Desloratadine orally disintegrating film composition, preparation method and application thereof

Abstract

The present invention provides a desloratadine orally dissolving film composition, a preparation method thereof, and applications thereof. The present invention provides a desloratadine orally dissolving film composition comprising an active drug, a film-forming material, a plasticizer, and a flavoring agent. The active drug is 8-chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo-[5,6]heptylcyclo[1,2-b]pyridine as shown in Formula I. The desloratadine orally dissolving film composition of the present invention has a good dissolution rate, does not leave a gritty feeling after dissolving in the oral cavity, has a uniform appearance, good flexibility, does not settle during the film solution preparation process, and meets content uniformity requirements. #imgabs0#

Description

[0001] This application claims priority to a prior application filed with the State Intellectual Property Office of China on November 16, 2022, with patent application number 202211432537.6, entitled "A Desloratadine Orally Dissolving Film Composition, Preparation Method, and Use Thereof." The entire text of the prior application is incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of pharmaceutical preparations, and in particular to a desloratadine orally dissolving film composition with simple process and good stability, and a preparation method and application thereof. Background Art

[0003] Chronic urticaria refers to temporary inflammatory congestion and tissue edema of the skin, mucous membranes, and blood vessels caused by various factors. Chronic urticaria lasts for more than 6 weeks and the cause is often uncertain. Clinical manifestations include wheals and plaques that occur on the trunk, face, or limbs of patients at irregular intervals. Attacks vary from several times a day to once every few days. Allergic rhinitis is a non-infectious chronic inflammation of the nasal mucosa after contact with allergens (such as dust mites, pollen, animal fur, etc.), manifested by sneezing, clear nasal discharge, itchy nose, nasal congestion, etc., and may also cause loss of smell, itchy eyes, and conjunctival congestion. The common clinical symptoms of the above two diseases interfere with people's normal life, work, study, and health.

[0004] Desloratadine (lurasidone hydrochloride) is an antiallergic drug developed by Merck for the relief of systemic and localized symptoms of chronic urticaria and allergic rhinitis. Desloratadine is a third-generation antihistamine that introduces a hydrophilic group into a classical H1 receptor antagonist, resulting in a non-classical H1 receptor antagonist. It has the advantages of high selectivity, no sedative side effects, no significant drug interactions, and a wide range of indications. Currently, clinical dosage forms include tablets, capsules, dry suspensions, and syrups. Tablets and capsules are difficult to swallow, making them less suitable for children and elderly patients. They are also inconvenient to take without water. Syrups are in multiple-dose packaging, making them difficult to carry and requiring a measuring cup to measure a fixed dose before oral administration, significantly impacting the convenience of medication. Dry suspensions still require dilution before use, making them inconvenient to take without water. Therefore, a new formulation with ease of use, good compliance, and stable quality was developed to address these issues.

[0005] Desloratadine is a white to off-white powder that is slightly soluble in water and soluble in ethanol and propylene glycol. Given the limited solubility of desloratadine itself, many patents disclose methods for solubilizing desloratadine. For example, patents CN102697711B, CN103721267A, CN105412106A, and WO2007096733A2 all use cyclodextrin as a solubilizing agent to increase the solubility of the drug in water; patent CN106667922A discloses a method for preparing a desloratadine solid dispersion, in which the drug exists in an amorphous form in the preparation, thereby increasing the solubility of the drug in water. Although the patents improve the solubility of desloratadine through different means, the final dosage forms prepared are mainly tablets, solutions, and granules, which cannot improve the compliance of patients with swallowing difficulties.

[0006] Therefore, there is a need to develop a dosage form of desloratadine that improves drug solubility and solves the problem of poor medication compliance among patients, and is particularly suitable for patients with dysphagia, so as to improve patient compliance. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a desloratadine orally dissolving film composition, a preparation method, and applications thereof in order to overcome the defects of the prior art such as low solubility of desloratadine, which limits its bioavailability, makes it inconvenient to take, and leads to poor patient compliance. The desloratadine orally dissolving film provided by the present invention has the advantages of being thin, having a good mouthfeel, being stable, being able to dissolve instantly in the mouth without drinking water, and having a fast oral absorption rate. Furthermore, the process is simple, the drug loading capacity is high, and the drug content uniformity is good. The problem of poor patient compliance is solved, and the desloratadine orally dissolving film is particularly suitable for patients with dysphagia.

[0008] The present invention provides a desloratadine orally dissolving film composition, which comprises an active drug, a film-forming material, a plasticizer and a flavoring agent. The active drug is 8-chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo-[5,6]heptylcyclo[1,2-b]pyridine as shown in Formula I;

[0009]

[0010] The desloratadine orally disintegrating film composition of the present invention preferably does not contain an organic solvent (such as ethanol).

[0011] The mass percentage of the active drug is preferably 1.0% to 30.0%, for example 5.0%, 7.6%, 8.3%, 8.7%, 9.0%, 9.8%, 10.0%, 11.5%, 12.3%, 13.6%, 14.2%, 14.5%, 15.0%, 15.4%, 15.5%, 16.0%, 16.6%, 16.7%, 20.0%, 28.6% or 30.0%, wherein the mass percentage refers to the mass of the active drug as a percentage of the total mass of the loratadine orally dissolving film composition.

