CN119837834B - Burisperidone long-acting microsphere and preparation method thereof - Google Patents
Burisperidone long-acting microsphere and preparation method thereofInfo
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- CN119837834B CN119837834B CN202411955819.3A CN202411955819A CN119837834B CN 119837834 B CN119837834 B CN 119837834B CN 202411955819 A CN202411955819 A CN 202411955819A CN 119837834 B CN119837834 B CN 119837834B
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Abstract
The invention belongs to the field of pharmaceutical preparations, and relates to a bripiprazole long-acting microsphere and a preparation method thereof, comprising the following steps of (1) dissolving bripiprazole and a degradable polymer in an organic solvent to obtain a drug-containing polymer solution as an oil phase; and (2) mixing the drug-containing polymer solution and the polyvinyl alcohol solution through a microfluidic technology to obtain an oil-in-water emulsion, and (3) solidifying, washing and freeze-drying the oil-in-water emulsion under the stirring condition to obtain the bripiprazole long-acting microsphere. According to the invention, the volatilization stirring time when the O/W colostrum is formed is regulated, so that the in-vitro release rate of the final microsphere is regulated, and the microsphere which is free from sudden release, lag phase and slow release can be screened out. The invention provides the bripiprazole long-acting microsphere which has the advantages of simple preparation process, easy industrial amplification, high encapsulation efficiency, large drug-loading capacity, uniform microsphere particle size distribution, round shape, good fluidity, good needle penetrating property and easy injection, has obvious slow release effect, can be used for reducing the fluctuation of blood concentration and effectively improving the compliance of psychopath.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a bripiprazole long-acting microsphere and a preparation method thereof.
Background
Bripiprazole (brexpiprazole) is an atypical antipsychotic having a modulating effect on the monoaminergic neurotransmission system in the brain, is a partial agonist of 5-hydroxytryptamine (5-HT 1A) and dopamine D2 receptors, a 5-hydroxytryptamine (5-HT 2A) receptor and dopamine alpha 1/2 receptor antagonist, and has a broad binding affinity for other central monoaminergic receptor subtypes, and has the structure shown in the following formula. The extrapyramidal response of bripiprazole is reduced compared to typical antipsychotics. The increased affinity of bripiprazole for 5-HT receptors, reduced activity at D2 receptors, better tolerability and lower incidence of akathisia side effects compared to atypical anti-sedative drug aripiprazole. Has better trend in clinical curative effect on negative symptoms and cognitive functions of the schizophrenia, and has quicker effect when being used for auxiliary treatment of depression.
The currently marketed dosage forms of bripiprazole are only tablets and orally disintegrating tablets, the target dosage is once daily, 2-4mg each time. Since the market, the global sales of bripiprazole has increased year by year, from dollars 0.51 to dollars 13.74. However, due to the specificity of mental diseases and the relatively long treatment course, patients often have poor compliance, which makes it difficult to administer the drugs regularly, and reduces the therapeutic effect. Meanwhile, the occurrence rate of the brain vascular adverse reaction of the senile patients related to senile dementia (such as stroke and transient ischemic attack) of the bupivazole tablet is increased, which is possibly related to that the common oral quick-release preparation easily reaches higher required concentration and the fluctuation of blood concentration is larger. Therefore, in order to improve the compliance of patients, reduce side effects and expand the application range of the patients, the development of the bripiprazole long-acting microsphere has important significance.
Patent WO 2023036003 A1 discloses a bupivazole long-acting preparation for injection and a preparation method thereof, in particular a microcrystalline injection. The drug crystals are dispersed in a micron-sized suspension form, the particle size distribution of the dosage form is wider, the fluctuation of the blood concentration is easy to be caused by the non-uniform particle size, and the smooth blood concentration is difficult to maintain. Meanwhile, the preparation process of the patent is complex, and industrial large-scale production is difficult to realize.
Patent CN 116531379A discloses a sustained-release composition of bripiprazole, a preparation method and application thereof, wherein dichloromethane is used as an organic solvent, three substances of polylactic acid, polylactic acid-glycolic acid copolymer and polycaprolactone are mixed according to a certain proportion to be used as a carrier, and an emulsifying solvent volatilization method is used for preparing the sustained-release composition of bripiprazole. The methylene dichloride solvent used in the prescription has great toxicity to human body, the solubility of the bripiprazole in the methylene dichloride is very small, and the oil phase takes the methylene dichloride as the solvent, so that the preparation of the microsphere with high drug loading capacity can not be realized. The polycaprolactone as the carrier component has collagen stimulation effect, can cause local tissue hardening, and has uncontrollable side effects for patients with immune diseases.
