The inhalation route, employed primarily for drugs acting in the respiratory tract, is now being extended for systemic macromolecule delivery. Despite the long-term use of inhalation technologies for therapeutic purposes, there still is room for improvement in a number of areas, including deposition efficiency, targeting, and sustained release for inhaled drugs. These challenges can be addressed in part by particle and device engineering for inhalation delivery. Currently, several novel particle engineering methods, such as spray freeze drying into liquids, supercritical fluid technology, and crystal engineering, are being developed to overcome the limitations of the conventional methods of spray drying and jet milling. Different engineered particles, such as amorphous glass particles for protein stabilization, spray-dried oligosaccharides and large porous particles for sustained delivery, and nanocrystals for improved cellular penetration, are being developed. New dry powder and liquid aerosol inhalation devices, such as the Nektar DPI system, AERx® (Aradigm), Spiros® (Dura Pharmaceuticals), and the Respimat® (Boehringer Ingelheim) are improving the deposition efficiency, ease of use, or dose reproducibility.

INTRODUCTION

Inhalation drug therapy has been used to treat respiratory conditions, such as asthma, cystic fibrosis, and obstructive lung disorders for several years. Other airway diseases, which may benefit from inhalation drug delivery, are bronchiectasis, pulmonary and bronchial infections, and ventilator-associated infections, such as pneumonia and sinusitis. Inhalation drug therapy allows direct delivery of medication to treat airway disorders, thereby reducing the dose of drugs, such as beclomethasone, by about 100-fold compared to their systemic dose.¹

While inhalation delivery permits better exposure of the drug to the respiratory tissues, drugs can readily diffuse into the systemic circulation due to the presence of a large absorptive alveolar surface (> 80 m2) with a thin epithelial lining.^2,3 In addition, epithelial surfaces of the lung express several receptors, some of which facilitate the transport of macromolecules and small hydrophilic drugs.⁴Indeed, many macromolecules are well absorbed from the lungs into the bloodstream, even in the absence of penetration enhancers. Leuprolide administered by inhalation has a bioavailability of 40%, which is much more than that observed with other non-invasive routes.⁵ Also, other peptides, including calcitonin, parathyroid hormone, and cetrorelix, have bioavailabilities of 28%, 30%, and 65%, respectively, when administered by the pulmonary route.^6-8 Thus, the lung is a promising portal for the systemic delivery of peptides, proteins, and other macromolecules.

Particle size of the inhaled powder or droplet or aerosol (used interchangeably in this manuscript) is a key factor determining the dosing efficiency, drug deposition in various regions, and the systemic absorption.⁹ Efficient delivery of drugs to the deep lungs, necessitates, amongst other factors, that aerosol particles are small enough to pass through the mouth, throat, and conducting airways and deposit in the deep lung, but not so small that they are exhaled out. Aerosol particle size is often expressed in terms of mass median aerodynamic diameter (MMAD), a parameter that is based on particle size, shape, and density.¹⁰ For a spherical particle, MMAD is equal to MMD (p^1/2), in which MMD is mass median diameter and r is the bulk density. For a non-spherical particle, MMAD is equal to MMD (p/x)^1/2, in which X is the shape factor. Thus, particles with larger than unit density will have actual diameters smaller than their MMAD and vice versa. The site of particle deposition within the lungs is clearly demarcated based on particle size. The upper airways (nose, mouth, larynx, and pharynx) and the branched anatomy of the tracheobronchial tree act as a series of filters for inhaled particles.¹⁰ Thus, aerosol particles with MMAD > 100 mm are trapped in the naso/oropharynx and generally do not enter the respiratory tract. Particles with MMAD > 10 mm come into contact with the upper respiratory tract (above trachea) and are eliminated quickly by mucociliary clearance. Particles with MMAD in the size range of 5 to10 mm are deposited in the large ciliated airways, and only particles having an MMAD in the size range of 1 to 5 mm reach the alveolar space.¹¹ On the other hand, particles < 1 mm can enter deep lungs but have a high tendency to be exhaled. Inspiratory flow rate is also critical for targeting the alveoli, with slow, deep inhalation favoring particle deposition in the deep lungs. Other considerations for efficient lung delivery include stabilization of the drugs, especially macromolecules, and the amenability of the powder to be dispersed into a fine aerosol. Thus, an ideal inhalation formulation would contain particles of a size range and composition acceptable for entrainment, lung deposition, and drug stabilization.

The goal of particle engineering is to incorporate desirable attributes, such as narrow size distribution, enhanced protein stability, improved dispersability, sustained release, or enhanced targeting, into the particles.¹² Some of these attributes can be introduced either through the use of novel excipients that are safe or by insightful control of particle characteristics, such as surface charge, size, shape, roughness, density, microviscosity, and surface energy. Engineered particles may be dispensed either in a liquid form, with specially designed devices, or as solid particles that have drug and excipients with desired shape, size, porosity, and drug-release characteristics.¹³ Particle engineering may be used to modulate release in the lungs, target certain areas in the lungs, avoid or elicit macrophage uptake, increase particle mass inhaled per breath, increase epithelial permeability and drug absorption, and improve therapeutic action.

CHALLENGES IN INHALATION DRUG DELIVERY

Efficiency of Deposition: Powder Entrainment, Dispersion & Deposition A primary challenge in inhalation drug delivery has been the inability to administer uniform doses from different devices. While this may be inconsequential with drugs that are not very potent and have large therapeutic indices, with potent macromolecules, it is very critical to control the doses. With different systems, there are different limitations, which result in dosing discrepancies. For instance, with dry powders consisting of micro- or nano-sized particles, the particles are adhesive, cohesive, and difficult to disperse, leading to highly variable dosing and poor aerosol performance.¹⁴ Dispersion requires the powder to overcome the inter-particulate forces binding the particles in bulk powder, and to become entrained as single particles in the inhaled airstreams. This problem can be overcome by device engineering wherein additional energy is provided to pre-aerosolize and enhance aerosolization or by particle engineering, which would allow the use of simple devices for effective drug delivery.

