Pulmonary Drug Administration Research Articles

Progress in Utilizing Chitosan-Based Nanoparticles for Pulmonary Drug Administration

The escalating prevalence of respiratory ailments poses a significant global public health challenge, ranking among the primary causes of mortality worldwide. Notably, diseases such as asthma, chronic obstructive pulmonary disease, pneumonia, cystic fibrosis, and lung cancer, alongside the emergence of respiratory diseases, notably those induced by the coronavirus family, have contributed substantially to global fatalities in the past two decades. Consequently, numerous studies have been undertaken to enhance the effectiveness of therapeutic interventions against these diseases, with a particular emphasis on nanomedicine-driven pulmonary drug delivery. As a result, the development of nanocarriers has emerged as a promising avenue to surmount the constraints associated with traditional therapies, aiming to elevate drug bioavailability at the intended site while minimizing undesired side effects. Within this domain, nanoparticles fashioned from chitosan (CS) exhibit distinct advantages over alternative nanocarriers owing to the inherent biological properties of chitosan, including its anti-inflammatory, antimicrobial, and mucoadhesive attributes. Furthermore, CS nanoparticles have demonstrated the potential to augment drug stability, extend the duration of action, refine drug targeting, regulate drug release kinetics, optimize the dissolution of poorly soluble drugs, and enhance the cell membrane permeability of hydrophobic drugs. These unique properties position CS nanoparticles as a promising candidate for optimizing drug performance following pulmonary administration. Consequently, this review endeavors to elucidate the potential of chitosan nanoparticles in the realm of pulmonary drug delivery, shedding light on how their intrinsic biological characteristics can ameliorate the treatment landscape of pulmonary diseases. Emphasis is placed on delineating the synergistic interplay between chitosan nanoparticles and the encapsulated drug, thereby offering insights into the prospective advancements in treating respiratory ailments.

The Role of Inhaled Chitosan-Based Nanoparticles in Lung Cancer Therapy.

Lung cancer is the leading cause of cancer-related mortality worldwide, largely due to the limited efficacy of anticancer drugs, which is primarily attributed to insufficient doses reaching the lungs. Additionally, patients undergoing treatment experience severe systemic adverse effects due to the distribution of anticancer drugs to non-targeted sites. In light of these challenges, there has been a growing interest in pulmonary administration of drugs for the treatment of lung cancer. This route allows drugs to be delivered directly to the lungs, resulting in high local concentrations that can enhance antitumor efficacy while mitigating systemic toxic effects. However, pulmonary administration poses the challenge of overcoming the mechanical, chemical, and immunological defenses of the respiratory tract that prevent the inhaled drug from properly penetrating the lungs. To overcome these drawbacks, the use of nanoparticles in inhaler formulations may be a promising strategy. Nanoparticles can assist in minimizing drug clearance, increasing penetration into the lung epithelium, and enhancing cellular uptake. They can also facilitate increased drug stability, promote controlled drug release, and delivery to target sites, such as the tumor environment. Among them, chitosan-based nanoparticles demonstrate advantages over other polymeric nanocarriers due to their unique biological properties, including antitumor activity and mucoadhesive capacity. These properties have the potential to enhance the efficacy of the drug when administered via the pulmonary route. In view of the above, this paper provides an overview of the research conducted on the delivery of anticancer drug-loaded chitosan-based nanoparticles incorporated into inhaled drug delivery devices for the treatment of lung cancer. Furthermore, the article addresses the use of emerging technologies, such as siRNA (small interfering RNA), in the context of lung cancer therapy. Particularly, recent studies employing chitosan-based nanoparticles for siRNA delivery via the pulmonary route are described.

