A preparation method of olprinone hydrochloride injection composition

Abstract

The invention discloses a method for preparing an olprinone hydrochloride injection composition, and belongs to the technical field of pharmaceutical compounds. The steps of the preparation method are as follows: after oligomeric polyethyleneimine and halogenated alcohol are mixed and dissolved, a weak alkaline reagent is added to react to obtain an intermediate, a long-chain alkyl acid is mixed with the intermediate and then acid-catalyzed to obtain a modified oligomeric polyethyleneimine, the modified oligomeric polyethyleneimine and olprinone are mixed according to a mass ratio of 20 to 40:1, and then hydrochloric acid is added and stirred to obtain olprinone hydrochloride; after olprinone hydrochloride is dissolved in water for injection, an alkaline solution is added to adjust the pH, and then water for injection is added to the fixed volume, and a filtrate is obtained by filtering with modified activated carbon, and the filtrate is sterilized and filled to obtain an olprinone hydrochloride injection composition. The present invention reduces the loss of the main drug component when olprinone hydrochloride is filtered with modified activated carbon by constructing an electrostatic repulsion system.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical compounds, and specifically provides a method for preparing an olprinone hydrochloride injection composition. Background Art

[0002] Olprinone hydrochloride injection is a typical selective phosphodiesterase III inhibitor. It improves hemodynamic parameters and exercise tolerance through the action of the upstream mechanism of the heart. It is used to treat congestive heart failure. It has the effects of enhancing myocardial contractility, dilating blood vessels, and improving the pathological state of heart failure. It has obvious effects on reducing the incidence and mortality of heart disease. In addition, studies have shown that olprinone hydrochloride can also be used to treat stroke, and has the effects of protecting the spleen and liver and relaxing bronchial smooth muscles.

[0003] The prior art records the common preparation methods of olprinone hydrochloride. Patent CN100560072C discloses an olprinone hydrochloride injection and its preparation method. The invention uses olprinone hydrochloride as the main drug component, adds injection water (as a solvent) and water-soluble excipients (including 3-20% lactose, mannitol, sorbitol and xylitol, etc., for making the main drug component dispersed stably and evenly), then filters it through needle activated carbon, and then adds acid-base buffer (including 0.005-3% citric acid-sodium citrate, tartaric acid-sodium tartrate and stearic acid-sodium stearate, etc.) to adjust to a specific pH range, and finally sterilizes and packages to obtain olprinone hydrochloride injection; Patent CN101919 814A discloses a method for preparing a stable olprinone hydrochloride injection, in which citric acid and sorbitol are dissolved in injection water, olprinone hydrochloride is added and mixed, and then the mixture is filtered through needle activated carbon, and then adjusted to a specified pH range with sodium hydroxide, and finally sterilized and packaged to obtain olprinone hydrochloride injection; Patent CN104161756B discloses an olprinone hydrochloride injection composition, in which the raw materials include olprinone hydrochloride, sorbitol, citric acid, polyethylene glycol and propylene glycol, and the composition is filtered through needle activated carbon and a filter membrane and then filled and sterilized to obtain a stable olprinone hydrochloride injection. The invention improves the stability of olprinone hydrochloride by compounding polyethylene glycol and propylene glycol.

[0004] Among the above methods, needle-grade activated carbon is used in filtration. Due to its low cost, needle-grade activated carbon is widely used in the filtration and impurity removal of injection solutions. However, due to the low selectivity of activated carbon adsorption, it will inevitably produce an extremely strong adsorption effect on the main drug component, oprinone hydrochloride, while adsorbing and removing impurities, thereby causing the loss of the main drug component. Therefore, a preparation method for reducing the loss of the main drug component of oprinone hydrochloride injection caused by activated carbon adsorption is designed, which has practical application value. Summary of the invention

[0005] In view of the deficiencies of the prior art, the present invention performs surface modification on olprinone and activated carbon respectively, so that the surfaces of both are loaded with the same positive charge, and through the repulsion of the same charges, the loss of the main drug component caused by adsorption by activated carbon is reduced, so as to solve the problems raised in the background technology. Specifically, the technical solution of the present invention includes the following contents:

[0006] A method for preparing an olprinone hydrochloride injection composition, the preparation method comprising the following steps:

[0007] The oligomeric polyethyleneimine and the halogenated alcohol are mixed and dissolved to form a mixed solution, a weak alkaline reagent is added to the mixed solution for mixed reaction to obtain an intermediate, and a long-chain alkyl acid is mixed with the intermediate to obtain a modified oligomeric polyethyleneimine through acid catalysis;

[0008] The modified oligomeric polyethyleneimine and olprinone are mixed in a mass ratio of 20 to 40:1, and then hydrochloric acid is added and stirred to obtain olprinone hydrochloride;

[0009] After the olprinone hydrochloride is dissolved in water for injection, an alkaline solution is added to adjust the pH, and then water for injection is added to make up the volume. The filtrate is filtered through modified activated carbon to obtain a filtrate, and the filtrate is sterilized and filled to obtain the olprinone hydrochloride injection composition.

[0010] Furthermore, the molecular weight of the oligomeric polyethyleneimine is 300-1500.

[0011] Furthermore, the halogenated alcohol includes 2,2,2-trichloroethanol, 2,2,2-trifluoroethanol or 2-bromoethanol, preferably 2,2,2-trichloroethanol or 2,2,2-trifluoroethanol. Such halogenated alcohol has multiple substituted halogen atom sites and sites for binding to multiple polyethyleneimines to form a cross-linked polyquaternary ammonium positively charged structure, which has the effect of enhancing hydrophilicity and positive charge.

[0012] Furthermore, the mass ratio of the oligomeric polyethyleneimine to the halogenated alcohol is 3 to 15:10.

[0013] Furthermore, the weak alkaline reagent includes an inorganic weak alkaline reagent and an organic weak alkaline reagent, the inorganic weak alkaline reagent includes sodium carbonate or sodium bicarbonate, and the organic weak alkaline reagent includes ammonia water, pyridine or triethylamine. Preferably, the weak alkaline reagent is an inorganic weak alkaline reagent. Since the organic weak alkaline reagent contains an amino group (or amine group), it is easy to compete with the oligomeric polyethyleneimine to combine with the halogenated alcohol to produce by-products, thereby reducing the reaction efficiency.

[0014] Furthermore, the long-chain alkyl acid includes dodecylbenzenesulfonic acid.

[0015] Furthermore, the conditions for the reaction of the mixed solution with the weak alkaline reagent include reaction pH=8-10, reaction temperature 50-80° C. and reaction time 4-7 h.

[0016] Furthermore, the mass ratio of the long-chain alkyl acid to the intermediate is 10-35:1-5, and the acid reagent used in the acid catalysis includes concentrated sulfuric acid or hydrochloric acid.

[0017] Furthermore, the alkaline solution includes sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate.

[0018] Furthermore, the pH value of the alkaline solution is adjusted to a range of 3.5 to 4.5.

[0019] Furthermore, the specific step of fixing the volume of the water for injection is: adding water for injection to the olprinone hydrochloride after adjusting the pH value to make up to 1000 ml.

[0020] Furthermore, the usage amount of the modified activated carbon is 0.05% to 0.1% of the total volume after being fixed with water for injection.

[0021] Furthermore, the preparation method of the modified activated carbon comprises the following steps:

[0022] The pyridine compound and ethyl bromide are mixed to form a mixed solution, and a base catalyst is added to the mixed solution and stirred for reaction for 1 to 3 hours to obtain a reaction solution;

[0023] The needle-use activated carbon is distributed in the reaction solution and immersed for 20 to 30 minutes under an ultrasonic power of 200 to 300 W to obtain the needle-use activated carbon after immersion;

[0024] The impregnated needle activated carbon is placed in a reaction kettle and stirred with a metal ion oxidant to react to obtain the modified activated carbon.

[0025] Furthermore, the pyridyl compound includes 3-hydroxypyridine or 4-hydroxypyridine.

[0026] Furthermore, the base catalyst includes sodium carbonate or sodium bicarbonate.

[0027] Furthermore, the metal ion oxidant includes ferric chloride or cupric chloride.

