Nebulization Time Research Articles

Anticancer drug delivery: Investigating the impacts of viscosity on lipid-based formulations for pulmonary targeting

Pulmonary drug delivery via aerosolization is a non-intrusive method for achieving localized and systemic effects. The aim of this study was to establish the impact of viscosity as a novel aspect (i.e., low, medium and high) using various lipid-based formulations (including liposomes (F1-F3), transfersomes (F4-F6), micelles (F7-F9) and nanostructured lipid carriers (NLCs; F10-F12)) as well as to investigate their impact on in-vitro nebulization performance using Trans-resveratrol (TRES) as a model anticancer drug. Based on the physicochemical properties, micelles (F7-F9) elicited the smallest particle size (12–174 nm); additionally, all formulations tested exhibited high entrapment efficiency (>89 %). Through measurement using capillary viscometers, NLC formulations exhibited the highest viscosity (3.35–10.04 m2/sec). Upon using a rotational rheometer, formulations exhibited shear-thinning (non-Newtonian) behaviour. Air jet and vibrating mesh nebulizers were subsequently employed to assess nebulization performance using an in-vitro model. Higher viscosity formulations elicited a prolonged nebulization time. The vibrating mesh nebulizer exhibited significantly higher emitted dose (ED), fine particle fraction (FPF) and fine particle dose (FPD) (up to 97 %, 90 % and 64 µg). Moreover, the in-vitro release of TRES was higher at pH 5, demonstrating an alignment of the release profile with the Korsmeyer-Peppas model. Thus, formulations with higher viscosity paired with a vibrating mesh nebulizer were an ideal combination for delivering and targeting peripheral lungs.

Standard technical specifications for methacholine chloride (Methacholine) bronchial challenge test (2023)

Standard technical specifications for methacholine chloride (Methacholine) bronchial challenge test (2023)

The Use of an Inspiration-Synchronized Vibrating Mesh Nebulizer for Prolonged Inhalative Iloprost Administration in Mechanically Ventilated Patients-An In Vitro Model.

Mechanically ventilated patients suffering from acute respiratory distress syndrome (ARDS) frequently receive aerosolized iloprost. Because of prostacyclin's short half-life, prolonged inhalative administration might improve its clinical efficacy. But, this is technically challenging. A solution might be the use of inspiration-synchronized vibrating mesh nebulizers (VMNsyn), which achieve high drug deposition rates while showing prolonged nebulization times. However, there are no data comparing prolonged to bolus iloprost nebulization using a continuous vibrating mesh nebulizer (VMNcont) and investigating the effects of different ventilation modes on inspiration-synchronized nebulization. Therefore, in an in vitro model of mechanically ventilated adults, a VMNsyn and a VMNcont were compared in volume-controlled (VC-CMV) and pressure-controlled continuous mandatory ventilation (PC-CMV) regarding iloprost deposition rate and nebulization time. During VC-CMV, the deposition rate of the VMNsyn was comparable to the rate obtained with the VMNcont, but 10.9% lower during PC-CMV. The aerosol output of the VMNsyn during both ventilation modes was significantly lower compared to the VMNcont, leading to a 7.5 times longer nebulization time during VC-CMV and only to a 4.2 times longer nebulization time during PC-CMV. Inspiration-synchronized nebulization during VC-CMV mode therefore seems to be the most suitable for prolonged inhalative iloprost administration in mechanically ventilated patients.

Predicting Inhaled Drug Dose Generated by Mesh Nebulizers.

