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146]

Original Article

Design, formulation and evaluation of nicotine chewing gum

Abolfazl Aslani, Sahar Rafiei
Department of Pharmaceutics, School of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical
Sciences, Isfahan, Iran

Abstract 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 Pharmaceutics, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
E-mail: [email protected]
Received: 20.02.2012, Accepted: 09.07.2012

INTRODUCTION

Access this article online Tobacco use through cigarette smoking is the
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leading avoidable cause of death in the world; it
www.advbiores.net kills almost 4 million people each year. According
to the World Health Organization, 10 million
DOI: smokers will die per year by 2030.[1] There are over
10.4103/2277-9175.100175 4000 chemicals in cigarette smoke, [2] including
43 carcinogenic compounds and 400 other toxins

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.

How to cite this article: Aslani A, Rafiei S. Design, formulation and evaluation of nicotine chewing gum. Adv Biomed Res 2012;1:57.

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Aslani and Rafiei: Formulation of nicotine chewing gum

such as nicotine, tar, carbon monoxide, as well as such as nicotine, caffeine, fluoride, dimenhydrinate,
formaldehyde, ammonia, hydrogen cyanide, arsenic, chlorhexidine, etc.[11]
and dichlorodiphenyltrichloroethane (DDT). [3] Nicotine
is the main active component in cigarette that Nicotine chewing gum is currently available in the
reinforces individual smoking behavior. However, market either as 2 or 4 mg preparations. The gums
there are other ingredients of tobacco and not release a controlled amount of nicotine in mouth
nicotine that lead to the mortality and morbidity.[4] that is absorbed directly through the buccal mucosa,
People become dependent on the nicotine in cigarette producing nicotine plasma concentrations which are
because it raises the levels of special chemicals, such about half that is produced by smoking a cigarette.[8]
as dopamine and norepinephrine, in their brains.[5] A limitation of commercially available nicotine gums
Smoking cessation at any age decreases the morbidity. is their slow rate of nicotine release and consequently
When people stop smoking, the levels of those the slow onset of their therapeutic effects.
chemicals fall, and reactions of body appear as nicotine
withdrawal syndrome such as craving for tobacco, The unpleasant taste of nicotine gums is, however,
irritability, nervousness, difficulty concentrating, a major challenge with respect to the patients’
impatience, insomnia, and increased appetite.[6] acceptance and compliance with suggested dosing
regimens.[13] Thus, the present study was carried
Nicotine replacement therapy (NRT) can help smokers out to develop nicotine gums with improved taste
to quit smoking by replacing some of the nicotine and quality as a favorable dosage form for NRT. We
generally gained from cigarettes.[7] It decreases many formulated the gums using nicotine hydrogen tartrate
of the physiological and psychomotor withdrawal due to its faster release rate. This may produce a
symptoms usually experienced after smoking cessation more rapid onset of craving relief, and thus greater
and may thus enhance the chance of remaining clinical benefits.[14]
abstinent.[8]
MATERIALS AND METHODS
NRT products include chewing gum, transdermal
Chemicals
patch, nasal spray, oral inhaler, and tablet.[4] The first
Nicotine tartrate was purchased from Sigma-Aldrich
product of NRT to become widely accessible was the
Co. LLC. (Berlin, Germany). Elvasti, 487, Stick, and
chewing gum.[8] The Food and Drug administration
Fruit C gum bases were obtained from Gilan Ghoot
(FDA) confirmed the prescription use of nicotine
Company, (Rasht, Iran). Flavors of eucalyptus,
chewing gum as smoking cessation aid in 1984 and
peppermint, banana, cola, and cinnamon were gifted
its nonprescription sale in 1995.[6]
by Goltash Company, (Isfahan, Iran), and flavors
of cherry, tutti-frutti and raspberry by Farabi
The chewing gum is one of the new methods of oral
Pharmaceutical Company, (Isfahan, Iran). Sugar,
transmucosal drug delivery and is a useful tool for
glycerin, sodium saccharin, aspartame, stevia, zinc
systemic drug delivery.[9] Advantages of chewing
acetate, sodium acetate, and sodium chloride were of
gum over conventional drug delivery system include: pharmaceutical grade.
Rapid onset of action, high bioavailability, easy
consumption without the need of water, higher patient Preparation of nicotine chewing gum
compliance, and fewer side effects like dry mouth and The nicotine gum was formulated using the gum
decrease in toxicity.[10] Formulations of medicated bases, sugar, liquid glucose, glycerin, a sweetener
chewing gums may include active components, gum (aspartame, stevia, liquorice, or sodium saccharin),
base, filler, softeners, sweetening agents, flavoring a taste-masking material (zinc acetate, sodium
agents, and emulsifiers.[11] Medicated chewing gums acetate, or sodium chloride), and a flavoring agent.
are formulated to release the majority of their The mixture of gum bases was softened at 60°C.
active component within 20–30 min. Factors such as Nicotine tartrate, sugar, liquid glucose, glycerin, and
intensity of chewing the gum and amount of saliva other ingredients [Table 1] were added to the base
produced influence the drug release and absorption to which was finally added the flavor at 40°C. The
in the buccal cavity.[12] uniform mixture was cut into the pieces of suitable
shape and size and kept at room temperature for 48
In general, decrease in drug concentration upon h [Table 1]. The medicated gums so prepared were
dilution with saliva and its disappearance from buccal coated by acacia aqueous solution (2% w/v). Sugar
cavity due to unwanted ingestion are the disadvantages dusting followed by acacia–sugar–calcium carbonate
of medicated chewing gums. Chewing gums as a drug coating was carried out until a smooth surface was
delivery system are, however, functional for medicines produced.

