Oral sustained-release nicotine salt formulation, and preparation method and application thereof

Abstract

The application provides an oral sustained-release nicotine salt preparation and a preparation method and application thereof, and the oral sustained-release nicotine salt preparation comprises a core framework, a nicotine base, a pH regulator, an adhesion agent, a film forming agent and a filler; the core framework comprises Eudragit E, sodium alginate and citric acid. The oral sustained-release nicotine salt preparation provided by the application adopts a core framework system with a specific pH response dual-release control mechanism, the mild pre-crosslinking of sodium alginate and citric acid ensures the normal sustained-release absorption of nicotine in the oral cavity, and the components in the unconscious swallowing self-assemble in situ to form a gastric insoluble release barrier in the stomach environment, and are automatically converted into an enteric delayed release mode, so that the situation that the nicotine components are exposed to the gastric environment is effectively blocked, and the tolerance and safety of beginners are greatly improved.

Description

Technical Field

[0001] This invention belongs to the technical field of smokeless tobacco products, specifically relating to an oral sustained-release nicotine salt preparation, its preparation method and application, and particularly to an oral sustained-release nicotine salt preparation with a stable oral sustained-release and gastric pH-responsive release inhibition mechanism, its preparation method and application. Background Technology

[0002] Oral tobacco products are increasingly sought after by consumers due to their smokeless nature. Among them, sustained-release nicotine salt preparations are a major category. Currently, commercially available nicotine oral preparations (such as nicotine pouches and chewing tobacco) primarily absorb nicotine through the oral mucosa, continuously releasing it through saliva. However, consumers inevitably swallow some of the nicotine during use, especially with chewing tobacco. Some of the nicotine salts and their associated organic acids that are not absorbed by the oral mucosa will directly enter the stomach with saliva, leading to the following consequences: On the one hand, nicotine, at high local concentrations in the stomach, stimulates nicotine receptors in the gastrointestinal tract, promoting excessive secretion of gastric acid and gastrin, relaxing the lower esophageal sphincter and inducing reflux and heartburn. On the other hand, nicotine constricts gastric mucosal microvessels, inhibits prostaglandin synthesis, and damages the gastric mucus protective barrier. The organic acids such as benzoic acid and citric acid that are combined further lower the pH in the stomach locally, forming a superimposed stimulation with nicotine-induced acid secretion, which can easily cause adverse reactions such as stomach pain, bloating, diarrhea, nausea, and dry heaving.

[0003] On the other hand, if an enteric-coated design is adopted to avoid stomach irritation, all nicotine must be swallowed into the intestines for release, losing the pathway of stable and slow release into the brain via the mouth. This results in low bioavailability, delayed onset of action, and concentrated absorption of the entire small intestine, which causes a sharp increase in portal vein nicotine concentration, temporarily saturating the liver's CYP2A6 metabolic enzymes and increasing the liver's instantaneous metabolic load. People with weak liver function are prone to nicotine and its metabolites accumulation, increasing the potential risk of hepatotoxicity.

[0004] CN117223881A discloses a nicotine-containing oral product containing free nicotine and nicotine salts. The product, by weight percentage, comprises 0.3-4% free nicotine, 0.75-10% nicotine salts, 20-50% matrix, 3-20% cork oak, 2-10% licorice, 5-30% water, with the remainder being additives; the pH is 7-9. By adding licorice, the product can suppress the throat hit of nicotine, improving the taste. Furthermore, the sweet aroma of licorice reduces the need for flavorings and sweeteners. The addition of cork oak to the raw materials allows for nicotine absorption, significantly increasing the nicotine release time in the user's mouth, extending the overall experience, improving product flowability, and reducing production costs.

[0005] CN115997965A discloses a nicotine-slow-release oral cigarette and its preparation method, comprising a mixture of nicotine salts, cellulose, flavoring agents, humectants, and antioxidants. This invention utilizes the different release rates of nicotine salts formed from nicotine and different organic acids during oral consumption. By compounding various solid nicotine organic acid salts, it ensures a stable strength over a longer period during oral consumption, allowing for a uniform, slow, and sustained release of nicotine in the mouth, providing consumers with a long-lasting and mild physiological satisfaction, while effectively reducing irritation to the digestive tract.