Behavior of Self‐Disintegrating Microparticles at the Air/Mucus Interface

In recent years, highly specialized nanoscopic drug carriers have been developed, which can, e.g., traverse biological barriers, protect drugs against harsh physiological conditions, and release such drugs in a controlled manner. However, for the delivery of particles via the respiratory pathway, aerodynamic diameters in the range of several micrometers are required to achieve good lung deposition and biodistribution. To combine the favorable properties of inhalable, micron‐sized particles with the advantages of nanosized drug carriers, herein, dry‐powder, hybrid microparticles (h‐μPs), which disintegrate upon contact with moist surfaces (as present in the lung) to release the embedded nanoparticles into the mucosa, are introduced. Furthermore, a microfluidic setup, which mimics the air–gel interface of the mucosal airway epithelium, is presented. With this setup, the interaction of airborne h‐μPs with the mucosal interface on a microscopic level is investigated. In detail, the influence of the h‐μP charge on their deposition efficiency is tested and it is found that this process is governed by a combination of electrostatic interactions between the mucosal surface and the h‐μPs as well as hygroscopic effects. Thus, this approach can help to optimize inhalable drug carriers to increase the efficiency of pulmonary drug administration via the respiratory pathway.

ЭФФЕКТИВНОСТЬ ЛЕЧЕНИЯ БОЛЬНЫХ ТУБЕРКУЛЕЗОМ ЛЕГКИХ С ПРЕ-ШЛУ И ШЛУ M. tuberculosis C ИСПОЛЬЗОВАНИЕМ РАЗЛИЧНЫХ СПОСОБОВ ВВЕДЕНИЯ ПРОТИВОТУБЕРКУЛЕЗНЫХ ПРЕПАРАТОВ

Aim: to evaluate effectiveness of treatment of patients with extensively drug resistant (XDR) or pre-extensively drug resistant (pre-XDR) pulmonary TB using parenteral administration of TB drugs. Materials and methods. We carried out a prospective open cohort study of 143 patients with pulmonary TB hospitalized in 2022. The patients were divided into two groups according to the route of drug administration. The main group consisted of 74 patients, who received parenteral TB drugs before sputum conversion followed by oral drug administration. Parenteral drug administration was indicated to patients with severe intoxication syndrome, advanced TB process, or concomitant gastrointestinal diseases. The control group consisted of 69 patients, who received all TB drugs orally. Oral drug administration was also indicated to patients with difficult venous access. Results. Sputum conversion was observed by the third month of treatment much faster in the main group than in the control group. Treatment effectiveness by cavity closure did not differ between the groups. Conclusion. Intravenous administration of TB drugs contributes to rapid sputum conversion, which allows earlier patient discharge from hospital or surgical treatment.

Development of extra-fine particles containing nanosized meloxicam for deep pulmonary delivery: In vitro aerodynamic and cell line measurements

Pulmonary drug administration provides a platform for the effective local treatment of various respiratory diseases. Application of nano-sized active ingredients results in higher bioavailability because of their large specific surface area. Extra-fine dry powder inhalers reach the smaller airways, further improving therapeutic efficiency. Poorly water-soluble meloxicam was the selected active ingredient. We aimed to decrease the particle size into the nano range by wet milling and producing extra-fine inhalable particles via nano spray-drying. The diameter of the drug was reduced to 138 nm. The particle size of the dry products was between 1.1 and 1.5 µm, and the dispersed diameter was between 500 and 800 nm. Owing to the excipients (poly-vinyl-alcohol, leucine), the spray-dried particles presented nearly spherical morphology. The drug became partially amorphous. Thanks to the improved surface area, the solubility and the released and the diffused amount of the meloxicam increased in artificial lung media. The in vitro aerodynamic measurements showed that the leucine-containing formulations had outstanding fine particle fraction (FPF) deposition with 1.3 µm mass median aerodynamic diameter (MMAD). The aerodynamic particle counter test also proved the extra-fine aerodynamic particle size. The in vitro cell line experiments revealed the non-cytotoxicity of the products and the suppression of the interleukin concentration. Overall, the powders are suitable for deep pulmonary delivery and the local treatment of lung inflammations.

