A brexpiprazole oral film, a preparation method thereof, and use thereof

Abstract

This invention provides a birepiperazole oral film, its preparation method, and its application. The birepiperazole oral film comprises the following components: an active pharmaceutical ingredient and a film-forming material. The active pharmaceutical ingredient is 7-[4-(4-benzo[B]thiophene-4-yl-1-piperazine)butoxy]-2(1H)-quinolinone as shown in Formula I and / or a pharmaceutically acceptable salt thereof. The particle size D of the active pharmaceutical ingredient is... 90 ≤70μm; the film-forming material is one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, and hydroxypropyl cellulose; and it does not contain dimethyl silicone oil. The birepiperazole oral film of the present invention has a good dissolution rate, does not have a gritty feel after dissolving in the oral cavity, has a uniform appearance, good flexibility, and does not settle during the preparation of the film solution, and the content uniformity meets the requirements.

Description

[0001] This application claims priority to the earlier application filed on September 22, 2023 with China National Intellectual Property Administration, patent application number 202311227319.3, entitled "An iripepiperazole oral film, its preparation method and application". Technical Field

[0002] This invention relates to a birepiperazole oral film, its preparation method, and its application. Background Technology

[0003] REXULTI (brand name: iriperazole) was jointly developed by Otsuka Pharmaceutical Co., Ltd. of Japan and Lundbeck Pharmaceutical Ltd. of Denmark. It was approved by the FDA in July 2015. The dosage form is tablets, with strengths of 0.25mg, 0.5mg, 1mg, 2mg, 3mg and 4mg.

[0004] Iripiparazole tablets, as a 5-HT1A receptor and dopamine D2 receptor agonist and a 5-HT2A receptor antagonist, are clinically used to treat major depressive disorder and schizophrenia. For the treatment of major depressive disorder, the starting dose is 0.5 mg / day or 1 mg / day, then increased to a target dose of 2 mg once daily, with a maximum recommended dose of 3 mg / day. For the treatment of schizophrenia, the starting dose is 1 mg / day, with a recommended target dose of 2 to 4 mg once daily, and a maximum recommended dose of 4 mg / day. Iripiparazole has broad activity across multiple monoamine systems, exhibiting decreased activity against some dopamine D2 receptor agonists and increased affinity for specific 5-HT receptors (such as 5-HT1A, 5-HT2A, and 5-HT7), resulting in better efficacy and tolerability, and reducing adverse reactions such as akathisia, restlessness, or insomnia.

[0005] Buripiperazole (7-[4-(4-benzo[B]thiophene-4-yl-1-piperazine)butoxy]-2(1H)-quinolinone) is a white or off-white crystalline powder that is almost insoluble in water and has a bitter and numbing irritant effect, which can cause significant irritation to the oral mucosa.

[0006] Iripiparazole tablets must disintegrate in the stomach before releasing the drug, resulting in a slow onset of action and limiting bioavailability. They are also inconvenient to take; as a treatment for mental illnesses, patients with this indication often have poor adherence to treatment, frequently refusing treatment, hiding medication, or vomiting. Patent document CN105078910A discloses a method for preparing iripiparazole orally disintegrating tablets, using lyophilization technology to prepare lyophilized orally disintegrating tablets containing iripiparazole, thus accelerating disintegration and improving dissolution. However, this technology is relatively cumbersome, requiring specialized equipment for production, resulting in high product costs. Furthermore, the prepared formulation is easily broken, making it unsuitable for transportation and increasing packaging and shipping difficulties. Additionally, the tablets must not come into contact with water before administration, increasing the demands on patients and negatively impacting compliance in patients with schizophrenia.

[0007] Patent document CN105395528A discloses an iripepiazole oral instant film. However, because iripepiazole is almost insoluble in water, it is difficult to disperse in a hydrophilic adhesive. During the coating and drying process, the drug is prone to agglomeration, thus affecting the uniformity of the active ingredient content. Furthermore, patients may experience unpleasant taste after taking it, affecting compliance.

