CN113413372A - Long-acting injectable microsphere based on aripiprazole microcrystalline aggregates and preparation method thereof - Google Patents

Long-acting injectable microsphere based on aripiprazole microcrystalline aggregates and preparation method thereof Download PDF

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CN113413372A
CN113413372A CN202110675792.2A CN202110675792A CN113413372A CN 113413372 A CN113413372 A CN 113413372A CN 202110675792 A CN202110675792 A CN 202110675792A CN 113413372 A CN113413372 A CN 113413372A
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dichloromethane
aripiprazole
microspheres
microsphere
mixed solvent
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毛世瑞
胡迎莉
张欣
李惠玲
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Shenyang Pharmaceutical University
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Abstract

The invention provides long-acting injectable microspheres based on aripiprazole microcrystal aggregates with a core-shell structure and without release lag phase and oral supplementation and a preparation method thereof. The long-acting injectable microsphere is prepared by taking a mixed solvent with a certain proportion as an oil phase and taking a polylactic acid-glycolic acid copolymer as an adhesive and a shell, and agglomerating and adhering aripiprazole microcrystals to form a spherical entity of a core. The drug-loading rate of the microspheres of the long-acting injectable microsphere drug preparation is 35-65 percent by mass, the average particle size of the microspheres is less than 25 mu m, the intramuscular injection has good needle passing performance, no need of additional oral supplement of aripiprazole preparation is needed, only half of the drug-loading dose of the preparation on the market can reach the effective blood concentration, and the drug release period can reach more than 30 days.

Description

Long-acting injectable microsphere based on aripiprazole microcrystalline aggregates and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to long-acting injectable microspheres based on aripiprazole microcrystalline aggregates with a core-shell structure and without release lag phase and oral supplementation and a preparation method thereof.
Background
Aripiprazole (Aripiprazole) is one of the first-choice drugs for resisting schizophrenia in clinic at present, has effects on dopamine D2, D3, 5-HT1A and 5-HT2A receptors, can perform a biphasic regulation effect on a nervous system, and has the advantages of good curative effect, low adverse reaction, reduction of recurrence rate and the like. Due to the special treatment of the mental patients, the long-acting injection with high compliance has higher clinical value and convenient application. The long-acting injection microsphere has long drug release period, obviously reduces the drug delivery frequency, has stable blood concentration and low toxic and side effects of the drug, and greatly improves the compliance of patients.
Currently, there are marketed products of Abilify Maintena and arista, which are jointly developed and produced by tsukamur japan pharmacy and Alkermes ltd. The two preparations are aripiprazole microcrystal suspension which can be stably released in a human body through intramuscular injection, but the two preparations have the defects that the dissolution of aripiprazole microcrystal into systemic circulation is slow in the initial injection stage, the blood concentration is low, the effective treatment concentration cannot be achieved, and a proper amount of aripiprazole tablets need to be additionally orally taken within 14 days or 21 days after the initial injection to achieve the treatment effect. This reduces the convenience of use of long acting injections and patient compliance to some extent, increasing the complexity of the treatment.
Japanese patent application CN106389357A to Otsuka discloses a freeze-dried aripiprazole formulation which provides a freeze-dried aripiprazole powder exhibiting good dispersibility and uniformly dispersed by reconstitution with water. The formulation is a freeze-dried microcrystalline suspension rather than a microsphere product. Meanwhile, the preparation has high requirement on the particle size for keeping good dispersibility, and the aripiprazole and the carrier thereof are ground for multiple times by a wet grinding method, so that the crystal form transformation of the aripiprazole is easily caused, and the release property of the drug is changed. Finally, the preparation is freeze-dried by spray freeze drying to obtain a freeze-dried preparation, and the effective treatment concentration can not be reached in the early stage of administration after the intramuscular injection is compounded by water.
Japanese patent application CN1870980A of Otsuka corporation discloses a method for preparing a controlled-release sterile injectable aripiprazole formulation comprising aripiprazole having a desired average particle size and a carrier therefor. The average particle size of the preparation is 1-30 μm, and the preparation has the problems of large particle size, high injection requirement and the like. And moreover, the aripiprazole microcrystal with the required granularity is obtained by multiple wet grinding, the preparation process is complex, the preparation period is long, the sterile environment is easy to damage in the preparation process, and the industrial production is not facilitated.
Japanese patent application CN101801342A of Otsuka discloses a process for preparing an aripiprazole suspension and a process for lyophilizing, in which aripiprazole is mixed with a carrier to form a primary suspension, pulverized by a high shear or a colloid mill, and then emulsified and dispersed by a high pressure jet. The average grain diameter of the preparation is 1-10 mu m, two times of crushing processes are needed, and the problems of complex preparation process, long preparation period and the like exist.
Us patent application CN102133171A to Alkermes corporation discloses an injectable composition of aripiprazole rather than a microsphere product. The preparation is administrated in a concentrated bolus injection mode, the average diameter of the aripiprazole microcrystal is about 30-80 mu m, and the particle size of the drug is large, so a tackifier is needed to enable the drug particles in the suspension to be always in a suspension state, the stability is poor, a needle head is easy to block, a patient feels obvious in pain during injection, and meanwhile, injection difficulty is caused.
Patent application CN105663057A of the university of Chinese pharmacy discloses aripiprazole lyophilized powder which is easily dispersed by compounding with water, the average particle size is 1-15 μm, the drug needs to be micronized in advance and then is crushed and ground with a carrier for two times, crystal form transformation easily occurs in the grinding process, and the problem of whether the early-stage drug release can reach the effective concentration is not solved.
Patent application CN108498456A of Lizhu pharmaceutical group discloses aripiprazole sustained-release microspheres with a reticular skeleton structure and a preparation method thereof. The preparation related to the patent application takes methylene dichloride as an oil phase, the drug loading range is 65-80%, aripiprazole is filled in small holes of a carrier framework, the average particle size is less than 20 μm, and the effective concentration can be reached at the initial administration stage. Although the application of the Lizhu pharmaceutical group is excellent in the formulation properties compared with other products under investigation, it still leaves much room for improvement in the drug release properties.