Formulation and Evaluation of Doxofylline-Loaded Polymeric Micelles for Pulmonary Administration

The pulmonary administration of drugs offers advantages over administration by intravenous injection. The present research work was to prepare polymeric micelles nanomicelles containing Doxofylline as dry powder for inhalation. In order to bypass the drawbacks of predictable preparations, nanotechnology-based drug delivery systems for pulmonary administration and pulmonary targeting have been oppressed. The work was aimed towards formulating the Doxofylline loaded Soluplus nanomicelles with polymer Soluplus by film hydration technique in different ratios. The nanomicelles so prepared were characterized for its particle size, ζ-potential, XRD, SEM, drug content and drug release rate. Soluplus Doxofylline Polymeric Micelles showed mean size of 70.73nm and Zeta Potential is - 8.71. The Drug Entrapment Efficiency is 87.7% and The Drug Loading Capacity is 10%. In-Vitro study reveals the drug release is 44%. Conclusion: The Doxofylline-Soluplus Polymeric Nanomicelles could have the significant value in the treatment of Asthama and COPD.
 Keywords: Polymeric Nanomicelles, Asthama, COPD, Doxofylline, Film Hydration Technique, Lyophilisation, Dry powder for Inhalation.

Engineered-inhaled particles: Influence of carbohydrates excipients nature on powder properties and behavior

Pulmonary drug administration has long been used for local or systemic treatment due to several advantages. Dry powder inhalers emerge as the most promising due to efficiency, ecologic, and drug stability concerns. Coarse lactose-carrier is still the gold standard when inhalation powders are developed. Despite some efforts to produce new types of powders, the lung drug deposition is still poorly controlled, which will ultimately impact therapeutic effectiveness.In this study, we developed “engineered-inhalation powders” using the spray-drying technique. Multiple carbohydrates excipients were binary mixed and combined with two active pharmaceutical ingredients for asthma therapy (budesonide and formoterol). Particle morphology, from spherical to deflated shapes, was characterized by the number and the depth of dimples measured from SEM images. We define a new characteristic deflation ratio ξ as the product between the number of dimples and their depth. Six different powders having opposite morphologies have been selected and we have demonstrated a linear correlation between the fine particle fraction and the deflation ratio of produced powders.Overall, we showed first that the morphology of inhalable powder can be finely tuned by spray-drying technique when excipients varied. Secondly, we developed stable inhalation powders that simultaneously induced high fine particle fractions (>40%) for two drugs due to their deflated surface. The stability has been evaluated for up to 2 months at room temperature.

Design and evaluation of folate-modified liposomes for pulmonary administration in lung cancer therapy

Pulmonary drug administration for the treatment of lung cancer is useful because the drug is directly delivered to the lung tissues with minimal invasiveness and higher efficiency compared to other conventional methods. However, it is critical to enhance drug accumulation in the lung cancer tissues to achieve sufficient therapeutic efficacy. The submicron-sized liposome (ssLip) preparation is one of the most promising approaches to enhance drug accumulation in the lungs; however, ssLips prepared for conventional inhalation do not have tumour selectivity. Therefore, in this study, we prepared folate (FA)-modified ssLip (FA-ssLip) to enhance drug accumulation in folate receptor (FR)-expressing lung cancer cells, and evaluated its physicochemical properties and potential as a drug carrier in pulmonary administration. In addition, we prepared rapamycin (RM-an autophagy-inducing anticancer drug)-loaded FA-ssLip (RM/FA-ssLip) and investigated its anti-tumour effect. FA-ssLip showed excellent nanoparticle properties with submicron size (approximately 120 nm) and high lung accumulation in lung cancer mouse model-bearing LL2 cells—a mouse Lewis lung carcinoma cell line. RM/FA-ssLip showed significant cytotoxic activity in FR-expressing cancer cells. In addition, pulmonary administration of RM/FA-ssLip extended the survival of LL2 cell tumour-bearing mice. Taken together, our results suggest the potential of FA-ssLip as a pulmonary drug carrier for the efficient treatment of lung cancer.

Microencapsulated Isoniazid-Loaded Metal-Organic Frameworks for Pulmonary Administration of Antituberculosis Drugs.

