A chitosan nicotine pouch composition and a process for preparing the same

Abstract

This invention relates to the field of nicotine product technology, and discloses a chitosan nicotine bag composition and its preparation process, comprising: placing modified chitosan in pure water, adding an acid-base adjuster to adjust the pH value, obtaining a modified chitosan solution; preparing a nicotine aqueous solution, adding a crosslinking agent to dissolve it, obtaining a crosslinking agent nicotine aqueous solution; adding the crosslinking agent nicotine aqueous solution dropwise to the modified chitosan solution to undergo crosslinking and salt formation reactions, obtaining a nicotine salt nanoparticle suspension; drying the nicotine salt nanoparticle suspension to obtain solid nicotine salt nanoparticles; filling the solid nicotine salt nanoparticles as a filling matrix into a breathable bag material and heat-sealing and cutting. This invention utilizes the multi-site electrostatic crosslinking reaction between modified chitosan, a crosslinking agent, and nicotine to generate a dense three-dimensional network structure, encapsulating and fixing the nicotine internally, preventing damage from high temperature and humidity, controlling water absorption and swelling, and achieving continuous and gradual release.

Description

Technical Field

[0001] This invention relates to the field of nicotine product technology, specifically to a chitosan nicotine bag composition and its preparation process. Background Technology

[0002] Existing nicotine sachets typically adsorb nicotine directly within plant fibers or polymer matrices. Free nicotine is volatile and easily dissipates during manufacturing processes and product storage, reducing the chemical stability of the nicotine sachet composition. When the non-woven breathable sachet material comes into contact with the user's saliva, the simply adsorbed free nicotine rapidly diffuses into the oral cavity in large quantities. This rapid and significant release of free nicotine can cause momentary irritation to the oral mucosa, diminishing the user experience.

[0003] In the process of preparing drug-loaded microparticles, conventional mixing methods cannot control the rate at which reactants enter the reaction system. Without a slightly acidic environment and shear force intervention, the encapsulation reaction is incomplete, and the resulting aggregated microspheres are prone to agglomeration and growth, leading to uneven particle size distribution. Conventional heating and stirring processes exacerbate the volatilization and loss of nicotine.

[0004] Existing drying operations employ conventional drying and dehydration processes. The high-temperature heating in these processes can easily cause the collapse and destruction of the three-dimensional porous network structure of the polymer carrier, preventing the particles from forming a powder morphology that meets the requirements of quantitative filling equipment. Direct filling of powder with uneven morphology distribution leads to deviations in the total nicotine content of a single nicotine pouch composition. This results in the composition not matching the dosage limits for oral mucosal absorption, and a single use of a nicotine pouch composition with excessively high nicotine content increases the risk of adverse reactions in users. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a chitosan nicotine bag composition and its preparation process, which solves the problems of free nicotine being easily volatile and degraded, uncontrollable drug release rate, and significant irritation to the oral mucosa in existing nicotine release carriers.

[0006] To achieve the above objectives, the present invention provides the following technical solution: In a first aspect, the present invention provides a chitosan nicotine bag composition comprising a nonwoven breathable bag material and solid nicotine salt nanoparticles filled into the nonwoven breathable bag material as a filling matrix. The solid nicotine salt nanoparticles are made from the following raw materials in parts by weight: 30-80 parts modified chitosan; 15-50 parts nicotine; 1-15 parts acid-base regulator; and 10 parts crosslinking agent.

[0007] By employing the above technical solution, and using modified chitosan as the polymer matrix framework, along with the synergistic addition of acid-base regulators and crosslinking agents, crosslinking and salt-forming reactions occur after mixing with nicotine, thus obtaining solid nicotine salt nanoparticles with nanoscale core-shell or network structures. The specific mechanism is as follows: In a pH environment controlled by an acid-base regulator, the amino groups on the modified chitosan molecular chain undergo protonation, forming a positively charged polymeric polyelectrolyte. Simultaneously, free nicotine in the liquid phase is partially converted into positively charged nicotine ions. When a multivalent negatively charged crosslinking agent is added, the anionic groups of the crosslinking agent strongly electrostatically attract the protonated amino groups of the modified chitosan, initiating an ionic crosslinking reaction. During the nucleation and contraction of this crosslinked network, nicotine molecules and nicotine ions are encapsulated and trapped within the three-dimensional polymeric network structure generated by the crosslinking, while simultaneously completing the salt formation reaction, ultimately precipitating out solid nicotine salt nanoparticles with uniform particle size distribution.

[0008] This composition transforms highly volatile and irritating free nicotine into a stable nano-inclusion complex. When the nonwoven breathable bag material comes into contact with oral saliva, the outer modified chitosan network undergoes limited swelling, and the internal nicotine salts slowly diffuse outward through the swollen pores, thereby achieving a stable and continuous release of nicotine. This reduces the instantaneous irritation of the oral mucosa by free nicotine and improves the chemical stability and shelf life of the product.

[0009] Preferably, the modified chitosan is one or more selected from carboxymethyl chitosan, carboxyethyl chitosan, gallic acid chitosan, succinyl chitosan, and polyacrylic acid chitosan. The acid-base adjuster is one or more selected from malic acid, tartaric acid, acetic acid, salicylic acid, sodium carbonate, and sodium bicarbonate. The crosslinking agent is one or more selected from sodium citrate, sodium tripolyphosphate, sodium hexametaphosphate, and sodium pyrophosphate.

[0010] By adopting the above technical solution, the modified chitosan selected exhibits superior water solubility and biocompatibility compared to ordinary chitosan, maintaining its soluble state over a wider pH range, which is beneficial for the uniformity of subsequent cross-linking reactions. The selected acid-base regulators include organic acids and weakly basic salts, which can construct a buffer system conducive to chitosan dechaining and nicotine ionization. The selected cross-linking agents are all small molecules or oligomeric salts containing multiple anionic coordination sites. These substances can form multi-site electrostatic cross-links with multiple amino cations on the modified chitosan chains, resulting in a cross-linked network with moderate density, which can both lock in nicotine and achieve appropriate degradation and release upon contact with saliva.

[0011] Secondly, the present invention provides a preparation process for a chitosan nicotine bag composition, comprising the following steps: The modified chitosan was placed in a reaction vessel containing pure water. The reaction vessel was placed in a constant temperature water bath. Under magnetic stirring, an acid-base regulator was added. The pH value of the mixture was monitored and adjusted in real time using a pH meter. After the modified chitosan was completely dissolved to form a uniform, particle-free solution, pure water was added to adjust the concentration of the modified chitosan, thus obtaining the modified chitosan solution.

[0012] Nicotine was placed in a solution preparation container, and pure water was added to dissolve and prepare a nicotine aqueous solution. A cross-linking agent was added to the nicotine aqueous solution, and the mixture was stirred continuously until it was completely dissolved without separation. Pure water was added to adjust the concentration of the cross-linking agent, and a cross-linking agent nicotine aqueous solution was obtained.

[0013] The modified chitosan solution was kept under magnetic stirring. The obtained crosslinking agent nicotine aqueous solution was slowly added dropwise to the modified chitosan solution through a constant pressure dropping funnel. After the addition was completed, the mixture was stirred continuously to carry out crosslinking and salt formation reactions, and a nicotine salt nanoparticle suspension was obtained.

