Bicolor nicotine oral soluble film and preparation method thereof

Abstract

The invention discloses a bicolor nicotine oral soluble film and a preparation method thereof. According to the double-color nicotine oral dissolving film, one side is a nicotine film with a certain color, the other side is a synergistic substance film with other colors, and the areas of the two parts can be matched according to the dosage requirements of nicotine and synergistic substances; producers and consumers can conveniently distinguish and select product types, dosage proportions can be visually distinguished, and the consumers can conveniently distinguish and select products according to the demand quantity of nicotine by themselves. The product is directly absorbed through oral mucosa, the smokeless problem is solved, and the influence of a smoking mode on the nicotine absorption rate is avoided. Due to the double-color single-layer film design, the appearance is novel, and the user experience is improved; the preparation method is simple and easy to operate and can be used for large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of nicotine products, and particularly relates to a two-color nicotine orodispersible film and a preparation method thereof. Background Art

[0002] Nicotine, also known as nicotine, is an alkaloid that has an excitatory effect on the central nervous system. It acts on the central neurotransmitter system through nicotinic receptors, increasing the release of dopamine (DA), thereby causing euphoria. It is the main component of tobacco that causes dependence and tolerance. It has a high affinity for the α4β2 subunit of the nicotine acetylcholine receptor (nAchR). When the neuronal nAchR is activated, a biological effect is produced, leading to addiction.

[0003] Overall, nicotine has a strong addictive effect. In order to prevent the abuse of nicotine and protect the health and safety of the public, countries strictly regulate nicotine, and the nicotine content in electronic cigarettes is basically limited to 20 mg / g or less. However, the decrease in nicotine content will lead to a decrease in satisfaction. In the published patent CN118766127A (a multi-component compound nicotine preparation and its preparation method and application), a multi-component compound nicotine preparation is provided, which compounds nicotine with acetylcholine receptor agonists, dopamine secretion regulators, monoamine oxidase inhibitors and organic acids, etc., and utilizes the synergistic effect between the substances to effectively improve the satisfaction of the nicotine preparation formula and reduce the addictiveness. However, when the electronic cigarette is inhaled, the absorption rate of nicotine is easily affected by the smoking method. The absorption amount is relatively high when deep or frequent inhalation is high, while for consumers with sensitive respiratory tracts, the number of deep inhalations and puffs is significantly reduced, resulting in a low nicotine absorption rate, and the effect of addiction relief will be correspondingly reduced.

[0005] Most of the existing smoke-free products are in the form of single nicotine, such as snus, chewing gum, etc. Most of the existing compound products are in the form of atomized products. Under the global ban on the spread of tobacco smoke in public places, the use of products is greatly restricted. Due to the limitations of atomization technology, some macromolecular substances cannot be absorbed through atomization. Therefore, it is necessary to develop a nicotine product that can solve the problem of smoke-free tobacco products and improve the nicotine absorption rate. Summary of the invention

[0006] In view of the shortcomings of the prior art, the present invention aims to provide a two-color nicotine orodispersible film and a preparation method thereof, which has the advantages of being simple and easy to operate.

[0007] The two-color nicotine orodispersible film of the present invention has a yellow (or another color) nicotine film on one side and a co-substance film of another color on the other side. The area sizes of the two parts can be proportioned according to the dosage requirements of nicotine and co-substances. For example, the size of the orodispersible film is 1 cm * 2 cm, with a 1 cm * 1 cm yellow nicotine film on the left and a 1 cm * 1 cm co-substance film of another color on the right. The present invention applies the orodispersible film technology to smokeless tobacco products, which not only solves the problem of smokeless tobacco products, but also enables the orodispersible film products to be directly absorbed through the oral mucosa, avoiding the influence of smoking methods on the nicotine absorption rate.

[0008] An orodispersible film is an ultra-thin and portable innovative drug dosage form. After being placed on the patient's tongue or oral mucosa tissue, the film is wetted by saliva, hydrated and decomposed, and the drug is slowly released and absorbed by the mucosa. In this way, without drinking or chewing, the drug is directly absorbed into the blood without being damaged by the liver, increasing its bioavailability.

