The increasing incidence of respiratory diseases such as cystic fibrosis, asthma, chronic obstructive pulmonary disease, infectious diseases, lung cancer and tuberculosis, makes pulmonary drug delivery a main point of focus in current drug delivery research. Dry-powder inhalers (DPIs) have become a widely popular means of drug delivery via the lungs. Currently, over 40% of patients suffering from asthma and chronic obstructive pulmonary disease use DPI formulations and this number is expected to grow in the future. Despite extensive research on DPIs during the last 40 years, these formulations suffer from low drug-delivery efficiency to the lungs. The most attractive approach to improve the efficiency of DPI formulations is the use of engineered drug or carrier particles. In doing this, formulation scientists should ensure a uniform blend with the drug and carrier, and reproducible release of the drug from the carrier while using the device.
In terms of DPI formulation, a number of different carriers have been used; however, lactose is employed most frequently since it is a widely used and a safe excipient in other solid dosage form formulations such as tablet and capsule formulations, it is available from various suppliers, and the taste/sensation produced upon inhalation reassures the patient that a dose has been taken. Insufficient detachment of drug from the carrier due to strong interparticulate forces is the major cause of low delivery efficiency encountered with most DPIs Citation[1]. Commercially available lactose-based carrier products from different suppliers have been shown to differ in the particle size and distribution, shape, surface rugosity, amorphous content, water content, hygroscopicity, anomeric composition, presence of fine and surface charge, all of which may lead to varying delivery profiles of the inhaled drug Citation[2–4].
Despite the extensive research on lactose as a carrier in DPI formulations Citation[2–6], it still suffers from some serious pitfalls including unsuitability for diabetic patients, interaction with certain drugs containing amino groups, for example, formotrol and budesonide, and interaction with peptides and protein drugs due to its reducing function Citation[7]. Lactose powder can also interact with moisture-sensitive drugs, which can jeopardize the chemical stability of drugs in the formulation. In addition, the main source of lactose production is bovine, thus transmissible spongiform encephalopathy is a point of concern Citation[8]. Moreover, lactose formulations are not suitable for lactose intolerant patients Citation[9]. These shortcomings clearly indicate that there is a serious need to explore alternative carriers to replace lactose in DPI formulations where possible.
Excipients such as mannitol, sorbitol, dextrose, trehalose, maltitol, erythritol, xylitol, maltose and raffinose have been suggested as alternative carriers in DPIs Citation[10]. However, on closer inspection, the chances of these potential carriers ever becoming successful DPI carriers, with the properties meeting the required conditions, is slim. Among the aforementioned carriers, mannitol exhibits particularly great promise as an attractive carrier in DPI systems Citation[11–14]; mannitol does not have a reducing effect, gives an obvious sweet aftertaste (useful indicator that the dose is taken), is not hygroscopic and is a suitable carrier for the aerosol delivery of proteins. Two mannitol-based DPI formulations have recently been approved for marketing: Aridol®, containing D-mannitol, was approved by the US FDA in 2010 as a pulmonary diagnostic agent; Bronchitol®, also containing mannitol, was approved for marketing in Australia and Europe in 2011 and 2012, respectively, for the treatment of cystic fibrosis in adults. Like lactose, commercially available mannitol may not demonstrate the ideal performance in DPIs and therefore particle engineering is required to manipulate the physicochemical properties of mannitol particles to tailor the particles as a suitable carrier for specific DPI systems. Designing an ideal carrier for DPI formulation is still a challenge as there is no absolute conclusion on the ideal physicochemical properties, micromeritics and morphology for a carrier. For example, there are conflicting reports on the effect of size of carrier on fine particle fraction (FPF) Citation[5,15,16]. This might be due, in part, to the presence of different drugs with different surface properties used in various studies. Similar controversy exists over the effect of elongated particles on carriers.
Even if all the governing parameters controlling the aerosolization performance of DPI formulations are identified, it would be very challenging to design any carrier to meet all the ideal properties. In addition, the exact relationships between the physicochemical properties and their function in DPI formulations are not yet fully understood. Looking at the effect of one single independent physicochemical property on DPI performance is also challenging, as manipulating one property can often alter the other. Therefore, studies should not focus on one property and attention should be given equally to all other properties that could vary alongside the particular property being studied. This complex relationship between physical properties of the carriers and drug delivery to the respiratory tract has triggered research towards variables that are expected to influence the interparticulate forces and also towards exploring and standardizing the techniques for the characterization and quantification of these variables. There are many factors reported in the literature that might change the performance of DPI formulations including powder flow, size, density, the type of polymorphic form and surface property. These properties affect the DPI performance by controlling the interparticulate adhesion and cohesion of formulation blends. A technique was developed to measure cohesive–adhesive balance in order to predict the dispersion mechanisms and in vitro deposition performance of various drug–sugar carrier combinations Citation[17,18]. For example, particle surface properties such as shape and roughness or smoothness are expected to influence the interparticulate forces (adhesion and cohesion). Therefore, the controversial conclusions reported in the literature regarding the effect of these carrier surface properties on DPI performance are most likely due to an optimum level of roughness being required for an optimum cohesive–adhesive balance, resulting in the most ideal carrier performance.
