An oral film containing ebastine and its preparation method

Abstract

The present invention relates to an oral film containing ebastine and a preparation method thereof, belonging to the field of pharmaceutical technology. During the preparation of the mucilage, methylcellulose and polyacrylic resin are used as film-forming agents. When the mass ratio of the film-forming agent to purified water is controlled at 1:3 to 5, and the mass ratio of polyacrylic resin to methylcellulose in the film-forming agent is 0.5 to 2.5:1, the resulting mucilage is a viscous paste, the film has good flexibility and film-forming property, the film has no insoluble substances and good flexibility, has no bitter taste in terms of taste, has a cool and sweet taste, the active ingredient dissolves rapidly and fully, has good dissolution effect, stability, taste masking effect and compliance. Compared with the existing dosage forms on the market, it is more suitable for the elderly and children and has great clinical significance.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to an oral film containing ebastine and a preparation method thereof. Background Art

[0002] Allergic conjunctivitis, allergic rhinitis (seasonal and perennial), and chronic idiopathic urticaria are relatively common chronic diseases in life. The common symptoms of allergic rhinitis are paroxysmal sneezing, clear nasal discharge, nasal congestion, and nasal itching, and some are accompanied by hyposmia; chronic idiopathic urticaria is an allergic disease caused by various factors. Generally, its systemic symptoms are milder than those of acute urticaria. The wheals appear and disappear from time to time, but they often occur repeatedly for several months or years, and occasionally there will be an acute attack, with manifestations similar to those of acute urticaria. Red wheals of different sizes will appear in the itchy area, which can be round, oval, or irregular in shape. According to the data of the World Health Organization, 20% - 30% of the global population is troubled by allergic symptoms, and the number of patients is showing an increasing trend year by year. For moderate to severe allergic diseases, drugs are the only treatment method. The incidence of allergies in China is similar to that in foreign countries, and 270 million people are troubled by allergies of different degrees. Especially in the coastal or alpine regions, hundreds of millions of people suffer from allergic rhinitis or allergic asthma, and the incidence of this disease is showing a rapid upward trend, thus driving the growth of the antihistamine drug market.

[0003] Antihistamine drugs are mostly used in the market. Commonly used first-generation antihistamines include chlorpheniramine, diphenhydramine, doxepin, promethazine, ketotifen, etc., and second-generation antihistamines include cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine, acrivastine, ebastine, epinastine, mizolastine, olopatadine, etc.

[0004] Ebastine is a potent, highly selective, and specific H1 receptor blocker. It was first developed by Almirall-Prodesfarma (now Almirall) in Spain. In December 1989, tablets and oral solutions were approved for marketing in Spain. Among them, the 10mg ebastine tablets were imported and marketed in China in 2014. The oral solution of ebastine, trade name Currently, it has not been imported and marketed in China.

[0005] Chinese Patent CN105687128A discloses an ebastine oral liquid preparation and its preparation method, which includes ebastine, pH regulator, solubilizer, flavoring agent, sweetening agent, preservative, defoaming agent, cosolvent and water. Using water as the carrier, the solubility of ebastine in the solution is improved by adding a solubilizer and a cosolvent. However, the active ingredient in the obtained oral preparation has poor stability, is not easy to store, is not easy to swallow for infants and comatose patients, and the liquid preparation has a large volume, making it inconvenient to carry, transport and store. Especially, it has a bitter taste, and simply adding a sweetening agent cannot effectively cover up the bitterness, resulting in poor clinical compliance.

[0006] Therefore, it is of great significance to develop a method with simple preparation process, stable and controllable process, high production efficiency, and to obtain an oral film with stable quality. Summary of the Invention

[0007] The object of the present invention is to provide an oral film containing ebastine on the basis of the existing technology. The film has no insoluble matter, good flexibility, no bitter taste in terms of taste, has a cool and sweet taste, has good film-forming property, dissolution effect, stability, taste masking effect and compliance. Compared with the existing dosage forms on the market, it is more suitable for the elderly and children, and has great clinical significance.

[0008] Another object of the present invention is to provide a preparation method of the above oral film.

[0009] The technical solution of the present invention is as follows:

[0010] An oral film containing ebastine is made of the following components in parts by weight: 1 - 10 parts of the active ingredient ebastine, 10 - 30 parts of surfactant, 10 - 50 parts of glycerol, 1 - 10 parts of lactic acid, 10 - 30 parts of film-forming agent, 2 - 5 parts of titanium dioxide and 2 - 8 parts of flavoring agent. Among them, the film-forming agent is polyacrylic resin and methylcellulose; the plasticizer is polyoxyethylene 40 hydrogenated castor oil.

[0011] In a preferred embodiment, for the oral film containing ebastine provided by the present invention, during its preparation process, the active ingredient ebastine is first dissolved in an aqueous lactic acid solution to form a medicinal solution. The obtained medicinal solution is mixed evenly with a mucilage made of a film-forming agent, glycerol and water, a surfactant, a flavoring agent and titanium dioxide, then defoamed to make a film, and an oral film is obtained.

