JP2023158617A - Use of anabasine in heating-type non-combustion electronic delivery product, solid flake, and method for producing the same - Google Patents

Abstract

To provide use of anabasine in a heating-type non-combustion electronic delivery product.SOLUTION: Use of anabasine in a heating-type non-combustion electronic delivery product is provided. Compared with a conventional technology, a new method of using anabasine is provided, and solid flakes are produced by using the anabasine and a smoking agent, a filler, an adhesive, a vegetable fiber, water, and an essence through different processes. The solid flakes do not contain a tobacco filler or nicotine (salt), a tobacco filler or nicotine (salt) of an existing technology or product can be replaced, there is no apparent throat hit, and safety is high. The anabasine forms an aerosol with the smoking agent to promote emission, efficient anabasine delivery can be achieved, an experience similar to that of nicotine can be provided, and a new method enables replacement with a current heating-type non-combustion electronic delivery product.SELECTED DRAWING: Figure 9

Description

The present invention relates to the use of anabasine in heated, non-combustible electron delivery products and is in the field of electron delivery products.

As people pay more and more attention to health and the environment, the research and development of new tobacco products that can effectively reduce the amount of harmful components released by tobacco is becoming the focus of the development of the tobacco industry around the world. Currently, the more typical one is heated non-combustible tobacco products (also known as cold cigarettes), which heat the filler through a special heating source, and when heated, the nicotine in the cut tobacco is released. It volatilizes to generate smoke, meeting the needs of smokers, and unlike traditional rolled cigarettes, the cut tobacco of heated non-combustible tobacco products is in the heating state rather than burning, so it is not the high-temperature combustion decomposition of traditional cigarettes. The harmful components produced by the e-cigarette are reduced, which can reduce the harmful components of mainstream smoke, and at the same time, it can also overcome the drawback that e-cigarettes do not have the taste of real cigarettes. As a result, heated, non-combustible tobacco products are becoming increasingly popular with consumers.

Currently, heated non-combustible tobacco products have nicotine as the main ingredient, have high biological toxicity, strong irritation, and obvious throat hit. Therefore, how to improve the biological safety and irritation properties of heated, non-combustible tobacco products has become an urgent problem to be solved in the art.

The present invention seeks to provide the use of anabasine in heated, non-combustible electron delivery products. The heated non-combustion electron delivery product provided by the present invention has the same experience as the existing heated non-combustion electron delivery product, is less irritating and highly safe.

In order to achieve the above object of the invention, the present invention provides the following technical solutions.

The present invention provides the use of anabasine in heated, non-combustible electron delivery products.

Preferably, anabasine and smoke agents, fillers, adhesives, plant fibers, water, and essences are used to produce solid flakes for heated, non-combustible electron delivery products according to various processes.

The present invention further provides a solid flake, the solid flake comprising 0.5-5% anabasine, 5-20% smoke agent, 40-60% filler, 3-5% adhesive, 1-3% vegetable fiber. , manufactured from raw materials containing 0.1-2% essence and the balance of water.

Preferably, said anabasine is used in free form.

Preferably, the anabasine comprises (-)-S-anabasine, (-)-R-anabasine, or (±)-anabasine.

Preferably, the fuming agent is glycerol and/or propylene glycol.

Preferably, the filling is a herbaceous plant.

Preferably, the adhesive is polyanionic cellulose and/or carboxymethylcellulose.

The present invention also provides a method for producing solid flakes according to the above technical solution,
The method includes the step of mixing anabasine, smoke agent, filler, adhesive, vegetable fiber, essence, and water, and then using a rolling method or a slurry method to obtain solid flakes.

The present invention also provides a method for producing solid flakes according to the above technical solution,
a step (1) of mixing anabasine, a smoke agent, essence, and water to obtain a coating liquid;
Step (2) of mixing the filler, adhesive, and vegetable fibers, pulping them, and forming them into a base sheet;
Coating the base sheet obtained in step (2) with the coating liquid obtained in step (1), and then obtaining solid flakes by a papermaking method or a dry papermaking method (3),
The steps (1) and (2) are executed in no particular order.

