MOTION OF AIR WITHIN THE HUMAN TRACHEOBRONCHIAL TREE

Knowledge of factors affecting the behavior and fate of inhaled particulate matter is of fundamental importance to the scientific disciplines of inhalation toxicology and aerosol therapy. Since particles are entrained and transported by airstreams, flow fields exert a great influence upon the deposition patterns of toxic substances and pharmacologic drugs within the human lung. In a series of independent works, ^1-3 Martonen et al. have documented the effects of distinct morphological features of airways upon lung fluid dynamics. Herein, those systematic investigations are integrated into a cohesive view of the motion of inhaled air. As a direct result, improved surrogates of the human lung can be developed. Specifically, it is established that the following elements must be included in future experimental and theoretical models describing airway conditions and particle dosimetry: laryngeal effects, cartilaginous rings and carinal ridges. If these factors are included such laboratory and mathematical models can become more physiologically realistic and be important components of future risk assessment and medical protocols.     

A review of co-milling techniques for the production of high dose dry powder inhaler formulation

Drug delivery by inhalation offers several advantages compared to other dosage forms, including rapid clinical onset, high bioavailability, and minimal systemic side effects. Drug delivery to the lung can be achieved as liquid suspensions or solutions in nebulizers and pressurized metered-dose inhalers (pMDI), or as dry powders in dry powder inhalers (DPIs). Compared to other delivery systems, DPIs are, in many cases, considered the most convenient as they are breath actuated and do not require the use of propellants. Currently, the delivery of low drug doses for the treatment of lung conditions such as asthma and chronic obstructive pulmonary disease are well established, with numerous commercial products available on the market. The delivery of low doses can be achieved from either standard carrier- or aggregate-based formulations, which are unsuitable in the delivery of high doses due to particle segregation associated with carrier active site saturation and the cohesiveness of micronized aggregates which have poor flow and de-agglomeration properties. High-dose delivery is required for the treatment of lung infection (i.e. antibiotics) and in the emerging application of drug delivery for the management of systemic conditions (i.e. diabetes). Therefore, there is a demand for new methods for production of high-dose dry powder formulations. This paper presents a review of co-mill processing, for the production of high-efficiency inhalation therapies, including the jet mill, mechanofusion, or ball mill methodologies. We investigate the different techniques, additives, and drugs studied, and impact on performance in DPI systems.     

The Janus faces of nanoparticles

There is an paradox apparent in the fact that nanoparticles have potential use in nanomedicine for imaging and therapy, whereas combustion-derived NP are thought to be responsible for adverse health effects of air pollution. The nanotechnology industry is in the process of producing a number of new nanoparticles which are as-yet unquantified with regard to both hazard and potential for human exposure. The toxicology of combustion-derived nanoparticles is developing and there is now considerable understanding of how they might drive both adverse lung and cardiovascular effects, including the importance of small size, large relative surface area and oxidative stress. Medicinal nanoparticles are being developed and tested on a case-by-case basis using testing protocols from biomaterials and drug safety and with regard to risk-benefit. There are considerable differences in physical and chemical properties and biodegradability between medicinal nanoparticles and the industrial and combustion-derived nanoparticles studied by particle toxicologists and we would anticipate that the bulk of medicinal NP types will be of low toxicity. However, to resolve the nanoparticle paradox there is a need to advance understanding of the characteristics that control acute and chronic toxicity, translocation, biodegradation and elimination of all of the types of particles likely to gain access to the human body. Much would be gained in this area by collaboration between particle toxicologists and nanopharmacologists.     

Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung Epithelium

Noninvasive aerosol inhalation is an established method of drug delivery to the lung, and remains a desirable route for nucleic‐acid‐based therapeutics. In vitro transcribed (IVT) mRNA has broad therapeutic applicability as it permits temporal and dose‐dependent control of encoded protein expression. Inhaled delivery of IVT‐mRNA has not yet been demonstrated and requires development of safe and effective materials. To meet this need, hyperbranched poly(beta amino esters) (hPBAEs) are synthesized to enable nanoformulation of stable and concentrated polyplexes suitable for inhalation. This strategy achieves uniform distribution of luciferase mRNA throughout all five lobes of the lung and produces 101.2 ng g^?1 of luciferase protein 24 h after inhalation of hPBAE polyplexes. Importantly, delivery is localized to the lung, and no luminescence is observed in other tissues. Furthermore, using an Ai14 reporter mouse model it is identified that 24.6% of the total lung epithelial cell population is transfected after a single dose. Repeat dosing of inhaled hPBAE‐mRNA generates consistent protein production in the lung, without local or systemic toxicity. The results indicate that nebulized delivery of IVT‐mRNA facilitated by hPBAE vectors may provide a clinically relevant delivery system to lung epithelium.     

