Lurasidone hydrochloride oral film composition, preparation method and use thereof

Abstract

The present disclosure discloses a lurasidone hydrochloride oral film composition, preparation method and use thereof. The present disclosure discloses the lurasidone hydrochloride oral film composition including an active pharmaceutical, a film-forming material, a plasticizer and a flavoring agent, wherein the active pharmaceutical is (3aR,4S,7R,7aS)-2-((1R,2R)-2-[4-(1.2-benzisothiazol3-yl)piperazine-1-methyl]cyclohexylmethyl)hexahydro-4.7-methylene-2H-isoindole-1,3-dione hydrochloride denoted by the following formula I. The lurasidone hydrochloride oral film composition of the present disclosure has a good dissolution rate, a uniform appearance, a good flexibility, and a uniformity content meeting the requirement. Moreover, during the preparation process of the film liquid of the composition, sedimentation of the film will not occur. After the composition is dissolved in the user’s mouth, the user does not have any gritty feeling.

Description

[Technical Field]

[0001] This invention relates to the field of pharmaceutical preparations, specifically to a simple-to-prepare, stable orally disintegrating film composition of lurasidone hydrochloride, its preparation method and uses. [Previous Technology]

[0002] This invention claims priority to the prior application filed on November 4, 2021, with China National Intellectual Property Administration, patent application number 202111301406.X, entitled "A Lurasidone Hydrochloride Oral Dissolving Film Composition, Its Preparation Method and Application". The entire contents of the prior application are incorporated herein by reference.

[0003] Schizophrenia is a serious mental disorder. According to the World Health Organization, more than 21 million people worldwide suffer from schizophrenia, and it is the eighth leading cause of disability among people aged 15 to 44. As of the end of 2016, the number of registered schizophrenia patients in China was approximately 4.05 million. Existing medications for schizophrenia can be broadly divided into two categories: typical antipsychotics, also known as first-generation antipsychotics; and atypical antipsychotics, which generally have dopamine D2 / 5-HT2A receptor antagonistic effects, also known as second-generation antipsychotics. Since 2010, the market size of psychotropic drugs in sample hospitals in China has grown from 1.25 billion yuan to 2.47 billion yuan in 2015, with a compound annual growth rate of 14.6% over five years. Given that the pathogenesis of schizophrenia is not fully understood, the limitations of existing treatments, and adverse reactions, there is a clinical need for medications with better efficacy and fewer adverse reactions. The lack of psychiatric medical resources in China indicates a huge potential market for psychotropic drugs. However, during the acute phase of schizophrenia, patients often refuse medication, hide medication in their mouths, or spit it out, resulting in widespread medication adherence problems. Therefore, tablets and capsules are often ineffective for these patients, and easier-to-use formulations should be considered for schizophrenia. In light of this, it is necessary to provide a new formulation that is convenient to use, has good compliance, and stable quality to address the aforementioned issues.

[0004] Lurasidone hydrochloride is a novel atypical antipsychotic drug jointly developed by Takeda Pharmaceutical and Sumitomo Pharmaceutical for the treatment of schizophrenia and bipolar depression. Currently, the clinical dosage form is a regular tablet. However, regular tablets are difficult to swallow, making them unsuitable for children and elderly patients, and also inconvenient to take without water.

[0005] Therefore, there is a need to develop a dosage form of lurasidone hydrochloride to address the problem of poor patient compliance, especially suitable for patients with dysphagia, so as to improve patient compliance. [Summary of the Invention]

[0006] This invention provides a lurasidone hydrochloride orally dissolving film composition comprising an active pharmaceutical ingredient, a film-forming material, a plasticizer, and a flavoring agent. The active pharmaceutical ingredient is a compound as shown in Formula I, namely (3aR,4S,7R,7aS)-2-((1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazine-1-methyl]cyclohexylmethyl)hexahydro-4,7-methylene-2H-isoindole-1,3-dione hydrochloride (lurasidone hydrochloride); Formula I

[0007] According to an embodiment of the present invention, the weight percentage of the active drug is preferably 1% to 60%, such as 10% to 55%, or 10% to 50%, such as 52.1%, 47.2%, 41.7%, 41.3%, 38.5%, 35.7%, 33.3%, 30.0% or 25.0%, where the weight percentage refers to the percentage of the weight of the active drug to the total weight of the lurasidone hydrochloride orally disintegrating film composition.

