A vitamin ad oral soluble film composition, its preparation method and application

Abstract

The application provides a vitamin AD oral dissolving film composition, a preparation method and application thereof. The vitamin AD oral dissolving film composition comprises an active drug and a pharmaceutical excipient, the pharmaceutical excipient comprises one or more of a film-forming material, an emulsifier, a solubilizer, a plasticizer, an antioxidant and a flavoring agent, the active drug is 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraen-1-ol as shown in formula I and 9,10-secocholesta-5,7,10(19)-triene-3beta-ol as shown in formula II. The composition has a good dissolution rate, does not have a sand feeling after being dissolved in the oral cavity, has a uniform appearance, good flexibility, does not have sedimentation during the preparation of the film liquid, and has a content uniformity meeting the requirements.

Description

[0001] This application claims priority to the following earlier application: patent application No. 202210223843.2, filed with the China National Intellectual Property Administration on March 7, 2022, entitled "A Vitamin AD Oral Dissolving Film Composition, Its Preparation Method and Application". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention relates to vitamin AD oral dissolving film compositions, their preparation methods, and their applications. Background Technology

[0003] Vitamin A, also known as retinol, is a fat-soluble vitamin that exists in animal-based foods in the form of free aldehydes or esters. It is abundant in fats, proteins, dairy products, and liver. Retinol is essential for maintaining human growth, development, reproduction, and cell membrane stability, and plays a crucial role in vision. Retinaldehyde is constantly depleted through metabolism in the body and needs to be replenished promptly through the oxidation of vitamin A.

[0004] Vitamin D3, also known as cholecalciferol, is a type of vitamin D and has been proven to be the true active form of vitamin D in the body. Vitamin D3 is a fat-soluble vitamin and is known as the "sunshine vitamin" because most people can synthesize their own vitamin D using ultraviolet rays and cholesterol in their skin when their skin is moderately exposed to sunlight. Its main functions in the body are: (1) to increase the body's absorption of calcium and phosphorus, so that the levels of plasma calcium and plasma phosphorus reach saturation; (2) to promote growth and bone calcification, and promote healthy teeth; (3) to increase phosphorus absorption through the intestinal wall and increase phosphorus reabsorption through the renal tubules; (4) to maintain normal levels of citrate in the blood; and (5) to prevent amino acid loss through the kidneys.

[0005] According to the regulations of the Ministry of Health and the Department of Pediatrics, children need to start taking vitamin A and D supplements 15 days after birth and continue until they are 2 years old. This is because children under 2 years old are prone to rickets, and vitamin D is mainly used to prevent rickets, while vitamin A plays a significant role in preventing night blindness and improving immune function.

[0006] Given the fat-soluble nature of vitamins A and D, currently marketed products are mainly soft capsule drops. Among them, Yikexin, developed by Shandong Dayin Marine Biological Pharmaceutical Co., Ltd., has held the number one market share in children's vitamin AD supplements for many years. Yikexin Vitamin AD 3:1 ratio: 0-1 year old, each capsule contains 1500 IU of vitamin A and 500 IU of vitamin D3; over 1 year old, each capsule contains 2000 IU of vitamin A and 700 IU of vitamin D3, meeting the recommended standards of the "Chinese National Formulary (Children's Edition)". However, it is worth noting that due to the material characteristics of soft capsule formulations, this product requires the dropper tip to be soaked in boiling water for 30 seconds to melt the capsule before dripping the contents into the infant's mouth. The usage method is slightly complicated, and the dosage is not accurate. In addition, to improve the solubility of vitamins A and D, oily excipients are added to the system, affecting the taste.

[0007] Therefore, there is an urgent need for a dosage form that is more convenient to take, more accurate in dosage, and has a better taste, so as to provide more choices for infants and young children. Summary of the Invention

[0008] The technical problem to be solved by this invention is to provide a vitamin AD oral dissolving film composition, its preparation method, and its application, which are completely different from existing technologies. The vitamin AD oral dissolving film composition of this invention has the advantages of thin thickness, good taste, stable properties, and immediate dissolution in the oral cavity without the need for drinking water, as well as rapid oral absorption. Furthermore, it features a simple process, high drug loading capacity, and good drug content uniformity, thus solving the problem of poor patient compliance.