[0012] The detailed preparation process is as follows: First, dissolve the film-forming agent in water and stir until dissolved, then add glycerol and stir evenly to make a mucilage; mix the active ingredient ebastine with the aqueous lactic acid solution until completely dissolved, then pour it into the mucilage and mix, add the remaining components (surfactant, flavoring agent and titanium dioxide), stir until completely dissolved, use a coating machine to make a wet film with uniform thickness, and then dry and demold to obtain the ebastine oral film.

[0013] Among them, the flavoring agent is one or several of sorbitol, sucralose, glycerol, menthol, mannitol, sodium saccharin, strawberry essence, apple essence or berry essence; preferably, the flavoring agent is sorbitol, sucralose, strawberry essence and menthol.

[0014] In the present invention, the active ingredient ebastine dissolves depending on the pH environment. Using an aqueous lactic acid solution to dissolve ebastine can effectively improve the solubility and stability of ebastine. Therefore, it is very important to control the dosage of lactic acid.

[0015] In the present invention, the type and dosage of the film-forming agent are crucial for the film-forming property, dissolution effect and stability of the oral film of the present invention. During the experiment of exploring the film-forming agent, the present invention found that using methylcellulose and polyacrylic resin with good water solubility as the film-forming agent and strictly controlling their dosage and ratio, the obtained mucilage is a viscous paste with good film-forming property, no insoluble matter in the film, good flexibility, no bitterness in taste, cool and sweet, and has good dissolution effect, stability, taste masking effect and compliance. Compared with the existing dosage forms on the market, it is more suitable for the elderly and children and has great clinical significance.

[0016] However, using other similar film-forming agents, such as polyacrylate, gelatin, starch and ethylcellulose, it is difficult to obtain the desired effect. For example, when methylcellulose is replaced with ethylcellulose, during the preparation of the mucilage, more bubbles and insoluble particles are generated, the obtained film has poor flexibility, slow and incomplete dissolution and release, and poor chemical stability.

[0017] In the present invention, the mass ratio of polyacrylic resin to methylcellulose in the film-forming agent will affect the appearance, dissolution degree and stability of the finished product. Controlling the mass ratio of polyacrylic resin to methylcellulose in the film-forming agent to be 0.5 - 2.5:1, which can be but is not limited to 0.5:1, 0.8:1, 1.0:1, 1.2:1, 1.5:1, 1.8:1, 2.0:1, 2.2:1 or 2.5:1, the obtained film has good flexibility, rapid and complete dissolution, and good chemical stability. In a preferred embodiment, the mass ratio of polyacrylic resin to methylcellulose in the film-forming agent is 1.0 - 1.5:1, and further preferably, the mass ratio of polyacrylic resin to methylcellulose in the film-forming agent is 1:1. When the mass ratio of polyacrylic resin to methylcellulose in the film-forming agent is too high or too low, for example, when the mass ratio of polyacrylic resin to methylcellulose is 3:1, during the preparation of the mucilage, the obtained mucilage is viscous, has more bubbles, poor film-forming property, the obtained film has poor flexibility, is hard in texture, slow and incomplete dissolution, and poor chemical stability.

[0018] In the present invention, during the preparation of the mucilage, the amounts of the film-forming agent and water have a great influence on the properties, film-forming ability and appearance of the film of the mucilage. When the mass ratio of the film-forming agent to purified water is controlled at 1:3 to 5, which can be but is not limited to 1:3, 1:4 or 1:5, the obtained mucilage has a moderate viscosity, good film-forming ability, the obtained film tablets dissolve rapidly and completely, and have good chemical stability. When the mass ratio of the film-forming agent to water is too high or too low, for example, when the mass ratio of the film-forming agent to purified water is 1:2 or 1:6, the film-forming ability of the mucilage is poor, resulting in poor flexibility and stability of the prepared oral film tablets.

[0019] In a preferred embodiment, the oral film tablets containing ebastine mentioned in the present invention are made of the following components in parts by weight: 1 part of the active component ebastine, 15 - 20 parts of polyoxyethylene 40 hydrogenated castor oil, 20 - 40 parts of glycerol, 2 - 6 parts of lactic acid, 15 - 25 parts of a film-forming agent, 3 - 5 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, and 0.05 part of menthol; the mass ratio of polyacrylic resin to methylcellulose in the film-forming agent is 0.5 - 2.5:1.

[0020] In a more preferred embodiment, the oral film tablets containing ebastine mentioned in the present invention are made of the following components in parts by weight: 1 part of the active component ebastine, 15 parts of polyoxyethylene 40 hydrogenated castor oil, 20 - 30 parts of glycerol, 2 - 6 parts of lactic acid, 20 parts of a film-forming agent, 4 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, and 0.05 part of menthol; the mass ratio of polyacrylic resin to methylcellulose in the film-forming agent is 1.0 - 1.5:1.

[0021] For example, the oral film tablets containing ebastine mentioned in the present invention are made of the following components in parts by weight: 1 part of the active component ebastine, 15 parts of polyoxyethylene 40 hydrogenated castor oil, 20 parts of glycerol, 2 parts of lactic acid, 10 parts of polyacrylic resin, 10 parts of methylcellulose, 4 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, and 0.05 part of menthol.

