Powder Aerosol Research Articles

Pulmonary and Regional Deposition of Nebulized and Dry Powder Aerosols in Ferrets.

The utilization of ferrets as a non-clinical model for disease is rapidly increasing within drug development. Many of these models include respiratory diseases that involve targeted drug delivery via nose-only inhalation. While the deposition patterns within other non-clinical models (mice, rats, canines, and non-human primates) have been well studied, the local and regional deposition of aerosols in ferrets has not been well characterized. Therefore, inhalation aerosols were developed, radiolabeled and the radiolabeling methods validated to support SPECT-CT imaging and quantification of regional deposition within ferrets. The studies were conducted with one liquid formulation and one dry powder formulation (two concentrations of dry powder). Additionally, both aerosols were polydisperse and therefore reflect the majority of pharmaceutical aerosols. Overall, the studies showed lung deposition fractions between 5 and 10% with median aerodynamic particle sizes of 2.5 and 2.8μm. The lung deposition fraction of the liquid aerosol was ~ 9%, nearly double observed in rats with a similarly sized aerosol. Analysis of respiratory tract (oropharynx, laryngopharynx, trachea, bifurcation area, and lung) deposition indicates increased deposition of the liquid aerosol compared to the dry powder aerosol, however, when this analysis was refined to the pulmonary region (trachea, bifurcation, and lung) the deposition was similar between formulations. These data provide the first description of the regional deposition of inhalation aerosols in ferrets with standard nose-only inhalation procedures. These data can be used for calculations of both total and regional doses within ferret inhalation drug delivery.

Effects of the antibiotic component on in-vitro bacterial killing, physico-chemical properties, aerosolization and dissolution of a ternary-combinational inhalation powder formulation of antibiotics for pan-drug resistant Gram-negative lung infections

Combinational antibiotic formulations have emerged as an important strategy to combat antibiotic resistance. The main objective of this study was to examine effects of individual components on the antimicrobial activity, physico-chemical properties, aerosolization and dissolution of powder aerosol formulations when three synergistic drugs were co-spray dried. A ternary dry powder formulation consisting of meropenem (75.5 %w/w), colistin (15.1 %w/w) and rifampicin (9.4 %w/w) at the selected ratio was produced by spray drying. The ternary formulation was characterized for in-vitro antibacterial activity, physico-chemical properties, surface composition, aerosol performance and dissolution. All of the formulations demonstrated excellent aerosolization behavior achieving a fine particle fraction of >70%, which was substantially higher than those for the Meropenem-SD and Colistin-Meropenem formulations. The results indicated that rifampicin controlled the surface morphology of the ternary and binary combination formulations resulting in the formation of highly corrugated particles. Advanced characterization of surface composition by XPS supported the hypothesis that rifampicin was enriched on the surface of the combination powder formulations. All spray-dried formulations were amorphous and absorbed substantial amount of water at the elevated humidity. Storage at the elevated humidity caused a substantial decline in aerosolization performance for the Meropenem-SD and Colistin-Meropenem, which was attributed to increased inter-particulate capillary forces or particle fusion. In contrast, the ternary combination and binary Meropenem-Rifampicin formulations showed no change in aerosol performance at the elevated storage humidity conditions; attributable to the enriched hydrophobicity of rifampicin on the particle surface that acted as a barrier against moisture condensation and particle fusion. Interestingly, in the ternary formulation rifampicin enrichment on the surface did not interfere with the dissolution of other two components (i.e. meropenem and colistin). Our study provides an insight on the impact of each component on the performance of co-spray dried combinational formulations.

