International Journal of Pharmaceutics 283 (2004) 1–9
`
`A review of the development of Respimat® Soft MistTM Inhaler
`R. Dalbya,1, M. Spallekb,∗
`
`, T. Voshaarc
`a Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 North Pine Street, Baltimore MD 21201-1180, USA
`b Department Drug Delivery, Boehringer Ingelheim Pharma GmbH and Co. KG, Ingelheim, Germany
`c Medical Clinic III, Bethanien Krankenhaus, Moers, Germany
`
`Received 3 January 2004; received in revised form 6 June 2004; accepted 7 June 2004
`Available online 20 August 2004
`
`Abstract
`
`Respimat® Soft MistTM Inhaler (SMI) is a new generation inhaler from Boehringer Ingelheim developed for use with respiratory
`drugs. The device functions by forcing a metered dose of drug solution through a unique and precisely engineered nozzle (the
`uniblock), producing two fine jets of liquid that converge at a pre-set angle. The collision of these two jets generates the soft
`mist. The soft mist contains a high fine particle fraction of approximately 65 to 80%. This is higher than aerosol clouds from
`conventional portable inhaler devices, such as pressurised metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). In
`addition, the relatively long generation time of the aerosol cloud (approximately 1.5 s) facilitates co-ordination of inhalation and
`actuation – a major problem with pMDIs. These features, together with the slow velocity of the soft mist, result in larger amounts
`of the drug reaching the lungs and less being deposited in the oropharynx compared with either pMDIs or DPIs. Generation of
`the soft mist from Respimat® SMI is purely mechanical, so propellants are not necessary. The innovative design of Respimat®
`SMI, using water-based drug formulations, ensures patients receive consistent and reliable doses of the drug with each actuation.
`The device was initially tested in scintigraphic lung deposition studies and produced encouraging results when compared with
`the chlorofluorocarbon-based pMDI (CFC-MDI). Subsequent clinical studies have confirmed that Respimat® SMI is effective
`and safe in delivering bronchodilators to patients with asthma or chronic obstructive pulmonary disease.
`© 2004 Published by Elsevier B.V.
`
`Keywords: Respimat® Soft MistTM; Inhaler (SMI); Lung deposition; Fine particle fraction; Aerosol; Obstructive lung disease; Inhaler device
`
`∗
`
`Corresponding author. Tel.: +49 6132 77 98774;
`fax: +49 6132 77 3823.
`E-mail addresses: rdalby@rx.umaryland.edu (R. Dalby),
`michael.spallek@ing.boehringer-ingelheim.com (M. Spallek).
`1 Tel.: +1 410 706 3245; fax: +1 410 706 0346.
`
`0378-5173/$ – see front matter © 2004 Published by Elsevier B.V.
`doi:10.1016/j.ijpharm.2004.06.018
`
`1. Introduction
`
`Inhalation therapy has led to considerable improve-
`ments in the treatment of obstructive airways diseases,
`such as asthma and chronic obstructive pulmonary dis-
`ease (COPD). As the drug is delivered directly to its
`site of action, a low dose can be used to produce a
`therapeutic response and, consequently, side effects
`
`Liquidia's Exhibit 1061
`Page 1
`
`

