Re3pir'atoriy Drug Delivery
`
`
`Essential Theory 8:: Practice-
`
`
`
`St‘e'phen Newmz'm
`
`with cohiribufions from
`Paula Afldeijsbfz; Reta Byron, Richard Dalby
`and-Iaanné Pear:
`
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`

`Respiratory Drug Delivery:
`Essential Theory and Practice
`
`Stephen Newman
`with contributions from
`
`Paula Anderson, Peter Byron, Richard Dalby
`and Joanne Peart
`
`Stephen Newman, PhD.
`Scientific Consultant
`Nottingham
`United Kingdom
`steve.newman@physics.org
`
`Paula Anderson. MD.
`Divmon of PulmonaryI 3.
`Critical Care Medicine
`Urlwcrsity oi Arkansas for Medical Scrences
`43m Wes: Markham, Slot 55$
`Lucie Rock. AP. F2205
`
`Richard Dalby. Ph D
`School ol‘ Pharmacy
`Unwersny of Maryland. Baltimore
`20 North Pine Street.
`Baltlrnore. MD ZIEOI
`
`Pelcr Byron. PhD.
`Sci-moi of Pharmacy
`Virginia Commonwcakh University
`4 IO North IIth Street
`Richmond.VA 23298
`
`joanne FEJI'I. PhD.
`School of Pharmacy
`Vlrglnla Commonwealth University
`4 In North Ilm Street
`Richmond.VA 23298
`
`11113.0 (15dim
`
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`1098?654321
`
`ISBN: 1-933722-26-6
`Copyright © 2009 Respiratory Drug Delivery OnlineNC U
`All rights reserved.
`
`This book is protected by copyright. No part of it may be reproduced stored in a
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`system. or
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`
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`
`While every el'i‘ort has been made by the publishers. editors. and authors to ensure
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`orthe authors and may not represent those of either RDD Online or VCU.
`
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`
`HUD Unlirw
`Respiratory Drug Denver;-
`
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`ttttti East Leigh Street. Suite In
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`
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`

`9 F
`
`igure 5. Schematic of the structure of the alveolar wall.
`
`BHCKE‘I’OUHU to Pulrtlortury Drug Del-wry
`
`Deposited particle
`
`Alveolar
`epithelial
`cells
`
`Red blood
`cell
`
` \
`
`Tight iunccion
`
`IO urn
`
`Surfactant
`layer
`
`Interstitium
`
`Capillary if
`endochelium
`
`Capillaryr
`
`The nlveoli contain macrophages that may engulf deposited material by
`phagocytosis. and either transport it to the foot of the mucociliary escalator. or
`transfer it into lymph nodes. This is another important lung defense mechanism.
`but it probably applies more to solid particles than to soluble drugI substances The
`alveoli also contain cstcrascs that may inactivate deposited drugs in ways that
`depend on their chemical structure. Some molecules such as nicotine are believed
`to pass intact through the air r blood barrier. while large peptides can undergo
`significant enzymatic degradation [Adjei and Gupta. l99‘ll.
`
`Airflow and breathing
`
`The lungs are highly elastic. and normal (tidal) breathing by an adult involves
`displacement of about 500 mL of air Deep breathing can result in the inhalation
`and exhalation of muclt larger volumes. During inhalation. the diaphragm and the
`intercostal muscles contract
`to expand the lungs. Negative pressure is created
`within the lungs. resulting in the inhalation of air. The normal breathing rate in
`adults is around IS breaths per minute. but higher breathing rates and smaller tidal
`volumes occur in infants and young children. The duty cycle is the fraction of the
`total respiratory cycle during which someone is inhaling [(‘ollis e1 uI.. I990 l. in
`healthy subjects. the duty cycle is slightly less than 0.5. but may be significantly
`less than 0.5 in patients with some lung diseases [Nikanden l997]. A possible
`consequence is that some patients receiving drug from ncbulizers by tidal
`breathing could have less time available than healthy subjects to actually inhale
`drug into the lungs.
`
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`15
`Bin'kgthui-i lL- c'uIrI CHIC“; Dun? Del-29'.
`
`
`Table 3. Pulmonary drug delivery: major advantages for locally acting
`and systemically acting drugs.
