New frontiers in aerosol delivery during mechanical ventilation

The scientific basis for inhalation therapy in mechanically-ventilated patients is now firmly established. A variety of new devices that deliver drugs to the lung with high efficiency could be employed for drug delivery during mechanical ventilation. Encapsulation of drugs within liposomes could increase the amount of drug delivered, prolong the effect of a dose, and minimize adverse effects. With improved inhalation devices and surfactant formulations, inhaled surfactant could be employed for several indications in mechanically-ventilated patients. Research is unraveling the causes of some disorders that have been poorly understood, and our improved understanding of the causal mechanisms of various respiratory disorders will provide new applications for inhaled therapies.     

Poly (DL-lactide-co-glycolide) nanoparticle-based inhalable sustained drug delivery system for experimental tuberculosis

OBJECTIVES: To improve the bioavailability of antitubercular drugs (ATDs) as well as to assess the feasibility of administering ATDs via the respiratory route, this study reports the formulation of three frontline ATDs, i.e. rifampicin, isoniazid and pyrazinamide encapsulated in poly (DL-lactide-co-glycolide) nanoparticles suitable for nebulization. METHODS: Drug-loaded nanoparticles were prepared by the multiple emulsion technique, vacuum-dried and nebulized to guinea pigs. The formulation was evaluated with respect to the pharmacokinetics of each drug and its chemotherapeutic potential in Mycobacterium tuberculosis infected guinea pigs. RESULTS: The aerosolized particles exhibited a mass median aerodynamic diameter of 1.88 +/- 0.11 microm, favourable for bronchoalveolar lung delivery. A single nebulization to guinea pigs resulted in sustained therapeutic drug levels in the plasma for 6-8 days and in the lungs for up to 11 days. The elimination half-life and mean residence time of the drugs were significantly prolonged compared to when the parent drugs were administered orally, resulting in an enhanced relative bioavailability (compared to oral administration) for encapsulated drugs (12.7-, 32.8- and 14.7-fold for rifampicin, isoniazid and pyrazinamide, respectively). The absolute bioavailability [compared to intravenous (i.v.) administration] was also increased by 6.5-, 19.1- and 13.4-fold for rifampicin, isoniazid and pyrazinamide, respectively. On nebulization of nanoparticles containing drugs to M. tuberculosis infected guinea pigs at every 10th day, no tubercle bacilli could be detected in the lung after five doses of treatment whereas 46 daily doses of orally administered drug were required to obtain an equivalent therapeutic benefit. CONCLUSIONS: Nebulization of nanoparticles-based ATDs forms a sound basis for improving drug bioavailability and reducing the dosing frequency for better management of pulmonary tuberculosis.     

Alginate-based oral drug delivery system for tuberculosis: pharmacokinetics and therapeutic effects

Alginate microparticles were developed as oral sustained delivery carriers for antitubercular drugs in order to improve patient compliance. In the present study, pharmacokinetics and therapeutic effects of alginate microparticle encapsulated antitubercular drugs, i.e. isoniazid, rifampicin and pyrazinamide were examined in guinea pigs. Alginate microparticles containing antitubercular drugs were evaluated for in vitro and in vivo release profiles. These microparticles exhibited sustained release of isoniazid, rifampicin and pyrazinamide for 3-5 days in plasma and up to 9 days in organs. Peak plasma concentration (Cmax), Tmax, elimination half-life (t1/2e) and AUC0- infinity of alginate drugs were significantly higher than those of free drugs. The encapsulation of drug in alginate microparticles resulted in up to a nine-fold increase in relative bioavailability compared with free drugs. Chemotherapeutic efficacy of alginate drug microspheres against experimental tuberculosis showed no detectable cfu values at 1:100 and 1:1000 dilutions of spleen and lung homogenates. Histopathological studies further substantiated these observations, thus suggesting that application of alginate-encapsulated drugs could be useful in the effective treatment of tuberculosis.     

