Nicotine solid atomized preparation with throat-clearing and sore-throat-relieving effects

Abstract

The invention belongs to the technical field of nicotine compositions, and particularly relates to a nicotine solid atomized preparation with throat-clearing and sore-throat-relieving effects. According to the preparation, the throat-clearing and sore-throat-relieving functional components are added and are controlled to be mainly deposited at the oropharynx, so that the nicotine is delivered, and meanwhile, the symptoms such as oral pharyngitis and dry mouth caused by electronic cigarette smoking are relieved. When the preparation is used, phase change is avoided, nicotine atomization can be achieved at normal temperature or low temperature (smaller than or equal to 60 DEG C), the conditions of ketone substances, metal leaching and the like cannot be generated, and meanwhile electronic waste cannot be generated; the nicotine component is micronized, second-hand smoke exposure is reduced, the nicotine component is solid aerosol, granular sensation of the throat of the tobacco is reduced, throat hitting sensation closer to that of the cigarette is generated, and therefore the better effect of replacing the cigarette can be achieved, and the conversion rate of replacing the cigarette is increased. In addition, a solid formula is adopted, transportation and carrying are convenient, and the problems of liquid leakage during transportation, liquid leakage during shelving, non-lasting fragrance retention and the like do not exist.

Description

Technical Field

[0001] The invention belongs to the technical field of nicotine compositions, and in particular relates to a nicotine solid atomization preparation having the effects of clearing the throat and relieving pharyngitis. Background Art

[0002] The traditional tobacco industry that uses tobacco leaves has experienced hundreds of years of development. The research on the health hazards of smoking traditional cigarettes has been very comprehensive. The aerosol of traditional tobacco contains more than 7,000 substances including tar, nicotine, and carbon monoxide, which can cause irreversible damage to multiple organs of the human body. The industry problem of how to satisfy the addiction while minimizing the harm to the human body has promoted the birth and development of new smoking alternatives.

[0003] Electronic cigarettes are a new type of smoking alternative product that is currently more widely accepted. Electronic cigarettes are also called electronic nicotine delivery systems (ENDS). They are mainly composed of batteries, heated atomizers, and cartridges that store tobacco oil. The tobacco oil is heated to form a liquid aerosol for human inhalation. Although electronic cigarettes can reduce harm compared to traditional cigarettes, they still have the following problems:

[0004] 1) The heating phase transition temperature of e-cigarettes is about 240°C. Compared with the high temperature generated by cigarette combustion (about 800°C), there are still potential harmful substances caused by heating phase transition in the e-cigarette liquid aerosol, such as the generation of aldehydes and the leaching of heavy metal elements.

[0005] 2) The aerosols produced by e-cigarettes are mostly nano-sized, which can be carried into the environment with the respiratory airflow. In addition to causing higher environmental exposure to nicotine, they also bring exposure to flavoring substances, which still poses health risks to non-smokers. E-cigarettes do not solve the problem of exposure to secondhand smoke from cigarettes.

[0006] 3) For long-term smokers, their oropharynx has increased tolerance to nicotine due to long-term smoking. The nicotine carried by the liquid aerosol produced by e-cigarettes is often not able to achieve the throat hit of nicotine because of its nano-scale nature, so they feel that it is not enough to relieve their addiction psychologically, thus hindering the effect of replacing cigarettes. In addition, studies have shown that e-cigarettes can cause harm to the oropharynx, causing symptoms such as oropharyngeal inflammation and dry mouth.

[0007] 4) The e-cigarette oil is a liquid formula, which may cause leakage during transportation, leakage when stored, and burning during heating. In addition, the flavor contained in the liquid oil will be lost as the storage time increases, and the fragrance will not last long.

[0008] 5) The lithium batteries in electronic cigarette devices pose a safety hazard, and electronic waste pollutes the environment. Summary of the invention

[0009] Therefore, the technical problem to be solved by the present invention is to overcome the above-mentioned defects of the electronic cigarette in the prior art, thereby providing a nicotine solid atomization preparation with the effect of clearing the throat and relieving pharyngitis.

[0010] To this end, the present invention provides the following technical solutions:

[0011] The present invention provides a nicotine solid aerosol preparation with throat clearing and pharyngeal relief effects, comprising the following components in percentage by mass: based on nicotine, 0.05-15% of a nicotine component; 1.8-40% of a throat clearing and pharyngeal relief component; 3.5-40% of flavor particles; 0.05-30% of a taste improver; and the remainder being a carrier;

[0012] Wherein, the particle size D90 of the nicotine component is ≤10 μm; and the particle size D90 of the throat clearing and relieving swallowing component is ≤50 μm.

[0013] Optionally, the composition comprises the following components in percentage by mass: based on nicotine, 0.1-12.5% ​​of nicotine component; 5-30% of throat clearing and relieving component; 8-30% of flavor particles; and 0.1-20% of taste improver.

[0014] Optionally, the composition comprises the following components in percentage by mass: based on nicotine, 0.1-10% of nicotine component; 5-20% of throat clearing and relieving component; 8-25% of flavor particles; and 0.15-15% of taste improver.

[0015] Optionally, the particle size of the flavor particles is D90≤50μm, D10≥5μm;

[0016] and / or, the particle size D90 of the taste improver is ≤50 μm;

[0017] And / or, the particle size D90 of the carrier is ≤200 μm, and the particle size D10 is ≥3 μm.

