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2~/06 '94 12:30 "~48 2203 303362 AENBIF0 Koeln ~OI/P.NATu 01~ AEROSOL I~EDIC]/qE :' Vo~ 6, N~n~ 1, ~93 ," ~ CEL / ffect of pH on Nicotine Absorption and Side Effects Produced by Aerosolized Nicotine / / 7, $'.G. BURCH, .P. GANN, M. OLSEN, P.J. ANDERSON, F.C. HILLER, and'M.L. ]ERBLAND ~r .... ~" ~ ~tmona~e~on/ll~ Joh~ L. M~aettan~ 43~ Wear S~nrh Street, ~nle Rock, AR ABS~It~ACr Nicotin~ aerosol could prove to l:e a useful aid to smoking cessation. In previOUS studies, • subjects complain~I of unpleasant side effects that seemed to be due to local irritation from the inhaled aerosol. The purpose of the current study was to compare nicotine absorption and side effects from inhalation of nlcodn¢ aerosols of varying FLU/. Ten healthy smokers inhaIed aerosols made from nicotine soIutlons with a pH of 11, 7.5, or 5.6. The measuxed particle size was 8.5 gm MMAD. We measured ~erial pl~.~a-~ nicotine con'cent_radons and evaluated 4 side effecu: cough, throat burning, diz~ness, and salivation. Increasing pH was associated with a higher mean rise in plasma nicotine concentration. N~wever, there was no difference in the incidence of side effec~ seen with the three aerosols. We conclude that a more alkaline aerosol enhances absorption from the respiratory tract. The large particle size may be responsible for the apparent irritant effects of the aerosol and the relatively Iazge dose required to aeNeve levels comparable ~o INTRODUCIqON Delivery of nicotine a~ an aerosol may have potential in nicotine replacement therapy for smoking cessation. Optimal nlcoti~e replacement,may require reproducing the rapid peak nicotine levels seen in cqgarette smoking, ~o that the smoker s nicodnc dependency can be temporarily satisfied while the behavioral aspects of smoking can be =eared (1). Nicotine gum and transdm-mal nicotine patches, the only commercially available forms of tricotine x-eplacement, fail to achieve the rapid peak nicotine levels produced by ~moking (:2.4). Long-term success rates with nicotine gum have been modest, tho6gh superior to placebo gum when used in conjunction with behavior modification (:5-7). Less is known about the potential for long-reran success with transdermd nicotine patches (8,9). Due ~o r.he tremendous impact of cigarette smoking on our nation's health, there is an urgent need for better methods of smoking cessation. In a previous study, we gave 5 nag of' aerosoH~,ed nicotine with a pH of 1 ~ to smokers and preduced nicotine levels which were similar to those reached with cigarettes and supeigor to those KEY WORDS:' Nicotine aerosol,'~moking cessation,"pardcle size~ni¢otine addietion'~

'94 12:~0 ~49 220~ ~0~$62 ~NBIFO Koeln ~ CEL produced by 2 mg nicotine gum (10). Cough was a limiting s~de effect in tha~ s~ud~, Other ~nvesdgam~ have shown ~at ~e free base fo~ of nico~nc, w~ch pr~o~nates at ~ alkahne pH, i~ absorbed morn efficiently across mucous membranes ~h~ ~¢ s~t f~ at an addle pH (11). $~nce dg~ ~oke is ~e whem~ ci~¢ue smoke is acidic, the pH of cig~ smoke may contribute m i~s ~t~ ~t~t eff~t on ~e ~ay (12,13). We ~smla~ th~ incr~sing ~e pH of ~e nicotine ae~osoI ~ght faNIi~te nico~ne abso~fion but ~ght Nso ~cre~e the side efNc~s produced by the aerosol. The pu~ose of th~ stud~ ' to temple aisle abso~oa ~d side ~f~ts ~m ~hNation of Ncot~c aerosols vf v~ing p~ AND M:E'I-t-IODS Snbject Sele~on We recruited I0 healthy smokers for the study. Nine of ~hese were healthy hospital employee.~. The subjects ranged in age from 28 to 60 with a mean age of 40. No .