Design, formulation and evaluation of nicotine chewing gum

Abstract

Nicotine replacement therapy (NRT) can help smokers to quit smoking. Nicotine chewing gum has attracted the attention from pharmaceutical industries to offer it to consumers as an easily accessible NRT product. However, the bitter taste of such gums may compromise their acceptability by patients. This study was, therefore, designed to develop 2 and 4 mg nicotine chewing gums of pleasant taste, which satisfy the consumers the most.
Nicotine, sugar, liquid glucose, glycerin, different sweetening and taste-masking agents, and a flavoring agent were added to the gum bases at appropriate temperature. The medicated gums were cut into pieces of suitable size and coated by acacia aqueous solution (2% w/v), sugar dusting, followed by acacia-sugar-calcium carbonate until a smooth surface was produced. The gums' weight variation and content uniformity were determined. The release of nicotine was studied in pH 6.8 phosphate buffer using a mastication device which simulated the mastication of chewing gum in human. The Latin Square design was used for the evaluation of organoleptic characteristics of the formulations at different stages of development.
Most formulations released 79-83% of their nicotine content within 20 min. Nicotine-containing sugar-coated gums in which aspartame as sweetener and cherry and eucalyptus as flavoring agents were incorporated (i.e. formulations F(19-SC) and F(20-SC), respectively) had optimal chewing hardness, adhering to teeth, and plumpness characteristics, as well as the most pleasant taste and highest acceptability to smokers.
Taste enhancement of nicotine gums was achieved where formulations comprised aspartame as the sweetener and cherry and eucalyptus as the flavoring agents. Nicotine gums of pleasant taste may, therefore, be used as NRT to assist smokers quit smoking.

Full text

Advanced Biomedical Research | October - December 2012 | Vol 1 | Issue 4 1
Background: Nicotine replacement therapy (NRT) can help smokers to quit smoking. Nicotine chewing gum
has attracted the attention from pharmaceutical industries to offer it to consumers as an easily accessible
NRT product. However, the bitter taste of such gums may compromise their acceptability by patients. This
study was, therefore, designed to develop 2 and 4 mg nicotine chewing gums of pleasant taste, which
satisfy the consumers the most.
Materials and Methods: Nicotine, sugar, liquid glucose, glycerin, different sweetening and taste-masking
agents, and a flavoring agent were added to the gum bases at appropriate temperature. The medicated
gums were cut into pieces of suitable size and coated by acacia aqueous solution (2% w/v), sugar dusting,
followed by acacia–sugar–calcium carbonate until a smooth surface was produced. The gums’ weight
variation and content uniformity were determined. The release of nicotine was studied in pH 6.8 phosphate
buffer using a mastication device which simulated the mastication of chewing gum in human. The Latin
Square design was used for the evaluation of organoleptic characteristics of the formulations at different
stages of development.
Results: Most formulations released 79–83% of their nicotine content within 20 min. Nicotine-containing
sugar-coated gums in which aspartame as sweetener and cherry and eucalyptus as flavoring agents were
incorporated (i.e. formulations F19-SC and F20-SC, respectively) had optimal chewing hardness, adhering to
teeth, and plumpness characteristics, as well as the most pleasant taste and highest acceptability to smokers.
Conclusion: Taste enhancement of nicotine gums was achieved where formulations comprised aspartame
as the sweetener and cherry and eucalyptus as the flavoring agents. Nicotine gums of pleasant taste may,
therefore, be used as NRT to assist smokers quit smoking.
Key Words: Nicotine chewing gum, nicotine replacement therapy, nicotine addiction, smoking cessation
Address for correspondence:
Dr. Abolfazl Aslani, Department of Pharmaceucs, School of Pharmacy and Pharmaceucal Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
E-mail: aslani@pharm.mui.ac.ir
Received: 20.02.2012, Accepted: 09.07.2012
Abstract
Design, formulation and evaluation of nicotine chewing gum
Abolfazl Aslani, Sahar Raei
Department of Pharmaceucs, School of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical
Sciences, Isfahan, Iran
Original Article
Access this article online
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Website:
www.advbiores.net
DOI:
10.4103/2277-9175.100175
INTRODUCTION
Tobacco use through cigarette smoking is the
leading avoidable cause of death in the world; it
kills almost 4 million people each year. According
to the World Health Organization, 10 million
smokers will die per year by 2030.[1] There are over
4000 chemicals in cigarette smoke,[2] including
43 carcinogenic compounds and 400 other toxins
How to cite this article: Aslani A, Raei S. Design, formulation and evaluation of nicotine chewing gum. Adv Biomed Res 2012;1:57.
