N-methyl nicotine and salt, composition, preparation method and application thereof

Abstract

The invention belongs to the technical field of auxiliary smoking cessation, and particularly relates to N-methyl nicotine as well as a salt, a composition, a preparation method and application thereof. According to the invention, the smoking cessation convenience can be improved, and the smoking cessation effect is improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of assisting smoking cessation, and particularly relates to N-methylnicotine and salts, compositions, preparation methods and uses thereof. BACKGROUND

[0002] It is well known that smoking is harmful to health, and nicotine is a functional substance in cigarettes, which makes people excited and can refresh the mind. Because nicotine cannot be absorbed through the digestive tract, people are forced to deliver nicotine to the lungs through aerosol by burning tobacco, and then into the human body through the blood. In this process, a large amount of nicotine and tar are input into the lungs in the form of aerosol and deposited in the lungs. The lungs, as respiratory organs, can only theoretically inhale air and moisture, and are not born with the ability to metabolize other substances. A large amount of tar is accompanied by smoking, which is a substance that the lungs cannot metabolize, and ultimately causes emphysema, chronic obstructive pulmonary disease and lung cancer, and other lung diseases.

[0003] Nicotine cannot be absorbed by the digestive system through oral methods, and the main reason is that nicotine is an alkaloid, which can cause a variety of physiological reactions if directly enters the stomach. First, nicotine can stimulate the gastric mucosa, causing submucosal blood vessels to constrict and spasm, leading to ischemia and hypoxia of the gastric mucosa, and damaging the integrity of the gastric mucosa. Nicotine can also relax the pyloric sphincter, causing motor dysfunction, and causing bile and duodenal juice to flow back into the stomach, further damaging the gastric mucosa. The bile acid in the bile has a great damaging effect on the gastric mucosa, which can cause gastric mucosal erosion and bleeding. In addition, nicotine entering the stomach can also increase gastric peristalsis and promote gastric acid secretion. The increase in the content of gastric acid can damage the gastric mucosa and impair the barrier function of the gastric mucosa, making it prone to gastric inflammation and ulceration. Nicotine can also affect the synthesis of prostaglandins in the gastric mucosa, which plays an important role in protecting the integrity of the gastric mucosa, and a decrease in the synthesis of prostaglandins can increase the difficulty of gastric mucosal repair.

[0004] Currently, there are seven types of drugs for smoking cessation, including five nicotine replacement therapy (NRT) drugs (nicotine chewing gum, nicotine inhaler, nicotine lozenge, nicotine nasal spray and nicotine patch) and two non-nicotine drugs (varenicline tartrate tablets and sustained-release bupropion hydrochloride tablets).

[0005] Nicotine replacement therapy provides nicotine to the human body to replace or partially replace nicotine obtained from tobacco, thereby reducing nicotine withdrawal symptoms such as lack of concentration, anxiety, irritability, and low mood. NRT drugs for smoking cessation are safe and effective, and can double the likelihood of long-term smoking cessation. Although they cannot completely eliminate withdrawal symptoms, they can alleviate the discomfort of smokers during the smoking cessation process to varying degrees.

[0006] The patent application with the patent application publication number CN 117164553 A discloses a synthesis method of 6-methyl nicotine and an application of 6-methyl nicotine in tobacco tar. The main principle is that the oral impact of 6-methyl nicotine on users is stronger than that of traditional nicotine. Users can still obtain strong oral impact in the case of less smoking of 6-methyl nicotine, so that the inhalation amount of 6-methyl nicotine can be reduced, and the addiction of users to electronic cigarettes can be reduced. It mainly enters the human body through inhalation, and it only reduces the amount of dependence, and cannot really quit smoking. SUMMARY

[0007] The technical problem to be solved by the present application is to provide N-methyl nicotine and its salt, composition, preparation method and use, to improve the convenience of smoking cessation and improve the effect of smoking cessation.

[0008] The present application provides a kind of N-methyl nicotine, its structural formula is as follows: .

