Nicotine orally disintegrating tablet with multi-layer composite sustained-release structure and preparation method of nicotine orally disintegrating tablet

Abstract

The invention provides a nicotine orally disintegrating tablet with a multi-layer composite sustained-release structure and a preparation method of the nicotine orally disintegrating tablet. The nicotine orally disintegrating tablet comprises an inner layer, a middle layer and an outer layer, wherein the middle layer and the outer layer sequentially coat the inner layer from inside to outside; the outer layer comprises nicotine, instant starch and a lubricant; the middle layer comprises nicotine, ethyl cellulose, polyethylene glycol and a flow aid; the inner layer comprises the following components: nicotine nanoparticles coated with chitosan and sodium tripolyphosphate, an oral microenvironment regulator and a filling agent. According to the nicotine orally disintegrating tablet provided by the invention, due to the gradient coating structure design of the inner layer, the middle layer and the outer layer, the multi-stage accurate release of nicotine, namely early-stage quick release, middle-stage stable release and later-stage slow release, is realized, the reactions of dizziness, vomiting and the like caused by excessive release of nicotine are avoided, and the use comfort is improved. Meanwhile, the pH value of the oral cavity is adjusted, micro-ecological balance of the oral cavity is maintained, the content of volatile sulfide in breath is reduced, and breath is refreshed.

Description

Technical Field

[0001] This invention belongs to the field of smokeless tobacco products technology, specifically relating to a nicotine orally disintegrating tablet with a multi-layered composite sustained-release structure and its preparation method. Background Technology

[0002] Most existing nicotine oral products use a single-layer or double-layer structure. The single-layer structure can only achieve the single function of "rapid release" or "slow release", and cannot achieve both. Although the double-layer structure attempts to distinguish the release stages, there is no clear functional gradient between the two layers, which can easily lead to problems such as too rapid release in the early stage (causing dizziness and nausea) or insufficient release in the later stage (failing to meet the continuous needs). There is a lack of targeted slow-release structure design.

[0003] CN119185163A discloses a nicotine bag absorbed through the oral mucosa, which relies on a combination of "granules + burst beads" and the release point is affected by the randomness of the burst beads breaking.

[0004] CN117205183A discloses a nicotine oral film, which includes nicotine salt, film-forming material and acidity regulator. The disclosed nicotine oral film only adjusts the release rate by pH and cannot form a multi-stage release curve.

[0005] Existing products have a limited range of tastes and flavors, failing to provide users with a pleasant experience. They also neglect the impact on the oral microenvironment, easily causing pH imbalances and bacterial disturbances during use, thus affecting oral health. Therefore, there is an urgent need to design a nicotine orally disintegrating tablet based on a three-layer composite structure. Through the functional division and synergy of each layer, this tablet can achieve multi-stage sustained release of nicotine, filling a gap in current technology. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the present invention aims to provide a nicotine orally disintegrating tablet with a multi-layered composite sustained-release structure and its preparation method. The nicotine orally disintegrating tablet provided by the present invention has a multi-stage sustained-release function. Through gradient coating and component adaptation of the inner, middle and outer layers, the nicotine release rate is precisely controlled to meet the "immediate-stable-continuous" usage requirements. It can satisfy both the immediate and maintenance needs of nicotine, and freshen breath, thus solving the problems of excessively rapid initial nicotine release and insufficient release in the later stages of traditional products.

[0007] To achieve this objective, the present invention adopts the following technical solution:

[0008] In a first aspect, the present invention provides a nicotine orally disintegrating tablet with a multi-layered composite sustained-release structure, the nicotine orally disintegrating tablet comprising an inner layer and a middle layer and an outer layer that are sequentially coated from the inside out;

[0009] The outer layer comprises nicotine, instant starch, and lubricant;

[0010] The middle layer comprises nicotine, ethyl cellulose, polyethylene glycol, and a flow aid;

[0011] The inner layer comprises chitosan and sodium tripolyphosphate-coated nicotine nanoparticles, oral microenvironment modifiers, and fillers.

[0012] The nicotine orally disintegrating tablets provided by this invention have a three-layer composite structure. They release nicotine rapidly in the initial stage to meet the immediate need for nicotine; release it stably in the middle stage to maintain the effective concentration of nicotine; and release it slowly in the later stage to ensure the supply of nicotine. At the same time, they release oral microenvironment regulators to regulate oral pH, inhibit harmful bacteria in the oral cavity, maintain the balance of oral microecology, reduce the content of volatile sulfur compounds in breath, and ensure fresh breath.

