Spray Drying of Therapeutics: Influence of Excipients · 2017. 10. 9. · In study 3 dose...
Transcript of Spray Drying of Therapeutics: Influence of Excipients · 2017. 10. 9. · In study 3 dose...
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Inhaled Drug Delivery
16-17 November 2016
Spray Drying of
Therapeutics: Influence of
Excipients
Dr. Satyanarayana Somavarapu
UCL School of Pharamcy
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UCL SCHOOL OF PHARMACY
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Respiratory tract infections (RTIs)
• RTIs- 3.1 million deaths per year as estimated by WHO in 2012
• Tuberculosis- 1.3 million deaths per year as estimated by WHO in 2012
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UCL SCHOOL OF PHARMACY
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Treatment of pulmonary infections
First line of treatment is antibiotics given oral/IV
• Ciprofloxacin- 750mg
• Azithromycin- 250/500mg
• Levofloxacin- 750mg
• Amikacin IV- 20-30mg/kg
• Tobramycin IV- 10mg/kg
• Rifampicin IV infusion- 600mg
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Antibiotics given locally as a nebulization
(clinical trials)
Arikace® - INSMED
• Liposomal amikacin
inhalation solution-
560mg/once daily
• To enter phase III trials
• Sustained release of
amikacin
• Designated by FDA-
breakthrough status for
refractory lung infection in
2014
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Antibiotics given locally as a dry powder inhalation:
(marketed)
TOBI® Podhaler-
Novartis
• Tobramycin
Pulmosphere™
inhalation powder
• 112mg (3 capsules)/
twice daily
• Improved lung functions
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Antibiotics given locally as a nebulization:
(marketed)
Caystone®-
Gilead sciences
• Aztreonam inhalation
solution
• Antibiotic resistance
is rare
• Cystic fibrosis,
COPD, pneumonia
• Superior to TOBI®
(TIS)
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Antibiotics given locally as a nebulization
(clinical trials)
Aeroquin™
Aptalis Pharmaceuticals
• Levofloxacin inhalation
solution
• Phase III results
announced
• Cystic fibrosis, COPD
• Reduction on
Pseudomonas aeruginosa
density
• Broad spectrum of activity
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Approved anti-infective aerosol formulationsFORMULATION NAME ANTMICROBIAL DEVICE AND DOSE ADVANTAGES INDICATIONS
TOBI®- Tobramycin inhalation
solution USP (TIS)
Novartis
Tobramycin
Aminoglycoside
Nebulization PARI-
LC® PLUS
300 mg nebulized
twice daily
Improved lung function, prevention of pulmonary
exacerbations
CF
COPD
CB
VAP
CAP
BRAMITOB®
Chiesi Farmaceutici
Tobramycin
Aminoglycoside
Nebulization
300 mg nebulized
twice daily
Improved lung function, prevention of pulmonary
exacerbations
CF
CAP
TOBI®- Tobramycin PulmoSphere™
inhalation powder USP (TIP)
Novartis
Tobramycin
Aminoglycoside
Podhaler
112 mg (28
mg/capsule) 4
capsules twice daily
Improved lung function, well tolerated and safe,
prevention of exacerbations
CF
COPD
CB
VAP
CAYSTONE®
Aztreonam inhalation solution (AZLI)
Gilead Sciences Inc.
Aztreonam lysine
Monobactam
PARI eFlow
nebulization- Altera®
handset
75 mg thrice daily
Safe and efficacious in prevention of lung
exacerbations, no antibiotic resistance evident,
superior lung function improvement to TIS
CF
COLOMYCIN®
Forest Laboratories
Colistimethate sodium
Polymyxin
PARI eFlow®
nebulization
80-160 mg twice daily
Eradication of P.aeruginosa CF
PROMIXINE® (TADIM®)
Profile Pharma Ltd.