DEVELOPMENT OF SURROGATE LUNG SYSTEMS WITH CONTROLLED THERMODYNAMIC ENVIRONMENTS TO STUDY HYGROSCOPIC PARTICLES: AIR POLLUTANTS AND PHARMACOLOGIC DRUGS

An objective of this text is to demonstrate advantages of interdisciplinary efforts, specifically, applications of engineering technology to health effects issues. The work describes the development of surrogate systems of the human lung for use in studies of hygroscopic growth kinetics and related deposition of inhaled particles. The models have become increasingly more physiologically realistic. Notable accomplishments are the successful simulations of in vivo environmental conditions, namely: (1)temperature and relative humidity atmospheres;(2)airstream profiles and thermodynamic processes; and,(3)lung morphology. Measurements of hygroscopic characteristics of a laboratory aerosol (NaCl) and bronchodilator drugs used in aerosol therapy were made using one of the models and are reported herein. The data clearly demonstrate the respective effects of respiratory tract geometry and particle chemical composition upon the behavior of inhaled substances. The surrogate lungs, offering unique research opportunities detailed within, are intended for experimental investigations that are complementary to inhalation exposures with human subjects.     

PREDICTING REGIONAL LUNG DOSAGES OF A NEBULIZED SUSPENSION: PULMICORT® (BUDESONIDE)

A method for estimating the regional lung dosages of a nebulized suspension is presented and applied to Pulmicort® & lpar;budesonide) suspension (4 ml, 0.5 mg/ml) nebulized with three Pari LC + nebulizers driven by a Pulmo-Aide compressor. The methodology combines experimental measurements of the nebulized aersol with a mathematical lung depositor model By adding medlylene blue as tracer for the water, cascade impaction with UV spectrophotometry is used to characterize the distribution of both budesonide and water in the inhaled droplets. Tidal breathing is simulated experimentally using a breath simulator to estimate the amount of inhaled drug. A valve system allows cascade impaction to occur at a constant flow rate of 28.3 l/min. while inhalation at 18 1/min. occurs through the nebulizer. Lung dosages (as % of inhaled dose) obtained with the methodology are in good agreement with values observed in vivo by previous researchers using pharmacokinetic methods with the LC+ nebulizer and the present budesonide formulation. Budesonide is found to be preferentially contained in the larger droplets, and calculated regional lung dosages show that an assumption of homogeneous distribution of the budesonide in the inhaled droplets is incorrect.     

Osmotically Controlled Oral Drug Delivery*

It is advantageous to deliver some drugs with short half-life, and which are to be given frequently for chronic ailments, in the form of controlled-release (CR) formulations. The orally administered drugs, in the form of conventional matrix or reservoir type formulations, pose problems of bioavailability fluctuations due to gastric pH variations. Moreover, the release of drug(s) from these systems is affected by the hydrodynamic conditions of the body. Osmotically controlled drug delivery systems utilize the principles of osmotic pressure for the controlled delivery of active agent(s). The release rate of drug(s) from these systems is independent of the physiological factors of the gastrointestinal (GI) tract to a large extent. In the present review, theory underlying the delivery of drugs from osmotic systems is presented. Different types of oral osmotic systems, their advantages over conventional matrix and reservoir types of systems, and their applications are also discussed. Finally, some of the limitations, adverse effects, and patent and market status of these systems are reviewed. These systems form a major segment of drug delivery products. Because of their advantages and strong market potential, it appears that the future of osmotic systems in rate-controlled oral drug delivery is promising.     

Osmotically controlled oral drug delivery

It is advantageous to deliver some drugs with short half-life, and which are to be given frequently for chronic ailments, in the form of controlled-release (CR) formulations. The orally administered drugs, in the form of conventional matrix or reservoir type formulations, pose problems of bioavailability fluctuations due to gastric pH variations. Moreover, the release of drug(s) from these systems is affected by the hydrodynamic conditions of the body. Osmotically controlled drug delivery systems utilize the principles of osmotic pressure for the controlled delivery of active agent(s). The release rate of drug(s) from these systems is independent of the physiological factors of the gastrointestinal (GI) tract to a large extent. In the present review, theory underlying the delivery of drugs from osmotic systems is presented. Different types of oral osmotic systems, their advantages over conventional matrix and reservoir types of systems, and their applications are also discussed. Finally, some of the limitations, adverse effects, and patent and market status of these systems are reviewed. These systems form a major segment of drug delivery products. Because of their advantages and strong market potential, it appears that the future of osmotic systems in rate-controlled oral drug delivery is promising.     

