A method for preparing a laurocapram aripiprazole suspension

Abstract

The application belongs to the technical field of medicine, and particularly relates to a preparation method of laurocapram aripiprazole suspension, which comprises the following steps: (a) obtaining a mother liquor by mixing laurocapram aripiprazole, a first surfactant and water; (b) homogenizing the mother liquor to form an intermediate suspension with D90 of 10-25 microns; (c) heating the intermediate suspension; (d) when the intermediate suspension obtained in step (c) is cooled to room temperature, mixing with a standby solution containing a second surfactant to obtain laurocapram aripiprazole suspension.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for preparing a lauroyl aripiprazole suspension. Background Technology

[0002] A suspension is a heterogeneous system in which a solid drug is dispersed in a liquid medium. The drug is generally poorly soluble and contains stabilizers such as surfactants or polymers. The medium is water (or oil). Based on the size of the dispersed drug particles, suspensions can be classified into nano-suspensions and micro-suspensions. They can be administered orally, intramuscularly, subcutaneously, or intravenously. Micro-suspensions are generally administered via intramuscular injection. After injection, a drug reservoir forms at the injection site, where the drug slowly dissolves, is released, and is absorbed, thus achieving a long-lasting effect. They are primarily used to treat chronic diseases requiring long-term medication. Several micro-suspensions are currently on the market, mainly for the treatment of schizophrenia. Dosing once every few weeks or months is sufficient to achieve the desired therapeutic effect, greatly improving patient compliance.

[0003] Currently, technologies for achieving long-acting injectable formulations include forming insoluble salts, such as olanzapine dihydroxynaphthyl; using lactide and glycolide to form sustained-release microspheres, such as leuprorelin sustained-release microspheres and risperidone sustained-release microspheres; and forming prodrugs, such as aripiprazole lauroyl and palmide palmitate.

[0004] CN102525915B discloses a sustained-release injectable formulation, its preparation method, and its use. This invention protects injectable formulations of aripiprazole or pharmaceutically acceptable salts thereof that are non-aqueous carriers, but does not cover lauroyl aripiprazole.

[0005] CN110025572A discloses alopiperazole lauroyl suspension and its preparation method. The suspension obtained by this method using a media grinding method can be administered once every 4 to 8 weeks without the need for redispersing before administration, which can improve the convenience of clinical use. However, the original drug often adheres to the instrument during the grinding process, resulting in the loss of the original drug, and the grinding process is also very time-consuming.

[0006] CN105012236A discloses a long-acting non-aqueous carrier injection solution and its preparation method. This method can stably release the drug for at least 4 weeks, but the introduction of exogenous organic solvents into the injection solution poses a potential biotoxicity to humans, especially when administered intravenously. Summary of the Invention

[0007] To address the problems existing in the prior art, this invention provides a method for preparing a lauroyl aripiprazole suspension that is free of organic solvent residue, has a simple preparation process, is suitable for industrial production applications, has stable processing, a narrow particle size distribution of the suspension, and good reproducibility.

[0008] Specifically, the present application provides a preparation method of laurocapram aripiprazole suspension, comprising the following steps:

[0009] (a) combining laurocapram aripiprazole, a first surfactant and water to obtain a mother liquor;

[0010] (b) homogenizing the mother liquor to form an intermediate suspension with D90 between 10 and 25 μm;

[0011] (c) heating the intermediate suspension;

[0012] (d) combining the intermediate suspension obtained in step (c) with a standby solution containing a second surfactant to obtain laurocapram aripiprazole suspension when cooled to room temperature;

[0013] wherein the first surfactant is a non-ionic surfactant with HLB between 4 and 10, preferably HLB between 6 and 9;

[0014] the second surfactant is a non-ionic surfactant with HLB between 11 and 20, preferably HLB between 15 and 17.

[0015] In the above method, preferably, the homogenization process in step (b) is 3-10 cycles at 50-60 bar pressure and 4-12 cycles at 70-100 bar pressure in a high-pressure homogenizer; preferably 3-5 cycles at 50 bar pressure and 6-8 cycles at 100 bar pressure in a high-pressure homogenizer; more preferably 4 cycles at 50 bar pressure and 8 cycles at 100 bar pressure in a high-pressure homogenizer.

[0016] Further preferably, the temperature of homogenization in step (b) is 20°C or lower.

[0017] Further preferably, the homogenization of the mother liquor in step (b) forms an intermediate suspension with D50 between 5 and 15 μm and D90 between 10 and 25 μm; preferably the homogenization of the mother liquor in step (b) forms an intermediate suspension with D10 between 1 and 10 μm, D50 between 5 and 15 μm, D90 between 10 and 25 μm, and Span≤2.

[0018] In the above method, preferably, the heating temperature in step (c) is 40-70°C, preferably 50-70°C, such as 55-65°C, more preferably 50-60°C; the heating maintenance time is 10-90 min, preferably 10-60 min, more preferably 18-24 min. The heating temperature and heating time can be adjusted as appropriate according to the actual situation, for example, when the heating temperature is higher, for example, the temperature is 70°C, the heating maintenance time is appropriately shortened, for example, 10 min-20 min, such as 10 min, 15 min or 18 min, etc.; when the heating temperature is lower, for example, the temperature is 70°C, the heating maintenance time is appropriately extended, for example, 16 min or more, such as 20 min, 30 min, 60 min or 90 min; when the heating temperature is moderate, such as 50-60°C, the heating maintenance time is usually 15 min, 18 min, 20 min, 24 min, 25 min or 30 min, etc. It is found in the research process that when the heating temperature is too high, such as 75°C or higher, the control of particle size is not good, and the particle size usually cannot meet the requirement of ideal release rate; and when the temperature is too low, such as lower than 40°C, and the heating time is short, the control of particle size is also not ideal, and the particle size is usually small, which cannot meet the target particle size requirement, thereby affecting the in vitro and in vivo release time.

[0019] The heating time is 10-60 min, preferably the heating temperature is 55-65°C, and the heating time is 10-60 min.

[0020] In the above method, preferably, the D10 of the laurocapernazine in step (a) is between 10-250 μm, the D50 is between 20-500 μm, and the D90 is between 40-1000 μm; further preferably, the D10 of the laurocapernazine in step (a) is between 10-150 μm, the D50 is between 20-300 μm, and the D90 is between 40-500 μm.

[0021] In the above method, preferably, further comprising recrystallizing the laurocapernazine in step (a) so that the D10 is between 10-250 μm, the D50 is between 20-500 μm, and the D90 is between 40-1000 μm, preferably the D10 is between 10-150 μm, the D50 is between 20-300 μm, and the D90 is between 40-500 μm;

[0022] The recrystallization comprises the following steps: dissolving the laurocapernazine in a good solvent, then adding a poor solvent for mixing, and then cooling, separating and drying;

[0023] The good solvent comprises at least one of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, acetone, preferably the good solvent comprises ethyl acetate or isopropyl acetate, and optionally further comprises Tween, wherein the concentration of Tween in the good solvent is 0-10 mg / mL;

[0024] The poor solvent is selected from at least one of pentane, cyclopentane, hexane, cyclohexane, methylcyclohexane, n-heptane, octane, nonane, decane, undecane, dodecane, ethanol, methanol, preferably the poor solvent is n-heptane;

[0025] The solid-liquid ratio of laurocapernazine to the good solvent is 1:(1-5) g / mL.

[0026] The volume ratio of the good solvent to the poor solvent is 1:(1-10).

[0027] Further preferably, the cooling comprises natural cooling to room temperature, or gradient cooling: cooling to 20-50℃ at a cooling rate of 0.5-5℃ / min, holding for 0-5 h, and then cooling to 5-20℃ within 2-10 h, holding at this temperature for 5-24 h.

[0028] Optionally, the above recrystallization step is repeated one or more times to prepare laurocapernazine with a target particle size; or the above recrystallization method is combined with a high-pressure homogenizer.

[0029] In the above method, further preferably, the mass ratio of laurocapernazine to water in step (a) is 1:(1-5), preferably 1:(2-3); the amount of the first surfactant is 1-5% (w / w) of the mass of laurocapernazine, preferably 1-3% (w / w).

