Model-based meta-analysis of salbutamol pharmacokinetics and practical implications for doping control.

Salbutamol was included in the prohibited list of the World Anti-Doping Agency (WADA) in 2004. Although systemic intake is banned, inhalation for asthma is permitted but with dosage restrictions. The WADA established a urinary concentration threshold to distinguish accordingly prohibited systemic self-administration from therapeutic prescription by inhalation. This study aimed at evaluating the ability of the WADA threshold to differentiate salbutamol therapeutic use from violation of antidoping rules. Concentration-time profile of salbutamol in plasma and its excretion in urine was characterized through a model-based meta-analysis of individual and aggregate data collected after administration of a large range of doses following different modes of administration and under a variety of conditions. The developed model adequately fitted salbutamol plasma and urine concentration-time profiles of the 13 selected studies. Model-based simulations confirmed that a wide range of salbutamol urine concentrations might be measured after drug intake. Although violation of the WADA Code can be strongly suspected in individuals showing very high salbutamol urine concentrations, uncertainty remains for values close to the WADA threshold as they can be compatible with both permitted therapeutic use and violation. Although not entirely discriminant, the current WADA rule is globally supported by our appraisal. It could be further improved by a slight and reasonable adjustment of inhaled daily dosages allowed for therapeutic use. Our model might help antidoping experts in the evaluation of suspected doping cases through confronting the athlete's urine measurements with their allegations about salbutamol treatment.

Superhydrophobic Surface for Enhancing the Bioavailability of Salbutamol Sulfate from Cross-Linked Microspheres: Formulation, Characterization, and in vivo Evaluation.

INTRODUCTION: The aim of the work was to formulate salbutamol sulfate (SB) microspheres by using superhydrophobic surface (SHS) under different processing factors for improving its encapsulation efficiency, controling its release rate, and hence enhancing its bioavailability. METHODS: Cross-linked microspheres of chitosan (CN) and carrageenan (KN) were made on a SHS under a glutaraldehyde-saturated atmosphere. The formulations were designed and optimized based on 42 factorial design. Percentage encapsulation efficiency (%EE), particle size, swelling ratio, and in vitro release rate were characterized, and the in vivo performance of optimized formula was investigated in beagle dogs. RESULTS: The results showed that the prepared microspheres have a high %EE (97.11±0.78%) for F13. The swelling ratio was 4.2 at the end of the 8 hours for the optimized formula, and the in vitro release rate was controlled for 12 hours. In vivo study verified that there was a 1.61-fold enhancement in SB bioavailability from optimized formula (F13) compared to market tablet. CONCLUSION: The study suggested that microspheres prepared from CN/KN crosslinking on an SHS using glutaraldehyde atmosphere is a promising technique that can encapsulate and sustain the release of water-soluble drugs such as SB in addition to improving its in vivo pharmacokinetic profile.

Effects of salbutamol on the kinetics of sevoflurane and the occurrence of early postoperative pulmonary complications in patients with mild-to-moderate chronic obstructive pulmonary disease: A randomized controlled study.

Bronchodilators dilate the bronchi and increase lung volumes, thereby improving respiratory physiology in patients with chronic obstructive pulmonary disease (COPD). However, their effects on sevoflurane kinetics remain unknown. We aimed to determine whether inhaled salbutamol affected the wash-in and wash-out kinetics of sevoflurane and the occurrence of early postoperative pulmonary complications (PPCs) in patients with COPD undergoing elective surgery. This randomized, placebo-controlled study included 63 consecutive patients with COPD allocated to the salbutamol (n = 30) and control groups (n = 33). The salbutamol group received salbutamol aerosol (2 puffs of ~200 µg) 30 min before anesthesia induction and 30 min before surgery completion. The control group received a placebo. Sevoflurane kinetics were determined by collecting end-tidal samples from the first breaths at 1, 2, 3, 4, 5, 7, 10, and 15 min before the surgery (wash-in) and after closing the vaporizer (wash-out). PPCs were recorded for 7 days. The salbutamol group had higher end-tidal to inhaled sevoflurane ratios (p<0.05, p<0.01) than the control group, from 3 to 10 min during the wash-in period, but no significant differences were observed during the wash-out period. The arterial partial pressure of oxygen to the fraction of inhaled oxygen was significantly higher in the salbutamol group at 30 (320.3±17.6 vs. 291.5±29.6 mmHg; p = 0.033) and 60 min (327.8±32.3 vs. 309.2±30.5 mmHg; p = 0.003). The dead space to tidal volume ratios at 30 (20.5±6.4% vs. 26.3±6.0%, p = 0.042) and 60 min (19.6±5.1% vs. 24.8±5.5%, p = 0.007) and the incidence of bronchospasm (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.23-0.67, p = 0.023) and respiratory infiltration (OR 0.52, 95% CI, 0.40-0.65, p = 0.017) were lower in the salbutamol group. In patients with COPD, salbutamol accelerates the wash-in rate of sevoflurane and decreases the occurrence of postoperative bronchospasm and pulmonary infiltration within the first 7 days.

