WO2017198224A1 - Composition pharmaceutique de rémimazolam - Google Patents

Composition pharmaceutique de rémimazolam Download PDF

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Publication number
WO2017198224A1
WO2017198224A1 PCT/CN2017/085141 CN2017085141W WO2017198224A1 WO 2017198224 A1 WO2017198224 A1 WO 2017198224A1 CN 2017085141 W CN2017085141 W CN 2017085141W WO 2017198224 A1 WO2017198224 A1 WO 2017198224A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydroxyethyl starch
remiazolam
composition
solution
composition according
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/CN2017/085141
Other languages
English (en)
Chinese (zh)
Inventor
杨晓容
陈钟威
卢韵
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.)
Jiangsu Hengrui Medicine Co Ltd
Original Assignee
Jiangsu Hengrui Medicine 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 Jiangsu Hengrui Medicine Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Priority to CN201780004159.2A priority Critical patent/CN108289897B/zh
Publication of WO2017198224A1 publication Critical patent/WO2017198224A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • the present invention is in the field of pharmaceutical preparations, and in particular relates to a composition comprising remimagazole and a pharmaceutically acceptable salt thereof.
  • Remiazolam is a sedative superior to the similar products currently in use, with rapid onset and failure, stable sedation, short recovery time, short half-life, inactive metabolites, predictable pharmacokinetics, and wide therapeutic window
  • the potential for interaction between drugs is low, and flumazenil can reverse the sedative effect and will not calm again. It was developed to obtain a new drug that combines the active activities of midazolam and propofol while discarding related defects. According to the results of the study, remiazolam is superior to these two products already on the market and is a breakthrough new chemical entity that is highly likely to become the new gold standard in the field of sedation/anaesthesia.
  • CN101501019A discloses benzenesulfonate and its polymorphs, and discloses a series of possible compositions thereof, but does not disclose how to obtain a stable composition; CN103221414A discloses remarazol The p-toluenesulfonate and its polymorph, but no composition thereof are disclosed.
  • CN103202815A discloses a lyophilized formulation of remamazepine containing mannitol or glycine, but the concentration of remiazolam in such a solution before or after lyophilization Lower, the relative proportion of excipients is higher, and a large amount of solution is required for clinical use, which is very inconvenient.
  • CN104968348A discloses a combination of a benzodiazepine compound and at least one hygroscopic excipient, in particular lactose and/or dextran, but the excipient lactose is an animal-derived excipient due to possible residual impurities therein. Protein, there is a certain safety risk when injected in large quantities.
  • Rimamazol is hydrolyzed in aqueous solution as well as in long-term storage to produce inactive impurities as shown in formula (II), so it is necessary to provide a stable composition of remiazolam.
  • It is an object of the present invention to provide a composition comprising remimagazole or a pharmaceutically acceptable salt thereof and hydroxyethyl starch.
  • the hydroxyethyl starch may be selected from any model, such as hydroxyethyl starch 200/0.5, hydroxyethyl starch 130/0.4, preferably hydroxyethyl starch 130/0.4.
  • composition of the present invention is allowed to stand at 50 ° C for 7 days to increase the amount of impurities present in the form of the compound of the formula (II) or its salt by no more than 0.15%; or to leave the compound of the formula (II) or its salt at 50 ° C for 14 days.
  • the amount of impurities present in the form does not increase by more than 0.3%, preferably 0.2%, more preferably not more than 0.2%.
  • the composition does not contain mannitol or gan Amino acid.
  • the ratio of remiazolam or a pharmaceutically acceptable salt thereof to hydroxyethyl starch is not particularly limited, and in a preferred embodiment of the present invention, remiazolam or a pharmaceutically acceptable thereof
  • the weight ratio of salt to hydroxyethyl starch is from 1:0.1 to 1000, preferably from 1:1 to 1:50, more preferably from 1:1 to 1:20, most preferably from 1:1 to 1:10.
  • the composition is a lyophilized formulation.
  • a monosaccharide may also be added to the compositions of the present invention.
  • the monosaccharide may be selected from the group consisting of glucose, fructose, galactose, mannose, galactose, glucosamine and the like.
  • the lyophilized preparation of the present invention is reconstituted with water to the volume before lyophilization, and is determined according to the method of the Chinese Pharmacopoeia 2010 edition two appendix VI H, the pH of the solution is 2-7, more preferably 2-5. Most preferably 2 to 4.
  • the lyophilized formulation of the present invention can be reconstituted using various aqueous diluents to provide solutions for injection, such as water for injection, physiological saline, aqueous 5% dextrose, and the like, which are widely known in the art.
  • the ratio of the hydroxyethyl starch to the monosaccharide is not particularly limited, and in a preferred embodiment of the present invention, the weight ratio of the hydroxyethyl starch to the monosaccharide is from 1:9 to 9:1, more preferably 1:5. 5:1, most preferably 1:3 to 3:1.
  • the concentration of remazolium (in terms of free base) in the solution obtained by lyophilization or reconstitution with an aqueous diluent is about 0.5 to 30 mg/ml, preferably 1 to 20 mg/ml. It is particularly preferably 2 to 15 mg/ml.
  • the pharmaceutically acceptable salt of remiazolam may be a benzenesulfonate, a p-toluenesulfonate, an isethionate or the like.
  • the solution for injection can be reconstituted to obtain a clear solution after slight shaking, and the reconstitution time is less than 3 min, more preferably less than 2 min, most preferably less than 1.5 min; long time after dissolution or dilution Stabilization does not precipitate drug crystals.
  • the present invention provides a method of inhibiting degradation of remimalam or a pharmaceutically acceptable salt thereof to a compound of formula (II) or a salt thereof, the method comprising adding a hydroxy group as described above Ethyl starch or hydroxyethyl starch and monosaccharide.
  • hydroxyethyl starch, monosaccharides, and combinations thereof are capable of inhibiting the degradation of remazolam or a pharmaceutically acceptable salt thereof to a compound of formula (II) or a salt thereof, thereby further solving The problem of stability; hydroxyethyl starch, monosaccharide and combinations thereof are much stronger than the known glycine, mannitol, lactose and other common excipients.
  • the present invention provides a method of preparing a composition comprising remiazolam and a pharmaceutically acceptable salt thereof, which is simple in operation, good in reproducibility, and easy to industrialize.
  • the method includes the following steps:
  • the method further comprises the step of lyophilizing the solution obtained in step 3).
  • the product needs to have good stability, and the composition provided by the present invention exhibits excellent stability after drying, and the reconstitution rate does not change after standing.
  • the pharmaceutical preparation of the present invention is usually obtained by the following steps:
  • the solution is lyophilized.
  • Two bottles of the product were reconstituted with 2.0 ml of water for injection, reconstituted with a 5 ml syringe and a suitable needle, and the time required for the solid to completely dissolve was recorded.
  • the lyophilized products of the respective examples were reconstituted rapidly, and the appearance, the reconstitution time, and the appearance of the solution after reconstitution did not change significantly during storage at a high temperature of 50 ° C, and the CNS7054 related substance grew slowly, showing excellent stability.
  • the prescription for further addition of monosaccharides showed better stability.
  • Example II lactose prescription (A01P310 prescription) published in CN104968348A and the example 6 glycine prescription of CN103202815A, and prepare a remazole lyophilized powder needle by freeze-drying a sample disclosed in the patent at a high temperature of 50 ° C.
  • the stability was investigated under the conditions, and the results are shown in Table 1. Further, the lactose and glycine prescription lyophilized product and the lyophilized product of Example 4, Example 7 and Example 10 were respectively reconstituted with water for injection, and the stability of the solution at room temperature was examined. The results were compared. The results are shown in Table 3.
  • Table 1 The results of Table 1, Table 2 and Table 3 show that the stability of the rimazolam composition lyophilized product of the present invention at high temperature and the stability of the solution after reconstitution are superior to the patent prescription, especially remarazol and A combination of hydroxyethyl starch and a monosaccharide.

