inhaler project report

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Design and development of a novel dry powder inhalation(DPI) aerosol drug delivery device for the treatment of

acute asthmatic episodes

Annemarie K. Alderson, Annie Saha, Stephanie T. Shaulis, Robert J. Toth

BioE 1160/1161: Senior Design, University of Pittsburgh, Department of Bioengineering

April 29, 2005

Abstract

Asthma is a chronic, constrictive disease of the intrapulmonary airways affecting a significant andincreasing number of individuals. Pharmaceutical therapy of acute asthmatic episodes with drug deliverydirectly to the respiratory tract through oral inhalation has been successfully implemented in practically allasthma sufferers. The use of either metered-dose inhalers (MDIs) and/or dry powder inhalers (DPIs) isubiquitous among the vast majority of individuals with the condition. However, current devices of thesetypes fall short of desired patient preferences, particularly in mobility and robustness. Therefore, was thegoal of this project to design and develop a dry-powder type, single-dose, disposable inhaler. The device iscompletely self contained, ruggedly constructed, lightweight, small, ergonomically designed, and activelymobile. The device is applicable to asthmatic individuals who desire a temporary alternative to traditionaldevices during physical activity and/or in extreme environmental settings (running, bicycling, swimming,skiing, various sports and outdoor activities, at the beach, etc.). The device was designed utilizingSolidworks solid modeling software, and computationally analyzed with the COSMOSFloWorkscomputational fluid dynamics (CFD) functionality within Solidworks. Prototyping of the device wasperformed through Quickparts.com a custom rapid prototyped parts supplier. The functional prototypewas developed within the time table of the project, and aerosol dispersion and flow testing was conductedin the Aerosol Drug Delivery and Pulmonary Biomechanics Laboratory under the direction of Timothy E.Corcoran, PhD at the University of Pittsburgh. The time table for detailed design, prototyping, and testingwas four months (January April, 2005).

Keywords: Asthma; Bronchodilator; Aerosol; Nebulizer; Metered-does inhaler (MDI); Dry powder inhaler(DPI); Product design specifications (PDS)

Contents

1. Introduction....... 022. Asthma.. 03

2.1. Characterization of the disease. 032.2. Methods of treatment 042.3. Principles of drug delivery to the respiratory tract... 06

3. Oral inhalation aerosol technology .. 073.1. Nebulizers. 083.2. Meter-dose inhalers (MDIs).. 093.3. Dry powder inhalers (DPIs).. 12

4. Design considerations... 134.1. MDIs vs. DPIs... 134.2. Aerosol generation mechanism. 144.3. Product design specifications 14

5. Design methods. 175.1. Initial design decisions... 17

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5.2. Solid model design methodology. 186. Design results.... 247. Design analyses, modification, and validation.. .. 26

7.1. Model-8 analyses.. 267.2. Prototype modifications 297.3. Final analyses and validation 32

8. Conclusions 349. Acknowledgements 35References.. 35

1. Introduction

One of the most chronic conditions affecting individuals in the United States isasthma. Simply defined, asthma is an immuno-mediated condition characterized byincreased resistance to airflow in intrapulmonary airways in response to various non-specific chemical and physical stimuli [1]. The condition manifests itself in common

symptoms including breathlessness, chest tightness, nighttime and/or early morningcoughing episodes, and episodes of wheezing exaggerated and forced breathing [1,2].Asthma is a rapidly escalating pulmonary disease.

The prevalence of asthma has been increasing since the early 1980s for all age,sex, and racial groups [3]. The overall age-adjusted prevalence of asthma rose from 30.7per 1,000 population in 1980 to a 2-year average of 53.8 per 1,000 in 1993-94 [3]. Thisrepresents an increase of 75 percent [3]. The prevalence among children ages 5 to 14increased 74 percent, from 42.8 per 1,000 in 1980 to an average of 74.4 per 1,000 in1993-94 [3]. Among children up to four years of age, asthma prevalence increased 160percent, from 22.2 per 1,000, the lowest prevalence among any age group, to a 2-yearaverage of 57.8 per 1,000 in 1993-94, the second highest prevalence behind children 5 to

14 [3]. Thus, asthma is an obviously increasingly common condition.As of 2001, 20.3 million Americans have reported suffering form asthma [4]. In

terms of the effects of the condition on the healthcare industry, in 2000 alone there were10.4 million asthma-related visits to outpatient hospital clinics and private physicianoffices, 1.8 million emergency room visits for asthma related problems, 465,000 inpatienthospitalizations, and 4,487 deaths attributable to asthma-related complications [4]. Thistranslated to an estimated $14 billion in related healthcare costs that year [5].

As the above statistics indicate, the market for asthma-related medical devices islarge and is increasing along with the increasing trends in the incidence of the disease. Inaddition, the current options in treatment technology do not completely satisfy the needsand preferences of individuals afflicted with the disease. This is especially true in the

area of prescription drug delivery. In particular, while the pharmaceutical agents and thedevices utilized to deliver those agents to the respiratory tract the primary site oflocalized asthma treatment have found widespread effectiveness in treating thecondition through symptom mitigation; the delivery devices, inhalers especially, possessa number of significant limitations that oftentimes prove a hindrance to asthmaticindividuals. These limitations include limited environmental exposure; reduced orprecluded functionality under non-ideal operating conditions; fragile construction;delicate operating mechanisms; inconvenient and inefficient shape, size, and weight; and

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significant impairment to active portability. Therefore, it was the goal of this project todevelop, design, prototype, and test a novel aerosol drug delivery device that addressesthe limitation delineated above.

This document presents the preliminary research conducted in preparation for thedesign and development of the proposed device as well as the methods and results of the

design work itself. This includes a brief review of asthma, characterization and treatmentof the disease, a review of the current oral inhalation technology, the technicalconsiderations implemented in the device design, a detailed project plan outlining thedesign methods, and the analyses and validation of the developed device.

