WO2023019993A1 - Dronedarone hydrochloride injection composition, preparation method therefor and application thereof - Google Patents
Dronedarone hydrochloride injection composition, preparation method therefor and application thereof Download PDFInfo
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- 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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- dronedarone hydrochloride
- cyclodextrin
- injection composition
- dronedarone
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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
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- 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
Description
本申请要求享有2021年8月16日向中国国家知识产权局提交的，专利申请号为202110936257.8，发明名称为“盐酸决奈达隆注射组合物、其制备方法及应用”的在先申请的优先权权益。所述在先申请的全文通过引用的方式结合于本申请中。This application claims the priority of the previous application submitted to the State Intellectual Property Office of China on August 16, 2021, with the patent application number 202110936257.8 and the invention name "Dronedarone Hydrochloride Injection Composition, Its Preparation Method and Application" rights and interests. The entirety of said prior application is incorporated by reference into this application.
本发明属于药物组合物领域，具体涉及一种盐酸决奈达隆注射组合物、其制备方法及应用。The invention belongs to the field of pharmaceutical compositions, and in particular relates to a dronedarone hydrochloride injection composition, its preparation method and application.
心律失常(cardiac arrhythmia)是一种常见的疾病，且发病率极高，心律失常的出现，严重危害着患者的身体健康，同时对患者的心理造成一定程度的影响。心律失常是由于窦房结激动异常或激动产生于窦房结以外，激动的传导缓慢、阻滞或经异常通道传导，即心脏活动的起源和(或)传导障碍导致心脏搏动的频率和(或)节律异常。心律失常是心血管疾病中重要的一组疾病。它可单独发病亦可与心血管病伴发。可突然发作而致猝死，亦可持续累及心脏而衰竭。根据心律失常发作时的心室率，可将心律失常大致分为快速性心律失常和缓慢性心律失常。由于心律失常的多发性和不定性，当不宜口服给药时常选用胺碘酮注射液进行治疗。然而胺碘酮注射液中碘离子导致的不良反应，另外胺碘酮的超长半衰期且同时为肝酶抑制剂，也限制了其在临床中的应用，因此亟待开发一种适用于不宜口服给药患者的抗心律失常注射剂。Arrhythmia (cardiac 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. 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.
盐酸决奈达隆是由赛诺菲公司研发，2009年7月1日于FDA首次上市，商品 名为MULTAQ(迈达龙)，上市剂型为片剂，规格为400mg，用于治疗心律不齐，可降低阵发性或持续性房颤(AF)或房扑(AFL)，最近发作的AF/AFL和相关的心血管危险因素(例如，年龄>70岁)的患者发生心血管疾病的风险，有窦性心律或将进行心脏复律的，高血压，糖尿病，先前的脑血管意外，左心房直径≥50mm或左心室射血分数[LVEF]<40％)。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%).
盐酸决奈达隆(Dronedarone hydrochloride)，化学名为N-(2-丁基-3-(4-(3-二丁基氨基丙氧基)苯甲酰基)苯并呋喃-5-基)甲磺酰胺盐酸盐，分子式C 31H 44N 2O 5S·HCl，分子量593.2；决奈达隆的化学结构式如下： 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:
盐酸决奈达隆在水中几乎不溶，易溶于二氯甲烷和甲醇。盐酸决奈达隆在水性溶液中的溶解度呈现pH依赖性，在pH值为3-5有最大的溶解度，约为1-2mg/ml；在pH值为6-7溶解度显著降低；当pH＝7时其溶解度约为10μg/ml。由于其较差的水溶性，目前没有开发出注射剂。Dronedarone hydrochloride is almost insoluble in water, but easily soluble in dichloromethane and methanol. The solubility of dronedarone hydrochloride in an aqueous solution is pH-dependent, and has a maximum solubility at a pH value of 3-5, which is about 1-2 mg/ml; at a pH value of 6-7, the solubility is significantly reduced; when pH= At 7 o'clock, its solubility is about 10 μg/ml. Due to its poor water solubility, no injections have been developed so far.
