WO2018049997A1 - Composition pharmaceutique à base de pemetrexed disodique et son procédé de préparation - Google Patents

Composition pharmaceutique à base de pemetrexed disodique et son procédé de préparation Download PDF

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Publication number
WO2018049997A1
WO2018049997A1 PCT/CN2017/100352 CN2017100352W WO2018049997A1 WO 2018049997 A1 WO2018049997 A1 WO 2018049997A1 CN 2017100352 W CN2017100352 W CN 2017100352W WO 2018049997 A1 WO2018049997 A1 WO 2018049997A1
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WO
WIPO (PCT)
Prior art keywords
pemetrexed disodium
pharmaceutical composition
injection
pemetrexed
water
Prior art date
Application number
PCT/CN2017/100352
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English (en)
Chinese (zh)
Inventor
李晓强
任晋生
钱勇
Original Assignee
南京先声东元制药有限公司
江苏先声药业有限公司
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Application filed by 南京先声东元制药有限公司, 江苏先声药业有限公司 filed Critical 南京先声东元制药有限公司
Publication of WO2018049997A1 publication Critical patent/WO2018049997A1/fr

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Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • 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

Definitions

  • the technical field of the pharmaceutical preparation of the invention relates to a pharmaceutical composition and a preparation method thereof, in particular to a pharmaceutical composition of pemetrexed disodium and a preparation method thereof.
  • Pemetrexed disodium its chemical name is: N-[4-[2-(2-amino-4,7-dihydro-4-carbonyl-1H-pyrrole[2,3-d]-pyrimidine-5 -yl)ethyl]benzoyl]-L glutamic acid disodium salt.
  • the molecular formula is: C20H19N5Na2O6.
  • Pemetrexed disodium 2.5 hydrate is clinically used, and its chemical structure is:
  • Pemetrexed is an antifolate preparation whose structure contains a pyrrolizidine group, which inhibits cell growth by disrupting the normal metabolic process of folate-dependent cells and inhibiting cell replication.
  • pemetrexed inhibits the activity of thymidylate synthase, dihydrofolate reductase, and glycinamide nucleotide formyltransferase, which are essential enzymes for the synthesis of folic acid and are involved in thymidine nucleus. Bioresynthesis of glycosides and purine nucleotides.
  • Pemetrexed enters the cell by a carrier carrying folic acid and a folate-binding protein transport system on the cell membrane.
  • pemetrexed Once pemetrexed enters the cell, it is converted to the form of polyglutamate by the action of folate polyglutamate synthetase.
  • Polyglutamate remains in the cell and becomes an inhibitor of thymidylate synthase and glycinamide nucleotide formyltransferase.
  • Polyglutamination exhibits a time-concentration-dependent process in tumor cells with a low concentration in normal tissues. The half-life of the polyglutamate metabolite in the tumor cells is prolonged, thereby prolonging the action time of the drug in the tumor cells.
  • pemetrexed It is speculated from the mechanism of action of pemetrexed that it should be a broad-spectrum anti-tumor drug. Preclinical and clinical studies have also shown that in addition to the two approved indications, pemetrexed has a certain effect on a variety of other solid tumors. Moreover, pemetrexed and more The combination of other anticancer drugs has synergistic effects and can reduce toxicity, which brings hope to some patients who suffer from drug resistance problems and have no suitable drugs available.
  • Pemetrexed disodium has poor stability, is prone to degradation under high temperature and oxidizing conditions, and produces impurities which may cause toxic side effects. It is not suitable for injections requiring high temperature sterilization, and thus pemetrexed disodium is usually It is made into lyophilized powder injection, but in the process of transportation and storage, the existing pemetrexed disodium lyophilized powder injection is often caused by the temperature control is not strict, resulting in a significant increase in the content of impurities in the lyophilized powder injection. There is no suggestion to improve the above deficiencies in the technical and public knowledge.
  • CN102525955A discloses a process for preparing pemetrexed disodium for injection.
  • the prescription is: pemetrexed disodium 200g, mannitol 200g, hydrochloric acid or sodium hydroxide and 10000mL of water for injection, the technical solution can not significantly improve the stability of the preparation.
  • CN102266298A discloses a pharmaceutical composition of pemetrexed disodium.
  • Formulation 110 parts of pemetrexed disodium, 60-105 parts of trehalose, 0-40 parts of lyophilized excipient; the excipient is selected from one or more of mannitol, sorbitol and lactose, preferably Mannitol.
  • the technical problem solved is that pemetrexed disodium is unstable and easily degraded, and it is conventional to add an antioxidant, but the stability of the solution is difficult to meet the requirements of the preparation, and the liquid preservation solution has the problem of degradation of the active ingredient and the increase of related substances, resulting in a decrease in efficacy. And the risk of adverse reactions.
  • Lilly has listed a lyophilized preparation, and mannitol is the only excipient with remarkable curative effect.
  • infusion of lyophilized powder for injection often occurs during infusion pain, and even local inflammatory reactions occur.
  • pemetrexed disodium sometimes needs to be combined with hormonal drugs or local anesthetics to reduce patients.
  • Most of the local stimulating effects of the drug are due to the strong irritancy of the main drug itself, but some cases are due to the compatibility between the main and auxiliary drugs, and the latter can be solved by changing the type and proportion of the auxiliary materials.
  • the amount of the auxiliary material used in the preparation is too large, which has a large influence on the main drug and is likely to cause side effects.
  • CN101411710A discloses a pemetrexed disodium lyophilized powder injection and a preparation method thereof. Prescription: 50 parts of pemetrexed disodium, 10 to 50 parts of mannitol, 0.1 to 1 part of sodium sulfite, pH 7-8.