Targeting
Deposition site and pattern of inhaled drugs influence both the therapeutic effect and the occurrence of adverse events. While the drugs intended for systemic delivery benefit from alveolar deposition, the intended target site for some drugs, such as beta-blockers and corticosteroids intended for local action, is unclear. For instance, in patients with asthma, the eosinophilic inflammatory process is located widespread through the large and small airways. However, recent evidence indicates that inflammation is also present in the alveoli.^15,16 In addition to the location of the disease, the location of the adrenergic, cholinergic, and gluococorticoid receptors are also of importance. b2 receptors are located in both the large and small airways and alveoli. However, the main effect of inhaled b2 sympathomimetic agents is exerted in the compartments where smooth muscles are present, ie, in the upper airways. Thus, inhalation of a b2-agonist with a low MMAD would not be expected to result in improved efficacy compared to a b2-agonist with a larger MMAD.¹⁷ The same would be the case with cholinergic receptors as they have preponderance in the proximal airways. Interestingly, glucocorticoid receptors are ubiquitous in the airways and alveoli but have the highest concentration in the alveoli.¹⁸ Therefore, it is believed that administration of inhaled corticosteroids into the alveolar region may be clinically advantageous. Indeed, it was shown that HFA 134a-beclomethasone with a MMAD of 1.1 mm had a similar clinical effect as a 2 to 2.5 times higher dose of CFC-beclomethasone dipropionate with a MMAD of 3.5 mm.¹⁹ In some disease cases such as in cystic fibrosis patients, drug particles need to reach the bronchioles, where the disease process usually begins.²⁰ Also, for drugs intended for systemic action, the rate and extent of absorption from various regions of the lungs into the bloodstream is not completely understood. Most of the research has pointed toward particle properties being the primary determinant in the regional deposition within the lung.²¹ However, other patient-related factors, including breathing patterns of a patient, pathological conditions in the lung, and device-related factors, may also influence targeting. Indeed, in patients with constricted airways or obstructive lung diseases, the deposition of particles is mostly in the central airways. This does not allow for the efficient absorption of drugs intended for systemic delivery.²² Breath pattern, breath frequency, and volume inhaled also affect the site of deposition of aerosols. Breathing at low flow rate (< 20 L/min-1), breath holding for 5 to 10 seconds on completion of inhalation, and increasing the inhaled volume by deep breathing seem to provide extra residence time for particles in the alveoli, especially those with a diameter close to 0.5 mm, which are known to sediment in the alveolar region.^23,24 Attempts have been made to improve lung deposition of drugs by using devices with spacers that take the propellant droplets through a longer path, allowing evaporation. However, optimal lung deposition is only 20% as many large droplets, which would otherwise be deposited in the oropharynx, are retained within the spacers.²⁵

Sustained Delivery
Another challenge in the respiratory delivery of molecules is overcoming the clearance mechanisms in the lungs.11 This challenge becomes more important for chronically administered drugs, which require sustained-release systems, typically drug-polymer composite particles. Multiple particle clearance mechanisms exist within the lung, and these exhibit regional variation.²⁶ In the upper airways, the mucociliary escalator efficiently clears particles whereas macrophages in the lower airways scavenge particles and shorten drug action. Alveolar macrophages can clear particles from the alveolar region in four ways: 1) transport along the alveolar surface to the mucociliary escalator; 2) internal enzymatic degradation; 3) translocation to the tracheobronchial lymph; and/or 4) clearance by a combination of the interstitial lymphatic system and mucociliary transport.^27,28 Thus, development of useful sustained-release formulations for use in the respiratory tract presents additional challenges because apart from controlling drug release in the lung environment, the drug particles need to avoid removal by the lung clearance mechanisms for the period of drug delivery.^29,30

Another issue that may be more relevant to macromolecules administered by inhalation but not necessarily confined to them is the degradation of molecules in the lung. The enzymatic degradation within the lungs, although less severe compared to the gastrointestinal tract, represents an important metabolic barrier limiting the absorption of drugs through the lungs.³¹ Some therapeutic peptides that are degraded in the lungs are salmon calcitonin, vasoactive intestinal peptide, Substance P, Met- and Leu-Enkephalin, and leutinizing hormone releasing hormone (LHRH) and its analogs.^32,35 Figure 1 shows the barriers to macromolecule absorption and sustained delivery in the respiratory tract.

Most of the challenges mentioned previously can be addressed in part by particle engineering approaches. Some of the limitations can be overcome by device engineering. Table 1 summarizes the different types of engineered particles prepared for inhalation delivery and the unique advantages of each of these particles.

PARTICLE ENGINEERING FOR IMPROVING INHALATION DELIVERY

Many academic and industrial laboratories have sought to improve aerosol delivery efficiency by modifying particle properties, such as particles size, porosity, surface roughness, and elongation ratios.