[0012] The film-forming material is a drug carrier, preferably one or more of xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hydroxypropyl methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, polyoxyethylene, pullulan, acrylic acid copolymer, polylactic acid and silicone rubber. The mass percentage of the film-forming material is preferably 20% to 70%, for example, 20.0%, 23.0%, 24.7%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, 51.2%, 53.2%, 53.3%, 55.0%, 56.6%, 32.6%, 64.1%, 60.3%, 66.7%, 57.1%, 57.6%, 60.0%, 61.9%, 62.6%, 65.0%, 66.7%, 68.9% or 70.0%. The mass percentage refers to the percentage of the mass of the film-forming material to the total mass of the orally dissolving loratadine film composition.

[0013] The plasticizer is used to lower the glass transition temperature of the film, increase plasticity and toughness, and improve elongation. It is preferably one or more of polyethylene glycol, glycerol, propylene glycol, silicone oil, polypropylene glycol, and hexylene glycol. The mass percentage of the plasticizer is preferably 0% to 30%, for example, 3.0%, 4.6%, 4.9%, 5.0%, 5.7%, 6.2%, 6.4%, 6.7%, 6.8%, 7.2%, 7.4%, 10.0%, 10.7%, 11.7%, 12.0%, 14.3%, 15.0%, 16.7%, 19.1%, 20.0%, 22.7%, 25.0%, or 30.0%. The mass percentage refers to the percentage of the mass of the plasticizer to the total mass of the orally dissolving loratadine film composition.

[0014] The flavoring agent acts as a flavoring agent in the film, and is preferably one or more of aspartame, sucralose, fructose, sucrose, stevioside, glycyrrhizin, flavors (e.g., strawberry flavor, orange flavor, etc.), spices, menthol, sodium chloride, saccharin, and saccharin sodium. The weight percentage of the flavoring agent is preferably 5.0% to 20.0%, for example, 5.0%, 8.6%, 8.0%, 9.8%, 10.0%, 10.7%, 11.4%, 14.5%, 12.8%, 12.0%, 13.3%, 13.8%, 15.0%, or 20.0%, wherein the weight percentage refers to the percentage of the weight of the flavoring agent to the total weight of the orally dissolving loratadine film composition.

[0015] The desloratadine orally dissolving film composition of the present invention may further include one or more of a pH regulator, a disintegrant, a saliva stimulant, a solubilizer, an absorption promoter, a stabilizer, a filler, a colorant, an anti-adhesive agent, and an antibacterial agent.

[0016] In the present invention, the pH regulator refers to a substance that has a pH regulating effect, and is selected from one or more of hydrochloric acid, citric acid, sodium citrate and sodium hydroxide.

[0017] When the desloratadine orosoluble film composition contains a pH regulator, the total mass of the desloratadine orosoluble film composition does not include the mass of the pH regulator.

[0018] In the present invention, the disintegrant refers to an excipient that promotes the rapid disintegration of the drug into small particles in the gastrointestinal tract, and is preferably one or more of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, starch, microcrystalline cellulose, and pregelatinized starch. The percentage of the disintegrant is preferably 0 to 10.0%, and the mass percentage refers to the percentage of the mass of the disintegrant to the total mass of the orally disintegrating film composition of loratadine.

[0019] In the present invention, the saliva stimulant refers to a substance that stimulates saliva production, preferably one or more of citric acid, tartaric acid, malic acid, and mannitol. The saliva stimulant content is preferably 0-15.0%, and the mass percentage refers to the percentage of the mass of the saliva stimulant to the total mass of the oro-loratadine film-dissolving composition.

[0020] The solubilizer is used to increase the solubility of the drug, and is preferably one or more of cyclodextrin, polyethylene glycol-15 hydroxystearate, and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. The solubilizer preferably has a mass percentage of 20% to 40%, such as 20.0%, 30.0%, 36.2%, or 40.0%, where the mass percentage refers to the percentage of the mass of the solubilizer to the total mass of the orally dissolving loratadine film composition.

[0021] The absorption enhancer promotes drug absorption and is preferably one or more of benzalkonium chloride, cetylpyridinium chloride, cyclodextrin, edetic acid, polysorbate (e.g., polysorbate 80), menthol, and sodium lauryl sulfate. The mass percentage of the absorption enhancer is preferably 0 to 5.0%, more preferably 0.1 to 5.0%, where the mass percentage refers to the percentage of the mass of the absorption enhancer to the total mass of the orally dissolving loratadine film composition.

[0022] In the present invention, the stabilizer is a substance that stabilizes the finished product, preferably one or more of disodium edetate, vitamin C, vitamin E, povidone, cyclodextrin, poloxamer, Tween, Span, colloidal silicon dioxide, sodium sulfite, sodium bisulfite, cysteine ​​hydrochloride, sodium metabisulfite, and sodium thiosulfate. The stabilizer content is preferably 0-30.0%, more preferably 0-20.0%, for example, 5.0%, 8.6%, 6.9%, 10.0%, 15.0%, 20.0%, 16.4%, 9.0%, 22.80%, 25.0%, or 30.0%. The mass percentage refers to the percentage of the mass of the stabilizer to the total mass of the orally dissolving loratadine film-forming composition.

[0023] In the present invention, the filler refers to a solid substance added to a material to improve material properties, increase volume, increase weight, and reduce material costs, preferably one or more of mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose. The filler content is preferably 0-55.0%, more preferably 0-50.0%, for example, 9.3%, 10.0%, 20.0%, 30.0%, 40.0%, 45.0%, 49.4%, 45.9%, 50.0%, or 55.0%. The mass percentage refers to the percentage of the filler's mass to the total mass of the orally dissolving loratadine film-forming composition.

