The SimInhale International ConferenceCurrent Challenges and Future Opportunities for

Inhalation Therapies. A cross-disciplinary perspective

Athens, 30 September – 2 October 2019

WG1 PresentationParticle engineering/processing

of inhaled medicines for local/systemic action

Alessandra RossiFood and Drug DepartmentUniversity of Parma, Italy

✦ address a range of fundamental knowledge gaps whose closing is aprerequisite to improving many other aspects of pulmonary delivery ofmedicine

Optimal deposition sites

Effects of lung disease on deposition, dissolution and absorption

Aim

Effects of airway geometry

Systemic therapies

✦ White paper on effects of lung disease on the deposition-dissolution-absorption pathway

WG1 Achievements

✦ White paper on airway geometry effects on deposition patterns

✦ Library of powders classified by the excipients used

✦ Training of ECIs and other interested scientists in emerging particle-engineering technologies

✦ White paper on Emerging inhaled nanomedicines and associatedexcipient technologies

From Particles to Powders for Inhalation

Particle engineering

Particle engineering

✦ Narrow particle size distribution

✦ Improved dispersibility

✦ Enhanced drug stability

✦ Optimized bioavailability

✦ Sustained release and/or specific targeting

✦ Specifics of inhaler design and drug delivery requirements

Particulate properties and their effects on respiratory drug delivery

Particle characteristics Effects on formulation

Temperature, pressure, solvents, pH, additives,yield, recovery, manufacturing complexity

Crystallinity, polymorphism, higroscopicity,impurities, solubility, dissolution rate

Particle size distribution, shape, porosity/density

Surface morphology, energetics and electrostaticPowder bulk density, agglomeration,cohesiveness, flow properties

Co-formulation/blending; composition/coating

Formulation, dispersion media

Process economics, development risks and costs

Physical and chemical stability, bioavailability,toxicity

Aerosolisation behaviour, in vitro and in vivodeposition profiles, bioavailability

Powder handling, inhaler filling, dose metering,storage stability, shelf-life, dose uniformity andconsistency

Dose uniformityModified or extended release, toxicity

Type of inhalerMode of administration

Rigid + PorousRigid + NonporousViscoelastic

Fractured

Shriveled

Rigid + Porous

Rigid + Nonporous

Major-

Minor Fractures

Viscoelastic + Nonporous

Inflated

Collapsed

Deformed

Spongy

gas temperaturebelow boiling point

gas temperatureabove boiling point

Spray-dried particles

Solvent power and volatility influence texture andsurface chemistry of spray-dried microparticles

Constant evaporation rate modelEvaporation rate constant (κ) = droplet surface areareduction in time

The Peclet number (Pe) can predict the particleformation process and the resulting particleproperties

Pe = k/8D

D is the diffusion coefficient.

Scanning Electron Microscopy

Tobramycin_raw materialTobramycin-Na Stearate 99:1

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Parlati et al.. Pharm Res 26 (2009) 1084-92

Tobramycin AerosolRespirability and Particle Dissolution

Energy Dispersive Spectroscopy-Scanning Electron Microscopy

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10152025303540

Ba… T… T0 T… T… T1 T… T2

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Parlati et al.. Pharm Res 26 (2009) 1084-92

Particle formation process

Spray dried amikacin powder for inhalation in cystic fibrosis patients: Aquality by design approach for product construction

Silvia Belotti a,1, Alessandra Rossi a,1, Paolo Colombo a, Ruggero Bettini a,Dimitrios Rekkas b, Stavros Politis b, Gaia Colombo c, Anna Giulia Balducci d,Francesca Buttini a,*aDepartment of Pharmacy, University of Parma, Viale delle Scienze 27/A, Parma 43124, Italyb School of Pharmacy, University of Athens, Panepistimiopolis Zografou, Athens 15771, GreececDepartment of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 17/19, Ferrara 44121, Italyd Interdepartmental Center, Biopharmanet-TEC, University of Parma, Viale delle Scienze 27/A, Parma 43124, Italy

A R T I C L E I N F O

Article history:Received 14 May 2014Accepted 28 May 2014Available online 2 June 2014

Keywords:Dry powder inhaler (DPI)AmikacinCystic fibrosisHalf-fractional factorial designOrally inhaled drug product (OIDP)

A B S T R A C T

An amikacin product for convenient and compliant inhalation in cystic fibrosis patients was constructedby spray-drying in order to produce powders of pure drug having high respirability and flowability.An experimental design was applied as a statistical tool for the characterization of amikacin spray dryingprocess, through the establishment of mathematical relationships between six Critical Quality Attributes(CQAs) of the finished product and five Critical Process Parameters (CPPs).The surface-active excipient, PEG-32 stearate, studied for particle engineering, in general did not benefitthe CQAs of the spray dried powders for inhalation. The spray drying feed solution required the inclusionof 10% (v/v) ethanol in order to reach the desired aerodynamic performance of powders. All desirablefunction solutions indicated that the favourable concentration of amikacin in the feed solution had to bekept at 1% w/v level. It was found that when the feed rate of the sprayed solution was raised, an increase inthe drying temperature to the maximum value (160 !C) was required to maintain good powderrespirability. Finally, the increase in drying temperature always led to an evident increase in emitted dose(ED) without affecting the desirable fine particle dose (FPD) values.The application of the experimental design enabled us to obtain amikacin powders with both ED and FPD,well above the regulatory and scientific references. The finished product contained only the activeingredient, which keeps low the mass to inhale for dose requirement.

