Product Design
When Nicotine Is Not Nicotine
Abstract
Describes preliminary studies of ART fillers oversprayed with nicotine citrate [NC], ethanol [AE] and nicotine as the base [FB]. Says these data indicate Central Nervous System [CNS] effects on Pattern-reversal evoked potential [PREP] are greater than expected, indicates nicotine delivery of cigarettes made to Merit specifications containing NC are half as effective in transport and delivery when compared to FB, and FB is perceived as having higher "mouth/throat impact." Describes experiments, presents data and suggests Phase I ART sudies be pursued utilizing cigarettes oversprayed with FB to further elucidate nicotine delivery.
Fields
- Notes
Potassium hydroxide [1310-58-3] Potassium hydrate; Caustic potash; Lye; potassa; Potassium hydroxide (K(OH)); Caustic potash, liquid; HKO 56.0973 [source:Chemfinder.com]###
- Rank
- 1
- Author
- Gullotta, Frank Paul, Ph.D. (Tobacco chemist, Philip Morris, Cologne, Germany '94)Developed and used EEG techniques to study relationship between nicotine addiction and blend properties. Worked moved off-shore in 1986 to avoid discovery.
- Hayes, Cindy
- Martin, B.R.
- Recipient
- Spielberg, Howard L. (PM Research Professional)Research Professional
- Charles, James L., Ph.D. (PM, R&D VP, Pharmacologist, Industry Expert)Vice President of Research and a scientist for Philip Morris, Inc. Vice President of Research for Philip Morris, Inc. in 1986 and then again from 1992 to 1993.
- Ellis, Cathy Lynn, Ph.D. (PM VP of Worldwide Scientific Affairs)Director of Research at Philip Morris U.S.A. in 1994. In 1997 was Senior VP of R&D at PM (2505370877). Osdene protégé.
- Hempfling, Walter, Ph.D. (Associate Principal Scientist, PM, c. 1997)Reported to Robert A. Fenner,
- Houghton, Kenneth S., Ph.D. (Senior VP of R&D at Philip Morris)Defense
- Kinser, Robin Dale (Manager, Analytical Research, PM, 1997)Joined PM in Sept. 1976 and prior to his position in 1997 was Manager of Product Research. Reported to Richard P. Solana (2505370877)
- *Myracle, James L. (use Myracle, James L.)PM manager
- Hypothesis
- Design changes over timeChanges in cigarette design over the past half century.
- Free Nicotine
- Introduction of new/unconventional productsResearch and development of novel nicotine delivery devices and experimental tobacco designs.
- Low-yield cigarettesModification of low yield products to assure that adequate levels of nicotine delivery are maintained, and effects of yield changes on toxicity and dependence.
- Mainstream constituent yieldsModification of selected mainstream smoke constituents in response to health concerns.
- Nicotine transport, transfer, and uptakeDesign changes which alter nicotine delivery or effect how the product causes and maintains dependence, including transfer of nicotine from tobacco to smoke, and uptake into the body.
- Use of additivesModification of tobacco products through use of additives and measuring effects on dependence, behavior, and toxicity.
- Use of tobacco processing/ blendsModification of tobacco products through changes in tobacco processing and use of blends, and measuring effects on dependence, behavior, and toxicity.
- Neurobiology
- Sensory effectsTechnologies used to measure, control, or alter sensory effects
- Keyword
- Alkalinity (High pH, Basic)
- Central nervous system (CNS)
- Delivery modification
- Evoked response
- Flavor (Taste)
- Free nicotine (Unprotonated or unionized nicotine)
- Gas chromatography
- High impact/low tar
- Mouth feel (Mouthfull)
- Nicotine delivery (Smoke nicotine or nicotine yield)
- Nicotine manipulation
- Per puff deliveryPer puff tar, per puff nicotine, and per puff CO
- Sensory response
- Smoke pHAcidity/ baseness, scale from 0-14, 7 neutral
- Smoothness/Harshness (Attribute measure)
- Total particulate matter (TPM or Tar)
- Additive
- Equimolar nicotine
- Ethanol
- Citric acid
- Potassium hydroxide
- Smoke Constituent
- Nicotine
- Nicotine salts
- Total particulate matter
- Design Component
- Nicotine content (Tobacco nicotine content)Total nicotine in the unburnt tobacco rod
- Nicotine transfer efficiency (NTE)
- Operation/Project
- Project ART (Denicotinized cigarette)
- Named Organization
- INBIFO, Intitut Fur Biologische Forschung (Philip Morris' secret biological research lab in Europe)"INBIFO" stands for Institut Fur Biologische Forschung, or Institute for Biological Research. It is located in Germany. Philip Morris acquired Inbifo on June 30, 1971. Its stated mission was "quantitative biological product evaluation" by using "comprehensive toxicological and physiological testing. Major activities are listed as: product evaluation and modifications, product ingredients and ETS-related technical knowledge and smoke components. Inhalation toxicology was a key feature of Inbifo. (Derived from Bates No. 2505235055/5088)
- Philip Morris Companies Inc. (Parent company of Philip Morris USA, Kraft, Miller)America's seventh-largest industrial enterprise in 1993, owns Kraft, Miller Brewing, General Foods, and more.