发明内容Contents of the invention
本发明提供了一种盐酸决奈达隆包合物，其包括盐酸决奈达隆和环糊精，所述的环糊精不包括未带取代基的β-环糊精。The invention provides a dronedarone hydrochloride inclusion compound, which comprises dronedarone hydrochloride and cyclodextrin, and the cyclodextrin does not include β-cyclodextrin without substituents.
根据本发明的实施方案，所述的环糊精可以选自α-环糊精、γ环糊精、羟丙基-β-环糊精和磺丁基-β-环糊精中的一种或多种。According to an embodiment of the present invention, the cyclodextrin may be selected from one of α-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin or more.
根据本发明的实施方案，所述的环糊精优选为羟丙基-β-环糊精和/或磺丁基-β-环糊精。According to an embodiment of the present invention, the cyclodextrin is preferably hydroxypropyl-β-cyclodextrin and/or sulfobutyl-β-cyclodextrin.
根据本发明的实施方案，所述的环糊精与所述的盐酸决奈达隆的摩尔比值优选为0.1～100，进一步优选0.2～10，再进一步优选0.3～5，例如1、1.25、2、2.5、3、3.8、4、5、10、20。According to an embodiment of the present invention, 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.
根据本发明的实施方案，所述的盐酸决奈达隆包合物优选由盐酸决奈达隆和环糊精组成，所述的环糊精不包括未带取代基的β-环糊精。所述的环糊精优选α-环糊精、γ环糊精、羟丙基-β-环糊精和磺丁基-β-环糊精中的一种或多种。According to an embodiment of the present invention, the inclusion compound of dronedarone hydrochloride preferably consists of dronedarone hydrochloride and cyclodextrin, and the cyclodextrin does not include β-cyclodextrin without substituents. The cyclodextrin is preferably one or more of α-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin.
本发明还提供了一种盐酸决奈达隆注射组合物，其包括盐酸决奈达隆、环糊精、等渗调节剂和注射用水，以及任选含有或不含有的pH调节剂、抗氧化剂，所述的环糊精不包括未带取代基的β-环糊精。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 β-cyclodextrin without substituents.
根据本发明的一种实施方案，所述盐酸决奈达隆注射组合物包括盐酸决奈达隆、环糊精、等渗调节剂、pH调节剂、抗氧化剂和注射用水，所述的环糊精不包括未带取代基的β-环糊精。According to one embodiment of the present invention, 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 β-cyclodextrin.
根据本发明的一种实施方案，所述的盐酸决奈达隆注射组合物优选其由盐酸决奈达隆、环糊精、等渗调节剂、pH调节剂、抗氧化剂和注射用水组成，所述的环糊精不包括未带取代基的β-环糊精。According to one embodiment of the present invention, 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 β-cyclodextrins without substituents.
本发明中，所述的环糊精可以选自α-环糊精、γ环糊精、羟丙基-β-环糊精和磺丁基-β-环糊精中的一种或多种；优选羟丙基-β-环糊精和/或磺丁基-β-环糊精。In the present invention, the cyclodextrin can be selected from one or more of α-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin ; preferably hydroxypropyl-β-cyclodextrin and/or sulfobutyl-β-cyclodextrin.
根据本发明的实施方案，所述的环糊精与所述的盐酸决奈达隆与的摩尔比值优选0.1～100，进一步优选0.2～10，再进一步优选0.3～5，例如1、1.25、2、2.5、3、3.8、4、5、10、20。According to an embodiment of the present invention, 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.
根据本发明的实施方案，所述的等渗调节剂为能够调节渗透压的物质，例如为氯化钠和/或葡萄糖。According to an embodiment of the present invention, the isotonic regulator is a substance capable of regulating osmotic pressure, such as sodium chloride and/or glucose.
根据本发明的实施方案，所述的等渗调节剂的浓度可以为0.1mg/ml～10mg/ml，例如1mg/ml～10mg/ml，比如0.2mg/ml、0.95mg/ml、1mg/ml、1.0005mg/ml、1.5mg/ml、2mg/ml、4mg/ml或10mg/ml，所述的浓度是指等渗调节剂的质量与盐酸决奈达隆注射组合物体积的比值。According to an embodiment of the present invention, 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.
根据本发明的实施方案，所述的pH调节剂为能够调节溶液pH的物质，例如醋酸、枸橼酸、枸橼酸钠、磷酸、氢氧化钠、碳酸钠、碳酸氢钠、磷酸氢二钠和磷酸二氢钠中的一种或多种。According to an embodiment of the present invention, 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.