[0013] Preferably, the outer layer comprises, by weight, 10-25 parts nicotine, 60-70 parts instant starch, and 1-2 parts lubricant.

[0014] The nicotine can be present in weight portions of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, or 25 parts, etc.

[0015] The instant starch can be in the following weight proportions: 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 parts.

[0016] The weight percentage of the lubricant can be 1 part, 1.1 parts, 1.2 parts, 1.3 parts, 1.4 parts, 1.5 parts, 1.6 parts, 1.7 parts, 1.8 parts, 1.9 parts, or 2 parts, etc.

[0017] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0018] Preferably, the components of the middle layer include, by weight, 15-20 parts nicotine, 40-70 parts ethyl cellulose, 20-30 parts polyethylene glycol, and 3-5 parts flow aid.

[0019] The nicotine can be present in weight portions of 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 parts, etc.

[0020] The weight parts of the ethyl cellulose can be 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, or 70 parts, etc.

[0021] The weight parts of the polyethylene glycol can be 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 parts, etc.

[0022] The weight percentage of the glial agent can be 3 parts, 3.2 parts, 3.5 parts, 3.7 parts, 4 parts, 4.3 parts, 4.5 parts, 4.8 parts, or 5 parts, etc.

[0023] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0024] Preferably, the inner layer comprises, by weight, 1-10 parts of nicotine nanoparticles coated with chitosan and sodium tripolyphosphate, 5-15 parts of oral microenvironment modifier, and 10-20 parts of filler.

[0025] The nicotine nanoparticles can be present in weight parts of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 parts, etc.

[0026] The oral microenvironment modifier can be present in weight parts of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 parts, etc.

[0027] The filler can be present in weight parts of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 parts, etc.

[0028] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0029] Preferably, in the components of the inner layer, the mass ratio of nicotine, chitosan and sodium tripolyphosphate is (20-35):(50-60):(10-15).

[0030] The specific point values ​​in (20-35) can be 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35, etc.

[0031] The specific point values ​​in (50-60) can be 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60, etc.

[0032] The specific point values ​​in (10-15) can be 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 or 15, etc.

[0033] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0034] Preferably, the mass ratio of the outer layer, middle layer and inner layer is (1-5):(2-7):(1-6).

[0035] The specific point values ​​in (1-5) can be 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5, etc.

[0036] The specific point values ​​in (2-7) can be 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5 or 7, etc.

[0037] The specific point values ​​in (1-6) can be 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6, etc.

[0038] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0039] Preferably, the chitosan and sodium tripolyphosphate-coated nicotine nanoparticles are prepared by a method comprising the following steps:

[0040] Chitosan was dissolved in an aqueous organic acid solution, mixed with nicotine, and then an aqueous sodium tripolyphosphate solution was added and stirred. The mixture was then spray-dried to obtain nicotine nanoparticles coated with chitosan and sodium tripolyphosphate.

[0041] The inner layer of this invention uses chitosan and sodium tripolyphosphate to encapsulate nicotine into nanoparticles, which has a better sustained-release effect, adapts to the release of components in the outer and middle layers, controls the nicotine release process within a reasonable range, meets the user's need for nicotine, and has a better sensory evaluation.

[0042] Preferably, the organic acid in the aqueous solution has a mass percentage content of 0.8-3%, for example, it can be 0.8%, 0.9%, 1%, 1.2%, 1.5%, 1.7%, 2%, 2.3%, 2.5%, 2.8% or 3%, etc.

[0043] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0044] Preferably, the organic acid includes any one or a combination of at least two of acetic acid, citric acid, lactic acid, or malic acid.

[0045] Preferably, the mass ratio of chitosan to the aqueous organic acid solution is 1:(100-300).

[0046] The specific point values ​​in (100-300) can be 100, 120, 150, 170, 200, 230, 250, 280 or 300, etc.

[0047] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0048] Preferably, the sodium tripolyphosphate aqueous solution contains 2-3% sodium tripolyphosphate by mass, for example, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, or 3%.

[0049] Preferably, the stirring speed is 1000-2000 rpm, for example, 1000 rpm, 1100 rpm, 1200 rpm, 1300 rpm, 1400 rpm, 1500 rpm, 1600 rpm, 1700 rpm, 1800 rpm, 1900 rpm, or 2000 rpm; the stirring time is 30-60 min, for example, 30 min, 32 min, 25 min, 27 min, 40 min, 43 min, 45 min, 48 min, 50 min, 55 min, or 60 min.