Prevention of Restenosis by Local Drug Delivery

Local drug therapy for preventing restenosis after angioplasty has been investigated for over a decade. Biologically active agents ranging from drugs to genes can be delivered locally using a wide variety of catheters. Microspheres, liposomes, and polymers have been used to enhance drug retention at the delivery site. More recently stents have been investigated as devices to attain local drug delivery, either by coating with polymers, seeding with genetically modified cells or by using them as a source of local radiation. Though the best method of delivering agents locally remains undefined, this approach is likely to emerge as an essential mode of therapy in the near future.     

Aérosolthérapie au cours de l’assistance respiratoire non invasive

Noninvasive ventilation (NIV) and high flow nasal therapy (HFT) are increasingly used in intensive care units. Patients undergoing these respiratory supports often require inhaled therapies, mainly bronchodilators. The principles of aerosol practice in intubated patients in part apply to NIV. Aerosol therapy may nevertheless be challenging because of spontaneous non-controlled breathing and the noninvasive interfaces used.Bench studies evaluating aerosol therapy during NIV show that, with single limb circuits, a greater amount of aerosol is delivered when the aerosol generator is placed between the leak port and the patient. Bench studies of HFT, mainly in pediatric models, show encouraging results, provided that the aerosol generator is positioned closed to the humidification chamber.Clinical studies, only available for NIV, show that significant drug amounts are delivered to the lungs of healthy subject. In patients with obstructive lung disease, significant bronchodilation has been observed after bronchodilator nebulization in the NIV circuit. It is therefore feasible to practice aerosol therapy during NIV in the clinical setting. Some studies even suggested an additive or even synergistic effect of both therapies. If confirmed, those results may trigger specific NIV delivery in order to improve therapeutic efficacy of inhaled drugs. Bench results of aerosol therapy during HFT need to be confirmed in the clinical setting.     

Extracorporeal membrane oxygenation and inhaled sedation in coronavirus disease 2019-related acute respiratory distress syndrome

Coronavirus disease 2019 (COVID-19) related acute respiratory distress syndrome (ARDS) is a severe complication of infection with severe acute respiratory syndrome coronavirus 2, and the primary cause of death in the current pandemic. Critically ill patients often undergo extracorporeal membrane oxygenation (ECMO) therapy as the last resort over an extended period. ECMO therapy requires sedation of the patient, which is usually achieved by intravenous administration of sedatives. The shortage of intravenous sedative drugs due to the ongoing pandemic, and attempts to improve treatment outcome for COVID-19 patients, drove the application of inhaled sedation as a promising alternative for sedation during ECMO therapy. Administration of volatile anesthetics requires an appropriate delivery. Commercially available ones are the anesthetic gas reflection systems AnaConDa^® and MIRUS^TM, and each should be combined with a gas scavenging system. In this review, we describe respiratory management in COVID-19 patients and the procedures for inhaled sedation during ECMO therapy of COVID-19 related ARDS. We focus particularly on the technical details of administration of volatile anesthetics. Furthermore, we describe the advantages of inhaled sedation and volatile anesthetics, and we discuss the limitations as well as the requirements for safe application in the clinical setting.     

Lectin-functionalized poly (lactide-co-glycolide) nanoparticles as oral/aerosolized antitubercular drug carriers for treatment of tuberculosis

