Oral soluble film and preparation method thereof

Abstract

The invention relates to the technical field of oral soluble film products, and discloses an oral soluble film and a preparation method thereof. The water content of the oral soluble film is larger than 5%, the tensile strength of the oral soluble film is not smaller than 10 MPa, the oral soluble film comprises a film forming material, an active substance, a first water locking agent and a second water locking agent, and the first water locking agent and the second water locking agent are synergists. The oral soluble film is high in moisture content, the loading capacity of active ingredients can be improved, the oral soluble film is high in dissolution speed in the mouth and fresh and cool in taste, the first water locking agent and the second water locking agent can form a three-dimensional network structure, and the toughness of the nicotine oral soluble film can be improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of oral products, in particular to an oral dissolving film and a preparation method thereof. BACKGROUND

[0002] The nicotine oral dissolving film is a new type of nicotine replacement therapy, which has the advantages of precise dosage, rapid effect, portability and the like. The oral dissolving film in the related art usually uses hydroxypropyl methyl cellulose (HPMC) as a film-forming base material, and the water content is usually controlled at about 3-4% (low water content) to ensure the film quality and stability. However, the low water content limits the loading amount of active ingredients such as nicotine salt, cooling agent and sweetener, so that the active ingredients are easy to be precipitated, and the film has a dry and slow dissolving speed and is sticky. Moreover, even if high loading of the active ingredients is achieved, the film body is easy to be brittle under the condition of high loading, and the mechanical strength is insufficient. The related art improves the flexibility by increasing the amount of plasticizer or by adjusting the proportion of the film-forming material, but the film body is too soft or has too high hygroscopicity, the mechanical strength is still insufficient, and too high hygroscopicity easily causes the growth of microorganisms, so that an additional preservative is needed, which affects the product safety. SUMMARY

[0003] To solve the above technical problems, the present application provides an oral dissolving film with relatively high water content and a preparation method thereof.

[0004] The present application discloses an oral dissolving film, the water content of the oral dissolving film is greater than 5%, and the tensile strength of the oral dissolving film is not less than 10 MPa. The oral dissolving film comprises a film-forming material, an active substance, a first water-retention agent and a second water-retention agent, wherein the first water-retention agent and the second water-retention agent are synergistic agents.

[0005] In an implementation manner of the present application, the first water-retention agent comprises sodium hyaluronate; and the second water-retention agent comprises at least one of trehalose, sodium alginate and hydroxypropyl starch.

[0006] In an implementation manner of the present application, one of the first water-retention agent and the second water-retention agent comprises trehalose, and the other comprises xanthan gum; or one of the first water-retention agent and the second water-retention agent comprises sodium alginate, and the other comprises hydroxypropyl starch.

[0007] In an implementation manner of the present application, the water content of the oral dissolving film is 6.5%-7.5%.

[0008] In an implementation manner of the present application, the elongation at break of the oral dissolving film is greater than or equal to 50%.

[0009] In an implementation manner of the present application, the active substance comprises an active molecule, and the mass fraction of the active molecule in the oral dissolving film is 2%-3.5%.

[0010] In an implementation form of the application, the film-forming material comprises at least one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, pullulan, amylose, polyfructose, polyvinyl alcohol, polyethylene glycol, povidone, gelatin and chitosan; and / or the active substance comprises at least one of nicotine and nicotine derivatives.

[0011] In an implementation form of the application, the orally dissolving film further comprises at least one of a sweetener, a cooling agent, a pH regulator, a flavoring agent, a plasticizer.

[0012] In an implementation form of the application, the orally dissolving film comprises, in mass parts, 8-12 parts of the film-forming material, 0.5-1.5 parts of the first water-retention agent, 2-4 parts of the second water-retention agent, 2-3.5 parts of the active substance, and further comprises 0.2-0.5 parts of the cooling agent, 0.1-0.3 parts of the sweetener, 1-2 parts of the plasticizer, and 2-3 parts of the flavoring agent.