2. Asthma

2.1. Characterization of the disease

A diagnosis of asthma is generally considered appropriate in patients in whom

episodes of wheezy breathlessness, with intervals of relative or complete freedom fromsymptoms, can be shown to be associated with variations in resistance to flow inintrapulmonary airways [1]. In such patients, abnormal increases in expiratory airflowresistance can usually be demonstrated in response to various non-specific chemical andphysical stimuli [1]. These stimuli have been shown to include triggers as varied assecondhand smoke, dust and dust mites, environmental air pollution, cockroach allergen,pet dander and fur, mold and mildew, high air humidity, freezing temperatures,thunderstorm-generated ozone, food and/or drug additives, emotional states, andstrenuous physical activity [6]. Moreover, asthma may develop in individuals who sufferfrom other chronic bronchopulmonary diseases, such as bronchiectasis or emphysema, inwhich the specific pathology of the disease induces asthmatic symptoms in the diseased

respiratory tract [1,2].Antigen-antibody reactions of several types, due to inhaled triggering stimuli,have been shown to be concerned in the pathogenesis of asthma [1]. The most frequentand probably the best understood of these reactions is that observed in a group of patientswho have an inherited genetic susceptibility to develop hypersensitivity to a range ofpotentially antigenic substances as a result of the minor exposures to the small amountsinevitability present from time to time in respired air [1]. The resulting immunologicreactions are IgE immunoglobin mediated [1,2]. Other types of antigen-antibody reactionhave been shown to be involved in some cases of asthma. For instance, heavy exposureto inhalation of certain organic and inorganic compounds can cause sensitization, notdependent upon any genetic susceptibility in the person exposed, and accompanied by the

development of precipitating antibody; and subsequent exposure may then give rise to thecommon asthma symptoms [1,6]. These symptoms usually include any number of thefollowing; breathlessness, chest tightness, coughing episodes, and episodes of wheezydyspnoea, otherwise known simply as wheezing [1]. All of the above symptoms aremanifestations of the increased resistance to airflow due to constriction of the respiratorytract, particularly the bronchioles [1,6].

Upon IgE immunoglobin reaction in the respiratory tract, a number ofinflammatory mediators play an interactive role in the constriction of the bronchioles [7].

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Acute asthmatic episodes are now thought to be connected to IgE reaction through theactions of mast cells, which are pervasive in bronchial tissue [7]. Mast cells are known topossess an excess of 10,000 high affinity receptors for activated IgE [7]. Once mast cellsbind with IgE, they have been shown to secrete a number of inflammatory chemicalsincluding histamine, various leukotrienes, and various prostaglandins [7]. These

substances have been linked to smooth muscle contraction in the bronchioles, therebyinducing bronchoconstriction and thus asthmatic episodes [7].The other major triggering mechanism for asthma is exercise and hyperventilation

inducement [8]. There are two major schools of thought on the mediation of exercise andhyperventilation induced asthma, both of which provide explanations for triggeringmechanisms in addition to the possibility that the increased breathing rate associated withexercise and hyperventilation simply might bring in more external chemical stimuli [8,9].It has been shown that changes in the physical environment inside the respiratory tractdue to rapid breathing, particularly changes in air temperature and humidity, can incitebronchoconstriction through changed osmolarity within the bronchial tissue [8]. Changesin osmolarity have also been linked to mast cell recruitment and activation in the

respiratory tract [8]. The second school of thought involves direct neurologicalmediation of bronchoconstriction [9]. The respiratory tract is innervated throughout itslength, but especially the bronchial regions [9]. The nerves are part of the autonomicnervous system and retain partial control of bronchial tone through smooth muscle cellaction [9]. In terms of sole nervous effects contributing to asthma, several types of

autonomic defects have been proposed including enhanced cholinergic, -adrenergic, and

non-adrenergic non-cholinergic (NANC) excitatory mechanisms, or reduced -adrenergic

and NANC inhibitory mechanisms [9].Despite the varied mechanisms implicated in the development and perpetuation of

asthma, they have, for the most part, been reconciled into a contributory theory, where anumber of different triggering stimuli coupled with immuno-inflammatory, neural, and

physical processes all play a role in the condition [7,9]. The complex interplay oftriggering stimuli and physiological response in asthma results in complicated treatmentmethods for the disease.

2.2. Methods of treatment

Despite the chronic nature of asthma, it is most commonly treated in an acutemanner. This is primarily due to the lack of development of any successful diseasemitigation therapies [10]. Therefore, all pharmacological treatments for asthma aredisease or symptomatic control measures [10]. The lack of an effective treatment ineliminating the pathology does not preclude total recovery from or elimination of the

disease in afflicted individuals. Complete recoveries with apparent elimination of allsymptoms have been observed in some asthmatics predominately in children [3].However, this occurrence cannot be correlated to pharmacological therapy and is mostlikely a case of so-called growing out of the disease [3]. The control medication forasthma is often classified into four categories; immunotherapy or allergy desensitizationshots, anti-IgE monoclonal antibody therapy, long-term control medications, and quick-relief medications [10-12].

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The first two classifications involve mitigation of the immuno-inflammatoryreactions implicated in asthma [12]. Immunotherapy involves a series of injections ofasthma triggering allergens to induce desensitization [12]. Anti-IgE injections, such asomalizumab (Xolair), block the action of IgE immunoglobin and thereby eliminate theinitiation of the inflammatory reactions implicated in asthma [12]. These therapies are

less common in the treatment of asthma than are the aerosol-type medications.Long-term control medications are typically taken on a daily or twice-daily basisto achieve and maintain control of persistent asthma [10]. They include corticosteroids,

long-acting 2-agonists, leukotiene modifiers, sodium cromoglycate, and theophylline

[10,13]. Table-1 below presents the most common drugs in each category.

Table-1: Common drug treatments for asthma [10-13].

Drug name Brand name Drug type

Long-term control medications

fluticasone Flovent inhaled corticosteroid

budesonide Pulmicort inhaled corticosteroid

triamicinolone Azmacort inhaled corticosteroid

flunisolide Aerobid inhaled corticosteroid

beclomethasone Ovar inhaled corticosteroid

salmeterol Serevent long-acting 2-agonists

formoterol Foradil long-acting 2-agonists

montelukast Singulair leukotiene modifier

zafirlukast Accolate leukotiene modifier

sodium cromoglycate Intal mechanism not known

nedocromil Tilade mechanism not known

theophylline Uniphyl mechanism not known

Quick-relief medications

albuterol Proventil/Ventolin short-acting 2-agonists

pirbuterol Maxair short-acting 2-agonists

ipratropium Atrovent anticholinergic

Corticosteroids act in an anti-inflammatory manner by inhibiting local recruitment ofmast cells through suppression of the formation of cytokines the chemical mediatorsresponsible for the progression of the asthmatic reaction from IgE-antigen complex to

smooth muscle contraction [10]. Long-acting 2-agonists induce bronchodilation by

binding to -adrenergic receptors in bronchial tissue and inducing smooth muscle cellrelaxation [10]. Leukotriene modifiers function by blocking leukotriene production orinterfering with receptors in the airways. Inhibited leukotriene action reducesinflammation of the airways and thereby lessens the symptoms of asthma [11]. Sodiumcromoglycate, nedocromil, and theophylline are three drugs whose mechanisms of actionare not well characterized but are known to effectively reduce asthma symptoms [11,13].Sodium cromoglycate is especially effective. It is thought to prevent antigen-inducedrelease of mediators from mast cells through an unknown mechanism, however, it has

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also been shown to possess bronchodilator properties through action on smooth musclescells [13]. Effective control of asthma in 60-70% of patients is observed with sodiumcromoglycate [13].

