DEVELOPMENT OF A BUCCAL BIOADHESIVE NICOTINE TABLET
FORMULATION FOR SMOKING CESSATION
G. İkinci1, S. Şenel1, C.G. Wilson2, M. Şumnu1
1
2
Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 06100
Ankara-Turkey
University of Strathclyde, Department of Pharmaceutical Sciences, SIBS, Glasgow G4 0NR,
Scotland-UK
INTRODUCTION
Nicotine has a potential use as a therapeutic drug
for aiding smoking cessation. Chewing gums,
transdermal patches, inhalators, sublingual tablets
and intranasal sprays are commercially available
but still with some practical and cost problems.
Nicotine, which is a diacidic base (pKa values=3.4
and 8.2), is ionized at low pH values (1). To
increase its absorption from the oral mucosa it is
necessary to keep the pH of the mouth above 8.
Carbomer and alginic acid sodium salt are widely
used as bioadhesive polymers for buccal drug
delivery (2, 3).
The aim of this study was to prepare a suitable
tablet formulation using bioadhesive polymers for
nicotine delivery via the buccal route. Nicotine
hydrogen tartrate (NHT), which is more stable
than nicotine base (4), was used in the
formulations. A pH-increasing additive was also
added into the formulations, which would increase
the absorption of NHT from the buccal mucosa.
MATERIALS AND METHODS
Materials
Nicotine hydrogen tartrate and alginic acid
sodium salt (NaAlg) (medium viscosity) (Sigma,
St. Louis, USA), hydroxypropyl methylcellulose
(HPMC) (Methocel K4M, Colorcon, England),
carbomer (CP) (Carbopol 974P NF, BF
Goodrich, Cleveland, USA), magnesium stearate
(MgSt) and magnesium hydroxide (E. Merck,
Germany) were used as received.
Preparation of Tablets
Tablets were prepared by direct compression of
the mixture of the bioadhesive polymers, NHT
and the pH-increasing additive (magnesium
hydroxide). 1 % magnesium stearate was used as
lubricant. Tablets were compressed on a single
punch-tablet machine Korsch EK/O using flat
non-beveled punch of 12 mm diameter. Thickness
of the tablets were between 1.0-1.2 mm.
Composition of the formulations is given in
Table 1.
Table 1. Composition of the tablet
formulations (mg)
NHT
A1
A2
A3
A4
20
20
20
20
CP:HPMC
20:80
40:60
60:40
80:20
Mg(OH)2
MgSt
30
30
30
30
1,5
1,5
1,5
1,5
30
30
30
30
1,5
1,5
1,5
1,5
NaAlg:HPMC
B1
B2
B3
B4
20
20
20
20
20:80
40:60
60:40
80:20
In vitro release of NHT
Release of NHT from tablets was studied
using a modified Franz diffusion cell. The
dissolution medium was 22 mL phosphate
buffer saline (PBS) (pH 7.4). Uniform
mixing of the medium was provided by
magnetic stirring. To provide unidirectional
release, each bioadhesive tablet was
embedded in paraffin wax in a glass die
having a central hole 12 mm in diameter,
which was placed at the top of the receptor
site. Samples of 1 mL were taken from the
medium at certain time intervals and
replaced with the same amount of PBS. The
samples were filtered and assayed for NHT
at 259 nm using a UV 160A Shimadzu
spectrophotometer. pH of the samples were
measured during the release studies.
RESULTS AND DISCUSSION
Release of NHT from formulations
containing CP and NaAlg is shown in
Figs.1 and 2, respectively. In all
formulations, the released amount of NHT
increased with decreasing HPMC content.
Release of NHT from these formulations
appears to be controlled by diffusion. These
formulations remained intact during the 8 h
period. Only with formulation A4, a diphasic
release was obtained which can be attributed to
the rapid hydration and erosion of the tablet.
the pH around 8 whereas with tablets
containing NaAlg, the pH change was
rather under control.
7,6
A2
A3
A4
3
4
5
7,2
80
pH
% Released
A1
7,4
100
7,0
6,8
60
6,6
A1
A2
A3
A4
40
20
6,4
0,5
1
2
6
7
8
Time (h)
0
0
1
2
3
4
5
6
7
8
Time (h)
Fig. 3. Changes in the pH of the medium
during release studies of formulations
containing CP:HPMC
8,6
Fig. 1. Release of NHT from formulations
containing CP:HPMC
pH
% Released
B1
B2
B3
B4
8,2
7,8
100
7,4
80
7,0
6,6
60
0,5
B1
B2
B3
B4
40
20
1
2
3
4
5
6
7
2
3
4
5
6
7
8
Time (h)
0
0
1
8
Time (h)
Fig. 2. Release of NHT from formulations
containing NaAlg:HPMC
Changes in pH of the dissolution medium during
release studies are shown in Figs. 3 and 4.
Significant changes were observed in pH for
polymers used at different ratios. With increasing
amount of CP, the pH decreased significantly
whereas with NaAlg containing formulations, pH
increased with the increased amount of the
polymer. These results can be explained by the
anionic structure of CP and cationic structure of
NaAlg. In our preliminary studies, it was found
that magnesium hydroxide increased the pH
during permeation studies and enhanced
permeation of NHT through bovine buccal
mucosa. The amount of magnesium hydroxide
incorporated into the tablet formulations
containing CP was not sufficient enough to keep
Fig. 4. Changes in the pH of the medium
during release studies of formulations
containing NaAlg:HPMC
CONCLUSION
Controlled release of NHT was achieved
using two different polymer mixtures
(CP:HPMC
and
NaAlg:HPMC).
Bioadhesive properties and in vivo
performance of the developed tablets are
under investigation.
References
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İkinci G, Y Çapan, S Şenel, E Alaaddinoğlu, T
Dalkara, A A Hıncal, Pharmazie, 55, 762-765,
2000
2.
Save T, Venkitachalan P, Drug Dev Ind Pharm,
20, 3005-30015, 1994
3.
Oakley D M, Swarbrick J, J Pharm Sci, 76, 866871, 1987
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P,Nankervis R, Faraj N F, Smith A, Davis S S,
Illum L, J Control Rel, 79, 243-254, 2002