e-cigarettes: lessons for inhalation technologists

e-cigarettes:Whatcaninhalationtechnologists

learnfromthem?PhilippeRogueda- 7July2016

@3iseminarChiesi

IncollaborationwithDr. PhilipChiLipKwokandMs.LuHouTheUniversityofHongKong

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Contentoutline

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e-cigs:thecontext

e-liquids

Devices

Performance

Whatcanwelearn?


e-cigs:acontext

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Theglobale-cigarettemarketisexpectedtogrowover$50billionby2025,atanestimatedCAGRof22.36%from2015to2025.Themarketwillwitnessastaggeringgrowthuntil2017,bywhenmostoftheregulatoryandpolicyframeworkwillfallintoplace.Thegrowthratewillsignificantly increasethereafter,withsignificant revenuegenerationfromevolvingmarketsofAPACandEurope.(http://www.prnewswire.com/news-releases/global-e-cigarette--vaporizer-market-2015-2025---analysis--forecasts-for-the-50-billion-industry-300124050.html)

Agrowingmarketthatischangingbecauseofnewregulations.

e-liquidsanddevicesaremostlyunregulatedanduntil recentlydidnotneedtofollowanyregulations.

Somecountrieshavebannede-cigarettes:Singapore.Otherswouldliketo:HongKong.


e-cigs:acontext

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9March2016- https://www.statista.com/chart/4475/the-state-of-e-cigarette-consumption-in-britain/


e-cigs:acontext

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45MsmokersintheUS.2,75Millione-cigarettessmokers.

29%ofpeopleoftrye-cigarettesquitsmokingafter6months.

Year e-cigsannualsalesUS$

2015 2,875,000,000

2014 1,700,00,000

2013 1,000,000

2012 500,000,000

2011 195,000,000

2010 82,000,000

2009 39,000,000

2008 20,000,000

USA– 2014- http://www.statisticbrain.com/electronic-cigarette-statistics/


e-cigs:acontext

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“OutofJuice:Salesofe-cigarettedeviceslikecigarettesdownconsiderablyin2015”17Nov2015– WallStreetJournalhttp://www.wsj.com/articles/e-cig-sales-rapidly-lose-steam-1447798921


e-cigs:acontext

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NewregulationfromtheFDA,5May2016.

http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm499234.htm

Theserequirements include:

-Registeringmanufacturingestablishmentsandproviding product listingstotheFDA;

-Reportingingredients, andharmfulandpotentiallyharmfulconstituents;

-RequiringpremarketreviewandauthorizationofnewtobaccoproductsbytheFDA.


e-liquids

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e-liq

uids

Fromwww.e-liquidaustralia.com


e-liquids

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e-liq

uids

E-liquidscomposition: 5basicingredients

Glycerol+Propyleneglycol+Water+Nicotine+Flavourings

“Food-approvedsubstances”

Andahostofcontaminants-additives:nitrosamines (fromnicotine),aldehydes,solvents, colorings, andheavymetalscomingfromthedeviceortheingredients.

Phys.Chem.Properties:Glycerol:Bp 290oC(C3H8O3,MW92.09)Propyleneglycol:Bp 188oC(C3H8O2,MW76.09)Nicotine:Bp 247oC (C10148B2,MW162.23)

Glycerolandpropylene glycolareusedinartificialtheatricalsmokeandasadditivesintobaccocigarettes.


e-liquids

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e-liq

uids

Onenametoremember:KonstantinosFarsalinos.

Thetoxicityofe-liquids seemstostemfromflavourings.

Propyleneglycolandglycerolarecurrentlynotareasonforconcern,although theirlong termeffectsonthelungshavenotbeenstudied.

Nicotineine-cigsisnotareasonforconcern,expectthattheircontentisnotalwaysfullycontrolled.

