Portable Inhalation Research Articles

Simple, and highly efficient edge-effect surface acoustic wave atomizer

Conventional surface acoustic wave (SAW) atomizers require a direct water supply on the surface, which can be complex and cumbersome. This paper presents a novel SAW atomizer that uses lateral acoustic wetting to achieve atomization without a direct water supply. The device works by simply pressing a piece of wetted paper strip against the bottom of an excited piezoelectric transducer. The liquid then flows along the side to the unmodified surface edge, where it is atomized into a well-converging mist in a stable and sustainable manner. We identified this phenomenon as the edge effect, using numerical simulation results of surface displacement mode. The feasibility of the prototype design was demonstrated by observing and investigating the integrated process of liquid extraction, transport, and atomization. We further explored the hydrodynamic principles of the change and breakup in liquid film geometry under different input powers. Experiments demonstrate that our atomizer is capable of generating high-quality fine liquid particles stably and rapidly even at very high input power. Compared to conventional SAW atomizer, the dispersion of mist width can be scaled down by 70%, while the atomization rate can be increased by 37.5%. Combined with the advantages of easy installation and robustness, the edge effect-based atomizer offers an attractive alternative to current counterparts for applications requiring high efficiency and miniaturization, such as simultaneous synthesis and encapsulation of nanoparticles, pulmonary drug delivery and portable inhalation therapy.

Assessing the effectiveness of inhalation therapy in patients with chronic airway diseases: A new digital measurement

BackgroundThis study aimed to evaluate the effectiveness of inhalation therapy in patients with chronic airway diseases via the use of a new multiparametric inhalation assessment device. MethodsA multiparametric inhalation evaluation device (PF810, UBREATH, Zhejiang, China) that could simulate common inhalation devices with 6 different levels (0-V) of resistance was used in this study. The device was considered suitable if the three parameters of peak inspiratory flow rate (PIFR), effective inspiratory time (EIT), and breath-hold time (BHT) after inspiration met the minimum requirements. ResultsA total of 4,559 tests were performed. The qualification rates of 0-V resistance gear from low to high were 3.38 % (I), 8.42 % (0), 15.31 % (II), 16.71 % (III), 20.27 % (IV), and 46.91 % (V). The COPD patients in the 3 experimental groups had the lowest percentages of isolates classified as resistant 0, III, and V, which were 5.65 %, 11.93 %, and 40.43 %, respectively. The lowest percentage was 39.67 % (V) for insufficient EIT and 18.40 % (V) for BHT less than 5 s after inspiration. The results of 149 subjects who had used the inhalation device showed that the VIE and EIT at 0 levels were significantly greater than those before training (Z= -5.651, -5.646, P < 0.001). The VIE and EIT at I-III and V significantly increased after training (all P < 0.05). ConclusionsPatients using portable inhaler devices do not always inhale with adequate flow patterns. The multiparametric inhalation assessment device may be useful in outpatient settings.

Controlling therapeutic protein expression via inhalation of a butter flavor molecule.

Precise control of the delivery of therapeutic proteins is critical for gene- and cell-based therapies, and expression should only be switched on in the presence of a specific trigger signal of appropriate magnitude. Focusing on the advantages of delivering the trigger by inhalation, we have developed a mammalian synthetic gene switch that enables regulation of transgene expression by exposure to the semi-volatile small molecule acetoin, a widely used, FDA-approved food flavor additive. The gene switch capitalizes on the bacterial regulatory protein AcoR fused to a mammalian transactivation domain, which binds to promoter regions with specific DNA sequences in the presence of acetoin and dose-dependently activates expression of downstream transgenes. Wild-type mice implanted with alginate-encapsulated cells transgenic for the acetoin gene switch showed a dose-dependent increase in blood levels of reporter protein in response to either administration of acetoin solution via oral gavage or longer exposure to acetoin aerosol generated by a commercial portable inhaler. Intake of typical acetoin-containing foods, such as butter, lychees and cheese, did not activate transgene expression. As a proof of concept, we show that blood glucose levels were normalized by acetoin aerosol inhalation in type-I diabetic mice implanted with acetoin-responsive insulin-producing cells. Delivery of trigger molecules using portable inhalers may facilitate regular administration of therapeutic proteins via next-generation cell-based therapies to treat chronic diseases for which frequent dosing is required.

