WO2019158043A1 - Solution d'hydrate de chloral stable, son procédé de préparation et son utilisation - Google Patents

Solution d'hydrate de chloral stable, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2019158043A1
WO2019158043A1 PCT/CN2019/074833 CN2019074833W WO2019158043A1 WO 2019158043 A1 WO2019158043 A1 WO 2019158043A1 CN 2019074833 W CN2019074833 W CN 2019074833W WO 2019158043 A1 WO2019158043 A1 WO 2019158043A1
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WIPO (PCT)
Prior art keywords
acid
chloral hydrate
solution
hydrate solution
chloral
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Application number
PCT/CN2019/074833
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English (en)
Chinese (zh)
Inventor
云琦
陶亮
张蓉
郑永刚
孙媛媛
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特丰制药有限公司
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Publication of WO2019158043A1 publication Critical patent/WO2019158043A1/fr

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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/11—Aldehydes
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a sedative and hypnotic pharmaceutical preparation, and more particularly to a chloral hydrate solution suitable for oral use in a child patient after dilution. Further, the present invention relates to a method for preparing the hydrated chloral solution and the use of the hydrated chloral solution in the preparation of a sedative and hypnotic drug.
  • chloral hydrate oral solution is generally used as a sedative hypnotic for pediatric examination.
  • Hydrated chloral hydrate mainly inhibits the up-regulation system of brainstem reticular structure, causing near-physiological sleep. It has a fast onset, long duration of action, does not shorten rapid eye movement sleep, has mild effect, no accumulation in the body, and less adverse reactions.
  • chloral hydrate oral solution is the longest application, the most widely used, the most mature application, the largest amount of sedative and hypnotic drugs in pediatric examinations in China. It has become the drug of choice for sedation and hypnosis in clinical pediatric examination in China. There are no suitable alternatives.
  • the present invention provides a hydrated chloral solution comprising chloral hydrate, a pharmaceutically acceptable acid and water, wherein the chloral hydrate has a mass concentration of 40% to 80%.
  • the pH of the chloral hydrate solution is preferably from 1.0 to 2.9.
  • the present invention provides a stable chloral hydrate solution comprising the following components: chloral hydrate, monohydrate or anhydrous citric acid, and purified water, wherein the chloral hydrate The mass concentration is from 44% to 80%, and the pH of the chloral hydrate solution is from 1.0 to 2.9.
  • the present invention provides a method for preparing a chloral hydrate solution, characterized in that the preparation steps include:
  • the present invention provides a method for preparing the stabilized chloral hydrate solution, the preparation steps of which include:
  • citric acid solution having a pH of 1.0 to 2.9;
  • the invention provides the use of a chloral hydrate solution of the invention in the manufacture of a medicament for use as a sedative hypnotic formulation.
  • the invention provides a chloral hydrate solution of the invention for use as a sedative hypnotic formulation.
  • the invention provides the use of sedative and hypnotic in a patient, particularly a pediatric patient, comprising administering to the patient an effective amount of a chloral hydrate solution of the invention.
  • the beneficial effects of the invention are that the chloral hydrate solution of the invention effectively improves the product stability of the chloral hydrate solution by reducing the pH value of the solution while increasing the concentration of chloral hydrate (for example, reducing the generation of degradants) The traits did not change after storage, no crystals were precipitated).
  • Figure 1 shows the effect of different pH values on the amount of chloroform formed in a chloral hydrate solution.
  • the present invention provides a chloral hydrate solution comprising chloral hydrate, a pharmaceutically acceptable acid, and water (preferably purified water), wherein the chloral hydrate has a mass concentration of 40% to 80% (For example, 44%-80%, 44%-70%, 44%-60% or 44%-50%), the pH of the chloral hydrate solution is preferably 1.0-2.9.
  • the present invention provides a hydrated chloral solution, wherein the pharmaceutically acceptable acid is an inorganic or organic acid, wherein
  • the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and any combination thereof;
  • the organic acid is selected from the group consisting of formic acid, acetic acid, acetic anhydride, acetoacetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, Oxalic acid, malonic acid, succinic acid (succinic acid), glutaric acid, adipic acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, tartaric acid, ascorbic acid, gallic acid, benzene
  • the present invention provides a hydrated chloral solution, wherein the pharmaceutically acceptable acid is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, malic acid, tartaric acid, fumaric acid, citric acid monohydrate Or anhydrous citric acid.
  • the pharmaceutically acceptable acid is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, malic acid, tartaric acid, fumaric acid, citric acid monohydrate Or anhydrous citric acid.
  • the invention provides a hydrated chloral solution, wherein the pharmaceutically acceptable acid is monohydrate or anhydrous citric acid.
  • the present invention provides a chloral hydrate solution comprising the following components: chloral hydrate, monohydrate or anhydrous citric acid, and purified water, wherein the quality of the chloral hydrate The concentration is from 44% to 80%, and the pH of the chloral hydrate solution is from 1.0 to 2.9.
  • the chloral hydrate solution has a pH of from 1.0 to 2.0.
  • the chloral hydrate solution has a pH of from 1.2 to 1.6.
  • the chloral hydrate has a mass concentration of 75%.
  • the pH of the chloral hydrate solution is from 1.31 to 2.0.