[0009] This invention provides a vitamin AD oral dissolving film composition comprising an active pharmaceutical ingredient and pharmaceutical excipients, wherein the pharmaceutical excipients include one or more of film-forming materials, emulsifiers, solubilizers, plasticizers, antioxidants and flavoring agents, and wherein the active pharmaceutical ingredient is vitamin A (as shown in Formula I, 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatraen-1-ol) and vitamin D (as shown in Formula II, 9,10-open-cholesterol-5,7,10(19)-trien-3beta-ol);

[0010]

[0011] According to an embodiment of the present invention, the active pharmaceutical ingredient vitamin A has a mass percentage content of 0.2% to 15%, for example 1% to 12% or 0.2% to 0.8%, for example 0.39%, 0.49%, 0.68%, 5%, 8%, 9%, 9.9%, 10%, 10.76% or 11%, wherein the mass percentage content refers to the percentage of the mass of the active pharmaceutical ingredient vitamin A to the total mass of the vitamin AD oral dissolving film composition.

[0012] In some embodiments, the pharmaceutical excipients contain at least a film-forming material, an emulsifier, a solubilizer, a plasticizer, an antioxidant, and a flavoring agent.

[0013] In some implementations, the pharmaceutical excipient contains at least a film-forming material, a plasticizer, and a flavoring agent.

[0014] According to an embodiment of the present invention, the mass percentage content of the active pharmaceutical ingredient vitamin D is 0.01% to 0.05%, for example 0.01%, 0.02%, 0.035% or 0.04%, wherein the mass percentage content refers to the percentage of the mass of the active pharmaceutical ingredient vitamin D to the total mass of the vitamin AD oral dissolving film composition.

[0015] According to embodiments of the present invention, the film-forming material is a drug carrier, preferably one or more of xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, maltodextrin, agar, sodium alginate, zein, methylcellulose, hydroxypropyl methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene, pullulan, acrylic acid copolymer, polylactic acid, and silicone rubber. In some embodiments, the film-forming material is selected from methylcellulose, hydroxypropyl methylcellulose, maltodextrin, or pullulan. In still other embodiments, the film-forming material is a mixture of hydroxypropyl methylcellulose of different grades, for example, a mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose K4M.

[0016] According to an embodiment of the present invention, the mass percentage of the film-forming material is 40% to 85%, preferably 40.0% to 60.0% or 60.1% to 80%, for example 45%, 50%, 60%, 72%, 72.72%, 75% or 79%, wherein the mass percentage refers to the percentage of the mass of the film-forming material to the total mass of the vitamin AD oral dissolving film composition.

[0017] According to embodiments of the present invention, the emulsifier acts as an emulsifier and is preferably one or more selected from polysorbate (e.g., polysorbate 80), triglyceride linoleate, and sodium lauryl sulfate. In some embodiments, the emulsifier is selected from polysorbate and / or triglyceride linoleate.

[0018] According to an embodiment of the present invention, the mass percentage of the emulsifier is 2% to 10%, for example 1%, 4%, 8% or 10%, wherein the mass percentage refers to the percentage of the mass of the emulsifier relative to the total mass of the vitamin AD oral dissolving film composition.

[0019] According to embodiments of the present invention, the solubilizer is used to improve the solubility of the drug, and is preferably one or more selected from cyclodextrin, polyethylene glycol-15-hydroxystearate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and olive oil. In some embodiments, the solubilizer is selected from cyclodextrin and / or olive oil.

[0020] According to an embodiment of the present invention, the mass percentage of the solubilizer is 1% to 30%, for example 3%, 6%, 10%, 20% or 26%, wherein the mass percentage refers to the percentage of the mass of the solubilizer to the total mass of the vitamin AD oral dissolving film composition.