Patent CN 118477048A discloses a bripiprazole sustained-release microsphere and a preparation method thereof. The emulsification and volatilization time is more than 4 hours, the volatilization and solidification are controlled at different temperatures, the process is complex, and the production efficiency is low. The preparation process adopts a stator-rotor shearing emulsification mode, is limited by batch difference in the amplifying process, different batch causes different parameters of a shearing mixer, and the problems of large quantity and uneven stirring/shearing easily occur in the amplifying production process, and the encapsulation rate and the microsphere yield are also greatly reduced, so that the preparation process has great challenges in the amplifying process.
Disclosure of Invention
In order to solve the technical problems, the invention uses a benzyl alcohol/ethyl acetate system which is safer than methylene dichloride as an organic solvent. Polylactic acid and polycaprolactone are not used, and only the safer degradable polymer, namely polylactic acid-glycolic acid copolymer, is used as a carrier for encapsulating the medicine, so that a certain uncontrollable risk factor is avoided. Meanwhile, the micro-fluidic technology is adopted to prepare the bupivazole sustained-release microsphere for injection with uniform particle size, and the microsphere is round in shape, good in fluidity, good in needle penetrating property, easier to inject, simple in preparation method, and capable of remarkably improving the encapsulation rate and drug loading rate of the traditional method.
The first object of the invention is to provide a preparation method of a bripiprazole long-acting microsphere, which comprises the following steps:
step (1), dissolving the bripiprazole and a degradable polymer in an organic solvent according to a mass ratio of 1:1-1:10 to obtain a drug-containing polymer solution as an oil phase;
Dissolving polyvinyl alcohol in water to obtain a first water phase with the concentration of 0.1-1.5%, mixing the oil phase and the first water phase in the step (1) according to the volume ratio of 1:1-1:45 by a microfluidic technology, wherein the flow rate ratio of the oil phase to the first water phase is 1:1-1:45, volatilizing an organic solvent after colostrum is obtained, and controlling the volatilizing proportion to be 0-20%, thus obtaining the oil-in-water emulsion;
Adding the oil-in-water emulsion obtained in the step (2) into a second water phase serving as a curing phase for curing, wherein the volume of the curing phase is 0.05-1.0L/g microsphere, the curing time is 2-6h, and washing and drying are carried out after curing is completed to obtain the bripiprazole long-acting microsphere;
in step (1), the degradable polymer is polylactic acid-glycolic acid copolymer or polylactic acid;
In the step (1), the organic solvent forming the oil phase is a benzyl alcohol-ethyl acetate mixed solvent system.
In the step (1), the bripiprazole is dissolved in benzyl alcohol to obtain a bripiprazole solution, the polylactic acid-glycolic acid copolymer or polylactic acid is dissolved in ethyl acetate to obtain a polymer solution, and then the bripiprazole solution and the polymer solution are mixed with each other and dispersed by vortex to obtain the oil phase.
As a further optimization scheme, in the step (1), the mass concentration of the bripiprazole solution is 2% -20%, and the mass concentration of the degradable polymer solution is 4% -35%.
As a further optimization scheme, in the step (1), the mixing ratio of the bripiprazole solution and the polymer solution is controlled, so that the mass ratio of the bripiprazole to the degradable polymer is 1:1-1:5.
As a further optimization scheme, in the step (2), the concentration of the polyvinyl alcohol solution is 0.1-1%.
As a further optimization scheme, in the step (2), the oil-in-water emulsion is obtained by conveying an oil phase and a first water phase into a microfluidic reactor by a pump and mixing.
As a further optimization scheme, in the step (2), the flow rate ratio of the oil phase to the first water phase in the microfluidic reactor is 1:1-1:20.
As a further optimization scheme, in the step (2), the volatilization proportion of the organic solvent in the primary emulsion is controlled to be 0-15%.
As a further optimization scheme, in the step (3), the volume of a solidification phase is 0.1-0.5L/g microsphere.
The second object of the invention is to provide the bupivazole long-acting microsphere prepared by the method. The prepared bripiprazole long-acting microsphere has high encapsulation rate, large drug-loading capacity, uniform microsphere particle size distribution, round morphology, good fluidity and needle penetrating property and is easier to inject.
The beneficial effects of the invention are as follows:
The preparation method of the invention can obtain the long-acting sustained-release microsphere of the bripiprazole with high encapsulation efficiency, large drug-loading rate, uniform particle size, round shape and excellent needle penetrating property, and has lasting sustained-release effect which can last for six months.
