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.

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.

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.

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."

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.

Formulation Design of Dry Powders for Inhalation.

Drugs for inhalation are no longer exclusively highly crystalline small molecules. They may also be amorphous small molecules, peptides, antibodies, and myriad types of engineered proteins. The evolution of respiratory therapeutics has created a need for flexible formulation technologies to engineer respirable particles. These technologies have enabled medicinal chemists to focus on molecular design without concern regarding compatibility of physicochemical properties with traditional, blend-based technologies. Therapeutics with diverse physicochemical properties can now be formulated as stable and respirable dry powders. Particle engineering technologies have also driven the deployment of new excipients, giving formulators greater control over particle and powder properties. This plays a key role in enabling efficient delivery of drugs to the lungs. Engineered powder and device combinations enable aerosols that largely bypass the mouth and throat, minimizing the inherent variability among patients that arises from differences in oropharyngeal and airway anatomies and in breathing profiles. This review explores how advances among molecules, particles, and powders have transformed inhaled drug product development. Ultimately, this scientific progress will benefit patients, enabling new classes of therapeutics to be formulated as dry powder aerosols with improved efficacy, reduced variability and side effects, and improved patient adherence.

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.

Solid-state stability of spray-dried insulin powder for inhalation: chemical kinetics and structural relaxation modeling of Exubera above and below the glass transition temperature.

The effect of temperature on the chemical stability of an amorphous spray-dried insulin powder formulation (Exubera) was evaluated in the solid state at constant moisture content. The chemical stability of the powder was assessed using reversed-phase high-performance liquid chromatography (RP-HPLC) and high-performance-size exclusion chromatography (HP-SEC). The major degradants in spray-dried insulin produced during heat stressing were identified as A21-desamidoinsulin (A21) and high molecular weight protein (HMWP). As expected, the rates of formation of A21 and HMWP were observed to increase with temperature. A stretched-time kinetic model (degradation rate is proportional to the square root of time) was applied to the degradant profiles above and below the glass transition temperature (T(g)) and apparent reaction rate constants were determined. Below T(g), isothermal enthalpy of relaxation measurements were used to assess the effect of temperature on molecular mobility. The formation of A21 and HMWP was found to follow an Arrhenius temperature dependence above and below the T(g). Comparison of reaction rate constants to those estimated from structural relaxation experiments suggests that the reaction pathways to form A21 and HMWP below the T(g) may be coupled with the molecular motions involved in structural relaxation.

Trileucine improves aerosol performance and stability of spray-dried powders for inhalation.

For particles to be useful medicinal aerosols, not only their aerodynamic diameter has to be on the order of a few micrometers but also they have to be chemically and physically stable. Manufacture of respirable particles is a technical challenge because as particles are reduced in size by conventional milling techniques, their cohesiveness greatly increases and physical and chemical stability is often compromised by the formation of amorphous material. In the present study, we describe the use of trileucine for the preparation of dry powders suitable for inhalation via spray drying of a wide range of drugs (i.e., asthma therapeutics such as albuterol and cromolyn, and anti-infectives such as netilmicin and gentamicin, as well as therapeutic proteins and peptides such as human growth hormone and salmon calcitonin). The glass transition of spray-dried trileucine is dependent on the pH and can be correlated with the proportion of the anion, cation, and zwitterion concentration in solution. Trileucine glass transition is relatively high ( approximately 104 degrees C) enabling long-term room temperature stability. The solubility of trileucine is dependent on the pH and is lowest at neutral pH ( approximately 6.8 mg/mL). Trileucine's low aqueous solubility enables the formation of low-density corrugated particles and promotes the formation of trileucine coated spray-dried particles, resulting in superior aerosol performance. Trileucine is surface active and promotes the formation of spray-dried powders with a reduced cohesiveness as demonstrated by a decrease in the measured surface energy which correlates with an observed improvement in aerosol performance. Additionally, trileucine competes with the protein on the air/water interface resulting in an additional depression of surface tension in solution which correlates with a decreased denaturation and aggregation in the solid state.

