CN115554253B - Aripiprazole freeze-dried preparation for injection capable of stably releasing medicine and preparation method thereof - Google Patents
Aripiprazole freeze-dried preparation for injection capable of stably releasing medicine and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of pharmacy, and discloses an aripiprazole lyophilized preparation for injection capable of releasing drugs smoothly and a preparation method thereof. The freeze-dried preparation comprises more than or equal to 60% of aripiprazole, 2-10% of sodium carboxymethylcellulose, 14-20% of mannitol and buffer salt. The particle size distribution of the aripiprazole lyophilized preparation after being re-dissolved and suspended is d90=9-26 μm, d50=3-12 μm, d10=0.9-2.5 μm, and the particle size distribution span d90-d10=7.8-25 μm. The invention limits the particle size distribution and the span of the aripiprazole lyophilized preparation in a specific interval, and can reach the steady blood concentration within 24 hours after injection, and the long-acting stable release can be realized without additional oral auxiliary treatment. The preparation method can accurately control the particle size distribution and the wide particle size distribution span of the freeze-dried preparation, and the freeze-dried preparation has high particle size stability after reconstitution and reconstruction.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to an aripiprazole freeze-dried preparation for injection with stable drug release and a preparation method thereof.
Background
Aripiprazole is an anti-schizophrenia drug, and the anhydrous substance of aripiprazole has good solubility, and the dissolution rate of aripiprazole can reach more than 80% in gastric juice environment, usually in several hours, so that the aripiprazole is an oral tablet (trade name) Has high bioavailability. In general, patients with schizophrenia need long-term maintenance treatment, the drug release period is prolonged, the drug administration frequency can be reduced, and the long-acting sustained-release injection of aripiprazole which is marketed is provided with a large scale of ABILIFY->And ARISTADA from ALKEMES.
ABILIFY for administration of the tsukamurella once a monthAfter the anhydrous aripiprazole is converted into the crystalline form of aripiprazole monohydrate, the solubility is reduced and the drug release period is 1 to 8 weeks. Although->Long-acting release of 1 administration per month can be satisfied, but also due to low solubility of aripiprazole particles, absorption of aripiprazole in the systemic circulation after intramuscular injection is slow and prolonged, and it is necessary that the plasma concentration of aripiprazole gradually increases to the maximum plasma concentration after multiple intramuscular administrations. Median Tmax for gluteus muscles is 5-7 days, median Tmax for deltoid muscles is 4 days.
At the first injection of ABILIFYAfter that, an oral adjuvant therapy of 14 days is required to achieve an effective blood concentration at the time of initial treatment. For omission of the next injection beyond the fifth or sixth week, oral aripiprazole is still required for 14 days at the restart of the next injection, which presents a great inconvenience to the mental patient and his caretaker, adding to the complexity of the treatment.
Patent CN1870980B discloses a ball milling process to reduce the average particle size of the active ingredient aripiprazole monohydrate to 1-10 μm, preferably 2.5 μm. The aripiprazole monohydrate is prepared by adopting a jet crystallization technology, and the API and the preparation have narrower particle size distribution. However, it is disclosed in this invention that when the average particle size is about 1 μm, aripiprazole will be released during a period of less than about 3 weeks, preferably about 2 weeks.
The patent CN101801342B adopts a high-pressure homogenization method to obtain a preparation having an average particle diameter of about 1 to 10 μm, preferably 2.5 μm, and a narrow particle diameter distribution, and does not solve the problems of slow release and short release period at the initial administration stage of aripiprazole particles.
Patent CN106389357a discloses a freeze-dried preparation of aripiprazole having an average particle size of about 1 to 10 μm, preferably 2.5 μm. The invention suggests that smaller particle size particles with a higher ratio may result in poor water dispersibility, and spray freeze-dried particles with exceptionally small particle sizes tend to have poor water dispersibility, preferably removing the smaller particle size particles.
Alternes developed Aristata, a long-acting injectable suspension of aripiprazole for month Gui Xiana administered once for 2 months, and month Gui Xiana aripiprazole had lower solubility than aripiprazole, and a long-acting sustained release preparation with a specific release period was obtained by using nanocystal technology. Early administration of aristar a requires 21 days of oral adjunctive therapy, or higher doses and 1 day of oral adjunctive therapy.
The prior market varieties are narrow particle size distribution preparations of aripiprazole, keep uniform and stable particles, improve the re-solubility while avoiding poor water dispersibility caused by small particle size particles with higher proportion, and provide longer period release so as to meet the actual needs, but also bring the defect of slow release in the initial stage of drug administration. The dissolution rate of large particles is slower than that of small particles, and the small particle size active ingredient with a lower ratio brings about the problem of slower release at the initial stage of administration, and the blood concentration is usually required to be quickly increased to be within the therapeutic window depending on oral administration or high dosage, while the large particle size active ingredient with a lower ratio brings about a shorter drug release period.
In addition, the prior art also solves the defect of slow drug release by adding a mixed solvent, for example, in patent CN105078898B, besides adding a high molecular polymer to prepare microspheres, the drug release characteristic is regulated by introducing a mixed solvent of benzyl alcohol and dimethyl sulfoxide, but the introduction of the solvent increases the risk of solvent toxicity and the complexity and safety risk of the preparation process.
Disclosure of Invention
In order to solve the technical problems, firstly, the invention provides the aripiprazole freeze-dried preparation for injection for stable drug release, the particle size distribution of the aripiprazole freeze-dried preparation and the span (D90-D10) are limited in a specific interval, the stable blood concentration can be achieved within 24 hours after injection, the long-acting stable release (up to 12 weeks) can be achieved without additional oral auxiliary treatment, and the medication compliance of patients can be greatly improved. Secondly, the invention provides a preparation method of the aripiprazole freeze-dried preparation for injection, which can accurately control the particle size distribution and the wide particle size distribution span, and the preparation method has strong controllability, and the prepared freeze-dried preparation has high particle size stability after reconstitution and reconstruction, and is suitable for industrial production.
The specific technical scheme of the invention is as follows:
in a first aspect, the invention provides a freeze-dried aripiprazole preparation for injection with stable drug release, which comprises the following components in percentage by mass: aripiprazole is more than or equal to 60%; 2-10% of sodium carboxymethylcellulose; 14-20% of mannitol; buffer salts for adjusting the pH of the suspension to 6.5-7.5 prior to lyophilization.
