e-Cigarettes: lessons for Inhalation technologists

e-cigarettes:
What can inhalation technologists
learn from them?
Philippe Rogueda - 7 July 2016
@ 3i seminar Chiesi
In collaboration with Dr. Philip Chi Lip Kwok and Ms. Lu Hou
The University of Hong Kong
1© Copyright Aedestra Ltd 2016. All rights reserved.
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© Copyright Aedestra Ltd 2016. All rights reserved.
2

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3

Content outline
4
e-cigs: the context
e-liquids
Devices
Performance
What can we learn?

e-cigs: a context
5
e-cigscontext
The global e-cigarette market is expected to grow over $50 billion by
2025, at an estimated CAGR of 22.36% from 2015 to 2025. The market
will witness a staggering growth until 2017, by when most of the
regulatory and policy framework will fall into place. The growth rate will
significantly increase thereafter, with significant revenue generation from
evolving markets of APAC and Europe.
(http://www.prnewswire.com/news-releases/global-e-cigarette--vaporizer-market-2015-2025---analysis--forecasts-for-
the-50-billion-industry-300124050.html)
A growing market that is changing because of new regulations.
e-liquids and devices are mostly unregulated and until recently did not
need to follow any regulations.
Some countries have banned e-cigarettes: Singapore. Others would like
to: Hong Kong.

e-cigs: a context
6
e-cigscontext
9 March 2016 - https://www.statista.com/chart/4475/the-state-of-e-cigarette-consumption-
in-britain/

e-cigs: a context
7
e-cigscontext
45 M smokers in the US. 2,75 Million e-cigarettes smokers.
29% of people of try e-cigarettes quit smoking after 6 months.
Year e-cigs
annual sales US $
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: a context
8
e-cigscontext
“Out of Juice: Sales of e-cigarette devices like cigarettes down
considerably in 2015”
17 Nov 2015 – Wall Street Journal
http://www.wsj.com/articles/e-cig-sales-rapidly-lose-steam-1447798921

e-cigs: a context
9
e-cigscontext
New regulation from the FDA, 5 May 2016.
http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm4
99234.htm
These requirements include:
-Registering manufacturing establishments and providing product listings to
the FDA;
-Reporting ingredients, and harmful and potentially harmful constituents;
-Requiring premarket review and authorization of new tobacco products by
the FDA.

e-liquids
10
e-liquids
From www.e-liquidaustralia.com

e-liquids
11
e-liquids
E-liquids composition: 5 basic ingredients
Glycerol + Propylene glycol + Water + Nicotine + Flavourings
“Food-approved substances”
And a host of contaminants-additives: nitrosamines (from nicotine),
aldehydes, solvents, colorings, and heavy metals coming from the device
or the ingredients.
Phys. Chem. Properties:
Glycerol: Bp 290oC (C3H8O3, MW 92.09)
Propylene glycol: Bp 188oC (C3H8O2, MW 76.09)
Nicotine: Bp 247oC (C10148B2, MW 162.23)
Glycerol and propylene glycol are used in artificial theatrical smoke and
as additives in tobacco cigarettes.

e-liquids
12
e-liquids
One name to remember: Konstantinos Farsalinos.
The toxicity of e-liquids seems to stem from flavourings.
Propylene glycol and glycerol are currently not a reason for concern,
although their long term effects on the lungs have not been studied.
Nicotine in e-cigs is not a reason for concern, expect that their content is
not always fully controlled.
“Glycerin has been identified as a natural component of oriental tobacco
(0.34–0.48%), flue-cured tobaccos (0.07–0.12%), and burley (0.23–
0.31%) … In the cigarette, glycerin helps to retain moisture and prevents
drying out of the tobacco. Glycerin is typically applied to tobacco at levels
of 1–5%”. Toxicological evaluation of glycerin as a cigarette ingredient.
E.L. Carmines, C.L. Gaworski. Food and Chemical Toxicology 43 (2005)
1521–1539.

Toxicity of e-liquids
13
Performance
Toxicity of e-liquids can stem from:
-the degradation of glycerine and propylene glycol
-solvents
-heavy metals
…. but mostly from flavourings.
Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. MaciejLukasz
Goniewicz et al. Tobaco Control. TobControl doi:10.1136/tobaccocontrol-2012-050859.

Devices
14
Devcies
2013 Background Paper on E-cigarettes Electronic Nicotine Delivery
Systems (https://escholarship.org/uc/item/13p2b72n#page-5)

Devices
15
Devcies
Battery + Atomizer + Tank + Mouthpiece

Devices
16
Devcies
A typical cigarette burns off tobacco at ~900oC.
An electronic cigarette resistance would typically reach 200-400oC.
Devices are very unreliable.
The aerosolisation mechanism of e-cigs is mostly unknown:
evaporation/condensation? But how? What droplets are generated?
Devices have high resistance, how does this affect deposition?
Do devices produce nano or micro particles?
Most of the tests on cigarettes and e-cigs use filters or only report data
below 1 um, often below 100 nm.

Devices
17
Devcies
Kimree, made in China: cartomizer
Cartomizer (wick based system): layers of gauze are wrapped around a
center tube with a wick and a vertical heating coil. The gauze saturates the
wick, and the heating coil vaporizes the liquid.

