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Dl
tfM
Dl
dT
il
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tiM
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ithtC
fl
tiEf
ft
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elop
men
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ono
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iple
Com
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ithou
tCof
orm
ulat
ion
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ctD
evel
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fMon
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ual
and
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ombi
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outC
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atio
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fect
Dev
elop
men
t of M
ono,
Dua
l, an
d Tr
iple
Com
bina
tion
pMD
Isw
ithou
t Cof
orm
ulat
ion
Effe
ctp
,,
pp
Vidy
aJo
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einh
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avid
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shi,
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id L
echu
gaB
alle
ster
os, B
rad
Flyn
n, R
einh
ard
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ing,
Rob
ert S
chul
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rian
Nog
a,
RH
iC
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kd
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idi
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arris
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arris
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min
gs, J
ason
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peck
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Sar
vajn
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Pear
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rape
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Ab
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Res
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Abs
trac
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esul
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bstr
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Res
ults
Ci
MD
IEli
iC
fl
iEf
fC
linic
alco
mpa
rison
ofco
mbi
natio
npM
DI
prod
ucts
for
the
Phos
phol
ipid
mic
ropa
rtic
les
asso
ciat
eith
API
Cos
uspe
nsio
npM
DIE
limin
ates
Cof
orm
ulat
ion
Effe
ct:
Clin
ical
com
paris
onof
com
bina
tion
pMD
Ipr
oduc
tsfo
rth
ePh
osph
olip
id m
icro
part
icle
s as
soci
ate
with
API
C
osus
pens
ion
pMD
I Elim
inat
es C
ofor
mul
atio
n Ef
fect
:tre
atm
ento
fast
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and
CO
PD
isco
mpl
icat
edbe
caus
ein
vitro
pp
pi
tl
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tbl
iA
eros
olpe
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man
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ento
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bina
tion
treat
men
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Dis
com
plic
ated
beca
use
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trol
ff
hi
ih
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mic
rocr
ysta
lsto
form
ast
able
cosu
spen
sion
Aer
osol
per
form
ance
is in
depe
nden
t of o
ther
com
pone
nts
in c
ombi
natio
nae
roso
lper
form
ance
ofea
chac
tive
inth
eco
mbi
natio
nm
ayno
tm
icro
crys
tals
to fo
rm a
sta
ble
cosu
spen
sion
aero
solp
erfo
rman
ceof
each
activ
ein
the
com
bina
tion
may
not
bi
lt
tth
tf
thi
diid
lt
fbe
equi
vale
ntto
that
ofth
ein
divi
dual
com
pone
nts
orfro
mS
EM
Imag
esof
Pho
spho
lipid
Mic
ropa
rticl
es(le
ftbe
equ
ae
oa
oe
ddu
aco
poe
so
obi
tii
hih
thd
ff
thS
EM
Imag
es o
f Pho
spho
lipid
Mic
ropa
rticl
es (l
eft
t)
di
ti
tt
(lft
btt
dco
mbi
natio
nsin
whi
chth
edo
seof
one
orm
ore
ofth
eto
p) a
nd in
terio
r nan
ostru
ctur
e (le
ft bo
ttom
and
35
%35
%
GP
com
pone
nts
isva
ried
Cos
uspe
nsio
n up
on a
ctua
tion
(rig
ht)
MF
GP
com
pone
nts
isva
ried.
