A controlled release, mouth pouch nicotine product and method of making same

Abstract

This invention discloses a controlled-release oral nicotine pouch product and its preparation method, belonging to the technical field of tobacco substitutes. The product consists of an outer breathable pouch and an inner functional core. The inner functional core contains a nicotine salt-cyclodextrin inclusion complex and additives. The inclusion complex is formed by the host-guest inclusion interaction of nicotine tartrate and cyclodextrin, with the cyclodextrin selected from β-cyclodextrin or hydroxypropyl-β-cyclodextrin. The additives include a filler matrix, a pH adjuster, and water. When the cyclodextrin is β-cyclodextrin, a sodium alginate-dominant filler matrix is ​​used to prepare a sustained-release product, with a nicotine release of no more than 50% within 15 minutes. When the cyclodextrin is hydroxypropyl-β-cyclodextrin, a xylitol-dominant filler matrix is ​​used to prepare an immediate-release product, with a nicotine release of no less than 60% within 15 minutes. This invention achieves precise control of nicotine release rate by selecting different cyclodextrins and adjusting the filling matrix, pH and moisture content without changing the type of nicotine salt. The preparation process is simple, reproducible and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of tobacco substitute technology, specifically, it relates to a controlled-release oral nicotine product and its preparation method. Background Technology

[0002] Smoking articles typically deliver nicotine to the user by burning tobacco. The combustion of tobacco creates or releases various substances associated with health risks. Therefore, existing technologies have proposed various forms of nicotine delivery that do not rely on tobacco combustion, including chewing gum, patches, sprays, lozenges, and oral nicotine products in pouches.

[0003] Oral nicotine products typically consist of an outer packaging made of a saliva-permeable material and contents encapsulated within the outer packaging. The contents generally include a nicotine source, a filler matrix, water, a pH adjuster, and other permitted excipients. During use, saliva penetrates the contents through the outer packaging, causing the nicotine source to dissolve, dissociate, and diffuse from the matrix outwards. The released nicotine further permeates through the oral mucosa.

[0004] For nicotine products packaged in oral pouches, the nicotine release rate, cumulative release amount, and oral mucosal penetration rate are crucial factors affecting nicotine delivery performance. If the nicotine release rate is too slow, effective nicotine delivery is difficult to achieve in the initial stages of use; if the release rate is too fast, a large amount of nicotine may be released in a short period, resulting in insufficient subsequent release. Therefore, it is desirable to obtain either immediate-release products with a faster initial release rate or sustained-release products with a longer duration of release, depending on the design requirements of different products.

[0005] The form in which nicotine exists significantly affects its stability, solubility, and release behavior. Free nicotine exhibits volatility and oxidation sensitivity, making it prone to loss or property changes during production and storage. To address these issues, current technologies typically convert nicotine into salts or bind, adsorb, encapsulate, or form non-covalent complexes with ion exchange resins, polysaccharides, cellulose, or other carriers, thereby transforming nicotine into a form more suitable for storage and processing.

[0006] Nicotine tartrates are relatively stable in solid form and easy to weigh and process, making them a suitable nicotine source for nicotine products packaged in sachets. However, the release of nicotine tartrates in aqueous environments depends not only on the amount added but also on factors such as salt dissolution and dissociation, local pH of the composition, moisture content, the properties of the filling matrix, and the diffusion rate of nicotine within the matrix. Therefore, different products using the same amount of nicotine tartrates may still exhibit different release and permeation curves.

[0007] For example, CN114390922A discloses a nicotine bag containing a nicotine source, a pH adjuster, and a filler. The nicotine source can be a nicotine salt or nicotine bound to an ion exchange resin, and the release is adjusted by limiting the solubility of the powder composition. CN115997965A discloses a nicotine-slow-release oral cigarette, which achieves slow release by compounding nicotine benzoate, nicotine tartrate, and nicotine alginate, utilizing the differences in release rates of different nicotine organic acid salts. CN116195764B discloses a solid nicotine-alginate and an oral cigarette containing this salt, to reduce the nicotine release rate and prolong the release time. CN113924004B discloses a nicotine pouch composition comprising sugar alcohol, water-insoluble fiber, 8% to 65% by weight of water, and nicotine, and points out that the content of sugar alcohol, fiber, and water can affect the density, processing properties, and release of water-soluble components of the composition. CN119699630A discloses a sustained-release oral product in which nicotine or nicotine salts are encapsulated in microcapsules, and nicotine release is controlled by water-soluble polyhydroxy compounds and moisture regulation.

[0008] The aforementioned existing technologies regulate nicotine release by adjusting the type of nicotine salt, combining different nicotine salts, using ion exchange resins, microencapsulation, moisture content, and filling matrix. However, these technologies typically rely on changing the type of nicotine salt, combining multiple nicotine sources, or controlling the filler and moisture content as primary methods. They have not yet sufficiently explored technical solutions for achieving differentiated release characteristics by utilizing different cyclodextrins to form inclusion complexes with nicotine tartrates while keeping the type of nicotine salt constant.

[0009] Cyclodextrins are a class of cyclic oligosaccharides with relatively hydrophobic cavities and hydrophilic outer surfaces, capable of forming inclusion complexes with suitable guest substances through non-covalent interactions such as hydrophobic interactions, van der Waals forces, and hydrogen bonds. Different cyclodextrins vary in cavity size, substituent structure, water solubility, and host-guest binding ability, which may result in different inclusion efficiencies, hydration rates, dissociation rates, and release characteristics for the same guest substance. β-Cyclodextrin, hydroxypropyl-β-cyclodextrin, and γ-cyclodextrin have different structures and physicochemical properties, and theoretically, they could produce different inclusion and release effects on nicotine tartrates.

[0010] However, current technology has not fully utilized the property differences between β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and γ-cyclodextrin to form inclusion complexes with these cyclodextrins, compare their release curves under the same conditions, and screen for inclusion complexes with relatively rapid-release and relatively sustained-release characteristics. Furthermore, there is a lack of systematic research on how the pH, moisture content, and filling matrix of the composition further affect nicotine release after the inclusion complexes are added to the nicotine bag.

[0011] The release of nicotine from the pouch matrix to the outside of the pouch does not equate to its ability to penetrate the oral mucosa at the same rate. Nicotine mucosal permeation is also affected by factors such as the pH of the release medium, the ionization state of nicotine, and the effective concentration. Therefore, it is insufficient to fully evaluate the delivery performance of a product based solely on the nicotine release amount at a single time point; it is necessary to combine in vitro release curves and permeation curves to compare different inclusion systems and formulation conditions.

[0012] In summary, there is an urgent need in this field to develop a nicotine tartrate cyclodextrin inclusion complex. By comparing the inclusion complexes formed by nicotine tartrate and different cyclodextrins, inclusion complexes with immediate-release and sustained-release characteristics can be screened. Furthermore, the effects of pH, moisture content, and filling matrix on its release and permeation behavior can be studied, so as to obtain nicotine delivery systems with different target release performance without changing the type of nicotine salt. Summary of the Invention

[0013] In view of the shortcomings of the prior art, the purpose of this invention is to provide a controlled-release oral nicotine pouch product and its preparation method, so as to solve the problem that the nicotine release rate in existing oral nicotine pouch products is difficult to control precisely.

[0014] To achieve the above-mentioned technical objectives, the inventors utilized different cyclodextrins (β-CD, HP-β-CD, γ-CD) to form inclusion complexes with the same guest molecule, nicotine tartrate (NHT). By taking advantage of the differences in the cavity size, water solubility, and other structural features of the different cyclodextrins, as well as the three key formulation factors of pH, moisture content, and filling matrix, the inventors achieved differentiated regulation of NHT release and permeation behavior.

