Review For reprint orders, please contact [email protected]

The PulmoSphere™ platform for pulmonary drug delivery Spray–dried PulmoSphere™ formulations comprise phospholipid-based small, porous particles. Drug(s) may be incorporated in or with PulmoSphere formulations in three formats: solution-, suspension-, and carrier-based systems. The multiple formats may be administered to the respiratory tract with multiple delivery systems, including portable inhalers (pressurized, metered-dose inhaler and dry-powder inhaler), nebulizers, and via liquid dose instillation in conjunction with partial liquid ventilation. The PulmoSphere platform (particles, formats, delivery systems) enables pulmonary delivery of a broad range of drugs independent of their physicochemical properties and lung dose. The engineered particles provide significant improvements in lung targeting and dose consistency, relative to current marketed inhalers. The US FDA approval of TOBI® Podhaler™ (Novartis; Basel, Switzerland) for the treatment of chronic Pseudomonas aeruginosa infections in cystic fibrosis (CF) patients marks a significant milestone in the development of engineered particles for inhalation and, in particular, the PulmoSphere™ technology. Three of the top ten pharmaceutical companies now utilize Pulmo­Sphere formulations in the development of their inhalation products, with Bayer (Berlin, Germany) [1] and AstraZeneca (Pearl Therapeutics; CA, USA) [2], recently advancing PulmoSphere-based products into Phase III clinical development. This manuscript provides an overview of the PulmoSphere technology, focusing on the broad utility of the platform for pulmonary drug delivery. What is a PulmoSphere? PulmoSphere formulations comprise small porous particles with characteristic spongelike particle morphology (Figure 1) [3–63]. In preferred embodiments, the particles are made up of two materials endogenous to the lungs: distearoylphosphatidylcholine (DSPC) and CaCl2, in a 2:1 molar ratio [57]. The particles have a mass median diameter (geometric size) between 1 and 5 µm, and a tapped density between 0.01 and 0.5 g/cm3. PulmoSphere particles are manufactured by spray–drying, a method for producing a dry powder by rapidly evaporating a liquid feedstock with a heated gas (Figure  2) [3–7]. The spray–drying process can be divided into four subprocesses: preparation of a liquid feedstock, atomization of the liquid to form droplets, drying of the liquid droplets to form fine particles, 10.4155/TDE.14.3 © 2014 Future Science Ltd

and collection of these particles with a cyclone separator. For PulmoSphere formulations, the liquid feedstock comprises a submicron oil-inwater emulsion [64], where the oil droplets serve as pore formers, creating the desired sponge-like particle morphology [3–7]. The evaporation of the volatile liquid components in the atomized droplet during spray– drying can be described as a “coupled heat and mass transport problem” [4]. As described by Tsapis et al. there are two characteristic times that are critical from a particle design perspective [65]. These determine the morphology and distribution of solid components within the spray– dried particles. They are the time required for the droplet to dry via convection (tc) and the time required for the dissolved or dispersed components to diffuse from the edge of the atomized droplet to its center, td. The ratio of these two characteristic times defines a dimensionless mass transport number termed the Peclet number (Pe) (Equation 1):

Jeffry Weers* & Thomas Tarara Novartis Pharmaceuticals Corporation, San Carlos, CA 94070, USA *Author for correspondence: Tel.: +1 650 622 1568 [email protected]

R2 Pe = xd = drop xc xc D

Equation 1

where Rdrop is the radius of the atomized droplet and D is the diffusion coefficient of the solutes or dispersed particles present in the liquid feedstock. In the limit where drying of atomized droplets is sufficiently slow (Pe > 1) and components have insufficient time to diffuse throughout the atomized droplet, the slowdiffusing components will be enriched at the surface of the drying droplet. In such a case, low density particles with a core/shell distribution of components occurs [3–6,65]. Owing to their large size, emulsion droplets diffuse very slowly and accumulate at the 278

Ther. Deliv. (2014) 5(3)

surface of the receding droplet [1–4]. As the drying process continues, the evaporating droplet is comprised of a shell enriched in these slowdiffusing emulsion droplets that enclose the remaining aqueous solution. Eventually, the remaining aqueous phase and higher boiling-oil phase evaporate through the shell, leaving behind pores in place of the original emulsion droplets. As such, the particle surface becomes enriched in the components making up the slow-diffusing emulsion droplets (i.e., DSPC and CaCl2). The hydrophobic surface created by enrichment of the diacyl phospholipid contributes to the decreased interparticle cohesive forces observed for PulmoSphere powders, which in turn enables the excellent powder fluidization and dispersibility noted for PulmoSphere aerosols [8,10,13,35,36]. The principal materials (excipients and process aids) utilized in PulmoSphere formulations, and their role in the manufacturing process and final drug product are summarized in Table 1. Phosphatidylcholines (also known as lecithins) are natural components of cell membranes and the primary lipid constituent of human pulmonary surfactant. Phosphatidylcholines from natural and synthetic sources are present in several approved pulmonary products, including exogenous pulmonary surfactants (e.g., Survanta®, Abbott Laboratories [IL,USA]), and pressurized metered-dose inhaler (pMDI) formulations (e.g., Atrovent® and Combivent®, Boehringer Ingelheim [Ingelheim, Germany]), where they serve as dispersion stabilizers. Calcium chloride is a normal component of physiological f luids (e.g., concentration in epithelial lining fluid is 2.8–3.4 mM) [66]. Calcium levels in the human body are tightly regulated due to its importance in cellular and neuromuscular function. In addition to its use in PulmoSphere formulations, CaCl 2 is also an approved excipient in nebulized DNase (Pulmozyme®, Genentech [CA, USA]). The calcium ions are thought to interact with the phosphate moiety of the phosphocholine headgroup in DSPC, resulting in bulk powders with improved environmental robustness [57,58]. The observed benefits include: significant increases in the gel–liquid crystal phase transition temperature (Tm) of the phospholipid; spray–dried powders with decreased moisture sensitivity (i.e., Tm values that are only weakly dependent on increases in relative humidity); deceased particle sintering at elevated temperatures [58]. Perfluorooctyl bromide (PFOB), a brominated perfluorocarbon, is utilized as the dispersed oil future science group

