Epinastine hydrochloride oral dissolving film composition, preparation method therefor, and use thereof

Abstract

Disclosed are an epinastine hydrochloride oral dissolving film composition, a preparation method therefor, and use thereof. The present invention provides an epinastine hydrochloride oral dissolving film composition comprising an active drug, a film-forming material, and a flavoring agent. The active drug is one or more of 3-amino-9,13-dihydro-1H-dibenzo[c,f]-imidazo[1,5-a]azepine hydrochloride, which is represented by formula I, and a solvate thereof. The epinastine hydrochloride oral dissolving film composition of the present invention has the advantages of a small thickness, rapid disintegration, stable properties, good mechanical properties, a pleasant taste, instant oral dissolution without the need for water, and quick oral absorption. Moreover, the composition is uniform in appearance and good in flexibility, and the process is simple; no sedimentation occurs in the process of preparing a film solution; the content uniformity meets the requirement, and the drug loading capacity is high.

Description

Orally disintegrating film composition of epinastine hydrochloride, preparation method and application thereof

[0001] This application claims the priority of the prior application with the patent application number 202410453859.1, the title of which is "Orally disintegrating film composition of epinastine hydrochloride, preparation method and application thereof", filed on April 16, 2024 with the State Intellectual Property Office of China. The entire contents of the prior application are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to the field of pharmaceutical preparations, in particular to an orally disintegrating film composition of epinastine hydrochloride, a preparation method and application thereof. BACKGROUND

[0003] Allergic rhinitis, also known as allergic rhinitis, can occur at any age, including infancy, and most patients develop the disease before the age of 20. There is no gender difference in the onset of the disease. The Allergy, Asthma and Immunology Research journal published a guideline for the diagnosis and treatment of allergic rhinitis, which states that allergic rhinitis is the most common chronic and refractory disease in rhinology, and the prevalence has increased significantly in recent years. Epidemiological data shows that in the past six years, the prevalence of allergic rhinitis in China has increased from 11.1% to 17.6%, with an increase of 100 million people. Urticaria is a common allergic disease of the skin and mucous membranes, mainly caused by temporary increased vascular permeability of the skin and mucous membranes. There is no obvious racial and gender difference in the occurrence of urticaria, and it can occur at any age. Professor Zheng Jie cited statistics from "West's Internal Medicine" that 90%-95% of people have experienced urticaria at some point in their lives. Chinese data shows that the incidence of chronic urticaria in China is 1.5%. According to the American Allergy Society, the incidence of allergic diseases is about 20%-40% of the total population, making it the sixth most common chronic disease in the United States. The World Health Organization (WHO) has listed this type of disease as a "disease to be studied and prevented in the 21st century".

[0004] Epinastine hydrochloride, as a second-generation oral antihistamine, has the effect of selectively inhibiting peripheral H1 receptors, and epinastine hydrochloride is difficult to pass through the blood-brain barrier, has weak H1 receptor antagonistic effect on the central nervous system, and has no central sedative effect and anticholinergic effect. It is mainly used in the treatment of allergic rhinitis, as well as urticaria, eczema, dermatitis, pruritus, psoriasis, allergic bronchial asthma, etc.

[0005] Currently marketed epinastine hydrochloride preparations are mainly tablets and granules, which have poor adaptability for children and patients with swallowing disorders. Patent document CN115671078A discloses an epinastine orally disintegrating film composition and a preparation method thereof. The epinastine orally disintegrating film prepared according to the method of the patent has the disadvantages of bitter taste and low tensile strength. SUMMARY

[0006] The present application solves the technical problem of overcoming the defects of existing epinastine hydrochloride, such as bitter taste and low tensile strength, and provides a new epinastine hydrochloride orally disintegrating film composition, a preparation method and application thereof. The epinastine hydrochloride orally disintegrating film composition has the advantages of thin thickness, rapid disintegration, stable properties, good mechanical properties, good taste, immediate dissolution in the oral cavity without the need for drinking water, and fast oral absorption speed.

[0007] The present application provides an epinastine hydrochloride orally disintegrating film composition comprising an active drug, a film-forming material and a taste masking agent; the active drug is one or more of 3-amino-9,13-dihydro-1H-dibenzo[c,f]-imidazo[1,5-a]azepine hydrochloride (epinastine hydrochloride) and solvates thereof as shown in formula I;

[0008] According to an embodiment of the present application, the mass percentage content of the active drug is 1.0% to 30.0%, for example 5.0 to 20.0%, and exemplary values are 2.0%, 3.0%, 4.0%, 4.3%, 4.7%, 5.0%, 5.8%, 6.0%, 7.0%, 7.8%, 8.0%, 8.8%, 9.0%, 10.0%, 11.0%, 12.0%, 13.0%, 13.3%, 14.0%, 14.1%, 15.0%, 16.0%, 16.7%, 17.0%, 18.0%, 19.0%, 20.0%, 21.0%, 22.0% or 25.0%, and the mass percentage content refers to the mass of the active drug accounting for the percentage of the total mass of the epinastine hydrochloride orally disintegrating film composition.