根据本发明的实施方案，所述的pH调节剂的浓度可以为0～10.0mg/ml。According to an embodiment of the present invention, the concentration of the pH regulator may be 0-10.0 mg/ml.
在一种实施方案中，所述的pH调节剂的浓度可以为1.0～10.0mg/ml。In one embodiment, the concentration of the pH regulator may be 1.0-10.0 mg/ml.
例如，所述的pH调节剂的浓度为0.005mg/ml、0.06mg/ml、0.0075mg/ml、0.11mg/ml、3.0mg/ml、3.2mg/ml、2.8mg/ml或2.0mg/ml，所述的浓度是指pH调节剂的质量与盐酸决奈达隆注射组合物体积的比值。For example, 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.
根据本发明的实施方案，所述的抗氧化剂例如可以选自L-半胱氨酸盐酸盐、亚硫酸钠、亚硫酸氢钠、没食子酸丙酯、谷胱甘肽、硫代硫酸钠、硫脲、巯基乙酸、焦亚硫酸钠、焦亚硫酸钾、维生素C和维生素E中的一种或多种。According to an embodiment of the present invention, 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.
根据本发明的实施方案，所述的抗氧化剂的浓度可以为0.001mg/ml-0.002mg/ml，例如0.001mg/ml或0.002mg/ml，所述的浓度是指抗氧化剂的质量与盐酸决奈达隆注射组合物体积的比值。According to an embodiment of the present invention, 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.
本发明中，所述的水优选为注射用水。In the present invention, the water is preferably water for injection.
根据本发明的实施方案，所述的盐酸决奈达隆注射组合物可以为以下任一处方：According to an embodiment of the present invention, the dronedarone hydrochloride injection composition can be any of the following prescriptions:
处方1：12mg/ml盐酸决奈达隆、28.8mg/ml羟丙基-β环糊精、2mg/ml枸橼酸、1mg/ml枸橼酸钠、1mg/ml氯化钠、0.001mg/ml亚硫酸氢钠和5ml水，其中各组分的占比为其质量与盐酸决奈达隆注射组合物总体积的比值；Prescription 1: 12mg/ml dronedarone hydrochloride, 28.8mg/ml hydroxypropyl-β 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;
处方2：12mg/ml盐酸决奈达隆、57.6mg/ml羟丙基-β环糊精、1.6mg/ml枸橼酸、1.6mg/ml枸橼酸钠、2mg/ml葡萄糖、0.002mg/ml亚硫酸氢钠和5ml水，其中各组分的占比为其质量与盐酸决奈达隆注射组合物总体积的比值；Prescription 2: 12mg/ml dronedarone hydrochloride, 57.6mg/ml hydroxypropyl-β 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;
处方3：12mg/ml盐酸决奈达隆、43.4mg/ml璜丁基-β环糊精、1.2mg/ml枸橼酸、1.6mg/ml枸橼酸钠、4mg/ml氯化钠、0.001mg/ml维生素C和5ml水，其中各组分的占比为其质量与盐酸决奈达隆注射组合物总体积的比值；Prescription 3: 12mg/ml dronedarone hydrochloride, 43.4mg/ml sulfonyl-β 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;
处方4：12mg/ml盐酸决奈达隆、86.8mg/ml璜丁基-β环糊精、0.6mg/ml枸橼酸、1.4mg/ml枸橼酸钠、10mg/ml葡萄糖、0.002mg/ml维生素C和5ml水，其中各组分的占比为其质量与盐酸决奈达隆注射组合物总体积的比值；Prescription 4: 12mg/ml dronedarone hydrochloride, 86.8mg/ml sulfonyl-β 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;
处方5：8mg/ml盐酸决奈达隆、30mg/ml羟丙基-β环糊精、2mg/ml氯化钠、和10ml水，其中各组分的占比为其质量与盐酸决奈达隆注射组合物总体积的比值；Prescription 5: 8mg/ml dronedarone hydrochloride, 30mg/ml hydroxypropyl-β 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;
处方6：8mg/ml盐酸决奈达隆、90mg/ml璜丁基-β环糊精、1.0mg/ml氯化钠和10ml水，其中各组分的占比为其质量与盐酸决奈达隆注射组合物总体积的比值；Prescription 6: 8mg/ml dronedarone hydrochloride, 90mg/ml sulfonyl-β 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;