[0018] Optionally, the nicotine component is prepared by micronizing nicotine or its salt and auxiliary materials;

[0019] Optionally, in the nicotine component, the mass percentage of nicotine or its salt is ≥10%;

[0020] Optionally, the nicotine salt is selected from at least one of nicotine malate, nicotine salicylate, nicotine tartrate, nicotine levulinate, nicotine benzoate, nicotine citrate, nicotine fumarate and nicotine propionate;

[0021] Optionally, the excipient is a pharmaceutical inhalation grade excipient; further optionally, the excipient is selected from at least one of lactose, mannitol, trehalose, magnesium stearate, leucine, and erythritol.

[0022] Optionally, the throat clearing and relieving swallowing component is obtained by mixing and granulating the throat clearing and relieving swallowing extract and an inhalable excipient;

[0023] Optionally, in the throat clearing and relieving swallowing component, the throat clearing and relieving swallowing extract accounts for ≥15% by weight;

[0024] Optionally, the inhalable excipient is selected from at least one of lactose, mannitol, erythritol, leucine and glycine.

[0025] Optionally, the raw materials of the throat clearing and relieving throat extract include the following raw materials in parts by weight: 60-80 parts of mint, 40-60 parts of honeysuckle, 20-40 parts of forsythia, 60-80 parts of Sterculia lychnophora, 40-60 parts of isatis root, and 60-80 parts of dandelion;

[0026] Preferably, the raw materials of the throat clearing and relieving throat extract include the following raw materials in parts by weight: 60-72 parts of mint, 42-53 parts of honeysuckle, 20-29 parts of forsythia, 62-70 parts of Sterculia lychnophora, 42-53 parts of isatis root, and 60-72 parts of dandelion;

[0027] Optionally, the preparation method of the throat clearing and relieving throat extract is: mixing the raw materials, extracting with a solvent, and concentrating to obtain a fluid extract, which is the throat clearing and relieving throat extract.

[0028] Optionally, the flavor particles are obtained by mixing the flavor base component with a carrier and granulating them;

[0029] Optionally, in the flavor particles, the mass proportion of the flavor base component is 5 to 20%;

[0030] Optionally, the flavor particles further include an anti-sticking agent; preferably, the anti-sticking agent is selected from at least one of magnesium stearate, stearic acid, and phospholipids;

[0031] Optionally, the carrier in the flavor particles is selected from at least one of sugar and amino acid, wherein the sugar is composed of one or more sugars or sugar alcohols;

[0032] Optionally, the sugar is selected from at least one of lactose, mannitol, trehalose, erythritol, isomalt, sorbitol, xylitol, glucose, fructose, and sucrose;

[0033] Optionally, the amino acid is selected from at least one of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, glutamine, methionine, arginine, serine, threonine, cysteine, and proline.

[0034] Optionally, the taste modifier includes at least one of a sweetener, a cooling agent, and an anti-sticking agent;

[0035] Optionally, the sweetener is selected from at least one of neotame, acesulfame potassium, aspartame, and sucralose;

[0036] Optionally, the cooling agent is selected from N,2,3-trimethyl-2-isopropylbutyramide (WS-23), N-ethyl-2-isopropyl-5-methylcyclohexanecarboxamide (WS-3), (+)-neoisomenthol, (-)-neoisomenthol, (-)-isomenthol, p-menthyl-3,8-diol, (+)-isomenthol, (-)-neoisomenthol, (2R)-3-(1-methoxy)propane-1,2-diol, (2RS)-3-(1-methoxy)propane-1,2-diol, p-menthyl-3-hydroxy-1-glyceride (WS-3 0), p-menthyl-3-hydroxy acid-1-vinyl glycerol ester (WS-4), (-)-isopiperitol, (+)-menthol, (+)-neomenthol, (2S)-3-(1-menthoxy)propane-1,2-diol, menthone glycerol ketal, menthyl lactate, N-tert-butyl p-menthyl-3-carboxamide (WS-14), (-)-menthol, N-(4-methoxyphenyl) p-menthyl-3-carboxamide (WS-13), ethyl acetate (N-ethyl p-menthyl-3-carboxamide) (WS-5), and borneol;

[0037] Optionally, the anti-sticking agent is selected from at least one of magnesium stearate, stearic acid, and phospholipids.

[0038] Optionally, the carrier is selected from at least one of sugar or sugar alcohol;

[0039] Optionally, the carrier is selected from at least one of lactose, mannitol, erythritol, isomalt, sorbitol, xylitol, glucose, fructose and sucrose.

[0040] The technical solution of the present invention has the following advantages:

[0041] The nicotine solid atomization preparation with throat clearing and throat relieving effect provided by the present invention, by adding throat clearing and throat relieving effect ingredients, and controlling its main deposition in the oropharynx, thereby achieving delivery of nicotine, while relieving symptoms such as oropharyngeal inflammation and dry mouth caused by smoking electronic cigarettes. The preparation has no phase change when used, and the atomization of nicotine can be achieved at room temperature or low temperature (≤60°C), and ketone substances and metal leaching and the like will not be produced, and electronic waste will not be produced at the same time; the nicotine component is micronized to reduce secondhand smoke exposure, and the nicotine component is a solid aerosol, and the granularity of the tobacco throat is restored to produce a throat hitting feeling closer to cigarettes, so as to achieve a better effect of replacing cigarettes and improve the conversion rate of replacing cigarettes. In addition, the present invention adopts a solid formula, which is convenient for transportation and carrying, and there is no problem of leakage during transportation, leakage when shelving, and the problem of not lasting fragrance.

