Patent Application
20250082869
The present invention relates to the field of biomedicine, and in particular, to a nebulization cup and application in nebulized inhalation administration thereof, especially in nebulized inhalation administration of a preventive and/or therapeutic drug for a respiratory disease (such as SARS-CoV-2 vaccine).
At present, one of the treatments for respiratory diseases is nebulized inhalation administration, which disperses the liquid drug into fine mist droplets by using a nebulizer and inhales them through a patient's nose or mouth. The nebulized drug directly acts on the target organs, which can increase the local concentration of the drug to achieve the therapeutic effect. Nebulized inhalation has a very good therapeutic effect on bronchiolitis, asthmatic bronchitis, bronchial asthma, acute and chronic bronchitis, acute laryngitis and acute pneumonia and the like.
Nebulized inhalation vaccine is a vaccine that achieves immunization by nebulized inhalation. The so-called nebulized inhalation immunization means that the vaccine is nebulized into tiny particles through a nebulizer, and these tiny particles enter the respiratory tract and lungs through breathing inhalation to stimulate mucosal immunization.
The equipment and devices for implementing the nebulized inhalation therapy and immunization are very important for the implementation and quality of therapy and immunization, and have attracted great attention from researchers. The existing nebulized administration devices in the prior art mainly use the mode of nebulizing while inhaling for administration, and it is necessary to guide the subject before administration. For children and even many adults, the inhalation and absorption of drug mist is often greatly affected due to improper control of the frequency of inhalation administration and self-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 inoculation, it is an urgent problem to provide a nebulized administration device which can prevent cross-infection, reduce cost with and achieve high inhalation inoculation efficiency.
Additionally, when using a nebulization cup for nebulized inhalation, the atomized medication mist tends to liquefy and form droplets on the walls of the cup due to static electricity, which cannot be normally inhaled by the human body. Therefore, it is necessary to add an antistatic agent to the nebulization cup to resist static electricity and prevent the liquefaction and residue of the medication mist. The dosage of the antistatic agent also has a significant impact on the medication mist. When the content of the antistatic agent is low, there is more deposition of the mist and a larger residue; when the content of the antistatic agent is high, it can affect the molding of the cup, the tactile sensation, and pose a threat to the effective amount of the atomized medication mist. Therefore, it is urgent to find the appropriate antistatic agent and the optimal dosage of the antistatic agent to ensure the effectiveness of the medication atomization.
In order to overcome the shortcomings of the prior art, the present invention provides a nebulization cup and application thereof. The nebulization cup can be used for collecting and carrying the drug mist generated by the nebulizer, and providing the drug mist be inhaled by the subject to achieve the effects of treatment and immunization.
In a first aspect of the present invention, a nebulization cup is provided, the nebulization cup includes a cup body and a cup lid, and an antistatic agent is added to the cup body.
Specifically, an antistatic agent is further added to the cup lid.
Specifically, the antistatic agent may be an anionic antistatic agent (such as alkyl sulfonate, alkyl phosphate, copolymer salt of maleic anhydride and other monomer copolymer salts, polyacrylate, polystyrene sulfonate), a zwitterionic antistatic agent (such as amphoteric alkyl imidazoline salt, alkyl amino acid), a nonionic antistatic agent (such as polyhydroxy alcohol fatty acid ester (such as glycerol fatty acid ester, sorbitan fatty acid ester)), polyethylene oxide additive (such as polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty ether, polyoxyethylene alkylbenzene ether, polyoxyethylene alkylamine and the like), a polymer antistatic agent (such as polyoxyethylene fatty ether, polyoxyethylene alkylbenzene ether, polyethylene glycol fatty acid ester, polyacrylic acid derivative), or a composite antistatic agent and the like, especially a nonionic antistatic agent or a polymer antistatic agent.
Further, the non-ionic antistatic agent mentioned is preferably selected from one of or a combination of more than one of fatty alcohol ethoxylates, alkyl phenol ethoxylates, and mono- and di-glycerides of fatty acids; the amphoteric antistatic agent is alkyl dicarboxymethyl ammonium succinimide and/or dodecyl dimethyl betaine; the polymeric antistatic agent is selected from one of or a combination of more than one of ethylene oxide-propylene oxide adducts of ethylenediamine, poly(4-vinylpyridine) type polymeric soaps, octylphenyl styrenes, and styrene sulfonate copolymeric soaps.
Cationic quaternary ammonium salts have strong adhesion to polymer materials and good antistatic properties, and are also a kind of antistatic agents that are widely used in plastics. But they are irritating to skin and are toxic, so they do not belong to the selection range of the present invention.