[0021] According to embodiments of the present invention, the plasticizer is used to lower the glass transition temperature of the membrane, increase its plasticity and toughness, and improve its elongation. Preferably, it is one or more of polyethylene glycol, glycerin, propylene glycol, silicone oil, polypropylene glycol, hexanediol, and purified water. In some embodiments, the plasticizer is selected from glycerin and / or purified water.

[0022] According to an embodiment of the present invention, the mass percentage of the plasticizer is 0-30%, for example 0-7.0% or 3.0%-21.0%, exemplary of 5%, 5.5%, 5.94%, 6.0%, 6.45%, 9%, 18%, 19% or 21%, wherein the mass percentage refers to the percentage of the mass of the plasticizer to the total mass of the vitamin AD oral dissolving film composition.

[0023] According to embodiments of the present invention, the antioxidant plays a stabilizing role in the vitamin AD oral dissolving film composition, preferably one or more of tert-butylhydroquinone, vitamin C (ascorbic acid), and vitamin E; but excluding butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tea polyphenols, and glutathione. In some embodiments, the antioxidant is selected from vitamin C and / or vitamin E.

[0024] According to an embodiment of the present invention, the antioxidant has a mass percentage content of 0-8%, preferably 0.1%-8%, more preferably 0.1%-5%, 1.0%-2.0% or 5.5%-7%, for example 0.5%, 1%, 2%, 5.5%, 5.94% or 6%, wherein the mass percentage content refers to the percentage of the antioxidant mass in the total mass of the vitamin AD oral dissolving film composition.

[0025] According to an embodiment of the present invention, the flavoring agent plays a flavoring role in the vitamin AD oral soluble film composition, preferably one or more of aspartame, sucralose, fructose, sucrose, steviol glycoside, glycyrrhizin, flavoring, fragrance, menthol, saccharin and sodium saccharin.

[0026] According to embodiments of the present invention, the flavoring agent is preferably 0-10% or 1%-10% by mass, for example 0-2.0% or 1.1%-10.0%, or even 2.1%, 2.3%, 3.1%, 3.3%, 3.4%, 5.3%, 5.4%, 5.9%, 6.3%, 7.4%, or 9.4% by mass, whereby the mass percentage refers to the percentage of the flavoring agent by mass relative to the total mass of the vitamin AD oral dissolving film composition.

[0027] According to an embodiment of the present invention, the vitamin AD oral disintegrating film composition of the present invention may further include a disintegrant, or a combination of a disintegrant with one or more of a filler, a colorant, a thickener and an anti-adhesive.

[0028] According to an embodiment of the present invention, the disintegrant refers to an excipient that causes the vitamin AD oral disintegrating film composition to rapidly disintegrate into small particles in the gastrointestinal tract, preferably one or more of low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, sodium carboxymethyl starch, starch, microcrystalline cellulose and pregelatinized starch.

[0029] According to an embodiment of the present invention, the percentage content of the disintegrant is 0 to 10.0%, for example 0 or 4%, and the mass percentage content refers to the percentage of the mass of the disintegrant relative to the total mass of the vitamin AD oral dissolving film composition.

[0030] According to embodiments of the present invention, the filler refers to a solid substance added to a material that can improve the material's properties, or increase its volume or weight, thereby reducing the material's cost. Preferably, it is one or more of mannitol, povidone, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin, and trehalose. In some embodiments, the filler is mannitol and / or povidone.

[0031] According to an embodiment of the present invention, the percentage content of the filler is 0 to 15.0%, for example 0, 2%, 5%, 7% or 11%, and the mass percentage content refers to the percentage of the mass of the filler to the total mass of the vitamin AD oral dissolving film composition.

[0032] According to an embodiment of 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 method of application, and reduce the patient's aversion to taking the medication, preferably one or more of titanium dioxide, pigments, and lakes.

[0033] According to an embodiment of the present invention, the colorant content is 0-7.0%, preferably 0-4.0%, 0-0.2%, 0.3%-4.0%, or 2.1%-6.0%, and the mass percentage refers to the percentage of the mass of the colorant to the total mass of the vitamin AD oral dissolving film composition.