[0014] The obtained nicotine salt nanoparticle suspension was subjected to freeze-drying or spray-drying to obtain solid nicotine salt nanoparticles.

[0015] Solid nicotine salt nanoparticles were filled into non-woven breathable bag material using a quantitative filling equipment as a filling matrix. The bag was then heat-sealed and cut using a hot-press sealing equipment to obtain a chitosan nicotine bag composition.

[0016] By adopting the above technical solution, the preparation process is divided into three core stages: independent dissolution of modified chitosan, premixing of nicotine and cross-linking agent, and dropwise addition of the two-phase solution. The mechanism of the reaction process is as follows: Nicotine and crosslinking agent are mixed in the aqueous phase in advance so that the free anions of crosslinking agent are spatially close to and uniformly dispersed with nicotine molecules.

[0017] A constant-pressure dropping funnel was used to slowly add the crosslinking agent and nicotine into the modified chitosan system, controlling the rate at which they entered the system. At the interface where the droplets contacted, the locally concentrated crosslinking anions rapidly captured the cationic binding sites on the modified chitosan chains, causing the polymer chains to quickly coil and encapsulate the surrounding nicotine molecules into the newly formed crosslinked microspheres.

[0018] By continuously stirring to provide shear force, the further aggregation and growth of the aggregated microspheres are limited, maintaining them at the nanoscale and forming a stable suspension system. Finally, a drying and dehydration process causes the polymer network to shrink and solidify, resulting in solid nicotine salt nanoparticles with good flowability, suitable for mechanized filling.

[0019] Preferably, the specific steps for obtaining the modified chitosan solution are as follows: 30-80 parts by mass of modified chitosan are placed in a reaction vessel containing pure water. The reaction vessel is placed in a constant temperature water bath. Under the conditions of 30-50℃ and 500-800rpm magnetic stirring speed, 1-15 parts by mass of acid-base adjuster are added. The pH value of the mixture is monitored and adjusted to 4.5-6.5 in real time using a pH meter. After the modified chitosan is completely dissolved to form a uniform, particle-free solution, pure water is added to adjust the concentration of modified chitosan to 5-25mg / mL, thus obtaining the modified chitosan solution.

[0020] The specific steps to obtain the cross-linking agent nicotine aqueous solution are as follows: 15-50 parts by mass of nicotine are placed in a solution preparation container, pure water is added to dissolve and prepare the nicotine aqueous solution, 10 parts by mass of cross-linking agent are added to the nicotine aqueous solution, and the mixture is stirred continuously at 20-30℃ until it is completely dissolved and there is no layering. Pure water is added to adjust the concentration of the cross-linking agent to 2-20 mg / mL, and the cross-linking agent nicotine aqueous solution is obtained.

[0021] By adopting the above technical solution, the temperature, stirring speed, pH value, and material concentration parameters for each reaction stage were limited. A temperature of 30–50℃ combined with a stirring speed of 500–800 rpm overcomes the problem of excessive local viscosity during the dissolution of modified chitosan, while preventing degradation of the polymer chains due to excessively high temperatures. Strictly controlling the pH value within the slightly acidic range of 4.5–6.5 ensures full extension of the chitosan molecular chains and maximum protonation of the amino groups, providing sufficient active sites for subsequent crosslinking. The preparation temperature of the crosslinking agent nicotine aqueous solution is controlled at 20–30℃ to prevent the loss of volatile nicotine during processing.

[0022] Preferably, the specific steps for obtaining the nicotine salt nanoparticle suspension are as follows: the modified chitosan solution is kept at a temperature of 30-50°C and a magnetic stirring speed of 500-800 rpm, and the obtained crosslinking agent nicotine aqueous solution is slowly added dropwise to the obtained modified chitosan solution through a constant pressure dropping funnel. After the addition is completed, the mixture is stirred continuously for 30-120 min to carry out crosslinking and salt formation reaction, thereby obtaining the nicotine salt nanoparticle suspension.

[0023] By adopting the above technical solution, maintaining a reaction temperature of 30–50°C and high-speed stirring, and providing a reaction window of 30–120 minutes after the addition is completed, the electrostatic crosslinking reaction can proceed fully at the thermodynamic and kinetic levels. The continuous shear force during this period can break the macroscopic flocculation caused by crosslinking, promote the redistribution of stress within the crosslinking network, and ultimately form a uniformly sized and thermodynamically stable nano-suspension phase.

[0024] Preferably, the specific steps for freeze-drying include: filtering the obtained nicotine salt nanoparticle suspension using a vacuum filtration device, and then freeze-drying it in a freeze dryer; further, after the freeze-drying is completed, grinding the nanoparticles using a mechanical grinding device and sieving them through a standard test sieve to obtain solid nicotine salt nanoparticles.

[0025] Preferably, the specific steps for spray drying are as follows: the obtained nicotine salt nanoparticle suspension is transported to a spray drying device for spray drying, the dried powder is separated and collected, and solid nicotine salt nanoparticles are obtained.

[0026] Preferably, the chitosan nicotine pouch composition has a single-piece size of 1.0cm × 3.0cm and a total nicotine content of 2.0–4.0mg / piece.

[0027] By employing the above-mentioned technical solutions, freeze-drying utilizes the principle of sublimation for dehydration, preserving the three-dimensional porous network structure of nanoparticles to the greatest extent and avoiding network collapse and nicotine thermal degradation caused by heating; spray drying utilizes instantaneous high-temperature heat exchange to rapidly nucleate and pulverize droplets, resulting in powders with good sphericity and excellent flowability. Both methods can transform suspensions into solid powders that meet quantitative filling requirements. By limiting the size of individual tablets and the nicotine loading within a specified range, the pharmacokinetic characteristics of absorption through the oral mucosa are aligned, ensuring that a single use meets physiological needs while avoiding the risk of toxic side effects due to dosage overload.

[0028] This invention provides a chitosan nicotine pouch composition and its preparation process. It has the following beneficial effects: 1. This invention prepares solid nicotine salt nanoparticles by mixing and reacting modified chitosan, nicotine, pH regulators, and crosslinking agents. The modified chitosan undergoes protonation in a pH environment created by the pH regulator, converting some of the free nicotine into nicotine ions. The crosslinking agent initiates an ionic crosslinking reaction, forming a three-dimensional polymer network structure. Nicotine molecules and nicotine ions are embedded and trapped within this network. When the nonwoven breathable bag material comes into contact with saliva, the modified chitosan network swells, and the embedded nicotine salt diffuses outward through the swollen pores, reducing the instantaneous irritation of free nicotine to the oral mucosa and improving the chemical stability of the chitosan-nicotine bag composition.

[0029] 2. This invention breaks down the preparation process into three stages: independent dissolution of modified chitosan, mixing of nicotine and crosslinking agent, and slow dropwise addition of the crosslinking agent-nicotine aqueous solution to the modified chitosan solution. This controls the rate at which the crosslinking agent and nicotine enter the modified chitosan system. During the preparation process, an acid-base regulator is used to control the mixed system to be in a slightly acidic environment, maintain a constant heating temperature and magnetic stirring speed, prevent nicotine loss, and provide shear force to prevent the agglomeration and growth of microspheres, thus promoting the full electrostatic crosslinking reaction and obtaining a nicotine salt nanoparticle suspension with uniform particle size distribution.

