NAMA : TRI WAHYUNINGSIH

NIM : G 701 17 107

KELAS :B
TUGAS BIOFARMASETIKA
SOAL
Carilah sebuah jurnal internasional berbahasa inggris dalam kurun waktu 10 tahun terakhir ,temanya
tentang formulasi sediaan sistem pernafasan, lakukan review tentang keterbaruan metode/formula ,
cara evaluasi dan kesimpulan dari penelitian tersebut. Sertakan alamat download jurnal di review dan
lampirkan jurnal asli.
JAWABAN :
Jurnal yang akan sy review , berjudul “DEVELOPMENT AN INHALED DRY-POWDER
FORMULATION OF TOBRAMYCIN USING PULMOSPHERETM
TECHNOLOGY”(Pengembangan Formulasi Serbuk Kering yang Dihirup Tobramycin Menggunakan
Teknologi PulmoSphere)”

DEVELOPMENT AN INHALED DRY-

JUDUL JURNAL POWDER FORMULATION OF TOBRAMYCIN
USING PULMOSPHERETM TECHNOLOGY

AEROSOL OBAT DAN PARU OBAT

JURNAL
PENGIRIMAN

VOLUME DAN HALAMAN Volume 24 hal 175-182

TAHUN 2011

David E. Geller, MD, Jeffry Weers, Ph.D., dan

PENULIS
Silvia Heuerding, Ph.D

REVIEWER Tri wahyuningsih

TANGGAL 20 Maret 2020

 Tujuan utama di dalam penelitian ini adalah agar
dapat mengefisienkan waktu penggunaan
nebulezier antibiotik. Terutama pada pasien
penyakit kronis seperti CF pasien-pasien ini
mungkin diperlukan untuk mengolah banyak
setiap hari terapi inhalasi kronis, termaksud
bronkodilator dan antibiotik inhalasi. Selain waktu
penggunaan alat nebu ini juga memerlukan arus
TUJUAN PENELITIAN
listrik dan harus di simpan di lemari pendingin
dapat menyebabkan ketidak nyamanan pasien
dalam menggunakanya kembali. Sehingga di
lakukan penelitian perkembangan terbaru dalam
rekaysa partikel, khususnya pengembangan
pulmosphere teknologi. Dan memberikan bukti
untuk potensi bubuk kering meningkatkan
kepatuhan pasien.
Subjek penelitian ini adalah pasien CF kronis
terinfeksi Pa. Sehingga memerlukan perawatan
SUBJEK PENELITIAN antibiotik hirup. Dengan pengunaan antibiotik
tobramycin yang di berikan dalam bentuk bubuk
kering dengan teknologi pulmoshophere.
Pengembangan formulasi partikel PulmoSphere
yang diproduksi oleh proses pengeringan semprot
emulsionbased, yang dirancang untuk
menciptakan partikel berpori dengan spons-seperti
morfologi. ( 15,22,23) Proses pengeringan semprot
dapat dibagi menjadi empat subproses: (1)
persiapan bahan baku, (2) atomisasi, (3)
METODE/FORMULASI PENELITIAN pengeringan, dan (4) koleksi (Gambar. 1).
Submikron minyak dalam air tetesan emulsi yang
dibuat oleh tekanan tinggi homogenisasi per fl
uorooctyl bromide (Per fl ubron) dalam air. ( 24)
Tetesan minyak yang tersebar secara stabil
terhadap pengasaran oleh monolayer dari rantai
panjang fosfolipid [yaitu,
distearoylphosphatidylcholine (DSPC)]. Rantai
 panjang phosphatidylcholines, seperti DSPC,
adalah komponen utama dari endogen paru
surfaktan. ( 25) Bahan aktif farmasi (yaitu,
tobramycin) yang tergabung dalam emulsi dengan
melarutkannya dalam fase air terus menerus.
bahan baku yang dihasilkan kemudian atomisasi
dengan kembar fl nozzle uid ke dalam aliran udara
panas. Setiap tetesan mengandung sejumlah besar
tetesan emulsi tersebar. Selama tahap awal proses
pengeringan, fase air terus menerus mulai
menguap mengarah ke penurunan diameter droplet
dikabutkan. Emulsi tetesan terkonsentrasi pada
antarmuka dari tetesan surut, sedangkan
tobramycin yang mudah berdifusi ke pusat tetesan
menguap. Sebagai pengeringan terus, shell
terbentuk pada permukaan tetesan dikabutkan;
shell terdiri terutama dari eksipien hadir dalam
tetesan emulsi. Setelah pengeringan lebih lanjut,
per fl ubron menguap, meninggalkan pori-pori
dalam partikel. Volatile per fl ubron dikumpulkan
dalam proses spraydrying. Partikel dipisahkan dari
aliran udara dengan pemisah siklon. Karena waktu
pengeringan singkat(di urutan
milidetik),tobramycin hadir sebagai padatan amorf
dalam partikel semprot-kering.
PulmoSphere teknologi adalah proses pengeringan
semprot berbasis emulsi yang memungkinkan produksi
partikel berpori cahaya, formulasi kering bubuk, yang
memperlihatkan peningkatan aliran dan dispersi dari
inhaler bubuk kering pasif. Ulasan ini mengeksplorasi
karakteristik mendasar dari teknologi PulmoSphere,
DEFINISI PULMOSPHERE
dengan fokus pada pengembangan formulasi bubuk
kering dari tobramycin untuk pengobatan paru kronis
Pseudomonas aeruginosa (Pa) infeksi pada pasien CF.
formulasi bubuk kering ini menyediakan substansial
ditingkatkan intrapulmonary deposisi efisiensi,
pengiriman lebih cepat, dan administrasi lebih nyaman
 lebih formulasi nebulasi. Ketersediaan lebih efisien dan
pilihan pengobatan yang nyaman dapat meningkatkan
kepatuhan pengobatan, dan dengan demikian terapi
hasil di CF.
Dengan pengunaan antibiotik aerosol mengunakan
teknologi tersebut meningkatkan kulitas hidup dan
HASIL PENELITIAN peningkatan kepatuhan pengunaan obat tersebut
kepada pasien yang bisa dilihat dri jumlah
responden pada tabel 3.
dapat mengefisienkan waktu pengunaan obat
antibitik inhalasi. Dan dapat meningkatkan
KELEBIHAN PENELITIAN
kepatuhan pasieen dalam menggunakan obat
sehingga respon klinik tubuh lebih mebaik.
Keterbatasan campuran obat untuk memberikan
KEKURANGAN PENELITIAN
dosis bbesar ke paru-paru.
Antibiotik aerosol untuk pengobatan Pa
membentuk suatu kesatuan bagian dari rejimen
pengobatan pada pasien CF dengan kronis infeksi
saluran napas, meskipun saat ini mereka terkait
beban waktu yang tinggi dan ketidaknyamanan
lainnya. Bubuk kering inhalasi dengan DPI
portabel adalah alternatif yang menarik
nebulisasi; dan menggunakan teknologi
PulmoSphere memberikan muatan obat yang
tinggi ke paru-paru yang diperlukan untuk
pengobatan yang efektif ment. Formulasi TIP
PulmoSphere disampaikan bersama Inhaler T-326
telah menunjukkan keamanan dan kemanjuran
secara klinis uji coba, dan memiliki banyak
keunggulan dibandingkan antibiotik nebulasi otics,
KESIMPULAN PENELITIAN termasuk pengiriman yang lebih cepat, kemudahan
penggunaan, portabilitas, respon mengurangi
kebutuhan untuk pembersihan, dan penyimpanan
suhu kamar. Ini mengantisipasi bahwa beban
pengobatan berkurang dan membaik konsistensi
dosis yang diberikan oleh TIP dapat diterjemahkan
menjadi lebih baik kepatuhan pengobatan dan
hasil terapi yang lebih baik untuk CF pasien
dengan infeksi saluran napas Pa.
 Pengembangan klinis awal TIP termasuk dosis-
eskalasi studi untuk menentukan dosis TIP yang
merupakan setara secara makokinetik, dalam hal
serum tobramycin dan paparan paru-paru, dengan
dosis TIS yang disetujui (TOBI ® , 300mg larutan
tobramycin / 5mL bebas pengawet). Itu dosis TIP
yang menunjukkan tobramycin sistemik yang
sebanding paparan 300 mg TIS adalah empat
kapsul yang mengandung total dosis tobramycin
112mg. (9) Yang penting, serum kadar bramycin
relatif rendah (sekitar 1 μg / mL) ke tingkat
sistemik yang terkait dengan menghasilkan
toksisitas dengan tobramycin intravena (10-12μg /
mL). (39) Berdasarkan ini data dosis TIP 112mg
dua kali sehari dipilih untuk evaluasi dalam studi
Fase III. Dua studi Fase III telah dilakukan pada
pasien dengan CF berumur! 6 tahun. Penelitian
pertama, secara acak uji coba double-blind,
terkontrol plasebo di TIS naif secara relatif Pasien
CF, menilai kemanjuran dan keamanan TIP (total
dosis tobramycin 112mg) dua kali sehari (28 hari
pengobatan) dan 28 hari cuti pengobatan) melalui
T-326 Inhaler. TIP Im- terbukti FEV 1 %
diprediksi dibandingkan dengan plasebo pada hari
ke 28 (paling tidak kuadrat perbedaan rata-rata ¼
13,3, p ¼ 0,0016). Yang penting, itu perbaikan
EVALUASI PENELITIAN dibandingkan dengan plasebo dipertahankan pada
akhir siklus lengkap pertama (hari ke 56). TIP juga
mengurangi dahak Pa kepadatan, rawat inap yang
berhubungan dengan pernapasan, dan tambahan
penggunaan antipseudomonal versus plasebo. (36)
Hasil uji coba terkontrol plasebo dikonfirmasi
dalam percobaan komparator aktif Fase III yang
baru saja diselesaikan, yang menunjukkan bahwa
kemanjuran TIP sebanding dengan dosis TIS yang
disetujui. (35) Dalam penelitian yang sama,
dimodifikasi Kuesioner Kepuasan Pengobatan
untuk Pengobatan (TSQM) menunjukkan bahwa
pasien menilai TIP lebih nyaman dan memuaskan
daripada TIS; berarti penilaian pasien signifikan
secara signifikan lebih besar untuk efektivitas (p
<0,0001), kenyamanan (p <0,0001), dan kepuasan
global (p ¼ 0,0018) dalam TIP dibandingkan
kelompok perlakuan TIS. Hasil yang
menguntungkan dari modifikasi TSQM sebagian
terkait dengan kemudahan penggunaan dan
waktu administrasi yang lebih pendek untuk TIP
(rata-rata: 5,6 vs 19,7 menit, masing-
masing). (35) TIP pada umumnya ditoleransi
dengan baik di Indonesia kedua studi Tahap III.
Karena sejumlah besar bubuk dikirim ke paru-
paru, ada kekhawatiran apakah TIP akan
ditoleransi pada pasien CF. (12) Kekhawatiran ini
sebagian besar tidak berdasar, karena TIP
 ditoleransi dengan baik oleh sebagian besar pasien
di kedua studi Tahap III. (35,36) Profil keamanan
TIP serupa dengan TIS, dengan pengecualian
batuk, disfonia, dan dysgeusia, yang lebih tinggi
pada pasien yang diobati dengan TIP. (35)
Meskipun kejadian efek samping ini lebih tinggi
untuk TIP, tidak ada perbedaan dalam kepuasan
pengobatan skor untuk efek samping antar
kelompok. (35) Yang penting, batuk tampaknya
tidak terkait dengan bronkospasme; (36) lebih
tepatnya, refleks postinhalasi dengan beban bubuk
yang tinggi mungkin mendasari tingkat batuk yang
dilaporkan lebih tinggi pada yang diobati dengan
TIP versus TIS pasien. Kami berspekulasi bahwa
ada pelaporan yang berbeda pola batuk untuk TIP
versus TIS, seperti kebanyakan pasien dan peneliti
berpengalaman dengan administrasi nebulasi trasi
tobramycin. Secara keseluruhan, hasil uji klinis
untuk Tanggal menunjukkan bahwa TIP adalah
pengobatan yang aman dan efektif untuk infeksi
paru Pa kronis pada pasien CF berusia 6 tahun.