“Glycerinhasbeen identifiedasanaturalcomponentoforientaltobacco(0.34–0.48%),flue-cured tobaccos(0.07–0.12%),andburley(0.23–0.31%)…Inthecigarette,glycerinhelps toretainmoistureandpreventsdryingoutofthetobacco.Glycerinistypicallyapplied totobaccoatlevelsof1–5%”.Toxicologicalevaluationofglycerinasacigaretteingredient.E.L.Carmines,C.L.Gaworski.FoodandChemicalToxicology43(2005)1521–1539.


Toxicityofe-liquids

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ance

Toxicityofe-liquidscanstemfrom:-thedegradationofglycerine andpropyleneglycol-solvents-heavymetals

….but mostlyfromflavourings.

Levelsofselectedcarcinogensandtoxicantsinvapour fromelectroniccigarettes.Maciej LukaszGoniewicz etal.Tobaco Control.TobControl doi:10.1136/tobaccocontrol-2012-050859.


Devices

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Dev

cies

2013BackgroundPaperonE-cigarettesElectronicNicotineDeliverySystems(https://escholarship.org/uc/item/13p2b72n#page-5)


Devices

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Dev

cies

Battery+Atomizer+Tank+Mouthpiece


Devices

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Dev

cies

Atypicalcigaretteburnsofftobaccoat~900oC.

Anelectroniccigaretteresistancewould typicallyreach200-400oC.

Devicesareveryunreliable.

Theaerosolisation mechanismofe-cigsismostlyunknown:evaporation/condensation? Buthow?Whatdropletsaregenerated?Deviceshavehigh resistance,howdoesthisaffectdeposition?

Dodevicesproducenano ormicroparticles?

Mostofthetestsoncigarettesande-cigsusefiltersoronly reportdatabelow1um,oftenbelow100nm.


Devices

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Dev

cies

Kimree,madeinChina:cartomizer

Cartomizer(wickbasedsystem):layersofgauzearewrappedaroundacentertubewithawickandaverticalheatingcoil.Thegauzesaturatesthewick,andtheheatingcoilvaporizestheliquid.


Devices

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Dev

cies


Performance

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Perf

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ance

Measurements:-TryingtobringPharm.Sci.methodsintotheworldofvaping.-SYMPATECInhaler&Helos.-flowrate:2L/min.-NoNGI/ACImeasurementatthisstage.

Liquids:-mixturesofwater,EtOH,glycerol,propyleneglycol.-nonicotine.-noflavouring.

Deviceused:commercialdevice:Kimree,singleuse.

#8 #14

water 14.33% 25%

EtOH 0.14% 25%

Glycerol 71.33% 25%

PropyleneGlycol 14.33% 25%


Performance

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Perf

orm

ance

Glycerine/propylene glycoldrivetheaerosolisation.Particlesareinthemicrometerrange.Ourresultsindicateminimalnanoparticles ...thequestion iswhy?


Performance

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Perf

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ance

Results:-testdonewithoutnicotine.-cannotvaporise purewater.-propyleneglygol andglycerincontrolthevapingprocess.-dropletsofglycerol/glycerinareintherespirablerange.-dropletsarelargerthanclaimbyBritishAmericanTobacco.

Discussion/questions:-whyarethedropletswemeasuresolarge?-whyareothertestsevidencingnanodroplets?-wherewouldthenicotinebefound? Asavapour? Inthedroplets?-isthislungdelivery?orsublingualdelivery?-whatistheroleofthenanodroplets inenhancingdelivery?-whatcanwedototranslatethevapingdevicesandtheuseofpropyleneglycolandglycerintoOINDPs?


Performance

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Perf

orm

ance

Dropletsizemeasurementofe-cigaretteaerosols.KevinMcAdam,RossCabot,JessicaHunt,CanerUYurten,JohnMcAughey.FirstGlobalForumOnNicotine,Warsaw,Poland:27-28June2014

Influentialparametersonparticleconcentrationandsizedistribution inthemainstreamofe-cigarettes.F.C.Fuoco,G.Buonanno, L.Stabile,P.Vigo.EnvironmentalPollution 184(2014)523e529.

E-cigsvs.traditionalcigarettes:nomicro-droplets!...why?