[0015] Specifically, the objective of this invention is achieved as follows: a controllable release oral nicotine bag product, comprising an outer breathable bag and an inner functional core, wherein the inner functional core is prepared from a nicotine salt-cyclodextrin inclusion complex and additives;

[0016] The inclusion complex is formed by the host-guest inclusion interaction of cyclodextrin and nicotine tartrate.

[0017] The cyclodextrin is selected from one of β-cyclodextrin and hydroxypropyl-β-cyclodextrin;

[0018] The additives include a filler matrix, a pH adjuster, and water; the filler matrix is ​​a mixture of microcrystalline cellulose and sodium alginate, or a mixture of microcrystalline cellulose and xylitol.

[0019] When the cyclodextrin is β-cyclodextrin, the formulation of the internal functional core is as follows: 60 parts β-cyclodextrin-nicotine salt inclusion complex, 140-170 parts microcrystalline cellulose, 35-50 parts sodium alginate, a pH adjuster for adjusting the pH of the internal functional core to 8.2-8.8, and purified water for adjusting the water content of the internal functional core to 9-11%; thereby obtaining a sustained-release oral nicotine bag product.

[0020] When the cyclodextrin is hydroxypropyl-β-cyclodextrin, the formulation of the internal functional core is as follows: 108 parts HP-β-cyclodextrin-nicotine salt inclusion complex, 30-50 parts microcrystalline cellulose, 90-110 parts xylitol, a pH adjuster for adjusting the pH of the internal functional core to 8.2-8.8, and purified water for adjusting the water content of the internal functional core to 9-11%; thereby obtaining an immediate-release oral nicotine product in a sachet.

[0021] Definition of release rate:

[0022] In this invention, the sustained-release oral nicotine product refers to a product that, under artificial saliva release conditions, releases no more than 50% of the total nicotine content within 15 minutes and no more than 65% of the total nicotine content within 30 minutes, and continues to release nicotine within 30-60 minutes, exhibiting a fully released characteristic. When the total nicotine content within the bag is 2 mg, the sustained-release oral nicotine product releases no more than 1 mg of nicotine within 15 minutes, no more than 1.3 mg of nicotine within 30 minutes, and continues to release nicotine within 30-60 minutes.

[0023] In this invention, the immediate-release oral nicotine product refers to a product that, under artificial saliva release conditions, releases no less than 60% of the total nicotine content within 15 minutes and no less than 70% of the total nicotine content within 30 minutes. When the total nicotine content within the bag is 2 mg, the immediate-release oral nicotine product releases no less than 1.2 mg of nicotine within 15 minutes and no less than 1.4 mg of nicotine within 30 minutes.

[0024] More preferably, in the oral nicotine pouch product as described above, when the cyclodextrin is β-cyclodextrin, the formulation of the internal functional core is: 60 parts β-cyclodextrin-nicotine salt inclusion complex, 145-160 parts microcrystalline cellulose, 36-42 parts sodium alginate, a pH adjuster for adjusting the pH of the internal functional core to 8.4-8.6, and purified water for adjusting the water content of the internal functional core to 9-11%; thereby obtaining a sustained-release oral nicotine pouch product.

[0025] More preferably, in the oral nicotine sachet product as described above, when the cyclodextrin is hydroxypropyl-β-cyclodextrin, the formulation of the internal functional core is: 108 parts HP-β-cyclodextrin-nicotine salt inclusion complex, 40-46 parts microcrystalline cellulose, 95-105 parts xylitol, a pH adjuster for adjusting the pH of the internal functional core to 8.4-8.6, and purified water for adjusting the water content of the internal functional core to 9-11%; thereby obtaining an immediate-release oral nicotine sachet product.

[0026] More preferably, in the oral nicotine pouch product as described above, the pH adjuster is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium citrate, and potassium citrate.

[0027] More preferably, in the oral nicotine packaged product as described above, the additives further contain one or more of the following: humectant, flavoring agent, preservative, antioxidant, and anti-caking agent.

[0028] More preferably, in the oral nicotine packaged product as described above, the humectant is propylene glycol, glycerol, or sorbitol; the flavoring agent is flavoring, sucralose, acesulfame potassium, xylitol, or steviol glycosides; the preservative is potassium sorbate or sodium benzoate; the antioxidant is vitamin E or plant polyphenols; and the anti-caking agent is silicon dioxide or magnesium stearate.

[0029] More preferably, in the oral nicotine bag product described above, the material of the outer breathable bag body is food-grade breathable non-woven fabric.

[0030] In addition, the present invention also provides a method for preparing the above-mentioned oral nicotine bag product, the method comprising the following steps:

[0031] (1) Dissolve cyclodextrin in deionized water, heat to 55~65 ℃ to fully dissolve, and then cool to room temperature;

[0032] (2) Under stirring conditions, the prepared nicotine tartrate solution is slowly added dropwise to the cyclodextrin solution;

[0033] (3) Adjust the pH of the system to 7-11 with an alkaline solution and continue stirring to carry out the inclusion reaction;

[0034] (4) After the reaction is complete, adjust the pH of the system to 5.7-6.3 with an acid solution;

[0035] (5) After being refrigerated at 3~6 ℃ for 20~24 h, the inclusion complex was obtained by freeze drying;

[0036] (6) Mix the inclusion complex, the filling matrix and the pH adjuster evenly to obtain a powdered mixture;

[0037] (7) Adjust the moisture content of the powder mixture by adding purified water;

[0038] (8) Mix the mixture after adjusting the moisture content evenly, package it in a food-grade breathable non-woven bag and seal it to obtain oral nicotine products.

[0039] More preferably, in step (8), the pH of the system is adjusted to 9-11 using an alkaline solution.

[0040] More preferably, the stirring time for the inclusion reaction in step (8) is 2 to 6 hours, the stirring temperature is 25 to 65°C, and the stirring rate is 250 to 650 rpm·min. -1 .

[0041] Compared with the prior art, the oral nicotine pouch product and its preparation method provided by the present invention have the following advantages and advancements:

[0042] (1) It achieves "one salt for multiple uses" and obtains differentiated release without changing the type of nicotine salt. Existing technologies often require changing the type of nicotine salt (such as benzoate, tartrate, alginate, etc.) or compounding to change the release characteristics, which increases the complexity of the formulation and the difficulty of quality control. This invention can make the same nicotine tartrate exhibit completely different release behaviors simply by selecting different cyclodextrins (β-CD, HP-β-CD). That is, the β-CD-NHT inclusion complex combined with a specific filler matrix prepared a sustained-release nicotine product, which reached the maximum release in 11 minutes, with a smooth, continuous and complete release; the HP-β-CD-NHT inclusion complex combined with a specific filler matrix prepared an immediate-release nicotine product, which was fully released within 5 minutes. This strategy simplifies raw material management, reduces production complexity, and ensures the uniformity of nicotine source.