The PulmoSphere™ platform for pulmonary drug delivery phase in the emulsion feedstock. Due to its extensive clinical development as a contrast agent, synthetic oxygen carrier and liquid ventilation medium, considerable preclinical and clinical safety data are available. Large doses of PFOB (up to 30 ml/kg body weight) have been instilled into the lungs in support of partial liquid ventilation [67–70]. Based on pulmonary safety studies in nonhuman primates, the calculated permitted daily exposure according to residual solvent guidelines set by the International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH Q3C) is about 1 g/day [Alliance Pharmaceutical Corporation , Unpublished Data]. This is orders of magnitude in excess of the anticipated PFOB levels delivered

in PulmoSphere powders, where residual concentrations of less than 0.5% w/w are typically measured in spray–dried powders. PFOB is captured with high efficiency in the manufacturing process, and the volatile organic compound is subsequently recycled and/or destroyed by incineration. Additional excipients may be incorporated within PulmoSphere particles. These include buffers, salts (e.g., common ions) and glassformers (e.g., trehalose or sucrose) to enable improvements in the physical or chemical stability of the drug product. Polymers (e.g., hydroxyethylstarch) may also be utilized to control the clearance of API from the lungs [17,59]. These, and other functional excipients, are used only

A

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Key Term Small porous particles:

Engineered particles with a low tapped density (90% w/w DSPC [35]. The micromeritic properties of solution-based PulmoSphere powders (e.g., size, density, specific surface–area, porosity) may be controlled by variation of the volume fraction of the oil phase in the emulsion feedstock [14], with the geometric size of the pores controlled to some degree by the size of the emulsion droplets. These concepts are illustrated for spray–dried PulmoSphere particles, comprising 50% w/w gentamicin sulfate (Table 2 & Figure 3) [3]. When a solution of gentamicin is spray–dried with no dispersed emulsion droplets (foil = 0, where foil is the volume fraction of oil in the liquid feedstock), the resulting particles are smooth spheres with a particle density approximately equivalent to the true density of the particles as measured by helium pcynometry (rtrue = 1.264 g/cm3; Table  2). The measured tapped density should be less than the true density, owing to the presence of void spaces between particles. As discussed previously, the formation of solid particles is a consequence of the low Peclet number and high diffusivity of the small molecule drug substance. In contrast, the presence of the slow diffusing emulsion droplets in the atomized droplets leads to core-shell formation with increased hollow voids in the particles as the volume fraction of oil is increased. Increases in the volume fraction of the oil phase also results in an increase in the total number of emulsion droplets. This leads to shell formation earlier in the drying process, effectively locking-in a larger geometric size for the spraydried particles, and increasing the size of a hollow core within the particles. Thus, modulation of the volume fraction of PFOB provides exquisite control of the physicochemical properties of the spray–dried particles.

Table 1. Principal excipients and process aids utilized in the PulmoSphere™ technology. Component

Structure

Class

Role in feedstock

Role in particle

DSPC

C44H88NO8P

Excipient

Emulsifier

Shell former (increase dispersibility)

Calcium chloride

CaCl2

Excipient

Water for injection H2O

Surface modifier (increases electrostatic repulsion between emulsion droplets) Process aid Continuous phase in emulsion

Surface modifier (increase gel to liquid crystal phase transition of DSPC) None (residual solvent in powder)

PFOB

Process aid Dispersed oil phase in emulsion

None (residual solvent in powder)

C8F17Br

DSPC: Distearoylphosphatidylcholine; PFOB: Perfluorooctyl bromide.

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The PulmoSphere™ platform for pulmonary drug delivery

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Table 2. Influence of the volume fraction of oil phase of particle properties for a 50% w/w formulation of gentamicin sulfate. fPFOB

VMD (µm)

Surface area (m2/g)

rtapped (g/cm3 )

Porosity (%)

0

3.0

2.0

1.24

1.9

0.1

3.4

25.7

0.35

72.3

0.3

5.8

72.4

0.17

86.6

0.5

7.3

56.9

0.05

96.0

TEM

SEM

Particle cross-sections were imaged with TEM, while particle morphologies were imaged with SEM. The VMD was obtained via laser diffraction. fPFOB: Volume fraction of perfluorooctyl bromide; rtapped: Tapped density; SEM: Scanning electron microscopy; TEM: Transmission electron microscopy; VMD: Volume weight mean diameter. Adapted with permission from [3] © Virginia Commonwealth University (2000).

The impact of variations in emulsion droplet size on particle morphology is illustrated in Figure  3. The ratio of PFOB/DSPC controls the size of the emulsion droplets in the feedstock. The mass mean diameter of the emulsion droplets was: 120 nm (PFOB/ DSPC = 10), 170 nm (PFOB/DSPC = 20), 260 nm (PFOB/DSPC = 40), and 860 nm (PFOB/DSPC = 80). Larger emulsion droplets lead to larger pore sizes in the spray–dried powders, although the material properties of the API and the spray–drying conditions also influence pore size. „„Suspension-based

PulmoSphere formulations For suspension-based PulmoSphere formulations, the API is dispersed as fine particles in the continuous phase of the oil-in-water emulsion [4,20,23,33,45–50]. On drying, the API particles are coated with a porous layer of the PulmoSphere excipients (Figure 1E–G). The dispersed API particles may be crystalline or amorphous. future science group

The particles may be prepared by either topdown or bottom-up manufacturing processes (Chan and Kwok [70], and references therein). Top-down manufacturing processes include jet milling, ball milling, media milling, and highpressure homogenization. Bottom-up processes include: spray–drying, spray–freeze–drying, supercritical fluid technologies (rapid expansion and antisolvent), templating and microfabrication, lithography, and other particle precipitation techniques (e.g., spinodal decomposition). Particle precipitation may be done in the presence of ultrasonic energy to induce crystallization of the API, if desired. To facilitate effective coating of the API with the PulmoSphere excipients, it is desirable to have the mass median diameter of the dispersed API particles be 2.0 µm or less, with 90% of the particles less than approximately 5.0 µm [7]. One key requirement for the suspensionbased PulmoSphere process is the maintenance of the physical form of the API during processing. For crystalline APIs, drug that is dissolved www.future-science.com

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Review | Weers & Tarara A

B

5 µm

D

5 µm

C

5 µm

5 µm

Figure 3. Influence of variations in the perfluorooctyl bromide/ distearoylphosphatidylcholine ratio on particle morphology for 50% w/w gentamicin PulmoSphere™ particles (solution-based PulmoSphere format). (A) PFOB/DSPC = 10; (B) PFOB/DSPC = 20; (C) PFOB/DSPC = 40; (D) PFOB/DSPC = 80.

in the feedstock will typically be converted into an amorphous solid in the spray-dried drug product. The dissolved fraction for a given API in the feedstock can be calculated from Equation 2 . Dissolved(%) = 100(S API)(m fil)(1 zPFOB) (C solids)(Dnom) Equation 2

Key Terms Spray-blending: Spray–

drying process utilizing an atomizer with multiple spray nozzles with noninteracting plumes. The feedstock composition and pump rate can be independently controlled for each nozzle enabling intimate blends of micron-sized particles of differing compositions and/or micromeritic properties to be achieved.