[0030] In the above method, further preferably, the weight of the second surfactant is 0.1-0.7 times, preferably 0.2-0.5 times, the weight of the first surfactant.

[0031] In the above method, further preferably, the first surfactant is Span 20; the second surfactant is Tween 20; and the standby solution further comprises an inorganic salt, which is selected from one or more of potassium carbonate, sodium carbonate, potassium chloride, sodium chloride, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, magnesium phosphate, magnesium sulfate, ferrous sulfate, manganese sulfate, copper sulfate, and calcium carbonate.

[0032] In the above method, further preferably, the particle size distribution of the obtained laurocapernazine suspension is: D10 is 2-10 μm, D50 is 10-30 μm, and D90 is less than 65 μm, preferably D10 is 4-10 μm, D50 is 10-20 μm, and D90 is 15-35 μm.

[0033] Detailed description of the invention

[0034] Unless otherwise indicated, all parts and percentages specified in the present application are on a weight basis and the test and characterization methods used are those current as of the filing date of the present application. If the definition of a specific term disclosed in the prior art is inconsistent with any of the terms provided in the present application, the term definition provided in the present application shall prevail.

[0035] The words "preferred," "further preferred," "more preferred" and the like in the present specification do not designate an absolute level of preference, but indicate relative preferences. In some instances, a preferred embodiment can provide certain advantages. However, other embodiments can also be preferred under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the present application. Sources for components not mentioned in the present application are commercially available.

[0036] There is a need in the art for formulations containing aripiprazole prodrug that, when administered to a patient, provide a therapeutic amount of aripiprazole, and there is a need to develop a method for preparing such formulations that enables aripiprazole prodrug, lauroyl aripiprazole, to be configured into a long-acting or sustained-release formulation that provides an improved therapeutic amount of aripiprazole over a longer period of time when administered to a patient.

[0037] The present inventors have found, after earnest research to solve the above problems, that a sample obtained by mixing lauroyl aripiprazole with a specific first surfactant and then homogenously heating under certain conditions and then post-treating has the optimal detection particle size, and the appropriate particle size distribution is of great significance for achieving a high bioavailability and excellent in vivo sustained-release effect.

[0038] The first aspect of the present application provides a method for preparing a lauroyl aripiprazole suspension, comprising the following steps:

[0039] (a) obtaining a mother liquor by mixing lauroyl aripiprazole with a first surfactant and water;

[0040] (b) homogenizing the mother liquor to form an intermediate suspension having a D90 of 10-25 μm;

[0041] (c) heating the intermediate suspension;

[0042] (d) when the intermediate suspension obtained in step (c) is cooled to room temperature, combining with a standby solution containing a second surfactant to obtain a lauroyl aripiprazole suspension.

[0043] In the process of the present application, there is no restriction on the source of the raw drug of laurocapernazine, which can be any one commercially available or prepared by any method known to those skilled in the art, and the laurocapernazine prepared can be further treated by recrystallization.

[0044] Laurocapernazine is a water-insoluble antipsychotic drug, and the surfactant can play a role in physical separation by forming a space or electrostatic barrier around the drug, preventing the aggregation of drug particles.

[0045] Therefore, within the scope of the present application, several known surfactants used in the physical separation of small molecules are suitable. These known surfactants include nonionic surfactants, anionic surfactants, cationic surfactants or amphoteric surfactants.

[0046] Preferably, the suitable first surfactant used in the present application is a surfactant with an HLB value between 4 and 10, preferably a nonionic surfactant with an HLB value between 6 and 9, more preferably an HLB value between 8 and 9. The HLB value, i.e. the hydrophilic-lipophilic balance, is a value used to represent the hydrophilic or lipophilic capacity of a surfactant.

[0047] As suitable first surfactants with an HLB value between 4 and 10, including but not limited to sorbitan monooleate, sorbitan monopalmitate, sorbitan laurate, propylene glycol fatty acid ester, diethylene glycol fatty acid ester, methyl glucoside sesqui-stearate, polyoxyethylene dioleate, tetraethylene glycol monostearate, tetraethylene glycol monooleate, tetraethylene glycol monolaurate, polyoxypropylene stearate, polyoxyethylene lanolin ether, polyoxyethylene fatty acid, polyoxyethylene lauryl ether, hexaethylene glycol monostearate. Among them, the first surfactant particularly preferred for use in the present application is a sorbitan ester surfactant, in particular those named with Span or Span, including Span 20, Span 40, Span 60, Span 80, etc., and Span 20 (HLB = 8.6) is the first surfactant particularly preferred for use in the present application.

[0048] In step (a) of the preparation method of the present application, it can be that Span 20 and water are mixed and then combined with laurocapernazine to obtain the mother liquor, or that Span 20 is mixed with laurocapernazine and then dispersed in water to obtain the mother liquor, and the present application has no restriction on this, i.e. the order of addition of the raw materials in step (a) can be any order. To obtain better results, specifically, the mass ratio of laurocapernazine to water in step (a) is preferably 1:(1-5), more preferably 1:(2-3), and the amount of Span 20 added is preferably 1-5% relative to the mass of laurocapernazine, more preferably 1-3%, and further preferably 1-2%.

[0049] Generally speaking, in the nanosuspension, the aggregation between the small particles of the active pharmaceutical ingredient is a bad phenomenon, so the surfactant is usually used to make the dispersion more uniform. However, for the preparation method of the present application, through research, only dispersion is emphasized in the general process, and the best effect cannot be obtained. On the contrary, the active pharmaceutical ingredient is flocculated by using a specific substance first, and then heated to make it aggregate appropriately before being dispersed, and a more suitable and stable particle size distribution can be obtained unexpectedly. The research results show that when Span 20 and laurocapram are mixed, a suitable initial flocculation stage can be obtained. If Span 20 is replaced by Tween 20 at this stage, it is very unsatisfactory, which also confirms that the addition order of Tween 20 and Span 20 can change the aggregation state, and it is convenient for the subsequent process to achieve a suitable target particle size distribution.

[0050] After obtaining the initial flocculation stage, homogenization can make the flocculation stage more stable. Homogenization is a treatment process for making the dispersed particles in the suspension (or emulsion) system smaller, which plays a role in reducing the size of the dispersion. In the present application, the homogenization treatment can be high-pressure homogenization, high-speed homogenization, high-shear emulsification or micro-jet homogenization, etc. The present application does not have any limitation on this, as long as the intermediate suspension with D90 between 10-25 μm can be formed.

[0051] The size of the dispersion obtained after homogenization is often smaller than that before homogenization. In the research, through optimization, the mother liquor is homogenized in step (b) to form an intermediate suspension with D90 between 10-25 μm, at this time, Span 20 and laurocapram in the mother liquor exist in the system with a smaller particle size. Further, the mother liquor is homogenized in step (b) to form an intermediate suspension with D50 between 5-15 μm, D90 between 10-25 μm, further preferably D10 between 1-10 μm, D50 between 5-15 μm, D90 between 10-25 μm, Span≤2, a suitable particle size is helpful to obtain better dispersion effect when dispersed by the second surfactant, so as to obtain the same particle size distribution as the marketed drug Aristada, and achieve the same sustained release effect.

[0052] D10, D50, D90 all represent the particle size parameters; D10 refers to the particle size corresponding to the cumulative particle size distribution of 10% of a sample, and its physical meaning is that the particles with a particle size less than it account for 10%; D50 refers to the particle size corresponding to the cumulative particle size distribution percentage of 50% of a sample; its physical meaning is that the particles with a particle size greater than it account for 50%, and the particles with a particle size less than it also account for 50%, D50 is also called the median diameter or the median particle size, and is commonly used to represent the average particle size of a powder; D90 refers to the particle size corresponding to the cumulative particle size distribution of 90% of a sample, and its physical meaning is that the particles with a particle size less than it account for 90%.

[0053] Span is a measure of the width of the particle size distribution of a sample.