[0013] The application further discloses a preparation method of the orally dissolving film, for preparing the orally dissolving film, comprising the following steps: obtaining a film-forming liquid, the film-forming liquid comprising a film-forming material, an active substance, a first water-retention agent and a second water-retention agent, wherein the first water-retention agent and the second water-retention agent are synergistic agents; injecting the film-forming liquid into a pre-set mold, injection molding to obtain a film piece; and drying the film piece to obtain the orally dissolving film, wherein the water content of the orally dissolving film is greater than 6%, and the tensile strength of the orally dissolving film is not less than 10 MPa.

[0014] The application provides an orally dissolving film and a preparation method thereof, and the preparation of the orally dissolving film using the first water-retention agent and the second water-retention agent can ensure that the water content of the orally dissolving film is greater than 5%, which helps to improve the loading capacity of the active substance such as nicotine salt, and also improves the dissolution speed and taste of the film piece. The tensile strength of the orally dissolving film is not less than 10 MPa, which can ensure the toughness of the orally dissolving film. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 The preparation process flow chart of the nicotine orally dissolving film of Example 1 is shown in FIG. 1.

[0016] Figure 2 The dissolution ratio curve of the nicotine orally dissolving film of Example 1 and the nicotine orally dissolving film prepared by the traditional process is shown in FIG. 2.

[0017] Figure 3 The morphology characterization diagram of the nicotine orally dissolving film of Example 1 and the nicotine orally dissolving film prepared by the traditional process is shown in FIG. 3, wherein a, c and e are the morphology diagrams of the nicotine orally dissolving film of Example 1, b, d and f are the morphology diagrams of the nicotine orally dissolving film prepared by the traditional process, the magnification of a and b is 5000 times, the magnification of c and d is 1000 times, and the magnification of e and f is 250 times. DETAILED DESCRIPTION

[0018] The application will be described in further detail below with specific embodiments. In the following embodiments, many details are described in order to provide a more thorough understanding of the present application. However, it will be apparent to one skilled in the art that some features that are not described in detail can be omitted in different cases, or can be replaced by other materials, methods. In some cases, some operations related to the present application are not shown or described in the specification in order to avoid the core part of the present application being overwhelmed by too much description, and it is not necessary to describe these related operations in detail for those skilled in the art, who can fully understand the related operations according to the description in the specification and general technical knowledge in the art. In addition, the features, operations or characteristics described in the specification can be combined in any appropriate way to form various embodiments. At the same time, the steps or actions in the method description can also be sequentially adjusted or adjusted in a manner that is obvious to those skilled in the art. Therefore, the order in the specification is only for the purpose of clearly describing a certain embodiment, and does not mean that it is the necessary order, unless otherwise stated that a certain order must be followed.

[0019] In order to further illustrate the present application, the nicotine oral film, the film-forming liquid and the preparation method thereof provided by the present application are described in detail below in combination with embodiments. However, it should be understood that these embodiments are implemented on the premise of the technical solutions of the present application, and detailed implementation manners and specific operation processes are given, which are only for further illustrating the features and advantages of the present application, and are not a limitation on the claims of the present application, and the protection scope of the present application is not limited to the following embodiments.

[0020] In the related art, although the hot air drying has low cost, the water distribution is uneven, and the water activity is difficult to control, which limits the storage stability of the oral film. The present application uses at least two water locking agents such as sodium hyaluronate and trehalose which have a synergistic effect to form a stable hydrogen bond three-dimensional network structure, effectively lock water, and improve the toughness and stability of the film. And adopt two-stage vacuum drying step, the first stage quickly removes the surface moisture, the second stage slowly releases the deep layer moisture, ensures the balance of the water in and outside the film, and finally controls the water activity below 0.33.

[0021] An embodiment of the present application provides an oral film, the water content of the oral film is greater than 5%, and the tensile strength of the oral film is not less than 10 MPa, the oral film comprises a film-forming material, an active substance, a first water locking agent and a second water locking agent, wherein the first water locking agent and the second water locking agent are synergistic agents.

[0022] The first water locking agent and the second water locking agent with synergistic effect are added in the oral film, which can lock more water to the maximum extent.

[0023] In one embodiment, the first water-locking agent comprises sodium hyaluronate, and the second water-locking agent comprises at least one of trehalose, sodium alginate, and hydroxypropyl starch.