[0009] According to an embodiment of the present application, the film-forming material is a carrier of the active drug, and is selected from one or more of xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hypromellose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene, pullulan, maltodextrin, acrylic acid copolymer, polylactic acid and silicone rubber. For example, the film-forming material is one or more of polyvinyl alcohol, hypromellose and maltodextrin.

[0010] According to embodiments of the present application, the film forming material is present in an amount of 25.0% to 60.0%, such as 30.0% to 60.0% or 25.0% to 45.0%, illustratively 25.0%, 26.6%, 30.0%, 32.0%, 33.3%, 35.0%, 39.1%, 40.0%, 41.7%, 42.3%, 42.7%, 43.4%, 45.0%, 46.5%, 47.2%, 50.0%, or 55.0%, by weight of the total weight of the film composition.

[0011] According to embodiments of the present application, the taste masking agent is a substance used to mask the unpleasant taste of the active drug, reduce the oral absorption of the active drug, and is selected from one or more of a sweetener, a bitter taste receptor inhibitor, a flavor, a bitter taste masking agent, a resin, and Eudragit, for example. The sweetener is selected from one or both of Acesulfame K and Aspartame, for example. The bitter taste receptor inhibitor is glycine. The flavor is selected from one or more of orange flavor, strawberry flavor, and pineapple flavor. The bitter taste masking agent is orange bitter taste masking agent. The resin is selected from one or more of polacrillin potassium (also known as polacrilin potassium), polacrillin potassium (also known as polacrilin potassium), and sodium polystyrene sulfonate. The Eudragit is selected from Eudragit NE 30D (copolymer of ethyl acrylate and methyl methacrylate (2:1)), Eudragit RD 100 (a mixture of Eudragit RL and sodium carboxymethylcellulose (9:1)), and Eudragit RL (copolymer of ethyl acrylate, methyl methacrylate, and chloromethyl-trimethylammonioethyl methacrylate (1:2:0.2)), for example. In some embodiments, the taste masking agent is selected from one or more of polacrillin potassium and sodium polystyrene sulfonate.

[0012] According to embodiments of the present application, the taste masking agent is present in an amount of 10.0% to 50.0%, such as 15.0% to 45.0% or 30.0% to 50.0%, illustratively 15.0%, 16.7%, 20.0%, 25.0%, 28.2%, 30.0%, 34.9%, 35.4%, 37.7%, 39.1%, 39.9%, 40.0%, 42.7%, 41.7%, or 45.0%, by weight of the total weight of the film composition.

[0013] According to embodiments of the present application, the oral fast dissolving film composition of epinastine hydrochloride can further comprise one or more of a disintegrant, a plasticizer, a flavoring agent, a filler, and a coloring agent. In some embodiments, the oral fast dissolving film composition of epinastine hydrochloride consists of an active drug, a film forming material, a taste masking agent, and a flavoring agent; in some embodiments, the oral fast dissolving film composition of epinastine hydrochloride consists of an active drug, a film forming material, a taste masking agent, a plasticizer, and a flavoring agent; in some embodiments, the oral fast dissolving film composition of epinastine hydrochloride consists of an active drug, a film forming material, a taste masking agent, a plasticizer, a flavoring agent, and a coloring agent; in some embodiments, the oral fast dissolving film composition of epinastine hydrochloride consists of an active drug, a film forming material, a taste masking agent, a plasticizer, a flavoring agent, a coloring agent, and a disintegrant; in some embodiments, the oral fast dissolving film composition of epinastine hydrochloride consists of an active drug, a film forming material, a taste masking agent, a plasticizer, a flavoring agent, and a disintegrant; in some embodiments, the oral fast dissolving film composition of epinastine hydrochloride consists of an active drug, a film forming material, a taste masking agent, a plasticizer, a flavoring agent, and a filler.

[0014] According to embodiments of the present application, the disintegrant refers to an auxiliary material that promotes rapid disintegration of the oral fast dissolving film into small particles in the gastrointestinal tract, and is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch.

[0015] According to embodiments of the present application, the disintegrant has a mass percentage content of 0-5.0%, for example 0, 2.1%, 2.3%, 2.5%, or 2.7%, the mass percentage content referring to the percentage of the mass of the disintegrant with respect to the total mass of the oral fast dissolving film composition of epinastine hydrochloride.

