J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54

I SSN: 2231-3354
Received on: 11-06-2012
Revised on: 17-06-2012
Accepted on: 23-06-2012
DOI: 10.7324/J APS.2012.2706
























Prashant K. Pagare, Chandrakant S.
Satpute, Varsha M. J adhav,
Vilasrao Kadam
Bharati Vidyapeeths Collegeof
Pharmacy, University of Mumbai,
Sector-8, C.B.D., Belapur, Navi
Mumbai- 400614, Maharashtra,
I ndia























For Correspondence
Prashant K. Pagare,
Bharati Vidyapeeths Collegeof
Pharmacy, Sector-8, C.B.D.,
Belapur, Navi Mumbai- 400614,
Maharashtra, I ndi a.
Tel: 91-22-27571122,
Fax: 91-22-17578142,
Mobile: 91-9892877370

Medicated Chewing Gum: A Novel Drug Delivery
System


Prashant K. Pagare, Chandrakant S. Satpute, Varsha M. Jadhav and
Vilasrao Kadam
ABSTRACT

In the recent years scientific and technological advancements have been made in the
research and development of oral drug delivery systems. The reasons that the oral route
achieved such popularity may be primarily due to its ease of administration. Chewing gumis
one of the very popular oral confectionary products. It is a potentially useful means of
administering drugs either locally or systematically via, the oral cavity. The medicated chewing
gumhas through the recent years gained increasing acceptance as a drug delivery system.
Chewing gum known as gumbase (insoluble gumbase resin) contains elastomers, emulsifiers,
fillers, waxes, antioxidants, softners, sweeteners, food colorings, flavoring agents, and in case of
medical chewing gum, active substances. It offers various advantages over conventional drug
delivery systems. Unlike chewable tablets, medicated chewing gums are not supposed to be
swallowed and may be removed fromthe site of application without resorting to invasive
means. Moreover medicated chewing gums require the active and continuous masticatory
activities for activation and continuation of drug release. An In-vitro apparatus was specially
designed and constructed for release testing of medicated chewing gums. Medicated chewing
gums are excellent mobile drug delivery systems for self-medication as it is convenient and can
be administered discretely without water.


Keywords: Oral drug delivery, chewing gum, patient compliance, mobile drug delivery system,
mouth diseases.
INTRODUCTION

Now-a-days most of the drugs are formulated into various solid dosage forms including
the most popular ones like Tablets, capsules etc. and semi-solid dosage forms such as creams,
ointments, gels etc. Chewing gum is being used worldwide since ancient times after man
experienced the pleasure of chewing a variety of substance. It can be used as a convenient
modified release drug delivery system. Chewing gum has been used for centuries to clean the
mouth and freshen the breath (Jacobsen et al., 2004). One thousand years ago the Mayan Indians
chewed the tree resin (Chicle) fromthe sapodilla tree to clean their teeth and freshen their breath.

J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54



















The first commercial chewing gumState of Maine pure
spruce gum was marketed in 1948 in the U.S.A. The first patent
was filed in 1869 (Conway et al., 2003). The gumwas intended as
dentifrices but it has never been marketed. The first Medicated
chewing gum Aspergum was launched in 1928. This chewing
gumis still available and contains acetylsalicylic acid. Another
commercially available medicated chewing gumis dimenhydrinate
containing chewing gum for motion sickness. However, chewing
gumdid not gain acceptance as a reliable drug delivery system
until 1978, when nicotine chewing gum became available. In 1991,
Chewing Gum was approved as a term for pharmaceutical dosage
formby the commission of European Council. Moreover, there is
need of reformulation of existing drug into New Drug Delivery
Systems (NDDS) to extend or protect product patents thereby
delaying, reducing or avoiding generic erosion at patent expiry.
Today improved technology and extended know how have made it
possible to develop and manufacture medicated-chewing gumwith
pre-defined properties. MCG is one of them. Owing to new social
and behavioral trends in the past modern age, such as the growing
consumer health awareness and increasing attention to safety
products, chewing gum has been known for a new image and
potential. Chewing gumtoday is gaining consideration as a vehicle
or a delivery system to administer active principles that can
improve health and nutrition.
MCG represents the newest system with potential uses in
pharmaceuticals, over the counter medicines and nutraceuticals
(Lee et al., 2001). The drugs intended to act in oral cavity often
have low water/saliva solubility and chewing gum constitute a
valuable delivery systemfor such drugs.

Definition
Medicated Chewing Gum (MCG) is a novel drug delivery
system containing masticatory gum base with pharmacologically
active ingredient and intended to use for local treatment of mouth
diseases or systemic absorption through oral mucosa. MCG is
considered as vehicle or a drug delivery system to administer
active principles that can improve health and nutrition.

Why Use Chewing Gum As A Drug Delivery System?
Chewing gum provides new competitive advantages over
conventional drug delivery system:
Fast onset of action and high bioavailability
Pleasant taste
Higher compliance (easy and discreet administration
without water)
Ready for use
High acceptance by children (Lamb et al., 1993)

Fewer side effects
Low dosage gives high efficacy as hepatic first pass
metabolismis avoided. The controlled release rate also reduces the
risk of side effects, as high plasma peak concentrations are
avoided.

Systemic effect
Active substances can be absorbed through the buccal
mucosa and/or through the GI tract when saliva is swallowed.
Once the active substance is present in the blood, systemic affect
can be obtained (Lamb et al., 1993).

Fast onset of action
Fast onset of systemic effect is seen for active substances
absorbed through the buccal mucosa, as the active substances pass
by the jugular veins directly to the systemic circulation.

Local effect
Chewing gumis an obvious drug delivery systemfor local
treatment of diseases in the oral cavity and in the throat, as
sustaining the release of active substances may deliberately
prolong exposure.

Effect on dry mouth ( xerostomia)
Dry mouth is a side effect of many types of medicament
(e.g. antidepressants) and it is also part of the symptomatology of
several diseases (e.g. sjogrens syndrome-an autoimmune disorder
characterized by lymphocytic infiltration of the salivary and
lacrimal glands) (Sjgren et al., 2002). Chewing gumstimulates
salivary secretion thereby decreasing dryness in the mouth.

