2001: An Odyssey in Inhaler
`Formulation and Design
`
`T.M. Crowder, M.D. Louey,V.V. Sethuraman, H.D.C. Smyth and A.J. Hickey*
`
`T
`
`he history of inhaler development
`in modern times can be traced to
`the metering valve and propellants
`(pressurized metered-dose inhalers
`[pMDIs]) used in the delivery of therapies
`for the treatment of asthma in the 1950s
`(3). This was followed closely by the some-
`what-primitive dry-powder inhalers (DPIs)
`in the 1970s (Intal-Cromolyn-A Mono-
`graph, Fisons Corporation, Bedford, MA,
`1973). Throughout this period nebulizers
`were used to deliver drugs in an aqueous
`solution. However, the solution was dis-
`pensed independently of the nebulizer, and
`the two substances were combined in the
`home or the hospital. Recently, aqueous-
`solution metering systems have been de-
`veloped that are handheld and similar in
`application to pMDIs and DPIs (4,5).
`Since our review in 1997 (1), research
`and development activity in this field has
`broadened. This may be explained in part
`by the demise of the Kyoto Treaty on
`Global Warming (6), which has refocused
`activities in the area of alternative pro-
`pellant formulation. More important,
`research into alternative approaches to
`powder and solution formulation and sta-
`bility has increased. This review is in-
`tended to reflect the interest and growth
`that have occurred in the field of pharma-
`ceutical inhalation aerosol technology in
`the past four years.
`
`pMDI devices
`PMDIs have been used for more than 40
`years and are well accepted by most pa-
`tients as a means of administering medi-
`cation. They are the most widely used in-
`halation delivery device, with an estimated
`800 million units produced in the year
`2000 (7). Traditional pMDI systems com-
`prise an aerosol container, a metering
`
`valve, a drug substance in suspension or
`solution, excipients, and a liquefied pro-
`pellant that provides the energy for
`aerosolization. Dose administration typi-
`cally involves depressing the valve via an
`actuator that also functions as a mouth-
`piece. Despite the popularity of pMDIs,
`these systems have some disadvantages
`(see Table I). Many of the advances in
`pMDI device and formulation technology
`during the past 10 years have sought to
`address these deficiencies. A specific event
`that initiated much of the progress seen
`in recent years was the 1987 signing of the
`Montreal Protocol on Substances that De-
`plete the Ozone Layer.
`Worldwide concern over the possible
`deleterious effects of chlorofluorocarbons
`(CFCs) on the stratospheric ozone led to
`the signing of the Montreal Protocol,
`which committed the signatory nations to
`cease production of CFCs by 1996. Al-
`though specific exemptions, which were
`defined as essential, were granted for uses
`of CFCs, the pharmaceutical industry was
`forced to find alternative propellants for
`pMDIs. The existing pMDI propellants —
`CFC 11, 12, and 14 — had no immediate
`replacements. However, because several
`hydrofluoroalkanes (HFAs) shared simi-
`lar desirable characteristics (nonflam-
`mable, chemically stable, similar vapor
`pressures, and non-ozone depleting), they
`were investigated as possible substitutes
`for CFCs. After extensive testing, the pro-
`pellant tetrafluoroethane (HFA 134a) was
`demonstrated to have toxicology and
`safety profiles at least as safe as CFC pro-
`pellants and since then has been incorpo-
`rated into pMDIs approved by regulatory
`agencies (7–9).
`Despite the similarities with the CFCs,
`many additional difficulties in substitut-
`Pharmaceutical Technology JULY 2001 99
`
`We previously have reviewed
`inhaler technology, generally
`(1), and dry-powder inhaler
`technology, specifically (2).
`Numerous advances have
`occurred in the intervening
`period in the technology
`associated with the
`formulation and delivery of
`aerosols for the treatment of
`pulmonary and systemic
`diseases.
