A nebulizer cup and its application in nebulizer inhalation drug administration

Abstract

The present invention discloses an atomizing cup and its application in atomizing inhalation drug administration, in particular, its application in atomizing inhalation drug administration of drugs for the prevention and / or treatment of respiratory diseases (e.g., SARS-CoV-2 vaccines). After adding an antistatic agent, the atomizing cup can effectively maintain the stability of the drug aerosol for a certain period of time, the particle size state is relatively stable, the drug residue in the cup is small, the effective inhalable amount is guaranteed, the drug administration operation is simple and convenient, the vaccination efficiency can be significantly improved, and it can be used for large-scale vaccination.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and specifically to a nebulizer cup and its application in nebulized inhalation drug administration, in particular to its application in nebulized inhalation drug administration of preventive and / or therapeutic drugs for respiratory diseases (such as SARS-CoV-2 vaccines). Background Art

[0002] At present, one treatment method for respiratory diseases is aerosol inhalation, which uses a nebulizer to disperse the drug solution into fine droplets, which are inhaled through the patient's nose or mouth. The aerosolized drug directly acts on the target organ, which can increase the local concentration of the drug and achieve a therapeutic effect. Aerosol inhalation has a very good therapeutic effect on bronchiolitis, asthmatic bronchitis, bronchial asthma, acute and chronic bronchitis, acute laryngitis, acute pneumonia, etc.

[0003] Nebulized inhalation vaccines are vaccines that are administered through nebulized inhalation. The so-called nebulized inhalation immunization refers to the use of a nebulizer to atomize the vaccine into tiny particles. These tiny particles enter the respiratory tract and lungs through inhalation, stimulating mucosal immunity.

[0004] The equipment and devices that realize this kind of atomized inhalation treatment and immunization are very important for the implementation and quality of treatment and immunization, and have received great attention from researchers and researchers. The existing atomized drug delivery devices in the prior art mainly use the method of drug delivery by atomization and inhalation at the same time, which requires guidance to the subjects before drug delivery. Children and even many adults often greatly affect the inhalation and absorption of drug mist due to improper control of the frequency of inhalation drug delivery and their own breathing, which is very unfavorable for immunization. In addition, for immunization, in order to prevent cross infection, the part of the device for inhalation by the subject should be disinfected or discarded after use. In view of the necessity of large-scale vaccination, it is an urgent problem to provide an atomized drug delivery device that can prevent cross infection while reducing costs and has high inhalation vaccination efficiency.

[0005] In addition, when using an atomizer cup for atomization inhalation, the atomized medicine mist is easily liquefied on the cup wall to form droplets due to static electricity and cannot be inhaled normally by the human body. Therefore, it is necessary to add an antistatic agent to the atomizer cup to resist static electricity and prevent the liquefaction and residue of the medicine mist. The amount of the antistatic agent will also have a great impact on the medicine mist. When the antistatic agent content is low, the medicine mist will deposit more and the residual amount will be large; when the antistatic agent content is high, it will affect the forming and touch of the cup body and threaten the effective amount of the atomized medicine mist. Therefore, it is urgent to find a suitable antistatic agent and the optimal antistatic agent and content to ensure the effectiveness of the atomization of the medicine solution. Summary of the invention

[0006] In order to overcome the deficiencies of the prior art, the present invention provides a nebulizer cup and its application, wherein the nebulizer cup can be used to collect and carry the drug mist generated by the nebulizer for inhalation by a subject to achieve therapeutic or immune effects.

[0007] In a first aspect of the present invention, an atomizer cup is provided, comprising a cup body and a cup cover, wherein an antistatic agent is added to the cup body.

[0008] Specifically, an antistatic agent is also added to the cup cover.

[0009] Specifically, the antistatic agent can be one or a combination of two or more of anionic antistatic agents (such as alkyl sulfonates, alkyl phosphates, salts of copolymers of maleic anhydride and other monomers, polyacrylates, polystyrene sulfonates), zwitterionic antistatic agents (such as zwitterionic alkyl imidazolinium salts, alkyl amino acids), nonionic antistatic agents (such as fatty acid polyol esters (such as glycerol fatty acid esters, sorbitan fatty acid esters), polyethylene oxide additives (such as polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty ethers, polyoxyethylene alkylphenyl ethers, polyoxyethylene alkylamines, etc.), polymer antistatic agents (such as polyoxyethylene fatty ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyacrylic acid derivatives) and composite antistatic agents, in particular nonionic antistatic agents and / or polymer antistatic agents.

[0010] Furthermore, the nonionic antistatic agent is preferably one of fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether, and glycerol monofatty acid ester, or a combination of two or more thereof; the zwitterionic antistatic agent is preferably alkyl dicarboxymethyl ammonium ethyl lactone and / or dodecyl dimethyl betaine; and the polymer antistatic agent is preferably one of ethylene oxide propylene oxide adduct of ethylenediamine, poly 4-vinylpyridine type polysoap, octyl styrene, and styrene sulfonic acid copolymer polysoap, or a combination of two or more thereof.

[0011] Cationic quaternary ammonium salts have strong adhesion to polymer materials and good antistatic properties. They are also a type of antistatic agent that is widely used in plastics. However, they are irritating to the skin and are toxic. Therefore, they are not included in the selection scope of the present invention.

[0012] In some embodiments of the present invention, an antistatic agent is added to the cup body, wherein the content of the antistatic agent is above 0.03% (w / w), in particular above 0.05%, for example 0.03%-10% (such as 0.05%, 0.1%, 0.2%, 0.25%, 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%), in particular 0.05%-5%.

[0013] In some embodiments of the present invention, an antistatic agent is added to the cup cover, wherein the content of the antistatic agent is above 0.03% (w / w), in particular above 0.05%, for example 0.03%-10% (such as 0.05%, 0.1%, 0.2%, 0.25%, 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%), in particular 0.05%-5%.