`

`2
`
`R. Dalby et al. / International Journal of Pharmaceutics 283 (2004) 1–9
`
`are minimised. Additionally, inhaled drug delivery cir-
`cumvents the limitations imposed by first-pass hepatic
`metabolism and fast absorption results in an onset of
`action that is more rapid than that achieved by oral ad-
`ministration.
`The efficacy of an inhaled drug is largely depen-
`dent on the amount of the drug deposited in the lungs
`and its topographical anatomical distribution; this is
`influenced by various interacting factors, including the
`characteristics of the aerosol, the type of delivery de-
`vice used, the mode of inhalation and the architecture of
`the airways (Ganderton, 1997; Pavia, 1997). The char-
`acteristics of the aerosol will affect the amount of drug
`reaching the lung. The method by which fine particles
`are produced for pulmonary delivery and the size distri-
`bution of these particles significantly affects drug depo-
`sition within the airways (Newman, 1984; Pavia, 1997).
`It may be possible to deliver drugs more precisely by
`using aerosols with a defined particle size distribution;
`for example, particles with a diameter of 2–5 ␮m are
`generally deposited in the smaller bronchioles and pe-
`ripheral airways (Ariyananda et al., 1996). Larger parti-
`cles tend to be deposited in the upper airways, whereas
`those smaller than 2 ␮m are, to a large extent, breathed
`in and out of the alveoli with minimal actual deposi-
`tion (Pavia, 1997; Ariyananda et al., 1996; Matthys,
`1990); small particles that do manage to deposit in the
`alveoli may be rapidly absorbed and exert no pharma-
`codynamic effect (Pritchard, 2001). A study by Zanen
`et al. found that the optimal particle size for ␤2 ago-
`nist and anticholinergic aerosols in patients with severe
`airflow obstruction was approximately 3 ␮m (Zanen et
`al., 1996). More recently, the effects of bronchodilator
`particle size on airway drug deposition in asthmatic pa-
`tients was studied (Usmani et al., 2003). Monodisperse
`salbutamol aerosols of 1.5, 3 and 6 ␮m in size were in-
`haled and lung function changes were determined; the
`3 and 6 ␮m aerosols were significantly more effective
`bronchodilators than the 1.5 ␮m aerosol.
`Several types of portable devices are currently avail-
`able for the delivery of drugs by inhalation; these
`include the chlorofluorocarbon (CFC) and hydroflu-
`oroalkane (HFA) pressurised metered dose inhalers
`(pMDIs), and the dry powder inhalers (DPIs). The
`CFC-MDI has been the cornerstone of asthma and
`COPD maintenance therapy for many years. How-
`ever, many patients experience problems in using CFC-
`MDIs and do not obtain optimal therapeutic benefit
`
`from their medication (Giraud and Roche, 2002). The
`limitations of the pMDI, and the move to eliminate
`CFC propellants for environmental reasons, have accel-
`erated the development of alternative inhaler devices.
`Inherent in the development of these new devices has
`been a determination to improve on known device de-
`ficiencies (Steed et al., 1997).
`Respimat® Soft MistTM Inhaler (SMI) is a new
`generation inhaler that uses mechanical power from
`a spring rather than liquid-gas propellant to generate
`an aerosol cloud suitable for inhalation. This article
`reviews the development of Respimat® SMI and de-
`scribes how the latest advances in aerosol technology
`have been used in order to improve upon existing in-
`haler performance.
`
`2. Respimat® SMI
`
`Respimat® SMI is a new generation, propellant-
`free, multi-dose inhaler developed by Boehringer In-
`gelheim. The term ‘soft mist’ is used to describe both
`the mechanism of aerosol generation and the qualities
`of the aerosol cloud. Respimat® SMI does not belong
`to any of the existing categories of inhaler device and
`represents an innovative approach to patient-oriented
`inhalation therapy.
`
`2.1. Rationale for the development of Respimat®
`SMI
`
`Respimat® SMI was developed in order to overcome
`the limitations of traditional inhaler devices and to meet
`the need for a convenient propellant-free inhaler that
`could effectively deliver aerosols from solutions. Cur-
`rently, the most common inhaler devices used for bron-
`chodilator and anti-inflammatory drug administration
`are pMDIs and DPIs; both have inherent disadvantages
`relating to lung deposition and ease of use.
`The pMDI produces particles that travel very fast,
`generating a high-velocity cloud over a short period
`of time. Two consequences of this are deposition of
`the drug on the back of the throat (the oropharynx)
`and difficulties in synchronising the generation of the
`dose with inspiration. Only about 10–20% of the dose
`released from CFC-MDIs is deposited in the lungs;
`the remainder of the dose is lost through impaction in
`
`Liquidia's Exhibit 1061
`Page 2
`
`