Devices
18
Devcies

Performance
19
Performance
Measurements:
-Trying to bring Pharm. Sci. methods into the world of vaping.
-SYMPATEC Inhaler & Helos.
-flow rate: 2 L/min.
-No NGI/ACI measurement at this stage.
Liquids:
-mixtures of water, EtOH, glycerol, propylene glycol.
-no nicotine.
-no flavouring.
Device used: commercial device: Kimree, single use.
#8 #14
water 14.33 % 25 %
EtOH 0.14 % 25 %
Glycerol 71.33 % 25 %
Propylene Glycol 14.33 % 25 %

Performance
20
Performance
Glycerine/propylene glycol drive the aerosolisation.
Particles are in the micrometer range.
Our results indicate minimal nanoparticles ... the question is why?

Performance
21
Performance
Results:
-test done without nicotine.
-cannot vaporise pure water.
-propylene glygol and glycerin control the vaping process.
-droplets of glycerol/glycerin are in the respirable range.
-droplets are larger than claim by British American Tobacco.
Discussion/questions:
-why are the droplets we measure so large?
-why are other tests evidencing nanodroplets?
-where would the nicotine be found? As a vapour? In the
droplets?
-is this lung delivery? or sublingual delivery?
-what is the role of the nanodroplets in enhancing delivery?
-what can we do to translate the vaping devices and the use of
propylene glycol and glycerin to OINDPs?

Performance
22
Performance
Droplet size measurement of
e-cigarette aerosols. Kevin
McAdam, Ross Cabot, Jessica
Hunt, Caner U Yurten, John
McAughey. First Global
Forum On Nicotine, Warsaw,
Poland: 27-28 June 2014
Influential parameters on
particle concentration and
size distribution in the
mainstream of e-
cigarettes. F.C. Fuoco, G.
Buonanno, L. Stabile, P.
Vigo. Environmental
Pollution 184 (2014)
523e529.
E-cigs vs. traditional cigarettes: no micro-droplets!...why ?

Performance
23
Performance
Nanoparticles in
cigarette smoke; real-
time undiluted
measurements by a
scanning mobility
particle sizer. Wouter
D. van Dijk & Simone
Gopal & Paul T. J.
Scheepers. Anal
Bioanal Chem (2011)
399:3573–3578.
E-cigs vs. traditional cigarettes: what happens above 100 nm?
Traditional cigarettes are filtered. Are measurements methods correct?

Performance
24
Performance
Comparison of the
aerosol produced by
electronic cigarettes
with conventional
cigarettes and the
shisha. J.-F. Bertholona,
M.H. Becquemina, M.
Roya,F. Royd, D. Ledure,
I. Annesi Maesanof,B.
Dautzenberg. Revue des
Maladies Respiratoires
(2013) 30, 752—757
E-cigs vs. cigarettes.: no micro droplets.
Was a filter used with the e-cigs? … or are the methods predictive of the
results? (i.e. one can only find what one is looking for).

Performance
25
Performance
Evaporation and
condensation of
multicomponent electronic
Cigarette droplets and
conventional cigarette
smoke particles
in an idealized G3–G6
triple bifurcating unit.
Y.Feng, C.Kleinstreuer,
A.Rostami. Journal of
Aerosol Science 80 (2015)
58–74
One model seems to indicate microparticles.
Theoretical studies of water/glycerol/propylene glycol/nicotine mixtures.

Performance
26
Performance
The aerosol characteristics of cigarettes is usually measured in “density”
or optical parameters , appropriate for a smoke/gas cloud, but not much
use for e-cigs that are droplets.
The few particle/droplet diameter analysis from the literature indicate
nanoparticles. We do not see these.
There is a method issue: the vaping/tobacco industry uses instruments fit
for droplets <1 um, we use a wider range. They use filters on cigarettes,
we don’t.
The vaping industry is interested in comparing their products to
cigarettes, is this skewing the results?
Knowing the correct particle size and aerosolisation mechanism is
important to understand the risk and benefits of e-cigs as a delivery
systems.

Nicotine delivery
27
Performance
e-cigs do not deliver higher doses of nicotine
Nicotine absorption from electronic cigarette use: comparison between first and
new-generation devices. Konstantinos E. Farsalinos et al. Sci Rep. 2014; 4: 4133.

What can we learn?
28
Mootpoints
E-cigarettes developers are ahead of pharmaceutical scientists in
formulating with new excipients.
Vaping devices offer new delivery technology.
The large scale use of propylene glycol and glycerine opens new
formulation horizons. Their use should be monitored: this is a worldwide
real scale in vivo clinical/epidemiology study.
Are we witnessing nanodroplet lung delivery?
The performance and reliability of e-cigarettes is poor if not random.
The aerosolisation mechanism is not understood.
More likely to be evaporation/condensation driven.
Sub-lingual or lung delivery?: that is a moot point. Flavouring can only be
felt in the mouth or smelt via the nose, is that due to large droplets?
Nicotine absorption can be effective via the mouth or via the lungs.
Clinical efficacy is anecdotal but could be real.
e-cigs have a better safety profile than cigarettes, but may be equally
addictive and bring in new degradation products.

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.
Merxin Ltd
Generic Medical Devices Made Easy
www.merxin.com

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e-Cigarettes: lessons for Inhalation technologists

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