Quick-relief medications, otherwise termed rescue medications, rapidly stop thesymptoms of an abrupt asthma attack [11]. A number of long-term medications also

possess short-term effects, and thus, are utilized in a dual manner [11]. However, thereare medications that act only in a short-term manner; the most common of these are listedin Table-1 [11]. These drugs act as bronchodilators that act rapidly to relax smoothmuscle cells and dilate the airways [10,11].

While most of these drugs are effective asthma treatments when givensystemically, it has been conclusively shown that their effectiveness is vastly increasedwhen applied locally to the respiratory tract [11]. Therefore, the majority of asthmamedications are delivered directly to the respiratory tract [11]. However, there a numberof aspects of inhalation drug delivery that complicates this route of administration.

2.3. Principles of drug delivery to the respiratory tract

The respiratory tract is a complex system of branching tubes of progressivelydecreasing size [14]. A system of drug administration has to deliver the drugs into andthrough these tubes in order for it to reach its site of action which, for drugs to treatasthma, is regarded as being in the conducting airways [14]. The progressive reduction insize through an ever-increasing number of airways presents a severe challenge to thedrug, since the drug particles are constantly having to change direction and, in movingthrough air of progressively decreasing velocity, have an increasing tendency to deposit[14]. Premature deposition prior to the bronchial region, where asthma symptomsactively manifest, significantly decreases the effectiveness of the treatment [14].Therefore, a drug delivery system to the respiratory tract must account for all majorfactors affecting deposition, which for the purposes of design are listed in Table-2.

Table-2: Major factors affecting drug deposition in the lungs (adapted from[14]).

Particle properties Diameter DensityShapeChargeChemical composition:

SolubilityHygroscopicity

Aerosol properties ConcentrationParticle size rangeBolus or continuous cloudVelocity of sprayEvaporation of propellants

Respiratory tract properties Geometry (variability)Presence of diseaseHumidity

Breathing patterns Residence time(breath-holding)

Volumetric flow rate(breathing rate, tidal volume)

Mouth or nasal breathing

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The predominate factors that relate to delivery device design are the aerosol properties.While the particle properties, respiratory tract properties, and breathing patterns have animpact on device design, they are oftentimes beyond the control of the specific devicedesign, and as such, do not have as significant an effect as the aerosol properties. It is thegeneration of an effective aerosol that is the primary design goal of the delivery device.

For orally inhaled drugs the rates of availability are usually very rapid and can beexpressed in terms of the extent (i.e. the percentage of the delivered dose) and thedistribution (i.e. where the drug is deposited) [14]. To be an effective delivery device, adesign should maximize the extent and localize the distribution. This is accomplished bydesigning for efficient deposition within the proper portion of the respiratory tract.

There are three basic mechanisms by which particles can deposit in the respiratorytract upon inhalation; inertial impaction, sedimentation, and Brownian motion [14].Impaction occurs when a particle has sufficient inertia such that it is unable to travel withthe air stream when it changes direction as an airway branches [14]. It then impacts onthe airway surface, often at the bifurcation [14]. For common drugs utilized to treat

asthma, impaction is important for particles above 5m in size [14]. Particles between

0.6 and 5 m are able to move with the air stream but in the lower air velocities existingin the conducting bronchial airways their mass causes them to sediment, or settle out of

the air stream, and deposit [14]. Deposition of particles less then 0.6 m occurs by

Brownian motion where the individual submicron-sized particles move at velocities andin directions within the bulk air stream [14]. Particles in this size range to do deposit atany particular location within the respiratory tract [14]. As these mechanisms indicate,

the 0.6-5 m range is the target for maximally efficient deposition in the bronchioles

[14].In order to deliver particles of the proper size into the respiratory tract, the

delivery device must fluidize or aerosolize the drug such that agglomeration is eliminated[15]. There are a number of mechanisms by which this is accomplished depending upon

the phase of the drug, i.e. liquid or solid based [15]. The predominate mechanismsclassify the three major types of oral inhalation aerosol drug delivery devices utilizedcurrently.

3. Oral inhalation aerosol technology

Oral inhalation drug delivery requires the delivery device to aerosolize the drugcompound. There are three major methods to aerosolize drug compounds; liquid drugscan be volatilized with compressed air or oxygen mixtures that are subsequently breathedin, liquid solutions or solid powders can be pneumatically fluidized into a dispersed

aerosol stream that is inhaled, or solid powders can be dispersed into a stream ofpassively inhaled air [16,17]. These three mechanisms are the basis for operation ofnebulizers, metered-dose inhalers (MDIs) and dry-powder inhalers (DPIs) respectively[16,17]. The specific principles and important considerations governing the operation ofthese three technologies are discussed in turn below. It is important to note that thediscussions treat the three device types in a general manner and are based upon commonprinciples. They are not based upon any particular name-brand device.

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3.1. Nebulizers

Nebulizers are of two primary types; air-driven or jet nebulizers and ultrasonicnebulizers [17]. Jet nebulizers operate on the principle that by passing air at high speedover the end of a capillary tube, liquid may be drawn up the tube from a reservoir in

which it is immersed an example of the Venturi or Bernoulli Effect [17,18]. When theliquid reaches the end of the capillary tube, it is drawn into the airstream and formsdroplets that disperse to become an aerosol (Figures-1,2) [17,18].

Figure-1: Schematic of jet nebulizer (adapted from [17]).

An ultrasonic nebulizer uses a piezoelectric transducer to induce waves in a reservoir ofdrug solution [17]. Interference of these waves at the reservoir surface leads to theproduction of droplets in the atmosphere above the reservoir [17]. An airstream is passedthrough this atmosphere to transport the droplets as an aerosol [17].

Figure-2: Standard jet-type nebulizer (www.adam.com).

AirInlet

Air Inlet foraerosol generation

Baffle

AirOutlet

Capillary Tube

Drug Solution

. .. .. .. . .. . . . . . . .. .. .

... . .

. .. . . .Aerosol . . .

