Dry Powder Inhaler Formulations Research Articles

A multilayer hollow nanocarrier for pulmonary co-drug delivery of methotrexate and doxorubicin in the form of dry powder inhalation formulation

Lung cancer is the number one cause of cancer deaths in the global population and remains difficult to treat mainly because of the absence of targeted drug delivery stages and restrictions related with delivery of drugs to deep lung tissues. The aim of the present study was to develop a noninvasive, patient-convenient formulation for the targeted delivery of chemotherapeutics to cancer cells located in the deep lung tissue. A PEGylated paramagnetic hollow-nanosphere was fabricated, fully characterized and used as a nanocarrier for pulmonary co-delivery of Doxorubicin (DOX) and Methotrexate (MTX). In first step, magnetic-silica nanoparticles were synthesized and then coated with amino/acrylate groups and derivatized with polyethylene glycol (PEG). Finally, silica was removed to provide hollow structured nanoparticles. The biocompatibility of blank carriers and the efficiency of MTX-DOX-loaded carriers were also approved by MTT assay and DAPI staining. The aerosolization performance of nanoparticles embedded microspheres were assessed by next generation impactor. The almost natural zeta potential and obvious decrease in silica content observed by EDX and removal of intense silica characteristic peak at FTIR analyses approved the successful removal of silica layer and preparation of hollow-nanospheres. The successful PEGylation of multilayer magnetic hollow-nanospheres catalyzed by boric acid was confirmed by presence of amide groups in FTIR spectra. The developed polymeric nanoparticle showed quite appropriate loading capacity for both DOX and MTX (48%) because of designing adequate negatively and positively charged sites for both drugs. The cytotoxicity assays proved the safety of blank nanoparticles and efficacy of drugs-loaded nanoparticles on lung cancer A549 cell lines. The developed dry powder inhalation formulation of nanoparticles showed appropriate aerosolization performance (fine particle fraction around 22%). It was concluded that these outcomes may open the potentials for efficient pulmonary co-delivery of MTX and DOX to the carcinogenic tissues.

Novel Inhalable Ciprofloxacin Dry Powders for Bronchiectasis Therapy: Mannitol-Silk Fibroin Binary Microparticles with High-Payload and Improved Aerosolized Properties.

Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory disease associated with the high morbidity and mortality. Long-term intermittent therapy by inhalable antibiotics has recently emerged as an effective approach for NCFB treatment. However, the effective delivery of antibiotics to the lung requires administering a high dose to the site of infection. Herein, we investigated the novel inhalable silk-based microparticles as a promising approach to deliver high-payload ciprofloxacin (CIP) for NCFB therapy. Silk fibroin (SF) was applied to improve drug-payload and deposit efficiency of the dry powder particles. Mannitol was added as a mucokinetic agent. The dry powder inhaler (DPI) formulations of CIP microparticles were evaluated in vitro in terms of the aerodynamic performance, particle size distribution, drug loading, morphology, and their solid state. The optimal formulation (highest drug loading, 80%) exhibited superior aerosolization performance in terms of fine particle fraction (45.04 ± 0.84%), emitted dose (98.10 ± 1.27%), mass median aerodynamic diameter (3.75 ± 0.03μm), and geometric standard deviation (1.66 ± 0.10). The improved drug loading was due to the electrostatic interactions between the SF and CIP by adsorption, and the superior aerosolization efficiency would be largely attributed to the fluffy and porous cotton-like property and low-density structure of SF. The presented results indicated the novel inhalable silk-based DPI microparticles of CIP could provide a promising strategy for the treatment of NCFB.

Evaluation of Nanocarrier-Based Dry Powder Formulations for Inhalation with Special Reference to Anti-Tuberculosis Drugs.

Pulmonary tuberculosis (TB) is a leading cause of death worldwide and is caused by the pathogen Mycobacterium tuberculosis (MTb). As treatment for TB, dry powders for inhalation (DPIs) are considered stable compared with nebulizers and metered dose inhalers and are suitable for high-dose formulations. Although extensive research has been done over the last two to three decades on nanocarrier-based DPIs for targeting MTb infection, none of the anti-TB DPI formulations have reached the market. Challenges in the proper assessment of nanocarrier-based DPIs due to the complexity of lungs is one of the reasons. In this review, the details of in vitro evaluation parameters of nanocarriers and nanocarrier-based DPIs along with their need and basic principles are discussed. Further, the thorough in vitro, ex vivo, and in vivo pharmacological evaluations, together with their procedures wherever required, are covered. The different evaluation parameters during process development, release specifications, and stability studies suggested by U.S. Food and Drug Administration Center for Drug Evaluation and Research to apply for new drug applications and abbreviated new drug applications of DPIs are also discussed. Lastly, the evaluation parameters for DPIs provided in European, United States, British, and Indian pharmacopeias are summarized.

