Pulmonary delivery of inhalable nanoparticles: dry powder inhalers

Pulmonary administration of inhalable nanoparticles (NPs) is an emerging area of interest. Dry powder inhalers may offer particular advantages for pulmonary administration of NPs. This article reviews research performed on the formulation of inhalable NPs as dry powder to achieve deep-lung deposition and enhance NP redispersibility. Moreover, the article summarizes up-to-date in vivo applications of inhalable NPs as dry powder inhalers.     

Preparation and characterization of spray dried inhalable powders containing chitosan nanoparticles for pulmonary delivery of isoniazid

The aim of this study was to prepare spray dried inhalable powders containing isoniazid-loaded chitosan/tripolyphosphate (TPP) nanoparticles for sustained delivery of the drug to the lung. Nanoparticles were prepared by ionic gelation method. In-vitro drug release study indicated that the rate of drug release from nanoparticles was decreased by increasing the amount of chitosan. Entrapment of isoniazid into chitosan/TPP nanoparticles decreased minimum inhibitory concentrations (MIC) of the drug against mycobacterium avium intracellulare. Nanoparticles were spray dried using excipients such as lactose, mannitol and maltodextrin alone or with leucine. Results showed that the obtained powders had different aerosolization property. It was observed that by adding leucine, the particle size of microparticles deceased and the process yield and fine particle fraction (FPF) increased significantly. The in-vitro deposition data indicated that spray drying of isoniazid-loaded nanoparticles with lactose in the presence of leucine resulted in the production of inhalable powders with the highest FPF (45%).     

Preparation and characterization of spray dried inhalable powders containing chitosan nanoparticles for pulmonary delivery of isoniazid

The aim of this study was to prepare spray dried inhalable powders containing isoniazid-loaded chitosan/tripolyphosphate (TPP) nanoparticles for sustained delivery of the drug to the lung. Nanoparticles were prepared by ionic gelation method. In-vitro drug release study indicated that the rate of drug release from nanoparticles was decreased by increasing the amount of chitosan. Entrapment of isoniazid into chitosan/TPP nanoparticles decreased minimum inhibitory concentrations (MIC) of the drug against mycobacterium avium intracellulare. Nanoparticles were spray dried using excipients such as lactose, mannitol and maltodextrin alone or with leucine. Results showed that the obtained powders had different aerosolization property. It was observed that by adding leucine, the particle size of microparticles deceased and the process yield and fine particle fraction (FPF) increased significantly. The in-vitro deposition data indicated that spray drying of isoniazid-loaded nanoparticles with lactose in the presence of leucine resulted in the production of inhalable powders with the highest FPF (45%).     

Formulation optimization and characterization of spray dried microparticles for inhalation delivery of doxycycline hyclate

The local delivery of antibiotics in the treatment of infectious respiratory diseases is an attractive alternative to deliver high concentration of antimicrobials directly to the lungs and minimize systemic side effects. In this study, inhalable microparticles containing doxycycline hyclate, sodium carboxymethylcellulose, leucine and lactose were prepared by spray drying of aqueous ethanol formulations. Box-Behnken design was used to study the influence of various independent variables such as polymer concentration, leucine concentration, ethanol concentration and inlet temperature of the spray dryer on microparticle characteristics. The microparticles were characterized in terms of particle morphology, drug excipient interaction, yield, entrapment efficiency, Carr's index, moisture content, thermal properties, X-ray powder diffraction, aerosolization performance and in vitro drug release. The effect of independent variables on spray dryer outlet temperature was also studied. The overall shape of the particles was found to be spherical like doughnuts in the size range of 1.16-5.2 μm. The optimized formulation (sodium carboxymethylcellulose concentration 14% w/v, leucine concentration 33% w/v, ethanol concentration 36% v/v, inlet temperature of 140°C) exhibited the following properties: yield 56.69%, moisture content 3.86%, encapsulation efficiency 61.74%, theoretical aerodynamic diameter 3.11 μm and Carr's index 23.5% at an outlet temperature 77°C. The powders generated were of a suitable mass median aerodynamic diameter (4.89 μm) with 49.3% fine particle fraction and exhibited a sustained drug release profile in vitro.     

