Pulmonary Drug Delivery Systems Research Articles

Advances in Aerogels Formulations for Pulmonary Targeted Delivery of Therapeutic Agents: Safety, Efficacy and Regulatory Aspects.

Aerogels are the 3D network of organic, inorganic, composite, layered, or hybrid-type materials that are used to increase the solubility of Class 1 (low solubility and high permeability) and Class 4 (poor solubility and low permeability) molecules. This approach improves systemic drug absorption due to the alveoli's broad surface area, thin epithelial layer, and high vascularization. Local therapies are more effective and have fewer side effects than systemic distribution because inhalation treatment targets the specific location and raises drug concentration in the lungs. The present manuscript aims to explore various aspects of aerogel formulations for pulmonary targeted delivery of active pharmaceutical agents. The manuscript also discusses the safety, efficacy, and regulatory aspects of aerogel formulations. According to projections, the global respiratory drug market is growing 4-6% annually, with short-term development potential. The proliferation of literature on pulmonary medicine delivery, especially in recent years, shows increased interest. Aerogels come in various technologies and compositions, but any aerogel used in a biological system must be constructed of a material that is biocompatible and, ideally, biodegradable. Aerogels are made via "supercritical processing". After many liquid phase iterations using organic solvents, supercritical extraction, and drying are performed. Moreover, the sol-gel polymerization process makes inorganic aerogels from TMOS or TEOS, the less hazardous silane. The resulting aerogels were shown to be mostly loaded with pharmaceutically active chemicals, such as furosemide-sodium, penbutolol-hemisulfate, and methylprednisolone. For biotechnology, pharmaceutical sciences, biosensors, and diagnostics, these aerogels have mostly been researched. Although aerogels are made of many different materials and methods, any aerogel utilized in a biological system needs to be made of a substance that is both biocompatible and, preferably, biodegradable. In conclusion, aerogel-based pulmonary drug delivery systems can be used in biomedicine and non-biomedicine applications for improved sustainability, mechanical properties, biodegradability, and biocompatibility. This covers scaffolds, aerogels, and nanoparticles. Furthermore, biopolymers have been described, including cellulose nanocrystals (CNC) and MXenes. A safety regulatory database is necessary to offer direction on the commercialization potential of aerogelbased formulations. After that, enormous efforts are discovered to be performed to synthesize an effective aerogel, particularly to shorten the drying period, which ultimately modifies the efficacy. As a result, there is an urgent need to enhance the performance going forward.

The Role of Pulmonary Drug Delivery in Modern Therapeutics: An Overview.

The pulmonary drug delivery system is a promising and evolving technology in which the prescribed medicine is breathed through the lungs, and subsequently, it enters the circulation via the alveolar epithelium. This category of pulmonary drug delivery system is an appealing and non-invasive administration method. Pulmonary drug delivery is most commonly utilized to treat airway problems by providing locally active medicines directly to their site of action. The dose required to have a pharmacological effect is reduced when medicines are delivered directly to their site of action. In addition to locally acting medications, the pulmonary route can be utilized to deliver compounds with systemic effects, such as in the case of insulin inhalation therapy for systemic absorption. Particle size, bioavailability, device compatibility, and other aspects must be addressed, including the formulation of drugs into an acceptable dosage for inhalation with sufficient stability. This formulation must also be used in conjunction with a suitable inhaler device that produces an aerosol with a particle or droplet size that assures deposition in the required targeted area of the pulmonary system. Recent advancements in pulmonary drug delivery include the development of targeted nanoparticles and inhalable biologics, which enhance drug absorption and efficacy while minimizing systemic side effects. Future directions focus on personalized medicine approaches and advanced inhalation technologies, although limitations such as variable patient adherence and the need for precise dosing continue to pose challenges.

Development of a Formulation and In Vitro Evaluation of a Pulmonary Drug Delivery System for a Novel Janus Kinase (JAK) Inhibitor, CPL409116.

