1. INTRODUCTION:

Nebulizers (NBs) are traditional pulmonary medication delivery devices¹. They have been employed to treat respiratory conditions for several years². Since being developed at the start of the 20^th century, NBs have been the most ancient method of producing aerosols. They can be utilized for any age and any level of illness. Over the previous 25 years, there hasn't been much of a change in their core design or functionality³. One popular technique for creating medicinal aerosols is nebulization from a medication solution. In order to deliver by nebulization, a medicine must first be distributed in a liquid, typically aqueous, medium.

The medication particles are enclosed within the aerosol droplets, which are inhaled following the application of a dispersion force (either an ultrasonic wave or a gas jet)⁴. Nebulization has a number of benefits. For example, certain inhalation medications are only accessible as solutions, which call for NBs. Second, some people need help to correctly use traditional techniques such as dry powder inhalers or metered-dose inhalers. Furthermore, compared to alternative aerosol-generating devices, some patients prefer the nebulizer ⁵. Currently, there are two types of NBs that are commercially available: (i) jet (or pneumatic) small-volume NBs and (ii) ultrasonic NBs. While ultrasonic NBs use the opposite piezoelectric effect to transform alternating current into high-frequency acoustic energy, jet NBs are based on the venturi principle. Figure 1 depicts the layout of a jet nebulizer's main components ⁶. The primary characteristics of both nebulizer types are the length of treatment for each use, the particle size distributions generated, and the aerosol medication output. Small formulation modifications may also have an impact on inhaled mass, particle size distribution, and treatment duration. Typically, medication solutions are formulated to maximize drug solubility and stability. Brand-specific variations likely have a bigger influence than formulation variations in nebulizers. The physiological advantages of both NBs are nearly equal, and clinicians or patients typically choose the device based on personal taste rather than an obvious advantage of one method over another ⁷. The jet nebulizer operates on the basis of the Bernoulli principle ⁸, which states that compressed gas, such as oxygen or air, is delivered through a small opening to produce a low-pressure zone at the liquid feed tube's neighboring end. This causes the solution to be evacuated, pulling the medication up from the fluid reservoir and shattering it into tiny droplets in the gas stream ⁹.

Figure 1. The main components of jet nebulizer (Own creation).

Nebulization of numerous medications in a variety of dosages is possible with the right equipment and formulation. Effective use of NBs, however, requires a thorough understanding of their operation and the variables affecting their performance. The features of the medication solution and the device's design are just two of the many variables that affect how effective nebulizer therapy is ¹⁰. Further, some drawbacks of using a few NBs are the low deposition efficiency of the drug in the target area and the deposition of the drug in the lungs of the patients. Thus, in concern with Patient Safety, this review aims at a comparative evaluation of Nebulizer Devices Present in the market and their Effect on users, which has been detailed in the sections below.

2. Clinical Applications:

Beyond technological advancements, the clinical use of NBs and their medical applications have advanced significantly. Drug suspensions and solutions are occasionally aerosolized for inhalation using NBs. Usually, they are employed when the patient's lack of coordination or severe congestion of the airways precludes the use of other devices ¹¹. Moreover, NBs are utilized for medications like enzymes, antibiotics, and mucolytics that cannot be prepared as DPI or MDI ^12,13 or have not been developed yet. Additionally, nebulization of anticholinergic medications and ß2-agonists is a standard procedure for acute asthma ¹⁰. Even with limited drug delivery efficiency, NBs can nevertheless have the necessary clinical impact for powerful medications as ß2-agonists and corticosteroids ¹⁴ when dosed in quantities less than 1 milligram. Nonetheless, effective systems are essential for the delivery of antibiotics that are dosed in milligrams to minimize the length of time needed for inhaling the entire prescribed dose and to provide adequate therapeutic efficacy. Additionally, increased efficiency is needed for the pulmonary administration of novel therapeutic compounds such as proteins and peptides, complicated liposome formulations, or genetic material comprising viral vectors ¹⁵. Recently, M. Farncombe and colleagues reviewed three individual patient case studies in their research on the clinical use of nebulized opioids for the management of dyspnea in patients with terminal cancer. The results showed that this treatment was safe and effective in controlling dyspnea. Depending on their history of opioid usage, the patients received treatment with morphine, hydromorphone, or anileridine at different dosages. At this Center, more formal studies are being initiated ¹⁶. From a clinical perspective, these systems are not only used to administer drugs to patients suffering from asthma, cystic fibrosis, chronic obstructive pulmonary disease, and other chronic lung conditions; additionally, there is still a great interest in creating inhalable formulations for both systemic and local illnesses, and current trends indicate novel uses such as targeted lung cancer treatments¹⁷, gene therapy, and needle-free vaccines.

3. Mechanism: Physics behind Nebulizer Devices:

Nebulizer devices operate on different designs based on the same fundamental idea. Compressed air is fed through a small opening in a standard jet nebulizer, entraining the medication solution from one or more capillaries primarily through momentum transfer ¹⁸. The intricate process of liquid break-up is mostly determined by the design of the nozzle and often involves a blend of secondary droplet breakage and turbulent rupture of the unstable liquid column. In its most basic form, a solid liquid jet is immediately impounded by air. To refine the droplet size distribution to the necessary range for inhalation, large droplets impact one or more baffles. The only droplets that can follow the air's streamlines and get past the baffle are smaller ones with less inertia. Figure 1 depicts a jet nebulizer design with an open vent that uses the venturi principle. A portion of the inspiratory airflow might enter the nebulization chamber due to the vent. By increasing droplet entrainment from the nozzle area, the auxiliary airflow lowers the droplet concentration inside this chamber ¹⁹.

