Dronedarone liposome preparation for injection and preparation method thereof

Abstract

The invention discloses a dronedarone liposome preparation for injection and a preparation method of the dronedarone liposome preparation, and belongs to the field of preparation of pharmaceutical preparations. The dronedarone liposome preparation for injection comprises an active component and a pharmaceutical adjuvant, the active component is dronedarone or a pharmaceutically acceptable salt thereof; the pharmaceutic adjuvants comprise a phospholipid material, a stabilizer and an emulsifier; the dronedarone liposome preparation comprises the following components in percentage by weight: 10%-30% of an active component, 50%-80% of a phospholipid material, 2%-15% of a stabilizer and 0.5%-5% of an emulsifier, wherein the emulsifier is selected from cholate. The dronedarone lipidosome for injection is prepared by adopting a lipidosome process, the problems of low solubility and slow in-vitro dissolution rate of dronedarone are solved, the prepared dronedarone lipidosome preparation for injection is high in encapsulation efficiency, good in stability and high in bioavailability, the maximum concentration after redissolution can reach 50 mg / ml, and meanwhile, the liver first-pass effect of oral administration is avoided.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparation preparation, and particularly relates to a dronedarone liposome preparation for injection and a preparation method thereof. Background Art

[0002] Dronedarone is a new type of Class III antiarrhythmic drug. Its chemical structure is similar to amiodarone (amiodarone) but does not contain iodine. It has similar electrophysiological effects to amiodarone but eliminates iodine-related adverse reactions. It can be used for patients with sinus rhythm with a history of paroxysmal or persistent atrial fibrillation to reduce the risk of hospitalization due to atrial fibrillation (AF).

[0003] Dronedarone tablets (Dronedarone, Mai Da Long) were developed by French company Sanofi-Aventis. They are the only new antiarrhythmic drug approved for long-term rhythm control in the past decade. They were approved for marketing in the United States and Europe in July and November 2009, respectively, and were approved for import and marketing in China in August 2012. They are used for patients with sinus rhythm who have a history of paroxysmal or persistent atrial fibrillation to reduce the risk of hospitalization due to atrial fibrillation (AF).

[0004] Dronedarone is a poorly soluble drug with poor stability. When prepared into an injectable preparation using conventional formulation technology, it has problems such as poor solubility, low drug loading, and poor stability, which affect the efficacy and therapeutic effect of the drug. Dronedarone needs to be specially treated to improve the solubility, drug loading and stability of the drug.

[0005] Patent CN102908307A discloses a dronedarone hydrochloride pharmaceutical composition for injection and its preparation method, which is composed of amorphous dronedarone hydrochloride, sodium chloride, and cysteine ​​hydrochloride, and amorphous dronedarone hydrochloride is prepared by spray drying technology for solubilization. Amorphous drug delivery systems belong to thermodynamically and kinetically unstable systems. Dronedarone in an amorphous state has the characteristics of easy crystallization and precipitation, and the drug is easily oxidized in aqueous solution. The preparation method has stability risks, and the aqueous solution injection increases the difficulty and cost of production, storage and transportation.

[0006] Patent CN115702878B discloses a dronedarone hydrochloride injection composition, a preparation method and application thereof, comprising dronedarone hydrochloride, cyclodextrin, an isotonicity regulator, a pH regulator, an antioxidant and water for injection, and solubilizing the composition by preparing a dronedarone hydrochloride-cyclodextrin inclusion compound. Cyclodextrin inclusion compounds have high requirements for the matching of the cavity and the ligand, poor binding strength, low encapsulation rate, and a complex manufacturing process, making industrial production difficult. Summary of the invention

[0007] In order to solve the defects of poor stability and complicated process of preparing dronedarone injection in the prior art, the present invention provides a dronedarone liposome preparation for injection and a preparation method thereof. The dronedarone liposome preparation prepared by the present invention can avoid the liver first-pass effect of oral administration, and the preparation has the advantages of high encapsulation rate, good stability, high bioavailability, slow blood clearance rate, and reduced toxicity of free drugs, and is suitable for patients who are not suitable for oral administration. On the other hand, the method for preparing the dronedarone liposome preparation of the present invention is simple to operate, short production time, and suitable for industrial production.

[0008] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0009] A dronedarone liposome preparation for injection, comprising an active ingredient and pharmaceutical excipients;

[0010] The active ingredient is dronedarone or a pharmaceutically acceptable salt thereof;

[0011] The pharmaceutical excipients include phospholipid materials, stabilizers, and emulsifiers;

[0012] The contents of the components of the dronedarone liposome preparation are as follows by weight percentage:

[0013] Active ingredient……………………10%~30%,

[0014] Phospholipid material……………………50%-80%,

[0015] Stabilizer…………………………2%-15%,

[0016] Emulsifier……………………0.5%-5%.

[0017] The emulsifier is selected from bile salts, and specifically can be selected from one or more of sodium cholate, sodium glycocholate, sodium taurocholate, sodium deoxycholate and the like.

[0018] The phospholipid material is selected from a combination of neutral phospholipids and negatively charged phospholipids; preferably, the ratio of the neutral phospholipid to the negatively charged phospholipid combination is 1:1-1:3.