`
`Advantages for local treatments in the lungs
`Drugs effective in low doses campared to oral route
`Low incidence of systemic side effects
`Rapid onset ol drug action. eg. compared to oral close
`
`Advantages for systemic treatments via the lungs
`Avoidance of iniections for drugs that are not absorbed orally
`Rapid onset of drug action. e.g. compared to subcutaneous dose
`
`important clinical atlvttntugcs for
`Direct deliver) to the airways leads to sct-eml
`locally acting drugs i‘Ttiblt: 3 1. First. a relatively small dose is needed. As shown in
`Figure 8A. inhaled doses ol‘ 200 pg albutcrol and 500 pg tcrhtitaline by pMDl are
`therapeutically equivalenl
`in oral doses of several milligrams iC-cbbic. 1982!.
`Second. the low dose. coupled with the use of rclalivel).r sale inhuled compounds.
`resulls in a
`low incidence of systemic suit: clients. For
`instance.
`inhaled
`corticosteroids are no“ accepted as I'intl line thcnipy for asthma. and cause for fewer
`systemic side cchcts than oral corticosteroids tBamcs. Zillltli, Finally. as shown in
`Figure SB. the onset ul'drug action when giten by inhalation i5 l‘tflal'lhfl) rapid
`{within minutes for inhaled broncliodilritorsl. and this Is a wry valuable :itiribule
`when treating sudden uheezing attacks in asthma lKiihlci' and Fleischer. lllllll].
`
`Advantages of the pulmonary route for systemically
`acting drugs
`
`l'rom givutg drugs by ll'lt.‘ pulmonary route for
`Further adianlagcs may result
`systemic therapy [Table 31. Many drugs are either not absorbed from the
`gastrointestinal tract. or have such variable absorption. that they need to be git-en
`parcnlerall} {often by subcutaneous injection: if they are in stand any chance ol'
`being delivered predictablyr it) the required site In the body (Davis. I‘JWJ. The use
`of insulin in diabetic patients is an example of this. but some patients may be
`unwilling to inject
`themselves regularly. The puIinonary epithelium offers an
`injection‘l'rce portal of'entry t0 the body For drugs than are poorly absorbed when
`given orally tAdjei and Gupta.
`l99'li. The pulmonary route also has advantages
`For \actinc delivery. In the developing world. the need to immunize by inieclinn is
`a serious limitation. which could be overcome by delivering vaccines by inhalation
`l Lauhc. 20%]. These issues are discussed in more detail in Chapter It).
`
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`

`'-""7.'JI'-,'
`'-’—". t3i:"l .
`_'_5.
`__
`'_-I'
`_
`.'= -.'
`.-'v-
`16
`
`
`l_;-1.-Ir F".'j|:"-I_E
`
`Figure 8.Two important advantages of the pulmonary route for locally
`acting drugs. (A) The inhaled dose needed to treat asthma is much
`smaller than the oral dose (Gebbie. I982); note that the close axis is
`logarithmic. (B) Bronchodilators given by inhalation act faster than
`those given orally (Kéhler and Fleischer, 2000).
`
`A
`
`i Albuterol
`
`I Terbutaline
`
`
`
`pMDI dose
`
`Tablet dose
`
`U?
`
`40
`
`i
`3
`
`/ Inhaled dose: peak response i5-3O min
`,fi.
`'
`'
`-:>-..
`
`
`
`LungfunctionIncrease.33
`
`
`
`\
`
`0
`
`I5
`5
`4
`3
`2
`Time post dose. h
`
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`Bcickgrfiwr.‘ in 51i.'.-‘r'la.-'-it.- ; D‘s}? Dem. -_—-.i
`
`17
`
`The rttpid onset of action for drugs given h_v the pulmonary route can also lie
`tIIiliretl for systemically acting drugs. the most obvious example being found til
`the control of pain associated With a “nutty of conditions including inigriiiiie and
`cancer tC'liitplcr Hit. The future of pulmonary drug dclitcry is likely to favor
`s} fitL‘t‘llIEitlLV acting products” more litill'l has [teen the case in the past.
`
`Limitations of the pulmonary route
`
`The advantages ofthe pulmonary route are somewhat oil'set by the fact that giving
`drugs l1}.r
`inhultitioii
`is more complex than giving drugs by mouth. Successful
`pulliiontir} drug deliver}r depends on depositing drug on the lung tum-av surfaces.
`to facilitate either a local effect or systemic absorption. Deposition may be
`required in the long as a whole. or in some specific lung region.
`
`in other words as dispersions or
`inhaled drugs are given ‘JS :tctosolit.
`suspensions ol'solid panicles or liquid droplets in air. In order to deliver an aerosol
`to its target site. the particle or droplet size must be correct. and the inhalation
`technique must be appropriate. Aerosol particles or droplets should be smaller than
`about ‘3 pm in diameter iftlicv arc to have a good chance of penetrating into the
`lungs lCliapter 3t.
