Nicotine releasing agent for buccal cigarettes as well as preparation method and application of nicotine releasing agent

Abstract

The invention provides a nicotine releasing agent for buccal cigarettes and a preparation method and application of the nicotine releasing agent, and belongs to the technical field of tobaccos. The nicotine releasing agent for the buccal cigarette comprises cyclodextrin nanometer sponge with a three-dimensional porous nanometer structure and nicotine salt embedded and / or adsorbed and loaded on the cyclodextrin nanometer sponge, and cyclodextrin / cyclodextrin derivatives and a covalent cross-linking agent are subjected to a cross-linking reaction to form the cyclodextrin nanometer sponge.

Description

Technical Field

[0001] This disclosure relates to the field of tobacco technology, and in particular to a nicotine release agent for oral smoking, its preparation method, and its application. Background Technology

[0002] Smokeless tobacco products are a type of tobacco alternative that allows nicotine to be absorbed through the oral mucosa. They have gained attention due to their advantages, including no need for burning, no smoke, ease of use, and relatively low health risks. Nicotine, as the main active ingredient in smokeless tobacco products, directly determines the sensory quality and user experience of the product.

[0003] Currently, nicotine in oral tobacco products mainly comes from tobacco extracts, free nicotine, or nicotine salts, and is often loaded onto a carrier to achieve a sustained-release effect. However, existing carriers still have significant drawbacks: insufficient release regulation, resulting in excessively rapid initial release that causes oral irritation, and incomplete release in later stages that affects the continued satisfaction of use; poor carrier stability, easily affected by the oral environment (such as fluctuations in saliva pH and temperature) and excipients in the formulation (such as acid-base regulators), leading to uncontrollable release behavior and severely restricting the continuity and comfort of the user experience. Summary of the Invention

[0004] In view of this, the main objective of this disclosure is to provide a nicotine release agent for oral smoking, a method for preparing the same, and its application, in order to at least partially solve at least one of the aforementioned technical problems.

[0005] To achieve the above objectives, the technical solution disclosed herein is as follows:

[0006] In one aspect of this disclosure, a nicotine release agent for oral cigarettes is provided, comprising a cyclodextrin nanosponge having a three-dimensional porous nanostructure and nicotine salts embedded and / or adsorbed on the cyclodextrin nanosponge, wherein,

[0007] Cyclodextrin nanosponges are formed by cross-linking cyclodextrin / cyclodextrin derivatives with covalent cross-linking agents.

[0008] In another aspect of this disclosure, a method for preparing a nicotine-releasing agent for oral smoking is provided, comprising:

[0009] After melting the covalent crosslinking agent, a cyclodextrin / cyclodextrin derivative solution is added, and a cyclodextrin nanosponges are obtained after a crosslinking reaction. The molar ratio of cyclodextrin / cyclodextrin derivative to covalent crosslinking agent is 1:1~8.

[0010] Cyclodextrin nanosponges were dispersed in a nicotine salt solution and stirred to obtain a nicotine composition, wherein the mass ratio of cyclodextrin nanosponges to the nicotine salt was 1~5:1.

[0011] In another aspect of this disclosure, a mouthwash is provided, comprising the above-mentioned nicotine release agent and mouthwash excipients, wherein the nicotine release agent is added to the mouthwash at an amount of 28.57% to 40%.

[0012] According to the nicotine release agent disclosed herein, cyclodextrin nanosponges are used as a highly efficient loading carrier. Utilizing the three-dimensional porous structure of the cyclodextrin nanosponges, nicotine salts are encapsulated and adsorbed, ensuring rapid release of nicotine salts (release rate exceeding 50% within 5 minutes). Furthermore, the release performance can be controlled by adjusting the degree of cross-linking. In addition, this release agent maintains good release stability when coexisting with commonly used excipients in oral cigarettes. Moreover, its preparation process is simple and suitable for large-scale production. This solution provides a new approach to improving the user experience and upgrading oral cigarette products. Attached Figure Description

[0013] Figure 1 The infrared spectra of cyclodextrin nanosponges prepared with different molar ratios of β-cyclodextrin and diphenyl carbonate in the embodiments of this disclosure, as well as the infrared spectra of β-cyclodextrin and diphenyl carbonate.

[0014] Figure 2 The particle size distribution diagram shows the cyclodextrin nanosponges prepared with different molar ratios of β-cyclodextrin and diphenyl carbonate in the embodiments of this disclosure.

[0015] Figure 3 Cyclodextrin nanosponges prepared with β-cyclodextrin and diphenyl carbonate in different molar ratios, and atomic force microscopy images of β-cyclodextrin;

[0016] Figure 4 This is a photograph of the cyclodextrin nanosponges in Embodiment 3 of this disclosure;

[0017] Figure 5 This is a test graph showing the specific surface area and pore size distribution curves of the cyclodextrin nanosponges in Example 3 of this disclosure;

[0018] Figure 6 The specific surface area and pore size distribution curves of β-cyclodextrin are shown in the test diagram.

[0019] Figure 7 The ultraviolet absorption spectra of the nicotine-releasing agent and tartrate nicotine salt in Example 3 of this disclosure are shown.

[0020] Figure 8 The infrared spectra of the nicotine release agent, cyclodextrin nanosponges, and tartrate nicotine salt in Example 3 of this disclosure are shown.

[0021] Figure 9 Standard curves of tartrate nicotine salts at different concentrations at 259 nm;

[0022] Figure 10 The interaction diagrams are shown for cyclodextrin nanosponges DPC-CDNS-1:4 with tartrate nicotine salt at different mass ratios in Examples 6 to 9.