[0043] (2) The preparation process is mature and reliable, with good industrial applicability. The inclusion complex preparation method (solution stirring method + freeze drying) and nicotine bag assembly process used in this invention are both mature pharmaceutical / food industry technologies with low equipment requirements, simple operation, and easy scale-up. Orthogonal experiments were used to optimize and determine the optimal process parameters for each cyclodextrin system. The process verification results showed that the average inclusion rate of the β-CD-NHT inclusion complex was 71.45%, with an RSD of 3.11%; the average inclusion rate of the HP-β-CD-NHT inclusion complex was 54.05%, with an RSD of 3.02%. The processes of the two optimized systems showed good reproducibility and were suitable for industrial mass production. Attached Figure Description

[0044] Figure 1The figures show the in vitro release curves of the inclusion complexes; where a: cumulative release curve of β-CD-NHT inclusion complex; b: cumulative release curve of HP-β-CD-NHT inclusion complex; c: cumulative release curve of γ-CD-NHT inclusion complex; d: cumulative release curves of the three inclusion complexes.

[0045] Figure 2 The curves show the effects of pH, moisture content, and filler matrix on nicotine release; where a: β-CD-NHT; b: HP-β-CD-NHT; c: γ-CD-NHT.

[0046] Figure 3 The curves show the effects of cyclodextrin type and feed phase pH on nicotine permeation in vitro.

[0047] Figure 4 Examples 2-8: Nicotine sustained-release curves of oral nicotine pouches containing β-CD-NHT.

[0048] Figure 5 Example 9-5: Nicotine sustained-release curves of oral nicotine pouches containing HP-β-CD-NHT.

[0049] Figure 6 Examples 16-22: Nicotine sustained-release curves of oral nicotine pouches containing γ-CD-NHT. Detailed Implementation

[0050] The following examples further describe the implementation process and beneficial effects of the method of the present invention. The examples are for illustrative purposes only and do not limit the scope of protection of the present invention. At the same time, obvious changes made by those skilled in the art based on the examples are also included within the scope of the present invention.

[0051] Example 1: Optimization of cyclodextrin inclusion complexation process and the effect of key formulation factors on the release behavior of nicotine inclusion complexes.

[0052] 1. Method

[0053] 1.1 Materials and Instruments

[0054] Nicotine ditartrate dihydrate (NHT), β-CD, HP-β-CD, γ-CD, microcrystalline cellulose (MCC), xylitol, sodium alginate, sodium carbonate, sodium bicarbonate, sodium hydroxide, artificial saliva, physiological saline, non-woven bags; porcine oral mucosa.

[0055] The main instruments include a high-performance liquid chromatograph, a vacuum freeze dryer, a constant temperature magnetic stirrer, a heat sealing device, and a Franz diffusion cell.

[0056] 1.2 Preparation of NHT-cyclodextrin inclusion complex

[0057] Inclusion complexes were prepared using β-CD, HP-β-CD, and γ-CD as host molecules and NHT as guest molecules, respectively. A certain amount of cyclodextrin was added to deionized water and dissolved completely under heating conditions (55–65 °C). After cooling to room temperature, the solution was continuously stirred on a magnetic stirrer (350–450 rpm·min). -1 The NHT solution was slowly added dropwise to the cyclodextrin solution to ensure uniform dispersion of the guest molecules. Since the protonation state of nicotine in NHT is affected by pH, the deprotonation rate of nicotine increases under alkaline conditions, enhancing molecular hydrophobicity and facilitating host-guest inclusion with the hydrophobic cavities of cyclodextrin. Therefore, the pH of the system was adjusted to 7–11 using 1 mol / L NaOH solution, and stirring was continued under these conditions. After the reaction was complete, the pH was adjusted to 5.7–6.3 using 1 mol / L HCl solution to improve the stability of the solution. The resulting solution was refrigerated at 3–6 °C for 20–24 h, and then freeze-dried to obtain β-CD-NHT, HP-β-CD-NHT, and γ-CD-NHT inclusion complexes.

[0058] Simultaneously, corresponding physical mixtures were prepared. NHT and CDs were simply mixed according to the proportions used in the preparation of the inclusion complexes to obtain physical mixtures of β-CD-NHT, HP-β-CD-NHT, and γ-CD-NHT, respectively.

[0059] 1.3 Single-factor analysis

[0060] Using inclusion rate as the evaluation index, the effects of core-to-wall ratio, stirring time, stirring temperature, stirring rate, and pH of the inclusion solution on the inclusion rate of nicotine salt-cyclodextrin inclusion complex were investigated through preliminary experiments and literature review.

[0061] 1.3.1 Core-to-wall ratio

[0062] Following the preparation method in 1.2, the stirring time was 4 h, the stirring temperature was 55 ℃, and the stirring rate was 450 rmp·min. -1 The pH of the inclusion solution was 11, and the effects of the molar ratio of core material to wall material of 1:1, 1:2, 1:3, 1:4, and 1:5 on the inclusion rate of the inclusion compound were investigated.

[0063] 1.3.2 Stirring time

[0064] Following the preparation method in 1.2, the core-to-wall ratio was 1:3, the stirring temperature was 55℃, and the stirring rate was 450 rpm·min. -1The pH of the inclusion solution was 11, and the effects of stirring times of 2 h, 3 h, 4 h, 5 h, and 6 h on the inclusion rate of the inclusion compound were investigated.

[0065] 1.3.3 Stirring temperature

[0066] Following the preparation method in 1.2, the core-to-wall ratio was 1:3, the stirring time was 4 h, and the stirring rate was 450 rpm·min. -1 The pH of the inclusion solution was 11, and the effects of stirring temperatures of 25 ℃, 35 ℃, 45 ℃, 55 ℃, and 65 ℃ on the inclusion rate of the inclusion compound were investigated.

[0067] 1.3.4 Stirring speed

[0068] Following the preparation method in 1.2, with a core-to-wall ratio of 1:3, a stirring time of 4 hours, a stirring temperature of 55°C, and an inclusion solution pH of 11, the effects of a stirring speed of 250 rpm were investigated. -1 350 rmp·min -1 450 rmp·min -1 550 rmp·min -1 650 rmp·min -1 The effect on the inclusion rate of inclusion compounds.

[0069] 1.3.5 pH of inclusion solution

[0070] Following the preparation method in 1.2, the core-to-wall ratio was 1:3, the stirring time was 4 h, the stirring temperature was 55 ℃, and the stirring rate was 450 rmp·min. -1 The effects of inclusion solution pH values ​​of 7, 8, 9, 10, and 11 on the inclusion rate of the inclusion compound were investigated.

[0071] 1.4 Inclusion rate determination

[0072] High-performance liquid chromatography (HPLC) was used to determine the nicotine content in samples. A C18 column was used, with a flow rate of 1.0 mL / min, a column temperature of 40 ℃, an injection volume of 5 μL, and a detection wavelength of 259 nm. The mobile phase consisted of acetonitrile, triethylamine, ammonium acetate, and ultrapure water, with the pH adjusted to 6.0 using acetic acid solution. A series of standards with concentrations ranging from 12 to 384 μg / mL were prepared using nicotine isopropanol standard solution. A linear relationship between nicotine concentration and peak area was established, and the resulting standard curve was Y = 4653.7X + 95.388 (Figure 1), with a correlation coefficient R² = 0.9999, indicating that the method has good linearity.

[0073] The inclusion rate was calculated based on the actual measured nicotine content in the inclusion compound and the total amount of nicotine added during the preparation process. 30 mg of each of the three inclusion compounds were accurately weighed, dissolved, and filtered through a 0.45 μm filter membrane. The nicotine content was determined by high-performance liquid chromatography (HPLC). Each experiment was performed in triplicate, and the results were expressed as mean ± standard deviation. The encapsulation rate of the inclusion compounds was calculated using formula (1), where EE is the nicotine inclusion efficiency (%); M1 is the mass of the inclusion compound (mg); X is the nicotine content per milligram of the inclusion compound (mg / mg); and M2 is the mass of nicotine added during the reaction (mg).