[0028] Furthermore, the molar ratio of the pyridyl compound to ethyl bromide is 1:1-4.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) The present invention modifies oligomeric polyethyleneimine having multiple amine sites to make it into a modified oligomeric polyethyleneimine having a multi-positively charged quaternary ammonium structure. A portion of the positive charges on the surface of the oligomeric polyethyleneimine are used to fix olprinone through electrostatic adsorption with nitrogen oxides with lone electron pairs on the surface of olprinone; the other portion of the positive charges are exposed on the outer surface of olprinone and repel each other through electrostatic repulsion with modified activated carbon modified by positive charges, so that when olprinone hydrochloride is adsorbed by the modified activated carbon, the loss of the main drug component caused by the adsorption of the modified activated carbon is reduced.

[0031] (2) The present invention utilizes a small molecule pyridine structure to synthesize a small molecule quaternary ammonium derivative with a positive charge, and then uses needle-grade activated carbon for impregnation and adsorption to the surface of the needle-grade activated carbon, and then performs oxidative polymerization on the surface of the needle-grade activated carbon to generate a large molecule quaternary ammonium derivative. The large molecule quaternary ammonium derivative generated in this way is not easy to fall off from the surface of the needle-grade activated carbon, thereby improving the stability of the modified activated carbon in carrying positive charges.

[0032] (3) It was unexpectedly discovered through the examples that the modified oligomeric polyethyleneimine designed by the present invention can not only modify the surface positive charge of olprinone, but also play a role similar to that of a surfactant such as a dispersant and a stabilizer. This may be because the constructed modified oligomeric polyethyleneimine has a hydrophilic quaternary ammonium positive charge "head structure" and a long-chain alkyl hydrophobic "tail structure", which is similar to the spatial structure of a surfactant, thereby achieving stable dispersion of olprinone. Therefore, when olprinone hydrochloride is prepared into an olprinone hydrochloride injection composition, there is no need to add additional pharmaceutical excipients such as polyethylene glycol and propylene glycol to improve the stable dispersion performance of olprinone hydrochloride in the solution. DETAILED DESCRIPTION

[0033] The technical solution of the present invention will be clearly and completely described below through the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0034] Unless otherwise specified, the raw materials and reagents used in the present invention are commercially available or can be prepared by known methods.

[0035] The relevant reagents and raw materials information are as follows:

[0036] Oligomeric polyethyleneimine, 2,2,2-trichloroethanol, 2,2,2-trifluoroethanol, 2-bromoethanol, sodium carbonate, sodium bicarbonate, ammonia water, pyridine, triethylamine, dodecylbenzenesulfonic acid, concentrated sulfuric acid (Chinese medicine), hydrochloric acid, sodium hydroxide, potassium hydroxide, ethyl bromide, 3-hydroxypyridine, 4-hydroxypyridine, anhydrous magnesium sulfate, ferric chloride and cupric chloride were purchased from Shanghai Aladdin Reagent Co., Ltd.

[0037] Concentrated sulfuric acid and hydrochloric acid were purchased from Sinopharm Reagent Co., Ltd.

[0038] Activated carbon for injection was purchased from Shaanxi Ruichengkang Pharmaceutical Technology Co., Ltd.

[0039] Preparation Example 1:

[0040] The preparation of modified activated carbon specifically includes the following steps:

[0041] 0.1 mol of 3-hydroxypyridine (16.3 g) and 0.1 mol of ethyl bromide (56 g) were weighed and placed in a flask, and 80 ml of ethanol was added to the flask to mix and dissolve the two, and then 7.23 g of sodium carbonate was added and mixed and stirred, and the stirring speed was set to 100 r / min. After stirring and reacting for 1 hour, the ethanol was evaporated under reduced pressure and treated with a cation exchange membrane to obtain a reaction solution; 10 g of needle-grade activated carbon powder was weighed and added to the reaction solution, and the solution was immersed in an ultrasonic cleaner at a power of 200 W for 20 minutes, and the impregnated needle-grade activated carbon was collected by filtration, and the impregnated needle-grade activated carbon was rinsed with 100 ml of deionized water. After the rinsing was completed, the impregnated needle-grade activated carbon was mixed with a volume of 100 ml and a concentration of 1 mol l / L of copper chloride solution were placed in a reactor, and nitrogen was introduced to replace the air in the reactor. After the replacement, the reactor was heated to 30°C, and the reaction was stirred at 200r / min for 4h. The activated carbon was collected by filtration, and the activated carbon was rinsed three times with 100ml of deionized water, placed in a vacuum drying oven, dried at 60°C for 10h, and naturally cooled to obtain modified activated carbon.