[0054] In the research, in order to obtain the above-mentioned suitable particle size distribution of the intermediate suspension, i.e., to obtain the intermediate suspension with D10 of 1-10 μm, D50 of 5-15 μm, and D90 of 10-25 μm, high-speed homogenization or high-pressure homogenization can be used, for example, when high-pressure homogenization is used, the operating parameters of the high-pressure homogenizer can be adjusted, and the preferred homogenization process is as follows: 60-120 s of circulation at 50-60 bar pressure in the high-pressure homogenizer (or 3-10 cycles at 50-60 bar pressure), 90-180 s of circulation at 70-100 bar pressure (or 4-12 cycles at 70-100 bar pressure); more preferably, 60 s of circulation at 50 bar pressure (or 3-5 cycles at 50 bar pressure), and 120 s of circulation at 100 bar pressure (or 6-8 cycles at 100 bar pressure). The temperature of homogenization is usually room temperature or below room temperature, and the preferred temperature of homogenization is 20°C or below 20°C. If the temperature is too high, the ability of Span 20 will decrease.

[0055] The particle size of the intermediate suspension obtained by homogenization is reduced, which can obtain a stronger flocculation force in the subsequent process, and further giving a certain amount of heat can make the flocculation effect more significant, thereby achieving appropriate aggregation. Here, in order to further improve the flocculation effect to make it produce appropriate aggregation, the method of giving heat can be any method that can increase the temperature inside the system, such as heating, light irradiation, etc., and the preferred method is heating.

[0056] The heating temperature can be appropriately lowered when the heating temperature is high, and the heating maintenance time can be appropriately prolonged when the heating temperature is relatively low. In consideration of the above, the heating temperature is preferably 40-80°C, for example, 40-70°C, more preferably 50-70°C, particularly preferably 55-65°C, for example, the heating temperature is 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, etc.; correspondingly, the heating maintenance time is preferably 10-60 min, more preferably 10-30 min, for example, the heating maintenance time is 15 min, 18 min, 20 min, 22 min, 25 min, 27 min, 30 min, 33 min, 35 min, 40 min, 45 min, 50 min, etc.; preferably, the heating temperature is 65-75°C, and the heating maintenance time is 10-30 min; most preferably, the heating temperature is 55-65°C, and the heating maintenance time is 10-60 min. Through the optimization of the heating process, the problem that the particle size is too small after high-pressure homogenization to reach the target particle size is solved.

[0057] The intermediate suspension solution is heated and then combined with the standby solution containing the second surfactant to obtain the laurocapernazine suspension. The intermediate suspension solution can be mixed with the standby solution after being placed at room temperature, or can be mixed with the standby solution immediately after heating is stopped, and is preferably combined with the standby solution after being placed at room temperature after heating. The amount of the standby solution is preferably 5-10% (w / w) of the total mass of the mother liquor, more preferably 6-9% (w / w).

[0058] The second surfactant is preferably a surfactant with HLB between 11 and 20, for example, including but not limited to polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene oxypropylene oleate, polyoxyethylene monooleate, polyoxyethylene monostearate, polyoxyethylene monopalmitate, alkyl aryl sulfonate, triethanolamine oleate, polyoxyethylene oleyl ether, polyoxyethylene monolaurate, polyoxyethylene alkyl phenol ether, polyoxyethylene lauryl ether, polyoxyethylene castor oil, polyoxyethylene cetyl alcohol, polyoxyethylene oxypropylene stearate. Among them, the second surfactant particularly preferred for the present application is polyoxyethylene sorbitan ester surfactant, especially those named products with Tween or Tween, including Tween 20, Tween 40, Tween 60, Tween 65, Tween 80, Tween 65, etc., among which more preferably Tween with HLB between 15 and 17, Tween 20 (HLB = 16.7) is an especially preferred second surfactant of the present application, preferably the amount of Tween 20 is 0.1-0.7 times, more preferably 0.2-0.5 times, the total mass of the first surfactant Span 20, at which time the dispersibility of the flocculated laurocapernazine technical material is better.

[0059] In the preparation method of the present application, the suitable stock solution comprises the second surfactant mentioned above, and further comprises inorganic salt and water, preferably the stock solution comprises Tween 20, inorganic salt and water. Preferably in the stock solution of the present application, the mass ratio of Tween 20, inorganic salt and water is 1:(4-6):(40-60), more preferably 1:(4-6):(45-50).

[0060] The inorganic salt includes but is not limited to potassium carbonate, sodium carbonate, potassium chloride, sodium chloride, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, magnesium phosphate, magnesium sulfate, ferrous sulfate, manganese sulfate, copper sulfate, calcium carbonate and the like. Preferably at least one of the inorganic salts listed above, more preferably the inorganic salt comprises sodium chloride and disodium hydrogen phosphate, further preferably comprises a mixture of sodium chloride, disodium hydrogen phosphate (anhydrous), disodium hydrogen phosphate (monohydrate), and the mass ratio of sodium chloride, disodium hydrogen phosphate (anhydrous), disodium hydrogen phosphate (monohydrate) is 1:(0.05-0.5):(0.01-0.1), preferably 1:(0.1-0.3):(0.01-0.05). Among them, disodium hydrogen phosphate (anhydrous) means anhydrous disodium hydrogen phosphate, and disodium hydrogen phosphate (monohydrate) means disodium hydrogen phosphate monohydrate. The addition of inorganic salt (especially sodium chloride, disodium hydrogen phosphate (anhydrous), disodium hydrogen phosphate (monohydrate)) can avoid the problem of increased drug solubility caused by possible degradation of Tween 20 during stirring.

[0061] In the aforementioned steps (a) to (d), preferably at least one step is carried out under stirring, more preferably each of steps (a) to (d) is carried out under stirring, the stirring rate is adjusted according to actual needs, and the stirring can be manual stirring, magnetic stirring or mechanical stirring, which is not limited by the present application.

[0062] During the preparation of the suspension, in order to obtain a specific target particle size of the suspension, the inventors have conducted a large number of studies, and found that the uneven particle size of the raw drug may affect the particle size of the suspension prepared in the subsequent process, and further affect the sustained-release effect of the suspension. Therefore, the inventors propose to first recrystallize the laurocapram aripiprazole raw drug to obtain a uniform and suitable particle size, and further study to determine that the most suitable particle size of the raw drug is D10 of 10-250 μm, D50 of 20-500 μm, and D90 of 40-1000 μm. Therefore, before the aforementioned step (a), the commercially available or obtained laurocapram aripiprazole can also be further purified by recrystallization method to obtain laurocapram aripiprazole with higher purity and suitable particle size, and the recrystallization step is optional. The D10 of the laurocapram aripiprazole obtained after recrystallization is between 10-250 μm, the D50 is between 20-500 μm, and the D90 is between 40-1000 μm.

[0063] "Optional" means that the subsequently described event or circumstance can or can not occur, and thus the description includes instances where the event or circumstance occurs and instances where it does not. For example, optional recrystallization of laurocapernazine means that recrystallization can be performed, or recrystallization can not be performed.

[0064] Preferably, the D10 of laurocapernazine in step (a) is between 10 and 250 μm, the D50 is between 20 and 500 μm, and the D90 is between 40 and 1000 μm; more preferably, the D10 of laurocapernazine in step (a) is between 10 and 200 μm, the D50 is between 20 and 400 μm, and the D90 is between 40 and 800 μm; still more preferably, the D10 of laurocapernazine in step (a) is between 10 and 150 μm, the D50 is between 20 and 300 μm, and the D90 is between 40 and 500 μm.

[0065] Namely, before step (a) described above, laurocapernazine is optionally recrystallized. Further, before step (a) described above, laurocapernazine is optionally recrystallized to obtain laurocapernazine D10 between 10 and 250 μm, D50 between 20 and 500 μm, and D90 between 40 and 1000 μm, preferably D10 between 10 and 200 μm, D50 between 20 and 400 μm, and D90 between 40 and 800 μm, more preferably D10 between 10 and 150 μm, D50 between 20 and 300 μm, and D90 between 40 and 500 μm, for example D10 between 10 and 25 μm, D50 between 35 and 50 μm, and D90 between 100 and 120 μm; or D10 between 20 and 25 μm, D50 between 40 and 50 μm, and D90 between 110 and 120 μm.