OBJECTIVES: This study was carried out to explore lectin-functionalized poly (lactide-co-glycolide) nanoparticles (PLG-NPs) as bioadhesive drug carriers against tuberculosis (TB), in order to reduce the drug dosage frequency of antitubercular drugs and thus improve patient compliance in TB chemotherapy. METHODS: Wheat germ agglutinin (WGA)-coated PLG-NPs were prepared by a two-step carbodiimide procedure. This formulation was administered to guinea pigs through the oral/aerosol route for a detailed pharmacokinetic and chemotherapeutic evaluation. Immunological or hepatotoxic effects of WGA lectin, if any, were also determined. RESULTS: WGA-functionalized PLG-NPs were in the size range of 350-400 nm, with binding of 3-3.5 microg of WGA/mg of PLG-NPs and drug encapsulation efficiency of 54%-66%. Upon administration of lectin-coated PLG-NPs through the oral/aerosol route, the presence of drugs in plasma was observed for 6-7 days for rifampicin and 13-14 days for isoniazid and pyrazinamide. However, upon administration of uncoated PLG-NPs (oral/aerosolized) rifampicin was detectable in plasma for 4-6 days, whereas isoniazid and pyrazinamide were detectable for 8-9 days. All three drugs were present in lungs, liver and spleen for 15 days. Administration of WGA-coated PLG-NPs caused a significant (P < 0.001) increase in the relative bioavailability of antitubercular drugs. Chemotherapeutic studies revealed that three doses of oral/nebulized lectin-coated nanoparticles fortnightly could yield undetectable mycobacterial colony forming units (cfu); this was achievable with 45 doses of oral free drugs. CONCLUSION: WGA-functionalized PLG-NPs could be potential drug carriers for antitubercular drugs through the oral as well as aerosol route for effective TB control.     

Aerosolized gentamicin reduces the burden of tuberculosis in a murine model

Tuberculosis (TB) is a major infectious disease problem: 1.7 million people annually die due to TB. Emergence of drug-resistant Mycobacterium tuberculosis and the lack of new antibiotics have exacerbated the situation. There is an urgent need to develop or repurpose drugs against TB. We evaluated inhaled gentamicin as direct respiratory system-targeted therapy in a murine model of TB. Aerosolized-gentamicin-treated mice showed significantly reduced lung M. tuberculosis loads and fewer granulomas relative to untreated controls. These results suggest that direct delivery of antibiotics to the respiratory system may provide therapeutic benefit to conventional treatment regimes for treatment of pulmonary TB.     

Subcutaneous nanoparticle-based antitubercular chemotherapy in an experimental model

Poly (DL-lactide-co-glycolide) (PLG) nanoparticles encapsulating three front-line antitubercular drugs, i.e. rifampicin, isoniazid and pyrazinamide, were prepared by the multiple emulsion technique and administered subcutaneously to mice for pharmacokinetic/chemotherapeutic study. A single subcutaneous dose of drug-loaded PLG nanoparticles resulted in sustained therapeutic drug levels in the plasma for 32 days and in the lungs/spleen for 36 days. The mean residence time and absolute bioavailability were increased several-fold as compared with unencapsulated drugs. Further, drug-loaded PLG nanoparticles resulted in undetectable bacterial counts in the lungs and spleen of Mycobacterium tuberculosis-infected mice, thereby demonstrating a better chemotherapeutic efficacy, as compared with daily free drug treatment. Hence, injectable PLG nanoparticles hold promise for increasing drug bioavailability and reducing dosing frequency for better management of tuberculosis.     

Therapeutic efficacies of isoniazid and rifampin encapsulated in lung-specific stealth liposomes against Mycobacterium tuberculosis infection induced in mice.

One recent promising development in the modification of drug formulations to improve chemotherapy is the use of a liposome-mediated drug delivery system. The efficacies of isoniazid and rifampin encapsulated in lung-specific stealth liposomes were evaluated by injecting liposomal drugs and free drugs into tuberculous mice twice a week for 6 weeks. Liposome-encapsulated drugs at and below therapeutic concentrations were more effective than free drugs against tuberculosis, as evaluated on the basis of CFUs detected, organomegaly, and histopathology. Furthermore, liposomal drugs had marginal hepatotoxicities as determined from the levels of total bilirubin and hepatic enzymes in serum. The elimination of mycobacteria from the liver and spleen was also higher with liposomal drugs than with free drugs. The encapsulation of antitubercular drugs in lung-specific stealth liposomes seems to be a promising therapeutic approach for the chemotherapy of tuberculosis.     