The pursuit of targeted therapies for cytokine-dependent diseases has led to the discovery of Janus kinase (JAK) inhibitors, a promising class of drugs. Among them, CPL409116, a selective dual JAK and rho-associated protein kinase inhibitor (ROCK), has demonstrated potential for treating conditions such as pulmonary fibrosis exacerbated by the COVID-19 pandemic. This study investigated the feasibility of delivering CPL409116 via inhalation, with the aim of minimizing the systemic adverse effects associated with oral administration. Two micronization methods, jet milling and spray drying, were assessed for CPL409116, with spray drying chosen for its ability to produce an amorphous form of the compound. Moreover, parameters such as the mixing energy, drug load, and force control agent significantly influenced the fine particle fraction (FPF), a critical parameter for pulmonary drug delivery. This study provides insights into optimizing the formulation parameters to enhance the delivery efficiency of CPL409116 to the lungs, offering potential for improved therapeutic outcomes in cytokine-dependent pulmonary diseases.

Quality by Design in Pulmonary Drug Delivery: A Review on Dry Powder Inhaler Development, Nanotherapy Approaches, and Regulatory Considerations.

Dry powder inhalers (DPIs) are state-of-the-art pulmonary drug delivery systems. This article explores the transformative impact of nanotechnology on DPIs, emphasizing the Quality Target Product Profile (QTPP) with a focus on aerodynamic performance and particle characteristics. It navigates global regulatory frameworks, underscoring the need for safety and efficacy standards. Additionally, it highlights the emerging field of nanoparticulate dry powder inhalers, showcasing their potential to enhance targeted drug delivery in respiratory medicine. This concise overview is a valuable resource for researchers, physicians, and pharmaceutical developers, providing insights into the development and commercialization of advanced inhalation systems.

Development of SIMPATEC-USP: An abbreviated impactor for rapid testing of inhalation devices

Cascade impactors like the Andersen Cascade Impactor (ACI) and Next Generation Impactor (NGI) are complex and costly due to multiple stages. This study introduces SIMPATEC-USP (Simplified Impactor Developed at the University of São Paulo), a low-cost, single-stage alternative meeting US Pharmacopeia standards for testing dry powder inhalers (DPIs). SIMPATEC-USP simplifies particle retention into a single Petri dish stage, eliminating multi-stage complexity. Its design includes a straightforward closure system for easy assembly/disassembly. A collection chamber holds a glass Petri dish with filter paper for final filtration, ensuring efficient aerosol product collection. SIMPATEC-USP also offers potential use with culture media for applications like antibacterial screening. Operating at 30 L/min, SIMPATEC-USP consists of three parts: a single-stage chamber, an L-shaped tube mimicking the trachea, and a vacuum pump. Aerosol particles are deposited onto the Petri dish via a nozzle, and the collected sample is weighed to determine drug concentration. Tested with inhalation-grade lactose, SIMPATEC-USP effectively collects and analyzes particles, allowing for rapid aerodynamic comparison of formulations, capsule retention assessment, and sample collection for drug release studies. The results demonstrate that it is possible to evaluate the performance of three inhalation devices regarding the mass migrating to the collection plate and that retained within the device itself. In conclusion, SIMPATEC-USP is highly suitable for exploratory studies and educational activities in pharmaceutical technology and pulmonary drug delivery systems.

Improved camptothecin encapsulation and efficacy by environmentally sensitive block copolymer/chitosan/fucoidan nanoparticles for targeting lung cancer cells