[0008] According to embodiments of the present invention, the film-forming material is a drug carrier, preferably one or more of xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hydroxypropyl methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene, pullulan, acrylic acid copolymer, polylactic acid, and silicone rubber. In some embodiments, the film-forming material is polyvinyl alcohol, hydroxypropylcellulose, a mixture of polyvinyl alcohol and polyethylene glycol 6000, or a mixture of hydroxyethylcellulose and pullulan.

[0009] According to an embodiment of the present invention, the weight percentage of the film-forming material is 20% to 60%, for example 30% to 50%, such as 57.0%, 50.0%, 47.0%, 45.8%, 41.7%, 41.3%, 38.5%, 37.7%, 35.7%, 33.0% or 31.2%, where the weight percentage refers to the percentage of the weight of the film-forming material to the total weight of the lurasidone hydrochloride orally dissolving film composition.

[0010] According to an embodiment of the present invention, the plasticizer is used to lower the glass transition temperature of the film, increase plasticity and toughness, and improve elongation, and is preferably one or more of polyethylene glycol, glycerin, propylene glycol, silicone oil, polypropylene glycol, and hexanediol.

[0011] According to an embodiment of the present invention, the plasticizer has a weight percentage of 0 to 20%, for example 16.0%, 9.4%, 8.3%, 5.2%, 5.0%, 4.7%, 4.5%, 4.3% or 0, wherein the weight percentage refers to the percentage of the weight of the plasticizer to the total weight of the lurasidone hydrochloride oral dissolving film composition.

[0012] According to an embodiment of the present invention, the flavoring agent plays a flavoring role in the film agent, and is preferably one or more of aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, flavoring, fragrance, menthol, sodium chloride, citric acid, saccharin and sodium saccharin.

[0013] According to an embodiment of the present invention, the weight percentage of the flavoring agent is 0-25.0%, preferably 3.0%-25.0%, for example 17.7%, 17.1%, 16.4%, 12.5%, 10.4%, 10.0%, 9.5%, 9.4%, 8.3%, 5.0% or 3.0%, wherein the weight percentage refers to the percentage of the weight of the flavoring agent to the total weight of the lurasidone hydrochloride oral dissolving film composition.

[0014] According to an embodiment of the present invention, the lurasidone hydrochloride orally disintegrating film composition may further include a disintegrant, or a combination of a disintegrant with one or more of a saliva stimulant, a filler, a colorant, an anti-adhesion agent and an antibacterial agent.

[0015] According to an embodiment of the present invention, the disintegrant refers to an excipient that causes the drug to rapidly disintegrate into small particles in the gastrointestinal tract, preferably one or more of low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, starch, microcrystalline cellulose and pregelatinized starch.

[0016] According to an embodiment of the present invention, the weight percentage of the disintegrant is preferably 0 to 10.0%, for example 3.6%, 6.9%, 7.0% or 7.1%, wherein the weight percentage refers to the percentage of the weight of the disintegrant relative to the total weight of the lurasidone hydrochloride oral disintegrating film composition.

[0017] According to an embodiment of the present invention, the saliva stimulant refers to a substance that stimulates saliva production, preferably one or more of tartaric acid, malic acid and mannitol.

[0018] According to an embodiment of the present invention, the weight percentage of the saliva stimulant is 0 to 10.0%, for example 0.6%, 0.9%, 6.9%, 7.0%, 7.1% or 7.7%, wherein the weight percentage refers to the percentage of the weight of the saliva stimulant to the total weight of the lurasidone hydrochloride oral disintegrating film composition.

[0019] According to an embodiment of the present invention, the filler refers to a solid substance that can be added to the material to improve the material performance, or to increase volume and weight, and reduce the cost of the material. It is preferably one or more of mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose.