  • the technical problem solved is that the stability of pemetrexed disodium is poor, and it is easy to be degraded under high temperature, oxidation and light conditions, and impurities which may cause toxic and side effects are generated, and the stability of the lyophilized preparation is poor, and the compatibility solution cannot be used in clinical use. Leave it for a long time. However, its freeze-drying is complicated and the production cost is high, so it is not suitable for promotion.
  • CN102106833A discloses a pemetrexed disodium lyophilized powder injection and a preparation method thereof.
  • the technical problem solved is that the stability of pemetrexed disodium is poor. It is prone to degradation under high temperature and oxidizing conditions to produce impurities which may cause toxic side effects, and is not suitable for supporting injection.
  • the existing pemetrexed disodium lyophilized powder needle is often used in transportation and storage process because of the temperature control is not strict. The content is significantly increased.
  • CN1907284A discloses a pharmaceutical composition of pemetrexed disodium containing pemetrexed and a stabilizer in a weight ratio of 5:2-7, and the stabilizer is selected from the group consisting of arginine, cysteine and methionine. Or glycine or the like, further may be added with a pharmaceutically acceptable excipient such as dextran, mannitol or lecithin, and preferably the excipient is mannitol in an amount of 0.5 to pemetrexed. 1:1, preferably 0.7:1.
  • the amount of amino acids used in the prior art is very large, increasing the cost of the drug and other invisible adverse factors.
  • the technical problem to be solved by the present invention is to provide a pharmaceutical composition of pemetrexed disodium having good stability, and in particular, the present invention provides a pharmaceutical composition of pemetrexed disodium, the pharmaceutical composition Containing pemetrexed disodium, a stabilizer and an excipient, wherein the weight ratio of pemetrexed disodium to the stabilizer is 50:0.5 to 5.0, and the weight ratio to the excipient is 50:5 to 50,
  • the stabilizer is selected from the group consisting of methionine and the excipient is selected from the group consisting of mannitol.
  • the pemetrexed disodium is a hydrate, preferably 2.5 hydrate.
  • the weight ratio of pemetrexed disodium to the stabilizer according to the present invention is It is preferably 50: 2.0 to 3.0, further preferably 50: 2.0, 50: 2.5, and 50: 3.0.
  • the weight ratio of pemetrexed disodium to the excipient is from 50:20 to 40, preferably from 50:25 to 35, further preferably from 50:28, 50:30 or 50:32.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be prepared by a lyophilization process to obtain a lyophilized powder injection.
  • the lyophilized powder injection is prepared by the following steps: stabilizing agent and excipient are dissolved in water for injection, adding pemetrexed disodium, stirring and dissolving, adding activated carbon to stir, filtering, and the filtrate is placed in a freeze dryer. Pre-freezing, to -30 ⁇ -40 ° C for 2.5 to 4 hours, preferably maintain In the hour, the vacuum is sublimated to obtain the powder injection.
  • the weight ratio of the water for injection to pemetrexed disodium is 0.05 to 100:1, preferably The amount of the activated carbon is 0.05 to 1% of the water for injection, preferably The activated carbon stirring time is 2 to 60 minutes, preferably Minute; the pre-freezing temperature is -20 ⁇ -40 ° C, preferably The vacuum sublimation time is 20 to 120 hours, preferably hour.
  • the technical solution of the present invention can be carried out by measuring the pemetrexed disodium content and measuring the impurities by a known method, such as the method described in CN102206218A.
  • the lyophilized powder preparation provided by the invention is suitable for human clinical application and veterinary use for animals.
  • cisplatin for the treatment of unresectable or surgically ineffective malignant pleural mesothelioma; single drug can treat locally advanced and metastatic non-small cell lung cancer after early chemotherapy.
  • the lyophilized preparation auxiliary material provided by the invention is easily available, does not contain other organic solvents, can be placed at room temperature, can be obtained by dilution with isotonic saline before use, and can be used for parenteral administration.
  • the invention achieves the requirement of pharmaceutically stable pemetrexed preparation which can be prepared for parenteral administration, has less dosage of preparation auxiliary materials, and has the advantages of stable color and long storage period, and avoids pemetrexed to the utmost extent. Degradation of adversely related substances.
  • the obtained product is a white-like block with a full shape and good resolubility.
  • the obtained product is a white-like block with a full shape and good resolubility.
  • the obtained product is a white-like block with a full shape and good resolubility.
  • the obtained product is a white-like block with a full shape and good resolubility.
  • the resulting product is light yellow with cracks.
  • the resulting product is light yellow with tiny particles on the surface.
  • the resulting product is light yellow, cracked, and sprayed.
  • the resulting product is light yellow, cracked, and sprayed.
  • the resulting product has collapse and voids.
  • the sample was taken, the label was removed, and the film was allowed to stand for 10 days under the light intensity of 4500 Lx, and samples were taken on the 5th day and the 10th day, respectively, and the appearance of the sample, the clarity of the solution, the impurities, and the content were examined.
  • the results show that the sample of the present invention has an impurity increase of no more than 4.1% after 10 days of intense light irradiation, and good stability results are obtained.
  • the samples were taken and placed at 60 ° C for 10 days, and samples were taken on the 5th and 10th days respectively, and the properties of the samples, the clarity and color of the solution, the impurities, and the contents were examined.
  • the results show that the sample of the present invention has an impurity increase of not more than 6% after 10 days at 60 ° C, and good stability results are obtained.