[0024] In the present invention, the colorant refers to a substance that can improve the appearance color of the preparation, can be used to identify the concentration of the preparation, distinguish the application method, and reduce the patient's aversion to taking the medicine. It is preferably one or more of titanium dioxide, pigments, and lakes (such as FD&C Red 40 Aluminum Lake). The percentage of the colorant is preferably 0-2.0%, for example, 0.1%, 0.2%, 0.8%, 1.1%, 1.2%, 1.3%, 1.5%, or 2.0%. The mass percentage refers to the percentage of the mass of the colorant to the total mass of the orally dissolving loratadine film-forming composition.

[0025] In the present invention, the anti-adherent agent is capable of improving the performance of the preparation and preventing adhesion between preparations, and is preferably one or more of talc, magnesium stearate, and calcium stearate. The anti-adherent agent preferably has a content of 0 to 2.0%, and the mass percentage refers to the percentage of the mass of the anti-adherent agent to the total mass of the orally dissolving loratadine film-forming composition.

[0026] In the present invention, the antibacterial agent refers to a substance capable of inhibiting bacterial production, preferably one or more of methylparaben, ethylparaben, and sodium thiosulfate. The antibacterial agent content is preferably 0-1.0%, and the mass percentage refers to the mass percentage of the antibacterial agent relative to the total mass of the orally disintegrating loratadine film composition.

[0027] The desloratadine orally dissolving film composition of the present invention can be any of the following formulations:

[0028] Prescription A: 5.0% to 20.0% desloratadine, 30.0% to 65.0% film-forming material, 0 to 40.0% solubilizer (e.g., cyclodextrin), 5.0% to 25.0% glycerol, 0 to 10.0% filler (e.g., mannitol), 10.0% to 15.0% flavoring agent (e.g., sucralose), and 0.8% to 1.3% colorant (e.g., titanium dioxide); the film-forming material is selected from polyvinyl alcohol, hydroxyethyl cellulose, hypromellose, and pullulan; the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition;

[0029] Formulation B: 15.0% to 30.0% desloratadine, 55.0% to 70.0% film-forming material, and 10.0% to 20.0% plasticizer (e.g., glycerol and / or propylene glycol), wherein the film-forming material is selected from polyvinyl alcohol, hypromellose, and pullulan; the mass percentages described refer to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0030] Formulation C: 10.0% to 20.0% desloratadine, 55.0% to 65.0% film-forming material and 10.0% to 15.0% plasticizer (e.g., glycerol and / or propylene glycol), 0 to 10.0% stabilizer (e.g., disodium edetate and / or vitamin C), 8.0% to 15.0% flavoring agent (e.g., sucralose and / or essence), and 0.1% to 0.2% colorant (e.g., FD&C Red No. 40 aluminum lake); the film-forming material is selected from polyvinyl alcohol and / or hypromellose; the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition;

[0031] Formulation D: 10.0% to 15.0% desloratadine, 20.0% to 25.0% film-forming material (e.g., polyvinyl alcohol), 3.0% to 5.0% plasticizer (e.g., glycerin and / or propylene glycol), 40.0% to 55.0% filler (e.g., microcrystalline cellulose and / or mannitol), 0 to 10.0% stabilizer (e.g., disodium edetate and / or vitamin C), 5.0% to 10.0% flavoring agent (e.g., sucralose and / or essence), and 0.1% to 0.2% colorant (e.g., FD&C Red No. 40 aluminum lake); the mass percentages mentioned refer to the mass percentage of each component relative to the total mass of the desloratadine orally dissolving film composition;

[0032] Formulation E: 5.0% to 10.0% desloratadine (e.g., 8.3%), 55.0% to 60.0% film-forming material (e.g., hypromellose), 5.0% to 10.0% plasticizer (e.g., glycerin and / or propylene glycol), 10.0% to 20.0% stabilizer (e.g., disodium edetate and / or vitamin C), 8.0% to 12.0% flavoring agent, 0.1% to 0.2% coloring agent (e.g., FD&C Red No. 40 aluminum lake), and pH adjuster (e.g., hydrochloric acid). The pH of the formulation is 1.7 to 2.2 (e.g., 1.7, 1.8, 1.9, 2.0, 2.1, or 2.2). The flavoring agent is selected from one or more of sucralose, essence, sodium chloride, and menthol. The mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition.

[0033] Formulation F: 5.0% to 10.0% desloratadine, 50.0% to 70.0% film-forming material (e.g., hypromellose), 5.0% to 10.0% plasticizer (e.g., glycerol and / or propylene glycol), 0 to 20.0% stabilizer (e.g., disodium edetate and / or vitamin C), 8.0% to 15.0% flavoring agent, 0.1% to 0.2% colorant (e.g., FD&C Red No. 40 aluminum lake), and pH adjuster (e.g., hydrochloric acid). The pH of the formulation is 1.7 to 2.2 (e.g., 1.7, 1.8, 1.9, 2.0, 2.1, or 2.2). The flavoring agent is selected from one or more of sucralose, essence, sodium chloride, and menthol. The mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition.