[0042] Preparation Example 2:

[0043] The preparation of modified activated carbon specifically includes the following steps:

[0044] 0.1 mol of 3-hydroxypyridine (16.3 g) and 0.2 mol of ethyl bromide (112 g) were weighed and placed in a flask, and 150 ml of ethanol was added to the flask to mix and dissolve the two, and then 12.83 g of sodium bicarbonate was added and mixed and stirred, and the stirring speed was set to 100 r / min. After stirring and reacting for 2 hours, the ethanol was evaporated under reduced pressure and treated with a cation exchange membrane to obtain a reaction solution; 10 g of needle-grade activated carbon powder was weighed and added to the reaction solution, and the solution was immersed in an ultrasonic cleaner at a power of 250 W for 25 minutes, and the impregnated needle-grade activated carbon was collected by filtration, and the impregnated needle-grade activated carbon was rinsed with 100 ml of deionized water. After the rinsing was completed, the impregnated needle-grade activated carbon was mixed with a volume of 100 ml and a concentration of 1 mol l / L of ferric chloride solution were placed in a reactor, and nitrogen was introduced to replace the air in the reactor. After the replacement, the reactor was heated to 40°C, and the reaction was stirred at 200r / min for 6h. The activated carbon was collected by filtration, and the activated carbon was rinsed three times with 100ml of deionized water, placed in a vacuum drying oven, dried at 60°C for 10h, and naturally cooled to obtain modified activated carbon.

[0045] Preparation Example 3:

[0046] The preparation of modified activated carbon specifically includes the following steps:

[0047] 0.1 mol of 4-hydroxypyridine (16.3 g) and 0.4 mol of ethyl bromide (224 g) were weighed and placed in a flask, and 250 ml of ethanol was added to the flask to mix and dissolve the two, and then 24.03 g of sodium bicarbonate was added and mixed and stirred, and the stirring speed was set to 100 r / min. After stirring and reacting for 3 hours, the ethanol was evaporated under reduced pressure and treated with a cation exchange membrane to obtain a reaction solution; 10 g of needle-grade activated carbon powder was weighed and added to the reaction solution, and the solution was immersed in an ultrasonic cleaner at a power of 300 W for 30 minutes, and the impregnated needle-grade activated carbon was collected by filtration, and the impregnated needle-grade activated carbon was rinsed with 100 ml of deionized water. After the rinsing was completed, the impregnated needle-grade activated carbon was mixed with a volume of 100 ml and a concentration of 1 mol l / L of ferric chloride solution were placed in a reactor, and nitrogen was introduced to replace the air in the reactor. After the replacement, the reactor was heated to 50°C, and the reaction was stirred at 200r / min for 6h. The activated carbon was collected by filtration, and the activated carbon was rinsed three times with 100ml of deionized water, placed in a vacuum drying oven, dried at 60°C for 10h, and naturally cooled to obtain modified activated carbon.

[0048] Embodiment 1:

[0049] A method for preparing an olprinone hydrochloride injection composition comprises the following steps:

[0050] Weigh 6 g of low-molecular-weight polyethyleneimine with a molecular weight of 300 and 20 g of 2-bromoethanol respectively and place them in a flask, then add 30 g of methanol to mix and dissolve, then drop ammonia water, and stop adding ammonia water when the pH value is adjusted to 8. Put the flask in a water bath at a temperature of 50°C, heat and react for 4 hours, and then evaporate the methanol under reduced pressure to obtain an intermediate solution; weigh 30 g of dodecylbenzenesulfonic acid and 3 g of the intermediate solution in a beaker, add 3.3 g of hydrochloric acid and 3.3 g of anhydrous magnesium sulfate and mix well, heat to 60°C and react for 2 hours to obtain modified low-molecular-weight polyethyleneimine, and weigh 100 g of 2-bromoethanol. Take 20g of the modified oligomeric polyethyleneimine solution and mix it with 1g of olprinone, then add hydrochloric acid and stir at room temperature until all the solid olprinone hydrochloride is precipitated, stop adding hydrochloric acid, add water for injection to dissolve the solid olprinone hydrochloride, then add sodium hydroxide solution dropwise to adjust the pH value to 3.5, then add water for injection to make the total volume 1000ml, add 0.5g of the modified activated carbon in Preparation Example 1 to 1000ml of the olprinone hydrochloride solution, stir and adsorb for 30min, filter and collect the filtrate, and then sterilize and fill the filtrate to obtain the olprinone hydrochloride injection composition.

