Atomizable and inhalable liquid formulations, cartridges, and aerosol generating systems

Abstract

The embodiments of this application disclose a liquid formulation, a cartridge for an aerosol generating system, and an aerosol generating system, wherein the liquid formulation comprises a solvent and ambroxol hydrochloride, and the atomization conversion rate of the ambroxol hydrochloride in the liquid formulation is 90% or more, or the atomization conversion rate of the ambroxol hydrochloride is 80% or more, or the atomization conversion rate of the ambroxol hydrochloride is 70% or more, or the atomization conversion rate of the ambroxol hydrochloride is 60% or more.

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims the priority of a Chinese patent application with an application number of 202310361703.6 and an invention title of "Atomizable and Inhalable Liquid Preparation, Cartridge and Aerosol Generation System", which was filed with the China National Intellectual Property Administration on March 31, 2023, and all of its contents are incorporated herein by reference.

[0002] The embodiments of this application relate to the field of aerosol - generating devices, and in particular, to atomizable and inhalable liquid preparations, cartridges, and aerosol generation systems.

Background Art

[0003] Ambroxol hydrochloride (AMB) is a semi - synthetic derivative of basicin extracted from the Indian shrub Adhatoda vasica, and is an in - vivo active metabolite of bromhexine. It has high safety, few side effects, can be used in children, and is widely used clinically. Ambroxol hydrochloride is mainly used to promote the discharge of viscous secretions in the respiratory tract and reduce mucus retention, so it has a remarkable expectorant effect and is suitable for acute or chronic respiratory diseases accompanied by abnormal sputum secretion and expectoration dysfunction.

[0004] Clinically, it is often treated by slowly intravenous injection of AMB injection.

[0005] Chinese Patent CN110179772A discloses administering an inhalable ambroxol hydrochloride solution by modern medical aerosol devices (such as compressed air or oxygen nebulizers, ultrasonic nebulizers, vibrating mesh nebulizers, etc.), but medical nebulizer devices are usually not portable.

Summary of the Invention

[0006] The embodiments of this application are An atomizable and inhalable liquid preparation for an electronic nebulizer, Solvent and, ambroxol hydrochloride, The atomization conversion rate of ambroxol hydrochloride in the liquid formulation, which is heated and atomized by the electronic atomizer to form an aerosol, is 90% or more. Alternatively, the atomization conversion rate of the ambroxol hydrochloride is 80% or more. Alternatively, the atomization conversion rate of the ambroxol hydrochloride is 70% or more. Alternatively, the present invention provides a liquid formulation that can be atomized and inhaled, wherein the atomization conversion rate of the ambroxol hydrochloride is 60% or more.

[0007] In the above example, ambroxol hydrochloride is prepared as a liquid formulation that can be atomized and inhaled, and an aerosol is generated by adding this liquid formulation to an electronic atomizer and atomizing it by electric heating. On the one hand, all current electronic atomizers are designed to be portable, making them easy for users to carry, improving patient compliance, and enriching the range of applications in clinical treatment. On the other hand, although the boiling point of ambroxol hydrochloride is approximately 468°C, the operating temperature range of current electronic atomizers is approximately 100°C to 500°C, so ambroxol hydrochloride can undergo azeotrope with the common solvent in the electronic atomizer, generating an aerosol.

[0008] Furthermore, by preparing ambroxol hydrochloride as a liquid formulation and heating and atomizing it using an electronic atomizer, the aerosol conversion performance was measured, and it was found that the atomization conversion rate of ambroxol hydrochloride is high through heated atomization measurement. Measurement using the atomization measurement method provided in the examples of this application showed that the atomization conversion rate of a liquid formulation containing a certain amount of ambroxol hydrochloride is 90% or more, and the mass percentage content is set to approximately 0.1% to 1%. When the content of ambroxol hydrochloride in the liquid formulation is adjusted to a certain range, the conversion rate of ambroxol hydrochloride is 80% or more, and furthermore, when the content of ambroxol hydrochloride in the liquid formulation is adjusted to a different range, or when the electronic atomizer is changed and a different electronic atomizer is used, the conversion rate of ambroxol hydrochloride is 70% or more, or the conversion rate of ambroxol hydrochloride is 60% or more. Here, different electronic atomizers are configured to have different heating power or to use different atomization core components.

[0009] Therefore, in the process of the user inhaling the aerosol generated by atomizing the above liquid formulation, ambroxol hydrochloride can be inhaled into the lungs, reach the alveoli, be rapidly absorbed, and enter the bloodstream, resulting in high biological efficacy. Consequently, the therapeutic effect can also be fully achieved by preparing ambroxol hydrochloride as a liquid formulation and inhaling the liquid formulation of ambroxol hydrochloride by atomization.

