Effects of saline nebulization on SARS-CoV-2 RNA spreading and exhaled bio-aerosol particles in COVID-19 patients.

BACKGROUND: Nebulized therapy is the mainstay for treating obstructive airway diseases, but there is heightened concern about the potential risk for SARS-CoV-2 transmission during nebulization in COVID-19 patients. AIM: To investigate the effects of 0.9% saline nebulization on SARS-CoV-2 RNA spreading in 11 COVID-19 patients (five females, mean age 62.45 ± 9.31 years); also to ascertain whether saline nebulization changed the number of exhaled bio-aerosol particles in six out of the 11 patients. METHODS: Air samples were collected using suction pumps equipped with 0.45 µm PTFE filters and positioned around the patient's bed. Exhaled particles were quantified by using an optical particle counter. FINDINGS: At baseline (i.e. before nebulization) SARS-CoV-2 was detected more frequently in the pumps close to the patient than in those far away. After saline nebulization, the detection of SARS-CoV-2 in the pumps close to the patient was comparable to that observed at baseline. In the pumps far from the patient, saline nebulization slightly, but not significantly, increased SARS-CoV-2 RNA detection compared to baseline. Overall, no significant changes in the SARS-CoV-2 RNA detection were observed after saline nebulization. At baseline, exhaled particle emission varied among patients, with two of them showing higher emission of particles than the remaining patients. Saline nebulization induced a marked decrease in exhaled particles in the two patients who displayed high emission at baseline, whereas no changes were observed in the remaining patients. Saline nebulization did not significantly change SARS-CoV-2 RNA spreading. CONCLUSION: Saline nebulization does not significantly increase SARS-CoV-2 spreading.

Dry powder inhalation: past, present and future.

INTRODUCTION: Early dry powder inhalers (DPIs) were designed for low drug doses in asthma and COPD therapy. Nearly all concepts contained carrier-based formulations and lacked efficient dispersion principles. Therefore, particle engineering and powder processing are increasingly applied to achieve acceptable lung deposition with these poorly designed inhalers. Areas covered: The consequences of the choices made for early DPI development with respect of efficacy, production costs and safety and the tremendous amount of energy put into understanding and controlling the dispersion performance of adhesive mixtures are discussed. Also newly developed particle manufacturing and powder formulation processes are presented as well as the challenges, objectives, and new tools available for future DPI design. Expert opinion: Improved inhaler design is desired to make DPIs for future applications cost-effective and safe. With an increasing interest in high dose drug delivery, vaccination and systemic delivery via the lungs, innovative formulation technologies alone may not be sufficient. Safety is served by increasing patient adherence to the therapy, minimizing the use of unnecessary excipients and designing simple and self-intuitive inhalers, which give good feedback to the patient about the inhalation maneuver. For some applications, like vaccination and delivery of hygroscopic formulations, disposable inhalers may be preferred.

Nasal powders of thalidomide for local treatment of nose bleeding in persons affected by hereditary hemorrhagic telangiectasia.

In this work nasal powder formulations of thalidomide were designed and studied to be used by persons affected by hereditary hemorrhagic telangiectasia as a complementary anti-epistaxis therapy, with the goal of sustaining the effect obtained with thalidomide oral treatment after its discontinuation for adverse effects. Three nasal powders were prepared using as carriers ß-CD or its more hydrophilic derivatives such as hydropropyl-ß-CD and sulphobutylether-ß-CD and tested with respect to technological and biopharmaceutical features after emission with active and passive nasal powder devices. For all formulated powders, improved dissolution rate was found compared to that of the raw material, making thalidomide promptly available in the nasal environment at a concentration favouring an accumulation in the mucosa. The very limited transmucosal transport measured in vitro suggests a low likelihood of significant systemic absorption. The topical action on bleeding could benefit from the poor absorption and from the fact that about 2-3% of the thalidomide applied on the nasal mucosa was accumulated within the tissue, particularly with the ß-CD nasal powder.

Ex vivo permeation of tamoxifen and its 4-OH metabolite through rat intestine from lecithin/chitosan nanoparticles.