Alamat download : https://scholar.google.co.id/

JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY
Volume 24, Number 4, 2011
Invited Review
ª Mary Ann Liebert, Inc.
Pp. 175–182
DOI: 10.1089/jamp.2010.0855

Development of an Inhaled Dry-Powder Formulation of

Tobramycin Using PulmoSphere Technology

David E. Geller, M.D.,1 Jeffry Weers, Ph.D.,2 and Silvia Heuerding, Ph.D.3

Abstract

At present, the only approved inhaled antipseudomonal antibiotics for chronic pulmonary infections in patients with cystic
fibrosis (CF) are nebulized solutions. However, prolonged administration and cleaning times, high administration
frequency, and cumbersome delivery technologies with nebulizers add to the high treatment burden in this patient
population. PulmoSphere technology is an emulsion-based spray-drying process that enables the production of light
porous particle, dry-powder formulations, which exhibit improved flow and dispersion from passive dry powder inhalers.
This review explores the fundamental characteristics of Pulmo-Sphere technology, focusing on the development of a dry
powder formulation of tobramycin for the treatment of chronic pulmonary Pseudomonas aeruginosa (Pa) infection in
CF patients. This dry powder formulation provides substantially improved intrapulmonary deposition efficiency, faster
delivery, and more convenient adminis-tration over nebulized formulations. The availability of more efficient and
convenient treatment options may improve treatment compliance, and thereby therapeutic outcomes in CF.

Key words: PulmoSphere , dry powder inhaler, nebulization; cystic fibrosis, tobramycin, tobramycin inhalation powder
(TIP )

Introduction CA, USA)]. Tobramycin and aztreonam inhalation solutions have

C hronic pulmonary infection with Pseudomonas aeru-ginosa
(Pa) is a significant cause of morbidity and mor-tality in patients with
(1)
cystic fibrosis (CF). Effective antibiotic therapy directed against
this pathogen is an integral part of the daily treatment regimen for CF
(2)
patients chronically in-fected with Pa. Pa infection is primarily
localized to the endobronchial space in CF. Therefore, aerosol
delivery of antibiotics is an attractive option for treating these
infections. Inhaled antibiotics deliver high doses directly to the site of
infection, while minimizing systemic exposure and risk of
toxicity.(2)
At present, the only approved inhaled antibiotic treat-ments are
nebulizer solutions, specifically, tobramycin in-halation solution
[TIS (TOBI ; Novartis AG, Switzerland; Bramitob ; Chiesi
Farmaceutici S.p.A., Italy)], colistimethate sodium (Colomycin ;
Forest Laboratories, Inc, UK; and Promixin ; Profile Pharma, Ltd,
UK; in a few European Countries only), and more recently,
aztreonam inhalation solution [AZLI (Cayston ; Gilead Sciences,
Inc., Forest City,
demonstrated efficacy and safety in CF patients with chronic Pa
infection.(3,4) TIS is recommended by the Cystic Fibrosis
Foundation guidelines for treatment of chronic Pa infection in CF
patients 6 years.(5) Despite that, less than 70% of qualified
patients in the US CF Patient Registry were prescribed TIS in
(6)
2008. Also, most patients who are pre-scribed TIS have far
fewer prescription refills than necessary to maintain alternate
(7)
month cycles. A variety of reasons may exist for the disconnect
between real-world usage of inhaled antibiotics and
recommendations in the treatment guidelines.
Time burden is an important factor in chronic diseases like CF.
These patients may be required to administer many daily chronic
inhaled therapies, including bronchodilators, muco-lytics,
hypertonic saline, and inhaled antibiotics. These aerosol
treatments, added to airway clearance maneuvers, take patients an
average of almost 2 h to complete.(8) TIS is administered twice
daily with the PARI-LC PLUS or com-parable jet nebulizer (with
(9)
a suitable compressor) over a period of 15–20 min. Aztreonam
for inhalation solution is

1
Aerosol Research Laboratory and Cystic Fibrosis Center, Nemours Children’s Clinic, Orlando, Florida.
2Novartis Pharmaceuticals Corporation, San Carlos, California.
3
Novartis Pharma AG, Basel, Switzerland.

175
176
administered with an electronic vibrating mesh nebulizer (Altera ;
Pari Innovative Manufacturers, Inc., Midlothian, VA, USA). The
solution only takes 2–3 min to inhale, and is administered three
times a day versus twice a day for TIS. Furthermore, both
aztreonam inhalation solution and colis-timethate must be
reconstituted immediately before nebuli-zation, increasing the
handling time and delivery complexity for these antibiotics. All
nebulizers require regular cleaning after each use to prevent
bacterial contamination and to en-sure that the performance of the
device is not compromised. This is a time-consuming process,
(10)
and many patients do not clean their nebulizer as directed. In
addition to the time burden, nebulizer/compressor combinations
are noisy, bulky, and require a power source. Furthermore,
tobramycin and aztreonam inhalation solutions must be stored in
a re-frigerator, decreasing convenience.
The ability to deliver therapeutic doses of antibiotics with a
portable inhaler in a fraction of the time required for the entire
process of nebulization would be a significant advance that may
(9)
improve patient compliance and clinical out-comes. The
principal reason that nebulizers have been utilized for aerosol
delivery of anti-infectives lies in the high
lung doses required for effective treatment. For example, the lung
dose for TIS is approximately 35 mg. (11) Recent devel-
opments in particle engineering, in particular the develop-ment of
PulmoSphere technology, has enabled the delivery of a large
amount of dry powder (up to 25 mg) to the lungs in a single
(12)
actuation.
Early development of dry powder antipseudomonal
antibiotic formulations
Traditional formulation approaches for producing dry powders
for inhalation have relied on ‘‘top-down’’ manufacturing
methods, where large crystalline drug particles are milled
(micronized) to produce fine crystals with a median diameter
suitable for inhalation (i.e., 1–5 mm). The microniza-tion process
is analogous to throwing a crystal ball against a steel wall. The
crystal shatters into millions of pieces, with a broad particle size
distribution and limited control of particle morphology. Milling
generally produces particles with flat interfaces with the potential
for large areas of contact and strong interparticle cohesive forces.
Moreover, milling pro-cesses often produce charged surfaces with
amorphous char-acter, leading to an increased tendency for
particles to agglomerate. Owing to the strong interparticle
cohesive for-ces, fine micronized drug particles are often blended
with
coarse lactose carrier particles to improve powder flow and
(13,14)
fluidization. Nonetheless, cohesive forces between the
micronized drug and carrier particles remain strong, and lung
delivery efficiencies of 10–30% of the nominal dose are typi-cally
(12,15)
observed. The high percentage of carrier particles [typically
(13,14)
about 65:1 weight for weight (w/w)], and the
moderate lung delivery efficiencies limit the maximum lung
dose that can be delivered with standard micronized blends to just
a few milligrams per inhalation. (12)
The limitations of micronized drug blends to deliver large
doses of drug to the lungs was illustrated for aminoglyco-
(16,17)
sides. In these studies, 15–32 inhalations of micronized
gentamicin were needed to deliver a therapeutic dose. Completing
such a large number of inhalations is time con-suming and not
feasible in clinical practice. Despite this,
GELLER ET AL.
patients preferred the dry powder inhaler (DPI) delivery system to
either the nebulizer or intravenous administration in this single-
dose study, providing evidence for the poten-tial of dry powders
(16)
to improve adherence.
PulmoSphere technology
The evolution of ‘bottom-up’ processing methods (e.g., spray
drying) where the drug substance is dissolved in a solvent and
then precipitated to produce fine particles, affords greater control
of particle properties, including particle size and distribution,
morphology, porosity, density, and surface
energy.(12) These factors are critical in controlling bulk powder
(12,14,18,19)
properties such as powder flow and dispersibility.
The improved powder properties are achieved without the
addition of carrier particles. Consequently, drug loadings as high
as 90–95% w/w are possible.(12,20)
The decreased interparticle cohesive forces achieved with
spray-dried powders, particularly those with highly porous
surfaces, leads to improvements in lung delivery efficiencies,
(18,19)
with up to 60% of the nominal dose delivered to the lungs.
The increases in drug loading and lung delivery
enable more effective delivery of high doses of anti-infectives in
fewer inhalations. The spray-dried powders discussed herein
typically have interpatient variabilities in total lung
deposition of 10–20%, versus 30–50% for micronized drug
blends.(20,21) Delivery of porous particles is also largely in-
dependent of the patient’s peak inspiratory flow rate, further
reducing dosing variability.(18,19)
Formulation development
PulmoSphere particles are manufactured by an emulsion-
based spray-drying process, designed to create porous parti-cles
with a sponge-like morphology.(15,22,23) The spray-drying
process can be divided into four subprocesses: (1) feedstock
preparation, (2) atomization, (3) drying, and (4) collection (Fig.
1). Submicron oil-in-water emulsion droplets are created by high-
pressure homogenization of perfluorooctyl bromide (Perflubron)
(24)
in water. The dispersed oil droplets are stabi-lized against
coarsening by a monolayer of a long-chain phospholipid [i.e.,
distearoylphosphatidylcholine (DSPC)]. Long-chain
phosphatidylcholines, such as DSPC, are the principal
components of endogenous pulmonary surfac-tant.(25) The active
pharmaceutical ingredient (i.e., tobramycin) is incorporated in the
emulsion by dissolving it in the con-tinuous water phase. The
resulting feedstock is then atomized with a twin fluid nozzle into
a hot air stream. Each droplet contains a large number of
dispersed emulsion droplets. During the initial stages of the
drying process, the continuous water phase begins to evaporate
leading to decreases in the diameter of the atomized droplet.
Emulsion droplets are concentrated at the interface of the
receding droplet, whereas the tobramycin readily diffuses to the
center of the evaporat-ing droplet. As the drying continues, a shell
is formed at the surface of the atomized droplet; the shell is made
up primarily of the excipients present in the emulsion droplets.
After fur-ther drying, the perflubron evaporates, leaving behind
pores in the particle. The volatile perflubron is collected in the
spray-drying process. The particles are separated from the
airstream with cyclone separators. Owing to the short drying time
(in the order of milliseconds), tobramycin is present as an
amorphous solid in the spray-dried particles. The role of the
AN INHALED DRY POWDER FORMULATION OF TOBRAMYCIN 177

FIG. 1. Schematic of the PulmoSphere manufacturing process. An emulsion-based feedstock is prepared by high-pressure
homogenization. The emulsion consists of oil droplets (Perflubron) dispersed in a continuous water phase. The oil droplets are
stabilized by a monolayer of a phospholipid (distearoylphosphatidylcholine). The tobramycin drug substance and cal-cium chloride
excipient are dissolved in the continuous phase of the emulsion. The feedstock is atomized with a twin fluid nozzle into a spray dryer.
As the atomized droplets containing dispersed emulsion droplets are dried, the slow diffusing emulsion droplets are concentrated at the
droplet interface. As the drying continues, a shell is formed at the surface of the atomized droplet. Eventually, the Perflubron
evaporates leaving behind pores in the particle shell. The resulting dry powder comprising porous particles is collected from the
airstream with a cyclone separator.

components used in the manufacturing process and in the final
spray-dried particles is delineated in Table 1.
PulmoSphere particles: physical characteristics
Scanning electron microscopic images of micronized drugs and
spray-dried tobramycin inhalation powder (TIP ) particles are
shown in Figure 2. Micronized drug substances (Fig. 2a) are
typically characterized by smooth
plate-like crystals, with a broad particle size distribution ranging
from tens of nanometers to a few microns. The mi-cronized drug
is highly agglomerated with smaller crystals (less than 1 mm)
adhering to larger crystals. The agglomerates are often tens of
microns in size. Owing to their rectangular shape, the area of
contact between the small crystals and the larger sized crystals is
high. In contrast, spray-dried Pul-moSphere particles (Fig. 2b and
c) are spheroidal, with geometric sizes between 1 and 5 mm, and
a more uniform

Table 1. Role of materials used in the manufacture of porous particles via the Pulmosphere process

