Nicotine-citrate and preparation method thereof, and nicotine oral delivery product

Abstract

The invention belongs to the technical field of nicotine products, and particularly relates to nicotine-citrate, a preparation method thereof and a nicotine oral delivery product. The nicotine-citrate provided by the invention is in a solid form. After the nicotine-citrate in the solid form is in contact with liquid, such as saliva in the oral cavity, the nicotine-citrate in the solid form is subjected to a solid-liquid-liquid change process, that is, the solid is firstly dissolved into a liquid state and then dispersed into the saliva, and compared with the relatively viscous liquid nicotine-citrate, the nicotine-citrate in the solid form can be slowly, uniformly and stably released in the oral cavity; the sustained and stable slow-release effect is realized.

Description

Technical Field

[0001] This application belongs to the technical field of nicotine products, and particularly relates to nicotine-citrate, its preparation method, and nicotine oral delivery products. Background Art

[0002] Common delivery methods of nicotine include respiratory system delivery. Specifically, an electronic heating atomization means is used to atomize a solid or liquid aerosol matrix containing nicotine to generate an aerosol, and then the aerosol is inhaled into the mouth and absorbed through the lungs.

[0003] Since the respiratory system delivery method generates a large amount of harmful gases, researchers have tried to find various alternative methods. Among various alternative methods, the method of orally delivering nicotine has attracted attention because it does not generate harmful gases and is convenient to use. This method usually mixes nicotine with an acidulant to form a nicotine salt, and then mixes it with other food additives and packs it into a non-woven bag to make a buccal pouch. However, existing nicotine buccal pouches generally have the disadvantages of too fast release rate, inability to continuously and stably release slowly, and difficulty in providing a continuous and long-lasting physiological satisfaction. Summary of the Invention

[0004] The purpose of this application is to provide a nicotine-citrate, its preparation method, and nicotine oral delivery products, aiming to solve the problem that nicotine oral delivery products have too fast release rate in the mouth and cannot continuously and stably release slowly.

[0005] To achieve the above application purpose, the technical solution adopted in this application is as follows:

[0006] In the first aspect, this application provides a nicotine-citrate in solid form.

[0007] When the nicotine-citrate in solid form comes into contact with a liquid, such as saliva in the mouth, it will undergo a "solid → liquid → liquid" change process, that is, the solid first melts into a liquid state and then disperses into the saliva. Compared with the viscous liquid nicotine-citrate, it can release slowly, evenly and stably in the mouth, and has the effect of continuous and stable slow release.

[0008] In some embodiments, the molar ratio of citric acid to nicotine contained in the nicotine-citrate is 1:(2 - 3), preferably 1:(2.5 - 3).

[0009] The nicotine-citrate includes citric acid and nicotine bound to each other by hydrogen bonds. When the molar ratio of citric acid to nicotine is 1:(2 - 3), the salt formed by the combination of nicotine and citric acid shows a solid form rather than a viscous liquid state, which is beneficial to slowing down the release rate of the nicotine-citrate and achieving the purpose of continuous and stable slow release.

[0010] In some embodiments, nicotine citrate is in one or more of crystalline form and amorphous form. Preferably, 0.1% to 100% of nicotine citrate is in crystalline form, more preferably more than 50% of nicotine citrate is in crystalline form, and still more preferably 80% to 100% of nicotine citrate is in crystalline form.

[0011] That is, the nicotine citrate solid can be completely amorphous, can be partially crystalline and partially amorphous, or can be completely crystalline. In any case, the nicotine citrate has a continuous and stable sustained-release effect in the oral cavity, and the higher the crystallinity, the better the sustained-release effect.

[0012] In some embodiments, the crystalline form of nicotine citrate includes one or more of needle shape, flake shape, square shape, and irregular shape.

[0013] Nicotine citrate solids with different crystalline forms all have a continuous sustained-release effect in the oral cavity. Especially in the rod-like structure (belonging to the needle shape), the sustained-release effect is better.

[0014] In a second aspect, the present application provides a method for preparing nicotine citrate, including the following steps:

[0015] Mix citric acid and nicotine, and react to obtain nicotine citrate in solid form.

