Nicotine product

Abstract

The invention discloses a nicotine product, the nicotine product comprises a nicotine release system, an aroma release system, a slow release matrix and a safety and fullness regulation and control system, the slow release matrix comprises HPMC E3 instant gel, the viscosity of the HPMC E3 instant gel is 1.8-2.2 cP, and the crosslinking degree of the HPMC E3 instant gel is 8-10%. According to the nicotine product disclosed by the invention, the accumulative release rate of nicotine within 5 minutes can reach 85-90%.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of nicotine product production, in particular to a nicotine product. BACKGROUND

[0002] The nicotine product is a product capable of releasing nicotine in the oral cavity or nasal cavity. In the existing nicotine product, the dissolution / disintegration rate of the nicotine product is difficult to accurately control. If the dissolution rate of the nicotine product is too fast, the nicotine will be released in an instant, causing dizziness or nausea and other discomfort reactions of the user. If the dissolution rate of the nicotine product is too slow, the nicotine product will stay for too long (such as more than 30 minutes), causing the user to have an impatient emotional reaction. SUMMARY

[0003] The main purpose of the present application is to provide a nicotine product, which solves the technical problem that the dissolution / disintegration rate of nicotine is difficult to accurately control.

[0004] To achieve the above purpose, the present application provides a nicotine product, which comprises:

[0005] a nicotine release system;

[0006] an aroma release system;

[0007] a slow-release matrix, which comprises HPMC E3 fast-dissolving gel, the viscosity of the HPMC E3 fast-dissolving gel is 1.8-2.2 cP, and the cross-linking degree of the HPMC E3 fast-dissolving gel is 8-10%; and

[0008] a safety and fullness regulation system.

[0009] Optionally, the viscosity of the HPMC E3 fast-dissolving gel is 1.9-2.1 cP, and the cross-linking degree of the HPMC E3 fast-dissolving gel is 8.5-9.5%.

[0010] Optionally, the nicotine product is suitable for an oral cavity saliva environment, and the HPMC E3 fast-dissolving gel can form a three-dimensional network structure with a porosity of 20-35% within 3 seconds in the oral cavity saliva environment.

[0011] Optionally, the porosity of the three-dimensional network structure is 25-30%.

[0012] Optionally, the proportion of the HPMC E3 fast-dissolving gel is 18-22 parts based on 1000 parts of the total amount of the nicotine product.

[0013] The slow-release matrix comprises sodium alginate, the concentration of the sodium alginate is 0.3-1.2%, and the proportion of the sodium alginate is 5-15% of the proportion of the HPMC E3 fast-dissolving gel.

[0014] Optionally, the slow-release matrix comprises HPMC K4M instant gel, viscosity of the HPMC K4M instant gel is 0.8-1.8 cP, cross-linking degree of the HPMC K4M instant gel is 5-10%, and the ratio of the HPMC K4M instant gel to the HPMC E3 instant gel is 1:1-3:1, the total amount of the nicotine product is 1000 parts, and the sum of the parts of the HPMC E3 instant gel and the HPMC K4M instant gel is 18-30.

[0015] Optionally, the slow-release matrix further comprises microencapsulated nicotine, the microencapsulated nicotine comprises gelatin and gum arabic in a mass ratio of 0.8:1-1.2:1, and the particle size of the microencapsulated nicotine is 200-300 nm.

[0016] Optionally, the total amount of the nicotine product is 1000 parts, and the part of the microencapsulated nicotine is 8-12.

[0017] Optionally, the nicotine release system comprises a combination of nicotine salt and penetration enhancer, the nicotine salt comprises citrate and lactate in a mass ratio of 4:1-6:1, the particle size of the nicotine salt is 80-120 nm, and the total amount of the nicotine product is 1000 parts, and the part of the nicotine salt is 30-38.

[0018] Optionally, the penetration enhancer combination comprises a ternary penetration enhancer and an ethanol penetration enhancer synergist, the ternary penetration enhancer comprises menthol derivative, eucalyptol and azone in a molar ratio of 3:1:0.3, and the ethanol penetration enhancer synergist comprises food-grade ethanol in a concentration of 8%, the total amount of the nicotine product is 1000 parts, the part of the ternary penetration enhancer is 4.2-9.1, and the part of the ethanol penetration enhancer synergist is 24-30.

[0019] Optionally, the aroma release system comprises peppermint oil, porous silica carrier essence, β-cyclodextrin inclusion compound and liposome-encapsulated essence.

[0020] Optionally, the peppermint oil comprises menthol in an amount of 94-96%, and the total amount of the nicotine product is 1000 parts, and the part of the peppermint oil is 10-15.

[0021] Optionally, the mesoporous pore size of the porous silica carrier essence is 35-45 nm, the porosity of the porous silica carrier essence is 55-65%, the essence loading capacity of the porous silica carrier essence is 40-50%, the total amount of the nicotine product is 1000 parts, and the part of the porous silica carrier essence is 6-9.

[0022] Optionally, the β-cyclodextrin inclusion compound comprises β-cyclodextrin and essence in a mass ratio of 1.8:1-2.2:1, and the inclusion rate of the β-cyclodextrin inclusion compound is 95-96%; the amount of the β-cyclodextrin inclusion compound is 9-16 parts based on 1000 parts of the total amount of the nicotine product.

[0023] Optionally, the liposome-encapsulated essence comprises soybean lecithin and cholesterol in a molar ratio of 5.5:1-6.5:1, and the particle size of the liposome-encapsulated essence is 100-140 nm; the amount of the liposome-encapsulated essence is 12-20 parts based on 1000 parts of the total amount of the nicotine product.