[0016] According to embodiments of the present application, the plasticizer refers to a substance used to reduce the glass transition temperature of the film, increase plasticity and toughness, and improve the elongation rate, and is selected from one or more of glycerol, propylene glycol, silicone oil, polypropylene glycol, and hexylene glycol.

[0017] According to embodiments of the present application, the plasticizer has a mass percentage content of 0-20.0%, for example 5.0-10.0%, and exemplary values are 0, 4.3%, 4.4%, 4.7%, 5.8%, 6.6%, 6.7%, 7.8%, 4.2%, 7.0%, 5.0%, or 10.0%, the mass percentage content referring to the percentage of the mass of the plasticizer with respect to the total mass of the oral fast dissolving film composition of epinastine hydrochloride.

[0018] According to embodiments of the present application, the flavoring agent refers to a substance that plays a flavoring role in the film, and is selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycoside, glycyrrhizin, essence (e.g., strawberry powder essence), flavor, menthol, sodium chloride, saccharin, and sodium saccharin.

[0019] According to embodiments of the present application, the flavoring agent has a mass percentage content of 0-15.0%, such as 0-10.0% or 5.0%-15.0%, and exemplary values are 3.9%, 4.2%, 4.3%, 4.4%, 4.9%, 5.0%, 5.2%, 6.7%, 7.0%, 8.0%, 8.4%, 13.6%, or 13.85%, wherein the mass percentage content refers to the mass percentage of the flavoring agent in the total mass of the oral dissolving film composition of epinastine hydrochloride.

[0020] According to embodiments of the present application, the filler refers to a solid substance that is added to the material to improve the performance of the material, or to increase the volume, weight, and reduce the cost of the material, and is selected from one or more of mannitol, starch, microcrystalline cellulose, pregelatinized starch, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose.

[0021] According to embodiments of the present application, the filler has a mass percentage content of 0-10.0%, such as 0 or 8.1%, wherein the mass percentage content refers to the mass percentage of the filler in the total mass of the oral dissolving film composition of epinastine hydrochloride.

[0022] According to embodiments of the present application, the coloring agent refers to a substance that can improve the appearance of the color of the preparation, be used to identify the concentration of the preparation, distinguish the application method, and reduce the aversion of patients to taking the medicine, and is selected from one or more of titanium dioxide, pigments, and color lakes.

[0023] According to embodiments of the present application, the coloring agent has a mass percentage content of preferably 0-2.0%, such as 0, 0.5%, 0.9%, 1.4%, or 1.7%, wherein the mass percentage content refers to the mass percentage of the coloring agent in the total mass of the oral dissolving film composition of epinastine hydrochloride.

[0024] According to embodiments of the present application, the oral dissolving film composition of epinastine hydrochloride contains or consists of an active drug, a film-forming material, a plasticizer, a taste-masking agent, and a flavoring agent.

[0025] The active drug has a mass percentage of 5.0% to 20.0%, the film-forming material has a mass percentage of 25.0% to 45.0%, the plasticizer has a mass percentage of 5.0% to 10.0%, the taste masking agent has a mass percentage of 30.0% to 50.0%, and the flavoring agent has a mass percentage of 5.0% to 15.0%;

[0026] Preferably, the film-forming material is selected from polyvinyl alcohol and / or hypromellose;

[0027] The plasticizer is glycerol;

[0028] The taste masking agent is selected from sodium polystyrene sulfonate and / or potassium acesulfame.

[0029] According to an embodiment of the present application, the epinastine hydrochloride orally dissolving film composition can have any of the following formulations:

[0030] Formulation 1: 20.0% epinastine hydrochloride, 32.0% polyvinyl alcohol, 40.0% sodium polystyrene sulfonate, and 8.0% sucralose, the mass percentage referring to the mass of each component accounting for the percentage of the total mass of the epinastine hydrochloride orally dissolving film composition;

[0031] Formulation 2: 5.8% epinastine hydrochloride, 46.5% hypromellose, 5.8% glycerol, 34.9% potassium acesulfame, 3.5% stevioside, and 3.5% essence (strawberry powder essence), the mass percentage referring to the mass of each component accounting for the percentage of the total mass of the epinastine hydrochloride orally dissolving film composition;

[0032] Formulation 3: 4.7% epinastine hydrochloride, 47.2% hypromellose, 4.7% glycerol, 37.7% potassium acesulfame, 5.2% sucralose, and 0.5% lake (allure red aluminum lake), the mass percentage referring to the mass of each component accounting for the percentage of the total mass of the epinastine hydrochloride orally dissolving film composition;