The bupivazole slow release microsphere prepared by the method has excellent performance, the carrier material is a safer polylactic acid-glycolic acid copolymer, and other polymers such as polycaprolactone and polylactic acid are not needed to be added to adjust the proportion, so that the bupivazole slow release microsphere is safer and more friendly to organisms.
The invention also discovers that the release speed of the microsphere can be regulated by controlling the volatilization proportion of the organic solvent, thus obtaining the bripiprazole microsphere which has no burst release, no release lag phase and ideal release speed, and the encapsulation rate and drug loading rate of the microsphere can not be reduced.
Drawings
In order that the invention may be more readily understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings, in which:
FIG. 1 is a scanning electron microscope image of a slow release microsphere according to example 1 of the present invention.
FIG. 2 is a scanning electron microscope image of the sustained release microsphere of example 4 of the present invention.
FIG. 3 is a scanning electron microscope image of the sustained release microsphere of comparative example 1 of the present invention.
FIG. 4 is a scanning electron microscope image of the slow release microsphere of comparative example 2 of the present invention.
FIG. 5 is an in vitro release profile of the sustained release microspheres of examples 1-6, 9, 10 and comparative example 2 of the present invention.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and specific examples, which are not intended to be limiting, so that those skilled in the art will better understand the invention and practice it.
In the present invention, unless otherwise indicated, the raw materials used are existing products, and specific preparation operations and performance tests are conventional techniques. For example, stirring is a conventional technique, and the organic solvent is removed in a fume hood by a conventional stirring and volatilizing method.
In the present invention, unless otherwise indicated, freeze-drying is carried out using a freeze-dryer model FDU-2110.
Example 1
210Mg of bripiprazole was dissolved in 3ml of benzyl alcohol to obtain a bripiprazole solution, 420mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=90 kDa) was dissolved in 4ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. 7mL of oil phase and 35mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 20mL/min, the obtained emulsion is stirred and volatilized to remove 5% of the weight of the emulsion, then a dispersion system is poured into 125mL of ultrapure water, the mixture is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Example 2
210Mg of bripiprazole was dissolved in 3ml of benzyl alcohol to obtain a bripiprazole solution, 420mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=130 kDa) was dissolved in 4ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. 7mL of oil phase and 35mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 20mL/min, the obtained emulsion is stirred and volatilized to remove 5% of the weight of the emulsion, then a dispersion system is poured into 125mL of ultrapure water, the mixture is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Example 3
210Mg of bripiprazole was dissolved in 3ml of benzyl alcohol to obtain a bripiprazole solution, 420mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=130 kDa) was dissolved in 4ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. 7mL of oil phase and 35mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 20mL/min, the obtained emulsion is stirred and volatilized to remove 9.5% of the weight of the emulsion, then the dispersion system is poured into 125mL of ultrapure water, the mixture is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Example 4
210Mg of bripiprazole was dissolved in 3ml of benzyl alcohol to obtain a bripiprazole solution, 420mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=130 kDa) was dissolved in 4ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. 7mL of oil phase and 35mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a micro-reactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 20mL/min, the obtained emulsion is directly poured into 125mL of ultrapure water without stirring and volatilizing, solidification is carried out for 2 hours, water is used for washing for 3 times after filtration, and the bripiprazole microsphere powder is obtained after freeze drying.
Example 5
200Mg of bripiprazole was dissolved in 4ml of benzyl alcohol to obtain a bripiprazole solution, 400mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=130 kDa) was dissolved in 6ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. 10mL of oil phase and 50mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 20mL/min, the obtained emulsion is stirred and volatilized to remove 2% of the weight of the emulsion, then a dispersion system is poured into 160mL of ultrapure water, the dispersion system is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Example 6
160Mg of bripiprazole was dissolved in 4ml of benzyl alcohol to obtain a bripiprazole solution, 480mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=130 kDa) was dissolved in 8ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. And (3) conveying 12mL of oil phase and 60mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20mL/min by using a advection pump, stirring and volatilizing the obtained emulsion to remove 5% of the weight of the emulsion, pouring the dispersion system into 225mL of ultrapure water, solidifying for 2 hours, filtering, washing with water for 3 times, and freeze-drying to obtain the bripiprazole microsphere powder.
