Carboxymethyl soybean polysaccharide-based mouth dissolving film and preparation method thereof

Abstract

This invention belongs to the technical field of oral film formulations and pharmaceutical excipients, and discloses a carboxymethyl soybean polysaccharide-based oral dissolving film and its preparation method. The oral dissolving film, by dry basis weight, comprises 30-50 parts of carboxymethyl soybean polysaccharide, 10-25 parts of compound modified vegetable oil, 5-15 parts of composite emulsifier, and 5-20 parts of compound disintegrant. The compound modified vegetable oil is composed of hydrogenated soybean oil and polar modified vegetable oil; the composite emulsifier is composed of soybean phospholipids and a nonionic emulsifier; and the compound disintegrant is composed of crospovidone and sodium carboxymethyl starch. In preparation, the carboxymethyl soybean polysaccharide is first dissolved to form an aqueous phase. Then, the oil phase components and emulsifier are pre-emulsified and added dropwise to the aqueous phase. Subsequently, the compound disintegrant is added, followed by defoaming, coating, drying, peeling, and slitting to obtain the oral dissolving film. The oral dissolving film obtained by this invention possesses good flexibility, film-forming stability, compatibility with hydrophobic oral active ingredients, and rapid dissolution performance.

Description

Technical Field

[0001] This invention belongs to the field of oral film formulations and pharmaceutical excipients, specifically relating to a carboxymethyl soybean polysaccharide-based oral dissolving film and its preparation method. Background Technology

[0002] Orally dissolving films are thin-film formulations that can be rapidly wetted, disintegrated, or dissolved in the oral saliva environment. They offer advantages such as no need for drinking water, convenient administration, suitability for people with swallowing difficulties, and portability, and have been increasingly applied in the fields of pharmaceuticals, nutritional supplements, and functional oral preparations. Existing orally dissolving films typically use hydroxypropyl methylcellulose, polyvinyl alcohol, gelatin, starch, or other water-soluble polymers as film-forming materials, and add excipients such as plasticizers, emulsifiers, and disintegrants to improve the film's flexibility and solubility.

[0003] However, traditional synthetic or semi-synthetic membrane materials still have certain shortcomings in terms of natural sourcing, safety, and biodegradability. Although some natural polysaccharide membrane materials have good biocompatibility and water solubility, they are prone to problems such as dry film brittleness, insufficient mechanical strength, poor taste, and moisture absorption and deformation during storage when formed alone. Carboxymethyl soybean polysaccharide is derived from plant polysaccharides and has good water solubility, film-forming properties, and safety, making it suitable as a natural oral dissolving membrane substrate. However, the membrane layer formed by it still needs improvement in terms of flexibility, crack resistance, and compatibility with hydrophobic oral active ingredients. To improve the flexibility of polysaccharide membranes, existing technologies usually add small molecule plasticizers such as glycerol and polyethylene glycol. However, these plasticizers are prone to migration, moisture absorption, or causing the membrane layer to become sticky, resulting in unsatisfactory long-term storage stability. If oily or hydrophobic components are introduced to improve flexibility and the loading capacity of hydrophobic active ingredients, it is easy to cause membrane liquid stratification, dry film turbidity, surface oil separation, and prolonged oral dissolution time. Therefore, how to stably introduce an oily and flexible phase into a carboxymethyl soybean polysaccharide hydrophilic membrane matrix while maintaining membrane uniformity, storage stability, and rapid dissolution is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0004] To address the shortcomings mentioned in the background section, the present invention aims to provide a carboxymethyl soybean polysaccharide-based oral dissolving film and its preparation method. The oral dissolving film, by dry basis mass, comprises carboxymethyl soybean polysaccharide, a compound modified vegetable oil, a composite emulsifier, and a compound disintegrant. The compound modified vegetable oil is composed of hydrogenated soybean oil and polar modified vegetable oil; the composite emulsifier is composed of soybean lecithin and a nonionic emulsifier; and the compound disintegrant is composed of crospovidone and sodium carboxymethyl starch. In preparation, the carboxymethyl soybean polysaccharide is first dissolved to form an aqueous phase. Then, the compound modified vegetable oil and the composite emulsifier are pre-emulsified and added dropwise to the aqueous phase. Subsequently, the compound disintegrant is added, followed by defoaming, coating, drying, peeling, and slitting to obtain the oral dissolving film. This invention improves the flexibility, film-forming stability, and compatibility of hydrophobic oral active ingredients in the polysaccharide film, while maintaining rapid oral dissolution performance.

[0005] The objective of this invention can be achieved through the following technical solutions: A carboxymethyl soybean polysaccharide-based oral soluble film, based on dry weight after removing moisture, comprises the following components: 30-50 parts of carboxymethyl soybean polysaccharide, 10-25 parts of compound modified vegetable oil, 5-15 parts of compound emulsifier, and 5-20 parts of compound disintegrant. The degree of substitution of the carboxymethyl soybean polysaccharide is 0.3-0.8, and the viscosity of a 1% aqueous solution at 25°C is 10-50 mPa·s; the compound modified vegetable oil is composed of hydrogenated soybean oil and polar modified vegetable oil, and the weight ratio of hydrogenated soybean oil to polar modified vegetable oil is 0.5:1-4:1, wherein the polar modified vegetable oil is selected from at least one of epoxidized soybean oil, acetylated soybean oil, hydroxylated soybean oil, and hydroxylated castor oil; The composite emulsifier is composed of soybean lecithin and a nonionic emulsifier, wherein the weight ratio of the nonionic emulsifier to soybean lecithin is 1:1 to 5:1, and the nonionic emulsifier is selected from at least one of polysorbate 80, polyglycerol fatty acid ester, and sucrose fatty acid ester; the compound disintegrant is composed of crospovidone and sodium carboxymethyl starch, wherein the weight ratio of crospovidone to sodium carboxymethyl starch is 1:3 to 3:1.