Elucidating the Effect of Fine Lactose Ratio on the Rheological Properties and Aerodynamic Behavior of Dry Powder for Inhalation.

Dry powder inhaler (DPI) is recognized as the first choice for lung diseases' treatment. However, it lacks a universal way for DPI formulation development. Fine lactose is commonly added in DPIs to improve delivery performance; however, the fine ratio-dependent mechanism is unclear. Therefore, the objective of this study is to explore the influence of fine lactose ratio on DPI powder properties and aerodynamic behavior, and the fine lactose ratio-dependent mechanism involved during powder fluidization and lung deposition. Here salbutamol sulfate was used as a model drug, Lactohale® 206 as coarse carrier, and Lactohale® 300 as fine component; the mixtures were prepared at 1% drug content, with fine content up to 20%. It was shown that with the fine addition, flowability of the mixtures was improved, interaction among particles was increased, and the presence of fines could help to improve DPI's aerosolization performance. When the fines added were less than 3%, the "active site" hypothesis played a leading role. When the added fines were over 3% but less than 10%, fluidization enhancement mechanism was more important. After the added fines reaching 10%, aggregate mechanism started to dominate. However, FPF cannot be further increased once the fines reached 20%. Moreover, the correlations between FPF and dynamic powder parameters were verified in ternary mixtures, and cohesion had a greater impact on FPF than that of flowability. In conclusion, adding lactose fines is an effective way to improve lung deposition of DPI, with the concrete mechanism lactose fine ratio dependent.

Repurposing Melt Degradation for the Evaluation of Mixed Amorphous-Crystalline Blends.

Medicine regulators require the melting points for crystalline drugs, as they are a test for chemical and physical quality. Many drugs, especially salt-forms, suffer concomitant degradation during melting; thus, it would be useful to know if the endotherm associated with melt degradation may be used for characterising the crystallinity of a powder blend. Therefore, the aim of this study was to investigate whether melt-degradation transitions can detect amorphous content in a blend of crystalline and amorphous salbutamol sulphate. Salbutamol sulphate was rendered amorphous by freeze and spray-drying and blended with crystalline drug, forming standards with a range of amorphous content. Crystalline salbutamol sulphate was observed to have a melt-degradation onset of 198.2±0.2°C, while anhydrous amorphous salbutamol sulphate prepared by either method showed similar glass transition temperatures of 119.4±0.7°C combined. Without the energy barrier provided by the ordered crystal lattice, the degradation endotherm for amorphous salbutamol sulphate occurred 50°C below the melting point, with an onset of 143.6±0.2°C. The enthalpies for this degradation transition showed no significant difference between freeze- and spray-dried samples (p>0.05). Distinct from convention, partial integration of the crystalline melt-degradation endotherm was applied to the region 193-221°C which had no contribution from the degradation of amorphous salbutamol sulphate. The linear correlation of these partial areas with amorphous content, R2=0.994, yielded limits of detection and quantification of 0.13% and 0.44% respectively, independent of drying technique. Melt-degradation transitions may be re-purposed for the measurement of amorphous content in powder blends, and they have potential for evaluating disorder more generally.

Pharmacokinetics of salmeterol and its main metabolite α-hydroxysalmeterol after acute and chronic dry powder inhalation in exercising endurance-trained men: Implications for doping control.