Development of porous particles using dextran as an excipient for enhanced deep lung delivery of rifampicin

This study aimed to develop a dry powder inhaler (DPI) formulation for enhanced deep lung delivery of rifampicin using dextrans of different molecular weights. Porous particles were formed by a spray-drying method, which was designed based on the Peclet number. The morphology of particles containing both rifampicin and dextran was dependent on the dextran concentration. The D50 values of SDPs containing rifampicin and dextran 40 or 70 at ratios of less than 1:10 were below 5 μm. The specific surface area values of spray-dried particles containing rifampicin and dextran 40 or 70 of more than 1:10 were over 20 m2/g, assuming that an increase in specific surface area was indicative of an increase in the formation ratio of a porous structure. DPI formulations that contained higher amounts of dextran had higher rifampicin contents. Thus, the formulations containing a dextran: rifampicin ratio of 1:20 had approximately 100% drug encapsulation.The formation of the porous particles can be explained by the related Peclet number, which correlates with the viscosity and surface tension of the ethanol-water solution used in preparing the particles. It was noted that the existence ratio of the porous particles increased as the viscosity of the mixed solution was increased. Furthermore, an increase in the proportion of dextran resulted in higher rifampicin loading into the particles and the formation of finer particle fractions (FPF) (<7.0 μm at a rate of 28.3 L/min, <4.8 um at a rate of 60.0 L/min). The formulations containing rifampicin and both dextrans at a ratio of more than 1:10 consisted of approximately 50% FPF at a rate of 28.3 L/min and 60.0 L/min. The results indicate that dextran is suitable to obtain porous particles via spray-drying. Additionally, the existence ratio of the porous particles can be improved by increasing the viscosity of the solution used in the preparation of the particles.

A PHASE 1/1B STUDY OF AN INHALED FORMULATION OF ITRACONAZOLE IN HEALTHY VOLUNTEERS AND ASTHMATICS

Introduction Oral itraconazole has variable pharmacokinetics and risks of significant adverse events (AEs) associated with high plasma exposure. A dry powder inhalation formulation of itraconazole (ITRA) is being developed to treat Allergic Bronchopulmonary Aspergillosis (ABPA). This study was conducted to evaluate safety, tolerability and pharmacokinetics of ITRA in healthy volunteers and asthmatics. Methods The study was a 3-part, multi-center, open-label study. Healthy volunteers (n=5-6/cohort) received either single (Part 1 - 5mg, 10mg, 25mg, 35mg) or multiple doses of ITRA (Part 2 -10mg, 20mg, 35mg) over 14d. In Part 3 stable, adult asthmatics received a single dose of 20mg ITRA or 200mg of oral itraconazole in a 2-period cross-over design. Itraconazole plasma (Parts 1-3) and sputum (Part 3) concentrations were evaluated. Results All study drug-related AEs were mild, and no moderate, severe or serious study drug-related AEs were reported. The most common drug-related AE was the infrequent occurrence of mild cough. At steady-state, ITRA resulted in plasma exposure (AUC0-24h) that was 100-400 fold lower across doses tested than reported for oral itraconazole. In asthmatics, ITRA achieved Cmax sputum concentrations 45-fold higher and plasma AUC0-24h concentrations 85-fold lower than oral itraconazole. Conclusions ITRA was safe and well-tolerated under the study conditions tested, and achieved significantly higher lung and lower plasma exposure compared to oral itraconazole, supporting the potential of ITRA to improve upon both the efficacy and safety profile observed with oral itraconazole in patients with ABPA.

