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WO2023078171A1 - Composition pharmaceutique liquide contenant du fosaprépitant, son procédé de préparation et son utilisation - Google Patents

Composition pharmaceutique liquide contenant du fosaprépitant, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2023078171A1
WO2023078171A1 PCT/CN2022/128205 CN2022128205W WO2023078171A1 WO 2023078171 A1 WO2023078171 A1 WO 2023078171A1 CN 2022128205 W CN2022128205 W CN 2022128205W WO 2023078171 A1 WO2023078171 A1 WO 2023078171A1
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WO
WIPO (PCT)
Prior art keywords
fosaprepitant
pharmaceutical composition
liquid pharmaceutical
composition containing
acid
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.)
Ceased
Application number
PCT/CN2022/128205
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English (en)
Chinese (zh)
Inventor
陈志祥
金海刚
郭桢
付俊
王婷婷
应述欢
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.)
Shanghai Bocimed Pharmaceutical Co Ltd
Original Assignee
Shanghai Bocimed Pharmaceutical Co Ltd
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 Shanghai Bocimed Pharmaceutical Co Ltd filed Critical Shanghai Bocimed Pharmaceutical Co Ltd
Priority to CN202280047203.9A priority Critical patent/CN117693347B/zh
Publication of WO2023078171A1 publication Critical patent/WO2023078171A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