[0024] Optionally, the safety and satiety regulation system comprises maltitol, vanillin synergist, glyceryl triacetate and magnesium stearate.

[0025] Optionally, the particle size of the maltitol is 50-70 μm; the amount of the maltitol is 18-28 parts based on 1000 parts of the total amount of the nicotine product.

[0026] Optionally, the purity of the vanillin synergist is greater than or equal to 99%, and the particle size of the vanillin synergist is 7-8 μm; the amount of the vanillin synergist is 0.8-1.5 parts based on 1000 parts of the total amount of the nicotine product.

[0027] Optionally, the glyceryl triacetate is of pharmaceutical grade, and the purity of the glyceryl triacetate is greater than or equal to 99%; the amount of the glyceryl triacetate is 1.5-3 parts based on 1000 parts of the total amount of the nicotine product.

[0028] Optionally, the magnesium stearate is of pharmaceutical grade, the purity of the magnesium stearate is greater than or equal to 98.0%, and the loose density of the magnesium stearate is 0.2-0.3 g / cm 3 ; the amount of the magnesium stearate is 0.5-1.2 parts based on 1000 parts of the total amount of the nicotine product.

[0029] In the nicotine product of the present application, through the synergistic design of low viscosity (1.8-2.2 cP) and low crosslinking degree (8-10%), the HPMC E3 instant gel can form a three-dimensional network structure with 20-35% porosity in the oral cavity saliva environment within 3 seconds. This three-dimensional network structure can regulate the initial release rate of nicotine through porosity, and at the same time realize the subsequent slow release by using the swelling properties of the gel matrix, so that the cumulative release rate of nicotine reaches 85-90% within 5 minutes.

[0030] The microcapsule-embedded nicotine has a release characteristic with a half-life of 1.2 minutes, can form a synergistic slow-release structure with the HPMC E3 instant gel, and optimize the slow-release effect of nicotine. The HPMC E3 instant gel and the microcapsule-embedded nicotine synergistically act, and can achieve a cumulative release rate of 90-95% of nicotine within 5 minutes.

[0031] The nicotine product of the present application has good aroma release effect, the aroma intensity at 10 seconds is between 75-80 ppm, and the retention rate of the main aroma components is about 90%.

[0032] The nicotine product of the present application has good nicotine absorption effect, and the peak blood concentration is between 2.3-2.4 ng / ml. DETAILED DESCRIPTION

[0033] The technical solutions in the embodiments of the present application will be described below clearly and completely. Obviously, the described embodiments are only some of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0034] In addition, the description of "first", "second" and the like in the present application is only for the purpose of description, and cannot be understood as indicating or implying the relative importance of the indicated technical features or implicitly indicating the number of the indicated technical features. Therefore, the features defined with "first", "second" can explicitly or implicitly include at least one of the features. In addition, "and / or" throughout the text includes three solutions, for example, A and / or B includes A technical solution, B technical solution, and A and B simultaneously meet the technical solution; in addition, the technical solutions of each embodiment can be combined with each other, but it must be based on the realization of those skilled in the art, when the combination of technical solutions appears contradictory or unachievable, it should be considered that the combination of technical solutions does not exist, nor within the scope of protection claimed by the present application.

[0035] The present application proposes a nicotine product, which can be used in the oral cavity, and can be a mouth dissolving product or a sublingual product.

[0036] The nicotine product of the present application comprises a slow-release matrix, which can be a 5-minute precision slow-release matrix. The slow-release matrix comprises HPMC E3 fast-dissolving gel. HPMC E3 is one of hydroxypropyl methylcellulose, which can bind raw material particles together to form tablets or granules with certain hardness and formability. The swelling coefficient of HPMC E3 after water absorption can reach hundreds of times, which can significantly improve the disintegration and dissolution release rate of nicotine. HPMC E3 also has film-forming properties, which can be used to prepare oral films or sublingual films, and the prepared oral films or sublingual films have good dissolution performance. HPMC E3 can also be used for film coating of tablets or capsules, which can protect, improve the appearance and control the release of nicotine. HPMC E3 can participate in the composition of the slow-release system, adjust the release rate of nicotine in the body, and prolong the release time of nicotine.

[0037] In the slow-release matrix of the present application, the viscosity of HPMC E3 fast-dissolving gel is 1.8-2.2 cP, and the cross-linking degree is 8-10%. Therefore, the HPMC E3 fast-dissolving gel can form a three-dimensional network structure with a porosity of 20-35% in the oral cavity within 3 seconds. This three-dimensional network structure can regulate the initial release rate of nicotine through porosity, and then achieve slow release by using the swelling properties of the gel matrix, so that the cumulative release rate of nicotine reaches 85-90% (average or any value) within 5 minutes. The overall drug release curve of HPMC E3 fast-dissolving gel determines the final precision of nicotine release within 5 minutes. When the cross-linking degree of HPMC E3 fast-dissolving gel exceeds 10%, the gel film-forming speed increases but the porosity decreases, which not only causes the release of nicotine to lag, but also cannot complete more than 85% of the release amount within 5 minutes.

[0038] Further, the viscosity of HPMC E3 fast-dissolving gel can be 1.9-2.1 cP, 1.9-2.0 cP, 1.9-2.2 cP, 2.0-2.1 cP, 2.1-2.2 cP, 1.8-2.0 cP, 1.8-1.9 cP or 1.8-2.1 cP, etc. Further, the viscosity of HPMC E3 fast-dissolving gel can be 1.8 cP, 1.9 cP, 2.0 cP, 2.1 cP or 2.2 cP, etc. Further, the viscosity of HPMC E3 fast-dissolving gel is 2 cP.