Formulation and evaluation of carrier-free dry powder inhaler containing sildenafil

Pulmonary delivery of sildenafil for the treatment of pulmonary arterial hypertension could overcome the limitations of intravenous and oral administration routes, such as poor patient compliance and systemic side effects. In this study, a carrier-free dry powder inhaler (DPI) formulation was developed, using spray drying technique and L-leucine as a dispersibility enhancer. Sildenafil citrate salt and sildenafil free base were evaluated for drug transport using a Calu-3 cell model, and their suitability for DPI production by spray drying was tested. Characteristics of the resultant carrier-free DPI powders were examined, namely crystallinity, morphology, size distribution, density, zeta potential, and aerodynamic performance. A Box-Behnken design was adopted to optimize the formulation and process conditions, including leucine amount, fraction of methanol in spraying solvent, and inlet temperature. While both sildenafil forms exhibited sufficient permeability for lung absorption, only sildenafil base resulted in DPI powders which were stable for 6months. The introduction of leucine into the formulations effectively enhanced aerodynamic performance of the powders and particles with favorable size, shape, and density were produced. The optimal DPI formulation determined from experimental design possesses excellent aerodynamic performance with 89.39% emitted dose and 80.08% fine particle fraction, indicating the possibility of incorporating sildenafil into carrier-free DPIs for pulmonary delivery.

Dry powder inhaler formulations of poorly water-soluble itraconazole: A balance between in-vitro dissolution and in-vivo distribution is necessary

Formulating poorly water-soluble drug, itraconazole (ITZ), as dry powder inhaler (DPI) may be more effective for the treatment of invasive pulmonary Aspergillosis than intravenous injection and oral administration. It is necessary to improve the dissolution of ITZ because the alveolar lining fluid is limited and thus the dissolution of ITZ in the lung may be slow and incomplete. However, too fast dissolution may result in over-absorption into the circulation and thus insufficient distribution in the lung. The purpose of this study is to understand the relationship between in-vitro dissolution and in-vivo distribution of ITZ from DPI formulations. Two DPI formulations (F1 and F2) with identical compositions and similar aerodynamic behaviors were fabricated by hot melt extrusion and thus jet-milling. ITZ was formulated with mannitol as fine solid crystal suspension system to effectively improve its dissolution. In-vitro dissolution tests and in-vivo pharmacokinetic studies indicated that F1 released faster than F2 under both sink and non-sink conditions, but exhibited a lower lung retention and higher plasma absorption than F2. These results suggested that although dissolution enhancement of poorly water-soluble drugs in pulmonary delivery may be necessary to overcome problems such as local irritation and quick elimination by macrophages, it may have an impact on the distribution of the drug between the lung and the plasma. A balance between airway dissolution and systemic absorption should be taken into consideration when developing DPI formulations of poorly water-soluble ITZ.

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.

Design of Spray-dried Porous Particles for Sugar-based Dry Powder Inhaler Formulation

For efficient and deeper drug delivery into the lungs via dry powder inhalers (DPIs), we designed porous spray-dried particles (SDPs) containing anti-tuberculosis drugs and sugar-based excipients. The SDPs were prepared by spray-drying ethanol solutions containing isoniazid and/or rifampicin and sucrose, maltose, or highly branched cyclic dextrin (HBCD). Solid-state fluorescence emission spectroscopy showed that 1-naphthoic acid (1-NPA), a model drug, was dispersed in a molecular dispersion/solid solution, suggesting high potential of HBCD as an excipient in DPIs. 1-NPA was dispersed not only as active pharmaceutical ingredient (API) molecules with HBCD, but also as fine crystals. Morphological examination showed that the fine particles of HBCD/anti-tuberculosis drugs were porous, indicating high aerodynamic performance. Isoniazid and rifampicin could also be incorporated into the HBCD matrix. HBCD formulations exhibited higher released doses and fine-particle fractions than sucrose and maltose formulations, and could incorporate both hydrophilic and hydrophobic drugs.

Chitosan nanoparticles as a promising approach for pulmonary delivery of bedaquiline

The purpose of the present research work was to explore chitosan nanoparticles (NPs) of a novel anti-tubercular drug, bedaquiline (BDQ) in order to reduce dose and side effects associated with oral BDQ formulation. The NPs were fabricated using ionic gelation method and evaluated for particle size, zeta potential, entrapment efficiency and drug loading. Plackett Burman was used as screening design. Two level three-factor factorial design was applied for optimization. Following freeze drying of NPs, the powder obtained was mixed with lactose pre-blend to obtain a respirable powder. In vitro deposition studies were performed using non-viable cascade impactor. In vitro cytotoxicity and in vivo toxicity studies were performed. In vivo pharmacokinetics of NPs formulation was compared with conventional dry powder inhaler (DPI) formulation and oral drug solution. Polymer amount, TPP concentration and probe sonication time were the significant factors. Optimized batch showed particle size of 109.7 ± 9.3 nm with a zeta potential of 36 ± 2.1 mV. In vitro and in vivo toxicity studies unveiled better safety profile of NPs in comparison to conventional DPI and oral solution. Pharmacokinetic studies manifested higher concentration of BDQ in lungs via developed formulation. Therefore, the developed formulation could efficiently deliver BDQ into the lungs.