Aerosol drug delivery to the lungs during nasal high flow therapy: an in vitro study

BackgroundAerosol delivery through a nasal high flow (NHF) system is attractive for clinicians as it allows for simultaneous administration of oxygen and inhalable drugs. However, delivering a fine particle fraction (FPF, particle wt. fraction < 5.0 μm) of drugs into the lungs has been very challenging, with highest value of only 8%. Here, we aim to develop an efficient nose-to-lung delivery system capable of delivering improved quantities (FPF > 16%) of dry powder aerosols to the lungs via an NHF system.MethodsWe evaluated the FPF of spray-dried mannitol with leucine with a next generation impactor connected to a nasopharyngeal outlet of an adult nasal airway replica. In addition, we investigated the influence of different dispersion (20–30 L/min) and inspiratory (20–40 L/min) flow rates, on FPF.ResultsWe found an FPF of 32% with dispersion flow rate at 25 L/min and inspiratory flow rate at 40 L/min. The lowest FPF (21%) obtained was at the dispersion flow rate at 30 L/min and inspiratory flow rate at 30 L/min. A higher inspiratory flow rate was generally associated with a higher FPF. The nasal cannula accounted for most loss of aerosols.ConclusionsIn conclusion, delivering a third of inhalable powder to the lungs is possible in vitro through an NHF system using a low dispersion airflow and a highly dispersible powder. Our results may lay the foundation for clinical evaluation of powder aerosol delivery to the lungs during NHF therapy in humans.

Pharmacokinetic drug evaluation of CVT-301 for the treatment of Parkinson’s disease

ABSTRACTIntroduction: Levodopa (LD), in combination with a decarboxylase inhibitor, is a mainstay and the most effective therapeutic agent in the treatment of Parkinson’s disease (PD). Unfortunately, during chronic treatment with this agent, ON–OFF phenomena and dyskinesia appear. Despite the many medical treatment options available, unpredictable OFF episodes can still occur and be severe and disabling. A rescue therapy that provides a rapid and predictable ON response for patients with OFF periods would be of great value for such patients.Areas covered: CVT-301 is a self-administered dry powder aerosol inhaled formulation of LD that is being developed as a self-administered treatment for OFF periods. The PK profile of CVT-301, the efficacy, and the safety highlighted in randomized clinical trials will be reviewed.Expert opinion: CVT-301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism and less plasma-level variability.List of Abbreviations: PD: Parkinson’s disease; LD: Levodopa; CD: Carbidopa; AADC: aromatic L-amino acid decarboxylase; IR: immediate-release; FPD: fine particle dose; GI: gastrointestinal; PK: pharmacokinetic; CVs: coefficient of variation; UPDRS: Unified Parkinson’s Disease Rating Scale; AEs: adverse events; FEV: forced expiratory volume; FVC: forced vital capacity; DLCO: diffuse lung CO ; tmax: time to maximum concentration

Preparation and Characterization of Spherical Amorphous Solid Dispersion with Amphotericin B.

In the present study, new polymer microspheres of amphotericin B (AmB) were prepared by a spray drying technique using cyclodextrin polymers (Poly-CD) to improve the solubility and dissolution of AmB, to prevent in vivo toxic AmB aggregations. Formulations were characterized through scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermal analysis, Raman spectroscopy, particle size, drug purity test and in vitro release studies. The analysis indicated that the chemical structure of AmB remained unchanged in the amorphous solid dispersion, but the structure was changed from crystalline to amorphous. AmB was completely release from such optimized formulations in dissolution media in 40 min. This work may contribute to a new generation of spherical amorphous solid dispersion using a cyclodextrin polymer, which has implications for the possibility of drug development for oral utilization or as powder aerosols for pulmonary administration.

Correction: Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis.

[This corrects the article DOI: 10.1371/journal.pone.0204495.].

Impact of capsule type on aerodynamic performance of inhalation products: A case study using a formoterol-lactose binary or ternary blend

