Low refrigeration effect composite propellants for inhalation aerosols, and methods of making and using the same

Abstract

The present application relates to low refrigeration effect composite propellant for inhalation aerosol and its preparation method and application. The composite propellant is prepared from single propellant, monosaccharide and short chain alcohol according to the following mass ratio: single propellant 89.8-98.99, monosaccharide 0.01-0.2, short chain alcohol 1-10; the single propellant is HFA134a and / or HFA227; the monosaccharide is selected from at least one of C5-C6 monosaccharide; the short chain alcohol is selected from at least one of C2-C4 alkyl alcohol. The composite propellant has low refrigeration effect, small irritation to patients with respiratory diseases, can improve patient compliance, and promote the clinical application of inhalation aerosol.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a low refrigeration effect composite propellant for inhalation aerosols and a preparation method and application thereof. BACKGROUND

[0002] An inhalation aerosol is a "drug-device-in-one" pulmonary inhalation drug delivery formulation composed of a drug, a propellant and a pressure-resistant container. It is commonly used in clinical practice to deliver therapeutic drugs for respiratory diseases such as asthma and chronic obstructive pulmonary disease. In recent years, inhalation aerosols for delivering anti-infective, anti-fibrotic and anti-tumor drugs have also entered the laboratory research or preclinical research stage. Due to its low preparation cost, inhalation aerosols have high potential for industrial conversion. However, the market share of inhalation aerosols in the pulmonary inhalation formulation market is only about 36% (2021 data). The main reason for the low market share of inhalation aerosols is that the respiratory tract irritation induced by the refrigeration effect of the propellant seriously affects patient compliance, and patients are less inclined to use inhalation aerosols.

[0003] The airway in the human respiratory system mainly includes nasopharynx, trachea, bronchus and alveoli. The epithelium and mucosa of these parts are sensitive to physical stimuli such as cold. It must be noted that inhalation aerosols are commonly used in clinical practice to deliver drugs for the treatment of respiratory diseases, and patients with respiratory diseases often have pathological changes in the airway epithelium and mucosa. Therefore, such patients are more sensitive to cold stimulation than healthy people. The refrigeration effect of the propellant (mainly HFA-134a or HFA-227) in the inhalation aerosol is strong when it vaporizes. It is in a gaseous state at room temperature and normal pressure, and is filled into a pressure-resistant container by high-pressure filling. When administered, the high pressure of the propellant is released to drive the formation of a drug-containing aerosol, which rapidly vaporizes after entering the airway, causing a sudden temperature drop, which may cause strong cold stimulation to patients with respiratory diseases, reducing patient compliance. Only by weakening the refrigeration effect of the propellant and improving patient compliance can the clinical application of inhalation aerosols be promoted.

[0004] To address this issue, the current main solution in the clinical, industrial and academic fields is to complex inhalation aerosols with spacers. Spacers can provide a buffer effect before the drug-containing aerosol enters the airway, allowing the refrigeration effect of propellant vaporization to occur outside the airway, reducing the cold stimulation to patients. Although this strategy can avoid the problem, it still has several limitations: (1) special connection ports are required to complex inhalation aerosol pressure-resistant containers of various brands with spacers, and the design and production of special connection ports is time-consuming and costly; (2) the drug-containing aerosol may undergo unstable phenomena such as sedimentation and adhesion in the spacer, reducing the amount of drug entering the patient's respiratory system; (3) training patients to use spacers requires additional medical resources; (4) for some clinical application scenarios such as first aid, the use of spacers may delay the treatment opportunity. SUMMARY

[0005] Based on this, the purpose of the present application is to provide a low refrigeration effect composite propellant for inhalation aerosols, which can reduce the refrigeration effect of the propellant from the source without compounding the aerosol storage tank, improve patient compliance, promote the clinical conversion and application of inhalation aerosols.

[0006] To achieve the above-mentioned purpose of the application, the present application comprises the following technical solutions.

[0007] A composite propellant prepared from single propellant, monosaccharide and short-chain alcohol in the following mass ratio:

[0008] Single propellant 89.8-98.99

[0009] Monosaccharide 0.01-0.2

[0010] Short-chain alcohol 1-10;

[0011] The single propellant is HFA134a and / or HFA227;

[0012] The monosaccharide is selected from at least one of C5-C6 monosaccharides;

[0013] The short-chain alcohol is selected from at least one of C2-C4 alkyl alcohols.

[0014] In some embodiments, the monosaccharide is selected from at least one of C6 monosaccharides.

[0015] In some embodiments, the monosaccharide is selected from at least one of glucose, fructose, galactose and mannose.

[0016] In some embodiments, the short-chain alcohol is selected from at least one of ethanol, isopropanol and tert-butyl alcohol.

[0017] In some embodiments, the total mass of the composite propellant is 5-10 g.

[0018] In some embodiments, the composite propellant is prepared from raw materials in the following mass ratio:

[0019] HFA134a 89.8-94.95

[0020] Glucose 0.05-0.2

[0021] Ethanol 5-10.

[0022] In some embodiments, the composite propellant is prepared from raw materials in the following mass ratio:

[0023] HFA227 97.96-98.99

[0024] Mannose 0.01-0.04

[0025] Tert-butyl alcohol 1-2.

[0026] In some embodiments, the composite propellant is prepared from raw materials in the following mass ratio:

[0027] HFA134a 97.98-97.99

[0028] Fructose 0.01-0.02

[0029] Short-chain alcohol 2;

[0030] The short-chain alcohol is a mixture of ethanol and isopropyl alcohol, and the mass ratio of the ethanol and isopropyl alcohol is 0.5-1.5:1.

[0031] In some embodiments, the composite propellant is prepared from raw materials in the following mass ratio:

[0032] HFA134a 91.94-95.97

[0033] Monosaccharide 0.03-0.06

[0034] Ethanol 4-8;

[0035] The monosaccharide is a mixture of galactose and glucose, and the mass ratio of the galactose and glucose is 1:1-3.

[0036] The application also provides a preparation method of the composite propellant.

[0037] A preparation method of the composite propellant, comprising the following steps:

[0038] (1) sequentially adding the monosaccharide and the short-chain alcohol into a pressure-resistant container, and stirring in a gas bath stirring box;

[0039] (2) installing a quantitative valve on the pressure-resistant container, filling the monosaccharide propellant into the pressure-resistant container by using a propellant filling machine, and stirring in a gas bath stirring box to obtain the composite propellant.

[0040] In some embodiments, the temperature of the gas bath stirring box in step (1) is 20-30°C, and the stirring rate is 25-100 rpm.

[0041] In some embodiments, the temperature of the gas bath stirring box in step (2) is 20-30°C, and the stirring rate is 25-100 rpm.

[0042] In some embodiments, the pressure-resistant container is an aluminum pressure-resistant container with a specification of 10 mL.

