Conference Proceedings
`
`Dry Powder Inhalers: An Overview
`
`Paul J Atkins PhD
`
`Introduction
`Powder Inhalers Today
`Unit-Dose Devices
`Multi-Dose Devices
`Factors That Impact Performance and Patient Acceptance
`DPI Development
`Future DPI Developments
`Summary
`
`Dry powder inhalers (DPIs) are a widely accepted inhaled delivery dosage form, particularly in
`Europe, where they currently are used by a large number of patients for the delivery of medications
`to treat asthma and chronic obstructive pulmonary disease. The acceptance of DPIs in the United
`States after the slow uptake following the introduction of the Serevent Diskus in the late 1990s has
`been driven in large part by the enormous success in recent years of the Advair Diskus. This
`combination of 2 well-accepted drugs in a convenient and simple-to-use device has created an
`accepted standard in pulmonary delivery and disease treatment that only a few years ago could not
`have been anticipated. The DPI offers good patient convenience, particularly for combination
`therapies, and also better compliance. The design and development of any powder drug-delivery
`system is a highly complex task. Optimization of the choice of formulation when matched with
`device geometry is key. The use of particle engineering to create a formulation matched to a simple
`device is being explored, as is the development of active powder devices in which the device inputs
`the energy, making it simpler for patients to receive the correct dose. Patient interface issues are
`also critically important. However, one of the most important factors in pulmonary delivery from
`a DPI is the requirement for a good-quality aerosol, in terms of the aerosol’s aerodynamic particle size,
`and its potential to consistently achieve the desired lung deposition in vivo. Key words: dry powder inhaler,
`DPI, lactose, aerosol, asthma, bronchodilator, chronic obstructive pulmonary disease, COPD, corticosteroids,
`drug delivery.
`[Respir Care 2005;50(10):1304–1312. © 2005 Daedalus Enterprises]
`
`Introduction
`
`The most frequent use of inhalation therapy is for the
`treatment of obstructive airway diseases, including asthma
`
`Paul J Atkins PhD is affiliated with Oriel Therapeutics, Research Trian-
`gle Park, North Carolina.
`
`Paul J Atkins PhD presented a version of this article at the 36th RESPI-
`RATORY CARE Journal Conference, Metered-Dose Inhalers and Dry Pow-
`der Inhalers in Aerosol Therapy, held April 29 through May 1, 2005, in
`Los Cabos, Mexico.
`
`and chronic obstructive pulmonary disease, using drugs
`such as short-acting and long-acting ␤ agonists, cortico-
`steroids, and anti-cholinergic agents. Traditionally, these
`agents have been delivered via pressurized metered-dose
`inhaler (MDI). However, in recent years, dry powder in-
`halers (DPIs) have gained wider use, particularly in the
`United States, partly because of the introduction of the
`
`Correspondence: Paul J Atkins PhD, Oriel Therapeutics, PO Box 14087,
`630 Davis Drive, Research Triangle Park NC 27709. E-mail:
`patkins@orieltherapeutics.com.
`
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`DRY POWDER INHALERS: AN OVERVIEW
`
`first combination of a long-acting ␤ agonist (salmeterol)
`and a corticosteroid (fluticasone propionate) in a conve-
`nient multi-dose DPI (Advair Diskus, GlaxoSmithKline,
`Research Triangle Park, North Carolina).1
`Key to all inhalation dosage forms (either MDI or DPI)
`is the need to generate the optimum “respirable dose”
`(particles ⬍ 5.0 ␮m) of a therapeutic agent that will reach
`the site of action (ie, the lung). This is a critical perfor-
`mance feature in the rational design and selection of a
`pulmonary delivery system. Historically, MDIs have
`achieved lung deposition of 5–15% of the delivered dose.
`Current DPIs have similar efficiency, but they have a num-
`ber of advantages over MDIs, including the fact that they
`are breath-actuated and therefore require less coordination
`than a conventional press-and-breathe MDI. Furthermore,
`they do not contain chlorofluorocarbon propellants, which
`have been implicated in atmospheric ozone depletion2 and
`are being phased out. In addition, the more recently de-
`veloped multi-dose DPIs have either a dose counter or
`indicator that tells the patient how much medication re-
`mains in the inhaler, which is another feature that differ-
`entiates DPIs from currently available MDIs.
