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WO2023019993A1 - Composition d'injection de chlorhydrate de dronédarone, son procédé de préparation et son application - Google Patents

Composition d'injection de chlorhydrate de dronédarone, son procédé de préparation et son application Download PDF

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Publication number
WO2023019993A1
WO2023019993A1 PCT/CN2022/087977 CN2022087977W WO2023019993A1 WO 2023019993 A1 WO2023019993 A1 WO 2023019993A1 CN 2022087977 W CN2022087977 W CN 2022087977W WO 2023019993 A1 WO2023019993 A1 WO 2023019993A1
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WIPO (PCT)
Prior art keywords
dronedarone hydrochloride
cyclodextrin
injection composition
dronedarone
ratio
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/CN2022/087977
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English (en)
Chinese (zh)
Inventor
郭桢
付俊
卢鹏程
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
Shanghai Bocimed Pharmaceutical Research Co Ltd
Original Assignee
Shanghai Bocimed Pharmaceutical Co Ltd
Shanghai Bocimed Pharmaceutical Research Co Ltd
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Publication of WO2023019993A1 publication Critical patent/WO2023019993A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the invention belongs to the field of pharmaceutical compositions, and in particular relates to a dronedarone hydrochloride injection composition, its preparation method and application.
  • Arrhythmia cardiac arrhythmia
  • Arrhythmia is a common disease, and the incidence rate is extremely high. The appearance of arrhythmia seriously endangers the patient's physical health, and at the same time has a certain degree of impact on the patient's psychology.
  • Arrhythmia is due to abnormal sinoatrial node excitation or excitation outside the sinoatrial node, the conduction of the excitation is slow, blocked or conducted through abnormal channels, that is, the origin of cardiac activity and (or) conduction disorders lead to the frequency and (or) heart beat ) abnormal rhythm.
  • Arrhythmia is an important group of diseases in cardiovascular diseases. It can occur alone or be associated with cardiovascular disease. It can cause sudden death due to sudden onset, and it can also continue to involve the heart and fail.
  • arrhythmia According to the ventricular rate at the time of arrhythmia attack, arrhythmia can be roughly divided into tachyarrhythmia and bradyarrhythmia. Due to the multiple and uncertain nature of arrhythmias, amiodarone injection is often used for treatment when oral administration is not suitable. However, the adverse reactions caused by iodide ions in amiodarone injection, and the super-long half-life of amiodarone and being a liver enzyme inhibitor at the same time also limit its clinical application, so it is urgent to develop a drug that is suitable for oral administration. Antiarrhythmic injections for drug patients.
  • Dronedarone hydrochloride was developed by Sanofi, and it was first listed on the FDA on July 1, 2009.
  • the trade name is MULTAQ (Meidalong), and the listed dosage form is a tablet with a specification of 400mg. to reduce the risk of cardiovascular disease in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), recent onset AF/AFL, and associated cardiovascular risk factors (eg, age >70 years) , with sinus rhythm or about to undergo cardioversion, hypertension, diabetes mellitus, previous cerebrovascular accident, left atrial diameter ⁇ 50 mm or left ventricular ejection fraction [LVEF] ⁇ 40%).
  • AF paroxysmal or persistent atrial fibrillation
  • AFL atrial flutter
  • LVEF left atrial diameter
  • LVEF left ventricular ejection fraction
  • Dronedarone hydrochloride (Dronedarone hydrochloride), the chemical name is N-(2-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)benzofuran-5-yl)methyl Sulfonamide hydrochloride, molecular formula C 31 H 44 N 2 O 5 S ⁇ HCl, molecular weight 593.2; the chemical structural formula of dronedarone is as follows:
  • Dronedarone hydrochloride is almost insoluble in water, but easily soluble in dichloromethane and methanol.
  • the invention provides a dronedarone hydrochloride inclusion compound, which comprises dronedarone hydrochloride and cyclodextrin, and the cyclodextrin does not include ⁇ -cyclodextrin without substituents.
  • the cyclodextrin may be selected from one of ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin or more.
  • the cyclodextrin is preferably hydroxypropyl- ⁇ -cyclodextrin and/or sulfobutyl- ⁇ -cyclodextrin.
  • the molar ratio of the cyclodextrin to the dronedarone hydrochloride is preferably 0.1-100, more preferably 0.2-10, further preferably 0.3-5, for example 1, 1.25, 2 , 2.5, 3, 3.8, 4, 5, 10, 20.
