Lung diseases, including COVID-19, pneumonia, chronic obstructive pulmonary disease (COPD), asthma, lung cancer, cystic fibrosis (CF), and tuberculosis (TB), are a huge threat to human health. The treatment and diagnosis of these diseases are becoming increasingly challenging. Currently, the pulmonary pathway has been used to deliver various drugs for the treatment of lung diseases, such as antibiotics, proteins, peptides, chemotherapeutic agents, interferons, antitrypsins, protease inhibitors, deoxyribonucleic acid, vaccines, etc [1]. However, the occurrence of adverse effects of chemotherapy, drug-resistant bacteria, side effects that may be significantly toxic, and poor drug delivery necessitates the development of more promising therapeutic approaches [2]. The term “nanoparticle” stands for both nanocapsules and nanospheres, which are distinguished by their morphological structure [3]. They are particles within the size range from 1 to 1000 nm, including liposomes, solid lipid nanoparticles, polymer nanoparticles, polymer micelles, nanocrystals, etc [3]. Despite their unique properties, nanoparticles face challenges related to their aerosolization efficiency, potential aggregation leading to poor dispersibility, and intricate engineering requirements for precise dosing [4]. The approach of incorporating nanoparticles within microparticles, often referred to as “nano-in-microparticles,” is a strategy employed to harness the advantages of both nanoparticle and microparticle technologies while improving aerodynamic properties [4]. Nano-in-micro is a promising approach that has been developed for DPIs to embed the drug with nanosize (<1 μm) in microparticles (<5 μm), taking advantage of optimized lung deposition and bypassing clearance mechanisms [5]. Delivery of nanoparticles to the lungs in the form of dry powder inhalers loaded with appropriate therapeutic agents and incorporating smart features to overcome various pulmonary obstacles holds great promise as they can help localize the target tissues and enhance therapeutic efficacy while minimizing systemic side effects [2]. The inhalation route was not the initial choice due to the inconvenience and inefficiency of early aerosol drug delivery techniques, erratic dosing, and lack of portability [6]. However, tremendous innovations have occurred over the past 50 years, and product developers can now choose among portable dry powder inhalers (DPI), pressurized metered dose inhalers (pMDI), soft mist inhalers (SMI), and nebulizers, which provide reproducible and efficient delivery to the lungs. Dry powder inhalers are becoming increasingly popular for pulmonary inhalation formulations due to their better stability, ease of use, absence of projectiles and atmospheric contamination, and high drug-carrying capacity compared to liquid inhalation formulations [7]. Therefore, it is the focus of discussion in this review.

DPI is a preparation consisting of a solid micronized API alone or mixed with a suitable carrier in the form of a capsule, blister, or multi-dose reservoir, using a specially designed dry powder inhalation device, in which the patient inhales an aerosolized drug into the lungs. The first dry powder inhalation device, the Spinhaler®, was developed in 1971, and Bell et al. [8] developed this device for the administration of sodium cromoglycate in powder form, to avoid the use of a parabolic agent and reduce the dose. Typically, the drug mixture, which often includes a carrier to aid in the flow of the powder (most notably lactose), is prefilled into a hard gelatin capsule, which is then loaded into the device, the capsule is punctured by pressure, and the patient inhales a dose of the drug. Dry powder inhalation devices have been updated through three generations (Fig. 1). The third generation of DPIs employs active inhalation technology, which disperses and delivers the medication without the aid of a breathing airflow, using applied energy, such as compressed air or a motor-driven turbine [9], or by using voltage. These active inhalation devices achieve accurate and quantitative drug delivery independent of respiratory airflow and frequency with good reproducibility.

Teva Pharmaceutical Industries Ltd. Received approval from the FDA (U.S. Food and Drug Administration) in 2018. They introduced the first digital DPI with Bluetooth and sensors. Patients aged 4 and above may use the digital rescue inhaler ProAir Digihaler to treat or prevent bronchospasm caused by reversible obstructive airway diseases, including asthma and COPD, as well as exercise-induced bronchospasm. Digihaler expanded with the approval of AirDuo Digihaler and ArmonAir Digihaler in 2019 and 2020. Asthma sufferers aged 12 and above often get prescriptions for these drugs. AirDuo Digihaler is intended to address symptoms like wheezing, whereas ArmonAir Digihaler is recommended for long-term therapy [10]. The two devices are similar to the ProAir Digihaler in that they both use digital technology to help the user breathe more easily. Despite its late arrival, DPI is becoming more popular for the following reasons: (1) DPI's solid formulation is more stable than the nebulizer and pMDI's liquid formulation [11]. (2) It does not use propellants like freon (CFC) or hydrofluoroalkane (HFA), which prevent ozone depletion and greenhouse gas emissions [12]. (3) It is user-friendly and permits high-dose administration [13]. In addition, because of the respiratory activation mechanism of the majority of DPIs, coordination between patient inhalation and device activation is not necessary. These breath-activated DPIs need vigorous inhaling to fluidize the drug powder and create a sufficient drug aerosol. Although most patients can do it, generating adequate inspiratory airflow is difficult for children and patients with severe lung injury [14].