[0008] Therefore, there is an urgent need to develop formulations of biriperazole that are convenient to take, stable in nature, have good patient compliance, high bioavailability, and / or suitable for industrial production. Summary of the Invention

[0009] This invention provides an birepiperazole oral film formulation comprising the following components: an active pharmaceutical ingredient and a film-forming material, wherein the active pharmaceutical ingredient is 7-[4-(4-benzo[B]thiophene-4-yl-1-piperazine)butoxy]-2(1H)-quinolinone (i.e., birepiperazole) as shown in Formula I and / or a pharmaceutically acceptable salt thereof, and the active pharmaceutical ingredient has a particle size D 90 ≤70μm; the film-forming material is selected from one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, and hydroxypropyl cellulose; the birepiperazole oral film is free of dimethyl silicone oil;

[0010]

[0011] According to an embodiment of the present invention, the active drug particle size D 90 ≤70.0μm, can be D 90 ≤65.0μm or D 90≤50.0μm, such as 1.0μm, 2.0μm, 3.0μm, 4.0μm, 5.0μm, 6.0μm, 7.0μm, 8.0μm, 9.0μm, 9.7μm, 10.0μm, 11.0μm, 12.0μm, 13.0μm, 14.0μm, 15.0μm, 16.0μm, 17.0μm, 18.0μm, 19.0μm, 20.0μm, 21.0μm, 22.0μm, 23.0μm, 24.0μm, 25.0μm, 26.0μm, 27.0μm, 27.8μm, 29.0μm, 30.0μm, 31.0μm, 32.0μm, 33.0μm, 34.0μm, 35.0μm, 35.1μm, 36.0μm, 37.0μm, 38.0μm, 39.0μm, 40.0μm, 41.0μm, 42.0μm, 43.0μm, 44.0μm, 45.0μm, 45.6μm, 46.0μm, 47.0μm, 48.0μm, 49.0μm, 50.0μm, 55.0μm, 60.0μm or 65.0μm.

[0012] According to an embodiment of the present invention, the mass percentage of the active drug can be 1.0% to 50.0%, or 4.0% to 40.0%, for example 40.0%, 35.0%, 30.0%, 25.0%, 23.8%, 20.0%, 16.7%, 15.0%, 13.8%, 10.0%, 8.7%, or 4.3%, whereby the mass percentage refers to the percentage of the mass of the active drug relative to the total mass of the birepiperazole oral film.

[0013] According to an embodiment of the present invention, the mass percentage of the film-forming material can be 30.0% to 80.0%, or 40.0% to 75.0%, or 40.0% to 70.0%, for example 65.2%, 61.7%, 57.9%, 56.5%, 50.0% or 47.6%, whereby the mass percentage refers to the percentage of the mass of the film-forming material to the total mass of the birepiperazole oral film.

[0014] According to an embodiment of the present invention, the birepiperazole oral film may further include one or more of plasticizers, sweeteners, disintegrants, fillers, and colorants.

[0015] According to an embodiment of the present invention, the plasticizer refers to a substance used to lower the glass transition temperature of the film, increase plasticity and toughness, and improve elongation, and is selected from one or more of polyethylene glycol, glycerin, propylene glycol, silicone oil other than dimethyl silicone oil, polypropylene glycol, and hexanediol.

[0016] According to an embodiment of the present invention, the mass percentage of the plasticizer can be 0 to 30.0%, or 10.0% to 30.0%, for example 28.0%, 26.0%, 24.1%, 23.8%, 20.8%, 17.4%, 15.0%, 4.0% or 0, wherein the mass percentage refers to the percentage of the mass of the plasticizer to the total mass of the birepiperazole oral film.

[0017] According to an embodiment of the present invention, the sweetener refers to a substance that plays a flavoring role in the film-forming agent, and is selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, flavorings, fragrances, saccharin, and sodium saccharin.