`

`R. Dalby et al. / International Journal of Pharmaceutics 283 (2004) 1–9
`
`3
`
`the oropharynx (Newman et al., 1981). HFA-MDIs are
`similarly inefficient; only one HFA-MDI formulation
`has shown lung deposition >50% (Leach et al., 1998).
`Many patients, particularly children and the elderly, are
`unable to co-ordinate actuation of pMDIs with inhala-
`tion, which is crucial for proper lung deposition; thus
`the amount of drug reaching the lungs is both small
`and variable. Numerous other inhaler technique errors
`have been observed with pMDIs, including stopping
`inhalation when the aerosol hits the back of the throat
`(Pavia, 1997). The soft mist generated by Respimat®
`SMI travels much slower and lasts much longer than
`aerosol clouds from other devices. The relatively long
`period over which the dose from Respimat® SMI is re-
`leased facilitates co-ordination of actuation and inhala-
`tion compared with pMDIs. This should help the pa-
`tient to achieve the correct inhaler technique, which is
`important for successful long-term treatment. Further-
`more, Respimat® SMI is easy and convenient to use; it
`retains the ‘user-friendliness’ of pMDIs, but does not
`require cumbersome spacer devices to slow the aerosol
`cloud and reduce oropharyngeal deposition (Denyer et
`al., 2000).
`DPIs are breath-actuated and therefore require no
`co-ordination between device actuation and inhalation.
`However, both the aerosolisation and delivery of the
`drug to the lung are dependent on an adequate inspi-
`ratory effort from the patient. Airflow achieved early
`in the inspiratory profile deaggregates the drug from
`its carrier powder (usually lactose) and determines the
`particle size distribution of the aerosol. Because of the
`great variability in inspiratory flow, both between pa-
`tients and within an individual patient, the proportion
`of the metered dose that is inhaled varies consider-
`ably, but is typically quite low (Meakin et al., 1998).
`A large fraction of the drug often remains bound to
`the carrier and deposits in the oropharynx (Ganderton,
`1997,1999). For some DPIs, lung deposition is lower
`than that seen with pMDIs (Newman, 1999; Zainudin
`et al., 1990). Importantly, some powder formulations
`are extremely moisture-sensitive; adsorption of mois-
`ture can significantly increase powder cohesiveness,
`leading to decreased generation of fine particles during
`inhalation.
`Energy to generate the soft mist delivered by
`Respimat® SMI comes from a compressed spring in-
`side the inhaler; consequently, the particle size pro-
`duced from the device is not dependent on the patient’s
`
`inspiratory effort. Moreover, Respimat® SMI generates
`an aerosol cloud from a solution rather than a powder,
`avoiding moisture adsorption and powder agglomer-
`ation problems. These characteristics ensure that the
`dose delivered with each actuation from Respimat®
`SMI remains uniform.
`Respimat® SMI is designed to be environmentally
`friendly and to increase lung deposition and reduce
`oropharyngeal deposition of the drug compared with
`pMDIs and DPIs, without the use of spacer devices.
`One design goal was to realise clinical improvements
`and minimise side effects by lowering the nominal in-
`haled dose compared with conventional delivery sys-
`tems.
`
`2.2. The concept of a soft mist inhaler
`
`The generation of an inhalable aerosol from a drug
`solution requires the metered dose of liquid to be
`converted into appropriately sized droplets without
`the use of propellants. One technique involves the
`use of electrical energy to produce vibrations (which
`is common in ultrasonic and piezo-electric devices).
`A second approach is to use mechanical energy to
`force drug solution through a nozzle. Respimat®
`SMI derives mechanical energy from a spring that
`can be easily compressed by the patient (Zierenberg
`et al., 1996). The spring mechanism ensures that the
`aerosol is generated by a reliable and reproducible
`energy source and, consequently, dose and particle
`size distribution of the aerosol are independent of the
`variable inspiratory flow of the patient.
`The soft mist concept was initially demonstrated in
`a prototype model, which consisted of a metal pump
`body and a syringe serving as a solution reservoir. A
`lever arm was used to simultaneously compress the
`spring and withdraw a metered volume of drug solu-
`tion from the reservoir. The liquid was forced through
`a two-channel nozzle upon release of the spring, result-
`ing in aerosol generation. The droplet size distribution
`in the aerosol was demonstrated to be in the range suit-
`able for inhalation (Zierenberg, 1999; Zierenberg and
`Eicher, 2002).
`Following further development of this early pro-
`totype,
`including the introduction of the uniblock
`nozzle (see below),
`the device was successfully
`used in lung deposition studies in healthy volunteers
`
`Liquidia's Exhibit 1061
`Page 3
`
`

`

`4
`
`R. Dalby et al. / International Journal of Pharmaceutics 283 (2004) 1–9
`
`(Steed et al., 1995a,b). Additional refinement of the
`device occurred after patient focus groups evaluated
`four different design prototypes. The preferred version
`of the device was used for phase II and phase III clinical
`trials. Several additional aesthetic modifications have
`been made to the device in advance of its launch onto
`the market. These include a hinged cap, colour-coded
`to identify specific drug classes contained in the device,
`and a transparent base to allow easy identification of
`the drug product (Fig. 1). A schematic illustration of
`the device is shown in Fig. 2.
`The marketed device delivers 120 metered actua-
`tions and has a dose indicator to remind patients when
`a new prescription is needed. A locking mechanism
`automatically prevents the use of the device after all
`120 actuations have been delivered. This ensures that
`there is no detectable ‘tail-off’, commonly seen with
`pMDIs, during which reduced doses are delivered close
`to container exhaustion. Spray content uniformity of
`doses delivered via Respimat® SMI was established
`gravimetrically, using 10 devices from three batches
`(Spallek et al., 2002). The delivered volume was con-
`
`Fig. 1. The marketed version of Respimat® Soft MistTM Inhaler.
`
`Fig. 2. Schematic illustration of Respimat® Soft MistTM Inhaler, showing the key components of the device and details of the uniblock (Spallek
`et al., 2002).
`
`Liquidia's Exhibit 1061
`Page 4
`
`