Emulsion Solvent Evaporation
Modified emulsion solvent evaporation methods have been used for the preparation of porous particles with low bulk densities.³⁶ For instance, large-porous poly(lactic-co-glycolic) acid microparticles were prepared by emulsifying an aqueous bovine serum albumin solution with polymer solution in methylene chloride. The mass-mean size of the particles was 9.9 mm with a geometric standard deviation (GSD) of 1.4 mm, and the bulk density was 0.43 g/cc. Also, PLGA particles encapsulating insulin and testosterone were prepared using emulsion solvent evaporation methods.³⁷

Spray Drying
Spray drying with different excipients has been the most widely used method to prepare porous particles. Large porous albuterol sulfate particles were prepared by spray drying a cosolvent aqueous solution (85% ethanol) containing a combination of human serum albumin (18%), lactose (18%), dipalmitoyl phosphatidylcholine (DPPC, 60%), and albuterol sulfate.³⁸ Also, dry-powder porous particles of insulin and immunoglobulin with high aerosolization efficiency have been produced using spray drying.^38,39 The large porous particle structure was obtained by spray drying at conditions that produced a thin-walled hollow-particle structure that collapsed during drying to yield crumpled-paper type particles. In an interesting study, Vanbever et al evaluated the effects of powder composition, solution properties, and spray drying parameters on the geometrical properties of the spray dried powders.⁴⁰ Powder composition substantially affected particle size, density, and morphology. DPPC concentration had an important impact on particle size, density, and shape. With increasing DPPC concentration, there was an increase in geometric diameter, decrease in density, and the particle morphology was transformed from toroidal (zero to 30% DPPC) to sponge-like (60% DPPC) to spherical (90% DPPC). In general, inclusion of lactose resulted in smaller and heavier particles, while albumin inclusion formed larger particles with low density.

A two-step process consisting of emulsification followed by spray drying has also been used to prepare different engineered particles, including lipid-based vaccine microparticles containing inactivated influenza virus. Initially, a fluorocarbon-in-water emulsion stabilized with saturated phosphatidylcholine was prepared and used as a feed solution for spray drying. Hydrophilic agents, such as the immune-active compounds and hydroxyethyl starch (HES) were added in aqueous solution just before spray drying. Typically, the size of the particles was between 1 to 5 mm and the density <= 0.2 g/cm3. This method has additional advantages over the spray drying and emulsion solvent evaporation methods as it allows for higher encapsulation efficiencies and the rapid escape of fluorocarbon allows for the preparation of highly porous structures with low aerodynamic diameters suitable for inhalation.⁴¹

The disadvantage with spray drying is that the high temperatures used can degrade macromolecules, and some polymers cannot be spray dried to form particles suitable for lung delivery. Also, some concerns remain with respect to a change induced in the solid-state characteristics of spray-dried products, particularly crystallinity.

Spray Freezing Into Liquid
Spray freezing into liquid has been introduced with an aim to overcome some of the limitations of spray drying. Spray freezing into liquid (SFL) is a novel particle engineering technology in which a feed solution containing an active pharmaceutical ingredient (API) and pharmaceutical excipients is atomized beneath the surface of a cryogenic liquid, such as liquid nitrogen.⁴² The impingement of the feed solution onto the cryogenic liquid results in intense atomization of the feed solution into micro-droplets, which freeze instantly in the cryogenic phase. The microparticles are suspended in the continuous cryogenic phase and can be separated by sieving or evaporation of the cryogen. When the frozen microparticles are collected, the solvent can be removed by lyophilization. The size as well as porosity of the microparticles produced by the process is dependent upon the processing parameters, such as the velocity of the spray, the diameter of the nozzle orifice, and the temperature and flow rate of the cryogenic liquid.⁴³ Other physicochemical properties, such as crystallinity and encapsulation efficiency, are also influenced by the processing conditions. SFL has been used to prepare porous microparticles of insulin, albuterol sulfate-PEG particles, and to enhance the dissolution rates of poorly soluble drugs, such as danazol and carbamazepine.⁴⁴

Crystallization
Particles for inhalation are rarely used directly after crystallization. Generally, the crystals are allowed to grow to maturity in a crystallization medium, and the resulting crystals are harvested by filtration, followed by drying and subsequent processing by high-energy milling to produce micron-sized drug particles. This processing can cause disruption of the crystal structure and creation of amorphous domains, resulting in products, which are highly charged, cohesive, and difficult to process.⁴⁵ Some of these problems are being overcome by crystal engineering. Crystal engineering of drugs and carriers can play a significant role in the formulation of engineered particles for dry powder inhalation aerosols. For instance, increasing the surface smoothness of lactose carriers by means of crystal engineering has been reported to increase the percentage of fine particle fraction of salbutamol sulphate aerosol.⁴⁶ Also, increasing the elongation ratio of the lactose carrier increased the fine particle fraction and dispersability of salbutamol sulfate after aerosolization of the formulations from both the Rotahaler® and the Cyclohaler®.⁴⁷ Crystal engineering is possible by restricting or modulating nucleation and crystal growth by judicious additions to the crytallisation mediums. For example, the facial growth rates of the adipic acid crystals were reduced by the presence of both anionic and cationic surfactants. An anionic agent (sodium tetrapropyl benzene sulphonate) caused the production of needle-like particles, whereas a cationic surfactant (trimethyl dodecyl ammonium chloride) led to the formation of thin plates or flakes. In the field of aerosol science, the use of elongated particles has attracted interest. Fibers and needle-like crystals have aerodynamic diameters almost independent of their length, and the diameter is approximately equal to the shortest dimension of the particle in question. Using crystal engineering, Larhrib et al formed needle-shaped salbutamol and lactose crystals with lengths less than < 6 mm and a width between 0.5 and 1 mm.⁴⁸ These elongated particles exhibited improved in vitro deposition, suggesting their better utility for deep lung delivery.⁴⁸