[0039] Further, the cross-linking degree of the HPMC E3 fast-dissolving gel can be 8.5-9.5%, 8.2-9.7%, 8.9-9.1%, 9.5-10%, 8.9-9.9%, 9.1-9.3%, or 9.0-9.5%, etc. Further, the cross-linking degree of the HPMC E3 fast-dissolving gel can be 8%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.9%, 9.9%, or 10%. Further, the cross-linking degree of the HPMC E3 fast-dissolving gel is 9%.

[0040] Further, the porosity of the three-dimensional network structure formed by the HPMC E3 fast-dissolving gel in the oral saliva environment is 25-30%, 27-28%, 22.5-27.5%, 26.5-30%, 25-28%, or 27.5-32%, etc. Further, the porosity of the three-dimensional network structure can be 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34%, 34.5%, or 35%, etc. Further, the porosity of the three-dimensional network structure is 27.5%.

[0041] The proportion of the HPMC E3 fast-dissolving gel can be 18-22, based on the total amount of the nicotine product being 1000 parts. Further, the proportion of the HPMC E3 fast-dissolving gel can be 19-22, 19-21, 20-22, 18-20, or 18-19, etc. Further, the proportion of the HPMC E3 fast-dissolving gel can be 18, 19, 19.5, 20, 20.5, 21, 21.5, or 22, etc.

[0042] The slow-release matrix can include sodium alginate, and the concentration of the sodium alginate can be 0.3-1.2%. The proportion of the sodium alginate can be 5-15% of the proportion of the HPMC E3 fast-dissolving gel, in other words, the proportion of the sodium alginate can be 0.9-3.3 (the proportion of the HPMC E3 fast-dissolving gel is 18-22). The sodium alginate can form a gel network in the oral environment by reacting with the micro-Ca 2+ The reaction forms a gel network, and the gel network formed by the sodium alginate and the three-dimensional network structure formed by the HPMC E3 fast-dissolving gel can synergistically optimize the slow-release effect.

[0043] Further, the concentration of sodium alginate can be 0.6-0.8%, 0.3-0.75%, or 0.75-1.2%. Further, the concentration of sodium alginate can be 0.3%, 0.6%, 0.75%, 0.8%, or 1.2%.

[0044] Further, the proportion of sodium alginate can be 8-12%, 10-15%, 5-12%, or 5-8% of the proportion of HPMC E3 fast-soluble gel. Further, the proportion of sodium alginate can be 5%, 8%, 10%, 11%, 12%, or 15% of the proportion of HPMC E3 fast-soluble gel.

[0045] The sustained-release matrix can further include HPMC K4M fast-soluble gel. By mixing the HPMC K4M fast-soluble gel with the HPMC E3 fast-soluble gel, the swelling and drug release performance of the gel as a whole can be changed to adapt to the release requirements of nicotine in different nicotine salts.

[0046] The viscosity of the HPMC K4M fast-soluble gel can be 0.8-1.8 cP, the cross-linking degree of the HPMC K4M fast-soluble gel can be 5-10%, the proportion ratio of the HPMC K4M fast-soluble gel to the HPMC E3 fast-soluble gel can be 1:1-3:1, and the sum of the proportions of the HPMC E3 fast-soluble gel and the HPMC K4M fast-soluble gel can be 18-30, based on 1000 parts of the total amount of the nicotine product.

[0047] Further, the viscosity of the HPMC K4M fast-soluble gel can be 1.2-1.4 cP, 0.8-1.2 cP, 1.3-1.4 cP, 1.2-1.8 cP, or 0.8-1.3 cP. Further, the viscosity of the HPMC K4M fast-soluble gel can be 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, or 1.8 cP.

[0048] Further, the cross-linking degree of the HPMC K4M fast-soluble gel can be 6-8%, 5-6%, 7-8%, 6-10%, or 5-8%. Further, the cross-linking degree of the HPMC K4M fast-soluble gel can be 5%, 6%, 7%, 8%, or 10%.

[0049] Further, the proportion ratio of the HPMC K4M fast-soluble gel to the HPMC E3 fast-soluble gel can be 1:1-2:1, 1.5:1-2:1, 1:1-1.5:1, or 2:1-3:1. Further, the proportion ratio of the HPMC K4M fast-soluble gel to the HPMC E3 fast-soluble gel can be 1:1, 1.5:1, 2:1, or 3:1.

[0050] Further, the sum of the portions of HPMC E3 fast gelling and HPMC K4M fast gelling can be 18-22, 19-21, 20-24, 21-23, or 23-30. Further still, the sum of the portions of HPMC E3 fast gelling and HPMC K4M fast gelling can be 18, 19, 20, 21, 22, 23, 24, or 30.

[0051] The sustained-release matrix can also include microencapsulated nicotine, which includes gelatin and gum arabic. Gelatin is a natural polymer material with good film-forming property, biocompatibility, and biodegradability. It can form a tough film under certain conditions to encapsulate nicotine, playing a protective and isolating role. Gum arabic is also a natural polymer substance with good water solubility and emulsifying property. Gum arabic can interact with gelatin to form a stable complex, which helps to improve the stability and encapsulation efficiency of the microcapsules, and also helps to regulate the release performance of the microcapsules.

[0052] The mass ratio of gelatin and gum arabic is 0.8:1-1.2:1, and the particle size of the microencapsulated nicotine is 200-300 nm. The portion of the microencapsulated nicotine can be 8-12, based on the total amount of 1000 parts of the nicotine product. Thus, the microencapsulated nicotine has a release characteristic of a half-life of 1.2 minutes, and can form a synergistic sustained-release structure with the HPMC E3 fast gelling, thereby optimizing the sustained-release effect of nicotine. The HPMC E3 fast gelling and the microencapsulated nicotine synergize with each other, and can achieve a cumulative release rate of 90-95% (average or any value) of nicotine within 5 minutes.

