In order to overcome this limitation, two main strategies have been followed: nebulization of nanocarriers as a colloidal suspension or associating the system with microsized carriers. The latter approach could be accomplished by either mixing nanocarriers along with inert carriers such as inhalable lactose or mannitol or by embedding the nanosized system into microparticles Figure 4.
The amino acid leucine is another candidate to be taken into consideration, since it prevents aggregation due to surfactant behaviour and antiadherent properties at low concentration. Dipalmitoylphosphatidylcholine DPPC is a phospholipid normally used to prepare nanosystems for pulmonary delivery because it is the major lipid component of lung surfactant and is relatively non-toxic. Improvement of the aerodynamic properties of the nanocarriers can be achieved following, e. In order to prepare inhalable powders, the spray-drying technique is widely used.
This method of producing dry powder is based on evaporating the solvent from a liquid or suspension, achieving solid-state particles presenting appropriate MMAD that ensures drug deposition in the tracheobronchial and deep alveolar regions. Lyophilization, or freeze-drying, has also been explored as an approach to produce stable dry powder that could be administered by DPIs or after rehydration in the appropriate buffer.
Both methods produce a powder form that will enhance NP stability, avoiding polymer hydrolysis and drug loss. As with other inhalable drugs, NPs should meet quality measures of isotonicity, sterility, neutral pH value between 3 and 8. The success of this product has encouraged new developments in this field. Both liposomal formulations were administered once daily with a 28 day treatment phase and a 28 day off stage with a follow-up period.
In this case, patients presented a low incidence of adverse effects and the formulations were overall well tolerated. After analysis of some preliminary results, the authors postulated that liposomal amikacin was safe and effective. The efforts of the scientific community in the development of respirable DDSs have given rise to an extensive literature on antibiotic-loaded NPs that will be overviewed in the following section according to therapeutic group.
Moghaddam et al. It was observed that the addition of leucine to the formulations led to the best FPF These results could be explained by the non-polar side chain of leucine, which improves flowability due to its antiadherent properties. Top row, left: scanning electron microscopy image of clarithromycin-loaded NPs. Top row, right: release profile of clarithromycin-loaded polymeric NPs. Bottom row: four scanning electron microscopy micrographs of clarithromycin-loaded PLGA NPs after spray-drying with different excipients— a mannitol and l -leucine NPs; b lactose and l -leucine NPs; c mannitol; and d lactose.
Reproduced with permission from Moghaddam et al. Cheow et al. In a subsequent study, 63 these nanoformulations were evaluated against E. NPs displayed biphasic release profiles over a 6 day period. This biphasic release permitted a high initial antibiotic concentration followed by an extended release profile presenting a drug concentration above the minimum biofilm inhibitory concentration value i. This biphasic profile seems to be required for the successful eradication of the biofilm and to minimize the exacerbation due to the higher antibiotic susceptibility of the surviving cells. Another work investigating quinolone encapsulation was reported by Duan et al.
In vitro aerosol dispersion of the spray-dried powders was performed using an NGI. However, ofloxacin powders retained partial crystallinity in certain compositions depending on the DPPC ratio. Hence, on this occasion, the use of DPPC improved the aerosol dispersion of moxifloxacin NPs after spray-drying, leading to powder-form carriers useful for the treatment of pulmonary infections. Chono et al.
In the in vivo study, drug distribution in epithelial lining fluid ELF was analysed after the aerosolization of PEGylated liposomes and uncoated liposomes and it was observed that the elimination rate of ciprofloxacin from ELF was significantly slower for PEGylated liposomes compared with uncoated liposomes and also the AUC and mean residence time were higher.
Moreover, the evaluation of their antibacterial effects against pathogenic microorganisms in ELF showed strong activity against bacteria such as P. Finally, they also observed that the liposomes led to no lung tissue damage and that PEGylated liposomes did not show cytotoxic effects at the dose assessed.
Altogether, the authors concluded that PEGylated liposomes may be a suitable pulmonary DDS allowing ciprofloxacin dose reduction against lung infections. Ong et al. The characterization of nebulized aerosols by NGI studies revealed liposome diameters of 4. The respirable fraction of the formulation was quantified at Moreover, when the nebulizer-adapted TSI was coupled to a Calu-3 cell culture, it was demonstrated that the formulation allowed slow and controlled release of the drug. Liposomal ciprofloxacin was found to be as active as the free drug against P.
In addition, MBC testing showed that the liposomal formulation against P. On the other hand, the ciprofloxacin-loaded liposomes did not provide an improvement in the bactericidal activity against S. Nonetheless, in order to provide an in-depth analysis of ciprofloxacin liposomes, the same group 67 used different in vitro and ex vivo methodologies to examine the release mechanisms from the inhalation delivery systems and their effect on drug disposition, comparing them with an in vivo assay performed by Yim et al.
In vitro activity against S. Reproduced with permission from Ong et al. Sweeney et al. By means of a numerical deposition model developed by Finlay et al. This drug concentration would be above the MIC and thus could inhibit the growth of many pathogens, such as P.