PREDICTING REGIONAL LUNG DOSAGES OF A NEBULIZED SUSPENSION: PULMICORT® (BUDESONIDE)

ABSTRACT

A method for estimating the regional lung dosages of a nebulized suspension is presented and applied to Pulmicort® & lpar;budesonide) suspension (4 ml, 0.5 mg/ml) nebulized with three Pari LC + nebulizers driven by a Pulmo-Aide compressor. The methodology combines experimental measurements of the nebulized aersol with a mathematical lung depositor model By adding medlylene blue as tracer for the water, cascade impaction with UV spectrophotometry is used to characterize the distribution of both budesonide and water in the inhaled droplets. Tidal breathing is simulated experimentally using a breath simulator to estimate the amount of inhaled drug. A valve system allows cascade impaction to occur at a constant flow rate of 28.3 l/min. while inhalation at 18 1/min. occurs through the nebulizer. Lung dosages (as % of inhaled dose) obtained with the methodology are in good agreement with values observed in vivo by previous researchers using pharmacokinetic methods with the LC+ nebulizer and the present budesonide formulation. Budesonide is found to be preferentially contained in the larger droplets, and calculated regional lung dosages show that an assumption of homogeneous distribution of the budesonide in the inhaled droplets is incorrect.     

LUNG CANCER IN RATS FROM PROLONGED EXPOSURE TO HIGH CONCENTRATIONS OF CARBONACEOUS PARTICLES: IMPLICATIONS FOR HUMAN RISK ASSESSMENT

High incidences of lung cancers have been observed in a number of studies in which rats were chronically exposed by inhalation to high concentrations of diesel engine exhaust and carbon black particles. These particles have previously been viewed as being relatively innocuous compared with other particles such as benzo[a]pyrene that are carcinogenic because of specific chemical properties. Studies with mice and Syrian hamsters exposed to similar concentrations of diesel exhaust did not produce an excess of lung cancer or yielded equivocal outcomes. Diesel exhaust soot and carbon black particles are readily inhaled and deposited in the pulmonary region, where they are retained with a long half-life because of their low solubility. Substantial evidence indicates that the increased incidence of rat lung cancers results from the accumulation of large burdens of particles in the lungs, altered clearance of particles from the lungs, persistent inflammation, increased cell turnover, and induction of mutations in lung epithelial cells. The mutations and subsequent tumors are hypothesized to occur as a result of persistent inflammation and increased cell turnover rather than as a result of direct interaction of chemical constituents of the particles with DNA of lung cells. The observed effects in rats appear to be threshold phenomena that occur only with prolonged exposure to high concentrations of particles. Thus the rat lung cancer findings at high concentrations should not be extrapolated to low concentrations using the linearized multistage model typically used as a default assumption for assessing (he cancer risk of chemicals. This article reviews past approaches to evaluating the carcinogenic risk of diesel exhaust and carbon black and suggests alternative approaches to characterizing their human cancer risk.     

Promising opportunities and potential risk of nanoparticle on the society

The ever‐promising opportunities and the uses of NP in our life are increasing but their present and future potential risks on the animals, plants and microorganisms are not well discussed elsewhere. In this review, the authors have systematically discussed the toxic effect of the uses of NP on animals, plants and microorganisms including human health. They have also discussed about the bioaccumulation of these NP in the food chain. Finally, they have provided some possible suggestions for the uses of NP to reduce the detrimental effect on the environment.Inspec keywords: nanoparticles, health and safety, toxicology, microorganismsOther keywords: ever‐promising opportunities, plants, microorganisms, toxic effect, human health, nanoparticle, food chain, bioaccumulation     

Investigations on pharmacokinetics and biodistribution of polymeric and solid lipid nanoparticulate systems of atypical antipsychotic drug: effect of material used and surface modification