[0022] For example, the oral film tablets containing ebastine mentioned in the present invention are made of the following components in parts by weight: 1 part of the active component ebastine, 15 parts of polyoxyethylene 40 hydrogenated castor oil, 20 parts of glycerol, 4 parts of lactic acid, 10 parts of polyacrylic resin, 10 parts of methylcellulose, 4 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, and 0.05 part of menthol.

[0023] For example, the oral film containing ebastine mentioned in the present invention is made of the following components in parts by weight: 1 part of the active ingredient ebastine, 15 parts of polyoxyl 40 hydrogenated castor oil, 20 parts of glycerol, 6 parts of lactic acid, 10 parts of polyacrylic resin, 10 parts of methyl cellulose, 4 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, and 0.05 part of menthol.

[0024] For example, the oral film containing ebastine mentioned in the present invention is made of the following components in parts by weight: 1 part of the active ingredient ebastine, 15 parts of polyoxyl 40 hydrogenated castor oil, 30 parts of glycerol, 4 parts of lactic acid, 10 parts of polyacrylic resin, 10 parts of methyl cellulose, 4 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, and 0.05 part of menthol.

[0025] For example, the oral film containing ebastine mentioned in the present invention is made of the following components in parts by weight: 1 part of the active ingredient ebastine, 15 parts of polyoxyl 40 hydrogenated castor oil, 20 parts of glycerol, 4 parts of lactic acid, 12 parts of polyacrylic resin, 8 parts of methyl cellulose, 4 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, and 0.05 part of menthol.

[0026] The present invention also provides a method for preparing the above oral film, which comprises the following steps:

[0027] (1) Preparation of the medicinal solution: After sieving the active ingredient ebastine, add it to the lactic acid aqueous solution and stir until dissolved to obtain the medicinal solution containing ebastine;

[0028] (2) Preparation of the mucilage: Add the film-forming agent to water, stir until dissolved, and then add glycerol and stir evenly to prepare the mucilage;

[0029] (3) Mixing: Mix the medicinal solution obtained in step (1), polyoxyl 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol, titanium dioxide and the mucilage obtained in step (2) evenly;

[0030] (4) Defoaming: Defoam the mixed solution obtained in step (3);

[0031] (5) Film formation: Press the defoamed mixed solution into a thin film with a thickness of 0.1 - 0.2 mm to form a wet film, demold after drying, cut, and package to obtain the oral film.

[0032] In a preferred embodiment, in step (1), the active ingredient ebastine is sieved through a 60 - 100 mesh sieve, for example, 60 mesh, 80 mesh or 100 mesh, and preferably, the active ingredient ebastine is sieved through an 80 mesh sieve.

[0033] In a preferred embodiment, in step (2), the mass ratio of the film-forming agent to water is 1:3 to 5; the mass ratio of polyacrylic resin to methylcellulose in the film-forming agent is 0.5 to 2.5:1, preferably 1.0 to 1.5:1.

[0034] In a preferred embodiment, in step (3), the plasticizer is polyoxyethylene 40 hydrogenated castor oil. The flavoring agent is one or more of sorbitol, sucralose, glycerol, menthol, mannitol, saccharin sodium, strawberry essence, apple essence or berry essence; preferably, the flavoring agent is sorbitol, sucralose, strawberry essence and menthol.

[0035] In a preferred embodiment, in step (5), the drying temperature is 50 to 70 °C, which can be but is not limited to 50 °C, 60 °C or 70 °C. Further preferably, the drying temperature is 60 °C.

[0036] Adopting the technical solution of the present invention, the advantages are as follows:

[0037] (1) The oral film containing ebastine provided by the present invention uses methylcellulose and polyacrylic resin as film-forming agents. When the ratio of the film-forming agent to purified water is controlled to be 1:3 to 5, and the ratio of polyacrylic resin to methylcellulose in the film-forming agent is 0.5 to 2.0:1, the prepared ebastine oral film has no insoluble matter, good flexibility, no bitterness in terms of taste, has a cool and sweet taste, the active ingredient dissolves rapidly and fully, the film has good flexibility, has good film-forming property, dissolution effect, stability, taste masking effect and compliance. Compared with the existing dosage forms on the market, it is more suitable for the elderly and children and has great clinical significance.

[0038] (2) In the process of preparing the oral film, ebastine is added to the lactic acid aqueous solution, so that the active ingredient is completely dissolved, protecting the active ingredient and effectively improving the solubility and stability of ebastine; titanium dioxide is added as a light-shielding agent to further improve the stability of the active ingredient; the whole preparation process is simple, stable and controllable, the sample dissolves rapidly, has a good taste and chemical stability. Specific embodiments

[0039] The present invention will be further explained and illustrated below through specific examples and comparative examples, but this is not a limitation to the present invention. Those skilled in the art can make any modifications, equivalent substitutions or improvements according to the basic idea of the present invention, and all should be included within the scope of the present invention.