[0043] In some embodiments, the quantitative valve in step (2) is a 50 μL quantitative valve.

[0044] The application also provides the use of the composite propellant, comprising the following technical scheme.

[0045] The use of the composite propellant in the preparation of the inhalation aerosol with low refrigeration effect.

[0046] The application also provides an inhalation aerosol, comprising the following technical scheme.

[0047] An inhalation aerosol prepared from components comprising a drug and the above-mentioned propellant.

[0048] In some embodiments, the mass ratio of the drug and the propellant is 0.3:5-10.

[0049] The application also provides a preparation method of the inhalation aerosol, comprising the following technical scheme.

[0050] A preparation method of the inhalation aerosol, comprising the following steps:

[0051] (1) sequentially adding the monosaccharide, short-chain alcohol and drug into a pressure-resistant container, and stirring in a gas bath stirring box;

[0052] (2) installing a quantitative valve on the pressure-resistant container, filling the monosaccharide propellant into the pressure-resistant container by using a propellant filling machine, and stirring in a gas bath stirring box, to obtain the inhalation aerosol.

[0053] In some embodiments, the temperature of the gas bath stirring box in step (1) is 20-30℃, and the stirring rate is 25-100 rpm.

[0054] In some embodiments, the temperature of the gas bath stirring box in step (2) is 20-30℃, and the stirring rate is 25-100 rpm.

[0055] In some embodiments, the pressure-resistant container is an aluminum pressure-resistant container with a specification of 10 mL.

[0056] In some embodiments, the quantitative valve in step (2) is a 50 μL quantitative valve.

[0057] The low refrigeration effect composite propellant for the inhalation aerosol, the preparation method and the use thereof have the following advantages and beneficial effects:

[0058] The inventor of the present application analyzes and finds that the existing propellant has strong intermolecular fluorine-hydrogen bond, and the key reason for producing refrigeration effect is that the fluorine-hydrogen bond is broken in the gasification process and absorbs heat. Therefore, on the basis of the analysis, the present application prepares a composite propellant by combining the existing propellant with monosaccharide and short-chain alcohol in a certain ratio. The hydroxyl groups in the molecular structure of monosaccharide and short-chain alcohol can compete for the original binding site of fluorine-hydrogen bond, replace part of the fluorine-hydrogen bond with weaker oxygen-hydrogen bond, reduce the heat absorption in the gasification process, and thus reduce the refrigeration effect. On this basis, the composite propellant is prepared into an inhalation aerosol, which can reduce the cold stimulation to patients with respiratory diseases during administration, improve the patient compliance, and promote the clinical application of the inhalation aerosol.

[0059] In the composite propellant system of the present application, HFA134a or HFA227 accounts for a large proportion to ensure aerosol generation effect; monosaccharide contains multiple hydroxyl groups in the molecule, has a large competition effect on fluorine-hydrogen bond, and is the main reason for inhibiting the refrigeration effect of the system; short-chain alcohol inhibits the refrigeration effect of the system while regulating the polarity of the system, provides a suitable dissolution environment for each component, and improves the compatibility of the propellant and monosaccharide. Under the compounding effect of each component in a reasonable ratio, the obtained composite propellant has low refrigeration effect, good quality uniformity and reproducibility, and high stability. In addition, each component is a substance with high biological safety, and has good clinical conversion prospect.

[0060] The inventor finds through series of experimental researches that the refrigeration effect of the composite propellant is significantly reduced, and can be reduced to about 23% of that of a single propellant at most; the composite propellant has almost no irritability to lung fibrosis disease model animals (irritative cough frequency is far less than 1 time / 10 min), and is significantly lower than that of a single propellant (irritative cough frequency can reach 5.0 times / 10 min). Therefore, the composite propellant prepared by the present application can effectively reduce the refrigeration effect, reduce the irritation to the respiratory tract in pathological state, and improve the patient compliance. BRIEF DESCRIPTION OF DRAWINGS

[0061] Figure 1 It is a schematic diagram of intermolecular hydrogen bond of HFA134a (left) and HFA227 (right);

[0062] Figure 2 It is a schematic diagram of intermolecular hydrogen bond of HFA134a and monosaccharide (upper left), HFA134a and short-chain alcohol (lower left), HFA227 and monosaccharide (upper right), and HFA227 and short-chain alcohol (lower right);

[0063] Figure 3 It is a temperature-pull curve of glucose-ethanol-HFA134a composite propellant in Example 1: system 1 (upper left), system 2 (upper right), system 3 (lower left), and system 4 (lower right);

[0064] Figure 4 Temperature-press cycle curves for the mannose-tert-butanol-HFA 227 composite propellant of Example 2: system 5 (upper left), system 6 (upper right), system 7 (lower left), and system 8 (lower right);

[0065] Figure 5 Temperature-press cycle curves for the fructose-ethanol / isopropanol-HFA 134a composite propellant of Example 3: system 9 (upper left), system 10 (upper right), system 11 (middle left), system 12 (middle right), system 13 (lower left), and system 14 (lower right);

[0066] Figure 6 Temperature-press cycle curves for the galactose / glucose-ethanol-HFA 134a composite propellant of Example 4: system 15 (upper left), system 16 (upper right), system 17 (middle left), system 18 (middle right), system 19 (lower left), and system 20 (lower right);

[0067] Figure 7 Temperature-press cycle curves for the single propellant of Comparative Example 3: comparative system 1 (upper left), comparative system 2 (upper right), comparative system 3 (lower left), and comparative system 4 (lower right);

[0068] Figure 8 Temperature-press cycle curves for the ethanol-HFA 134a propellant of Comparative Example 4: comparative system I (left) and comparative system J (right);

[0069] Figure 9 Temperature-press cycle curves for the ribose-tert-butanol-HFA 227 composite propellant of Comparative Example 5: comparative system K (upper left), comparative system L (upper right), comparative system M (lower left), and comparative system N (lower right);

[0070] Figure 10 Biological safety study results for systems 1, 5, 9, and 15 of Examples 1 to 4: cough frequency of C57BL / 6J mice (upper left), cough frequency of C57BL / 6J mice of a lung fibrosis model (upper right), weight change curve of C57BL / 6J mice (lower left), and weight change curve of C57BL / 6J mice of a lung fibrosis model (lower right);

[0071] Figure 11 Biological safety study results for comparative systems 1 to 4 of Comparative Example 6: cough frequency of C57BL / 6J mice (upper left), cough frequency of C57BL / 6J mice of a lung fibrosis model (upper right), weight change curve of C57BL / 6J mice (lower left), and weight change curve of C57BL / 6J mice of a lung fibrosis model (lower right). DETAILED DESCRIPTION

[0072] The technical solutions of the present application are further illustrated below through specific examples. Those skilled in the art should understand that the examples are only for the purpose of understanding the present application and should not be regarded as specific limitations of the present application.