The present study focuses on the effect of material used for the preparation of nanoparticulate (NP) systems and surface modification on the pharmacokinetics and biodistribution of atypical antipsychotic, olanzapine (OLN). NP carriers of OLN were prepared from two different materials such as polymer (polycaprolactone) and solid lipid (Glyceryl monostearate). These systems were further surface modified with surfactant, Polysorbate 80 and studied for pharmacokinetics–biodistribution in Wistar rats using in-house developed bioanalytical methods. The pharmacokinetics and biodistribution studies resulted in a modified and varied distribution of NP systems with higher area under curve (AUC) values along with prolonged residence time of OLN in the rat blood circulation. The distribution of OLN to the brain was significantly enhanced with surfactant surface-modified NP systems, followed by nonsurface-modified NP formulations as compared with pure OLN solution. Biodistribution study demonstrated a low uptake of obtained NP systems by kidney and heart, thereby decreasing the nephrotoxicity and adverse cardiovascular effects. By coating the NP with surfactant, uptake of macrophage was found to be reduced. Thus, our studies confirmed that the biodistribution OLN could be modified effectively by incorporating in NP drug delivery systems prepared from different materials and surface modifications. A judicious selection of materials used for the preparation of delivery carriers and surface modifications would help to design a most efficient drug delivery system with better therapeutic efficacy.     

Aging effects on airflow distribution and micron-particle transport and deposition in a human lung using CFD-DPM approach

Understanding the transportation and deposition (TD) of inhaled aerosol particles in human lung airways is important for health risk assessment and therapeutic efficiency of targeted drug delivery. The particle TD into a human lung depends on lung anatomy, breathing pattern, as well as particle properties. The breathing capacity and lung airway diameters can be reduced by about 10% every 10 years after the age of 50. However, the age-specific particle TD in human lungs, particularly in the aged, has not been well understood in literature. This study investigates the particle TD in the lungs of people aged 50–70 years, using computational fluid dynamics (CFD). A new cutting method that splits the lung model into different sections has been developed as a feasible CFD method to simulate the particle TD in G0 to G14 lung airways. The inhalation of micron scale particles with three diameters (5 μm, 10 μm and 20 μm) and a constant air flow rate in inhalation is considered. It is found that different sized particles are deposited in different generation airways. Nearly 100% of 20 μm particles are deposited in the upper lung airways (G0-G5) and no particles pass through G7. Particles can go into deeper airways as their diameter decreases. When the particle size is decreased to 5 μm, over 48% of particles can pass through G14 and enter the deeper lung airways. An increase in age causes more particles to deposit in the upper airway and fewer particles to enter the deeper airways.     

Multimodal Precision Imaging of Pulmonary Nanoparticle Delivery in Mice: Dynamics of Application,Spatial Distribution,and Dosimetry

Targeted delivery of nanomedicine/nanoparticles (NM/NPs) to the site of disease (e.g., the tumor or lung injury) is of vital importance for improved therapeutic efficacy. Multimodal imaging platforms provide powerful tools for monitoring delivery and tissue distribution of drugs and NM/NPs. This study introduces a preclinical imaging platform combining X‐ray (two modes) and fluorescence imaging (three modes) techniques for time‐resolved in vivo and spatially resolved ex vivo visualization of mouse lungs during pulmonary NP delivery. Liquid mixtures of iodine (contrast agent for X‐ray) and/or (nano)particles (X‐ray absorbing and/or fluorescent) are delivered to different regions of the lung via intratracheal instillation, nasal aspiration, and ventilator‐assisted aerosol inhalation. It is demonstrated that in vivo propagation‐based phase‐contrast X‐ray imaging elucidates the dynamic process of pulmonary NP delivery, while ex vivo fluorescence imaging (e.g., tissue‐cleared light sheet fluorescence microscopy) reveals the quantitative 3D drug/particle distribution throughout the entire lung with cellular resolution. The novel and complementary information from this imaging platform unveils the dynamics and mechanisms of pulmonary NM/NP delivery and deposition for each of the delivery routes, which provides guidance on optimizing pulmonary delivery techniques and novel‐designed NM for targeting and efficacy.     

Biocompatibility, efficacy and biodistribution of Gelucire-stabilized nanoparticles engineered for docetaxel delivery

Docetaxel is a potent anticancer agent that will benefit greatly from alternative delivery systems that can overcome several reported adverse effects due to the drug itself and/or the solvent system in the current clinical formulation. In this regard, a new nanoparticle delivery system for docetaxel was prepared from Gelucire-based nanoemulsions by using binary mixtures of Gelucire 44/14 and cetyl alcohol as NP matrix materials. Various amounts of docetaxel (50-1000 microg/ml) were added to the oil phase of the nanoemulsions prior to obtaining solid nanoparticles. The nanoparticles (100-140 nm) achieved high entrapment efficiency (> or = 89%) of docetaxel which was maintained upon storage at 4 degrees C and 25 degrees C. Additional data indicated the Gelucire component in NP played influential roles in drug release possibly by facilitating diffusion from NPs and/or accelerating erosion of NP matrix. Docetaxel-loaded nanoparticles did not cause any significant red blood cell lysis or platelet aggregation nor activate macrophages. Also in-vitro antitumor efficacy in human lung adenocarcinoma cells was demonstrated based on cell cytotoxicity, production of reactive oxygen species and reduction of mitochondrial potential. Enhancement of in-vitro antitumor effects of docetaxel with Gelucire-based NPs could be ascribed to improved particle dispersion and efficient cell permeability. Studies in BALB/c mice demonstrated the stability/retention of NPs in blood circulation and the potential in facilitating docetaxel absorption across the peritoneal cavity. The nanoparticles reported herein may be effective as novel biocompatible and effective delivery systems for docetaxel.     