[0014] In some embodiments of the present invention, antistatic agents are added to both the cup body and the cup cover.

[0015] Specifically, the antistatic agent can be added to the cup body and / or cup cover by adding the antistatic agent raw material component to the raw materials for its preparation, or by adding the antistatic masterbatch to the raw materials for its preparation, especially by adding the antistatic masterbatch to the raw materials for its preparation. The antistatic agent and antistatic masterbatch can be selected from suitable commercial products according to the plastic material of the cup body and / or cup cover.

[0016] Furthermore, a mist inlet and a suction nozzle are provided on the cup cover.

[0017] Specifically, the mist inlet can be opened at any suitable position of the cup cover, such as the edge, the center, especially the edge of the cup cover; a closure member can also be provided at the mist inlet to facilitate closing the mist inlet before the atomizer cup is used.

[0018] Specifically, the suction nozzle protrudes from the cup cover and is connected to the space inside the cup body. It can be in any shape suitable for the subject to inhale mist, such as tubular or conical. The suction port end of the suction nozzle can be in a circular, elliptical or other shape suitable for the subject to suck. The suction port of the suction nozzle can also be provided with a closure to facilitate closing the suction nozzle before the nebulizer cup is used.

[0019] Specifically, the cup cover can be made of plastic, especially medical grade plastic, such as polypropylene (PP), polyethylene (PE), polyvinyl chloride (PVC), polystyrene (PS), polycarbonate (PC), polylactic acid (PLA), etc., especially PP and PLA; specifically, the cup cover is transparent.

[0020] Specifically, the material of the cup body can be plastic, especially medical grade plastic, for example, polypropylene (PP), polyethylene (PE), polyvinyl chloride (PVC), polystyrene (PS), polycarbonate (PC), polylactic acid (PLA), etc., especially PP and PLA; specifically, the cup body is transparent.

[0021] Specifically, the cup body and the cup cover can be integrally formed, or can be detachably arranged, for example, connected by threads or snaps.

[0022] Specifically, the shape of the cup body can be any suitable shape, such as a cylindrical shape, a truncated cone shape that is wide at the top and narrow at the bottom and tapers, etc.

[0023] Specifically, a handle may be provided on the side wall of the cup body to facilitate taking the atomizer cup.

[0024] Specifically, the volume of the atomizer cup can be 300-800 ml (e.g., 300, 350, 400, 450, 500, 550, 600, 700, 800 ml), in particular 500 ml.

[0025] In a second aspect of the present invention, a method for preparing the atomizer cup according to the first aspect is provided, which comprises the step of adding an antistatic agent component or an antistatic masterbatch to the raw materials for preparing the cup body.

[0026] In some embodiments of the present invention, the method further comprises the step of adding an antistatic agent component or an antistatic masterbatch to the raw materials for preparing the cup cover.

[0027] Specifically, the method further comprises a molding step, such as molding by extrusion, injection molding, compression molding, blow molding, and the like.

[0028] In the third aspect of the present invention, there is provided use of the nebulizer cup described in the first aspect in preparing a device for nebulized inhalation drug delivery.

[0029] Specifically, the application is the use of the above-mentioned nebulizer cup in the preparation of a device for aerosol inhalation administration of drugs for the prevention and / or treatment of respiratory diseases.

[0030] Specifically, the device comprises the nebulizer cup described in the first aspect of the present invention, and a nebulizer; more specifically, the nebulizer can be an ultrasonic nebulizer, a compression nebulizer, a vibrating mesh nebulizer or other suitable nebulizers, especially a vibrating mesh nebulizer.

[0031] Specifically, the drug is a vaccine, such as pneumococcal vaccine, influenza vaccine, coronavirus vaccine, varicella vaccine, Newcastle virus vaccine, measles vaccine, tuberculosis vaccine, dust mite allergy vaccine, etc.

[0032] In some embodiments of the invention, the coronavirus vaccine is a SARS-CoV-2 vaccine.

[0033] Specifically, the SARS-CoV-2 vaccine can be a recombinant adenovirus vector vaccine, into which the S protein gene of SARS-CoV-2 is inserted; more specifically, the above-mentioned recombinant adenovirus may also contain other structural protein (such as M protein, E protein, N protein) genes (full-length or partial sequence) of SARS-CoV-2.

[0034] Specifically, the above-mentioned adenovirus can be a human adenovirus (such as AdHu2, AdHu5, etc.), an animal adenovirus vector such as a chimpanzee adenovirus vector (such as AdC6, AdC7, AdC36, AdC68, etc.); in some embodiments of the present invention, the above-mentioned adenovirus is AdHu5.

[0035] Specifically, the content of the recombinant adenovirus in the recombinant adenovirus vector vaccine is 1×10 9 ~5×10 11 VP / ml (specifically 2×10 9 , 4×10 9 , 6×10 9 , 8×10 9 , 1×10 10 , 2×10 10 , 4×10 10 , 6×10 10 , 8×10 10 , 1×10 11 , 2×10 11 , 3×10 11 , 4×10 11 , 5×10 11 VP / ml).

[0036] Specifically, the unit dose of the above-mentioned drug is 0.05-0.5 ml (e.g. 0.05, 0.1, 0.2, 0.3, 0.4, 0.5 ml), especially 0.05-0.2 ml, 0.1 ml.

[0037] In a fourth aspect of the present invention, a nebulization inhalation drug delivery device is provided, which comprises the nebulization cup described in the first aspect of the present invention and a nebulizer.

[0038] Specifically, the nebulizer can be an ultrasonic nebulizer, a compression nebulizer, a vibrating mesh nebulizer or other suitable nebulizers, especially a vibrating mesh nebulizer.