Supercritical Fluid Technology
The conventional methods of engineered particle preparation described previously are useful for small molecules, such as budesonide.⁴⁹ However, a number of restrictions apply for large molecules. For instance, the high temperatures used in spray drying can degrade macromolecules. Indeed, spray drying of insulin resulted in a 40% loss in bioactivity and conformational changes from a-helix to the inactive b-sheet structure.⁵⁰ Although spray freeze-drying aims to overcome some of these limitations and is useful for the production of large porous particles with aerodynamic diameters suitable for deep lung delivery, bovine serum albumin exhibited a substantial degradation and loss of activity upon spray freeze-drying. In addition, aggregation was observed with trypsinogen processed using this method.⁵¹ Also, the residual methylene chloride associated with particles prepared by these processes was 3000 to 30000 ppm, which is above the USP limit (500 ppm) for these solvents.⁵² Furthermore, current crystallization practice albeit vastly improved, has continuing challenges in particle formation, process control, and scale-up. Also, it has limited scope for particle engineering and design; therefore, new approaches are being developed. To overcome some of these disadvantages, supercritical fluid (SCF) derived processes are also being explored for the preparation of delivery systems. SCFs are substances that, at temperature and pressure above their critical points (Tc and Pc respectively), exist as a single phase with several advantageous properties of both liquids and gases. SCFs have liquid-like densities and hence, solvating characteristics that are similar to those of liquids, yet have mass transfer properties similar to gases. In recent years, interest in SCF methods for engineering drug particles with well-defined crystallographic, chemical, and physical properties has grown. Indeed, various materials ranging from inorganic and organic small molecular weight drugs to proteins and polymers as well as drug-excipient co-formulations have been processed successfully, with narrow size distributions, controlled solid-state properties, and high-purity and low-residual solvent levels. Furthermore, SCFs have also been used to produce irregular shaped, porous particles for drug delivery to the lungs.⁵³

Recently, an environmentally benign SCF technology-based process using SC CO has been developed to engineer large porous polymeric-microparticles of deslorelin, a peptide drug, for inhalation.⁵⁴ The process involved exposure of microparticles prepared using an emulsion solvent-evaporation method to SCF conditions. Upon SC CO treatment (1200 psi, 33 ?C for 30 minutes), the particle size of the deslorelin PLGA 50:50 microparticles increased from 2.2 to 13.8 µm, the porosity increased from 39% to 92.38%, the mean pore diameter increased from 90 to 190 nm, and the bulk density reduced from 0.7 to 0.082 g/cc. Mass spectroscopy and circular dichroism studies indicated that the deslorelin integrity (primary and secondary structure) was unaffected. In addition, SC CO has a high affinity for organic solvents and enables their removal from drug delivery systems. Therefore, the residual solvent content was reduced from 4500 ppm to below detection limit (< 25 ppm).

PARTICLE ENGINEERING FOR SUSATINED DELIVERY FOLLOWING INHALATION

Particle engineering to achieve sustained drug release in the lungs has involved strategies similar to other parts of the body, including encapsulation within a polymeric matrix, coating drug particles with an insoluble material (eg, polymeric substance), embedding the drug in a lipid matrix, and complexing the drug to large molecular weight, slowly absorbing molecules. However, modulating the release of drug from aerosol particles is only one aspect of achieving sustained drug action in the lungs. Without a means to avoid the rapid natural clearance of particles from the lungs, sustained-release drug particles release only a fraction of drug prior to clearance either by the mucociliary escalator or by alveolar macrophages in the deep lungs.29 Large porous particles, characterized by large geometric diameters (~10-20 mm) and low bulk densities (< 0.4 g/cc), yielding aerodynamic diameters of ~ 1-5 mm for optimal lung deposition, have received special attention in this regard as they possess the potential of avoiding alveolar macrophage clearance due to their large geometric size. This enables the use of large porous particles for sustained drug release in the lungs.³⁷ Indeed, in vitro studies with large-porous PLGA particles of deslorelin, a peptide drug, indicated that the uptake of deslorelin from these particles into respiratory epithelial cells (Calu-3 and A549) and rat alveolar macrophages was decreased by 87%, 91%, and 50% respectively, compared to conventional small non- porous particles, suggesting the ability of these particles to avoid macrophage uptake and sustain lung delivery.⁵⁴ Furthermore, in vivo studies in rats indicated that following intratracheal administration, these large porous particles sustained systemic delivery better than small conventional particles up to 7 days, according to Koushik et al in a personal communication. Table 2 summarizes the different large-porous particles prepared thus far for sustained local/systemic delivery in the lungs.

Although sustained drug delivery through the deep lungs seems to be an attractive therapeutic option, and large porous particles seem to offer a means to achieve this goal, a number of concerns still exist. The possibility of immune reactions to proteins and peptides delivered over long periods to the lung is a safety issue. Also, introduction of excipients, such as polymers, lipids, and ester derivatives in high quantities into the lungs, can be toxic or immunogenic and may accumulate in the lungs with a number of harmful consequences. What is a GRAS substance for other routes may not be safe for the lungs. This is another challenge that must be overcome by particulate systems in addition to lung clearance mechanisms.

