Pulmonary administration of drugs is gaining much importance in the latest research as it offers several advantages for the treatment of local or systemic diseases. Three major inhalation systems have been proposed for the aerosolization of drugs: nebulizers, metered-dose inhalers (MDIs) and dry powder inhalers (DPIs). Currently, DPIs, which deliver medication to the lungs in the form of a dry powder, represent the most promising system due to higher drug deposition in the deep lung. In addition, DPI inhalation systems do not use inhalation propellant gases detrimental to the environment and do not depend on the patient’s coordination during the inhalation process [1
]. Besides local therapies developed against asthma or chronic obstructive pulmonary disease (COPD), lung administration using DPI has emerged as an alternative administration route for biopharmaceuticals like genes or peptides treating local and systemic diseases [4
]. As mentioned by de Boer et al., the expectations for vaccination through the pulmonary route are currently high [5
Drug efficacy is dependent on drug pulmonary deposition which depends on both the inhalation device performance and the aerosolization characteristics of the powder filled within it. Thus, when using DPIs for the aerosolization of drugs, the drug–device combination must be optimal to reach maximal drug efficacy. DPIs can be either “single-dose”, which use individual drug doses inside blisters or capsules, or “multi-dose” inhalers, which are basically composed of a reservoir filled with the drug powder. The design of new devices can intimately influence the lung delivery of drugs and should not be neglected [2
]. However, this review is exclusively focused on powder particle engineering.
In order to reach the deep pulmonary drug deposition goal, DPI must ideally contain a powder made of the active pharmaceutical ingredients (API) coformulated with a range of excipients, which are chosen based on their precise functions within the powder, leading to optimal aerosolization performances and, consequently, high deposition into pulmonary regions. Traditionally, a sugar-based carrier (e.g., lactose, mannitol) is used in order to increase the poor aerosolization properties of API intended for lung delivery. Indeed, due to the low dosage of the API in some formulations and to the presence of cohesive fine particles which have high propensity to aggregate, pulmonary active drugs are almost never used alone but are combined with a carrier or “flow-aid”. Physical interparticulate forces between the carrier and API occur but are generally too intense, leading to poor delivery of drugs into the lung because of incomplete API–carrier dissociation [8
]. Hence, the main challenge in drug aerosolization is to obtain the highest dose fraction deposition in the lower airways [9
]. This criterion is experimentally defined as the fine particle fraction (FPF) and represents the proportion of emitted particles that have a lower particle size than the diameter of the upper airway, fixed at 5 µm [10
]. As shown in Figure 1
, the FPF for DPI containing adhesive carrier–drug powder mixtures is equal to only 14%, while 21% of the drug is lost in the oropharyngeal sphere and 65% are not released from the carrier. These results were obtained in vitro from thirteen commercial DPIs using a next generation impactor (NGI). It is obvious that to reach the desired situation in which at least 49% of the drug is available for lung deposition (Figure 1
B), the drug dispersion in the air following the patient’s aspiration and the volatility of the powder should be increased [5
Recently, a new strategy has emerged as very promising and innovative way to increase the pulmonary deposition of drugs. The development of carrier-free particles has been proposed to improve the uniformity and dispersibility of inhaled powders and consequently to increase the therapeutic activity of respirable drugs [9
]. Different types of carrier-free particles are already on the market such as spheroids produced by the agglomeration of micronized budesonide (Pulmicort®
) or porous particles called PulmoSpheres®
composed of tobramycin and PulmoSpheres®
]. Moreover, different kinds of carrier-free particles are under study and investigation. For instance, Zhang et al. have very recently developed large porous microparticles loading budesonide using the single emulsion (O/W) solvent evaporation method with Poly(lactide-co-glycolide) and Poly(vinyl pyrrolidone) showing an FPF of ~21% [11
]. Another new type of carrier-free particle, which is not well categorized yet, has emerged in recent years, and is characterized by a solid core surrounded by an outer layer. These particles are, most of the time, produced by spray drying [12
], and have a low particle size (2–10 µm) with a wrinkled, rough surface. For a better understanding, these particles are named in this review as “composite-corrugated particles”.
shows a schematic representation of these composite-corrugated particles made of a sugar-based core (yellow) encompassed by a shell layer (blue). By using this new strategy of powder production, there is no problem of blend uniformity or disaggregation since the API is entirely embedded in excipients. Understanding the importance of sugar properties and those of other excipients can lead to the development of particles containing different APIs that are effective for pulmonary delivery.
The spray-drying technique is suitable for the accurate engineering of inhalable particles since multiple parameters (Nozzle air flow, Inlet temperature, Solid content) can be modified during the production process which will impact, among other factors, the size, the morphology and the water content of microparticles [14
]. Other techniques such as spray-freeze-drying and supercritical fluids could be used and are already reviewed by others [15
In this review, we focus on the development of composite-corrugated particles produced by spray drying. All excipients used to produce composite particles will be listed in this work with special attention to their physico-chemical properties such as the glass transition temperature (Tg), the hygroscopicity and the Péclet number, all impacting the final powder behavior. Moreover, materials forming the core and/or the outer layer of microparticle powders are detailed and compared. Special attention is given to the spray-drying technique where the most important parameters, which influence the process yield and the powder morphology, are explained. Finally, the relation between particle properties such as surface texture and their behavior as well as DPI effectiveness will be dissected. Overall, this review gives an overview of the characteristics of all excipients used to develop composite-corrugated particles and their effectiveness to induce high aerosolization performance. The understanding of the closed relation between particle material composition and spray-drying process parameters, impacting final powder properties, could help in the development of promising DPI systems suitable for local or systemic drug delivery.