[0006] More preferably, the degree of substitution of the carboxymethyl soybean polysaccharide is 0.45 to 0.65, and the viscosity of a 1% aqueous solution at 25°C is 20 to 40 mPa·s.

[0007] More preferably, the polar modified vegetable oil is epoxidized soybean oil, and the weight ratio of hydrogenated soybean oil to epoxidized soybean oil is 1:1 to 2:1.

[0008] More preferably, the nonionic emulsifier is polysorbate 80, and the weight ratio of the nonionic emulsifier to soybean lecithin is 2:1 to 3:1.

[0009] More preferably, the weight ratio of the cross-linked polyvinylpyrrolidone to sodium carboxymethyl starch is 1:1 to 1:2.

[0010] More preferably, the hydrogenated soybean oil has a melting point of 50-70°C and an iodine value of no more than 15gI2 / 100g; the epoxidized soybean oil has an epoxy value of 5.5%-7.5% and an acid value calculated as KOH of no more than 1.0mg / g.

[0011] More preferably, the orally disintegrating film further includes a hydrophobic oral active ingredient, which accounts for 0.1% to 15% of the total dry weight of the orally disintegrating film, and the hydrophobic oral active ingredient is selected from one or more of ibuprofen, curcumin, vitamin D3, coenzyme Q10, and melatonin.

[0012] More preferably, the dry film thickness of the oral dissolving film is 0.05-0.25 mm, the water content based on the total mass of the oral dissolving film is 3%-10%, and the complete dissolution time of the oral dissolving film measured in artificial saliva at 37°C is no more than 30 s.

[0013] A method for preparing a carboxymethyl soybean polysaccharide-based oral dissolving film includes the following steps: S1. Dissolve carboxymethyl soybean polysaccharide in deionized water to obtain an aqueous solution of carboxymethyl soybean polysaccharide; S2. Hydrogenated soybean oil, polar modified vegetable oil, soybean lecithin, and nonionic emulsifier are mixed to obtain an oil phase mixture; when the oral dissolving membrane includes a hydrophobic oral active ingredient, the hydrophobic oral active ingredient is also added to the oil phase mixture; the oil phase mixture is sheared and pre-dispersed to obtain a pre-dispersed oil phase; S3. The pre-dispersed oil phase is added dropwise to the carboxymethyl soybean polysaccharide aqueous solution and dispersed to obtain an oil-containing film liquid; S4. Add cross-linked polyvinylpyrrolidone and sodium carboxymethyl starch to the oil-containing film solution for dispersion to obtain a film-forming solution; S5. The film-forming solution is degassed, coated, dried, peeled and slit to obtain a carboxymethyl soybean polysaccharide-based oral soluble film.

[0014] More preferably, in step S2, the shear pre-dispersion temperature is 55–75°C, and the shear pre-dispersion time is 10–30 min; in step S3, the dropping rate of the pre-dispersed oil phase is 1–2 mL / min, and dispersion continues for 15–40 min after the dropping is completed; in step S4, cross-linked polyvinylpyrrolidone and sodium carboxymethyl starch are added after the pre-dispersed oil phase has been dropped and dispersed; in step S5, the drying temperature is 45–60°C, and the drying time is 1–3 h.

[0015] The beneficial effects of this invention are: This invention uses carboxymethyl soybean polysaccharide as the main film-forming substrate and limits its degree of substitution and aqueous solution viscosity range. This allows it to form a uniform, continuous hydrophilic film while maintaining good water solubility and film-forming properties, providing a foundation for rapid wetting and stable film formation in oral dissolving films. By adding a compound modified vegetable oil consisting of hydrogenated soybean oil and polar modified vegetable oil, the problems of brittleness and insufficient flexibility after drying of single polysaccharide films can be improved. Hydrogenated soybean oil helps improve the structural stability of the film layer, while polar modified vegetable oil helps improve the flexibility of the film layer and its resistance to... The compatibility of hydrophobic oral active ingredients is improved through a composite emulsifier composed of soybean lecithin and nonionic emulsifiers. This improves the interfacial compatibility between the oil phase and the aqueous phase of carboxymethyl soybean polysaccharide, ensuring stable dispersion of the modified vegetable oil in the film-forming solution and reducing film separation, dry film turbidity, and oil separation and breakage during storage. A composite disintegrant composed of crospovidone and sodium carboxymethyl starch promotes water penetration and diffusion into the film layer, accelerating film disintegration and dissolution, and preventing a significant extension of the dissolution time of the oral soluble film due to the introduction of oily components. Furthermore, the process sequence of oil phase pre-dispersion, dropwise dispersion, post-addition of the composite disintegrant, and low-temperature drying for film formation improves the uniformity of the film-forming solution and the quality of the dry film. Performance test results show that the carboxymethyl soybean polysaccharide-based oral soluble film obtained by this invention has good mechanical strength, flexibility, rapid solubility, and storage stability, and exhibits a certain degree of loading adaptability to hydrophobic oral active ingredients. Attached Figure Description

[0016] The invention will now be further described with reference to the accompanying drawings.

