Drug composition and brexpiprazole oral dissolving film

Abstract

The present invention provides a drug composition and a brexpiprazole oral dissolving film. The drug composition includes brexpiprazole, a film-forming material and a plasticizer, and the D of the brexpiprazole is 90 25μm≦D 90 Meet ≦50 μm. The pharmaceutical composition provided by the present invention can achieve good dissolution rate, and has the same therapeutic effect and safety as original pharmaceutical tablets. At the same time, the brexpiprazole oral dissolving film provided by the present invention has the advantages of improved drug content uniformity, controllable dissolution rate, simple preparation process, and simple formulation auxiliary.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from a Chinese patent application filed on June 16, 2022, bearing application number 202210682418.X and entitled "Drug composition and brexpiprazole oral dissolving film," the entire contents of which are incorporated herein by reference in their entirety. [Technical Field]

[0002] The present invention relates to a pharmaceutical composition, and further to an oral dissolving film of brexpiprazole. [Background technology]

[0003] Brexpiprazole tablets were jointly developed by Otsuka Pharmaceutical Co., Ltd. of Japan and Lundbeck A / S of Denmark for the treatment of schizophrenia and major depression. They were approved for marketing by the FDA in July 2015 and are available in tablet form (0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg) under the trade name REXULTI. The molecular formula is C 25 H 27 It is N3O2S, has a molecular weight of 433.57, and has the following structural formula: JPEG0007760615000001.jpg2270

[0004] In clinical care, hospitalized patients with mental illnesses are prone to medication refusal during medication treatment, which can be expressed as direct refusal, hiding medication, or fake medication (putting medication under the tongue or in the mouth, pretending to take it, and then spitting it out when staff are not looking), and this prevents the expected therapeutic effect from being achieved for the illness.Furthermore, the incidence of medication refusal among patients who have been hospitalized for less than two weeks can be as high as 90%.

[0005] Oral dissolving films are a new oral dosage form that has been developed both domestically and internationally in recent years. They are taken by placing the oral dissolving film on the tongue, which usually dissolves completely within 30 seconds and then swallowed with saliva. They are not likely to stick to the mouth after administration and dissolve quickly, making them valuable in meeting clinical needs that cannot be met by existing dosage forms. Oral dissolving films are advantageous in controlling the drug-hiding behavior of patients with psychiatric disorders, which in turn improves patient compliance and indirectly improves therapeutic efficacy.

[0006] Brexpiprazole is a white or off-white crystalline powder, belongs to BCS2 class, and has low solubility and hypertonicity, so the dissolution rate of the active ingredient is the main factor affecting its bioavailability.

[0007] Patent CN105395528A discloses a brexpiprazole oral rapidly dissolving film and a method for preparing the same, but the oral dissolving film has a slow dissolution rate of about 50% in 60 minutes, and is soft and easily deformed when pulled, making it difficult to commercialize.Patent JP2013253038A discloses a brexpiprazole oral rapidly dissolving film and a method for preparing the same, but the formulation contains a large amount of auxiliary agents and is prepared as a two-layer film, which makes the preparation process complicated and the production costs high. Summary of the Invention

[0008] In response to the problems in the prior art, the present invention provides a brexpiprazole oral dissolving film and a preparation method thereof, which has improved drug content uniformity, a controllable dissolution rate, a simple preparation process, and simple formulation auxiliary agents.

[0009] In order to achieve the object of the present invention, the following technical means are adopted.

[0010] In a first aspect, the present invention provides a composition comprising brexpiprazole, a film-forming material and a plasticizer, and a D 90 is 25μm≦D 90Provide a drug composition that meets the requirements of ≦50 μm.

[0011] The present inventors have unexpectedly discovered that by controlling the particle size of brexpiprazole within a certain range, it is possible to achieve a controllable dissolution rate, with good reproducibility, and the same therapeutic effect and safety as original pharmaceutical tablets. At the same time, by preparing it as a brexpiprazole orally dissolving film, it is possible to maintain the same dissolution rate as original pharmaceutical tablets and improve patient compliance, and the brexpiprazole orally dissolving film can absorb the drug through the oral mucosa and exert a systemic effect. In some embodiments, the D 90 is 25 μm, 25.7 μm, 27.5 μm, 30 μm, 30.3 μm, 32.5 μm, 35 μm, 37.1 μm, 37.5 μm, 40 μm, 42.5 μm, 45 μm, 47.5 μm, 48.4 μm, or 50 μm. 90 In the present invention, the particle size D of the brexpiprazole drug substance 90 When the particle size D of the drug substance is controlled between 25μm and 50μm, the dissolution can be stably controlled, and the difference in dissolution at the same time point does not exceed 10%. The prepared brexpiprazole orally dissolving film can achieve bioavailability equivalent to that of oral tablets. 90 If the particle size is less than 25 μm, the dissolution rate will be too fast and uncontrollable, and if the dissolution rate is too fast, there is a risk that the fluctuations in blood concentration in the body will be too large. 90 If the particle size is 50 μm or more, the dissolution rate becomes slow.