[0074]

[0075] 1.5 Optimization of the encapsulation process

[0076] Based on previous single-factor experiments, the core-to-wall ratio (molar ratio), inclusion time, inclusion temperature, stirring rate, and inclusion pH were selected as the main factors to be investigated. Inclusion rate was used as the evaluation index, and orthogonal experiments were employed to optimize the preparation process of the CDs-NHT inclusion complex. Appropriate factor levels were set for different cyclodextrin systems based on their single-factor experimental results, and the influence of each factor on the inclusion rate was evaluated through range analysis and variance analysis.

[0077] 1.6 In vitro release experiment

[0078] NHT and CDs-NHT inclusion complexes were placed in non-woven bags of the same specifications and sealed (ensuring consistent nicotine content in all samples). The prepared samples were then placed in artificial saliva (pH 6.8–7.0) and subjected to in vitro release experiments at a water bath of 37.0 ± 0.1 °C. Samples were taken at set time points, and an equal volume of fresh artificial saliva was added simultaneously. After membrane treatment, the nicotine content of the sample solution was determined by high-performance liquid chromatography (HPLC). The cumulative release amount and cumulative release rate were calculated, and release curves were plotted. The nicotine content was determined using HPLC according to the aforementioned method, and the cumulative nicotine release amount was calculated and a release curve was plotted by substituting the values ​​into the standard equation.

[0079]

[0080] Among them, C nicotine C represents the cumulative release of nicotine. n and C i Where n and i are the nicotine concentrations, n and i are the sampling times, V0 is the initial solution volume, and V0 is the initial solution volume. E M0 represents the sampling volume, and M0 represents the initial mass of nicotine added.

[0081] 1.7 Influence of Key Formulation Factors on the Release Behavior of Nicotine Inclusion Complexes

[0082] To systematically investigate the effects of different process factors on the release behavior of nicotine active ingredients in nicotine inclusion complexes, this section of the experiment focuses on inclusion complex type, filler type, system pH, and moisture content as the main factors. A single-factor variable control method was used to evaluate the release performance of three inclusion complexes. Except for the target factor, all other preparation conditions were kept consistent across experimental groups to ensure that the experimental results objectively reflect the influence of a single factor on nicotine release behavior.

[0083] Each group was converted to contain 2 mg of nicotine free base equivalent per bag, and the amount of inclusion compound added was corrected according to the measured inclusion rate; the filling mass of a single bag was 250 mg. The inclusion compound, pH adjuster, purified water, and filling matrix were mixed evenly, packed into non-woven fabric bags, and heat-sealed. The pH adjuster was a mixture of sodium carbonate and sodium bicarbonate in a 1:1 mass ratio, and the target pH was obtained by adjusting its dosage. The MCC-type matrix was 100% MCC; the xylitol-dominant matrix had a xylitol to MCC mass ratio of 7:3; and the sodium alginate-dominant matrix had a sodium alginate to MCC mass ratio of 2:8. Experimental groups are shown in Table 1.

[0084] Table 1. Experimental Design of Factors Affecting Inclusion Compound Release

[0085]

[0086] 1.8 Inclusion Complex Simulated In Vitro Permeation Test

[0087] In vitro permeation experiments of the inclusion complex were conducted using a transdermal diffusion cell. Fresh pig heads were purchased from the local market. The inner buccal mucosa tissue was carefully separated, surface residues were removed, and the tissue was stored at -20 °C. Before the experiment, the pig oral mucosa was thawed naturally, cut to an appropriate size, and fixed between the supply and receiving chambers of the diffusion cell. During fixation, the epithelial layer of the mucosa faced the supply chamber, and the connective tissue surface faced the receiving chamber. The effective permeation area of ​​the diffusion cell was 3.14 cm², and the volume of the receiving chamber was 18 mL. The supply chamber, the pig oral mucosa, and the receiving chamber were tightly fixed with flange clamps to ensure a good membrane interface seal during the experiment.

[0088] Before the experiment, physiological saline was added to both the supply and receiving chambers, and the mixture was equilibrated at 37 ℃ for 1 hour to allow the porcine oral mucosa to reach equilibrium. After equilibration, both chambers were emptied. Based on the in vitro release experiment results, 5 mL of the release solution obtained at 15 min was added to the supply chamber for each sample, and physiological saline was added to the receiving chamber. The pH of the release solution in the supply chamber was measured before the experiment. To investigate the effect of pH on nicotine osmotic behavior, the pH of the release solution was adjusted to 8.5 and 9.5, respectively, with the unadjusted release solution serving as a control. During the experiment, a magnetic rotor was placed in the receiving chamber, and the rotation speed was 300 rpm·min. -1Continuous stirring was performed to maintain a uniform nicotine concentration in the receiving chamber. The in vitro permeation experiment was conducted at 37 °C for 2 h.

[0089] Samples of 200 μL were taken from the receiving chamber at 15, 30, 60, 90, and 120 min, and immediately replenished with an equal volume of fresh physiological saline preheated to 37 °C to maintain a constant volume in the receiving chamber. The nicotine content of the samples was determined using the HPLC method established in Chapter 2, and the nicotine concentration in the receiving chamber at each time point was calculated by substituting the values ​​into the standard curve. The cumulative nicotine permeability was further calculated using the formula.

[0090]

[0091] In the formula, P n M0 represents the cumulative nicotine permeation rate at the nth sampling time point; M0 represents the initial total amount of nicotine in the supply chamber at the start of the permeation experiment, in μg; C n V represents the nicotine concentration in the receiving chamber sample at the nth time point, in μg / mL. r V is the volume of the receiving chamber (18 mL); s A represents the volume of each sample taken (0.2 mL); A represents the effective osmotic area (3.14 cm²). 2 ); This represents the sum of nicotine concentrations in the receiving chamber samples at all time points prior to the nth sampling point.

[0092] 1.9 Statistical Analysis

[0093] Each experimental group was tested three times, and the results were recorded as mean ± standard deviation (SD). One-way ANOVA was used to test the significance of differences between groups. The significance level was set at p < 0.05. Plotting was performed using Origin 2025.

[0094] 2 Results and Discussion

[0095] 2.1 Inclusion rates of different cyclodextrin systems

[0096] After optimization through orthogonal experiments, the optimal preparation conditions for the β-CD-NHT inclusion complex were: molar ratio 1:3, inclusion temperature 35℃, and inclusion rotation speed 650 rpm·min. -1 The optimal preparation conditions for the HP-β-CD-NHT inclusion complex are: inclusion time 4 h, inclusion pH 10; molar ratio 1:5, inclusion temperature 65 ℃, and inclusion rotation speed 450 rmp·min. -1The optimal preparation conditions for the γ-CD-NHT inclusion complex are: inclusion time 4 h, inclusion pH 11; molar ratio 1:4, inclusion temperature 45℃, and inclusion rotation speed 450 rpm·min. -1 Inclusion time: 5 hours; Inclusion pH: 9.