[0017] Figure 1 This is a comparison of the dissolution curves of the orally dissolving films prepared in artificial saliva in Example 3 and Comparative Example 3 of the present invention. Detailed Implementation

[0018] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0019] Unless otherwise stated, all raw materials used in the embodiments and comparative examples of this invention are commercially available products, preferably pharmaceutical grade, food grade, or products that meet the requirements for preparing oral dissolving films of this invention. The carboxymethyl soybean polysaccharide is a water-soluble carboxymethylated soybean polysaccharide with a degree of substitution of 0.3–0.8 and a viscosity of 1% aqueous solution at 25°C of 10–50 mPa·s. The hydrogenated soybean oil in the compound modified vegetable oil is commercially available hydrogenated soybean oil with a melting point of 55–65°C and an iodine value not exceeding 15 g I2 / 100 g. The polar modified vegetable oil is selected from at least one of epoxidized soybean oil, acetylated soybean oil, hydroxylated soybean oil, and hydroxylated castor oil; in the following embodiments, epoxidized soybean oil is used as an example of polar modified vegetable oil, wherein the epoxy value of epoxidized soybean oil is 5.5%–7.5%, and the acid value calculated as KOH is not greater than 1.0 mg / g. The soybean lecithin, polysorbate 80, polyglycerol fatty acid ester, and sucrose fatty acid ester are all commercially available emulsifiers, and the crospovidone and sodium carboxymethyl starch are both commercially available disintegrants for oral preparations. The hydrophobic oral active ingredient can be selected from one or more of ibuprofen, curcumin, vitamin D3, coenzyme Q10, and melatonin. The above raw materials can be dried, sieved, or pre-dispersed using conventional methods before use.

[0020] Example 1: This example provides a method for preparing a carboxymethyl soybean polysaccharide-based oral dissolving film, comprising the following steps: S1. Weigh out 30 parts by dry weight (after removing moisture), 10 parts by weight of compound modified vegetable oil, 5 parts by weight of compound emulsifier and 5 parts by weight of compound disintegrant. The degree of substitution of carboxymethyl soybean polysaccharide is 0.3, and the viscosity of its 1% aqueous solution at 25℃ is 15 mPa·s. The compound modified vegetable oil consists of hydrogenated soybean oil and epoxidized soybean oil, with a weight ratio of 0.5:1. The compound emulsifier consists of soybean lecithin and polyglycerol fatty acid ester, with a weight ratio of 1:1. The compound disintegrant consists of crospovidone and sodium carboxymethyl starch, with a weight ratio of 1:3.

[0021] S2. Slowly add 30 parts of carboxymethyl soybean polysaccharide to deionized water. The amount of deionized water is 250% of the total dry weight of the oral soluble film. Stir while adding, and control the temperature at 45℃ to fully dissolve the carboxymethyl soybean polysaccharide and obtain a uniform carboxymethyl soybean polysaccharide aqueous solution.

[0022] S3. Mix 3.33 parts hydrogenated soybean oil and 6.67 parts epoxidized soybean oil, heat to 65°C, and after the oil phase is evenly mixed, add 2.5 parts soybean lecithin and 2.5 parts polyglycerol fatty acid ester, and pre-emulsify at 4000 r / min at 65°C for 30 min to obtain a pre-dispersed oil phase.

[0023] S4. Slowly add the pre-dispersed oil phase to the carboxymethyl soybean polysaccharide aqueous solution at a rate of 1 mL / min, while stirring during the addition process to ensure that the oil phase is evenly dispersed in the aqueous phase; after the addition is completed, continue stirring and dispersing for 40 min to obtain an oil-containing film solution.

[0024] S5. Add 1.25 parts of cross-linked polyvinylpyrrolidone and 3.75 parts of sodium carboxymethyl starch to the oil-containing film solution, and continue stirring until evenly dispersed to obtain a film-forming solution; degas the film-forming solution under vacuum for 10 minutes until there are no obvious bubbles, and then coat it with a doctor blade to form a film with a wet film thickness of 0.2 mm. Then dry it at 45℃ for 3 hours. After drying, peel off the film and cut it to obtain a carboxymethyl soybean polysaccharide-based oral soluble film.

[0025] Example 2: This example provides a method for preparing a carboxymethyl soybean polysaccharide-based oral dissolving film, comprising the following steps: S1. Weigh out 50 parts by dry weight (after removing moisture), 25 parts by weight of compound modified vegetable oil, 15 parts by weight of compound emulsifier, and 20 parts by weight of compound disintegrant. The degree of substitution of carboxymethyl soybean polysaccharide is 0.8, and the viscosity of its 1% aqueous solution at 25℃ is 45 mPa·s. The compound modified vegetable oil consists of hydrogenated soybean oil and epoxidized soybean oil, with a weight ratio of 4:1. The compound emulsifier consists of soybean lecithin and sucrose fatty acid ester, with a weight ratio of 5:1. The compound disintegrant consists of crospovidone and sodium carboxymethyl starch, with a weight ratio of 3:1.