The aerodynamic performance of a dry powder for inhalation depends on the formulation and the dry powder inhaler (DPI). In the case of capsule-based DPIs, the capsule also plays a role in the powder aerosolisation and the dispersion of the micronized drug during the inhalation. This study evaluated the impact of gelatine capsules (Quali-G™ and Hard Gelatine Capsules for DPIs), cold-gelled hypromellose (HPMC) capsules (Quali-V®-I and Vcaps®) and thermal-gelled HPMC capsules (Vcaps®Plus) from Qualicaps® and Capsugel® respectively, on the delivered dose (DD), fine particle dose (FPD), and capsule retention for formoterol-lactose binary and ternary blends. This study used a low resistance Axahaler® DPI based on the RS01 design (Plastiape, Italy). Similar trends were observed with the different capsule types that packaged both dry powder formulations. The highest DD and FPD and the lowest formoterol capsule retention were observed with cold-gelled HPMC capsules such as Quali-V-I® and Vcaps®, without significant differences between these capsules (p > 0.05, one-way ANOVA with Newman-Keuls post-hoc test) for both dry powders. Therefore, the capsule composition and manufacturing process have an influence on aerodynamic performance. In addition, the ternary blend showed higher DDs and FPDs but also higher capsule retention in comparison to the binary blend.

Efficacy of pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of tuberculosis.

New therapeutic strategies are needed to treat drug resistant tuberculosis (TB) and to improve treatment for drug sensitive TB. Pyrazinamide (PZA) is a critical component of current first-line TB therapy. However, the rise in PZA-resistant TB cases jeopardizes the future utility of PZA. To address this problem, we used the guinea pig model of TB and tested the efficacy of an inhaled dry powder combination, referred to as Pyrazinoic acid/ester Dry Powder (PDP), which is comprised of pyrazinoic acid (POA), the active moiety of PZA, and pyrazinoic acid ester (PAE), which is a PZA analog. Both POA and PAE have the advantage of being able to act on PZA-resistant Mycobacterium tuberculosis. When used in combination with oral rifampicin (R), inhaled PDP had striking effects on tissue pathology. Effects were observed in lungs, the site of delivery, but also in the spleen and liver indicating both local and systemic effects of inhaled PDP. Tissue granulomas that harbor M. tuberculosis in a persistent state are a hallmark of TB and they pose a challenge for therapy. Compared to other treatments, which preferentially cleared non-necrotic granulomas, R+PDP reduced necrotic granulomas more effectively. The increased ability of R+PDP to act on more recalcitrant necrotic granulomas suggests a novel mechanism of action. The results presented in this report reveal the potential for developing therapies involving POA that are optimized to target necrotic as well as non-necrotic granulomas as a means of achieving more complete sterilization of M. tuberculosis bacilli and preventing disease relapse when therapy ends.

Nicotine-loaded chitosan nanoparticles for dry powder inhaler (DPI) formulations – Impact of nanoparticle surface charge on powder aerosolization

The aim of this study is to demonstrate the role of surface charge of nicotine loaded or unloaded chitosan (CS) nanoparticles on the dispersibility from dry powder inhaler (DPI) formulations. The nanoparticles were prepared using glutaraldehyde crosslinking of the amino groups of chitosan in a water-in-oil emulsion. Using dynamic light scattering (DLS) the particle size, size distribution and the zeta potential of nanoparticles were measured. The morphological characteristics were studied using SEM. The fine particle fractions (FPFs) of nanoparticles were determined by a twin stage impinger (TSI) using a Rotahaler at 60 L/min flow rate. The FPF of nanoparticles could be correlated to the surface charge i.e., FPFs were increased with increasing surface charge, which reduced with increased concentration of the drug. The FPF from the large carrier (lactose) based formulations was significantly higher (p < 0.001) than those of formulations without carriers. The higher FPF from the large carrier-based formulations was independent of zeta potential and thought to be associated with high impaction. These results suggested the mechanism of nicotine loaded CS nanoparticle dispersion without large carriers was dependent on the zeta potential, which was linked to the agglomeration or deagglomeration behaviour of particles.

Formulation of High-Performance Dry Powder Aerosols for Pulmonary Protein Delivery.