`DPIs do, however, suffer from some inherent disadvan-
`tages, including the fact that they require moderate inspira-
`tory effort to draw the formulation from the device; some
`patients are not capable of such effort. Furthermore, there
`is only a limited number of drugs available in a multi-dose
`format, with some drugs being available only in unit-dose
`formats. These unit-dose devices are perceived as complex
`and confusing for patients.3 In a recent review, Frijlink and
`De Boer claimed that “well designed DPIs are highly ef-
`ficient systems for pulmonary drug delivery. However,
`they are also complicated systems, the performance of
`which relies on many aspects, including design. . . , pow-
`der formulation, and airflow generated by the patient.”4
`This paper will review the currently available DPIs, fo-
`cusing primarily on the United States market, evaluate the
`key performance variables of these DPIs, including patient
`preferences, and provide some insights into potential fu-
`ture developments of DPIs for the delivery of agents to
`treat respiratory diseases and systemic diseases.
`
`Powder Inhalers Today
`
`Today there are essentially 2 types of DPI: those in
`which the drug is packaged into discrete individual doses
`(in a gelatin capsule or a foil-foil blister) and those that
`contain a reservoir of drug from which doses are metered
`out.5 Both are now widely available around the world and
`are gaining broad acceptance as suitable alternatives to
`MDIs. There is clearly considerable interest in these de-
`vices, because they do not require chlorofluorocarbon pro-
`pellant to disperse the drug and are therefore ozone-friendly.
`Furthermore, DPIs obviate coordination of actuation and
`
`inspiration (a limitation of MDIs) because DPIs are essen-
`tially breath-actuated. However, this breath-actuation is
`also one of their disadvantages. Some DPIs require in-
`spiratory flow of ⱖ 60 L/min to effectively de-aggregate
`the powder,6,7 which cannot always be achieved by all
`asthmatic patients, particularly infants. All the currently
`available DPIs suffer from this potential drawback and can
`be characterized as “passive” inhalers (ie, the patient pro-
`vides the energy to suck the drug from the device). This
`has prompted several companies to evaluate ways of pro-
`viding energy in the inhaler, which is leading to the de-
`velopment of several “active” DPIs, although none of these
`are currently available commercially.
`
`Unit-Dose Devices
`
`With a single-dose DPI, a powder-containing capsule is
`placed in a holder inside the DPI, the capsule is opened
`within the device, and then the powder is inhaled. The
`spent capsule must be discarded after use and a new cap-
`sule inserted for the next dose. The concept of the first
`capsule-based device (the Spinhaler) was first described in
`the early 1970s, by Bell and colleagues,8 who had devel-
`oped this device for the administration of powdered so-
`dium cromoglycate. Briefly, the drug mixture, which often
`includes a bulk carrier to aid powder flow, is pre-filled into
`a hard gelatin capsule and loaded into the device. After
`activation of the device, which pierces the capsule, the
`patient inhales the dose, which is dispensed from the vi-
`brating capsule by means of inspired air. This product is
`no longer available in the United States.
`A similar DPI (Rotahaler, GlaxoSmithKline), which has
`also been available for many years, delivers albuterol. With
`the Rotahaler, the drug mixture is also in a hard capsule.
`The capsule is inserted into the device, broken open inside
`the device, and the powder is inhaled through a screened
`tube (Fig. 1).9,10 Again, this product is no longer available
`in the United States.
`Although these single-dose devices have performed well
`in clinical use for many years, the main criticism of them
`is the cumbersome nature of loading the capsule, which
`might not be easily accomplished by a patient who is
`undergoing an asthma attack and requires immediate de-
`livery of the drug. This is clearly very relevant for devices
`that deliver short-acting bronchodilators. In addition, el-
`derly patients may not have the manual dexterity to ac-
`complish all the necessary maneuvers to take the capsule
`from the package, load it, and pierce the capsule in the
`device. However, despite the perception that unit-dose de-
`vices are not patient-friendly and are not easy to use, sev-
`eral introductions of single-dose DPIs have occurred over
`the last few years using similar designs (eg, Foradil Aerol-
`izer, made by Novartis/Schering-Plough, and Spiriva
`HandiHaler, made by Boehringer Ingelheim/Pfizer).11,12
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`DRY POWDER INHALERS: AN OVERVIEW
`
`to deliver both ␤ agonists (formoterol, terbutaline) and
`combinations (formoterol and budesonide), in the United
`States this device is only available to deliver the inhaled
`corticosteroid budesonide (Pulmicort Turbuhaler).15
`One of the drawbacks for the Turbuhaler, which may
`have contributed to its limited acceptance in the United
`States, is its variable delivery at different flow rates.5,16
`This has also been the major criticism of several recently
`developed reservoir-type DPIs17 and may limit their intro-
`duction into the United States. It is, however, important to
`note that Schering-Plough recently announced approval of
`their reservoir DPI for the delivery of the inhaled cortico-
`steroid mometasone (Asmanex Twisthaler).18
`To address issues associated with multiple dosing and
`consistent dose-to-dose delivery, in the late 1980s Glaxo
`developed the Diskhaler,19 which was used to deliver a
`range of drugs, including albuterol, beclomethasone, sal-
`meterol, fluticasone, and the anti-viral agent zanamivir.
