Vaping Liquids: A Formulator’s Dream?

Vaping Liquids: A Formulator’s Dream
Philippe Rogueda - 7 December 2017
@ DDL28
In collaboration with:
Philip Kwok - University of Sydney Pharmacy Dpt
Neel Desai - UCL School of Pharmacy
1© Copyright Aedestra Ltd 2017. All rights reserved.
Inhalation products made easy
www.aedestra.com

Disclaimer & Copyrights
The information contained in this presentation is copyrighted.
Copyrights: All copyrights reserved. Aedestra Ltd, 2017.
Viewers may use the information contained within these slides for internal purposes according to
copyrights laws of Hong Kong. They may not use nor distribute the information to any third party
without Aedestra’s explicit concern. Reference to Aedestra’s authorship and copyright ownership
must be made in any private or public disclosure.
This presentation contains the personal opinions and thoughts of the presenters and may not be
assumed to represent the opinion of Aedestra Ltd nor of any employer or company or learned
society with whom the presenters might be or might have been associated.
Aedestra Ltd makes no representation to the accuracy of the information contained therein.
Aedestra Ltd declines any responsibility on the use of the information contained in these slides.
Aedestra Ltd does not recommend any course of action resulting directly or indirectly from the
information presented in these slides.
2© Copyright Aedestra Ltd 2017. All rights reserved.

Generic Medical Devices Made Easy
3© Copyright Merxin Ltd 2017. All rights reserved. The Merxin name and logo are trademarks of Merxin Ltd.
Merxin is a generic inhaler device designer and developer that supplies off-the-shelf
generic devices to accelerate and reduce the cost of the development of inhaled products.
#ReduceCost #ReduceRisk #IncreaseSuccess
www.merxin.com

© Copyright Aedestra Ltd 2017. All rights reserved.
Content outline
4
Abstract
e-liquids composition
Zoom on PG & VG
Risks associated with PG &VG
What should the industry do?

DDL 2017 Abstract
5
Abstract Summary
e-liquids used in e-cigarettes are treasure troves of excipients: propylene glycol, ethylene glycol,
vegetable glycerine, flavourings of all sorts, nicotine, and even water! This is an excipient armoury
that scientists would love to access to develop more stable, more flexible inhalation formulations.
Propylene glycol and vegetable glycerine are the main constituents of e-liquids, with
concentrations in excess of 90% w/w. This is magnitudes higher than the nearest inhalation
products: Clenil Modulite, Qvar and Symbicort pMDI are formulated with ethanol (typically 5 to
10% w/w) or glycerol (< 5% w/w) or polyethylene glycol (< 0.3 % w/w).
The pharmaceutical industry has been very conservative about using new excipients in inhaled
delivery. The high levels of excipients used in e-liquids are an opportunity for formulations
scientists to explore new formulation spaces. Molecules that are insoluble in water of HFA
propellants could be formulated as solutions.
The mass use of e-liquids is akin to giant worldwide open source clinical and epidemiology trials of
new excipients. The evidence of their side effects is currently ambiguous, often clouded by the
presence of flavourings, but also because of the combustion in vaping hardware. So far, the
dangers of the inhalation of high levels of propylene glycol of glycerol remain moot.
This is good news for formulators. What should the industry do? Test new excipients? Or sit on the
fence and let new formulation opportunities go to the vaping industry? Inhaled drug delivery has
missed the vaping wave, will it miss the new excipients wave?