`tind even smaller than this if they are to reach the most
`peripheral aint-ays. Therefore. it is necessary to design both inhaler dcv ices and
`drug formulations tlittt iii-ill tlelivcr an adequate amount ot‘ drug in appiopriately
`sized particles or droplets. The drug doses required for inhalation range from a fee
`micrograms for some bronchodilatoni.
`to several hundred milligrams for some
`antibiotics. and not all inhaler devices are suitable for deliwriitg drug dose» 3 l mg.
`
`Since an inhaled nirstreain is required to cart) the drug aerosol into the lungs.
`the way the patient iiiltales is also important. For one type of inhaler lnebulizei'st.
`normal "tidal“ breathing is oilen adequate [Chapter 5:. but for others a precise
`inhalation technique must be learned that involves actuation of the inhaler at the
`stone time as breathing in slowly [for pMDls. L'ltaptcr fit or inhaling forcefully
`(for most DPls. Chapter 3}. Hence. the pntient's cooperation and skill in using an
`inhaler correctly tire essential parts of successful pulmonary. drug delitery. This
`i'eqLIireirient places demands on Itcaltlicure professionals to help ensure that
`inhaler.» tire used correctly. especially to utoid "crucial“ errors in inhaler technique
`that can lead to zero lung dose (Newman. Ellllt’il. In addition. patients must adhere
`to tor comply with} their prescribed treiiti'nenl
`tFink anti Rubin. Eiltlfii Poor
`adherence to prescribed inhalation therapy is a major limitation in its success
`thiti. 2llllfiht.
`litit
`it
`l'lilti also been pointed out
`that mung to the pussihilit) of
`incorrect inhaler technique. some patients inc)r adhere to the treatment regimen
`and still get no clinieiil benefit tEi-eiui'LL llltloi.
`
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`

`18
`
`Resp-rotor". Dru-:2 Defer-arr E Sic-rm! Theory and F'ntrtrce
`
`The lungs have molt-ed so as to minimize the entry of inhaled particles. and
`til'OplCIa [by depositing them in the upper airways}. and to remove tltem once
`deposition has occurred tog. h)
`t11tlc:1ctlltit'}-' clear-utter: or cngultittent by alveolar
`macrophages] Pulmonary drug delivery must.
`to some extent. circunwent Iltesc
`utttuntl
`lung dcibtlhc ntcchttnisttts tLabiria anti Dolottelt. 2003}. Furthermore.
`asthma and (UPI) an: oltcu clttn‘uctcrizcd byutrttu) Ititrrt'nring. which can prevent
`
`in drug. crostol penetrating to "It requircd deposition site. In extreme situations. for
`cttttttple in CF or hronehiectaais. mucus plugs can cutttplclcly obstruct airways.
`Despite these diiTiculties. the potential advantages of pulmonaryr drug delivery
`make II an attractive option for an incrcuaittgly \tidc range ot'drup.
`
`1.5 HISTORY OF PULMONARY DRUG DELIVERY
`
`The beginnings of inhalation therapy
`
`inhalation therapy is often considered a modern phenomenon. but in Fact account:-
`ol‘its use can be found in the records of ancient Hebrew. Chinese. Indian. (.ircek.
`Arabic and Roman cultures tZiment.
`INS}. These ancient remedies usually
`involtcd aromatic fumes and incense; derit cd either from natural plant essences
`or from burning organic materials.
`
`The origins. of inhalation therapy for respitatory conditions may lie in
`traditional Ayurvcdic medicine in India about 4.000 years ago tAitderson. .2005].
`which involved smoking herbal prcparattons with bronchodilating properties.
`Medicatncnts were ground into powders. made into pastes. and then ignited.
`In
`about
`ISO-t) Bl . the Ebers papyrus from ancient Egypt described how the smoke
`Front burning henbane tan antieholinergic compound) was inhaled after the plant
`had been placed on a hot brick tEllul-Micallcl‘. 2000:. Steam inhalations were
`used by followers of both Hippocrates (in ancient Greece] and Galen tin ancient
`Rome}. For treatment of puIntonary and laryngeal disorders. Hippocrates can
`probably be credited with the first inhaler device. a pot thIt a reed through which
`tapon. eouid be inhaled.
`
`The recreational and therapeutic use of tobacco was discovered about 2.0m
`years ago in South America. and crude inhalers included a decorated wooden plate
`used in conjunction \ntlt a hollow wooden mouthpiece. together with ornately
`cart-ed pipes (Sanders. 2011?]. North American Indians smoked "pipes ofpeacc".