Different studies frequently report conflicting results. There are various reasons behind this confusion, the most important being the length, width and depth of surface roughness, parameters which are rarely reported. Measurement and quantification of the above parameters is still difficult to achieve with a high degree of accuracy and reproducibility using the currently available techniques. From a logical point of view, if the scale of the surface roughness is smaller than the size of the adhering drug particles, then the segregation of drug/carrier is minimized, the stability of the powder blend is improved and the adhesion of drug to the carrier is weak due to the small contact area, thus facilitating drug detachment from the carrier. However, deep crevices, clefts and large discontinuities can have a negative effect on drug detachment from the carrier.
One interesting approach to modifying mannitol particles toward better aerosolization performance is treating excess commercial carrier particles in a saturated solution of the same carrier to generate mannitol with nano-scale surface roughness Citation[11]. This is an interesting approach as the time of treatment can gear up the mannitol properties towards a better aerosolization performance. In addition, no toxic organic solvent is required in the process. The application of this technique to mannitol samples has led to significantly enhanced FPF of salbutamol sulphate in comparison to commercial mannitol (2.5-fold increase in FPF).
Mannitol is also an ideal excipient to be used in freeze–dried formulations to achieve superior pulmonary drug delivery. Studies by Kaialy and Nokhodchi et al. have demonstrated that the value of FPF of salbutamol sulphate increased to 46.9% using this technique, which is the highest value reported for this drug in the literature Citation[12]. This type of processed mannitol is also better than the spray-dried mannitol and can be expected to be used in future DPI formulations.
In addition to the application of mannitol as an efficient DPI carrier, mannitol has been suggested as an excellent ternary component to improve the efficiency of DPI systems containing lactose as the carrier Citation[19]. Recently, ternary additives (i.e., carrier fines or force control agents)have been used in DPI formulations in order to aid the detachment of drugs from the carriers during the inhalation process. Of crucial consideration when using this technique are particle size and concentration of the ternary components, which directly influence drug inhalation behavior. In the literature, wide ranges of concentrations (ranging from 5 to 37.5%) have been reported as the optimal fine ternary additive concentration in DPI formulations to achieve the maximum FPF. Unfortunately, the effect of the (all important) shape and surface properties of fine additives are not well studied to date. Recently, more detailed studies by Kaialy and Nokhodchi incorporated engineered fine mannitol particles of different shapes alongside the coarse lactose particles Citation[19]. The study demonstrated that the more elongated fine mannitol particles perform better and are able to significantly enhance the aerosolization performance of the model drug (salbutamol). In addition as the amount of incorporated fines is less than 5%, the flow of the formulations will not be compromised. The proposed explanation for better performance in the presence of fines is the coverage of hot spots (or active sites) on the coarse carrier by the fines or formation of aggregates between fines and drug particles. When applying this technique, it must be noted that the type of inhaler device may affect the performance of fines in optimizing the aerosolization behavior of drugs from DPI formulations.
Finally, it is worth mentioning that there are different grades of mannitol on the market with different particle morphologies and research reports comparing these commercial mannitol products, in terms of their aerosolization performance, are scarce; none exists that compares the use of mannitol with different drugs.
The restriction of lactose as a carrier for DPIs has been a barrier to the development of new carriers and has limited the potential of pulmonary drug delivery. The authors believe that interest in using DPIs will increase in the future and with the growing scientific and technological progress in this area, diseases such as diabetes, neurological diseases, cystic fibrosis and cancer may be treated via pulmonary delivery systems. In particular, the need for safer and more efficient carriers suitable for a wide range of drugs has become greater than ever. This is of special interest since many new chemical entities have biological origin, and therefore the reducing sugar function of lactose might interfere with these types of molecules. The design of a new carrier, such as mannitol, with improved surface properties and better drug delivery capabilities will make DPIs the therapy of choice for a variety of diseases.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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