Fabrication and evaluation of stable amorphous polymer-drug composite particles via a nozzle-free ultrasonic nebulizer.

We present a promising method for producing amorphous drug particles using a nozzle-free ultrasonic nebulizer with polymers, specifically polyvinylpyrrolidone (PVP), poly(acrylic acid) (PAA), and Eudragit® S 100 (EUD). Model crystalline phase drugs-Empagliflozin, Furosemide, and Ilaprazole-are selected. This technique efficiently produces spherical polymer-drug composite particles and demonstrates enhanced stability against humidity and thermal conditions, compared to the drug-only amorphous particles. The composite particles exhibit improved water dissolution compared to the original crystalline drugs, indicating potential bioavailability enhancements. While there are challenges, including the need for continuous water supply for ultrasonic component cooling, dependency on the solubility of polymers and drugs in volatile organic solvents, and mildly elevated temperatures for solvent evaporation, our method offers significant advantages over traditional approaches. It provides a straightforward, flexible process adaptable to various drug-polymer combinations and consistently yields spherical amorphous solid dispersion (ASD) particles with a narrow size distribution. These attributes make our method a valuable advancement in pharmaceutical drug formulation and delivery.

A surfactant-free approach: Novel one-step ultrasonic nebulizer spray method to generate amphiphilic Janus particles.

HYPOTHESIS: A solvent evaporation-induced phase separation method, which is based on the preferential partitioning of two or more immiscible materials after solvent evaporation on providing heat, has been one of the main strategies for synthesis of Janus particles (JPs). Considering this approach, it should be possible to synthesize surfactant free-JPs in continuous flow by the ultrasonic nebulizer spray method. EXPERIMENTS: Two polymers, polystyrene and polymethylmethacrylate, were dissolved in dichloromethane, and droplets of a precursor solution generated by an ultrasonic nebulizer were then conveyed through a borosilicate glass cylinder with two heating zones. The solvent evaporation-induced phase separation occurred in a single flow process, which resulted in the preferential partitioning of two incompatible polymers in the droplets, leading to the formation of the spherical bicompartmental JPs. FINDINGS: The successful fabrication of spherical JPs was observed at high polymer concentrations (1.5 and 2.0 wt%), and at elevated temperature (40-75 °C). The fluorescent compartmentalization of JPs was confirmed. Furthermore, the interfacial arrangement of JPs at oil-water interface was studied. A detailed explanation of theoretical prediction of interfacial configurations of JPs was provided. Lastly, the generated JPs were proved as Pickering stabilizers at the oil-water interface.

Development and technical validation of an ultrasound nebulizer to deliver intraperitoneal pressurized aerosols in a rat colon cancer peritoneal metastases model.

BACKGROUND/AIM: To develop and validate a nebulizer device for anti-cancer research on pressurized intraperitoneal aerosol supply in a preclinical peritoneal metastases (PM) rat model. MATERIAL AND METHODS: For aerosol generation, an ultrasonic nebulizer (USN) was modified. Aerosol analyses were performed ex-vivo by laser diffraction spectrometry (LDS). Intraperitoneal (IP) 99mtechnetium sodium pertechnetate (99mTc) aerosol distribution and deposition were quantified by in-vivo single photon emission computed tomography (SPECT/CT) and compared to liquid IP instillation of equivalent volume/doses of 99mTc with and without capnoperitoneum. PM was induced by IP injection of HCT116-Luc2 human colon cancer cells in immunosuppressed RNU rats. Tumor growth was monitored by bioluminescence imaging (BLI), 18F-FDG positron emission tomography (PET) and tissues examination at necropsy. RESULTS: The USN was able to establish a stable and reproducible capnoperitoneum at a pressure of 8 to 10 mmHg. LDS showed that the USN provides a polydisperse and monomodal aerosol with a volume-weighted diameter of 2.6 µm. At a CO2 flow rate of 2 L/min with an IP residence time of 3.9 s, the highest drug deposition efficiency was found to be 15 wt.-%. In comparison to liquid instillation, nebulization showed the most homogeneous IP spatial drug deposition. Compared to BLI, 18F-FDG-PET was more sensitive to detect smaller PM nodules measuring only 1-2 mm in diameter. BLI, 18F-FDG PET and necropsy analyses showed relevant PM in all animals. CONCLUSIONS: The USN together with the PM rat model are suitable for robust and species-specific preclinical pharmacological studies regarding intraperitoneal delivery of pressurized aerosolized drugs and cancer research.