~ubject had slgnificant past or present illness by history, and all were current smokers. Tim subjects smoked an average of 26 cigarettes per day (range, I0 - 40). All gave informed consent for the study. Nicotine Solurion~ The solngons for aerosolization were prepared by first mixing L-nicotine (Eastman Kodak, Rochester, N. Y.) whh normal saline to a concentration of 130 mg,/ml, This solution had a pH of I 1. Addition,"-J SOlUTions with pH's of 7.5 and 5.6 were made by titration with hydrochloric acid. A dosimeter (Erich Jaeger Gmblt & Co. KG, Wiirzburg, Federal Republic of German,,') equipped with a Sandoz jet nebulizer was used to produce the aerosol, A diagram of ~he dosimeter'h shown in Figure 1. "Fnis dosimeter generates the aerosol just after the beginning of inspiration and accurately controls the quanfiW, firn~ng, and dumdon of acrosolization. A pressure transducer loca~cd adjacent to ~he mouthpiece dctccts when the subject generates negative 2 mm of water pressure. At th~s point a compressor is activate, The driving pressure of Lhe compressor was measured and found to be 15 psi. The duradon of aerosolization can be preset to a desired time inlerval during inspiration. A flow r.-,te w~s calculated for the nebullzatlon eonta.iner by aerosolizing a solution of normal saline for ap~'eset, time and weighing the container, plus .saline berore and after aerosolization. By this me,hod,. our dosimeter was found to dehver 0.0062 ml/sec. Each aerosolizafion or "puff" was 0.6 seconds m duration. Using the solution described above, this combination would be predicted to give a dose of 0.484 mg of nicotine per puff. To confirm that this amount of nicotine was really being delivered, we did several trial runs in which we collected the aerosolized nicotine onto filters and extracted lhe nicotine, which was then quantified by gas chromatography. A calibrating syringe was used to mimic a subject's tidal breathing. One 500 ml "breath" was drawn every 30 seconds for 5 minutes to w~ggcr 10 nebulizations as in the subject trials, This process was ca-tied out four times and the results were averaged, Aerosol Particle Size . We mcasured the particle size' output of the Sandoz nebulizer, since the solution itself might influence the particle ~izc. Particle size output of nicotine solution was m~asumd by a 6.-stage Sierra cascade impactor (Anderson Instruments, Atlanta, GA). Nicoline solution (130 mg/ml) was nebulized in 0.6 second pulses every 30 second~ for $ mlnutes and delivered to the cascade impactor, which was a~mched directly to thc mouthpiece of the dosimeter. This arrangement simulated as closely as possible the delivery of nicodne to a human subject. Nicotine was extracted from the filters and the amount collected at each stage of the impaemr was measured by gas chromatography. Inhalation l:'rotocol Subjects were asked to abstain from smoking for at least 1 hour prior to the inhalation. During each tri~l, the ,~.84 mg of nicotine rata/dose divided into 10 puffs given 30 seconds apart cwer a 5 ~]006