Respirable agglomerate:

Agglomerate of a micronized drug (geometric diameter: 1–5 µm) particle with small porous carrier particles (geometric diameter: 1–5 µm), or between drug containing PulmoSphere™ particles (solution- or suspension-based PulmoSphere formats), wherein the agglomerate has an aerodynamic diameter between 1 and 5 µm.

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Where SAPI is the solubility of the API in the emulsion (mg/ml), m fill is the fill mass (mg), fPFOB is the volume fraction of PFOB (v/v), Csolids is the solids content in the feedstock (mg/ml), and Dnom is the nominal dose (mg). API dissolution can become problematic for potent drugs (Dnom< 100 µg), even when the solubility is on the order of 0.1 mg/ml [60]. API dissolution can be limited by both formulation and process controls. The solubility of the API can be modified by selection of an alternative salt form, via control of the ionization state of the API through manipulation of pH, or via the addition of a common ion. For example, adjustment of the pH of ciprofloxacin markedly decreases solubility from 3.6 mg/ml for the hydrochloride salt at pH 4.3, to 0.07 mg/ml for the zwitterionic form at pH 7.5 [61]. Similarly, addition of the common ion sodium maleate to suspensions of the bronchodilator indacaterol maleate decreases the solubility of indacaterol from 0.2  to 0.005 mg/ml [60]. Ther. Deliv. (2014) 5(3)

Process strategies to limit API dissolution include decreasing the temperature of the feedstock to limit solubility, spray–drying at a higher solids content, and a novel spray-blending strategy, where particles formulated at a high drug loading (to limit API dissolution) are blended with placebo particles in a single-step particle creation and blending process [60]. In sprayblending, the two different types of particles are created via spray–drying with a custom-built atomizer containing multiple twin fluid nozzles [55,60,71]. The atomizer enables independent control of the composition, and feed rate of the materials supplying each nozzle. The intimate blends of particles are created ‘one particle at a time’ enabling excellent blend uniformity. The particles are typically designed to have the same size, morphology and surface composition, and differ primarily in the presence or absence of API in the particle core. Given the similarity of the particles, the particles in the spray-blend have little tendency to segregate during filling, shipping or on storage [60]. If desired, different particle size distributions can be created from each nozzle. The suspension-based PulmoSphere process has been advanced into late-stage clinical development. Ciprofloxacin inhalation powder (Bayer Pharmaceuticals) is currently in Phase III clinical development for the treatment of Pseudomonas aeruginosa infections in non-CF bronchiectasis [45–50], and amphotericin B inhalation powder (Novartis Pharmaceuticals Corporation) has been advanced to an end-of-Phase II meeting with Health Authorities for prophylaxis against invasive pulmonary aspergillosis in immunocompromised patients [33]. „„Carrier-based

PulmoSphere formulations For carrier-based PulmoSphere formulations, small porous PulmoSphere particles are used as carrier particles, forming ordered mixtures with micronized API (Figure 1H) [27–32,51,52,62]. A key aspect of the ordered mix between API and small porous particle carriers is that the micronized drug is able to adhere strongly to the small porous particles. The goal is not to disperse the drug from the carrier during a patient’s inhalation. Rather, it is for the patient to inhale the respirable agglomerates into their lungs. Under this scenario, the physicochemical properties of the API and its content in the powder become less important. This is in stark contrast to ordered mixtures of coarse lactose and micronized drug, where both the adhesive future science group

The PulmoSphere™ platform for pulmonary drug delivery forces between drug and carrier, and the cohesive forces between the micronized drug particles are critical in the resulting bulk powder properties and aerosol drug delivery [72,73]. Carrier-based PulmoSphere formulations are prepared in a two-step manufacturing process. In the first step, PulmoSphere carrier particles are prepared by the standard PulmoSphere manufacturing process. In the second step, a cosuspension of the small porous carrier particles and micronized drug are formed in a nonsolvent liquid medium (e.g., perfluorooctyl bromide, hydrofluoroalkane propellant). For dry-powder formulations, the nonsolvent may be removed in a subsequent drying step [62]. For pMDI formulations, the solvent removal process occurs via evaporation of the propellant at the time of patient use [27–32]. The suspension- and carrier-based PulmoSphere formats are close cousins that differ only in the placement of the API particles. For the suspensionbased format, the drug particles are present within the PulmoSphere particle, whereas in the carrier-based format, the structure is inverted with the drug particles adhered to the outside of the PulmoSphere particle. Hence, many of the principles (e.g., geometric particle size distribution) that govern formulation of suspension-based PulmoSphere particles also apply to carrier-based PulmoSphere formulations. It is worth noting that all PulmoSphere formats result in the formation of respirable agglomerates. The aerodynamic diameter of a respirable agglomerate (d a) is related to the geometric size of the agglomerate (dg) and the agglomerate density (ragg) via Equation 3: da = dg

tagg |t 0

Equation 3

Here, ‘r0’ is the unit density (of spherical calibration spheres), and c is the dynamic shape factor, defined by the ratio of the drag force on a particle, or particle agglomerate, to the drag force on a volume-equivalent sphere of the same velocity. Hence a ‘spherical’ agglomerate with dg = 10 µm, ragg = 0.1 g/cm3, would have da = 3 µm. In general, the solubility of most drugs in PFOB is very poor. As a result, one advantage of the nonaqueous spray–drying process relative to the conventional aqueous-based PulmoSphere spray–drying process is that it enables formulation of APIs with poor chemical and/ future science group