Ketamine Inhalation Alters Behavior and Lower Urinary Tract Function in Mice.

We aimed to evaluate behavioral and lower urinary tract changes in mice using a novel ketamine inhalation model mimicking human ketamine abusers and compare the results to those obtained using a ketamine intraperitoneal injection model. C57BL/6N mice were placed in a transparent acrylic observation cage connected to an ultrasonic nebulizer producing ketamine (KI) or saline (SI) fog. The mice were given KI or SI fog twice a week for three months. In another experiment arm, the mice were given intraperitoneal ketamine injections (KP) or saline injections (SP) twice a week for three months. The presence of urine ketamine (>100 ng/mL) was determined using a quick test kit. Locomotor activity was recorded by video using the open field test. Lower urinary tract function was assessed using urine spots, cystometry and histology. KI and KP mice crossed the center more frequently and traveled farther than SI and SP mice. Only KI mice, however, demonstrated popcorn-like jumping, and frequent center crossing. Detrusor overactivity, reduced cystometric bladder capacity, and denuded mucosa were observed in both KI and KP mice. Ketamine inhalation induces behavioral and lower urinary tract changes in mice that are comparable to intraperitoneal ketamine injections.

Anaesthesia for Awake Fiberoptic Intubation: Ultrasound-Guided Airway Nerve Block versus Ultrasonic Nebulisation with Lignocaine.

BACKGROUND: In anticipated difficult airway, awake fiberoptic guided intubation should be the ideal plan of management. It requires sufficient upper airway anesthesia for patient's comfort and cooperation. We compared the efficacy of ultrasound guided airway nerve blocks and ultrasonic nebulisation with lignocaine for airway anesthesia before performing awake fibreoptic guided intubation. METHODS: This prospective, randomised study included sixty consenting adult patients of both genders (American Society of Anesthesiologists' physical status 1-3) with anticipated difficult airway undergoing surgery. Ultrasound guided airway nerve blocks group received ultrasound-guided bilateral superior laryngeal (1 ml of 2% lignocaine) and transtracheal recurrent laryngeal (2 ml of 2% lignocaine) airway nerve blocks and ultrasonic nebulisation with lignocaine group received ultrasonic nebulisation of 4 ml of lignocaine 4%. The primary outcome was to compare the time required to intubate, whereas the secondary outcomes were to compare cough reflex and gag reflex, hemodynamic changes, number of attempts required, and  comfort score during awake fibreoptic guided intubation in both the groups. RESULTS: The time taken for intubation was significantly lower in the ultrasound guided airway nerve blocks group 69.27±21.85 s than ultrasonic nebulisation with lignocaine group 92.43 ± 42.90 s (p = 0.015). Hemodynamic variables changed during the procedure but the values were comparable in both groups. There were no statistical differences in cough and gag reflexes, number of attempts, and comfort score in both groups. CONCLUSIONS: This study shows that significant lesser time required for performing awake fiberoptic intubation when patient received ultrasound guided airway nerve block in comparison to ultrasonic nebulisation for airway anaesthesia.

Design of an ultrasonic piezoelectric injection port for analysis of thermally unstable compounds using corona discharge ion mobility spectrometry.

This paper reports on a novel ultrasonic injection port designed and constructed to analyze thermally unstable chemical compounds using corona discharge ion mobility spectrometry (CD-IMS). In order to achieve the highest possible efficiency with the device, some parameters such as the solvent type, carrier gas flow rate and sample volume were exhaustively investigated. Through a comparative study conducted, it was revealed that unlike the thermal desorption system, the proposed ultrasonic injection port could easily be used for the analysis of some thermally unstable compounds such as carbaryl, propoxur and vitamin B1, by means of CD-IMS. To evaluate the potential of the device, carbaryl, extracted from different samples by dispersive liquid-liquid microextraction technique, was quantitatively analyzed. The CD-IMS-based results brought forth the detection limit of 0.03 mg L-1, and dynamic range of 0.1-10.0 mg L-1 with the determination coefficient of 0.9981. The relative standard deviations for one day and three consecutive days were 4 and 6%, respectively. Further, the spiked samples of agricultural wastewater, underground water, and tomato analyzed culminated in the recovery values of 83%, 98% and 82%, respectively. The satisfactory results proved an acceptable capability of the sample introduction system, to be conveniently used for routine analysis of thermally unstable compound, without any tedious derivatization.