处方7：8mg/ml盐酸决奈达隆、90mg/ml璜丁基-β环糊精、0.005mg/ml枸橼酸、1.0mg/ml氯化钠和10ml水，其中各组分的占比为其质量与盐酸决奈达隆注射组合物总体积的比值；Prescription 7: 8mg/ml dronedarone hydrochloride, 90mg/ml sulfobutyl-β 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;
处方8：8mg/ml盐酸决奈达隆、30mg/ml璜丁基-β环糊精、0.005mg/ml枸橼酸、1.5mg/ml葡萄糖、0.001mg/ml亚硫酸氢钠和10ml水，其中各组分的占比为其质量与盐酸决奈达隆注射组合物总体积的比值；Prescription 8: 8mg/ml dronedarone hydrochloride, 30mg/ml sulfonyl-β 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;
处方9：8mg/ml盐酸决奈达隆、60mg/ml璜丁基-β环糊精、0.01mg/ml枸橼酸、0.05mg/ml枸橼酸钠、1mg/ml氯化钠、0.0005mg/ml葡萄糖和10ml水，其中各组分的占比为其质量与盐酸决奈达隆注射组合物总体积的比值；Prescription 9: 8mg/ml dronedarone hydrochloride, 60mg/ml sulfonyl-β 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;
处方10：8mg/ml盐酸决奈达隆、120mg/ml璜丁基-β环糊精、0.01mg/ml枸橼酸、0.1mg/ml枸橼酸钠、0.2mg/ml葡萄糖、0.001mg/ml维生素C和10ml水，其中各组分的占比为其质量与盐酸决奈达隆注射组合物总体积的比值。Prescription 10: 8mg/ml dronedarone hydrochloride, 120mg/ml sulfobutyl-β 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.
根据本发明的实施方案，所述盐酸决奈达隆注射组合物的pH为3.0～7.0。According to an embodiment of the present invention, the pH of the dronedarone hydrochloride injection composition is 3.0-7.0.
在一种实施方案中，所述盐酸决奈达隆注射组合物的pH为3.0～6.0，例如3.0、4.0、5.0、6.0或7.0。In one embodiment, 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.
本发明还提供了所述的盐酸决奈达隆注射组合物的制备方法，其包括以下步骤：The present invention also provides a preparation method of the dronedarone hydrochloride injection composition, which comprises the following steps:
步骤1：将环糊精水溶液与盐酸决奈达隆进行包合，得到盐酸决奈达隆环糊精包合物；Step 1: Inclusion complexing an aqueous cyclodextrin solution with dronedarone hydrochloride to obtain a cyclodextrin inclusion compound of dronedarone hydrochloride;
步骤2：将步骤1得到的盐酸决奈达隆包合物与等渗调节剂及水，以及任选加入或不加入的pH调节剂、抗氧化剂混合，得到所述的盐酸决奈达隆注射组合物；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;
或者，步骤2：将步骤1得到的盐酸决奈达隆包合物与等渗调节剂、以及任选加入或不加入的pH调节剂、抗氧化剂混合，得到所述的盐酸决奈达隆注射组合物。Alternatively, 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.
在一种实施方式中，步骤2：将步骤1得到的盐酸决奈达隆包合物与等渗调节剂、抗氧化剂及水混合，得到所述的盐酸决奈达隆注射组合物。In one embodiment, 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.
在一种实施方式中，步骤2：将步骤1得到的盐酸决奈达隆包合物与等渗调节剂、抗氧化剂混合，得到所述的盐酸决奈达隆注射组合物。In one embodiment, 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.
根据本发明的实施方案，步骤1所述的盐酸决奈达隆包合物可以采用本领域中的常规包合条件进行，本发明中优选采用以下包合条件：According to an embodiment of the present invention, 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:
步骤1中，所述的环糊精水溶液的质量浓度优选1％～50％，进一步优选5％～30％，例如9％、15％、20％或30％，所述的质量浓度是指环糊精的质量与环糊精水溶液总质量的百分比。In step 1, 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.