`
`T.M. Crowder is a research professor in
`the Department of Biomedical Engineering at
`the University of North Carolina at Chapel Hill
`(UNC-CH) and founder and president of Oriel
`Therapeutics, Inc. M.D. Louey is a post-
`doctoral fellow in the School of Pharmacy at
`UNC-CH. V.V. Sethuraman is a graduate
`student in the Department of Biomedical
`Engineering at UNC-CH. H.D.C. Smyth is
`a post-doctoral fellow in the School of Phar-
`macy at UNC-CH. A.J. Hickey is a pro-
`fessor at the Division of Drug Delivery and
`Disposition, School of Pharmacy and Bio-
`medical Engineering at UNC-CH and founder
`of Oriel Therapeutics, Inc., tel. 919.962.0223,
`fax 919.966.0197, e-mail ahickey@unc.edu.
`
`*To whom all correspondence should be
`addressed
`
`1
`
`3M COMPANY 2021
`Mylan Pharmaceuticals Inc. v. 3M Company
`IPR2015-02002
`
`

`
`Formulation changes
`
`Plume modifications
`
`Device changes
`
`Figure 1: Areas of advancement in pMDI
`technology.
`
`ing HFAs for CFCs in existing pMDI med-
`ications have been identified. The modi-
`fied solubilities of drug and excipients used
`in the HFA propellant systems have cre-
`ated the need for alternative formulation
`strategies. The compatibility of pMDI
`components such as valves and container
`walls with HFAs also has been problem-
`atic. Changing pMDIs to use CFC-free
`propellants has challenged formulation
`scientists to improve the performance of
`pMDI products to provide more efficient
`and targeted drug delivery. The following
`classifications of recent advances in pMDI
`technology, as illustrated in Figure 1, are
`arbitrary and by no means an exhaustive
`listing of the coverage found in industry
`literature and reports. Most of the cita-
`tions listed come from the patent litera-
`ture written in the past two to three years.
`For other useful reviews of advances in
`pMDI technology before these, the reader
`is urged to consult Bowman and Green-
`leaf (10), Ross and Gabrio (7), and Mc-
`Donald and Martin (11).
`
`Formulation-related pMDI advances
`Propellant patents. The patent literature
`from the past decade reveals significant re-
`search into alternative propellant systems
`for pMDIs (patents may be searched on-
`line at www.uspto.gov). Many of the patents
`refer to HFAs and, in particular, to HFA
`134a and/or HFA 227 combinations with
`cosolvents (e.g., US Pat. No. 6054488, WO
`99/965460). It must be noted that many
`patents have been or are subject to legal
`opposition, and it is still unclear which
`patents will be upheld (10). Alternative pro-
`pellants such as compressed gases (US Pat.
`No. 6,032,836), dimethylether, and propane
`(12) also have been investigated.
`Excipients. Many of the surfactants used
`in stabilizing suspension formulations in
`CFC propellants have much-reduced solu-
`bility in HFA systems (13). The lowered
`surfactant concentration in HFA formu-
`lations adversely affects suspension sta-
`bility and dose reproducibility because of
`rapid particle agglomeration and settling.
`Recent examples of efforts to overcome
`the complexities of suspension stability in
`HFA propellants include
`l incorporation of HFA-miscible cosol-
`vents into the formulation (US Pat. No.
`5,225,183, US Pat. No. 5,683,677, US Pat.
`No. 5,605,674, WO 91/04011, WO 95/
`17195, WO 99/65460)
`l inclusion of various surfactant systems
`(US Pat. No. 5,118,494, US Pat. No.
`5,492,688, WO 91/11073, WO 92/00107)
`l encapsulation of drug particles (Cana-
`dian Pat. App. No. 2,136,704)
`l use of perforated microparticles (WO
`99/16422).
`l use of other stabilizing excipients (US
`Pat. No. 6,136,294).
`
`Table I: Pros and cons of pMDIs (97).
`Advantages
`Portability and durability
`Active delivery (requires little inspiratory effort)
`Long shelf life
`Microbial robustness
`Low cost of production
`Disadvantages
`Time-dependent dose variation (shaking, priming, dose tailing)
`Cold sensation because of propellant evaporation
`Oropharyngeal deposition because of high aerosol velocities
`Coordination of breathing required during actuation
`Variable deposition depending on inhalation maneuver
`Environmental concerns
`
`100 Pharmaceutical Technology JULY 2001
`
`Device-related pMDI advances
`Containers, valves, and seals. Compatibility
`of propellants, excipients, and solvents with
`the components of the valve and container
`greatly influences performance of pMDIs.