Colistimethate sodium
Polymyxin
I-neb® AAD®
Nebulization
80-160 mg twice daily
Eradication of P.aeruginosa CF
COLOBREATHE®
Forest Laboratories
Colistimethate sodium
Polymyxin
Turbospin inhaler
device-
125 mg twice daily
Safe, well tolerated, efficacy similar to TIS CF
NEBUPENT®
APP Pharmaceutical, LLC
Pentamidine isethionate
Antifungal
Respirgard® II
Nebulizer System
300 mg/4 weeks
Safer as compared to its parenteral form
Pentamidine 300 or PentacarinatPneumocystis carinii pneumonia
AEROQUIN™
Levofloxacin inhalation solution
(Aptalis Pharma, Inc/ Forest
laboratories)
Levofloxacin
Fluoroquinolone
PARI eFLOW®
nebulization
In study 3 dose levels-
120 mg or 240 mg
once daily or 240 mg
twice a day
Decrease in P.aeruginosa density, reduced need
for other anti-P.aeruginosa antibiotic, well
tolerated, broad spectrum activity
Similar efficacy to TOBI in CF patients from
Phase III clinical trial studies
CF
COPD
Merchant et. al, Current Pharmaceutical Design, 2016
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UCL SCHOOL OF PHARMACY
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Anti-infective aerosol formulations in clinical
trials
FORMULATION NAME ANTIMICROBIALDEVICE AND
DOSEADVANTAGES INDICATIONS
ARIKAYCE™
Liposomal amikacin for
inhalation
Insmed Inc.
(Phase III clinical trials)
Amikacin
aminoglycoside
PARI eFLOW®
nebulization
560 mg once
daily
Sustained release of Amikacin,
well tolerable, reduction in
P.aeruginosa density
CF
Non-tuberculous
mycobacterial infections
ABELCET® (Aerosolized
Abelcet®)
Amphotericin B lipid
complex for nebulization
(Phase II clinical trials)
Amphotericin B
Antifungal
50 mg
nebulized once
daily for four
days
Reduction in parenteral side
effects of Abelcet® viz. nausea,
vomiting, disseminated fusariosis
and withdrawal
Invasive fungal infections
in pediatric patients with
acute leukemia
CIPROINHALE
Ciprofloxacin
PulmoSphere™ inhalation
powder (CPIP)
Bayer HeathCare
(Phase III clinical trials)
Ciprofloxacin
Fluoroquinolone
Powder
Inhalation
In study at 2
dose levels-
32.5 mg or
48.75 mg twice
daily
High concentration in the lungs,
decrease in P.aeruginosa density
CF
COPD
Non-CF bronchiectasis
Merchant et. al, Current Pharmaceutical Design, 2016
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Why inhalation
• Non-invasive delivery of drugs
• Avoid first pass metabolism and distribution problems
• Direct delivery to site
• Reduction in drug dosage and frequency
• Rapid onset of action
• Huge surface area for quick local action
• Local as well as systemic administration eg: Exubera®
pMDI Nebulizers DPIs
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Traditional technique of micronization with
inhale lactose• Drugs normally micronized with carriers like inhale lactose, however,
amount which reaches the peripheral lung is low around 20-30%
• An increase in deposition
of powder from stage 1 to
8 with increased lactose
addition
• However, dosage
reduction
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. Pathway of the inhaled antibiotic after deposition on the mucus layer.After depositing in the airways, the aerosol particle needs to
dissolve in the airway surface layer or mucus layer. Next, the antibiotic needs to diffuse to the site where the bacter...
Aukje C. Bos, Kimberly M. Passé, Johan W. Mouton, Hettie M. Janssens, Harm A.W.M. Tiddens
The fate of inhaled antibiotics after deposition in cystic fibrosis: How to get drug to the bug? ☆
Journal of Cystic Fibrosis, 2016, Available online 26 October 2016
http://dx.doi.org/10.1016/j.jcf.2016.10.001
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Dry Powder Inhalation Formulations
Carrier
Drug
Mixing & De-mixing Uniformity
Drug – Carrier
interaction
(adhesive)
Drug – Drug
interaction
(cohesive)
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Engineering dry powder particles
• Pollens associated with pollen asthma, allergic rhinitis etc.
• Easily inhalable due to small size and low density
• Aerodynamic diameter 1-5µ-> hence reaches terminal
bronchi
SEM micrographs of pollen grains
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CHITOSAN
CHITOSAN
Mucoadhesive
Biodegradable
Biocompatible
Increasedrug
bioavailablity
Hydrophilic
Cationic
Antibacterialeffect
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CHITOSAN DERIVATIVESHighly functionalized groups on backbone help to synthesize
derivatives having various properties viz.