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Jet nebulizers are by far the most commonly used type [18]. They utilizecompressed gas from an air or oxygen mixture cylinder, hospital air-line, or electriccompressor to provide both the bulk gas flow and the gas to the aerosol generation orifice[18]. A baffle is a standard component of a jet nebulizer [18]. It functions to provide asurface for aerosolized droplets to impact and subsequently coalescence, thus draining

back into the reservoir [18]. This is important to ensure proper droplet size for effectivebronchial deposition [18]. Aerosolized droplets are accelerated to a velocity sufficientfor more than 99% of the droplet mass to impact the baffles or on the nebulizer wall [18].Only 1% of the aerosol mass leaves the nebulizer and is inhaled directly [18]. Due to thismethod of operation, a typical treatment takes approximately 5 to 30 minutes to dispensedepending on how much medication is to be administered [18]. Thus, drug delivery withnebulizers is very time intensive compared to the other drug delivery options. However,nebulizers are the most efficient inhalation delivery devices due to the manner of aerosolgeneration [18]. Specifically, inhaled liquid droplets travel into the respiratory tract insignificantly larger fractions as compared to solid aerosols, which tend to succumb to alarge ingestion effect where significant amounts of the aerosol are swallowed [17].

Nebulizers possess a number of additional disadvantages that tend to favor the useof alternative delivery devices outside a clinical setting. These include cost, size, andcomplications. Nebulizer systems can cost upward of $250 compared to MDIs and DPIswhich cost less than 10% of that cost [18]. Furthermore, nebulizer systems are relativelylarge, especially the gas tank and/or compressor, compared to MDIs and DPIs which canusually fit in the palm of the hand [18]. Finally, the use of nebulizers has been implicatedin the development of respiratory tract and lung infections [18]. Therefore, nebulizerequipment must be cleaned and sterilized on a regular basis and the air filtered [18].These disadvantages lead the majority of asthmatic individuals to use MDIs and DPIs astheir respiratory drug delivery devices of choice.

3.2. Metered-dose inhalers (MDIs)

The pressurized metered-dose inhaler (MDI) was conceived of in 1955 by IrvinePorush and George Maison in response to observed difficulty in inhaling aerosolized drugtreatments from squeeze-bulb glass nebulizers [19]. They were awarded a patent on thefirst MDI in 1959, and their invention saw only minor modifications and cosmeticupdates until the late 1980s when advances in materials and metering technology allowedfor miniaturization of the device [19]. MDIs incorporate a propellant, under pressure, togenerate a metered dose of an aerosol through an atomization nozzle [20,21]. MDIs arethe most widely used inhalation drug delivery device, with an estimated 800 million unitsproduced in 2000 [20,21]. MDIs consist of several components: the active substanceformulated with propellant, surfactants/solvents termed excipients, and the drug; acontainer; a metering valve crimped onto the container; an actuator that connects themetering valve to an atomization nozzle; and a mouth piece [20,21]. Additionally,holding chambers or spacers may also form part of the delivery system by connection tothe actuator mouthpiece [20,21]. The current incarnation of an MDI is diagrammed in

Figures-3,4 [20,21]. A metered volume (typically between 20 and 100 L) of the

drug/excipient/propellant blend is expelled from the canister via the valve and quicklypasses through the actuator orifice where atomization occurs [20,21].

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Figure-3: Basic components of an MDI system [20].

Figure-4: Cutaway schematic of and MDI (http://www.3M.com)

Current research and development on MDI systems primarily concerns thechemical propellants [20]. Chlorofluorocarbons (CFCs) have been utilized as thechemical propellants in MDIs for almost 50 years [20]. There are three different CFCsthat have found applicability in MDIs: CFC-11, CFC-12, and CFC-114 [20]. However,due to concern over environmental effects of CFCs the FDA in conjunction with the EPAhas set a series of standards governing the phase-out of CFC-MDIs [20]. Specifically,once two non-ozone-depleting propellants are marketed with identical or superiorcharacteristics in MDIs, CFCs will be phased out of use in the devices [20]. Twopromising candidates receiving much attention are from the hydrofluorocarbon family:HFA 134a and HFA 227ea [20]. These propellants along with the CFCs (Figure-5,

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Table-3) account for all chemical propellants encountered in all MDI applications (Table-4).

Figure-5: Chemical structures of CFC and HFA propellants [20].

Table-3: Physicochemical properties of MDI propellants [20].

Table-4: Common marketed MDIs and their chemical composition [20].

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The design and development of MDI systems is complicated by the necessaryintegration of numerous principles within one device [21]. An effective MDI mustintegrate a pressure vessel, nozzle, valve assembly into one device that is intuitive tooperate and which provides a conformable interface with the mouth of a user.Furthermore, the chemical principles governing the drug/excipient/propellant mixture and

the fluid mechanical principles governing the fluidization of the aerosol must beaccounted for. Consequently, it is understandable why a successful design has beenfundamentally unchanged for over 50 years.

3.3. Dry powder inhalers (DPIs)

A dry powder inhaler (DPI), like a metered dose inhaler, is a handheld device thatdelivers a precisely measured dose of asthma medicine into the lungs. Both quick reliefmedicine (inhaled bronchodilators) and long-term control medicine (inhaledcorticosteroids) can be delivered to the airways using a DPI [22]. Unlike metered doseinhalers, where slow inhalation is needed to acquire the full benefit of the medication,

DPIs require the user to breathe in quickly and forcefully to automatically activate theproper flow of medication [22,23]. Since there are no propellants used in DPIs, the usermust inhale with more force than when using a metered dose inhaler [23]. It is usuallyrecommended that to receive full benefit from a DPI, the user should hold his or herbreath for approximately ten seconds (or longer, if possible) after inhaling [23]. It isimportant that the user does not breathe out through a DPI, because the moisture in thebreath can cause powder agglomeration thereby clogging the mechanism, making it lessefficient for, or precluding, future uses [22,23].

In a DPI, the asthma medication comes in a dry powder form [22,24]. A smallcapsule, disk, or compartment inside the inhaler device is used to hold the medication[22,24]. Manufacturing of DPIs for drug administration requires powders with desirablecharacteristics [22]. Specifically, as noted above, upon aerosolization, the powder

particles must be within the 0.6-5 m range [22]. In order to ensure compliance with this

requirement, a number of processing methods are utilized to generate powders of properproperties [22]. These methods include spray drying, spray freeze drying, controlledevaporation of droplets, solvent precipitation, recrystallization, fluid energy milling, andnano-milling [22]. In addition to the drug powder, DPI formulations often include anumber of additional additives termed excipients as in MDI technology [22]. Thesesubstances include lubricants or anti-adherents which minimize agglomeration uponaerosolization, desiccants, and for some drugs carrier particles [22]. The most common

dry powder excipient is lactose [22]. Fine lactose (~5 m) can function as a lubricant and

as a carrier particle depending upon the specific formulation [22]. As a lubricant, lactose

functions to ensure particle dispersion upon inhalation by interfering with drug particle-drug particle interactions [22]. As a carrier, it functions as a substrate to which the drugcompound is immobilized [22]. The lactose-drug complex is then inhaled and deposits inthe respiratory tract [22]. Because DPIs utilize powdered medications, the need to keepthem dry is crucial. As such, DPIs should not be stored in damp environments.Moreover, one of the major drawbacks to DPIs is their incompatibility with humidenvironments.