[0006] CN121080651A discloses a nicotine sustained-release gel, a nicotine release system, a nicotine oral product, and a preparation method thereof. The nicotine sustained-release gel has a film-forming time of less than or equal to 15 seconds, a film thickness of 0.1–0.12 mm, a porosity of 25–50%, a release rate control range of 0.6–0.8 mg / min, and an 8-hour cumulative release rate ≥95%. This invention's nicotine sustained-release gel can achieve slow release of nicotine with good release effect.

[0007] However, none of the above solutions effectively prevented the product ingredients from entering the digestive tract, nor could they solve the problem of nicotine irritation to the stomach. Therefore, how to provide an oral sustained-release nicotine salt formulation that can achieve both oral sustained release and effective prevention of stomach irritation has become an urgent problem to be solved. Summary of the Invention

[0008] To address the shortcomings of existing technologies, the present invention aims to provide an oral sustained-release nicotine salt formulation, its preparation method, and its application. The oral sustained-release nicotine salt formulation provided by the present invention employs a core framework system with a specific pH-responsive dual release regulation mechanism. Mild pre-crosslinking of sodium alginate and citric acid ensures normal sustained-release absorption of nicotine in the oral cavity. Meanwhile, unintentionally swallowed components self-assemble in situ in the gastric environment to form a gastric insoluble release barrier, automatically switching to an enteric-coated delayed-release mode. This effectively blocks nicotine leakage into the gastric environment, significantly improving the tolerance and safety for novice users.

[0009] To achieve this objective, the present invention adopts the following technical solution: In a first aspect, the present invention provides an oral sustained-release nicotine salt formulation, the oral sustained-release nicotine salt formulation comprising a core matrix, nicotine base material, pH adjuster, adhesive, film-forming agent and filler; The core framework includes Eutrapeptide E, sodium alginate, and citric acid.

[0010] This invention employs a core framework system with a pH-responsive dual drug release regulation mechanism. Sodium alginate and citric acid are pre-formed into pre-crosslinked particles, which are then mixed with Eureka E and compressed into tablets. This avoids the problem of localized aggregation of citric acid during physical mixing. In the acidic environment of the stomach, the pre-crosslinked particles respond rapidly, with citric acid being preferentially released. This guides Eureka E to bind directionally with sodium alginate, forming a more ordered triple network and creating an in-situ release barrier insoluble in gastric juice. It automatically switches to an enteric-coated delayed-release mode, effectively preventing nicotine exposure and burst release in the stomach, significantly reducing adverse reactions such as gastric acid secretion, reflux, and burning pain, and improving efficacy. Tolerability and safety: This allows for normal sustained-release absorption of nicotine in the oral cavity, while unintentionally swallowed components self-assemble in situ in the gastric environment to form a gastric insoluble release-blocking barrier, automatically switching to an enteric-coated delayed-release mode. This effectively blocks the leakage of nicotine components in the gastric environment, significantly improving the tolerance and safety for novice users. Sodium alginate and citric acid pre-form partially cross-linked particles. After entering the gastric juice, these particles undergo in situ secondary cross-linking under the action of gastric acid, utilizing the remaining active sites to electrostatically complex and synergistically with Eutrapeptide E, constructing a denser release-blocking barrier and further enhancing its density.

[0011] In some embodiments, the oral sustained-release nicotine salt formulation comprises, by weight, 20-60 parts of core matrix, 1-15 parts of nicotine base, 0.5-5 parts of pH adjuster, 2-12 parts of adhesive, 1-8 parts of film-forming agent, 0.3-6 parts of taste modifier and 25-70 parts of filler.

[0012] The core skeleton can be in quantities of 20, 25, 30, 35, 40, 45, 50, 55, or 60 parts, etc.; the nicotine base can be in quantities of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 parts, etc.; the pH adjuster can be in quantities of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 parts, etc.; and the adhesive can be in quantities of 2, 3, 4, 5, 6, 7, 8, or 9 parts. The quantities of film-forming agents can be 10, 11, or 12 parts, etc.; the quantities of flavor modifiers can be 1, 2, 3, 4, 5, 6, 7, or 8 parts, etc.; the quantities of taste modifiers can be 0.3, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, or 6 parts, etc.; and the quantities of fillers can be 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70 parts, etc., but are not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0013] In some embodiments, the nicotine base material comprises any one or a combination of at least two of nicotine tartrate, nicotine citrate, or nicotine malate.