Preparation and Characterization of Beclomethasone Dipropionate Solvates

Active pharmaceutical ingredients in dry powder inhaler (DPI) formulations need to have well-defined material properties. These can be influenced by the choice of processing parameters. The impact of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 1-pentanol, and acetone on the crystallization of beclomethasone dipropionate (BDP), an anti-inflammatory agent, was studied using X-ray powder diffraction, thermal analysis, gas chromatography with mass spectrometry, scanning electron microscopy, and atomic force microscopy. Crystallization from methanol, 1-butanol, and 1-pentanol resulted in particulate BDP with a predominantly anhydrous character. In contrast, BDP solvates were formed using ethanol, 1-propanol, 2-propanol, or acetone. The solvates had different crystalline structures depending on the solvent used. Distinct thermal properties confirmed the inclusion of ethanol, 1-propanol, 2-propanol, and acetone within the crystalline BDP host. Furthermore, the size, shape, and surface characteristics o...

Effect of powder properties on the aerosolization performance of nanoporous mannitol particles as dry powder inhalation carriers

ABSTRACT Carrier based dry powder inhalers (DPIs) are common vehicles for pulmonary delivery of active pharmaceutical ingredients (APIs), thus powder properties of carrier would generate a pronounced impact on the two dominant delivery stages of the DPIs. In our previous study, a novel modified carrier, the nanoporous mannitol carriers (NPMCs) was prepared to achieve satisfactory aerosolization performance. While the aerosolization performance enhancement mechanism of NPMCs based DPI was still uncovered. The purpose of this study was to explore the relationship between the powder property of NPMCs and the aerosolization performance of their corresponding DPI formulations. Particle size analysis of NPMCs was assessed by Sympatec® dynamic laser diffraction. Powder property of NPMCs was performed by FT4 powder rheometer. Aerosolization performance was evaluated by the next generation impactor to simulate the deposition profile of NPMCs based DPI formulations in respiratory tract. Similar particle size distribution was observed among the NPMCs formulations (p > 0.05), which were appropriate for DPIs. And NPMCs exhibited superior flowability, aeration and permeability behaviors in FT4 tests, meanwhile higher fine particle fraction (FPF) values in NGI test comparing to the nonporous mannitol. Further, two positive correlations between the basic flow energy (BFE) and ρb (R2 = 0.901), specific energy and ρb values (R2 = 0.912) were obtained in NPMC systems, respectively. The relationship between BFE and FPF was explored quantitatively as well, and it revealed an inverse correlation (R2 = 0.934). Therefore, the aerosolization performance enhancement of NPMCs based DPI could be reasonably explained by powder property of carriers quantified by the FT4 powder rheometer, which was a promising tool for the design of DPI carrier.

Development of a new formulation of roflumilast for pulmonary drug delivery to treat inflammatory lung conditions

The aim of this study was to develop roflumilast dry powder inhaler (DPI) formulations by spray drying using hydroxypropyl-β-cyclodextrin (HPβCD) and to determine their suitability for pulmonary delivery. Different feed solution concentrations, solvent systems and spray drying parameters were used to obtain the formulations which were characterized using X-ray powder diffraction, thermal analysis, scanning electron microscopy, particle size distribution, bulk and tapped density, specific surface area, dynamic vapour sorption, in vitro deposition properties using a Next Generation Impactor (NGI) and transepithelial permeability. Microparticles spray dried from ethanol were wrinkled and amorphous, exhibiting high glass transition temperatures while those from methanol:n-butyl acetate consisted of irregularly shaped porous particles partially crystalline. All formulations presented low density, particle size and residual solvent content exhibiting high depositon in the lower stages of the NGI. Mass median aerodynamic diameters (MMADs) were in the range of 3.32–4.49 μm, with high fine particle fractions (FPF < 5 μm). Stability studies demonstrated no significant modifications in the solid-state nature and in the aerolisation performance of the selected formulation which presented a Papp of 8.73 × 10−6 ± 4.70 × 10−7 cm/s. The developed roflumilast DPI formulations have potential therapeutic applications in the treatment of lung diseases.