[0097] For the β-CD-NHT inclusion complex, orthogonal experimental results showed that the molar ratio had the greatest impact on the inclusion rate, followed by inclusion time, stirring rate, inclusion temperature, and pH. Process validation revealed that the inclusion rates of the β-CD-NHT inclusion complex in three parallel trials were 73.46%, 69.06%, and 71.83%, with an average inclusion rate of 71.45% and an RSD of 3.11%. This indicates that β-CD and NHT can form a relatively stable inclusion system, and the preparation process has good reproducibility. The molar ratio is also a major factor affecting the inclusion rate of the HP-β-CD-NHT inclusion complex. Although the average inclusion rate of HP-β-CD-NHT is lower than that of β-CD-NHT and γ-CD-NHT, the fluctuation between parallel samples is small, indicating that the system has good process stability under optimized conditions. The average inclusion efficiency of the γ-CD-NHT inclusion complex reached 82.85%, higher than that of β-CD-NHT and HP-β-CD-NHT, indicating that the larger cavity size of γ-CD may provide more favorable spatial accommodation conditions for NHT molecules. However, its RSD was 5.98%, significantly higher than the other two inclusion complexes, suggesting that the γ-CD-NHT system may be more sensitive to preparation conditions and has relatively weak process reproducibility.

[0098] In summary, the type of cyclodextrin affects the inclusion efficiency and process stability of NHT. γ-CD-NHT exhibits the highest inclusion rate, possibly related to the larger cavity size of γ-CD; β-CD-NHT combines high inclusion rate with good repeatability; HP-β-CD-NHT has a relatively low inclusion rate but good process stability. These results indicate that the cavity size, water solubility, and structural flexibility of cyclodextrin collectively influence the inclusion behavior of NHT.

[0099] Table 2 Validation of Inclusion Process

[0100]

[0101] 2.2 Effect of Cyclodextrin Type on Nicotine Release

[0102] In vitro release experiments were conducted to compare the release behavior of NHT, CDs-NHT inclusion complexes, and their corresponding physical mixtures in artificial saliva at 37 °C. Preliminary experiments determined the total testing time to be 15 min, with sampling and testing at 2-min intervals. The endpoint of the curve in the figure represents the maximum release amount detected for each sample within 15 min and its corresponding time. Because an equal volume of fresh artificial saliva was replenished after sampling, the nicotine concentration in the subsequent medium gradually decreased due to dilution. Experimental results are as follows: Figure 1 As shown, all three cyclodextrin inclusion complexes altered the release process of NHT, but the different cyclodextrin systems exhibited significantly different release characteristics.

[0103] In the β-CD-NHT system ( Figure 1 a) The NHT feedstock was rapidly released within 1-5 min, reaching a release amount of 2.588 mg at 5 min. The β-CD-NHT physical mixture showed a gradual increase within 1-7 min, indicating that simple mixing can affect the NHT release process to some extent, but its essence is still mainly determined by the rapid dissolution of NHT and the dispersing effect of β-CD. In contrast, the β-CD-NHT inclusion complex released significantly more slowly, with its release amount gradually increasing from a lower level at 1 min, reaching a maximum release amount of 2.874 mg within the recorded time at 11 min. This result shows that β-CD inclusion not only improves the final release level but also delays the early release of NHT.

[0104] The HP-β-CD-NHT inclusion complex exhibited a faster release characteristic (Figure 1b). Its release reached 1.241 mg at 1 min and 2.904 mg at 5 min, showing a more complete release compared to NHT. The HP-β-CD-NHT physical mixture showed a slightly higher release in the early stages, indicating that the high water solubility of HP-β-CD promotes the rapid dispersion and dissolution of NHT in aqueous media; however, the final release of the inclusion complex was slightly higher than that of the physical mixture, indicating that the inclusion structure still contributes to improving the completeness of NHT release. HP-β-CD is a hydroxypropylated derivative of β-CD, and its high water solubility and strong hydration ability generally facilitate rapid wetting, dissolution, and dissociation of the inclusion complex in aqueous media. Therefore, HP-β-CD-NHT did not exhibit the significant delayed release characteristic of β-CD-NHT, but rather more closely resembled the characteristic of "rapid and relatively complete release". Similar studies have also pointed out that even if β-CD and HP-β-CD contain the same guest molecule, they may exhibit different release characteristics due to differences in water solubility and structural flexibility.

[0105] The release of the γ-CD-NHT inclusion complex was the most rapid.Figure 1 c) The release amount reached 2.358 mg at 1 min and 2.845 mg at 3 min, significantly faster than β-CD-NHT and HP-β-CD-NHT. The release amount of the γ-CD-NHT physical mixture was lower than that of the inclusion complex, indicating that the solid dispersion state and release properties of NHT were altered after γ-CD complexed with NHT.

[0106] Further comparison of the three inclusion compounds shows that ( Figure 1 d) The release rates generally followed the order: γ-CD-NHT > HP-β-CD-NHT > β-CD-NHT. γ-CD-NHT reached a high release level within 3 minutes, while HP-β-CD-NHT was fully released within 5 minutes, both exhibiting rapid release. β-CD-NHT, however, required 11 minutes to reach its maximum release level, demonstrating a relatively sustained-release characteristic. This difference suggests that the type of cyclodextrin plays a crucial regulatory role in NHT release behavior, and its mechanism may be related to cavity size, water solubility, inclusion stability, and the hydration / dissociation rate of the inclusion complex.

[0107] 2.3 Influence of Key Formulation Factors on Nicotine Release

[0108] Based on the comparative results of the release performance of different cyclodextrin inclusion complexes, this study further selected β-CD-NHT, HP-β-CD-NHT, and γ-CD-NHT as key formulation factors for investigation. The experiment used MCC-type filler matrix, pH 8.5, and 10% moisture content as baseline conditions to investigate the effects of pH, moisture content, and filler matrix on the release behavior of the three inclusion complexes.

[0109] 2.3.1 Effect of pH on nicotine release

[0110] Under conditions where the filling matrix was of type MCC and the moisture content was 10%, the release curves of the three inclusion complexes were compared at pH 7.5, 8.5, and 9.5. The β-CD-NHT system corresponded to groups B0, B3, and B4; the HP-β-CD-NHT system corresponded to groups F0, F3, and F4; and the γ-CD-NHT system corresponded to groups G0, G3, and G4.

[0111] Depend on Figure 2The results show that pH changes mainly affect the three inclusion systems in the early and middle stages of release, while the cumulative release amounts of each group tend to be similar in the later stages. For the β-CD-NHT system, the pH 7.5 group had a relatively high cumulative release amount in the early stage, while the pH 8.5 group had a slower initial release. As the release time increased, the curves of each group gradually approached each other, indicating that pH mainly affects the early release process of β-CD-NHT, and has a relatively limited impact on the final release amount. For the HP-β-CD-NHT system, the pH 9.5 group had the fastest initial release rate, followed by the pH 7.5 group, and the pH 8.5 group was relatively slow. However, after about 20 minutes, all groups gradually entered a plateau phase, and the differences between groups decreased significantly. For the γ-CD-NHT system, the three curves showed some overlap in the early stage of release: the pH 9.5 group had a relatively slow initial release, but the release rate accelerated subsequently, reaching a high cumulative release amount in the middle stage; the pH 7.5 group had a relatively fast initial release, but the increase was smaller in the later stage; by 60 minutes, the cumulative release amounts of each group were basically similar.

[0112] The above results indicate that the effect of pH on nicotine release is significantly cyclodextrin type-dependent, and the three inclusion systems did not exhibit a completely consistent monotonic trend. This may be because pH not only affects the dissociation of nicotine tartrate and the ionization state of nicotine, but may also alter the hydration, dissociation, and host-guest balance of the inclusion complex. Overall, pH has a more significant regulatory effect on the early release of HP-β-CD-NHT, while its effect on the final cumulative release of β-CD-NHT and γ-CD-NHT is relatively limited.