Cell distribution and cytokine levels in induced sputum from healthy subjects and patients with asthma after using different nebulizer techniques.

BACKGROUND: Sputum induction is an important noninvasive method for analyzing bronchial inflammation in patients with asthma and other respiratory diseases. Most frequently, ultrasonic nebulizers are used for sputum induction, but breath-controlled nebulizers may target the small airways more efficiently. This treatment may produce a cell distribution similar to bronchoalveolar lavage (less neutrophils and more macrophages) and provide deeper insights into the underlying lung pathology. The goal of the study was to compare both types of nebulizer devices and their efficacy in inducing sputum to measure bronchial inflammation, i.e., cell composition and cytokines, in patients with mild allergic asthma and healthy controls. METHODS: The population of this study consisted of 20 healthy control subjects with a median age of 17 years, range: 8-25 years, and 20 patients with a median age of 12 years, range: 8-24 years, presenting with mild, controlled allergic asthma who were not administered an inhaled steroid treatment. We induced sputum in every individual using both devices on two separate days. The sputum weight, the cell composition and cytokine levels were analyzed using a cytometric bead assay (CBA) and by real-time quantitative PCR (qRT-PCR). RESULTS: We did not observe significant differences in the weight, cell distribution or cytokine levels in the sputum samples induced by both devices. In addition, the Bland-Altman correlation revealed good concordance of the cell distribution. As expected, eosinophils and IL-5 levels were significantly elevated in patients with asthma. CONCLUSIONS: The hypothesis that sputum induction with a breath-controlled "smart" nebulizer is more efficient and different from an ultrasonic nebulizer was not confirmed. The Bland-Altman correlations showed good concordance when comparing the two devices. TRIAL REGISTRATION: NCT01543516 Retrospective registration date: March 5, 2012.

Aerosolization of Zn-DTPA Decorporation Agent Using Jet and Ultrasonic Nebulizers.

BACKGROUND: Chelating agents such as diethylenetriamine pentaacetic acid (DTPA) can be used as a decorporation drug in the zinc (Zn) form to treat internal radioactive contamination after exposure to plutonium or americium in a nuclear accident. Although Zn-DTPA is normally administered intravenously, inhalation of Zn-DTPA in aerosol form is a better route for direct delivery to the lungs. This work investigates the feasibility of synthesizing Zn-DTPA from three common chemicals and aerosolizing it using a jet or ultrasonic nebulizer. METHODS: The particle size distribution (PSD) of this decorporation agent at different concentrations were tested in vitro using two different methods: inertial impaction and aerodynamic time of flight. The particles were generated using either a jet nebulizer or an ultrasonic nebulizer. Two parameters, namely the mass median aerodynamic diameter and the geometric standard deviation, were assessed to determine the PSD of the generated aerosols. These parameters were obtained for different concentrations of Zn-DTPA using both nebulizers. RESULTS AND CONCLUSIONS: Zn-DTPA was successfully synthesized for decorporation purposes. Aerosol particles within the inhalable range were successfully generated by both nebulizers from four different concentrations of Zn-DTPA. It was found that the medication concentration did not affect the PSD of Zn-DTPA. The ultrasonic nebulizer was observed to produce a slightly larger aerosol particle size and required slightly longer treatment periods to deliver an effective dose to the lungs when compared with the jet nebulizer. Both nebulizers can be sustainably run to administer the agent for effective decorporation treatment of a large population after any major nuclear accident.

Faraday Waves-Based Integrated Ultrasonic Micro-Droplet Generator and Applications.