[0016] By directly mixing and reacting citric acid with nicotine, the nicotine citrate solid of the embodiments of the present application can be obtained.

[0017] In some embodiments, the molar ratio of citric acid to nicotine is 1:(2 to 3), preferably 1:(2.5 to 3).

[0018] In some embodiments, the reaction temperature is 55 to 75 °C, preferably 65 to 75 °C.

[0019] The reaction time is 0.5 to 3 h, preferably 1 to 2 h.

[0020] Reacting at this temperature for a certain time can successfully obtain nicotine citrate in solid form, and has the advantage of short reaction time.

[0021] In some embodiments, after the reaction, it includes the steps of cooling the reaction mixture and adding seed crystals to the reaction mixture.

[0022] The seed crystals used include solid citric acid. The molar amount of the seed crystals is less than or equal to 10% of the citric acid as the reactant, for example, 0.0001% to 10% of the citric acid as the reactant, preferably 0.0001% to 1%. The volume of the seed crystals is 0.01 to 3 mm 3 .

[0023] After adding the seed crystal, a solid can slowly precipitate from the reaction mixture, and the obtained solid has a moderate volume, so that the nicotine-citrate solid has a good sustained-release effect. Moreover, using the citric acid solid as the seed crystal will not introduce new impurities.

[0024] In a third aspect, the present application provides a nicotine oral delivery product, including the nicotine-citrate of the first aspect above.

[0025] After this nicotine oral delivery product is put into the mouth, it can slowly, evenly and stably release nicotine-citrate, that is, it has a continuous and stable sustained-release effect. This is beneficial to continuously maintaining the nicotine content in the patient's blood, effectively suppressing the patient's appetite, and helping the patient to quit nicotine. Description of the Drawings

[0026] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following will briefly introduce the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings in the following description are only some embodiments of the present application. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0027] Figure 1 Schematic diagram of the preparation process of nicotine-citrate in Example 1;

[0028] Figure 2 Electron micrographs of nicotine-citrate in Examples 1 to 4;

[0029] Figure 3 Electron micrographs of nicotine-citrate in Examples 5 and 6;

[0030] Figure 4 Physical diagram of nicotine-citrate in Comparative Example 1;

[0031] Figure 5 Release curve graph of nicotine-citrate in the nicotine oral pouch. Detailed Description of the Embodiments

[0032] In order to make the technical problems to be solved, technical solutions and beneficial effects of the present application clearer, the following further details the present application in combination with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0033] In this application, the term "and / or" describes the association relationship of associated objects, indicating that there can be three relationships. For example, A and / or B can represent: A exists alone, A and B exist simultaneously, and B exists alone. Here, A and B can be singular or plural. The character " / " generally indicates that the associated objects before and after are in an "or" relationship.

[0034] In this application, "at least one" means one or more, and "a plurality" means two or more. "At least one of the following" or similar expressions refer to any combination of these items, including any combination of single items or plural items. For example, "at least one of a, b, or c", or "at least one of a, b, and c" can both represent: a, b, c, a - b (i.e., a and b), a - c, b - c, or a - b - c, where a, b, and c can be single or multiple respectively.

[0035] It should be understood that in various embodiments of this application, the magnitudes of the sequence numbers of the above processes do not mean the order of execution. Some or all of the steps can be executed in parallel or sequentially. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation to the implementation process of the embodiments of this application.

[0036] The terms used in the embodiments of this application are only for the purpose of describing specific embodiments, and are not intended to limit this application. The singular forms of "a", "the", and "said" used in the embodiments of this application and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise.

[0037] The terms "first" and "second" are only used for descriptive purposes to distinguish objects such as substances from each other, and should not be understood as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. For example, without departing from the scope of the embodiments of this application, the first XX can also be referred to as the second XX, and similarly, the second XX can also be referred to as the first XX. Thus, the features defined with "first" and "second" can explicitly or implicitly include one or more of such features.

[0038] In the first aspect of the embodiments of this application, a nicotine - citrate is provided, which is in solid form.