[0020] According to an embodiment of the present invention, the filler has a weight percentage of 0 to 10.0%, for example 6.0% or 3.0%, wherein the weight percentage refers to the percentage of the weight of the filler relative to the total weight of the lurasidone hydrochloride oral dissolving film composition.

[0021] According to an embodiment of the present invention, the coloring agent 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, preferably one or more of titanium dioxide, pigments, and lakes.

[0022] According to an embodiment of the present invention, the weight percentage of the colorant is 0 to 5.0%, for example 1.1%, 1.0% or 0.8%, wherein the weight percentage refers to the percentage of the weight of the colorant to the total weight of the lurasidone hydrochloride oral dissolving film composition.

[0023] According to an embodiment of the present invention, the anti-adhesion agent refers to an agent that can improve the performance of the formulation and prevent adhesion between formulations, and is preferably one or more of talc, magnesium stearate, and calcium stearate.

[0024] According to an embodiment of the present invention, the weight percentage of the anti-adhesion agent is 0 to 5.0%, for example 0.7% or 0.8%, wherein the weight percentage refers to the percentage of the weight of the anti-adhesion agent to the total weight of the lurasidone hydrochloride oral dissolving film composition.

[0025] According to an embodiment of the present invention, the antibacterial agent refers to a substance capable of inhibiting bacterial growth, preferably one or more of methylparaben, ethylparaben, and sodium thiosulfate.

[0026] According to an embodiment of the present invention, the weight percentage of the antibacterial agent is 0 to 1.0%, for example 0.6%, and the weight percentage refers to the percentage of the weight of the antibacterial agent to the total weight of the lurasidone hydrochloride oral disintegrating film composition.

[0027] According to an embodiment of the present invention, the lurasidone hydrochloride orally disintegrating film composition can be any of the following formulations:

[0028] Formula 1: 47.2% lurasidone hydrochloride, 33.0% hydroxypropyl cellulose, 9.4% glycerin, 9.4% sucralose and 1.0% titanium dioxide;

[0029] Formula 2: 30.0% lurasidone hydrochloride, 45.0% polyvinyl alcohol, 12.0% polyethylene glycol 6000, 5.0% sucralose, 3.5% menthol, 0.9% mannitol, 3.0% lactose and 0.6% methylparaben;

[0030] Formula 3: 33.3% lurasidone hydrochloride, 45.8% polyvinyl alcohol, 8.3% glycerin, 3.3% sodium chloride, 4.2% citric acid, 4.3% sucralose, 0.4% flavoring and 0.4% menthol;

[0031] Formula 4: 25.0% lurasidone hydrochloride, 50.0% polyvinyl alcohol, 16.0% glycerin, 2.5% steviol glycosides, 0.5% flavoring and 6.0% lactose;

[0032] Formula 5: 41.3% lurasidone hydrochloride, 24.8% hydroxyethyl cellulose, 16.5% pullulan, 8.3% glycerol, 8.3% sucralose and 0.8% titanium dioxide;

[0033] Formula 6: 47.2% lurasidone hydrochloride, 28.3% hydroxyethyl cellulose, 9.4% pullulan, 4.7% glycerol, 9.4% sucralose and 1.0% titanium dioxide;

[0034] Formula 7: 52.1% lurasidone hydrochloride, 20.8% hydroxyethyl cellulose, 10.4% pullulan, 5.2% glycerol, 10.4% sucralose and 1.1% titanium dioxide;

[0035] Formula 8: 41.7% lurasidone hydrochloride, 25.0% hydroxyethyl cellulose, 16.7% pullulan, 5.0% glycerin, 8.3% sucralose, 1.7% menthol, 0.8% talc and 0.8% titanium dioxide;

[0036] Formula 9: 38.5% lurasidone hydrochloride, 23.1% hydroxyethyl cellulose, 15.4% pullulan, 4.5% glycerin, 7.7% sucralose, 1.5% menthol, 0.8% flavoring, 7.7% citric acid and 0.8% talc;

[0037] Formula 10: 35.7% lurasidone hydrochloride, 21.4% hydroxyethyl cellulose, 14.3% pullulan, 4.3% glycerin, 7.1% sodium carboxymethyl starch, 7.1% sucralose, 1.4% menthol, 0.8% flavoring, 7.1% citric acid and 0.8% talc.