[0023] Figure 11 This is a physical image of the nicotine-releasing agent in Example 7 of this disclosure;

[0024] Figure 12 The release performance curves of the nicotine releasing agent in Examples 8, 10-13 and Comparative Example 1 of this disclosure are shown.

[0025] Figure 13 The graphs show the nicotine release performance of the nicotine release agents of Example 8 and Comparative Example 1, as well as the nicotine release agents with added sodium bicarbonate and citric acid. Detailed Implementation

[0026] To make the objectives, technical solutions, and advantages of this disclosure clearer, the following detailed description is provided in conjunction with specific embodiments.

[0027] The endpoints and any values ​​of the ranges disclosed in this disclosure are not limited to the precise ranges or values, and such ranges or values ​​should be understood to include values ​​close to such ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be regarded as specifically disclosed in this disclosure.

[0028] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit this disclosure. The terms “comprising,” “including,” etc., as used herein indicate the presence of the stated features, steps, operations, and / or components, but do not exclude the presence or addition of one or more other features, steps, operations, or components.

[0029] Existing oral tobacco products suffer from problems such as poor controllability of nicotine release, excessively rapid initial release leading to a poor user experience, and insufficient stability when coexisting with other excipients (such as sodium bicarbonate / citric acid).

[0030] In the process of developing this disclosure, it was discovered that cyclodextrins (CDs) are a class of cyclic oligosaccharides composed of glucose units. Their molecular structure is truncated pyramidal, and the internal hydrophobic cavity and external hydrophilic surface endow them with unique advantages as small molecule carriers, including improved stability, enhanced solubility, and regulation of release rate. While using them as nicotine carriers can achieve the inclusion of nicotine salts, the loading capacity is limited, the means of regulating the release rate are scarce, and the structure is easily disturbed in complex formulations.

[0031] Based on this, this disclosure proposes a nicotine release agent for oral cigarettes, its preparation method, and its application. This release agent connects cyclodextrin / cyclodextrin derivatives through a cross-linking agent to form a three-dimensional porous network structure, forming a cyclodextrin nanosponge (CDNS). Utilizing its unique porous structure and large specific surface area, a dual nicotine salt loading mechanism of "encapsulation-adsorption" is constructed. Not only is the specific encapsulation of nicotine salt achieved through the internal cavity of cyclodextrin, but the adsorption of nicotine salt is also achieved through the material surface and pores. This forms a synergistic release mechanism combining "rapid surface desorption" and "continuous skeletal diffusion," enabling nicotine salt to take effect quickly to match the user's immediate sensory needs. At the same time, the spatial constraint effect of the cross-linked network enables controllable and continuous release of nicotine to prolong the user experience. Furthermore, the three-dimensional porous network structure provides good physicochemical stability for the nicotine release agent, making it suitable for the complex formulation environment of oral cigarettes. In addition, the appropriate cavity size of the cyclodextrin / cyclodextrin derivative itself ensures the stability of nicotine loading, enabling the nicotine release agent to play a key role in the loading and release of nicotine salts, providing a new technical path for the performance optimization of oral cigarette products.

[0032] According to one aspect of the present disclosure, a nicotine release agent for oral smoking is provided, comprising a cyclodextrin nanosponge having a three-dimensional porous nanostructure and nicotine salts embedded and / or adsorbed on the cyclodextrin nanosponge, wherein the cyclodextrin nanosponge is formed by a crosslinking reaction of cyclodextrin / cyclodextrin derivatives with a covalent crosslinking agent.

[0033] The nicotine release agent disclosed herein utilizes the three-dimensional porous network structure of cyclodextrin nanosponges to regulate the loading and release behavior of nicotine salts. Compared to the inclusion mechanism of cyclodextrin relying on a single hydrophobic cavity, the nicotine release agent of this disclosure forms a multiple loading mechanism of surface adsorption and cavity inclusion. Nicotine salt molecules are abundantly enriched on the high specific surface area of ​​the nanosponges, while some molecules can still enter the pores of the cyclodextrin nanosponges. When nicotine salt molecules enter the pores, they are constrained by their geometric space, resulting in a decrease in the diffusion coefficient and thus improving the stability of the system. Multiple forces work together to ensure a good loading of the nicotine release agent and directly affect its subsequent release kinetics. When the nicotine release agent comes into contact with the release medium, the nicotine salts adsorbed on its surface and in the shallow pores are rapidly desorbed, achieving rapid onset of action; subsequently, the molecules encapsulated in the deep pores and cavities are slowly released through diffusion, thus achieving a continuous supply.

[0034] According to embodiments of this disclosure, the specific surface area of ​​the cyclodextrin nanosponges is 17~50 m²·g. -1The pore volume is 11.5~45 cm³ / g. The high specific surface area can effectively increase the surface adsorption sites of nicotine salts, enabling them to desorb rapidly upon contact with oral saliva; the well-developed pore structure not only provides a high loading capacity, but also enables the slow release of internal nicotine salts through confined diffusion.

[0035] According to embodiments of this disclosure, cyclodextrins include any one of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin; cyclodextrin derivatives include any one of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, and sulfobutyl ether-β-cyclodextrin. Cyclodextrins and their derivatives provide hydrophobic cavities of tunable size, providing a basis for the inclusion of nicotine molecules.

[0036] The covalent crosslinking agent includes any one of diphenyl carbonate, citric acid, epichlorohydrin, and glutaraldehyde. The covalent crosslinking agent can form a stable three-dimensional network with cyclodextrin nanosponges through crosslinking reaction, forming a high specific surface area and good pore structure, which significantly improves the loading efficiency.