[0012] In some embodiments, the D 90 30μm≦D 90 Meets ≦50μm.

[0013] In some embodiments, the D 90 is 30 μm <D 90 Meets ≦50μm.

[0014] In some embodiments, the D 90 is 30 μm <D 90 Meets <50μm.

[0015] In some embodiments, the D 90 30.3μm≦D 90 Meets ≦50μm.

[0016] In some embodiments, the plasticizer is one or more selected from polyethylene glycol, glycerin, triethyl citrate, or polysorbate, hi some examples, the plasticizer is polysorbate 80, polyethylene glycol 400, or other polyethylene glycols that can be used as plasticizers (e.g., polyethylene glycol 600, polyethylene glycol 800, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000).

[0017] In some embodiments, the film-forming material is one or more selected from the group consisting of povidone, copovidone, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, sodium carboxymethylcellulose, pectin, guar gum, pullulan, sodium alginate, chitosan, polyvinyl alcohol-polyethylene glycol copolymer, and xanthan gum. In some examples, the film-forming material is povidone K29 / 32, copovidone VA64, hypromellose E5, hypromellose E15, hypromellose E50, and hydroxypropyl cellulose SSL.

[0018] In some embodiments, the mass percentage content of brexpiprazole in the drug composition is 2% to 40%. In some embodiments, the mass percentage content of brexpiprazole in the drug composition is 2% to 24%. In some embodiments, the mass percentage content of brexpiprazole in the drug composition is 3% to 20% by mass. In some examples, the mass percentage content of brexpiprazole in the drug composition is 2%, 3%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 25%, 30%, 35%, or 40%. In the present invention, by controlling the mass content of brexpiprazole within the above range, particularly within 3% to 20%, the prepared formulation can achieve stable and controllable dissolution.

[0019] In some embodiments, the ratio of the mass of brexpiprazole to the total mass of the film-forming material and plasticizer is 1:(2 to 50). In some embodiments, the ratio of the mass of brexpiprazole to the total mass of the film-forming material and plasticizer is 1:(4 to 35). In some examples, the ratio of the mass of brexpiprazole to the total mass of the film-forming material and plasticizer is 1:2, 1:4, 1:6, 1:8, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, or 1:50. In the present invention, by controlling the ratio of the mass of brexpiprazole to the total mass of the film-forming material and plasticizer within the above range, the formulation can achieve stable and controllable dissolution.

[0020] In some embodiments, the ratio of the mass of the film-forming material to the mass of the plasticizer is (2-50): 1. In some embodiments, the ratio of the mass of the film-forming material to the mass of the plasticizer is (5-20): 1. In some examples, the ratio of the mass of the film-forming material to the mass of the plasticizer is 2:1, 5:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1, 40:1, 45:1, or 50:1.

[0021] In some embodiments, the drug composition comprises or consists of, by weight, 2 parts brexpiprazole, 5 to 80 (e.g., 5, 6, 8, 10, 12, 15, 20, 30, 40, 50, 60, 70, or 80, etc.) parts film-forming material, and 0.2 to 10 (e.g., 0.2, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) parts plasticizer.

[0022] In some embodiments, the drug composition comprises or consists of, by weight, 2 parts brexpiprazole, 5 to 60 (e.g., 5, 6, 8, 10, 12, 15, 20, 30, 40, 50, or 60, etc.) parts film-forming material, and 0.5 to 10 (e.g., 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) parts plasticizer.

[0023] In a second aspect, the present invention provides a drug suspension comprising the drug composition according to the first aspect of the invention and water.

[0024] In some embodiments, the viscosity of the drug suspension is greater than 3500 mPa·s. In some embodiments, the viscosity of the drug suspension is 3500-15000 mPa·s. In some embodiments, the viscosity of the drug suspension is 3500-10000 mPa·s. In some examples, the viscosity of the drug suspension is 3500 mPa·s, 4000 mPa·s, 5000 mPa·s, 6000 mPa·s, 7000 mPa·s, 8000 mPa·s, 9000 mPa·s, 10000 mPa·s, 11000 mPa·s, 12000 mPa·s, 13000 mPa·s, 14000 mPa·s, or 15000 mPa·s. The inventors have found that when the viscosity of the drug suspension is ≥ 3500 mPa·s, preferably in the range of 3500 mPa·s to 15000 mPa·s, good drug content uniformity can be achieved after degassing, and more preferably, the viscosity range is 3500 mPa·s to 10000 mPa·s, and when the viscosity of the drug suspension is within this range, the drug content uniformity meets the standard and stratification does not occur.