Example 7
120Mg of bripiprazole was dissolved in 3ml of benzyl alcohol to obtain a bripiprazole solution, 240mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=130 kDa) was dissolved in 3ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. 6mL of oil phase and 30mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 20mL/min, the obtained emulsion is stirred and volatilized to remove 5% of the weight of the emulsion, then a dispersion system is poured into 90mL of ultrapure water, the mixture is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Example 8
120Mg of bripiprazole was dissolved in 2ml of benzyl alcohol to obtain a bripiprazole solution, 360mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=12 kDa) was dissolved in 4ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. 6mL of oil phase and 30mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 12mL/min, the obtained emulsion is stirred and volatilized to remove 5% of the weight of the emulsion, then a dispersion system is poured into 90mL of ultrapure water, the mixture is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Example 9
480Mg of bripiprazole was dissolved in 4ml of benzyl alcohol to obtain a bripiprazole solution, 480mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=90 kDa) was dissolved in 4ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing to obtain an oil phase. 8mL of oil phase and 40mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 20mL/min, the obtained emulsion is stirred and volatilized to remove 5% of the weight of the emulsion, then a dispersion system is poured into 135mL of ultrapure water, the solution is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Example 10
160Mg of bripiprazole was dissolved in 4ml of benzyl alcohol to obtain a bripiprazole solution, 480mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=12 kDa) was dissolved in 8ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. And (3) conveying 12mL of oil phase and 60mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL into a microreactor at a flow rate ratio of 1:5 and a total flow rate of 20mL/min by a advection pump, stirring the obtained emulsion to volatilize 8.5% of the weight of the emulsion, pouring the dispersion system into 225mL of ultrapure water, solidifying for 2 hours, filtering, washing with water for 3 times, and freeze-drying to obtain the bripiprazole microsphere powder.
Example 11
4G of bripiprazole is weighed and dissolved in 20g of benzyl alcohol to obtain a bripiprazole solution, 8g of polylactic acid is weighed and dissolved in 16g of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution are mutually mixed and dispersed by vortex to be used as an oil phase. And (3) conveying the oil phase and the 1% polyvinyl alcohol aqueous solution to a micro-reactor at a flow rate ratio of 1:5 by a advection pump, pouring the obtained emulsion into 6000mL of ultrapure water, solidifying for 6 hours, filtering, washing with water for 3 times, and freeze-drying to obtain the bripiprazole microsphere powder.
Example 12
4G of bripiprazole is weighed and dissolved in 16g of benzyl alcohol to obtain a bripiprazole solution, 20g of polylactic acid-glycolic acid copolymer is weighed and dissolved in 37g of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution are mutually mixed and dispersed by vortex to be used as an oil phase. And (3) conveying the oil phase and the 0.1% polyvinyl alcohol aqueous solution to a microreactor at a flow rate ratio of 1:20 by a advection pump, stirring the obtained emulsion to volatilize 15% of the weight of the emulsion, pouring the dispersion system into 2400mL of ultrapure water, solidifying for 6 hours, filtering, washing with water for 3 times, and freeze-drying to obtain the bripiprazole microsphere powder.
Comparative example 1
120Mg of bripiprazole was weighed and dissolved in 2mL of benzyl alcohol to obtain a bripiprazole solution, 240mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=90 kDa) was weighed and dissolved in 2mL of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing to obtain an oil phase. And then dripping the oil phase into 20mL of polyvinyl alcohol water solution with the concentration of 0.01g/mL, stirring and volatilizing the obtained emulsion to remove 5% of the weight of the emulsion, pouring the dispersion system into 120mL of ultrapure water, stirring for 2h, filtering, washing with water for 3 times, and freeze-drying to obtain the bripiprazole microsphere powder.
Comparative example 2
40Mg of bripiprazole was weighed and dissolved in 1mL of benzyl alcohol to obtain a bripiprazole solution, 120mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=12 kDa) was dissolved in 2mL of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortex as an oil phase. And then dripping the oil phase into 15mL of polyvinyl alcohol water solution with the concentration of 0.01g/mL, stirring and volatilizing the obtained emulsion to remove 5% of the weight of the emulsion, pouring the dispersion system into 90mL of ultrapure water, stirring for 2h, filtering, washing with water for 3 times, and freeze-drying to obtain the bripiprazole microsphere powder.
Comparative example 3
40Mg of bripiprazole was weighed and dissolved in 1mL of benzyl alcohol to obtain a bripiprazole solution, 120mg of polylactic acid-glycolic acid copolymer (molar ratio of carboxyl terminated glycolide to glycolide=75:25, mw=12 kDa) was dissolved in 2mL of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortex as an oil phase. And then dripping the oil phase into 15mL of polyvinyl alcohol water solution with the concentration of 0.01g/mL, stirring and volatilizing the obtained emulsion to remove 5% of the weight of the emulsion, pouring the dispersion system into 90mL of ultrapure water, stirring for 2h, filtering, washing with water for 3 times, and freeze-drying to obtain the bripiprazole microsphere powder.