[0034] The desloratadine orally dissolving film composition of the present invention may also be any of the following formulations:

[0035] Prescription 1: 13.6% desloratadine, 11.4% polyvinyl alcohol, 39.8% hypromellose, 22.7% glycerol, 11.4% sucralose and 1.1% titanium dioxide, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0036] Prescription 2: 8.7% desloratadine, 7.2% polyvinyl alcohol, 25.4% hypromellose, 36.2% cyclodextrin, 7.2% glycerol, 14.5% sucralose and 0.8% titanium dioxide, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0037] Prescription 3: 15.4% desloratadine, 38.5% hydroxyethyl cellulose, 25.6% pullulan, 6.4% glycerol, 12.8% sucralose and 1.3% titanium dioxide, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0038] Prescription 4: 14.5% desloratadine, 36.1% hydroxyethyl cellulose, 24.2% pullulan, 12.0% glycerol, 12.0% sucralose and 1.2% titanium dioxide, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0039] Prescription 5: 16.0% desloratadine, 40.0% hydroxyethyl cellulose, 13.3% pullulan, 6.8% glycerol, 13.3% sucralose, 9.3% mannitol and 1.3% titanium dioxide, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0040] Prescription 6: 16.6% desloratadine, 66.7% hypromellose and 16.7% glycerol, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0041] Prescription 7: 16.6% desloratadine, 66.7% hypromellose and 16.7% propylene glycol, the mass percentages mentioned refer to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0042] Prescription 8: 28.6% desloratadine, 57.1% polyvinyl alcohol and 14.3% glycerol, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0043] Prescription 9: 28.6% desloratadine, 57.1% polyvinyl alcohol and 14.3% propylene glycol, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0044] Prescription 10: 20.0% desloratadine, 60.0% pranolol and 20.0% glycerol, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0045] Prescription 11: 20.0% desloratadine, 60.0% pranolol and 20.0% propylene glycol, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0046] Prescription 12: 15.5% desloratadine, 61.9% hypromellose, 11.7% glycerin, 1.5% sucralose, 9.2% flavor and 0.2% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0047] Prescription 13: 15.5% desloratadine, 61.9% hypromellose, 11.7% propylene glycol, 1.5% sucralose, 9.2% flavor and 0.2% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0048] Prescription 14: 14.2% desloratadine, 56.6% hypromellose, 10.7% glycerin, 8.6% disodium edetate, 1.4% sucralose, 8.4% flavor and 0.1% lake, the mass percentages refer to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition;

[0049] Prescription 15: 14.2% desloratadine, 56.6% hypromellose, 10.7% glycerin, 8.6% vitamin C, 1.4% sucralose, 8.4% flavor and 0.1% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0050] Prescription 17: 12.3% desloratadine, 24.7% polyvinyl alcohol, 4.9% glycerol, 49.4% microcrystalline cellulose (MCC), 1.2% sucralose, 7.4% flavor and 0.1% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0051] Prescription 18: 12.3% desloratadine, 24.7% polyvinyl alcohol, 4.9% glycerol, 49.4% mannitol, 1.2% sucralose, 7.4% flavor and 0.1% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition;

[0052] Prescription 19: 11.5% desloratadine, 23.0% polyvinyl alcohol, 4.6% glycerol, 45.9% microcrystalline cellulose (MCC), 6.9% edetate disodium, 1.1% sucralose, 6.9% flavor and 0.1% lake, the mass percentages mentioned refer to the mass percentage of each component to the total mass of the desloratadine orally dissolving film composition;

[0053] Prescription 20: 11.5% desloratadine, 23.0% polyvinyl alcohol, 4.6% glycerol, 45.9% microcrystalline cellulose (MCC), 6.9% edetate disodium, 1.1% sucralose, 6.9% flavor and 0.1% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition;

[0054] Prescription 21: 8.3% desloratadine, 57.6% hypromellose, 6.2% propylene glycol, 16.4% edetate disodium, 3.3% sucralose, 1.6% sodium chloride, 1.6% menthol, 4.9% flavor, 0.1% FD&C Red No. 40 aluminum lake, and 3.7% hydrochloric acid (the mass concentration refers to the percentage of the mass of hydrogen chloride to the mass of the hydrochloric acid aqueous solution, and the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition, and the pH of the composition is 1.8);

[0055] Prescription 22: 8.3% desloratadine, 57.6% hypromellose, 6.2% propylene glycol, 16.4% edetate disodium, 3.3% sucralose, 1.6% sodium chloride, 1.6% menthol, 4.9% orange flavor, 0.1% FD&C Red No. 40 aluminum lake, and 3.7% hydrochloric acid (the mass concentration refers to the percentage of the mass of hydrogen chloride to the mass of the hydrochloric acid aqueous solution, and the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition, and the pH of the composition is 2.2);

[0056] Prescription 23: 8.3% desloratadine, 57.6% hypromellose, 6.2% propylene glycol, 16.4% edetate disodium, 3.3% sucralose, 1.6% sodium chloride, 1.6% menthol, 4.9% orange flavor, 0.1% FD&C Red No. 40 aluminum lake, and 3.7% hydrochloric acid (the mass concentration refers to the percentage of the mass of hydrogen chloride to the mass of the hydrochloric acid aqueous solution, and the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition, and the pH of the composition is 2.0);

[0057] Prescription 24: 8.3% desloratadine, 57.6% hypromellose, 6.2% propylene glycol, 16.4% edetate disodium, 3.3% sucralose, 1.6% sodium chloride, 1.6% menthol, 4.9% flavor, 0.1% FD&C Red No. 40 aluminum lake, and 3.7% hydrochloric acid (the mass concentration refers to the percentage of the mass of hydrogen chloride to the mass of the hydrochloric acid aqueous solution, and the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition, and the pH of the composition is 1.7);