[0018] According to an embodiment of the present invention, the mass percentage of the sweetener can be 0% to 10.0%, or 5.0% to 10.0%, for example 8.7%, 8.6%, 4.8%, 0.8% and 0.7%, wherein the mass percentage refers to the percentage of the mass of the sweetener to the total mass of the birepiperazole oral film.

[0019] According to an embodiment of the present invention, the disintegrant refers to an excipient that promotes the rapid disintegration of the drug into small particles in the gastrointestinal tract, and is selected from one or more of low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, crospovidone sodium carboxymethyl starch and starch.

[0020] According to an embodiment of the present invention, the mass percentage of the disintegrant can be 0 to 10.0%, for example 1.0%, 2.0%, 3.0%, 3.4%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0% or 0, wherein the mass percentage refers to the percentage of the mass of the plasticizer to the total mass of the birepiperazole oral film.

[0021] According to an embodiment of the present invention, the filler refers to a solid substance added to a material that can improve the material's properties or increase its volume, weight, or reduce its cost, and is selected from one or more of microcrystalline cellulose, pregelatinized starch, mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose.

[0022] According to an embodiment of the present invention, the mass percentage of the filler can be 0 to 60.0%, for example 50.0%, 45.0%, 40.0%, 35.0%, 30.4%, 25.0%, 20.0%, 10.0% or 0, wherein the mass percentage refers to the percentage of the mass of the filler to the total mass of the birepiperazole oral film.

[0023] According to an embodiment of the present invention, the colorant refers to a substance that can improve the appearance color of the preparation, can be used to identify the concentration of the preparation, distinguish the method of application, and reduce the patient's aversion to taking the medication, and is selected from one or more of titanium dioxide, pigments, and lakes.

[0024] According to an embodiment of the present invention, the mass percentage of the colorant can be 0 to 5.0%, for example 0.1%, 0.5%, 1.0%, 2.0% or 0, wherein the mass percentage refers to the percentage of the mass of the colorant to the total mass of the birepiperazole oral film.

[0025] According to some embodiments of the present invention, the birepiperazole oral film comprises or is mainly composed of the following components: birepiperazole, film-forming material, plasticizer, sweetener, and filler; the birepiperazole D 90 ≤65.0μm.

[0026] According to some embodiments of the present invention, the birepiperazole oral film comprises or is mainly composed of the following components: birepiperazole, film-forming material, plasticizer, sweetener, and disintegrant; the birepiperazole D 90 ≤65.0μm.

[0027] According to some embodiments of the present invention, the birepiperazole oral film comprises or is mainly composed of the following components: birepiperazole, film-forming material, plasticizer, colorant, and disintegrant; the birepiperazole D 90 ≤65.0μm.

[0028] According to some embodiments of the present invention, the birepiperazole oral film comprises or is mainly composed of the following components: birepiperazole, film-forming material, plasticizer, sweetener, and colorant; the birepiperazole D 90 ≤65.0μm.

[0029] According to some embodiments of the present invention, the birepiperazole oral film comprises or is mainly composed of the following components:

[0030] 4.0–15.0% biriperazole, 50.0–75.0% hydroxypropyl methylcellulose, 10.0–30.0% glycerin, 5–10% sweetener and 0–0.5% colorant, wherein the biriperazole D 90 ≤65.0μm.

[0031] According to an embodiment of the present invention, the birepiperazole oral film can be selected from any of the following formulations:

[0032] Formula 1: 16.7% biriperazole, 45.0% hydroxypropyl methylcellulose, 16.7% polyvinyl alcohol, 20.8% glycerin and 0.8% sucralose, wherein biriperazole D 90 It is 27.8 μm;

[0033] Formula 2: 13.8% biriperazole, 57.9% hydroxypropyl methylcellulose, 24.1% glycerin, 0.7% steviol glycosides, and 3.5% crospovidone, wherein biriperazole D 90 It is 27.8 μm;