[0050] Preferably, the inlet air temperature for spray drying is 140-190℃, for example, it can be 140℃, 145℃, 150℃, 155℃, 160℃, 165℃, 170℃, 175℃, 180℃, 185℃ or 190℃.

[0051] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0052] Preferably, the oral microenvironment modifier includes any one or a combination of at least two of phloretin, paeonol, quercetin, or magnolol.

[0053] Preferably, the oral microenvironment modifier includes phloretin, paeonol, quercetin, and magnolol.

[0054] This invention preferentially uses phloretin, paeonol, quercetin, and magnolol as oral microenvironment regulators. The four have a synergistic effect, which can protect the oral mucosa, regulate the oral pH value, inhibit harmful bacteria in the oral cavity, maintain the oral microecological balance, reduce the content of volatile sulfur compounds in breath, and ensure fresh breath.

[0055] Preferably, the mass ratio of phloretin, paeonol, quercetin and magnolol is (3-6):(2-3):(3-7):(2-4).

[0056] The specific point values ​​in (3-6) can be 3, 3.2, 3.5, 3.7, 4, 4.3, 4.5, 4.8, 5, 5.5 or 6, etc.

[0057] The specific point values ​​in (2-3) can be 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3, etc.

[0058] The specific point values ​​in (3-7) can be 3, 3.2, 3.5, 3.7, 4, 4.3, 4.5, 4.8, 5, 5.5, 6, 6.5 or 7, etc.

[0059] The specific point values ​​in (2-4) can be 2., 2.2, 2.5, 2.7, 3, 3.3, 3.5, 3.8 or 4, etc.

[0060] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0061] Preferably, the lubricant comprises any one or a combination of at least two of magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitate stearate, sodium lauryl sulfate, or sodium stearate fumarate.

[0062] Preferably, the number average molecular weight of the polyethylene glycol is 1000-6000, for example, it can be 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500 or 6000.

[0063] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0064] Preferably, the flow aid comprises micronized silica gel and / or talc.

[0065] Preferably, the filler comprises any one or a combination of at least two of lactose, fructose, xylose, sucrose, trehalose, mannose, maltose, mannitol, sorbitol, or xylitol.

[0066] Preferably, the outer layer also includes a sweetener.

[0067] Preferably, the outer layer further comprises 3-5 parts by weight of sweetener.

[0068] The sweetener can be present in parts by weight of 3, 3.2, 3.5, 3.7, 4, 4.3, 4.5, 4.8, or 5 parts, etc.

[0069] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0070] Preferably, the sweetener includes any one or a combination of at least two of aspartame, erythritol, sucralose, isomaltitol, acesulfame potassium, neotame, saccharin, sucrose, glucose, maltose, or fructose.

[0071] Preferably, the outer layer also includes a cooling agent.

[0072] Preferably, the outer layer further comprises 5-8 parts by weight of a cooling agent.

[0073] The cooling agent can be expressed in parts by weight of 5, 5.2, 5.5, 5.7, 6, 6.3, 6.5, 6.8, 7, 7.5, or 8 parts, etc.

[0074] Other specific point values ​​within the range of the above values ​​can be selected, and will not be elaborated on here.

[0075] Preferably, the cooling agent comprises any one or a combination of at least two of the following: peppermint flavor, menthol, ethyl menthane formamide, menthone, menthyl acetate, or limonene.

[0076] In a second aspect, the present invention provides a method for preparing nicotine orally disintegrating tablets as described in the first aspect, the method comprising:

[0077] Nicotine, instant starch, and lubricant are mixed to obtain the outer layer material; nicotine, ethyl cellulose, polyethylene glycol, and a flow aid are mixed to obtain the middle layer material; nicotine nanoparticles, oral microenvironment modifiers, and fillers are mixed to obtain the inner layer material.

[0078] The inner layer material is sequentially coated with a middle layer material and an outer layer material, and then compressed into a tablet to obtain the nicotine orally disintegrating tablet.

[0079] Preferably, the preparation process of the outer layer material further includes the addition of sweeteners and / or cooling agents.

[0080] Preferably, the mixing process further includes a step of crushing and sieving.