Pulmonary delivery of biologics is of great interest, as it can be used for the local treatment of respiratory diseases or as a route to systemic drug delivery. To reach the full potential of inhaled biologics, a formulation platform capable of producing high performance aerosols without altering protein native structure is required. A formulation strategy using Particle Replication in Non-wetting Templates (PRINT) was developed to produce protein dry powders with precisely engineered particle morphology. Stability of the incorporated proteins was characterized and the aerosol properties of the protein dry powders was evaluated in vitro with an Andersen Cascade Impactor (ACI). Model proteins bovine serum albumin (BSA) and lysozyme were micromolded into 1 μm cylinders composed of more than 80% protein, by mass. Extensive characterization of the incorporated proteins found no evidence of alteration of native structures. The BSA formulation produced a mass median aerodynamic diameter (MMAD) of 1.77 μm ± 0.06 and a geometric standard deviation (GSD) of 1.51 ± 0.06 while the lysozyme formulation had an MMAD of 1.83 μm ± 0.12 and a GSD of 1.44 ± 0.03. Protein dry powders manufactured with PRINT could enable high-performance delivery of protein therapeutics to the lungs.

Efficient Nose-to-Lung Aerosol Delivery with an Inline DPI Requiring Low Actuation Air Volume.

To demonstrate efficient aerosol delivery through an in vitro nasal model using a dry powder inhaler (DPI) requiring low actuation air volumes (LV) applied during low-flow nasal cannula (LFNC) therapy. A previously developed LV-DPI was connected to a LFNC system with 4mm diameter tubing. System connections and the nasal cannula interface were replaced with streamlined components. To simulate nasal respiration, an in vitro nasal model was connected to a downstream lung simulator that produced either passive or deep nasal respiration. Performance of a commercial mesh nebulizer system was also considered. For the optimized system, steady state cannula emitted dose was 75% of the capsule loaded dose. With cyclic nasal breathing, delivery efficiency to the tracheal filter was 53-55% of the loaded dose, which was just under the design target of 60%. Compared with a commercially available mesh nebulizer, the optimal LV-DPI was 40-fold more efficient and 150 times faster in terms of delivering aerosol to the lungs. The optimized LV-DPI system is capable of high efficiency lung delivery of powder aerosols through a challenging nasal cannula interface.

A novel method for studying airway hyperresponsiveness in allergic guinea pigs in vivo using the PreciseInhale system for delivery of dry powder aerosols

Inhaled adenosine receptor agonists induce bronchoconstriction and inflammation in asthma and are used as bronchial challenge agents for the diagnosis of asthma and in respiratory drug development. Recently developed dry powder aerosols of adenosine have several advantages over nebulised adenosine 5′-monophosphate (AMP) as bronchial challenge agents. However, reverse translation of this bronchial challenge technique to pre-clinical drug development is limited by the difficulty of administering powder aerosols to animals. The aim of the current study was to develop methods for delivering powder aerosols of adenosine receptor agonists to sensitised guinea pigs (as a model of allergic asthma) and evaluate their effect as challenge agents for the measurement of airway responsiveness. The PreciseInhale system delivered micronised AMP and adenosine powders, with mass median aerodynamic diameters of 1.81 and 3.21 μm and deposition fractions of 31 and 48% in the lungs, respectively. Bronchoconstrictor responses in passively sensitised, anaesthetised, spontaneously breathing guinea pigs were compared to responses to nebulised and intravenously administered AMP and adenosine. AMP- and adenosine-induced bronchoconstriction following all routes of administration with the magnitude of response ranking intravenous > dry powder > nebulisation, probably reflecting differences in exposure to the adenosine agonists delivered by the different routes. In conclusion, the PreciseInhale system delivered AMP and adenosine dry powder aerosols accurately into the lungs, suggesting this method can be used to investigate drug effects on airway responsiveness.

Description of Particle Size, Distribution, and Behavior of Talc Preparations Commercially Available Within the United States.