Prediction of the onset of crystallization of amorphous sucrose below the calorimetric glass transition temperature from correlations with mobility.

The objective of the present work is to determine if crystallization onset observed for an amorphous solid correlate with relaxation time at temperatures above and below the calorimetric glass transition (T(g)). Crystallization onset of spray-dried and freeze-dried amorphous sucrose were measured calorimetrically. Relaxation times measured in two temperature ranges by different techniques (isothermal calorimetry, dielectric spectroscopy) followed the expected modified Vogel-Tammann-Fulcher (VTF) behavior when extrapolated to a temperature near T(g). However, the change in slope was more conspicuous for freeze-dried sucrose, indicating that amorphous materials generated using different techniques differ in their mobilities for temperatures below T(g). Dielectric relaxation time values obtained above T(g) were well correlated to onset of crystallization. The model predicted 21 days for crystallization onset for spray-dried samples stored 7 K below T(g), compared to the experimentally observed crystallization onset of 17 days. Onset times versus temperature for freeze-dried sucrose, however, show a change in slope on approaching T(g), with the onsets somewhat decoupling from measured mobility for temperatures below T(g). Molecular mobility in amorphous materials at temperatures both above and below T(g) can be correlated to macroscopic physical change such as crystallization, but prediction of crystallization onset from relaxation time is only qualitatively correct at temperatures well below T(g).

Rapid assessment of the structural relaxation behavior of amorphous pharmaceutical solids: effect of residual water on molecular mobility.

PURPOSE: Use RH-perfusion microcalorimetry and other analytical techniques to measure the interactions between water vapor and amorphous pharmaceutical solids; use these measurements and a mathematical model to provide a mechanistic understanding of observed calorimetric events. MATERIALS: Isothermal microcalorimetry was used to characterize interactions of water vapor with a model amorphous system, spray-dried raffinose. Differential scanning calorimetry was used to measure glass transition temperature, T (g). High-sensitivity differential scanning calorimetry was used to measure enthalpy relaxation. X-ray powder diffraction (XRPD) was used to confirm that the spray-dried samples were amorphous. Scanning electron microscopy (SEM) was used to examine particle morphology. Gravimetric vapor sorption was used to measure moisture sorption isotherms. Thermogravimetric analysis (TGA) was used to measure loss on drying. RESULTS: A moisture-induced thermal activity trace (MITAT) provides a rapid measure of the dependence of molecular mobility on moisture content at a given storage temperature. At some relative humidity threshold, RH(m), the MITAT exhibits a dramatic increase in the calorimetric rate of heat flux. Simulations using calorimetric data indicate that this thermal event is a consequence of enthalpy relaxation. CONCLUSIONS: RH-perfusion microcalorimetry is a useful tool to determine the onset of moisture-induced physical instability of glassy pharmaceuticals and could find a broad application to determine appropriate storage conditions to ensure long-term physical stability. Remarkably, thermal events measured on practical laboratory timescales (hours to days) are relevant to the stability of amorphous materials on much longer, pharmaceutically relevant timescales (years). The mechanistic understanding of these observations in terms of enthalpy relaxation has added further value to the use of RH-perfusion calorimetry as a rapid means to characterize the molecular mobility of amorphous solids.

Optimisation of powders for pulmonary delivery using supercritical fluid technology.

Supercritical fluid technology exploited in this work afforded single-step production of respirable particles of terbutaline sulphate (TBS). Different crystal forms of TBS were produced consistently, including two polymorphs, a stoichiometric monohydrate and amorphous material as well as particles with different degrees of crystallinity, size, and morphology. Different solid-state and surface characterisation techniques were applied in conjunction with measurements of powder flow properties using AeroFlow device and aerosol performance by Andersen Cascade Impactor tests. Improved fine particle fraction (FPF) was demonstrated for some powders produced by the SCF process when compared to the micronised material. Such enhanced flow properties and dispersion correlated well with the reduced surface energy parameters demonstrated by these powders. It is shown that semi-crystalline particles exhibited lower specific surface energy leading to a better performance in the powder flow and aerosol tests than crystalline materials. This difference of the surface and bulk crystal structure for selected powder batches is explained by the mechanism of precipitation in SCF which can lead to surface conditioning of particles produced.