~(06 ' 94 12:31 "~49 2203 303362 AINBIFO Koeln ~++ CEL rnlnut¢ perlod (~[me 0-5 n:dnu~es) dtw/~g nor-mai fid~ breathing bcg~nni~g ac functi~al capaci~. Each subj~t p~o~ed on~ ~ ~ ~ach p~ ~lufion f~r a total ~f 3 ~s, BI~ samples were ~wn ju~ ~Hor to ~ ~{ug of {nhahfion (time zero) ~d at 2.5 minus inte~als for 115 ~utcs. S~ple~ were put on ~c¢ ~fl ~iamly ce~fug~ t~ sep~ate the p~asm~ fo[ analysis. Nicotine ex~action was pe~o~ according ro m= m¢~ho~ previously aescrioes uslng e~ylnom~co~¢ ~ ~ ~t~m~ s~ ~ subs~u~t gas chmm~to~phic ~alysis S~dc cff~u du~ ~o ~e ~ffon were ev~tm~ subjec~v¢ly, vaffems were asscss~ for side effete: cough, t~t burning, ~s, ~d ~vadon. Each s~p~om was given a ~om of O (none), I (~id), 2 (m~emte), or 3 (s¢v~), and ~ scores were add~ for a ~o~al sid~ effec~ Subjects wc~ informed th~ if ~y of the side effects caus~ excessive discomfo~, ~hcy ~ould ~ coll~ctin~ bag nebullze~ beake~ ~]007 FIGURE I. Diagram of the Jaeger dosimeter. (Reproduced with .permission from Rcfez'ence 25) RESULTS Data from the 4 dos~-sxwacfion ~'ials ~ave a mean ex~"actcfl dose of 4,57 mg nicotin~ 4.39 to 4.74 rag). This amount comp~es favorably with ~ predicted acrosolized dos~ of 4.~4 mg ni~fin~ ~¢ me~ pa~cle s~c of ~c a~osolh~ nicotine w~ 8.5 ~m ~ss ~ian acr~yna~c ~e m~n plea ~ofine lev~ls ms~ g n~m], 12 n~ml, ~d !g n~ml from bas~llne l~v~ls ~ aerosols of pH 5.6, 7.5, and 11. respectively (~i~re 1), Oor subj~ had baselin~ nico~nz Icvcls du~ to recent smo~ng, ~d thee w~ no s~gnificant difference in ~e mean base, he for ~ 3 pH ~s, ~e p~ n~co~a Icwl for ~ach pH o¢~w~ at 7.5 ~nutcs. Plasma nicodn= I~v~Is verbs time demons~t~ ~at increasing a~osol pH co,elated with bigh~ nico~nc levels ~m 2). ~c ~s ~ ni~c Icvsl ~el~c to ~ak ) at each dmc intc~al for each ~ solution was anal~ and the results ~s displayed in the table. An analysis of v~ancc showed a significant 47

~4'/06 '94 i~:31 "~49 ~203 303362 ~II%~BIF0 Koeln ->->~ CEL [~008 30- 10- 0- I L i i "- l T I'-- ! ! ! i ~ i'-- 0 2 4 6 ~ 10 ~ 14 TIME (min) FIGURE 2: Pla.~ma nicotine levels versus tim~ after inha/adon of nicutia~ aerosol of pH 5,8, 7.5, aad 1 I. Inserts show $,]~.M. t'or cach pH, d/florence in r.he nicotine levels produced by" the three acrosoIs e~ 7.5 and 10 minutes ( p < 0.05 ). Compa.radve t-~cs'~ ber,veen pH pairs at these dmc period-¢ showed a significant increase ~n plasma nicotine l~v~Is for all comparisons except pH 5.6 "versus pH "7.5 at "/.5 and 10 minutes. TABLE -- T-test Comparisons Between pH Pairs at 7.5 and 10 Minutes p;-I_Comparison s 7.5 rn{rt 10 5.6 vs 7.5 .051 .1t2 7.5 vs 11 .037" ,029" =Significant difference at the p < 0.05 level. Four side effects wcrc observed during th~ inhalation: cough, throat burning, dizziness, and s~[vation, The means of the surtm of the side effect scores were 3.2, 3.5, and 3.0 for pH 5.6, 7 5, and 1 I, respectively. The mean score for each individu-,=.l fide effect did not appca.r to differ among /he zhz¢~ pH ~'oups ( l~g~.~e 3). 48

24/06 ' 94 12:32 "~49 2203 303362 A£N'BIF0 Koeln ~.~ CEL [~009 DISCUSSION Our data indicated that the pH of the nicotine aerosol signiflc~fly affe, cts the absorption of nicotine. Increasing ~he aerosol pI-I produced sJgnificandy higher p~k plasma nicotin~ levels. These results were similar to previously reported effects of pH on nicotine absorption across mucous membranes ( I 1 ). An appreciable rise'm nicotine level occurred rapidly with each pH, however. Th~s f'mdLng is in agreement with earlier reports that aerosol absorption of nicofin~ is depcndem ~an absorp~on across buccal mucosa (I,5). Th~ pH of th~ nicotine aez'osol did not ~ter side effects. This finding was somewhat surprising, since cigar smoke is reported ~o be more irritating to the airways and is known to be more aJ.k~ne than ¢~ga~tte smoke. Cigar smokers may inha.]e less than cigarctm smokers due ~o the irritant effects of the cigar smoke (I 1,12 ). Wc had previously hypothcsiz~ that panicle size might be responsiblc for some of the side effects seen with aerosolized nicotine (I6). In the current