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Drugs need to enter the systemic circulation efficiently before they can cross the blood-brain barrier and reach the central nervous system. Although the respiratory tract is not a common route of administration for delivering drugs to the central nervous system, it has attracted increasing interest in recent years for this purpose.In this article, we compare pulmonary delivery to three other common routes (parenteral, oral, and intranasal) for delivering drugs to the central nervous system. Recent studies delivering drugs for different neurological disorders via inhalation are then discussed to illustrate the strengths of pulmonary delivery.Recent studies provide strong evidence and rationale to support inhaling neurological drugs. Since inhalation can achieve improved pharmacokinetics and rapid onset of action for multiple drugs, it is a noninvasive and efficient method to deliver drugs to the central nervous system. Future research should focus on delivering other small and macro-molecules via the lungs for different neurological conditions.

The use of cannabidiol (CBD) for treating brain disorders has gained increasing interest. While the mechanism of action of CBD in these conditions is still under investigation, CBD has been shown to affect numerous different drug targets in the brain that are involved in brain disorders. Here we review the preclinical and clinical evidence on the potential therapeutic use of CBD in treating various brain disorders. Moreover, we also examine various drug delivery approaches that have been applied to CBD. Due to the slow absorption and low bioavailability with the current oral CBD therapy, more efficient routes of administration to bypass hepatic metabolism, particularly pulmonary delivery, should be considered. Comparison of pharmacokinetic studies of different delivery routes highlight the advantages of intranasal and inhalation drug delivery over other routes of administration (oral, injection, sublingual, buccal, and transdermal) for treating brain disorders. These two routes of delivery, being non-invasive and able to achieve fast absorption and increase bioavailability, are attracting increasing interest for CBD applications, with more research and development expected in the near future.

Particles and droplets produced from pharmaceutical inhaler devices are naturally charged. Previous in silico and in vitro studies have shown that the levels of these electrostatic charges may pote...

Cough is an adverse effect that may hinder the delivery of drugs into the lungs. Chemical or mechanical stimulants activate the transient receptor potential in some airway afferent nerves (C‐fibres or A‐fibres) to trigger cough. Types of inhaler device and drug, dose, excipients and formulation characteristics, including pH, tonicity, aerosol output and particle size may trigger cough by stimulating the cough receptors. Release of inflammatory mediators may increase the sensitivity of the cough receptors to stimulants. The cough‐provoking effect of aerosols is enhanced by bronchoconstriction in diseased airways and reduces drug deposition in the target pulmonary regions. In this article, we review the factors by which inhalation products may cause cough.

While nanoparticulate drugs for deep lung delivery hold promise for particular disease treatments, their size-related physical instability and tendency of being exhaled during breathing remain major challenges to their inhaled formulation development. Here we report a viable method for converting drug nanosuspensions into inhalable, stable and redispersible nano-agglomerates through combined in-situ thermal gelation and spray drying. Itraconazole (ITZ) nanosuspensions were prepared by flash nanoprecipitation, and co-spray dried with two different grades of the gel-forming polymer, methylcellulose (MC M20 and MC M450) as protectants. MC M20 was found superior in protecting ITZ nanoparticles against thermal stress (through nanoparticle entrapment within its gel network structure) during spray drying. In terms of redispersibility, an Sf/Si ratio (i.e., ratio of nanoparticle sizes after and before spray drying) of unity (1.02 ± 0.03), reflecting full particle size preservation, was achieved by optimizing the suspending medium content and spray drying parameters. Formulation components, nanosuspension concentration and spray drying parameters all showed a significant impact on the aerosol performance of the resulting agglomerates, but an absence of defined trends or correlations. Overall, the MC-protected nano-agglomerates displayed excellent in-vitro aerosol performance with fine particle fractions higher than 50% and mass median aerodynamic diameters within the 2-3 µm range, which are ideal for deep lung delivery.

Multi-drug-resistant tuberculosis (MDR-TB) is a huge public health problem. The treatment regimen of MDR-TB requires prolonged chemotherapy with multiple drugs including second-line anti-TB agents associated with severe adverse effects. Capreomycin, a polypeptide antibiotic, is the first choice of second-line anti-TB drugs in MDR-TB therapy. It requires repeated intramuscular or intravenous administration five times per week. Pulmonary drug delivery is non-invasive with the advantages of local targeting and reduced risk of systemic toxicity. In this study, inhaled dry powder formulation of capreomycin targeting the lung was developed using spray drying technique. Among the 16 formulations designed, the one containing 25% capreomycin (w/w) and spray-dried at an inlet temperature of 90 °C showed the best overall performance with the mass median aerodynamic diameter (MMAD) of 3.38 μm and a fine particle fraction (FPF) of around 65%. In the pharmacokinetic study in mice, drug concentration in the lungs was approximately 8-fold higher than the minimum inhibitory concentration (MIC) (1.25 to 2.5 µg/mL) for at least 24 h following intratracheal administration (20 mg/kg). Compared to intravenous injection, inhaled capreomycin showed significantly higher area under the curve, slower clearance and longer mean residence time in both the lungs and plasma.