[0053] When the mass ratio of gelatin and gum arabic is 0.8:1-1.2:1 and the particle size of the microencapsulated nicotine is 200-300 nm, they can interact with each other well to form a uniform and stable coacervate, thereby better encapsulating nicotine. If the ratio of the two deviates from this range, it can cause changes in the properties of the coacervate, such as the toughness and permeability of the film, which in turn affects the encapsulation efficiency, particle size, and release rate of the microcapsules, etc. If the proportion of gelatin is too high, the film of the microcapsule will be too tough, resulting in a slower release rate of nicotine. If the proportion of gum arabic is too high, the stability of the microcapsule will decrease, and problems such as rupture can occur.

[0054] Further, the mass ratio of gelatin and gum arabic is 0.9:1-1.1:1, 0.9:1-1:1, 1:1-1.2:1, or 0.8:1-1.1:1. Further still, the mass ratio of gelatin and gum arabic is 0.8:1, 0.9:1, 1:1, 1.1:1, or 1.2:1.

[0055] Further, the particle size of the microcapsule-embedded nicotine is 220-280 nm, 250-280 nm, 200-250 nm, or 220-250 nm, etc. Further, the particle size of the microcapsule-embedded nicotine is 200 nm, 220 nm, 250 nm, 280 nm, or 300 nm.

[0056] Further, the amount of the microcapsule-embedded nicotine is 9-11 parts, based on 1000 parts of the total amount of the nicotine product. Further, the amount of the microcapsule-embedded nicotine is 8, 9, 10, 11, or 12 parts, based on 1000 parts of the total amount of the nicotine product.

[0057] The nicotine product of the present application comprises a nicotine release system, which can be a super-fast nicotine release system. The nicotine release system comprises a combination of a nicotine salt and a penetration enhancer. The nicotine salt can be a super-micro-nano nicotine salt. The nicotine salt comprises citrate and lactate in a mass ratio of 4:1-6:1, and the particle size of the nicotine salt is 80-120 nm, and the amount of the nicotine salt is 30-38 parts, based on 1000 parts of the total amount of the nicotine product. Under the control of the sustained-release matrix, the dissolution rate of the nicotine salt in the oral cavity is relatively appropriate, and the stimulation to the oral cavity is relatively small.

[0058] Compared with free nicotine, nicotine in the form of citrate has significantly reduced stimulation to the oral and throat mucosa, making the user feel softer during inhalation and not producing a strong choking sensation, thereby improving the use experience. Citric acid is a naturally occurring organic acid in fruits such as lemons and oranges, and has higher safety compared with some other synthetic acids, and has relatively small potential harm to the human body. Nicotine in the form of citrate can make the release of nicotine more stable, better meet the user's demand for nicotine, and avoid the adverse effects of rapid and large release of nicotine. Citric acid itself has a certain flavor, which can improve the taste of the nicotine salt to some extent, making it closer to the aroma after natural tobacco burning during smoking, and allowing the user to obtain a better sensory experience.

[0059] The pH value of the lactate salt is relatively low, usually around 4.0±0.5, and the lower pH value makes it less irritating to the throat and brings a softer taste without a strong choking sensation, improving the user's experience. At the same time, lactate is also a "more natural" nicotine salt with higher safety. Lactate has moderate nicotine release characteristics, which can meet the user's demand for nicotine to some extent, so that nicotine can be released relatively stably, avoiding too fast or too slow release of nicotine.

[0060] Further, the mass ratio of citrate and lactate is 4.8:1-5.2:1, 4.8:1-5:1, 5:1-6:1, or 5:1-5.2:1. Further, the mass ratio of citrate and lactate is 4:1, 4.8:1, 5:1, 5.2:1, or 6:1.

[0061] Further, the particle size of the nicotine salt is 90-110 nm, 100-110 nm, 80-100 nm, 110-120 nm, or 90-100 nm. Further, the particle size of the nicotine salt is 80 nm, 90 nm, 100 nm, 110 nm, or 120 nm.

[0062] Further, the nicotine salt can be 33-36, 34-35, 32-35, or 33-38 parts, based on 1000 parts of the total amount of the nicotine product. Further, the nicotine salt can be 30, 32, 33, 34, 35, 36, or 38 parts, based on 1000 parts of the total amount of the nicotine product.

[0063] The nicotine product of the present application includes a penetration enhancer combination. The penetration enhancer combination includes a ternary penetration enhancer. The ternary penetration enhancer can destroy the lipid layer of the mucosa to accelerate absorption. The ternary penetration enhancer includes a menthol derivative, eucalyptol, and azone.

[0064] The menthol derivative can effectively enhance the ability of nicotine to penetrate the skin barrier, has low irritation and high safety, and is suitable for oral products. The menthol derivative has a certain penetration-enhancing effect on the release of nicotine, and can produce a synergistic effect when used in combination with other penetration enhancers, thereby improving the penetration amount of nicotine. The menthol derivative retains a certain cooling sensation because it is derived from menthol (naturally occurring in peppermint oil), and can improve the discomfort of the skin mucosa to nicotine.

[0065] The penetration mechanism of eucalyptol is similar to that of the menthol derivative, and eucalyptol can also destroy the lipid structure of the stratum corneum and reduce the resistance of the mucosal barrier to promote the penetration of nicotine. When eucalyptol is used in combination with the menthol derivative, the penetration-enhancing effect can be synergistically enhanced.