[0009] A preparation method of a two-color nicotine orodispersible film of the present invention includes the following steps:

[0010] S1. Take 5-10 parts by mass of nicotine brine solution, add 10-25 parts by mass of plasticizer, 1-2.5 parts by mass of flavoring agent, an appropriate amount of coloring agent, and add water to make up to a total system of 30-40 parts by mass, and stir into a mixed solution; add 60-70 parts by mass of film-forming material to the solution, stir to obtain a uniform and continuous film solution, and control the viscosity to be 20000-50000 mPa·s; remove bubbles by ultrasonic treatment to obtain 100 parts by mass of nicotine film solution;

[0011] S2. Take 5-10 parts by mass of co-substance aqueous solution, add 10-25 parts by mass of plasticizer, 1-2.5 parts by mass of flavoring agent, an appropriate amount of coloring agent with a color different from that in step S1, and add water to make up to a total system of 30-40 parts by mass, and stir into a mixed solution; add 60-70 parts by mass of film-forming material to the solution, stir to obtain a uniform and continuous film solution, and control the viscosity to be 20000-50000 mPa·s; remove bubbles by ultrasonic treatment to obtain 100 parts by mass of co-substance film solution;

[0012] S3. Scrap the nicotine film solution and the co-substance film solution onto two adjacent areas, separate them in the middle with a thin plate, remove the thin plate after scraping, scrape to make the film thickness of the two areas the same and control the film thickness to be 0.5 mm - 1 mm, dry the wet film at 55°C - 60°C, peel off the dried nicotine film and co-substance film, and cut the nicotine film together with the co-substance film into pieces according to the designed nicotine and co-substance contents to obtain the two-color nicotine orodispersible film.

[0013] Preferably, the nicotine brine solution is an aqueous solution prepared by mixing nicotine and an organic acid in a molar ratio of 1:1 and dissolving them in water. The organic acid is tartaric acid, lactic acid, citric acid, benzoic acid, gluconic acid, malic acid, acetic acid, levulinic acid, salicylic acid or sorbic acid.

[0014] Preferably, the nicotine content in the nicotine brine solution is 40% by mass.

[0015] Preferably, the plasticizer is at least one of glycerol, polyethylene glycol, propylene glycol, and Tween 80.

[0016] Preferably, the flavoring agent is at least one of food flavoring agents such as mint flavor, strawberry flavor, lemon flavor, citronella flavor, grape flavor, rose flavor, and sweet orange flavor.

[0017] Preferably, the coloring agent is a food coloring such as carotenoid (orange-yellow), anthocyanin (magenta), chlorophyll (green), curcumin (yellow), sunset yellow (orange-yellow), carmine (red), or brilliant blue (blue).

[0018] Preferably, the film-forming material is one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyoxyethylene, polyvinyl alcohol, gum arabic, xanthan gum, or agar.

[0019] Preferably, the synergistic substance is melatonin, caffeine, arecoline, sparteine, varenicline, theanine, γ-aminobutyric acid, or selegiline.

[0020] Preferably, the nicotine film is yellow, and the synergistic substance is melatonin. Melatonin has been pretreated with phospholipid bilayer wrapping before preparation, and the melatonin film is red.

[0021] By adjusting the addition amount and concentration, the orally dissolving film of the present invention can have any nicotine or synergistic substance content per unit area. For example, for an area of 1 cm 2 with a thickness of 0.8 mm, it contains 12 mg of nicotine (converted according to the content of nicotine salt), or any other appropriate amount. Under the condition of a determined dose, the orally dissolving film can have any appropriate shape according to the ratio of nicotine to the synergistic substance, such as rectangular, rounded rectangular, oval, circular, etc.

[0022] The present invention also provides a two-color nicotine orodispersible film prepared according to the described method. In this two-color nicotine orodispersible film, different co-substances can be used according to different needs of consumers; the orodispersible film has two colors, one part is a yellow (or another color) nicotine film, and the other part is a film containing co-substances, with different colors according to different co-substances. And for the whole film, according to the nicotine content and the content of co-substances, the areas of the two-color films are different. The present invention utilizes the fact that nicotine and co-substances have the same or synergistic physiological effects, combines the co-substances with nicotine on one film, reduces the dosage of nicotine in the product, thereby reducing the pungent and irritating feeling of nicotine, and the added co-substances can play different roles when used together with nicotine.

[0023] The orodispersible film prepared by the present invention is slowly dissolved by saliva in the oral cavity. Due to the pH buffering effect of saliva, nicotine and co-substances can be absorbed by the oral mucosa. At the same time, different effects are achieved according to different co-substances.