[0038] The present invention also provides a method for preparing the above-mentioned lurasidone hydrochloride oral dissolving film composition, which includes the following steps:

[0039] 1) The film-forming material is heated and dissolved in water at 60℃~70℃ to form a solution;

[0040] 2) Add all components except the active drug and film-forming material to the solution obtained in step 1), stir evenly to obtain a blank gel solution;

[0041] 3) Place the active drug in the blank gel solution obtained in step 2), stir until it is evenly dispersed, and stir under vacuum to remove bubbles to obtain drug-containing gel;

[0042] 4) The drug-containing adhesive is evenly coated onto the release film using a coating machine, heated, dried, and cut to obtain the lurasidone hydrochloride oral dissolving film composition.

[0043] According to an embodiment of the present invention, the thickness of the lurasidone hydrochloride orally dissolving film composition is 10 μm to 300 μm, for example, 10 μm to 300 μm.

[0044] According to an embodiment of the present invention, the lurasidone hydrochloride oral disintegrating film composition can completely disintegrate within 2 minutes in 1000 mL of simulated saliva at 37℃±1℃.

[0045] The present invention also provides the use of the described lurasidone hydrochloride oral disintegrating film composition in the preparation of medicaments for the treatment and / or prevention of depression.

[0046] The present invention also provides a method for treating and / or preventing depression, which involves administering a therapeutically effective amount of the said lurasidone hydrochloride oral dissolving film composition to a patient in need.

[0047] According to an embodiment of the present invention, the lurasidone hydrochloride oral dissolving film composition is a pharmaceutical preparation.

[0048] The beneficial effects of the present invention: The lurasidone hydrochloride oral dissolving film composition of the present invention has the advantages of thin thickness, good taste, stable properties, good dissolution rate, and immediate dissolution in the oral cavity without the need for drinking water, without a gritty feeling after dissolving in the oral cavity, and rapid oral absorption. It also has a uniform appearance, good flexibility, and is simple to prepare. No sedimentation occurs during the preparation of the film solution, the content uniformity meets the requirements, and the drug loading capacity is high. It solves the defects of existing formulations such as inconvenience in administration and poor patient compliance, and is particularly suitable for patients with dysphagia.

[0049] Term Definitions and Explanations

[0050] Unless otherwise stated, the definitions of terms recorded in this application specification and the claims of the invention application, including definitions as examples, exemplary definitions, preferred definitions, and specific definitions in embodiments, can be arbitrarily combined and combined with each other. Such combinations and combinations shall fall within the scope of this application specification.

[0051] The term "therapeutic effective amount" refers to the amount of the active pharmaceutical ingredient of the present invention sufficient to achieve the intended application (including, but not limited to, the treatment of diseases as defined below). The therapeutic effective amount may vary depending on factors such as the intended application (in vitro or in vivo), or the subject being treated and the condition of the disease, such as the subject's weight and age, the severity of the disease, and the route of administration, which can be readily determined by those skilled in the art. The specific dosage will vary depending on factors such as the specific active ingredient selected, the administration regimen, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system on which it is delivered.

Implementation Method

[0053] Detailed Implementation

[0054] 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 only 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.

[0055] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods. Experimental methods in the following examples that do not specify specific conditions were performed according to conventional methods and conditions, or according to the product instructions.