The inhalation of drugs: advantages and problems

Inhalation is a very old method of drug delivery, and in the 20th century it became a mainstay of respiratory care, known as aerosol therapy. Use of inhaled epinephrine for relief of asthma was reported as early as 1929, in England. An early version of a dry powder inhaler (DPI) was the Aerohalor, used to administer penicillin dust to treat respiratory infections. In the 1950s, the Wright nebulizer was the precursor of the modern hand-held jet-venturi nebulizer. In 1956, the first metered-dose inhaler (MDI) was approved for clinical use, followed by the SpinHaler DPI for cromolyn sodium in 1971. The scientific basis for aerosol therapy developed relatively late, following the 1974 Sugarloaf Conference on the scientific basis of respiratory therapy. Early data on the drug-delivery efficiency of the common aerosol delivery devices (MDI, DPI, and nebulizer) showed lung deposition of approximately 10-15% of the total, nominal dose. Despite problems with low lung deposition with all of the early devices, evidence accumulated that supported the advantages of the inhalation route over other drug-administration routes. Inhaled drugs are localized to the target organ, which generally allows for a lower dose than is necessary with systemic delivery (oral or injection), and thus fewer and less severe adverse effects. The 3 types of aerosol device (MDI, DPI, and nebulizer) can be clinically equivalent. It may be necessary to increase the number of MDI puffs to achieve results equivalent to the larger nominal dose from a nebulizer. Design and lung-deposition improvement of MDIs, DPIs, and nebulizers are exemplified by the new hydrofluoroalkane-propelled MDI formulation of beclomethasone, the metered-dose liquid-spray Respimat, and the DPI system of the Spiros. Differences among aerosol delivery devices create challenges to patient use and caregiver instruction. Potential improvements in aerosol delivery include better standardization of function and patient use, greater reliability, and reduction of drug loss.     

Multifunctional nanoparticles for targeted delivery of immune activating and cancer therapeutic agents

Nanoparticles (NPs) have been extensively investigated for applications in both experimental and clinical settings to improve delivery efficiency of therapeutic and diagnostic agents. Most recently, novel multifunctional nanoparticles have attracted much attention because of their ability to carry diverse functionalities to achieve effective synergistic therapeutic treatments. Multifunctional NPs have been designed to co-deliver multiple components, target the delivery of drugs by surface functionalization, and realize therapy and diagnosis simultaneously. In this review, various materials of diverse chemistries for fabricating multifunctional NPs with distinctive architectures are discussed and compared. Recent progress involving multifunctional NPs for immune activation, anticancer drug delivery, and synergistic theranostics is the focus of this review. Overall, this comprehensive review demonstrates that multifunctional NPs have distinctive properties that make them highly suitable for targeted therapeutic delivery in these areas.     

Rational design of yolk–shell nanostructures for drug delivery

Yolk–shell nanoparticles (YSNPs) are a new class of hollow nanostructures, and their unique properties can be utilized in drug delivery systems. The recent progress in YSNPs-based carriers is highlighted in drug delivery systems. Doxorubicin hydrochloride, ceftriaxone sodium, and methotrexate are three of the most common drugs that are used in this field. According to the reported studies, the materials used most often as yolk–shells are magnetic nanoparticles and polymers. The used methods for synthesizing a diverse array of YSNPs are classified based on their core structures. Various properties of YSNPs include their high drug-loading capacity, and their ability to decrease drug toxicity and satisfactorily and efficiently release drugs.

The recent progress in yolk–shell nanoparticles (YSNPs) as a new class of hollow nanostructures applied for drug delivery.     

Formulations and nebulizer performance

To deliver a drug by nebulization, the drug must first be dispersed in a liquid (usually aqueous) medium. After application of a dispersing force (either a jet of gas or ultrasonic waves), the drug particles are contained within the aerosol droplets, which are then inhaled. Some drugs readily dissolve in water, whereas others need a cosolvent such as ethanol or propylene glycol. Some drugs are delivered as suspensions, and the efficiency of nebulizers can be different for solutions and suspensions. Solutions are delivered more efficiently with most devices. In general, conventional ultrasonic nebulizers should not be used to aerosolize suspensions, because of low efficiency. Newer strategies to improve the delivery of non-water-soluble drugs include the use of liposomes and the milling of the drug into very small "nanoparticles." In addition to the active therapeutic ingredient and solvents, drug formulations may include buffers (the solubility of some medications is influenced by pH), stabilizers, and, in the case of multi-dose preparations, antibacterial agents. Though formulations are designed to optimize drug solubility and stability, changes in formulation can also affect inhaled mass, particle size, and treatment time, though the differences between nebulizer brands probably have a greater impact than differences in formulation. Ultrasonic and jet nebulizers may damage protein and other complex agents through heat or shear stress. Additives to multi-dose formulations, especially antimicrobial and chelating agents, may cause adverse events, so there is a trend towards single-use, preservative-free vials.     