[0010] Compared to ultrasonic atomizers, which generate water mist by decomposing the molecular structure of a liquid matrix through high-frequency vibrations of a mesh atomizing element, electronic atomizers generate aerosols by heating the liquid matrix to its boiling point through an electric heating process. Liquid formulations containing ambroxol hydrochloride, when processed using an electronic atomizer, produce aerosols with a particle size of mostly ≤1 μm. This is advantageous for deep deposition of the aerosol into the bronchi and lungs, particularly deep into the alveoli, making it suitable for drug administration to the lower respiratory tract and lungs. Since ambroxol hydrochloride has excellent efficacy in treating respiratory diseases, atomizing liquid formulations containing ambroxol hydrochloride using an electronic atomizer is advantageous for maximizing the therapeutic effect of ambroxol hydrochloride. Furthermore, atomizing liquid formulations containing ambroxol hydrochloride using an electronic atomizer results in less residue of the generated ambroxol hydrochloride aerosol in the oral cavity, less gastric irritation, and improved user compliance. Furthermore, the electronic atomizer is configured as an active suction type, where the heating system is activated by the user's active inhalation, and the user inhales an aerosol containing ambroxol hydrochloride generated by electrolysis, further improving user compliance.

[0011] In some examples, the weight percentage of ambroxol hydrochloride in the liquid formulation is 0.01% to 2%, or the weight percentage of ambroxol hydrochloride in the liquid formulation is 0.1% to 1%.

[0012] When ambroxol hydrochloride is administered intravenously, the daily dose for adults is limited to 45 mg or less, and can be increased to 90 mg in severe cases. Therefore, based on the volume of smoke per puff of the electronic atomizer and the number of puffs inhaled per day by the user, the ambroxol hydrochloride content can be controlled to within 2%, allowing the user to alleviate unpleasant lung symptoms such as pneumonia and asthma with multiple inhalations per day.

[0013] Furthermore, measurements of the atomization effect of the ambroxol hydrochloride liquid formulation showed that when the weight percentage of ambroxol hydrochloride in the liquid formulation was controlled to approximately 1%, the conversion rate from ambroxol hydrochloride in the liquid formulation to an aerosol was almost always over 90%, and sometimes even approached 100%. Therefore, controlling the weight percentage of ambroxol hydrochloride in the liquid formulation to within 1% is advantageous for improving the conversion rate.

[0014] The above-mentioned ambroxol hydrochloride is a pharmaceutical-grade raw material and can be prepared by methods reported in the prior art.

[0015] In some examples, the solvent comprises at least one of propylene glycol, vegetable glycerin, water, or ethanol.

[0016] In some embodiments, the weight percentage of propylene glycol in the liquid formulation is 20% to 80%. Furthermore, the specific mass percentage of propylene glycol in the liquid formulation may be any value selected from 20% to 80%.

[0017] In some examples, the weight percentage of the vegetable glycerin in the liquid formulation is 30% to 70%. Furthermore, the specific mass percentage of the vegetable glycerin in the liquid formulation may be any value selected from 30% to 70%.

[0018] In some embodiments, the weight percentage of water in the liquid formulation is 10% to 50%. Furthermore, the specific mass percentage of water in the liquid formulation may be any value selected from 10% to 50%.

[0019] The propylene glycol mentioned above may be 1,2-propylene glycol or 1,3-propylene glycol.

[0020] Propylene glycol and vegetable glycerin, as solvents commonly seen in electronic atomizers, have excellent performance in terms of increasing the amount of smoke and controlling the fluidity of liquid formulations. Therefore, by using propylene glycol and vegetable glycerin as the main solvent components and simultaneously adding an appropriate amount of water or ethanol as a solvent according to the increase in the weight percentage content of ambroxol hydrochloride in the liquid formulation, the solubility of ambroxol hydrochloride in the liquid formulation can be enhanced.

[0021] It is necessary to control the water content in the above liquid formulation within an appropriate range. The addition of water to the solvent is beneficial for improving the solubility of ambroxol hydrochloride. However, when the water content in the solvent increases, the risk of liquid leakage during addition to the electronic atomizer and the risk that users inhale excessive condensate increase. Therefore, it is necessary to control the water content within the above range.

[0022] In some embodiments, the particle size range of the aerosol generated by atomizing the ambroxol hydrochloride is 0.2 μm to 3 μm.

[0023] In some embodiments, the liquid formulation further includes at least one of edible essence, sweetener or cooling agent.

[0024] The above edible essence is for enhancing the taste and aromatic flavor of the aerosol itself formed by atomizing the liquid formulation. The types of edible essence include one or more of fruit flavor, floral flavor, mint flavor, tea flavor.

[0025] The weight percentage range of the above edible essence in the liquid formulation is about 0% to 10%. Its specific content can be set to any content within 0% to 10% according to the needs of flavor adjustment of the liquid formulation. For example, the specific weight percentage content of the edible essence is 5%.