The present invention provides the use of anabasine in heated, non-combustible electron delivery products. The present invention applies anabasine with low biological toxicity and less irritation to heated non-combustion electron delivery products to improve safety and taste and improve irritation of heated non-combustion electron delivery products. I can do it. The results of the example show that the CETI8 V3.0 electronic cigarette smoking machine was used for smoking, the fixed smoking period was 3 seconds, the smoking frequency was 30 seconds, the smoking volume was 55 mL, and the amount of anabasine released in the heated non-combustion electronic delivery product was reaches 50-220 μg/puff (alkaloid mass of sip aerosol in standard smoking mode), indicating that it meets the needs of various consumers.

Mortality of rats during exposure to NIC aerosol inhalation doses of 87 mg/kg, 43.5 mg/kg, 26.1 mg/kg, and 8.7 mg/kg is shown. Figure 3 shows a non-linear fitting curve between the inhaled dose of NIC and the rat mortality results. Mortality of rats during exposure to ANA aerosol inhalation doses of 174 mg/kg, 130 mg/kg, 87 mg/kg, and 43.5 mg/kg is shown. Figure 3 shows a non-linear fitting curve between the inhaled dose of ANA and the rat mortality results. It shows the change in body weight of male rats during the subacute toxicity test of ANA. It shows the changes in body weight of female rats during the subacute toxicity test of ANA. It shows the dietary changes of male rats during the subacute toxicity test of ANA. It shows the dietary changes of female rats during the subacute toxicity test of ANA. The results of histopathological examination of ANA test animals are shown.

The present invention provides the use of anabasine in heated, non-combustible electron delivery products.

In the present invention, said anabasine is preferably manufactured into solid flakes for heated non-combustion electronic delivery products according to different processes using fuming agents, fillers, adhesives, plant fibers, water, essences. That's true.

In the present invention, the solid flakes preferably include, in percent by weight, 0.5-5% of anabasine, 5-20% of smoke agent, 40-60% of filler, 3-5% of adhesive, 1-5% of vegetable fibers. 3%, essence 0.1-2% and water balance.

The present invention further provides solid flakes, in weight percent, 0.5-5% anabasine, 5-20% smoke agent, 40-60% filler, 3-5% adhesive, 1-3% vegetable fiber, It is manufactured from the raw materials of 0.1-2% essence and a balance of water.

In weight percent, the raw material for producing the solid flakes according to the invention comprises 0.5 to 5%, preferably 1 to 5%, more preferably 1 to 3%, even more preferably 1 to 2% of anabasine. including. In the present invention, said anabasine is preferably used in free form, said anabasine preferably comprising (+)-R-anabasine, (-)-R-anabasine, or (±)-anabasine. In the present invention, the source of anabasine is not particularly limited, and commercially available products well known to those skilled in the art may be used. In the present invention, the biotoxicity of the anabasine is low, the molecular weight is small, and it is easily volatile, so that under the action of fuming agents, anabasine can be effectively delivered to the human body, resulting in the same experience effect as nicotine.

In percent by weight, the raw material for producing the solid flakes according to the invention further comprises 5 to 20%, preferably 5 to 15%, more preferably 10 to 15% of fuming agent. In the present invention, the smoke generating agent is preferably glycerol and/or propylene glycol, and when the smoke generating agent is glycerin and propylene glycol, the mass ratio of the glycerin and propylene glycol is preferably 3:1 or 2:1. be. In the present invention, the source of the smoke generating agent is not particularly limited, and commercially available products well known to those skilled in the art may be used. In the present invention, the fuming agent can promote the release of anabasine and achieve effective delivery of anabasine to the human body.

The raw material for producing the solid flakes according to the invention comprises, in weight percent, 40-60%, preferably 50-60%, of filler. In the present invention, the filling is preferably a herbaceous plant, more preferably one or more of green tea, mint and coffee, and when the filling is green tea and mint, the mass ratio of the green tea and mint is is preferably 5:1, and when the filling is green tea and coffee, the mass ratio of said green tea and coffee is preferably 5:1. The present invention is not particularly limited to the source of the filler, and commercially available products well known to those skilled in the art may be used. In the present invention, the filler plays a filling role in the solid flakes, and can reduce the cost of the solid flakes.