`This device uses a circular disk that contains either 4 or 8
`powder doses, which typically would be sufficient drug for
`1–2 days of treatment; the empty disk is then discarded
`and a new disk is inserted in the device. The doses are
`maintained in separate aluminum blister reservoirs until
`just before inspiration. On priming the device, the alumi-
`num blister is pierced and its contents drop into the dosing
`chamber. This device had limited commercial success, pri-
`marily because it held only a few doses per disk and was
`perceived as very cumbersome to load (Fig. 2).20 It was
`used in the United States for the delivery of fluticasone
`propionate to pediatric patients, although the product has
`now been withdrawn. It was also used (in a modified form)
`to deliver the anti-influenza agent zanamivir, although,
`again, the use was not widespread.
`Further improvements in patient convenience and ease
`of use were incorporated into the next generation of multi-
`dose DPI, called the Diskus. This product was introduced
`in the late 1990s. Initially it delivered salmeterol or fluti-
`casone, but in 2001 a version was released that contains a
`combination salmeterol-plus-fluticasone formulation (Ad-
`vair Diskus). This is a true multi-dose device; it contains
`60 doses (one month’s therapy) in a foil-foil aluminum
`strip that is indexed, and the dose blister is only opened
`just prior to patient inspiration (Fig. 3).20,21 Consistent
`performance,5 broad patient acceptance,22,23 and the grow-
`ing use of combination therapy (long-acting ␤agonist plus
`inhaled corticosteroid) for asthma have allowed the Diskus
`to become the accepted standard multi-dose powder de-
`livery device (Fig. 4).
`
`Factors That Impact Performance
`and Patient Acceptance
`
`Currently available DPIs are all passive systems, mean-
`ing that the patient must provide the energy to disperse the
`
`Fig. 1. Examples of unit-dose dry powder inhalers (DPIs). A: Ro-
`tahaler and Rotacap (contains albuterol). B: Diagram of Rotahaler.
`C: Spiriva Handihaler. (Diagram from Reference 10, with permis-
`sion. Photograph C courtesy of Boehringer Ingelheim/Pfizer.)
`
`The Foradil device has been poorly accepted since its
`introduction. This may be related to the need to store the
`capsules refrigerated. With the recently introduced Spiriva
`Handihaler it is too early to evaluate the degree of patient
`acceptance of this device, although it is complex and re-
`quires at least 7 distinct steps to deliver the dose. For some
`patients, 2 inhalations are required to completely empty
`the capsule and achieve the therapeutic dose, which adds
`to the degree of complexity for the patient when using this
`device. Furthermore, there have been recent reports3 of
`patients ingesting the capsules instead of placing the cap-
`sule in the device and inhaling the contents. This is clearly
`not desirable.
`
`Multi-Dose Devices
`
`Given the inherent limitations of single-dose devices, in
`the past decade or so there has been considerable focus on
`developing multi-dose DPIs. The development of multi-
`dose DPIs was pioneered by the AB Draco company (now
`a division of AstraZeneca), with their Turbuhaler.13 This
`device was truly the first metered-dose powder delivery
`system. The drug formulation is contained within a storage
`reservoir and can be dispensed into the dosing chamber by
`a simple back-and-forth twisting action on the base of the
`device. The device is capable of working at a moderate
`flow rate and also delivers carrier-free particles as well as
`lactose-based formulations.14 Although the Turbuhaler is
`widely available in Europe and Canada, and has been used
`
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`DRY POWDER INHALERS: AN OVERVIEW
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`Table 1.