An in-depth review on a new ultrasonic micro-droplet generator which utilizes megahertz (MHz) Faraday waves excited by silicon-based multiple Fourier horn ultrasonic nozzles (MFHUNs) and its potential applications is presented. The new droplet generator has demonstrated capability for producing micro droplets of controllable size and size distribution and desirable throughput at very low electrical drive power. For comparison, the serious deficiencies of current commercial droplet generators (nebulizers) and the other ultrasonic droplet generators explored in recent years are first discussed. The architecture, working principle, simulation, and design of the multiple Fourier horns (MFH) in resonance aimed at the amplified longitudinal vibration amplitude on the end face of nozzle tip, and the fabrication and characterization of the nozzles are then described in detail. Subsequently, a linear theory on the temporal instability of Faraday waves on a liquid layer resting on the planar end face of the MFHUN and the detailed experimental verifications are presented. The linear theory serves to elucidate the dynamics of droplet ejection from the free liquid surface and predict the vibration amplitude onset threshold for droplet ejection and the droplet diameters. A battery-run pocket-size clogging-free integrated micro droplet generator realized using the MFHUN is then described. The subsequent report on the successful nebulization of a variety of commercial pulmonary medicines against common diseases and on the experimental antidote solutions to cyanide poisoning using the new droplet generator serves to support its imminent application to inhalation drug delivery.

Efficient management and maintenance of ultrasonic nebulizers to prevent microbial contamination.

AIM: To seek the cause of Burkholderia cepacia complex (Bcc) infection outbreak and evaluate the efficacy of new methods for nebulizer maintenance. METHODS: We investigated the annual number of Bcc isolates recovered from clinical samples in our hospital between 1999 and 2013. Swab samples were randomly collected for bacterial culture before patient use from 10 each of the two machine types in August 2001; these included 20 samples from each of the following: Drain tubes, operating water chambers, oscillators, and nebulizing chambers. In addition, 10 samples each of nebulizer solutions before and after use were cultured. For environmental investigation, 10 samples were collected from sinks in the nurse stations of the wards where patients positive for Bcc were hospitalized. Numbers of Bcc isolates were compared before and after introduction of new methods for nebulizer maintenance in October 2001. In addition, randomly amplified polymorphic DNA (RAPD) assay was applied to find the genetic divergence of the Bcc isolates obtained from clinical samples and nebulizers. RESULTS: From January 1999 to December 2013, a total of 487 Bcc isolates were obtained from clinical specimens from 181 patients. Notably, 322 (66.1%) Bcc isolates were obtained from clinical specimens from 1999 to 2001, including 244 (115 patients) from sputum and 34 (11 patients) from blood. During this period, 14 isolates were obtained from nebulizer components. Among these, six were derived from nebulizer drain tubes, five from operating water chambers, and one from the oscillator before patient use, and two from nebulizer solutions after patient use. When Bcc was isolated from the nebulizer solution after patient use, Bcc was simultaneously detected in other parts of the nebulizer. Bcc was not isolated from any nebulizer solution before use. RAPD assays revealed similar DNA profiles in isolates obtained from patients and nebulizers. Investigation revealed damaged diaphragms in many nebulizers. The new maintenance methods for nebulizers, including restriction of the usage period, thorough disinfection, and routine check for diaphragm breakage, remarkably reduced Bcc isolation (165 isolates from patients in 12 years and 0 isolate from nebulizers in periodical sampling). In particular, Bcc has been isolated from blood from only one patient since the new methods were introduced. CONCLUSION: Appropriate maintenance of ultrasonic nebulizers is crucial for preventing Bcc contamination of nebulizers and subsequent respiratory tract and blood infections.

Physicochemical aspects and efficiency of albuterol nebulization: comparison of three aerosol types in an in vitro pediatric model.

BACKGROUND: Advances in nebulizer design have produced both ultrasonic nebulizers and devices based on a vibrating mesh (vibrating mesh nebulizers), which are expected to enhance the efficiency of aerosol drug therapy. The aim of this study was to compare 4 different nebulizers, of 3 different types, in an in vitro model using albuterol delivery and physical characteristics as benchmarks. METHODS: The following nebulizers were tested: Sidestream Disposable jet nebulizer, Multisonic Infra Control ultrasonic nebulizer, and the Aerogen Pro and Aerogen Solo vibrating mesh nebulizers. Aerosol duration, temperature, and drug solution osmolality were measured during nebulization. Albuterol delivery was measured by a high-performance liquid chromatography system with fluorometric detection. The droplet size distribution was analyzed with a laser granulometer. RESULTS: The ultrasonic nebulizer was the fastest device based on the duration of nebulization; the jet nebulizer was the slowest. Solution temperature decreased during nebulization when the jet nebulizer and vibrating mesh nebulizers were used, but it increased with the ultrasonic nebulizer. Osmolality was stable during nebulization with the vibrating mesh nebulizers, but increased with the jet nebulizer and ultrasonic nebulizer, indicating solvent evaporation. Albuterol delivery was 1.6 and 2.3 times higher with the ultrasonic nebulizer and vibrating mesh nebulizers devices, respectively, than with the jet nebulizer. Particle size was significantly higher with the ultrasonic nebulizer. CONCLUSIONS: The in vitro model was effective for comparing nebulizer types, demonstrating important differences between nebulizer types. The new devices, both the ultrasonic nebulizers and vibrating mesh nebulizers, delivered more aerosolized drug than traditional jet nebulizers.