[0066] The recrystallization method described above can be any recrystallization method known in the art, and in addition, non-recrystallization methods such as physical grinding, etc. can be used, and the present application does not limit the recrystallization method in any way, as long as the laurocapernazine obtained in step (a) has D10 between 10 and 250 μm, D50 between 20 and 500 μm, and D90 between 40 and 1000 μm.

[0067] As the recrystallization method, for example, the following methods can be listed: solvent evaporation method (a method of evaporating a crystallization solvent from a crystallization system), gas phase diffusion method (a method of evaporating a crystallization solvent into a compound), cooling method (a method of cooling a crystallization system (or a solution of the compound)), solvent evaporation method (a method of evaporating a crystallization solvent from a crystallization system), poor solvent addition method (a method of adding a poor solvent of a compound to a crystallization system), seed addition method (a method of adding a seed containing a compound to a crystallization system), and the like. In order to further solve the problems of uneven particle size of the drug substance and the fragility of the drug substance, the inventors have further researched and determined a suitable recrystallization process, and therefore in some embodiments, the recrystallization step of the present application comprises: dissolving the laurocapernazine sample in a good solvent, then adding a poor solvent, and then cooling, separating and drying.

[0068] The good solvent includes but is not limited to ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, acetone, preferably at least one of the above-mentioned good solvents, more preferably the good solvent includes ethyl acetate or isopropyl acetate; and further comprising or not comprising Tween in the good solvent, the concentration of Tween in the good solvent is 0-10 mg / mL, preferably 0-3 mg / mL, more preferably 0-2 mg / mL.

[0069] The poor solvent includes but is not limited to pentane, cyclopentane, hexane, cyclohexane, methylcyclohexane, n-heptane, octane, nonane, decane, undecane, dodecane, ethanol, methanol, preferably at least one of the above-mentioned poor solvents, more preferably the poor solvent is n-heptane.

[0070] In some embodiments, the solid-liquid ratio of the laurocapernazine sample to the good solvent solution is 1:(1-5) g / mL, preferably 1:(1-2) g / mL, and further preferably 1:(1-1.5) g / mL.

[0071] In some embodiments, the volume ratio of the good solvent to the poor solvent is 1:(1-10), preferably 1:(1-3), and further preferably 1:2.

[0072] The cooling process can be constant low-temperature cooling or gradient low-temperature cooling. The mixed solution is moved into a 60°C biochemical incubator before cooling starts, and the cooling is performed by setting the program of the instrument, preferably gradient low-temperature cooling, for example, the gradient cooling program is as follows: cooling at a rate of 0.5-5°C / min to 20-50°C, maintaining for 0-5 h, then cooling to 5-20°C within 2-10 h, and maintaining at this temperature for 5-24 h.

[0073] Preferably, the laurocapernazine bulk drug D10 obtained by the above laurocapernazine recrystallization process has a D10 of 10-250 μm, a D50 of 20-500 μm, and a D90 of 40-1000 μm, preferably a D10 of 10-200 μm, a D50 of 20-400 μm, and a D90 of 40-800 μm, more preferably a D10 of 10-150 μm, a D50 of 20-300 μm, and a D90 of 40-500 μm, for example a D10 of 10-25 μm, a D50 of 35-50 μm, and a D90 of 100-120 μm; or a D10 of 20-25 μm, a D50 of 40-50 μm, and a D90 of 110-120 μm. It has been found that the particle size distribution is a key attribute affecting in vivo performance, and for the preparation process of the suspension of the present application as described above, it is important to control the final particle size distribution of the suspension by mixing laurocapernazine with a specific first surfactant and then homogenizing to form an intermediate suspension with a specific particle size distribution, which is a key step to obtain the initial flocculation stage, and further post-treatment as described above can further ensure that the particle size distribution of the final product is consistent with the marketed drug.

[0074] The laurocapernazine suspension obtained by the preparation process of the present application has a D10 of 2-10 μm, a D50 of 10-30 μm, and a D90 of less than 65 μm, preferably a D10 of 5-10 μm, a D50 of 10-25 μm, and a D90 of 25-35 μm, or preferably a D10 of 4-10 μm, a D50 of 10-20 μm, and a D90 of 15-35 μm, which has the same particle size range as the marketed drug Aristada, and can make the suspension achieve appropriate long-acting performance.

[0075] In another embodiment of the present application, there is provided:

[0076] A method for preparing a laurocapernazine suspension, characterized in that it comprises the following steps:

[0077] (a) obtaining a mother liquor by combining laurocapernazine, a first surfactant, and water;

[0078] (b) homogenizing the mother liquor to form an intermediate suspension with a D90 of 10-25 μm;

[0079] (c) heating the intermediate suspension;

[0080] (d) when the intermediate suspension obtained in step (c) is cooled to room temperature, combining it with a standby solution containing a second surfactant to obtain a laurocapernazine suspension.

[0081] The mother liquor is homogenized in step (b) to form an intermediate suspension with D50 between 5-15 μm and D90 between 10-25 μm.

[0082] The first surfactant is a non-ionic surfactant with HLB between 4-10, preferably HLB between 6-9.

[0083] The second surfactant is a non-ionic surfactant with HLB between 11-20, preferably HLB between 15-17.

[0084] The homogenization process in step (b) is performed in a high pressure homogenizer at 50-60 bar for 60-120 s and at 70-100 bar for 90-180 s.

[0085] The temperature of homogenization in step (b) is 20°C or lower.

[0086] The heating temperature in step (c) is 40-80°C and the heating time is 10-60 min.

[0087] The laurocapernazine in step (a) has D10 between 10-250 μm, D50 between 20-500 μm and D90 between 40-1000 μm.

[0088] Alternatively, the laurocapernazine in step (a) is recrystallized to have D10 between 10-250 μm, D50 between 20-500 μm and D90 between 40-1000 μm.

[0089] The standby solution further comprises an inorganic salt.

[0090] The obtained laurocapernazine suspension has D10 between 5-10 μm, D50 between 10-25 μm and D90 between 25-35 μm.

[0091] Beneficial effects: The preparation process of the present application mixes laurocapernazine with a specific first surfactant, then homogenizes and heats under certain conditions, and then post-treats, so that the obtained sample has the best particle size range, and therefore can be used for long-acting sustained-release preparations, and when used in patients, it can provide improved therapeutic amount of drug molecules for a longer period of time, and experiments show that the present application can achieve the same particle size distribution and sustained-release effect as the marketed drug Aristada, and can continuously release drugs stably for at least 1 month, and the process is simpler, more convenient, efficient, non-toxic, sterile, safe, and more economical. BRIEF DESCRIPTION OF DRAWINGS

[0092] Figure 1The in vivo average blood concentration-time curve of the laurocapernazine suspension prepared in Example 7, 8-2 of the present application is shown. DETAILED DESCRIPTION

[0093] The present application is described in detail below by way of examples, which can only be used to further illustrate the present application and cannot be understood as limiting the protection of the present application. Non-essential changes and adjustments made by the skilled in the art based on the content of the present application still fall within the protection scope of the present application. Unless otherwise specified, the reagents and equipment in the examples are as follows.

[0094] Reagents: laurocapernazine (Suzhou Chu Kai), Tween 20 (Tween 20, Croda Inc), sorbitan monolaurate (Span 20, Croda Inc), sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride;

[0095] Equipment: ATS high-pressure homogenizer (Antu Nano Technology Co., Ltd.), HORIBA LA-960V2 laser particle size analyzer (HORIBA Co.), cooling circulator (Changcheng Science and Trade Co., Ltd.).