Cancer nanotheranostics: Strategies,promises and impediments

Cancer has remained one of the most indomitable conundrums for scientists over centuries due to its multifarious etiology. While improved therapeutic and diagnostic approaches have commendably augmented the rate of survival of cancer patients, a holistic riddance from the ailment is still implausible. Hence, further explorations to scout for novel strategies of cancer therapy and diagnosis are necessary. Theranostics (amalgamation of therapy and diagnostics) has emerged as one of the avant-garde strategies, which provides a two-pronged advantage in cancer management. This integrative approach has found immense relevance in light of nanotechnology. Nanoparticles can be customized (loaded with a mélange of therapeutic drugs and diagnostic probes) to develop theranostic properties, thereby constructing nanotheranostic agents. These nano-composites are lucrative tools for cancer cell obliteration and simultaneous monitoring of the drug action, and can also be tailored for targeted drug delivery. Nanotheranostic agents have emerged as a prudent ploy for synchronized cancer intervention and detection of the ‘route and reach’ of the drugs. In this review, we discuss the diversified state-of-the-art facets of theranostic nanoparticles, including various nanoparticle-based platforms as well as the plethora of reported therapeutic drugs, aptamers, markers and diagnostic molecules that have found use in the precincts of nanotheranostics.     

Odorranalectin-conjugated nanoparticles: Preparation, brain delivery and pharmacodynamic study on Parkinson's disease following intranasal administration

Odorranalectin (OL) was recently identified as the smallest lectin with much less immunogenicity than other members of the lectin family. In this study, to improve nose-to-brain drug delivery and reduce the immunogenicity of traditional lectin modified delivery system, OL was conjugated to poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles and its biorecognitive activity on nanoparticles was verified by haemagglutination tests. Nose-to-brain delivery characteristic of OL-conjugated nanoparticles (OL-NP) was investigated by in vivo fluorescence imaging technique using DiR as a tracer. Besides, urocortin peptide (UCN), as a macromolecular model drug, was incorporated into nanoparticles and evaluated for its therapeutic efficacy on hemiparkinsonian rats following intranasal administration by rotation behavior test, neurotransmitter determination and tyrosine hydroxylase (TH) test. The results suggested that OL modification increased the brain delivery of nanoparticles and enhanced the therapeutic effects of UCN-loaded nanoparticles on Parkinson's disease. In summary, the OL-NPs could be potentially used as carriers for nose-to-brain drug delivery, especially for macromolecular drugs, in the treatment of CNS disorders.     

Inhalation therapy in invasive and noninvasive mechanical ventilation

PURPOSE OF REVIEW: The aim of this article is to discuss the various factors that influence aerosol delivery in mechanically ventilated patients and clarify optimal techniques for aerosol administration in this patient population. Clinical use of various inhaled therapies in patients receiving invasive and noninvasive mechanical ventilation is also discussed. RECENT FINDINGS: With optimal techniques for using pressurized metered-dose inhalers and nebulizers in ventilator circuits, the efficiency of inhaled drug delivery in mechanically ventilated patients is comparable to that in ambulatory patients. Techniques for enhancing inhaled drug delivery during noninvasive positive pressure ventilation are also being investigated. SUMMARY: Pressurized metered-dose inhalers of bronchodilator and corticosteroid aerosols are more efficient and convenient to use than nebulizers for routine therapy in ventilated patients. Nebulizers are, however, more versatile and are employed to generate aerosols of bronchodilators, corticosteroids, antibiotics, prostaglandins, surfactant, and mucolytic agents. Factors influencing drug delivery during noninvasive positive pressure ventilation are not fully understood as yet, and further work is needed to enhance drug delivery in this setting. Improvements in drug formulations and the design and efficiency of aerosol generating devices have led to increasing application of inhaled therapies in mechanically ventilated patients.     