[0073] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0074] The terms "comprising" and "having", and any variations thereof, used in the present application are intended to cover the non-exclusive inclusion. For example, a process, method, device, product or equipment comprising a series of steps is not limited to the listed steps or modules, but optionally further comprises steps not listed, or optionally further comprises other steps inherent to the process, method, product or equipment.

[0075] In the present application, "a plurality of" refers to two or more. "And / or", which describes the association between the associated objects, means that there can be three relationships, for example, A and / or B can mean that A exists alone, A and B exist together, and B exists alone. The character " / " generally represents that the associated objects before and after are in an "or" relationship.

[0076] The inventors found that the main reason for the strong refrigeration effect of the propellant is that HFA134a-HFA134a or HFA227-HFA227 molecules form fluorine-hydrogen bonds (as shown in Figure 1 Due to the strong electronegativity of fluorine atoms, the adsorption force on the positive hydrogen nucleus is strong, so the bond energy of the fluorine-hydrogen bond is high, and the heat energy required to break the fluorine-hydrogen bond during the gasification process of the propellant is large, resulting in a strong refrigeration effect, which is macroscopically manifested as a sudden drop in temperature. On the basis of this analysis, the principle of reducing the refrigeration effect of the composite propellant system constructed in the present application is as follows Figure 2The inventors found that after adding monosaccharides such as glucose, fructose, galactose or mannose and short-chain alcohols such as ethanol, isopropyl alcohol or tert-butyl alcohol into the propellant (HFA134a or HFA227) system, the monosaccharides and short-chain alcohols can compete with the propellant molecules for the original fluorine-hydrogen bond binding sites to form oxygen-hydrogen bonds. The electronegativity of oxygen atoms is much lower than that of fluorine atoms, so the bond energy of oxygen-hydrogen bonds is much lower than that of fluorine-hydrogen bonds. After replacing part of the fluorine-hydrogen bonds with oxygen-hydrogen bonds, the heat energy consumed in the hydrogen bond breaking process during the gasification of the system is reduced, and thus the refrigeration effect is reduced. In the composite propellant system of the application, HFA134a or HFA227 accounts for a large proportion, which can ensure the aerosol generation effect; the monosaccharide molecules contain multiple hydroxyl groups, which have a large competition effect on the fluorine-hydrogen bond, and are the main reason for inhibiting the refrigeration effect of the system; the short-chain alcohol can not only inhibit the refrigeration effect of the system, but also regulate the polarity of the system to provide a suitable dissolution environment for each component and improve the compatibility of the propellant and the monosaccharide. Under the compounding action of each component in a reasonable ratio, the obtained composite propellant has a low refrigeration effect, good quality uniformity and reproducibility, and high stability.

[0077] Example 1: Preparation of glucose-ethanol-HFA134a composite propellant

[0078] Glucose and ethanol were sequentially added to a 10 mL aluminum pressure-resistant container, which was placed in a 25°C air bath stirring box and stirred at a rate of 50 rpm. Then a 50 μL quantitative valve was installed on the pressure-resistant container using a sealing machine, and HFA134a was filled into the aluminum pressure-resistant container using a propellant filling machine. Then the aluminum pressure-resistant container was stirred in a 25°C air bath stirring box at a rate of 50 rpm to obtain the composite propellant.

[0079] Systems 1-4 and meth-3 were prepared by the above steps. In system 1, the mass ratio of glucose-ethanol-HFA134a was 0.05:5:94.95; in system 2, the mass ratio of glucose-ethanol-HFA134a was 0.1:5:94.9; in system 3, the mass ratio of glucose-ethanol-HFA134a was 0.1:10:89.9; in system 4, the mass ratio of glucose-ethanol-HFA134a was 0.2:10:89.8; in system meth, the mass ratio of glucose-ethanol-HFA134a was 0.8:5:94.2; in system eth, the mass ratio of glucose-ethanol-HFA134a was 0.1:1:98.9; and in system 3, the mass ratio of glucose-ethanol-HFA134a was 0.1:25:74.9. The total mass of glucose, ethanol and HFA134a in each system was 10 g.

[0080] The prepared systems 1-4 and a-d were evaluated for total actuations, dose delivered per actuation and storage leakage rate. The total actuations test method was as follows: the sample was taken, the valve was pressed, the content was released into ultrapure water (receiving liquid), the interval between each press was not less than 5 s, and the total actuations were recorded. The dose delivered per actuation test method was as follows: the sample was taken, shaken and 5 actuations were discarded. The weight was accurately measured, one actuation was ejected, the weight was again accurately measured, and the difference between the two weights was the delivered dose. Three actuations were continuously measured; a number of actuations were discarded until n / 2 actuations (n was the total actuations), and then 4 actuations were continuously measured; a number of actuations were continuously discarded, and the last 3 actuations were measured. The average of 10 delivered doses per actuation was calculated. The storage leakage rate test method was as follows: the sample was accurately weighed, and then stored at 25±2°C and a relative humidity of 55±10% in a light-proof environment for 3 months. The sample was taken out, accurately weighed again, and the weight loss was calculated. The storage leakage rate was calculated by dividing the weight loss by the original weight of the sample.

[0081] The results showed that the total actuations of systems 1-4 were all more than 180, indicating that the systems were suitable for long-term use (more than 3 months) of once-daily administration preparations; the dose delivered per actuation was about 54 mg, which was good in reproducibility and reflected the quality uniformity; and the storage leakage rate was almost 0, proving that the systems had high stability. The glucose-ethanol-HFA134a composite propellant could be used for the preparation of inhalation aerosols.

[0082] However, compared with systems 1-4, the total actuations and the dose delivered per actuation of systems a and b had large variations. The reason was that the glucose content was too high (system a) or the ethanol content was too low (system b), resulting in easy precipitation of glucose in the composite propellant and reducing the quality uniformity. Although the total actuations and the dose delivered per actuation of system c were relatively close to those of systems 1-4, the storage leakage rate was significantly increased, about 6 times that of systems 1-4, indicating that the system had poor stability. The reason was that the ethanol content in system c was high, which increased the volatility of the liquid formulation. It can be seen that the monosaccharide content in the composite propellant cannot be too high, and the short-chain alcohol content cannot be too low or too high.

[0083] Table 1 Evaluation results of total actuations, dose delivered per actuation and storage leakage rate of systems 1-4 and a-c

[0084]

[0085]

[0086] Comparative Example 1: Preparation of glucose-HFA134a propellant

[0087] Into a 10 mL aluminum pressure container, glucose was added and stirred in a 25°C air-bath shaker at a rate of 50 rpm. Then a 50 μL metering valve was installed on the pressure container using a crimping machine, and HFA 134a was filled into the aluminum pressure container using a propellant filling machine. The resulting mixture was stirred in a 25°C air-bath shaker at a rate of 50 rpm.