[0113] 2.3.2 Effect of Moisture Content on Nicotine Release

[0114] With all substrates being MCC type and pH 8.5, moisture contents of 5%, 10%, and 15% were set. Specifically, the β-CD-NHT system corresponds to groups B0, B5, and B6; the HP-β-CD-NHT system corresponds to groups F0, F5, and F6; and the γ-CD-NHT system corresponds to groups G0, G5, and G6.

[0115] All three inclusion systems showed an overall trend of accelerated nicotine release in the initial and middle stages of release with increasing moisture content. In the β-CD-NHT system, the 15% water group had a higher cumulative release in the early and middle stages of release, while the 5% water group released relatively slowly, and its cumulative release in the later stages was lower than that of the 10% and 15% water groups, indicating that increasing the moisture content can, to some extent, reduce the release delay of the β-CD-NHT system. In the HP-β-CD-NHT system, the 15% water group also showed a faster initial release rate, while the 5% water group released relatively slowly overall; as time progressed, the 10% and 15% water groups gradually reached similar plateau levels, while the final release of the 5% water group remained relatively low. In the γ-CD-NHT system, the 15% water group had a significantly higher cumulative release in the initial stages of release, but the three curves gradually converged in the later stages, indicating that moisture content mainly affected the early release rate of γ-CD-NHT and had a smaller impact on the final release level.

[0116] Higher initial moisture content may facilitate prewetting of the filler matrix, promote hydration and dissociation of inclusion complexes, and accelerate the diffusion of nicotine within the bag matrix. Under lower moisture conditions, the time required for the release medium to enter the matrix and form a continuous diffusion channel is longer, resulting in a certain release delay. Compared to HP-β-CD-NHT and γ-CD-NHT, β-CD-NHT exhibits a more pronounced sustained release characteristic under low moisture conditions, indicating that the moisture state has a more significant regulatory effect on the sustained-release system.

[0117] 2.3.3 Effect of Filler Matrix on Nicotine Release

[0118] Under conditions of pH 8.5 and moisture content of 10%, the filling matrices of MCC type, xylitol-dominant type, and sodium alginate-dominant type were compared. Among them, the β-CD-NHT system corresponds to groups B0, B1, and B2; the HP-β-CD-NHT system corresponds to groups F0, F1, and F2; and the γ-CD-NHT system corresponds to groups G0, G1, and G2.

[0119] The filler matrix significantly affected the release curves of all three inclusion systems. In the β-CD-NHT system, the xylitol-dominant matrix significantly accelerated nicotine release and reached the plateau phase earlier; the sodium alginate-dominant matrix released the slowest, with the release process lasting until about 60 minutes; the MCC-type matrix exhibited release characteristics intermediate between the two. The HP-β-CD-NHT system showed a similar pattern: the xylitol-dominant matrix reached a high release rate at the initial time point, the sodium alginate-dominant matrix showed a significant early release delay, and the MCC-type matrix was in between. In the γ-CD-NHT system, the xylitol-dominant matrix also promoted early release, while the sodium alginate-dominant matrix significantly reduced the initial release rate, but gradually caught up with time, and the cumulative release amounts of the three groups were basically similar by 50–60 minutes.

[0120] The aforementioned differences may be related to the solubility, water absorption, and hydration structure of the filling matrix. Xylitol is readily soluble in water, and its dissolution process can increase the matrix porosity and promote the penetration of the release medium, thereby accelerating the dissolution of inclusion complexes and nicotine diffusion. Sodium alginate swells after absorbing water and forms a viscous hydration layer, increasing the resistance to nicotine diffusion. MCC, as a water-insoluble porous framework, has a release-regulating effect that generally falls between the two. All three inclusion systems exhibit a general pattern of "xylitol-dominated type releasing faster, sodium alginate-dominated type releasing slower, and MCC type in between," indicating that the filling matrix has a more consistent regulatory direction on nicotine release compared to pH and water content.

[0121] 2.4 Effects of Cyclodextrin Type and Feed Phase pH on Nicotine In Vitro Permeation

[0122] Depend on Figure 3 It was found that during the 120 min period, the cumulative permeability of the β-CD-NHT, HP-β-CD-NHT, γ-CD-NHT, and unencapsulated nicotine tartrate (NHT) groups all increased continuously with time, indicating that nicotine can be continuously transferred to the receiving side through the porcine oral mucosa. Under different feed phase pH values, the permeation curves of each sample showed a relatively obvious separation trend, with the cumulative permeability being higher at pH 9.5 and relatively lower at pH 7.0, indicating that the feed phase pH is an important factor affecting nicotine permeation across the oral mucosa.

[0123] For the β-CD-NHT inclusion complex, the cumulative permeability of the pH 8.5 and pH 9.5 groups was generally higher than that of the pH 7.0 group. In the first 60 min of the experiment, the permeation rate of the pH 9.5 group was relatively faster, reaching approximately 47% cumulative permeability at 60 min; thereafter, the increase gradually decreased. The pH 8.5 group was slightly lower than the pH 9.5 group in the early stages, but continued to increase between 60 and 120 min, reaching approximately 53% for both groups at 120 min. In contrast, the pH 7.0 group maintained a lower cumulative permeability level throughout the experiment, reaching approximately 37% at 120 min. These results indicate that increasing the pH of the feed phase can promote the mucosal permeation of nicotine in the β-CD-NHT system, and the continuous increasing trend in the pH 8.5 group in the later stages may be related to the slow dissociation of β-CD-NHT and the sustained maintenance of the permeable nicotine concentration in the feed phase.

[0124] The HP-β-CD-NHT inclusion complex exhibited a relatively stable cumulative permeation process under all three pH conditions. The curves for pH 8.5 and pH 9.5 groups were quite similar within 15–90 min, both higher than that of the pH 7.0 group. By 120 min, the cumulative permeation rate was approximately 45% for the pH 9.5 group, approximately 41% for the pH 8.5 group, and approximately 35% for the pH 7.0 group. Compared to β-CD-NHT, the curves for HP-β-CD-NHT showed relatively less separation between different pH groups, indicating a more gradual response to pH changes during its permeation process. This may be related to the high hydrophilicity and water solubility of HP-β-CD, allowing the inclusion complex to hydrate and dissociate more quickly in the supply medium, thus reducing the limitation of the inclusion complex dissociation process on the subsequent permeation rate.

[0125] The γ-CD-NHT inclusion complex exhibited a relatively obvious staged permeation characteristic. The pH 9.5 group maintained a high cumulative permeation rate at all time points, approximately 31% and 41% at 30 min and 60 min, respectively, reaching approximately 46% at 120 min. The pH 8.5 group showed a certain permeation delay in the early stage of the experiment, with a lower cumulative permeation rate than the pH 7.0 group within 15–30 min; however, its cumulative permeation rate increased rapidly after 30 min, exceeding that of the pH 7.0 group at 90 min, and approaching that of the pH 9.5 group at 120 min. The pH 7.0 group showed a certain permeation rate in the early stage, but the increase significantly decreased after 90 min, eventually stabilizing at approximately 35%. This phenomenon suggests that under pH 8.5 conditions, there may be an asynchronous process between the dissociation of the γ-CD-NHT inclusion complex and the transmembrane transport of nicotine, resulting in its permeation characteristic of "delay in the early stage and increase in the later stage."