[0056] Example 1

[0057] The formula is shown in Table 1:

[0058] Table 1 Example Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 raw materials Lurasidone Hydrochloride 5 g (47.2%) 5.1 g (30.0%) 5 g (33.3%) 5 g (25.0%) 5 g (41.3%) 5 g (47.2%) 5 g (52.1%) 5 g (41.7%) 5 g (38.5%) 5 g (35.7%) Film-forming materials Polyvinyl alcohol / 7.7 g (45.0%) 6.88 g (45.8%) 10 g (50.0%) / / / / / / Hydroxyethyl cellulose / / / / 3 g (24.8%) 3 g (28.3%) 2 g (20.8%) 3 g (25%) 3 g (23.1%) 3 g (21.4%) Hydroxypropyl cellulose 3.5 g (33.0%) / / / / / / / / / pullulan / / / / 2 g (16.5%) 1 g (9.4%) 1 g (10.4%) 2 g (16.7%) 2 g (15.4%) 2 g (14.3%) Polyethylene glycol 6000 / 2 g (12.0%) / / / / / / / / plasticizer glycerin 1 g (9.4%) / 1.25 g (8.3%) 3.2 g (16%) 1 g (8.3%) 0.5 g (4.7%) 0.5 g (5.2%) 0.6 g (5.0%) 0.6 g (4.5%) 0.6 g (4.3%) Disintegrant Sodium carboxymethyl starch / / / / / / / / / 1 g (7.1%) Flavorings Sucralose 1 g (9.4%) 0.9 g (5.0%) 0.63 g (4.3%) / 1 g (8.3%) 1 g (9.4%) 1 g (10.4%) 1 g (8.3%) 1 g (7.7%) 1 g (7.1%) Steviosides / / / 0.5 g (2.5%) / / / / / / Sodium chloride / / 0.5 g (3.3%) / / / / / / / Menthol / 0.6 g (3.5%) 0.06 g (0.4%) / / / / 0.2 g (1.7%) 0.2 g (1.5%) 0.2 g (1.4%) essence / / 0.06 g (0.4%) 0.1 g (0.5%) / / / / 0.1 g (0.8%) 0.1 g (0.8%) Citric acid / / 0.63 g (4.2%) / / / / / 1 g (7.7%) 1 g (7.1%) Anti-adhesive talcum powder / / / / / / / 0.1 g (0.8%) 0.1 g (0.8%) 0.1 g (0.8%) Disintegrant Sodium carboxymethyl starch / / / / / / / / / / Saliva stimulants Mannitol / 0.2 g (0.9%) / / / / / / / / filler lactose / 0.5 g (3.0%) / 1.2 g (6.0%) / / / / / / Colorant Titanium dioxide 0.1 g (1.0%) / / / 0.1 g (0.8%) 0.1 g (1.0%) 0.1 g (1.1%) 0.1 g (0.8%) / / antibacterial agent Methylparaben / 0.1 g (0.6%) / / / / / / / / Purified water* 170 230 200 280 160 150 150 170 170 160 / Total weight** 10.6 g 17.1 g 15.0 g 20.1 g 12.1 g 10.6 g 9.6 g 12.0 g 13.0 g 14.0 g * indicates removal during the preparation process; ** indicates the weight of raw materials and auxiliary materials after water removal; Percentage of each component = weight of each component / (total weight**) × 100%.

[0059] Preparation method:

[0060] 1) The film-forming material is heated and dissolved in water at 60℃~70℃ to form a solution;

[0061] 2) Add all components except the active drug and film-forming material to the solution obtained in step 1), stir evenly to obtain a blank gel solution;

[0062] 3) Place the active drug in the blank gel solution obtained in step 2), stir until it is evenly dispersed, and stir under vacuum to remove bubbles to obtain drug-containing gel;

[0063] 4) The drug-containing adhesive solution obtained in step 3) after degassing is evenly coated onto the release film using a coating machine, heated, dried and cut to obtain the lurasidone hydrochloride oral dissolving film composition.

[0064] 1. Disintegration Time Test

[0065] Lurasidone orally disintegrating film formulations were prepared according to the formulations of Examples 1 to 10 using the preparation method provided by the present invention, and their disintegration time was determined. The specific determination method is as follows:

[0066] Take 6 tablets of the medicated film obtained from each example, take 1 tablet each time, gently place it in 1000 ml of artificial saliva at 37℃±1℃, and observe the time for complete disintegration of the product under static conditions. The results are shown in Table 2.