Wherein, the particle size distribution of the aripiprazole lyophilized preparation after being re-dissolved and suspended is as follows: d90 =9-26 μm, d50=3-12 μm, d10=0.9-2.5 μm, and the particle size distribution span d90-d10=7.8-25 μm (note: the invention designates D90-D10 as the particle size distribution span for evaluating the width of the particle size distribution).
As described in the background section, the injectable aripiprazole formulation of the prior art has the disadvantages of short release period and need of oral adjuvant therapy in the initial stage. Although there are reports of solving the above technical problems by adding a mixed solvent, the introduction of the solvent increases the risk of toxicity of the solvent and also increases the complexity and safety risk of the preparation process. Therefore, the invention discovers that under the particle size distribution (d90=9-26 μm, d50=3-12 μm, d10=0.9-2.5 μm) and the particle size distribution span (d90-d10=7.8-25 μm) within the specific range, the steady-state blood concentration can be achieved within 24 hours after injection, the steady release can be achieved for 12 weeks without additional oral auxiliary treatment, and the medication compliance of patients can be greatly improved.
In conclusion, the solution of the invention can solve various defects of the original marketed products without introducing new solvents or substances under the original conditions of the marketed products, has controllable cost, remarkably improved and simultaneously controlled clinical risks, and has obvious clinical advantages. Oral administration by mental patients can significantly increase the caretaker's burden of monitoring the administration conditions, reducing medication compliance. According to the invention, rapid release is realized at the initial stage of administration, long-time oral administration is not needed, the blood concentration is more stable, adverse reaction is reduced, the release period is longer, the administration frequency of a patient is reduced, the medication compliance of the patient is improved in multiple directions, and the burden of a caretaker can be greatly reduced.
Preferably, the aripiprazole lyophilized preparation for injection for smooth drug release comprises the following components in percentage by mass: aripiprazole is more than or equal to 70%; 2-6% of sodium carboxymethylcellulose; 14-20% of mannitol; buffer salts for adjusting the pH of the suspension to 6.5-7.5 prior to lyophilization.
Wherein, the particle size distribution of the aripiprazole lyophilized preparation after being re-dissolved and suspended is as follows: d90 D50=3-12 μm, d10=0.9-2.5 μm, and the particle size distribution span d90-d10=10-25 μm.
Further, the aripiprazole lyophilized preparation for injection for smooth drug release comprises the following components in percentage by mass: 74-81% of aripiprazole; 2-6% of sodium carboxymethylcellulose; 16-20% of mannitol; buffer salts for adjusting the pH of the suspension to 6.5-7.5 prior to lyophilization.
Wherein, the particle size distribution of the aripiprazole lyophilized preparation after being re-dissolved and suspended is as follows: d90 D50=3-12 μm, d10=0.9-2.5 μm, and the particle size distribution span d90-d10=13-25 μm.
Preferably, the aripiprazole is one or more of aripiprazole anhydride and aripiprazole solvate.
Preferably, the buffer salt is one or more of sodium dihydrogen phosphate, sodium hydroxide, sodium phosphate, disodium hydrogen phosphate, sodium acetate and phosphoric acid.
Preferably, the solvate of aripiprazole is aripiprazole monohydrate.
In a second aspect, the invention provides a method for preparing an aripiprazole lyophilized formulation for injection, comprising the steps of:
(1) Preparation of sterile aripiprazole suspension:
(1.1) A sterile powder of aripiprazole is dispersed in a pretreatment solution containing sodium carboxymethylcellulose, mannitol and buffer salts to form a pre-mixed suspension having a pH of 6.5-7.5.
(1.2) circularly grinding the premixed suspension, and taking out grinding fluid in at least 2 batches; wherein the first batch is taken out after grinding until the D90 is not more than 35 mu m; the last batch was ground to a D50 of no more than 3 μm and removed.
(1.3) mixing and dispersing the grinding liquid taken out from the different batches in the step (1.2) to obtain sterile aripiprazole suspension;
the particle size distribution of the sterile aripiprazole suspension is: d90 D50=3-12 μm, d10=0.9-2.5 μm, and the particle size distribution span d90-d10=7.8-25 μm.
The specific cyclic grinding process can ideally control the particle size and the particle size distribution span to form stable suspension, and the process is simple and easy to operate; meanwhile, the mixed dispersion mode of stirring, shearing or ultrasonic is combined, and the ground suspension is further dispersed, so that the problem of reduced water dispersibility caused by the aggregation tendency of the aripiprazole with small particle size can be solved.
(2) And (3) freeze drying:
(2.1) transferring the sterile aripiprazole suspension into an open container, cooling to-45 to-35 ℃ at a cooling rate of 0.5-1.0 ℃/min, pre-freezing, and maintaining for 1-4 hours.
(2.2) drying for the first time, heating to-10 ℃ to 5 ℃ at a heating rate of 0.2-0.3 ℃/min, and maintaining the vacuum pressure at 0.1-0.2mbar for 30-48h.
(2.3) drying for the second time, heating to 5-25 ℃ at a heating rate of 0.5-1 ℃/min, charging nitrogen to 300-760mT, and sealing the container.
The ratio of the transformation of the aripiprazole monohydrate into the aripiprazole anhydride in the obtained aripiprazole lyophilized preparation is not higher than 20%.
The freeze-drying process of the invention has the following advantages:
(a) The freeze-drying process with the specific process parameters can endow the particle size of the freeze-dried preparation with good re-dissolution stability (the freeze-dried preparation needs to be re-dissolved and re-formed before injection, and the particle size of the freeze-dried preparation needs to be maintained as consistent as possible with the suspension before freeze-drying). If the process parameters are not within the above-mentioned ranges, the particle size reconstitution stability may be significantly reduced.
(b) We have found during the course of the study that the ratio of aripiprazole anhydride to aripiprazole monohydrate in the lyophilized formulation can greatly affect the release profile of the lyophilized formulation. Through further research, we found that the ratio of aripiprazole anhydride to the total amount of aripiprazole is optimal within 20%. However, during the suspension of step (1), the sterile powder of aripiprazole will be completely converted to aripiprazole monohydrate upon exposure to water. Therefore, the invention can partially (less than or equal to 20 percent) convert the aripiprazole monohydrate into the aripiprazole anhydride in the freeze-drying process on the basis of meeting the particle size re-dissolution stability of the freeze-dried preparation by optimizing the freeze-drying process, thereby improving the drug release performance of the freeze-dried preparation. If the process is not properly controlled, it is liable to cause excessive conversion of aripiprazole monohydrate.