[0024] The present invention has the following advantages:

[0025] 1. For the two-color nicotine orodispersible film product of the present invention, because the colors of the films containing co-substances are different, it is convenient for producers and consumers to distinguish and select product types. The method of the present invention can be applied to the combined production of any two or more substances containing nicotine and substances having synergistic effects. The present invention solves the problems of combined production and use of two or more substances that cannot be mixed with each other (because of different chemical properties, direct mixing will result in chemical instability) by preparing a two-color spliced film.

[0026] 2. For the two-color nicotine orodispersible film product of the present invention, because the areas of the nicotine film and the co-substance film are different, the dosage ratio can be visually distinguished, which is convenient for consumers to distinguish and select products according to their own nicotine requirements.

[0027] 3. For the two-color nicotine orodispersible film product of the present invention, the contents of nicotine and co-substances can be designed according to requirements. During the smoking cessation process, the amount of nicotine can be gradually reduced by cycle to achieve the purpose of smoking cessation.

[0028] 4. For the preparation method of the two-color nicotine orodispersible film of the present invention, a two-color single-layer film design is adopted, with novel appearance and improved user experience. The film is prepared by the coating method (doctor blade method). The film solution containing nicotine and the film solution containing co-substances are respectively scrape-coated onto the connected areas of the plastic film to form a wet film, and then the wet film is dried in a ventilated oven. After the film is completely dried, the obtained dry film is divided into appropriate dosage units of appropriate sizes by cutting according to the dosage ratio requirements of nicotine and co-substances, and packaged into appropriate storage units. This preparation method can be used for large-scale production with stable quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 It is the appearance of the night-sedating and smoking-cessation type orally dissolving film (yellow / red bicolor) prepared in Example 1. Figure 2 It is the appearance of the refreshing and smoking-cessation type (red / green) bicolor orally dissolving film prepared in Example 2. Figure 3 It is the appearance of the anxiety-relieving type (green / purple) bicolor orally dissolving film prepared in Example 3. Figure 4 It is the appearance of the night-sedating and smoking-cessation type (green / red) bicolor orally dissolving film prepared in Example 14. Figure 5 It is the appearance of the night-sedating and smoking-cessation type (green / yellow) bicolor orally dissolving film prepared in Example 14. Figure 6 It is the appearance of the night-sedating and smoking-cessation type (red / yellow) bicolor orally dissolving film prepared in Example 14. Detailed implementation manners

[0030] The following examples are for further illustration of the present invention rather than limitation thereof.

[0031] I. Night-sedating and smoking-cessation type orally dissolving film

[0032] The night-sedating and smoking-cessation type orally dissolving film is a nicotine + melatonin system: Melatonin activates MT1 / MT2 receptors, regulates the circadian rhythm, shortens the sleep latency of smokers, inhibits the excessive release of NE in the locus coeruleus, and relieves the nocturnal awakening caused by nicotine withdrawal.

[0033] In the night-sedating and smoking-cessation type orally dissolving film, the synergistic substance is melatonin, the nicotine content can be 0.1 - 3 mg, and the melatonin content can be 1 - 5 mg; different doses are used according to different requirements; the two sides of the orally dissolving film have different colors, one side, i.e., the nicotine side, is yellow, and the other side, i.e., the melatonin side, is red; among them, melatonin has been pretreated with phospholipid bilayer encapsulation to prevent photolysis and improve water solubility.

[0034] Specific examples are as follows:

[0035] Example 1

[0036] The overall design of the night-sedating and smoking-cessation type orally dissolving film in this example is shown in Table 1.

