Inhaled Medicines: Past, Present, and Future.

The purpose of this review is to summarize essential pharmacological, pharmaceutical, and clinical aspects in the field of orally inhaled therapies that may help scientists seeking to develop new products. After general comments on the rationale for inhaled therapies for respiratory disease, the focus is on products approved approximately over the last half a century. The organization of these sections reflects the key pharmacological categories. Products for asthma and chronic obstructive pulmonary disease include ß -2 receptor agonists, muscarinic acetylcholine receptor antagonists, glucocorticosteroids, and cromones as well as their combinations. The antiviral and antibacterial inhaled products to treat respiratory tract infections are then presented. Two "mucoactive" products-dornase α and mannitol, which are both approved for patients with cystic fibrosis-are reviewed. These are followed by sections on inhaled prostacyclins for pulmonary arterial hypertension and the challenging field of aerosol surfactant inhalation delivery, especially for prematurely born infants on ventilation support. The approved products for systemic delivery via the lungs for diseases of the central nervous system and insulin for diabetes are also discussed. New technologies for drug delivery by inhalation are analyzed, with the emphasis on those that would likely yield significant improvements over the technologies in current use or would expand the range of drugs and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of approved orally inhaled drug products for a variety of respiratory diseases and for systemic administration should be helpful in making judicious decisions about the development of new or improved inhaled drugs. These aspects include the choices of the active ingredients, formulations, delivery systems suitable for the target patient populations, and, to some extent, meaningful safety and efficacy endpoints in clinical trials.

Spray-Dried PulmoSphere™ Formulations for Inhalation Comprising Crystalline Drug Particles.

Over the past 20 years, solution-based spray dried powders have transformed inhaled product development, enabling aerosol delivery of a wider variety of molecules as dry powders. These include inhaled proteins for systemic action (e.g., Exubera®) and high-dose inhaled antibiotics (e.g., TOBI® Podhaler™). Although engineered particles provide several key advantages over traditional powder processing technologies (e.g., spheronized particles and lactose blends), the physicochemical stability of the amorphous drug present in these formulations brings along its own unique set of constraints. To this end, a number of approaches have been developed to maintain the crystallinity of drugs throughout the spray drying process. One approach is to spray dry suspensions of micronized drug(s) from a liquid feed. In this method, minimization of drug particle dissolution in the liquid feed is critical, as dissolved drug is converted into amorphous domains in the spray-dried drug product. The review explores multiple formulation and engineering strategies for decreasing drug dissolution independent of the physicochemical properties of the drug(s). Strategies to minimize particle dissolution include spray blending of particles of different compositions, formation of respirable agglomerates of micronized drug with small porous carrier particles, and use of common ions. The formulations extend the range of doses that can be delivered with a portable inhaler from about 100 ng to 100 mg. The spray-dried particles exhibit significant advantages in terms of lung targeting and dose consistency relative to conventional lactose blends, while still maintaining the crystallinity of drug(s) in the formulated drug product.

Ciprofloxacin Dry Powder for Inhalation (ciprofloxacin DPI): Technical design and features of an efficient drug-device combination.

Bronchiectasis is a chronic respiratory disease with heterogeneous etiology, characterized by a cycle of bacterial infection and inflammation, resulting in increasing airway damage. Exacerbations are an important cause of morbidity and are strongly associated with disease progression. Many patients with bronchiectasis suffer from two or more exacerbations per year. However, there are no approved therapies to reduce or delay exacerbations in this patient population. Ciprofloxacin DPI is in development as a long-term, intermittent therapy to reduce exacerbations in patients with non-cystic fibrosis (CF) bronchiectasis and evidence of respiratory pathogens. Ciprofloxacin DPI combines drug substance, dry powder manufacturing technology, and an efficient, pocket-sized, dry powder inhaler to deliver an effective antibiotic directly to the site of infection, with minimal systemic exposure and treatment burden. Here we review the drug substance and particle engineering (PulmoSphere™) technology used, and key physical properties of Ciprofloxacin Inhalation Powder, including deposition, delivered dose uniformity, consistency, and stability. Design features of the T-326 Inhaler are described in relation to lung targeting, safety and tolerability of inhalation powders, as well as treatment burden and adherence. If approved, Ciprofloxacin DPI may provide a valuable treatment option for those with frequent exacerbations and respiratory pathogens.