[0026] S2. Add 50 portions of carboxymethyl soybean polysaccharide to deionized water in batches. The amount of deionized water is 350% of the total dry weight of the oral soluble film. Keep stirring during the addition process and control the temperature at 65℃ to fully hydrate and dissolve the carboxymethyl soybean polysaccharide, so as to obtain a uniform and viscous aqueous solution of carboxymethyl soybean polysaccharide.

[0027] S3. Add 20 parts of hydrogenated soybean oil and 5 parts of epoxidized soybean oil to a container, heat to 70°C and stir until well mixed; then add 2.5 parts of soybean lecithin and 12.5 parts of sucrose fatty acid ester, and continue to pre-emulsify at 70°C and 4000 r / min for 10 min to obtain a pre-dispersed oil phase.

[0028] S4. Slowly add the pre-dispersed oil phase dropwise to the carboxymethyl soybean polysaccharide aqueous solution at a rate of 2 mL / min. Stir during the addition process to gradually disperse the oil phase into the polysaccharide aqueous phase. After the oil phase is added, continue stirring and dispersing for 15 min to obtain an oil-containing film solution.

[0029] S5. Add 15 parts of cross-linked polyvinylpyrrolidone and 5 parts of sodium carboxymethyl starch to the oil-containing film solution, and continue stirring until the powder is evenly dispersed to obtain the film-forming solution. After allowing the film-forming solution to stand to remove large air bubbles, vacuum degas for 10 minutes, and then coat it into a wet film using a doctor blade coating method. The wet film coating thickness is 0.25 mm. Then dry it at 60℃ for 1 hour. After drying, peel off the film and cut it to obtain carboxymethyl soybean polysaccharide-based oral soluble film.

[0030] Example 3: This example provides a method for preparing a carboxymethyl soybean polysaccharide-based oral dissolving film, comprising the following steps: S1. Based on the dry weight after removing moisture, take 40 parts of carboxymethyl soybean polysaccharide, 15 parts of compound modified vegetable oil, 10 parts of compound emulsifier, and 12 parts of compound disintegrant. The degree of substitution of carboxymethyl soybean polysaccharide is 0.5, and the viscosity of its 1% aqueous solution at 25℃ is 30 mPa·s. The compound modified vegetable oil consists of hydrogenated soybean oil and epoxidized soybean oil, with a weight ratio of 1.5:1. The compound emulsifier consists of soybean lecithin and polysorbate 80, with a weight ratio of 2.5:1. The compound disintegrant consists of crospovidone and sodium carboxymethyl starch, with a weight ratio of 1:1.5.

[0031] S2. Slowly sprinkle 40 parts of carboxymethyl soybean polysaccharide into deionized water. The amount of deionized water is 250% of the total dry weight of the oral soluble film. Stir while adding the water and control the temperature at 55℃ to fully hydrate and dissolve the carboxymethyl soybean polysaccharide to obtain a uniform polysaccharide aqueous phase.

[0032] S3. Add 9 parts of hydrogenated soybean oil and 6 parts of epoxidized soybean oil to an oil phase container, heat to 65°C and stir until evenly mixed, then add 2.86 parts of soybean lecithin and 7.14 parts of polysorbate 80, and pre-emulsify at 4000 r / min at 65°C for 20 min to obtain a pre-dispersed oil phase.

[0033] S4. Add the pre-dispersed oil phase dropwise to the polysaccharide aqueous phase at a rate of 1.5 mL / min, while stirring during the addition; after the addition is complete, continue stirring and dispersing for 25 min to obtain a uniformly dispersed oil-containing film solution.

[0034] S5. Add 4.8 parts of crospovidone and 7.2 parts of sodium carboxymethyl starch to the oil-containing film solution, and continue stirring to evenly disperse the compound disintegrant, thus obtaining the film-forming solution. Vacuum degas the film-forming solution for 10 minutes until there are no obvious bubbles, and then coat it into a wet film using a doctor blade coating method. The wet film coating thickness is 0.2 mm. Then dry it at 55℃ for 1.5 h. After drying, peel it off and cut it to obtain a carboxymethyl soybean polysaccharide-based oral soluble film.

[0035] Example 4: This example provides a method for preparing a carboxymethyl soybean polysaccharide-based oral dissolving film, comprising the following steps: S1. Based on the dry weight after removing moisture, take 40 parts carboxymethyl soybean polysaccharide, 15 parts compound modified vegetable oil, 10 parts compound emulsifier, 12 parts compound disintegrant, and 2 parts curcumin. The degree of substitution of carboxymethyl soybean polysaccharide is 0.5, and the viscosity of its 1% aqueous solution at 25℃ is 30 mPa·s. The compound modified vegetable oil consists of 9 parts hydrogenated soybean oil and 6 parts epoxidized soybean oil. The compound emulsifier consists of 2.86 parts soybean lecithin and 7.14 parts polysorbate 80. The compound disintegrant consists of 4.8 parts crospovidone and 7.2 parts sodium carboxymethyl starch. Curcumin is added as a hydrophobic oral active ingredient, accounting for 2.53% of the total dry weight of the oral disintegrating film.

[0036] S2. Slowly add 40 parts of carboxymethyl soybean polysaccharide to deionized water. The amount of deionized water is 250% of the total dry weight of the oral soluble film. Stir continuously during the addition process and control the temperature at 55℃ to fully hydrate and dissolve the carboxymethyl soybean polysaccharide to obtain a uniform polysaccharide aqueous phase.