4. Basic equipment and types of Nebulizer Devices^20,21.

A nebulizer system or nebulizer kit is used to perform nebulization. There are five primary parts of jet NBs, which are the most utilized type of NBs. A schematic representation of a Nebulizer device and its parts is shown in figure 2 below:

a) Compressor:
The compressor is the component of the nebulizer system that powers its operation. This apparatus is designed to firmly drive outside air via a nozzle fixed to tubing. The compressor has a power supply linked to it.

b) Tubing:
The tubing transfers pressurized air from the compressor to the medication cup, where the liquid medicine is transformed into vapor, aerosol, or mist.

c) Top of Form

d) Medication-cup:
The liquid medication is poured into this container. Through the tube, pressurized air supplied by the compressor transforms the liquid medication into an aerosol or mist in this cup.

e) Facemask/Mouthpiece:
The patient wears either a face mask or a mouthpiece, through which they inhale the medicine mist. When using a face mask, it's important to ensure a snug fit. For a mouthpiece, the patient should hold it securely between their teeth with their lips fully covering it.

f) Nebulizer-filter:
The nebulizer system's filters are a crucial component. NBs aid in the transformation of the liquid medication into an aerosolized form by compressing and pumping the surrounding air or oxygen. This air is filtered to help eliminate particulate matter from the compressed air before it reaches the medication cup. Regular checks and replacements of the filter are recommended.

Figure 2. Nebulizer device and its parts (Own creation inspired by Ibrahim and Bono et al.,)

Nebulizers (NBs) come in two primary varieties: jet and ultrasonic. Additional varieties are indicated in figure 3. While the ultrasonic nebulizer produces aerosolized drugs solutions using energy from high-frequency sound waves, the jet nebulizer employs compressed air. The majority of the droplets that are given to the patient by pneumatic NBs fall within the respirable size range of 1-5 mm due to baffles built into the construction of the device. Ultrasonic NBs employ electricity to create respirable droplets out of a liquid ¹⁶.

4.1 Pneumatic nebulizers:

Pneumatic NBs are the original and oldest in the market and have been used for aerosol generation with little or no change in design and performance over the last two to three decades. These NBs are most commonly used even in the present era for bronchodilator (BD) administration. Since bronchodilators are relatively low-cost, slight efforts are taken to advance the performance of these NBs. When administering BDs, patients typically favour low-cost nebulizers over high-performance ones ²². A compressed gas supply serves as the engine for liquid atomization in the operation of a pneumatic nebulizer. A zone of negative pressure is created when compressed gas is delivered by a jet. Entrained in the gas stream, the solution to be aerosolized is sheared into a liquid film. Surface tension causes this film to become unstable and split into droplets. By adding a baffle to the aerosol stream, bigger particles are forced back into the liquid reservoir, and smaller ones are produced ²³.

4.2 Breath-Enhanced nebulizers:

The patient's airflow is considered when developing a nebulizer in the traditional manner. Certain contemporary NBs employ the traditional crafty design with valves. Breathing through the nebulizer during inspiration is the only way to strengthen the nebulizer's output while using the open-vent form of the device. A one-way valve keeps the patient's discharge from entering the nebulizer chamber during the exhalation. Nebulizer production significantly improves with an increasing intake during inhalation, which is a potential benefit of the open-vent nebulizer type. Examples of breath-enhanced jet NBs are PARI LC Plus (PARI, Midlothian, VA), PARI LCD (PARI, Midlothian, VA), and Nebu Tech (Salter Labs, Arvin, CA) ²⁴.

4.3 Breath-Actuated nebulizers:

Aerosol waste throughout the exhalation can be eradicated if the nebulizer is simply active only throughout inhalation. Ways to manually actuate the nebulizer throughout the inhalation have been accessible for the last 25-30 years. It’s conjointly of interest to note that these design styles are usually employed in mechanical ventilator-actuated machines. Breath-actuated NBs that are electrically and pneumatically operated have just recently hit the market. Several clinical studies have also proven their role in clinical use. Breath-actuated Jet NBs are exemplified by Aero Eclipse (Monoghan/Trudell Medical International, London, Ontario, Canada). There is little medication loss to the environment from these NBs because they produce aerosol in response to the patient's inspiratory maneuver ²⁵.

4.4 Continuous nebulizers:

Since the early Nineties, there has been extensive clinical and educational interest shown in using continuous aerosolized BDs for the treatment of acute asthma attacks ²⁶. According to this research, this medical intervention is safer and only marginally more effective than intermittent nebulization; hence, it should be preferred in patients with the most severe respiratory issues ²⁷.

4.5 Nebulizers for Specific Applications:

When it is desired to prevent aerosolized medication contamination in a close environment, specially manufactured small-volume NBs should be utilized. Unidirectional valves and filters are installed on the nebulizer to prevent cross-contamination of the environment. These machines produce extremely small particle sizes, with MMADs of 1-2 mm. This is essential to improve the drug's alveolar deposition. A drying chamber and a nebulizer make up the apparatus. The MMAD of the particles is reduced to about 1.3 m in the drying chamber ²⁸.

4.6 Ultrasonic nebulizers:

Ultrasonic NBs have been clinically accessible since the Sixties. Small volume inaudible NBs are commercially accessible for delivery of inhaled BDs. However, many studies have reported a larger medicine response with ultrasonic NBs than with alternative aerosol generators. Ultrasonic NBs have conjointly been used throughout mechanical ventilation, wherever they need additives, wherein they do not augment tidal volume. This nebulizer produces particle sizes of approximately 1–6-mm MMAD ²⁹.