`

`R. Dalby et al. / International Journal of Pharmaceutics 283 (2004) 1–9
`
`5
`
`Fig. 3. Spray content uniformity data (of an aqueous solution) over 120 actuations delivered via Respimat® Soft MistTM Inhaler (with 10 devices
`from 3 batches) (delivered volume ± S.D.) (Spallek et al., 2002).
`
`sistent throughout 120 actuations of the device and no
`‘tail-off’ effect was observed (Fig. 3).
`Respimat® SMI is similar in size to pMDIs and DPIs
`(such as the Turbohaler®).
`
`2.3. Mode of action of Respimat® SMI
`
`Medication to be delivered by Respimat® SMI is
`stored as a solution in the drug cartridge. The cartridge
`consists of an aluminium cylinder containing a double-
`walled, plastic, collapsible bag, which contracts as the
`solution is withdrawn.
`The initially sterile solution may be formulated
`with either ethanol, which acts both as a solvent
`and preservative, or water, with added preservatives
`(e.g. benzalkonium chloride). Either strategy main-
`tains the microbial stability of the solution follow-
`ing initial puncture of the cartridge prior to first
`use of the device by the patient. Tests on used car-
`tridges have shown that patient use of Respimat®
`SMI does not result in microbiological contamina-
`tion of the inhalation solution (Schmelzer and Bagel,
`2001).
`◦
`The energy from a 180
`twist of the device base com-
`presses the spring. This transfers a pre-defined metered
`volume of the inhalation solution from the drug car-
`
`tridge, through a capillary tube (via a non-return valve),
`to the pump cylinder. When the patient depresses the
`dose-release button, the energy of the spring forces the
`metered volume of drug solution into the uniblock.
`The uniblock is the key element of Respimat® SMI,
`consisting of a nozzle fed by multiple extremely fine
`filter channels. In the initial prototype of Respimat®
`SMI, the nozzle openings were tiny holes pierced into
`a stainless steel disk; however, this design was not suit-
`able for mass production (Spallek et al., 2002). The
`problem was overcome by the development of a minia-
`ture ‘sandwich’ concept, the uniblock, composed of
`a structured silicon wafer bonded to a small (2 mm
`× 2.5 mm) borosilicate glass plate (Fig. 2). Inlet, out-
`let and filter channels (which prevent the nozzle from
`becoming blocked) are etched into the silicon wafer
`using a technique derived from microchip production
`technology (Zierenberg et al., 1996; Zierenberg, 1999;
`Zierenberg and Eicher, 2002; Spallek et al., 2002). This
`allows the units to be produced on a large scale with
`high precision and accuracy. The configuration of the
`inlet and outlet channels is engineered to produce a
`high fine particle fraction (droplets <5.8 ␮m in diame-
`ter). The robustness of the uniblock (and the device as
`a whole) has been confirmed by rigorous mechanical
`testing (Spallek et al., 2002).
`
`Liquidia's Exhibit 1061
`Page 5
`
`