`
`Resistance of 5 Dry Powder Inhalers
`
`Inhaler
`
`Manufacturer
`
`Rotahaler
`Spinhaler
`Diskhaler/Diskus
`HandiHaler
`Turbuhaler
`
`(Adapted from Reference 4.)
`
`GlaxoSmithKline
`Sanofi-Aventis
`GlaxoSmithKline
`Boehringer Ingelheim
`AstraZeneca
`
`Resistance
`(H2O/L/s)
`
`0.015
`0.016
`0.032
`0.042
`0.044
`
`Table 1 shows that there are important differences in re-
`sistance among the DPIs, and this difference in resistance
`causes differences in drug delivery efficiency between these
`devices.
`The patient labeling for DPIs reveals some interesting
`statistics. For example, with the Spiriva Handihaler,12 the
`powder is delivered at a flow as low as 20 L/min. How-
`ever, when tested under standardized in vitro conditions,
`the HandiHaler delivers a mean of only 10.4 ␮g (or 58%
`of the nominal dose) when tested at a flow of 39 L/min for
`3.1 s (for a total of 2 L ofinspired volume). For patients
`with chronic obstructive pulmonary disease (mean forced
`expiratory volume in the first second 1.02 L, 37.6% of
`predicted), their median peak inspiratory flow through the
`HandiHaler was only 30.0 L/min (range 20.4 – 45.6 L/min).
`That relatively low flow impacts the amount of drug the
`patient receives, and the patient instructions include a pro-
`vision for a second inhalation if all the powder has not
`been evacuated from the capsule.
`Under standard in vitro test conditions, Advair Diskus1
`delivers 93 ␮g, 233 ␮g, and 465 ␮g of fluticasone propi-
`onate and 45 ␮g of salmeterol base per blister from the
`100/50 ␮g, 250/50 ␮g, and 500/50 ␮g products, respec-
`tively, when tested at a flow of 60 L/min for 2 seconds. In
`contrast to the HandiHaler, adult patients with obstructive
`lung disease and severely compromised lung function
`(mean forced expiratory volume in the first second 20 –
`30% of predicted) achieved mean peak inspiratory flow of
`82.4 L/min (range 46.1–115.3 L/min) through the Diskus.
`Furthermore, adolescents (n ⫽ 13, age 12–17 years) and
`adults (n ⫽ 17, age 18 –50 years) with asthma inhaling
`maximally through the Diskus had a mean peak inspira-
`tory flow of 122.2 L/min (range 81.6 –152.1 L/min). Among
`pediatric patients with asthma inhaling maximally through
`the Diskus, mean peak inspiratory flow was 75.5 L/min
`(range 9.0 –104.8 L/min) among the 4-year-old patient set
`(n ⫽ 20) and 107.3 L/min (range 82.8 –125.6 L/min) among
`the 8-year-old patient set (n ⫽ 20).1
`Thus, it is important that physicians recognize that these
`devices will deliver different amounts of drug to different
`patients, and the lung delivery depends on patient factors,
`
`Fig. 2. Relenza Diskhaler. (Photograph courtesy of GlaxoSmith-
`Kline. Diagram from Reference 20, with permission.)
`
`powder from the device. The performance of these devices
`depends on both the formulation and the geometry of the
`air path in the device. Thus, frequently these delivery sys-
`tems tend to be compound-specific and, without substan-
`tial re-formulation efforts, are not used to deliver other
`compounds. Typical formulations in DPIs are either drug
`alone (eg, budesonide in the Turbuhaler) or drug blended
`with a carrier, typically lactose (eg, formoterol in the Fo-
`radil Aerolizer). The requirement for specific DPI formu-
`lations is addressed in Hickey’s contribution to this Jour-
`nal Conference,24 but I will make some general observations
`regarding current DPI products.
`The particle size distribution, both in vitro and, more
`importantly, in vivo, depends on the patient’s ability to
`pull a certain airflow through the device to create the shear
`force that disperses the particles. In general, a higher shear
`leads to a higher percentage of smaller particles, which
`may be beneficial, depending on the drug being delivered.
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`DRY POWDER INHALERS: AN OVERVIEW
`
`Fig. 3. Schematic of the Diskus powder inhaler. (From Reference 20, with permission.)