[0014] In some embodiments, the mass ratio of E to sodium alginate is (1-1.5):1, such as 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5:1, etc., and the mass ratio of citric acid to sodium alginate is 1:(4-10), such as 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10, etc., but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0015] The aforementioned core framework and its formulation, characterized by a pH-responsive dual drug release regulation mechanism, enable spontaneous in vivo drug release via shunt: In the oral environment (pH 6.2-7.2), the core framework is only slightly hydrated, preventing the formation of a dense barrier. The matrix slowly dissolves, allowing nicotine salts to continuously diffuse outwards and be smoothly absorbed into the bloodstream through the sublingual and buccal mucosa, bypassing the first-pass effect of the portal vein and achieving a gentle onset of action and central comfort. Nicotine components, carried by saliva and detached from the matrix, are swallowed into the stomach (pH < 5.0). There, they are immediately encapsulated by protonated association with the surrounding core framework components, rapidly forming a hydrophobic, dense gel layer that completely encapsulates and seals the nicotine and organic acids. This barrier remains stable, insoluble, and impermeable in gastric juices, effectively isolating the drug. Outside the gastric mucosa, it does not release active substances that cause irritation. When the encapsulated system is transported to the small intestine and the pH returns to above 6.0, the barrier rehydrates and dissolves, and the nicotine salt is slowly released. It is absorbed through the intestinal villi into the portal vein, and after high-intensity first-pass metabolism by the liver's CYP2A6 enzyme, a small amount of incompletely metabolized nicotine enters the systemic circulation and slowly enters the brain, forming a low-amplitude blood drug replenishment in the later stage. This avoids the rebound craving caused by the rapid drop in blood drug after oral release, and also avoids the problem of excessively high portal vein drug concentration in fully enteric-coated formulations, significantly reducing the instantaneous first-pass metabolic load on the liver. In this way, the release of nicotine components is automatically regulated, blocking the superimposed gastrointestinal irritation caused by the acid-stimulating effect of nicotine and the local acidification of organic acids, significantly reducing the incidence of acid reflux, heartburn, stomach pain, diarrhea, and central nausea and vomiting, and greatly improving the tolerance of novice users.

[0016] In some embodiments, the pH adjuster is selected from any one or a combination of at least two of sodium bicarbonate, sodium carbonate, trisodium citrate, or disodium hydrogen phosphate.

[0017] In some embodiments, the adhesive includes any one or a combination of at least two of hydroxypropyl methylcellulose (HPMC), carbomer, xanthan gum, or guar gum.

[0018] In some embodiments, the film-forming agent includes any one or a combination of at least two of polyvinyl alcohol, hydroxypropyl cellulose, or chitosan.

[0019] In some embodiments, the filler comprises microcrystalline cellulose.

[0020] In some embodiments, the oral sustained-release nicotine salt formulation further includes a taste modifier, which includes any one or a combination of at least two of the following: peppermint flavor, menthol, ethyl menthane formamide, menthone, menthyl acetate, limonene, aspartame, erythritol, sucralose, isomaltitol, acesulfame potassium, neotame, saccharin, sucrose, glucose, maltose, or fructose.

[0021] In some embodiments, the oral sustained-release nicotine salt formulation may be in the form of an oral film, lozenge, oral gel, or chewable granules.

[0022] Secondly, the present invention provides a method for preparing the oral sustained-release nicotine salt formulation as described above, the method comprising the following steps: S1. Preparation of pre-crosslinked particles: Sodium alginate is mixed with citric acid and wetting agent and granulated, then dried to obtain pre-crosslinked particles; S2, Total Mixing: The pre-crosslinked particles obtained in step S1 are mixed with Eutrapeptide E, nicotine base material, pH adjuster, adhesive, film-forming agent and filler to obtain total mixed powder; S3. Molding and preparation: The total mixed powder obtained in step S2 is compressed into tablets to obtain the oral sustained-release nicotine salt preparation.

[0023] In the above preparation, sodium alginate and citric acid are pre-formed into pre-crosslinked particles before being mixed with E and compressed into tablets, avoiding the problem of local aggregation of citric acid during physical mixing. In the gastric acid environment, the pre-crosslinked particles respond rapidly, and citric acid is preferentially released, guiding E to bind directionally with sodium alginate to form a more ordered triple network. It also forms a release barrier in situ that is insoluble in gastric juice, automatically switching to an enteric-coated delayed-release mode, effectively avoiding nicotine exposure and burst release in the stomach, significantly reducing adverse reactions such as gastric acid secretion, reflux, and burning pain, and improving tolerability and safety.