[0034] Formula 3: 23.8% biriperazole, 47.6% polyvinyl alcohol, 23.8% glycerin, 2.4% steviol glycosides and 2.4% fragrance, wherein biriperazole D 90 It is 27.8 μm;

[0035] Formula 4: 4.3% biriperazole, 34.8% polyvinyl alcohol, 21.7% hydroxypropyl cellulose, 6.5% sucralose, 2.2% flavoring, and 30.5% microcrystalline cellulose, wherein biriperazole D... 90 It is 27.8 μm;

[0036] Formula 5: 8.7% biriperazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerin, 4.3% steviol glycosides, 4.3% fragrance, and 0.1% lake; the biriperazole D... 90 It is 9.7 μm;

[0037] Formula 6: 8.7% biriperazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerin, 4.3% steviol glycosides, 4.3% fragrance, and 0.1% lake; the biriperazole D... 90 It is 16.5 μm;

[0038] Formula 7: 8.7% biriperazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerin, 4.3% steviol glycosides, 4.3% fragrance, and 0.1% lake; the biriperazole D... 90 It is 27.8 μm;

[0039] Formula 8: 8.7% biriperazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerin, 4.3% steviol glycosides, 4.3% fragrance, and 0.1% lake; the biriperazole D... 90 It is 35.1 μm;

[0040] Formula Nine: 8.7% biriperazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerin, 4.3% steviol glycosides, 4.3% fragrance, and 0.1% lake; the biriperazole D... 90 It is 45.6 μm;

[0041] Formula 10: 40.0% biriperazole, 50.0% polyvinyl alcohol, 4.0% glycerin, 2.0% titanium dioxide and 4.0% crospovidone, wherein biriperazole D 90 It is 45.6 μm.

[0042] According to an embodiment of the present invention, the thickness of the birepiperazole oral film is 10-100 μm, for example 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm or 90 μm.

[0043] The present invention also provides a method for preparing the aforementioned birepiperazole oral film, which includes the following steps:

[0044] 1) Dissolve one or more of the water-soluble excipients such as plasticizers, sweeteners, disintegrants, fillers, and colorants in purified water, and then add the film-forming material to dissolve it;

[0045] 2) Mix the insoluble excipients in the prescription with the solution obtained in step 1) to obtain a suspension;

[0046] 3) Add the active drug to the solution obtained in step 2) and mix thoroughly;

[0047] 4) Defoam the suspension obtained in step 3) to obtain a defoamed suspension;

[0048] 5) The defoamed suspension obtained in step 4) is coated onto the substrate, dried, and a film is formed to obtain bripiprazole oral film.

[0049] According to an embodiment of the present invention, the mixing in step 2) is preferably homogeneous mixing.

[0050] The present invention also provides the use of the aforementioned birepiperazole oral film in the preparation of medicaments for treating central nervous system diseases.

[0051] According to an embodiment of the present invention, the central nervous system disease may be major depressive disorder or schizophrenia.

[0052] The present invention also provides a method for treating central nervous system diseases, which involves administering a therapeutically effective amount of the aforementioned birepiperazole oral film to a patient in need.

[0053] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0054] The reagents and raw materials used in this invention are all commercially available.

[0055] The beneficial effects of this invention are:

[0056] The birepiperazole oral film of the present invention has at least one of the following advantages:

[0057] It has good dissolution, rapid disintegration, and no gritty feeling after dissolving in the mouth. It has a uniform appearance, good flexibility, and stable properties (e.g., stable chemical properties, stable dissolution, stable mechanical strength, and / or stable folding endurance). At the same time, it does not settle during the preparation of the membrane solution, and the content uniformity meets the requirements.

[0058] Terminology Definitions and Explanations

[0059] The term "multiple" refers to two or more kinds, such as two, three or more kinds.