Preferably, in the step (1.2), 3 or more batches of the mixture are ground and taken out; the first batch is taken in an amount of not less than 1/5 of the total weight of the premixed suspension.
Preferably, in the step (1.3), the mixing and dispersing are stirring treatment, shearing treatment or ultrasonic treatment.
The grinding medium acts on the aripiprazole particles of the active ingredient under the drive of a stirring shaft running at a high speed, so that the particles are broken, a large amount of smaller particles are instantaneously generated, the small particles have higher surface energy, particle aggregates tend to be formed before the small particles are fully contacted with pretreatment liquid containing sodium carboxymethyl cellulose, and the aggregates existing in the grinding liquid or the active ingredient which is not fully ground can cause local irritation after administration. After grinding, the suspension is subjected to deagglomeration means such as stirring, shearing or ultrasound, and the active ingredients are further wetted and dispersed in the auxiliary material solution.
Preferably, the sodium carboxymethyl cellulose is added in step (1.1) in whole or in two batches; wherein the first batch is added in step (1.1) at a ratio of not less than 17wt%; the remainder was the second batch, and sterile aripiprazole suspension was added prior to lyophilization. Preferably, the concentration of sodium carboxymethyl cellulose in the sterile aripiprazole suspension prior to lyophilization is from 0.2 to 2.2 weight percent.
In the research process, the invention discovers that if the suspension is directly freeze-dried after being prepared, the freeze-dried preparation is easy to be bonded with the bottom of a container after freeze-drying. Therefore, the sodium carboxymethyl cellulose can be preferably added in two batches, and the sodium carboxymethyl cellulose is added before freeze drying in the second batch, so that the phenomenon of sticking to the bottom of the freeze-dried preparation can be effectively avoided, the uniformity of the freeze-dried preparation can be improved, and ideal redissolution can be brought. Furthermore, after all sodium carboxymethylcellulose has been added, it is necessary to ensure that the concentration of sodium carboxymethylcellulose in the suspension is maintained between 0.2 and 2.2% by weight.
Preferably, the concentration of sodium carboxymethyl cellulose in the sterile aripiprazole suspension prior to lyophilization is from 0.5 to 1.3 weight percent.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention provides an aripiprazole freeze-dried preparation for injection capable of stably releasing medicine, the particle size distribution and the span (D90-D10) of the aripiprazole freeze-dried preparation are limited in a specific interval, the stable blood concentration can be achieved within 24 hours after injection, long-acting stable release (up to 12 weeks) can be achieved without additional long-time oral auxiliary treatment, and the medication compliance of patients can be greatly improved.
(2) The invention provides a cyclic grinding process capable of accurately controlling particle size distribution and wide particle size distribution span, the grinding process is high in controllability, and the freeze-dried preparation with the target particle size distribution and span can be obtained according to the process.
(3) The invention provides a freeze-drying process capable of improving the particle size reconstitution stability and drug release performance of a freeze-dried preparation, and the prepared freeze-dried preparation has high particle size stability after reconstitution and is suitable for industrial production. Meanwhile, the process can effectively control the ratio of the aripiprazole monohydrate to the aripiprazole anhydride within a target range, thereby further improving drug release.
(4) The invention can supplement proper amount of sodium carboxymethyl cellulose into the suspension before freeze drying, can obviously improve the phenomenon of sticking the bottom of the freeze-dried product, improves the uniformity of the freeze-dried preparation and brings ideal redissolution.
(5) According to the technical scheme, under the original condition of the products on the market, the defects of the original products on the market can be overcome without introducing new solvents or substances, the cost is controllable, the clinical risk is controlled while the obvious improvement is achieved, and the clinical advantage is obvious. Oral administration by mental patients can significantly increase the caretaker's burden of monitoring the administration conditions, reducing medication compliance. According to the technical scheme, quick release is realized at the initial period of administration, long-time oral administration is not needed, the blood concentration is more stable, adverse reaction is reduced, the release period is longer, the administration frequency of a patient is reduced, the medication compliance of the patient is improved in multiple directions, and the burden of a caretaker is greatly reduced.
(6) The freeze-dried preparation of the invention keeps long-acting release, and the peak blood concentration Cmax is obviously lower than that of the products on the market, thereby being beneficial to reducing the occurrence of adverse reactions.
Drawings
FIG. 1 is a graph of in vivo drug administration in rats;
fig. 2 is a graph of the time profile of the drug in dogs.
Detailed Description
The invention is further described below with reference to examples.
General examples
The aripiprazole freeze-dried preparation for injection capable of stably releasing medicine comprises the following components in percentage by mass: aripiprazole is more than or equal to 60%; 2-10% of sodium carboxymethylcellulose; 14-20% of mannitol; buffer salts for adjusting the pH of the suspension to 6.5-7.5 prior to lyophilization. Wherein, the particle size distribution of the aripiprazole lyophilized preparation after being re-dissolved and suspended is as follows: d90 D50=3-12 μm, d10=0.9-2.5 μm, and the particle size distribution span d90-d10=7.8-25 μm.
Preferably, the aripiprazole lyophilized preparation for injection for smooth drug release comprises the following components in percentage by mass: aripiprazole is more than or equal to 70%; 2-6% of sodium carboxymethylcellulose; 14-20% of mannitol; buffer salts for adjusting the pH of the suspension to 6.5-7.5 prior to lyophilization. Wherein, the particle size distribution of the aripiprazole lyophilized preparation after being re-dissolved and suspended is as follows: d90 D50=3-12 μm, d10=0.9-2.5 μm, and the particle size distribution span d90-d10=10-25 μm.
Further, the aripiprazole lyophilized preparation for injection for smooth drug release comprises the following components in percentage by mass: 74-81% of aripiprazole; 2-6% of sodium carboxymethylcellulose; 14-20% of mannitol; buffer salts for adjusting the pH of the suspension to 6.5-7.5 prior to lyophilization. Wherein, the particle size distribution of the aripiprazole lyophilized preparation after being re-dissolved and suspended is as follows: d90 D50=3-12 μm, d10=0.9-2.5 μm, and the particle size distribution span d90-d10=13-25 μm.