Anatomy And Physiology Of The Oral Mucosa
(Rhodus et al., 1991; Rathbone et al., 1996; Squier et al., 1996)

The oral mucosa can be subdivided into two general
regions, the outer vestibule and oral cavity.
Microscopically the oral mucosa consists of three main layers:
The oral epithelium;
The lamina propria;
The sub mucosa.



Fig. 1: ChicleCollected FromSapodilla Tree.

J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54






























The oral epithelium
The epithelium of mouth consists of stratified,
squamous epithelium, which can be keratinized or non
keratinized. Keratinized epithelium is dehydrated, mechanically
tough and chemically resistant. It is found in oral cavity
subject to mechanical stress such as mucosa of gingival and
hard palate (roof of mouth). Non-keratinized epithelium is
relatively flexible and is found in areas such as the soft
palate , the floor of mouth , the lips and the cheeks. The
epithelium of the oral cavity is supported by the basement
membrane, which separates the epithelium from the underlying
connective tissue layer (the lamina propria). Oral epithelium
broadly similar to stratified squamous epithelia found
elsewhere in the body , for example the skin , in that cells are
produce by mitosis in the basal layer of the epithelium and
these proliferating cells push existing cells towards the surface
The phase of this process are represented in four morphological
layers:

Basal layer;
Prickle cell layer;
Intermediate layer;
Superficial layer: Structural changes that occur during
this upward transit, from basal to superficial layer,
include the cells becoming





























Larger in size;
More flattened: the cuboidal cells of the basal layer are
more polygonal shape in prickle cell layer , become
slightly flattened in the intermediate layer and more
flattened in the superficial layer .
More proteinaceous: increasing amount of protein are
found in the cells (for both keratinized and non
keratinized epithelium) toward the epithelial surface,
in the formof protein monofilaments;
Less viable : there is an absence of organelles in
superficial cells, indicates that these cells are no longer
viable.

The lamina propria
The lamina propria contents a sheet of connective
tissue containing collagen elastic fiber and cellular components
in hydrated ground substance. It also carries blood capillaries
and nerve fibers that serves the mucosa . It is through the
blood vessels in the lamina propria that drug moieties can
gain the entry in systemic circulation.

The salivary glands
Saliva is a hypotonic ,watery secretion containing
variable amount of mucus , enzyme, antibodies and inorganic
ions .The surface of mucus membrane is constantly washed

Fig. 2: Generalized Structure of Oral Mucosa

J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54

by a stream of about 0.5 to 2L of saliva daily produce in the
salivary gland the chief secretion is supplied by three pairs
of glands, the parotid, the sub maxillary , and the sublingual
glands.
The presence of saliva in mouth is important for two
main reasons:
Drug permeation across moist membranes occurs
much more readily than across non mucous
membranes; compared to drug absorption across the
GI track and skin,
Drug are commonly administered to mouth in
clinical setting in solid dosage form. The drug must
therefore first dissolve in saliva before it can be
absorbed across the oral mucosa ; that is the drug
cannot be absorbed directly from the tablet.

MERITS OF THE MCG (PHARMACOLOGICAL)

The active component absorbed at the oral level avoids
the enterohepatic circulation and the associated metabolism
(Conway et al., 2003).
The product is rapidly released from the gum after a short
period of mastication; some absorption takes place directly through
the oral mucosa depending upon the active ingredient. Importantly,
not being swallowed, the gum does not reach the stomach, which
means that the GIT suffers less from the excipients and the
iatrogenic effects. (observed with some galenical form) (Conway et
al., 2003).
Moreover the stomach does not suffer fromdirect contact
with high concentration of the active principle, thus reducing the
risk of intolerance of the gastric mucosae (Conway et al., 2003).
The fraction of the product reaching the stomach is
conveyed by the saliva and delivered continuously and regularly.
Others:
Relaxes and eases tension.
Freshens the breath.
Decreases ear discomfort when flying.
Satisfies snack craving.
Cleans teeth after meals.
Its fun.

DEMERITS OF THE MCG (PHARMACOLOGICAL)

If you chew gumon a regular basis, please consider the
following:
Chewing gumcauses unnecessary wear and tear of the
cartilage that acts as a shock absorber in the jaw joints. Once
damaged this area can create pain and discomfort for lifetime (Weil
et al., 1978).
You use eight different facial muscles to chew.
Unnecessary chewing can create chronic tightness in 2 of these
muscles located close to the temples. This can put pressure on the
nerves contributing to chronic intermittent headaches (Weil et al.,
1978).
You have six salivary glands located throughout mouth
that are stimulated to produce and release saliva whenever you
chew. Producing a steady streamof saliva for chewing gum is a
waste of energy and resources that otherwise could be used for
essential metabolic activities.
Most of the chewing gums are sweetened with aspartame:
long use causes cancer, diabetes, neurological disorder and birth
defects.
Flavor color etc. may cause allergic reaction.
Long termfrequent use causes increase release of mercury
vapor fromdental amalgam filling. However medicated chewing
gums do not normally require extensive chewing or consumption
to a great extent.

MERITS OF THE MCG (OVER OTHER DOSAGE FORMS)

Dose not requires water to swallow. Hence can be taken
anywhere (Morjaria et al., 2004).
Advantageous for patients having difficulty in
swallowing.
Excellent for acute medication (Conway et al., 2003).
Counteracts dry mouth, prevents candidiasis and caries.
Highly acceptable by children (Morjaria et al., 2004).
Avoids First Pass Metabolism and thus increases the
bioavailability of drugs (Conway et al., 2003).
Fast onset due to rapid release of active ingredients in
buccal cavity and subsequent absorption in systemic
circulation (Conway et al., 2003).
Gum does not reach the stomach. Hence G.I.T. suffers
less fromthe effects of excipients.
Stomach does not suffer fromdirect contact with high
concentrations of active principles, thus reducing the risk
of intolerance of gastric mucosa (Conway et al., 2003).
Fraction of product reaching the stomach is conveyed by
saliva delivered continuously and regularly. Duration of
action is increased.
Aspirin, Dimenhydrinate and Caffeine shows faster
absorption through MCG than tablets.