The development of DPI formulations is based on two approaches. The first is based on carrier-drug formulations, which primarily use inhalation-grade lactose, the only carrier approved by the U.S. Food and Drug Administration (FDA) for use in dry powder inhalation; however, DPI formulations based on lactose carriers are generally not recommended for use in patients with known lactose allergies [15]. Furthermore, the development of carrier-based formulations is challenging as far as the mixing process and lactose properties are concerned. In industrial practice, milling remains the preferred technology for the manufacture of carriers and respirable particles; the process has a long history, requires less labor and capital investment, and is considered a cost-effective technology [16]. Jet milling is one of the most common milling techniques, where particles are milled in a compressed gas by simultaneous jets of air that promote particle collision and abrasion, however, this technique lacks control over particle characteristics such as particle morphology, shape, crystallinity, and surface properties [17]. In addition, this high-energy process can induce localized lattice disruption of the milled crystals, which will increase the powder amorphous content and hygroscopic tendency [18]. If proper treatment is not carried out afterward to promote controlled recrystallization, the resulting powder may show changes in surface properties and the formation of solid bridges between particles when exposed to harsh environments with high temperatures and relative humidity [19]. Another problem is that, depending on the particle size, lattice structure, surface energy, and surface area, the milled particles can acquire a strong electrostatic charge [20]. High electrostatic charges on powders have been reported to interfere with content homogeneity and capsule filling, thus affecting the homogeneity of individual dosimetry [21]. In addition, these charges can enhance the cohesion between particles. This phenomenon hinders the depolymerization of particles and promotes drug retention in the inhaler during dispersion, affecting the performance of the aerosol [22]. Overall, all these issues may pose potential challenges to the stability and performance of milled powder formulations. Therefore, the development of a second approach based on the preparation of nanoscale polymers as carrier DPI formulations was considered necessary.

The second approach is based on the preparation of nanoscale aggregates as carriers for the delivery of pulmonary drugs to the lungs [23]. Nanotechnology is a leading technology in the 21st century, and technological innovations in the field of the electronics industry have been particularly prominent. It has long been expected that the development of nanotechnology will also lead to advances in drug development; in particular, in terms of multifunctionality, the development of nanotechnology capable of encapsulating drugs and functioning as a drug delivery system in vivo (drug retention, sustained release, targeting, and so on) has been a major concern focus [4]. Functional nanoparticles, such as liposomes, solid lipid nanoparticles, polymeric nanoparticles, micelles, polymeric micelles, exosomes, etc., are attractive drug delivery systems for solubilization, stabilization, sustained release, prolonged tissue retention, and tissue targeting of a variety of encapsulated drugs. For its clinical application in the treatment of lung diseases, the development of DPI formulations of nanoparticles aimed at reducing interparticle attraction and improving DPI performance is considered practical because of the following advantages: (1) it is non-invasive and can be delivered directly into the lungs, with the potential to achieve a relatively homogeneous distribution of the drug dosage in the alveoli [24]; and (2) the lungs interact with nanoparticles with biological components is minimal, allowing for sustained drug release and thus reduced dosing frequency [24]; (3) good atomization behavior with desirable stability during processing, administration, and storage [25]; (4) nanoparticles can overcome pulmonary mucus clearance with a reduced incidence of side effects [26]; and (5) minimize the physical instability associated with their liquid state, improve patient compliance, and enable targeted pulmonary drug delivery [27]; (6) most of the drugs delivered in the lungs are hydrophobic, and nanoparticles can also be used to improve the bioavailability of insoluble hydrophobic drugs [28]. However, to produce effective nanoparticle inhalation dry powders, innovative and comprehensive formulation strategies must be pursued in terms of composition and powdering, which can result in dry powders with particles designed to have physical properties suitable for pulmonary delivery via inhalation, as well as effective reconstitution of nanoparticles that will maintain their original physical properties and functionality after the powder is dissolved [29]. Since nanocarrier systems can be easily applied to the airways and are available in a variety of types, DPI formulations of nanoparticles can be used to treat several respiratory diseases, such as lung cancer, obstructive lung diseases, including COPD, asthma, and CF; and infectious diseases, including tuberculosis and pneumonia [30].