Self-sealing MEMS spray-nozzles to prevent bacterial contamination of portable inhalers for aqueous drug delivery

Pulmonary drug delivery by portable inhalers is the gold standard in lung disease therapy. An increasing focus on environmentally friendly inhalation currently spurs the development of propellant-free devices. However, the absence of propellants in the drug creates a need for suitable sealing systems that can ensure the pathogenic safety of devices. Traditionally, liquid drug inhalers incorporate a spray nozzle and a separate check valve. Here we show a fully integrated MEMS-based spray system for aqueous drug solutions and demonstrate its bacterial safety. The device comprises a thin silicon membrane with spray orifices, which self-seal against a compliant parylene valve seat underneath. This sealing system prevents bacterial ingrowth in its default closed state, while actuation lifts the membrane from the valve seat upon pressurization and sprays an inhalable aerosol from the nozzles. To seal against bacterial contamination effectively, we found that a contact force between the valve seat and the membrane (featuring the spray nozzles) is needed. In our testing, both self-sealing and an otherwise identical unvalved version of the spray chip can be bacterially safe in continued use when thoroughly cleaned of excess fluids and subjected to low bacterial loads for brief periods. However, when directly exposed to 10^{7} CFU/ml of our test organism Citrobacter rodentium for 24 h, unvalved systems become contaminated in nearly 90% of cases. In contrast, self-sealing spray chips reduced contamination probability by 70%. This development may enable preservative-free drug formulations in portable inhalers that use propellant-free aqueous drug solutions.

3D-Printing Enables Fabrication of Swirl Nozzles for Fast Aerosolization of Water-Based Drugs

Portable inhalers are used for delivering drugs to the lung in the form of aerosols and form the standard treatment for diseases such as Asthma, COPD, and cystic fibrosis. However, for aqueous drug formulations, spray nozzle chips have so far been restricted to cleanroom manufacture due to their small feature sizes. Here we present a spring-actuated 3D-printed swirl nozzle that sprays an aqueous drug solution, matching propellant-containing inhalers in aerosolization time. The use of two-photon polymerization enables the small nozzle feature size of 100 $\mu \text{m}$ and device print times of only 4 min, making serial mass-fabrication a viable option. Our 35 bar spring-operated swirl nozzle prototype achieves mean volumetric particle sizes of 12.5 ${\mu }\text{m}$ on doses of 100 ${\mu }\text{l}$ , aerosolized in 270 ms, as fast as a propellant-driven inhaler. [2021-0002]

Prospects for Inhalation Delivery of Medical Protectors against Radiation Damage

Abstract—The possibilities of improving medical protectors administered by inhalation for urgent assistance in emergency situations are discussed in this paper. The advantages of this method of administration are characterized, and the expediency of using portable dry powder inhalers as a technical means of drug delivery is substantiated. The sources containing information on the inhalation use of drugs from various pharmacological groups has been examined. Radioprotective agents (cystamine, indraline, naphthyzine), radioprotective agents for prophylactic use (estradiol), means of preventing and arresting the primary reaction to radiation (ondansetron, metoclopramide, metacin), radiomitigators (analogs of granulocyte colony stimulating factor (G-CSF), growth hormone, betaleukin), and incorporated binding agents radionuclides (pentacin) should be considered as the most promising medical preparations for inhalation under exposure to radiation factors. This is determined by the presence of effective inhalation forms approved for medical use and registered in the Russian Federation, as well as their technological feasibility.

A macrophage-targeted platform for extending drug dosing with polymer prodrugs for pulmonary infection prophylaxis