4.7 Mesh nebulizers:

Mesh inhalation therapy has become more popular due to recent advancements in nebulizer technologies, which use micro pump expertise to create aerosols. To obtain aerosol, they push liquid drugs through several holes in a very thin mesh or aperture plate. Mesh NBs have low residual volume, a mostly fine-particle fraction that reaches the peripheral respiratory organ, consistent and increased aerosol generation efficiency, and the capacity to nebulize at low drug quantities. Due to the higher effectiveness of mesh NBs, drug formulation dosages may need to be changed to prevent drug-related side effects. As a result, patients should be constantly monitored for side effects and clinical responses over the course of treatment ³⁰. Even though those NBs have many advantages, mesh NBs have several drawbacks. for instance, the administration of viscous medications and solutions that block mesh holes. Mesh network bars are divided into two groups: active mesh networks and passive mesh networks. When an electrical current is applied, a piezo component in active mesh NBs contracts and expands, vibrating to release aerosol when the drug comes into contact with it. The eFlow ® (PARI, Starnberg, Germany) and Aeroneb ® (Aerogen, Galway, Ireland) are examples of active mesh NBs, whereas the Micro air NE-U22 ® (Omron, pitched battle, IL) can be a passive mesh nebulizer ³¹. The 6000 tapered hole perforated plate in passive mesh NBs is filled with aerosol by means of an electrical device horn that creates passive vibrations. Micro air NE-U22 is embodied by passes through mesh NBs (Omron).

4.8 Smart nebulizers:

Smart NBs work on the principle of patient inhalation pattern and determine the flow rate accordingly. These NBs analyze the breathing pattern throughout the nebulization.

Figure 3. Different types of Nebulizers

5. Patient factors influencing Nebulizer Performance:

One limitation of NB inhalation therapy is the medicine's poor drug deposition efficiency in the targeted region. Just 10% of the dose that is delivered by the nebulizer will, on average, reach the site of action ³³. Effective use of NBs, however, requires a thorough understanding of their mechanism of action as well as the patient characteristics that affect how well they function. To prescribe the appropriate dose and comprehend the discrepancy between the intended nominal dose and the amount of it delivered to the lung, one must be familiar with the fundamentals of nebulization ³⁴. A basic factor to consider is the laboratory evaluation, which is mandatory before the combination can be used by the patient because if it does not consider it may lea dot lung deposition of the drug which will ultimately lead to adverse reactions. Since it typically requires a lot of time and effort to inhale the prescribed prescription on a regular basis, the low compliance is comprehensible ⁹. Another aspect of the daily routine is the maintenance of the nebulizer. The nebulizer must be cleaned and disinfected to avoid contamination and potential infections; however, the cleaning chemical may pose a risk to patient safety ³⁵. Moreover, the way in which you breathe through the nebulizer affects the amount that is really inhaled. It affects where deposition occurs. Nevertheless, the physiology of the lung and its clinical state, which establishes the inspiratory system's geometry, complicate the deposition in the lung. The patient should be encouraged to breathe deeply and slowly to enhance aerosol penetration and deposition in the lungs ³⁰. The most popular use of NBs is in the delivery of BDs, and it is widely known that nebulized BDs cause a physiological reaction. Given their low cost, BDs are not under much commercial pressure to enhance nebulizer performance. The market typically favours low-cost nebulizers over high-performance ones ³⁶.

Figure 4. Patient factors influencing Nebulizer performance

Airway caliber influences the lung delivery of nebulized BDs³⁷. Numerous research investigations have documented increased aerosol lung penetration in individuals with stable asthma and acute airway constriction during heliox breathing ³⁶. Apart from these, some other patient-related factors may also influence nebulizer performance, such as Treatment procedure, Availability of different NBs, Time burden, and Adherence. Figure 4 lists such factors and other artifacts that result in poor performance of nebulizer are described in the below section.

6. Other artifacts that result in poor performance of nebulizer:

Many factors affect the effectiveness of nebulizer therapy, including as the device's design and the properties of the medication solution. The nebulizer's efficacy may alter over time due to improper cleaning, maintenance, and disinfection practices ³⁸. The medication output rate and the aerosol droplet size distribution are the two primary characteristics that are typically utilized to assess the effectiveness of NBs. The nebulizer's design and operating environment dictate these characteristics. A crucial factor in the actual deposition in the lung is the droplet size distribution. When moderate flow rates of 60 l/min are used, the percentage of droplets with an aerodynamic diameter of 1 to 5 micrometers is preferred for central and deep lung penetration. The oropharynx and upper airways will be affected by bigger droplets, which will be mostly exhaled. However, smaller droplets will be mostly exhaled ³⁹.

Figure 5. Other artifacts that result in poor performance of nebulizer

Steckel H. and colleagues' work highlights the variations in droplet size throughout the course of the nebulization period when employing a Multisonic ultrasonic nebulizer and a Pari Boy air-jet. The results were associated with variations in the nebulizing solution's temperature, concentration, surface tension, viscosity, and saturated vapor pressure. The use of the jet nebulizer has resulted in an increase and then a decrease in droplet size. This observation might be explained by the temperature drop of about 7ºC in the jet nebulizer reservoir during the first two minutes, which raised the nebulizing solution's viscosity. Following this initial phase, the drug's increasing concentration caused the surface tension to decrease, which in turn caused the droplet size to shrink. On the other hand, an increase in temperature of around 20ºC was noted in the nebulizing solution during the first 6 minutes when using the ultrasonic nebulizer. This led to a decrease in droplet size, viscosity, and surface tension, as well as an increase in saturated vapor pressure. Once more, this resulted in lower average droplet sizes ⁴⁰. Another crucial element to consider when comparing NBs is the medication output rate. Nebulizers with a high output rate are the best choice for controlling the nebulization time when administering a high dose to the lungs. The aerosolized volume or aerosolized mass of pharmaceuticals can be used to characterize the output of NBs ⁴¹. The size of droplets is reduced by increased gas flow via the compressor in a jet nebulizer or increased piezoelectric crystal vibration frequency in an ultrasonic nebulizer. In addition to this, a few other variables that are indicated in Figure 5 may also affect nebulizer performance because of the possibility of NB mechanical properties changing while in use. It is not possible to find the NBs' average utilization time ²⁸.