Physical Characterization of Tobramycin Inhalation Powder: II. State Diagram of an Amorphous Engineered Particle Formulation.

Tobramycin Inhalation Powder (TIP) is a spray-dried engineered particle formulation used in TOBI Podhaler, a drug-device combination for treatment of cystic fibrosis (CF). A TIP particle consists of two phases: amorphous, glassy tobramycin sulfate and a gel-phase phospholipid (DSPC). The objective of this work was to characterize both the amorphous and gel phases following exposure of TIP to a broad range of RH and temperature. Because, in principle, changes in either particle morphology or the solid-state form of the drug could affect drug delivery or biopharmaceutical properties, understanding physical stability was critical to development and registration of this product. Studies included morphological assessments of particles, thermal analysis to measure the gel-to-liquid crystalline phase transition (Tm) of the phospholipid and the glass transition temperature (Tg) of tobramycin sulfate, enthalpy relaxation measurements to estimate structural relaxation times, and gravimetric vapor sorption to measure moisture sorption isotherms of TIP and its components. Collectively, these data enabled development of a state diagram for TIP-a map of the environmental conditions under which physical stability can be expected. This diagram shows that, at long-term storage conditions, TIP is at least 50 °C below the Tg of the amorphous phase and at least 40 °C below the Tm of the gel phase. Enthalpy relaxation measurements demonstrate that the characteristic structural relaxation times under these storage conditions are many orders of magnitude greater than that at Tg. These data, along with long-term physicochemical stability studies conducted during product development, demonstrate that TIP is physically stable, remaining as a mechanical solid over time scales and conditions relevant to a pharmaceutical product. This met a key design goal in the development of TIP: a room-temperature-stable formulation (3-year shelf life) that obviates the need for refrigeration for long-term storage. This has enabled development of TOBI Podhaler-an approved inhaled drug product that meaningfully reduces the treatment burden of CF patients worldwide.

The Impact of Inspiratory Flow Rate on Drug Delivery to the Lungs with Dry Powder Inhalers.

Current marketed dry powder inhalers utilize the energy from patient inspiration to fluidize and disperse bulk powder agglomerates into respirable particles. Variations in patient inspiratory flow profiles can lead to marked differences in total lung dose (TLD), and ultimately patient outcomes for an inhaled therapeutic. The present review aims to quantitate the flow rate dependence in TLD observed for a number of drug/device combinations using a new metric termed the Q index. With this data in hand, the review explores key attributes in the design of the formulation and device that impact flow rate dependence. The review also proposes alternative in vitro methods to assess flow rate dependence that more closely align with in vivo observations. Finally, the impact of variations in flow rate on lung function for inhaled bronchodilators is summarized.

Physical Characterization of Tobramycin Inhalation Powder: I. Rational Design of a Stable Engineered-Particle Formulation for Delivery to the Lungs.

A spray-dried engineered particle formulation, Tobramycin Inhalation Powder (TIP), was designed through rational selection of formulation composition and process parameters. This PulmoSphere powder comprises small, porous particles with a high drug load. As a drug/device combination, TOBI Podhaler enables delivery of high doses of drug per inhalation, a feature critical for dry powder delivery of anti-infectives for treatment of cystic fibrosis. The objective of this work was to characterize TIP on both the particle and molecular levels using multiple orthogonal physical characterization techniques. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), electron spectroscopy for chemical analysis (ESCA), and Raman measurements show that a TIP particle consists of two phases: amorphous, glassy tobramycin sulfate with a glass transition temperature of about 100 °C and a gel-phase phospholipid (DSPC) with a gel-to-liquid-crystal transition temperature of about 80 °C. This was by design and constituted a rational formulation approach to provide Tg and Tm values that are well above the temperatures used for long-term storage of TIP. Raman and ESCA data provide support for a core/shell particle architecture of TIP. Particle surfaces are enriched with a porous, hydrophobic coating that reduces cohesive forces, improving powder fluidization and dispersibility. The excellent aerosol dispersibility of TIP enables highly efficient delivery of fine particles to the respiratory tract. Collectively, particle engineering has enabled development of TOBI Podhaler, an approved inhaled drug product that meaningfully reduces the treatment burden to cystic fibrosis patients worldwide.