Enhanced Dispersibility and Deposition of Spray-dried Powders for Pulmonary Gene Therapy

Spray-drying represents a viable alternative to freeze-drying for preparing dry powder dispersions for delivering macromolecules to the lung. The dispersibility of spray-dried powders is limited however, and needs to be enhanced to improve lung deposition and subsequent biological activity. In this study, we investigate the utility of leucine as a dry powder dispersibility enhancer when added prior to spray-drying a model non-viral gene therapy formulation (lipid:polycation:pDNA, LPD). Freeze-dried lactose–LPD, spray-dried lactose–LPD and spray-dried leucine–lactose–LPD powders were prepared. Scanning electron microscopy showed that leucine increased the surface roughness of spray-dried lactose particles. Particle size analysis revealed that leucine-containing spray-dried powders were unimodally dispersed with a mean particle diameter of 3.12 μm. Both gel electrophoresis and in vitro cell (A549) transfection showed that leucine may compromise the integrity and biological functionality of the gene therapy vector. The deposition of the leucine containing powder was however significantly enhanced as evidenced by an increase in gene expression mediated by dry powder collected at lower stages of a multistage liquid impinger (MSLI). Further studies are required to determine the potential of leucine as a ubiquitous dispersibility enhancer for a variety of pulmonary formulations.     

Enhanced dispersibility and deposition of spray-dried powders for pulmonary gene therapy

Spray-drying represents a viable alternative to freeze-drying for preparing dry powder dispersions for delivering macromolecules to the lung. The dispersibility of spray-dried powders is limited however, and needs to be enhanced to improve lung deposition and subsequent biological activity. In this study, we investigate the utility of leucine as a dry powder dispersibility enhancer when added prior to spray-drying a model non-viral gene therapy formulation (lipid:polycation:pDNA, LPD). Freeze-dried lactose-LPD, spray-dried lactose-LPD and spray-dried leucine-lactose-LPD powders were prepared. Scanning electron microscopy showed that leucine increased the surface roughness of spray-dried lactose particles. Particle size analysis revealed that leucine-containing spray-dried powders were unimodally dispersed with a mean particle diameter of 3.12 microm. Both gel electrophoresis and in vitro cell (A549) transfection showed that leucine may compromise the integrity and biological functionality of the gene therapy vector. The deposition of the leucine containing powder was however significantly enhanced as evidenced by an increase in gene expression mediated by dry powder collected at lower stages of a multistage liquid impinger (MSLI). Further studies are required to determine the potential of leucine as a ubiquitous dispersibility enhancer for a variety of pulmonary formulations.     

Rifampicin Pulmospheres for Pulmonary Delivery

Dry powder inhalation formulations of rifampicin were prepared. Spray drying was used to prepare pulmospheres and their physicochemical characteristics were evaluated. Spray dried pulmospheres containing rifampicin were mixed with inhalable lactose for preparing dry powder inhalation formulations. These formulations were further characterized to evaluate the feasibility of developing effective treatments for pulmonary tuberculosis.     

Colistin Powders with High Aerosolisation Efficiency for Respiratory Infection: Preparation and In Vitro Evaluation

In many respiratory infections caused by multi-drug-resistant Gram-negative bacteria, colistin is often the last-line drug for treatment despite its nephrotoxicity when administered parenterally. Inhalation therapy of colistin has great potential to improve the efficacy while reducing adverse effects. In this study, inhalable powder formulations of colistin (sulphate) were produced via spray drying. The colistin powders were found to have intact antimicrobial activity against Acinetobacter baumannii measured by broth micro-dilution. Both the raw material and spray-dried formulations were amorphous and absorbed significant amount of water up to 30% (w/w) at relative humidity (RH) of at least 70%. The spray-dried formulations were physically stable in the amorphous form at 60% RH and 25°C, having a high aerosol efficiency (emitted dose >86% and fine particle fraction total >83%) which remained unchanged after a 3-month storage. Storage at an elevated RH of 75% resulted in the aerosolisation performance significantly decreased, and at RH 90%, the formulation particles fused together (but without re-crystallisation). Although spray drying has been extensively used for generating inhalable drug particles, this is the first report that colistin powder can be physically stable in the amorphous form at ambient conditions, indicating that spray-drying approach is suitable for producing inhalable colistin powder formulation.     