[0025] In some embodiments, the D of brexpiprazole in the drug suspension 90 In some embodiments, the D of brexpiprazole in the drug suspension is 25 μm to 50 μm. 90 In some embodiments, the D of brexpiprazole in the drug suspension is 25 μm to 40 μm. 90 is 25 μm, 27.5 μm, 30 μm, 32.5 μm, 35 μm, 37.5 μm, 40 μm, 42.5 μm, 45 μm, 47.5 μm or 50 μm.

[0026] In some embodiments, the drug suspension comprises or consists of, by weight, 2 parts brexpiprazole, 5 to 80 (e.g., 5, 6, 8, 10, 12, 15, 20, 30, 40, 50, 60, 70, or 80, etc.) parts film-forming material, 0.2 to 10 (e.g., 0.2, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) parts plasticizer, and 50 to 150 (e.g., 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150, etc.) parts water.

[0027] In some embodiments, the drug suspension comprises or consists of, by weight, 2 parts brexpiprazole, 5 to 60 (e.g., 5, 6, 8, 10, 12, 15, 20, 30, 40, 50, or 60, etc.) parts film-forming material, 0.5 to 10 (e.g., 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) parts plasticizer, and 60 to 120 (e.g., 60, 70, 80, 90, 100, 110, or 120, etc.) parts water.

[0028] In a third aspect, the present invention provides a brexpiprazole oral dissolving film comprising the drug composition according to the first aspect of the present invention or prepared using the drug suspension according to the second aspect of the present invention as a raw material.

[0029] In a fourth aspect, the present invention provides a method for producing a composition comprising: (1) dispersing brexpiprazole in water, adding and mixing a film-forming material and a plasticizer to obtain a drug suspension; (2) degassing the drug suspension; (3) applying the drug suspension obtained in step (2) to a patient.

[0030] In some embodiments, in step (1), the brexpiprazole is dispersed in water by high-speed homogenization for 15 to 60 minutes (e.g., 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes).

[0031] In some embodiments, in step (1), the film-forming material and plasticizer are added and mixed for 15 to 60 minutes (eg, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes).

[0032] In some embodiments, in step (2), degassing is performed using a vacuum degasser.

[0033] In some embodiments, in step (2), the vacuum defoamer may be a vacuum centrifugal defoamer or a vacuum drying oven.

[0034] In some embodiments, in step (3), the coating temperature is 50 to 80° C. In some embodiments, the coating temperature is 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., or 80° C.

[0035] In some embodiments, the preparation method includes the steps of adding brexpiprazole to purified water and homogenizing at high speed for, for example, 30 minutes, then transferring the homogenized sample to a stirring device, starting the stirring device, adding a film-forming material and a plasticizer, and stirring for, for example, 30 minutes to obtain a suspension, then degassing the suspension using a vacuum centrifugal degasser, then spreading the suspension evenly on an applicator, fixing it, adjusting the blade to zero, setting the heating temperature to 50 to 80°C, and applying to obtain the brexpiprazole oral dissolving film.

[0036] The present invention controls the particle size of the active ingredient in the brexpiprazole orally dissolving film, thereby achieving a dissolution rate with excellent controllability and reproducibility in the gastrointestinal tract and achieving bioavailability equivalent to that of tablets. The present invention controls the viscosity of the coating suspension, thereby meeting the standards for uniformity of drug content and preventing content segregation. The brexpiprazole orally dissolving film of the present invention has good stability and palatability. When the brexpiprazole orally dissolving film of the present invention is placed in the oral cavity of a subject, the drug enters the gastrointestinal tract together with saliva and is absorbed after the film dissolves. DETAILED DESCRIPTION OF THE INVENTION

[0037] In order to clarify the objectives, technical solutions and advantages of the present invention, the present invention will be described in more detail below in conjunction with examples. The specific examples described herein are only for illustrating the present invention and are not intended to limit the present invention.