[0039] When the nicotine - citrate in solid form comes into contact with a liquid, such as saliva in the oral cavity, it will undergo a "solid → liquid → liquid" change process, that is, the solid first melts into a liquid state and then disperses into the saliva. Compared with the viscous liquid nicotine - citrate, it can be slowly, evenly, and stably released in the oral cavity, having a continuous and stable slow - release effect.

[0040] In some embodiments, in the nicotine-citrate, the molar ratio of citric acid to nicotine is 1:(2-3), preferably 1:(2.5-3), such as any one of the point values 1:2, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3 or the range between any two point values.

[0041] The nicotine-citrate includes citric acid and nicotine that are bound to each other by hydrogen bonds. When the molar ratio of citric acid to nicotine is 1:(2-3), the salt formed by the combination of nicotine and citric acid exhibits a solid form rather than a viscous liquid state, which is beneficial to slowing down the release rate of the nicotine-citrate and achieving the purpose of continuous and stable sustained release.

[0042] In some embodiments, the nicotine-citrate is in one or more of a crystalline form and an amorphous form. Preferably, 0.1% to 100% of the nicotine-citrate is in a crystalline form. More preferably, more than 50% of the nicotine-citrate is in a crystalline form. Even more preferably, 80% to 100% of the nicotine-citrate is in a crystalline form. Here, 0.1% to 100% of the nicotine-citrate being in a crystalline form refers to the proportion of the area in the nicotine-citrate that is in a crystalline form, and / or the mass proportion of the part in a crystalline form, and / or the volume proportion of the part in a crystalline form.

[0043] That is, the nicotine-citrate solid can be completely amorphous, or can be partially crystalline and partially amorphous, or can be completely crystalline. In any case, the nicotine-citrate has a continuous and stable sustained release effect in the oral cavity, and the higher the crystallinity, the better the sustained release effect.

[0044] In some embodiments, the crystalline form of the nicotine-citrate includes one or more of needle-like, flake-like, square-like, and irregular shapes.

[0045] The crystalline form, which can also be called the geometric shape of the crystal, can directly observe the crystalline form of the nicotine-citrate through an electron microscope. Among them, the needle-like crystal has a long and thin needle-like appearance, presenting a fibrous structure or a rod-like structure (which can also be called a columnar structure, and it can be various forms such as a quadrangular column, a hexagonal column, an octagonal column, etc.), and the length is much larger than the diameter, and usually has a highly perfect long-axis orientation. The flake-like crystal presents a thin and flat shape in three-dimensional space. The square-like includes one or more of regular polyhedron shapes and rhombic polyhedron shapes, such as one or more of a regular cube, a rhombic cube, a regular hexahedron, a rhombic hexahedron, a regular octahedron, a rhombic octahedron, a regular dodecahedron, and a rhombic dodecahedron. Preferably, the crystalline form of the nicotine-citrate includes needle-like, and more specifically includes a rod-like structure.

[0046] Preferably, the crystal form of nicotine citrate is needle-shaped. Its diameter can be 0.1-10 μm, preferably 0.5-5 μm, such as any one of the point values of 0.1 μm, 0.5 μm, 1 μm, 3 μm, 5 μm, 7 μm, 9 μm, 10 μm or the range between any two point values. Its length can be 1-50 μm, preferably 10-35 μm, such as any one of the point values of 1 μm, 10 μm, 20 μm, 30 μm, 35 μm, 40 μm, 50 μm or the range between any two point values. Its aspect ratio can be 1.5-100, preferably 10-40, such as any one of the point values of 1.5, 3, 10, 20, 30, 50, 70, 90, 100 or the range between any two point values.

[0047] Nicotine-citrate solids with different crystal forms all have a sustained-release effect in the oral cavity. Especially in the rod-shaped structure (belonging to the needle-shaped), the sustained-release effect is better.

[0048] In some embodiments, nicotine citrate includes one or more of blocky and powdery forms.

[0049] Nicotine-citrate solids exhibit sustained-release characteristics in different physical forms, which can meet different product requirements and be applicable to different preparation processes of nicotine oral delivery products.