`

`6
`
`R. Dalby et al. / International Journal of Pharmaceutics 283 (2004) 1–9
`
`Fig. 4. Photographs, taken at intervals of 0.2 s, showing the generation of the Soft MistTM from Respimat® Soft MistTM Inhaler (Hochrainer
`and H¨olz, 2001).
`
`The metered drug solution is forced through the
`channels in the uniblock, producing two fine jets of
`liquid at the outlet; these converge at a precisely set an-
`gle (Zierenberg, 1999; Zierenberg and Eicher, 2002),
`generating a slow-moving cloud of inhalable parti-
`cles – the soft mist (Hochrainer and H¨olz, 2001). The
`soft mist emerges from the nozzle with a velocity ap-
`proximately one-tenth of the speed of release of an
`aerosol cloud from a pMDI (Newman et al., 1996).
`Hochrainer and H¨olz compared the velocity of the
`aerosol cloud and the aerosol generation time (spray
`duration) from Respimat® SMI with those delivered
`from various CFC– and HFA-MDIs (Hochrainer and
`H¨olz, 2001). They found that aerosol clouds gener-
`ated from Respimat® SMI were considerably slower-
`moving and had a longer spray duration time compared
`with either CFC- or HFA-MDIs (Fig. 4).
`A high proportion of the droplets in the aerosol cloud
`from Respimat® SMI fall into the fine particle fraction
`(droplets of <5.8 ␮m in diameter) (Wachtel and Ziegler,
`2002; Spallek et al., 2002); these droplets are likely
`to be deposited in the lungs after inhalation. Studies
`on an aqueous solution of fenoterol and an ethano-
`lic solution of flunisolide delivered from Respimat®
`SMI have shown that fine particle fractions are approx-
`imately 66% for the aqueous formulation and 81% for
`the ethanolic formulations (Zierenberg, 1999; Zieren-
`berg and Eicher, 2002). Fig. 5 shows a typical example
`of the particle size distribution of an aqueous solution
`measured in an Andersen Cascade Impactor (Spallek
`et al., 2002). For comparison, the fine particle fractions
`of the aerosols delivered by pMDIs and DPIs are typ-
`ically less than 40% (van Noord et al., 2000; Steed et
`al., 1997; Newman et al., 1998; Hill and Slater, 1998;
`Kamin et al., 2002).
`
`Because Respimat® SMI generates a slow-moving
`aerosol cloud with a high fine particle fraction, ra-
`diolabelled aerosols imaged by gamma scintigraphy
`have been able to demonstrate that less of the dose
`from Respimat® SMI is deposited in the orophar-
`ynx and more reaches the lungs than with pMDIs
`and DPIs (Newman et al., 1996, 1998; Steed et al.,
`1997; Wilding et al., 2002). Newman et al. investi-
`gated lung and oropharyngeal deposition of flunisolide
`administered to 12 healthy subjects via Respimat®
`SMI, pMDI or pMDI plus Inhacort® spacer (Newman
`et al., 1996). Mean whole lung deposition of flu-
`nisolide from Respimat® SMI (39.7%) was signifi-
`cantly higher than from pMDI (15.3%) or pMDI plus
`spacer (28.0%). Typical scans of the distribution of
`radiolabelled aerosol from each device are shown in
`Fig. 6. In a more recent study, in 12 healthy volunteers,