[0037] S3. Add 9 parts hydrogenated soybean oil and 6 parts epoxidized soybean oil to the oil phase container, heat to 65°C and stir to mix well. Then add 2 parts curcumin that have been treated with an 80-mesh sieve and continue stirring to pre-disperse the curcumin in the oil phase. Subsequently, add 2.86 parts soybean lecithin and 7.14 parts polysorbate 80 and pre-emulsify at 4000 r / min at 65°C for 20 min to obtain a pre-dispersed oil phase containing curcumin. Avoid strong light exposure during the pre-emulsification process.

[0038] S4. The pre-dispersed oil phase containing curcumin is slowly added dropwise to the polysaccharide aqueous phase at a rate of 1.5 mL / min. Stirring is maintained during the dropwise addition process to gradually disperse the oil phase containing curcumin into the carboxymethyl soybean polysaccharide aqueous phase. After the dropwise addition is completed, stirring and dispersion is continued for 25 min to obtain an oil-containing film solution containing curcumin.

[0039] S5. Add 4.8 parts of crospovidone and 7.2 parts of sodium carboxymethyl starch to the curcumin-containing oil-containing film solution, and continue stirring until evenly dispersed to obtain a film-forming solution. Vacuum degas the film-forming solution for 10 minutes until no obvious bubbles are present, and then coat it into a wet film using a doctor blade coating method. The wet film coating thickness is 0.2 mm. Then dry it at 55℃ for 1.5 h. After drying, peel off the film and cut it to obtain a curcumin-loaded carboxymethyl soybean polysaccharide-based oral soluble film.

[0040] Comparative Example 1: This comparative example does not include compound modified vegetable oil, and replaces the compound modified vegetable oil with an equal amount of carboxymethyl soybean polysaccharide. The specific steps are as follows: S1. Based on the dry weight after removing moisture, take 55 parts of carboxymethyl soybean polysaccharide, 10 parts of compound emulsifier, and 12 parts of compound disintegrant, without adding compound modified vegetable oil. The degree of substitution of carboxymethyl soybean polysaccharide is 0.5, and the viscosity of a 1% aqueous solution at 25℃ is 30 mPa·s. The compound emulsifier consists of 2.86 parts of soybean lecithin and 7.14 parts of polysorbate 80, with a weight ratio of polysorbate 80 to soybean lecithin of 2.5:1. The compound disintegrant consists of 4.8 parts of crospovidone and 7.2 parts of sodium carboxymethyl starch, with a weight ratio of crospovidone to sodium carboxymethyl starch of 1:1.5.

[0041] S2. Slowly add 55 parts of carboxymethyl soybean polysaccharide to 90% of the total deionized water. The total amount of deionized water is 250% of the total dry weight of the oral soluble film. Stir while adding, and control the temperature at 55℃ to fully hydrate and dissolve the carboxymethyl soybean polysaccharide to obtain a uniform polysaccharide aqueous phase.

[0042] S3. Take the remaining 10% of deionized water, add 2.86 parts of soybean lecithin and 7.14 parts of polysorbate 80 to it, stir and disperse at 55°C to obtain an emulsifier dispersion.

[0043] S4. Slowly add the emulsifier dispersion to the polysaccharide aqueous phase while stirring. After the addition is complete, continue stirring and dispersing for 25 minutes to obtain the mixed membrane solution.

[0044] S5. Add 4.8 parts of crosslinked polyvinylpyrrolidone and 7.2 parts of sodium carboxymethyl starch to the mixed film solution, and continue stirring until evenly dispersed to obtain the film-forming solution. Vacuum degas the film-forming solution for 10 minutes until no obvious bubbles are present, and then coat it into a wet film using a doctor blade coating method. The wet film coating thickness is 0.2 mm. Then dry it at 55℃ for 1.5 h. After drying, peel it off and cut it to obtain the oral dissolving film of Comparative Example 1.

[0045] Comparative Example 2: This comparative example does not use a compound emulsifier, and replaces the compound emulsifier with an equal amount of carboxymethyl soybean polysaccharide. The specific steps are as follows: S1. Based on the dry weight after removing moisture, take 50 parts of carboxymethyl soybean polysaccharide, 15 parts of compound modified vegetable oil, and 12 parts of compound disintegrant, without adding compound emulsifier. The degree of substitution of carboxymethyl soybean polysaccharide is 0.5, and the viscosity of its 1% aqueous solution at 25℃ is 30 mPa·s. The compound modified vegetable oil consists of 9 parts of hydrogenated soybean oil and 6 parts of epoxidized soybean oil, with a weight ratio of 1.5:1. The compound disintegrant consists of 4.8 parts of crospovidone and 7.2 parts of sodium carboxymethyl starch, with a weight ratio of 1:1.5.

[0046] S2. Slowly add 50 parts of carboxymethyl soybean polysaccharide to deionized water. The amount of deionized water is 250% of the total dry weight of the oral soluble film. Stir while adding the water and control the temperature at 55℃ to fully hydrate and dissolve the carboxymethyl soybean polysaccharide to obtain a uniform polysaccharide aqueous phase.

[0047] S3. Add 9 parts hydrogenated soybean oil and 6 parts epoxidized soybean oil to the oil phase container, heat to 65°C and stir to mix evenly; without adding soybean lecithin and polysorbate 80, continue to treat at 65°C and 4000 r / min at high speed for 20 min to obtain the oil phase treated product.