[0030] 3. This invention transforms nicotine salt nanoparticle suspensions into powder form through freeze-drying or spray-drying. Freeze-drying utilizes the sublimation principle to dehydrate and preserve the three-dimensional porous network structure of the nanoparticles, avoiding network collapse caused by heating. Spray drying dehydrates the droplets into powder, resulting in solid nicotine salt nanoparticles that meet the filling conditions of quantitative filling equipment. Finally, the solid nicotine salt nanoparticles are filled into non-woven breathable bags using quantitative filling equipment. The individual size and total nicotine content of the chitosan nicotine bag composition are controlled by heat sealing and cutting using a heat-sealing device, meeting the dosage limit for absorption through the oral mucosa and avoiding adverse reactions caused by excessive single use. Attached Figure Description

[0031] Figure 1 This is a particle size distribution diagram of the nicotine salt nanoparticle suspension of the present invention; Figure 2 This is a test graph showing the change in nicotine concentration under different ultrafiltration centrifugation times according to the present invention; Figure 3 This is a thermodynamic stability test diagram of the solid nicotine salt nanoparticles of the present invention; Figure 4 This is a graph showing the in vitro balanced release rate test of the chitosan nicotine bag composition of the present invention; Figure 5 This is a graph showing the accelerated storage stability test of the chitosan-nicotine bag composition of the present invention. Figure 6 This is a graph showing the swelling rate test of the chitosan-nicotine bag composition of the present invention. Detailed Implementation

[0032] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to test examples. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] Examples 1-3:

[0034] Example 1:

[0035] This embodiment provides a preparation process for a chitosan nicotine bag composition, including the following steps: S1. Place 50 parts by mass of modified chitosan into a reaction vessel containing pure water (the modified chitosan is one or more of carboxymethyl chitosan, carboxyethyl chitosan, gallic acid chitosan, succinyl chitosan, and polyacrylic acid chitosan; in this embodiment, carboxymethyl chitosan is used as the modified chitosan). Place the reaction vessel in a constant temperature water bath. Under the conditions of 35°C and 600 rpm magnetic stirring speed, add 8 parts by mass of acid-base adjuster (the acid-base adjuster is one or more of malic acid, tartaric acid, acetic acid, salicylic acid, sodium carbonate, and sodium bicarbonate; in this embodiment, a mixture of malic acid and acetic acid is used as the acid-base adjuster). Monitor and adjust the pH of the mixture to 4.5 in real time using a pH meter. After the carboxymethyl chitosan is completely dissolved to form a uniform, particle-free solution, add pure water to adjust the concentration of carboxymethyl chitosan to 20 mg / mL, thus obtaining a carboxymethyl chitosan solution with a concentration of 20 mg / mL. S2. Place 30 parts by mass of nicotine into a solution preparation container, add pure water to dissolve and prepare a nicotine aqueous solution, add 10 parts by mass of crosslinking agent (the crosslinking agent is one or more of sodium citrate, sodium tripolyphosphate, sodium hexametaphosphate, and sodium pyrophosphate; in this embodiment, sodium hexametaphosphate is used as the crosslinking agent), and continue stirring and mixing at 25°C until completely dissolved and without layering. Add pure water to adjust the concentration of sodium hexametaphosphate to 3 mg / mL to obtain a sodium hexametaphosphate nicotine aqueous solution with a sodium hexametaphosphate concentration of 3 mg / mL. S3. The obtained carboxymethyl chitosan solution with a concentration of 20 mg / mL was kept at a temperature of 35℃ and a magnetic stirring speed of 600 rpm. The obtained sodium hexametaphosphate nicotine aqueous solution with a concentration of 3 mg / mL was slowly added dropwise to the obtained carboxymethyl chitosan solution with a concentration of 20 mg / mL through a constant pressure dropping funnel. After the addition was completed, the mixture was stirred for 30 min to carry out cross-linking and salt formation reaction, and a nicotine salt nanoparticle suspension was obtained. S4. The obtained nicotine salt nanoparticle suspension was filtered by vacuum filtration equipment, placed in a freeze dryer for freeze drying, and after freeze drying, it was ground by mechanical grinding equipment and sieved through a standard test sieve to obtain solid nicotine salt nanoparticles. S5. The obtained solid nicotine salt nanoparticles were filled into non-woven breathable bag material using a quantitative filling equipment as a filling matrix. After heat sealing and cutting by a hot-press sealing equipment, a chitosan nicotine bag composition with a single piece size of 1.0cm×3.0cm and a total nicotine content of 3.0mg / piece was obtained.

[0036] Example 2:

[0037] This embodiment provides a preparation process for a chitosan nicotine bag composition, including the following steps: S1. Place 80 parts by mass of modified chitosan into a reaction vessel containing pure water (the modified chitosan is one or more of carboxymethyl chitosan, carboxyethyl chitosan, gallic acid chitosan, succinyl chitosan, and polyacrylic acid chitosan; in this embodiment, polyacrylic acid chitosan is used as the modified chitosan). Place the reaction vessel in a constant temperature water bath. Under the conditions of 50°C and 800 rpm magnetic stirring speed, add 15 parts by mass of an acid-base adjuster (the acid-base adjuster is one or more of malic acid, tartaric acid, acetic acid, salicylic acid, sodium carbonate, and sodium bicarbonate; in this embodiment, tartaric acid is used as the acid-base adjuster). Monitor and adjust the pH value of the mixture to 6.5 in real time using a pH meter. After the polyacrylic acid chitosan is completely dissolved to form a uniform, particle-free solution, add pure water to adjust the concentration of polyacrylic acid chitosan to 25 mg / mL, thus obtaining a polyacrylic acid chitosan solution with a concentration of 25 mg / mL. S2. Place 50 parts by weight of nicotine into a solution preparation container, add pure water to dissolve and prepare a nicotine aqueous solution, add 10 parts by weight of crosslinking agent (the crosslinking agent is one or more of sodium citrate, sodium tripolyphosphate, sodium hexametaphosphate and sodium pyrophosphate, in this embodiment the crosslinking agent is sodium tripolyphosphate), and continue to stir and mix at 30°C until completely dissolved and without layering, add pure water to adjust the concentration of sodium tripolyphosphate to 20 mg / mL, and obtain a sodium tripolyphosphate nicotine aqueous solution with a sodium tripolyphosphate concentration of 20 mg / mL; S3. The obtained polyacrylic acid chitosan solution with a concentration of 25 mg / mL was kept at a temperature of 50℃ and a magnetic stirring speed of 800 rpm. The obtained sodium tripolyphosphate nicotine aqueous solution with a concentration of 20 mg / mL was slowly added dropwise to the obtained polyacrylic acid chitosan solution with a concentration of 25 mg / mL through a constant pressure dropping funnel. After the addition was completed, the mixture was stirred for 120 min to carry out cross-linking and salt formation reaction, and a nicotine salt nanoparticle suspension was obtained. S4. The obtained nicotine salt nanoparticle suspension is transported to a spray drying equipment for spray drying treatment, and the dried powder is separated and collected to obtain solid nicotine salt nanoparticles. S5. The obtained solid nicotine salt nanoparticles were filled into non-woven breathable bag material using a quantitative filling equipment as a filling matrix. After heat sealing and cutting by a hot-press sealing equipment, a chitosan nicotine bag composition with a single piece size of 1.0cm×3.0cm and a total nicotine content of 4.0mg / piece was obtained.