study, we measured the particle size that resuke.d when nicotine solution was ~¢rosolized from the $~mdoz n~bullzer. We found a faiHy mass median diameter of 8.5 ~.rn. Particles of this size are predicted to deposit preferemially in the upper mimvays (17). Using the theoretical mode! ofg, dolfa, d coworkc.rs and condi~io, s sirnt~la~ing the nicotine exposure, predicted deposition is as follows: larynge.ml 55%, tracheobronchial 9%, and acinar 12% (1~). This degree of ]-~ryngeal deposition may have contributed to our subjects' symptoms of cough and th~oax irritation. The relatively large p~'dclc size creates a potentia! paradox with respect ~o our attempt understand the site of absorption of the nicotine aerosol. Cigarette smoke confine much smaller particles, which have been shown to deposit in distal lung ~gions. The smoke ~Iso cont~dns nicotine in a vapor phase. Cigarette smoking produces peak nicorin6 levels as rapidly as when nicotine is given intravenously (15). This phenomenon has bccn presumed to be duc ~o diets1 lung absorption (15). Studies in both dogs and hum:ms have shown that nicotine solution instilled into peripheral lung units via a cntheter pr,xluces nicotine levels as r'apidly as the intravenous route, whiIe absorption from solufionplacad into the trachea is much slower (19,20), Nasal nieettn,~ solution has also bccn shown to produce rapid peak levels. Peak levels of nicotine from nicotine gum and patches have been shown to occur much more slowly th~n with either cigarette smoke oc in~ravenous nicotine (2..4). These f'mdings ~upponcd the idea that rapid peak levels rcquire.d deposition in either the distal lung or d~e nail passages. In our study, rapid absorption occurred with an aerosol whose pm'ficle size wo,qd no~/~ expected to achieve much distal tung dcposition. 49

2~/06 '94 12:32 ~49 2203 303362 ;fN~BIFO Koeln ~-~ CEL The ~htively large total dose of nicot{ne that we gave may help to explain our findings. The dose used w~ four to five times that of a standard cigarette, yet it only increascxt the nicotine level by 8 to lg nffml, which is at the lower range of levels produced by one ties_mite. We speculated tlxat despite the large MMAD of the aerosol, at high doses a sufficient number of smaller pin-deles must have reached distai lung regions. Whi!e we cannot completeIy rule out the possibility, that nicotine was rapidly absorbed from sites in the oropharynx and large airways, the previous studies cited do not support this idea (11,19,20), Lux and Frecker reposed that they prep~.d ~ smatl-pa~cle nicotine aerosoI with a M..MAD of 0.5I~m (22). The pII of the aerosol wa.~ 5.5, and the calculated inhaI~ dose was ] me. They measured nicotine levels every five minutes for one hour and reporied a mean peak nicotine level of ~6 nmol/liter, or 7.6 ng/ml. However, .the baseline nicotine level and dxe timing of t~e peak were reported. It is not known whether a nicotine aerosol could be used as a form- of nicotine replacement during smokSng cessation. Our findings point out practicaI considerations of efficlen¢)' and side eft-cots which in theory might be overcome with a small-particle aerosol. Whether a niconne aerosol would prove effective in tl~e cessation process is even less clear, Two forms of nicotine replacement are av-~qable: nicotine gum and transdermal nicodne patches, NicotSne absorption from both forms is slow, so th.