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

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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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.


Polymyxin

I-neb® AAD®

Nebulization

80-160 mg twice daily

Eradication of P.aeruginosa CF

COLOBREATHE®

Forest Laboratories


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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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

ABELCETÂ® (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

. 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

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

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

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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• 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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• 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

Proliposomes

Sucrose carrier

Phospholipid coating

Ethanolic solution of

phospholipid

Water

Sucrose/NaCl

solution

Isotonic liposome

preparation

Novel Soluplus ®- Itraconazole dry powder formulations for lung delivery

Merchant et al conference abstract 2014

METHOD

Hydrophilic residue

Hydrophobic residuesSOLUPLUS®

ITZ

Soluplus® nanoparticlesencapsulating ITZ

• Soluplus® nanoparticles containing varying ratios of hydrophobic drug wasprepared by thin film evaporation technique

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

SURFACE MORPHOLOGY: ELECTRON MICROSCOPY:

•

TEM images of ITZ loaded Soluplus® nanocarriersSEM micrographs of nanocarriers spray-dried to form dry powder microparticles

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

Spray Drying of Therapeutics: Influence of Excipients · 2017. 10. 9. · In study 3 dose...

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