根据本发明的实施方案，步骤1中，所述的包合的温度优选为20℃～80℃，进一步优选为40℃～70℃，例如60℃。According to an embodiment of the present invention, in step 1, the inclusion temperature is preferably 20°C-80°C, more preferably 40°C-70°C, for example 60°C.
根据本发明的实施方案，步骤1中，所述的包合的时间优选为0.5小时～20小时，进一步优选为1小时～10小时，例如7小时。According to the embodiment of the present invention, in step 1, the inclusion time is preferably 0.5 hour to 20 hours, more preferably 1 hour to 10 hours, for example 7 hours.
根据本发明的实施方案，在所述的盐酸决奈达隆包合物的制备方法中，所述的混合优选为搅拌混合。According to an embodiment of the present invention, in the preparation method of the inclusion compound of dronedarone hydrochloride, the mixing is preferably stirring mixing.
根据本发明的一种实施方案，步骤1优选采用以下后处理步骤：盐酸决奈达隆溶于环糊精水溶液中，进行包合，包合结束后，冷却、过滤、干燥，得到所述的盐酸决奈达隆包合物。According to one embodiment of the present invention, 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.
根据本发明的实施方案，步骤1的后处理步骤中，所述的冷却的温度优选为10℃～30℃，进一步优选为20℃～25℃。According to an embodiment of the present invention, in the post-processing step of step 1, the cooling temperature is preferably 10°C-30°C, more preferably 20°C-25°C.
根据本发明的实施方案，步骤1的后处理步骤中，所述的过滤优选采用滤芯进行。所述的滤芯的孔径优选为0.22微米～0.8微米。According to an embodiment of the present invention, in the post-processing step of step 1, 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.
根据本发明的实施方案，步骤1的后处理步骤中，所述的干燥方式优选选自冷冻干燥、减压干燥、常压干燥和喷雾干燥中的一种或多种，进一步优选为冷冻干燥和/或喷雾干燥。所述的冷冻干燥可以为真空冷冻干燥。According to an embodiment of the present invention, in the post-processing step of step 1, 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.
根据本发明的实施方案，制得的盐酸决奈达隆注射组合物的pH为3.0～7.0。According to the embodiment of the present invention, the pH of the prepared dronedarone hydrochloride injection composition is 3.0-7.0.
在一种实施方案中，制得的盐酸决奈达隆注射组合物的pH为3.0～6.0，例如3.0、4.0、5.0、6.0或7.0。In one embodiment, 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.
本发明还提供了所述的盐酸决奈达隆注射组合物在制备制剂中的应用。The present invention also provides the application of the dronedarone hydrochloride injection composition in the preparation of preparations.
根据本发明的实施方案，所述的制剂可以为注射剂。According to an embodiment of the present invention, the preparation may be an injection.
根据本发明的实施方案，所述的注射剂的规格可以为8ml。According to the embodiment of the present invention, the specification of the injection may be 8ml.
根据本发明的一种实施方案，所述的注射剂的浓度可以为5～12mg/ml，例如为10mg/ml；以盐酸决奈达隆在注射剂中的浓度计；优选地，所述盐酸决奈达隆在注射剂中至少以盐酸决奈达隆包合物形式存在。According to one embodiment of the present invention, 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.
本发明还提供一种注射剂，含有所述的盐酸决奈达隆注射组合物。The present invention also provides an injection containing the dronedarone hydrochloride injection composition.
本发明还提供了所述盐酸决奈达隆注射剂的制备方法，包括由所述的盐酸决奈达隆注射组合物优选用微孔滤膜精滤，灌装、灭菌后，得到盐酸决奈达隆注射剂。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.
本发明还提供了所述的盐酸决奈达隆注射组合物在制备治疗和/或预防心律失常的药物中的应用。The present invention also provides the use of the dronedarone hydrochloride injection composition in the preparation of drugs for treating and/or preventing arrhythmia.
本发明还提供了治疗和/或预防心律失常的方法，其为给患者施用有效剂量的所述的盐酸决奈达隆注射组合物或制剂。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.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明中，所述的室温是指环境温度为10℃～35℃。In the present invention, the room temperature refers to an ambient temperature of 10°C to 35°C.