Tuberculosis (TB) is an infectious disease that causes a great number of deaths in the world (1.5 million people per year). This disease is currently treated by administering high doses of various oral anti-TB drugs for prolonged periods (up to 2 years). While this regimen is normally effective when taken as prescribed, many people with TB experience difficulties in complying with their medication schedule. Furthermore, the oral administration of standard anti-TB drugs causes severe side effects and widespread resistances. Recently, we proposed an original platform for pulmonary TB treatment consisting of mannitol microspheres (Ma MS) containing iron (III) trimesate metal–organic framework (MOF) MIL-100 nanoparticles (NPs). In the present work, we loaded this system with the first-line anti-TB drug isoniazid (INH) and evaluated both the viability and safety of the drug vehicle components, as well as the cell internalization of the formulation in alveolar A549 cells. Results show that INH-loaded MOF (INH@MIL-100) NPs were efficiently microencapsulated in Ma MS, which displayed suitable aerodynamic characteristics for pulmonary administration and non-toxicity. MIL-100 and INH@MIL-100 NPs were efficiently internalized by A549 cells, mainly localized in the cytoplasm. In conclusion, the proposed micro-nanosystem is a good candidate for the pulmonary administration of anti-TB drugs.

A Pathway From Porous Particle Technology Toward Tailoring Aerogels for Pulmonary Drug Administration

Pulmonary drug delivery has recognized benefits for both local and systemic treatments. Dry powder inhalers (DPIs) are convenient, portable and environmentally friendly devices, becoming an optimal choice for patients. The tailoring of novel formulations for DPIs, namely in the form of porous particles, is stimulating in the pharmaceutical research area to improve delivery efficiency. Suitable powder technological approaches are being sought to design such formulations. Namely, aerogel powders are nanostructured porous particles with particularly attractive properties (large surface area, excellent aerodynamic properties and high fluid uptake capacity) for these purposes. In this review, the most recent development on powder technologies used for the processing of particulate porous carriers are described via updated examples and critically discussed. A special focus will be devoted to the most recent advances and uses of aerogel technology to obtain porous particles with advanced performance in pulmonary delivery.

Metabolic Glycoengineering Enables the Ultrastructural Visualization of Sialic Acids in the Glycocalyx of the Alveolar Epithelial Cell Line hAELVi.

The glycocalyx—a plethora of sugars forming a dense layer that covers the cell membrane—is commonly found on the epithelial surface of lumen forming tissue. New glycocalyx specific properties have been defined for various organs in the last decade. However, in the lung alveolar epithelium, its structure and functions remain almost completely unexplored. This is partly due to the lack of physiologically relevant, cost effective in vitro models. As the glycocalyx is an essential but neglected part of the alveolar epithelial barrier, understanding its properties holds the promise to enhance the pulmonary administration of drugs and delivery of nanoparticles. Here, using air-liquid-interface (ALI) cell culture, we focus on combining metabolic glycoengineering with glycan specific electron and confocal microscopy to visualize the glycocalyx of a recently immortalized human alveolar epithelial cell line (hAELVi). For this purpose, we applied different bioorthogonal labeling approaches to visualize sialic acid—an amino sugar that provides negative charge to the lung epithelial glycocalyx—using both fluorescence and gold-nanoparticle labeling. Further, we compared mild chemical fixing/freeze substitution and standard cytochemical electron microscopy embedding protocols for their capacity of contrasting the glycocalyx. In our study, we established hAELVi cells as a convenient model for investigating human alveolar epithelial glycocalyx. Transmission electron microscopy revealed hAELVi cells to develop ultrastructural features reminiscent of alveolar epithelial type II cells (ATII). Further, we visualized extracellular uni- and multilamellar membranous structures in direct proximity to the glycocalyx at ultrastructural level, indicating putative interactions. The lamellar membranes were able to form structures of higher organization, and we report sialic acid to be present within those. In conclusion, combining metabolite specific glycoengineering with ultrastructural localization presents an innovative method with high potential to depict the molecular distribution of individual components of the alveolar epithelial glycocalyx and its interaction partners.