[0088] Comparative systems A to D were prepared by the above procedure. In comparative system A, the mass ratio of glucose to HFA 134a was 0.05:99.95; in comparative system B, the mass ratio of glucose to HFA 134a was 0.1:99.9; in comparative system C, the mass ratio of glucose to HFA 134a was 0.15:99.85; and in comparative system D, the mass ratio of glucose to HFA 134a was 0.2:99.8. The total mass of glucose and HFA 134a in each system was 10 g.

[0089] Comparative systems A to D prepared in this comparative example were evaluated for total actuations, dose delivered per actuation, and storage leakage rate, using the same test method as in Example 1.

[0090] The results showed that, although the storage leakage rates of comparative systems A to D were almost zero, the total actuation variations were very large; the dose delivered per actuation was about 31 to 50 mg, with a very large fluctuation range, indicating that the reproducibility was very poor, and the mass uniformity of the glucose-HFA 134a propellant was very poor, which could not be used for the preparation of inhalation aerosols.

[0091] Table 2. Evaluation results of total actuations, dose delivered per actuation, and storage leakage rate of comparative systems A to D

[0092] Group Total actuations Delivery dose per actuation (mg) Storage leakage rate (%) Comparative system A 148±25 50.3±9.2 0.03±0.01 Comparative system B 152±37 31.5±10.4 0.03±0.00 Comparative system C 151±32 47.1±11.5 0.03±0.01 Comparative system D 150±26 50.7±9.7 0.05±0.02

[0093] The mass uniformity of the propellant prepared in this comparative example was very poor. The reason was that, compared with the composite propellant in Example 1, the prescription composition of this comparative example lacked ethanol. Ethanol has a potential solubilization effect with HFA 134a, which can improve the solubility of glucose in the system by adjusting the polarity, and avoid the precipitation of glucose during the administration or storage process. If there is no ethanol in the system, glucose may precipitate during the administration or storage process, affecting the mass uniformity. Therefore, the performance of the composite propellant in Example 1 in terms of total actuations and dose delivered per actuation was significantly better than that of Comparative Example 1.

[0094] Comparative Example 2: Preparation of glucose-n-pentanol-HFA 134a composite propellant

[0095] Add glucose and n-pentanol sequentially to a 10mL aluminum pressure-resistant container, and stir at 50rpm in a 25℃ air bath mixing chamber. Then, install a 50μL metering valve on the pressure-resistant container using a sealing machine, fill the aluminum pressure-resistant container with HFA134a using a propellant filling machine, and stir again at 50rpm in a 25℃ air bath mixing chamber to obtain the final product.

[0096] Comparative systems E to H were prepared using the steps described above. In comparative system E, the mass ratio of glucose to n-pentanol to HFA134a was 0.05:5:94.95; in comparative system F, the mass ratio was 0.1:5:94.9; in comparative system G, the mass ratio was 0.1:10:89.9; and in comparative system H, the mass ratio was 0.2:10:89.8. The total mass of glucose, n-pentanol, and HFA134a in each system was 10 g.

[0097] The comparative systems E to H prepared in this comparative example were evaluated for total number of presses, delivery dose per press, and storage leakage rate, using the same testing methods as in Example 1.

[0098] The results showed that although the storage leakage rate of the control systems E to H was almost zero, the total number of presses varied greatly; the delivery dose per press was around 41 to 52 mg, with a large fluctuation range, indicating poor reproducibility. The glucose-n-pentanol-HFA134a composite propellant had poor quality uniformity and could not be used for the preparation of inhaled aerosols.

[0099] Table 3. Evaluation results of total number of puffs, delivery dose per puff, and storage leakage rate for comparison systems E to H.

[0100] Group Total actuations Delivery dose per actuation (mg) Storage leakage rate (%) Comparative system E 153±15 41.4±10.0 0.05±0.02 Comparative system F 150±17 45.8±7.9 0.04±0.01 Comparative system G 152±13 49.1±10.4 0.02±0.00 Comparative system H 155±14 52.3±8.6 0.04±0.02

[0101] The composite propellant prepared in this comparative example exhibited poor quality uniformity. This is because, unlike the composite propellant in Example 1 which used ethanol as a short-chain alcohol, this comparative example used n-pentanol. This demonstrates that the specific type of short-chain alcohol has a significant impact on the quality of the prepared composite propellant. Only by combining short-chain alcohols within the scope of this invention with monosaccharides can a composite propellant with better quality uniformity be prepared. As the carbon skeleton lengthens, the physicochemical properties of short-chain alcohols, such as polarity, change. When n-pentanol is introduced into the composite propellant system, its compatibility with monosaccharides and propellants may be lower compared to ethanol. Therefore, the composite propellant in Example 1 performs better than Comparative Example 2 in terms of total clicks and dose delivered per click.

[0102] Example 2: Preparation of mannose-tert-butanol-HFA227 composite propellant

[0103] Into a 10 mL aluminum pressure container, mannitol and t-butanol were added in sequence, and the container was placed in a 30°C air-bath stirring box and stirred at a speed of 100 rpm. Then, a 50 μL metering valve was installed on the pressure container using a sealing machine, and HFA 227 was filled into the aluminum pressure container using a propellant filling machine, and the container was stirred at a speed of 100 rpm in a 30°C air-bath stirring box to obtain the propellant.

[0104] Systems 5-8 were prepared by the above procedure. In system 5, the mass ratio of mannitol-t-butanol-HFA 227 was 0.01:1:98.99; in system 6, the mass ratio of mannitol-t-butanol-HFA 227 was 0.02:1:98.98; in system 7, the mass ratio of mannitol-t-butanol-HFA 227 was 0.02:2:97.98; and in system 8, the mass ratio of mannitol-t-butanol-HFA 227 was 0.04:2:97.96. The total mass of mannitol, t-butanol and HFA 227 in each system was 8 g.

[0105] Systems 5-8 prepared in this example were evaluated for total actuations, dose delivered per actuation and storage leakage rate, using the same test method as in Example 1.

[0106] The results showed that the total actuations of systems 5-8 were all more than 150, indicating that the systems were suitable for long-term use (more than 3 months) of once-daily administration; the dose delivered per actuation was about 52 mg, which was good in reproducibility and reflected good mass uniformity; and the storage leakage rate was almost zero, proving high stability. The mannitol-t-butanol-HFA 227 composite propellant can be used for the preparation of inhalation aerosols.