- Research & Development
- Cigarette Testing Services Division
- Brand
- Merit (PM)
- Subject
- acids (additives)
- additives
- CNS/Brain (Effects)
- nicotine technology
- nicotine analogues (Technology)
- pH Manipulation (Technology)
- Puff Count (Measures)
- Sensory Effects—Impact (Effects)
- Sensory Effects—Taste (Effects)
- Smoke Constituents
- Smoke Delivery/Transport (Measures)
- Smoke Nicotine (Measures)
- Test/Inhalation (Testing)
- Transfer to Smoke (Measures)
Document Images
°l i~ '94 15:45 ~-4.Q °"0:~ $03382 INBIFI] K,-,eln
~020 02S
A'I'rORNEY WORK PRODUOT~
I N T ~ R - 0 F F I C E C 0 KK E S P 0 N D EN C Z
To: .~. L. Spielbezg Dane:
From: ,F. P, Gullotca, C, S, Hayes, B. R. MAruln
Subject: .~hen Nicotine is not Nicotine
SU~AKY
PaC~ern-reversal evoked
order ~o as~es~ the cen~3~l nervou~ ~ys~a~ ~CNS) effects p~oducad by the
filler~ were overspr~yed wi~h e~ulmolar nicotine as either ~he ba~e (~) or
s~rea~ nlcon~e delivery.
were appro~i~a~iy half ~he magnitude of ~ho~e ob~ained wi~h FB and unex-
~rac~ed cigare~e~. ~e~e findings indlca~e ~ha~ fu~r~ CNS ~die~ shoul~
be conducted v~h F~ cl~ara~s,
Dana obtained in the ~=el£minary ART scudy~ indicaued tha~ the smoking
of a cigarette made t~ ~eri~ specifications resul~ed in CN$ effects gre~ter
than ~ould have have been predle~e4, based upon p~evious studies. However,
~hese praviou~ studies employed cigarettes made from filler ~hat had been
The da~a obtained with the low tar blend elba:erie in ~he preliminary
ART s~udy led us to po~=ul~e that nieotin~ delivered f~om NC cigarettes
m/gh: be less effectively transported or ~ansferred, possibly due to pH
effects. Consequently, we conducted a study comparin~ CNS and subjective
effect~ produced by ~he smoking of NC cigarettes t~ the effects produced by
the smoklsg of cigarettes made from filler ~ha~ had been ovezsprayed ~ith
equlmoiar amounts of nlco~ine as ~he base (FB cigarettes).
21, 12 94 1,5:46 ~-49 2203 3t)3362 INBIFO Koeln
@021 025
Three hand-~ade cigarette types were tested. The cigarettes were
prepared from the same batch of ~RT-extracted filler, using Meri~ blanks.
Cigarette AE was made from filler over,prayed winh an euhanel vehicle only.
Cigarette FB w~s oversprayed wi~h nlecnine as ~he base in an e~hanol
vehicle. Cigarette NC was made fro= filler oversprayed ~i~h nicotine as the
cltra~e in an ethanol vehicle. Target levels for bo~h cigarettes were 2.15%
nicotine. For c~g~ettes FE and NO, 20% additional nicotine was ~praye/ un
the filler ~ correct f~r possible !osse~ durin~ preparation.