[0126] The non-inclusion NHT group exhibited a clear pH dependence. The cumulative permeability of the pH 9.5 group reached approximately 43% at 15 min, significantly higher than the pH 8.5 and pH 7.0 groups at the same time point, further increasing to approximately 59% by 120 min. The cumulative permeability of the pH 8.5 group increased steadily over time, reaching approximately 48% at 120 min; the pH 7.0 group had the lowest overall permeability, reaching approximately 40% at 120 min. Compared to the three inclusion complexes, the non-inclusion NHT exhibited a higher initial permeability level at pH 9.5, possibly because it does not require the host-guest inclusion complex dissociation process, allowing for faster formation of nicotine in a form favorable for transmembrane partitioning after the supply phase pH increases.

[0127] From the perspective of mechanism of action, the oral mucosal penetration of nicotine is closely related to its ionization state. As the pH of the feed phase increases, the proportion of unionized nicotine increases, and its lipid solubility and partitioning ability in the mucosa are correspondingly enhanced, thus facilitating its passage through the oral mucosa. Conversely, under lower pH conditions, nicotine mainly exists in a protonated form, limiting its transmembrane diffusion ability. Therefore, all samples generally exhibited higher cumulative permeability at pH 9.5, while the pH 7.0 group showed relatively lower rates.

[0128] Comprehensive comparison revealed that the pH of the feed phase determines the overall level of nicotine transmembrane permeation, while the type of cyclodextrin further influences the permeation curve. Unencapsulated NHT exhibited rapid initial permeation at high pH conditions; β-CD-NHT showed a more sustained permeation process at pH 8.5 and 9.5; HP-β-CD-NHT showed relatively gradual changes across pH groups; and γ-CD-NHT exhibited a delayed initial permeation followed by a catch-up effect at pH 8.5. These results indicate that the in vitro release of nicotine is not entirely equivalent to its transmucosal permeation; the dissociation behavior of inclusion complexes, the ionization state of nicotine, and the mucosal partitioning process collectively determine its permeation characteristics. Therefore, in the design of nicotine pouch formulations, it is necessary to comprehensively consider the type of cyclodextrin and the pH of the matrix to coordinate the nicotine release rate with the oral mucosal permeation process.

[0129] 3. Conclusion

[0130] This study prepared three monocyclodextrin inclusion complexes: β-CD-NHT, HP-β-CD-NHT, and γ-CD-NHT, with inclusion efficiencies of 71.45%, 54.05%, and 82.85%, respectively. The three systems exhibited differentiated release characteristics: β-CD-NHT released relatively slowly, γ-CD-NHT released the fastest, and HP-β-CD-NHT fell in between. Increasing the moisture content generally accelerated nicotine release in the initial and middle stages; xylitol-dominant matrices promoted release, while sodium alginate-dominant matrices delayed release; the effect of pH on release was cyclodextrin type-dependent. In vitro permeation results in porcine oral mucosa showed that a higher feed phase pH generally benefited from increased cumulative permeation. Therefore, the cyclodextrin type determines the basic release characteristics of the inclusion system, and pH, moisture content, and filler matrix can further regulate the nicotine bag release process, with feed phase pH being a crucial factor affecting transmucosal permeation.

[0131] Examples 2-8: Preparation of oral nicotine pouches containing β-CD-NHT

[0132] Table 3 Formulations (parts by weight) for Examples 2-8

[0133]

[0134] Note: The β-CD-NHT inclusion complex contains 9.50% nicotine tartrate, and the pH adjuster is a mixture of sodium carbonate and sodium bicarbonate in a mass ratio of 1:1.

[0135] Examples 2-8 prepared a series of oral nicotine pouch products containing β-CD-NHT, the formulations of which are shown in Table 3. The preparation process includes the following steps:

[0136] (1) Mix the β-CD-NHT inclusion complex, the filling matrix and the pH adjuster evenly to obtain a powder mixture;

[0137] (2) Adjust the moisture content of the mixed powder by adding the prescribed amount of purified water;

[0138] (3) Mix the mixture after adjusting the moisture content evenly, take the material according to the standard of 2 mg nicotine free base per bag, package it in non-woven bags and seal it with a heat sealer to obtain β-CD-NHT oral nicotine products.

[0139] Examples 9-15: Preparation of oral nicotine pouches containing HP-β-CD-NHT

[0140] Table 4. Formulations (parts by weight) for Examples 9-15

[0141]

[0142] Note: The percentage of nicotine tartrate in the HP-β-CD-NHT inclusion complex is 5.28%, and the pH adjuster is a mixture of sodium carbonate and sodium bicarbonate in a mass ratio of 1:1.

[0143] Examples 9-15 prepared a series of oral nicotine pouches containing HP-β-CD-NHT, the formulations of which are shown in Table 4. The preparation process includes the following steps:

[0144] (1) Mix the HP-β-CD-NHT inclusion complex, the filler matrix and the pH adjuster evenly to obtain a powder mixture;

[0145] (2) Adjust the moisture content of the mixed powder by adding the prescribed amount of purified water;

[0146] (3) Mix the mixture after adjusting the moisture content evenly, take the material according to the standard of 2 mg nicotine free base per bag, package it in non-woven bags and seal it with a heat sealer to obtain HP-β-CD-NHT oral nicotine products.

[0147] Examples 16-22: Preparation of oral nicotine pouches containing γ-CD-NHT

[0148] Table 5. Formulations (parts by weight) for Examples 16-22

[0149]

[0150] Note: The γ-CD-NHT inclusion complex contains 7.92% nicotine tartrate, and the pH adjuster is a mixture of sodium carbonate and sodium bicarbonate in a 1:1 mass ratio.

[0151] Examples 16-22 prepared a series of oral nicotine pouch products containing γ-CD-NHT, the formulations of which are shown in Table 5. The preparation process includes the following steps:

[0152] (1) Mix the γ-CD-NHT inclusion complex, the filling matrix and the pH adjuster evenly to obtain a powder mixture;

[0153] (2) Adjust the moisture content of the mixed powder by adding the prescribed amount of purified water;

[0154] (3) Mix the mixture after adjusting the moisture content evenly, take the material according to the standard of 2 mg of nicotine free base per bag, package it in non-woven bags and seal it with a heat sealer to obtain γ-CD-NHT oral nicotine products.

[0155] Example 23: Testing the nicotine sustained-release performance of nicotine pouches

[0156] This test example evaluated the sustained-release performance of the nicotine pouches prepared in the previous examples. The test procedure is as follows:

[0157] The nicotine pouch product from the above examples was placed in 10 mL of artificial saliva at pH 6.8–7.0 and kept at a constant temperature of 37.0 ± 0.1 °C. Precise 1 mL samples were taken at 1, 3, 5, 7, 9, 11, 13, 15, 20, 30, 40, 50, and 60 min. An equal volume and temperature of fresh release medium (artificial saliva) were added after each sampling (to simulate the cumulative nicotine release in the oral cavity, artificial saliva was added after each sampling as saliva was continuously secreted). The nicotine content in the samples was determined using high-performance liquid chromatography (HPLC), the cumulative nicotine release was calculated, and a release curve was plotted with time on the x-axis and cumulative release on the y-axis.

