WO2023169439A1 - Vitamin ad orally dissolving film composition and preparation method therefor and application thereof - Google Patents

Vitamin ad orally dissolving film composition and preparation method therefor and application thereof Download PDF

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Publication number
WO2023169439A1
WO2023169439A1 PCT/CN2023/080158 CN2023080158W WO2023169439A1 WO 2023169439 A1 WO2023169439 A1 WO 2023169439A1 CN 2023080158 W CN2023080158 W CN 2023080158W WO 2023169439 A1 WO2023169439 A1 WO 2023169439A1
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Prior art keywords
vitamin
film composition
mass
mass percentage
percentage
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PCT/CN2023/080158
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French (fr)
Chinese (zh)
Inventor
郭桢
王爱慧
郭宁
付俊
王婷婷
应述欢
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上海云晟研新生物科技有限公司
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Publication of WO2023169439A1 publication Critical patent/WO2023169439A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets

Definitions

  • the present invention relates to a vitamin AD orally dissolving film composition, its preparation method and application.
  • Vitamin A also known as retinol, is a fat-soluble vitamin that exists in animal foods in the form of free aldehydes or esters and is abundant in fat, protein, milk, and liver. Retinol is necessary to maintain human growth, development, reproduction and the stability of cell membranes, and plays an important role in visual processes. Retinal is replenished and consumed due to constant metabolism in the body, and it needs to be replenished in time through oxidation of vitamin A.
  • 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 known as the "sunshine vitamin" because most people can synthesize their own vitamin D using ultraviolet rays and cholesterol in the skin when the skin is moderately exposed to the sun.
  • vitamin AD is mainly used to prevent and treat vitamin AD deficiency diseases, such as rickets, night blindness and tetany.
  • vitamin AD deficiency diseases such as rickets, night blindness and tetany.
  • rickets the number of children suffer from vitamin D deficiency rickets in the south, and the figure reaches 30%-40% in the north.
  • 20% of children in rural areas are deficient in vitamin A.
  • Expert Dai Yaohua pointed out that to know whether a child is deficient in vitamin A, it is not necessary to measure the vitamin A content in the blood.
  • Some epidemiological data show that if there are children with night blindness in your community, then the children in this place may basically everybody is deficient in vitamin A and needs to be prevented.
  • subclinical vitamin A deficiency also called borderline deficiency
  • Such children often show reduced resistance and are susceptible to respiratory and digestive tract infections.
  • vitamin AD In accordance with the regulations of the Ministry of Health and Pediatrics. Children need to start taking vitamin AD supplements 15 days after birth and continue taking them until they are 2 years old. Because children under 2 years old are prone to rickets, vitamin D is mainly used to prevent rickets, and vitamin A is used to prevent rickets. It plays a significant role in preventing night blindness and improving immune function.
  • the technical problem to be solved by the present invention is to provide a vitamin AD orally soluble film composition, its preparation method and application that is completely different from the existing technology.
  • the vitamin AD orally soluble film composition of the present invention has the advantages of thin thickness, good taste, stable properties, and can be instantly dissolved in the mouth without drinking water, and has fast oral absorption speed. At the same time, it has a simple process, high drug loading capacity, and high drug content. The uniformity is good, which solves the problem of poor patient compliance when taking medication.
  • the invention provides a vitamin AD orally dissolving film composition, which contains active drugs and pharmaceutical excipients.
  • the pharmaceutical excipients include film-forming materials, emulsifiers, solubilizers, plasticizers, antioxidants and flavoring agents.
  • the active drug is vitamin A (as shown in formula I, 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexene-1 -base)-2,4,6,8-nonatetraen-1-ol) and vitamin D (as shown in formula II, 9,10-secocholester-5,7,10(19)-triene -3beta-alcohol);
  • the mass percentage of the active drug vitamin A is 0.2% to 15%, such as 1% to 12% Or 0.2 ⁇ 0.8%, such as 0.39%, 0.49%, 0.68%, 5%, 8%, 9%, 9.9%, 10%, 10.76% or 11%, the mass percentage refers to the active drug vitamin A
  • the mass accounts for the percentage of the total mass of the vitamin AD orally dissolving film composition.
  • the pharmaceutical excipients contain at least film-forming materials, emulsifiers, solubilizers, plasticizers, antioxidants and flavoring agents.
  • the pharmaceutical excipients contain at least film-forming materials, plasticizers and flavoring agents.
  • the mass percentage content of the active drug vitamin D is 0.01% to 0.05%, such as 0.01%, 0.02%, 0.035% or 0.04%.
  • the mass percentage content refers to the active drug vitamin D.
  • the mass accounts for the percentage of the total mass of the vitamin AD orally dissolving film composition.
  • the film-forming material is a drug carrier, preferably xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, maltodextrin, agar, seaweed Sodium phosphate, corn gluten, methylcellulose, hypromellose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene One or more of ethylene, pullulan, acrylic copolymer, polylactic acid and silicone rubber.
  • the film-forming material is selected from methylcellulose, hypromellose, maltodextrin, or pullulan.
  • the film-forming material is a mixture of hypromellose of different specifications, such as a mixture of hypromellose E5 and hypromellose K4M.
  • the mass percentage of the film-forming material is 40% to 85%, preferably 40.0% to 60.0% or 60.1% to 80%, such as 45%, 50%, 60%, 72% , 72.72%, 75% or 79%.
  • the mass percentage refers to the mass of the film-forming material as a percentage of the total mass of the vitamin AD orally dissolving film composition.
  • the emulsifier plays an emulsifying effect, and is preferably one or more of polysorbate (such as polysorbate 80), triglyceride linoleate and sodium lauryl sulfate.
  • the emulsifier is selected from polysorbates and/or triglyceryl linoleate.
  • the mass percentage of the emulsifier is 2% to 10%, such as 1%, 4%, 8% or 10%.
  • the mass percentage refers to the mass of the emulsifier. Percentage of the total mass of the vitamin AD orally dissolving film composition.
  • the solubilizer is used to improve the solubility of the drug, preferably cyclodextrin, polyethylene glycol-15 hydroxystearate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol One or more of alcohol graft copolymer and olive oil.
  • the solubilizing agent is selected from cyclodextrin and/or olive oil.
  • the mass percentage of the solubilizer is 1% to 30%, such as 3%, 6%, 10%, 20% or 26%, and the mass percentage refers to the solubilizer.
  • the mass of the solvent accounts for the percentage of the total mass of the vitamin AD orally dissolving film composition.
  • the plasticizer is used to reduce the glass transition temperature of the film and increase the plasticity and toughness,
  • one or more of polyethylene glycol, glycerin, propylene glycol, silicone oil, polypropylene glycol, hexylene glycol and purified water is preferred.
  • the plasticizer is selected from glycerol and/or purified water.
  • the mass percentage of the plasticizer is 0 to 30%, such as 0 to 7.0% or 3.0% to 21.0%, and examples are 5%, 5.5%, 5.94%, and 6.0%. , 6.45%, 9%, 18%, 19% or 21%.
  • the mass percentage refers to the mass percentage of the plasticizer to the total mass of the vitamin AD orally dissolving film composition.
  • the antioxidant plays a stabilizing role in the vitamin AD orally soluble film composition, preferably one of tert-butyl hydroquinone, vitamin C (ascorbic acid) and vitamin E or Various; but does not include butylated hydroxyanisole (BHA), dibutylated hydroxytoluene (BHT), tea polyphenols and glutathione.
  • the antioxidant is selected from vitamin C and/or vitamin E.
  • the mass percentage of the antioxidant is 0 to 8%, preferably 0.1% to 8%, preferably 0.1% to 5%, 1.0% to 2.0% or 5.5% to 7%, For example, 0.5%, 1%, 2%, 5.5%, 5.94% or 6%.
  • the mass percentage refers to the mass percentage of the antioxidant to the total mass of the vitamin AD orally dissolving film composition.
  • the flavoring agent plays a flavoring role in the vitamin AD orally soluble film composition, preferably aspartame, sucralose, fructose, sucrose, stevioside, glycyrrhizin, One or more of flavor, flavor, menthol, saccharin and saccharin sodium.
  • the mass percentage of the flavoring agent is preferably 0 to 10% or 1% to 10%, such as 0 to 2.0% or 1.1% to 10.0%, for example, 2.1%, 2.3%, 3.1%, 3.3%, 3.4%, 5.3%, 5.4%, 5.9%, 6.3%, 7.4% or 9.4%.
  • the mass percentage refers to the mass of the flavoring agent in the total vitamin AD orally soluble film composition. Percentage of mass.
  • the vitamin AD orally dissolving film composition of the present invention may further include a disintegrant, or one of a disintegrant and a filler, a colorant, a thickener and an anti-adhesive agent, or Various combinations.
  • the disintegrant refers to an auxiliary material that promotes the vitamin AD orally soluble film composition to rapidly disintegrate into small particles in the gastrointestinal tract, preferably low-substituted hydroxypropyl cellulose, cross-linked polyethylene One or more of vitriol, croscarmellose sodium, carboxymethyl starch sodium, starch, microcrystalline cellulose and pregelatinized starch.
  • the percentage content of the disintegrant is 0 to 10.0%, such as 0 or 4%.
  • the mass percentage content refers to the mass percentage of the disintegrant in the vitamin AD oral dissolving film combination. percentage of the total mass of the substance.
  • the filler refers to a solid substance that can be added to the material to improve the performance of the material, or can increase the volume, increase the weight, and reduce the cost of the material, preferably mannitol, povidone, sucrose, glucose, One or more of maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose.
  • the filler is mannitol and/or povidone.
