIPO (PCT)
Prior art keywords
solution
pemetrexed
pharmaceutical composition
hemiheptahydrate
composition
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PCT/IB2013/059388
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English (en)
Inventor
Vimal Kumar Shrawat
Rafiuddin
Vinod Kumar Singh
Bhagat Raj PIPAL
Akshay Kant CHATURVEDI
Shivakumar PRADEEP
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Shilpa Medicare Limited
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Publication of WO2014060962A1 publication Critical patent/WO2014060962A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • aspects of the present invention relates to pharmaceutical composition
  • pharmaceutical composition comprising crystalline pemetrexed dipotassium hydrate and process for preparation thereof.
  • Pemetrexed (S)-2-(4-(2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3- d]pyrimidin-5-yl)ethyl)benzamido)pentanedioic acid and has the following chemical structure:
  • Pemetrexed disodium is the most common salt of pemetrexed di acid.
  • Pemetrexed disodium heptahydrate is the active ingredient of Eli Lilly and Company's ALIMTA® injectable composition.
  • Pemetrexed disodium heptahydrate has the following chemical structure:
  • Pemetrexed disodium is a multi-targeted antifolate that strongly inhibits various folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT).
  • TS thymidylate synthase
  • DHFR dihydrofolate reductase
  • GARFT glycinamide ribonucleotide formyltransferase
  • Pemetrexed disodium has been proved effective on a wide variety of solid tumors in clinical trials.
  • pemetrexed disodium is commercial available in USA, European Union, Canada, Japan and China etc. for treatment of malignant pleural stromal tumor as a first-line drug, and local advanced and metastatic non-small cell lung cancer as a second-line drug.
  • pemetrexed disodium is a unique chemotherapeutic agent in the market currently.
  • pemetrexed disodium has a comparative efficacy and reduced toxicities compared with the standard drug Docetaxel.
  • the clinical studies of pemetrexed disodium in the treatment of breast, bowel, pancreatic, head and neck, gastric and bladder cancers are still ongoing.
  • Riebesehl et al in US6,686,365 provides a pharmaceutical composition comprising pemetrexed, at least one antioxidant selected from the group consisting of monothioglycerol, L-cysteine, and thioglycolic acid, and a pharmaceutically acceptable excipient.
  • WO2008/021411A2 provide processes for the preparation of lyophilized pharmaceutically acceptable salts of pemetrexed diacid, in particular, pemetrexed disodium salt, directly from pemetrexed diacid or salts thereof, i.e., without isolating the obtained pemetrexed salt prior to lyophilizing it.
  • WO2010/030598 A2 application describes Pharmaceutical formulations comprising amorphous pemetrexed or its salts, and processes to prepare the formulations.
  • WO2012/015810 A2 discloses long term storage stable pemetrexed-containing liquid pharmaceutical compositions.
  • the compositions can include pemetrexed or pharmaceutically acceptable salts thereof; an antioxidant selected from lipoic acid, dihydrolipoic acid, methionine and mixtures thereof; a chelating agent selected from lactobionic acid, sodium citrate, tribasic and mixtures thereof; and a pharmaceutically acceptable fluid.
  • the pH of the compositions is in a range of about 8 to about 9.5 and total impurities in the range of less than about 5%.
  • CN 101081301 Al discloses medicine composition containing pemetrexed, at least one kind of antioxidant as additive selected from L-arginine, L-glutathione, L-methionine and L- tryptophan, and pharmaceutically acceptable excipient.
  • CN 1907284 Al discloses a pharmaceutical composition comprising pemetrexed, characterized in that to contain pemetrexed and stabilizer in composition, its weight ratio is Chelius et al in US7,138,521 describes a stable crystalline heptahydrate form of pemetrexed disodium salt.
  • the patent states that pemetrexed can exist in the form of a heptahydrate which is more stable than the previously known 2.5 hydrate and shows that the primary advantage of the heptahydrate crystalline form over the 2.5 hydrate crystal form is its stability and also with respect to formation of related substances. It also shows that when the heptahydrate is subjected to elevated temperatures, low humidity, and/or vacuum, it is converted to the 2.5 hydrate (hemi-pentahydrate) crystal form by loss of water.