`
`Fig. 5. Typical aerodynamic particle size distribution for the aerosol
`generated by Respimat® Soft MistTM Inhaler, using an aqueous drug
`solution and an Andersen cascade impactor (relative humidity >90%)
`(cumulative mass fraction; % ± S.D.) (Spallek et al., 2002).
`
`Liquidia's Exhibit 1061
`Page 6
`
`

`

`R. Dalby et al. / International Journal of Pharmaceutics 283 (2004) 1–9
`
`7
`
`Fig. 6. Scintigraphic scans from one individual showing the deposition of radiolabelled aerosol in the lungs immediately after administration of
`a single dose of 250 ␮g flunisolide delivered via Respimat® Soft MistTM Inhaler, pressurised metered dose inhaler (pMDI) or pMDI plus spacer,
`on each of three study days (Newman et al., 1996).
`
`Table 1
`The distribution of a metered dose of fenoterol in the lungs and
`oropharynx of 12 healthy subjects using Respimat® Soft MistTM
`Inhaler (SMI), a pressurised metered dose inhaler (pMDI) or a pMDI
`plus spacer as the delivery device
`
`Amount of fenoterol (as % metered dose)
`
`Respimat®
`SMI
`
`pMDI
`
`pMDI plus
`spacer
`
`(Newman et al., 1998). Additionally, Respimat® SMI
`deposited more of the fenoterol dose in the central,
`intermediate, and peripheral lung regions than either
`the pMDI or the pMDI plus spacer. The mean oropha-
`ryngeal deposition of fenoterol was significantly lower
`via Respimat® SMI than via the pMDI (37.1% versus
`71.7% of metered dose, respectively).
`
`39.2 (12.7)
`Whole lung
`Central lung zone 11.0 (3.7)
`Intermediate lung
`14.1 (4.9)
`zone
`Peripheral
`zone
`Oropharynx
`Delivery device
`Exhaled air
`
`lung
`
`14.1 (4.8)
`
`37.1 (10.4)
`21.9 (6.1)
`1.9 (1.7)
`
`11.0 (4.9)
`3.1 (1.1)
`3.7 (1.8)
`
`9.9 (3.4)
`2.5 (0.9)
`3.6 (1.2)
`
`4.2 (2.1)
`
`3.8 (1.5)
`
`71.7 (7.4)
`16.7 (5.4)
`0.6 (0.4)
`
`3.6 (2.4)
`86.2 (5.2)
`0.4 (0.3)
`
`2.4. Clinical performance of Respimat® SMI
`
`Because Respimat® SMI increases the amount of
`drug deposited in the lungs, Boehringer Ingelheim ex-
`pected that inhaled drugs would maintain their efficacy
`even when smaller nominal doses than would normally
`be delivered by a pMDI were administered. This con-
`cept has been tested in a number of clinical studies.
`Respimat® SMI is being developed for use with a
`range of drugs for the treatment of asthma or COPD.
`Some of these studies have been conducted using a
`fixed combination of ipratropium bromide (IB) and
`fenoterol hydrobromide (FEN) (Berodual®); IB/FEN
`is indicated for the symptomatic treatment of airway
`narrowing in patients with asthma or COPD. Five clin-
`
`The proportions of fenoterol deposited in the delivery device and
`detected in the exhaled air are also shown. Fenoterol distribution
`was detected by gamma scintigraphy. Data are given as mean and
`S.D. (Newman et al., 1998).
`
`whole lung deposition of the bronchodilator fenoterol
`was greater when delivered by Respimat® SMI com-
`pared with pMDI or pMDI plus spacer (Table 1)
`
`Liquidia's Exhibit 1061
`Page 7
`
`