  • the percentage content of the filler is 0 to 15.0%, such as 0, 2%, 5%, 7% or 11%, and the mass percentage content refers to the mass of the filler. Percentage of the total mass of the vitamin AD orally dissolving film composition.
  • the colorant refers to a substance that can improve the appearance color of the preparation, and can be used to identify the concentration of the preparation, distinguish application methods and reduce the patient's aversion to taking medicine, preferably titanium dioxide, pigments and lakes. one or more.
  • the colorant percentage is 0-7.0%, preferably 0-4.0%, 0-0.2%, 0.3%-4.0% or 2.1%-6.0%, and the mass
  • the content refers to the percentage of the mass of the coloring agent to the total mass of the vitamin AD orally soluble film composition.
  • the thickening agent plays a thickening role, preferably one or more of alginic acid, starch, pectin and agar.
  • the mass percentage of the thickener is 0 to 15%, such as 0 to 1.0% or 1.1% to 10.0%, and for example 1.0% or 10.0%.
  • the mass percentage Content refers to the percentage of the mass of the thickener to the total mass of the vitamin AD orally soluble film composition.
  • the anti-adhesive agent can improve the performance of the preparation and avoid adhesion between preparations, and is preferably one or more of talc, magnesium stearate and calcium stearate.
  • the percentage content of the anti-adhesive agent is 0 to 1.0%, such as 0.01%.
  • the mass percentage content refers to the mass of the anti-adhesive agent in the total mass of the vitamin AD orally dissolving film composition. percentage.
  • the vitamin AD orally soluble film composition can be any of the following formulas:
  • Formula 1 0.49% vitamin A, 0.01% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 3.00% olive oil, 12.00% glycerin, 9.00% purified water, 2.50 % sucralose, 0.80% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
  • Formula 2 0.49% vitamin A, 0.01% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 3.00% olive oil, 12.00% glycerin, 9.00% purified water, 1.00 % alginic acid, 1.50% sucralose, 0.80% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
  • Formula three 0.49% vitamin A, 0.01% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 3.00% olive oil, 12.00% glycerin, 9.00% purified water, 1.00 % alginic acid, 1.50% sucralose, 0.80% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% povidone;
  • Formula 4 0.49% vitamin A, 0.01% vitamin D, 50.00% maltodextrin, 4.00% polysorbate 80, 4.00% linoleic acid triglyceride, 3.00% olive oil, 10.00% glycerin, 9.00% purified water, 1.00 % alginic acid, 4.50% sucralose, 0.80% flavor, 1.00% vitamin C, 1.00% vitamin E, 0.20% titanium dioxide and 11.00% mannitol;
  • Formula 5 0.39% vitamin A, 0.01% vitamin D, 60.00% maltodextrin, 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, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
  • Formula six 0.68% vitamin A, 0.02% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 6.00% olive oil, 12.00% glycerin, 6.00% purified water, 2.50 % sucralose, 0.60% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
  • Formula 7 0.39% vitamin A, 0.01% vitamin D, 60.00% hypromellose, 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;
  • Formula 8 0.68% vitamin A, 0.02% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 6.00% olive oil, 12.00% glycerin, 6.00% purified water, 1.50 % sucralose, 0.60% flavor, 1.00% vitamin C, 1.00% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
  • Formula 9 0.39% vitamin A, 0.01% vitamin D, 45.00% hypromellose, 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;
  • Formula 10 0.39% vitamin A, 0.01% vitamin D, 40.00% hypromellose, 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% flavor, 0.05% vitamin C, 0.05% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
  • Formula 11 0.39% vitamin A, 0.01% vitamin D, 50.00% 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 2.00% mannitol;
  • Formula 12 0.39% vitamin A, 0.01% vitamin D, 50.00% 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, 4.89% flavor, 0.01% talc, 0.05% vitamin C, 0.05% vitamin E, 0.20% titanium dioxide and 2.00% mannitol;
  • Formula 13 0.39% vitamin A, 0.01% vitamin D, 40.00% hypromellose, 4.00% linoleic acid triglyceride, 25.00% cyclodextrin, 6.00% olive oil, 5.00% glycerol, 4.00% purified water , 4.00% sodium carboxymethyl starch, 4.50% trichloride Sucrose, 0.90% flavor, 0.05% vitamin C, 0.05% vitamin E, 0.20% titanium dioxide and 5.00% mannitol;
  • Formula 14 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% trichloride Sucrose, 1.80% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 11.00% povidone;
  • Formula 15 10.76% vitamin A, 0.04% vitamin D, 74.18% hypromellose (SH-E5), 4.82% hypromellose (K4M), 6.45% glycerin, 1.60% aspartame, 2.15 %Titanium dioxide;
  • Formula 16 9.9% vitamin A, 0.03% vitamin D, 68.29% hypromellose (SH-E5), 4.45% hypromellose (K4M), 5.94% glycerin, 1.48% aspartame, 5.94 % Vitamin E, 3.96% Titanium Dioxide.
  • the thickness of the vitamin AD orally dissolving film composition is 10 ⁇ m to 200 ⁇ m.
  • the vitamin AD orally soluble film composition can be completely dissolved in simulated saliva at 37 ⁇ 1°C within 1 minute and release vitamin AD.
  • the present invention also provides a preparation method of the vitamin AD orally soluble film composition, and the preparation method is selected from method one or method two;
  • the method one includes the following steps:
  • A1 Form a solution between the film-forming material and water
  • step A2) The solution obtained in step A1) is mixed with fillers, flavoring agents, plasticizers, colorants, antioxidants, fillers, thickeners, disintegrants and anti-sticking agents, stirred and dissolved to obtain a blank glue solution ;
  • step A3) Place the active drug, emulsifier and solubilizer into the blank glue solution obtained in step A2), stir and disperse evenly, and stir and defoam under vacuum conditions to obtain a drug-containing glue;
  • step A4) Evenly apply the medicated glue solution obtained in step A3) after degassing on the polyester tape with a spatula, heat, dry and cut to obtain the vitamin AD orally soluble film composition.
  • the second method includes the following steps:
  • step B2) The solution obtained in step B1) is mixed with the flavoring agent, plasticizer, colorant and antioxidant, stirred and dissolved to obtain a blank glue solution;
  • step B3 Place the active drug into the blank glue solution obtained in step B2), stir and disperse evenly, and stir and defoam under vacuum conditions to obtain a drug-containing glue solution;
  • step B4) First, apply the blank glue solution obtained in step B2) after degassing evenly on the polyester tape with a spatula, heat and dry it until the moisture content is about 10% to 15%, and continue to apply the blank glue solution obtained in step B3) after degassing. Apply the drug-containing glue evenly on top of the first layer of blank drug film, and heat and dry until the moisture content of the film is about 10% to 15%; use a spatula to evenly apply the blank glue on the double layer coated with the blank drug film and the drug-containing film The polyester tape of the film is heated, dried and cut to obtain a vitamin AD orally soluble film composition.
  • the first method for preparing the vitamin AD orally soluble film composition of the present invention produces a single-layer orally soluble film; the second method for preparing the vitamin AD orally soluble film composition produces a three-layer orally soluble film.
  • the present invention also provides the use of the vitamin AD orally soluble film composition in the preparation of medicines for treating and/or preventing vitamin AD deficiency diseases.
  • the present invention also provides a method for treating and/or preventing vitamin AD deficiency diseases, which includes administering a therapeutically effective amount of the vitamin AD orally dissolving film composition to a patient in need.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the vitamin AD orally soluble film composition of the present invention has a good dissolution rate, does not have a gritty feeling after being dissolved in the oral cavity, has a uniform appearance, good flexibility, and does not cause any problems during the preparation of the film solution. Sedimentation will occur and the content uniformity meets the requirements.
  • the vitamin AD orally dissolving film composition also has good stability.
  • step 2) Add fillers, flavoring agents, plasticizers, colorants, antioxidants, fillers, thickeners, disintegrants and anti-sticking agents to the solution obtained in step 1), stir and dissolve to obtain a blank glue liquid;
  • step 3 Place the active drug, emulsifier and solubilizer into the blank glue solution obtained in step 2), stir and disperse evenly, and stir and defoam under vacuum conditions to obtain a drug-containing glue;
  • step 4) Evenly apply the medicated glue solution obtained in step 3) after degassing on the polyester tape with a spatula, heat, dry and cut to obtain a vitamin AD orally soluble film composition.
  • step 2) Add flavoring agents, plasticizers, colorants, and antioxidants to the solution obtained in step 1), stir and dissolve, and obtain a blank glue solution;
  • step 3 Place the active drug into the blank glue solution obtained in step 2), stir and disperse evenly, and stir and defoam under vacuum conditions to obtain a drug-containing glue solution;
  • step 4 First, apply the blank glue solution obtained in step 2) after degassing evenly on the polyester tape with a spatula, heat and dry it until the moisture content is about 10% to 15%, and continue to apply the glue solution obtained in step 3) after degassing.
  • the drug-containing glue solution is evenly coated on top of the first layer of blank drug film, and heated and dried until the moisture content of the film is about 10% to 15%.
  • Use a spatula to evenly apply the blank glue solution on the polyester tape coated with the blank film and the double-layer film containing the drug, heat, dry and cut to obtain a vitamin AD orally soluble film composition.
  • the vitamin AD oral instant film preparation was prepared using the above corresponding preparation method, and the disintegration time limit of the film preparation was measured.
  • the specific measurement method is as follows:
  • the vitamin AD orally soluble film composition provided by the present invention has the advantages of thin thickness, good taste, stable properties, and can be instantly dissolved in the mouth without drinking water, and the oral absorption speed is fast. According to the stability results, it can be seen that the formulation of Example 15 has better stability in the product below 40°C.