[0026] The above sweetener is for enhancing the sweetness of the aerosol generated by atomizing the above liquid preparation. It should be noted that ambroxol hydrochloride itself has a certain degree of bitterness. By adding an appropriate amount of sweetener to the liquid preparation, it contributes to masking the bitterness of ambroxol hydrochloride itself, and greatly improves the comfort when the user inhales the aerosol containing ambroxol hydrochloride. The type of sweetener may be one or more selected from sodium cyclamate, xylitol, mogroside, acesulfame potassium, sodium saccharin, sucralose, aspartame, alitame, neohesperidin dihydrochalcone, neotame and stevioside.

[0027] The weight percentage range of the above sweetener in the liquid preparation is about 0% - 10%, and its specific content can be set to any content within 0% - 10% according to the needs of flavor adjustment of the liquid preparation. For example, the specific weight percentage content of the sweetener is 1%.

[0028] The above cooling agent is for enhancing the cooling effect of the aerosol generated by atomizing the above liquid preparation and further enhancing the comfort when the user inhales the aerosol. The cooling agent suitable for use in the above liquid preparation may be one or more of menthol, menthone, isomenthone, WS - 23 (2 - isopropyl - N,2,3 - trimethylbutylamide), WS - 3 (N - ethyl - p - menthyl - 3 - carboxamide), WS - 5 (N - (ethoxycarbonylmethyl) - p - alkane - 3 - carboxamide).

[0029] The weight percentage range of the above cooling agent in the liquid preparation is about 0 - 10%, and its specific content can be set to any content within 0% - 10% according to the needs of flavor adjustment of the liquid preparation. For example, the specific weight percentage content of the cooling agent is 2%.

[0030] The embodiment of the present application further provides an electronic atomizer cartridge containing the above liquid preparation.

[0031] The above-mentioned cartridge may be configured as a sealed container that can be sold separately and assembled into an electronic atomizer, in which case the liquid formulation inside flows to the atomizing core component in the electronic atomizer, where it is atomized by the atomizing core component to generate an aerosol.

[0032] The above-mentioned cartridge may be configured as an inseparable component of the electronic atomizer, and the liquid formulation inside it flows to the atomizing core component in the electronic atomizer, where it is atomized to generate an aerosol. When the liquid formulation inside the cartridge is completely consumed, at least a part of the electronic atomizer may be discarded.

[0033] Embodiments of this application further provide an aerosol generating system comprising the above-mentioned liquid formulation and an electronic atomizer for atomizing the liquid formulation to generate an aerosol.

[0034] In some embodiments, the electronic atomizer includes a ceramic core atomizer or a cotton core atomizer. [Brief explanation of the drawing]

[0035] To more clearly explain the technical solutions of the embodiments of the present invention, the drawings necessary for use in the embodiments of the present invention will be briefly described below. Naturally, the drawings described below represent only a part of the embodiments of the present invention, and those skilled in the art will be able to conceive of other drawings from these drawings without requiring any creative effort. [Figure 1] This is an HPLC chromatogram of a liquid formulation containing 0.5% ambroxol hydrochloride, provided in some examples of this application. [Figure 2] This is an HPLC chromatogram of an aerosol generated by atomizing a liquid formulation containing 0.5% ambroxol hydrochloride, as provided in some examples of this application. [Figure 3] This is an HPLC chromatogram of a liquid formulation containing 1% ambroxol hydrochloride, provided in some examples of this application. [Figure 4]This is an HPLC chromatogram of an aerosol generated by atomizing a liquid formulation containing 1% ambroxol hydrochloride, as provided in some examples of this application. [Figure 5] This is an aerosol particle size distribution diagram of ambroxol hydrochloride provided in some embodiments of this application. [Modes for carrying out the invention]

[0036] To facilitate understanding of this application, the application will be described in more detail below with reference to specific embodiments. The embodiments are intended solely to provide a clearer understanding of the technical features, objectives, and effects of this application and do not limit it.

[0037] Unless otherwise noted, the experimental methods used in the following examples are general methods.

[0038] Unless otherwise noted, all materials, equipment, etc., used in the following examples are available through commercial channels.

[0039] In Example 1 of this application, ambroxol hydrochloride was prepared as a liquid formulation that could be atomized and inhaled. This liquid formulation was atomized by an electronic atomizer to generate an aerosol containing ambroxol hydrochloride, and the stability of the substance itself before and after atomization was analyzed using high-performance liquid chromatography.

[0040] The materials and equipment used in Example 1 are as follows: Ingredients: Ambroxol hydrochloride (AMB), 1,2-propylene glycol, vegetable glycerin, diammonium hydrogen phosphate, phosphoric acid, acetonitrile. Equipment: Shimadzu LC-20A high-performance liquid chromatograph, Labsolutions workstation, Cerulean smoking machine, Sartorius BSA224S electronic balance.

[0041] 1. Prepare a liquid formulation of ambroxol hydrochloride. The weight percentages of each component in the liquid formulation were 0.5% ambroxol hydrochloride, 50% vegetable glycerin, 29.5% water, and 20% 1,2-propylene glycol.