Preferably, the aripiprazole is one or more of aripiprazole anhydride and aripiprazole solvate. The aripiprazole solvate is aripiprazole monohydrate. The buffer salt is one or more of sodium dihydrogen phosphate, sodium hydroxide, sodium phosphate, disodium hydrogen phosphate, sodium acetate and phosphoric acid.
A method for preparing a freeze-dried aripiprazole preparation for injection, comprising the following steps:
(1) Preparation of sterile aripiprazole suspension:
(1.1) A sterile powder of aripiprazole is dispersed in a pretreatment solution containing sodium carboxymethylcellulose, mannitol and buffer salts to form a pre-mixed suspension having a pH of 6.5-7.5.
(1.2) circularly grinding the premixed suspension, and taking out grinding fluid in at least 2 batches; wherein the first batch is taken out after grinding until the D90 is not more than 35 mu m; the last batch was ground to a D50 of no more than 3 μm and removed.
Preferably, in the step (1.2), 3 or more batches of the mixture are ground and taken out; the first batch is taken in an amount of not less than 1/5 of the total weight of the premixed suspension.
(1.3) mixing and dispersing (stirring, shearing or ultrasonic treatment) the grinding fluid taken out from the different batches in the step (1.2) to obtain sterile aripiprazole suspension; the particle size distribution of the sterile aripiprazole suspension is: d90 D50=3-12 μm, d10=0.9-2.5 μm, and the particle size distribution span d90-d10=7.8-25 μm.
(2) And (3) freeze drying:
(2.1) transferring the sterile aripiprazole suspension into an open container, cooling to-45 to-35 ℃ at a cooling rate of 0.5-1.0 ℃/min, pre-freezing, and maintaining for 1-4 hours.
(2.2) drying for the first time, heating to-10 ℃ to 5 ℃ at a heating rate of 0.2-0.3 ℃/min, and maintaining the vacuum pressure at 0.1-0.2mbar for 30-48h.
(2.3) drying for the second time, heating to 5-25 ℃ at a heating rate of 0.5-1 ℃/min, charging nitrogen to 300-760mT, and sealing the container. The ratio of the transformation of the aripiprazole monohydrate into the aripiprazole anhydride in the obtained aripiprazole lyophilized preparation is not higher than 20%.
Preferably, the sodium carboxymethyl cellulose is added in step (1.1) in whole or in two batches; wherein the first batch is added in step (1.1) in a ratio of at least 17wt%; the remainder was the second batch, and sterile aripiprazole suspension was added prior to lyophilization. The concentration of sodium carboxymethylcellulose in the sterile aripiprazole suspension prior to lyophilization is 0.2-2.2wt% (more preferably 0.5-1.3 wt%).
Example 1
1) 40g of sodium carboxymethylcellulose, 200g of mannitol and 3.8g of sodium dihydrogen phosphate were dissolved in 3916g of water for injection. The pH of the solution was adjusted to 7.0 with 1mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter. Dispersing 1040g of aripiprazole monohydrate in the filtered solution to form an aripiprazole pre-mixed suspension;
2) Grinding the premixed suspension by a Dyno-mill ball mill at 2000rpm, taking out grinding fluid in four batches, wherein the first three batches are respectively ground to D90 of 20 mu m, 12 mu m and 8 mu m, then taking out, taking out the grinding fluid, the taking amount of each batch is 1000g, continuously grinding the rest premixed suspension until D50 is 2 mu m (a Markov MS3000 laser particle size analyzer), transferring all the feed fluid to a collecting tank, and stirring, mixing and dispersing; diluting with water for injection to 8kg; filtering with 70 μm filter to obtain a canned food;
3) Adding the suspension into a penicillin bottle, transferring to a freeze dryer partition board for freeze drying, wherein the freeze drying process is as follows: the temperature of the partition plate is reduced to-40 ℃ at a cooling rate of 0.5 ℃/min, and the partition plate is kept pre-frozen for 1 hour; raising the temperature of the partition plate to-10 ℃ at a heating rate of 0.3 ℃/min, and performing primary drying under vacuum pressure of 0.2mbar for 48 hours; and (3) raising the temperature of the partition plate to 15 ℃ at a heating rate of 1 ℃/min for secondary drying, filling nitrogen to 400mT, adding plugs, taking out the sample from the box, and detecting that the anhydrous aripiprazole in the sample accounts for less than 10%.
Example 2
1) 5g of sodium carboxymethylcellulose, 18g of mannitol and 0.5g of sodium dihydrogen phosphate were dissolved in 566g of purified water. The pH of the solution was adjusted to 7.0 with 1mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter. Dispersing 104g of aripiprazole monohydrate in the filtered solution to form an aripiprazole pre-mixed suspension;
2) Grinding the premixed suspension by a MiniCer ball mill at 2500rpm, taking out grinding fluid in three batches, wherein the first two batches are respectively ground to have D90 of 35 mu m and 15 mu m and then taken out, the two batches are respectively taken out to have the output of 140g and 200g, the rest premixed suspension is continuously ground to have D50 of 3 mu m (a Markov MS3000 laser particle size analyzer), and all the feed fluid is stirred, mixed and dispersed after being transferred to a collecting tank; diluting with water for injection to 0.8kg;
3) Adding the suspension into a penicillin bottle, transferring to a freeze dryer partition board for freeze drying, wherein the freeze drying process is as follows: the temperature of the partition plate is reduced to-40 ℃ at a cooling rate of 0.7 ℃/min, and the partition plate is kept pre-frozen for 2 hours; raising the temperature of the partition plate to 0 ℃ at a heating rate of 0.2 ℃/min, and performing primary drying under vacuum pressure of 0.1mbar, and keeping for 30 hours to a freeze-drying end point; and (3) raising the temperature of the baffle plate to 25 ℃ at a heating rate of 1 ℃/min for secondary drying, filling nitrogen to 500mT, adding plugs, taking out the sample from the box, and detecting that the anhydrous aripiprazole accounts for 10-20% of the sample.