Background: The lung dose of nebulized drugs for spontaneous breathing is influenced by breathing patterns and nebulizer performance. This study aimed to develop a system for measuring breath patterns and a formula for estimating inhaled drugs, and then to validate the hypothesized prediction formula. Methods: An in vitro model was first used to determine correlations among the delivered dose, breath patterns, and doses deposited on the accessories and reservoirs testing with a breathing simulator to generate 12 adult breathing patterns (n = 5). A pressure sensor was developed to measure breathing parameters and used along with a prediction formula that accounted for the initial charge dose, respiratory pattern, and dose on the accessory and reservoir of a nebulizer. Three brands of nebulizers were tested by placing salbutamol (5.0 mg/2.5 mL) in the drug holding chamber. Ten healthy individuals participated in the ex vivo study to validate the prediction formula. The agreement between the predicted and inhaled doses was analyzed using the Bland-Altman plot. Results: The in vitro model showed that the inspiratory time to total respiratory cycle time (Ti/Ttotal; %) was significantly directly correlated with the delivered dose among the respiratory factors, followed by inspiratory flow, respiratory rate, and tidal volume. The ex vivo model showed that Ti/Ttotal was significantly directly correlated with the delivered dose among the respiratory factors, in addition to the nebulization time and accessory dose. The Bland-Altman plots for the ex vivo model showed similar results between the two methods. Large differences in inhaled dose measured at the mouth were observed among the subjects, ranging from 12.68% to 21.68%; however, the difference between the predicted dose and inhaled dose was lower, at 3.98%-5.02%. Conclusions: The inhaled drug dose could be predicted with the hypothesized estimation formula, which was validated by the agreement between the inhaled and predicted doses of breathing patterns of healthy individuals.

Facile and Controllable Ultrasonic Nebulization Method for Fabricating Ti3C2Tx‐Based Strain Sensor and Monitoring of Human Motion and Sound Wave

AbstractFlexible and wearable electronic devices hold great potential in electronic skins, health monitoring systems and soft robotics. Among them, flexible strain sensors with high performance are key components for wearable health monitoring devices. However, the facile and controllable preparation of highly sensitive sensors still faces significant challenges. By virtue of excellent conductivity of 2D transition metal carbids (MXenes), this work reports a facile and low‐cost fabrication strategy for large‐scale production of strain sensors. The sensitive layer is deposited on flexible interdigital electrodes by ultrasonic nebulization of Ti3C2Tx nanosheets. By controlling the nebulization time, different thicknesses of Ti3C2Tx films has a great influence on the performance of strain sensors. The Ti3C2Tx‐based strain sensor exhibits good sensing performances such as high GF (19.1) in the low strain range (≈0.25%–1.14%), short response time (0.7 s), and stable durability (over 1000 cycles). In practice, the potential applications of the strain sensor in sound frequency detection, human physiological signal monitoring and facial expression recognition are demonstrated. Finally, this work integrates the strain sensor with a miniaturized analyzer to assemble a wearable motion monitoring device for mobile healthcare. This study provides a facile strategy for fabricating flexible strain sensors in the field of wearable electronics.

Differential Performance and Lung Deposition of Levofloxacin with Different Nebulisers Used in Cystic Fibrosis.

We compared the performance and levofloxacin (Quinsair) lung deposition of three nebulisers commonly used in CF (I-Neb Advance, eFlow rapid, and LC Plus) with the approved nebuliser Zirela. The delivered dose, delivery rate, and aerosol particle size distribution (APSD) for each device were determined using the methods described in the Pharmacopeia. High-resolution computed tomography scans obtained from seven adult patients with mild CF were used to generate computer-aided, three-dimensional models of their airway tree to assess lung deposition using functional respiratory imaging (FRI). The eFlow rapid and the LC Plus showed poor delivery efficiencies due to their high residual volumes. The I-Neb, which only delivers aerosols during the inspiratory phase, achieved the highest aerosol delivery efficiency. However, the I-Neb showed the largest particle size and lowest delivery rate (2.9 mg/min), which were respectively associated with a high extrathoracic deposition and extremely long nebulisation times (>20 min). Zirela showed the best performance considering delivery efficiency (159.6 mg out of a nominal dose of 240 mg), delivery rate (43.5 mg/min), and lung deposition (20% of the nominal dose), requiring less than 5 min to deliver a full dose of levofloxacin. The present study supports the use of drug-specific nebulisers and discourages the off-label use of general-purpose devices with the present levofloxacin formulation since subtherapeutic lung doses and long nebulisation times may compromise treatment efficacy and adherence.

