Targeting drug delivery to the lungs by inhalation

Most drugs targeted to the respiratory tract are used for their local action. For example, ephidrine for nasal decongestion, beta-2 agonists for bronchodilatation, and inhaled steroids to suppress the inflammation seen in asthmatic airways. Since the drug is delivered directly to its required site, only a small quantity is needed for an adequate therapeutic response, and consequently there is a low incidence of systemic side effects compared with oral or intravenous administration. More recently, it has become apparent that the lining of the respiratory tract, from nasal mucosa to airways and alveoli, may be used for the absorption of a drug for its systemic effect. This route of administration may be particularly attractive if it avoids the metabolic destruction encountered when some drugs are administered by alternative routes (for instance, peptides and proteins are rapidly destroyed by peptidases when Oven by the oral route). If there is a lack ofclinical response to an aerosolized drug, it is important to question whether the drug has failed or whether delivery to the site of action is inadequate. To deliver therapeutic agents by inhalation to the lower respiratory tract, inhaled drug particles must have appropriate aerodynamic characteristics. In addition, the anatomy and pathophysiology of the patient's respiratory tract, mode of inhalation through the inhaler, and the characteristics of the inhalational device itself, may significantly affect drug deposition.     

Development of a size-dependent aerosol deposition model utilising human airway epithelial cells for evaluating aerosol drug delivery

Aerosol delivery to the airways of the human respiratory tract, followed by absorption, constitutes an alternative route of administration for compounds unsuitable for delivery by conventional oral and parenteral routes. The target for aerosol drug delivery is the airways epithelium, i.e. tracheal, bronchial, bronchiolar and alveolar cells, which become the site of drug deposition. These epithelial layers also serve as a barrier to the penetration of inhaled material. An in vitro model for aerosol deposition and transport across epithelia in the human airways may be a good predictor of in vivo disposition. The present preliminary studies begin an investigation that blends the dynamics of aerosol delivery and the basis of an in vitro simulated lung model to evaluate the transport properties of a series of molecular weight marker compounds across human-derived bronchiolar epithelial cell monolayers. An Andersen viable cascade impactor was used as a delivery apparatus for the deposition of size-segregated particles onto monolayers of small airway epithelial cells and Calu-3 cells. It was shown that these cell layers can withstand placement in the impactor, and that permeability can be tested subsequent to removal from the impactor.     

Convective dispersion during steady flow in the conducting airways of the human lung

The adverse health effects of inhaled particulate matter from the environment depend on its dispersion, transport, and deposition in the human airways. Similarly, precise targeting of deposition sites by pulmonary drug delivery systems also relies on characterizing the dispersion and transport of therapeutic aerosols in the respiratory tract. A variety of mechanisms may contribute to convective dispersion in the lung; simple axial streaming, augmented dispersion, and steady streaming are investigated in this effort. Flow visualization of a bolus during inhalation and exhalation, and dispersion measurements were conducted during steady flow in a three-generational, anatomically accurate in vitro model of the conducting airways to support this goal. Control variables included Reynolds number, flow direction, generation, and branch. Experiments illustrate transport patterns in the lumen cross section and map their relation to dispersion metrics. These results indicate that simple axial streaming, rather than augmented dispersion, is the dominant steady convective dispersion mechanism in symmetric Weibel generations 7-13 during normal respiration. Experimental evidence supports the branching nature of the airways as a possible contributor to steady streaming in the lung.     

Nanotechnology and pharmaceutical inhalation aerosols

Pharmaceutical inhalation aerosols have been playing a crucial role in the health and well being of millions of people throughout the world for many years. The technology's continual advancement, the ease of use and the more desirable pulmonary-rather-than-needle delivery for systemic drugs has increased the attraction for the pharmaceutical aerosol in recent years. But administration of drugs by the pulmonary route is technically challenging because oral deposition can be high, and variations in inhalation technique can affect the quantity of drug delivered to the lungs. Recent advances in nanotechnology, particularly drug delivery field have encouraged formulation scientists to expand their reach in solving tricky problems related to drug delivery. Moreover, application of nanotechnology to aerosol science has opened up a new category of pharmaceutical aerosols (collectively known as nanoenabled-aerosols) with added advantages and effectiveness. In this review, some of the latest approaches of nano-enabled aerosol drug delivery system (including nano-suspension, trojan particles, bioadhesive nanoparticles and smart particle aerosols) that can be employed successfully to overcome problems of conventional aerosol systems have been introduced.     