Design of dry powder inhalers to improve patient outcomes: it's not just about the device.

INTRODUCTION: Up to 50% of asthma/COPD patients make critical errors in dose preparation and dose inhalation with current marketed DPIs which negatively impact clinical outcomes. Others fail to adhere to their chronic treatment regimen. AREAS COVERED: For this review, we describe how a human-factors approach to design of a dry powder inhaler can be used to improve usability, proficiency, and functionality of DPIs, while effectively mitigating critical errors associated with DPIs. The review highlights the critical importance of utilizing improved formulations with monomodal aerodynamic particle size distributions to reduce variability associated with oropharyngeal filtering of particles, flow rate dependence, and co-formulation effects. EXPERT OPINION: Much of the variability in dose delivery with DPIs is associated with limitations of the bimodal APSDs inherent in current lactose blend formulations. Evidence supports that improved lung targeting and dose consistency can be achieved with drug-device combination products comprising spray-dried powders. Unfortunately, no data exists to assess whether these advances observed in in vitro and in vivo dose delivery studies will translate into improved clinical outcomes. Given the significant percentage of patients that receive suboptimal drug delivery with current DPIs it would behoove the industry to assess the efficacy of new approaches.

Targeting of Inhaled Therapeutics to the Small Airways: Nanoleucine Carrier Formulations.

Current dry powder formulations for inhalation deposit a large fraction of their emitted dose in the upper respiratory tract where they contribute to off-target adverse effects and variability in lung delivery. The purpose of the current study is to design a new formulation concept that more effectively targets inhaled dry powders to the large and small airways. The formulations are based on adhesive mixtures of drug nanoparticles and nanoleucine carrier particles prepared by spray drying of a co-suspension of leucine and drug particles from a nonsolvent. The physicochemical and aerosol properties of the resulting formulations are presented. The formulations achieve 93% lung delivery in the Alberta Idealized Throat model that is independent of inspiratory flow rate and relative humidity. Largely eliminating URT deposition with a particle size larger than solution pMDIs is expected to improve delivery to the large and small airways, while minimizing alveolar deposition and particle exhalation.

Optimizing Spray-Dried Porous Particles for High Dose Delivery with a Portable Dry Powder Inhaler.

This manuscript critically reviews the design and delivery of spray-dried particles for the achievement of high total lung doses (TLD) with a portable dry powder inhaler. We introduce a new metric termed the product density, which is simply the TLD of a drug divided by the volume of the receptacle it is contained within. The product density is given by the product of three terms: the packing density (the mass of powder divided by the volume of the receptacle), the drug loading (the mass of drug divided by the mass of powder), and the aerosol performance (the TLD divided by the mass of drug). This manuscript discusses strategies for maximizing each of these terms. Spray drying at low drying rates with small amounts of a shell-forming excipient (low Peclet number) leads to the formation of higher density particles with high packing densities. This enables ultrahigh TLD (>100 mg of drug) to be achieved from a single receptacle. The emptying of powder from capsules is directly proportional to the mass of powder in the receptacle, requiring an inhaled volume of about 1 L for fill masses between 40 and 50 mg and up to 3.2 L for a fill mass of 150 mg.

Impact of human behavior on inspiratory flow profiles in patients with pulmonary arterial hypertension using AOS™ dry powder inhaler device.