The raw material for producing the solid flakes according to the invention further comprises, in weight percent, 3-5%, preferably 4-5% of adhesive. In the present invention, the adhesive is preferably polyanionic cellulose and/or carboxymethylcellulose, more preferably polyanionic cellulose and carboxymethylcellulose, and when the adhesive is polyanionic cellulose and carboxymethylcellulose, the polyanionic The volume ratio of sterile cellulose and carboxymethylcellulose is preferably 1:1. The present invention is not particularly limited to the source of the adhesive, and commercially available products well known to those skilled in the art may be used. In the present invention, the adhesive functions as a binding agent for binding each raw material.

The raw material for producing the solid flakes according to the invention further comprises 1 to 3%, preferably 2 to 3%, of vegetable fibers in weight percent. In the present invention, the vegetable fiber is preferably wood pulp fiber. In the present invention, the size of the wood pulp fibers is not particularly limited, and may be selected according to common sense. In the present invention, there is no particular restriction on the source of the plant fibers, and commercially available products well known to those skilled in the art may be used. In the present invention, the vegetable fibers serve to increase the strength of the solid flakes.

The raw material for producing the solid flakes according to the invention further comprises, in weight percent, 0.1-2% essence, preferably 1-2% essence. In the present invention, the essence is preferably a plant extract or a synthetic essence, more preferably at least one of strawberry essence, mint essence, apple essence, and a refreshing agent, and even more preferably strawberry essence, mint essence, apple essence. two of an essence and a refreshing agent, and the essences are strawberry essence and mint essence, the mass ratio of the strawberry essence and mint essence is preferably 1:1, and the essences are strawberry essence and apple essence. In this case, the mass ratio of the strawberry essence and apple essence is preferably 2:1, and when the essence is strawberry essence and a refreshing agent, the mass ratio of the strawberry essence and the refreshing agent is preferably 1.5:1. It is. In the present invention, there is no particular restriction on the source of the essence, and commercially available products well known to those skilled in the art may be used. In the present invention, said essence is used to provide the necessary aroma to the solid flakes.

The raw materials for producing the solid flakes according to the invention include, in weight percent, also the balance of water. In the present invention, there is no particular restriction on the water supply source, and commercially available products well known to those skilled in the art may be used. In the present invention, the water is a solvent and serves to dissolve raw materials.

The present invention uses anabasine in combination with other ingredients to replace tobacco additives, and uses a heated non-combustion device to effectively deliver anabasine to the human body, resulting in an experiential effect similar to that of nicotine. I can do it.

Compared to conventional heat-not-burn solid tobacco products, the solid flakes provided by the present invention can reduce or replace the use of nicotine and reduce dependence on nicotine.

The anabasine used in the present invention has no obvious throat hit, is less irritating, and produces solid flakes that are heated in a heated non-combustion device to form an aerosol containing anabasine. It is a highly safe electron transfer product that is suitable for use in heated non-combustion devices and is suitable for use in heated non-combustion devices.

The anabasine provided by the present invention is characterized by a high content (mass percentage ≧98%), and the natural nicotine contains four nitrosamine components specific to tobacco: nitrosoanatabine NAT, nitrosonornicodine NNN, It does not contain nitrosoanabasin (NAB and methylnitrosaminopyridylbutanone (NNK)) and has high biological safety.

The results of the acute inhalation toxicity evaluation of anabasine and nicotine in rats showed that the inhalation half-lethal dose (LC50) value of anabasine was 125 mg/kg and the inhalation half-lethal dose (LC50) value of nicotine was 37.8 mg/kg. Compared to nicotine, anabasine is more biologically safe and can be used in heated, non-combustible electronic delivery products as an alternative to tobacco products.

The present invention also provides a method for producing solid flakes according to the above technical solution,
The method includes the step of mixing anabasine, smoke agent, filler, adhesive, vegetable fiber, essence, and water, and then using a rolling method or a slurry method to obtain solid flakes.

In the present invention, solid flakes are obtained by a rolling method or a slurry method after mixing anabasine, a smoke agent, a filler, an adhesive, a vegetable fiber, an essence, and water.