Component Role in process Role in drug product

Tobramycin Drug substance Drug substance

Distearoylphosphatidylcholine (DSPC) Emulsifier (surfactant) Principal excipient
Hydrophobic shell-former
Calcium chloride (CaCl2) Stabilize emulsion against Secondary excipient
flocculation and sedimentation Shell-former
Perflubron Process aid (pore-forming agent)
None: removed to residual levels
Water for irrigation Process aid (solvent for water-
soluble excipients and drug
substance)
None: removed to residual levels
Sulphuric acid pH adjustment and salt formation Counterion in salt form of drug substance
178
FIG. 2. Scanning electron microscope images of: (a) typical micronized drug particles, (b) TIP particles, and (c) TIP particle (closeup).
distribution of sizes. The particles are also highly porous with a
sponge-like morphology. The spheroidal shape and porous
surface decrease the area of contact between particles, leading to
less particle agglomeration. Moreover, despite the fact that
phospholipid makes up just 14% of the bulk com-position of the
particles, approximately 90% of the surface is made up of DSPC.
The enrichment of the DSPC at the surface is critical in lowering
the surface energy of the spray-dried particles, further aiding in
decreasing interparticle cohesive forces. Consequently,
PulmoSphere particles readily flow and disperse from portable
DPIs with little applied energy. In this regard, low inspiratory
effort is needed to generate an aerosol of the PulmoSphere
particles. Thus, younger patients ( 6 years old), and those with
reduced pulmonary function can consistently create the
inspiratory flow rate necessary to
deliver a full dose via the T-326 Inhaler (see below for further
information on this device). (9,26,27)
The oropharynx is an effective filter; therefore, particle size is
an extremely important consideration when creating novel inhaled
therapies. Models of aerosol deposition show that particles with a
diameter greater than 5 mm deposit in the oropharynx, whereas
particles ranging from 1 to 5 mm de-posit in the airways and
(28)
alveoli. PulmoSphere particles have median geometric
diameters (as determined by laser
diffraction) of 1.7–2.7 mm, and mass median aerodynamic
(29)
diameter <4 mm. This size range is ideal for targeting the
powder aerosol to the site of the Pa infection in the airways.
Dry powder inhaler development
TIP is delivered via the breath-actuated T-326 Inhaler
(Novartis Pharmaceuticals, San Carlos, CA, USA). The T-326
Inhaler is a portable, capsule-based DPI, which is mechanical
GELLER ET AL.
and does not require an external power source or electronics (Fig.
3).
The ability to achieve adequate inspiratory flow rates and
inhaled volumes is paramount for effective and reproducible dose
delivery.(26) As described earlier, PulmoSphere particles have
favorable characteristics to be effectively dispersed by the
inspiratory effort of CF patients. The T-326 Inhaler was designed
to have a low airflow resistance [approximately 0.08 (cm
H2O)½/LPM], to allow patients to generate high airflow rates, and
(29)
in turn, attain reliable dose delivery. The T-326 Inhaler
resistance is intermediate between the Diskus [R ¼ 0.07 (cm
H2O)½/LPM] and Turbohaler [R ¼ 0.11 (cm H2O)½/LPM] de-
vices, and significantly less than the Handihaler [R ¼ 0.18 (cm
½ (30,31)
H2O) /LPM]. A study was conducted to assess the
breathing profiles of 96 CF patients of varying age and disease
severity when asked to breathe forcefully through resistances that
span that of the T-326 Inhaler.(26,27) The results are presented
in Table 2. The young adults (n ¼ 24) and adults (n ¼ 39) had
mean peak flows of 79.3 L/min (SD 15.0) and 81.1 L/min (SD
14.4), respectively, and inhaled volumes of 1.63 L (SD 0.60) and
2.06 L (SD 0.68), whereas the 6–10-year-olds (n ¼ 33) reached
68.7 L/min (SD 13.1) and 1.2 L (SD 0.39). In turn, the breathing
profiles for various patient subgroups (pediatric, young adult, and
adult) were simulated in in vitro studies to assess powder
emptying from the capsule. The fill mass in the capsule was
selected to ensure that most patients (including pediatric pa-tients
as young as 6 years old) can effectively empty the contents of the
(27)
capsule in a single actuation. Indeed, provided the patient has
an inhaled volume >1.0 L, they will be able to empty more than
90% of the capsule contents, although the instructions for use call
for a second inhalation to ensure that all patients are able to empty
the capsule. Confirmation of dose delivery is easily accomplished
by inspecting the capsule postinhalation. If
AN INHALED DRY POWDER FORMULATION OF TOBRAMYCIN 179

FIG. 3. The portable breath-actuated T-326 Inhaler. A hypromellose capsule is loaded into the device by first removing the mouthpiece
and inserting the capsule into the chamber. The mouthpiece is screwed back onto the body. The button is depressed to pierce the
capsule, and the patient then inhales through the mouthpiece. The capsule rotates rapidly in the chamber causing powder to be emptied
from the capsule.

significant powder remains, the capsule may be reinserted and an
additional inhalation maneuver performed. (29)
The deposition fraction of TIP via the T-326 Inhaler is
approximately three times higher than that of TIS via the
PARI-LC Plus, as determined by gamma scintigraphic im-ages in
healthy volunteers.(20,32) Interpatient variability for
TIP was lower than TIS (17 vs. 24–40%) (Table 3). Reduced
interpatient variability is also observed for tobramycin con-
centrations in serum and sputum in CF patients. (9) Despite the
fact that the breathing pattern for liquid delivery (tidal breathing),
and dry powder delivery (forceful inhalation) differ significantly,
the relative distribution of tobramycin within the central,
intermediate, and peripheral airways is similar for both
formulations, with a trend for greater de-position in the peripheral
versus central airways.(20) The ratio
of peripheral to central deposition (P/C), for TIP was 1.6 0.4
versus 1.5 0.4 for TIS.(20) Based on 24-h clearance
studies, these P/C ratios correspond to deposition in non-
conducting peripheral airways of 66 and 63%, respective-ly.(33)
Serum pharmacokinetic profiles for TIS and TIP were also
comparable, indicating rapid dissolution of the amor-phous dry
powder into epithelial lining fluid, and compa-rable lung
(20)
clearance for the two formulations. In CF patients, the
distribution of tobramycin in the lungs will be more affected by
airway geometry and disease than by aerosol characteristics. (34) It
is expected that increases in
airway disease will result in comparable total lung deposi-tion,
with increased central deposition relative to the results presented
above for healthy volunteers. The deposition pat-
tern will also be dependent on the anatomy of the orophar-ynx
and the breathing pattern of the patient. (28) With that
said, PulmoSphere powders fluidize and disperse effectively even
at the extremes of the breathing patterns observed in patient
breathing studies (Table 2). For example, a study examining
aerosol performance showed that the delivered dose and
aerodynamic particle size distribution did not dif-fer significantly
with variations in temperature (ranging from
10 to 408C), relative humidity (ranging from 10 to 65%), and
flow rate (ranging from 40 to 85 L/min). (29) A flow rate of 40
L/min represents a flow rate more than 2 standard devia-tions
below the mean peak inspiratory flow rates measured for pediatric
patients in the breathing study (Table 2). In-deed, similar lung
exposures were observed for pediatric and
adult CF patients based on pharmacokinetic modeling of data
(35–37)
from TIP Phase III clinical development.
The TIP/T-326 Inhaler combination was designed to shorten
administration time versus the current nebulized
formulation of tobramycin, TIS. Administration times for TIP is
(9,35)
under 6 min, which is about 14 min faster than TIS.
Thus, TIP reduces the time burden by 28 min per day, not
including the time required to set up and clean the TIS nebulizer
and compressor. As mentioned earlier, most CF

Table 2. Inspiratory Flow and Demographics of CF Patients in Breathing Study(26,27)