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Abstract

Provided are a vitamin AD orally dissolving film composition and a preparation method therefor and an application thereof. The vitamin AD orally dissolving film composition contains an active drug and a pharmaceutical excipient; the pharmaceutical excipient contains one or more of a film-forming material, an emulsifier, a solubilizer, a plasticizer, an antioxidant, and a flavoring agent; and the active drug is 3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraen-1-ol and 9,10-Secocholesta-5,7,10(19)-triene-3beta-ol represented by formula II. The composition has a good dissolution rate, does not have a gritty feeling after dissolving in the mouth, and has a uniform appearance and good flexibility, moreover, no sedimentation occurs during the preparation of a film solution, and the content uniformity meets the requirements.

Description

一种维生素AD口溶膜组合物、其制备方法及应用A vitamin AD orally dissolving film composition, its preparation method and application
本申请要求享有下述在先申请的优先权权益：2022年3月7日向中国国家知识产权局提交的，专利申请号为202210223843.2，发明名称为“一种维生素AD口溶膜组合物、其制备方法及应用”的在先申请。所述在先申请的全文通过引用的方式结合于本申请中。This application claims to enjoy the priority rights of the following earlier applications: submitted to the State Intellectual Property Office of China on March 7, 2022, the patent application number is 202210223843.2, and the invention name is "A vitamin AD orally dissolving film composition and its preparation Prior application for "Methods and Applications". The entirety of said prior application is incorporated into this application by reference.
技术领域Technical field
本发明涉及维生素AD口溶膜组合物、其制备方法及应用。The present invention relates to a vitamin AD orally dissolving film composition, its preparation method and application.
背景技术Background technique
维生素A又称视黄醇，是一种脂溶性维生素，它以游离醛或酯的形式存在于动物性食物中，在脂肪、蛋白、乳法、肝中含量丰富。视黄醇是维持人体生长、发育、生殖和细胞膜的稳定性所必需的，在视觉过程中起重要作用。视黄醛在体内因不断代谢而补消耗，需要及时通过氧化维生素A予以补充。Vitamin A, also known as retinol, is a fat-soluble vitamin that exists in animal foods in the form of free aldehydes or esters and is abundant in fat, protein, milk, and liver. Retinol is necessary to maintain human growth, development, reproduction and the stability of cell membranes, and plays an important role in visual processes. Retinal is replenished and consumed due to constant metabolism in the body, and it needs to be replenished in time through oxidation of vitamin A.
维生素D3又称胆钙化醇，是维生素D的一种，被证明是维生素D在体内的真正活性形式。维生素D3是一种脂溶性维生素，被誉为“阳光维生素”，因为皮肤适度暴露在阳光下，大多数人就能利用紫外线和皮肤中的胆固醇合成自身的维生素D。其在体内的主要作用有：(1)提高机体对钙、磷的吸收，使血浆钙和血浆磷的水平达到饱和程度；(2)促进生长和骨骼钙化，促进牙齿健全；(3)通过肠壁增加磷的吸收，并通过肾小管增加磷的再吸收；(4)维持血液中柠檬酸盐的正常水平；(5)防止氨基酸通过肾脏损失。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 known as the "sunshine vitamin" because most people can synthesize their own vitamin D using ultraviolet rays and cholesterol in the skin when the skin is moderately exposed to the sun. Its main functions in the body are: (1) Improve the body's absorption of calcium and phosphorus, so that the levels of plasma calcium and plasma phosphorus reach saturation; (2) Promote growth and bone calcification, and promote healthy teeth; (3) Through the intestines The wall increases phosphorus absorption and reabsorption through the renal tubules; (4) maintains normal levels of citrate in the blood; (5) prevents the loss of amino acids through the kidneys.
在我国，维生素AD主要用来预防和治疗维生素AD缺乏性疾病，如佝偻病、夜盲症及手足抽搐症。据营养学调查数据显示，在南方地区，患有维生素D缺乏性佝偻病的孩子占20％左右，北方地区则达到了30％-40％。另外，基于对我国40个县的调查表明，在农村地区，20％的孩子都缺少维生素A。戴耀华专家指出，了解孩子体内是否缺乏维生素A，不一定要测血液里维生素A的含量，一些流行病学的资料表明，如果你所在的社区有孩子得夜盲症，那么，这个地方的孩子们可能基本上都缺维生素A，都需要来预防。另外，没有典型临床表现的亚临床维生素A缺乏(也称为边缘性缺乏)比例更高，这类孩子往往表现为抵抗力下降，易患呼吸道、消化道感染。In my country, vitamin AD is mainly used to prevent and treat vitamin AD deficiency diseases, such as rickets, night blindness and tetany. According to nutrition survey data, about 20% of children suffer from vitamin D deficiency rickets in the south, and the figure reaches 30%-40% in the north. In addition, based on a survey of 40 counties in my country, 20% of children in rural areas are deficient in vitamin A. Expert Dai Yaohua pointed out that to know whether a child is deficient in vitamin A, it is not necessary to measure the vitamin A content in the blood. Some epidemiological data show that if there are children with night blindness in your community, then the children in this place may basically Everyone is deficient in vitamin A and needs to be prevented. In addition, there is a higher proportion of subclinical vitamin A deficiency (also called borderline deficiency) without typical clinical manifestations. Such children often show reduced resistance and are susceptible to respiratory and digestive tract infections.
按照卫生部和儿科的规定。孩子出生后15天就需要开始补充维生素AD，一直持续服用到2岁。因为2岁以下的孩子容易得佝偻病，而维生素D主要是用来预防佝偻病，维生素A则对预 防夜盲症、提高免疫功能等方面起到显著的作用。In accordance with the regulations of the Ministry of Health and Pediatrics. Children need to start taking vitamin AD supplements 15 days after birth and continue taking them until they are 2 years old. Because children under 2 years old are prone to rickets, vitamin D is mainly used to prevent rickets, and vitamin A is used to prevent rickets. It plays a significant role in preventing night blindness and improving immune function.
鉴于维生素A和维生素D的脂溶性特性，目前上市的产品以软胶囊滴剂为主，其中山东达因海洋生物制药股份有限公司研发的伊可新多年来位居儿童维生素AD补充剂市场占有率第一。伊可新维生素AD 3:1配比0-1岁每粒含维生素A 1500IU、维生素D3 500IU，1岁以上每粒含维生素A 2000IU、维生素D3 700IU，符合《中国国家处方集(儿童版)》推荐标准。但值得关注的是，由于软胶囊制剂的材料特性，本品在使用时需要将滴嘴在开水中浸泡30秒，使胶片融化后将内容物滴入婴幼儿口中，使用方法略显繁复，且定量不准确；另外，为了提高维生素A和维生素D的溶解性，体系中加入了油性辅料，影响口感。In view of the fat-soluble properties of vitamin A and vitamin D, the products currently on the market are mainly soft capsule drops. Among them, Yikesin developed by Shandong Dyne Marine Biopharmaceutical Co., Ltd. has ranked first in the market share of children's vitamin AD supplements for many years. First. The ratio of Yikesin Vitamin AD 3:1 is 0-1 years old. Each pill contains vitamin A 1500IU and vitamin D3 500IU. Over 1 year old, each pill contains vitamin A 2000IU and vitamin D3 700IU. It complies with the "Chinese National Formulary (Children's Edition)" Recommended standards. However, it is worth noting that due to the material characteristics of the soft capsule preparation, when using this product, you need to soak the drip tip in boiling water for 30 seconds to melt the film and then drop the contents into the mouth of the infant. The usage method is slightly complicated and The quantification is inaccurate; in addition, in order to improve the solubility of vitamin A and vitamin D, oily excipients are added to the system, which affects the taste.
因此，亟需一款服药便利性更高，定量准确，口感更好的剂型，为婴幼儿提供更多的选择。Therefore, there is an urgent need for a dosage form that is more convenient for taking medication, has accurate rationing, and has a better taste to provide more choices for infants and young children.
发明内容Contents of the invention
本发明所要解决的技术问题是提供了一种与现有技术完全不同的维生素AD口溶膜组合物、其制备方法及应用。本发明的维生素AD口溶膜组合物，具有厚度薄、口感良好、性质稳定、且无需饮水即可在口腔内即刻溶化、口服吸收速度快的优点，同时工艺简单、载药量高、药物含量均匀度好，解决了患者服药顺应性差的问题。The technical problem to be solved by the present invention is to provide a vitamin AD orally soluble film composition, its preparation method and application that is completely different from the existing technology. The vitamin AD orally soluble film composition of the present invention has the advantages of thin thickness, good taste, stable properties, and can be instantly dissolved in the mouth without drinking water, and has fast oral absorption speed. At the same time, it has a simple process, high drug loading capacity, and high drug content. The uniformity is good, which solves the problem of poor patient compliance when taking medication.
本发明提供了一种维生素AD口溶膜组合物，其包含活性药物和药物辅料，所述的药物辅料包括成膜材料、乳化剂、增溶剂、增塑剂、抗氧剂和矫味剂中的一种或多种，所述的活性药物为维生素A(如式I所示，3,7-二甲基-9-(2,6,6-三甲基-1-环己烯-1-基)-2,4,6,8-壬四烯-1-醇)和维生素D(如式Ⅱ所示，9,10-开环胆甾-5,7,10(19)-三烯-3beta-醇)；
The invention provides a vitamin AD orally dissolving film composition, which contains active drugs and pharmaceutical excipients. The pharmaceutical excipients include film-forming materials, emulsifiers, solubilizers, plasticizers, antioxidants and flavoring agents. One or more, the active drug is vitamin A (as shown in formula I, 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexene-1 -base)-2,4,6,8-nonatetraen-1-ol) and vitamin D (as shown in formula II, 9,10-secocholester-5,7,10(19)-triene -3beta-alcohol);
根据本发明的实施方案，活性药物维生素A的质量百分含量为0.2％～15％，例如1％～12％ 或0.2～0.8％，例如0.39％，0.49％、0.68％、5％、8％、9％、9.9％、10％、10.76％或11％，所述的质量百分含量是指活性药物维生素A的质量占维生素AD口溶膜组合物总质量的百分比。According to an embodiment of the present invention, the mass percentage of the active drug vitamin A is 0.2% to 15%, such as 1% to 12% Or 0.2~0.8%, such as 0.39%, 0.49%, 0.68%, 5%, 8%, 9%, 9.9%, 10%, 10.76% or 11%, the mass percentage refers to the active drug vitamin A The mass accounts for the percentage of the total mass of the vitamin AD orally dissolving film composition.
在一些实施方案中，所述的药物辅料至少含有成膜材料、乳化剂、增溶剂、增塑剂、抗氧剂和矫味剂。In some embodiments, the pharmaceutical excipients contain at least film-forming materials, emulsifiers, solubilizers, plasticizers, antioxidants and flavoring agents.
在一些实施方案中，所述的药物辅料至少含有成膜材料、增塑剂和矫味剂。In some embodiments, the pharmaceutical excipients contain at least film-forming materials, plasticizers and flavoring agents.
根据本发明的实施方案，活性药物维生素D的质量百分含量为0.01％～0.05％，例如0.01％、0.02％、0.035％或0.04％，所述的质量百分含量是指活性药物维生素D的质量占维生素AD口溶膜组合物总质量的百分比。According to the embodiment of the present invention, the mass percentage content of the active drug vitamin D is 0.01% to 0.05%, such as 0.01%, 0.02%, 0.035% or 0.04%. The mass percentage content refers to the active drug vitamin D. The mass accounts for the percentage of the total mass of the vitamin AD orally dissolving film composition.
根据本发明的实施方案，所述的成膜材料为药物的载体，优选黄原胶、瓜尔胶、果胶、明胶、虫胶、阿拉伯胶、淀粉、糊精、麦芽糊精、琼脂、海藻酸钠、玉米朊、甲基纤维素、羟丙甲纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、聚乙烯醇、聚乙烯吡咯烷酮、聚乙二醇、聚氧乙烯、普鲁兰多糖、丙烯酸共聚物、聚乳酸和硅橡胶中的一种或多种。在一些实施方案中，所述成膜材料选自甲基纤维素、羟丙甲纤维素、麦芽糊精或普鲁兰多糖。在还一些实施方案中，所述成膜材料为不同规格的羟丙甲纤维素的混合物，例如为羟丙甲纤维素E5和羟丙甲纤维素K4M的混合物。According to an embodiment of the present invention, the film-forming material is a drug carrier, preferably xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, maltodextrin, agar, seaweed Sodium phosphate, corn gluten, methylcellulose, hypromellose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene One or more of ethylene, pullulan, acrylic copolymer, polylactic acid and silicone rubber. In some embodiments, the film-forming material is selected from methylcellulose, hypromellose, maltodextrin, or pullulan. In some embodiments, the film-forming material is a mixture of hypromellose of different specifications, such as a mixture of hypromellose E5 and hypromellose K4M.