In this study, thermo-sensitive poly(N-isopropyl acrylamide) (PNP) was polymerized with pH-sensitive poly(acrylic acid) (PAA) to prepare a PAA-b-PNP block copolymer. Above its cloud point, the block copolymer self-assembled into nanoparticles (NPs), encapsulating the anticancer drug camptothecin (CPT) in situ. Chitosan (CS) and fucoidan (Fu) further modified these NPs, forming Fu-CPT-NPs to enhance biocompatibility, drug encapsulation efficiency (EE), and loading content (LC), crucially facilitating P-selectin targeting of lung cancer cells through a drug delivery system. The EE and LC reached 82 % and 3.5 %, respectively. According to transmission electron microscope observation, these Fu-CPT-NPs had uniform spherical shapes with an average diameter of ca. 250 nm. They could maintain their stability in a pH range of 5.0–6.8. In vitro experimental results revealed that the Fu-CPT-NPs exhibited good biocompatibility and had anticancer activity after encapsulating CPT. It could deliver CPT to cancer cells by targeting P-selectin, effectively increasing cell uptake and inducing cell apoptosis. Animal study results showed that the Fu-CPT-NPs inhibited lung tumor growth by increasing tumor cell apoptosis without causing significant tissue damage related to generating reactive oxygen species in lung cancer cells. This system can effectively improve drug-delivery efficiency and treatment effects and has great potential for treating lung cancer.

Simulating aerosol droplet dynamics and coalescence in tracheal intubation insights from a CFD-DEM analysis of PSAR tube interactions

This study employed the Computational Fluid Dynamics-Discrete Element Method (CFD-DEM) to investigate targeted droplet delivery in tracheal intubation. Our findings reveal that droplet behavior and deposition patterns are significantly influenced by droplet size. Smaller droplets (3 μm and 5 μm) closely follow airflow, showing similar deposition patterns in both CFD-DEM and CFD-DPM simulations. In contrast, larger droplets (7.5 μm and 10 μm) demonstrate increased deposition, particularly in the bent section of the Point Source Release tube (PSAR tube), due to enhanced inertia following collisions and coalescence. The study highlights that larger droplets experience a higher frequency of coalescence, especially in curved tube sections. This leads to altered droplet size distribution at the outlet, affecting deposition in the lower respiratory tract. These insights are crucial for optimizing inhalation therapy devices, emphasizing the importance of considering droplet interactions in CFD simulations to accurately predict aerosol behavior in pulmonary drug delivery systems.

Chitosan-Based Nanocarriers for Pulmonary and Intranasal Drug Delivery Systems: A Comprehensive Overview of their Applications.

The optimization of respiratory health is important, and one avenue for achieving this is through the application of both Pulmonary Drug Delivery System (PDDS) and Intranasal Delivery (IND). PDDS offers immediate delivery of medication to the respiratory system, providing advantages, such as sustained regional drug concentration, tunable drug release, extended duration of action, and enhanced patient compliance. IND, renowned for its non-invasive nature and swift onset of action, presents a promising path for advancement. Modern PDDS and IND utilize various polymers, among which chitosan (CS) stands out. CS is a biocompatible and biodegradable polysaccharide with unique physicochemical properties, making it well-suited for medical and pharmaceutical applications. The multiple positively charged amino groups present in CS facilitate its interaction with negatively charged mucous membranes, allowing CS to adsorb easily onto the mucosal surface. In addition, CS-based nanocarriers have been an important topic of research. Polymeric Nanoparticles (NPs), liposomes, dendrimers, microspheres, nanoemulsions, Solid Lipid Nanoparticles (SLNs), carbon nanotubes, and modified effective targeting systems compete as important ways of increasing pulmonary drug delivery with chitosan. This review covers the latest findings on CS-based nanocarriers and their applications.

Highly distinctive linear and nonlinear rheological behaviors of mucin-based protein solutions as simulated normal and asthmatic human airway mucus