[0024] It should be noted that sodium hyaluronate forms hydrogen bonds with water in water, and can form stable hydrate substances with water molecules through hydrogen bonds. The water is wrapped on the surface or inside the molecules of sodium hyaluronate. The hydration of water molecules makes sodium hyaluronate a very effective water-locking agent, which can effectively "absorb" and retain water, so that the water is not easy to evaporate or lose in the film. The second water-locking agent also has a polar group. The second water-locking agent and sodium hyaluronate are connected to each other through hydrogen bonds to form a three-dimensional network structure, thereby "locking" water and preventing water loss. Taking sodium hyaluronate as the first water-locking agent and trehalose as the second water-locking agent as an example, trehalose is a disaccharide with strong water-locking properties. By acting together with sodium hyaluronate, a three-dimensional network structure is formed, which can enhance the water-locking effect of the film. In addition, sodium hyaluronate and trehalose also have strong hygroscopicity, which can attract water in the air and store it in the molecules. That is, sodium hyaluronate and trehalose attract and combine water through physical adsorption, thereby effectively "locking" water. In addition, trehalose forms micellar structures through the hydroxyl groups in its molecules, locking water in the micellar structures. The water-locking matrix of the micellar structure is very suitable for use in low temperature and dry conditions, which can significantly improve the stability of the substance.

[0025] In addition, since trehalose has good solubility in water, its dissolution speed in the oral cavity is usually fast, and contact with saliva in the oral cavity can accelerate its dissolution. Uniform mixing during the preparation of the film-forming liquid allows the trehalose to be uniformly distributed in the finished film. After contact with saliva, the three-dimensional network structure is destroyed due to the rapid dissolution of trehalose, accelerating the rupture and dissolution of the entire finished film, which can improve the dissolution speed of the finished film.

[0026] In one embodiment, one of the first water-locking agent and the second water-locking agent comprises trehalose, and the other comprises xanthan gum; or one of the first water-locking agent and the second water-locking agent comprises sodium alginate, and the other comprises hydroxypropyl starch.

[0027] Trehalose has multiple hydroxyl groups, making it have strong hydrophilicity, and xanthan gum also has acetyl groups, which are polar groups. While forming hydrogen bonds with water, respectively, hydrogen bonds can also be formed between trehalose and acetyl groups, achieving the purpose of synergistic water-locking. Similarly, sodium alginate and hydroxypropyl starch can also achieve synergistic water-locking.

[0028] In one embodiment, the water content of the orally dissolving film is 6.5% to 7.5%.

[0029] High water content can also improve the toughness and stability of the orally dissolving film.

[0030] In one embodiment, the elongation at break of the mouth dissolving film is greater than or equal to 50%.

[0031] In one embodiment, the active substance includes active molecules, and the mass fraction of the active molecules in the mouth dissolving film is 2% to 3.5%.

[0032] It should be noted that the active molecules refer to the molecules or ions that actually play a role in the active substance, such as nicotine in nicotine complex or nicotine inclusion, nicotine ions in nicotine salt, 6-methyl nicotine ions in 6-methyl nicotine salt, etc.

[0033] In one implementation of the present application, the film-forming material includes at least one of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, pullulan, amylose, polyfructose, polyvinyl alcohol, polyethylene glycol, povidone, gelatin and chitosan; and / or, the active substance includes at least one of nicotine and nicotine derivatives.

[0034] The amylose includes corn starch, potato starch, rice starch and waxy rice starch, etc., and has good water solubility.