[0066] The penetration-enhancing effect of azone has a "two-way" nature, which can promote the transdermal absorption of nicotine and also reduce the transdermal loss of nicotine. The long-chain alkyl group of azone can insert into the lipid bilayer of the stratum corneum of the skin, interact with the lipid molecules, disrupt the ordered arrangement of the lipid molecules, and change the lipid structure from a tight "gel state" to a loose "liquid crystal state", thereby reducing the resistance of the skin barrier and opening a penetration channel for nicotine. Azone can also synergistically enhance the penetration-enhancing effect with the menthol derivative.

[0067] The molar ratio of menthol derivative, eucalyptol and azone is 3:1:0.3. The amount of the ternary penetration enhancer can be 4.2-9.1, based on the total amount of the nicotine product being 1000 parts. Further, the amount of the ternary penetration enhancer can be 5-8, 7-8, 4.2-6 or 6-9.1. Further still, the amount of the ternary penetration enhancer can be 4.2, 5, 6, 7, 8 or 9.1.

[0068] The penetration enhancer combination further includes an ethanol penetration enhancer, which includes food-grade ethanol at a concentration of 8%. Ethanol is low in cost and widely available, and is compatible with most ingredients. Ethanol can enhance penetration at a low concentration. Ethanol can help azone to be more evenly distributed in the stratum corneum, and can enhance the ability of azone to destroy lipid structures. The volatility of ethanol can lower the temperature of the skin surface, enhance the cooling effect of the menthol derivative, and can enhance the temporary opening effect of the menthol derivative on the skin barrier.

[0069] The amount of the ethanol penetration enhancer can be 24-30, based on the total amount of the nicotine product being 1000 parts. Further, the amount of the ethanol penetration enhancer can be 26-28, 26-30, 24-27 or 26-27. Further still, the amount of the ethanol penetration enhancer can be 24, 26, 27, 28 or 30.

[0070] The nicotine product of the present application includes an aroma release system, which can be an aroma instant burst and sustained release system. The aroma release system includes peppermint oil, porous silica carrier fragrance, β-cyclodextrin inclusion compound and liposome-encapsulated fragrance.

[0071] The peppermint oil can be molecular distillation peppermint oil. The peppermint oil includes menthol at a content of 94-96%. The amount of the peppermint oil can be 10-15, based on the total amount of the nicotine product being 1000 parts. The cooling effect of menthol can mask the irritation of nicotine, making the taste softer and making the user feel more comfortable. At the same time, the smell of menthol can also mask the taste of tobacco to some extent, making the eating experience relatively "pleasant".

[0072] Further, the content of menthol can be 95.2-95.8%, 95.2-96%, 94-95.2% or 94-95.8%. Further still, the content of menthol can be 94%, 95.2%, 95.8% or 96%.

[0073] Further, the amount of the peppermint oil can be 12-13, 10-13, 12-14 or 12-15, based on the total amount of the nicotine product being 1000 parts. Further still, the amount of the peppermint oil can be 10, 12, 13, 14 or 15, based on the total amount of the nicotine product being 1000 parts.

[0074] The porous silicon of the porous silicon carrier flavor has abundant pore structure and large specific surface area, which enables it to adsorb a large amount of nicotine and flavor molecules and effectively wrap them inside the pores. The porous silicon is not prone to chemical reaction with nicotine and flavor, thereby ensuring the stability of the properties of the two and not affecting their effects and quality. The presence of the flavor can mask some irritating odor of nicotine itself, while bringing various different flavor experiences to the user, such as fruit flavor or mint flavor, and the porous silicon carrier can well carry the flavor, enabling uniform release of the flavor during use, so that the flavor is more rich and long-lasting.

[0075] The mesopore diameter of the porous silicon carrier flavor can be 35-45 nm. Further, the mesopore diameter of the porous silicon carrier flavor can be 37-43 nm, 40-43 nm, 35-40 nm, 40-45 nm or 37-40 nm. Further, the mesopore diameter of the porous silicon carrier flavor can be 35 nm, 37 nm, 40 nm, 43 nm or 45 nm.

[0076] The porosity of the porous silicon carrier flavor can be 55-65%. Further, the porosity of the porous silicon carrier flavor can be 58-62%, 55-58%, 58-60%, 60-65% or 58-65%. Further, the porosity of the porous silicon carrier flavor can be 55%, 58%, 60%, 62% or 65%.

[0077] The flavor loading of the porous silicon carrier flavor can be 40-50%. Further, the flavor loading of the porous silicon carrier flavor can be 43-47%, 43-45%, 40-45%, 45-50% or 40-43%. Further, the flavor loading of the porous silicon carrier flavor can be 40%, 43%, 45%, 47% or 50%.

[0078] The portion of the porous silicon carrier flavor can be 6-9, based on the total amount of the nicotine product being 1000 parts. Further, the portion of the porous silicon carrier flavor can be 7-8, 7-7.5, 7.5-9, 6-7.5 or 7-9, based on the total amount of the nicotine product being 1000 parts. Further, the portion of the porous silicon carrier flavor is 6, 7, 7.5, 8 or 9, based on the total amount of the nicotine product being 1000 parts.

[0079] The β-cyclodextrin inclusion essence is a complex formed by embedding the essence into β-cyclodextrin with the special structure of β-cyclodextrin. The embedding effect of β-cyclodextrin can seal the essence molecules in the hydrophobic cavity, isolate external interference, improve the stability of the essence, and significantly prolong the shelf life of the essence. The β-cyclodextrin inclusion can slow down the volatilization speed of the essence, achieve slow and long-lasting release of the fragrance. The essence may have a bitter taste, and the embedding of β-cyclodextrin can cover up the above defects and reduce the irritation of the essence to the oral mucosa. The hydrophilic outside of β-cyclodextrin can improve the solubility of the essence in the aqueous system.