Novel Approaches for the Treatment of Pulmonary Tuberculosis

Tuberculosis (TB) is a contagious airborne disease caused by Mycobacterium tuberculosis, which primarily affects human lungs. The progression of drug-susceptible TB to drug-resistant strains, MDR-TB and XDR-TB, has become worldwide challenge in eliminating TB. The limitations of conventional TB treatment including frequent dosing and prolonged treatment, which results in patient’s noncompliance to the treatment because of treatment-related adverse effects. The non-invasive pulmonary drug administration provides the advantages of targeted-site delivery and avoids first-pass metabolism, which reduced the dose requirement and systemic adverse effects of the therapeutics. With the modification of the drugs with advanced carriers, the formulations may possess sustained released property, which helps in reducing the dosing frequency and enhanced patients’ compliances. The dry powder inhaler formulation is easy to handle and storage as it is relatively stable compared to liquids and suspension. This review mainly highlights the aerosolization properties of dry powder inhalable formulations with different anti-TB agents to understand and estimate the deposition manner of the drug in the lungs. Moreover, the safety profile of the novel dry powder inhaler formulations has been discussed. The results of the studies demonstrated that dry powder inhaler formulation has the potential in enhancing treatment efficacy.

Preparation, optimization, and in vivo evaluation of an inhaled solution of total saponins of Panax notoginseng and its protective effect against idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive pulmonary disease that can cause fibrotic remodeling of the surrounding lung, thus leading to respiratory failure. Although IPF is the most common form of idiopathic interstitial pneumonia, the precise mechanisms underlying this condition remain unknown. In this study, we used total saponins of Panax notoginseng inhalation solution (TIS) to induce idiopathic bleomycin-induced pulmonary fibrosis in rats. The uniformity of delivery dose was investigated by analyzing the aerodynamic particle size distribution and drug stability. The potential of hydrogen potential of hydrogen (pH) of the inhalation solution was 7.0 and the solvent 0.9% NaCl solution, thus meeting physiological requirements for pulmonary drug administration. The delivery rate was 1.94 ± 0.16 mg·min−1 and the total dose was 17.40 ± 0.04 mg. TIS was composed of five key components: notoginsenoside R1, ginsenosides Rg1, ginsenosides Re, ginsenosides Rb1, and ginsenosides Rd. The mass median aerodynamic diameter (MMAD) for these five components were 3.62 ± 0.05 µm, 3.62 ± 0.06 µm, 3.65 ± 0.10 µm, 3.62 ± 0.06 µm, and 3.61 ± 0.05 µm, respectively. Fine particle fraction (FPF) was 66.24 ± 0.73%, 66.20 ± 0.89%, 66.07 ± 1.42%, 66.18 ± 0.79%, and 66.29 ± 0.70%, respectively. The MMAD for inhalation solutions needs to be 1–5 µm, which indicates that the components of TIS are suitable for inhalation. It is important to control the particle size of targeted drugs to ensure that the drug is delivered to the appropriate target tissue. In vitro experiments indicated that TIS exhibited high rates of deposition in lung tissue, thus indicating that pulmonary delivery systems may represent a good therapeutic option for patients.

Pulmonary delivery of rifampicin-loaded soluplus micelles against Mycobacterium tuberculosis

Tuberculosis (TB) stands as the second “most deadly infectious disease” behind AIDS. Rifampicin (RIF) represents one of the most effective anti-TB drugs of the “short-term” oral TB therapy. However, the main limitations of the oral treatment are related with the lack of patient adherence and the development of multi-drug resistant Mycobacterium tuberculosis (Mtb) strains. Recently, the pulmonary administration of anti-TB drugs has become an attractive alternative to improve TB therapy. Hence, we have developed a respirable nanocarrier based on RIF-loaded polymeric micelles (PMs), employing a commercially available graft-copolymer of poly (vinyl caprolactam)-poly (vinyl acetate)-poly (ethylene glycol) (Soluplus). The RIF apparent aqueous solubility was increased (14.3-fold) and the micellar system was ranged in the nanoscale (~107 nm). Then, according to its in vitro aerodynamic behavior, our nanoformulation represented a suitable system for deep lung drug delivery. Interestingly, these inhalable RIF-loaded PMs enhanced (up to 2.5-fold) the in vitro drug microbicidal activity in Mtb-infected THP-1 macrophages versus a RIF solution. In addition, the biodistribution studies of the radiolabelled (99mTc) PMs demonstrated their lung accumulation over 24 hs in rats. Overall, this novel nanoformulation stands as an attractive platform for a potential inhalable TB therapy.