  • the chloral hydrate solution has a pH of from 1.61 to 2.0.
  • the monohydrate or anhydrous citric acid is present in a concentration of from 0.5% to 1%, preferably from about 0.7% to about 0.1%.
  • the present invention provides a method for preparing a hydrated chloral solution, characterized in that the preparation steps include:
  • the pH of the acid solution prepared in step 1) of the process is from 1.0 to 2.0, preferably from 1.2 to 1.6.
  • the pH of the acid solution prepared in step 1) of the process is from 1.31 to 2.0.
  • the pH of the acid solution prepared in step 1) of the process is from 1.61 to 2.0.
  • the present invention provides a method for preparing the hydrated chloral solution, the preparation steps of which include:
  • the pH of the citric acid solution prepared in step 1) of the process is from 1.0 to 2.0, preferably from 1.2 to 1.6.
  • the pH of the citric acid solution prepared in step 1) of the process is from 1.31 to 2.0.
  • the pH of the citric acid solution prepared in step 1) of the process is from 1.61 to 2.0.
  • step 2) of the process stirring is carried out at a rotational speed of from 100 to 500 r/min, preferably 300 r/min, to completely dissolve the chloral hydrate.
  • the amount of the degradant (for example, chloroform or trichloroacetic acid) is expressed in the form of the amount ( ⁇ g) of the degradation product per 1 g of chloral hydrate.
  • the present invention dissolves chloral hydrate in an aqueous solution of citric acid of different pH values to prepare chloral hydrate having the same concentration.
  • Solution concentration of about 10%
  • chloral hydrate solution with different pH values and potting in a clear glass bottle, placed in an environment of 60 ° C ⁇ 2 ° C for 5 days, after testing its degradation product chloroform
  • Figure 1 shows the relationship of this change. According to the results shown in Fig. 1, the amount of the degradation product chloroform increased as the pH of the chloral hydrate solution increased, and the pH at the critical point of the change was about 2.9.
  • the chloral hydrate solution preferably has a pH of 1.0 to 2.9.
  • the present invention prepares a chloral hydrate solution having a pH of 2.0 with different concentrations of chloral hydrate, and potting in a transparent glass bottle, placed at 60 ° C After 5 days in an environment of ⁇ 2 ° C, the contents of the degradation products of chloroform and trichloroacetic acid in the solution were measured, and the results are shown in Table 1.
  • the chloral hydrate solution of the present invention has a lower pH value and a higher concentration, this will result in a poor mouthfeel of the product and a certain irritation, which is not suitable for direct administration. Therefore, before taking the chloral hydrate solution of the present invention, it can be diluted with a single syrup, water or juice as a diluent to improve the mouthfeel and reduce irritation.
  • the chloral hydrate content refers to the percentage relative to the labeled amount (i.e., the theoretical content of chloral hydrate per label or the labeling content of each formulation unit).
  • a chloral hydrate solution (pH 1.98) having a mass concentration of 50% was prepared in a manner similar to the above.
  • a chloral hydrate solution (pH 2.01) having a mass concentration of 50% was prepared according to a method similar to the above.
  • Example 2 The chloral hydrate preparations of different hospitals in China and the chloral hydrate solution prepared in Example 1 - Example 3 of the present invention are respectively placed under high temperature (60 ° C ⁇ 2 ° C) and illumination (4500 lx ⁇ 500 lx). The product traits were observed on day 0 and day 10, respectively, and the pH, degradation products and contents were examined. The results are shown in Table 2.
  • the chloral hydrate solution prepared in Examples 4-8 was placed under high temperature (60 ° C ⁇ 2 ° C), and the chloral hydrate content and the degradation product content were observed on the 0th day and the 5th day, and the results are shown in the following table. .
  • the chloral hydrate preparations of different hospitals in China and the chloral hydrate solution prepared in Examples 1 to 3 of the present invention are placed at 40 ⁇ 2 ° C according to the provisions of the accelerated stability test in the Chinese Pharmacopoeia 2015 edition. Accelerated stability test was carried out under the condition of RH 75% ⁇ 5%, and samples were taken at 0, 1, 2, 3, and 6 months, respectively, and pH value, degradant and content were observed, and the results are shown in Table 3.
  • the chloral hydrate solution provided by the invention can be stored for a period of up to 24 months at room temperature, and the amount of the degradation product chloroform is less than 60 ⁇ g/g. It has excellent stability and controllability, effectively solves the problem of poor stability in conventional conventional preparations, and is suitable for commercial mass production.
  • Example 1 Using a single syrup as a diluent, the present invention, Example 1, and Example 3 of the present invention were respectively prepared to prepare a chloral hydrate solution having a specification of 1 ml: 100 mg.
  • the chloral hydrate preparations of different hospitals in China and the chloral hydrate solution prepared by using the first embodiment of the present invention, the second embodiment of the present invention or the third embodiment of the present invention were used for clinical trials to observe the sedative and hypnotic effects.
  • a total of 360 children who underwent sedation were enrolled.
  • the age ranged from 1 month to 3 years old.
  • the children who were allergic to chloral hydrate and severe liver and kidney dysfunction were randomly divided into Nanjing *** hospital preparation group.
  • the groups were fed according to the doctor's prescription before the examination.
  • the sedative and hypnotic effects of each group were observed and compared.
  • the sedative effect was expressed by efficiency (the ratio of the number of successful examinations to the total number of people). The results are shown in Table 5.