Widespread use of talc pleurodesis remains controversial for many providers concerned by adverse events such as respiratory failure, which are sometimes fatal. Particle talc size has been implicated in these adverse effects, mainly on the basis of animal studies utilizing large amounts of talc or in observational studies performed on different continents with different talc preparations and doses. Our aim was to determine the particle size and distribution of only the commercially available US-talc preparations and whether the fluid content can affect this distribution. Commercially available US talc was evaluated under scanning electron microscopy and dynamic light scattering (DLS). Distribution of talc particle size was obtained in saline and various protein-based solutions. Talc particle size by DLS was performed with commercially available Sterile Talc Powder and Sclerosol Intrapleural Aerosol. Sterile Talc Powder demonstrated a median diameter of 26.57 μm with a range of particle sizes from 0.399 μm to 100.237 μm. Sclerosol demonstrated a median diameter of 24.49 μm with a range of particle sizes from 0.224 μm to 100.237 μm. The exposure of talc to a protein rich environment (bovine serum albumin and human pleural fluid) led to the development of measureable, new, larger aggregated particle (>100 μm). Currently available US talc seems to have size characteristics similar to previous described "graded" talc preparations. The exposure of talc to a protein rich environment seems to modify the overall distribution of talc particle size when examined by DLS.

SHetA2 Dry Powder Aerosols for Tuberculosis: Formulation, Design, and Optimization Using Quality by Design.

Tuberculosis (TB) is a life threatening pulmonary infection caused by Mycobacterium tuberculosis (MTB). Current treatments are complex, lengthy, and associated with severe side effects that decrease patient compliance and increase the probability of the emergence of drug resistant strains. Thus, more effective drugs with little to no side effects are needed to diversify the armamentarium against the global TB epidemic. SHetA2, an anticancer compound with null toxicity at doses much higher than the effective dose, was recently discovered to be active against MTB. In the present study, a dry powder formulation of SHetA2 for pulmonary delivery was developed to overcome its poor aqueous solubility and to maximize its concentration in the lungs, the main site of TB infection. Using quality by design (QbD) methodology, three different formulations of SHetA2 microparticles (MPs) were designed, manufactured, and optimized, SHetA2 alone, SHetA2 PLGA, and SHetA2 mannitol MPs, to maximize the drug dose, target alveolar macrophages, and increase drug solubility, respectively. The resulting three SHetA2 MP formulations had spherical shape with particle size ranging from 1 to 3 μm and a narrow size distribution, suitable for uniform delivery to the alveolar region of the lungs. Upon dispersion with the Aerolizer dry powder inhaler (DPI), all three SHetA2 MP formulations had aerodynamic diameters smaller than 3.3 μm and fine particle fractions (FPF4.46) greater than 77%. SHetA2 remained chemically stable after MP manufacture by spray drying, but the drug transformed from the crystalline to the amorphous form, which significantly enhanced the solubility of SHetA2. Using a custom-made dissolution apparatus, the FPF4.46 of SHetA2 MP dissolved much faster and to a greater extent (21.19 ± 4.40%) than the unprocessed drug (3.51 ± 0.9%). Thus, the physicochemical characteristics, in vitro aerosol performance, and dissolution rate of the optimized SHetA2 MPs appear to be suitable to achieve therapeutic concentrations in the lungs.

Pulmonary Pharmacokinetics of Colistin following Administration of Dry Powder Aerosols in Rats.

Colistin has been administered via nebulization for the treatment of respiratory tract infections. Recently, dry powder inhalation (DPI) has attracted increasing attention. The current study aimed to investigate the pharmacokinetics (PK) of colistin in epithelial lining fluid (ELF) and plasma following DPI and intravenous (i.v.) administration in healthy Sprague-Dawley rats. Rats were given colistin as DPI intratracheally (0.66 and 1.32 mg base/kg of body weight) or i.v. injection (0.66 mg base/kg). Histopathological examination of lung tissue was performed at 24 h. Colistin concentrations in both ELF and plasma were quantified, and a population PK model was developed and compared to a previously published PK model of nebulized colistin in rats. A two-compartment structural model was developed to describe the PK of colistin in both ELF and plasma following pulmonary or i.v. administration. The model-estimated clearance from the central plasma compartment was 0.271 liter/h/kg (standard error [SE] = 2.51%). The transfer of colistin from the ELF compartment to the plasma compartment was best described by a first-order rate constant (clearance of colistin from the ELF compartment to the plasma compartment = 4.03 × 10-4 liter/h/kg, SE = 15%). DPI appeared to have a higher rate of absorption (time to the maximum concentration in plasma after administration of colistin by DPI, ≤10 min) than nebulization (time to the maximum concentration in plasma after administration of colistin by nebulization, 20 to 30 min), but the systemic bioavailabilities by the two routes of administration were similar (∼46.5%, SE = 8.43%). Histopathological examination revealed no significant differences in inflammation in lung tissues between the two treatments. Our findings suggest that colistin DPI is a promising alternative to nebulization considering the similar PK and safety profiles of the two forms of administration. The PK and histopathological information obtained is critical for the development of optimal aerosolized colistin regimens with activity against lung infections caused by Gram-negative bacteria.