Relative to healthy subjects, patients with pulmonary arterial hypertension often present with decreased respiratory muscle strength, resulting in decreased maximum inspiratory pressure. Little is known about the impact of reduced respiratory muscle strength on the ability to achieve the peak inspiratory pressures needed for effective drug delivery when using portable dry powder inhalers (≥1.0 kPa). The objective of this study was to assess the impact of inhaler resistance and patient instruction on the inspiratory flow profiles of pulmonary arterial hypertension patients when using breath-actuated dry powder inhalers. The inspiratory flow profiles of 35 patients with pulmonary arterial hypertension were measured with variants of the RS01 dry powder inhaler. Profiles were determined with a custom inspiratory flow profile recorder. Results showed that going from the low resistance RS01 dry powder inhaler to the high resistance AOS® dry powder inhaler led to increases in mean peak inspiratory pressures for pulmonary arterial hypertension subjects from 3.7 kPa to 6.5 kPa. Instructions that ask pulmonary arterial hypertension subjects to inhale with maximal effort until their lungs are full led to a mean peak inspiratory pressures of 6.0 kPa versus 2.1 kPa when the same subjects are asked to inhale comfortably. Significant decreases in mean peak inspiratory pressures are also observed with decreases in lung function, with a mean peak inspiratory pressures of 7.2 kPa for subjects with FEV1 > 60% predicted, versus 3.3 kPa for those subjects with FEV1 < 50% predicted. In conclusion, despite having reduced respiratory muscle strength, subjects with pulmonary arterial hypertension can effectively use a breath-actuated dry powder inhaler. The probability of achieving effective dose delivery may be increased by using dry powder inhalers with increased device resistance, particularly when subjects do not follow the prescribed instructions and inhale comfortably.

Assessment of pinch force strength in patients with pulmonary arterial hypertension in the era of AOS® dry powder inhaler based therapies.

Over the last two decades treatment options have drastically improved for patients with pulmonary arterial hypertension (PAH). In the recent times, there is renewed interest in dry powder inhaler (DPI) based inhaled therapies in the treatment of PAH. PAH patients are well known to have respiratory and other muscle weakness either related to the disease itself or due to the underlying diseases like connective tissue disease (CTD). CTD PAH patients are at particular disadvantage as there is a concern if they have enough strength to press the buttons on the inhaler device, needed to pierce the drug capsule inside the device. Additionally, CTD PAH patients develop hand deformities making it difficult to use devices. To our knowledge, this is the first study to systematically examine the pinch force strength needed to pierce the capsule in DPI devices in patients with PAH. We enrolled 35 patients and our results showed that all PAH patients were able to generate enough pinch strength needed to pierce the capsule regardless of the etiology of PAH.

Safety, Tolerability, and Pharmacokinetics of RT234 (Vardenafil Inhalation Powder): A First-in-Human, Ascending Single- and Multiple-Dose Study in Healthy Subjects.

Background: RT234 (vardenafil inhalation powder) is being developed for pulmonary administration "as needed", to acutely improve exercise tolerance and symptoms in patients with pulmonary arterial hypertension (PAH). Methods: This single-center, open-label, randomized study in 32 healthy adult subjects evaluated single and multiple inhalation doses of RT234, for safety, tolerability, and pharmacokinetics (PKs). Results: RT234 was generally safe and well tolerated at single doses of 0.2-2.4 mg and after repeated dose administration of up to 2.4 mg q4h for four doses daily for 9 days. The most common treatment-emergent adverse events were mild-to-moderate headaches. There was no evidence of pulmonary irritation or inflammation. Vardenafil was absorbed very rapidly after inhalation as RT234, independent of dose level and number of doses administered. The tmax occurred at the time that the first blood sample following completion of dosing. After Cmax was achieved, plasma vardenafil concentrations declined rapidly in an exponential fashion that appeared to be parallel among dose levels. Vardenafil plasma concentrations and PK parameters increased in a dose-proportional manner. Vardenafil systemic exposure was notably greater after oral administration of 20 mg vardenafil tablets (Levitra®) than after administration of any dose level of RT234. During repeated dose administration of RT234, Cmax was attained rapidly following each dose and in a pattern similar to that observed after single-dose administration. Minor accumulation, characterized by very low mean morning predose vardenafil concentrations (<0.5 ng/mL), occurred after q4h dosing of up to four doses per day for 9 days. Taken together, these findings show that no clinically important vardenafil accumulation is likely after repeated-dose administration of RT234. Mean vardenafil t1/2 values were comparable after single- and repeated-dose administration. Conclusions: Comparative plasma vardenafil bioavailability data from this study provide scientific justification for reliance on Food and Drug Administration findings for Levitra tablets. These findings support further evaluation of RT234 for as-needed treatment of patients with PAH. The Clinical Trials Registration number is ACTRN12618001077257.

The Confusing World of Dry Powder Inhalers: It Is All About Inspiratory Pressures, Not Inspiratory Flow Rates.