[0035] The nicotine includes natural nicotine and synthetic nicotine, and the nicotine derivatives include one or more of nicotine salt, nicotine in a matrix such as sugar matrix or organic metal complex, nicotine-resin polymer, nicotine inclusion complex and non-covalently bound nicotine. Among them, the non-covalently bound nicotine includes nicotine lactate, nicotine malate, nicotine salicylate, nicotine cyclodextrin inclusion complex, nicotine hydrochloride, nicotine dihydrochloride, nicotine tartrate, nicotine tartrate dihydrate, nicotine sulfate, nicotine zinc chloride, nicotine benzoate, etc. The nicotine derivatives also include nicotine containing substituents, such as one or more of the following: hexamethyl nicotine, hexamethyl nicotine lactate, hexamethyl nicotine malate, hexamethyl nicotine salicylate, hexamethyl nicotine cyclodextrin inclusion complex, hexamethyl nicotine hydrochloride, hexamethyl nicotine dihydrochloride, hexamethyl nicotine tartrate, hexamethyl nicotine tartrate dihydrate, hexamethyl nicotine sulfate, hexamethyl nicotine zinc chloride, hexamethyl nicotine benzoate.

[0036] In some embodiments, in order to meet the needs of different users, the active substance can include substances with medical properties; or, the active substance can include substances with specific active properties, such as caffeine, theophylline, vitamins, capsaicin, etc.

[0037] In one embodiment, the mouth dissolving film further includes at least one of sweeteners, cooling agents, pH adjusters, flavoring agents, plasticizers.

[0038] The addition of sweeteners, cooling agents, pH adjusters, flavoring agents, plasticizers and the like can help to improve the mouthfeel of the mouth dissolving film.

[0039] The cooling agent includes at least one of N-ethyl-p-menthane-3-carboxamide (i.e. WS-3), N-ethyl-2-isopropyl-5-methylcyclohexanecarboxamide (i.e. WS-4), 2-isopropyl-N,2,3-trimethylbutanamide (i.e. WS-23), glyceryl-1,2,3-tris(ethoxymethoxycarbamate) (i.e. WS-30), menthyl lactate, monomenthyl succinate, menthyl glyoxylate, menthyl acetate, (±)-menthone and d-(+)-neomenthol.

[0040] The sweetener includes at least one of acesulfame acid, acesulfame potassium, alitame, aspartame, aspartame derivatives, neotame, sodium cyclamate (N-cyclohexylsulfamic acid sodium), calcium cyclamate, erythritol, xylitol, maltitol, mannitol, sorbitol, isomalt and tagatose, xylose, glycyrrhizin, stevia, d-allosucrose, d-allose, saccharin, sucralose and gluconic acid.

[0041] The plasticizer includes at least one of propylene glycol, glycerol, polyethylene glycol and sorbitol. The flavoring agent is not limited to a specific taste of essence, but can be any edible essence, such as mixed berry essence.

[0042] In one embodiment, the mouth dissolving film includes, in mass parts, 8-12 parts of film forming material, 0.5-1.5 parts of first water retaining agent, 2-4 parts of second water retaining agent, 2-3.5 parts of active substance, 0.2-0.5 parts of cooling agent, 0.1-0.3 parts of sweetener, 1-2 parts of plasticizer and 2-3 parts of flavoring agent, and the rest is solvent.

[0043] The solvent can be purified water, and the plasticizer is glycerol.

[0044] One embodiment of the present application provides a preparation method of a mouth dissolving film, for preparing the aforementioned mouth dissolving film, including: obtaining a film forming solution, the film forming solution including film forming material, active substance, first water retaining agent and second water retaining agent, wherein the first water retaining agent and the second water retaining agent are synergistic agents; injecting the film forming solution into a pre-set mold, injection molding to obtain a film piece; and drying the film piece to obtain the mouth dissolving film, wherein the water content of the mouth dissolving film is greater than 6%, and the tensile strength of the mouth dissolving film is not less than 10 MPa.

[0045] In a specific embodiment, the film forming solution preparation step includes: swelling the film forming material and the first water retaining agent in the solvent at a certain temperature for a certain time, then adding the second water retaining agent for homogeneous mixing, then adding the active substance, sweetener and cooling agent for mixing, and finally performing vacuum degassing under certain conditions to obtain the film forming solution.

[0046] In a specific embodiment, the swelling time is 40 min and the swelling temperature is 50℃. In other embodiments, the swelling temperature and the swelling time are adjusted according to the specific preparation process and are not limited thereto.

[0047] In a specific embodiment, the vacuum degassing is performed at 0.09 MPa, and the vacuum degassing time is 15 min. Similarly, the vacuum degassing conditions are also adjusted according to the specific preparation process and are not specifically limited.