Impact of Targeted Bundles to Reduce the Nebulization Time Gap from Prescription to Administration among Red Triaged Patients in Emergency Department: An Quality Improvement Initiative

Background: Severe exacerbation of asthma are potentially life-threatening and therefore require prompt care and frequent management. Important aspects of early treatment includes recognition of early signs and symptoms of breathing difficulty and timely prescription and administration of therapeutic agents. A subsequent delay in receiving nebulization during an acute exacerbation of asthma can leads to cardiac arrest and even death.
 Aim: To reduce the gap in administration of nebulization from its prescription time among red triaged patients by 50% from its baseline.
 Setting and Design: This interventional study was conducted among red triaged patients in emergency department of tertiary care hospital, India.
 Material and Methods: Baseline information was collected during first 4 weeks to find gap in administration of nebulization from its prescription time. Fish bone analysis and process map were laid down to analyse the situation. The intervention using targeted bundles was done via 3 PDSA (PDSA1: indenting the nebulizers, PDSA 2: training of doctors and nurses, PDSA 3; introducing equipment checklist) to reduce the gap. A run chart using time series analysis model was used to compare the pre and post intervention nebulization gap.
 Results: Total 74 patients (30 in pre- intervention, 44 in post intervention) admitted in red triaged area were observed for nebulization gap from prescription to administration. Median time for nebulization gap before intervention was 46.5 minutes which reduced to 15 minutes in post intervention phase.
 Conclusion: This bundles of targeted interventions was successful to reduce the nebulization gap.

Cystic Fibrosis Foundation Nebulizer and Compressor Accessibility Survey.

Although guidelines for inhaled therapies for individuals with cystic fibrosis (CF) are available, recommendations for compressors/nebulizers to optimize care are lacking. The CF Foundation (CFF) convened a multidisciplinary task force to assess the use, durability, accessibility, and cost burden of compressors/nebulizers. Online surveys were developed and distributed to 287 CFF programs and adults with CF and parents of children with CF (adults with CF/parents). Health care providers from 38 states completed the survey (59% response rate). Respiratory therapists were mostly responsible to coordinate ordering nebulizers and compressors. Durable medical equipment companies were the most common source of acquisition of compressors (71.8%) and nebulizers (45.9%). A majority of health care providers did not feel the compressors were durable (51.1%) or that they could get enough nebulizers to their patients (69.2%). Barriers to procure compressors were reported. The survey was completed by 734 adults with CF/parents from 48 states. Most adults with CF/parents rated their compressor as durable (65.8%); however, 85.5% of respondents reported some user-experience problem(s). "Hoses popping off" and "increased nebulization time" were most commonly reported. Almost 20% of respondents did not have access to a compressor at some point in the previous year. Most adults with CF/parents did not change compressor filters per manufacturer's recommendation (40% never). Adults with CF/parents reported performing a median of 4 inhaled treatments per day. Median use of nebulizers was 6 months. Most adults with CF/parents thought they had enough nebulizers (53.7%). Individuals with CF doing more inhaled treatments reported more compressor malfunctions. The median out-of-pocket expense was $75-99 and $50-74 for compressors and nebulizers, respectively. Although the perceptions of health care providers and adults with CF/parents differed to a certain extent, the surveys uncovered several significant issues that may compromise quality of care. Improvement in access to devices and education are needed.

Impact of phospholipids, surfactants and cholesterol selection on the performance of transfersomes vesicles using medical nebulizers for pulmonary drug delivery