[0048] S4. Slowly add the oil phase to the polysaccharide aqueous phase at a rate of 1.5 mL / min, while stirring during the addition process to disperse the oil phase as much as possible in the carboxymethyl soybean polysaccharide aqueous phase; after the addition is completed, continue stirring and dispersing for 25 min to obtain an oil-containing film solution.

[0049] S5. Add 4.8 parts of cross-linked polyvinylpyrrolidone and 7.2 parts of sodium carboxymethyl starch to the oil-containing film solution, and continue stirring until dispersed to obtain a film-forming solution. After vacuum degassing the film-forming solution for 10 min, coat it into a wet film using a doctor blade coating method. The wet film coating thickness is 0.2 mm. Then dry it at 55℃ for 1.5 h. After drying, peel it off and cut it to obtain the oral dissolving film of Comparative Example 2.

[0050] Comparative Example 3: This comparative example does not include a compound disintegrant, and uses an equal amount of carboxymethyl soybean polysaccharide instead of a compound disintegrant. The specific steps are as follows: S1. Based on the dry weight after removing moisture, take 52 parts of carboxymethyl soybean polysaccharide, 15 parts of compound modified vegetable oil, and 10 parts of compound emulsifier, without adding compound disintegrant. The degree of substitution of carboxymethyl soybean polysaccharide is 0.5, and the viscosity of its 1% aqueous solution at 25℃ is 30 mPa·s. The compound modified vegetable oil consists of 9 parts of hydrogenated soybean oil and 6 parts of epoxidized soybean oil, with a weight ratio of 1.5:1. The compound emulsifier consists of 2.86 parts of soybean lecithin and 7.14 parts of polysorbate 80, with a weight ratio of 2.5:1 between polysorbate 80 and soybean lecithin.

[0051] S2. Slowly add 52 parts of carboxymethyl soybean polysaccharide to deionized water. The amount of deionized water is 250% of the total dry weight of the oral soluble film. Stir while adding, and control the temperature at 55℃ to fully hydrate and dissolve the carboxymethyl soybean polysaccharide to obtain a uniform polysaccharide aqueous phase.

[0052] S3. Add 9 parts of hydrogenated soybean oil and 6 parts of epoxidized soybean oil to an oil phase container, heat to 65°C and stir until evenly mixed, then add 2.86 parts of soybean lecithin and 7.14 parts of polysorbate 80, and pre-emulsify at 4000 r / min at 65°C for 20 min to obtain a pre-dispersed oil phase.

[0053] S4. Slowly add the pre-dispersed oil phase to the polysaccharide aqueous phase at a rate of 1.5 mL / min, while stirring during the addition process, so that the oil phase is gradually dispersed into the carboxymethyl soybean polysaccharide aqueous phase; after the addition is completed, continue stirring and dispersing for 25 min to obtain an oil-containing film solution.

[0054] S5. Since no cross-linked polyvinylpyrrolidone and sodium carboxymethyl starch were added in this comparative example, the oil-containing film solution obtained in step S4 was used directly as the film-forming solution. The film-forming solution was degassed under vacuum for 10 minutes until no obvious bubbles were found. Then, it was coated into a wet film using a doctor blade coating method. The wet film coating thickness was 0.2 mm. It was then dried at 55°C for 1.5 h. After drying, it was peeled off and cut to obtain the oral dissolution film of Comparative Example 3.

[0055] Comparative Example 4: In this comparative example, the compound disintegrant was added to the aqueous phase of carboxymethyl soybean polysaccharide in advance, and then the pre-emulsified oil phase was added dropwise. The specific steps are as follows: S1. Based on the dry weight after removing moisture, take 40 parts of carboxymethyl soybean polysaccharide, 15 parts of compound modified vegetable oil, 10 parts of compound emulsifier, and 12 parts of compound disintegrant. The degree of substitution of carboxymethyl soybean polysaccharide is 0.5, and the viscosity of its 1% aqueous solution at 25℃ is 30 mPa·s. The compound modified vegetable oil consists of 9 parts of hydrogenated soybean oil and 6 parts of epoxidized soybean oil, with a weight ratio of 1.5:1. The compound emulsifier consists of 2.86 parts of soybean lecithin and 7.14 parts of polysorbate 80, with a weight ratio of 2.5:1. The compound disintegrant consists of 4.8 parts of crospovidone and 7.2 parts of sodium carboxymethyl starch, with a weight ratio of 1:1.5.

[0056] S2. Slowly add 40 parts of carboxymethyl soybean polysaccharide to deionized water, the amount of deionized water being 250% of the total dry weight of the oral soluble film. Stir while adding, and control the temperature at 55℃ to fully hydrate and dissolve the carboxymethyl soybean polysaccharide to obtain a polysaccharide aqueous phase. Then add 4.8 parts of cross-linked polyvinylpyrrolidone and 7.2 parts of sodium carboxymethyl starch to the polysaccharide aqueous phase, and continue stirring and dispersing to obtain a polysaccharide aqueous phase containing a compound disintegrant.

[0057] S3. Add 9 parts of hydrogenated soybean oil and 6 parts of epoxidized soybean oil to an oil phase container, heat to 65°C and stir evenly, then add 2.86 parts of soybean lecithin and 7.14 parts of polysorbate 80, and pre-emulsify at 4000 r / min at 65°C for 20 min to obtain a pre-dispersed oil phase.