  • US 8,088,919 provide crystalline forms of pemetrexed diacid, and processes for the preparation thereof.
  • pemetrexed di sodium salt or its diacid often referred as pemetrexed.
  • pemetrexed pemetrexed di sodium salt or its diacid
  • the present inventors have found a stable formulation of new salt form of pemetrexed diacid as Pemetrexed dipotassium hemiheptahydrate, which is stable and usable for intended therapeutic purposes.
  • composition comprising pemetrexed dipotassium and its hydrates and process for preparation thereof.
  • a pharmaceutical composition comprising pemetrexed di potassium hemiheptahydrate characterized by X-ray powder diffraction pattern containing at least 5 characteristic 29° diffraction angle peaks selected from the XRPD peak set of 5.00, 13.70, 16.90, 20.00, 21.40, 23.6, 24.2 and 28.30 ⁇ 0.20 2 ⁇ °, and a pharmaceutically acceptable amount of an excipient, wherein said composition is having moisture content less than 5% w/w.
  • the present invention relates to a lyophilized composition of pemetrexed di potassium hemiheptahydrate, wherein the composition is characterized by X-ray powder diffraction pattern containing at least 5 characteristic 29° diffraction angle peaks selected from the XRPD peak set of 4.03, 4.26, 5.28, 11.53, 18.83, 21.76, 22.16, 24.75, 25.36, 25.98, 26.60, 27.92, 28.25, 31.78, 32.76, 34.38, 34.98, 38.78, 44.14 and 47.23 ⁇ 0.2° 2 ⁇ .
  • the invention further relates to pharmaceutical composition
  • pharmaceutical composition comprising pemetrexed di potassium hemiheptahydrate and a pharmaceutically acceptable amount of an excipient effective to form a lyophilized cake.
  • the lyophilized preparations of the invention may contain one or more Cryoprotectants or a combination thereof.
  • the invention relates to pharmaceutical composition
  • pharmaceutical composition comprising pemetrexed di potassium hemiheptahydrate, wherein a moisture content of the formulation is preferably less than about 5% by weight.
  • the present invention also relates to pharmaceutical composition
  • pharmaceutical composition comprising about lOmg/ml to about lOOmg/ml of pemetrexed di potassium hemiheptahydrate calculated as pemetrexed; excipients comprising about lOmg/ml to about 200mg/ml of the excipient, wherein the excipient comprising at least one Cryoprotectant, and a solvent selected from water, DMSO, ethanol and acetonitrile.
  • the present invention also relates to pharmaceutical composition
  • pharmaceutical composition comprising about lOmg/ml to about lOOmg/ml of pemetrexed di potassium hemiheptahydrate calculated as pemetrexed; excipients comprising about lOmg/ml to about 200mg/ml of the excipient, wherein the excipient comprising at least one Cryoprotectant, and water.
  • step 2) optionally filtering the solution obtained in step 2) to obtain a filtered solution
  • step e freezing the solution obtained in step 4) to form a frozen solution; and f) freeze drying the frozen solution to form the pharmaceutical composition, wherein the composition is having moisture content less than 5% w/w and substantially free of any additional pH modifier.
  • step d) filtering the solution obtained in step d) through 0.2 ⁇ filter to obtain a filtered solution
  • step f) freezing the solution obtained in step e) to form a frozen solution
  • the present invention relates to the lyophilized formulation that may be reconstituted with aqueous solution, comprising distilled or sterile water for injection or saline or physiological saline, wherein the saline comprises at least one of a 0.9% solution of sodium chloride, a 0.45%> or a 0.225%) solution of sodium chloride or bacteriostatic water for injection which optionally comprises methylparaben and/or propylparaben and/or 0.9% benzyl alcohol.
  • a method of treating a patient for cancer comprising reconstituting a pharmaceutical composition by combining a lyophilized powder with an aqueous solution to form the reconstituted pharmaceutical composition that is free of visual particles; and injecting the reconstituted pharmaceutical composition intravenously into a patient.