The aim of this study is to formulate and optimize novel transfersome formulations for pulmonary drug delivery. Transfersome formulations (F1 – F18) were prepared by a thin-film method using three phospholipids (Soya phosphatidylcholine (SPC), Dimyristoly phosphatidylcholine (DMPC) and Hydrogenated soya phosphatidylcholine (HSPC)), in combination with three different surfactants (Tween 80, Span 80 and Span 20) with or without cholesterol, employing Beclomethasone dipropionate (BDP) as the model drug. Nano-transfersome formulations post-extrusion were delivered to a Two-stage Impinger (TSI) via three medical nebulizers (i.e. Air-jet, Ultrasonic and Vibrating mesh nebulizer). Based on the physicochemical properties, formulations F1 (SPC and Tween 80), F7 (DMPC and Tween 80) and F13 (HSPC and Tween 80) demonstrated significantly smaller VMD (162.34 ± 6.48, 198.66 ± 6.64, and 183.52 ± 7.34 nm), and significantly higher entrapment efficiency (97.56 ± 2.45, 95.67 ± 4.26 and 95.06 ± 3.38%). Based on nebulization performance, the Ultrasonic nebulizer exhibited the shortest nebulization time for formulations F1, F7 and F13 (i.e. 17.88 ± 2.45, 19.26 ± 2.04 and 19.59 ± 2.12 min), and higher output rate (212.04 ± 11.54, 194.61 ± 10.27 and 192.43 ± 9.84 mg/min), when compared to Air-jet and Vibrating mesh nebulizers. Irrespective of nebulizer type, significantly higher BDP deposition was observed in the lower stage of TSI for the F1 formulation (on average of 61%), whereas a higher amount of BDP was deposited in the upper stage of TSI using the F7 formulations (49%). Moreover, Formulation F1 in combination with Air-jet nebulizer demonstrated higher emitted dose (ED) and fine particle fraction (FPF) (82% and 83%), when compared to the counterpart formulations and nebulizer types investigated. This study has demonstrated that based on nebulizer performance, BDP deposition and formulation type; the F1 formulation in combination with an Air-jet nebulizer is most optimal for lower respiratory tract deposition, whereas the F7 formulation in combination with an Ultrasonic nebulizer is ideal for upper respiratory tract deposition.

Robustness of aerosol delivery of amikacin liposome inhalation suspension using the eFlow® Technology

The purpose of these studies was to understand the effect on product performance of batch-to-batch variability in both the amikacin liposome inhalation suspension (ALIS) formulation and its delivery device, the Lamira® nebulizer system, designed and manufactured by PARI (PARI Pharma GmbH, Munich, Germany). Three batches of ALIS spanning a range of lipid concentrations (43, 48 and 54 mg/mL) were tested with nine PARI inhalation devices that varied within the production process of the vibrating membrane with respect to hole geometry. Three hole geometry clusters were built including a geometry close to the mean geometry (median) and two geometries deviating from the mean geometry with smaller (smaller) and larger (larger) holes. The output parameters included the nebulization rate, the aerosol droplet size distribution, the liposome vesicle size post-nebulization, and the fraction of amikacin that remained encapsulated post-nebulization. Across the 27 experimental combinations of three formulation batches and nine devices, the nebulization time varied between 12 and 15 min with the fastest nebulization rate occurring with the combination of low lipid concentration and larger hole geometry (0.68 g/min) and the slowest nebulization rate occurring with the combination of high lipid concentration and the smaller hole geometry (0.59 g/min). The mean liposome vesicle size post-nebulization ranged from 269 to 296 nm across all experimental combinations which was unchanged from the control samples (276–292 nm). While all three batches contained > 99% encapsulated amikacin prior to nebulization, the nebulization process resulted in a consistent generation of ~ 35% unencapsulated amikacin (range: 33.8% to 37.6%). There was no statistically significant difference in the generated aerosol particle size distributions. The mass median aerodynamic diameters (MMAD) ranged from 4.78 µm to 4.98 µm, the geometric standard deviations (GSD) ranged from 1.61 to 1.66, and the aerosol fine particle fraction (FPF < 5 µm) ranged from 50.3 to 53.5%. The emitted dose (ED) of amikacin ranged from 473 to 523 mg (80.2 to 89.3% of loaded dose (LD)) and the fine particle dose (FPD < 5 µm) ranged from 244 to 278 mg (41.4 to 47.1% of label claim (LC)). In conclusion, while variations in the lipid concentration of the ALIS formulation and the device hole geometry had a small but significant impact on nebulization time, the critical aerosol performance parameters were maintained and remained within acceptable limits.