[0039] In a fifth aspect of the present invention, there is provided use of the nebulizer cup described in the first aspect in nebulized inhalation drug administration.

[0040] Specifically, the application is the use of the above-mentioned nebulizer cup in the nebulized inhalation administration of drugs for the prevention and / or treatment of respiratory diseases.

[0041] Specifically, in this application, the drug has the corresponding definition described in the third aspect of the present invention.

[0042] In a sixth aspect of the present invention, a method for drug administration by nebulization inhalation is provided, comprising the step of administering the drug to a subject through the nebulizer cup described in the first aspect.

[0043] Specifically, the method is an aerosol inhalation immunization method, wherein the drug is a vaccine, such as pneumococcal vaccine, influenza vaccine, coronavirus vaccine, varicella vaccine, Newcastle virus vaccine, measles vaccine, tuberculosis vaccine, dust mite allergy vaccine, etc.; in some embodiments of the present invention, the vaccine is a coronavirus vaccine, in particular a SARS-CoV-2 vaccine.

[0044] Specifically, the SARS-CoV-2 vaccine can be a recombinant adenovirus vector vaccine, into which the S protein gene of SARS-CoV-2 is inserted; more specifically, the above-mentioned recombinant adenovirus may also contain other structural protein (such as M protein, E protein, N protein) genes (full-length or partial sequence) of SARS-CoV-2.

[0045] Specifically, the above-mentioned adenovirus can be a human adenovirus (such as AdHu2, AdHu5, etc.), an animal adenovirus vector such as a chimpanzee adenovirus vector (such as AdC6, AdC7, AdC36, AdC68, etc.); in some embodiments of the present invention, the above-mentioned adenovirus is AdHu5.

[0046] Specifically, the content of the recombinant adenovirus in the recombinant adenovirus vector vaccine is 1×10 9 ~5×10 11 VP / ml (specifically 2×10 9 , 4×10 9 , 6×10 9 , 8×10 9 , 1×10 10 , 2×10 10 , 4×10 10 , 6×10 10 , 8×10 10 , 1×10 11 , 2×10 11 , 3×10 11 , 4×10 11 , 5×10 11 VP / ml).

[0047] Specifically, the unit dose of the above vaccine is 0.05-0.5 ml (e.g. 0.05, 0.1, 0.2, 0.3, 0.4, 0.5 ml), especially 0.05-0.2 ml, 0.1 ml.

[0048] Specifically, the method comprises the following steps:

[0049] (1) Atomizing the drug through a nebulizer;

[0050] (2) collecting the drug mist generated in step (1) through the atomization cup;

[0051] (3) The subject inhales the drug mist through the nozzle of the nebulizer cup.

[0052] Specifically, step (3) is performed within 30 seconds (s) (e.g., 20s, 15s, 10s, 5s) after completing the mist collection, and in particular, step (3) is performed within 10s after completing the mist collection.

[0053] Specifically, the atomizer in step (1) can be an ultrasonic atomizer, a compression atomizer, a vibrating mesh atomizer or other suitable atomizers, in particular a vibrating mesh atomizer.

[0054] like Figure 1-6 As shown, the atomization cup includes a cup body 1 and a cup cover 2, and the cup cover includes an atomization port 21, a flip baffle 22, a connection portion between the flip baffle and the cup cover 23, a suction nozzle 24, a plug 25, a positioning line 26, and a pull tab 27. The flip baffle 22 is opened by holding the pull tab 27, and the atomizer is connected to the cup through the atomization port 21. When the liquid medicine is atomized, the mist generated enters the cup through the atomization port 21, and the subject can inhale the mist through the suction nozzle 24 to achieve vaccination. After the vaccination is completed, the positioning line 26 is pulled off by holding the plug 2-5, and then the plug 25 is plugged into the suction nozzle 24 to seal the suction nozzle 24. In addition, the flip baffle 22 is pressed down to be level with the surface of the cup cover to seal the atomization port 21. Sealing the suction nozzle 24 and the atomization port 21 can ensure that the residual mist in the cup will not overflow into the air, protecting the environment from being contaminated by biological products.

[0055] Furthermore, a suction nozzle 24 is provided at the top of the cup cover 2 near the edge, and the suction nozzle 24 protrudes from the surface of the cup cover 2 .

[0056] Furthermore, the cup cover 2 also includes a plug 25, and a plug-in portion 251 is provided at the lower end of the plug 25. The outer edge contour of the plug-in portion 251 is the same as the inner wall contour of the suction nozzle 24, so that the plug 25 can be plugged into the suction nozzle 24 and the suction nozzle 24 can be sealed.

[0057] Furthermore, the plug 25 is provided with a positioning portion 252 extending toward the periphery perpendicular to the plugging portion 251 , and the contour dimension of the positioning portion 252 is greater than the contour dimension of the plugging portion 251 .

[0058] Furthermore, a hand-holding portion 253 is provided at the upper end of the plug 25 perpendicular to the positioning portion, so that the plug 25 can be manually inserted and removed.

[0059] Furthermore, the plug 25 is located at the edge of the cup cover 2 , and the plug 25 is fixed on the cup cover 2 via two positioning lines 26 .

[0060] Furthermore, a rectangular pull tab 27 perpendicular to the flip baffle 22 is provided near the edge of the flip baffle 22 .

[0061] Furthermore, the atomization port 21 and the suction nozzle 24 provided on the top of the cup cover 2 are both located near the edge and on both sides of the central axis, and the suction nozzle 24 on the top of the cup cover 2 is elliptical.

[0062] Specifically, the atomizer cup is disposable to avoid cross infection.