Methodology for the measurement of mucociliary function in the mouse by scintigraphy.

The objective of the study was to develop a scintigraphic method for measurement of airway mucociliary clearance in small laboratory rodents such as the mouse. Previous investigations have characterized the secretory cell types present in the mouse airway, but analysis of the mucus transport system has been limited to in vitro examination of tissue explants or invasive in vivo measures of a single airway, the trachea. Three methods were used to deposit insoluble, radioisotopic colloidal particles: oropharyngeal aspiration, intratracheal instillation, and nose-only aerosol inhalation. The initial distribution of particles within the lower respiratory tract was visualized by gamma-camera, and clearance of particles was followed intermittently over 6 h and at the conclusion, 24 h postdelivery. Subsets of mice underwent lavage for evidence of tissue inflammation, and others were restudied for reproducibility of the methods. The aspiration and instillation methods of delivery led to greater distributions of deposited activity within the lungs, i.e., approximately 60--80% of the total respiratory tract radioactivity, whereas the nose-only aerosol technique attained a distribution of 32% to the lungs. However, the aerosol technique maximized the fraction of particles that cleared the airway over a 24-h period, i.e, deposited onto airway epithelial surfaces and cleared by mucociliary function such that lung retention at 24 h averaged 57% for delivery by aerosol inhalation and > or =80% for the aspiration or intratracheal instillation techniques. Particle delivery methods did not cause lung inflammation/injury with use of inflammatory cells and chemoattractant cytokines as criteria. Scintigraphy can discern particle deposition and clearance from the lower respiratory tract in the mouse, is noninvasive and reproducible, and includes the capability for restudy and lung lavage when time course or chronic treatments are being considered.     

Characterization and Deposition of Respirable Large- and Small-Particle Bioaerosols

The deposition patterns of large-particle microbiological aerosols within the respiratory tract are not well characterized. A novel system (the flow-focusing aerosol generator [FFAG]) which enables the generation of large (>10-μm) aerosol particles containing microorganisms under laboratory conditions was characterized to permit determination of deposition profiles within the murine respiratory tract. Unlike other systems for generating large aerosol particles, the FFAG is compatible with microbiological containment and the inhalational challenge of animals. By use of entrapped Escherichia coli cells, Bacillus atrophaeus spores, or FluoSphere beads, the properties of aerosols generated by the FFAG were compared with the properties of aerosols generated using the commonly available Collison nebulizer, which preferentially generates small (1- to 3-μm) aerosol particles. More entrapped particulates (15.9- to 19.2-fold) were incorporated into 9- to 17-μm particles generated by the FFAG than by the Collison nebulizer. The 1- to 3-μm particles generated by the Collison nebulizer were more likely to contain a particulate than those generated by the FFAG. E. coli cells aerosolized using the FFAG survived better than those aerosolized using the Collison nebulizer. Aerosols generated by the Collison nebulizer and the FFAG preferentially deposited in the lungs and nasal passages of the murine respiratory tract, respectively. However, significant deposition of material also occurred in the gastrointestinal tract after inhalation of both the small (89.7%)- and large (61.5%)-particle aerosols. The aerosols generated by the Collison nebulizer and the FFAG differ with respect to mass distribution, distribution of the entrapped particulates, bacterial survival, and deposition within the murine respiratory tract.     

Effects of Localized Hydrophilic Mannitol and Hydrophobic Nelfinavir Administration Targeted to Olfactory Epithelium on Brain Distribution

Many nasally applied compounds gain access to the brain and the central nervous system (CNS) with varying degree. Direct nose-to-brain access is believed to be achieved through nervous connections which travel from the CNS across the cribriform plate into the olfactory region of the nasal cavity. However, current delivery strategies are not targeted to preferentially deposit drugs to the olfactory at cribriform. Therefore, we have developed a pressurized olfactory delivery (POD) device which consistently and non-invasively deposited a majority of drug to the olfactory region of the nasal cavity in rats. Using both a hydrophobic drug, mannitol (log P = -3.1), and a hydrophobic drug, nelfinavir (log P = 6.0), and POD device, we compared brain and blood levels after nasal deposition primarily on the olfactory region with POD or nose drops which deposited primarily on the respiratory region in rats. POD administration of mannitol in rats provided a 3.6-fold (p < 0.05) increase in cortex-to-blood ratio, compared to respiratory epithelium deposition with nose drop. Administration of nelfinavir provided a 13.6-fold (p < 0.05) advantage in cortex-to-blood ratio with POD administration, compared to nose drops. These results suggest that increasing the fraction of drug deposited on the olfactory region of the nasal cavity will result in increased direct nose-to-brain transport.     