Comparative example 4
40Mg of bripiprazole was weighed and dissolved in 1mL of benzyl alcohol to obtain a bripiprazole solution, 120mg of polylactic acid-glycolic acid copolymer (molar ratio of carboxyl terminated glycolide to glycolide=50:50, mw=12 kDa) was weighed and dissolved in 2mL of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortex to obtain an oil phase. And then dripping the oil phase into 15mL of polyvinyl alcohol water solution with the concentration of 0.01g/mL, stirring and volatilizing the obtained emulsion to remove 5% of the weight of the emulsion, pouring the dispersion system into 90mL of ultrapure water, stirring for 2h, filtering, washing with water for 3 times, and freeze-drying to obtain the bripiprazole microsphere powder.
Comparative example 5
120Mg of bripiprazole was dissolved in 1.3mL of benzyl alcohol to obtain a bripiprazole solution, 120mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=90 kDa) was dissolved in 0.7mL of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing to obtain an oil phase. And then dripping the oil phase into 10mL of polyvinyl alcohol water solution with the concentration of 0.01g/mL, stirring and volatilizing the obtained emulsion to remove 5% of the weight of the emulsion, pouring the dispersion system into 60mL of ultrapure water, stirring for 2h, filtering, washing with water for 3 times, and freeze-drying to obtain the bripiprazole microsphere powder.
Comparative example 6
120Mg of bripiprazole was dissolved in 3ml of benzyl alcohol to obtain a bripiprazole solution, 360mg of polylactic acid-glycolic acid copolymer (molar ratio of carboxyl terminated glycolide to glycolide=50:50, mw=12 kDa) was dissolved in 6ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. 9mL of oil phase and 45mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 20mL/min, the obtained emulsion is stirred and volatilized to remove 5% of the weight of the emulsion, then a dispersion system is poured into 125mL of ultrapure water, the mixture is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Comparative example 7
120Mg of bripiprazole was dissolved in 3ml of benzyl alcohol to obtain a bripiprazole solution, 360mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=12 kDa) was dissolved in 6ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. 9mL of oil phase and 27mL of polyvinyl alcohol aqueous solution with the concentration of 0.005g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:3 and the total flow rate of 20mL/min, the obtained emulsion is stirred and volatilized to remove 5% of the weight of the emulsion, then a dispersion system is poured into 125mL of ultrapure water, the mixture is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Comparative example 8
480Mg of bripiprazole was dissolved in 4ml of benzyl alcohol to obtain a bripiprazole solution, 480mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=90 kDa) was dissolved in 4ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing to obtain an oil phase. 8mL of oil phase and 40mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 20mL/min, the obtained emulsion is stirred and volatilized to remove 5% of the weight of the emulsion, then a dispersion system is poured into 135mL of ultrapure water, the solution is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Comparative example 9
200Mg of bripiprazole was dissolved in 4ml of benzyl alcohol to obtain a bripiprazole solution, 400mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=12 kDa) was dissolved in 6ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. 10mL of oil phase and 50mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 20mL/min, the obtained emulsion is stirred and volatilized to remove 5% of the weight of the emulsion, then a dispersion system is poured into 125mL of ultrapure water, the mixture is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Comparative example 10
210Mg of bripiprazole was dissolved in 3ml of dimethyl sulfoxide to obtain a bripiprazole solution, 420mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=130 kDa) was dissolved in 4ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing to obtain an oil phase. 7mL of oil phase and 35mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 20mL/min, the obtained emulsion is stirred and volatilized to remove 5% of the weight of the emulsion, then a dispersion system is poured into 125mL of ultrapure water, the mixture is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Comparative example 11
210Mg of bripiprazole was dissolved in 3ml of methylene chloride to obtain a bripiprazole solution, 420mg of polylactic acid-glycolic acid copolymer (molar ratio of ester-terminated glycolide to glycolide=75:25, mw=130 kDa) was dissolved in 4ml of ethyl acetate to obtain a polymer solution, and the bripiprazole solution and the polymer solution were mixed with each other and dispersed by vortexing as an oil phase. 7mL of oil phase and 35mL of polyvinyl alcohol aqueous solution with the concentration of 0.01g/mL are conveyed into a microreactor through a advection pump at the flow rate ratio of 1:5 and the total flow rate of 20mL/min, the obtained emulsion is stirred and volatilized to remove 5% of the weight of the emulsion, then a dispersion system is poured into 125mL of ultrapure water, the mixture is solidified for 2 hours, filtered, washed with water for 3 times, and freeze-dried to obtain the bripiprazole microsphere powder.