  • the inclusion compound of dronedarone hydrochloride preferably consists of dronedarone hydrochloride and cyclodextrin, and the cyclodextrin does not include ⁇ -cyclodextrin without substituents.
  • the cyclodextrin is preferably one or more of ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin.
  • the present invention also provides a dronedarone hydrochloride injection composition, which includes dronedarone hydrochloride, cyclodextrin, an isotonic regulator and water for injection, and optionally contains or does not contain a pH regulator and an antioxidant , the cyclodextrin does not include ⁇ -cyclodextrin without substituents.
  • the dronedarone hydrochloride injection composition comprises dronedarone hydrochloride, cyclodextrin, an isotonic regulator, a pH regulator, an antioxidant and water for injection, and the cyclodextrin Glycerin does not include unsubstituted ⁇ -cyclodextrin.
  • the dronedarone hydrochloride injection composition is preferably composed of dronedarone hydrochloride, cyclodextrin, an isotonic regulator, a pH regulator, an antioxidant and water for injection, so Said cyclodextrins do not include ⁇ -cyclodextrins without substituents.
  • the cyclodextrin can be selected from one or more of ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin ; preferably hydroxypropyl- ⁇ -cyclodextrin and/or sulfobutyl- ⁇ -cyclodextrin.
  • the molar ratio of the cyclodextrin to the dronedarone hydrochloride is preferably 0.1-100, more preferably 0.2-10, further preferably 0.3-5, for example 1, 1.25, 2 , 2.5, 3, 3.8, 4, 5, 10, 20.
  • the isotonic regulator is a substance capable of regulating osmotic pressure, such as sodium chloride and/or glucose.
  • the concentration of the isotonic regulator may be 0.1 mg/ml to 10 mg/ml, such as 1 mg/ml to 10 mg/ml, such as 0.2 mg/ml, 0.95 mg/ml, 1 mg/ml , 1.0005 mg/ml, 1.5 mg/ml, 2 mg/ml, 4 mg/ml or 10 mg/ml
  • the concentration refers to the ratio of the mass of the isotonic regulator to the volume of the dronedarone hydrochloride injection composition.
  • the pH regulator is a substance capable of adjusting the pH of the solution, such as acetic acid, citric acid, sodium citrate, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate and one or more of sodium dihydrogen phosphate.
  • the concentration of the pH regulator may be 0-10.0 mg/ml.
  • the concentration of the pH regulator may be 1.0-10.0 mg/ml.
  • the concentration of the pH regulator is 0.005mg/ml, 0.06mg/ml, 0.0075mg/ml, 0.11mg/ml, 3.0mg/ml, 3.2mg/ml, 2.8mg/ml or 2.0mg/ml
  • the concentration refers to the ratio of the mass of the pH regulator to the volume of the dronedarone hydrochloride injection composition.
  • the antioxidant can be selected from, for example, L-cysteine hydrochloride, sodium sulfite, sodium bisulfite, propyl gallate, glutathione, sodium thiosulfate, thiourea , thioglycolic acid, sodium metabisulfite, potassium metabisulfite, vitamin C and vitamin E in one or more.
  • the concentration of the antioxidant can be 0.001mg/ml-0.002mg/ml, such as 0.001mg/ml or 0.002mg/ml, the concentration refers to the quality of the antioxidant and hydrochloric acid The ratio of the volume of the nedarone injection composition.
  • the water is preferably water for injection.