The coronavirus disease 2019 (COVID-19) is an unprecedented pandemic that has severely impacted global public health and the economy. Hydroxychloroquine administered orally to COVID-19 patients was ineffective, but its antiviral and anti-inflammatory actions were observed in vitro. The lack of efficacy in vivo could be due to the inefficiency of the oral route in attaining high drug concentration in the lungs. Delivering hydroxychloroquine by inhalation may be a promising alternative for direct targeting with minimal systemic exposure. This paper reports on the characterisation of isotonic, pH-neutral hydroxychloroquine sulphate (HCQS) solutions for nebulisation for COVID-19. They can be prepared, sterilised, and nebulised for testing as an investigational new drug for treating this infection. The 20, 50, and 100 mg/mL HCQS solutions were stable for at least 15 days without refrigeration when stored in darkness. They were atomised from Aerogen Solo Ultra vibrating mesh nebulisers (1 mL of each of the three concentrations and, in addition, 1.5 mL of 100 mg/mL) to form droplets having a median volumetric diameter of 4.3–5.2 µm, with about 50–60% of the aerosol by volume &lt, 5 µm. The aerosol droplet size decreased (from 4.95 to 4.34 µm) with increasing drug concentration (from 20 to 100 mg/mL). As the drug concentration and liquid volume increased, the nebulisation duration increased from 3 to 11 min. The emitted doses ranged from 9.1 to 75.9 mg, depending on the concentration and volume nebulised. The HCQS solutions appear suitable for preclinical and clinical studies for potential COVID-19 treatment.

The manufacture of dry powders for pulmonary drug delivery is complicated by stringent requirements for the aerodynamic size distribution and solid-state properties of the powder. Micronization is ...

Systemic administration of antifungal agents for the treatment of pulmonary aspergillosis is limited by the poor lung deposition and severe adverse effects. In contrast, pulmonary delivery allows a higher amount of drug to be delivered directly to the infection site and therefore a lower dose is required. This study aimed to develop porous and inhalable voriconazole dry powder with good lung deposition by spray freeze drying (SFD), using tert-butyl alcohol (TBA) as a co-solvent. A three-factor two-level full factorial design approach was used to investigate the effect of total solute concentration, drug content and co-solvent composition on the aerosol performance of the SFD powder. In general, the SFD voriconazole powder exhibited porous and spherical structure, and displayed crystalline characteristics. The analysis of factorial design indicated that voriconazole content was the most significant variable that could influence the aerosol performance of the SFD powders. The formulations that contained a high voriconazole content (40% w/w) and high TBA concentration in the feed solution (70% v/v) displayed the highest fine particle fraction of over 40% in the Next Generation Impactor study in which the powder was dispersed with a Breezhaler® at 100 L/min. In addition, the fine particle dose of the SFD powder showed a faster dissolution rate when compared to the unformulated voriconazole. Intratracheal administration of SFD voriconazole powder to mice resulted in a substantially higher drug concentration in the lungs when comparing to the group that received an equivalent dose of liquid voriconazole formulation intravenously, while a clinically relevant plasma drug concentration was maintained for at least two hours. Overall, an inhalable voriconazole dry powder formulation exhibiting good aerosol property and lung deposition was developed with clinical translation potential.

Cocrystallization represents an emerging approach to tackle the issues associated with pharmaceutical product performance and processing, owing to its capability of modifying a variety of physicochemical properties. In this study, we sought to modify the crystal form of itraconazole (ITZ) with suberic acid (SUB) via rapid solvent removal methods, namely rotary evaporation and spray drying. A phase pure ITZ-SUB cocrystal, which could not be obtained by traditional cocrystallization methods, was successfully prepared by rotary evaporation. The new cocrystal was confirmed by powder X-ray diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. Spray drying was further employed for particle engineering of ITZ-SUB to achieve optimal pulmonary delivery. By manipulating the critical processing parameters, inhalable ITZ-SUB agglomerates with a mass median aerodynamic diameter of 2.56 ± 2.27 μm and fine particle fraction of 64.10% w/w were reproducibly prepared. The inhalable po...

Inhaled drugs are routinely used for the treatment of respiratory-supported patients. To date, pressurized metered dose inhalers and nebulizers are the two platforms routinely employed in the clinical setting. The scarce utilization of the dry powder inhaler (DPI) platform is partly due to the lack of in vivo data that proves optimal delivery and drug efficacy are achievable. Additionally, fitting a DPI in-line to the respiratory circuit is not as straightforward as with the other aerosol delivery platforms. Importantly, there is a common misconception that the warm and humidified inspiratory air in respiratory supports, even for a short exposure, will deteriorate powder formulation compromising its delivery and efficacy. However, some recent studies have dispelled this myth, showing successful delivery of dry powders through the humidified circuit of respiratory supports. Compared with other aerosol delivery devices, the use of DPIs during respiratory supports possesses unique advantages such as rapid delivery and high dose. In this review, we presented in vitro studies showing various setups employing commercial DPIs and effects of ventilator parameters on the aerosol delivery. Inclusion of novel DPIs was also made to illustrate characteristics of an ideal inhaler that would give high lung dose with low powder deposition loss in tracheal tubes and respiratory circuits. Clinical trials are urgently needed to confirm the benefits of administration of dry powders in ventilated patients, thus enabling translation of powder delivery into practice.