[0038] Test Method Dissolution method: Samples were taken according to USP IV using the paddle method, with a 0.1M hydrochloric acid solution as the dissolution medium, a rotation speed of 50 rpm, and sampling times of 5 min, 15 min, and 30 min. After sampling, the release rate was measured using HPLC. All the following formulations, except for the reference formulation, were analyzed using this analytical method. The dissolution results were expressed as an average value (N=3). Viscosity measurement: Measurement is performed using a rotational digital viscometer (LICHEN). A sample with an appropriate amount of fluidity is taken and placed in a beaker. Rotate the No. 3 rotor. 6 At a speed of rpm, the rotor is immersed vertically in the center of the sample, and the liquid level is brought up to the rotation liquid level mark. The sample and rotor in the measuring container are kept at a constant temperature of 25±0.5°C, and the sample temperature is maintained uniform. The rotor begins to rotate, and after the pointer stabilizes, the value is read to obtain the sample viscosity, expressed in centipoise (mPa·s). Particle size detection: Use Malvern Laser Particle Size Analyzer MS3000 to measure particle size. Use water as a dispersant and measure the sample according to the instrument's operating protocol. Set the stirring speed to 500 rpm. The number of measurements is 3. After confirming that the stirring is in operation, click Start to initialize the instrument and automatically aim. After the background measurement is completed, manually add the sample until the light blocking degree reaches the range, press the Start key to measure, and finally obtain the measurement data D. 90 "D 90 " indicates that 90% of the particles have a particle size lower than the specified value. For example, D 90 :9.6 μm means that 90% of the particles have a particle diameter of less than 9.6 μm, and μm refers to microns. Comparative Example 1 Dissolution test of reference formulation (brexpiprazole tablets)

[0039] Brexpiprazole tablets (REXULTI, 2 mg, lot number: BMS05420A, manufacturer: Otsuka Pharmaceutical Co., Ltd.) were dissolved in 0.1 M hydrochloric acid solution. Dissolution method: According to USP II method, the paddle method was used, the dissolution medium was 0.1 M hydrochloric acid solution, the rotation speed was 50 rpm, and the sampling time (unit: min): 5 / 15 / 30. After sampling, the release rate was measured using HPLC, and the results are shown in Table 1.

[0040] JPEG0007760615000002.jpg24147Comparative example 2 D 90 Consideration of different pH values ​​for 3.96 μm

[0041] Preparation process: The prescribed amount of brexpiprazole was weighed and slowly added to purified water and homogenized at high speed for 30 minutes. The sample was then transferred to a stirrer, the stirrer was started, and hypromellose and polyethylene glycol were slowly added and stirred for 30 minutes. The pH of the coating suspension for Formulation 1 was then measured and recorded. 0.1 M sodium bicarbonate solution was added sequentially to the coating suspensions for Formulations 2, 3, and 4 to adjust the pH to 8.30, 10.41, and 12.13, respectively. The prepared coating suspensions were then degassed in a vacuum centrifugal degasser and the viscosity was measured. The substrate was then flattened on the coating device, fixed, the blade was adjusted to zero, and the heating temperature was set to 50-80°C. After coating was complete, the sample was cut to a certain size and subjected to dissolution measurement. The amounts of ingredients used for each formulation are shown in Table 2 below.

[0042] JPEG0007760615000003.jpg79148

[0043] The sample prepared according to the above recipe was eluted in 0.1 M hydrochloric acid, and the results are shown in Table 3 below.

[0044] JPEG0007760615000004.jpg50150

[0045] As a result, D 90 = 3.96 μm, all drug films applied at different pH levels from 6.66 to 12.13 rapidly dissolved, with over 85% dissolved in 15 minutes. This was faster than the dissolution of the original drug tablets, which could lead to excessive absorption by patients and large fluctuations in blood concentration, potentially causing adverse reactions. Comparative example 3D 90 Consideration of different deposition materials for =3.96μm

[0046] Preparation process: The prescribed amount of brexpiprazole was weighed and slowly added to purified water, followed by high-speed homogenization for 30 minutes. The sample was then transferred to a mixing device, and hypromellose and polyethylene glycol were slowly added and stirred for 30 minutes. The resulting coating suspension was then degassed in a vacuum centrifugal defoamer and the viscosity was measured. The substrate was then flattened on the coating device, fixed, the blade was adjusted to zero, and the heating temperature was set to 50-80°C. After coating was complete, the sample was cut to a certain size and subjected to dissolution measurement. The amounts of ingredients used for each formulation are shown in Table 4 below.

[0047] JPEG0007760615000005.jpg78149

[0048] The samples prepared according to the above recipe were eluted in 0.1 M hydrochloric acid, and the results are shown in Table 5 below.