[0040] Example 1

[0041] Formulation of oral film (1000 preparation unit amounts):

[0042]

[0043]

[0044] The preparation method comprises the following steps:

[0045] (1) Preparation of the liquid medicine: After passing ebastine through an 80-mesh sieve, it is added to a lactic acid aqueous solution made of 20 g of water and lactic acid, and stirred until dissolved to obtain the liquid medicine containing ebastine;

[0046] (2) Preparation of the mucilage: Polyacrylic resin and methylcellulose are added to 60 g of water, stirred until dissolved, and then glycerol is added and stirred evenly to prepare the mucilage;

[0047] (3) Mixing: The liquid medicine containing ebastine obtained in step (1), polyoxyethylene 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol, titanium dioxide are mixed evenly with the mucilage obtained in step (2);

[0048] (4) Defoaming: The mixed solution obtained in step (3) is defoamed with a centrifugal defoaming machine (TD5A-WS defoaming machine, Yinen Experimental Instruments);

[0049] (5) Film forming: The defoamed mixed solution is pressed into a thin film with a thickness of 0.1 - 0.2 mm with a film coating machine (JTFM520, Hangzhou Zixu Technology) to form a wet film, dried at 60 °C (SHH-200HWD-2, Yongsheng Instruments), then demolded, cut, and packaged to obtain the oral film tablets.

[0050] Example 2

[0051] Formulation of the oral film tablets (1000 preparation unit amounts):

[0052]

[0053] The preparation method comprises the following steps:

[0054] (1) Preparation of the liquid medicine: After passing ebastine through an 80-mesh sieve, it is added to a lactic acid aqueous solution made of 20 g of water and lactic acid, and stirred until dissolved to obtain the liquid medicine containing ebastine;

[0055] (2) Preparation of the mucilage: Polyacrylic resin and methylcellulose are added to 80 g of water, stirred until dissolved, and then glycerol is added and stirred evenly to prepare the mucilage;

[0056] (3) Mixing: The liquid medicine containing ebastine obtained in step (1), polyoxyethylene 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol, titanium dioxide are mixed evenly with the mucilage obtained in step (2);

[0057] (4) Defoaming: Defoam the mixed solution obtained in step (3) using a centrifugal defoaming machine (TD5A-WS defoaming machine, Yinen Experimental Instruments).

[0058] (5) Film forming: Use a film coating machine (JTFM520, Hangzhou Zixu Technology) to press the defoamed mixed solution into a thin film with a thickness of 0.1 - 0.2 mm to form a wet film, dry it at 60°C (SHH-200HWD-2, Yongsheng Instruments), then demold, cut, and package to obtain the oral film.

[0059] Example 3

[0060] Formulation of the oral film (per 1000 dosage units):

[0061]

[0062] Its preparation method includes the following steps:

[0063] (1) Preparation of the medicinal solution: After sieving ebastine through an 80-mesh sieve, add it to a lactic acid aqueous solution made of 20 g of water and lactic acid, and stir until dissolved to obtain a medicinal solution containing ebastine.

[0064] (2) Preparation of the mucilage: Add polyacrylic resin and methylcellulose to 100 g of water, stir until dissolved, and then add glycerol and stir evenly to prepare the mucilage.

[0065] (3) Mixing: Mix the medicinal solution containing ebastine obtained in step (1), polyoxyl 40 hydrogenated castor oil, sorbitol, sucralose, strawberry flavor, menthol, titanium dioxide with the mucilage obtained in step (2) evenly.

[0066] (4) Defoaming: Defoam the mixed solution obtained in step (3) using a centrifugal defoaming machine (TD5A-WS defoaming machine, Yinen Experimental Instruments).

[0067] (5) Film forming: Use a film coating machine (JTFM520, Hangzhou Zixu Technology) to press the defoamed mixed solution into a thin film with a thickness of 0.1 - 0.2 mm to form a wet film, dry it at 60°C (SHH-200HWD-2, Yongsheng Instruments), then demold, cut, and package to obtain the oral film.

[0068] Example 4

[0069] Formulation of the oral film (per 1000 dosage units):

[0070]

[0071]

[0072] Its preparation method includes the following steps:

[0073] (1) Preparation of the medicinal solution: After passing ebastine through an 80-mesh sieve, it is added to a lactic acid aqueous solution made of 20 g of water and lactic acid, and stirred until dissolved to obtain a medicinal solution containing ebastine;

[0074] (2) Preparation of the mucilage: Polyacrylic resin and methylcellulose are added to 100 g of water, stirred until dissolved, and then glycerol is added and stirred evenly to prepare the mucilage;

[0075] (3) Mixing: The medicinal solution containing ebastine obtained in step (1), polyoxyethylene 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol, titanium dioxide are mixed evenly with the mucilage obtained in step (2);

[0076] (4) Defoaming: The mixed solution obtained in step (3) is defoamed using a centrifugal defoaming machine (TD5A-WS defoaming machine, Yinen Experimental Instruments);

[0077] (5) Film forming: The defoamed mixed solution is pressed into a thin film with a thickness of 0.1 - 0.2 mm using a film coating machine (JTFM520, Hangzhou Zixu Technology) to form a wet film, which is dried at 60 °C (SHH-200HWD-2, Yongsheng Instruments) and then demolded, cut, and packaged to obtain the oral film tablets.