[0037] Table 1 Night-sedating and smoking-cessation type orally dissolving film

[0038]

[0039] The preparation process is as follows:

[0040] S1. Place 5 g of nicotine tartrate aqueous solution (the nicotine tartrate aqueous solution is prepared by mixing nicotine and tartaric acid in a molar ratio of 1:1 and dissolving them in water, with the nicotine content being 40% by mass fraction. The nicotine content is 40% by mass fraction) in a suitable container, add 16 g of plasticizer (glycerol), 1 g of flavoring agent (cherry mint essence), an appropriate amount of coloring agent (curcumin), and make up to a total mass of 30 g with purified water. Stir well to form a mixed solution; add 70 g of film-forming material (hydroxypropyl methylcellulose) to the solution, stir at room temperature to obtain a uniform and continuous film solution, and measure the viscosity of the film solution until the viscosity of the film solution is 20,000 - 50,000 mPa·s; remove the bubbles from the film solution by ultrasonic treatment at 30 kHz to obtain 100 g of nicotine film solution for standby;

[0041] S2. Place 5 g of melatonin aqueous solution (where the melatonin content is 40% by mass fraction) in a suitable container, add 16 g of plasticizer (glycerol), 1 g of flavoring agent (cherry mint essence), an appropriate amount of coloring agent (carmine), and make up to a total mass of 30 g with purified water. Stir well to form a mixed solution; add 70 g of film-forming material (hydroxypropyl methylcellulose) to the solution, stir at room temperature to obtain a uniform and continuous film solution, and measure the viscosity of the film solution until the viscosity of the film solution is 20,000 - 50,000 mPa·s; remove the bubbles from the film solution by ultrasonic treatment at 30 kHz to obtain 100 g of melatonin film solution for standby;

[0042] S3. Spread the two film solutions onto two adjacent areas on a plastic film. To prevent the two liquids from diffusing into each other, a thin plate can be used for temporary isolation in the middle. After spreading, remove the thin plate. The film thickness is 0.6 mm. The nicotine content in the nicotine film is 1 mg / cm 2 and the melatonin content in the melatonin film is 1 mg / cm 2 . Place the wet film in a forced-air drying oven and dry it at 55 °C. Peel the dried nicotine film and melatonin film from the plastic film, cut and pack them into 1 cm × 4 cm rectangular blocks according to the ratio requirements of nicotine and melatonin (where the nicotine film is 1 cm × 3 cm and the melatonin film is 1 cm × 1 cm, that is, the nicotine content is 3 mg and the melatonin content is 1 mg) to obtain an orally dissolving film.

[0043] The orally dissolving film prepared in this example can also be cut into rectangular blocks of other different sizes and ratios according to the dosage requirements. The appearance of the orally dissolving film is as Figure 1 shown.

[0044] II. Refreshing and Smoking-Cessation Type Bicolor Orally Dissolving Film

[0045] The refreshing and nicotine-withdrawal-preventing two-color orally disintegrating film is a nicotine + caffeine system: caffeine blocks the A2-A receptor, offsetting the fatigue caused by nicotine withdrawal. In terms of dopamine regulation, nicotine activates dopamine neurons in the VTA region, while caffeine inhibits DA reuptake, prolonging the action time of dopamine and thus the satisfaction time.

[0046] The nicotine content in the refreshing and nicotine-withdrawal-preventing two-color orally disintegrating film can be 2 mg, and the caffeine content can be 8 - 30 mg; different doses can be used according to different needs; caffeine has been pretreated by embedding in sodium alginate-chitosan microspheres (drug loading rate 82%) to improve its stability.

[0047] The specific embodiments are as follows:

[0048] Example 2

[0049] The overall design of the refreshing and nicotine-withdrawal-preventing two-color orally disintegrating film in this example is shown in Table 2.

[0050] Table 2 Refreshing and nicotine-withdrawal-preventing two-color orally disintegrating film

[0051]

[0052]

[0053] The preparation process is as follows:

[0054] S1. Compared with step S1 of Example 1, except that the coloring agent is replaced with carmine, the rest are the same;

[0055] S2. Place 10 g of an aqueous caffeine solution (where the caffeine content is 80% by mass fraction) in a suitable container, add 16 g of a plasticizer (glycerol), 1 g of a flavoring agent (cherry mint essence), and an appropriate amount of a coloring agent (chlorophyll), and make up to a total mass of 30 g with purified water, and stir evenly to form a mixed solution; add 70 g of a film-forming material (hydroxypropyl methylcellulose) to the solution, stir at room temperature to obtain a uniform and continuous film solution, and measure the viscosity of the film solution until the viscosity of the film solution is 20000 - 50000 mPa·s; remove the bubbles from the film solution by ultrasonic treatment at 30 kHz to obtain 100 g of caffeine film solution for standby;