`possibly containing hallucinogenic substances tDessanges. 20m t.
`
`In the i'i'th and 18th centuries. the conditions treated by inhatation were not
`necessarily confined to the rBsI‘III‘alOI’)‘ tract. For instance. inhalation of certain
`tumors was thought to protect against plague. and some physicians were protective
`
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`19
`i F5. P.Jirt-tLJ.-‘r.-.-:,- D'ni '_J'.‘-'-tr'|t
`B.'i.-_'-;;t.jt-_;.-t
`
`
`Figure 9.Twu vapor inhalers dating from the nineteenth century. (A)
`The metal Dr Siegel inhaler. (B) The ceramic Oxford Inhaler. Images
`courtesy of Mark Sanders. tnhatatorlumxom.
`
`
`
`clothing coupled with a beaklike facetnaslt containing :1 cloth impregnated with
`spices or sulfur in an attempt to prewnt Infection tZimettt. “RSI.
`
`Vapor inhalers
`
`Tlte term "inhaler" “as first coined in His by the English physician John Madge.
`who described a system involving a pewter tankard from which opium vapor was
`inhaled to treat cough tMudgc. ”78]. Developments nl'this concept included the
`use ul'tenpots from which patients inhaled via the spout. Various designs ol‘ steam
`inhaler. often ceramic in cumpoaition. Wen:
`in use during the |9Ih century.
`sometimes to deliver aromatic substances such as menthol tthure 9:. Steam
`inhalers included the Dr Nelson inhaler. which can still be purchased today. ill the
`Nth century. drug. inhalation seems to have been targeted particularly towards the
`treatment of consumption ltubcrculosis]. although Henry Hyde Salter's treatise
`from tltc lflt‘itls described a nutttber of inhaled t'etttedies fut asthma lSaltet'. lilo? I.
`At
`that
`time.
`the British Pharmacopoeia listed I'it-e inhaled vapor remedies
`thydmcyaitic acid. chlorine. creosote. hemlock and iodine} which are obviously
`very different from the drugs with winch we are familiar today.
`
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`Resp-War. Dun; {Jensen Essentuiu‘ Thrace-a cmc Prod-ct:
`20
`———-—_—._————_
`
`Figure l0. Asthma cigarettes were once widely used; two different
`brands are shown. Images courtesy of Mark Sanders. inhalotorium.com.
`
`
`
`Early aerosol inhalers
`
`The first atomizers were developed in the mid 19th century. This was significant
`because these devices delivered therapy in the form ol‘liquid droplets as opposed to
`vapor. Rooms called "inhalatoriums" became popular at thermal spas. most notably
`in Geritiany. when: patients inhaled droplets formed from mineral waters that were
`shattered by impaction against the walls ot'tlte room. These inhaled thermal waters
`sometimes contained turpentine. petroleum or other potentiain harmful additives
`tDessanges. zoo! I. The Sales—Citrons "pulvensateur" was invented and marketed in
`I358 to allow patients to inhale spa haters \\'i'llluLIl visiting a spa. Use ot‘this device
`was recommended for treatment of not only asthma. bronchitis.
`laryngtlis and
`pharvltgitis. but also tuberculosis and sleeplessness iO'Callaghan et al.. 2:103].
`These early atomizers evolved into Itebulizers using principles ol'aerosol generation
`ver} similar to those still employed today IC‘Itaptet 5}.
`
`At the stan of the 20th century. asthma cigarettes [Figure Ill} vvere popular
`for treatment ol‘ asthma. These contained Datum v-rrtimmiiimi as well as other
`agents {GrossmaiL 19941. A elmieal
`trial slum-ed that one brand nl‘ asthma
`cigarettes “as actuall} as efficacious as. an inhaler containing the antielinlinergle
`compound ipratropiurn bromide :Elliott and Reid.
`twill]. Cigarette smoke
`
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`Burl: git-tor; rt; Fireman-Ir, Uri-3? DEJJ-é .-
`
`21
`
`coitlaim i'i ittitture of solid riarlteler- and gooey. and it has been nuggesied ”till the
`asthma cigiirelte was the first trul) portable inhaler Il:.\'L‘1'ilI‘Il. Elitliii
`
`In liihal. the first dry powder aisletu I'or Inhalation “at: dcm'ihed to at potent.
`the iittcittor
`recognizing correctly that
`the I'ortiiulzittoit needed to he I‘inei}
`pulverized and kept dry (Sanders, 2iJii't'] The ettrhttlie smoke hall {Stu-ll. Jillil ].