Example 3
1) 5g of sodium carboxymethylcellulose, 22g of mannitol and 0.26g of sodium dihydrogen phosphate were dissolved in 562g of purified water. The pH of the solution was adjusted to 7.0 with 1mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter. Dispersing 104g of aripiprazole monohydrate in the filtered solution to form an aripiprazole pre-mixed suspension;
2) Grinding the premixed suspension by a NetzschDV15-300 ball mill at a rotating speed of 1500rpm, taking out grinding fluid in three batches, wherein the first two batches are respectively ground to a D90 value of 30 mu m and a 15 mu m, the two batches are respectively taken out to a quantity of 140g, the rest premixed suspension is continuously ground to a D50 value of 1 mu m (a Markov MS3000 laser particle size analyzer), transferring all the feed liquid to a collecting tank, stirring and mixing, and stirring for 10min by a shearing head; diluting with water for injection to 0.8kg;
3) Adding the suspension into a penicillin bottle, transferring to a freeze dryer partition board for freeze drying, wherein the freeze drying process is as follows: the temperature of the partition plate is reduced to-40 ℃ at a cooling rate of 1 ℃/min, and the partition plate is kept pre-frozen for 4 hours; raising the temperature of the partition plate to-5 ℃ at a heating rate of 0.2 ℃/min, and performing primary drying under vacuum pressure of 0.1mbar for 40 hours; and (3) raising the temperature of the partition plate to 20 ℃ at a heating rate of 1 ℃/min for secondary drying, filling nitrogen to 600mT, adding plugs, taking out the sample from the box, and detecting that the anhydrous aripiprazole accounts for 10-20% of the sample.
Example 4
1) 36g of sodium carboxymethylcellulose, 260g of mannitol and 3.8g of sodium dihydrogen phosphate were dissolved in 3860g of purified water. The pH of the solution was adjusted to 7.0 with 1mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter. Dispersing 1040g of aripiprazole monohydrate in the filtered solution to form an aripiprazole pre-mixed suspension;
2) Grinding the premixed suspension by a NetzschDV600 ball mill at 1000rpm, taking out grinding fluid in three batches, wherein the first two batches are respectively ground to D90 of 20 mu m and 10 mu m, the two batches are respectively taken out, the rotation speed is adjusted to 2000rpm, the rest premixed suspension is continuously ground to D50 of 1 mu m (a Markov MS3000 laser particle size analyzer), and stirring and mixing the whole material fluid after the material fluid is transferred to a collecting tank, and performing ultrasonic dispersion for 10min; diluting with water for injection to 9kg; filtering with 50 μm filter to obtain a canned food;
3) Adding the suspension into a penicillin bottle, transferring to a freeze dryer partition board for freeze drying, wherein the freeze drying process is as follows: the temperature of the partition plate is reduced to-40 ℃ at a cooling rate of 0.7 ℃/min, and the partition plate is kept pre-frozen for 3 hours; raising the temperature of the partition plate to-5 ℃ at a heating rate of 0.3 ℃/min, and performing primary drying under vacuum pressure of 0.1mbar for 40 hours; and (3) raising the temperature of the partition plate to 20 ℃ for secondary drying, adding a plug after nitrogen is filled to 760mT, taking out the sample from the box, and detecting that the anhydrous aripiprazole in the sample accounts for less than 10%.
Example 5
1) 24g of sodium carboxymethylcellulose, 220g of mannitol and 3.6g of sodium dihydrogen phosphate were dissolved in 3912g of purified water. The pH of the solution was adjusted to 7.0 with 1mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter. Dispersing 1040g of aripiprazole monohydrate in the filtered solution to form an aripiprazole pre-mixed suspension;
2) Grinding the premixed suspension by a NetzschDV600 ball mill at a rotating speed of 1500rpm, taking out grinding liquid in three batches, wherein the first two batches are respectively ground to a D90 value of 30 mu m and a D90 value of 20 mu m, the two batches are respectively taken out, the rotating speed is regulated to 2500rpm, the rest premixed suspension is continuously ground to a D50 value of 3 mu m (a Markov MS3000 laser particle size analyzer), and stirring and mixing the whole liquid after the liquid is transferred to a collecting tank, and performing ultrasonic dispersion for 5min; 2kg of 1% sodium carboxymethylcellulose solution was added to 4.2kg of the suspension, diluted to 7kg with water for injection; filtering with 70 μm filter to obtain a canned food;
3) Adding the diluted suspension into a penicillin bottle, transferring to a freeze dryer partition plate for freeze drying, wherein the freeze drying process is as follows: the temperature of the partition plate is reduced to-40 ℃ at a cooling rate of 0.7 ℃/min, and the partition plate is kept pre-frozen for 3 hours; raising the temperature of the partition plate to-5 ℃ at a heating rate of 0.3 ℃/min, and performing primary drying under vacuum pressure of 0.1mbar for 40 hours; and (3) raising the temperature of the partition plate to 15 ℃ at a heating rate of 0.8 ℃/min for secondary drying, adding nitrogen to 500mT, adding a plug, taking out the sample from the box, and detecting that the anhydrous aripiprazole in the sample accounts for less than 10%.
Example 6
0.5kg of the milled suspension of example 5 was diluted to 1kg with water for injection to prepare the following formulation,
prescription 1: taking 100g of the diluted suspension in the example 5;
prescription 2: taking 100g of the diluted suspension in the example 5, and adding 0.3g of sodium carboxymethylcellulose;
prescription 3: taking 100g of the diluted suspension in the example 5, and adding 0.5g of sodium carboxymethylcellulose;
prescription 4: taking 100g of the diluted suspension in the example 5, and adding 1.03g of sodium carboxymethylcellulose;
prescription 5: 100g of the diluted suspension in example 5 was taken and 2.15g of sodium carboxymethylcellulose was added.
Adding the suspension in the prescription 1-5 into a penicillin bottle, transferring to a freeze dryer partition board for freeze drying, wherein the freeze drying process is as follows: the temperature of the partition plate is reduced to-40 ℃ at a cooling rate of 0.7 ℃/min, and the partition plate is kept pre-frozen for 3 hours; raising the temperature of the partition plate to-5 ℃ at a heating rate of 0.3 ℃/min, and performing primary drying under vacuum pressure of 0.1mbar for 40 hours; and (3) raising the temperature of the partition plate to 15 ℃ for secondary drying, adding a plug after nitrogen is filled to 600mT, taking out the sample from the box, and detecting that the anhydrous aripiprazole in the sample accounts for less than 10%.