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Many types of DPIs are currently available and each has a different operatingmechanism. Consequently, there is no one general mechanism that could be described aswas the case with MDIs. Furthermore, a description of each mechanism of even the mostcommon DPIs is beyond the scope of this report. However, the major types bearmentioning. Some DPIs, including Inhalator, Spinhaler, and Rotahaler, must have

the medication loaded each time they are used [22]. Others, such as Diskhaler, havepreloaded disks with a certain number of doses [22]. Turbuhaler and Accuhaler aretwo DPIs that have as many as 200 doses stored in the device [22]. Since all DPIs rely onthe force of the users inhalation in order to properly deliver the medication into thelungs, DPIs are not recommended for children under the age of five, people with severeasthma or those suffering a severe attack [22].

The primary advantage of using a dry powder inhaler is that it is breath-activated,so that the user does not need to coordinate activating the inhaler (dispensing themedication) with inhaling the medication [23]. Instead, the flow of medication isactivated by simply breathing in. Additionally, DPIs do not require propellants so theyare more environmentally-friendly than metered dose inhalers [22]. Several

disadvantages of DPIs are that they are often more expensive than the equivalent metereddose inhaler and they may be difficult and cumbersome to load [23]. For example, theRotahaler requires the user to carry a supply of medication capsules with them becauseit can only hold one capsule at a time [22]. If a single capsule is not sufficient to stop theasthma attack, the user must load another capsule in order to receive additionalmedication.

The design and development of DPI systems is very flexible due to the fact thatthere are countless mechanisms whereby dry powder capsules can be aerosolized andinhaled. A design is only limited by the constraints of the particular specifications for adevice. Accordingly, it is understandable that there are numerous different DPI designseach with their own unique characteristics.

4. Design considerations

As the above discussions indicate, there are numerous factors that must beconsidered when designing an inhalation drug delivery device based on aerosolization.However, the most pertinent consideration is by far the mechanism that will be utilized togenerate the drug aerosol. Since the proposed drug delivery device is to be by designmobile and for use in an acute, quick-relief manner, the choice of aerosolizationmechanism is between that of an MDI or a DPI. Accordingly, what follows is adiscussion of the benefits and detriments of the respective technologies and the logic and

motivation behind the ultimate mechanism choice for the proposed device design.

4.1. MDIs vs. DPIs

In terms of effectiveness in the delivery of asthma treatment medications,numerous clinical studies have reported the therapeutic equivalence of MDIs and DPIs[14]. While differences in the deposition characteristics under controlled conditions havebeen demonstrated, the effective dose delivery is analogous between the two device types

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with established powder production and processing procedures for DPIs [25]. Moreover,the goals of this project were not pharmaceutically related, but rather were simply todevelop a device that met the deficiencies of current devices in terms of ruggedness,mobility, and versatility. Therefore, it was practical and logistic factors that weighedmost heavily on the choice of aerosol generation mechanism.

Ideally, it would have been prudent to design two devices, one MDI-based andthe other DPI-based, each with analogous product specifications so that consumers wouldhave the choice of which aerosol generation mechanism they prefer. However, given thescope and resources allocated for this project, such an undertaking was notaccomplishable. Given the limited time frame, monetary resources, personnel, andproduction equipment for detailed design, prototyping, and testing; the project had to beespecially limited in scope and of relatively simple execution. In order the meet theserequirements, the overall device design was as simplified as possible. Considering theprinciples involved in the operation of MDIs versus DPIs; DPIs were clearly the less-complex, more straightforward to execute technology.

A DPI-type novel device would be more rapidly designed, prototyped, and tested

than an MDI-based design. An MDI design would require work with chemicalpropellants, metering valves, pressure vessels, filling equipment, and a vast number ofadditional considerations that the DPI design would preclude. The design, prototyping,and testing of a relatively simple mechanical mechanism to activate a dry powder fittedwithin a casing that meets the design specifications is well within the constraints of theproject. Therefore, a DPI-type device was chosen to be designed and developedconsistent with the design specifications.

4.2. Aerosol generation mechanism

The aerosol generation mechanisms in current DPIs are as varied as the number ofdifferent devices on the market. Each device generates the aerosol based upon thefunctionality of the device, i.e. pre-loaded multi-dose disks, re-loadable devices bothmulti-dose and single-dose, pre-loaded single-dose devices, etc. It was of crucialimportance that the specific mechanism be consistent with the intended specifications andoperation of the device. Accordingly, the utilized mechanism was consistent withrugged, impact-resistant, and reliable operation. The general principles of the aerosolgeneration mechanism were similar to that of current technology, but different enough topreclude patent infringement.

4.3. Product design specifications

Any respiratory drug delivery device must possess certain general characteristicsand features to be a successful design. These characteristics and features are summarizedin Tables-5 and 6 respectively [19]. These characteristics and features are important toan effective design regardless of the specific type of mechanism utilized and the uniquefeatures of any one device. However, it is the mechanism itself and the unique featuresof a design that provide a market for the device. Therefore, it is important to design anaerosol drug delivery device with distinctive characteristics that improve upon existingdevices or are novel.

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Table-5: Desirable characteristics of respiratory drug delivery devices of major interest [19].

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Table-6: Features of an ideal respiratory delivery device [19].

It is the improvements and novelty of a design that are the important aspects of theproduct design specifications (PDS) for the purposes of detailed design work. While acomplete discussion of the product design specifications for the proposed device isbeyond the scope of this report, it is important to note those specifications thatsignificantly impact the detailed design of the device.

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As previously noted, the device was of the DPI-type. Thus, the aerosolizationmechanism was consistent with this specification. Moreover, the device was to belightweight, single-use-only, disposable, and extremely rugged. These specifications hada profound effect upon the choice of materials of which the device will be constructed.In addition, the ergonomic and size properties specified for the device affect the external

shape, which had implications for the internal mechanism. Thus, it was important to taketime to work out the design details before subsequent prototyping and testing in order toeliminate any waste of the limited time or material/monetary resources.

5. Design methods

5.1. Initial design decisions

The actual development of any computational or physical prototype of the devicewas initially precluded by a number of design options that required finalization before

subsequent model development. These specifications included decisions regardingmaterials of construction, anthropometry, ergonomics, human factors considerations andpharmaceutical options and associated dosing constraints.

In accordance with the design specifications of lightweight yet ruggedconstruction and weather and water resistance, it was initially decided that a polymer-based plastic was the best option. This was consistent with the construction of predicatedevices, which all are constructed from a specified plastic material. Seven plastics wereevaluated in terms of material density (a lightweight material was desired), materialstrength (a material that could absorb significant impact was desired), and materialhardness (a soft plastic material was desired). The important physical properties of therespective materials are presented in Table 7.