[0158] from Figure 4 It can be seen that the release of the β-CD-NHT system is relatively slow, with further delayed release in Example 4. The release amount was 0.74 mg at 15 min, 1.20 mg at 30 min, and nearly complete release at 60 min, indicating that the β-CD-NHT system, especially under sodium alginate-dominated filling matrix conditions, has obvious slow-release characteristics and near-complete release. Figure 5 It can be seen that the HP-β-CD-NHT system has a relatively fast release rate. In Example 10, the release amount exceeded 1.3 mg at 1 min and 1.84 mg at 15 min, indicating that the HP-β-CD-NHT system has a significant immediate-release characteristic and can be used as an immediate-release inclusion complex system. Examples 2-3 and 5-8 can all achieve sustained nicotine release, but their sustained-release effect is still different compared with Example 4. Among them, Examples 2-3 have a relatively high nicotine release amount in the early stage of release and a fast release rate, which is difficult to fully reflect the early release delay characteristic required for sustained-release products. Although the release process of Examples 5-8 can be changed by adjusting the amount of pH adjuster or the moisture content, the overall release amount at 15 min and 30 min is higher than that of Example 4, and the release delay is not as good as that of Example 4. Therefore, although Examples 2-3 and 5-8 can be used as release regulation implementation methods, they are not the preferred sustained-release examples of this invention. Examples 9 and 11-15 all exhibited a relatively rapid release trend, but compared to Example 10, these examples had lower nicotine release levels in the initial release phase, or a relatively delayed plateau phase, and their immediate-release characteristics were not as prominent as in Example 10. Therefore, considering the initial release levels, plateau phase time, and release characteristic differentiation of the release curves, this invention preferably uses Example 4 as a sustained-release example and Example 10 as an immediate-release example. Figure 6It can be seen that although the γ-CD-NHT system exhibits relatively rapid release under certain formulation conditions, its final release amount is lower than that of the β-CD-NHT and HP-β-CD-NHT systems. Approximately 20% remains unreleased within 60 minutes, failing to achieve the same level of complete release as the aforementioned two systems. This indicates that the γ-CD-NHT system lacks sufficient nicotine release integrity in orally packaged products. Furthermore, the release behavior of the γ-CD-NHT system is significantly influenced by formulation factors, with marked differences in release curves between different embodiments. Therefore, the γ-CD-NHT system is not suitable as a preferred representative system for immediate or sustained-release formulations in this invention.

[0159] at the same time, Figures 4-6 The results indicate that fillers affect nicotine release. Xylitol-dominant filler matrices accelerate release, while sodium alginate-dominant filler matrices delay it. The amount of pH adjuster added also regulates the release process, affecting the initial release rate, but the degree of influence depends on the type of inclusion complex. Moisture content promotes nicotine release. Higher moisture content facilitates the entry of the release medium into the bag and promotes the wetting, dissolution, and diffusion of the inclusion complex, while release is relatively slower under low moisture conditions, indicating that increasing moisture content accelerates nicotine release.

[0160] In summary, the β-CD-NHT system can be used as a sustained-release system, while the HP-β-CD-NHT system can be used as an immediate-release system. The nicotine release rate can be controlled by selecting different cyclodextrin inclusion complexes and adjusting the filling matrix, pH, and moisture content.

Claims

1. A controlled-release oral nicotine pouch product, comprising an outer breathable pouch and an inner functional core, characterized in that, The internal functional core is prepared from nicotine salt-cyclodextrin inclusion complex and additives; The inclusion complex is formed by the host-guest inclusion interaction of cyclodextrin and nicotine tartrate. The cyclodextrin is selected from one of β-cyclodextrin and hydroxypropyl-β-cyclodextrin; The additives include a filler matrix, a pH adjuster, and water; the filler matrix is ​​a mixture of microcrystalline cellulose and sodium alginate, or a mixture of microcrystalline cellulose and xylitol. When the cyclodextrin is β-cyclodextrin, the formulation of the internal functional core is as follows: 60 parts β-cyclodextrin-nicotine salt inclusion complex, 140-170 parts microcrystalline cellulose, 35-50 parts sodium alginate, a pH adjuster for adjusting the pH of the internal functional core to 8.2-8.8, and purified water for adjusting the water content of the internal functional core to 9-11%; thereby obtaining a sustained-release oral nicotine bag product. When the cyclodextrin is hydroxypropyl-β-cyclodextrin, the formulation of the internal functional core is as follows: 108 parts HP-β-cyclodextrin-nicotine salt inclusion complex, 30-50 parts microcrystalline cellulose, 90-110 parts xylitol, a pH adjuster for adjusting the pH of the internal functional core to 8.2-8.8, and purified water for adjusting the water content of the internal functional core to 9-11%; thereby obtaining an immediate-release oral nicotine product in a sachet.

2. The oral nicotine pouch product according to claim 1, characterized in that, When the cyclodextrin is β-cyclodextrin, the formulation of the internal functional core is as follows: 60 parts of β-cyclodextrin-nicotine salt inclusion complex, 145-160 parts of microcrystalline cellulose, 36-42 parts of sodium alginate, a pH adjuster for adjusting the pH of the internal functional core to 8.4-8.6, and purified water for adjusting the water content of the internal functional core to 9-11%; thereby obtaining a sustained-release oral nicotine product in a sachet.

3. The oral nicotine pouch product according to claim 1, characterized in that, When the cyclodextrin is hydroxypropyl-β-cyclodextrin, the formulation of the internal functional core is as follows: 108 parts HP-β-cyclodextrin-nicotine salt inclusion complex, 40-46 parts microcrystalline cellulose, 95-105 parts xylitol, a pH adjuster for adjusting the pH of the internal functional core to 8.4-8.6, and purified water for adjusting the water content of the internal functional core to 9-11%; thereby obtaining an immediate-release oral nicotine product in a sachet.

4. The oral nicotine pouch product according to claim 1, characterized in that, The pH adjuster is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium citrate, and potassium citrate.

5. The oral nicotine pouch product according to claim 1, characterized in that, The additives also contain one or more of the following: humectants, flavoring agents, preservatives, antioxidants, and anti-caking agents.

6. The oral nicotine pouch product according to claim 5, characterized in that, The humectant is propylene glycol, glycerol, and sorbitol; the flavoring agent is flavoring, sucralose, acesulfame potassium, xylitol, and steviol glycosides; the preservative is potassium sorbate and sodium benzoate; the antioxidant is vitamin E and plant polyphenols; and the anti-caking agent is silicon dioxide and magnesium stearate.

7. The oral nicotine pouch product according to any one of claims 1-6, characterized in that, The material of the outer breathable bag is food-grade breathable non-woven fabric.

8. A method for preparing a nicotine product in a sachet according to claim 1, characterized in that, The method includes the following steps: (1) Dissolve cyclodextrin in deionized water, heat to 55~65 ℃ to fully dissolve, and then cool to room temperature; (2) Under stirring conditions, the prepared nicotine tartrate solution is slowly added dropwise to the cyclodextrin solution; (3) Adjust the pH of the system to 7-11 with an alkaline solution and continue stirring to carry out the inclusion reaction; (4) After the reaction is complete, adjust the pH of the system to 5.7-6.3 with an acid solution; (5) After being refrigerated at 3~6 ℃ for 20~24 h, the inclusion complex was obtained by freeze drying; (6) Mix the inclusion complex, the filling matrix and the pH adjuster evenly to obtain a powdered mixture; (7) Adjust the moisture content of the powder mixture by adding purified water; (8) Mix the mixture after adjusting the moisture content evenly, package it in a food-grade breathable non-woven bag and seal it to obtain oral nicotine products.

9. The method for preparing a nicotine product in a sachet according to claim 8, characterized in that, In step (8), the pH of the system is adjusted to 9-11 using an alkaline solution.

10. The method for preparing the oral nicotine bag product according to claim 8, characterized in that, The stirring time for the inclusion reaction in step (8) is 2–6 hours, the stirring temperature is 25–65°C, and the stirring rate is 250–650 rpm·min. -1 .

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