An oral formulation of nicotine for release and absorption in the colon: its development and pharmacokinetics

Abstract

Aims: Ulcerative colitis is predominantly a disease of nonsmokers and transdermal nicotine has therapeutic value in active disease; however side-effects are troublesome. The aim of this study was to develop an oral formulation of nicotine which would be slowly released in the colon over 6 h, and to examine its pharmacokinetic profile in 12 healthy volunteers, with measurements of serum nicotine and cotinine, its principal metabolite.

Methods: Nicotine was combined with a polyacrylic carbomer, Carbopol 974P which was incorporated into 13 different vehicles and their release profiles examined in vitro. The polyglycolized glyceride, Gelucire 50/13, was chosen for subsequent kinetic studies because it consistently produced a suitable release pattern which was linear. Capsules containing 3 mg nicotine, combined with carbomer in Gelucire 50/13, were coated with an acrylic resin Eudragit L; this ensured the capsule would remain intact until the ileum. On 2 separate days, 6 and 15 mg nicotine, contained in 2 and 5 capsules, respectively, were administered to 12 subjects, all nonsmokers, mean age 28 years. Serial blood measurements were taken for 36 h, serum nicotine and cotinine concentrations were measured by gas liquid chromatography.

Results: There was considerable intersubject variability in the nicotine and cotinine values. Plasma nicotine levels began to rise about 4 h after ingestion of the capsules, corresponding with the oro-caecal transit time. Cmax nicotine values were 2.2 and 5 ng ml-1, obtained 7 h after the ingestion of 6 and 15 mg, respectively, of the formulation. The corresponding Cmax values for cotinine were 37 and 94.4 ng ml-1, occurring after 9-10 h. The mean for elimination half-lives in the 24 studies, including the 6 and 15 mg doses, for nicotine were 4.3+/-2.7 h and for cotinine 16.8+/-7.5 h. With 6 mg nicotine-carbomer, only 1 of 12 volunteers had possible side-effects, but with the 15 mg dose 11 out of the 12 reported adverse effects which were systemic or gastrointestinal in nature-their timing corresponded with peak serum concentrations of nicotine.

Conclusions: An oral formulation of nicotine has been developed; in the ileum and colon, this becomes available for slow linear release over 6 h and delivers high concentrations of nicotine for topical effect on the colon. 6 mg Nicotine was well tolerated, whilst 15 mg gave both systemic and gastrointestinal side-effects. High concentrations of topical nicotine in the colon are achieved with relatively low systemic bioavailablity-reflected by the Cmax and AUC values for nicotine. This, or comparable formulations, may be of therapeutic value in ulcerative colitis.

Figure 1

The in vitro dissolution profile, over 6 h, of nicotine carbomer in three different vehicles—Gelucire 50/13, 44/14 and 53/10, showing differing patterns of release.

Figure 2

The in vitro dissolution of nicotine carbomer in Gelucire 50/13 from four separate capsules and their mean values at time points over 6 h.

Figure 3

The time-concentration curves for nicotine and cotinine in 12 healthy volunteers over 36 h after the ingestion of 6 mg and 15 mg nicotine carbomer. There is a wide intersubject variation in concentrations, in all four graphs the same symbol is used for each subject, for example subject 3 is represented by —▴—.

Figure 4

Mean time-concentration curves for nicotine and cotinine calculated from the individual values over 36 h, in the 12 healthy volunteers.