[0009] The N-methyl nicotine is a cation, i.e. a quaternary ammonium salt cation.

[0010] The present application provides a kind of N-methyl nicotine salt, which is a salt formed by the N-methyl nicotine and an acid. The acid is preferably an organic acid, and more preferably, the acid is malic acid or benzoic acid.

[0011] The present application provides a composition comprising the N-methyl nicotine salt, and further comprising excipients for various dosage forms. Preferably, the dosage form is an oral preparation.

[0012] When the oral preparation is chewing gum, the excipients are resin base (mainly natural rubber, synthetic rubber, rosin derivative, vinyl copolymer or / and hydrogenated vegetable oil), sugar alcohol, and sugar (mainly composed of powdered sugar and / or sugar syrup). The weight ratio of resin base, sugar alcohol, and sugar is 30:30:30. The addition amount of N-methyl nicotine salt is 0.1-3% of the total weight of the components.

[0013] The present application provides a preparation method of the N-methyl nicotine salt. The steps are as follows: nicotine reacts with iodomethane, the reaction is carried out in an alkaline environment (adjusting pH to above 10), and then mixing with an acid to obtain the N-methyl nicotine salt.

[0014] In one embodiment, the base in the alkaline environment is one or more of carbonate (potassium carbonate or sodium carbonate, etc.), sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium ethoxide, and potassium ethoxide.

[0015] In one embodiment, the organic solvent for the reaction is acetone or anhydrous methanol.

[0016] In one embodiment, nicotine is dissolved in an organic solvent to obtain a nicotine solution, and then methyl iodide is added to the nicotine solution; the mixture is uniformly mixed to perform a reaction to obtain N-methyl nicotine iodide; the N-methyl nicotine iodide is dissolved in an organic solvent, and ion exchange is performed through an ion exchange resin containing an acid to obtain N-methyl nicotine salt.

[0017] The embodiment of the present application provides a use of the N-methyl nicotine salt for preparing a substance for quitting smoking or an electronic cigarette, preferably for preparing a substance for quitting smoking.

[0018] The present application has the beneficial effect that nicotine has strong irritation, high content nicotine can stimulate the throat, enter the stomach to stimulate gastric acid reaction, and in severe cases can cause stomach swelling and pain and even cause esophageal reflux or vomiting. The present application can be orally ingested, and the stimulation to the digestive system is weak, which can be gently absorbed by the oral cavity and stomach, thereby realizing oral inhalation, and compared with burning inhalation, the damage to the lungs can be significantly reduced. Compared with the absorption of nicotine through the digestive system, the harm to the body is negligible. This is also the principle of some smoking cessation drugs. After changing to an oral mode, the damage of substances such as tar (for traditional cigarettes), glycerol, and propylene glycol (for heated cigarettes and electronic cigarettes) to the lungs can be eliminated.

[0019] The present application uses nicotine as the basic structure, modifies some functional groups thereof, reduces the effect on the gastrointestinal tract, and realizes the absorption of the digestive tract of the nicotine-like substance. Compared with the burning aerosol, the present application has no high-temperature cracking product, and the main component is more pure, which can significantly improve the health level and reduce various health risks caused by smoking.

[0020] The present application uses the synthesized N-methyl nicotine salt to replace traditional nicotine in the application of oral tobacco and beverages. Since the stimulation of N-methyl nicotine salt to users is very small and can be basically ignored, users can ingest a large amount of N-methyl nicotine salt through the oral cavity or digestive tract without causing swelling and pain in the oral cavity or stomach. Therefore, in the case of nicotine addiction dependence of users, N-methyl nicotine salt can be absorbed through the oral cavity or digestive tract to avoid the damage of tar and other substances to the lungs, and at the same time, the effect of quitting smoking can be achieved. DETAILED DESCRIPTION

[0021] In the following, the technical solutions in the embodiments of the present application will be described clearly and completely in combination with the drawings in the embodiments of the present application, so that those skilled in the art can better understand the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work should fall within the scope of protection of the present application.