[0058] Prescription 25: 9.8% desloratadine, 68.9% hypromellose, 7.4% propylene glycol, 3.9% sucralose, 2.0% sodium chloride, 2.0% menthol, 5.9% flavor, 0.1% FD&C Red No. 40 aluminum lake, and 3.7% hydrochloric acid (the mass concentration refers to the percentage of the mass of hydrogen chloride to the mass of the hydrochloric acid aqueous solution, and the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition. The pH of the prescription is 1.8);

[0059] Prescription 26: 9.0% desloratadine, 62.6% hypromellose, 6.7% propylene glycol, 9.0% edetate disodium, 3.6% sucralose, 1.8% sodium chloride, 1.8% menthol, 5.4% flavor, 0.1% FD&C Red No. 40 aluminum lake, and 3.7% hydrochloric acid (the mass concentration refers to the percentage of the mass of hydrogen chloride to the mass of the hydrochloric acid aqueous solution, and the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition. The pH of the prescription is 1.8);

[0060] Prescription 27: 7.6% desloratadine, 53.2% hypromellose, 5.7% propylene glycol, 22.8% edetate disodium, 3.0% sucralose, 1.5% sodium chloride, 1.5% menthol, 4.6% flavor, 0.1% FD&C Red No. 40 aluminum, and 3.7% hydrochloric acid (the mass concentration refers to the percentage of the mass of hydrogen chloride to the mass of the hydrochloric acid aqueous solution, and the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition). The pH of the prescription is 1.8.

[0061] When a pH regulator is included, the pH of the desloratadine orally dissolving film composition can be 1.5 to 2.5, such as 1.7, 1.8, 1.9, 2.0 or 2.2.

[0062] In the present invention, the mass percentage of each component in the desloratadine orally dissolving film composition is 100%. However, it should be understood that there may be a rounding error of ±0.2% due to rounding of values.

[0063] The present invention also provides a method for preparing the desloratadine orally dissolving film composition, wherein the first method comprises the following steps:

[0064] 1) Pretreatment of raw materials and auxiliary materials: raw materials are sieved through a 30-mesh sieve, and auxiliary materials are sieved through a 60-mesh sieve;

[0065] 2) dissolving all components except the active drug and film-forming material in water to form a solution;

[0066] 3) adding the film-forming material to the solution obtained in step 2), heating and stirring at 60° C. to 70° C. to obtain a blank glue solution after dissolving;

[0067] 4) placing the active drug into the blank glue obtained in step 3), stirring until uniformly dispersed, and stirring and degassing under vacuum conditions to obtain drug-containing glue;

[0068] 5) The drug-containing adhesive obtained in step 4) after degassing is evenly coated on a polyester tape with a scraper, and then heated, dried, and cut to obtain a desloratadine orally dissolving film composition.

[0069] Method 2 includes the following steps:

[0070] 1) Pretreatment of raw materials and auxiliary materials: raw materials are sieved through a 30-mesh sieve, and auxiliary materials are sieved through a 60-mesh sieve;

[0071] 2) Add membrane-forming material to purified water, heat and stir at 60°C to 70°C, and dissolve to obtain blank glue solution;

[0072] 3) adding the prescribed amount of other components except the active ingredient to the blank glue obtained in step 2), adding the active drug after cooling, stirring until uniformly dispersed, and stirring and degassing under vacuum conditions to obtain the drug-containing glue;

[0073] 4) The drug-containing adhesive obtained in step 3) after degassing is evenly coated on a polyester tape with a scraper, and then heated, dried, and cut to obtain a desloratadine orally dissolving film composition.

[0074] Method 3 includes the following steps:

[0075] 1) Adjust the temperature to 40°C, add the prescribed amount of flavoring agent (essence), stabilizer, plasticizer and colorant, add solvent and disperse evenly to obtain a solution;

[0076] 2) lowering the temperature of the solution obtained in step 1) to below 25° C., adding the active drug (e.g., desloratadine), adjusting the pH value using a pH adjuster to the target pH value, and then gradually adding a film-forming material (e.g., hypromellose) at 25° C. and uniformly dispersing the mixture to obtain a glue intermediate;

[0077] 3) The glue intermediate obtained in step 2) is coated, dried at 40° C., cut, and packaged to obtain a desloratadine orally dissolving film composition.

[0078] The thickness of the desloratadine orally disintegrating film composition is 10 μm to 200 μm, for example, 61 μm, 64 μm, 65 μm, 67 μm, 68 μm, 69 μm, 70 μm, 71 μm, 72 μm, 73 μm, 74 μm, 75 μm, 79 μm, 80 μm or 83 μm.

[0079] The desloratadine orally disintegrating film composition can be completely dissolved in simulated saliva at 37±1°C within 2 minutes, especially within 1 minute (for example, 18 seconds, 20 seconds, 21 seconds, 22 seconds, 24 seconds, 25 seconds, 26 seconds, 27 seconds, 28 seconds, 29 seconds, 30 seconds, 31 seconds, 34 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 54 seconds or 60 seconds), and release desloratadine.

[0080] The present invention also provides use of the desloratadine orally dissolving film composition in preparing a medicine for treating and / or allergic rhinitis and allergic rhinitis.

[0081] The present invention also provides a method for treating and / or allergic rhinitis and allergic rhinitis. The method comprises administering a therapeutically effective amount of the desloratadine orosoluble film composition to a patient in need.

[0082] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0083] The reagents and raw materials used in the present invention are commercially available.