7. Dealing with artifacts /Designs to Boost Nebulizer Performance:

Patient characteristics may have an impact on the generated aerosol's lung deposition. Because medication solutions for NBs cannot currently be provided effectively in a short amount of time, patient compliance with nebulizer therapy is quite low ⁴². Different methods can be used to create tiny drug particles for vibrating membrane nanoparticles (NBs), jet, or ultrasonic NBs. Certain more recent nebulization technologies have been developed for more portable applications. Modern NBs use a variety of basic droplet generation and breakup methods, which impact the device's functionality and usefulness for nebulizing different formulations ^43,44. Nebulizer performance is primarily determined by the respirable dose that the patient receives. Other significant factors are nebulization time, cost, convenience of use, and cleaning and sterilization needs. For patients to comply in an outpatient situation, nebulization time is crucial ⁴⁵. In recent years, many nebulizer scripts are available to minimize the nebulization time and quantity of aerosol lost throughout the exhalation. This led to the discovery of reservoir baggage to gather aerosol throughout the exhalation, the utilization of a ventilated style to extend the nebulizer output throughout the exhalation (breath-enhanced NBs), and NBs that solely generate aerosol throughout the inhalation only (breath-actuated NBs). As a result of these designing styles, there is an improvement in drug delivery to the patient, these new designs have the potential to minimize treatment time, which in turn improve patient compliance and safety with nebulizer medical care ⁴⁶.

Siavash M et al. have developed and tested the inaugural Iranian ultrasonic desktop nebulizer model. This desktop nebulizer includes a flow regulator, allowing patients to adjust the drug flow rate according to their needs. Operating at a frequency of 1.63 MHz, the piezoelectric component of the nebulizer produces particle sizes ranging from 0.5 to 6.0 μm, which are optimal for efficient absorption by the lungs. The nebulizer offers a minimum spraying rate of 0.4 ml/min and a maximum rate of 3.36 ml/min, while consuming 52 Watts of power. These specifications make it suitable for both home and hospital use ⁴⁷. The performance parameters of 12 commercially available NBs (6 ultrasonic and 6 jets) used in the treatment of cystic fibrosis (CF) were the subject of another study carried out by the AFLM. Tobramycin (T), colistin (C), and amiloride (A) medication solutions were used to evaluate the NBs, which were coupled to a circuit that mimicked the ventilation of a CF adult and child. Drug granulometry (G%), percentage of efficiently aerosolized drug (EA%), drug concentration modification in the nebulizer reservoir (ΔC), and volume of drug solution supplied in 10 minutes during the simulated inspiratory phase (VI) were used to evaluate nebulizer performance. The ultrasonic devices produced a substantially greater VI for each of the three research medications than the jet NBs (p < 0.0001). The ventilation rate had no effect on VI. In terms of granulometry, it was discovered that, after ultrasonic nebulization, larger proportions of T and A were contained in droplets with diameters ranging from 0.5 to 5.0 µm. Drug type had an impact on drug concentration alterations, which were unaffected by the nebulizer utilized. Over concentration of T and A were noted (ΔC = +10.5 ± 18.6 and +13.4 ± 8.9%, respectively). The ultrasonic devices had an EA% that was, on average, larger than the jet NBs (17.3 ± 6.7 and 9.7 ± 9.6%, respectively). It is important to precisely test NBs before clinical use to provide the most effective nebulizer/drug combinations, as this study demonstrated the large heterogeneity in performance across different types of nebulizers ⁴⁸. Therefore, the optimal approach or approaches to improve nebulizer performance may be revealed by a comparative evaluation, which is covered in the following section.

8. Comparative Evaluation:

Comparative evaluation of devices present form generations in the market is given in table 1 and mesh device accomplishments versus breath-enhanced jet device is given in table 2. This paper speaks of differences in mechanisms and principles of devices endorsed in the market and their influence on patient safety. All NBs presented below have different mechanisms different, nebulization time, different capacity, different residual volume, and diverse flow rates.

Table 1: Nebulizer Devices Comparative Evaluation ^7,49,50

Type	Jet Nebulizer		Ultrasonic nebulizer	Mesh Nebulizer			Smart NBs
Generation	1^st Generation NBs		2^nd Generation NBs				3^rd Generation NBs
Principle	Works on principle of generating negative pressure created by patients breathing effort	Sense patient’s inhalation flow and deliver aerosol only on inspiration	Piezoelectric crystal pulsating at high frequencies (1-3 MHz) so as to crop aerosol		Micropump technology utilizes a mechanism to propel liquid medications through numerous small openings in an ultra-thin mesh or aperture plate, resulting in the generation of aerosols.		Smart NBs employ adaptational aerosol delivery (AAD®) technology, that analyses the patient’s respiration pattern so as to see the temporal order of AAD throughout inhalation
					Active Mesh nebulizer	Passive mesh nebulizer/Vibrating mesh technology
					Employ a piezo element that swells and contracts when an electrical current is applied, vibrating a precisely drilled mesh that encounters the drug to produce aerosol.	Use a transducer horn that induces passive vibrations in the perforated plate with 6000 tapered holes to produce aerosol	Patients breathing pattern
	Breath enhanced e.g.Pari	Breath actuated
Examples	Pari LC plus , Nebutech	AeroEclipse	M neb (Nebutech)		Aeroneb ® (Aerogen, Galway, Ireland), eFlow ® (PARI, Starnberg, Germany),	Micro air NE-U22 ® (Omron, Bannockburn, IL)	I-neb (Philips Respironics, Newark, USA) ,AKITA (Activaero, Gemunden/Wohra, Germany).
Nebulizer Output	0.2-04 mL/minute		0.25-0.6 mL/minute		> 0.25 mL/minute		Depends on patient Inhalation pattern
Residual Volume	> 1.2 milliliter		Negligible		Negligible		Negligible
Nebulization time	5 to 15 minutes		1 to 8 minutes		1-to 10 minutes		Depends on patient Inhalation pattern
MMAD	4 to 6 microns