[0033] Formulation 4: 4.3% epinastine hydrochloride, 42.7% polyvinyl alcohol, 4.3% glycerol, 42.7% sodium polystyrene sulfonate, 4.3% aspartame, and 1.7% lake (allure red aluminum lake), the mass percentage referring to the mass of each component accounting for the percentage of the total mass of the epinastine hydrochloride orally dissolving film composition;

[0034] Formulation 5: 10.0% epinastine hydrochloride, 10.0% hypromellose, 35.0% polyvinyl alcohol, 10.0% glycerol, 30.0% sodium polystyrene sulfonate, and 5.0% sucralose, the mass percentage referring to the mass of each component accounting for the percentage of the total mass of the epinastine hydrochloride orally dissolving film composition;

[0035] Prescription 6: 8.8% of epinastine hydrochloride, 43.4% of polyvinyl alcohol, 4.4% of glycerin, 35.4% of polacrillin potassium, 4.4% of sucralose, 0.9% of lake (allura red aluminum lake), and 2.7% of sodium carboxymethyl starch, the mass percentage referring to the mass of each component accounting for the percentage of the total mass of the epinastine hydrochloride orally disintegrating film composition;

[0036] Prescription 7: 7.8% of epinastine hydrochloride, 39.1% of hypromellose, 7.8% of glycerin, 39.1% of sodium polystyrene sulfonate, 3.9% of sucralose, and 2.3% of sodium carboxymethyl starch, the mass percentage referring to the mass of each component accounting for the percentage of the total mass of the epinastine hydrochloride orally disintegrating film composition;

[0037] Prescription 8: 16.7% of epinastine hydrochloride, 41.7% of maltodextrin, 4.2% of glycerin, 16.7% of sodium polystyrene sulfonate, 4.2% of sucralose, 2.5% of menthol, 1.7% of essence (strawberry powder essence), 1.7% of titanium dioxide, 2.5% of sodium carboxymethyl starch, and 8.1% of pregelatinized starch, the mass percentage referring to the mass of each component accounting for the percentage of the total mass of the epinastine hydrochloride orally disintegrating film composition;

[0038] Prescription 9: 14.1% of epinastine hydrochloride, 42.3% of polyvinyl alcohol, 7.0% of glycerin, 28.2% of sodium polystyrene sulfonate, 3.5% of sucralose, 1.4% of essence (strawberry powder essence), 1.4% of lake (allura red aluminum lake), and 2.1% of sodium carboxymethyl starch, the mass percentage referring to the mass of each component accounting for the percentage of the total mass of the epinastine hydrochloride orally disintegrating film composition;

[0039] Prescription 10: 10.0% of epinastine hydrochloride, 40.0% of polyvinyl alcohol, 5.0% of glycerin, 40.0% of sodium polystyrene sulfonate, and 5.0% of sucralose, the mass percentage referring to the mass of each component accounting for the percentage of the total mass of the epinastine hydrochloride orally disintegrating film composition;

[0040] Prescription 11: 13.3% of epinastine hydrochloride, 26.6% of polyvinyl alcohol, 6.6% of glycerin, 26.6% of polacrillin potassium, 13.3% of sodium polystyrene sulfonate, 13.3% of sucralose, and 0.3% of menthol, the mass percentage referring to the mass of each component accounting for the percentage of the total mass of the epinastine hydrochloride orally disintegrating film composition;

[0041] Prescription 12: 13.3% of epinastine hydrochloride, 33.3% of polyvinyl alcohol, 6.7% of glycerin, 26.7% of polacrillin potassium, 13.3% of sodium polystyrene sulfonate, and 6.7% of sucralose, the mass percentage referring to the mass of each component accounting for the percentage of the total mass of the epinastine hydrochloride orally disintegrating film composition.

[0042] According to embodiments of the present application, the Epinastine Hydrochloride Orally Disintegrating Film Composition has a thickness of 10 μm to 300 μm, for example, 10 μm to 100 μm, for example, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm or 100 μm.

[0043] According to embodiments of the present application, the Epinastine Hydrochloride Orally Disintegrating Film Composition is capable of completely disintegrating within 2 minutes (for example, 33 seconds, 37 seconds, 41 seconds, 59 seconds, 54 seconds, 38 seconds, 49 seconds, 40 seconds, 52 seconds or 65 seconds) in 20 mL of simulated saliva at 37 ± 1 °C.