`Conventional materials used with CFCs
`have been found to sometimes cause sub-
`optimal operation of the device because
`of elastomer swelling, extraction, poor lu-
`brication, and adsorption of the formula-
`tion to container walls (14). Examples of
`recent patents dealing with such issues in-
`clude US Pat. No. 6,006,745 that describes
`polymer materials for metered valves that
`are compatible with HFAs and US Pat. No.
`6,143,277 that describes coating the inside
`of aerosol containers with fluorocarbon
`and nonfluorocarbon polymers.
`Actuation mechanism. As outlined in
`Table I, a major concern of pMDI deliv-
`ery is the requirement for patients to syn-
`chronize their breathing inspiration with
`the actuation of the aerosol device. Poor
`patient technique with pMDI use is re-
`ported to occur in about 38% of users
`(15). Thus, certain strategies have been
`used to assist in the coordination of in-
`haler actuation with patient breathing pat-
`terns. A well-known example is Smartmist
`(Aradigm, Hayward, CA), which analyzes
`inspiratory flow rates and automatically
`actuates the pMDI on the basis of this in-
`formation. A similar concept of a breath-
`activated pMDI is described in WO99/-
`65551, and US Pat. No. 6,095,141.
`Spacers, plume modifiers. In addition to
`differences in solubility characteristics,
`HFA and CFC propellants have different
`vapor pressures (11,16). The higher vapor
`pressure of HFA 134a can result in in-
`creased plume velocities, leading to greater
`impaction of the aerosol in the oropha-
`rynx (17). This inertial deposition causes
`poor delivery to the lung (18). Several dif-
`ferent approaches to reducing oropha-
`ryngeal deposition include
`l added spacer devices or integrated spacer
`mouthpieces, e.g., Azmacort pMDI
`(Rhône-Poulenc Rorer Pharmaceuticals,
`Inc., Collegeville, PA), Aerohaler (Be-
`spak, UK), Spacehaler (Evans Medical,
`UK)
`l decreasing plume velocity using airflow
`modifications within the device hous-
`ing (e.g., US Pat. No. 6,062,214 describes
`a mouthpiece that creates a vortex air-
`flow using a restrictive duct, and US Pat.
`
`www.pharmaportal.com
`
`2
`
`

`
`Controller
`
`Battery
`
`Solution
`
`Baffle
`
`Medication
`chamber
`
`Programmed
`selection
`button
`
`Reset button
`
`Handpiece
`
`Mouthpiece
`
`Programmed
`selection
`button
`
`Coiled
`air tubing
`
`vibrates when electrical energy is applied.
`The vibrations cause the solution or sus-
`pension to come in contact with the con-
`cave side of the plate and pass through the
`orifices, resulting in an aerosol (4). This
`device allows the aerosol particle size to
`be adjusted by changing the size of the ori-
`fices. Another advantage is the flexibility
`of dosing; one can select single or mul-
`tiple doses from a container. The device is
`breath-actuated, allowing for reproducible
`dosing. In addition, the system has been
`shown to be suitable for the delivery of li-
`posomes (23). The device can be used to
`store freeze-dried compounds, which can
`be dissolved in a solution (also stored in
`the device) immediately before being
`aerosolized. This is particularly useful in
`the case of proteins and peptides, which
`are more stable in the solid state (1).
`Another breath-activated, aqueous de-
`livery system, the AERx (Aradigm), has
`been developed (4) and was described in
`a previous review (1). This system has
`been shown to be useful in the delivery
`of peptide drugs (25), narcotics (26), and
`insulin (27).
`A portable, piezoelectric aqueous de-
`livery system has been developed for the
`delivery of drugs in solution (see Figure
`2) (28). The device incorporates a breath-
`activated piezoelectric dispenser head, and
`a sensor and controller are used to con-
`trol the dose delivered depending on the
`inhalation flow rate generated by the pa-
`tient. The inhaler can be used for the de-
`livery of analgesics, peptides, and proteins.