[0042] The nicotine solid aerosol preparation with throat clearing and pharyngeal relief provided by the present invention controls the particle sizes of components such as taste improvers and flavor particles so that more of them are deposited in the oropharynx, thereby achieving the purpose of further improving the taste and enhancing the effect of replacing cigarettes. DETAILED DESCRIPTION

[0043] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0044] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0045] The principle of the present invention is: from the basic theory of respiratory drug delivery, when the aerodynamic diameter of the inhaled particles is within 8μm, its deposition mode in the respiratory tract is mainly gravity sedimentation, and it is mainly deposited in the lungs; when the aerodynamic diameter of the particles is ≥10μm, its deposition mode is mainly inertial impact, and it is mainly deposited in the oropharynx. Therefore, this technology forms a micron-sized solid powder of nicotine or its salts (including single salts and double salts) through a micronization process, so that it is mainly deposited in the lungs, and reaches the brain through the rich blood flow in the lungs to exert the effect of relieving addiction, while the throat-clearing and pharyngeal health care ingredients, flavor particles, taste improvers, and carrier particle sizes are controlled within an appropriate range, so that they are mainly deposited in the oropharynx, exerting the effects of improving taste and clearing the throat and relieving pharyngitis. A more specific technical scheme is as follows:

[0046] 1. Nicotine or its salt and / or excipients are subjected to air flow milling or spray drying technology to form a particle size of D90≤10μm, preferably D90≤8μm, preferably D90≤6μm, more preferably D90≤3.5μm, and D10≥0.4μm, wherein the excipients are of pharmaceutical inhalation grade, including but not limited to lactose, mannitol, trehalose, magnesium stearate, leucine, and erythritol.

[0047] 2. The weight of nicotine or its salt (calculated as nicotine) is 0.05-15%, preferably 0.1-12.5%, and more preferably 0.1-10%. Different specifications can be set according to the nicotine dosage tolerated by smokers. For example, in some embodiments, nicotine accounts for 1.5% by weight, which is suitable for electronic cigarette users; in some embodiments, nicotine accounts for 5% by weight, which is suitable for electronic cigarette users with a smoking age of more than 10 years; in some embodiments, nicotine accounts for 8% by weight, which is suitable for traditional cigarette users.

[0048] 3. The nicotine salt may be nicotine malate, nicotine salicylate, nicotine tartrate, nicotine levulinate, nicotine benzoate, nicotine citrate, nicotine fumarate, nicotine propionate, preferably nicotine malate, nicotine levulinate, nicotine benzoate.

[0049] 4. Throat-clearing and throat-relief component: Based on the theory of traditional Chinese medicine, a compound with good throat-clearing and throat-relief effect is obtained by combining medicinal and edible herbal plants with antibacterial and anti-inflammatory, wind-clearing and heat-clearing, diuretic and stranguria-relieving effects. The compound includes at least: mint, honeysuckle, forsythia, Sterculia lychnophora, Radix Isatidis, and dandelion. The formula is explained as follows: mint is pungent and cool, dispels wind-heat, clears the head, and can detoxify and relieve throat; honeysuckle and forsythia have a fragrant smell, which can not only dispel wind-heat, clear heat and detoxify, but also eliminate filth and turbidity. The three are combined to strengthen the function of dispersing wind-heat and relieve throat pain. Sterculia lychnophora is a traditional medicinal and edible material for clearing throat and throat, with the functions of clearing heat, moistening the lungs, relieving throat pain, and detoxification. Isatis lychnophora is bitter, cold in nature, and belongs to the heart and stomach meridians. It has the functions of clearing heat and detoxification, cooling blood and relieving throat pain, and is often used for fever and sore throat. Dandelion is a perennial herb of the Asteraceae family. The whole plant tastes sweet and bitter and is cold in nature. It can clear away heat and detoxify, disperse stagnation and reduce swelling, and can also act as a diuretic and relieve stranguria.

[0050] 5. The weight parts of the raw materials of the compound are as follows: 60-80 parts of mint, 40-60 parts of honeysuckle, 20-40 parts of forsythia, 60-80 parts of sterculia lychnophora, 40-60 parts of isatis root, and 60-80 parts of dandelion; more preferably, 60-72 parts of mint, 42-53 parts of honeysuckle, 20-29 parts of forsythia, 62-70 parts of sterculia lychnophora, 42-53 parts of isatis root, and 60-72 parts of dandelion.

[0051] 6. Preparation of throat clearing and relieving pharyngitis extract: Peppermint, honeysuckle, forsythia, Sterculia lychnophora, Radix Isatidis, and Taraxacum officinale are prepared by a heating reflux method including but not limited to, and the extraction solvent used is not limited to an ethanol-water solvent. After 1 or 2 or 3 or 4 or more extractions, the extract is collected by filtration, the filter residue is removed, and the ethanol is recovered under reduced pressure and concentrated to obtain a compound fluid extract. The compound fluid extract and inhalable excipients are spray-dried, freeze-dried, or vacuum-dried to obtain a compound dry powder (i.e., throat clearing and relieving pharyngitis component). Among them, the inhalable excipient is preferably one or a combination of lactose, mannitol, erythritol, leucine, and glycine. The weight of the compound dry powder formula accounts for 2 to 40%, preferably 5 to 30%, and more preferably 5 to 20%.