Table-7: Plastic materials of construction options and associated properties [27].

Plastics Comparison

Plastic Type Density (g/cc)Impact Strength

(J/cm)Rockwell Hardness

[R]

ABS 1.08 6.40 115

LD-polyethylene 0.91 6.94 60

PET 1.30 1.40 110

Polypropylene 1.07 11.50 91

Polystyrene 1.00 2.94 75

PVC 1.37 13.90 80

ABS/PVC Blend 0.98 12.50 102

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In consideration of the above materials, it was most desirable to minimize the density andhardness values while maximizing the impact strength. Unfortunately, no one specificmaterial possessed all of the optimal properties. Consequently, a compromise had to bemade with the most acceptable choice being low density polyethylene (LDPE). Thechoice of LDPE minimized both density and hardness. As a result, the chosen material of

construction would provide for the lightest weight and softest device possible.Accordingly, the design specifications in terms of product weight and minimal userimpact during physical collisions were effectively met. However, LDPE did not possessthe impact strength of some of the other plastics options. Therefore, the compromise wasmade regarding the materials impact strength. Nonetheless, the impact strength ofLDPE is sufficient for its application in the device since it does not necessarily need to bemaximized as long as it is high enough to withstand the magnitude of any foreseeableimpacts during portability of the device, which it adequately achieves. In addition,LDPE possesses a unique property that makes it the optimal material of constructiondespite its lower impact strength. Specifically, LDPE is heat-sealable [27]. Two separatecomponents constructed of LDPE can be readily bonded simply through the application

of site-directed heat through filaments, wires, etc. The strength of the heat-sealed bondcan also be modulated through the temperature and time exposure during the sealingprocess [27]. This property has exiting implications on the future design of the overallsealing mechanism of the device, an aspect of the design not considered as a part of thisproject.

In order to design a prototype for use for individuals varying in size,anthropometric considerations were evaluated to determine the average size mouth forboth males and females. Anthropometric considerations were evaluated to determine anappropriate size for the mouthpiece to maximize comfort and ease of use for a hostof asthmatics. It was also decided to use the current inhaler models on the market asguidance on the assumption that the companies had done a plethora of research indesigning an optimal mouthpiece. Using various anthropometric data, the lip widths forpeople of various races and ages was approximately from commissure to commissureranged from 29-38 mm, and the lip heights from base of columella to tubercle rangedfrom 19-29 mm [28]. After researching anthropometry, the final mouthpiece size waschosen to be cylindrical witha 20 mm diameter and 20 mm in length.

Another main component to the design considerations was the mass of the drug tobe loaded into the device. The prototype needed to have adequate space to hold and sealthe amount of medication needed to be inhaled by the user. Delving into the current

research for inhalers on the market, it was determined that about 25 mg 1 mg was the

total load dosage of both the excipient lactose and bronchodilator albuterol sulfate in a33% w/w composition. [29].

5.2. Solid model design methodology

The design of the DPI device began with conceptual hand-illustrations of how itwould look. These included descriptions of both the internal and external geometry ofthe device. These early conceptual drawings were refined in terms of incorporating theanthropometric considerations regarding hand and mouth size and shape in relation to theexternal geometry of the device and the mouthpiece design. In addition, the choice of

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albuterol sulfate as the bronchodilator drug compound and micronized lactose as theexcipient for a total dosage of 25 mg placed constraints on the internal dimensions of thedevice that were reflected in these drawing refinements. The refined drawings were thenconverted to solid models in Solidworks. Solidworks is a feature-based dynamic solidmodeling software package. It allows for the creation of single solid part representations

and organized groupings of such parts in dynamic assemblies. Once transferred to solidmodel format, the conceptual device models could then be readily modified.In order to incorporate all of the design considerations into a prototype device

consistent with the project goals, an iterative design process was implemented. Acomputational fluid dynamics (CFD) simulation was performed on the initial conceptualdevice solid model. The CFD was performed utilizing the COSMOSFloWorksfunctionality within Solidworks. The simulations were turbulent and time-independentwith air as the process fluid. Physiologic boundary conditions determined frompulmonary mechanics were implemented, and the bulk average volumetric flowratethrough the device was chosen as the primary convergence parameter due to itsimportance in obtaining aerosol dynamics within the device consistent with the effective

recruitment, dispersion, and deposition of 5 m drug particles. The results of the CFDsimulations were then used as a guide to modify and refine the solid models of the devicein order to improve the CFD predicted fluid behavior within the device. Once thesemodifications were implemented, the resulting version of the solid model was used to re-perform a comparable CFD simulation. This design cycle was then repeated until a solidmodel was developed that adequately met the design considerations and performed asdesired through CFD simulation.

Summarizing the implementation of this process, a total of 10 solid models ofdifferent devices were developed. Each subsequent solid model was developed basedupon the previous model with the aid of the CFD simulation results in performing themodifications and refinements. The initial CFD results on the early solid models

indicated the presence of significant rotational flow patterns within the body of thedevice.

Figure-6: Early solid model representation of device.

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Figure-7: Initial CFD results indicating rotational flow patterns.

Initially it was thought that these rotational patterns were a consequence of the internalgeometry of the device and the orientation of the two pressure inlets. These patterns were

unacceptable because such air flow would be inefficient at recruiting drug particles fromwithin the device and dispersing them from the device through the mouth and depositingthem within the airways. In order the effectively achieve such dispersion and deposition,a bulk flow of air directly through the device would be ideal. Accordingly, the firstmodifications made to the device solid model were changes of the internal geometry ofthe device and of the orientation and number of the pressure inlets in order eliminate therotational patterns and obtain bulk flow directly through the internal body of the device.These modifications are reflected in Figures 8 and 9.

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Figure-8: Model-3 CFD results.


Various changes were made in the internal geometry and pressure inlet orientation from

Models 1 through 6, with the consistent result being the presence of rotational flowpatterns in the CFD simulation results. It was at Model-6 that the source of theserotational flow patterns was determined. From Model-1 through Model-6, a mixed set ofboundary conditions consisting of an ambient (atmospheric) static pressure boundarycondition at the inlets and a specified 60 L/min volumetric flowrate as the outletboundary condition. This flow was chosen because it has been found to be the medianinspiratory flowrate for individuals during inhalation drug therapy [30]. It was thesemixed boundary conditions that were the source of the rotations. Specifically, by

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specifying a pressure at the inlets and a flowrate at the outlet, the computational solverwas generating the rotational patterns in order to establish the necessary pressure dropacross the device consistent with the specified flow. In a sense, the mixed boundaryconditions were over constraining the system.