Preclinical evaluation of aerosol administration systems using Positron Emission Tomography

Pulmonary administration of drugs has recently gained attention because it exhibits numerous advantages compared to oral or intravenous administration. The administration of aerosols for inhalation to animals, however, remains a critical challenge and only a few methods of administration have been developed. Herein, we compare the regional distribution of aerosols in the lungs of wild type rats after pulmonary administration using three different methods: (a) The Penn-Century MicroSprayer® Aerosolizer; (b) an in-house designed aerosol generation system; and (c) the Aeroneb® Lab Micropump Nebulizer. Both the regional distribution and the fraction of aerosol deposited in the lungs were determined by means of radiolabelling of the aerosol followed by in vivo and ex vivo Positron Emission Tomography (PET) imaging and dissection and gamma counting. Endotracheal insufflation using the PennCentury MicroSprayer resulted in >85% of the administered dose accumulated in the lungs, with a non-uniform distribution of the radioactivity in different lobes and a low animal-to-animal reproducibility. Administration using the in-house designed and the Aeroneb nebulizers resulted in a uniform distribution over the lungs, but only a small fraction of the nebulized activity (ca. 0.1%) was deposited in the lungs.

Cyclodextrin-based nanocarriers containing a synergic drug combination: A potential formulation for pulmonary administration of antitubercular drugs

Tuberculosis (TB) remains a major global health problem. The use of ethionamide (ETH), a main second line drug, is associated to severe toxic side-effects due to its low therapeutic index. In this challenging context, “booster” molecules have been synthetized to increase the efficacy of ETH. However, the administration of ETH/booster pair is mostly hampered by the low solubility of these drugs and the tendency of ETH to crystallize. Here, ETH and a poorly water-soluble booster, so-called BDM43266, were simultaneously loaded in polymeric β-cyclodextrin nanoparticles (pβCyD NPs) following a “green” protocol. The interaction of ETH and BDM43266 with pβCyD NPs was investigated by complementary techniques. Remarkably, the inclusion of ETH and BDM43266 pβCyD NPs led to an increase of their apparent solubility in water of 10- and 90-fold, respectively. Competition studies of ETH and BDM43266 for the CyD cavities of pβCyD NPs corroborated the fact that the drugs did not compete with each other, confirming the possibility to simultaneously co-incorporate them in NPs. The drug-loaded NP suspensions could be filtered through 0.22μm filters. Finally, the drug-loaded NPs were passed through a Microsprayer® to evaluate the feasibility to administer pβCyD NPs by pulmonary route. Each spray delivered a constant amount of both drugs and the NPs were totally recovered after passage through the Microsprayer®. These promising results pave the way for a future use of pβCyD NPs for the pulmonary delivery of the ETH/BDM43266 pair.

Targeted delivery of liquid microvolumes into the lung

The ability to deliver drugs to specific sites in the lung could radically improve therapeutic outcomes of a variety of lung diseases, including cystic fibrosis, severe bronchopneumonia, chronic obstructive pulmonary disease, and lung cancer. Using conventional methods for pulmonary drug administration, precise, localized delivery of exact doses of drugs to target regions remains challenging. Here we describe a more controlled delivery of soluble reagents (e.g., drugs, enzymes, and radionuclides) in microvolume liquid plugs to targeted branches of the pulmonary airway tree: upper airways, small airways (bronchioles), or the most distal alveoli. In this approach, a soluble liquid plug of very small volume (<1 mL) is instilled into the upper airways, and with programmed air ventilation of the lungs, the plug is pushed into a specific desired (more distal) airway to achieve deposition of liquid film onto the lung epithelium. The plug volume and ventilation conditions were determined by mathematical modeling of plug transport in a tubular geometry, and targeted liquid film deposition was demonstrated in rat lungs by three different in vivo imaging modalities. The experimental and modeling data suggest that instillation of microvolumes of liquid into a ventilated pulmonary airway could be an effective strategy to deliver exact doses of drugs to targeted pathologic regions of the lung, especially those inaccessible by bronchoscopy, to increase in situ efficacy of the drug and minimize systemic side effects.

Pulmonary monoclonal antibody delivery via a portable microfluidic nebulization platform.