Anti-bacterial properties
Controlled/ sustained release
Mucoadhesive or mucolytic properties
Cationic charge
Self-assembling micellization
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Synthesis of Chitosan Derivative- Organic solvent soluble (Highly hydrophobic)
Scheme for synthesis of HCD
Solubility Study Degree of Substitution (DS) by TNBS Assay
Structural analysis of HCD
FTIR
NMR
DSC
XRD
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Synthesis of Chitosan Derivative
Solubility of Chitosan and HCD
NMR spetra of HCD
FTIR Spectra of – a) Chitosan; and b) HCD
NMR spetra of – Chitosan
Hydrophobic Chitosan Derivative (HCD) 18
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Preparation of rifampicin inhalable
powders
• Hydrophobic octanoyl
chitosan (OC) synthesized
• Rifampicin loaded into the
OC nanoparticles via
double emulsion technique
• Nanoparticles formed were
spray-dried to obtain dry
powdersNano spray-dryer B-90
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Engineering particle morphology
• SEM and TEM micrographs Corrugated particle
surface for lower
density and better
aerodynamic
performance
All particles within
respirable range of 1-
5 microns
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Engineering particle morphology
• SEM and TEM micrographs of low degree hydrophobic OC nanoparticles
encapsulating rifampicin:
Low density porous nanoparticles encapsulating rifampicin for better aerodynamic
performance
All particles within the respirable range of 1-5 microns
Uniform spherical micelles around 30nm in size on re-dispersion
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In-vitro aerodynamic deposition studies-
Next generation impactor
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Aerodynamic behaviour
Fine particle fraction (FPF)
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European Journal of Pharmaceutics and Biopharmaceutics xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
European Journal of Pharmaceutics
and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb
Research paper
Engineering hydrophobically modified chitosan for enhancing the dispersion
of respirable microparticles of levofloxacin
Zahra Merchant a, Kevin M.G. Taylor a, Paul Stapleton a, Sana A. Razak a, Nitesh Kunda b, Iman
Alfagih b,c, Khalid Sheikh a, Imran Y. Saleem b, Satyanarayana Somavarapu a,⇑a University College London School of Pharmacy, London, United Kingdom b School of Pharmacy & Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom c Department of Pharmaceutics, King Saud University, Riyadh, Saudi Arabia
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Antibiotics given locally as dry powder inhalation
(clinical trials)
iSPERSE® inhaled dry powder technology-Pulmatrix Inc.•Levofloxacin inhalation powder
•Phase Ib clinical study-results published May 5, 2014
•Respirable fractions of 55% over wide inspiratory flow rate
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Preparation of levofloxacin inhalable
powders
Nano spray-dryer B-90
• Amphiphilic octanoyl chitosan
(OC) synthesized
• Levofloxacin loaded into the
self-assembled OC micelles
• Nanomicelles formed were
spray-dried from organic solvent
to obtain powders
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Toxicity studies- MTT assay
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MINIMUM INHIBITORY CONCENTRATION
P.A. Pseudomonas aeruginosa
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Engineering particle morphology
• SEM micrographs
Corrugated particle surface for lower density and better aerodynamic
performance
All particles within respirable range of 1-5 microns
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Engineering particle size
Sympatec
Non spray-dried
outside respirable
range (µm)
Spray-dried within
respirable range (µm)
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In-vitro aerodynamic deposition studies-
Next generation impactor
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Key findings
• Successfully modified chitosan by addition of Octanoyl
groups
• Prepared respirable dry powders using nano spray-dryer
B-90; high yields
• Amount of excipients is low hence high amount of drug
can be delivered
• Low density surface corrugated particles, size 1-5µm
• Hydrophobically modified chitosan increases FPF and
hence potential deposition in peripheral respiratory tract.