Table 2: Mesh Device Accomplishments Vs Breath-enhanced jet Device 7,25,53

Sr.no	Name	MMAD	Output rate mL/min	Res. Volin ml	Nebulizer type
1	Micro air NE-U22V	4-7 µ	0.2-0.3	0.3	Standard
2	Aeroneb Go	3-5 µ	0.3-0.5	0.3-0.9	Standard
3	Aeroneb Pro	3-5 µ	0.3-0.5	<0.3	Standard
4	eFlow rapid	3-5 µ	0.3-0.7	>1.2	Breath enhanced
5	Pari LC+	4-6 µ	0.2-0.3	>1.2	Breath enhanced

Table 3: Patents on NDD

Inventors	Patent number	Summary of the invention and Reference	Date of patent
James D. PipkinRupert O. ZimmererDiane O. ThompsonGerold L. Mosher	US20180154015A1	This patent describes an inhalable formulation containing SAE-CD and a corticosteroid, designed for administration to individuals via nebulization using any standard nebulizer. The formulation can be packaged as part of a kit and administered as an aqueous solution. Alternatively, it can be stored in various forms such as a dry powder, ready-to-use solution, or concentrated composition. The formulation is utilized in an improved nebulization system for delivering corticosteroids via inhalation. SAE-CD included in the formulation significantly enhances the chemical stability of budesonide. The patent also outlines a method for administering the formulation via inhalation, with the option of using conventional nasal delivery devices as well ⁵⁵.	2019-02-19
Louis Thomas Germinario John H. Hebrank Charles Eric Hunter Thomas P. Stern	US20190125985A1	A researcher received patent protection for a droplet delivery system, and associated techniques for giving a patient consistent, accurate dosage for pulmonary usage are revealed. The droplet delivery apparatus consists of a housing, an ejector mechanism, a reservoir, and one or more differential pressure sensors. When a preset pressure change within the housing is detected by the differential pressure sensor, the user can immediately activate the droplet delivery device. After that, the droplet delivery device is turned on to produce a stream of droplets that are expelled with an average diameter within the respirable size range, i.e., less than approximately 5 μm, to target the user's pulmonary system ⁵⁶.	2017-05-03
W. Robert Addington Stuart P. Miller Robert E. Stephens	US9452270B2	W. Robert's coworker was awarded a patent for a nozzle assembly concept in the field of nebulizers and nasal drug delivery. The idea involves forming a medication reservoir in the lower part of the nebulizer body and covering it to create an enclosed medication reservoir. A reservoir cover supports a nozzle assembly that consists of an airline with an inlet and an outlet on one end, as well as a venturi nozzle and venturi outlet. When the nebulizer is in operation, the venturi nozzle is situated inside the patient's oral cavity, and the airline, venturi nozzle, and discharge outlet are all horizontally aligned. Via a suction tube, medication is sucked upward, combined with air that travels via a venturi nozzle, and then nebulized before being released through the nebulizer outlet. The venturi nozzle and suction line are formed together and replaceable as one unit ⁵⁷.	2014-03-04
Per Gisle Djupesland	US20160045687A1	Per Gisle filled a patent for an apparatus or method for delivering a substance, such as one or more of a triptan, a topical steroid or carbon dioxide gas, to the nasal cavity of a subject, in particular for the treatment of headaches, for example, migraine, or rhinosinusitis, for example, chronic rhinosinusitis, optionally with polyps, the method comprising the steps of fitting a nosepiece to one nostril of the subject, delivering the substance through the nosepiece to the posterior region of the nasal cavity of the subject ⁵⁸.	2014-03-26
Per Gisle Djupesland Ramy A. Mahmoud John Messina	US20150144129A1	In order to treat headaches like migraines or rhinosinusitis like chronic rhinosinusitis, with or without polyps, a researcher developed a method of administering a substance, such as one or more triptans, nasal steroids, or carbon dioxide gas, to a subject's nasal cavity. The method involves fitting a nosepiece to one nostril of the subject and administering the substance through the nosepiece to the posterior region of the nasal cavity of the subject ⁵⁹.	2014-06-25
Felino V. Cortez, JR.William F. Niland Peter Boyd George Mc Garrity Carl Buyer	US8561607B2	The patent holder discovered systems and assemblies of nebulizers. A reservoir and a nebulizer are part of a nebulizer assembly, which creates an aerosolized gas. The aerosolized gas is passed through an aerosolized gas outlet. The nebulizer's outlet port is connected to a breathing gas mixing chamber, which entrains nebulized medication into a breathing gas. Additionally offered is a system and technique for heating medication in a reservoir and adding it to a gas flow⁶⁰.	2010-02-05
Randall S. Hickle	US8882703B2	A patent application was recently approved for a variety of techniques and tools that help with medical and/or surgical procedures carried out without the use of "general anesthesia," which is defined in the specification as the "unconscious" state that a patient experiences after taking medication from an anesthetist or anesthesiologist. Drug infusions that do not cause the patient to fall asleep or go into general anesthesia are administered and maintained by the devices in a safe and efficient manner. A patient health monitor that measures and transmits signals to a processor or other computational device about the patient's health condition is one example of a device that follows an embodiment of the invention ⁶¹.	2007-03-27
Andre Rustad David Rivera Charlie Atlas	US7267120B2	A patent was given to a researcher for his invention of an atomizing nebulizer that describes how to dispense a material or medication. The reservoir base of the nebulizer is releasably fastened to the effluent vent cap, which together enclose a diffuser and an integrated dispersion baffle. The nebulizer is further constructed with an uptake lumen or channel that ends in a nozzle jet. In order to enhance the dispersion of any one of these substances, the diffuser dispersing baffle is positioned in relation to the jet nozzle to optimum atomization of the material. Additionally, the reservoir base has a pressured fluid-accelerating input tube that, when received within the diffuser uptake lumen or channel, is ended with a metering orifice that works in conjunction with the nozzle jet. When this is the case, the nozzle jet axially registers both above and below the orifice to create a vacuum space that is in contact with a capillary interstice that is formed between the interior surface of the diffuser lumen or channel and the walls of the exterior of the inlet tube ⁶².	2007-09-11
Yehuda IvriCheng H. Wu	US8561604B2	The apparatus and methods for nebulizing liquids are the subject of the current invention. An apparatus including a thin shell member with a front surface, a rear surface, and many perforations extending between them is provided in one illustrative implementation. From the back surface to the front surface, the holes taper to become smaller. Additionally, a liquid supplier is offered, which supplies a pre-measured volume of liquid to the back surface. A vibrator vibrates the thin shell member's front surface to expel liquid droplets from the thin shell member⁶³.	2007-02-12
Yehuda IvriCheng H. Wu	US6640804B2	The innovation offers equipment and procedures for nebulizing liquids. An apparatus including a thin shell member with a front surface, a rear surface, and many perforations extending between them is provided in one illustrative implementation. From the back surface to the front surface, the holes taper to become smaller. Additionally, a liquid supplier is offered, which supplies a pre-measured volume of liquid to the back surface. A vibrator vibrates the thin shell member's front surface to expel liquid droplets from the thin shell member⁶⁴.	2003-11-04