DEMERITS OF THE MCG (OVER OTHER DOSAGE
FORMS)

Risk of over dosage with MCG compared with chewable
tablets or lozenges that can be consumed in a considerable
number and within much shorter period of time (J acobsen
et al., 2004).
Sorbitol present in MCG formulation may cause flatulence,
diarrhoea.
Additives in gum like flavouring agent, Cinnamon can
cause Ulcers in oral cavity and Licorice cause
Hypertension.
Chlorhexidine oromucosal application is limited to short
term use because of its unpleasant taste and staining
properties to teeth and tongue.
J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54

Chewing gum have been shown to adhere to different
degrees to enamel dentures and fillers.
Prolong chewing on gum may result in pain in facial
muscles and earache in children.

Mechanism of Drug Transport (Rathbone et al., 1996; Squier et
al., 1996)
During the chewing process, most of the medications
contained within the drug product are released into the saliva and
are either absorbed through buccal mucosa or swallowed or
absorbed through GIT.
Major pathways of drug transport across buccal mucosa
follow simple fickian diffusion. Passive diffusion occurs in
accordance without the pH partition theory. Some carrier mediated
transport also observed. Equation for drug flux is:
J = DKp/Ce
Where,
J = drug flux
D = diffusivity
Kp = partition coefficient
Ce = concentration gradient
h = diffusional path length
It shows (h) that the flux may be increased by decreasing
the diffusional resistance of the membrane by making it more fluid,
increasing the solubility of the drug in the saliva immediately
adjacent to the epitheliumor enhancing the lipophilicity through
pro-drug modification. Because of the barrier properties of the tight
buccal mucosa, the rate limiting step is the movement of the drug
molecules across the epithelium.
Two pathways of permeation across the buccal mucosa are
transcellular and paracellular. Permeability coefficient typically
ranges from1x10
-5
to 2x10
-10
cm/s. The pathway of drug transport
across oral mucosa may be studied using:
Microscopic techniques using fluorescent dyes
Autoradiography and
Confocal laser scanning microscopic procedures.


Fig. 3: Routes and Mechanisms for Drug Transport across Epithelia.
FACTORS AFFECTING MUCOSAL DRUG DELIVERY
(Rathbone et al., 1996; Rider et al., 1992; Rindum et al., 1993;
Rowe et al., 2003)

Membrane factor
Regional difference in both permeability and thickness
affect both the rate and the extent of drug reaching the systemic
circulation. Keratinisation and composition also affect systemic
mucosal delivery. Additional factors such as absorptive membrane
thickness, blood supply, blood/lymph drainage, cell renewal rate,
and enzyme content will also govern the rate and extent of drug
absorption.

Environmental factor
Saliva
It is composed of water 99% and pH of 6.5
to 7.5 depending on the flow rate and location. And increase in the
salivary flow rate leads to the secretion of watery saliva.
Stimulated saliva secretion affects the filmthickness and aids in
the easy migration of the test compounds. Salivary pH is also
important for the passive diffusion of the unionized drug.

Salivary glands
Drug delivery system should be placed either over a duct
or adjacent to the salivary duct because it may result in excessive
washout of drug or rapid dissolution of the system making it
difficult to achieve high local drug concentration.

Chewing time and chewing rate
Time should be around 20 to 30 min. the rate of chewing
also affects the drug release. The average chewing rate is about 60
chews/min.

Aqueous solubility of the drug
Release of the water soluble drug (solubility >1:10) about
75% or more during 5 mins of chewing and 90% or more during 15
mins of chewing at a rate of 60 chews per min. Drug with the
aqueous solubility between 1:10 and 1:300 demonstrate upto 60%
release during ten minutes of chewing and between 60% and 90%
when the gum is chewed for 15 mins. The release of the drug
which is only slightly water soluble can only be expected to be
small i.e. less than 5% even if the gumis chewed for 30 mins.

% of drug
The release of fluoride from a chewing gum (1g)
containing 0.1 mg and 1mg NaF (aqueous solubility 1:25) has been
compared. The percentage of the drug retained in the gumfor two
formulations are similar. Indeed the percentage released for 0.1 mg
and 1mg fluoride are very similar after 8 mins. at 75% and 80%
respectively.

Contact Time
The local or systemic effect is dependent on time of
contact of MCG in oral cavity. In clinical trial chewing time of 30
minutes was considered close to ordinary use.
J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54

Physicochemical properties of active ingredient
Physicochemical properties of active ingredient plays very
important role in release of drug fromMCG.
The saliva soluble ingredients will be immediately
released within few minutes whereas lipid soluble drugs are
released first into the gumbase and then released slowly.

Inter individual variability
The chewing frequency and chewing intensity which
affect the drug release fromMCG may vary fromperson to person.
In-vitro study prescribed by European Pharmacopoeia suggest 60
cycles per minute chewing rate for proper release of active
ingredient (European Pharmacopoeia. Strasbourg, 2004).

Formulation factor
Composition and amount of gum base affect rate of
release of active ingredient. If lipophilic fraction of gum is
increased, the release rate is decreased (European Pharmacopoeia.
Strasbourg, 2004).

CONCEPT OF FORMULATION DEVELOPMENT
(Abelson et al., 1990; Christrup et al., 1990; Pedersen et al., 1990;
Rindumet al., 1993)
A piece of chewing gumusually consists of gumcore,
which may or may not be coated.
The core is composed of an insoluble gumbase resin,
elastomers, emulsifiers, fillers, waxes, antioxidants and softeners,
sweeteners, flavoring agents, and in case of medical chewing gum,
active substances. The water content of chewing gumis very low
and no preservative is needed. The gum base determines the basic
characteristics of the product, e.g. the texture: is soft or hard to
chew? Does it crumble? Does it stick to the teeth? The gumbase
also determines the release profile of active substances and
changing the gum base composition may therefore change the
release profile.