[0060] The term "mainly composed of..." means that the sum of the masses of these components accounts for not less than 85% of the total mass of the birepiperazole oral film, for example not less than 90%, exemplarily 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0061] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0062] The term "therapeutic effective amount" refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are looking for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. Detailed Implementation

[0063] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0064] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products, or can be prepared by known methods, or selected according to the product instructions.

[0065] Examples 1-10: The prescriptions are shown below (% in the table represents weight percentage).

[0066]

[0067]

[0068] Purified water * As a solvent and wetting agent, it is removed during the process.

[0069] Preparation method:

[0070] 1) Dissolve water-soluble excipients such as plasticizers, sweeteners, and disintegrants in purified water, and then add the film-forming material to dissolve it;

[0071] 2) Mix the insoluble excipients in the prescription with the solution obtained in step 1) to obtain a suspension;

[0072] 3) Add the active ingredient to the solution obtained in step 2) and mix well;

[0073] 4) Defoam the suspension obtained in step 3) to obtain a defoamed suspension;

[0074] 5) The defoamed suspension obtained in step 4) is coated onto the substrate, dried, and a film is formed to obtain bripiprazole oral film.

[0075] Comparative Examples 1-3

[0076] Comparative Example 1 was prepared by repeating Example 4 of the invention patent application CN115192549A; Comparative Example 2 was prepared by replacing the dimethyl silicone oil in Comparative Example 1 with glycerin. The formulations are shown below (% in the table are weight percentages).

[0077]

[0078] Purified water * As a solvent and wetting agent, it is removed during the process.

[0079] During the preparation of Comparative Example 1, it was found that after adding dimethyl silicone oil to the formulation (Comparative Example 1), the drug film would peel off from the substrate on its own during the drying process. Since the small-scale test was carried out by manual cutting, no problem was observed. However, after the formulation was transferred to large equipment, it was found that due to the peeling problem, Comparative Example 1 could not be accurately cut and packaged, which was not conducive to mass production.

[0080] However, in Comparative Example 2, replacing dimethyl silicone oil with glycerin effectively avoided the aforementioned problems.

[0081] The applicant replicated the preparation of Comparative Example 3 in Example 5 of the invention patent CN115192549A: the prescription is as shown above (% in the table is weight percentage), and the prescription was prepared using the process in CN115192549A and the process of the present invention.

[0082] The results showed that in CN115192549A, bripiprazole and the film-forming material dissolved simultaneously. When the bripiprazole particle size was too large, film formation occurred during the dissolution of the film-forming material, causing bripiprazole to be trapped in the film-forming matrix, which was not conducive to dispersion. 90When the particle size is >30 μm, the uniformity of the adhesive mixture is poor. However, this invention optimizes the process by first dissolving the film-forming material and then adding bripiprazole. Under the action of a high-speed shear press, bripiprazole can be well dispersed, thus achieving a higher concentration of bripiprazole D. 90 Even at a size greater than 30 μm, qualified finished products can still be prepared.

[0083] Test case

[0084] Content detection method: Octadecylsilane-bonded silica gel was used as the packing material; phosphate buffer-acetonitrile (70:30) was used as the mobile phase; the flow rate was 1.0 ml per minute; the column temperature was 40℃; the detection wavelength was 275 nm; the injection volume was 10 μl; and the run time was 10 minutes.

[0085] Related substances test method: Octadecylsilane-bonded silica gel was used as the packing material; phosphate buffer was used as mobile phase A; phosphate buffer-acetonitrile (35:65) was used as mobile phase B; gradient elution was performed, the detection wavelength was 275 nm; the flow rate was 1.0 ml per minute; the column temperature was 40 ℃; and the injection volume was 50 μl.

[0086] Dissolution test methods other than those in Table 3: use 900 ml of pH 4.3 acetate buffer containing 0.1% polysorbate 20 as the dissolution medium; rotate at 50 rpm; take samples after 30 minutes.