Seven cigarettes of each type were given to ~. Esperdy~ Using gas
chromatographic ~echniq~es, E~perdy de,ermined that the fillers for ~hese
cigarettes contained an average % nicotine of 0.08, 2.10 and 2~37 for
¢IgaretueS AE, FB and NC, re~pectlvely.~ The pH of these fillers was
determined to be: AE, 5~8; FB, 6.4~ and NC, 5.2.$
¥~ff x puff smoke analysis in the Cigarette Testing Services Division
indicated chat cigarette ~B ~elivered 0,76 mg nicotine/cigarette for ~ puffs
and cigarette NC delivered 0.70 mg nicotine~cigarette for 8 puffs. Smoke
analysis of cigarette AE indlc~ed that no nlco~ine was de~ected. The puff
X puff n~cotine dellve~y was very similar for cigarettes FB and NC~ h~wever,
it Nu~ be n~ed ~hat these results are from a non-snandard analysis using
fewer ~han the recommended numb~ of ci~areu~es.~
Twelve R&D smoke~s served as subjects for =he study. The~e twelve
~uhJac=s were a subset of the twenty who participated in the preliminary ART
study. The mean tar and nicotine delivery of the cigarettes tha~ r~he
subjects normally smoked was 8,62 (S.D, - 4.12) mg/~i~t, and 0,71 (S.D.
0.26) mg/clgt., respectively.
The subjects were irm~uc~ed Co abstain from smoking for ~wo hours and
from ingesting ca£felne for one hour prior ~o ~estln~. A doubie-blin~
procedure wa~ employee, where neither ~he subjects nor the experimenters
weTe informed about which cigarette was being te~ted.
A!l subjects smoked each cigarette using a con=rolled smoking proce-
dure. The con~rolled smoking ~rocedure ~!nimi~es bo~h inter- and in~r~-
21,12 94 15:4[~ ~-49 2203 31336~ I.k'BIFO Eoeln
~I)22.'I.i25
subject variability with respect =o how =igarettes are smoked.~ In
current study, the subjects were required =o take eight p~ffs (excluding
l~h¢ing puff) on each cigarette. The inter-puff interval was held at
.Pre- and post-smoking PREP~ were recorded from two scalp loci. One
electrode was positioned over midllne occipital cortex (i~.~, Oz), while the
second was positioned over mldline parietal Co=rex (~, Pz).~ The PREP
waveform components that were measured were: Po, N~ P~ and N~ latencies and
Po-N~, N~-P~ and P~-N= amplitudes. However, only P~ latency effects at 0
will be discussed in this mem~.
The data were analyzed using ~ two-factor repeated measures analysis of
variance (ABOVA)~ One ~actor an~ly'zed for ~he ~i~ference between pze- and
pos~-smokin~ values~ while the second factor analyzed for the d~ere~¢es
a~ong cigarettes. Followin~ ~he ~OVAs, the data were further analy~ed
usln~ p_o~_=th~ ~l~iple ¢o~arisons te~t~. Additionally, a paired t-test
those obtained with ~e low tar blend cigarette in ~e ?relimina~ ~T
At the end of each experlmen=al session, suSJeets were =equlred
complete a 5al~ot (seven point s¢aie) evalu~=in~ the cigarette that was
smoked. "Mouth/throat impact" and "liking" s~ores were ~nalyzed
Previous work? has demom~trated =hat the latency of,nhe P: component =f
is smoked. ~n the current study, both cigarettes ~B and cigarette NC
produced s=a~is~ica!ly si~nffieant post=smokin~ latency decreases. However,
the magnitude of the latency decrease was not ~he same for both cigarettes.
Cigarette FB produced a P~ latency decrease of ~.29 mace. Cigarette NC
produced a P~ laue~cy decrease of i.II mace. The latency ~ between
-3-
21,12 94
15:47
I ~P I FO l(,:~e in
blend c~re~te produced a P~ latency decrease of 2.84 msec~ A paired t-
~es~ revealed ~ha~ th~ latency e~fects produced by the i~w tar blend
.e~f~_~s ~hig~hvere~_o~arab~e.~o__~h~ unex~raetg~_~i~arett~.