`A portable, breath-activated delivery
`system, the Halolite (Medic-Aid, UK) has
`been developed with a deflector to switch
`on the aerosolization of a solution dur-
`ing inspiration and switch it off during
`exhalation (see Figure 3). It also monitors
`the inspiratory flow for three cycles and
`then generates the aerosol at the appro-
`priate point on the inspiratory cycle. The
`device is capable of producing a precise
`dose and prevents waste of the drug dur-
`ing exhalation (29).
`A device that uses an electric field to
`form an aerosol of fine droplets from a
`liquid has been developed (see Figure 4)
`(Battelle Pulmonary Therapeutics, Colum-
`bus, OH) (30). The aerosol formed from
`this system is almost monodisperse. The
`total delivered dose, dose reproducibility,
`and particle-size distributions generated
`
`www.pharmaportal.com
`
`Figure 3: Halolite delivery system (Medic-Aid,
`UK).
`
`will contribute less than 0.1% of the total
`worldwide greenhouse emissions (20).
`Thus it is likely, given the Montreal Pro-
`tocol experience, that HFA propellants will
`be around for use in pMDIs for at least
`the next two decades.
`
`Aqueous delivery systems
`Nebulizers are drug delivery systems that
`can be used to generate solutions or sus-
`pensions for inhalation. Nebulizers have
`some advantages over pMDIs and DPIs.
`These devices typically are capable of
`producing small droplets from a solution
`or suspension that are suitable for deep
`lung delivery (1). Patient coordination of
`aerosol delivery is not as critical for achiev-
`ing a therapeutic effect as it is for pMDIs
`or DPIs. In addition, aqueous solutions
`often are easily formulated for use in nebu-
`lizers and other aqueous delivery systems
`(13). Two types of nebulizers currently are
`marketed: jet and ultrasonic. Jet nebuliz-
`ers use the Venturi Effect to draw solution
`through a capillary tube and disperse
`droplets in air at high velocity. Ultrasonic
`nebulizers use an oscillating, ultrasonic
`vibration that is conveyed by means of a
`piezoelectric transducer to a solution that
`creates droplets suitable for inhalation
`(13). Nebulizers are not portable and re-
`quire an external source of energy. Re-
`cently, aqueous delivery systems have been
`developed to overcome these problems.
`A portable, battery-powered aerosol
`generator has been developed (AeroGen,
`Sunnyvale, CA) to deliver aerosols from
`drugs in solutions or suspensions. The in-
`haler consists of a curved aperture plate
`placed in the actuator mouthpiece that
`
`Switch
`
`Airflow
`
`Sensor
`
`Nozzles
`
`Piezoelectric
`dispenser
`head
`
`Mouthpiece
`
`Figure 2: Piezo inhaler (modified from US
`Patent 6,196,218).
`
`No. 6,095,141 describes a device that im-
`pinges an air jet onto the aerosol plume
`that is moving in the opposite direction)
`l US Pat. No. 6,095,141 also describes a
`device that decreases the aerosol plume
`length, allowing inspiration of a greater
`proportion of the emitted dose.
`
`The Kyoto Protocol and environmen-
`tal concerns with HFAs
`Despite being non-ozone depleting, HFA
`propellants are not completely environ-
`mentally friendly. A specific concern for
`HFA 134a is the effect of its degradation
`products on the environment. HFA 134a
`degrades to trifluoroacetic acid and may
`harm wetland areas (19).
`In addition, hydrofluoroalkanes con-
`tribute to the greenhouse effect. HFA 134a
`and HFA 227 have less global warming
`potential than the CFC propellants (20)
`have, but if ratification of the Kyoto Pro-
`tocol occurs, the reduction in greenhouse
`gases may affect HFA propellants. How-
`ever, recent reports suggest that the like-
`lihood of the US government signing the
`Kyoto treaty is slim at best (6,21,22). Even
`without emission reduction limits, it is es-
`timated that by 2005, HFAs from pMDIs
`102 Pharmaceutical Technology JULY 2001
`
`3
`
`

`
`Figure 4: Battelle electrohydrodynamic
`delivery system (Battelle Therapeutic Systems,
`Columbus, OH).