[0038] Example 3:

[0039] This embodiment provides a preparation process for a chitosan nicotine bag composition, including the following steps: S1. Place 30 parts by mass of modified chitosan into a reaction vessel containing pure water (the modified chitosan is one or more of carboxymethyl chitosan, carboxyethyl chitosan, gallic acid chitosan, succinyl chitosan, and polyacrylic acid chitosan; in this embodiment, succinyl chitosan is used as the modified chitosan). Place the reaction vessel in a constant temperature water bath. Under the conditions of 30°C and 500 rpm magnetic stirring speed, add 1 part by mass of an acid-base adjuster (the acid-base adjuster is one or more of malic acid, tartaric acid, acetic acid, salicylic acid, sodium carbonate, and sodium bicarbonate; in this embodiment, a mixture of malic acid and sodium carbonate is used as the acid-base adjuster). Monitor and adjust the pH of the mixture to 5.0 in real time using a pH meter. After the succinyl chitosan is completely dissolved to form a uniform, particle-free solution, add pure water to adjust the concentration of succinyl chitosan to 5 mg / mL, thus obtaining a succinyl chitosan solution with a concentration of 5 mg / mL. S2. Place 15 parts by mass of nicotine into a solution preparation container, add pure water to dissolve and prepare a nicotine aqueous solution, add 10 parts by mass of crosslinking agent (the crosslinking agent is one or more of sodium citrate, sodium tripolyphosphate, sodium hexametaphosphate and sodium pyrophosphate, and sodium pyrophosphate is used in this embodiment) to the nicotine aqueous solution, stir and mix continuously at 20°C until completely dissolved and without layering, add pure water to adjust the concentration of sodium pyrophosphate to 2 mg / mL, and obtain a sodium pyrophosphate nicotine aqueous solution with a sodium pyrophosphate concentration of 2 mg / mL; S3. The obtained succinyl chitosan solution with a concentration of 5 mg / mL was kept at a temperature of 30℃ and a magnetic stirring speed of 500 rpm. The sodium pyrophosphate nicotine aqueous solution with a concentration of 2 mg / mL was slowly added dropwise to the obtained succinyl chitosan solution with a concentration of 5 mg / mL through a constant pressure dropping funnel. After the addition was completed, the mixture was stirred for 90 min to carry out cross-linking and salt formation reaction, and a nicotine salt nanoparticle suspension was obtained. S4. The obtained nicotine salt nanoparticle suspension was filtered by vacuum filtration equipment, placed in a freeze dryer for freeze drying, and after freeze drying, it was ground by mechanical grinding equipment and sieved through a standard test sieve to obtain solid nicotine salt nanoparticles. S5. The obtained solid nicotine salt nanoparticles were filled into non-woven breathable bag material using a quantitative filling equipment as a filling matrix. After heat sealing and cutting by a hot-press sealing equipment, a chitosan nicotine bag composition with a single piece size of 1.0cm×3.0cm and a total nicotine content of 2.0mg / piece was obtained.

[0040] Comparative Examples 1-4: Comparative Example 1: Compared with Example 1, the difference is that in step S1, 50 parts by weight of carboxymethyl chitosan is replaced with 50 parts by weight of unmodified chitosan, and the rest are the same.

[0041] Comparative Example 2: Compared with Example 1, the difference is that in step S2, 10 parts by mass of sodium hexametaphosphate are replaced with 10 parts by mass of sodium chloride, and the rest are the same.

[0042] Comparative Example 3: Compared with Example 2, the difference is that step S1 removes the addition of 15 parts by weight of tartaric acid and the operation of real-time monitoring and adjustment of the pH value of the mixed system to 6.5 using a pH meter; all other steps are the same.

[0043] Comparative Example 4: Compared with Example 3, the difference is that 10 parts by weight of sodium pyrophosphate are transferred to step S1 and added simultaneously with 30 parts by weight of succinyl chitosan to a reaction vessel containing pure water. In step S2, only 15 parts by weight of nicotine are used to prepare a nicotine aqueous solution with pure water. All other steps are the same.

[0044] Test Examples 1-6: Test Example 1: The nicotine salt nanoparticle suspensions obtained in Examples 1, 2, 3, 1, 2, 3, and 4 were placed in clean glass sample bottles. Pure water was added to the glass sample bottles for dilution, and the transmittance of each group of nicotine salt nanoparticle suspensions was adjusted to the range required by the dynamic light scattering instrument test standard.

[0045] The diluted nicotine salt nanoparticle suspension was drawn up with a syringe and slowly injected into a quartz cuvette specifically designed for dynamic light scattering (DLS), removing any air bubbles inside the cuvette. The cuvette was then placed in the sample chamber of the DLS, the ambient temperature was set to 25°C, and the DLS was run to record the particle size (nm) and particle volume percentage (%).

[0046] The nicotine salt nanoparticle suspension, after particle size testing, was transferred to a zeta potential testing cell. Electrodes were inserted, and an electric field was applied at 25°C. The zeta potential (mV) of the particles was measured and recorded. Each group of samples was tested in parallel three times, and the average value was recorded as the test data.

[0047] Table 1. Average Particle Size and Zeta Potential Test Data of Nicotine Salt Nanoparticle Suspension

[0048] Figure 1This is a particle size distribution diagram of the nicotine salt nanoparticle suspension of the present invention. The horizontal axis of the diagram represents the particle size (nm), and the vertical axis represents the particle volume percentage (%). The curves in the diagram represent the changes in particle volume percentage under different particle sizes for Examples 1, 2, 3, Comparative Examples 1, 2, 3, and 4, respectively.

[0049] in conclusion: According to Table 1 and Figure 1 The data shows that the average particle size of the nicotine salt nanoparticle suspensions obtained in Examples 1, 2, and 3 is in the range of 176.2 nm to 289.7 nm. Figure 1 The particle size distribution curve shows a single peak with a narrow peak width, and the zeta potential is in the range of +8.6mV to +14.1mV. The amino and carboxyl groups carried on the modified chitosan molecular chain undergo electrostatic neutralization and bridging crosslinking reactions with the polyvalent anions in nicotine and crosslinking agents to form a dense molecular network coating layer. The reduction of free charge in the system leads to a decrease in the zeta potential, generating uniformly dispersed nanoscale particles.

[0050] According to Table 1 and Figure 1 The data shows that Comparative Example 1, which did not use modified chitosan, had an average particle size of 854.9 nm and a Zeta potential of +32.8 mV. Figure 1 The peak of the distribution curve shifted later and the distribution became wider. Unmodified chitosan lacks carboxyl reaction sites, resulting in a lower crosslinking density between molecular chains. Unmodified chitosan cannot form a regular condensation crosslinking system with sodium hexametaphosphate and nicotine, leading to particle aggregation and a high accumulation of positive surface charge.

[0051] According to Table 1 and Figure 1 The data shows that in Comparative Example 2, using sodium chloride instead of sodium hexametaphosphate resulted in an average particle size of 1342.5 nm and a Zeta potential as high as +45.3 mV. Sodium chloride, being a monovalent salt, cannot provide multi-site electrostatic crosslinking capability, preventing the polymer molecular chains from contracting into particles. The chitosan molecules remained in a free, extended state with a large amount of unneutralized charge exposed on their surface. Comparative Example 3, without adding an acid-base adjuster to regulate pH, resulted in an average particle size of 711.8 nm. The unadjusted pH environment caused a decrease in the solubility and chain segment extension of polyacrylic acid chitosan in pure water, reduced internal ionization, increased steric hindrance hindering subsequent crosslinking reactions, and the formation of aggregates with uneven particle size.