`

`8
`
`R. Dalby et al. / International Journal of Pharmaceutics 283 (2004) 1–9
`
`ical studies of IB/FEN delivered via Respimat® SMI
`have already been completed.
`In phase II, a dose-ranging and a cumulative dose-
`response study were conducted in adult asthmatics
`(Goldberg et al., 2001; Kunkel et al., 2000); the first
`of these demonstrated a dose-response relationship for
`IB/FEN delivered via Respimat® SMI, producing safe
`and efficacious bronchodilation in asthmatic patients
`(Goldberg et al., 2001). The cumulative dose study
`showed that Respimat® SMI improves the delivery of
`IB/FEN compared with pMDIs, providing an equipo-
`tent bronchodilatory effect at only one-half of the cu-
`mulative dose needed with a pMDI (Kunkel et al.,
`2000).
`Three phase III trials have been completed; two of
`these were in asthma patients–one in adults (Vincken
`et al., 2004) and one in children (von Berg et al., 2004)
`and the third was in COPD patients (Kilfeather et al.,
`2004). The results showed that Respimat® SMI enables
`a 50% reduction of the nominal daily dose of IB/FEN
`in patients with asthma or COPD while offering simi-
`lar therapeutic efficacy and safety to the corresponding
`CFC-MDI (which was used with a spacer in the paedi-
`atric study) (Vincken et al., 2004; von Berg et al., 2004;
`Kilfeather et al., 2004).
`
`3. Conclusions
`
`The performance of the inhaler device is critical for
`optimal drug delivery, lung deposition and subsequent
`clinical effects. Respimat® SMI represents an inno-
`vative approach to inhalation therapy; this propellant-
`free, multi-dose inhaler generates an inhalable aerosol
`cloud (the soft mist) with superior properties to those
`produced by existing devices, such as pMDIs and DPIs.
`The soft mist generated by Respimat® SMI is pro-
`duced by the collision of two jets of liquid forced
`through a specially designed nozzle. The aerosol cloud
`is much slower moving than those produced by pMDIs
`and DPIs and contains a much higher fine particle frac-
`tion than most of these devices. In addition, the aerosol
`generation time (cloud duration) is longer compared
`with pMDIs and DPIs. The combination of these fea-
`tures improves the efficiency of drug delivery via in-
`halation by increasing the proportion of the inhaled
`dose that is deposited in the lung. This benefit has been
`
`validated in clinical studies, in which Respimat® SMI
`has been shown to allow a reduction in the dose of
`a combination bronchodilator compared with delivery
`via CFC-MDI, while offering the same level of thera-
`peutic efficacy and safety. Therefore, the development
`of Respimat® SMI represents a significant step forward
`in pulmonary drug delivery.
`
`References
`
`Ariyananda, P.L., Agnew, J.E., Clarke, S.W., 1996. Aerosol delivery
`systems for bronchial asthma. Postgrad. Med. J. 72, 151–156.
`Denyer, J., Pavia, D., Zierenberg, B., 2000. New liquid aerosol de-
`vices for inhalation therapy. Eur. Respir. Rev. 10, 187–191.
`Ganderton, D., 1997. General factors influencing drug delivery to the
`lung. Respir. Med. 91 (Suppl. A), 13–16.
`Ganderton, D., 1999. Targeted delivery of inhaled drugs: current
`challenges and future goals. J. Aerosol Med. 12 (Suppl. 1),
`S3–S8.
`Giraud, V., Roche, N., 2002. Misuse of corticosteroid metered-dose
`inhaler is associated with decreased asthma stability. Eur. Respir.
`J. 19, 246–251.
`Goldberg, J., Freund, E., Beckers, B., Hinzmann, R., 2001. Improved
`delivery of fenoterol plus ipratropium bromide using Respimat®
`compared with a conventional metered dose inhaler. Eur. Respir.
`J. 17, 225–232.
`Hill, L.S., Slater, A.L., 1998. A comparison of the performance of
`two modern multidose dry powder asthma inhalers. Respir. Med.
`92, 105–110.
`Hochrainer, D., H¨olz, H., 2001. Comparison of the velocities of
`clouds delivered from Respimat® soft mist inhaler and metered
`dose inhalers. J. Aerosol Med. 14 (3), 386P1–386P5, abstract.
`Kamin, W.E., Genz, T., Roeder, S., Scheuch, G., Trammer, T., Juene-
`mann, R., Cloes, R.M., 2002. Mass output and particle size distri-
`bution of glucocorticosteroids emitted from different inhalation
`devices depending on various inspiratory parameters. J. Aerosol
`Med. 15, 65–73.
`Kilfeather, S.A., Ponitz, H.H., Beck, E., Schmidt, P., Lee, A.L.,
`Bowen, I.R., Hesse, C.W., 2004. Improved delivery of iprat-
`ropium bromide/fenoterol from Respimat® Soft MistTM Inhaler
`in patients with COPD. Respir. Med. 98, 387–397.
`Kunkel, G., Magnussen, H., Bergmann, K.C., Juergens, U.R., de
`Mey, C., Freund, E., Hinzmann, R., Beckers, B., 2000. Respimat®
`(a new soft mist inhaler) delivering fenoterol plus ipratropium
`bromide provides equivalent bronchodilation at half the cumula-
`tive dose compared with a conventional metered dose inhaler in
`asthmatic patients. Respiration 67, 306–314.
`Leach, C.L., Davidson, P.J., Boudreau, R.J., 1998. Improved airway
`targeting with the CFC-free HFA-beclomethasone metered-dose
`inhaler compared with CFC-beclomethasone. Eur. Respir. J. 12,
`1346–1353.
`Matthys, H., 1990. Inhalation delivery of asthma drugs. Lung 168
`(Suppl.), 645–652.
`
`Liquidia's Exhibit 1061
`Page 8
`
`