Tamoxifen citrate is an anticancer drug slightly soluble in water. Administered orally, it shows great intra- and inter-patient variations in bioavailability. We developed a nanoformulation based on phospholipid and chitosan able to efficiently load tamoxifen and showing an enzyme triggered release. In this work the permeation of tamoxifen released from lecithin/chitosan nanoparticles across excised rat intestinal wall mounted in an Ussing chamber was investigated. Compared to tamoxifen citrate suspension, the amount of the drug permeated using the nanoformulation was increased from 1.5 to 90 times, in absence or in presence of pancreatin or lipase, respectively. It was also evidenced the formation of an active metabolite of tamoxifen, 4-hydroxy tamoxifen, however, the amount of metabolite permeated remained roughly constant in all experiments. The effect of enzymes on intestinal permeation of tamoxifen was shown only when tamoxifen-loaded nanoparticles were in intimate contact with the mucosal surface. The encapsulation of tamoxifen in lecithin/chitosan nanoparticles improved the non-metabolized drug passing through the rat intestinal tissue via paracellular transport.

Towards the bioequivalence of pressurised metered dose inhalers 1: design and characterisation of aerodynamically equivalent beclomethasone dipropionate inhalers with and without glycerol as a non-volatile excipient.

A series of semi-empirical equations were utilised to design two solution based pressurised metered dose inhaler (pMDI) formulations, with equivalent aerosol performance but different physicochemical properties. Both inhaler formulations contained the drug, beclomethasone dipropionate (BDP), a volatile mixture of ethanol co-solvent and propellant (hydrofluoroalkane-HFA). However, one formulation was designed such that the emitted aerosol particles contained BDP and glycerol, a common inhalation particle modifying excipient, in a 1:1 mass ratio. By modifying the formulation parameters, including actuator orifice, HFA and metering volumes, it was possible to produce two formulations (glycerol-free and glycerol-containing) which had identical mass median aerodynamic diameters (2.4µm±0.1 and 2.5µm±0.2), fine particle dose (⩽5µm; 66µg±6 and 68µg±2) and fine particle fractions (28%±2% and 30%±1%), respectively. These observations demonstrate that it is possible to engineer formulations that generate aerosol particles with very different compositions to have similar emitted dose and in vitro deposition profiles, thus making them equivalent in terms of aerosol performance. Analysis of the physicochemical properties of each formulation identified significant differences in terms of morphology, thermal properties and drug dissolution of emitted particles. The particles produced from both formulations were amorphous; however, the formulation containing glycerol generated particles with a porous structure, while the glycerol-free formulation generated particles with a primarily spherical morphology. Furthermore, the glycerol-containing particles had a significantly lower dissolution rate (7.8%±2.1%, over 180min) compared to the glycerol-free particles (58.0%±2.9%, over 60min) when measured using a Franz diffusion cell. It is hypothesised that the presence of glycerol in the emitted aerosol particles altered solubility and drug transport, which may have implications for BDP pharmacokinetics after deposition in the respiratory tract.

Critical characteristics for corticosteroid solution metered dose inhaler bioequivalence.

Determining bioequivalence for solution pressurized metered dose inhalers (pMDI) is difficult because the critical characteristics of such products are poorly defined. The aim of this study was to elucidate the non-aerodynamic properties of the emitted aerosol particles from two solution pMDI products that determine their biopharmaceutical differences after deposition. Novel particle capture and analysis techniques were employed to characterize the physicochemical and biopharmaceutical properties of two beclomethasone dipropionate (BDP) products: QVAR and Sanasthmax. The BDP particles emitted from the Sanasthmax inhaler were discernibly different those emitted from QVAR in terms of size (50% larger, less porous), solid state (less crystalline) and dissolution (20-fold slower). When deposited onto the surface of respiratory epithelial cell layers, QVAR delivered ∼50% more BDP across the cell layer in 60 min than Sanasthmax. Biopharmaceutical performance was not attributable to individual particle properties as these were manifold with summative and/or competing effects. The cell culture dissolution-absorption model revealed the net effect of the particle formed on drug disposition and was predictive of human systemic absorption of BDP delivered by the test inhalers. This illustrates the potential of the technique to detect the effect of formulation on the performance of aerosolized particles and contribute to assessment of bioequivalence.

Methacholine dry powder inhaler as a new tool for bronchial challenge test.