After review of CFD theory and the operational capabilities of

COSMOSFloWorks, it was determined that the boundary conditions should be changedfrom the mixed pressure/flow set to a consistent set of pressure boundary conditions. Theinlet boundary condition was kept at ambient pressure and the outlet boundary conditionwas set at a total pressure of 1 mmHg below ambient. This pressure was determinedfrom pulmonary mechanics. Specifically, intralveolar pressure is 2 mmHg belowambient [31]. It has been shown that the resistive pressure loss from the alveoli throughthe airways to the mouth is approximately 1 mmHg [31]. Therefore, during inspiration,an average of -1 mmHg pressure is drawn at the mouth, and therefore at the mouthpiecewhere the boundary condition is implemented.

The improved boundary conditions were implemented for a simple simulation totest their effectiveness as part of Model-7.


Once implemented, the consistent pressure boundary conditions eliminated the rotationalpatterns and resulted in bulk flow through the device. Despite the source of the rotationalflow patterns being the over-constraining boundary conditions, the internal geometry ofthe device still created a flow pattern that was excessively turbulent and would notefficiently recruit the drug particles from within the body of the device, disperse them

from the device through the mouth and upper airways, and effectively deposit themwithin the lower airways. Therefore, Model-8 was redesigned to simplify the internalgeometry and thereby create aerosol dynamics within the device consistent with the

efficient recruitment, dispersion, and deposition of 5 m sized drug particles. The

resulting model and associated CFD simulation results demonstrated the optimalcharacteristics for the device.

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These patterns were indicative of a bulk flow through the device consistent with thedesired dynamics. The CFD simulations calculated average fluid flow velocities in thetwo regions (pressure inlet, body of the device) corresponding to Reynolds numbers of10307 and 3436 respectively. Two Reynolds numbers were calculated due to the largechange in diameter between the two regions. These numbers were indicative of a

transitional or turbulent flow regime which was consistent with the choice of a turbulentsimulation. However, the magnitudes of the numbers and the corresponding turbulencewere sufficiently low to still effectively result in drug particle recruitment and dispersion.Furthermore, the simulation gave a bulk flow through the device consistent with thoseobserved in inhalation drug therapies, specifically 32.5 L/min. As a consequence ofModel-8 achieving the desired performance and complying with the specified designconsiderations, it was subsequently physically prototyped.

6. Design results

Model-8 was the preliminary result of the implementation of the iterative designmethodology. It was physically prototyped through Quickparts.com, an online distributorof custom rapid prototyped parts. Quickparts.com utilizes uploaded solid modelcomputational files (.STL format) and creates the part from a proprietary ABS-likeplastic formulation using the stereolithography rapid prototyping technique.

Stereolithography (SLA) is often considered the pioneer of the rapid prototypingindustry with the first commercial system introduced in 1988 by 3D Systems. The systemconsists of an Ultra-Violet Laser, a vat of photo-curable liquid resin, and a controllingsystem. A platform is lowered into the resin (via an elevator system), such that thesurface of the platform is a layer-thickness below the surface of the resin. The laser beamthen traces the boundaries and fills in a two-dimensional cross section of the model,

solidifying the resin wherever it touches. Once a layer is complete, the platform descendsa layer thickness, resin flows over the first layer, and the next layer is built. This processcontinues until the model is complete. Once the model is complete, the platform rises outof the vat and the excess resin is drained. The model is then removed from the platform,washed of excess resin, and then placed in a UV oven for a final curing. The model isthen finished by smoothing the "stair-steps" [32].

Unfortunately, the method that would be required to fabricate the device out ofthe end-type material LDPE would be injection molding. The fabrication of aninjection molded LDPE prototype would have required the production of die-cast custommolds, which, costing upwards of $10,000 dollars under the most conservative estimateswas beyond the resources available for the project. However, to perform device

validation testing, an analogous device fabricated from any plastic-type material wouldsuffice and therefore, the rapid-prototyped device was applicable. This was because theaerosol generation was primarily a function of the boundary conditions and the internalgeometry of the device itself, with the material of construction possessing a negligiblerole.

The resulting physical prototype was fabricated in two separate components. Theseparate component construction was established in order to simplify the repeated

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loading and unloading as well as intermediate washes necessary during the testing andvalidation of the device.

Figure-12: Model-8 and resulting physical prototype.

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Figure-13: Model-8 and resulting physical prototype.

7. Design analyses, modifications, and validation

Pursuant with the design considerations and project goals set forth at the onset ofthe project, the physical prototype was validated in terms of the effectiveness of therecruitment and dispersion of drug particles from the device under inhalation therapyconditions. A major shortcoming of the project as completed was the inability tofabricate the device out of the LDPE material, and thus, the inability to physically

prototype and validate the sealing mechanism and environmental performance of thedevice. However, the testing and validation of the aerosol dynamics within the deviceprovided a firm foundation upon which to base the success of the project.

7.1. Model-8 analyses

The physical prototype of Model-8 was initially tested in terms of the ability toeffectively recruit the drug particles from the device with a physiological flowrate and

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disperse those particles from the device in a manner that corresponded to effective airwaydeposition. Specifically, it was desired to demonstrate a significant fraction of the

particle distribution from the device representing sizes of 5 m or less. This is pursuant

with respirable particle sizes that would deposit in the bronchial region of the airways asindicated in Figure-14.

Figure-14: Particle size distributions and the corresponding airway deposition [33].

This was performed using a Malvern Mastersizer device. The Mastersizer utilizes laserdiffraction by the particles to determine the particle size distribution in a stream offluidized solids. The device functions by aerosolizing the solid drug compound from thedevice by pulling a negative pressure through vacuum line in a manner analogous toinspiration during drug therapy situations. The fluidized drug particles are then drawnthrough a glass chamber where the incident laser beam contacts the solid particles in theair stream and is diffracted based upon the size of the particles. In relative terms, smallparticles bend the beam by large angles whereas large particles bend the beam by small

angles. The device detector is calibrated in order to determine particle size distributionbased upon aspirated samples.

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Figure-15: The Mastersizer laser sizing device.

The developed device was tested with the Mastersizer using 25 mg of a 33% w/wblend of micronized atropine sulfate and lactose excipient. In practice the inhaler devicewould utilize albuterol sulfate as the active drug compound, however, it was not availablein micronized form at the time of these testing activities, and therefore, the atropine wasused. It should be noted that these tests were on the particle dynamics related to thedevice only, and consequently, any micronized solid powder would have functionedadequately in place of active drug. On average, the vacuum line generates a maximum of45 L/min of air flow through the inlet port. In order to establish a baseline set of data, theatropine/lactose blend was sized from open air off of the end of a laboratory spatula.This provided no additional resistance to flow and the maximal 45 L/min was availablefor particle recruitment. Figure-16 presents the results of this test in terms of particle

distribution.