  • Fig. 1 is Illustration of X-ray powder diffraction (XRPD) pattern of Crystalline Pemetrexed dipotassium hemiheptahydrate, prepared according to Reference Example.
  • XRPD X-ray powder diffraction
  • Fig. 2 is Illustration of X-ray powder diffraction (XRPD) pattern of Crystalline Pemetrexed dipotassium hemiheptahydrate composition, prepared according to Example 3.
  • XRPD X-ray powder diffraction
  • Fig. 3 is Illustration of X-ray powder diffraction (XRPD) pattern of Placebo lyophilized composition, prepared according to Example 5.
  • XRPD X-ray powder diffraction
  • aspects of the present invention provide pharmaceutical composition comprising pemetrexed dipotassium and its hydrates and process for preparation thereof.
  • a pharmaceutical composition comprising pemetrexed di potassium hemiheptahydrate characterized by X-ray powder diffraction pattern containing at least 5 characteristic 29° diffraction angle peaks selected from the XRPD peak set of 5.00, 13.70, 16.90, 20.00, 21.40, 23.6, 24.2 and 28.30 ⁇ 0.20 2 ⁇ °, and a pharmaceutically acceptable amount of an excipient, wherein said composition is having moisture content less than 5% w/w.
  • composition in one aspect of the present invention, it relates to a lyophilized compositionof pemetrexed di potassium hemiheptahydrate, wherein the composition is characterized by X-ray powder diffraction pattern containing at least 5 characteristic 29° diffraction angle peaks selected from the XRPD peak set of 4.03, 4.26, 5.28, 11.53, 18.83, 21.76, 22.16, 24.75, 25.36, 25.98, 26.60, 27.92, 28.25, 31.78, 32.76, 34.38, 34.98, 38.78, 44.14 and 47.23 ⁇ 0.2° 2 ⁇ .
  • Table-1 Characteristic XRPD Peaks of Crystalline Pemetrexed dipotassium hemiheptahydrate S.No. Angle (2 ⁇ °) ⁇ 0.20 d Spacing Value (A 0 )
  • composition refers to any of various dosage forms suitable for administration of a drug, such as parenterally, intra- peritoneally, intravenously, intra-arterially, intramuscularly, subcutaneously, orally etc.
  • the invention provides pharmaceutical composition comprising pemetrexed di potassium hemiheptahydrate and a pharmaceutically acceptable amount of an excipient effective to form a lyophilized cake.
  • the lyophilized preparations of the invention may contain one or more Cryoprotectants or a combination thereof.
  • Cryoprotectants (often referred as bulking agent) that have "generally regarded as safe” (GRAS) status from the United States Food and Drug Administration (FDA) are well known in the art of pharmaceutical lyophilization and tend to strengthen the structure of the resulting lyophilized cake.
  • Bulking agents include saccharides, preferably monosaccharides or oligosaccharides, sugar alcohols, and mixtures thereof. More specifically, bulking agents used in the present invention include sucrose, dextrose, maltose, lactose, sorbitol, glycine, mannitol and dextran. A most preferred bulking agent is mannitol.
  • the present invention also relates to pharmaceutical composition comprising pemetrexed di potassium hemiheptahydrate, wherein a moisture content of the formulation is preferably less than about 5% by weight.
  • the present invention also relates to pharmaceutical composition comprising about lOmg/ml to about lOOmg/ml of pemetrexed di potassium hemiheptahydrate calculated as pemetrexed; excipients comprising about lOmg/ml to about 200mg/ml of the excipient, wherein the excipient comprising at least one Cryoprotectant, and a solvent selected from water, DMSO, ethanol and acetonitrile.
  • the present invention also relates to pharmaceutical composition
  • pharmaceutical composition comprising about lOmg/ml to about lOOmg/ml of pemetrexed di potassium hemiheptahydrate calculated as pemetrexed; excipients comprising about lOmg/ml to about 200mg/ml of the excipient, wherein the excipient comprising at least one Cryoprotectant, and water.
  • the pharmaceutical composition comprises about 33.37mg/ml pemetrexed di potassium hemiheptahydarte calculated as equivalent to about 25mg/ml of pemetrexed, and about 25 to 27 mg/ml of the excipient as mannitol, which in reconstitution solution comprises a pH value of about 6 to about 8.