[0063] The atomizing cup provided by the present invention can be used for the atomization inhalation administration of drugs for the prevention and / or treatment of respiratory diseases. Atomization therapy mainly refers to aerosol inhalation therapy. The so-called aerosol refers to tiny solid or liquid particles suspended in the air. Therefore, atomization inhalation therapy is to use an atomizing device to disperse the drug into tiny droplets or particles, suspend it in the gas, and enter the respiratory tract and lungs. The deposition of fog particles will affect the properties of the fog particles. The physical mechanisms that cause the deposition of fog particles are: impact deposition, gravity deposition, dispersion deposition, electrostatic attraction deposition and interception deposition. In order to eliminate the influence of the deposition caused by electrostatic attraction on the fog particles, previous studies have found that adding food-grade antistatic agents such as edible vegetable oil raw materials to drug preparations will cause the volume of atomized particles to be greater than 20 microns and cannot be delivered. It is selected to be treated with an electrostatic elimination device (such as an ion wind rod, an ion wind gun, an ion fan, etc.) before the atomizing cup is used. The effect of eliminating static electricity is certain. Although the actual effect on the deposition of preparation fog particles is improved to a certain extent, the effect is relatively limited.

[0064] The present invention selects to add antistatic agent to the material of the atomizer cup, and the combination of transparent plastic material and antistatic agent can make the water droplets themselves maintain stability and achieve an ideal atomization effect. The reason may be: the antistatic principle is to form a conductive layer on the surface of the material, thereby reducing its surface resistivity and allowing the generated static charge to leak quickly. In addition to playing the antistatic role, adding antistatic agent directly to the transparent plastic material may improve the smoothness of the plastic material surface and reduce the interception and deposition caused by the friction between the mist particles and the plastic material surface. Since the addition of antistatic agent does not play a simple antistatic or smoothing role, the present invention selects the mist volume, the inhalable amount of mist, the residual rate of liquid medicine, and the aerodynamics of the aerosol after atomization as comprehensive indicators to study the specific amount of antistatic agent used in the atomizer cup, and finds that the amount of antistatic agent used in 0.03%-10% (mass percentage) can meet the use needs, and when the amount of antistatic agent used in 0.05-5% (mass percentage), the comprehensive index is better. Specifically, when no antistatic agent is added, the transparent plastic atomizer cup has poor mist-carrying capacity and a high rate of residual drug solution, making it almost unusable; when the dosage is 0.03%, the antistatic effect and the comprehensive performance of mist inhalation are reduced; but when the addition amount is increased to 6% or 10%, its antistatic property will increase according to the dose-effect relationship, but the comprehensive performance of mist inhalation has decreased. It can be seen that adding a specific amount of antistatic agent can effectively maintain the stability of drug mist within a certain period of time (for example, within 20 seconds). Its particle size is stable, and there is less drug residue in the cup, ensuring effective inhalable amount and deposition rate. The structural design of the atomizer cup further improves the inhalation performance, especially when applied to the vaccine field, the drug administration operation is simple and convenient, which can significantly improve the vaccination efficiency and can be used for large-scale vaccination. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 The figure shows a schematic structural diagram of the atomizer cup of the present invention, wherein the atomizer cup comprises a cup body 1 and a cup cover 2.

[0066] Figure 2 It is a schematic diagram of the structure of the atomizer cup cover of the present invention, wherein the left figure is a top view and the right figure is a cross-sectional view, wherein an atomizer port 21, a flip baffle 22, a connection portion 23 between the flip baffle and the cup cover, a suction nozzle 24, a plug 25, a positioning line 26, and a pull tab 27 are shown.

[0067] Figure 3 Shown Figure 2 A schematic plan view of the middle plug, including an inserting portion 251, a positioning portion 252, and a hand-holding portion 253.

[0068] Figure 4 Shown Figure 2 A schematic top view of the middle plug, including a positioning portion 252 and a hand-holding portion 253.

[0069] Figure 5 Shown Figure 2 A bottom view of the middle plug, wherein the plugging portion is 251 and the positioning portion is 252.

[0070] Figure 6 Shown is a schematic diagram of the three-dimensional structure of the atomizer cup cover of the present invention.

[0071] Figure 7 The figure shows the test results of the inhalable amount of mist after the atomizer cups of different materials and different treatments carry the mist for 20 seconds. DETAILED DESCRIPTION

[0072] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0073] In the present invention, "subject" refers to a human being who receives the administration method (especially the aerosol inhalation immunization method) of the present invention.

[0074]

[00136] Various publications, patents, and published patent specifications are cited herein, the disclosures of which are incorporated by reference in their entireties.

[0075] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0076] Example 1 Effect of antistatic agent on mist carrying capacity of atomizer cup

[0077] 1. Experimental purpose:

[0078] The effect of adding different antistatic agents on the mist carrying capacity of the atomizer cup was studied.

[0079] 2. Experimental Design

[0080] Nebulized model drug: CanSino recombinant novel coronavirus vaccine (adenovirus type 5 vector) liquid formulation

[0081] Nebulization volume: 0.1ml.

[0082] Antistatic agent A is: fatty acid alcohol polyoxyethylene ester (anionic antistatic agent)

[0083] Antistatic agent B is: sodium secondary alkyl sulfonate (anionic antistatic agent)

[0084] Antistatic agent C is: polyethylene glycol ester (non-ionic antistatic agent)

[0085] Antistatic agent D is: fatty acid alkanolamide (non-ionic antistatic agent)

[0086] Antistatic agent E is: polyethylene oxide (polymer antistatic agent)

[0087] Antistatic agent F is: sodium polystyrene sulfonate (polymer antistatic agent)

[0088] Antistatic agent G is: alkyl dicarboxymethyl ammonium betaine (zwitterionic antistatic agent)

[0089] Antistatic agent H is: dodecyl dimethyl betaine (zwitterionic antistatic agent)

[0090] The atomizer cups treated by different methods are:

[0091] Atomizer cup 1: atomizer cup (PP) and cup cover (PP);