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Aslani and Rafiei: Formulation of nicotine chewing gum

Table 1: Formulations of nicotine chewing gum with different ingredients

Ingredients (mg) Formulations
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 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 120 63 189 126 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 150 150 150 218 220 200 200 200 200 200 200 200 200 200 200 200 200 200
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 spectrophotometer. The experiment was repeated
flavoring agent in the formulation F16 three times. The standard curve of nicotine tartrate
Formulation Flavoring agent was linear [y = 0.0198x + 0.0089 (R2 = 0.9995)] at
F19 Cherry concentrations ranging 5–60 µg/ml.
F20 Eucalyptus
F21 Peppermint In vitro drug release
F22 Banana A mastication device which simulated the mastication
F23 Cola of chewing gum in human was used to perform the
F24 Tutti-frutti drug release study. The device consisted of a piston
F25 Raspberry
which strokes the gum (60 strokes/min) at different
points on a random base and a chamber which holds
All formulations were preliminary investigated for the gum and the release medium (pH 6.8 phosphate
considering the effect of different flavoring agents buffer). Water (37°C) was circulated through a jacket
on masking the bitter taste of nicotine. Selected around the receiver chamber to simulate the in vivo
formulations according to organoleptic characteristics temperature.[17]
were prepared by using flavoring of cherry, eucalyptus,
peppermint, banana, cola, tutti-frutti, and raspberry Aliquots of 1 ml were removed at 0, 5, 10, 15, 20, 25,
[Table 2]. 30, and 45 min, and their absorbance were measured
at 260.8 nm, as described before. The test was repeated
Weight variation three times.
Ten chewing gums of each formulation were weighed.
The average weight and standard deviation were Evaluating the organoleptic characteristics of nicotine
calculated.[15] chewing gums
The Latin Square design was used for the preliminary
Uniformity of content evaluation of organoleptic characteristics of the
Ten nicotine gums were selected randomly. [16] formulations. Ten smokers were asked to chew each
Each gum was first dissolved in 50 ml chloroform. gum (F1–F18 formulations) for 20 min and express their
Phosphate buffer pH 6.8 was then used to extract opinions about chewing hardness, gum adhering to
drug into the aqueous phase. The amount of nicotine teeth, the plumpness, and the taste, according to the
was determined by measuring the drug absorbance at Likert scale of 1–5 (very poor = 1, poor = 2, average =
260.8 nm using a Shimadzu UV-1240 model UV-visible 3, good = 4, and excellent = 5). The subjects were asked

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Aslani and Rafiei: Formulation of nicotine chewing gum