Increased Release
Many drugs used today are lipophilic in nature; these are
partially soluble in the gum bases. Consequently they exhibit a
slow release rate fromthe chewing gumand only small percentage
of the total amount of the drug incorporated is released even after
prolonged chewing time. For such drugs following correction is
required:

Addition of a buffering agent
Folic acid is beneficial for gingivitis. Three different
chewing gum formulations of slightly water soluble B vitamin,
folic acid (5mg/piece)
Contain NaHCO
3
(11mg/piece)
Contain both NaHCO
3
and Na
2
CO
3
(5.5mg and
6.9mg/piece)
No buffering agent
Both in vivo and in vitro activity was carried out and it
was found that the release of drug is higher, in a and b as compared
to c and release profile from a and b formulation is satisfactory for
its intended purpose.

Coating with and hydrophilic gum
Nystatin, slightly water soluble finely divided particles
coated with Arabic gum. When uncoated the drug was incorporated
into chewing gum at 4% release observed and this amount
increased to 24% when coated drug was incorporated into gum.

Solubilising agent
The affect of addition various solubilising agents to a
chewing gum formulation on the release rate has been studied for
different drug. In a study with nystatin, non ionic surfactant
Cremophor RH40, Tween 60 and Panadan AB90 were added.
The drug release was observed to increase with factor of
50-70 with upto 95%. While opposite effects were observed during
the study of metronidazole and propanolol HCL with glycerol and
span 20. It is conclude that by testing the addition of different
solubilising agents to the chewing gum, it will often be possible to
find an agent that substantially increases the release.

Solid dispersion
For miconazole some carriers were studied including
PEG, PVP, Xylitol and carbamide. Because of the solid dispersion
release rate increased to a large extent over the first few minutes of
mastication.

Sustained release of the drug
The sustained release of the drug can be achieved by one
of the following methods:

Particle size of the drug
Reduction of particle size of an incorporated ingredient
might be valuable approach to retard the release of the drug from
chewing gum.

Drug-Ion exchange complex
Nicotine is liquid with boiling point 247C, basic in
nature with pKa 3.12 and 8.02 and freely soluble. When
incorporated into ordinary gum composition, its release occur
rapidly but undesirable for its clinical use which requires smoking
substitute that should be uniform and last for at least 20 mins
The cation exchanger used in the marketed nicorette
chewing gum is amberliteIRP 64, a weak acidic methacrylic acid
polymer and nicotine complex product is referred to nicotine
polacrilex.

Coating and embedding
Different coating principles and different coating agents
such as PVP and cellulose compounds have been used in order to a
prolonged release of flavor and sweetener from chewing gum.
Embedding a drug in hydrophobic matrix consisting of lecithin,
synthetic waxes or mixtures there of reduced release rate of drug
from chewing gum.

J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54

Adsorption
A flavor was adsorbed into silica gel which as then
dispersed throughout a thermoplastic material such as cellulose-2-
hydroxy propyl-ether. The release rate reduced from35% to 20%
during 20 mins of mastication.

Requirement of drug
Molecular size
Molecular wt. less than 100 dalton are rapidly transported
through buccal mucosa.

Lipid solubility
For non-ionisable compound as lipophilicity rises, the
drug permeability typically increases. To maximize absorption
rate, a drug should be available in the salivary filmat its solubility
limit.

Ionization
For ionisable drugs maximumpermeation occurs at the
pH at which ionization is least.

Rate of drug absorption
For Transcellular route is pH dependant. Such
dependency results frommembrane/aqueous partition coefficient
for an ionisable drug is pH dependant.

COMPONENTS OF THE MCG

Chewing gumis a mixture of natural or synthetic gums
and resins, sweetened with sugar, corn syrup, artificial sweeteners
and may also contain colouring agents and flavour. The basic raw
material for all CG is natural gum Chicle, obtained from the
sapodilla tree. Chicle is very expensive and difficult to procure
therefore other natural gum or synthetic materials like
polyvinylacetate and similar polymers can be used as gumbase.
Typically Chewing Gumcomprises two parts
Water insoluble chewable gumbase portion (Zyck et al.,
2003)
Water-soluble bulk portion (Zyck et al., 2003)

Water insoluble gum base generally comprises of
(Conway et al., 2003; Zyck et al., 2003)

Elastomers (40-70% by wt. of gum base).
Elastomer provides elasticity and controls gummy texture.
Natural elastomer: Natural rubbers like Latex or Natural gums such
as Jelutong, Lechi Caspi, Perillo, and Chicle.

Plastisizers (3-20% by wt. of gum base).
These are used to regulate cohesiveness of product. These
are again divided into Natural and Synthetic.
Natural Plastisizers include Natural rosin esters like
Glycerol Esters or Partially hydrogenated Rosin, Glycerol Esters of
Polymerized Esters, Glycerol Esters of Partially dimerized Rosin &
Pentaerythritol Esters of Rosin. Synthetic Plastisizers
include Terpene Resins derived from -pinene and/or d-limonene.
Fillers or Texturizers (2-60% by wt. of gum base).
Provide texture, improve chewability, and provide
reasonable size of the gumlump with low dose drug.
Commonly used fillers are Magnesium and Calcium
Carbonate, Ground Limestone, Magnesium and Aluminum
Silicate, Clay, Alumina, Talc, Titanium Oxide & Mono/ di/ tri
CalciumPhosphate.

Water soluble portions comprises of
Softners and Emulsifiers
These are added to the chewing gumin order to optimize
the chewability and mouth feel of the gum. Softners include
Glycerin, Lecithin, Tallow, Hydrogenated Tallow, Mono/ di/ tri-
Glycerides, Fatty acids like Stearic acid, Palmitic acid, Oleic acid
and Linoleic acid.

Colourants and Whiteners
May include FD & C type dyes and lakes, fruit and
vegetable extracts, TitaniumDioxide.

Sweeteners (50-65% of gum base composition)
These are of two types, Aqueous and Bulk. Aqueous
Sweeteners can be used as softners to blend the ingredients and
retain moisture. These include Sorbitol, hydrogenated Starch
hydrolysates and Corn Syrups. Corn syrup keeps gumfresh and
flexible.
Bulk Sweeteners include Sugar and Sugarless
components. Sugar Components include Saccharides like Sucrose,
Dextrose, Maltose, Dextrin, Fructose, Galactose, Corn Syrup.
Sugarless Components include sugar alcohols such as Sorbitol,
Manitol, Xylitol, hydrogenated Starch hydrolysate. High intensity
artificial Sweeteners can also be included to provide longer lasting
sweetness and flavour perception e.g. Sucralose, Aspartame, salt of
Acesulfame, Alitame, Saccharin, Glycerrhizin, Dihydrochalcones.