[0092] Atomizer cup 2: atomizer cup (PP + 0.1% antistatic agent A) and cup cover (PP + 0.1% antistatic agent A);

[0093] Atomizer cup 3: atomizer cup (PP + 0.1% antistatic agent B) and cup cover (PP + 0.1% antistatic agent B);

[0094] Atomizer cup 4: atomizer cup (PP + 0.1% antistatic agent C) and cup cover (PP + 0.1% antistatic agent C);

[0095] Atomizer cup 5: Atomizer cup (PP + 0.1% antistatic agent D) and cup cover (PP + 0.1% antistatic agent D)

[0096] Atomizer cup 6: atomizer cup (PP + 0.1% antistatic agent E) and cup cover (PP + 0.1% antistatic agent E);

[0097] Atomizer cup 7: atomizer cup (PP + 0.1% antistatic agent F) and cup cover (PP + 0.1% antistatic agent F);

[0098] Atomizer cup 8: atomizer cup (PP + 0.1% antistatic agent G) and cup cover (PP + 0.1% antistatic agent G);

[0099] Atomizer cup 9: Atomizer cup (PP + 0.1% antistatic agent H) and cup cover (PP + 0.1% antistatic agent H)

[0100] Detection / inhalation method: Detect 20s after atomization.

[0101] Number of repetitions per set: 3 times.

[0102] 3. Testing conditions

[0103] Testing equipment: one ten-thousandth balance;

[0104] 4. Experimental results and analysis

[0105] When atomizing 0.1 ml of the recombinant novel coronavirus vaccine diluent, using an untreated PP atomizer cup, the mist condensed rapidly to the cup wall, and only a small amount of mist remained in the cup 20 seconds after atomization. After adding 0.1% of anionic, nonionic or polymer antistatic agents to the atomizer cup, the antistatic effect and mist volume were improved.

[0106] Residual volume in the cup body and cup cover after atomization

[0107] Before the experiment, use a 1 / 10,000 balance to weigh the cup body + cup cover. After the atomization is completed and the mist is absorbed, weigh it again with a 1 / 10,000 balance:

[0108] Residual rate of drug solution = (weight after atomization - weight before atomization) / weight of atomized drug solution × 100%

[0109] The results are shown in the table below:

[0110] Table 1 Effect of antistatic agent on residual amount of load-bearing mist

[0111]

[0112] Results and Analysis:

[0113] When atomizing with an untreated atomizer cup, a large amount of mist remains in the cup. The mist-carrying performance of the atomizer cup with zwitterionic antistatic agent is significantly improved, while the mist-carrying performance of the atomizer cup with anionic, nonionic or polymer antistatic agent is significantly improved.

[0114] Example 2 Effect of different antistatic agent contents on the mist carrying capacity of the atomizer cup

[0115] 1. Experimental purpose:

[0116] The mist carrying effect of the atomizer cup treated by different methods was studied.

[0117] 2. Experimental Design

[0118] Nebulized model drug: CanSino recombinant novel coronavirus vaccine (adenovirus type 5 vector) liquid formulation

[0119] Nebulization volume: 0.1ml.

[0120] Antistatic agent A is a polymer type: polyethylene glycol fatty acid ester

[0121] Antistatic agent B is non-ionic: polyoxyethylene sorbitan fatty acid ester

[0122] Antistatic agent C is anionic: potassium hexadecyl phosphate

[0123] Antistatic agent D is a zwitterionic type: dodecyl dimethyl quaternary ethyl salt

[0124] The atomizer cups treated by different methods are:

[0125] Atomizer cup 1: atomizer cup (PP) and cup cover (PP);

[0126] Atomizer cup 2: atomizer cup (PLA) and cup cover (PLA);

[0127] Atomizer cup 3: Atomizer cup (PP) and cup cover (PP), ion air gun blows to remove static electricity;

[0128] Atomizer cup 4: Atomizer cup (PLA) and cup cover (PLA), ion air gun blows to remove static electricity;

[0129] Atomizer cup 5-1: atomizer cup (PP + 0.03% antistatic agent A) and cup cover (PP + 0.03% antistatic agent A);

[0130] Atomizer cup 5-2: atomizer cup (PLA + 0.03% antistatic agent A) and cup cover (PLA + 0.03% antistatic agent A);

[0131] Atomizer cup 5-3: atomizer cup (PP + 0.03% antistatic agent B) and cup cover (PP + 0.03% antistatic agent B);

[0132] Atomizer cup 5-4: atomizer cup (PLA + 0.03% antistatic agent B) and cup cover (PLA + 0.03% antistatic agent B);

[0133] Atomizer cup 5-5: atomizer cup (PP + 0.03% antistatic agent C) and cup cover (PP + 0.03% antistatic agent C);

[0134] Atomizer cup 5-6: atomizer cup (PLA + 0.03% antistatic agent C) and cup cover (PLA + 0.03% antistatic agent C);

[0135] Atomizer cups 5-7: atomizer cups (PP + 0.03% antistatic agent D) and cup covers (PP + 0.03% antistatic agent D);

[0136] Atomizer cups 5-8: atomizer cups (PLA + 0.03% antistatic agent D) and cup covers (PLA + 0.03% antistatic agent D);

[0137] Atomizer cup 6-1: atomizer cup (PP + 0.05% antistatic agent A) and cup cover (PP + 0.05% antistatic agent A);

[0138] Atomizer cup 6-2: atomizer cup (PLA + 0.05% antistatic agent A) and cup cover (PLA + 0.05% antistatic agent A);

[0139] Atomizer cup 6-3: atomizer cup (PP + 0.05% antistatic agent B) and cup cover (PP + 0.05% antistatic agent B);

[0140] Atomizer cup 6-4: atomizer cup (PLA + 0.05% antistatic agent B) and cup cover (PLA + 0.05% antistatic agent B);