DEVICE ENGINEERING FOR IMPROVING INHALATION DELIVERY

The early aerosol delivery devices have been relatively inefficient, wasteful, or difficult to use. For example, with the early passive dry powder inhalers, such as the Turbuhaler® (AstraZeneca) or the Rotahaler® (GlaxoSmithKline) the requirement to inspire vigorously to add enough energy to obtain an optimal drug dose was a major limitation.⁵⁵ The pMDI requires synchronization of actuation and inhalation to achieve successful lung deposition, and drug delivery is only 5% to 20% of the label dose, even with good technique. Also, some of these devices have a poor precision, resulting in high intra-subject and inter-subject variability.⁵⁶ Jet and ultrasonic nebulizers waste drug by having large dead volumes, by nebulizing during exhalation, and by forming polydisperse aerosols that have a high percentage of droplets that are too large to reach the lungs.⁵⁷

To address some of these issues, many companies have engineered innovative aerosol devices. The basic strategy in device engineering has been to combine standard pharmaceutical technology with sophisticated inhaler devices that produced a fine aerosol of roughly 1 to 5 mm-sized particles dependably. Also, in order to increase the efficiency and dose reproducibility of dry powder inhalers, the new devices incorporate patient independent energy sources. Examples of such systems include the Nektar and the 3M delivery devices, which are pneumatic systems.

In the Nektar system, the dry insulin particles are placed in individual blisters that could be loaded into an inhaler whose energy source resembled an air gun. The inhaler, "shoots" the powder into a standing cloud in a transparent chamber, and then the standing insulin-particle cloud is inhaled through a slow deep breath.⁵⁸ Powder dispersion and inspiration control are accomplished by the TransJector^TM, a small (3.2 x 2.6 x 2.6 cm) flow-amplifier component driven by a charge of about 10 mg of pressurized air. The sudden sonic discharge of this mass of air through small jets in the TransJector is responsible for the extraction, de-agglomeration, and dispersion of the powder. This event occurs within 80 milliseconds. More than 90% (by mass) of the particles in the aerosol extracted from the chamber have aerodynamic particle diameters less than 5 microns, and a high fraction of the starting mass is delivered.

Dura Pharmaceuticals, Inc., has a proprietary Spiros pulmonary delivery technology, which uses electro-mechanical energy to disperse powders. The device has a breath-actuated switch that turns on a battery-operated motor. The motor spins an impeller, which whips the powdered drug into an aerosolized cloud that is inhaled by the patient. Because the energy required to aerosolize the drug comes from the battery-powered motor, the drug can be delivered to the lungs over a broad range of inspiratory rates. Also, recently, Dura has invented a new technology to deliver a uniform drug dose, with low inspiratory effort, without the need for a battery-powered motor.⁵⁹ For most DPIs, drug deposition is greater at higher flow rates. However, the Spiros DPI is an exception as it is meant to operate optimally at 15 L/min. At 15 L/min, drug deposition is approximately 40%, and the deposition decreases if the patient breathes faster. This is an improvement as lung deposition with Turbuhaler is ~ 25%, and it is 15% with the Diskus®/Accuhaler® DPI (GlaxoSmithKline). Oriel Therapeutics has developed a technology (Oriel Powder Device) that applies an electronic signal to a DPI, enabling the device rather than patient effort to drive the delivery of the drug. A piezo-electric polymer creates a nonlinear vibratory signal with a frequency and amplitude specifically matched to a particular pharmaceutical powder compound. This acoustic energy drives drug delivery. Early research data demonstrated the consistency of drug delivery made possible by Oriel's technology for multiple formulations, as well as for delivery of pure drug compounds. Albuterol/lactose blends, for example, show the same delivery with optimized signals despite having different particle size distributions.

Examples of new liquid aerosol generation devices include systems that force pressurized liquid through nozzles, such as the Respimat and the AERx systems. The Respimat is a novel, compact, propellant free, multi-dose inhaler that employs a spring to push drug solution through a nozzle, which generates a slow moving aerosol. Deposition studies show that the Respimat can deliver 39% to 44% of a dose to the lungs. Clinical studies with asthma and chronic obstructive pulmonary diseases show that the Respimat is 2 to 8 times as effective as a metered dose inhaler.⁶⁰

The AERx device uses sophisticated electronics to deliver aerosol from a single-dose blister, using an integral, disposable nozzle array. There is an extrusion of a liquid drug solution through small plates into which laser-etched holes had been drilled. The plates could be discarded after each use, permitting maintenance of solution sterility, a principal concern for liquid-based protein solutions. The electronics control dose expression and titration, timing of aerosol generation with the breath, and provide feedback for proper inhalation technique. Lung deposition has been claimed to range from 50% to 80% of the loaded dose, with remarkable reproducibility.⁶¹ AERx has been tested with a variety of drugs, for both topical and systemic delivery, including rhDNase (dornase alfa), insulin, and opiods.⁶²

The Aerodose® Inhaler developed by Aerogen, Inc., acts on a similar principle of liquid extrusion except it uses domed aperture plates containing numerous precision- formed holes surrounded by a vibrating element. Aperture plate vibration results in a micropumping action that creates a fine droplet, low-velocity aerosol suitable for lung deposition. Varying the size of the precision-formed holes will proportionately determine the particle size of the aerosol droplets. The size of the precision-formed holes also influences the aerosolization rate of the aerosol generator. Aerosolization is triggered by inspiratory flow rates >15 L/min. When aerosolization is triggered, the amount of drug aerosolized per inhalation is controlled by the software that permits aerosolization for pre-set intervals.

Other inhaler devices that require mention are the Acu-Breathe^TM (Respirics, Inc.) and the Ventaira Inhalers (Ventaira, Pharmaceuticals, Inc.). The Ventaira Inhalers use a pulmonary delivery platform called Mystic^TM Technology. This platform is based on an aerosolization principle known as electrohydrodynamics (EHD), which employs electrostatic energy (strong electric field charges particles, which ultimately break up) to create fine aerosols from formulated drug solutions or suspensions. The device reproducibly creates a soft mist aerosol cloud that can be readily inhaled over the entire range of physiological inspiratory flow rates (infant through adult) encountered in clinical practice. The process is enabled by an electrically energized nozzle through which the liquid drug formulation is delivered. The high aerosol production efficiency translates to high and reproducible lung deposition, whilst minimizing formulation complexity in early clinical studies. Mystic Technology has shown significant potential for broad applications to many drug products and clinical needs and has resulted in the introduction of the Mystic line of pulmonary delivery devices; all utilizing the same EHD-based aerosol generation technology and common subsystems. Table 3 lists some of the key new devices developed for improving inhalation delivery.