[0034] According to an embodiment of the present invention, the thickener serves a thickening function and is preferably one or more of alginic acid, starch, pectin, and agar.

[0035] According to an embodiment of the present invention, the mass percentage of the thickener is 0-15%, for example 0-1.0% or 1.1%-10.0%, or even 1.0% or 10.0%, wherein the mass percentage refers to the percentage of the mass of the thickener to the total mass of the vitamin AD oral dissolving film composition.

[0036] According to an embodiment of the present invention, the anti-adhesion agent refers to an agent that can improve the performance of the formulation and prevent adhesion between formulations, preferably one or more of talc, magnesium stearate and calcium stearate.

[0037] According to an embodiment of the present invention, the percentage content of the anti-adhesive is 0 to 1.0%, for example 0.01%, and the mass percentage content refers to the percentage of the mass of the anti-adhesive relative to the total mass of the vitamin AD oral dissolving film composition.

[0038] According to an embodiment of the present invention, the vitamin AD oral dissolving film composition can be any of the following formulations:

[0039] Formula 1: 0.49% Vitamin A, 0.01% Vitamin D, 60.00% Maltodextrin, 2.00% Polysorbate 80, 2.00% Triglycerides of Linoleate, 3.00% Olive Oil, 12.00% Glycerin, 9.00% Purified Water, 2.50% Sucralose, 0.80% Flavoring, 0.50% Vitamin C, 0.50% Vitamin E, 0.20% Titanium Dioxide, and 7.00% Mannitol;

[0040] Formula 2: 0.49% Vitamin A, 0.01% Vitamin D, 60.00% Maltodextrin, 2.00% Polysorbate 80, 2.00% Triglycerides of Linoleate, 3.00% Olive Oil, 12.00% Glycerin, 9.00% Purified Water, 1.00% Alginic Acid, 1.50% Sucralose, 0.80% Flavoring, 0.50% Vitamin C, 0.50% Vitamin E, 0.20% Titanium Dioxide, and 7.00% Mannitol;

[0041] Formula 3: 0.49% Vitamin A, 0.01% Vitamin D, 60.00% Maltodextrin, 2.00% Polysorbate 80, 2.00% Triglycerides of Linoleate, 3.00% Olive Oil, 12.00% Glycerin, 9.00% Purified Water, 1.00% Alginic Acid, 1.50% Sucralose, 0.80% Flavoring, 0.50% Vitamin C, 0.50% Vitamin E, 0.20% Titanium Dioxide, and 7.00% Povidone;

[0042] Formula 4: 0.49% Vitamin A, 0.01% Vitamin D, 50.00% maltodextrin, 4.00% polysorbate 80, 4.00% triglycerides of linoleic acid, 3.00% olive oil, 10.00% glycerin, 9.00% purified water, 1.00% alginic acid, 4.50% sucralose, 0.80% flavoring, 1.00% Vitamin C, 1.00% Vitamin E, 0.20% titanium dioxide, and 11.00% mannitol;

[0043] Formula 5: 0.39% Vitamin A, 0.01% Vitamin D, 60.00% Maltodextrin, 2.00% Polysorbate 80, 2.00% Triglycerides of Linoleate, 6.00% Olive Oil, 12.00% Glycerin, 6.00% Purified Water, 2.50% Sucralose, 0.90% Flavor, 0.50% Vitamin C, 0.50% Vitamin E, 0.20% Titanium Dioxide, and 7.00% Mannitol;

[0044] Formula 6: 0.68% Vitamin A, 0.02% Vitamin D, 60.00% Maltodextrin, 2.00% Polysorbate 80, 2.00% Triglycerides of Linoleate, 6.00% Olive Oil, 12.00% Glycerin, 6.00% Purified Water, 2.50% Sucralose, 0.60% Flavoring, 0.50% Vitamin C, 0.50% Vitamin E, 0.20% Titanium Dioxide, and 7.00% Mannitol;