Age group n Age (year) FEV1 (% of predicted) Inhaled volume (L) PIF (LPM) Inspiratory time (sec)
6–10 33 Mean 8.4 92.0 1.20 68.7 1.65
(pediatric) SD 1.3 15.5 0.39 13.1 0.43
11–18 24 Mean 15.0 68.6 1.63 79.3 1.82
(young adult) SD 2.4 29.6 0.60 15.0 0.49
>18 39 Mean 32.9 54.1 2.06 81.1 2.39
(adult) SD 9.3 27.1 0.68 14.4 0.72
180
Table 3. Lung deposition for TIP and TIS in healthy volunteers
as determined by gamma scintigraphy
TIP (T-326 TIS (PARI-LC
Inhaler)(20) Plus)(32)
Nominal dose 80 mg 300 mg
of tobramycin
Deposition
Lung 34.2% (27 mg) 9.2% (27 mg)
Oropharynx 43.6% (35 mg) 16.0% (48 mg)
Device 21.7% (17 mg) 43.5% (131 mg)
Exhaled 0.2% (0 mg) 28.3% (85 mg)
Total lung deposition 27.4 mg 27.3 mg
Intersubject variability 17% 24%
patients do not clean their nebulizer as directed, and the
majority of nebulizers have been found to be contaminat-ed.
(38)
The T-326 Inhaler requires minimal cleaning, and no
disinfection, and can be disposed of after several uses. Due to the
dry nature of the TIP formulation, the T-326 Inhaler has the added
convenience that it only needs to be wiped with a dry cloth after
each use as it does not come into contact with aqueous solutions,
and therefore growth of bacteria is not promoted. It is possible
that improved ease of use, reduced administration time, and
minimal cleaning requirements may translate into improved
patient adherence and therefore potentially improved therapeutic
outcomes.
Powder filling and packaging
TIP is filled into hypromellose capsules. Hypromellose was
chosen over gelatine due to its decreased tendency to fracture at
the low relative humidity storage conditions re-quired to maintain
physical stability of the amorphous solid. In order to protect the
amorphous TIP from the adverse ef-fects of moisture, the bulk
capsules are packaged in coated aluminium blisters. The T-326
Inhaler is also stored in a case between use to prevent moisture
uptake by residual powder in the device. Unlike tobramycin and
aztreonam inhalation solutions, TIP is kept at room temperature.
The size of the capsule and the achievable powder fill mass for
TIP were determined based on the ability of the average pediatric
patient (age 6–10 years) to empty the contents of the capsule in a
(21)
single inhalation.
Clinical development of tobramycin inhalation powder
The early clinical development of TIP included a dose-
escalation study to determine the dose of TIP that is phar-
macokinetically equivalent, in terms of tobramycin serum and
lung exposures, to the approved dose of TIS (TOBI , 300 mg
tobramycin/5 mL preservative-free solution). The dose of TIP that
showed comparable systemic tobramycin exposure to 300 mg TIS
(9)
was four capsules containing a total dose 112 mg tobramycin.
Importantly, the serum to-bramycin levels were low
(approximately 1 mg/mL) relative to systemic levels associated
with producing toxicity with intravenous tobramycin (10–12
(39)
mg/mL). Based on these data a dose of TIP 112 mg twice
daily was chosen for eval-uation in Phase III studies.
Two Phase III studies have been performed in patients with CF
aged 6 years. The first study, a randomized,
GELLER ET AL.
double-blind, placebo-controlled trial in relatively TIS- naı¨ve CF
patients, assessed the efficacy and safety of TIP (total dose 112
mg tobramycin) twice daily (28 days on-treatment and 28 days
off-treatment) via the T-326 Inhaler. TIP im-proved FEV1 %
predicted versus placebo at day 28 (least squares mean difference
¼ 13.3, p ¼ 0.0016). Importantly, the improvement over placebo
was maintained at the end of the first complete cycle (day 56).
TIP also reduced sputum Pa density, respiratory-related
hospitalizations, and additional antipseudomonal use versus
placebo.(36)
The results of the placebo-controlled trial were confirmed in a
recently completed Phase III active-comparator trial,
which showed that the efficacy of TIP is comparable to the
(35)
approved dose of TIS. In the same study, a modified
Treatment Satisfaction Questionnaire for Medication (TSQM)
demonstrated that patients rate TIP as more convenient and
satisfying than TIS; mean patient assessments were signifi-cantly
greater for effectiveness ( p < 0.0001), convenience ( p < 0.0001),
and global satisfaction ( p ¼ 0.0018) in the TIP versus TIS
treatment group. The favorable results of the modified TSQM is
related in part to the ease of use and shorter administration time
for TIP (average: 5.6 vs. 19.7 minutes, respectively).(35) TIP was
generally well tolerated in both Phase III studies.
Owing to the large amount of powder being delivered to the
lungs, there were concerns as to whether TIP would be tolerated
(12)
in the CF patients. These concerns were largely
unfounded, as TIP was well tolerated by most patients in both
(35,36)
Phase III studies. The safety profile of TIP is similar
to that of TIS, with the exception of cough, dysphonia, and
dysgeusia, which are higher in patients treated with TIP. (35)
Although the incidence of these adverse events was higher for
TIP, there was no difference in the treatment satisfaction score for
side effects between groups. (35) Importantly, cough does not
appear to be related to bronchospasm;(36) rather, a postinhalation
reflex to the high powder load may underlie the higher reported
cough rate in TIP- versus TIS-treated patients. We speculate that
there was a different reporting pattern of cough for TIP versus
TIS, as most patients and investigators are experienced with the
nebulized adminis-tration of tobramycin. Overall, the results of
clinical trials to date indicate that TIP is a safe and effective
treatment for chronic Pa lung infection in CF patients aged 6
years.
Additional applications for pulmosphere technology
PulmoSphere technology was originally developed to treat
ventilator associated pneumonia in intubated patients undergoing
(40)
partial liquid ventilation. The porous particles were designed
to effectively stabilize drug suspensions in the fluorinated media
used in liquid ventilation. The technology was later applied to the
(41)
stabilization of suspensions in hy-drofluoroalkane propellants,
and eventually to dry pow-der delivery.(18,20,42,43)
PulmoSphere technology is a true ‘‘platform,’’ having dem-
onstrated utility across multiple classes of therapeutics and
delivery systems. To date, PulmoSphere formulations have been
evaluated in 18 clinical trials. There are currently six drugs under
active Investigational New Drug applications in
Phase II clinical development or later. These include three anti-
infectives: tobramycin(9,20,35,36) and ciprofloxacin(44) to
treat chronic Pa infections in CF patients, and amphotericin B to
AN INHALED DRY POWDER FORMULATION OF TOBRAMYCIN
treat invasive pulmonary aspergillosis in immunocompro-mised
(45)
patients. Other patient populations with Pa airway infections
that may benefit from antimicrobial DPI formula-tions include
non-CF bronchiectasis, chronic bronchitis, and chronic
obstructive pulmonary disease (COPD). PulmoSphere
formulations (both DPI and metered-dose inhaler) of long-acting
muscarinic antagonists, long-acting beta-agonists, and inhaled
corticosteroids are in development for treating
bronchoconstriction and inflammation in patients with asth-
ma/COPD. Dry powder PulmoSphere formulations are ex-pected
to improve lung targeting, and dose consistency for
asthma/COPD therapeutics. (18,19) This may ultimately enable
improvements in treatment compliance, as poor inhaler tech-nique
(18,20)
is a major driver for inconsistent dosing.
Beyond the products currently in development, Pulmo-Sphere
formulations have shown promise in the delivery of biologicals
including peptides, proteins, antibodies,(46) and mucosal
vaccines.(47) Additionally, dispersion of porous PulmoSphere
particles in hydrofluoroalkane propellants in-creases delivered
dose and improves dose content unifor-mity versus conventional
suspension formulations, which
may improve lung delivery efficiency for suspension-based pMDI
formulations.(42,43)
Discussion
Aerosol antibiotics for the treatment of Pa form an integral
part of the treatment regimen in CF patients with chronic airways
infection, although they are currently associated with a high time
burden and other inconveniences. Dry powder inhalation with a
portable DPI is an attractive alternative to nebulization; and using
PulmoSphere technology delivers the high payload of drug to the
lungs needed for effective treat-ment. The PulmoSphere
formulation of TIP delivered with the T-326 inhaler has
demonstrated safety and efficacy in clinical trials, and has
numerous advantages over nebulized antibi-otics, including faster
delivery, ease of use, portability, re-duced need for cleaning, and
room temperature storage. It is anticipated that the reduced
treatment burden and improved dose consistency afforded by TIP
may translate into improved treatment compliance and better
therapeutic outcomes for CF patients with Pa airway infections.
Acknowledgments
The authors take full responsibility for the content of the paper.
Writing and editorial assistance (funded by Novartis Pharma AG)
was provided by Melanie Stephens, ACUMED , UK.
Author Disclosure Statement
Dr. Geller has relationships with Aires, Aradigm, Bayer, CSL
Behring, Discovery Labs, Genentech, Gilead Sciences, Inc., MAP
Pharmaceuticals, Mpex, NanoBio, Novartis Phar-maceuticals,
Pharmaxis, Philips Respironics, Teva, Talecris, and Vertex. Silvia
Heuerding and Jeffry Weers are employees of Novartis
Pharmaceuticals.
References
1. Emerson J, Rosenfeld M, McNamara S, Ramsey B, and Gibson
RL: Pseudomonas aeruginosa and other predictors of
181
mortality and morbidity in young children with cystic fi-brosis.
Pediatr Pulmonol. 2002;34:91–100.
2. Geller DE: Aerosol antibiotics in cystic fibrosis. Respir Care.
2009;54:658–670.
3. Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB,
Williams-Warren J, VasilJev-KM, Borowitz D, Bowman CM,
Marshall BC, Marshall S, and Smith AL: Intermittent ad-
ministration of inhaled tobramycin in patients with cystic
fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N
Engl J Med. 1999;340:23–30.
4. Retsch-Bogart GZ, Quittner AL, Gibson RL, Oermann CM,
McCoy KS, Montgomery AB, and Cooper PJ: Efficacy and
safety of inhaled aztreonam lysine for airway Pseudomonas in
cystic fibrosis. Chest. 2009;135:1223–1232.
5. Flume PA, O’Sullivan BP, Robinson KA, Goss CH, Rosen-blatt
RL, Kuhn RJ, and Marshall BC: Cystic fibrosis pulmo-nary
guidelines: chronic medications for maintenance of lung health.
Am J Respir Crit Care Med. 2007;176:957–969.
6. Cystic Fibrosis Foundation Patient Registry. 2008 Annual Data
Report to the Center Directors. Bethesda, MD: Cystic Fi-
brosis Foundation Patient Registry.
7. Briesacher B, Quittner A, Saiman L, Fouayzi H, Sacco P, and
Quittel L: Adherence to tobramycin inhaled solution and health
care utilization. Am J Respir Crit Care Med. 2009;179 [Abstract
A1183].
8. Sawicki GS, Sellers DE, and Robinson WM: High treatment
burden in adults with cystic fibrosis: challenges to disease self-
management. J Cyst Fibros. 2009;8:91–96.
9. Geller DE, Konstan MW, Smith J, Noonberg SB, and Conrad
C: Novel tobramycin inhalation powder in cystic fibrosis
subjects: pharmacokinetics and safety. Pediatr Pulmonol.
2007;42:307–313.
10. Saiman L, and Garber E: Infection control in cystic fibrosis:
barriers to implementation and ideas for improvement. Curr Opin
Pulmon Med. 2009;15:626–631.
11. Geller DE, Pitlick WH, Nardella PA, Tracewell WG, and
Ramsey BW: Pharmacokinetics and bioavailability of aero-
solized tobramycin in cystic fibrosis. Chest. 2002;122:219–226.
12. Weers J, Clark A, and Challoner P. High dose inhaled powder
delivery: challenges and techniques. In: RN Dalby, PR Byron, J
Peart, JD Suman, and SJ Farr (eds). Respiratory Drug Delivery
IX. Amy Davis Biggs, River Grove, IL; pp. 281–288, 2004.
13. Zeng XM, Tee SK, Martin GP, and Marriott C: Effects of mixing
procedure and particle size distribution of carrier particles on the
deposition of salbutamol sulphate from dry powder inhaler
formulations. In: Proceedings of Drug Delivery to the Lungs
VII. London; pp. 40–43, 1996.
14. Zeng XM, Martin GP, and Marriott C: Particulate Interactions
in Dry Powder Formulations for Inhalation. Taylor & Francis,
London; 2001.
15. Clark AR, Borgstro¨m L: In vitro testing of pharmaceutical
aerosols and predicting lung deposition from in vitro mea-
surements. In: H Bisgard, C O’Callaghan, GC Smaldone (eds).
Drug Delivery to the Lung. Marcel Dekker, New York; Chapter
4, pp. 105–142, 2002.
16. Crowther-Labiris NR, Holbrook AM, Chrystyn H, MacLeod SM,
and Newhouse MT: Dry powder versus intravenous and
nebulized gentamycin in cystic fibrosis and bronchiec-tasis: a
pilot study. Am J Respir Crit Care Med. 1999;160:1711–1716.
17. Goldman JM, Bayston SM, O’Connor S, and Meigh RE. In-haled
micronised gentamycin powder: a new delivery sys-tem. Thorax.
1990;5:939–940.
182
18. Duddu SP, Sisk SA, Walter YH, Tarara TE, Trimble KR, Clark
AR, Eldon MA, Elton RC, Pickford M, Hirst PH, Newman SP,
and Weers JG: Improved lung delivery from a passive dry
powder inhaler using an engineered Pulmo-Sphere powder.
Pharm Res. 2002;19:689–695.
19. Weers JG, Bell J, Chan H-K, Cipolla D, Dunbar C, Hickey AJ,
Smith IJ: Pulmonary formulations: what remains to be done? J
Aerosol Med Pulm Drug Deliv. 2010;Suppl 2:S5–S23.
20. Newhouse MT, Hirst PH, Duddu SP, Walter YH, Tarara TE,
Clark AR, and Weers JG: Inhalation of a dry powder to-bramycin
pulmosphere formulation in healthy volunteers. Chest.
2003;124:360–366.
21. Borgstro¨m L, Olsson B, and Thorsson L: Degree of throat
deposition can explain the variability in lung deposition of
inhaled drugs. J Aerosol Med. 2006;19:473–483.
22. Weers JG, Tarara TE, and Clark AR. Design of fine particles for
pulmonary drug delivery. Expert Opin Drug Del. 2007;4: 297–
313.
23. Dellamary LA, Tarara TE, Smith DJ, Woelk CH, Adractas A,
Costello M, Gill H, Weers JG: Hollow porous particles in
metered dose inhalers. Pharm Res. 2000;17:168–174.
24. Krafft MP, Riess JG, Weers JG: The design and engineering of
oxygen-delivering fluorocarbon emulsions. In: S Benita (ed).
Submicron Emulsions in Drug Targeting and Delivery.
Harwood Academic Publishers, Amsterdam; pp. 235–333, 1998.
25. Notter RH: Lung surfactants: basic science and clinical ap-
plications. In: C Lenfant (ed). Lung Biology in Health and
Disease. Marcel Dekker, New York; 2000.
26. Tiddens HA, Geller DE, and Challoner P: Effect of dry powder
inhaler resistance on the the inspiratory flows and volumes of
patients with cystic fibrosis of six years and older. J Aerosol
Med. 2006;19:456–465.
27. Standaert TA, Speirs RJ, Rao N, Ung K, Tep V, Lin T, Rourke
AM, and Challoner P: Young cystic fibrosis patients can ef-
fectively use a novel high-payload capsule-based dry pow-der
inhaler with tobramycin powder for inhalation (TPI). Pediatr
Pulmonol. 2004;38(Suppl 27):284.
28. Geller DE: The science of aerosol delivery in cystic fibrosis.
Pediatr Pulmonol. 2008;43:S5–S17.
29. Haynes A, Nakamura J, Heng C, Heuerding S, Thompson G, and
Malcolmson R: Aerosol performance of tobramycin in-halation
powder. In: Dalby RN, Byron PR, Peart J, Suman JD, Farr SJ,
Young PM (eds). Respiratory Drug Delivery 2010.
Davis Healthcare International Publication, River Grove, IL; pp.
701–706, 2010.
30. Chrystyn H: Effects of device design on patient compliance:
comparing the same drug in different devices. In Dalby RN,
Byron PR, Peart J, Suman JD, Young PM (eds). Respiratory
Drug Delivery Europe 2009. Davis Healthcare International
Publication, River Grove, IL; pp. 105–116, 2009.
31. Chodosh S, Flanders JS, Kesten S, Serby CW, Hochrainer D, and
Witek TJ: Effective delivery of particles with the Han-dihaler dry
powder inhalation system over a range of chronic obstructive
pulmonary disease severity. J Aerosol Med. 2001;14:309–315.
32. Challoner PB, Flora MG, Hirst PH, Klimowicz MA, New-man
SP, Schaeffler BA, Speirs RJ, Wallis SJ: Gamma scin-tigraphy
lung deposition comparison of TOBI in the Pari LC Plus
nebulizer and the Aerodose inhaler. Am J Respir Crit Care Med.
2001;163:A83.
33. Newman SP, Hirst PH, Pitcairn GR, and Clark AR: Under-
standing regional lung deposition in gamma scintigraphy. In
Dalby RN, Byron PR, Farr SJ (eds). Respiratory Drug Delivery
VI. Interpharm Press, Buffalo Grove, IL; pp. 9–16, 1998.
GELLER ET AL.
34. Clark AR: Beyond the throat: preferred methods of assessing
regional distribution in the lung. In: RN Dalby, PR Byron, J
Peart, JD Suman, SJ Farr, PM Young (eds). Respiratory Drug
Delivery 2010. Davis Healthcare International Publishing, River
Grove, IL; pp. 235–244, 2010.
35. Konstan MW, Flume PA, Kappler M, Chiron R, Higgins M,
Brockhaus F, Zhang J, Angyalosi G, He E, and Geller DE:
Safety, efficacy and convenience of tobramycin inhalation
powder in cystic fibrosis patients: the EAGER trial. J Cystic
Fibros. 2010 [Epub ahead of print].
36. Konstan MW, Geller DE, Minic´ P, Brockhaus F, Zhang J, and
Angyalosi G: Tobramycin inhalation powder for Pseudomo-
nas aeruginosa infection in cystic fibrosis: the EVOLVE trial.
Pediatr Pulmonol. 2010 [Epub ahead of print].
37. Wu K, Carter A, Geller DE, and Sahasranaman S: Population
pharmacokinetics of tobramycin inhalation powder in cystic
fibrosis patients. Pediatr Pulmonol. 2010;Suppl 33:306–307.
38. Lester MK, Flume PA, Gray SL, Anderson D, and Bowman CM:
Nebulizer use and maintenance by cystic fibrosis pa-tients: a
survey study. Respir Care. 2004;49:1504–1508.
39. Sweetman SC: In: Martindale: The Complete Drug Reference.
(online) London: Pharmaceutical Press. Available from: http://
www.medicinescomplete.com (Accessed June 29, 2009).
40. Dickson EW, Heard SO, Tarara TE, Weers JG, Brueggemann
BA, and Doern GV: Liquid ventilation with perflubron in the
treatment of rats with pneumococcal pneumonia. Crit Care Med.
2002;30:393–395.
41. Tarara TE, Hartman M, Gill H, Kennedy A, and Weers JG:
Characterization of suspension-based metered dose inhaler
formulations comprised of spray-dried budesonide crystals
dispersed in HFA-134a. Pharm Res. 2004;21:1607–1614.
42. Weers J: Dispersible powders for inhalation applications. Innovat
Pharm Tech. 2000;1:114–116.
43. Weers J, and Tarara T: Pulmonary delivery of a fluor-oquinolone.
WO/2009/140587, 2009.
44. Lee JD, Kugler AR, Samford LK, Gerety RJ, and Eldon MA:
Amphotericin B Inhalation Powder (ABIP) is well-tolerated with low
systemic amphotericin B exposure in healthy subjects (abstract P118). In:
Program and Abstracts of the 2nd Meeting of Advances Against
Aspergillosis (Athens, Greece), pp. 214–215, 2006.
45. Dellamary L, Smith DJ, Bloom A, Bot S, Guo GR, Deshmuk H,
Costello M, and Bot A: Rational design of solid aerosols for
immunoglobulin delivery by modulation of aerodynamic and
release characteristics. J Control Rel. 2004;95:489–500.
46. Wang L, Bot S, Smith D, Guo GR, Phillips B, Dellamary L, and
Bot A: Basic immunological properties of spray-dried lipid
microparticles developed for nasal and systemic ad-ministration
of vaccines. STP Pharma Sci. 2002;12:53–61.
Received on September 1, 2010
in final form, February 10, 2011
Reviewed by:
Harm Tiddens
Address correspondence to:
David E. Geller, M.D.
Aerosol Research Laboratory and Cystic Fibrosis Center
Nemours Children’s Clinic
496 South Delaney Avenue
Suite 406A
Orlando, FL 32801
E-mail: dgeller@nemours.org
This article has been cited by:

1. Reinhard Vehring, Herm Snyder, David Lechuga‐Ballesteros. Spray Drying 179-216. [Crossref]
2. Jennifer J. Meerburg, Eleni-Rosalina Andrinopoulou, Aukje C. Bos, Hwain Shin, Marcel van Straten, Kamal Hamed,
Paul Mastoridis, Harm A.W.M. Tiddens. Effect of Inspiratory Maneuvers on Lung Deposition of Tobramycin
Inhalation Powder: A Modeling Study. Journal of Aerosol Medicine and Pulmonary Drug Delivery, ahead of print.
[Abstract] [Full Text] [PDF] [PDF Plus] [Supplementary Material]
3. Qiyue Wang, Yan Shen, Gujie Mi, Dongsheng He, Yue Zhang, Yerong Xiong, Thomas J. Webster, Jiasheng Tu. 2020.
Fumaryl diketopiperazine based effervescent microparticles to escape macrophage phagocytosis for enhanced
treatment of pneumonia via pulmonary delivery. Biomaterials 228, 119575. [Crossref]
4. Angelika Jüptner, Regina Scherließ. 2020. Spray Dried Formulations for Inhalation—Meaningful Characterisation
of Powder Properties. Pharmaceutics 12:1, 14. [Crossref]
5. Anne M. Akkerman-Nijland, Mina Yousofi, Bart L. Rottier, Hester Van der Vaart, Johannes G. M. Burgerhof,
Henderik W. Frijlink, Daan J. Touw, Gerard H. Koppelman, Onno W. Akkerman. 2020. Eradication of Pseudomonas
aeruginosa in cystic fibrosis patients with inhalation of dry powder tobramycin. Therapeutic Advances in
Respiratory Disease 14, 175346662090527. [Crossref]
6. Dominique N. Price, Nitesh K. Kunda, Rajaun Ellis, Pavan Muttil. 2020. Design and Optimization of a
Temperature-Stable Dry Powder BCG Vaccine. Pharmaceutical Research 37:1. . [Crossref]
7. Cecilia Velino, Francesca Carella, Alessio Adamiano, Maurizio Sanguinetti, Alberto Vitali, Daniele Catalucci,
Francesca Bugli, Michele Iafisco. 2019. Nanomedicine Approaches for the Pulmonary Treatment of Cystic
Fibrosis. Frontiers in Bioengineering and Biotechnology 7. . [Crossref]
8. Shuji Ohsaki, Ryosuke Mitani, Saki Fujiwara, Hideya Nakamura, Satoru Watano. 2019. Effect of Particle –Wall
Interaction and Particle Shape on Particle Deposition Behavior in Human Respiratory System. Chemical and
Pharmaceutical Bulletin 67:12, 1328-1336. [Crossref]
9. Jeffry Weers. 2019. Comparison of Phospholipid-Based Particles for Sustained Release of Ciprofloxacin
Following Pulmonary Administration to Bronchiectasis Patients. Pulmonary Therapy 5:2, 127-150. [Crossref]
10. Miriam Braunstein, Anthony J. Hickey, Sean Ekins. 2019. Why Wait? The Case for Treating Tuberculosis with
Inhaled Drugs. Pharmaceutical Research 36:12. . [Crossref]
11. David L. Hava, Lisa Tan, Patrick Johnson, Aidan K. Curran, Jason Perry, Steve Kramer, Katie Kane, Pauline Bedwell,
Gary Layton, Clarie Swann, Dennis Henderson, Naimat Khan, Lucy Connor, Litza McKenzie, Dave Singh, James Roach. 2019.
A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study
safety, tolerability and pharmacokinetics. British Journal of Clinical Pharmacology . [Crossref]
12. Mohammad A.M. Momin, Bhamini Rangnekar, Ian Larson, Shubhra Sinha, Shyamal C. Das. 2019. Dry powder
formulation combining bedaquiline with pyrazinamide for latent and drug-resistant tuberculosis. Advanced
Powder Technology 30:11, 2473-2482. [Crossref]
13. Duy-Khiet Ho, Brittany L.B. Nichols, Kevin J. Edgar, Xabier Murgia, Brigitta Loretz, Claus-Michael Lehr. 2019.
Challenges and strategies in drug delivery systems for treatment of pulmonary infections. European Journal of
Pharmaceutics and Biopharmaceutics 144, 110-124. [Crossref]
14. Bhamini Rangnekar, Mohammad A.M. Momin, Basanth Babu Eedara, Shubhra Sinha, Shyamal C. Das. 2019. Bedaquiline
containing triple combination powder for inhalation to treat drug-resistant tuberculosis. International
Journal of Pharmaceutics 570, 118689. [Crossref]
15. Ragan A. Pitner, Phillip G. Durham, Ian E. Stewart, Steven G. Reed, Gail H. Cassell, Anthony J. Hickey,
Darrick Carter. 2019. A Spray-Dried Combination of Capreomycin and CPZEN-45 for Inhaled Tuberculosis Therapy.
Journal of Pharmaceutical Sciences 108:10, 3302-3311. [Crossref]
16. Farkas Dale, Hindle Michael, Bonasera Serena, Bass Karl, Longest Worth. Development of an Inline Dry Powder
Inhaler for Oral or Trans-Nasal Aerosol Administration to Children. Journal of Aerosol Medicine and Pulmonary
Drug Delivery, ahead of print. [Abstract] [Full Text] [PDF] [PDF Plus]
17. Valentina Sala, Alessandra Murabito, Alessandra Ghigo. 2019. Inhaled Biologicals for the Treatment of Cystic
Fibrosis. Recent Patents on Inflammation & Allergy Drug Discovery 13:1, 19-26. [Crossref]
18. Basanth Babu Eedara, Ian G. Tucker, Zoran D. Zujovic, Thomas Rades, Jason R. Price, Shyamal C. Das. 2019. Crystalline

adduct of moxifloxacin with trans-cinnamic acid to reduce the aqueous solubility and dissolution rate for improved

residence time in the lungs. European Journal of Pharmaceutical Sciences 136, 104961. [Crossref]
19. Laura M. Trandafir, Magdalena M. Leon, Otilia Frasinariu, Ginel Baciu, Gianina Dodi, Elena Cojocaru. 2019. Current Practices and

Potential Nanotechnology Perspectives for Pain Related to Cystic Fibrosis. Journal of Clinical Medicine 8:7, 1023. [Crossref]

20. Banaschewski, Hofmann. 2019. Inhaled Antibiotics for Mycobacterial Lung Disease. Pharmaceutics 11:7, 352. [Crossref]

21. Carla Sardo, Enea Gino Di Domenico, Barbara Porsio, Davide De Rocco, Roberto Santucci, Fiorentina Ascenzioni, Gaetano Giammona,

Gennara Cavallaro. 2019. Nanometric ion pair complexes of tobramycin forming microparticles for the treatment of Pseudomonas
aeruginosa infections in cystic fibrosis. International Journal of Pharmaceutics 563, 347-357. [Crossref]

22. Theerthankar Das, Huai-Jin Choong, Yee Chin Kwang, Hak-Kim Chan, Jim Manos, Philip Chi Lip Kwok, Hien T. T.
Duong. 2019. Spray-Dried Particles of Nitric Oxide-Modified Glutathione for the Treatment of Chronic Lung
Infection. Molecular Pharmaceutics 16:4, 1723-1731. [Crossref]
23. Jeffry G. Weers, Danforth P. Miller, Thomas E. Tarara. 2019. Spray-Dried PulmoSphere™ Formulations for
Inhalation Comprising Crystalline Drug Particles. AAPS PharmSciTech 20:3. . [Crossref]
24. Caterina Cristallini, Niccoletta Barbani, Letizia Ventrelli, Chiara Summa, Sara Filippi, Tania Capelôa, Emanuela
Vitale, Carlo Albera, Barbara Messore, Claudia Giachino. 2019. Biodegradable microparticles designed to efficiently
reach and act on cystic fibrosis mucus barrier. Materials Science and Engineering: C 95, 19-28. [Crossref]
25. Stewart Yeung, Daniela Traini, Alan Tweedie, David Lewis, Tanya Church, Paul M. Young. 2019. Effect of Dosing
Cup Size on the Aerosol Performance of High-Dose Carrier-Based Formulations in a Novel Dry Powder Inhaler.
Journal of Pharmaceutical Sciences 108:2, 949-959. [Crossref]
26. Dominique N. Price, Nitesh K. Kunda, Pavan Muttil. 2019. Challenges Associated with the Pulmonary Delivery of
Therapeutic Dry Powders for Preclinical Testing. KONA Powder and Particle Journal 36:0, 129-144. [Crossref]
27. Hong-Goo Lee, Dong-Wook Kim, Chung-Woong Park. 2018. Dry powder inhaler for pulmonary drug delivery: human
respiratory system, approved products and therapeutic equivalence guideline. Journal of Pharmaceutical
Investigation 48:6, 603-616. [Crossref]
28. Mohammad A.M. Momin, Ian G. Tucker, Shyamal C. Das. 2018. High dose dry powder inhalers to overcome the
challenges of tuberculosis treatment. International Journal of Pharmaceutics 550:1-2, 398-417. [Crossref]
29. Stephanie A. Montgomery, Ellen F. Young, Phillip G. Durham, Katelyn E. Zulauf, Laura Rank, Brittany K. Miller,
Jennifer D. Hayden, Feng-Chang Lin, John T. Welch, Anthony J. Hickey, Miriam Braunstein. 2018. Efficacy of
pyrazinoic acid dry powder aerosols in resolving necrotic and non-necrotic granulomas in a guinea pig model of
tuberculosis. PLOS ONE 13:9, e0204495. [Crossref]
30. Francesca Buttini, Anna Giulia Balducci, Gaia Colombo, Fabio Sonvico, Serena Montanari, Giovanna Pisi,
Alessandra Rossi, Paolo Colombo, Ruggero Bettini. 2018. Dose administration maneuvers and patient care in
tobramycin dry powder inhalation therapy. International Journal of Pharmaceutics 548:1, 182-191. [Crossref]
31. Regina Scherließ, Christian Etschmann. 2018. DPI formulations for high dose applications – Challenges and
opportunities. International Journal of Pharmaceutics 548:1, 49-53. [Crossref]
32. Stewart Yeung, Daniela Traini, David Lewis, Paul M. Young. 2018. Dosing challenges in respiratory therapies.
International Journal of Pharmaceutics 548:1, 659-671. [Crossref]
33. Imco Sibum, Paul Hagedoorn, Anne Haaije de Boer, Henderik Willem Frijlink, Floris Grasmeijer. 2018. Challenges
for pulmonary delivery of high powder doses. International Journal of Pharmaceutics 548:1, 325-336. [Crossref]
34. Stephen P. Newman. 2018. Delivering drugs to the lungs: The history of repurposing in the treatment of
respiratory diseases. Advanced Drug Delivery Reviews 133, 5-18. [Crossref]
35. Ashlee D. Brunaugh, Hugh D.C. Smyth. 2018. Formulation techniques for high dose dry powders. International
Journal of Pharmaceutics 547:1-2, 489-498. [Crossref]
36. Pamela J. McShane, Jeffry G. Weers, Thomas E. Tarara, Alfred Haynes, Preeti Durbha, Danforth P. Miller, Tobias Mundry,