Design of ciprofloxacin-loaded nano-and microcomposite particles for dry powder inhaler formulations: preparation, in vitro characterisation, and antimicrobial efficacy

In this study, ciprofloxacin hydrochloride (CIP)-loaded poly-ε-caprolactone (PCL) nanoparticles were prepared for pulmonary administration. CIP-loaded PCL nanoparticles were prepared using solid-in-oil-in-water (s/o/w) emulsion solvent evaporation method, and the effects of various formulation parameters on the physicochemical properties of the nanoparticles were investigated. PCL nanoparticles showed spherical shapes with particle sizes around 143–489 nm. Encapsulation efficiency was found to be very low because of water-solubility properties of CIP. However, the surface modification of nanoparticles with chitosan caused an increase in the encapsulation efficiency of nanoparticles. At drug release study, CIP-loaded PCL nanoparticles showed initial burst effect for 4 h and then continuously released for 72 h. Nanocomposite microparticles containing CIP-loaded PCL nanoparticles were prepared freeze-drying method and mannitol was used as carrier material. Tapped density and MMADt results show that nanocomposite microparticles have suitable aerodynamic properties for pulmonary administration. Antimicrobial efficacy investigations showed that CIP-encapsulated PCL nanoparticles and nanocomposite microparticles inhibited the growth of bacteria. Also, when the antimicrobial activity of the nanoparticles at the beginning and at the sixth month was examined, it was found that the structure of the particulate system was still preserved. These results indicated that nanocomposite microparticles containing CIP-loaded PCL nanoparticles can be used for pulmonary delivery.

Chitosan-based binary dry powder inhaler carrier with nanometer roughness for improving in vitro and in vivo aerosolization performance.

Suitable nanometer roughness favors interactions between drugs and carriers, and it is a promising approach to enhance the aerosolization performance of carrier-based dry powder inhalers (DPIs). In this study, by altering the molecular migration rates, chitosan-based binary carriers (CBBCs) with nanometer roughness were fabricated for DPIs. Comprehensive physicochemical characterizations were conducted to elucidate the formation mechanism of the CBBCs. It was hypothesized that different constituent ratios in the formulations would result in different assembling of the particles and diverse roughness scales. The fine particle fractions (FPF, approximately 40~60%) of nanometer roughness CBBC-based DPI formulations were satisfactory, demonstrating the enhancement of the in vitro aerodynamic performance. The positive correlation (R2 = 0.9883) between the nanometer roughness and FPF was revealed, and the surface roughness of 20nm might achieve the best aerosolization performance. CBBCs (optimal formulations) showed no difference in cytotoxicity on A549 and Calu-3 cells (p > 0.05). Additionally, the increased Cmax and AUC0-8h of the formulation with the nanometer roughness (p < 0.05) were observed in pharmacokinetic studies, which resulted from the improved in vivo aerosolization performance. In summary, the CBBCs were a prospective tool to improve the in vitro and in vivo aerosolization performance of DPIs. Graphical abstract ᅟ.

Characterization and aerosolization performance of mannitol particles produced using supercritical assisted atomization

Different shapes and sizes of water-soluble mannitol (MAN) particles were prepared using a supercritical assisted atomization (SAA) process. The needle-shaped and spheroidal mannitol particles were prepared using water and aqueous ethanol, respectively, as solvent of the MAN solution. The size of mannitol particles increased with increasing the concentrations of MAN solution and deceased with increasing saturator temperatures and CO2-solution flow ratios. The in vitro aerodynamic behavior of the mannitol particles as dry powder inhaler (DPI) formulations was investigated using an Andersen cascade impactor. The effects of the morphology and the size of mannitol particle on powder deagglomeration and flowability were evaluated. In vitro aerosolization tests showed that the spheroidal particles favor deagglomeration of mannitol powder and the fine particle fraction (FPF) was enhanced by the excellent powder flowability of the larger mannitol microparticles.