[0045] Formula 7: 0.39% Vitamin A, 0.01% Vitamin D, 60.00% Hydroxypropyl Methylcellulose, 2.00% Polysorbate 80, 2.00% Linoleic Acid Triglyceride, 6.00% Olive Oil, 12.00% Glycerin, 6.00% Purified Water, 2.50% Sucralose, 0.90% Flavor, 1.00% Vitamin C, 0.20% Titanium Dioxide, and 7.00% Mannitol;

[0046] Formula 8: 0.68% Vitamin A, 0.02% Vitamin D, 60.00% Maltodextrin, 2.00% Polysorbate 80, 2.00% Triglycerides of Linoleate, 6.00% Olive Oil, 12.00% Glycerin, 6.00% Purified Water, 1.50% Sucralose, 0.60% Flavoring, 1.00% Vitamin C, 1.00% Vitamin E, 0.20% Titanium Dioxide, and 7.00% Mannitol;

[0047] Formula Nine: 0.39% Vitamin A, 0.01% Vitamin D, 45.00% Hydroxypropyl Methylcellulose, 4.00% Polysorbate 80, 4.00% Linoleic Acid Triglyceride, 6.00% Olive Oil, 5.00% Glycerin, 4.00% Purified Water, 4.00% Sodium Carboxymethyl Starch, 10.00% Alginic Acid, 4.50% Sucralose, 4.90% Flavor, 0.05% Vitamin C, 0.05% Vitamin E, 0.20% Titanium Dioxide, and 7.00% Mannitol;

[0048] Formula 10: 0.39% Vitamin A, 0.01% Vitamin D, 40.00% Hydroxypropyl Methylcellulose, 5.00% Pullulan, 6.00% Polysorbate 80, 4.00% Linoleic Acid Triglyceride, 6.00% Olive Oil, 5.00% Glycerin, 4.00% Purified Water, 4.00% Sodium Carboxymethyl Starch, 10.00% Alginic Acid, 4.50% Sucralose, 2.90% Flavoring, 0.05% Vitamin C, 0.05% Vitamin E, 0.20% Titanium Dioxide, and 7.00% Mannitol;

[0049] Formula 11: 0.39% Vitamin A, 0.01% Vitamin D, 50.00% Methylcellulose, 4.00% Polysorbate 80, 4.00% Triglycerides of Linoleate, 6.00% Olive Oil, 5.00% Glycerin, 4.00% Purified Water, 4.00% Sodium Carboxymethyl Starch, 10.00% Alginic Acid, 4.50% Sucralose, 4.90% Flavoring, 0.05% Vitamin C, 0.05% Vitamin E, 0.20% Titanium Dioxide, and 2.00% Mannitol;

[0050] Formula Twelve: 0.39% Vitamin A, 0.01% Vitamin D, 50.00% Methylcellulose, 4.00% Polysorbate 80, 4.00% Triglycerides of Linoleate, 6.00% Olive Oil, 5.00% Glycerin, 4.00% Purified Water, 4.00% Sodium Carboxymethyl Starch, 10.00% Alginic Acid, 4.50% Sucralose, 4.89% Flavor, 0.01% Talc, 0.05% Vitamin C, 0.05% Vitamin E, 0.20% Titanium Dioxide, and 2.00% Mannitol;

[0051] Formula 13: 0.39% Vitamin A, 0.01% Vitamin D, 40.00% Hydroxypropyl Methylcellulose, 4.00% Triglyceride Linoleate, 25.00% Cyclodextrin, 6.00% Olive Oil, 5.00% Glycerin, 4.00% Purified Water, 4.00% Sodium Carboxymethyl Starch, 4.50% Sucralose, 0.90% Flavoring, 0.05% Vitamin C, 0.05% Vitamin E, 0.20% Titanium Dioxide, and 5.00% Mannitol;

[0052] Formula Fourteen: 0.49% Vitamin A, 0.01% Vitamin D, 50.00% Maltodextrin, 1.00% Polysorbate 80, 10.00% Olive Oil, 10.00% Glycerin, 9.00% Purified Water, 1.00% Alginic Acid, 4.50% Sucralose, 1.80% Flavoring, 0.50% Vitamin C, 0.50% Vitamin E, 0.20% Titanium Dioxide, and 11.00% Povidone;