[0044] The present application also provides a method for preparing the Epinastine Hydrochloride Orally Disintegrating Film Composition, comprising the following steps:

[0045] 1) preparing an active pharmaceutical aqueous solution;

[0046] 2) adding a taste masking agent to the active pharmaceutical aqueous solution obtained in step 1), stirring to obtain a drug-loaded resin suspension;

[0047] 3) mixing the drug-loaded resin suspension obtained in step 2) with a film-forming material, or further mixing one or more of a flavoring agent, a plasticizer, a disintegrant, a colorant and a filler, and thoroughly stirring to obtain a uniform glue solution;

[0048] 4) removing bubbles from the uniform glue solution obtained in step 3) under vacuum, coating, drying, cutting and packaging to obtain the Epinastine Hydrochloride Orally Disintegrating Film Composition.

[0049] According to embodiments of the present application, in step 1), the water is preferably purified water.

[0050] According to embodiments of the present application, in step 2), the stirring time is preferably more than 1 hour.

[0051] The present application also provides the use of the Epinastine Hydrochloride Orally Disintegrating Film Composition in the preparation of a medicament for treating and / or preventing bronchial asthma, allergic rhinitis, urticaria, eczema, dermatitis, pruritus and psoriasis vulgaris with itching.

[0052] According to embodiments of the present application, the Epinastine Hydrochloride Orally Disintegrating Film Composition is a pharmaceutical preparation. The pharmaceutical preparation can be in the form of an orally disintegrating film.

[0053] The present application also provides a method for treating bronchial asthma, allergic rhinitis, urticaria, eczema, dermatitis, pruritus and psoriasis vulgaris with itching, which comprises administering to a patient in need thereof a therapeutically effective amount of the Epinastine Hydrochloride Orally Disintegrating Film Composition.

[0054] Unless otherwise indicated, the definitions of the terms in the specification and claims hereof include the definitions of the terms as they are each used in this specification and the examples and can be used in any combination or sub-combination thereof. Such combinations and sub-combinations should be construed as being within the scope of the present specification.

[0055] The term "therapeutically effective amount" refers to an amount of a pharmaceutical active ingredient of the present application sufficient to achieve the intended application, including but not limited to the treatment of a disease as defined below. The therapeutically effective amount can vary depending on the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the particular active ingredient chosen, the dosing regimen followed, 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 carried.

[0056] The term "plurality" means two or more, for example two, three or more.

[0057] The above-mentioned preferred conditions can be combined in any manner without departing from the common general knowledge of the skilled person, thereby obtaining preferred embodiments of the present application.

[0058] The reagents and materials used in the present application are commercially available.

[0059] Advantages of the present application: The eptastine hydrochloride orally disintegrating film composition of the present application has the advantages of thin thickness, good taste, stable properties, good dissolution rate, immediate dissolution in the oral cavity without drinking water, no grit feeling after dissolution in the oral cavity, fast oral absorption speed, uniform appearance, good flexibility, simple process, no sedimentation during the preparation of the film liquid, uniform content, high drug loading. The present application solves the defects of inconvenient taking and poor patient compliance of the existing preparations, and is particularly suitable for patients with difficulty in swallowing. DETAILED DESCRIPTION

[0060] The present application is further illustrated by the following examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples, for which no specific conditions are indicated, are selected according to conventional methods and conditions, or according to the instructions of the commercial products.

[0061] Examples 1-12: The formulations are shown in Table 1

[0062] Table 1

[0063] Table 1-continued

[0064] * indicates removal during the process;

[0065] ** indicates the weight of the raw and auxiliary materials after water removal.

[0066] Preparation method:

[0067] 1) An active pharmaceutical aqueous solution is prepared;

[0068] 2) A taste masking agent is added to the active pharmaceutical aqueous solution obtained in step 1), and stirred to obtain a drug-loaded resin suspension;

[0069] 3) The drug-loaded resin suspension obtained in step 2) is mixed with a film-forming material, or further mixed with one or more of a flavoring agent, a plasticizer, a colorant, and a filler, and stirred thoroughly to obtain a uniform gum solution;

[0070] 4) The uniform gum solution obtained in step 3) is vacuumed to remove air bubbles, coated, dried, cut, and packaged to obtain the said epinastine hydrochloride oral film composition.

[0071] Comparative Example 1-2

[0072] The epinastine hydrochloride oral film was prepared according to the preparation method of Example 2 and Example 6 in patent CN115671078A, as Comparative Example 1-2, and the specific prescription is shown in Table 2.

[0073] Table 2

[0074] Test Example

[0075] The disintegration, dissolution, mechanical strength, palatability, content, and related substance level of the epinastine hydrochloride oral film preparations obtained from the examples and comparative examples of the present application were investigated.

[0076] 1. Disintegration Time Test

[0077] The disintegration time of the epinastine hydrochloride oral film preparations obtained from Example 1-12 and Comparative Example 1-2 was determined, and the specific determination method is as follows:

[0078] Take 6 pieces of the drug film obtained from each example, and take 1 piece each time, and gently place it in a petri dish with a diameter of about 8 cm containing 20 ml of 37±1℃ artificial saliva. Under static state, observe the time of complete disintegration of the product, and the results are shown in Table 3.