Drug Delivery to the Lungs (DDL2017), 2017 - Philippe Rogueda et al.
Vaping Liquids: A Formulator’s Dream?
Philippe Rogueda1
, Philip Kwok2
1
Merxin Ltd, The Apex, 2 Sheriffs Orchard, Coventry, CV1 3PP, UK
2
Faculty of Pharmacy, The University of Sydney, Pharmacy and Bank Building, Science Road, Camper down,
NSW 2006, Australia
Summary
e-liquids used in e-cigarettes are treasure troves of excipients: propylene glycol, ethylene glycol, vegetable
glycerine, flavourings of all sorts, nicotine, and even water! This is an e armoury that scientists would love to access
to develop more stable, more flexible inhalation formulations.
Propylene glycol and vegetable glycerine are the main constituents of e-liquids, with concentrations in excess of
90% w/w. This is magnitudes higher than the nearest inhalation products: Clenil Modulite, Qvar and Symbicort pMDI
are formulated with ethanol (typically 5 to 10% w/w) or glycerol (< 2% w/w) or polyethylene glycol (< 0.3 % w/w).
The pharmaceutical industry has been very conservative about using new excipients in inhaled delivery. The high
levels of excipients used in e-liquids are an opportunity for formulations scientists to explore new formulation
spaces. Molecules that are insoluble in water of HFA propellants could be formulated as solutions.
The mass use of e-liquids is akin to a giant worldwide open source clinical and epidemiology trials of new excipients.
The evidence of their side effects is currently ambiguous, often clouded by the presence of flavourings, but also
because of the combustion in vaping hardware. So far, the dangers of the inhalation of high levels of propylene
glycol of glycerol remain moot.
This is good news for formulators. What should the industry do? Test new excipients? Or sit on the fence and let
new formulation opportunities go to the vaping industry? Inhaled drug delivery has missed the vaping wave, will it
miss the new excipients wave?
Introduction
The rise of e-cigarettes has been meteoric, the global e-cigs market is expected to grow over USD 50 billion by
2025, with 2.2 million e-cigs users in Britain alone in 2015, and 2.75 million e-cig smokers in the US out of a
population of 45 million smokers [1]
. e-cigs are inhaled drug delivery systems for nicotine. Unlike inhaled drug
delivery therapies, they are not much regulated and consequently do away with the barriers and common practices
of the pharma industry and readily mix excipients to improve product performance.
The use of excipients at high concentrations to control product performance is a dream come true for formulation
scientists: free from safety and regulatory constraints, new products can be created. The uptake of these
adventurous formulations by smokers and vapers is both exciting and worrying. Exciting because it opens a new
formulation universe and worrying because it pushes users in unknown toxicological territories. The mass use of e-
liquids is akin to a giant worldwide open source clinical and epidemiology trial of new excipients, and vapers are
paying for it. Following this informal trial and learning how these excipients affect users or not is a must. There is
much to gain from looking at an industry that has outpaced the inhalation industry with the use of excipients.
The composition of e-liquids relies on 5 basic ingredients: glycerol (vegetable glycerine, herein VG), propylene
glycol (herein PG), flavourings (an endless list of possibilities), nicotine (the active ingredient) and water. These are
mixed liberally from a number of sources. The main component of the e-liquids is PG. A typical composition would
be 60 %w/w PG, 0-40 %w/w VG, 0-20 %w/w ethylene glycol (EG), 0-10% nicotine and 5 %w/w flavourings[2]. These
concentrations of PG and VG and the presence of flavourings is well above what would be considered acceptable
in a pMDI, nebule or nasal spray. The e-liquid industry justification for the use of these excipients is that they are
GRAS (generally regarded as safe) according to the FDA concept of food additives. The premise is that if it can be
eaten it might be OK to inhale.
In addition to the liquid themselves, one should mention a host of contaminants. The excipients are not always
sourced from the most reliable of suppliers, and no extractables and leachables studies are mandatory:
nitrosamines, aldehydes, heavy metals can be expected. Of these ingredients only one is truly toxic and lethal:
nicotine, but curiously no one challenges its presence.
The use of PG and VG is to solubilise nicotine. Both are ordinary components of tobacco in cigarettes, where they
are used as humectants to prevent the drying out of tobacco leaves. VG has been identified as a natural component
of oriental tobacco and flue cured tobaccos, typically at low concentrations below 0.5 %w/w[3]
. PG has the