[0049] JPEG0007760615000006.jpg34147

[0050] D 90 = 3.96 μm, drug suspensions prepared with different models were used, coated according to the above preparation process, and then cut into the corresponding shapes to measure dissolution. The results showed that all of the coated drug films had rapid dissolution, with more than 85% dissolution in 15 minutes, which was too rapid for the body to absorb, causing large fluctuations in blood concentration. Comparative Example 4: Dissolution of intraoral dissolving film prepared with reference to CN105395528A

[0051] Preparation process: Formulation 6: First, the prescribed amounts of acesulfame K, glycerin, polyethylene glycol, hypromellose, and polysorbate 80 were added to an aqueous solution and stirred to dissolve, then gelatin and xanthan gum were added and thoroughly dissolved in a water bath at 60-70°C to obtain a gelatin blank gum solution, to which brexpiprazole was then added and stirred until uniformly dispersed to obtain a brexpiprazole-containing gum solution, which was then stirred under vacuum to degass. The degassed drug-containing gum solution was evenly coated on a substrate with a blade, dried by heating at 70-80°C, and cut to a specified size to obtain a brexpiprazole oral dissolving film, which was then used to measure dissolution.

[0052] Formulation 7: First, the above amounts of acesulfame K, glycerin, and polysorbate were added to an aqueous solution and stirred to dissolve, then gelatin was added and thoroughly dissolved in a water bath at 60-70°C to obtain a gelatin blank gum solution, brexpiprazole was then added and stirred until uniformly dispersed to obtain a brexpiprazole-containing gum solution, which was then stirred under vacuum to degass, and the degassed drug-containing gum solution was evenly coated on a substrate with a blade, heated to 70-80°C to dry, and cut to a specified size to obtain a brexpiprazole oral dissolving film, which was then used to measure dissolution.

[0053] The amounts of ingredients used in each formulation are shown in Table 6 below.

[0054] JPEG0007760615000007.jpg75147

[0055] The samples prepared according to the above recipe were eluted in 0.1 M hydrochloric acid, and the results are shown in Table 7 below.

[0056] JPEG0007760615000008.jpg29147

[0057] As a result, formulations 6 and 7 had slow dissolution, dissolving less than 50% in 30 minutes, and the prepared intraoral dissolving films were soft and easily deformed when pulled, making industrial production difficult. Comparative Example 5: Dissolution of intraoral dissolving film prepared with reference to JP2013253038A

[0058] Preparation process: (1) The prescribed amounts of hypromellose, maltitol, sucralose, and polyethylene glycol were added to an aqueous solution and stirred to dissolve. Titanium dioxide was then added and stirred until uniformly dispersed, yielding a support layer suspension. The suspension was then degassed by vacuum centrifugation. The degassed suspension was then evenly coated onto the substrate with a blade and dried at 70-80°C. (2) The prescribed amounts of HPC SSL, maltitol, sucralose, and flavor were added to an aqueous solution and stirred to dissolve. Brexpiprazole was then added and stirred until uniformly dispersed, yielding a drug layer suspension. The suspension was then degassed by vacuum centrifugation. The degassed drug layer suspension was then evenly coated onto the substrate with a blade and dried at 70-80°C. The resulting film was then cut to a specified size to obtain a brexpiprazole oral dissolution film for dissolution testing. The amounts of ingredients used for each formulation are shown in Table 8 below.

[0059] JPEG0007760615000009.jpg108149

[0060] The samples prepared according to the above recipe were eluted in 0.1 M hydrochloric acid, and the results are shown in Table 9 below.

[0061] JPEG0007760615000010.jpg29147

[0062] The brexpiprazole oral dissolving film disclosed in JP2013253038A contains a large amount of additives and is prepared as a two-layer film, which requires a complicated preparation process, a large amount of additives, and high process costs. Within the range of drug substance particle size in this patent, there is a large difference in dissolution rate, and D 90 The brexpiprazole oral dissolving film with a drug substance particle size of 9.6 μm was used, and 86% was dissolved in 30 minutes. 90 When using an oral dissolving film of brexpiprazole with a drug substance particle size of 60.8 μm, less than 50% dissolution occurred in 30 minutes, the dissolution rate was uncontrollable, and there was a large difference between product lots, which affected the quality of the product. Example 1: Oral dissolving films of brexpiprazole with different drug substance particle sizes

[0063] Preparation process: The prescribed amount of brexpiprazole was weighed and slowly added to purified water and homogenized at high speed for 30 minutes. The sample was then transferred to a stirrer, the stirrer was started, and hypromellose and polyethylene glycol were slowly added and stirred for 30 minutes. The prepared coating suspension was then degassed in a vacuum centrifugal defoamer and the viscosity was measured. The substrate was then flattened on the coating device, fixed, the blade was adjusted to zero, and the heating temperature was set to 50-80°C. After coating was complete, the sample was cut to a certain size and subjected to dissolution measurement. The amounts of ingredients used for each formulation are shown in Table 10 below.

[0064] JPEG0007760615000011.jpg80149

[0065] The samples prepared according to the above recipe were eluted in 0.1 M hydrochloric acid, and the results are shown in Table 11 below.