Test example 1 microsphere drug loading and encapsulation efficiency
The preparation method comprises the steps of taking octadecylsilane chemically bonded silica as a filler, taking 0.15% phosphoric acid and acetonitrile (68:32) as mobile phases, detecting the wavelength to be 215nm, respectively weighing 10mg of the bripiprazole microspheres prepared in examples 1-10 and comparative examples 1-11, adding dimethyl sulfoxide to dissolve the microspheres, adding 0.15% phosphoric acid solution to fix the volume to 100mL, shaking uniformly, taking part of solution for 12500rpm centrifugation, taking supernatant, and carrying out HPLC analysis to obtain the total drug concentration. 10mg of microspheres were weighed, added with 0.15% phosphoric acid solution to a volume of 10mL, and the supernatant was analyzed by HPLC to determine the free drug concentration. The total medicine amount-free medicine amount is the medicine-carrying amount, and the calculation formulas of the medicine-carrying amount and the encapsulation rate are as follows:
table 1 drug loading and encapsulation efficiency of microspheres of different examples and comparative examples
| Sample preparation | Theoretical drug loading (%) | Drug loading (%) | Encapsulation efficiency (%) |
| Example 1 | 33.33 | 31.93 | 99.81 |
| Example 2 | 33.33 | 30.15 | 99.96 |
| Example 3 | 33.33 | 34.22 | 98.22 |
| Example 4 | 33.33 | 30.71 | 99.96 |
| Example 5 | 33.33 | 32.63 | 99.92 |
| Example 6 | 25.00 | 23.70 | 99.94 |
| Example 7 | 33.33 | 32.21 | 99.24 |
| Example 8 | 25.00 | 24.53 | 99.65 |
| Example 9 | 50.00 | 42.19 | 98.44 |
| Example 10 | 25.00 | 22.73 | 98.74 |
| Example 11 | 33.33 | 30.33 | 99.78 |
| Example 12 | 16.67 | 16.15 | 99.86 |
| Comparative example 1 | 33.33 | 25.35 | 98.75 |
| Comparative example 2 | 25.00 | 18.01 | 99.57 |
| Comparative example 3 | 25.00 | 19.07 | 98.14 |
| Comparative example 4 | 25.00 | 14.36 | 55.94 |
| Comparative example 5 | 25.00 | 17.69 | 89.09 |
| Comparative example 6 | 25.00 | 16.93 | 82.34 |
| Comparative example 7 | 25.00 | 21.50 | 84.71 |
| Comparative example 8 | 25.00 | 13.00 | 75.49 |
| Comparative example 9 | 25.00 | 5.01 | 9.64 |
| Comparative example 10 | 33.33 | 15.83 | 44.35 |
| Comparative example 11 | 33.33 | / | / |
The present invention employs a manner of dropping the oil phase into the water phase and stirring to prepare the bupivazole microspheres in comparative examples 1 to 5. The microspheres prepared by the method have the advantages that most samples can reach more than 95% of encapsulation rate, but the overall difference is still large, the process loss of the medicine in the process is large, and the medicine loading rate is much smaller than the theoretical medicine loading rate. While attempts have been made to vary different factors, such as the use of different amounts of raw materials, varying the polymer molecular weight, adjusting the ratio of solvents, adjusting different polymer end cap types, etc., these attempts have failed to completely improve the problems with encapsulation efficiency and drug loading to achieve the desired results. In addition, the mass transfer process of the process has large influence on the volume, and once the process is amplified, the process parameters need to be readjusted, so that the amplified production has high difficulty.
In the invention, in examples 1-10 and comparative examples 6-11, two-phase solutions are input into a microfluidic device by adopting microfluidics to prepare the bripiprazole microsphere, and a large number of process conditions such as a convection speed ratio and a total flow rate, a stirring volatilization time, a polymer and a ratio, a solvent system, a curing condition and the like are tried to be explored, and the following findings are found.
As shown in Table 1, examples 2-4 changed the stirring volatilization degree, and had little effect on the microsphere encapsulation efficiency and drug loading, indicating that the process has good stability. The molecular weight of the polylactic acid-glycolic acid copolymer adopted in examples 1, 2 and 8 is different, and the effect on the microsphere encapsulation efficiency and drug loading is not great, which shows that the PLGA molecular weight change does not form a limiting factor in a certain range. However, when PLGA was changed to carboxyl end-capped and the molar ratio of lactide to glycolide was 50:50 in comparative example 6, a significant decrease in encapsulation efficiency and drug loading was observed, indicating that the end-capping group of PLGA had a significant impact on the preparation of the bripiprazole microsphere. In contrast, a protocol that selects PLGA with an ester end cap and a lactide to glycolide molar ratio of 75:25 is desirable. Furthermore, the use of dimethyl sulfoxide as an organic solvent in comparative example 10 resulted in a lower encapsulation efficiency, whereas in comparative example 11, due to the limited solubility of bripiprazole in methylene chloride, a large amount of drug leakage occurred during the preparation, and the finally collected microspheres were so few that no effective test could be performed. In contrast, benzyl alcohol/ethyl acetate solvent systems help to increase the solubility of bripiprazole and achieve higher encapsulation and drug loading.
As shown in Table 1, from the viewpoints of encapsulation efficiency and drug loading, the preferred formulations are examples 1-10, the encapsulation efficiency of the prepared microspheres is above 98%, and the drug loading is close to the theoretical drug loading. In the microsphere with the drug loading ratio of 1:1 prepared by the microfluidic technology in the embodiment 9, the drug loading can reach 42%, and the encapsulation efficiency can reach more than 98%. Despite extensive searches for relevant literature, patent and market information, no bripiprazole microsphere products have been found that can achieve high drug loading of 40% or more while ensuring such high encapsulation efficiency.
As shown in table 1, it was also found that the O/W colostrum prepared by the microfluidic technology in example 4 was directly cured without stirring, and microspheres with an encapsulation efficiency of 99% or more could be obtained, and the difference between the drug loading and the theoretical drug loading was also small. The scheme is particularly remarkable in terms of process simplification, greatly quickens the production progress on the premise of guaranteeing the quality, and is particularly suitable for industrial production.
Test example 2 microsphere particle size
The microspheres prepared in examples 1 to 10 and comparative examples 1 to 11 were divided into three parts, and each was dispersed in water, and the particle size of the microspheres was measured by using a BT-2001 laser particle size distribution analyzer, and the results are shown in Table 2.
TABLE 2 microsphere particle sizes for the different examples and comparative examples
As can be seen from Table 2, in examples 6, 8 and 10, when the molecular weight of the polylactic acid-glycolic acid copolymer is smaller, the particle size of the prepared microspheres is smaller, and compared with other examples, the small-particle-size microspheres are collected by a smaller screen, the screen is easy to block, the microspheres are difficult to wash, the efficiency is low, and the method is not suitable for industrial production. When the molecular weight of the polylactic acid-glycolic acid copolymer is above 90kDa, the microsphere with the particle size of 50-80 mu m can be prepared by a flow control device, the particle size is uniform, and the penetrating needle property is good. In addition, when the drug loading ratio of the microspheres prepared by the preparation process of direct dripping is increased to 1:1 and 1:2 (comparative example 1 and comparative example 9), the particle size is larger than 100 mu m, and the microspheres are not suitable for intramuscular injection. Examples 1-5, 7, 9 are therefore preferred formulations from a particle size perspective.
Test example 3 microsphere morphology and Angle of repose measurement
The appropriate amount of microspheres prepared in examples 1 and 4 and comparative examples 1 and 2 were taken, and the morphology of the microspheres was measured by using a scanning electron microscope, and the results are shown in FIGS. 1 to 4.
TABLE 3 measurement of the repose angles of microspheres for different examples and comparative examples
| Sample preparation | Angle of repose |
| Example 1 | 37.6° |
| Example 4 | 38.3° |
| Comparative example 1 | 44.9° |
| Comparative example 2 | 45.2° |
The result of the repose angle shows that the bupivazole microsphere prepared by the microfluidic technology has smaller repose angle and better fluidity.
According to the measurement results of a scanning electron microscope and an angle of repose, the bripiprazole microsphere prepared by the microfluidic technology is more round, has better fluidity and good needle penetrating property, and is easier to inject.
Test example 4 in vitro Release of microspheres
2G of sodium hydroxide was weighed and dissolved in 500mL of water, 105mL was discarded, 6.8g of potassium dihydrogen phosphate and 605mL of water were added to dissolve together, and 2g of cetyltrimethylammonium bromide was further added to obtain a PBS solution containing 0.2% cetyltrimethylammonium bromide having a release medium of pH 7.4.