Elisabeth Operschall, J. Stuart Elborn. 2018. Ciprofloxacin Dry Powder for Inhalation (ciprofloxacin DPI): Technical design and
features of an efficient drug–device combination. Pulmonary Pharmacology & Therapeutics 50, 72-79. [Crossref]

37. Mohammad A.M. Momin, Ian G. Tucker, Colin S. Doyle, John A. Denman, Shyamal C. Das. 2018. Manipulation of spray-drying
conditions to develop dry powder particles with surfaces enriched in hydrophobic material to achieve high
aerosolization of a hygroscopic drug. International Journal of Pharmaceutics 543:1-2, 318-327. [Crossref]
38. Francesco Blasi, Vincenzo Carnovale, Giuseppe Cimino, Vincenzina Lucidi, Donatello Salvatore, Barbara Messore,
Marta Bartezaghi, Elisa Muscianisi, Pasquale Alberto Porpiglia. 2018. Treatment compliance in cystic fibrosis
patients with chronic Pseudomonas aeruginosa infection treated with tobramycin inhalation powder: The FREE
study. Respiratory Medicine 138, 88-94. [Crossref]
39. Mohammad A.M. Momin, Ian G. Tucker, Colin S. Doyle, John A. Denman, Shubhra Sinha, Shyamal C. Das. 2018. Co-spray
drying of hygroscopic kanamycin with the hydrophobic drug rifampicin to improve the aerosolization of kanamycin powder
for treating respiratory infections. International Journal of Pharmaceutics 541:1-2, 26-36. [Crossref]
40. Andrea S Melani, Nicola Lanzarone, Paola Rottoli. 2018. The pharmacological treatment of bronchiectasis.
Expert Review of Clinical Pharmacology 11:3, 245-258. [Crossref]
41. Arcadia Woods, Khondaker Miraz Rahman. 2018. Antimicrobial molecules in the lung: formulation challenges and
future directions for innovation. Future Medicinal Chemistry 10:5, 575-604. [Crossref]
42. Jake Irvine, Afrina Afrose, Nazrul Islam. 2018. Formulation and delivery strategies of ibuprofen: challenges
and opportunities. Drug Development and Industrial Pharmacy 44:2, 173-183. [Crossref]
43. Kelly Zatta, Luiza Frank, Luciano Reolon, Lucas Amaral-Machado, Eryvaldo Egito, Maria Gremião, Adriana
Pohlmann, Silvia Guterres. 2018. An Inhalable Powder Formulation Based on Micro- and Nanoparticles Containing
5-Fluorouracil for the Treatment of Metastatic Melanoma. Nanomaterials 8:2, 75. [Crossref]
44. Zara Sheikh, Hui Xin Ong, Michele Pozzoli, Paul M Young, Daniela Traini. 2018. Is there a role for inhaled
anti-inflammatory drugs in cystic fibrosis treatment?. Expert Opinion on Orphan Drugs 6:1, 69-84. [Crossref]
45. Anthony J. Hickey. Introduction—Historical Perspective 1-14. [Crossref]
46. Anthony J. Hickey. Dosage Forms 15-31. [Crossref]

47. Tomasz R. Sosnowski. 2018. Powder Particles and Technologies for Medicine Delivery to the Respiratory System:
Challenges and Opportunities. KONA Powder and Particle Journal 35:0, 122-138. [Crossref]
48. Barbara Porsio, Maria Grazia Cusimano, Domenico Schillaci, Emanuela Fabiola Craparo, Gaetano Giammona, Gennara
Cavallaro. 2017. Nano into Micro Formulations of Tobramycin for the Treatment of Pseudomonas aeruginosa
Infections in Cystic Fibrosis. Biomacromolecules 18:12, 3924-3935. [Crossref]
49. A.G. Ogienko, E.G. Bogdanova, N.A. Trofimov, S.A. Myz, A.A. Ogienko, B.A. Kolesov, A.S. Yunoshev, N.V.
Zubikov, A.Yu. Manakov, V.V. Boldyrev, E.V. Boldyreva. 2017. Large porous particles for respiratory drug
delivery. Glycine-based formulations. European Journal of Pharmaceutical Sciences 110, 148-156. [Crossref]
50. Federico Lavorini, Massimo Pistolesi, Omar S. Usmani. 2017. Recent advances in capsule-based dry powder
inhaler technology. Multidisciplinary Respiratory Medicine 12:1. . [Crossref]
51. Michele Dario Manniello, Pasquale Del Gaudio, Rita P. Aquino, Paola Russo. 2017. Clarithromycin and N -
acetylcysteine co-spray-dried powders for pulmonary drug delivery: A focus on drug solubility. International
Journal of Pharmaceutics 533:2, 463-469. [Crossref]
52. Shahid Sukhbir Kaur. 2017. Pulmonary drug delivery system: newer patents. Pharmaceutical Patent Analyst 6:5, 225-244. [Crossref]

53. Michael Lau, Paul M. Young, Daniela Traini. 2017. A review of co-milling techniques for the production of high
dose dry powder inhaler formulation. Drug Development and Industrial Pharmacy 43:8, 1229-1238. [Crossref]
54. James Greenwood, Carsten Schwarz, Urte Sommerwerck, Edward F Nash, Michael Tamm, Weihua Cao, Paul Mastoridis,
Laurie Debonnett, Kamal Hamed. 2017. Ease of use of tobramycin inhalation powder compared with nebulized
tobramycin and colistimethate sodium: a crossover study in cystic fibrosis patients with pulmonary Pseudomonas
aeruginosa infection. Therapeutic Advances in Respiratory Disease 11:7, 249-260. [Crossref]
55. Stephen P Newman. 2017. Drug delivery to the lungs: challenges and opportunities. Therapeutic Delivery 8:8, 647-661. [Crossref]

56. J. E. Moore, P. Mastoridis. 2017. Clinical implications of Pseudomonas aeruginosa location in the lungs of
patients with cystic fibrosis. Journal of Clinical Pharmacy and Therapeutics 42:3, 259-267. [Crossref]
57. Kamal Hamed, Laurie Debonnett. 2017. Tobramycin inhalation powder for the treatment of pulmonary Pseudomonas
aeruginosa infection in patients with cystic fibrosis: a review based on clinical evidence. Therapeutic
Advances in Respiratory Disease 11:5, 193-209. [Crossref]
58. A. H. de Boer, P. Hagedoorn, M. Hoppentocht, F. Buttini, F. Grasmeijer, H. W. Frijlink. 2017. Dry powder
inhalation: past, present and future. Expert Opinion on Drug Delivery 14:4, 499-512. [Crossref]
59. Jeffry Weers, Andy Clark. 2017. The Impact of Inspiratory Flow Rate on Drug Delivery to the Lungs with Dry
Powder Inhalers. Pharmaceutical Research 34:3, 507-528. [Crossref]
60. Paola Rogliani, Luigino Calzetta, Angelo Coppola, Francesco Cavalli, Josuel Ora, Ermanno Puxeddu, Maria Gabriella Matera, Mario

Cazzola. 2017. Optimizing drug delivery in COPD: The role of inhaler devices. Respiratory Medicine 124, 6-14. [Crossref]

61. Wee Wallace B., Tavernini Scott, Martin Andrew R., Amirav Israel, Majaesic Carina, Finlay Warren H.. 2017. Dry

Powder Inhaler Delivery of Tobramycin in In Vitro Models of Tracheostomized Children. Journal of Aerosol
Medicine and Pulmonary Drug Delivery 30:1, 64-70. [Abstract] [Full Text] [PDF] [PDF Plus]
62. Emanuela F Craparo, Barbara Porsio, Domenico Schillaci, Maria G Cusimano, Dario Spigolon, Gaetano Giammona,
Gennara Cavallaro. 2017. Polyanion–tobramycin nanocomplexes into functional microparticles for the treatment
of Pseudomonas aeruginosa infections in cystic fibrosis. Nanomedicine 12:1, 25-42. [Crossref]
63. Qi Zhou, Li Qu, Hak-Kim Chan. Pulmonary Delivery of Antibiotics for Respiratory Infections 131-150. [Crossref]
64. Bing Zhu, Matteo Padroni, Gaia Colombo, Gary Phillips, John Crapper, Paul M. Young, Daniela Traini. 2016. The
development of a single-use, capsule-free multi-breath tobramycin dry powder inhaler for the treatment of
cystic fibrosis. International Journal of Pharmaceutics 514:2, 392-398. [Crossref]
65. Alfred Haynes, David Geller, Jeffry Weers, Brian Ament, Richard Pavkov, Richard Malcolmson, Laurie Debonnett,
Paul Mastoridis, Anthony Yadao, Silvia Heuerding. 2016. Inhalation of tobramycin using simulated cystic
fibrosis patient profiles. Pediatric Pulmonology 51:11, 1159-1167. [Crossref]
66. M. M. Lipp, R. Batycky, J. Moore, M. Leinonen, M. I. Freed. 2016. Preclinical and clinical assessment of inhaled
levodopa for OFF episodes in Parkinsons disease. Science Translational Medicine 8:360, 360ra136-360ra136. [Crossref]

67. A.J. Hickey, P.G. Durham, A. Dharmadhikari, E.A. Nardell. 2016. Inhaled drug treatment for tuberculosis: Past
progress and future prospects. Journal of Controlled Release 240, 127-134. [Crossref]
68. Heba F. Salem, Rasha M. Kharshoum, Lekaa F. Abdel Hakim, Mohamed E. Abdelrahim. 2016. Edge activators and a
polycationic polymer enhance the formulation of porous voriconazole nanoagglomerate for the use as a dry
powder inhaler. Journal of Liposome Research 26:4, 324-335. [Crossref]
69. Ashkan K. Yazdi, Hugh D.C. Smyth. 2016. Carrier-free high-dose dry powder inhaler formulation of ibuprofen: Physicochemical

characterization and in vitro aerodynamic performance. International Journal of Pharmaceutics 511:1, 403-414. [Crossref]

70. Keith T. Ung, Nagaraja Rao, Jeffry G. Weers, Daniel Huang, Hak-Kim Chan. 2016. Design of spray dried insulin
microparticles to bypass deposition in the extrathoracic region and maximize total lung dose. International
Journal of Pharmaceutics 511:2, 1070-1079. [Crossref]
71. A.J. Hickey. Introduction 1-9. [Crossref]
72. Francesca Buttini, Gaia Colombo. Formulation Strategies for Antitubercular Drugs by Inhalation 197-212. [Crossref]

73. David L. Hava, Jean C. Sung. Treatments for Mycobacterial Persistence and Biofilm Growth 325-345. [Crossref]
74. Ellen F. Young, Anthony J. Hickey, Miriam Braunstein. Testing Inhaled Drug Therapies for Treating Tuberculosis
111-130. [Crossref]
75. Jennifer Wong, Maurizio Ricci, Hak-Kim Chan. Spray Drying Strategies to Stop Tuberculosis 161-196. [Crossref]
76. Anthony De Soyza, Timothy Aksamit. 2016. Ciprofloxacin dry powder for inhalation in non-cystic fibrosis
bronchiectasis. Expert Opinion on Orphan Drugs 4:8, 875-884. [Crossref]
77. Matthias Griese, Gerhard Scheuch. 2016. Delivery of Alpha-1 Antitrypsin to Airways. Annals of the American
Thoracic Society 13:Supplement_4, S346-S351. [Crossref]
78. Gemma O'Connor, Laura E. Gleeson, Aidan Fagan-Murphy, Sally-Ann Cryan, Mary P. O'Sullivan, Joseph Keane. 2016. Sharpening

nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies
and strategies for targeted respiratory delivery. Advanced Drug Delivery Reviews 102, 33-54. [Crossref]