[0051] Embodiment 2:

[0052] A method for preparing an olprinone hydrochloride injection composition comprises the following steps:

[0053] Weigh 10g of low-molecular-weight polyethyleneimine with a molecular weight of 500 and 20g of 2-bromoethanol respectively and place them in a flask, then add 40g of ethanol to mix and dissolve, then drop pyridine, stop adding pyridine when the pH value is adjusted to 9, put the flask in a water bath at a temperature of 60°C, heat and react for 5h, and then evaporate and remove ethanol under reduced pressure to obtain an intermediate solution; weigh 50g of dodecylbenzenesulfonic acid and 8g of the intermediate solution in a beaker, add 5.8g of concentrated sulfuric acid and 5.8g of anhydrous magnesium sulfate and mix well, heat to 65°C and react for 2h to obtain modified low-molecular-weight polyethyleneimine. Amine, 30g of modified oligomeric polyethyleneimine solution was mixed with 1g of olprinone, and then hydrochloric acid was added and stirred at room temperature until all solid olprinone hydrochloride was precipitated, and the addition of hydrochloric acid was stopped. Water for injection was added to dissolve the solid olprinone hydrochloride, and potassium hydroxide solution was added dropwise to adjust the pH value to 3.5, and then water for injection was added to make the total volume 1000ml, 1g of the modified activated carbon in Preparation Example 1 was added to 1000ml of the olprinone hydrochloride solution, and stirred for adsorption for 30min, and the filtrate was collected by filtration, and the filtrate was sterilized and filled to obtain the olprinone hydrochloride injection composition.

[0054] Embodiment 3:

[0055] A method for preparing an olprinone hydrochloride injection composition comprises the following steps:

[0056] Weigh 20g of low-molecular-weight polyethyleneimine with a molecular weight of 1500 and 20g of n-butyl chloride respectively and place them in a flask, then add 40g of acetone to mix and dissolve, then drop triethylamine, and stop adding triethylamine when the pH value is adjusted to 10. Put the flask in a water bath at a temperature of 70°C, heat and react for 6h, and then evaporate and remove acetone under reduced pressure to obtain an intermediate solution; measure 60g of dodecylbenzenesulfonic acid and 10g of the intermediate solution in a beaker, add 7g of concentrated sulfuric acid and mix evenly, heat to 70°C and react for 3h to obtain modified low-molecular-weight polyethyleneimine, measure After 30 g of the modified oligomeric polyethyleneimine solution was mixed with 1 g of olprinone, hydrochloric acid was added and stirred at room temperature until all solid olprinone hydrochloride was precipitated. The addition of hydrochloric acid was stopped, and water for injection was added to dissolve the solid olprinone hydrochloride. Sodium carbonate solution was added dropwise to adjust the pH value to 4.0, and then water for injection was added to make the total volume 1000 ml. 0.5 g of the modified activated carbon in Preparation Example 2 was added to 1000 ml of the olprinone hydrochloride solution, and stirred and adsorbed for 30 minutes. The filtrate was filtered and collected, and the filtrate was sterilized and filled to obtain the olprinone hydrochloride injection composition.

[0057] Embodiment 4:

[0058] A method for preparing an olprinone hydrochloride injection composition comprises the following steps:

[0059] Weigh 30g of low-molecular-weight polyethyleneimine with a molecular weight of 1500 and 20g of 2,2,2-trichloroethanol respectively and place them in a flask, then add 50g of acetone to mix and dissolve, then drop sodium carbonate, adjust the pH value to 10 and stop adding sodium carbonate, put the flask in a water bath at 80°C, heat and react for 7h, and then evaporate and remove acetone under reduced pressure to obtain an intermediate solution; weigh 80g of dodecylbenzenesulfonic acid and 12g of the intermediate solution in a beaker, add 9.2g of concentrated sulfuric acid and mix well, heat to 75°C and react for 3h to obtain a modified low-molecular-weight polyethyleneimine. Amine, 40g of modified oligomeric polyethyleneimine solution was mixed with 1g of olprinone, and then hydrochloric acid was added and stirred at room temperature until all solid olprinone hydrochloride was precipitated, and the addition of hydrochloric acid was stopped. Water for injection was added to dissolve the solid olprinone hydrochloride, and sodium carbonate solution was added dropwise to adjust the pH value to 4.0, and then water for injection was added to make the total volume 1000ml, 1g of the modified activated carbon in Preparation Example 2 was added to 1000ml of the olprinone hydrochloride solution, and stirred for adsorption for 30min, and the filtrate was collected by filtration, and the filtrate was sterilized and filled to obtain the olprinone hydrochloride injection composition.