Pulmonary melioidosis is a bacterial disease with high morbidity and a mortality rate that can be as high as 40% in resource-poor regions of South Asia. This disease burden is linked to the pathogen's intrinsic antibiotic resistance and protected intracellular localization in alveolar macrophages. Current treatment regimens require several antibiotics with multi-month oral and intravenous administrations that are difficult to implement in under-resourced settings. Herein, we report that a macrophage-targeted polyciprofloxacin prodrug acts as a surprisingly effective pre-exposure prophylactic in highly lethal murine models of aerosolized human pulmonary melioidosis. A single dose of the polymeric prodrug maintained high lung drug levels and targeted an intracellular depot of ciprofloxacin to the alveolar macrophage compartment that was sustained over a period of 7 days above minimal inhibitory concentrations. This intracellular pharmacokinetic profile provided complete pre-exposure protection in a BSL-3 model with an aerosolized clinical isolate of Burkholderia pseudomallei from Thailand. This total protection was achieved despite the bacteria's relative resistance to ciprofloxacin and where an equivalent dose of pulmonary-administered ciprofloxacin was ineffective. For the first time, we demonstrate that targeting the intracellular macrophage compartment with extended antibiotic dosing can achieve pre-exposure prophylaxis in a model of pulmonary melioidosis. This fully synthetic and modular therapeutic platform could be an important therapeutic approach with new or re-purposed antibiotics for melioidosis prevention and treatment, especially as portable inhalation devices in high-risk, resource-poor settings.

A Self-Sealing Spray Nozzle for Aerosol Drug Delivery

Chronic lung disease is commonly treated using portable inhaler systems. By design, these inhalers come into repeated contact with the mouth region of patients and are therefore subject to bacterial contamination and ingrowth. To enable the safe delivery of an aerosol from a drug reservoir of such an inhaler, the reservoir needs to be protected from pathogens. Here we demonstrate a self-sealing aerosol spray nozzle, a system that seals each spray orifice on nozzle level in its default closed state and sprays a liquid Rayleigh-jet upon actuation. The sealing mechanism is realized by placing a thin membrane with spray orifices on top of a valve seat. The membrane behavior and spray performance of the self-sealing spray chip were found to be identical to an equivalent non-sealing design. This sealing system may enable the safe reuse of spray chips for multiple spray operations over an extended period, lowering the cost of treatment while increasing patient compliance. [2019-0252]

Prospects for the development of technical devices and dosage forms for the use of medical protection.

The article assesses the current level of technical devices and dosage forms intended for the use of medical protective equipment, discusses global trends and prospects for their short-term and medium-term development. Considered foreign samples autoinjectors, portable inhalers, patch pump, nasal, transdermal and buccal forms. Presents indicators of the effectiveness of various dosage forms, their advantages and disadvantages, discusses ways to overcome the latter in the provision of medical care in the prehospital stages and in transporting the wounded and affected. When assessing the possibility of using medical protection in various technical devices or dosage forms, it is necessary to consider the characteristics of their manufacturability and the readiness of the domestic production base for mass production and state registration as medicines or medical products. It was concluded that in the short term for the development of domestic medical remedies it is advisable to introduce inhaled and intranasal forms of drugs for use in the prehospital medical care.

The use of Penthrox (methoxyflurane) in trauma patients

Penthrox (methoxyflurane) is an inhaled analgesic. It is a non-invasive, lightweight, portable handheld inhaler indicated for the emergency relief of moderate-to-severe pain in conscious adult patients with trauma. It is becoming very popular in the pre-hospital setting and in the emergency department and has been proven to reduce acute pain within 6–10 inhalations. One 3 ml bottle will provide effective analgesic relief for up to 30 minutes (continuous use) or 1 hour (intermittent use). With very few drug interactions and a short half-life, it is the ideal analgesic for conscious patients. However, it is not recommended to use regularly and should not replace a good analgesic approach.

Aerosol Deposition Characteristics During Exhalation Through Nose Treatment: Relationship between Impaction Parameter and Deposition Ratio