Fabrication, characterization and optimization of nanostructured lipid carrier formulations using Beclomethasone dipropionate for pulmonary drug delivery via medical nebulizers

Aerosolization is a non-invasive approach in drug delivery for localized and systemic effect. Nanostructured lipid carriers (NLCs) are new generation versatile carriers, which offer protection from degradation and enhance bioavailability of poorly water soluble drugs. The aim of this study was to develop and optimize NLC formulations in combination with optimized airflow rates (i.e. 60 and 15 L/min) and choice of medical nebulizers including Air jet, Vibrating mesh and Ultrasonic nebulizer for superior aerosolization performance, assessed via a next generation impactor (NGI). Novel composition and combination of NLC formulations (F1 – F15) were prepared via ultrasonication method, employing five solid lipids (glycerol trimyristate (GTM), glycerol trilaurate (GTL), cetyl palmitate (CP), glycerol monostearate (GMS) and stearic acid (SA)); and three liquid lipids (glyceryl tributyrate (GTB), propylene glycol dicaprylate/dicaprate (PGD) and isopropyl palmitate (IPP)) in 1:3 w/w ratios (i.e. combination of one solid and one liquid lipid), with Beclomethasone dipropionate (BDP) incorporated as the model drug. Out of fifteen BDP-NLC formulations, the physicochemical properties of formulations F7, F8 and F10 exhibited desirable stability (one week at 25 °C), with associated particle size of ~241 nm, and >91% of drug entrapment. Post aerosolization, F10 was observed to deposit notably smaller sized particles (from 198 to 136 nm, 283 to 135 nm and 239 to 157 nm for Air jet, Vibrating mesh and Ultrasonic nebulizers, respectively) in all stages (i.e. from stage 1 to 8) of the NGI, when compared to F7 and F8 formulations. Six week stability studies conducted at 4, 25 and 45 °C, demonstrated F10 formulation stability in terms of particle size, irrespective of temperature conditions. Nebulizer performance study using the NGI for F10 identified the Air jet to be the most efficient nebulizer, depositing lower concentrations of BDP in the earlier stages (1–3) and higher (circa 82 and 85%) in the lateral stages (4–8) using 60 and 15 L/min airflow rates, when compared to the Vibrating mesh and Ultrasonic nebulizers. Moreover, at both airflow rates, the Air jet nebulizer elicited a longer nebulization time of ~42 min, facilitating aerosol inhalation for prophylaxis of asthma with normal tidal breathing. Based on characterization and nebulizer performance employing both 60 and 15 L/min airflow rates, the Air jet nebulizer offered enhanced performance, exhibiting a higher fine particle dose (FPD) (90 and 69 µg), fine particle fraction (FPF) (70 and 54%), respirable fraction (RF) (92 and 69%), and lower mass median aerodynamic diameter (MMAD) (1.15 and 1.62 µm); in addition to demonstrating higher drug deposition in the lateral parts of the NGI, when compared to its counterpart nebulizers. The F10 formulation used with the Air jet nebulizer was identified as being the most suitable combination for delivery of BDP-NLC formulations.

In Vitro Evaluation of a Vibrating-Mesh Nebulizer Repeatedly Use over 28 Days.

This in vitro study evaluates the performance of a disposable vibrating-mesh nebulizer when used for 28 days. A lung model was used to simulate the breathing pattern of an adult with chronic obstructive pulmonary disease. The vibrating-mesh nebulizer was used for three treatments/day over 28 days without cleaning after each test. Results showed that the inhaled drug dose was similar during four weeks of use (p = 0.157), with 16.73 ± 4.46% at baseline and 15.29 ± 2.45%, 16.21 ± 2.21%, 17.56 ± 1.98%, and 17.13 ± 1.81%, after the first, second, third, and fourth weeks, respectively. The particle size distribution, residual drug volume, and nebulization time remained similar across four weeks of use (p = 0.110, p = 0.763, and p = 0.573, respectively). Mesh was inspected using optical microscopy and showed that approximately 50% of mesh pores were obscured after 84 runs, and light penetration through the aperture plate was significantly reduced after the 21st use (p < 0.001) with no correlation to nebulizer performance. We conclude that the vibrating-mesh nebulizer delivered doses of salbutamol solution effectively over four weeks without cleaning after each use even though the patency and clarity of the aperture plate were reduced by the first week of use.