Effects of bronchodilator particle size in asthmatic patients using monodisperse aerosols.

Aerosol particle size influences airway drug deposition. Current inhaler devices are inefficient, delivering a heterodisperse distribution of drug particle sizes where, at best, 20% reaches the lungs. Monodisperse aerosols are the appropriate research tools to investigate basic aerosol science concepts within the human airways. We hypothesized that engineering such aerosols of albuterol would identify the ideal bronchodilator particle size, thereby optimizing inhaled therapeutic drug delivery. Eighteen stable mildly to moderately asthmatic patients [mean forced expiratory volume in 1 s (FEV1) 74.3% of predicted] participated in a randomized, double-blind, crossover study design. A spinning-top aerosol generator was used to produce monodisperse albuterol aerosols that were 1.5, 3, and 6 microm in size, and also a placebo, which were inhaled at cumulative doses of 10, 20, 40, and 100 microg. Lung function changes and tolerability effects were determined. The larger particles, 6 and 3 microm, were significantly more potent bronchodilators than the 1.5-microm and placebo aerosols for FEV1 and for the forced expiratory flow between exhalation of 25 and 75% of forced vital capacity. A 20-microg dose of the 6- and 3-microm aerosols produced FEV1 bronchodilation comparable to that produced by 200 microg from a metered-dose inhaler. No adverse effects were observed in heart rate and plasma potassium. The data suggest that in mildly to moderately asthmatic patients there is more than one optimal beta2-agonist bronchodilator particle size and that these are larger particles in the higher part of the respirable range. Aerosols delivered in monodisperse form can enable large reductions of the inhaled dose without loss of clinical efficacy.     

Regional differences in bioavailability of an opioid tetrapeptide in vivo in rats after administration to the respiratory tract

TArPP (Tyr-D-Arg-Phe-Phe-NH(2)), 1-10 micromol/kg, was administered to anesthetized rats by nasal microinfusion, intratracheal microinfusion, intratracheal nebulization, aerosol inhalation, and i.v. bolus and infusion. Plasma concentrations of TArPP and its deamidated metabolite were determined by LC-MS-MS.Regional differences in bioavailability (F), first-pass metabolism, and absorption rate were found for TArPP after delivery to the respiratory tract. Absorption was rapid after both pulmonary and nasal administration (t(max) approximately 10-20 min). After nasal microinfusion, F was 52 +/- 9%. For all the pulmonary groups, F was higher (72-114%). First-pass metabolism of TArPP was lower in the lung than in the nasal cavity. It is evident that the pulmonary route is attractive for successful systemic delivery of small, hydrophilic and enzymatic susceptible peptides.     

Particle Deposition in a Child Respiratory Tract Model: In Vivo Regional Deposition of Fine and Ultrafine Aerosols in Baboons

To relate exposure to adverse health effects, it is necessary to know where particles in the submicron range deposit in the respiratory tract. The possibly higher vulnerability of children requires specific inhalation studies. However, radio-aerosol deposition experiments involving children are rare because of ethical restrictions related to radiation exposure. Thus, an in vivo study was conducted using three baboons as a child respiratory tract model to assess regional deposition patterns (thoracic region vs. extrathoracic region) of radioactive polydisperse aerosols ([d16–d84], equal to [0.15 µm–0.5 µm], [0.25 µm–1 µm], or [1 µm–9 µm]). Results clearly demonstrated that aerosol deposition within the thoracic region and the extrathoraic region varied substantially according to particle size. High deposition in the extrathoracic region was observed for the [1 µm–9 µm] aerosol (72%±17%). The [0.15 µm–0.5 µm] aerosol was associated almost exclusively with thoracic region deposition (84%±4%). Airborne particles in the range of [0.25 µm–1 µm] showed an intermediate deposition pattern, with 49%±8% in the extrathoracic region and 51%±8% in the thoracic region. Finally, comparison of baboon and human inhalation experiments for the [1 µm–9 µm] aerosol showed similar regional deposition, leading to the conclusion that regional deposition is species-independent for this airborne particle sizes.     