[0107] Table 4. Evaluation results of total actuations, dose delivered per actuation and storage leakage rate of systems 5-8

[0108] Group Total actuations Delivery dose per actuation (mg) Storage leakage rate (%) System 5 150±0 52.3±0.2 0.04±0.02 System 6 154±1 51.5±0.4 0.03±0.00 System 7 152±1 52.1±0.7 0.05±0.01 System 8 152±2 51.7±1.4 0.04±0.01

[0109] Example 3: Preparation of fructose-ethanol / isopropanol-HFA 134a composite propellant

[0110] Into a 10 mL aluminum pressure container, fructose, ethanol and isopropanol were added in sequence, and the container was placed in a 20°C air-bath stirring box and stirred at a speed of 25 rpm. Then, a 50 μL metering valve was installed on the pressure container using a sealing machine, and HFA 134a was filled into the aluminum pressure container using a propellant filling machine, and the container was stirred at a speed of 25 rpm in a 20°C air-bath stirring box to obtain the propellant.

[0111] Systems 9-14 were prepared by the above steps. In system 9, the mass ratio of ethanol-isopropanol was 3:2, and the mass ratio of fructose-ethanol / isopropanol-HFA 134a was 0.01:2:97.99; in system 10, the mass ratio of ethanol-isopropanol was 1:1, and the mass ratio of fructose-ethanol / isopropanol-HFA 134a was 0.01:2:97.99; in system 11, the mass ratio of ethanol-isopropanol was 1:2, and the mass ratio of fructose-ethanol / isopropanol-HFA 134a was 0.01:2:97.99; in system 12, the mass ratio of ethanol-isopropanol was 3:2, and the mass ratio of fructose-ethanol / isopropanol-HFA 134a was 0.02:2:97.98; in system 13, the mass ratio of ethanol-isopropanol was 1:1, and the mass ratio of fructose-ethanol / isopropanol-HFA 134a was 0.02:2:97.98; in system 14, the mass ratio of ethanol-isopropanol was 1:2, and the mass ratio of fructose-ethanol / isopropanol-HFA 134a was 0.02:2:97.98. The total mass of mannose, ethanol / isopropanol and HFA 134a in each system was 6 g.

[0112] Systems 9-14 prepared in this example were evaluated for total actuations, dose delivered per actuation and storage leakage rate, and the test method was the same as in Example 1.

[0113] The results showed that the total actuations of systems 9-14 were all over 120, indicating that the systems were suitable for long-term use (more than 3 months) of once-a-day administration; the dose delivered per actuation was about 49 mg, showing good reproducibility and embodying the quality uniformity; the storage leakage rate was almost 0, proving high stability. The fructose-ethanol / isopropanol-HFA 134a composite propellant can be used for the preparation of inhalation aerosols.

[0114] Table 5 Evaluation results of total actuations, dose delivered per actuation and storage leakage rate of systems 9-14

[0115] Group Total actuations Delivery dose per actuation (mg) Storage leakage rate (%) System 9 123±1 49.0±0.7 0.03±0.01 System 10 122±0 48.5±0.4 0.02±0.00 System 11 121±1 48.7±0.6 0.05±0.02 System 12 124±2 48.5±2.4 0.05±0.01 System 13 123±1 48.9±1.7 0.04±0.01 System 14 123±2 49.2±1.1 0.03±0.01

[0116] Example 4: Preparation of galactose / glucose-ethanol-HFA 134a composite propellant

[0117] Galactose, glucose and ethanol were sequentially added to an aluminum pressure-resistant container of 10 mL size, which was placed in a 25°C air-bath stirring box and stirred at a rate of 75 rpm. Then a 50 μL metering valve was installed on the pressure-resistant container using a sealing machine, and HFA 134a was filled into the aluminum pressure-resistant container using a propellant filling machine. The resulting mixture was stirred in a 25°C air-bath stirring box at a rate of 75 rpm.

[0118] System 15-20 were prepared by the above steps. In system 15, the mass ratio of galactose-glucose was 1:1, and the mass ratio of galactose / glucose-ethanol-HFA 134a was 0.03:4:95.97; in system 16, the mass ratio of galactose-glucose was 1:2, and the mass ratio of galactose / glucose-ethanol-HFA 134a was 0.03:4:95.97; in system 17, the mass ratio of galactose-glucose was 1:3, and the mass ratio of galactose / glucose-ethanol-HFA 134a was 0.03:4:95.97; in system 18, the mass ratio of galactose-glucose was 1:1, and the mass ratio of galactose / glucose-ethanol-HFA 134a was 0.06:8:91.94; in system 19, the mass ratio of galactose-glucose was 1:2, and the mass ratio of galactose / glucose-ethanol-HFA 134a was 0.06:8:91.94; in system 20, the mass ratio of galactose-glucose was 1:3, and the mass ratio of galactose / glucose-ethanol-HFA 134a was 0.06:8:91.94. The total mass of galactose / glucose, ethanol and HFA 134a in each system was 5 g.

[0119] The systems 15-20 prepared in this example were evaluated for total actuations, dose delivered per actuation and storage leakage rate, and the test method was the same as in Example 1.

[0120] The results showed that the total actuations of systems 15-20 were all more than 110, indicating that the systems were suitable for long-term use (more than 3 months) of once-a-day administration; the dose delivered per actuation was about 45 mg, showing good reproducibility and reflecting good quality uniformity; the storage leakage rate was almost zero, proving high stability. The galactose / glucose-ethanol-HFA 134a composite propellant can be used for the preparation of inhalation aerosols.

[0121] Table 6 Evaluation results of total actuations, dose delivered per actuation and storage leakage rate of systems 15-20

[0122] Group Total actuations Delivery dose per actuation (mg) Storage leakage rate (%) System 15 111±0 45.8±0.9 0.05±0.02 System 16 115±3 45.5±0.3 0.04±0.01 System 17 112±2 46.1±0.5 0.04±0.02 System 18 113±1 45.2±1.2 0.03±0.01 System 19 111±0 45.1±2.9 0.03±0.02 System 20 114±4 46.3±2.4 0.04±0.00

[0123] Example 5: Investigation of refrigeration effect of composite propellant

[0124] Systems 1-20 in Examples 1-4 were used to investigate the refrigeration effect. A plastic pipe (3 cm in diameter) with a length of 5 cm, 10 cm or 15 cm was added outside the quantitative valve, and an electronic thermometer was placed at the center of the end of the plastic pipe. The valve was pressed once every 1 s, and the temperature at the initial and 1st-10th actuation at different measuring distances was recorded. The temperature-actuation curve was plotted, and the average temperature drop at the 1st, 5th and 10th actuation was calculated, denoted as ΔT1, ΔT5 and ΔT10, respectively, reflecting the refrigeration effect. 10

[0125] The investigation results are shown in Table 7. Figure 3-6 ​As shown in Table 7, systems 1-20 showed similar trends. The temperature measured at each temperature measuring distance decreased to different degrees after each time the valve was pressed. It was preliminarily determined that the temperature decrease at the 5-15 cm temperature measuring distance decreased in turn. The refrigeration effect was quantitatively analyzed in combination with the average temperature decrease values in Table 7. The average temperature decrease of each system at the 5, 10, 15 cm temperature measuring distance was in the range of 1.7-11.1, 0.8-7.6, 0.4-6.0 °C, respectively, ΔT1, ΔT5, ΔT 10 were in the range of 0.4-3.2, 1.8-7.6, 4.0-11.1 °C, respectively. Therefore, the complex propellant administered by one press, five presses and ten presses can induce a temperature decrease of at most 3.2, 7.6 and 11.1 °C, respectively.