[0024] In some embodiments, the drying temperature in step S1 is 50-70°C and the time is 1-4 hours.

[0025] In some embodiments, step S1 involves drying until the moisture content of the particles is less than 3%.

[0026] In some embodiments, the mixing in step S2 further includes mixing with a taste modifier.

[0027] In some embodiments, the wetting agent in step S3 includes an aqueous solution of water or ethanol.

[0028] Thirdly, the present invention also provides the application of the oral sustained-release nicotine salt formulation as described above in the preparation of smokeless tobacco products.

[0029] Compared with the prior art, the present invention has the following beneficial effects: This invention provides an oral sustained-release nicotine salt formulation. By employing a core framework system with a pH-responsive dual release regulation mechanism, it achieves normal sustained-release absorption of nicotine in the oral cavity. Meanwhile, unintentionally swallowed components self-assemble in situ in the gastric environment to form a gastric insoluble release-blocking barrier, automatically switching to an enteric-coated delayed-release mode. This effectively blocks nicotine leakage into the gastric environment, significantly improving tolerability and safety for novice users. Specifically, it includes: Compared to existing single-oral sustained-release nicotine formulations, this invention utilizes a core framework system that is uniformly dispersed within the matrix, enabling spontaneous component diversion within the human digestive tract: nicotine salts normally retained in the oral cavity are released slowly through diffusion, and are smoothly absorbed via the buccal and sublingual mucosa, directly entering the systemic circulation, bypassing the portal vein and liver first-pass effect. This results in a gradual increase in blood drug concentration without sharp peaks, significantly reducing acute intolerance reactions such as dizziness, nausea, and retching caused by a sudden influx of large amounts of nicotine into the brain; the abnormal excitation level of the vagus nerve is significantly reduced, and excessive gastric acid secretion and relaxation of the lower esophageal sphincter are significantly alleviated, reducing the risk of gastroesophageal reflux and upper abdominal burning pain from upstream. For the unconscious swallowed components that inevitably occur during the human oral process, the system can form a dense barrier in situ in the highly acidic environment of the stomach, completely encapsulating and sealing the nicotine salt and the salt-forming organic acids. It is insoluble and impermeable in gastric juice, completely eliminating the dual stimulation caused by the swallowed components directly contacting the gastric mucosa, and significantly reducing the risk of stomach pain, abdominal distension, intestinal motility disorders and long-term flora imbalance. The swallowed portion of the drug is transported to the neutral environment of the small intestine before slowly dissolving and releasing the drug. After absorption, it enters the liver via the portal vein, where it undergoes a high-intensity first-pass metabolism under the action of the CYP2A6 enzyme system. Most of the original nicotine is converted into cotinine, which has no central nervous system activity. Only a small amount of residual drug enters the systemic circulation and slowly reaches the brain, providing only a gentle baseline replenishment of blood drug levels in the later stages. This avoids the irritability and rebound cravings caused by a sharp drop in blood drug concentration after oral release. At the same time, because the swallowed portion is only a small amount of substance naturally lost during sublingual administration, it avoids the problem of a sudden increase in portal vein nicotine concentration caused by concentrated absorption in the small intestine of enteric-coated formulations. The liver CYP2A6 enzyme is not highly saturated in a short period of time, and the instantaneous metabolic load is significantly reduced, reducing the risk of nicotine accumulation and potential hepatotoxicity in individuals with weakened liver function. The overall system has a single molded structure, eliminating the need for pre-preparation of two differentiated particles for physical compounding. The process is simpler and suitable for industrial mass production, systematically improving physiological tolerance and overall user comfort while ensuring nicotine satisfaction. Detailed Implementation

[0030] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0031] In the following example, polyvinyl alcohol was purchased from Tianjin Juhengda Chemical Co., Ltd.

[0032] Chitosan was purchased from Zhejiang Yuanfeng Biotechnology Co., Ltd.

[0033] Microcrystalline cellulose was purchased from Huzhou Linghu Xinwang Chemical Co., Ltd.

[0034] Example 1 This embodiment provides an oral sustained-release nicotine lozenge, prepared from the following raw materials (in parts by weight): 7 parts nicotine tartrate, 3 parts sodium bicarbonate, 7 parts hydroxypropyl methylcellulose, 26 parts Utec E100, 20 parts sodium alginate, 4 parts citric acid, 5 parts polyvinyl alcohol, and 49 parts microcrystalline cellulose.