In vitro and in vivo aspects of cascade impactor tests and inhaler performance: A review

The purpose of this review is to discuss the roles of cascade impactor (CI) data in inhaler assessment and to examine the relationship between aerodynamic particle size distribution (APSD) and the clinical response to inhaled drugs. A systematic literature search of studies linking APSD to clinical response was undertaken. Two distinct roles for CI-generated data were identified: (1) the control of inhaler/drug product quality; and (2) the provision of data that may be predictive of particle deposition in the respiratory tract. Method robustness is required for the former application, combined with simplicity in operation, resulting in rudimentary attempts to mimic the anatomy of the respiratory tract. The latter necessitates making the apparatus and its operation more closely resemble patient use of the inhaler. A CI cannot perfectly simulate the respiratory tract, since it operates at constant flow rate, while the respiratory cycle has a varying flow-time profile. On the basis of a review of studies linking APSD to clinical response of inhaled drugs, it is concluded that attempts to use CI-generated data from quality control testing to compare products for bioequivalence are likely to have only limited success, as links between laboratory-measured APSD, particle deposition in the respiratory tract, and clinical response are not straightforward.     

CFD simulation of aerosol delivery to a human lung via surface acoustic wave nebulization

Administration of drug in the form of particles through inhalation is generally preferable in the treatment of respiratory disorders. Conventional inhalation therapy devices such as inhalers and nebulizers, nevertheless, suffer from low delivery efficiencies, wherein only a small fraction of the inhaled drug reaches the lower respiratory tract. This is primarily because these devices are not able to produce a sufficiently fine drug mist that has aerodynamic diameters on the order of a few microns. This study employs computational fluid dynamics to investigate the transport and deposition of the drug particles produced by a new aerosolization technique driven by surface acoustic waves (SAWs) into an in silico lung model geometrically reconstructed using computed tomography scanning. The particles generated by the SAW are released in different locations in a spacer chamber attached to a lung model extending from the mouth to the 6th generation of the lung bronchial tree. An Eulerian approach is used to solve the Navier–Stokes equations that govern the airflow within the respiratory tract, and a Lagrangian approach is adopted to track the particles, which are assumed to be spherical and inert. Due to the complexity of the lung geometry, the airflow patterns vary as it penetrates deeper into the lung. High inertia particles tend to deposit at locations where the geometry experiences a significant reduction in cross section. Our findings, nevertheless, show that the injection location can influence the delivery efficiency: Injection points close to the spacer centerline result in deeper penetration into the lung. Additionally, we found that the ratio of drug particles entering the right lung is significantly higher than the left lung, independent of the injection location. This is in good agreement with this fact that the most of airflow enters to the right lobes.     

Theoretical study of nasal deposition

A theory is derived to calculate the regional and total deposition of aerosol particles in the nasal passages during inhalation. The particle size studied range from 0.2 to 10.0 μm diameter. The deposition is calculated in five regions; (I) the region filled with nasal hair, (II) the nasal valve, (III) the expansion region, (IV) the turbinate region and (V) the posterior bend. Equations are derived to determine the deposition caused by direct impaction on the nasal hairs and bends of the passages. The calculations show the deposition due to direct impaction does not account for the amount or location of deposited particles measured in experiments. Secondary flows have been speculated to exist in the expansion region after the nasal valve and an equation is derived to estimate the deposition caused by the secondary flows. The calculated deposition, due to direct impaction and secondary flows, shows general agreement with the experiment as to the predicted amount and location of deposited particles.     

Modified Spinning Top Homogeneous Spray Apparatus for Use in Experimental Respiratory Disease Studies

The May spinning top generator was adapted to a modified Henderson tube for producing large aerosol particles (>4 mum) to obtain almost exclusive upper respiratory tract deposition of infectious aerosols in exposed mice. The system was installed in a biological safety cabinet to permit experimentation with pathogens. A novel mechanism utilizing parts from a machinists micrometer and the mechanical stage from a light microscope was developed for the spinning top generator as a means for precisely positioning the liquid feed needle. Aerosol light-scatter properties were continuously analyzed to provide relative measures of particle size distribution and aerosol concentration. When mice were exposed to influenza virus aerosols in which none of the virus was contained in particles with aerodynamic diameters <4 mum, essentially all of the virus was deposited in the upper respiratory tract tissues.     