[0126] Table 7 ΔT1, ΔT5, ΔT 10 (Units: °C)

[0127]

[0128] Comparative Example 3: Refrigeration effect of single propellant

[0129] A 50 μL quantitative valve was installed on a 10 mL aluminum pressure-resistant container using a sealing machine, and the aluminum pressure-resistant container was filled with HFA 134a or HFA 227 in the filling machine to obtain the same.

[0130] Comparative systems 1-4 were prepared by the above steps. Comparative system 1 was 10 g of HFA 134a; comparative system 2 was 8 g of HFA 227; comparative system 3 was 6 g of HFA 134a; and comparative system 4 was 5 g of HFA 134a.

[0131] The refrigeration effect of comparative systems 1-4 was investigated, and the method was the same as in Example 5.

[0132] The results are shown in Table 8. Figure 7 As shown in Table 8, comparative systems 1-4 showed similar trends. The temperature measured at each temperature measuring distance decreased to different degrees after each time the valve was pressed. It was preliminarily determined that the temperature decrease at the 5-15 cm temperature measuring distance decreased in turn. The refrigeration effect was quantitatively analyzed in combination with the average temperature decrease values in Table 8. The average temperature decrease of each comparative system at the 5, 10, 15 cm temperature measuring distance was in the range of 10.5-21.7, 5.4-19.5, 1.1-14.7 °C, respectively, ΔT1, ΔT5, ΔT 10 were in the range of 1.1-10.7, 7.7-14.6, 14.1-21.7 °C, respectively. Therefore, the single propellant administered by one press, five presses and ten presses can induce a temperature decrease of at most 10.7, 14.6 and 21.7 °C, respectively.

[0133] Table 8: ΔT1, ΔT5, ΔT10 of comparative systems 1-4 at 5, 10, 15 cm temperature measuring distance 10 (unit: °C)

[0134]

[0135] Comparing the data of Example 5 with those of Comparative Example 1, we have: ΔT1: the lowest value, the composite propellant is 36.36% of the single propellant; the highest value, the composite propellant is 29.91% of the single propellant. ΔT5: the lowest value, the composite propellant is 23.38% of the single propellant; the highest value, the composite propellant is 52.05% of the single propellant. ΔT10: the lowest value, the composite propellant is 28.37% of the single propellant; the highest value, the composite propellant is 51.15% of the single propellant. It can be seen that the average cooling effect of the composite propellant in Example 5 is significantly lower than that of the single propellant in Comparative Example 1. In terms of the average cooling effect, the cooling effect of the composite propellant is reduced to 29.91-36.36%, 23.38-52.05% and 28.37-51.15% of the single propellant in single-dose administration, five-dose administration and ten-dose administration, respectively. Therefore, the composite propellant system can effectively reduce the cooling effect, especially in single-dose administration.

[0136] Comparative Example 4: Cooling effect of ethanol-HFA134a propellant

[0137] Ethanol was added to a 10 mL aluminum pressure-resistant container, which was placed in a 25°C air bath stirring box and stirred at a rate of 75 rpm. Then a 50 μL quantitative valve was installed on the pressure-resistant container using a sealing machine, and HFA134a was filled into the aluminum pressure-resistant container using a propellant filling machine. The resulting mixture was stirred at a rate of 75 rpm in a 25°C air bath stirring box.

[0138] Comparative systems I and J were prepared by the above steps. In comparative system I, the mass ratio of ethanol to HFA134a was 5:94.95; in comparative system J, the mass ratio of ethanol to HFA134a was 10:89.8. The total mass of ethanol and HFA134a in each system was 10 g.

[0139] Comparative systems I and J were taken for cooling effect investigation, and the method was the same as that in Example 5.

[0140] The results of the investigation are shown in Table 8: Figure 8The comparative systems I and J showed similar trends. The temperature measured at each measuring distance decreased to different degrees with each press of the valve. It was preliminarily determined that the temperature drop at the measuring distances of 5-15 cm decreased in turn. The refrigeration effect was quantitatively analyzed in combination with the average temperature drop values in Table 9. The average temperature drop of each comparative system at the measuring distances of 5, 10, and 15 cm was in the ranges of 8.4-16.9, 3.9-13.5, and 0.8-9.8°C, respectively, ΔT1, ΔT5, and ΔT 10 were in the ranges of 0.8-8.6, 5.1-10.7, and 9.7-16.9°C, respectively. Therefore, the ethanol-HFA 134a propellant can induce a temperature drop of up to 8.6, 10.7, and 16.9°C with single press, five presses, and ten presses, respectively.

[0141] Table 9 ΔT1, ΔT5, and ΔT 10 (Units: °C)

[0142]

[0143] Comparing Example 5 with the data of Comparative Example 4, ΔT1: the lowest value was 50.00% of the ethanol-HFA 134a propellant, and the highest value was 37.21% of the ethanol-HFA 134a propellant. ΔT5: the lowest value was 35.29% of the ethanol-HFA 134a propellant, and the highest value was 71.03% of the ethanol-HFA 134a propellant. ΔT 10 : the lowest value was 41.24% of the ethanol-HFA 134a propellant, and the highest value was 65.68% of the ethanol-HFA 134a propellant. It can be seen that the average temperature drop of the composite propellant in Example 5 was significantly lower than that of the ethanol-HFA 134a propellant in Comparative Example 3. In terms of the average temperature drop representing the refrigeration effect, the refrigeration effect of the composite propellant was reduced to 32.29-50.00, 35.29-71.03, and 41.24-65.68% of that of the ethanol-HFA 134a propellant with single press, five presses, and ten presses, respectively. Therefore, the composite propellant system was superior to the ethanol-HFA 134a propellant system in terms of reducing the refrigeration effect.

[0144] Refrigeration effect of the ribose-tert-butyl alcohol-HFA 227 composite propellant

[0145] Add ribose and tert-butanol sequentially to a 10mL aluminum pressure-resistant container, and stir at 100rpm in a 30℃ air bath stirring box. Then, install a 50μL metering valve on the pressure-resistant container using a sealing machine, fill the aluminum pressure-resistant container with HFA227 using a propellant filling machine, and stir again at 100rpm in a 30℃ air bath stirring box to obtain the final product.