In the present invention, the filler is preferably ground before use. In the present invention, there is no particular restriction on the pulverization operation, and the filler may be pulverized to meet usage requirements.

The present invention does not have any special limitations on the operation of mixing said anabasine, smoke agent, filler, adhesive, vegetable fiber, essence, water, and uses technical solutions for preparing mixed materials well known to those skilled in the art. Just use it.

In the present invention, there is no particular restriction on the specific operations of the rolling method and the slurry method, and operations well known to those skilled in the art may be used.

The present invention also provides a method for producing solid flakes according to the above technical solution,
a step (1) of mixing anabasine, a smoke agent, essence, and water to obtain a coating liquid;
Step (2) of mixing the filler, adhesive, and vegetable fibers, pulping them, and forming them into a base sheet;
Coating the base sheet obtained in step (2) with the coating liquid obtained in step (1), and then obtaining solid flakes by a papermaking method or a dry papermaking method (3),
The steps (1) and (2) are executed in no particular order.

In the present invention, a coating liquid is obtained by mixing anabasine, a fuming agent, essence, and water.

The present invention does not impose any particular limitations on the operation of mixing anabasine, smoke agent, essence and water, and any technical solutions for preparing mixed materials well known to those skilled in the art may be used.

In the present invention, the filler, adhesive, and vegetable fibers are mixed and pulped into a base sheet.

In the present invention, the filler is preferably ground before use. In the present invention, there is no particular restriction on the pulverization operation, and the filler may be pulverized to meet usage requirements.

The operation of mixing the filler, adhesive and vegetable fibers in the present invention is not particularly limited, and any technical solutions for preparing mixed materials well known to those skilled in the art may be used. The present invention is not particularly limited to the pulping and papermaking operations, and operations well known to those skilled in the art may be used.

After the coating liquid and base sheet are obtained, the present invention coats the coating liquid on the base sheet, and then uses a papermaking method or a dry papermaking method to obtain solid flakes.

In the present invention, there is no particular restriction on the coating operation, and any coating operation well known to those skilled in the art may be used. In the present invention, there are no particular limitations on the specific operations of the papermaking method and dry papermaking method, and operations well known to those skilled in the art may be used.

The manufacturing method provided by the present invention has a simple process and is suitable for industrial production.

The technical solution of the present invention will be explained clearly and completely below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some, but not all, embodiments of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative work fall within the protection scope of the present invention.

Example 1
The solid flakes were made from the following ingredients in weight percent: 1% (±)-anabasine, 15% smoke agent, 60% filler, 5% adhesive, 3% vegetable fiber, 2% essence, and the balance water.

Here, the smoke agent is glycerol and propylene glycol (mass ratio is 2:1), the filler is green tea, the adhesive is carboxymethyl cellulose, the vegetable fiber is wood pulp fiber, and the essence is strawberry essence and mint essence (ratio is 1:1). ) and
The method for producing the solid flakes includes:
(±)-Anabasine, smoke agent, crushed filler, adhesive, vegetable fiber, essence and water are mixed and then rolled and dried to obtain solid flakes.

A CETI8 V3.0 electronic cigarette smoking machine was used to smoke the solid flakes produced in Example 1, and for electronic cigarette smoking, the electronic cigarette smoking mode recommended by CORESTA (fixed smoking duration was 3 seconds, smoking frequency was The release of anabasine in a heated non-combustion device was determined by GC-FID analysis using a Cambridge filter to capture the total particulate matter in the aerosol. It was shown that the amount reached 100 μg/puff.

Example 2
The solid flakes were made from the following raw materials: 3% (±)-anabasine, 10% smoke agent, 60% filler, 5% adhesive, 3% vegetable fiber, 2% essence, and the balance water in the following weight percentages: Ta.

Here, the smoke agent is glycerol and propylene glycol (mass ratio 3:1), the filler is green tea and mint (mass ratio 5:1), and the adhesive is polyanionic cellulose and carboxymethyl cellulose (volume ratio 1:1). ), the plant fibers are wood pulp fibers, the essences are strawberry essence and apple essence (mass ratio 2:1),
The method for producing the solid flakes includes:
(±) - Form a slurry after mixing anabasine, smoke agent, filler after grinding, adhesive, vegetable fiber, essence and water, spread it evenly on a circulating metal belt, dry and peel off, solid flakes was created.