[0079] Table 3

[0080] 2. Dissolution Test

[0081] The dissolution of the epinastine hydrochloride oral film preparations of Example 1 to Example 12, Comparative Example 1, and Comparative Example 2 was determined, and the specific determination method is as follows:

[0082] Test medium: 900 ml pH 1.2 hydrochloric acid solution (37℃±0.5℃).

[0083] Dissolution method: The second method of dissolution and release determination in Chinese Pharmacopoeia 2020 edition (paddle method), the rotation speed is 50 rpm.

[0084] Sampling time: 30 min.

[0085] Take 6 pieces of each example of hydrochloric acid eptastine oral dissolving film preparation, and measure the dissolution according to the above method. The average dissolution results are shown in Table 4.

[0086] Table 4

[0087] 3. Mechanical strength test

[0088] A texture analyzer (model: Rapid TA + , manufacturer: Shanghai Tengbu Instrument Technology Co., Ltd.) was used to test the mechanical strength of the hydrochloric acid eptastine oral dissolving film preparations of examples 1 to 12, comparative example 1 and comparative example 2. The results are shown in Table 5.

[0089] Table 5

[0090] According to the mechanical strength test results, comparative example 1 and comparative example 2 have lower tensile strength, and are more likely to break, damage and break during storage and transportation under the action of external mechanical force.

[0091] 4. Palatability evaluation

[0092] Referring to the Technical Guidelines for Design and Evaluation of Children's Drug Taste (Trial) and the literature Li Pan, Han Xue, Lin Junzhi, Jiang Hong, Yang Ming, Zhang Dingkun, Han Li. Application and development of sensory test in drug taste evaluation [J]. Chinese Pharmaceutical Journal, 2017, 52(22): 1971-1975, 6 volunteers were selected to evaluate the palatability of each example and comparative example by using bitterness value grade evaluation method and multi-factor investigation evaluation method.

[0093] According to the quality attributes of the oral dissolving film, the palatability was evaluated from the aspects of appearance, bitterness, sweetness, and foreign body sensation in the mouth, etc. Among them, bitterness and foreign body sensation in the mouth were the main scoring items, and appearance and sweetness were the bonus items. The grade and scoring rules are shown in Table 6:

[0094] Table 6

[0095] According to the palatability evaluation results, the scores of Example 4, Example 7, Example 3, Example 11, Example 12 and Example 2 are all above 16, and the palatability is good, while the taste of Comparative Example 1 and Comparative Example 2 is poor.

[0096] 5. Content and related substances

[0097] The content and related substances of Example 2, Example 3, Example 4, Example 7, Example 11 and Example 12 were detected by using a high performance liquid chromatograph under the influence of high temperature 50℃, and the results are shown in Table 7.

[0098] Table 7

[0099] According to the detection results of the content and related substances, the stability of the orally dissolving film of the present application is good.

[0100] According to the above experimental data, the orally dissolving film composition of the present application has the advantages of thin thickness, rapid disintegration, stable properties, good mechanical properties, good taste, no need to drink water for immediate dissolution in the oral cavity, and fast oral absorption speed.