[0019] Preferably, the neutral phospholipid is selected from one or more of dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, phosphatidylethanolamine, dipalmitoylphosphatidylethanolamine and distearoylphosphatidylcholine.

[0020] Preferably, the negatively charged phospholipid is selected from one or more of phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, dilauroylphosphatidylglycerol, dipalmitoylphosphatidic acid, dimyristoylphosphatidylglycerol, distearoylphosphatidylglycerol, and dipalmitoylphosphatidylglycerol.

[0021] The stabilizer is selected from one or more of mannitol, D-glucose, lactose, sucrose, trehalose, polyethylene glycol, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide, dextran and methylcellulose.

[0022] Preferably, the average molecular weight of the polyethylene glycol is 2000-6000.

[0023] On the other hand, the present invention also provides a method for preparing a dronedarone liposome preparation for injection, wherein the method for preparing the dronedarone liposome preparation for injection is a thin film dispersion method, and the method specifically comprises the following steps:

[0024] (1) dissolving the active ingredient and the phospholipid material in an organic solvent to form a uniform liposome solution, controlling the system temperature at 20° C. to 80° C. to remove the solvent, and allowing the material to form a uniform film;

[0025] (2) dissolving a stabilizer and bile salts in water to form a stabilizer aqueous solution;

[0026] (3) adding the stabilizer aqueous solution in step (2) to the homogenized film in step (1), stirring to disperse the film, and preparing dronedarone liposomes by microfluidization homogenization and emulsification;

[0027] (4) removing the solvent from the dronedarone liposomes obtained in step (3) to obtain a dronedarone liposome preparation for injection.

[0028] Furthermore, the step (1) removes the solvent by means of reduced pressure rotary evaporation to form a homogeneous film; further preferably, the vacuum degree of the reduced pressure rotary evaporation is -0.7 bar to -0.9 bar.

[0029] Furthermore, the organic solvent in step (1) is selected from one or a mixture of ethanol, isopropanol, n-hexane, tert-butanol, dichloromethane, chloroform, and acetone, and more preferably the organic solvent is a mixed solvent of dichloromethane and ethanol in a volume ratio of 4:1.

[0030] Furthermore, in the step (1), the w / v ratio of the active ingredient to the organic solvent is 1:10 to 30.

[0031] Furthermore, the film dispersion method in step (3) can be stirring in a water bath at 20-80°C.

[0032] Furthermore, the cavity diameter used in the microfluidic homogenization emulsification in step (3) is 50-75 μm, and the homogenization pressure is 5 kpsi-30 kpsi.

[0033] Furthermore, the method for removing the solvent in step (4) is selected from freeze drying, spray drying, and rotary evaporation, and freeze drying is more preferred.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] 1. The present invention adopts liposome technology to prepare dronedarone liposomes for injection, which solves the problems of low solubility and slow in vitro dissolution rate of dronedarone. The prepared dronedarone liposome preparation for injection has high encapsulation rate, good stability, high bioavailability, and a maximum concentration of 50 mg / ml after reconstitution, while avoiding the first-pass effect of oral administration in the liver.

[0036] 2. The present invention adopts a microfluidization homogenization emulsification method to prepare dronedarone liposomes, which avoids the denaturation of lipid materials caused by ultrasonic radiation, and the obtained liposome particle size is extremely small, which can reach below 50nm. At the same time, in order to avoid the problem that the liposome particle size is too small, unstable, easy to re-aggregate, etc., the present invention creatively adds bile salt excipients to the liposome solution, which can effectively prevent the aggregation of small-particle liposomes after microfluidization homogenization emulsification, and obtain uniform and stable nano-scale liposomes. The dronedarone liposomes for injection prepared by this method can significantly slow down the blood clearance rate and reduce the toxicity of free drugs.

[0037] 3. Compared with the conventional ultrasonic method for thin film dispersion, the process of preparing liposomes in the present invention has better reproducibility, uniform liposome particle size, easy quality control, simple operation, short production time, and is suitable for industrial production. DETAILED DESCRIPTION

[0038] In order to better understand the content of the present invention, the following is further described in conjunction with the examples, but the content of the present invention is not limited to these examples. The various raw materials and reagents used in the embodiments and test examples are commercially available unless otherwise specified.

[0039] Example 1

[0040] (1) 80 g of nedarone, 110 g of distearoylphosphatidylcholine, 110 g of dipalmitoylphosphatidylglycerol, and 20 g of phosphatidic acid were placed in an eggplant-shaped bottle, and 2 L of a mixed solvent of dichloromethane and ethanol in a volume ratio of 4:1 was added, and the mixture was stirred in a 60° C. water bath until dissolved to form a clear and transparent uniform liposome solution;

[0041] (2) placing the eggplant-shaped bottle described in step (1) in a 60° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0042] (3) The eggplant-shaped bottle described in step (2) is transferred to a 40° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0043] (4) Take 50 g of polyethylene glycol 4000 and 5 g of sodium cholate, add them to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0044] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 60° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0045] (6) The first-level dronedarone liposome solution described in step (5) was circulated three times by a microfluidizer at a pressure of 25,000 psi, and insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0046] (7) The secondary dronedarone liposome solution described in step (6) is dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and placed in a freeze dryer to remove the solvent, and the pre-freezing temperature is -40°C to obtain a dronedarone liposome preparation for injection. The preparation is packaged according to a specification of 80 mg / vial (80 mg in the specification is the mass of the active ingredient, the same below), and is recorded as Preparation 1.