[0067] Table 2 Example Disintegration time (s) 1 47±9 2 51±12 3 63±6 4 53±4 5 67±15 6 49±9 7 44±6 8 52±5 9 54±8 10 27±9

[0068] 2. Determination of dissolution results

[0069] The dissolution curve of the orally dissolving film formulation of lurasidone hydrochloride prepared according to the formulation of Example 3 was determined. The specific determination method is as follows:

[0070] Test media: 900 ml pH 1.2 hydrochloric acid solution (37℃±0.5℃), 900 ml pH 3.8 acetate buffer solution (37℃±0.5℃).

[0071] Dissolution method: Chinese Pharmacopoeia 2020 Edition 0931 Dissolution and Release Determination Method II (Paddle Method), rotation speed 50 rpm.

[0072] Sampling time: 5 min, 10 min, 15 min, 20 min, 30 min.

[0073] Take 6 tablets of lurasidone hydrochloride oral dissolving film preparation and determine the dissolution curve according to the above method. The results are shown in Table 3 and Figures 1-2.

[0074] Table 3 Medium conditions Sampling time 5 min 10 min 15 min 20 min 30 min pH 1.2 hydrochloric acid solution Cumulative dissolution 86.0% 93.7% 94.9% 96.4% 96.6% Relative Standard Deviation (RSD) 2.70% 2.46% 2.51% 2.45% 2.42% Medium conditions Sampling time 5 min 10 min 15 min 20 min 30 min pH 3.8 acetate buffer solution Cumulative dissolution 81.4% 88.6% 90.3% 91.4% 92.9% Relative standard deviation (RSD) 4.96% 2.87% 2.45% 2.45% 2.60%

[0075] 3. Results related to substances

[0076] The relevant substance detection method for the lurasidone hydrochloride oral dissolving membrane prepared according to the formulation of Example 3 is as follows:

[0077] 3.1 Description of related substance analysis methods

[0078] (1) Chromatographic conditions instrument High-performance liquid chromatograph equipped with ultraviolet detector chromatographic column Inertsil ODS 3V 4.6 mm × 250 mm, 5 μm Mobile phase A 2.72 g / L potassium dihydrogen phosphate buffer (dissolve 2.72 g of potassium dihydrogen phosphate in 1000 ml of ultrapure water, add 2 ml of triethylamine, and adjust the pH to 3.0 with phosphate) - methanol (95∶5) Mobile phase B 2.72 g / L potassium dihydrogen phosphate buffer (dissolve 2.72 g of potassium dihydrogen phosphate in 1000 ml of ultrapure water, add 2 ml of triethylamine, and adjust the pH to 3.0 with phosphoric acid) - methanol (20:80) Column temperature 35℃ Flow rate 0.8 ml / min Detection wavelength 230 nm diluent Acetonitrile-water (6:4) Injection volume 10 μl elution gradient

[0079] (2) Calculation

[0080] Impurities IM-2 and IM-4 are calculated using the principal component external standard method with correction factors; unknown impurities are calculated using the principal component external standard method without correction factors, and the total impurities are the sum of all known impurities and unknown impurities.

[0081] (3) Impurity limits

[0082] name IM-4 IM-2 Unknown single impurity Total impurities limit(%) 0.25 0.25 0.2 0.4

[0083] The results of the detection of related substances in the sample of Example 3 are shown in Table 4.

[0084] Table 4 Sample Information Largest unknown single impurity Total impurities Lurasidone hydrochloride oral dissolving film 0.05% 0.06%

[0085] Based on the above experimental data, the oral dissolving film composition of lurasidone hydrochloride provided by the present invention has the advantages of thin thickness, good taste, stable properties, low impurity content, and can be dissolved in the oral cavity without drinking water and has a fast oral absorption rate.

[0086] 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. [Simplified Explanation of the Diagram]

[0052] Figure 1 shows the dissolution curve of the oral film-dissolving formulation of lurasidone hydrochloride in Example 3 in hydrochloric acid solution at pH 1.2. Figure 2 shows the dissolution curve of the oral film-dissolving formulation of lurasidone hydrochloride in Example 3 in acetate buffer solution at pH 3.8.