10. CONCLUSION:

For many NBs, maintaining the operative medication level at the lung for an extended period of time is a necessary goal. However, due to patient variables and lung physiology, medications intended for nasal drug delivery have limited bioavailability, which makes it impossible to transfer the maximal amount of medication to the lung. Still a major developmental issue to be resolved, including stability, multiple dosing, and desired dose. 1st generation devices nebulizer devices that have been explained in this article have beaten a considerable lot of the impediments related to conventional jet and ultrasonic NBs, and they offer the adaptability to alter the aerosol attributes as per the clinical application for which they are utilized. With these devices' clinicians will have the option to control drug delivery to the respiratory tract. The nebulizer market in India is showing a growing trend year after year and will keep on developing in the future also. Recent advancements in device manufacturing will help patients as these devices use very low fill volume for nebulization, residual volume is also low and the flow rate is comparatively higher when contrasted with 1st generation devices. This overall is helping in the acceptability of such dosage form by patients which were considered a little difficult owing to the big size of the devices. Current devices on the market nebulize quickly and are small enough to fit in a pocket, which improves patient compliance. The review also comes to the conclusion that clinicians, pharmacists, nurses, and doctors have a responsibility to instruct patients on how to utilize specific nebulizers and devices. This review also concludes that there is a need for combi pack nebulizer dosage form which includes both nebulizer medication and device to properly deliver medicine in the required amount at the site of action.

11. DECLARATIONS:

· Copyright transfer form: Attached

· Certificate of Conflict of Interest: Attached

· Ethics approval and consent to participate: 'Not applicable'

· Consent for publication: 'Not applicable'.

12. ACKNOWLEDGEMENT:

I acknowledge thank to SSSM Arts, Science and Commerce College for providing facilities to write this paper.

13. REFERENCES:

1. Reychler G, Leal T, Roeseler J, Thys F, Delvau N, Liistro G. Effect of continuous positive airway pressure combined to nebulization on lung deposition measured by urinary excretion of amikacin. Respiratory Medicine. 2007; Oct 1; 101(10): 2051-5.

2. Respaud R, Vecellio L, Diot P, Heuzé-Vourc’h N. Nebulization as a delivery method for mAbs in respiratory diseases. Expert Opinion on Drug Delivery. 2015; 12(6): 1027-39.

3. Dolovich MB, Dhand R. Aerosol drug delivery: developments in device design and clinical use. The Lancet. 2011; 377(9770): 1032-45.

4. Courrier HM, Butz N, Vandamme TF. Pulmonary drug delivery systems: recent developments and prospects. Critical Reviews™ in Therapeutic Drug Carrier Systems. 2002;19(4-5).

5. Hapse SA, Tarkase KN, Jadhav AS, Dongare US. Study and evaluation of dry powder inhaler-a review. Research Journal of Pharmaceutical Dosage Forms and Technology. 2011; 3(3): 87-92.

6. Carvalho TC, McConville JT. The function and performance of aqueous aerosol devices for inhalation therapy. Journal of Pharmacy and Pharmacology. 2016; 68(5): 556-78.

7. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. British journal of clinical pharmacology. 2003; 56(6): 600-12.

8. Kaur R, Sharma JN. Deflection in Micro-Scale Thermoelastic simply-supported beams due to patch loading. Research Journal of Science and Technology. 2013; 5(1): 153-9.

9. Mukherjee B, Paul P, Dutta L, Chakraborty S, Dhara M, Mondal L, Sengupta S. Pulmonary Administration of Biodegradable Drug Nanocarriers for More Efficacious Treatment of Fungal Infections in Lungs: Insights Based on Recent Findings. InMultifunctional Systems for Combined Delivery, Biosensing and Diagnostics. 2017: 261-280.