[0078] Example 5

[0079] Formulation of the oral film tablets (1000 dosage unit amounts):

[0080]

[0081] Its preparation method includes the following steps:

[0082] (1) Preparation of the medicinal solution: After passing ebastine through an 80-mesh sieve, it is added to a lactic acid aqueous solution made of 20 g of water and lactic acid, and stirred until dissolved to obtain a medicinal solution containing ebastine;

[0083] (2) Preparation of the mucilage: Polyacrylic resin and methylcellulose are added to 100 g of water, stirred until dissolved, and then glycerol is added and stirred evenly to prepare the mucilage;

[0084] (3) Mixing: The medicinal solution containing ebastine obtained in step (1), polyoxyethylene 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol, titanium dioxide are mixed evenly with the mucilage obtained in step (2);

[0085] (4) Defoaming: The mixed solution obtained in step (3) is defoamed using a centrifugal defoaming machine (TD5A-WS defoaming machine, Yinen Experimental Instruments);

[0086] (5) Film formation: Use a film coating machine (JTFM520, Hangzhou Zixu Technology) to press the degassed mixed solution into a thin film with a thickness of 0.1 - 0.2 mm to form a wet film, dry it at 60°C (SHH - 200HWD - 2, Yongsheng Instruments), then demold, cut, and package to obtain oral film tablets.

[0087] Example 6

[0088] Formulation of oral film tablets (per 1000 dosage units):

[0089]

[0090] Its preparation method includes the following steps:

[0091] (1) Preparation of the medicinal liquid: After passing ebastine through an 80 - mesh sieve, add it to a lactic acid aqueous solution made of 20 g of water and lactic acid, and stir until dissolved to obtain a medicinal liquid containing ebastine.

[0092] (2) Preparation of the mucilage: Add polyacrylic resin and methylcellulose to 100 g of water, stir until dissolved, and then add glycerol and stir evenly to prepare the mucilage.

[0093] (3) Mixing: Mix the medicinal liquid containing ebastine obtained in step (1), polyoxyethylene 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol, titanium dioxide with the mucilage obtained in step (2) evenly.

[0094] (4) Defoaming: Use a centrifugal defoaming machine (TD5A - WS defoaming machine, Yinen Experimental Instruments) to defoam the mixed solution obtained in step (3).

[0095] (5) Film formation: Use a film coating machine (JTFM520, Hangzhou Zixu Technology) to press the degassed mixed solution into a thin film with a thickness of 0.1 - 0.2 mm to form a wet film, dry it at 60°C (SHH - 200HWD - 2, Yongsheng Instruments), then demold, cut, and package to obtain oral film tablets.

[0096] Example 7

[0097] Formulation of oral film tablets (per 1000 dosage units):

[0098]

[0099] Its preparation method includes the following steps:

[0100] (1) Preparation of the medicinal liquid: After passing ebastine through an 80 - mesh sieve, add it to a lactic acid aqueous solution made of 20 g of water and lactic acid, and stir until dissolved to obtain a medicinal liquid containing ebastine.

[0101] (2) Preparation of mucilage: Add polyacrylic resin and methylcellulose into 100 g of water, stir until dissolved, then add glycerol and stir evenly to prepare the mucilage;

[0102] (3) Mixing: Mix the solution containing ebastine obtained in step (1), polyoxyethylene 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol, titanium dioxide with the mucilage obtained in step (2) evenly;

[0103] (4) Defoaming: Use a centrifugal defoaming machine (TD5A-WS defoaming machine, Yinen Experimental Instruments) to defoam the mixed solution obtained in step (3);

[0104] (5) Film forming: Use a film coating machine (JTFM520, Hangzhou Zixu Technology) to press the defoamed mixed solution into a thin film with a thickness of 0.1 - 0.2 mm to form a wet film, dry it at 60 °C (SHH-200HWD-2, Yongsheng Instruments), then demold, cut, and package to obtain the oral film tablets.

[0105] Comparative Example 1

[0106] Formulation of oral film tablets (1000 preparation unit amounts):

[0107]

[0108]

[0109] Its preparation method includes the following steps:

[0110] (1) Preparation of the solution: After passing ebastine through an 80-mesh sieve, add it to a lactic acid aqueous solution made of 20 g of water and lactic acid, stir until dissolved to obtain a solution containing ebastine;

[0111] (2) Preparation of mucilage: Add polyacrylic resin and methylcellulose into 40 g of water, stir until dissolved, then add glycerol and stir evenly to prepare the mucilage;

[0112] (3) Mixing: Mix the solution containing ebastine obtained in step (1), polyoxyethylene 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol, titanium dioxide with the mucilage obtained in step (2) evenly;

[0113] (4) Defoaming: Use a centrifugal defoaming machine (TD5A-WS defoaming machine, Yinen Experimental Instruments) to defoam the mixed solution obtained in step (3);

[0114] (5) Film formation: Use a film coating machine (JTFM520, Hangzhou Zixu Technology) to press the degassed mixed solution into a thin film with a thickness of 0.1 - 0.2 mm to form a wet film, dry it at 60 °C (SHH - 200HWD - 2, Yongsheng Instruments), then demold, cut, and package to obtain oral film tablets.