Drug Delivery to the Lungs (DDL2017), 2017 - Vaping Liquids: A Formulator’s Dream?
disadvantage over VG that it oxidises at high temperatures into formaldehyde. e-cigs typically heat up the liquids at
400o
C, high enough for oxidation and decomposition to occur.
Zoom on PG & VG
Although PG & VG are present in tobacco cigarettes, no adverse effects have been attributed directly to their
presence. To review the effects of PG and VG one can look for evidence from other applications: theatre smoke,
bactericide in hospitals, aircraft de-icing and indeed pMDI and nasal products such as Clenil Modulite, Rhinaris and
Flunisolide nasal sprays.
Theatre smoke can be generated by the heating of neat PG or VG. These are used in plays and concerts regularly.
PG/VG/Ethylene Glycol mixtures are used to de-ice planes. Users, active and passive are regularly exposed to their
aerosols. For a while in the 1950’s and 1960’s PG vapour was used to clean paediatric hospital wards [4]
and was
deemed to be safe.
What is interesting is the use of PG and VG in inhalation products. Clenil modulite relies on small amounts of VG
<2 %w/w) and polyethylene glycol (PEG) (<6 %w/w) [5]
. Symbicort pMDi contains small amounts of PEG (<1 %w/w).
Flunisolide nasal spray contains PG (<10 %w/w) and PEG (<15 %w/w) PG and VG are therefore no strangers to
inhalation dosage forms. They are also good solubilisers for corticosteroids.
Risks associated with PG & VG
The risks associated with the regular use of aerosolised PG and VG have been reviewed in small a number of
studies of varying quality. The best reviews are published by Konstantinos [6]
. The evidence of their effect is mixed.
2 types of risks should be considered: short term risks associated with pathophysiological effects and long-term
effects or epidemiological.
A couple of studies have looked at the effects of aerosolised PG in theatres on crew and actors [7,8]
. The results
point at potential chronic work-related wheezing and chest tightness associated with increased cumulative exposure
to fogs over two years. “Acute cough and dry throat were associated with acute exposure to glycol-based fogs;
increased acute upper airway symptoms were associated with increased fog aerosol overall. Lung function was
significantly lower among those working closest to the fog source”. However, the larger study showed “no significant
changes in lung function or the vocal cords for those exposed to glycols. Also, exposure to glycols wasn’t associated
with increased rates of asthma”. An other study[9]
looked at the acute exposure of PG mist in aviation: “short
exposure to PG mist from artificial smoke generators may cause acute ocular and upper airway irritation in non-
asthmatic subjects. A few may also react with cough and slight airway obstruction”. These are all short-term effects.
A more recent study looked at 1,018 vapers and their perception of PG effects [10]
. 21.7% of vapers reported a
cough due to PG. 27.8% reported a sore or dry throat, was it PG or its decomposition products or even nicotine?
The vast majority of these people didn’t have symptoms for long (39.6% had symptoms for less than a week, and
75% had symptoms for less than a month). 3.8% reported experiencing severe sore throat.
The only reliable clinical data on the tolerability of PG comes two clinical studies on flunisolide nasal spray [11,12]
. In
them, the tolerability of two PG concentrations were compared. In both studies, a statistically significant reduction
of self-reported nasal burning, stinging and throat irritation in terms of severity, duration and tolerability was reported
with lower PG levels. However, these studies might have been biased since the sponsor was also the manufacturer
of the reduced PG formulation.
These studies do point that they are people who are sensitive to PG vapours although no study is systematic enough
nor representative of chronic exposure to be meaningful.
e-cigs and inhalation therapies are very different. e-cigs rely on heating PG to create an aerosol. This leads to
potentially harmful compounds. The quality of excipients is also a source of concern with e-cigs, as well as the use
of flavourings. These may bring about most of the side effects associated with e-cigs excipients. The data on the
toxicology of aerosolised PG and VG is at best ambiguous. The mass use of e-cigs does not seem to indicate
unexpected dangers. However, the long-term effects of the chronic inhalation of PG and VG are only starting to
unfold.
e-cigarettes developers are ahead of pharmaceutical scientists in formulating with new excipients. The large-scale
use of PG and VG opens new formulation horizons. Their use should be monitored: this is a worldwide real scale
in vivo clinical/epidemiology study. Let’s test the effective toxic profile of PG and VG in the lungs and bring back PG
and VG in inhaled formulations to formulate hydrophobic APIs.