In some embodiments of the present invention, an antistatic agent is added to the cup, the content of the antistatic agent is above 0.03% (w/w), especially above 0.05%, such as 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%), especially 0.05%-5%.
In some embodiments of the present invention, an antistatic agent is added to the cup lid, the content of the antistatic agent is more than 0.03% (w/w), especially more than 0.05%, such as 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%), especially 0.05%-5%.
In some embodiments of the present invention, an antistatic agent is added to both the cup body and the cup lid.
Specifically, the addition of the antistatic agent in the cup body and/or the cup lid may be achieved by adding the antistatic agent raw materials to its preparation raw materials, or by adding antistatic masterbatch to its preparation raw materials, especially by adding antistatic masterbatch to its preparation raw materials. The antistatic agent and the antistatic masterbatch may be selected from suitable commercial products according to the plastic material of the cup body and/or the cup lid.
Further, the cup lid is provided with a mist inlet and a suction nozzle.
Specifically, the mist inlet may be provided at any suitable position of the cup lid, such as the edge, the center, especially the edge of the cup lid; the mist inlet may also be provided with a closing member to facilitate closing the mist inlet before the nebulization cup is used.
Specifically, the suction nozzle is protrusively provided on the cup lid and communicated with the inner space of the cup. The suction nozzle may take any shape suitable for the subject to suck the mist, such as a round or conical shape, and the suction port end of the suction nozzle may take a shape suitable for the subject to suck, such as a round or oval shape. The suction port of the suction nozzle may also be provided with a closing member to facilitate closing the suction nozzle before the nebulization cup is used.
Specifically, the material of the cup lid may be a plastic, especially a medical grade plastic, such as polypropylene (PP), polyethylene (PE), polyvinyl chloride (PVC), polystyrene (PS), polycarbonate (PC), polylactic acid (PLA) and the like, especially PP and PLA. Specifically, the cup lid is transparent.
Specifically, the material of the cup body may be a plastic, especially a medical grade plastic, such as polypropylene (PP), polyethylene (PE), polyvinyl chloride (PVC), polystyrene (PS), polycarbonate (PC), polylactic acid (PLA) and the like, especially PP and PLA. Specifically, the cup body is transparent.
Specifically, the cup body and the cup lid may be integrally formed, or may be detachably provided, for example, connected by a screw thread or a buckle.
Specifically, the cup body may have any suitable shape, such as a cylindrical shape, a truncated cone shape with a tapered upper width and a lower width, and the like.
Specifically, the side wall of the cup body may also be provided with a handle to facilitate taking the nebulization cup.
Specifically, the volume of the nebulization cup may be 300 ml −800 ml (such as 300 ml, 350 ml, 400 ml, 450 ml, 500 ml, 550 ml, 600 ml, 700 ml, and 800 ml), especially 500 ml.
In a second aspect of the present invention, a method for preparing the nebulization cup described in the first aspect is provided. The method includes a step of adding an antistatic agent component or an antistatic masterbatch to the raw material for preparing the cup body.
In some embodiments of the present invention, the method further includes a step of adding an antistatic agent component or antistatic masterbatch to the raw material for preparing the cup lid.
Specifically, the method further includes a forming step, such as forming by extrusion, injection molding, compression molding, blow molding or other methods.
In a third aspect of the present invention, an application of the nebulization cup described in the first aspect in the preparation of a nebulized inhalation administration device is provided.
Specifically, the application is application of the nebulization cup in the preparation of a device for nebulized inhalation administration of a preventive and/or therapeutic drug for a respiratory disease.
Specifically, the device includes the nebulization cup described in the first aspect of the present invention, and a nebulizer; more specifically, the nebulizer may be an ultrasonic nebulizer, a compression nebulizer, a vibrating mesh screen nebulizer or other suitable nebulizers, especially a vibrating mesh screen nebulizer.
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, and the like.
In some embodiments of the present invention, the coronavirus vaccine is SARS-CoV-2 vaccine.
Specifically, the SARS-CoV-2 vaccine may be a recombinant adenovirus vector vaccine in which the S protein gene of SARS-CoV-2 is inserted into the recombinant adenovirus. More specifically, the recombinant adenovirus may also contain genes (full-length or partial sequences) of other structural proteins (such as M protein, E protein and N protein) of SARS-CoV-2.
Specifically, the above-mentioned adenovirus may be a human adenovirus (such as AdHu2 type, AdHu5 type and the like), an animal adenovirus vector such as a chimpanzee adenovirus vector (such as AdC6 type, AdC7 type, AdC36 type, AdC68 type and the like). In some embodiments of the present invention, the above-mentioned adenovirus is AdHu5.