[0115] Comparative Example 2

[0116] Formulation of oral film tablets (per 1000 dosage units):

[0117]

[0118] Its preparation method includes the following steps:

[0119] (1) Preparation of the medicinal solution: After passing ebastine through an 80 - mesh sieve, add it to a lactic acid aqueous solution made of 20 g of water and lactic acid, and stir until dissolved to obtain a medicinal solution containing ebastine.

[0120] (2) Preparation of the mucilage: Add polyacrylic resin and methylcellulose to 120 g of water, stir until dissolved, and then add glycerol and stir evenly to prepare the mucilage.

[0121] (3) Mixing: Mix the medicinal solution containing ebastine obtained in step (1), polyoxyl 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol, titanium dioxide with the mucilage obtained in step (2) evenly.

[0122] (4) Defoaming: Use a centrifugal defoaming machine (TD5A - WS defoaming machine, Yinen Experimental Instruments) to defoam the mixed solution obtained in step (3).

[0123] (5) Film formation: Use a film coating machine (JTFM520, Hangzhou Zixu Technology) to press the degassed mixed solution into a thin film with a thickness of 0.1 - 0.2 mm to form a wet film, dry it at 60 °C (SHH - 200HWD - 2, Yongsheng Instruments), then demold, cut, and package to obtain oral film tablets.

[0124] Comparative Example 3

[0125] Formulation of oral film tablets (per 1000 dosage units):

[0126]

[0127] Its preparation method includes the following steps:

[0128] (1) Preparation of the medicinal solution: After passing ebastine through an 80 - mesh sieve, add it to a lactic acid aqueous solution made of 20 g of water and lactic acid, and stir until dissolved to obtain a medicinal solution containing ebastine.

[0129] (2) Preparation of mucilage: Add polyacrylic resin and ethyl cellulose into 120 g of water, stir until dissolved, then add glycerol and stir evenly to prepare the mucilage;

[0130] (3) Mixing: Mix the solution containing ebastine obtained in step (1), polyoxyethylene 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol, titanium dioxide with the mucilage obtained in step (2) evenly;

[0131] (4) Defoaming: Use a centrifugal defoaming machine (TD5A-WS defoaming machine, Yinen Experimental Instruments) to defoam the mixed solution obtained in step (3);

[0132] (5) Film forming: Use a film coating machine (JTFM520, Hangzhou Zixu Technology) to press the defoamed mixed solution into a thin film with a thickness of 0.1 - 0.2 mm to make a wet film, dry it at 60 °C (SHH-200HWD-2, Yongsheng Instruments), then demold, cut, and package to obtain the oral film tablets.

[0133] Comparative Example 4

[0134] Formulation of oral film tablets (per 1000 dosage units):

[0135]

[0136] Its preparation method includes the following steps:

[0137] (1) Preparation of the solution: After passing ebastine through an 80-mesh sieve, add it to a lactic acid aqueous solution made of 20 g of water and lactic acid, stir until dissolved to obtain a solution containing ebastine;

[0138] (2) Preparation of mucilage: Add polyacrylic resin and methyl cellulose into 120 g of water, stir until dissolved, then add glycerol and stir evenly to prepare the mucilage;

[0139] (3) Mixing: Mix the solution containing ebastine obtained in step (1), polyoxyethylene 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol, titanium dioxide with the mucilage obtained in step (2) evenly;

[0140] (4) Defoaming: Use a centrifugal defoaming machine (TD5A-WS defoaming machine, Yinen Experimental Instruments) to defoam the mixed solution obtained in step (3);

[0141] (5) Film forming: Use a film coating machine (JTFM520, Hangzhou Zixu Technology) to press the defoamed mixed solution into a thin film with a thickness of 0.1 - 0.2 mm to make a wet film, dry it at 60 °C (SHH-200HWD-2, Yongsheng Instruments), then demold, cut, and package to obtain the oral film tablets.

[0142] Effect verification

[0143] 1. Observe the properties of the mucilage in the examples and comparative examples, and examine the appearance, film-forming property and taste of the film tablets. The results are shown in Table 1.

[0144] Table 1 Data of the mucilage properties, appearance, film-forming property and taste of the oral film tablets in the examples and comparative examples

[0145]

[0146]

[0147] As can be seen from the comparison in Table 1, for the oral film tablets obtained in Examples 1, 2, 3, 4, 5, 6 and 7 of the present invention, during the preparation of the mucilage, methylcellulose and polyacrylic resin with good water solubility are used as film-forming agents. When the mass ratio of the film-forming agent to purified water is 1:3 - 5, the mass ratio of polyacrylic resin to methylcellulose in the film-forming agent is 1.0 - 1.5:1; the obtained mucilage is a white to colorless viscous paste with good film-forming property. The film tablets have a white to colorless film appearance, no insoluble substances and good flexibility. In terms of taste, there is no bitterness, but a cool and sweet taste, with good taste masking effect and compliance. Compared with the existing market dosage forms, it is more suitable for the elderly and children and has great clinical significance.