[0052] According to Table 1 and Figure 1Data shows that, in Comparative Example 4, changing the order of addition resulted in an average particle size of 1083.4 nm. When the crosslinking agent and succinochitosan were added to pure water simultaneously, the succinochitosan underwent intermolecular and intramolecular self-crosslinking first, forming a gel network structure with repulsive properties. The subsequently added nicotine aqueous solution could not penetrate the already closed crosslinked network to encapsulate and form salts, leading to disordered particle size growth.

[0053] Test Example 2: Nicotine salt nanoparticle suspensions obtained in Examples 1, 2, 3, 1, 2, 3 and 4 were measured using a pipette and transferred to the upper inner tube of an ultrafiltration centrifuge tube containing an ultrafiltration membrane with a molecular weight cutoff of 10 kDa.

[0054] Set the ultrafiltration centrifuge ambient temperature to 25℃ and run the ultrafiltration centrifuge for centrifugation. At the set ultrafiltration centrifugation time points, collect the filtrate from the lower outer tube of the ultrafiltration centrifuge tube. Inject the collected filtrate into the injection system of the high-performance liquid chromatograph (HPLC), record the nicotine peak area in the chromatogram, and calculate the free nicotine concentration (mg / mL) in the filtrate based on the standard curve.

[0055] Solid nicotine salt nanoparticles were weighed using an analytical balance and placed in a volumetric flask. Methanol solution was added to the flask, and the flask was subjected to ultrasonic disruption to break down the chitosan cross-linking network, allowing the encapsulated nicotine to be completely released and dissolved into the methanol solution. The mixed solution was filtered and injected into a high-performance liquid chromatograph (HPLC) to determine the difference between the total nicotine mass and the free nicotine mass. The encapsulation efficiency (%) and drug loading (%) were calculated using the following formulas: Encapsulation efficiency equals the difference between the total nicotine mass and the free nicotine mass divided by the difference between the total nicotine mass and the free nicotine mass; drug loading equals the difference between the total nicotine mass and the free nicotine mass divided by the total mass of the solid nicotine salt nanoparticles.

[0056] Table 2. Data on encapsulation efficiency and drug loading of nicotine salt nanoparticles

[0057] Figure 2 This is a test graph showing the change in free nicotine concentration in the filtrate under different ultrafiltration centrifugation times according to the present invention. The horizontal axis of the graph represents the ultrafiltration centrifugation time (min), and the vertical axis represents the mass concentration of free nicotine in the filtrate (mg / mL). The curves in the graph represent the changes in the mass concentration of free nicotine in the filtrate of Examples 1, 2, 3, Comparative Examples 1, 2, 3, and 4 under different ultrafiltration centrifugation times.

[0058] in conclusion: According to Table 2 and Figure 2The data shows that the free nicotine concentration in the stabilized filtrate of Examples 1, 2, and 3 ranged from 1.41 mg / mL to 2.05 mg / mL. Figure 2 The curves of the representative examples are at the bottom and the change is gradual, with encapsulation efficiency reaching the range of 87.6% to 91.2%. The carboxyl groups provided by modified chitosan increase the water solubility of the polymer, and the modified chitosan reacts with nicotine and crosslinking agents to form a dense crosslinked three-dimensional network structure, which encapsulates and confines nicotine within the network space, reducing free release and increasing the nicotine loading capacity.

[0059] According to Table 2 and Figure 2 The data shows that, in Comparative Example 1 using unmodified chitosan, the concentration of free nicotine in the filtrate increased to 11.34 mg / mL. Figure 2 The corresponding curve height increased significantly, and the encapsulation efficiency decreased to 31.5%. Unmodified chitosan lacks carboxyl substituents and cannot undergo multi-site cross-linking reactions with nicotine and sodium hexametaphosphate, thus failing to construct a complete network encapsulation system. As a result, a large amount of nicotine did not enter the polymer interior and remained in a free state.

[0060] According to Table 2 and Figure 2 The data shows that, in Comparative Example 2, which used sodium chloride, the encapsulation efficiency was only 12.3%. Figure 2 The curve is at its highest point. Sodium chloride lacks polyvalent anions and cannot act as a bridge to initiate electrostatic cross-linking; the missing network structure prevents nicotine from aggregating and encapsulating. Comparative Example 3, after removing the pH adjuster, achieved an encapsulation rate of 58.9%. Polyacrylic acid chitosan does not dissolve completely in unadjusted pure water; the molecular chains are coiled, reducing exposed reaction sites and lowering the cross-linking density, thus weakening the nicotine loading capacity.

[0061] According to Table 2 and Figure 2 The data shows that, in Comparative Example 4, changing the order of material addition resulted in an encapsulation rate of 42.1% and a free nicotine concentration of 9.62 mg / mL in the filtrate. Sodium pyrophosphate first reacted with succinyl chitosan in pure water, resulting in self-crosslinking and the formation of a closed gel structure that created steric hindrance. The subsequently mixed nicotine aqueous solution was blocked from the network, preventing the internal encapsulation and salt formation reaction, thus leading to a high free nicotine concentration.

[0062] Test Example 3: One part by mass of the solid nicotine salt nanoparticles obtained in Examples 1, 2, 3, 1, 2, 3 and 4 were weighed using an analytical balance. The weighed solid nicotine salt nanoparticles were placed inside standard aluminum crucibles, and the standard aluminum crucibles were compacted and sealed using a tableting device.

[0063] The sealed standard aluminum crucible was transferred to the heating chamber of the differential scanning calorimeter, and an empty aluminum crucible of the same size was placed on the reference side of the differential scanning calorimeter as a test reference.

[0064] Turn on the differential scanning calorimeter (DSC) and introduce high-purity nitrogen into the heating chamber to provide a protective gas environment. Set the DSC heating program, gradually increasing the temperature from 50°C to 400°C. The DSC records the difference in heat absorption and release generated by the thermodynamic phase transition or decomposition reaction of solid nicotine salt nanoparticles at different temperature points. The system collects the temperature and heat flow data of each group of test samples and integrates them to obtain the experimental values ​​of the main thermal decomposition peak temperature (°C) and thermal decomposition enthalpy change (J / g).

[0065] Table 3. Differential Scanning Calorimetry Data of Nicotine Salt Nanoparticles

[0066] Figure 3 This is a thermodynamic stability test chart of the solid nicotine salt nanoparticles of the present invention. The horizontal axis of the chart represents temperature (°C), and the vertical axis represents heat flow (mW). The curves in the chart represent the changes in heat flow at different temperatures for Examples 1, 2, 3, Comparative Examples 1, 2, 3, and 4, respectively.