[0035] The preparation method is as follows: S1. Preparation of pre-crosslinked particles: Sodium alginate and citric acid are mixed evenly. The mixture is moistened with purified water to form a soft material, which is then granulated by passing it through a 20-mesh sieve. The granules are dried at 60℃ for 2 hours until the moisture content is <3% (citric acid and sodium alginate undergo esterification and pre-crosslinking under these conditions). The granules are then sieved through a 40-mesh sieve to obtain "citric acid-sodium alginate pre-crosslinked particles".

[0036] S2, Total Mixing: Mix the pre-crosslinked particles with Euteqi E100, nicotine tartrate, sodium bicarbonate, HPMC, and polyvinyl alcohol microcrystalline cellulose evenly.

[0037] S3, tableting: The tablets are made into oral tablets using the direct compression method (hardness controlled between 6 and 8 kp).

[0038] Example 2 This embodiment provides an oral sustained-release nicotine orally dissolving film, prepared from the following raw materials (in parts by weight): 1 part nicotine citrate, 0.5 parts sodium carbonate, 2 parts xanthan gum, 11 parts Utec E100, 9 parts sodium alginate, 0.9 parts citric acid, 1 part polyvinyl alcohol, and 25 parts microcrystalline cellulose.

[0039] The preparation method is the same as in Example 1.

[0040] Example 3 This embodiment provides an oral sustained-release nicotine lozenge, prepared from the following raw materials (in parts by weight): 15 parts nicotine malate, 5 parts sodium bicarbonate, 12 parts hydroxypropyl methylcellulose, 25 parts E100, 25 parts sodium alginate, 5 parts citric acid, 8 parts chitosan, and 70 parts microcrystalline cellulose.

[0041] The preparation method is the same as in Example 1.

[0042] Example 4 This embodiment provides an oral sustained-release nicotine lozenge. The raw materials used in its preparation are identical to those in Example 1, except that sodium alginate is not included and a portion of it is allocated proportionally to Eureka E100 and citric acid.

[0043] The preparation method is the same as in Example 1 (step S1 is deleted, and the rest are adapted).

[0044] Example 5 This embodiment provides an oral sustained-release nicotine lozenge. The raw materials used in its preparation are the same as in Example 1, except that they do not contain citric acid and the proportions of the reduced amount are allocated to E100 and sodium alginate.

[0045] The preparation method is the same as in Example 1 (step S1 is deleted, and the rest are adapted).

[0046] Example 6 This embodiment provides an oral sustained-release nicotine lozenge. The raw materials used in its preparation are the same as in Example 1, except that they do not contain E100 and the proportions of the ingredients are reduced and allocated to citric acid and sodium alginate.

[0047] The preparation method is the same as in Example 1.

[0048] Example 7 This embodiment provides an oral sustained-release nicotine lozenge, and the raw materials used in its preparation are the same as those in Example 1.

[0049] Except for step S1, where the drying temperature is 80°C and the time is 4 h (excessive pre-crosslinking), the preparation method is the same as in Example 1.

[0050] Comparative Example 1 This comparative example provides an oral sustained-release nicotine lozenge, prepared from the following raw materials (by weight): 7 parts nicotine tartrate, 3 parts sodium bicarbonate, 35 parts hydroxypropyl methylcellulose, 18 parts xylitol, 3 parts citric acid, 5 parts polyvinyl alcohol, and 42 parts microcrystalline cellulose.

[0051] The preparation method is described in Example 8.

[0052] Comparative Example 2 This comparative example provides an oral sustained-release nicotine lozenge, prepared from the following raw materials (by weight): 7 parts nicotine tartrate, 3 parts sodium bicarbonate, 7 parts hydroxypropyl methylcellulose, 5 parts polyvinyl alcohol, and 49 parts microcrystalline cellulose.

[0053] The preparation method is the same as in Example 1 (step S1 is deleted, and the rest are adapted).

[0054] Comparative Example 3 Nicotine-containing oral cigarettes are sold in a certain city.