Japanese Otsuka's patent application CN101742989A discloses a microsphere having a core/shell structure wherein aripiprazole is a solid core and a degradable polymeric PLGA shell coats all or most of the core. The aripiprazole core-shell microsphere related to the patent uses methylene dichloride as a solvent, the average particle size is 20-150 μm, the drug-loading rate is 55% -95%, although the slow release effect for one month can be realized, the disadvantages of large particle size of the microsphere, difficult injection and lower blood concentration at the early stage of release still exist.
In view of the disadvantages of the marketed products and the products under study, and the continuous clinical need of long-acting injectable aripiprazole formulations, there is an urgent need to provide a novel long-acting injectable aripiprazole formulation with good pharmacodynamic and pharmacokinetic properties and convenient clinical use.
Disclosure of Invention
The invention aims to provide long-acting injectable microspheres based on aripiprazole microcrystalline aggregates with a core-shell structure and without release lag phase and oral supplementation and a preparation method thereof. The long-acting injectable microsphere is prepared by taking a mixed solvent with a certain proportion as an oil phase and taking a polylactic acid-glycolic acid copolymer as an adhesive and a shell, and agglomerating and adhering aripiprazole microcrystals to form a spherical entity of a core. The drug-loading rate of the microspheres of the long-acting injectable microsphere drug preparation is 35-65 percent by mass, the average particle size of the microspheres is less than 25 mu m, the intramuscular injection has good needle passing performance, no need of additional oral supplement of aripiprazole preparation is needed, only half of the drug-loading dose of the preparation on the market can reach the effective blood concentration, and the drug release period can reach more than 30 days. The medicinal preparation greatly improves the compliance of patients, makes up the defects of products on the market, has small particle size, high medicament loading capacity, high yield and stable balling property, and can be suitable for large-scale production.
Specifically, the invention is realized by the following technical schemes:
in a first aspect, the invention provides long-acting injectable microspheres based on aripiprazole microcrystal aggregates with a core-shell structure, which have no release lag phase and do not need oral supplementation, wherein the microspheres take a mixed solvent with a certain proportion as an oil phase, take polylactic acid-glycolic acid copolymer as an adhesive and a shell, and aggregate and bond the aripiprazole crystallites to form a spherical entity of an inner core.
The drug loading of the microspheres is 35-65% by mass, preferably 40-60%.
The microspheres have an average particle size of less than 25 μm, preferably less than 20 μm, more preferably less than 10 μm, most preferably the microspheres have an average particle size of 9-16 μm and a span of less than 3, preferably less than 2.5.
The long-acting injectable microsphere can achieve effective blood concentration only by half the administration dosage of the preparation on the market without additional oral supplementation of aripiprazole preparation, and the drug release period can reach more than 30 days.
Alternatively, in the above long-acting injectable microsphere, the mixed solvent in a certain proportion is selected from the following combinations: dichloromethane and ethyl acetate, dichloromethane and acetone or dichloromethane and chloroform.
When the mixed solvent is formed by combining dichloromethane and ethyl acetate, the volume ratio of the dichloromethane to the ethyl acetate is 1:1-10: 1; when the mixed solvent is formed by combining dichloromethane and acetone, the volume ratio of the dichloromethane to the acetone is 1:1-10: 1; and when the mixed solvent is dichloromethane and chloroform, the volume ratio of the dichloromethane to the chloroform is 0.5:1-10: 1.
Alternatively, in the above long-acting injectable microsphere, the aripiprazole is an anhydrate, a monohydrate, a solvate, or a pharmaceutically acceptable salt thereof.
Alternatively, in the above long-acting injectable microsphere, the intrinsic viscosity of the polylactic acid-glycolic acid copolymer is 0.16 to 0.60dL/g, preferably 0.32 to 0.60 dL/g.
The weight-average molecular weight of the polylactic acid-glycolic acid copolymer is 13900-35000Da, preferably 30000-35000 Da.
The molar ratio of the two monomers of lactic acid and glycolic acid in the polylactic acid-glycolic acid copolymer is 50: 50-25: 75.
in a second aspect, the present invention provides a method for preparing the long-acting injectable microspheres described in the first aspect above, comprising the steps of:
1) adding the aripiprazole microcrystal and the polylactic acid-glycolic acid copolymer in the first aspect into a mixed solvent in a certain proportion to serve as an oil phase, and oscillating and dissolving in a water bath at a certain temperature;
2) injecting the solution obtained in the step 1) into a polyvinyl alcohol (PVA) aqueous phase solution with certain pH and at certain temperature under high-speed shearing, and emulsifying to obtain a uniform emulsion; and
3) solidifying the emulsion obtained in the step 2), volatilizing the solvent under the controlled temperature condition, centrifugally collecting after a certain time, washing and freeze-drying to obtain the aripiprazole microspheres.
Alternatively, in the above preparation method, in the step 1), the proportion of the mixed solvent is selected from the following combinations: dichloromethane and ethyl acetate, dichloromethane and acetone or dichloromethane and chloroform.
When the mixed solvent is formed by combining dichloromethane and ethyl acetate, the volume ratio of the dichloromethane to the ethyl acetate is 1:1-10: 1; when the mixed solvent is formed by combining dichloromethane and acetone, the volume ratio of the dichloromethane to the acetone is 1:1-10: 1; and when the mixed solvent is dichloromethane and chloroform, the volume ratio of the dichloromethane to the chloroform is 0.5:1-10: 1.
The certain temperature is 40-65 ℃, preferably 45-60 ℃.
Alternatively, in the above preparation method, in the step 2), the rotation number of the high-speed shearing is 6000-.
The certain temperature is below 15 deg.c, preferably below 12 deg.c.
The certain pH is greater than 7, preferably, 8-10.
In the aqueous phase solution, the concentration of the polyvinyl alcohol is 0.5-3.5% by mass volume percentage, preferably 1-3%.
The volume ratio of the solution obtained in the step 1) to the aqueous polyvinyl alcohol solution is 1:50-1:200, preferably 1:100-1: 150.
Alternatively, in the above production method, in step 3), the controlled temperature condition is that the temperature was lower than 15 ℃ for the previous hour, and thereafter the volatilization was maintained at 25 ℃.
The curing time of the microspheres is 2.5-4 h; the average particle size of the freeze-dried microspheres is 9-25 μm.
In a third aspect, the present invention provides a pharmaceutical formulation comprising long-acting injectable microspheres, wherein the pharmaceutical formulation comprises the long-acting injectable microspheres of the first aspect or the long-acting injectable microspheres prepared by the preparation method of the second aspect, and a pharmaceutically acceptable carrier.
Alternatively, in the above pharmaceutical formulation, the pharmaceutically acceptable carrier comprises a suspending agent, a surfactant, a pH adjusting agent, and/or an isotonicity adjusting agent.
The suspending agent comprises one or more of the following materials: hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, sodium alginate or glycerol.
The pH regulator comprises one or more of the following materials: sodium hydroxide or phosphoric acid.
The isotonicity adjusting agent includes one or more of the following materials: sodium chloride, glucose or mannitol.
The surfactant comprises one or more of the following materials: polysorbate 20, polysorbate 40, polysorbate 80, poloxamer or cremophor.
As an optional mode, the pharmaceutical preparation is a suspension of aripiprazole long-acting injectable microspheres, and the suspension is 0-5% by mass; 0-7% of a filler; adjusting the pH value to 6.5-7.5.
The aripiprazole of the present invention includes aripiprazole crystals, amorphous or amorphous forms, aripiprazole hydrate, solvate or anhydride.
Compared with the prior art, the invention has the following beneficial effects:
1. the sustained-release microsphere with the core-shell structure based on the aripiprazole microcrystalline aggregates does not need to be supplemented with an aripiprazole preparation orally after injection, can achieve effective blood concentration only by half the administration dosage of the preparation on the market, makes up the defect of the preparation on the market, improves the compliance of patients, and can release drugs cumulatively for at least 1 month.
2. Compared with the developing agent disclosed in CN108498456A, the sustained-release microsphere based on the aripiprazole microcrystal aggregates with the core-shell structure has different structures (the invention is the core-shell structure, the CN108498456A discloses a net-shaped skeleton structure) and different oil phase solvents (the invention is a mixed solvent, and the CN108498456A discloses a single solvent).
3. The sustained-release microsphere with the core-shell structure based on the aripiprazole microcrystal aggregate ensures that the drug-loading rate reaches 35-65% by mass percent under the condition of ensuring that the particle size is smaller, and solves the problems of injection pain, poor needle penetration, larger injection volume and the like of a long-acting injection.
4. The injectable aripiprazole microsphere suspension provided by the invention has good stability and can not cause injection difficulty. The aripiprazole sustained-release microspheres have good balling property, and aripiprazole anhydride, monohydrate or salt thereof is coagulated and bonded to form a spherical entity.
5. The inventor optimizes the prescription factors, preparation process and other influencing factors of the aripiprazole long-acting injectable microsphere through a large number of experiments to determine the optimal preparation method of the aripiprazole microsphere. The method has the advantages of simple preparation process, stable result and good reproducibility, and is expected to realize industrialization.
Drawings
Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1: in vitro release properties of formulations prepared from various organic solvents.
FIG. 2: example 9 scanning electron microscopy of microspheres.
FIG. 3: example 12 scanning electron microscopy of microspheres.
FIG. 4: example 13 scanning electron microscopy of microspheres.
FIG. 5: example 14 scanning electron microscopy of microspheres.
FIG. 6: example 9 scanning electron microscopy of microsphere cross-section.
FIG. 7: example 12 scanning electron microscopy of microsphere cross-section.
FIG. 8: example 13 scanning electron microscopy of microsphere cross section.
FIG. 9: example 14 scanning electron microscopy of microsphere cross-section.
FIG. 10: rat plasma concentration-time profiles for the microsphere samples prepared in example 9, example 12, example 13, and example 14.
Detailed Description
The invention is further illustrated with reference to specific examples. It should be understood that the specific embodiments described herein are illustrative only and are not limiting upon the scope of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products which are not known to manufacturers and are available from normal sources.
The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.
Example 1: selection of oil phase species
315mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer are mixed, wherein 3mL of single solvents of dichloromethane, ethyl acetate, acetone and chloroform and a mixed solvent (dichloromethane: ethyl acetate, dichloromethane: acetone and dichloromethane: chloroform) with a certain proportion are respectively added into the polylactic acid-glycolic acid copolymer (the intrinsic viscosity is 0.32-0.44dL/g, the weight-average molecular weight is 30500Da, and the molar ratio of polylactic acid to glycolic acid is 50:50), and the mixture is heated in a water bath at 55 ℃ and dissolved by shaking. Preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value to 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and is maintained at 25 ℃ after shearing for 30 s); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
Table 1: effect of different oil phase solvent types on the experiment
Oil phase solvent Description of the Experimental results
Methylene dichloride The microsphere has smooth surface and good balling property
Ethyl acetate The microspheres have rough surfaces and poor balling-up property
Acetone (II) The surface of the microsphere is rough,Poor balling-up property
Chloroform The microsphere has smooth surface and good balling property
Dichloromethane: ethyl acetate (4:1) The microsphere has smooth surface and good balling property
Dichloromethane: acetone (4:1) The microsphere has smooth surface and good balling property
Dichloromethane: chloroform (4:1) The microsphere has smooth surface and good balling property
In addition, we also examined the in vitro release behavior of microspheres prepared with each oil phase solvent. The specific experimental conditions are as follows: precisely weighing a certain amount of drug-loaded microspheres prepared by the oil phase solvents according to the method, placing the drug-loaded microspheres into a 15mL centrifuge tube, adding 10mL of release medium pH7.4PBS (containing 0.2% SDS), controlling the temperature at 37 +/-1 ℃, controlling the rotating speed at 100r/min, taking out all release liquid at 1, 2, 3, 5, 7, 10, 13, 17, 21, 25, 29, 30 and 32d respectively, replenishing an equal amount of fresh release medium in time, centrifuging to take supernatant, injecting samples according to the following chromatographic conditions, recording peak areas, calculating the cumulative release percentage of each group of microspheres, and drawing an in-vitro release curve.
Chromatographic conditions are as follows: a chromatographic column: a C18 column (150 mm. times.4.6 mm, 5 μm); mobile phase: 0.05mol/LNaH2PO4Aqueous solution (1% triethylamine, ph5.5 adjusted with phosphoric acid) -acetonitrile (50: 50); column temperature: room temperature; flow rate: 1.0 mL/min; detection wavelength: 217 nm; sample introduction amount: 20 μ L.
The solvent release behavior of each oil phase is compared as shown in fig. 1.
And (4) conclusion: when the mixed solvent is dichloromethane: ethyl acetate, dichloromethane: acetone or dichloromethane: in the case of chloroform, the obtained microspheres have good balling property and smooth surfaces. The drug loading (w/w) of the microspheres is 49-52%, the encapsulation rate is more than 80%, and the microsphere yield is high. In addition, compared with the use of a single solvent, the mixed solvent with different proportions can realize the regulation and control of the drug release rate, and provides a premise for obtaining the required release behavior. From this, it is preferable to use a mixed solvent as the oil phase.
Example 2: selection of the proportion of the solvent mixture
315mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer are mixed, wherein the polylactic acid-glycolic acid copolymer (the intrinsic viscosity is 0.32-0.44dL/g, the weight average molecular weight is 30500Da, the molar ratio of polylactic acid to glycolic acid is 50:50) is added with 3mL of mixed solvent (dichloromethane: ethyl acetate, dichloromethane: acetone, dichloromethane: chloroform) according to a certain proportion, and the mixed solvent is heated in a water bath at the temperature of 55 ℃ and is dissolved by shaking. Preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value of 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and is kept at 25 ℃ after shearing for 30 s); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
Table 2: effect of the Mixed solvent ratio on the experiment
Ratio of mixed solvents Description of the Experimental results
1:1 The surface of the microsphere has shrinkage and general balling property
2:1 The surface of the microsphere has shrinkage and general balling property
4:1 The microsphere has smooth surface and good balling property
6:1 The microsphere has smooth surface and good balling property
10:1 The microsphere has smooth surface and good balling property
And (4) conclusion: when the proportion of the mixed solvent is 4:1-10:1, the experimental effect is optimal, and the obtained microspheres have good balling property and smooth and complete surfaces.
Example 3: selection of oil-to-water phase ratio
315mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer (inherent viscosity is 0.32-0.44dL/g, weight average molecular weight is 30500Da, molar ratio of polylactic acid to glycolic acid is 50:50) are mixed, 3mL of mixed solvent (dichloromethane: ethyl acetate ═ 4:1) is added, and the mixture is dissolved by shaking at the water bath heating temperature of 55 ℃. Preparing 1% polyvinyl alcohol solution (w/v) with a certain volume, adding sodium hydroxide to adjust pH10, injecting the oil phase into polyvinyl alcohol under 10000rpm high-speed shearing for dispersing, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and is maintained at 25 ℃ after shearing for 30 s); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
Table 3: effect of oil-to-water ratio on the experiment
Oil-water phase ratio Description of the Experimental results
1:50 The microspheres are broken and have poor balling-up property
1:100 The microsphere has smooth surface and general sphericity
1:150 The microsphere has smooth surface and good balling property
1:200 The microsphere has smooth surface and good balling property
And (4) conclusion: when the water phase proportion is higher than 100, the experimental effect is optimal, and the obtained microspheres have good balling property and smooth and complete surfaces.
Example 4: selection of polyvinyl alcohol (PVA) concentration
315mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer (inherent viscosity is 0.32-0.44dL/g, weight average molecular weight is 30500Da, molar ratio of polylactic acid to glycolic acid is 50:50) are mixed, 3mL of mixed solvent (dichloromethane: ethyl acetate ═ 4:1) is added, and the mixture is dissolved by shaking at the water bath heating temperature of 55 ℃. Preparing 450mL (w/v) of polyvinyl alcohol solution with a certain concentration, adding sodium hydroxide to adjust the pH value of 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and then is maintained at 25 ℃) after shearing for 30 s; solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
Table 4: effect of PVA concentration on the experiment
PVA concentration (w/v) Description of the Experimental results
0.5％ The microsphere has smooth surface and general sphericity
1％ The microsphere has smooth surface and good balling property
1.5％ The microsphere has smooth surface and good balling property
2％ The microsphere has smooth surface and good balling property
3％ The microsphere has smooth surface and general sphericity
3.5％ The microsphere has smooth surface and general sphericity
And (4) conclusion: when the PVA concentration is 1-2%, the experimental effect is optimal, and the obtained microsphere has good balling property, smooth surface and integrity.
Example 5: selection of polyvinyl alcohol (PVA) pH
315mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer (inherent viscosity is 0.32-0.44dL/g, weight average molecular weight is 30500Da, molar ratio of polylactic acid to glycolic acid is 50:50) are mixed, 3mL of mixed solvent (dichloromethane: ethyl acetate ═ 4:1) is added, and the mixture is dissolved by shaking at the water bath heating temperature of 55 ℃. Preparing 450mL (w/v) of polyvinyl alcohol solution with the concentration of 1%, adding sodium hydroxide to adjust certain pH, injecting the oil phase into polyvinyl alcohol under 10000rpm high-speed shearing for dispersing, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and then is maintained at 25 ℃) after shearing for 30 s; solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
Table 5: effect of PVA pH on the experiment
pH of PVA Description of the Experimental results
7 The microsphere has smooth surface and general sphericity
8 The microsphere has smooth surface and general sphericity
9 The microsphere has smooth surface and good balling property
10 The microsphere has smooth surface and good balling property
11 The microsphere has smooth surface and good balling property
12 The microsphere has smooth surface and general sphericity
And (4) conclusion: when the pH value of PVA is 9-11, the experimental effect is optimal, and the obtained microsphere has good balling property, smooth surface and integrity.