[0042] 2. Collect the aerosol generated by atomizing ambroxol hydrochloride. An appropriate amount of liquid formulation was added to an electronic atomizer, drawn in using a Cerulean smoker, and the aerosol was collected using one Cambridge filter. The parameters of the smoker were a suction volume of 55 mL, a suction frequency of 30 s, a suction duration of 3 s, and a suction puff count of 50 puffs. The aerosol collected on the Cambridge filter was collected and extracted by shaking using the initial mobile phase.

[0043] 3. Chromatography conditions Referencing the measurement method for ambroxol hydrochloride-related substances in the 2020 edition of the Chinese Pharmacopoeia, a Thermo Fisher Acclaim 120 C18 (4.6*250 mm, 5 μm) chromatography column was used. The mobile phase was acetonitrile:0.01 mol / diammonium hydrogen phosphate solution (pH adjusted to 7.0 with phosphoric acid) = 50:50, the flow rate was 1.0 mL / min, the detection wavelength was 248 nm, and the column temperature was 30°C.

[0044] Referring to Figure 1, which shows the chromatogram of a liquid formulation of ambroxol hydrochloride, and Figure 2, which shows the chromatogram of the aerosol generated by atomizing ambroxol hydrochloride, a comparison of Figure 1 and Figure 2 reveals that after atomization, the peak shape of the chromatographic peak of ambroxol hydrochloride does not change significantly, and there are almost no extraneous peaks in Figure 2 compared to Figure 1. This indicates that after atomizing ambroxol hydrochloride by electric heating in an electronic atomizer, the components of the substance itself become stable, and the atomization process does not decompose the substance and affect its efficacy.

[0045] In Example 2 of this application, a liquid formulation containing 0.5% ambroxol hydrochloride by weight is used as an example, and the conversion rate for generating an aerosol by atomizing the ambroxol hydrochloride is calculated.

[0046] The materials and equipment used in Example 2 are as follows: Ingredients: Ambroxol hydrochloride (AMB), 1,2-propylene glycol, vegetable glycerin, diammonium hydrogen phosphate, phosphoric acid, acetonitrile. Equipment: Shimadzu LC-20A high-performance liquid chromatograph, Labsolutions workstation, Cerulean smoking machine, Sartorius BSA224S electronic balance.

[0047] 1. Prepare a liquid formulation of ambroxol hydrochloride. The weight percentages of each component in the liquid formulation were 0.5% ambroxol hydrochloride, 50% vegetable glycerin, 29.5% water, and 20% 1,2-propylene glycol.

[0048] 2. Collect the aerosol generated by atomizing ambroxol hydrochloride. An appropriate amount of liquid formulation was added to an electronic atomizer, drawn in using a Cerulean smoker, and the aerosol was collected using one Cambridge filter. The parameters of the smoker were a suction volume of 55 mL, a suction frequency of 30 s, a suction duration of 3 s, and a suction puff count of 50 puffs. The aerosol collected on the Cambridge filter was collected and extracted by shaking using the initial mobile phase.

[0049] 3. Chromatographic conditions used in high-performance liquid chromatography Referencing the measurement method for ambroxol hydrochloride-related substances in the 2020 edition of the Chinese Pharmacopoeia, a Thermo Fisher Acclaim 120 C18 (4.6*250 mm, 5 μm) chromatography column was used. The mobile phase was acetonitrile:0.01 mol / L diammonium hydrogen phosphate solution (pH adjusted to 7.0 with phosphoric acid) = 50:50, the flow rate was 1.0 mL / min, the detection wavelength was 248 nm, and the column temperature was 30°C.

[0050] 4. Measure the conversion rate of generating an aerosol by atomizing ambroxol hydrochloride. 4.1 Prepare a blank control solution and an ambroxol hydrochloride liquid formulation, and collect the ambroxol hydrochloride aerosol. Blank control: Initial mobile phase. Ambroxol hydrochloride liquid preparation: Take an appropriate amount of the liquid preparation and dilute it with the initial mobile phase. Extraction of ambroxol hydrochloride aerosol: Take the Cambridge filter used for aerosol collection and extract it by shaking using the initial mobile phase.

[0051] 4.2, Calculation method The atomization conversion rate is calculated using the formula A = w1 / w2 * 100%. A=Atomization conversion rate w1 = Mass percentage of ambroxol hydrochloride in aerosol w2 = Mass percentage of ambroxol hydrochloride in the liquid formulation

[0052] Table 1 below shows the results of atomization conversion rate measurements for liquid formulations containing 0.5% ambroxol hydrochloride by weight.