10. Le Brun PP, De Boer AH, Frijlink HW, Heijerman HG. A review of the technical aspects of drug nebulization. Pharmacy World and Science. 2000; 22(3): 75-81.

11. Patton JS, Brain JD, Davies LA, Fiegel J, Gumbleton M, Kim KJ, Sakagami M, Vanbever R, Ehrhardt C. The particle has landed—characterizing the fate of inhaled pharmaceuticals. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2010; Dec 1; 23(S2): S-71.

12. Nadig S, Rajeshwari R. Effectiveness of structured teaching programme on knowledge and techniques regarding metered dose inhalers (MDI) among bronchial asthma patients in selected hospitals of Mangalore taluk. International Journal of Advances in Nursing Management. 2016; 4(3): 223-34.

13. More S, Mirza J, Kale N, Gandhi M, Chaudhari R. Formulation and Development of a “Pressurised Metered Dose Inhalation” beclomethasone 250 mcg. Research Journal of Pharmacy and Technology. 2014; 7(9): 963-7.

14. Maurya PR, Joshi YM, Kadam VJ. A Review on Bronchial asthma. Research Journal of Pharmacology and Pharmacodynamics. 2013; Nov 21; 5(4): 257-65.

15. Ehrmann S, Chastre J, Diot P, Lu Q. Nebulized antibiotics in mechanically ventilated patients: a challenge for translational research from technology to clinical care. Annals of Intensive Care. 2017; Dec 1; 7(1): 78.

16. Farncombe M, Chater S. Clinical application of nebulized opioids for treatment of dyspnoea in patients with malignant disease. Supportive Care in Cancer. 1994; 2(3): 184-7.

17. Sen A, Kumar K, Khan S, Pathak P, Singh A. Current therapy in cancer: advances, challenges, and future directions. Asian Journal of Nursing Education and Research. 2024; 14(1): 77-4.

18. Yeo LY, Friend JR, McIntosh MP, Meeusen EN, Morton DA. Ultrasonic nebulization platforms for pulmonary drug delivery. Expert opinion on drug delivery. 2010; 7(6): 663-79.

19. Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. International Journal of Pharmaceutics. 2010; 392(1-2): 1-9.

20. Ibrahim M, Verma R, Garcia-Contreras L. Inhalation drug delivery devices: technology update. Medical Devices (Auckland, NZ). 2015; 8: 131.

21. Bono M, Ruff G, inventors; Bono, Michael, Ruff, Gary, assignee. Nebulizer and inhalation device containing same. United States Patent US 5,630,409. 1997 May 20.

22. Clark AR. Medical aerosol inhalers: past, present, and future. Aerosol Science and Technology. 1995; 22(4): 374-91.

23. Dalby R, Suman J. Inhalation therapy: technological milestones in asthma treatment. Advanced Drug Delivery Reviews. 2003; 55(7): 779-91.

24. Rau JL, Ari A, Restrepo RD. Performance comparison of nebulizer designs: constant-output, breath-enhanced, and dosimetric. Respiratory care. 2004; Feb 1; 49(2): 174-9.

25. Verdun AM, Blacker R, inventors; 1263152 Ontario Inc, assignee. Breath actuated nebulizer with valve assembly having a relief piston. United States Patent US 6,044,841. 2000 Apr 4.

26. Ramya A, Geetha P, Nandhini M, Raja M. The role of leukotriene receptor antagonist as an add on therapy to β2-Agonists in acute asthma. Research Journal of Pharmacy and Technology. 2019; Aug 8; 12(4): 1974-8.

27. Jayeshkumar SM, Yashvi P, Bhimani B, Patel G, Patel J, Patel U. Nebulization therapy for lung cancer. Research Journal of Pharmacy and Technology. 2019; 12(2): 920-34.

28. Dhand R. Intelligent nebulizers in the age of the Internet: The I-neb Adaptive Aerosol Delivery (AAD) system.

29. Harvey CJ, O'Doherty MJ, Page CJ, Thomas SH, Nunan TO, Treacher DF. Comparison of jet and ultrasonic nebulizer pulmonary aerosol deposition during mechanical ventilation. European Respiratory Journal. 1997; 10(4): 905-9.

30. Pritchard JN, Hatley RH, Denyer J, Hollen DV. Mesh nebulizers have become the first choice for new nebulized pharmaceutical drug developments. Therapeutic Delivery. 2018; 9(2): 121-36.

31. Elphick M, von Hollen D, Pritchard JN, Nikander K, Hardaker LE, Hatley RH. Factors to consider when selecting a nebulizer for a new inhaled drug product development program. Expert Opinion on Drug Delivery. 2015; 12(8): 1375-87.

32. Chandel A, Goyal AK, Ghosh G, Rath G. Recent advances in aerosolised drug delivery. Biomedicine and Pharmacotherapy. 2019; Apr 1; 112: 108601.

33. Rau JL. The inhalation of drugs: advantages and problems. Respiratory care. 2005; Mar 1; 50(3): 367-82.

34. Fink JB, Rubin BK. Problems with inhaler use: a call for improved clinician and patient education. Respiratory Care. 2005; Oct 1; 50(10): 1360-75.

35. Branch PS. Best Practice Guidelines for the Cleaning, Disinfection and Sterilization of Medical Devices in Health Authorities.

36. Murthy GL, Machale MU, Balireddy N, Chandrika C. Outlines of aerosols in pharmaceutical technology. Asian Journal of Research in Pharmaceutical Science. 2019; 9(3): 215-25.

37. Lipworth BJ, Clark DJ. Effects of airway calibre on lung delivery of nebulised salbutamol. Thorax. 1997; Dec 1; 52(12): 1036-9.