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or physical stability in water [62]. As such, the carrier-based PulmoSphere format enables formulation of API salts that hydrolyze, or disproportionate, in water [62]. Moreover, potent crystalline APIs with a finite solubility in water can be formulated with the carrier-based PulmoSphere process, without the risk of API dissolution and amorphous drug formation in the spray–drying process. The carrier-based PulmoSphere process is also ideal for formulating water-soluble APIs that have a finite solubility in hydrofluoroalkane propellants, when spray-dried using the solutionbased PulmoSphere process [27,28]. For solutionbased PulmoSphere particles with amorphous API, dissolution of small quantities of API in the propellant leads to coarsening of the particles via molecular diffusion (Ostwald ripening). Significant increases in the solubility of amorphous drug in propellant are often observed compared with the corresponding crystalline form of the drug. The carrier-based format allows the crystallinity of the drug to be maintained, thereby decreasing the potential for physical instability of the drug product on storage. Carrier-based PulmoSphere formulations of formoterol fumarate and glycopyrronium bromide and a fixed-dose combination (FDC) of the two APIs have been advanced into Phase III clinical development by AstraZeneca for the treatment of airway obstruction in chronic obstructive pulmonary disease (COPD) patients [2]. Development of a triple combination with an added corticosteroid (e.g., mometasone) looks promising [27–29,32]. „„FDCs

The development of FDCs of two or more APIs is possible in each of the PulmoSphere formats [27–32,55,60,62,63]. The choice of format will be dictated by a number of factors including dose, the physicochemical properties of the APIs and any potential component interactions between the APIs or with the excipients. Moreover, it is possible to incorporate more than one PulmoSphere format in a FDC, even within a single particle [63]. Figure  4 outlines the multiple options for formulating FDCs. In the first option, two or more APIs are spray-dried from a single feedstock [55,60,63]. Each API may be either dissolved or dispersed as fine particles in the feedstock. It has been demonstrated that FDCs comprising a water-soluble API (glycopyrrolate) and a water-insoluble API (indacaterol) can be coformulated from a single www.future-science.com

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D1, D2, En

D1, En

En D2, En

D1 D2

Figure 4. Examples of how multiple active pharmaceutical ingredients can be coformulated in PulmoSphere™ powders. (A) Two or more active pharmaceutical ingredients (APIs; D1, D2) are coformulated from a single feedstock into a single particle with PulmoSphere excipients (En); (B) two or more APIs are formulated from separate feedstocks into separate particles; (C) two or more API particles are adhered to PulmoSphere carrier particles in an ordered mixture [55] .

feedstock [63]. The resulting PulmoSphere particles contain three phase-separated domains in a single particle: amorphous glycopyrrolate, crystalline indacaterol and gel-phase phospholipid. Each of the three phases are chemically and physically stable, and the FDC exhibits excellent aerosol performance. In the second option, the APIs are spray-dried from separate feedstocks and are present in separate particles. These particles may be blended (e.g., in a sprayblending process) [55,60]. Finally, multiple APIs may be simply added to PulmoSphere carrier particles in the carrier-based PulmoSphere format [27–32,55,62]. PulmoSphere delivery systems Each of the PulmoSphere formats may be delivered to the lungs of a subject using any of multiple delivery systems. „„Partial

Key Term Homodispersion™: System

of finely divided porous particles in a liquid, wherein the liquid substantially permeates within the porous particles, and the continuous and dispersed phases are made up largely of the liquid medium, separated by an interfacial layer of drug and excipient.

284

liquid ventilation The PulmoSphere technology was originally developed with the aim of stabilizing suspensions of APIs in perfluorocarbon liquids for delivery in conjunction with partial liquid ventilation (PLV) [24–26,54]. In PLV, perfluorocarbon liquid (e.g., PFOB) is instilled into the lungs of patients up to a volume approximating a functional residual capacity [74,75]. Gas exchange within the medium is accomplished with a conventional mechanical ventilator. PLV has been investigated for the treatment of infant respiratory distress syndrome [67], and acute lung injury/adult respiratory distress syndrome in pediatric and adult patients [68,69]. PLV provides several potential advantages as a ventilation technique including: improved gas exchange, improved lung compliance, lung recruitment and prevention of alveolar collapse, redistribution of pulmonary blood flow, alveolar Ther. Deliv. (2014) 5(3)

tamponade, pulmonary lavage and anti-inflammatory properties. Drug delivery in conjunction with PLV provides a means to deliver APIs to nonventilated regions of the lung that may not be accessible to pharmaceutical aerosols [24–26,74]. The original hypothesis for stabilizing API suspensions in the ‘liquid Teflon medium’ centered on reductions in interparticle attractive forces via formation of a novel drug suspension termed a homodispersion™ [8,20,21,54]. In a homodispersion, the liquid perfluorocarbon medium is able to permeate within the hollow porous PulmoSphere particles, resulting in dispersed liquid and continuous phases that are identical, separated by an interfacial layer comprising API and excipient. Homodispersion formation improves suspension stability in two ways. First, the difference in density between the particles and liquid medium is minimized, resulting in a reduced tendency for particles to cream or sediment. Second, the hollow porous morphology of the particles minimizes the area of contact between particles, thereby reducing van der Waal’s forces and particle agglomeration. This is also enhanced by the rugosity of the particle surface. The nonaqueous PFOB suspensions may also be nebulized [56], preferably with catheter-based nebulizers through an endotracheal tube, or with vibrating mesh nebulizers. Only exploratory studies have been conducted with this embodiment of the PulmoSphere technology, with no products advanced into clinical development [56]. „„Metered-dose

inhalers The homodispersion concept was subsequently extended to the stabilization of suspensions of APIs in hydrofluoroalkane propellants for delivery as an aerosol with a pMDI [8,20,21,58]. The impact of homodispersion formation on suspension stability in HFA-134a is illustrated for albuterol sulfate PulmoSphere formulations in Figure 5 [8]. The improved suspension stability achieved with PulmoSphere formulations improves dose consistency across the contents of the inhaler in a shake-pause-fire testing scenario [8]. „„Dry-powder

inhalers The porous morphology and hydrophobic surface of PulmoSphere particles also reduce inter­p article cohesive forces in dry-powder inhaler (DPI) formulations [10,11,13,34]. At relative humidities less than 60%, interparticle cohesive forces are dominated by long-range future science group

