RESUMO
Pulmonary inflammations such as chronic obstructive pulmonary disease and cystic fibrosis are widespread and can be fatal, especially when they are characterized by abnormal mucus accumulation. Inhaled corticosteroids are commonly used for lung inflammations despite their considerable side effects. By utilizing particle engineering techniques, a combined dry powder inhaler (DPI) comprising nanosized ketoprofen-embedded mannitol-coated microparticles was developed. A nanoembedded microparticle system means a novel advance in pulmonary delivery by enhancing local pulmonary deposition while avoiding clearance mechanisms. Ketoprofen, a poorly water-soluble anti-inflammatory drug, was dispersed in the stabilizer solution and then homogenized by ultraturrax. Following this, a ketoprofen-containing nanosuspension was produced by wet-media milling. Furthermore, co-spray drying was conducted with L-leucine (dispersity enhancer) and mannitol (coating and mucuactive agent). Particle size, morphology, dissolution, permeation, viscosity, in vitro and in silico deposition, cytotoxicity, and anti-inflammatory effect were investigated. The particle size of the ketoprofen-containing nanosuspension was ~230 nm. SEM images of the spray-dried powder displayed wrinkled, coated, and nearly spherical particles with a final size of ~2 µm (nano-in-micro), which is optimal for pulmonary delivery. The mannitol-containing samples decreased the viscosity of 10% mucin solution. The results of the mass median aerodynamic diameter (2.4-4.5 µm), fine particle fraction (56-71%), permeation (five-fold enhancement), and dissolution (80% release in 5 min) confirmed that the system is ideal for local inhalation. All samples showed a significant anti-inflammatory effect and decreased IL-6 on the LPS-treated U937 cell line with low cytotoxicity. Hence, developing an innovative combined DPI comprising ketoprofen and mannitol by employing a nano-in-micro approach is a potential treatment for lung inflammations.
RESUMO
Pulmonary delivery is an alternative route of administration with numerous advantages over conventional routes of administration. It provides low enzymatic exposure, fewer systemic side effects, no first-pass metabolism, and concentrated drug amounts at the site of the disease, making it an ideal route for the treatment of pulmonary diseases. Owing to the thin alveolar-capillary barrier, and large surface area that facilitates rapid absorption to the bloodstream in the lung, systemic delivery can be achieved as well. Administration of multiple drugs at one time became urgent to control chronic pulmonary diseases such as asthma and COPD, thus, development of drug combinations was proposed. Administration of medications with variable dosages from different inhalers leads to overburdening the patient and may cause low therapeutic intervention. Therefore, products that contain combined drugs to be delivered via a single inhaler have been developed to improve patient compliance, reduce different dose regimens, achieve higher disease control, and boost therapeutic effectiveness in some cases. This comprehensive review aimed to highlight the growth of drug combinations by inhalation over time, obstacles and challenges, and the possible progress to broaden the current options or to cover new indications in the future. Moreover, various pharmaceutical technologies in terms of formulation and device in correlation with inhaled combinations were discussed in this review. Hence, inhaled combination therapy is driven by the need to maintain and improve the quality of life for patients with chronic respiratory diseases; promoting drug combinations by inhalation to a higher level is a necessity.