Mucus on the human airway surface normally provides a fluid barrier to trap and remove inhaled hazardous particulates such as viruses and bacteria, a physiological function known as mucus clearance. This function, however, can fail if the mucus has abnormal rheological properties, as in the case of certain lung diseases such as asthma. Despite its importance, airway mucus rheology has not been well studied so far, largely because of its complex nature and limited availability. Therefore, in this study, we prepared mucin-based protein solutions as simulated normal and asthmatic airway mucus (NM and AM, respectively) and subsequently studied them in both linear and nonlinear rheological conditions using either conventional steady-state or large amplitude oscillatory shear experiments together with nonlinear multi-mode Giesekus model analysis. We also examined the microscopic structure of the simulated airway mucus by optical or atomic force microscopy. We found that both NM and AM exhibited typical nonlinear rheological behaviors of protein solutions. However, as compared to NM, AM was much more solid-like, and the viscosity, yield stress, and dynamic modulus were more than ten times that of NM. These differences in macroscopic rheological behaviors between NM and AM could be attributed to their different microstructures. Taken together, this study provides evidence that airway mucus may dramatically change its rheological behaviors with changing chemical composition and microstructure as occurring in diseased conditions such as AM. Thus, the presented rheological assessment and modeling analysis, together with the microscopic characterization of simulated airway mucus, may have important values for better understanding the critical roles of mucus rheology in the determination of the mucus clearance function in health and disease as well as the development of pulmonary drug delivery systems.

In vitro and in ovo photodynamic efficacy of nebulized curcumin-loaded tetraether lipid liposomes prepared by DC as stable drug delivery system

Lung cancer is one of the most common causes of high mortality worldwide. Current treatment strategies, e.g., surgery, radiotherapy, chemotherapy, and immunotherapy, insufficiently affect the overall outcome. In this study, we used curcumin as a natural photosensitizer in photodynamic therapy and encapsulated it in liposomes consisting of stabilizing tetraether lipids aiming for a pulmonary drug delivery system against lung cancer. The liposomes with either hydrolyzed glycerol-dialkyl-glycerol tetraether (hGDGT) in different ratios or hydrolyzed glycerol-dialkyl-nonitol tetraether (hGDNT) were prepared by dual centrifugation (DC), an innovative method for liposome preparation. The liposomes’ physicochemical characteristics before and after nebulization and other nebulization characteristics confirmed their suitability. Morphological characterization using atomic force and transmission electron microscopy showed proper vesicular structures indicative of liposomes. Qualitative and quantitative uptake of the curcumin-loaded liposomes in lung adenocarcinoma (A549) cells was visualized and proven. Phototoxic effects of the liposomes were detected on A549 cells, showing decreased cell viability. The generation of reactive oxygen species required for PDT and disruption of mitochondrial membrane potential were confirmed. Moreover, the chorioallantoic membrane (CAM) model was used to further evaluate biocompatibility and photodynamic efficacy in a 3D cell culture context. Photodynamic efficacy was assessed by PET/CT after nebulization of the liposomes onto the xenografted tumors on the CAM with subsequent irradiation. The physicochemical properties and the efficacy of tetraether lipid liposomes encapsulating curcumin, especially liposomes containing hGDNT, in 2D and 3D cell cultures seem promising for future PDT usage against lung cancer.

Pulmonary drug delivery system: A review

An important route for the management of various drugs is the lung drug delivery system (PDDS). In recent years, the lungs have become increasingly concerned about the scientific and environmental value of treating lung diseases. Lung delivery of drugs has evolved into one of the most widely used routes of the planned or local drug rescuer Due to its potential localized lung function; drug delivery systems for the treatment of lung diseases are being developed. In this article, it is pointed out that PDSDS provides improved compliance with appropriate patient outcomes. In the traditional form, this novel drug delivery system has several advantages. Because of its potential therapeutic properties in the field of pulmonary embolism, the use of drug delivery systems (DDS) in the treatment of lung diseases is growing. This route also facilitates the placement of drugs in high-intensity areas within the patient-specific lungs, thereby reducing the total amount of medication administered to patients (10-20% of the peroral volume), and increasing local drug activity while minimizing side effects and systemic side effects and bypass the first-pass metabolism.