Nebulizers have considerable advantages over conventional inhalers for pulmonary drug administration, particularly because they do not require coordinated breath actuation to generate and deliver the aerosols. Nevertheless, besides being less amenable to miniaturization and hence portability, some nebulizers are prone to denature macromolecular drugs due to the large forces generated during aerosolization. Here, we demonstrate a novel portable acoustomicrofluidic device capable of nebulizing epidermal growth factor receptor (EGFR) monoclonal antibodies into a fine aerosol mist with a mass median aerodynamic diameter of approximately 1.1 μm, optimal for deep lung deposition via inhalation. The nebulized monoclonal antibodies were tested for their stability, immunoactivity, and pharmacological properties, which confirmed that nebulization did not cause significant degradation of the antibody. In particular, flow cytometry demonstrated that the antigen binding capability of the antibody is retained and able to reduce phosphorylation in cells overexpressing the EGFR, indicating that the aerosols generated by the device were loaded with stable and active monoclonal antibodies. The delivery of antibodies via inhalation, particularly for the treatment of lung cancer, is thus expected to enhance the efficacy of this protein therapeutic by increasing the local concentration where they are needed.

Impact of Drug Administration Route on Drug Delivery and Distribution into the Lung: An Imaging Mass Spectrometry Approach

During the last decade, significant technological improvements in mass spectrometry have had a great impact on drug discovery. The development of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) has set a new frontier for the study of the distribution of endogenous and exogenous molecules present within a tissue. MALDI-IMS is a surface sampling technique that allows not only the detection of multiple analytes but also gives the spatial distribution of those analytes. Active compounds for pulmonary disease need an optimal and well-studied delivery into the lungs, in order to assure distribution with greater penetration into the peripheral or the alveolar region of the lung to maximize the therapeutic effects. IMS is very useful in the field of drug discovery, showing drug delivery and distribution in the body and organs. In this study, we present a comparison between two different ways of carrying out pulmonary drug administration: inhalation of a nebulized aerosol of aqueous drug solutions and intratracheal administration, which is much simpler, not expensive and commonly used during in vivo screening. Tiotropium bromide is a long-acting anticholinergic medicine used for maintenance treatment of chronic obstructive pulmonary disease. In the present work, tiotropium was administered by nebulization and by intratracheal instillation to guinea pigs at doses able to induce significant anti-bronchoconstrictive activity. Lung samples were dissected, frozen, cryosectioned and coated with matrix (α-hydroxy-cinnamic acid). IMS analyses were performed using a MALDI-LTQ-Orbitrap XL. Using this technique we were able to compare different distributions of the drug depending on the method of administration.

Microparticles of rifampicin: comparison of pulmonary route with oral route for drug uptake by alveolar macrophages, phagocytosis activity and toxicity study in albino rats

Context: Tuberculosis (TB) is a chronic infectious disease with increasing incidence of drug resistance. Oral treatment for TB and multidrug resistance (MDR)-TB can have serious side effects. The causative agent of TB, Mycobacterium tuberculosis, resides in alveolar macrophages (AM). Pulmonary administration of anti-TB drugs can help in delivery of high concentration to AM. The ability of AM to phagocytose can also be utilized to generate mycobactericidal nitric oxide (NO) to improve efficacy of anti-TB drugs.Objective: To compare the uptake of rifampicin (RIF) by AM post oral and pulmonary administration of RIF microparticles (RM) and to compare hepatotoxicity and phagocytosis activity.Materials and Methods: RM were produced by spray drying process. RM were administered to rats through oral as well as intratracheal route. The uptake of RIF by AM and liver was measured. NO was measured in bronchoalveolar lavage (BAL) fluid. SGOT and SGPT levels were measured in serum.Results: Significantly higher (p < 0.05) concentration of RIF was found in AM post intratracheal administration. NO production was also significantly higher but less than toxic level. SGOT and SGPT levels as well as uptake of RIF by liver were indicative of no hepatotoxicity post intratracheal administration.Discussion: Phagocytosis of RM post intratracheal administration leads to significantly higher drug level in AM as well as production of significantly higher levels of NO.Conclusion: The administration of RM as dry powder inhalation (DPI) formulation may reduce treatment time of TB and chances of drug resistance TB.