  • the dronedarone hydrochloride injection composition can be any of the following prescriptions:
  • Prescription 1 12mg/ml dronedarone hydrochloride, 28.8mg/ml hydroxypropyl- ⁇ cyclodextrin, 2mg/ml citric acid, 1mg/ml sodium citrate, 1mg/ml sodium chloride, 0.001mg/ml ml sodium bisulfite and 5ml water, wherein the proportion of each component is the ratio of its mass to the total volume of the dronedarone hydrochloride injection composition;
  • Prescription 2 12mg/ml dronedarone hydrochloride, 57.6mg/ml hydroxypropyl- ⁇ cyclodextrin, 1.6mg/ml citric acid, 1.6mg/ml sodium citrate, 2mg/ml glucose, 0.002mg/ml ml sodium bisulfite and 5ml water, wherein the proportion of each component is the ratio of its mass to the total volume of the dronedarone hydrochloride injection composition;
  • Prescription 3 12mg/ml dronedarone hydrochloride, 43.4mg/ml sulfonyl- ⁇ cyclodextrin, 1.2mg/ml citric acid, 1.6mg/ml sodium citrate, 4mg/ml sodium chloride, 0.001 mg/ml vitamin C and 5ml water, wherein the proportion of each component is the ratio of its mass to the total volume of the dronedarone hydrochloride injection composition;
  • Prescription 4 12mg/ml dronedarone hydrochloride, 86.8mg/ml sulfonyl- ⁇ cyclodextrin, 0.6mg/ml citric acid, 1.4mg/ml sodium citrate, 10mg/ml glucose, 0.002mg/ml ml vitamin C and 5ml water, wherein the ratio of each component is the ratio of its mass to the total volume of the dronedarone hydrochloride injection composition;
  • Prescription 5 8mg/ml dronedarone hydrochloride, 30mg/ml hydroxypropyl- ⁇ cyclodextrin, 2mg/ml sodium chloride, and 10ml water, the proportion of each component is its mass to dronedarone hydrochloride The ratio of the total volume of the injection composition;
  • Prescription 6 8mg/ml dronedarone hydrochloride, 90mg/ml sulfonyl- ⁇ cyclodextrin, 1.0mg/ml sodium chloride and 10ml water, the proportion of each component is its mass to dronedarone hydrochloride The ratio of the total volume of the injection composition;
  • Prescription 7 8mg/ml dronedarone hydrochloride, 90mg/ml sulfobutyl- ⁇ cyclodextrin, 0.005mg/ml citric acid, 1.0mg/ml sodium chloride and 10ml water, the proportion of each component The ratio of its mass to the total volume of the dronedarone hydrochloride injection composition;
  • Prescription 8 8mg/ml dronedarone hydrochloride, 30mg/ml sulfonyl- ⁇ cyclodextrin, 0.005mg/ml citric acid, 1.5mg/ml glucose, 0.001mg/ml sodium bisulfite and 10ml water, Wherein the proportion of each component is the ratio of its mass to the total volume of the dronedarone hydrochloride injection composition;
  • Prescription 9 8mg/ml dronedarone hydrochloride, 60mg/ml sulfonyl- ⁇ cyclodextrin, 0.01mg/ml citric acid, 0.05mg/ml sodium citrate, 1mg/ml sodium chloride, 0.0005mg /ml glucose and 10ml water, wherein the proportion of each component is the ratio of its mass to the total volume of the dronedarone hydrochloride injection composition;
  • Prescription 10 8mg/ml dronedarone hydrochloride, 120mg/ml sulfobutyl- ⁇ cyclodextrin, 0.01mg/ml citric acid, 0.1mg/ml sodium citrate, 0.2mg/ml glucose, 0.001mg/ml ml of vitamin C and 10 ml of water, wherein the proportion of each component is the ratio of its mass to the total volume of the dronedarone hydrochloride injection composition.
  • the pH of the dronedarone hydrochloride injection composition is 3.0-7.0.
  • the pH of the dronedarone hydrochloride injection composition is 3.0-6.0, such as 3.0, 4.0, 5.0, 6.0 or 7.0.
  • the present invention also provides a preparation method of the dronedarone hydrochloride injection composition, which comprises the following steps:
  • Step 1 Inclusion complexing an aqueous cyclodextrin solution with dronedarone hydrochloride to obtain a cyclodextrin inclusion compound of dronedarone hydrochloride;
  • Step 2 Mix the inclusion compound of dronedarone hydrochloride obtained in step 1 with an isotonic regulator and water, as well as optionally added or not added pH regulators and antioxidants to obtain the dronedarone hydrochloride injection combination;
  • step 2 mix the inclusion compound of dronedarone hydrochloride obtained in step 1 with an isotonic regulator, and optionally added or not added pH regulators and antioxidants to obtain the dronedarone hydrochloride injection combination.
  • step 2 mix the inclusion compound of dronedarone hydrochloride obtained in step 1 with an isotonic regulator, an antioxidant and water to obtain the dronedarone hydrochloride injection composition.
  • step 2 mix the inclusion compound of dronedarone hydrochloride obtained in step 1 with an isotonic regulator and an antioxidant to obtain the dronedarone hydrochloride injection composition.
  • the inclusion compound of dronedarone hydrochloride described in step 1 can be carried out using conventional inclusion conditions in the art, and the following inclusion conditions are preferably used in the present invention:
  • the mass concentration of the cyclodextrin aqueous solution is preferably 1% to 50%, more preferably 5% to 30%, such as 9%, 15%, 20% or 30%, and the mass concentration refers to cyclodextrin The percentage of the quality of the essence to the total mass of the cyclodextrin aqueous solution.