Claims

1. A lurasidone hydrochloride orally dissolving film composition, wherein, The composition comprises: an active pharmaceutical ingredient, a film-forming material, a plasticizer, and a flavoring agent, wherein the active pharmaceutical ingredient is a compound as shown in Formula I, namely (3aR,4S,7R,7aS)-2-((1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazine-1-methyl]cyclohexylmethyl)hexahydro-4,7-methylene-2H-isoindole-1,3-dione hydrochloride of Formula I.

2. The lurasidone hydrochloride orally dissolving film composition as claimed in claim 1, wherein, The active pharmaceutical ingredient has a weight percentage of 1% to 60%, which refers to the percentage of the weight of the active pharmaceutical ingredient relative to the total weight of the lurasidone hydrochloride orally disintegrating film composition.

3. The lurasidone hydrochloride orally dissolving film composition as claimed in claim 1 or 2, wherein, The film-forming material is one or more of xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hydroxypropyl methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene, pullulan, acrylic acid copolymer, polylactic acid, and silicone rubber; and / or, the plasticizer is one or more of polyethylene glycol, glycerin, propylene glycol, silicone oil, polypropylene glycol, and hexanediol; and / or, the flavoring agent is one or more of aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, flavoring, fragrance, menthol, sodium chloride, citric acid, saccharin, and sodium saccharin.

4. The lurasidone hydrochloride orally dissolving film composition as described in any one of claims 1 to 3, wherein, The film-forming material has a weight percentage of 20% to 60%, which refers to the percentage of the quality of the film-forming material relative to the total weight of the lurasidone hydrochloride oral dissolving film composition; and / or, the plasticizer has a weight percentage of 0% to 20%, which refers to the percentage of the weight of the plasticizer relative to the total weight of the lurasidone hydrochloride oral dissolving film composition; the flavoring agent has a weight percentage of 0% to 25.0%, which refers to the percentage of the weight of the flavoring agent relative to the total weight of the lurasidone hydrochloride oral dissolving film composition.

5. The lurasidone hydrochloride orally dissolving film composition as described in any one of claims 1 to 4, wherein, The lurasidone hydrochloride orally disintegrating film composition further includes a disintegrant, or a combination of a disintegrant with one or more of a saliva stimulant, a filler, a colorant, an anti-adhesive, and an antibacterial agent.

6. The lurasidone hydrochloride orally dissolving film composition as claimed in claim 5, wherein, The disintegrant is one or more of low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, starch, microcrystalline cellulose, and pregelatinized starch; and / or, the salivary stimulant is one or more of tartaric acid, malic acid, and mannitol; and / or, the filler is one or more of mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose; and / or, the colorant is one or more of titanium dioxide, pigments, and lakes; and / or, the anti-adhesive is one or more of talc, magnesium stearate, and calcium stearate; and / or, the antibacterial agent is one or more of methylparaben, ethylparaben, and sodium thiosulfate.

7. The lurasidone hydrochloride orally dissolving film composition as claimed in claim 5 or 6, wherein, The disintegrant has a weight percentage of 0-10.0%, which refers to the percentage of the weight of the disintegrant in the total weight of the lurasidone hydrochloride orally dissolving film composition; and / or, the saliva stimulant has a weight percentage of 0-10.0%, which refers to the percentage of the weight of the saliva stimulant in the total weight of the lurasidone hydrochloride orally dissolving film composition; and / or, the filler has a weight percentage of 0-10.0%, which refers to the percentage of the weight of the filler in the total weight of the lurasidone hydrochloride orally dissolving film composition; and / or, the colorant has a weight percentage of 0-5.0%, which refers to the percentage of the weight of the colorant in the total weight of the lurasidone hydrochloride orally dissolving film composition; and / or, the anti-adhesion agent has a weight percentage of 0-5.0%, which refers to the percentage of the weight of the anti-adhesion agent in the total weight of the lurasidone hydrochloride orally dissolving film composition; and / or, The antibacterial agent has a weight percentage of 0-1.0%, which refers to the percentage of the weight of the antibacterial agent to the total weight of the lurasidone hydrochloride oral dissolving film composition.