[0058] S4. Slowly add the pre-dispersed oil phase to the polysaccharide aqueous phase containing the compound disintegrant at a rate of 1.5 mL / min, while stirring during the addition process; after the addition is completed, continue stirring and dispersing for 25 min to obtain the film-forming solution.

[0059] S5. Vacuum degassing of the film-forming solution for 10 minutes until no obvious bubbles are present, then coating it into a wet film using a doctor blade coating method. The wet film coating thickness is 0.2 mm. Then dry it at 55℃ for 1.5 h. After drying, peel it off and cut it to obtain the oral dissolution film of Comparative Example 4.

[0060] Performance testing To verify the beneficial effects of the present invention, the oral dissolving films obtained in Examples 1-4 and Comparative Examples 1-4 were subjected to the following performance tests.

[0061] (1) Appearance and membrane stability test: Take about 20 mL of the film-forming solution prepared in each group and place it in a transparent stoppered test tube. Let it stand at 25℃ for 24 h and observe whether layering, flocculation, oil droplet floating or settling occurs. Take another dried membrane and observe whether the membrane is uniform and whether there are bubbles, cracks, turbidity, oil separation or damage under natural light. Three parallel observations were conducted for each group.

[0062] (2) Tensile strength and elongation at break tests: The test procedures for film / sheet specimens were conducted in accordance with GB / T 1040.3-2006 "Determination of tensile properties of plastics - Part 3: Test conditions for films and sheets", and the specimen conditioning was performed in accordance with GB / T 2918-2018 "Standard environment for conditioning and testing of plastic specimens". Each group of oral fusion films was cut into strips with a width of 10 mm and a length of 80 mm. Before testing, the specimens were placed in an environment of 23℃ and 50% relative humidity for 24 hours, and the thickness at the middle of the specimens was measured. Tensile tests were performed using an electronic universal testing machine with an initial clamp spacing of 50 mm and a tensile speed of 50 mm / min. The tensile strength was calculated based on the specimen width and thickness, and the elongation at break was recorded. Five parallel specimens were tested in each group, and the average value of the results was taken.

[0063] (3) Test for complete dissolution time in artificial saliva: The test method was modified based on the disintegration time test method in General Chapter 0921 of the Chinese Pharmacopoeia. Artificial saliva with a pH of 6.8±0.1 was prepared. The artificial saliva composition was 0.40 g / L sodium chloride, 0.40 g / L potassium chloride, 0.795 g / L calcium chloride, 0.69 g / L sodium dihydrogen phosphate, and 1.00 g / L urea. It was preheated to 37℃±0.5℃. 20 mL of the solution was placed in a 50 mL beaker, and a 20 mm × 20 mm oral dissolution membrane sample was placed inside. The beaker was placed in a constant temperature shaker and shaken at 60 r / min. The time required for the membrane to completely dissolve from contact with the medium until no continuous membrane or sheet-like gel residue was observed was recorded as the complete dissolution time. Six samples were tested in each group, and the average value was taken.

[0064] (4) Storage stability test: Each group of oral dissolution membranes was sealed in aluminum-plastic composite bags and stored for 6 months at 25℃±2℃ and relative humidity of 60%±5%. The membranes were observed to see if they showed signs of moisture absorption and stickiness, cracks, turbidity, oil separation, damage or delamination. The complete dissolution time was retested after 6 months.

[0065] All oral dissolving films used for performance testing were obtained by peeling off dried films. The dry film thickness was measured using a thin film thickness gauge, and the moisture content was determined using the loss on drying method. The dry film thickness of the oral dissolving films obtained in Examples 1-4 was measured to be 0.10–0.13 mm, and the moisture content was 5.3%–6.5%.

[0066] The results are shown in Table 1 below.

[0067] Table 1. Results of comprehensive performance test of oral dissolving film

[0068] As shown in Table 1, the orally soluble membranes obtained in Examples 1-4 all exhibited good film-forming uniformity, mechanical flexibility, rapid solubility, and storage stability. Among them, Example 3 showed the best overall performance, indicating that carboxymethyl soybean polysaccharide, compound modified vegetable oil, compound emulsifier, and compound disintegrant formed a good synergistic effect. Specifically, carboxymethyl soybean polysaccharide constitutes a hydrophilic continuous membrane base, ensuring the basic film-forming and solubility of the membrane; the compound modified vegetable oil composed of hydrogenated soybean oil and epoxidized soybean oil can form a flexible oily phase in the membrane layer, improving the problem of easy cracking of single polysaccharide membranes; soybean phospholipids and nonionic emulsifiers can improve the dispersion stability of the oil phase in the polysaccharide aqueous phase, reducing stratification, turbidity, and oil separation; cross-linked polyvinylpyrrolidone and sodium carboxymethyl starch promote water entry into the membrane layer, accelerating disintegration and dissolution. Compared with Example 3, Comparative Example 1 showed a significant decrease in elongation at break, indicating that the lack of compound modified vegetable oil would lead to insufficient membrane flexibility; Comparative Example 2 showed stratification, turbidity, and oil separation, proving that the compound emulsifier plays a key role in the stable dispersion of the oil phase; Comparative Example 3 showed a significant increase in complete dissolution time, indicating that the compound disintegrant is an important factor in achieving rapid dissolution; Comparative Example 4 showed an increased dissolution time and uneven membrane, indicating that the post-addition of the disintegrant is more conducive to maintaining the homogeneity of the membrane solution and rapid dissolution performance.