[0067] in conclusion: According to Table 3 and Figure 3 The data shows that the main thermal decomposition peak temperatures of the solid nicotine salt nanoparticles obtained in Examples 1, 2 and 3 are concentrated in the range of 308.1℃ to 325.7℃. Figure 3 The thermal decomposition exothermic peak of the representative embodiment curve shifts overall to the high-temperature region. The carboxyl groups of the modified chitosan interact with nicotine and the cross-linking agent, resulting in electrostatic cross-linking and salt formation reactions. Free nicotine is transformed into nicotine salts with a more robust molecular structure, and a high-density three-dimensional network is formed simultaneously. The cross-linked network spatially binds the thermal motion of molecular chain segments, increasing the heat energy required to break intermolecular forces and crystallize the network, thus leading to an increase in overall thermodynamic stability and a delay in the thermal decomposition peak temperature.

[0068] According to Table 3 and Figure 3 The data shows that, in Comparative Example 1 using unmodified chitosan, the main thermal decomposition peak temperature was reduced to 268.5℃. Unmodified chitosan lacks carboxyl groups, thus losing the fundamental conditions for participating in multi-site cross-linking reactions and failing to form a regular salt lattice network with nicotine. Free and surface-adsorbed nicotine escapes and volatilizes at relatively low heating temperatures, and the chitosan substrate, lacking a protective network layer, undergoes premature thermal degradation, lowering the overall thermal decomposition peak temperature.

[0069] According to Table 3 and Figure 3 The data shows that Comparative Example 2, using sodium chloride, exhibited a main thermal decomposition peak temperature of only 260.3℃ and a thermal decomposition enthalpy of 134.6 J / g. Monovalent sodium chloride cannot act as a cross-linking bridge to induce intermolecular electrostatic cross-linking polymerization. The polymer lacks a salt-forming encapsulation structure, and network defects cause internal free matter to easily collapse under low-heat conditions. Comparative Example 3, without the addition of an acid-base regulator, had a main thermal decomposition peak temperature of 281.2℃. The pure water environment reduced the solubility of polyacrylic acid chitosan, and the incomplete unfolding of molecular chains hindered the large-scale execution of the salt-forming cross-linking reaction. This resulted in internal fracture defects in the material, weakening its ability to resist thermal damage.

[0070] According to Table 3 and Figure 3 The data shows that, in Comparative Example 4, changing the mixing order of substances, the main thermal decomposition peak temperature remained at 274.6℃. Sodium pyrophosphate and succinyl chitosan prematurely underwent an internal self-closing reaction, creating a gel network with steric repulsion properties. The subsequent contact with the nicotine aqueous solution was restricted by the gel network, unable to penetrate the network gaps to complete the encapsulation and salt formation process. The rapid volatilization of free nicotine upon heating caused the test curve to show a premature decomposition trend, failing to exhibit the high-temperature decomposition characteristics of densely cross-linked nicotine salts.

[0071] Test Example 4: Weigh out constant masses of the chitosan nicotine pouch compositions obtained in Examples 1, 2, 3, Comparative Examples 1, 2, 3, and 4. Place the weighed chitosan nicotine pouch compositions inside the glass dissolution vessel of an intelligent dissolution tester. Inject 500 ml of artificial saliva into the glass dissolution vessel, and set the temperature of the constant temperature water bath of the intelligent dissolution tester to 37°C. Turn on the intelligent dissolution tester and adjust the stirring paddle speed to 50 revolutions per minute.

[0072] At the preset sampling time points, 2 ml of nicotine-containing release medium was extracted from a glass dissolution vessel using a sampling needle, and 2 ml of preheated artificial saliva (37°C) was added to the glass dissolution vessel. The extracted release medium was filtered through a 0.45-micron microporous membrane and injected into a liquid chromatography sample vial. The chromatographic peak area of ​​nicotine in the sample vial was determined using a high-performance liquid chromatograph (HPLC). A pre-prepared nicotine standard concentration working curve was retrieved, and the cumulative nicotine release rate (%) corresponding to each sampling time point was calculated.

[0073] Table 4. Test data on cumulative nicotine release rate of chitosan nicotine pouch composition.

[0074] Figure 4This is an in vitro uniform release test chart of the chitosan nicotine bag composition of the present invention. The horizontal axis of the chart represents the sampling time (min), and the vertical axis represents the cumulative nicotine release rate (%). The curves in the chart represent the changes in the cumulative nicotine release rate of Examples 1, 2, 3, Comparative Examples 1, 2, 3, and 4 at different sampling times.

[0075] in conclusion: According to Table 4 and Figure 4 Data shows that the chitosan nicotine bag compositions obtained in Examples 1, 2, and 3 exhibited a cumulative nicotine release rate ranging from 11.1% to 14.5% at the 5-minute sampling time point, and from 92.1% to 96.8% at the 120-minute sampling time point. The modified chitosan provides carboxyl groups that increase polymer water solubility. Modified chitosan undergoes a multi-site cross-linking reaction with nicotine and the cross-linking agent to generate a cross-linked three-dimensional network. Artificial saliva gradually penetrates the three-dimensional network, causing polymer segments to swell in the artificial saliva environment. The internally encapsulated nicotine salts diffuse outward into the artificial saliva medium during the swelling process. The dense cross-linked network creates a steric hindrance effect on nicotine molecules, reducing the mass transfer rate of nicotine diffusion outward, avoiding a large initial burst of nicotine release, and maintaining a gradual and continuous release of nicotine.

[0076] According to Table 4 and Figure 4 The data shows that, in Comparative Example 1 using unmodified chitosan, the cumulative nicotine release rate increased to 45.6% at the 5-minute sampling time point. Figure 4 The curve representing Comparative Example 1 initially showed a sharp upward trend. Unmodified chitosan lacks carboxyl groups, and therefore cannot establish a complete cross-linked three-dimensional network with the cross-linking agent and nicotine. Nicotine is only adsorbed on the surface of unmodified chitosan or remains in a free state. Upon contact with artificial saliva, the adsorbed and free nicotine dissolves and detaches within a short time, resulting in a concentrated desorption characteristic in the initial stage of the release curve.

[0077] According to Table 4 and Figure 4The data shows that in Comparative Example 2, using sodium chloride as a crosslinking agent, the cumulative nicotine release rate reached 75.4% at the 10-minute sampling time point. Monovalent chloride and sodium ions cannot promote the crosslinking polymerization of the modified chitosan molecular chains, and no barrier structure restricting nicotine diffusion was formed within the system. Nicotine was directly exposed to artificial saliva and dissolved rapidly. In Comparative Example 3, without the addition of a pH adjuster, the cumulative nicotine release rate was 82.5% at the 30-minute sampling time point. The lack of pH adjustment caused a decrease in the chain segment expansion of polyacrylic acid chitosan in solution, resulting in incomplete crosslinking and the formation of a network structure with internal pores and defects. Artificial saliva rapidly entered the interior through these pores and defects, dissolving nicotine and accelerating the overall diffusion and release rate.

[0078] According to Table 4 and Figure 4 The data shows that in Comparative Example 4, where sodium pyrophosphate was mixed with succinyl chitosan beforehand, the cumulative nicotine release rate at the 120-minute sampling time point was only 78.1%. Sodium pyrophosphate induced succinyl chitosan to undergo early self-crosslinking, constructing a gel layer with repulsive properties. Some nicotine failed to penetrate into the gel layer to encapsulate and form salts, triggering an initial burst of nicotine release. Artificial saliva media had difficulty penetrating the solidified gel layer to dissolve the remaining small amount of nicotine, causing the later release curve to flatten and the final release rate to be lower.