As of 2020, use of beta2 -agonist salmeterol is restricted by the World Anti-Doping Agency (WADA) and is only permitted by inhalation at therapeutic doses not exceeding 200 µg in 24 h. In contrast to beta2 -agonists salbutamol and formoterol, WADA has not established a urine threshold for salmeterol despite its muscle hypertrophic actions observed in animals. Herein, we investigated plasma (0-4 h) and urine (0-24 h) concentrations (by ultra-high-performance liquid chromatography-tandem mass spectrometry [UHPLC-MS/MS]) of salmeterol and α-hydroxysalmeterol after dry powder inhalation at supratherapeutic (400 µg) and high therapeutic (200 µg) doses, and after seven consecutive days of therapeutic inhalation (200 µg × day-1 ) in 11 healthy endurance-trained men. During each trial, participants inhaled salmeterol before 1½ h moderate-intensity cycling. Mean ± SD maximum urine concentrations of salmeterol unadjusted for specific gravity reached 4.0 ± 1.6, 2.1 ± 1.5, and 2.2 ± 1.1 ng × ml-1 for 400 µg, 200 µg, and seven consecutive days of 200 µg, respectively, with corresponding maximum urine concentrations of α-hydroxysalmeterol being 11.6 ± 6.1, 5.7 ± 4.6, and 6.5 ± 2.6 ng × ml-1 . Within the relevant window for doping control (first 6 h post-inhalation), the present data (119 samples), along with 64 biobank urine samples, showed that a combined salmeterol and α-hydroxysalmeterol urine threshold with equal cut-offs of 3.3 ng × ml-1 was superior to a salmeterol-only threshold to discriminate therapeutic (200 µg) from supratherapeutic use (400 µg) with a sensitivity of 24% with 0% false positives when applying the WADA technical document (TD2019DL.v2) method of specific gravity adjustment. Thus, a combination of urine salmeterol and α-hydroxysalmeterol concentrations may be suitable for discriminating between therapeutic and supratherapeutic prohibited inhalation of salmeterol.

Predicted values for human total clearance of a variety of typical compounds with differently humanized-liver mouse plasma data.

Prediction of human pharmacokinetics is important in the preclinical stage. Values for total clearance of compounds from plasma should be one of the most important pharmacokinetic parameters for predictions. Although several physiological and empirical methods including single-species allometry for prediction of values for human clearance of compounds using humanized-liver mice have been reported, further improvement of prediction accuracies would be still expected. To optimize these approaches, we proposed methods for unbound intrinsic clearance in virtually 100% humanized-liver mouse by incorporating unbound plasma fractions of compounds in differently humanized-liver mice. Comparisons of prediction accuracies of values for human clearance of 15 model compounds were performed among our current physiological and previously reported models and single-species allometry using humanized-liver mice. Incorporation of the actual unbound plasma fractions of compounds and correction of residual mice hepatocyte in humanized-liver mice showed comparable prediction accuracy to that by single-species allometry. After exclusion of 3 compounds with large species differences in values of clearance and unbound plasma fractions between mice and humans out of 15 compounds, prediction accuracies were improved in the methods investigated. The previously and present reported physiological methods could show the good prediction accuracy of values for clearance of drugs from plasma.

Comparative pharmacokinetics of salbutamol inhaled from a pressurized metered dose inhaler either alone or connected to a newly enhanced spacer design.

BACKGROUND: Coordination between actuation of a pressurized metered dose inhaler (pMDI) and inhalation is a critical manoeuvre that many patients fail to perform correctly. pMDIs connected to spacers do not require hand-lung coordination. This study evaluated the relative lung and systemic bioavailability and oropharyngeal deposition of salbutamol post-inhalation from Ventolin® Evohaler® (GlaxoSmithKline) either alone following verbal inhaler technique counselling (VC) or connected to a newly improved Able Spacer® (AS). METHODS: In a two-period, randomized crossover study, 16 healthy adults inhaled 2 × 100 µg salbutamol puffs (1 min gap) from Ventolin using VC or AS. Immediately after each puff inhalation, each subject gargled with 20 mL water for oropharyngeal deposition (OD) determination. Urine samples were collected 0.5 h (pre-) and 0.5, 1.0 and 2.0 h post-inhalation. Urine was then pooled 2-24 h post-inhalation. The relative lung bioavailability (0-0.5 h urinary salbutamol excretion - USAL0.5) and systemic bioavailability (0-24 h urinary excretion of salbutamol and its metabolite - USALMET24) were determined. A one week washout separated VC and AS use. RESULTS: The mean (SD) USAL0.5 of VC and AS was 5.36 (4.48) and 12.80 (10.83) µg, respectively. The mean (SD) OD was 11.35 (3.37) and 0.48 (0.30) µg, respectively. VC and AS were significantly different in USAL0.5 and OD (p<0.001). USALMET24 was comparable (p>0.05). CONCLUSIONS: Compared with VC, AS doubled the inhaled salbutamol lung dose and minimised its precipitation in the oral cavity. The results suggest this inhalation aid can add therapeutic and safety benefits particularly in patients with continued pMDI technique issues despite repeated VC.