`
`Active
`
`Compressed air
`Inhale
`Pfeiffer
`5,875,776
`6,003,512
`
`Hammer/
`impactor
`5,469,843
`5,482,032
`6,142,146
`
`Impeller
`Spiros
`
`Complexity
`
`Airflow through powder
`Novolizer
`Bayer
`SkyePharma
`
`5,988,163
`
`Diskus
`5,505,196
`6,092,522
`6,102,035
`
`Use of turbulence
`5,437,271
`5,469,843
`5,724,959
`Cyclohaler
`Twisthaler
`Turbuhaler
`
`few years, surprisingly few mechanisms
`are used to disperse powdered pharma-
`ceuticals. Modifying the powder formu-
`lation is another research approach used
`to improve dispersion and is discussed in
`the next section of this article.
`DPIs can be divided into two classes:
`passive and active devices. Passive devices
`rely solely upon the patient’s inhalatory
`flow through the DPI to provide the en-
`ergy needed for dispersion. This method
`has the advantage of drug release auto-
`matically coordinat-
`ing with the patient’s
`inhalation (1). The
`disadvantage is that
`dispersion typically is
`highly dependent on
`the patient’s ability to
`inhale at an optimum
`flow rate. Depending
`on the inhaler design,
`this requirement may
`be difficult for some
`patients if the device’s
`resistance to airflow is
`high (32). Active de-
`vices have been under
`development for the
`past 10 years, but no
`active device has been
`approved yet. Similar
`to pMDIs, active de-
`vices use an external
`energy source for
`powder dispersion.
`This has the advan-
`tage of potentially re-
`ducing the depen-
`dence of uniform
`dosing on the patient’s capabilities. How-
`ever, without a feedback mechanism for
`the energy source, it is still possible that
`different patients will receive different
`doses. In addition, the complexity of these
`devices likely has contributed to their in-
`ability to achieve regulatory approval,
`which also could increase their cost.
`Passive devices have progressed in their
`complexity and performance since the in-
`troduction of Allen & Hanbury’s Rota-
`haler and Fison’s Spinhaler in the 1970s
`(33). The bulk of recent development in
`DPI technology has occurred at indus-
`trial organizations. Many of the tech-
`nologies developed are not yet named.
`Therefore, in many cases, the US patent
`
`Spinhaler
`Rotadisk
`5,375,281
`5,460,173
`5,699,789
`5,975,076
`
`Rotahaler
`Inhalator
`
`Passive
`
`Figure 5: Matrix of mechanisms of dispersion for selected DPI
`devices and patents. Here, complexity refers to the dispersion
`mechanism and not to the overall complexity of the device.
`
`can be controlled by changes in the drug
`formulation or electric field.
`
`DPIs — mechanisms of dispersion
`DPIs provide powder pharmaceuticals in
`aerosol form to patients. The powdered
`drug is either loaded by the user into the
`DPI before use or stored in the DPI. To
`generate an aerosol, the powder in its sta-
`tic state must be fluidized and entrained
`into the patient’s inspiratory airflow. The
`powder is subject to numerous cohesive
`and adhesive forces that must be overcome
`to be dispersed (2,31). Fluidization and
`entrainment require the input of energy
`to the static-powder bed. In spite of a
`plethora of patents issued during the past
`104 Pharmaceutical Technology JULY 2001
`
`number is cited rather than a trademark
`name. Little published data other than the
`patent descriptions are available for most
`of the DPI technology discussed. Figure
`5 divides mechanisms of dispersion into
`active and passive means, and the com-
`plexity of the mechanism is shown. The
`figure is not intended to represent the
`overall complexity of the device but only
`the dispersion mechanism. For example,
`many current designs include add-ons
`such as dose-counting means or disper-
`sion indicators. The complexity of these
`features is not discussed.
`Passive dispersion relies on the airflow
`generated by the user to aerosolize the
`powdered drug. All passive devices dis-
`perse the drug by passing the airflow
`through the powder bed. Early devices had
`very low dispersion of respirable-sized
`particles, often around 10% (34–36). In
`general, this poor performance can be at-
`tributed to the incomplete deaggregation
`of smaller drug particles from larger car-
`rier particles used as an aid to powder flow
`during dispersion. More modern devices
`use means of generating significant tur-
`bulence to aid in the deaggregation
`process. Turbulence can be provided by
`tortuous flow paths for the particle-laden
`airflow as in the AstraZeneca Turbuhaler,
`the Schering-Plough Twisthaler, and US
`patent 5,469,843; by changing the di-
`mensions of the airflow path (US Pat.