[0101] The above describes the embodiments of the present application. However, the present application is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. An orodispersible film composition of epinastine hydrochloride, characterized by, The orodispersible film composition of epinastine hydrochloride comprises: an active drug, a film-forming material, and a taste-masking agent; the active drug is one or more of 3-amino-9,13-dihydro-1H-dibenzo[c,f]-imidazo[1,5-a]azepine hydrochloride and solvates thereof as shown in Formula I; 2.The oral dissolving film composition of epinastine hydrochloride according to claim 1, wherein: the active pharmaceutical agent is present in an amount of 1.0% to 30.0% by weight of the total weight of the oral dissolving film composition. 3.The oral dissolving film composition of epinastine hydrochloride according to claim 1, wherein: the film-forming material is selected from one or more of xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hypromellose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene, pullulan, maltodextrin, acrylic acid copolymer, polylactic acid, and silicone rubber. 4.The oral dissolving film composition of epinastine hydrochloride according to claim 1, wherein: the taste-masking agent is selected from one or more of a sweetener, a bitter receptor inhibitor, a flavor, a bitter taste masking agent, a resin, and Eudragit; the sweetener is selected from one or both of acesulfame potassium and aspartame; the bitter receptor inhibitor is glycine; the flavor is selected from one or more of orange flavor, strawberry flavor, and pineapple flavor; the bitter taste masking agent is an orange bitter taste masking agent; the resin is selected from one or more of polacrillin potassium, polacrillin, and sodium polystyrene sulfonate; and the Eudragit is selected from Eudragit NE 30D (an ethyl acrylate and methyl methacrylate (2:1) copolymer), Eudragit RD 100 (a mixture of Eudragit RL and sodium carboxymethyl cellulose (9:1)), and Eudragit RL (an ethyl acrylate, methyl methacrylate, and chloro-trimethylammonioethyl methacrylate (1:2:0.2) copolymer). 5.The oral dissolving film composition of epinastine hydrochloride according to claim 1, wherein: the film-forming material is present in an amount of 25.0% to 60.0% by weight of the total weight of the oral dissolving film composition; the taste-masking agent is present in an amount of 10.0% to 50.0% by weight of the total weight of the oral dissolving film composition; the disintegrant is present in an amount of 1.0% to 20.0% by weight of the total weight of the oral dissolving film composition; the plasticizer is present in an amount of 1.0% to 20.0% by weight of the total weight of the oral dissolving film composition; the flavoring agent is present in an amount of 0.1% to 10.0% by weight of the total weight of the oral dissolving film composition; the filler is present in an amount of 0.1% to 10.0% by weight of the total weight of the oral dissolving film composition; and the colorant is present in an amount of 0.1% to 10.0% by weight of the total weight of the oral dissolving film composition. 6.The oral dissolving film composition of epinastine hydrochloride according to claim 5, wherein: the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, cross-linked polyplasdone, cross-linked sodium carboxymethyl cellulose, and sodium carboxymethyl starch; the plasticizer is selected from one or more of glycerol, propylene glycol, silicone oil, polypropylene glycol, and hexylene glycol; the flavoring agent is selected from one or more of aspartame, chloro-sucrose, fructose, sucrose, steviol glycoside, glycyrrhizin, a flavor, a spice, menthol, sodium chloride, saccharin, and sodium saccharin; and the filler is selected from one or more of mannitol, lactose, and dextrose. ​ ​ ​ ​ ​ 5. The oral dissolving film composition of epinastine hydrochloride according to claim 1, wherein: ​ ​ ​ ​ ​ ​ ​ ​ The filler is selected from one or more of mannitol, starch, microcrystalline cellulose, pregelatinized starch, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose; and / or, The coloring agent is selected from one or more of titanium dioxide, pigment and lake.

7. The oral dissolving film composition of epinastine hydrochloride according to claim 5, wherein: The mass percentage content of the disintegrant is 0-5.0%, the mass percentage content referring to the percentage of the mass of the disintegrant in the total mass of the oral dissolving film composition of epinastine hydrochloride; and / or, The mass percentage content of the plasticizer is 0-20.0%, the mass percentage content referring to the percentage of the mass of the plasticizer in the total mass of the oral dissolving film composition of epinastine hydrochloride; and / or, The mass percentage content of the flavoring agent is 0-15.0%, for example 0-10.0%, the mass percentage content referring to the percentage of the mass of the flavoring agent in the total mass of the oral dissolving film composition of epinastine hydrochloride; and / or, The mass percentage content of the filler is 0-10.0%, the mass percentage content referring to the percentage of the mass of the filler in the total mass of the oral dissolving film composition of epinastine hydrochloride; and / or, The mass percentage content of the coloring agent is 0-2.0%, the mass percentage content referring to the percentage of the mass of the coloring agent in the total mass of the oral dissolving film composition of epinastine hydrochloride.