  • the inclusion temperature is preferably 20°C-80°C, more preferably 40°C-70°C, for example 60°C.
  • the inclusion time is preferably 0.5 hour to 20 hours, more preferably 1 hour to 10 hours, for example 7 hours.
  • the mixing is preferably stirring mixing.
  • step 1 preferably adopts the following post-processing steps: dissolve dronedarone hydrochloride in an aqueous solution of cyclodextrin for clathrate, and after clathrate is completed, cool, filter, and dry to obtain the Inclusion compound of dronedarone hydrochloride.
  • the cooling temperature is preferably 10°C-30°C, more preferably 20°C-25°C.
  • the filtering is preferably performed using a filter element.
  • the pore size of the filter element is preferably 0.22 micron to 0.8 micron.
  • the drying method is preferably selected from one or more of freeze-drying, vacuum drying, normal pressure drying and spray drying, more preferably freeze-drying and drying. /or spray drying.
  • the freeze-drying can be vacuum freeze-drying.
  • the pH of the prepared dronedarone hydrochloride injection composition is 3.0-7.0.
  • the prepared dronedarone hydrochloride injection composition has a pH of 3.0-6.0, such as 3.0, 4.0, 5.0, 6.0 or 7.0.
  • the present invention also provides the application of the dronedarone hydrochloride injection composition in the preparation of preparations.
  • the preparation may be an injection.
  • the specification of the injection may be 8ml.
  • the concentration of the injection may be 5-12 mg/ml, for example, 10 mg/ml; based on the concentration of dronedarone hydrochloride in the injection; preferably, the dronedarone hydrochloride Darone exists at least in the form of inclusion complex of dronedarone hydrochloride in the injection.
  • the present invention also provides an injection containing the dronedarone hydrochloride injection composition.
  • the present invention also provides a preparation method of the dronedarone hydrochloride injection, comprising finely filtering the dronedarone hydrochloride injection composition with a microporous membrane, filling and sterilizing to obtain dronedarone hydrochloride Dylan injection.
  • the present invention also provides the use of the dronedarone hydrochloride injection composition in the preparation of drugs for treating and/or preventing arrhythmia.
  • the present invention also provides a method for treating and/or preventing arrhythmia, which comprises administering an effective dose of the dronedarone hydrochloride injection composition or preparation to a patient.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the room temperature refers to an ambient temperature of 10°C to 35°C.
  • the present invention overcomes the defects of low solubility of dronedarone hydrochloride, low in vitro dissolution rate, low bioavailability, and large dosage in the prior art, and provides a dronedarone hydrochloride injection Compositions, methods for their preparation and applications.
  • the dronedarone hydrochloride-cyclodextrin inclusion compound of the present invention has good stability, and the solubility in water is greatly improved, which is about 90 times higher than that of dronedarone hydrochloride (the solubility of the raw material in water is only 0.69 mg/ ml), high bioavailability, suitable for industrial production.
  • the preparation and operation of the dronedarone hydrochloride inclusion compound of the present invention is simple, and the prepared dronedarone hydrochloride inclusion compound is easy to prepare preparations.
  • the dronedarone hydrochloride composition and injection prepared by the invention have good stability and are suitable for arrhythmia patients who are not suitable for oral administration.
  • dronedarone hydrochloride determined according to high performance liquid chromatography (general rule 0512);
  • Test solution Take an appropriate amount of this product and dilute it with a solvent to make a solution containing about 0.08 mg of dronedarone per 1 mL.
  • Control solution Take an appropriate amount of dronedarone hydrochloride reference substance, accurately weigh it, dissolve it with a solvent and quantitatively dilute it to make a solution containing about 0.08 mg of dronedarone per 1 mL.
  • Chromatographic conditions use octadecylsilane bonded silica gel as a filler; use 0.2% triethylamine solution (accurately measure 2mL of triethylamine and place it in 1000mL water, mix well, adjust the pH value to 9.0 with phosphoric acid)-acetonitrile (10 :90) is the mobile phase; the flow rate is 1.0 mL per minute; the column temperature is 30° C.; the detection wavelength is 288 nm; the injection volume is 10 ⁇ L; the run time is 10 min.
  • Test solution Take an appropriate amount of this product and dilute it with a solvent to make a solution containing about 0.8 mg of dronedarone per 1 mL.
  • Control solution Accurately measure an appropriate amount of the test solution, and quantitatively dilute it with a solvent to prepare a solution containing about 1.6 ⁇ g of dronedarone per 1 mL.