As a result, it was found that the white adhesive sheet was present at the bottom of the bottle in the partially lyophilized products (prescriptions 1 and 2) and separated from the lyophilized cake. Whereas the lyophilized products of formulas 3-5 did not show bottom sticking. This phenomenon may be mainly attributed to the action of sodium carboxymethyl cellulose. The test proves that a certain amount of sodium carboxymethyl cellulose is supplemented into the prescription of the suspension before freeze-drying, so that the phenomenon of sticking the bottom of the freeze-dried product can be prevented, the freeze-dried product with uniform texture can be obtained, and the water dispersibility of the freeze-dried product can be improved.
Example 7
1) 5g of sodium carboxymethylcellulose, 18g of mannitol and 0.5g of sodium dihydrogen phosphate were dissolved in 566g of purified water. The pH of the solution was adjusted to 7.0 with 1mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter. Dispersing 104g of aripiprazole monohydrate in the filtered solution to form an aripiprazole pre-mixed suspension;
2) Grinding the premixed suspension by a MiniCer ball mill at 2500rpm, taking out grinding fluid in two batches, grinding the first batch until the D90 is 15 mu m, taking out 300g, continuously grinding the rest premixed suspension until the D50 is 1 mu m (a Markov MS3000 laser particle size analyzer), transferring all the feed liquid to a collecting tank, stirring and mixing, and stirring and dispersing for 10min; diluting with water for injection to 1kg;
3) Adding the suspension into a penicillin bottle, transferring to a freeze dryer partition board for freeze drying, wherein the freeze drying process is as follows: the temperature of the partition plate is reduced to-40 ℃ at a cooling rate of 0.7 ℃/min, and the partition plate is kept pre-frozen for 1 hour; raising the temperature of the partition plate to-5 ℃ at a heating rate of 0.3 ℃/min, and performing primary drying under vacuum pressure of 0.1mbar for 40 hours; and (3) raising the temperature of the partition plate to 5 ℃ at a heating rate of 0.5 ℃/min for secondary drying, maintaining for 5 hours, filling nitrogen to 600mT, adding plugs, taking out the sample, and detecting that the anhydrous matter of aripiprazole in the sample accounts for less than 10%.
Example 8
1) 5g of sodium carboxymethylcellulose, 18g of mannitol and 0.5g of sodium dihydrogen phosphate were dissolved in 566g of purified water. The pH of the solution was adjusted to 7.0 with 1mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter. Dispersing 104g of aripiprazole monohydrate in the filtered solution to form an aripiprazole pre-mixed suspension;
2) Grinding the premixed suspension by a MiniCer ball mill at 2000rpm, taking out grinding fluid in three batches, wherein the first two batches are respectively ground to D9015 and 12 mu m, the taking amount of the two batches is 200g, the rest premixed suspension is continuously ground to D50 of 1 mu m (a Markov MS3000 laser particle size analyzer), and all the feed fluid is stirred and mixed after being transferred to a collecting tank, sheared and dispersed for 30min; diluting with water for injection to 1kg;
3) Adding the suspension into a penicillin bottle, transferring to a freeze dryer partition board for freeze drying, wherein the freeze drying process is as follows: the temperature of the partition plate is reduced to-40 ℃ at a cooling rate of 0.7 ℃/min, and the partition plate is kept pre-frozen for 3 hours; raising the temperature of the partition plate to 5 ℃ at a heating rate of 0.3 ℃/min, and performing primary drying under vacuum pressure of 0.3mbar for 30 hours; and (3) raising the temperature of the partition plate to 20 ℃ at a heating rate of 1 ℃/min for secondary drying, filling nitrogen to 600mT, adding plugs, taking out the sample from the box, and detecting that the anhydrous aripiprazole in the sample accounts for less than 10%.
Example 9
1) 5g of sodium carboxymethylcellulose, 18g of mannitol and 0.5g of sodium dihydrogen phosphate were dissolved in 566g of purified water. The pH of the solution was adjusted to 7.5 with 1mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter. Dispersing 104g of aripiprazole monohydrate in the filtered solution to form an aripiprazole pre-mixed suspension;
2) Grinding the premixed suspension by a MiniCer ball mill at 2500rpm, taking out grinding fluid in two batches, grinding the first batch until the D90 μm is reached, taking out 400g, continuously grinding the rest premixed suspension until the D50 is 2 μm (a Markov MS3000 laser particle size analyzer), transferring all the feed liquid to a collecting tank, stirring and mixing, and shearing and dispersing for 30min; diluting with water for injection to 1kg;
3) Adding the suspension into a penicillin bottle, transferring to a freeze dryer partition board for freeze drying, wherein the freeze drying process is as follows: the temperature of the partition plate is reduced to-40 ℃ at a cooling rate of 0.7 ℃/min, and the partition plate is kept pre-frozen for 2 hours; raising the temperature of the partition plate to 0 ℃ at a heating rate of 0.3 ℃/min, and performing primary drying under vacuum pressure of 0.2mbar for 35 hours; and (3) raising the temperature of the partition plate to 15 ℃ at a heating rate of 1 ℃/min for secondary drying, filling nitrogen to 600mT, adding plugs, taking out the sample from the box, and detecting that the anhydrous aripiprazole in the sample accounts for less than 10%.
Example 10
1) 5g of sodium carboxymethylcellulose, 18g of mannitol and 0.5g of sodium dihydrogen phosphate were dissolved in 566g of purified water. The pH of the solution was adjusted to 6.5 with 1mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter. Dispersing 104g of aripiprazole monohydrate in the filtered solution to form an aripiprazole pre-mixed suspension;
2) Grinding the premixed suspension by a MiniCer ball mill at 2500rpm, taking out grinding fluid in three batches, wherein the first two batches are respectively ground to D90 of 25 and 15 mu m, the two batches are respectively taken out to 140g and 200g, the rest premixed suspension is continuously ground to D50 of 3 mu m (a Markov MS3000 laser particle size analyzer), and stirring and mixing the whole feed liquid after transferring to a collecting tank, and performing ultrasonic dispersion for 5min; diluting with water for injection to 1kg;
3) Adding the suspension into a penicillin bottle, transferring to a freeze dryer partition board for freeze drying, wherein the freeze drying process is as follows: the temperature of the partition plate is reduced to-40 ℃ at a cooling rate of 0.7 ℃/min, and the partition plate is kept pre-frozen for 3 hours; raising the temperature of the partition plate to 5 ℃ at a heating rate of 0.3 ℃/min, and performing primary drying under vacuum pressure of 0.2mbar for 30 hours; and (3) raising the temperature of the partition plate to 15 ℃ for secondary drying, adding a plug after nitrogen is filled to 300mT, taking out the sample from the box, and detecting that the anhydrous aripiprazole in the sample accounts for 10-20%.