79. Michele Dario Manniello, Pasquale Del Gaudio, Amalia Porta, Rita Patrizia Aquino, Paola Russo. 2016. Aerodynamic
properties, solubility and in vitro antibacterial efficacy of dry powders prepared by spray drying: Clarithromycin
versus its hydrochloride salt. European Journal of Pharmaceutics and Biopharmaceutics 104, 1-6. [Crossref]
80. Lan Chen, Tomoyuki Okuda, Xiang-Yun Lu, Hak-Kim Chan. 2016. Amorphous powders for inhalation drug delivery.
Advanced Drug Delivery Reviews 100, 102-115. [Crossref]
81. Hiroko Otake, Tomoyuki Okuda, Daiki Hira, Haruyoshi Kojima, Yasuhiro Shimada, Hirozazu Okamoto. 2016.
Inhalable Spray-Freeze-Dried Powder with L-Leucine that Delivers Particles Independent of Inspiratory Flow
Pattern and Inhalation Device. Pharmaceutical Research 33:4, 922-931. [Crossref]
82. Teresa Jong, Jian Li, David A.V. Morton, Qi (Tony) Zhou, Ian Larson. 2016. Investigation of the Changes in
Aerosolization Behavior Between the Jet-Milled and Spray-Dried Colistin Powders Through Surface Energy
Characterization. Journal of Pharmaceutical Sciences 105:3, 1156-1163. [Crossref]
83. Jeffry G Weers. 2016. Enhanced design of inhaled therapeutics: what does the future hold?. Therapeutic
Delivery 7:3, 145-148. [Crossref]
84. E. Vazquez-Espinosa, C. Marcos, T. Alonso, R.M. Giron, R.M. Gomez-Punter, E. Garcia-Castillo, E. Zamora, C. Cisneros,

J. Garcia, C. Valenzuela, J. Ancochea. 2016. Tobramycin inhalation powder (TOBI Podhaler ® ) for the treatment of lung

infection in patients with cystic fibrosis. Expert Review of Anti-infective Therapy 14:1, 9-17. [Crossref]
 85. María Moreno-Sastre, Marta Pastor, Amaia Esquisabel, José Luis Pedraz. The Use of Nanoparticles for
Antimicrobial Delivery 453-487. [Crossref]
86. John N Pritchard. 2015. Industry guidance for the selection of a delivery system for the development of novel
respiratory products. Expert Opinion on Drug Delivery 12:11, 1755-1765. [Crossref]
87. Dale R. Farkas, Michael Hindle, P. Worth Longest. 2015. Characterization of a New High-Dose Dry Powder Inhaler
(DPI) Based on a Fluidized Bed Design. Annals of Biomedical Engineering 43:11, 2804-2815. [Crossref]
88. Jeffry G. Weers, Danforth P. Miller. 2015. Formulation Design of Dry Powders for Inhalation. Journal of
Pharmaceutical Sciences 104:10, 3259-3288. [Crossref]
89. Gregory S. Sawicki, Christopher H. Goss. 2015. Tackling the increasing complexity of CF care. Pediatric
Pulmonology 50:S40, S74-S79. [Crossref]
90. Aurélie Schoubben, Paolo Blasi, Andrea Giontella, Stefano Giovagnoli, Maurizio Ricci. 2015. Powder, capsule and device: An

imperative ménage à trois for respirable dry powders. International Journal of Pharmaceutics 494:1, 40-48. [Crossref]

91. Danforth P. Miller, Trixie Tan, Thomas E. Tarara, John Nakamura, Richard J. Malcolmson, Jeffry G. Weers. 2015.
Physical Characterization of Tobramycin Inhalation Powder: I. Rational Design of a Stable Engineered-Particle
Formulation for Delivery to the Lungs. Molecular Pharmaceutics 12:8, 2582-2593. [Crossref]
92. Alberto Baldelli, Mohammed A. Boraey, David S. Nobes, Reinhard Vehring. 2015. Analysis of the Particle
Formation Process of Structured Microparticles. Molecular Pharmaceutics 12:8, 2562-2573. [Crossref]
93. Silvia Belotti, Alessandra Rossi, Paolo Colombo, Ruggero Bettini, Dimitrios Rekkas, Stavros Politis, Gaia Colombo, Anna Giulia

Balducci, Francesca Buttini. 2015. Spray-dried amikacin sulphate powder for inhalation in cystic fibrosis patients: The role of
ethanol in particle formation. European Journal of Pharmaceutics and Biopharmaceutics 93, 165-172. [Crossref]

94. Francesco Martinelli, Anna Giulia Balducci, Alessandra Rossi, Fabio Sonvico, Paolo Colombo, Francesca Buttini.
2015. “Pierce and inhale” design in capsule based dry powder inhalers: Effect of capsule piercing and motion
on aerodynamic performance of drugs. International Journal of Pharmaceutics 487:1-2, 197-204. [Crossref]
95. Kai Berkenfeld, Alf Lamprecht, Jason T. McConville. 2015. Devices for Dry Powder Drug Delivery to the Lung.
AAPS PharmSciTech 16:3, 479-490. [Crossref]
96. Anna Giulia Balducci, Ruggero Bettini, Paolo Colombo, Francesca Buttini. Drug Delivery Strategies for
Pulmonary Administration of Antibiotics 241-262. [Crossref]
97. Simone R. Carvalho, Alan B. Watts, Jay I. Peters, Robert O. Williams. Dry Powder Inhalation for Pulmonary
Delivery: Recent Advances and Continuing Challenges 35-62. [Crossref]
98. Chris Stockmann, Jessica K. Roberts, Venkata K. Yellepeddi, Catherine M. T. Sherwin. 2015. Clinical
Pharmacokinetics of Inhaled Antimicrobials. Clinical Pharmacokinetics 54:5, 473-492. [Crossref]
99. Jeffry Weers. 2015. Inhaled antimicrobial therapy – Barriers to effective treatment. Advanced Drug Delivery
Reviews 85, 24-43. [Crossref]
100. Qi (Tony) Zhou, Sharon Shui Yee Leung, Patricia Tang, Thaigarajan Parumasivam, Zhi Hui Loh, Hak-Kim Chan. 2015. Inhaled formulations and

pulmonary drug delivery systems for respiratory infections. Advanced Drug Delivery Reviews 85, 83-99. [Crossref]

101. Jeffry Weers. 2015. Reply to the comment by de Boer and Hoppentocht on: Inhaled Antimicrobial therapy –
Barriers to effective treatment, by J. Weers, Adv. Drug Deliv. Rev. (2015),
http://dx.doi.org/10.1016/j.addr.2014.08.013. Advanced Drug Delivery Reviews 85, e3-e5. [Crossref]
102. Jatinder Kaur Mukker, Ravi Shankar Prasad Singh, Hartmut Derendorf. 2015. Pharmacokinetic and pharmacodynamic
implications in inhalable antimicrobial therapy. Advanced Drug Delivery Reviews 85, 57-64. [Crossref]
103. Stass Heino, Delesen Heinz, Nagelschmitz Johannes, Staab Doris. 2015. Safety and Pharmacokinetics of Ciprofloxacin Dry
Powder for Inhalation in Cystic Fibrosis: A Phase I, Randomized, Single-Dose, Dose-Escalation Study. Journal of
Aerosol Medicine and Pulmonary Drug Delivery 28:2, 106-115. [Abstract] [Full Text] [PDF] [PDF Plus]
104. Susanne Ziffels, Norman L. Bemelmans, Phillip G. Durham, Anthony J. Hickey. 2015. In vitro dry powder inhaler
formulation performance considerations. Journal of Controlled Release 199, 45-52. [Crossref]
105. Ranjani Somayaji, Michael D Parkins. 2015. Tobramycin inhalation powder: an efficient and efficacious therapy for the
treatment of Pseudomonas aeruginosa infection in cystic fibrosis. Therapeutic Delivery 6:2, 121-137. [Crossref]
106. Michal Shteinberg, J. Stuart Elborn. 2015. Use of Inhaled Tobramycin in Cystic Fibrosis. Advances in Therapy 32:1, 1-9. [Crossref]

107. Gary M. Gladysz, Krishan K. Chawla. Techniques of Introducing Intentional Voids into Particles and Fibers 73-102. [Crossref]
108. Philip J. Kuehl, Alan Cherrington, Dan E. Dobry, Dale Edgerton, Dwayne T. Friesen, Charles Hobbs, Chet L. Leach, Brice Murri,

Doss Neal, David K. Lyon, David T. Vodak, Matthew D. Reed. 2014. Biologic Comparison of Inhaled Insulin Formulations: ExuberaTM
and Novel Spray-Dried Engineered Particles of Dextran-10. AAPS PharmSciTech 15:6, 1545-1550. [Crossref]

109. John N Pritchard, Rachael D Giles. 2014. Opportunities in respiratory drug delivery. Therapeutic Delivery
5:12, 1261-1273. [Crossref]
110. Harm A.W.M. Tiddens, Aukje C. Bos, Johan W. Mouton, Sunalene Devadason, Hettie M. Janssens. 2014. Inhaled
antibiotics: dry or wet?. European Respiratory Journal 44:5, 1308-1318. [Crossref]
111. Céline Sadek, Huashan Li, Pierre Schuck, Yannick Fallourd, Nicolas Pradeau, Cécile Le Floch-Fouéré, Romain
Jeantet. 2014. To What Extent Do Whey and Casein Micelle Proteins Influence the Morphology and Properties of
the Resulting Powder?. Drying Technology 32:13, 1540-1551. [Crossref]
112. Hoe Susan, Boraey Mohammed A., Ivey James W., Finlay Warren H., Vehring Reinhard. 2014. Manufacturing and
Device Options for the Delivery of Biotherapeutics. Journal of Aerosol Medicine and Pulmonary Drug Delivery
27:5, 315-328. [Abstract] [Full Text] [PDF] [PDF Plus]
113. Axel Dalhoff. 2014. Pharmacokinetics and Pharmacodynamics of Aerosolized Antibacterial Agents in Chronically
Infected Cystic Fibrosis Patients. Clinical Microbiology Reviews 27:4, 753-782. [Crossref]
114. Nathalie Wauthoz, Karim Amighi. 2014. Phospholipids in pulmonary drug delivery. European Journal of Lipid
Science and Technology 116:9, 1114-1128. [Crossref]
115. Peter van Hoogevest, Armin Wendel. 2014. The use of natural and synthetic phospholipids as pharmaceutical
excipients. European Journal of Lipid Science and Technology 116:9, 1088-1107. [Crossref]
116. Anthony J. Hickey. 2014. Controlled delivery of inhaled therapeutic agents. Journal of Controlled Release 190, 182-188. [Crossref]

117. A. A. Ogienko, S. A. Myz, E. V. Boldyreva, E. G. Zevak, A. G. Ogienko, A. Yu. Manakov, A. I. Ancharov, B. M.

Kuchumov, A. A. Krasnikov. 2014. Using SEM to design a new generation of drug forms. Bulletin of the Russian
Academy of Sciences: Physics 78:9, 868-873. [Crossref]
118. Qi (Tony) Zhou, Patricia Tang, Sharon Shui Yee Leung, John Gar Yan Chan, Hak-Kim Chan. 2014. Emerging inhalation
aerosol devices and strategies: Where are we headed?. Advanced Drug Delivery Reviews 75, 3-17. [Crossref]

119. M. Hoppentocht, P. Hagedoorn, H.W. Frijlink, A.H. de Boer. 2014. Technological and practical challenges of dry
powder inhalers and formulations. Advanced Drug Delivery Reviews 75, 18-31. [Crossref]
120. Anne Marie Healy, Maria Inês Amaro, Krzysztof J. Paluch, Lidia Tajber. 2014. Dry powders for oral inhalation
free of lactose carrier particles. Advanced Drug Delivery Reviews 75, 32-52. [Crossref]
121. David Cipolla, Boris Shekunov, Jim Blanchard, Anthony Hickey. 2014. Lipid-based carriers for pulmonary products:
Preclinical development and case studies in humans. Advanced Drug Delivery Reviews 75, 53-80. [Crossref]

122. Ivana d'Angelo, Claudia Conte, Maria Immacolata La Rotonda, Agnese Miro, Fabiana Quaglia, Francesca Ungaro.
2014. Improving the efficacy of inhaled drugs in cystic fibrosis: Challenges and emerging drug delivery
strategies. Advanced Drug Delivery Reviews 75, 92-111. [Crossref]
123. Cristina Loira-Pastoriza, Julie Todoroff, Rita Vanbever. 2014. Delivery strategies for sustained drug release
in the lungs. Advanced Drug Delivery Reviews 75, 81-91. [Crossref]
124. Bruce K. Rubin, Ronald W. Williams. 2014. Emerging aerosol drug delivery strategies: From bench to clinic.
Advanced Drug Delivery Reviews 75, 141-148. [Crossref]
125. Salome Juliette Koussoroplis, Geneviève Paulissen, Donatienne Tyteca, Hadi Goldansaz, Julie Todoroff, Céline Barilly, Catherine