[0146] Comparative systems K to N were prepared using the steps described above. In comparative system K, the mass ratio of ribose-tert-butanol-HFA227 was 0.01:1:98.99; in comparative system L, the mass ratio was 0.02:1:98.98; in comparative system M, the mass ratio was 0.02:2:97.98; and in comparative system N, the mass ratio was 0.04:2:97.96. The total mass of ribose, tert-butanol, and HFA227 in each system was 8 g.

[0147] The refrigeration effect was investigated using the control systems K to N, following the same method as described in Example 5.

[0148] The results of the investigation are as follows Figure 9 As shown, the comparison systems K to N exhibit similar trends. With each valve press, the temperature measured at each measuring distance decreased to varying degrees. Preliminary judgment indicates that the temperature drop decreases progressively from 5 to 15 cm. The refrigeration effect is quantitatively analyzed using the average temperature drop values ​​in Table 10. The average temperature drops for each comparison system at measuring distances of 5, 10, and 15 cm fall within the ranges of 4.4–14.2, 1.4–9.2, and 0.6–6.6 °C, respectively, with ΔT1, ΔT5, and ΔT... 10 The temperature ranges are 0.6–4.7, 3.1–8.5, and 6.2–14.2 °C, respectively. Therefore, single-click, five-click, and ten-click administration of the ribose-tert-butanol-HFA227 composite propellant can induce a temperature drop of up to 4.7, 8.5, and 14.2 °C, respectively.

[0149] Table 10 Comparison of ΔT1, ΔT5, and ΔT values ​​for systems G-J at measurement distances of 5, 10, and 15 cm. 10 (Unit: °C)

[0150]

[0151] The data of Example 5 and Comparative Example 5 are compared as follows: ΔT1: the lowest value, the composite propellant system 1-20 is 66.67% of ribose-t-butyl alcohol-HFA 227 composite propellant; the highest value, the composite propellant system 1-20 is 68.09% of ribose-t-butyl alcohol-HFA 227 composite propellant. ΔT5: the lowest value, the composite propellant system 1-20 is 58.06% of ribose-t-butyl alcohol-HFA 227 composite propellant; the highest value, the composite propellant system 1-20 is 89.41% of ribose-t-butyl alcohol-HFA 227 composite propellant. ΔT 10 : the lowest value, the composite propellant system 1-20 is 64.52% of ribose-t-butyl alcohol-HFA 227 composite propellant; the highest value, the composite propellant system 1-20 is 78.17% of ribose-t-butyl alcohol-HFA 227 composite propellant. It can be seen that the average cooling capacity of the composite propellant system 1-20 in Example 5 is significantly lower than that of the ribose-t-butyl alcohol-HFA 227 composite propellant in Comparative Example 5. In terms of the average cooling capacity, the refrigeration effect of the composite propellant system 1-20 is reduced to 66.67-68.09%, 58.06-89.41% and 64.52-78.17% of that of the ribose-t-butyl alcohol-HFA 227 composite propellant in single-dose administration, five-dose administration and ten-dose administration, respectively. Therefore, the composite propellant system 1-20 has a better refrigeration effect than the ribose-t-butyl alcohol-HFA 227 composite propellant system. The monosaccharides (glucose, galactose, fructose and mannose) selected in the composite propellant system 1-20 are hexoses (skeleton of 6 carbon atoms), while the monosaccharide (ribose) selected in the present comparative example is a pentose (skeleton of 5 carbon atoms). There are differences in the micro-interaction forces between hexoses and propellant molecules, resulting in stronger competition of hexoses for the fluorine-hydrogen bond binding sites of propellant molecules, and ultimately leading to a lower refrigeration effect of the composite propellant system 1-20.

[0152] Example 6: Biological safety study of composite propellant

[0153] The systems 1, 5, 9 and 15 in Examples 1-4 were used for biological safety study, which specifically included the number of irritating cough and body weight monitoring. The animal models used were C57BL / 6J mice and pulmonary fibrosis model C57BL / 6J mice, male (♂), weighing about 18 g, and the experimental animals had a 7-day adaptation period before the formal experiment. The mice were caught and fixed in a supine position after intraperitoneal injection of 1% (w / v) sodium pentobarbital (dose 80 mg / kg) anesthesia. The mouth of the mouse was exposed, and the exhaust port of the dosing valve of the aerosol bottle was carefully inserted, and the valve was pressed to administer.

[0154] Stimulating cough counting method: C57BL / 6J mice and pulmonary fibrosis model C57BL / 6J mice were each divided into three groups, and each group was given 1-3 times of pressurized valve administration (pressing once every 1 s). Immediately after administration, the mice were observed and recorded for the number of coughs within 10 min.

[0155] Body weight monitoring method: During the 14-day experimental period, C57BL / 6J mice and pulmonary fibrosis model C57BL / 6J mice were each given administration once at 9 o'clock on days 2, 4, and 6, and the mice were weighed at 21 o'clock every other day (i.e., on days 0, 2, 4, 6, 8, 10, and 12).

[0156] The results of the study are shown in Table 6. Figure 10

[0157] Without administration, neither C57BL / 6J mice nor pulmonary fibrosis model C57BL / 6J mice exhibited coughing. Administration of each system once did not induce coughing. After administration of system 5 three times, C57BL / 6J mice produced an average of 0.2 coughs within a 10-min observation period. After administration of system 9 twice, pulmonary fibrosis model C57BL / 6J mice produced an average of 0.2 coughs within a 10-min observation period; after administration of systems 5, 9, and 15 three times, pulmonary fibrosis model C57BL / 6J mice produced an average of 0.2-0.4 coughs within a 10-min observation period. Thus, the composite propellants had weak inducibility of stimulating cough in healthy mice and pulmonary fibrosis mice, and although the number of stimulating coughs in pulmonary fibrosis mice was slightly higher than that in healthy mice, it was still at a very low level (<0.4 times / 10 min). Therefore, the composite propellants had weak stimulation of the respiratory tract in a disease state.

[0158] During the 14-day experimental period, the body weights of C57BL / 6J mice and pulmonary fibrosis model C57BL / 6J mice steadily increased, and the average weight gain of C57BL / 6J mice (about 2 g) was slightly higher than that of pulmonary fibrosis model C57BL / 6J mice (about 1 g). Based on this, it can be concluded that the composite propellants had low overall toxicity to the model animals and did not affect their weight gain.

[0159] Comparative Example 6: Biological safety study of single propellants

[0160] The comparative systems 1-4 in Comparative Example 3 were subjected to a biological safety study, and the method was the same as in Example 6.