The PulmoSphere™ platform for pulmonary drug delivery van der Waal’s forces. For rigid spheres, van der Waal’s forces are directly proportional to the geometric particle diameter (d g ) and the Hamaker constant (A), and inversely proportional to the square of the separation distance (r) (Equation 4):

| Review

A

d d Ad g Fvdw = A e g1 g2 o = (rigid spheres) 6r2 d g1 + d g2 12r 2

t=0s

t = 30 s

t=4h

Equation 4

PulmoSphere platform What makes formulation of inhaled products especially challenging is the diversity of API properties and delivery requirements. APIs may be small molecules or macromolecules, hydrophilic or hydrophobic, soluble or insoluble, crystalline or amorphous. The site of action may be local to the lungs or in the systemic circulation, in the central lung or in the peripheral lung, intracellular or extracellular. Nominal doses may range from less than 10 µg, to more than 100 mg, with acute or chronic administration. The PulmoSphere technology in its array of formats and delivery systems represents a true platform for pulmonary drug delivery, able to deliver on these complex formulation challenges. To date, more than 60 APIs have been successfully formulated using the technology. These include 18 small molecules and eight macromolecules future science group

250

PulmoSphere™ RSD = 3% Proventil® HFA RSD = 91%

200 % Label claim

The force of attraction is strongly influenced by particle morphology. For the hollow porous particles pictured in Figure 1, these factors may be accounted for by replacing the geometric particle diameter in Equation 4 with an effective particle diameter, deff, defined by the effective interaction area [76]. For hollow porous particles, the distance between pores approximates the effective diameter, assuming that this distance is far less than the characteristic pore diameter. In this limit, the van der Waals forces are significantly less than that observed for micron-sized hard spheres. The reduced attractive forces markedly improve powder fluidization and dispersion, resulting in improvements in lung targeting and dose consistency relative to currently marketed DPIs. The selection of delivery system will depend upon a number of factors including: the specific requirements of the patient population, the nominal dose, the cost and the administration setting (at home or in the hospital), to name a few. The various combinations of PulmoSphere formats and delivery systems comprise the ‘PulmoSphere platform’.

150 100 50 0 Beginning

Middle Actuation

End

Figure 5. Comparison of the physical stability of albuterol sulfate suspensions in HFA-134a, and its potential impact on pulmonary drug delivery. (A) Presents a comparison of Proventil® HFA (left vial) and albuterol PulmoSphere formulations (right vial) immediately after shaking and at 30 s and 4 h post-shaking. The homodispersion-based PulmoSphere formulation exhibits excellent physical stability over the 4 h period, while sedimentation is observed within 30 s for the Proventil HFA formulation. (B) Shows the impact that poor physical stability may have on dosing at the beginning, middle and end of the canister. In this shake-pause-fire study, canisters were first shaken, followed by a 30 s pause, and then actuation of the device and quantitation of the delivered dose. The PulmoSphere formulation exhibits significantly less variability across the canister life as a result of its improved suspension stability [8] . For Proventil HFA, the albuterol dose is greater than the label claim at the beginning of the canister due to sampling from the sedimented drug layer, and decreases to less than the label claim at the end of the inhaler. RSD: Relative standard deviation in delivered dose uniformity observed relative to the label claim. Reprinted with permission from [8] © Samedan Ltd (2000).

for treatment or prophylaxis of infectious disease, 20 small molecules for the treatment of asthma/COPD, and an additional 15 APIs for treatment of various local and systemic diseases. Generally, the delivered dose exceeds 80% of the nominal dose, with a relative standard deviation of approximately 4% or less. Approximately 40–70% of the nominal dose is delivered to the lungs. Each of the PulmoSphere formats has been advanced through preclinical safety studies and into late-stage clinical development (Table  3). www.future-science.com

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Review | Weers & Tarara Table 3. Clinical development with PulmoSphere™ formulations (as of June, 2013). API

PSph format

Delivery system Status

Tobramycin

Solution DPI (T-326) PulmoSphere™

Ciprofloxacin

Suspension PulmoSphere

DPI (T-326)

Glycopyrrolate/formoterol, glycopyrrolate, formoterol

Carrier PulmoSphere

pMDI

Amphotericin B

Suspension PulmoSphere

DPI (T-326)

Glycopyrrolate/ Formoterol/ Carrier Budesonide PulmoSphere Indacaterol Suspension PulmoSphere

pMDI DPI (Concept1, Simoon)

Studies

Ref. [11,38–44]

Approved Marketed drug product for treating chronic Pseudomonas aeruginosa infections in CF patients. Five completed clinical studies encompassing more than 500 subjects [46–50] Phase III Completed clinical development through Phase IIb in CF and non-CF bronchiectasis. Five completed studies encompassing more than 400 subjects [51,52] Phase III Completed clinical development through Phase IIb: ten studies encompassing more than 1000 subjects (COPD) [Nektar End of Completed three Phase I studies in 57 Therapeutics, Phase II healthy volunteers. Completed end of Unpublished Data] Phase II meetings with Health Authorities for prophylaxis against invasive pulmonary aspergillosis indication. [76] Phase I A Phase I study was initiated with the triple combination for COPD [Novartis Proof of Completed three studies with more Pharmaceuticals concept than 100 subjects Corporation, Unpublished Data]

Budesonide

Suspension PulmoSphere

DPI (Eclipse®)

Proof of concept

Leuprolide

Solution PulmoSphere

DPI (Turbospin®)

Proof of concept

Albuterol

Solution PulmoSphere

pMDI

Proof of concept

Pharmacoscintigraphy study exploring flow rate dependence of budesonide PulmoSphere relative to Pulmicort® Turbuhaler® in ten healthy volunteers Pharmacokinetics study in 12 healthy volunteers

[10]

[Inhale Therapeutic Systems, Unpublished Data]

g scintigraphy study comparing albuterol PulmoSphere formulation to Ventolin® Evohaler® in nine healthy volunteers

[22]

API: Active pharmaceutical ingredient; CF: Cystic fibrosis; COPD: Chronic obstructive pulmonary disease; DPI: Dry-powder inhaler; pMDI: Pressurized metered-dose inhaler; PSph: Phosphoserine phosphatase.