Bulking agents
These are used if low calorie gumis desired. Examples of
low caloric bulking agents include Polydextrose, Oligofructose,
Inulin, Fructooligosaccharides, Guargum hydrolysate, Indigestible
Dextrin.

Flavouring Agents
A variety of flavouring agents are used to improve flavour
in chewing gumincludes essential oils, such as Citrus oil, fruit
essences, Peppermint oil, Spearmint oil, Mint oil, Clove oil & Oil
of Wintergreen. Artificial flavouring agents can also be used.

Active Component
In medicated chewing gum active pharmacological agent
may be present in core or coat or in both. The proportion of which
may vary from 0.5-30% of final gum weight. A small, unionized,
lipophilic and enzymatically stable active agent is likely to be
absorbed more readily. A saliva soluble ingredient will be
completely released within 10-15 minutes of chewing whereas
lipid soluble ingredient will dissolve in the gumbase and thereafter
J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54

be slowly and completely absorbed. MCG consists of masticatory
gumcore that may be coated. The core is composed of an aqueous
insoluble gum base which can be mixed with Sweeteners and
Flavours. The coating can be applied as a filmof polymers, waxes,
sweeteners, flavours and colour or a thick layer of sugar or sugar
alcohol.

MANUFACTURE OF THE MCG

Different methods employed for the manufacturing of CG
can be broadly classified into three main classes namely;
Conventional/ traditional Method (Melting).
Freezing, grinding and tabletting Method.
Direct Compression Method

Conventional/ traditional Method (Melting)
(Athanikar et al., 2001)
Components of gum base are softened or melted and
placed in a kettle mixer to which sweeteners, syrups, active
ingredients and other excipients are added at a definite time. The
gum is then sent through a series of rollers that form into
a thin, wide ribbon. During this process, a light coating of finely
powdered sugar or sugar substitutes is added to keep the gumaway
fromsticking and to enhance the flavour. In a carefully controlled
room, the gumis cooled for upto 48 hours.





























This allows the gumto set properly. Finally the gumis cut
to the desired size and cooled at a carefully controlled temperature
and humidity.

Limitations (Cherukuri et al, 1988)
Elevated temperature used in melting restricts the use of this
method for thermo labile drugs.
Melting and mixing of highly viscous gum mass makes
controlling of accuracy and uniformity of drug dose difficult.
Lack of precise form, shape or weight of dosage form.
Technology not so easily adaptable to incorporate the
stringent manufacturing conditions required for production of
pharmaceutical products.
Such a chewing gumcomposition is difficult to forminto
chewing gumtablets because of their moisture content (2-
8%). If attempted to grind and tablet such a composition
would jam the grinding machine, stick to blades, screens
adhere to punches and would be difficult to compress.

Cooling, Grinding and Tabletting Method
(Athanikar et al., 2001; Mochizuki et al., 1976)
This method has been developed with an attempt to lower
the moisture content and alleviate the problems mentioned in
conventional method.
































Fig. 4: Conventional/Traditional (Melting) Manufacture of aMedicated Chewing Gum.

J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54

Cooling and Grinding
The CG composition (base) is cooled to a temperature at
which the composition is sufficiently brittle and would remain
brittle during the subsequent grinding step without adhesion to the
grinding apparatus. The temperature required for cooling is
determined in part by the composition of the CG and is easily
determined empirically by observing the properties of the cooled
chewing gum composition. Generally the temperatures of the
refrigerated mixture is around -15
o
C or lower. Amongst the various
coolants like liquid nitrogen, hydrocarbon slush use of solid carbon
dioxide is preferred as it can give temperatures as low as -78.5
o
C, it
sublimes readily on warming the mixture, is not absorbed by the
chewing gumcomposition, does not interact adversely with the
processing apparatus and does not leave behind any residue which
may be undesirable or potentially hazardous. The refrigerated
composition is then crushed or ground to obtain minute fragments
of finely ground pieces of the composition. Alternatively, the steps
of cooling the chewing gumcomposition can be combined into a
single step. As an example, cooling the grinding apparatus itself
which can be done by contacting the grinding apparatus with a
coolant or by placing the grinding apparatus in a cooling jacket of
liquid nitrogen or other cold liquid. For more efficient cooling, the
chewing gum composition can be pre cooled prior to cooling to the
refrigeration temperature. Sometimes a mixture of chewing gum
composition, solid carbon dioxide and precipitated silica is ground
in a mill grinder in a first grinding step. Additional solid carbon
dioxide and silica are added to the ground composition, and the
composition is further ground in a second grinding step. This two-
step grinding process advantageously keep the chewing gum
composition at a very low temperature. The presence of solid
carbon dioxide also serves to enhance the efficiency of the grinding
process. The same process can be made multiple by adding
incorporating additional carbon dioxide and/or precipitated silica at
each step. Certain additives can be added to the chewing gum
composition to facilitate cooling, grinding and to achieve desired
properties of chewing gum. These include use of anti-caking agent
and grinding agent.

Use of anti-caking agent
An anti-caking agent such as precipitated silicon dioxide
can be mixed with chewing gumcomposition and solid carbon
dioxide prior to grinding. This helps to prevent agglomeration of
the subsequently ground chewing gumparticles.

Use of grinding agents
To prevent the gum from sticking to the grinding
apparatus, 2-8% by weight of grinding aid such as alkaline metal
phosphate, an alkaline earth metal phosphate or malto dextrin can
be incorporated. However practical use of these substances is
limited because these substances are highly alkaline and hence
would be incompatible with acidic ionisable therapeutic agents.
They also tend to remain in the composition and final chewing
gumtablet and thus may be problematic for therapeutic and safety
point of view. After the composition is ground to a powder, the
coolant can be removed by allowing the coolant to evaporate.
Alternatively it has been found that such a powdered mass when
warmed to room temperature from the refrigerated state, they
become cross linked or self adhere together to forman integrated
body which incorporates minute air bubbles in the texture between
the particles. This provides a chewing gumproduct that is light and
gives a soft chewing impression when chewed.