[0096] Example 1

[0097] 1.1 Recrystallization method of laurocapernazine raw material drug:

[0098] Before preparing the laurocapernazine suspension, the laurocapernazine is first recrystallized, and the steps are as follows:

[0099] (1) The laurocapernazine sample is added to ethyl acetate containing Tween 20 for dissolution, the Tween content in ethyl acetate is 1.5 mg / mL, and the solid-liquid ratio of laurocapernazine to ethyl acetate is 1:2 (g / mL);

[0100] (2) The solution of step (1) is heated to 70°C, and the laurocapernazine is completely dissolved, then n-heptane is added, and the volume ratio of ethyl acetate to n-heptane is 1:2, and the mixture is stirred uniformly under this temperature condition;

[0101] (3) The uniformly mixed solution of step (2) is moved to a 60°C biochemical incubator, cooled to 40°C at a cooling rate of 0.5°C / min, then kept at 0.5h, and then cooled to 15°C within 6h, and kept at this temperature for 12h;

[0102] (4) After step (3) is completed, the precipitated solid is separated and dried;

[0103] (5) The obtained sample was re-dissolved in the separated solution (solution after solid separation) of step (4) at 70°C, and Tween 20 was added again, so that the content of Tween in the mixed solution was 0.7 mg / mL, and the mixed solution was stirred uniformly at this temperature condition;

[0104] (6) The uniformly mixed solution of step (5) was moved into a biochemical incubator at 60°C, and was cooled to 40°C at a cooling rate of 0.5°C / min, and then was kept at 40°C for 0.5 h, and then was cooled to 15°C in 6 h, and was kept at 15°C for 12 h;

[0105] (7) After the end of step (6), the precipitated solid was separated and dried to obtain recrystallized lauroyl aripiprazole as a raw material for preparing lauroyl aripiprazole in lauroyl aripiprazole suspension, and the particle size is as recorded in the F1 / F2 raw material column in Table 2.

[0106] 1.2 Preparation of lauroyl aripiprazole suspension

[0107] The prescription composition of lauroyl aripiprazole suspension is shown in Table 1.

[0108] Table 1

[0109] Material name Amount (g / 160 g) Lauroyl aripiprazole 44.1 Tween 20 0.24 Span 20 0.6087 Sodium chloride 0.976 Disodium hydrogen phosphate (anhydrous) 0.1371 Monosodium phosphate (monohydrate) 0.0333 Water 113.9056

[0110] The preparation method of the suspension is as follows:

[0111] (1) According to the amount of the substances in Table 1, lauroyl aripiprazole and Span 20 were added to nine-tenths of the prescription amount of water, and stirred to obtain a mother liquor; and Tween 20, sodium chloride, disodium hydrogen phosphate (anhydrous), and sodium dihydrogen phosphate (monohydrate) were added to one-tenth of the prescription amount of water, and were dissolved completely to obtain a standby solution;

[0112] (2) The mother liquor obtained in (1) was passed through a high-pressure homogenizer, and was circulated at 50 bar for 60 s (or 4 times) and at 100 bar for 120 s (or 8 times) in sequence, and the temperature of the material liquid was controlled within 20°C, to obtain an intermediate suspension;

[0113] (3) The suspension obtained in (2) was heated at 75°C for 1 h, and was naturally cooled to room temperature;

[0114] (4) The suspension obtained in step (3) was added to the standby solution in step (1), and was mixed to obtain a suspension;

[0115] (5) The final sample was detected for particle size by HORIBA LA-960V2, and the results are shown in Table 2.

[0116] Example 2

[0117] 2. Recrystallization method of lauropride raw material drug:

[0118] The raw material lauropride in lauropride suspension is the same batch A1 lauropride obtained after being treated according to the recrystallization method of Example 1. The particle size is as recorded in Table 2 in the column of F1 / F2 raw material drug.

[0119] 2. Preparation of lauropride suspension:

[0120] The prescription composition of lauropride suspension is the same as that of Example 1. The preparation method of lauropride suspension is as follows:

[0121] (1) According to the amount of the substances in Table 1, lauropride and Span 20 are added to nine-tenths of the prescription amount of water, stirred to obtain a mother liquor; another ten percent of the prescription amount of water is taken, and Tween 20, sodium chloride, disodium hydrogen phosphate (anhydrous), and sodium dihydrogen phosphate (monohydrate) are added to make them completely dissolved, as a standby solution;

[0122] (2) The mother liquor obtained in (1) is passed through a high-pressure homogenizer, and is circulated at 50 bar pressure for 60 s (or 4 times) and at 100 bar pressure for 120 s (or 8 times) in sequence, with the temperature of the material liquid controlled within 20°C, to obtain an intermediate suspension;

[0123] (3) The standby solution in step (1) is added to the suspension obtained in (2) and mixed;

[0124] (4) The suspension obtained in step (3) is heated at 75°C for 1 h with stirring, and is naturally cooled to room temperature;

[0125] (5) The final sample is detected for particle size using HORIBA LA-960V2, and the results are shown in Table 2.

[0126] Example 3

[0127] 3. Recrystallization method of lauropride raw material drug:

[0128] Before preparing lauropride suspension, lauropride is recrystallized, and the steps are as follows:

[0129] (1) The lauropride obtained after recrystallization in Example 1 is dissolved again in the separation liquid (the solution after solid separation) of step (7) of the recrystallization treatment in Example 1 at 70°C; the solid-liquid ratio is 1:4 (g / mL).

[0130] (2) The clear solution dissolved in (1) is naturally cooled at room temperature, and when a small amount of solid precipitates, it is homogenized using a homogenizer for 5 min to accelerate precipitation;

[0131] (3) After step (2) is completed, the precipitated solid is separated and dried to obtain recrystallized lauroyl aripiprazole as a raw material for preparing lauroyl aripiprazole in lauroyl aripiprazole suspension, and the particle size is as recorded in Table 2 in the F3 / F4 raw material column.

[0132] 3.2 Preparation of lauroyl aripiprazole suspension:

[0133] The prescription composition of lauroyl aripiprazole suspension is the same as in Example 1. The preparation method of the suspension is as follows:

[0134] (1) According to the amount of the substances in Table 1, lauroyl aripiprazole and Span 20 are added to nine-tenths of the prescription amount of water, stirred to obtain a mother liquor; and Tween 20, sodium chloride, disodium hydrogen phosphate (anhydrous), and sodium dihydrogen phosphate (monohydrate) are added to one-tenth of the prescription amount of water to make a complete solution as a standby solution;

[0135] (2) The mother liquor obtained in (1) is passed through a high-pressure homogenizer, and is sequentially circulated at 50 bar for 60 s (or 4 times) and at 100 bar for 120 s (or 8 times), with the temperature of the material liquid controlled within 20°C, to obtain an intermediate suspension;

[0136] (3) The suspension obtained in (2) is heated at 70°C for 1 h and naturally cooled to room temperature;

[0137] (4) The suspension obtained in step (3) is added to the standby solution in step (1) and mixed to obtain a suspension;

[0138] (5) The final sample is detected for particle size using HORIBA LA-960V2, and the results are shown in Table 2.

[0139] Example 4

[0140] 4.1 Recrystallization method of lauroyl aripiprazole raw material:

[0141] The raw material lauroyl aripiprazole in lauroyl aripiprazole suspension is the same batch B1 batch of lauroyl aripiprazole obtained after being treated according to the recrystallization method of Example 3, and the particle size is as recorded in Table 2 in the F3 / F4 raw material column.

[0142] 4.2 Preparation of lauroyl aripiprazole suspension:

[0143] The prescription composition of lauroyl aripiprazole suspension is the same as in Example 1. The preparation method of the suspension is as follows:

[0144] (1) According to the amount of the substances in Table 1, laurocapernazine and Span 20 were added to nine-tenths of the amount of water, stirred to obtain a mother liquor; another ten-tenths of the amount of water was added to Tween 20, sodium chloride, disodium hydrogen phosphate (anhydrous), and sodium dihydrogen phosphate (monohydrate) to make the solution completely dissolved, as a standby solution;

[0145] (2) The mother liquor obtained in (1) was passed through a high-pressure homogenizer, and was circulated at 50 bar for 60 s (or 4 times) and at 100 bar for 120 s (or 8 times) in sequence, with the temperature of the material liquid controlled within 20℃, to obtain an intermediate suspension;

[0146] (3) The suspension obtained in (2) was heated at 70℃ for 0.5 h, and was naturally cooled to room temperature;

[0147] (4) The suspension obtained in step (3) was added to the standby solution in step (1) and mixed to obtain a suspension;

[0148] (5) The final sample was detected for particle size by HORIBA LA-960V2, and the results are shown in Table 2.