Protective and defensive airway reflexes in premature infants

The incidence of respiratory reactions to stimulation of the nasal and propharyngeal mucose was studied in 44 newborn premature infants. The inhalation of menthol fumes or the administration of drops of Mukoseptonex to the nasal mucosa caused transient respiratory arrest or a drop in the respiration rate. The heart rate rose during chemical stimulation of the nasal mucosa, possibly in association with a general arousal reaction. Mechanical stimulation of the nasal mucosal with a nylon fibre elicited an expulsive reaction in 95% of the cases. As distinct from experimental animals, sneezing was not preceded by a deep initial inspiration. Stimulation of the oropharyngeal region produced transient apnoea in 24.5% of the cases, in 18% expiratory reactions reminiscent of the expiration reflex, in 33% independent, intensive inspiratory reactions and in 24.5% cough. Cough from both the oropharyngeal and the laryngeal region had a pronounced inspiratory component. Independent inspiratory reactions may to some extent be co-responsible for the high incidence of aspirations in the neonatal period.     

Laminar airflow and nanoparticle or vapor deposition in a human nasal cavity model

The transport and deposition of nanoparticles, i.e., dp = 1-2 nm, or equivalent vapors, in the human nasal cavities is of interest to engineers, scientists, air-pollution regulators, and healthcare officials alike. Tiny ultrafine particles, i.e., dp < or = 5 nm, are of special interest because they are most rapidly absorbed and hence have an elevated toxic or therapeutic impact when compared to larger particles. Assuming transient laminar 3-D incompressible flow in a representative human nasal cavity, the cyclic airflow pattern as well as local and overall nanoparticle depositions were computationally simulated and analyzed. The focus was on transient effects during inhalation/exhalation as compared to the steady-state assumption typically invoked. Then, an equation for a matching steady-state inhalation flow rate was developed that generates the same deposition results as cyclic inhalation. Of special interest is the olfactory region where the narrow channel surfaces receive only about one-half of a percent of the inhaled nanoparticles because the airflow bypasses these recesses located in the superior-most portions in the geometrically complex nasal cavities.     

Lymphatic transport of orally administered drugs

Several therapeutic molecules such as lipophilic drugs and peptides suffer from the problems of low oral bioavailability. Improvement of their bioavailability and simultaneous prevention of the oral degradation of the prone molecules appears to be a challenge. Lymphatic system, which is responsible for the maintenance of fluid balance, immunity and metastatic spread of cancers, is also found to play a major role in the oral absorption of lipids and lipophilic drugs from intestine. The specialized structure of gut associated lymphoid tissue can be utilized as a gateway for the delivery of particulate systems containing drugs. Even though a large gap has existed in the field of lymphatic drug delivery, the introduction of a large number of lipophilic drugs and peptides has brought a renewed interest of research in this area. In this review, the mechanisms of intestinal lymphatic drug transport, approaches taken for the delivery of macromolecules, lipophilic and peptide drugs, biochemical barriers involved in intestinal drug absorption, and animal models used in the studies of intestinal lymphatic drug transport has been discussed.     

Raman characterization and chemical imaging of biocolloidal self-assemblies, drug delivery systems, and pulmonary inhalation aerosols: A review

This review presents an introduction to Raman scattering and describes the various Raman spectroscopy, Raman microscopy, and chemical imaging techniques that have demonstrated utility in biocolloidal self-assemblies, pharmaceutical drug delivery systems, and pulmonary research applications. Recent Raman applications to pharmaceutical aerosols in the context of pulmonary inhalation aerosol delivery are discussed. The "molecular fingerprint" insight that Raman applications provide includes molecular structure, drug-carrier/excipient interactions, intramolecular and intermolecular bonding, surface structure, surface and interfacial interactions, and the functional groups involved therein. The molecular, surface, and interfacial properties that Raman characterization can provide are particularly important in respirable pharmaceutical powders, as these particles possess a higher surface-area-to-volume ratio; hence, understanding the nature of these solid surfaces can enable their manipulation and tailoring for functionality at the nanometer level for targeted pulmonary delivery and deposition. Moreover, Raman mapping of aerosols at the micro- and nanometer level of resolution is achievable with new, sophisticated, commercially available Raman microspectroscopy techniques. This noninvasive, highly versatile analytical and imaging technique exhibits vast potential for in vitro and in vivo molecular investigations of pulmonary aerosol delivery, lung deposition, and pulmonary cellular drug uptake and disposition in unfixed living pulmonary cells.