[0048] In a specific embodiment, the film preparation step includes: first coating a layer of silicon-based nano release layer (thickness of silicon-based nano release layer ≤ 50 nm) on the surface of the mold, then adjusting the viscosity and moisture content of the film-forming solution to make the film-forming solution enter the preset mold; adjusting the injection molding parameters to obtain the film.

[0049] The nano release layer provided on the surface of the mold can ensure smooth demolding of the film and avoid residual stress.

[0050] In a specific embodiment, the viscosity of the film-forming solution is adjusted to 500 mPa·s, and the moisture content is 65%-75%.

[0051] In a specific embodiment, the injection molding parameters are: the mold temperature is 40-45℃, the injection molding pressure is 0.5-1.2 MPa, the holding pressure time is 30 s, and the thickness of the obtained film is 100 μm.

[0052] In a specific embodiment, the drying step includes two stages. In the first stage, the vacuum degree and temperature of the vacuum drying box are adjusted to quickly remove the moisture on the surface of the film and reduce the initial moisture content of the film surface to 5%; in the second stage, the vacuum degree of the vacuum drying box is adjusted to -0.1 MPa and the temperature is 30℃, so that the deep moisture of the film is released slowly, and the moisture content of the film is finally stabilized at 7.5%, to obtain a nicotine oral film. The vacuum degree of the first stage is less than that of the second stage, and the temperature of the first stage is greater than that of the second stage.

[0053] In the vacuum drying process, a two-stage drying process is adopted, and the drying temperature of the first stage is greater than that of the second stage, and the vacuum degree of the second stage is greater than that of the first stage. Compared with direct high-temperature drying, the water content of the nicotine oral film can be higher, and the water activity can be more accurately controlled.

[0054] Example 1

[0055] This embodiment provides a preparation method of a nicotine oral film, such as Figure 1 , the preparation method includes the following steps:

[0056] Film forming solution preparation step: Exemplarily, 11 parts of hydroxypropyl methyl cellulose (HPMC) and 1 part of sodium hyaluronate are swelled in 76.5 parts of pure water at 50°C for 40 min, then 3 parts of trehalose and 1 part of sodium alginate are uniformly mixed, and then 1 part of propylene glycol, 1 part of glycerol, 3 parts of nicotine salt, 0.3 parts of n, 2, 3-trimethyl-2-isopropyl butyramide, 2 parts of mixed berry flavor and 0.2 parts of sucralose are mixed, and then the mixture is uniformly mixed and degassed in a vacuum degassing machine under the condition of vacuum-0.09 MPa for 15 min to obtain a film forming solution. The viscosity of HPMC is 15 mPa·s, and the molecular weight of sodium hyaluronate is 200-400 million. The specific formula of the film forming solution can also be adjusted according to the actual production conditions and product demand.

[0057] It should be noted that by adding sodium hyaluronate and film forming material to water for swelling, and then adding trehalose, the trehalose will not completely absorb water and dissolve in the swelled solution, but will completely absorb water and dissolve in the mouth when used in the mouth. While achieving water absorption and moisturizing, it can also speed up the dissolution rate of the nicotine oral film in the mouth.

[0058] Injection molding step: a layer of silicon-based nano release layer (thickness of silicon-based nano release layer ≤50 nm) is coated on the surface of the mold, the film forming solution is injected into the mold, and the injection molding parameters are adjusted so that the mold temperature is 45°C, the injection pressure is 0.8 MPa, and the holding pressure time is 30 s; the film is formed by film forming. It should be noted that the specific process parameters of the injection molding step can be adjusted according to the actual production conditions.

[0059] Drying step: The drying step is divided into two stages. In the first stage, the vacuum degree of the vacuum drying box is adjusted to-0.05 MPa and the temperature is 45°C, the surface moisture of the film is quickly removed, and the initial moisture content of the film surface is reduced to 5%; in the second stage, the vacuum degree of the vacuum drying box is adjusted to-0.1 MPa and the temperature is 30°C, the deep moisture of the film is slowly released, and the final moisture content of the film is stabilized at 7.5%, to obtain the nicotine oral film. It should be noted that the specific process parameters of the drying step can be adjusted according to the actual production conditions.