[0037] Nicotine salts include any one of tartrate nicotine salts, malic acid nicotine salts, citric acid nicotine salts, and lactic acid nicotine salts. Organic acid nicotine salts, such as tartrate nicotine salts, possess good water solubility and stability, and can effectively combine with the porous structure of nano-sponges. In practical applications, the appropriate type of nicotine salt can be flexibly selected based on the specific requirements of the product regarding nicotine release rate, environmental adaptability, and taste characteristics.

[0038] According to embodiments of this disclosure, the cyclodextrin nanosponges comprise any one of the following structures: clustered, sheet-like, strip-like, porous continuous phase, or hemispherical aggregates. Different morphologies of cyclodextrin nanosponges exhibit varying specific surface areas, pore size distributions, and mechanical strengths, thereby influencing the loading and release behavior of nicotine salts. By selecting nanosponges with different microstructures, the nicotine salt release kinetics can be designed on demand, thereby meeting the diverse requirements of different types of oral tobacco products for release rate and duration.

[0039] According to embodiments of this disclosure, cyclodextrin nanosponges with different structures can be prepared by controlling the molar ratio of cyclodextrin / cyclodextrin derivatives to covalent crosslinking agents. For example, when the molar ratio of cyclodextrin / cyclodextrin derivatives to covalent crosslinking agents is 1:2, the cyclodextrin nanosponges structure is mainly clustered; when the molar ratio is 1:4, the cyclodextrin nanosponges structure is mainly sheet-like or strip-like; when the molar ratio is 1:6, the cyclodextrin nanosponges structure is mostly a porous continuous phase; and when the molar ratio is 1:8, the cyclodextrin nanosponges structure is mostly hemispherical aggregates.

[0040] According to embodiments of this disclosure, in an oral environment of 36.3°C to 37.2°C and pH 6.6 to 7.1: the nicotine salt release rate in the nicotine release agent is more than 50% within 5 minutes; the nicotine salt dissolution rate in the nicotine release agent is more than 40% within 5 minutes. This release characteristic ensures that the nicotine salt can be released quickly and absorbed by the mucosa in the initial stage of oral contact, significantly shortening the user's waiting time and effectively satisfying the user's immediate satisfaction and experience.

[0041] According to another aspect of this disclosure, a method for preparing a nicotine release agent for oral smoking is provided, comprising: melting a covalent crosslinking agent, adding a cyclodextrin / cyclodextrin derivative solution, and obtaining a cyclodextrin nanosponge after a crosslinking reaction, wherein the molar ratio of cyclodextrin / cyclodextrin derivative to covalent crosslinking agent is 1:1 to 8; dispersing the cyclodextrin nanosponge in a nicotine salt solution and stirring to obtain a nicotine composition, wherein the mass ratio of the cyclodextrin nanosponge to the nicotine salt is 1 to 5:1.

[0042] According to some specific embodiments of this disclosure, the molar ratio of cyclodextrin / cyclodextrin derivative to covalent crosslinking agent is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, etc. If the proportion of crosslinking agent is too low (e.g., less than 1:1), there will be too few crosslinking points, making it difficult to form a stable three-dimensional network structure of nanosponges. If the proportion of crosslinking agent is too high (e.g., greater than 1:8), the network structure will be too dense, and the porosity will decrease significantly, thereby affecting the specific surface area and pore volume of the cyclodextrin nanosponges. By adjusting the molar ratio of cyclodextrin / cyclodextrin derivative to covalent crosslinking agent within this range, the particle size, pore size distribution, and specific surface area of ​​the nanosponges can be effectively controlled, thereby achieving precise control over their nicotine loading capacity and release kinetics.

[0043] According to some specific embodiments of this disclosure, the mass ratio of cyclodextrin nanosponges to nicotine salts is 1:1, 2:1, 3:1, 4:1, 5:1, etc. In practical applications, the mass ratio of cyclodextrin nanosponges to nicotine salts can be flexibly adjusted according to specific needs (such as target nicotine content, desired release curve, etc.) to adjust the loading of nicotine salts, so as to adapt to the different requirements of different oral tobacco products for nicotine delivery rate and duration.

[0044] According to embodiments of this disclosure, by adjusting the molar ratio of cyclodextrin / cyclodextrin derivatives to covalent crosslinking agents, and the mass ratio of cyclodextrin nanosponges to nicotine salts, the crosslinking density and nicotine loading ratio of the nanosponges can be effectively controlled, thereby enabling the design of nicotine release rate and nicotine salt loading. The melt crosslinking and solution stirring process employed in this method is simple, the reaction conditions are mild, no complex equipment is required, and it possesses good reproducibility and scalability potential, providing a controllable and easily industrialized technical path for the development of oral tobacco products.

[0045] According to embodiments of this disclosure, the preparation method further includes: after stirring the reaction, freezing at -70 to -90°C for 8 to 12 hours, and then freeze-drying to obtain the nicotine release agent. For example, it can be frozen overnight at -80°C.

[0046] This low-temperature freezing step can effectively fix the distribution of nicotine salt in the porous structure of the nano-sponge, so that the nicotine salt and nano-sponge can be combined and solidified by quickly removing moisture through the freeze-drying process, inhibiting the migration or precipitation of nicotine salt with the medium, thereby improving the stability of the nicotine release agent during storage and use.

[0047] According to embodiments of this disclosure, the crosslinking reaction time is 3-6 hours, for example, 3 hours, 4 hours, 5 hours, 6 hours, etc. The stirring reaction time is 0.5-2 hours, for example, 0.5 hours, 1 hour, 1.5 hours, 2 hours, etc., achieving synergistic optimization of the stability of the cyclodextrin nanosponge structure and the nicotinic salt loading efficiency. Sufficient crosslinking time constructs a three-dimensional porous framework with ideal pore size, providing a stable embedding space for nicotinic salt; appropriate stirring reaction time ensures the uniform distribution of nicotinic salt in the pores.