[0053] Formula 15: 10.76% Vitamin A, 0.04% Vitamin D, 74.18% Hydroxypropyl Methylcellulose (SH-E5), 4.82% Hydroxypropyl Methylcellulose (K4M), 6.45% Glycerin, 1.60% Aspartame, 2.15% Titanium Dioxide;

[0054] Formula 16: 9.9% Vitamin A, 0.03% Vitamin D, 68.29% Hydroxypropyl Methylcellulose (SH-E5), 4.45% Hydroxypropyl Methylcellulose (K4M), 5.94% Glycerin, 1.48% Aspartame, 5.94% Vitamin E, 3.96% Titanium Dioxide.

[0055] According to an embodiment of the present invention, the thickness of the vitamin AD oral dissolving film composition is 10 μm to 200 μm.

[0056] According to an embodiment of the present invention, the vitamin AD oral dissolving film composition can completely dissolve within 1 minute in simulated saliva at 37±1°C, releasing vitamin AD.

[0057] The present invention also provides a method for preparing the vitamin AD oral dissolving film composition, wherein the preparation method is selected from method one or method two;

[0058] The first method includes the following steps:

[0059] A1) Form a solution of the film-forming material with water;

[0060] A2) The solution obtained in step A1) is mixed with filler, flavoring agent, plasticizer, colorant, antioxidant, thickener, disintegrant and anti-adhesive, and stirred and dissolved to obtain blank adhesive solution;

[0061] A3) Place the active drug, emulsifier and solubilizer into the blank gel solution obtained in step A2), stir and disperse evenly, stir and degas under vacuum to obtain drug-containing gel;

[0062] A4) The drug-containing adhesive solution obtained in step A3) after degassing is evenly coated onto a polyester belt with a scraper, heated, dried and cut to obtain the vitamin AD oral dissolving film composition.

[0063] The second method includes the following steps:

[0064] B1) Forming a solution by combining the film-forming material with a solvent;

[0065] B2) The solution obtained in step B1) is mixed with flavoring agent, plasticizer, colorant and antioxidant, stirred and dissolved to obtain blank adhesive solution;

[0066] B3) Place the active drug in the blank gel solution obtained in step B2), stir and disperse evenly, stir and degas under vacuum to obtain the drug-containing gel solution;

[0067] B4) First, use a scraper to evenly coat the blank adhesive solution obtained in step B2) after degassing onto the polyester tape, heat and dry it until the moisture content is about 10% to 15%. Then, use a scraper to evenly coat the drug-containing adhesive solution obtained in step B3) after degassing onto the first layer of blank drug film, heat and dry it until the moisture content of the film is about 10% to 15%. Use a scraper to evenly coat the blank adhesive solution onto the polyester tape coated with the blank drug film and the drug-containing film double layer, heat, dry and cut to obtain the vitamin AD oral dissolving film composition.

[0068] Method one of the preparation of the vitamin AD oral soluble film composition of the present invention yields a single-layer oral soluble film; method two of the preparation of the vitamin AD oral soluble film composition yields a three-layer oral soluble film.

[0069] The present invention also provides the use of the vitamin AD oral dissolving film composition in the preparation of medicaments for the treatment and / or prevention of vitamin AD deficiency diseases.

[0070] The present invention also provides a method for treating and / or preventing vitamin AD deficiency diseases, comprising administering a therapeutically effective amount of the said vitamin AD oral dissolving film composition to a patient in need.

[0071] The reagents and raw materials used in this invention are all commercially available.

[0072] The beneficial effects of the present invention are as follows: The vitamin AD oral dissolving film composition of the present invention has a good dissolution rate, does not have a gritty feeling after dissolving in the oral cavity, has a uniform appearance, good flexibility, does not settle during the preparation of the film solution, and meets the requirements for content uniformity.

[0073] Meanwhile, this vitamin AD oral dissolving film composition also exhibits good stability. Detailed Implementation

[0074] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0075] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0076] Examples 1-14

[0077] The prescriptions are shown in Tables 1-1 and 1-2 below.

[0078] Table 1-1

[0079]

[0080]

[0081] Table 1-2

[0082]

[0083]

[0084] Preparation method:

[0085] 1) Dissolve the film-forming material in water to form a solution;

[0086] 2) Add filler, flavoring agent, plasticizer, colorant, antioxidant, thickener, disintegrant and anti-sticking agent to the solution obtained in step 1), stir and dissolve to obtain blank adhesive solution;

[0087] 3) Place the active drug, emulsifier and solubilizer into the blank gel solution obtained in step 2), stir and disperse evenly, stir and degas under vacuum to obtain drug-containing gel;

[0088] 4) The defoamed drug-containing adhesive obtained in step 3) is evenly coated onto a polyester tape using a scraper, heated, dried, and cut to obtain a vitamin AD oral dissolving film composition.

[0089] Examples 15-16

[0090] The prescription is shown in Table 2 below.

[0091] Table 2

[0092]

[0093]

[0094] Preparation method:

[0095] 1) Dissolve the film-forming material in 80% ethanol to form a solution;

[0096] 2) Add flavoring agent, plasticizer, colorant and antioxidant to the solution obtained in step 1), stir and dissolve to obtain blank adhesive solution;

[0097] 3) Place the active drug in the blank gel solution obtained in step 2), stir and disperse evenly, stir and degas under vacuum to obtain the drug-containing gel solution;

[0098] 4) First, evenly coat the blank adhesive solution obtained in step 2) after degassing onto the polyester tape using a scraper, heat and dry until the moisture content is about 10% to 15%. Then, evenly coat the drug-containing adhesive solution obtained in step 3) after degassing onto the first layer of blank drug film, heat and dry until the moisture content of the film is about 10% to 15%. Evenly coat the blank adhesive solution onto the polyester tape coated with the blank film and the drug-containing film using a scraper, heat, dry, and cut to obtain the vitamin AD oral dissolving film composition.

[0099] Experimental Example 1

[0100] Vitamin AD oral instant-dissolving film formulations were prepared according to the formulations of Examples 1 to 16 using the corresponding preparation methods described above, and the disintegration time of the film formulations was determined. The specific determination methods are as follows:

[0101] Take any 6 tablets of the medicated film, and use 1 tablet each time. Gently place it in artificial saliva at 37±1℃ and observe the time it takes for the product to completely dissolve while it is standing. The results are shown in Table 3.

[0102] Table 3

[0103]

[0104]

[0105] Experiment Example 2

[0106] Samples were prepared according to the formulations in Examples 15 and 16, and stored under the following conditions after packaging. Stability tests were then conducted, and the results are shown in Table 4.

[0107] Table 4

[0108]

[0109] Note: The data in Table 4 are percentages of the active ingredients and their theoretical specifications under the corresponding conditions.

[0110] According to the disintegration time test data, the vitamin AD oral dissolving film composition provided by this invention has the advantages of thin thickness, good taste, stable properties, and immediate dissolution in the oral cavity without the need for drinking water, as well as rapid oral absorption. The stability results show that the formulation in Example 15 exhibits good stability in the product below 40°C.

[0111] Experimental Example 3

[0112] Samples were prepared according to the formulation of Example 13, packaged, and stored under the following conditions. Stability tests were then conducted, and the results are shown in Table 5.

[0113] Table 5

[0114]

[0115] Note: The data in Table 5 are percentages of the active ingredients and their theoretical specifications under the corresponding conditions.

[0116] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A vitamin AD oral dissolving film composition, characterized in that: The vitamin AD oral disintegrating film composition comprises an active pharmaceutical ingredient and pharmaceutical excipients; the active pharmaceutical ingredient is vitamin A and vitamin D. The pharmaceutical excipients consist of film-forming materials, plasticizers, flavoring agents, antioxidants, and colorants; The film-forming material is a mixture of hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose K4M; The mass percentage of the film-forming material is 60.0% to 80.0%. The plasticizer is glycerin, and the mass percentage of the plasticizer is greater than 0 and does not exceed 9%. The mass percentage refers to the percentage of the mass of the film-forming material or plasticizer relative to the total mass of the vitamin AD oral soluble film composition; The antioxidant mentioned is one or more of vitamin C and vitamin E; The vitamin AD oral dissolving film composition was prepared by the following method: B1) Forming a solution by combining the film-forming material with a solvent; B2) The solution obtained in step B1) is mixed with flavoring agent, plasticizer, colorant and antioxidant, stirred and dissolved to obtain blank adhesive solution; B3) Place the active drug in the blank gel solution obtained in step B2), stir and disperse evenly, stir and degas under vacuum to obtain the drug-containing gel solution; B4) First, the blank adhesive solution obtained in step B2) after degassing is evenly coated onto the polyester tape with a scraper, heated and dried to a moisture content of 10%~15%. Then, the drug-containing adhesive solution obtained in step B3) after degassing is evenly coated on the first layer of blank drug film, heated and dried to a moisture content of 10%~15%. The blank adhesive solution is evenly coated onto the polyester tape coated with the blank drug film and the drug-containing film double layer with a scraper, heated, dried and cut to obtain the vitamin AD oral dissolving film composition.

2. The vitamin AD oral dissolving film composition as described in claim 1, characterized in that: The vitamin A content is 0.2% to 15% by mass, whereby the mass percentage refers to the percentage of vitamin A by mass relative to the total mass of the vitamin AD oral dissolving film composition. And / or, The vitamin D content is 0.01% to 0.05% by mass, whereby the mass percentage refers to the percentage of vitamin D by mass relative to the total mass of the vitamin AD oral soluble film composition.

3. The vitamin AD oral dissolving film composition as described in claim 1, characterized in that: The vitamin A content is 0.2% to 0.8% by mass; and / or, The flavoring agent is one or more of aspartame, sucralose, fructose, sucrose, steviol, glycyrrhizin, flavoring, menthol, saccharin and sodium saccharin.

4. The vitamin AD oral dissolving film composition as described in claim 1, characterized in that: The antioxidant content is 0.1% to 8% by mass, whereby the mass percentage refers to the percentage of the antioxidant by mass relative to the total mass of the vitamin AD oral soluble film composition. And / or, The flavoring agent has a mass percentage content greater than 0 and not exceeding 10.0%, where the mass percentage content refers to the percentage of the flavoring agent's mass relative to the total mass of the vitamin AD oral dissolving film composition.

5. The vitamin AD oral dissolving film composition as described in claim 1, characterized in that: The antioxidant content is 5-7% by mass, which refers to the percentage of the antioxidant's mass in the total mass of the vitamin AD oral soluble film composition.

6. The vitamin AD oral dissolving film composition according to claim 1, characterized in that: The colorant mentioned is a pigment.

7. The vitamin AD oral dissolving film composition according to claim 1, characterized in that: The colorant is titanium dioxide.

8. The vitamin AD oral dissolving film composition as described in claim 1, characterized in that: The colorant has a mass percentage content of 0-7.0%, where mass percentage refers to the percentage of the colorant's mass relative to the total mass of the vitamin AD oral soluble film composition.

9. The vitamin AD oral dissolving film composition as described in claim 1, characterized in that: The vitamin AD oral dissolving film composition is selected from the following formulations: 9.9% Vitamin A, 0.03% Vitamin D, 68.29% Hydroxypropyl Methylcellulose SH-E5, 4.45% Hydroxypropyl Methylcellulose K4M, 5.94% Glycerin, 1.48% Aspartame, 5.94% Vitamin E, 3.96% Titanium Dioxide.

10. The vitamin AD oral dissolving film composition according to any one of claims 1 to 9, characterized in that: The thickness of the vitamin AD oral dissolving film composition is 10 μm to 200 μm; And / or, The vitamin AD oral dissolving film composition can completely dissolve within 1 minute in simulated saliva at 37±1℃, releasing vitamin AD.

11. The use of the vitamin AD oral dissolving film composition according to any one of claims 1 to 10 in the preparation of a medicament for treating and / or preventing vitamin AD deficiency diseases.

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