`fitsl described in Itlitli, did not iiti-‘oli-e stttnkittg. but contained poo-tier.
`It could
`be squeezed to deliver it cocktail ol‘ uttll1|3l1llllllfi in powder t‘ornt. The tiet rec was
`claimed to "positively cure" a range of'umicttotu.
`including asthma.
`ltayi'eter.
`bronchitis and snoring. and the manufacturers offered a 4ilh§lillttl2ll
`i‘mztrtciaI
`reward to users commuting an} ui‘ at similar range of problems alter purchasing a
`ettrbulit: smoke hall. subject to uttitpeeii‘ied conditions being full‘illetl.
`
`1.6 THE DEVELOPMENT OF MODERN INHALERS
`
`Nebu lize rs
`
`Inhalation of adrenaline or adrenaline analogues for asthma was initially reported
`in the first quarter of the 20th century IDeseunges. Biliil. Anderson. 2005i. and
`this practice beeitttte more common iii the 19305 and l9-‘iiis. “'Ilh the aid of glass
`or plastic handheld squeeze bulb nehulizers. The first nebulizerit tiriten by ‘dll’
`eotttpressors were described in the 19405. and ultrasonic ncbttlizers titade llimr
`first appearance in about
`I'JSil The glass DeVilbias tar-iii?“ jel Itehulizer was
`partlcolariy well known iMcreer.
`I‘i‘ill l- hut the plastic Wright nebulizer in the
`|95ii=r iWright. Hill: may hr: the true forerunner ol‘ modern (lei ice.» it'huptct SI.
`Remarkably. the first record of ttebulizetl Inhaled lllSullll dates from IIJZS [Patton
`ct
`itl.
`I999]. Howeter. early tlllclttrtts to deliwr insulin and other drugo b}
`ncholizer were not particularly owees-at‘ul. and were somettme» limited [1} mic
`efi'ects t('ltaptet Hit.
`in the earth 20111 century.
`the technical Ct‘ItiI'Ilcuiieu of'
`deliici'ittg drugs by itthalaliort were rtol t'ull} apprentited. In particular. pli} Sluiitllh
`were largely utiim-itt't: til'tltt.’ need For
`iiL‘H‘M‘il particles to lJL' made mull] enough to
`penetrate into the lungs
`
`pMDls
`
`Mt earl} aerosol generator dr'tiett h} the iapor PfL‘hilll'L‘ ol‘a fitopellitttl liquid “Lt:-
`tleset'ibeLI In ”W"? (Clark. IWSI. this l'teiit‘t'.r
`it deuce ohiclt met! tltc heat of the
`hunt! to IIIL'I'Uilhl: the \‘Upm' pressure sull‘ieiently I0 atonttye the expelletl
`liquid
`Houei er. the modem em L‘rll‘lllillfllioil therapi- really dates from Witt. a hen RiLet
`Laboratories tntt'odueed the first pMqu containing epinephrine or tsuprolerennl
`tTluei. 1W!” For
`l‘l'IClli} years. le)ls contained chlorot‘luorocatrbon (”I I
`
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`22
`
`RCSI."-‘z‘i‘i-‘.i‘, Drug Deli-err ESSEttI-{JI‘ incur. and Practice
`
`propellants that maintained a vapor pressure of several atmospheres inside the
`pMDi. and which dispensed an accurately metered quantity ot‘drug during each
`actuation {Chapter ht The introduction of the pMDI i'emlutionized ptlitnonnr}
`drug dclncry. because patients had access to a dciice which was convenient.
`portable. robust and ntultidose tNemnan. zoom.
`
`The discovery that ('Ft's damage the ozone layer was a significant drawback
`of the original pMDl-a. but many have now been reformulated with an 07m"?
`I'rietttlly propellant i McDonald and Martin. EIIUU l. Because some patients cannot
`use pMDIs successfully. auxiliary devices
`including spacers and holding
`chambers (Chapter 7] hate become available to help them (Newman. 2004i
`
`DPIS
`
`When inhaled antibiotics were firstgit'en In the |9405iTaplin ct :i|.. Isl-18L Abbott
`Laboratories developed a DPI
`tAcrohalor”)
`for
`this purpose [Chapter 8].
`However. the first suceessi'ul DPI {Spinhaier' l was introduced by Fisons in I970.