Using Polar Ion-Pairs to Control Drug Delivery to the Airways of the Lungs.

The rapid absorptive clearance of drugs delivered to the airways of the lungs means that many inhaled medicines have a short duration of action. The aim of this study was to investigate whether forming polar ion-pairs can modify drug absorption to slow down clearance from the airways. Salbutamol was used as a model drug and was formulated as ion-pairs in an aqueous solution with three negatively charged hydrophilic counterions: sulfate (molecular weight (MW) 142), gluconate (MW 218), and phytate (MW 736) (association constants of 1.57, 2.27, and 4.15, respectively) and one negatively charged hydrophobic counterion, octanoate (MW 166) (association constant, 2.56). All of the counterions were well tolerated by Calu-3 human bronchial epithelial cells when screened for toxicity in vitro using conditions that in silico simulations suggested maintain >80% drug-counterion association. The transport of salbutamol ion-pairs with higher polar surface area (PSA), i.e., the sulfate (PSA 52%), gluconate (PSA 50%), and phytate (PSA 79%) ion-pairs, was significantly lower compared to that of the drug alone (PSA 30%, p < 0.05). In contrast, the octanoate ion-pair (PSA 23%) did not significantly alter the salbutamol transport. The transport data for the gluconate ion-pair suggested that the pulmonary absorption half-life of the ion-paired drug would be double that of salbutamol base, and this illustrates the promise of increasing drug polarity using noncovalent complexation as an approach to control drug delivery to the airways of the lungs.

Population Pharmacokinetics of Intravenous Salbutamol in Children with Refractory Status Asthmaticus.

BACKGROUND: Intravenous salbutamol is used to treat children with refractory status asthmaticus, however insufficient pharmacokinetic data are available to guide initial and subsequent dosing recommendations for its intravenous use. The pharmacologic activity of salbutamol resides predominantly in the (R)-enantiomer, with little or no activity and even concerns of adverse reactions attributed to the (S)-enantiomer. OBJECTIVE: Our aim was to develop a population pharmacokinetic model to characterize the pharmacokinetic profile for intravenous salbutamol in children with status asthmaticus admitted to the pediatric intensive care unit (PICU), and to use this model to study the effect of different dosing schemes with and without a loading dose. METHODS: From 19 children (median age 4.9 years [range 9 months-15.3 years], median weight 18 kg [range 7.8-70 kg]) treated with continuous intravenous salbutamol at the PICU, plasma samples for R- and S-salbutamol concentrations (111 samples), as well as asthma scores, were collected prospectively at the same time points. Possible adverse reactions and patients' clinical data (age, sex, weight, drug doses, liver and kidney function) were recorded. With these data, a population pharmacokinetic model was developed using NONMEM 7.2. After validation, the model was used for simulations to evaluate the effect of different dosing regimens with or without a loading dose. RESULTS: A two-compartment model with separate clearance for R- and S-salbutamol (16.3 L/h and 8.8 L/h, respectively) best described the data. Weight was found to be a significant covariate for clearance and volume of distribution. No other covariates were identified. Simulations showed that a loading dose can result in higher R-salbutamol concentrations in the early phase after the start of infusion therapy, preventing accumulation of S-salbutamol. CONCLUSIONS: The pharmacokinetic model of intravenous R- and S-salbutamol described the data well and showed that a loading dose should be considered in children. This model can be used to evaluate the pharmacokinetic-pharmacodynamic relationship of intravenous salbutamol in children, and, as a next step, the effectiveness and tolerability of intravenous salbutamol in children with severe asthma.

Revealing the Regional Localization and Differential Lung Retention of Inhaled Compounds by Mass Spectrometry Imaging.