SUMMARY

Advances in particle engineering are allowing the development of particles with better dispersability, entrainment, suspendability, and deposition efficiency from dry powder inhalers. Particle engineering technologies, such as spray-freeze drying and supercritical fluid technology are permitting the formulation of thermolabile drugs into powders with controlled morphology. Delivery systems, such as large porous particles, are countering the natural particle clearance mechanisms to an extent and facilitating sustained drug delivery. Device engineering is reducing the patient effort during inhalation of powders and facilitating the generation of aerosols from solutions at the point of administration using hand-held, compact devices.

ACKNOWLEDGMENTS

The authors are thankful to the University of Nebraska Medical Center for the graduate fellowship award to Kavitha Koushik and to Dr. Boris Shekunov of Ferro Corporation for his valuable feedback during the preparation of this manuscript. This work was supported in part by the National Institute of Health Grants DK064172 and EY013842.

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REFERENCES

1. Edmonds ML, Camargo CA, Jr., Brenner BE, Rowe BH. Replacement of oral corticosteroids with inhaled corticosteroids in the treatment of acute asthma following emergency department discharge: a meta-analysis. Chest. 2002;121(6):1798-1805.
2. Groneberg DA, Witt C, Wagner U, Chung KF, Fischer A. Fundamentals of pulmonary drug delivery. Respir Med. 2003;97(4):382-387.
3. Agu RU, Ugwoke MI, Armand M, Kinget R, Verbeke N. The lung as a route for systemic delivery of therapeutic proteins and peptides. Respir Res. 2001;2(4): 198-209.
4. Kim KJ, Malik AB. Protein transport across the lung epithelial barrier. Am J Physiol Lung Cell Mol Physiol. 2003;284(2):L247-259.
5. Alcock R, Blair JA, O'Mahony DJ, Raoof A, Quirk AV. Modifying the release of leuprolide from spray dried OED microparticles. J Control Release. 2002;82 (2-3):429-440.
6. Codrons V, Vanderbist F, Verbeeck RK, Arras M, Lison D, Preat V, Vanbever R. Systemic delivery of parathyroid hormone (1-34) using inhalation dry powders in rats. J Pharm Sci. 2003;92(5):938-950.
7. Lizio R, Klenner T, Sarlikiotis AW, Romeis P, Marx D, Nolte T, Jahn W, Borchard G, Lehr CM. Systemic delivery of cetrorelix to rats by a new aerosol delivery system. Pharm Res. 2001;18(6):771-779.
8. Kobayashi S, Kondo S, Juni K. Pulmonary delivery of salmon calcitonin dry powders containing absorption enhancers in rats. Pharm Res. 1996;13(1):80-83.
9. Byron PR, Patton JS. Drug delivery via the respiratory tract. J Aerosol Med. 1994;7(1):49-75.
10. Byron PR, Roberts NS, Clark AR. An isolated perfused rat lung preparation for the study of aerosolized drug deposition and absorption. J Pharm Sci. 1986;75(2):168-171.
11. Schlesinger RB. Clearance from the respiratory tract. Fundam Appl Toxicol. 1985;5(3):435-450.
12. Edwards DA, Dunbar C. Bioengineering of therapeutic aerosols. Annu Rev Biomed Eng. 2002;4:3-107.
13. Wolff RK, Niven RW. Generation of aerosolized drugs. J Aerosol Med. 1994;7(1):89-106.
14. Crowder TM, Rosati JA, Schroeter JD, Hickey AJ, Martonen TB. Fundamental effects of particle morphology on lung delivery: predictions of Stokes' law and the particular relevance to dry powder inhaler formulation and development. Pharm Res. 2002;19(3):239-245.
15. Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med. 1996;154(5):1505-1510.
16. Kraft M. The distal airways: are they important in asthma? Eur Respir J. 1999;14(6):1403-1417.
17. Dekhuijzen PN. Inhaled corticosteroids for COPD. Ned Tijdschr Geneeskd. 2003;147(29):1398-1404.
18. Adcock IM, Gilbey T, Gelder CM, Chung KF, Barnes PJ. Glucocorticoid receptor localization in normal and asthmatic lung. Am J Respir Crit Care Med. 1996;154(3 Pt 1):771-782.
19. Busse WW, Brazinsky S, Jacobson K, Stricker W, Schmitt K, Vanden Burgt J, Donnell D, Hannon S, Colice GL. Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant. J Allergy Clin Immunol. 1999;104(6):1215-1222.
20. Geller DE, Pitlick WH, Nardella PA, Tracewell WG, Ramsey BW. Pharmacokinetics and bioavailability of aerosolized tobramycin in cystic fibrosis. Chest. 2002;122(1):219-226.
21. Byron PR. Prediction of drug residence times in regions of the human respiratory tract following aerosol inhalation. J Pharm Sci. 1986;75(5):433-438.
22. Suarez S, Hickey AJ. Drug properties affecting aerosol behavior. Respir Care. 2000;45(6):652-666.
23. Hakkinen AM, Uusi-Heikkila H, Jarvinen M, Saali K, Karhumaki L. The effect of breathing frequency on deposition of drug aerosol using an inhalation-synchronized dosimeter in healthy adults. Clin Physiol. 1999;19(3):269-274.
24. Dolovich M, Ruffin RE, Roberts R, Newhouse MT. Optimal delivery of aerosols from metered dose inhalers. Chest. 1981;80(6 Suppl):911-915.
25. Newman SP, Moren F, Pavia D, Little F, Clarke SW. Deposition of pressurized suspension aerosols inhaled through extension devices. Am Rev Respir Dis. 1981;124(3):317-320.
26. Oberdorster G, Utell MJ, Morrow PE, Hyde RW, Weber DA. Bronchial and alveolar absorption of inhaled 99mTc-DTPA. Am Rev Respir Dis. 1986;134(5):944-950.
27. Jones J. Clearance of inhaled particles from the alveoli: In: Clarke SW, eds. Aerosol and the Lung: Clinical and Experimental Aspects. London, England: Butterworth;1984.
28. Lehnert BE. Pulmonary and thoracic macrophage subpopulations and clearance of particles from the lung. Environ Health Perspect. 1992;97:17-46.
29. Hardy JG, Chadwick TS. Sustained release drug delivery to the lungs: an option for the future. Clin Pharmacokinet. 2000;39(1):1-4.
30. Corkery K. Inhalable drugs for systemic therapy. Respir Care. 2000;45(7):831-835.
31. Hussain A, Arnold JJ, Khan MA, Ahsan F. Absorption enhancers in pulmonary protein delivery. J Control Release. 2004;94(1):15-24.
32. Kobayashi S, Kondo S, Juni K. Study on pulmonary delivery of salmon calcitonin in rats: effects of protease inhibitors and absorption enhancers. Pharm Res. 1994;11(9):1239-1243.
33. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56(6):588-599.
34. Yang X, Ma JK, Malanga CJ, Rojanasakul Y. Characterization of proteolytic activities of pulmonary alveolar epithelium. Int J Pharm. 2000;195(1-2):93-101.
35. Wang L, Toledo-Velasquez D, Schwegler-Berry D, Ma JK, Rojanasakul Y. Transport and hydrolysis of enkephalins in cultured alveolar epithelial monolayers. Pharm Res. 1993;10(11):1662-1667.