[0141] Atomizer cup 6-5: atomizer cup (PP+0.05% antistatic agent C) and cup cover (PP+0.05% antistatic agent C);

[0142] Atomizer cup 6-6: atomizer cup (PLA + 0.05% antistatic agent C) and cup cover (PLA + 0.05% antistatic agent C);

[0143] Atomizer cup 6-7: atomizer cup (PP + 0.05% antistatic agent D) and cup cover (PP + 0.05% antistatic agent D);

[0144] Atomizer cups 6-8: atomizer cups (PLA + 0.05% antistatic agent D) and cup covers (PLA + 0.05% antistatic agent D);

[0145] Atomizer cup 7-1: atomizer cup (PP+0.5% antistatic agent A) and cup cover (PP+0.5% antistatic agent A);

[0146] Atomizer cup 7-2: atomizer cup (PLA + 0.5% antistatic agent A) and cup cover (PLA + 0.5% antistatic agent A);

[0147] Atomizer cup 7-3: atomizer cup (PP + 0.5% antistatic agent B) and cup cover (PP + 0.5% antistatic agent B);

[0148] Atomizer cup 7-4: atomizer cup (PLA + 0.5% antistatic agent B) and cup cover (PLA + 0.5% antistatic agent B);

[0149] Atomizer cup 7-5: atomizer cup (PP+0.5% antistatic agent C) and cup cover (PP+0.5% antistatic agent C);

[0150] Atomizer cup 7-6: atomizer cup (PLA + 0.5% antistatic agent C) and cup cover (PLA + 0.5% antistatic agent A);

[0151] Atomizer cup 7-7: atomizer cup (PP+0.5% antistatic agent D) and cup cover (PP+0.5% antistatic agent D);

[0152] Atomizer cup 7-8: atomizer cup (PLA + 0.5% antistatic agent D) and cup cover (PLA + 0.5% antistatic agent D);

[0153] Atomizer cup 8-1: atomizer cup (PP+5% antistatic agent A) and cup cover (PP+5% antistatic agent A);

[0154] Atomizer cup 8-2: atomizer cup (PLA + 5% antistatic agent A) and cup cover (PLA + 5% antistatic agent A);

[0155] Atomizer cup 8-3: atomizer cup (PP+5% antistatic agent B) and cup cover (PP+5% antistatic agent B);

[0156] Atomizer cup 8-4: atomizer cup (PLA + 5% antistatic agent B) and cup cover (PLA + 5% antistatic agent B);

[0157] Atomizer cup 8-5: atomizer cup (PP+5% antistatic agent C) and cup cover (PP+5% antistatic agent C);

[0158] Atomizer cup 8-6: atomizer cup (PLA + 5% antistatic agent C) and cup cover (PLA + 5% antistatic agent C);

[0159] Atomizer cup 8-7: atomizer cup (PP+5% antistatic agent D) and cup cover (PP+5% antistatic agent D);

[0160] Atomizer cup 8-8: atomizer cup (PLA + 5% antistatic agent D) and cup cover (PLA + 5% antistatic agent D); Atomizer cup 9-1: atomizer cup (PP + 6% antistatic agent A) and cup cover (PP + 6% antistatic agent A);

[0161] Atomizer cup 9-2: atomizer cup (PLA + 6% antistatic agent A) and cup cover (PLA + 6% antistatic agent A);

[0162] Atomizer cup 9-3: atomizer cup (PP+6% antistatic agent B) and cup cover (PP+6% antistatic agent B);

[0163] Atomizer cup 9-4: atomizer cup (PLA + 6% antistatic agent B) and cup cover (PLA + 6% antistatic agent B);

[0164] Atomizer cup 9-5: atomizer cup (PP+6% antistatic agent C) and cup cover (PP+6% antistatic agent C);

[0165] Atomizer cup 9-6: atomizer cup (PLA + 6% antistatic agent C) and cup cover (PLA + 6% antistatic agent C);

[0166] Atomizer cup 9-7: atomizer cup (PP+6% antistatic agent D) and cup cover (PP+6% antistatic agent D);

[0167] Atomizer cup 9-8: atomizer cup (PLA + 6% antistatic agent D) and cup cover (PLA + 6% antistatic agent D); Atomizer cup 10-1: atomizer cup (PP + 10% antistatic agent A) and cup cover (PP + 10% antistatic agent A);

[0168] Atomizer cup 10-2: atomizer cup (PLA + 10% antistatic agent A) and cup cover (PLA + 10% antistatic agent A);

[0169] Atomizer cup 10-3: atomizer cup (PP+10% antistatic agent B) and cup cover (PP+10% antistatic agent B);

[0170] Atomizer cup 10-4: atomizer cup (PLA + 10% antistatic agent B) and cup cover (PLA + 10% antistatic agent B);

[0171] Atomizer cup 10-5: atomizer cup (PP+10% antistatic agent C) and cup cover (PP+10% antistatic agent C);

[0172] Atomizer cup 10-6: atomizer cup (PLA + 10% antistatic agent C) and cup cover (PLA + 10% antistatic agent C);

[0173] Atomizer cup 10-7: atomizer cup (PP + 10% antistatic agent D) and cup cover (PP + 10% antistatic agent D);

[0174] Atomizer cup 10-8: atomizer cup (PLA + 10% antistatic agent D) and cup cover (PLA + 10% antistatic agent D);

[0175] Atomizer cup 11-1: atomizer cup (PP+0.1% antistatic agent A) and cup cover (PP+0.1% antistatic agent A);

[0176] Atomizer cup 11-2: atomizer cup (PLA + 0.1% antistatic agent A) and cup cover (PLA + 0.1% antistatic agent A);

[0177] Atomizer cup 11-3: atomizer cup (PP+0.1% antistatic agent B) and cup cover (PP+0.1% antistatic agent B);