本发明的有益效果：本发明克服了现有技术中盐酸决奈达隆溶解度小、体外溶出速度低、生物利用度低、给药剂量大等缺陷，而提供了一种盐酸决奈达隆注射组合物、其制备方法及应用。Beneficial effects of the present invention: 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.
本发明盐酸决奈达隆-环糊精包合物稳定性好、在水中的溶解度大大提高、比盐酸决奈达隆的溶解度提高了90倍左右(原料药在水中的溶解度仅为0.69mg/ml)，生物利用度高，适合于工业化生产。本发明的盐酸决奈达隆包合物制备操作简单，制得的盐酸决奈达隆包合物易于制备制剂。本发明所制备的盐酸决奈达隆组合物、注射剂，稳定性好，适用于不宜口服给药的心律失常患者。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.
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.
实施例1-4Example 1-4
实施例1-4盐酸决奈达隆组合物的处方如表1所示：The prescription of embodiment 1-4 dronedarone hydrochloride composition is shown in Table 1:
表1Table 1
实施例5-10Example 5-10
实施例5-10盐酸决奈达隆组合物的处方如表2所示：The prescription of embodiment 5-10 dronedarone hydrochloride composition is shown in Table 2:
表2Table 2
实施例1-10的制备工艺：将环糊精配成30％浓度的水溶液，加入处方量盐酸决奈达隆，60℃条件下搅拌7小时，放至室温，过滤，冷冻干燥，即得盐酸决奈达隆环糊精包合物。The preparation process of Examples 1-10: make cyclodextrin into a 30% aqueous solution, add the prescribed amount of dronedarone hydrochloride, stir at 60°C for 7 hours, let it cool to room temperature, filter, and freeze-dry to obtain hydrochloric acid Dronedarone Cyclodextrin Inclusion Compound.
将等渗调节剂、pH调节剂、抗氧化剂加入适量注射用水溶解，加入盐酸决奈达隆包合物，溶解，用pH调节剂调节pH至3～7。加水至配制量，所得溶液用微孔滤膜精滤，灌装，灭菌(121℃，15分钟)，即得盐酸决奈达隆注射剂成品。Add an appropriate amount of water for injection to dissolve the isotonic regulator, pH regulator and antioxidant, add dronedarone hydrochloride inclusion compound, dissolve, and adjust the pH to 3-7 with the pH regulator. Add water to the prepared amount, fine filter the resulting solution with a microporous membrane, fill it, and sterilize (121°C, 15 minutes) to obtain the finished dronedarone hydrochloride injection.
分别将上述实施例5-10样品放置于高温(60℃)和加速条件(40℃±2℃，75％RH±5％RH)，相应时间点取样检测，对盐酸决奈达隆含量、注射剂的pH值及有关物质进行测试。其中，盐酸决奈达隆含量及有关物质的检测方法如下：The above-mentioned samples of Examples 5-10 were respectively placed under high temperature (60°C) and accelerated conditions (40°C±2°C, 75%RH±5%RH), and samples were taken at corresponding time points for detection. The content of dronedarone hydrochloride, injection The pH value and related substances are tested. Among them, the detection methods of dronedarone hydrochloride content and related substances are as follows:
盐酸决奈达隆的含量：按照高效液相色谱法(通则0512)测定；Content of dronedarone hydrochloride: determined according to high performance liquid chromatography (general rule 0512);
溶剂：乙腈-水(体积比，60:40)；Solvent: acetonitrile-water (volume ratio, 60:40);
供试品溶液：取本品适量，用溶剂稀释制成每1mL中约含决奈达隆0.08mg的溶液。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.
对照溶液：取盐酸决奈达隆对照品适量，精密称定，用溶剂溶解并定量稀释制成每1mL中约含决奈达隆0.08mg的溶液。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.
色谱条件：用十八烷基硅烷键合硅胶为填充剂；以0.2％三乙胺溶液(精密量取三乙胺2mL置1000mL水中，混匀，用磷酸调节pH值至9.0)-乙腈(10:90)为流动相；流速为每分钟1.0mL；柱温30℃；检测波长为288nm；进样体积为10μL；运行时间为10min。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 μL; the run time is 10 min.
