Epinastine hydrochloride oral soluble film composition as well as preparation method and application thereof

Abstract

The invention discloses an epinastine hydrochloride oral soluble film composition as well as a preparation method and application thereof. The invention provides an epinastine hydrochloride oral soluble film composition. The epinastine hydrochloride oral soluble film composition comprises an active medicine, 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 as shown in a formula I and a solvate of the 3-amino-9, 13-dihydro-1H-dibenzo [c, f]-imidazo [1, 5-a] azepine hydrochloride. The epinastine hydrochloride oral soluble film composition has the advantages of being thin in thickness, rapid in disintegration, stable in property, good in mechanical property, good in taste, capable of being instantly dissolved in the oral cavity without drinking water and high in oral absorption speed, and is uniform in appearance, good in flexibility, simple in process, free of sedimentation in the preparation process of film liquid and suitable for large-scale production. The content uniformity meets the requirements, and the drug loading capacity is high.

Description

[0001] This application claims the priority of the prior application with the patent application number 202410453859.1, the title of "Epinastine Hydrochloride Oral Dissolving Film Composition, Its Preparation Method and Application", which was 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 epinastine hydrochloride oral dissolving film composition, its preparation method and application. 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 vascular permeability increase in 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 an oral second-generation 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 antagonism 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 oral dissolving film composition and its preparation method. The epinastine oral dissolving film prepared according to the patent method 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]

[0009] 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%, wherein 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.

[0010] 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.

[0011] 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.

[0012] 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, among others. For example, the sweetener is selected from one or both of Acesulfame K and Aspartame; 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; and 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)), among others. In some embodiments, the taste masking agent is selected from one or more of polacrillin potassium and sodium polystyrene sulfonate.

[0013] 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.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] According to an embodiment 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 (for example, strawberry powder essence), flavor, menthol, sodium chloride, saccharin, and sodium saccharin.

[0020] According to an embodiment of the present application, the flavoring agent has a mass percentage content of 0-15.0%, for example, 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 epinastine hydrochloride orally disintegrating film composition.

[0021] According to an embodiment of the present application, the filler refers to a solid substance that is added to a 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.

[0022] According to an embodiment of the present application, the filler has a mass percentage content of 0-10.0%, for example, 0 or 8.1%, wherein the mass percentage content refers to the mass percentage of the filler in the total mass of the epinastine hydrochloride orally disintegrating film composition.

[0023] According to an embodiment 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, pigment, and lake.

[0024] According to an embodiment of the present application, the coloring agent has a mass percentage content of preferably 0-2.0%, for example, 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 epinastine hydrochloride orally disintegrating film composition.

[0025] According to an embodiment of the present application, the epinastine hydrochloride orally disintegrating film composition contains or consists of an active drug, a film-forming material, a plasticizer, a taste-masking agent, and a flavoring agent.

[0026] 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%;

[0027] Preferably, the film-forming material is selected from polyvinyl alcohol and / or hypromellose;

[0028] The plasticizer is glycerol;

[0029] The taste masking agent is selected from sodium polystyrene sulfonate and / or potassium acesulfame.

[0030] According to an embodiment of the present application, the epinastine hydrochloride orally disintegrating film composition can have any of the following formulations:

[0031] 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 disintegrating film composition;

[0032] 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 disintegrating film composition;

[0033] 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 disintegrating film composition;

[0034] 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 disintegrating film composition;

[0035] 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 disintegrating film composition;

[0036] Formulation 6: 8.8% of epinastine hydrochloride, 43.4% of polyvinyl alcohol, 4.4% of glycerol, 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;

[0037] Formulation 7: 7.8% of epinastine hydrochloride, 39.1% of hypromellose, 7.8% of glycerol, 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;

[0038] Formulation 8: 16.7% of epinastine hydrochloride, 41.7% of maltodextrin, 4.2% of glycerol, 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;

[0039] Formulation 9: 14.1% of epinastine hydrochloride, 42.3% of polyvinyl alcohol, 7.0% of glycerol, 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;

[0040] Formulation 10: 10.0% of epinastine hydrochloride, 40.0% of polyvinyl alcohol, 5.0% of glycerol, 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;

[0041] Formulation 11: 13.3% of epinastine hydrochloride, 26.6% of polyvinyl alcohol, 6.6% of glycerol, 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;

[0042] Formulation 12: 13.3% of epinastine hydrochloride, 33.3% of polyvinyl alcohol, 6.7% of glycerol, 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.

[0043] 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.

[0044] 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.

[0045] The present application also provides a preparation method of the epinastine hydrochloride orally disintegrating film composition, comprising the following steps:

[0046] 1) preparing an active pharmaceutical water solution;

[0047] 2) adding a taste masking agent to the active pharmaceutical water solution obtained in step 1), stirring to obtain a drug-loaded resin suspension;

[0048] 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;

[0049] 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.

[0050] According to embodiments of the present application, in step 1), the water is preferably purified water.

[0051] According to embodiments of the present application, in step 2), the stirring time is preferably more than 1 hour.

[0052] The present application also provides 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] The term "plurality" means two or more, for example two, three or more.