Example 11
1) 5g of sodium carboxymethylcellulose, 18g of mannitol and 0.5g of sodium dihydrogen phosphate were dissolved in 566g of purified water. The pH of the solution was adjusted to 7.5 with 1mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter. Dispersing 104g of aripiprazole monohydrate in the filtered solution to form an aripiprazole pre-mixed suspension;
2) Grinding the premixed suspension by a MiniCer ball mill at 2500rpm, taking out grinding fluid in two batches, grinding the first batch until the D90 is 15 mu m, taking out 500g, continuously grinding the rest premixed suspension until the D50 is 1 mu m (a Markov MS3000 laser particle size analyzer), transferring all the feed liquid to a collecting tank, stirring and mixing, and shearing and dispersing for 30min; adding water for injection to dilute to 1kg; filtering with 40 μm filter;
3) Adding the suspension into a penicillin bottle, transferring to a freeze dryer partition board for freeze drying, wherein the freeze drying process is as follows: the temperature of the partition plate is reduced to-40 ℃ at a cooling rate of 0.7 ℃/min, and the partition plate is kept pre-frozen for 3 hours; raising the temperature of the partition plate to 0 ℃ at a heating rate of 0.3 ℃/min, and performing primary drying under vacuum pressure of 0.2mbar for 35 hours; and (3) raising the temperature of the partition plate to 15 ℃ at a heating rate of 1 ℃/min for secondary drying, filling nitrogen to 400mT, adding plugs, taking out the sample from the box, and detecting that the anhydrous aripiprazole in the sample accounts for less than 10%.
Example 12
1) 5.5g of sodium carboxymethylcellulose, 18g of mannitol and 0.5g of sodium dihydrogen phosphate were dissolved in 566g of purified water. The pH of the solution was adjusted to 7.5 with 1mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter.
Dispersing 104g of aripiprazole monohydrate in the filtered solution to form an aripiprazole pre-mixed suspension;
2) Grinding the premixed suspension by a MiniCer ball mill at 2500rpm, taking out grinding fluid in three batches, wherein the first two batches are respectively ground to D90 of 30 and 20 mu m, the two batches are respectively taken out to have the quantity of 200g, the rest premixed suspension is continuously ground to D50 of 3 mu m (a Markov MS3000 laser particle size analyzer), and the whole material fluid is stirred and mixed after being transferred to a collecting tank for 10min; adding water for injection to dilute to 1kg; filtering with 70 μm filter;
3) Adding the suspension into a penicillin bottle, transferring to a freeze dryer partition board for freeze drying, wherein the freeze drying process is as follows: the temperature of the partition plate is reduced to-40 ℃ at a cooling rate of 0.7 ℃/min, and the partition plate is kept pre-frozen for 3 hours; raising the temperature of the partition plate to 5 ℃ at a heating rate of 0.3 ℃/min, and performing primary drying under vacuum pressure of 0.2mbar for 30 hours; and (3) raising the temperature of the partition plate to 20 ℃ at a heating rate of 1 ℃/min for secondary drying, adding nitrogen to 600mT, adding a plug, taking out the sample from the box, and wherein the anhydrous matter of the aripiprazole accounts for 10-20%.
Particle size and Release results
After the freeze-dried preparation prepared in all examples is reconstituted by adding water, the particle size is detected by a Markov MS3000 laser particle size analyzer, and the in vitro release is detected by a Tian Fa RC8MD dissolution instrument. The control example is ABILIFYMAINTENA produced by tsukamurella.
TABLE 1 particle size and Release results
Note that: the invention relates to D90-D10 named as particle size distribution span, which is used for evaluating the width of particle size distribution.
Examples 1-12 all provide freeze-dried aripiprazole formulations having a D50 after suspension of between 3.0 and 12 μm and a particle size distribution span that is greater than that of the comparative examples, i.e., having a wider particle size distribution span. According to the examples it is shown that the smaller the particle size distribution D10, the faster the release tends to be for 1 min. In addition, the in vitro release rates of the examples of the present invention were found to be higher than those of the commercial formulations of the control examples in comparison with the control examples, and the release rates of the examples were found to be faster at the initial stage of administration. Even when D10 of the examples is the same or larger than that of the comparative examples, the 1min release rate is still faster, and the analysis reason may be mainly such as the limitation of the MS3000 laser particle size analyzer itself, the light scattering intensity is proportional to the fourth power of the particle size, the light scattering intensity of small-sized particles is lower, and the detection sensitivity for small-sized particles such as particles of 1 μm or less, particularly 500nm or less, obtained by the preparation process of the present invention is not high according to the detection principle thereof.
In vivo studies in rats
The aripiprazole composition was reconstituted with water and injected intramuscularly (50 mg/kg) into the rat leg. The aripiprazole was collected at 8h and 1, 3, 6, 9, 14, 21, 35 days after administration and the blood concentration of aripiprazole was measured. The results are shown in FIG. 1.
The comparative example had a particle size distribution span of 7.6 μm, and the blood concentration was low at the initial stage of administration, and was rapidly increased to the peak blood concentration Cmax, and gradually decreased to a blood concentration of less than 10ng/ml after 15 days.
The comparison of examples within the range of different particle size distribution spans and average particle size ranges in the present invention is selected, and the compositions with different particle size spans obtained by preparing the same amount of aripiprazole active ingredients according to examples 1, 4, 5 and 11 are taken as examples, so that the rapid release is realized, and the particle size spans of examples 1, 4 and 5 are respectively 13.1 μm, 9.7 μm and 19.6 μm, and the compositions show higher blood concentration at the initial administration period and lower Cmax. Meanwhile, the larger the particle size span is, the longer the release period is, and the blood concentration is more stable. Meanwhile, the peak plasma concentration Cmax in 5-7 days is lower than that of the control example, and the Cmax is obviously reduced along with the larger value of the particle size distribution span, namely the wider particle size distribution span, so that adverse reaction is reduced.