[0060] Film cutting and bagging step: the film is cut to 25 mm x 14 mm and bagged to obtain the nicotine oral film. In some embodiments, the oral film can also be other specifications, which are not limited in the present application.

[0061] Oral film index test

[0062] Equipment: coating machine, injection molding equipment

[0063] Sample: 1, traditional coating process proof sample, which uses HPMC as film forming material and adds sweetener and cooling agent. 2, sample of product film prepared by the method in example 1 after 24 hours. The sweetener and cooling agent of sample 1 and sample 2 are the same, and sample 1 is dried and formed in one step.

[0064] The moisture content in the nicotine oral film was determined by Karl Fischer moisture tester, and the detection method referred to GB / T 6283-2008 "Determination of Moisture Content in Chemical Products - Karl Fischer Method (General Method)".

[0065] The nicotine content was detected by high performance liquid chromatography. The detection steps were as follows: 1) dilute nicotine standard solution of a certain concentration, filter through filter membrane for standby; 2) treat sample (dissolve, ultrasonic, filter) to ensure sample uniformity; 3) set chromatographic conditions (C18 chromatographic column, mobile phase is methanol and water system, detection wavelength is 254 nm); 4) sample standard solution and sample solution in turn, record chromatogram, calculate nicotine content by external standard method.

[0066] Thickness gauge was used to detect thickness uniformity. The operation steps were as follows: calibrate the thickness gauge (such as micrometer) to zero position, then select multiple measurement points (such as center, four corner points) on the surface of the product film, and record the thickness values of each point.

[0067] Disintegration tester was used to detect the dissolution time of nicotine oral film at 37℃. The detection steps were as follows: 1) heat the water tank of disintegration tester to 37℃±0.5℃, and adjust the hanger device; 2) place the nicotine oral film in the hanger, immerse it in water, and start the disintegration tester; 3) observe and record the time when the film completely disintegrates (no debris remains).

[0068] Water activity meter was used to detect the water activity in the oral film. The detection steps referred to GB / T 23490-2009 "Determination of Water Activity of Food - Water Activity Meter Method".

[0069] The results obtained by detection were as follows Table 1

[0070] Stability test

[0071] Prepare 3 groups of sample 1 and product film prepared in example 1, each group has 20 samples, and place them in 25℃, 40% RH, 25℃, 60% RH, 35℃, 40% RH and 35℃, 60% RH environment respectively. On the 0th day, 1 month and 3 months, determine the moisture content, nicotine salt load and water activity of each sample. The moisture content is determined by Karl Fischer titration method, the nicotine salt load is determined by high performance liquid chromatography, and the water activity is determined by water activity meter. The test results are shown in Table 2.

[0072] Verify the dissolution effect of oral film-dissolution curve test

[0073] Equipment: Dissolution apparatus-paddle method;

[0074] Samples: one piece of orally disintegrating film produced using a conventional coating process (45.34 mg / g) KRZY000006, and one piece of orally disintegrating nicotine film from Example 1 (45.86 mg / g) KRZY000007;

[0075] Dissolution medium: artificial saliva - pH 6.8;

[0076] Sampling points: 30s, 1min, 3min, 5min, 7min, 10min, 15min, 20min;

[0077] Test conditions: heating temperature 37°C, speed 100r / min;

[0078] Analysis method: Nicotine content was detected by high performance liquid chromatography.

[0079] The test results are shown in Table 3 below:

[0080] Table 1

[0081] Indicator Conventional coating process Example 1 Moisture content 6.2％±0.5％ 7.5％±0.3％ Maximum loading of nicotine salt 2.8％ 3.4％ Thickness uniformity (RSD) 8.5％ 2.7％ 37°C pure water dissolution time (seconds) 20-25 22-28 Water activity (Aw) 0.38 0.31

[0082] Table 2

[0083]

[0084] Table 3

[0085] Time (min) Conventional coating process mouth dissolving film sample (mg / g) Injection molding process of the present invention mouth dissolving film sample (mg / g) 30S 0.45 1.35 1 0.90 3.25 3 1.80 3.65 5 2.70 3.85 7 3.40 4.28 10 4.05 4.50 15 4.11 4.50 20 4.12 4.50

[0086] According to the fitting release dynamic function: y = 100a(1-e -bt ) The dissolution rates of the nicotine orally dissolving films prepared by the conventional process and the process of Example 1 shown in Table 3 were analyzed, and the time when 80% of the nicotine was released was taken as the peak time. The release curves obtained were as follows: Figure 2 shown.