`containing powdered cromolyn sodium and lactose. packed in individual gelatin
`capsules [Bell et al.. I‘J‘tl 1. Many other DPIs have followed the Spinlialer into the
`market. The majority of recent devices contain multiple doses. and hence prm tde
`convenience similar to that of‘the pMDI [Smith and Parry-Billings. 2003}. Most
`DPis are breath actuated. since the powder formulation is dispersed. and then
`carried ittto the lungs. by the patient's inhalation [Chapter at. In “active“ DPls. the
`drug Formulation is dispersed by some means other than the patient '5 inspiratory
`eITort. For instance by an internal source of compressed air. One of these devices
`[Nektar Pulmonary [nhaler‘l‘t was marketed recently in the first commercially
`available inhaled insulin product. approved in early 2006 [Harper ct al.. 2007:.
`although this has subsequently been withdrawn from the market [Chapter if”. A
`range of sophisticated powder formulations {Chapter 8] has: been developed
`recently to ensure the efl'ieient and reproducible delivery of macromolecules
`IBechtold-Pcterson and [.ttessen. 200T].
`
`Metered dose liquid inhalers
`
`In ZUtJ-‘i. Boehringer Ingellteim marketed the first of a new category of inhaler
`device. the Restptntat' Soil Mitzim inhaler. This device contains a propellant-free
`liquid Formulation simiiat
`to those used in nebulizets. but
`in a multiple dose
`container. Each dose is delivered in a single breath. so the device has the
`portability and convenience ot‘pMDis and DPis {Dalhy et al.. 2004i Inhalers of
`this type are sometimes known as metered dose liquid inhalers. and it is likely that
`others will be marketed in due course {Chapter 9].
`
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`

`

`‘30:! elm-Tit.”- 30 r".t|"‘."uj.‘.t‘t.l ,: Drug Deme- }.
`
`23
`
`1.7 KEYS TO SUCCESS
`
`There hat-e been many tIGHJIlL‘un in pulmonary drug delivery mer the last two
`decades. nanny.I to a variety of factors including the phasing out ofCFCs and the
`desire to deliwr a u itler range nl‘drugs willt grctllet' elTicicncy and reproducibility
`{Nit-cit. HMS. Dnlby and Sumati, zonal. Pulmonary drug delivery has huge
`ptnential. ofi‘cring targeted therapy for many diseases- [Chapter It'll. While some
`therapies hate been tried unsuccessfully in the past. the difference now is that we
`understand the technical and patient related factors that must be controlled in
`order to achieve successful and ennsrstent pulmonary drug delivery
`
`The ltcy requirements
`summarized as:
`
`for successful pulmonary prttdttcls may
`
`be
`
`In
`
`inhaled drugs that are both elTeulite and safe
`
`Iii] well designed inhaler devices and formulations that deliver drug reproducibly
`In particles or droplets nflhe correct size. and
`
`[iii] education ol'botlt patients and hcnltheare professionals to ensure that inhalers
`an: used correctly. and that treatment regimens are adhered to.
`
`Detailed descriptions of inhaler systems for both topical and systemic drug delivery
`by the pulmonary route will be a major focus of subsequent chapters. Some
`inhalers are simple and inexpensive. while others are much more complex. and may
`be restricted to delivery of relatively expensive drug molecules. As discussed in
`Chapter IU. patients should only be git-en inhalers that they can and will use.
`
`REFERENCES
`
`Adjel. A.L.. and fiupttl. PK. (eds: ”997}. inhalation Delft-mn- ni' Filtetrtpeurtt'
`Putin't'h'x And Pmmiru. New York: Marcel Dekker.
`Anderson. PJ. {2005}. "History of aerosol therapy; liquid Itebulization to MDls
`and DPISI‘ Rexpr'r Carr. 50. i |39~ l ISO.
`Anderson. S.D.. Brannon.
`.I.D.. and C‘han. H.—K. (2002:. "Use ol' aerosols for
`bronchial provocation testing in the laboratory: where we haw been and
`where we are going." J Aerosol Med. 15. 3 | 3—324.
`l... and Swenson. E.W.
`Arborelius. M.. Minrner.
`(5.. Lindell. S.E.. Svanberg.
`(1970). "Four quadrant radiospirontclry in normal and diseased states." in
`Ptti‘mrmmjr [tit-m-rt‘grttt'rm n't'th Ralffnrtm‘h'th’h" Gilsott. AJ. and Smoak. WM.
`lads]. Springfield: Thomas. 2 lo—Eln
`ATS - ERS Task Force tittflfiat. "Standardisation ol‘ lung function testing
`standardisation of spirometry.“ Eur Respir J. 26. 315L338.