[0149] Example 5

[0150] 5.1 Recrystallization method of laurocapernazine bulk drug:

[0151] Before preparing the laurocapernazine suspension, the laurocapernazine was first recrystallized, and the steps were as follows:

[0152] (1) The laurocapernazine sample was added to the ethyl acetate solution containing Tween 20, the Tween content in the ethyl acetate was 1.5 mg / mL, and the solid-liquid ratio of laurocapernazine to ethyl acetate was 1:1.5 (g / mL).

[0153] (2) The solution of step (1) was heated to 70℃, and after the laurocapernazine was completely dissolved, n-heptane was added, and the volume ratio of ethyl acetate to n-heptane was 1:2, and the mixture was stirred uniformly under this temperature condition.

[0154] (3) The clear solution dissolved in (2) was naturally cooled at room temperature, and when a small amount of solid precipitated, a homogenizer was used to homogenize for 5 min to accelerate precipitation.

[0155] (4) After step (3) was completed, the precipitated solid was separated and dried to obtain the recrystallized laurocapernazine as a standby raw material for preparing laurocapernazine suspension, and the particle size is recorded in Table 2 as F5 / F6 bulk drug.

[0156] 5.2 Preparation of laurocapernazine suspension:

[0157] The prescription composition of laurocapernazine suspension is the same as that of Example 1. The preparation method of the suspension is as follows:

[0158] (1) According to the amount of the substances in Table 1, laurocapernazine and Span 20 were added to nine-tenths of the prescription amount of water, stirred to obtain a mother liquor; and Tween 20, sodium chloride, disodium hydrogen phosphate (anhydrous), and sodium dihydrogen phosphate (monohydrate) were added to one-tenth of the prescription amount of water to completely dissolve, as a standby solution;

[0159] (2) The mother liquor obtained in (1) was passed through a high-pressure homogenizer, and was circulated at 50 bar for 60 s (or 4 times) and at 100 bar for 120 s (or 8 times) in sequence, with the temperature of the material liquid controlled within 20°C, to obtain an intermediate suspension;

[0160] (3) The suspension obtained in (2) was heated at 50°C for 10 min and naturally cooled to room temperature;

[0161] (4) The suspension obtained in step (3) was added to the standby solution in step (1) and mixed to obtain a suspension;

[0162] (5) The suspension obtained in (4) was heated at 70°C for 30 min to obtain a final sample;

[0163] (6) The particle size of the final sample was detected by HORIBA LA-960V2, and the results are shown in Table 2.

[0164] Example 6

[0165] 6.1 Recrystallization method of laurocapernazine bulk drug:

[0166] The laurocapernazine in the laurocapernazine suspension is the same batch C1 laurocapernazine obtained after being treated according to the recrystallization method of Example 5, and the particle size is as recorded in Table 2 in the F5 / F6 bulk drug column.

[0167] 6.2 Preparation of laurocapernazine suspension:

[0168] The prescription composition of laurocapernazine suspension is the same as that of Example 1. The preparation method of the laurocapernazine suspension is as follows:

[0169] (1) According to the amount of the substances in Table 1, laurocapernazine and Span 20 were added to nine-tenths of the prescription amount of water, stirred to obtain a mother liquor; and Tween 20, sodium chloride, disodium hydrogen phosphate (anhydrous), and sodium dihydrogen phosphate (monohydrate) were added to one-tenth of the prescription amount of water to completely dissolve, as a standby solution;

[0170] (2) The mother liquor obtained in (1) was passed through a high-pressure homogenizer, and was circulated at 50 bar for 60 s (or 4 times) and at 100 bar for 120 s (or 8 times) in sequence, with the temperature of the material liquid being controlled within 20°C to obtain an intermediate suspension;

[0171] (3) The suspension obtained in (2) was heated at 50°C for 30 min, and was naturally cooled to room temperature;

[0172] (4) The suspension obtained in (3) was added to the standby solution in (1) and was mixed to obtain a suspension;

[0173] (5) The suspension obtained in (4) was heated at 75°C for 10 min to obtain a final sample;

[0174] (6) The particle size of the final sample was detected by HORIBA LA-960V2, and the results are shown in Table 2.

[0175] Example 7

[0176] 7. Recrystallization method of laurocapernazine raw material drug:

[0177] Before preparing laurocapernazine suspension, laurocapernazine was subjected to recrystallization treatment, and the steps were as follows:

[0178] (1) Laurocapernazine sample was added to ethyl acetate solution containing Tween 20, the Tween content in ethyl acetate was 1.5 mg / mL, and the solid-liquid ratio of laurocapernazine to ethyl acetate was 1:1.5 (g / mL).

[0179] (2) The solution of step (1) was heated to 70°C, and laurocapernazine was completely dissolved, then n-heptane was added, and the volume ratio of ethyl acetate to n-heptane was 1:2, and the mixture was stirred uniformly under this temperature condition.

[0180] (3) The uniformly mixed solution of step (2) was moved to a 60°C biochemical incubator, and was cooled to 40°C at a cooling rate of 0.5°C / min, then was kept at 40°C for 0.5 h, and then was cooled to 15°C within 6 h, and was kept at this temperature for 12 h.

[0181] (4) After the end of step (3), the precipitated solid was separated and dried to obtain recrystallized laurocapernazine as raw material for preparing laurocapernazine suspension, and the particle size is recorded in Table 2 as F7 raw material drug.

[0182] 7. Preparation of laurocapernazine suspension:

[0183] The prescription composition of laurocapernazine suspension was the same as that in Example 1. The preparation method of the suspension was as follows:

[0184] (1) According to the amount of the substances in Table 1, laurocapernazine and Span 20 were added to nine-tenths of the amount of water, stirred to obtain a mother liquor; another ten-tenths of the amount of water was added to Tween 20, sodium chloride, disodium hydrogen phosphate (anhydrous), and sodium dihydrogen phosphate (monohydrate) to completely dissolve, as a standby solution;

[0185] (2) The mother liquor obtained in (1) was passed through a high-pressure homogenizer, and was circulated at 50 bar for 60 s (or 4 times) and at 100 bar for 120 s (or 8 times) in sequence, with the temperature of the material liquid controlled within 20°C, to obtain an intermediate suspension;

[0186] (3) The suspension obtained in (2) was heated at 70°C for 18 min, and was naturally cooled to room temperature;

[0187] (4) The suspension obtained in step (3) was added to the standby solution in step (1) and mixed to obtain a suspension;

[0188] (5) The final sample was detected for particle size using HORIBA LA-960V2, and the results are shown in Table 2.

[0189] Example 8-1

[0190] 8-1.1 Recrystallization method of laurocapernazine raw material:

[0191] Before preparing the laurocapernazine suspension, the laurocapernazine was first recrystallized, and the steps were as follows:

[0192] (1) The laurocapernazine sample was added to an isopropyl acetate solution, and the solid-liquid ratio of laurocapernazine to isopropyl acetate was 1:1.4 (g / mL).

[0193] (2) The solution of step (1) was heated to 65°C until the laurocapernazine was completely dissolved, and then n-heptane was added, and the ratio of isopropyl acetate to n-heptane was 1:2. The mixture was stirred uniformly at this temperature.

[0194] (3) The temperature was lowered to 35°C at a rate of 0.5°C / min, and the solution was removed and intermittently homogenized using a homogenizer for 5 min to accelerate precipitation;

[0195] (4) After step (3) was completed, the precipitated solid was separated and dried to obtain recrystallized laurocapernazine as a raw material for preparing laurocapernazine suspension, and the particle size is as recorded in Table 2 in the F8-1 / 2 / 3 raw material column.

[0196] 8-1.2 Preparation of laurocapernazine suspension:

[0197] The prescription composition of laurocapernazine suspension is the same as that of Example 1. The preparation method of the suspension is as follows:

[0198] (1) According to the amount of the substances in Table 1, laurocapernazine and Span 20 were added to nine-tenths of the prescription amount of water, stirred to obtain a mother liquor; and Tween 20, sodium chloride, disodium hydrogen phosphate (anhydrous), and sodium dihydrogen phosphate (monohydrate) were added to one-tenth of the prescription amount of water to completely dissolve, as a standby solution;

[0199] (2) The mother liquor obtained in (1) was passed through a high-pressure homogenizer, and was sequentially circulated at 50 bar for 60 s (or 4 times) and at 100 bar for 120 s (or 8 times), with the temperature of the material liquid controlled within 20℃, to obtain an intermediate suspension;

[0200] (3) The suspension obtained in (2) was heated at 40℃ for 16 min and naturally cooled to room temperature;

[0201] (4) The suspension obtained in step (3) was added to the standby solution in step (1) and mixed to obtain a suspension;

[0202] (5) The final sample was detected for particle size using HORIBA LA-960V2, and the results are shown in Table 2.