[0058] 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.

[0059] The reagents and materials used in the present application are commercially available.

[0060] The present application has the following advantages: the eptastigmine hydrochloride orally dissolving 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, and 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

[0061] The present application will be further described by way of examples, but the present application is not limited to the examples described. The experimental methods in the following examples, for which no specific conditions are indicated, are carried out according to routine methods and conditions, or according to the instructions of the commercial suppliers.

[0062] Examples 1-12: The formulations are shown in Table 1

[0063] Table 1

[0064]

[0065]

[0066] Table 1 - continued

[0067]

[0068] * indicates removal during the process;

[0069] ** indicates the weight of the raw and auxiliary materials after removal of water.

[0070] Preparation method:

[0071] 1) An active pharmaceutical aqueous solution is prepared;

[0072] 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;

[0073] 3) A film-forming material is added to the drug-loaded resin suspension obtained in step 2), or further mixed with one or more of a flavoring agent, a plasticizer, a coloring agent, and a filler, and stirred thoroughly to obtain a uniform gum solution;

[0074] 4) The uniform gum solution obtained in step 3) is vacuumed to remove air bubbles, coated, dried, cut, and packaged to obtain the hydrochloric acid eptastine oral film composition.

[0075] Comparative Example 1-2

[0076] The hydrochloric acid eptastine 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.

[0077] Table 2

[0078]

[0079] Test Example

[0080] The disintegration, dissolution, mechanical strength, palatability, content, and related substance level of the hydrochloric acid eptastine oral film preparations obtained by the examples and comparative examples of the present application were investigated.

[0081] 1. Disintegration time test

[0082] The disintegration time of the hydrochloric acid eptastine oral film preparations obtained by Example 1-12 and Comparative Example 1-2 was determined, and the specific determination method was as follows:

[0083] Six pieces of the drug film obtained from each example were taken, one piece at a time, and gently placed in a petri dish with a diameter of about 8 cm containing 20 ml of 37±1℃ artificial saliva. The time for complete disintegration of the product was observed under static conditions, and the results are shown in Table 3.

[0084] Table 3

[0085] Example Disintegration time (s) Example 1 33 Example 2 37 Example 3 41 Example 4 59 Example 5 54 Example 6 38 Example 7 49 Example 8 40 Example 9 52 Example 10 65 Example 11 34 Example 12 40 Comparative Example 1 35 Comparative Example 2 22

[0086] 2. Dissolution test

[0087] The dissolution of the effervescent tablet formulations of Example 1 to Example 12, Comparative Example 1 and Comparative Example 2 was determined according to the following method:

[0088] Test medium: 900 ml of pH 1.2 hydrochloric acid solution (37 °C ± 0.5 °C).

[0089] Dissolution method: Method II (Paddle Method) in Chinese Pharmacopoeia 2020 edition 0931 Dissolution and Release Test, rotation speed 50 rpm.

[0090] Sampling time: 30 min.

[0091] Take 6 pieces of each example effervescent tablet formulation, and determine the dissolution according to the above method. The average dissolution results are shown in Table 4.

[0092] Table 4

[0093]

[0094] 3. Mechanical strength test

[0095] The mechanical strength of the effervescent tablet formulations of Example 1 to Example 12, Comparative Example 1 and Comparative Example 2 was tested using a texture analyzer (Model: Rapid TA + , manufacturer: Shanghai Tengbu Instrument Technology Co., Ltd.). The results are shown in Table 5.

[0096] Table 5

[0097]

[0098]

[0099]

[0100] According to the mechanical strength test results, the tensile strength of Comparative Example 1 and Comparative Example 2 is lower, and it is more prone to breakage, damage and folding during storage and transportation under the action of external mechanical force.

[0101] 4. Palatability evaluation

[0102] Reference is made to the Technical Guidelines for Taste Design and Evaluation of Medicines for Children (Trial) and the literature Li Pan, Han Xue, Lin Junzhi, Jiang Hong, Yang Ming, Zhang Dingkun, Han Li. Application and development of sensory test of volunteers in the evaluation of drug taste [J]. Chinese Journal of Pharmacy, 2017, 52 (22): 1971-1975. The bitterness value grade evaluation method and the multi-factor investigation evaluation method are comprehensively used to select 6 volunteers to evaluate the palatability of each example and the comparative example.

[0103] According to the quality attributes of the mouth dissolving film, the palatability is evaluated from the appearance, bitterness, sweetness, and oral foreign body sensation, wherein the bitterness and the oral foreign body sensation are the main scoring items, and the appearance and the sweetness are the bonus items. The grade and scoring rules are shown in Table 6:

[0104] Table 6

[0105]

[0106]

[0107]

[0108] 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.

[0109] 5. Content and related substances

[0110] The high temperature 50℃ condition influencing factor investigation of Example 2, Example 3, Example 4, Example 7, Example 11 and Example 12 is carried out using a high performance liquid chromatograph, the API content and the related substance content are detected, and the results are shown in Table 7.

[0111] Table 7

[0112]

[0113]

[0114] According to the content and related substance detection results, the mouth dissolving film of the application has good stability.