[0022] Embodiment 1 A preparation method of N-methylnicotine benzoate, comprising the following steps: 1. 1.62 g of nicotine is added into a previously prepared anhydrous ethanol solvent. In order to maintain the alkaline environment of the reaction system, potassium carbonate is added and the pH is accurately adjusted to 11. Then, 1.41 g of iodomethane is slowly added dropwise, and stirring is continued at a constant temperature of 60°C for 2 hours to ensure that the reaction is fully carried out.

[0023] 2. When the reaction reaches the predetermined time, i.e. the reaction is completed, the temperature of the reaction system is rapidly reduced to 0°C to terminate the reaction and avoid any possible side reactions. Then, the impurities generated in the reaction are removed by filtration, the ethanol solvent is evaporated under low temperature conditions, and the final product is treated by recrystallization to obtain pure N-methylnicotine iodide, whose nuclear magnetic resonance data is as follows:

[0024] 3. Then, the obtained N-methylnicotine iodide is redissolved in anhydrous ethanol solvent. Then, the solution is slowly passed through an ion exchange resin column combined with benzoic acid to realize accurate exchange of benzoate and iodide. After this step, the target product N-methylnicotine benzoate is successfully obtained, and the pure product of the reaction product is finally obtained by filtration and recrystallization.

[0025] The reaction route is as follows:

[0026] Embodiment 2 The resin base (natural rubber), erythritol, and sugar (syrup) are mixed together according to the ratio. The weight ratio of the resin base, erythritol, and sugar is 30:30:30.

[0027] An appropriate amount of water or other solvents is added, and the mixture is heated to a certain temperature to fully dissolve and mix.

[0028] During stirring, the additive, which is N-methylnicotine benzoate, is gradually added. The weight of N-methylnicotine benzoate is 1% of the total weight, so that the total of the resin base, sugar alcohol, sugar, and additive is 100%.

[0029] Continue stirring and heating until the mixture reaches the desired viscosity and texture.

[0030] The mixture is formed into the shape of chewing gum by pressing or injection molding, etc.

[0031] Cool, package and sell.

[0032] The product releases N-methyl nicotine salt during chewing in the mouth. Compared with nicotine, the substance has no irritation to the mouth, and after entering the body through the blood, it can replace nicotine to make people excited and refreshing. After long-term use, the body's dependence on nicotine can be completely eliminated.

[0033] Example 3 The beverage generally contains water, sweeteners, sour agents, preservatives, pigments, flavors, etc. Among them, the proportion of water ranges from 87 to 98%, the proportions of sweeteners, sour agents, preservatives, pigments, and food flavors are based on B 2760 "Hygienic Standard for the Use of Food Additives" and other relevant regulations. The amount of N-methyl nicotine benzoate is 2% (range 0.1-5% can be used), which is suitable for not producing irritation in the oral and throat parts.

[0034] When the body feels the need for nicotine, drinking this beverage can eliminate the craving for nicotine and achieve the effect of quitting smoking.

[0035] Considering the stability of N-methyl nicotine benzoate, the packaging of this beverage is preferably dark, and after opening, it should be consumed as soon as possible to avoid natural decomposition of N-methyl nicotine benzoate.

[0036] Example 4 N-methyl nicotine benzoate and sucrose, corn starch, stearic acid, and polyvinylpyrrolidone are mixed. The mass ratio of N-methyl nicotine benzoate is 10%, the mass ratio of sucrose is 20%, the mass ratio of corn starch is 20%, the mass ratio of stearic acid is 20%, and the mass ratio of polyvinylpyrrolidone is 30%. The capsule wall is wrapped with a gastric acid-resistant capsule. When the body has a demand for nicotine, 1-2 capsules (1 capsule weighs 0.5g) are taken with water, which can start to suppress the physiological demand for nicotine after 10-30 minutes. After taking multiple times, the body's dependence on nicotine can be significantly reduced.

[0037] Example 5 N-methyl nicotine salt can also be added to electronic cigarette liquid to replace nicotine as a functional substance.