[0052] 7. Flavor particles are generally made of flavor base components and carriers by spray drying, adsorption or freeze drying. The flavor base components are composed of a complex of multiple flavor raw materials. The carrier is generally composed of sugar and amino acids, wherein the sugar can be composed of one or more sugars or sugar alcohols, preferably: lactose, mannitol, trehalose, erythritol, isomalt, sorbitol, xylitol, glucose, fructose, sucrose, more preferably lactose, mannitol, erythritol; the amino acids are 20 common amino acids, namely glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, glutamine, methionine, arginine, serine, threonine, cysteine, proline, preferably glycine, leucine, isoleucine, more preferably leucine. Since most of the flavor components are low-melting-point, volatile ingredients, they will adhere and clump when prepared into powder, so anti-sticking agents are also included, including but not limited to magnesium stearate, stearic acid, lecithin, preferably magnesium stearate.

[0053] 8. Taste improvers include sweeteners and cooling agents. Sweeteners may be highly sweetened, such as neotame, acesulfame potassium, aspartame, sucralose, and neotame is more preferred. Cooling agents may be N,2,3-trimethyl-2-isopropylbutyramide (WS-23), N-ethyl-2-isopropyl-5-methylcyclohexanecarboxamide (WS-3), (+)-neoisomenthol, (-)-neoisomenthol, (-)-isomenthol, p-menthyl-3,8-diol, (+)-isomenthol, (-)-neoisomenthol, (2R)-3-(1-methoxy)propane-1,2-diol, (2RS)-3-(1-methoxy)propane-1,2-diol, p-menthyl-3-hydroxy acid-1-glyceride (WS-30), p-menthyl-3-hydroxy acid-1-vinylglyceride (WS-4), (-)-isopiperidin Menthol, (+)-menthol, (+)-neomenthol, (2S)-3-(1-menthoxy)propane-1,2-diol, menthone glycerol acetal, menthyl lactate, N-tert-butyl p-menthyl-3-carboxamide (WS-14), (-)-menthol, N-(4-methoxyphenyl) p-menthyl-3-carboxamide (WS-13), acetic acid (N-ethyl p-menthyl-3-carboxamide) ethyl ester (WS-5), borneol, one or two or more, more preferably: menthol, N-ethyl-2-isopropyl-5-methylcyclohexanecarboxamide (WS-3), N,2,3-trimethyl-2-isopropylbutyramide (WS-23). ​​Since most cooling agents are low melting point substances, there will be adhesion and agglomeration when controlling the particle size, so anti-sticking agents are also included, including but not limited to magnesium stearate, stearic acid, phospholipids, preferably magnesium stearate.

[0054] 9. The carrier plays a role in dispersing, weakly adsorbing active ingredients, and regulating fluidity in this technology. Including but not limited to a composition of one or more sugars or sugar alcohols, preferably lactose, mannitol, erythritol, isomalt, sorbitol, xylitol, glucose, fructose, sucrose, more preferably lactose, mannitol, erythritol; in addition, the particle size of the carrier is preferably D90≤200μm, D10≥3μm, preferably D90≤180μm, D10≥5μm, more preferably D90≤150μm, D10≥5μm, more preferably D90≤100μm, D10≥8μm. In some embodiments, the particle size D90 of the carrier can be around 50μm, in some embodiments, the carrier particle size D90 is around 80μm, and in more embodiments, the carrier particle size D90 is around 100μm.

[0055] 10. A nicotine solid aerosol preparation with throat clearing and throat relieving effects, comprising a nicotine component, a throat clearing and throat relieving component (including but not limited to: mint, honeysuckle, forsythia, Sterculia lychnophora, Radix Isatidis, dandelion), flavor particles, a taste improver, and a carrier, wherein the nicotine component includes but is not limited to nicotine or its salt and excipients co-micronized to obtain a micron-sized powder. The throat clearing and throat relieving component, flavor particles, taste improver, and carrier are made into a larger particle size (D90 ≥ 10 μm) by particle size control technology. Layered delivery is achieved through formulation technology, that is, nicotine-like components are delivered to the lungs, while the throat clearing and throat relieving component, flavor particles, taste improver, and carrier are deposited in the oropharynx. The nicotine component (in terms of nicotine) accounts for 0.05-15% by weight, preferably 0.1-12.5%, and more preferably 0.1-10%. The throat clearing and throat relieving component accounts for 1.8-40% by weight, preferably 5-30%, and more preferably 5-20%. The weight of the flavor particles accounts for 3.5-40%, preferably 8-30%, more preferably 8-25%. The taste improver accounts for 0.05-30%, preferably 0.1-20%, more preferably 0.15-15%. The total weight of the carrier accounts for 30-90%, more preferably 40-80%.

[0056] 11. When in use, the nicotine solid atomized powder is loaded into a capsule or a blister. In some embodiments, a capsule is selected. The capsule model can be selected from 00#, 0#, 1#, 2#, and 3# according to the amount of powder and the inhalation and emptying of the powder. Each capsule is filled with 5 to 100 mg of powder; preferably, each capsule is filled with 10 to 80 mg of powder; more preferably, each capsule is filled with 10 to 50 mg of powder.

[0057] 12. This technology product can use a capsule-type inhalation device. The principle of the device is similar to Revolizer (India, Cipla), and its appearance is like a cigarette. It can produce aerosols at normal smoking flow rates. Nicotine is deposited in the lungs due to its small aerodynamic particle size, quickly enters the blood, and penetrates the blood-brain barrier to produce a sense of satisfaction; while large-particle carriers, flavors, flavorings, and throat-clearing and throat-relief components are deposited in the oropharynx due to their large particle size, achieving the purpose of improving taste and oropharyngeal inflammation. The amount of each inhalation does not exceed 10 mg, preferably does not exceed 5 mg, and more preferably does not exceed 3 mg. Each capsule can be inhaled for at least 5 inhalations, preferably at least 10 inhalations, and more preferably at least 20 inhalations.

