RESUMEN
Tuberculosis places a staggering burden on human health globally. The new World Health Organisation End-TB Strategy has highlighted the urgent need for more effective TB vaccines to improve control of the disease. Protein-based subunit vaccines offer potential as safe and effective generators of protective immunity, and the use of particulate vaccine formulation and delivery by the pulmonary route may enhance local immunogenicity. In this study, novel particulate subunit vaccines were developed utilising biodegradable poly(lactic-co-glycolic acid) (PLGA) slow-release particles as carriers for the Mycobacterium tuberculosis lipoprotein MPT83, together with the adjuvants trehalose-dibehenate (TDB) or Monophosphoryl lipid A (MPL). Following delivery by the pulmonary or subcutaneous routes, the immunogenicity and protective efficacy of these vaccines were assessed in a murine model of M. tuberculosis infection. When delivered peripherally, these vaccines induced modest, antigen-specific Th1 and Th17 responses, but strong anti-MPT83 antibody responses. Mucosal delivery of the PLGA(MPT83) vaccine, with or without TDB, increased antigen-specific Th17 responses in the lungs, however, PLGA-encapsulated vaccines did not provide protection against M. tuberculosis challenge. By contrast, peripheral delivery of DDA liposomes containing MPT83 and TDB or MPL, stimulated both Th1 and Th17 responses and generated protection against M. tuberculosis challenge. Therefore, PLGA-formulated vaccines primarily stimulate strong humoral immunity, or Th17 responses if used mucosally, and may be a suitable carrier for vaccines against extracellular pathogens. This study emphasises the critical nature of the vaccine carrier, adjuvant and route of delivery for optimising vaccine efficacy against TB.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Inmunidad Humoral/efectos de los fármacos , Ácido Láctico/farmacología , Mycobacterium tuberculosis/inmunología , Ácido Poliglicólico/farmacología , Células Th17/efectos de los fármacos , Vacunas contra la Tuberculosis/inmunología , Tuberculosis/inmunología , Animales , Femenino , Recuento de Linfocitos , Ratones , Ratones Endogámicos C57BL , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Células Th17/inmunología , Tuberculosis/prevención & control , Vacunas contra la Tuberculosis/química , Vacunas de Subunidad/inmunología , Vacunas de Subunidad/farmacologíaRESUMEN
The design of a dry powder inhaler device has significant influence on aerosol performance; however, such influence may be different between the drug-only and carrier-based formulations. The present study aims to examine the potential difference on the dispersion between these distinct types of formulations, using Aerolizer(®) as a model inhaler with the original or modified (cross-grid) designs. A coupled CFD-discrete element method analysis was employed to determine the flow characteristics and particle impaction. Micronized salbutamol sulphate as a drug-only formulation and three lactose carrier-based formulations with various drug-to-carrier weight ratios 1:5, 1:10 and 1:100 were used. The in vitro aerosolization performance was assessed by a next-generation impactor operating at 100 L/min. Using the original device, FPFloaded was reduced from 47.5 ± 3.8% for the drug-only formulation to 31.8 ± 0.7%, 32.1 ± 0.7% and 12.9 ± 1.0% for the 1:5, 1:10 and 1:100 formulations, respectively. With the cross-grid design, powder-mouthpiece impaction was increased, which caused not only powder deagglomeration but also significant drug retention (doubling or more) in the mouthpiece, and the net result is a significant decrease in FPFloaded to 36.8 ± 1.2%, 20.9 ± 2.6% and 21.9 ± 1.5% for the drug-only, 1:5 and 1:10 formulations, respectively. In contrast, the FPFloaded of the 1:100 formulation remained the same at 12.1 ± 1.3%, indicating the increased mouthpiece drug retention was compensated by increased drug detachment from carriers caused by increased powder-mouthpiece impaction. In conclusion, this study has elucidated different effects and the mechanism on the aerosolization of varied dry powder inhaler formulations due to the grid design.
Asunto(s)
Aerosoles/química , Albuterol/química , Broncodilatadores/química , Portadores de Fármacos/química , Inhaladores de Polvo Seco/instrumentación , Diseño de Equipo/instrumentación , Administración por Inhalación , Aerosoles/administración & dosificación , Albuterol/administración & dosificación , Broncodilatadores/administración & dosificación , Química Farmacéutica , Comprensión , Portadores de Fármacos/administración & dosificaciónRESUMEN
Colistin has been increasingly used for the treatment of respiratory infections caused by Gram-negative bacteria. Unfortunately parenteral administration of colistin can cause severe adverse effects. This study aimed to develop an inhaled combination dry powder formulation of colistin and rifapentine for the treatment of respiratory infections. The combination formulation was produced by spray-drying rifapentine particles suspended in an aqueous colistin solution. The combination dry powder had enhanced antimicrobial activities against planktonic cells and biofilm cultures of Pseudomonas aeruginosa, with both minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC) values (2 and 4 mg/L, respectively) being half that of pure colistin (MIC 4 mg/L and MBIC 8 mg/L) and 1/16th that of pure rifapentine (MIC 32 mg/L and MBIC 64 mg/L). High aerosol performance, as measured via an Aerolizer device, was observed with emitted doses>89% and fine particle fraction (FPF) total>76%. The proportion of submicron particles of rifapentine particles was minimized by the attachment of colistin, which increased the overall particle mass and aerodynamic size distribution. Using the spray-drying method described here, stable particles of amorphous colistin and crystalline rifapentine were distributed homogeneously in each stage of the impinger. Unlike the colistin alone formulation, no deterioration in aerosol performance was found for the combination powder when exposed to a high relative humidity of 75%. In our previous study, surface coating by rifampicin contributed to the moisture protection of colistin. Here, a novel approach with a new mechanism was proposed whereby moisture protection was attributed to the carrier effect of elongated crystalline rifapentine particles, which minimized contact between hygroscopic colistin particles. This inhaled combination antibiotic formulation with enhanced aerosol dispersion efficiency and in vitro efficacy could become a superior treatment for respiratory infections.
Asunto(s)
Antiinfecciosos/administración & dosificación , Colistina/administración & dosificación , Inhaladores de Polvo Seco , Nanopartículas/administración & dosificación , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Rifampin/análogos & derivados , Administración por Inhalación , Antiinfecciosos/química , Biopelículas/efectos de los fármacos , Colistina/química , Combinación de Medicamentos , Sinergismo Farmacológico , Humanos , Pruebas de Sensibilidad Microbiana , Nanopartículas/química , Rociadores Nasales , Tamaño de la Partícula , Plancton/efectos de los fármacos , Polvos , Pseudomonas aeruginosa/crecimiento & desarrollo , Pseudomonas aeruginosa/fisiología , Rifampin/administración & dosificación , Rifampin/químicaRESUMEN
The efficacy of pharmaceutical aerosols relates to its deposition in the clinically relevant regions of the lungs, which can be assessed by in vivo lung deposition studies. Dry powder formulations are popular as devices are portable and aerosolisation does not require a propellant. Over the years, key advancements in dry powder formulation, device design and our understanding on the mechanics of inhaled pharmaceutical aerosol have opened up new opportunities in treatment of diseases through pulmonary drug delivery. This review covers these advancements and future directions for inhaled dry powder aerosols.
Asunto(s)
Sistemas de Liberación de Medicamentos , Inhaladores de Polvo Seco , Pulmón/efectos de los fármacos , Preparaciones Farmacéuticas/administración & dosificación , Aerosoles , Animales , Sistemas de Liberación de Medicamentos/instrumentación , Sistemas de Liberación de Medicamentos/métodos , Diseño de Equipo , Humanos , Insulina/administración & dosificación , Insulina/farmacocinética , Pulmón/metabolismo , Tamaño de la Partícula , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/metabolismo , Polvos , Electricidad Estática , Propiedades de Superficie , Distribución TisularRESUMEN
PURPOSE: To demonstrate the novel application of nano X-ray computed tomography (NanoXCT) for visualizing and quantifying the internal structures of pharmaceutical particles. METHODS: An Xradia NanoXCT-100, which produces ultra high-resolution and non-destructive imaging that can be reconstructed in three-dimensions (3D), was used to characterize several pharmaceutical particles. Depending on the particle size of the sample, NanoXCT was operated in Zernike Phase Contrast (ZPC) mode using either: 1) large field of view (LFOV), which has a two-dimensional (2D) spatial resolution of 172 nm; or 2) high resolution (HRES) that has a resolution of 43.7 nm. Various pharmaceutical particles with different physicochemical properties were investigated, including raw (2-hydroxypropyl)-beta-cyclodextrin (HßCD), poly (lactic-co-glycolic) acid (PLGA) microparticles, and spray-dried particles that included smooth and nanomatrix bovine serum albumin (BSA), lipid-based carriers, and mannitol. RESULTS: Both raw HßCD and PLGA microparticles had a network of voids, whereas spray-dried smooth BSA and mannitol generally had a single void. Lipid-based carriers and nanomatrix BSA particles resulted in low quality images due to high noise-to-signal ratio. The quantitative capabilities of NanoXCT were also demonstrated where spray-dried mannitol was found to have an average void volume of 0.117 ± 0.247 µm(3) and average void-to-material percentage of 3.5%. The single PLGA particle had values of 1993 µm(3) and 59.3%, respectively. CONCLUSIONS: This study reports the first series of non-destructive 3D visualizations of inhalable pharmaceutical particles. Overall, NanoXCT presents a powerful tool to dissect and observe the interior of pharmaceutical particles, including those of a respirable size.
Asunto(s)
Nanopartículas/química , Tecnología Farmacéutica/métodos , Tomografía Computarizada por Rayos X/métodos , 2-Hidroxipropil-beta-Ciclodextrina , Administración por Inhalación , Portadores de Fármacos/química , Ácido Láctico/química , Lípidos/química , Manitol/química , Tamaño de la Partícula , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Albúmina Sérica Bovina/química , Relación Señal-Ruido , beta-Ciclodextrinas/químicaRESUMEN
Inhaled pharmaceuticals are formulated and delivered differently according to the therapeutic indication. However, specific device-formulation coupling is often fickle, and new medications or indications also demand new strategies. The discontinuation of chlorofluorocarbon propellants has seen replacement of older metered dose inhalers with dry powder inhaler formulations. High-dose dry powder inhalers are increasingly seen as an alternative dosage form for nebulised medications. In other cases, new medications have completely bypassed conventional inhalers and been formulated for use with unique inhalers such as the Staccato® device. Among these different devices, integration of software and electronic assistance has become a shared trend. This review covers recent device and formulation advances that are forming the current landscape of inhaled therapeutics.
Asunto(s)
Química Farmacéutica/métodos , Sistemas de Liberación de Medicamentos/instrumentación , Sistemas de Liberación de Medicamentos/métodos , Pulmón/metabolismo , Tecnología Farmacéutica/instrumentación , Tecnología Farmacéutica/métodos , Administración por Inhalación , Química Farmacéutica/instrumentación , Inhaladores de Polvo Seco/instrumentación , Inhaladores de Polvo Seco/métodos , HumanosRESUMEN
Novel inhaled therapeutics including antibiotics, vaccines and anti-hypertensives, have led to innovations in designing suitable delivery systems. These emerging design technologies are in urgent demand to ensure high aerosolisation performance, consistent efficacy and satisfactory patient adherence. Recent vibrating-mesh and software technologies have resulted in nebulisers that have remarkably accurate dosing and portability. Alternatively, dry powder inhalers (DPIs) have become highly favourable for delivering high-dose and single-dose drugs with the aid of advanced particle engineering. In contrast, innovations are needed to overcome the technical constrains in drug-propellant incompatibility and delivering high-dose drugs with pressurised metered dose inhalers (pMDIs). This review discusses recent and emerging trends in pulmonary drug delivery systems.
Asunto(s)
Nebulizadores y Vaporizadores , Aerosoles , Sistemas de Liberación de Medicamentos , Humanos , Enfermedades Pulmonares/tratamiento farmacológico , Fármacos del Sistema Respiratorio/administración & dosificaciónRESUMEN
INTRODUCTION: Tuberculosis (TB) remains rampant throughout the world, in large part due to the lengthy treatment times of current therapeutic options. Rifapentine, a rifamycin antibiotic, is currently approved for intermittent dosing in the treatment of TB. Recent animal studies have shown that more frequent administration of rifapentine could shorten treatment times, for both latent and active TB infection. However, these results were not replicated in a subsequent human clinical trial. AREAS COVERED: This review analyses the evidence for more frequent administration of rifapentine and the reasons for the apparent lack of efficacy in shortening treatment times in human patients. Inhaled delivery is discussed as a potential option to achieve the therapeutic effect of rifapentine by overcoming the barriers associated with oral administration of this drug. Avenues for developing an inhalable form of rifapentine are also presented. EXPERT OPINION: Rifapentine is a promising active pharmaceutical ingredient with potential to accelerate treatment of TB if delivered by inhaled administration. Progression of current fundamental work on inhaled anti-tubercular therapies to human clinical trials is essential for determining their role in future treatment regimens. While the ultimate goal for global TB control is a vaccine, a short and effective treatment option is equally crucial.
Asunto(s)
Antituberculosos/administración & dosificación , Rifampin/análogos & derivados , Tuberculosis Pulmonar/tratamiento farmacológico , Administración por Inhalación , Animales , Esquema de Medicación , Humanos , Rifampin/administración & dosificaciónRESUMEN
PURPOSE: The potential for rifapentine-containing oral therapeutic regimens to significantly shorten the current six-month anti-tubercular treatment regimen is confounded by high plasma protein binding of rifapentine. Inhaled aerosol delivery of rifapentine, a more potent anti-tubercular antibiotic drug, in combination with other first-line antibiotics may overcome this limitation to deliver a high drug dose at the pulmonary site of infection. METHODS: A formulation consisting of rifapentine, moxifloxacin and pyrazinamide, with and without leucine, was prepared by spray-drying. This formulation was assessed for its physico-chemical properties, in vitro aerosol performance and antimicrobial activity. RESULTS: The antibiotic powders, with and without leucine, had similar median aerodynamic diameters of 2.58 ± 0.08 µm and 2.51 ± 0.06 µm, with a relatively high fine particle fraction of 55.5 ± 1.9% and 63.6 ± 2.0%, respectively. Although the powders were mostly amorphous, some crystalline peaks associated with the δ polymorph for the spray-dried crystalline pyrazinamide were identified. CONCLUSIONS: Stabilisation of the powder with 10% w/w leucine and protection from moisture ingress was found to be necessary to prevent overt crystallisation of pyrazinamide after long-term storage. In vitro biological assays indicated antimicrobial activity was retained after spray-drying. Murine pharmacokinetic studies are currently underway.
Asunto(s)
Antibióticos Antituberculosos/uso terapéutico , Rifampin/análogos & derivados , Tuberculosis/tratamiento farmacológico , Administración por Inhalación , Aerosoles , Animales , Antibióticos Antituberculosos/administración & dosificación , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Difracción de Polvo , Polvos , Rifampin/administración & dosificación , Rifampin/uso terapéuticoRESUMEN
PURPOSE: While most examples of nanoparticle therapeutics have involved parenteral or IV administration, pulmonary delivery is an attractive alternative, especially to target and treat local infections and diseases of the lungs. We describe a successful dry powder formulation which is capable of delivering nanoparticles to the lungs with good aerosolization properties, high loadings of nanoparticles, and limited irreversible aggregation. METHODS: Aerosolizable mannitol carrier particles that encapsulate nanoparticles with dense PEG coatings were prepared by a combination of ultrasonic atomization and spray freeze drying. This process was contrasted to particle formation by conventional spray drying. RESULTS: Spray freeze drying a solution of nanoparticles and mannitol (2 wt% solids) resulted in particles with an average diameter of 21 ± 1.7 µm, regardless of the fraction of nanoparticles loaded (0-50% of total solids). Spray freeze dried (SFD) powders with a 50% nanoparticle loading had a fine particle fraction (FPF) of 60%. After formulation in a mannitol matrix, nanoparticles redispersed in water to < 1 µm with hand agitation and to < 250 nm with the aid of sonication. Powder production by spray drying was less successful, with low powder yields and extensive, irreversible aggregation of nanoparticles evident upon rehydration. CONCLUSIONS: This study reveals the unique advantages of processing by ultrasonic spray freeze drying to produce aerosol dry powders with controlled properties for the delivery of therapeutic nanoparticles to the lungs.
Asunto(s)
Aerosoles/química , Portadores de Fármacos/química , Liofilización/métodos , Manitol/química , Nanopartículas/administración & dosificación , Ultrasonido/métodos , Nanopartículas/química , Tamaño de la Partícula , PolvosRESUMEN
Despite considerable research efforts towards effective treatments, tuberculosis (TB) remains a staggering burden on global health. Suitably formulated sub-unit vaccines offer potential as safe and effective generators of protective immunity. The Mycobacterium tuberculosis antigens, cutinase-like proteins (Culp) 1 and 6 and MPT83, were conjugated directly to the novel adjuvant Lipokel (Lipotek Pty Ltd), a TLR2 ligand that delivers antigen to immune cells in a self-adjuvanting context. Protein-Lipokel complexes were formulated as dry powders for pulmonary delivery directly to the lungs of mice by intra-tracheal insufflation, leading to recruitment of neutrophils and antigen presenting cell populations to the lungs at 72 h, that persisted at 7 days post immunisation. Significant increases in the frequency of activated dendritic cells were observed in the mediastinal lymph node (MLN) at 1 and 4 weeks after homologous boosting with protein-Lipokel vaccine. This was associated with the increased recruitment of effector CD4(+) and CD8(+) T-lymphocytes to the MLN and systemic antigen-specific, IFN-γ producing T-lymphocyte and IgG responses. Notably, pulmonary immunisation with either Culp1-6-Lipokel or MPT83-Lipokel powder vaccines generated protective responses in the lungs against aerosol M. tuberculosis challenge. The successful combination of TLR2-targeting and dry powder vaccine formulation, together with important practical benefits, offers potential for pulmonary vaccination against M. tuberculosis.
Asunto(s)
Mycobacterium tuberculosis/inmunología , Receptor Toll-Like 2/inmunología , Vacunas contra la Tuberculosis/inmunología , Tuberculosis/prevención & control , Vacunas Sintéticas/inmunología , Adyuvantes Inmunológicos/metabolismo , Administración Intranasal , Animales , Anticuerpos Antibacterianos/inmunología , Antígenos Bacterianos/genética , Antígenos Bacterianos/inmunología , Proteínas Bacterianas/genética , Proteínas Bacterianas/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Hidrolasas de Éster Carboxílico/genética , Hidrolasas de Éster Carboxílico/inmunología , Células Dendríticas/inmunología , Femenino , Inmunoglobulina G/inmunología , Interferón gamma/biosíntesis , Ganglios Linfáticos/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Mycobacterium tuberculosis/genética , Polvos/administración & dosificación , Receptor Toll-Like 2/metabolismo , Tuberculosis/inmunología , Vacunación/métodosRESUMEN
Treatment for tuberculosis (TB) using the standard oral antibiotic regimen is effective but inefficient, requiring high drug dosing and lengthy treatment times. Three concurrent first-line antibiotics recommended by the World Health Organization (WHO) guidelines are pyrazinamide, rifampicin and isoniazid. Combining these antibiotics in a novel formulation for dry powder inhalation (DPI) may facilitate rapid and efficient resolution of local and systemic infection. However, spray-dried individually, these antibiotics were found to be physically unstable. A solution of the three antibiotics, at the WHO-recommended ratio, was spray-dried. The collected powder was assessed by a series of in vitro methods to investigate aerosol performance, particle physico-chemical characteristics and dissolution profile. Particles obtained were spherical with a surface composed primarily of rifampicin, as identified by TOF-SIMS. A mass median aerodynamic diameter of 3.5 ± 0.1 µm and fine particle fraction (<5 µm) of 45 ± 3% indicated excellent aerosol performance. The combination powder was differentiated by the presence of rifampicin dihydrate and the delta polymorph of pyrazinamide. Quantitative analysis indicated individual particles contained the three antibiotics at the expected proportions (400:150:75 w/w). This excipient-free triple antibiotic DPI formulation could be used as a significant enhanced treatment for TB.
Asunto(s)
Antibióticos Antituberculosos/química , Polvos/química , Administración por Inhalación , Aerosoles/química , Química Farmacéutica/métodos , Inhaladores de Polvo Seco/métodos , Excipientes/química , Tamaño de la PartículaRESUMEN
BACKGROUND: Inhaled dry powder mannitol has established in vivo therapeutic efficacy for enhancing mucociliary function. However, a single dose necessitates multiple inhalations of a sizeable powder mass. Nebulization of mannitol by vibrating mesh devices has recently been shown in vitro to impart similar dosing in a comparable or lesser treatment time. Nevertheless, the limited solubility of mannitol restricted fluid concentrations to 150 mg/mL. The present study examines the feasibility of higher solubility polyols that presumably possess similar therapeutic properties to mannitol but deliverable at higher concentrations to shorten treatment time. A secondary aim is to compare delivery by two commercially available mesh nebulizers-the Aeroneb® Go and PARI eFlow Rapid. METHODS: A series of formulations containing three polyols (mannitol, sorbitol, and xylitol) of increasing concentration in 1% w/v sodium chloride were nebulized. Aerosol characteristics and treatment times were determined primarily by laser diffraction. RESULTS: RESULTS indicate viscosity is the primary determinant of vibrating mesh nebulizer performance. For both nebulizers, xylitol 334 mg/mL exhibits the greatest osmolar output-double that of 150 mg/mL mannitol. CONCLUSIONS: A nebulized xylitol solution has potential clinical application for promoting rapid mucociliary clearance. Both vibrating mesh nebulizers facilitate quick treatment times. Future in vivo studies would compare the efficacy of nebulized xylitol to commercial hyperosmolar agents and establish any potential polyol-associated antibacterial activity.
Asunto(s)
Sistemas de Liberación de Medicamentos , Manitol/administración & dosificación , Sorbitol/administración & dosificación , Xilitol/administración & dosificación , Administración por Inhalación , Diseño de Equipo , Estudios de Factibilidad , Manitol/química , Depuración Mucociliar , Nebulizadores y Vaporizadores , Cloruro de Sodio/química , Solubilidad , Sorbitol/química , Factores de Tiempo , Vibración , Viscosidad , Xilitol/químicaRESUMEN
This work provides a new understanding of critical process parameters involved in the production of inhalation aerosol particles by ultrasonic spray freeze drying to enable precise control over particle size and aerodynamic properties. A series of highly porous mannitol, lysozyme, and bovine serum albumin (BSA) particles were produced, varying only the solute concentration in the liquid feed, c(s), from 1 to 5 wt%. The particle sizes of mannitol, BSA, and lysozyme powders were independent of solute concentration, and depend only on the drop size produced by atomization. Both mannitol and lysozyme formulations showed a linear relationship between the computed Fine Particle Fraction (FPF) and the square root of c(s), which is proportional to the particle density, ρ, given a constant particle size d(g). The FPF decreased with increasing c(s) from 57.0% to 16.6% for mannitol and 44.5% to 17.2% for lysozyme. Due to cohesion, the BSA powder FPF measured by cascade impaction was less than 10% and independent of c(s). Ultrasonic spray freeze drying enables separate control over particle size, d(g), and aerodynamic size, d(a) which has allowed us to make the first experimental demonstration of the widely accepted rule d(a)=d(g)(ρ/ρ(o))(1/2) with particles of constant d(g), but variable density, ρ (ρ(o) is unit density).
Asunto(s)
Aerosoles , Liofilización/métodos , Material Particulado , Ultrasonido/métodos , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Sistemas de Liberación de Medicamentos , Rayos Láser , Manitol/química , Microscopía Electrónica de Rastreo , Muramidasa/química , Nanopartículas , Tamaño de la Partícula , Polvos , Albúmina Sérica Bovina/química , Espectrofotometría Ultravioleta , Temperatura , Difracción de Rayos XRESUMEN
Mucociliary clearance is compromised by airway surface liquid dehydration in respiratory disease states such as cystic fibrosis. Rehydration by hyperosmolar agents such as nebulised hypertonic saline and dry powder mannitol has demonstrated in vivo safety and efficacy for restoring mucociliary function. Mannitol, delivered as a nebulised formulation for this purpose, has not been investigated as yet. The current study examines the feasibility of delivering such a formulation using recent vibrating mesh technology. Nebulisation was conducted using an Aeroneb Go(TM) vibrating mesh nebuliser, and aerosol size was assessed by laser diffraction. Cascade impaction coupled with mass assay by high-performance liquid chromatography was used to confirm fluid uniformity and correlation with laser diffraction sizing. The following nebuliser formulations were prepared and aerosolised: deionised water, mannitol (150 mg/mL) aqueous solution, sodium chloride aqueous solution [0.2%, 1%, 3%, 5%, 7% (w/v)] and mannitol (150 mg/mL) in sodium chloride solution [0.2%, 1%, 3%, 7% (w/v)]. Mannitol aqueous solution was poorly nebulised, resulting in lengthy treatment times and large median droplet size. Addition of sodium chloride drastically improved nebuliser performance and aerosol characteristics. In vivo studies are necessary to confirm efficacy of nebulised mannitol. If substantiated, it could provide a pleasant-tasting alternative mucoactive agent with prolonged therapeutic action.