4. Aerosolization Performance Parameters
The previous sections explain how the choice of excipients/API mixture and spray-drying parameters influence the resulting powder particle properties. This paragraph describes how such properties impact particle powder behaviors. Figure 8
summarizes all physicochemical properties conditioning powder behaviors and consequently, DPI effectiveness.
According to the equation of the aerodynamic diameter (da
), multiple parameters can influence the behavior of particles:
Hence, da is the aerodynamic diameter, while C0, ρP, ρ0 and d0 stand for the feed solution concentration, the particle density, the unit density and the initial droplet diameter, respectively.
A first observation indicates that the da
is dependent on the feed concentration stock solution (C0
). As mentioned in Section 2.2.2
, a feed stock solution of 1% has been described as optimal to produce powder particles displaying an appropriate size (1–5 µm). Regarding this equation, it is easy to understand that the more the C0
increases, the more the da
increases. Wang et al. have recently shown that the da
of a spray-dried formulation of trehalose increased from 5.98 µm to 15.50 µm when feed solutions of 1mg/mL and 30mg/mL were, respectively, atomized [70
Second, the weaker the particle density (ρP
), the smaller the da
. This explains why some authors have investigated the potential of large porous particles to produce efficient DPI. The incorporation of pores within powder particles decreases the density, characterized by the relationship between the weight (m
) and the volume (V
). In the case of composite-corrugated particles, the decrease in density is induced by the roughness of particles. Indeed, as shown in Figure 9
, many authors have shown that their particles had a folded or rough surface.
Due to folding, the distance between these particles is smaller, which prevents friction, interlocking forces and/or water bridge formations. Indeed, Zhao et al. proved that a spherical formulation composed only of raffinose displays physical properties which are completely different to corrugated particles made of HPβCD and raffinose (ratio 60/40). While diameters were similar among experimental groups (d0.5 = 4 µm), bulk density, aeration and permeability results were highly different, indicating a higher sensitivity to the airflow for corrugated particles [26
Other authors who developed spray-dried particles with bovine serum albumin alone have studied in detail the degree of particle corrugation and surface morphology using scanning electron microscopy and atomic force microscopy. Due to modification of spray-drying processes, i.e., the feed concentration, the atomization rate and inlet temperature, different particles were produced. Hence, a reduction in the feed concentration induced the increase in surface corrugation. Moreover, using colloid probe microscopy, the adhesion forces between particles were evaluated and showed an inversed correlation between particle roughness and adhesion forces. Finally, a proportional correlation was found between the feed concentration (mg/mL), the particle roughness (nm) and the FPF (%) [71
]. For a complete review of techniques used to study the microstructural characterization of powders such as pore structure or surface roughness, refer to Elsayed et al. [72
Although the rough surface has shown great importance for respiratory deposition, Cui et al. have also warned about over-corrugated surfaces (Figure 10
]. Indeed, when surfaces are excessively folded, the particles become embedded in each other, inducing cohesion forces, agglomeration, and higher density, leading to poor aerosolization.
Another important parameter which is, most of the time, neglected is the electrostatic charges of powder particles. The contact between particles or with the device induces an exchange or donation of electrons during the production or inhalation process. The intensity of particle charges is dependent on many factors such as the particle size, morphology, surface, or water content [73
]. To the best of our knowledge, this parameter is generally not considered when carrier-free particles are developed. One example for carrier particles was presented by Karner et al. They showed that the higher the triboelectric charges, the higher the FPF (~30%) [20
]. However, in this study, mannitol was blended with salbutamol without spray drying, thus the size was 80 µm.
The importance of excipient characteristics has been largely discussed in previous sections which explained how this considerably impacts the hygroscopicity, the amorphous content or the morphology of final DPI.
Overall, it is clear that all parameters are closely related. While the atomization process influences the size of the particles, the size influences the aerodynamic diameter, itself influenced by the particle density or shape. Moreover, the choice of excipients determines the particle shape, the surface texture or the hygroscopicity. It seems very complicated to give numerical criteria that must be respected to produce DPI with high deposition performance even if trends can be found. Some physical parameters such as the size (0.5–5 µm), or technical factors such as solid content of the feed solution are well known to impact DPI performance. In this review, we have highlighted the importance of excipients’ characteristics in powder formulations in terms of Tg and hygroscopy, all parameters influencing the stickiness of the final powder. Moreover, it appears clearly that the morphology and surface texture of such small particles determine the aerosolization performance of powder particles.
5. Conclusions and Perspectives
This review describes the composition and the related lung deposition performance of carrier-free powder particles and more precisely of composite-corrugated particles. We have noticed that these particles are characterized by a solid sugar core surrounded by a corrugated outer layer with the drug directly embedded in it. The requirement of amino acids to form a hydrophobic layer around the core of the particle is not always necessary. Indeed, due to different physicochemical properties (molecular weight, Tg), the migration of material within the atomized droplet is different, leading to either a smooth or a wrinkled structure with a rough surface. The interest in cyclodextrins combined with other sugars has also been highlighted. A big improvement of these new formulations could be the fact that two or more active ingredients can be combined and consequently reach the same lung deposition. Moreover, with non-reducing sugars, having a high transition temperature (Tg), the amorphous state at room temperature is stable, which increases the product stability.
Regarding the morphology, the corrugated surface seems to be determinant in observing high deposition performance due to the reduction of interparticular forces, although more evidence is needed. Furthermore, additional studies are required to fully understand the importance of other particle properties such as the electrostatic charges. In the future, efforts should be made to ensure that a single excipient formulation can be used for different drugs, leading to the same pulmonary deposition.