~t prevention of withdrawal-related cravings relies on maint~ning a constant blood level of nicotine ~o ease symptoms throughout the day. This leuet is very low with the currently available 2 mg gum, and the pataent must chew the gum all day long to maintain even these low levels, so compliance has been a problem. Peak nicotine levels reported with nicotine patches have generally been higher th;m from 2 nag nlcodne gum (3,4), and the p.~tch is easier to use. Still, the relapse rate with nicotine ~atches has b~en very high (8,9). Thus, there have been some apparent advances in nicotine subst~tur.ion therapy without proven improvement in long-term quit rates, The h~gh rel,~pse rate ha.~ focused auention on the ne~ for improved b~havioral therapy andretapse prevention, Russell and Fey.erabend proposed that it may be the puff~by-puff nicotine bolus effect of cigm-ette smoking thst le.~ds to such fierce dependence, not just to mcotine itself but to that particu, lar form of nicotine, so that other forms of nicotine do not satisfy (I5), Nicotine aerosol would provioe a pattern of nleoth~e substitution that would be more like the use of cigarettes. In theory, it might be more successful in preventing withdrawal symptoms, allowing more padents ~o achieve initi.~l abstinence from smoldng. However these same features, such zs the rapid onset of action and the potential for high blood levels, are factors that might increase the potential for physical or behavioral dependence on the aerosol nicotine itself (23). It has been suggested that patients might vm-y in their degree of dependence on peak levels, trough levels, or combinations (15). Successful nicotine substitution might uIdmately utilize multiple modalities that could b~ tailored to e~ch patient. proposed that morn studies be done to evaluate the potential of rapid-deliver), system~, such as nicotine aerosol, particularly in combination with slow-deliver~ systems like gum or transdermal patches (24). In summary, we have shown that inhalation of an acrosolized nicotine solution produced rapid peak plamaa levels that increased significantly ~s the aerosol ptt was increased.. Side ef[ec, ts were not affee.ted by differences in pH and were thought to be due to the large particle size ot me aerosol. Further study would be needed to determine whether this form or" nicotine could be used ~ccesgully ~ nicotine substitution during ~moldng cessation. P,.EFERENCES SVENSSON C (1987). Clinical Pharmokinctics of Nicotine_ Clin Pharmokinetics; 12:30-46. RUSSF..LL M, JARVIS M, SUTHER.LAND ~L, FEYERABEND C (19~7). Nicotine replacement in smoking cessation: Absorption o~ nicotine vapor from smoke-tree cigarettes, ~IA/C,.A.; 257(~3):3262-3265,. MULLIGAN SC, MASTERSON JG, DEVANqE J(3, KELLY JG (1990). Clinical and pharmacokinetie properties of a want, dermal rfieotine patch. Clin Phm-macol Ther; 47;33t-7, BAN'NON YB, CO1ZISH J, CORR1GAN OI, DEVANE J(3, KAVANAGH M, MULLIGAN KS (1989). Transdermal deli,,,ery of nicotine in normal human volunteers: a single dose and multiple dose stud)'. Eur I Clin Pharmaeol; 37:285-290. JARVIS J'F, RAW M, RUSSELL, M.AH, FEYER.ABEND C (1982), Randomized, controlled u-ial of nicotine chewing gum. Br Med J; :285:537-540. 5o

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24/06 '94 12:33 24. 25. 2203 303362 AINBIFO Koeln *e~ CEL BF2qo~vn-z NL (I@gl). P.h~n~acodynan~cs ofnico~c: of~e ad~cdon. B~h ~e~er M~u~, Erich beget GmbH ~-rticle received on FkRrch 5, 1990 in final ~ormNovember 24, 1992 Revlewe~by: William D. _nennett Wolfqang Kre~!ing Ad~s9 reprint re~ests t~: ~rcia L. Erbl~d, M.D. Div. of P~m~na~d Critlc~ Care Univ. ~f ~kansas for ~cal Sciences 4301 West~kh~Street/Slot 555 Little ~ck, ~ 72205 ~012