有关物质：按照高效液相色谱法(通则0512)测定；Related substances: determined according to high performance liquid chromatography (general rule 0512);
溶剂：乙腈-水(体积比，60:40)；Solvent: acetonitrile-water (volume ratio, 60:40);
供试品溶液：取本品适量，用溶剂稀释制成每1mL中约含决奈达隆0.8mg的溶液。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.
对照溶液：精密量取供试品溶液适量，用溶剂定量稀释制成每1mL中约含决奈达隆1.6μg的溶液。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 μg of dronedarone per 1 mL.
色谱条件：用十八烷基硅烷键合硅胶为填充剂(推荐使用Waters XBridge Shield RP18，4.6mm×250mm，5μm或效能相当的色谱柱)；以0.2％三乙胺溶液(精密量取三乙胺2mL置1000mL水中，混匀，用磷酸调节pH值至9.0)为流动相A，以乙腈为流动相B；流速为每分钟0.8mL；柱温30℃；检测波长为246nm；进样体积为25μL；运行时间为50min。Chromatographic conditions: Use octadecylsilane bonded silica gel as filler (Waters XBridge Shield RP18, 4.6mm×250mm, 5μm or equivalent chromatographic column is recommended); use 0.2% triethylamine solution (accurately measure triethylamine) Put 2 mL of amine in 1000 mL of water, mix well, and adjust the pH value to 9.0 with phosphoric acid) as mobile phase A, and acetonitrile as mobile phase B; the flow rate is 0.8 mL per minute; the column temperature is 30 ° C; the detection wavelength is 246 nm; the injection volume is 25μL; the running time is 50min.
稳定性结果如下表3-5所示：The stability results are shown in Table 3-5 below:
表3高温60℃的含量结果 [1] Table 3 Content results at high temperature 60°C [1]
[1]含量结果指的是澄清溶液中的盐酸决奈达隆的测试含量与理论值的百分比，理论值指的是处方量盐酸决奈达隆在处方量注射用水中的浓度；[1] 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;
*：实施例10在放置过程中会析出，因此后续不继续考察稳定性。 * : Example 10 will precipitate out during placement, so follow-up does not continue to investigate stability.
由表3可知，高温5天、10天条件下，盐酸决奈达隆的含量结果较初始值几乎无变化。进一步进行高温30天和加速30天的测试，盐酸决奈达隆的含量结果较初始值相比也无明显变化，二者差值在0～5.0％范围内。说明，实施例5-10制备的盐酸决奈达隆注射剂具有良好的稳定性。It can be seen from Table 3 that under the condition of high temperature for 5 days and 10 days, the content of dronedarone hydrochloride was almost unchanged from the initial value. Further testing at high temperature for 30 days and accelerated 30 days showed that the content of dronedarone hydrochloride did not change significantly compared with the initial value, and the difference between the two was in the range of 0% to 5.0%. It shows that the dronedarone hydrochloride injection prepared in Examples 5-10 has good stability.
表4高温60℃的pH结果Table 4 pH results at high temperature 60°C
由表4可知，高温5天、10天条件下，盐酸决奈达隆的pH结果较初始值几乎无变化。进一步进行高温30天和加速30天的测试，盐酸决奈达隆的pH结果较初始值相比也无明显变化，二者差值在0～1.0范围内。说明，实施例5-9制备的盐酸决奈达隆注射剂具有良好的稳定性。It can be seen from Table 4 that under the condition of high temperature for 5 days and 10 days, the pH of dronedarone hydrochloride hardly changed from the initial value. Further testing at high temperature for 30 days and accelerated 30 days showed that the pH of dronedarone hydrochloride did not change significantly compared with the initial value, and the difference between the two was in the range of 0 to 1.0. It shows that the dronedarone hydrochloride injection prepared in Examples 5-9 has good stability.
表5高温60℃的有关物质结果 * Table 5 Results of related substances at high temperature of 60°C *
*低于0.05％的杂质不计入总杂。*Impurities below 0.05% are not included in the total impurities.