Background: For the treatment of respiratory disease, inhaled drug delivery aims to provide direct access to pharmacological target sites while minimizing systemic exposure. Despite this long-held tenet of inhaled therapeutic advantage, there are limited data of regional drug localization in the lungs after inhalation. The aim of this study was to investigate the distribution and retention of different chemotypes typifying available inhaled drugs [slowly dissolving neutral fluticasone propionate (FP) and soluble bases salmeterol and salbutamol] using mass spectrometry imaging (MSI). Methods: Salmeterol, salbutamol, and FP were simultaneously delivered by inhaled nebulization to rats. In the same animals, salmeterol-d3, salbutamol-d3, and FP-d3 were delivered by intravenous (IV) injection. Samples of lung tissue were obtained at 2- and 30-minute postdosing, and high-resolution MSI was used to study drug distribution and retention. Results: IV delivery resulted in homogeneous lung distribution for all molecules. In comparison, while inhalation also gave rise to drug presence in the entire lung, there were regional chemotype-dependent areas of higher abundance. At the 30-minute time point, inhaled salmeterol and salbutamol were preferentially retained in bronchiolar tissue, whereas FP was retained in all regions of the lungs. Conclusion: This study clearly demonstrates that inhaled small molecule chemotypes are differentially distributed in lung tissue after inhalation, and that high-resolution MSI can be applied to study these retention patterns.

Effect of Roughness on the Dispersion of Dry Powders for Inhalation: a Dynamic Visualization Perspective.

Dry powder inhalers have attracted more interest over the years in every aspect related to them. Interestingly, when focusing on the effects of particle morphology of the active or carrier (excipient), it is generally regarded particle size and shape to influence drug availability of aerosolized particles. However, to date, few studies have examined the effect of texture, i.e., roughness, on this relationship. The main objective of the present work is to gain a closer understanding of the influence of carrier morphology on the aerosolization performance of dry powder inhaler formulations. Image analysis and microscopy were used to visualize the aerosolization process. It is considered that the scale of morphological features on the surface of the carrier particles is responsible for the dispersion of the powder formulation, separation of the drug/carrier, and entrainment from a dry powder inhaler. Thus, for this study, the carrier particles of different surface roughness were mixed with micronized salbutamol sulphate. Aerosolization in vitro testing was used to evaluate the performance. The results indicate a connection between the qualitative surface roughness of coarse carriers and aerosolization performance during powder dispersibility. This investigation demonstrated that indeed, powder dispersion, a dynamic process, is influenced by the scale of the carrier morphology.

Delivered Lung Dose and Aerodynamic Particle Size Distribution of Salbutamol Pressurized Metered Dose Inhaler After Living Under Patients' Realistic Retention Environments.

Background: The impact of inhalers' postdispensing, real-life temperature and relative humidity (RH) environments on their delivered dose (DD) and aerodynamic particle size distribution (APSD) is usually overlooked. This work evaluated the salbutamol DD and APSD of Ventolin® Evohaler® (V) inhalers already been used and stored by respiratory patients. Methods: Adult patients, prescribed V for ≥3 months before study enrollment, were dispensed both new V to use and portable, handheld electronic temperature and RH data loggers to keep close to the given V before returning them both after 2-3 weeks. Patients' enrollment took place during summer (VS) and winter (VW) seasons. The returned V was then in vitro evaluated using the Next Generation Impactor, and compared with control V (VC) counterparts stored under 21°C and 46% RH. Results: The VS survived in fluctuating habitats of 21.2°C-40.4°C and 16.2%-63.2% RH, which significantly (p < 0.05) decreased the salbutamol DD from 80.4 to 70.5 µg compared with VC. This 12.3% DD reduction was accompanied with a decrease in the fine particle dose from 26.2 to 20.4 µg (p < 0.05), and an increase in the mass median aerodynamic diameter from 2.3 to 2.5 µm (p < 0.05). The VW and VC had equivalent DD and APSD. Conclusion: Patients using V are expected to receive smaller lung doses during the hot summer season compared with intentionally well-kept VC. To have equivalent lung deposition, V users should be advised to retain their inhalers around 20°C with minimal daily environmental fluctuations during summer times.

Inhaled salbutamol from aerolizer and diskus at different inhalation flows, inhalation volume and number of inhalations in both healthy subjects and COPD patients.