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

Abstract

L'invention concerne une solution d'hydrate de chloral, son procédé de préparation et son utilisation. La solution d'hydrate de chloral comprend de l'hydrate de chloral et un acide et de l'eau pharmaceutiquement acceptables. Une concentration massique de l'hydrate de chloral est comprise entre 40 % et 80 %, et la valeur de pH de la solution d'hydrate de chloral est comprise entre 1,0 et 2,9.
PCT/CN2019/074833 2018-02-13 2019-02-12 Solution d'hydrate de chloral stable, son procédé de préparation et son utilisation WO2019158043A1 (fr)

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CN201810148944 2018-02-13
CN201810148944.1 2018-02-13

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CN112656758A (zh) * 2020-12-03 2021-04-16 成都施贝康生物医药科技有限公司 一种稳定的水合氯醛糖浆、其制法、质量控制方法及应用
CN115671082B (zh) * 2021-07-22 2024-05-14 深圳先进技术研究院 水合氯醛在制备抑制苯丙胺类中枢神经兴奋剂复吸和依赖的药物中的应用
GB2617419B (en) 2022-07-18 2024-07-10 Atnahs Pharma Uk Ltd Stable composition of chloral hydrate

Citations (2)

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Publication number Priority date Publication date Assignee Title
DE102004049015A1 (de) * 2004-10-05 2006-04-06 G. Pohl-Boskamp Gmbh & Co. Kg Gelatinekapsel mit Chloralhydrat
CN104800154A (zh) * 2015-04-20 2015-07-29 赵柏松 小儿口服镇静剂

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DK2144863T3 (en) * 2007-04-05 2017-03-06 Microbide Ltd A PROCEDURE FOR STABILIZING AN ALDEHYD

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004049015A1 (de) * 2004-10-05 2006-04-06 G. Pohl-Boskamp Gmbh & Co. Kg Gelatinekapsel mit Chloralhydrat
CN104800154A (zh) * 2015-04-20 2015-07-29 赵柏松 小儿口服镇静剂

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GAN ZHIPING ET AL.: "Improvement Chloral Hydrate Solution Formulation", CHINESE JOURNAL OF HOSPITAL PHARMACY, vol. 19, no. 6, 31 December 1999 (1999-12-31), pages 371 *
SHENGCUN: "Toward better understanding of chloral hydrate stability in water:Kinetics, pathways, and influencing factors", CHEMOSPHERE, vol. 157, 31 December 2016 (2016-12-31), pages 18 - 24, XP029569111, ISSN: 0045-6535 *

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