Refereed/Peer-reviewed Epithelial surfaces protect exposed tissues in the body against intrusion of foreign materials, including xenobiotics, pollen and microbiota. The relative permeability of the various epithelia reflects their extent of exposure to the external environment and is in the ranking: intestinal≈ nasal ≥ bronchial ≥ tracheal > vaginal ≥ rectal > blood-perilymph barrier (otic), corneal > buccal > skin. Each epithelium also varies in their morphology, biochemistry, physiology, immunology and external fluid in line with their function. Each epithelium is also used as drug delivery sites to treat local conditions and, in some cases, for systemic delivery. The associated delivery systems have had to evolve to enable the delivery of larger drugs and biologicals, such as peptides, proteins, antibodies and biologicals and now include a range of physical, chemical, electrical, light, sound and other enhancement technologies. In addition, the quality-by-design approach to product regulation and the growth of generic products have also fostered advancement in epithelial drug delivery systems.

Spray drying is a rapid method for converting a liquid feed into dried particles for inhalation aerosols. Lactose is a major inhalation excipient used in spray-dried (SD) formulations. However, SD powders produced from solutions are usually amorphous hence unstable to moisture. This problem can potentially be minimized by spray drying a suspension (instead of solution) containing crystalline lactose particles and dissolved drugs. In the present study, the suspension formulation containing dissolved budesonide (BUD) or rifampicin (RIF) and suspended lactose crystals in isopropanol alcohol (IPA) were produced. For comparison, powders were also produced from solution formulations containing the same proportions of drug and lactose dissolved in 50:50 IPA/water as controls. These SD powders were stored at 25 °C/60% RH and 40 °C/75% RH for six months. The particulate properties and in vitro dispersion performance were examined at various storage time points. All powders obtained from spray drying of solutions recrystallized after one week of storage at 25 °C/60% RH. In contrast, SD BUD-lactose obtained from suspension did not change until after three-months of storage when the particle size increased gradually with morphology change and yet the crystallinity remained the same as determined by X-ray powder diffraction. For the SD RIF-lactose obtained from suspension, both particulate properties and in vitro powder dispersion performance showed no significant difference before and after storage at both storage conditions. To conclude, this is the first study to show that SD powder formulations obtained from suspensions containing lactose crystals demonstrated superior storage stability performance, which is desirable for inhaled powders.

Lactose is widely used as an approved excipient for dry powder inhaler (DPI) products. Spray drying technique is a rapid method for converting a liquid feed into inhalable dried particles. However, spray-dried (SD) lactose powders produced from solutions are mostly amorphous and particularly unstable when exposed to moisture. In the present study, we explored the use of spray drying suspensions containing crystalline lactose particles in an organic solvent, and investigated the physicochemical properties of the resulting powders. The solution formulation was spray dried as a control. Two conditioned crystalline lactose samples were used for suspension formulations: Lactohale (LH) 300 lactose and jet-milled (JM) lactose micronized from LH300. The suspension formulations each contained 12 mg/ml suspended crystalline lactose particles (either LH300 or JM lactose) in isopropyl alcohol. The solution formulation contained 60 mg/ml lactose in water. The SD powders were stored under 25 °C/60% RH and 40 °C/75% RH for 3 months. The particulate properties and in vitro dispersion performance were examined at various time points. The SD lactose obtained from solution recrystallized and was no longer dispersible after 1-day storage at both storage conditions. The suspension SD JM lactose powder showed deterioration in the particulate properties and dispersibility over time, but more gradually. In contrast, the SD LH300 powder was stable, with its particulate properties and dispersion performance (FPF: ~12%) remaining the same after 3-months storage at 25 °C/60% RH. The SD LH300 stored at 40 °C/75% RH showed no change in particulate properties, but the FPF decreased over 3 months. Overall, SD lactose powders obtained from suspension demonstrated superior stability performance compared to SD lactose obtained from solution.

Inflammation, the major hallmark of all chronic respiratory diseases is generally managed by inhaled corticosteroids. However, long term high dose treatment can result in significant side effects. Hence, there is a medical need for non-steroidal anti-inflammatory therapies to address airway inflammation. Phospholipids have been shown to reduce inflammation in several inflammatory conditions; however, their clinical translation has been limited to liposomal formulations traditionally used as drug carriers and their biological activity has not been investigated. Here we report the first application of empty liposomes as an anti-inflammatory treatment in airway inflammation. In the current study, liposomes (UTS-001) were prepared from cholesterol and a synthetic phospholipid (DOPC). The formulation was characterised in terms of size, charge, polydispersity index, morphology and stability as colloidal suspension and freeze-dried nanoparticles. Time-dependant uptake of UTS-001 in airway epithelial cells was observed which was inhibited by nystatin demonstrating that the uptake is via the caveolae pathway. In-vitro, in primary nasal epithelial cells, UTS-001 treatment successfully attenuated IL-6 levels following TNF-α stimulation. Consistent with the in-vitro findings, in-vivo, in the ovalbumin model of allergic airway inflammation, UTS-001 significantly reduced total immune cell counts in bronchoalveolar lavage fluid and reduced airway hyperresponsiveness in response to increasing doses of methacholine challenge. Therefore, our results establish UTS-001 as a potential anti-inflammatory treatment that may be useful as a therapeutic for lung inflammatory diseases.