Copyright: © 2012 Aslani. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction
in any medium, provided the original author and source are credited.
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Aslani and Rafiei: Formulation of nicotine chewing gum
2 Advanced Biomedical Research | October - December 2012 | Vol 1 | Issue 4
such as nicotine, tar, carbon monoxide, as well as
formaldehyde, ammonia, hydrogen cyanide, arsenic,
and dichlorodiphenyltrichloroethane (DDT).
[3] Nicotine
is the main active component in cigarette that
reinforces individual smoking behavior. However,
there are other ingredients of tobacco and not
nicotine that lead to the mortality and morbidity.[4]
People become dependent on the nicotine in cigarette
because it raises the levels of special chemicals, such
as dopamine and norepinephrine, in their brains.[5]
Smoking cessation at any age decreases the morbidity.
When people stop smoking, the levels of those
chemicals fall, and reactions of body appear as nicotine
withdrawal syndrome such as craving for tobacco,
irritability, nervousness, difficulty concentrating,
impatience, insomnia, and increased appetite.[6]
Nicotine replacement therapy (NRT) can help smokers
to quit smoking by replacing some of the nicotine
generally gained from cigarettes.[7] It decreases many
of the physiological and psychomotor withdrawal
symptoms usually experienced after smoking cessation
and may thus enhance the chance of remaining
abstinent.[8]
NRT products include chewing gum, transdermal
patch, nasal spray, oral inhaler, and tablet.[4] The first
product of NRT to become widely accessible was the
chewing gum.[8] The Food and Drug administration
(FDA) confirmed the prescription use of nicotine
chewing gum as smoking cessation aid in 1984 and
its nonprescription sale in 1995.[6]
The chewing gum is one of the new methods of oral
transmucosal drug delivery and is a useful tool for
systemic drug delivery.[9] Advantages of chewing
gum over conventional drug delivery system include:
Rapid onset of action, high bioavailability, easy
consumption without the need of water, higher patient
compliance, and fewer side effects like dry mouth and
decrease in toxicity.[10] Formulations of medicated
chewing gums may include active components, gum
base, filler, softeners, sweetening agents, flavoring
agents, and emulsifiers.[11] Medicated chewing gums
are formulated to release the majority of their
active component within 20–30 min. Factors such as
intensity of chewing the gum and amount of saliva
produced influence the drug release and absorption
in the buccal cavity.[12]
In general, decrease in drug concentration upon
dilution with saliva and its disappearance from buccal
cavity due to unwanted ingestion are the disadvantages
of medicated chewing gums. Chewing gums as a drug
delivery system are, however, functional for medicines
such as nicotine, caffeine, fluoride, dimenhydrinate,
chlorhexidine, etc.[11]
Nicotine chewing gum is currently available in the
market either as 2 or 4 mg preparations. The gums
release a controlled amount of nicotine in mouth
that is absorbed directly through the buccal mucosa,
producing nicotine plasma concentrations which are
about half that is produced by smoking a cigarette.[8]
A limitation of commercially available nicotine gums
is their slow rate of nicotine release and consequently
the slow onset of their therapeutic effects.
The unpleasant taste of nicotine gums is, however,
a major challenge with respect to the patients’
acceptance and compliance with suggested dosing
regimens.[13] Thus, the present study was carried
out to develop nicotine gums with improved taste
and quality as a favorable dosage form for NRT. We
formulated the gums using nicotine hydrogen tartrate
due to its faster release rate. This may produce a
more rapid onset of craving relief, and thus greater
clinical benefits.[14]
MATERIALS AND METHODS
Chemicals
Nicotine tartrate was purchased from Sigma-Aldrich
Co. LLC. (Berlin, Germany). Elvasti, 487, Stick, and
Fruit C gum bases were obtained from Gilan Ghoot
Company, (Rasht, Iran). Flavors of eucalyptus,
peppermint, banana, cola, and cinnamon were gifted
by Goltash Company, (Isfahan, Iran), and flavors
of cherry, tutti-frutti and raspberry by Farabi
Pharmaceutical Company, (Isfahan, Iran). Sugar,
glycerin, sodium saccharin, aspartame, stevia, zinc
acetate, sodium acetate, and sodium chloride were of
pharmaceutical grade.