Evaluation of buccal damage associated with acute inhalation exposure to 2,4-dichlorophenoxyacetic acid (2,4-D) in mice

BackgroundThe herbicide dichlorophenoxyacetic acid (2,4-D) is one of the most widely used crop spraying products in the world. Some pesticides induce the degranulation of mast cells and increase allergic responses. This is the first study to evaluate the damage to the oral mucosa after an experimental simulation of environmental inhalation exposure to the 2,4-D herbicide. The aim of this study was evaluate the possible oral damage caused by acute inhalation exposure to the herbicide 2,4-D.ResultsThere was a difference between the exposure concentrations in relation to tissue congestion intensity (p = 0.002) and mast cell counts (p = 0.002), a difference in the evaluation of the interaction between the exposure concentrations and nebulization time in the dorsum epithelium thickness (p = 0.013), and a significant correlation between the epithelial thickness and the number of nucleoli organizing regions on the dorsum of the tongue (p = 0.048).ConclusionsEven after acute exposure, the herbicide 2,4-D had the potential to damage the oral epithelium, especially at higher doses.

A Facile and Novel Approach to Manufacture Paclitaxel-Loaded Proliposome Tablet Formulations of Micro or Nano Vesicles for Nebulization

PurposeThe aim of this study was to develop novel paclitaxel-loaded proliposome tablet formulations for pulmonary drug delivery.MethodProliposome powder formulations (i.e. F1 – F27) were prepared employing Lactose monohydrate (LMH), Microcrystalline cellulose (MCC) or Starch as a carbohydrate carriers and Soya phosphatidylcholine (SPC), Hydrogenated soya phosphatidylcholine (HSPC) or Dimyristoly phosphatidylcholine (DMPC) as a phospholipid. Proliposome powder formulations were prepared in 1:5, 1:15 or 1:25 w/w lipid phase to carrier ratio (lipid phase; comprising of phospholipid and cholesterol in 1:1 M ratio) and Paclitaxel (PTX) was used as model anticancer drug.ResultsBased on flowability studies, out of 27 formulations; F3, F6, and F9 formulations were selected as they exhibited an excellent angle of repose (AOR) (17.24 ± 0.43, 16.41 ± 0.52 and 15.16 ± 0.72°), comparatively lower size of vesicles (i.e. 5.35 ± 0.76, 6.27 ± 0.59 and 5.43 ± 0.68 μm) and good compressibility index (14.81 ± 0.36, 15.01 ± 0.35 and 14.56 ± 0.14) via Carr’s index. The selected formulations were reduced into Nano (N) vesicles via probe sonication, followed by spray drying (SD) to get a dry powder of these formulations as F3SDN, F6SDN and F9SDN, and gave high yield (>53%) and exhibited poor to very poor compressibility index values via Carr’s Index. Post tablet manufacturing, F3 tablets formulation showed uniform weight uniformity (129.40 ± 3.85 mg), good crushing strength (14.08 ± 1.95 N), precise tablet thickness (2.33 ± 0.51 mm) and a short disintegration time of 14.35 ± 0.56 min, passing all quality control tests in accordance with British Pharmacopeia (BP). Upon nebulization of F3 tablets formulation, Ultrasonic nebulizer showed better nebulization time (8.75 ± 0.86 min) and high output rate (421.06 ± 7.19 mg/min) when compared to Vibrating mesh nebulizer. PTX-loaded F3 tablet formulations were identified as toxic (60% cell viability) to cancer MRC-5 SV2 cell lines while safe to normal MRC-5 cell lines.ConclusionOverall, in this study LMH was identified as a superior carbohydrate carrier for proliposome tablet manufacturing in a 1:25 w/w lipid to carrier ratio for in-vitro nebulization via Ultrasonic nebulizer.

Ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: understanding nebulization of aminoglycosides and colistin.

The original version of this article unfortunately contained a mistake. There was a typographical error in Figure 1: “Nebulization time ≤ 30 min” (first light blue square) should be replaced by “Nebulization time ≤ 90 min”. The authors apologize for the mistake.

Paclitaxel-loaded micro or nano transfersome formulation into novel tablets for pulmonary drug delivery via nebulization.