The aim of the present study was to demonstrate the effect of inhalation-flow, inhalation-volume and number of inhalations on aerosol-delivery of inhaled-salbutamol from two different dry powder inhalers (DPIs) in both healthy-subjects and chronic obstructive pulmonary disease (COPD) patients. Relative pulmonary-bioavailability and systemic-bioavailability of inhaled-salbutamol, delivered by Diskus and Aerolizer, was determined in 24-COPD patients and 24-healthy subjects. The healthy-subjects and the COPD-patients participated in the study for 7 days in which they received 4 study doses of 200 µg salbutamol (one slow-inhalation, two slow-inhalations, one fast-inhalation, and two fast-inhalations) in four alternative days with 24 hr washout period after each dose. Two urine-samples were collected from each study subjects. The first was provided 30 min post inhalation (USAL0.5), as an index of relative pulmonary-bioavailability, and the second was pooled to 24 hr post inhalation (USAL24), as an index of systemic-bioavailability. Fast-inhalation resulted in significantly higher USAL0.5 and USAL24 than slow-inhalation (p˂0.05) after one-inhalation in both healthy-subjects and COPD-patients but there was no significant difference between slow and fast-inhalation after two-inhalations. One-inhalation resulted in significantly higher USAL0.5 and USAL24 in healthy-subjects compared to COPD-patient at both slow and fast-inhalation (p˂0.05) except USAL0.5 with Diskus at slow-inhalation there was no significant difference. Also, two-inhalations resulted in significantly higher USAL0.5 and USAL24 compared to one-inhalation at slow-inhalation only (p˂0.05). No significant difference was found between Aerolizer and Diskus except in USAL0.5 of one slow-inhalation in both health-subjects and COPD-patients (p = 0.048 and 0.047, respectively). Device-formula relation is present at low inhalation-flow since Diskus resulted in significantly higher USAL0.5 and USAL24 in healthy-subjects compared to COPD-patient at slow inhalation than Aerolizer. It is essential to inhale-twice and as hard and deep as possible from each dose when using DPI especially with COPD-patients having poor inspiratory efforts such as elderly patients and children.

Development of a New Inhaler for High-Efficiency Dispersion of Spray-Dried Powders Using Computational Fluid Dynamics (CFD) Modeling.

Computational fluid dynamics (CFD) modeling offers a powerful tool for the development of drug delivery devices using a first principles approach but has been underutilized in the development of pharmaceutical inhalers. The objective of this study was to develop quantitative correlations for predicting the aerosolization behavior of a newly proposed dry powder inhaler (DPI). The dose aerosolization and containment (DAC) unit DPI utilizes inlet and outlet air orifices designed to maximize the dispersion of spray-dried powders, typically with low air volumes (~ 10 mL) and relatively low airflow rates (~ 3 L/min). Five DAC unit geometries with varying orifice outlet sizes, configurations, and protrusion distances were considered. Aerosolization experiments were performed using cascade impaction to determine mean device emitted dose (ED) and mass median aerodynamic diameter (MMAD). Concurrent CFD simulations were conducted to predict both flow field-based and particle-based dispersion parameters that captured different measures of turbulence. Strong quantitative correlations were established between multiple measures of turbulence and the experimentally observed aerosolization metrics of ED and MMAD. As expected, increasing turbulence produced increased ED with best case values reaching 85% of loaded dose. Surprisingly, decreasing turbulence produced an advantageous decrease in MMAD with values as low as approximately 1.6 µm, which is in contrast with previous studies. In conclusion, CFD provided valuable insights into the performance of the DAC unit DPI as a new device including a two-stage aerosolization process offering multiple avenues for future enhancements.

Aerosol Delivery Through an Adult High-Flow Nasal Cannula Circuit Using Low-Flow Oxygen.

BACKGROUND: There has been a growing trend toward delivering aerosolized medications using high-flow nasal cannula (HFNC). In some cases, patients who do not require high-flow oxygen to maintain adequate oxygenation may benefit from aerosol delivery while receiving low-flow oxygen via HFNC. The objective of this study was to quantify and compare the relative pulmonary and systemic delivery of salbutamol, with 2 different nebulizers, in patients with COPD receiving low-flow oxygen therapy through an HFNC. METHODS: Subjects were randomized to receive study doses of 5 mg salbutamol nebulized by either a jet nebulizer or a vibrating mesh nebulizer with a T-piece or spacer on days 1, 3, and 5 of admission. Subjects using the large spacer also received 2 puffs (100 µg each) of salbutamol via a pressurized metered-dose-inhaler prior to the nebulizer dose. Urinary salbutamol excretion 30 min post-inhalation and pooled samples of urinary salbutamol excretion up to 24 h post-inhalation were measured. On day 2, ex vivo studies were performed with salbutamol collected on filters placed between the HFNC and nebulizer, with drug eluted from filters and analyzed to determine inhaled dose. RESULTS: Twelve subjects (6 females), age 51.3 ± 11.2 y, were included. The vibrating mesh nebulizer demonstrated higher urinary salbutamol excretion at 30 min and 24 h post-inhalation compared to a jet nebulizer (P = .001 and P = .02, respectively). No significant difference was found between the T-piece and large-spacer configurations, even though the spacer provided a significantly larger emitted aerosol dose at the opening of the HFNC (P = .002). CONCLUSIONS: Aerosolized medication could be efficiently combined with low-flow oxygen, via HFNC, in COPD subjects without the need to interrupt the gas supply. The vibrating mesh nebulizer delivered larger doses to subjects compared to the jet nebulizer. However, there was no benefit of using the large spacer with HFNC in low-flow delivery, because the small inner diameter of the HFNC does not allow larger aerosol droplet sizes (preserved by the spacer) to reach the subject.

Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Accurately Predicts the Better Bronchodilatory Effect of Inhaled Versus Oral Salbutamol Dosage Forms.

BACKGROUND: Predicting local lung tissue pharmacodynamic (PD) responses of inhaled drugs is a longstanding challenge related to the lack of experimental techniques to determine local free drug concentrations. This has prompted the use of physiologically based pharmacokinetic (PBPK) modeling to potentially predict local concentration and response. A unique opportunity for PBPK model evaluation is provided by the clinical PD data for salbutamol, which in its inhaled dosage form (400 µg), produces a higher bronchodilatory effect than in its oral dosage form (2 mg) despite lower drug concentrations in blood. The present study aimed at evaluating whether inhalation PBPK model predictions of free drug in tissue would be predictive of these observations. METHODS: A PBPK model, including 24 airway generations, was parameterized to describe lung, plasma, and epithelial lining fluid concentrations of salbutamol administered intratracheally and intravenously to rats (100 nmol/kg). Plasma and lung tissue concentrations of unbound (R)-salbutamol, the active enantiomer, were predicted with a humanized version of the model and related to effect in terms of forced expiratory volume in 1 second (FEV1). RESULTS: In contrast to oral dosing, the model predicted inhalation to result in spatial heterogeneity in the target site concentrations (subepithelium) with higher free drug concentrations in the lung as compared with the plasma. FEV1 of inhaled salbutamol was accurately predicted from the PK/PD relationship derived from oral salbutamol and PBPK predictions of free concentration in airway tissue of high resistance (e.g., 6th generation). CONCLUSION: An inhalation PBPK-PD model was developed and shown predictive of local pharmacology of inhaled salbutamol, thus conceptually demonstrating the validity of PBPK model predictions of free drug concentrations in lung tissue. This achievement unlocks the power of inhalation PBPK modeling to interrogate local pharmacology and guide optimization and development of inhaled drugs and their formulations.

An Efficient, Lung-Targeted, Drug-Delivery System To Treat Asthma Via Microparticles.

BACKGROUND: Chronic diseases such as diabetes, asthma, and heart disease are the leading causes of death in developing countries. Public health plays an important role in preventing such diseases to improve individuals' quality of life. Conventional dosage schemes used in public health to cure various diseases generally lead to undesirable side effects and renders the overall treatment ineffective. For example, a required concentration of drug cannot reach the lungs using conventional methods to cure asthma. Microspheres have emerged as a confirmed drug-delivery system to cure asthma. METHOD: In this paper, a salbutamol-loaded poly lactic acid-co-glycolic acid-polyethylene glycol (PLGA-PEG) microsphere (SPP)-based formulation was prepared using a Buchi B-90 nanospray drier. Face-centered central composite design (CCD) was applied to optimize the spray-drying process. RESULTS: The drug content and product yield were found to be 72%±0.8% and 86%±0.4%, respectively; drug release (91.1%) peaked for up to 12 hrs in vitro. Microspheres obtained from the spray dryer were found to be shriveled. The experiments were carried out and verified using various groups of rabbits. In our study, the particle size (8.24 µm) was observed to be an essential parameter for drug delivery. The in vivo results indicated that the targeting efficacy and drug concentration in the lung was higher with the salbutamol-loaded PLGA-PEG SPP formulation (1,410.1±10.11 µg/g, 15 mins), as compared to the conventional formulation (92±0.56 µg/g, 10 min). The final product was stable under 5°C±2°C, 25°C±2°C, and 40°C±2°C/75%±5% relative humidity. In addition, these co-polymers have a good safety profile, as determined by testing on human alveolar basal epithelium A549 cell lines. CONCLUSION: Our results prove that microspheres are an alternative drug-delivery system for lung-targeted asthma treatments used in public health.