ã 2014 Elsevier B.V. All rights reserved.

1. Introduction

Cystic fibrosis (CF) is an autosomal recessive genetic disease inCaucasians. Mutations in the gene cystic fibrosis transmembraneregulator (CFTR) led to a defective chloride ion transport in theairway lumen, causing an abnormal accumulation of viscousmucus. CFTR mutations are grouped into five classes scaled fromnot synthesized CFTR protein (class I) to partly defective proteinproduction or processing (class V) (Amaral and Kunzelmann,

2007). The most common are the class II mutations (including theprevalent, F508del), which affect about 90% of CF patients. In thisclass, the misfolded protein is retained at the endoplasmicreticulum, and subsequently degraded in the proteasome, (Ratjenand Döring, 2002; Coffey and Ooi, 2012).

Cystic fibrosis in the lungs often gives rise to chronicpulmonary infections. Bacteria entering the lung and trappedin the mucus layer are difficult to remove through mucociliaryclearance. The therapy of CF infections consists of antibioticsadministered orally or intravenously (aminoglycosides, macro-lides). As the lung is the site of action, inhaled medications areadvantageously prescribed (Heijerman et al., 2009; Bruce et al.,2011; Balducci et al., 2014; Colombo et al., 2013). Thisadministration route concentrates the drug at the site ofinfection, limiting systemic exposure and side effects. However,substantial differences in inhalation administration techniquesexist. For instance, nebulizers, mostly used in hospitals and

Abbreviations: AMK, Amikacin; DPI, Dry Powder Inhaler; QbD, Quality byDesign; DoE, Design of Experiments; CQAs, Critical Quality Attributes; CPPs, CriticalProcess Parameters; LOD, Loss on Drying; ED, Emitted Dose; FPD, Fine Particle Dose.* Corresponding author. Tel.: +39 0521 906008; fax: +39 0521 905006.E-mail address: francesca.buttini@unipr.it (F. Buttini).

1 Equal contribution to the paper.

http://dx.doi.org/10.1016/j.ijpharm.2014.05.0550378-5173/ã 2014 Elsevier B.V. All rights reserved.

International Journal of Pharmaceutics 471 (2014) 507–515

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsev ier .com/locate / i jpharm

CQAs Range Values Negatively affected by Positively affected by

SD yield (%) 67 - 88 Waxy excipient High solid concentration

LOD (%) 7.6 - 9.7 Waxy excipient Drying temperature

Dv(0.5) (µm) 1.88 - 3.52 - High solid concentrationFeed rate

Bulk Density Agglomeration had a positive effect

Waxy excipientHigh solid concentration

Feed rate

Drying TemperatureEthanol (%)

ED (mg) 5.7 – 9.2 Waxy excipientFeed rate

Interaction between excipient and solid conc

FPD (mg) 3.5 – 6.1 Waxy excipient Interaction between excipient and ethanol

Half fractional factorial design (2 n-1)• Factor 1: Drying temp• Factor 2: Feed rate• Factor 3: Ethanol %• Factor 4: PEG_32 stearate %• Factor 5: Solid Conc16 experiments

Results

• Feed solution required theinclusion of 10% (v/v) ethanol

• Amikacin in the feed solution hadto be kept at 1% w/v level

• Increase in drying temperaturealways led to an evident increasein emitted dose (ED) withoutaffecting the fine particle dose(FPD) values.

• PEG-32 stearate did not benefitthe CQAs of the spray driedpowders Without excipient

With PEG32_Sterate

Belotti, S., et al. 2014. Int J Pharm 471, 507–515.

Research Paper

Spray-dried amikacin sulphate powder for inhalation in cystic fibrosispatients: The role of ethanol in particle formation

Silvia Belotti a, Alessandra Rossi a, Paolo Colombo a, Ruggero Bettini a, Dimitrios Rekkas b, Stavros Politis b,Gaia Colombo c, Anna Giulia Balducci d, Francesca Buttini a,e,⇑a Department of Pharmacy, University of Parma, Viale delle Scienze 27/A, Parma 43124, Italyb School of Pharmacy, University of Athens, Panepistimiopolis Zografou, Athens 15771, Greecec Department of Life Sciences and Biotechnology, University of Ferrara, via Fossato di Mortara 17/19, Ferrara 44121, Italyd Interdepartmental Center, Biopharmanet-TEC, University of Parma, Viale delle Scienze 27/A, Parma 43124, Italye Institute of Pharmaceutical Science, King’s College London, 150 Stamford Street, SE19NH London, United Kingdom

a r t i c l e i n f o

Article history:Received 26 January 2015Revised 18 March 2015Accepted in revised form 19 March 2015Available online 4 April 2015