Specifically, the content of recombinant adenovirus in the above-mentioned recombinant adenovirus vector vaccine is 1×109 VP/ml −5×1011 VP/ml (specifically, 2×109 VP/ml, 4×109 VP/ml, 6×109 VP/ml, 8×109 VP/ml, 1×1010 VP/ml, 2×1010 VP/ml, 4×1010 VP/ml, 6×1010 VP/ml, 8×1010 VP/ml, 1×1011 VP/ml, 2×1011 VP/ml, 3×1011 VP/ml, 4×1011 VP/ml, 5×1011 VP/ml).
Specifically, the unit dose of the above-mentioned drug is 0.05 ml −0.5 ml (such as 0.05 ml, 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, and 0.5 ml), especially 0.05 ml −0.2 ml, and 0.1 ml.
In a fourth aspect of the present invention, a nebulized inhalation administration device is provided. The nebulized inhalation administration device includes the nebulization cup according to the first aspect of the present invention, and a nebulizer.
Specifically, the nebulizer may be an ultrasonic nebulizer, a compression nebulizer, a vibrating mesh screen nebulizer and other suitable nebulizers, especially a vibrating mesh screen nebulizer.
In a fifth aspect of the present invention, an application of the nebulization cup described in the first aspect in nebulized inhalation administration is provided.
Specifically, the application is application of the nebulization cup in nebulized inhalation administration of a preventive and/or therapeutic drug for a respiratory disease.
Specifically, in this application, the drug has the corresponding definition described in the third aspect of the present invention.
In a sixth aspect of the present invention, a nebulized inhalation administration method is provided, which includes a step of administering a drug to a subject through the nebulization cup described in the first aspect.
Specifically, the method is a nebulized inhalation immunization method. The drug is a vaccine, such as pneumococcal vaccine, influenza vaccine, coronavirus vaccine, chickenpox vaccine, Newcastle virus vaccine, measles vaccine, tuberculosis vaccine, dust mite allergy vaccine and the like. In some embodiments of the present invention, the vaccine is a coronavirus vaccine, especially SARS-CoV-2 vaccine.
Specifically, the SARS-CoV-2 vaccine may be a recombinant adenovirus vector vaccine in which the S protein gene of SARS-CoV-2 is inserted. More specifically, the recombinant adenovirus may also contain genes (full-length or partial sequences) of other structural proteins (such as M protein, E protein and N protein) of SARS-CoV-2.
Specifically, the above-mentioned adenovirus may be a human adenovirus (such as AdHu2 type, AdHu5 type and the like), an animal adenovirus vector such as a chimpanzee adenovirus vector (such as AdC6 type, AdC7 type, AdC36 type, AdC68 type and the like). In some embodiments of the present invention, the above-mentioned adenovirus is AdHu5.
Specifically, the content of recombinant adenovirus in the above-mentioned recombinant adenovirus vector vaccine is 1×109 VP/ml −5×1011 VP/ml (specifically, 2×109 VP/ml, 4×109 VP/ml, 6×109 VP/ml, 8×109 VP/ml, 1×1010 VP/ml, 2×1010 VP/ml, 4×1010 VP/ml, 6×1010 VP/ml, 8×1010 VP/ml, 1×1011 VP/ml, 2×1011 VP/ml, 3×1011 VP/ml, 4×1011 VP/ml, 5×1011 VP/ml).
Specifically, the unit dose of the above-mentioned vaccine is 0.05 ml −0.5 ml (for example, 0.05 ml, 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, and 0.5 ml), especially 0.05 ml −0.2 ml, and 0.1 ml.
Specifically, the method includes the following steps:
Specifically, step (3) is performed within 30 seconds (s) after the completion of mist collection (for example, 20 s, 15 s, 10 s and 5 s), especially within 10 s after completion of mist collection.
Specifically, the nebulizer in step (1) may be an ultrasonic nebulizer, a compression nebulizer, a vibrating mesh screen nebulizer and other suitable nebulizers, especially a vibrating mesh screen nebulizer.
As shown in
Furthermore, the suction nozzle 24 is located near the edge at the top of the cup lid 2 and protrudes from the surface of the cup lid 2.
Furthermore, the cup lid 2 also includes a plug 25, the lower end of which has a plug-in part 251. The outer contour of the plug-in part 251 matches the inner wall contour of the suction nozzle 24, allowing the plug 25 to be inserted into the suction nozzle 24 and to seal it.
Furthermore, the plug 25 has a positioning part 252 extending outward from the plug-in part 251 perpendicularly, and the contour size of the positioning part 252 is larger than that of the plug-in part 251.