Example 6: selection of the dissolution temperature
315mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer (the intrinsic viscosity is 0.32-0.44dL/g, the weight-average molecular weight is 30500Da, the molar ratio of polylactic acid to glycolic acid is 50:50) are mixed, 3mL of mixed solvent (dichloromethane: ethyl acetate: 4:1) is added, and the mixture is heated in a water bath and shaken to be dissolved. Preparing 450mL (w/v) of polyvinyl alcohol solution with the concentration of 1%, adding sodium hydroxide to adjust the pH value of 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the first hour and then is maintained at 25 ℃) after shearing for 30 s; solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
Table 6: effect of dissolution temperature on the experiment
Dissolution temperature (. degree.C.) Description of the Experimental results
40 The microsphere has smooth surface and general sphericity
45 The microsphere has smooth surface and general sphericity
50 The microsphere has smooth surface and good balling property
55 The microsphere has smooth surface and good balling property
60 The microsphere has smooth surface and general sphericity
65 The microsphere has smooth surface and general sphericity
And (4) conclusion: when the dissolving temperature is 50-55 ℃, the experimental effect is optimal, and the obtained microspheres have good balling property and smooth and complete surfaces.
Example 7: selection of volatilization temperature
Aripiprazole 315mg and polylactic acid-glycolic acid copolymer 210mg were mixed, wherein the polylactic acid-glycolic acid copolymer (intrinsic viscosity 0.32-0.44dL/g, weight average molecular weight 30500Da, polylactic acid to glycolic acid molar ratio 50:50) was added in a volume ratio of 4:1 (dichloromethane: ethyl acetate, dichloromethane: acetone or dichloromethane: chloroform) by heating in a water bath at 55 ℃ with shaking. Preparing 450mL (w/v) of polyvinyl alcohol solution with the concentration of 1%, adding sodium hydroxide to adjust the pH value of the solution to 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition after shearing for 30 s; solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
Table 7: influence of volatilization temperature on experiment
Figure BDA0003121008320000121
And (4) conclusion: when the volatilization temperature is kept for low temperature volatilization for the first hour, the experimental effect is optimal, and the obtained microspheres have good balling property and smooth and complete surfaces.
Example 8: selection of the number of shear revolutions
Aripiprazole 315mg and polylactic acid-glycolic acid copolymer 210mg were mixed, wherein the polylactic acid-glycolic acid copolymer (intrinsic viscosity 0.32-0.44dL/g, weight average molecular weight 30500Da, polylactic acid to glycolic acid molar ratio 50:50) was added in a volume ratio of 4:1 (dichloromethane: ethyl acetate, dichloromethane: acetone or dichloromethane: chloroform) by heating in a water bath at 55 ℃ with shaking. Preparing 450mL (w/v) of polyvinyl alcohol solution with the concentration of 1%, adding sodium hydroxide to adjust the pH value of the solution to 10, injecting the oil phase into the polyvinyl alcohol under high-speed shearing at a certain revolution to disperse the oil phase, shearing the oil phase for 30s, and volatilizing the organic solvent under the controlled temperature condition (the temperature of the previous hour is lower than 15 ℃ and then is maintained at 25 ℃); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
Table 8: effect of shear rotation number on experiment
Figure BDA0003121008320000122
Figure BDA0003121008320000131
And (4) conclusion: when the shearing revolution is higher than 9k rpm, the experimental effect is optimal, and the obtained microspheres have good balling property and smooth and complete surfaces.
Example 9
315mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer (inherent viscosity is 0.32-0.44dL/g, weight average molecular weight is 30500Da, molar ratio of polylactic acid to glycolic acid is 50:50) are mixed, 3mL of mixed solvent (dichloromethane: ethyl acetate ═ 4:1) is added, and the mixture is dissolved by shaking at the water bath heating temperature of 55 ℃. Preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value of 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and is kept at 25 ℃ after shearing for 30 s); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
And (4) conclusion: the microsphere drug loading rate is 55.67% (w/w), the yield is 81.16%, the balling property is good, the microsphere surface is smooth and complete, the scanning electron microscope image of the obtained microsphere sample is shown in figure 2, and the cross section image is shown in figure 6. The cross section of the microsphere is clear, and the fine drug crystals with the diameters varying from 100-1000nm are uniformly distributed in the whole PLGA skeleton.
Example 10
Aripiprazole 210mg and polylactic acid-glycolic acid copolymer 210mg were mixed, wherein the polylactic acid-glycolic acid copolymer (intrinsic viscosity 0.32-0.44dL/g, weight average molecular weight 30500Da, molar ratio of polylactic acid to glycolic acid 50:50) was dissolved by adding 3mL of a mixed solvent (dichloromethane: chloroform: 4:1) and heating at 55 ℃ with shaking. Preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value of 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and is kept at 25 ℃ after shearing for 30 s); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
And (4) conclusion: the drug loading of the microsphere is 45.98% (w/w), the yield is 78.13%, the balling property is good, and the surface of the microsphere is smooth and complete.
Example 11
Mixing 140mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer (inherent viscosity 0.32-0.44dL/g, weight average molecular weight 30500Da, molar ratio of polylactic acid to glycolic acid 50:50), adding 3mL of mixed solvent (dichloromethane: ethyl acetate ═ 6: 1), and heating at 55 ℃ with shaking to dissolve. Preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value of 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and is kept at 25 ℃ after shearing for 30 s); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
And (4) conclusion: the microsphere has the advantages of 37.91% (w/w) of drug loading, 73.60% of yield, good balling property and smooth and complete microsphere surface.