Tabletting
Once the coolant has been removed fromthe powder, the
powder can be mixed with other ingredients such as binders,
lubricants, coating agents, sweeteners etc, all of which are
compatible with the components of the chewing gum base in a
suitable blender such as sigma mill or a high shear mixer.
Alternatively a Fluidized Bed Reactor (FBR) can be used. The use
of FBR is advantageous as it partially rebuilds the powder into
granules, as well as coats the powder particles or granules with a
coating agent thereby minimizing undesirable particle
agglomeration. The granules so obtained can be mixed with
antiadherents like talc. The mixture can be blended in a V type
blender, screened & staged for compression. Compression can be
carried out by any conventional process like punching.

Limitation
It requires equipment other than conventional tabletting
equipment and requires careful monitoring of humidity during the
tabletting process.

Use of directly compressible chewing gum excipients
(Athanikar et al., 2001; Mochizuki et al., 1976)
The manufacturing process can be accelerated if a directly
compressible chewing gumexcipient is available. The limitations
of melting & freezing can be overcome by the use of these.
PHARMAGUM

, is one such compactable gumsystemdeveloped

by SPI Pharma. Pharmagumis a mixture of polyol(s) & or sugars
with a chewing gumbase. It is available as directly compressible
powder, free flowing powder which can be compacted into a gum
tablet using conventional tablet press thus enabling rapid and low
cost development of a gum delivery system. It is manufactured
under CGMP conditions and complies with Food Chemicals Codex
specifications as well as with FDA, so they can be considered as
"Generally regarded as safe" (GRAS). Pharmagum

is available in
three forms namely S, M and C. Pharmagum

M has 50% greater

gum base compared to Pharmagum

S. Pharmagum

S consists
primarily of gumbase and sorbitol. Pharmagum

M contains
gumbase, mannitol & Isomalt. Release of nicotine fromdirectly
compressible nicotine gum formulations and from Nicorette

prepared by conventional methods have shown that use of
Pharmagum in formulation showed a faster release rate.
Formulations made with Pharmagum

M & S are similar to tablet

in appearance. Gums formed using compressible formulation are
10 times harder and crumble when pressure is applied resulting in
faster release than conventional methods. Use of Pharmagum S, M
and C enables formulators to utilize a gum delivery system quickly
& more cost effectively than by traditional methods. A novel drug
delivery systemcreates additional patient benefits that will add
J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54

new competitive advantages for a drug and, thus, conserve or
increase revenue. Chewing gum as drug delivery system holds
tremendous potential not only in smoking cessation and oral health
care arenas but also in other indications.

STABILITY OF THE MCG
The stability of chewing gumis comparable to most of
other solid delivery systems. Chewing gum normally contains little
water (2-5%) and the water can be bound to the other components
in the product and is therefore not very reactive. The water activity
(Aw) in chewing gum normally below 0.6 and typically (0.4-0.5) if
water content is very critical for stability of the drug, the chewing
gumcan be manufactured without water (less than 0.2). This will,
however, often make the product hygrosopic and affect the texture.
The low water content inhibits microbial growth in the chewing
gumduring storage. Antioxidants are normally added with the gum
base. Furthermore, the product can be protected against oxidation
by a sealed coat and by appropriate packaging. For every
temperature component, e.g. enzymes, the process temperature of
50-60C during mixing may create a stability problem. It is
however, possible to operate the process at lower temperature to
avoid this issue (European Pharmacopoeia).

QUALITY CONTROL OF THE MCG
Medicated chewing gumcomplies with the requirements
of the third edition of European pharmacopoeia (European
Pharmacopoeia).

Uniformity of content
Unless otherwise prescribed or justified and authorized,
medicated chewing gum with content of 2 mg or less than 2
percent of total mass comply with test A for uniformity of content
of single dose preparation. If the preparation contains more than
one active substance, the requirements applies only to those active
substances, which corresponds to the above condition.

Uniformity of mass
Uncoated medicated chewing gumand, unless otherwise
justified and authorized, coated medicated chewing comply with
the test for uniformity of mass of single dose preparations. If the
test uniformity of content is prescribed for all the active
substances, the test for uniformity of mass is not required.

Scientific Rationale for In Vitro Drug Release Determination
Currently, the USP monograph for nicotine polacrilex
gums does not contain a drug release test. Recently, much effort
has been spent describing the in vitro release kinetics of special
dosage forms, including medicated chewing gums (Siewert et al.,
2003; Moller et al., 1999; Yang et al., 2004). Due to the
complexity of the release mechanisms involved, researchers
proposed minimal requirements for experimental settings with
respect to the site of release and absorption. The performance tests,
however, must be able to detect the influence of critical
manufacturing variables, discriminate between different degrees of
product performance, and to some extent, describe the
biopharmaceutical quality of finished products. The scope,
purpose, and importance of release test shave been discussed
previously (Shah et al., 2006).
Besides the product quality tests, the drug release tests can
provide useful information about the characteristics of the product
itself, which includes but is not limited to the influence of the
composition of the gum and other excipients on drug release, a
main tool required primarily during product screening and
development, and to some extent the product performance in vivo.

Drug Release Testing Methodology
Ph. Eur. has adopted an apparatus to determine the release
rate from chewing gumformulations (European Pharmacopoeia.
General Monograph 2.9.25, 2008). The basic principle is a simple
masticatory movement employed to simulate the chewing action on
a piece of gum placed in a small chewing chamber containing a
known volume of buffer solution at a given temperature (European
Pharmacopoeia. General Monograph 2.9.25, 2008). The drug
release rate is influenced by the chewing rate and angle, which
provides the necessary shear force to expose new gumsurfaces and
is a requisite for further drug release.
The mechanism and kinetics of drug release fromchewing
gums have not yet been completely understood due to the
complexity of the formulation itself. The transition from the
inactive gum to the active dosage form is influenced by:
mechanical forces, temperature, wettability and water permeation.
As a general rule under sink conditions, the rate at which the drug
is released is directly proportional to the chewing frequency and
aqueous solubility of drug substance and is indirectly proportional
to the mass of the gumbase.