Atomization characteristics of 9.6 MHz directional surface acoustic wave for 1-micron spray system

Surface acoustic wave atomization is also effective for generating microparticles and nanoparticles, because of the small wavelength with the high frequency. In this work, a novel directional surface acoustic wave (SAW) atomizer via a novel 9.6 MHz unidirectional interdigital transducer (U-IDT), a driving interdigital transducer (D-IDT) and a reflector interdigital transducer (R-IDT), is proposed and studied for the 1-micron spray system, such as the pulmonary drug delivery system and high-precision film deposition system. The atomization characteristics of a water drop are evaluated with atomized droplet size, atomizing particle velocity, and atomizing rate. Around 1 µm atomized droplet diameter, 585 mm/s atomizing particle velocity, and 4.2 ml/min atomizing rate are achieved and investigated. Based on the 1-micron atomized droplet diameter and high diffusion velocity, a novel pulmonary drug delivery system with the SAW spray can be excepted as an effective non-intrusive treatment method. It is also suitable for microparticle and nanoparticle spray without the pump and fan systems in the fields of industry, cosmetics, medicine, and medical devices.

Inhaled pulmonary surfactant biomimetic liposomes for reversing idiopathic pulmonary fibrosis through synergistic therapeutic strategy

Idiopathic pulmonary fibrosis (IPF) stands as a highly heterogeneous and deadly lung disease, yet the available treatment options remain limited. Combining myofibroblast inhibition with ROS modulation in damaged AECs offers a comprehensive strategy to halt IPF progression, but delivering drugs separately to these cell types is challenging. Inspired by the successful application of pulmonary surfactant (PS) replacement therapy in lung disease treatment, we have developed PS nano-biomimetic liposomes (PSBs) to utilize its natural transport pathway for targeting AECs while reducing lung tissue clearance. In this collaborative pulmonary drug delivery system, PSBs composed of DPPC/POPG/DPPG/CHO (20:9:5:4) were formulated for inhalation. These PSBs loaded with ROS-scavenger astaxanthin (AST) and anti-fibrosis drug pirfenidone (PFD) were aerosolized for precise quantification and mimicking patient inhalation. Through aerosol inhalation, the lipid membrane of PSBs gradually fused with natural PS, enabling AST delivery to AECs by hitchhiking with PS circulation. Simultaneously, PFD was released within the PS barrier, effectively penetrating lung tissue to exert therapeutic effects. In vivo results have shown that PSBs offer numerous therapeutic advantages in mice with IPF, particularly in terms of lung function recovery. This approach addresses the challenges of drug delivery to specific lung cells and offers potential benefits for IPF patients.

AMELIORATION IN APPROACHES FOR ENHANCED PULMONARY DRUG DELIVERY

Pulmonary disorders including asthma, chronic obstructive pulmonary disorder (COPD), cystic fibrosis, and other severe conditions like cancer have indeed made pulmonary drug delivery systems, both, an area of interest as well as concern. The mortality rate, around 8%, has enabled researchers to develop novel technologies for efficient drug delivery and reduced side effects. As the drug delivery through inhalation involves two major influencing factors, that is, formulation type and the device used for inhalation, various strategies have been designed with an intent to upgrade the existing drug formulations and devices used. Apart from this, various targeting strategies including gene therapy and magnetic targeting so as to improve the target specificity of the administered drug in the regions of the pulmonary system have been developed. In spite of these advancements, pulmonary drug delivery appears to be challenging in terms of formulation design and animal model design as well as lack of availability of FDA-approved excipients for inhalation. Persistent efforts have been made by the researchers in combining various strategies to negate the drawbacks/limitations of pulmonary drug delivery so as to develop a drug delivery system with improved efficacy and negligible adverse effects.