Definitions

  • the invention relates to a liquid pharmaceutical composition containing fosaprepitant, its preparation method and application.
  • Nausea and vomiting is a common adverse reaction during or after cancer chemotherapy. This syndrome can have a significant impact on patients' functional status and quality of life, and patients may postpone chemotherapy plans and sometimes even refuse treatment because of CINV . Emetogenic reactions may be acute (within 24 hours after chemotherapy) or delayed (after 24 hours after chemotherapy). The underlying mechanisms of acute and delayed emesis are thought to be different. Current therapies include serotonin HT3 receptor antagonists such as ondansetron, tropisetron, and granisetron, and the dopamine receptor antagonist metoclopramide. These compounds had sufficient effect on acute CINV but not on delayed CINV.
  • Fosaprepitant dimeglumine is an active pharmaceutical ingredient for injection marketed by Merck Sharp & Dohme Corp.
  • Fosaprepitant is a water-soluble phosphorylated prodrug of aprepitant that is rapidly converted to aprepitant in vivo after intravenous (IV) administration.
  • Aprepitant is an antagonist of the human substance P neurokinin 1 (NK1) receptor.
  • NK1 human substance P neurokinin 1
  • fosaprepitant (or its salt) will be hydrolyzed into water-insoluble aprepitant under aqueous environment and high temperature conditions, even in solid state, such as in freeze-dried preparations, when the moisture control is not good, fusapitant Saprepitant remains hydrolytically degraded to form aprepitant. Therefore, in order to prevent crystallization and precipitation caused by aprepitant formed by the hydrolytic degradation of potential fosaprepitant during the shelf life of the product, the formulation of fosaprepitant dipglumine for injection contains polysorbate 80, as Solubilizer of aprepitant; and moisture control is very strict.
  • polysorbate 80 (a nonionic surfactant often used as a solubilizer for low-solubility products) can cause various adverse reactions, including severe infusion site reactions and potentially life-threatening allergic reactions; The possible protein residues in excipients and excipients will cause allergies, and the risk is high; the moisture control of freeze-dried products is strict, which makes the freeze-drying process difficult and consumes a lot of energy.
  • the invention provides a liquid pharmaceutical composition containing fosaprepitant, which comprises: a pharmaceutical active ingredient, a chelating agent, a stabilizer and a pH regulator, and the pharmaceutical active ingredient is fosaprepitant, which can be used pharmaceutically Accepted salt, hydrate or solvate; said liquid pharmaceutical composition containing fosaprepitant does not contain polysorbate 80 and lactose.
  • the pharmaceutically acceptable salt of fosaprepitant is preferably fosaprepitant dipeglumine salt.
  • the drug loading of the active ingredient of the drug is 1 mg/ml to 400 mg/ml, more preferably 3 mg/ml to 200 mg/ml, and the drug loading refers to that of fosaprepitant The ratio of the mass to the volume of the liquid pharmaceutical composition containing fosaprepitant.
  • the chelating agent is selected from one or more of citric acid, tartaric acid, gluconic acid and ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof; in one embodiment, The chelating agent is disodium edetate.
  • the mass ratio of the chelating agent to the active pharmaceutical ingredient is 1:8 to 1:56 (w/w), such as 1:50, 1:45, 1:40, 1:30, so The quality of the above-mentioned pharmaceutical active ingredients is based on the mass of fosaprepitant.
  • the stabilizer is selected from one or more of oleic acid, sodium oleate, acetate, carbonate, phosphate, citrate, tartrate and borate , preferably one or more of oleic acid, sodium oleate and phosphate.
  • the stabilizer is selected from oleic acid and/or sodium oleate.
  • the stabilizer is selected from one or more of acetate, carbonate, phosphate, citrate, tartrate and borate, preferably phosphate.
  • the stabilizer is selected from a mixture of oleic acid and phosphate, or a mixture of sodium oleate and phosphate.
  • the phosphate may be selected from one or both of disodium hydrogen phosphate and sodium dihydrogen phosphate, preferably disodium hydrogen phosphate.
  • the pH regulator is selected from hydrochloric acid, sulfuric acid, phosphoric acid, glutamic acid, aspartic acid, sodium hydroxide, tromethamine, arginine, lysine, histidine , one or more of meglumine.
  • the pH value of the liquid pharmaceutical composition containing fosaprepitant is in the range of 7.0-10.0, more preferably 7.5-9.5, such as 8.0, 8.5, 8.8, 9.0.
  • the amount of the stabilizer is 0.5-20% (W/V), such as 1-20% (W/V), such as 1-10% (W/V), the amount Refer to the percentage of the mass (g) of stabilizer and the total volume (mL) of the liquid pharmaceutical composition containing fosaprepitant;
  • the amount of oleic acid and/or sodium oleate is preferably 0.5-10% (W/V); In some embodiments, the amount of oleic acid and/or sodium oleate is 1-5% (W/V), such as 1.44% (W/V), 2% (W/V), 2.11% ( W/V), 2.88% (W/V), 4.23% (W/V);
  • the stabilizer when the stabilizer is selected from one or more of acetate, carbonate, phosphate, citrate, tartrate and borate, the acetate , carbonate, phosphate, citrate, tartrate and borate in an amount of one or more is preferably 0.5 to 10% (W/V); In some embodiments, the acetic acid The amount of one or more of salt, carbonate, phosphate, citrate, tartrate and borate is 1-5% (W/V), such as 1.6% (W/V), 2 %(W/V), 3%(W/V), 4%(W/V).
  • the fosaprepitant liquid pharmaceutical composition can be selected from any one of the following formulations:
  • Formulation 1 12.265% (W/V) fosaprepitant dimeglumine, 0.27% (W/V) EDTA-2Na, 1.44% (W/V) oleic acid, and adjust the pH with 0.1M/1.0M NaOH , pH 8.5 ⁇ 9.5.
  • Formulation 2 12.265% (W/V) Fosaprepitant Diglumine, 0.27% (W/V) EDTA-2Na, 2.88% (W/V) Oleic Acid, 3% (W/V) Dihydrogen Phosphate Sodium, and adjust the pH with 1.0M NaOH, pH 8.0-9.5.
  • the present invention also provides the application of the liquid pharmaceutical composition containing fosaprepitant in the preparation of pharmaceutical preparations.
  • the present invention also provides a pharmaceutical preparation, which contains the above-mentioned liquid pharmaceutical composition containing fosaprepitant.
  • the administration of the pharmaceutical preparation is parenteral administration, such as injection administration.
  • the pharmaceutical preparation can be an injection; clinically, intravenous infusion can be used. If intravenous infusion is used, it can be diluted with normal saline.
  • the dilution factor of the physiological saline is preferably 25 times to 500 times, more preferably 50 times to 125 times.
  • the pharmaceutical preparation may include a packaging material
  • the packaging material may be plastic, borosilicate glass or coated borosilicate glass.
  • plastic is selected from PVC (polyvinyl chloride), PP (polypropylene), PE (polyethylene), COP (cyclic olefin polymer), COC (cyclic olefin copolymer) and Aclar (Aclar, chlorotrifluoroethylene) One or more of copolymers and homopolymers).
  • the pharmaceutical preparation is used for treating diseases caused by NK-1 receptors, and the diseases caused by NK-1 receptors include but not limited to emesis.
  • the present invention also provides the application of the liquid pharmaceutical composition containing fosaprepitant in the preparation of NK-1 receptor antagonist.