Drug Delivery to the Lungs (DDL2017), 2017 - Philippe Rogueda et al.
1
McCarthy N: The state of e-cigarette consumption in Britain, https://www.statista.com/chart/4475/the-state-of-e-cigarette-
consumption-in-britain/, 2016; Accessed 4 November 2017 (on line only).
2
Hahn J, Monakhova Y B, Hengen J, Kohl-Himmelseher M, Schüssler J, Hahn H, Kuballa T, Lachenmeier D W: Electronic
cigarettes: overview of chemical composition and exposure estimation, Tobacco Induced Diseases 2014; 12:23, DOI
10.1186/s12971-014-0023-6 (on line only).
3
Carmines E L, Gaworski C L: Toxicological evaluation of glycerin as a cigarette ingredient, Food and Chemical Toxicology 2005;
43: pp1521–1539.
4
Puck T T, O. H. Robertson O H, Henry M. Lemon H M: The bactericidal action of propylene glycol vapor on microorgansims
suspended in air, J Exp Med 1942; 75(6): pp593–610.
5
Ganderton D, Lewis D, Davies R, Meakin B, Brambilla G, Church T: Modulite: a means of designing the aerosols generated by
pressurized metered dose inhalers, Respir Med 2002 Aug; 96: Suppl D:S3-8.
6
Farsalinos K E, Polosa R: Safety evaluation and risk assessment of electronic cigarettes as tobacco cigarette substitutes: a
systematic review, Ther Adv Drug Saf 2014; 5(2): 67–86.
7
Varughese S, Teschke K, Brauer M, Chow Y, van Netten C, Kennedy S M: Effects of theatrical smokes and fogs on respiratory
health in the entertainment industry, Am J Ind Med 2005; 47: pp411–418.  
8
Moline J M, Golden A L,Highland J H, Wilmarth K R, Kao A S: Health effects evaluation of theatrical smoke, haze and
pyrotechnics, 2000, Actors Equity. http://www.actorsequity.org/docs/safesan/finalreport.pdf. Accessed 4 November 2017 (on line
only).
9
Wieslander G, Norbäck D, T Lindgren T: Experimental exposure to propylene glycol mist in aviation emergency training: acute
ocular and respiratory effect, Occup Environ Med 2001; 58: pp649–655.
10
Exploring PG Allergy: Sensitivities, Allergies and What Vapers Can Do About It. 2 February 2017.
https://www.ecigarettedirect.co.uk/ashtray-blog/2017/02/vapers-pg-allergy-sensitivity.html. Accessed 4 November 2017 (on line
only).
11
Greenbaum J, Leznoff A, Schulz J, Mazza J, Tobe A, Miller D: Comparative tolerability of two formulations of Rhinalar
(flunisolide) nasal spray in patients with seasonal allergic rhinitis, Ann Allergy 1988; 61(4): pp305-310.
12
Ratner P, van Bavel J, Gross G, Bynum L, Munshi A: New formulation of aqueous flunisolide nasal spray in the treatment of
allergic rhinitis: comparative assessment of safety, tolerability, and efficacy, Allergy Asthma Proc 1996;17(3): pp149-56.
References

e-cigs: a context
6
Context
The global e-cigarette market is expected to grow over $50 billion by
2025. Some countries have banned e-cigarettes: Singapore. Others would
like to: Hong Kong. 45 M smokers in the US. 2,75 Million e-cigarettes
smokers. Market value in 2015: $ 2.9 Billion.
9 March 2016 - https://www.statista.com/chart/4475/the-state-of-e-cigarette-consumption-in-britain/

7
Context
People like to believe that MR Hon Lik (韩力) from Shenyang China
invented e-cigarettes. But there is prior art. It is fair to say he popularised
them.
17 August 1965: US 3,200,89 Herbert A. Gilbert
e-cigs: devices