[0069] In the description of this specification, references to terms such as "an embodiment," "example," "specific example," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0070] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the claimed invention.

Claims

1. A carboxymethyl soy polysaccharide based mouth-soluble film, characterized in that, Based on dry weight after removing moisture, it includes the following components: 30-50 parts of carboxymethyl soybean polysaccharide, 10-25 parts of compound modified vegetable oil, 5-15 parts of compound emulsifier and 5-20 parts of compound disintegrant; The degree of substitution of the carboxymethyl soybean polysaccharide is 0.3-0.8, and the viscosity of a 1% aqueous solution at 25°C is 10-50 mPa·s; the compound modified vegetable oil is composed of hydrogenated soybean oil and polar modified vegetable oil, and the weight ratio of hydrogenated soybean oil to polar modified vegetable oil is 0.5:1-4:1, wherein the polar modified vegetable oil is selected from at least one of epoxidized soybean oil, acetylated soybean oil, hydroxylated soybean oil, and hydroxylated castor oil; The composite emulsifier is composed of soybean lecithin and a nonionic emulsifier, wherein the weight ratio of the nonionic emulsifier to soybean lecithin is 1:1 to 5:1, and the nonionic emulsifier is selected from at least one of polysorbate 80, polyglycerol fatty acid ester, and sucrose fatty acid ester; the compound disintegrant is composed of crospovidone and sodium carboxymethyl starch, wherein the weight ratio of crospovidone to sodium carboxymethyl starch is 1:3 to 3:

1.

2. The carboxymethyl soy polysaccharide-based mouth-soluble film according to claim 1, characterized in that, The degree of substitution of the carboxymethyl soybean polysaccharide is 0.45 to 0.65, and the viscosity of a 1% aqueous solution at 25°C is 20 to 40 mPa·s.

3. The carboxymethyl soy polysaccharide based mouth-soluble film according to claim 1, characterized in that, The polar modified vegetable oil is epoxidized soybean oil, and the weight ratio of hydrogenated soybean oil to epoxidized soybean oil is 1:1 to 2:

1.

4. The carboxymethyl soybean polysaccharide-based oral dissolving film according to claim 1, characterized in that, The nonionic emulsifier is polysorbate 80, and the weight ratio of the nonionic emulsifier to soybean lecithin is 2:1 to 3:

1.

5. The carboxymethyl soybean polysaccharide-based oral dissolving film according to claim 1, characterized in that, The weight ratio of the cross-linked polyvinylpyrrolidone to sodium carboxymethyl starch is 1:1 to 1:

2.

6. The carboxymethyl soybean polysaccharide-based oral dissolving film according to claim 3, characterized in that, The hydrogenated soybean oil has a melting point of 50–70°C and an iodine value of no more than 15 gI2 / 100 g; the epoxidized soybean oil has an epoxy value of 5.5%–7.5% and an acid value calculated as KOH of no more than 1.0 mg / g.

7. The carboxymethyl soybean polysaccharide-based oral dissolving film according to claim 1, characterized in that, The oral dissolving film also includes a hydrophobic oral active ingredient, which accounts for 0.1% to 15% of the total dry weight of the oral dissolving film. The hydrophobic oral active ingredient is selected from one or more of ibuprofen, curcumin, vitamin D3, coenzyme Q10, and melatonin.

8. The carboxymethyl soybean polysaccharide-based oral dissolving film according to claim 1, characterized in that, The dry film thickness of the oral dissolving film is 0.05 to 0.25 mm, the water content based on the total mass of the oral dissolving film is 3% to 10%, and the complete dissolution time of the oral dissolving film measured in artificial saliva at 37°C is no more than 30 seconds.

9. A method for preparing a carboxymethyl soybean polysaccharide-based oral dissolving film according to any one of claims 1 to 8, characterized in that, Includes the following steps: S1. Dissolve carboxymethyl soybean polysaccharide in deionized water to obtain an aqueous solution of carboxymethyl soybean polysaccharide; S2. Hydrogenated soybean oil, polar modified vegetable oil, soybean lecithin, and nonionic emulsifier are mixed to obtain an oil phase mixture; when the oral dissolving membrane includes a hydrophobic oral active ingredient, the hydrophobic oral active ingredient is also added to the oil phase mixture; the oil phase mixture is sheared and pre-dispersed to obtain a pre-dispersed oil phase; S3. The pre-dispersed oil phase is added dropwise to the carboxymethyl soybean polysaccharide aqueous solution and dispersed to obtain an oil-containing film liquid; S4. Add cross-linked polyvinylpyrrolidone and sodium carboxymethyl starch to the oil-containing film solution for dispersion to obtain a film-forming solution; S5. The film-forming solution is degassed, coated, dried, peeled and slit to obtain a carboxymethyl soybean polysaccharide-based oral soluble film.

10. The preparation method according to claim 9, characterized in that, In step S2, the shear pre-dispersion temperature is 55–75℃, and the shear pre-dispersion time is 10–30 min; in step S3, the dropping rate of the pre-dispersed oil phase is 1–2 mL / min, and dispersion continues for 15–40 min after the dropping is completed; in step S4, cross-linked polyvinylpyrrolidone and sodium carboxymethyl starch are added after the pre-dispersed oil phase has been dropped and dispersed; in step S5, the drying temperature is 45–60℃, and the drying time is 1–3 h.

Images