Aerosol medicine exhalation through the nose treatment (ETN) has conducted as an effective treatment for Eosinophilic Chronic Rhinosinusitis (ECRS). In ETN, the patient inhales aerosol of inhaled corticosteroid (ICS) medicine from mouth using portable inhaler. Then a part of the aerosol still floas and remains in upper airway. When the patient exhales inhaled air through the nose, the aerosol is effectively transported on the walls of middle meatus and olfactory fissure. The mechanism of how ETN improves ECRS with asthma is still controversial even though ETN gets a lot of attention as a treatment method for ECRS with asthma. In this study, computational fluid dynamics (CFD) analysis of aerosol transport phenomena were performed based on patient CT data in order to evaluate the therapeutic effect of ETN numerically. Three cases were selected in this study, one is a patient who had ECRS with asthma and a history of endoscopic sinus surgery and the others are healthy cases. 3D anatomically accurate patient-specific models were reconstructed from the data obtained using multidetector CT scanner with medical imaging software package. The entire series was loaded into the software, and then the nasal-pharynx airway was identified in each of the axial images based on predefined threshold of - 300 Housfield units relative to the surrounding tissue. The nasal-pharynx airway models were exported into a CFD meshing software package to generate discrete volume cells. This study used both a Euler-Lagrange particle transport model for aerosol transport and a model for complex intranasal turbulent flow. This study analyzed both inhaled state and exhaled state, and compared the aerosol deposition characteristics under conditions by changing the particle diameter and flow rate of aerosol. As a result of CFD analysis, amount of aerosol deposition depended on particle diameter and flow rate, and tendency of aerosol deposition was consistent in all cases analyzed in this study. Furthermore, in the inhaled state, aerosol mainly deposited in nasal meatus areas where not contribute to treatment of ECRS. Exhaled state was more effective treatment for ECRS compared to the inhaled state. The results show advantages of ETN as well as CFD analysis will contribute further development of ENT.

Spray-Dried PulmoSphere™ Formulations for Inhalation Comprising Crystalline Drug Particles.

Over the past 20years, solution-based spray dried powders have transformed inhaled product development, enabling aerosol delivery of a wider variety of molecules as dry powders. These include inhaled proteins for systemic action (e.g., Exubera®) and high-dose inhaled antibiotics (e.g., TOBI® Podhaler™). Although engineered particles provide several key advantages over traditional powder processing technologies (e.g., spheronized particles and lactose blends), the physicochemical stability of the amorphous drug present in these formulations brings along its own unique set of constraints. To this end, a number of approaches have been developed to maintain the crystallinity of drugs throughout the spray drying process. One approach is to spray dry suspensions of micronized drug(s) from a liquid feed. In this method, minimization of drug particle dissolution in the liquid feed is critical, as dissolved drug is converted into amorphous domains in the spray-dried drug product. The review explores multiple formulation and engineering strategies for decreasing drug dissolution independent of the physicochemical properties of the drug(s). Strategies to minimize particle dissolution include spray blending of particles of different compositions, formation of respirable agglomerates of micronized drug with small porous carrier particles, and use of common ions. The formulations extend the range of doses that can be delivered with a portable inhaler from about 100ng to 100mg. The spray-dried particles exhibit significant advantages in terms of lung targeting and dose consistency relative to conventional lactose blends, while still maintaining the crystallinity of drug(s) in the formulated drug product.

TPP-dendrimer nanocarriers for siRNA delivery to the pulmonary epithelium and their dry powder and metered-dose inhaler formulations

The regulation of genes utilizing the RNA interference (RNAi) mechanism via the delivery of synthetic siRNA has great potential in the treatment of a variety of lung diseases. However, the delivery of siRNA to the lungs is challenging due to the poor bioavailability of siRNA when delivered intraveneously, and difficulty in formulating and maintaining the activity of free siRNA when delivered directly to the lungs using inhalation devices. The use of non-viral vectors such as cationic dendrimers can help enhance the stability of siRNA and its delivery to the cell cytosol. Therefore, in this work, we investigate the ability of a triphenylphosphonium (TPP) modified generation 4 poly(amidoamine) (PAMAM) dendrimer (G4NH2-TPP) to enhance the in vitro transfection efficiency of siRNA in a model of the pulmonary epithelium and their aerosol formulations in pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). Complexes of siRNA and G4NH2-TPP were prepared with varying TPP densities and increasing N/P ratios. The complexation efficiency was modulated by the presence of the TPP on the dendrimer surface, allowing for a looser complexation compared to unmodified dendrimer as determined by gel electrophoresis and polyanion competition assay. An increase in TPP density and N/P ratio led to an increase in the in vitro gene knockdown of stably green fluorescent protein (eGFP) expressing lung alveolar epithelial (A549) cells. G4NH2-12TPP dendriplexes (G4NH2 PAMAM dendrimers containing 12 TPP molecules on the surface complexed with siRNA) at N/P ratio 30 showed the highest in vitro gene knockdown efficiency. To assess the potential of TPP-dendriplexes for pulmonary use, we also developed micron particle technologies for both pMDIs and DPIs and determined their aerosol characteristics utilizing an Andersen Cascade Impactor (ACI). Mannitol microparticles encapsulating 12TPP-dendriplexes were shown to be effective in producing aerosols suitable for deep lung deposition for both pMDI formulations (fine particle fraction of 50–53%) and DPI formulations (fine particle fraction of 39%) with no impact on the in vitro gene knockdown efficiency of the siRNA. This work demonstrates the potential benefits of utilizing TPP-conjugated dendrimers in the formation of dendriplexes for siRNA delivery to the pulmonary epithelium and their aerosol formulation for local delivery to the lungs using portable inhalers.