[0060] Embodiment 5:

[0061] A method for preparing an olprinone hydrochloride injection composition comprises the following steps:

[0062] Weigh 30g of low-molecular-weight polyethyleneimine with a molecular weight of 1000 and 20g of 2,2,2-trichloroethanol respectively and place them in a flask, then add 50g of ethanol to mix and dissolve, then drop sodium bicarbonate, and stop adding sodium bicarbonate when the pH value is adjusted to 10, put the flask in a water bath at a temperature of 80°C, heat and react for 7h, and then evaporate and remove ethanol under reduced pressure to obtain an intermediate solution; weigh 105g of dodecylbenzenesulfonic acid and 15g of the intermediate solution in a beaker, add 12g of concentrated sulfuric acid and mix evenly, heat to 80°C and react for 4h to obtain a modified low-molecular-weight polyethyleneimine. Amine, 40g of modified oligomeric polyethyleneimine solution was measured and mixed with 1g of olprinone, and then hydrochloric acid was added and stirred at room temperature until all solid olprinone hydrochloride was precipitated, and the addition of hydrochloric acid was stopped, and water for injection was added to dissolve the solid olprinone hydrochloride, and then sodium bicarbonate solution was added dropwise to adjust the pH value to 4.5, and then water for injection was added to make the total volume 1000ml, and 0.5g of the modified activated carbon in Preparation Example 3 was added to 1000ml of the olprinone hydrochloride solution, and stirred and adsorbed for 30min, and the filtrate was collected by filtration, and the filtrate was sterilized and filled to obtain the olprinone hydrochloride injection composition.

[0063] Embodiment 6:

[0064] A method for preparing an olprinone hydrochloride injection composition comprises the following steps:

[0065] Weigh 30g of low-molecular-weight polyethyleneimine with a molecular weight of 1000 and 20g of 2,2,2-trifluoroethanol respectively and place them in a flask, then add 50g of ethanol to mix and dissolve, then drop sodium carbonate, and stop adding sodium carbonate when the pH value is adjusted to 9, put the flask in a water bath at a temperature of 70°C, heat and react for 6h, and then evaporate and remove ethanol under reduced pressure to obtain an intermediate solution; measure 105g of dodecylbenzenesulfonic acid and 15g of the intermediate solution in a beaker, add 12g of concentrated sulfuric acid and mix evenly, heat to 90°C and react for 4h to obtain modified low-molecular-weight polyethyleneimine , measure 40g of the modified oligomeric polyethyleneimine solution and mix it with 1g of olprinone, then add hydrochloric acid and stir at room temperature until all the solid olprinone hydrochloride is precipitated, stop adding hydrochloric acid, add water for injection to dissolve the solid olprinone hydrochloride, then add sodium bicarbonate solution dropwise to adjust the pH value to 4.5, then add water for injection to make the total volume 1000ml, add 1g of the modified activated carbon in Preparation Example 3 to 1000ml of the olprinone hydrochloride solution, stir and adsorb for 30min, filter and collect the filtrate, and then sterilize and fill the filtrate to obtain the olprinone hydrochloride injection composition.