Apparatus I. Chewing Gum Apparatus, CompendialPh. Eur.
The chewing apparatus for medicated chewing gum was
adopted by Ph. Eur. in 2000 (European Pharmacopoeia. Suppl.
General Chapter 2.9.25, 2000). Figure 5 shows the construction of
the apparatus. The chewing apparatus comprises a chewing
chamber, two horizontal pistons, and a third vertical piston
(tongue). The vertical piston operates alternatively with the two
horizontal pistons and makes sure the gumstays in the right place
between chews. If necessary, it is feasible to construct the machine
so that at the end of the chew the horizontal pistons rotate around
their own axes in opposite directions to each other to obtain
maximum chewing. The working procedure of this chewing
apparatus is described in Ph. Eur. (European
Pharmacopoeia. General Monograph 2.9.25, 2000, 2005, 2008).
Several studies (Yang et al., 2004; Jensen et al., 1988;
Christrup et al., 1986; Christrup et al., 1988; Faraj et al., 2007;
Pedersen et al., 1990; Pedersen et al., 1991) have
been carried out using the Ph. Eur. apparatus, and the results
indicate the methodology is rugged and reproducible.

Apparatus II. Alternative Chewing Gum Apparatus, Non
compendialWennergren
One of the non compendial apparatus commercially
available was designed by Wennergren (Kvist et al., 1999). The
J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54

schematic representation of the Wennergren chewing apparatus is
shown in Figure 6.
The chewing procedure consists of reciprocations of the
lower surface in combination with a shearing (twisting) movement
of the upper surface that provides mastication of the chewing gum
and at the same time adequate agitation of the test medium. The
upper jaw has a flat surface that is parallel to the central part of the
lower surface. The small brim of the lower surface is angled
upwards (45 degrees) so that the lower surface functions as a small
bowl with a flat bottom. This bowl prevents the chewing gum
fromsliding during mastication. Investigations of the performance
of the chewing apparatus with multiple drug products were
published by Wennergren et al. (Kvist et al., 1999). The influences
of different operational parameters of the chewing gumapparatus








































on drug release have been carefully investigated (Kvist et al.,
2000).

General Comments about Apparatus I and Apparatus II
Both the apparatus described have been well studied and
reported in the literature (Yang et al., 2004; Jensen et al., 1988;
Christrup et al., 1986; Christrup et al., 1988). The results show that
the apparatus can provide strong mechanical forces that influence
drug release and can prove to be a useful tool for drug release
testing of medicated chewing gums both in quality control as well
as in product development. To some extent relevance to in vivo
behavior has been demonstrated using both the apparatus (Kvist et
al., 1999; Christrup et al., 1986) which suggests their usefulness in
the quality control and product development environments.










































Fig. 5: Apparatus I Chewing GumApparatus Compendial Ph. Eur.

J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54














































































































Fig. 6: Apparatus II Chewing GumApparatus Non-Compendial - Wennergren


Table. 1: Worldwide marketed Medicated Chewing Gums.
Trade Mark Active Substance Aim Commercially Available
Aspergum Aspirin Pain relief North America
Nicorette Nicotine Smoking Cessation Worldwide
Nicotinelle Nicotine Smoking Cessation Western Europe, Australia
Trawell Dimenhydrinate Travel illness Italy, Switzerland
Superpep Dimenhydrinate Travel illness Germany, Switzerland
Chooz CalciumCarbonate Stomach & neutralization USA
Endykay Vit.C Vitamin C General Health Middle East, Uk
Stamil Vit.C Vitamin C General Health Australia
Source Vit.C Vitamin C General Health Australia
Brain DHA & CCE Enhanced brain activity J apan
Stay Alert Caffeine Alertness USA
Caf Coffee Caffeine Alertness J apan
Buzz Gum Guarana Alertness United Kingdom
Go Gum Guarana Alertness Australia
Chroma Slim CR Diet USA
Fluorette Fluoride Cariostatic USA
Vitaflo CHX Chlorhexidine Preventing tooth decay USA
Travvel Dimenhydrinate Motion sickness USA, Australia
V6 Xylitol Prevention of treatment of dental caries United Kingdom


Table. 2: Vitamins, minerals and Herbal Medicines.
Formulation Main Indications
1) Calcium500mg +CCP 100mg (CalciumCasein Peptide) CalciumSupplement
2) Chamomille( Matricaria) 25 or 100mg Mild Sedative
3) Coffee enriched with 150 mg caffeine Energiser, to increase intellectual performance
4) Ether 500 mg (Guar Galactomannan) Guar dietary fiber supplement, slimming agent
5) Ginger 50 or 100 or 150 mg Gastric stimulant, natural anti-emetic
6) Magnesiumand potassiumaspartate325 mg Magnesiumand potassiumdeficiency (sport gum)
7) Multivitamins (Betacarotene, Vit.C, B1, B2, B6, B12, Folic acid) Vitamin Supplement
8) Passion Flower +Camomile +Hawthorn +Linden tree Natural anti-stress-sedative-analgesic
9) Perilla dry extract 27 mg Natural anti-allergic
10) Zinc 12 mg Enzyme cofactor

J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54



















APPLICATIONS OF THE MCG

The MCGs can also be used as an alternative tool to
buccal and sublingual tablets which are intended to act
systemically because active ingredient is released more uniformly
and cover greater area of absorption in oral cavity. Oral diseases
are prevented or cured with MCG. MCGs can be used for systemic
effect in conditions like vitamin C deficiency, pain & fever,
alertness, motion sickness, smoking cessation, as well as for local
effect in conditions like plaque acid neutralization, fresh breath,
dental caries, antiplaque, fungal, and bacterial infections.
Prevention and cure of oral diseases is a prime target for chewing
gumformulations.