[0084] The positive improvement effect of the present invention is that the desloratadine orally dissolving film composition of the present invention has a good dissolution rate, does not leave a gritty feeling after dissolving in the oral cavity, has a uniform appearance, good flexibility, and does not undergo sedimentation during the film liquid preparation process, and the content uniformity meets the requirements. DETAILED DESCRIPTION

[0085] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0086] Example 1-5: The prescription is as follows:

[0087]

[0088]

[0089] ** Weight of raw materials after removing water

[0090] Preparation method:

[0091] 1) Pretreatment of raw materials and auxiliary materials: raw materials are sieved through a 30-mesh sieve, and auxiliary materials are sieved through a 60-mesh sieve;

[0092] 2) dissolving all components except the active drug and film-forming material in water to form a solution;

[0093] 3) adding the film-forming material to the solution obtained in step 2), heating and stirring at 60° C. to 70° C. to obtain a blank glue solution after dissolving;

[0094] 4) placing the active drug into the blank glue obtained in step 3), stirring until uniformly dispersed, and stirring and degassing under vacuum conditions to obtain drug-containing glue;

[0095] 5) The drug-containing adhesive obtained in step 4) after degassing is evenly coated on a polyester tape with a scraper, and then heated, dried, and cut to obtain a desloratadine orally dissolving film composition.

[0096] According to the prescriptions of Examples 1 to 5, desloratadine orally disintegrating film preparations were prepared using the preparation method provided by the present invention and their disintegration time was measured. The specific measurement method is as follows:

[0097] Take 6 films at random, one at a time, and gently place them in artificial saliva at 37±1℃. Leave them still and observe the time it takes for the product to completely dissolve.

[0098] Example Disintegration time (s) 1 37±7 2 28±3 3 39±4 4 43±5 5 32±4

[0099] According to the above experimental data, the desloratadine orally disintegrating film composition provided by the present invention has the advantages of thin thickness, good taste, stable properties, and can be dissolved in the mouth without drinking water and has a fast oral absorption rate.

[0100] Examples 6 to 11: The prescriptions are as follows:

[0101]

[0102] ** Weight of raw materials after removing water

[0103] Preparation method:

[0104] 1) Pretreatment of raw materials and auxiliary materials: raw materials are sieved through a 30-mesh sieve, and auxiliary materials are sieved through a 60-mesh sieve;

[0105] 2) Add membrane-forming material to purified water, heat and stir at 60°C to 70°C, and dissolve to obtain blank glue solution;

[0106] 3) adding the prescribed amount of other components except the active ingredient to the blank glue obtained in step 2), adding the active drug after cooling, stirring until uniformly dispersed, and stirring and degassing under vacuum conditions to obtain the drug-containing glue;

[0107] 4) The drug-containing adhesive obtained in step 3) after degassing is evenly coated on a polyester tape with a scraper, and then heated, dried, and cut to obtain a desloratadine orally dissolving film composition.

[0108] According to the prescriptions of Examples 6 to 11, desloratadine orally disintegrating film preparations were prepared using the preparation method provided by the present invention, and their film-forming properties, dissolution (orally disintegrating film pieces cut to appropriate sizes were placed in 200 ml of purified water and the dissolution was observed at room temperature), and film performance after overnight (conditions: 25° C., 55-70% RH) were investigated.

[0109]

[0110] Conclusion: The film-forming properties of Examples 6 to 11 are all ideal. When hypromellose is used as the film-forming material, both its film-forming properties and overnight observations show excellent and stable performance, making it suitable for scale-up. The formulations of Examples 6, 7, and 9 have even better stability.

[0111] Examples 12 to 16: The prescriptions are as follows:

[0112]

[0113]

[0114] ** Weight of raw materials after removing water

[0115] FD&C Red No. 40 Aluminum Lake refers to the conventional commercially available Fancy Red Aluminum Lake (Allura Red Aluminum Lake) reagent.

[0116] Preparation method:

[0117] 1) Pretreatment of raw materials and auxiliary materials: raw materials are sieved through a 30-mesh sieve, and auxiliary materials are sieved through a 60-mesh sieve;

[0118] 2) dissolving all components except the active drug and film-forming material in water to form a solution;

[0119] 3) adding the film-forming material to the solution obtained in step 2), heating and stirring at 60° C. to 70° C. to obtain a blank glue solution after dissolving;

[0120] 4) placing the active drug into the blank glue obtained in step 3), stirring until uniformly dispersed, and stirring and degassing under vacuum conditions to obtain drug-containing glue;

[0121] 5) The drug-containing adhesive obtained in step 4) after degassing is evenly coated on a polyester tape with a scraper, and then heated, dried, and cut to obtain a desloratadine orally dissolving film composition.

[0122] According to the prescriptions of Examples 12 to 16, desloratadine orally dissolving film preparations were prepared using the preparation method provided by the present invention and their stability at 60° C. was measured:

[0123]

[0124]

[0125] Examples 17-20: The prescriptions are as follows:

[0126]

[0127] ** Weight of raw materials after removing water

[0128] Preparation method:

[0129] 1) Pretreatment of raw materials and auxiliary materials: raw materials are sieved through a 30-mesh sieve, and auxiliary materials are sieved through a 60-mesh sieve;

[0130] 2) dissolving all components except the active drug and film-forming material in water to form a solution;

[0131] 3) adding the film-forming material to the solution obtained in step 2), heating and stirring at 60° C. to 70° C. to obtain a blank glue solution after dissolving;

[0132] 4) placing the active drug into the blank glue obtained in step 3), stirring until uniformly dispersed, and stirring and degassing under vacuum conditions to obtain drug-containing glue;

[0133] 5) The drug-containing adhesive obtained in step 4) after degassing is evenly coated on a polyester tape with a scraper, and then heated, dried, and cut to obtain a desloratadine orally dissolving film composition.