Microwave-induced combustion of crude oil for further rare earth elements determination by USN-ICP-MS.

A procedure for light and heavy crude oils digestion by microwave-induced combustion (MIC) is proposed for the first time for further rare earth elements (REE) determination by inductively coupled plasma mass spectrometry (ICP-MS) equipped with an ultrasonic nebulizer (USN). Samples of crude oil (API density of 10.8-23.5, up to 250 mg) were inserted in polycarbonate capsules and combusted using 20 bar of oxygen and 50 µL of 6 mol L(-1) ammonium nitrate as igniter. Nitric acid solutions (1-14.4 mol L(-1)) were evaluated for analyte absorption and a reflux step was applied after combustion (5 min of microwave irradiation at 1400 W) in order to achieve better analyte recoveries. Accuracy was evaluated using a spiked sample and also by comparison of results obtained by microwave-assisted digestion combined to ultraviolet radiation (MW-UV) and by neutron activation analysis (NAA). Using 3 mol L(-1) HNO3, quantitative recoveries (better than 97%) were obtained for all analytes. Blank values were always negligible. Agreement was higher than 96% for La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu and Y by comparison of results with those obtained by MW-UV and by NAA (only for La, Ce, Nd, Sm, and Yb). Residual carbon content in digests using MIC was always below 1%. As an advantage over conventional procedures for crude oil digestion, using MIC, it was possible to use diluted acid as absorbing solution, obtaining better limits of detection and avoiding interferences in REE determination by USN-ICP-MS.

In vitro comparison of five nebulizers during noninvasive ventilation: analysis of inhaled and lost doses.

BACKGROUND: Few studies on performance comparison of nebulizer systems coupled with a single-limb circuit bilevel ventilator are available. Most of these data compared the aerosol drug delivery for only two different systems. Using an adult lung bench model of noninvasive ventilation, we compared inhaled and lost doses of three nebulizer systems coupled with a single-limb circuit bilevel ventilator, as well as the influence of the nebulizer position. METHOD: Three vibrating mesh nebulizers (Aeroneb(®) Pro, Aeroneb(®) Solo, and NIVO(®)), one jet nebulizer (Sidestream(®)), and one ultrasonic nebulizer (Servo Ultra Nebulizer 145(®)) coupled with a bilevel ventilator were tested. They were charged with amikacin solution (500 mg/4 mL) and operated at two different positions: before and after the exhalation port (starting from the lung). The inhaled dose, the expiratory wasted dose, and the estimated lost dose were assessed by the residual gravimetric method. RESULTS: The doses varied widely among the nebulizer types and position. When the nebulizer was positioned before the exhalation port, the vibrating mesh nebulizer delivered the highest inhaled dose (p<0.001), the jet nebulizer the highest expiratory wasted dose (p<0.001), and the ultrasonic device the highest total lost dose (p<0.001). When the nebulizer was positioned after the exhalation port, the vibrating mesh nebulizers delivered the highest inhaled (p<0.001) and expiratory wasted doses (p<0.001), and the ultrasonic device the highest total lost dose (p<0.001). The most efficient nebulizers were NIVO and Aeroneb Solo when placed before the exhalation port. CONCLUSIONS: In a single-limb circuit bilevel ventilator, vibrating mesh nebulizers positioned between the exhalation port and lung model are more efficient for drug delivery compared with jet or ultrasonic nebulizers. In this position, the improved efficiency of vibrating mesh nebulizers was due to an increase in the inhaled dose and a reduction in the exhaled wasted dose compared with placement between the ventilator and the expiratory port. Because of the high total lost dose, the ultrasonic device should not be recommended. Nebulizer placement before the exhalation port increased the inhaled dose and decreased the expiratory wasted dose, except for the jet nebulizer.