Spray-dried respirable powders containing bacteriophages for the treatment of pulmonary infections

Myoviridae bacteriophages were processed into a dry powder inhalable dosage form using a low‐temperature spray‐drying process. The phages were incorporated into microparticles consisting of trehalose, leucine, and optionally a third excipient (either a surfactant or casein sodium salt). The particles were designed to have high dispersibility and a respirable particle size, and to preserve the phages during processing. Bacteriophages KS4‐ M, KS14, and cocktails of phages ΦKZ/D3 and ΦKZ/D3/KS4‐M were spray‐dried with a processing loss ranging from 0.4 to 0.8 log pfu. The aerosol performance of the resulting dry powders as delivered from an Aerolizer® dry powder inhaler (DPI) exceeded the performance of commercially available DPIs; the emitted mass and the in vitro total lung mass of the lead formulation were 82.7% and 69.7% of filled capsule mass, respectively. The total lung mass had a mass median aerodynamic diameter of 2.5–2.8 µm. The total in vitro lung doses of the phages, delivered from a single actuation of the inhaler, ranged from 10⁷ to 10⁸ pfu, levels that are expected to be efficacious in vivo. Spray drying of bacteriophages into a respirable dry powder was found to be feasible.     

Carbomer-modified spray-dried respirable powders for pulmonary delivery of salbutamol sulphate

The present study investigates the feasibility of using two types of carbomer (971 and 974) to prepare inhalable dry powders that exhibit modified drug release properties. Powders were prepared by spray-drying formulations containing salbutamol sulphate, 20-50% w/w carbomer as a drug release modifier and leucine as an aerosolization enhancer. Following physical characterization of the powders, the aerosolization and dissolution properties of the powders were investigated using a Multi-Stage Liquid Impinger and a modified USP II dissolution apparatus, respectively. All carbomer 974-modified powders and the 20% carbomer 971 powder demonstrated high dispersibility, with emitted doses of at least 80% and fine particle fractions of approximately 40%. The release data indicated that all carbomer-modified powders displayed a sustained release profile, with carbomer 971-modified powders obeying first order kinetics, whereas carbomer 974-modified powders obeyed the Higuchi root time kinetic model; increasing the amount of carbomer 971 in the formulation did not extend the duration of drug release, whereas this was observed for the carbomer 974-modified powders. These powders would be anticipated to deposit predominately in the lower regions of the lung following inhalation and then undergo delayed rather than instantaneous drug release, offering the potential to reduce dosing frequency and improve patient compliance.     

Particle Engineering for Pulmonary Drug Delivery

With the rapidly growing popularity and sophistication of inhalation therapy, there is an increasing demand for tailor-made inhalable drug particles capable of affording the most efficient delivery to the lungs and the most optimal therapeutic outcomes. To cope with this formulation demand, a wide variety of novel particle technologies have emerged over the past decade. The present review is intended to provide a critical account of the current goals and technologies of particle engineering for the development of pulmonary drug delivery systems. These technologies cover traditional micronization and powder blending, controlled solvent crystallization, spray drying, spray freeze drying, particle formation from liquid dispersion systems, supercritical fluid processing and particle coating. The merits and limitations of these technologies are discussed with reference to their applications to specific drug and/or excipient materials. The regulatory requirements applicable to particulate inhalation products are also reviewed briefly.     

Inhalable Antibiotic Delivery Using a Dry Powder Co-delivering Recombinant Deoxyribonuclease and Ciprofloxacin for Treatment of Cystic Fibrosis

Purpose  

To achieve efficient antibiotic delivery to the cystic fibrosis (CF) airway using a single inhalable powder co-encapsulating a mucolytic and an antibiotic.     

Carbomer-modified spray-dried respirable powders for pulmonary delivery of salbutamol sulphate

Abstract

The present study investigates the feasibility of using two types of carbomer (971 and 974) to prepare inhalable dry powders that exhibit modified drug release properties. Powders were prepared by spray-drying formulations containing salbutamol sulphate, 20–50% w/w carbomer as a drug release modifier and leucine as an aerosolization enhancer. Following physical characterization of the powders, the aerosolization and dissolution properties of the powders were investigated using a Multi-Stage Liquid Impinger and a modified USP II dissolution apparatus, respectively. All carbomer 974-modified powders and the 20% carbomer 971 powder demonstrated high dispersibility, with emitted doses of at least 80% and fine particle fractions of ～40%. The release data indicated that all carbomer-modified powders displayed a sustained release profile, with carbomer 971-modified powders obeying first order kinetics, whereas carbomer 974-modified powders obeyed the Higuchi root time kinetic model; increasing the amount of carbomer 971 in the formulation did not extend the duration of drug release, whereas this was observed for the carbomer 974-modified powders. These powders would be anticipated to deposit predominately in the lower regions of the lung following inhalation and then undergo delayed rather than instantaneous drug release, offering the potential to reduce dosing frequency and improve patient compliance.     

Investigating the interactions of amino acid components on a mannitol-based spray-dried powder formulation for pulmonary delivery: A design of experiment approach

Combining an amino acid and a sugar is a known strategy in the formulation of spray or freeze dried biomolecule powder formulations. The effect of the amino acid leucine in enhancing performance of spray-dried powders has been previously demonstrated, but interaction effects of several constituents which may provide multiple benefits, are less well-understood. A 3 factor 2 level (2³) factorial design was used to study the effects of leucine, glycine and alanine in a mannitol-based dry powder formulation on particle size, aerosolisation, emitted dose and cohesion. Other qualitative tests including scanning electronic microscopy and X-ray powder diffraction were also conducted on the design of experiment (DoE) trials. The results show that the use of glycine and/or alanine, though structurally related to leucine, did not achieve similar aerosol performance enhancing effects, rather the particle formation was hindered. However, when used in appropriate concentrations with leucine, the combination of amino acids produced an enhanced performance regardless of the presence of glycine and/or alanine, yielding significantly modified particle properties. The results from the DoE analyses also revealed the lack of linearity of effects for certain responses with a significant curvature in the model which would otherwise not be discovered using a trial-and-error approach.     

Evaluation of the survival of bacterial contaminants in an inhalable insulin powder.

Survival and growth of three model test bacterial species (Pseudomonas fluorescens, Staphylococcus epidermidis and Bacillus subtilis), present in the air and/or in the human respiratory tract, were tested in inhalable insulin-lactose powder under optimal relative humidity and temperature conditions (RH = 96% and optimal growth temperature for each bacterium of 26-37 degrees C) as well as representative indoor conditions (RH = 43% and T = 20 degrees C). The bacteria survived from 12 h to 7 days depending on the bacterial species and the test condition. P. fluorescens vegetative cells had the lowest and B. subtilis spores the highest survival rate. It was found that insulin-lactose powder does not support bacterial growth and that higher bacterial survival rate was found under representative indoor conditions. Selected experiments were performed with B. subtilis by adding sterile saliva into insulin-lactose powder to represent a typical condition for inhaler use. Furthermore, two other powders were tested with B. subtilis: one representing an inert powder without any nutrients (glass beads) and the other representing a powder with optimal nutrients (tryptic soy broth powder). The data indicate that the survival rate of B. subtilis did not change after the saliva was added and that the survival in insulin-lactose powder was similar to that in inert powder but lower than in powder with optimal nutrients. These results suggest that bacterial growth on residual powder in the inhaler under patient use conditions is unlikely and therefore the concern for patient safety is remote.     

Co-Spray-Dried Urea Cross-Linked Hyaluronic Acid and Sodium Ascorbyl Phosphate as Novel Inhalable Dry Powder Formulation

The pathogenesis and progression of several lung disorders is propagated by inflammatory and oxidative processes, which can be controlled by adjunctive inhaled therapies. The present study aimed to develop an inhalable dry powder formulation consisting of co-spray-dried urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate (SD HA-CL–SAP), a novel combination which was recently shown to possess anti-inflammatory, antioxidant, and wound healing properties. Native HA and SAP were co-spray dried (SD HA–SAP) and evaluated as control formulation. Yield (Y%) and encapsulation efficiency (EE%) were 67.0 ± 4.8% and 75.5 ± 7.2% for SD HA–SAP, 70.0 ± 1.5% and 66.5 ± 5.7% for SD HA-CL–SAP, respectively. Both formulations were shown to be suitable for lung delivery in terms of morphology, particle size (median volumetric diameter ～ 3.4 μm), physical and thermal stability, in vitro aerosol performance - respirable fraction: 30.5 ± 0.7% for SD HA–SAP and 35.3 ± 0.3% for SD HA-CL–SAP. SAP release was investigated using Franz cells and air-interface Calu-3 cell model (>90% of SAP transported within 4 h). The innovative SD HA-CL–SAP formulation holds potential as inhalable dry powder for the treatment of inflammatory lung disorders.     

Mechanistic models facilitate efficient development of leucine containing microparticles for pulmonary drug delivery

Mechanistic models of the spray drying and particle formation processes were used to conduct a formulation study with minimal use of material and time. A model microparticle vehicle suitable for respiratory delivery of biological pharmaceutical actives was designed. L-leucine was chosen as one of the excipients, because of its ability to enhance aerosol dispersibility. Trehalose was the second excipient. The spray drying process parameters used to manufacture the particles were calculated a priori. The kinetics of the particle formation process were assessed using a constant evaporation rate model. The experimental work was focused on the effect of increasing L-leucine mass fraction in the formulation, specifically its effect on leucine crystallinity in the microparticles, on powder density, and on powder dispersibility. Particle, powder and aerosol properties were assessed using analytical methods with minimal sample requirement, namely linear Raman spectroscopy, scanning electron microscopy, time-of-flight aerodynamic diameter measurements, and a new technique to determine compressed bulk density of the powder. The crystallinity of leucine in the microparticles was found to be correlated with a change in particle morphology, reduction in powder density, and improvement in dispersibility. It was demonstrated that the use of mechanistic models in combination with selected analytical techniques allows rapid formulation of microparticles for respiratory drug delivery using batch sizes of less than 80 mg.     

A Novel Inhalable Form of Rifapentine

Recent murine studies found that rifapentine, dosed daily, at least halved tuberculosis treatment times compared with standard rifampicin and isoniazid-containing regimens. However, in humans, an inhalable form of rifapentine may be necessary to considerably shorten treatment duration because of the physiological barriers associated with oral therapy. The current study compares two inhalable rifapentine dry powders—a novel pure crystalline form and an amorphous form—by a series of in vitro tests. The crystalline and amorphous powders had a mass median aerodynamic size of 1.68 ± 0.03 and 1.92 ± 0.01 μm, respectively, associated with a fine particle fraction of 83.2 ± 1.2% and 68.8 ± 2.1%, respectively. A quinone degradation product was identified in the amorphous powder stored for 1 month, whereas the crystalline form remained chemically stable after storage at both 0% and 60% relative humidity, 25°C, for at least 3 months. Solubilized rifapentine was well tolerated by pulmonary tissue and macrophage cells up to approximately 50 μM. The accumulation of rifapentine within alveolar macrophage cells was significantly higher than for rifampicin, indicating enhanced delivery to infected macrophages. The novel inhalable crystalline form of rifapentine is suitable for targeted treatment of tuberculosis infection and may radically shorten treatment duration. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.     

Dry powder inhaler formulation of lipid-polymer hybrid nanoparticles via electrostatically-driven nanoparticle assembly onto microscale carrier particles

Lipid-polymer hybrid nanoparticles have emerged as promising nanoscale carriers of therapeutics as they combine the attractive characteristics of liposomes and polymers. Herein we develop dry powder inhaler (DPI) formulation of hybrid nanoparticles composed of poly(lactic-co-glycolic acid) and soybean lecithin as the polymer and lipid constituents, respectively. The hybrid nanoparticles are transformed into inhalable microscale nanocomposite structures by a novel technique based on electrostatically-driven adsorption of nanoparticles onto polysaccharide carrier particles, which eliminates the drawbacks of conventional techniques based on controlled drying (e.g. nanoparticle-specific formulation, low yield). First, we engineer polysaccharide carrier particles made up of chitosan cross-linked with tripolyphosphate and dextran sulphate to exhibit the desired aerosolization characteristics and physical robustness. Second, we investigate the effects of nanoparticle to carrier mass ratio and salt inclusion on the adsorption efficiency, in terms of the nanoparticle loading and yield, from which the optimal formulation is determined. Desorption of the nanoparticles from the carrier particles in phosphate buffer saline is also examined. Lastly, we characterize aerosolization efficiency of the nanocomposite product in vitro, where the emitted dose and respirable fraction are found to be comparable to the values of conventional DPI formulations.     

Capreomycin inhalable powders prepared with an innovative spray-drying technique

The aim of the work was to produce inhalable capreomycin powders using a novel spray-drying technology. A 2³ factorial design was used to individuate the best working conditions. The maximum desirability was identified at the smallest mean volume diameter (d_v) and span, and the highest yield. Powders were characterized for size, morphology, flowability and aerodynamic properties. Mathematical models showed a good predictivity with biases lower than 20%. The maximum conformity with desirability criteria was obtained spraying a 10 mg/mL bacitracin solution at 111 °C with the 4 μm pore size membrane. By processing capreomycin sulfate with the parameters optimized for bacitracin, an inhalable powder was obtained (i.e., yield of 82%, d_v of 3.83 μm, and span of 1.04). By further optimization, capreomycin sulfate powder characteristics were improved (i.e., yield, ∼71%; d_v, 3.25 μm; span, 0.95). After formulation with lactose, emitted dose and respirable fraction of 87% and ∼27% were obtained, respectively. Two capreomycin sulfate powders with suitable properties for inhalation were produced using the nano spray-dryer B-90.