In vivo studies in dogs
After reconstitution of the aripiprazole composition in water, a 200mg dose was intramuscular injected into the hind limb of the dog. The aripiprazole blood concentration was measured 8h after dosing and by blood sampling at days 1, 3, 6, 9, 14, 21, 35, 42, respectively. The results are shown in FIG. 2.
After intramuscular injection of dogs, the blood concentration in the experimental dogs can be maintained for 21-60 days. The blood concentration of example 5 on 60 days is close to that of the control example on 21 days, compared with the control example, the slow release period is prolonged to 3 times of that of the control example, the blood concentration of other examples on 21 days is higher than that of the control example, the curve is more stable during administration, the administration interval in a human body of the control example is 4 weeks, and thus the slow release of the composition of the invention in the human body can be calculated to be 4-12 weeks.
According to FIG. 2, the comparative example had a particle size distribution span of 7.6. Mu.m, D50 of 3.1. Mu.m, and D10 of 1.2. Mu.m. Example 4 the particle size distribution span was 9.7 μm, D50 was 3.0 μm, D10 was 0.9 μm, and example 4 the smooth release of the drug profile was improved with a smaller particle size distribution span, and the release period was not shorter than that of the control example after 21 days with a slightly higher blood concentration.
The particle size distribution span of example 11 was 7.9 μm, D50 was 5.0 μm, D10 was 1.2 μm, which was slightly consistent with that of the control, D50 was greater, the drug release profile was smoother, and the 21-day plasma concentration was slightly higher than that of the control, and the release period was slightly longer than that of the control.
The particle size distribution span of example 1 was 13.1. Mu.m, D50 was 5.1. Mu.m, and D10 was 1.6. Mu.m. The particle size distribution span of example 11 was 7.8 μm, D50 was 5.0 μm and D10 was 1.2. Mu.m. Under the condition that the D50 is approximately the same, the particle size distribution span of the embodiment 1 is wider, the curve release is smoother when the canine medicine is taken in vivo, and the release period is prolonged. Example 5 has a particle size distribution span of 19.6 μm and a D50 of 12.0 μm, and the curve of the in vivo drug delivery of dogs is the most stable, and the drug delivery period is obviously prolonged.
The raw materials and equipment used in the invention are common raw materials and equipment in the field unless specified otherwise; the methods used in the present invention are conventional in the art unless otherwise specified.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and any simple modification, variation and equivalent transformation of the above embodiment according to the technical substance of the present invention still fall within the scope of the technical solution of the present invention.
Claims (7)
1. The aripiprazole freeze-dried preparation for injection capable of stably releasing medicine is characterized by comprising the following components in percentage by mass:
74-81% of aripiprazole;
2-6% of sodium carboxymethylcellulose;
14-20% of mannitol;
a buffer salt for adjusting the pH of the suspension to 6.5-7.5 before lyophilization;
the particle size distribution of the aripiprazole lyophilized preparation after being re-dissolved and suspended is as follows: d90 D50=3-12 μm, d10=0.9-2.5 μm, and the particle size distribution span is 13 μm < d90-d10 < 25 μm;
the aripiprazole is an aripiprazole anhydride, a mixture of aripiprazole monohydrate; the ratio of the aripiprazole anhydride in the obtained aripiprazole lyophilized preparation is not higher than 20%;
the preparation method of the aripiprazole lyophilized preparation for injection comprises the following steps:
(1) Preparation of sterile aripiprazole suspension:
(1.1) dispersing a sterile powder of aripiprazole in a pretreatment solution comprising sodium carboxymethylcellulose, mannitol and a buffer salt to form a pre-mixed suspension having a pH of 6.5-7.5;
(1.2) circularly grinding the premixed suspension, and taking out grinding fluid in at least 2 batches; wherein the first batch is taken out after grinding until the D90 is not more than 35 mu m; grinding the last batch until the D50 is not more than 3 mu m, and taking out;
(1.3) mixing and dispersing the grinding liquid taken out from the different batches in the step (1.2) to obtain sterile aripiprazole suspension; the particle size distribution of the sterile aripiprazole suspension is: d90 D50=3-12 μm, d10=0.9-2.5 μm, and the particle size distribution span is 13 μm < d90-d10 < 25 μm;
(2) And (3) freeze drying:
transferring the sterile aripiprazole suspension into an open container, cooling to-45 ℃ to-35 ℃ at a cooling rate of 0.5-1.0 ℃/min, pre-freezing, and keeping for 1-4h;
(2.2) performing primary drying, heating to-10-5 ℃ at a heating rate of 0.2-0.3 ℃/min, and maintaining the vacuum pressure at 0.1-0.2mbar for 30-48 hours;
(2.3) drying for the second time, heating to 5-25 ℃ at a heating rate of 0.5-1 ℃/min, charging nitrogen to 300-760mT, and sealing the container;
the ratio of the transformation of the aripiprazole monohydrate into the aripiprazole anhydride in the obtained aripiprazole lyophilized preparation is not higher than 20%.
2. The stable release aripiprazole lyophilized formulation for injection as defined in claim 1, wherein: the buffer salt is one or more of sodium dihydrogen phosphate, sodium hydroxide, sodium phosphate, disodium hydrogen phosphate, sodium acetate and phosphoric acid.
3. The aripiprazole lyophilized formulation for injection as defined in claim 1, characterized in that: in the step (1.2), more than 3 batches of grinding are carried out, and the grinding is taken out; the first batch is taken in an amount of not less than 1/5 of the total weight of the premixed suspension.
4. The aripiprazole lyophilized formulation for injection as defined in claim 1, characterized in that: in the step (1.3), the mixing and dispersing are stirring treatment, shearing treatment or ultrasonic treatment.
5. The aripiprazole lyophilized formulation for injection according to any one of claims 1-4, characterized in that: the sodium carboxymethyl cellulose is added in the step (1.1) in all or two batches; wherein the first batch is added in step (1.1) at a ratio of not less than 17wt%; the remainder was the second batch, and sterile aripiprazole suspension was added prior to lyophilization.
6. The aripiprazole lyophilized formulation for injection according to any one of claims 1-4, characterized in that: the concentration of sodium carboxymethylcellulose in the sterile aripiprazole suspension prior to lyophilization is 0.2-2.2wt%.
7. The aripiprazole lyophilized formulation for injection as defined in claim 6, wherein: the concentration of sodium carboxymethylcellulose in the sterile aripiprazole suspension prior to lyophilization is 0.5-1.3wt%.
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