[0048] According to another embodiment of this disclosure, a mouthwash is provided, comprising the above-mentioned nicotine release agent and mouthwash excipients, wherein the amount of nicotine release agent added to the mouthwash is 28.57% to 40%.

[0049] According to this disclosure, the oral cigarette, by introducing the nicotine release agent of this disclosure, exhibits a synergistic release mechanism of "rapid surface desorption" and "continuous skeletal diffusion" in the oral cavity environment. Nicotine dissolution can reach over 40% within 5 minutes and tends to stabilize after 30 minutes, meeting the needs of oral cigarettes for rapid onset and sustained effect. In terms of stability, its cross-linked three-dimensional network structure effectively resists interference from excipients and other additives, maintaining a stable release curve. Furthermore, by controlling the amount of nicotine release agent added to the oral cigarette, the nicotine content in the oral cigarette product can be adjusted to meet the differentiated needs of different consumers.

[0050] According to embodiments of this disclosure, the oral tobacco excipient includes at least one of sodium bicarbonate and citric acid; the mass ratio of the oral tobacco excipient to the nicotine salt in the nicotine release agent is ≤8.7%. The three-dimensional cross-linked network structure provided by the cyclodextrin nanosponges in the nicotine release agent can effectively block the interference of the excipient on the nicotine salt release behavior, significantly improving the stability of the nicotine release agent in complex formulation systems, thereby ensuring the nicotine release rate and dissolution degree.

[0051] To make the objectives, technical solutions, and advantages of this disclosure clearer, the following detailed description is provided in conjunction with specific embodiments. Unless otherwise specified, all methods described in the embodiments are conventional and can be performed according to the techniques or conditions described in the literature or the product manual.

[0052] Example 1

[0053] This disclosure provides a nicotine release agent, which is prepared by the following method.

[0054] Preparation of cyclodextrin nanosponges: 1.0625 g of diphenyl carbonate (DPC) was melted at 90 °C, and 5 g of β-cyclodextrin (β-CD) (the molar ratio of β-CD to DPC was 1:1) was added. The reaction was carried out for 5 h. After the reaction was completed, the nanosponges were washed with ultrapure water and extracted with acetone to remove unreacted DPC and β-CD, yielding a purified product. The purified product was dried at 60 °C for 24 h to prepare four different molar ratios of β-cyclodextrin and diphenyl carbonate, denoted as DPC-CDNS-1:1, and stored in sealed containers at room temperature for later use.

[0055] Nicotine salt loading: Cyclodextrin nanosponges DPC-CDNS (1:1) (40 mg / mL) were dispersed in a solution containing tartrate nicotine salt (NHT), with a mass ratio of cyclodextrin nanosponges to NHT of 2:1. The reaction was carried out at ambient temperature with stirring at 600 rpm for 1 hour to finally prepare the nicotine release agent, denoted as DPC-CDNS(1:1)-NHT(2:1).

[0056] Example 2

[0057] Example 2 of this disclosure provides a nicotine release agent. The difference between the preparation method of the nicotine release agent and that of Example 1 is that in the preparation of the cyclodextrin nanosponges, 2.126 g of DPC is melted at 90°C and then 5 g of β-CD (the molar ratio of β-CD to DPC is 1:2) is added to prepare the cyclodextrin nanosponges, which are denoted as DPC-CDNS (1:2).

[0058] The final nicotine release agent was prepared and denoted as DPC-CDNS(1:2)-NHT(2:1).

[0059] Example 3

[0060] Example 3 of this disclosure provides a nicotine release agent. The difference between the preparation method of the nicotine release agent and that of Example 1 is that in the preparation of the cyclodextrin nanosponges, 4.251 g of DPC is melted at 90°C and then 5 g of β-CD (the molar ratio of β-CD to DPC is 1:4) is added to prepare the cyclodextrin nanosponges, which are denoted as DPC-CDNS (1:4).

[0061] The final nicotine release agent was prepared and denoted as DPC-CDNS(1:4)-NHT(2:1).

[0062] Example 4

[0063] Example 4 of this disclosure provides a nicotine release agent. The difference between the preparation method of the nicotine release agent and that of Example 1 is that in the preparation of the cyclodextrin nanosponges, 6.375 g of DPC is melted at 90°C and 5 g of β-CD (the molar ratio of β-CD to DPC is 1:6) is added to prepare the cyclodextrin nanosponges, which are denoted as DPC-CDNS (1:6).

[0064] The final nicotine release agent was prepared and denoted as DPC-CDNS(1:6)-NHT(2:1).

[0065] Example 5

[0066] Example 5 of this disclosure provides a nicotine release agent. The difference between the preparation method of the nicotine release agent and that of Example 1 is that in the preparation of the cyclodextrin nanosponges, 17.004 g of DPC is melted at 90°C and 5 g of β-CD (the molar ratio of β-CD to DPC is 1:8) is added to prepare the cyclodextrin nanosponges, which are denoted as DPC-CDNS (1:8).

[0067] The final nicotine release agent was prepared and denoted as DPC-CDNS(1:8)-NHT(2:1).

[0068] The structures of cyclodextrin nanosponges prepared by different molar ratios of β-cyclodextrin and diphenyl carbonate in Examples 1 to 5 were characterized respectively.