BACKGROUND: The methacholine (MCH) challenge test is performed to detect bronchial hyperresponsiveness in subjects suffering from asthma. It is conducted by inhaling spasmogen substances at increasing doses and measuring FEV1-PD20 variation following the bronchoconstriction evoked. AIM: This paper describes a new method for MCH challenge test using pre-metered respirable powders of MCH at different doses for facilitating test execution. The availability of a series of pre-metered doses gives higher control over aerosolized dose and fine particle fraction (respirable dose), improving the accuracy and repeatability of the test. Dosimetric tests with MCH solution and pre-dosed powder challenge tests were clinically compared. METHODS AND MATERIALS: The inhalation powders were prepared by spray drying of solutions of methacholine, mannitol and hydroxypropylmethylcellulose in which different concentrations of MCH were included. The methacholine powders prepared were carefully characterized in terms of aerodynamic properties. RESULTS: Inhalation powders containing methacholine from 12.5 to 200 microg per metered dose, having a fine particle fraction between 40 and 60%, were prepared using mannitol and cellulose polymer. Eighteen subjects (12 hyperresponsive and six normal) were subjected to both the MCH solution and powder tests in random sequence. No significant differences in FEV1 and PD20 values were found between the challenge tests performed with liquid and powder formulations of methacholine. CONCLUSIONS: Powders of MCH having high respirability of the delivered doses can be prepared by spray drying. They allow for the performance of a challenge test using a dry powder inhaler. The powder dose series can be an alternative to the current dosimetric test with MCH solutions.

Back to basics: the development of a simple, homogenous, two-component dry-powder inhaler formulation for the delivery of budesonide using miscible vinyl polymers.

It was hypothesised that formulating a dry-powder inhaler (DPI) using a refined, smooth grade of lactose, without fines and a polymer coated drug microparticle should produce an homogeneous formulation in which aerosolization behaviour could be modified. Hence, the aim of this study was to develop a simple two component polymer coated-budesonide/lactose blend in which the drug microparticle adhesive forces could be optimised by modifying the drug coating in order to improve aerosolization from a DPI. Budesonide microparticles (1.83 +/- 0.03 microm) were coated with the vinyl polymers by adsorption and then spray-dried. The drug was blended with three different types of lactose, checked for uniformity of mixing and loaded into Pulvinal devices. The median volume particle size of all but one of the polymer coated microparticles remained below 4 microm after spray-drying and the content uniformity for all the blends >96%. Coating the budesonide with 0.01% poly(vinyl alcohol) increased the fine particle fraction (FPF) in the next generation impactor (NGI) from 29.1 +/- 0.7% to 52.8 +/- 1.0% and reduced the force of adhesion from 410 +/- 182 to 241 +/- 82 nN with smooth lactose. This illustrates that vinyl polymers could effectively modify adhesive interactions without the need for ternary components such as fines.

Multilayer PVA adsorption onto hydrophobic drug substrates to engineer drug-rich microparticles.

Despite the availability of numerous crystal engineering techniques, generating drug-rich microparticles with a predetermined size, morphology and crystallinity still represents a significant challenge. A microparticle manufacturing method has recently been developed that attempts to 'shield' the physicochemical properties of micronised drugs by the application of a microfine polymer coating. The aims of this study were to investigate the nature of the drug-polymer interactions and determine the effects of this manufacturing strategy upon release of the drug from the microparticles. The adsorption of poly(vinyl alcohol) (PVA) on the micronised hydrophobic drug surface was found to reach equilibrium between 23 and 27 h. The Freundlich isotherm model was shown to give the most accurate fit to the experimental data and thus multilayer adsorption was assumed. The adsorptive capacity (1/n) was specific to the substrate and PVA grade. An increase in the PVA (%) hydrolysis value caused 1/n to increase from 0.76 to 1.05 using budesonide and from 0.31 to 0.79 when betamethasone valerate (BMV) was used. Increasing the molecular weight of the adsorbing polymer caused a reduction in the strength of PVA-adsorbate interaction when budesonide was used as the substrate (from 0.76 to 0.59), whereas a three-fold increase (from 0.31 to 0.86) was achieved when the BMV substrate was employed. A proportion of the adsorbed polymer was shown to remain associated with the substrate during the spray-drying process and the polymer coating resulted in a significantly higher (p<0.05, ANOVA) amount of drug release in 60 min (ca. 100%) compared to budesonide alone.