[0056] S3. Spread the two film solutions onto two adjacent areas of a plastic film. To prevent the two liquids from diffusing into each other, a thin plate can be used for temporary isolation in the middle. After spreading, remove the thin plate. The film thickness is 0.6 mm, and the nicotine content in the nicotine film is 1 mg / cm 2 and the caffeine content in the caffeine film is 4 mg / cm 2, the wet film was placed in a forced-air drying oven and dried at 55 °C. The dried nicotine film and caffeine film were peeled off from the plastic film, and cut and packaged into 2 cm × 2 cm rectangular blocks according to the ratio requirements of nicotine and caffeine (where the nicotine film was 1 cm × 2 cm and the caffeine film was 1 cm × 2 cm, that is, the nicotine content was 2 mg and the caffeine content was 8 mg), obtaining the orally dissolving film.

[0057] The orally dissolving film prepared in this example can also be cut into rectangular blocks of other different sizes and ratios according to the dosage requirements. The appearance of the orally dissolving film is as Figure 2 shown, which is suitable for daily addiction relief, and uses the synergistic effect of caffeine to enhance the addiction relief effect of low-concentration nicotine.

[0058] III. Anxiety-relieving two-color orally dissolving film

[0059] The anxiety-relieving two-color orally dissolving film is a nicotine + arecoline system: Arecoline is an mAChR agonist, mainly targeting M1 / M3 receptors, relieving nicotine withdrawal anxiety. Low-dose arecoline (0.5 - 2 mg) can mildly stimulate the release of DA in the nucleus accumbens and synergistically with nicotine reduce the withdrawal restlessness.

[0060] The nicotine content in the anxiety-relieving two-color orally dissolving film can be 2 mg, and the arecoline content can be 1 mg; different doses can be used according to different needs; Arecoline has been pretreated with hydroxypropyl-β-cyclodextrin inclusion to mask the bitter taste of arecoline.

[0061] The specific embodiments are as follows:

[0062] Example 3

[0063] The overall design of the anxiety-relieving two-color orally dissolving film in this example is shown in Table 3.

[0064] Table 3 Anxiety-relieving two-color orally dissolving film

[0065]

[0066] The preparation process is as follows:

[0067] S1. Compared with step S1 of Example 1, except that the colorant is replaced with chlorophyll, the rest are the same;

[0068] S2. Place 5 g of arecoline aqueous solution (with arecoline content being 40% by mass fraction) in a suitable container, add 16 g of plasticizer (glycerol), 1 g of flavoring agent (cherry mint essence), and an appropriate amount of coloring agent (anthocyanin), make up to a total mass of 30 g with purified water, stir evenly to form a mixed solution; add 70 g of film-forming material (hydroxypropyl methylcellulose) to the solution, stir at room temperature to obtain a uniform and continuous film solution, and measure the viscosity of the film solution until the viscosity of the film solution is 20000 - 50000 mPa·s; remove bubbles from the film solution by ultrasonic treatment at 30 kHz to obtain 100 g of arecoline film solution for standby;

[0069] S3. Spread the two film solutions on two adjacent areas of a plastic film. To prevent the two liquids from diffusing into each other, a thin plate can be used for temporary isolation in the middle. After spreading, remove the thin plate. The film thickness is 0.6 mm. The nicotine content in the nicotine film is 1 mg / cm 2 , and the arecoline content in the arecoline film is 1 mg / cm 2 . Place the wet film in a forced-air drying oven and dry it at 55 °C. Peel the dried nicotine film and arecoline film from the plastic film, cut and pack them into rectangular blocks of 1.5 cm × 2 cm according to the ratio requirements of nicotine and arecoline (where the nicotine film is 1 cm × 2 cm and the arecoline film is 0.5 cm × 2 cm, that is, the nicotine content is 2 mg and the arecoline content is 1 mg) to obtain the orally dissolving film.

[0070] The orally dissolving film prepared in this example can also be cut into rectangular blocks of other different sizes and ratios according to the dosage requirements. The appearance of the orally dissolving film is as Figure 3 shown, which is suitable for daily addiction relief. Using arecoline to promote dopamine release, the synergistic effect can enhance the addiction relief feeling of low-concentration nicotine.

[0071] Examples 4 - 7

[0072] Examples 4 - 7 are different from S1 - S3 of Example 1 in step S3. To meet the needs of different consumers, different amounts of nicotine and melatonin are used (the specific dosages of each example are shown in Table 4). Gradually reduce the amount of nicotine to play a role in smoking cessation. However, the withdrawal reactions such as anxiety and insomnia caused by the reduction of nicotine amount can be alleviated or partially alleviated by increasing the amount of melatonin; therefore, the orally dissolving film prepared can achieve the purpose of gradually quitting smoking while reducing the withdrawal reactions. When consumers use it, they can gradually transition from Example 1 and Example 4 to Example 7 every two weeks.

[0073] Table 4 Dosages of nicotine and melatonin

[0074]

[0075] Examples 8 - 13

[0076] Examples 8 - 13 are different from S1 - S3 of Example 1 in that the components and dosages, as well as the preparation process, are different. See Table 5 for details.

[0077] Table 5 Component Dosages and Preparation Process

[0078] Example Plasticizer / g Flavoring agent / g Film-forming material / g Drying temperature ℃ Example 1 Glycerol 16 Cherry mint essence 1 Hydroxypropyl methylcellulose 70 55 Example 8 Polyethylene glycol 25 Sweet orange essence 1.5 Hydroxypropyl methylcellulose 60 60 Example 9 Glycerol 5, propylene glycol 5 Cherry mint essence 1 Hydroxypropyl methylcellulose 70 60 Example 10 Propylene glycol 20 Strawberry essence 1.2 Hydroxypropyl methylcellulose 70 50 Example 11 Glycerol 23 Cherry mint essence 1.2 Hydroxypropyl cellulose 65 55 Example 12 Glycerol 21 Grape essence 2.5 Polyvinylpyrrolidone 68 55 Example 13 (Tween 80) 18 Citronella essence 2 Polyoxyethylene 70 55

[0079] Comparative Examples 1 - 4

[0080] Comparative Examples 1 - 4 are different from S1 - S3 of Example 1 in that the amounts of nicotine and melatonin used are different. See Table 6 for specific dosages.

[0081] Table 6 Nicotine and Melatonin Dosages in Comparative Examples 1 - 4

[0082]

[0083] Comparative Examples 5 - 8

[0084] Comparative Examples 5 - 8 are different from S1 - S3 of Example 1 in that the components and dosages, as well as the preparation process, are different. See Table 7 for details.

[0085] Table 7 Component Dosages and Preparation Process in Comparative Examples 5 - 10

[0086] Example Plasticizer / g Flavoring agent / g Film-forming material / g Drying temperature ℃ Example 1 Glycerol 16 Cherry mint essence 1 Hydroxypropyl methylcellulose 70 55 Control Example 5 Glycerol 16 Cherry mint essence 1 Hydroxypropyl methylcellulose 80 55 Control Example 6 Glycerol 16 Cherry mint essence 1 Hydroxypropyl methylcellulose 50 55 Control Example 7 Glycerol 5 Cherry mint essence 1 Hydroxypropyl methylcellulose 70 55 Control Example 8 Glycerol 28 Cherry mint essence 1 Hydroxypropyl methylcellulose 70 55 Control Example 9 Glycerol 16 Cherry mint essence 1 Hydroxypropyl methylcellulose 70 40 Control Example 10 Glycerol 16 Cherry mint essence 1 Hydroxypropyl methylcellulose 70 80

[0087] Sample Testing:

[0088] Select 150 consumers and divide them into 15 groups, with 10 people in each group. Administer the orally dissolving film samples of Examples 1 - 13 and Comparative Examples 1 - 10 respectively, and conduct sensory evaluation during administration and withdrawal reactions after stopping administration for testing. The evaluation indicators are shown in Table 8, and the results are shown in Table 9.

[0089] Results: From Examples 1 - 13, it can be seen that the prepared orally dissolving films have good appearance and properties. After being administered orally, they can dissolve well in the mouth. However, for the orally dissolving films prepared in Comparative Examples 5 - 10, due to different processes, their appearance and properties are worse than those of the examples. When the content of the film - forming material is high, the dissolution is slow; when the content of the film - forming material is low, the film is soft; when the content of the plasticizer is high, the hardness is high; when the plasticizer content is low, the film cannot be formed; when the temperature is high, it is easy to melt; when the temperature is low, the moisture content is too high and the film cannot be formed.

[0090] From Example 1 and Comparative Examples 1 - 4, it can be seen that when the nicotine content is low during administration, the feeling of being intoxicated is not obvious and the effect of relieving addiction cannot be achieved. When the melatonin content is too low, the withdrawal reaction is obvious.