8
e-liquids
www.e-liquidaustralia.com

9
e-liquids
e-liquids composition: 5 basic ingredients
Glycerol + Propylene glycol + Water + Nicotine + Flavourings
A typical e-liquid composition might be:
propylene glycol (PG) 60 %w/w
glycerol (VG) 0-40% w/w
ethylene glycol 0-10%w/w
nicotine 0-10%w/w, variable strength
flavouring low %w/w
Hahn et al. Tobacco Induced Diseases (2014) 12:23 (DOI 10.1186/s12971-014-0023-6)
Why use PG or VG?
Nicotine is not soluble in water
PG and VG are good nicotine solvents and water scavengers
Cigarettes already contain PG and VG
VG: Bp 290oC - PG: Bp 188oC - Nicotine: Bp 247oC

10
e-liquids
“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 cigarettes, 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.
Glycerine is typically found in cigarettes at higher concentrations, up to
10%w/w in some cases.
Glycerine does not pyrolise at high temperature (900 oC, typically found
in e-cigarettes) unlike propylene glycol.

Zoom on PG & VG
11
PG&VG
PG is used to generate theatre smoke

Zoom on PG & VG
12
PG&VG
PG can be used as a bactericide in hospitals
The bactericidal action of propylene glycol vapor on microorgansims suspended in air J. Exp. Med. 1942 Jun 1; 75(6): 593–610

Zoom on PG & VG
13
PG&VG
PG mixtures are used to de-ice planes

Zoom on PG & VG
14
PG&VG
Glycerine is used at low concentration in Clenil Modulite (Chiesi)
Modulite: a means of designing the aerosols generated by pressurized metered dose inhalers. Ganderton D, Lewis D, Davies
R, Meakin B, Brambilla G, Church T. Respir Med. 2002 Aug;96 Suppl D:S3-8.

Zoom on PG & VG
15
PG&VG
PG is (was) used in Flunisolide nasal spray

Zoom on PG & VG
16
PG&VG
PG is used in nasal gels
Mixture of
polyethylene glycol 15%
propylene glycol 20%
in a gel adj

17
Risks
2 types of risks coexist:
Pathophysiology (short term)
Epidemiology (long term)
The mass use of e-liquids is a giant worldwide open source clinical and
epidemiology trial of new excipients.

18
Risks
Are PG & VG safe for inhalation?
Clenil HFA
Rhinaris
Flunisolide
PG does seem to be an irritant. PG can lead to throat irritation, burning and
stinging in the nose. The amount of evidence is limited.

19
Risks
Clinical evidence on the risks associated with the inhalation of PG
*Comparative tolerability of two formulations of Rhinalar (flunisolide) nasal spray in patients with
seasonal allergic rhinitis. Ann Allergy. 1988 Oct;61(4):305-10. Greenbaum J, Leznoff A, Schulz J,
Mazza J, Tobe A, Miller D.
Rhinalar vs Rhinalar with less PG - 122 patients (36 dropouts) - 4 weeks
“Statistical comparisons of patient evaluations of nasal burning and stinging with the two
formulations of Rhinalar showed a very significant difference in terms of severity (P less than
.001), duration (P less than .001), and tolerability (P = .006) in favour of the new formulation. A
reduction in severity of throat irritation with the new formulation was also shown to be
statistically significant (P = .006)”
*New formulation of aqueous flunisolide nasal spray in the treatment of allergic rhinitis:
comparative assessment of safety, tolerability, and efficacy. Allergy Asthma Proc. 1996 May-
Jun;17(3):149-56. Ratner P, van Bavel J, Gross G, Bynum L, Munshi A.
Flunisolide formulation with 2 different levels of PG 216 patients (131 dropouts) – 6 weeks
“Significantly fewer patients who were treated with the new formulation flunisolide reported
nasal burning and stinging when compared with the original formulation (P = 0.006)”