[0134] According to the prescriptions of Examples 17 to 20, desloratadine orally dissolving film preparations were prepared using the preparation method provided by the present invention and their stability at 60° C. was measured:

[0135]

[0136] Conclusion: When microcrystalline cellulose is used as a filler, the disintegration time is significantly faster, and the differences in related substances are not significant.

[0137] Example 21: The prescription is as follows:

[0138]

[0139] ** Weight of raw materials after removing water

[0140] The preparation method is as follows:

[0141] 1) Adjust the temperature to 40°C, add the prescribed amount of flavoring agent (essence), stabilizer, plasticizer and colorant, add solvent and disperse evenly to obtain a solution;

[0142] 2) lowering the temperature of the solution obtained in step 1) to below 25° C., adding the active drug desloratadine, and adjusting the pH value using a pH adjuster to the target pH value. Then, gradually adding a film-forming material (hydroxypropyl methylcellulose) at 25° C. and uniformly dispersing the mixture to obtain a glue intermediate;

[0143] 3) The glue intermediate obtained in step 2) is coated, dried at 40° C., cut, and packaged to obtain a desloratadine orally dissolving film composition.

[0144] The obtained samples were placed under 50°C, 40°C ± 2°C / relative humidity 75% ± 5% (stability data) to investigate stability. The obtained stability data are as follows:

[0145]

[0146] Conclusion: The product obtained by prescription 21 is very stable under high temperature conditions and even after accelerated treatment for 1 month.

[0147] Examples 22-24: The prescriptions are as follows:

[0148]

[0149] ** Weight of raw materials after removing water

[0150] The preparation method is as follows:

[0151] 1) Adjust the temperature to 40°C, add the prescribed amount of flavoring agent (essence), stabilizer, plasticizer and colorant, add solvent and disperse evenly to obtain a solution;

[0152] 2) lowering the temperature of the solution obtained in step 1) to below 25° C., adding the active drug desloratadine, and adjusting the pH value using a pH adjuster to the target pH value. Then, gradually adding the film-forming material hypromellose at 25° C. and dispersing uniformly to obtain a glue intermediate;

[0153] 3) The glue intermediate obtained in step 2) is coated, dried at 40° C., cut, and packaged to obtain a desloratadine orally dissolving film composition.

[0154] The obtained samples were placed under 50°C, 40°C ± 2°C / relative humidity 75% ± 5% (stability data) to investigate stability. The obtained stability data are as follows:

[0155]

[0156] Conclusion: When the pH value of the intermediate is set at 1.9±0.1, it has good stability.

[0157] Examples 25-27: The prescriptions are as follows:

[0158]

[0159] ** Weight of raw materials after removing water

[0160] The preparation method is as follows:

[0161] 1) Adjust the temperature to 40°C, add the prescribed amount of flavoring agent (essence), stabilizer, plasticizer and colorant, add solvent and disperse evenly to obtain a solution;

[0162] 2) lowering the temperature of the solution obtained in step 1) to below 25° C., adding the active drug desloratadine, and adjusting the pH value using a pH adjuster to the target pH value. Then, gradually adding the film-forming material hypromellose at 25° C. and dispersing uniformly to obtain a glue intermediate;

[0163] 3) The glue intermediate obtained in step 2) is coated, dried at 40° C., cut, and packaged to obtain a desloratadine orally dissolving film composition.

[0164] The obtained samples were placed under 50°C, 40°C ± 2°C / relative humidity 75% ± 5% (stability data) to investigate stability. The obtained stability data are as follows:

[0165]

[0166]

[0167] Conclusion: Using this method, when the system pH is adjusted to 1.8, the amount of EDTA-2Na in the formulation has no effect on the stability, and the formulation without EDTA-2Na has better stability.

Claims

1. A desloratadine orally dissolving film composition, characterized in that The invention comprises: an active drug, a film-forming material, a plasticizer and a flavoring agent, wherein the active drug is 8-chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo-[5,6]heptylcyclo[1,2-b]pyridine as shown in Formula I; The film-forming material is one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose and polyvinyl alcohol; The plasticizer is glycerol and / or propylene glycol; The flavoring agent is one or more of sucralose, essence and menthol; The mass percentage of the active drug is 7.6% to 30%, and the mass percentage refers to the percentage of the mass of the active drug to the total mass of the loratadine orally dissolving film composition; The mass percentage of the film-forming material is 20% to 70%, and the mass percentage refers to the percentage of the mass of the film-forming material to the total mass of the orally dissolving loratadine film composition; The mass percentage of the plasticizer is 3% to 30%, and the mass percentage refers to the percentage of the mass of the plasticizer to the total mass of the orally dissolving loratadine film composition; The weight percentage of the flavoring agent is 5.0% to 20.0%, and the weight percentage refers to the weight percentage of the flavoring agent to the total weight of the desloratadine orodissolving film composition; the desloratadine orodissolving film composition does not contain ethanol; 2. The desloratadine orally dissolving film composition according to claim 1, wherein: The desloratadine orally dissolving film composition further comprises a combination of one or more of a disintegrant, an absorption promoter, a stabilizer, a filler, and a colorant.

3. The desloratadine orally dissolving film composition according to claim 2, wherein: The disintegrant is one or more of starch, microcrystalline cellulose and pregelatinized starch; and / or, The absorption enhancer is one or more of cyclodextrin, edetic acid, and menthol; and / or, The stabilizer is one or more of disodium edetate, vitamin C, vitamin E, and cyclodextrin; and / or, The filler is one or more of mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose; and / or, The colorant is one or more of titanium dioxide, pigment and lake.