[0080] The β-cyclodextrin inclusion includes β-cyclodextrin and essence with a mass ratio of 1.8:1 to 2.2:1, the inclusion rate of the β-cyclodextrin inclusion is 95% to 96%, and the number of parts of the β-cyclodextrin inclusion is 9 to 16 based on 1000 parts of the total amount of the nicotine product.

[0081] Further, the mass ratio of β-cyclodextrin and essence is 1.9:1 to 2.1:1, 1.8:1 to 1.9:1, 2:1 to 2.2:1, 1.9:1 to 2:1, or 1.8:1 to 2:1, the inclusion rate of the β-cyclodextrin inclusion is 95.3% to 95.8%, 95% to 95.3%, 95.5% to 95.8%, 95.3% to 95.5%, or 95.5% to 96%, and the number of parts of the β-cyclodextrin inclusion is 11 to 14, 12 to 14, 9 to 11, 11 to 13, or 13 to 16. Further, the mass ratio of β-cyclodextrin and essence is 1.8:1, 1.9:1, 2:1, 2.1:1, or 2.2:1, the inclusion rate of the β-cyclodextrin inclusion is 95%, 95.3%, 95.5%, 95.8%, or 96%, and the number of parts of the β-cyclodextrin inclusion is 9, 10, 11, 12, 13, 14, 15, or 16.

[0082] Liposomes are closed vesicular structures formed by self-assembly of amphiphilic molecules such as phospholipids. The vesicular structure of liposomes can isolate the essence from the external environment, reducing its contact with oxygen, ultraviolet light, etc., thereby reducing the volatility of the essence and reducing the loss of the essence during storage or processing. When the liposomes enter the oral cavity, the membrane structure is destroyed at about 37°C, and the essence is released rapidly. The wrapping of liposomes can reduce the direct contact of the essence with the skin / mucosa, reducing the allergic or uncomfortable feeling of the user. Liposomes have good compatibility with biological tissues, and are particularly suitable for oral products. As a "carrier", liposomes can also uniformly disperse the essence in various matrices, avoiding turbidity, precipitation or stratification of the product, and ensuring uniform texture.

[0083] The liposome-encapsulated fragrance of the present application comprises soybean lecithin and cholesterol in a molar ratio of 5.5:1-6.5:1, and the particle size of the liposome-encapsulated fragrance is 100-140 nm, and the proportion of the liposome-encapsulated fragrance is 12-20 parts based on 1000 parts of the total amount of the nicotine product.

[0084] Further, the molar ratio of the soybean lecithin and the cholesterol is 5.8:1-6.2:1, 5.5:1-5.8:1, 6:1-6.2:1 or 5.8:1-6.5:1. Further, the molar ratio of the soybean lecithin and the cholesterol is 5.5:1, 5.8:1, 6:1, 6.2:1 or 6.5:1.

[0085] Further, the particle size of the liposome-encapsulated fragrance is 110-130 nm, 120-130 nm, 100-120 nm, 120-140 nm or 100-110 nm. Further, the particle size of the liposome-encapsulated fragrance is 100 nm, 110 nm, 120 nm, 130 nm or 140 nm.

[0086] Further, the proportion of the liposome-encapsulated fragrance is 15-17, 16-18, 12-15, 16-20 or 15-18 parts based on 1000 parts of the total amount of the nicotine product. Further, the proportion of the liposome-encapsulated fragrance is 12, 15, 16, 17, 18 or 20 parts based on 1000 parts of the total amount of the nicotine product.

[0087] The nicotine product of the present application comprises a safety and fullness regulation system, and the safety and fullness regulation system comprises maltitol, vanillin synergist, glyceryl triacetate and magnesium stearate.

[0088] The maltitol can adjust the taste of the product by using its own sweetness, mask some bitter taste of nicotine itself, and make the user feel more comfortable. In addition, due to the low heat and other characteristics of maltitol, some consumers who pursue relative health may feel that the product is more attractive.

[0089] The particle size of the maltitol is 50-70 μm, and the proportion of the maltitol is 18-28 parts based on 1000 parts of the total amount of the nicotine product. Further, the particle size of the maltitol is 55-65 μm, 55-70 μm, 50-55 μm, 55-60 μm or 50-65 μm, and the proportion of the maltitol is 22-24, 18-22, 18-23, 22-28 or 23-24 parts based on 1000 parts of the total amount of the nicotine product. Further, the particle size of the maltitol is 50 μm, 55 μm, 60 μm, 65 μm or 70 μm, and the proportion of the maltitol is 18, 22, 23, 24 or 28 parts based on 1000 parts of the total amount of the nicotine product.

[0090] Vanillin can act as a monoamine oxidase inhibitor, which can effectively inhibit the activity of monoamine oxidase, thereby reducing the decomposition of dopamine, enhancing the brain's response to nicotine, and allowing users to obtain stronger satisfaction. Vanillin has a strong milk aroma that can mask the bitter taste of nicotine, making the product smoother and more pleasant in taste, and improving the user's sensory experience.