Uncertainty in particulate deposition for 1 microm AMAD particles in an adult lung model

The ICRP 66 lung model may be used to determine dose estimates for members of the public via the inhalation pathway. A significant source of uncertainty in internal dosimetric modelling is due to particulate deposition in regions of the respiratory tract. Uncertainties in estimates of particulate deposition are present because model input parameters have their own inherent variability. These sources of uncertainty need to be examined in an effort to understand better model processes and to estimate better the doses received by individuals exposed through the inhalation pathway. An improved understanding of the uncertainty in particulate deposition will further guide research efforts and improve our ability to quantify internal dose estimates. The ICRP 66 lung deposition model is most sensitive to breathing rate when 1 microm AMAD particles are inhaled by members of the public. Uncertainties in deposition fractions are shown to span an order of magnitude with their distributions varying by gender for a particular lung region. The largest fractional deposition occurs in the deep lung alveolar and extrathoracic regions.     

Methods for reduction of cohesive forces between carrier and drug in DPI formulation

Dry powder inhaler (DPI) has become a well accepted drug delivery for pulmonary system to treat many related diseases including symptomatic and life threatening diseases. Successful delivery of dry powder to the lung requires careful consideration of powder production process, formulation and inhaler device. The formulation of DPI mostly comprises of lactose as a carrier for drug delivery. In DPI formulation, particulate interactions within the formulation govern both the drug dissociation from carrier particles and the disaggregation of drug into primary particles with a capacity to penetrate deep into lung. Two contradictory requirements must be fulfilled for this type of dry powder formulation. On one hand, adhesion between carrier and drug must be sufficient for the blend drug/carrier to be stable. On the other hand, adhesion drug/carrier has to be weak enough to enable the release of drug from carrier during patient inhalation. Thus the carrier use restricted due to detachment problem. Different methods are proposed to reduce the cohesive forces between drug and carrier to desired level. Various studies conducted for understanding the mechanism of deposition into lungs and making formulation with optimum carrier drug cohesive force. This review provides information on various processes involved in reducing the cohesive forces between drug and carrier, to a required level.     

In Vitro and in Vivo Deposition of Drug Particles Inhaled from Pressurized Aerosol and Dry Powder Inhaler

Abstract

Disodium cromoglycate particles were labelled with a pure ζ-radiator ^99mTc using a novel co-precipitation technique based on spray drying. Metered dose aerosols as well as a dry powder dosage form were prepared using these labelled drug particles. Fractional deposition of the drug particles was determined in vivo by means of gamma camera. Inhalation patterns of seven healthy volunteers were compared to deposition patterns evaluated in vitro using a modified cascade impactor. On average only 9 per cent of the aerosol dose deposited in a whole lung area and about 81 per cent in the upper airways of the volunteers. The in vitro results showed clearly greater deposition of the drug particles into the imitated bronchial and alveolar stages. The physiological factors of the human respiratory tract as well as the individual differences in the inhalation techniques seemed to have a significant influence to the deposition and aerodynamic behaviour of the inhaled drug particles. The in vitro results indicated, however, the similar differences between the two inhalation dosage forms as the in vivo evaluation did.     

Immunological properties of engineered nanomaterials

Most research on the toxicology of nanomaterials has focused on the effects of nanoparticles that enter the body accidentally. There has been much less research on the toxicology of nanoparticles that are used for biomedical applications, such as drug delivery or imaging, in which the nanoparticles are deliberately placed in the body. Moreover, there are no harmonized standards for assessing the toxicity of nanoparticles to the immune system (immunotoxicity). Here we review recent research on immunotoxicity, along with data on a range of nanotechnology-based drugs that are at different stages in the approval process. Research shows that nanoparticles can stimulate and/or suppress the immune responses, and that their compatibility with the immune system is largely determined by their surface chemistry. Modifying these factors can significantly reduce the immunotoxicity of nanoparticles and make them useful platforms for drug delivery.