Deposition of aerosols in the respiratory tract can be quantitatively and qualitatively studied by scintigraphy. The most commonly used radionuclide for this purpose is technetium-99m. The effects of various factors on particle deposition have been investigated by using radiolabeled aerosols in the past decade. Most of these studies were in vivo but some were in vitro or ex vivo. The factors examined include particle size, formulation, inhaler design, inhalation flowrate, body posture, and gravity. They have been shown to influence pulmonary deposition, nasal high flow nebulization, and intranasal delivery. A thorough understanding of the various factors is required for the advancement of respiratory-drug delivery. Scintigraphy is a powerful technique that can assist in this regard.

Graphical Abstract Unlabelled image, The therapeutic potential of small nucleic acids such as small interfering RNA (siRNA) to treat lung diseases has been successfully demonstrated in many in vivo studies. A major barrier to their clinical application is the lack of a safe and efficient inhaled formulation. In this study, spray freeze drying was employed to prepare dry powder of small nucleic acids. Mannitol and herring sperm DNA were used as bulking agent and model of small nucleic acid therapeutics, respectively. Formulations containing different solute concentration and DNA concentration were produced. The scanning electron microscope (SEM) images showed that the porosity of the particles increased as the solute concentration decreased. Powders prepared with solute concentration of 5% w/v were found to maintain a balance between porosity and robustness. Increasing concentration of DNA improved the aerosol performance of the formulation. The dry powder formulation containing 2% w/w DNA had a median diameter of 12.5 µm, and the aerosol performance study using next generation impactor (NGI) showed an emitted fraction (EF) and fine particle fraction (FPF) of 91% and 28% respectively. This formulation (5% w/v solute concentration and 2% w/w nucleic acid) was adopted subsequently to produce siRNA powder. The gel retardation and liquid chromatography assays showed that the siRNA remained intact after spray freeze drying even in the absence of delivery vector. The siRNA powder formulation exhibited a high EF of 92.4% and a modest FPF of around 20%. Further exploration of this technology to optimise inhaled siRNA powder formulation is warranted.

In vitro-in vivo correlation is the establishment of a predictive relationship between in vitro and in vivo data. In the context of cascade impactor results of orally inhaled pharmaceutical aerosols, this involves the linking of parameters such as the emitted dose, fine particle dose, fine particle fraction, and mass median aerodynamic diameter to in vivo lung deposition from scintigraphy data. If the dissolution and absorption processes after deposition are adequately understood, the correlation may be extended to the pharmacokinetics and pharmacodynamics of the delivered drugs. Correlation of impactor data to lung deposition is a relatively new research area that has been gaining recent interest. Although few in number, experiments and meta-analyses have been conducted to examine such correlations. An artificial neural network approach has also been employed to analyse the complex relationships between multiple factors and responses. However, much research is needed to generate more data to obtain robust correlations. These predictive models will be useful in improving the efficiency in product development by reducing the need of expensive and lengthy clinical trials.

A volume-based Monte Carlo simulation describing the distribution of polydisperse particles aerosolized in polydisperse droplets was developed. The algorithm addressed some major limitations found in previous models, particularly when the assumptions of the Poisson distribution, a parametric distribution frequently employed to describe the distribution process both deterministically and stochastically, may be less justified. A total of 144 simulations were conducted over combinations of four formulation factors, namely, the suspension concentration c, the ratio of the mass median diameter of the droplets to that of the particles R, and the geometric standard deviation of the droplet σd and that of the particle σp. Using the current algorithm, we found good agreements between simulated results and those from previous studies. The composition uniformity of the resultant clusters was improved with increasing c and/or R, and decreasing σp and σd. The exhaustive distribution of all simulated particles also allowed ready adaptation to infer other statistics of interest, such as the aerodynamic diameter of the resultant clusters. This approach is useful for prediction of the particle size distribution and chemical composition of powders produced by aerosolization and spray drying of suspensions.