[0081] Compared with the prior art, the present invention has the following beneficial effects:

[0082] The nicotine orally disintegrating tablets provided by this invention have a three-layer composite structure. They release nicotine rapidly in the initial stage to meet the immediate need for nicotine; release it stably in the middle stage to maintain the effective concentration of nicotine; and release it slowly in the later stage to ensure the supply of nicotine. At the same time, they release oral microenvironment regulators to regulate oral pH, inhibit harmful bacteria in the oral cavity, maintain the balance of oral microecology, reduce the content of volatile sulfur compounds in breath, and ensure fresh breath. Detailed Implementation

[0083] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0084] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0085] The sources of materials used in the following specific embodiments are as follows:

[0086] Raw material name Purchase manufacturer model Chitosan Yiwei Biotechnology Food-grade chitosan Instant starch Qufu Tianli Pharmaceutical Excipients Co., Ltd. Pregelatinized starch Ethyl cellulose Zhejiang Tianhe Food Biotechnology Food-grade ethyl cellulose Micronized silica Jiazhihe Biotechnology Food-grade micronized silica gel

[0087] Preparation Example 1

[0088] This preparation example provides nicotine nanoparticles, which are prepared by a method comprising the following steps:

[0089] 5.5g of chitosan was dissolved in 1100g of 1wt% acetic acid aqueous solution, mixed with 3g of nicotine, and then 48g of 2.5wt% sodium tripolyphosphate aqueous solution was added. The mixture was stirred at 1500rpm for 40min and spray-dried at an inlet air temperature of 165℃ to obtain the nicotine nanoparticles.

[0090] Preparation Example 2

[0091] This preparation example provides nicotine nanoparticles, which are prepared by a method comprising the following steps:

[0092] 6g of chitosan was dissolved in 600g of 2wt% citric acid aqueous solution, mixed with 3.5g of nicotine, and then 50g of 3wt% sodium tripolyphosphate aqueous solution was added. The mixture was stirred at 1000rpm for 60min and spray-dried at an inlet air temperature of 190℃ to obtain the nicotine nanoparticles.

[0093] Preparation Example 3

[0094] This preparation example provides nicotine nanoparticles, which are prepared by a method comprising the following steps:

[0095] 5g of chitosan was dissolved in 1500g of 3wt% lactic acid aqueous solution, mixed with 2g of nicotine, and then 50g of 2wt% sodium tripolyphosphate aqueous solution was added. The mixture was stirred at 2000rpm for 30min and spray-dried at an inlet air temperature of 140℃ to obtain the nicotine nanoparticles.

[0096] Example 1

[0097] This embodiment provides a nicotine orally disintegrating tablet, which is prepared by a method including the following steps:

[0098] (1) Preparation of outer layer material: By weight, 20 parts nicotine, 65 parts instant starch, 1.5 parts magnesium stearate, 4 parts aspartame and 7 parts menthol are mixed, pulverized and sieved to obtain the outer layer material.

[0099] Preparation of the middle layer material: By weight, mix 17 parts nicotine, 55 parts ethyl cellulose, 25 parts polyethylene glycol 3000 and 4 parts micronized silica gel, pulverize and sieve to obtain the middle layer material.

[0100] Preparation of inner layer material: By weight, 5 parts of nicotine nanoparticles provided in Preparation Example 1, 3 parts of phloretin, 2 parts of paeonol, 3 parts of quercetin, 2 parts of magnolol, and 15 parts of lactose are mixed, pulverized and sieved to obtain the final product.

[0101] (2) The inner layer material is coated with the middle layer material and the outer layer material in sequence, with a mass ratio of 1:5:1, and then compressed into tablets to obtain the nicotine orally disintegrating tablets.

[0102] Example 2

[0103] This embodiment provides a nicotine orally disintegrating tablet, which is prepared by a method including the following steps:

[0104] (1) Preparation of outer layer material: By weight, mix 25 parts nicotine, 70 parts instant starch, 2 parts calcium stearate, 3 parts erythritol and 8 parts menthol, pulverize and sieve to obtain the outer layer material;

[0105] Preparation of the middle layer material: By weight, mix 15 parts nicotine, 70 parts ethyl cellulose, 30 parts polyethylene glycol 1000 and 5 parts micronized silica powder, pulverize and sieve to obtain the middle layer material.

[0106] Preparation of inner layer material: By weight, 10 parts of nicotine nanoparticles provided in Preparation Example 2, 4 parts of phloretin, 2.5 parts of paeonol, 5 parts of quercetin, 3.5 parts of magnolol, and 20 parts of fructose are mixed, pulverized, and sieved to obtain the final product.