PulmoSphere formulations have been studied in more than 30 clinical trials involving more than 2000 subjects, including healthy volunteers and patients with asthma, COPD, CF, and non-CF bronchiectasis. Clinical development has been focused in two primary areas: the delivery of high doses of anti-infectives with a portable inhaler [11,33–50], and the development of potent asthma/COPD therapeutics and their FDCs [10,27–32]. The formulations have been well tolerated, and no significant preclinical or clinical safety concerns have been noted. PulmoSphere formulations have also demonstrated utility in the delivery of biologicals, particularly in the potentiation of immune responses for encapsulated vaccines [15–19,59]. 286

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„„Large

dose range Clinical studies have validated the capability of PulmoSphere formulations to deliver nominal doses of API with a portable inhaler from 600 ng to more than 100 mg, a range spanning nearly six orders of magnitude [10,28,33,38– 40,45–50]. In fact, PulmoSphere formulations have extended the dose range with portable inhalers beyond that attained previously on both the high and low ends of the dose spectrum, thereby enabling new product opportunities (e.g., inhaled antibiotics with a portable inhaler; Figure 6). Delivery of APIs in conjunction with PLV extends the dose range even further: doses as high as 1–100 g may be delivered to intubated future science group

The PulmoSphere™ platform for pulmonary drug delivery patients via the side-port in an endotracheal tube. Liquid-dose instillation of antibiotics may enable effective treatment of patients with severe pneumonia, in particular patients with hospital-acquired pneumonia [24–27,54].

| Review

independent of the drug loading of each API [27–32,60,62,63]. Improvements in dose consistency & lung targeting A key design feature implicit in all PulmoSphere formulations is the desire to reduce interparticle cohesive forces as a means to maximize lung targeting, and enable improvements in the consistency of pulmonary drug delivery. Inhalation errors can be divided into three categories: dose preparation errors, dose inhalation errors and failure-to-use errors [78]. The ultimate goal is to design a portable inhaler where dose preparation is intuitive and does not require subject training, where drug delivery is independent of a subject’s inhalation profile, and where patients are reminded and even incentivized to take their medication. There are three principal areas where PulmoSphere formulations contribute to significant improvements in dose consistency through reductions in the variability associated with dose inhalation. These are: reductions in the variability associated with particle filtering in the mouth-throat; lung delivery of APIs that are independent of a subject’s inhalation profile, and; reductions in the variability associated with coformulation of two or more APIs in a FDC.

„„API

properties The PulmoSphere technology provides a formulation solution for virtually any API, independent of its physical form and physicochemical properties. These include: APIs that are insoluble in water (SAPI  100 mg) and via liquid-dose instillation (max dose ≈ 100 g). With the exception of the gentamicin partial-liquid ventilation dose, all of the other API doses were delivered with portable inhalers in clinical studies. DPI: Dry-powder inhaler; pMDI: Pressurized metered-dose inhaler.

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Figure 7. Variability in total lung deposition versus total lung deposition. Data for spray–dried porous particles (e.g., PulmoSphere™ and large porous-particle formulations) are represented by the open triangles. RSD: Relative standard deviation from the mean value. Adapted from [79] and reproduced with permission from [12] © Mary Ann Liebert Inc. (2010). „„Variability

associated with mouth-throat filtering of particles The ‘lung dose’ is the fraction of the delivered dose that is able to bypass deposition in the upper respiratory tract (i.e., mouth and throat), and not be exhaled. Particle deposition in the mouth–throat is governed by inertial impaction, with deposition efficiency related to the Stokes number (Equation 5): Stk =

„„Drug

tp d g2 QC c d 2a QC c = 9hd 9hd Equation 5

where Stk is Stoke’s number, rp is the particle density, d g is the geometric diameter, d a is the aerodynamic diameter, Q is the volumetric flow rate, C c is the Cunningham correction factor, h is the viscosity of air, and d is the characteristic dimension of the obstacle. The key variables in the Stokes number are often combined and termed the inertial impaction parameter, d2 Q . Anatomical differences in the soft tissue in the mouth–throat (i.e., differences in d), play a significant role in the intersubject variability observed in total lung deposition. The variability in total a

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lung deposition increases with increases in d 2 Q, and is inversely proportional to total lung deposition (Figure 7). Porous-particle formulations enable highly efficient delivery to the lungs (total lung deposition of 40–70% of the nominal dose), markedly reducing variability to just 10–20% of total lung deposition [12]. To further emphasize this point, let us compare the total lung deposition and interpatient variability measured for marketed inhaled cortico­steroid formulations, and a corresponding PulmoSphere formulation (Figure 8) [10,80]. In this comparison, the lactose-blend formulation is the marketed fluticasone propionate formulation in Diskus ®(GlaxoSmithKline), the spheronized particles are the marketed budesonide formulation delivered from the Turbuhaler ® (AstraZeneca), and a PulmoSphere formulation that comprises spraydried budesonide particles delivered with the capsule-based Eclipse ® DPI. The left panel in Figure 8 demonstrates the significant increases in total lung deposition (expressed as a percentage of the nominal dose) observed for the PulmoSphere formulation (58% w/w) relative to the spheronized particles (36% w/w) and lactose blend (12% w/w). The increased lung deposition results in concomitant decreases in interpatient variability (right panel), which is consistent with the historical data for the large number of studies presented in Figure 7. Interpatient variability decreases from roughly 40% with the lactose blend to just 12% with the PulmoSphere formulation.

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delivery independent of the subject’s inhalation profile For passive DPIs, powder fluidization and dispersion is accomplished via the subject’s inspiratory effort. The mean-pressure drop (DP) for subjects with lung disease (e.g., asthma, COPD, CF) is approximately 4–5 kPa, and nearly all patients, including pediatrics, geriatrics, and patients with severe lung disease, can achieve a pressure drop of at least 1 kPa [13,81,82]. For a given pressure drop, subjects will achieve different inhalation f low rates (Q ), depending on the resistance of the device (R inhaler; Equation 6): Q=