Example 12
450mg of aripiprazole and 300mg of polylactic acid-glycolic acid copolymer (inherent viscosity 0.32-0.44dL/g, weight average molecular weight 30500Da, molar ratio of polylactic acid to glycolic acid 50:50) were mixed, 3mL of mixed solvent (dichloromethane: ethyl acetate 4:1) was added, and the mixture was heated at 55 ℃ and dissolved with shaking. Preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value to 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and is maintained at 25 ℃ after shearing for 30 s); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
And (4) conclusion: the microsphere drug loading rate is 56.23% (w/w), the yield is 89%, the balling property is good, the microsphere surface is smooth and complete, the scanning electron microscope image of the obtained microsphere sample is shown in figure 3, and the cross section image is shown in figure 7. The cross section of the microsphere is clear, and the fine drug crystals with the diameters varying from 100-1000nm are uniformly distributed in the whole PLGA skeleton.
Example 13
Aripiprazole 225mg and polylactic acid-glycolic acid copolymer 150mg were mixed, wherein the polylactic acid-glycolic acid copolymer (intrinsic viscosity 0.32-0.44dL/g, weight average molecular weight 30500Da, molar ratio of polylactic acid to glycolic acid 50:50) was dissolved by adding a mixed solvent (dichloromethane: ethyl acetate 4:1) 3mL, heating temperature 55 ℃ and shaking. And preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value to 10, controlling the temperature to be 12 ℃, dispersing the oil phase in the PVA aqueous phase solution by adopting a high-speed shearing instrument at the rotating speed of 10000rpm, performing volatilization and solidification for 3 hours after shearing for 30s, centrifuging to obtain microspheres, and freeze-drying.
And (4) conclusion: the microsphere drug loading rate is 55.21% (w/w), the yield is 78.14%, the balling property is good, the microsphere surface is smooth and complete, the scanning electron microscope image of the obtained microsphere sample is shown in figure 4, and the cross section image is shown in figure 8. The cross section of the microsphere is clear, and the fine drug crystals with the diameters varying from 100-1000nm are uniformly distributed in the whole PLGA skeleton.
Example 14
135mg of aripiprazole and 90mg of polylactic acid-glycolic acid copolymer (inherent viscosity 0.32-0.44dL/g, weight average molecular weight 30500Da, molar ratio of polylactic acid to glycolic acid 50:50) were mixed, 3mL of mixed solvent (dichloromethane: ethyl acetate 4:1) was added, and the mixture was heated at 55 ℃ and dissolved with shaking. And preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value to 10, controlling the temperature to be 12 ℃, dispersing the oil phase in the PVA aqueous phase solution by adopting a high-speed shearing instrument at the rotating speed of 10000rpm, performing volatilization and solidification for 3 hours after shearing for 30s, centrifuging to obtain microspheres, and freeze-drying.
And (4) conclusion: the microsphere drug loading is 54.16% (w/w), the yield is 71.23%, the balling property is good, the microsphere surface is smooth and complete, the scanning electron microscope image of the obtained microsphere sample is shown in figure 5, and the cross section image is shown in figure 9. The cross section of the microsphere is clear, and the fine drug crystals with the diameters varying from 100-1000nm are uniformly distributed in the whole PLGA skeleton.
Example 15
315mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer (inherent viscosity is 0.16-0.24dL/g, weight average molecular weight is 13900Da, molar ratio of polylactic acid to glycolic acid is 50:50) are mixed, 3mL of mixed solvent (dichloromethane: ethyl acetate ═ 10: 1) is added, and the mixture is dissolved by shaking at the water bath heating temperature of 55 ℃. Preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value of 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and is kept at 25 ℃ after shearing for 30 s); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
And (4) conclusion: the microsphere drug loading rate is 45.64% (w/w), the yield is 75.06%, the balling property is good, and the microsphere surface is smooth and complete.
Example 16
315mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer (intrinsic viscosity is 0.45-0.60dL/g, weight average molecular weight is 34800Da, molar ratio of polylactic acid to glycolic acid is 50:50) are mixed, 3mL of mixed solvent (dichloromethane: acetone ═ 4:1) is added, and the mixture is heated in a water bath at 55 ℃ and dissolved by shaking. Preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value of 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and is kept at 25 ℃ after shearing for 30 s); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
And (4) conclusion: the microsphere has the advantages of 49.78% (w/w) of drug loading, 82.97% of yield, good balling property and smooth and complete microsphere surface.
Example 17
315mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer (inherent viscosity is 0.32-0.44dL/g, weight average molecular weight is 30400Da, molar ratio of polylactic acid to glycolic acid is 65:35) are mixed, 3mL of mixed solvent (dichloromethane: chloroform: 6: 1) is added, and the mixture is dissolved by shaking at the water bath heating temperature of 55 ℃. Preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value of 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and is kept at 25 ℃ after shearing for 30 s); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
And (4) conclusion: the microsphere drug loading rate is 44.07% (w/w), the yield is 73.46%, the balling property is good, and the microsphere surface is smooth and complete.
Example 18
315mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer (inherent viscosity is 0.14-0.22dL/g, weight average molecular weight is 14500Da, molar ratio of polylactic acid to glycolic acid is 75:25) are mixed, 3mL of mixed solvent (dichloromethane: acetone ═ 6: 1) is added, and the mixture is dissolved by shaking at the water bath heating temperature of 55 ℃. Preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value of 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and is kept at 25 ℃ after shearing for 30 s); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
And (4) conclusion: the microsphere drug loading rate is 43.78% (w/w), the yield is 72.97%, the balling performance is good, and the microsphere surface is smooth and complete.
Example 19
315mg of aripiprazole and 210mg of polylactic acid-glycolic acid copolymer (inherent viscosity is 0.32-0.44dL/g, weight average molecular weight is 33500Da, molar ratio of polylactic acid to glycolic acid is 75:25) are mixed, 3mL of mixed solvent (dichloromethane: acetone ═ 10: 1) is added, and the mixture is dissolved by shaking at the water bath heating temperature of 55 ℃. Preparing 450mL (w/v) of 1% polyvinyl alcohol solution, adding sodium hydroxide to adjust the pH value of 10, injecting the oil phase into the polyvinyl alcohol under the high-speed shearing of 10000rpm to disperse, and volatilizing the organic solvent under the controlled temperature condition (the temperature is lower than 15 ℃ in the previous hour and is kept at 25 ℃ after shearing for 30 s); solidifying for 3h, centrifugally washing to obtain microspheres, and freeze-drying.