Dry powder inhalers (DPIs) all have the ability to aerosolize dry powders, but they each offer different operating mechanisms and resistances to inhaled airflow. This variety has resulted in both clinician and patient confusion concerning DPI performance, use, and effectiveness. Particularly, there is a growing misconception that a single peak inspiratory flow rate (PIFR) can determine a patient's ability to use a DPI effectively, regardless of its design or airflow resistance. For this review article, we have sifted through the relevant literature concerning DPIs, inspiratory pressures, and inspiratory flow rates to provide a comprehensive and concise discussion and recommendations for DPI use. We ultimately clarify that the controlling parameter for DPI performance is not the PIFR but the negative pressure generated by the patient's inspiratory effort. A pressure drop ∼≥1 kPa (∼10 cm H2O) with any DPI is a reasonable threshold above which a patient should receive an adequate lung dose. Overall, we explore the underlying factors controlling inspiratory pressures, flow rates and dispensing, and dispersion characteristics of the various DPIs to clarify that inspiratory pressures, not flow rates, limit and control a patient's ability to generate sufficient flow for effective DPI use.

Post-inhalation cough with therapeutic aerosols: Formulation considerations.

This review provides an assessment of post-inhalation cough with therapeutic aerosols. Factors that increase cough may be mitigated through design of the drug, formulation, and device. The incidence of cough is typically less than 5% for drugs with a nominal dose less than 1 mg, including asthma and COPD therapeutics. Cough increases markedly as the dose approaches 100 mg. This is due to changes in the composition of epithelial lining fluid (e.g., increases in osmolality, proton concentration). Whether an individual exhibits cough depends on their degree of sensitization to mechanical and chemical stimuli. Hypersensitivity is increased when the drug, formulation or disease result in increases in lung inflammation. Cough related to changes in epithelial lining fluid composition can be limited by using insoluble neutral forms of drugs and excipients.

Comparison of Phospholipid-Based Particles for Sustained Release of Ciprofloxacin Following Pulmonary Administration to Bronchiectasis Patients.

The rapid clearance of ciprofloxacin hydrochloride from the lungs following administration as an aerosol leads to poor efficacy in the treatment of pulmonary infections. The development of formulations capable of sustaining ciprofloxacin concentrations in the lungs has the potential to significantly improve antibacterial activity. The present review compares two approaches for sustaining levels of ciprofloxacin in the lungs, a liposomal formulation where ciprofloxacin is encapsulated in small unilamellar vesicles, and a dry powder formulation of the practically insoluble zwitterionic form of the drug. These two formulations recently completed large multicenter, phase 3 clinical studies in bronchiectasis patients. As such, they present a unique opportunity to examine the chemistry, manufacturing, and control of the dosage forms in addition to their tolerability and efficacy in more than 1000 bronchiectasis patients. Both formulations were generally well tolerated with most adverse events found to be mild to moderate in intensity. While the formulations were effective in reducing and/or eradicating infections, this did not lead to reductions in pulmonary exacerbations, the primary endpoint. The failures speak more to the heterogeneous nature of the disease and the difficulty in identifying bronchiectasis patients likely to exacerbate, rather than an inherent limitation of the formulations. While the formulations are similar in many respects, they also present some interesting differences. This review explores the implications of these differences on the treatment of respiratory infections.

Idealhalers Versus Realhalers: Is It Possible to Bypass Deposition in the Upper Respiratory Tract?

This review discusses how advances in formulation and device design can be utilized to dramatically improve lung targeting and dose consistency relative to current marketed dry powder inhalers (DPIs). Central to the review is the development of engineered particles that effectively bypass deposition in the upper respiratory tract (URT). This not only reduces the potential for off-target effects but it also reduces variability in dose delivery to the lungs resulting from anatomical differences in the soft tissue in the mouth and throat. Low-density porous particles are able to largely bypass URT deposition due to the fact that both the primary particles and their agglomerates are respirable. The low-density particles also exhibit dose delivery to the lungs that is largely independent of inspiratory flow rate across a range of flow rates that most subjects achieve with portable DPIs. Coupling this with delivery devices that are breath actuated, simple to operate (open-inhale-close), and have adherence-tracking capability enables drug delivery that is largely independent of how a subject inhales, with a user experience that is close to that of an "idealhaler."

Design of fine particles for pulmonary drug delivery.