  • the invention relates to lyophilized powder being suitable for reconstitution to form a liquid composition for parenteral administration, wherein the lyophilized powder is having moisture content less than 5% w/w.
  • the reconstituted pharmaceutical compositions of the present invention possess a pH value in the range of about 6 to about 8.
  • the invention provides a method of using a pharmaceutical composition for the manufacture of a medicament for the treatment of cancer in a mammal, wherein the pharmaceutical composition comprises pemetrexed dipotassium hemiheptahydrate and a pharmaceutically acceptable amount of an excipient effective to form a lyophilized cake, wherein the composition is having moisture content less than 5% w/w and substantially free of any additional pH modifier, the method comprising forming the medicament from the pharmaceutical composition.
  • compositions derived from pemetrexed dipotassium further encompass their physical properties for the compositions derived from pemetrexed dipotassium, wherein the properties include, but are not limited to, porosity, density, particle size, dispersion-ability, moisture content, pH, syringe- ability, injectability, particulate matter, and endotoxins.
  • the invention relates to a process for preparing a pharmaceutical composition containing a pemetrexed dipotassium hemiheptahydrate, which process comprises the steps of:
  • step 2) optionally filtering the solution obtained in step 2) to obtain a filtered solution
  • composition is having moisture content less than 5% w/w and substantially free of any additional pH modifier.
  • the invention relates to a process for preparing a pharmaceutical composition containing a pemetrexed dipotassium hemiheptahydrate, which process comprises the steps of:
  • step d) filtering the solution obtained in step d) through 0.2 ⁇ filter to obtain a filtered solution
  • step f) freezing the solution obtained in step e) to form a frozen solution
  • the invention relates to a process for preparing a pharmaceutical composition containing a pemetrexed dipotassium hemiheptahydrate, which process comprises the steps of:
  • step d) filtering the solution obtained in step d) through 0.2 ⁇ filter to obtain a filtered solution
  • step f) freezing the solution obtained in step e) to form a frozen solution
  • composition having moisture content less than 5% w/w, and substantially free of any additional pH modifier.
  • Additional pH modifier wherever used in entirety of the present specification, indicates organic or inorganic compounds used additionally to modify the pH of the final bulk solution before lyophilization.
  • no additional pH modifier before lyophilization is utilized in order to retain the identity and purity of pemetrexed dipotassium hemiheptahydrate compound.
  • This identity of pemetrexed dipotassium hemiheptahydrate compound may vary, if additional pH modifier(s) be utilized in the latter stages by displacing the potassium ions from the pemetrexed dipotassium hemiheptahydrate salt compound, in the lyophilized composition.
  • lyophilization process is employed for certain injectable pharmaceuticals that may exhibit poor active ingredient stability in aqueous solutions. Lyophilization process is suitable for injectable because it can be conducted under sterile conditions, which is a primary requirement for parenteral dosage forms. Cryoprotectants are excipients whose primary function is to protect the active constituent during a freezing process.
  • Lyophilization also known as freeze-drying is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from a solid to a vapor, without passing through a liquid phase.
  • the process consists of three separate, unique, and interdependent processes; a freezing phase, a primary drying phase (sublimation), and a secondary drying phase (desorption). These processes may be optimized to enhance the product stability as well as decrease the manufacturing costs.
  • a primary function of the freezing phase is to ensure that the entire container having the complex solution is completely frozen, prior to proceeding to a subsequent phase. Additionally, it is usually desired that these containers freeze in a uniform manner. While there are different ways that this can be accomplished, one option is to chill the containers after they are loaded onto the lyophilizer shelves and holding for 30-60 minutes prior to initiation of the freezing cycle. It is generally not practical to equilibrate the shelves to a freezing temperature, because of frost accumulation during the filling and loading of the containers.
  • the primary drying phase involves the removal of bulk water at a product temperature below the ice transition temperature under a vacuum (pressures typically between 50-300 mTorr).
  • This phase can be a critical one for stabilizing an active.