[0091] The purity of vanillin synergist can be greater than or equal to 99%, and the particle size of vanillin synergist can be 7-8 μm. The amount of vanillin synergist can be 0.8-1.5, based on the total amount of 1000 parts of the nicotine product. Further, the purity of vanillin synergist is 99.2-99.5%, 99.5-99.8%, or 99.4-99.5%, the particle size of vanillin synergist is 7.2-7.8 μm, 7.2-7.5 μm, 7-7.2 μm, or 7.5-7.8 μm, and the amount of vanillin synergist is 1.1-1.3, 1.2-1.4, 1.1-1.4, 0.8-1.2, or 1.3-1.4, based on the total amount of 1000 parts of the nicotine product. Further, the purity of vanillin synergist can be 99%, 99.2%, 99.4%, 99.5%, or 99.8%, the particle size of vanillin synergist can be 7 μm, 7.2 μm, 7.5 μm, 7.8 μm, or 8 μm, and the amount of vanillin synergist can be 0.8, 1.1, 1.2, 1.3, 1.4, or 1.5.

[0092] Glycerol triacetate can help stabilize the flavor components in the essence, making the flavor more persistent. Glycerol triacetate can also be used as a solvent, by mixing with other ingredients, to help form a stable effect.

[0093] The glycerol triacetate can be pharmaceutical grade glycerol triacetate, and the purity of the glycerol triacetate can be greater than or equal to 99%. The amount of glycerol triacetate can be 1.5-3, based on the total amount of 1000 parts of the nicotine product. Further, the purity of glycerol triacetate is 99.2-99.5%, 99.5-99.8%, or 99.4-99.5%, and the amount of glycerol triacetate is 1.9-2.5, 2.2-2.4, 1.5-2.2, 2.2-2.5, 2.5-3, or 2.2-3, based on the total amount of 1000 parts of the nicotine product. Further, the purity of glycerol triacetate can be 99%, 99.2%, 99.4%, 99.5%, 99.8%, and the amount of glycerol triacetate can be 1.5, 1.9, 2.2, 2.4, 2.5, or 3, based on the total amount of 1000 parts of the nicotine product.

[0094] The magnesium stearate can improve the processing performance of the preparation, and its lubricity can reduce the adhesion of the material in the tabletting or granulation process, ensuring the stability of tabletting. The hydrophobicity of the magnesium stearate can affect the dissolution and release rate of nicotine in the oral cavity, and indirectly regulate the release efficiency of nicotine.

[0095] The magnesium stearate can be a pharmaceutical grade magnesium stearate, and the purity of the magnesium stearate is greater than or equal to 98.0%, and the loose density of the magnesium stearate is 0.2-0.3 g / cm 3 The amount of the magnesium stearate can be 0.5-1.2 parts, based on 1000 parts of the total amount of the nicotine product. Further, the purity of the magnesium stearate can be 98.5-99.0%, 98.0-98.5%, or 98.2-98.5%, and the loose density of the magnesium stearate can be 0.22-0.28 g / cm 3 , 0.22-0.25 g / cm 3 , 0.2-0.25 g / cm 3 , 0.25-0.3 g / cm 3 , or 0.2-0.22 g / cm 3 The amount of the magnesium stearate can be 0.8-1.0, 0.5-0.8, 0.8-0.9, 0.9-1.2, or 0.8-1.2 parts, based on 1000 parts of the total amount of the nicotine product. Further, the purity of the magnesium stearate can be 98.0%, 98.2%, 98.5%, or 99.0%, and the loose density of the magnesium stearate can be 0.2 g / cm 3 , 0.22 g / cm 3 , 0.25 g / cm 3 , 0.28 g / cm 3 , or 0.3 g / cm 3 The amount of the magnesium stearate can be 0.5, 0.8, 0.9, 1.0, or 1.2 parts, based on 1000 parts of the total amount of the nicotine product.

[0096] The release effects of the nicotine products of different embodiments were determined in the present application, and the components of each embodiment are shown in Tables 1-3.

[0097] Table 1 Formulation of Examples 1-3

[0098]

[0099]

[0100] Table 2 Formulation of Examples 4-6

[0101]

[0102]

[0103] Formulation of Examples 7-9

[0104]

[0105]

[0106] The nicotine release was detected by USP paddle method (37°C, 0.1 mol / L HCl, 50 rpm), the maximum concentration (Cmax) was detected by HPLC, and the aroma release was detected by electronic nose. The results of Comparative Examples 1-3 (existing nicotine lozenges) and Examples 1-9 are shown in Table 4 below.

[0107] The results show that the nicotine and aroma release of the nicotine lozenges of the present application is significantly better than that of the existing nicotine lozenges. In the nicotine lozenges of the present application, the HPMC E3 fast-dissolving gel can achieve a cumulative release rate of 85-90% (average) within 5 minutes, the HPMC E3 fast-dissolving gel and the microcapsule-embedded nicotine can achieve a cumulative release rate of 90-95% (average) within 5 minutes, while the cumulative release rate of the existing nicotine lozenges is only about 75% at most within 5 minutes. The aroma intensity of the nicotine lozenges of the present application is between 75-80 ppm at 10 seconds, and the retention rate of the main aroma components is about 90%, while the aroma intensity of the existing nicotine lozenges is not more than 60 ppm at 10 seconds, and the retention rate of the main aroma components is only 82%. The nicotine lozenges of the present application have good nicotine absorption effect, and the peak blood concentration is 2.3-2.4 ng / ml, while the peak blood concentration of the existing nicotine lozenges is only 2.15 ng / ml at most.

[0108] Table 4: Results of nicotine and aroma release detection

[0109]

[0110]

Claims

1. A nicotine product, characterized in that, The nicotine products include: Nicotine release system; Aroma release system; The sustained-release matrix includes an HPMC E3 fast-dissolving gel having a viscosity of 1.8–2.2 cP and a crosslinking degree of 8–10%; and Safety and fullness control system.