[0055] Effect test: The products provided in Examples 1-7 and Comparative Examples 1-3 were tested. The products were placed in artificial saliva, enzyme-free artificial gastric juice, and enzyme-free artificial intestinal juice environments, respectively. To eliminate interference from enzyme activity, pH dependence was examined separately, and nicotine release was detected. The details are as follows: Artificial saliva: Using artificial saliva (formulation shown in the table below, pH=6.7) to create an artificial oral environment, a drug dissolution apparatus was used to test the release of nicotine lozenges provided in Examples 1-7 and Comparative Examples 1-2, and the commercially available nicotine lozenge provided in Comparative Example 3 in the oral cavity. The temperature was set to 37℃ and the rotation speed to 100 rpm. 1000 mL of artificial saliva was added to the dissolution vessel. 20 nicotine lozenges (total mass 40 mg) were placed in the dissolution vessel, and the rotation was started, which was recorded as 0 min. At 5 min, 10 min, 15 min, 20 min, 30 min, 40 min, and 60 min, 10 mL samples were taken and analyzed by HPLC (referring to GB / T 23355-2009 Determination of Nicotine in Total Particulate Matter of Cigarettes—Gas Chromatography, the same below), and 10 mL of artificial saliva was added as needed.

[0056] Artificial saliva formulation (solvent is water): The results are as follows: Enzyme-free artificial gastric juice: Based on the simplified enzyme-free formula of artificial gastric juice in the Chinese Pharmacopoeia: Take 16.4 mL of dilute hydrochloric acid (containing 10±0.5% HCl), add 800 mL of purified water, shake well, and then dilute with water to 1000 mL.

[0057] The gastric environment was simulated using enzyme-free artificial gastric fluid to investigate pH-triggered physicochemical self-assembly. A drug dissolution apparatus was used to test the gastric release inhibition effects of the nicotine lozenges provided in Examples 1-7 and Comparative Examples 1-2, and the commercially available nicotine cigarette provided in Comparative Example 3. The temperature was set at 37℃ and the rotation speed at 50 rpm. 500 mL of artificial gastric fluid was added to the dissolution vessel. Ten nicotine lozenges (total mass 20 mg) were placed in the dissolution vessel, and rotation was started; this was recorded as 0 min. At 5 min, 10 min, 15 min, 20 min, 30 min, 60 min, 90 min, and 120 min, 10 mL samples were taken for HPLC analysis, and 10 mL of artificial gastric fluid was added after each sample.

[0058] The results are as follows: Enzyme-free artificial intestinal fluid: A simplified formula based on the Chinese Pharmacopoeia (ChP) formula: Dissolve 6.8 g of potassium dihydrogen phosphate in 500 mL of water, adjust the pH to 6.8 with 0.1 mol / L sodium hydroxide solution, and bring the volume to 1000 mL.

[0059] Using an enzyme-free artificial intestinal fluid to simulate the intestinal environment, a drug dissolution analyzer was used to test the release of nicotine lozenges provided in Examples 1-7 in the intestine (since Examples 4 and Comparative Examples 1-3 were almost completely dissolved in gastric fluid, there would be almost no intestinal release during actual use). The temperature was set at 37°C and the rotation speed at 50 rpm. Twenty nicotine lozenges (total mass 40 mg) were placed in 1000 mL of enzyme-free artificial gastric fluid for 120 minutes to trigger the formation of a release barrier. The nicotine lozenges were then transferred to 1000 mL of artificial intestinal fluid, and the rotation was started. This was recorded as 0 min. At 5 min, 10 min, 15 min, 20 min, 30 min, 60 min, 90 min, and 120 min, 10 mL samples were taken for HPLC analysis, and 10 mL of artificial intestinal fluid was added.

[0060] The results are as follows: The three results show that sodium alginate and citric acid are slightly pre-crosslinked, forming a dense barrier insoluble in gastric juice in conjunction with Eutrapeptide E. In Example 1, the slight pre-crosslinking of sodium alginate and citric acid achieves both oral sustained release and gastric insolubility, ensuring stable intestinal release. In Example 7, the moderate pre-crosslinking of sodium alginate and citric acid results in slow oral release, affecting the user experience. Example 4, lacking sodium alginate, results in rapid oral and gastric release. Example 5, omitting citric acid, poses a risk of sudden intestinal release. Example 6, without Eutrapeptide E, results in rapid intestinal release.

[0061] In addition, the products provided in Example 1 and Comparative Example 3 were used by experts, who provided feedback on their experiences. The results showed that the commercially available nicotine cigarette in Comparative Example 3 released nicotine slowly during use, and nausea and other reactions began to be induced in the later stages of use over time. In contrast, Example 1, by adopting a core framework system design with a specific pH-responsive dual drug release regulation mechanism, showed a similar nicotine release, but the nausea symptoms were significantly reduced after use.