8. The lurasidone hydrochloride orally dissolving film composition as claimed in any one of claims 1 to 7, wherein, The lurasidone hydrochloride oral dissolving film composition is selected from any of the following formulations: Formulation 1: 47.2% lurasidone hydrochloride, 33.0% hydroxypropyl cellulose, 9.4% glycerin, 9.4% sucralose, and 1.0% titanium dioxide; Formulation 2: 30.0% lurasidone hydrochloride, 45.0% polyvinyl alcohol, 12.0% polyethylene glycol 6000, 5.0% sucralose, 3.5% menthol, 0.9% mannitol, 3.0% lactose, and 0.6% methylparaben; Formulation 3: 33.3% lurasidone hydrochloride, 45.8% polyvinyl alcohol, 8.3% glycerin, 3.3% sodium chloride, 4.2% citric acid, 4.3% sucralose, 0.4% flavoring, and 0.4% menthol; Formula 4: 25.0% lurasidone hydrochloride, 50.0% polyvinyl alcohol, 16.0% glycerin, 2.5% steviol glycosides, 0.5% flavoring, and 6.0% lactose; Formula 5: 41.3% lurasidone hydrochloride, 24.8% hydroxyethyl cellulose, 16.5% pullulan, 8.3% glycerin, 8.3% sucralose, and 0.8% titanium dioxide; Formula 6: 47.2% lurasidone hydrochloride, 28.3% hydroxyethyl cellulose, 9.4% pullulan, 4.7% glycerin, 9.4% sucralose, and 1.0% titanium dioxide; Formula 7: 52.1% lurasidone hydrochloride, 20.8% hydroxyethyl cellulose, 10.4% pullulan, 5.2% glycerin, 10.4% sucralose, and 1.1% titanium dioxide; Formula 8: 41.7% lurasidone hydrochloride, 25.0% hydroxyethyl cellulose, 16.7% pullulan, 5.0% glycerin, 8.3% sucralose, 1.7% menthol, 0.8% talc, and 0.8% titanium dioxide; Formula 9: 38.5% lurasidone hydrochloride, 23.1% hydroxyethyl cellulose, 15.4% pullulan, 4.5% glycerin, 7.7% sucralose, 1.5% menthol, 0.8% flavoring, 7.7% citric acid, and 0.8% talc; Formula 10: 35.7% lurasidone hydrochloride, 21.4% hydroxyethyl cellulose, 14.3% pullulan, 4.3% glycerin, 7.1% sodium carboxymethyl starch, 7.1% sucralose, 1.4% menthol, 0.8% flavoring, 7.1% citric acid, and 0.8% talc.

9. A method for preparing a lurasidone hydrochloride orally dissolving film composition as described in any one of claims 1 to 8, characterized by comprising the following steps: 1) heating and dissolving a film-forming material in water at 60°C to 70°C to form a solution; 2) adding all components except the active drug to the solution obtained in step 1), stirring until uniform to obtain a blank adhesive solution; 3) placing the active drug in the blank adhesive solution obtained in step 2), stirring until uniformly dispersed, and stirring under vacuum to remove bubbles, to obtain a drug-containing adhesive; 4) uniformly coating the drug-containing adhesive solution obtained in step 3) after degassing onto a release film using a coating machine, heating, drying, and cutting to obtain the lurasidone hydrochloride orally dissolving film composition; preferably, the thickness of the lurasidone hydrochloride orally dissolving film composition is 10 μm to 300 μm; and / or, the lurasidone hydrochloride orally dissolving film composition can completely disintegrate within 2 min in 1000 ml of simulated saliva at 37°C ± 1°C.

10. Use of a lurasidone hydrochloride orally disintegrating film composition as claimed in any one of claims 1 to 8 in the preparation of a medicament for treating and / or preventing depression.

Images