to rinse their mouths with water and wait for 20 min were most efficacious in removing the bitter taste of
before examining the next formulation. nicotine gums [Table 4]. Sugar coating improved the
appearance of gums; however, its effect on the taste
Further development of formulations was performed was only marginal [Table 5].
by altering the flavoring agent in the formulation
Table 3: Organoleptic characteristics of different nicotine
F16, indicated to be the most acceptable gum in the
chewing gums
preliminary evaluation [Table 2]. A panel test consisting
Formulation Chewing Plumpness Adhering to Taste*
of 20 smokers also was used in the same manner as hardness teeth
previously explained to evaluate acceptability of the F1 Very hard Little No 1
formulations. In the last stage, two formulations, (F19, F2 Hard Little No 1
F20), shown to be more acceptable to patients in the F3 Hard Much No 1
previous study, were sugar-coated and given to a new F4 Hard Suitable No 1.6
group of 30 smokers and evaluated as before. F5 Suitable Suitable No 1.7
F6 Suitable Suitable No 1.7
RESULTS F7 Suitable Suitable No 1.8
F8 Suitable Suitable No 1.7
Chewing gums weight variation and nicotine content F9 Suitable Suitable No 1.9
Weight variation of gums was within the USP- F10 Suitable Suitable Yes 2.5
recommended limit of ±5%. The mean drug content F11 Suitable Suitable No 1.7
was 1.94 ± 0.085 for 2 mg and 3.87 ± 0.125 for 4 mg F12 Suitable Suitable No 1.8
nicotine chewing gums, all satisfying the criteria F13 Suitable Suitable No 2.6
commonly required by USP for solid dosage forms. F14 Suitable Suitable No 3.1
F15 Suitable Suitable No 3.0
In vitro drug release from chewing gums F16 Suitable Suitable No 3.5
The release of nicotine from gum bases is shown in F17 Suitable Suitable No 3.1
Figure 1. About 83% and 79% nicotine was released F18 Suitable Suitable No 3.5
after 20 min from 2 and 4 mg gum, respectively. The *
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)
drug release was, however, 92% and 93% from 2 and
4 mg formulations, respectively, after 45 min.
Table 4: Taste evaluation of formulations F16 and F19–F25 with
different flavoring agents in nicotine gum formulations
Evaluation of organoleptic characteristics of nicotine
Formulations* Score**
chewing gum
1 2 3 4 5 Mean
Organoleptic characteristics of nicotine gums were
F16 2 5 8 5 - 2.8
dependent on the ingredients used. F 16 and F 18
F19 - 2 5 13 - 3.55
formulations (of 2 and 4 mg nicotine gums, respectively)
F20 1 2 6 11 - 3.35
exhibited acceptable physical characteristics with
F21 6 5 8 1 - 2.2
respect to chewing hardness, gum adhering to teeth,
F22 7 9 3 1 - 1.9
the plumpness, and the overall taste in preliminary F23 12 4 4 - - 1.6
evaluations [Table 3]. Further modification of F24 2 7 8 3 - 2.6
formulation F 16 using different flavoring agents F25 3 4 12 1 - 2.55
indicated that cherry and eucalyptus (F19 and F20) *
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
4 19 16
5 1 -
Mean 3.63 3.37
The taste was determined by 30 smokers using the Likert scale of 1–5 (Very poor
Figure 1: In vitro release of nicotine from 2 and 4 mg chewing gum in = 1, Poor = 2, Average = 3, Good = 4, and Excellent = 5) **The flavoring agents
pH 6.8 phosphate buffer at 37°C used in F19 and F20 formulations were cherry and eucalyptus, respectively

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Aslani and Rafiei: Formulation of nicotine chewing gum

DISCUSSION taste modification of chlorhexidine chewing gums by

aspartame, peppermint, and menthol,[17] others have
Nicotine gums can be considered as a dosage form which seen better effect with sorbitol and peppermint.[15]
is provided to smokers, helping them quit smoking. To However, in our study, peppermint showed an average
be demanded by patients, such medicated gums are effect on taste masking (compare F21 vs. F19 and F20)
required to have an optimal chewing volume, a long- [Table 4]. Thus, it is rational to design and perform
lasting taste, anti-adherent properties to the teeth, taste-modification investigations on each medication
and suitable organoleptic properties. Formulation and dosage form independently.
F1 was very hard due to the nature of Elvasti base
used. Elvasti, Stick, 487, and Fruit C bases have Formulations F16 and F18 released 83% and 79% of
different hardness. Elvasti and Fruit C bases have their nicotine content within 20 min, respectively.
the highest and the lowest hardness, respectively. This was in agreement with results obtained by
In formulations F2–F4, by using three other bases, Morjaria et al. on nicotine chewing gums, marketed
hardness of gum became less, but it was not suitable as Pharmagum®S, Pharmagum®M, and Nicorette®.[22]
yet. In formulations F5–F25, softness and hardness of
gum was desirable. In this study, for providing nicotine CONCLUSION
gum with suitable softness and hardness, equal ratios
of Elvasti, Stick, 487, and Fruit C bases were used, The results of this study showed that gum can be
but it is possible to use different ratios of these base a good carrier of nicotine. The best formulations
in other medicated and non-medicated chewing gums. according to organoleptic characteristics were F16 and
F18 for 2 and 4 mg gum, respectively. Aspartame and
Sodium saccharin with a sweetening power of 300–600 flavoring of cherry and eucalyptus were more effective
times higher than sucrose, though reported to enhance to eliminate the bitter taste of nicotine.
the effects of flavoring systems,[18] had little or no
effect on masking the bitter taste of nicotine gums ACKNOWLEDGMENT
[Table 3] (F4 and F5). Liquorice, a sweetening agent
This study was supported by Isfahan University of Medical
which is widely used in tobacco industry,[19] decreased
Sciences as a thesis research project numbered 389366.
the bitterness of nicotine only slightly [Table 3]
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