[0115] According to the above experimental data, the salt acid eprazinone mouth dissolving film composition provided by the application has the advantages of thin thickness, rapid disintegration, stable properties, good mechanical properties, good taste, no need to drink water to dissolve in the oral cavity, and fast oral absorption speed.

[0116] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, and the like made within the spirit and principle of the present application should be included in the scope of protection of the present application.

Claims

1. An orodispersible film composition of epinastine hydrochloride, characterized by, The oral dissolving 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 mass percentage of the active drug is 1.0% to 30.0%, wherein the mass percentage refers to the mass of the active drug accounting for the percentage of the total mass of the oral dissolving film composition of epinastine hydrochloride.

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, hydroxypropyl methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene, pullulan, maltodextrin, acrylic acid copolymer, polylactic acid, and silicone rubber; and / or, The mass percentage of the film forming material is 25.0% to 60.0%, for example, 30.0% to 60.0%, wherein the mass percentage refers to the mass of the film forming material accounting for the percentage of the total mass of the oral dissolving film composition of epinastine hydrochloride.

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 flavoring, a bitter taste masking agent, a resin, and Eudragit; for example, the sweetener is selected from one or both of acesulfame potassium and aspartame; the bitter receptor inhibitor is glycine; the flavoring is selected from one or more of orange flavoring, strawberry flavoring, and pineapple flavoring; the bitter taste masking agent is 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 (copolymer of ethyl acrylate and methyl methacrylate (2:1)), Eudragit RD 100 (mixture of Eudragit RL and sodium carboxymethyl cellulose (9:1)), and Eudragit RL (copolymer of ethyl acrylate, methyl methacrylate, and chloro-trimethylammonio-ethyl methacrylate (1:2:0.2)); and / or, The mass percentage of the taste masking agent is 10.0% to 50.0%, wherein the mass percentage refers to the mass of the taste masking agent accounting for the percentage of the total mass of the oral dissolving film composition of epinastine hydrochloride.

5. The oral dissolving film composition of epinastine hydrochloride according to claim 1, wherein: The oral dissolving film composition of epinastine hydrochloride further comprises one or more of a disintegrant, a plasticizer, a flavoring agent, a filler, and a coloring agent.

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; and / or, The plasticizer is selected from one or more of glycerol, propylene glycol, silicone oil, polypropylene glycol, and hexylene glycol; and / or, The flavoring agent is selected from one or more of aspartame, sucralose, fructose, sucrose, steviol glycosides, glycyrrhizin, essence, flavor, menthol, sodium chloride, saccharin, and sodium saccharin; and / or, 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 epinastine hydrochloride orally disintegrating film composition of 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 epinastine hydrochloride orally disintegrating film composition; 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 epinastine hydrochloride orally disintegrating film composition; 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 epinastine hydrochloride orally disintegrating film composition; 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 epinastine hydrochloride orally disintegrating film composition; 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 epinastine hydrochloride orally disintegrating film composition.

8. The epinastine hydrochloride orally disintegrating film composition of any one of claims 1-3, wherein: The epinastine hydrochloride orally disintegrating film composition 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 epinastine hydrochloride orally disintegrating film composition; Formulation 2: 5.8% epinastine hydrochloride, 46.5% hypromellose, 5.8% glycerol, 34.9% polacrillin potassium, 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 epinastine hydrochloride orally disintegrating film composition; Formulation 3: 4.7% epinastine hydrochloride, 47.2% hypromellose, 4.7% glycerol, 37.7% polacrillin potassium, 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 epinastine hydrochloride orally disintegrating film composition; 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 epinastine hydrochloride orally disintegrating film composition; Prescription 5: 10.0% of epinastine hydrochloride, 10.0% of hypromellose, 35.0% of polyvinyl alcohol, 10.0% of glycerin, 30.0% of sodium polystyrene sulfonate and 5.0% of sucralose, the mass percentage referring to the percentage of the mass of each component in the total mass of the epinastine hydrochloride oral dissolving film composition; Prescription 6: 8.8% of epinastine hydrochloride, 43.4% of polyvinyl alcohol, 4.4% of glycerin, 35.4% of potassium clavulanate, 4.4% of sucralose, 0.9% of lake and 2.7% of sodium carboxymethyl starch, the mass percentage referring to the percentage of the mass 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 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 percentage of the mass 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 referring to the percentage of the mass 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 referring to the percentage of the mass 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 referring to the percentage of the mass 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 potassium clavulanate, 13.3% of sodium polystyrene sulfonate, 13.3% of sucralose and 0.3% of menthol, the mass percentage referring to the percentage of the mass 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 potassium clavulanate, 13.3% of sodium polystyrene sulfonate and 6.7% of sucralose, the mass percentage referring to the percentage of the mass 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) and stirring to obtain a drug-loaded resin suspension; 3) adding film forming material into the drug-loaded resin suspension obtained in step 2), or further adding one or more of flavoring agent, plasticizer, colorant and filler, mixing, stirring thoroughly 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 said epinastine hydrochloride oral film composition.

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

Images