Pulmonary delivery of mucus-traversing PF127-modified silk fibroin nanoparticles loading with quercetin for lung cancer therapy

The mucosal barrier remains a major barrier in the pulmonary drug delivery system, as mucociliary clearance in the airway accelerates the removal of inhaled nanoparticles (NPs). Herein, we designed and developed the inhalable Pluronic F127-modified silk fibroin NPs loading with quercetin (marked as QR-SF (PF127) NPs), aiming to solve the airway mucus barrier and improve the cancer therapeutic effect of QR. The PF127 coating on the SF NPs could attenuate the interaction between NPs and mucin proteins, thus facilitating the diffusion of SF(PF127) NPs in the mucus layer. The QR-SF (PF127) NPs had particle sizes of approximately 200 nm with negatively charged surfaces and showed constant drug release properties. Fluorescence recovery after photobleaching (FRAP) assay and transepithelial transport test showed that QR-SF (PF127) NPs exhibited superior mucus-penetrating ability in artificial mucus and monolayer Calu-3 cell model. Notably, a large amount of QR-SF (PF127) NPs distributed uniformly in the mice airway section, indicating the good retention of NPs in the respiratory tract. The mice melanoma lung metastasis model was established, and the therapeutic effect of QR-SF (PF127) NPs was significantly improved in vivo. PF127-modified SF NPs may be a promising strategy to attenuate the interaction with mucin proteins and enhance mucus penetration efficiency in the pulmonary drug delivery system.

Poly(sebacic acid) microparticles loaded with azithromycin as potential pulmonary drug delivery system: Physicochemical properties, antibacterial behavior, and cytocompatibility studies

Recurrent bacterial infections are a common cause of death for patients with cystic fibrosis and chronic obstructive pulmonary disease. Herein, we present the development of the degradable poly(sebacic acid) (PSA) microparticles loaded with different concentrations of azithromycin (AZ) as a potential powder formulation to deliver AZ locally to the lungs. We characterized microparticle size, morphology, zeta potential, encapsulation efficiency, interaction PSA with AZ and degradation profile in phosphate buffered saline (PBS). The antibacterial properties were evaluated using the Kirby-Bauer method against Staphylococcus aureus. Potential cytotoxicity was evaluated in BEAS-2B and A549 lung epithelial cells by the resazurin reduction assay and live/dead staining. The results show that microparticles are spherical and their size, being in the range of 1–5 μm, should be optimal for pulmonary delivery. The AZ encapsulation efficiency is nearly 100 % for all types of microparticles. The microparticles degradation rate is relatively fast – after 24 h their mass decreased by around 50 %. The antibacterial test showed that released AZ was able to successfully inhibit bacteria growth. The cytotoxicity test showed that the safe concentration of both unloaded and AZ-loaded microparticles was equal to 50 μg/ml. Thus, appropriate physicochemical properties, controlled degradation and drug release, cytocompatibility, and antibacterial behavior showed that our microparticles may be promising for the local treatment of lung infections.

Engineering Ferroptosis Inhibitors as Inhalable Nanomedicines for the Highly Efficient Treatment of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) refers to chronic progressive fibrotic interstitial pneumonia. It is called a "tumor-like disease" and cannot be cured using existing clinical drugs. Therefore, new treatment options are urgently needed. Studies have proven that ferroptosis is closely related to the development of IPF, and ferroptosis inhibitors can slow down the occurrence of IPF by chelating iron or reducing lipid peroxidation. For example, the ferroptosis inhibitor deferoxamine (DFO) was used to treat a mouse model of pulmonary fibrosis, and DFO successfully reversed the IPF phenotype and increased the survival rate of mice from 50% to 90%. Given this, we perceive that the treatment of IPF by delivering ferroptosis inhibitors is a promising option. However, the delivery of ferroptosis inhibitors faces two bottlenecks: low solubility and targeting. For one thing, we consider preparing ferroptosis inhibitors into nanomedicines to improve solubility. For another thing, we propose to deliver nanomedicines through pulmonary drug-delivery system (PDDS) to improve targeting. Compared with oral or injection administration, PDDS can achieve better delivery and accumulation in the lung, while reducing the systemic exposure of the drug, and is an efficient and safe drug-delivery method. In this paper, three possible nanomedicines for PDDS and the preparation methods thereof are proposed to deliver ferroptosis inhibitors for the treatment of IPF. Proper administration devices and challenges in future applications are also discussed. In general, this perspective proposes a promising strategy for the treatment of IPF based on inhalable nanomedicines carrying ferroptosis inhibitors, which can inspire new ideas in the field of drug development and therapy of IPF.