[0203] Example 8-2

[0204] 8-2.1 Recrystallization method of laurocapernazine bulk drug:

[0205] The laurocapernazine in the laurocapernazine suspension is the same batch D1 laurocapernazine obtained after being treated according to the recrystallization method of Example 8-1, and the particle size is as recorded in Table 2 in the column of F8-1 / 2 / 3 bulk drug.

[0206] 8-2.2 Preparation of laurocapernazine suspension:

[0207] The prescription composition of laurocapernazine suspension is the same as that of Example 1. The preparation method of the suspension is as follows:

[0208] (1) According to the amount of the substances in Table 1, laurocapernazine and Span 20 were added to nine-tenths of the prescription amount of water, stirred to obtain a mother liquor; and Tween 20, sodium chloride, disodium hydrogen phosphate (anhydrous), and sodium dihydrogen phosphate (monohydrate) were added to one-tenth of the prescription amount of water to completely dissolve, as a standby solution;

[0209] (2) The mother liquor obtained in (1) was passed through a high-pressure homogenizer, and was sequentially circulated at 50 bar for 60 s (or 4 times) and at 100 bar for 120 s (or 8 times), with the temperature of the material liquid controlled within 20℃, to obtain an intermediate suspension;

[0210] (3) The suspension obtained in (2) was heated at 50 °C for 24 min and naturally cooled to room temperature;

[0211] (4) The suspension obtained in (3) was added to the standby solution in (1) and mixed to obtain a suspension;

[0212] (5) The final sample was detected for particle size using HORIBA LA-960V2, and the results are shown in Table 2.

[0213] Example 8-3

[0214] 8-3.1 Recrystallization method of lauropride raw material drug:

[0215] The lauropride raw material drug in the lauropride suspension of Example 8-1 was the same batch D1 lauropride obtained after being treated according to the recrystallization method of Example 8-1, and the particle size is recorded in Table 2 as F8-1 / 2 / 3 raw material drug.

[0216] 8-3.2 Preparation of lauropride suspension:

[0217] The prescription composition of the lauropride suspension was the same as that of Example 1. The preparation method of the suspension is as follows:

[0218] (1) According to the amount of the substances in Table 1, lauropride and Span 20 were added to nine-tenths of the prescription amount of water, and stirred to obtain a mother liquor; another one-tenth of the prescription amount of water was taken, and Tween 20, sodium chloride, disodium hydrogen phosphate (anhydrous), and sodium dihydrogen phosphate (monohydrate) were added and dissolved completely as a standby solution;

[0219] (2) The mother liquor obtained in (1) was passed through a high-pressure homogenizer, and was circulated at 50 bar pressure for 60 s (or 4 times) and at 100 bar pressure for 120 s (or 8 times) in sequence, and the temperature of the material liquid was controlled within 20 °C to obtain an intermediate suspension;

[0220] (3) The suspension obtained in (2) was heated at 60 °C for 18 min and naturally cooled to room temperature;

[0221] (4) The suspension obtained in (3) was added to the standby solution in (1) and mixed to obtain a suspension;

[0222] (5) The final sample was detected for particle size using HORIBA LA-960V2, and the results are shown in Table 2.

[0223] Example 9

[0224] 9.1 Recrystallization method of lauropride raw material drug:

[0225] The raw material aripiprazole lauroxil in aripiprazole lauroxil suspension is the same as in Example 8-1, and is the D2 batch of aripiprazole lauroxil obtained after treatment according to the recrystallization method of Example 8-1. The particle size is as recorded in Table 2 in the F9 raw material column.

[0226] 9.2 Preparation of aripiprazole lauroxil suspension:

[0227] The prescription composition of aripiprazole lauroxil suspension is the same as in Example 1. The preparation method of the suspension is as follows:

[0228] (1) According to the amount of the substances in Table 1, aripiprazole lauroxil and Span 20 were added to nine-tenths of the prescription amount of water, stirred to obtain a mother liquor; and Tween 20, sodium chloride, disodium hydrogen phosphate (anhydrous), and sodium dihydrogen phosphate (monohydrate) were added to one-tenth of the prescription amount of water, and dissolved completely to obtain a standby solution;

[0229] (2) The mother liquor obtained in (1) was stirred uniformly to obtain an intermediate suspension;

[0230] (3) The suspension obtained in (2) was heated at 70°C for 1 h, and naturally cooled to room temperature;

[0231] (4) The suspension obtained in step (3) was added to the standby solution in step (1), mixed to obtain a suspension;

[0232] (5) The final sample was detected for particle size using HORIBA LA-960V2, and the results are shown in Table 2.

[0233] Example 10

[0234] 10.1 Recrystallization method of aripiprazole lauroxil raw material:

[0235] The raw material aripiprazole lauroxil in aripiprazole lauroxil suspension is the same as in Example 8-1, and is the D2 batch of aripiprazole lauroxil obtained after treatment according to the recrystallization method of Example 8-1. The particle size is as recorded in Table 2 in the F10 raw material column.

[0236] 10.2 Preparation of aripiprazole lauroxil suspension:

[0237] The prescription composition of aripiprazole lauroxil suspension is the same as in Example 1. The preparation method of the suspension is as follows:

[0238] (1) According to the amount of substances in Table 1, laurocapernazine and Span 20 and ninety-ninths of the amount of Tween 20 in the prescription are added to ninety-ninths of the amount of water in the prescription, stirred to obtain a mother liquor; another tenth of the amount of Tween 20, sodium chloride, disodium hydrogen phosphate (anhydrous), sodium dihydrogen phosphate (monohydrate) in the prescription is added to one-tenth of the amount of water to completely dissolve as a standby solution;

[0239] (2) The mother liquor obtained in (1) is passed through a high-pressure homogenizer, and is sequentially circulated at 50 bar for 60 s (or 4 times) and at 100 bar for 120 s (or 8 times), with the temperature of the material liquid controlled within 20°C, to obtain an intermediate suspension;

[0240] (3) The suspension obtained in (2) is heated at 70°C for 1 h and naturally cooled to room temperature;

[0241] (4) The suspension obtained in step (3) is added to the standby solution in step (1) and mixed to obtain a suspension;

[0242] (5) The final sample is detected for particle size by HORIBA LA-960V2, and the results are shown in Table 2.

[0243] Example 11

[0244] 11.1 Recrystallization method of laurocapernazine raw material drug:

[0245] The composition of the laurocapernazine suspension is the same as in Example 1.

[0246] The raw material laurocapernazine in the laurocapernazine suspension is the D2 batch of laurocapernazine obtained after being treated according to the recrystallization method of Example 8-1, and the particle size is as recorded in Table 2 in the F11 raw material drug column.

[0247] 11.2 Preparation of laurocapernazine suspension:

[0248] The prescription composition of the laurocapernazine suspension is the same as in Example 1. The preparation method of the suspension is as follows:

[0249] (1) According to the amount of substances in Table 1, laurocapernazine and Tween 20 are added to ninety-ninths of the amount of water in the prescription, stirred to obtain a mother liquor; Span 20, sodium chloride, disodium hydrogen phosphate (anhydrous), sodium dihydrogen phosphate (monohydrate) are added to one-tenth of the amount of water to completely dissolve as a standby solution;

[0250] (2) The mother liquor obtained in (1) is passed through a high-pressure homogenizer, and is sequentially circulated at 50 bar for 60 s (or 4 times) and at 100 bar for 120 s (or 8 times), with the temperature of the material liquid controlled within 20°C, to obtain an intermediate suspension;

[0251] (3) The suspension obtained in (2) was heated at 70 °C for 1 h, and then naturally cooled to room temperature;

[0252] (4) The suspension obtained in (3) was added to the prepared solution in (1), mixed, and a suspension was obtained;

[0253] (5) The final sample was detected for particle size using a HORIBA LA-960V2, and the results are shown in Table 2.