`

`R. Dalby et al. / International Journal of Pharmaceutics 283 (2004) 1–9
`
`9
`
`Meakin, B.J., Ganderton, D., Panza, I., Ventura, P., 1998. The effect
`of flow rate on drug delivery from the Pulvinal, a high-resistance
`dry powder inhaler. J. Aerosol Med. 11, 143–152.
`Newman, S.P., Pavia, D., Moren, F., Sheahan, N.F., Clarke, S.W.,
`1981. Deposition of pressurised aerosols in the human respiratory
`tract. Thorax 36, 52–55.
`Newman, S.P., 1984. Production of radioaerosols. Butterworths,
`London.
`Newman, S.P., Steed, K.P., Reader, S.J., Hooper, G., Zierenberg, B.,
`1996. Efficient delivery to the lungs of flunisolide aerosol from
`a new portable hand-held multidose nebulizer. J. Pharm. Sci. 85,
`960–964.
`Newman, S.P., Brown, J., Steed, K.P., Reader, S.J., Kladders, H.,
`1998. Lung deposition of fenoterol and flunisolide delivered us-
`ing a novel device for inhaled medicines. Chest 113, 957–963.
`Newman, S.P., 1999. Use of gamma scintigraphy to evaluate the
`performance of new inhalers. J. Aerosol Med. 12 (Suppl. 1),
`S25–S31.
`Pavia, D., 1997. Efficacy and safety of inhalation therapy in chronic
`obstructive pulmonary disease and asthma. Respirology 2 (Suppl.
`1), S5–S10.
`Pritchard, J.N., 2001. The influence of lung deposition on clinical
`response. J. Aerosol Med. 14 (Suppl. 1), S19–S26.
`Schmelzer, C., Bagel, S., 2001. Microbiological integrity of Respi-
`mat soft mist inhaler (SMI) cartridges after use in COPD patients.
`J. Aerosol Med. 14 (3), 385P1–385P3.
`Spallek, M., Hochrainer, D., Wachtel, H., 2002. Optimizing nozzles
`for soft mist inhalers. Respiratory Drug Delivery VIII 2, 375–378.
`Steed, K.P., Freund, B., Towse, L., Newman, S.P., 1995a. High lung
`deposition of fenoterol from BINEB®, a novel multiple dose
`nebuliser device. Eur. Respir. J. 8 (Suppl. 19), 204s.
`Steed, K.P., Zierenberg, B., Reader, S., Newman, S.P., 1995b. Lung
`deposition of flunisolide from BINEB, a novel multiple dose
`nebuliser, is twice that from a pressurised metered dose inhaler.
`Eur. Respir. J. 8 (Suppl. 19).
`Steed, K.P., Towse, L.J., Freund, B., Newman, S.P., 1997. Lung and
`oropharyngeal depositions of fenoterol hydrobromide delivered
`from the prototype III hand-held multidose Respimat nebuliser.
`Eur. J. Pharm. Sci. 5, 55–61.
`Usmani, O.S., Biddiscombe, M.F., Nightingale, J.A., Underwood,
`S.R., Barnes, P.J., 2003. Effects of bronchodilator particle size in
`
`asthmatic patients using monodisperse aerosols. J. Appl. Physiol.
`95, 2106–2112.
`van Noord, J.A., Smeets, J.J., Creemers, J.P.H.M., Greefhorst, L.P.,
`Dewberry, H., Cornelissen, P.J., 2000. Delivery of fenoterol
`via Respimat®, a novel soft mist inhaler. Respiration 67, 672–
`678.
`Vincken, W., Bantje, T., Middle, M.V., Gerken, F., Moonen, D.,
`2004. Long-term efficacy and safety of ipratropium bromide plus
`fenoterol via Respimat® Soft MistTM Inhaler (SMI) versus a pres-
`surised metered-dose inhaler in asthma. Clin. Drug Invest. 24,
`17–28.
`von Berg, A., Jeena, P.M., Soenamtri, P.A., Vertruyen, A., Schmidt,
`P., Gerken, F., Razzouk, H., 2004. Efficacy and safety of ipra-
`tropium bromide plus fenoterol inhaled via Respimat® Soft
`MistTM Inhaler vs. a conventional metered dose inhaler plus
`spacer in children with asthma. Pediatr. Pulmonol. 37, 264–
`272.
`Wachtel, H., Ziegler, J., 2002. Improved assessment of inhaler device
`performance using laser diffraction. Respiratory Drug Delivery
`VIII 2, 379–382.
`Wilding, I.R., Pitcairn, G.R., Reader, S., Pavia, D., Newman, S.P.,
`2002. Respimat® Soft Mist Inhaler delivers inhaled corticos-
`teroid to the lungs more efficiently than a Turbuhaler dry powder
`inhaler or a pressurized metered dose inhaler. A. A. P. S. Pharm.
`Sci. 4 (4), W4130, abstract.
`Zainudin, B.M.Z., Biddiscombe, M., Tolfree, S.E.J., Short, M., Spiro,
`S.G., 1990. Comparison of bronchodilator responses and deposi-
`tion patterns of salbutamol inhaled from a metered dose inhaler,
`as a dry powder, and as a nebulised solution. Thorax 45, 469–473.
`Zanen, P., Go, L.T., Lammers, J.W., 1996. Optimal particle size for
`beta 2 agonist and anticholinergic aerosols in patients with severe
`airflow obstruction. Thorax 51, 977–980.
`Zierenberg, B., Eicher, J., Dunne, S., Freund, B., 1996. Boehringer
`Ingelheim nebulizer BINEB® a new approach to inhalation ther-
`apy. Respir. Drug Deliv. V, 187–193.
`Zierenberg, B., 1999. Optimizing the in vitro performance of
`Respimat®. J. Aerosol Med. 12 (Suppl. 1), S19–S24.
`Zierenberg, B., Eicher, J., 2002. The Respimat, a new soft mist inhaler
`for delivering drugs to the lungs. In: Rathbone, M.J., Hadgraft, J.,
`Roberts, M.S. (Eds.), Modified-release drug delivery technology.
`Marcel Dekker, New York, pp. 925–933.
`
`Liquidia's Exhibit 1061
`Page 9
`
`