20
Risks
Non clinical evidence
*Effects of theatrical smokes and fogs on respiratory health in the entertainment industry. Am. J.
Ind. Med. 47:411–418, 2005. Sunil Varughese ,Kay Teschke ,Michael Brauer ,Yat Chow ,Chris van
Netten , Susan M. Kennedy.
Exposure effects to Theatrical fogs (glycol or mineral oil aerosols). 101 employees, 19 sites,
measuring lung function, and acute and chronic symptoms. “Chronic work-related wheezing and
chest tightness were significantly associated with increased cumulative exposure to fogs over the
previous 2 years. Acute cough and dry throat were associated with acute exposure to glycol-based
fogs; increased acute upper airway symptoms were associated with increased fog aerosol overall.
Lung function was significantly lower among those working closest to the fog source. Mineral oil-
and glycol-based fogs are associated with acute and chronic adverse effects on respiratory health
among employees.”
*Health effects evaluation of theatrical smoke, haze and pyrotechnics. 2000, Actors Equity.
A study looking of 439 actors for 2 years. The results showed no significant changes in lung
function or the vocal cords for those exposed to glycols. Also, exposure to glycols wasn’t
associated with increased rates of asthma. But those exposed to the highest levels were more
likely to report nose, throat and breathing-related symptoms. These actors also had some
inflammation of the vocal cords.

21
Risks
Non clinical evidence
*Experimental exposure to propylene glycol mist in aviation emergency training: acute ocular and
respiratory effects. Occup Environ Med 2001;58:649–655. G Wieslander, D Norbäck, T Lindgren.
27 subjects. 1 minute exposure. 309 mg/m3 fog concentration, symptoms emasured 15 minutes
after exposure.
“Short exposure to PG mist from artificial smoke generators may cause acute ocular and upper
airway irritation in non-asthmatic subjects. A few may also react with cough and slight airway
obstruction”

22
Risks
e-cigs smokers evidence: allergy or sensitivity to PG seems to be the main
source of side effects.
*Exploring PG Allergy: Sensitivities, Allergies and What Vapers Can Do About It. 2 February 2017.
https://www.ecigarettedirect.co.uk/ashtray-blog/2017/02/vapers-pg-allergy-sensitivity.html
Survey of 1,018 vapers by an e-liquid supplier in an attempt to shed more light on the issue of PG
sensitivity and allergy. 81 % of people who responded had been vaping for longer than a year, and
almost 88 % had quit smoking entirely. PG influence was subjective.
21.7 % vapers reported a cough due to PG.
27.8 % reported a sore or dry throat. The vast majority of these people didn’t have symptoms for
long (39.6 % only had symptoms for less than a week, and 75 % had symptoms for less than a
month).
3.8 % reported experiencing severe sore throat.

23
Risks
https://www.ecigarettedirect.co.uk/ashtray-blog/2017/02/vapers-pg-allergy-sensitivity.html

Toxicity of e-liquids
24
Toxicity of e-liquids can stem from:
-the degradation of glycerin and propylene glycol
-solvents
-heavy metals
…. but mostly from flavourings.
Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Maciej Lukasz
Goniewicz et al. Tobaco Control. TobControl doi:10.1136/tobaccocontrol-2012-050859.
Risks

25
Whatshouldwedo?
The main sources of concern in e-liquids are:
• Combustion by-products
• Undetermined quality of excipients
• Use of flavourings
The evidence of the toxicity of PG and VG at high concentrations is
ambiguous.
e-cigarettes developers are ahead of pharmaceutical scientists in
formulating with new excipients: monitor the use of PG and VG in e-cigs.
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. Let’s test the effective toxic
profile of PG and VG in the lungs and Introduce PG and VG more readily
in inhaled formulations to formulate hydrophobic APIs.

Vaping Liquids: A Formulator’s Dream?

Recommended

Recommended

More Related Content

Similar to Vaping Liquids: A Formulator’s Dream?

Similar to Vaping Liquids: A Formulator’s Dream? (20)

More from Philippe Rogueda

More from Philippe Rogueda (10)

Recently uploaded

Recently uploaded (20)

Vaping Liquids: A Formulator’s Dream?