Nebulized drug delivery in respiratory medicine: what does the future hold?

In the later half of the 20th century, nebulized therapy was in decline, but in the 21st century the prospects for the expanded use of nebulized therapy within respiratory medicine look bright. The advent of mesh nebulizers, which combine the universal applicability of the nebulizer in the treatment of all respiratory patients with the convenience of portable inhaler use, is ideally timed to capitalize on the forecast of increased numbers of patients who will require nebulized therapy in the future. This special report will highlight some of the opportunities that the development of mesh nebulizers presents in the field of respiratory medicine.

Guiding Inspiratory Flow: Development of the In-Check DIAL G16, a Tool for Improving Inhaler Technique.

Portable inhalers are divisible into those that deliver medication by patient triggering (pMDIs: a gentle slow inhalation) and those that use the patient's inspiratory effort as the force for deaggregation and delivery (DPIs: a stronger deeper inspiratory effort). Patient confusion and poor technique are commonplace. The use of training tools has become standard practice, and unique amongst these is an inspiratory flow meter (In-Check) which is able to simulate the resistance characteristics of different inhalers and, thereby, guide the patient to the correct effort. In-Check's origins lie in the 1960s peak expiratory flow meters, the development of the Mini-Wright peak flow meter, and inspiratory flow assessment via the nose during the 1970s–1980s. The current device (In-Check DIAL G16) is the third iteration of the original 1998 training tool, with detailed and ongoing assessments of all common inhaler resistances (including combination and breath-actuated inhaler types) summarised into resistance ranges that are preset within the device. The device works by interpolating one of six ranges with the inspiratory effort. Use of the tool has been shown to be contributory to significant improvements in asthma care and control, and it is being advocated for assessment and training in irreversible lung disease.

Inhaler Characteristics in Asthma

The history of inhaled therapy goes back a surprisingly long way. More than 4,000 years ago, in India, the vapour of plants from the nightshade family placed on hot bricks was inhaled to alleviate breathing difficulties. The bronchodilators, derived from these plants, and compounds related to them, have played a significant part in therapeutic aerosol delivery over the years and remain important in the treatment of lung diseases today. The development of inhaled therapy has accelerated over the past 60 years with the arrival of the first truly portable inhaler in 1956 to relieve the symptoms of asthma. Initially, only bronchodilators were delivered from these devices, but as the true nature of asthma was revealed, inhaled corticosteroids were introduced to treat the underlying inflammation that is a major component of asthma. Further advances have led to long-acting bronchodilators becoming available, and combination therapies containing both longacting bronchodilators and corticosteroids in one inhaler. Asthma therapy has come a long way in a comparatively short time with over 230 device and drug combinations available for treating the disease. However, despite enormous investment asthma remains a huge healthcare problem. The number of people with asthma continues to grow with over 300 million people affected worldwide and 250,000 annual deaths attributed to the disease. It affects people of all ages and has a varying degree of severity. In this article, we look at the ideal characteristics for asthma inhalers and highlight some of the most important reasons for the failure of current asthma treatments.

Producing nitric oxide by pulsed electrical discharge in air for portable inhalation therapy.