Physical stability of salmon calcitonin spray-dried powders for inhalation.

The effects of excipient crystallinity and water content on the physical stability of salmon calcitonin (sCT) in a spray-dried powder for inhalation have been investigated. sCT was dissolved in water with and without mannitol and then spray dried using a Büchi 190 spray dryer. The spray dried powders were stored for 5 days at 0, 29, 51, 58, 69, and 84% relative humidity at ambient temperature. The crystalline content, water content, secondary structure, and aggregation rates were determined for each powder immediately following spray drying and after storage at various relative humidities. In addition, the water sorption isotherms and reactivity to water vapor were determined using DVS and isothermal calorimetry, respectively. No sCT aggregation occurred during the spray drying process. Crystallinity depended on the amount of mannitol in the formulation. Powders containing up to 50% mannitol were fully amorphous, and those containing 70 and 90% mannitol contained some crystalline polyol. The powders remained aggregate free for over 2 years when stored below the critical RH (e.g., <20% for the powder containing 30% mannitol). Above this RH, sCT aggregation increased as a function of time. The amount of aggregate observed correlates with the amount of intermolecular beta-sheet formed, determined by FTIR. The sCT aggregation rate in powders containing 70% mannitol was significantly lower than that in powders containing 30% mannitol at all RH tested, presumably because of a higher ratio of amorphous mannitol to sCT, which inhibits the formation of beta-sheet structure. Moisture-induced crystallization of mannitol was observed in all powders stored at RH >50%. The moisture induced thermal activity trace (MITAT) offers a useful description on the physical stability of the spray dried powders. In conclusion, spray drying sCT and sCT/mannitol mixtures yields dry powders that contain physically intact peptide. In addition, sCT aggregation and mannitol crystallization in spray dried powders can be prevented during long-term storage if stored in low humidity environments, which can be easily assessed by MITAT.

Microcalorimetric measurement of the interactions between water vapor and amorphous pharmaceutical solids.

PURPOSE: Use a microcalorimetric technique to measure the interactions between water vapor and amorphous pharmaceutical solids and describe the relationship between long-term physical stability and the storage relative humidity (RH) at constant temperature. METHODS: A thermal activity monitor was used to characterize interactions of water vapor with spray-dried amorphous sucrose, lactose, raffinose, and sodium indomethacin. Differential scanning calorimetry was used to measure glass transition temperature, Tg. X-ray powder diffraction was used to confirm that the spray-dried samples were amorphous. Scanning electron microscopy was used to examine particle morphology. Specific surface area was determined by BET analysis of nitrogen and krypton adsorption isotherms. RESULTS: The moisture-induced thermal activity traces (MITATs) of the materials in this study exhibit general behavior that helps explain the effect of moisture content on the physical stability of the glassy phase at a given storage temperature. At some RH threshold, RHm, the MITAT exhibits a dramatic increase in the energy of interaction between water vapor and the glass that cannot be explained by a phase or morphology change. Calorimetric data indicate that water vapor-solid interactions are reversible below RHm; above RHm, energetic hysteresis is observed and water-water interactions predominate. In addition, the MITAT was deconvoluted into sorptive and nonsorptive components, making it possible to assign the observed heat flow to unique thermal events. Samples stored at a RH just below RHm for more than 2 months show no evidence of morphology or phase change. In addition, the MITAT can be deconvoluted into sorptive and nonsorptive components by using a twin-calorimeter arrangement. This analysis provides specificity to the microcalorimetric analysis and helps explain the nature of the physical changes that occur during the hydration glassy phase. CONCLUSIONS: The MITAT is a useful tool to determine the onset of moisture-induced physical instability of glassy pharmaceuticals and may find a broad application to determine appropriate storage conditions to ensure long-term physical stability.