pp
(g
)30
%30
%M
FG
Pp
30%
30%
Mi
id
GP
l(l
ftS
pray
drie
dlo
wde
nsity
poro
uspa
rticl
esge
nera
teun
iform
and
Mic
roni
zed
GP
alon
e (le
ft 25
%
ed
25%
ed
Spr
aydr
ied
low
dens
itypo
rous
parti
cles
gene
rate
unifo
rman
dvi
al) a
nd m
icro
nize
d G
P
ere
ere
stab
leco
susp
ensi
ons
with
mic
roni
zed
APIs
acro
ssw
ide
dose
)co
susp
ensi
onw
ith20
%
ve
20%
ve
stab
leco
susp
ensi
ons
with
mic
roni
zed
APIs
,ac
ross
wid
edo
seco
susp
ensi
on w
ith
hh
liid
2µm
20%
co
20%
co
rang
esfo
ral
lpr
inci
pal
clas
ses
ofre
spira
tory
ther
apeu
tics
inph
osph
olip
id
2 µm
Rec
15%
Rec
rang
esfo
ral
lpr
inci
pal
clas
ses
ofre
spira
tory
ther
apeu
tics
ind
ld
til
biti
ithl
ff
mic
ropa
rticl
es (r
ight
via
l) 10
0 nm
15
%
F R
15%
P R
mon
o,du
alan
dtri
ple
com
bina
tions
,with
aero
solp
erfo
rman
ceof
p(
g)
dem
onst
ratin
gfo
rmat
ion
of
M
GP
mon
o,du
alan
dtri
ple
com
bina
tions
,with
aero
solp
erfo
rman
ceof
hAP
Ib
ii
dd
tf
thb
tf
dem
onst
ratin
g fo
rmat
ion
of
di
til
10%
%
10%
%
100
nm
each
API
bein
gin
depe
nden
tof
the
num
ber
orty
peof
co-
drug
-mic
ropa
rticl
e 10
%
%
gp
ypsu
spen
ded
AP
Isen
sem
bles
that
rem
ain
5%5%
susp
ende
dA
PIs
.as
soci
ated
even
upon
5%5%
pas
soci
ated
eve
n up
on
tti
(h
actu
atio
n (a
s sh
own
on
0%0%
Ext
ensi
vein
vitro
char
acte
rizat
ion
ofP
earl’
stri
ple
com
bina
tion
pict
ure
on th
e rig
ht)
Gly
copy
rrol
ate
Pho
spho
lipid
InhalerT
hroat
12
34
56
7Filte
rInhaler
USP
12
34
56
7Filte
rE
xten
sive
invi
troch
arac
teriz
atio
nof
Pea
rls
tripl
eco
mbi
natio
np
g)
Gly
copy
rrol
ate
Pho
spho
lipid
M
icro
parti
cles
InhalerT
hroat
12
34
56
7Filte
rInhaler
USP
Throat
12
34
56
7Filte
r (F)
MD
Isco
ntai
ning
aLA
MA
aLA
BA
and
anIC
San
dth
eir
crys
tals
Mic
ropa
rticl
esThroat
(F)
MD
Is,
cont
aini
nga
LAM
A,
aLA
BA
and
anIC
S,
and
thei
ry
MFMon
othe
rapy
MF/GPDou
bleCo
mbina
tion
GPMon
othe
rapy
MF/GPDou
bleCo
mbina
tion
corr
espo
ndin
gdo
uble
and
mon
oM
DIs
dem
onst
rate
rem
arka
ble
pMD
Iwith
Mic
roni
zed
Act
ive4
Cos
uspe
nsio
npM
DI
MF Mon
othe
rapy
MF/GP Dou
ble Co
mbina
tion
GP Mon
othe
rapy
MF/GP Dou
ble Co
mbina
tion
corr
espo
ndin
gdo
uble
and
mon
oM
DIs
,dem
onst
rate
rem
arka
ble
hi
lbi
lih
il
bili
dl
fpM
DI w
ith M
icro
nize
d A
ctiv
eC
osus
pens
ion
pMD
I
MF/FF
Dou
bleCo
mbina
tion
MF/GP/FF
TripleCo
mbina
tion
GF/FF
Dou
bleCo
mbina
tion
MF/GP/FF
TripleCo
mbina
tion
chem
ical
stab
ility
,ph
ysic
alst
abili
tyan
dae
roso
lper
form
ance
asMF/FF Dou
ble Co
mbina
tion
MF/GP/FF Triple Co
mbina
tion
GF/FF Dou
ble Co
mbina
tion
MF/GP/FF Triple Co
mbina
tion
chem
ical
stab
ility
,ph
ysic
alst
abili
tyan
dae
roso
lper
form
ance
asd
btt
thth
tffi
it
biti
MD
Igo
odas
orbe
tter
than
the
mos
tef
ficie
ntco
mbi
natio
npM
DIs
35%
good
aso
bee
ae
ose
ce
cob
ao
ps
tlil
bl35
%
FFcu
rren
tlyav
aila
ble.