[0053] JPEG2026511786000001.jpg33152Note: w: Mass percentage of ambroxol hydrochloride in aerosol / liquid formulation A: Atomization conversion rate

[0054] Referring to Figure 1, which shows the chromatogram of a liquid formulation containing 0.5% ambroxol hydrochloride by weight, and Figure 2, which shows the chromatogram of the aerosol generated by atomizing the above ambroxol hydrochloride liquid formulation, the atomization conversion rate of 0.5% ambroxol hydrochloride measured by the above calculation method is 98.21%. Therefore, the material components of the aerosol formed by converting ambroxol hydrochloride in the liquid formulation are stable, and the conversion efficiency is high.

[0055] In Example 3 of this application, a liquid formulation containing 1% ambroxol hydrochloride by mass is used as an example, and the conversion rate for generating an aerosol by atomizing the ambroxol hydrochloride is calculated.

[0056] The materials and equipment used in Example 3 are as follows: Ingredients: Ambroxol hydrochloride (AMB), 1,2-propylene glycol, vegetable glycerin, diammonium hydrogen phosphate, phosphoric acid, acetonitrile. Equipment: Shimadzu LC-20A high-performance liquid chromatograph, Labsolutions workstation, Cerulean smoking machine, Sartorius BSA224S electronic balance.

[0057] 1. Prepare a liquid formulation of ambroxol hydrochloride. The weight percentages of each component in the liquid formulation were 1% ambroxol hydrochloride, 50% vegetable glycerin, 29% water, and 20% 1,2-propylene glycol.

[0058] 2. Collect the aerosol generated by atomizing ambroxol hydrochloride. An appropriate amount of liquid formulation was added to an electronic atomizer, drawn in using a Cerulean smoker, and the aerosol was collected using one Cambridge filter. The parameters of the smoker were a suction volume of 55 mL, a suction frequency of 30 s, a suction duration of 3 s, and a suction puff count of 50 puffs. The aerosol collected on the Cambridge filter was collected and extracted by shaking using the initial mobile phase.

[0059] 3. Chromatographic conditions used in high-performance liquid chromatography Referencing the measurement methods for AMB-related substances in the 2020 edition of the Chinese Pharmacopoeia, a Thermo Fisher Acclaim 120 C18 (4.6*250 mm, 5 μm) chromatography column was used. The mobile phase was acetonitrile:0.01 mol / L diammonium hydrogen phosphate solution (pH adjusted to 7.0 with phosphoric acid) = 50:50, the flow rate was 1.0 mL / min, the detection wavelength was 248 nm, and the column temperature was 30°C.

[0060] 4. Measure the conversion rate of generating an aerosol by atomizing ambroxol hydrochloride. 4.1 Prepare a blank control solution and an ambroxol hydrochloride liquid formulation, and collect the ambroxol hydrochloride aerosol. Blank control: Initial mobile phase. Ambroxol hydrochloride nebulizer: Take an appropriate amount of nebulizer and dilute it with the initial mobile phase. Extraction of ambroxol hydrochloride aerosol: Take the Cambridge filter collected during aerosol collection and extract it by shaking using the initial mobile phase.

[0061] 4.2, Calculation method The atomization conversion rate is calculated using the formula A = w1 / w2 × 100%. A=Atomization conversion rate w1 = Mass percentage of ambroxol hydrochloride in aerosol w2 = Mass percentage of ambroxol hydrochloride in the liquid formulation

[0062] Table 2 below shows the results of atomization conversion rate measurements for a liquid formulation containing 1% ambroxol hydrochloride by mass.

[0063] JPEG2026511786000002.jpg34152Note: w: Mass percentage of ambroxol hydrochloride in aerosol / liquid formulation A: Atomization conversion rate

[0064] Referring to Figure 3, which shows the chromatogram of the liquid formulation of ambroxol hydrochloride, and Figure 4, which shows the chromatogram of the aerosol generated by atomizing ambroxol hydrochloride, a comparison of Figure 3 and Figure 4 reveals that after atomization, the peak shape of the chromatographic peak of ambroxol hydrochloride does not change significantly, and there are almost no extraneous peaks in Figure 4 compared to Figure 3. This indicates that the substance components of ambroxol hydrochloride are stable after atomization, and the atomization process does not decompose the substance and affect the drug's efficacy.

[0065] The atomization conversion rate of 1% ambroxol hydrochloride, as measured by the above calculation method, was 98.5.

[0066] In Example 4 of this application, a liquid formulation containing 0.5% ambroxol hydrochloride by weight is used as an example, and the uniformity of conversion to an aerosol is analyzed by taking multiple inhalations and analyzing the weight of ambroxol hydrochloride in the aerosol per puff.

[0067] The mass percentages of each component in the liquid formulation were 0.5% ambroxol hydrochloride, 50% vegetable glycerin, 20% 1,2-propylene glycol, and 29.5% water.

[0068] The liquid formulations of the above examples were added to an electronic atomizer, and the mixture was inhaled using a Cerulean smoking machine. The aerosol was collected using one Cambridge filter, and the Cambridge filter was collected once for every 25 puffs inhaled, for a total of 250 puffs inhaled. The measured aerosol conversion rates are shown in Table 3 below.