`
`Fig. 4. Serevent Diskus (left) and Advair Diskus (right) powder inhalers. (Courtesy of GlaxoSmithKline.)
`
`such as inspiratory flow, patient inhalation technique, and
`device resistance.
`One of the key factors with DPIs is that the various
`DPIs require different techniques to achieve an appro-
`priate therapeutic dose, unlike MDIs, with which, in
`general, the inhalation technique is the same. Thus, ease
`of use and clear, concise instructions are required. In a
`recent publication by Melani and colleagues,25 some
`interesting observations were made linking patient-
`
`training with ease of use. In many device-handling stud-
`ies the simple conclusions are that patients find device
`A better than device B, although often the criteria eval-
`uated have been extremely subjective. In a recent study26
`conducted in Germany and Holland, it was shown that
`in elderly patients (mean age 60 years), approximately
`two thirds (n ⫽ 254) were able to use the Diskus suc-
`cessfully, without any problems, compared with less
`than 30% of the patients using HandiHaler. This is at-
`
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`DRY POWDER INHALERS: AN OVERVIEW
`
`tributable to the complex nature of the unit-dose system
`versus the simpler multi-dose system. In contrast, the
`study by Melani et al25 showed that adherence to in-
`structions was poorer with the Diskus and Turbuhaler
`than with another unit-dose device (the Aerolizer). In-
`deed, in that study, which examined over 1,400 patients
`in Italy, the authors concluded that adherence to correct
`inhaler use was similar across DPIs and, indeed, be-
`tween the DPIs studied (Aerolizer, Turbuhaler, and Dis-
`kus) and an MDI. This was attributed in part to appro-
`priate training prior to product use. Thus, one of the
`critical factors in ensuring that patients receive the ap-
`propriate medication from the currently available pas-
`sive DPIs is the provision of appropriate training and
`device education by the health-care provider.
`
`DPI Development
`
`Historically, drug particles for inhalation have been pro-
`duced by a milling (micronization) process that creates
`particles of 1.0 –3.0 ␮m (this is absolutely necessary for
`inhalation). Of critical importance in the development of
`DPI products is the evaluation, optimization, and control
`of flow and dispersion (de-aggregation) characteristics of
`the formulation. These typically consist of micronized drug
`blended with a carrier (eg, lactose). The properties of these
`blends are a function of the principal adhesive forces that
`exist between particles, including van der Waals forces,
`electrostatic forces, and the surface tension of adsorbed
`liquid layers.27 Particle size distribution of the drug and
`the excipient (lactose) are optimized during early formu-
`lation development studies to ensure consistent aerosol
`cloud formation during subsequent clinical evaluation.
`The efficiency of dispersion of DPI aerosols, relative to
`the various geometric diameters of the particles, may also
`be an important factor. Specifically, dispersion requires
`the powder to overcome interparticulate forces that bind
`particles in bulk powder and to become entrained as single
`particles in the inhalatory air stream. Interparticulate forces
`are dominated by the van der Waals force for particles in
`the respiratory size range. All other factors being equal,
`the van der Waals force will decrease as the geometric
`particle size increases. Thus, in general terms, the proba-
`bility of deposition in the deep lung is at odds with effi-
`ciency of dispersion for DPIs.
`Environmental factors, especially temperature and hu-
`midity, are key factors that can impact DPI formulation
`stability and performance. The impact of these are studied
`in early development studies, and often the humidity ef-
`fects negatively impact the formulation (particularly for
`lactose blends), making it more cohesive and therefore
`more difficult to disperse. This will be to some extent
`dependent on the device/formulation combination, and typ-
`ically reservoir devices have a poorer ability to protect the
`
`formulation from moisture effects. Hence, many of the
`DPIs now available have secondary packing (a foil over-
`wrap) to protect them from moisture effects until just prior
`to use.
`Some years ago Brown28 alluded to the complexities
`involved in the design and development of a DPI. In much
`the same way as for an MDI, the combination of formu-
`lation (drug and carrier), the way that it is presented to the
`device, and the design of the dosing device itself all con-
`tribute to the overall performance of the dosage form. The
`requirement to use micronized drug with small particles, to
`achieve good aerodynamic properties of the dispersed pow-
`der, is confounded by the need to develop formulations
`that fill easily and accurately.29 It is also important that
`changes in the physical nature of the formulation on trans-
`portation and storage are studied and do not adversely
`affect the product performance.