A CETI8 V3.0 electronic cigarette smoking machine was used to smoke the solid flakes produced in Example 2, and for electronic cigarette smoking, the electronic cigarette smoking mode recommended by CORESTA (fixed smoking duration was 3 seconds, smoking frequency was The release of anabasine in a heated non-combustion device was determined by GC-FID analysis using a Cambridge filter to capture the total particulate matter in the aerosol. It was shown that the amount reached 180 μg/puff.

Example 3
The solid flakes were made from the following ingredients in weight percent: 5% (±)-anabasine, 10% smoke agent, 60% filler, 5% adhesive, 3% vegetable fiber, 2% essence, and the balance water.

Here, the smoke agent is glycerol, the filler is green tea and coffee (mass ratio is 5:1), the adhesive is carboxymethyl cellulose, the vegetable fiber is wood pulp fiber, and the essence is strawberry essence and refreshing agent (mass ratio is 1). .5:1),
The method for producing the solid flakes includes:
(±)-A step (1) of mixing anabasine, a smoke agent, an essence, and water to obtain a coating liquid;
A step (2) of mixing the crushed filler, adhesive, and vegetable fibers into a pulp, and making a paper into a base sheet;
The method includes a step (3) of coating the base sheet obtained in step (2) with the coating liquid obtained in step (1) above, and then obtaining solid flakes by a papermaking method or a dry papermaking method.

A CETI8 V3.0 electronic cigarette smoking machine was used to smoke the solid flakes produced in Example 3, and for electronic cigarette smoking, the electronic cigarette smoking mode recommended by CORESTA (fixed smoking duration was 3 seconds, smoking frequency was The release of anabasine in a heated non-combustion device was determined by GC-FID analysis using a Cambridge filter to capture the total particulate matter in the aerosol. It was shown that the amount reached 205 μg/puff.

Example 4
The solid flakes were produced from the following raw materials in weight percent: 1% (-)-S-anabasine, 15% smoke agent, 60% filler, 5% adhesive, 3% vegetable fiber, 2% essence, and the balance water. Ta.

Here, the smoke agent is glycerol and propylene glycol (mass ratio is 2:1), the filler is green tea, the adhesive is carboxymethyl cellulose, the vegetable fiber is wood pulp fiber, and the essence is strawberry essence and mint essence (mass ratio is 1:1),
The method for producing the solid flakes includes:
The method includes a step of mixing (-)-S-anabasine, a smoke agent, a crushed filler, an adhesive, a vegetable fiber, an essence, and water, and then rolling and drying the mixture to obtain solid flakes.

A CETI8 V3.0 electronic cigarette smoking machine was used to smoke the solid flakes produced in Example 1, and for electronic cigarette smoking, the electronic cigarette smoking mode recommended by CORESTA (fixed smoking duration was 3 seconds, smoking frequency was The release of anabasine in a heated non-combustion device was determined by GC-FID analysis using a Cambridge filter to capture the total particulate matter in the aerosol. It was shown that the amount reached 98 μg/puff.

Example 5
The solid flakes were produced from the following raw materials in weight percent: 1% (-)-R-anabasine, 15% smoke agent, 60% filler, 5% adhesive, 3% vegetable fiber, 2% essence, and the balance water. Ta.

Here, the smoke agent is glycerol and propylene glycol (mass ratio is 2:1), the filler is green tea, the adhesive is carboxymethyl cellulose, the vegetable fiber is wood pulp fiber, and the essence is strawberry essence and mint essence (mass ratio is 1:1),
The method for producing the solid flakes includes:
The method includes a step of mixing (-)-R-anabasine, a smoke agent, a crushed filler, an adhesive, a vegetable fiber, an essence, and water, and then rolling and drying the mixture to obtain solid flakes.