[0050] The second aspect of the embodiments of the present application provides a preparation method of nicotine citrate, including the following steps:

[0051] Mix citric acid with nicotine and react to obtain nicotine citrate in solid form.

[0052] By directly mixing citric acid with nicotine and reacting, nicotine-citrate solids of the embodiments of the present application can be obtained.

[0053] In some embodiments, the molar ratio of citric acid to nicotine is 1:(2-3), preferably 1:(2.5-3), such as any one of the point values of 1:2, 1:2.2, 1:2.4, 1:2.5, 1:2.6, 1:2.8, 1:3 or the range between any two point values.

[0054] In some embodiments, the reaction temperature is 55-75 °C, preferably 65-75 °C, such as any one of the point values of 55 °C, 60 °C, 65 °C, 70 °C, 75 °C or the range between any two point values.

[0055] The reaction time is 0.5-3 h, preferably 1-2 h, such as any one of the point values of 0.5 h, 1.5 h, 2 h, 2.5 h, 3 h or the range between any two point values.

[0056] Reacting at this temperature for a certain period of time can successfully obtain nicotine citrate in solid form, and it has the advantage of a short reaction time.

[0057] In some embodiments, after the reaction is completed, it includes the steps of cooling the reaction mixture and adding seed crystals to the reaction mixture.

[0058] The cooling rate can be set to 5 - 15 °C / min, such as any one of 5 °C / min, 7 °C / min, 9 °C / min, 10 °C / min, 11 °C / min, 13 °C / min, 15 °C / min or the range between any two point values. It can be cooled to ambient temperature, such as cooled to 20 - 30 °C. In actual operation, it can be naturally cooled. Before cooling, the reaction mixture can also be filtered, and then the filtrate is cooled.

[0059] Among the raw materials used in the reaction, citric acid is a solid and nicotine is an oily liquid. The reaction mixture in the above ratio is usually a liquid. Cooling in the above manner is beneficial to maintaining the liquid state of the reaction mixture and not precipitating solids during the cooling process.

[0060] The seed crystals used include solid citric acid. The molar amount of the seed crystals is less than or equal to 10% of the citric acid as a reactant, such as 0.0001% - 10% of the citric acid as a reactant, preferably 0.0001% - 1%. In actual operation, the volume of the added seed crystals is 0.01 - 3 mm 3 such as 0.01 mm 3 0.1 mm 3 0.5 mm 3 1 mm 3 1.5 mm 3 3 mm 3 or the range between any two point values. Before adding the seed crystals, the reaction mixture can be allowed to stand for a period of time, such as 60 s - 10 min, such as any one of 60 s, 120 s, 1 min, 5 min, 10 min or the range between any two point values.

[0061] After adding the seed crystals, solids can slowly precipitate from the reaction mixture, and the obtained solids have a moderate volume, so that the nicotine citrate solid has a good sustained-release effect. Moreover, using citric acid crystals as seed crystals will not introduce new impurities.

[0062] At the same time, the seed crystals have an appropriate addition amount, which is not only beneficial to promoting crystal formation and improving the regularity of the crystals, but also does not affect the ratio between citric acid and nicotine in the whole system, so that the required nicotine citrate solid can be obtained smoothly.

[0063] In some embodiments, the reaction is carried out with stirring, and the stirring speed can be set to 100 - 1200 rpm, for example, any one of 100 rpm, 500 rpm, 1000 rpm, 1200 rpm or the range between any two of these point values.

[0064] In the third aspect of the embodiments of the present application, a nicotine oral delivery product is provided, including the nicotine-citrate of the first aspect above.

[0065] After this nicotine oral delivery product is put into the mouth, it can release nicotine-citrate slowly, evenly and stably, that is, it has the effect of continuous and stable slow release. This is beneficial to continuously maintaining the nicotine content in the patient's blood, effectively suppressing the patient's appetite, and helping the patient to quit nicotine.

[0066] In some embodiments, the dosage form of the nicotine oral delivery product includes one or more of nicotine oral pouches, nicotine lozenges, nicotine chewing gums (chewing gums), and preferably includes nicotine oral pouches.