  • Example 0 days 5 days 10 days Example 5 101.3 101.7 101.0
  • Example 6 103.2 102.1 101.9
  • Example 7 100.9 101.0 100.4
  • Example 8 100.3 99.8 100.5
  • Example 9 100.9 100.7 100.8
  • the content result refers to the percentage between the tested content of dronedarone hydrochloride in the clarified solution and the theoretical value, and the theoretical value refers to the concentration of the prescribed amount of dronedarone hydrochloride in the prescribed amount of water for injection;
  • Example 10 will precipitate out during placement, so follow-up does not continue to investigate stability.
  • Example 0 days 5 days 10 days Example 5 6.0 5.8 6.1
  • Example 6 5.7 5.3 5.1
  • Example 7 4.9 4.9 4.9
  • Example 8 3.0 3.0 3.0
  • Example 9 5.5 5.5 5.5
  • the molecular formula is: C 27 H 36 N 2 O 5 S
  • the prescription of this example is the same as that of Example 7, and the preparation process is as follows: make cyclodextrin into an aqueous solution with a concentration of about 9%, add the prescribed amount of dronedarone hydrochloride, stir at 60°C for 7 hours, let it cool to room temperature, filter, Freeze-dry to obtain dronedarone hydrochloride cyclodextrin inclusion compound.
  • the obtained finished product is a clear solution.
  • the ratio of the tested content of dronedarone hydrochloride to the theoretical value is nearly 100%, indicating that the concentration of dronedarone hydrochloride in the injection is about 8mg/ml.
  • the stability of the injection of this embodiment can at least reach the stability of Examples 5-9.

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Abstract

La présente invention concerne une composition d'injection de chlorhydrate de dronédarone, un procédé de préparation de celle-ci et une application de celle-ci, et concerne spécifiquement une composition d'injection de chlorhydrate de dronédarone, qui comprend du chlorhydrate de dronédarone, de la cyclodextrine, un agent d'ajustement isoosmotique, un agent d'ajustement du pH, un antioxydant et de l'eau pour l'injection. La cyclodextrine ne comprend pas de β-cyclodextrine sans substituant. Le composé d'inclusion de chlorhydrate de dronédarone-cyclodextrine présente une bonne stabilité, a une solubilité considérablement améliorée dans l'eau, a une solubilité améliorée d'environ 90 fois par comparaison avec la solubilité du chlorhydrate de dronédarone, a une biodisponibilité élevée, et convienne à une production industrielle. De plus, l'opération de préparation du composé d'inclusion de chlorhydrate de dronédarone est simple, et il est facile pour le composé d'inclusion d'hydrochlorure de dronédarone préparé d'être préparé dans une préparation. L'injection de chlorhydrate de dronédarone préparée présente une bonne stabilité, et peut être utilisée pour des patients souffrant d'arythmie cardiaque qui ne sont pas appropriés pour une administration orale.
PCT/CN2022/087977 2021-08-16 2022-04-20 Composition d'injection de chlorhydrate de dronédarone, son procédé de préparation et son application Ceased WO2023019993A1 (fr)

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MARCOLINO ANA ISA PEDROSO, MACEDO LETÍCIA BUENO, NOGUEIRA-LIBRELOTTO DANIELE RUBERT, FERNANDES JOANA RODRIGUES, BENDER CAROLINE RA: "Preparation, characterization and in vitro cytotoxicity study of dronedarone hydrochloride inclusion complexes", MATERIALS SCIENCE AND ENGINEERING C, ELSEVIER SCIENCE S.A., CH, vol. 100, 1 July 2019 (2019-07-01), CH , pages 48 - 61, XP055922931, ISSN: 0928-4931, DOI: 10.1016/j.msec.2019.02.097 *
MARCOLINO ANA ISA PEDROSO, MACEDO LETÍCIA BUENO, NOGUEIRA-LIBRELOTTO DANIELE RUBERT, VINARDELL MARÍA PILAR, ROLIM CLARICE MADALENA: "Comparative evaluation of the hepatotoxicity, phototoxicity and photosensitizing potential of dronedarone hydrochloride and its cyclodextrin-based inclusion complexes", PHOTOCHEMICAL & PHOTOBIOLOGICAL SCIENCES, ROYAL SOCIETY OF CHEMISTRY , CAMBRIDGE, GB, vol. 18, no. 6, 12 June 2019 (2019-06-12), GB , pages 1565 - 1575, XP055922935, ISSN: 1474-905X, DOI: 10.1039/C8PP00559A *

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