2. The nicotine product according to claim 1, characterized in that, The HPMC E3 instant gel has a viscosity of 1.9–2.1 cP and a crosslinking degree of 8.5–9.5%.

3. The nicotine product according to claim 1, characterized in that, The nicotine product is suitable for the oral saliva environment, and the HPMC E3 fast-dissolving gel forms a film within 3 seconds in the oral saliva environment and forms a three-dimensional network structure with a porosity of 20-35%.

4. The nicotine product according to claim 3, characterized in that, The porosity of the three-dimensional mesh structure is 25-30%.

5. The nicotine product according to claim 1, characterized in that, Based on a total of 1000 parts of the nicotine product, the number of parts of the HPMC E3 instant gel is 18 to 22.

6. The nicotine product according to claim 1, characterized in that, The sustained-release matrix includes sodium alginate, the concentration of which is 0.3-1.2%, and the amount of sodium alginate is 5-15% of the amount of HPMC E3 instant gel.

7. The nicotine product according to claim 1, characterized in that, The sustained-release matrix includes HPMC K4M instant gel, the HPMC K4M instant gel has a viscosity of 0.8-1.8 cP, the HPMC K4M instant gel has a crosslinking degree of 5-10%, and the ratio of HPMC K4M instant gel to HPMC E3 instant gel is 1:1-3:

1. Based on a total nicotine product of 1000 parts, the sum of the parts of HPMC E3 instant gel and HPMC K4M instant gel is 18-30.

8. The nicotine product according to claim 1, characterized in that, The sustained-release matrix further includes microcapsule-encapsulated nicotine, wherein the microcapsule-encapsulated nicotine comprises gelatin and gum arabic in a mass ratio of 0.8:1 to 1.2:1, and the particle size of the microcapsule-encapsulated nicotine is 200 to 300 nm.

9. The nicotine product according to claim 8, characterized in that, Based on a total of 1000 parts of the nicotine product, the number of parts of nicotine encapsulated in the microcapsules is 8 to 12.

10. The nicotine article according to any one of claims 1 to 9, characterized in that, The nicotine release system comprises a combination of nicotine salt and a penetration enhancer. The nicotine salt comprises citrate and lactate in a mass ratio of 4:1 to 6:1, and the particle size of the nicotine salt is 80 to 120 nm. Based on a total amount of 1000 parts of the nicotine product, the amount of nicotine salt is 30 to 38 parts.

11. The nicotine product according to claim 10, characterized in that, The penetration enhancer combination includes a ternary penetration enhancer and an ethanol penetration enhancer synergist. The ternary penetration enhancer includes a menthol derivative, eucalyptol, and azone in a molar ratio of 3:1:0.

3. The ethanol penetration enhancer synergist includes 8% food-grade ethanol. Based on a total of 1000 parts of the nicotine product, the ternary penetration enhancer accounts for 4.2 to 9.1 parts, and the ethanol penetration enhancer accounts for 24 to 30 parts.

12. The nicotine article according to any one of claims 1 to 9, characterized in that, The aroma release system includes peppermint oil, porous silica-carrier fragrance, β-cyclodextrin inclusion complex, and liposome-encapsulated fragrance.

13. The nicotine product according to claim 12, characterized in that, The peppermint oil comprises 94-96% menthol; and the peppermint oil comprises 10-15 parts per 1000 parts of the total amount of the nicotine product.

14. The nicotine product according to claim 12, characterized in that, The porous silicon carrier fragrance has a mesopore size of 35-45 nm, a porosity of 55-65%, and a fragrance loading of 40-50%; based on a total of 1000 parts of the nicotine product, the number of parts of the porous silicon carrier fragrance is 6-9.

15. The nicotine product according to claim 12, characterized in that, The β-cyclodextrin inclusion complex comprises β-cyclodextrin and flavoring in a mass ratio of 1.8:1 to 2.2:1, and the inclusion rate of the β-cyclodextrin inclusion complex is 95% to 96%; based on a total amount of 1000 parts of the nicotine product, the number of parts of the β-cyclodextrin inclusion complex is 9 to 16.

16. The nicotine product according to claim 12, characterized in that, The liposome-encapsulated flavor comprises soybean lecithin and cholesterol in a molar ratio of 5.5:1 to 6.5:1, and the particle size of the liposome-encapsulated flavor is 100 to 140 nm; based on a total of 1000 parts of the nicotine product, the number of parts of the liposome-encapsulated flavor is 12 to 20.

17. The nicotine article according to any one of claims 1 to 9, characterized in that, The safety and fullness regulation system includes maltitol, vanillin synergist, triacetylglycerol, and magnesium stearate.

18. The nicotine article according to claim 17, characterized in that, The maltitol has a particle size of 50-70 μm; based on a total of 1000 parts of the nicotine product, the maltitol comprises 18-28 parts.

19. The nicotine product according to claim 17, characterized in that, The vanillin synergist has a purity of ≥99% and a particle size of 7-8 μm; based on a total of 1000 parts of the nicotine product, the vanillin synergist comprises 0.8-1.5 parts.

20. The nicotine article according to claim 17, characterized in that, The triacetin is pharmaceutical grade and has a purity of 99% or higher; the triacetin comprises 1.5 to 3 parts per 1000 parts of the nicotine product.

21. The nicotine product according to claim 17, characterized in that, The magnesium stearate is pharmaceutical grade, with a purity greater than or equal to 98.0%, and a bulk density of 0.2–0.3 g / cm³. 3 Based on a total nicotine product of 1000 parts, the amount of magnesium stearate is 0.5 to 1.2 parts.

Images