[0058] The technical solution of the present invention is further described below in conjunction with specific embodiments.

[0059] Example 1

[0060] This embodiment provides a nicotine component: the specific preparation method is:

[0061] 25 g of nicotine levulinate and 25 g of erythritol were dissolved in a 15% ethanol solution with a solid content of 10%. A spray dryer Buchi 290 was used with a feed rate of 5 ml / min, an air inlet temperature of 120°C, an air outlet temperature of 100°C, an atomization pressure of 5 bar, and a fan frequency of 80% to obtain nicotine levulinate-erythritol co-spray-dried powder. The particle size was measured using a Synpatek laser particle size analyzer (model: HELOS-OASIS), and the D90 was 5 μm and the D10 was 0.71 μm, referred to as nicotine powder 1.

[0062] Example 2

[0063] This embodiment provides a nicotine component: the specific preparation method is:

[0064] 20 g of nicotine malate and 25 g of lactose were dissolved in 15% ethanol solution with a solid content of 10%. A spray dryer Buchi 290 was used with a feed rate of 3 ml / min, an air inlet temperature of 80°C, an air outlet temperature of 60°C, an atomization pressure of 5 bar, and a fan frequency of 100% to obtain nicotine malate-lactose co-spray-dried powder. The particle size was measured using a Synpatek laser particle size analyzer (model: HELOS-OASIS), and the D90 was 5.5 μm and the D10 was 0.55 μm, referred to as nicotine powder 2.

[0065] Example 3

[0066] This embodiment provides a nicotine component: the specific preparation method is:

[0067] 25 g of nicotine benzoate and 25 g of lactose were dissolved in 15% ethanol solution with a solid content of 10%. A spray dryer Buchi 290 was used with a feed rate of 3 ml / min, an air inlet temperature of 80°C, an air outlet temperature of 60°C, an atomization pressure of 5 bar, and a fan frequency of 90% to obtain nicotine benzoate-lactose co-spray-dried powder. The particle size was measured using a Synpatek laser particle size analyzer (model: HELOS-OASIS), and the D90 was 4.5 μm and the D10 was 0.53 μm, referred to as nicotine powder 3.

[0068] Example 4

[0069] This embodiment provides two nicotine components: the specific preparation method is:

[0070] 10 g of nicotine tartrate and 0.4 g of magnesium stearate were mixed in a three-dimensional mixer at a mixing speed of 49 rpm for 20 min, and 5 g of the mixture was mixed in a jet mill at a crushing pressure of 6 to 8 bar, a venturi pressure of 6 to 8 bar, and a screw speed of 100 to 500 rpm to obtain nicotine tartrate-magnesium stearate co-micronized powder. The particle size was measured using a Synpatek laser particle size analyzer (model: HELOS-OASIS), and the D90 was 3.2 μm. , D10 is 0.69μm, referred to as nicotine powder 4-1; the remaining 5g of the mixture was crushed by a jet mill with a crushing pressure of 1-3bar, a Venturi pressure of 2-4bar, and a screw speed of 100-500rpm to obtain nicotine tartrate-magnesium stearate co-powder, and the particle size was measured by a Synpatek laser particle size analyzer (model: HELOS-OASIS), and D90 was 12μm, D10 was 0.82μm, referred to as nicotine powder 4-2.

[0071] Example 5

[0072] This embodiment provides two throat clearing and pharyngeal relieving components: the specific preparation method is:

[0073] 120g of mint, 80g of honeysuckle, 40g of forsythia, 120g of sterculia lychnophora, 80g of isatis root and 120g of dandelion were put into a heating reflux device, with a volume ratio of ethanol to water of 1:1, a solid-liquid ratio (V solvent: V raw material) of 3:1, a reflux temperature of 80°C, a reflux time of 2h, and repeated 3 times. The extract was passed through an 80-mesh sieve, the filtrate was combined, and the ethanol was recovered under reduced pressure and concentrated to obtain a fluid extract. The fluid extract and 350g of lactose were dissolved in 2000mL of a 15% ethanol solution, and 1000ml of the solution to be sprayed was taken and dried using a spray dryer Buchi The mixture was spray dried using a Buchi 290 at a rate of 10 ml / min, an inlet air temperature of 140°C, an outlet air temperature of 120°C, an atomization pressure of 5 bar, and a fan frequency of 100% to obtain a dry powder of a throat clearing and relieving throat component. The particle size was measured using a Simpatek laser particle size analyzer (model: HELOS-OASIS), and the D90 was 35 μm and the D10 was 6.5 μm, which is referred to as compound powder 1-1. The remaining 1000 ml of the solution to be spray dried was spray dried using a spray dryer Buchi 290 at a rate of 20 ml / min, an inlet air temperature of 140°C, an outlet air temperature of 120°C, an atomization pressure of 3 bar, and a fan frequency of 100% to obtain a dry powder of a throat clearing and relieving throat component. The particle size was measured using a Simpatek laser particle size analyzer (model: HELOS-OASIS), and the D90 was 46 μm and the D10 was 8.0 μm, which is referred to as compound powder 1-2.