[0069] JPEG2026511786000003.jpg71152Note: A: Atomization conversion rate

[0070] Table 3 shows that the weight difference of ambroxol hydrochloride in the aerosol collected every 25 puffs was small, and the conversion rate was always greater than 90%. This indicates that the conversion rate of ambroxol hydrochloride in the liquid formulation is relatively stable and has good uniformity. It should be noted that in the table above, there are cases where the atomization conversion rate is greater than 100%, but this is mainly due to deviations in the values ​​caused by the accuracy of the measurement method, the precision of the equipment, etc.

[0071] It should be explained that the number of puffs set in most currently used electronic atomizers is around 500, and in the above experiment, when the weight stability of ambroxol hydrochloride in the aerosol was measured every 25 puffs, it was found to be of good uniformity. Therefore, it has been sufficiently demonstrated that the effect of alleviating unpleasant symptoms is relatively uniform when the user repeatedly inhales the aerosol containing ambroxol hydrochloride multiple times, and ambroxol hydrochloride is suitable for atomized inhalation using an electronic atomizer.

[0072] In Example 5 of this application, the particle size distribution of ambroxol hydrochloride aerosol was measured using a smoking machine manufactured by Shenzhen Heyuan Technology Co., Ltd. and a HELOS BR laser particle size analyzer from Sympatec GmbH, Germany.

[0073] The measurement methods used are as follows: An R1 lens (measurement range 0.1 μm to 35 μm) was selected, and logarithmically spaced particle size channels were collected. In the submicron range, there were 10 channels for actual signal measurement, providing very high particle size resolution. The suction mode of the electronic atomizer was set to a suction volume of 55 mL, a suction duration of 3 s, and a suction interval of 30 s, resulting in a square wave suction curve. Each sample was measured three times in parallel, with three puffs of suction each time. The measurement results were averaged, with one time slice every 100 milliseconds, for a total of 30 slices with suction of less than 3 seconds, and the flow rate was 18.3 L / min.

[0074] JPEG2026511786000004.jpg22151

[0075] Table 4 shows that the median particle size of the ambroxol hydrochloride aerosol was 0.53 μm. Figure 5 shows the particle size distribution of the ambroxol hydrochloride aerosol. The aerosols exhibited a unimodal distribution, approximately log-normal, with the particle sizes mainly ranging from 0.2 μm to 1 μm, and a small number of aerosols ranging from 1 μm to 3 μm.

[0076] One thing to explain is that because ambroxol hydrochloride has a small aerosol particle size, its taste is more delicate.

[0077] Example 5 of this application provides a liquid formulation containing ambroxol hydrochloride suitable for atomization using an electronic atomizer, wherein the weight percentage range of ambroxol hydrochloride in the liquid formulation is 0.01% to 2%, or the weight percentage range of ambroxol hydrochloride in the liquid formulation is 0.1% to 1%.

[0078] When ambroxol hydrochloride is used as a tablet, the daily dose for adults is limited to 4 mg or less. Based on the volume of smoke per puff of the electronic atomizer and the number of puffs inhaled by the user per day, the ambroxol hydrochloride content is controlled to within 2%, allowing the user to alleviate unpleasant symptoms of rhinitis and asthma with multiple inhalations per day.

[0079] Furthermore, measurements of the atomization effect of the ambroxol hydrochloride liquid formulation showed that when the weight percentage of ambroxol hydrochloride in the liquid formulation was controlled to approximately 0.1% to 1%, the conversion rate from ambroxol hydrochloride in the liquid formulation to an aerosol was almost always over 90%, and sometimes even approached 100%. Therefore, controlling the weight percentage of ambroxol hydrochloride in the liquid formulation to within 0.1% to 1% is advantageous for improving the conversion rate.

[0080] In some examples, the solvent comprises at least one of propylene glycol, vegetable glycerin, water, or ethanol.

[0081] In some examples, the weight percentage of propylene glycol in the inhalation formulation composition is 20% to 80%.

[0082] In some examples, the weight percentage of plant glycerin in the inhalation formulation composition is 30% to 70%.

[0083] The propylene glycol mentioned above can be selected as either 1,2-propylene glycol or 1,3-propylene glycol. Propylene glycol and vegetable glycerin are commonly used solvents in electronic atomizers and exhibit excellent performance in increasing vapor volume and controlling the fluidity of liquid formulations. Therefore, by using propylene glycol and vegetable glycerin as the main solvent components, and simultaneously adding an appropriate amount of water or ethanol as a solvent in proportion to the weight percentage content of ambroxol hydrochloride in the liquid formulation, the solubility of ambroxol hydrochloride in the liquid formulation can be increased.

[0084] In some examples, the atomization conversion rate of ambroxol hydrochloride is 90% or higher, or the atomization conversion rate of ambroxol hydrochloride is 80% or higher, or the atomization conversion rate of ambroxol hydrochloride is 70% or higher.