12Mg of the bripiprazole microspheres prepared in examples 1-6, 9, 10 and comparative example 2 were weighed into 100mL conical flasks with stoppers, 100mL of 0.2% cetyltrimethylammonium bromide in PBS was added, placed into a 37℃water bath thermostatic shaker, 1mL were taken at various time points, centrifuged (8000 rpm,5 min) and a small portion of the supernatant was analyzed to retain samples. After all the old release medium of the residual microspheres is removed, the residual microspheres are replaced by fresh release medium, and the lofting is continued. The samples were analyzed by high performance liquid chromatography, the cumulative release percentage was calculated, and the release profile of cumulative release percentage versus time was plotted. The results are shown in FIG. 5.
From fig. 5, it can be seen that the bupivazole microsphere can achieve a sustained release effect for 2 months or more. Examples 1 and 9 show that the larger the drug loading, the faster the release. Examples 3, 4, 6, 9 show that the O/W colostrum is formed with different stirring times and different release rates, which also shows that the release rate can be adjusted by controlling the volatility of the organic solvent. And the in vitro release profile of the sustained release microspheres prepared by the same formulation using a drip process (comparative example 2) and a microfluidic process (example 6), respectively, it was found that the release was relatively slower with the formulation of the microfluidic process.
The above embodiments are illustrative for the purpose of illustrating the technical concept and features of the present invention so that those skilled in the art can understand the content of the present invention and implement it accordingly, and thus do not limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
Claims (5)
1. The preparation method of the bripiprazole long-acting microsphere is characterized by comprising the following steps:
dissolving the bripiprazole and the degradable polymer in an organic solvent to obtain a drug-containing polymer solution as an oil phase;
Dissolving polyvinyl alcohol in water to obtain a first water phase with the concentration of 0.1-1.5%, mixing the oil phase and the first water phase in the step (1) according to the volume ratio of 1:1-1:45 by a microfluidic technology, wherein the flow rate ratio of the oil phase to the first water phase is 1:1-1:45, volatilizing an organic solvent after obtaining colostrum, and controlling the volatilizing proportion to be 0-20%, thus obtaining the oil-in-water emulsion;
Adding the oil-in-water emulsion obtained in the step (2) into a second water phase serving as a curing phase for curing, wherein the volume of the curing phase is 0.05-1.0L/g microsphere, the curing time is 2-6h, and washing and drying are carried out after curing is completed to obtain the bripiprazole long-acting microsphere;
In the step (1), the degradable polymer is an ester-terminated polylactic acid-glycolic acid copolymer, wherein the molar ratio of lactide to glycolide is 75:25, and the weight average molecular weight of the degradable polymer is 90 kDa-130 kDa;
In the step (1), the organic solvent forming the oil phase is a benzyl alcohol-ethyl acetate mixed solvent system;
In the step (1), the bripiprazole is dissolved in benzyl alcohol to obtain a bripiprazole solution, and the polylactic acid-glycolic acid copolymer or polylactic acid is dissolved in ethyl acetate to obtain a polymer solution;
in the step (1), controlling the mixing ratio of the bripiprazole solution and the polymer solution to ensure that the mass ratio of the bripiprazole to the degradable polymer is 1:1-1:5;
In the step (2), the concentration of the polyvinyl alcohol solution is 0.1-1%;
In the step (2), the flow rate ratio of the oil phase to the first water phase in the microfluidic reactor is 1:1-1:20;
In step (1), the mass concentration of the bripiprazole solution is 6.3% and the mass concentration of the degradable polymer solution is 10.4%, or the mass concentration of the bripiprazole solution is 4.6% and the mass concentration of the degradable polymer solution is 6.9%, or the mass concentration of the bripiprazole solution is 10.3% and the mass concentration of the degradable polymer solution is 11.7%.
2. The method for preparing the bripiprazole long-acting microsphere according to claim 1, wherein in the step (2), the oil-in-water emulsion is obtained by mixing an oil phase and a first aqueous phase by a pump into a microfluidic reactor.
3. The method for preparing a long-acting bripiprazole microsphere according to claim 1, wherein in the step (2), the volatilization ratio of the organic solvent in the colostrum is controlled to be 0-15%.
4. The method for preparing a long-acting microsphere of bripiprazole according to claim 1, wherein in the step (3), the volume of the solidification phase is 0.1 to 0.5L/g microsphere.
5. A bripiprazole long-acting microsphere characterized by being produced according to the method of any one of claims 1 to 4.
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