• Synthesized polymer and formulations showed evidence of
no toxicty on A549 cell line
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Marketed amphotericin formulations
1. FUNGIZONE® - Amphotericin B deoxycholate-1 mg/kg
2. ABELCET® -Amphotericin B Lipid Complex-5 mg/kg
3. AMPHOTEC®- Amphotericin B Sodium cholestryl sulphate complex-
3 to 4 mg/kg
4.AMBISOME®-Amphotericin B Liposomal- 5 mg/kg
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Pulmonary fungal infections
• High mortality
• Toxicity
• Organ implantation, chemotherapy
• Route of administration
• Recently FDA granted orphan drug designation to
Nektar's amphotericin B inhalation powder
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•JPP 2010, 62: 821–828 •© 2010 The Authors
•Journal compilation © 2010
Royal Pharmaceutical
Society of Great Britain
•Received November 13,
2009 Accepted March 4,
2010
•DOI
10.1211/jpp.62.07.0002
ISSN 0022-3573
•Research Paper
•Chitosan-coated antifungal formulations for nebulisation
•Yacoub Y. Albasarah, Satyanarayana Somavarapu, Paul
Stapleton and Kevin M.G. Taylor
•Department of Pharmaceutics, School of Pharmacy, University of London, London, UK
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Proliposomes
Sucrose carrier
Phospholipid coating
Ethanolic solution of
phospholipid
Water
Sucrose/NaCl
solution
Isotonic liposome
preparation
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Novel Soluplus ®- Itraconazole dry powder formulations for lung delivery
Merchant et al conference abstract 2014
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METHOD
Hydrophilic residue
Hydrophobic residuesSOLUPLUS®
ITZ
Soluplus® nanoparticlesencapsulating ITZ
• Soluplus® nanoparticles containing varying ratios of hydrophobic drug wasprepared by thin film evaporation technique
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PREPARATION OF DRY POWDERS
Spray-drying Büchi B-290
Dry powder microparticles
Soluplus® nanocarriers
• These nanocarriers encapsulating ITZ were spray-dried to produce drypowder microparticles suitable for inhalation
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SURFACE MORPHOLOGY: ELECTRON MICROSCOPY:
•
TEM images of ITZ loaded Soluplus® nanocarriersSEM micrographs of nanocarriers spray-dried to form dry powder microparticles
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E) IN-VITRO ANTI-MICROBIAL TEST- Minimum inhibitory concentration
• The minimum inhibitory conc (MIC) assay performed on Candida sppdemonstrated no significant change in inhibitory concentration of ITZ onencapsulation in Soluplus® nanoparticles
FORMULTION MINIMUM INHIBITORY CONCENTRATION (µg/ml)
Candida albicans Candida tropicalis
24 hrs 48 hrs 24 hrs 48 hrs
ITZ 2 2 4 4
Soluplus >64 >64 >64 >64
Soluplus® : ITZ (1:100) nanoparticles
2 2 4 4
Soluplus® : ITZ (1:100) microparticles
2 2 4 4
Table 2: MIC of raw materials and formulation (n=3)
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To enhance the solubility of Amphotericin B using
Compound X
Design and develop Amphotericin B dry powder
formulations for treatment of pulmonary fungal infections
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Images of SOLUBILIZATION of AmpB in distilled water when co-grounded with Compound X
SOLUBILITY TESTS OF AMPHOTERICIN B
Compound X is a GRAS approved excipient
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SURFACE MORPHOLOGY- SEM
Compound X Co-grounded AmpB:compound X
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Spray-dried AmpB:compound X Spray-driedAmpB:compound X:Lactose
Spray-dried
AmpB:compound X:L-leucine
SURFACE MORPHOLOGY- SEM
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IN-VITRO AERODYNAMIC DEPOSITION
-1
0
1
2
3
4
5
6
7
CO
ncen
trati
on
(m
g)
Stages
CG AMPB:compound X SD AmpB:compound X SD AmpB:compound X:LEU SD AmpB:compound X:LAC
16.95% 37.85 % 56.75% 42.23%
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Conclusions:• The inhalation route is an attractive way to
deliver drugs directly to the affected site in the lungs,
reducing drug dosage (eg: antibiotics)
reducing drug resistance,
reducing systemic drug toxicity (eg: Nephrotoxicity of AmpB and
Rifampicin)
reducing drug metabolism and hence inactivation (eg;Isoniazid)
consequently improving efficacy of the drug
• Nanomedicine is an attractive tool to encapsulate drugs within carriershelp in improving dispersion on inhalation
protect drug from inactivating enzymes in the lungs (eg:
antibiotics)
reduce drug toxicity,
targeting strategies
possibility of reduction of dosing frequency by formulating
controlled release nanoparticles/liposomes (eg: Arykace®)
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Local delivery to the lungs
Delivery to the brain through
the lungs
Eg: Levodopa for Parkinson’s
Systemic delivery through
the lungs
Eg: Exubera®infections
cancerfibrosis
Nanomedicine
Inhalation
Hand in hand
Polymer science
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Acknowledgments• AstraZeneca Common wealth association DBT
India
• Professor Kevin Taylor
• Dr Paul Stapleton
• Dr. Saleem Imran
• Dr. Ketan Sharma
• Dr Kailash Petkar
• Zahra Merchant