[0085] Measurements using the atomization measurement method provided in the embodiments of this application have shown that the atomization conversion rate of a liquid formulation containing a certain amount of ambroxol hydrochloride is 90% or more, and the weight percentage content of ambroxol hydrochloride in the liquid formulation is set to approximately 1% or less. When the content of ambroxol hydrochloride in the liquid formulation is adjusted to a certain range, the conversion rate of ambroxol hydrochloride is 80% or more, and when the weight percentage content of ambroxol hydrochloride in the liquid formulation is adjusted to a different range, or when the electronic atomizer is changed and a different electronic atomizer is used, the conversion rate of ambroxol hydrochloride is lower than 70%. Here, different electronic atomizers are configured to have different heating power or to use different atomizing core components.

[0086] In some embodiments, the liquid formulation further comprises at least one of an edible essence, a sweetener, or a cooling agent.

[0087] The above-mentioned edible essences are intended to enhance the taste and aroma of the aerosol itself, which is formed by atomizing the liquid formulation. The types of edible essences include one or more of the following: fruit flavors, floral flavors, mint flavors, and tea flavors.

[0088] The weight percentage range of the above-mentioned food essence in the liquid formulation is approximately 0-10%, and its specific content can be set to any amount between 0% and 10% depending on the needs for flavor adjustment of the liquid formulation.

[0089] The above sweetener is intended to enhance the sweetness of the aerosol generated by atomizing the above liquid formulation. It should be noted that ambroxol hydrochloride itself has a certain degree of bitterness, so adding an appropriate amount of sweetener to the liquid formulation contributes to improving the taste. The type of sweetener may be one or more selected from neotame, sodium cyclamate, sucralose, aspartame, stevioside, and acesulfame potassium.

[0090] The weight percentage range of the above sweetener in the liquid formulation is approximately 0% to 10%, and its specific content can be set to any amount between 0% and 10% depending on the needs for flavor adjustment of the liquid formulation.

[0091] The above-mentioned cooling agent enhances the cooling effect of the aerosol generated by atomizing the above-mentioned liquid formulation, and further enhances the comfort level for the user when inhaling the aerosol. Suitable cooling agents for use in the above-mentioned liquid formulation may be one or more of the following: peppermint, menthone, isomenthon, WS-23 (2-isopropyl-N,2,3-trimethylbutylamide), WS-3 (N-ethyl-p-menthyl-3-carboxamide), and WS-5 (N-(ethoxycarbonylmethyl)-p-alkane-3-carboxamide).

[0092] The weight percentage range of the above-mentioned cooling agent in the liquid formulation is approximately 0-10%, and its specific content can be set to any amount between 0% and 10% depending on the needs for flavor adjustment of the liquid formulation.

[0093] It should be explained that the inventors measured the atomization performance of more than 20 types of pharmaceuticals and found that most pharmaceuticals are unsuitable for atomization inhalation using an electronic atomizer. For example, the atomization conversion rate of clenbuterol hydrochloride is less than 10%, the atomization conversion rate of sodium cromoglycate is less than 15%, and the atomization conversion rate of terbutaline sulfate is less than 50%. Due to the low conversion rate, the content of the active ingredient in the aerosol is low, and even if the user inhales it multiple times, it is difficult to obtain an effect that alleviates unpleasant symptoms. On the other hand, the liquid formulation containing ambroxol hydrochloride provided in the examples of this application has a high conversion rate and high uniformity in converting the active ingredient into an aerosol after atomization using an electronic atomizer, resulting in unexpected technical effects. Therefore, it is suitable for preparation as a liquid formulation and atomization using an electronic atomizer to generate an aerosol, allowing the user to inhale the aerosol and alleviate unpleasant symptoms.

[0094] Example 6 of this application provides a cartridge for an electronic atomizer that contains a liquid formulation containing ambroxol hydrochloride.

[0095] The above-mentioned cartridge may be configured as a sealed container that can be sold separately and assembled into an electronic atomizer, in which case the liquid formulation inside flows to the atomizing core component in the electronic atomizer, where it is atomized by the atomizing core component to generate an aerosol.

[0096] The above-mentioned cartridge may be configured as an inseparable component of the electronic atomizer, and the liquid formulation inside it flows to the atomizing core component in the electronic atomizer, where it is atomized to generate an aerosol. When the liquid formulation inside the cartridge is completely consumed, at least a part of the electronic atomizer may be discarded.

[0097] Embodiment 7 of this application provides an aerosol generation system comprising the above-mentioned liquid formulation and an electronic atomizer for atomizing the liquid formulation to generate an aerosol.

[0098] In some embodiments, the electronic atomizer includes a ceramic core atomizer or a cotton core atomizer.