Chemical compound studied in this article:Amikacin sulphate (PubChem CID:45357036)

Keywords:Amikacin sulphateDry powder inhalerPeclet numberMicroparticlesCystic fibrosis

a b s t r a c t

A Central Composite Design (CCD) was applied in order to identify positive combinations of the produc-tion parameters of amikacin sulphate spray-dried powders for inhalation, with the intent to expand theexperimental space defined in a previous half-fractional factorial design. Three factors, namely dryingtemperature, feed rate and ethanol proportion, have been selected out of the initial five. In addition,the levels of these factors were increased from two to three and their effect on amikacin respirabilitywas evaluated. In particular, focus was given on the role of ethanol presence on the formation of themicroparticles for inhalation.

The overall outcome of the CCD was that amikacin respirability was not substantially improved, as theoptimum region coincided with areas already explored with the fractional factorial design. However,expanding the design space towards smaller ethanol levels, including its complete absence, revealedthe crucial role of this solvent on the morphology of the produced particles. Peclet number and drug solu-bility in the spraying solution helped to understand the formation mechanism of these amikacin sulphatespray-dried particles.

! 2015 Elsevier B.V. All rights reserved.

1. Introduction

Lung infections in Cystic Fibrosis (CF) patients caused byPseudomonas aeruginosa are efficiently managed with antibacterialdrugs. These treatments require high doses of antibiotics. However,using the pulmonary route, the inhaled drug is directly depositedon the site of infection providing higher local concentrations withlower doses compared to systemic administration. Dry powderinhalers are able to deliver high payloads of drug in a shorter time,offering a convenient alternative to solutions for nebulization [1].However, high doses of powders can raise adverse effects during

the administration, such as cough and choking. Consequently,there are two approved administration strategies for deliveringhigh doses of powdered drugs to the lung of the patients [2]. Thefirst used a single pre-metered capsule reservoir containing thewhole dose to be extracted by successive inhalation acts, such aswith the Colobreathe" product [3]. The second strategy consistedin splitting the dose in multiple capsule reservoirs. In TOBI"-Podhaler, the dry powder of tobramycin formulation (112 mg dis-persed in approximately 200 mg of powder) is administered by theconsecutive inhalation of four capsules content. An evolution ofthese delivery systems is the use of new disposable devices, cap-able to gradually release the dose loaded in the device reservoirin alternative to hard capsules [4,5].

The performance of a dry powder inhaler is governed byformulation characteristics. Particle engineering strategies havebeen adopted to optimize size, morphology and structure of micro-particles, in order to maximize the respirable fraction of the drug,without compromising the powder flow properties [6,7]. Since the

http://dx.doi.org/10.1016/j.ejpb.2015.03.0230939-6411/! 2015 Elsevier B.V. All rights reserved.

Abbreviations: CCD, Central Composite Design; CF, cystic fibrosis; CQAs, CriticalQuality Attributes; CPPs, Critical Process Parameters; DoE, Design of Experiments;ED, Emitted Dose; FPD, Fine Particle Dose.⇑ Corresponding author at: Department of Pharmacy, University of Parma, Viale

delle Scienze 27/A, Parma 43124, Italy. Tel.: +39 0521 906008; fax: +39 0521905006.

E-mail address: francesca.buttini@unipr.it (F. Buttini).

European Journal of Pharmaceutics and Biopharmaceutics 93 (2015) 165–172

Contents lists available at ScienceDirect

European Journal of Pharmaceutics and Biopharmaceutics

journal homepage: www.elsevier .com/locate /e jpb

Central Composite Design• Drying temperature: 150°C,

165°C, 180°C• Feed rate: 2 ml/min, 3.5 ml/min, 5

ml/min• Ethanol presence. 0%, 5%, 10%15 experiments

Fine Particle DoseEmitted Dose

Amikacin from waterAmikacin from waterAmikacin from water:ethanol

Solvent power and volatility influence texture and surface chemistry of spray-dried microparticles

Pe = K8D

The Peclet number (Pe) can predict the particle formation process and the resulting particle properties

Evaporation rate constant, k = droplet surface area reductionin time (cm2/s)D is the diffusion coefficient of dissolved substance in thesprayed solution

Pe ≤ 1 Pe > 1

Dense particle Empty shell particle

Droplet Water/EtOH mixtures

Water

Vehring. Pharm Res (2008) 25:999–1022Belotti, et al. Eur J Pharm Biopharm (2015) 93:165-172

Aknowledgements

Prof. Paolo ColomboProf. Francesca Buttini

Prof. Dimitriis M. RekkasProf. Jelena DurisProf. Sandra Cvijic

Jelisaveta IgnjatovicGreta AdorniSilvia Belotti

Georgia ZaromytidouAgnese Montepietra

Chiara Lombardi

Prof. Stavros KassinosMr. Toumazis Toumazi

Prof. Elias Fattal