[0148] In Comparative Examples 1 and 2, the mass ratio of the film-forming agent to purified water is 1:2 and 1:6 respectively, and the film-forming property of the mucilage is poor, resulting in poor flexibility of the prepared oral film tablets; in Comparative Example 3, the film-forming agent is polyacrylic resin and ethylcellulose, and the water solubility of ethylcellulose is poor, resulting in many white particles in the mucilage and poor film-forming property, and there are also some insoluble substances in the prepared oral film tablets. In Comparative Example 4, during the preparation of the mucilage, the mass ratio of polyacrylic resin to methylcellulose in the film-forming agent is 3:1, the prepared mucilage is too viscous, generates more bubbles under stirring, and the obtained oral film tablets also have many small and dense bubbles, with a hard texture and poor flexibility.

[0149] 2. Detect the dissolution rate of the samples in the examples and comparative examples

[0150] Table 2 Detection results of the dissolution rate of the samples in the examples and comparative examples

[0151]

[0152]

[0153] As can be seen from Comparative Table 1, the oral membrane tablets obtained in Examples 1, 2, 3, 4, 5, 6 and 7 of the present invention dissolve rapidly and sufficiently, with more than 85% dissolved in 15 minutes. While in Comparative Example 1, the dissolution and release are slower and incomplete; in Comparative Example 2, the ratio of the film-forming agent to water is 1:6, and the dissolution and release are too fast; in Comparative Example 3, the film-forming agent is polyacrylic resin and ethyl cellulose, and the dissolution and release are slower and incomplete; in Comparative Example 4, the mass ratio of polyacrylic resin to methylcellulose is 3:1. Compared with Examples 4 and 6, the dissolution and release in Comparative Example 4 are slower, and the dissolution and release are incomplete in 30 minutes.

[0154] 3. Detect the stability data of the examples and comparative examples

[0155] The methods for the stress testing are based on the Chinese Pharmacopoeia 2020 Edition: (1) High temperature test: Take this product, remove the outer packaging, take 4 tablets, place them in a drug high temperature test chamber at 60°C for testing, and sample at 0, 5, 10, and 30 days respectively to detect related substances. (2) High humidity test: Take this product, remove the outer packaging, take 4 tablets, place them in a constant humidity closed container (75% RH) for placement, the temperature is room temperature (25°C), and sample at 0, 5, 10, and 30 days respectively to detect related substances. (3) Strong light irradiation test: Take this product, remove the outer packaging, take 4 tablets, place them under strong light irradiation with a light intensity of 4500 lx ± 500 lx, the temperature is room temperature (25°C), and sample at 0, 5, 10, and 30 days respectively to detect related substances.

[0156] Table 3 High temperature test of examples and comparative examples

[0157]

[0158] As can be seen from Comparative Table 3, for the oral membrane tablets obtained in Examples 1, 2, 3, 4, 5, 6 and 7 of the present invention, at 5 days, 10 days and 30 days under high temperature conditions, the contents of single impurities and total impurities are low, the increase of impurities is small, and the chemical stability is good; while in Comparative Examples 1, 2, 3 and 4, with the extension of time, the contents of single impurities and total impurities increase significantly, and the stability is significantly poor.

[0159] Table 4 High humidity test of examples and comparative examples

[0160]

[0161] As can be seen from Comparative Table 4, for the oral membrane tablets obtained in Examples 1, 2, 3, 4, 5, 6 and 7 of the present invention, at 5 days, 10 days and 30 days under high humidity conditions, the contents of single impurities and total impurities are low, the increase of impurities is small, and the chemical stability is good; while in Comparative Examples 1, 2, 3 and 4, with the extension of time, the contents of single impurities and total impurities increase significantly, and the stability is significantly poor.

[0162] Table 5 Strong light irradiation experiment of the embodiments and comparative examples

[0163]

[0164]

[0165] From Table 5, it can be seen that the oral films obtained in Examples 1, 2, 3, 4, 5, 6 and 7 of the present invention have low contents of single impurities and total impurities, small growth of impurities, and good chemical stability under strong light irradiation for 5 days, 10 days and 30 days; while in Comparative Examples 1, 2, 3 and 4, the contents of single impurities and total impurities increase significantly with the extension of time, and the stability is obviously poor.

[0166] From the results of the experiments on the influencing factors in the embodiments and comparative examples, it can be seen that the films obtained in Examples 1, 2, 3, 4, 5, 6, and 7 of the present invention have good stability under the conditions of 60°C, high humidity 75% RH, and light, while the films obtained in Comparative Examples 1, 2, 3, and 4 have poor stability under the conditions of 60°C, high humidity 75% RH, and light, and the impurities increase more.

[0167] The above results show that when the ratio of film-forming agent to purified water is set at 1:3-5, and the ratio of polyacrylic acid resin to methylcellulose in the film-forming agent is 0.5-2.0:1, the prepared Ebastine oral film has no insoluble matter and good flexibility, no bitter taste, a cool and sweet taste, good film-forming property, dissolution effect, stability, taste-masking effect and compliance, and is more suitable for the elderly and children than existing dosage forms on the market, and has great clinical significance.