[0087] Mechanical strength testing: A texture analyzer (model: R birepiperazole d TA) was used. + (Manufacturer: Shanghai Tengba Instrument Technology Co., Ltd.) Mechanical strength test was conducted on the biriperazole oral dissolving film formulation;

[0088] After powering on, install the tensile testing module, perform force calibration and height calibration, and set the height to 2mm;

[0089] The thickness and width of the oral solution membrane were measured using a thickness gauge and a ruler, and the cross-sectional area of ​​the oral solution membrane (mm²) was calculated. 2 );

[0090] After the thickness and width of the oral slurry membrane have been measured, fix it on the texture analyzer, making the cross-section to be measured perpendicular to the stretching direction of the equipment, and record the maximum force and sample height.

[0091] Tensile strength (MPa) = maximum force (gf) ÷ 10² ÷ cross-sectional area (mm²) 2 );

[0092] Percentage elongation = maximum force distance (mm) ÷ sample height (mm) × 100%.

[0093] Folding endurance: the number of times a folded membrane breaks or shows obvious creases after being folded in the same position; specifically, fold it 180° along the middle of the oral fusion membrane, unfold it, and then repeat the folding to observe whether the oral fusion membrane breaks.

[0094] Buripiperazole oral films were prepared according to Examples 1-10 and Comparative Examples 2 and 3. The properties, content, content uniformity, related substances, dissolution rate, dissolution curve, mechanical properties and disintegration time of the buripiperazole oral films were tested.

[0095] Table 1. Results of tests on the properties, content, content uniformity, and dissolution of birepiperazole oral film.

[0096]

[0097]

[0098] Based on the above results, biriperazole oral film formulation in D 90 When the particle size is ≤70.0μm, oral film preparations with good properties and content uniformity can be obtained, and the content and dissolution rate meet the requirements.

[0099] 1. Related substances test for birepiperazole oral film

[0100] Table 2. Related substances test results for birepiperazole oral film.

[0101]

[0102] Based on the above results, the related substances of the birepiperazole oral film prepared in Examples 1-10 meet the requirements.

[0103] 2. Dissolution curve test of biriperazole oral film.

[0104] Dissolution method: According to the Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0931, Method II—Paddle method, add a settling basket: 50 rpm, 900 ml dissolution medium, and temperature of 37℃.

[0105] Table 3. Dissolution curve analysis of birepiperazole oral film.

[0106]

[0107] Data show that the dissolution curves of the birepiperazole oral film formulations in Examples 1-10 are not significantly different from those of the control drug (trade name: REXULTI).

[0108] 3. Mechanical strength test of biriperazole oral film

[0109] The mechanical strength test results of the birepiperazole orally disintegrating film formulation are shown in Table 4.

[0110] Table 4 Mechanical strength test results of birepiperazole orally dissolving films prepared in Examples 1-10 and Comparative Example 2

[0111]

[0112]

[0113]

[0114] Data shows that the bripiprazole orally soluble films prepared in Examples 1-10 of this invention have good tensile strength, while the films in Comparative Example 2 have poor tensile strength and are brittle.

[0115] 4. Disintegration time test of biriperazole oral film

[0116] The disintegration time of the birepiperazole oral film prepared in the embodiments of the present invention and Comparative Example 2 was determined by the following specific methods:

[0117] Six medicated films obtained from each example were randomly selected. One film was taken each time and gently placed in a petri dish with a diameter of about 8 cm containing 20 ml of artificial saliva at 37±1℃. The time for complete disintegration was observed under static conditions. The results are shown in Table 5.

[0118] Table 5. Average Disintegration Time Test Table for Examples 1-10 and Comparative Example 2

[0119]

[0120]

[0121] Based on the above results, the oral film formulations of the embodiments and comparative examples of the present invention can rapidly disintegrate in a short period of time.