Novel dry powder inhaler formulation containing antibiotic using combined technology to improve aerodynamic properties

Dry Powder Inhaler (DPI) could offer a propellant-free, easy-to-use powder form ensuring better stability than liquid dosage forms. Therefore the development of traditional carrier-based and carrier-free new generation systems is a determinative factor in the field of DPI formulation. The purpose of our research work was to combine these two systems, utilizing their beneficial properties to produce a novel pulmonary drug delivery system containing ciprofloxacin hydrochloride (CIP). Co-spray drying, surface smoothing and the preparation of an interactive physical mixture were applied as the technological procedures of sample preparation. The carrier-based and carrier-free formulations, as well as the developed novel product were compared to each other. Structural investigations were made by X-ray powder diffraction and micrometric properties (habit, bulk density) were determined. Particle interactions were also evaluated to investigate surface free energy, cohesive-adhesive forces, and spreading coefficient. In vitro aerodynamic properties (mass median aerodynamic diameter), fine particle fraction (FPF) and emitted dose of DPIs were measured using Andersen Cascade Impactor. A novel in silico Stochastic Lung Model was also used to quantify the amount of particles deposited at the target area. The novel-formulated composition presented amorphous spherical particles with an average size of about 2 μm. The in vitro aerodynamic investigations showed a variance in FPF as a function of formulation method (carrier-based: 24%, carrier-free: 54% and applying the novel combination method: 63%). The in silico deposition results were in line with the in vitro measurements and yielded increased lung doses for the sample prepared by the combined technology. This novel DPI formulation provides an opportunity for a more effective therapy with deeper deposition of CIP.

Dosing challenges in respiratory therapies

The pulmonary route of administration has been commonly used for local lung conditions such as asthma and chronic obstructive pulmonary disease (COPD). Recently, with the advent of new technologies available for both formulation and device design, molecules usually delivered at high doses, such as antibiotics and insulin to treat cystic fibrosis (CF) and diabetes, respectively, can now be delivered by inhalation as a dry powder. These molecules are generally delivered in milligrams instead of traditional microgram quantities. High dose delivery is most commonly achieved via dry powder inhalers (DPIs), breath activated devices designed with a formulated powder containing micronized drug with aerodynamic diameters between 1 and 5 µm. The powder formulation may also contain other excipients and/or carrier particles to improve the flowability and aerosol dispersion of the powder. A drawback with high doses is that the formulation contains a great number of fine particles, leading to a greater degree of cohesive forces, producing strongly bound agglomerates. With greater cohesive forces holding fine particles together, higher dispersion forces are needed for efficient de-agglomeration and aerosolisation. This requirement of greater dispersion forces has led to different dry powder formulations and vastly different inhaler designs. The purpose of this review is to evaluate the different formulation types, various DPI devices currently available, and how these affect the aerosolisation process and delivery of high dosed inhalable dry powder formulations to the lungs.

A new therapeutic avenue for bronchiectasis: Dry powder inhaler of ciprofloxacin nanoplex exhibits superior ex vivo mucus permeability and antibacterial efficacy to its native ciprofloxacin counterpart

Non-cystic fibrosis bronchiectasis (NCFB) characterized by permanent bronchial dilatation and recurrent infections has been clinically managed by long-term intermittent inhaled antibiotic therapy among other treatments. Herein we investigated dry powder inhaler (DPI) formulation of ciprofloxacin (CIP) nanoplex with mannitol/lactose as the excipient for NCFB therapy. The DPI of CIP nanoplex was evaluated against DPI of native CIP in terms of their (1) dissolution characteristics in artificial sputum medium, (2) ex vivo mucus permeability in sputum from NCFB and healthy individuals, (3) antibacterial efficacy in the presence of sputum against clinical Pseudomonas aeruginosa strains (planktonic and biofilm), and (4) cytotoxicity towards human lung epithelial cells. Despite their similarly fast dissolution rates in sputum, the DPI of CIP nanoplex exhibited superior mucus permeability to the native CIP (5–7 times higher) attributed to its built-in ability to generate highly supersaturated CIP concentration in the sputum. The superior mucus permeability led to the CIP nanoplex’s higher antibacterial efficacy (>3 log10 CFU/mL). The DPI of CIP nanoplex exhibited similar cytotoxicity towards the lung epithelial cells as the native CIP indicating its low risk of toxicity. These results established the promising potential of DPI of CIP nanoplex as a new therapeutic avenue for NCFB.

Formulation techniques for high dose dry powders

Delivery of drugs to the lungs via dry powder inhaler (DPI) is a promising approach for the treatment of both local pulmonary conditions and systemic diseases. Though DPIs are widely used for the pulmonary deposition of potent bronchodilators, anticholinergics, and corticosteroids, there is growing interest in the utilization of this delivery system for the administration of high drug doses to the lungs, as made evident by recent regulatory approvals for anti-microbial, anti-viral and osmotic agents. However, the formulation of high dose DPIs carries several challenges from both a physiological and physicochemical standpoint. This review describes the various formulation techniques utilized to overcome the barriers associated with the pulmonary delivery of high dose powders.