[0067] The nicotine-citrate solid can be used to make various forms of nicotine oral delivery products, all of which can exert its effect of continuous and stable slow release.

[0068] The nicotine oral pouch can include nicotine-citrate and food additives, and the mixture composed of nicotine-citrate and food additives is encapsulated in a water-insoluble bag (such as a non-woven bag).

[0069] The food additives include one or more of cyclodextrin, cellulose, sweeteners, buffering agents, humectants, flavoring agents, dispersing agents, and each additive is usually in solid form.

[0070] The following can be referred to for various food additives:

[0071] Cyclodextrin can be β-cyclodextrin. The molecular formula of β-cyclodextrin is C 42 H 70 O 35 , white to light yellow powder, with a slightly specific aroma of pectin, slightly sweet and slightly sour in taste.

[0072] Cellulose, which is the main component of plant cell walls, is linearly polymerized by many glucose molecules with β-1,4 glycosidic bonds. It is abundant in oats and whole beans and is usually insoluble in water.

[0073] Sweeteners are food additives that can make food taste sweet, including one or more of sodium saccharin, sodium cyclamate, acesulfame potassium, aspartame, neotame, sucralose.

[0074] Buffers, also known as acid-base stabilizers, are generally salts, such as salts of strong acids and weak bases or salts of weak acids and strong bases. During reactions or storage, buffers can gradually release acids or bases to maintain a stable acid-base value. Exemplary buffers include one or more of sodium bicarbonate and sodium hydrogen phosphate.

[0075] Humectants are a type of food additive that helps maintain a stable moisture content in food, including one or more of sodium tripolyphosphate, sodium hexametaphosphate, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium pyrophosphate, disodium dihydrogen pyrophosphate, calcium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate.

[0076] Flavorants refer to substances added to food to enhance flavor or aroma, such as rose, lavender, mint, jasmine, sandalwood, cinnamon, pepper, fennel, etc.

[0077] Dispersants are a type of surfactant that has both lipophilic and hydrophilic properties within a molecule, such as sodium carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, povidone, polysorbate, etc.

[0078] The solutions of the present application will be described below in conjunction with specific examples.

[0079] Example 1

[0080] Add 0.2 mmol of (s)-nicotine and 0.1 mmol of citric acid to a 20 mL round-bottom flask containing a magnetic stir bar, place it on a heating magnetic stirrer and connect to a vacuum pump, stir thoroughly at 70 °C and 1000 rpm for 1.5 h and then filter. Quickly transfer the filtrate to a warm clean beaker and wait for the beaker and the filtrate to cool naturally to room temperature (about 25 °C), with a cooling time of 5 min. Then use clean tweezers to pick up extremely small (with a volume between 0.01 mm 3 ~3 mm 3 ) rhombic citric acid solid and put it into the cooled filtrate to initiate crystallization of the filtrate. The experimental procedure is as Figure 1 shown. After waiting for the crystallization to be completely formed, pour out the nicotine-citrate.

[0081] The electron micrograph of the nicotine-citrate in this example is as Figure 2 shown, and it can be observed that it has an irregular shape.

[0082] Example 2

[0083] The difference between this example and Example 1 is that the molar amounts of (s)-nicotine and citric acid are 0.22 mmol and 0.1 mmol, respectively.

[0084] The electron micrograph of the nicotine-citrate obtained in this example is as Figure 2 shown, and it can be observed that it has an irregular shape and large particles.

[0085] Example 3

[0086] The difference between this example and Example 1 is that the molar amounts of (s)-nicotine and citric acid are 0.24 mmol and 0.1 mmol, respectively.

[0087] The electron micrograph of the nicotine-citrate obtained in this example is as Figure 2 shown, and it can be observed that it has an irregular shape and the particles are slightly coarser.

[0088] Example 4

[0089] The difference between this example and Example 1 is that the molar amounts of (s)-nicotine and citric acid are 0.26 mmol and 0.1 mmol, respectively.