[0047] Example 2

[0048] (1) 40 g of nedarone, 150 g of dipalmitoylphosphatidylcholine, and 150 g of distearoylphosphatidylglycerol were placed in an eggplant-shaped bottle, and 2 L of a mixed solvent of chloroform and tert-butyl alcohol in a volume ratio of 4:1 was added, and the mixture was stirred in a water bath at 60° C. until dissolved to form a clear and transparent uniform liposome solution;

[0049] (2) placing the eggplant-shaped bottle described in step (1) in a 60° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0050] (3) The eggplant-shaped bottle described in step (2) is transferred to a 40° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0051] (4) Take 30 g of polyvinyl pyrrolidone K30 and 5 g of sodium cholate, add them to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0052] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 60° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0053] (6) The first-level dronedarone liposome solution described in step (5) was circulated three times by a microfluidizer at a pressure of 30,000 psi, and the insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0054] (7) The secondary dronedarone liposome solution described in step (6) was placed in a spray dryer to remove the solvent, and the spray inlet temperature was 80° C. to obtain a spray-dried powder, which was packaged into 5 ml vials, 37.5 mg per bottle, for a total of 1000 vials, to obtain a dronedarone liposome preparation for injection. The preparation was packaged according to the specification of 40 mg / vial, recorded as Preparation 2.

[0055] Example 3

[0056] (1) 110 g of nedarone, 50 g of dilauroylphosphatidylcholine, 145 g of dimyristoylphosphatidylglycerol, and 2 g of phosphatidylinositol were placed in an eggplant-shaped bottle, and 2 L of a mixed solvent of acetone and ethanol in a volume ratio of 3:2 was added, and the mixture was stirred in a 40° C. water bath until dissolved to form a clear and transparent uniform liposome solution;

[0057] (2) placing the eggplant-shaped bottle described in step (1) in a 40° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0058] (3) The eggplant-shaped bottle described in step (2) is transferred to a 20° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0059] (4) Take 50 g of mannitol and 18 g of sodium cholate, add them to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0060] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 40° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0061] (6) The first-level dronedarone liposome solution described in step (5) was circulated three times by a microfluidizer at a pressure of 5000 psi, and the insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0062] (7) The secondary dronedarone liposome solution described in step (6) is dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and placed in a freeze dryer to remove the solvent, and the pre-freezing temperature is -40°C to obtain a dronedarone liposome preparation for injection. The preparation is packaged according to the specification of 110 mg / vial, and is recorded as Preparation 3.

[0063] Example 4

[0064] (1) 80 g of nedarone, 141 g of dimyristoylphosphatidylcholine, and 141 g of phosphatidylglycerol were placed in an eggplant-shaped bottle, and 2 L of a mixed solvent of n-hexane and isopropanol in a volume ratio of 3:2 was added, and the mixture was stirred in a 40° C. water bath until dissolved to form a clear and transparent uniform liposome solution;

[0065] (2) placing the eggplant-shaped bottle described in step (1) in a 40° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0066] (3) The eggplant-shaped bottle described in step (2) is transferred to a 20° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0067] (4) Take 8 g of D-glucose and 5 g of sodium glycocholate, add them to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0068] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 40° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0069] (6) The first-level dronedarone liposome solution described in step (5) was circulated three times by a microfluidizer at a pressure of 25,000 psi, and insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0070] (7) The secondary dronedarone liposome solution described in step (6) was dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and placed in a freeze dryer to remove the solvent, and the pre-freezing temperature was -40°C to obtain a dronedarone liposome preparation for injection. The preparation was packaged according to the specification of 80 mg / vial, and recorded as Preparation 4.

[0071] Example 5

[0072] (1) 80 g of nedarone, 127 g of phosphatidylethanolamine, 42 g of dilauroylphosphatidylglycerol and 85 g of phosphatidylserine were placed in an eggplant-shaped bottle, 2 L of a mixed solvent of n-hexane and isopropanol in a volume ratio of 3:2 was added, and the mixture was stirred in a 60° C. water bath until dissolved to form a clear and transparent uniform liposome solution;

[0073] (2) placing the eggplant-shaped bottle described in step (1) in a 60° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0074] (3) The eggplant-shaped bottle described in step (2) is transferred to a 40° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0075] (4) Take 30 g of methylcellulose and 11 g of sodium taurocholate, add them to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0076] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 60° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0077] (6) The first-level dronedarone liposome solution of step (5) was passed through a microfluidizer and circulated three times at a pressure of 10,000 psi, and the insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0078] (7) The secondary dronedarone liposome solution described in step (6) is dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and placed in a freeze dryer to remove the solvent, and the pre-freezing temperature is -40°C to obtain a dronedarone liposome preparation for injection. The preparation is packaged according to the specification of 80 mg / vial, and is recorded as Preparation 5.