Dry powder inhalers for optimal drug delivery

Dry powder inhalers (DPIs) have been available for delivering drugs to the lungs for over 30 years. In the last decade there has been a big increase in DPI development, resulting partly from recognised limitations in other types of inhaler device. Many companies are developing DPIs for asthma and chronic obstructive pulmonary disease (COPD) therapy, and there is increasing recognition of the potential role of DPI systems for other therapies, such as inhaled antibiotics and peptides/proteins. Optimised drug delivery may be achieved not only by improvements to devices, but also via more sophisticated formulations that disperse easily in the inhaled air-stream and which may often be delivered by relatively simple inhaler devices. DPIs could become the device category of choice for a wide range of inhaled therapies, involving both local and systemic drug delivery.     

New perspectives in nanomedicine

Recent advances in nanotechnology have revolutionised all aspects of life, from engineering to cosmetics. One of the most exciting areas of development is that of nanomedicine. Due to their size (less than 100 nm in one aspect), nanoparticles exhibit properties that are unlike that of the same material in bulk size. These unique properties are being exploited to create new diagnostics and therapeutics for application in a broad spectrum of organ systems. Indeed, nanoparticles are already being developed as effective carriers of drugs to target regions of the body that were previously hard to access using traditional drug formulation methods. However, in addition to their role as a vehicle for drug delivery, nanoparticles themselves have the potential to have therapeutic benefit. Through manipulation of their elemental composition, size, shape, charge and surface modification or functionalisation it may be possible to target particles to specific organs where they may elicit their therapeutic effect. In this review we will focus on the recent advances in nanotechnology for therapeutic applications with a particular focus on the respiratory system, cancer and vaccinations. In addition we will also address developments in the field of nanotoxicology and the need for concomitant studies in to the toxicity of emerging nanotechnologies. It is possible that the very properties that make nanoparticles a desirable technology for therapeutic intervention may also lead to adverse health effects. It is thus important to determine, and appreciate, the fine balance between the efficacy and toxicity of nanomedicine.     

Lung models: strengths and limitations

The most widely used particle dosimetry models are those proposed by the National Council on Radiation Protection, International Commission for Radiological Protection, and the Netherlands National Institute of Public Health and the Environment (the RIVM model). Those models have inherent problems that may be regarded as serious drawbacks: for example, they are not physiologically realistic. They ignore the presence and commensurate effects of naturally occurring structural elements of lungs (eg, cartilaginous rings, carinal ridges), which have been demonstrated to affect the motion of inhaled air. Most importantly, the surface structures have been shown to influence the trajectories of inhaled particles transported by air streams. Thus, the model presented herein by Martonen et al may be perhaps the most appropriate for human lung dosimetry. In its present form, the model's major "strengths" are that it could be used for diverse purposes in medical research and practice, including: to target the delivery of drugs for diseases of the respiratory tract (eg, cystic fibrosis, asthma, bronchogenic carcinoma); to selectively deposit drugs for systemic distribution (eg, insulin); to design clinical studies; to interpret scintigraphy data from human subject exposures; to determine laboratory conditions for animal testing (ie, extrapolation modeling); and to aid in aerosolized drug delivery to children (pediatric medicine). Based on our research, we have found very good agreement between the predictions of our model and the experimental data of Heyder et al, and therefore advocate its use in the clinical arena. In closing, we would note that for the simulations reported herein the data entered into our computer program were the actual conditions of the Heyder et al experiments. However, the deposition model is more versatile and can simulate many aerosol therapy scenarios. For example, the core model has many computer subroutines that can be enlisted to simulate the effects of aerosol polydispersity, aerosol hygroscopicity, patient ventilation, patient lung morphology, patient age, and patient airway disease.