8. The oral dissolving film composition of epinastine hydrochloride according to any one of claims 1-3, wherein: The oral dissolving film composition of epinastine hydrochloride is any one of the following formulations: Formulation 1: 20.0% epinastine hydrochloride, 32.0% polyvinyl alcohol, 40.0% sodium polystyrene sulfonate and 8.0% sucralose, the mass percentage content referring to the percentage of the mass of each component in the total mass of the oral dissolving film composition of epinastine hydrochloride; Formulation 2: 5.8% epinastine hydrochloride, 46.5% hypromellose, 5.8% glycerol, 34.9% potassium polacrillin potash, 3.5% steviol glycosides and 3.5% essence, the mass percentage content referring to the percentage of the mass of each component in the total mass of the oral dissolving film composition of epinastine hydrochloride; Formulation 3: 4.7% epinastine hydrochloride, 47.2% hypromellose, 4.7% glycerol, 37.7% potassium polacrillin potash, 5.2% sucralose and 0.5% lake, the mass percentage content referring to the percentage of the mass of each component in the total mass of the oral dissolving film composition of epinastine hydrochloride; Formulation 4: 4.3% epinastine hydrochloride, 42.7% polyvinyl alcohol, 4.3% glycerol, 42.7% sodium polystyrene sulfonate, 4.3% aspartame and 1.7% lake, the mass percentage content referring to the percentage of the mass of each component in the total mass of the oral dissolving film composition of epinastine hydrochloride; Formulation 5: 10.0% epinastine hydrochloride, 10.0% hypromellose, 35.0% polyvinyl alcohol, 10.0% glycerol, 30.0% sodium polystyrene sulfonate and 5.0% sucralose, the mass percentage content referring to the percentage of the mass of each component in the total mass of the oral dissolving film composition of epinastine hydrochloride; Prescription 6: 8.8% of epinastine hydrochloride, 43.4% of polyvinyl alcohol, 4.4% of glycerin, 35.4% of polacrillin potassium, 4.4% of sucralose, 0.9% of lake and 2.7% of sodium carboxymethyl starch, the mass percentage refers to the mass percentage of each component in the total mass of the epinastine hydrochloride oral dissolving film composition; Prescription 7: 7.8% of epinastine hydrochloride, 39.1% of hydroxypropyl methyl cellulose, 7.8% of glycerin, 39.1% of sodium polystyrene sulfonate, 3.9% of sucralose and 2.3% of sodium carboxymethyl starch, the mass percentage refers to the mass percentage of each component in the total mass of the epinastine hydrochloride oral dissolving film composition; Prescription 8: 16.7% of epinastine hydrochloride, 41.7% of maltodextrin, 4.2% of glycerin, 16.7% of sodium polystyrene sulfonate, 4.2% of sucralose, 2.5% of menthol, 1.7% of essence (strawberry powder essence), 1.7% of titanium dioxide, 2.5% of sodium carboxymethyl starch and 8.1% of pregelatinized starch, the mass percentage refers to the mass percentage of each component in the total mass of the epinastine hydrochloride oral dissolving film composition; Prescription 9: 14.1% of epinastine hydrochloride, 42.3% of polyvinyl alcohol, 7.0% of glycerin, 28.2% of sodium polystyrene sulfonate, 3.5% of sucralose, 1.4% of essence, 1.4% of lake and 2.1% of sodium carboxymethyl starch, the mass percentage refers to the mass percentage of each component in the total mass of the epinastine hydrochloride oral dissolving film composition; Prescription 10: 10.0% of epinastine hydrochloride, 40.0% of polyvinyl alcohol, 5.0% of glycerin, 40.0% of sodium polystyrene sulfonate and 5.0% of sucralose, the mass percentage refers to the mass percentage of each component in the total mass of the epinastine hydrochloride oral dissolving film composition; Prescription 11: 13.3% of epinastine hydrochloride, 26.6% of polyvinyl alcohol, 6.6% of glycerin, 26.6% of polacrillin potassium, 13.3% of sodium polystyrene sulfonate, 13.3% of sucralose and 0.3% of menthol, the mass percentage refers to the mass percentage of each component in the total mass of the epinastine hydrochloride oral dissolving film composition; Prescription 12: 13.3% of epinastine hydrochloride, 33.3% of polyvinyl alcohol, 6.7% of glycerin, 26.7% of polacrillin potassium, 13.3% of sodium polystyrene sulfonate and 6.7% of sucralose, the mass percentage refers to the mass percentage of each component in the total mass of the epinastine hydrochloride oral dissolving film composition.

9. A process for the preparation of an oral fast dissolving film composition of epinastine hydrochloride according to any one of claims 1 to 8, characterized by, The preparation method comprises the following steps: 1) preparing an active drug aqueous solution; 2) adding a taste masking agent to the active drug aqueous solution obtained in step 1), stirring to obtain a drug-loaded resin suspension; 3) adding a film-forming material to the drug-loaded resin suspension obtained in step 2), or further adding one or more of a flavoring agent, a plasticizer, a coloring agent and a filler, mixing and stirring sufficiently to obtain a uniform glue solution; 4) removing bubbles from the uniform glue solution obtained in step 3) under vacuum, coating, drying, cutting and packaging to obtain the epinastine hydrochloride oral dissolving film composition.

10. Use of the oral fast dissolving film composition of epinastine hydrochloride according to any one of claims 1 to 8 for the manufacture of a medicament for the treatment and / or prevention of bronchial asthma, allergic rhinitis, urticaria, eczema, dermatitis, pruritus associated with atopic dermatitis.

11. A method of treating bronchial asthma, allergic rhinitis, urticaria, eczema, dermatitis, pruritus associated with atopic dermatitis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1. administering to a patient in need thereof a therapeutically effective amount of the oral fast dissolving film composition of epinastine hydrochloride according to any one of claims 1 to 8.

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