[0066] Embodiment 7:

[0067] A method for preparing an olprinone hydrochloride injection composition comprises the following steps:

[0068] Weigh 30g of oligomeric polyethyleneimine with a molecular weight of 1000 and 20g of 2,2,2-trichloroethanol respectively and place them in a flask, then add 50g of ethanol to mix and dissolve, then drop sodium bicarbonate, and stop adding sodium bicarbonate when the pH value is adjusted to 10. Put the flask in a water bath at 80°C, heat and react for 7h, and then evaporate under reduced pressure to remove ethanol to obtain a modified oligomeric polyethyleneimine solution. 40g of the modified oligomeric polyethyleneimine solution is mixed with 1g of olprinone, and then hydrochloric acid is added and stirred at room temperature until all precipitates are dissolved. Solid olprinone hydrochloride was obtained, and the addition of hydrochloric acid was stopped. 40 g of polyethylene glycol and 10 g of ethylene glycol were added to the solid olprinone hydrochloride, and then water for injection was added to mix and dissolve. Then, sodium bicarbonate solution was added dropwise to adjust the pH value to 4.5, and finally water for injection was added to make the total volume 1000 ml. 0.5 g of the modified activated carbon in Preparation Example 3 was added to 1000 ml of the olprinone hydrochloride solution, and the mixture was stirred and adsorbed for 30 min. The filtrate was collected by filtration, and the filtrate was sterilized and filled to obtain the olprinone hydrochloride injection composition.

[0069] Embodiment 8:

[0070] A method for preparing an olprinone hydrochloride injection composition comprises the following steps:

[0071] Weigh 30g of oligomeric polyethyleneimine with a molecular weight of 1000 and 20g of 2,2,2-trifluoroethanol respectively and place them in a flask, then add 50g of ethanol to mix and dissolve, then drop sodium carbonate, and stop adding sodium carbonate when the pH value is adjusted to 9. Put the flask in a water bath at a temperature of 70°C, heat the reaction for 6h, and then evaporate the ethanol under reduced pressure to obtain a modified oligomeric polyethyleneimine solution. 40g of the modified oligomeric polyethyleneimine solution is mixed with 1g of olprinone, and then hydrochloric acid is added and stirred at room temperature until all precipitated into a solid. The solid olprinone hydrochloride was prepared, and the addition of hydrochloric acid was stopped. 40 g of sorbitol, 8 g of propylene glycol and 1 g of citric acid were added to the solid olprinone hydrochloride, and then water for injection was added to mix and dissolve. Then, sodium bicarbonate solution was added dropwise to adjust the pH value to 4.5. Finally, water for injection was added to make the total volume 1000 ml. 1 g of the modified activated carbon in Preparation Example 3 was added to 1000 ml of the olprinone hydrochloride solution, and the mixture was stirred and adsorbed for 30 min. The filtrate was collected by filtration, and the filtrate was sterilized and filled to obtain the olprinone hydrochloride injection composition.

[0072] Comparative Example 1:

[0073] Weigh 40g of oligomeric polyethyleneimine solution and mix with 1g of olprinone, then add hydrochloric acid and stir at room temperature until all precipitated to form solid olprinone hydrochloride, stop adding hydrochloric acid, add 40g of polyethylene glycol, 10g of ethylene glycol and 1g of citric acid and mix with solid olprinone hydrochloride, then add water for injection to mix and dissolve, then add sodium bicarbonate solution dropwise to adjust the pH value to 4.5, finally add water for injection to make the total volume 1000ml, add 0.5g of needle-grade activated carbon to 1000ml of olprinone hydrochloride solution, stir and adsorb for 30min, filter and collect the filtrate, and then sterilize and fill the filtrate to obtain the olprinone hydrochloride injection composition.

[0074] Comparative Example 2:

[0075] Weigh 40g of oligomeric polyethyleneimine solution and mix with 1g of olprinone, then add hydrochloric acid and stir at room temperature until all precipitated to form solid olprinone hydrochloride, stop adding hydrochloric acid, add 40g of sorbitol, 8g of propylene glycol and 1g of citric acid and mix with solid olprinone hydrochloride, then add water for injection to mix and dissolve, then add sodium bicarbonate solution dropwise to adjust the pH value to 4.5, finally add water for injection to make the total volume 1000ml, add 1g of needle-grade activated carbon to 1000ml of olprinone hydrochloride solution, stir and adsorb for 30min, filter and collect the filtrate, and then sterilize and fill the filtrate to obtain the olprinone hydrochloride injection composition.