[0161] The results of the study are shown in Table 6. Figure 11

[0162] ​​C57BL / 6J mice and C57BL / 6J mice with pulmonary fibrosis did not cough when no drug was administered. After 2 administrations of Comparative System 2, C57BL / 6J mice coughed an average of 0.2 times during a 10 min observation period; after 3 administrations of Comparative Systems 2, 3, and 4, C57BL / 6J mice coughed an average of 0.2-0.4 times during a 10 min observation period. After 1 administration of Comparative Systems 1, 2, 3, and 4, C57BL / 6J mice with pulmonary fibrosis coughed an average of 0.8 times during a 10 min observation period; after 2 administrations, C57BL / 6J mice with pulmonary fibrosis coughed an average of 1.4-2.4 times during a 10 min observation period; after 3 administrations, C57BL / 6J mice with pulmonary fibrosis coughed an average of 3.4-5.0 times during a 10 min observation period. The single propellants were weakly inductive of irritating cough in healthy mice, but were strongly inductive of irritating cough in mice with pulmonary fibrosis, inducing cough up to 5 times in 10 min. Thus, the single propellants had some irritating effect on the respiratory tract in the disease state.

[0163] During the 14 day experimental period, the body weight of C57BL / 6J mice and C57BL / 6J mice with pulmonary fibrosis increased steadily, and the average weight gain of C57BL / 6J mice (about 2 g) was slightly higher than that of C57BL / 6J mice with pulmonary fibrosis (about 1 g). It can be concluded that the single propellants had low overall toxicity to the model animals and did not affect their weight gain.

[0164] Comparing the results in Comparative Example 6 with those in Comparative Example 6, it can be seen that the composite propellant and the single propellant had weak irritating effects on the respiratory tract of healthy model animals, and neither the composite propellant nor the single propellant affected the weight gain of the model animals; however, the composite propellant had a significantly lower irritating effect on the respiratory tract of model animals in the pulmonary fibrosis disease state than the single propellant, which is conducive to avoiding unpredictable toxic side effects and improving patient compliance, and thus the composite propellant with low refrigeration effect is more suitable than commercially available single propellants for the preparation of inhalation aerosols for the treatment of respiratory diseases.

[0165] Example 7: Preparation of an inhalation aerosol based on a composite propellant

[0166] Referring to the prescription composition and process parameters of Systems 1, 5, 9, and 15 in Examples 1-4, phenethyl isothiocyanate (PEITC) was selected as a model drug, and an inhalation aerosol was prepared. A monosaccharide, PEITC (300 mg), and a short-chain alcohol were sequentially added to a 10 mL aluminum pressure-resistant container, which was placed in a stirring oven. Then, a 50 μL metering valve was installed on the pressure-resistant container using a valve sealer, HFA 134a or HFA 227 was filled into a propellant filling machine, and the mixture was stirred in a stirring oven to obtain the inhalation aerosol. The prepared inhalation aerosols were designated as Formulations 1-4.

[0167] The prepared formulations 1-4 were evaluated for total actuations, total drug amount, delivered dose per actuation, drug amount per actuation and storage leakage rate, wherein the total actuations, delivered dose per actuation and storage leakage rate were tested according to the method of Example 1. The total drug amount was tested as follows: the test sample was taken, the valve was pressed, and the content was released into a certain volume of acetone (receiving liquid), with an interval of no less than 5 s between each time of pressing, and the concentration of PEITC in the receiving liquid was determined by high performance liquid chromatography (HPLC) to convert into the total drug amount. The drug amount per actuation was tested as follows: the test sample was taken, shaken and 5 actuations were discarded. The valve was pressed, and 3 actuations were continuously sprayed into acetone; a number of actuations were discarded until n / 2 actuations, and then 4 actuations were continuously sprayed; a number of actuations were continuously discarded, and the last 3 actuations were sprayed. The concentration of PEITC in the receiving liquid was determined by HPLC to calculate the average drug amount of 10 actuations.

[0168] The results showed that the total actuations of formulations 1-4 were more than 180, 150, 120 and 110 respectively, which could be used for long-term application (more than 3 months) if administered once a day; the total drug amount was about 285 mg (i.e. the encapsulation rate reached 95%), the delivered dose per actuation was about 54, 52, 49 and 45 mg respectively, the drug amount per actuation was in the range of 1.51-2.48 mg, which had good reproducibility and reflected the quality uniformity; the storage leakage rate was almost 0, which proved the high stability. The values of total actuations, delivered dose per actuation and storage leakage rate of the formulations were close to those of the complex propellants without drug (i.e. the original systems 1, 5, 9, 15). These results proved that the inhalation aerosol prepared based on the complex propellants had good quality uniformity and stability, and was predicted to have good disease treatment effect and application conversion potential.

[0169] Table 11 Evaluation results of total actuations, total drug amount, delivered dose per actuation, drug amount per actuation and storage leakage rate of formulations 1-4

[0170]

[0171] The technical features of the above-described embodiments can be combined in any manner. For the sake of brevity, not all possible combinations of the technical features in the above-described embodiments are described, however, as long as the combinations of the technical features do not contradict each other, they should be considered within the scope of the present disclosure.

[0172] The above-described embodiments only express several implementation manners of the present disclosure, and the description is relatively specific and detailed, but it should not be understood as a limitation on the scope of the patent. It should be pointed out that, for ordinary skilled persons in the art, some modifications and improvements can be made without departing from the concept of the present disclosure, and these all belong to the protection scope of the present disclosure. Therefore, the protection scope of the patent of the present disclosure should be subject to the appended claims.

Claims

1. A composite propellant, characterized in that, It is prepared from the following raw materials in the following mass ratio: HFA134a 89.8~94.95 Glucose 0.05~0.2 Ethanol 5~10.

2. The composite propellant according to claim 1, characterized in that, The total mass of the composite propellant is 5-10g.

3. A method for preparing the composite propellant according to any one of claims 1-2, characterized in that, Includes the following steps: (1) Add the glucose and the ethanol to the pressure-resistant container in sequence, and stir in a gas bath stirring box; (2) Install a metering valve on the pressure vessel, fill the pressure vessel with the HFA134a using a propellant filling machine, and stir it in a gas bath mixing tank to obtain the product.

4. The method for preparing the composite propellant according to claim 3, characterized in that, The temperature of the air bath mixing chamber mentioned in step (1) is 20℃~30℃, and the mixing speed is 25 rpm~100 rpm; and / or, The temperature of the air bath mixing chamber in step (2) is 20℃~30℃, and the mixing speed is 25 rpm~100 rpm; and / or, The pressure-resistant container is an aluminum pressure-resistant container with a capacity of 10 mL; and / or, The metering valve mentioned in step (2) is a 50 μL metering valve.

5. The use of the composite propellant according to any one of claims 1-2 in the preparation of an inhalation aerosol with low cooling effect.

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