[0254] Table 2: Particle size distribution test results

[0255]

[0256]

[0257] In Table 2 above, F1 / F2 raw materials represent the raw materials of laurocapram aripiprazole after recrystallization treatment in Example 1 or Example 2, respectively; F1 / F2 intermediates represent the intermediate suspensions of Example 1 or Example 2, respectively; F1 represents the laurocapram aripiprazole suspension finally obtained in Example 1; F2 represents the laurocapram aripiprazole suspension finally obtained in Example 2; and the remaining symbols listed in the table are as follows.

[0258] The above examples studied the effects of heating temperature, heating time, surfactant type, and addition order on the particle size of the suspension. The experimental results showed that when the heating temperature is too high, for example, more than 70 °C (such as 75 °C) or too low (such as less than 40 °C), the effect on the particle size of the suspension is relatively large; when the heating maintenance time is increased, for example, the intermediate suspension is heated before and after mixing with the prepared solution, even if the heating maintenance time is shortened, it will also cause the particle size to increase to varying degrees; the addition order and type of the first surfactant and the second surfactant have a large effect on the particle size of the suspension. When the heating temperature is 40-70 °C, the heating maintenance time is 10-60 min, especially when the heating temperature is 50-70 °C, such as 55-65 °C, the heating maintenance time is 10-60 min, and the first surfactant is Span 20 and the second surfactant is Tween 20, and the mother liquor is first passed through high-pressure homogenization and then mixed with the prepared solution to prepare the suspension, the suspension has the best particle size range.

[0259] Test Example 1: Dissolution test

[0260] Using the suspension prepared in Examples 8-3 as the sample (F8-3) and aripiprazole lauroyl injection as the reference formulation (trade name: Aristada; Alkermes, Inc.) as the control, the dissolution rate was tested using the paddle method at 50 rpm. The dissolution medium was 0.2% SDS pH 7.4 phosphate buffer, with a medium volume of 900 mL and a medium temperature of 37 °C. Samples were taken and tested at 0 min, 5 min, 10 min, 120 min, 30 min, 60 min, 120 min, 180 min, 360 min, 480 min, 600 min, and 1440 min. The test results are shown in Table 1.1 below.

[0261] Table 1.1 Dissolution test results

[0262] Sampling time (min) 2052T - Reference formulation F8-3 0 0 0 5 4.13 2.88 10 5.89 4.69 20 10.39 10.26 30 14.94 17.77 60 26.91 28.92 120 43.69 45.32 180 54.50 57.93 360 67.69 69.23 480 71.74 73.01 600 74.26 75.54 1440 79.21 80.58

[0263] Test Example 2: Pharmacokinetic Study

[0264] Eight male rats were divided into two groups and injected with formulations F7 and F8-2 from Examples 7 and 8-2, respectively, at a dose of 103 mg / kg via intramuscular injection in the calf. To evaluate the release characteristics of the formulations in vivo, blood samples were collected at 0, 3, 6, 9, 14, 17, 21, 24, and 28 days before administration, and the plasma concentration of aripiprazole was measured at each time point.

[0265] Table 2.1 Pharmacokinetic Test Results

[0266]

[0267] From the drug-time curve ( Figure 1 As shown in Table 2.1, formulations F7 and F8-2 can be continuously released for at least 28 days. max All are 9 days, with F7's C max The C should be lower than F8-2. max The F7, on the other hand, shows a trend toward longer release cycles.

[0268] The above experimental results show that the preparation method of lauroyl aripiprazole protected by this invention can achieve the same particle size distribution as the marketed drug Aristada. Therefore, this method can achieve the same sustained-release effect as the marketed drug Aristada, and can continuously and stably release the drug for at least one month. The process is simpler, more convenient, more efficient, non-toxic, sterile, and has a high safety factor, and is also more economical.

Claims

1. A process for the preparation of a suspension of aripiprazole laurate characterized in that, The method comprises the following steps: (a) mixing laurocapernazine, a first surfactant and water to obtain a mother liquor; (b) homogenizing the mother liquor to form an intermediate suspension with D10 of 1-10 μm, D50 of 5-15 μm and D90 of 10-25 μm; (c) heating the intermediate suspension; (d) cooling the intermediate suspension obtained in step (c) to room temperature and mixing with a standby solution containing a second surfactant to obtain a laurocapernazine suspension; The first surfactant is Span 20; The second surfactant is Tween 20; The weight of the second surfactant is 0.1-0.7 times the weight of the first surfactant; The heating temperature in step (c) is 40-70°C, and the heating time is 18-24 min; The particle size distribution of laurocapernazine in the laurocapernazine suspension obtained in step (d) is: D10 of 4-10 μm, D50 of 10-20 μm and D90 of 15-35 μm.

2. The production method according to claim 1, wherein The homogenization process in step (b) is: 3-10 cycles at 50-60 bar and 4-12 cycles at 70-100 bar in a high-pressure homogenizer.

3. The production method according to claim 1, wherein The homogenization process in step (b) is: 3-5 cycles at 50 bar and 6-8 cycles at 100 bar in a high-pressure homogenizer.

4. The production method according to claim 1, wherein The homogenization process in step (b) is: 4 cycles at 50 bar and 8 cycles at 100 bar in a high-pressure homogenizer.

5. The production method according to claim 1, wherein The homogenization temperature in step (b) is 20°C or lower.

6. The production method according to claim 1, wherein The homogenization process in step (b) is: 3-10 cycles at 50-60 bar and 4-12 cycles at 70-100 bar in a high-pressure homogenizer.

7. The production method according to claim 1, wherein The heating temperature in step (c) is 50-70°C.

8. The production method according to claim 1, wherein The heating temperature in step (c) is 50-60°C, and the heating time is 18-24 min.

9. The production method according to claim 1, wherein The D10 of laurocapernazine in step (a) is 10-150 μm, the D50 is 20-300 μm and the D90 is 40-500 μm.

10. The production method according to any one of claims 1 to 9, wherein The D10 of laurocapernazine in step (a) is 10-150 μm, the D50 is 20-300 μm and the D90 is 40-500 μm. The recrystallization comprises the following steps: dissolving laurocapernazine in a good solvent, then adding a poor solvent, and then cooling, separating and drying. The good solvent comprises at least one of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate and acetone. The poor solvent is selected from at least one of pentane, cyclopentane, hexane, cyclohexane, methylcyclohexane, n-heptane, octane, nonane, decane, undecane, dodecane, ethanol and methanol. The solid-liquid ratio of laurocapernazine to the good solvent is 1:(1-5) g / mL. The volume ratio of the good solvent to the poor solvent is 1:(1-10).

11. The production method according to claim 10, wherein The recrystallization step described above is repeated one or more times, and / or the solution is homogenized using a homogenizer after cooling to accelerate the precipitation of solids.

12. The production method according to claim 10, wherein The good solvent includes ethyl acetate or isopropyl acetate; the poor solvent is n-heptane.

13. The production method according to claim 12, characterized by, The good solvent further comprises Tween, wherein the concentration of Tween in the good solvent is 0-10 mg / mL.

14. The production method according to any one of claims 1 to 9, wherein The mass ratio of aripiprazole lauroxil to water in step (a) is 1:(1-5); the amount of the first surfactant is 1-5% (w / w) of the mass of aripiprazole lauroxil.

15. The production method according to any one of claims 1 to 9, wherein The mass ratio of aripiprazole lauroxil to water in step (a) is 1:(2-3).

16. The production method according to any one of claims 1 to 9, wherein The amount of the first surfactant in step (a) is 1-3% (w / w) of the mass of aripiprazole lauroxil.

17. The production method according to any one of claims 1 to 9, wherein The weight of the second surfactant is 0.2-0.5 times the weight of the first surfactant.

18. The production method according to any one of claims 1 to 9, wherein The standby solution further comprises an inorganic salt, and the inorganic salt is selected from one or more of potassium carbonate, sodium carbonate, potassium chloride, sodium chloride, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate.

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