Performance

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Perf

orm

ance

Nanoparticlesincigarettesmoke;real-timeundilutedmeasurementsbyascanningmobilityparticlesizer.WouterD.vanDijk &SimoneGopal&PaulT.J.Scheepers.AnalBioanal Chem(2011)399:3573–3578.

E-cigsvs.traditionalcigarettes:whathappensabove100nm?Traditionalcigarettesarefiltered.Aremeasurementsmethodscorrect?


Performance

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Perf

orm

ance Comparison ofthe

aerosolproducedbyelectroniccigaretteswithconventionalcigarettesandtheshisha.J.-F.Bertholona,M.H.Becquemina,M.Roya,F.Royd,D.Ledure,I.Annesi Maesanof,B.Dautzenberg.RevuedesMaladiesRespiratoires(2013)30,752—757

E-cigsvs.cigarettes.:nomicrodroplets.

Wasafilterusedwiththee-cigs?…orarethemethodspredictiveof theresults?(i.e.onecanonlyfindwhatoneislooking for).


Performance

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Perf

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ance

Evaporationandcondensation ofmulticomponent electronicCigarettedropletsandconventional cigarettesmokeparticlesinanidealizedG3–G6triplebifurcatingunit.Y.Feng,C.Kleinstreuer,A.Rostami.Journal ofAerosolScience80(2015)58–74

Onemodelseemstoindicatemicroparticles.Theoreticalstudiesofwater/glycerol/propyleneglycol/nicotinemixtures.


Performance

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Perf

orm

ance

Theaerosolcharacteristicsofcigarettesisusuallymeasuredin“density”oropticalparameters,appropriateforasmoke/gascloud,butnotmuchusefore-cigsthataredroplets.

Thefewparticle/dropletdiameteranalysisfromtheliteratureindicatenanoparticles.Wedonotseethese.

Thereisamethod issue:thevaping/tobaccoindustryusesinstruments fitfordroplets<1um,weuseawiderrange.Theyusefiltersoncigarettes,wedon’t.

Thevaping industry isinterestedincomparing theirproducts tocigarettes,isthisskewingtheresults?

Knowing thecorrectparticlesizeandaerosolisation mechanism isimportant tounderstand theriskandbenefitsofe-cigsasadeliverysystems.


Nicotinedelivery

27

Perf

orm

ance

e-cigsdonotdeliverhigherdosesofnicotine

Nicotineabsorption fromelectroniccigaretteuse:comparisonbetweenfirstandnew-generationdevices.Konstantinos E.Farsalinos etal.SciRep.2014;4:4133.


Whatcanwelearn?

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E-cigarettesdevelopersareaheadofpharmaceuticalscientistsinformulating withnewexcipients.Vapingdevicesoffernewdeliverytechnology.Thelargescaleuseofpropyleneglycolandglycerine opensnewformulation horizons.Theiruseshouldbemonitored: thisisaworldwiderealscaleinvivoclinical/epidemiology study.Arewewitnessingnanodroplet lungdelivery?

Theperformanceandreliabilityofe-cigarettesispoor ifnotrandom.Theaerosolisation mechanismisnotunderstood.Morelikelytobeevaporation/condensation driven.Sub-lingualorlungdelivery?: thatisamootpoint.Flavouring canonlybefeltinthemouthorsmeltviathenose,isthatduetolargedroplets?Nicotineabsorption canbeeffectiveviathemouthorviathelungs.

Clinicalefficacyisanecdotalbutcouldbereal.e-cigshaveabettersafetyprofile thancigarettes,butmaybeequallyaddictiveandbring innewdegradationproducts.

Merxin is a generic inhaler device supplier that supplies off-the-shelf generic devices to accelerate and reduce the cost of the development inhaled products.

MRX001 a generic version of Diskus® is its leading product.

Merxin Ltd was incorporated in the UK in January 2016.

Merxin is currently raising funds and clients’ interest.

Philippe Rogueda is a co-founder and director of Merxin Ltd.

MerxinLtd

Generic Medical Devices Made Easy

www.merxin.com

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