[0079] Example 6

[0080] (1) 80 g of donedarone, 120 g of dipalmitoylphosphatidylethanolamine, and 143 g of dipalmitoylphosphatidic acid were placed in an eggplant-shaped bottle, 2 L of a mixed solvent of dichloromethane and ethanol in a volume ratio of 4:1 was added, and the mixture was stirred in a water bath at 80° C. until dissolved to form a clear and transparent uniform liposome solution;

[0081] (2) placing the eggplant-shaped bottle described in step (1) in a water bath at 80° C. and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0082] (3) The eggplant-shaped bottle described in step (2) is transferred to a 60° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film is slowly formed on the inner wall of the eggplant-shaped bottle;

[0083] (4) Take 30 g of polyethylene glycol 6000 and 2 g of sodium deoxycholate, add them to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0084] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a water bath at 80° C. for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0085] (6) The first-level dronedarone liposome solution described in step (5) was circulated three times by a microfluidizer at a pressure of 25,000 psi, and insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0086] (7) The secondary dronedarone liposome solution described in step (6) was dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and the vials were placed in a rotary evaporator to remove the solvent at a water bath temperature of 60° C., thereby obtaining a dronedarone liposome preparation for injection. The preparation was packaged according to the specification of 80 mg / vial, recorded as Preparation 6.

[0087] Comparative Example 1

[0088] (1) 80 g of nedarone and 240 g of distearoylphosphatidylcholine were placed in an eggplant-shaped bottle, and 2 L of a mixed solvent of dichloromethane and ethanol in a volume ratio of 4:1 was added, and the mixture was stirred in a 60° C. water bath until dissolved to form a clear and transparent uniform liposome solution;

[0089] (2) placing the eggplant-shaped bottle described in step (1) in a 60° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0090] (3) The eggplant-shaped bottle described in step (2) is transferred to a 40° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0091] (4) Take 50 g of polyethylene glycol 4000 and 5 g of sodium cholate, add them to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0092] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 60° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0093] (6) The first-level dronedarone liposome solution described in step (5) was circulated three times by a microfluidizer at a pressure of 25,000 psi, and insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0094] (7) The secondary dronedarone liposome solution described in step (6) was dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and placed in a freeze dryer to remove the solvent, and the pre-freezing temperature was -40°C to obtain a dronedarone liposome preparation for injection. The preparation was packaged according to the specification of 80 mg / vial, and recorded as comparative preparation 1.

[0095] Comparative Example 2

[0096] (1) 80 g of nedarone, 220 g of dipalmitoylphosphatidylglycerol, and 20 g of phosphatidic acid were placed in an eggplant-shaped bottle, and 2 L of a mixed solvent of dichloromethane and ethanol in a volume ratio of 4:1 was added, and the mixture was stirred in a 60° C. water bath until dissolved to form a clear and transparent uniform liposome solution;

[0097] (2) placing the eggplant-shaped bottle described in step (1) in a 60° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0098] (3) The eggplant-shaped bottle described in step (2) is transferred to a 40° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0099] (4) Take 50 g of polyethylene glycol 4000 and 5 g of sodium cholate, add them to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0100] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 60° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0101] (6) The first-level dronedarone liposome solution described in step (5) was circulated three times by a microfluidizer at a pressure of 25,000 psi, and insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0102] (7) The secondary dronedarone liposome solution described in step (6) was dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and placed in a freeze dryer to remove the solvent, and the pre-freezing temperature was -40°C to obtain a dronedarone liposome preparation for injection. The preparation was packaged according to the specification of 80 mg / vial, and recorded as comparative preparation 2.

[0103] Comparative Example 3

[0104] (1) 160 g of nedarone, 70 g of distearoylphosphatidylcholine, 70 g of dipalmitoylphosphatidylglycerol, and 20 g of phosphatidic acid were placed in an eggplant-shaped bottle, and 2 L of a mixed solvent of dichloromethane and ethanol in a volume ratio of 4:1 was added, and the mixture was stirred in a 60° C. water bath until dissolved to form a clear and transparent uniform liposome solution;

[0105] (2) placing the eggplant-shaped bottle described in step (1) in a 60° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0106] (3) The eggplant-shaped bottle described in step (2) is transferred to a 40° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0107] (4) Take 50 g of polyethylene glycol 4000 and 5 g of sodium cholate, add them to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0108] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 60° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0109] (6) The first-level dronedarone liposome solution described in step (5) was circulated three times by a microfluidizer at a pressure of 25,000 psi, and insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0110] (7) The secondary dronedarone liposome solution described in step (6) was dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and placed in a freeze dryer to remove the solvent, and the pre-freezing temperature was -40°C to obtain a dronedarone liposome preparation for injection. The preparation was packaged according to the specification of 80 mg / vial, and recorded as comparative preparation 3.

[0111] Comparative Example 4

[0112] (1) 80 g of nedarone, 110 g of distearoylphosphatidylcholine, 110 g of dipalmitoylphosphatidylglycerol, and 20 g of phosphatidic acid were placed in an eggplant-shaped bottle, and 2 L of a mixed solvent of dichloromethane and ethanol in a volume ratio of 4:1 was added, and the mixture was stirred in a 60° C. water bath until dissolved to form a clear and transparent uniform liposome solution;

[0113] (2) placing the eggplant-shaped bottle described in step (1) in a 60° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0114] (3) The eggplant-shaped bottle described in step (2) is transferred to a 40° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0115] (4) Take 50 g of polyethylene glycol 4000, add it to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0116] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 60° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0117] (6) The first-level dronedarone liposome solution described in step (5) was circulated three times by a microfluidizer at a pressure of 25,000 psi, and insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0118] (7) The secondary dronedarone liposome solution described in step (6) was dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and placed in a freeze dryer to remove the solvent, and the pre-freezing temperature was -40°C to obtain a dronedarone liposome preparation for injection. The preparation was packaged according to the specification of 80 mg / vial, and recorded as comparative preparation 4.