`5,437,271); or by using impactor plates
`that also reduce the emission of large par-
`ticles (US Pat. No. 5,724,959). A device de-
`veloped by Innovative Devices (US Pat.
`Nos. 6,209,538 and 5,988,163) addresses
`the desirability of dispersing powder at
`optimal flow rates via channels in which
`operation is flow dependent. Initially, flow
`is diverted around the drug and is allowed
`to pass through the drug only when the
`optimal flow rate has been obtained. This
`device bridges the gap between passive and
`active devices by adding active features to
`a passive device.
`Active devices use mechanisms such as
`springs or batteries to store energy that
`can be released to facilitate powder dis-
`persion. The best-known active devices
`are the delivery systems from Inhale (San
`Carlos, CA) and the Spiros inhalers from
`Dura (San Diego, CA). The Inhale device
`uses compressed air generated by the user
`through a spring-loaded pump mecha-
`
`www.pharmaportal.com
`
`4
`
`

`
`nism to disperse the powdered drug. A
`few other patents identified in Figure 5
`use compressed air (US Pat. Nos. 5,875,776
`and 6,003,512) or a vacuum (US Pat.
`No. 6,138,673) to provide energy for dis-
`persion. The Spiros DPI uses a battery-
`driven impeller to disperse drug powder.
`The impeller operates only when the pa-
`tient inhales through the DPI to ensure
`that dosing does not occur when not in
`use (37). Only one other mechanism of
`dispersion has been patented. This mecha-
`nism uses a hammer or other means of
`impaction to dislodge drug from a pow-
`der bed typically contained on a blister
`strip (US Pat. Nos. 5,469,843, 5,482,032,
`and 6,142,146). Few published data are
`available for the active devices because
`most of their development has occurred
`in a proprietary atmosphere. Some of the
`patented technology, both for active and
`passive devices, is only conceptual.
`
`Powder formulations
`For lung deposition, drug particles gener-
`ally are required to be smaller than 5-µm
`aerodynamic diameter. They may be pre-
`pared using either size-reduction methods
`such as milling or particle-construction
`methods such as condensation, evapora-
`tion, or precipitation (31). Historically, res-
`pirable particles are produced by jet-
`milling, where there is little control over
`the particle size, shape, or morphology (38).
`The resulting fractured particles are highly
`electrostatic and cohesive. Alternative meth-
`ods of particle generation include spray-
`drying, solvent evaporation or extraction,
`and supercritical fluid condensation (39).
`Particles smaller than 10 µm generally
`exhibit poor flow properties because of
`their high interparticle forces. Formula-
`tion strategies to improve the flowability
`of respirable particles include the con-
`trolled agglomeration of drug particles
`and adhesion onto excipient carrier par-
`ticles in the form of interactive mixtures.
`The agglomerates or interactive mixtures
`are required to be strong enough to with-
`stand processing, storage, or transport
`processes but weak enough to allow drug
`deaggregation and dispersion during ac-
`tuation. Controlled agglomeration is ob-
`tained by feeding micronized powders
`through a screw feeder, followed by spher-
`onization in a rotating pan or drum. This
`method may be used for formulations
`106 Pharmaceutical Technology JULY 2001
`
`containing a drug alone (40) or drug–
`lactose blends (41). Factors affecting the
`aerosol dispersion of carrier-based for-
`mulations include drug and carrier prop-
`erties such as size, shape, surface rough-
`ness, chemical composition and crystalline
`state, the drug–carrier ratio, and the pres-
`ence of ternary components.
`The drug particle size affects the aerosol
`dispersion. Different-sized spray-dried
`mannitol (2.7–7.3 µm) and disodium cro-
`moglycate (2.3–5.2 µm) particles were ex-
`amined (42,43). Because of less cohesion,
`higher aerosol dispersion was observed in
`larger particles; however, lower fine par-
`ticle fraction (FPF) was produced because
`of a smaller proportion of fine particles
`and a greater impaction on the throat and
`upper stages of the impinger. Condition-
`ing or surface modification of drug par-
`ticles may reduce aggregation and improve
`aerosol dispersion. The amorphous con-
`tent of particles may be reduced by treat-
`ment with water vapor in controlled tem-
`perature and relative humidity conditions
`(44) or treatment in a vacuum oven (45).