36. Fiegel J, Ehrhardt C, Schaefer UF, Lehr CM, Hanes J. Large porous particle impingement on lung epithelial cell monolayers-toward improved particle characterization in the lung. Pharm Res. 2003;20(5):788-796.
37. Edwards DA, Hanes J, Caponetti G, Hrkach J, Ben-Jebria A, Eskew ML, Mintzes J, Deaver D, Lotan N, Langer R. Large porous particles for pulmonary drug delivery. Science. 1997;276(5320):1868-1871.
38. Vanbever R, Ben-Jebria A, Mintez J, Langer R, Edwards DA. Sustained release of insulin from insoluble inhaled particles. Drug Dev Res. 1999;48:178-185.
39. Bot AI, Tarara TE, Smith DJ, Bot SR, Woods CM, Weers JG. Novel lipid-based hollow-porous microparticles as a platform for immunoglobulin delivery to the respiratory tract. Pharm Res. 2000;17(3):275-283.
40. Vanbever R, Mintzes JD, Wang J, Nice J, Chen D, Batycky R, Langer R, Edwards DA. Formulation and physical characterization of large porous particles for inhalation. Pharm Res. 1999;16(11):1735-1742.
41. Bot AI, Smith DJ, Bot S, Dellamary L, Tarara TE, Harders S, Phillips W, Weers JG, Woods CM. Receptor-mediated targeting of spray-dried lipid particles coformulated with immunoglobulin and loaded with a prototype vaccine. Pharm Res. 2001;18(7):971-979.
42. Barron MK, Young TJ, Johnston KP, Williams RO, III. Investigation of processing parameters of spray freezing into liquid to prepare polyethylene glycol polymeric particles for drug delivery. AAPS PharmSciTech. 2003;4(2):E12.
43. Rogers TL, Hu J, Yu Z, Johnston KP, Williams RO, III. A novel particle engineering technology: spray-freezing into liquid. Int J Pharm. 2002;242(1-2):93-100.
44. Rogers TL, Nelsen AC, Sarkari M, Young TJ, Johnston KP, Williams RO, III. Enhanced aqueous dissolution of a poorly water soluble drug by novel particle engineering technology: spray-freezing into liquid with atmospheric freeze-drying. Pharm Res. 2003;20(3):485-493.
45. Zeng XM, Martin GP, Marriott C, Pritchard J. Crystallization of lactose from carbopol gels. Pharm Res. 2000;17(7):879-886.
46. Ganderton D. The generation of respirable cloud from coarse powder aggregates. J Biopharm Sci. 1992;3:101-105.
47. Zeng XM, Martin AP, Marriott C, Pritchard J. The influence of carrier morphology on drug delivery by dry powder inhalers. Int J Pharm. 2000;200(1):93-106.
48. Larhrib H, Martin GP, Marriott C, Prime D. The influence of carrier and drug morphology on drug delivery from dry powder formulations. Int J Pharm. 2003;257(1-2):283-296.
49. Duddu SP, Sisk SA, Walter YH, Tarara TE, Trimble KR, Clark AR, Eldon MA, Elton RC, Pickford M, Hirst PH, Newman SP, Weers JG. Improved lung delivery from a passive dry powder inhaler using an Engineered PulmoSphere powder. Pharm Res. 2002;19(5):689-695.
50. Maa YF, Nguyen PA, Andya JD, Dasovich N, Sweeney TD, Shire SJ, Hsu CC. Effect of spray drying and subsequent processing conditions on residual moisture content and physical/biochemical stability of protein inhalation powders. Pharm Res. 1998;15(5):768-775.
51. Sonner C, Maa YF, Lee G. Spray-freeze-drying for protein powder preparation: particle characterization and a case study with trypsinogen stability. J Pharm Sci. 2002;91(10):2122-2139.
52. Thoma K, Schluetermann B. Relationships between manufacturing parameters and pharmaceutical-technological requirements on biodegradable microparticles. Part 3: Pharmaceutical and technological investigations on the particle size distribution of local anesthetics containing biodegradable microspheres. Pharmazie. 1992;47(3):198-202.
53. Tong HH, Shekunov BY, York P, Chow AH. Characterization of two polymorphs of salmeterol xinafoate crystallized from supercritical fluids. Pharm Res. 2001;18(6):852-858.
54. Koushik K, Kompella UB. Preparation of large porous deslorelin-PLGA microparticles with reduced residual solvent content and cellular uptake using a supercritical CO2 process. Pharm Res. 2003(Accepted for publication).
55. Geller DE. New liquid aerosol generation devices: systems that force pressurized liquids through nozzles. Respir Care. 2002;47(12):1392-1404.
56. Dolovich M. New propellant-free technologies under investigation. J Aerosol Med. 1999;12 (Supplement 1-S9-17).
57. Dolovich M. New delivery systems and propellants. Can Respir J. 1999;6(3):290-295.
58. Skyler JS, Cefalu WT, Kourides IA, Landschulz WH, Balagtas CC, Cheng SL, Gelfand RA. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomised proof-of-concept study. Lancet. 2001;357(9253):331-335.
59. Nelson H, Kemp JP, Bieler S, Vaughan LM, Hill MR. Comparative efficacy and safety of albuterol sulfate Spiros inhaler and albuterol metered-dose inhaler in asthma. Chest. 1999;115(2):329-335.
60. Zierenberg B. Optimizing the in vitro performance of Respimat. J Aerosol Med. 1999;12 (Suppl 1-S19-24).
61. Schuster J, Rubsamen R, Lloyd P, Lloyd J. The AERx aerosol delivery system. Pharm Res. 1997;14(3):354-357.
62. Ward ME, Woodhouse A, Mather LE, Farr SJ, Okikawa JK, Lloyd P, Schuster JA, Rubsamen RM. Morphine pharmacokinetics after pulmonary administration from a novel aerosol delivery system. Clin Pharmacol Ther. 1997;62(6):596-609.
63. Wang J, Ben-Jebria A, Edwards DA. Inhalation of estradiol for sustained systemic delivery. J Aerosol Med. 1999;12(1):27-36.
64. Kraft WK, Steiger B, Beussink D, Quiring JN, Fitzgerald N, Greenberg HE, Waldman SA. The pharmacokinetics of nebulized nanocrystal budesonide suspension in healthy volunteers. J Clin Pharmacol. 2004;44(1):67-72.
65. Ostrander KD, Bosch HW, Bondanza DM. An in-vitro assessment of a NanoCrystal beclomethasone dipropionate colloidal dispersion via ultrasonic nebulization. Eur J Pharm Biopharm. 1999;48(3):207-215.
66. Davidson IG, Langner EJ, Plowman SV, Blair JA. Release mechanism of insulin encapsulated in trehalose ester derivative microparticles delivered via inhalation. Int J Pharm. 2003;254(2):211-222.
67. Sham JO, Zhang Y, Finlay WH, Roa WH, Lobenberg R. Formulation and characterization of spray-dried powders containing nanoparticles for aerosol delivery to the lung. Int J Pharm. 2004;269(2):457-467.
68. Tsapis N, Bennett D, Jackson B, Weitz DA, Edwards DA. Trojan particles: large porous carriers of nanoparticles for drug delivery. Proc Natl Acad Sci U S A. 2002;99(19):12001-12005.
69. Ben-Jebria A, Chen D, Eskew ML, Vanbever R, Langer R, Edwards DA. Large porous particles for sustained protection from carbachol-induced bronchoconstriction in guinea pigs. Pharm Res. 1999;16(4):555-561.