[0122] 5. Stability test of biriperazole oral film

[0123] Biriperazole oral films were prepared according to Example 7, and cut to 1 mg and 2 mg specifications respectively. After packaging in polyester / aluminum / polyethylene pharmaceutical composite film bags, the stability of the biriperazole oral film was investigated under long-term test (25℃±2℃ / 40%RH±5%RH) and accelerated test (40℃±2℃ / 75%RH±5%RH) conditions. The results are as follows:

[0124] (1) Results of related substance testing

[0125]

[0126] (2) Dissolution test results

[0127] Specification 0 days Accelerate June Long-term June 1mg 97％ 92％ 94％ 2mg 90％ 90％ 88％

[0128] (3) Content detection results

[0129] Specification 0 days Accelerate June Long-term June 1mg 99.7％ 99.7％ 99.4％ 2mg 99.2％ 99.4％ 99.1％

[0130] (4) Mechanical strength test results

[0131]

[0132]

[0133] (5) Results of flexural endurance test

[0134]

[0135]

[0136] Based on the above experimental data, it can be seen that the birepiperazole oral disintegrating film composition provided by the present invention has the advantages of thin thickness, rapid disintegration, stable properties, good mechanical properties, and instantaneous dissolution in the oral cavity without the need for drinking water, and rapid oral absorption.

[0137] This invention overcomes the shortcomings of existing technologies, such as the requirement that ibuprofen tablets must disintegrate in the stomach before releasing the drug, resulting in slow onset of action, limited bioavailability, inconvenience of administration, and poor patient compliance. It provides an ibuprofen oral film formulation, its preparation method, and its application. This ibuprofen oral film formulation has the advantages of being thin, having a good taste, stable properties, and dissolving instantly in the mouth without the need for water, resulting in rapid oral absorption. Furthermore, it features a simple process, high drug loading capacity, and good drug content uniformity, solving the problems of poor medication compliance, drug stagnation, and vomiting in schizophrenia patients. It is particularly suitable for patients with swallowing difficulties.

[0138] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An ibuprofen oral film, characterized in that, The birepiperazole oral film is prepared from the following components: 4.0~15.0% biriperazole, 50.0~75.0% hydroxypropyl methylcellulose, 10.0~30.0% glycerin, 5~10% sweetener, 0~0.5% colorant, 0~10.0% disintegrant, and 0~60.0% filler; the mass percentage refers to the percentage of each component's mass to the total mass of the biriperazole oral film. The aforementioned irapiazole D 90 ≤65.0μm.

2. The birepiperazole oral film as described in claim 1, characterized in that: The active drug particle size D 90 ≤50.0μm.

3. The birepiperazole oral film as described in claim 1, characterized in that: The hydroxypropyl methylcellulose has a mass percentage content of 50.0% to 70.0%.

4. The birepiperazole oral film as described in claim 1, characterized in that: The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, crospovidone sodium carboxymethyl starch and starch; And / or, The filler is selected from one or more of microcrystalline cellulose, pregelatinized starch, mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol and dextrin.

5. The birepiperazole oral film as described in claim 1, characterized in that: The birepiperazole oral film is selected from any of the following formulations: Formula 2: 13.8% biriperazole, 57.9% hydroxypropyl methylcellulose, 24.1% glycerin, 0.7% steviol glycosides, and 3.5% crospovidone, wherein biriperazole D... 90 It is 27.8 μm; Formula 5: 8.7% biriperazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerin, 4.3% steviol glycosides, 4.3% fragrance, and 0.1% lake; the biriperazole D... 90 It is 9.7 μm; Formula 6: 8.7% biriperazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerin, 4.3% steviol glycosides, 4.3% fragrance, and 0.1% lake; the biriperazole D... 90 It is 16.5 μm; Formula 7: 8.7% biriperazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerin, 4.3% steviol glycosides, 4.3% fragrance, and 0.1% lake; the biriperazole D... 90 It is 27.8 μm; Formula 8: 8.7% biriperazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerin, 4.3% steviol glycosides, 4.3% fragrance, and 0.1% lake; the biriperazole D... 90 It is 35.1 μm; Formula Nine: 8.7% biriperazole, 65.2% hydroxypropyl methylcellulose, 17.4% glycerin, 4.3% steviol glycosides, 4.3% fragrance, and 0.1% lake; the biriperazole D... 90 It is 45.6 μm.