And (4) conclusion: the microsphere drug loading rate is 45.64% (w/w), the yield is 75.06%, the balling property is good, and the microsphere surface is smooth and complete.
Example 20: measurement of particle diameter
The particle size and the particle size distribution of the aripiprazole long-acting microsphere are measured by a BT-9300s laser particle size analyzer. The specific method comprises the following steps: a certain amount of aripiprazole microspheres are taken and added into deionized water, ultrasonic treatment is carried out for 1min to ensure that the aripiprazole microspheres are fully dispersed (the refractive index of a medium is 1.333, the range of the shading rate is 5-12), and each sample is subjected to parallel determination for three times. By volume mean diameter (D)v,50) As a measure of the geometric diameter of the particles, the Span (Span) was used as a measure of the particle size distribution range of the particles, and the Span value was calculated by the following formula:
Figure BDA0003121008320000181
in the formula, Dv,10、Dv,50、Dv,90The particle diameters at 10%, 50%, and 90% of the frequency in the cumulative distribution graph of particle diameters (the curve plotted with the cumulative frequency as the ordinate and the particle diameter as the abscissa) are shown, respectively.
Example 21: pharmacokinetic experiments
The aripiprazole microspheres prepared in example 9, example 12, example 13 and example 14 of the present invention were prepared into formulations by a specific method: weighing quantitative microspheres, adding a suspending agent (CMC-Na 4%) and a filling agent (mannitol 5%) in a certain mass percentage to prepare a stable suspension.
Adult, healthy rats, 24, weighing about 250g, were selected. It was randomly divided into 4 groups of 6: 4 groups of aripiprazole microspheres, 12.5mg/Kg aripiprazole microsphere, example 9, example 12, example 13 and example 14 (the dose is selected according to the conditions that the recommended clinical dose of the aripiprazole preparation on the market is 300-400mg/mL, the human is 60Kg according to the conversion of the body surface area, the rat equivalent dose is 25-50 mg/kg., two doses of 12.5mg/Kg and 25mg/Kg are selected in advance for carrying out pre-experiments, and according to the results of the pre-experiments, half of the recommended dose of the suspension on the market can be used for achieving the effective steady-state blood concentration, so 12.5mg/Kg is selected as the administration dose of the preparation) are respectively injected into the right thigh of 12.5mg/Kg, 11d, 13d, 15d, 19d, 23d, 27d and 31d to respectively collect 1mL plasma samples at 3h, 6h, 2d, 4d, 7d, 11d, 13d, 15d, 19d, 23d, 27d and 31d after administration, placing in polyethylene tube anticoagulated with heparin, centrifuging at 12000rpm for 10min, storing the separated plasma in refrigerator at-20 deg.C, and testing.
Plasma sample treatment: the aripiprazole plasma sample is processed by liquid-liquid extraction, 500 μ L of plasma is precisely measured, the plasma is placed in an EP tube, 50 μ L of pre-prepared internal standard solution (perphenazine with 5 μ g/mL) and 200 μ L of saturated sodium carbonate solution are added, and the mixture is vortexed and mixed for 3 min. Then 3mL ethyl acetate was added for extraction, and the mixture was vortexed and mixed for 5 min. Then, the mixture was centrifuged at 12000rpm for 10min, and the whole supernatant was removed and purged with nitrogen in a constant temperature water bath at 40 ℃ until the solvent was evaporated. The sample was analyzed by reconstitution with 200. mu.L of mobile phase.
Chromatographic conditions are as follows: a chromatographic column: thermo C18(5.0 μm, 150X 4.0 mm); mobile phase: methanol: ammonium acetate solution (containing 1% triethylamine (w/v)) (80: 20); column temperature: 30 ℃; flow rate: 1.0 mL/min; detection wavelength: 257 nm; sample introduction amount: 20 μ L.
The mean plasma concentration-time curves in the self-prepared rats for the four groups of examples are shown in fig. 10.
As can be seen, the blood concentrations of the self-made prescription and the commercial preparation in the four groups of examples have double peaks. The effective concentration range of aripiprazole in rats reported in the literature is about 18-55 ng/mL. By taking the effective concentration range of 18-55ng/mL as a reference, compared with the original developed agent Abilify, the time for achieving the effective treatment concentration after the self-prepared prescription administration of the four groups of examples is different, but the advantage in the whole drug release period is obvious, except the prescription group of example 14, the blood concentration of other prescription groups is generally maintained in the effective concentration in the whole drug release period, and the fluctuation degree is small. In all home-made formulations, the time to reach an effective concentration in the formulation group of example 13 was about 6 hours, which is closest to the time to peak when aripiprazole tablets are orally administered. The concentration interval of the two peaks is 9 days, is consistent with the concentration interval of the two peaks of Abilify in the original research, and the blood concentration is higher than that of the original preparation in the whole release period and is maintained in an effective concentration range, the fluctuation is small, the release is close to stable release, the aripiprazole preparation can be realized without oral supplementation, the cumulative release reaches the treatment requirement of more than one month, and the advantages are obvious compared with the preparation on the market.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

Claims (10)

1. Long-acting injectable microspheres based on aripiprazole microcrystalline aggregates with core-shell structure without release lag phase, without oral supplementation, characterized in that: the microspheres take a mixed solvent with a certain proportion as an oil phase, a polylactic acid-glycolic acid copolymer as an adhesive and a shell, the aripiprazole microcrystals are coagulated and bonded to form a spherical entity of an inner core, the drug-loading rate of the microspheres is 35-65% by mass, preferably 40-60%, the average particle size of the microspheres is less than 25 μm, preferably less than 20 μm, more preferably less than 10 μm, most preferably, the average particle size of the microspheres is 9-16 μm, the span is less than 3, preferably less than 2.5, the long-acting injectable microspheres do not need to be additionally orally supplemented with an aripiprazole preparation, the effective blood concentration can be reached only by half the administration dose of the preparation on the market, and the drug release period can reach more than 30 days.