[0091] Table 8 Evaluation Indicators

[0092]

[0093] Table 9 Evaluation Results

[0094]

[0095]

[0096] Note: In the table, "-" indicates that this item is not involved in the evaluation.

[0097] Example 14

[0098] It is different from S1 - S3 in Example 1 in that: (1) the colorant in step S1 is replaced with chlorophyll, and the colorant in step S2 is replaced with carmine; (2) the colorant in step S1 is replaced with chlorophyll, and the colorant in step S2 is replaced with curcumin; (3) the colorant in step S1 is replaced with carmine, and the colorant in step S2 is replaced with curcumin; then it is cut into rectangular blocks of different sizes and proportions according to the dosage requirements, and the orally dissolving films prepared are successively as shown in Figure 4 、 5 、6.

Claims

1. A preparation method of a two-color nicotine orodispersible film, characterized in that It includes the following steps: S1. Take 5 - 10 parts by mass of nicotine brine solution, add 10 - 25 parts by mass of plasticizer, 1 - 2.5 parts by mass of flavoring agent, an appropriate amount of coloring agent, and add water to make up to a total system of 30 - 40 parts by mass, and stir to form a mixed solution; add 60 - 70 parts by mass of film-forming material to the solution, stir to obtain a uniform and continuous film solution, control the viscosity to be 20000 - 50000 mpa.s; remove bubbles by ultrasonic treatment to obtain 100 parts by mass of nicotine film solution; S2. Take 5 - 10 parts by mass of aqueous solution of synergistic substance, add 10 - 25 parts by mass of plasticizer, 1 - 2.5 parts by mass of flavoring agent, an appropriate amount of coloring agent whose color is different from that in step S1, and add water to make up to a total system of 30 - 40 parts by mass, and stir to form a mixed solution; add 60 - 70 parts by mass of film-forming material to the solution, stir to obtain a uniform and continuous film solution, control the viscosity to be 20000 - 50000 mpa.s; remove bubbles by ultrasonic treatment to obtain 100 parts by mass of synergistic substance film solution; S3. Scrap the nicotine film solution and the synergistic substance film solution onto two adjacent areas, separate them in the middle with a thin plate, remove the thin plate after scraping, scrape to make the film thickness of the two areas the same and control the film thickness to be 0.5 mm - 1 mm, dry the wet film at 55°C - 60°C, peel off the dried nicotine film and the synergistic substance film, and cut the nicotine film together with the synergistic substance film into pieces according to the designed nicotine and synergistic substance contents to obtain a two-color nicotine orally dissolving film.

2. The method according to claim 1, characterized in that, The nicotine brine solution is an aqueous solution prepared by mixing nicotine and organic acid in a molar ratio of 1:1 and dissolving them in water, and the organic acid is tartaric acid, lactic acid, citric acid, benzoic acid, gluconic acid, malic acid, acetic acid, levulinic acid, salicylic acid or sorbic acid.

3. The method according to claim 2, wherein The nicotine content in the nicotine brine solution is 40% by mass fraction.

4. The method according to claim 1, wherein The plasticizer is at least one of glycerol, polyethylene glycol, propylene glycol, and Tween 80.

5. The method according to claim 1, characterized in that The flavoring agent is at least one of edible flavors such as mint flavor, strawberry flavor, lemon flavor, citronella flavor, grape flavor, rose flavor, and sweet orange flavor.

6. The method according to claim 1, wherein The coloring agent is an edible pigment such as carotenoid, anthocyanin, chlorophyll, curcumin, sunset yellow, carmine or brilliant blue.

7. The method according to claim 1, characterized in that, The film-forming material is one of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyoxyethylene, polyvinyl alcohol, gum arabic, xanthan gum or agar.

8. The method according to claim 1, wherein The synergistic substance is melatonin, caffeine, arecoline, cytisine, varenicline, theanine, γ-aminobutyric acid or selegiline.

9. The method according to claim 1, characterized in that, The nicotine film is yellow, the synergistic substance is melatonin, and melatonin has been pretreated with phospholipid bilayer wrapping before preparation, and the melatonin film is red.

10. A two-color nicotine orally dissolving film prepared by the method according to any one of claims 1 - 9.

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