Vaping Liquids: A Formulator s Dream

Transcription

1 Inhalation products made easy Vaping Liquids: A Formulator s Dream Philippe Rogueda - 7 December DDL28 In collaboration with: Philip Kwok - University of Sydney Pharmacy Dpt Neel Desai - UCL School of Pharmacy 1

2 Disclaimer & Copyrights The information contained in this presentation is copyrighted. Copyrights: All copyrights reserved. Aedestra Ltd, 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

3 Generic Medical Devices Made Easy 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 Copyright Merxin Ltd All rights reserved. The Merxin name and logo are trademarks of Merxin Ltd. 3

4 Content outline e-liquids composition Zoom on PG & VG Risks associated with PG &VG What should the industry do? 4

5 Context e-cigs: a context The global e-cigarette market is expected to grow over $50 billion by 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

6 Context e-cigs: devices 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 6

7 e-liquids e-liquids composition 7

8 e-liquids e-liquids composition 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 /s ) 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 290 o C - PG: Bp 188 o C - Nicotine: Bp 247 o C 8

9 e-liquids e-liquids composition Glycerin has been identified as a natural component of oriental tobacco ( %), flue-cured tobaccos ( %), and burley ( %) 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) 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 o C, typically found in e-cigarettes) unlike propylene glycol. 9

10 PG & VG Zoom on PG & VG PG is used to generate theatre smoke 10

11 PG & VG Zoom on 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 Jun 1; 75(6):

12 PG & VG Zoom on PG & VG PG mixtures are used to de-ice planes 12

13 PG & VG Zoom on 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 Aug;96 Suppl D:S

14 PG & VG Zoom on PG & VG PG is (was) used in Flunisolide nasal spray 14

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

16 Risks Risks associated with PG & VG 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. 16

17 Risks Risks associated with PG & VG 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. 17

18 Risks Risks associated with PG & VG 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 Oct;61(4): Greenbaum J, Leznoff A, Schulz J, Mazza J, Tobe A, Miller D. Rhinalar vs Rhinalar with less PG 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 May- Jun;17(3): 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) 18

19 Risks Risks associated with PG & VG Non clinical evidence *Effects of theatrical smokes and fogs on respiratory health in the entertainment industry. Am. J. Ind. Med. 47: , 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 oiland 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. 19

20 Risks Risks associated with PG & VG Non clinical evidence *Experimental exposure to propylene glycol mist in aviation emergency training: acute ocular and respiratory effects. Occup Environ Med 2001;58: 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 20

21 Risks Risks associated with PG & VG 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 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 % vapers reported a cough due to PG % 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. 21

22 Risks Risks associated with PG & VG 22

23 Risks Toxicity of e-liquids 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: /tobaccocontrol Copyright Aedestra Ltd All rights reserved. 23

24 What should we do? What should the industry do? 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. 24

25 inhalation products made easy