  • the goal is to identify the glass transition temperature (Tg') for the formulation.
  • Tg' is the temperature at which there is a reversible change of state between a viscous liquid and a rigid, amorphous glassy state.
  • DSC differential scanning calorimeter
  • the collapse temperature is observed to be about 2-5°C greater than the Tg'.
  • the shelf temperature is set such that the target product temperature is maintained near or below the Tg' of the formulation throughout the removal of As the solvent is progressively removed from the formulation containers, the product temperature will approach and reach the shelf temperature since it is no longer cooled by water sublimation.
  • the removal of solvent vapor can be tracked using a moisture detector, or by monitoring the decrease in pressure difference between a capacitance manometer and a thermocouple pressure gauge or by a pressure drop measurement.
  • the optimization of the primary dry cycle involves a removal of solvent as quickly as possible without causing cake collapse and subsequent product instability.
  • the secondary drying phase is the final segment of the lyophilization cycle, where residual moisture is removed from a formulation's interstitial matrix by desorption with elevated temperatures and/or reduced pressures.
  • the final moisture content of a lyophilized formulation which can be measured by Karl Fischer or other methods, is important because if the solid cake contains too much residual moisture, the stability of the active can be compromised. Hence, it is imperative that one achieves a moisture level as low as possible.
  • the shelf temperature is typically elevated to accelerate desorption of water molecules.
  • the duration of the secondary drying phase is usually short.
  • the residual moisture is generally significantly greater than desired.
  • One alternative is to purge the sample chamber of the lyophilizer with alternating cycles of an inert gas such as nitrogen, to facilitate displacement of bound water.
  • an inert gas such as nitrogen
  • the advantages of lyophilization include: ease of processing a liquid, which simplifies aseptic handling; enhanced stability of a dry powder; removal of water without excessive heating of the product; enhanced product stability in a dry state; and rapid and easy dissolution of reconstituted product.
  • the product is dried without elevated temperatures, thereby eliminating adverse thermal effects, and then stored in the dry state in which there are relatively few stability problems.
  • freeze dried products are often more soluble, dispersions are stabilized, and products subject to degradation by oxidation or hydrolysis are protected.
  • compositions to be freeze dried are frequently in aqueous solutions, ranging from about 0.01 to 40% by weight concentrations of total solids.
  • aqueous solutions ranging from about 0.01 to 40% by weight concentrations of total solids.
  • an improvement in stability of the lyophilizate, compared to a solution, is due to the absence of water in the lyophilizate.
  • a pharmacologically active constituent of many pharmaceutical products is present in such small quantities that, if freeze dried alone, it may not give a composition of suitable mass, and in some cases its presence would be hard to detect visually. Therefore, excipients are often added to increase the amount of solids present. In most applications it is desirable for a dried product cake to occupy essentially the same volume as that of the original solution. To achieve this, the total solids content of the original solution is frequently about 10 to 25% by weight.
  • Cryoprotectants or Bulking substances that are useful for this purpose, often in combination, include, but are not limited to, sodium or potassium phosphates (monobasic potassium phosphate, potassium dihydrogen phosphate, etc.), citric acid, tartaric acid, gelatin, lactose and other carbohydrates such as dextrose, mannitol and dextran, and occasionally preservatives.
  • Various excipients contribute appearance characteristics to the cake, such as dull and spongy, sparkling and crystalline, firm or friable, expanded or shrunken, and uniform or striated. Therefore formulations of a composition to be freeze dried should be a result of consideration not only of the nature and stability characteristics required during the liquid state, both freshly prepared and when reconstituted before use, but also the characteristics desired in the final lyophilized cake.
  • the injectable pharmaceutical formulations may optionally include one or more other pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include any one or more of: antibacterial preservatives, such as one or more of phenylmercuric nitrate, thiomersal, benzalkonium chloride, benzethonium chloride, phenol, cresol, and chlorobutanol; antioxidants including one or more of ascorbic acid, sodium sulfite, sodium bisulfite and sodium metabisulfite; chelating agents such as ethylenediamine tetraacetic acid (EDTA); buffers including one or more of acetate, citrate, tartarate, phosphate, benzoate and bicarbonate buffers; tonicity contributors including one or more of sodium chloride, potassium chloride, dextrose, mannitol, sorbitol and lactose; and alkaline substances including one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and meglu
  • a sterile vessel containing pemetrexed dipotassium for administration to a subject in need thereof.
  • the sterile vessel containing a pharmaceutical formulation according to the present invention may be a vial, syringe, or ampoule.
  • the headspace of a vial should contain less than about 8% (eight percent) v/v oxygen, or in the range of about 2% to about 5% v/v oxygen, or in the range of about 3% to about 5% v/v oxygen.
  • the headspace of the vial can be adjusted to minimize the formulation contact with oxygen. It is generally desired that the headspace is not more than about one-third of the total volume of the container, with the contents occupying at least about two-thirds of the total volume of the container. For example, 5 ml of product may be contained in a 7.5 ml vial.
  • antioxidants can be included. If a greater headspace ratio is desired, then the concentration of an antioxidant may be adjusted as necessary.
  • compositions and pharmaceutical formulations in lyophilized form, wherein the compositions after reconstitution form a clear solution within 3 minutes or less of gentle agitation.
  • the reconstituted pharmaceutical composition may be injectable intravenously or intraperitoneal or intramuscular.
  • the reconstitution of lOOmg vial according to the present invention comprise reconstitution with aqueous solutions ranging between 4 to 5ml,similarly 500 mg vial according to the present invention comprise reconstitution with aqueous solution ranging between 18 to 25 ml, it is preferable to reconstitute either size of the vial to provide a solution containing about 25mg/ml of pemetrexed. Due to high soluble nature of the composition according to the present invention it requires less amount of aqueous solution for reconstitution over the prior art formulation of pemetrexed disodium, The aqueous solution of an approximately 10 to 50% less amount may be used in preparing the reconstitution over the prior art formulation of pemetrexed disodium. Owing to the advantage of compositions of the present invention a reconstitution solution devoid of sodium content may provide cardio protective role for the patients suffering with cardiac disorders due to use of sodium ion.
  • kits provided for delivery of the pemetrexed or its salts.
  • a kit according to the present invention comprises a container holding the drug composition, a sterile reconstitution vehicle, and a sterile syringe.
  • the area used for processing the compositions and formulations of the present invention generally should comply with the requirements given in the current United States Pharmacopoeia ("USP") for parenteral dosage forms.
  • USP United States Pharmacopoeia
  • compositions for parenteral administration can be lyophilized powder, suspensions, emulsions or aqueous or non-aqueous sterile solutions.
  • the residual moisture levels in the lyophilized composition impact the storage stability of the lyophilized composition for a desired temperature and duration. Desirably, the amount of residual moisture in the lyophilized composition should be less than about 5% w/w.
  • Reconstitution of the lyophilized composition (which can be stored for an extended period of time at typical storage temperatures), typically just before administration to the patient, utilizes an appropriate liquid medium to produce a solution, suspension, dispersion, or emulsion.
  • a reconstitution medium may include sterile water, water for injection, a pH buffered solution, or 5% dextrose solution (D5W). The reconstitution is usually performed at room temperature, however other temperatures may also be considered.
  • the reconstituted lyophilized composition should pass the current United States Pharmacopeia (USP) Test 788 particulate matter specifications.
  • USP United States Pharmacopeia
  • the USP particulate matter test defines the amount of foreign particulate matter, as observed by optical microscopy. According to Test 788, the limit in each product container for foreign particulate matter having sizes greater than or equal to 10 ⁇ is 3000, and for particles having sizes greater than or equal to 25 ⁇ is 300.
  • Bulk density is described as untapped or tapped. Untapped bulk density of a substance is the undisturbed packing density of that substance and tapped bulk density relates to the packing density after tapping a bed of substance until no change in the packing density is seen. Bulk density and tapped density can be determined using a compendial bulk density apparatus, a suitable method being given in United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005, at pages 2638-2639.
  • Pemetrexed dipotassium hydrate is prepared by the example as given below.
  • Ethyl alcohol is added gradually (325 ml) within 60-90 minutes at 0-10°C under continuous stirring.
  • the solution temperature is raised gradually to 20-25°C under stirring.
  • Example 1-2 Pemetrexed Di Potassium Hemiheptahydrate composition
  • the pH of the solution is adjusted, as needed, to about 6.6 to 7.8 using 0.5N sodium hydroxide solution or 0.5N hydrochloric acid solution.
  • the volume is made up to 20 mL with the remaining water and mixed well.
  • Example 2 For Example 2, 20 mL of the solution from step 5) is filled into 50 mL depyrogenated USP type I glass vials and the vials are loosely stoppered with slotted sterile bromobutyl rubber stoppers.
  • Example 7 For Example 1, 4 mL of the solution from step 5) is filled into 10 mL USP type I glass vials and the vials are loosely stoppered with slotted sterile bromobutyl rubber stoppers.
  • Example 1 and 2 are stored at 40°C and 75% RH for 3 months and analyzed for pH, water content (by Karl-Fisher), drug assay, and other parameters. The results are tabulated below, where drug assays are percentages of the label pemetrexed content.
  • Samples from Examples 1 and 2 were stored at 40 C and 75% RH, and at 30 C and 75% RH, for 3 months to assess the stability pattern. The stability pattern observed was consistent in comparison of initial analysis.
  • step 2) Pemetrexed dipotassium hemiheptahydrate is added to the step 2) solution and dissolved with continuous stirring, and the solution pH is determined;
  • the pH of the bulk solution is adjusted to 7.20using 0.5N potassium hydroxide solution or 0.5N hydrochloric acid solution.
  • the volume is made up to 20 mL with the remaining water and mixed well.
  • the pH of the final bulk solution is determined.
  • Example 4 For Example 4, 20 mL of the solution from step 6) is filled into 50 mL depyrogenated USP type I glass vials and the vials are loosely stoppered with slotted sterile bromobutyl rubber stoppers.
  • Example 3 For Example 3, 4 mL of the solution from step 6) is filled into 10 mL USP type I glass vials and the vials are loosely stoppered with slotted sterile bromobutyl rubber stoppers.
  • Lyophilization cycle parameters are as follows: Temperature Ramp Soak duration Pressure Pressure Condenser
  • Example 5-6 Placebo lyophilized compositions
  • Example 5&6 are Placebo lyophilized compositions for Example 3 & 4 Pemetrexed lyophilized compositions respectively.
  • the pH of the bulk solution is adjusted to 7.20using 0.5N potassium hydroxide solution or 0.5N hydrochloric acid solution.
  • the volume is made up to 20 mL with the remaining water and mixed well.
  • the pH of the final bulk solution is determined. 6)
  • the final bulk solution is filtered through 0.2 ⁇ filter.
  • Example 6 For Example 6, 20 mL of the solution from step 6) is filled into 50 mL depyrogenated USP type I glass vials and the vials are loosely stoppered with slotted sterile bromobutyl rubber stoppers.
  • Example 5 For Example 5, 4 mL of the solution from step 6) is filled into 10 mL USP type I glass vials and the vials are loosely stoppered with slotted sterile bromobutyl rubber stoppers.
  • Example 3 Pemetrexed Di Potassium Hemiheptahydrate composition(100mg/vial) &Example 5 placebo lyophilized composition were subjected to X-ray powder diffraction (XRPD) study.
  • XRPD X-ray powder diffraction
  • Fig. 2 is theillustration of XRPD pattern of Crystalline Pemetrexed dipotassium hemiheptahydrate composition, prepared according to Example 3.
  • Fig. 3 is theillustration of XRPD pattern of Placebo lyophilized composition, prepared according to Example 5.
  • wt% refers to percent by weight. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g. "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant de l'hydrate de dipotassium de pémétrexed et les utilisations de celles-ci. L'invention concerne également un procédé de préparation de compositions lyophilisées d'hémiheptahydrate de dipotassium de pémétrexed.
PCT/IB2013/059388 2012-10-17 2013-10-16 Formulations à base de dipotassium de pémétrexed WO2014060962A1 (fr)

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WO2016001792A1 (fr) * 2014-06-30 2016-01-07 Shilpa Medicare Limited Formulations à base de dipotassium de pémétrexed
EP3074015A1 (fr) * 2013-11-25 2016-10-05 Shilpa Medicare Limited Procédé de préparation de sel dipotassique de pémétrexed cristallin
EP3090746A4 (fr) * 2013-12-30 2017-08-09 Samyang Biopharmaceuticals Corporation Composition pharmaceutique ne contenant pas d'antioxydant et son procédé de préparation
EP3305283A4 (fr) * 2015-05-28 2019-01-09 Samyang Biopharmaceuticals Corporation Composition pharmaceutique stabilisée et son procédé de préparation
WO2020198614A1 (fr) * 2019-03-27 2020-10-01 Fluidigm Canada Inc. Panel d'anticorps lyophilisés
WO2020222151A1 (fr) * 2019-05-01 2020-11-05 Intas Pharmaceuticals Ltd. Composition pharmaceutique aqueuse stable et prête à l'emploi de pemetrexed

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CN101417998A (zh) * 2007-10-24 2009-04-29 重庆医药工业研究院有限责任公司 一种培美曲塞盐的纯化方法
WO2010031357A1 (fr) * 2008-09-22 2010-03-25 重庆医药工业研究院有限责任公司 Trois nouvelles formes de cristaux de diacide de pemetrexed et leur procédé de préparation
WO2012134392A1 (fr) * 2011-03-25 2012-10-04 Scinopharm Taiwan Ltd Procédé pour la production d'un sel de pémétrexed
CN102838602A (zh) * 2011-06-21 2012-12-26 重庆医药工业研究院有限责任公司 培美曲塞氧化物及其制备方法

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CN101417998A (zh) * 2007-10-24 2009-04-29 重庆医药工业研究院有限责任公司 一种培美曲塞盐的纯化方法
WO2010031357A1 (fr) * 2008-09-22 2010-03-25 重庆医药工业研究院有限责任公司 Trois nouvelles formes de cristaux de diacide de pemetrexed et leur procédé de préparation
WO2012134392A1 (fr) * 2011-03-25 2012-10-04 Scinopharm Taiwan Ltd Procédé pour la production d'un sel de pémétrexed
CN102838602A (zh) * 2011-06-21 2012-12-26 重庆医药工业研究院有限责任公司 培美曲塞氧化物及其制备方法

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3074015A1 (fr) * 2013-11-25 2016-10-05 Shilpa Medicare Limited Procédé de préparation de sel dipotassique de pémétrexed cristallin
EP3074015A4 (fr) * 2013-11-25 2017-05-03 Shilpa Medicare Limited Procédé de préparation de sel dipotassique de pémétrexed cristallin
EP3090746A4 (fr) * 2013-12-30 2017-08-09 Samyang Biopharmaceuticals Corporation Composition pharmaceutique ne contenant pas d'antioxydant et son procédé de préparation
US10300063B2 (en) 2013-12-30 2019-05-28 Samyang Biopharmaceuticals Corporation Pharmaceutical composition not containing antioxidant and preparation method therefor
WO2016001792A1 (fr) * 2014-06-30 2016-01-07 Shilpa Medicare Limited Formulations à base de dipotassium de pémétrexed
US9789113B2 (en) 2014-06-30 2017-10-17 Shilpa Medicare Limited Pemetrexed dipotassium formulations
EP3305283A4 (fr) * 2015-05-28 2019-01-09 Samyang Biopharmaceuticals Corporation Composition pharmaceutique stabilisée et son procédé de préparation
US10456362B2 (en) 2015-05-28 2019-10-29 Samyang Biopharmaceuticals Corporation Stabilized pharmaceutical composition and method for preparing same
WO2020198614A1 (fr) * 2019-03-27 2020-10-01 Fluidigm Canada Inc. Panel d'anticorps lyophilisés
WO2020222151A1 (fr) * 2019-05-01 2020-11-05 Intas Pharmaceuticals Ltd. Composition pharmaceutique aqueuse stable et prête à l'emploi de pemetrexed

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