Subjectively, clgare~te FB wa~ perceived as having hi,her mo~th/throst
impac~ (~ - 5.08 y~. 3,58) and was liked le~s (~ - 2.83 v~&~. ~.35) than
cigarette NC.~ We postula:ed that ~h~s finding was ~e to ~he use Of the
controlled smoking procedure. Controlled sm~klng does no~ permit the
subjects to modify the ~anner in which they ~oke in response to changing
£n .mourh/thzoa= impact (~ - 4.45 ~_.~. 3.~5). However, ~ smoking
resulted in comparable llk£n~ scores for ~igare~es FB (~ - ~.00) and NC
(~ - 3.82),~ Since flavor m~dification studies will employ I~
smoking, differential liking ~t~res tha~ were ob~alned usin~ the ~on~rolled
proaedure will not be ~f c~nsequence.
In s,~._ary, the resulta of ~h~ current s~udy demonstrate ~hat
reties made from filler oversprayed with nicotine as the base (FB) produced
CN$ effects comparable ~o cho~e ob~aine~ vi~h unextra~ted ci~are~es with
simile~r mainstream nic~tlne deliveries. Ci~arette~ made from fille~ over-
sD~ayed with nicotine as ~he citrate (NC) produce CNS &ffects which
approx~etely half the magnitude of those oDtained with ~e FB or
in~icate that we should conduct Phase ~ ~T s~udies using cigare~te~
fro~ filler ove~sprayed wi~h a nicotine as the
-4-
i 4% C. A. ~.7~ 0.~3833 38.3333
2 2% C. a. 5.]0 0.03933 39.3333
3 t% C. ~. 5.30 0.03~00 3~.0000
$ CONTROL 5.80 0.03467 34.6667
5 I% KO~ 6.5C 0.03333 33.3333
6 2% KOH ?.05 0.03193 31.3333
7 4~ KOH 7.9~ 0.D2933 29.3333
8 8% KOH 8,BO 0.02593 25.3333
0 additive 9 %~T~ iN]C/PAD)/~PM 10
7.866~
7.2000
6,9333
6.6667
6.266~
5.0667
38.3333
39.3333
36.0000
34.6667
33,3333
31.3333
29.3333
25.3~33
11 TOTAL NZC
7.6667
7.8667
7,2~00
6.9333
6.6667
6.2667
5. 0667
5.0667
2,3~000~
2.490000
1.936667
2.q20000
1.89000~
2.00666~
2.21000~
2.3666.67
~22,133333
125.q00000
'32.966667
:33.000000
~1.20000~
75,233333
" 126,05D000
1 4% C. A. 6.156522 0.057739
2 2% C- A. 6.330508 Q,06457~
3 1% C, A, 5.37963~ 0.09!57~
4 CONTSOL 6.980769 0.095~92
5 1% KOH 5.670000 O.lZl20O
7 4% ROB 7.53~091 0.256~77
2.30213
2.5[540
1.96963
2.45300
1.930~
2.04787
2.28523
2.49272
0.929139
]. 4)09780
1.6,73746
1.345291
2.092831
2.01:1850
3. 292151
5. 056732
m
Gul!o~=a, F, P., Hayes, C. S. and Mar~In, B. R. Completion of Pre!iml-
nary A~T Study. Memo to H. L. Splelbe~g, i989, June I.
2. E~perdy, R, C. PM Notebook No. 8818, pp. 41 and 49-50.
3. Mar~in, B. R. PM NoteSook No. 8843, p. 14.
4. Martin, B. R. PM Notebook No. S843, pp. 6-10,
Gul~ot=a, F. P, and Shultz, C, J. The effects of cigarette smoking on
the elee==iCal act(vf=y ~ the human brain: Studies on ~he pattern
rev~rzal evoked potential. Special Report NO. 82-097~ 1982, March 24.
Federation. ~lce~oencephaio~raphy and Clinical Neurophys~o~o~y.
371-575, 1955,
Gullotta, F. P. and Hayes, C. $. 1620 Annual Report
logical Studies. Re~ort No. $a.165, 1984, June i.
Eleetr~phys~-
8. Martin, B. R. Notebook
9. M~rtin, ~. R. Notebook
J. L. Charles
W. P. Hempfl~n&
K. S. Houghton,
R. D. Kinser
5. L. Myracle