Cos
spen
sion
pMD
IElim
inat
esM
icro
nied
API
PSD
Effe
cts
FFy
0se
cond
s
5se
cond
s0
seco
nds
15se
cond
s
30se
cond
s30
%C
osus
pens
ion
pMD
I Elim
inat
es M
icro
nize
d A
PI P
SD E
ffect
sFF
0 se
cond
s
5 se
cond
s
0 se
cond
s
15 s
econ
ds
30 s
econ
dsp
pC
linic
alex
perie
nce
with
aLA
MA
and
LAB
Aco
mbi
natio
n25
%
d
Clin
ical
expe
rienc
ew
itha
LAM
Aan
dLA
BA
com
bina
tion
25%
ed
dem
onst
rate
sth
atP
earl’
sco
susp
ensi
onte
chno
logy
has
the
20%
ere
dem
onst
rate
sth
atP
earl
sco
susp
ensi
onte
chno
logy
has
the
Tabl
e3
Mic
roni
zed
drug
PSD
byla
serd
iffra
ctio
nEq
uiva
lent
perf
orm
ance
fora
llac
tives
inco
mbi
natio
n20
%
ove
pote
ntia
lof
beco
min
gth
ene
xtge
nera
tion
com
bina
tion
pMD
ITa
ble
3. M
icro
nize
d dr
ug P
SD b
y la
ser d
iffra
ctio
nEq
uiva
lent
per
form
ance
for a
ll ac
tives
in c
ombi
natio
n
eco
pote
ntia
lof
beco
min
gth
ene
xtge
nera
tion
com
bina
tion
pMD
Iq
pre
gard
less
ofdo
seor
phys
icoc
hem
ical
prop
ertie
s15
%
Re
prod
uctp
latfo
rm(1
-3)
Mic
roni
zed
rega
rdle
ss o
f dos
e or
phy
sico
chem
ical
pro
pert
ies
FF
prod
uctp
latfo
rm(1
3).
Mic
roni
zed
Dx 1
0(µ
m)
x 50
(µm
)x 9
0(µ
m)
Span
gp
yp
p10
%
% F
Dru
g10
(µ)
50(µ
)90
(µ)
Spa
Tbl
1Fi
til
fti
(FPF
)d
MM
AD
fth
idi
idl
t10
%
%
gM
F0
41
12
82
2Ta
ble
1. F
ine
part
icle
frac
tion
(FPF
) and
MM
AD
s of
the
indi
vidu
al c
ompo
nent
s M
F0.
41.
12.
82.
2p
()
pf
ICS/
LAM
A/L
AB
At
il
biti
did
blbi
ti5%
GP
05
13
30
18
of a
n IC
S/LA
MA
/LA
BA
trip
le c
ombi
natio
n, c
orre
spon
ding
dou
ble
com
bina
tions
M
ater
ials
and
Met
hods
GP
0.5
1.3
3.0
1.8
FF0
61
94
11
8g
and
sing
leco
mpo
nent
pMD
Is0%
Mat
eria
lsan
dM
etho
dsFF
0.6
1.9
4.1
1.8
and
sing
le c
ompo
nent
pM
DIs
0%M
ater
ials
and
Met
hods
Pl
fl
tii
MD
If
lt
dith
Act
ives
inFP
F(%
)M
MA
D(µ
m)
Inhaler
USP
1
23
45
67
Filte
r P
earl
form
ulat
ions
are
susp
ensi
onpM
DIs
form
ulat
edw
ithA
ctiv
es in
FPF
(%)
MM
AD
(µ
m)
Throat
(F)
pp
mic
roni
zed
activ
essu
chas
FF(a
t5μg
/act
uatio
n)G
P(a
t36
Com
bin
atio
nM
FG
PFF
MF
GP
FFh
/bl
bm
icro
nize
dac
tives
such
asFF
(at
~5μg
/act
uatio
n),
GP
(at
~36
Com
bin
atio
nM
FG
PFF
MF
GP
FFFF M
onothe
rapy
MF/FF Dou
ble Co
mbina
tion
Con
clus
ions
(μg
)(
μg/a
ctua
tion)
and
MF
(at~
50μg
/act
uatio
n)co
susp
ende
dw
ithM
F/G
P/FF
5959
633
53
53
0GF/FF
Dou
bleCo
mbina
tion
MF/GP/FF
TripleCo
mbina
tion
Con
clus
ions
μg/a
ctua
tion)
,and
MF
(at~
50μg
/act
uatio
n)co
susp
ende
dw
ithM
F/G
P/FF
5959
633.
53.
53.
0GF/FF Dou
ble Co
mbina
tion
MF/GP/FF Triple Co
mbina
tion
Con
clus
ions
spra
y-dr
ied
low
dens
itym
icro
parti
cles
ina
hydr
oflu
oroa
lkan
eM
F/G
P56
563.
73.