Preparation of nicotine chewing gum
The nicotine gum was formulated using the gum
bases, sugar, liquid glucose, glycerin, a sweetener
(aspartame, stevia, liquorice, or sodium saccharin),
a taste-masking material (zinc acetate, sodium
acetate, or sodium chloride), and a flavoring agent.
The mixture of gum bases was softened at 60°C.
Nicotine tartrate, sugar, liquid glucose, glycerin, and
other ingredients [Table 1] were added to the base
to which was finally added the flavor at 40°C. The
uniform mixture was cut into the pieces of suitable
shape and size and kept at room temperature for 48
h [Table 1]. The medicated gums so prepared were
coated by acacia aqueous solution (2% w/v). Sugar
dusting followed by acacia–sugar–calcium carbonate
coating was carried out until a smooth surface was
produced.
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Aslani and Rafiei: Formulation of nicotine chewing gum
Advanced Biomedical Research | October - December 2012 | Vol 1 | Issue 4 3
All formulations were preliminary investigated for
considering the effect of different flavoring agents
on masking the bitter taste of nicotine. Selected
formulations according to organoleptic characteristics
were prepared by using flavoring of cherry, eucalyptus,
peppermint, banana, cola, tutti-frutti, and raspberry
[Table 2].
Weight variation
Ten chewing gums of each formulation were weighed.
The average weight and standard deviation were
calculated.[15]
Uniformity of content
Ten nicotine gums were selected randomly.[16]
Each gum was first dissolved in 50 ml chloroform.
Phosphate buffer pH 6.8 was then used to extract
drug into the aqueous phase. The amount of nicotine
was determined by measuring the drug absorbance at
260.8 nm using a Shimadzu UV-1240 model UV-visible
spectrophotometer. The experiment was repeated
three times. The standard curve of nicotine tartrate
was linear [y = 0.0198x + 0.0089 (R2 = 0.9995)] at
concentrations ranging 5–60 µg/ml.
In vitro
drug release
A mastication device which simulated the mastication
of chewing gum in human was used to perform the
drug release study. The device consisted of a piston
which strokes the gum (60 strokes/min) at different
points on a random base and a chamber which holds
the gum and the release medium (pH 6.8 phosphate
buffer). Water (37°C) was circulated through a jacket
around the receiver chamber to simulate the in vivo
temperature.[17]
Aliquots of 1 ml were removed at 0, 5, 10, 15, 20, 25,
30, and 45 min, and their absorbance were measured
at 260.8 nm, as described before. The test was repeated
three times.
Evaluating the organoleptic characteristics of nicotine
chewing gums
The Latin Square design was used for the preliminary
evaluation of organoleptic characteristics of the
formulations. Ten smokers were asked to chew each
gum (F1–F18 formulations) for 20 min and express their
opinions about chewing hardness, gum adhering to
teeth, the plumpness, and the taste, according to the
Likert scale of 1–5 (very poor = 1, poor = 2, average =
3, good = 4, and excellent = 5). The subjects were asked
Table 1: Formulations of nicotine chewing gum with different ingredients
Ingredients (mg) Formulations
F1F2F3F4F5F6F7F8F9F10 F11 F12 F13 F14 F15 F16 F17 F18
Nicotine 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 4 4
Gum bases
Elvasti 12 0 63 189 12 6 70 70 70 70 70 70 70 70 70 70 70 70 70 70
487 - 24 72 48 70 70 70 70 70 70 70 70 70 70 70 70 70 70
Stick - 24 72 48 70 70 70 70 70 70 70 70 70 70 70 70 70 70
Fruit C - 9 27 18 70 70 70 70 70 70 70 70 70 70 70 70 70 70
Sugar 532 532 532 550 500 500 500 500 500 500 500 500 500 500 500 500 500 500
Liquid glucose 15 0 15 0 15 0 218 220 200 200 200 200 200 200 200 200 200 200 200 200 200
Glycerol 16 16 16 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20
Aspartame - - - - - - - - - - - - - 2 2 2 2 3
Sodium saccharin - - - 2 2 - - - - - - - - - - - - -
Liquorice - - - - - 20 20 20 20 20 20 20 20 20 20 - - -
Stevia - - - - - - 2 10 10 10 10 10 5 - - - - -
Sodium chloride - - - - - - - - - - 10 10 - - - - - -
Sodium acetate - - - - - - 10 5 20 - - - - - - - - -
Zinc acetate - - - - - - - - - 10 - - 10 20 - - - -
Cola - - - - - - 10 - - - - - - - - - - -
Banana 10 10 10 - - - - - - - - - - - - - - -
Peppermint - - - 10 - - - - - - - - - - - - - -
Eucalyptus - - - - 10 10 - - - - - - - - - - - -
Cinnamon - - - - - - - 10 10 10 10 15 15 15 15 15 15 15
Table 2: Formulations of nicotine chewing gum by altering the
flavoring agent in the formulation F16
Formulation Flavoring agent
F19 Cherry
F20 Eucalyptus
F21 Peppermint
F22 Banana
F23 Cola
F24 Tutti-frutti
F25 Raspberry
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Aslani and Rafiei: Formulation of nicotine chewing gum
4 Advanced Biomedical Research | October - December 2012 | Vol 1 | Issue 4
to rinse their mouths with water and wait for 20 min
before examining the next formulation.