[0074] Example 6

[0075] This embodiment provides a throat clearing and relieving swallowing component: the specific preparation method is:

[0076] 160 g of mint, 120 g of honeysuckle, 80 g of forsythia, 160 g of sterculia lychnophora, 120 g of isatis root and 160 g of dandelion were put into a heating reflux device, with a volume ratio of ethanol to water of 1:1, a solid-liquid ratio (V solvent: V raw material) of 6:1, a reflux temperature of 110 ° C, a reflux time of 4 h, and repeated 5 times. The extract was passed through an 80-mesh sieve, the filtrate was combined, and the ethanol was recovered under reduced pressure and concentrated to obtain a fluid extract. The fluid extract and 350 g of lactose were dissolved in 2000 mL of a 15% ethanol solution and dried using a spray dryer Buchi The mixture was spray dried at 290 °C with an injection speed of 10 ml / min, an inlet air temperature of 140 °C, an outlet air temperature of 120 °C, an atomization pressure of 5 bar, and a fan frequency of 100% to obtain a dry powder of the throat clearing and relieving component. The particle size was detected by a Synpatek laser particle size analyzer (model: HELOS-OASIS), and the D90 and D10 were 48 μm and 7.3 μm, respectively. The compound powder was referred to as compound powder 2.

[0077] Example 7

[0078] This embodiment provides a flavor particle: the specific preparation method is:

[0079] 10 g of Yunnan flue-cured tobacco flavor base was added to 190 g of lactose monohydrate and mixed with a high-speed mixer to obtain inhalable powder flavor particles loaded with Yunnan flue-cured tobacco flavor base. The particle size was measured using a Sympatec laser particle size analyzer (model: HELOS-OASIS), and the D90 was 48 μm and the D10 was 8.0 μm.

[0080] Example 8 Formulation Investigation

[0081] The samples were prepared according to the following formula and the throat hit score was evaluated:

[0082] Table 1

[0083]

[0084] *Nicotine powder is dosed based on actual nicotine measurement.

[0085] The above formula was filled into 3# capsules, and the taste was evaluated using the Revolizer inhalation device. Users with more than 20 years of smoking experience and who have not used e-cigarettes (abbreviated as: Y20), users with more than 10 years of smoking experience who have used e-cigarettes as a substitute for smoking (abbreviated as: YE10), and e-cigarette users for 1 to 5 years (abbreviated as: E5) were selected, and the throat hit was used as the taste evaluation indicator for evaluation, and scored on a scale of 0-10. The higher the score, the stronger the throat hit. Among them, 0-2 points represent "extremely low" throat hit; 2-4 points represent "relatively low" throat hit; 4-6 points represent "medium" throat hit; 6-8 points represent "relatively strong" throat hit; 8-10 points represent "extremely strong" throat hit. The specific scoring results are shown in the table below:

[0086] Table 2

[0087]

[0088] For people who smoke traditional cigarettes, the nicotine dosage of 2.5-3.0mg has a throat hit similar to that of traditional cigarettes, or even slightly stronger than that of cigarettes. Compared with electronic cigarettes, they are more willing to accept this technology product; for people who smoke both traditional cigarettes and electronic cigarettes, they prefer 1.0-2.0mg nicotine dosage, and 0.5-1.0mg nicotine dosage is more suitable for electronic cigarette users. And the advantages of no smoke and no pollution to the environment have been unanimously recognized by the product testing group.

[0089] Comparing prescriptions 1 to 4, the throat hits of different nicotine salts are similar, and the order is: nicotine tartrate ≈ nicotine malate ≥ nicotine benzoate ≥ nicotine levulinate. Comparing prescriptions 5 and 9, adding equal amounts of different compound dry powders has little effect on the taste of throat hit. Comparing prescriptions 6 and 10, adding equal amounts of nicotine tartrate spray powder, prescription 10 with a larger particle size brings a stronger throat hit due to the increased deposition of nicotine in the oropharynx. For prescriptions 6 and 11, adding equal amounts of compound dry powders of different particle sizes has little effect on the throat hit.

[0090] Example 9 Changes in Nicotine Craving

[0091] In view of the fact that e-cigarette users and cigarette-to-e-cigarette users have replaced smoking through e-cigarettes, people who smoke traditional cigarettes were selected as the research subjects. Twenty adult traditional cigarette users were recruited, with a smoking age of ≥ 20 years, smoking 10 to 20 cigarettes per day, and inhaling 1 cigarette every 1 hour on average.

[0092] The craving cycle of the test groups was studied.

[0093] Smoking after 10 pm the night before is prohibited, and smoking is prohibited after getting up in the morning. The study starts at 8 am, and the nicotine craving value at 8 am is filled in. The craving value range is 0 to 10 points. The higher the score, the greater the craving for smoking. Among them, 0-2 points represent no; 2-4 points represent low; 4-6 points represent medium; 6-8 points represent strong; 8-10 represents extreme. The specific results are shown in the table below:

[0094] Table 3

[0095]

[0096]

[0097] As shown in Table 3, the 20 subjects had a long smoking history, so their smoking cycles were similar and their craving scores were uniform, indicating that their smoking behaviors were highly similar due to long-term smoking. Moreover, since smoking was prohibited after 10 pm the night before, the craving value for smoking behavior after getting up in the morning was as high as 9.02. For those who could feel satisfied 5 minutes after smoking, the average craving score was 2.52. For those who felt satisfied 30 minutes after smoking, the craving score increased to 5.81. Through questioning, some subjects indicated that they had a desire to smoke cigarettes, but it was not strong. After smoking for 1 hour, the craving score increased to 8.40. The subjects generally expressed a strong desire for cigarettes, which they could not bear and must be satisfied immediately. For the subsequent smoking cycle, it also showed a smoking cycle similar to that at 8 o'clock in the morning.