  • the present invention also provides a method for treating diseases caused by NK-1 receptors, which is to take an effective dose of the fosaprepitant-containing liquid pharmaceutical composition or the pharmaceutical preparation to a patient in need.
  • diseases caused by NK-1 receptor include but not limited to vomiting.
  • the liquid pharmaceutical composition containing fosaprepitant of the present invention has simple preparation process, good physical and chemical stability, convenient clinical use without reconstitution, low risk of microbial contamination in the preparation process, and is suitable for Advantages of industrial production.
  • % (W/V) refers to the percentage of the mass (g) of the component to the total volume (mL) of the liquid pharmaceutical composition containing fosaprepitant.
  • therapeutically effective amount refers to an amount of a pharmaceutically active ingredient of the invention sufficient to achieve the intended use, including but not limited to the treatment of diseases as defined below.
  • a therapeutically effective amount may vary depending on the intended application (in vitro or in vivo), or the subject and the disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, etc., which can be readily determined by one of ordinary skill in the art.
  • the specific dosage will vary depending upon the particular active ingredient chosen, the dosing regimen upon which it is administered, whether it is administered in combination with other compounds, the timing of administration, the tissue administered and the physical delivery system employed .
  • Prescription 1 Prescription 2
  • Prescription 3 Fosaprepitant Diglumine mg 245.3 245.3 245.3 EDTA-2Na mg 5.4 5.4 5.4 Oleic acid mg 28.8 28.8 28.8 0.1mol/LNaOHml 1 1 1 pH regulator qs pH 8.79 qs pH 9.00 qs pH 9.29 Dilute to ml 2 2 2
  • An exemplary preparation method for forming stable fosaprepitant compositions of prescriptions 1 to 3 is described here: after adding prescription amounts of EDTA-2Na, oleic acid, and 0.1M sodium hydroxide solution, according to the dissolution of the solution, add 1M Sodium hydroxide solution, until stirring and dissolving, then add API (fosaprepitant dimeglumine), and adjust to the target pH value with 1M NaOH/20% HCl diluent.
  • the prepared medicinal solution is pre-filtered with a 0.45 ⁇ m filter element, filled and sealed to obtain the final product.
  • Stability of simulated stability lofting place at 60°C for 24 hours, and temporarily store in a refrigerator at 2-8°C. Observe the appearance of stability samples before and after refrigeration, and detect related substances after refrigeration. The test results are shown in Table 2.
  • the prepared medicinal solution is pre-filtered with a 0.45 ⁇ m filter element, filled and sealed to obtain the final product.
  • the prepared medicinal solution is pre-filtered with a 0.45 ⁇ m filter element, filled and sealed to obtain the final product.
  • prescription 14 cementitrate buffer solution
  • prescription 15 tartaric acid buffer solution
  • prescription 16 boric acid buffer solution
  • the prepitant content is basically 0.2-0.3%), especially the prescription 14,0h aprepitant content is 0.99%, much higher than other prescriptions.
  • prescription 14-citrate buffer solution and prescription 15-tartrate buffer solution had the highest aprepitant content, exceeding 4%.
  • the slowest increase in aprepitant content was in the prescription 11-phosphate buffer system, and the final aprepitant content was the lowest, which was 3.32%.
  • the increase of aprepitant is the least, and the system is the most stable.
  • the prescription (prescription 4) of oleic acid alone has a clear and transparent appearance and good physical stability.
  • the stability was further improved, and the growth rate of aprepitant was significantly reduced. It shows that the phosphate root system has a certain stabilizing effect on the stability of the product, and the greater the concentration, the more stable the system.
  • the above prescription was prepared according to the preparation method in Implementation 2.
  • the product was placed upside down and placed at high temperatures of 25°C and 40°C to test its stability.
  • it is compared with the marketed preparation (trade name EMEND, licensee: MERCK SHARP&DOHME CORP., manufacturer Patheon Manufacturing Services LLC, batch number: T037941).
  • the data are shown in Table 11.
  • *Aprepitant is the active ingredient, calculated by area normalization and not included in the total miscellaneous calculation.
  • Sample stability of simulated clinical dilution use the above 40°C-10 day prescription 21 samples, dilute 75 times with 0.9% sodium chloride, place at 25°C, take samples at 0, 4, 8, and 24 hours respectively, and observe the diluted samples The appearance of the diluted drug solution was detected to detect the fosaprepitant content and related substances.
  • *Aprepitant is the active ingredient, calculated by area normalization and not included in the total miscellaneous calculation.
  • the test results of the stability of the diluent showed that the content of API was stable, the aprepitant remained basically unchanged, the growth of total impurities was small, and the stability of the diluent was good.
  • Prescription 21 After Prescription 21 is placed at a high temperature of 80°C for 4 hours, observe the appearance and detect related substances. Simulate the stability of the clinically diluted sample, dilute it 75 times with 0.9% sodium chloride, place it at 25°C, take samples at 0, 14, and 24 hours respectively, observe the appearance of the diluted sample, and detect the related substances of the diluted medicinal solution.
  • the commercial preparation (trade name EMEND, licensee: MERCK SHARP&DOHME CORP., manufacturer Patheon Manufacturing Services LLC, batch number: T037941) was used for comparison.
  • *Aprepitant is the active ingredient, calculated by area normalization and not included in the total miscellaneous calculation.
  • the liquid pharmaceutical composition containing fosaprepitant provided by the present invention has a simple preparation process, although the active ingredient aprepitant is increased, the physical and chemical stability is still good, and the physical and chemical stability of the administered sample after simulating clinical dilution is simple. Both chemical stability was good.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composition pharmaceutique liquide contenant du fosaprépitant, son procédé de préparation et son utilisation. La composition pharmaceutique liquide contenant du fosaprépitant comprend un principe actif pharmaceutique, un agent chélatant, un agent stabilisant et un régulateur de pH. Le principe actif pharmaceutique comprend du fosaprépitant, et un sel, un hydrate ou un solvate pharmaceutiquement acceptable de la composition pharmaceutique liquide contenant du fosaprépitant. La composition pharmaceutique liquide contenant du fosaprépitant ne contient pas de polysorbate 80 et de lactose. La composition pharmaceutique liquide contenant du fosaprépitant présente les avantages d'un procédé de préparation simple, d'une bonne stabilité physique et chimique, d'une commodité d'utilisation clinique, d'une non-nécessité de redissolution, d'un faible risque de pollution microbienne dans le procédé de préparation, d'une adéquation à la production industrielle, et similaires.
PCT/CN2022/128205 2021-11-02 2022-10-28 Composition pharmaceutique liquide contenant du fosaprépitant, son procédé de préparation et son utilisation Ceased WO2023078171A1 (fr)