Further development of formulations was performed
by altering the flavoring agent in the formulation
F16, indicated to be the most acceptable gum in the
preliminary evaluation [Table 2]. A panel test consisting
of 20 smokers also was used in the same manner as
previously explained to evaluate acceptability of the
formulations. In the last stage, two formulations, (F19,
F20), shown to be more acceptable to patients in the
previous study, were sugar-coated and given to a new
group of 30 smokers and evaluated as before.
RESULTS
Chewing gums weight variation and nicotine content
Weight variation of gums was within the USP-
recommended limit of ±5%. The mean drug content
was 1.94 ± 0.085 for 2 mg and 3.87 ± 0.125 for 4 mg
nicotine chewing gums, all satisfying the criteria
commonly required by USP for solid dosage forms.
In vitro drug release from chewing gums
The release of nicotine from gum bases is shown in
Figure 1. About 83% and 79% nicotine was released
after 20 min from 2 and 4 mg gum, respectively. The
drug release was, however, 92% and 93% from 2 and
4 mg formulations, respectively, after 45 min.
Evaluation of organoleptic characteristics of nicotine
chewing gum
Organoleptic characteristics of nicotine gums were
dependent on the ingredients used. F16 and F18
formulations (of 2 and 4 mg nicotine gums, respectively)
exhibited acceptable physical characteristics with
respect to chewing hardness, gum adhering to teeth,
the plumpness, and the overall taste in preliminary
evaluations [Table 3]. Further modification of
formulation F16 using different flavoring agents
indicated that cherry and eucalyptus (F19 and F20)
Figure 1: In vitro
release of nicotine from 2 and 4 mg chewing gum in
pH 6.8 phosphate buffer at 37°C
were most efficacious in removing the bitter taste of
nicotine gums [Table 4]. Sugar coating improved the
appearance of gums; however, its effect on the taste
was only marginal [Table 5].
Table 3: Organoleptic characteristics of different nicotine
chewing gums
Formulation Chewing
hardness
Plumpness Adhering to
teeth
Taste*
F1Very hard Little No 1
F2Hard Little No 1
F3Hard Much No 1
F4Hard Suitable No 1.6
F5Suitable Suitable No 1.7
F6Suitable Suitable No 1.7
F7Suitable Suitable No 1.8
F8Suitable Suitable No 1.7
F9Suitable Suitable No 1.9
F10 Suitable Suitable Yes 2.5
F11 Suitable Suitable No 1.7
F12 Suitable Suitable No 1.8
F13 Suitable Suitable No 2.6
F14 Suitable Suitable No 3.1
F15 Suitable Suitable No 3.0
F16 Suitable Suitable No 3.5
F17 Suitable Suitable No 3.1
F18 Suitable Suitable No 3.5
*The taste was determined by 10 smokers using the Likert scale of 1–5
(Very poor = 1, Poor = 2, Average = 3, Good = 4, and Excellent = 5)
Table 4: Taste evaluation of formulations F16 and F19 –F25 with
different flavoring agents in nicotine gum formulations
Formulations*Score**
1 2 3 4 5 Mean
F16 2 5 8 5 - 2.8
F19 - 2 5 13 - 3.55
F20 1 2 6 11 - 3.35
F21 6 5 8 1 - 2.2
F22 7 9 3 1 - 1.9
F23 12 4 4 - - 1. 6
F24 2 7 8 3 - 2.6
F25 3 4 12 1 - 2.55
*The taste was determined by 20 smokers using the Likert scale of 1–5 (Very
poor = 1, Poor = 2, Average = 3, Good = 4, and Excellent = 5) **The flavoring
agents used in F16 and F19 –F25 formulations were cinnamon, cherry, eucalyptus,
peppermint, banana, cola, tutti-frutti, and raspberry, respectively
Table 5: The taste-masking effects of cherry or eucalyptus as
flavoring agent in nicotine sugar-coated gum formulations
Scores*Formulations**
F19- SC F20-SC
1 0 1
2 2 3
3 8 10
419 16
5 1 -
Mean 3.63 3.37
The taste was determined by 30 smokers using the Likert scale of 1–5 (Very poor
= 1, Poor = 2, Average = 3, Good = 4, and Excellent = 5) **The flavoring agents
used in F19 and F20 formulations were cherry and eucalyptus, respectively
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Aslani and Rafiei: Formulation of nicotine chewing gum