A simplistic approach was adopted to manufacture novel paclitaxel (PTX) loaded protransfersome tablet formulations for pulmonary drug delivery. The large surface area offered by the pulmonary system acts as a desirable site for anti-cancer drug deposition; offering localized effect within the lungs. Protransfersomes are dry powder formulations, whereas transfersomes are liquid dispersions containing vesicles generated from protransfersomes upon hydration. Protransfersome powder formulations (F1-F27) (referred as Micro formulations based on transfersomes vesicles size post hydration) were prepared by employing a phospholipid (Soya phosphatidylcholine (SPC)), three different carbohydrate carriers (Lactose monohydrate, LMH; Microcrystalline cellulose, MCC; and Starch), three surfactants (i.e. Span 80, Span 20 and Tween 80) in three different lipid phase to carrier ratios (i.e. 1:05, 1:15 and 1:25 w/w), with the incorporation of PTX as a model drug. Hydrophobic chain of SPC may enhance PTX solubility, entrapment and targetted delivery via transfersome vesicles. Out of the 27 Micro protransfersome formulations, PTX-loaded LMH powder formulations F3, F6 and F9 (i.e. 1:25 w/w lipid phase to carrier ratio) exhibited excellent powder flowability via angle of repose (AOR) and good compressibility index due to associated smaller and uniform particle size and shape of LMH. Following hydration, these formulations also showed smaller volume median diameters (VMD) in micrometres (5.65±0.85-6.76±0.61µm) and PTX entrapment of 93-96%. Hydrated transfersome formulations (F3, F6 and F9) were converted into Nano size via probe sonication and referred to as Nano formulations. These Nano formulations were converted into dry powder via spray drying (SD) (F3NSD, F6NSD and F9NSD) or freeze drying (FD) (F3NFD, F6NFD and F9NFD). Post manufacture of protransfersome tablets (i.e. 9 formulations), quality control tests were conducted in accordance to British Pharmacopeia (BP). Only the Micro formulations protransfersome tablets (i.e. F3, F6 and F9) passed the uniformity of weight test, exhibited high crushing strength and tablet thickness when compared to SD or FD protransfersome tablets. Micro protransfersome formulations (i.e. F3, F6 and F9) into tablets demonstrated a shorter nebulization time and high output rate when using Ultrasonic nebulizer compared to Vibrating mesh nebulizer (i.e. Omron NE U22). Based on formulations, characterizations and nebulizer performance; Micro protransfersome tablet formulations F3, F6 and F9 (i.e. 1:25 w/w) and Ultrasonic nebulizer were found to be a superior combination, eliciting enhanced output efficiency. Moreover, PTX-loaded F3, F6 and F9 tablet formulations (10%) exhibited toxicity (60, 68 and 67% cell viability) to cancer MRC-5 SV2 (i.e. immortalized human lung cells) while safe to MRC-5 (normal lung fibroblast cells) cell lines.

Comparison of the performance of inhalation nebulizer solution and suspension delivered with active and passive vibrating-mesh device

In the clinical use of nebulizers, the drug and device are sold separately and combined together when at use. Obviously, the matching of formulation and device is very important for the performance of nebulizer. In this study, the combinatorial influences of vibrating-mesh device and formulations were investigated. Two types of vibrating-mesh nebulizers (i.e. Aeroneb Pro nebulizer and Omron mircoAir NE-U22 nebulizer) and two types of inhalation liquids (i.e. albuterol inhalation solution and budesonide suspension) were used for comparison. The stabilities of drug (temperature, pH, osmolality, and concentration) were monitored during nebulization, and in vitro lung depositions of different drug-device combinations were measured under several breathing patterns. During nebulization, the properties of liquid in reservoir were overall stable by using vibrating-mesh nebulizer. In addition, the output rates of albuterol were higher than that of budesonide, and the nebulization time of the Aeroneb Pro nebulizer was shorter, but the total aerosol outputs of Omron nebulizer were higher. Furthermore, a “slow deep breathing”pattern will contribute to more drugs delivered into the lung. As the results of equivalence analysis between pharmacopeial testing and several breathing patterns, it was inferred that the existing pharmacopeial testing likely overestimates the dose reaching the pediatric lung. We conclude that in order to be an effective medication for patient, for a given formulation, a suitable device should be recommended based on specific drug composition and site of action. In addition, a multiple realistic breathing patterns rather than a single standardized adult breathing pattern should be considered in the evaluation of inhaled drug, which is neglected by current compendial method.