Powder aerosol delivery through nasal high-flow system: In vitro feasibility and influence of process conditions

We aimed to obtain fundamental information for potential pulmonary delivery of powder aerosols using a clinically-approved nasal high-flow system (AIRVO), with spray-dried mannitol (SD-Man) being a model powder. Compressed air exiting the AIRVO at set ‘dispersion’ air flow rates dispersed SD-Man loaded in an Osmohaler® into a human nasal airway replica (NAR) coupled downstream to a Next Generation Impactor (NGI) running at specific ‘inspiratory’ flow rates. Increasing the dispersion flow rate from 30 to 60L/min increased powder deposition in the NAR from 50 to 70% of the emitted dose, while decreased the NGI deposition from 50 to 30% of the emitted dose. The inspiratory flow rate did not affect powder deposition in the NAR and NGI. In contrast, as the inspiratory flow rate was increased from 15 to 40L/min, powder recovery, emitted fraction, and fine particle fraction below 5μm (as aerosol performance indices) were increased from 90, 30 and 5% to 97, 45 and 8% of the loaded dose, respectively. The dispersion flow rate did not change the performance indices. Importantly, heating and humidification of dispersion airflow, loaded doses, and nasal cannula sizes did not greatly affect the aerosol characteristics.

Dry powder aerosols to co-deliver antibiotics and nutrient dispersion compounds for enhanced bacterial biofilm eradication

The purpose of this study was to formulate a dry powder for inhalation containing a combination treatment for eradication of Pseudomonas aeruginosa bacterial biofilms. Dry powders containing an antibiotic (ciprofloxacin hydrochloride, CH) and nutrient dispersion compound (glutamic acid, GA) at a ratio determined to eliminate the biofilms were generated by spray drying. Leucine was added to the spray dried formulation to aid powder flowability. A central composite design of experiments was performed to determine the effects of solution and processing parameters on powder yield and aerodynamic properties.Combinations of CH and GA eradicated bacterial biofilms at lower antibiotic concentrations compared to CH alone. Spray dried powders were produced with yields up to 43% and mass mean aerodynamic diameters (MMAD) in the respirable range. Powder yield was primarily affected by variables that determine cyclone efficiency, i.e. atomizer and solution flow rates and solution concentration; while MMAD was mainly determined by solution concentration. Fine particle fractions (FPF)<4.46μm and <2.82μm of the powders ranged from 56 to 70% and 35 to 46%, respectively. This study demonstrates that dry powder aerosols containing high concentrations of a combination treatment effective against P. aeruginosa biofilms could be developed with high yield, aerodynamic properties appropriate for inhalation, and no loss of potency.

Investigation of Lung Pharmacokinetic of the Novel PDE4 Inhibitor CHF6001 in Preclinical Models: Evaluation of the PreciseInhale Technology.