[0038] A reasonable e-liquid formula consists of glycerol, propylene glycol, water, sweetener, flavoring, pH control agent, preservative, and N-methyl nicotine benzoate. The content of glycerol, propylene glycol and water ranges from 80-95% (mass ratio), wherein the ratio of glycerol, propylene glycol and water ranges from 4:3:3 to 3:2:5. That is, the proportion of glycerol ranges from 30-40%, the proportion of propylene glycol ranges from 20-30%, and the proportion of water ranges from 30% to 50%. The proportion of flavoring is 0.1-10% (mass ratio) of the total mass, the proportion of sweetener is 0.1-10% (mass ratio), the proportion of N-methyl nicotine benzoate is 0.2-5% (mass ratio), preferably 2%, and no additional nicotine is added. When the human body has a demand for nicotine, after a certain number of puffs, the physiological demand for nicotine can be inhibited within 2-10 minutes. After multiple uses, the body's dependence on nicotine can be significantly reduced.

[0039] Example 6 To test the oral and gastrointestinal effects of N-methyl nicotine salt, a comparative experiment of oral intake of N-methyl nicotine salt and traditional nicotine was conducted in practice.

[0040] Sample No. 1 is a chewing gum containing 2% N-methyl nicotine salt (i.e., Example 2), Sample No. 2 is a water solution containing 2% N-methyl nicotine salt (2% (mass ratio) of N-methyl nicotine benzoate is dissolved in mineral water to obtain), Sample No. 3 is a snus containing 2% nicotine (purchased from the market), and Sample No. 4 is a water solution containing 2% nicotine (2% (mass ratio) of nicotine benzoate is dissolved in mineral water to obtain).

[0041] In the experiment, 4 groups of test subjects were selected (the inclusion criteria were: all male, aged 30-50 years old, all with more than 10 years of smoking habit, and in good health without underlying diseases, with 10 people in each group). The test subjects were asked to use two types of nicotine (i.e., Samples Nos. 1-4).

[0042] The experimental scheme for snus and chewing gum is as follows: 1. Experimental subjects: each participant.

[0043] 2. Product intake: for chewing gum and snus products, each participant should take a single dose (one piece) each time.

[0044] 3. Chewing process: place the product in the mouth and chew until the taste or irritation is significantly reduced.

[0045] 4. Spit out: after chewing to the desired extent, the product should be spit out to avoid swallowing.

[0046] 5. Oral cleaning: then, thoroughly rinse the mouth with pure water to remove residual product components in the mouth.

[0047] 6. Time interval: After the first intake and cleaning the mouth, wait for one hour, then proceed to the next product intake.

[0048] 7. Repeat the experiment: Repeat the experiment three times in one day, following the above steps.

[0049] The experimental protocol for N-methylnicotine benzoate and nicotine benzoate in purified water is as follows: Objective: This experiment aims to assess the physiological effects of N-methylnicotine benzoate and nicotine benzoate at low concentrations on the human body.

[0050] Experimental materials: Purified water, N-methylnicotine benzoate, nicotine benzoate.

[0051] Experimental steps: 1. Solution preparation: Accurately weigh N-methylnicotine benzoate and nicotine benzoate, and prepare 2% (mass) solutions respectively.

[0052] 2. Intake method: Participants need to hold the solution in the mouth for 10 seconds, then slowly swallow.

[0053] 3. Frequency of consumption: Continue to sip the solution until you feel that the physiological effect has reached a saturation state.

[0054] 4. Physiological response recording: Record and describe the physiological sensations when the saturation state is reached.

[0055] 5. Experimental period: The experiment is conducted continuously for three days, once a day, with a 24-hour interval between each experiment.

[0056] Safety and ethical considerations: Before the experiment, participants must fully understand the purpose, steps, and potential risks of the experiment and sign an informed consent form. During the experiment, a professional should supervise to ensure the safety of the participants. If the participant experiences any discomfort during the experiment, the experiment should be stopped immediately and medical help should be sought.