Recent heightened interest in inhaled bacteriophage (phage) therapy for combating antibacterial resistance in pulmonary infections has led to the development of phage powder formulations. Although phages have been successfully bioengineered into inhalable powders with preserved bioactivity, the stabilization mechanism is yet unknown. This paper reports the first study investigating the stabilization mechanism for phages in these powders. Proteins and other biologics are known to be preserved in dry state within a glassy sugar matrix at storage temperatures (T s) at least ~50°C below the glass transition temperature (T g). This is because at (T g − T s) >50°C, molecules are sufficiently immobilized with reduced reactivity. We hypothesized that this glass stabilization mechanism may also be applicable to phages comprising mostly of proteins. In this study, spray dried powders of Pseudomonas phage PEV20 containing lactose and leucine as excipients were stored at 5, 25 or 50°C and 15 or 33% relative humidity (RH), followed by assessment of bioactivity (PEV20 stability) and physical properties. PEV20 was stable with negligible titer loss after storage at 5°C/15% RH for 250 days, while storage at 33% RH caused increased titer losses of 1 log10 and 3 log10 at 5 and 25°C, respectively. The plasticizing effect of water at 33% RH lowered the T g by 30°C, thus narrowing the gap between T s and T g to 19–28°C, which was insufficient for glass stabilization. In contrast, the (T g − T s) values were higher (range, 46–65°C) under the drier condition of 15% RH, resulting in the improved stability which corroborated with the vitrification hypothesis. Furthermore, phage remained stable (≤1 log10) when the (T g − T s) value lay between 26–48°C, but became inactivated as the value fell below 20°C. In conclusion, this study demonstrated that phage can be sufficiently stabilized in spray dried powders by keeping the (T g − T s) value above 46°C, thus supporting the vitrification hypothesis that phages are stabilized by immobilization inside a rigid glassy sugar matrix. These findings provide a guide to better manufacture and storage practices of inhaled phage powder products using for translational medicines.

The development of small interfering RNA (siRNA) formulation for pulmonary delivery is a key to the clinical translation of siRNA therapeutics for the treatment of respiratory diseases. Most inhalable siRNA powder formulations published to date were limited by the siRNA content which was often too low to be clinically relevant. This study aimed to prepare inhalable siRNA powder formulations that contained high siRNA loading of over 6% w/w by spray drying, with human serum albumin (HSA) investigated as a dispersion enhancer to improve the aerosol performance. The effect of siRNA, HSA and solute concentrations in the formulations were evaluated systemically using factorial analyses. All the spray dried siRNA powders exhibited excellent aerosol performance with fine particle fraction (FPF) consistently over 50% in all the formulations. An enrichment of HSA on the particle surface was observed. Surface corrugation was more prominent as HSA composition increased. Importantly, the bioactivity of siRNA was successfully preserved upon spray drying as demonstrated in the in vitro transfection study, and up to 78% of intact siRNA retained in the spray dried powder. Overall, HSA is an effective dispersion enhancer and spray drying is an appropriate technique to produce inhalable dry powder with high siRNA loading for further investigation.

Antibiotic resistance in pathogenic bacteria has emerged as a big challenge to human and animal health and significant economy loss worldwide. Development of novel strategies to tackle antibiotic resistance is of the utmost priority. In this study, we combined glutathione (GSH), a master antioxidant in all mammalian cells, and nitric oxide, a proven biofilm-dispersing agent, to produce GSNO. The resazurin biofilm viability assay, crystal violet biofilm assay, and confocal microscopy techniques showed that GSNO disrupted biofilms of both P. aeruginosa PAO1 and multidrug resistant A. baumaunii (MRAB 015069) more efficiently than GSH alone. In addition, GSNO showed a higher reduction in biofilm viability and biomass when combined with antibiotics. This combination treatment also inhibited A. baumaunii (MRAB 015069) growth and facilitated human foreskin fibroblast (HFF-1) confluence and growth simultaneously. A potentially inhalable GSNO powder with reasonable aerosol performance and antibiofilm activity was produced by spray drying. This combination shows promise as a novel formulation for treating pulmonary bacterial infections.

Pulmonary route is the main route of drug delivery for patients with asthma and chronic obstructive pulmonary diseases, offering several advantages over the oral route. Determining the amount of drug deposited onto various parts of the respiratory tract allows for a good correlation to clinical efficacy of inhalation drug devices. However, current in vitro cascade impactors measure only the aerodynamic particle size distribution, which does not truly represent the in vivo deposition pattern in human respiratory tract. In this study, a human upper respiratory tract model was fabricated using a 3D printer and subsequently characterized for its dimensional accuracy, surface finishing and air leaking. The effects of using a spacer and/or various airflow rates were also investigated. To assess this in vitro model, the deposition pattern of a model drug, namely, salbutamol sulphate, was tested. The resultant deposition pattern of salbutamol sulphate from a metered dose inhaler at 15 L per minute with the spacer, showed no significant difference from that of a published radiological in vivo study performed in adult humans. In addition, it was also found that the deposition pattern of salbutamol at 35 L per minute was comparable to the results of another published study in human. This in vitro model, showing reasonable in vitro-in vivo correlation, may provide opportunities for personalized medicine in special populations or disease states.