`Surface modification by adhesion of nano-
`particles onto the drug particles may in-
`crease aerosol dispersion. Hydrophilic sili-
`cic acid and hydroxypropyl methylcellulose
`phthalate nanoparticles increased device
`emission and respirable fractions of pran-
`lukast hydrate in both drug-alone and
`carrier-based formulations (46,47).
`Conflicting reports exist on the influ-
`ence of drug concentration in carrier-
`based DPI formulations. Increasing drug
`concentration may increase or reduce the
`respirable fraction (48–51).
`The particle size, shape, surface mor-
`phology, and chemical composition of car-
`rier particles can influence aerosol dis-
`persion. Increased drug deposition is
`generally observed with smaller carrier
`size (50–53) and increased proportion of
`fine particles (54,56). However, the car-
`rier size did not affect the FPF in some
`formulations (56,57). Higher FPF was pro-
`duced with larger carrier sizes (within
`63–90 mm) (49). The use of coarse carrier
`systems caused poor dispersion of ne-
`docromil, whereas the use of fine carrier
`particles and high-shear mixing tech-
`niques physically disrupted the drug–drug
`contacts and promoted deaggregation
`(58). Elongated carriers increased aerosol
`dispersibility and drug FPF, possibly be-
`
`cause of increased duration in the air-
`stream drag forces (59). Carriers with
`smooth surfaces produced higher res-
`pirable fractions (59–61). Low-respirable
`fractions were obtained from carriers with
`macroscopic surface roughness or smooth
`surfaces. High-respirable fractions were
`obtained from carriers with microscopic
`surface roughness where smaller contact
`area and reduced drug adhesion occurred
`at the tiny surface protrusions (62). A
`modification of carrier formulation in-
`volves the use of soft, friable lactose pel-
`lets containing micronized lactose par-
`ticles, which break down into primary
`particles during inhalation (63). The drug
`material may be coated onto the lactose
`pellets. Carrier particles with good pow-
`der flow characteristics exhibited reduced
`adhesion from a solid surface and pro-
`duced higher drug deposition (64).
`In vitro drug deposition has been ex-
`amined using different grades of lactose
`carrier. The higher FPF of salbutamol
`sulphate obtained from anhydrous and
`medium lactose was attributed to a higher
`proportion of fine particles and smooth
`surface roughness (65). The higher FPF
`of nacystelyn obtained from anhydrous
`b-lactose was attributed to its intermedi-
`ate surface roughness (49). Other sugars
`were investigated as fine and coarse car-
`riers (66). Higher FPF was obtained using
`a mannitol coarse carrier, possibly because
`of a higher fine-particle content and more
`elongated shape. Mixtures with an added
`fine-particle carrier produced higher FPF
`with little difference observed between the
`fine-carrier type.
`The addition of fine ternary compo-
`nents has increased the FPF of various
`drug particles. Ternary components ex-
`amined include magnesium stearate, lac-
`tose, L-leucine, PEG 6000, and lecithin
`(48,67–70). Although the mechanism for
`improved FPF by ternary components has
`not been fully characterized, possible ex-
`planations include the saturation of ac-
`tive sites on the carrier, electrostatic in-
`teractions, and drug redistribution on the
`ternary component.
`Recent developments in the improve-
`ment of DPI formulation efficiency are
`focused on particle engineering tech-
`niques. Improved aerosol dispersion of
`particles may be achieved by cospray-
`drying with excipients such as sodium
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`5
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`

`
`been much speculation on the potential
`delivery of locally and systemically acting
`drugs such as analgesics (fentanyl and
`morphine), antibiotics, peptides (insulin,
`vasopressin, growth hormone, calcitonin,
`and parathyroid hormone), RNA/DNA
`fragments for gene therapy, and vaccines.
`However, the only new therapy provided
`using DPI formulations is zamamivir (Re-
`lenza, GlaxoSmithKline, Research Trian-
`gle Park, NC), which is mainly targeted at
`the upper respiratory tract for the treat-
`ment of influenza.