[0087] Orally disintegrating film surface morphology characterization test

[0088] A Prisma E environmental scanning electron microscope was used.

[0089] like Figure 3 As shown, at the same magnification, the orally dissolving film prepared by the traditional process precipitates more crystals than the orally dissolving film prepared by the preparation method of Example 1, and the precipitated crystal particles are larger, and the depth and density of the surface pits are greater.

[0090] As shown in the data in Table 1, compared with the orally disintegrating film produced by the traditional process, the injection molding process of the present application shows significant advantages in terms of moisture content, nicotine salt loading and film thickness uniformity.

[0091] The moisture content reached 7.5% ± 0.3%, while the traditional process only reached 6.2% ± 0.5. This difference reflects the advantages of the preparation process of the present application in improving moisture retention and ensuring the flexibility of the film. Higher moisture content not only helps to increase the load of active ingredients (such as nicotine salt), but also improves the dissolution speed and taste of the film. In addition, the maximum load of nicotine salt of the finished product obtained in Example 1 reached 3.4%, which is significantly higher than the 2.8% of the oral film prepared by the traditional process. This shows that the preparation method of Example 1 helps to maintain the uniform distribution of active ingredients of nicotine oral film, avoids precipitation, and can better utilize nicotine salt in the film-forming solution, improving product performance. The thickness uniformity of the film of the nicotine oral film of Example 1 (RSD value of 2.7%) is much better than that of the oral film prepared by the traditional process (RSD value of 8.5%). This excellent uniformity ensures the consistency of the quality of the film, helps to release nicotine uniformly, and thus improves the quality control ability of the product.

[0092] As shown in Table 2, under different humidity and temperature conditions, the moisture content, nicotine salt load and water activity of the nicotine oral film prepared by the preparation method of Example 1 change less, showing its strong stability. Specifically, under the condition of 25℃, 40% RH, the moisture content of the oral film prepared by Example 1 only decreased by 0.2% after 1 month, the nicotine salt load remained at 3.3%, and the water activity was 0.30, with a small change range. In contrast, the moisture content of the oral film prepared by the traditional process decreased by 0.2% after 1 month, the nicotine salt load decreased by 0.1%, and the water activity increased to 0.37, indicating that the loss of moisture and active ingredients of the traditional process sample was more significant during storage.

[0093] Under the condition of 35℃, 60% RH, the moisture content of the oral film of Example 1 only decreased by 0.4% after 3 months, while the moisture content of the oral film of the traditional process decreased by 0.6%. This shows that the oral film of Example 1 exhibits stronger stability under different environments, can effectively reduce the loss of moisture and active ingredients, and ensure the long-term quality of the product.

[0094] As shown in Table 3 and Figure 2As shown, compared with the nicotine oral film prepared by the traditional process, the nicotine oral film prepared by the process of Example 1 has a significant advantage in dissolution speed. In artificial saliva at 37°C, the oral film of Example 1 releases 1.35 mg of nicotine within 30 seconds, while the traditional process only releases 0.45 mg. Over time, the oral film of Example 1 releases 3.25 mg of nicotine at 1 min, while the oral film prepared by the traditional process releases 0.90 mg of nicotine. This shows that the oral film of Example 1 not only improves the nicotine load, but also speeds up the dissolution speed, providing faster nicotine delivery for users and significantly improving the product experience.

[0095] In summary, the preparation method of the oral film provided in the present application has excellent performance in water content, nicotine load, film thickness uniformity, dissolution speed, and tensile strength, and the overall effect is better than that of the traditional oral film preparation method.