`
`UNITED THERAPEUTICS, EX. 2003
`WATSON LABORATORIES V. UNITED THERAPEUTICS. |PR2017-01621
`Page 13 of 37
`
`

`

`
`
`AEROSOL PROPERTIES AND
`
`DEPOSITION PRINCIPLES
`
`Stephen Newman
`
`2.1 AEROSOLS
`
`ix used In dclum :Iruga I'nr bmh ILIL‘iII and .xynlumiu
`'l'lu~ puimunzu'} mun:
`Il'camncnls r('huptur Im. in aurnsnl parucIL‘s 0r drunk-ls. hucnlsl'lcally. nu :Icl'usul
`I: u dispersion or hlJNpL‘INIUH ul' mlul p:ll1iL‘IC$ m' IIquI Llluplcb II: n guhumlr
`mudrum {Dulm rah. I‘J‘J'H. ullhuugh a mum: pupulm dcl'mnmn may cquulc ucrmulw
`u IIII pl'cnulizul ucmsul npru} can» ISL'Iurra and ‘imllcr. IDT’JJ. Acmsoh nccurling
`m mcryday IIIL- mu": :1 hrnud apcctrum uI'qm-s {Figure I] Some :acruwa'. \‘lICIl as
`Ihnm: mum! in cigurclrc minke. 2m: var} mm“ 1 , Ii
`1 pm dinn'lclch. \\|n‘rc:L.~.ntI1crs
`men J: ('IL1Ll-J.\ ur'pnllcn grains mu} wmum puruuics SH pm (IHIIHL‘IL'I w lurgc:
`Il..'lhIlI.\ umI DuImIL-EL 21:03]. The we range nl' mturcsr
`for puimunm} mug
`LIL‘IIHJH !~;I|}pt'\l\ll‘m11ui_\ ”5 II] um. u'hliu‘nnh [in-w [1:1I'lIcIc-x ur LITHFIL‘I’R unmIIl-I
`[I‘Iun :ihfim 5 plm diiln‘lclcr can he cnmldclod “IL-:11 I'm mlmkmnn mm Il'u: lengw
`
`11'LII_\
`.-\
`Iu‘lclmlispchc
`Immnmqwrw u:
`I‘m CIIIIL'I'
`Ina}
`:\L‘l'l'|.\0I>
`munmlinpcrw ucrmul Ls mm:
`in “Inch all
`[IIL‘ PilflIL‘IL'h iII'L' email} 1hr.- mll'IIL' ni/U
`Sum: liihnr'iliur'} insh'llmcllla such .Lx th‘ .xpun'ung dm‘ generator m unmlcnmlnm
`ucl'vr-UI gcncrulnl'
`l Mur'L‘L‘I'. WK I
`I um pruducc alcrusoh than an; \UI} ulmu In this
`idqu. \ irmulh uII plun'nmccuiiuul nul'umlx .m: hcrcrodlspcrw I'ul' pulydtspclwl In
`L‘huluulul. aim-c Ihcy column pumclcs nr druplcb u llI'l u l11'nunlxpcc1rum n1'x12L-a
`
`29
`
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`

`

`I'Il'ltl Prof-Hr:
`Realm-firth} Dru-g De'ueay £35».~I.'-u: Them;
`3O
`
`
`Figure I. Size distributions of different aerosols encountered in
`everyday life. compared with those of pharmaceutical aerosols.
`
` 0
`
`0.05
`
`0.I
`
`0.2
`
`5
`
`2
`I
`0.5
`Aerosol diameter. urn
`
`
`IO
`
`20
`
`50
`
`to
`is most cont-enient
`it
`For the purpose of discussing their size distributions.
`describe both solid and liquid aerosol dispersions as “particles" The single most
`Important characteristic ofan aerosol particle is Its size ti.e_ its diameter]. and the
`particle size distribution of a lteterodisperse aerosol can then be described In terms
`of the frequency with which particle number. particle volume or particle mass
`occurs as l] function ol‘ diameter. The count median diameter tCMDl. volume
`median diameter (VMDJ and mass tttedian diameter (MMDJ are. respectively. the
`aerosol diameters above and below which halrthe number of particles. halt the
`volume of the distribution. and halfthe mass ot'the distribution resides. Providing
`all particles in the dispersion have the same density. then VMD and Nith are
`numerically equivalent tSwil‘t. 1993}.