[0066] JPEG0007760615000012.jpg66144

[0067] As a result, the particle size of the drug substance D 90 When the particle size D of the drug substance is controlled between 25 μm and 50 μm, the dissolution can be stably controlled, the difference in dissolution at the same time point does not exceed 10%, and 90 If the particle size is less than 25 μm, the dissolution rate will be too fast and uncontrollable, and if the dissolution rate is too fast, the fluctuations in blood concentration in the body may be too large. 90 If the particle size is 50 μm or more, the dissolution rate is slow. Example 2: Consideration of content uniformity

[0068] Preparation process: The prescribed amount of brexpiprazole was weighed and slowly added to purified water, followed by high-speed homogenization for 30 minutes. The sample was then transferred to a stirrer, the stirrer was turned on, and hypromellose and polyethylene glycol were slowly added and stirred for 30 minutes. The prepared coating suspension was then degassed overnight in a vacuum drying oven. The vacuum drying oven was set at a pressure of -0.08 MPa and a temperature of 25°C. The amounts of the ingredients used in the formulation are shown in Table 12 below.

[0069] After degassing, the viscosity was measured and found to be 1916 mPa·s for Formulation 16.

[0070] JPEG0007760615000013.jpg58150

[0071] The uniformity of blended content refers to the uniformity of the drug suspension before and after thorough mixing and degassing of the sample. In the examples, three samples were taken from different positions in the mixing tank, including the upper, middle, and lower layers, immediately before and after degassing. The brexpiprazole content of each sample was measured, and the relative standard deviation (RSD) was calculated. RSD = standard deviation / arithmetic mean of the calculation results. An RSD of 3% or less indicates good content uniformity, and an RSD of 3% or more indicates poor content uniformity. The results of blended content uniformity are shown in Table 13 below.

[0072] JPEG0007760615000014.jpg58149

[0073] The results showed that the drug suspension of Formulation 16 had good sample content uniformity at different positions before degassing, with an RSD of ≦3%. However, after degassing, the sample content uniformity was not good, with an RSD of >3%, indicating that the drug had separated into layers, with a low drug content in the upper layer and a high drug content in the lower layer, indicating that the drug had settled. Example 3: Consideration of content uniformity

[0074] Preparation process: The prescribed amount of brexpiprazole was weighed and slowly added to purified water, followed by high-speed homogenization for 30 minutes. The sample was then transferred to a mixing device, and hypromellose E5LV and polyethylene glycol 400 were slowly added and stirred for 30 minutes. The resulting coating suspension was then degassed using a vacuum centrifugal degasser. The parameters for the vacuum centrifugal degasser were as follows: Stage 1: 300 rpm, 1 minute, no vacuum; Stage 2: 750 rpm, 1 minute, vacuum level -0.04 MPa; Stage 3: 1000 rpm, 2 minutes, vacuum level -0.04 MPa; Stage 4: 700 rpm, 1.5 minutes, vacuum level -0.04 MPa; Stage 5: 400 rpm, 0.5 minutes, vacuum level -0.04 MPa. The amounts of the ingredients used in the formulation are shown in Table 14 below.

[0075] After degassing, the viscosity was measured and found to be 1920 (mPa·s).

[0076] JPEG0007760615000015.jpg59150

[0077] The uniformity of blended content refers to the uniformity of the drug suspension before and after thorough mixing and degassing of the sample. In the examples, three samples were taken from different positions in the mixing tank, including the upper, middle, and lower layers, immediately before and after degassing. The brexpiprazole content of each sample was measured, and the relative standard deviation (RSD) was calculated. RSD = standard deviation / arithmetic mean of the calculation results. An RSD of 3% or less indicates good content uniformity, while an RSD of 3% or more indicates poor content uniformity. The results of blended content uniformity are shown in Table 15 below.

[0078] JPEG0007760615000016.jpg58147

[0079] The results showed that the drug suspension of Formulation 17 had good sample content uniformity at different positions before degassing, but after degassing, the sample content uniformity was not good with RSD > 3%, indicating that the drug was separated into layers, with the drug content in the upper layer being low and the drug content in the lower layer being high, indicating that the drug had settled. Example 4: Consideration of content uniformity

[0080] The preparation process and sampling for content uniformity were the same as in Example 3, and the degassing method was a vacuum centrifugal degassing machine. The amounts of ingredients used in each formulation are shown in Table 16 below. The results of the mixed content uniformity are shown in Tables 17, 18, 19, and 20 below.