[0119] Comparative Example 5

[0120] (1) 80 g of nedarone, 110 g of distearoylphosphatidylcholine, 110 g of dipalmitoylphosphatidylglycerol, and 20 g of phosphatidic acid were placed in an eggplant-shaped bottle, and 2 L of a mixed solvent of dichloromethane and ethanol in a volume ratio of 4:1 was added, and the mixture was stirred in a 60° C. water bath until dissolved to form a clear and transparent uniform liposome solution;

[0121] (2) placing the eggplant-shaped bottle described in step (1) in a 60° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0122] (3) The eggplant-shaped bottle described in step (2) is transferred to a 40° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0123] (4) Take 50 g of polyethylene glycol 4000 and 5 g of Tween 80, add them to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0124] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 60° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0125] (6) The first-level dronedarone liposome solution described in step (5) was circulated three times by a microfluidizer at a pressure of 25,000 psi, and insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0126] (7) The secondary dronedarone liposome solution described in step (6) was dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and placed in a freeze dryer to remove the solvent, and the pre-freezing temperature was -40°C to obtain a dronedarone liposome preparation for injection. The preparation was packaged according to the specification of 80 mg / vial, and recorded as comparative preparation 5.

[0127] Comparative Example 6

[0128] (1) 80 g of nedarone, 110 g of distearoylphosphatidylcholine, 110 g of dipalmitoylphosphatidylglycerol, and 20 g of phosphatidic acid were placed in an eggplant-shaped bottle, and 2 L of a mixed solvent of dichloromethane and ethanol in a volume ratio of 4:1 was added, and the mixture was stirred in a 60° C. water bath until dissolved to form a clear and transparent uniform liposome solution;

[0129] (2) placing the eggplant-shaped bottle described in step (1) in a 60° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0130] (3) The eggplant-shaped bottle described in step (2) is transferred to a 40° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0131] (4) Take 50 g of polyethylene glycol 4000 and 5 g of sodium cholate, add them to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0132] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 60° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0133] (6) subjecting the first-level dronedarone liposome solution described in step (5) to ultrasonication for 30 minutes, circulating three times at a pressure of 25,000 psi, and removing insoluble matter by column chromatography to obtain a second-level dronedarone liposome solution;

[0134] (7) The secondary dronedarone liposome solution described in step (6) was dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and placed in a freeze dryer to remove the solvent, and the pre-freezing temperature was -40°C to obtain a dronedarone liposome preparation for injection. The preparation was packaged according to the specification of 80 mg / vial, and recorded as comparative preparation 6.

[0135] Comparative Example 7

[0136] (1) 80 g of nedarone, 110 g of distearoylphosphatidylcholine, 110 g of dipalmitoylphosphatidylglycerol, and 20 g of phosphatidic acid were placed in an eggplant-shaped bottle, and 2 L of a mixed solvent of dichloromethane and ethanol in a volume ratio of 4:1 was added, and the mixture was stirred in a 60° C. water bath until dissolved to form a clear and transparent uniform liposome solution;

[0137] (2) placing the eggplant-shaped bottle described in step (1) in a 60° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0138] (3) The eggplant-shaped bottle described in step (2) is transferred to a 40° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0139] (4) Take 5 g of sodium cholate, add it to 500 ml of water, and stir until dissolved to obtain an emulsifier aqueous solution;

[0140] (5) slowly adding the emulsifier aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 60° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0141] (6) The first-level dronedarone liposome solution described in step (5) was circulated three times by a microfluidizer at a pressure of 25,000 psi, and insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0142] (7) The secondary dronedarone liposome solution described in step (6) was dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and placed in a freeze dryer to remove the solvent, and the pre-freezing temperature was -40°C to obtain a dronedarone liposome preparation for injection. The preparation was packaged according to the specification of 80 mg / vial, and recorded as comparative preparation 7.

[0143] Comparative Example 8

[0144] (1) 220 g of nedarone, 100 g of dilauroylphosphatidylcholine, 290 g of dimyristoylphosphatidylglycerol, and 4 g of phosphatidylinositol were placed in an eggplant-shaped bottle, and 2 L of a mixed solvent of acetone and ethanol in a volume ratio of 3:2 was added, and the mixture was stirred in a 40° C. water bath until dissolved to form a clear and transparent uniform liposome solution;

[0145] (2) placing the eggplant-shaped bottle described in step (1) in a 40° C. water bath and performing vacuum rotary evaporation with a vacuum degree of -0.8 bar to remove most of the organic solvent;