[0098] The above subjects were divided into two groups, and the two groups were placed in different rooms. One group smoked prescription 7 in Example 8, and the other group smoked traditional cigarettes, and their exhaled gas was collected using a special vacuum cleaner. The craving score of 0 to 10 was used to evaluate the urgency of the smokers' demand for nicotine. The higher the score, the more urgent the demand for nicotine.

[0099] Smoking is prohibited after 10 pm the night before, and it is stipulated that smoking is prohibited after getting up in the morning. The first puff is taken at 8 am, and the nicotine craving value at 8 am is filled in. The smoking behavior is monitored for 4 cycles. The specific test results are shown in the table below:

[0100] Table 4

[0101]

[0102]

[0103] The experimental results show that the product of this technology has a similar craving cycle as traditional cigarettes, and the trend of the craving value decreasing after smoking is also relatively similar. In principle, it is confirmed that this product can achieve a good conversion of traditional cigarettes.

[0104] Each cigarette smoked by the test group contained 8.4 mg of nicotine, prescription 7 contained 0.88 mg of nicotine, and prescription 10 contained 0.7 mg of nicotine. The smoke from the prescription 7 and cigarettes was collected and the content was measured. The results are as follows:

[0105] Table 5

[0106] Group Total nicotine output per person per 4 cigarettes mg Prescription 7 groups Not detected Prescription 10 sets Not detected Cigarette Group 18.75

[0107] Theoretically, 4 cigarettes contain 33.6 mg, about 18.75 mg is discharged into the environment, and theoretically only 14.85 is inhaled by the human body. This shows that in addition to environmental pollution, the secondhand smoke brought by cigarettes still has a high exposure to inhalable nicotine aerosols for non-smokers exposed to the secondhand smoke environment, which indirectly verifies the harm of secondhand smoke. No nicotine exposure was detected in the prescription 7 group, which is more environmentally friendly.

[0108] Example 10: Effect of replacing cigarettes in 3 months

[0109] The above 20 traditional cigarette smokers were selected to conduct a statistical comparison study on the number of cigarettes smoked per day and the number of cigarettes smoked by Prescription 7 in Example 8. The specific test results are shown in the following table:

[0110] Table 6

[0111]

[0112]

[0113] Before changing cigarettes, the average number of cigarettes smoked per week was as high as 102.37. After changing cigarettes, the types of cigarettes smoked changed. Traditional cigarette smokers still prefer to smoke cigarettes, but the smoking replacement rate in the first week reached about 30%, indicating that smokers themselves still prefer healthier ways. However, the smoking behavior has been going on for years and cannot be transformed immediately. However, judging from the weekly trend, the smoking replacement rate of this technology product reached 44% after 12 weeks, which is a significant improvement, and the smoking replacement rate also shows an increasing trend.

[0114] Example 11 Improved throat clearing and relieving pharyngitis (study period 6 months)

[0115] In response to oropharyngeal inflammation caused by long-term e-cigarette smoking, this technology improves the occurrence of inflammation by adding throat-clearing and throat-relief extracts. 60 SD rats (200±20g) were selected and divided into 3 groups, with 20 rats in each group. One group was exposed to the aerosol environment generated by the RELX 5th generation e-cigarette for a long time, one group was exposed to the powder aerosol environment generated by the powder mist generator (prescription 5 was selected here), and one group was exposed to the powder aerosol environment generated by the powder mist generator (prescription 6 was selected here). The throat-clearing and throat-relief effect was counted based on the number of oropharyngeal inflammation occurrences.

[0116] The conversion between animals and humans is as follows: Dose of animal B (mg) = W × Dose of animal A (mg / kg) × Weight of animal B. The conversion factor between humans and rats is 0.63. See the table below for specific test results:

[0117] Table 7

[0118]

[0119]

[0120] *Significant difference compared with the e-cigarette group.

[0121] That is, the average monthly incidence of oropharyngeal inflammation in rats that smoked conventional e-cigarettes reached 19.57%, while the incidence in prescription groups 5 and 6 was around 12%, which was significantly different from the e-cigarette group, indicating that oropharyngeal inflammation can indeed be improved by adding throat-clearing and relieving pharyngeal Chinese herbal extracts.

[0122] In addition, the frequency and amount of water drunk by rats exposed to e-cigarette aerosol conditions were also higher than those in prescription groups 5 and 6. It is speculated that e-cigarettes may cause dry mouth symptoms, while this technology product has a milder condition. However, because this experiment mainly focused on the probability of oropharyngeal inflammation, the amount of water drunk was not specifically counted.

[0123] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the scope of protection of the invention.

Claims

1. A nicotine solid aerosol preparation having the effect of clearing the throat and relieving pharyngitis, characterized in that: The composition comprises the following components in percentage by mass: 0.05-15% of nicotine component, 1.8-40% of throat clearing component, 3.5-40% of flavor particles, 0.05-30% of taste improver, and the balance is carrier; Wherein, the particle size D90 of the nicotine component is ≤10 μm; and the particle size D90 of the throat clearing and relieving swallowing component is ≤50 μm.

2. The nicotine solid aerosol preparation having the effect of clearing the throat and relieving pharyngitis according to claim 1, characterized in that: The invention comprises the following components in percentage by mass: based on nicotine, the nicotine component comprises 0.1-12.5%; the throat clearing and relieving component comprises 5-30%; the flavor granules comprises 8-30%; and the taste improving agent comprises 0.1-20%.