2. The long-acting injectable microsphere of claim 1, wherein: the mixed solvent in a certain proportion is selected from the following combinations: dichloromethane and ethyl acetate, dichloromethane and acetone or dichloromethane and chloroform; when the mixed solvent is formed by combining dichloromethane and ethyl acetate, the volume ratio of the dichloromethane to the ethyl acetate is 1:1-10: 1; when the mixed solvent is formed by combining dichloromethane and acetone, the volume ratio of the dichloromethane to the acetone is 1:1-10: 1; and when the mixed solvent is dichloromethane and chloroform, the volume ratio of the dichloromethane to the chloroform is 0.5:1-10: 1.
3. The long-acting injectable microsphere of claim 1 or claim 2, wherein: the aripiprazole is an anhydrate, a monohydrate, a solvate or a pharmaceutically acceptable salt thereof.
4. The long-acting injectable microsphere according to any one of claims 1 to 3, characterized in that: the inherent viscosity of the polylactic acid-glycolic acid copolymer is 0.16-0.60dL/g, preferably 0.32-0.60 dL/g; the weight-average molecular weight of the polylactic acid-glycolic acid copolymer is 13900-35000Da, preferably 30000-35000 Da; the molar ratio of the two monomers of lactic acid and glycolic acid in the polylactic acid-glycolic acid copolymer is 50: 50-25: 75.
5. a method of preparing long-acting injectable microspheres according to any one of claims 1 to 4 comprising the steps of:
1) adding the aripiprazole microcrystal and the polylactic acid-glycolic acid copolymer of any one of claims 1-4 into a certain proportion of mixed solvent as an oil phase, and dissolving in water bath oscillation at a certain temperature;
2) injecting the solution obtained in the step 1) into a polyvinyl alcohol (PVA) aqueous phase solution with certain pH and at certain temperature under high-speed shearing, and emulsifying to obtain a uniform emulsion; and
3) solidifying the emulsion obtained in the step 2), volatilizing the solvent under the controlled temperature condition, centrifugally collecting after a certain time, washing and freeze-drying to obtain the aripiprazole microspheres.
6. The method of claim 5, wherein: in step 1), the mixed solvent in a certain proportion is selected from the following combinations: dichloromethane and ethyl acetate, dichloromethane and acetone or dichloromethane and chloroform; when the mixed solvent is formed by combining dichloromethane and ethyl acetate, the volume ratio of the dichloromethane to the ethyl acetate is 1:1-10: 1; when the mixed solvent is formed by combining dichloromethane and acetone, the volume ratio of the dichloromethane to the acetone is 1:1-10: 1; and, when the mixed solvent is a combination of dichloromethane and chloroform, the volume ratio of dichloromethane to chloroform is 0.5:1 to 10: 1; the certain temperature is 40-65 ℃, preferably 45-60 ℃.
7. The method of claim 5, wherein: in step 2), the rotation speed of the high-speed shearing is 6000-; said certain temperature is lower than 15 ℃, preferably lower than 12 ℃; said certain pH is greater than 7, preferably, 8-10; in the aqueous phase solution, the concentration of the polyvinyl alcohol is 0.5 to 3.5 percent, preferably 1 to 3 percent by mass volume; the volume ratio of the solution obtained in the step 1) to the aqueous polyvinyl alcohol solution is 1:50-1:200, preferably 1:100-1: 150.
8. The method of claim 5, wherein: in the step 3), the temperature condition is controlled to be that the temperature in the previous hour is lower than 15 ℃, and then the temperature is kept to volatilize at 25 ℃; the curing time of the microspheres is 2.5-4 h; the average particle size of the freeze-dried microspheres is 9-25 μm.
9. A pharmaceutical formulation comprising long-acting injectable microspheres, characterized by: the pharmaceutical preparation comprises the long-acting injectable microsphere of any one of claims 1 to 4 or prepared by the preparation method of any one of claims 5 to 8, and a pharmaceutically acceptable carrier.
10. The pharmaceutical formulation of claim 9, wherein: the pharmaceutically acceptable carrier comprises a suspending agent, a surfactant, a pH adjusting agent, and/or an isotonicity adjusting agent; the suspending agent comprises one or more of the following materials: hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, sodium carboxymethylcellulose, sodium alginate or glycerol; the pH regulator comprises one or more of the following materials: sodium hydroxide or phosphoric acid; the isotonicity adjusting agent includes one or more of the following materials: sodium chloride, glucose or mannitol; and, the surfactant comprises one or more of the following materials: polysorbate 20, polysorbate 40, polysorbate 80, poloxamer or cremophor.
CN202110675792.2A 2021-06-18 2021-06-18 Long-acting injectable microsphere based on aripiprazole microcrystalline aggregates and preparation method thereof Pending CN113413372A (en)

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CN115212174A (en) * 2022-07-18 2022-10-21 辉粒药业(苏州)有限公司 Aripiprazole-loaded long-acting slow-release microsphere and preparation method thereof
CN116473927A (en) * 2023-06-07 2023-07-25 深圳聚生生物科技有限公司 Preparation method and application of injectable PLA microspheres

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CN108498456A (en) * 2018-05-16 2018-09-07 丽珠医药集团股份有限公司 A kind of Aripiprazole sustained-release micro-spheres and preparation method thereof

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Publication number Priority date Publication date Assignee Title
CN115212174A (en) * 2022-07-18 2022-10-21 辉粒药业(苏州)有限公司 Aripiprazole-loaded long-acting slow-release microsphere and preparation method thereof
CN115212174B (en) * 2022-07-18 2024-02-20 辉粒药业(苏州)有限公司 Aripiprazole-loaded long-acting slow-release microsphere and preparation method thereof
CN116473927A (en) * 2023-06-07 2023-07-25 深圳聚生生物科技有限公司 Preparation method and application of injectable PLA microspheres
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Application publication date: 20210921