6. The birepiperazole oral film as described in claim 1, characterized in that: The active drug has a particle size of 30.0 μm < D 90 ≤65.0μm.

7. The birepiperazole oral film as described in claim 1, characterized in that, The birepiperazole oral film is prepared by a method comprising the following steps: 1) Dissolve one or more of the water-soluble excipients such as glycerin, sweetener, disintegrant, filler, and colorant in purified water, and then add hydroxypropyl methylcellulose to dissolve it. 2) Mix the insoluble excipients in the prescription with the solution obtained in step 1) to obtain a suspension; 3) Add the active drug to the solution obtained in step 2) and mix thoroughly; 4) Defoam the suspension obtained in step 3) to obtain a defoamed suspension; 5) The defoamed suspension obtained in step 4) is coated onto the substrate, dried, and a film is formed to obtain bripiprazole oral film.

8. A birepiperazole oral film, characterized in that, The birepiperazole oral film is selected from any of the following formulations: Formula 1: 16.7% biriperazole, 45.0% hydroxypropyl methylcellulose, 16.7% polyvinyl alcohol, 20.8% glycerin, and 0.8% sucralose, wherein biriperazole D... 90 It is 27.8 μm; Formula 3: 23.8% biriperazole, 47.6% polyvinyl alcohol, 23.8% glycerin, 2.4% steviol glycosides, and 2.4% fragrance, wherein biriperazole D... 90 It is 27.8 μm; Formula 4: 4.3% biriperazole, 34.8% polyvinyl alcohol, 21.7% hydroxypropyl cellulose, 6.5% sucralose, 2.2% flavoring, and 30.5% microcrystalline cellulose, wherein the biriperazole D... 90 It is 27.8 μm; Formula 10: 40.0% biriperazole, 50.0% polyvinyl alcohol, 4.0% glycerin, 2.0% titanium dioxide, and 4.0% crospovidone, wherein the biriperazole D... 90 It is 45.6 μm.

9. The method for preparing the birepiperazole oral film as described in any one of claims 1 to 6, characterized in that, The preparation method includes the following steps: 1) Dissolve one or more of the water-soluble excipients such as glycerin, sweetener, disintegrant, filler, and colorant in purified water, and then add hydroxypropyl methylcellulose to dissolve it. 2) Mix the insoluble excipients in the prescription with the solution obtained in step 1) to obtain a suspension; 3) Add the active drug to the solution obtained in step 2) and mix thoroughly; 4) Defoam the suspension obtained in step 3) to obtain a defoamed suspension; 5) The defoamed suspension obtained in step 4) is coated onto the substrate, dried, and a film is formed to obtain bripiprazole oral film.

10. The method for preparing the birepiperazole oral film as described in claim 8, characterized in that, The preparation method includes the following steps: 1) Dissolve one or more of the water-soluble excipients such as plasticizers, sweeteners, disintegrants, fillers, and colorants in purified water, and then add the film-forming material to dissolve it; The plasticizer is glycerin, the filler is microcrystalline cellulose, and the film-forming material is hydroxypropyl methylcellulose and / or polyvinyl alcohol; 2) Mix the insoluble excipients in the prescription with the solution obtained in step 1) to obtain a suspension; 3) Add the active drug to the solution obtained in step 2) and mix thoroughly; 4) Defoam the suspension obtained in step 3) to obtain a defoamed suspension; 5) The defoamed suspension obtained in step 4) is coated onto the substrate, dried, and a film is formed to obtain bripiprazole oral film.

11. The use of the birepiperazole oral film formulation according to any one of claims 1 to 8 in the preparation of a medicament for treating central nervous system diseases.

12. The application as described in claim 11, characterized in that: The central nervous system disease mentioned is major depressive disorder or schizophrenia.

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