This study investigated the effect of modifying the Aerolizer® inhaler design and material on bipolar charging of a powder aerosol. The modified inhalers included various grid configurations, mouthpiece lengths, air inlet sizes, and were also constructed of different materials (acrylonitrile butadiene styrene, acetal, low density polyethylene, nylon, polypropylene, and stainless steel). The novel BOLAR™ (Dekati Ltd., Kangasala, Finland) was used to characterise bipolar charge and mass distributions. All of the tested inhalers showed spray-dried mannitol powder carried significantly different positive and negative charges that had higher magnitudes than the measured net charge. The estimated elementary charges per particle indicated the aerosols carried significant levels of charge that may potentially influence particle deposition in the lungs. Increasing the grid voidage decreased the magnitude of charging, as did reducing the air inlet size, whereas mouthpiece length had no obvious effect. The observed effects on charging due to modifications to the inhaler design could be explained by a difference in the level of contacts due to impaction between the particles and the inhaler internal surface. Bipolar charge of mannitol did not differ when dispersed by inhalers constructed of different materials. This could be attributed to various potential factors such as the very brief contact time between the powder and the inhaler material, as well as coating of the inhaler interior by the powder which effectively renders the surface to be mannitol-like. Overall, the comparable q/m profiles across all the inhaler designs and inhaler materials indicated charging correlated with the mass distributions and modifications to the inhaler did not affect the qualitative bipolar charge characteristics of mannitol powder.

Although 3D printing (3DP) has long been an integral part of industries such as aviation and automotive, its use in healthcare, especially the pharmaceutical industry, is relatively new and currently receiving close attention. At the beginning of 2018, we reviewed the applications of 3DP for drug delivery and drug testing [1]. Due to the rapid development of this field, it is necessary to summarize the latest development in this field after 2 years. In this article, we reviewed the three major areas in pharmaceutical applications. First, drug delivery system is the most studied subject, including controlled release, polypills, gastrofloating, orodispersibles and microneedles. Second, 3DP also helped the development of pharmaceutical devices, including pharmacy dispensing aids and drug eluting devices. Lastly, we reviewed the pharmaceutical models for drug testing, covering acellular and cellular models. We also summarized the materials used in the mentioned articles and their regulatory status for pharmaceutical applications to provide references for future research.

Spray freeze drying is a particle engineering technique that allows the production of porous particles of low density with excellent aerosol performance for inhalation. There are a number of operating parameters that can be manipulated in order to optimise the powder properties. In this study, a two-fluid nozzle was used to prepare spray freeze dried formulation of voriconazole, a triazole antifungal agent for the treatment of pulmonary aspergillosis. A full factorial design approach was adopted to explore the effects of drug concentration, atomisation gas flow rate and primary drying temperature. The aerosol performance of the spray freeze dried powder was evaluated using the next generation impactor (NGI) operated with different inhaler devices and flow rates. The results showed that the primary drying temperature played an important role in determining the aerosol properties of the powder. In general, the higher the primary drying temperature, the lower the emitted fraction (EF) and the higher the fine particle fraction (FPF). Formulations that contained the highest voriconazole concentration (80% w/w) and prepared at a high primary drying temperature (−10 °C) exhibited the best aerosol performance under different experimental conditions. The high concentration of the hydrophobic voriconazole reduced surface energy and cohesion, hence better powder dispersibility. The powders produced with higher primary drying temperature had a smaller particle size after dispersion and improved aerosol property, possibly due to the faster sublimation rate in the freeze-drying step that led to the formation of less aggregating or more fragile particles. Moreover, Breezhaler®, which has a low intrinsic resistance, was able to generate the best aerosol performance of the spray freeze dried voriconazole powders in terms of FPF.

Conventional nebulisation has the disadvantages of low aerosol output rate and potential damage to macromolecules due to high shear (jet nebulisation) or cavitation (ultrasonic nebulisation). HYDRA (HYbriD Resonant Acoustics) technology has been shown to overcome these problems by using a hybrid combination of surface and bulk sound waves to generate the aerosol droplets. We report the first in vivo human lung deposition study on such droplets. Twelve healthy adult subjects inhaled saline aerosols radiolabelled with technetium-99 m complexed with diethylene triamine penta-acetic acid (99mTc-DTPA). The distribution of the aerosolised droplets in the lungs was imaged by single photon emission computed tomography combined with low dose computed tomography (SPECT/CT). The volume median diameter and geometric standard deviation of the droplets were 1.32 ± 0.027 µm and 2.06 ± 0.040, respectively. The mean delivery efficiency from the nebuliser into the body was 51.2%. About 89.1 ± 4.3% and 2.3 ± 1.4% of the inhaled radiolabelled dose deposited in the lungs and oropharynx, respectively. The deposition was symmetrical and diffusive between the two lungs, with a mean penetration index of 0.82. Thus, the prototype HYDRA nebuliser showed excellent in vivo aerosol deposition performance, demonstrating its potential to be further developed for clinical applications.