[0079] Test Example 5: Two portions by mass of the chitosan nicotine bag compositions obtained in Examples 1, 2, 3, 1, 2, 3, and 4 were accurately weighed using an analytical balance. The weighed chitosan nicotine bag compositions were then laid flat in an open glass petri dish in a constant temperature and humidity chamber.

[0080] The internal test environment parameters of the constant temperature and humidity test chamber were set to 40℃ and 75% respectively. The accelerated aging program of the constant temperature and humidity test chamber was started to keep the chitosan nicotine bag composition in a continuous high temperature and high humidity environment.

[0081] At the set accelerated storage time point, 0.2 parts by mass of the chitosan nicotine bag composition sample affected by environmental factors were removed from an open glass petri dish. The removed chitosan nicotine bag composition sample was placed in a stoppered conical flask containing methanol solvent and subjected to ultrasonic extraction in an ultrasonic cleaner to break down the cross-linked network and allow the remaining nicotine components to fully dissolve into the methanol solvent.

[0082] The supernatant was extracted from the stoppered conical flask, filtered through a microporous membrane, and injected into the injection system of the high-performance liquid chromatograph (HPLC). The peak area in the HPLC chromatogram was measured, and the actual nicotine mass was obtained by combining the nicotine standard curve. The nicotine retention rate (%) at each accelerated storage time point was calculated.

[0083] Table 5. Accelerated Storage Stability Test Data for Chitosan Nicotine Bag Compositions

[0084] Figure 5 This is a test chart of the accelerated storage stability of the chitosan nicotine bag composition of the present invention. The horizontal axis of the chart represents the accelerated storage time (days), and the vertical axis represents the nicotine retention rate (%). The curves in the chart represent the changes in nicotine retention rate of Examples 1, 2, 3, Comparative Examples 1, 2, 3, and 4 under different accelerated storage times.

[0085] in conclusion: According to Table 5 and Figure 5 Data shows that the chitosan nicotine bag compositions obtained in Examples 1, 2, and 3 maintained a nicotine retention rate between 87.2% and 90.4% at the 60-day accelerated storage time point. The carboxyl groups carried by the modified chitosan molecular chain provide a basis for multi-site binding with the crosslinking agent and nicotine. After mixing, electrostatic neutralization and crosslinking reactions occur, generating a dense three-dimensional network structure. The three-dimensional network structure encapsulates and fixes the nicotine inside the polymer, forming strong steric hindrance. The polymer network blocks the direct contact damage of the internal nicotine molecules by the external high temperature and humidity environment, limits the volatilization loss of free nicotine under high temperature conditions, and maintains the component stability of the chitosan nicotine bag composition under accelerated aging.

[0086] According to Table 5 and Figure 5 The data shows that, in Comparative Example 1, which used unmodified chitosan, the nicotine retention rate decreased to 54.8% at the 60-day accelerated storage time point. Unmodified chitosan lacks carboxyl substituents, and therefore cannot establish a regular and tight three-dimensional cross-linking barrier with the cross-linking agent. A large amount of nicotine remained in a surface-attached or free state. This free nicotine under high temperature and humidity conditions underwent rapid degradation and volatilization, resulting in a drop in the nicotine retention rate.

[0087] According to Table 5 and Figure 5The data shows that in Comparative Example 2, where sodium chloride was used instead of the multivalent crosslinking agent, the nicotine retention rate was only 48.2% at the 60-day accelerated storage time. Sodium chloride, as a monovalent salt, could not act as a bridge to promote multi-site electrostatic crosslinking of the modified chitosan molecules. The polymer system failed to form a network structure encapsulating nicotine, resulting in rapid deterioration of the nicotine due to direct exposure to high temperature and humidity. Comparative Example 3, without the addition of an acid-base adjuster, achieved a nicotine retention rate of 68.3% at the 60-day accelerated storage time. The polyacrylic acid chitosan did not dissolve sufficiently in the unadjusted pH system, and the insufficient molecular chain extension caused numerous local vacancies in the crosslinking reaction. External moisture and heat penetrated these vacant areas, accelerating the nicotine loss process.

[0088] According to Table 5 and Figure 5 The data shows that, in Comparative Example 4, changing the order of material addition resulted in a low nicotine retention rate of 61.5% at the 60-day accelerated storage time point. Sodium pyrophosphate first reacted with succinyl chitosan in the aqueous solution, undergoing an internal self-crosslinking reaction to form a gel-like barrier layer with repulsive properties. Subsequently added nicotine solution could not penetrate the barrier layer to bind within the network, and most of the nicotine remained in the outer space of the gel layer. The exposed nicotine rapidly leaked out in the accelerated storage environment, causing the curve representing Comparative Example 4 in the test spectrum to show a continuously steep downward trend.

[0089] Test Example 6: Two portions by mass of the chitosan nicotine bag compositions obtained in Examples 1, 2, 3, 1, 2, 3, and 4 were accurately weighed using an analytical balance. The weighed chitosan nicotine bag compositions were placed in a test tube fitted with a glass frit filter plate at the bottom, and the initial total mass of the test tube and the chitosan nicotine bag compositions was recorded.

[0090] The temperature of the constant-temperature water bath was kept constant at 37℃. A beaker containing artificial saliva with a pH of 6.8 was placed in the constant-temperature water bath for preheating. The test tube containing the chitosan nicotine bag composition was vertically immersed in the artificial saliva in the beaker, with the liquid level of the artificial saliva slightly higher than the plane of the glass frosted filter plate, to promote the absorption of the artificial saliva by the chitosan nicotine bag composition through capillary action, resulting in polymer swelling.

[0091] Upon reaching the set immersion time, the test tube is vertically removed from the artificial saliva and taken off the liquid surface. The test tube is then transferred to a flat work surface pre-lined with absorbent filter paper and allowed to stand for the set time, allowing the absorbent filter paper to remove any remaining free artificial saliva from the bottom of the glass frit filter plate. The processed test tube is then weighed on an analytical balance, and the swelling rate (%) corresponding to each immersion time is calculated using the difference between the current total mass and the initial total mass.

[0092] Table 6. Data on swelling rate of chitosan nicotine pouch composition

[0093] Figure 6 This is a graph showing the swelling rate test of the chitosan nicotine bag composition of the present invention. The horizontal axis of the graph represents the soaking time (min), and the vertical axis represents the swelling rate (%). The curves in the graph represent the changes in swelling rate of Examples 1, 2, 3, Comparative Examples 1, 2, 3, and 4 under different soaking times.

[0094] in conclusion: According to Table 6 and Figure 6 Data shows that the swelling rates of the chitosan nicotine bag compositions obtained in Examples 1, 2, and 3 ranged from 125.4% to 140.6% at the 120-minute immersion time. The carboxyl groups provided by the modified chitosan not only increased the hydrophilicity of the polymer segments but also formed a multi-site electrostatic crosslinking reaction with the multivalent crosslinking agent and nicotine molecules, creating a stable three-dimensional crosslinked network. Artificial saliva penetrated the network, causing the polymer segments to expand and absorb water. The elastic contraction force generated at the crosslinked network nodes offset the osmotic pressure caused by continued external water penetration. A dynamic balance between water absorption and network constraint was formed within the polymer, allowing the chitosan nicotine bag composition to maintain a moderate and gradual swelling state, thus preserving the integrity of the overall structure.