`The use of formulation additives to
`enhance drug uptake also has been con-
`sidered. The nature of these absorption
`promoters is based on a variety of mecha-
`nisms, not all of which are fully elucidated.
`The most well-known are the classical ab-
`sorption enhancers such as bile salts and
`surfactants, which are known to disrupt
`cell membranes and open tight junctions
`rendering epithelia more permeable (84).
`This has been followed by the use of small
`particulates containing drug, which may
`find their way across epithelia intact. Many
`of these particulate approaches have yet
`to be published with respect to lung de-
`livery, but some companies have relevant
`technology such as Nanosystems, PDC,
`and BioSante.
`An alternative approach involves the
`close association of a carrier molecule with
`peptides and proteins for transport across
`the epithelium (85). The mechanism of
`improved uptake is not fully characterized
`for these molecules with respect to the
`lung epithelium. The maximum doses that
`can be delivered to the lungs limit the sys-
`temic delivery of drugs. However, the po-
`tential advantage of all of the particulate
`or molecular transport promoters is that
`they may improve the bioavailability of
`the drug, maximizing the proportion of
`the dose that reaches the site of action.
`This is particularly important for macro-
`molecules, which may not be delivered ef-
`fectively by any other route of adminis-
`tration (86). The safety implications of
`using any agent that modifies the physi-
`ology of the lung must be fully considered
`if it is to be adopted for any commercially
`viable product (87).
`
`Conclusion
`Changes in the delivery of inhaled phar-
`maceuticals come at a time when the po-
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`
`(PGA). Surfactants
`such as dipalmitoyl
`phosphatidylcholine
`may be incorporated
`to further improve
`powder flow, aerosol
`dispersion, and lung
`deposition (80).
`Drug or peptide
`encapsulated hollow
`microcapsules are free
`flowing, easily deag-
`gregated and produce
`high-respirable frac-
`tions. Wall materials
`include HSA (81) or PGA and PLA (82).
`Reduced dissolution may be obtained by
`coating with fatty acids such as palmitic
`acid (81) or lipid soluble surfactants such
`as Span 85 (82). The PulmoSphere small,
`hollow particles (with 5-mm geometric di-
`ameters and bulk densities less than 0.1
`g/mL) are spray-dried from emulsions of
`drug, phospha-tidylcholine, and perfluo-
`rocarbon.
`Current commerical DPI formulations
`are based on drug agglomerates or carrier-
`based interactive mixtures. Excipients act
`as diluents and stablility enhancers and
`improve flowability and aerosol dis-
`persibility. Because lactose is the only US-
`approved excipient for DPI formulations,
`there is a need for safe alternatives. Sug-
`gestions have included carbohydrates such
`as fructose, glucose, galactose, sucrose,
`trehalose, raffinose, and melezitose; aldi-
`tols such as mannitol and xylitol; mal-
`todextrins, dextrans, cyclodextrins, and
`amino acids such as glycine, arginine, ly-
`sine, aspartic acid, and glutamic acid; and
`peptides such as HSA and gelatin. To
`mask the unpleasant taste of some inhaled
`drug compounds, flavoring particles con-
`taining maltodextrin and peppermint oil
`can be incorporated into dry-powder for-
`mulations (85). Large-sized particles en-
`hance mouth deposition and reduce lung
`deposition.
`Commercial formulations predomi-
`nantly deliver bronchodilators, anticho-
`linergics, and corticosteriods for the local
`treatment of asthma and chronic airway
`obstruction. New formulations contain
`multiple drug components such as fluti-
`casone and salmeterol. This causes further
`complications in the particle interactions
`involved with powder systems. There has
`
`Figure 6: Historical and projected market size for respiratory
`products.
`
`chloride (56) and human serum albumin
`(HSA) (71). Respirable-sized particles
`composed of hydrophobic drug and hy-
`drophilic excipients were produced by
`simultaneous spray-drying of separate
`solutions through a coaxial nozzle (72).
`Therapeutically active peptide particles
`have been produced by spray-drying with
`good flow and dispersibility properties,
`including insulin (73), a-1-antitrypsin
`(74), and b-interferon (75). The addition
`of stabilizing excipients such as mannitol
`and HSA generally is required. Spray-dried