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

Abstract

Une composition pharmaceutique de pemetrexed disodique contient du pemetrexed disodique, un stabilisant et un excipient. Le rapport pondéral du pemetrexed disodique au stabilisant est de 50 : 0,5-5,0, et le rapport pondéral du pemetrexed disodique à l'excipient est de 50 : 5-50. Le stabilisant est choisi parmi la méthionine, et l'excipient est choisi parmi le mannitol.
PCT/CN2017/100352 2016-09-18 2017-09-04 Composition pharmaceutique à base de pemetrexed disodique et son procédé de préparation WO2018049997A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610828428.4 2016-09-18
CN201610828428.4A CN107837237B (zh) 2016-09-18 2016-09-18 一种培美曲塞二钠药物组合物及其制备方法

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WO2018049997A1 true WO2018049997A1 (fr) 2018-03-22

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1907284A (zh) * 2006-07-28 2007-02-07 南京依诺维医药科技有限公司 含有培美曲塞的药物组合物
WO2014167585A1 (fr) * 2013-04-12 2014-10-16 Actavis Group Ptc Ehf. Formulation de pemetrexed

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1907284A (zh) * 2006-07-28 2007-02-07 南京依诺维医药科技有限公司 含有培美曲塞的药物组合物
WO2014167585A1 (fr) * 2013-04-12 2014-10-16 Actavis Group Ptc Ehf. Formulation de pemetrexed

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CN107837237A (zh) 2018-03-27
CN107837237B (zh) 2019-11-05

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