Spray freeze drying is an attractive technology to produce powder formulation for inhalation. It can be used to generate large porous particles which tend to aerosolize efficiently and do not aggregate readily. It also avoids material to be exposed to elevated temperature. In this study, we reported the use of two-fluid nozzle to produce spray freeze dried powder of small interfering RNA (siRNA). The effect of atomization gas flow rate and liquid feed rate were inspected initially using herring sperm DNA (hsDNA) as nucleic acid model. The atomization gas flow rate was found to have a major impact on the aerosol properties. The higher the atomization gas flow rate, the smaller the particle size, the higher the fine particle fraction (FPF). In contrast, the liquid feed rate had very minor effect. Subsequently, spray freeze dried siRNA powder was produced at various atomization gas flow rates. The particles produced were highly porous as examined with the scanning electron microscopy, and the structural integrity of the siRNA was demonstrated with gel electrophoresis. The gene-silencing effect of the siRNA was also successfully preserved in vitro. The best performing siRNA formulation was prepared at the highest atomization gas flow rate investigated with a moderate FPF of 30%. However, this was significantly lower than that obtained with the corresponding hsDNA counterparts (FPF ∼57%). A direct comparison between the hsDNA and siRNA formulations revealed that the former exhibited a lower density, hence a smaller aerodynamic diameter despite similar geometric size.

The Bipolar Charge Analyzer (BOLAR) was evaluated for measuring bipolar electrostatic charge and mass distributions of powder aerosols generated from a dry powder inhaler. Mannitol powder (5, 10, and 20 mg) was dispersed using an Osmohaler inhaler into the BOLAR at air flow rates of 30 or 60 L/min. As the aerosol sample was drawn through the BOLAR, the air flow was divided into six equal fractions. Five of them entered individual detection tubes with a defined cutoff diameter in the range of 0.95 to 16.36 μm (depending on the flow rate) and the remaining (i.e., the sixth) fraction passed through a reference chamber. The aerosols that entered the detection tubes were separated according to the particle charge polarity (positive, negative, or neutral) and charge was measured by separate electrometers. The deposited powder of a single actuation from the inhaler was chemically assayed using high performance liquid chromatography. Additionally, the aerosol measurements were conducted on a modified Classic Electrical Low Pressure Impactor (ELPI) for comparison of the net specific charge per size fraction. Spray-dried mannitol carried significantly different positively and negatively charged particles in each of the five defined particle size fractions. The charge-to-mass ratio (q/m) of positively charged particles ranged from +1.11 to +32.57 pC/μg and negatively charged particles ranged from -1.39 to -9.25 pC/μg, resulting in a net q/m of -3.08 to +13.34 pC/μg. The net q/m values obtained on the modified ELPI ranged from -5.18 to +4.81 pC/μg, which were comparable to the BOLAR measurements. This is the first full report to utilize the BOLAR to measure bipolar charge and mass distributions of a powder aerosol. Positively and negatively charged particles were observed within each size fraction, and their corresponding q/m profiles were successfully characterized. Despite some potential drawbacks, the BOLAR has provided a new platform for investigating bipolar charge in powder aerosols for inhalation.

Pharmaceutical solids are likely to accumulate electrostatic charge through handling processes encountered both in industry and during clinical use. Important advances in the past decade have continued to improve our understanding and enabled better control of electrostatics. Although certain areas have been studied more extensively than others, much remains unexplored at the fundamental level and in vivo deposition studies are required to confirm the impact of charged aerosols in humans. This review has summarised the key fundamentals, highlighted the relevance in industrial and clinical settings, evaluated the factors that influence charging and discussed measurement techniques with regards to pharmaceutical powders. The understanding gained could potentially have regulatory implications, and could assist in the development and manufacture of pharmaceutical powders and their delivery systems.

This review discusses recent developments in the manufacture of inhalable dry powder formulations. Pulmonary drugs have distinct advantages compared with other drug administration routes. However, requirements of drugs properties complicate the manufacture. Control over crystallization to make particles with the desired properties in a single step is often infeasible, which calls for micronization techniques. Although spray drying produces particles in the desired size range, a stable solid state may not be attainable. Supercritical fluids may be used as a solvent or antisolvent, which significantly reduces solvent waste. Future directions include application areas such as biopharmaceuticals for dry powder inhalers and new processing strategies to improve the control over particle formation such as continuous manufacturing with in-line process analytical technologies.

Pulmonary delivery of short interfering RNA (siRNA) has been widely studied in both animal and clinical studies to treat various respiratory diseases by gene silencing through RNA interference. Some of these studies showed that the administration of naked siRNA (without the use of any delivery vectors) could achieve satisfactory gene silencing effect, a unique feature to pulmonary delivery. Liquid aerosols were mostly used with very limited studies on the use of powder aerosols for siRNA. In this study, siRNA was co-spray dried with mannitol and l-leucine, the latter being a dispersion enhancer. To the best of our knowledge, this is the first time that siRNA in its naked form was formulated into an inhalable dry powder using spray drying technology. The aerosol performance of the powder was evaluated by Next Generation Impactor (NGI). The presence of l-leucine in the formulation could improve the aerosolization of siRNA-containing powders. Results from the X-ray photoelectron spectroscopy (XPS) suggested that l-leucine was enriched on the particle surface and promote powder dispersion. Among the different siRNA formulations being examined, the one that contained 50% w/w of l-leucine exhibited the best aerodynamic performance, with a high emitted fraction (EF) of around 80% and a modest fine particle fraction (FPF) of 45%. Importantly, the integrity of siRNA was successfully retained as evaluated by gel retardation assay and high performance liquid chromatography (HPLC).