[0146] (3) The eggplant-shaped bottle described in step (2) is transferred to a 20° C. water bath and subjected to reduced pressure rotary evaporation to remove the remaining organic solvent, with a vacuum degree of -0.9 bar; a uniform milky white, translucent, smooth, flat phospholipid film slowly forms on the inner wall of the eggplant-shaped bottle;

[0147] (4) Take 100 g of mannitol and 36 g of sodium cholate, add them to 500 ml of water, and stir until dissolved to obtain a stabilizer aqueous solution;

[0148] (5) slowly adding the stabilizer aqueous solution described in step (4) into the eggplant-shaped bottle described in step (3), and continuously stirring in a 40° C. water bath for 30 min to allow the phospholipid membrane to be completely dispersed in the stabilizer solution, thereby obtaining a primary dronedarone liposome solution;

[0149] (6) The first-level dronedarone liposome solution described in step (5) was circulated three times by a microfluidizer at a pressure of 5000 psi, and the insoluble matter was removed by column chromatography to obtain a second-level dronedarone liposome solution, which was milky white with a blue glow and no stratification or precipitation;

[0150] (7) The secondary dronedarone liposome solution described in step (6) was dispensed into 5 ml vials, 0.5 ml per vial, for a total of 1000 vials, and placed in a freeze dryer to remove the solvent, and the pre-freezing temperature was -40°C to obtain a dronedarone liposome preparation for injection. The preparation was packaged according to the specification of 220 mg / vial, and recorded as comparative preparation 8.

[0151] Experimental Example 1: Study on liposome particle size

[0152] Add 2 ml of normal saline to each of Preparation 1 to Preparation 6 and Comparative Preparation 1 to Comparative Preparation 8, respectively, and shake to dissolve to obtain a reconstituted solution. The reconstituted solution should be milky white without stratification and precipitation.

[0153] The secondary liposome solutions and reconstituted solutions of Preparation 1-Preparation 6, Comparative Preparation 1, Comparative Preparation 4-Comparative Preparation 8 were taken, and the liposome particle size was measured using a laser particle size analyzer and wet dispersion with purified water as the medium according to the requirements of the third method (light scattering method) of the particle size and particle size distribution determination method of the Chinese Pharmacopoeia. The results are shown in Table 1 below:

[0154] Table 1 Particle size test results of liposome solution and reconstituted solution

[0155]

[0156] The results show that the liposome particle size of Preparation 1-Preparation 6 prepared in all examples can be controlled within 50nm D50 and within 100nm D90. The particle size is small and the distribution is concentrated, which is beneficial to systemic drug delivery and reduces the recognition and uptake of opsonins in the blood, prolongs the blood clearance time, and reduces the toxic effects of free drugs.

[0157] Comparing Preparation 1 and Comparative Preparation 1, Comparative Preparation 1 uses all-neutral phospholipids as lipid materials, and the liposome particle size is significantly larger than that of Preparation 1. The combination of neutral phospholipid materials and negatively charged phospholipid materials can stabilize the liposome structure on the basis of its formation, effectively solving the problem of liposomes agglomerating into agglomerates after formation to increase the particle size, and greatly improving the formability of liposomes.

[0158] Comparing Preparation 1 with Comparative Preparation 4 and Comparative Preparation 5, no bile salt material was added to the composition of Comparative Preparation 4, and non-bile salt emulsifiers were added to Comparative Preparation 5, and the liposome particle size increased significantly compared with Preparation 1. The particle size of the liposomes after microfluidization homogenization is too small, and the characteristic of easy aggregation is more prominent. It is impossible to maintain the particle size of small-sized liposomes without increasing by relying solely on negatively charged phospholipids. Bile salts, as ionic emulsifiers, are added to the liposome solution before microfluidization homogenization. In combination with the microfluidization homogenization process and negatively charged phospholipid materials, liposomes with extremely small particle sizes can still not aggregate with each other, thereby maintaining the liposome particle size below 100nm, while other emulsifiers cannot achieve the same effect.

[0159] Comparing Preparation 1 and Comparative Preparation 6, Comparative Preparation 6 uses ultrasonic dispersion method to disperse liposomes in thin films, and the particle size range of the prepared liposomes is above 300nm, which is much higher than that of Preparation 1, and the particle size distribution range is not concentrated. The ultrasonic method cannot prepare liposomes with small particle size. Compared with the ultrasonic method, the microfluidization homogenization process used in Preparation 1 can rely on high-speed collision to provide effective energy transfer, achieving the effect of reducing the liposome particle size to below 100nm.

[0160] Comparing Preparation 1 and Comparative Preparation 7, no stabilizer was added to the composition of Comparative Preparation 7, which could not effectively protect the freeze-dried liposomes, thus causing the liposome particle size to grow after reconstitution. The stabilizer in Preparation 1 can highly modify the surface structure of the liposomes and prevent the particle size of the liposomes from growing by forming a dense conformation cloud.

[0161] After reconstitution, the comparative preparation 8 was turbid and had no blue opalescence, and failed to form a stable liposome solution.

[0162] Test Example 2: Encapsulation Efficiency & Concentration Study

[0163] Add 2 ml of physiological saline to each of Preparation 1 to Preparation 6 and Comparative Preparation 1 to Comparative Preparation 7, respectively, and shake to dissolve to obtain a reconstituted solution. The reconstituted solution should be milky white without stratification and precipitation.