DP R inhaler E quation 6 future science group

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Marketed dry powder products are often described in terms of their minimum flowrate requirements. It is generally perceived that pediatric patients and patients with severe lung disease may not be able to effectively use DPIs [83]. While this may be a significant concern for dry powders comprising spheronized particles or lactose blends, it is less critical with PulmoSphere formulations, where modulation of interparticle cohesive forces enables effective powder deagglomeration at low flow rates [12,13]. For example, significant differences in lung delivery efficiency as a function of f low rate are observed for spheronized budesonide particles in the Pulmicort Turbuhaler: 27.7% of the metered dose at a flow rate of 60 l/min (DP = 5.2 kPa), and 14.8% at a flow rate of 35 l/min (DP = 1.8 kPa) [84] . Increasing peak-inspiratory f low rate impacts total lung deposition in two opposing ways: via increases in inertial impaction in the mouth–throat, which decreases total lung deposition, and via increases in powder deagglomeration, which increases total lung deposition [13]. Proper design of a drug–device combination product, makes it possible to balance these two effects, enabling drug delivery that is independent of flow rate over a wide range of pressure drops across a DPI [10,12,13]. Figure 9 is a plot of the deviation from mean lung deposition for a series of porous particle formulations (within a given study) obtained via gamma scintigraphy, versus the pressure drop achieved by the subject during the inhalation maneuver. Porous-particle formulations can achieve f low rate independence in lung deposition in healthy volunteers over a range of pressure drops extending from approximately 0.5–10 kPa [12]. The observed interpatient variability in total lung deposition was just 12%. It is especially remarkable that this includes, not only the variability associated with the large range of pressure drops studied, but also the differences in deposition resulting from anatomical differences in the mouth–throat. The observed f low rate independence has been demonstrated across multiple formulations (e.g., PulmoSphere particles, large porous particles) and devices (both capsule-based and blister-based inhalers). For example, Duddu et al. found that normal subjects were able to achieve 57.7% total lung deposition for a PulmoSphere formulation of budesonide when asked to inhale forcefully through the Eclipse DPI, and 57.0% when asked to inhale

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Figure 8. Comparison of the impact of total lung deposition of inhaled corticosteroid on interpatient variability in total lung deposition. For the PulmoSphere formulation there were eight subjects, while for the spheronized particle and lactose blend formulations were studied in 21 subjects. RSD: Relative standard deviation. Data taken from [10,80].

comfortably (expressed as a percentage of the nominal dose) [10]. Note this data is plotted in Figure 8. www.future-science.com

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Figure 9. Plot of the variability in total lung deposition for porous, engineered particles as a function of the pressure drop across the inhaler. Each point represents an individual subject. Adapted with permission from [12] © Mary Ann Liebert Inc. (2010).

Achieving flow-rate independence in total lung deposition requires that the inertial impaction parameter, d2 Q , be constant with variations in flow rate [13]. Weers et al. explored the impact of variations in inhalation profile on deposition of PulmoSphere vehicle particles post-throat in the idealized Alberta throat model and Next Generation Impactor [13]. The independence of the in vitro lung dose correlated with independence in the inertial parameter, d2 Q . Deposition on individual stages within the Next Generation Impactor (constant d2 Q ) was found to be consistent with variations in flow rate from 18 l/min (1 kPa) to 46 l/min (6 kPa), with a blister-based DPI (Simoon, Novartis Pharmaceuticals Corporation). The degree of powder dispersion of an ensemble of engineered particles with variations in flow rate can be regulated via modulation of the micromeritic properties of the powder (e.g., geometric size, porosity, density, rugosity), or via design of device-specific features to achieve a constant d2 Q [13]. PulmoSphere formulations in passive inhalers have been demonstrated to achieve constant d2 Q over a wide range of pressure drops [13]. A recent study with the TOBI Podhaler studied the impact of variations in patient inhalation maneuver on tobramycin deposition in the idealized Alberta mouth–throat model [37]. Excellent in vitro/in vivo correlations, with respect to total lung deposition, have been observed for these models of realistic throats. In this study, the breathing profiles of 38 CF a

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patients ranging in age and disease severity were assessed. Breathing profiles representative of patients across the patient population were selected; the profiles had peak inspiratory flow rates ranging from 48.9 l/min (DP = 1.6 kPa) to 88.4 l/min (DP = 5.4 kPa), and inhaled volumes ranging from 0.9–2.9 l. The in vitro lung dose (i.e., deposition post-Alberta throat) varied over a narrow range, from 59–63% of the label claim. In other studies, drug delivery with PulmoSphere formulations in portable inhalers was also found to be largely independent of other inhalation parameters, such as the ramp time to peak flow and the inhaled volume [13,37]. Overall, the results clearly demonstrate that lung delivery of PulmoSphere particles can be achieved independent of a subject’s inhalation profile over a broad range of inspiratory profiles that are representative of a large cross-section of a selected patient population. „„Reductions

in variability in FDCs Coformulation of multiple APIs can be achieved in each of the PulmoSphere formats. One key regulatory aspect of these FDCs is that the pulmonary delivery of each API should be the same whether it is delivered as the monocompound or in combination with one or more additional APIs. In lactose blends, there is generally a strong coformulation effect on aerosol performance [85]. The problem is significant enough that some groups have turned to the development of sophisticated devices that package each API separately, and concurrently deliver the contents of the two packages in a single inhalation [86]. In contrast, PulmoSphere formulations enable FDCs without introducing complexity into device designs. This is illustrated in Figure  10 for the carrier-based PulmoSphere format [28]. Here, the aerodynamic particle size distributions of glycopyrrolate are comparable when this bronchodilator is formulated as a monotherapy, in a dual combination with formoterol fumarate, or in a triple combination with formoterol and mometasone. Similar results are observed with the other PulmoSphere formats, where the APIs are coformulated in a single particle [62,63]. PulmoSphere formulations enable effective delivery of APIs that are independent of the presence of a second or third API in the formulation, and its content in the spray-dried formulation. Coformulation of two or more APIs in a single formulation increases the probability of future science group

The PulmoSphere™ platform for pulmonary drug delivery

Limitations of the PulmoSphere platform As with any technology, the PulmoSphere technology has some inherent limitations: The presence of calcium ions in the formulation may lead to compatibility issues with some APIs and excipients (e.g., buffers);

n

The base technology for the solution-based PulmoSphere format, which leads to formation of amorphous API, does not contain glass-forming excipients (e.g., carbohydrates). Incorporation of carbohydrates in the formulation may lower the Tm of the DSPC, potentially decreasing the physical stability of the formulation or constraining the process parameters on the spray-dryer. Hence, the PulmoSphere technology may not be ideal for formulation of some proteins that require glassy stabilization to maintain chemical stability;

n

PulmoSphere powder formulations are susceptible to the deleterious effects of water on aerosol per forma nce. Decrea ses in

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compatibility issues between the various APIs and between the APIs and the excipients. The PulmoSphere technology in its various formats offers multiple strategies to mitigate these issues. For example, in carrier-based PulmoSphere formulations, there are typically about two orders of magnitude more carrier particles (smaller size and lower density relative to coarse lactose carriers) than there are drug particles. Given that the APIs are strongly adhered to the carrier particles, the large ratio of carrier particles to drug particles provides a spatial separation to prevent interaction of the various APIs. This physical barrier concept centered on ordered mixtures of API and small porous, carrier particles has been whimsically referred to as the ‘Fed-Ex process’, where the hundreds of PulmoSphere carrier particles are able to physically and chemically stabilize the drug substance in much the same way that packing peanuts isolate and stabilize fragile goods on shipping. Similarly, the sprayblending process enables physical separation of two or more APIs in their own core-shell particles [60,71]. In general, the phosphatidylcholine excipient is also inherently less chemically reactive than lactose, which may participate in various chemical reactions (e.g., Maillard reactions with proteins) [87].