38. Boe J, Dennis JH, O'driscoll BR, Bauer TT, Carone M, Dautzenberg B, Diot P, Heslop K, Lannefors L. European Respiratory Society Guidelines on the use of nebulizers: Guidelines prepared by a European Respiratory Society Task Force on the use of nebulizers. European Respiratory Journal. 2001; Jul 1; 18(1): 228-42.

39. Dailey LA, Schmehl T, Gessler T, Wittmar M, Grimminger F, Seeger W, Kissel T. Nebulization of biodegradable nanoparticles: impact of nebulizer technology and nanoparticle characteristics on aerosol features. Journal of Controlled Release. 2003; Jan 9; 86(1): 131-44.

40. Steckel H, Eskandar F. Factors affecting aerosol performance during nebulization with jet and ultrasonic nebulizers. European Journal of Pharmaceutical Sciences. 2003; Aug 1; 19(5): 443-55.

41. Berg E, Svensson JO, Asking L. Determination of nebulizer droplet size distribution: a method based on impactor refrigeration. Journal of Aerosol Medicine. 2007; Jun 1; 20(2): 97-104.

42. Laube BL, Benedict GW, Dobs AS. Time to peak insulin level, relative bioavailability, and effect of site of deposition of nebulized insulin in patients with noninsulin-dependent diabetes mellitus. Journal of Aerosol Medicine. 1998; 11(3): 153-73.

43. Knoch M, Finlay W. Nebulizer technologies. Drugs and The Pharmaceutical Sciences. 2003; 126: 849-56.

44. Martin AR, Finlay WH. nebulizers for drug delivery to the lungs. Expert Opinion on Drug Delivery. 2015; Jun 3; 12(6): 889-900.

45. Pleasants RA, Hess DR. Aerosol delivery devices for obstructive lung diseases. Respiratory Care. 2018; Jun 1; 63(6): 708-33.

46. Alshlowi MO. The Impact of Aerosol Devices and Delivery Interfaces on Aerosol Deposition in Children Receiving Noninvasive Ventilation.

47. Siavash M, Rahrovi A, Olamazadeh S, Esmaili M. Production and Clinical Application of the First Iranian Ultrasonic Desktop Nebulizer. Advanced Biomedical Research. 2018; 7(1): 114.

48. Faurisson F, Dessanges JF, Grimfeld A, Beaulieu R, Kitzis MD, Peytavin G, Lefebvre JP, Farinotti R, Sautegeau A. Nebulizer performance: AFLM study. Respiration. 1995; 62(Suppl. 1): 13-8.

49. Kacmarek RM, Stoller JK, Heuer A. Egan's Fundamentals of Respiratory Care E-Book. Elsevier Health Sciences; 2019; Dec 18.

50. Rau JL. Design principles of liquid nebulization devices currently in use. Respiratory Care. 2002; Nov; 47(11): 1257.

51. Mittal G, Kumar N, Rawat H, Chopra MK, Bhatnagar A. A radiometric study of factors affecting drug output of jet nebulizers. Indian Journal of Pharmaceutical Sciences. 2010; Jan; 72(1): 31.

52. Zanaty OM, El Metainy SA. A comparative evaluation of nebulized dexmedetomidine, nebulized ketamine, and their combination as premedication for outpatient pediatric dental surgery. Anesthesia and Analgesia. 2015; Jul 1; 121(1): 167-71.

53. Hickle RS, inventor; Scott Laboratories Inc, assignee. Apparatus and method for providing a conscious patient relief from pain and anxiety associated with medical or surgical procedures. United States patent US 6,745,764. 2004 Jun 8.

54. Sampoornam W. Research patent. Asian Journal of Nursing Education and Research. 2012; Apr 1; 2(2): 73.

55. Pipkin JD, Zimmerer RO, Thompson DO, Mosher GL, inventors; CydexInc, assignee. Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid. United States Patent US 10,207, 008. 2019 Feb 19.

56. Germinario LT, Hebrank JH, Hunter CE, Stern TP, inventors; Pneuma Respiratory Inc, assignee. Methods for treatment of pulmonary lung diseases with improved therapeutic efficacy and improved dose efficiency. United States Patent Application US 16/098,800. 2019 May 2.

57. Ballini F, inventor; MefarSpA, assignee. Micronized douche device for cleasing nasal and neighboring cavities. United States patent US 5,649,530. 1997 Jul 22.

58. Djupesland PG, inventor; OptiNose AS, assignee. Nasal administration. United States patent application US 14/780,277. 2016 Feb 18.

59. Djupesland PG, Mahmoud RA, Messina J, inventors; OptiNose AS, assignee. Nasal administration. United States Patent application US 14/315,132. 2015 May 28.

60. Cortez FV, Niland WF, Boyd P, McGarrity G, Buyer C, inventors; VapothermInc, assignee. Heated nebulizer devices, nebulizer systems, and methods for inhalation therapy. United States Patent US 8,561,607. 2013 Oct 22.

61. Hickle RS, inventor; Scott Laboratories Inc, assignee. Drug delivery in association with medical or surgical procedures. United States Patent US 8,882,703. 2014 Nov 11.

62. Emerson JH, inventor. Aspirator for administering medicine. United States patent US 2,535,844. 1950 Dec 26.

63. Bologna WJ, inventor; Columbia Laboratories Inc, assignee. Dispensing vial for feminine hygiene products. United States Patent Application US 29/019,916. 1996 Nov 5.

64. Ivri Y, Wu CH, inventors; AerogenInc, assignee. Liquid dispensing apparatus and methods. United States Patent US 6,640,804. 2003 Nov 4.

Received on 22.03.2024 Modified on 12.06.2024

Research J. Pharm. and Tech 2024; 17(11):5605-5615.

DOI: 10.52711/0974-360X.2024.00855