根据本发明的实施方案，所述的成膜材料的质量百分含量为40％～85％，优选40.0％～60.0％或60.1％～80％，例如45％、50％、60％、72％、72.72％、75％或79％，所述的质量百分含量是指成膜材料的质量占维生素AD口溶膜组合物总质量的百分比。According to the 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%, such as 45%, 50%, 60%, 72% , 72.72%, 75% or 79%. The mass percentage refers to the mass of the film-forming material as a percentage of the total mass of the vitamin AD orally dissolving film composition.
根据本发明的实施方案，所述的乳化剂起乳化作用，优选聚山梨酯(例如聚山梨酯80)、亚油酸三甘酯和十二烷基硫酸钠中的一种或多种。在一些实施方案中，所述乳化剂选自聚山梨酯和/或亚油酸三甘酯。According to an embodiment of the present invention, the emulsifier plays an emulsifying effect, and is preferably one or more of polysorbate (such as polysorbate 80), triglyceride linoleate and sodium lauryl sulfate. In some embodiments, the emulsifier is selected from polysorbates and/or triglyceryl linoleate.
根据本发明的实施方案，所述的乳化剂的质量百分含量为2％～10％，例如1％、4％、8％或10％，所述的质量百分含量是指乳化剂的质量占维生素AD口溶膜组合物总质量的百分比。According to the embodiment of the present invention, the mass percentage of the emulsifier is 2% to 10%, such as 1%, 4%, 8% or 10%. The mass percentage refers to the mass of the emulsifier. Percentage of the total mass of the vitamin AD orally dissolving film composition.
根据本发明的实施方案，所述的增溶剂用于提高药物的溶解度，优选环糊精、聚乙二醇-15羟基硬脂酸酯、聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物和橄榄油中的一种或多种。在一些实施方案中，所述增溶剂选自环糊精和/或橄榄油。According to the embodiment of the present invention, the solubilizer is used to improve the solubility of the drug, preferably cyclodextrin, polyethylene glycol-15 hydroxystearate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol One or more of alcohol graft copolymer and olive oil. In some embodiments, the solubilizing agent is selected from cyclodextrin and/or olive oil.
根据本发明的实施方案，所述的增溶剂的质量百分含量为1％～30％，例如3％、6％、10％、20％或26％，所述的质量百分含量是指增溶剂的质量占维生素AD口溶膜组合物总质量的百分比。According to the embodiment of the present invention, the mass percentage of the solubilizer is 1% to 30%, such as 3%, 6%, 10%, 20% or 26%, and the mass percentage refers to the solubilizer. The mass of the solvent accounts for the percentage of the total mass of the vitamin AD orally dissolving film composition.
根据本发明的实施方案，所述的增塑剂用于降低膜的玻璃转化温度，增加塑性和韧性， 提高拉伸率，优选聚乙二醇、甘油、丙二醇、硅油、聚丙二醇、己二醇和纯化水中的一种或多种。在一些实施方案中，所述增塑剂选自甘油和/或纯化水。According to an embodiment of the present invention, the plasticizer is used to reduce the glass transition temperature of the film and increase the plasticity and toughness, To increase the stretch rate, one or more of polyethylene glycol, glycerin, propylene glycol, silicone oil, polypropylene glycol, hexylene glycol and purified water is preferred. In some embodiments, the plasticizer is selected from glycerol and/or purified water.
根据本发明的实施方案，所述的增塑剂的质量百分含量为0～30％，例如0～7.0％或者3.0％～21.0％，示例性为5％、5.5％、5.94％、6.0％、6.45％、9％、18％、19％或21％，所述的质量百分含量是指增塑剂的质量占维生素AD口溶膜组合物总质量的百分比。According to the embodiment of the present invention, the mass percentage of the plasticizer is 0 to 30%, such as 0 to 7.0% or 3.0% to 21.0%, and examples are 5%, 5.5%, 5.94%, and 6.0%. , 6.45%, 9%, 18%, 19% or 21%. The mass percentage refers to the mass percentage of the plasticizer to the total mass of the vitamin AD orally dissolving film composition.
根据本发明的实施方案，所述的抗氧剂在所述维生素AD口溶膜组合物中起稳定作用，优选叔丁基对苯二酚、维生素C(抗坏血酸)和维生素E中的一种或多种；但不包括丁基羟基茴香醚(BHA)、二丁基羟基甲苯(BHT)、茶多酚和谷胱甘肽。在一些实施方案中，所述抗氧剂选自维生素C和/或维生素E。According to an embodiment of the present invention, the antioxidant plays a stabilizing role in the vitamin AD orally soluble film composition, preferably one of tert-butyl hydroquinone, vitamin C (ascorbic acid) and vitamin E or Various; but does not include butylated hydroxyanisole (BHA), dibutylated hydroxytoluene (BHT), tea polyphenols and glutathione. In some embodiments, the antioxidant is selected from vitamin C and/or vitamin E.
根据本发明的实施方案，所述的抗氧剂的质量百分含量为0～8％，优选0.1％～8％，优选0.1％～5％、1.0％～2.0％或5.5％～7％，例如0.5％、1％、2％、5.5％、5.94％或6％，所述的质量百分含量是指抗氧剂的质量占维生素AD口溶膜组合物总质量的百分比。According to the embodiment of the present invention, the mass percentage of the antioxidant is 0 to 8%, preferably 0.1% to 8%, preferably 0.1% to 5%, 1.0% to 2.0% or 5.5% to 7%, For example, 0.5%, 1%, 2%, 5.5%, 5.94% or 6%. The mass percentage refers to the mass percentage of the antioxidant to the total mass of the vitamin AD orally dissolving film composition.
根据本发明的实施方案，所述的矫味剂在所述维生素AD口溶膜组合物中起矫味作用，优选阿司帕坦、三氯蔗糖、果糖、蔗糖、甜菊苷、甘草甜素、香精、香料、薄荷醇、糖精和糖精钠中的一种或多种。According to an embodiment of the present invention, the flavoring agent plays a flavoring role in the vitamin AD orally soluble film composition, preferably aspartame, sucralose, fructose, sucrose, stevioside, glycyrrhizin, One or more of flavor, flavor, menthol, saccharin and saccharin sodium.
根据本发明的实施方案，所述的矫味剂的质量百分含量优选0～10％或1％～10％，例如0～2.0％或1.1％～10.0％，再例如2.1％、2.3％、3.1％、3.3％、3.4％、5.3％、5.4％、5.9％、6.3％、7.4％或9.4％，所述的质量百分含量是指矫味剂的质量占维生素AD口溶膜组合物总质量的百分比。According to the embodiment of the present invention, the mass percentage of the flavoring agent is preferably 0 to 10% or 1% to 10%, such as 0 to 2.0% or 1.1% to 10.0%, for example, 2.1%, 2.3%, 3.1%, 3.3%, 3.4%, 5.3%, 5.4%, 5.9%, 6.3%, 7.4% or 9.4%. The mass percentage refers to the mass of the flavoring agent in the total vitamin AD orally soluble film composition. Percentage of mass.
根据本发明的实施方案，本发明所述的维生素AD口溶膜组合物，可以进一步包括崩解剂，或者崩解剂与填充剂、着色剂、增稠剂和抗粘剂中的一种或多种的组合。According to embodiments of the present invention, the vitamin AD orally dissolving film composition of the present invention may further include a disintegrant, or one of a disintegrant and a filler, a colorant, a thickener and an anti-adhesive agent, or Various combinations.
根据本发明的实施方案，所述的崩解剂是指促使所述维生素AD口溶膜组合物在胃肠道中迅速崩解成小粒子的辅料，优选低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、淀粉、微晶纤维素和预胶化淀粉中的一种或多种。According to the embodiment of the present invention, the disintegrant refers to an auxiliary material that promotes the vitamin AD orally soluble film composition to rapidly disintegrate into small particles in the gastrointestinal tract, preferably low-substituted hydroxypropyl cellulose, cross-linked polyethylene One or more of vitriol, croscarmellose sodium, carboxymethyl starch sodium, starch, microcrystalline cellulose and pregelatinized starch.
根据本发明的实施方案，所述的崩解剂的百分含量为0～10.0％，例如0或4％，所述的质量百分含量是指崩解剂的质量占维生素AD口溶膜组合物总质量的百分比。According to the embodiment of the present invention, the percentage content of the disintegrant is 0 to 10.0%, such as 0 or 4%. The mass percentage content refers to the mass percentage of the disintegrant in the vitamin AD oral dissolving film combination. percentage of the total mass of the substance.
根据本发明的实施方案，所述的填充剂是指加入物料中可以改善物料性能，或能增容、增重，降低物料的成本的固体物质，优选甘露醇、聚维酮、蔗糖、葡萄糖、麦芽糖、乳糖、山梨醇、木糖醇、麦芽糖醇、半乳糖醇、赤藓糖醇、糊精和海藻糖中的一种或多种。在一些实施方案中，所述填充剂为甘露醇和/或聚维酮。 According to the embodiment of the present invention, the filler refers to a solid substance that can be added to the material to improve the performance of the material, or can increase the volume, increase the weight, and reduce the cost of the material, preferably mannitol, povidone, sucrose, glucose, One or more of maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose. In some embodiments, the filler is mannitol and/or povidone.
根据本发明的实施方案，所述的填充剂的百分含量为0～15.0％，例如0、2％、5％、7％或11％，所述的质量百分含量是指填充剂的质量占维生素AD口溶膜组合物总质量的百分比。According to the embodiment of the present invention, the percentage content of the filler is 0 to 15.0%, such as 0, 2%, 5%, 7% or 11%, and the mass percentage content refers to the mass of the filler. Percentage of the total mass of the vitamin AD orally dissolving film composition.
根据本发明的实施方案，所述的着色剂是指能改善制剂的外观颜色，可用来识别制剂的浓度、区分应用方法和减少病人对服药的厌恶感的物质，优选二氧化钛、色素和色淀中一种或多种。According to the embodiment of the present invention, the colorant refers to a substance that can improve the appearance color of the preparation, and can be used to identify the concentration of the preparation, distinguish application methods and reduce the patient's aversion to taking medicine, preferably titanium dioxide, pigments and lakes. one or more.
根据本发明的实施方案，所述的着色剂百分含量为0～7.0％，优选为0～4.0％、0～0.2％、0.3％～4.0％或2.1％～6.0％，所述的质量百分含量是指着色剂的质量占维生素AD口溶膜组合物总质量的百分比。According to the embodiment of the present invention, the colorant percentage is 0-7.0%, preferably 0-4.0%, 0-0.2%, 0.3%-4.0% or 2.1%-6.0%, and the mass The content refers to the percentage of the mass of the coloring agent to the total mass of the vitamin AD orally soluble film composition.
根据本发明的实施方案，所述的增稠剂起增稠作用，优选海藻酸、淀粉、果胶和琼脂中的一种或多种。According to the embodiment of the present invention, the thickening agent plays a thickening role, preferably one or more of alginic acid, starch, pectin and agar.
根据本发明的实施方案，所述的增稠剂的质量百分含量为0～15％，例如0～1.0％或1.1％～10.0％，再例如1.0％或10.0％，所述的质量百分含量是指增稠剂的质量占维生素AD口溶膜组合物总质量的百分比。According to the embodiment of the present invention, the mass percentage of the thickener is 0 to 15%, such as 0 to 1.0% or 1.1% to 10.0%, and for example 1.0% or 10.0%. The mass percentage Content refers to the percentage of the mass of the thickener to the total mass of the vitamin AD orally soluble film composition.
根据本发明的实施方案，所述的抗粘剂是指能改善制剂的性能，避免制剂间的黏连，优选滑石粉、硬脂酸镁和硬脂酸钙中一种或多种。According to the embodiment of the present invention, the anti-adhesive agent can improve the performance of the preparation and avoid adhesion between preparations, and is preferably one or more of talc, magnesium stearate and calcium stearate.
根据本发明的实施方案，所述的抗粘剂百分含量为0～1.0％，例如0.01％，所述的质量百分含量是指抗粘剂的质量占维生素AD口溶膜组合物总质量的百分比。According to the embodiment of the present invention, the percentage content of the anti-adhesive agent is 0 to 1.0%, such as 0.01%. The mass percentage content refers to the mass of the anti-adhesive agent in the total mass of the vitamin AD orally dissolving film composition. percentage.
根据本发明的实施方案，所述的维生素AD口溶膜组合物可以为以下任一配方：According to an embodiment of the present invention, the vitamin AD orally soluble film composition can be any of the following formulas:
配方一：0.49％维生素A、0.01％维生素D、60.00％麦芽糊精、2.00％聚山梨酯80、2.00％亚油酸三甘酯、3.00％橄榄油、12.00％甘油、9.00％纯化水、2.50％三氯蔗糖、0.80％香精、0.50％维生素C、0.50％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula 1: 0.49% vitamin A, 0.01% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 3.00% olive oil, 12.00% glycerin, 9.00% purified water, 2.50 % sucralose, 0.80% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