[0107] (2) The inner layer material is coated with the middle layer material and the outer layer material in sequence, with a mass ratio of 2:7:3, and then compressed into tablets to obtain the nicotine orally disintegrating tablets.

[0108] Example 3

[0109] This embodiment provides a nicotine orally disintegrating tablet, which is prepared by a method including the following steps:

[0110] (1) Preparation of outer layer material: By weight, mix 10 parts nicotine, 60 parts instant starch, 1 part zinc stearate, 5 parts sucralose and 5 parts menthone, crush and sieve to obtain the outer layer material.

[0111] Preparation of the middle layer material: By weight, mix 20 parts nicotine, 40 parts ethyl cellulose, 20 parts polyethylene glycol 6000 and 3 parts micronized silica powder, pulverize and sieve to obtain the middle layer material.

[0112] Preparation of inner layer material: By weight, 1 part of nicotine nanoparticles provided in Preparation Example 3, 1.8 parts of phloretin, 0.9 parts of paeonol, 2.1 parts of quercetin, 1.2 parts of magnolol, and 10 parts of xylose are mixed, pulverized, and sieved to obtain the final product.

[0113] (2) The inner layer material is coated with the middle layer material and the outer layer material in sequence, with a mass ratio of 1:6:1, and then compressed into tablets to obtain the nicotine orally disintegrating tablets.

[0114] Example 4

[0115] This embodiment provides a nicotine orally disintegrating tablet, which differs from Example 1 only in that: no phloretin is added, and its reduced proportion is allocated to paeonol, quercetin and magnolol, while the other raw materials and steps remain unchanged.

[0116] Example 5

[0117] This embodiment provides a nicotine orally disintegrating tablet, which differs from Example 1 only in that: paeonol is not added, and its reduced proportion is allocated to phloretin, quercetin, and magnolol, while the other raw materials and steps remain unchanged.

[0118] Example 6

[0119] This embodiment provides a nicotine orally disintegrating tablet, which differs from Example 1 only in that: quercetin is not added, and its proportion is reduced and allocated to phloretin, paeonol and magnolol, while the other raw materials and steps remain unchanged.

[0120] Example 7

[0121] This embodiment provides a nicotine orally disintegrating tablet, which differs from Example 1 only in that: no magnolol is added, and its reduced proportion is allocated to phloretin, paeonol and quercetin, while the other raw materials and steps remain unchanged.

[0122] Comparative Example 1

[0123] This comparative example provides a nicotine orally disintegrating tablet, which is prepared by a method comprising the following steps:

[0124] (1) Preparation of outer layer material: By weight, 20 parts of nicotine nanoparticles provided in Preparation Example 1, 65 parts of instant starch, 1.5 parts of magnesium stearate, 4 parts of aspartame, and 7 parts of peppermint flavoring are mixed, pulverized and sieved to obtain the outer layer material.

[0125] Preparation of the middle layer material: By weight, mix 17 parts nicotine, 55 parts ethyl cellulose, 25 parts polyethylene glycol 3000 and 4 parts micronized silica gel, pulverize and sieve to obtain the middle layer material.

[0126] Preparation of inner layer material: By weight, mix 5 parts nicotine, 3 parts phloretin, 2 parts paeonol, 3 parts quercetin, 2 parts magnolol, and 15 parts lactose, pulverize and sieve to obtain the final product;

[0127] (2) The inner layer material is coated with the middle layer material and the outer layer material in sequence, with a mass ratio of 1:5:1, and then compressed into tablets to obtain the nicotine orally disintegrating tablets.

[0128] Comparative Example 2

[0129] This comparative example provides a nicotine orally disintegrating tablet, which is prepared by a method comprising the following steps:

[0130] (1) Preparation of outer layer material: By weight, mix 20 parts nicotine, 65 parts instant starch, 1.5 parts magnesium stearate, 4 parts aspartame and 7 parts peppermint flavoring, pulverize and sieve to obtain the outer layer material.

[0131] Preparation of the middle layer material: By weight, 17 parts of nicotine nanoparticles provided in Preparation Example 1, 55 parts of ethyl cellulose, 25 parts of polyethylene glycol 3000, and 4 parts of micronized silica powder are mixed, pulverized, and sieved to obtain the middle layer material.