[0076] The stability test (test temperature: 35±5°C, relative humidity: 70%±5%) was carried out on the olprinone hydrochloride obtained after sterilization and filling in Examples 1 to 8 and Comparative Examples 1 to 2. The test results are shown in Tables 1 and 2 below:

[0077] Table 1 Statistical table of relevant substance content test results

[0078]

[0079]

[0080] Table 2 Statistical table of content detection of main drug ingredient olprinone hydrochloride

[0081] 0 months 3 months 6 months 12 months Example 1 95.5 94.4 94.1 93.9 Example 2 95.9 95.8 95.4 95.1 Example 3 97.6 97.5 97.3 97.1 Example 4 98.5 98.2 97.8 97.7 Example 5 99.8 99.4 98.6 98.1 Example 6 100.1 100.0 99.5 99.1 Example 7 98.7 98.1 97.9 97.8 Example 8 99.2 98.9 97.5 97.2 Comparative Example 1 87.1％ 86.9％ 86.8％ 86.6％ Comparative Example 2 89.5％ 89.4％ 89.1％ 88.8％

[0082] It can be seen from the data in Tables 1 and 2 above that the loss of the main drug component caused by the adsorption of olprinone hydrochloride by activated carbon can be reduced by constructing an electrostatic repulsion system, and the modified oligomeric polyethyleneimine with a multi-site positively charged quaternary ammonium structure has the property of stably dispersing olprinone hydrochloride in the solution, avoiding the additional addition of pharmaceutical excipients and synergistically promoting the uniform and stable dispersion of olprinone hydrochloride.

[0083] The above-described embodiments provide a detailed description of the technical solutions and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected.

Claims

1. A method for preparing an olprinone hydrochloride injection composition, characterized in that: The preparation method comprises the following steps: The oligomeric polyethyleneimine and the halogenated alcohol are mixed and dissolved to form a mixed solution, a weak alkaline reagent is added to the mixed solution for mixed reaction to obtain an intermediate, and a long-chain alkyl acid is mixed with the intermediate to obtain a modified oligomeric polyethyleneimine through acid catalysis; The modified oligomeric polyethyleneimine and olprinone are mixed in a mass ratio of 20 to 40:1, and then hydrochloric acid is added and stirred to obtain olprinone hydrochloride; After the olprinone hydrochloride is dissolved in water for injection, an alkaline solution is added to adjust the pH, and then water for injection is added to make up the volume, and the filtrate is filtered through modified activated carbon to obtain a filtrate, and the filtrate is sterilized and filled to obtain the olprinone hydrochloride injection composition; The preparation method of the modified activated carbon comprises the following steps: The pyridine compound and ethyl bromide are mixed to form a mixed solution, and a base catalyst is added to the mixed solution and stirred for reaction for 1 to 3 hours to obtain a reaction solution; The needle-use activated carbon is distributed in the reaction solution and immersed for 20 to 30 minutes under an ultrasonic power of 200 to 300 W to obtain the needle-use activated carbon after immersion; The impregnated needle activated carbon is placed in a reaction kettle and stirred with a metal ion oxidant to obtain the modified activated carbon; The molecular weight of the oligomeric polyethyleneimine is 300-1500.

2. The method for preparing an olprinone hydrochloride injection composition according to claim 1, characterized in that: The halogenated alcohol includes 2,2,2-trichloroethanol, 2,2,2-trifluoroethanol or 2-bromoethanol.

3. The method for preparing an olprinone hydrochloride injection composition according to claim 1, characterized in that: The mass ratio of the oligomeric polyethyleneimine to the halogenated alcohol is 3-15:

10.

4. The method for preparing an olprinone hydrochloride injection composition according to claim 1, characterized in that: The long-chain alkyl acid is dodecylbenzenesulfonic acid.

5. The method for preparing an olprinone hydrochloride injection composition according to claim 1, characterized in that: The conditions for the reaction of the mixed solution with the weak alkaline reagent are reaction pH=8-10, reaction temperature 50-80° C. and reaction time 4-7 h.

6. The method for preparing an olprinone hydrochloride injection composition according to claim 1, characterized in that: The mass ratio of the long-chain alkyl acid to the intermediate is 10-35:1-5.

7. The method for preparing an olprinone hydrochloride injection composition according to claim 1, characterized in that: The pyridine compound is 3-hydroxypyridine or 4-hydroxypyridine, the base catalyst is sodium carbonate or sodium bicarbonate, and the metal ion oxidant is ferric chloride or cupric chloride.

8. An olprinone hydrochloride injection composition prepared by the method for preparing an olprinone hydrochloride injection composition according to any one of claims 1 to 7.

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