配方二：0.49％维生素A、0.01％维生素D、60.00％麦芽糊精、2.00％聚山梨酯80、2.00％亚油酸三甘酯、3.00％橄榄油、12.00％甘油、9.00％纯化水、1.00％海藻酸、1.50％三氯蔗糖、0.80％香精、0.50％维生素C、0.50％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula 2: 0.49% vitamin A, 0.01% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 3.00% olive oil, 12.00% glycerin, 9.00% purified water, 1.00 % alginic acid, 1.50% sucralose, 0.80% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
配方三：0.49％维生素A、0.01％维生素D、60.00％麦芽糊精、2.00％聚山梨酯80、2.00％亚油酸三甘酯、3.00％橄榄油、12.00％甘油、9.00％纯化水、1.00％海藻酸、1.50％三氯蔗糖、0.80％香精、0.50％维生素C、0.50％维生素E、0.20％二氧化钛和7.00％聚维酮；Formula three: 0.49% vitamin A, 0.01% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 3.00% olive oil, 12.00% glycerin, 9.00% purified water, 1.00 % alginic acid, 1.50% sucralose, 0.80% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% povidone;
配方四：0.49％维生素A、0.01％维生素D、50.00％麦芽糊精、4.00％聚山梨酯80、4.00％亚油酸三甘酯、3.00％橄榄油、10.00％甘油、9.00％纯化水、1.00％海藻酸、4.50％三氯蔗糖、0.80％香精、1.00％维生素C、1.00％维生素E、0.20％二氧化钛和11.00％甘露醇； Formula 4: 0.49% vitamin A, 0.01% vitamin D, 50.00% maltodextrin, 4.00% polysorbate 80, 4.00% linoleic acid triglyceride, 3.00% olive oil, 10.00% glycerin, 9.00% purified water, 1.00 % alginic acid, 4.50% sucralose, 0.80% flavor, 1.00% vitamin C, 1.00% vitamin E, 0.20% titanium dioxide and 11.00% mannitol;
配方五：0.39％维生素A、0.01％维生素D、60.00％麦芽糊精、2.00％聚山梨酯80、2.00％亚油酸三甘酯、6.00％橄榄油、12.00％甘油、6.00％纯化水、2.50％三氯蔗糖、0.90％香精、0.50％维生素C、0.50％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula 5: 0.39% vitamin A, 0.01% vitamin D, 60.00% maltodextrin, 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, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
配方六：0.68％维生素A、0.02％维生素D、60.00％麦芽糊精、2.00％聚山梨酯80、2.00％亚油酸三甘酯、6.00％橄榄油、12.00％甘油、6.00％纯化水、2.50％三氯蔗糖、0.60％香精、0.50％维生素C、0.50％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula six: 0.68% vitamin A, 0.02% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 6.00% olive oil, 12.00% glycerin, 6.00% purified water, 2.50 % sucralose, 0.60% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
配方七：0.39％维生素A、0.01％维生素D、60.00％羟丙甲纤维素、2.00％聚山梨酯80、2.00％亚油酸三甘酯、6.00％橄榄油、12.00％甘油、6.00％纯化水、2.50％三氯蔗糖、0.90％香精、1.00％维生素C、0.20％二氧化钛和7.00％甘露醇；Formula 7: 0.39% vitamin A, 0.01% vitamin D, 60.00% hypromellose, 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;
配方八：0.68％维生素A、0.02％维生素D、60.00％麦芽糊精、2.00％聚山梨酯80、2.00％亚油酸三甘酯、6.00％橄榄油、12.00％甘油、6.00％纯化水、1.50％三氯蔗糖、0.60％香精、1.00％维生素C、1.00％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula 8: 0.68% vitamin A, 0.02% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 6.00% olive oil, 12.00% glycerin, 6.00% purified water, 1.50 % sucralose, 0.60% flavor, 1.00% vitamin C, 1.00% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
配方九：0.39％维生素A、0.01％维生素D、45.00％羟丙甲纤维素、4.00％聚山梨酯80、4.00％亚油酸三甘酯、6.00％橄榄油、5.00％甘油、4.00％纯化水、4.00％羧甲基淀粉钠、10.00％海藻酸、4.50％三氯蔗糖、4.90％香精、0.05％维生素C、0.05％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula 9: 0.39% vitamin A, 0.01% vitamin D, 45.00% hypromellose, 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;
配方十：0.39％维生素A、0.01％维生素D、40.00％羟丙甲纤维素、5.00％普鲁兰多糖、6.00％聚山梨酯80、4.00％亚油酸三甘酯、6.00％橄榄油、5.00％甘油、4.00％纯化水、4.00％羧甲基淀粉钠、10.00％海藻酸、4.50％三氯蔗糖、2.90％香精、0.05％维生素C、0.05％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula 10: 0.39% vitamin A, 0.01% vitamin D, 40.00% hypromellose, 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% flavor, 0.05% vitamin C, 0.05% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
配方十一：0.39％维生素A、0.01％维生素D、50.00％甲基纤维素、4.00％聚山梨酯80、4.00％亚油酸三甘酯、6.00％橄榄油、5.00％甘油、4.00％纯化水、4.00％羧甲基淀粉钠、10.00％海藻酸、4.50％三氯蔗糖、4.90％香精、0.05％维生素C、0.05％维生素E、0.20％二氧化钛和2.00％甘露醇；Formula 11: 0.39% vitamin A, 0.01% vitamin D, 50.00% 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 2.00% mannitol;
配方十二：0.39％维生素A、0.01％维生素D、50.00％甲基纤维素、4.00％聚山梨酯80、4.00％亚油酸三甘酯、6.00％橄榄油、5.00％甘油、4.00％纯化水、4.00％羧甲基淀粉钠、10.00％海藻酸、4.50％三氯蔗糖、4.89％香精、0.01％滑石粉、0.05％维生素C、0.05％维生素E、0.20％二氧化钛和2.00％甘露醇；Formula 12: 0.39% vitamin A, 0.01% vitamin D, 50.00% 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, 4.89% flavor, 0.01% talc, 0.05% vitamin C, 0.05% vitamin E, 0.20% titanium dioxide and 2.00% mannitol;
配方十三：0.39％维生素A、0.01％维生素D、40.00％羟丙甲纤维素、4.00％亚油酸三甘酯、25.00％环糊精、6.00％橄榄油、5.00％甘油、4.00％纯化水、4.00％羧甲基淀粉钠、4.50％三氯 蔗糖、0.90％香精、0.05％维生素C、0.05％维生素E、0.20％二氧化钛和5.00％甘露醇；Formula 13: 0.39% vitamin A, 0.01% vitamin D, 40.00% hypromellose, 4.00% linoleic acid triglyceride, 25.00% cyclodextrin, 6.00% olive oil, 5.00% glycerol, 4.00% purified water , 4.00% sodium carboxymethyl starch, 4.50% trichloride Sucrose, 0.90% flavor, 0.05% vitamin C, 0.05% vitamin E, 0.20% titanium dioxide and 5.00% mannitol;
配方十四：0.49％维生素A、0.01％维生素D、50.00％麦芽糊精、1.00％聚山梨酯80、10.00％橄榄油、10.00％甘油、9.00％纯化水、1.00％海藻酸、4.50％三氯蔗糖、1.80％香精、0.50％维生素C、0.50％维生素E、0.20％二氧化钛和11.00％聚维酮；Formula 14: 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% trichloride Sucrose, 1.80% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 11.00% povidone;
配方十五：10.76％维生素A、0.04％维生素D、74.18％羟丙甲纤维素(SH-E5)、4.82％羟丙甲纤维素(K4M)、6.45％甘油、1.60％阿司帕坦、2.15％二氧化钛；Formula 15: 10.76% vitamin A, 0.04% vitamin D, 74.18% hypromellose (SH-E5), 4.82% hypromellose (K4M), 6.45% glycerin, 1.60% aspartame, 2.15 %Titanium dioxide;
配方十六：9.9％维生素A、0.03％维生素D、68.29％羟丙甲纤维素(SH-E5)、4.45％羟丙甲纤维素(K4M)、5.94％甘油、1.48％阿司帕坦、5.94％维生素E、3.96％二氧化钛。Formula 16: 9.9% vitamin A, 0.03% vitamin D, 68.29% hypromellose (SH-E5), 4.45% hypromellose (K4M), 5.94% glycerin, 1.48% aspartame, 5.94 % Vitamin E, 3.96% Titanium Dioxide.
根据本发明的实施方案，所述维生素AD口溶膜组合物的厚度为10μm～200μm。According to an embodiment of the present invention, the thickness of the vitamin AD orally dissolving film composition is 10 μm to 200 μm.
根据本发明的实施方案，所述维生素AD口溶膜组合物，在37±1℃的模拟唾液中1min内能够完全溶解，并释放维生素AD。According to an embodiment of the present invention, the vitamin AD orally soluble film composition can be completely dissolved in simulated saliva at 37±1°C within 1 minute and release vitamin AD.
本发明还提供了所述的维生素AD口溶膜组合物的制备方法，制备方法选自方法一或方法二；The present invention also provides a preparation method of the vitamin AD orally soluble film composition, and the preparation method is selected from method one or method two;
所述方法一包括以下步骤：The method one includes the following steps:
A1)将成膜材料与水形成溶液；A1) Form a solution between the film-forming material and water;
A2)步骤A1)得到的溶液与填充剂、矫味剂、增塑剂、着色剂、抗氧剂、填充剂、增稠剂、崩解剂和抗粘剂混合、搅拌溶化后得空白胶液；A2) The solution obtained in step A1) is mixed with fillers, flavoring agents, plasticizers, colorants, antioxidants, fillers, thickeners, disintegrants and anti-sticking agents, stirred and dissolved to obtain a blank glue solution ;
A3)将活性药物、乳化剂和增溶剂置于步骤A2)得到的空白胶液中，搅拌并分散均匀，在真空条件下搅拌脱泡，得含药胶；A3) Place the active drug, emulsifier and solubilizer into the blank glue solution obtained in step A2), stir and disperse evenly, and stir and defoam under vacuum conditions to obtain a drug-containing glue;
A4)将脱泡后的步骤A3)得到的含药胶液用刮刀均匀涂布于聚酯带上，加热、干燥、切割，得所述维生素AD口溶膜组合物。A4) Evenly apply the medicated glue solution obtained in step A3) after degassing on the polyester tape with a spatula, heat, dry and cut to obtain the vitamin AD orally soluble film composition.
所述方法二包括以下步骤：The second method includes the following steps:
B1)将成膜材料与溶剂形成溶液；B1) Form a solution with the film-forming material and the solvent;
B2)步骤B1)得到的溶液与矫味剂、增塑剂、着色剂和抗氧剂混合、搅拌溶化后得空白胶液；B2) The solution obtained in step B1) is mixed with the flavoring agent, plasticizer, colorant and antioxidant, stirred and dissolved to obtain a blank glue solution;
B3)将活性药物置于步骤B2)得到的空白胶液中，搅拌并分散均匀，在真空条件下搅拌脱泡，得含药胶液；B3) Place the active drug into the blank glue solution obtained in step B2), stir and disperse evenly, and stir and defoam under vacuum conditions to obtain a drug-containing glue solution;
B4)先将脱泡后的步骤B2)得到的空白胶液用刮刀均匀涂布于聚酯带上，加热、干燥至水分约10％～15％，继续将脱泡后的步骤B3)得到的含药胶液均匀涂布在第一层空白药膜上方，加热干燥至膜的水分约10％～15％；将空白胶液用刮刀均匀涂布于涂有空白药膜及含药膜双层 膜的聚酯带上，加热、干燥、裁切，得维生素AD口溶膜组合物。B4) First, apply the blank glue solution obtained in step B2) after degassing evenly on the polyester tape with a spatula, heat and dry it until the moisture content is about 10% to 15%, and continue to apply the blank glue solution obtained in step B3) after degassing. Apply the drug-containing glue evenly on top of the first layer of blank drug film, and heat and dry until the moisture content of the film is about 10% to 15%; use a spatula to evenly apply the blank glue on the double layer coated with the blank drug film and the drug-containing film The polyester tape of the film is heated, dried and cut to obtain a vitamin AD orally soluble film composition.
本发明所述维生素AD口溶膜组合物的制备方法一制得单层口溶膜；所述维生素AD口溶膜组合物的制备方法二制得三层口溶膜。The first method for preparing the vitamin AD orally soluble film composition of the present invention produces a single-layer orally soluble film; the second method for preparing the vitamin AD orally soluble film composition produces a three-layer orally soluble film.
本发明还提供了所述的维生素AD口溶膜组合物在制备治疗和/或预防维生素AD缺乏性疾病的药物中的应用。The present invention also provides the use of the vitamin AD orally soluble film composition in the preparation of medicines for treating and/or preventing vitamin AD deficiency diseases.
本发明还提供了一种治疗和/或预防维生素AD缺乏性疾病的方法，包括向需要的患者施用治疗有效量的所述的维生素AD口溶膜组合物。The present invention also provides a method for treating and/or preventing vitamin AD deficiency diseases, which includes administering a therapeutically effective amount of the vitamin AD orally dissolving film composition to a patient in need.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的有益效果：本发明的维生素AD口溶膜组合物，具有良好的溶出速率，在口腔中溶解后不会有沙砾感、且外观均一、柔韧性好、同时在膜液配制过程中不会发生沉降，含量均一性符合要求。Beneficial effects of the present invention: The vitamin AD orally soluble film composition of the present invention has a good dissolution rate, does not have a gritty feeling after being dissolved in the oral cavity, has a uniform appearance, good flexibility, and does not cause any problems during the preparation of the film solution. Sedimentation will occur and the content uniformity meets the requirements.
同时，该维生素AD口溶膜组合物还具有良好的稳定性。At the same time, the vitamin AD orally dissolving film composition also has good stability.
具体实施方式Detailed ways
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。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 examples are only illustrative and explain the present invention and should not be construed as limiting the scope of the present invention. All technologies implemented based on the above contents of the present invention are covered by the scope of protection intended by the present invention.
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.
实施例1-14Examples 1-14
处方如下表1-1和1-2所示。The prescriptions are shown in Tables 1-1 and 1-2 below.
表1-1