Particle design for inhalation is characterized by advances in particle processing methods and the utilization of new excipients. Processing methods such as spray drying allow control over critical particle design features, such as particle size and distribution, surface energy, surface rugosity, particle density, surface area, porosity and microviscosity. Control of these features has enabled new classes of therapeutics to be delivered by inhalation. These include therapeutics that have a narrow therapeutic index, require a high delivered dose, and/or elicit their action systemically. Engineered particles are also being utilized for immune modulation, with exciting advances being made in the delivery of antibodies and inhaled vaccines. Continued advances are expected to result in 'smart' therapeutics capable of active targeting and intracellular trafficking.

Design of spray dried insulin microparticles to bypass deposition in the extrathoracic region and maximize total lung dose.

Inhaled drugs all too often deliver only a fraction of the emitted dose to the target lung site due to deposition in the extrathoracic region (i.e., mouth and throat), which can lead to increased variation in lung exposure, and in some instances increases in local and systemic side effects. For aerosol medications, improved targeting to the lungs may be achieved by tailoring the micromeritic properties of the particles (e.g., size, density, rugosity) to minimize deposition in the mouth-throat and maximize the total lung dose. This study evaluated a co-solvent spray drying approach to modulate particle morphology and dose delivery characteristics of engineered powder formulations of insulin microparticles. The binary co-solvent system studied included water as the primary solvent mixed with an organic co-solvent, e.g., ethanol. Factors such as the relative rate of evaporation of each component of a binary co-solvent mixture, and insulin solubility in each component were considered in selecting feedstock compositions. A water-ethanol co-solvent mixture with a composition range considered suitable for modulating particle shell formation during drying was selected for experimental investigation. An Alberta Idealized Throat model was used to evaluate the in vitro total lung dose of a series of spray dried insulin formulations engineered with different bulk powder properties and delivered with two prototype inhalers that fluidize and disperse powder using different principles. The in vitro total lung dose of insulin microparticles was improved and favored for powders with low bulk density and small primary particle size, with reduction of deposition in the extrathoracic region. The results demonstrated that a total lung dose >95% of the delivered dose can be achieved with engineered particles, indicating a high degree of lung targeting, almost completely bypassing deposition in the mouth-throat.

Inhalation of tobramycin using simulated cystic fibrosis patient profiles.

INTRODUCTION: TOBI® Podhaler™ is a capsule-based drug-device combination (tobramycin inhalation powder [TIP] 28 mg capsules via unit-dose dry powder T-326 Inhaler [Podhaler™]) developed for treatment of Pseudomonas aeruginosa infection in cystic fibrosis (CF). We explored how inspiratory flow profiles and mouth-throat geometries affect drug delivery with the T-326 Inhaler. METHODS: Inspiratory flow profiles were recorded from 38 subjects aged 6-71 who had CF and varying degrees of lung function impairment. Ten of the inspiratory flow profiles were simulated in the laboratory using a custom breath simulator to determine delivered dose (DD) from the T-326 Inhaler. In vitro total lung dose (TLDin vitro ) was measured using four anatomical throat models, ranging from a child to a large adult. RESULTS: Aerosol performance was assessed across a range of inspiratory flow profiles. Mean DD ranged from 88.8% to 97.0% of declared capsule content. TLDin vitro ranged from 54.8% to 72.4% of capsule content between the flow profile/throat options tested, and the mean TLDin vitro across the range of flow profiles and anatomical throats tested was 63 ± 5%. CONCLUSIONS: Our findings indicate that the T-326 Inhaler provides reliable drug delivery at flow rates likely to be achieved by a broad spectrum of patients with CF. Importantly, forceful inhalation was not required to achieve a robust TLDin vitro . Pediatr Pulmonol. 2016;51:1159-1167. © 2016 Wiley Periodicals, Inc.

Inhaled antimicrobial therapy - barriers to effective treatment.

Inhaled antibiotics dramatically improve targeting of drug to the site of respiratory infections, while simultaneously minimizing systemic exposure and associated toxicity. The high local concentrations of antibiotic may enable more effective treatment of multi-drug resistant pathogens. This review explores barriers to effective treatment with inhaled antibiotics. In addition, potential opportunities for improvements in treatment are reviewed.