[0178] Atomizer cup 11-4: atomizer cup (PLA + 0.1% antistatic agent B) and cup cover (PLA + 0.1% antistatic agent B);

[0179] Atomizer cup 11-5: atomizer cup (PP+0.1% antistatic agent C) and cup cover (PP+0.1% antistatic agent C);

[0180] Atomizer cup 11-6: atomizer cup (PLA + 0.1% antistatic agent C) and cup cover (PLA + 0.1% antistatic agent C);

[0181] Atomizer cup 11-7: atomizer cup (PP + 0.1% antistatic agent D) and cup cover (PP + 0.1% antistatic agent D);

[0182] Atomizer cup 11-8: atomizer cup (PLA + 0.1% antistatic agent D) and cup cover (PLA + 0.1% antistatic agent D);

[0183] Atomizer cup 12-1: atomizer cup (PP+12% antistatic agent A) and cup cover (PP+12% antistatic agent A);

[0184] Atomizer cup 12-2: atomizer cup (PLA + 12% antistatic agent A) and cup cover (PLA + 12% antistatic agent A);

[0185] Atomizer cup 12-3: atomizer cup (PP+12% antistatic agent B) and cup cover (PP+12% antistatic agent B);

[0186] Atomizer cup 12-4: atomizer cup (PLA + 12% antistatic agent B) and cup cover (PLA + 12% antistatic agent B);

[0187] Atomizer cup 12-5: atomizer cup (PP+12% antistatic agent C) and cup cover (PP+12% antistatic agent C);

[0188] Atomizer cup 12-6: atomizer cup (PLA + 12% antistatic agent C) and cup cover (PLA + 12% antistatic agent C);

[0189] Atomizer cup 12-7: atomizer cup (PP+12% antistatic agent D) and cup cover (PP+12% antistatic agent D);

[0190] Atomizer cup 12-8: atomizer cup (PLA + 12% antistatic agent D) and cup cover (PLA + 12% antistatic agent D);

[0191] 3. Testing conditions

[0192] Testing equipment: SYMPATEC HELOS & INHALER laser particle size analyzer for inhalation aerosol and powder aerosol testing.

[0193] Detection / inhalation method: Detect 20s after atomization.

[0194] Number of repetitions per set: 3 times.

[0195] Detection indicators: duration of the interval of optical concentration Copt (Optical Concentration / %) ≥ 20% and the optical concentration at the corresponding time point;

[0196] 4. Experimental results and analysis

[0197] The area under the optical concentration-time curve of the mist was calculated and recorded as "AUC" (%*S) to characterize the amount of mist. The mist amount was used as an indicator to study the material of the atomizer cup. Figure 7 Results and analysis:

[0198] When atomizing 0.1 ml of the recombinant novel coronavirus vaccine diluent and using an untreated atomizing cup, the mist condensed rapidly to the cup wall, and only a small amount of mist remained in the cup 20 seconds after atomization. The atomizing cup was purged with an ion air gun to remove static electricity and then used to carry mist. The results showed that the inhalable amount increased 20 seconds after atomization, but the effect was still poor. After adding 0.03% antistatic agent to the atomizing cup, the antistatic effect and mist volume were improved; after adding 0.05% or 0.5% antistatic agent to the atomizing cup, the cup's ability to carry mist was further improved, and the effect was significantly better than that after the ion air gun removed static electricity. When the addition amount was 6% and 10%, the antistatic property would increase according to the dose-effect relationship, but the mist volume would decrease.

[0199] Residual volume in the cup body and cup cover after atomization

[0200] Before the experiment, use a 1 / 10,000 balance to weigh the cup body + cup cover. After the atomization is completed and the mist is absorbed, weigh it again with a 1 / 10,000 balance:

[0201] Residual rate of drug solution = (weight after atomization - weight before atomization) / weight of atomized drug solution × 100%

[0202] The results are shown in the table below:

[0203] Table 2 AUC of drug solution in different nebulizer cups

[0204]

[0205]

[0206] Table 3 Average residual rate of drug solution in different atomizer cups

[0207]

[0208] Results and Analysis:

[0209] As the content of antistatic agent changes, the residual amount of drug mist in the atomizer cup also changes. When the content of antistatic agent is 0.03%-10%, the residual amount of drug mist in the atomizer cup is small, and the result is better than or basically the same as the atomizer cup treated with static electricity by a deionizing air gun. When the content of antistatic agent is 0.05%-5%, the effect of preventing drug mist residue in different atomizer cups is the best.

[0210] Example 3 Effect of inhalation using a nebulizer cup on vaccine particle size

[0211] 1. Experimental purpose

[0212] Study the effect of antistatic atomizer cup on carrying mist.

[0213] 2. Experimental Design

[0214] Model aerosolized drug: CanSino recombinant novel coronavirus vaccine (adenovirus type 5 vector, liquid preparation)

[0215] Nebulization volume: 0.1ml.

[0216] Atomizer cup: Atomizer cups 6-1, 6-3, 7-1, 7-3, 8-1, and 8-3 in Example 2 were used for the study.

[0217] 3. Testing conditions

[0218] Testing equipment: Inhalation preparation particle size tester.

[0219] Detection conditions: Detection was performed 10 seconds after atomization.

[0220] Test items: Particle size (X 10.3 , X 50.3 , X 90.3 ), the proportion of particles with a size less than 5.25 microns.

[0221] 4. Experimental results and analysis

[0222] The aerodynamic distribution of the aerosol after atomization using the nebulizer cup was tested using an inhalation preparation particle size detector, and the test was performed three times in parallel. See the table below:

[0223] Table 4 Aerodynamic distribution results of aerosol after atomization

[0224]

[0225] Results and Analysis:

[0226] Using a PP material nebulizer cup with an antistatic agent content of 0.05%-5%, the aerodynamic particle size of the detected mist and the particle size less than 5.25 microns are similar, with no significant difference, and meet the requirements of nebulized inhalation drug administration.