Table 1-1

表1-2

Table 1-2

制备方法：Preparation:
1)将成膜材料溶于水中，形成溶液；1) Dissolve the film-forming material in water to form a solution;
2)向步骤1)得到的溶液中加入填充剂、矫味剂、增塑剂、着色剂、抗氧剂、填充剂、增稠剂、崩解剂和抗粘剂，搅拌溶化后得空白胶液；2) Add fillers, flavoring agents, plasticizers, colorants, antioxidants, fillers, thickeners, disintegrants and anti-sticking agents to the solution obtained in step 1), stir and dissolve to obtain a blank glue liquid;
3)将活性药物、乳化剂和增溶剂置于步骤2)得到的空白胶液中，搅拌并分散均匀，在真空条件下搅拌脱泡，得含药胶；3) Place the active drug, emulsifier and solubilizer into the blank glue solution obtained in step 2), stir and disperse evenly, and stir and defoam under vacuum conditions to obtain a drug-containing glue;
4)将脱泡后的步骤3)得到的含药胶液用刮刀均匀涂布于聚酯带上，加热、干燥、切割，得维生素AD口溶膜组合物。4) Evenly apply the medicated glue solution obtained in step 3) after degassing on the polyester tape with a spatula, heat, dry and cut to obtain a vitamin AD orally soluble film composition.
实施例15-16Example 15-16
处方如下表2所示。The prescription is shown in Table 2 below.
表2

Table 2

制备方法：Preparation:
1)将成膜材料溶于80％乙醇中，形成溶液；1) Dissolve the film-forming material in 80% ethanol to form a solution;
2)向步骤1)得到的溶液中加入矫味剂、增塑剂、着色剂、抗氧剂，搅拌溶化后得空白胶液；2) Add flavoring agents, plasticizers, colorants, and antioxidants to the solution obtained in step 1), stir and dissolve, and obtain a blank glue solution;
3)将活性药物置于步骤2)得到的空白胶液中，搅拌并分散均匀，在真空条件下搅拌脱泡，得含药胶液；3) Place the active drug into the blank glue solution obtained in step 2), stir and disperse evenly, and stir and defoam under vacuum conditions to obtain a drug-containing glue solution;
4)先将脱泡后的步骤2)得到的空白胶液用刮刀均匀涂布于聚酯带上，加热、干燥至水分约10％～15％，继续将脱泡后的步骤3)得到的含药胶液均匀涂布在第一层空白药膜上方，加热干燥至膜的水分约10％～15％。将空白胶液用刮刀均匀涂布于涂有空白膜及含药膜双层膜的聚酯带上，加热、干燥、裁切，得维生素AD口溶膜组合物。4) First, apply the blank glue solution obtained in step 2) after degassing evenly on the polyester tape with a spatula, heat and dry it until the moisture content is about 10% to 15%, and continue to apply the glue solution obtained in step 3) after degassing. The drug-containing glue solution is evenly coated on top of the first layer of blank drug film, and heated and dried until the moisture content of the film is about 10% to 15%. Use a spatula to evenly apply the blank glue solution on the polyester tape coated with the blank film and the double-layer film containing the drug, heat, dry and cut to obtain a vitamin AD orally soluble film composition.
实验例1Experimental example 1
按照实施例1至实施例16的处方，采用上述相应的制备方法制备得到维生素AD口腔速溶膜制剂，并测定膜制剂的崩解时限，具体测定方法如下：According to the prescriptions of Examples 1 to 16, the vitamin AD oral instant film preparation was prepared using the above corresponding preparation method, and the disintegration time limit of the film preparation was measured. The specific measurement method is as follows:
任取药膜6片，每次取1片，轻轻置于37±1℃人工唾液中，静置状态下，观察本品完全溶解的时间。结果如表3所示。Take 6 pieces of the medicine film at will, 1 piece at a time, gently place it in artificial saliva at 37±1°C, and observe the time for the product to completely dissolve while standing. The results are shown in Table 3.
表3

table 3

实验例2Experimental example 2
按照实施例15、16处方制备样品，包装后存放条件如下，进行稳定性测试，稳定性结果如表4所示。Samples were prepared according to the prescriptions of Examples 15 and 16, and the storage conditions after packaging were as follows. Stability testing was performed. The stability results are shown in Table 4.
表4
Table 4
注：表4中的数据为相应条件下活性成分与其理论规格的百分比。 Note: The data in Table 4 are the percentages of active ingredients and their theoretical specifications under corresponding conditions.
根据崩解时限实验数据可见本发明提供的维生素AD口溶膜组合物，具有厚度薄、口感良好、性质稳定、且无需饮水即可在口腔内即刻溶化、口服吸收速度快的优点。根据稳定性结果可以看出，实施例15的处方在产品中40℃以下稳定性较好。According to the disintegration time limit experimental data, it can be seen that the vitamin AD orally soluble film composition provided by the present invention has the advantages of thin thickness, good taste, stable properties, and can be instantly dissolved in the mouth without drinking water, and the oral absorption speed is fast. According to the stability results, it can be seen that the formulation of Example 15 has better stability in the product below 40°C.
实验例3Experimental example 3
按照实施例13处方制备样品，包装后存放条件如下，进行稳定性测试，稳定性结果如表5所示。Samples were prepared according to the prescription of Example 13, and the storage conditions after packaging were as follows. Stability testing was performed. The stability results are shown in Table 5.
表5
table 5
注：表5中的数据为相应条件下活性成分与其理论规格的百分比。Note: The data in Table 5 is the percentage of active ingredients to their theoretical specifications under corresponding conditions.
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。 The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiment. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (10)