Figure-16: Open air aerosolization results with atropine/lactose test blend.

Volume (%) of Blend from Vial

0

10

2030

40

50

60

70

80

90

100

0.1 1 10 100

Particle Diameter (um)

34%

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As indicated in the figure, under optimal conditions, approximately 34% of the total drugmixture volume was respirable. This corresponded to a large fraction of the 33% by masscomponent composition of atropine. Figure-17 presents analogous results for the

physical prototype of Model-8.

Figure-17: Aerosolization from Model-8 prototype.

From Figure-17 it was evident that the majority of the particles dispersed from the devicewere above respirable size. In additional, through qualitative observation it wasdiscovered that only a small fraction of the total 25 mg dose loaded into the device wasexiting. These results were attributed to insufficient airflow through the device.Specifically, when attached to the inlet port of the Mastersizer, only 8 L/min of airflowwas being pulled through the device, compared to 45 L/min in open air. As a result, theprototype and the design as a whole had to be modified.

7.2. Prototype modifications

Due to the inadequate flow through the device, modifications had to be made thatwould decrease the fluid resistance within the device and thereby increase flow. Since

the internal geometry of the device body was a function of anthropometry and dosageconsiderations, the only option was modification of the pressure inlets. It was initiallydecided to increase the diameter of the pressure inlet from 2 mm to 3mm. Thiscorresponded to a decrease by a factor of 9/4 in the apparent resistance through thepressure inlet. The resulting Model-9 was evaluated qualitatively through CFD in orderto determine the general effect of the diameter increase.

Volume (%) of Blend from Inhaler

0

10

20

3040

50

60

70

80

90

100

0.1 1 10 100 1000


11%

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The CFD results indicated only a slight increase in the average flow through the device.It was also determined that the qualitative flow pattern illustrated in Figures 11 and 18,specifically the flow separation at the top of the internal device chamber, may becontributing to the inadequate dynamics. This led to the decision to create a secondpressure inlet, symmetric with the first through the mid-plane of the device. These designchanges were reflected in Model-10.

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The CFD results on Model-10 represented a significant improvement in airflow throughthe device. Specifically, the predicted bulk air flowrate through the device went up to42.4 L/min. These promising CFD results led to the implementation of both the diameter

increase and the addition of a second pressure inlet in the prototyped device. Themodifications where made to the device and the resulting Model-10 was tested with theMastersizer.

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7.3. Final analyses and validation

After the modifications were made to the prototype, it was re-tested in theMastersizer in an identical manner as the initial tests. Figures 20 and 21 present theresults of these tests.

Figure-20: Particle distribution from modified prototype.

Figure-21: Particle distribution from modified prototype.

Volume (%) of Blend from Redesigned Inhaler- First

Run

0

10

2030

40

50

60

70

80

90

100

0.1 1 10 100


51%

Volume (%) of Blend from Redesigned Inhaler-

Second Run

010

20

30

40

50

60

70

80

90

100

0.1 1 10 100


63%

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Two representative runs of the device through the Mastersizer indicated 51% and 63% of

the total dosage volume was below the 5 m respirable particle size. Visual observation

indicated that the total 25 mg dose was completely evacuated from the device. Theseresults surpass the baseline open air results in terms of delivering an inhaled dose ofpredominately respirable drug. These results were interpreted as demonstrating that the

device successfully delivered a total dosage of micronized bronchodilating drug in anacceptably respirable form. The successful results led to the fabrication of the finalphysical prototype (Model-10) from quickparts.com with the validated modificationsincorporated into the fabrication itself.

Figure-22: Final physical prototype.

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Measurement of the flowrate through the final device gave an average of 38 L/min.Comparing this flowrate to the CFD predicted flow of 42.4 L/min, the use of CFD as adesign tool to guide the intuitive design of the device was validated.

Ultimately, it was concluded that the iterative CFD-guided design methodologywas successfully implemented with the resulting physical prototype performing as

designed. Specifically, drug particle dispersion less than 5 m was observed witheffective separation of drug and excipient indicated by the particle size distributionobtained from the device. Flow through the device was measured at levels consistentwith physiologic inspiration levels. These metrics combined to provide a generalconfidence in the device in terms of effective drug deposition within the proper regions ofthe airways.

8. Conclusions

Asthma is a chronic disease that shows not signs of being eliminated from the

patient population. Due to the pervasive nature of the disease, and the unique manner inwhich it is treated pharmaceutically, the market for respiratory drug delivery devices totreat asthma is exceptionally large. However, despite the large market, some asthmatics,especially those who retain an active lifestyle, are not completely satisfied with theaerosol drug delivery options available in terms of robustness and versatility of thedevices. Thus, there exists a market for rugged and weather-resistant aerosol drugdelivery devices that can be used in outdoor settings and can withstand the rigors ofphysical activities. Accordingly, the developed device aimed to meets these demands.Through the use of a DPI-type mechanism, the developed device provided acomplimentary option for DPI users during sports and other outdoor activities or in anysituation where conventional DPIs are not suited to the physical environment.

The detailed design of the proposed device made use of Solidworks solid-modeling software and the various associated functionalities in order to design andcomputationally model the device. The device was prototyped through Quickparts.com,and was tested with the assistance of Dr. Timothy E. Corcoran in the Aerosol DrugDelivery and Pulmonary Biomechanics Laboratory at the University of Pittsburgh.

The device has been shown to be capable of full evacuation and effectivedispersion of a 25 mg combined dosage of albuterol sulfate bronchodilator and lactoseexcipient. The device therefore shows the potential to effectively function as an aerosoldrug delivery vehicle for the treatment of minor and acute asthmatic episodes.

At this point in the development of the device, the external and internal geometryof the device has been designed and validated. To complete the design to a functional

level, the internal sealing mechanism for the drug compound and the coupling of thatmechanism to the external sealing mechanism must be finalized. At that point, a fullyfunctional prototype could be completed, contingent upon the ability to fabricate thedevice from the LDPE material.

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9. Acknowledgements

The authors would like to acknowledge Dr. Timothy E. Corcoran, the director of theAerosol Drug Delivery and Pulmonary Biomechanics Laboratory in the University of

Pittsburgh School of Medicine for his mentorship in the initial planning and execution ofthe design. His expert knowledge of aerosol drug delivery was proven invaluable indetermining the course of the design for the device and in the validation. Finally, specialthanks to the generous gift of Dr. Hal Wrigley and Dr. Linda Baker, and the Departmentof Bioengineering for providing the $500 working budget for the project.

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inhaler project report

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