[0132] Preparation of inner layer material: By weight, mix 5 parts nicotine, 3 parts phloretin, 2 parts paeonol, 3 parts quercetin, 2 parts magnolol, and 15 parts lactose, pulverize and sieve to obtain the final product;

[0133] (2) The inner layer material is coated with the middle layer material and the outer layer material in sequence, with a mass ratio of 1:5:1, and then compressed into tablets to obtain the nicotine orally disintegrating tablets.

[0134] Comparative Example 3

[0135] This comparative example provides a nicotine orally disintegrating tablet, which is prepared by a method comprising the following steps:

[0136] (1) Preparation of outer layer material: By weight, 17 parts nicotine, 55 parts ethyl cellulose, 25 parts polyethylene glycol 3000 and 4 parts micronized silica gel are mixed, pulverized and sieved to obtain the outer layer material.

[0137] Preparation of the middle layer material: By weight, 5 parts of nicotine nanoparticles provided in Preparation Example 1, 3 parts of phloretin, 2 parts of paeonol, 3 parts of quercetin, 2 parts of magnolol, and 15 parts of lactose are mixed, pulverized and sieved to obtain the middle layer material.

[0138] Preparation of inner layer material: By weight, mix 20 parts nicotine, 65 parts instant starch, 1.5 parts magnesium stearate, 4 parts aspartame, and 7 parts peppermint flavoring, pulverize and sieve to obtain the final product;

[0139] (2) The inner layer material is coated with the middle layer material and the outer layer material in sequence, with a mass ratio of 1:5:1, and then compressed into tablets to obtain the nicotine orally disintegrating tablets.

[0140] Comparative Example 4

[0141] This comparative example provides a nicotine orally disintegrating tablet, which is prepared by a method comprising the following steps:

[0142] (1) Preparation of outer layer material: By weight, 5 parts of nicotine nanoparticles provided in Preparation Example 1, 3 parts of phloretin, 2 parts of paeonol, 3 parts of quercetin, 2 parts of magnolol and 15 parts of lactose are mixed, pulverized and sieved to obtain the outer layer material.

[0143] Preparation of the middle layer material: By weight, mix 20 parts nicotine, 65 parts instant starch, 1.5 parts magnesium stearate, 4 parts aspartame, and 7 parts peppermint flavoring, pulverize and sieve to obtain the middle layer material.

[0144] Preparation of inner layer material: By weight, mix 17 parts nicotine, 55 parts ethyl cellulose, 25 parts polyethylene glycol 3000 and 4 parts micronized silica powder, pulverize and sieve to obtain the final product;

[0145] (2) The inner layer material is coated with the middle layer material and the outer layer material in sequence, with a mass ratio of 1:5:1, and then compressed into tablets to obtain the nicotine orally disintegrating tablets.

[0146] Comparative Example 5

[0147] This comparative example provides a commercially available nicotine oral cigarette.

[0148] Test Example 1

[0149] Artificial saliva (formulation shown in Table 1, pH=6.7) was used to simulate the oral cavity environment. A drug dissolution analyzer was used to test the release of nicotine orally disintegrating tablets provided in Examples 1-3 or Comparative Examples 1-4, and the commercially available nicotine smoke provided in Comparative Example 5, in the oral cavity. The temperature was set to 37℃ and the rotation speed to 100 rpm. Artificial saliva was added to a 1000 mL dissolution vessel. The nicotine orally disintegrating tablets were placed in the dissolution vessel, and the rotation was started; this was recorded as 0 min. At 5 min, 10 min, 15 min, 20 min, 30 min, 40 min, and 60 min, 10 mL samples were taken for HPLC analysis, and 10 mL of artificial saliva was added after each sample.

[0150] The test results are shown in Table 2. Commercially available nicotine products have excessively low release levels in the initial stages of nicotine absorption, failing to meet immediate cravings. Conversely, their release levels are excessively high in the later stages of absorption, resulting in a rapid, abrupt release that provides little comfort. Furthermore, the explosive release of nicotine in the later stages is highly irritating, causing dizziness and vomiting. This invention, through the design and formulation of a specific three-layer composite structure, synergistically controls nicotine release within a reasonable range, balancing immediate relief in the initial stages of absorption with the need for stable maintenance during absorption. Changing the position of each layer would result in a lower nicotine release level in the early, middle, and later stages of absorption, failing to meet immediate nicotine cravings. The inner layer, with nicotine encapsulated in chitosan and sodium tripolyphosphate to form nanoparticles, provides better sustained-release effects, adapting to the release of components in the outer and middle layers, thus controlling the nicotine release process within a reasonable range. When nicotine nanoparticles are placed in the outer layer, the nicotine release remains at a low level during the ingestion process, which cannot meet the immediate needs. When nicotine nanoparticles are placed in the middle layer, it is difficult to achieve the release level required to maintain nicotine levels in the later stages of ingestion.