[0164] The secondary liposome solutions and the reconstituted solutions of Preparations 1 to 6, Comparative Preparations 2, Comparative Preparations 3, Comparative Preparations 6, and Comparative Preparations 7 were taken and tested for encapsulation efficiency and drug active ingredient concentration using a high performance liquid chromatograph with methanol as the diluent according to the requirements of the high performance liquid chromatography method of the Chinese Pharmacopoeia. The results are shown in Table 2 below:

[0165] Table 2 Liposome solution and reconstituted solution encapsulation efficiency test results

[0166] sample Liposome solution encapsulation rate % Encapsulation rate of solution after reconstitution % Concentration after reconstitution mg / ml Preparation 1 95.7 95.6 38.2 Preparation 2 96.6 96.1 19.2 Preparation 3 92.1 92.3 50.8 Preparation 4 94.3 93.9 37.6 Preparation 5 95.3 95.3 38.1 Preparation 6 96.1 96.0 38.4 Comparative preparation 2 75.6 67.2 26.9 Comparative preparation 3 73.9 52.0 41.6 Comparative Preparation 6 84.4 62.2 24.9 Comparative Preparation 7 95.8 80.4 32.2

[0167] The results show that the encapsulation rate of the liposomes of Preparations 1 to 6 prepared in all examples can reach more than 90%, and the concentration of the active ingredient of the drug after reconstitution can reach up to 50 mg / ml, which effectively solves the problems of low solubility of dronedarone, low encapsulation rate and difficulty in preparing injections.

[0168] Comparing Preparation 1 and Comparative Preparation 2, Comparative Preparation 1 uses all negatively charged phospholipids as lipid materials, and the liposome solution encapsulation rate and the encapsulation rate after reconstitution are significantly lower than those of Preparation 1. The combination of neutral phospholipid materials and negatively charged phospholipid materials can make the liposome structure denser, the encapsulation effect better, the encapsulation rate high and not easy to leak.

[0169] Comparing Preparation 1 and Comparative Preparation 3, in the liposome composition of Comparative Preparation 3, the active ingredient ratio is 43%, the phospholipid material ratio is 43%, and the ratio of active ingredient to phospholipid material is 1:1. The proportion of phospholipid material is too small, and the active ingredient cannot be completely encapsulated. The stability after encapsulation is poor and it is very easy to leak. According to comparative studies, when the proportion of active ingredients is between 10% and 30% and the proportion of phospholipid materials is between 50% and 80%, such as Preparation 1, the best encapsulation effect can be achieved. At this time, the encapsulation rate is high and it is not easy to leak.

[0170] Comparing Preparation 1 and Comparative Preparation 6, the microfluidization homogenization process used in Preparation 1 has a higher encapsulation rate than the ultrasonic process of Comparative Preparation 6, while avoiding the leakage problem caused by the denaturation of phospholipid materials under the influence of ultrasound.

[0171] Comparing Preparation 1 and Comparative Preparation 7, no stabilizer was added to the composition of Comparative Preparation 7, which could not effectively protect the freeze-dried liposomes, thus causing liposome leakage after reconstitution and a decrease in encapsulation efficiency. The stabilizer in Preparation 1 can highly modify the surface structure of the liposomes and improve the stability of the liposomes during the drying process, storage process and in the blood by forming a dense conformational cloud.

[0172] Test Example 3: Stability Study

[0173] Take one tube each of preparation 1 to preparation 6 and comparative preparation 1 to comparative preparation 7, seal them, place them at 4°C, 25°C and 40°C for 6 months, add 2 ml of physiological saline to each tube, shake to dissolve, and obtain the reconstituted solution. The reconstituted solution should be milky white without stratification and precipitation. The encapsulation rate was measured to evaluate the stability of dronedarone liposomes. The results are shown in Table 3 below:

[0174] Table 3 Stability test results

[0175]

[0176] The results showed that the encapsulation rates of the liposomes of Formulations 1 to 6 prepared in all the examples could reach over 90% after being sealed and stored for 6 months under different temperature conditions, indicating that the storage stability of the preparations was good.

[0177] The encapsulation efficiency of comparative preparations 2, 3, 6, and 7 decreased slightly after being stored at 4°C for 6 months. The encapsulation efficiency of comparative preparations 2, 3, 6, and 7 decreased significantly after being stored at 25°C for 6 months. The encapsulation efficiency of comparative preparations 2, 3, 6, and 7 decreased significantly after being stored at 40°C for 6 months. Compared with preparation 1, the stability was poor under each storage condition.

[0178] In comparative preparation 2, only negatively charged phospholipid materials were used for preparing liposomes, and the liposome structure was not dense enough, which caused the problem of easy leakage. Preparation 1 used a combination of neutral phospholipids and negatively charged phospholipids as liposome materials, which effectively made the liposomes have high encapsulation effect and stability at the same time, and solved the problem of liposome aggregation.

[0179] In comparison, the active ingredient ratio in preparation 3 is too high, while the phospholipid material ratio is too low. A small amount of phospholipid material cannot encapsulate all active ingredients, resulting in low encapsulation efficiency, poor stability and easy leakage. The ratio of active ingredients and phospholipid materials used in preparation 1 can maximize the liposome encapsulation efficiency, while also giving the liposome a better particle size and stability.