Priority Applications (1)

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CN202280047203.9A CN117693347B (zh) 2021-11-02 2022-10-28 含福沙匹坦的液体药物组合物、其制备方法及应用

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CN202111286261.0 2021-11-02

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TW (1) TW202333742A (fr)
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104042572A (zh) * 2013-03-12 2014-09-17 江苏奥赛康药业股份有限公司 一种含福沙匹坦二甲葡胺的注射用组合物及其制备方法
CN104414980A (zh) * 2013-08-22 2015-03-18 成都苑东药业有限公司 一种注射用福沙匹坦二甲葡胺组合物及其制备方法
CN106943358A (zh) * 2016-01-06 2017-07-14 山东新时代药业有限公司 福沙匹坦二甲葡胺冻干粉针及其制备方法
US20170216205A1 (en) * 2016-02-01 2017-08-03 Heron Therapeutics, Inc. Emulsion formulations of an nk-1 receptor antagonist and uses thereof
CN112243376A (zh) * 2018-05-18 2021-01-19 美国司贝士制药公司 福沙匹坦的组合物和制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10610532B2 (en) * 2015-08-03 2020-04-07 Leiutis Pharmaceuticals Pvt. Ltd. Liquid formulations of fosaprepitant
US20200316097A1 (en) * 2019-02-28 2020-10-08 Ravishanker Kovi Storage-stable ready-to-use injectable formulations of fosaprepitant dimeglumine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104042572A (zh) * 2013-03-12 2014-09-17 江苏奥赛康药业股份有限公司 一种含福沙匹坦二甲葡胺的注射用组合物及其制备方法
CN104414980A (zh) * 2013-08-22 2015-03-18 成都苑东药业有限公司 一种注射用福沙匹坦二甲葡胺组合物及其制备方法
CN106943358A (zh) * 2016-01-06 2017-07-14 山东新时代药业有限公司 福沙匹坦二甲葡胺冻干粉针及其制备方法
US20170216205A1 (en) * 2016-02-01 2017-08-03 Heron Therapeutics, Inc. Emulsion formulations of an nk-1 receptor antagonist and uses thereof
CN112243376A (zh) * 2018-05-18 2021-01-19 美国司贝士制药公司 福沙匹坦的组合物和制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MARK ALLEN T. BIBERA ET AL.,: "Potential cross-reactivity of polysorbate 80 and cremophor: A case report", JOURNAL OF ONCOLOGY PHARMACY PRACTICE, vol. 26, no. 5, 31 December 2020 (2020-12-31), pages 1279 - 1281, XP009546029 *

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CN117693347A (zh) 2024-03-12
TW202333742A (zh) 2023-09-01
CN117693347B (zh) 2025-07-25

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