[0151] Table 1

[0152] composition Concentration (mM) Sodium chloride 10 Sodium hydrogen phosphate 2.4 Potassium dihydrogen phosphate 2.5 Citric acid 0.15 Potassium bicarbonate 15 Magnesium chloride 1.5 Calcium chloride 1.5

[0153] Table 2

[0154]

[0155] Test Example 2

[0156] The main cause of abnormal breath is the increased content of volatile sulfur compounds (VSCs) in the oral cavity. A breath analyzer and an OralChroma™ portable gas chromatograph (ABILIT, Japan) were used to detect changes in the total concentration of VSCs in breath before and after using the nicotine orally disintegrating tablets provided in Examples 1-7 or Comparative Examples 3-4, and the commercially available nicotine provided in Comparative Example 5. Subjects used test samples. One hour later, the sampler was inserted approximately 3 cm into the subject's oral cavity. The sampler was pushed and pulled three times with the mouth closed. The sampler was then removed from the oral cavity, and the gas was pushed to the 1 mL mark. The sampler was then inserted into the instrument's inlet and the gas was pushed in for detection. This was repeated three times, and the average value was taken. The change in VSCs was calculated as: VSCs change = VSCs content after use - VSCs content before use.

[0157] The test results are shown in Table 3. The present invention, through the design and formulation of a three-layer composite structure, synergistically controls the release of each component. Phloretin, paeonol, quercetin and magnolol have a synergistic effect, which can protect the oral mucosa, regulate the oral pH value, inhibit harmful bacteria in the oral cavity, maintain the oral microecological balance, reduce the content of volatile sulfur compounds in breath, and ensure fresh breath.

[0158] Table 3

[0159] Test sample VSCs change value (ppb) Example 1 -187 Example 2 -210 Example 3 -165 Example 4 -185 Example 5 -179 Example 6 -173 Example 7 -141 Comparative Example 3 -181 Comparative Example 4 -183 Comparative Example 5 -35

[0160] Test Example 3

[0161] Referring to the "Sensory Evaluation Method for Bagged Oral Cigarettes QYNZY.J07.053_2017", relevant smoking evaluation experts were organized to score the nicotine oral disintegrating tablets provided in Examples 1-7 or Comparative Examples 1-4, and the commercially available nicotine oral cigarettes provided in Comparative Example 5.

[0162] The test results are shown in Table 4. This invention, through the design and formulation of a three-layer composite structure, synergistically controls the release of nicotine within a reasonable range, balancing the immediate relief at the initial stage of nicotine absorption with the need for stable maintenance during the absorption process. The inner layer, with chitosan and sodium tripolyphosphate encapsulating nicotine into nanoparticles, exhibits better sustained-release effects, adapting to the release of components in the outer and middle layers, thus controlling the nicotine release process within a reasonable range. Phloretin, paeonol, quercetin, and magnolol have a synergistic effect, protecting the oral mucosa, regulating oral pH, inhibiting harmful oral bacteria, maintaining oral microecological balance, reducing the content of volatile sulfur compounds in breath, and ensuring fresh breath.

[0163] Table 4

[0164]

[0165] This invention illustrates a nicotine orally disintegrating tablet with a multilayered composite sustained-release structure and its preparation method through the above embodiments. However, this invention is not limited to the above embodiments, meaning that this invention does not necessarily rely on the above embodiments for implementation. Those skilled in the art should understand that any improvements to this invention, equivalent substitutions of the raw materials in the product, addition of auxiliary components, and selection of specific methods, etc., all fall within the protection and disclosure scope of this invention.

[0166] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0167] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A nicotine orally disintegrating tablet with a multi-layered composite sustained-release structure, characterized in that, The nicotine orally disintegrating tablets include an inner layer and a middle layer and an outer layer that are sequentially wrapped from the inside out; The outer layer comprises nicotine, instant starch, and lubricant; The middle layer comprises nicotine, ethyl cellulose, polyethylene glycol, and a flow aid; The inner layer comprises chitosan and sodium tripolyphosphate-coated nicotine nanoparticles, oral microenvironment modifiers, and fillers.