[0069] Figure 1 The images show the infrared spectra of cyclodextrin nanosponges prepared with different molar ratios of β-cyclodextrin and diphenyl carbonate in the embodiments of this disclosure, as well as the infrared spectra of β-cyclodextrin and diphenyl carbonate.

[0070] like Figure 1 As shown, cyclodextrin nanosponges prepared with β-CD and DPC at different molar ratios, and DPC and β-CD in the 4000-1000 cm⁻¹ range were compared. -1The functional group absorption peaks in the wavenumber range revealed that the cyclodextrin nanosponge retained the characteristic peaks of hydroxyl (-OH), carbon-hydrogen bond (-CH), and ether bond (COC) of β-CD, and also introduced the characteristic peak of carbonyl (C=O) of DPC, indicating that β-cyclodextrin and diphenyl carbonate in a 1:(1~8) molar ratio can be successfully crosslinked to form the prepared cyclodextrin nanosponge.

[0071] Figure 2 The particle size distribution diagram shows the cyclodextrin nanosponges prepared by different molar ratios of β-cyclodextrin and diphenyl carbonate in the embodiments of this disclosure.

[0072] like Figure 2 As shown, the particle size of cyclodextrin nanosponges prepared with different β-CD and DPC molar ratios was determined by zeta-size. It was found that as the molar ratio of β-CD to DPC changed from 1:1 to 1:8, the particle size also increased from 78.8 nm to 619.6 nm, indicating that the increase of DPC content will increase the particle size of the prepared DPC-CDNS.

[0073] Figure 3 Cyclodextrin nanosponges prepared with different molar ratios of β-cyclodextrin and diphenyl carbonate, and atomic force microscopy images of β-cyclodextrin.

[0074] like Figure 3 As shown, compared with β-CD, the particle size of cyclodextrin nanosponges is significantly increased. As the molar ratio of β-CD to DPC changes from 1:1 to 1:8, the microstructure of cyclodextrin nanosponges also changes from discrete and uniform spherical (1:1) to gradually agglomerate, forming plate-like / strip-like (1:4), porous continuous phase (1:6), and finally becoming a larger hemispherical aggregate (1:8).

[0075] Based on data from infrared spectroscopy, particle size analysis, and atomic force microscopy, cyclodextrin nanosponges DPC-CDNS (1:4) with a particle size of approximately 400 nm were selected for further testing and characterization.

[0076] Figure 4 This is a photograph of the cyclodextrin nanosponges in Embodiment 3 of this disclosure.

[0077] like Figure 4 As shown, the cyclodextrin nano-sponge DPC-CDNS (1:4) is a white powder.

[0078] Figure 5 This is a test graph showing the specific surface area and pore size distribution of the cyclodextrin nanosponges in Example 3 of this disclosure.

[0079] Figure 6 This is a test graph showing the specific surface area and pore size distribution of β-cyclodextrin.

[0080] Table 1 compares the specific surface area and pore volume size data of β-CD and DPC-CDNS (1:4).

[0081] Table 1

[0082]

[0083] like Figure 5 , Figure 6 As shown in Table 1, BET surface area measurements were performed on the cyclodextrin nanosponges DPC-CDNS (1:4) and β-CD, respectively. It was found that in the region of higher relative pressure (P / P0>0.9), the adsorption capacity of DPC-CDNS (1:4) showed a sharp upward trend, indicating the presence of a pore structure formed by the aggregation of macropores or mesopores. The adsorption capacity of β-CD was significantly lower than that of DPC-CDNS (1:4), indicating a smaller specific surface area and pore volume. Further BJH (Barrett-Joyner-Halenda) pore size distribution curves showed that the pore size distribution of DPC-CDNS (1:4) had obvious peaks in the mesoporous range (2~50 nm), indicating a relatively concentrated mesoporous structure, which is one of the reasons for its high adsorption capacity. In contrast, the pore size distribution of β-CD not only had low peaks but also a narrow distribution range and a smaller pore volume, directly resulting in its lower adsorption capacity compared to the cyclodextrin nanosponges.

[0084] Furthermore, the loading of nicotine salts in Examples 1 to 5 was analyzed.

[0085] Figure 7 The images show the ultraviolet absorption spectra of the nicotine release agents and tartrate nicotine salts in Examples 1-5 of this disclosure.

[0086] like Figure 7 As shown, the characteristic absorption peak of tartrate nicotine salt was measured at 259 nm by UV-Vis spectrophotometer. The nicotine release agents in Examples 1-5 also showed this characteristic absorption peak at 259 nm, indicating that tartrate nicotine salt has been successfully loaded onto cyclodextrin nanosponges.

[0087] Figure 8 The infrared spectra of the nicotine release agent, cyclodextrin nanosponges, and tartrate nicotine salt in Example 3 of this disclosure are shown.

[0088] like Figure 8As shown, the cyclodextrin nanosponges (DPC-CDNS(1:4)), tartrate nicotinic acid salt (NHT), and nicotine release agents (DPC-CDNS(1:4)-NHT(2:1)) were characterized by infrared spectroscopy. The functional group absorption characteristics in the wavenumber range of 4000-1000 cm⁻¹ were compared. It was found that the nicotine release agent retained the characteristic peaks of the cyclodextrin nanosponges (such as -OH peak, COC stretching vibration peak, etc.) and also had the characteristic peaks of NHT (such as CC / CN stretching vibration peak, etc.). This further shows that tartrate nicotinic acid salt has been successfully loaded onto the cyclodextrin nanosponges, verifying the effective construction of the nicotine release agent.

[0089] A standard curve of tartrate nicotinic acid salt at 259 nm was plotted to quantitatively calculate the loading efficiency of tartrate nicotinic acid salt on cyclodextrin nanosponges.