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Figure 10. Aerodynamic particle size distributions of GP in various carrier-based PulmoSphere™ pMDI formulations. The aerodynamic particle size distributions are similar for the placebo particles, and for GP formulated as a mono-therapy, or in a binary combination with FF, or a ternary combination with FF and mometasone furoate. The pressurized metered-dose inhaler equipped with a 50 µl metering valve is designed to deliver 10, 40, and 100 µg of formoterol fumarate, glycopyrrolate, and mometasone furoate along with 300 µg of PulmoSphere placebo particles (93.4% DSPC, 6.6% CaCl2). FF: Formoterol fumarate; GP: Glycopyrrolate. Reprinted with permission from [28] © American Chemical Society (2012).

fine-particle fraction of approximately 20% may be observed following aerosol administration at elevated relative humidity. This can be mitigated by selection of an alternative delivery system if needed. Future perspective The utility of the PulmoSphere platform has been demonstrated for the delivery of highdose antibiotics (up to doses >100 mg) [34] and FDCs of low-dose asthma/COPD therapeutics (down to doses < 1 µg) [28] with portable inhalers. All of these products have been lifecycle extensions of approved APIs. As these products emerge onto the market, the risks associated with the development of the technology, as well as perceived regulatory risks, diminish and it will no longer considered to be a high risk to develop a new chemical entity with the technology (i.e., one is no longer stacking risks). Hence, it is likely that the PulmoSphere platform will begin to be applied to the development of new chemical entities, www.future-science.com

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Review | Weers & Tarara Key Term Particle engineering:

Rational design of structured microparticles (e.g., composition, morphology, particle size distribution) fit for their intended purpose.

including potential new drugs in other indications, including pulmonary arterial hypertension, idiopathic pulmonary fibrosis, in addition to novel asthma/COPD and CF therapeutics. The potential for use of PulmoSphere formulations in conjunction with liquid ventilation also remains largely untapped, and is an exciting area for research and development. The broad utility of the PulmoSphere platform, with respect to being able to formulate APIs with a broad range of physicochemical properties into a wide range of physical forms, allows the medicinal chemist to focus on designing molecules for therapeutic effect, without necessarily having to focus on designing the physical properties of the resulting molecules. To date, most molecules for pulmonary delivery have followed the Lipinski rule of five for oral drugs [88]. Particle engineering opens the door to formulating molecules with poor solubility and permeability for local or systemic delivery via inhalation. Finally, PulmoSphere formulations enable drug delivery that is largely independent of how a patient inhales through a portable inhaler. Combined with advances in inhaler design to reduce errors associated with dose preparation, and the introduction of telehealth capability to track patient adherence, it is anticipated that significant improvements in dose consistency

and patient adherence will be achieved, possibly leading to improved outcomes. Acknowledgements J Weers and T Tarara wish to thank all of the scientists who have contributed to the development of the PulmoSphere platform. In particular, the authors would like to single out the contributions of: L Dellamary, H Gill, B English, D Smith, A Bot, E Schutt, T Pelura, H DeLong and A Kabalnov (Alliance Pharmaceutical Corp), A Clark, J Patton, A Smith, R Vehring, D Miller, R Malcolmson, A Haynes, J Nakamura, M Hartman, K Walsh, L Hachmann, D Maltz, A Gupta, and D Huang (Inhale Therapeutic Systems).

Financial & competing interests disclosure The authors are employees of Novartis Pharmaceuticals Corporation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

In memoriam The authors wish to dedicate this article to the memory of Duane Roth. Without Duane’s leadership and vision, it is unlikely that the research team at Alliance Pharmaceutical Corp. would have had the opportunity to conceive and develop the PulmoSphere™ platform.

Executive summary What is a PulmoSphere™? „„

PulmoSphere formulations comprise small porous particles (mass median diameter = 1–5 µm) manufactured by spray drying a perfluorooctyl bromide-in-water emulsion.

The principal excipients in PulmoSphere formulations comprise a 2:1 molar ratio of distearoylphosphatidylcholine to calcium chloride. PulmoSphere formats „„

„„

Active pharmaceutical ingredients are incorporated in PulmoSphere formulations in three formats: in solution-based formulations, the active pharmaceutical ingredient is dissolved in the continuous phase of the emulsion feedstock; in suspension-based formulations, the active pharmaceutical ingredient is dispersed as fine particles in the emulsion, and; in carrier-based formulations the active pharmaceutical ingredient is adhered to the surface of PulmoSphere particles in an ordered mixture. The fine PulmoSphere particles in their various formats form respirable agglomerates.

Fixed dose combinations of two or more active pharmaceutical ingredients may be spray-dried from a single feedstock, from separate feedstocks, or incorporated using the carrier-based format. PulmoSphere delivery systems „„

PulmoSphere formulations may be administered to the lungs of a patient with a variety of delivery systems including: dry powder inhalers, metered dose inhalers, nebulizers, and via liquid-dose instillation through the side port of an endotracheal tube in intubated patients. PulmoSphere platform „„

„„

The PulmoSphere platform comprises small porous particles, the different formats for incorporating active pharmaceutical ingredient and the different delivery systems.

„„

The breadth of the PulmoSphere platform provides a delivery solution for virtually any pulmonary product opportunity, enabling significant improvements in lung targeting and dose consistency relative to current marketed products.

„„

PulmoSphere formulations and other particle engineering strategies offer tremendous potential for expanding the product opportunities in the inhalation space.

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References Papers of special note have been highlighted as: n of interest nn of considerable interest 1

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Demonstrates how drug/device combinations comprising PulmoSphere™ powders can be adjusted to achieve lung delivery, independent of a subject’s inhalation profile.

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et al. Cosuspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers. Langmuir 28, 15015–15023 (2012).

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