Size Distribution of Colistin Delivery by Different Type Nebulizers and Concentrations During Mechanical Ventilation.

Although aerosol delivery through mechanical ventilators has been used to administer various medications, little is known of administration with colistin. This in vitro evaluation aimed to evaluate size distribution of colistin delivery by different types of nebulizers and concentrations during mechanical ventilation. Colistin methanesulfonate (colistin) for injection was dissolved in 6 mL of distilled water to produce a low concentration (L; 156 mg) and a high concentration (H; 312 mg). A dose volume of 6 mL was placed in a vibrating mesh nebulizer (VMN) and a jet nebulizer (JN). The inhaled mass (mean ± SD) of the VMN-L (53.80 ± 14.79 mg) was greater than both the JN-L (19.82 ± 3.34 mg, P = 0.001) and JN-H (31.72 ± 4.48 mg, P = 0.017). The nebulization time of the VMN-L (42.35 ± 2.30 min) was two times longer than the JN-L (21.12 ± 0.8 min) or JN-H (21.65 ± 0.42 min; P < 0.001). The mass median aerodynamic distal to the endotracheal tube was within a similar range at 2.03 to 2.26 μm (P = 0.434), independent of neb or formulation concentration. In conclusion, the VMN-L yields greater inhaled mass than the JN with either concentration. Therefore, a standard nominal dose of colistin results in a higher delivered dose during mechanical ventilation with a VMN compared with a JN and may be considered the preferred device. If JN must be used, multiple doses of low concentration colistin may compensate for poor delivery performance.

Aerosolization Performance of Jet Nebulizers and Biopharmaceutical Aspects.

In this work, 13 jet nebulizers, some of which in different configurations, were investigated in order to identify the biopharmaceutical constraints related to the quality attributes of the medicinal products, which affect their safety, efficiency, compliance, and effectiveness. The aerosolization parameters, including the aerosol output, aerosol output rate, mass median aerodynamic diameter, and fine particle fraction, were determined according to the European Standard EN 13544-1, using sodium fluoride as a reference formulation. A comparison between the aerosol output nebulization time and the fine particle fraction displayed a correlation between the aerosol quality and the nebulization rate. Indeed, the quality of the nebulization significantly increased when the rate of aerosol emission was reduced. Moreover, the performance of the nebulizers was analyzed in terms of respirable delivered dose and respirable dose delivery rate, which characterize nebulization as the rate and amount of respirable product that could be deposited into the lungs. Depending on which of these two latter parameters was used, the nebulizers showed different performances. The differences, in terms of the rate and amount of delivered aerosol, could provide relevant information for the appropriate choice of nebulizer as a function of drug product, therapy, and patient characteristics.

Pharmacokinetics and safety of tobramycin nebulization with the I-neb and PARI-LC Plus in children with cystic fibrosis: A randomized, crossover study.

AimsWe aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I‐neb device to the standard PARI‐LC Plus nebulizer in children with cystic fibrosis.MethodsA randomized, open‐label, crossover study was performed. In 2 separate study visits, blood samples from 22 children were collected following TIS nebulization with I‐neb (75 mg) and PARI‐LC Plus (300 mg). Study visits were separated by 1 month, in which 1 of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian PK modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard estimated glomerular filtration rate values, biomarkers for tubular injury (KIM‐1 and NAG) were measured. Patient and nebulizer satisfaction were assessed.ResultsInhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and estimated glomerular filtration rate revealed no abnormalities. However, increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest TIS‐induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I‐neb.ConclusionsNebulization of 75 mg TIS with the I‐neb in children with cystic fibrosis resulted in comparable systemic exposure to 300 mg TIS with the PARI‐LC Plus and was well tolerated and preferred over the PARI‐LC Plus. Long‐term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury.