Good Aerosol Performance Research Articles

Exploration of Nanomedicine-Based Dry Powder Inhalation Formulation Co-Loaded with Erlotinib and Curcumin for Treatment of Non-Small Cell Lung Cancer

Erlotinib is used as first-line chemotherapy for the treatment of non-small cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancers. Curcumin has potential antitumor effects in different types of cancer including NSCLS with additional chemopreventive and radioprotective effects. The aim of the study was to develop erlotinib and curcumin co-loaded dry powder inhalation (EC-DPI) formulation using nanoprecipitation technique with a goal of achieving a stronger cytotoxic effect against A549 cancer cells. The optimized DPI formulation resulted in suitable particle size (313.28 ± 26.19 nm), polydispersity index (0.156 ± 0.016) and zeta potential (29.4 ± 1.22 mV). Carr’s index (6.62 ± 1.43) and Hausner ratio (1.058 ± 0.03) demonstrated excellent flowability of the powder. The fine particle fraction (64.7 ± 7.8%) and mass median aerodynamic diameter (2.98 ± 0.04 [Formula: see text]m) of the optimized formulation revealed good aerosol performance and its suitability for direct delivery to the lungs. In-vitro cytotoxic potential of EC-DPI was determined against A549 cancer cells and compared with curcumin-loaded DPI formulation (C-DPI) and erlotinib-loaded DPI formulation (E-DPI). The IC[Formula: see text] values for E-DPI and C-DPI were found to be 36.6 ± 2.4 [Formula: see text]M and 24.4 ± 2.7 [Formula: see text]M, respectively. The IC[Formula: see text] value for EC-DPI was 20.5 ± 2.1 [Formula: see text]M confirming the synergistic effect of both drugs against A549 cancer cells. The internalization of the drug inside A549 cells was detected by a cellular uptake study. The EC-DPI demonstrated the highest cellular uptake (0.07 ± 0.006 ng/[Formula: see text]g) followed by the formulation containing curcumin (0.05 ± 0.003 ng/[Formula: see text]g) and erlotinib (0.03 ± 0.004 ng/[Formula: see text]g) alone at the end of 6 h. Hence, the developed DPI formulation can be considered as a potential therapeutic approach for the direct delivery of erlotinib and curcumin to treat NSCLC.

Preparation and characterization of lysozyme loaded liposomal dry powder inhalation using non-ionic surfactants

Delivering protein drugs through dry powder inhalation (DPI) remains a significant challenge. Liposomes offer a promising solution, providing protection for proteins from external environment and controlled release capabilities. Furthermore, the use of non-ionic surfactants plays a crucial role in protecting the activity of proteins because of how the surfactants positioning themselves at the liquid–gas interface during the spray-drying process. In this study, lysozyme-loaded liposomal DPI formulations were prepared using various non-ionic surfactants, including polysorbate 80, poloxamer 188, poloxamer 407, and sucrose stearate. Lysozyme solution and 1,2-distearoyl-sn-glycero-3-phosphatidylcholine liposomes were subjected through high-pressure homogenization to form lysozyme-loaded liposomes. Formulations of homogenized lysozyme liposomes were spray-dried and further characterized. The particle size of reconstituted liposomal lysozyme DPI was from 129.5 to 816.9 nm. The formulations showed encapsulation efficiency up to 32.5% with zeta potential value of around − 30 mV, and spherical structures were observed. The aerosol dispersion performance of the dry powder inhalers was evaluated with emitted doses reaching up to 103% and fine particle fractions up to 28.4%. Significantly higher lysozyme activity was confirmed in formulation with drug to PS 80 ratio of 1: 0.5 w/w (92.1%) compared to that of formulation containing no surfactant (59.8%). The formulation stood out as the only formulation that maintained protein activity while demonstrating good aerosol performance.

Aerosolizable Plasmid DNA Dry Powders Engineered by Thin-film Freezing.

This study was designed to test the feasibility of using thin-film freezing (TFF) to prepare aerosolizable dry powders of plasmid DNA (pDNA) for pulmonary delivery. Dry powders of pDNA formulated with mannitol/leucine (70/30, w/w) with various drug loadings, solid contents, and solvents were prepared using TFF, their aerosol properties (i.e., mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF)) were determined, and selected powders were used for further characterization. Of the nine dry powders prepared, their MMAD values were about 1-2µm, with FPF values (delivered) of 40-80%. The aerosol properties of the powders were inversely correlated with the pDNA loading and the solid content in the pDNA solution before TFF. Powders prepared with Tris-EDTA buffer or cosolvents (i.e., 1,4-dioxane or tert-butanol in water), instead of water, showed slightly reduced aerosol properties. Ultimately, powders prepared with pDNA loading at 5% (w/w), 0.25% of solid content, with or without Tris-EDTA were selected for further characterization due to their overall good aerosol performance. The pDNA powders exhibited a porous matrix structure, with a moisture content of < 2% (w/w). Agarose gel electrophoresis confirmed the chemical integrity of the pDNA after it was subjected to TFF and after the TFF powder was actuated. A cell transfection study confirmed that the activity of the pDNA did not change after it was subjected to TFF. It is feasible to use TFF to produce aerosolizable pDNA dry powder for pulmonary delivery, while preserving the integrity and activity of the pDNA.

Using thin film freezing to minimize excipients in inhalable tacrolimus dry powder formulations.

We investigated the feasibility of preparing high-potency tacrolimus dry powder for inhalation using thin film freezing (TFF). We found that using ultra-rapid freezing can increase drug loading up to 95% while maintaining good aerosol performance. Drug loading affected the specific surface area and moisture sorption of TFF formulations, but it did not affect the chemical stability, physical stability, and dissolution of tacrolimus. Tacrolimus remained amorphous after storage at 40°C/75% RH, and 25°C/60% RH for up to 6months. Lactose functioned as a bulking agent, and it had little to no effect as a stabilizer for amorphous tacrolimus due to a lack of interaction between the drug and excipient. Additionally, the aerosol performance of TFF tacrolimus/lactose (95/5) did not significantly change after six months of storage at 25°C/60% RH. For processing parameters, the solids content and the processing temperature did not affect the aerosol performance of tacrolimus. Furthermore, both low- and high-resistance RS01 showed optimal and consistent aerosol performance over the 1-4kPa pressure drop range. In conclusion, TFF is a suitable technology for producing inhalable powder that contain high drug loading and have less flow rate dependence.

Repurposing Losartan as Dry Powder Inhalation (DPI) for Asthma Related Cardiovascular Complications

Our previous work published suggests that systemic administration of losartan is effective against asthma and asthma related implications. Dry powder inhalation (DPI) formulations as dosage forms are gaining momentum because of their propellant‐free nature, improved physical and chemical stability, low drug dose requirements and high systemic absorption. We developed a dry powder inhalation (DPI) formulation of losartan to treat the symptoms of asthma‐related cardiovascular complications. In this study, we evaluated the compatibility of some common DPI excipients with losartan and their ability to improve critical aerodynamic properties of the formulation to make it suitable for pulmonary drug delivery. There are different manufacturing techniques available for developing DPI formulations including milling, freeze‐drying, and spray drying (SD). We used SD in the current study to develop our formulation. The screening studies were performed by following one factor at a time approach (OFAT). We used amino acids and sugars, either alone or in combination to develop the DPI formulation by using SD technique. The SD conditions were kept constant at 110°C inlet temperature, 100% aspiration, 10% (approx. 3ml/min) pump rate, and 601 liters/hour gas flow rate. The developed formulations were characterized for their physicochemical, aerodynamic, and solid‐state properties. Particle size (&lt;5μm) is critical to understand the deposition behavior of the DPI. Our formulations have the particle size distribution of the 50% of the particles (Dx50) below the respirable range that is &lt;6μm. The fine particle fraction (2.2 – 3.4μm) of our formulation is 53.72%, which is the amount of dose that is actually reaching the lungs and shows therapeutic activity. The respirable fraction (3.4 – 5.3 μm) of our formulation is 70.90%, which is the amount of drug that is within the inhalable range. The solid‐state characterization studies, including differential scanning calorimetry, powder X‐ray diffraction studies indicate the drug in the formulation is amorphous, and the excipients and carrier used help to keep the formulation stable. The drug‐excipient compatibility was proved by quantitatively and qualitatively analyzing the samples using High‐Performance Liquid Chromatography (HPLC) and Fourier Transform Infrared Spectroscopic (FT‐IR). The developed formulations showed good aerosol performance and can be used for preclinical work for further evaluation of therapeutic efficacy of the losartan in asthma models.

Production of fast-dissolving low-density powders for improved lung deposition by spray drying of a nanosuspension

We combined high-energy wet media milling and spray drying to engineer dry powders for inhalation consisting of geometrically large, low-density particles with superior aerodynamic properties and fast dissolution. Peclet number proved to be a useful instrument to guide choice of the additives and process conditions for generating low-density powders by spray drying. Composite dry powders consisted of milled and stabilized budesonide nanoparticles, leucine or albumin as matrix formers, and ammonium carbonate as a pore former. Powders of different composition showed fairly large and comparable geometric particle sizes (de,50 > 4.4 µm) with effective densities strongly depending on the present matrix former. Powders with lowest density reached an aerosol performance of up to 60%, which is well above most commercial, carrier-based products. It was also demonstrated that the nanomilling step was indispensable to yield such good aerosol performance. Dissolution of aerodynamically classified particle fractions showed a very fast onset and was largely completed within 30 min irrespective of the formulation and the impactor stage. Mathematical kinetic modeling was used to deduce the API dissolution rate coefficient from the results obtained using a modified USP 2 apparatus. Dissolution rate was found to be determined by the properties of the API nanoparticles rather than those of the composite particles. The employment of industrially established, solely water-based processes allows introducing the presented approach as a platform technology for the development of well-performing pulmonary formulations.

Novel Budesonide Particles for Dry Powder Inhalation Prepared Using a Microfluidic Reactor Coupled With Ultrasonic Spray Freeze Drying

Budesonide (BDS) is a potent active pharmaceutical ingredient, often administered using respiratory devices such as metered dose inhalers, nebulizers, and dry powder inhalers. Inhalable drug particles are conventionally produced by crystallization followed by milling. This approach tends to generate partially amorphous materials that require post-processing to improve the formulations’ stability. Other methods involve homogenization or precipitation and often require the use of stabilizers, mostly surfactants. The purpose of this study was therefore to develop a novel method for preparation of fine BDS particles using a microfluidic reactor coupled with ultrasonic spray freeze drying, and hence avoiding the need of additional homogenization or stabilizer use. A T-junction microfluidic reactor was employed to produce particle suspension (using an ethanol-water, methanol-water, and an acetone-water system), which was directly fed into an ultrasonic atomization probe, followed by direct feeding to liquid nitrogen. Freeze drying was the final preparation step. The result was fine crystalline BDS powders which, when blended with lactose and dispersed in an Aerolizer at 100 L/min, generated fine particle fraction in the range 47.6% ± 2.8% to 54.9% ± 1.8%, thus exhibiting a good aerosol performance. Subsequent sample analysis confirmed the suitability of the developed method to produce inhalable drug particles without additional homogenization or stabilizers. The developed method provides a viable solution for particle isolation in microfluidics in general.

In vitro evaluation of novel inhalable dry powders consisting of thioridazine and rifapentine for rapid tuberculosis treatment

Thioridazine is an orally administered antipsychotic drug with potential for treatment of drug-resistant tuberculosis (TB). However, drug-induced adverse cardiac effects have been reported when thioridazine was used at an efficacious oral dose of 200mg/day to treat TB. Pulmonary delivery of thioridazine could be a rational approach to reduce dose-related side effects while enabling high drug concentrations at the primary site of infection. The present study compares in vitro aerosol performance, storage stability, and in vitro antimicrobial activity and cytotoxicity of two inhalable powders composed of thioridazine and a first-line anti-TB drug, rifapentine. Formulation 1 is a combination of amorphous thioridazine and crystalline rifapentine, while Formulation 2 consisted of both drugs as amorphous forms. Both thioridazine-rifapentine formulations were found suitable for inhalation with a total fine particle fraction (<5μm) of 68–76%. The two powders had similar MIC90 to rifapentine alone, being 0.000625μg/mL and 0.005μg/ml against Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv, respectively. In contrast, thioridazine alone had a MIC90 of 12.5μg/mL and 500μg/mL, against M. tuberculosis H37Ra and M. tuberculosis H37Rv, respectively, demonstrating no synergistic anti-TB activity. However, thioridazine and rifapentine in a ratio of 1:3 enhanced the killing of M. tuberculosis H37Ra within the human monocyte-derived macrophages (THP-1) compared to the single drug treatments. Both powders showed an acceptable half maximal inhibitory concentration (IC50) of 31.25μg/mL on both THP-1 and human lung epithelial (A549) cells. However, Formulation 1 showed greater chemical stability than Formulation 2 after three months of storage under low humidity (vacuum) at 20±3°C. In conclusion, we have demonstrated a novel inhalable powder consisted of amorphous thioridazine and crystalline rifapentine (Formulation 1) with a good aerosol performance, potent anti-TB activity and storage stability, which deserves further in vivo investigations.

Evaluation of High-Performance Curcumin Nanocrystals for Pulmonary Drug Delivery Both In Vitro and In Vivo.

This paper focused on formulating high-performance curcumin spray-dried powders for inhalation (curcumin-DPIs) to achieve a high lung concentration. Curcumin-DPIs were produced using wet milling combined with the spray drying method. The effects of different milling times on particle size and aerodynamic performance were investigated. The curcumin-DPIs were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), and in vitro dissolution. Furthermore, the in vivo pharmacokinetic behavior and tissue distribution after pulmonary administration were also evaluated. Results showed that the drug dissolution was significantly enhanced by processing into curcumin-DPIs. The aerodynamic results indicated that the DPIs displayed a good aerosol performance. The plasma curcumin concentration was obviously enhanced by inhalation, and most of the curcumin-DPIs were deposited in the lung. This study demonstrated that inhalation was an effective way to carry drug to the lung, and curcumin-DPIs were hopeful for lung cancer treatment in the future.Electronic supplementary materialThe online version of this article (doi:10.1186/s11671-015-1085-y) contains supplementary material, which is available to authorized users.

Responsive hydrogel nanoparticles for pulmonary delivery

Nanoparticles represent one of the most widely studied classes of advanced drug delivery platforms in recent years due to a wide range of unique properties and capabilities that can be utilized to improve upon traditional drug administration. Conversely, hydrogel nanoparticles (HNPs) – also called nanogels – represent a unique class of materials that combine the intrinsic advantages of nanotechnology with the inherent capabilities of hydrogels. Responsive hydrogels pose a particularly interesting class of materials that can sense and respond to external stimuli and previous reports of inhalable hydrogel particles have highlighted their potential in pulmonary delivery. Here, we synthesized two different pH-responsive HNPs, designated HNP120 and HNP270, by incorporating functional monomers with a common crosslinker and characterized their physicochemical properties. One of the HNP systems was selected for incorporation into a composite dry powder by spray drying, and the aerodynamic performance of the resulting powder was evaluated. The HNP120s displayed a hydrodynamic diameter of approximately 120 nm in their fully swollen state and a minimal diameter of around 80 nm while the HNP270s were approximately 270 nm and 115 nm, respectively. Electron microscopy confirmed particle size- and morphological uniformity of the HNPs. The HNP120s were spray dried into composite dry powders for inhalation and cascade impaction studies showed good aerosol performance with a mass median aerodynamic diameter (MMAD) of 4.82 ± 0.37 and a fine particle fraction > 30%. The HNPs released from the spray dried composites retained their responsive behavior thereby illustrating the potential for these materials as intelligent drug delivery systems that combine the advantages of nanotechnology, lung targeting through pulmonary delivery, and stimuli-responsive hydrogels.

Inhalable spray-dried formulation of D-LAK antimicrobial peptides targeting tuberculosis

Tuberculosis (TB) is a global disease that is becoming more difficult to treat due to the emergence of multidrug resistant (MDR) Mycobacterium tuberculosis. Inhalable antimicrobial peptides (AMPs) are potentially useful alternative anti-TB agents because they can overcome resistance against classical antibiotics, reduce systemic adverse effects, and achieve local targeting. The aims of the current study were to produce inhalable dry powders containing d-enantiomeric AMPs (D-LAK120-HP13 and D-LAK120-A) and evaluate their solid state properties, aerosol performance, and structural conformation. These two peptides were spray dried with mannitol as a bulking agent at three mass ratios (peptide:mannitol 1:99, 1:49, and 1:24) from aqueous solutions. The resultant particles were spherical, with those containing D-LAK120-HP13 being more corrugated than those with D-LAK120-A. The median volumetric diameter of the particles was approximately 3μm. The residual water content of all powders were <3% w/w and crystalline, due to the low hygroscopicity and crystallinity of mannitol, respectively. The mannitol changed from a mixture of alpha- and beta-forms to delta form with an increasing proportion of AMP in the formulation. The emitted fraction and fine particle fraction of the powders when dispersed from an Osmohaler® at 90L/min were about 80% and 50–60% of the loaded dose, respectively, indicating good aerosol performance. Circular dichroism data showed that D-LAK120-HP13 dissolved in Tris buffer at pH 7.15 was of a disordered conformation. In contrast, D-LAK120-A showed greater α-helical conformation. Since the conformations of the AMPs were comparable to the controls (unprocessed peptides), the spray drying process did not substantially affect their secondary structures. In conclusion, spray dried powders containing d-enantiomeric AMPs with preserved secondary molecular structures and good aerosol performance could be successfully produced. They may potentially be used for treating MDR-TB when delivered by inhalation.

Combined Inhaled Salbutamol and Mannitol Therapy for Mucus Hyper-secretion in Pulmonary Diseases

This study focuses on the co-engineering of salbutamol sulphate (SS), a common bronchodilator, and mannitol (MA), a mucolytic, as a potential combination therapy for mucus hypersecretion. This combination was chosen to have a synergic effect on the airways: the SS will act on the β2-receptor for relaxation of smooth muscle and enhancement of ciliary beat frequency, whilst mannitol will improve the fluidity of mucus, consequently enhancing its clearance from the lung. A series of co-spray-dried samples, containing therapeutically relevant doses of SS and MA, were prepared. The physico-chemical characteristics of the formulations were evaluated in terms of size distribution, morphology, thermal and moisture response and aerosol performance. Additionally, the formulations were evaluated for their effects on cell viability and transport across air interface Calu-3 bronchial epithelial cells, contractibility effects on bronchial smooth muscle cells and cilia beat activity using ciliated nasal epithelial cells in vitro. The formulations demonstrated size distributions and aerosol performance suitable for inhalation therapy. Transport studies revealed that the MA component of the formulation enhanced penetration of SS across the complex mucus layer and the lung epithelia cells. Furthermore, the formulation in the ratios of SS 10(-6) and MA 10(-3) M gave a significant increase in cilia beat frequency whilst simultaneously preventing smooth muscle contraction associated with mannitol administration. These studies have established that co-spray dried combination formulations of MA and SS can be successfully prepared with limited toxicity, good aerosol performance and the ability to increase ciliary beat frequency for improving the mucociliary clearance in patients suffering from hyper-secretory diseases, whilst simultaneously acting on the underlying smooth muscle.

Effects on Aerosol Performance of Mixing of Either Budesonide or Beclomethasone Dipropionate With Albuterol and Ipratropium Bromide

Mixing of nebulized drugs is common in real life, but its consequences on aerosol output and granulometry are poorly known. In an in vitro study I evaluated the effects on aerosol output, drug output, and aerosol particle size characteristics of mixing either beclomethasone dipropionate or budesonide with albuterol and ipratropium bromide. I tested the SideStream and VentStream-Pro nebulizers, run with the AirClinic compressor. Using the same fill volume in all experiments, I nebulized and evaluated each studied drug alone, and 2 drug mixtures: beclomethasone plus albuterol plus ipratropium; and budesonide plus albuterol plus ipratropium. I measured aerosol output via gravimetrics. I measured drug delivery by collecting the aerosol on a filter in the inspiratory limb, and the residual solution in the reservoir and the circuit after nebulization, and assayed those liquids with chromatography. I measured particle size distribution via cascade impaction. Mixing tended to reduce drug output and to increase mass median aerodynamic diameter with the SideStream, but not always with the VentStream-Pro. However, the drug output always remained satisfactory and the mass median aerodynamic diameters were within the respirable range. When nebulized alone, the respirable mass of bronchodilators ranged from 18% to 40% of the nominal dose; when mixed, it ranged from 13% to 37%. When nebulized alone, the respirable mass of corticosteroids ranged from 10% to 24% of the nominal dose; when mixed, it ranged from 10% to 17%. Both the SideStream and VentStream-Pro have good aerosol performance in nebulizing budesonide or beclomethasone dipropionate alone, and when mixed with albuterol and ipratropium bromide.

Production of Ultrafine Sumatriptan Succinate Particles for Pulmonary Delivery

Drug particle physical properties are critical for the efficiency of a drug delivered to the lung. The purpose of this study was to produce ultrafine sumatriptan succinate particles for inhalation. Sumatriptan succinate particles were produced via reactive precipitation without any surfactants. Several low toxic organic solvents such as acetone, isopropanol, and tetrahydrofuran were investigated as the reaction medium. And the dry powder was obtained via spray drying. FT-IR, HPLC, SEM and XRD were exploited to characterize the physicochemical properties of the ultrafine sumatriptan succinate dry powder. The aerosol performance of the powder was evaluated using an Aeroliser connected to a multi stage liquid impinger operating at 60 l/min. The mean particle size of the ultrafine sumatriptan succinate particles obtained under optimum conditions was in the range of 630-679 nm and consequently they were in the respirable range. The spray-dried powder whose fine particle fraction was increased up to 50.6 +/- 8.2% showed good aerosol performance whereas the vacuum-dried powder was approximate 18.2 +/- 3.0%. Good aerosol performance ultrafine sumatriptan succinate particles could be produced by reactive precipitation without any additives followed by spray drying at the optimum parameters.

Characterization and aerodynamic evaluation of spray dried recombinant human growth hormone using protein stabilizing agents

The effect of the protein stabilizers on the stability and aerosol performance of spray dried recombinant human growth hormone (SD rhGH) was investigated. rhGH solution was spray dried alone, with polysorbate 20 (at three concentrations of 0.05%, 0.01%, and 0.005%), Zn 2+ (by Zn 2+:rhGH molar ratio of 2:1 and 4:1), and/or lactose (by lactose:rhGH weight ratio of 2:1). Size exclusion chromatography (SEC) analysis of spray dried powders demonstrated that of all the potential protein stabilizers, the combination of polysorbate 20 (0.05%), Zn 2+ (Zn 2+:rhGH molar ratio of 2:1) and lactose (lactose:rhGH weight ratio of 2:1) was the most effective at protecting rhGH against aggregation during spray drying. The results of circular dichroism (CD) analysis revealed that using of polysorbate 20 (in all concentrations) and Zn 2+ (by Zn 2+:rhGH molar ratio of 2:1) together in the formulations would preserve rhGH conformational stability during the process. The particle size distribution data obtained by laser diffraction method showed all SD rhGH formulations had volume median diameter and mean diameter below 5 μm. The characterization of the aerosol performance of the spray dried powders by Andersen cascade impactor (ACI) showed that by increasing the concentration of polysorbate 20 in the formulations the aerodynamic efficiency of the resultant particles was reduced. In conclusion, the optimum amounts of polysorbate 20, Zn 2+ and lactose satisfied both physical stability during spray drying process (2.37% aggregation) and good aerosol performance (fine particle fraction; FPF = 38.52%).