A CETI8 V3.0 electronic cigarette smoking machine was used to smoke the solid flakes produced in Example 1, and for electronic cigarette smoking, the electronic cigarette smoking mode recommended by CORESTA (fixed smoking duration was 3 seconds, smoking frequency was The release of anabasine in a heated non-combustion device was determined by GC-FID analysis using a Cambridge filter to capture the total particulate matter in the aerosol. It was shown that the amount reached 102 μg/puff.

performance test:
The aerosol inhalation half-lethal dose (LC50) and non-injurious effective dose (NOAEL) of anabasine (ANA) were calculated by acute inhalation toxicity studies in SD rats and compared with the acute inhalation toxicity results of nicotine (NIC). Based on the results of the acute inhalation toxicity test, further conduct a subacute toxicity test study of ANA to evaluate the degree of damage and harm to respiratory tissues and the whole body after ANA enters the animal body through the respiratory tract; It also provided a safety evaluation for the use of ANA in electronic delivery products.

1. Materials and methods 1.1 Specimen ANA, purity ≧98%, pale yellow oily liquid, NIC, purity ≧95%, yellow oily liquid, propylene glycol (PG), vegetable glycerin (VG)
1.2 Preparation of test articles and test grouping Blank control group (Sham Control) inhaled air, negative control group (Vehicle Control) test articles were prepared according to the mass ratio PG:VG = 50:50, 1% ANA , 5% ANA was prepared according to the mass ratio ANA:PG:VG=5:47.5:47.5, and 10% ANA was prepared according to the mass ratio ANA:PG:VG=5:47.5:47.5. was prepared according to the mass ratio ANA:PG:VG = 10:45:45, 15% ANA was prepared according to the mass ratio ANA:PG:VG = 15:42.5:42.5, and 20% ANA was prepared according to the mass ratio ANA:PG:VG = 15:42.5:42.5. :PG:VG=20:40:40, 1% NIC was prepared according to mass ratio NIC:PG:VG=1:49.5:49.5, 3% NIC was prepared according to mass ratio NIC:PG:VG = 3:48.5:48.5, 5% NIC was prepared according to the mass ratio NIC:PG:VG = 5:47.5:47.5, 10% NIC was prepared according to the mass ratio NIC:PG:VG =10:45:45.
1.3 Test animals and housing environment SPF grade SD rats were used, half male and half female. After introducing the animals, an adaptation check was performed, there were 2 animals per cage during the adaptation period, the adaptation time was 12-13 days, and a health check was performed and the weight was weighed on the day of introduction. The feed is sterilized nutritional powder at the regular price, drinking water is not restricted, the temperature of the animal room is 20-25℃, the humidity is 45%-70%, the photoperiod is automatically controlled, and the light and dark are adjusted each day. It was 12 hours.
1.4 Test Equipment HRH-BAG1 Impact Liquid Aerosol Generator, HRH-MNE3026 Small Animal Single Concentration Oronasal Exposure System, Beijing Huironghe Technology Co., Ltd., 3321 Pharmaceutical Aerosol Particle Size Analysis System, TSI Corporation, USA.
1.5 Acute Toxicity Test According to the requirements of OECD Chemical Testing Guidelines for Acute Inhalation Toxicity Test (NO.403, 2009), there are 5 male and 5 male rats, and the animals are tested at HRH-MNE3026 small animal single concentration. Attach the retainer in the oronasal exposure system holder to the poison gas cabinet, seal the poison gas cabinet, and inject the blank control group (Sham Control), negative control group (Vehicle Control), 4 ANA test product aerosols (5 mg/L), 4 All rats were exposed to two NIC test article aerosols (5 mg/L) for 4 hours. During the exposure period, clinical observations were made and the number of dead and living animals in each group was counted. Thereafter, surviving rats were continuously observed for 14 days. LC50 and NOAEL values were calculated for gas ANA and NIC inhalation, respectively.
1.6 Subacute toxicity test Based on the comprehensive evaluation of the ANA acute toxicity test, the ANA inhalation NOAEL was used as the maximum exposure dose, and the blank control group (Sham Control) and negative control group (Vehicle Control) were randomly assigned according to body weight. , divided into 5 groups: ANA high, medium, and low dose groups, with 10 animals in each group, half male and half female. When divided into groups, the weight of animals within a group did not exceed ±20% of the mean body weight. Each animal was placed in an HRH-MNE3026 Small Animal Single Concentration Oronasal Exposure System retainer, the retainer was attached to the poison gas cabinet, the poison gas cabinet was sealed, and exposure continued once a day for 28 days.
Observation of clinical symptoms: During the 28-day nasal inhalation exposure period, the irritation, morbidity, and mortality of the experimental animals were observed, and the animals' body weights and food intake were measured regularly.
Pathological examination: At the end of the experiment, gross necropsy was performed on all surviving animals. A thorough and careful macroscopic observation of the animals during dissection was performed, including the respiratory and metabolic systems (lungs, liver, kidneys, etc.), and the gross pathological changes of each animal were recorded in detail.
1.7 Data processing and result analysis The number of animals in each group, symptoms, mortality, survival rate, and frequency of various lesions during gross anatomy and histopathological examination were counted respectively, and the number of animals in each group and the The incidence of the above items in animals of each sex and the mean and standard deviation of body weight at different time points were calculated.

