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

Abstract

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.

Introduction

The development of inhaled dry powder formulations has gained a great attention over the past two decades. Pulmonary drug delivery is considered a non-invasive approach for the treatment of various chronic diseases. It overcomes several limitations associated with conventional dosage forms. Lungs are characterized by their large surface area (100 m²), abundant blood supply, high permeability of the thin peripheral epithelial layer (0.2–0.7 μm), low enzymatic activity, and the ability to avoid first-pass metabolism. This makes the pulmonary route an attractive route for drug targeting and achieving rapid onset of action. Hence, pulmonary drug delivery systems have been widely evaluated for drug delivery, both locally and systemically [1]. Also, various biopharmaceutics, therapeutic proteins, peptides, analgesics, enzymes, vaccines, and SiRNA have been studied for pulmonary drug delivery [2].

However, the development of pulmonary drug delivery is associated with several challenges. The rate-limiting step often depends on the successful delivery of particles to deep lungs. The deposition of particles upon inhalation is governed by gravitational sedimentation, inertial impaction, diffusion, or a combination thereof, depending on the aerodynamic particle size, shape, and density of the formulation [3,4]. An aerodynamic particle size between 1 and 5 μm is optimum and allows particles sedimentation by gravitational force in the central and peripheral parts of the lung. Particles with aerodynamic size less than 1 μm are eliminated rapidly by exhalation or coughing. Whereas, particles bigger than 5 μm deposit by inertial impaction and stay in the upper respiratory tract [5]. Upon deposition in deep lungs, soluble drug particles dissolve and gives local action or become absorbed and produce systemic action. The absorption of the particles depends on the physicochemical properties of the drug and the carrier particles.

The solubility and permeability of the formulation are important factors that control the rate and extent of drug absorption [6]. Consequently, active pharmaceutical ingredients with high solubility such as protein and peptides rapidly dissolve, making them a good candidate for pulmonary drug delivery. However, the delivery of drugs with low solubility and sustained release formulations is challenging as the rate and extent of absorption depend on their dissolution rate, stability, and the contact surface between the formulation and the lung epithelial tissue. The approximate volume for the lung fluids is around 15–70 mL, however, the actual volume available for solubilizing the inhaled formulations is still unknown making it difficult to predict their in-vivo dissolution rate [7]. Further, the thickness of the epithelial tissue differs between the upper, lower, and deep respiratory tract affecting the contact surface. Even though surfactants present in the lungs could enhance the solubility of some drugs, the phospholipid components of the surfactants could also interact with some drug molecules such as therapeutic proteins and peptides, leading to their deactivation and aggregation [8].

As a result of this complex nature of the airways and heterogenous properties of different area of the lungs, the factors affecting inhaled particle dissolution and drug absorption is still unclear. Only few numbers of studies have studied drug particle interaction with the airway mucus lining of the lungs [[9], [10], [11]]. The dissolution, permeation, and absorption of inhaled salbutamol and indomethacin was investigated by Cingolani et al. as a model drugs of Biopharmaceutics Classification System (BCS) class III (high solubility/low permeability) and class II drugs (low solubility/high permeability, respectively [9]. Drug loaded DPIs were insufflated into multiple air-liquid interfaced layers of the broncho-epithelial cell line Calu-3 or thin layers of porcine tracheal mucus mounted onto Transwells® inserts. The study demonstrated that the permeability of salbutamol was hindered by the mucus while the permeability of indomethacin was higher. It was observed that the mucus lining enhanced the dissolution profile of the poorly soluble drug indomethacin. This indicates that the drug-mucus interaction plays an essential role that controls the dissolution and absorption of inhaled drug particles depending on their physicochemical properties.

The second barrier in pulmonary drug delivery is the achievement of sustained drug release to minimize the dosing frequency for patients with chronic lung diseases such as chronic obstructive pulmonary disorder (COPD), pulmonary hypertension, asthma, and cystic fibrosis. Sustained drug delivery is controlled by several clearance mechanisms in the lungs such as mucociliary clearance and macrophage uptake in the upper and lower respiratory tract, respectively [6]. As most of the formulations target the deep lungs, alveolar macrophages are the primary challenge. The alveolar macrophages are sensitive to particles of size range 0.5–5 μm [12]. Consequently, most inhaled products have a short half-life and must be administrated multiple times a day to achieve their therapeutic effect. This impacts patient compliance and treatment efficiency [13].

Several particle engineering techniques have been studied to overcome the limitations of pulmonary drug delivery. These include the use of a carrier to formulate controlled pulmonary drug delivery systems such as swellable microparticles [[14], [15], [16], [17]], large porous microparticles [[18], [19], [20]], solid lipid nanoparticles [[21], [22], [23]], nanocomposite microparticles [[24], [25], [26]], and liposomes [[27], [28], [29]]. The controlled release system minimizes dosing frequency, reduces side effects, and enhances patient compliance [13]. Despite the extensive research, there are only a few controlled-release inhalable biotherapeutic marketed products. This can be attributed to the previously mentioned obstacles associated with the development of a safe and effective pulmonary drug delivery system.

This comprehensive review will focus on the innovative strategies for DPI formulation development and the tools to overcome formulation challenges. The article will also discuss the factors affecting particle deposition in the lungs, recent particle engineering techniques, commonly used polymers and excipients, important aspects for the evaluation of DPI formulations, and some current and promising applications for pulmonary drug delivery systems.