4. The desloratadine orally dissolving film composition according to claim 3, wherein: The percentage content of the disintegrant is 0-10.0%, and the mass percentage content refers to the mass percentage of the disintegrant to the total mass of the orally disintegrating loratadine film composition; and / or, The mass percentage of the absorption enhancer is 0.1% to 5%, and the mass percentage refers to the mass percentage of the absorption enhancer to the total mass of the loratadine orally dissolving film composition; and / or, The percentage of the stabilizer is 0-20.0%, and the mass percentage refers to the mass of the stabilizer as a percentage of the total mass of the loratadine orally dissolving film composition; and / or, The filler content is 0-50.0%, and the mass percentage refers to the mass of the filler as a percentage of the total mass of the loratadine orally dissolving film composition; and / or, The percentage content of the colorant is 0-2.0%, and the mass percentage content refers to the percentage of the mass of the colorant to the total mass of the orally dissolving loratadine film composition.

5. The desloratadine orally dissolving film composition according to claim 1, wherein: The desloratadine orally dissolving film composition can be any of the following formulations: Prescription 1: 13.6% desloratadine, 11.4% polyvinyl alcohol, 39.8% hypromellose, 22.7% glycerol, 11.4% sucralose and 1.1% titanium dioxide, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition; Prescription 2: 8.7% desloratadine, 7.2% polyvinyl alcohol, 25.4% hypromellose, 36.2% cyclodextrin, 7.2% glycerol, 14.5% sucralose and 0.8% titanium dioxide, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition; Prescription 12: 15.5% desloratadine, 61.9% hypromellose, 11.7% glycerin, 1.5% sucralose, 9.2% flavor and 0.2% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition; Prescription 13: 15.5% desloratadine, 61.9% hypromellose, 11.7% propylene glycol, 1.5% sucralose, 9.2% flavor and 0.2% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition; Prescription 14: 14.2% desloratadine, 56.6% hypromellose, 10.7% glycerin, 8.6% disodium edetate, 1.4% sucralose, 8.4% flavor and 0.1% lake, the mass percentages refer to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition; Prescription 15: 14.2% desloratadine, 56.6% hypromellose, 10.7% glycerin, 8.6% vitamin C, 1.4% sucralose, 8.4% flavor and 0.1% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition; Prescription 17: 12.3% desloratadine, 24.7% polyvinyl alcohol, 4.9% glycerol, 49.4% microcrystalline cellulose, 1.2% sucralose, 7.4% flavor and 0.1% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition; Prescription 18: 12.3% desloratadine, 24.7% polyvinyl alcohol, 4.9% glycerol, 49.4% mannitol, 1.2% sucralose, 7.4% flavor and 0.1% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition; Prescription 19: 11.5% desloratadine, 23.0% polyvinyl alcohol, 4.6% glycerol, 45.9% MCC, 6.9% edetate disodium, 1.1% sucralose, 6.9% flavor and 0.1% lake, wherein the mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally dissolving film composition; Prescription 20: 11.5% desloratadine, 23.0% polyvinyl alcohol, 4.6% glycerol, 45.9% microcrystalline cellulose, 6.9% vitamin C, 1.1% sucralose, 6.9% flavor and 0.1% lake. The mass percentage refers to the percentage of the mass of each component to the total mass of the desloratadine orally disintegrating film composition.

6. The method for preparing the desloratadine orally dissolving film composition according to any one of claims 1 to 5, wherein Method 1 includes the following steps: 1) Pretreatment of raw materials and auxiliary materials: raw materials are sieved through a 30-mesh sieve, and auxiliary materials are sieved through a 60-mesh sieve; 2) dissolving all components except the active drug and film-forming material in water to form a solution; 3) adding the film-forming material to the solution obtained in step 2), heating and stirring at 60° C. to 70° C. to obtain a blank glue solution after dissolving; 4) placing the active drug into the blank glue obtained in step 3), stirring until uniformly dispersed, and stirring and degassing under vacuum conditions to obtain drug-containing glue; 5) evenly coating the drug-containing adhesive obtained in step 4) after degassing on a polyester tape with a spatula, heating, drying, and cutting to obtain a desloratadine orally dissolving film composition; Method 2 includes the following steps:

1. Pretreatment of raw and auxiliary materials: raw materials should be screened through 30 mesh sieve, and auxiliary materials should be screened through 60 mesh sieve; 2. Add membrane-forming material to purified water, heat and stir at 60℃~70℃, and dissolve to obtain blank glue solution; 3. Add the prescribed amount of other components except the active ingredient to the blank glue obtained in step 2, add the active drug after cooling, stir until uniformly dispersed, and stir and degas under vacuum conditions to obtain drug-containing glue; 4. The drug-containing adhesive obtained in step 3 after degassing is evenly coated on a polyester tape with a spatula, and then heated, dried, and cut to obtain a desloratadine orally dissolving film composition.

7. The desloratadine orally disintegrating film composition according to any one of claims 1 to 5, wherein: The thickness of the desloratadine orally dissolving film composition is 10 μm to 200 μm; and / or, The desloratadine orally disintegrating film composition can be completely dissolved in simulated saliva at 37±1° C. within 2 minutes and release desloratadine.

8. Use of the desloratadine orosoluble film composition according to any one of claims 1 to 5 in the preparation of a medicament for alleviating systemic and local symptoms of chronic urticaria and allergic rhinitis.

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