Local Therapy
(Dalai et al., 1999; Ferno et al., 1974; Dodds et al., 1991)
Chewing Gum can control the release rate of active
substances providing a prolonged local effect. It also re-elevates
plaque pH which lowers intensity and frequency of dental caries.
Fluoride containing gums have been useful in preventing dental
caries in children and in adults with xerostomia. Chlorhexidine
chewing gumcan be used to treat gingivitis, periodontitis, oral and
pharyngeal infections. It can also be used for inhibition of plaque
growth. Chlorhexidine chewing gum offers large flexibility in its
formulation as it gives less staining of the teeth and is distributed
evenly in the oral cavity. The bitter taste of chlorhexidine can be
masked quite well in a chewing gum formulation (Pedersen et al.,
1990; Rindumet al., 1993) Clinical trials involving patients with
oral candidiasis have shown that miconazole chewing gum is at
least as sufficient as miconazole oral gel in the treatment of fungal
infections in the mouth. A miconazole chewing gumis yet to be
launched (Pedersen et al., 1990; Rindumet al., 1993)

Systemic therapy
Chewing gumcan be used in treatment of minor pains,
headache and muscular aches. Chewing gum formulation
containing nicotine (Nemeth et al., 1988) and Lobeline have been


















clinically tested as aids to smoking cessation. Active substances
like chromium, guaran and caffeine are proved to be efficient in
treating obesity. Chromiumis claimed to reduce craving for food
due to an improved blood-glucose balance. Caffeine and guaran
stimulate lipolysis and have a thermogenic effect (increased energy
expenditure) and reduce feeling of hunger. Xerostomia, Allergy,
Motion sickness, Acidity, Cold and Cough, Diabetes, Anxiety, etc
are all indications for which chewing gum is a means of drug
delivery. Medicated chewing gum is used to counteract dental
caries by stimulation of saliva secretion. Non-medicated chewing
gums increases plaque pH, stimulates saliva flow and decrease
decay.

FUTURE TRENDS

Chewing gumis no longer seen simply as confectionary.
It not only offers clinical benefits but also is an attractive, discrete
and efficient drug delivery system. A few decades ago, the only
treatment for some diseases was surgical procedure but now more
and more diseases can be treated with Novel Drug Delivery
Systems. Generally, it takes time for a new drug delivery system to
establish itself in the market and gain acceptance by patients,
however chewing gum is believed to manifest its position as a
convenient and advantageous drug delivery systemas it meets the
high quality standards of pharmaceutical industry and can be
formulated to obtain different release profiles of active substances.
The potential of MCG for buccal delivery, fast onset of action and
the opportunity for product line extension makes it an attractive
delivery form. Reformulation of an existing product is required for
patent protection, additional patient benefits and conservation of
revenues. Dental health chewing gum is here to stay, as is
medicated gumfor smoking cessation and travel sickness. A bright
future for a preparation with a long history.

Chromium (Pittler et al., 2003; Martin et al., 2006)
Insulin's little helper is the mineral chromiumpicolinate,
which makes your body's cells more sensitive to the effects of
Table. 3: Oral Hygiene Products
Formulation Main Indication
1) BenzethoniumChloride 1.5 mg Antibacterial product for oral hygiene
2) Cetylpyridinium1 mg Disinfectant for sore throat
3) Chlorhexidine 1 mg Antiseptic for oral activity
4) Gingko biloba 5 mg or 20 mg Anti-inflammatory for gingivitis
5) Green Tea concentrated extract Mouth deodorizer with anti plaque activity
6) Green treeconcentrated extract +propoli 50 mg Natural remedy for sore throat with anti-plaque activity.
7) Propolis 50 mg and 100 mg Natural remedy for sore throat
8) Sodiumfluoride 0.56 mg Prevention of dental caries
9) Sodiumfluoride 1.12 mg Prevention of dental caries
10) Vitamin C 30 mg +Thyme extract 12.5 mg Sore throat and gingivitis

Table. 4: Pharmaceutical Products
Formulation Main Indications
1) Aspirin 500 mg Analgesic
2) Dextromethorphan 10 mg Anti-Cough
3) Dimenhydrinate 25 mg Anti-emetic, motion sickness
4) Dropropizine 15 mg Anti-cough
5) Nicotine 2 mg Smoking cessation
6) Sucralfate 200 mg Treatment of peptic ulcer
7) Tryothricine 0.5 mg Gingivitis, apthe, sore throat
8) Vitamin C 500 mg Vitamin C deficiency

J ournal of Applied Pharmaceutical Science 02 (06); 2012: 40-54

insulin. Numerous studies have shown that taking chromium
picolinate supplements can curb excessive levels of insulin and
make insulin receptors more responsive to its effects. By way of
analogy, chromiumpicolinate helps to reset your body is insulin
and blood sugar thermostat. Without the peaks and troughs of high
and low blood sugar and the subsequent craving to increase blood
sugar levels, you no longer have the instinctual urge to consume
high carbohydrate diet.
In 2005, researchers put chromiumto the test by giving
113 carbohydrate cravers either daily chromium picolinate
supplements or placebo pills for eight weeks. At the end of the
study, the participants receiving chromiumpicolinate (but not the
placebo) had almost totally overcome their frequent sugar
cravings. What's more, they also had lower overall daily food
intake, meaning that they didn't compensate for their sugar
cravings by eating more from other food groups. The dosage of
chromiumpicolinate used in this study was 600 mcg per day (3 x
200 mcg tablets per day).

CONCLUSION

For most drugs there are realistic possibilities of
formulating them into a suitable chewing gumdelivery system,
although active agents with an extremely bitter taste may not be
suitable candidates. Poorly water-soluble drugs require specialized
formulation techniques to promote release, and these techniques
are reasonably well developed. Dental health chewing gum for
caries prevention has come to stay and the indications are that it
will be accepted widely in future. Chewing gum for smoking
cessation will also remain despite the fact that nicotine patches
have grown in popularity lately. This is because the very act of
chewing gumalso provides a physical substitute for the smoking
habit and thereby increases the possibility of successful quitting.
Although, it has a good potential to become a convenient
alternative approach to improve patient compliance, it still remains
as a field to be explored to the fullest. Finally, in the future, we
may see drugs formulated into chewing gumin preference to other
delivery systems to deliver drugs locally to the oral cavity. The
reason is simple - that the chewing gum delivery system is
convenient, easy to administer anywhere, anytime and its pleasant
taste improves patient compliance.

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