[0090] The electron micrograph of the nicotine-citrate obtained in this example is as Figure 2 shown, and it can be observed that some of them have a crystal morphology. The crystal grains are rod-shaped, the estimated diameter of the crystal grains is 0.8 - 2 μm, the estimated length is 2.5 - 16 μm, and the estimated aspect ratio is 1.5 - 13.

[0091] Example 5

[0092] The difference between this example and Example 1 is that the molar amounts of (s)-nicotine and citric acid are 0.28 mmol and 0.1 mmol, respectively.

[0093] The electron micrograph of the nicotine-citrate obtained in this example is as Figure 3 shown, and it can be observed that most of the nicotine-citrate has a crystal morphology. The crystal grains are rod-shaped, the estimated diameter of the crystal grains is 0.6 - 4 μm, the estimated length is 12 - 40 μm, and the estimated aspect ratio is 4 - 62.

[0094] Example 6

[0095] The difference between this example and Example 1 is that the molar amounts of (s)-nicotine and citric acid are 0.3 mmol and 0.1 mmol, respectively.

[0096] The electron micrograph of the nicotine-citrate obtained in this example is as Figure 3 shown, and it can be observed that the nicotine-citrate is basically in a crystal morphology. The crystal grains are all rod-shaped, the estimated diameter of the crystal grains is 1 - 4 μm, the estimated length is 10 - 35 μm, and the estimated aspect ratio is 3 - 30.

[0097] Comparative Example 1

[0098] The difference between this comparative example and Example 1 is that the molar amounts of (s)-nicotine and citric acid are 0.1 mmol and 0.1 mmol, respectively.

[0099] In this comparative example, a solid could not be obtained, and the nicotine citrate obtained was a thick substance, as Figure 4 shown.

[0100] Application Example

[0101] Using a pharmaceutical mixer, 15 mg of nicotine citrate was mixed evenly with 15.0 mg of β-cyclodextrin, 15.0 mg of cellulose, 10.0 mg of sweetener (sucralose), 15.0 mg of buffer (sodium bicarbonate), 10.0 mg of humectant (sodium tripolyphosphate), 5.0 mg of flavoring agent (rose), and 15.0 mg of dispersant (sodium carboxymethylcellulose), and then filled into a non-woven fabric sachet to prepare a nicotine buccal pouch.

[0102] In addition, 15.0 mg of β-cyclodextrin, 15.0 mg of cellulose, 10.0 mg of sweetener, 15.0 mg of buffer, 10.0 mg of humectant, 5.0 mg of flavoring agent, and 15.0 mg of dispersant were mixed evenly and filled into a non-woven fabric sachet as a blank control group.

[0103] (1) Release performance of the nicotine buccal pouch

[0104] The test of the release performance was carried out according to the experimental methods of GB / T 18886-2019 and DIN 53160-1:2010. Before the experiment, the prepared artificial saliva (pH 6.8) was added to the reservoir bottle and kept at a constant temperature of 37.0 ± 0.1 °C in a constant temperature water bath. Six open flow-through cells with dimensions of 1.0 cm × 2.0 cm × 3.0 cm were taken as the simulated oral cavity, the temperature of the flow-through cell was set at 37.0 ± 0.1 °C, and it was connected to the reservoir bottle. The liquid flow rate of the reservoir bottle was set at 0.5 mL / min to flow the artificial saliva into the flow-through cell. After setting the parameters of the simulated dissolution device, the buccal pouch to be tested was placed into the simulated oral cavity. Under the drive of the motor, the artificial teeth descended to press the buccal pouch to simulate the human sucking process. After reaching the preset conditions, 2 mL of the effluent was accurately collected every 4 min for a total of 60 min. 2 mL of the solution was taken and made up to 10 mL with simulated artificial saliva, and the relative abundance of the nicotine citrate content was detected by LC / MS-MS, and the relative abundance of the relative cumulative release amount of nicotine citrate was calculated, as shown in Table 1 and Figure 5 shown.

[0105] [Table 1]

[0106]

[0107] Table 1 and Figure 5 reflect:

[0108] 1) Blank control group

[0109] Blank control group

[0110] Nicotine citrate was not detected during the whole test, indicating that nicotine citrate was not contained in various additives in the nicotine lozenge, so the interference of additives could be excluded.