8sp
ray-
drie
dlo
wde
nsity
mic
ropa
rticl
esin
ahy
drof
luor
oalk
ane
MF/
GP
5656
3.7
3.8
MF/
FF57
603
53
1Fi
gure
1A
erod
ynam
icP
SD
ofM
FG
Pan
dFF
inP
earl
The
Pea
rlco
susp
ensi
onpM
DIp
latfo
rmen
able
s:
(HFA
)pro
pella
ntM
F/FF
5760
3.5
3.1
Figu
re1.
Aer
odyn
amic
PS
Dof
MF,
GP,
and
FFin
Pea
rlC
iM
DI
ii
lt
dlft
hb
dTh
e P
earl
cosu
spen
sion
pM
DI p
latfo
rm e
nabl
es :
(HFA
)pro
pella
nt.
/G
P/FF
6062
34
28
Cos
uspe
nsio
npM
DIs
iseq
uiva
lent
rega
rdle
ssof
the
num
ber
and
GP/
FF60
623.
42.
8p
pq
gty
peof
drug
sin
the
form
ulat
ion
and
tole
rate
sva
riabi
lity
inpa
rticl
eTh
iti
lt
ih
hli
idd
li
hlid
/ MF
543
6ty
peof
drug
sin
the
form
ulat
ion
and
tole
rate
sva
riabi
lity
inpa
rticl
e•
Sea
mle
sstra
nsiti
onfro
mm
ono
todu
alto
tripl
eTh
ese
mic
ropa
rticl
esco
ntai
nph
osph
olip
idan
dca
lciu
mch
lorid
eM
F54
3.6
size
dist
ribut
ion
ofth
em
icro
nize
ddr
ug(s
how
nin
Tabl
e3.
)•
Sea
mle
ss tr
ansi
tion
from
mon
o to
dua
l to
tripl
e
Thes
em
icro
parti
cles
cont
ain
phos
phol
ipid
and
calc
ium
chlo
ride
ith
tif
21
dt
ith
dt
tG
P57
37
size
dist
ribut
ion
ofth
em
icro
nize
ddr
ug(s
how
nin
Tabl
e3.
)co
mbi
natio
nsin
the
ratio
of2:
1an
dar
epr
esen
tin
the
prod
uct
ata
GP
573.
7co
mbi
natio
nsp
pco
ncen
tratio
nof
300μg
/act
uatio
nFF
613
0co
ncen
tratio
nof
~300
μg/a
ctua
tion.
FF61
3.0
Cos
uspe
nsio
npM
DIe
nabl
eslo
ngte
rmph
ysic
alD
lif
it
lliA
PI
ithth
fll
iμg
Aver
age
5758
623
63
63
0C
osus
pens
ion
pMD
I ena
bles
long
term
phy
sica
l •
Del
iver
yof
mic
rocr
ysta
lline
AP
Iwith
the
follo
win
gAv
erag
e57
5862
3.6
3.6
3.0
stab
ility
ofpa
rtia
llyso
lubl
eac
tives
Del
iver
y of
mic
rocr
ysta
lline
AP
I with
the
follo
win
g f
tt
il
ilbl
Sta
bilit
yw
asas
sess
edby
stor
ing
the
tripl
eco
mbi
natio
nM
DIs
atRSD
(%)
33
22
34
53
7st
abili
ty o
f par
tially
sol
uble
act
ives
feat
ures
not
pre
viou
sly
avai
labl
e :
Sta
bilit
yw
asas
sess
edby
stor
ing
the
tripl
eco
mbi
natio
nM
DIs
atRSD
(%
)3
32
2.3
4.5
3.7
yp
yp
y40
°C/7
5%R
Hfo
ilov
erw
rapp
edw
ithde
sicc
antf
or6
mon
ths
and
Rang
e54
-59
56-6
060
-63
3.5-
3.7
3.4-
3.8
2.8-
3.1
40C
/75%
RH
,foi
love
rwra
pped
with
desi
ccan
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oat
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lter
Ref
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ces
Rel
ease
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F64
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efer
ence
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Ref
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ces
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oat
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Ore
villo
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ose
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sche
rTA
lam
eda
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erC
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velg
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late
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ered
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o at
40
C/7
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H, M
MA
D: 3
µm ,
%FP
F: 6
3%1.