BIOGRAPHIES

Ms. Kavitha Koushik is a PhD candidate at the University of Nebraska Medical Center in Omaha, Nebraska, working under the supervision of Dr. Uday B. Kompella. Ms. Koushik earned her BS degree in Pharmacy from the Bombay College of Pharmacy, Mumbai, India. She is a recipient of the 2002 AAPS PDD/PT Graduate Symposium Award sponsored by Procter & Gamble. Ms. Koushik is currently focusing her research on the systemic delivery of peptide drugs via the respiratory route.

Dr. Uday B. Kompella is an Associate Professor of Pharmaceutics and Ophthalmology at the University of Nebraska Medical Center (UNMC) in Omaha, Nebraska. He is the current Chair of the AAPS Regulatory Sciences (RS) section and a member of the AAPS Nominations and Publications Committees. A 1997 recipient of the AAPS New Investigator Award in Pharmaceutics and the Pharmaceutical Technologies, Dr. Kompella is also one of the Founders and the past Chair of the AAPS Ocular Drug Delivery & Disposition focus group of AAPS. His research interests include drug delivery via ocular, nasal, and pulmonary routes, and ongoing research in his laboratory includes developing drug delivery approaches for diabetic complications and lung tumors. Dr. Kompella earned his BS and MS in Pharmacy in India and his PhD in Pharmaceutical Sciences from the University of Southern California.