Furthermore, the plug 25 has a hand-held part 253 at the top end of the positioning part, which allows for manual insertion and removal of the plug 25.
Furthermore, the plug 25 is located at the edge of the cup lid 2 and is fixed on the cup lid 2 by two positioning lines 26.
Furthermore, there is a rectangular pull tab 27 adjacent to the edge of the flip flap 22, perpendicular to the flip flap 22.
Furthermore, both the nebulization port 21 and the suction nozzle 24 located at the top of the cup lid 2 are near the edge and on both sides of the central axis. The suction nozzle 24 at the top of the cup lid 2 is oval-shaped.
Specifically, the nebulization cup is disposable to avoid cross-infection.
The nebulization cup provided by the present invention may be used for nebulized inhalation administration of a preventive and/or therapeutic drug for a respiratory disease. Nebulization therapy mainly refers to aerosol inhalation therapy. Aerosol refers to tiny solid or liquid particles suspended in the air. Therefore, the nebulized inhalation therapy is to use the nebulization device to disperse the drug into tiny droplets or particles, which are suspended in the gas and enter the respiratory tract and lungs. The deposition of mist particles will affect the properties of mist particles. The physical mechanisms of mist deposition include impact deposition, gravity deposition, dispersion deposition, electrostatic attraction deposition and interception deposition. In order to eliminate the effect of deposition caused by electrostatic attraction on the mist particles, previous research have found that adding a food-grade antistatic agent such as edible vegetable oil raw material to the pharmaceutical preparations will cause the volume of the nebulized particles to be greater than 20 microns, which could not be delivered. The nebulization cup is treated with a static elimination device (such as ion wind wand, ion wind gun, ion fan and the like) before the nebulization cup is used. The effect of eliminating static electricity is definite. Actually, although the effect on the deposition of preparation mist particles has been improved to some extent, the effect is relatively limited.
According to the present invention, the antistatic agent is added to the material of the nebulization cup, and the combination of transparent plastic material and antistatic agent can keep the water droplets stable and achieve an ideal nebulization effect. The reason may be that the principle of antistatic is to form a conductive layer on the surface of the material, thereby reducing its surface resistivity and making the generated static charge leak quickly. In addition to the antistatic effect, adding the 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. As the antistatic agent does not play a simple antistatic or smoothing role, the present invention chooses the amount of mist, inhalable amount of mist, residual rate of liquid drug and aerodynamics of nebulized aerosol as comprehensive indexes to research the specific antistatic agent dosage of the nebulization cup, and it is found that the dosage of antistatic agent in 0.03%-10% (mass percentage) can meet the use needs, and the comprehensive indexes are better when the dosage of antistatic agent is 0.05%-5% (mass percentage). Specifically, when no antistatic agent is added, the transparent plastic nebulization cup has poor mist-carrying capacity, and the residual rate of liquid drug is high, which is almost unusable. When the dosage is 0.03%, the anti-static effect and the comprehensive performance of mist inhalation decrease. However, when the dosage is increased to 6% or 10%, the antistatic property will increase according to the dose-effect relationship, but the comprehensive performance of mist inhalation decreases. Therefore, adding a certain amount of antistatic agent can effectively maintain the stability of drug mist within a certain period of time (for example, within 20 s). The particle size is stable, the drug residue in the cup is less, and the effective inhalable amount and deposition rate are ensured. The structural design of the nebulization cup further improves the inhalation performance, especially when it is used in the field of vaccines. The administration operation is simple and convenient, the inoculation efficiency can be obviously improved, and it can be used for large-scale inoculation.
Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by those skilled in the art related to the present invention.
In the present invention, a “subject” refers to a human who is subjected to the administration method according to the present invention (especially the nebulized inhalation immunization method).
The disclosures of various publications, patents, and disclosed patent specifications cited herein are incorporated herein by reference in their entirety.
The technical solutions 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 thereof. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work shall fall within the protection scope of the present invention.
To research the effect of nebulizer cups carrying mist when different antistatic agents are added.
Detection equipment: Analytical balance with a precision of one part in ten thousand.
When nebulizing 0.1 ml of diluted recombinant novel coronavirus vaccine, using a PP material nebulizer cup without any treatment, the mist rapidly condensed on the walls of the cup, and only a small amount of mist remained in the cup 20 seconds after nebulization. After adding 0.1% anionic, nonionic, or polymeric antistatic agents to the nebulizer cup, both the antistatic effect and the amount of mist were improved.