Experimental Results 2.1 NIC Acute Inhalation Toxicity Test The aerosol concentration, NIC inhalation dose, and particle size distribution of the poison cabinet during the exposure period are shown in Table 1.

Note: In Table 1, MMAD is the mass median aerodynamic diameter of the aerosol and GSD is the geometric standard deviation.

Observation of clinical symptoms: The proportion of dead and moribund animals during exposure was reached 92.7%, 67.3%, 10.6%, and 2.5% (as shown in Figure 1, when the NIC aerosol inhalation dose was 87 mg/kg, 43.5 mg/kg, and 26.1 mg/kg). , and the mortality rate of rats during exposure at 8.7 mg/kg). Non-dead animals were observed continuously for 14 days until the end of the study and there were no abnormal changes.

According to the statistics of inhaled dose and rat mortality, Graphpad Prism 9.0 was used for non-linear fitting (as shown in Figure 2, which is the non-linear fitting curve of NIC inhaled dose and rat mortality). The calculated LC50 value of NIC aerosol inhalation in SD rats is 37.8 mg/kg, and the NOAEL dose of NIC aerosol inhalation in SD rats is 7.14 mg/kg/day, converted to human equivalent dose (HED). The human equivalent dose (HED) calculated according to the coefficient was 1.13 mg/kg/day.

2.2 ANA Acute Inhalation Toxicity Test The aerosol concentration, ANA inhalation dose, and particle size distribution of the poison cabinet during the exposure period are shown in Table 2.

Observation of clinical symptoms: When the inhaled doses of ANA aerosol were 174 mg/kg, 130 mg/kg, 87 mg/kg, and 43.5 mg/kg, respectively, the proportion of dead and moribund animals during exposure was 84.3%, respectively. , 52.0%, 6.0%, and 1.5% (as shown in Figure 3, the ANA aerosol inhalation doses were 174 mg/kg, 130 mg/kg, 87 mg/kg, and 43.5 mg/kg). mortality rate of rats during exposure). Non-dead animals were observed continuously for 14 days until the end of the study and there were no abnormal changes.

According to the statistics of inhalation dose and rat mortality results, Graphpad Prism 9.0 was used for nonlinear fitting (as shown in Figure 4, which is the nonlinear fitting curve of NIC inhalation dose and rat mortality results) and calculated. The obtained ANA aerosol inhalation LC50 value for SD rats was 125 mg/kg. The NOAEL dose of ANA aerosol inhalation in SD rats was 23.6 mg/kg/day, and the human equivalent dose (HED) calculated according to the human equivalent dose (HED) conversion factor was 3.75 mg/kg/day.

2.3 Subacute Toxicity Test The maximum dose of ANA aerosol inhalation in the poison cabinet during the exposure period was NOAEL (23.6 mg/kg/day), lasting 28 days at 63 minutes per exposure and once a day. Aerosol concentration, ANA inhalation dose and particle size distribution are shown in Table 3.