[0095] According to Table 6 and Figure 6 The data shows that, in Comparative Example 1, using unmodified chitosan, the swelling rate increased to 281.5% at the 120-minute immersion time. Unmodified chitosan lacks carboxyl active groups and cannot establish a binding three-dimensional cross-linking barrier with the cross-linking agent molecules. The polymer segments stack only with weak intermolecular forces; upon contact with artificial saliva, the polymer segments rapidly disperse and uncoil, allowing the artificial saliva to enter the polymer's internal space without obstruction, resulting in a disordered expansion of the absorbed water volume.

[0096] According to Table 6 and Figure 6The data shows that Comparative Example 2, using sodium chloride as the control salt, achieved a swelling rate as high as 312.1% at the 120-minute immersion time point. The monovalent ions generated by the dissociation of sodium chloride lack the bridging function to connect multiple modified chitosan molecular chains, resulting in a loosely mixed system. Upon the introduction of water, the polymer matrix structure rapidly disintegrated and underwent an unlimited swelling reaction. Comparative Example 3, without the addition of an acid-base adjuster, achieved a swelling rate of 218.4% at the 120-minute immersion time point. The polyacrylic acid chitosan failed to completely dissolve and expand in the unadjusted aqueous environment, and the electrostatic cross-linking reaction was limited to localized areas. Uncross-linked defective areas experienced rapid water penetration and volume expansion upon contact with artificial saliva, increasing the overall swelling rate.

[0097] According to Table 6 and Figure 6 The data shows that, in Comparative Example 4, changing the order of substance addition resulted in a low swelling rate of 62.3% at the 120-minute immersion time. Sodium pyrophosphate first undergoes a self-crosslinking reaction with succinyl chitosan in the aqueous phase, pre-constructing a dense, closed surface gel layer with water-repellent properties. Artificial saliva has difficulty penetrating the surface gel layer into the internal matrix via capillary action, thus blocking the contact and adsorption process between the internal polymer chains and water molecules, severely limiting the overall water absorption and swelling.

Claims

1. A chitosan nicotine pouch composition, characterized in that, The invention comprises a nonwoven breathable bag material and solid nicotine salt nanoparticles as a filling matrix, which are then filled into the nonwoven breathable bag material. The solid nicotine salt nanoparticles are made from the following raw materials in parts by weight: Modified chitosan: 30-80 parts; Nicotine: 15-50 servings; Acid-base regulator: 1-15 parts; Crosslinking agent: 10 parts.

2. The chitosan nicotine pouch composition according to claim 1, characterized in that, The modified chitosan is one or more of carboxymethyl chitosan, carboxyethyl chitosan, gallic acid chitosan, succinyl chitosan, and polyacrylic acid chitosan; The acid-base regulator is one or more of malic acid, tartaric acid, acetic acid, salicylic acid, sodium carbonate, and sodium bicarbonate. The crosslinking agent is one or more of sodium citrate, sodium tripolyphosphate, sodium hexametaphosphate, and sodium pyrophosphate.

3. A preparation process for the chitosan nicotine pouch composition according to any one of claims 1 to 2, characterized in that, Includes the following steps: The modified chitosan was placed in a reaction vessel containing pure water. The reaction vessel was placed in a constant temperature water bath. Under magnetic stirring, an acid-base regulator was added. The pH value of the mixture was monitored and adjusted in real time using a pH meter. After the modified chitosan was completely dissolved to form a uniform, particle-free solution, pure water was added to adjust the concentration of the modified chitosan, thus obtaining a modified chitosan solution. Nicotine was placed in a solution preparation container, and pure water was added to dissolve and prepare a nicotine aqueous solution. A cross-linking agent was added to the nicotine aqueous solution, and the mixture was stirred continuously until it was completely dissolved without separation. Pure water was added to adjust the concentration of the cross-linking agent, and a cross-linking agent nicotine aqueous solution was obtained. The modified chitosan solution was kept under magnetic stirring, and the obtained crosslinking agent nicotine aqueous solution was slowly added dropwise to the modified chitosan solution through a constant pressure dropping funnel. After the addition was completed, the mixture was stirred continuously to carry out crosslinking and salt formation reactions, and a nicotine salt nanoparticle suspension was obtained. The obtained nicotine salt nanoparticle suspension was subjected to freeze-drying or spray-drying to obtain solid nicotine salt nanoparticles. The obtained solid nicotine salt nanoparticles were filled into a non-woven breathable bag material using a quantitative filling equipment, and then heat-sealed and cut using a hot-press sealing equipment to obtain the chitosan nicotine bag composition.

4. The preparation process according to claim 3, characterized in that, The specific steps to obtain the modified chitosan solution are as follows: 30-80 parts by weight of the modified chitosan were placed in a reaction vessel containing pure water. The reaction vessel was placed in a constant temperature water bath. Under the conditions of 30-50°C and 500-800 rpm magnetic stirring speed, 1-15 parts by weight of the acid-base adjuster were added. The pH value of the mixture was monitored and adjusted to 4.5-6.5 in real time using a pH meter. After the modified chitosan was completely dissolved to form a uniform, particle-free solution, pure water was added to adjust the concentration of the modified chitosan to 5-25 mg / mL, thus obtaining the modified chitosan solution.

5. The preparation process according to claim 3, characterized in that, The specific steps to obtain the crosslinking agent nicotine aqueous solution are as follows: 15-50 parts by weight of the nicotine were placed in the solution preparation container, and pure water was added to dissolve and prepare the nicotine aqueous solution. 10 parts by weight of the crosslinking agent were added to the nicotine aqueous solution. The mixture was stirred and mixed continuously at a temperature of 20-30°C until it was completely dissolved and there was no layering. Pure water was added to adjust the concentration of the crosslinking agent to 2-20 mg / mL to obtain the crosslinking agent nicotine aqueous solution.

6. The preparation process according to claim 3, characterized in that, The specific steps to obtain the nicotine salt nanoparticle suspension are as follows: The modified chitosan solution was kept at a temperature of 30-50°C and a magnetic stirring speed of 500-800 rpm. The obtained crosslinking agent nicotine aqueous solution was slowly added dropwise to the modified chitosan solution through the constant pressure dropping funnel. After the addition was completed, the mixture was stirred for 30-120 min to carry out crosslinking and salt formation reaction, and the nicotine salt nanoparticle suspension was obtained.

7. The preparation process according to claim 3, characterized in that, The specific steps for performing the freeze-drying process are as follows: The obtained nicotine salt nanoparticle suspension was filtered using a vacuum filtration device and then placed in a freeze dryer for freeze drying.

8. The preparation process according to claim 3, characterized in that, After the freeze-drying process is completed, the particles are ground by mechanical grinding equipment and sieved through a standard test sieve to obtain the solid nicotine salt nanoparticles.

9. The preparation process according to claim 3, characterized in that, The specific steps for performing the spray drying process are as follows: The obtained nicotine salt nanoparticle suspension was transported to a spray drying device for spray drying treatment, and the dried powder was separated and collected to obtain the solid nicotine salt nanoparticles.

10. The preparation process according to claim 3, characterized in that, The chitosan nicotine pouch composition has a single-piece size of 1.0cm × 3.0cm and a total nicotine content of 2.0–4.0mg / piece.

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