Preclinical evaluation of new chemical entities (NCEs) designed to be administered by inhalation route requires lung administration to rodents, especially in the discovery phase. Different administration methods have been used until now, but more efforts are required to obtain controlled and reproducible lung deposition when only small amounts of neat powder material are available. The PreciseInhale platform used in the present study enables well-controlled powder aerosol exposures with only small amounts of micronized neat material, providing data on inhalation pharmacokinetic (PK) of NCEs at a very early stage. The DustGun aerosol technology uses compressed air to generate a respirable aerosol from milligram-amounts of powder that is delivered to one animal at a time. The new methodology was used to investigate the inhalation PK and lung retention in the rat of the novel Chiesi PDE4 inhibitor CHF6001 in three exposure models of the PreciseInhale platform: nose-only, intratracheally intubated rat, and the isolated, ventilated, and perfused rat lung. Results were compared with data from two other pulmonary delivery systems commonly used in preclinical studies: liquid instillation and powder insufflation. Administration of micronized CHF6001 using the PreciseInhale system yielded lung exposures in the same range as the other tested devices, but the reproducibility in lung deposition was improved. The initial amount of CHF6001 in lungs at the first sampling time point was close to the predetermined target dose. Tracheal deposition with PreciseInhale (0.36 ± 0.22 μg) was significantly less than with other tested delivery systems: PennCentury (23.7 ± 3.2 μg) and Airjet (25.6 ± 7.2 μg). The PreciseInhale platform enabled the administration of CHF6001 powder with good accuracy and reproducibility, with low tracheal deposition. The new platform can be used at an early discovery stage to obtain inhalatory PK data for respirable aerosols of neat NCE powder without excipients and with minimal use of dry powder formulation work.

Inhaled powder formulation of naked siRNA using spray drying technology with l-leucine as dispersion enhancer

Pulmonary delivery of short interfering RNA (siRNA) has been widely studied in both animal and clinical studies to treat various respiratory diseases by gene silencing through RNA interference. Some of these studies showed that the administration of naked siRNA (without the use of any delivery vectors) could achieve satisfactory gene silencing effect, a unique feature to pulmonary delivery. Liquid aerosols were mostly used with very limited studies on the use of powder aerosols for siRNA. In this study, siRNA was co-spray dried with mannitol and l-leucine, the latter being a dispersion enhancer. To the best of our knowledge, this is the first time that siRNA in its naked form was formulated into an inhalable dry powder using spray drying technology. The aerosol performance of the powder was evaluated by Next Generation Impactor (NGI). The presence of l-leucine in the formulation could improve the aerosolization of siRNA-containing powders. Results from the X-ray photoelectron spectroscopy (XPS) suggested that l-leucine was enriched on the particle surface and promote powder dispersion. Among the different siRNA formulations being examined, the one that contained 50% w/w of l-leucine exhibited the best aerodynamic performance, with a high emitted fraction (EF) of around 80% and a modest fine particle fraction (FPF) of 45%. Importantly, the integrity of siRNA was successfully retained as evaluated by gel retardation assay and high performance liquid chromatography (HPLC).

Effect of Relative Humidity on Bipolar Electrostatic Charge Profiles of dry Powder Aerosols.

This work investigated the effect of relative humidity (RH) on bipolar electrostatic charge profiles of dry powder inhaler aerosols using the Bipolar Charge Analyzer (BOLAR). Two commercial products, Pulmicort® (400μg, budesonide) and Bricanyl® (500μg, terbutaline sulfate) Turbuhaler®, were used as model dry powder inhalers (DPIs) in this study. Three individual doses from each Turbuhaler® were sampled at 15, 40, 65 and 90% RH. Subsequently, charge and mass profiles were determined for each dispersion. The aerosols from these two Turbuhaler® DPI were bipolarly charged, with larger particles carrying negative charge and smaller particles positive charge. Particles changed polarity around 2.60-4.17μm and 0.95-2.60μm for Pulmicort® and Bricanyl®, respectively. The effect of RH on particles differed between DPIs even though the mass output was not significantly affected. The net charge profiles of Pulmicort® were relatively independent of RH, whereas those of Bricanyl® showed a reduction in the charge magnitude with increasing RH. Both positive and negative charge profiles followed a similar trend with the change in RH and individually they had higher magnitudes than the measured net charge. This study showed drug-specific bipolar charging of the Turbuhaler® DPI aerosols at varied RHs. Bricanyl® was more susceptible to RH and showed decreased bipolar and net charge levels with increasing RH, in comparison to Pulmicort®.