  1. 一种维生素AD口溶膜组合物，其特征在于，所述维生素AD口溶膜组合物包含活性药物和药物辅料，所述的药物辅料包括成膜材料、乳化剂、增溶剂、增塑剂、抗氧剂和矫味剂中的一种或多种，所述的活性药物为维生素A(如式I所示，3,7-二甲基-9-(2,6,6-三甲基-1-环己烯-1-基)-2,4,6,8-壬四烯-1-醇)和维生素D(如式Ⅱ所示，9,10-开环胆甾-5,7,10(19)-三烯-3beta-醇)；
    A vitamin AD orally soluble film composition, characterized in that the vitamin AD orally soluble film composition contains active drugs and pharmaceutical excipients, and the pharmaceutical excipients include film-forming materials, emulsifiers, solubilizers, plasticizers, One or more antioxidants and flavoring agents, the active drug is vitamin A (as shown in formula I, 3,7-dimethyl-9-(2,6,6-trimethyl -1-cyclohexen-1-yl)-2,4,6,8-nonatetraen-1-ol) and vitamin D (as shown in formula II, 9,10-secocholester-5,7 ,10(19)-triene-3beta-ol);
  2. 如权利要求1所述的维生素AD口溶膜组合物，其特征在于：The vitamin AD orally dissolving film composition according to claim 1, characterized in that:
    所述的维生素A的质量百分含量为0.2％～15％，例如0.2～0.8％，所述的质量百分含量是指维生素A的质量占维生素AD口溶膜组合物总质量的百分比；The mass percentage of vitamin A is 0.2% to 15%, such as 0.2 to 0.8%. The mass percentage refers to the mass of vitamin A as a percentage of the total mass of the vitamin AD orally soluble film composition;
    和/或，and / or,
    所述的维生素D的质量百分含量为0.01％～0.05％，所述的质量百分含量是指维生素D的质量占维生素AD口溶膜组合物总质量的百分比。The mass percentage of vitamin D is 0.01% to 0.05%, and the mass percentage refers to the mass of vitamin D as a percentage of the total mass of the vitamin AD orally soluble film composition.
  3. 如权利要求1或2所述的维生素AD口溶膜组合物，其特征在于：The vitamin AD orally soluble film composition according to claim 1 or 2, is characterized in that:
    所述的成膜材料为黄原胶、瓜尔胶、果胶、明胶、虫胶、阿拉伯胶、淀粉、糊精、麦芽糊精、琼脂、海藻酸钠、玉米朊、甲基纤维素、羟丙甲纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、聚乙烯醇、聚乙烯吡咯烷酮、聚乙二醇、聚氧乙烯、普鲁兰多糖、丙烯酸共聚物、聚乳酸和硅橡胶中的一种或多种；The film-forming materials are xanthan gum, guar gum, pectin, gelatin, shellac, gum arabic, starch, dextrin, maltodextrin, agar, sodium alginate, corn gluten, methylcellulose, hydroxyl Propylene methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene, pullulan, acrylic acid copolymer, poly One or more of lactic acid and silicone rubber;
    和/或， and / or,
    所述的乳化剂为聚山梨酯(例如聚山梨酯80)、亚油酸三甘酯和十二烷基硫酸钠中的一种或多种；The emulsifier is one or more of polysorbate (such as polysorbate 80), triglyceride linoleate and sodium lauryl sulfate;
    和/或，and / or,
    所述的增溶剂为环糊精、聚乙二醇-15羟基硬脂酸酯、聚乙烯已内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物和橄榄油中的一种或多种；The solubilizer is one or more of cyclodextrin, polyethylene glycol-15 hydroxystearate, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and olive oil. kind;
    和/或，and / or,
    所述的增塑剂为聚乙二醇、甘油、丙二醇、硅油、聚丙二醇、己二醇和纯化水中的一种或多种；The plasticizer is one or more of polyethylene glycol, glycerol, propylene glycol, silicone oil, polypropylene glycol, hexylene glycol and purified water;
    和/或，and / or,
    所述的抗氧剂为叔丁基对苯二酚、维生素C、和维生素E中的一种或多种；不包括BHA、BHT、茶多酚和谷胱甘肽；The antioxidant is one or more of tert-butylhydroquinone, vitamin C, and vitamin E; it does not include BHA, BHT, tea polyphenols and glutathione;
    和/或，and / or,
    所述的矫味剂为阿司帕坦、三氯蔗糖、果糖、蔗糖、甜菊苷、甘草甜素、香精、香料、薄荷醇、糖精和糖精钠中的一种或多种。The flavoring agent is one or more of aspartame, sucralose, fructose, sucrose, stevioside, glycyrrhizin, essence, spice, menthol, saccharin and saccharin sodium.
  4. 如权利要求1～3任一项所述的维生素AD口溶膜组合物，其特征在于：The vitamin AD orally soluble film composition according to any one of claims 1 to 3, characterized in that:
    所述的成膜材料的质量百分含量为40％～85％，例如40.0％～60.0％或60.1％～80.0％，所述的质量百分含量是指成膜材料的质量占维生素AD口溶膜组合物总质量的百分比；The mass percentage of the film-forming material is 40% to 85%, such as 40.0% to 60.0% or 60.1% to 80.0%. The mass percentage refers to the mass of the film-forming material accounting for the vitamin AD oral solution. Percentage of the total mass of the membrane composition;
    和/或，and / or,
    所述的乳化剂的质量百分含量为2％～10％，所述的质量百分含量是指乳化剂的质量占维生素AD口溶膜组合物总质量的百分比；The mass percentage of the emulsifier is 2% to 10%, and the mass percentage refers to the mass percentage of the emulsifier to the total mass of the vitamin AD orally soluble film composition;
    和/或，and / or,
    所述的增溶剂的质量百分含量为1％～30％，所述的质量百分含量是指增溶剂的质量占维生素AD口溶膜组合物总质量的百分比；The mass percentage of the solubilizer is 1% to 30%, and the mass percentage refers to the mass of the solubilizer as a percentage of the total mass of the vitamin AD orally soluble film composition;
    和/或，and / or,
    所述的增塑剂的质量百分含量为0～30％，例如0～7.0％或者3.0％～21.0％所述的质量百分含量是指增塑剂的质量占维生素AD口溶膜组合物总质量的百分比；The mass percentage of the plasticizer is 0 to 30%, such as 0 to 7.0% or 3.0% to 21.0%. The mass percentage refers to the mass of the plasticizer in the vitamin AD oral dissolving film composition. Percentage of total mass;
    和/或，and / or,
    所述的抗氧剂的质量百分含量为0.1％～8％，例如0.1％～5％、1.0％～2.0％或5.5％～7％，所述的质量百分含量是指抗氧剂的质量占维生素AD口溶膜组合物总质量的百分比； The mass percentage content of the antioxidant is 0.1% to 8%, such as 0.1% to 5%, 1.0% to 2.0% or 5.5% to 7%. The mass percentage content refers to the antioxidant content. The mass as a percentage of the total mass of the vitamin AD orally dissolving film composition;
    和/或，and / or,
    所述的矫味剂的质量百分含量为0～10.0％，例如0～2.0％或1.1％～10.0％，所述的质量百分含量是指矫味剂的质量占维生素AD口溶膜组合物总质量的百分比。The mass percentage of the flavoring agent is 0 to 10.0%, such as 0 to 2.0% or 1.1% to 10.0%. The mass percentage refers to the weight of the flavoring agent in the vitamin AD orally soluble film combination. percentage of the total mass of the substance.
  5. 如权利要求1～4任一项所述的维生素AD口溶膜组合物，其特征在于：所述的维生素AD口溶膜组合物，进一步包括崩解剂，或者崩解剂与填充剂、着色剂、增稠剂和抗粘剂中的一种或多种的组合。The vitamin AD orally soluble film composition according to any one of claims 1 to 4, characterized in that: the vitamin AD orally soluble film composition further includes a disintegrant, or a disintegrant and a filler, and a coloring agent. One or a combination of one or more of agents, thickeners and anti-sticking agents.
  6. 如权利要求5所述的维生素AD口溶膜组合物，其特征在于：The vitamin AD orally soluble film composition according to claim 5, characterized in that:
    所述的崩解剂为低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、淀粉、微晶纤维素和预胶化淀粉中的一种或多种；The disintegrant is one of low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, starch, microcrystalline cellulose and pregelatinized starch. species or species;
    和/或，and / or,
    所述的填充剂为甘露醇、聚维酮、蔗糖、葡萄糖、麦芽糖、乳糖、山梨醇、木糖醇、麦芽糖醇、半乳糖醇、赤藓糖醇、糊精和海藻糖中的一种或多种；The filler is one of mannitol, povidone, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose or variety;
    和/或，and / or,
    所述的着色剂为二氧化钛、色素和色淀中一种或多种；The colorant is one or more of titanium dioxide, pigments and lakes;
    和/或，and / or,
    所述的增稠剂为海藻酸、淀粉、果胶和琼脂中的一种或多种；The thickening agent is one or more of alginic acid, starch, pectin and agar;
    和/或，and / or,
    所述的抗粘剂为滑石粉、硬脂酸镁和硬脂酸钙中一种或多种。The anti-sticking agent is one or more of talc, magnesium stearate and calcium stearate.
  7. 如权利要求5或6所述的维生素AD口溶膜组合物，其特征在于：The vitamin AD orally soluble film composition according to claim 5 or 6, is characterized in that:
    所述的崩解剂的质量百分含量为0～10.0％，所述的质量百分含量是指崩解剂的质量占维生素AD口溶膜组合物总质量的百分比；The mass percentage of the disintegrant is 0 to 10.0%, and the mass percentage refers to the mass percentage of the disintegrant to the total mass of the vitamin AD orally soluble film composition;
    和/或，and / or,
    所述的填充剂的质量百分含量为0～15.0％，所述的质量百分含量是指填充剂的质量占维生素AD口溶膜组合物总质量的百分比；The mass percentage of the filler is 0 to 15.0%, and the mass percentage refers to the percentage of the mass of the filler to the total mass of the vitamin AD orally soluble film composition;
    和/或，and / or,
    所述的着色剂的质量百分含量为0～7.0％，例如0～4.0％、0～0.2％、0.3～4.0％或2.1％～6.0％，所述的质量百分含量是指着色剂的质量占维生素AD口溶膜组合物总质量的百分比；The mass percentage of the colorant is 0 to 7.0%, such as 0 to 4.0%, 0 to 0.2%, 0.3 to 4.0% or 2.1% to 6.0%. The mass percentage refers to the colorant. The mass as a percentage of the total mass of the vitamin AD orally dissolving film composition;
    和/或，and / or,
    所述的增稠剂的质量百分含量为0～15％，例如0～1.0％或1.1％～10.0％所述的质量百分 含量是指增稠剂的质量占维生素AD口溶膜组合物总质量的百分比；The mass percentage of the thickener is 0 to 15%, such as 0 to 1.0% or 1.1% to 10.0%. Content refers to the percentage of the mass of the thickener to the total mass of the vitamin AD orally soluble film composition;
    和/或，and / or,
    所述的抗粘剂百分含量为0～1.0％，所述的质量百分含量是指抗粘剂的质量占维生素AD口溶膜组合物总质量的百分比。The anti-adhesive agent percentage is 0 to 1.0%, and the mass percentage refers to the mass percentage of the anti-adhesive agent to the total mass of the vitamin AD orally dissolving film composition.
  8. 如权利要求1～7任一项所述的维生素AD口溶膜组合物，其特征在于：The vitamin AD orally soluble film composition according to any one of claims 1 to 7, is characterized in that:
    所述的维生素AD口溶膜组合物选自以下任一配方：The vitamin AD orally soluble film composition is selected from any of the following formulas:
    配方一：0.49％维生素A、0.01％维生素D、60.00％麦芽糊精、2.00％聚山梨酯80、2.00％亚油酸三甘酯、3.00％橄榄油、12.00％甘油、9.00％纯化水、2.50％三氯蔗糖、0.80％香精、0.50％维生素C、0.50％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula 1: 0.49% vitamin A, 0.01% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 3.00% olive oil, 12.00% glycerin, 9.00% purified water, 2.50 % sucralose, 0.80% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