Nonetheless, more experimental outcomes should be provided in order to ensure the robustness of these estimations. As another strategy, Liu et al. Liposomes were administered to rats by intratracheal instillation. The drug concentration in the lung was higher for the liposomal antibiotic than for the free drug, e. Bioavailability results also confirmed that liposomal ciprofloxacin was able to reach the lung and provide high drug concentrations at the target site. In addition, an in vivo pulmonary irritation test showed ciprofloxacin liposomes were able to minimize modification and irritation of the lungs after intratracheal instillation in rats.
From these results, it can be inferred that successful pulmonary delivery of a liposomal formulation was achieved with a high concentration of ciprofloxacin at the target site. Alhariri et al. In a further in vivo assay, intratracheal administration of the liposomes was studied in rats chronically infected with P.
Another tobramycin-loaded formulation was evaluated by Pilcer et al. It was confirmed that the NP-coated tobramycin increased the FPD during inhalation, which was explained by the fact that coating the drug with NPs could reduce powder agglomeration and cohesion with other particles. In conclusion, mixing tobramycin-loaded NPs and microparticle dry powders with low levels of sodium glycocholate resulted in a suitable DDS for treating lung diseases as it offered effective pulmonary delivery.
Tobramycin encapsulation was also described by Ungaro et al. Spray-drying was performed in order to obtain micrometre-sized dry powder particles using lactose as an inert carrier. The drug release was optimal, providing a burst release followed by maintained liberation of the drug for a month. This could be due to the biphasic extended antibiotic release profiles of the NPs that in turn liberated small amounts of drug into the media that were very likely below the MIC.
Rukholm et al. MIC and time—kill studies were performed with free and liposomal gentamicin against P. The authors explained these results by the possible fusion of the liposomes with the outer bacterial membrane, which may have led to increased penetration of the antibiotic. Finally, in in vitro time—kill studies, only the 4-fold MIC liposomal formulation demonstrated improved antimicrobial activity against the antibiotic-resistant strain by achieving complete bacterial eradication in 6 h, whereas the free drug needed 24 h to eradicate the bacteria.
The authors concluded that the liposomal gentamicin formulation was effective, presenting an improved killing time and prolonged antimicrobial activity against P. In an attempt to decrease drug toxicity and improve dosing by drug targeting, Ghaffari et al. Both SLNs presented activity against P. The authors hypothesized that besides the sustained drug release profile, SLNs have the advantage of improving the antibacterial activity of amikacin due to diffusion enhancement across the bacterial membrane.
In a further study related to amikacin, Varshosaz et al. The drug release profile displayed a continuous and sustained pattern for h. In the subsequent in vivo experiment, 99m Tc-labelled amikacin SLNs or free 99m Tc-amikacin were administered by the inhalation route, detecting a similar signal in the lung for both formulations.
It is worth mentioning that pulmonary-administered SLNs presented higher drug concentrations in the stomach than intravenous administration, which might be related to swallowing exhaled particles after administration. Finally, the authors concluded that SLNs seem to be a promising inhaled carrier for improving the efficacy of amikacin in CF as well as reducing the dose frequency due to sustained drug release and could, therefore, decrease drug toxicity, especially nephrotoxicity.
Pastor et al. Both lipid NPs presented antimicrobial activity against clinically isolated P. Cell experiments using the A cell line showed that lipid NPs were able to significantly reduce antibiotic toxicity. Next, an in vivo biodistribution assay was conducted after nebulizing infrared IR -labelled NLCs into mice.
It was observed that NLCs spread homogenously throughout the lungs, whereas no signal could be detected in other organs. The IR intensity was detectable 48 h after administration, suggesting that the dosing interval could be prolonged by the use of these NPs. Pulmonary infections are often persistent and recurrent. A potential therapeutic approach is to target the delivery of antibiotics directly to the site of infection as a mechanism to increase and maintain the local drug concentration.
In recent years, the encapsulation of antimicrobial drugs into nanocarriers has appeared as a powerful tool for enhancing therapeutic effectiveness against infectious diseases and minimizing side effects of the drugs. The inhalation route has gained much attention as a promising alternative administration route for the treatment of pulmonary infections. Tight control over the geometric size and morphology of particles resulted in aerosols with narrow aerodynamic size distributions that would be able to reach the deep-lung region and appropriately deliver the antibiotic to the site of infection.
Here, the current progress and challenges in synthesizing NP systems for delivering various antimicrobial drugs are reviewed. The published data stated that DDSs for inhalation therapy are able to decrease the antibiotic dose administered, thereby reducing toxicity as well as enhancing patient compliance and adherence to the treatment. Much has been studied in order to overcome the resistance of common antibiotics, yet additional efforts are needed.
Overall, the scientific community should pay attention to the formulation of DDSs to improve lung deposition and anti-infective therapy.
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Therefore, further tailoring of currently available DDSs is required in order to translate this technological advance into clinical benefits. We express our gratitude to the Oxford Language Editing service for improving and correcting the English throughout this paper.
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