`The development of DPIs has traditionally linked a spe-
`cific formulation to a particular device geometry that then
`creates a pneumatic dispersion of the powder to overcome
`the interparticulate forces and create the aerosol.30 How-
`ever, in the past decade, the notion of producing particles
`of a specific size, density, and morphology has evolved,
`and has the potential to lead to important advances in
`pulmonary drug delivery. This advance was recently re-
`viewed by Peart and Clarke31 and by Koushik and
`Kompella.32 The underlying principle is that enhanced per-
`formance can be controlled by formulation changes (eg,
`generating highly porous particles with large geometric
`diameters but small aerodynamic diameters), an approach
`characterized as “particle engineering.” These complex for-
`mulations are then coupled with a simple delivery device.
`This is clearly a subject of interest for formulation scien-
`tists as they strive to develop more efficient powder de-
`livery systems.
`The goal of delivering micronized powders is a chal-
`lenging one. Because of their very nature, these types of
`powders are highly cohesive. Their high inter-particulate
`forces make them difficult to de-aggregate: hence, the need
`for high inspiratory flow and turbulent airflow within DPIs.
`Inclusion of a carrier can aid in the de-aggregation pro-
`cess, but it can also lead to problems with absorption of
`atmospheric moisture. The alternative approach to achiev-
`ing efficient dispersion of these highly cohesive powders
`is to provide an energy source for dispersion within the
`device itself, and a number of companies are pursuing this
`approach. An outline review of some of these approaches
`is provided below as part of a prediction of future DPI
`developments.
`
`Future DPI Developments
`
`The delivery of powdered medication for the treatment
`of lung ailments has been known for centuries, is well
`
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`DRY POWDER INHALERS: AN OVERVIEW
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`Table 2. Aerosol-Dispersion Mechanisms of Dry Powder Inhalers
`
`Mechanism
`
`Inhaler
`
`Manufacturer
`
`Venturi effect
`
`Impact bodies
`
`Discharge channels
`
`Cyclone chambers
`
`Easyhaler
`
`Clickhaler
`CertiHaler
`
`Turbuhaler
`Twisthaler
`
`Pulvinal
`Airmax
`Novolizer
`Taifun
`
`Orion
`
`Innovata Biomed (IB)
`SkyePharma
`
`AstraZeneca
`Schering Plough
`
`Chiesi
`Ivax
`Viatris
`LAB International
`(formerly Focus
`Inhalation)
`
`Pressurized air*
`
`Inhance
`Aspirair
`
`Nektar
`Vectura
`
`Battery powered*
`
`(Inhaler names not
`yet released)
`
`Microdose Technologies
`Oriel Therapeutics
`
`*Active powder inhaler (Adapted from Reference 4.)
`
`documented,33 and is addressed by Anderson in her con-
`tribution to this conference.34 Despite this extensive his-
`tory, and in part fuelled by a need for alternative pulmo-
`nary delivery methods, as the MDI is undergoing
`environmental challenge, innovative ways to deliver drugs
`to the lungs continue to be pursued today. As can be seen
`from the previous discussion, the goal of de-aggregating
`highly cohesive powder for delivery to the lung in a pow-
`dered form is a challenging one.30 The small dose size
`required for many of these potent drugs is a confounding
`factor in developing optimal DPIs. Nevertheless, today it
`is estimated that annually approximately 100 million multi-
`dose DPIs are used, on a global basis. This compares with
`approximately 400 million MDIs. Most of the DPIs con-
`tain lactose-based formulations. There has been some con-
`cern raised about the use of lactose carriers in asthma
`patients who have lactose intolerance,35 although the in-
`cidence of this is believed to be small.
`As has been discussed by others,4,30 there are only a
`limited number of mechanisms for dispersing powdered
`drugs (Table 2). Many of these devices are now available
`commercially, although only the Turbuhaler is currently
`available in the United States.
`Much interest has been focused recently on developing
`delivery systems that de-aggregate the powder,30 –32 as this
`effectively minimizes formulation-development work.
`Some of these systems are extremely complex in operation
`and may prove difficult to achieve in everyday operations.