Uyttenhove, Jacques Van Snick, Didier Cataldo, Rita Vanbever. 2014. PEGylation of antibody fragments greatly increases their
local residence time following delivery to the respiratory tract. Journal of Controlled Release 187, 91-100. [Crossref]

126. John Gar Yan Chan, Jennifer Wong, Qi Tony Zhou, Sharon Shui Yee Leung, Hak-Kim Chan. 2014. Advances in Device
and Formulation Technologies for Pulmonary Drug Delivery. AAPS PharmSciTech 15:4, 882-897. [Crossref]
127. Stanley B Fiel. 2014. Aerosolized antibiotics in cystic fibrosis: an update. Expert Review of Respiratory
Medicine 8:3, 305-314. [Crossref]
128. Deborah A O'Neil, Douglas Fraser-Pitt. 2014. Progress towards next-generation therapeutics for cystic
fibrosis. Future Medicinal Chemistry 6:9, 1067-1079. [Crossref]
129. Yahya Rahimpour, Maryam Kouhsoltani, Hamed Hamishehkar. 2014. Alternative carriers in dry powder inhaler

formulations. Drug Discovery Today 19:5, 618-626. [Crossref]

130. P Bäckman, H Adelmann, G Petersson, C B Jones. 2014. Advances in Inhaled Technologies: Understanding the
Therapeutic Challenge, Predicting Clinical Performance, and Designing the Optimal Inhaled Product. Clinical
Pharmacology & Therapeutics 95:5, 509-520. [Crossref]
131. Jim Thigpen, Brian Odle. 2014. Intravenous and Inhaled Antimicrobials at Home in Cystic Fibrosis Patients.
Home Health Care Management & Practice 26:2, 101-109. [Crossref]
132. Young Paul M., Crapper John, Philips Gary, Sharma Ketan, Chan Hak-Kim, Traini Daniela. 2014. Overcoming Dose
Limitations Using the Orbital® Multi-Breath Dry Powder Inhaler. Journal of Aerosol Medicine and Pulmonary Drug
Delivery 27:2, 138-147. [Abstract] [Full Text] [PDF] [PDF Plus]
133. Srinivas R.B. Behara, P. Worth Longest, Dale R. Farkas, Michael Hindle. 2014. Development of high efficiency
ventilation bag actuated dry powder inhalers. International Journal of Pharmaceutics 465:1-2, 52-62. [Crossref]
134. J.-C. Dubus, L. Bassinet, F. Chedevergne, B. Delaisi, N. Desmazes-Dufeu, G. Reychler, L. Vecellio. 2014. Mucoviscidose
et traitements inhalés : quoi de neuf en 2013 ?. Revue des Maladies Respiratoires 31:4, 336-346. [Crossref]

135. Paul B. Myrdal, Poonam Sheth, Stephen W. Stein. 2014. Advances in Metered Dose Inhaler Technology: Formulation
Development. AAPS PharmSciTech 15:2, 434-455. [Crossref]
136. Bradley S. Quon, Christopher H. Goss, Bonnie W. Ramsey. 2014. Inhaled Antibiotics for Lower Airway Infections.
Annals of the American Thoracic Society 11:3, 425-434. [Crossref]
137. Stephen Newman. 2014. Improving inhaler technique, adherence to therapy and the precision of dosing: major
challenges for pulmonary drug delivery. Expert Opinion on Drug Delivery 11:3, 365-378. [Crossref]
138. Jeffry Weers, Thomas Tarara. 2014. The PulmoSphere™ platform for pulmonary drug delivery. Therapeutic Delivery
5:3, 277-295. [Crossref]
139. Jason D Ehrick, Jennifer Wylie, Adrian P Goodey, Ying Li, Oscar Liu, Brent Donovan. 2014. Orally inhaled
fixed-dose combination products for the treatment of asthma and chronic obstructive pulmonary disease: not
simple math. Therapeutic Delivery 5:3, 297-317. [Crossref]
140. L Ting, S Aksenov, S G Bhansali, R Ramakrishna, P Tang, D E Geller. 2014. Population Pharmacokinetics of Inhaled
Tobramycin Powder in Cystic Fibrosis Patients. CPT: Pharmacometrics & Systems Pharmacology 3:2, e99. [Crossref]
141. Srinivas R. B. Behara, Dale R. Farkas, Michael Hindle, P. Worth Longest. 2014. Development of a High Efficiency Dry Powder

Inhaler: Effects of Capsule Chamber Design and Inhaler Surface Modifications. Pharmaceutical Research 31:2, 360-372. [Crossref]

142. Darragh Murnane, Victoria Hutter, Marie Harang. Pharmaceutical Aerosols and Pulmonary Drug Delivery 221-269. [Crossref]

143. Darragh Murnane, Marc B. Brown. The Challenges of Paediatric Pulmonary Drug Delivery 253-272. [Crossref]

144. Bhargava Kandala, Günther Hochhaus. Pharmacometrics in Pulmonary Diseases 349-382. [Crossref]

145. Frederic Tewes, Carsten Ehrhardt, Anne Marie Healy. 2014. Superparamagnetic iron oxide nanoparticles (SPIONs) -
loaded Trojan microparticles for targeted aerosol delivery to the lung. European Journal of Pharmaceutics and
Biopharmaceutics 86:1, 98-104. [Crossref]
146. Sarah Claus, Claudius Weiler, Joerg Schiewe, Wolfgang Friess. 2014. How can we bring high drug doses to the
lung?. European Journal of Pharmaceutics and Biopharmaceutics 86:1, 1-6. [Crossref]
147. Kate McKeage. 2013. Tobramycin Inhalation Powder: A Review of Its Use in the Treatment of Chronic Pseudomonas
aeruginosa Infection in Patients with Cystic Fibrosis. Drugs 73:16, 1815-1827. [Crossref]
148. Heather Conway, Kelly J. Dix, Jacob D. McDonald, Rodney A. Miller, Henry G. Wall, Ronald K. Wolff, Matthew D. Reed. 2013.

Comparison of inhalation toxicity studies of gentamicin in rats and dogs. Inhalation Toxicology 25:13, 714-724. [Crossref]

149. Geng Tian, P. Worth Longest, Xiang Li, Michael Hindle. 2013. Targeting Aerosol Deposition to and Within the
Lung Airways Using Excipient Enhanced Growth. Journal of Aerosol Medicine and Pulmonary Drug Delivery 26:5,
248-265. [Abstract] [Full Text] [PDF] [PDF Plus]
150. Heino Stass, Boris Weimann, Johannes Nagelschmitz, Claudia Rolinck-Werninghaus, Doris Staab. 2013.
Tolerability and Pharmacokinetic Properties of Ciprofloxacin Dry Powder for Inhalation in Patients With Cystic
Fibrosis: A Phase I, Randomized, Dose-Escalation Study. Clinical Therapeutics 35:10, 1571-1581. [Crossref]
151. Chad C Smutney, Marshall Grant, P Spencer Kinsey. 2013. Device factors affecting pulmonary delivery of dry
powders. Therapeutic Delivery 4:8, 939-949. [Crossref]
152. Ivanka Galeva, Michael W. Konstan, Mark Higgins, Gerhild Angyalosi, Florian Brockhaus, Simon Piggott, Karen

Thomas, Alexander G. Chuchalin. 2013. Tobramycin inhalation powder manufactured by improved process in cystic

fibrosis: the randomized EDIT trial. Current Medical Research and Opinion 29:8, 947-956. [Crossref]
153. Heino Stass, Johannes Nagelschmitz, Stefan Willmann, Heinz Delesen, Abhishek Gupta, Sybille Baumann. 2013. Inhalation of a Dry

Powder Ciprofloxacin Formulation in Healthy Subjects: A Phase I Study. Clinical Drug Investigation 33:6, 419-427. [Crossref]

154. Yoen-Ju Son, P. Worth Longest, Geng Tian, Michael Hindle. 2013. Evaluation and modification of commercial dry
powder inhalers for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation.
European Journal of Pharmaceutical Sciences 49:3, 390-399. [Crossref]
155. Garima Sharma, Wunlapa Mueannoom, Asma B.M. Buanz, Kevin M.G. Taylor, Simon Gaisford. 2013. In vitro
characterisation of terbutaline sulphate particles prepared by thermal ink-jet spray freeze drying.
International Journal of Pharmaceutics 447:1-2, 165-170. [Crossref]
156. Jeffry Weers, Keith Ung, John Le, Nagaraja Rao, Brian Ament, George Axford, David Maltz, Leo Chan. 2013. Dose
Emission Characteristics of Placebo PulmoSphere® Particles Are Unaffected by a Subject's Inhalation Maneuver.
Journal of Aerosol Medicine and Pulmonary Drug Delivery 26:1, 56-68. [Abstract] [Full Text] [PDF] [PDF Plus]
157. Yoen-Ju Son, P. Worth Longest, Michael Hindle. 2013. Aerosolization characteristics of dry powder inhaler
formulations for the excipient enhanced growth (EEG) application: Effect of spray drying process conditions on
aerosol performance. International Journal of Pharmaceutics 443:1-2, 137-145. [Crossref]
158. S. Stegemann, S. Kopp, G. Borchard, V.P. Shah, S. Senel, R. Dubey, N. Urbanetz, M. Cittero, A. Schoubben, C.
Hippchen, D. Cade, A. Fuglsang, J. Morais, L. Borgström, F. Farshi, K.-H. Seyfang, R. Hermann, A. van de
Putte, I. Klebovich, A. Hincal. 2013. Developing and advancing dry powder inhalation towards enhanced
therapeutics. European Journal of Pharmaceutical Sciences 48:1-2, 181-194. [Crossref]
159. Francesca Ungaro, Ivana d' Angelo, Agnese Miro, Maria I. La Rotonda, Fabiana Quaglia. 2012. Engineered PLGA nano- and micro-

carriers for pulmonary delivery: challenges and promises. Journal of Pharmacy and Pharmacology 64:9, 1217-1235. [Crossref]

160. Francesca Buttini, Paolo Colombo, Alessandra Rossi, Fabio Sonvico, Gaia Colombo. 2012. Particles and powders: Tools of
innovation for non-invasive drug administration. Journal of Controlled Release 161:2, 693-702. [Crossref]
161. Peter Greally, Paul Whitaker, Daniel Peckham. 2012. Challenges with current inhaled treatments for chronic Pseudomonas

aeruginosa infection in patients with cystic fibrosis. Current Medical Research and Opinion 28:6, 1059-1067. [Crossref]

162. Meenakshi Bothra, Rakesh Lodha, Sushil Kumar Kabra. 2012. Tobramycin for the treatment of bacterial pneumonia
in children. Expert Opinion on Pharmacotherapy 13:4, 565-571. [Crossref]
163. Wunlapa Mueannoom, Amon Srisongphan, Kevin M.G. Taylor, Stephan Hauschild, Simon Gaisford. 2012. Thermal ink -
jet spray freeze-drying for preparation of excipient-free salbutamol sulphate for inhalation. European Journal
of Pharmaceutics and Biopharmaceutics 80:1, 149-155. [Crossref]
164. Manfred Ballmann, Alan Smyth, David E. Geller. 2011. Therapeutic approaches to chronic cystic fibrosis respiratory
infections with available, emerging aerosolized antibiotics. Respiratory Medicine 105, S2-S8. [Crossref]

165. David E. Geller, Susan Madge. 2011. Technological and behavioral strategies to reduce treatment burden and
improve adherence to inhaled antibiotics in cystic fibrosis. Respiratory Medicine 105, S24-S31. [Crossref]
166. Michael D Parkins, J Stuart Elborn. 2011. Tobramycin Inhalation Powder™: a novel drug delivery system for treating chronic

Pseudomonas aeruginosa infection in cystic fibrosis. Expert Review of Respiratory Medicine 5:5, 609-622. [Crossref]

167. David Lechuga-Ballesteros, Brian Noga, Reinhard Vehring, R Harris Cummings, Sarvajna K Dwivedi. 2011. Novel
cosuspension metered-dose inhalers for the combination therapy of chronic obstructive pulmonary disease and
asthma. Future Medicinal Chemistry 3:13, 1703-1718. [Crossref]
168. Martin J Donovan, Aileen Gibbons, Matthew J Herpin, Stephen Marek, Shayna L McGill, Hugh DC Smyth. 2011. Novel
dry powder inhaler particle-dispersion systems. Therapeutic Delivery 2:10, 1295-1311. [Crossref]
169. K.D. Bruce, G.B. Rogers, N. Patel. 2011. Microbiological insights into respiratory infections and the

opportunities for inhaled therapy. Journal of Drug Delivery Science and Technology 21:4, 301-309. [Crossref]