2. The nicotine orally disintegrating tablet according to claim 1, characterized in that, The outer layer comprises, by weight, 10-25 parts nicotine, 60-70 parts instant starch, and 1-2 parts lubricant; The components of the middle layer, by weight, include 15-20 parts nicotine, 40-70 parts ethyl cellulose, 20-30 parts polyethylene glycol, and 3-5 parts flow aid; The inner layer comprises, by weight, 1-10 parts of nicotine nanoparticles coated with chitosan and sodium tripolyphosphate, 5-15 parts of oral microenvironment modifier, and 10-20 parts of filler. In the inner layer, the mass ratio of nicotine, chitosan, and sodium tripolyphosphate is (20-35):(50-60):(10-15); The mass ratio of the outer layer, middle layer and inner layer is (1-5):(2-7):(1-6).

3. The nicotine orally disintegrating tablet according to claim 1 or 2, characterized in that, The chitosan and sodium tripolyphosphate-coated nicotine nanoparticles were prepared by a method comprising the following steps: Chitosan was dissolved in an aqueous organic acid solution, mixed with nicotine, and then an aqueous sodium tripolyphosphate solution was added and stirred. The mixture was then spray-dried to obtain nicotine nanoparticles coated with chitosan and sodium tripolyphosphate.

4. The nicotine orally disintegrating tablet according to claim 3, characterized in that, The organic acid aqueous solution contains 0.8-3% organic acid by mass. Preferably, the organic acid includes any one or a combination of at least two of acetic acid, citric acid, lactic acid, or malic acid; Preferably, the mass ratio of chitosan to the aqueous organic acid solution is 1:(100-300); Preferably, the sodium tripolyphosphate aqueous solution contains 2-3% sodium tripolyphosphate by mass. Preferably, the stirring speed is 1000-2000 rpm and the stirring time is 30-60 min; Preferably, the inlet air temperature for the spray drying is 140-190°C.

5. The nicotine orally disintegrating tablet according to any one of claims 1-4, characterized in that, The oral microenvironment modifier includes any one or a combination of at least two of phloretin, paeonol, quercetin, or magnolol; Preferably, the oral microenvironment modifier includes phloretin, paeonol, quercetin, and magnolol; Preferably, the mass ratio of phloretin, paeonol, quercetin and magnolol is (3-6):(2-3):(3-7):(2-4).

6. The nicotine orally disintegrating tablet according to any one of claims 1-5, characterized in that, The lubricant includes any one or a combination of at least two of magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitate stearate, sodium lauryl sulfate, or sodium stearate fumarate. Preferably, the number-average molecular weight of the polyethylene glycol is 1000-6000; Preferably, the flow aid comprises micronized silica gel and / or talc; Preferably, the filler comprises any one or a combination of at least two of lactose, fructose, xylose, sucrose, trehalose, mannose, maltose, mannitol, sorbitol, or xylitol.

7. The nicotine orally disintegrating tablet according to any one of claims 1-6, characterized in that, The outer layer also includes sweeteners; Preferably, the outer layer further comprises 3-5 parts by weight of sweetener; Preferably, the sweetener includes any one or a combination of at least two of aspartame, erythritol, sucralose, isomaltitol, acesulfame potassium, neotame, saccharin, sucrose, glucose, maltose, or fructose.

8. The nicotine orally disintegrating tablet according to any one of claims 1-7, characterized in that, The outer layer also includes a cooling agent; Preferably, the outer layer further comprises 5-8 parts by weight of a cooling agent; Preferably, the cooling agent comprises any one or a combination of at least two of the following: peppermint flavor, menthol, ethyl menthane formamide, menthone, menthyl acetate, or limonene.

9. The method for preparing nicotine orally disintegrating tablets according to any one of claims 1-8, characterized in that, The method includes: Nicotine, instant starch, and lubricant are mixed to obtain the outer layer material; nicotine, ethyl cellulose, polyethylene glycol, and a flow aid are mixed to obtain the middle layer material; nicotine nanoparticles, oral microenvironment modifiers, and fillers are mixed to obtain the inner layer material. The inner layer material is sequentially coated with a middle layer material and an outer layer material, and then compressed into a tablet to obtain the nicotine orally disintegrating tablet.

10. The method according to claim 9, characterized in that, The preparation process of the outer layer material also includes the addition of sweeteners and / or cooling agents; Preferably, the mixing process further includes a step of crushing and sieving.

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