[0111] 2) Comparative example 1

[0112] For the curve corresponding to Comparative example 1, within 0 - 10 min, the curve slope was significantly greater than that of the curves of Examples 1 - 6. This trend indicates that the nicotine lozenge of Comparative example 1 was rapidly released in the oral environment; after 15 min, the release amount of nicotine citrate gradually reached the maximum value, and the overall release time did not exceed 32 min, indicating that the viscous nicotine citrate of Comparative example 1 did not have the effect of slow release.

[0113] 3) Examples 1 - 6

[0114] For the curves corresponding to Examples 1 - 6, within 0 - 10 min (for Examples 5 and 6, it was 0 - 7 min), the curve slope was less than that of Comparative example 1. This trend indicates that the nicotine lozenges of Examples 1 - 6 had a certain slow - release effect in the oral environment compared with Comparative example 1. And within this time period, in the order of Examples 1 - 6, the curve slope gradually decreased, that is, in the order of Examples 1 - 6, the slow - release effect of the nicotine lozenge was getting better.

[0115] Within 12 - 32 min (for Examples 5 and 6, it was 8 - 32 min), the curve slopes of Examples 1 - 6 further decreased, indicating that the release rate of nicotine citrate further decreased. And within this time period, in the order of Examples 1 - 6, the cumulative release amount of nicotine citrate gradually decreased, and the slow - release effect of the nicotine lozenge was getting better. Among them, for Examples 5 and 6, especially Example 6, the cumulative release amount curve was smoother in this stage, having an excellent slow - release effect.

[0116] After 35 min, the curve slope increased, and then the cumulative release amount of nicotine citrate gradually reached the maximum value. At the same time, the overall release time of Examples 1 - 6 could reach more than 50 min, with a long duration.

[0117] It can be seen that the solid - state nicotine citrate in Examples 1 - 6 could be slowly, evenly and stably released in the oral cavity, having a continuous and stable slow - release effect. Moreover, with the increase of the crystallinity of the solid nicotine citrate, the slow - release speed further decreased and the duration was longer. This was beneficial to continuously maintain the nicotine content in the patient's blood, effectively inhibit the patient's appetite, and help the patient quit nicotine.

[0118] (2) Sensory evaluation of nicotine oral pouches

[0119] Referring to the sensory evaluation standards of GB17399-2016 and YC / T 138-1998, a sensory scoring standard for nicotine oral pouches was established and sensory evaluation was carried out. A 10-point system was used for scoring. Twenty sensory evaluation experts were hired to conduct sensory evaluation according to the scoring standard. The average value of all experts' evaluations was taken as the final result, and SPSS21 software was used to perform variance analysis on the results. Twenty evaluation experts respectively conducted sensory evaluation on the oral irritation, smoothness of taste, sweetness and dizziness feeling of all samples, and gave corresponding scores within the range of 0-10 points. The specific sensory scoring standards are as follows, and the statistics are shown in Table 2.

[0120] Oral irritation: very large (9), relatively large (8), slightly large (5), present (3), small (1);

[0121] Smoothness of taste: good (9), relatively good (8), moderate (5), relatively poor (3), poor (1);

[0122] Sweetness: sweet (9), relatively sweet (8), moderate (5), slightly sweet (3), not sweet (1);

[0123] Dizziness feeling: fast (9), relatively fast (8), moderate (5), slightly fast (3), not fast (1).

[0124] [Table 2]