    配方二：0.49％维生素A、0.01％维生素D、60.00％麦芽糊精、2.00％聚山梨酯80、2.00％亚油酸三甘酯、3.00％橄榄油、12.00％甘油、9.00％纯化水、1.00％海藻酸、1.50％三氯蔗糖、0.80％香精、0.50％维生素C、0.50％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula 2: 0.49% vitamin A, 0.01% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 3.00% olive oil, 12.00% glycerin, 9.00% purified water, 1.00 % alginic acid, 1.50% sucralose, 0.80% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
    配方三：0.49％维生素A、0.01％维生素D、60.00％麦芽糊精、2.00％聚山梨酯80、2.00％亚油酸三甘酯、3.00％橄榄油、12.00％甘油、9.00％纯化水、1.00％海藻酸、1.50％三氯蔗糖、0.80％香精、0.50％维生素C、0.50％维生素E、0.20％二氧化钛和7.00％聚维酮；Formula three: 0.49% vitamin A, 0.01% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 3.00% olive oil, 12.00% glycerin, 9.00% purified water, 1.00 % alginic acid, 1.50% sucralose, 0.80% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% povidone;
    配方四：0.49％维生素A、0.01％维生素D、50.00％麦芽糊精、4.00％聚山梨酯80、4.00％亚油酸三甘酯、3.00％橄榄油、10.00％甘油、9.00％纯化水、1.00％海藻酸、4.50％三氯蔗糖、0.80％香精、1.00％维生素C、1.00％维生素E、0.20％二氧化钛和11.00％甘露醇；Formula 4: 0.49% vitamin A, 0.01% vitamin D, 50.00% maltodextrin, 4.00% polysorbate 80, 4.00% linoleic acid triglyceride, 3.00% olive oil, 10.00% glycerin, 9.00% purified water, 1.00 % alginic acid, 4.50% sucralose, 0.80% flavor, 1.00% vitamin C, 1.00% vitamin E, 0.20% titanium dioxide and 11.00% mannitol;
    配方五：0.39％维生素A、0.01％维生素D、60.00％麦芽糊精、2.00％聚山梨酯80、2.00％亚油酸三甘酯、6.00％橄榄油、12.00％甘油、6.00％纯化水、2.50％三氯蔗糖、0.90％香精、0.50％维生素C、0.50％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula 5: 0.39% vitamin A, 0.01% vitamin D, 60.00% maltodextrin, 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, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
    配方六：0.68％维生素A、0.02％维生素D、60.00％麦芽糊精、2.00％聚山梨酯80、2.00％亚油酸三甘酯、6.00％橄榄油、12.00％甘油、6.00％纯化水、2.50％三氯蔗糖、0.60％香精、0.50％维生素C、0.50％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula six: 0.68% vitamin A, 0.02% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 6.00% olive oil, 12.00% glycerin, 6.00% purified water, 2.50 % sucralose, 0.60% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
    配方七：0.39％维生素A、0.01％维生素D、60.00％羟丙甲纤维素、2.00％聚山梨酯80、2.00％亚油酸三甘酯、6.00％橄榄油、12.00％甘油、6.00％纯化水、2.50％三氯蔗糖、0.90％香精、1.00％维生素C、0.20％二氧化钛和7.00％甘露醇；Formula 7: 0.39% vitamin A, 0.01% vitamin D, 60.00% hypromellose, 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;
    配方八：0.68％维生素A、0.02％维生素D、60.00％麦芽糊精、2.00％聚山梨酯80、2.00％亚油酸三甘酯、6.00％橄榄油、12.00％甘油、6.00％纯化水、1.50％三氯蔗糖、0.60％香精、1.00％ 维生素C、1.00％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula 8: 0.68% vitamin A, 0.02% vitamin D, 60.00% maltodextrin, 2.00% polysorbate 80, 2.00% linoleic acid triglyceride, 6.00% olive oil, 12.00% glycerin, 6.00% purified water, 1.50 % sucralose, 0.60% flavor, 1.00% Vitamin C, 1.00% Vitamin E, 0.20% Titanium Dioxide and 7.00% Mannitol;
    配方九：0.39％维生素A、0.01％维生素D、45.00％羟丙甲纤维素、4.00％聚山梨酯80、4.00％亚油酸三甘酯、6.00％橄榄油、5.00％甘油、4.00％纯化水、4.00％羧甲基淀粉钠、10.00％海藻酸、4.50％三氯蔗糖、4.90％香精、0.05％维生素C、0.05％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula 9: 0.39% vitamin A, 0.01% vitamin D, 45.00% hypromellose, 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;
    配方十：0.39％维生素A、0.01％维生素D、40.00％羟丙甲纤维素、5.00％普鲁兰多糖、6.00％聚山梨酯80、4.00％亚油酸三甘酯、6.00％橄榄油、5.00％甘油、4.00％纯化水、4.00％羧甲基淀粉钠、10.00％海藻酸、4.50％三氯蔗糖、2.90％香精、0.05％维生素C、0.05％维生素E、0.20％二氧化钛和7.00％甘露醇；Formula 10: 0.39% vitamin A, 0.01% vitamin D, 40.00% hypromellose, 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% flavor, 0.05% vitamin C, 0.05% vitamin E, 0.20% titanium dioxide and 7.00% mannitol;
    配方十一：0.39％维生素A、0.01％维生素D、50.00％甲基纤维素、4.00％聚山梨酯80、4.00％亚油酸三甘酯、6.00％橄榄油、5.00％甘油、4.00％纯化水、4.00％羧甲基淀粉钠、10.00％海藻酸、4.50％三氯蔗糖、4.90％香精、0.05％维生素C、0.05％维生素E、0.20％二氧化钛和2.00％甘露醇；Formula 11: 0.39% vitamin A, 0.01% vitamin D, 50.00% 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 2.00% mannitol;
    配方十二：0.39％维生素A、0.01％维生素D、50.00％甲基纤维素、4.00％聚山梨酯80、4.00％亚油酸三甘酯、6.00％橄榄油、5.00％甘油、4.00％纯化水、4.00％羧甲基淀粉钠、10.00％海藻酸、4.50％三氯蔗糖、4.89％香精、0.01％滑石粉、0.05％维生素C、0.05％维生素E、0.20％二氧化钛和2.00％甘露醇；Formula 12: 0.39% vitamin A, 0.01% vitamin D, 50.00% 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, 4.89% flavor, 0.01% talc, 0.05% vitamin C, 0.05% vitamin E, 0.20% titanium dioxide and 2.00% mannitol;
    配方十三：0.39％维生素A、0.01％维生素D、40.00％羟丙甲纤维素、4.00％亚油酸三甘酯、25.00％环糊精、6.00％橄榄油、5.00％甘油、4.00％纯化水、4.00％羧甲基淀粉钠、4.50％三氯蔗糖、0.90％香精、0.05％维生素C、0.05％维生素E、0.20％二氧化钛和5.00％甘露醇；Formula 13: 0.39% vitamin A, 0.01% vitamin D, 40.00% hypromellose, 4.00% linoleic acid triglyceride, 25.00% cyclodextrin, 6.00% olive oil, 5.00% glycerol, 4.00% purified water , 4.00% sodium carboxymethyl starch, 4.50% sucralose, 0.90% flavor, 0.05% vitamin C, 0.05% vitamin E, 0.20% titanium dioxide and 5.00% mannitol;
    配方十四：0.49％维生素A、0.01％维生素D、50.00％麦芽糊精、1.00％聚山梨酯80、10.00％橄榄油、10.00％甘油、9.00％纯化水、1.00％海藻酸、4.50％三氯蔗糖、1.80％香精、0.50％维生素C、0.50％维生素E、0.20％二氧化钛和11.00％聚维酮；Formula 14: 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% trichloride Sucrose, 1.80% flavor, 0.50% vitamin C, 0.50% vitamin E, 0.20% titanium dioxide and 11.00% povidone;
    配方十五：10.76％维生素A、0.04％维生素D、74.18％羟丙甲纤维素(SH-E5)、4.82％羟丙甲纤维素(K4M)、6.45％甘油、1.60％阿司帕坦、2.15％二氧化钛；Formula 15: 10.76% vitamin A, 0.04% vitamin D, 74.18% hypromellose (SH-E5), 4.82% hypromellose (K4M), 6.45% glycerin, 1.60% aspartame, 2.15 %Titanium dioxide;
    配方十六：9.9％维生素A、0.03％维生素D、68.29％羟丙甲纤维素(SH-E5)、4.45％羟丙甲纤维素(K4M)、5.94％甘油、1.48％阿司帕坦、5.94％维生素E、3.96％二氧化钛。Formula 16: 9.9% vitamin A, 0.03% vitamin D, 68.29% hypromellose (SH-E5), 4.45% hypromellose (K4M), 5.94% glycerin, 1.48% aspartame, 5.94 % Vitamin E, 3.96% Titanium Dioxide.
  9. 如权利要求1～8任一项所述的维生素AD口溶膜组合物，其特征在于：The vitamin AD orally soluble film composition according to any one of claims 1 to 8, is characterized in that:
    所述的维生素AD口溶膜组合物的厚度为10μm～200μm； The thickness of the vitamin AD orally dissolving film composition is 10 μm to 200 μm;
    和/或，and / or,
    所述的维生素AD口溶膜组合物，在37±1℃的模拟唾液中1min内能够完全溶解，并释放维生素AD。The vitamin AD orally soluble film composition can be completely dissolved in simulated saliva at 37±1°C within 1 minute and release vitamin AD.
  10. 如权利要求1～9任一项所述的维生素AD口溶膜组合物在制备治疗和/或预防维生素AD缺乏性疾病的药物中的应用。 The application of the vitamin AD orally soluble film composition according to any one of claims 1 to 9 in the preparation of medicines for treating and/or preventing vitamin AD deficiency diseases.
PCT/CN2023/080158 2022-03-07 2023-03-07 Vitamin ad orally dissolving film composition and preparation method therefor and application thereof WO2023169439A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118304279A (en) * 2024-03-27 2024-07-09 青岛双鲸药业股份有限公司 Calcitriol self-microemulsion mouth dissolving film and preparation method thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003055201A (en) * 2001-08-13 2003-02-26 Lion Corp Solubilized composition containing vitamin a compounds and method for stabilizing vitamin a compounds
CN105963321A (en) * 2016-05-03 2016-09-28 哈尔滨医科大学 Compound vitamin E oral drug membrane and preparation method thereof
CN105982072A (en) * 2015-02-10 2016-10-05 苏州百益倍肯新材料科技有限公司 Vitamin D3 calcium carbonate oral cavity instant films and preparation method thereof
US20190111139A1 (en) * 2016-04-22 2019-04-18 Dantor Biotech Ag Vitamin preparation
CN114073683A (en) * 2021-09-27 2022-02-22 广州汇元医药科技有限公司 Vitamin orally-dissolving film agent and preparation method thereof
CN114903874A (en) * 2021-02-09 2022-08-16 上海现代药物制剂工程研究中心有限公司 Vitamin D3 oral dissolving film agent and preparation method thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003055201A (en) * 2001-08-13 2003-02-26 Lion Corp Solubilized composition containing vitamin a compounds and method for stabilizing vitamin a compounds
CN105982072A (en) * 2015-02-10 2016-10-05 苏州百益倍肯新材料科技有限公司 Vitamin D3 calcium carbonate oral cavity instant films and preparation method thereof
US20190111139A1 (en) * 2016-04-22 2019-04-18 Dantor Biotech Ag Vitamin preparation
CN105963321A (en) * 2016-05-03 2016-09-28 哈尔滨医科大学 Compound vitamin E oral drug membrane and preparation method thereof
CN114903874A (en) * 2021-02-09 2022-08-16 上海现代药物制剂工程研究中心有限公司 Vitamin D3 oral dissolving film agent and preparation method thereof
CN114073683A (en) * 2021-09-27 2022-02-22 广州汇元医药科技有限公司 Vitamin orally-dissolving film agent and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TING QU, CHEN YAN, QIAO HONGYAN, LIU LIANG, LI XIAOHONG: "Determination Method for Compound Vitamin E Oral Pellicle ", CHINA PHARMACEUTICALS, vol. 29, no. 3, 5 February 2020 (2020-02-05), pages 50 - 53, XP093089682 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118304279A (en) * 2024-03-27 2024-07-09 青岛双鲸药业股份有限公司 Calcitriol self-microemulsion mouth dissolving film and preparation method thereof

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