3. The nicotine solid aerosol preparation having the effect of clearing the throat and relieving pharyngitis according to claim 1, characterized in that: The invention comprises the following components in percentage by mass: based on nicotine, the nicotine component comprises 0.1-10%; the throat clearing and relieving component comprises 5-20%; the flavor granules comprises 8-25%; and the taste improver comprises 0.15-15%.

4. The nicotine solid aerosol preparation having the effect of clearing the throat and relieving pharyngitis according to any one of claims 1 to 3, characterized in that: The particle size of the flavor particles is D90≤50μm, D10≥5μm; and / or, the particle size D90 of the taste improver is ≤50 μm; And / or, the particle size D90 of the carrier is ≤200 μm, and the particle size D10 is ≥3 μm.

5. The nicotine solid aerosol preparation having the effect of clearing the throat and relieving pharyngitis according to claim 4, characterized in that: The nicotine component is prepared by micronizing nicotine or its salt and auxiliary materials; Optionally, in the nicotine component, the mass percentage of nicotine or its salt is ≥10%; Optionally, the nicotine salt is selected from at least one of nicotine malate, nicotine salicylate, nicotine tartrate, nicotine levulinate, nicotine benzoate, nicotine citrate, nicotine fumarate and nicotine propionate; Optionally, the excipient is a pharmaceutical inhalation grade excipient; further optionally, the excipient is selected from at least one of lactose, mannitol, trehalose, magnesium stearate, leucine, and erythritol.

6. The nicotine solid aerosol preparation having the effect of clearing the throat and relieving pharyngitis according to claim 4, characterized in that: The throat clearing and relieving swallowing component is obtained by mixing and granulating the throat clearing and relieving swallowing extract and an inhalable auxiliary material; Optionally, in the throat clearing and relieving swallowing component, the throat clearing and relieving swallowing extract accounts for ≥15% by weight; Optionally, the inhalable excipient is selected from at least one of lactose, mannitol, erythritol, leucine and glycine.

7. The nicotine solid aerosol preparation having the effect of clearing the throat and relieving pharyngitis according to claim 6, characterized in that: The raw materials of the throat clearing and relieving throat extract include the following raw materials in parts by weight: 60-80 parts of mint, 40-60 parts of honeysuckle, 20-40 parts of forsythia, 60-80 parts of Sterculia lychnophora, 40-60 parts of isatis root, and 60-80 parts of dandelion; Preferably, the raw materials of the throat clearing and relieving throat extract include the following raw materials in parts by weight: 60-72 parts of mint, 42-53 parts of honeysuckle, 20-29 parts of forsythia, 62-70 parts of Sterculia lychnophora, 42-53 parts of isatis root, and 60-72 parts of dandelion; Optionally, the preparation method of the throat clearing and relieving throat extract is: mixing the raw materials, extracting with a solvent, and concentrating to obtain a fluid extract, which is the throat clearing and relieving throat extract.

8. The nicotine solid aerosol preparation having the effect of clearing the throat and relieving pharyngitis according to claim 4, characterized in that: The flavor granules are obtained by mixing the flavor base component with a carrier and granulating them; Optionally, in the flavor particles, the mass proportion of the flavor base component is 5 to 20%; Optionally, the flavor particles further include an anti-sticking agent; preferably, the anti-sticking agent is selected from at least one of magnesium stearate, stearic acid, and phospholipids; Optionally, the carrier in the flavor particles is selected from at least one of sugar and amino acid, wherein the sugar is composed of one or more sugars or sugar alcohols; Optionally, the sugar is selected from at least one of lactose, mannitol, trehalose, erythritol, isomalt, sorbitol, xylitol, glucose, fructose, and sucrose; Optionally, the amino acid is selected from at least one of glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, glutamine, methionine, arginine, serine, threonine, cysteine, and proline.

9. The nicotine solid aerosol preparation having the effect of clearing the throat and relieving pharyngitis according to claim 4, characterized in that: The taste modifier includes at least one of a sweetener, a cooling agent, and an anti-sticking agent; Optionally, the sweetener is selected from at least one of neotame, acesulfame potassium, aspartame, and sucralose; Optionally, the cooling agent is selected from N,2,3-trimethyl-2-isopropylbutyramide, N-ethyl-2-isopropyl-5-methylcyclohexanecarboxamide, (+)-neoisomenthol, (-)-neoisomenthol, (-)-isomenthol, p-menthyl-3,8-diol, (+)-isomenthol, (-)-neoisomenthol, (2R)-3-(1-methoxy)propane-1,2-diol, (2RS)-3-(1-methoxy)propane-1,2-diol, p-menthyl-3-hydroxy ... at least one of 1-glyceride, p-menthyl-3-hydroxy-1-vinyl glyceride, (-)-isopiperitol, (+)-menthol, (+)-neomenthol, (2S)-3-(1-menthoxy)propane-1,2-diol, menthone glycerol ketal, menthyl lactate, N-tert-butyl p-menthyl-3-carboxamide, (-)-menthol, N-(4-methoxyphenyl) p-menthyl-3-carboxamide, ethyl acetate (N-ethyl p-menthyl-3-carboxamide), and borneol; Optionally, the anti-sticking agent is selected from at least one of magnesium stearate, stearic acid, and phospholipids.

10. The nicotine solid aerosol preparation having the effect of clearing the throat and relieving pharyngitis according to claim 4, characterized in that: The carrier is selected from at least one of sugar or sugar alcohol; Optionally, the carrier is selected from at least one of lactose, mannitol, erythritol, isomalt, sorbitol, xylitol, glucose, fructose and sucrose.

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