Ore
villo
CJ,
St R
ose
E, F
isch
er T
, Ala
med
a P,
Rei
sner
C. A
nov
el g
lyco
pyrro
late
met
ered
dos
e in
hale
rfor
mul
atio
nde
mon
stra
tes
supe
riorb
ronc
hodi
lato
reffi
cacy
rela
tive
topl
aceb
oan
d6
mo
at 4
0C
/75%
RH
, MM
AD
: 3.2
µm ,
%FP
F: 5
9%in
hale
r for
mul
atio
n de
mon
stra
tes
supe
rior b
ronc
hodi
lato
r effi
cacy
rela
tive
to p
lace
bo a
nd
com
para
ble
effic
acy
and
safe
tyto
Spi
riva®
Han
diha
ler®
inpa
tient
with
CO
PD
Am
JR
espi
rC
rit,
µ,
com
para
ble
effic
acy
and
safe
ty to
Spi
riva®
Han
diha
ler®
in p
atie
nt w
ith C
OP
D A
m. J
. Res
pir.
Crit
. C
are
Med
2010
;181
:A44
50Fi
gure
2:A
erod
ynam
icP
SD
ofG
Pin
atri
ple
com
bina
tion
Spra
y-dr
ied
phos
phol
ipid
/CaC
l 2po
rous
part
icle
Car
e M
ed.,
2010
; 181
: A44
50.
2M
arja
son
JO
revi
lloC
JS
tRos
eE
Ferg
uson
GT
Vehr
ing
RJo
shiV
Dw
ived
iSR
eisn
erC
Figu
re 2
:. A
erod
ynam
ic P
SD
of G
P in
a tr
iple
com
bina
tion
Spra
ydr
ied
phos
phol
ipid
/CaC
l 2po
rous
par
ticle
2. M
arja
son
J, O
revi
llo C
J, S
t Ros
e E
, Fer
guso
n G
T, V
ehrin
g R
, Jos
hi V
, Dw
ived
i S, R
eisn
er C
. A
tf
ft
dh
kiti
filf
lfi
dbi
tif
ll
td
cosu
spen
sion
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Ish
ows
stab
leae
roso
lper
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ance
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r0,3
,IC
Scr
ysta
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MA
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tal
LABA
crys
tal
Ass
essm
ent o
f saf
ety
and
phar
mac
okin
etic
pro
file
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nov
el fi
xed
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bina
tion
of g
lyco
pyrro
late
and
f
tlH
FAM
DIi
hlth
lt
AJ
Ri
Cit
CM
d20
1018
1A4
455
cosu
spen
sion
pM
DI
show
s st
able
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osol
per
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ance
afte
r 0, 3
, d
6th
tt4
0°C
/75%
RH
ICS
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tal
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A cr
ysta
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ryst
alfo
rmot
erol
HFA
pM
DI i
n he
alth
y vo
lnte
ers
Am
. J. R
espi
r. C
rit. C
are
Med
., 2
010;
181
: A44
55.
3Q
iD
FG
TO
illC
JL
kA
StR
AFi
hT
Gk
HR
iC
Aan
d 6
mon
ths
stor
age
at 4
0°C
/75%
RH
.3.
Qui
nn D
, Fer
guso
n G
T., O
revi
llo C
J, L
ucke
yA
, St R
ose
A, F
isch
er T
, Gra
nko
H, R
eisn
er C
. A
nove
l for
mot
erol
fum
arat
e m
eter
ed d
ose
inha
ler f
orm
ulat
ion
dem
onst
rate
s co
mpa
rabl
e br
onch
odila
tor e
ffica
cy re
lativ
e to
For
adil®
Aer
oliz
er®
and
favo
rabl
e sa
fety
out
com
es in
pat
ient
s w
ith C
OP
D. A
m. J
. Res
pir.
Crit
. Car
e M
ed.,
2010
; 181
: A44
58.
4. .
Del
lam
ary,
LA
, Tar
ara,
TE
, Sm
ith, D
J, W
oelk
, CH
, Adr
acta
s, A
, Cos
tello
, ML,
Gill,
H, W
eers
, J G
. y,
,,
,,
,,
,,
,,
,,
,,
Hol
low
por
ous
parti
cles
in m
eter
ed d
ose
inha
lers
, Pha
rm. R
es.,
2000
; 17:
168
-174
.P
rese
nted
onM
ay8t
hat
RD
D20
11B
erlin
Ger
man
yp
p,
,;
Pre
sent
ed o
n M
ay 8
th, a
t RD
D 2
011,
Ber
lin, G
erm
any
Recommended