Advanced Biomedical Research | October - December 2012 | Vol 1 | Issue 4 5
DISCUSSION
Nicotine gums can be considered as a dosage form which
is provided to smokers, helping them quit smoking. To
be demanded by patients, such medicated gums are
required to have an optimal chewing volume, a long-
lasting taste, anti-adherent properties to the teeth,
and suitable organoleptic properties. Formulation
F1 was very hard due to the nature of Elvasti base
used. Elvasti, Stick, 487, and Fruit C bases have
different hardness. Elvasti and Fruit C bases have
the highest and the lowest hardness, respectively.
In formulations F2–F4, by using three other bases,
hardness of gum became less, but it was not suitable
yet. In formulations F5–F25, softness and hardness of
gum was desirable. In this study, for providing nicotine
gum with suitable softness and hardness, equal ratios
of Elvasti, Stick, 487, and Fruit C bases were used,
but it is possible to use different ratios of these base
in other medicated and non-medicated chewing gums.
Sodium saccharin with a sweetening power of 300–600
times higher than sucrose, though reported to enhance
the effects of flavoring systems,[18] had little or no
effect on masking the bitter taste of nicotine gums
[Table 3] (F4 and F5). Liquorice, a sweetening agent
which is widely used in tobacco industry,[19] decreased
the bitterness of nicotine only slightly [Table 3]
(F6). Similarly, sodium salts were not efficacious in
masking the bitter taste [Table 3] (F7–F9 and F11–F12).
This was not in agreement with other reports on the
positive effects of sodium salts on the bitter taste
improvement.[20]
Zinc acetate in formulations F10 and F13–F14 had a
moderate effect in masking the bitterness of nicotine
[Table 3]. It seems that zinc influences oral perception
by eliciting the taste itself, interfering with the normal
function of a taste system, and eliciting astringency.[21]
In our study, aspartame exhibited the strongest effect
on modifying the bitter taste of nicotine gums [Table 3]
(F16–F18). The amount of aspartame used seemed to
be important too (compare F17 and F18) [Table 3]. The
effect of aspartame was, however, reduced where
other sweeteners were also added to the formulations
[Table 3] (F14, F15).
The effects of various flavoring agents investigated
through formulations F16 and F19–F25 [Table 4]
indicated that cherry and eucalyptus produced the
most pleasing taste (F19, F20). The overall effects of
sweeteners and flavoring agents on taste modification
seem to be dependent on the type of dosage form
as well as active and inactive ingredients used in
the formulation. While some have reported bitter
taste modification of chlorhexidine chewing gums by
aspartame, peppermint, and menthol,[17] others have
seen better effect with sorbitol and peppermint.[15]
However, in our study, peppermint showed an average
effect on taste masking (compare F21 vs. F19 and F20)
[Table 4]. Thus, it is rational to design and perform
taste-modification investigations on each medication
and dosage form independently.
Formulations F16 and F18 released 83% and 79% of
their nicotine content within 20 min, respectively.
This was in agreement with results obtained by
Morjaria et al. on nicotine chewing gums, marketed
as Pharmagum®S, Pharmagum®M, and Nicorette®.[22]
CONCLUSION
The results of this study showed that gum can be
a good carrier of nicotine. The best formulations
according to organoleptic characteristics were F16 and
F18 for 2 and 4 mg gum, respectively. Aspartame and
flavoring of cherry and eucalyptus were more effective
to eliminate the bitter taste of nicotine.
ACKNOWLEDGMENT
This study was supported by Isfahan University of Medical
Sciences as a thesis research project numbered 389366.
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