[0081] JPEG0007760615000017.jpg55149

[0082] JPEG0007760615000018.jpg59149

[0083] The results showed that the drug suspension of Formulation 18 had good sample content uniformity at different positions before degassing, but after degassing, the sample content uniformity was not good with RSD > 3%, indicating that the drug was separated into layers, with the drug content in the upper layer being low and the drug content in the lower layer being high, indicating that the drug had settled.

[0084] JPEG0007760615000019.jpg58147

[0085] The results showed that the drug suspension of formulation 19 had good content uniformity at different positions of the sample before and after degassing, with RSD<3%.

[0086] JPEG0007760615000020.jpg58148

[0087] The results showed that the drug suspension of formulation 20 had good content uniformity at different positions of the sample before and after defoaming, with RSD<3%.

[0088] JPEG0007760615000021.jpg60147

[0089] The results showed that the drug suspension of formulation 21 had good content uniformity at different positions of the sample before and after defoaming, with RSD<3%.

[0090] As can be seen from Tables 16 to 20, when the viscosity of the drug suspension is ≥ 3500 mPa·s, good content uniformity can be achieved after degassing. Preferably, the viscosity range is 3500 mPa·s to 15000 mPa·s, and when the viscosity of the drug suspension is within this range, good content uniformity can be achieved after degassing. More preferably, when the viscosity range is 3500 mPa·s to 10000 mPa·s, and when the viscosity of the drug suspension is within this range, further improved content uniformity can be achieved after degassing. Example 5 Accelerated Stability Experiments

[0091] An accelerated stability experiment was conducted on the brexpiprazole oral dissolving film prepared according to Formulation 13, and the results of dissolution in 0.1 M hydrochloric acid are shown in Table 21 below. All impurities and dissolution results completely met the acceptance criteria within the accelerated period.

[0092] JPEG0007760615000022.jpg33145

[0093] The relevant substance standards were established with reference to the 2020 edition of the Chinese Pharmacopoeia, Four Parts General Provisions 0512.

[0094] The results for the materials are shown in Table 22.

[0095] JPEG0007760615000023.jpg81147Example 6 Human PK test

[0096] A pharmacokinetic study was conducted on volunteers. They were divided into four groups: one group was administered 2 mg of brexpiprazole orally dissolving films (Formulation 10, Formulation 12, and Formulation 15) and the other group was administered 2 mg of brexpiprazole tablets (REXULTI, 2 mg, Lot No.: BMS05420A, Manufacturer: Otsuka Pharmaceutical Co., Ltd.). Using brexpiprazole tablets as the control, blood samples were taken at 0 min before each dose and 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 120, 144, 168, 216, and 312 hours after each dose. Plasma brexpiprazole concentrations were measured using LC-MS / MS. The results are shown in Table 23.

[0097] JPEG0007760615000024.jpg77152

[0098] The average peak blood concentration times for the brexpiprazole orally dissolving films of Formulations 10, 12, and 15 were 1.80 hours, 4.00 hours, and 6.50 hours, respectively, and the average peak blood concentration time for the orally administered tablets was 5.40 hours. As a result, by controlling the particle size of the drug substance, it is possible to effectively control the blood concentration of brexpiprazole in the body and shorten the peak blood concentration time. D 90 If the peak concentration is 9.6 μm, the peak concentration will exceed 22% of the tablet, and if the peak concentration is too high, it may cause adverse reactions. 90 = 60.8 μm, the peak concentration is not equivalent to that of the oral tablet, and D 90 = 30.3 μm, the bioavailability of the brexpiprazole orally dissolving film can reach bioequivalence with that of the orally administered tablet. Example 7 Consideration of the ratio of film-forming material to active pharmaceutical ingredient

[0099] Preparation process: The prescribed amount of brexpiprazole was weighed and slowly added to purified water, followed by high-speed homogenization for 30 minutes. The sample was then transferred to a mixing device, and hypromellose and polyethylene glycol were slowly added and stirred for 30 minutes. The resulting coating suspension was then degassed in a vacuum centrifugal defoamer. The substrate was then flatly spread on the coating device, fixed, the blade was adjusted to zero, and the heating temperature was set to 50-80°C. After coating was complete, the sample was cut to a certain size and subjected to dissolution measurement. The amounts of ingredients used for each formulation are shown in Table 24 below.

[0100] JPEG0007760615000025.jpg61146

[0101] The samples prepared according to the above recipe were eluted in 0.1 M hydrochloric acid, and the results are shown in Table 25 below.