由表5可知，高温5天、10天条件下，盐酸决奈达隆的有关物质结果较初始值几乎无变化。进一步进行高温30天和加速30天的测试，盐酸决奈达隆的有关物质结果较初始值相比也无明显变化。说明，实施例5-9制备的盐酸决奈达隆注射剂具有良好的稳定性。It can be seen from Table 5 that under the conditions of high temperature for 5 days and 10 days, the results of related substances of dronedarone hydrochloride were almost unchanged from the initial values. Further testing at high temperature for 30 days and accelerated 30 days showed that the results of related substances of dronedarone hydrochloride did not change significantly compared with the initial values. It shows that the dronedarone hydrochloride injection prepared in Examples 5-9 has good stability.
其中，已知杂质IM-A的结构如下：Wherein, the structure of known impurity IM-A is as follows:
分子式为：C 27H 36N 2O 5S The molecular formula is: C 27 H 36 N 2 O 5 S
分子量为：500.65Molecular weight: 500.65
化学名为：N-[2-丁基-3-[4-[3-(丁基氨基)丙氧基]苯甲酰基]-5-苯并呋喃基]甲 磺酰胺。Chemical name: N-[2-butyl-3-[4-[3-(butylamino)propoxy]benzoyl]-5-benzofuryl]methanesulfonamide.
实施例11Example 11
本实施例处方与实施例7相同，制备工艺如下：将环糊精配成约9％浓度的水溶液，加入处方量盐酸决奈达隆，60℃条件下搅拌7小时，放至室温，过滤，冷冻干燥，即得盐酸决奈达隆环糊精包合物。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.
将等渗调节剂、pH调节剂、抗氧化剂加入适量注射用水溶解，加入盐酸决奈达隆包合物，溶解，用pH调节剂调节pH至3～7。加水至配制量，所得溶液用微孔滤膜精滤，灌装，灭菌(121℃，15分钟)，即得盐酸决奈达隆注射剂成品。Add an appropriate amount of water for injection to dissolve the isotonic regulator, pH regulator and antioxidant, add dronedarone hydrochloride inclusion compound, dissolve, and adjust the pH to 3-7 with the pH regulator. Add water to the prepared amount, fine filter the resulting solution with a microporous membrane, fill it, and sterilize (121°C, 15 minutes) to obtain the finished dronedarone hydrochloride injection.
得到的成品为澄清溶液，经上述含量测试，盐酸决奈达隆的测试含量与理论值之比近乎100％，说明盐酸决奈达隆的注射剂中的浓度约为8mg/ml。同时，本实施例注射剂的稳定性至少能够达到实施例5-9的稳定性。The obtained finished product is a clear solution. After the above content test, 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. Simultaneously, the stability of the injection of this embodiment can at least reach the stability of Examples 5-9.
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The embodiments of the present invention have been described above. However, the present invention is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.
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| CN (1) | CN115702878B (en) |
| TW (1) | TW202320751A (en) |
| WO (1) | WO2023019993A1 (en) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2817750B1 (en) * | 2000-12-11 | 2003-02-21 | Sanofi Synthelabo | DRONEDARONE PHARMACEUTICAL COMPOSITION FOR PARENTERAL ADMINISTRATION |
| EP2428511A1 (en) * | 2010-09-09 | 2012-03-14 | USV Limited | Synthesis of dronedarone and salts thereof |
| CN102908307A (en) * | 2011-08-03 | 2013-02-06 | 天津市嵩锐医药科技有限公司 | Dronedarone hydrochloride pharmaceutical composition for injection and preparation method thereof |
| CN103169691B (en) * | 2011-12-22 | 2016-08-17 | 深圳信立泰药业股份有限公司 | A kind of dronedarone or the powder of its salt and pharmaceutical composition prepared therefrom |
| CN105412027B (en) * | 2015-11-13 | 2018-10-26 | 青岛市海慈医疗集团 | A kind of preparation method of Dronedarone hydrochloride tablet |
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2022
- 2022-04-20 WO PCT/CN2022/087977 patent/WO2023019993A1/en not_active Ceased
- 2022-04-20 CN CN202210438565.2A patent/CN115702878B/en active Active
- 2022-04-20 TW TW111115119A patent/TW202320751A/en unknown
Non-Patent Citations (2)
| Title |
|---|
| 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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| TW202320751A (en) | 2023-06-01 |
| CN115702878B (en) | 2024-05-10 |
| CN115702878A (en) | 2023-02-17 |
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