[0057] Data recording: Record the date, time, amount consumed, and physiological responses of the participants for each experiment in detail.

[0058] Add 2% (mass ratio) of N-methylnicotine benzoate and nicotine benzoate to purified water, sip, hold in the mouth for 10 seconds, then swallow. Continue to drink until you feel that the physiological effect has reached a saturation state. Record the physiological sensations at that time. This experiment is conducted separately for three consecutive days, repeated once a day, with a 24-hour interval between each experiment.

[0059] Record their physical sensations, and the final results are shown in Table 1.

[0060] Table 1: Physiological experience of different nicotine salts in various products

[0061] The score ranges from 1 to 10 (grading basis: 1-2 is basically no feeling, 3-4 is feeling, 5 is moderate feeling, 6-7 is strong feeling, 8-9 is the upper limit of physiological feeling that can be tolerated, and 10 is not given in principle). Impact and irritability measure the maximum intensity and duration of stimulation, respectively, and physiological satisfaction is the body's feeling after smoking. Taste is the overall oral sensation. The lower the impact and irritability, the better, and the higher the physiological satisfaction and taste, the better.

[0062] Example 7 To compare the binding ability of nicotine, N-methyl nicotine salt and key protein in human body-nicotine acetylcholine receptor, the N-methyl nicotine salt was used to measure the addictive ability of human body. First, the active ingredients of the core drug were successfully obtained through the PubChem database and saved as an SDF format file. At the same time, the structural information of the key target protein was collected from the PDB database. Next, the target was finely processed using Pymol-2.1.0 software, including removing water molecules and small molecule ligands, etc., to ensure the accuracy of the structure. In order to carry out subsequent molecular docking research, further hydrogenation and charge distribution were carried out for the target using AutoDock Tools-1.5.6, and finally saved as a pdbqt format.

[0063] After preparing the receptor (key target) and ligand (drug active ingredient), the vina-2.0 tool built-in pyrx software was used to carry out molecular docking simulation. This process can accurately calculate the binding energy between the ligand and the receptor, and generate the corresponding result file. It is worth noting that the Affinity (kcal / mol) value is an important indicator, which represents the binding ability between the ligand and the receptor; the lower the binding energy, the more stable the ligand and the receptor are combined.

[0064] In order to visually display and analyze the docking results, Pymol software (https: / / pymol.org / 2) was used for 3D visualization processing. DiscoveryStudio 2020 Client (https: / / discover.3ds.com / discovery-studio-visualizer-download) was also used to generate and analyze 2D images, so as to more comprehensively understand the interaction between the ligand and the receptor. Throughout the research process, the key indicator of binding energy is always the focus, because low binding energy means better binding stability, which is crucial for drug development.

[0065] Nicotine forms AIkyl interaction with LEU141, LEU131, ARG101, ASN129 of the protein and Carbon Hydrogen Bond interaction with ASN129, with a docking binding energy of -4.5 kcal / mol.

[0066] N-methylnicotine salt forms Carbon Hydrogen Bond interaction with GLN88 of the protein and AIkyl interaction with TYR86, with a docking binding energy of -4.7 kcal / mol.

[0067] The table of the specific docking binding energy is shown in Table 2.

[0068] Table 2 Binding energy of components and target points

[0069] It is generally considered that the docking energy value less than -4.25 kcal / mol indicates certain binding activity between the two, less than -5.0 kcal / mol indicates better binding activity, and less than -7.0 kcal / mol indicates strong binding activity.

[0070] From the data in Table 2, the binding data of nicotine and the receptor is -4.5 kcal / mol, which indicates that nicotine can bind but does not contain strong addiction. The binding energy of N-methylnicotine salt is -4.7 kcal / mol, which means that N-methylnicotine salt can replace nicotine, but also does not have strong addiction. Considering that N-methylnicotine salt is more gentle to the gastrointestinal tract, it can be considered to have the potential to replace nicotine.

