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`
`AstraZenecIa Ex. 2119 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01326
`
`

`
`'
`
`TABLE I. Commands Which May -be
`Administered hy 9215.6-iiierai
`Routes {Ether Than
`in-travemms aw Intramuscular
`
`Reute
`
`ifompeunds
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`<:0rtic0s1:ercsids', cronmiyn
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`metaprotérfizndl,
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`missian fmm Dfaheres {Suppl 2],
`28, 53~57
`("I 979).
`
`Astrazeneca Ex. 2119 p. 2
`
`

`
`.. EXERCISE
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`
`19 p. 3
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`

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`AstraZen%:Ic Ex. 2119 p. 4
`
`

`
`
`
`---Pe-rcutcmea-us -A-dminis-truth:-n
`=== Th-ewontermwzast -layers cf human -ski-n cenaisa
`" (if the epidermis ané tbs--t:E-arm-is-{sea Fig.-- 1-)}-
`--
`Illrugs -pan-e-tmte the -epidermis--at ta-tes.deim*
`-- -mined---large-ly -by---their---oil-/water partiiien
`'== eoefficien-is, ===wat:1=~s(:lublr3 == mo}:-:culv:S bttin
`-- "virtual-iy -excluded; Th-e under}-ying -darmié
`-- consists of? loosely arrangad-conraéctive tissug
`==
`an-d==is mow freelyrpermeable.Na-riou-5 pl-13-1‘-_
`-- macd-kitm-ii'c---mod'el& haw been examineé --ta:
`-describe. -the percutaneoils absoa-ptien of a drug
`from tapitally applied vehicles (26, 27):. Th:
`"=
`- perm:-taneou-s route is -used primarily in sit»-
`-
`-uati-urns where drug acti-on--is -L0 be--upsm an
`-=
`apm-"1 W011-Ild"0£’ upen the==superfici-al rlayersruf
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`t'h¢"stratua'E1'C0rneum-; if-the pathologic acm-
`- dition -is-"in the de,-e-per layefs of the -epid§-zsmis
`"=
`{Sr in {he-dermis; topical drug therapy m-ayrbe
`-
`ineffective. -For -example, ant-iba-ctéria-1 -and
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`- skin in-fecti-ous when given in-ally -or -by -injeo
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`absarptio-n fear systemic effacts-are the tepical-- =
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`he desad--paren-teral-1}’, an-cl tapical n-itrogl-ya
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`{If angina. Accurate--titration---of"the dose-91“
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`‘usual "dase is l'—2"in;, as squeezcd-fmm--tl1e" -
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`é;drfii'nistei'ed by" this réuté ifs"indica"te.d in "Table" 2
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`--
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`== temlal -vehicl-ea for delivering drugs fmm the :-
`--site of subcn-tane<)us- inje-C-ti-on -ta spe€i-fic--tar-
`--
`-- gels within-the body; Liposemes---3-rs hydrated --
`-- liquid crystals--for-med when phowholigids are --
`=3-l10wed=1o swell in aqueous media. In a= recen-t
`==
`--s=tud;y £13) -un-ilamel-lar- vesinies--c<;msist'i'ng af --
`--distearoyl -phos=ph2tidylch(:li-n;e,-- -cholesterol,
`--
`== and Emma sugar and==amiin0»suga-r derivative-s ==
`--6f--c'h0lesteml---were--shown to be po'terItialEy-
`--
`-- useful i-ndavelopi-ng -Eiposomc--systems capable --
`== <3f5=_provifiing-gont=r0l-la-d==rel-ease, -Gf’ therapezu-tic ==
`.. agemfi...
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`===.mrradermaI A'dmirt£srr=a-zien ===
`
`---Intra-dermal -injecti_0n:s"'are used pre:domi— --
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`== route for systemic: ==act=ivity, ==1:2-attic‘-:ula:r3y -far
`==
`-- ya-cci-nes,
`-has been illustrated in "several
`--
`-- s-tudics.---
`
`--
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`-- us-ua-1Si-ts:-forintradermal-in}:-sctia-:>nis---the 2111-
`--
`-- {e-rio-r surface--of--the ferearm. The--volume sf --
`
`== s0=luticsn= -tha-t===m-ay===be== admin-is=‘zered===i;t1== this ==
`
`-- manner is only ab-eiiut 0.1--‘ml;
`In-trader-ma-l injection -is-freq'ue'ntly use.-d for --
`administering antigens in tests for allergic
`"
`-- reactions (19): Alcahol-is given by intradéwmal
`-- injection far t-hetreatmen-t of pruritus vulvae --
`(20): Whil=e--system‘-ii: 31::-s=:-n-~ptio'n fun-h an im
`" tradermal--injectiowsite is u3ual_1y's1ow;this "
`-- route is---useful in--deli-verin-g agents-fori'rnrnu~ --
`nizatiofi (2-l).===An ifi'tratieI'*'m£§l iI'ij'eCti0'r”n of 031
`-- mi of an A;sia'n- influen;:a"vaccine prod-uce_s"'a "
`-- rise --in---antibody titer wmpiarab-le m "that -
`achieved w=ith==:a s%1br§uti‘i'I3e€)uS'in_§ecti0Il‘()f“1 ml
`" 0f the same -v':a¢c'ine' (22-, 23). A‘ recefit study "
`" by Halperiri er. al; -{Z2-=3) confirmed the‘ su_'pe-
`"
`-- rinrity of £he--lmm2mog'e-nicity---0f--the int'ra- --
`ciermal =-reu'te==f43_sr='A;/Vicwri-a=/75 Vaccine‘; but
`"
`-- failcdto shew any diffeirmrce in inlrgdérmal
`-- and --subcutaneous '"1'Uut.es ‘for --A/New ".ler- --
`“ sezy/76 ‘(Swin-Le Flu)“‘v.aCc:_ihatia=n"; "‘l“-l1s'a;.11'lr1'c:»%it%s
`‘-
`" izoncluded thm: in"t'lm¢s"c>fvaccine-jsh<:2r'tag€fthe
`"
`-- intraderrnal
`r<)‘u'tci,"'V/hich i-nmlves "smaller "
`
`“ diisefifi, may"-be“impor1an't. In a‘:':ldi‘ti€m,_ less -lccél
`" irrltatiun -maybe‘ assqciattté with i11t'r:iéei*m'§1l
`-- ihan--with subcutan-cans"i;-1ject'ic:fis-'(2.5). "
`
`‘-
`"
`
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`
`Jcaumzxl of me ?arc:ater::l Drag Associazion
`
`;
`
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`
`M lsllazeneca Exjllzi 19 p. 5
`
`
`
`
`
`xx;.;ly.2:35
`
`

