Inhalable microparticles as drug delivery systems to the lungs in a dry powder formulations

Abstract

Inhalation-administrated drugs remain an interesting possibility of addressing pulmonary diseases. Direct drug delivery to the lungs allows one to obtain high concentration in the site of action with limited systemic distribution, leading to a more effective therapy with reduced required doses and side effects. On the other hand, there are several difficulties in obtaining a formulation that would meet all the criteria related to physicochemical, aerodynamic and biological properties, which is the reason why only very few of the investigated systems can reach the clinical trial phase and proceed to everyday use as a result. Therefore, we focused on powders consisting of polysaccharides, lipids, proteins or natural and synthetic polymers in the form of microparticles that are delivered by inhalation to the lungs as drug carriers. We summarized the most common trends in research today to provide the best dry powders in the right fraction for inhalation that would be able to release the drug before being removed by natural mechanisms. This review article addresses the most common manufacturing methods with novel modifications, pros and cons of different materials, drug loading capacities with release profiles, and biological properties such as cytocompatibility, bactericidal or anticancer properties.

Keywords: drug delivery systems to lungs; dry powder inhalers; inhalers; microparticles; pulmonary therapies.

Graphical abstract

Figure 1.

Construction and operation of inhaler devices: pressurized metered dose inhaler (pMDI) [30], dry powder inhaler (DPI) [31], soft mist inhaler (SMI) [32], air jet nebulizer, ultrasonic nebulizer and vibrating mesh nebulizer [33]. All the pictures adapted with permission.

Figure 2.

Areas and mechanisms of MPs deposition depending on their aerodynamic diameter (D_ae).

Figure 3.

Diagram of the equipment and the process of conventional spray drying [59]. The picture adapted with permission.

Figure 4.

SEM images of MPs based on different polysaccharides manufactured using spray-drying method: (A) Budesonide-loaded chitosan swellable MPs [61], (B) salbutamol-loaded hyaluronic acid MPs [62], (C) chondroitin sulfate/isoniazid/rifabutin MPs produced with water–ethanol as solvent (mass ratio of 10/1/0.5) [63], (D) rifampicin and phytoglycogen (1/5, w/w) prepared in solvents containing 50% ethanol by volume [64], (E) fucoidan/isoniazid/rifabutin MPs (mass ratios of 10/1/0.5) [65] and (F) locust bean gum/isoniazid/rifabutin MPs (mass ratio of 10/1/0.5) [66]. All the pictures adapted with permission.

Figure 5.

Comparison of the deposition in vivo of PLGA MPs obtained by spray-drying in solvent with DCM:methanol ratio 100:0 (A) and 70:30 (B) (**p < 0.01, Tukey’s test) [85]. The picture adapted with permission.

Figure 6.

Various PLGA MPs obtained in different conditions and for different purposes. (A) Non-porous and porous MPs with various morphologies due to the changing homogenization rate and surfactants—single emulsification [82]; (B) spray-dried MPs with the mixture of DCM: methanol 70:30 [85]; (C) spray-dried MPs modified with 0.2% of leucine for non-spherical morphology for increased FPF [88]; (D) surface-modified with PEG-2000 MPs obtained by premix membrane double emulsification to avoid macrophage uptake [87]; (E) N-acetyl cysteine surface-modified MPs obtained by double emulsification for better mucus presentation [89]; (F) porous by the use of ammonium bicarbonate MPs obtained by double emulsification [90] and porous MPs from double emulsification; (G) with internal pores, loaded with doxorubicin [91]; and (H) with external pores, loaded with artesunate [92]. All the pictures adapted with permission.

Figure 7.

(A and B) The viability of the A549 cells after incubation in the supernatants from DOX-co-loaded MPs. (A): P00—control, PD0—DOX-loaded, P0G—p53-loaded, PDG DOX-co-p53-loaded PLGA MPs [90], (B): MP-1—control, MP-2—miR-519c-loaded, MP-3—DOX-loaded, MP-4—DOX-co-miR-519c-loaded PLGA MPs [107], and the lung weights after in vivo test of BALB/c mice 4 weeks after H226 cancer cells implementation and DOX/TRAIL-loaded PLGA MPs pulmonary administration (*P < 0.015 over group I; **P < 0.005 over group II; and ***P < 0.05 over group IV) [91]. All the pictures adapted with permission.

Figure 8.

SEM images of solid lipid MPs: (A) dilyceryl behenate MPs loaded with budesonide [123]; (B) glycerol behenate MPs loaded with budesonide [124]; (C) glyceryl dibehenate MPs loaded with solubutomal sulfate [126]; (D) glyceryl behenate MPs loaded with quercetin [127]; (E) tristearin with PEG modification loaded with cisplatin [128]; (F) glycerol tripalmitate with chitosan modification loaded with fluticasone propionate [129]; (G) phospholipids loaded with amphotericin B [130]. All the pictures adapted with permission.

Figure 9.

SEM images of inhalable composite NPs embedded within MPs: (A) Azi/NAC, (B) Cipro/NAC, (C) Tobr/NAC [143]; (D) lactose monohydrate based Trojan NPs, (E) trehalose-based Trojan NPs, (F) raffinose-based Trojan NPs [144]; (G) chitosan NPs/lactose-PEG3000 [145]; (H) PLGA/PLGA [141]; and (I) PLGA/mannitol [142]. All the pictures adapted with permission.

Figure 10.

Multistage process of formulation inhalable MPs.

Figure 11.

Scheme of a multistage cascade impactor (A) [151] and single stage (B) [152]. The pictures adapted with permission.

Figure 12.

Advantages and disadvantages of using animal studies of pulmonary drug delivery to the lungs [169]. The picture adapted with permission.