[0227] Example 4 Comparison of the inhalable amount using the antistatic atomizer cup inhalation method and the commercially available mouth inhalation method

[0228] 1. Experimental purpose

[0229] Traditional nebulized inhalation (i.e., inhalation through the mouth) involves breathing while atomizing, and the drug is brought into the lungs through breathing. Inhalation through a nebulizer cup requires collecting the mist into the nebulizer cup and then inhaling it in one breath. This example studies the amount of drug that can be inhaled in one breath using an antistatic nebulizer cup to carry the mist, and compares it with the inhalation method using a mouthpiece.

[0230] 2. Experimental Design

[0231] Model aerosolized drug: CanSino recombinant novel coronavirus vaccine (adenovirus type 5 vector) liquid formulation

[0232] Nebulization volume: 0.1ml.

[0233] Atomizer cup: The 6-1 atomizer cup in Example 2 was used for the study.

[0234] 3. Testing conditions

[0235] Mouth-to-mouth inhalation method: Breathing simulator adult breathing pattern, collects inhalable drugs onto the filter membrane.

[0236] Atomizer cup inhalation method: adjust the pump inhalation speed to 15L / min, connect the filter membrane fixture to the pump. Connect the cup mouth to the filter membrane connection port 10s after the atomization ends, and collect the mist into the filter membrane.

[0237] 4. Experimental results and analysis

[0238] Each method was repeated 6 times. After the end, the vaccine on the filter membrane was washed and the virus particles were quantified by ELISA method. The results are shown in the following table:

[0239] Table 5 Inhalable volume test results

[0240]

[0241] Results and Analysis:

[0242] The results showed that the inhalable amount when using the nebulizer cup was 48.3%, which was not significantly different from the method of inhalation through the mouth. The results show that the nebulizer cup can be used to replace the mouth.

[0243] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

[0244] The aforementioned embodiments and methods described in the present invention may be varied based on the ability, experience and preference of those skilled in the art.

[0245] In the present invention, merely listing the steps of the method in a certain order does not constitute any limitation on the order of the method steps.

Claims

1. An atomizing cup, characterized in that: It comprises a cup body and a cup cover, wherein the cup body is made of plastic; an antistatic agent is added to the cup body; in terms of mass percentage, the content of the antistatic agent added to the cup body is 0.05%-0.5%; the nebulizer cup is used for nebulized inhalation administration of vaccines.

2. The atomizer cup according to claim 1, characterized in that: The cup body is made of transparent plastic selected from the group consisting of polypropylene (PP), polylactic acid (PLA), polyethylene (PE), polyvinyl chloride (PVC), polystyrene (PS), and polycarbonate (PC).

3. The atomizer cup according to claim 1, characterized in that: The cup cover is made of plastic; the plastic is selected from the group consisting of polypropylene (PP), polylactic acid (PLA), polyethylene (PE), polyvinyl chloride (PVC), polystyrene (PS), and polycarbonate (PC).

4. The atomizer cup according to claim 1, characterized in that: An antistatic agent is added to the cup cover; in terms of mass percentage, the content of the antistatic agent added to the cup cover is 0.03%-10%.

5. The atomizer cup according to claim 4, characterized in that: In terms of mass percentage, the content of the antistatic agent added to the cup cover is 0.05-5%.

6. The atomizer cup according to claim 1, characterized in that: The cup cover is provided with a mist inlet and a suction nozzle.

7. The atomizer cup according to claim 6, characterized in that: A sealing piece is provided at the mist inlet; and a sealing piece is provided at the suction port of the suction nozzle.

8. The atomizer cup according to any one of claims 1 to 7, characterized in that: The antistatic agent is selected from one or a combination of two or more of anionic antistatic agents, zwitterionic antistatic agents, nonionic antistatic agents and polymer antistatic agents.

9. The atomizer cup according to claim 8, characterized in that: The anionic antistatic agent is selected from one or a combination of two or more of alkyl sulfonates, alkyl phosphates, salts of copolymers of maleic anhydride and other monomers, polyacrylates and polystyrene sulfonates; the zwitterionic antistatic agent is amphoteric alkyl imidazoline salts and / or alkyl amino acids; the nonionic antistatic agent is fatty acid polyol esters and / or polyethylene oxide additives; the polymer antistatic agent is selected from one or a combination of two or more of polyoxyethylene fatty ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters and polyacrylic acid derivatives.

10. The atomizer cup according to claim 9, characterized in that: The nonionic antistatic agent is selected from one or a combination of two or more of fatty alcohol polyoxyethylene ether, alkylphenol polyoxyethylene ether and glycerol monofatty acid ester; the zwitterionic antistatic agent is alkyl dicarboxymethyl ammonium betaine and / or dodecyl dimethyl betaine; the polymer antistatic agent is selected from one or a combination of two or more of ethylenediamine ethylene oxide propylene oxide adduct, poly 4-vinylpyridine type polysoap, octyl styrene and styrene sulfonic acid copolymer polysoap.

11. The atomizer cup according to claim 1, characterized in that: The volume of the atomizer cup is 300-800 ml.

12. The atomizer cup according to claim 11, characterized in that: The volume of the atomizer cup is 500 ml.

13. A method for preparing the atomizer cup according to any one of claims 1 to 12, characterized in that: The preparation method comprises the step of adding antistatic agent components or antistatic masterbatch to the raw materials for preparing the cup body and / or the cup cover.

14. Use of the nebulizer cup according to any one of claims 1 to 12 in preparing a device for nebulized inhalation drug delivery.

15. The use according to claim 14, characterized in that: The application is the use of the nebulizer cup in a device for preparing a nebulized inhalation administration of vaccines for respiratory diseases.

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