Pharmacokinetics and safety of salbutamol/ambroxol fixed-dose combination granules in healthy Chinese subjects
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OBJECTIVES: The aim of the study was to investigate the pharmacokinetics and tolerability of salbutamol/ambroxol fixed-dose combination granules following single and multiple dosing in healthy Chinese subjects. MATERIALS AND METHODS: This was a randomized, open-label, two-period, one-sequence study (n = 12). Each subject received a single oral dose in period 1 and multiple doses in period 2. Plasma concentrations of these two components were determined using a validated LC-MS/MS method. Adverse events (AEs) were documented throughout the study. Investigators evaluated AEs in terms of frequency, duration, intensity, seriousness, outcome, and relationship to study drugs. RESULTS: Following single dosing, Cmax values were 8.07 ± 1.31 ng/mL and 25.7 ± 6.5 ng/mL for salbutamol and ambroxol, respectively. The corresponding T1/2 values were 8.15 ± 3.13 hours and 9.31 ± 2.27 hours, respectively. Moreover, no statistical differences in the pharmacokinetics of salbutamol and ambroxol in subjects receiving single or multiple dosage were observed. Single- and multiple-dose oral administration of fixed-dose combination granules were safe and well tolerated in healthy Chinese subjects. Drug hypersensitivity syndrome did not occur during our study. CONCLUSION: The pharmacokinetics of salbutamol and ambroxol in the fixed-dose combination granules were not affected by dosing duration, and gender differences seemed to have no effect on the pharmacokinetics of salbutamol and ambroxol after a single dose and multiple doses of the medication.
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Performance of Large Spacer Versus Nebulizer T-Piece in Single-Limb Noninvasive Ventilation.

BACKGROUND: Predosing patients with COPD with salbutamol by using a pressurized metered-dose-inhaler (pMDI) as a bronchodilator was hypothesized to improve the distribution of the subsequent nebulized dose. This study determined the effect of a pMDI preliminary bronchodilator dose on the aerosol delivered by a mesh nebulizer during single-limb noninvasive ventilation. METHODS: Twelve subjects with COPD who received noninvasive ventilation were enrolled in a randomized, open-label, urinary pharmacokinetic study. A bi-level ventilator with a dry single-limb circuit and the fixed expiratory port was set in the spontaneous mode, with initial inspiratory and expiratory pressures of 20 and 5 cm H2O respectively, a 1:3 inspiratory-expiratory ratio, and 15 breaths/min. Salbutamol was administered via a mesh nebulizer with a large spacer or T-piece placed between the fixed-orifice expiratory valve and the oronasal mask. In vivo dosing methods were randomized for days 1, 3, and 5 of the study. On each day, a 1-mL respirable solution that contained 5,000 µg salbutamol was nebulized by using a mesh nebulizer with 3 setting: (1) T-piece, (2) large spacer, and (3) large spacer plus pMDI. Only with the large spacer plus pMDI setting, 2 pMDI doses, which contained 100 µg salbutamol each, were actuated before nebulization. Urine samples were collected at 0.5 h (as an index of pulmonary bioavailability) and pooled up to 24 h after dosing (as an index of systemic absorption). On day 2, ex vivo studies were performed for the 3 setting with salbutamol collected onto filters placed before the mask. The drug was eluted from the filters and analyzed to determine the inhaled dose. RESULTS: A large spacer plus pMDI showed a trend to deliver a higher fraction (percentage of nominal dose) of both ex vivo filters and 0.5-h urinary salbutamol. The 0.5-h urinary salbutamol excreted with a large spacer plus pMDI (1.99%) was larger than with the T-piece (1.73%) and large spacer (1.78%). This trend did not extend to the 24-h levels, in which bioavailability with the large spacer plus pMDI (49.9%) was lower than with the T-piece (52.8%) and with the large spacer (54.3%). However, no differences were significant. CONCLUSIONS: The T-piece and large spacer were equally efficient for salbutamol delivery from the mesh nebulizer in patients with COPD and on single-limb noninvasive ventilation. Adding a preliminary bronchodilator dose by pMDI prenebulization showed a trend toward greater pulmonary bioavailability of nebulized salbutamol and may be worth considering to maximize delivery of salbutamol to patients who are severely ill.