EP4294365A1 - Utilisation d'une solution de concentré de pemetrexed - Google Patents

Utilisation d'une solution de concentré de pemetrexed

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Publication number
EP4294365A1
EP4294365A1 EP22707096.8A EP22707096A EP4294365A1 EP 4294365 A1 EP4294365 A1 EP 4294365A1 EP 22707096 A EP22707096 A EP 22707096A EP 4294365 A1 EP4294365 A1 EP 4294365A1
Authority
EP
European Patent Office
Prior art keywords
solution
pemetrexed
concentrate
use according
infusion
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22707096.8A
Other languages
German (de)
English (en)
Inventor
Edgar Schridde
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Stada Arzneimittel AG
Original Assignee
Stada Arzneimittel AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Stada Arzneimittel AG filed Critical Stada Arzneimittel AG
Publication of EP4294365A1 publication Critical patent/EP4294365A1/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K9/08—Solutions

Definitions

  • the present invention relates to the use of a liquid pharmaceutical pemetrexed concentrate solution comprising
  • Pemetrexed is the international non-proprietary name (INN (International
  • Pemetrexed is a drug from the group of
  • lung cancer a) pleural mesothelioma (a type of cancer of the lining of the lungs, usually caused by exposure to asbestos), where it is used with cisplatin in patients who have not received chemotherapy before and whose cancer cannot be removed by surgery. b) advanced "non-small cell" lung cancer of the "non-squamous” type, where it is used either with cisplatin in previously untreated patients or alone in patients who have previously received anticancer medicines. It can also be used as maintenance therapy in patients who have received platinum-based chemotherapy.
  • pemetrexed is based on the blocking of both thymidilate synthase and dihydrofolate reductase and glycinamide ribonucleotide formyl transferase, which inhibits the folate-dependent biosynthesis of thymidine and purine nucleotides (cf. Mutschler Drug Effects, Textbook of Pharmacology and Toxicology, 9 Edition, Academicliche Verlagsgesellschaft mbH Stuttgart, 2008, pp. 919-920; ISBN 978-3-8047-1952-1).
  • Pemetrexed is sold under the brand name Alimta ® in the dosage form of a lyophilisate with strengths of 100 mg and 500 mg.
  • the sterile lyophilisate is first reconstituted with 0.9% saline to give a solution of 25 mg/ml pemetrexed dosed at the recommended dose of 500 mg/m2 body surface area and after further dilution to 0.9 % saline diluted to 100 ml, administered intravenously over 10 minutes.
  • Chemical and physical stability of the lyophilisate obtained by reconstitution The pemetrexed solution obtained and the infusion solution made from it is specified as only 24 hours.
  • EP 2 854 765 had proposed a liquid pharmaceutical solution for parenteral administration, containing a solvent, pemetrexed or a pharmaceutically acceptable salt thereof, and acetylcysteine or sodium 2-mercaptoethanesulfonate as an antioxidant.
  • the object of the present invention is to use a liquid pharmaceutical concentrate solution, comprising
  • this object is achieved in that the concentrate solution is used to produce an infusion solution using a dilution solution, with the infusion solution being stable for a period of more than 72 hours after it has been prepared.
  • the term “stability” is understood to mean the definition drawn up by the Working Group for Pharmaceutical Process Engineering (APV), according to which "stability” means the quality of the drug that conforms to the specification up to the end of the term specified by the manufacturer.
  • the quality of the drug is determined by the active ingredient content and purity, the sensory perceptible, physical-chemical and microbiological properties, with the active ingredient content within the scope of the present invention not falling below 95.0% of the nominal value until the end of the shelf life of the infusion solution may.
  • the infusion solution after its preparation is stable for a period of longer than 72 hours and up to 100 days, more preferably for a period of longer than 72 hours and up to 80 days preferably for a period greater than 72 hours and up to 50 days, more preferably for one Period of longer than 72 hours and up to 35 days, more preferably for a period of longer than 72 hours and up to 28 days, more preferably for a period of longer than 72 hours and up to 21 days, more preferably for a period of longer than 72 hours and up to 14 days and even more preferably for a period longer than 72 hours and up to 7 days.
  • the infusion solution is stable for a period of longer than 84 hours and up to 100 days after its preparation, more preferably for a period of longer than 84 hours and up to 80 days, more preferably for a period of longer than 84 hours and up to 50 days, more preferably for a period of longer than 84 hours and up to 35 days, more preferably for a period of longer than 84 hours and up to 28 days for a period greater than 84 hours and up to 21 days, more preferably for a period greater than 84 hours and up to 14 days, and even more preferably for a period greater than 84 hours and up to 7 days.
  • the infusion solution is stable for a period of longer than 96 hours and up to 100 days after its preparation, more preferably for a period of longer than 96 hours and up to 80 days, more preferably for a period longer than 96 hours and up to 50 days, more preferably for a period longer than 96 hours and up to 35 days, more preferably for a period longer than 96 hours and up to 28 days for a period longer than 96 hours and up to 21 days, more preferably for a period longer than 96 hours and up to 14 days and even more preferably for a period greater than 36 hours and up to 7 days.
  • the infusion solution is stable after its production at a temperature of 2 °C to 8 °C for the aforementioned periods of time, optionally at a relative humidity (when stored) of 60% and /or optionally with the exclusion of light.
  • the diluting solution is a sodium chloride or a glucose solution.
  • the sodium chloride solution is a 0.9% sodium chloride solution with the solvent water or if the glucose solution is a 5% glucose solution with the solvent water.
  • the dilution solution is a sodium chloride solution, in particular a 0.9% sodium chloride solution with the solvent water.
  • the dilution solution contains a second antioxidant, it being particularly preferred in this connection if the second antioxidant is the same as the first antioxidant of the Peinetrexed concentrate solution. If a second antioxidant is included in the dilution solution, the stability of the resulting infusion solution can be further improved.
  • solvent of the pemetrexed concentrate solution is selected from the group consisting of water, polyethylene glycol and ethanol and mixtures of two or more of the solvents mentioned. It was found that the solvents or solvent mixtures mentioned have good dissolving properties for the active substance and the first antioxidant, do not adversely affect the stability of the active substance pemetrexed and do not promote particle formation in the concentrate solution.
  • the solvent of the concentrate solution is water.
  • the pemetrexed in the concentrate solution in the form of its
  • Pemetrexed disodium salt is contained dissolved.
  • Pemetrexed disodium salt has relatively good solubility properties.
  • pemetrexed concentrate solutions with a relatively high
  • Pemetrexed concentration are provided that show a high stability of the active ingredient and do not tend to cloudiness or the formation of precipitation. Such concentrates have a high level of patient acceptance and can be handled easily and safely by medical personnel.
  • the content of the concentrate solution of pemetrexed or of a pharmaceutically acceptable salt thereof (based on the free pemetrexed) is 0.1 mg/ml to 100 mg/ml, more preferably 5 mg /ml to 80 mg/ml, more preferably 10 mg/ml to 50 mg/ml and more preferably 20 mg/ml to 40 mg/ml.
  • the concentrate solution shows only a relatively low tendency to particle formation and thus associated turbidity of the solution or formation of precipitate.
  • the content of the concentrate solution of pemetrexed or a pharmaceutically acceptable salt thereof (based on the free pemetrexed) is 10 mg/ml, 20 mg/ml, 25 mg/ml, 40 mg /ml or 50 mg/ml.
  • the content of the infusion solution of pemetrexed or a pharmaceutically acceptable salt thereof (based on the free pemetrexed) is 2 mg/ml to 15 mg/ml, preferably 3 mg/ml to 13mg/ml.
  • the infusion solution shows a relatively high stability in the concentration intervals mentioned.
  • the antioxidant is acetylcysteine. It was found that acetylcysteine (or N-acetyl-L-cysteine) in the concentrate solution and thus ultimately also in the infusion solution causes a relatively high stability of the pemetrexed and that a corresponding concentrate solution/infusion solution can be stored for a relatively long time without that it becomes cloudy or even a precipitate forms from it or that the active substance concentration falls below the required value of the stability criterion.
  • acetylcysteine is contained as an antioxidant in the concentrate solution, the concentrate solution and the infusion solution having a pH in the range of 7.5 to 11.5, more preferably a pH in the range of 8.0 to 10.5 and even more preferably a pH in the range of 8.2 to 8.2 10.5. It was found that the active ingredient is characterized by a relatively high stability in the stated pH value ranges, in particular with regard to oxidative degradation, both in the concentrate solution and in the infusion solution.
  • the antioxidant is sodium 2-mercaptoethanesulfonate. It was found that sodium 2-mercaptoethanesulfonate in the concentrate solution and in the infusion solution causes a relatively high stability of the pemetrexed and that a corresponding concentrate solution and the resulting infusion solution can be stored for a relatively long time.
  • the concentrate solution and the infusion solution have a pH value in a range from 7.5 to 11.5, more preferably a pH in a range of 8.0 to 10.5, more preferably a pH in a range of 8.0 to 10.0 and further preferably a pH in a range of 8.3 to 9.3. It was found that the active substance in the concentrate solution and in the infusion solution is characterized by a relatively high stability, in particular with regard to oxidative degradation, at the pH value intervals mentioned.
  • the The antioxidant content of the concentrate solution is 0.1 mg/ml to 100 mg/ml, more preferably 0.5 mg/ml to 20 mg/ml, even more preferably 1.0 mg/ml to 5 mg/ml and more preferably 1 mg/ml to 3 mg/ml. It was found that the active substance in the concentrate solution and in the infusion solution is characterized by a relatively high stability, in particular with regard to oxidative degradation, with regard to the concentration intervals mentioned for the concentrate solution.
  • the concentrate solution also comprises one or more pharmaceutical excipients selected from the group consisting of salts, carbohydrates for toning, chelating agents for complexing heavy metals, acids for pH adjustment, bases for pH adjustment, buffer substances and preservatives for microbial preservation of the solution.
  • pharmaceutical excipients selected from the group consisting of salts, carbohydrates for toning, chelating agents for complexing heavy metals, acids for pH adjustment, bases for pH adjustment, buffer substances and preservatives for microbial preservation of the solution.
  • the concentrate solution contains mannitol for toning.
  • the dilution solution contains an antimicrobial preservative. Accordingly, the resulting infusion solution then also contains the antimicrobial preservative, which is why longer storage of the prepared infusion solution is unproblematic from a microbial point of view.
  • a typical subject provided by the present invention relates to the use of a liquid pharmaceutical concentrate solution comprising - water as a solvent;
  • pemetrexed or a pharmaceutically acceptable salt thereof, in particular pemetrexed disodium; such as
  • Another typical object provided by the present invention relates to the use of a liquid pharmaceutical concentrate solution comprising
  • pemetrexed or a pharmaceutically acceptable salt thereof, in particular pemetrexed disodium; such as
  • Another object provided by the present invention relates to a method for producing a pemetrexed infusion solution, wherein - providing a liquid pharmaceutical concentrate solution comprising: - a solvent; - pemetrexed or a pharmaceutically acceptable salt thereof; and - acetylcysteine and/or sodium 2-mercaptoethanesulfonate as a first antioxidant, - a dilution solution is added to the concentrate solution or the concentrate solution is added to a dilution solution, and - the resulting mixture of concentrate solution and dilution solution is stored for at least 12 hours.
  • the mixture obtained from the concentrate solution by adding a dilution solution has high stability, so that it can be used as an infusion solution even after storage for at least 12 hours. Larger quantities of infusion solution can thus be produced from the concentrate solution, as these can still be used 12 hours after production.
  • the resulting mixture of concentrate solution and dilution solution is stored for longer than 24 hours, according to another embodiment longer than 30 hours, according to another embodiment longer than 36 hours and according to yet another embodiment longer than 48 hours.
  • the resulting mixture of concentrate solution and dilution solution is longer than 48 hours, according to another embodiment longer than 60 hours and according to yet another embodiment longer than 72 hours.
  • the resulting mixture of concentrate solution and dilution solution is stored for longer than 84 hours, according to another embodiment longer than 96 hours, and according to yet another embodiment longer than 110 hours.
  • the resulting mixture of concentrate solution and dilution solution is stored for up to 100 days, according to a further embodiment for up to 80 days, and according to a still further embodiment for up to 50 days.
  • the resulting mixture of concentrate solution and dilution solution is stored for up to 35 days, in another embodiment for up to 28 days, and in yet another embodiment for up to 21 days.
  • the resulting mixture of concentrate solution and dilution solution is stored for up to 14 days, and according to a further embodiment for up to 7 days.
  • the resulting mixture of concentrate solution and dilution solution is stored at a temperature of 2°C to 8°C.
  • the resulting mixture of concentrate solution and dilution solution is stored at a relative humidity of 60%, and according to a further embodiment, the resulting mixture of concentrate solution and dilution solution is stored with the exclusion of light. According to a particularly preferred embodiment, the resulting mixture of concentrate solution and dilution solution is stored at a temperature of 2° C. to 8° C. and with the exclusion of light.
  • the dilution solution is a sodium chloride or a glucose solution.
  • the sodium chloride solution is a 0.9% sodium chloride solution with the solvent water or if the glucose solution is a 5% glucose solution with the solvent water.
  • the dilution solution is a sodium chloride solution, in particular a 0.9% sodium chloride solution with the solvent water.
  • the dilution solution contains a second antioxidant, it being particularly preferred in this connection if the second antioxidant is the same as the first antioxidant of the concentrate solution.
  • the solvent of the concentrate solution is selected from the group consisting of water, polyethylene glycol and ethanol and from mixtures of two or more of the solvents mentioned.
  • the solvent of the concentrate solution is water.
  • the pemetrexed is contained dissolved in the concentrate solution in the form of its disodium salt.
  • the content of pemetrexed or a pharmaceutically acceptable salt thereof (based on the free pemetrexed) in the concentrate solution is 0.1 mg/ml to 100 mg/ml, more preferably 5 mg /ml to 80 mg/ml, more preferably 10 mg/ml to 50 mg/ml and more preferably 20 mg/ml to 40 mg/ml.
  • the content of the concentrate solution of pemetrexed or of a pharmaceutically acceptable salt thereof (based on the free pemetrexed) is 10 mg/ml, 20 mg/ml, 25 mg/ml, 40 mg /ml or 50 mg/ml.
  • the content of the resulting mixture of concentrate solution and dilution solution or the infusion solution of pemetrexed or of a pharmaceutically acceptable salt thereof (based on the free pemetrexed) is 2 mg/ml to 15 mg/ml. ml, preferably 3 mg/ml to 13 mg/ml.
  • the antioxidant is acetylcysteine.
  • the concentrate solution and the resulting mixture of concentrate solution and dilution solution or the infusion solution have a pH in the range from 7.5 to 11 ,5, more preferably a pH in a range of 8.0 to 10.5 and even more preferably a pH in a range of 8.2 to 10.5.
  • the antioxidant is sodium 2-mercaptoethanesulfonate.
  • the concentrate solution and the resulting mixture of concentrate solution and dilution solution or the infusion solution have a pH value in a range of 7, 5 to 11.5, more preferably a pH in a range of 8.0 to 10.5, even more preferably a pH in a range of 8.0 to 10.0 and further preferably a pH in a range of 8.3 to 9.3.
  • the antioxidant content of the concentrate solution is 0.1 mg/ml to 100 mg/ml, more preferably 0.5 mg/ml to 20 mg/ml, even more preferably 1 0 mg/ml to 5 mg/ml and more preferably 1 mg/ml to 3 mg/ml.
  • the concentrate solution also comprises one or more pharmaceutical excipients selected from the group consisting of salts, carbohydrates for toning, chelating agents for complexing heavy metals, acids for pH adjustment, bases for pH adjustment, buffer substances and preservatives for microbial preservation of the solution.
  • pharmaceutical excipients selected from the group consisting of salts, carbohydrates for toning, chelating agents for complexing heavy metals, acids for pH adjustment, bases for pH adjustment, buffer substances and preservatives for microbial preservation of the solution.
  • the concentrate solution contains mannitol for toning.
  • the dilution solution contains an antimicrobial preservative.
  • the resulting mixture of concentrate solution and dilution solution or the resulting infusion solution then also contains the antimicrobial preservative.
  • the concentrate is provided in a hermetically sealed container.
  • the hermetically sealed container According to one embodiment, the hermetically sealed
  • Containers formed from a material that is impermeable to oxygen.
  • the hermetically sealed container is made of glass.
  • the hermetically sealed container is a vial. Vials are known from the prior art. These are so-called injection bottles, which are often in the form of vials with a plastic stopper and an aluminum flanged cap, with the plastic stopper having its smallest thickness in the middle for easier piercing.
  • the dilution solution is provided in a hermetically sealed container.
  • the hermetically sealed container is preferably formed of a material that is not permeable to oxygen.
  • the hermetically sealed container is a plastic container, preferably a flexible plastic bag.
  • the dilution solution is added to the concentrate solution with the exclusion of air, in particular the exclusion of oxygen.
  • one of the solutions can be removed by means of a syringe from a first hermetically sealed container which contains one of the solutions, concentrate or dilution solution.
  • the syringe can be fitted with a needle and the needle can be stuck through the wall of the container.
  • the container can be provided with a device, for example a stopper, in particular a plastic stopper, which can be pierced particularly easily with a needle.
  • the respective solution can also be transferred, for example, using a line made of a material that is not permeable to oxygen.
  • a typical concentrate is a solution comprising water as the solvent, 10 mg/ml to 50 mg/ml pemetrexed disodium salt
  • the solution having a pH of 8.0 to 10, 5 and preferably a pH of 8.5 to 10.5.
  • Another typical concentrate is a solution comprising
  • Disodium salt (based on the free pemetrexed) and 0.5 mg/ml to 20 mg/ml and preferably 1.0 mg/ml to 5 mg/ml 2 -
  • Mercaptoethanesulfonate sodium as an antioxidant wherein the solution has a pH of 8.0 to 10.0 and preferably a pH of 8.3 to 9.3.
  • a further object provided by the present invention relates to an infusion solution as obtained with the method described above.
  • a further object provided by the present invention relates to the use of the infusion solution as described above for the treatment of lung cancer.
  • the infusion solution is used for the treatment of malignant pleural mesothelion or advanced non-small cell lung cancer of the non-squamous type
  • 1 ml of pemetrexed concentrate solution contains:
  • Example 1 For the preparation of the composition according to Example 1 in a 30 liter batch, 90% of the required amount of water for injection purposes (20° C. to 25° C.) was placed in the batch tank and then gassed with nitrogen for at least 10 minutes until the oxygen content was ⁇ 0.5 mg/l lay.
  • the total amount of acetylcysteine was introduced into the template while stirring and stirred until complete dissolution. Thereafter, the total amount of mannitol was introduced into the template with stirring and stirred until complete dissolution.
  • the pH was adjusted to a pH of 9.0 +/- 0.1 with 10% (w/w) sodium hydroxide solution and, if necessary, with 10% (w/w) hydrochloric acid. Thereafter, the total amount of pernetrexed disodium was introduced into the solution thus obtained with stirring and stirred until complete dissolution.
  • the pH was then adjusted to pH 9.0 +/- 0.1 with 10% (w/w) sodium hydroxide solution and optionally with 10% (w/w) hydrochloric acid.
  • the resulting formulation was made up to the desired final weight/volume with water for injections and stirred until dissolved.
  • the pH was then adjusted to pH 9.0 +/- 0.1 with 10% (w/w) sodium hydroxide solution and, if necessary, with 10% (w/w) hydrochloric acid.
  • the batch obtained in this way was then gassed with nitrogen for at least 10 minutes until the oxygen content was ⁇ 0.5 mg/l.
  • the batch solution obtained in this way was blanketed with nitrogen in the batch vessel and sealed tightly. After taking the in-process control sample, the solution was sterile filtered (20 °C to 25 °C) through sterilized
  • the solution (20 °C to 25 °C) was filled under aseptic conditions in 20.50 ml portions into heat-sterilized 20R DIN vials (Fiolax glass; 500 mg).
  • the vial was pre-, filling- and post-gassing with sterile nitrogen. After putting on the hollow stopper and crimping the vial, after washing the outside, drying and checking for leaks (upside down storage; 12 hours), terminal sterilization was carried out in the final container (121 °C, 20 min) before storage at 2 °C to 8 °C.
  • Example 2
  • Infusion solutions with a concentration of 3.5 mg/ml, 7.0 mg/ml or 12.5 mg/ml pemetrexed (calculated as free pemetrexed; is present in the infusion solution as pemetrexed disodium) were prepared.
  • a total of six infusion bags with infusion solution were prepared for each of the specified pemetrexed concentrations, one for each measuring point of the storage period (cf. tables in example 3).
  • the infusion solutions/infusion bags prepared in this way were stored at a temperature of 2° C. to 8° C. with the exclusion of light.
  • the infusion solutions prepared according to Example 2 were after the respective storage period based on the monograph no. 10.0/2637 (title: "Pemetrexed disodium pentahydrate") of the European Pharmacopoeia Ph. Eur 5214 to 5217 by means of HPLC for their pemetrexed content and for their content of pemetrexed Impurities examined (the pemetrexed impurities A to D given below in Tables 1 to 3 are chemically specified in the aforementioned monograph).
  • Pemetrexed was separated using an RP-C8 phase column and directly quantified using UV detection at 285 nm.
  • Pemetrexed disodium heptahydrate CRS was dissolved in water for chromatography R to 200.0 ml.
  • Acetate buffer 1.7 ml of acetic acid 99% R and 900 ml of water for chromatography R were mixed.
  • the solution was adjusted to pH 5.3 with a solution of sodium hydroxide R (760 g -1 ) in chromatographic water R and diluted with chromatographic water R to 1000 ml.
  • Solution A Solution of ammonium formate R (1.45 gl -1 ) in chromatographic water R adjusted to pH 3.5 with anhydrous formic acid R.
  • Reference solution a 20 mg pemetrexed disodium heptahydrate CRS
  • Reference solution b For the preparation of impurities B and C in situ, 30 mg pemetrexed disodium heptahydrate CRS
  • Reference solution c The contents of a vial containing the
  • Pemetrexed impurity mixture CRS (impurities A and D) was dissolved in 1.0 mL of chromatographic water R.
  • Impurity identification The supplied chromatogram of the pemetrexed impurity mixture CRS and the chromatogram obtained with reference solution c were used to identify the peaks of impurities A and D. The chromatogram obtained with reference solution b was used to identify the peaks of impurities B and C.
  • Sample solutions the infusion solutions were diluted to a nominal pemetrexed concentration of 0.2 mg/ml using water for HPLC R prior to their HPLC measurement.
  • concentration of pemetrexed disodium heptahydrate in reference solution a was used to calculate the percentages for each impurity.

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

Abstract

La présente invention concerne l'utilisation d'une solution de concentré pharmaceutique liquide, comprenant : un solvant ; du Pemetrexed ou un de ses sels pharmaceutiquement acceptables ; et de l'acétylcystéine et/ou 2-mercaptoéthanesulfonate de sodium en tant que premier agent antioxydant. L'invention vise à proposer une utilisation de ladite solution de concentré, qui permet d'obtenir une valeur d'utilisation relativement élevée pour l'utilisateur. À cet effet, la solution de concentré est utilisée pour la préparation d'une solution de perfusion au moyen d'une solution de dilution, la solution de perfusion étant stable après sa production pendant une durée supérieure à 72 heures.
EP22707096.8A 2021-02-21 2022-02-18 Utilisation d'une solution de concentré de pemetrexed Pending EP4294365A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP21158312.5A EP4046626A1 (fr) 2021-02-21 2021-02-21 Utilisation d'une solution concentrée de pemetrexed
PCT/EP2022/054099 WO2022175463A1 (fr) 2021-02-21 2022-02-18 Utilisation d'une solution de concentré de pemetrexed

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EP4294365A1 true EP4294365A1 (fr) 2023-12-27

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EP21158312.5A Pending EP4046626A1 (fr) 2021-02-21 2021-02-21 Utilisation d'une solution concentrée de pemetrexed
EP22707096.8A Pending EP4294365A1 (fr) 2021-02-21 2022-02-18 Utilisation d'une solution de concentré de pemetrexed

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EP (2) EP4046626A1 (fr)
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Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102012010774A1 (de) 2012-05-31 2013-12-05 Stada Arzneimittel Ag Pharmazeutische Pemetrexed-Lösung
US10966982B2 (en) * 2018-11-20 2021-04-06 Cipla Limited Stable pharmaceutical formulations of pemetrexed

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EP4046626A1 (fr) 2022-08-24

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