[0090] Figure 9 Standard curves for different concentrations of tartrate nicotine salt at 259 nm.

[0091] By scanning the absorption spectra of tartrate nicotine salt-loaded cyclodextrin nanosponges before and after, and based on Figure 9 The standard curves shown were used to calculate the nicotine salt loading efficiency of β-CD and the nicotine release agents of Examples 1 to 5. Table 2 lists the nicotine salt loading efficiency of the nicotine release agents in Examples 1 to 5 of this disclosure.

[0092] Table 2

[0093]

[0094] As shown in Table 2, when the mass ratio of cyclodextrin nanosponges to tartrate nicotine salt was 2:1, the loading efficiency of tartrate nicotine salt increased from 55.1±0.6% to 76.9±6.4% by adjusting the molar ratio of β-CD to DPC (1∶1~1∶8). This indicates that different loading rates of nicotine salt can be achieved by changing the molar ratio of the crosslinking agent DPC, with DPC-CDNS (1:4) showing the highest nicotine salt loading efficiency. However, when the mass ratio of β-CD to NHT was 2∶1, the loading efficiency of nicotine salt was only 47.0±3.6%, significantly lower than that of the cyclodextrin nanosponges. This is presumably because the cyclodextrin nanosponges are porous three-dimensional network structures formed by cyclodextrin through a crosslinking agent, possessing a higher specific surface area and pore volume, thus providing more nicotine salt embedding sites.

[0095] Example 6

[0096] This disclosure provides a nicotine release agent in Example 6. The preparation method of this nicotine release agent differs from that of Example 3 in that the mass ratio of cyclodextrin nanosponges to NHT is 0.5:1.

[0097] The final nicotine release agent was prepared and denoted as DPC-CDNS(1:4)-NHT(0.5:1).

[0098] Example 7

[0099] This disclosure provides a nicotine release agent in Example 7. The preparation method of this nicotine release agent differs from that of Example 3 in that the mass ratio of cyclodextrin nanosponges to NHT is 1:1.

[0100] The final nicotine release agent was prepared and denoted as DPC-CDNS(1:4)-NHT(1:1).

[0101] Example 8

[0102] This disclosure provides a nicotine release agent in Example 8. The preparation method of this nicotine release agent differs from that of Example 3 in that the mass ratio of cyclodextrin nanosponges to NHT is 2.5:1.

[0103] The final nicotine release agent was prepared and denoted as DPC-CDNS(1:4)-NHT(2.5:1).

[0104] Example 9

[0105] Example 9 of this disclosure provides a nicotine release agent. The preparation method of this nicotine release agent differs from that of Example 3 in that the mass ratio of cyclodextrin nanosponges to NHT is 4:1.

[0106] The final nicotine release agent was prepared and denoted as DPC-CDNS(1:4)-NHT(4:1).

[0107] The interaction between NHT and cyclodextrin nanosponges DPC-CDNS-1:4 in Examples 6-9 was evaluated using the continuous variation method.

[0108] Figure 10 The diagram shows the interaction between cyclodextrin nanosponges DPC-CDNS-1:4 and tartrate nicotine salt at different mass ratios in Examples 6 to 9.

[0109] like Figure 10 As shown, the strongest interaction occurs when the mass ratio of cyclodextrin nanosponges DPC-CDNS (1:4) to NHT is 2.5. This indicates that in Example 7, when the mass ratio of cyclodextrin nanosponges DPC-CDNS (1:4) to NHT is 2.5, nicotinic salt and cyclodextrin nanosponges form a stable host-guest complex. This represents a well-matched state between nicotinic salt and cyclodextrin nanosponges under the combined influence of geometric dimensions, chemical properties, and environmental conditions, rather than random physical adsorption.

[0110] Figure 11 This is a physical image of the nicotine-releasing agent in Example 7 of this disclosure.

[0111] like Figure 11 As shown, the nicotine-releasing agent in Example 7 is still white, compared to the actual image of the cyclodextrin nanosponges DPC-CDNS-1:4 ( Figure 4 Regarding nicotine, its appearance changes slightly with the addition of nicotine loading. Figure 4 It appears as a fine white powder overall, while from Figure 11 As can be seen, the product is a slightly coarse white granular substance.

[0112] Example 10

[0113] This disclosure provides a nicotine release agent in Example 10. The preparation method of this nicotine release agent differs from that of Example 8 in that: in the preparation of the cyclodextrin nanosponges, 1.0625 g of DPC is melted at 90°C, and then 5 g of β-CD (the molar ratio of β-CD to DPC is 1:1) is added to prepare the cyclodextrin nanosponges, denoted as DPC-CDNS (1:1).

[0114] The final nicotine release agent was prepared and denoted as DPC-CDNS(1:1)-NHT(2.5:1).

[0115] Example 11

[0116] This disclosure provides a nicotine release agent in Example 11. The preparation method of this nicotine release agent differs from that of Example 8 in that: in the preparation of the cyclodextrin nanosponges, 2.126 g of DPC is melted at 90°C, and then 5 g of β-CD (the molar ratio of β-CD to DPC is 1:2) is added to prepare the cyclodextrin nanosponges, denoted as DPC-CDNS (1:2).

[0117] The final nicotine release agent was prepared and denoted as DPC-CDNS(1:2)-NHT(2.5:1).

[0118] Example 12

[0119] This disclosure provides a nicotine release agent in Example 12. The preparation method of this nicotine release agent differs from that of Example 8 in that: in the preparation of the cyclodextrin nanosponges, 6.375 g of DPC is melted at 90°C, and then 5 g of β-CD (the molar ratio of β-CD to DPC is 1:6) is added to prepare the cyclodextrin nanosponges, denoted as DPC-CDNS (1:6).