[0102] JPEG0007760615000026.jpg50146

[0103] As a result, when brexpiprazole accounts for 3% to 20%, the formulation can achieve stable and controllable dissolution. Example 8: Consideration of the types of film-forming materials

[0104] Preparation process: The prescribed amount of brexpiprazole was weighed and slowly added to purified water, followed by high-speed homogenization for 30 minutes. The sample was then transferred to a stirring device, and the film-forming material and plasticizer were slowly added and stirred for 30 minutes. The resulting coating suspension was then degassed in a vacuum centrifugal degasser. The substrate was then flatly spread on the coating device, the substrate was secured, the blade was adjusted to zero, and the heating temperature was set to 50-80°C. After coating was complete, the sample was cut to a specified size and subjected to dissolution measurement. The amounts of components used for each formulation are shown in Table 26 below. The results of dissolution of the samples prepared with each formulation in 0.1 M hydrochloric acid are shown in Table 27 below.

[0105] JPEG0007760615000027.jpg91147

[0106] JPEG0007760615000028.jpg45147

[0107] The results show that formulations 26 to 30 can achieve stable and controllable dissolution even when different types of film-forming materials are used.

[0108] The technical solution of the present invention is not limited to the above specific embodiments, and any technical modifications made based on the technical solution of the present invention are included within the protection scope of the present invention.

Claims

1. A pharmaceutical composition for preparing an oral dissolving film, comprising brexpiprazole, a film-forming material and a plasticizer, 90 is 25 μm≦D 90 ≦50 μm, the plasticizer is selected from one or more of polyethylene glycol, glycerin, triethyl citrate, and polysorbate; the film-forming material is selected from one or more of povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol-polyethylene glycol copolymer, and xanthan gum; the ratio of the mass of the brexpiprazole to the total mass of the film-forming material and the plasticizer is 1:(2 to 50); A drug composition, wherein the ratio of the mass of the film-forming material to the mass of the plasticizer is (2-50):

1.

2. The mass percentage content of the brexpiprazole in the pharmaceutical composition is 2% to 24%; and / or The D of brexpiprazole 90 is 30 μm<D 90 The pharmaceutical composition according to claim 1, characterized in that it satisfies the requirement of ≦50 μm.

3. The mass percentage content of the brexpiprazole in the pharmaceutical composition is 3% to 20%; and / or The D of brexpiprazole 90 30.3 μm≦D 90 The pharmaceutical composition according to claim 1, characterized in that it satisfies the requirement of ≦50 μm.

4. 2. The pharmaceutical composition of claim 1, wherein the plasticizer is polyethylene glycol 400 and / or the film-forming material is hypromellose E5LV.

5. the ratio of the mass of the brexpiprazole to the total mass of the film-forming material and the plasticizer is 1:(4-35); and / or The pharmaceutical composition according to claim 1, characterized in that the ratio of the mass of the film-forming material to the mass of the plasticizer is (5-20):

1.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the pharmaceutical composition comprises, by weight, 2 parts of brexpiprazole, 5 to 80 parts of a film-forming material, and 0.2 to 10 parts of a plasticizer.

7. The pharmaceutical composition according to claim 6, characterized in that the pharmaceutical composition comprises, by weight, 5 to 60 parts of a film-forming material and / or 0.5 to 10 parts of a plasticizer.

8. A drug suspension for preparing an oral dissolving film, comprising the drug composition according to any one of claims 1 to 5 and water, wherein the viscosity of the drug suspension exceeds 3500 mPa·s.

9. 9. The drug suspension according to claim 8, wherein the viscosity of the drug suspension is 3,500 to 15,000 mPa·s.

10. 9. The drug suspension according to claim 8, wherein the viscosity of the drug suspension is 3,500 to 10,000 mPa·s.

11. The drug suspension comprises:

9. The drug suspension of claim 8, comprising, by weight, 2 parts brexpiprazole, 5 to 80 parts film-forming material, 0.2 to 10 parts plasticizer, and 50 to 150 parts water.

12. The drug suspension comprises:

9. The drug suspension of claim 8, comprising, by weight, 2 parts brexpiprazole, 5 to 60 parts film-forming material, 0.5 to 10 parts plasticizer, and 60 to 120 parts water.

13. A brexpiprazole oral dissolving film comprising the drug composition according to any one of claims 1 to 7.

14. (1) a step of dispersing brexpiprazole in water, adding and mixing a film-forming material and a plasticizer to obtain a drug suspension, wherein the viscosity of the drug suspension exceeds 3500 mPa s; (2) subjecting the drug suspension to a degassing treatment; (3) applying the drug suspension obtained in step (2).

15. In step (1), the brexpiprazole is dispersed in water by high-speed homogenization for 15 to 60 minutes, and / or a film-forming material and a plasticizer are added and mixed for 15 to 60 minutes, and / or In step (2), a degassing treatment is performed using a vacuum degasser, and / or 15. The method according to claim 14, wherein in step (3), the temperature of the application is 50 to 80°C.

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