An Overview of Recently Published Patents on Pulmonary Drug Delivery Devices.

The pulmonary drug delivery system is a minimally invasive method of administering drugs with systemic and localised activity. Since 4000 BC, inhalation therapy has been known to the Indians. The most effective and suitable pulmonary drug delivery methods have been used for controlling diseases like asthma, chronic obstructive pulmonary disorder (COPD), TB(Tuberculosis), lung cancer, cystic fibrosis, and pulmonary hypertension. Examples of pulmonary medication delivery devices- Metered dose inhalers (MDIs), nebulizers, and dry powder inhalers (DPIs) in the latest patent 2022 that have undergone numerous advancements over the years have been focused on in this article. Some promising patented design advancements of nebulizers are humidifier breathing circuits to control liquid contamination, technologically advanced nebulizers to increase pressure detection and nebulizer disinfection system to decrease or eliminate contagions in expelled air are highlighted in this article. Some noticed formulation-related advancements for inhalational dry powder patented in the year 2022, are mentioned in this article. Development of heat-stable dry powder to solve instability of inhaled protein and peptide powder at high temperatures. The inability of dry powder inhaler devices to administer low doses is solved by designing an affordable and side effects-free inhaler. pMDI manufacturing process is simplified by manufacturing tablets to be administered in pMDI. An aid is developed to lessen the activation force and keep the dose count within budget. The patented advancement in the pulmonary drug delivery system can help in the improvement of patient compliance and drug delivery efficacy.

A comprehensive overview of dry powder inhalers for pulmonary drug delivery: Challenges, advances, optimization techniques, and applications

Dry powder inhaler (DPI) is an attractive dosage form for local and systemic pulmonary drug delivery. However, designing DPIs with adequate physicochemical properties is challenging. The development of novel pulmonary drug delivery systems requires the selection of suitable particle engineering techniques, carriers, and excipients. In addition, optimization of physico-chemical properties of such systems is critical for their efficient delivery and drug release. This review highlights the recent advances in the field of inhalable dry powder formulations with a special emphasis on the current particle engineering techniques, challenges in the development of novel pulmonary drug delivery systems, selection of a suitable carrier and excipients, and the evaluation of factors impacting aerosolization. Lastly, the review also discusses the current and emerging applications of DPIs for local and systemic drug delivery.

Engineered lipid liquid crystalline nanoparticles as an inhaled nanoplatform for mucus penetration enhancement.

Nanocarrier-assisted pulmonary drug delivery system has been widely employed for lung local disease treatment due to its enhanced drug lesion accumulation and reduced systematical side effects. However, the mucus barriers covered on the epithelia of trachea and bronchial tree construct a dense barrier for inhaled nanocarrier transport, which compromises the therapeutical effects. In this study, a lipid liquid crystalline nanoparticle NLP@Z with surface zwitterion material hexadecyl betaine (HB) modification and N-acetylcysteine (NAC) encapsulation was presented to exert the combination strategy of mucus-inert surface and mucus degradation. The HB modification endowed NLP@Z mucus-inert surface to inhibit the interaction between NLP@Z and mucins, and the encapsulated NAC could effectively degrade the mucins and further decrease the mucus viscosity. This combination strategy was proved to significantly promote the mucus penetration performance and enhance epithelial cell uptake. In addition, the proposed NLP@Z was equipped with desired nebulization property, which could be served as a potential pulmonary delivery nanoplatform. In summary, the proposed NLP@Z highlights the employment of the combination strategy for mucus penetration enhancement in pulmonary delivery, which may become a versatile platform for lung disease therapy.