[0120] The final nicotine release agent was prepared and denoted as DPC-CDNS(1:6)-NHT(2.5:1).

[0121] Example 13

[0122] This disclosure provides a nicotine release agent in Example 13. The preparation method of this nicotine release agent differs from that of Example 8 in that: in the preparation of the cyclodextrin nanosponges, 17.004 g of DPC is melted at 90°C, and then 5 g of β-CD (the molar ratio of β-CD to DPC is 1:8) is added to prepare the cyclodextrin nanosponges, denoted as DPC-CDNS (1:8).

[0123] The final nicotine release agent was prepared and denoted as DPC-CDNS(1:8)-NHT(2.5:1).

[0124] Comparative Example 1

[0125] Comparative Example 1 of this disclosure provides a nicotine release agent, the preparation method of which includes: dispersing β-CD in a solution containing NHT, wherein the mass ratio of β-CD to NHT is 2.5:1. The reaction is carried out at ambient temperature with stirring at 600 rpm for 1 hour to finally obtain the nicotine release agent, denoted as β-CD-NHT.

[0126] The nicotine release performance of the nicotine release agents in Examples 8, 10-13 and Comparative Example 1 of this disclosure was analyzed under simulated human oral environment (37°C, artificial saliva). The specific test methods are as follows.

[0127] First, prepare artificial saliva: Weigh out potassium dihydrogen phosphate (0.225 g), sodium chloride (0.165 g), potassium chloride (0.375 g), potassium carbonate (0.265 g), calcium chloride dihydrate (0.0075 g), and magnesium chloride hexahydrate (0.085 g), dissolve them in water, then adjust the pH to 6.86 and dilute to volume in a 500 mL volumetric flask.

[0128] Then, the nicotine release agent was placed in a simulated human oral environment (37℃, artificial saliva) to investigate its nicotine release performance. Samples were taken at 0 minutes, 1 minute, 3 minutes, 5 minutes, 7 minutes, 10 minutes, 15 minutes, and 30 minutes, and the same volume of artificial saliva was added simultaneously. The degree of dissolution could be calculated by measuring the absorbance values ​​of the samples taken at different time points and substituting them into the following release formula (Ⅰ).

[0129] (I)

[0130] Among them, V e : Volume of artificial saliva replacement (mL);

[0131] V0: Total volume of the released medium (mL);

[0132] C i : Solution concentration (mL) at the i-th displacement sampling;

[0133] m drug Total mass of drug carried by nanoparticles (mg);

[0134] n: Number of times artificial saliva is replaced;

[0135] E r Dissolution rate (%)

[0136] Figure 12 The figures show the release performance curves of the nicotine release agents in Examples 8, 10-13, and Comparative Example 1 of this disclosure. Specifically, A is a dissolution curve of cyclodextrin nanosponges-nicotine salt within 30 minutes; B is a dissolution curve of cyclodextrin nanosponges-nicotine salt within 5 minutes.

[0137] like Figure 12 As shown, the nicotine-releasing agents in Examples 8, 10-13, and Comparative Example 1 of this disclosure all exhibit a rapid release trend, and the degree of dissolution tends to stabilize after 30 minutes. Meanwhile, from... Figure 12 In B, it was found that the nicotine release rate and dissolution rate of the nicotine release agent in Examples 8 and 10-13 were significantly higher than those of the nicotine release agent in Comparative Example 1 within 5 minutes, and the dissolution rate could reach 40% to 80% within 5 minutes.

[0138] Based on the above analysis, the reason why the nicotine release rate and dissolution degree of the nicotine release agent in this embodiment are higher than those in the comparative example is that the specific surface area and pore volume of the cyclodextrin nanosponges are significantly higher than those of cyclodextrin, thus the cyclodextrin nanosponges have a relatively large drug loading capacity. Nicotine salts, as hydrophilic drugs, can be encapsulated in the cyclodextrin nanosponges, and some nicotine salts are also loaded on the cyclodextrin nanosponges in the form of "surface adsorption." This portion can be rapidly desorbed upon contact with artificial saliva, and then the nicotine salts in the cyclodextrin nanosponges framework are slowly replenished, resulting in a dissolution degree of 40%~80% within 5 minutes. Furthermore, the release efficiency and dissolution degree of nicotine release agents prepared with different β-CD to DPC molar ratios are different, indicating that changing the DPC content can affect the pore structure and the number of binding sites of the cyclodextrin nanosponges, thereby affecting the nicotine release performance of the nicotine release agent. Compared with nicotine release agents prepared with β-CD to DPC molar ratios of 1:1, 1:2, 1:6, and 1:8, the nicotine release agent prepared with a β-CD to DPC molar ratio of 1:4 exhibits significantly higher nicotine release rate and dissolution degree.

[0139] In addition, to investigate the effects of oral tobacco product excipients such as sodium bicarbonate (Na2CO3) and citric acid (CA) on the stability of the nicotine release agent in the embodiments of this disclosure, the nicotine release performance of the nicotine release agent in the presence of sodium bicarbonate and citric acid was tested.

[0140] In a simulated oral environment (37°C, artificial saliva), the nicotine release performance of 20 mg Example 8 (DPC-CDNS (1:4)-NHT (2.5:1)) and 20 mg Comparative Example 1 (β-CD-NHT) with added excipients (26 mg sodium bicarbonate and 20 mg citric acid) was investigated. Samples were taken at 0, 1, 3, 5, 7, 10, 15, and 30 minutes, and the same volume of artificial saliva was added simultaneously. The absorbance values ​​of the samples taken at different time points were measured and substituted into the release formula (I) to calculate the degree of dissolution, thereby analyzing the effect of oral tobacco excipients on the nicotine salt release performance of nicotine release agents.