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

Abstract

L'invention concerne une composition pharmaceutique de rémimazolam. En particulier, l'invention concerne une composition pharmaceutique comprenant du rémimazolam ou un sel pharmaceutiquement acceptable de celui-ci et un amidon hydroxyéthyle et/ou une composition monosaccharidique. La composition selon la présente invention présente un temps de reconstitution court après séchage du rémimazolam, et est pratique pour un médicament clinique et présente une bonne stabilité.
PCT/CN2017/085141 2016-05-20 2017-05-19 Composition pharmaceutique de rémimazolam Ceased WO2017198224A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780004159.2A CN108289897B (zh) 2016-05-20 2017-05-19 一种瑞马唑仑的药物组合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610340803 2016-05-20
CN201610340803.0 2016-05-20

Publications (1)

Publication Number Publication Date
WO2017198224A1 true WO2017198224A1 (fr) 2017-11-23

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/085141 Ceased WO2017198224A1 (fr) 2016-05-20 2017-05-19 Composition pharmaceutique de rémimazolam

Country Status (2)

Country Link
CN (1) CN108289897B (fr)
WO (1) WO2017198224A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111514103A (zh) * 2020-05-18 2020-08-11 安徽省逸欣铭医药科技有限公司 一种稳定的瑞马唑仑注射液组合物及其制备方法
CN114668766A (zh) * 2020-12-25 2022-06-28 江苏恒瑞医药股份有限公司 一种瑞马唑仑的药物组合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104546675A (zh) * 2014-12-25 2015-04-29 海南卫康制药(潜山)有限公司 一种艾司唑仑组合物冻干片及其制备方法
CN104968348A (zh) * 2012-05-22 2015-10-07 Paion英国有限公司 包含短效苯二氮杂*类化合物的组合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104968348A (zh) * 2012-05-22 2015-10-07 Paion英国有限公司 包含短效苯二氮杂*类化合物的组合物
CN104546675A (zh) * 2014-12-25 2015-04-29 海南卫康制药(潜山)有限公司 一种艾司唑仑组合物冻干片及其制备方法

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CN108289897B (zh) 2020-07-28
CN108289897A (zh) 2018-07-17

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