Infants and children constitute a patient group that has unique requirements in pulmonary drug delivery. Since their lungs develop continuously until they reach adulthood, the airways undergo changes in dimensions and number. Computational models have been devised on the growth dynamics of the airways during childhood, as well as the particle deposition mechanisms in these growing lungs. The models indicate that total aerosol deposition in the body decreases with age, while deposition in the lungs increases with age. This has been observed on paediatric subjects in in vivo studies. Issues unique to children in pulmonary drug delivery include their lower tidal volume, highly variable breathing patterns, air leaks from facemasks, and the off-label or unlicensed use of pharmaceutical products due to lack of clinical data for this age group. The aerosol devices used are essentially those developed for adult patients that have been adapted to paediatric use. Facemasks should be used with nebulisers and spacers for infants and young children. An idealised throat that mimic the average particle deposition in paediatric throats has been designed to obtain more clinically relevant aerosol dispersion data in vitro. More effort should be spent on studying particle deposition in the paediatric lung and developing products specific for this subpopulation to meet their needs.

Many newly discovered drug molecules have low aqueous solubility, which results in low bioavailability. One way to improve their dissolution is to formulate them as nanoparticles, which have high specific surface areas, consequently increasing the dissolution rate and solubility. Nanoparticles can be produced via top-down or bottom-up methods. Top-down techniques such as wet milling and high pressure homogenisation involve reducing large particles to nano-sizes. Some pharmaceutical products made by these processes have been marketed. Bottom-up methods such as precipitation and controlled droplet evaporation form nanoparticles from molecules in solution. To minimise aggregation upon drying and promote redispersion of the nanoparticles upon reconstitution or administration, hydrophilic matrix formers are added to the formulation. However, the nanoparticles will eventually agglomerate together after dispersing in the liquid and hinders dissolution. Currently there is no pharmacopoeial method specified for nanoparticles. Amongst the current dissolution apparatus available for powders, the flow-through cell has been shown to be the most suitable. Regulatory and pharmacopoeial standards should be established in the future to standardise the dissolution testing of nanoparticles. More nanoparticle formulations of new hydrophobic drugs are expected to be developed in the future with the advancement of nanotechnology. However, the agglomeration problem is inherent and difficult to overcome. Thus the benefit of dissolution enhancement often cannot be fully realised. On the other hand, chemical strategies such as modifying the parent drug molecule to form a more soluble salt form, prodrug, or cyclodextrin complexation are well established and have been shown to be effective in enhancing dissolution. Thus the value of nanoformulations needs to be interpreted in the light of their limitations. Chemical approaches should also be considered in new product development.

An anti-solvent sonocrystallisation technique was applied for the production of salbutamol sulphate fine particles for the dry powder inhaler (DPI) formulations. The effects of process variables, namely sonication power (watt, W) and volume ratio of anti-solvent to solute solution on the particle characteristics of salbutamol sulphate were investigated. Depending on process variables, fine particles of salbutamol sulphate with a size distribution in a range of 2 μm to 5 μm were successfully produced. Spray drying of sonocrystallised anti-solvent suspension produced micron size crystalline salbutamol sulphate. Emitted dose of this powder was 42% that was significantly enhanced compared to amorphous form produced by spray drying technique. This value was measured by the fine particle fraction (FPF emitted ) for the blend of coarse lactose (CoL) and spray-dried sonocrystallised salbutamol sulphate. The data acquired from this study demonstrates the potential of designed process for the production of particles with micron size distributions and highly crystalline form, particularly for DPI formulation.

Aerosols emitted from metered dose inhalers (MDIs) are generally electrically charged and bipolar in nature. Although a spacer can effectively dampen the charge magnitude of aerosols, the electrostatic interactions between the positively and negatively charged particles and the spacer have not yet been characterized separately. The Bipolar Charge Analyzer (BOLAR) was employed to investigate interactions between the spacer and the charged aerosols. Three individual actuations of Tilade® MDI were introduced without a spacer and through an antistatic AeroChamber Plus® Z Stat®, an uncoated and a detergent-coated AeroChamber Plus® spacer into the BOLAR at 60 L/min. Charge and mass profiles were determined. The surface potential of spacers followed the order of uncoated > detergent-coated > antistatic spacer. The spacers had minimal impact on the positively charged particles but the charge magnitude of the negatively charged particles was in the opposite order as the spacer surface potential. The charge-to-mass ratio of particles had little alteration for all measurements. Negatively charged particles had a higher tendency to deposit on the spacer walls, possibly due to their higher abundance in the confined spacer volume. The bipolar data may prove useful for designing better MDIs and spacers and modelling lung deposition of charged aerosol particles.