Inhalation of nitric oxide (NO) produces selective pulmonary vasodilation and is an effective therapy for treating pulmonary hypertension in adults and children. In the United States, the average cost of 5 days of inhaled NO for persistent pulmonary hypertension of the newborn is about $14,000. NO therapy involves gas cylinders and distribution, a complex delivery device, gas monitoring and calibration equipment, and a trained respiratory therapy staff. The objective of this study was to develop a lightweight, portable device to serve as a simple and economical method of producing pure NO from air for bedside or portable use. Two NO generators were designed and tested: an offline NO generator and an inline NO generator placed directly within the inspiratory line. Both generators use pulsed electrical discharges to produce therapeutic range NO (5 to 80 parts per million) at gas flow rates of 0.5 to 5 liters/min. NO was produced from air, as well as gas mixtures containing up to 90% O2 and 10% N2. Potentially toxic gases produced in the plasma, including nitrogen dioxide (NO2) and ozone (O3), were removed using a calcium hydroxide scavenger. An iridium spark electrode produced the lowest ratio of NO2/NO. In lambs with acute pulmonary hypertension, breathing electrically generated NO produced pulmonary vasodilation and reduced pulmonary arterial pressure and pulmonary vascular resistance index. In conclusion, electrical plasma NO generation produces therapeutic levels of NO from air. After scavenging to remove NO2 and O3 and filtration to remove particles, electrically produced NO can provide safe and effective treatment of pulmonary hypertension.

Poly(amidoamine) dendrimer nanocarriers and their aerosol formulations for siRNA delivery to the lung epithelium.

Small interfering RNA (siRNA)-based therapies have great promise in the treatment of a number of prevalent pulmonary disorders including lung cancer, asthma and cystic fibrosis. However, progress in this area has been hindered due to the lack of carriers that can efficiently deliver siRNA to lung epithelial cells, and also due to challenges in developing oral inhalation (OI) formulations for the regional administration of siRNA and their carriers to the lungs. In this work we report the ability of generation four, amine-terminated poly(amidoamine) (PAMAM) dendrimer (G4NH2)–siRNA complexes (dendriplexes) to silence the enhanced green fluorescent protein (eGFP) gene on A549 lung alveolar epithelial cells stably expressing eGFP. We also report the formulation of the dendriplexes and their aerosol characteristics in propellant-based portable OI devices. The size and gene silencing ability of the dendriplexes was seen not to be a strong function of the N/P ratio. Silencing efficiencies of up to 40% are reported. Stable dispersions of the dendriplexes encapsulated in mannitol and also in a biodegradable and water-soluble co-oligomer were prepared in hydrofluoroalkane (HFA)-based pressurized metered-dose inhalers (pMDIs). Their aerosol characteristics were very favorable, and conducive to deep lung deposition, with respirable fractions of up to 77%. Importantly, siRNA formulated as dendriplexes in pMDIs was shown to keep its integrity after the particle preparation processes, and also after long-term exposures to HFA. The relevance of this study stems from the fact that this is the first work to report the formulation of inhalable siRNA with aerosol properties suitable to deep lung deposition using pMDIs devices that are the least expensive and most widely used portable inhalers. This study is relevant because, also for the first time, it shows that siRNA–G4NH2 dendriplexes can efficiently target lung alveolar epithelial A549 cells and silence genes even after siRNA has been exposed to the propellant environment.

The PulmoSphere™ Platform for Pulmonary Drug Delivery

Spray-dried PulmoSphere™ formulations comprise phospholipid-based small, porous particles. Drug(s) may be incorporated in or with PulmoSphere formulations in three formats: solution-, suspension-, and carrier-based systems. The multiple formats may be administered to the respiratory tract with multiple delivery systems, including portable inhalers (pressurized, metered-dose inhaler and dry-powder inhaler), nebulizers, and via liquid dose instillation in conjunction with partial liquid ventilation. The PulmoSphere platform (particles, formats, delivery systems) enables pulmonary delivery of a broad range of drugs independent of their physicochemical properties and lung dose. The engineered particles provide significant improvements in lung targeting and dose consistency, relative to current marketed inhalers.

The Emperor's New Clothes II—time for regulators to wake up and take responsibility for unnecessary asthma morbidity: time for the second aerosol ‘transition’

The rate of technological improvement continues to accelerate. Regulators in every field dealing with consumer products continue to set ever higher standards to protect consumers from adverse events and use...