`
`The particle size distribution expressed by number has limited value for
`pharmaceutical aerosols. because it is likely to gne a misleading impression of
`potential drug delivery. In a heterodisperse aerosol distribution. relatitely little
`drug maSs is carried by the smallest particles. even when they are present in large
`numbers. For instance. a thousand l um particles only carry the same amount of
`drug. as a single It) urn particle. and thus it is best to describe the size distribution
`in terms of either mass or volume.
`In the example shown in Figure 2. a
`hetcmdisperse and bimodal aerosol is shown with a CMD of approximately 1 pm.
`but an MMD ofapproximately 5 pin.
`
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`

`36
`
`Ruhr-- 5-. Drug Dela-er, {SSEI‘L-j Them.
`
`in: Pl-Zfl'l-CE
`
`X = l.«l.t;infi.l:),,2.l.':tf
`
`lat]
`
`Equation 3
`
`is the [fittnningham slip enrreetrnn
`is the :ri: \tsutstl). and t
`it
`in this L‘Liililllltl'l.
`I'nelnr. a term which allmts litr the I'ael Ihzit It particles tile sull‘ieiettlly small. they
`may "slip" hettteen gas molecules instead ul' eulliding it hit them. ( has a value
`close In unity in: a I“ tint particle. lItIl ils ittagnilude increases “Ill‘l decreasing
`particle size. and is approximately l.J tor a l tint particle lJennittgs. I982“.
`
`ll'h is greater Iltnn nrequnl to the distance to Iheuimay wall. then the parliele
`\\'lll LlepnsiL If the inhaled \t'lltlmclrlt.‘ llnn rate [volume per unit timer is Q. then
`the pml‘mbllll) of inertial itttpaettun is prupitrtinnal tit the "impacliun pummeler".
`“hit-h is the prutluet 0.3.0 tPhaten er al.. IWI. Finlay.
`lettltt Experimental
`studies have confirmed that upper airway depositinn increases itt prupurlion In this
`pnmittetertl..ipprnunn and Albert. l‘lt‘t‘Jt. When aerosol is inhaled \ inn nut-rim min:
`| em ditttttetcr.t1s neeurs liir some kinds ol‘inhalcr dei ice. at high speedjet may
`he Formed as the uemsol enters the upper atma} s. and deposition may depend
`upon the aerodynamic dittnteter and the jet \elneity tFinlay et ill" 2002i. Inertial
`nnpaetinn in the upper airways may he the dominant depusitmn process For
`acmsnls released I't'uttt some inhaler devices such as pressurized metered dose
`inhalers lpMDls. Chapter h] and dry powder inhalers l Dle t'hzipter ill.
`
`The total airway Chas:- sectional arett..i\. within the lungs is lowest in tire first
`the airway generations tChupter I]. and consequently the linear velocity or [he
`flirfitrcflm W = Q-“Al is relatively high. Therefore. impuetinn within the lungs is
`cnncentratcd mainly in the larger. :11an central nim-ays, LL‘. airway genemtions I will
`in the Weibel lung mndel thibel. “963]. More distnll}r in the lungs. the airslrettin
`velocity decreases markedly nwing to the dramatic increase in total airway emss
`sectional area. so that
`inertial
`impaction becomes \Cl'} unlikely in peripheral
`airways. Turbulence cfi‘ccts may also enhance depesruun In the upper airways and
`m the large central ainvays ol'the lungs ISection 2.4].
`
`Gravitational sedimentation
`
`ll' pharmaceutical aerosols penetrate to the small enndueting airways t generations
`8-- l (at and alvenli. gravitational sedimentation is generally the dominant deposniott
`process. Deposition by grayitatinnttl sedimentation occurs when aerosol partieleti
`fall under grayity nnln an airway wall. either during slow Inhalation or during
`breath holding.
`
`When a particle settles tinder grarity in still air. it accelerates in a terminal
`telueity. L1,. which is directly pmpurtiena] to 0,3. the square of its aeindynamic
`diameter. At this vclneity. a balance is maintained between the downwards force
`
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`

`P’i-r'vJSrJ' F'IIJr'Ei-‘Igg _|::.
`
`r L-JQ‘I'IIIISIIJI'JH
`
`37
`
`of grant) ltlcceleratiun (it and lltc tipttintls l‘mcc duc to air t'cs1slancc oi drag
`IBritin and Blanchard I‘I‘lll. when:
`
`U. = D}.C.GI Ian
`
`Equation-1
`
`iltliquatinn-l.(”.11tharmrespcetn'cl}.titci'tinnmgltnm <in correction [Elena-anti
`air viscosity as prct Iousl} described. As the residence time ol'a particle \t itllin tut}-
`pttrl ol' the lung increases.
`the likelihood that it wil