[0125] Case Oral irritation Smoothness of taste Sweetness Feeling of intoxication Example 1 9.2 2.4 6.1 8.9 Average score <![CDATA[9.2±0.97 a > <![CDATA[2.4±0.92 ac > <![CDATA[6.1±0.96 b > <![CDATA[8.9±0.99 c > Example 2 8.1 3.1 6.2 7.8 Average score <![CDATA[8.1±0.94 b > <![CDATA[3.1±0.89 c > <![CDATA[6.2±0.97 d > <![CDATA[7.8±0.91 ac > Example 3 7.3 4.1 6.4 6.7 Average score <![CDATA[7.3±0.98 d > <![CDATA[4.1±0.95 b > <![CDATA[6.4±0.94 c > <![CDATA[6.7±0.95 ab > Example 4 5.1 6.1 6.3 5.3 Average score <![CDATA[5.1±0.93 c > <![CDATA[6.1±0.91 d > <![CDATA[6.3±0.91 a > <![CDATA[5.3±0.98 a > Example 5 2.9 8.1 6.5 4.5 Average score <![CDATA[2.9±0.98 ac > <![CDATA[8.1±0.99 c > <![CDATA[6.5±0.97 ad > <![CDATA[4.5±0.92 b > Example 6 0.3 9.5 6.8 4.1 Average score <![CDATA[0.3±0.97 ab > <![CDATA[9.5±0.98 bc > <![CDATA[6.8±0.93 a > <![CDATA[4.1±0.98 ab > Blank control group 0 1.5 6.1 0 Average score 0.0 <![CDATA[1.5±0.92 a > <![CDATA[6.1±0.98 bc > 0.0

[0126] Note: The superscript letters a, b, c, d indicate significant differences between the examples or comparative examples (P<0.05).

[0127] Table 2 shows that in the order of Example 1 to Example 6, the oral irritation of the nicotine oral pouches gradually decreases, the smoothness of taste becomes higher and higher, and the dizziness feeling can be reduced, which is beneficial to helping patients quit nicotine; in addition, different nicotine-citrates have little effect on sweetness. In particular, the nicotine oral pouches made with the nicotine-citrates of Example 5 and Example 6 have the advantages of smooth and delicate taste and low irritation.

[0128] The above are only the preferred embodiments of the present application and are not intended to limit the present application. Any modifications, equivalent replacements and improvements made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A nicotine-citrate, characterized in that The nicotine-citrate is in solid form.

2. Nicotine-citrate according to claim 1, characterized in that The molar ratio of citric acid to nicotine contained in the nicotine-citrate is 1:(2-3); And / or, the nicotine-citrate is in one or more of a crystalline form and an amorphous form.

3. Nicotine-citrate according to claim 1 or 2, characterized in that The molar ratio of citric acid to nicotine contained in the nicotine-citrate is 1:(2.5-3); And / or, 0.1% to 100% of the nicotine-citrate is in crystalline form.

4. Nicotine-citrate according to claim 3, characterized in that More than 50% of the nicotine-citrate is in crystalline form.

5. Nicotine-citrate according to claim 4, characterized in that 80% to 100% of the nicotine-citrate is in a crystalline form.

6. Nicotine-citrate according to claim 2, characterized in that The crystal form of the nicotine-citrate salt includes one or more of needle-shaped, flake-shaped, square-shaped, and irregular shapes.

7. A method for preparing nicotine-citrate, characterized in that: The steps include: The citric acid is mixed with nicotine to react to obtain nicotine-citrate in a solid form.

8. The method for preparing nicotine-citrate according to claim 7, characterized in that: The molar ratio of the citric acid to the nicotine is 1:(2-3); And / or, the reaction temperature is 55-75°C; And / or, the reaction time is 0.5 to 3 hours; And / or, after the reaction is completed, the steps of cooling the reaction mixture and adding seed crystals to the reaction mixture are included.

9. The method for preparing nicotine-citrate according to claim 8, characterized in that: The molar ratio of the citric acid to the nicotine is 1:(2.5-3); And / or, the reaction temperature is 65-75°C; And / or, the reaction time is 1 to 2 hours; And / or, the seed crystals include solid citric acid.

10. The method for preparing nicotine-citrate according to claim 8 or 9, characterized in that: The molar amount of the seed crystals is less than or equal to 10% of the citric acid as a reactant; And / or, the volume of the seed crystal is 0.01 to 3 mm 3 .

11. The method for preparing nicotine-citrate according to claim 8 or 9, characterized in that: The molar amount of the seed crystals is 0.0001% to 10% of the citric acid as a reactant.

12. A nicotine oral delivery product, characterized in that: The nicotine-citrate according to any one of claims 1 to 6.

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