[0071] Example 8 In order to explore the smoking amount and addiction dependence of N-methylnicotine salt, a replacement experiment of N-methylnicotine salt on traditional nicotine was carried out. The specific experimental design is as follows: 1. Selection of subjects: 20 Sprague Dawley rats with established nicotine dependence were selected as experimental animals.

[0072] 2. Experimental grouping: randomly divided into two groups, 10 rats in each group: experimental group (N-methylnicotine salt aqueous solution) and control group (normal saline).

[0073] 3. Experimental materials: Drinking water containing N-methylnicotine salt (content of 2%).

[0074] Normal saline.

[0075] 4. Experimental procedure: The experimental group consumed water containing N-methylnicotine salt every day.

[0076] The control group consumed pure water every day.

[0077] After a week, both groups of animals were simultaneously provided with the opportunity to expose to nicotine-containing aerosol (nicotine content in aerosol 2%) and the number of times and duration of stay in the area containing nicotine aerosol were observed.

[0078] 5. Data collection: 6. Experimental period: In this experiment, 1 month was used as the experimental period to observe the long-term effect.

[0079] 7. End of experiment: Human termination: For animals showing extreme discomfort, appropriate pain management or humane termination should be provided.

[0080] Follow-up observation: Follow-up observation was conducted on surviving animals until they returned to normal.

[0081] The number of times and duration of stay in the area containing nicotine aerosol were counted for both groups of rats. The results showed that after consuming N-methylnicotine salt, the number of times the rats entered the area containing nicotine decreased by 50%, and the average duration of stay decreased by 21%. It can be considered that after consuming N-methylnicotine salt, the addiction to nicotine can be significantly reduced, and it has the beneficial effect of reducing nicotine intake.

[0082] Those skilled in the art will understand that the above discussion of any embodiment is only exemplary and is not intended to suggest that the scope of protection of the present application is limited to these examples; under the idea of the present application, the above embodiments or technical features in different embodiments can also be combined, the steps can be implemented in any order, and there are many other changes of different aspects of one or more embodiments of the present application as described above. In order to be brief, they are not provided in detail.

[0083] One or more embodiments of the present application are intended to cover all such alternatives, modifications and variations falling within the broad scope of the present application. Therefore, any omissions, modifications, equivalent replacements, improvements, etc. made within the spirit and principles of one or more embodiments of the present application should be included in the scope of protection of the present application.

Claims

1. An N-methylnicotine, characterized in that, Its structural formula is as follows: 。 2. An N-methylnicotine salt, characterized in that, It is a salt formed from N-methylnicotine and acid as described in claim 1.

3. The N-methylnicotine salt as described in claim 2, characterized in that, The acid is malic acid or benzoic acid.

4. A composition characterized in that, It includes the N-methylnicotine salt as described in claim 2 or 3, and also includes excipients for preparing various dosage forms.

5. A method for preparing N-methylnicotine salt as described in claim 2 or 3, characterized in that, Nicotine reacts with iodomethane in an alkaline environment, and then is mixed with an acid to obtain the N-methylnicotine salt.

6. The method for preparing N-methylnicotine salt as described in claim 5, characterized in that, The alkali in the alkaline environment is one or more of carbonates, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium ethoxide, and potassium ethoxide.

7. The method for preparing N-methylnicotine salt as described in claim 5, characterized in that, The organic solvent for the reaction is acetone or anhydrous ethanol.

8. The method for preparing N-methylnicotine salt as described in claim 5, characterized in that, Nicotine and alkali are dissolved in an organic solvent to obtain a nicotine solution. Iodomethane is then added to the nicotine solution. The mixture is stirred evenly and reacted to obtain N-methylnicotine iodide. The N-methylnicotine iodide is dissolved in an organic solvent and ion-exchanged through an acid-containing ion exchange resin to obtain N-methylnicotine salt.

9. Use of the N-methylnicotine salt as described in claim 2 or 3, characterized in that, The N-methylnicotine salt is used to prepare substances for quitting smoking or electronic cigarettes.

10. The use as described in claim 9, characterized in that, The N-methylnicotine salt is used to prepare a substance for quitting smoking.

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