[0062] The data above shows that the product provided by this invention achieves normal sustained-release absorption of nicotine in the oral cavity by adopting a specific core framework system with a pH-responsive dual drug release regulation mechanism. It effectively avoids the leakage of nicotine components in the gastric environment and automatically converts to an enteric-coated delayed-release mode in the intestinal environment. In this way, it achieves automated release regulation of nicotine components, blocks the superimposed gastrointestinal irritation caused by the acid-secreting effect of nicotine and the local acidification of organic acids, significantly reduces the incidence of acid reflux, heartburn, stomach pain, diarrhea, and central nausea and vomiting, and greatly improves the tolerance of novice users. It has significant advantages compared with existing technologies.

[0063] The applicant declares that this invention illustrates the oral sustained-release nicotine salt preparation, its preparation method, and its application through the above embodiments. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily rely on the above embodiments for implementation. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials in the product, addition of auxiliary components, and selection of specific methods, etc., all fall within the protection and disclosure scope of this invention.

[0064] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0065] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. An oral sustained-release nicotine salt formulation, characterized in that, The oral sustained-release nicotine salt formulation includes a core matrix, nicotine base, pH adjuster, adhesive, film-forming agent, and filler; The core framework includes Eutrapeptide E, sodium alginate, and citric acid.

2. The oral sustained-release nicotine salt formulation according to claim 1, characterized in that, The oral sustained-release nicotine salt formulation comprises, by weight, 20-60 parts of core matrix, 1-15 parts of nicotine base, 0.5-5 parts of pH adjuster, 2-12 parts of adhesive, 1-8 parts of film-forming agent, 0.3-6 parts of taste modifier and 25-70 parts of filler.

3. The oral sustained-release nicotine salt formulation according to claim 1 or 2, characterized in that, The nicotine base material includes any one or a combination of at least two of nicotine tartrate, nicotine citrate, or nicotine malate.

4. The oral sustained-release nicotine salt formulation according to any one of claims 1-3, characterized in that, The mass ratio of E to sodium alginate is (1-1.5):1, and the mass ratio of citric acid to sodium alginate is 1:(4-10).

5. The oral sustained-release nicotine salt formulation according to any one of claims 1-4, characterized in that, The pH adjuster is selected from any one or a combination of at least two of sodium bicarbonate, sodium carbonate, trisodium citrate, or disodium hydrogen phosphate.

6. The oral sustained-release nicotine salt formulation according to any one of claims 1-5, characterized in that, The adhesive includes any one or a combination of at least two of hydroxypropyl methylcellulose, carbomer, xanthan gum or guar gum; And / or, the film-forming agent includes any one or a combination of at least two of polyvinyl alcohol, hydroxypropyl cellulose or chitosan; And / or, the filler comprises microcrystalline cellulose; And / or, the oral sustained-release nicotine salt formulation further includes a taste modifier, which includes any one or a combination of at least two of the following: peppermint flavor, menthol, ethyl menthane formamide, menthone, menthyl acetate, limonene, aspartame, erythritol, sucralose, isomaltitol, acesulfame potassium, neotame, saccharin, sucrose, glucose, maltose, or fructose.

7. The oral sustained-release nicotine salt formulation according to any one of claims 1-6, characterized in that, The oral sustained-release nicotine salt formulations may be in the form of oral films, lozenges, oral gels, or chewable granules.

8. A method for preparing an oral sustained-release nicotine salt formulation according to any one of claims 1-7, characterized in that, The preparation method includes the following steps: S1. Preparation of pre-crosslinked particles: Sodium alginate is mixed with citric acid and wetting agent and granulated, then dried to obtain pre-crosslinked particles; S2, Total Mixing: The pre-crosslinked particles obtained in step S1 are mixed with Eutrapeptide E, nicotine base material, pH adjuster, adhesive, film-forming agent and filler to obtain total mixed powder; S3. Molding and preparation: The total mixed powder obtained in step S2 is compressed into tablets to obtain the oral sustained-release nicotine salt preparation.

9. The preparation method according to claim 8, characterized in that, The drying temperature in step S1 is 50-70℃, and the drying time is 1-4 hours; And / or, the mixing in step S2 further includes mixing with a taste modifier; And / or, the wetting agent in step S3 includes an aqueous solution of water or ethanol.

10. The use of an oral sustained-release nicotine salt formulation according to any one of claims 1-7 in the preparation of smokeless tobacco products.

Images