Claims

1. An oral film containing ebastine, characterized in that, It is made from the following components in parts by weight: 1 part of the active component ebastine, 15 - 20 parts of polyoxyethylene 40 hydrogenated castor oil, 20 - 40 parts of glycerol, 2 - 6 parts of lactic acid, 15 - 25 parts of film-forming agent, 3 - 5 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, 0.05 part of menthol; the mass ratio of polyacrylic resin to methyl cellulose in the film-forming agent is 0.5 - 2.5:1; during its preparation process, first dissolve the active component ebastine in the lactic acid aqueous solution to make a medicinal solution, mix the obtained medicinal solution evenly with the mucilage made from the film-forming agent, glycerol and water, polyoxyethylene 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol and titanium dioxide, then defoam and make into film sheets to obtain the oral film sheets; wherein, the mass ratio of the film-forming agent to water is 1:3 - 5.

2. The oral film containing ebastine according to claim 1, characterized in that, The oral film sheets are made from the following components in parts by weight: 1 part of the active component ebastine, 15 parts of polyoxyethylene 40 hydrogenated castor oil, 20 - 30 parts of glycerol, 2 - 6 parts of lactic acid, 20 parts of film-forming agent, 4 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, 0.05 part of menthol; the mass ratio of polyacrylic resin to methyl cellulose in the film-forming agent is 1.0 - 1.5:

1.

3. The oral film containing ebastine according to claim 2, wherein, The oral film sheets are made from the following components in parts by weight: 1 part of the active component ebastine, 15 parts of polyoxyethylene 40 hydrogenated castor oil, 20 parts of glycerol, 2 parts of lactic acid, 10 parts of polyacrylic resin, 10 parts of methyl cellulose, 4 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, 0.05 part of menthol.

4. The oral film containing ebastine according to claim 2, wherein, The oral film sheets are made from the following components in parts by weight: 1 part of the active component ebastine, 15 parts of polyoxyethylene 40 hydrogenated castor oil, 20 parts of glycerol, 4 parts of lactic acid, 10 parts of polyacrylic resin, 10 parts of methyl cellulose, 4 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, 0.05 part of menthol.

5. The oral film containing ebastine according to claim 2, wherein The oral film sheets are made from the following components in parts by weight: 1 part of the active component ebastine, 15 parts of polyoxyethylene 40 hydrogenated castor oil, 20 parts of glycerol, 6 parts of lactic acid, 10 parts of polyacrylic resin, 10 parts of methyl cellulose, 4 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, 0.05 part of menthol.

6. The oral film containing ebastine according to claim 2, wherein The oral film sheets are made from the following components in parts by weight: 1 part of the active component ebastine, 15 parts of polyoxyethylene 40 hydrogenated castor oil, 30 parts of glycerol, 4 parts of lactic acid, 10 parts of polyacrylic resin, 10 parts of methyl cellulose, 4 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, 0.05 part of menthol.

7. The oral film containing ebastine according to claim 2, wherein The oral film is prepared from the following components in parts by weight: 1 part of active ingredient ebastine, 15 parts of polyoxyl 40 hydrogenated castor oil, 20 parts of glycerol, 4 parts of lactic acid, 12 parts of polyacrylic resin, 8 parts of methylcellulose, 4 parts of titanium dioxide, 2 parts of sorbitol, 1 part of sucralose, 0.05 part of strawberry essence, and 0.05 part of menthol.

8. The preparation method of the oral film containing ebastine according to claim 1, characterized in that, It comprises the following steps: (1) Preparation of the liquid medicine: After passing the active ingredient ebastine through a 60 - 100 mesh sieve, it is added to an aqueous lactic acid solution and stirred until dissolved to obtain a liquid medicine containing ebastine. (2) Preparation of the mucilage: The film - forming agent is added to water and stirred until dissolved, and then glycerol is added and stirred evenly to prepare the mucilage; wherein, the mass ratio of the film - forming agent to water is 1:3 - 5. (3) Mixing: The liquid medicine obtained in step (1), polyoxyl 40 hydrogenated castor oil, sorbitol, sucralose, strawberry essence, menthol, titanium dioxide and the mucilage obtained in step (2) are mixed evenly. (4) Defoaming: The mixed solution obtained in step (3) is defoamed. (5) Film - making: The defoamed mixed solution is pressed into a thin film with a thickness of 0.1 - 0.2 mm to form a wet film, which is demolded after drying, cut, and packaged to obtain the oral film, wherein the drying temperature is 50 - 70 °C.

9. The preparation method of the oral film containing ebastine according to claim 8, characterized in that In step (1), the ebastine passes through an 80 - mesh sieve; the mass ratio of polyacrylic resin to methylcellulose in the film - forming agent is 1.0 - 1.5:

1.

10. The preparation method of the oral film containing ebastine according to claim 8, characterized in that, In step (5), the drying temperature is 60 °C.

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