`In addition, some designs that have already been achieved
`(eg, Inhance device for the delivery of 1 mg or 3 mg of
`inhaled insulin, Nektar Therapeutics, San Carlos, Califor-
`
`Fig. 5. Prototype of the Nektar PDS (“pulmonary delivery system”)
`for Exubera. The device slides open and closed like a telescope,
`for compact carrying and portability. The patient opens the device,
`inserts the foil blister (which contains the powdered medicine),
`and pumps the handle, which compresses a small amount of air
`inside the device. When the patient pushes the button, the com-
`pressed air is released at high velocity, which aerosolizes the pow-
`der and sends the aerosol into the chamber, where it is a station-
`ary cloud. The patient then inhales the aerosol from the chamber.
`The patient receives the medicine first, followed by a volume of air,
`which helps push the drug deep into the lung. (Courtesy of Nektar
`Therapeutics.)
`
`nia) are probably too bulky to be fully portable. Others are
`pursuing smaller and more compact options. A review of
`the full range of these delivery systems is beyond the
`scope of this paper, but there are a couple of subjects
`worth exploring.
`A multi-dose reservoir device is now under review
`with the United States Food and Drug Administration
`for the delivery of formoterol (Foradil Certihaler, Skye-
`Pharma, San Diego, California; Novartis, East Hanover,
`New Jersey).36 This would be a major advance, as it
`would provide a second long-acting ␤agonist in a multi-
`dose powder form. In addition, the first use of an active
`DPI is currently being sought for the delivery of pul-
`monary insulin (Exubera, Pfizer/Sanofi-Aventis,
`li-
`censed from Nektar Therapeutics, Fig. 5). The device
`uses an air pump system that disperses the insulin pow-
`der into a spacer chamber, from which the patient can
`
`1310
`
`RESPIRATORY CARE • OCTOBER 2005 VOL 50 NO 10
`
`Liquidia's Exhibit 1038
`Page 7
`
`

`

`DRY POWDER INHALERS: AN OVERVIEW
`
`then inhale. Approval of such a device will pave the
`way for future developments in this area, and many
`companies are seeking to follow the path that Nektar
`Therapeutics has pioneered. In our laboratories37 we are
`working to use vibration to disperse powder efficiently
`and achieve consistent aerosol delivery. Others are us-
`ing various different techniques. Details of these early
`development efforts have been extensively de-
`scribed.4,31,32
`
`Summary
`
`DPIs are a widely accepted inhaled delivery dosage form,
`particularly in Europe where they are currently used by an
`estimated 40% of patients to treat asthma and chronic
`obstructive pulmonary disease. Their use will continue to
`grow. The acceptance of DPIs in the United States, after
`the slow uptake following the introduction of Serevent
`Diskus in the late 1990s, has been driven in large part by
`the enormous success in recent years of Advair Diskus.
`This combination of 2 well-accepted drugs in a convenient
`and simple-to-use device has created an accepted standard
`in pulmonary delivery and disease treatment that only a
`few years ago could not have been anticipated. The DPI
`offers good patient convenience, particularly for combina-
`tion therapies, and also better compliance. Adherence may
`be better, but only if there is sufficient effort put in place
`to clearly teach the correct use of the device.
`The design and development of any powder drug deliv-
`ery system is a highly complex task. Optimization of the
`choice of formulation when matched with device geome-
`try is key. The use of particle engineering to create a
`formulation matched to a simple device is being explored,
`as well as the development of active powder devices that
`supply the energy, making it simpler for patients to receive
`the correct dose. Both of these avenues are being pursued
`by a number of companies and will result in further ad-
`vances in DPI technology. Patient interface issues are also
`critically important. However, common to the develop-
`ment of all systems is an appreciation that one of the most
`important factors in pulmonary delivery from a DPI is the
`requirement for a good-quality aerosol (in terms of the
`aerodynamic particle size of the cloud generated) and its
`potential to consistently achieve the desired regional dep-
`osition in vivo. This has been the goal of many scientists
`over many years and we are still short of that goal. Today
`there is still no ideal DPI, unlike the MDI, which has been
`used ubiquitously. More work is required to ensure that
`DPIs are made available that are simple, easy to use, and
`independent of patient effort. Today, if we can make drugs
`on a chip, we should be able to make better DPIs!
`
`REFERENCES
`
`1. GlaxoSmithKline. Advair Diskus 100/50 (fluticasone 100mcg and
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`8. Bell JH, Hartley PS, Cox JS. Dry powder aerosols. I. A new powder
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`10. Clark T, Rees