[0099] A ceramic core atomizer includes a porous fluid guide and a heating element coupled to the porous fluid guide. The porous fluid guide is made from a porous material, which includes microporous ceramics, microporous glass ceramics, microporous glass, or foamed metals. The heating element may be a metallic material, metal alloy, graphite, carbon, conductive ceramic, or a composite material of a metallic material and other ceramic materials having appropriate impedance. Suitable metallic or alloy materials include at least one of nickel, cobalt, zirconium, titanium, nickel alloys, cobalt alloys, zirconium alloys, titanium alloys, nickel-chromium alloys, nickel-iron alloys, iron-chromium alloys, titanium alloys, iron-manganese-aluminum alloys, or stainless steel.

[0100] The cotton core atomizer includes a fluid guide element and a heating element coupled to the fluid guide element. The fluid guide element is made of fibrous cotton, and the manufacturing material of the heating element in the cotton core atomizer is almost the same as the manufacturing material of the heating element in the ceramic core atomizer.

[0101] An electronic atomizer includes not only an atomizing core component but also a battery component for supplying power for operation.

[0102] The electronic atomizer is preferably configured as a small, portable device that is easy for the user to carry with them at any time and can be used to alleviate unpleasant symptoms of rhinitis and asthma at any time.

[0103] Compared to ultrasonic atomizers, which generate water mist by decomposing the molecular structure of a liquid matrix through high-frequency vibrations of a mesh atomizing element, electronic atomizers generate aerosols by heating the liquid matrix to its boiling point through an electric heating process. Liquid formulations containing ambroxol hydrochloride, when processed using an electronic atomizer, produce aerosols with a particle size of mostly ≤1 μm. This is advantageous for deep deposition of the aerosol into the bronchi and lungs, particularly deep into the alveoli, making it suitable for drug administration to the lower respiratory tract and lungs. Since ambroxol hydrochloride has excellent efficacy in treating respiratory diseases, atomizing liquid formulations containing ambroxol hydrochloride using an electronic atomizer is advantageous for maximizing the therapeutic effect of ambroxol hydrochloride. Furthermore, atomizing liquid formulations containing ambroxol hydrochloride using an electronic atomizer results in less residue of the generated ambroxol hydrochloride aerosol in the oral cavity, less gastric irritation, and improved user compliance. Furthermore, the electronic atomizer is configured as an active suction type, where the heating system is activated by the user's active inhalation, and the user inhales an aerosol containing ambroxol hydrochloride generated by electrolysis, further improving user compliance.

[0104] It should be noted that while the specification and drawings of this application illustrate preferred embodiments of this application, they are not limited to the embodiments described herein. Furthermore, those skilled in the art may make improvements and modifications based on the above description, all of which shall fall within the scope of protection of the claims attached to this application.

Claims

1. A liquid formulation that can be atomized and inhaled for use with an electronic atomizer, Ambroxol hydrochloride and, A solvent, and The atomization conversion rate of ambroxol hydrochloride in the liquid formulation, which is heated and atomized by the electronic atomizer to form an aerosol, is 90% or more. Alternatively, the atomization conversion rate of the ambroxol hydrochloride is 80% or more. Alternatively, the atomization conversion rate of the ambroxol hydrochloride is 70% or more. Alternatively, a liquid formulation that can be atomized and inhaled, characterized in that the atomization conversion rate of the ambroxol hydrochloride is 60% or more.

2. The atomizable and inhalable liquid formulation according to claim 1, characterized in that the weight percentage of the ambroxol hydrochloride in the liquid formulation is 0.01% to 2%, or the weight percentage of the ambroxol hydrochloride in the liquid formulation is 0.1% to 1%.

3. The atomizable and inhalable liquid formulation according to claim 1, characterized in that the solvent comprises at least one of propylene glycol, vegetable glycerin, water, or ethanol.

4. The atomizable and inhalable liquid formulation according to claim 3, characterized in that the weight percentage of propylene glycol in the liquid formulation composition is 20% to 80%.

5. The atomizable and inhalable liquid formulation according to claim 3, characterized in that the weight percentage of the plant glycerin in the liquid formulation composition is 30% to 70%.

6. The atomizable and inhalable liquid formulation according to claim 3, characterized in that the weight percentage of water in the liquid formulation is 10% to 50%.

7. The atomizable and inhalable liquid formulation according to claim 1, characterized in that the particle size range of the aerosol formed by atomizing the ambroxol hydrochloride in the liquid formulation by the electronic atomizer is 0.2 μm to 3 μm.

8. The atomizable and inhalable liquid formulation according to claim 1, characterized in that the liquid formulation further comprises at least one of a food essence, a sweetener, or a cooling agent.

9. A cartridge for an electronic atomizer, characterized in that it contains a liquid formulation that can be atomized and inhaled according to any one of claims 1 to 8.

10. An aerosol generating system comprising a liquid formulation that can be atomized and inhaled according to any one of claims 1 to 8, and an electronic atomizer for heating and atomizing the liquid formulation to generate an aerosol.

11. The aerosol generating system according to claim 10, characterized in that the electronic atomizer includes a ceramic core atomizer or a cotton core atomizer.

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