Subacute inhalation toxicity: The body weight changes of male and female test rats in each dose group during the 28-day administration period are shown in Figures 5 and 6. ), Figure 6 shows the change in body weight of female rats during the ANA subacute toxicity experiment), and Figures 7 and 8 show the changes in food intake (Figure 7 shows the change in food intake of male rats during the ANA subacute toxicity experiment). Figure 8 shows the changes in food intake of female rats during the ANA subacute toxicity experiment), and the changes in organ weights are shown in Tables 4 and 5.

As can be seen from Figures 5 to 8 and Tables 4 and 5, subacute inhalation toxicity, including body weight, food intake, organ weight, etc., was observed between male and female test rats in each dose group during the 28-day administration period. There was no statistically significant difference (P>0.05).

Bronchoalveolar lavage fluid AM (alveolar macrophages), MONO (monocytes), Lym (lymphocytes), Neut (neutrophils), TP (total protein), ALP (alkaline phosphatase), LDH (lactate dehydrogenase)), etc., and there was no statistical difference compared to the control group (P>0.05). Test data are shown in Tables 6 and 7.

Hematology Indices When the hematology parameters of different dose groups of male and female test animals were examined, there was no significant difference in each index (P>0.05), the results are shown in Tables 8 and 9.

Histopathological examination After the test, the tissues of the test animals were sliced and the tissues of the liver, heart, spleen, lung, kidney, etc. were stained and subjected to pathological examination. The results are shown in Figure 9. shows the histopathological examination results of ANA test animals, where 100x magnification, HE staining, and control group (sham control and vehicle control) and high dose group (10x %ANA) No obvious pathological changes were observed in the animal tissues.

In conclusion, there were no statistically significant differences in body weight, food intake, organ weight, etc. between different groups of rats (P>0.05), and blood, urine, bronchoalveolar lavage fluid, and histopathological examination. None of the specimens showed any abnormal changes.

A comprehensive comparison of the results of inhalation exposure toxicity studies of anabasine and nicotine showed that the inhalation tolerated dose of anabasine in humans is 3.75 mg/kg/day, and the inhalation tolerated dose for NIC is 1.13 mg/kg/day. It turned out to be. This indicates that the biotoxicity of anabasine is lower than that of nicotine and that the use of anabasine in electronic delivery products is more biologically safe than nicotine.

The above are only preferred embodiments of the present invention, and those skilled in the art can make some improvements and modifications without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the present invention. It must be pointed out that it should be considered as

Claims (10)

Use of anabasine in heated, non-combustible electron delivery products. Claim characterized in that the anabasine and smoke agents, fillers, adhesives, plant fibers, water, essences are used to produce solid flakes for heated non-combustible electronic delivery products according to different processes. Use as described in 1. Solid flakes containing 0.5-5% anabasine, 5-20% smoke agent, 40-60% filler, 3-5% adhesive, 1-3% vegetable fiber, and 0.1-2% essence. Solid flakes characterized in that they are produced from raw materials containing a balance of water. Solid flakes according to claim 3, characterized in that the anabasine is used in free form. 4. The solid flake according to claim 3, wherein the anabasine comprises (-)-S-anabasine, (-)-R-anabasine, or (±)-anabasine. Solid flakes according to claim 3, characterized in that the smoke agent is glycerol and/or propylene glycol. Solid flakes according to claim 3, characterized in that the filling is herbaceous. Solid flakes according to claim 3, characterized in that the adhesive is polyanionic cellulose and/or carboxymethylcellulose. Any one of claims 3 to 8, characterized in that it comprises a step of mixing anabasine, a smoke agent, a filler, an adhesive, a vegetable fiber, an essence, and water, and then obtaining solid flakes by a rolling method or a slurry method. A method for producing solid flakes as described in . a step (1) of mixing anabasine, a smoke agent, essence, and water to obtain a coating liquid;
Step (2) of mixing the filler, adhesive, and vegetable fibers, pulping them, and forming them into a base sheet;
Coating the base sheet obtained in step (2) with the coating liquid obtained in step (1), and then obtaining solid flakes by a papermaking method or a dry papermaking method (3),
The method for producing solid flakes according to any one of claims 3 to 8, characterized in that steps (1) and (2) are performed in no particular order.