`
`TABLE I1. Rsgi-anal lllepesition of Unit Density Spheres in Relatiicnship to Particle: Size
`
`.
`..
`139)
`
`}3’e1-‘cent Aerosalflegosition fur Tiéa! Volume Gf 7511 ml
`_Particle
`Traclaeobrunithial
`Pulmonary
`Biameter,
`-Nasopharyngeal
`Region Tetal
`Region
`Regina
`(ism)
`
`
`
`..
`
`51
`
`59
`
`82.
`
`66
`
`0.31‘
`
`0.96
`
`fi.j2El
`3.69
`
`-1.0
`2.0
`
`3.0
`4.0-
`
`0
`
`0
`
`0
`.0
`
`4
`41
`
`55
`as
`
`1
`
`{J93
`_
`
`
`80
`6.50
`100
`0.2‘
`.7
`99
`-10.0
` %mm_____
`
`23
`20
`25
`3S
`31
`24
`10
`
`3i
`22
`32
`8'1
`93
`.97
`99
`
`The ai-veoli are separated. from the capilia-ry
`S-ystam by the -a1veQ1ar—c3.piiiary membrane,
`which forms an aiiwblood barrier of about
`0.24 8 mm in tl1i'(:l'-mess. The proximity of the
`L:ap£.il.ary endetheiiam ta the alve-zzli permits
`very efficient esxclianga 03° sub.sta_nc$s, -and a
`zficih.
`;:'m_lm:.0nar'y bleed supply‘ assures ‘rapid
`' 1‘*2m0¥9;l ‘of any substance that may penetrate.
`j the alveaiamzajpillarry membrane.
`Drugs can be 'i:ntrod§1c:ed into that mspitatary
`If system -as gases or as Einhalation aeraseis. Best‘
`j-- cxampiss (if lil_1.¢ farmer are the general -anes»
`[3 tin-=:.t;i::s 31:01! 35 ttther -and chléirofcérm. Diffusitzn
`_3 aicress the-alvaol-arwcapiliary membrane does
`33 rsdt 0.fE’a.r any significant res'is'tanc::
`to the.
`:2 transfer of "gases bxatwsen tha, lung and biood,
`-T and they am jalm'ost' instantaneczusly absorbed
`3:. {'33. 31').
`fX6i‘0S€I-l$ are fine stxspensions ax’ dispcrsiam;
`I3; af solid or iiqiiifi particlizzs. in gases. Ti1.e.actii2e
`I;;'i:ngredi-eat i-s.dEis:s0'lved_ er sugpem-dad in a Ei-
`j;-quified prapeiiani sygtem, from which are
`j5: aerosol is predu-cad. Upon inhaalatien, éepm
`3 sitien. {if aerosoi -particies may occur within the
`ff -respiratory ai-rways by impactien, -iedimenr
`ii;-tatiran, er diffuéi-am €32).
`Impacticrii usually
`occurs in the ‘nasal p'h-arynx and tracheal-
`tmchial ‘tree when the airstreasn in which 3
`
`gaarticla is ilawing changes -direction. For 3
`given drug, -particle size. is the primazry fa-cmr
`governing the bjiaavailability Qf iniiaiatien
`
`'
`
`emtmcribecemhesg léiffl, Vol. 34. Na. 6
`
`489
`
`aerasals. Aerasoi particles" la.rgc:1* than 1.6" ,u.:m
`are almost compieztely deposited in tl‘s<3'n'a§(i«
`pharyngeai regicm. Smaller particles penetrate
`daeepér in the res'pi'rat0'ry tract, with same dem
`p£3$E‘ti,013'lr": the passages. reauiting in iocal ac-
`tivity. Tha mgixzsn.-al depositimi of different s-its
`particies in the respiratory tract is shew-n in
`Tahie ii (29),
`Most '§€‘A"GS0l pa_rti€i::s will adsorb -moisture
`as they pass through the respiratory traaczt, and
`the resultant growth in particle size <:o.ntrib-
`tltés to.dép0siti0n. Systemic afiscrrfiption ixtcurs
`m;ain'ly after the partieles reach ‘and deposit in
`the a.lve<:.rl.', dissolve: in the "alveolar" fluid, and
`are t;r.a'nsp0'rt'ed through the alveoiarcgpi-llary
`membrane intc the capillary blood system.
`The.optirnu:m size for this purpose is about 1~2
`,u.m.
`The prcsancc of elcctricai cha_rg_es on pan
`ticlcsal-so has an effect on their-depcssition.
`Smaii pa-rti-cies in. particular show marked
`increases in deposition in the nasophairynx
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