Residual amount in the cup body+cup cover after nebulization
Before the experiment, the weight of the cup body+cup cover was measured using an analytical balance with a precision of one part in ten thousand. After the nebulization ended and the mist was inhaled, the weight was measured again using the same balance:
Residual rate of the drug solution=(Weight after nebulization−Weight before nebulization)/Weight of the nebulized drug solution×100%
The results are shown in the table below:
When nebulizing with a nebulization cup that has not been treated in any way, a large amount of mist remains inside the cup. The performance of nebulization cups carrying mist is significantly improved when amphoteric antistatic agents are added. Meanwhile, the performance of nebulization cups carrying mist is markedly enhanced when anionic, nonionic, or polymeric antistatic agents are added.
To research the effect of nebulization cups treated by different methods on carrying mist.
Calculate the area under the mist optical concentration-time curve, referred to as “AUC” (%*S), to represent the amount of mist, and use the amount of mist as an indicator to study the material of the Nebulization cup. The results are shown in
When nebulizing 0.1 ml of diluted recombinant novel coronavirus vaccine using a Nebulization cup that has not been treated, the mist rapidly condenses on the cup wall, and only a small amount of mist remains in the cup 20 seconds after nebulization. After treating the Nebulization cup with an ion air gun to remove static electricity for carrying mist, the results show an increase in inhalable volume 20 seconds after nebulization, but the effect is still not satisfactory. After adding 0.03% antistatic agent to the Nebulization cup, both the antistatic effect and the amount of mist are improved; after adding 0.05% or 0.5% antistatic agent to the Nebulization cup, the performance of the cup in carrying mist is further improved, and its effect is significantly better than that after static electricity removal by the ion air gun. When the addition amount is 6% or 10%, according to the dose-effect relationship, the antistatic property will increase, but the amount of mist decreases.
Residual amount in cup body+cup lid after nebulization
Before the experiment, a one-ten-thousand balance is used to weigh the cup body+cup lid. After the nebulization is completed, a one-ten-thousand balance is used to weigh again after the mist is inhaled:
Residual rate of liquid drug=(weight after nebulization minus weight before nebulization)/weight of nebulized liquid drug×100%
The results are shown in the table below.
As the content of the antistatic agent changes, the residue of the mist in the nebulization cup is also continuously changing. When the content of the antistatic agent is between 0.03% and 10%, the residue of the mist in the nebulization cup is minimal, and the results are superior to or essentially the same as those of the nebulization cups treated with static removal by an ionized air gun. When the content of the antistatic agent is between 0.05% and 5%, the effect of preventing mist residue in different nebulization cups reaches its optimum.
To research the effect of anti-static nebulization cup on mist carrying by nebulization cups.
The aerodynamic distribution of aerosol nebulized by the nebulization cup is detected by the inhalation preparation particle size detector, and the detection is carried out three times in parallel, as shown in the table below.
The PP nebulization cup is used, and the content of antistatic agent is 0.05%-5%. The aerodynamic particle size of the detected mist is similar to that of the particle size less than 5.25 microns with no significant difference, and it meets the requirements of nebulized inhalation administration.
Traditional nebulized inhalation administration (that is, inhalation through suction nozzle) adopts nebulizing while inhaling, which brings drugs to the lungs. If it is replaced by nebulization cup inhalation, it is necessary to collect the mist in the nebulization cup and then inhale it in one breath. In this embodiment, the amount of drug in the way of one-breath inhalation after using the antistatic nebulization cup to carry the mist is researched, and the comparison is made with the way of inhaling through a suction nozzle.
Suction nozzle inhalation mode: the adult breathing mode of the respiration simulator, which collects the inhalable drug to the filter membrane.
Nebulization cup suction mode: the suction speed of the pump is adjusted to 15 L/min, and the filter fixing device is connected to the pump. 10 s after the end of the nebulization, the cup mouth is connected to the filter membrane connection port, and the mist is collected to the filter membrane.
Each mode is repeated 6 times. After that, the vaccine on the filter is eluted, and the virus particles are quantified by ELISA method. The results are shown in the following table.
The results show that the inhalable amount when using the nebulization cup for administration is 48.3%, which is not significantly different from the inhalable amount when using the suction nozzle. The results show that the nebulization cup may be used to replace the suction nozzle.
The foregoing descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modification, equivalent replacement and the like. made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.
The foregoing embodiments and methods described in the present invention may be different based on the abilities, experiences and preferences of those skilled in the art.
In the present invention, the listing of the steps of a method in a certain order does not constitute any restriction on the order of the steps of the method.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202111429885.3 | Nov 2021 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/130338 | 11/7/2022 | WO |