[0180] Test Example 4: Plasma Clearance Study

[0181] Take appropriate amounts of preparation 1 and comparative preparation 6, add 2 ml of physiological saline respectively, shake to dissolve, and obtain a reconstituted solution, which should be milky white without stratification and precipitation. The reconstituted solution is diluted 100 times with physiological saline as a diluent to prepare a dronedarone liposome solution.

[0182] Take an appropriate amount of the active ingredient and prepare a free drug solution with a concentration of 2 mg / ml using pH 4.5 buffer as a diluent.

[0183] Nine SD rats were randomly divided into three groups and injected with dronedarone liposome solution and free drug solution, respectively. The dose of 1.2 mg / kg was slowly pushed through the rat tail vein. 0.5 ml of blood was collected from the venous plexus of the retina at 5 minutes, 2 hours, 8 hours, 24 hours, 48 ​​hours, 72 hours, 108 hours, and 288 hours after administration. The blood was centrifuged for 5 minutes to separate the plasma. After the blood samples were processed, HPLC analysis was performed, and the plasma drug concentration was calculated by the standard curve external standard method.

[0184] The results are shown in Table 4 below:

[0185] Table 4 Plasma clearance test results

[0186]

[0187]

[0188] The pharmacokinetic parameters are:

[0189] C t (ng / mL): corresponds to plasma concentration;

[0190] T 1 / 2z (h): terminal elimination half-life;

[0191] CL (L / h): plasma clearance rate.

[0192] The plasma clearance rate of dronedarone liposome preparation for injection in rats was significantly lower than that of free drug solution and comparative preparation 6, and the elimination half-life and the time of circulation in the blood were significantly prolonged. Dronedarone prepared as small-particle liposomes can effectively prevent the liposomes from being recognized and taken up by opsonins in the blood, greatly prolonging the time of drug circulation in the blood, thereby reducing the toxic effects of the drug.

Claims

1. A liposome preparation of dronedarone for injection, characterized in that: Including active ingredients and pharmaceutical excipients; The active ingredient is dronedarone or a pharmaceutically acceptable salt thereof; The pharmaceutical excipients include phospholipid materials, stabilizers, and emulsifiers; The contents of the components of the dronedarone liposome preparation are as follows by weight percentage: Active ingredient……………………10%~30%, Phospholipid material……………………50%-80%, Stabilizer…………………………2%-15%, Emulsifier……………………0.5%-5%; The emulsifier is bile salt.

2. The liposome preparation of dronedarone for injection according to claim 1, characterized in that: The bile salts are selected from one or more of sodium cholate, sodium glycocholate, sodium taurocholate and sodium deoxycholate.

3. The liposome preparation of dronedarone for injection according to claim 1, characterized in that: The phospholipid material is a composition of neutral phospholipids and negatively charged phospholipids; the ratio of the neutral phospholipids to the negatively charged phospholipids is 1:1-1:

3.

4. The liposome preparation of dronedarone for injection according to claim 3, characterized in that: The neutral phospholipid is selected from one or more of dilauroylphosphatidylcholine, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, phosphatidylethanolamine, dipalmitoylphosphatidylethanolamine and distearoylphosphatidylcholine.

5. The liposome preparation of dronedarone for injection according to claim 3, characterized in that: The negatively charged phospholipids are selected from one or more of phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, phosphatidic acid, dilauroylphosphatidylglycerol, dipalmitoylphosphatidic acid, dimyristoylphosphatidylglycerol, distearoylphosphatidylglycerol, and dipalmitoylphosphatidylglycerol.

6. The liposome preparation of dronedarone for injection according to claim 1, characterized in that: The stabilizer is selected from one or more of mannitol, D-glucose, lactose, sucrose, trehalose, polyethylene glycol with an average molecular weight of 2000-6000, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylamide, dextran, and methyl cellulose.

7. The method for preparing the liposome preparation of dronedarone for injection according to any one of claims 1 to 6, characterized in that: The thin film dispersion method is adopted, and the method specifically comprises the following steps: (1) dissolving the active ingredient and the phospholipid material in an organic solvent to form a uniform liposome solution, controlling the system temperature at 20° C. to 80° C. to remove the solvent, and allowing the material to form a uniform film; (2) dissolving a stabilizer and bile salts in water to form a stabilizer aqueous solution; (3) adding the stabilizer aqueous solution in step (2) to the homogenized film in step (1), stirring to disperse the film, and preparing dronedarone liposomes by microfluidization homogenization and emulsification; (4) removing the solvent from the dronedarone liposomes obtained in step (3) to obtain a dronedarone liposome preparation for injection.

8. The preparation method according to claim 7, characterized in that: The step (1) removes the solvent by rotary evaporation under reduced pressure to form a homogeneous film.

9. The preparation method according to claim 7, characterized in that: The organic solvent in step (1) is selected from one or a mixture of ethanol, isopropanol, n-hexane, tert-butanol, dichloromethane, chloroform and acetone.

10. The preparation method according to claim 7, characterized in that: The cavity diameter used in the microfluidic homogenization emulsification in step (3) is 50-75 μm, and the homogenization pressure is 5 kpsi-30 kpsi.

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