[0141] Figure 13 The graphs show the nicotine release performance of the nicotine release agents of Example 8 and Comparative Example 1, as well as the nicotine release agents with added sodium bicarbonate and citric acid.

[0142] like Figure 13 As shown, for the nicotine release agent in Comparative Example 1 (β-CD-NHT+Na2CO3+CA) with added sodium bicarbonate and citric acid, both the nicotine release rate and dissolution rate decreased. However, for the nicotine release agent in Example 8 (DPC-CDNS(1:4)-NHT(2.5:1)+Na2CO3+CA) with added sodium bicarbonate and citric acid, the addition of sodium bicarbonate and citric acid had virtually no effect on the nicotine release rate and dissolution rate, indicating that the nicotine release agent obtained by loading nicotine salts onto cyclodextrin nanosponges has good stability. This may be because, in the formation of the cyclodextrin nanosponges, crosslinking agents such as carbodiimide are used to build a dense network of β-CD units. After nicotine salt molecules enter the pores, they are geometrically confined, reducing the diffusion coefficient and thus improving their stability. In addition, in practical applications, rapidly solidifying the nanostructure by freeze-drying after loading nicotine salts onto cyclodextrin nanosponges can further reduce the migration of nicotine salts and improve their stability.

[0143] In summary, the nicotine sustained-release agent disclosed herein achieves efficient loading (loading rate of over 55%) and controlled release of nicotine salts through the three-dimensional porous structure of cyclodextrin nanosponges. In a simulated oral environment, it exhibits a synergistic effect of rapid onset (release rate >50% within 5 minutes) and sustained release. Its cross-linked network structure provides excellent stability, maintaining unchanged release performance even in the presence of excipients such as sodium bicarbonate / citric acid. Oral cigarette products using this release agent combine rapid gratification with sustained-release properties, are adaptable to complex formulation environments, and support precise customization of release behavior through adjustments to process parameters, providing an innovative solution for performance upgrades and differentiated development of oral cigarette products.

[0144] The specific embodiments described above further illustrate the purpose, technical solutions, and beneficial effects of this disclosure. It should be understood that the above descriptions are merely specific embodiments of this disclosure and are not intended to limit this disclosure. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this disclosure should be included within the protection scope of this disclosure.

Claims

1. A nicotine release agent for oral smoking, characterized in that, The nicotine-releasing agent comprises a cyclodextrin nanosponge with a three-dimensional porous nanostructure and nicotine salts embedded in and / or adsorbed on the cyclodextrin nanosponge, wherein... The cyclodextrin nanosponges are formed by a cross-linking reaction between cyclodextrin / cyclodextrin derivatives and a covalent cross-linking agent.

2. The nicotine-releasing agent according to claim 1, characterized in that, The specific surface area of ​​the cyclodextrin nanosponges is 17~50 m²·g. -1 ; The pore volume is 11.5~45 cm³ / g.

3. The nicotine-releasing agent according to claim 1 or 2, characterized in that, The cyclodextrin includes any one of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin; The cyclodextrin derivatives include any one of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, and sulfobutyl ether-β-cyclodextrin; The covalent crosslinking agent includes any one of diphenyl carbonate, citric acid, epichlorohydrin, and glutaraldehyde; The nicotine salts include any one of tartrate nicotine salts, malic acid nicotine salts, citric acid nicotine salts, and lactic acid nicotine salts.

4. The nicotine-releasing agent according to claim 1, characterized in that, The cyclodextrin nanosponges include any one of the following structures: clustered, sheet-like, strip-like, porous continuous phase, or hemispherical aggregates.

5. The nicotine-releasing agent according to claim 1, characterized in that, In an oral environment of 36.3~37.2℃ and pH 6.6~7.1: The nicotine release agent contains nicotine salts with a release rate of over 50% within 5 minutes; The nicotine release agent has a nicotine salt dissolution rate of over 40% within 5 minutes.

6. A method for preparing a nicotine-releasing agent for oral smoking, characterized in that, The preparation method includes: After melting the covalent crosslinking agent, a cyclodextrin / cyclodextrin derivative solution is added, and a cyclodextrin nanosponges are obtained after a crosslinking reaction. The molar ratio of the cyclodextrin / cyclodextrin derivative to the covalent crosslinking agent is 1:1~8. The cyclodextrin nanosponges are dispersed in a nicotine salt solution and stirred to obtain a nicotine composition, wherein the mass ratio of the cyclodextrin nanosponges to the nicotine salt is 1~5:

1.

7. The preparation method according to claim 6, characterized in that, The cross-linking reaction takes 3-6 hours; The stirring reaction time is 0.5~2h.

8. The preparation method according to claim 6, characterized in that, It also includes, After stirring and reacting, the mixture is frozen at -70 to -90°C for 8 to 12 hours, and then freeze-dried to obtain the nicotine release agent.

9. A type of oral cigarette, characterized in that, The oral cigarette includes the nicotine-releasing agent and oral cigarette excipients as described in any one of claims 1 to 5, wherein the amount of the nicotine-releasing agent added to the oral cigarette is 28.57% to 40%.

10. The oral cigarette according to claim 9, characterized in that, The oral tobacco adjuvant includes at least one of sodium bicarbonate and citric acid; The mass ratio of the oral tobacco excipient to the nicotine salt in the nicotine release agent is ≤8.7%.

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