[0096] Compared with the traditional process, the preparation process of the present application optimizes the film-forming liquid formula, injection molding process and drying process, successfully improves the moisture content and stability of the film, especially in water retention performance, significantly improves the mechanical strength and toughness of the film, and ensures its long shelf life, which can extend the shelf life to 24 months. The traditional process has certain problems of uneven water distribution and poor film thickness control during film formation, which leads to the fact that the moisture content and nicotine load cannot reach the best level, and the efficiency is low in terms of drying time and quality control. Although the coating process is relatively mature, its potential for improving film quality is limited.

[0097] The present application uses sodium hyaluronate and trehalose to synergistically lock water, greatly improving the water retention ability of the film, enhancing its toughness and taste, allowing it to melt in a short time, and effectively avoiding the precipitation problem in the traditional process. By precisely controlling the thickness and water activity of the film, the product after film formation has obvious advantages in stability, active ingredient release, and mechanical properties.

[0098] Therefore, the preparation method of the nicotine oral film of the present application not only overcomes the defects of the traditional process, but also provides a reliable solution for the efficient production of high-moisture and fast-dissolving nicotine oral films, and has broad market application prospects.

[0099] The above uses specific examples to describe the present application, which is only used to help understand the present application and does not limit the present application. For those skilled in the art to which the present application belongs, according to the idea of the present application, a number of simple deductions, deformations or substitutions can be made.

Claims

1. An orally disintegrating film, characterized in that: The orally dissolving film has a water content greater than 5%, and a tensile strength of not less than 10 MPa. The orally dissolving film comprises a film-forming material, an active substance, a first water-locking agent, and a second water-locking agent, wherein the first water-locking agent and the second water-locking agent are synergists.

2. The orally dissolving film according to claim 1, wherein The first water-locking agent includes sodium hyaluronate; The second water-locking agent includes at least one of trehalose, sodium alginate and hydroxypropyl starch.

3. The orally dissolving film according to claim 1, wherein One of the first water-locking agent and the second water-locking agent comprises trehalose, and the other comprises xanthan gum; or One of the first water-locking agent and the second water-locking agent includes sodium alginate, and the other includes hydroxypropyl starch.

4. The orally dissolving film according to claim 1, wherein The water content of the orally disintegrating film is 6.5% to 7.5%.

5. The orally dissolving film according to claim 1, wherein The elongation at break of the orally disintegrating film is greater than or equal to 50%.

6. The orally dissolving film according to claim 1, wherein The active substance includes active molecules, and the mass fraction of the active molecules in the orally disintegrating film is 2% to 3.5%.

7. The orally dissolving film according to any one of claims 1 to 6, characterized in that The film-forming material comprises at least one of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, pullulan, amylose, fructosan, polyvinyl alcohol, polyethylene glycol, povidone, gelatin and chitosan; and / or, The active substance includes at least one of nicotine and a nicotine derivative.

8. The orally dissolving film according to any one of claims 1 to 6, characterized in that The orally dissolving film further comprises at least one of a sweetener, a cooling agent, a pH regulator, a flavoring agent, and a plasticizer.

9. The orally dissolving film according to claim 1, wherein Measured in parts by mass, the orally dissolving film includes 8-12 parts of the film-forming material, 0.5-1.5 parts of the first water-locking agent, 2-4 parts of the second water-locking agent, 2-3.5 parts of the active substance, and the orally dissolving film also includes 0.2-0.5 parts of a cooling agent, 0.1-0.3 parts of a sweetener, 1-2 parts of a plasticizer, and 2-3 parts of a flavoring agent.

10. A method for preparing an orally disintegrating film, characterized in that: For preparing the orally dissolving film according to any one of claims 1 to 9, comprising: Obtaining a film-forming solution, wherein the film-forming solution includes a film-forming material, an active substance, a first water-locking agent and a second water-locking agent, wherein the first water-locking agent and the second water-locking agent are synergists; injecting the film-forming liquid into a preset mold, performing injection molding, and obtaining a membrane; The film sheet is dried to obtain the orally disintegrating film, wherein the water content of the orally disintegrating film is greater than 6%, and the tensile strength of the orally disintegrating film is not less than 10 MPa.

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